Retrospective evaluation of patients undergoing amputation surgery due to diabetic foot ulcers
Gamze Küçükosman, Bengü Gülhan Aydın, Gizem Alkım Yılmaz
Department of Anesthesiology and Reanimation, Zonguldak Bülent Ecevit University, Faculty of Medicine, Zonguldak, Turkey
DOI: 10.4328/ACAM.20578 Received: 2021-03-09 Accepted: 2021-08-26 Published Online: 2021-09-20 Printed: 2021-10-01 Ann Clin Anal Med 2021;12(10):1083-1087
Corresponding Author: Gamze Küçükosman, Department of Anesthesiology and Reanimation, Faculty of Medicine, Bülent Ecevit University, Zonguldak, Turkey. E-mail: firstname.lastname@example.org P: +90 532 566 25 71 F: +90 372 261 27 68 Corresponding Author ORCID ID: https://orcid.org/0000-0001-5224-0258
Aim: This study aims to determine the characteristics of patients undergoing major lower extremity amputation (LEA) surgery due to diabetic foot ulcers.
Material and Methods: The study was conducted by scanning files between January 2016 and December 2018. Patients were divided into two groups as survivors and non-survivors over the course of a 30-day follow-up period.
Results: The files of 43 patients (25 men, 18 women; mean age: 67±11 years) were examined. Thirty-seven of those patients underwent below-the-knee amputation and 5 of the surgeries were urgent. It was observed that 56% of the patients were in the ASA 3 and 40% were in the ASA 4 risk group. There was no significant difference between the groups in terms of age, gender, amputation level, surgical procedure, number of comorbidities, ASA risk group, postoperative laboratory values, or follow-up location (p>0.05). However, preoperative albumin levels were found to be lower in patients who died (p=0.02). General anesthesia was applied for 3 of the patients who died (p=0.08). It was determined that 23 patients were hospitalized postoperatively in intensive care for close hemodynamic follow-up and none of them needed a ventilator. During the postoperative 30-day follow-up period, the mortality rate was 9.3% and mean time to death was determined as 15.4±20 days. Three of 4 patients died due to cardiac reasons while 1 patient died because of respiratory failure.
Discussion: Since there were no significant differences in our study except low albumin levels among non-survivors, we think that supporting diabetic patients with nutritional programs in the preoperative period with a multidisciplinary approach will affect the treatment process positively.
Keywords: Diabetic Foot Ulcers, Amputation, Mortality
Diabetes, which is steadily increasing in both frequency and morbidity, is a serious health problem with its complications. Untreated foot ulcers and resulting lower extremity amputations (LEAs) in diabetic patients are among the common complications of diabetes [1, 2]. It was reported that 10-25% of all diabetic patients have a risk of developing diabetic foot ulcers and 50-70% of amputation surgeries are caused by diabetic foot ulcers [3, 4]. Patients who have amputation surgeries due to diabetes are generally elderly patients with a high number of comorbidities and high risk for surgical intervention . Although the mortality rates reported after diabetic foot amputation differ, the mortality rate in the first year is between 30% and 50%. Among the causes of death, heart diseases, stroke, chronic kidney failure, and sepsis are frequently noted .
In our study, we aimed to retrospectively evaluate patients who had undergone major LEA surgery for diabetic foot ulcers.
Material and Methods
After obtaining the approval of the local ethics committee, the study was completed by scanning the files of patients who underwent major LEA surgery between January 2016 and December 2018 in a tertiary university hospital. Study data were obtained by retrospective examination of the hospital automation system and anesthesia records. Records of 72 patients who underwent major LEA surgery were identified and 43 patients who underwent major LEA surgery for diabetic foot ulcers were included. The diagnosis of type 2 diabetes mellitus in all patients was confirmed by an endocrinologist according to fasting plasma glucose, preoperative HbA1c values, and previous drug reports obtained from hospital records. Transtibial, knee disarticulation, transfemoral, and hip disarticulation amputations were defined as major LEAs. Minor amputations (tarsal, metatarsal, and digital joints; n: 7 people), traumatic amputations (n: 4 people), and amputations due to peripheral circulatory disorders (n: 17 people) and malignancy (n: 1 person) were not included in the study. Failure of wound healing following appropriate infection control and wound debridement or the presence of serious systemic comorbidities that hinder treatment were identified as major LEA indications. The following data were examined: demographic characteristics of the patients; amputation level (below the knee, above the knee); surgical procedure (emergency, elective); number of existing diseases (<4 diseases, ≥4 diseases); American Society of Anesthesiologists (ASA) risk score; anesthesia method [general, regional, combined (general + regional/peripheral nerve block), peripheral nerve block] and time; preoperative HbA1c and albumin values; preoperative and postoperative hemoglobin (Hb), leukocyte, urea, creatinine, and glucose values; amount of crystalloid administered intraoperatively; preoperative hospitalization duration; postoperative follow- up location [service, intensive care unit (ICU)]; reason for admission to the ICU (respiratory support, inability to awaken, close hemodynamic follow-up, cardiopulmonary resuscitation, multiple organ failure); presence of mechanical ventilator need; length of postoperative ICU stay and total length of stay in the hospital; fate of the patient (survivor, non-survivor); and cause of mortality (respiratory, cardiac reasons) and time to death. Thirty-day mortality and survival data were taken from hospital database records. Patients (n=43) were divided into two groups as survivors (n=39) and non-survivors (n=4) during the postoperative 30-day follow-up.
SPSS 24.00 for Windows (IBM Corp., Armonk, NY, USA) was used for statistical evaluation. Results were expressed as mean ± standard deviation (mean±SD) for continuous values and as frequency (n) and percentage (%) for frequency data. The categorical data were analyzed by chi-square test. For statistical evaluations, p<0.05 was considered significant.
Of the patients who underwent major LEA surgery due to diabetic foot ulcers, 25 (58.1%) were male, 18 (41.9%) were female, and the mean age was 67.7±11.1 years. While 37 (86%) of the patients underwent below-the-knee amputation, 6 (14%) had above-the-knee amputation; 5 (11.6%) of the surgeries were performed under emergency conditions and 38 (88.4%) under elective conditions. Half of the non-surviving patients had ≥4 additional diseases. It was observed that 4.7% of the patients were in the ASA 2 risk group, 55.8% were in ASA 3, and 39.5% were in ASA 4; half of the patients who died were ASA 3 and the other half were ASA 4. There was no statistically significant difference between the groups in terms of age, gender, amputation level, surgical procedure, number of comorbidities, or ASA risk group (p>0.05) (Table 1). While general anesthesia was applied for 3 (75%) of the patients who died, regional anesthesia (spinal anesthesia) was applied for 1 (25%) non-surviving patient. There was no statistically significant difference between the groups in terms of anesthesia management (p=0.08) (Table 1). It was observed that the duration of anesthesia of the non-surviving patients was longer, but there was no statistically significant difference between the groups (p=0.38) (Table 1).
The preoperative mean HbA1c value of our patients was calculated as 8.2±2.1%, while mean albumin was 2.7±0.5 g/ dL, Hb was 10±1.5 g/dL, leukocyte level was 12.2±5.1 mm3, urea was 52.8±34 mg/dL, creatinine was 1.4±1.4 mg/dL, and glucose was 195±95 mg/dL. Similarly, postoperative mean Hb was calculated as 9.8±1.1 g/dL, leukocyte level as 12.4±4.4 mm3, urea as 47.6±38.4 mg/dL, creatinine as 1.3±1.6 mg/dL, and glucose as 200±89.4 mg/dL. There was no statistically significant difference between the two groups in terms of these preoperative and postoperative laboratory values, except for the albumin value measured preoperatively (p>0.05). Albumin levels were found to be lower in non-surviving patients (p=0.02) (Table 2).
It was observed that the mean amount of crystalloid administered intraoperatively to all our patients was 1532.14±642.95 mL and there was no difference between the groups (p=0.12). It was determined that 23 patients were admitted to the ICU for close hemodynamic follow-up in the postoperative period and no patient needed mechanical ventilation support. There was no significant difference between the groups in terms of postoperative patient follow-up location (p=0.11).
No significant difference was found between the groups in terms of the mean length of stay in the preoperative period, postoperative ICU stay, or hospital stay (p>0.05) (Table 3). During the postoperative 30-day follow-up, mortality was determined as 9.3% (n=4), while the mean time to death among these patients was determined as 15.37±20.01 days. Three of 4 patients who were taken to the ICU postoperatively died due to cardiac failure and 1 patient died due to respiratory failure.
Our study, in which we examined patients who underwent major LEA for foot ulcers, one of the most common complications of diabetes, sought to identify these patients in terms of some specific characteristics. In this study, no statistical difference was found in the patients who died compared to surviving patients except for lower albumin levels among non-survivors. During the 30-day follow-up, the mortality rate was determined as 9.3%.
Kalpakçı et al.  stated in their study that the rate of surgeries performed for diabetic foot problems was 2.47 times higher in the age group of 60-69 compared to the age group of 43-59 and 9.4 times higher in the age group of 70 and over. Thus, advanced age was an important risk factor in cases of diabetic foot amputation. In the same study, the risk of diabetic foot amputation increased with age, and additional pathologies such as diabetes duration and atherosclerosis were added in the process as an expected result. In our study, the mean age of patients who underwent major LEA surgery for foot ulcers was 67.7±11.1 years. The fact that the mean age of our patients who died from amputation due to diabetic foot ulcers (72.5±14.45 years) was higher than the mean age of the surviving patients (67.28±10.88 years) suggests that the incidence of diabetes- related complications increased with increasing age, similar to the findings seen in the literature.
It was reported in many studies that male gender is an important risk factor for diabetic foot amputations . The higher frequency of amputation due to diabetic foot ulcers in men in our study is consistent with the literature.
Arıkan et al.  reported that the most common surgical procedures in patients with diabetic foot ulcers were below- the-knee amputation (59.5%) and above-the-knee amputation (23.8%). Gutman et al.  also reported that 44% of 118 diabetic patients underwent small joint, 40.6% below-the-knee, and 15.2% above-the-knee amputation. Subramaniam et al.  found the mean survival to be 52 and 20 months among patients with below-the-knee and above-the-knee amputations, respectively. The same study revealed that diabetes was not a determinant in 30-day mortality or 3-year survival, but it was a determinant in 1-year survival. Amputation level and renal diseases were reported as important determinants of 30-day mortality. Based on this information, the authors suggested that below-the-knee amputations should be considered as medium-risk and above-the-knee amputations as high-risk surgeries. In our study, it was observed that 86% of the patients had below-the-knee amputations and 14% had above-the-knee amputations, and 3 patients died.
It was reported in the literature that age, gender, and amputation level are well-known risk factors for mortality in patients undergoing diabetic amputation . The limited number of patients included in our study suggests that more comprehensive studies should be conducted to determine whether parameters such as age, gender, and amputation level are risk factors for mortality.
Scott et al.  reported trends of increasing perioperative mortality in patients with renal impairment who undergo surgery for LEA for diabetes and peripheral vascular disease outside of standard working hours. They also found that the average survival after amputations performed during working hours was longer than survival in the case of amputations performed outside of working hours (39 months and 11 months, respectively). They reported that increased urgency of the surgery may affect the possible outcomes with the coexistence of more comorbidities and emergency amputations with the participation of less experienced surgeons and anesthesiologists. In our study, it was observed that all of the patients who were operated on under emergency conditions (11.6%) were operated on during standard working hours, and 4 of them survived while 1 died.
The ASA risk score is a classification system used by anesthesiologists to predict surgical mortality and morbidity in the postoperative period by considering the patient’s preoperative status . Scott et al.  reported more than a fourfold increase in 30-day mortality and a twofold increase in long-term mortality in patients with an ASA risk score of ≥4 who underwent LEA surgery. Some authors have stated that an increased ASA score is a risk factor for increased perioperative and long-term morbidity after amputation . Considering the patients’ comorbid diseases and general conditions, we thought that this scoring method determined early hospital mortality well, but we could not determine whether the ASA score was a risk factor for mortality in patients with amputation due to diabetic foot ulcers. However, the patients followed in the postoperative ICU had ASA scores of 3 and 4, ≥4 comorbidities, and ages of ≥70 years. Moreover, we found that 50% of our patients who died had ASA scores of 3 and 50% had ASA scores of 4.
Blood glucose level and HbA1c level, reflecting the last 3-4 months of glycemic status, are indicators that evaluate long- term glycemic control before surgery . In their study, Aragón- Sánchez and Lázaro-Martínez  stated that pre-admission glycemic control based on HbA1c in the prospective follow-up of 81 patients with diabetic foot ulcers who underwent surgery for osteomyelitis had no effect on clinical outcomes. Stratton et al.  reported in their study that when HbA1c decreased by 1%, the risk of death from amputation decreased by 43%. It is known that hyperglycemia increases the length of hospital stay and rate of admission to intensive care, and it is an important factor affecting morbidity and mortality . The mean HbA1c value of our patients was 8.2±2.1%. It was observed that both HbA1c and preoperative and postoperative glucose values were lower among non-surviving patients. We believe that the longer preoperative hospitalization periods of these patients were effective in the preoperative blood glucose regulation and that providing for preoperative glycemic control in all patients will increase the survival rate.
Scott et al.  showed that the type of anesthesia was not associated with survival in patients undergoing major LEA surgery, but the probability of 30-day mortality associated with neuraxial anesthesia increased. This contrasts with studies showing better survival with regional anesthesia . In our study, anesthesiologists had a tendency to choose general anesthesia for patients with ASA scores of ≤3, and 32 patients receiving general anesthesia had ASA scores of 2. Patients with high mortality risk were more likely to receive neuraxial anesthesia (including 1 patient who died, ASA 3 risk group, spinal anesthesia). Four patients who underwent peripheral nerve block were ASA 3 and 4 patients were ASA 4.
It is reported that the nutritional status of patients before amputation can be measured by total lymphocyte count (TLC) and serum albumin level. Specifically, TLC should be >1500 and albumin level should be at least 3.0 g/dL. In patients with low immune resistance or malnutrition, surgery should be postponed until these conditions improve slightly, and poor glycemic control is a factor that increases the amputation rate [20, 21]. It was also reported in the literature that low serum albumin level and white blood cell count of >12.0 cells/μL are associated with an increased risk of amputation in cases of diabetic foot ulcers, whereas leukocytosis was reported to be associated with poor clinical outcomes in cases of diabetic foot ulcers [22, 23]. Scott et al.  reported that in-hospital mortality was associated with lower serum albumin, Hb, and sodium concentrations and higher concentrations of urea, creatinine, and potassium in patients undergoing LEA. We did not collect data for all these variables and could not compare these findings in terms of mortality due to limited data. However, the preoperative albumin levels in our study were 2.7±0.5 g/dL, albumin levels were found to be quite low in the patients who died (≤2.3 g/dL), and the mean preoperative and postoperative leukocyte counts were found to be ≥12.0 cells/μL, signifying that our findings are consistent with the literature.
Beyaz et al.  reported a first 30-day mortality rate of 16% in patients who underwent large bone amputation due to diabetes complications. In the same study, it could not be clearly concluded whether early mortality was due to the reasons for surgery or to surgical complications. In a study involving 19,727 patients in which factors affecting early hospital mortality were evaluated in patients who underwent orthopedic surgery, 237 (1.23%) patients were reported to have died in the early period after surgery. In the same study, it was stated that the surgical procedure with the highest mortality rate was amputation surgery (6.35%) . In other studies, the mortality rate among cases of major diabetic amputation was reported as 31-41% in 1 year of follow-up and 68-77% in 5 years of follow-up . In our study, postoperative 30-day mortality was found to be 9.3%, while mean time to death was found to be 15.37±20.01 days. Furthermore, 17 (39.5%) of our patients had ≥4 diseases. All of the patients who died had coronary artery disease and half of them had ≥4 diseases. We think that the relatively low number of patients with additional internal pathologies increased the survival rate in the present study. It was observed that our patients who died were taken to the ICU postoperatively for hemodynamic follow-up purposes, and 3 of those patients died due to cardiac causes while 1 died due to respiratory causes during the first 30 days of follow-up. The shorter follow-up period in this study compared to the literature made the survival rate of our patients seem higher and also explains the difference between studies.
This study has some limitations. Our biggest handicap was that we could not determine the factors affecting mortality in cases of amputations due to diabetic foot ulcers as a result of the study’s retrospective nature and limited number of patients. In order to determine the causes of mortality in patient samples, we think that including the habits of the patients (smoking, alcohol, etc.), their education status, and the duration of dialysis in patients receiving dialysis treatment will allow for more valuable studies. Studies involving larger patient series are also needed.
In conclusion, since there were no significant differences in our study other than the low albumin levels among non-survivors, we think that supporting diabetic patients with nutritional programs in the preoperative period with a multidisciplinary approach will affect the treatment process positively.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
1. Boulton AJ, Vileikyte L, Ragnarson-Tennvall G, Apelqvist J. The global burden of diabetic foot disease. Lancet. 2005; 366:1719-24.
2. Schaper NC, Andros G, Apelqvist J, International Working Group on Diabetic foot Specific guidelines for the diagnosis and treatment of peripheral arterial syndrome in a patient with diabetes and ulceration of the foot. Diabetes Metab Res.2012; 28:236-7.
3. Reiber GE, Bowker JH, Pfefier MA. Epidemiology of foot ulcers and amputation in the diabetic foot. In: The diabetic foot. 6th ed. St Louis,Mo Inc;2001;p.1332.
4. Olgun N, Eti Aslan F, Coşansu G, Çelik S. Diabetes Mellitus. İçinde: Dahili ve Cerrahi Hastalıklarda Bakım. Karadakovan A. ve Eti Aslan F (editörler). 4.Baskı, 2.cilt. Ankara: Akademisyen Kitabevi; 2017.p.795.
5. Apelqvist J, Larsson J. What is the most effective way to reduce incidende of amputation in the diabetic foot? Diabetes Metab Res Rev 2000;16:75-83.
6. Icks A, Haastert B, Scheer M, Giani G, Morbach S, Glaeske G, Genz J, Hoffmann F. Time-dependent impact of diabetes on mortality in patients after major lower extremity amputation. Diabetes Care. 2011;34:1350-4.
7. Kalpakçı P, Sezer RE, Yılmaz S, Öztürk H, Erturhan S. Cumhuriyet Üniversitesi Hastanesi’nde 2007-2012 döneminde diyabetik ayağa bağlı operasyon olan hastaların özellikleri ile yaş ve cinsiyetin diyabetik ayak operasyonlarını tahmin ettirici etkisi, Türk Aile Hek Derg. 2014;18:54-7.
8. Monteiro- Soares MI, Boyko EJ, Ribeiro J, Ribeiro I, Dinis-RibeiroM. Predicrive factors for diabetic foot ulceration:a systematic review.Diabetes Metab Res Rev. 2012; 28:574-600.
9. Arıkan Y, Kuzgun Ü, Sever C, Armağan R. Diyabetik ayak yarası olan hastalara multidisipliner yaklaşımda ortopedinin yeri. Şişli Etfal Hastanesi Tıp Bülteni 2010; 44: 110.
10. Gutman M, Kaplan O, Scornick Yet al. Gangrene of the lower lims in diabetic patients: A malignant complication. Am J Surg.1987;154:305-8.
11. Subramaniam B, Pomposelli F, Talmor D, Park KW. Perioperative and long- term morbidity and mortality after above-knee and below-knee amputations in diabetics and nondiabetics. Anesth Analg. 2005;100:1241-7.
12. Scott SWM, Bowrey S, Clarke D, Choke E, Bown MJ, Thompson JP. Factors influencing short- and long-term mortality after lower limb amputation. Anaesthesia. 2014; 69:249-58.
13. Parenti N, Reggiani ML, Percudani D, Melotti RM. Reliability of American Society of Anesthesiologists physical status classification. Indian J Anaesth. 2016;60:208-14
14. Nelson MT, Greenblatt DY, Soma G, Rajimanickam V, Greenberg CC, Kent KC. Preoperative factors predict mortality after major lower-extremity amputation. Surgery. 2012;152:685-94.
15. Moghissi ES, Korytkowski MT, Dinardo M, et al. American association of clinical endocrinologists; american diyabetes association. American association of clinical endocrinologists and american diyabetes association consensus statement on inpatient glycemic control. Diyabetes Care. 2009;32:1119-31.
16. Aragón-Sánchez J, Lázaro-Martínez JL. Impact of perioperative glycaemia and glycated haemoglobin on the outcomes of the surgical treatment of diabetic foot osteomyelitis. Diabetes Res Clin Pract 2011; 94: 83-5.
17. Stratton IM, Adler AI, Neil HAW, Matthews DR, Manley SE, Cull CA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321:405- 12.
18. Yavuz D, Yazıcı D, Özcan S, Tarçın Ö, Deyneli O, Akalın S. Hyperglycemia İn Hospitalized Patients. Marmara Medical Journal. 2013;26:68-71.
19. Khan SA, Qianyi RL, Liu C, Ng EL, Fook-Chong S, Tan MGE. Effect of anaesthetic technique on mortality following major lower extremity amputation: a propensity score-matched observational study. Anaesthesia. 2013;68:612-20.
20. Casey J, Flinn WR, Yao JS, Fahey V, Pawlowski J, Bergan JJ. Correlation of immune and nutritional status with wound complications in patients undergoing vascular operations. Surgery. 1983;93:822-7.
21. Dickhaut SC, DeLee JC, Page CP. Nutritional status: importance in predicting wound-healing after amputation. J Bone Joint Surg Am 1984;66:71-5.
22. Eneroth M, Apelqvist J, Stenstrom A. Clinical characteristics and outcome in 223 diabetic patients with deep foot infections. Foot Ankle Int. 1997;18:716-22.
23. Lipsky BA, Sheehan P, Armstrong DG, et al. Clinical predictors of treatment failure for diabetic foot infections: data from a prospective trial. Int Wound J.2007;4:30-8.
24. Beyaz S, Guler UO, Bagir GS. Factors affecting lifespan following below-knee amputation in diabetic patients. Acta Orthop Traumatol Turc. 2017;51:393-97.
25. Beyaz S. Early period hospital mortality after orthopedic surgery and affecting factors. Cukurova Med J. 2019;44:977-83.
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Gamze Küçükosman, Bengü Gülhan Aydın, Gizem Alkım Yılmaz. Retrospective evaluation of patients undergoing amputation surgery due to diabetic foot ulcers. Ann Clin Anal Med 2021;12(10):1083-1087
Effect of robot-assisted gait training on quality of life and depression in patients with hemiplegia
Merve Akdeniz Leblebicier 1, Ismail Saracoglu 2, Fatima Yaman 1, Emre Sahın 1
1 Department of Physical Medicine and Rehabilitation, Faculty of Medicine, 2 Department of Physiotherapy and Rehabilitation, Faculty of Health Sciences, Kutahya Health Sciences University, Kutahya, Turkey
DOI: 10.4328/ACAM.20605 Received: 2021-03-22 Accepted: 2021-07-20 Published Online: 2021-09-18 Printed: 2021-10-01 Ann Clin Anal Med 2021;12(10):1088-1092
Corresponding Author: Merve Akdeniz Leblebicier, Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Kutahya Health Sciences University, 43000, Kutahya, Turkey. E-mail: email@example.com P: +90 505 297 26 11 Corresponding Author ORCID ID: https://orcid.org/0000-0002-6147-300X
Aim: Robot-assisted gait training may affect functional activity,depression and quality of life in chronic stroke.In this study, we aimed to investigate the ef- ficacy of robot-assisted gait training (RAGT) on quality of life and depression in patients diagnosed with hemiplegia due to an ischemic or hemorrhagic stroke.
Material and Methods: The study included 45 participants, including 19 chronic stroke cases in the intervention group (IG) (64.74±6.46 years) and 26 chronic stroke cases in the control group (CG) (63.88±8.76 years) who met the selection criteria. IG received RAGT in addition to conventional physiotherapy, while CG received only conventional physiotherapy. Patients were evaluated with the Functional Independence Measure (FIM), the Stroke-Specific Quality of Life Scale (SS-QOL) and the Beck Depression Inventory (BDI) before treatment, immediately after treatment (post-treatment), and three months after treatment (follow-up).
Results: Both post-treatment and third-month follow-up FIM scores significantly increased in IG (p=0.026 and p=0.011, respectively); however, there was no sig- nificant improvement in CG compared with the baseline values (p=0.180 and p=0.181, respectively). There was no significant difference in the SS-QOL scores for post-treatment and third-month follow-up measurements in either group compared with the baseline values (p= 0.856 and p= 0.349, respectively for IG and p= 0.545 and p= 0.186, respectively for CG). After treatment, BDI scores significantly improved in IG (p= 0.050), but there was no significant improvement in CG (p= 0.181) compared with the baseline values. The third-month follow-up BDI scores did not differ significantly in either group compared with baseline values (p = 0.156 for IG and p = 0.977 for CG).
Discussion: Robot-assisted rehabilitation,in addition to conventional physiotherapy, might be preferred to conventional physiotherapy alone in increasing pa- tients’ independence in self-care.
Keywords: Robot-Assisted Gait Training;Hemiplegia; Quality of Life; Depression
Stroke is a common serious and disabling healthcare problem throughout the world . It is defined as an impairment of brain functions that causes sudden and rapidly developing clinical symptoms lasting more than 24 hours, or death. This is an important health problem that negatively affects the quality of life . Rehabilitation of gait disorder after a stroke is one of the most important goals to increase functional activity, quality of life, and social participation . Loss of muscle strength and balance are the most important causes of gait disturbance in stroke cases . Robot-assisted therapy has been widely used for gait rehabilitation in several neurological disorders . When combined with regular physiotherapy, it leads to further improvements in the mobility of stroke cases. Robot-assisted therapy devices provide autonomous training, where patients can engage in repeated and intense practices of goal-directed tasks leading to improvements in motor function . There are various robot-assisted gait trainers to facilitate intensive walking training for people with a stroke, such as Lokomat® (Hocoma, Switzerland). Walking with the Lokomat® is accompanied by repetitive walking practices guided by a physiotherapist. This workstation device consists of a treadmill, a body weight support system, and bilateral exoskeletal components, which provide actuation at the hips and knees . This has been found to improve walking functions in both acute- subacute and chronic periods in hemiplegic patients. Studies have found that patients whohave received robot-assisted gait training (RAGT) are more successful in independent walking than those who have undergone only conventional exercise therapy . In a recent Cochrane review of 23 randomized controlled trials with 999 stroke patients, results showed that stroke patients who had received robot-assisted gait training in combination with physiotherapy were more likely to achieve independent walking than patients who had only received conventional gait training . In another study with 56 stroke patients, robot-assisted therapy in combination with conventional physiotherapy produced greater improvement in gait function than conventional gait training alone . In the post-stroke period, depression mood symptoms are very common. In addition, cognitive disorders occur in approximately 2/3 of the patients who have had a stroke. The presence of cognitive and psychological disorders has been correlated with reduced quality of life and poor socialization. Furthermore, it negativelyaffects rehabilitation prognosis . RAGT has been reported to increase motivation and courage of patients . It can also be stated that this treatment has a biofeedback effect, since patients are able to watch themselves on a screen when walking during RAGT. Therefore, it is hypothesized that RAGT may also affect depression and quality of life. There are various studies investigating the effectiveness of robotic rehabilitation in gait parameters, balance and functional status, but only a few studies have addressed its effectiveness in reducing depression. Thus, the aim of this study was to determine the effects of RAGT on functional activity, quality of life and depression in patients diagnosed with hemiplegia due to an ischemic or hemorrhagic stroke.
Material and Methods
This was a quasi-experimental study in which participants were assigned without randomizationto either the intervention group (IG) or control group (CG). All patients acknowledged their understanding and willingness to participate by providing signed consent. The study was conducted between April 2019 and January 2020 at Kutahya Health Sciences University Hospital, Turkey. This study was approved by the Ethics Committee of Kutahya Health Sciences University on March 18, 2019 (No:2019/02-7).
Recruitment and setting
Participants with hemiplegia who presented to the outpatient clinic of the Physical Medicine and Rehabilitation Department of Kutahya Health Sciences University Hospital during the study period were screened for eligibility by an independent physician and invited to participate in the study if found eligible. All participants were informed in advance about the procedures and assessments to be performed in the study, and those who agreed to participate signed consent forms.
• Aged 18-75 years
• Diagnosed with hemiplegia due to cerebrovascular disease
• A history of hemiplegia at least six months ago
• Having a mini-mental test score above 21
• No hearing or vision problems
• Not taking any medication that could affect balance Exclusion criteria
• Being uncooperative
• Having an additional systemic disease
• Having uncontrolled hypertension
• Presence of heart failure
After determining whether participants were to be included in IG or CG, the participants were evaluated by a blinded researcher (F.Y.), and then underwent four weeks of treatment applied by a different researcher (I.S.). Participants were reevaluated by the same blinded researcher (F.Y.) at the fourth week and again at the 12th week. The patients in IG received RAGT in addition to routine exercise therapy, while those in CG received only routine exercise therapy.
Intervention group (RAGT in addition to conventional physiotherapy): The patients in IG received RAGT in addition to conventional physiotherapy.RAGT, the Lokomat® system of Robogait® was used. Body weight support was adjusted to a minimum without knee buckling or toe dragging. The walking speed was gradually increased up to 1.5 km/h . In the first session, 50% body weight support was applied. After every walking session, the walking speed was readjusted to the patient’s walking ability . The device was placed on the patient, and then the patient’s hip, knee, and ankle joint axes were consistently positioned with the exoskeleton orthosis to adjust joint movements in an individualized manner . All patients in this group underwent 20 sessions of RAGT (45 minutes per session, five sessions per week for four weeks) in addition to 28 sessions of conventional physiotherapy (60 minutes per session, seven sessions per week for four weeks). Control group (conventional physiotherapy only): The control group received standard conventional physiotherapy. Physiotherapy sessions were focused on gait rehabilitation, such as exercising trunk stability, step initiation, and weight support on the paretic leg . The program also included patient-specific neurofacilitation techniques, range of motion exercises, upper and lower extremity strengthening exercises to the anti-spastic muscles, motor skill training, and assistive device use training. All patients in this group underwent only 28 sessions of conventional physiotherapy (60 minutes per session, seven sessions per week for four weeks).
Data regarding the participants’ age, gender, height, body weight, body mass index, duration, side and type of stroke, and educational level were recorded in a previously prepared assessment form during face-to-face interviews. The participants’ functional status, quality of life and depression status were assessed using the methods described below. All the assessments were repeated before treatment, at four weeks (post-treatment), and at 12 weeks after treatment (follow-up) by the same physician (F.Y.) who was blinded to the interventions. Functional status was the primary outcome measure, whereas the quality of life and depression scores were the secondary outcome measurements.
Assessment of functional status
The functional status of the patients was evaluated with the Functional Independence Measure (FIM), which uses a scoring based on a seven-point scale (1: total assistance, 7: complete independence) in the categories of self-care, sphincter control, mobility, locomotor function, communication, and social perception. In the FIM, 13 items evaluate motor functions and five evaluate cognitive functions. The validity and reliability studies of the Turkish version of the scale were undertaken by Küçükdeveci et al. , who found it suitable for use in Turkish society.
Assessment of the quality of life
The Stroke-Specific Quality of Life Scale (SS-QOL) was used to evaluate the quality of life. This scale consists of 12 subscales containing 49 items to evaluate the quality of life of people diagnosed with a stroke. The items of SS-QOL are evaluated with a score ranging from 1 to 5. Higher scale scores indicate higher quality of life. Hakverdioglu et al.  showed that the Turkish version of SS-QOL was valid and reliable to measure the quality of life of patients with a stroke.
Assessment of depression
The depression levels of the participants were evaluated using the Beck Depression Inventory (BDI), consisting of 21 items, each offering at least four possible responses (0-3), ranging in intensity. According to the total scores obtained, 0-9 areconsidered normal, 10-19 are mild depression, 20-30 are moderate depression, and 31-63 are severe depression. The validity and reliability of the Turkish version of the BDI were shown by Ulusoy et al..
The required sample size was calculated using G*Power software .Repeated-measures analysis of variance (ANOVA) with interaction within-between factors was used. The FIM score was the primary outcome measure. The effect size of FIM was estimated to be moderate (effect size = 0.25) for the group × time interaction intensity values in the study of Shahin et al . For a statistical power of 0.80 and an α level of 0.05, it was estimated that a sample size of 36 participants (18 participants in each group) was necessary.
The principal investigator was blinded to the group allocation during assessment and was not involved in the participants’ treatment sessions or in data analysis process. The participants were asked not to mention their group to the researcher that performed the assessment (F.Y.).
The group distribution was dependent on the participant’s time of presentation to the physical therapy department. Participants who presented to the outpatient clinic between April and May 2019 were allocated in control group, and then all the consecutive patients were included in IG between June and July 2019 (Figure 1).
Statistical Package for the Social Sciences (SPSS, IBM, Armonk, NY, USA), version 21.0 was used for statistical analyses. Continuous variables are given as mean ± standard deviation values, and categorical variables as numbers (percentages). Analyses were conducted as per protocol. Intergroup comparisons of categorical variables were performed using the chi-square test. For the comparisons of the independent groups, the independent-samples t-test was used when parametric test assumptions were met, and the Mann–Whitney U test was used for non-parametric data. For the comparisons of the dependent groups, the repeated measures analysis of variance and the Friedman test were used.
This study was completed with a total of 45 participants (25 males, 20 females), including 19 chronic stroke cases in IG (64.74 ± 6.46 years) and 26 chronic stroke cases in CG (63.88 ± 8.76 years). The participants’ age, gender, height, body weight, body mass index, stroke duration, side of stroke, type of stroke and education levels are shown in Table 1 by group. In the comparison of the demographic data of the patients included in the study, no statistically significant difference was found except for weight (p=0.010).
There were no significant differences between the groups in term of the FIM scores before treatment (96.31 ± 15.23 in IG and 86.26 ± 18.32 in CG, p = 0.510). Both post-treatment and third-month follow-up FIM scores significantly increased in IG (p = 0.026 and p = 0.011, respectively), but there was no significant improvement in CG (p = 0.180 and p = 0.181, respectively) compared with the baseline values. When the mean FIM values were compared between the two groups, there was a significant difference in favor of IG (p = 0.032) (Table 2). Secondary Outcomes
There were no significant differences between the groups in relation to the SS-QOL scores before treatment (128.42 ± 20.94 in IG and 128.46 ± 23.7 in CG, p = 0.854). The post- treatment and third-month follow-up SS-QOL scores did not significantly differ in IG (p = 0.856 and p = 0.349, respectively) or CG (p = 0.545 and p = 0.186, respectively) compared with the baseline values. There was also no significant difference between the meanSS-QOL scores of the two groups (p = 0.827) (Table 2).
No significant differences were observed between the groups in terms of the BDI scores before treatment (9.89 ± 4.56 for IG and 10.69 ± 5.08 for CG, p = 0.458). After treatment, the BDI scores significantly improved in IG (p = 0.050), but there was no significant improvement in CG (p = 0.181) compared with the baseline values. The third-month follow-up BDI scores did not significantly differ in either group compared with baseline values (p = 0.156 for IG and p = 0.977 for CG). There was also no significant difference between the mean BDI scores of the two groups (p = 0.704) (Table 2).
The majority of previous studies in the literature examined the effectiveness of RAGT on walking capacity, speed and balance and reported RAGT to be an effective method to increase these parameters [19,20]. We hypothesized that these clinical effects of RAGT would also positively contribute to the quality of life, functionality and mood. In this study, we aimed to examine the potential functional and patient mood effects of Lokomat® training, which is based on computerized visual feedback known to increase patient output and motivation.
In the present study, both patient groups showed an improvement in FIM scores at the end of the treatment period, but the change was statistically significant only in IG. This result shows that robot-assisted rehabilitation might be a promising adjuvant therapy and could be superior to only conventional physiotherapy when combined with conventional physiotherapy in increasing patients’ independence in self-care. In a previous study investigating the functional and psychological effects of robot-assisted therapy on 40 patients with spinal cord injury, a significant improvement was found in the quality of life scales and BDI scores compared to CG receiving only conventional therapy . In another study involving 60 patients with spinal cord injury, a significant improvement was found in FIM and ambulation in the RAGT group compared to CG receiving only conventional therapy . Improvement in the FIM scale, which evaluates self-care, sphincter control, transfer, communication, social participation, memory, and problem solving, continues until the third month, even if the patients are in the chronic period. This shows that RAGT does not only affect parameters related to walking, but it has a wider effect area covering functionality.
In our study, the post-treatment and third-month follow-up SS-QOL scores of IG and CG did not significantly differ. Many studies attempting to determine why early rehabilitation can provide better results have shown that it plays a major role in neural recovery and neuroplasticity [22,23]. Therefore, the lack of changes in the quality of life scores of our patients can be explained by the chronic period of the disease.
In our study, BDI significantly improved in IG, although there was no significant improvement in CG compared with the baseline values. Depression is a frequent complication of stroke, which worsens the course of post-stroke neurological disorders and decreases quality of life . Consequently, it negatively affects the treatment and rehabilitation processes. A previous study found a relationship between walking distance and quality of life scores in patients with a stroke . Another study investigating the relationship between disability and depression found depression to be associated with functional impairment after a stroke . A case report showed a significant improvement in function, psychological and cognitive status after Lokomat® training in a chronic stroke case . In our study, we considered that RAGT would increase the walking capacity and functional independence of stroke cases, which would, in turn, improve their quality of life and mood. However, we did not see any positive changes in BDI scores in our third-month evaluation. We also did not observe any superiority of RAGT compared to the conventional group depending on time. Although RAGT was effective immediately after treatment, it did not have any additional effect or superiority in the long term, which can be attributed to many factors in the patients’ lives that could affect their mood during the three-month follow-up period. The limitations of this study are the lack of randomization in patient grouping, no questions about the patients’ dominant extremity or the presence of neglect syndrome, and a short follow-up period of three months.
Many previous studies have described the efficacy of RAGT in improving motor and ambulatory function in patients with a stroke. In our study, we considered that RAGT would improve walking capacity and functional independence in chronic stroke cases and consequently lead to an improvement in their quality of life and mood. Both patient groups showed improvements in FIM at the end of the treatment period, but the change was statistically significant only in IG that had received RAGT. This result shows that RAGT, in addition to conventional physiotherapy might be preferred to conventional physiotherapy alone to increase patients’ independence in self-care.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
1. Langhorne P, Bernhardt J, Kwakkel G. Stroke rehabilitation. Lancet. 2011; 377(9778):1693-702.
2. Nichols-Larsen DS, Clark PC, Zeringue A, Greenspan A, Blanton S. Factors influencing stroke survivors’ quality of life during subacute recovery. Stroke. 2005; 36(7):1480-4.
3. Langhammer B, Stanghelle JK, Lindmark B. Exercise and health-related quality of life during the first year following acute stroke: a randomized controlled trial. Brain Inj. 2008; 22(2):135-45.
4. Srivastava S, Kao PC, Kim SH, Stegall P, Zanotto D, Higginson JS. Assist- as-needed robot-aided gait training improves walking function in individuals following stroke. IEEETrans Neural Syst Rehabil Eng. 2015; 23(6):956–63.
5. Calabro RS, Reitano S, Leo A, De Luca R, Melegari C, Bramanti P. Can robot-assisted movement training (Lokomat) improve functional recovery and psychological well-being in chronic stroke? Promising findings from a case study. Funct Neurol. 2014; 29(2):139-41.
6. Johnson MJ, Feng X, Johnson LM, Winters JM. Potential of a suite of robot/ computer-assisted motivating systems for personalized, home-based, stroke rehabilitation. J Neuroengineering Rehabil. 2007; 4:6.
7. Van Kammen K, Boonstra A, van der Woude LHV, Reinders-Messelink HA, Otter R. The combined effects of guidance force, bodyweight support and gait speed on muscle activity during able-bodied walking in the Lokomat. Clin Biomech. 2016; 36: 65-73.
8. Morone G, Iosa M, Bragoni M, De Angelis D, Venturiero V, Coiro P, et al. Who may have durable benefit from robotic gait training? A 2-year follow-up randomized controlled trial in patients with subacute stroke. Stroke. 2012; 43(4):1140-2.
9. Mehrholz J, Elsner B, Werner C, Kugler J, Pohl M. Electromechanical-assisted training for walking afterstroke: updated evidence. Stroke. 2013; 44(10):127-8.
10. Peurala SH, Airaksinen O, Huuskonen P, Jakala P, Juhakoski M, Sandell K, et al. Effects of intensive therapy using gait trainer or floor walking exercises early after stroke. J Rehabil Med. 2009; 41(3):166-73.
11. Sturm JW, Donnan GA, Dewey HM, Macdonell RAL, Gilligan AK, Srikanth V, et al. Quality of life after stroke: the North East Melbourne Stroke Incidence Study (NEMESIS). Stroke. 2004; 35(10):2340-5.
12. Shahin AA, Shawky SA, Rady HM, Effat DA, Abdelrahman SK, Mohamed E, et al. Effect of robotic assisted gait training on functional and psychological improvement in patients with incomplete spinal cord injury. J Nov Physiother Phys Rehabil. 2017; 4:83-6.
13. Kim JS, Lee JH, Hwang WS, Pyo H, Yang SP, Lim MH. Clinical Characteristics of Proper Robot-Assisted Gait Training Group in Non-ambulatory Subacute Stroke Patients. Ann Rehabil Med. 2016; 40(2):183-9.
14. Seo SJ, Yang HS, Jung S, Kang CS, Jang S, Kim DH. Effect of reducing assistance during robot assisted gait training on step length asymmetry in patients with hemiplegic stroke A randomized controlled pilot trial. Medicine. 2018; 97(33): e11792.
15. Küçükdeveci AA, Yavuzer G, Elhan AH, Sonel B, Tennant A. Adaptation of the Functional Independence Measure for use in Turkey. Clin Rehabil. 2001; 15(3):311-9.
16. Yönt GH, Khorshid L. Turkish version of the stroke-specific quality of life scale. Int Nurs Rev. 2012; 59(2):274-80.
17. Ulusoy M, Sahin NH, Erkmen H. The Beck anxiety inventory: psychometric properties. J Cogn Psychother. 1998; 12(2):163-72.
18. Faul F, Erdfelder E, Lang AG, Buchner A. G* Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behavior Research Methods. 2007; 39:175-91.
19. Bruni MF, Melegari C, Cola MC, Bramanti A, Bramanti P, Calabro RS. What does best evidence tell us about robotic gait rehabilitation in stroke patients: A systematic review and meta-analysis. J Clin Neurosci. 2018; 48:11-17.
20. Swinnen E, Beckwée D, Meesuen R, Baeyens JP, Kerckhofs E. Does Robot- Assisted Gait Rehabilitation Improve Balance in Stroke Patients? A Systematic Review. Top Stroke Rehabil. 2014; 21(2):87-100.
21. Shin JC, Kim YJ, Park HK, Kim NY. Effect of robotic-assisted gait training in patients with incomplete spinal cord injury. Ann Rehabil Med. 2014; 38(6):719-25.
22. Turton A, Pomeroy V. When should upper limb function be trained after stroke? Evidence for and against early intervention. NeuroRehabilitation 2002; 17(3):215-24.
23. Liepert J, Bauder H, Wolfgang HR, Miltner WH, Taub E, Weiller C. Treatment- induced cortical reorganization after stroke in humans. Stroke. 2000; 31(6):1210-6.
24. Sivolap YP, Damulin IV. Stroke and depression. Zh Nevrol Psikhiatr Im S S Korsakova. 2019; 119(9):143-7.
25. Hong E.Comparison of quality of life accordingtocommunitywalking in strokepatients. J Phys Ther Sci. 2015; 27(7):2391-3.
26. Srivastava A, Taly AB, Gupta A, Murali T. Post-stroke depression: prevalence and relationship with disability in chronic stroke survivors. Ann Indian Acad Neurol. 2010; 13(2):123-7.
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Merve Akdeniz Leblebicier, Ismail Saracoglu, Fatima Yaman, Emre Sahın. Effect of robot-assisted gait training on quality of life and depression in patients with hemiplegia. Ann Clin Anal Med 2021;12(10):1088-1092
Risk factors for Delirium after major surgery
Fadime Çınar 1, Fatma Eti Aslan 2
1 Department of Nursing, Nişantaşı University, Hıgh School of Health Scıences, 2 Department of Nursing, Bahçeşehir University, Faculty of Health Sciences, Istanbul, Turkey
DOI: 10.4328/ACAM.20647 Received: 2021-04-07 Accepted: 2021-08-14 Published Online: 2021-08-24 Printed: 2021-10-01 Ann Clin Anal Med 2021;12(10):1093-1097
Corresponding Author: Fadime Çınar, Department of Nursing, Nişantaşı University, High School of Health Sciences, Istanbul, Turkey. E-mail: firstname.lastname@example.org P: +90 (212) 692 88 06 Corresponding Author ORCID ID: https://orcid.org/0000-0002-9017-4105
Aim: The high prevalence of delirium in surgical clinics and risk factors need to be determined for evidence-based practices to prevent the adverse effects it causes in the early period. This study aimed to determine the development of delirium and associated risk factors in patients over 65 years of age after major surgical intervention.
Material and Method: This study was conducted as a descriptive and relation-seeker type study and it was held between September 2018-April 2019. Age- appropriate criteria for a total of 100 patients aged ≥65 who created the climb sample were used. The study used the Delirium Screening Scale (Nu-DESC) as data collection tools, Surgeon Before-During-Post-intervention Risk Factors Evaluation Form and a Mini-Mental Test. The SPPS 25.0 statistics package program was used to evaluate the data.
Results: Delirium was more common in men aged 75 years and over who were using multiple drugs, long anesthesia duration, high serum cytokine levels, low hemoglobin and albumin levels, and the results were statistically significant (p<0.05).
Discussion: Evidence-based effective treatment protocols for delirium after major surgery and risk factors for preventive interventions should be determined. When designing future delirium prevention strategies or in future etiological studies, they should focus on delirium-prone patients based on these risk factors.
Keywords: Delirium; Major surgery; Old population; Postoperative Delirium
Postoperative delirium (POD); Delirium, which can be seen after surgical intervention, occurs with sudden consciousness and disorientation due to physical or physiopathological reasons. It is defined as an acute neuropsychiatric syndrome characterized by temporary and reversible dysfunction of the brain. In addition to these assumptions in its physiopathology, delirium, in the classification made by taking psychomotor behavior changes into account, is divided into 3 (three) categories as hypoactive, hyperactive and mixed type.
These are  in the hyperactive delirium table, the psychomotor activity of the patient has increased; extremely sensitive to stimuli (i), the patient’s psychomotor activity and sensitivity to stimuli are reduced in the hypoactive delirium table (ii), the mix delirium is a type of delirium in which the patient has a hyperactive and hypoactive picture during the day (iii). Postoperative delirium-related risk factors are evaluated as preoperative, intraoperative and postoperative risk factors . Preoperative risk factors for delirium are age 80 and over , male gender , presence of urinary catheter , low serum albumin levels and lower body mass index , use of risky drugs and multiple drugs , low hemoglobin level, respiratory system diseases, fever, hypocalcemia, azotemia, liver function test disorders, glucose disorders, hyperamylasemia, hyperbilirubinemia, serum sodium-potassium disorders, metabolic acidosis, cognitive-auditory and visual disorders, inactivity, sleep disturbance . Risk factors during surgery; the duration of surgical intervention and anesthesia, the type of anesthesia used, the depth of sedation, the amount of blood lost, hypotension, blood transfusion due to blood loss  are the duration of the surgical procedure. Delirium risk factors in the post-surgical period are fluid after surgery, electrolyte imbalances, infections, and postoperative hypoxia .
There is a need to determine the risk factors for evidence- based practices to prevent delirium at a high rate in surgical clinics and to prevent the negative effects it causes in the early period. These preventive practices will provide early diagnosis of delirium, reduce morbidity and mortality rates, and will positively affect diagnosis-treatment costs. In addition, with this study, which requires a multidisciplinary team approach, it will be able to raise awareness of health professionals about predicting-prevention in the care and management of delirium patients. This study was conducted to determine the development of delirium and associated risk factors in patients over 65 years of age after major surgical intervention.
Material and Methods
The research was conducted as a descriptive and relation- seeker type study. It was held in the Orthopedics and Cardiovascular Surgery clinics of a training research hospital between September 2018 and May 2019.
In this study, patients were evaluated in terms of delirium one day before surgery and an average of 3 days after surgery. The population of the study consisted of patients aged 65 years and over who were hospitalized in the orthopedic clinic for cardiac surgery at the hip prosthesis surgery and cardiovascular surgery clinic, who accepted voluntary participation in the study, and gave verbal and written consent. The study was conducted with 100 patients who met the inclusion criteria without selecting the sample. Those under 65 years of age, those with the Standard Mini Mental State Assessment Test (MMSE) score less than 24, patients with a history of delirium prior to surgery, patients with a history of neurological or mental illness, those using sedatives or antidepressants, infection or chronic inflammatory conditions, patients taking glucocorticoids from time to time, using anti-inflammatory drugs at least 3 days prior to surgery, having communication disabilities, alcohol or drug addiction were not included. This study was conducted to determine the development of delirium and associated risk factors in patients over 65 years of age after major surgical intervention. Hypotheses tested in research;
i. H1; There is a difference between preoperative risk factors in patients with and without delirium.
ii. H2; There is a difference between the inoperative risk factors of patients with and without delirium.
iii. H3; There is a difference between postoperative risk factors in patients with and without delirium.
Data Collection and Tools
All study data before, during, after, and during the implementation phase were collected by the researcher. Introductory Features Form
This form included twelve questions to determine the age, gender, marital status, educational status, medical diagnosis, comorbid chronic diseases, smoking, alcohol use status, continuous drug use status.
Pre-During-Post- Surgery Risk Assessment Form
This form, which was developed using the literature, include three-stage follow-up forms that include delirium-related risk factors before surgery, during and after surgical intervention .
Nursing Delirium Screening Scale (Nu-DESC)
This scale was used to screen delirium before and after surgery. It consists of five items: disorientation, inappropriate behavior, inappropriate communication, illusions/hallucinations, and psychomotor slowing . The items are evaluated using 0, 1 and 2 points. In this study, the Turkish validity and reliability study of the scale was carried out first. Analyses were performed for the specificity, sensitivity, and diagnostic accuracy (ROC) of Nu-DESC. Cut off value was > 1 as a result of ROC analysis. The sensitivity at the breakpoint was 92.27 and specificity was determined as 92.72.
Standardized Mini-Mental State Evaluation
This test was developed in 1975. Its validity and reliability in Turkish were tested in 2002. It is the most commonly used test for dementia screening . It consists of 11 questions and is rated on a 30-point scale. Normal level is indicated by 24–30, 18–23 points indicate mild dementia, and 6–17 points correspond to severe dementia. In this study, the first evaluations of all patients were made within 24 hours of their admission to the hospital. Patients with a score of < 23 at the first evaluation were excluded from the study.
Ethical Aspect of the Research
Approval was obtained from the Ethics Committee of XXX University Clinical Research (Decision number: KIA2018 / 195) and the chief physician of the hospital where the study was conducted, in terms of the applicability of the study. Before completing the data collection forms, patients were informed about the study and their written and verbal consent was obtained.
Evaluation of Data
The IBM SPSS 25.0 (SPSS Inc., Chicago, IL, USA) package program was used to evaluate the data. The Kolmogorov- Smirnov, Shapiro Wilk-W test was performed and it was found that the data did not show a normal distribution. the Mann- Whitney U test, the Kruskal-Wallis test, and the Chi-square test were used. The results were evaluated at a 95% confidence interval and p <0.05 significance level.
Delirium developed in 23% of the patients (n = 23). This difference was statistically significant (p <0.05). It was determined that delirium developed more on the 1st day after surgery, and no new delirium was observed after the 3rd day, and the difference was statistically significant (p <0.05). Hypoactive delirium was in 18 patients, hyperactive delirium in 2 patients and myxdelirium in 3 patients. It was found that in 1 patient, hypoactive delirium turned into musky delirium (Table 1).
Preoperative risk factors of the patients were evaluated (Table 1). It was determined that there was a significant difference (p <0.05) between patients with and without delirium in age, gender, duration of drug use, and variables. It was determined that patients with delirium were mostly males (p <0.05). While the presence of chronic disease was detected in all patients (p> 0.05), there was a significant difference between patients who developed delirium and those who did not. The duration of drug use was found to be significantly different in patients with and without delirium (p <0.05). It was found statistically significant (p = 0.042 <0.05) according to the number of drugs. It was determined that the difference was caused by the use of 4-6 drugs. The values of the presence of visual impairment and the use of glasses were statistically significant (p <0.05). The values for the presence of incurable pain before surgery were statistically significant (p <0.05). There was no significant difference in laboratory findings, except for albumin value (p> 0.05). It was found that the albumin value, which may be associated with delirium after surgery, was low in patients who developed delirium (Table 1).
The difference between mean surgical duration scores during the surgical intervention, mean duration of the anesthesia applied, and mean scores of the pO2 level during the surgical intervention were found to be statistically significant (P <0.05), (Table 2).
While there was a significant difference between the patients who developed delirium and those who did not develop delirium after surgery, the number of drugs used, the presence of visual impairment, the presence of risky drugs, the presence of urinary catheters, untreatable pain, p02 and albumin values in laboratory findings (p <0.05), there was no significant difference between other risk factors (p> 0.05), (Table 3).
In this study, the relationship between risk factors in surgical processes and delirium was evaluated. “H1: There was a difference between preoperative risk factors in patients with and without delirium. H2: There was a difference between risk factors for surgical sequence in patients with and without delirium. H3: The difference between postoperative risk factors in patients with and without delirium were confirmed.
It was determined that delirium developed more on the 1st day after surgery, and no new delirium was observed after the 3rd day, and the difference was statistically significant (p <0.05).
Hypoactive delirium was in 18 patients, hyperactive delirium in 2 patients, and myxdelirium in 3 patients. It was found that in 1 patient, the hypoactive delirium turned into musky delirium. With these results, it was determined that the delirium incidence was very low and the type of delirium that developed was hypoactive. In a study by Lin et al. (2015), the most common type of delirium was mixed type with 47.05 percent, followed by hypoactive delirium with 38.24 percent . According to a systematic review, the most common delirium type in 2011 is mixed (55%) and hypoactive (46%) delirium . It was determined that the results obtained in our study are supported by the literature.
In the study, mean age was found to be higher in patients with delirium than in those without delirium (p <0.05). In one study, it was stated that increasing age was related to the cause of delirium, and this confirms our result . In the literature, it has been reported that the incidence of delirium is higher in male patients and that male gender is a risk factor in this respect . Advanced age, decreased cognitive function, and multiple drug use are known risk factors for delirium . The results obtained in the study are supported by the literature. Diabetes and hypertension were found to be high in patients who developed delirium as a chronic disease (p <0.05). It is thought that these results are due to the fact that the sample of the study consists of patients aged 65 and over, and there are comorbid problems in this age group. In a study, it was reported that there is a significant relationship between increasing comorbid diseases and delirium. Our results are supported by the literature. The duration of drug use was found to be significantly different in patients with and without delirium (p <0.05). In addition, the number of risky drugs used in these delirium patients and the presence of untreatable pain were found to be higher than patients without delirium, while the albumin value was found to be low.
It was determined that the mean duration of surgery, duration of anesthesia and p02 points of patients with delirium were higher than the mean scores of patients without delirium, and there was a significant difference. The literature reports about prolonged surgery and anesthesia duration, hypoxia, and delirium development after surgery . The results obtained are supported by the literature.
In this study, the development of delirium was found to be higher in patients who underwent general anesthesia. Although different results were reported on the effect of the type of anesthesia on the development of delirium after surgery, there are studies indicating that general anesthesia is a risk factor for delirium after surgery. Monk et al. (2011) found that spinal anesthesia decreased the delirium incidence in patients with hip fracture . In a published meta-analysis, it was reported that the type of anesthesia was not effective in terms of delirium development, but that postoperative cognitive function was significantly impaired in patients receiving general anesthesia . The urinary catheter is an important risk factor for delirium as it leads to physical limitation and disrupts physiological functions .
There are studies reporting that low serum albumin levels and body mass index below normal as an indicator of malnutrition are associated with delirium . It is reported that some drugs and multiple drug use cause delirium . Low hemoglobin level, respiratory system diseases, fever, hypocalcemia, azotemia, impaired liver function tests, glucose disorders, hyperamylasemia, hyperbilirubinemia, serum sodium-potassium disorders, metabolic acidosis, cognitive-auditory and visual disturbances, inactivity, sleep disturbance are important risk factors . In the literature, it has been emphasized that high rates of BUN (Blood Urea Nitrogen) -creatinine are associated with delirium . Björkelund et al. (2010) also found a significant relationship between delirium and high serum potassium, creatinine levels and low hemoglobin concentrations . In this study, it was found that BUN and creatinine values were higher in patients with delirium, and hemoglobin and albumin values were low. It was determined that the obtained results were supported by the literature.
It was found that the presence of risk factors for delirium in patients with delirium before, during and after surgery was higher than in other patients who did not develop delirium. It is necessary to identify and prevent the risk factors effective in delirium development before, during and after surgery to prevent and reduce delirium that may occur after surgery. Based on these results:
i. Determination of risk factors in predicting, recognizing and monitoring delirium development guides preventive interventions. Therefore, when designing future strategies for the prevention of delirium or in future etiological studies, it is recommended to focus on delirium-prone patients based on these risk factors.
ii. It is recommended to carry out an interdisciplinary study involvinga wider patient group and their nurses to support this study and obtain evidence-based results.
iii. It is recommended to develop scales for the diagnosis of delirium, to train health professionals on this issue, and to add these screening methods to daily routine follow-up.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
1. Sanders RD, Pandharipande PP, Davidson AJ, Ma D, Maze M. Anticipating and managing postoperative delirium and cognitive decline in adults. BMJ. 2011; 343. DOI: https://doi.org/10.1136/bmj.d4331
2. Bilotta F, Lauretta MP, Borozdina A, Mizikov VM, Rosa G. Postoperative delirium: risk factors, diagnosis and perioperative care. Minerva Anestesiol 2013; 79 (9):1066-76.
3. Pehlivan G. Risk factors and prevention of postoperative delirium. Turkish Medical Student Journal. 2015; 2 (2):107-10.
4. Noimark D. Predicting the onset of delirium in the postoperative patient. Age Ageing. 2009; 38 (4):368-73. DOI:10.1093/ageing/afp024
5. Mouzopoulos G, Vasiliadis G, Lasanianos N, Nikolaras G, Morais E, Kaminaris M. Fascia iliaca block prophylaxis for hip fracture patients at risk for delirium: a randomized placebo-controlled study. Journal of Orthopedics and Traumatology. 2009; 10 (3):127-33. DOI:10.1007/s10195-009-0062-6
6. Staus R. Delirium in the older adult orthopedic patient: predisposing, precipitating, and organic factors. Orthopedic Nursing. 2011; 30 (4):231-8. doi: 10.1097/NOR.0b013e3182247c79.
7. Clegg A, Young J.B Which medications to avoid in people at risk of delirium: a systematic review. Age and Ageing, 2010; 40( 1): 23-9. DOI: 10.1093/ageing/ afq140
8. Crimi C, Bigatello LM. The Clinical Significance of Delirium in the Intensive Care Unit. Transl Med UniSa. 2012; 2(1):1-9.
9. Le Y, Liu S, Peng M, Tan C, Liao Q, Duan K, et al. Aging differentially affects the loss of neuronal dendritic spine, neuroinflammation and memory impairment at rats after surgery. PLoS One. 2014; 9(9):e106837. DOI:10.1371/journal. pone.0106837
10. DeWitt MA. Present time, the Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Classification of Diseases. US: The American Psychiatric Association Publishing Textbook of Neuropsychiatry and Clinical Neurosciences. 2018.p.185-201.
11. Gaudreau J D, Gagnon P, Harel F, Tremblay A, Roy M.A. Fast, systematic, and continuous delirium assessment in hospitalized patients: the nursing delirium screening scale. Journal of Pain and symptom management. 2005; 29 (4):368-75. DOI:10.1016/j.jpainsymman.2004.07.009
12. Güngen C, Ertan T, Eker E, Yaşar R, Engin F. Validity and reliability of the standardized mini-mental test in the diagnosis of mild dementia in the Turkish population. 2002; Turkish Journal of Psychiatry. 13 (4):273-81.
13. Lin WL, Chen YF, Wang J. Factors associated with the development of delirium in elderly patients in intensive care units. Journal of Nursing Research. 2015; 23 (4):322-9. DOI: 10.1097/JNR.0000000000000082.
14. Cerejeira J, Mukaetova-Ladinska E.B A. Clinical Update on Delirium: From Early Recognition to Effective Management. Nursing Research and Practice. 2011; 1-12. DOI:10.1155/2011/875196.
15. Chaput AJ, Bryson GL. Postoperative delirium: risk factors and management: continuing professional development. Canadian Journal of Anesthesia/Journal Canadien d’anesthésie. 2012; 59 (3):304-20. DOI:10.1155/2011/875196.
16. Deiner S, Silva Gerstein J.H. Postoperative delirium and cognitive dysfunction. British Journal of Anesthesia. 2009; 103(1):41- 6. DOI:10.1155/2011/875196
17. Björkelund KB, Hommel A, Thorngren KG, Gustafson L, Larsson S, Lundberg D. Reducing delirium in elderly patients with hip fracture: a multifactorial intervention study. Acta Anaesthesiologica Scandinavica. 2010; 54 (6):678-88. DOI:10.1111/j.1399-6576.2010.02232.x
18. Mazandarani M, Yousefshahi F, Abdollahi M, Hamishehkar H, Barkhordari K, Boroomand, MA, et al. Comparison of hypertonic saline versus normal saline on cytokine profile during CABG. DARU. 2012; 20 (1):49. DOI:10.1186/2008-2231- 20-49
19. Monk TG, Price C.C. Postoperative cognitive disorders. Curr Opin Crit Care. 2011; 17( 4):376-81. DOI: 10.1097/MCC.0b013e328348bece
20. Mason S.E, Noel-Storr A, Ritchie C.W. The impact of general and regional anesthesia on the incidence of postoperative cognitive dysfunction and postoperative delirium: a systematic review with meta-analysis. Journal of Alzheimer’s Disease. 2010; 22 (3):67-79. DOI: 10.3233/JAD-2010-101086
21. Dasgupta M, Dumbrell A.C. Preoperative risk assessment for delirium after noncardiac surgery: a systematic review. Journal of the American Geriatrics Society. 2006; 54 (10):1578-89. DOI:10.1111/j.1532-5415.2006.00893.x
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Fadime Çınar, Fatma Eti Aslan. Risk factors for Delirium after major surgery. Ann Clin Anal Med 2021;12(10):1093-1097
Alteration of butyrylcholinesterase level in cholelithiasis patients after laparoscopic cholecystectomy: Do butyrylcholinesterase levels affect lipid metabolism?
Durmuş Ayan 1, Hacı Bolat 2, Esma Özmen 3, İsmail Sarı 3
1 Department of Medical Biochemisrty, Niğde Ömer Halisdemir University, Research and Training Hospital, 2 Department of General Surgery, Niğde Ömer Halisdemir University, Research and Training Hospital, 3 Department of Medical Biochemisrty, Niğde Ömer Halisdemir University, Faculy of Medicine, Niğde, Turkey
DOI: 10.4328/ACAM.20655 Received: 2021-04-13 Accepted: 2021-06-20 Published Online: 2021-07-10 Printed: 2021-10-01 Ann Clin Anal Med 2021;12(10):1098-1102
Corresponding Author: Durmuş Ayan, Nigde Research and Training Hospital, Medical Biochemistry Department, 5100, Niğde, Turkey. E-mail: email@example.com P: +90 5536338185 Corresponding Author ORCID ID: https://orcid.org/0000-0003-2615-8474
Aim: Cholelithiasis (gallbladder stone) is a disease with a high incidence worldwide. The disease is multifactorial and various factors such as gender, age, obe- sity and use of oral contraceptives are held responsible for the development of the disease. In addition, lipid disorder is observed in more than 50% of patients with cholelithiasis. Laparoscopic cholecystectomy (LC) is one of the most frequently used surgical methods in the treatment of cholelithiasis, and there are data indicating that lipid profile changes and metabolic syndrome (MetS) develop after the operation. In this study, we aimed to investigate whether there is a change in lipid profile and Butyrylcholinesterase (BChE) activity, which affects lipid metabolism, in cholelithiasis patients after LC.
Material and Methods: In our study, 31 patients (obese and non-obese) who applied to the general surgery clinic of Nigde Omer Halisdemir University Training and Research Hospital were included. Blood samples were taken from the patients before LC and 6 months after the operation, and the lipid levels and BChE enzyme activity were examined using spectrophotometric method.
Results: According to the results, it was determined that the total cholesterol (p=0.015) and LDL (p=0.010) levels significantly decreased after LC, while no significant difference was found in the other parameters examined (p>0.05). In addition, it was observed that there was no significant correlation between the lipid profile examined both before and after LC and BChE activity level.
Discussion: According to the data obtained, the significant decrease in LDL and total cholesterol after LC indicates that this operation causes a positive change at least within a period of 6 months in the lipid profile of patients.
Keywords: Butyrylcholinesterase; Laparoscopic Cholecystectomy; Lipid Metabolism; Cholelithiasis; Lipid Profile
Cholelithiasis (gallbladder stone) can develop in individuals due to obesity, diabetes, and hyperlipidemia, increased bile cholesterol content with the effect of estrogen, bacterial infections and liver diseases . Both environmental and genetic factors are effective in the pathogenesis of the disease . Cholecystectomy is the most effective and preferred treatment method for cholelithiasis today . Cholecystectomy can be performed in two different ways: open cholecystectomy and laparoscopic cholecystectomy (LC). Among these two operations, LC is the most frequently used method worldwide and attracts attention as one of the most popular surgical applications today [2, 4]. Applied for a long time, cholecystectomy has been accepted as a safe procedure with no harmful effects on individuals, and has become the preferred operation for symptomatic cholelithiasis today. At the same time, LC is a surgical procedure with minimal mortality and morbidity rates and ideal results in the short and long term . In addition, although LC seems to be an intervention with the lowest risk and complications for cholelithiasis patients, recent studies have reported that this surgical procedure increases the risk of metabolic syndrome (MetS), which has become a common public health problem in populations today [1, 6]. MetS is defined as the combination of a number of risk factors such as central fat, high blood pressure, low HDL, high triacylglycerol (TAG) and hyperglycemia [7, 8]. It has been determined that the rate of development of various complications such as dyslipidemia, non-alcoholic fatty liver disease and hyperglycemia was observed in patients who underwent cholecystectomy . These complications are also closely associated with MetS . In addition, a significant increase in body mass index (BMI) and waist circumference has been reported in patients who underwent cholecystectomy. These data also support the thoughts that the risk of developing MetS after cholecystectomy is increased. It is understood that many of the complications that develop after cholecystectomy related to MetS are associated with lipid metabolism . Since the gallbladder is an important organ in the digestion of lipids, it may be possible that there will be significant changes in the level and metabolism of lipids after cholecystectomy. In addition, in some other studies, it has been observed that TC, HDL, LDL, VLDL and TG levels significantly changed after cholecystectomy [12, 13]. Human butyrylcholinesterase enzyme is an enzyme in glycoprotein structure, which is mainly synthesized in the liver (BChE, EC.126.96.36.199). Enzyme activity is also found in the brain, pancreas and plasma, as well as in the liver. This enzyme is also called pseudo or non-neuronal cholinesterase [14, 15]. The fact that BChE is particularly effective on hydrophilic and hydrophobic cholinesterase has led to a focus on the pharmacological and toxicological functions of the enzyme. The enzyme provides hydrolysis of therapeutic and/or addictive drugs containing many esters such as succinylcholine, aspirin, irinotecan, heroin, and cocaine . In addition, many clinical studies have revealed that varying serum BChE activity levels were associated with diseases such as obesity, impaired lipid metabolism, type 2 diabetes, and cardiovascular diseases, hypertension, hyperlipidemia, and hyperthyroidism [17-19]. Apart from all these, in a limited number of studies, a significant relationship has been found between BChE activity and LDL and VLDL levels . In addition, it has been revealed that BChE significantly increases lipid metabolism and adipose tissue lipid deposits; however, the mechanism of these effects of BChE has not been elucidated in all aspects . In this study, we aimed to examine whether there is a change in lipid profile and BChE activity levels after LC and to determine whether there is a correlation between lipid profile and BChE enzyme activity on obese and non-obese individuals.
Material and Methods
Composition of the Study Group
The study group composed of 31 volunteers (obese and non- obese) who applied to the general surgery clinic of Nigde Omer Halisdemir University Training and Research Hospital with complaints of abdominal pain, pain reaching the right shoulder, abdominal swelling, and who diagnosed with symptomatic cholelithiasis by ultrasonography.
The following patients were included in the study
• Non-obese (BMI<30 kg / m2)
• Obese (BMI=30-39.9 kg / m2)
• Diagnosis of symptomatic cholelithiasis
Exclusion Criteria were as follows:
• Morbid obesity (BMI> 40 kg / m2)
• Nephrotic syndrome,
• Coronary heart disease,
• Any hormonal disease
• Receiving antihyperlipidemic therapy,
• Any previous bowel surgery
Prior to the study, approval was obtained from the Ethics Committee of Nigde Omer Halisdemir University Non- Interventional Clinical Research (No. 2021/34)
Collection of Blood Samples
After each of the individuals included in the patient group was informed in detail, and read and signed the informed consent form, blood samples were taken into 5 mL sterile biochemistry tubes with gel before and 6 months after the operation. After the blood samples taken from the patients were centrifuged at 4000 rpm for 10 minutes, their serum was separated and stored at -80 oC until the study day.
Measurement of HDL, TG, TC, LDL, BChE Levels
Serum samples obtained from the patients before the study day were removed from -80 degrees and kept at -40 oC for a while, then at -20 oC and then at 2-8 oC, and then they were taken to room temperature and prepared for the study. Lipid profile (HDL, Triglyceride, Total cholesterol, LDL) levels of patient serum samples were measured with the Roche Cobas c501 device by spectrophotometric method. According to the lipid profile results obtained, the LDL value was calculated according to the Friedewald formula. BChE enzyme levels were measured with the colorimetric method in Roche Cobas c501 device. In the colorimetric method, cholinesterase catalyzes the hydrolysis of butyrylthiocholine to thiocholine and butyrate. Thiocholine suddenly reduces the yellow hexacyanoferrate (III) to an almost colorless hexacyanoferrate (II). This color reduction is measured photometrically. Analytical performances of the method for BChE were determined as intra-day precision [1st sample (5916 ± 28, CV = 0.5%) 2nd sample (7313 ± 38, CV = 0.5%)] and inter-day precision [3rd sample (1002 ± 26, CV = 2.6%) 4th sample (6683 ± 74, CV = 1.1%)]. The measurement on the device was calculated as U/L. The reference range of BChE enzyme levels for both male and female gender was determined by the manufacturer as 4260-12920 U/L.
The SPSS-15 software for Windows was used for statistical analysis. Analysis of parameters showing normal distribution was performed with the Paired-Samples T- test used for the dependent two-group analysis, and analysis of parameters not showing a normal distribution was performed with the Wilcoxon test, and the Mann-Whitney u test used for the dependent two-group analysis. Correlation analyses of the groups were calculated using Pearson’s correlation for values with normal distribution and Spearman’s correlation for parameters that do not show a normal distribution. Alpha significance level was taken as <0.05.
As presented in Table 1, there were a total of 31 cholelithiasis patients in our study group, 8 males (26%), 23 females (74%). The mean age of the patients was 47.8 ± 2.3 years. When the study group is grouped in terms of BMI, it consists of 18 obese (58%) and 13 non-obese (42%) individuals.
According to the data we obtained, a statistically significant difference was found between cholesterol (p=0.015) and LDL (p=0.010) values before and after LC. However, no statistically significant difference was found in the values of BChE (p=0.215), TG (p=0.289), HDL (p=0.315), fasting blood glucose (p=0.651), creatinine (p = 0.580), total protein (p=0.155) and albumin (p=0.101) (Table 2).
According to the correlation test results, a significant positive correlation was found between albumin and HDL levels measured after LC (p=0.049; r:0.357). In addition, a weak positive correlation was analyzed for these two parameters, although not significant (p=0.07; r=0.376). However, there was no statistically significant correlation between other parameters examined before and after LC (p>0.05). When the study group was classified into two subgroups as obese (n=18) and non-obese (n=13) and evaluated in terms of the measured parameters, it was found that the LDL level after LC significantly decreased in both obese and non-obese groups (p<0.05), (Figure 1). No significant difference was observed in terms of other parameters examined (p>0.05), (Figure 1, 2) Finally, when the correlations between the parameters measured before and after LC of the obese group and the non-obese group were analyzed, a weak negative correlation (p=0.039, r:-0.489) was found between the pre-LC BChE values and the glucose value of obese individuals, and there was no statistically significant correlation between these two parameters in the same group measured after LC (p>0.05). In the group of non-obese individuals, no statistically significant correlation was found between the parameters examined before and after LC (p>0.05). (Figure 2)
In our study, it was investigated whether there is a change in serum lipid profile and BChE enzyme levels in patients with cholelithiasis after LC. As a result of the data we obtained, it was found that plasma total cholesterol and LDL levels significantly decreased after LC in cholelithiasis patients (p <0.05), while there was no significant difference in VLDL, HDL and TG levels. According to our knowledge, although there is no study investigating the change in the BChE enzyme level using LC application in patients with cholelithiasis, there are various studies investigating lipid profiles after LK in cholelithiasis patients . In two different studies, Al-Kataan has found a significant decrease in total cholesterol, TG and LDL levels 1 month after LC application in 60 cholelithiasis patients, while a significant increase has been found in HDL levels . In a study by Gill and Gupta, it has been determined that while a significant decrease in total cholesterol and TG levels was found in 50 patients with gallbladder stone, 1 month after cholecystectomy, HDL levels increased significantly. In addition, no significant difference has been observed in LDL and VLDL levels one month after the operation . Considering these studies, although there are significant changes in lipid profile values after LC in cholelithiasis patients, there are some contradictory results. In this contradiction, the number of individuals examined in the study and the time elapsed after the operation may play an important role. Therefore, studies that will examine the changes in lipid levels after LC in a longer period and in more individuals are required. Researchers focused more on the changes in lipid levels after LC. However, there have not been enough studies on the mechanism of these changes.
The BChE enzyme is also synthesized by extrahepatic tissues, mainly the liver. BChE is especially secreted from adipose tissue outside the liver and its secretion is related to the fat mass. Although BChE is mostly used as a liver function test, it is an enzyme that is also effective in the conversion of VLDL to LDL . In addition, the study has revealed a significantly positive correlation between serum BChE enzyme levels and LDL, total cholesterol and triglyceride levels . Similarly, Alacantara et al. also have found a strong positive correlation between BChE and TG, total cholesterol and LDL levels. In addition, a negative correlation between BChE and HDL levels has been analyzed . In addition, in another study, a positive correlation has been found between BChE enzyme and LDL in patients with hepatocellular carcinoma . Based on these studies, it is understood that there is a significant relationship between BChE enzyme levels and serum lipid levels, especially LDL. Therefore, in our study, we also determined the activity of this enzyme before and after LC in order to examine the relationship between BChE enzyme levels and serum lipid levels. As a result of the data we obtained, although a statistically significant value was not reached, there was a moderate decrease in BChE enzyme activity after LC (7578 ± 1600 U / L) compared to before LC (7996 ± 1698 U / L). Although a significant decrease in LDL level after the operation suggests that there may be a correlation between these two parameters, no significant correlation was found between BChE and any parameter before and after LC in our analyzes.
In addition to the BChE enzyme, our study is used to evaluate serum albumin and total protein levels, the liver synthesis capacity . Failure to detect a significant difference after LC in terms of all 3 parameters in our study may indicate that there is no problem with the postoperative liver synthesis capacity in patients. In addition to all these, a history of cardiovascular disease was determined as an exclusion criterion when creating the patient group in our study. However, based on the study by Rejendra et al  together with the lipid profile, the BChE/ HDL ratio was evaluated as a “complementary risk factor” for cardiovascular disease in order to assess the risk of unknown cardiovascular disease. It was determined that there was no statistically significant difference in BChE / HDL ratio in terms of values obtained before and after LC. Finally, in our study, the patient group was classified into two groups as obese and non- obese individuals according to their BMI values. When evaluated statistically in terms of parameters measured before and after LC, it was observed that only LDL levels decreased significantly in both obese and non-obese groups after LC, while there was no significant difference in terms of any other parameter.
In conclusion, the fact that liver function tests such as BChE, albumin and total protein did not change significantly 6 months after LC, and that the lipid profile showed a significant decrease in total cholesterol and LDL levels support the idea that LC is a reliable and advantageous application in patients with cholelithiasis. However, our findings should be supported by comprehensive studies with a large number of people. Limitations of the Study:
First of all, our study is planned as a pilot study for other detailed studies that we will conduct. Although our study was well planned, more significant results can be obtained with the data obtained from examining different parameters by increasing the number of patients. Secondly, by determining gene polymorphisms that are thought to be effective in BChE enzyme activity, the changes of BChE activity and lipid profiles can be examined at genetic level in a similar study group. In addition, when the study group was formed, the patients’ post-operative drug use should be determined as an exclusion criterion or their drug use should be controlled in detail. In addition, in order to better elucidate the effects of the currently popular cholecystectomy methods, the study should be examined in both open and LC forms. Thus, the effects of the two surgical methods can be evaluated together.
Scientific Responsibility Statement
Animal and human rights statement
Conflict of interest
1. Littlefield A, Lenahan C. Cholelithiasis: Presentation and Management. J Midwifery Womens Health. 2019; 64(3):289-97. DOI: 10.1111/jmwh.12959
2. Lammert F, Gurusamy K, Ko CW, Miquel JF, Méndez-Sánchez N, Portincasa P, et al. Gallstones. Nat Rev Dis Primers. 2016; 2:16024. DOI: 10.1038/nrdp.2016.24
3. Portincasa P, Di Ciaula A, Wang HH, Moschetta A, Wang DQ. Medicinal treatments of cholesterol gallstones: old, current and new perspectives. Curr Med Chem. 2009; 16(12):1531-42. DOI: 10.2174/092986709787909631
4. Portincasa P, Di Ciaula A, de Bari O, Garruti G, Palmieri VO, Wang DQ. Management of gallstones and its related complications. Expert Rev Gastroenterol Hepatol. 2016; 10(1):93-112. DOI: 10.1586/17474124.2016.1109445
5. Sanford DE. An Update on Technical Aspects of Cholecystectomy. Surg Clin North Am. 2019; 99(2):245-58. DOI: 10.1016/j.suc.2018.11.005
6. Ruhl CE, Everhart JE. Relationship of non-alcoholic fatty liver disease with cholecystectomy in the US population. Am J Gastroenterol. 2013; 108(6):952-8. DOI: 10.1038/ajg.2013.70
7. Sherling DH, Perumareddi P, Hennekens CH. Metabolic Syndrome. J Cardiovasc Pharmacol Ther. 2017; 22(4):365-7. DOI: 10.1177/1074248416686187
8. Mendrick DL, Diehl AM, Topor LS, Dietert RR, Will Y, La Merrill MA, et al. Metabolic Syndrome and Associated Diseases: From the Bench to the Clinic. Toxicol Sci. 2018; 162(1):36-42. DOI: 10.1093/toxsci/kfx233
9. Hajong R, Dhal MR, Naku N, Kapa B. Incidence of nonalcoholic fatty liver disease in patients undergoing laparoscopic cholecystectomy. J Family Med Prim Care. 2018; 7(6):1375-8. DOI: 10.4103/jfmpc.jfmpc_193_18
10. Almeda-Valdés P, Cuevas-Ramos D, Alberto Aguilar-Salinas C. Metabolic syndrome and non-alcoholic fatty liver disease. Ann Hepatol. 2009; 8(Suppl.1):S18-24. DOI: 10.1016/S1665-2681(19)31822-8
11. Yener O, Aksoy F, Demir M, Özçelık A, Erengül C. Gallstones associated with nonalcoholic steatohepatitis (NASH) and metabolic syndrome. Turk J Gastroenterol. 2010; 21(4):411-5. DOI: 10.4318/tjg.2010.0128
12. Randell EW, Mathews MS, Zhang H, Seraj JS, Sun G. Relationship between serum butyrylcholinesterase and the metabolic syndrome. Clin Biochem. 2005; 38(9):799-805. DOI: 10.1016/j.clinbiochem.2005.04.008
13. Alcântara VM, Chautard-Freire-Maia EA, Scartezini M, Cerci MS, Braun- Prado K, Picheth G. Butyrylcholinesterase activity and risk factors for coronary artery disease. Scand J Clin Lab Invest Suppl. 2002; 62(5):399-404. DOI: 10.1080/00365510260296564
14. Rahimi Z, Ahmadi R, Vaisi-Raygani A, Rahimi Z, Bahrehmand F, Parsian A. Butyrylcholinesterase (BChE) activity is associated with the risk of preeclampsia: influence on lipid and lipoprotein metabolism and oxidative stress. J Matern Fetal Neonatal Med. 2013;26(16):1590-4. DOI: 10.3109/14767058.2013.795534
15. Benner A, Lewallen N, Sadiq NM. Biochemistry, Pseudocholinesterase. Treasure Island (FL): StatPearls Publishing; 2020.
16. Molina-Pintor IB, Rojas-García AE, Bernal-Hernández YY, Medina- Díaz IM, González-Arias CA, Barrón-Vivanco BS. Relationship between butyrylcholinesterase activity and lipid parameters in workers occupationally exposed to pesticides. Environ Sci Pollut Res Int. 2020; 27(31):39365-74. DOI: 10.1007/s11356-020-08197-2
17. Li B, Sedlacek M, Manoharan I, Boopathy R, Duysen EG, Masson P, et al. Butyrylcholinesterase, paraoxonase, and albumin esterase, but not carboxylesterase, are present in human plasma. Biochem Pharmacol. 2005; 70(11): 1673-84. DOI: 10.1016/j.bcp.2005.09.002
18. Iwasaki T, Yoneda M, Nakajima A, Terauchi Y. Serum butyrylcholinesterase is strongly associated with adiposity, the serum lipid profile and insulin resistance. Intern Med. 2007;46(19):1633-9. DOI: 10.2169/internalmedicine.46.0049
19. Santarpia L, Grandone I, Contaldo F, Pasanisi F. Butyrylcholinesterase as a prognostic marker: a review of the literature. J Cachexia Sarcopenia Muscle. 2013; 4:31-9. DOI: 10.1007/s13539-012-0083-5
20. Agirgol B, Yilmaz U, Isleten F, Semerci E, Kutsal C. Correlation of Serum Butyrylcholinesterase Activity with Preoperative Anxiety and Lipid Levels. Turk Biyokim Derg. 2008; 33:9-13.
21. Chen VP, Gao Y, Geng L, Stout BM, Jensen MD, Brimijoin S. Butyrylcholinesterase deficiency promotes adipose tissue growth and hepatic lipid accumulation in male mice on high-fat diet. Endocrinology. 2016; 157:3086–95. DOI: 10.1210/en.2016-1166
22. Gill GS, Gupta K. Pre-and Post-operative comparative analysis of serum lipid profile in patients with cholelithiasis. Int J Appl Basic Med Res. 2017;7(3):186. DOI: 10.4103/2229-516X.212968
23. Motta M, Giugno I, Ruello P, Pistone G, Di Fazio I, Malaguarnera M. Lipoprotein (a) behaviour in patients with hepatocellular carcinoma. Minerva Med. 2001; 92(5):301-5.
24. Santarpia L, Grandone I, Contaldo F, Pasanisi F. Butyrylcholinesterase as a prognostic marker: a review of the literature. J Cachexia Sarcopenia Muscle. 2013;4(1): 31-9. DOI: 10.1007/s13539-012-0083-5
25. Jain R, Kutty KM, Huang SN, Kean K. Pseudocholinesterase/high- density lipoprotein cholesterol ratio in serum of normal persons and of hyperlipoproteinemics. Clin Chem. 1983; 29(6):1031-3.
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Durmuş Ayan, Hacı Bolat, Esma Özmen, İsmail Sarı. Alteration of butyrylcholinesterase level in cholelithiasis patients after laparoscopic cholecystectomy: Do butyrylcholinesterase levels affect lipid metabolism? Ann Clin Anal Med 2021;12(10):1098-1102
Gastrointestinal stromal tumor: Retrospective evaluation of twenty cases
Deniz Öçal 1, Yılmaz Özdemir 1, Ahmet Erkan Bilici 2
1 Department of Gastrointestinal Surgery, 2 Department of Pathology, Erzurum Regional Education and Research Hospital, Erzurum, Turkey
DOI: 10.4328/ACAM.20658 Received: 2021-04-14 Accepted: 2021-07-28 Published Online: 2021-08-10 Printed: 2021-10-01 Ann Clin Anal Med 2021;12(10):1103-1107
Corresponding Author: Deniz Öçal, Department of Gastroenterology Surgery, Erzurum Regional Education and Research Hospital, Erzurum, Turkey. E-mail: firstname.lastname@example.org P: +90 505 297 33 30 Corresponding Author ORCID ID: https://orcid.org/0000-0002-8084-8866
Aim: In this study, we aimed to evaluate the clinico-pathological findings and treatment methods of 20 cases operated for intra-abdominal gastrointestinal stromal tumor.
Material and Methods: The data of 20 cases operated at Erzurum Regional Education and Research Hospital, Erzurum, Turkey between 2015 to 2020 were retrospectively analyzed. Gastrointestinal stromal tumor (GIST) locations, surgical methods, histopathological diagnosis, postoperative medical treatments were discussed.
Results: Eleven (55%) patients were male, and nine (45%) were female, and the mean age of all patients was 57.7 ± 11.42 (39-76) years. Most of the tumor was in the stomach (70%). Abdominal pain and bleeding were the main symptoms at admission. The mean diameter of the tumors was 61.5 ± 30.3 mm (10- 120 mm). The most common surgical technique was laparoscopic gastric wedge resection in 7 patients (35%). Seven patients were classified as high risk, 6 as medium risk, 5 as low risk and 2 patients as a very low risk on pathological evaluation. CD117 expression was positive in all patients, and CD34 expression was found to be positive in 15 (75%) patients.
Discussion: Gastrointestinal stromal tumors are mainly located intraabdominally. The most common symptoms are abdominal pain and bleeding. Symptoms depend on the location of the tumor in the abdomen. The main purpose of surgery is the complete resection of the mass performed with a negative surgical margin. Minimally invasive methods can be applied safely in GISTs.
Keywords: Gastrointestinal stromal tumor; Histopathology; Surgical treatment; Minimal invasive surgery
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract . Studies show that the incidence of the GIST is 10 to 15 cases per million. In GIST, a significant relationship between incidence and geographical distribution, race and gender could not be shown . It can be seen that after the 2000s ,there has been an increase in the incidence of GIST. This has been reported to be a result of improvement criteria rather than a true incidence increase .
GISTs can occur anywhere in the gastrointestinal tract from the esophagus to the anus. More than 90% of GISTs are from the gastrointestinal system (GIS), most often (%51) from the stomach, followed by the small intestine (%36), colon (%7), rectum (%5) and esophagus (%1) rarely mesentery, peritoneum, omentum and also it is seen rarely in the intra-abdominal organs such as liver, pancreas, ovary and uterus . The most common metastasis sites of GISTs are liver and abdominal membranes, peritoneum, mesentery and omentum .
Inside and around the myenteric plexus of the intestine, there are pacemaker interstitial Cajal cells responsible for primary gastrointestinal system peristalsis. GISTs are thought to be mesenchymal tumors arising from the precursors of Cajal cells. Cajal cells contain c-kit gene protein that regulates intracellular events. The immune marker of c-kit is CD 117. A mutation in the c-kit proto-oncogene is involved in the pathogenesis of GISTs. As a result, cell growth is stimulated and/or apoptosis is inhibited .
The first step in the treatment of GISTs is surgical complete resection. Surgery is potentially curative for primary GISTs that do not metastasize. The probability of recurrence will depend on the malignant potential risk classification criteria. Tumors are resistant to traditional chemotherapy. In 2002, the first tyrosine kinase inhibitor was used to treat metastatic disease. It is currently used successfully as an adjuvant or neoadjuvant . In this study, we aimed to contribute to the literature by presenting symptoms, diagnostic methods, surgical methods and pathological findings of patients operated for gastrointestinal stromal tumors in our clinic.
Material and Methods
The files of 20 patients who were operated with a diagnosis of GIST at the Department of Gastrointestinal Surgery, Erzurum Regional Education and Research Hospital, Erzurum, Turkey between 2015 and 2020 were retrospectively analyzed after ethical approval (Ethics Committee Decision Number: 2020/12-125). Demographic data, clinical findings, imaging tools, treatment modalities of the cases were recorded. From the operation notes, the location of the tumor, surgery type, tumor diameter, the presence of invasion into the surrounding tissues, and the status of metastases were evaluated. Tumor diameter and mitosis rate were determined in the histopathological examination of the tumor. CD-117, CD-34, SMA, S-100, Desmin, Vimentin, DOG-1 stainings were performed immunohistochemically. Tumors were categorized as very low, low, medium and high risk according to their potential for malignancy. Adjuvant or neoadjuvant treatment protocols of the cases were recorded. The survival status of the patients was checked by phone call.
A total of 20 patients were included in the study. The mean age of the patients was 57.7 ± 11.42 (39-76) years, 11 of them were men (55%), 9 were women (45%). The most common admission symptoms were abdominal pain and bleeding, while other rare symptoms were weight loss, anorexia, dysphagia and rapid satiety. Half of all patients had abdominal pain, and 4 (20%) patients had gastrointestinal bleeding. Massive bleeding was not observed in any of our GIST cases. All bleeding cases were applied with the complaint of melena not required erythrocyte suspension. None of the patients had tumor marker elevation. Contrast-enhanced abdominal tomography was performed in all cases preoperatively, except for the case of GIST, which was incidentally detected due to trauma. Endoscopic ultrasonography was performed to confirm the diagnosis in all stomach localized GISTs. PET was used in extra-gastric GIST patients. MRI was not used in any patient at the time of diagnosis. At the preoperative evaluation, only one patient had distance metastasis (liver metastasis). This patient was operated after 12 months of neoadjuvant tyrosine kinase inhibitor therapy.
All patients were operated with general anesthesia. While only one patient was operated under emergency conditions due to trauma, the other patients were operated under elective conditions. It was seen that 14 (70%) of all cases originated from the stomach, 4 from the jejunum, one from the duodenum, and one from the ileum. The mean diameter of the tumors was 61.5 ± 30.3 mm (10-120 mm). In the intraoperative evaluation of a patient who operated under emergency condition, incidentally, jejunum located GIST was seen and the mass was resected. In addition, half of all patients were operated with minimally invasive surgery (laparoscopic or robotic). Laparoscopic gastric wedge resection was performed in 6 of 14 gastric GIST patients, and 3 of 14 gastric GIST patients underwent robotic subtotal gastrectomy. One patient with jejunum located GIST was operated with laparoscopic segmental resection. All of the patients who started their surgery with a minimally invasive method were completed with the same method. Preoperative and peroperative features of the patients are seen in Table 1. Two (10%) patients were at very low risk, 5 (25%) patients were at low risk, 6 (30%) were at medium risk, and 7(35%) were at high risk in pathological evaluation. A spindle cell pattern was seen in 16 patients (80%), epithelioid pattern in 2 patients (10%), and a mix pattern in 2 patients (10%). CD 117 was 100 % positive, CD 34 was 75% positive. DOG-1 positivity was seen in 9 of 10 patients. SMA was positive in 5 of 13 patients. Desmin-positivity was seen in only one patient (1/19). S100 was positive in 1 of 15 patients. The postoperative features of the patients are presented in Table 2.
The mean length of hospital stay was 8.55 ± 2.7 days (4-16). The morbidity and mortality rates of the study were 30% and 5%, respectively. The most common complication was surgical site infection with 15% (2 of 3 at port side, and 1 of 3 at abdominal incision). A patient who died due to cranial trauma on postoperative day 8 was incidentally detected to have Jejunum localized GIST. The mean postoperative follow-up time was 36.95 ± 17.08 months (0-61). No patient died, except for the patient who died in the early postoperative period.
The gastrointestinal system is a long path that continues with each other from mouth to anus. The most common type of cancer in this system is adenocarcinoma . The second most common type is squamous cell cancer. Apart from the common types, gastrointestinal stromal tumor (GIST), lymphoma, carcinoid tumor and leiomyosarcoma are other types of gastrointestinal system tumors. In this study, it was aimed to evaluate GIST cases, which are rare in the gastrointestinal tract, together with our surgical experience.
GIST is of mesenchymal origin and constitutes approximately 80% of all gastrointestinal mesenchymal tumors . Although GISTs are rarely seen in the pediatric age group, the average age at which they are most common is 60 years, and they have an almost equal distribution in female and male populations . In our study, the mean age was 57.7 ±11.42 (39-76) years, and the male to female ratio was 1.2 (11 male, 9 female), compatible with the literature.
GIST is mostly asymptomatic at an early stage and is detected incidentally during surgical interventional, radiological examination, or endoscopy performed for another reason. In symptomatic GIST, symptoms are not specific to GIST, but they cause complaints according to the location and the size of the tumor. The most common symptoms are abdominal pain (50- 70%), gastrointestinal bleeding (20-30%) and abdominal mass (5-10%) as well as nausea, vomiting, dysphagia, weight loss, bloating, perforation and obstruction . In our study, the most common symptoms were abdominal pain and gastrointestinal bleeding. GISTs often grow towards the abdominal cavity and become large masses in the abdomen, signs of intestinal obstruction are relatively rare. In our study, only one case had obstruction findings. This case was located at the terminal ileum and was treated with segmental resection and right hemicolectomy.
Although CT is the most common radiological method used for the diagnosis of GIST, endoscopic ultrasonography, magnetic resonance imaging and positron emission tomography are used as auxiliary tests. However, no radiological examination is sufficient to make a definitive diagnosis of GIST . Abdominal CT with dynamic triphasic contrast, EUS and PET were performed on all our patients in the preoperative period as an imaging tool. No patient underwent MRI in the preoperative period.
Biopsy and evaluation with immunohistochemistry are required for the definitive diagnosis of GIST. Preoperative routine fine-needle aspiration biopsy is not recommended for GIST suspicious masses. Since it carries the risk of disruption of the capsule integrity of the tumor and implantation of tumor cells. A preoperative biopsy is necessary only for neoadjuvant treatment in cases with suspected GIST that cannot be surgically removed or is considered to be a risky surgery . In the GIST, tumor size, mitotic rate, patient age and tumor localization are considered as independent prognostic factors . Tumor rupture and the presence of metastasis at the time of diagnosis have a significant negative effect on the disease- free period and are associated with a poor prognosis . It is thought that the invasion of the surrounding tissue of the tumor and the advanced age of the patient are effective in the aggressiveness of the tumor . It has been reported that small intestinal GISTs with the same size and mitosis ratio have a worse course than gastric GISTs. It is accepted that the location with the best overall survival is the esophagus, and the small intestine is the worst . In our series, there were only stomach and small intestine GISTs.
Since GISTs have a very low tendency to lymphogenous metastasis, routine lymph node dissection is not required during surgical treatment . Since there are not many infiltrative tumors, a clean border can be obtained easily. The standard treatment in GIST is surgical complete resection. It is important to remove the tumor with a clean surgical margin without perforating it . Partial resection of the stomach or segmental resection of the intestine is usually sufficient for treatment. Since it is possible to achieve surgical principles for GISTs with minimally invasive methods, laparoscopic resections are widely applied, especially for gastric GIST. Clean surgical margins were obtained in all of our patients who were operated in our series.
All GISTs are considered to have malignancy potential. Fletcher et al. used the maximum tumor diameter and mitosis (50 BBAs) in 2002 to determine the malignity potentials of GISTs. They divided GIST into four groups as very low risk, low risk, medium risk and high risk. Immunohistochemically, GISTs show 95% staining with CD117, 60-80% with CD34 and 30-40% with SMA. Staining with S-100 and desmin is extremely rare . In our study, CD 117 positivity was 100%, DOG-1 positivity 90% and CD 34 positivity 75%. Desmin-positivity was seen only in one patient (1/19), while SMA was positive in 5 of 13 and S100 in 1 of 15 patients.
Synchronous monitoring of a GIST with another malignant tumor is reported to be between 4.5-35% in the literature. Gastrointestinal adenocarcinoma, prostatic adenocarcinoma, lymphoma, leukemia and breast cancer are the most common GIST-related cancers . Most of the associations of gastrointestinal adenocarcinoma and GIST have been presented as case reports only. In our study, GIST was detected incidentally in 3 cases in a patient who underwent Whipple for pancreatic head tumor, in the third part of the duodenum, in the jejunum in a case operated for gastric adenocarcinoma, and in a case in the stomach corpus.
There may be lymphatic metastases of GISTs at a rate of 0-3.4%. It can also metastasize to the liver, lungs and bones by a hematogenous route . About 15-30% of patients with GIST have metastases at the time of diagnosis. Distant metastases are most common in the liver (50–60%) and peritoneum (20–40%). Although GISTs of ≤ 2 cm have been reported to be metastatic with a low frequency (but not 0%) . The spread to the lungs and bone is very low. Rectal GIST especially often metastasizes to the lungs . Only one of our patients had liver metastasis.
A neoadjuvant tyrosine kinase inhibitor is the standard treatment for patients with unresectable locally advanced tumor, recurrence, and widespread metastasis, a general condition unsuitable for surgery and a positive for c-kit receptor . In addition, preoperative tyrosine kinase inhibitors effectively reduce the size of the tumor and allow organ-preserving surgery in specific locations such as the stomach, cardia, duodenum, and rectum. The optimal duration of preoperative imatinib use should be determined jointly by multidisciplinary team members following the response to treatment. Patients who are initially unsuitable for surgical treatment should be reevaluated for surgery within 1 year after tyrosine kinase inhibitor therapy and surgical treatment should be recommended to patients who are eligible for surgery. Postoperative tyrosine kinase inhibitors significantly prolong both progression-free survival and overall survival of patients . On the preoperative evaluation, only one patient had liver metastasis. This patient was operated after 12 months of neoadjuvant tyrosine kinase inhibitor therapy. Previous studies have reported that the overall and grade III–V complication rates were 9–58% and 0–18%, respectively (23, 24). On the other hand, according to data from the USA, the 5-year GIST-specific mortality rate was 12.9% . In our study, the overall complication rate was 30%, which was suitable with the literature, and the overall mortality was 5%, which was lower than in the literature. In our study, the mortality rate was lower than in the literature, as patients were followed up only for the first 30 days after surgery.
The most common location of GIST is the stomach. Resection with a negative surgical margin is the basic curative procedure in primary and non-metastatic tumors. Minimally invasive methods can be applied safely. Neoadjuvant and adjuvant protocols should be evaluated and decided by a multidisciplinary team, considering the diameter of the tumor, age of the patient, general condition, location of the tumor and prognostic factors.
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1. Casali P, Abecassis N, Bauer S, Biagini R, Bielack S, Bonvalot S, et al. Soft tissue and visceral sarcomas: ESMO–EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018; 29( Suppl. 4):iv51-67.
2. Søreide K, Sandvik OM, Søreide JA, Giljaca V, Jureckova A, Bulusu VR. Global epidemiology of gastrointestinal stromal tumours (GIST): a systematic review of population-based cohort studies. Cancer Epidemiol. 2016; 40:39-46.
3. Ma GL, Murphy JD, Martinez ME, Sicklick JK. Epidemiology of gastrointestinal stromal tumors in the era of histology codes: results of a population-based study. Cancer Epidemiol Biomarkers Prev. 2015; 24(1):298-302.
4. Tran T, Davila JA, El-Serag HB. The epidemiology of malignant gastrointestinal stromal tumors: an analysis of 1,458 cases from 1992 to 2000. Am J Gastroenterol. 2005; 100(1):162-8.
5. Buchdunger E, O’Reilley T, Wood J. Pharmacology of imatinib (STI571). Eur J Cancer. 2002; 38(Suppl. 5):S28-36.
6. Heinrich MC, Corless CL, Demetri GD, Blanke CD, Von Mehren M, Joensuu H, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003 ;21(23):4342-9.
7. Demetri GD, Von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002 ;347(7):472-80.
8. Kalaycı T, Iliklerden UH. Emergency gastric cancer: Are there any differences between indications, morbidity, and mortality? International Medicine.2021;3(2):50-8.
9. Joensuu H, Fletcher C, Dimitrijevic S, Silberman S, Roberts P, Demetri G. Management of malignant gastrointestinal stromal tumours. Lancet Oncol. 2002; 3(11):655-64.
10. Burkill GJ, Badran M, Al-Muderis O, Meirion Thomas J, Judson IR, Fisher C, et al. Malignant gastrointestinal stromal tumor: distribution, imaging features, and pattern of metastatic spread. Radiology. 2003; 226(2):527-32.
11. Koo D-H, Ryu M-H, Kim K-M, Yang H-K, Sawaki A, Hirota S, et al. Asian consensus guidelines for the diagnosis and management of gastrointestinal stromal tumor. Cancer Res Treat. 2016; 48(4):1155.
12. Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol. 2006; 23(2):70-83.
13. Hohenberger P, Ronellenfitsch U, Oladeji O, Pink D, Ströbel P, Wardelmann E, et al. Pattern of recurrence in patients with ruptured primary gastrointestinal stromal tumour. Br J Surg. 2010; 97(12):1854-9.
14. Emory TS, Sobin LH, Lukes L, Lee DH, O’Leary TJ. Prognosis of gastrointestinal smooth-muscle (stromal) tumors: dependence on anatomic site. Am J Surg Pathol. 1999; 23(1):82-7.
15. DeMatteo RP, Lewis JJ, Leung D, Mudan SS, Woodruff JM, Brennan MF. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg. 2000; 231(1):51.
16. Pidhorecky I, Cheney RT, Kraybill WG, Gibbs JF. Gastrointestinal stromal tumors: current diagnosis, biologic behavior, and management. Ann Surg Oncol. 2000; 7(9):705-12.
17. Liszka Ł, Zielińska-Pająk E, Pająk J, Gołka D, Huszno J. Coexistence of gastrointestinal stromal tumors with other neoplasms. J Gastroenterol. 2007; 42(8):641-9.
18. Anis H, Selma K, Amine S, Houcine M, Montassar K. Gastric synchronous stromal tumor and adenocarcinoma: A fortuitous association. J Clin Exp Pathol. 2017; 7(4):1000320.
19. Nieto EA, Aufroy AL, Pórtulas ED, Cladera PR, Fernández RO, Martin AD, et al. Gastrointestinal stromal tumors: experience in 49 patients. Clinical and Translational Oncology. 2006; 8(8):594-8.
20. Coe TM, Fero KE, Fanta PT, Mallory RJ, Tang C-M, Murphy JD, et al. Population- based epidemiology and mortality of small malignant gastrointestinal stromal tumors in the USA. Journal of Gastrointestinal Surgery. 2016; 20(6):1132-40.
21. D’amato G, Steinert DM, McAuliffe JC, Trent JC. Update on the biology and therapy of gastrointestinal stromal tumors. Cancer Control. 2005; 12(1):44-56.
22. Neuhaus SJ, Clark MA, Hayes AJ, Thomas JM, Judson I. Surgery for gastrointestinal stromal tumour in the post-imatinib era. ANZ J Surg. 2005; 75(3):165-72.
23. Rutkowski P, Nowecki Z, Nyckowski P, Dziewirski W, Grzesiakowska U, Nasierowska-Guttmejer A, et al. Surgical treatment of patients with initially inoperable and/or metastatic gastrointestinal stromal tumors (GIST) during therapy with imatinib mesylate. J Surg Oncol. 2006; 93(4):304-11.
24. Sym SJ, Ryu MH, Lee JL, Chang HM, Kim TW, Kim HC, et al. Surgical intervention following imatinib treatment in patients with advanced gastrointestinal stromal tumors (GISTs). J Surg Oncol. 2008; 98(1):27-33.
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Deniz Öçal, Yılmaz Özdemir, Ahmet Erkan Bilici. Gastrointestinal stromal tumor: Retrospective evaluation of twenty cases. Ann Clin Anal Med 2021;12(10):1103- 1107
Knowledge, attitudes and practices determinant’s regarding hypertension in Moroccan hypertensive patients
Abdeslam El Kardoudi 1, Kamal Kaoutar 1, Ahmed Chetoui 1, Keltoum Boutahar 1, Soufiane Elmoussaoui 1, 2, Fatiha Chigr 1, Mohamed Najimi 1
1 Biological Engineering Laboratory, Faculty of Sciences and Techniques, Sultan Moulay Slimane University, Beni Mellal, 2 Mohamed VI Hospital University, Marrakesh, Morocco
DOI: 10.4328/ACAM.20660 Received: 2021-04-17 Accepted: 2021-07-20 Published Online: 2021-08-09 Printed: 2021-10-01 Ann Clin Anal Med 2021;12(10):1108-1113
Corresponding Author: Abdeslam El Kardoudi, Biological Engineering Laboratory, Faculty of Sciences and Techniques, Sultan Moulay Slimane University, Beni Mellal, 23000, Morocco. E-mail: email@example.com P: +21 2675932983 Corresponding Author ORCID ID: https://orcid.org/0000-0002-3847-2818
Aim: The level of knowledge, attitudes and practices (KAP) of hypertension (HTN) determine largely the control of the disease. This study aimed to assess the KAP level regarding hypertension and its determinants in hypertensive patients residing in the Beni Mellal city, Morocco.
Material and Methods: A cross-sectional survey was carried out among 390 hypertensive patients attending primary health centres in the Beni Mellal city during 2019. Socio-demographic and clinical characteristics and data about KAP were collected using a structured questionnaire.
Results: The mean age of participants was 57.11 ± (11.42) years. Female participants were dominant (67.2%). Assessment of KAP of participants stated that 57.43% had good knowledge, 53.84% positive attitudes and 39.74% had good practices. Multivariate analysis revealed that advanced age (51 to 60 years (AOR (Adjusted Odds Ratio) 2.87[95% CI 1.58-5.21], p<0.05), ≥61 years (AOR 1.82 [CI 95% 1.01-3.29], p<0.05), low income (AOR 3.52 [CI95% 1.80-6.90], p<0.05) and the follow-up treatment in association with diet (AOR 6.23[CI 95% 1.33-29.04], p<0.05) were significantly associated with high knowledge scores. The oldest (AOR 2.045 [CI 95% 1.17-3.56], p<0.05), the widowed/er (AOR 5.06 [CI 95% 1.00-25.48], p<0.05) and those with low income (AOR 1.81 [CI 95%1.04- 3.13], p<0.05) had positive attitudes. Low income was also associated with good practices (AOR 3.57 [CI 95% 2.04-6.23], p<0.05).
Discussion: Our results indicated that the participants’ KAP level was relatively low. Therefore, special attention should be given to elderly hypertensive patients, those with low monthly income, widowers and those combining treatments and diet.
Keywords: Hypertension; Knowledge; Attitudes; Practices; Determinants
Hypertension (HTN) constitutes the main risk factor for cardiovascular diseases . This disease kills an estimated nine million people each year . In addition, the control rate has not improved steadily , and the prevalence of non-adherence to treatment is still high . This could be indicative of the weakness in knowledge, attitudes and practices (KAP) of pathology, notwithstanding the role that HTN KAPs play in the control and management of the disease . Thus, a low level of knowledge can lead to bad practices, and therefore poor control of BP  and negatively affect the lifestyle of hypertensives patients . It has been found that about three-fourths of hypertensives patients in developed and developing countries inadequately manage their disease . Also, hypertensives patients’ attitudes have a significant impact on the management of the disease, they largely determine the practices adopted by patients . The KAP level of HTN depends on a set of factors. In America, the KAP level was determined by age, ethnicity, gender, education and income . Sadeq and Lafta in Iraq showed that the level of knowledge was significantly associated with age, gender and the presence of the family history of the disease. The same, attitude was significantly associated with age, educational level and family history, while practices were significantly associated with age and duration of disease .
In a study conducted in Zimbabwe by Chimberengwa et al., (2019), it was discovered that gender, educational level, and disease duration all have a substantial impact on the disease’s KAP level . Studies on the assessment of KAP and its associated factors in developing countries are very scarce and limited; they are even non-existent in the Arab Maghreb countries to our knowledge.
In Morocco, a study carried out by Tazi et al., (2003) reported that the prevalence of hypertension was 33.6% and 78% were unaware that they are sick, and 87.3% of treated hypertensive patients had uncontrolled BP . A similar prevalence was found by Ziyyat et al., (2014) in the East of Morocco . An international multicentre study by Nejjari et al., (2013) showed that the prevalence of hypertension was 45.4% . On the other hand, Alami et al., (2017) reported that more than half of the hypertensive patients included in their study did not achieve adequate blood pressure control . In the same line, Essayagh et al., (2019) have shown that the prevalence of uncontrolled high blood pressure represented 73% , and the prevalence of drug non-adherence represented 91% .
However, these studies were not addressed to KAP. Since poorer blood pressure control and non-adherence to treatment may be linked to insufficient knowledge and inadequate attitudes and practices of people with hypertension, and fill this crucial gap, the present study aimed to assess the level KAP of hypertension and to investigate its determinants in Moroccan hypertensive patients.
Material and Methods
Type of study and population
This was a cross-sectional survey aimed to determine KAP levels and associated factors among 390 hypertensives attending the primary health centres in Beni Mellal city between January and March 2019. A systematic sampling method was adopted. Participants aged 18 years and above, physically and mentally capable of providing the data necessary and willing to participate in the study were included. Pregnant women, health providers and hospitalized patients were excluded.
Using a questionnaire administered through a face-to- face interview, we collected socio-demographic, clinical characteristics, self-care practices and, KAP of hypertensive patients. One mark was given for a correct answer and a zero for an incorrect. The cut-off points for knowledge were stratified into two levels: poor (0–9) and good (>9). Attitudes scoring levels were stratified as negative (0–5) and positive (>5). The level of practices was divided into poor (0–4) and good (>4). Ethical approval
The approval for this study was obtained from the Moroccan Ministry of Health on March 03, 2016 (reference number: 6397-3/3/2016). Participation was voluntary and anonymous. Participants were informed about the study objective and they also read carefully and signed the consent form. All data were confidential and protected at all stages of the study. Statistical analyses
Statistical analysis was carried out using SPSS version 19. The χ2 test was used to assess the statistical significance between the dependent variable (KAP level) and potential explanatory variables. All significant variables in the χ2 test analysis (p<0.05) were considered in the multivariate logistic regression model to determine independent factors associated with KAP level.
The study group consisted of 390 hypertensive patients, among whom female participants predominated (67.2%). The mean age of the participants was 57.11 ± (11.42) years. The married participants were the most represented. In addition, 44.4% of our sample were illiterate and 75.4% were unemployed. Hypertensives with a disease duration of less than 5 years accounted for 46.7%, as shown in Table 1.
Knowledge, attitudes and practices regarding HTN
The ideal diastolic figure was recognized by 18.72% surveyed, the headache was the most identified sign (92.05%), and cardiovascular complications were reported by 72.82%. The majority of respondents (95.12%) declared following a diet and taking medication, while 23.07% used traditional treatment. Practices aiming to reduce salt and fat in the diet were reported by 87.69% and 70%, respectively. In addition, 33.07% of the participants thought that it was possible to stop antihypertensive therapy, 18.72% thought that they could take it at any time of the day, 38.47% thought that being overweight doesn’t constitute a risk for hypertension and finally, 23.07% perceive HTN as a curable disease (Table 2).
Multivariate analysis model
The multivariate analysis (Table 3) shows that the probability of having good knowledge was significant in hypertensive patients aged 50 to 60 years and ≥61 years ((p=0.046 CI95%: 1.01- 3.29),(p=0.001CI95%:1.58-5.21)),inparticipantswithincome <3000MAD (p=0.001 CI95%: 1.80-6.90), in patients who followed a combination of diet and drugs (p=0.02 CI95% : 1.33-29.04).
The results showed also that hypertensive patients aged more than 60 years (p=0.01 CI95%: 1.17-3.56), the widowed hypertensives (p=0.04 CI95%: 1.00-25.48) and, participants who had a monthly income below 3000MAD (p=0.03 CI95%: 1.04-3.13) have all positive attitudes. Regarding practices, hypertensive patients with an income <3000MAD adopt good practices (p=0.001; CI95%: 2.04-6.23).
This study have demonstrated that the rate of hypertension incidence is higher among respondents aged over 50 years, which is consistent with the study conducted by Essayagh T, et al. ; they found that 88.3% of hypertensive patients were aged over 50 years, in addition, Ziyyat et al., (2014) reported that the frequency of HTN was 52.6% and 51.5% for subjects aged over 70 years among women and men, respectively . This association is logical, because the human body accumulates, over time, the risk factors for HTN .
Our findings also revealed that the hypertension patients were predominantly females, similar to other studies [10,14,13]. A possible explanation for this could be that hormonal changes in females play an essential role in the mechanism of hypertension, which may lead to a higher prevalence of the disease in women than in men .
This study found that hypertension was more prevalent in married participants, which was in accordance with national study that reported that married people had a greater risk of developing hypertension . This could be due to the fact that marriage may adversely affect physical health and increase the risk of certain diseases by putting more pressure on individuals, such as childbirth and the negatively changing lifestyles of married individuals .
Our results showed that the level of KAP was relatively low. Furthermore, the determinants of KAP level were advanced age, low monthly income, a combination of diet and drugs, and marital status. The scarcity of studies addressing the KAP towards HTN in Morocco did not allow us to compare our results with other national studies.
Comparing our results with those generated by surveys mainly carried out in developing countries showed that the KAP scores are similar. A study conducted in Iraq (Baghdad) by Sadeq and Lafta showed that 60.1% of respondents had good knowledge, 81.9% had positive attitudes and 24.5% had good practices . In Saudi Arabia, it has been reported that the hypertensives surveyed had good knowledge of positive attitudes, but an insufficient level of practice [17,18]. Besides, a study carried out in Jordan concluded that most of the participants were well informed and had positive attitudes towards hypertension . However, other studies have found high KAP scores compared to our study. In Nigeria, where scores were 56.56% for good knowledge, 95.56% for positive attitudes and 57.19% for good practice , as well as in the USA and in Mongolia . According to these findings, cultural, socio-demographic and economic similarities may be responsible for the resemblance of the results for the studies carried out in Arab-Muslim contexts with those in other contexts.
Concerning factors associated with KAP level, regression analysis showed that there was a highly significant association between age and good knowledge, which is in accordance with the findings of the Iraqi study reporting that older people showed better knowledge than younger people . Similarly, in the USA, in Mongolia and in Nigeria, studies have shown that the more the hypertensive person advances in age, the more they show good knowledge [7,21,20].
In contrast, other studies conducted in Saudi Arabia [17,18] showed that the level of knowledge decreases with advancing age. It should be inferred that fear of developing complications from the disease, affected hypertensives begins to request, read and collect information about the disease and promote their long-term health and well-being. Also, as the severity of HTN is accentuated in older people, therefore this category of hypertensive patients learns more about hypertension to take the necessary preventive measures[8,14].
Regarding income, respondents with low monthly income had a good level of knowledge, which is in line with a study carried out by the employees of the ministerial department in Lomé in Togo. They reported that 87.4% of employees had a poor level . However, a study leaded in Nigeria asserted that principally patients with high-income level had good knowledge of HTN . Besides, many studies have suggested that hypertension negatively affects populations in low- and middle-income countries with weak health systems . Fear of not being able to cover the expenses linked to the management of hypertension complications, especially, cardiovascular diseases, seems to be the major reason for which patients with low income ask more about their disease to manage it correctly and subsequently to prevent complications.
The treatment modality had a significant effect on the level of knowledge. Thus, hypertensives following both a diet and antihypertensive treatment have shown a higher level of knowledge than those who follow a diet only. In the same line, a Palestinian study claimed that follow-up antihypertensive therapy is one of the factors associated with higher scores of knowledge on hypertension .
Concerning the factors that influence the attitudes, our results are consistent with previous study also reporting a positive attitude in older people  When the marital status is considered, our results are in accordance with others studies that found that marital status was significantly associated with high score of positive attitudes, which were more presented in unmarried people [24,25]. This may be due to the fact that widowers, who were previously married people, frequented health facilities more and met their staff, who gave them educational messages. Concerning income, the results depicted in our study are in agreement with those reported in Lomé in Togo, showing that positive attitudes are more developed among those who have a low socioeconomic level . In contrast to our study, the Palestinian study found that high income was associated with higher attitude scores. Also, this opposition has been affirmed by other studies [21,7]. Finally, our study showed that older hypertensive patients perceive positively their disease. Similarly, previous studies have shown that the majority of older patients, when diagnosed with hypertension, became frustrated and started to read, ask about, and collect information about their condition . In fact, positive attitudes of elderly hypertensive subjects can be explained by their high level of knowledge about their disease [8,14].
In terms of practice, a statistically significant association was found between low income and good practices. In contrast, studies have shown that a higher socioeconomic level of hypertensive patients makes it possible to cover the expenses linked to treatment and follow-up, and therefore, ensure good control of their disease [21,7]. Besides, in Saudi Arabia, a study has shown that good practices are associated with high socioeconomic status , other studies concluded that bad practices, in particular, poor treatment, could be associated with the high cost of drugs and inability to cover them . Indeed, hypertensive patients who have sufficient financial resources, engaged less in practices in favour of the control and good management of hypertension, besides, they expressed no feeling of fear or worry (negative attitude) because they could afford to cover the costs associated with their illness’s treatment and complications. However, hypertensive patients with low socio-economic levels have adopted good practices, fearing to develop hypertension complications and not being able to cover the resulting expenses, so they invest more in secondary prevention.
It was the first study of this type and with such an objective carried out in Morocco. The response rate in this study was high (94.75%). In contrast, the generalization of these results has certain limitations. First, the sample was limited to patients belonging to the population served by PHCF of Beni Mellal. The second limitation was the inability of the cross-sectional study to determine a causal relationship between the KAP and characteristics of hypertensive patients. Finally, there was no standardized instrument for measuring KAP about hypertension. Conclusions
This study showed that the KAP level of the hypertensives surveyed was relatively low. Our finding revealed that advanced age, low income and the follow-up treatment in association with diet were significantly associated with high knowledge scores. The widowed/er and those with low income had positive attitudes. For practices, low income was the only factor associated with good practices. Thus, further effective health education programs are greatly needed to improve the KAP of hypertension in the studied population.
We would like to thank all the hypertensive patients who participated in this study.
Scientific Responsibility Statement
Animal and human rights statement
Funding: A part of this study was funded by the national centre for scientific and technical research type B priority research projects (M. Najimi) 2015-2020.
Conflict of interest
No conflicts of interest have been declared.
1. Nejjari C, Arharbi M, Chentir M-T, Boujnah R, Kemmou O, Megdiche H, et al. Epidemiological Trial of Hypertension in North Africa (ETHNA): an international multicentre study in Algeria, Morocco and Tunisia. J Hypertens. 2013; 31(1):49- 62. DOI: 10.1097/HJH.0b013e32835a6611.
2. Dorans KS, Mills KT, Liu Y, He J. Trends in prevalence and control of hypertension according to the 2017 American college of cardiology/American heart association (ACC/AHA) guideline. J Am Heart Assoc. 2018; 7(11). DOI: 10.1161/JAHA.118.008888.
3. Essayagh M, Essayagh T, Essayagh S. Drug non-adherence in hypertensive patients in Morocco, and its associated risk factors. European Journal of Cardiovascular Nursing. 2021; 20(4):324-30. DOI: 10.1093/eurjcn/zvaa002.
4. Malik A, Yoshida Y, Erkin T, Salim D, Hamajima N. Hypertension-related knowledge, practice and drug adherence among inpatients of a hospital in Samarkand, Uzbekistan. Nagoya J Med Sci. 2014; 76(3-4):255–63.
5. Kumar C, Sagar V, Kumar M, Kiran K. Awareness about hypertension and its modifiable risk factors among adult population in a rural area of Ranchi district of Jharkhand, India. International Journal of Community Medicine and Public Health. 2016; 3(5):1069–73.DOI: 10.18203/2394-6040.ijcmph20161359
6. Bollampally M, Chandershekhar P, Kumar K, Surakasula A, Srikanth S, Reddy T. Assessment of patient’s knowledge, attitude and practice regarding hypertension. Int J Res Med Sci. 2016; 4(8):3299–304. DOI: 10.18203/2320-6012. ijrms20162283.
7. Oliveria SA, Chen RS, McCarthy BD, Davis CC, Hill MN. Hypertension knowledge, awareness, and attitudes in a hypertensive population. J Gen Intern Med. 2005; 20(3):219–25. DOI: 10.1111/j.1525-1497.2005.30353.x.
8. Sadeq R, Lafta RK. Knowledge, attitude and practice about hypertension in hypertensive patients attending hospitals in Baghdad, Iraq. SE Asia J Pub Health. 2017; 7(1):29–34. DOI: 10.3329/seajph.v7i1.34676
9. Chimberengwa PT, Naidoo M, cooperative inquiry group. Knowledge, attitudes and practices related to hypertension among residents of a disadvantaged rural community in southern Zimbabwe. Isangula KG, editor. PLoS One. 2019; 14(6):e0215500. DOI: 10.1371/journal.pone.0215500.
10. Tazi MA, Abir-Khalil S, Chaouki N, Cherqaoui S, Lahmouz F, Sraïri JE, et al. Prevalence of the main cardiovascular risk factors in Morocco: results of a National Survey, 2000. J Hypertens. 2003; 21(5):897–903. DOI: 10.1097/00004872- 200305000-00013.
11. Ziyyat A, Ramdani N, Bouanani NEH, Vanderpas J, Hassani B, Boutayeb, A et al. Epidemiology of hypertension and its relationship with type 2 diabetes and obesity in eastern Morocco. Springer Plus. 2014; 3(1):644. DOI:10.1186/2193- 1801-3-644.
12. Alami M, El Hattaoui M, Seqat M, Sadik J, Aouad A, Benghanem Gharbi M. Control of blood pressure and cardiovascular risk in Moroccan patients with newly diagnosed hypertension: a 3-month observational study in primary care. Therapeutic Advances in Cardiovascular Disease. 2017; 11(2):49–56. DOI: 10.1177/1753944716677242.
13. Essayagh T, Essayagh M, El Rhaffouli A, Khouchoua M, Bukassa Kazadi G, Khattabi A, et al. Prevalence of uncontrolled blood pressure in Meknes, Morocco, and its associated risk factors in 2017. PLoS One. 2019; 14(8):e0220710. DOI: 10.1371/journal.pone.0220710.
14. Mohammed AH, Hassan BAR, Suhaimi AM, Ali AHHD. Hypertension knowledge, awareness, and attitude among the hypertensive population in Kuala Lumpur and rural areas in Selangor, Malaysia. J Public Health (Berl). 2019; DOI:10.1007/ s10389-019-01160-7.
15. Shirani S, Gharipour M, Khosravi A, Kelishadi R, Habibi HR, Abdalvand A, et al. Gender differences in the prevalence of hypertension in a representative sample of Iranian population: the Isfahan healthy heart program. Acta Biomed. 2011; 82(3):223–9.
16. Wang J, Sun W, Wells GA, Li Z, Li T, Wu J, et al. Differences in prevalence of hypertension and associated risk factors in urban and rural residents of the north eastern region of the people’s republic of China: A cross-sectional study. PLoS One. 2018; 13(4):e0195340. DOI: 10.1371/journal.pone.0195340.
17. Siddiqua A, Mohammed AA, Alahmari EA, Hadaddi FA, Saleh NA. Study on the knowledge, attitude and practice (KAP) of patients with hypertension in Aseer hospital, Asir region; Saudi Arabia. Int J Res Pharm Sci. 2017; 7(2):37–41.
18. Bakhsh LA, Adas AA, Murad MA, Nourah RM, Hanbazazah SA, Aljahdali AA, et al. Awareness and knowledge on hypertension and its self- care practices among hypertensive patients in Saudi Arabia. AIMDR. 2017; 2(5). DOI: 10.21276/ aimdr.2017.3.5.ME13.
19. Yasein N, Shhakhatreh F, Suleiman A, Barghouti F, Halaseh L, Abdulbaqi N. Knowledge, attitudes and practices on hypertension in patients attending family practice clinics. Health Med J. 2011; 5.
20. Aghoja OC, Okinedo PO, Odili VU. Knowledge, attitude and practice of hypertensive patients towards hypertension in a secondary health care facility in delta state. UK Journal of Pharmaceutical Biosciences. 2017; 5(2):24. DOI: 10.20510/ukjpb/5/i2/155972.
21. Demaio AR, Dugee O, Amgalan G, Maximenco E, Munkhtaivan A, Graeser S, et al. Protocol for a national, mixed-methods knowledge, attitudes and practices survey on non-communicable diseases. BMC Public Health. 2011; 11(1):961. DOI: 10.1186/1471-2458-11-961.
22. Yayehd K, Damorou F, Ehlan E, Kara P, N’Da NW, Tété Y, et al. Knowledge about arterial hypertension, attitudes and lifestyle among the employees of a ministerial department in Lomé, Togo. Angiology. 2012; 64(3):10
23. Lloyd-Sherlock P, Beard J, Minicuci N, Ebrahim S, Chatterji S. Hypertension among older adults in low- and middle-income countries: prevalence, awareness and control. Int J Epidemiol. 2014; 43(1):116–28. DOI: 10.1093/ije/dyt215
24. Sa’adeh HH, Darwazeh RN, Khalil AA, Zyoud SH. Knowledge, attitudes and practices of hypertensive patients towards prevention and early detection of chronic kidney disease: a cross sectional study from Palestine. Clin Hypertens. 2018; 24(1):6. DOI: 10.1186/s40885-018-0091-7
25. Manfredini R, De Giorgi A, Tiseo R, Boari B, Cappadona R, Salmi R, et al. Marital status, cardiovascular diseases, and cardiovascular risk factors: a review of the evidence. J Womens Health (Larchmt). 2017; 26(6):624–32. DOI: 10.1089/ jwh.2016.6103
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Abdeslam El Kardoudi, Kamal Kaoutar, Ahmed Chetoui, Keltoum Boutahar, Soufiane Elmoussaoui, Fatiha Chigr, Mohamed Najimi. Knowledge, attitudes and practices determinant’s regarding hypertension in Moroccan hypertensive patients. Ann Clin Anal Med 2021;12(10):1108-1113
Associated factors of medication non-adherence for tuberculosis in Moroccan patients
Sanaa El Bahlaoui 1, Meryeme El Marini 1, Mounir Ouzir 1, 2
1 Higher Institute of Nursing Professions and Health Techniques, ISPITS Beni Mellal, Regional Hospital Center, Beni Mellal, 2 Department of Biology, Faculty of Science, University Mohammed V, Rabat, Morocco
DOI: 10.4328/ACAM.20661 Received: 2021-04-17 Accepted: 2021-06-18 Published Online: 2021-06-29 Printed: 2021-10-01 Ann Clin Anal Med 2021;12(10):1114-1118
Corresponding Author: Mounir Ouzir, Group of Research in Physiology and Physiopathology, Department of Biology, Faculty of Science, University Mohammed V, Rabat, Morocco & Higher Institute of Nursing Professions and Health Techniques, ISPITS Beni Mellal, Regional Hospital Center – DCHIRA District – Beni Mellal Morocco. E-mail: firstname.lastname@example.org P: 00212668541237 Corresponding Author ORCID ID: https://orcid.org/0000-0001-6835-9755
Aim: In Morocco, tuberculosis is endemic and therapeutic adherence remains unsatisfactory. The objective of our study is to describe the factors influencing therapeutic adherence in tuberculosis patients in Morocco.
Material and Methods: In this cross-sectional study, 98 patients were recruited at the Center for Diagnosis and Treatment of Respiratory Diseases (CDTMR) of Beni Mellal, Morocco. Data were collected through face-to-face interview using a pre-structured questionnaire and analyzed with a binary regression model to highlight factors that may lead to poor adherence.
Results: Our results showed that 46.9% of the patients had good adherence and 53.1% had poor adherence. In addition, binary regression analysis showed that four factors significantly influenced the break in the continuity of treatment, namely: the communication problems with the healthcare staff, the means of transport used to reach the Health Center, stock-outs of anti-tuberculosis drugs, and the frequent closures of the Health Center.
Discussion: In Morocco, therapeutic adherence remains a major challenge in the care of tuberculosis patients. Monitoring programs and patient education are needed to end the major barriers to adherence. In addition, the restructuring of the health establishments to improve proximity and accessibility, and the continuous supply of drugs could help to good therapeutic compliance.
Keywords: Tuberculosis, Adherence, Morocco
Tuberculosis is a major public health concern worldwide. According to WHO, 10 million people contracted tuberculosis and 1.5 million died of it in 2018 (including 251,000 infected with HIV), especially in low- and middle-income countries (available at: https://www.who.int/tb/publications/global_ report/gtbr2019_ExecutiveSummary_fr.pdf?ua=1). In Morocco, tuberculosis remains endemic and still a significant public health problem. The epidemiological data for 2016 show a total of 31,542 cases of tuberculosis, all forms combined, corresponding to an incidence of 91 per 100,000 population (available at: http://www.sante.gov.ma/Documents/2017/03/Lutte%20 Antituberculeuse%20au%20Maroc_%20progr%C3%A8s%20 d%C3%A9fis%20et%20perspectives.pdf). The management of tuberculosis is organized within the framework of a new Moroccan National Strategic Plan (PSN 2018-2021) based on WHO recommendations. The aim of this plan is to reduce mortality associated with this disease by strengthening the detection of new cases and improving conditions of treatment and monitoring of patients (available at: https://www.smmg. ma/publications/documents/1-programme-national-de-lutte- contre-la-tuberculose/file.html). Despite this plan, several cases of interruption of anti-tuberculosis treatment have been recorded in Morocco [1, 2]. In fact, the consequences of poor adherence to treatment are serious for the individual and for the community, including relapse, prolonged treatment, increased risk of death, prolonged infectious period, and the development of multidrug-resistant strains . Thus, improving adherence has become an important objective in a large number of therapeutic strategies, since non-adherence greatly impacted the effectiveness of the treatments prescribed . Medication non-adherence can be affected by various factors, which can be linked to patient, treatment, healthcare staff, and the organization of health services [5-8]. In Morocco, there is very little data available in the literature on the factors associated with tuberculosis therapeutic adherence. This work aimed to assess the factors related to therapeutic adherence in Moroccan tuberculosis patients.
Material and Methods
All tuberculosis patients treated at the Center for Diagnosis and Treatment of Respiratory Diseases (CDTMR) of Beni Mellal, Morocco, in 2017 were included in this study. The study was carried out on a sample of 98 patients with sputum smear- positive tuberculosis. Patients with non-tuberculous pneumonia, those with extra-pulmonary tuberculosis, and patients who were on anti-bacillary therapy for less than a month were excluded.
Socio-demographic variables noted were sex, age, level of education, marital status, occupation, urban or rural origin, and the presence or absence of health insurance. Other variables such as tuberculosis cases (new case, relapse, failure) smoking status, associated diseases (diabetes, high blood pressure, etc.), BCG vaccination, and hospitalization were also noted.
Good therapeutic adherence was defined as patients who had completed the treatment with no history of non-adherence. Data were collected using a semi-structured interview after obtaining informed consent from each participant. The study was approved by the local research ethics committee.
Results were expressed as frequency and percentage. Categorical variables were analyzed using the Chi-square. Variables with significant p-values (p<0.05) from univariate analysis were included in binary logistic regression analysis using the Forward Stepwise (Likelihood Ratio) method to identify factors predicting medication adherence. SPSS version 20 was used for data analysis.
1. Sociodemographic and clinical characteristics of patients
The study involved 98 patients, 54.1% of them were men (n = 53). Patient characteristics are presented in Table 1. The two age groups with the greatest percentage of the tuberculosis cases were 20-45 years old and >45years old, accounting for 45.9% and 35.7% of total tuberculosis cases, respectively. Regarding marital status, 51% of the patients were married, 49% were single, widowed, or divorced. We also note that 33.7% of the patients were illiterate, 24.5% had reached a primary school level, and 41.8% had reached a secondary level or superior.
The majority of cases lived in urban areas (n = 68, 69.4%), the rest (n = 30, 30.6%) lived in rural localities close to Beni Mellal. There were 40 unemployed study subjects (40.8%) and 53 with no health insurance (54.1%).
Clinically, the vast majority of patients (81.6%) were new cases of tuberculosis, and relapses in 13.3% of cases. Only 5 cases were reported as therapeutic failure (5.1%). The majority of patients (65.3%) were already hospitalized for tuberculosis. Also, 17.43% of our patients had comorbidities associated with tuberculosis, including diabetes (n = 6), hypertension (n = 8), cardiopathy (n = 2) and asthma (n = 1). Only 24.5% (n = 24) did not receive the BCG tuberculosis vaccine and 22.4% (n = 22) were smokers.
2. Adherence rate
Regarding the therapeutic adherence to therapy, our results showed that more than half of the patients (53.1%) had poor adherence and 46.9% had good adherence. No significant differences were observed between the two categories in terms of sociodemographic and clinical characteristics (Table 1).
3. Factors influencing medication adherence
Several reasons have been put forward by patients for non- adherence, including the distance between patient residence and health facilities (Table 2). In fact, 77.6% of the patients declared that they were far from the CDTMR, while 30.6% were far from a nearby health center. This shows that the health center remains more accessible to patients than the CDTMR. To access the health center, 73.5% of the subjects walk, while the rest use public transportation. In addition, patients stated that they had problems with the supply of anti-bacillary medication by the health center either because of the depletion of the stock (50%) or because of its closure (34%). Communication problems have also been reported. Thus, more than half of the patients (53.1%) were dissatisfied with the reception given to them by the healthcare staff at the health center, and 41.8% of them had difficulty in communication. In addition, 56.1% of patients reported a lack of necessary information and explanations concerning their disease and the duration of treatment by healthcare staff. The absence of informative posters on tuberculosis in the health center was reported by the majority of patients (82.7%).
The univariate analysis identified six factors that were significantly associated with medication adherence. These were as follows: the proximity of the patient’s residence to the health center (p=0.002), the quality of reception by the healthcare staff at the health center (p=0.028), the closure of the health center (p=0.001), the means of transport used to reach the health center (p<0.001), tuberculosis treatment availability at the health center (p<0.001), communication problems with the healthcare staff at the health center (p=0.031).
4. Factors predicting medication adherence
The variables that were significantly related to high adherence in univariate analysis were entered into binary regression analysis with a forward stepwise (Likelihood Ratio) method. Table 3 shows the results of the binary logistic regression analysis identifying significant factors that predict medication adherence. Six significant factors from the univariate analysis were included in the binary logistic regression model. Only four variables (closure of the Health Center, means of transport used to reach the Health Center, tuberculosis treatment availability at the Health Center, communication problems with the healthcare staff at the Health Center) of all six variables entered, remained after Forward Stepwise (Likelihood Ratio) method. Our model was statistically significant (χ2 (4) = 39.4, p<0.001) and explained 44.2% of the variation in medication adherence level (Nagelkerke R2 = 0.442). Significant factors that were independently associated with medication adherence were as follows: tuberculosis treatment availability at the health center [OR 0.187 (95% CI: 0.064-0.546); p=0.002], communication problems with the healthcare staff at the health center [OR 4.573 (95% CI: 1.575-13.283); p=0.005], closure of the health center [OR 0.246 (95% CI: 0.081-0.747); p=0.013], and the means of transport used to reach the health center [OR 0.252 (95% CI: 10.066-0.955); p=0.043].
The aim of the current study was to determine factors related to medication adherence in Moroccan tuberculosis patients. In our sample, we note that 46.9% of patients were able to correctly observe their anti-tuberculosis treatment, which remains very low compared to other studies; 76% in South Africa , 73% and in Nigeria . In addition, none of the socio-demographic (such as age, gender, education level, place of residence, marital status, and profession) or clinical (smoking habit, associated comorbidities, BCG vaccine, hospitalization) characteristics significantly affected the level of medication adherence. According to univariate analysis, six independent factors significantly affect adherence. Some factors were linked to the organization of the health system such as the shortage of anti- tuberculosis drugs and the frequent closure of the health center have shown a significant influence on medication adherence, which is in line with the results of other studies carried out in other African countries [8, 11]. These results suggest that for good adherence to treatment, it is essential to ensure the supply of health centers with the necessary anti-tuberculosis drugs and to ensure continuity of services there even during strikes and holidays.
Moreover, the distance between the Health Center and the patient’s home and the means of transport used to reach the health center emerged as significant factors for good adherence to treatment, which suggests that providing transportation for those who live far from health centers would be beneficial for good adherence. Consistent with these findings, studies conducted in many countries showed that there was an association between the distance to health facility and the level of medical adherence [12-14]. Thus, the health facilities should be structured to reconcile proximity and accessibility and thus ensure the quality and continuity of care for tuberculosis patients.
Moreover, therapeutic adherence has been shown to be associated with the quality of the relationship between the healthcare staff and the patient . This is supported by our results showing that the quality of the reception of patients by the staff of the Health Center and the communication problems affect therapeutic adherence. In fact, an adequate healthcare staff-patient relationship implies mutual trust and the capacity for mutual listening in order to guarantee good adherence and avoid therapeutic failure. Patients should also be educated and informed about the different aspects of their disease in order to improve adherence to treatment.
In this study, the binary logistic regression model using forward stepwise based on the Likelihood Ratio had good predictive ability for medication adherence. In this model, the closure of the health center, the means of transport used to reach the health center, tuberculosis treatment availability at the health center, and communication problems with the healthcare staff at the health center were found to be independent predictors of medication adherence.
Limitations of the study
This study has some limitations that should be mentioned. In particular, the limited sample size and the use of a face- to-face interview to assess adherence, which may therefore overestimate the prevalence of medication adherence. The final limitation is that the study is only for the Beni Mellal region and questions can be raised over how representative this would be for other regions in Morocco and other countries.
Poor adherence to anti-tuberculosis treatment is a recurring problem in third world countries [16-18]. Specifically, tuberculosis remains endemic in Morocco, and medication adherence remains unsatisfactory. There is a clear need for intervention programs aimed at monitoring medication adherence. These programs must deal with the different causes and factors that generate medication non-adherence.
Scientific Responsibility Statement
Animal and human rights statement
Conflict of interest
1. Tachfouti N, Slama K, Berraho M, Elfakir S, Benjelloun MC, El Rhazi K, et al. Determinants of tuberculosis treatment default in Morocco: results from a national cohort study. Pan Afr Med J. 2013; 14:121; DOI:10.11604/ pamj.2013.14.121.2335.
2. Dooley KE, Lahlou O, Knudsen J, Elmessaoudi MD, Cherkaoui I, El Aouad R. Risk factors for tuberculosis treatment failure, default, or relapse and outcomes of retreatment in Morocco. BMC Public Health. 2011; 11(1):140. DOI: 10.1186/1471- 2458-11-140.
3. Groupe de travail du conseil supérieur d’hygiène publique, France. Observance et suivi de traitement (Observance and treatment follow-up). Médecine et Maladies Infectieuses. 2004; 34(8-9):386–90. DOI: 10.1016/j.medmal.2004.07.020
4. Benoit M, Pon J, Zimmermann MA. Comment évaluer la qualité de l’observance? (Expert opinion on APAP (prolonged action atypical antipsychotic agents). How to evaluate the quality of observations). L’Encéphale/Encephale. 2009; Suppl. 3: S87-90. DOI:10.1016/S0013-7006(09)75542-3.
5. M’Boussa J, Martins H, Adicolle-Metoul JM, Loubaki F. L’influence des facteurs socio-culturels sur les abandons du traitement de la tuberculose pulmonaire. Médecine d’Afrique Noire. 1999; 46(10).
6. Slama K, Tachfouti N, Obtel M, Nejjari C. Factors associated with treatment default by tuberculosis patients in Fez, Morocco. East Mediterr Health J. 2013; 19 (8):687-93.
7. Ibrahim LM, Hadejia IS, Nguku P, Dankoli R, Waziri NE, Akhimien MO, et al. Factors associated with interruption of treatment among Pulmonary Tuberculosis patients in Plateau State, Nigeria. 2011. Pan Afr Med J. 2014; 17:78. doi:10.11604/ pamj.2014.17.78.3464. DOI: 10.11604/pamj.2014.17.78.3464
8. Nimagan S, Bopaka RG, Diallo MM, Diallo BD, Diallo MB, Sow OY. Facteurs prédictifs de l’échec de traitement antituberculeux en Guinée Conakry. Pan Afr Med J. 2015; 22:146. DOI: 10.11604/pamj.2015.22.146.7216.
9. Kastien-Hilka T, Rosenkranz B, Schwenkglenks M, Bennett BM, Sinanovic E. Association between health-related quality of life and medication adherence in pulmonary tuberculosis in South Africa. Front Pharmacol. 2017; 8:919. DOI: 10.3389/fphar.2017.00919.
10. Obadiora AH. Comparative influence of health locus of control on medication adherence among tuberculosis and HIV-positive outpatients in Edo State, Nigeria. International Journal of Psychology and Counselling. 2016; 8(3):18-27. DOI: 10.5897/IJPC2015.0337.
11. Kisambu J, Nuwaha F, Sekandi JN. Adherence to treatment and supervision for tuberculosis in a DOTS programme among pastoralists in Uganda. Int J Tuberc Lung Dis. 2014;18(7):799-803. DOI: 10.5588/ijtld.13.0753.
12. Woimo TT, Yimer WK, Bati T, Gesesew HA. The prevalence and factors associated for anti-tuberculosis treatment non-adherence among pulmonary tuberculosis patients in public health care facilities in South Ethiopia: a cross- sectional study. BMC Public Health. 2017; 17(1):269. DOI: 10.1186/s12889-017- 4188-9.
13. Naing NN, D’Este C, Isa AR, Salleh R, Bakar N, Mahmod MR. Factors contributing to poor compliance with anti-TB treatment among tuberculosis patients. Southeast Asian J Trop Med Public Health. 2001;32(2):369-82.
14. Mishra P, Hansen EH, Sabroe S, Kafle KK. Socio-economic status and adherence to tuberculosis treatment: a case-control study in a district of Nepal. Int J Tuberc Lung Dis. 2005; 9(10):1134-9.
15. Illoye-Ayet M, Okemba-Okombi FH. Facteurs inhérents à l’observance du traitement antituberculeux au centre antituberculeux de Brazzaville. Revue des Maladies Respiratoires. 2016; 33: A224. DOI: 10.1016/j.rmr.2015.10.485.
16. Dje Bi ID, Anon JC, Yeo L, Bi YT, Achi V, Meliane NS. Facteurs de mauvaise observance au traitement antituberculeux à Bouaké. Revue des Maladies Respiratoires. 2019; 36: A258-9. DOI: 10.1016/j.rmr.2018.10.600.
17. Mejri I, Saad SB, Daghfous H, Megdiche L, Tritar F. Facteurs associés à la mauvaise observance du traitement antituberculeux. Revue des Maladies Respiratoires. 2017; 34: A223. DOI: 10.1016/j.rmr.2016.10.533.
18. Ngangro NN, Ngarhounoum D, Ngangro MN, Rangar N, des Fontaines VH, ChauvinP. Évaluation des facteurs associés aux abandons du traitement antituberculeux au Tchad. Médecine et Santé Tropicales. 2013; 23(1):60-5. DOI: 10.1684/mst.2013.0159.
Download attachments: 10.4328:ACAM.20661
Sanaa El Bahlaoui, Meryeme El Marini, Mounir Ouzir. Associated factors of medication non-adherence for tuberculosis in Moroccan patients. Ann Clin Anal Med 2021;12(10):1114-1118
Incidence of congenital gallbladder anomalies and clinical significance
Ibrahim Batmaz 1, Yeliz Gül 2, Cengiz Sanli 3, Gülay Bulu 4, Ahmet Senocak 5, Salih Burcin Kavak 5
1 Department of Obstetrics and Gynecology, Hani State Hospital, Diyarbakır, 2 Department of Radiology, Fethi Sekin City Hospital, Elazığ, 3 Department of Obstetrics and Gynecology, Fethi Sekin City Hospital, Elazığ, 4 Department of Obstetrics and Gynecology, Kovancılar State Hospital, Elazığ, 5 Department of Obstetrics and Gynecology, Firat University, School of Medicine, Elazığ, Turkey
DOI: 10.4328/ACAM.20662 Received: 2021-04-18 Accepted: 2021-07-05 Published Online: 2021-07-29 Printed: 2021-10-01 Ann Clin Anal Med 2021;12(10):1119-1122
Corresponding Author: Salih Burcin Kavak, Professor, Firat University, School of Medicine, Department of Obstetrics and Gynecology, 23000, Elazig, Turkey. E-mail: email@example.com P: +90 424 233 35 55 / +90 424 233 21 24 GSM: +90 505 865 83 06 F: +90 424 237 91 38 Corresponding Author ORCID ID: https://orcid.org/0000-0002-6318-5175
Aim: In this study, we aimed to investigate the prevalence of congenital gall bladder anomalies and their importance in perinatal follow-up.
Material and Methods: This study was conducted by retrospectively examining the data of 3080 patients who applied to Firat University Gynecology and Ob- stetrics Outpatient Clinic between 14-37 weeks of gestation between December 2018 and November 2020. Obstetric characteristics of the patients such as age, pregnancy number, abortion, parity and body mass index were recorded. In all cases, the fetal gallbladder was examined in the axial plane, used to measure the abdominal circumference. Routine evaluation was performed in the axial plane of the abdomen, where other structures such as the stomach and umbilical vein were visible in this plane. After monitoring the gall bladder, the echogenicity of its contents, the shape of the sac and its position in the abdomen were evaluated. The ultrasonographic features of the cases with gallbladder abnormalities detected were recorded.
Results: Between the dates of the study, 2120 pregnant women were included in the study. Gallbladder abnormality was detected in five cases. Accordingly, the incidence of gallbladder abnormalities was found to be 0.23%. The incidence of gall bladder abnormalities in the study population was found to be 1/370. Gallbladder abnormality was isolated in all cases, and no chromosomal abnormality was found. No additional anomalies were found in newborn babies in the postpartum controls of the cases.
Discussion: Gallbladder evaluation is part of extended fetal screening. Gallbladder anomalies appear as relatively rare and mostly benign anatomical variations. By informing the family, it is ensured that appropriate follow-up in postnatal life is obtained.
Keywords: Gall Bladder; Anomalies, Ultrasonography; Incidence
Congenital gall bladder anomalies are extremely rare anomalies. They can be part of an isolated, chromosomal, and syndromic condition. Although not an integral part of the prenatal examination, the American Institute of Ultrasonography (AIUM) has recommended the evaluation of the gallbladder in its detailed fetal anatomical ultrasonography recommendations since 2017 . The frequency of gall bladder anomalies is generally not included in the literature. However, the prevalence of gallstones was reported as 4.7 per 1000 births , the prevalence of bladder duplications as 1 in 4000 births , or the prevalence of bladders not permanently observed in the fetal examination as 1 out of 875 births . On sonographic examination, the fetal gall bladder appears as a mostly pear- like anechoic structure in the right upper abdomen, to the right of the intrahepatic part of the umbilical vein. The gall bladder can normally be detected in all cases in the second trimester of pregnancy and its sizes from 13 weeks to term have been published . Most of the gallbladder anomalies are benign in nature and their relationship with chromosomal and structural anomalies has not been clearly revealed. There is gallbladder growth arrest, most likely as part of the severity of the anomaly, and most cases have abnormalities in more than one organ [6, 7]. However, in the presence of genetic diseases such as cystic fibrosis, failure of monitoring the gall bladder may be the only warning sign .
In this study, we aimed to examine the gall bladder anomalies detected in our study.
Material and Methods
The study was conducted on pregnant women who were in the second or third trimester of pregnancy, and applied to the outpatient clinic for routine fetal evaluation. Written consent was taken from all pregnant women for fetal ultrasonography examination. After the approval of the local ethics committee (Board decision number 2019/10/01), the records of the pregnant women who underwent fetal examination between December 2018 and November 2020 were retrospectively reviewed. The obstetric characteristics of the cases such as age, number of pregnancies, parity, body mass index were recorded. Cases with major congenital anomaly, cases with a high risk (1/270 and above) in combined or triple test, and cases with multiple pregnancy were excluded from the study. Gestational age was determined according to the last menstrual date in cases with regular menstruation and according to the first period crown- rump distance in other cases. The ultrasonographic examination of all fetuses was performed by the same physician, who is an expert in maternal-fetal medicine. Transabdominal route was used for sonographic examinations. Broad band convex 2-6 MHz multi-frequency high-resolution ultrasonography device (Voluson E6 BT 18, General Electric, Zipf, Austria) was used for the examination. In all cases, the fetal gallbladder was examined in the axial plane, used to measure the abdominal circumference. Routine evaluation was performed in the axial plane of the abdomen, where other structures such as the stomach and umbilical vein were visible in this plan. After monitoring the gallbladder, the echogenicity of its contents, the shape of the bladder and its position in the abdomen were evaluated. In the right upper quadrant of the fetal abdomen, the presence of a typically pear-shaped, anechoic structure was considered normal gallbladder, while any echogenic structure, shape anomaly and deviation in the location were considered abnormal and the findings were recorded.
The evaluation of the data was made with the SPSS 21.00 program. Descriptive statistics were used.
Records of 3080 cases who underwent fetal examination between December 2018 and November 2020 were reviewed. When cases with major anomalies or high- risk screening tests were excluded, 2120 cases were included in the study. The cases examined were between 14-37 weeks of gestation. The gallbladder was evaluated as abnormal in 5 cases between the dates of the study. When the patients in the second period of pregnancy were examined, the mean week of gestation of the patients was found to be 21.16 ± 1.24. When the patients in the third period of pregnancy were examined, the mean week of gestation was found to be 36.25 ± 1.29. The ages of the patients were between 19 and 42, and the mean age of pregnant patients who were examined was 26.19 ± 4.56 years. The mean number of pregnancies of the patients was 2.34 ± 1.56, the mean number of parity of the patients was 1.17 ± 1.41, the mean number of abortions of the patients was 0.4 ± 0.8 and the the mean number of curettage of the patients was 0.07 ± 0.21. Obstetric characteristics of the patients are shown in Table 1.
When gallbladder anomalies were examined among 2120 cases, in 1 case (22 weeks gestation), the gallbladder duplication was detected (0.05%) (Figure1), in 2 cases (22 and 24 weeks of gestation), the gallbladder was not observed (0.09%) and in 2 cases (21 and 34 weeks gestation) bile sludge was detected (0.09%) (Figure2).
When all cases are considered, the frequency of fetal gallbladder anomaly was found as 0.23%. Chromosomal anomaly or additional anomaly was not found in any of the 5 cases with gallbladder anomaly, and the cases were considered isolated anomalies. It was detected from the patient records that five cases had normal postpartum examinations. Two cases gave birth in an external center. These cases were reached by phone after delivery. It was learned that no additional findings were found in the babies, and there was no finding of chromosomal anomaly. The patients whose gallbladder could not be observed were called for follow-up at two-week intervals. In the case with 22 weeks of gestation, the gall bladder was visualized at the control examination two weeks later, and in the case with 24 weeks of gestation, the gallbladder was visualized at the control examination four weeks later. There was no case whose gallbladder could not be permanently visualized between the dates of the study.
Since advances in ultrasound technology allow for a more detailed examination of the fetus, expanded fetal evaluation includes the evaluation of many fetal structures, including the gall bladder . Fetal gall bladder examination is still not a part of standard fetal examination [9, 10]. However, with the accumulation of experience in this field, fetal gall bladder anomalies started to be examined more frequently, and an increasing number of studies on this subject appeared in the literature [7, 11, 12].
Gall bladder anomalies are rare and the frequency of anomalies is not clear. Studies have emphasized that it is 1 in 4000 and 1 in 875 births [3, 4]. In our study, the anomaly prevalence was found to be 2.3 per 1000 deliveries (0.23%). As the number of studied population increases, the frequency of detected anomalies is likely to increase. The fetal gallbladder develops in the fourth week of pregnancy from the caudal part of the foregut. At 12 weeks, bile production begins . It can be monitored by ultrasound from the 13th week of pregnancy . When the literature is reviewed, gallbladder anomalies are agenesis, biliary atresia, gallbladder sludge or stones, double gallbladder and the presence of aberrant gallbladder mostly located on the left [2, 12, 14, 15]. If the gallbladder is not observed during the fetal examination, the fetus should be followed up. Fortunately, in many cases, the gallbladder will be detected later. The gallbladder is a dynamic organ and has the ability to relax and contract .
During the period we conducted the study, the gallbladder was not observed in 1 fetus, and the presence of the gallbladder was confirmed in the control examination performed 10 days later. However, isolated agenesis or bile duct atresia should be kept in mind in the presence of a gallbladder that cannot be permanently monitored during intermittent examinations . On the other hand, there is a risk of cystic fibrosis in these cases .
In the case of gallbladder anomalies, other structural and chromosomal anomalies should be investigated. This is especially true in cases where the gallbladder cannot be observed in successive examinations. In the study conducted by Shen et al., Trisomy 18 was found in one case, where the gallbladder could not be displayed persistently and Triploidy was found in another . However, it is clear that there will be additional problems in many organ systems in both chromosomal anomalies. In the same study, isolated agenesis was detected in 1 case, and Cystic Fibrosis was detected in further evaluation, and pregnancy was terminated. A case of left isomerism among structural anomalies was also reported. In the study conducted by Yayla et al., structural anomalies as well as chromosomal anomalies were detected, and in 22.6% of these cases, fetal anomalies were detected. It has also been emphasized that as the severity of the anomaly increases, the frequency the gall bladder, which cannot be displayed increases .
All cases of stones or bile sludge that can be observed in the gallbladder have a good prognosis and usually disappear after one year of follow-up . In our study, 1 case with bile sludge at 34 weeks of gestation was detected, and it did not cause any problems in the postpartum period.
Another gallbladder anomaly is duplications. The double gallbladder is a rare anatomic disorder of the biliary tract caused by the proliferation of 1 primordium or 2 primordia. Many cases are diagnosed in adulthood. It has been reported to occur in one in 4000 births . Confirmation with postnatal magnetic resonance (MR) cholangiopancreatography is recommended . Due to insufficient literature data, there is no clear information about the frequency of additional anomalies. In our 1 case, double gallbladder was detected, no additional anomaly was found, and the postpartum diagnosis was confirmed. Limitations
Limiting factors of our study are the retrospective nature of the study and the small sample size.
In conclusion, gallbladder evaluation is part of extended fetal screening. Gallbladder anomalies appear as relatively rare and mostly benign anatomical variations. By informing the family, it is ensured that appropriate follow-up in postnatal life is obtained.
Scientific Responsibility Statement
Animal and human rights statement
Conflict of interest
1. AIUM Practice Parameter for the Performance of Detailed Second- and Third- Trimester Diagnostic Obstetric Ultrasound Examinations. J Ultrasound Med. 2019; 38(12):3093-100. DOI: 10.1002/jum.15163.
2. Sepulveda W, Wong AE. Echogenic material in the fetal gallbladder: prevalence, sonographic spectrum, and perinatal outcome in an unselected third- trimester population. J Matern Fetal Neonatal Med. 2018; 33(7):1162-70. DOI: 10.1080/14767058.2018.1517310
3. Botsford A, McKay K, Hartery A, Hapgood C. MRCP imaging of duplicate gallbladder: a case report and review of the literature. Surg Radiol Anat. 2015; 37(5):425–9. DOI: 10.1007/s00276-015-1456-1
4. Di Pasquo E, Kuleva M, Rousseau A, Vitucci A, Sonigo P, Chardot C, et al. Outcome of non-visualization of fetal gallbladder on second-trimester ultrasound: cohort study and systematic review of literature. Ultrasound Obstet Gynecol. 2019; 54(5):582-8. DOI: 10.1002/uog.20252
5. Goldstein I, Tamir A, Weisman A, Jakobi P, Copel JA. Growth of the fetal gallbladder in normal pregnancies. Ultrasound Obstet Gynecol. 1994; 4(4):289– 93. DOI: 10.1046/j.1469-0705.1994.04040289.x
6. Shen O, Rabinowitz R, Yagel S, Gal M. Absent gallbladder on fetal ultrasound: prenatal findings and postnatal outcome. Ultrasound Obstet Gynecol. 2011; 37(6):673-7. DOI: 10.1002/uog.8861
7. Kesrouani A, Nassif N, Nasr B, Choueiry E, Chalouhi G. Ultrasound characteristics and outcome of prenatally diagnosed fetal cholelithiasis. J Matern Fetal Neonatal Med. 2019; 32(12):2095-9. DOI: 10.1080/14767058.2018.1424819
8. Bergougnoux A, Jouannic JM, Verneau F, Bienvenu T, Gaitch N, Raynal C, et al. Isolated Nonvisualization of the Fetal Gallbladder Should Be Considered for the Prenatal Diagnosis of Cystic Fibrosis. Fetal Diagn Ther. 2019; 45(5):312-16. DOI: 10.1159/000489120
9. Salomon LJ, Alfirevic Z, Berghella V, Bilardo C, Hernandez-Andrade E, Johnsen SL, et al. ISUOG Clinical Standards Committee. Practice guidelines for performance of the routine mid-trimester fetal ultrasound scan. Ultrasound Obstet Gynecol. 2011; 37(1) 116-26. DOI: 10.1002/uog.8831
10. American Institute of Ultrasound in Medicine. AIUM practice guideline for the performance of obstetric ultrasound examinations. J Ultrasound Med. 2013; 32(6):1083-101. DOI: 10.7863/ultra.32.6.1083
11. Lin HY, Lee RC. Is right-sided ligamentum teres hepatis always accompanied by left-sided gallbladder? Case reports and literature review. Insights Imaging. 2018; 9(6):955-60. DOI: 10.1007/s13244-018-0671-9
12. Yayla M, Bayık RNE. Undetectable gall bladder in fetus: what to do? Peirnatal Journal. 2016; 24(1):11–19. DOI:10.2399/prn.16.0241004
13. Moore KL. The Developing Human: Clinically Oriented Embryology. 3rd edition. Philadelphia, PA: WB Saunders; 1982.
14. Maggi U, Farris G, Carnevali A, Borzani I, Clerici P, Agosti M, et al. Prenatal and accurate perinatal diagnosis of type 2 H or ductular duplicate gallbladder. BMC Pediatr. 2018; 18(1):38. DOI: 10.1186/s12887-018-1043-9
15. Wong LS, Rusby J, Ismail T. Left-sided Gall Bladder: A Diagnostic and Surgical Challenge. ANZ J Surg. 2001; 71(9):557–8. DOI: 10.1046/j.1440- 1622.2001.02195.x
16. Tanaka Y, Senoh D, Hata T. Is there a human fetal gallbladder contractility during pregnancy? Hum Reprod. 2000; 15(6):1400–2. DOI:10.1093/ humrep/15.6.1400
17. Bronshtein M, Weiner Z, Abramovici H, Filmar S, Erlik Y, Blumenfeld Z. Prenatal diagnosis of gallbladder anomalies–report of 17 cases. Prenat Diagn. 1993; 13(9):851–61. DOI: 10.1002/pd.1970130909
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Ibrahim Batmaz, Yeliz Gül, Cengiz Sanli, Gülay Bulu, Ahmet Senocak, Salih Burcin Kavak. Incidence of congenital gallbladder anomalies and clinical significance. Ann Clin Anal Med 2021;12(10):1119-1122
Retrospective evaluation of chest computed tomography findings of the patients diagnosed with COVID-19
Alev Gunaldi, Esra Ummuhan Mermi Yetis
Department of Radiology, University of Maltepe, Faculty of Medicine, Istanbul, Turkey
DOI: 10.4328/ACAM.20663 Received: 2021-04-19 Accepted: 2021-06-29 Published Online: 2021-07-16 Printed: 2021-10-01 Ann Clin Anal Med 2021;12(10):1123-1127
Corresponding Author: Alev Gunaldi, University of Maltepe, Faculty of Medicine, Department of Radiology, Bağlarbaşı Mahallesi, Sakızağacı Sk. No:3, 34844 Maltepe, Istanbul, Turkey. E-mail: firstname.lastname@example.org P: +90 850 811 02 51 F: +90 216 399 00 60 Corresponding Author ORCID ID: https://orcid.org/0000-0001-6612-1735
Aim: In our study, we aimed to analyze laboratory findings, presentation symptoms and thoracic CT findings of patients who were admitted to the emergency department of our hospital with symptoms of COVID-19, had positive results of RT-PCR tests, and were referred to our radiology clinic.
Material and Methods: Patients’ demographic data such as age and gender, symptoms on admission, PCR and CT outcomes were recorded and analyzed. In CT examinations, laterality, the presence of consolidation and/or ground-glass opacities (GGO), and central and/or peripheral distribution were analyzed.
Results: A total of 74 patients aged 20-87 years who were found to be COVID-19 positive using RT-PCR test were included in our study. When examining the initial admission symptoms, patients were found to have complaints such as fever, cough, shortness of breath, weakness and sore throat. When the thorax CT findings of the patients included in the study were examined, bilateral and unilateral involvement, anterior and posterior localization, presence of apical involvement, peripheral and central distribution, multilobar and unilobar involvement, GGO, consolidation, vascular thickening, crazy paving, fibroatelectasis, subpleural band, air bronchogram, pleural effusion, pleural thickening, cavitation and mediastinal LAP findings were detected.
Discussion: It is still premature to use CT alone instead of RT-PCR. However, the findings accumulated in the literature show that a trend has begun to develop in this regard. A definitive diagnosis must be confirmed by CT scan in patients who show typical symptoms of COVID-19, even though the PCR test is negative, especially in adults.
Keywords: COVID-19; Radiology; Computed Tomography; RT-PCR
The coronavirus-2019 disease (COVID-19), caused by coronavirus 2 (SARS-CoV-2), which emerged in Wuhan, China’s Hubei province in December 2019 and progressed with severe acute respiratory syndrome, is still spreading rapidly all over the world . COVID-19 pneumonia causes severe respiratory disease, and its main clinical symptoms are fever, cough, shortness of breath, myalgia and weakness [2, 3]. Symptoms such as diarrhea, hemoptysis and headache are also among the symptoms of COVID-19 disease . Early diagnosis is very important, since the source of infection can be not only symptomatic patients, but also patients in the incubation period.
The mortality rate from COVID-19 pneumonia has been reported to be high in some populations with comorbidities such as diabetes and hypertension, especially in the elderly [5, 6]. The epidemic was declared a pandemic by the World Health Organization (WHO) in March 2020, and according to WHO data, around 1 million deaths were recorded with 32.7 million cases all over the world on 27/09/2020 (available at: https:// covid19.who.int/).
The socio-economic impacts of the highly contagious COVID-19 disease also continue to increase. Although studies to find vaccines and drugs for COVID-19 pneumonia continue, no specific vaccine or drug treatment has yet been found. The gold standard method used to detect COVID-19 pneumonia is the reverse transcription polymerase chain reaction (RT-PCR) test. Although the RT-PCR test is thought to have high specificity, the sensitivity of this method is reported as low as 60-70% . Therefore, chest computed tomography (CT) is frequently used together with RT-PCR. Thorax CT is known to be more sensitive compared to RT-PCR, but thorax CT may also be normal in the early period of the disease and in asymptomatic cases. In imaging studies, it is difficult to distinguish COVID-19 from influenza A virus, influenza B virus, cytomegalovirus, adenovirus, respiratory syncytial virus, SARS-CoV, MERS coronavirus and other viral pneumonias as well as pneumonia caused by bacterial pneumonia .
In our study, we aimed to analyze the laboratory findings, presentation symptoms and thoracic CT findings of patients who were admitted to the emergency department of our hospital with symptoms of COVID-19, who had positive results of RT-PCR tests, and were referred to our radiology clinic.
Material and Methods
A total of 74 patients who were admitted to the emergency service of our hospital with COVID-19 symptoms between 15/03/2020 and 15/06/2020 tested positive for COVID-19 using the RT-PCR test, and who were referred to our clinic for radiological imaging were included in our study. Our study has a retrospective design and was conducted in a single center. Necessary permissions and ethics committee approval were obtained before starting the study. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki. Demographic data of the patients such as age and gender, presentation symptoms (fever, cough, dyspnea, myalgia, etc.), contact history, laboratory findings (leukocyte, CRP), ground glass opacities (GGO), consolidations, paving (crazy-paving) finding, typical CT findings such as vascular enlargement, air bronchogram, bronchial wall thickening and bronchiectasis, reticulation, subpleural lines, linear opacities, fibrosis, Halo sign, Inverse halo sign (Atoll’s sign), air bubble and pleural thickening, and the presence of atypical CT findings such as pleural effusion, pericardial effusion, lymphadenopathy, the appearance of budded branches were investigated and recorded.
CT Acquisition Technique
As part of our hospital’s COVID-19 guidelines, after the RT- PCR swabs, all patients underwent chest CT to determine the presence or absence of viral pneumonia. All chest CT examinations were performed with patients in the supine position during end inspiration without contrast medium injection. Chest CT was performed on a 128-slice CT scanner (GE Revolution EVO 64 Slice CT Scanner; GE Medical Systems, Milwaukee, Wis) dedicated for COVID-19 patients only. The following technical parameters were used: tube voltage, 120 kV; tube current modulation, 100–250 mAs; spiral pitch factor, 0.98; and collimation width, 0.625. Reconstructions were performed using the convolution kernel BONEPLUS (GE Medical Systems) at a slice thickness of 1.25 mm. The decontamination of the room consisted of surface disinfection with 62%–71% ethanol or 0.1% sodium hypochlorite. After each chest CT examination, passive air exchange was performed for 40–60 minutes. Disposable bed covers were used during each examination, and the CT device and room was completely disinfected after each patient’s examination.
SPSS 23.0 (SPSS Inc. USA) was used for the statistical analysis of the data obtained in the study. Continuous variables are expressed as mean ± standard deviation, minimum and maximum values, and categorical variables as numbers and percentages. The p-values <0.05 were considered statistically significant.
A total of 74 patients aged 20-87 years who tested positive for COVID-19 sing the RT-PCR test were included in our study. Forty of the patients were male (54.1%) and 34 were female (45.9%). In terms of gender, there was no statistically significant difference between males and females (p> 0.05). The mean age of all patients was 51.74 ± 18.23 years. The mean age of men was 52.8 ± 18.23 years, and the mean age of women was 50.64 ± 18.58 years. In terms of mean age, no statistically significant difference was found between male and female patients in terms of age (p> 0.05).
When the initial admission symptoms of the patients were examined, it was found that they presented with complaints such as fever, cough, shortness of breath, weakness and sore throat. The mean fever of the patients at the time of admission was 37.0 ± 0.7 (min-max: 36-39) degrees. When each of the admission symptoms was examined separately, only fever was detected in 11 patients, only cough in 19 patients, and malaise in 7 patients. The remaining 37 patients were determined to present with more than one symptom. When the laboratory data of the patients included in the study were examined, the mean leukocyte value was 7.27 ± 3.07 (min-max: 2.85-17.77 K / uL). The leukocyte value was found to be 7.18 ± 3.07 (min-max: 2.86-16.08 K / uL) in male patients and 7.30 ± 3.04 (min-max: 2.85-17.77 K / uL) in female patients. The leukocyte value in 50 cases (67.6%) was within the normal reference range. It was found that 15 patients (20.3%) had low leukocyte levels and 9 (12.2%) had high leukocyte values.
When the CRP values of the patients were examined, while the mean CRP levels were within the normal range in 32 patients (43.2%), it was found to be increased in 42 patients (56.8%). When the thorax CT findings of the patients included in the study were examined, bilateral and unilateral involvements, anterior and posterior localization, presence of apical involvement, peripheral and central distribution, multilobar and unilobar involvements, GGO, consolidation, vascular thickening, crazy paving, fibroatelectasis, subpleural band, air bronchogram, pleural effusion, pleural thickening, cavitation and mediastinal LAP findings were detected. Thoracic CT findings of the patients are presented in Table 1.
No Reverse Halo and appearance of budded branches findings were found in any of the 74 patients included in the study. Sample CT images of the patients are shown in Figures 1-3.
Diagnosis of COVID-19 pneumonia is based on clinical symptoms, RT-PCR testing, CT scanning, and serology blood tests. The most common laboratory abnormalities in positive RT-PCR patients are leukopenia, thrombocytopenia, elevated CRP and inflammatory markers, increased cardiac biomarkers, decreased albumin, and liver kidney and liver function [8, 9]. In our study, we examined the admission symptoms, laboratory results and thorax CT findings of patients in whom COVID-19 diagnosis was confirmed with RT-PCR test.
In our study, the average age of the patients was 52. In the study by Yurdaisik et al. with 50 patients, the average age was 54 . Similarly, Wang et al. reported that the average age was 56 in their study in which they analyzed COVID-19 patients . When we examine the initial presentation symptoms of 74 patients included in the study, we have found that they most frequently presented with fever, cough, shortness of breath and malaise. In other studies, previously published in the literature, it was reported that the most common presentation symptoms were fever, cough, shortness of breath, and malaise [10, 12]. When we examine the laboratory findings of the patients, while the mean CRP level was within the normal range in 32 patients (43.2%), it was found to be increased in 42 patients (56.8%). Looking at previous studies examining COVID-19 patients, Li et al. reported that CRP was within the normal reference range in 56 patients (43%), and increased CRP in 75 patients (57%) . In a study conducted by Chen et al., 63 of 73 COVID-19 patients (86%) had increased CRP levels and in the studies conducted by Guan et al., it was observed that CRP increased in 481 (60.7%) of 793 COVID-19 patients .
Some of the previously reported studies in the literature reported a decrease in leukocyte ratio [4, 13, 14], and some reported that the leukocyte ratio increased in COVID-19 patients [15, 16]. When we examine laboratory tests of the patients, we found that the leukocyte value of 50 COVID-19 patients (67.6%) was in the normal reference range, the leukocyte value of 15 patients (20.5%) decreased, and the leukocyte value increased in 9 patients (11.2%). In the study of Chen et al. in which 99 COVID-19 patients were analyzed in China, it was reported that 24 patients (24%) had an increase in leukocyte levels and in 9 patients (9%), there was a decrease in leukocyte levels . When we examine the CT findings of our study, we found that a total of 52 patients (70.3%) had lung involvement, 45 of them had bilateral and 7 had unilateral involvement. Bilateral involvement was found in 91% of the patients in the study conducted by Caruso et al. in Italy, in 86% of the patients in the study by Song et al.  and in 75% of the patients in the study by Bai et al. . As in our study, it is seen that bilateral involvement is much higher than unilateral involvement in other studies reported in the literature. Seventeen of these involvements are located posteriorly, and 35 are anterior/ posterior located. Again, apical involvement was observed in 20 patients.
Among 52 patients with involvement (70.3%), 40 (78%) had peripheral distribution and 12 (22%) had peripheral + central distribution. Similar to our study, in the study conducted by Zhou et al., the peripheral distribution rate of COVID-19 patients was reported as 77.4% . In a study by Xu et al., they reported that the peripheral distribution was observed in 78% of the patients , and in another study conducted by Harrison et al., it was reported that 80.4% of the patients had peripheral distribution .
In patients with involvement, 50 of the involvements (96.1%) were found to be multilobar involvement and 2 patients (3.9%) had unilobar involvement. In the study by Sana et al. investigating 919 COVID-19 patients, the rate of multilobar involvement was reported as 78.8% .
When the literature is reviewed, studies have shown that the most prominent CT finding of COVID-19 patients is GGO. In our study, 51 of the 74 patients (69.0%) had GGO and 13 (17.6%) had consolidation. In the study conducted by Song et al., GGO rate was reported as 76.5% . Similarly, in the study conducted by Shi et al., the GGO rate was 65.4% and the consolidation rate was 17.3% . In a meta-analysis evaluating a total of 13 studies, the incidence of GGO was reported to be 69% . Other CT findings in patients with involvement are as follows: fibroatelectasis in 23 patients (31.1%), subpleural band in 23 patients (31.1%), crazy paving in 12 patients (16.2%), vascular thickening in 6 patients (8.1%), mediastinal LAP in 5 patients (6.7%), traction bronchiectasis in 3 patients (4.1%), air bronchogram in 2 patients (2.7%), pleural thickening in 2 patients (2.7%), cavitation in 1 patient (1.3%), and pleural effusion in 1 patient (1.3%).
Limitations of the Study
First of all, our study was conducted in a single center. On the other hand, the number of participants in our study was relatively high compared to similar studies. Other hemogram parameters, such as neutrophil, monocyte, platelet, and mean platelet volume, which have been widely investigated in studies, could also be studied. However, this would have made it difficult to focus on the CT findings, which was the main purpose of the study. We believe that the findings of our study will contribute to the existing evidence. However, our findings should be supported by large-series multi-center studies.
The pandemic caused by the COVID-19 virus continues to affect many people around the world and causes the death of many people. Vaccine/drug development efforts continue in many countries, including our country. However, unfortunately, even if an effective vaccine is found, it will best be applied to large populations in the second half of 2021. Considering all these, the importance of early diagnosis and treatment in COVID-19 comes to the fore. The low sensitivity and high prevalence of false negatives of the gold standard RT-PCR test necessarily require confirmation of the diagnosis by other methods. Laboratory parameters have a certain diagnostic value. However, laboratory findings vary widely between studies. In this case, chest CT is of great importance as a diagnostic confirmatory. Especially as the pandemic continues, the importance of breast CT will gradually increase. It is still premature to use CT alone instead of RT-PCR. However, the findings accumulated in the literature show that a trend has begun to develop in this regard. A definitive diagnosis must be confirmed by CT scan in patients who show typical symptoms of COVID-19, even though the PCR test is negative, especially in adults.
Scientific Responsibility Statement
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with
the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Conflict of interest
1. Pollard CA, Morran MP, Nestor-Kalinoski AL. The COVID-19 pandemic: a global health crisis. Physiol Genomics. 2020; 52(11):549-57.
2. Caruso D, Zerunian M, Polici M, Pucciarelli F, Polidori T, Rucci C, et al. Chest CT features of COVID-19 in Rome, Italy. Radiology. 2020; 3:201237.
3. Yurdaisik I. Effectiveness of Computed Tomography in the Diagnosis of Novel Coronavirus-2019. Cureus. 2020; 12(5):e8134.
4. Sun P, Qie S, Liu Z, Ren J, Xi J. Clinical characteristics of 50466 patients with 2019-nCoV infection. J Med Virol. 2020.
5. Ai T, Yang Z, Hou H, Zhan C, Chen C, Lv W, et al. Correlation of Chest CT and RT-PCR Testing in Coronavirus Disease 2019 (COVID-19) in China: A Report of 1014 Cases. Radiology. 2020; 296(2):E32-40.
6. Fang Y, Zhang H, Xie J, Lin M, Ying L, Pang P, et al. Sensitivity of Chest CT for COVID-19: Comparison to RT-PCR. Radiology. 2020; 200432.
7. Corman VM, Landt O, Kaiser M, Molenkamp R, Meijer A, Chu DK, et al. Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR. Euro Surveill. 2020; 25(3):2000045.
8. Paranjpe I, Russak A, De Freitas JK, Lala A, Miotto R, Vaid A, et al. Clinical Characteristics of Hospitalized Covid-19 Patients in New York City. medRxiv. 2020; DOI: 10.1101/2020.04.19.20062117
9. Zhu J, Zhong Z, Ji P, Li H, Li B, Pang J, et al. Clinicopathological characteristics of 8697 patients with COVID-19 in China: a meta-analysis. Fam Med Commun Health. 2020; 8(2):e000406.
10. Yurdaisik I, Nurili F. Evaluation of Chest CT Findings in 50 Coronavirus Disease 2019 (COVID-19) Patients Treated in Turkey. Cureus. 2020; 12(5):e8252.
11. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020; 323(11):1061-9.
12. Li X, Zeng W, Li X, Chen H, Shi L, Li X, et al. CT imaging changes of corona virus disease 2019(COVID-19): a multi-center study in Southwest China. J Transl Med. 2020; 18(1):154.
13. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020; 382(18):1708-20.
14. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020; 395(10223):497-506.
15. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020; 395(10229):1054-62.
16. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020; 395(10223):507-13.
17. Song F, Shi N, Shan F, Zhang Z, Shen J, Lu H, et al. Emerging 2019 Novel Coronavirus (2019-nCoV) Pneumonia. Radiology. 2020; 295(1):210-17.
18. Bai HX, Hsieh B, Xiong Z, Halsey K, Choi JW, Tran TML, et al. Performance of Radiologists in Differentiating COVID-19 from Non-COVID-19 Viral Pneumonia at Chest CT. Radiology. 2020; 296(2):E46-54.
19. Xu X, Yu C, Qu J, Zhang L, Jiang S, Huang D, et al. Imaging and clinical features of patients with 2019 novel coronavirus SARS-CoV-2. Eur J Nucl Med Mol Imaging. 2020; 47(5):1275-80.
20. Harrison EA, Wu JW. Vaccine confidence in the time of COVID-19. Eur J Epidemiol. 2020; 35(4):325-30.
21. Salehi S, Abedi A, Balakrishnan S, Gholamrezanezhad A. Coronavirus Disease 2019 (COVID-19): A Systematic Review of Imaging Findings in 919 Patients. AJR Am J Roentgenol. 2020; 215(1):87-93.
22. Shi H, Han X, Jiang N, Cao Y, Alwalid O, Gu J, et al. Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. Lancet Infect Dis. 2020; 20(4):425-34.
23. Wan S, Li M, Ye Z, Yang C, Cai Q, Duan S, et al. CT Manifestations and Clinical Characteristics of 1115 Patients with Coronavirus Disease 2019 (COVID-19): A Systematic Review and Meta-analysis. Acad Radiol. 2020; 27(7):910-21.
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Alev Gunaldi, Esra Ummuhan Mermi Yetis. Retrospective evaluation of chest computed tomography findings of the patients diagnosed with COVID-19. Ann Clin Anal Med 2021;12(10):1123-1127
Clinicopathological factors breast cancer recurrence and the effect of molecular subtypes
Şeref Dokcu, Mehmet Ali Çaparlar
Department of Oncological Surgery, Ankara University Faculty of Medicine, Ankara, Turkey
DOI: 10.4328/ACAM.20664 Received: 2021-04-19 Accepted: 2021-06-07 Published Online: 2021-06-26 Printed: 2021-10-01 Ann Clin Anal Med 2021;12(10):1128-1131
Corresponding Author: Şeref Dokcu, General Surgery Specialist and Surgical Oncology Research Assistant, Surgical Oncology Department, Ankara University, Faculty of Medicine, Cebeci Research and Application Hospital Balkiraz, Cebeci, No:6, 06620 Çankaya, Ankara, Turkey. E-mail: email@example.com P: +90 533 443 43 33 Corresponding Author ORCID ID: https://orcid.org/0000-0003-1807-8108
Aim: The prognostic and predictive factors for breast cancer are well defined today. However, there is still no information available to help us determine pos- sible recurrence localizations. Our study aimed to examine the clinicopathological variables that affect metastatic behavior of breast cancer and its relation- ship with molecular subtypes.
Material and Methods: Two hundred patients with breast cancer operated in a surgical oncology clinic were included in our study. Clinicopathological and demographic characteristics were recorded retrospectively from the hospital database. The patients were categorized per the TNM staging system. According to the immunohistochemical results, the subtypes were defined as luminal A, luminal B/human epidermal growth factor receptor 2+(HER2+), luminal B/HER2-, HER2-rich, and triple-negative (TNBC). Survival analyzes were estimated using the Kaplan-Meier method. Variables that were statistically significant in the univariate analysis were then included in the multivariate analysis using the Cox proportional hazards regression model. The relationship between categori- cal variables was analyzed using the chi-square (χ 2test) test. Statistical analysis was made at a 95% confidence interval. A p-value higher than 0.05 was considered statistically significant.
Results: The most common recurrence was observed in bone tissue (59%). A significant correlation was found between recurrence localizations and molecular subtypes (p=0.025). Luminal subtypes were mostly related to bones, and non-luminal subtypes were mostly associated with visceral and brain metastases. Approximately 1/3 of the metastases were in the form of multiorgan involvement. Factors affecting tumor recurrence were tumor size (p=0.029), axillary lymph node involvement (p=0.047), LVI status (p=0.018), histological grade of the tumor (p=0.028), TNM stage (p=0.035), and local stage (p=0.019).
Discussion: The new clinical/diagnostic staging system, including molecular subtypes, can enable us to better predict the probability of distant recurrence and their possible localization.
Keywords: Breast Cancer; Clinicopathological Characteristics; Luminal Subtype; Recurrence
Despite modern strategies for follow-up and treatment, up to 30% of patients with postoperative breast cancer (BC) develop distant disease recurrence. However, we still do not have comprehensive information about tumor spread and regional recurrence patterns . Survival has improved significantly as a result of early diagnosis and treatment. Also, the number of women who need follow-up after treatment has increased significantly. The primary purpose of follow-up includes early detection of distant and near recurrences and second primary tumors. The incidence of recurrence after initial treatment is affected by prognostic factors such as age, histological grade, axillary lymphatic involvement, hormone receptor status, vascular invasion, and initial treatment status [2, 3].
In parallel with the increasing understanding of cancer biology, significant advances have been made in treatment. Genomic studies have shown that breast cancer is not a single disease, but a heterogeneous group of diseases. These studies will guide us in determining the personalized treatment profile. There are staging systems to guide us in determining our follow-up and treatment strategies. The TNM staging system is a projection of the clinicopathological status based on key parameters such as tumor size, node state, and metastatic disease state. However, studies have shown that the metastatic character of the tumor also carries genomic signatures. This heterogeneous nature of breast cancer also explains the difficulty in predicting the progression of the disease. The gene profile expresses itself at receptor levels as detected by immunohistochemical (IHC) staining. Accordingly, breast cancer is divided into five intrinsic subgroups. These are predominantly Luminal-like subtypes (Luminal) expressing estrogen receptor (ER) and progesterone receptor (PR), basal-like triple-negative subtypes (TNBC) that overexpress HER2 but are rich in HER2 negative for estrogen- progesterone expression and do not predominantly express ER, PR, or HER2 receptors. However, for comprehensive characterization, to reveal the full heterogeneity of breast cancer, all genome profiling that is not routinely used is needed .
In this study, we aimed to examine the relationship between molecular subtypes and the TNM stage to help us understand the spread pattern in patients with breast cancer who were operated on but recurred. Recognition and appreciation of these clinically different subgroups of BC can help us predict different outcomes and provide new insights into disease management. With the increasing understanding of tumor biology, it is hoped that ongoing and future clinical trials will transform into better outcomes for patients.
Material and Methods
Our study was initiated with the approval of the Ankara University Faculty of Medicine Hospital Ethics Committee Decision number: İ10-623-20). Written informed consent was obtained from all participants.
Two hundred twenty-one patients operated on for breast cancer in the Surgical Oncology Clinic between 2010 and 2020 were included in the study. Twenty-one patients were excluded due to missing data. The hospital database was analyzed retrospectively. From the pathological examination results of the patients, ER, PR, and HER2 status, KI-67 percentage, tumor type, size and histological grade, lymphovascular invasion (LVI) status, axillary lymph node involvement status were recorded. Besides, the patients’ age, menopause status, and the type of surgical procedure performed were examined and recorded in the digital patient files. Thirty-nine of the patients had various organ recurrences. Distant recurrence was defined as BC recurrence beyond the margins of the ipsilateral breast, chest wall, or regional lymph nodes. The sites of distant recurrence were categorized as follows: bone, brain (including leptomeninges), liver, lung, distant nodal (including supraclavicular internal mammary nodules other than ipsilateral axillary), and multiple organ recurrence.
We classified patients according to the recommendations of the St. Gallen International Expert Consensus Report (2013) for molecular breast cancer subtypes. The patients were categorized by the receptor status of their primary tumor as follows: Luminal A (ER + and/or PR + and HER2-, Ki-67 < 14%); luminal B /HER2- (ER + and/or PR +, HER2- and Ki-67 ≥ 14%); luminal B/HER2 + (ER + and/or PR +, HER2+, any Ki- 67); HER2-rich (ER- and PR- and HER2 +) and TNBC (ER- and PR- and HER2-) . ER and PR status were determined using immunohistochemical staining (IHC). Tumors were considered HER2-positive only if they showed HER2 amplification (ratio> 2) using 3+ staining with IHC staining or fluorescent in situ hybridization (FISH). Tumors were also classified as Luminal and non-luminal based on hormone receptor expression.
They were staged according to the TNM system based on the American Joint Committee on Cancer (AJCC) 18th Edition (stage 1A,1B,2A,2B,3A,3B,3C,4) . Tumors were also classified by their local stages as local (stages 1, 2) and locally advanced stage (stage3).
Descriptive statistical analyzes were performed and all data were presented as mean ± standard deviation (SD), number, percentage, maximum and minimum values. Survival curves were estimated using the Kaplan-Meier method, and the significance of the differences between these curves was determined using the log-rank test. Variables that were statistically significant in the univariate analysis were then included in the multivariate analysis using the Cox proportional hazards regression model. The relationship between categorical variables was analyzed using the chi-square (χ 2 test) test. Statistical analysis was done at a 95% confidence interval. A P-value higher than 0.05 was considered statistically significant (all reported p-values were two-tailed).
All 200 patients included in the study were women. The mean follow-up period was 104.9±3.5 months; 19.5% (n=39) patients had recurrence, while 80.5% (n=161) did not. According to the menopausal status, 45% of the patients (n=90) were premenopausal, 55% (n=110) were post-menopausal; 54% (n=108) of the patients were right breast and 46% (n=92) were left breast patients. The patients’ mean age was 53.5±5.2 (28- 84) years, and the mean KI-67 percentage was 28.8±17.7. Half of the patients had no axillary involvement. Mastectomy procedure was performed in approximately half of the patients, and breast-conserving surgery was performed in the other half. The most common histological type was invasive ductal carcinoma 68% (n=136), followed by lobular carcinoma (19.n=38) and other histological types with decreasing frequency. The mean number of pathological lymph nodes removed was 4.4±3 (1-28), and the mean number of total lymph nodes removed was 12±7.2 (1-35). The distribution of clinicopathological characteristics by groups is presented in Table 1.
A significant correlation was found in χ2 analysis between recurrent regions and molecular subtypes (p=0.025). Bone metastases were mainly associated with luminal subtypes, while visceral metastases were associated with non-luminal subtypes.
The most common metastatic sites were 59% bone, 23% lung, 20.5% liver, 15.4% axilla, 10% distant nodal, and 7.6% brain. One-third of these metastasis sites had multiorgan involvement, and in general, the liver and lungs accompanying bone metastases were in the form of different combinations, albeit a little. All but two of the bone metastases were associated with luminal subtype breast cancer. Internal organ involvement accompanied two non-luminal metastases. While axillary recurrences were equally distributed, 2 of the three patients with brain metastases had TNBC subtype.
The mean follow-up period of patients with recurrence was 58 ±28(1-154) months, respectively 1,2,5,10 years disease- free survival rate (DFS) was (DFS) 96.7%-93.2%-87.3%- 72.9%. In the cox regression analysis, factors affecting tumor recurrence were found as tumor size (p=0.029), axillary lymph node involvement (p=0.047), LVI status (p=0.018), histological grade of the tumor (p=0.028), TNM stage (p=0.035), local stage (p=0.019). However, there was no significant relationship between menopausal status, tumor histology, receptor status, type of surgery and axillary involvement (P > 0.05)
Our study examined the relationship between recurrence sites, molecular subtypes, and other clinicopathological variables after recurrence in patients operated on for breast cancer. Knowing the variables that determine the disease’s natural course helps define different patient groups by the likelihood of relapse due to the disease. The risk of recurrence development was high in tumors with LVI, pathological involvement at the axilla, high histological grade and size, and advanced local stage at the initial diagnosis time. The most common metastasis area was bone, mainly consisting of tumor recurrences with a luminal subtype. Non-luminal subtypes were mostly associated with visceral recurrences. In particular, the TNBC subtype was mostly accompanied by brain metastases.
Our results are in line with the current literature, [7- 9]. In the study conducted by Geurts et al. with 362 recurrence cases, it was reported that recurrences usually occur in the first year after diagnosis and in the form of distant metastasis. They reported young age (<40), tumor size (T2, T3) and high tumor histological grade (Grades 2, 3), axillary positive lymph nodes, multifocality, and a patient not receiving chemotherapy as prognostic factors for first recurrence .
A recently published study from Denmark reported 5-year breast cancer recurrence rates of 18% bone and 5% visceral metastasis in a sample of 23,478 breast cancer patients . Except for patients with widespread metastases, there are two main disease patterns in recurrent breast cancer. Patients with ER +/PR + (luminal) tumors tend to develop more bone metastases but no brain metastases. The situation is opposite in patients with ER−/PR−(non-luminal) tumors . Clinically, the most common metastasis sites are organs such as bone, lung, central nervous system, liver [1,13]. In our study, the most common metastasis site was bone (59%), followed by organs such as lung, liver, distant nodal regions, and brain. Multiorgan involvement was present in one-third of the metastases. These involvements were generally in the form of combinations of organ involvement accompanying bone involvement. Locoregional recurrences (15%) were in the form of axillary involvement, except for one patient with local recurrence. In our study, bone metastases were mostly observed in luminal subtype tumors. While locoregional recurrences were evenly distributed, visceral and brain metastases were more common in non-luminal subtypes. In addition to classical prognostic factors, breast cancer types are closely associated with the risk of recurrence and outcomes, and its prognostic value is widely recognized and guides clinicians [14-17]
Breast cancer recurrence patterns describe a complex interaction of seed and soil factors, including tumor circulation, proliferation, angiogenesis, and the target tissue’s microenvironment. Some relationships between major molecular subtypes and propagation patterns have been identified. HER2 and ER expression status have been associated with an increased risk of lung and bone metastases. Overall, TNBC has a worse prognosis than other genotypes with the same stage. Metastatic TNBC is accompanied by significantly greater visceral involvement compared to other breast cancers, associated with a dramatic increase in the risk of lung and CNS recurrence .
In autopsies performed in patients with breast cancer, the most common cause of death was various organ metastases, accounting for 42% of all deaths. Interestingly, in this study involving 166 cadavers, involvement was observed in unexpected areas. Although these areas included endocrine organs (40%), the lungs (28%), cardiovascular system (21%), and genitourinary system (21%), metastases to bones (10%) and CNS (14%) were very rare . These results show that the detected metastases represent the tip of the iceberg. In reality, the frequency of metastasis is much higher than it appears. Breast cancer is the second most common cause of CNS metastases. There is a common belief that tumors with lobular histology tend to metastasize to leptomeningeal areas . Two of our three patients who showed brain metastasis had lobular histology.
A new clinical/diagnostic staging process, including molecular subtypes, may better predict the likelihood of distant recurrence and their anatomical location. Recognition of different molecular subtypes clinically can help to evaluate distant recurrences and their possible localization.
Besides these studies, machine learning models that include serum biomarkers and hormone receptors can effectively predict breast cancer metastasis at least three months in advance . Studies conducted have shown an excessive fear of recurrence in women patients, which may affect the prognosis. It was reported that understanding the risk of systemic recurrence, especially in patients with a favorable prognosis, will mean risk communication between clinician and patient, better understanding of risk among patients, and improvements in quality of life [20,21].
In conclusion, data on the long-term risk of breast cancer recurrence from population-based patient samples are insufficient since the vast majority of published studies use selected patient samples, such as hospital-based cohorts. More population-based randomized studies are needed to determine prognostic factors affecting recurrence patterns and their threshold values.
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Conflict of interest
1. Buonomo OC, Caredda E, Portarena I, Vanni G, Orlandi A, Bagni C, et al. New insights into the metastatic behavior after breast cancer surgery, according to well-established clinicopathological variables and molecular subtypes. PLoS One. 2017;12(9):1–17.
2. Witteveen A, Vliegen IMH, Sonke GS, Klaase JM, IJzerman MJ, Riesling S. Personalisation of breast cancer follow-up: a time-dependent prognostic nomogram for the estimation of annual risk of locoregional recurrence in early breast cancer patients. Breast Cancer Res Treat. 2015;152(3):627–36.
3. Wallgren A, Bonetti M, Gelber RD, Goldhirsch A, Castiglione-Gertsch M, Holmberg SB, et al. Risk factors for locoregional recurrence among breast cancer patients: Results from International Breast Cancer Study Group Trials I through VII. J Clin Oncol. 2003;21(7):1205–13.
4. Potti A, Dressman HK, Bild A, Riedel RF, Chan G, Sayer R, et al. Genomic signatures to guide the use of chemotherapeutics. Nat Med. 2006;12(11):1294– 300.
5. Goldhirsch A, Winer EP, Coates AS, Gelber RD, Piccart-Gebhart M, Thürlimann B, et al. Personalizing the treatment of women with early breast cancer: Highlights of the st gallen international expert consensus on the primary therapy of early breast Cancer 2013. Ann Oncol. 2013;24(9):2206–23.
6. Giuliano AE, Connolly JL, Edge SB, Mittendorf EA, Rugo HS, Solin LJ, et al. Breast Cancer-Major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(4):290–303.
7. Holleczek B, Stegmaier C, Radosa JC, Solomayer EF, Brenner H. Risk of loco- regional recurrence and distant metastases of patients with invasive breast cancer up to ten years after diagnosis – Results from a registry-based study from Germany. BMC Cancer. 2019;19(1):1–14.
8. van Roozendaal LM, Smit LHM, Duijsens GHNM, de Vries B, Siesling S, Lobbes MBI, et al. Risk of regional recurrence in triple-negative breast cancer patients: a Dutch cohort study. Breast Cancer Res Treat. 2016;156(3):465–72.
9. Aalders KC, Postma EL, Strobbe LJ, Van Der Heiden-Van Der Loo M, Sonke GS, Boersma LJ, et al. Contemporary locoregional recurrence rates in young patients with early-stage breast cancer. J Clin Oncol. 2016;34(18):2107–14.
10. Geurts YM, Witteveen A, Bretveld R, Poortmans PM, Sonke GS, Strobbe LJA, et al. Patterns and predictors of first and subsequent recurrence in women with early breast cancer. Breast Cancer Res Treat. 2017;165(3):709–20.
11. Cronin-Fenton D, Kjærsgaard A, Nørgaard M, Amelio J, Liede A, Hernandez RK, et al. Breast cancer recurrence, bone metastases, and visceral metastases in women with stage II and III breast cancer in Denmark. Breast Cancer Res Treat. 2018;167(2):517–28.
12. Maki DD, Grossman RI. Patterns of disease spread in metastatic breast carcinoma: Influence of estrogen and progesterone receptor status. Am J Neuroradiol. 2000;21(6):1064–6.
13. Altundag K, Bondy ML, Mirza NQ, Kau SW, Broglio K, Hortobagyi GN, et al. Clinicopathologic characteristics and prognostic factors in 420 metastatic breast cancer patients with central nervous system metastasis. Cancer. 2007;110(12):2640–7.
14. Park S, Koo JS, Kim MS, Park HS, Lee JS, Lee JS, et al. Characteristics and outcomes according to molecular subtypes of breast cancer as classified by a panel of four biomarkers using immunohistochemistry. Breast. 2012;21(1):50–7.
15. Lowery AJ, Kell MR, Glynn RW, Kerin MJ, Sweeney KJ. Locoregional recurrence after breast cancer surgery: A systematic review by receptor phenotype. Breast Cancer Res Treat. 2012;133(3):831–41.
16. Ribelles N, Perez-Villa L, Jerez JM, Pajares B, Vicioso L, Jimenez B, et al. Pattern of recurrence of early breast cancer is different according to intrinsic subtype and proliferation index. Breast Cancer Res. 2013;15(5):R98.
17. De Azambuja E, Cardoso F, De Castro G, Colozza M, Mano MS, Durbecq V, et al. Ki-67 as prognostic marker in early breast cancer: A meta-analysis of published studies involving 12 155 patients. Br J Cancer. 2007;96(10):1504–13.
18. Kennecke H, Yerushalmi R, Woods R, Cheang MCU, Voduc D, Speers CH, et al. Metastatic behavior of breast cancer subtypes. J Clin Oncol. 2010;28(20):3271–7.
19. Hagemeister FB, Buzdar AU, Luna MA, Blumenschein GR. Causes of death in breast cancer a clinicopathologic study. Cancer. 1980;46(1):162–7.
20. Hawley ST, Janz NK, Griffith KA, Jagsi R, Friese CR, Kurian AW, et al. Recurrence risk perception and quality of life following treatment of breast cancer. Breast Cancer Res Treat. 2017;161(3):557–65.
21. Koch L, Bertram H, Eberle A, Holleczek B, Schmid-Höpfner S, Waldmann A, et al. Fear of recurrence in long-term breast cancer survivors – Still an issue. Results on prevalence, determinants, and the association with quality of life and depression from the Cancer Survivorship – A multi-regional population-based study. Psychooncology. 2014;23(5):547–54.
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Şeref Dokcu, Mehmet Ali Çaparlar. Clinicopathological factors breast cancer recurrence and the effect of molecular subtypes. Ann Clin Anal Med 2021;12(10):1128-1131
Evaluation of ocular surface parameters in children with inflammatory bowel disease
Esra Polat 1, Betül İlkay Sezgin Akçay 2, Aslıhan Doğan Dursun 2, Nelgin Gerenli 1, Hasret Civan Ayyıldız 3
1 Department of Pediatric Gastroenterology, University of Health Sciences, Umraniye Training and and Research Hospital, 2 Department of Ophtalmology, University of Health Sciences, Umraniye Training and Research Hospital, 3 Department of Pediatric Gastroenterology, University of Health Sciences, Bakırköy Dr. Sadi Konuk Training and Research Hospital, Istanbul, Turkey
DOI: 10.4328/ACAM.20666 Received: 2021-04-23 Accepted: 2021-09-15 Published Online: 2021-09-16 Printed: 2021-10-01 Ann Clin Anal Med 2021;12(10):1132-1135
Corresponding Author: Esra Polat, Elmalıkent Mahallesi, Adem Yavuz Cd., 34764, Umraniye, Istanbul, Turkey. E-mail: firstname.lastname@example.org P: +90 505 550 01 70 F: +90 216 632 71 24 / +90 216 632 71 21 Corresponding Author ORCID ID: https://orcid.org/0000-0002-0185-0344
Aim: Inflammatory bowel disease (IBD), in the form of ulcerative colitis (UC) or Crohn’s disease (CD), is a chronic condition that primarily leads to bowel inflammation but also affects other organ systems via systemic immune response. Involvement of the ocular system can be observed and dry eye is a common problem in IBD patients. There is currently no research that has studied dry eye among children with IBD. In this study, the effects of the chronic inflammatory process on tear production and ocular surface findings were evaluated in pediatric IBD patients.
Material and Methods: Twenty-nine children aged 6-18 years with remission of IBD and 20 healthy children were included in the study. Dry eye disease was studied using the Schirmer test, tear break-up time, corneal staining with the Oxford grading scale, and non-invasive tear break-up time (NTBUT) with videokeratoscopy.
Results: There was a statistically significant difference between UC and CD patients and between CD patients and control subjects in terms of NTBUT (p=0.009 and p=0.033, respectively). A weak positive correlation was found between age and test duration in the patient group (p=0.03, r=0.39).
Discussion: Evaluation of NTBUT with videokeratoscopy can facilitate the early diagnosis of dry eye in pediatric IBD patients. Destructive complications of dry eye and ocular surface inflammation can be prevented with regular follow-up.
Keywords: Ophthalmology, Dry Eye, Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) is a chronic disease triggered by an abnormal elevated inflammatory response of the intestinal mucosa against common enteric bacteria in people who have a genetic predisposition. Ulcerative colitis (UC) and Crohn’s disease (CD) are two different forms of IBD . The incidence of IBD is approximately 25-30% up to 20 years, and the disease has a more severe course in pediatric cases than adulthood .
IBD in pediatric patients affects growth, development, education, and social life in later years with an increasing incidence. Extraintestinal involvement (EIM) is common in IBD patients, and luminal antigens are thought to be the result of a systemic immune response caused by increased intestinal permeability. Many organs and systems may be affected due to systemic inflammation in IBD patients. Extraintestinal findings may occur in 6-40% of patients with IBD. Extraintestinal symptoms may appear at any time during the disease and may also be the first sign of the disease before intestinal symptoms appear . This process may have a different course than the intestinal inflammatory process. Colitis or ileocolitis is more troublesome for EIMs than isolated small bowel involvement . Joints, eyes, skin, liver, and bile ducts are the most common sites of involvement outside of the gastrointestinal system. Hematological anomalies, increased tendency to thrombosis, and hearing loss are also very common conditions in IBD patients [5-8]. Similar to other extraintestinal findings in IBD, ocular findings may also occur during the course of the disease or before bowel findings are observed. Episcleritis, anterior uveitis, and blepharitis are the most frequent findings of ocular involvement. In addition, the fact that the disease affects the vascular structures is another important reason for the occurrence of ocular system findings in IBD patients. Dry eye is another common eye condition in IBD patients [9, 10]. The tear glands, cornea, and conjunctiva are also affected by this systemic inflammatory process, resulting in impaired tear production .
To the best of our knowledge, no studies on dry eye parameters in pediatric IBD patients have been reported. In this research, we focus on how chronic inflammatory processes affect tear production and ocular surface findings in pediatric IBD patients.
Material and Methods
Twenty-nine children aged 6-18 years with IBD in the remission period were included in this study. Twenty healthy children who applied to the ophthalmology clinic for a routine eye examination were enrolled as the control group. Ethics committee approval was obtained from the İstanbul University of Health Sciences Kanuni Sultan Süleyman Training and Research Hospital. The study was conducted in accordance with the Declaration of Helsinki. Before patients were included in the study, detailed information about the study was given and informed consent was obtained. Demographic characteristics of the patients were recorded. Exclusion criteria were preexisting ocular disease such as glaucoma or uveitis, previous ocular surgery, abnormal eyelid position and closure, disorders of the nasolacrimal drainage system, and usage of contact lenses, as well as extraintestinal manifestations of IBD such as episcleritis, corneal infiltrates, and uveitis. Patients and controls were also excluded if they had used any eye drops in the last two weeks before the eye examination. Age, disease duration, and medications used within the 12 months prior to evaluation and concurrent medications were recorded. Two experienced ophthalmologists examined all patients and controls. Each patient underwent full ophthalmologic examination including measurements of best corrected visual acuity using a Snellen chart, slit-lamp examination of the eyelid, and examination of the conjunctiva, cornea, pupils, iris, and fundus. Intraocular pressure was measured by non-contact air puff. Dry eye disease was studied using the Schirmer test, tear break-up time (TBUT), corneal staining with the Oxford grading scale, and non- invasive tear break-up time (NTBUT) with videokeratoscopy (Sirius Scheimpflug-Placido topography system, CSO, Florence, Italy) .
For TBUT measurement, a fluorescent-impregnated paper wetted with a drop of sterile saline solution was touched to the lower bulbar conjunctiva and the tear film was examined under cobalt blue light. The time between the last blink and the appearance of the first dry spot was recorded as TBUT, and less than 10 seconds was considered abnormal. Presence of corneal staining with fluorescein is represented by punctate dots on a series of panels. The Oxford grading scale divides corneal staining into six groups according to severity from 0 (absent) to 5 (severe) and the examiner compares the corneal staining pattern .
For the Schirmer test, a 35 × 5 mm filter paper strip was used without applying corneal anesthesia. The wetting values of the paper and the amount of tears produced during 5 minutes were calculated by placing the strip on the lateral third of the lower eyelid.
Videokeratoscopy was used for NTBUT measurement. With this method, the integrity of the tear film spread over the anterior surface of the cornea of the patients over time was evaluated. The initial TBUT was expressed as the time (seconds) between the moment the eyelid was opened again after one or more blinks. For videokeratoscopic measurement, the patient’s chin was positioned in the appropriate position and with correct focus. When the image became clear, the measurement was started by pressing a joystick button. The system automatically started measuring when the patient blinked twice, and the acquisition automatically stopped after the patient closed his or her eyelid.
SPSS 22 (IBM Corp., Armonk, NY, USA) was used for analyses. The Kolmogorov-Smirnov test was used for assessment of normal distribution. Data were expressed as mean ± standard deviation or median and range for continuous variables; for categorical variables, data were expressed as numbers and percentages (%). Comparisons of groups were made by the Student t-test and Mann-Whitney U tests, while analysis of correlations between variables was performed with the Pearson rank correlation coefficient. Values of p<0.05 were considered statistically significant.
This study included 29 IBD patients in remission (8 male, 21 female; 16 UC, 13 CD; mean age: 14.7±2.64 years) and 20 control subjects (3 male, 17 female). The mean disease duration of the patients was 32.1±12.3 months. Eleven IBD patients were receiving oral mesalamine therapy, 12 patients mesalamine and azathioprine therapy, 4 patients mesalamine and infliximab therapy, 1 patient infliximab-only therapy, and 1 patient mesalamine, infliximab, and azathioprine therapy. There was no significant difference between the IBD patients and control groups in terms of TBUT (p=0.50), corneal epithelial fluorescein staining (p=0.23), or Schirmer test (p=0.14).
The total test times of videokeratoscopy were 15±2.69 seconds and 15.3±2.7 seconds for the IBD and control groups, respectively, while the NTBUT times were 11.7±5.56 seconds and 12.4±4.9 seconds for the IBD and control groups, respectively. The total test times of videokeratoscopy (p=0.21) and NTBUT (p=0.50) were not significantly different between the IBD and control groups. The NTBUT value of CD patients (9.8±5.8) did not meet the clinical diagnostic criterion for dry eye, but it was found to be significantly lower than the values obtained among the UC patients and the control group (p=0.042).
There was no significant difference between the UC and CD patients in terms of TBUT (p=0.51), corneal epithelial fluorescein staining (p=0.43), Schirmer test (p=0.22), and total test time of videokeratoscopy (p=0.24). NTBUT times were 13.8±4.3 seconds, 9.8±5.8 seconds, and 12.4±4.59 seconds for the UC, CD, and control groups, respectively. There was a statistically significant difference between UC and CD patients and between CD patients and controls in terms of NTBUT (p=0.009 and p=0.033, respectively) (Figure 1).
According to the Pearson rank correlation coefficient, a weak positive correlation was found between age and test duration in the patient group (p=0.03, r=0.39). There was no correlation between drugs used in the treatment of the disease and TBUT, corneal epithelial fluorescein staining, or Schirmer test.
IBD is a group of chronic inflammatory diseases that cause systemic, immune-mediated, bowel damage; it is possible that organs and systems beyond the intestines may also be affected by this inflammation [1-3, 13]. The etiopathogenesis of IBD is thought to be the result of a dysregulated immune response to gut microbiota in a genetically predisposed host . EIMs have been confirmed to occur in 25-40% of IBD cases, affecting the musculoskeletal and mucocutaneous systems, the skin, and the hepatobiliary tract. However, EIMs may also occur before the classic signs of the disease are seen .
Ophthalmological manifestations of IBD in the literature were first reported by Crohn, who described keratomalacia and xerophthalmia in two UC patients in 1925. The incidence of ocular complications of IBD manifestations are reported to be seen more frequently in cases of CD than UC [14-18].
Knox et al. categorized ocular complications into 3 groups: primary, secondary, and incidental . For the management of primary ocular complications (keratopathy, uveitis, episcleritis, and scleritis), conservative or surgical treatment of the intestinal inflammation is usually sufficient. Secondary ocular complications can occur after primary complications or as a complication of treatment (posterior subcapsular cataract formation as a result of corticosteroid administration, scleromalacia due to scleritis, and night blindness due to hypovitaminosis as a result of a diet low in vegetables or intestinal resection). Conjunctivitis, photophobia, and subconjunctival hemorrhage are ocular symptoms that do not appear to be associated with IBD . Since ocular involvement may precede the emergence of intestinal symptoms, early diagnosis may also be effective in preventing long-term complications of IBD . On the other hand, the presence of ocular symptoms may not necessarily mean the presence of an active intestinal disease flare .
In this study, we evaluated dry eye disease in pediatric IBD patients and an age-matched control group. According to our results, there was a significant difference between UC and CD patients and between CD patients and controls in terms of NTBUT as measured by videokeratoscopy. The NTBUT value of CD patients (9.8±5.8) did not meet the clinical diagnostic criterion for dry eye, but it was found to be significantly lower than the values obtained among UC patients and the control group. It was observed that there were no dry eye findings that could be evaluated as clinically significant in the pediatric IBD patients included in this study. There were no differences between the groups in terms of the Schirmer test, TBUT, or corneal epithelial fluorescein staining.
Doğan et al. found that tear film quality was lower in IBD patients compared to a control group, but there was no significant difference in tear film quality between UC and CD patients . Felekis et al. analyzed 60 IBD patients (37 with UC and 23 with CD) in terms of dry eye disease with Schirmer’s tests and rose- Bengal corneal staining and concluded that 50% of the patients had dry eye complaints (23). Cury and Moss found that dry eye disease was present in 44% of the patients in their study, with 48 CD patients, 40 UC patients, and 24 controls . Lee et al. examined 36 patients with CD and 25 patients with UC and reported that the most common incidental ocular manifestation was dry eye disease at a rate of 57% compared to 21.3% in the control group . The most common ocular complication in two different countries was reported as dry eye by Cury and Moss . Li et al. reported ophthalmological EIMs including dry eye disease at a rate of 2% in IBD patients in the Chinese population, a rate significantly lower than those reported in studies of Caucasian patients .
Barta et al. compared the tear film parameters and subjective symptoms of dry eye disease in IBD (UC or CD) patients with those of healthy controls and reported that the objective dry eye parameters were better in UC patients than in CD patients. CD patients tended to develop dry eye disease more frequently than UC patients . Curry and Moss stated that aminosalicylic acid (ASA) intake of more than 3 g per day was associated with dry eye . In a cohort study conducted with 305 patients, the frequency of dry eye was found to be 41.7%, and it was reported that symptoms and ocular inflammation were not proportional. Barta et al. did not find any association between ASA treatment and dry eye, but they did find statistical significance in terms of dry eye parameters between the CD and UC groups among patients who received immunosuppressive therapy and TNF- alpha blocking agents . We did not find any statistical significance between CD and UC patients in terms of the drugs used in treatment and dry eye disease.
Regular ophthalmologic follow-up of patients is important not only for dry eye disease but also for early diagnosis and treatment of all possible ophthalmologic complications. The NTBUT is a non-invasive method in comparison to the standard TBUT measurement. Eye examination by NTBUT by videokeratoscopy for pediatric IBD patients may aid in early diagnosis of dry eye. Thus, regular follow-up of these patients may be preventive in terms of complications due to ocular surface inflammation.
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Conflict of interest
1. Okou DT, Kugathasan S. Role of genetics in pediatric inflammatory bowel disease. Inflamm Bowel Dis. 2014;20(10): 1878–84.
2. IBD Working Group of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition. Inflammatory bowel disease in children and adolescents: recommendations for diagnosis–the Porto criteria. J Pediatr Gastroenterol Nutr. 2005;41(1):1-7.
3. Levine JS, Burakoff R. Extraintestinal manifestations of inflammatory bowel disease. Gastroenterol Hepatol (N Y). 2011;7(4):235-41.
4. Fine S, Nee J, Thakuria P, Duff B, Farraye FA, Shah SA. Ocular, Auricular, and Oral Manifestations of Inflammatory Bowel Disease. Dig Dis Sci. 2017;62(12):3269- 79.
5. Ardizzone S, Puttini PS, Cassinotti A, Bianchi Porro G. Extraintestinal manifestations of inflammatory bowel disease. Dig Liver Dis 2008;40(2):253–9.
6. Troncoso LL, Biancardi AL, de Moraes HV Jr, Zaltman C. Ophthalmic manifestations in patients with inflammatory bowel disease: A review. World J Gastroenterol. 2017;23(32):5836-48.
7. Cloché V, Buisson A, Tréchot F, Batta B, Locatelli A, Favel C, et al. Ocular symptoms arenot predictive of ophthalmologic inflammation in inflammatory boweldisease. Dig Liver Dis. 2013;45(3):195-9.
8. Jose FA, Heyman MB. Extraintestinal manifestations of inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2008;46:124–33.
9. Harbord M, Annese V, Vavricka SR, Allez M, Barreiro-de Acosta M, Boberg KM, et al; European Crohn’s and Colitis Organisation. The First European Evidence- based Consensus on Extra-intestinal Manifestations in Inflammatory Bowel Disease. J Crohns Colitis. 2016;10(3):239-54.
10. Onal IK, Yuksel E, Bayrakceken K, Demir MM, Karaca EE, Ibis M, et al. Measurement and clinical implications of choroidal thickness in patients with inflammatory bowel disease. Arq Bras Oftalmol. 2015;78(5):278-82.
11. Yamaguchi T. Inflammatory Response in Dry Eye. Invest Ophthalmol Vis Sci. 2018;59(14):DES192-DES199.
12. Bron AJ, Evans VE, Smith JA. Grading of corneal and conjunctival staining in the context of other dry eye tests. Cornea 2003;22:640–50.
13. Lee HJ, Song HJ, Jeong JH, Kim HU, Boo SJ, Na SY. Ophthalmologic manifestations in patients with inflammatory bowel disease. Intest Res. 2017;15(3):380-387.
14. Barta, Z., Czompa, L., Rentka, A., Zold, E., Remenyik, J., Biro, A., et al. Evaluation of Objective Signs and Subjective Symptoms of Dry Eye Disease in Patients with Inflammatory Bowel Disease. Biomed Res Int. 2019;2019:8310583.
15. Doğan M, Özcan S, Acartürk G, Özdemir Ç. Conjunctival Impression Cytology and TearFilm Changes in Patients With Inflammatory Bowel Disease. Eye Contact Lens. 2018 ;44 Suppl 2:S420-S5.
16. Czompa L, Barta Z, Ziad H, Nemeth G, Rentka A, Aszalos Z, et al. Corneal Manifestations of Inflammatory Bowel Disease. Semin Ophthalmol. 2019;34(7- 8):543-50.
17. Chidi-Egboka NC, Briggs NE, Jalbert I, Golebiowski B. The ocular surface in children: A review of current knowledge and meta analysis of tear filmstability and tear secretion in children. Ocul Surf. 2019;17(1):28-39.
18. Bhandari V, Reddy JK, Relekar K, Ingawale A, Shah N. Non-invasive assessment of tear film stability with a novel corneal topographer in Indian subjects. Int Ophthalmol. 2016;36(6):781-90.
19. Knox DL, Schachat AP, Mustonen E. Primary, secondary and coincidental ocular complications of Crohn’s disease. Ophthalmology. 1984 ;91(2):163-73. 20. Doğan AŞ, Gürdal C, Köylü MT. Does Dry Eye Affect Repeatability of Corneal Topography Measurements? Turk J Ophthalmol. 2018;48(2):57-60.
21. Yilmaz S, Aydemir E, Maden A, Unsal B. The prevalence of ocular involvement in patients with inflammatory bowel disease. Int J Colorectal Dis. 2007;22(9):1027- 30.
22. Czompa L, Barta Z, Ziad H, Nemeth G, Rentka A, Aszalos Z, et al. Corneal Manifestations of Inflammatory Bowel Disease. Semin Ophthalmol. 2019;34(7- 8):543-50.
23. Felekis T, Katsanos K, Kitsanou M, Trakos N, Theopistos V, Christodoulou D, et al.. Spectrum and frequency of ophthalmologic manifestations in patients with inflammatory bowel disease: a prospective single-center study. Inflamm Bowel Dis. 2009;15(1):29-34.
24. Cury DB, Moss AC. Ocular manifestations in a community-based cohort of patients with inflammatory bowel disease. Inflamm Bowel Dis. 2010;16(8):1393- 6.
25. Li YC, Li WZ, Wu CR, Feng Y, Ren L, Mi C, et al. Prevalence and characteristics of ophthalmological extra-intestinal manifestations in Chinese patients with inflammatory bowel disease. Int J Ophthalmol. 2016;9(10):1476-9.
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Esra Polat, Betül İlkay Sezgin Akçay, Aslıhan Doğan Dursun, Nelgin Gerenli, Hasret Civan Ayyıldız. Evaluation of ocular surface parameters in children with inflammatory bowel disease. Ann Clin Anal Med 2021;12(10):1132-1135
Pain catastrophizing in patients with primary dysmenorrhea: Its relationship with temperament traits and impulsivity
Hatice Harmancı 1, Jule Eriç Horasanlı 2
1 Department of Psychology, Faculty of Social Sciences and Humanities, KTO Karatay University, 2 Department of Gynecology and Obstetrics, Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
DOI: 10.4328/ACAM.20669 Received: 2021-04-26 Accepted: 2021-06-17 Published Online: 2021-07-02 Printed: 2021-10-01 Ann Clin Anal Med 2021;12(10):1136-1140
Corresponding Author: Hatice Harmancı, KTO Karatay University, Psychology Department, C Block, 42020, Karatay, Konya, Turkey. E-mail: email@example.com P: +90 505 355 81 94 Corresponding Author ORCID ID: https://orcid.org/0000-0003-4064-5391
Aim: The objective of this study was to evaluate the relationship between clinical pain and pain catastrophizing (PC) cognition in primary dysmenorrhea (PD). Moreover, this study evaluates the effects of temperament characteristics and impulsivity levels on PC.
Material and Methods: In this study, 258 patients who were diagnosed with PD and met the inclusion criteria were included. According to the Andersch and Milsom Scale, the patients were divided into two groups. Group 1 consisted of those whose functionality was impaired at moderate and severe levels due to pain, whereas Group 2 consisted of those whose functionality was not impaired at all and those who are mildly affected. Socio-demographic data form and the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire, Pain Catastrophizing Scale, and the Short Form of Barratt Impulsive- ness Scale were applied to all patients.
Results: The functionality of patients with PD was significantly impaired by 53.1%, and the main symptom determining functionality was pain. The total and subscale PCS score averages in Group 1 were significantly higher than those in Group 2. Cyclothymic temperament and impulsivity explained 20% of the vari- ance on PC.
Discussion: Psychological factors have an important role in managing PD. For this reason, both gynecological and psychiatric evaluations of patients with PD during treatment and the multidisciplinary treatment approach to be applied when necessary will improve the patients’ quality of life and help them easily cope with symptoms.
Keywords: Primary Dysmenorrhea; Pain Catastrophizing; Temperament; Impulsivity
Primary dysmenorrhea (PD) is a gynecological problem that develops without organic pathology and is common in young women. Its most basic symptom is abdominal pain, which occurs with the onset of menstrual bleeding and continues for 2–3 days. Pain is mostly localized in the suprapubic region, but can spread to the waist and lower legs. The severity of pain varies among women and has intermittent and spasmodic characteristics . In addition, physical and mental complaints can accompany the pain. PD is considered a public health problem, as its symptoms disrupt a person’s functionality in work, school, and social areas and cause economic losses .
The most important symptom determining functionality in dysmenorrhea is pain. Pain perception, which is a subjective concept, depends on biopsychosocial factors, and mutual interactions between these factors exist . In the literature, psychiatric disorders frequently accompany dysmenorrhea. According to these studies, mental complaints increase patients’ sensitivity to their bodily sensations and make them perceive their somatic complaints more negatively . Somatic complaints recurring in each menstrual period can create a feeling of helplessness, causing deterioration in perception of pain, and may cause pain catastrophizing (PC) . The concept of PC, which contains negative pain cognition, such as terrible and unbearable pain, is an expression of mental strain in chronic painful diseases  and is considered an important factor in determining the prognosis of PD .
Studies examining the type of personality of patients with dysmenorrhea have revealed that neurotic personality traits are more pronounced in these patients [7,8]. In addition, according to these studies, personality traits are effective in influencing an individual’s perception and management of pain in chronic painful diseases. Moreover, a neurotic personality characterized by a predisposition to experiencing negative emotions, emotional imbalance, and failure in interpersonal relationships comes to the fore [9,10]. Goubert et al. (2004) have determined that people with neurotic characteristics perceive pain as a threat, catastrophize pain, and, therefore, have difficulty managing the pain. The same study has revealed that neuroticism is the intermediary factor between the severity of pain and PC .
In the literature, studies have examined the personality characteristics of patients with dysmenorrhea. However, no studies have focused on temperament characteristics and examined the effect of temperament on pain. Similarly, no studies have assessed the level of PC in patients with PD. Thus, this study examined the relationship between clinical pain and PC cognition that is common in PD. Furthermore, this study evaluated the effects of temperament characteristics and impulsivity levels on PC.
Material and Methods
Participants and study design
This was a cross-sectional and descriptive study. The research group was composed of patients who applied to a University Hospital, Obstetrics and Gynecology Clinic between February 2018 and March 2019 and presented with severe menstrual pain. The study included women diagnosed with PD, aged between 18 and 45 years, and volunteered to participate in the study. Patients diagnosed with secondary dysmenorrhea, those with a history of psychiatric illness, those with any disease that may be related to pain, those who have any impediment in filling the scale forms used in the study because of any physical or mental disorder, and those who did not complete the scale forms and did not sign the informed consent form were excluded from this study.
Two hundred fifty-eight patients were finally enrolled in this study and divided into two groups according to their level of functionality using the Andersch and Milsom Scale . Group 1 included patients whose functionality was moderately (grade 2) or severely (grade 3) affected by dysmenorrhea, and Group 2 consisted of those whose functionality was not affected at all (grade 0), and those who were rarely affected (grade 1). Participants in both groups were asked to complete the prepared scale forms after completing the necessary medical procedures. In this study, we used a sociodemographic data form and the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire (TEMPS-A), Pain Catastrophizing Scale (PCS), and the Short Form of Barratt Impulsiveness Scale (BIS-11-SF). The study was conducted according to Helsinki Declaration. We obtained necessary permits for this study from KTO Karatay University’s Ethics Board of Drug and Non-Medical Device Researches (26.12.2017; no: 2017/008).
Socio-demographic data form; The form has been prepared by the authors. The form included open-ended questions on participants’ age, years of education, occupation, marital status, and general health status.
Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire (TEMPS-A); The scale was developed by Akiskal (1996) to evaluate the dominant affective temperament in individuals . The scale, which is based on self-notification has five subdimensions: depressive, hyperthymic, irritable, cyclothymic, and anxious temperament. Validity and reliability studies on the Turkish version of the scale were conducted by Vahip et al. (2005) , which have reported a reliability, calculated separately for each temperament characteristic, between 0.73 and 0.93 and Cronbach’s alpha between 0.77 and 0.85.
Pain Catastrophizing Scale (PCS); The scale was developed by Sullivan et al. (1995) to determine the level of catastrophizing associated with the feelings and thoughts of people having pain symptoms . The self-reporting-based scale is a Likert- type scale. The scale has three subdimensions: rumination, magnification, and helplessness. The study on the Turkish scale’s validity and reliability was conducted by Ugurlu et al. (2017) , who have reported reliability between 0.73 and 0.93, Cronbach’s alpha of 0.95, and internal consistency coefficient of 0.83.
Barratt Impulsiveness Scale Short Form (BIS-11-SF); The scale developed to measure individuals’ level of impulsivity was revised by Patton et al. (1995) . The Likert-type scale is based on self-reporting and has three subdimensions: non- planning impulsiveness, motor impulsiveness, and attention impulsivity. The study on the validity and reliability of the Turkish version of the scale was conducted by Tamam et al. (2013) , who have reported that the Cronbach’s alpha value was between 0.64 and 0.82, and the internal consistency coefficient was high, although it varied in the subdimensions. Statistical Analyses
The obtained data were analyzed using the Statistical Package for Social Sciences version 25.0 (IBM Corp., Armonk, NY, USA). The results are presented in number, percentage, and average. Regression analysis was performed to examine the relationships between variables and whether PC, impulsivity, and temperament variables differ in patient groups, and hierarchical regression analysis was performed on independent groups using a t-test to determine the predictive effects of temperament characteristics and impulsivity on PC.
The study was conducted on 258 patients diagnosed with PD who met the inclusion criteria. In all patients, the primary complaint was pain. According to the Andersch and Milsom Scale, 42 of the women were grade 0, 79 were grade 1, 21 were grade 2, and 116 were grade 3. Furthermore, 137 patients (53.1%) whose functionality was significantly affected by pain were included in Group 1 (grade 2 + grade 3); 121 patients (46.9%) whose functionality was rarely affected by pain or unaffected were included in Group 2 (grade 0 + grade 1). In this way, the variables were examined to differentiate the pain perception in people who have received the same diagnosis. Demographic variables were similar in both groups. The demographic characteristics of all groups are shown in Table 1. According to the study results, total and subscale PCS score averages in Group 1 were significantly higher than those in Group 2. When both groups were examined according to their temperament characteristics, depressive, cyclothymic, irritable, and anxious temperament scores in Group 1 were significantly higher. The total BIS-11-SF scores, motor impulsiveness and attentional impulsiveness subscale scores in Group 1 were significantly higher than those in Group 2. The subscale scores and results of the t-test are shown in Table 2.
Significant results were obtained in the correlation analysis between PC levels, temperament characteristics, and impulsivity of patients in Group 1. In addition, significant positive correlations were observed between cyclothymic temperament (r = 0.244) and the total PCS score, and between irritable temperament (r = 0.269) and the total PCS score. A significant positive correlation was found between cyclothymic temperament (r = 0.210) and the helplessness subscale of PCS and between irritable temperament (r = 0.220) and the helplessness subscale of PCS. Moreover, a significant positive correlation was perceived between magnification and irritable temperament (r = 0.251), magnification and anxious temperament (r = 0.181), rumination and cyclothymic temperament (r = 0.280), and irritable temperament (r = 0.272) and anxious temperament (r = 0.194). A weak positive correlation was determined between PCS and impulsivity in the rumination and attentional impulsiveness subscales (r = 0.173). A hierarchical regression analysis was performed to examine the predictive effects of personality traits and impulsivity on PC in patients with PD. Within this context, analyses on multiple correlation problems were conducted, and the Durbin–Watson value was determined to be 1.64. In the study of Model 1 in Table 3, temperament characteristics in patients with PD have a positive and significant predictive effect on PC (F =11.13; p < 0.05). The adjusted R2 value is 0.16. This result shows that temperament characteristics explain 16% of the variance on PC. In the second model, the addition of impulsivity variables explained the variance of 4%, and this change in R2 was significant (F = 9.15; p < 0.05). Considering the values in Model 1, only cyclothymic temperament has a significant predictive effect on PC. A 1-point change in cyclothymic temperament causes a 0.32-point change in PC. In Model 2, attentional impulsiveness had an additional significant contribution in the model (p < 0.05). All independent variables appear to explain the 20% variance in PC.
This study found that the functionality of patients with PD was significantly impaired by 53.1%, and the main symptom determining functionality was pain. PC levels of the patients with impaired functionality are significantly higher, and PC cognition is affected by the temperament characteristics and impulsivity levels.
Pain is a chronic and life-threatening symptom that patients with PD experience at an early age . Pain beginning in adolescence, when brain development continues, negatively affects the cognitive development of patients with PD, predisposing them to depression  and other mental disorders . Depression and anxiety increase pain sensitivity and sensitivity to a more negative perception of somatic complaints . The mental health of patients with dysmenorrhea affects their perception of pain and ability to find rational solutions for pain. In the study by Cosic et al. (2013) involving 149 participants, PC was significantly higher in women with dysmenorrhea, and these patients used more analgesic drugs . McPeak et al. (2018) have reported that PC was more common in women with secondary dysmenorrhea due to endometriosis, which significantly impaired these patients’ quality of life . PC is a cognitive error in which a person describes the pain they are experiencing in a more catastrophized way and unbearable than it is. In this study, unlike publications in the literature, only patients with PD were evaluated. It was concluded that PC scores were significantly higher in the group with more impaired functionality than those diagnosed with the same disease. From this viewpoint, the results of the research were evaluated in line with the literature.
Personality is the sum of all traits an individual has genetically and those subsequently acquired that differentiate them from others. Although temperament and personality are concepts used interchangeably, temperament more often represents the genetic dimension of personality . In the literature, no studies have examined the temperament characteristics of patients with dysmenorrhea, and different results were reported in studies investigating personality characteristics. In the study by Khalajinia et al. (2008), introverted, neurotic, and insecure personality traits were more pronounced in patients with dysmenorrhea . Among studies involving patients with PD only, some have suggested that neurotic, anxious, and extroverted personality traits  are observed more in these patients, where others have suggested that the personality traits of these patients do not differ . In this study, patients with PD had higher scores in depressive, cyclothymic, irritable, and anxious temperament characteristics. These temperament scores were significantly higher in patients with impaired functionality. Depressive, cyclothymic, irritable, and anxious temperament traits are associated with neurotic personality traits. The results of this study were evaluated based on these comments and in compliance with the literature.
Impulsivity, which is considered a personality trait, is characterized by problems including impatience, intolerance, and lack of attention . In the literature, few studies have examined the level of impulsivity in patients with dysmenorrhea. In these studies, impulsive traits may be observed in patients with dysmenorrhea whose quality of life is impaired, and self- mutilating behaviors are more common in these patients . This study found that impulsivity and its subscales, motor and attentional impulsiveness, were significantly increased in patients with PD with intense, excessive pain. PD, in which pain is a cyclical and severe symptom, is difficult to tolerate for an individual with impulsive characteristics. It is also difficult to expect that these individuals will develop a rational assessment of pain and be able to produce a healthy solution. When evaluated from this viewpoint, our findings are compliant with the literature.
Pain perception is a cognitive function affected by many variables, such as individual personality and temperament characteristics, mental status, and environmental factors. In the literature, studies have focused on the relationship between pain perception in chronic painful diseases and personality traits. According to Muris et al. (2008), neurotic personality traits reduce a person’s tolerance to pain, as a result of which pain is experienced in a catastrophized way, making the pain severe . According to Nitch et al. (2004), difficulty in managing pain and emotional difficulties in chronic painful diseases lead to exacerbation of neurotic personality traits . In the literature, no studies have investigated the relationship of pain perception with personality or temperament characteristics in patients with dysmenorrhea. According to the hierarchical regression model in this study, which we think will contribute to the literature in this sense, cyclothymic temperament explains 16% of PC. This finding has been interpreted as an individual with a cyclothymic temperament, where emotional lability and intolerance are evident, can cause PC by negating PD pain to a greater extent than it actually is. When we added the impulsivity component to the established model, we found that only attention deficit was 4%. There are no studies in the literature examining the relationship between PC and impulsivity. The effects of attention deficit on PC are not high; however, it has been thought that it can disrupt the rational assessment of pain by difficulty in focusing on what is being experienced in the process of pain and cause failure of pain management.
In conclusion, an important symptom determining functionality in PD is pain. In patients with severe pain, pain perception is impaired, and the pain is catastrophized. PC differs according to the individual’s temperament characteristics and the level of impulsivity. In addition to the gynecological treatment of patients with PD with poor symptom management, conducting a psychiatric evaluation and implementing the necessary interventions are important. Multidisciplinary evaluation will increase individuals’ quality of life and make a positive contribution to their functionality.
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Animal and human rights statement
Conflict of interest
1. De Sanctis V, Soliman AT, Elsedfy H, Soliman NA, Elalaily R, El Kholy M. Dysmenorrhea in adolescents and young adults: a review in different countries. Acta Biomed. 2016; 87(3):233-46.
2. Emans SJ, Laufer RL, Goldstein DP. Pediatric and Adolescent gynecology. Philadelphia: Lippincott, Williams&Wilkins; 2005.
3. Patel V, Tanksale V, Sahasrabhojanee M, Gupte S, Nevrekar P. The burden and determinants of dysmenorrhea: a population-based survey of 2262 women in Goa, India. BJOG. 2016; 113(4):453-63.
4. McPeak AE, Allaire C, Williams C, Albert A, Lisonkova S, Yong PJ. Pain catastrophizing and pain health-related quality-of-life in endometriosis. Clin J Pain. 2018; 34(4):349-56.
5. Eccleston C, Crombez G, Scotford A, Clinch J, Connell H. Adolescents chronic pain: patterns and predictors of emotional distress in adolescents with chronic pain and their parents. Pain. 2004; 108(3):221-9.
6. Carey ET, Martin CE, Siedhoff MT, Bair ED, As-Sanie S. Biopsychosocial correlates of persistent postsurgical pain in women with endometriosis. Int J Gynaecol Obstet. 2014; 124(2):169-73.
7. Khalajinia Z, Refahi S, Dehghan MH. Assessment of personality traits in dysmenorrheic young women. Res J Biol Sci. 2008; 3(8):944-6.
8. Faramarzi M, Salmalian H. Association of psychologic and nonpsychologic factors with primary dysmenorrhea. Iran Red Crescent Med J. 2014; 16(8):e16307.
9. Muris P, Meesters C, van den Hout A, Wessels S, Franken I, Rassin E. Personality and temperament correlates of pain catastrophizing in young adolescents. Child Psychiatry Hum Dev. 2007; 38(3):171-81.
10. Nitch SR, Boone KB. Normal personality correlates of chronic pain subgroups. J Clin Psychol Med Setting. 2004; 11(3):203-9.
11. Goubert L, Crombez G, Van Damme S. The role of neuroticism, pain catastrophizing and pain-related fear in vigilance to pain: a structural equations approach. Pain. 2004; 107(3):234-41.
12. Andersch B, Milsom I. An epidemiologic study of young women with dysmenorrhea. Am J Obstet Gynecol. 1982; 144(6):655-60.
13. Akiskal HS. The temperamental foundations of affective disorders, interperonal origin and course of affective disorders. London Gaskell: Royal College of Psychiatrists; 1996.
14. Vahip S, Kesebir S, Alkan M, Yazici O, Akiskal KK, Akiskal HS. Affective temperaments in clinically-well subjects in Turkey: initial psyhometric data on the TEMPSA. J Affect Disord. 2005; 85(1-2):113-25.
15. Sullivan MJ, Bishop SR, Pivik J. The pain catastrophizing scale: development and validation. Psychol Assess. 1995; 7(4):524–32.
16. Ugurlu M, Ugurlu GK, Erten S, Caykoylu A. Validity of Turkish form of Pain Catastrophizing Scale and modeling of the relationship between pain-related disability with pain intensity, cognitive, and emotional factors. Psychiatry and Clinical Psychopharmacology. 2017; 27(2):189-96.
17. Patton JH, Stanford MS, Barratt ES. Factor structure of the Barratt impulsiveness scale. J Clin Psychol. 1995; 51(6):768-74.
18. Tamam L, Gulec H, Karatas G. Short form of Barratt ımpulsiveness scale (BIS- 11-SF) Turkish adaptation study. Noro Psikiyatr Ars. 2013; 50(2):130-4.
19. Walsh TM, LeBlanc L, McGrath PJ. Menstrual pain intensity, coping, and disability: the role of pain catastrophizing. Pain Med. 2003; 4(4):352-61.
20. Beal SJ, Dorn LD, Sucharew HJ, Sontag-Padilla L, Pabst S, Hillman J. Characterizing the longitudinal relations between depressive and menstrual symtoms in adolescent girls. Psychosom Med. 2014; 76(7):547-54.
21. Gagua T, Tkeshelashvili B, Gagua D, Mchedlishvili N. Assessment of anxiety and depression in adolescents with primary dysmenorrhea: a case-control study. J Pediatr Adolesc Gynecol. 2013; 26(6):350-4.
22. Zuckerman RM, Silton RL, Tu FF, Eng JS, Hellman KM. Somatic symptoms in women with dysmenorrhea and noncyclic pelvic pain. Arch Womens Ment Health.
23. Cosic A, Ferhatovic L, Banozic A, Kraljevic S, Maric A, Sapunar D, et al. Pain catastrophizing changes during the menstrual cycle. Psychol Health Med. 2013; 18(6): 735-41.
24. Yasar O, Yildirim D, Turhan S. Primary dysmenorrhea and personality. Jinekoloji-Obstetrik ve Neonatoloji Tıp Dergisi/ Journal of Gynecology-Obstetrics and Neonatology Medicine. 2020; 17(2):364-7.
25. Liu X, Liu ZZ, Fan F, Jia CX. Menarche and menstrual problems are associated with non-suicidal self-injury in adolescent girls. Arch Womens Ment Health. 2018; 21(6): 649-56.
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Hatice Harmancı, Jule Eriç Horasanlı. Pain catastrophizing in patients with primary dysmenorrhea: Its relationship with temperament traits and impulsivity. Ann Clin Anal Med 2021;12(10):1136-1140
A study of the possible role of taurine, a cystine catabolic product, on adipogenesis in vitro
Hagar Elkafrawy 1, 2, Radwa Mehanna 2, 3, Fayrouz Ali 1, Ayman Barghash 1, Iman Dessouky 1, Amany Elshorbagy 3
1 Department of Medical Biochemistry, 2 Center of Excellence for Research in Regenerative Medicine and Applications (CERRMA), 3 Department of Physiology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
DOI: 10.4328/ACAM.20673 Received: 2021-04-27 Accepted: 2021-06-29 Published Online: 2021-07-30 Printed: 2021-10-01 Ann Clin Anal Med 2021;12(10):1141-1146
Corresponding Author: Hagar Elkafrawy, Department of Medical Biochemistry, Center of Excellence for Research in Regenerative Medicine and Applications (CERRMA), Faculty of Medicine, Alexandria University, Alexandria, Egypt. E-mail: firstname.lastname@example.org P: +20 100 966 75 96 Corresponding Author ORCID ID: https://orcid.org/0000-0002-1591-1689
Aim: Taurine is a sulfur-containing product of the sulfur amino acid cysteine via the inducible enzyme cysteine dioxygenase (CDO). Plasma cysteine is associ- ated with human obesity, but it is unknown whether this is mediated by cysteine itself or also through its catabolic products.
The aim of this study was to test the role of taurine in adipogenesis through inducing adipogenic differentiation of stromal vascular fraction (SVF) progenitors and preadipocytes in cystine-limiting media with and without taurine supplementation.
Material and Methods: Adipogenic differentiation was induced at limiting cystine concentrations with or without 30 μM taurine supplementation. Oil Red O staining of accumulated lipid and mRNA expression of PPARG1 were assessed as endpoints of adipogenic differentiation. mRNA expression of CDO1 was also measured.
Results: From day 3 of differentiation, small lipids droplets started to appear. On day 8 of differentiation, the cells rounded up to a more spherical shape, and clusters of mature adipocytes filled with lipid droplets were clearly visible. Oil Red O staining showed no difference in lipid accumulation in cells differentiated with or without taurine supplementation (percent area stained = 4.6% vs. 4.7%, P= 0.97), and no difference in lipid droplet size (P= 0.25). Gene expression analysis also revealed no significant effect of taurine supplementation on mRNA expression of PPARG1 (P= 0.92) or CDO1 (P= 0.086).
Discussion: In conclusion, taurine supplementation had no significant influence on adipogenesis in the presence of limiting cysteine concentrations. The mecha- nistic effects of different sulfur- containing compounds on human adipogenesis deserve further investigations.
Keywords: Cystine; Taurine; Adipogenesis; Obesity; Sulfur Amino Acids
Sulfur amino acids (SAA) play a crucial role in the maintenance of cellular redox state and capacity to detoxify free radicals, reactive oxygen species and other toxic compounds . Methionine and cysteine are the two primary sulfur amino acids in mammals. Methionine is an essential amino acid, obtained from the diet, while cysteine is a semi-essential amino acid synthesized from methionine . Taurine is the most abundant free amino acid in the body and is synthesized in mammals in 2 ways: either from the oxidation of cysteine via cysteine dioxygenase (CDO), or from the oxidation of cysteamine by cysteamine (2-aminoethanethiol) dioxygenase (ADO) . Emerging evidence suggests that SAA are linked to energy metabolism in humans . Plasma total cysteine was correlated with obesity and fat mass in humans , dietary animal models also suggest a role of cysteine in the regulation of body fat mass . In vitro, ascending cystine concentrations enhanced adipogenic differentiation of 3T3-L1 cells in a dose-dependent manner . Cysteine dioxygenase (CDO) catabolizes excess cysteine and is necessary for hypotaurine/taurine production from cysteine. A number of animal studies have revealed anti- obesity effects of taurine [6,7]. However, limited data are available regarding the effects of taurine on body weight and obesity in humans .
CDO concentration in liver and adipose tissue is regulated by cysteine availability via regulation of CDO degradation . Cysteine dioxygenase might be a co-activator of PPARγ, and is required for adipogenesis via recruitment of PPARγ to the promoters of target genes .
PPARγ induces adipogenic differentiation and lipid accumulation by modulating several genes that regulate adipogenesis, lipid uptake and lipid metabolism . The insulin-sensitizing action of PPARγ agonists such as thiazolidinedione results from their ability to regulate the expression of proteins that modulate insulin action and serve as adipose remodeling agents that direct lipids into subcutaneous fat tissue containing small, insulin- responsive adipocytes . Taurine accumulated markedly both intracellularly and in the culture medium of mature adipocytes when medium was supplemented with cysteine . In rats, adipose tissue, like the liver, was shown to be an important site for the regulation of cysteine levels and for hypotaurine/taurine synthesis , but little evidence is available in humans.
The aim of the present study was to investigate whether the effects of cysteine on adipogenesis  are mediated by its catabolic product, taurine.
Material and Methods
The study was conducted at the Center of Excellence for Research in Regenerative Medicine Applications (CERRMA), Alexandria Faculty of Medicine. The experimental protocols were approved by the Medical Ethics Committee (IRB NO: 00012098-FWA- NO: 00018699), Faculty of Medicine, Alexandria University, Egypt. Human adipose tissue samples
Human white adipose tissue lipoaspirate (WAT) was obtained during elective abdominal liposuction procedures performed at Alexandria University Hospitals from 3 women who had given written informed consent. Donors were selected to be free of chronic disease as assessed by medical history and routine laboratory tests. Samples were obtained using the Water-Jet Assisted Liposuction (WAL) technique , and the sampling conditions during liposuction were optimized to ensure the quality of the cells obtained.
Isolation and culture of adipocyte precursor cells
The protocol for the isolation and culture of adipocyte precursor cells was modified from Bunnell et al , the steps are detailed below, and summarized in Figure 1. All cell culture reagents were obtained from Sigma-Aldrich (St. Louis, MO, US). Tissue culture plastics were obtained from Corning Incorporated Life Sciences (Corning, NY, US).
Isolation of adipocyte precursor cells
The lipoaspirate was washed several times with an equal volume of PBS + antibiotic /antimycotic (100 I.U./mL penicillin, 100 μg/mL streptomycin and 2.50 μg/mL amphotericin) until the adipose layer was yellow in color. For each wash, PBS was added, the bottle was gently swirled to mix, left for separation and infra-natant was aspirated and discarded. The final lipid layer was digested with 0.1% collagenase type IA dissolved in an equal volume of PBS, then filtered. The collagenase/ lipid mixture was then placed in a shaking 37 °C water bath for approximately 1 hour, and was gently swirled every 5-10 min to allow better digestion. After digestion, the infranatant containing the SVF was aspirated and an equal volume of complete media was added [DMEM 4.5 g/L glucose with L-glutamine, 10% fetal bovine serum and 1% antibiotics] to inactivate the collagenase, then centrifuged for 10 min at 300xg to collect the pellet of SVF. All SVF pellets were collected into one centrifuge tube, passed over 100 μm cell strainer, then centrifuged for 5 min at 300xg. Lysis of RBCs was done to yield a clear SVF pellet.
Cell culture and monitoring
After isolation, cells were then counted, and seeded into a 12- well plate (seeding density: 30000 cell/cm2) in complete media in 37c 5% CO2 incubator. The cells were monitored daily using an inverted phase contrast microscope, and the media was changed every 2 days. When the cells reached 75- 80% confluence, the adipocyte differentiation protocol was applied. The cells were then daily monitored until the 8th day of differentiation. Samples for PCR were collected on days 0 and 4 of differentiation, while Oil Red O staining was performed on day 8 (end of the differentiation protocol).
Differentiation of adipocyte precursor cells at different cystine concentrations
Methionine- and cysteine-deplete DMEM (Sigma-Aldrich #D0422) supplemented with 30 μM L-methionine (Sigma-Aldrich #M5308) and variable concentrations (10-50 μM) of L-cystine (Sigma-Aldrich #C7602) from individual stock solutions of L-methionine (20 mM) dissolved in H2O and L-cystine (10 mM) dissolved in 0.2 M HCl, were used. The concentration of cystine and methionine (30 μM) was selected based on previous studies in 3T3-L1 adipocytes .
To induce differentiation, cells were treated (on day 0) with an induction medium  (containing 1 μM dexamethasone, 58 μg/mL insulin, 0.5 mM 3-isobutyl-1-methylxanthine, and 200 μM indomethacin) and media was replaced with fresh induction media on day 2. On day 4, the cells were treated with insulin medium (containing 10 μg/mL insulin), and the medium was changed every 2 days till day 8, when clusters of mature adipocytes filled with lipid droplets were visible.
Effect of taurine supplementation on lipid accumulation and adipogenic gene expression.
To test the hypothesis that the CDO product, taurine, is the mediator of cystine effect on adipogenesis, human SVF was cultured under low cystine concentrations (15 μM) with or without 30 μM taurine supplementation. Then, Oil Red O staining and gene expression analysis of CDO1 and PPARG1 mRNA were assessed.
Reverse transcription-quantitative polymerase chain reaction (RTqPCR)
Isolation and reverse transcription of RNA
On day 0 and day 4 of differentiation, cells were washed twice with ice-cold PBS, lysed by 500 μL Qiazole and frozen at −80 °C until RNA isolation. Total RNA was isolated using a spin protocol (Qiagen RNeasy Mini Kit #74104). RNA concentrations and quality (260/280 ratio) were determined on a Nanodrop Spectrophotometer and stored at −80 °C. Total RNA (12.5–25 ng/μL) was reverse transcribed using a high-capacity cDNA reverse transcription kit (Life Technologies #4374966) on an Applied Biosystems GeneAmp PCR System thermal cycler with the following settings: 25 °C for 10 min, 37 °C for 120 min, 85 °C for 5 s, and 4 °C on hold. cDNA was stored at -20 until qPCR experiments.
qPCR and data quantification
Gene-specific regions were amplified from cDNA (5–10 ng/μL) with primers (100 nM each; Biosearch Technologies (Novato, CA, US)) and Maxima SYBR Green/ROX kit (Thermo Scientific #K0221) on an Applied BiosystemsTM StepOneTM Real-Time PCR System with the following settings: 25 μL reaction, 95°C for 10 min, followed by 40 cycles; 95°C for 15s, 60°C for 30s and 72°C for 30 s. Gene expression analysis was performed using the relative quantification (ΔΔCt) method. Results are presented as fold change relative to β-actin (2−ΔΔCt). The primer sequences are listed in Table (1).
Oil Red O triglyceride staining
To assess lipid accumulation, Oil Red O staining was performed on differentiated mature adipocytes on the 8th day of differentiation as described . Images were taken with an inverted camera-equipped microscope (Olympus CKX41) at 200x magnification and analyzed for mean lipid droplet size and percentage of lipid area using Fiji image analysis software (NIH, Bethesda, USA).
Data are presented as mean ± SEM and are compared across groups using Student’s independent t-test. P<0.05 was considered statistically significant. GraphPad Prism (version 8.3.1. for Windows) was used for data analysis.
Morphologic appearance of differentiated mature adipocytes in culture on days 3-8 of differentiation
Morphologic changes were closely monitored during differentiation.Startingfromthe3rddayofdifferentiation, small lipids droplets started to appear. On the 8th day of differentiation, the cells rounded up to a more spherical shape from a more elongated fibroblast shape, and clusters of mature adipocytes filled with lipid droplets were clearly visible. Adipocyte number and lipid droplet size increased in differentiated mature adipocytes cultured at ascending cystine concentrations.
Effect of taurine supplementation on lipid accumulation
In view of previous findings that taurine is markedly accumulated both intracellularly and in in the culture medium of mature adipocytes, but not preadipocytes in response to cysteine , we sought to test the hypothesis that the CDO product, taurine, is the mediator of cystine effect on adipogenesis . Morphologically, Oil Red O staining showed no difference in cells differentiated at low cystine with or without taurine supplementation (Figure 2. A). Quantification of the percentage lipid area stained revealed no significant difference in response to taurine supplementation (P= 0.97), (Figure 2.B). There was also no significant difference in the size of lipid droplets in cells differentiated in taurine-supplemented media versus non- supplemented media (P =0.251) (Figure 2.C).
Effect of taurine supplementation on adipogenic gene expression
Gene expression analysis also revealed that 30 μM taurine supplementation in the culture medium showed no significant increase in expression of PPARG (p=0.918) and CDO mRNA (p=0.086) compared to low cystine (Figure 3).
Evidence from epidemiological studies, animal models and murine adipocytes suggest that cyst(e)ine availability is related to adiposity and enhanced adipogenic differentiation [3,5]. However the mechanisms of cystine effect on adipogenesis need further investigations. Taurine, a catabolic product of cysteine is thought to play a role in adipogenesis. The aim of our
study was to investigate whether the effect of cystine on adipogenesis  is mediated through its catabolic product, taurine.
Extracellular cystine was previously shown to enhance adipogenic differentiation and PPARg expression in 3T3L1 cells in a dose-dependent manner . In the current study, we started by testing similar cystine concentrations (10-50 μM) on the differentiation of human preadipocytes . To induce differentiation of preadipocytes, our differentiation cocktail  included insulin, dexamethasone, IBMX. Indomethacin was used as PPARg agonist instead of rosiglitazone, since indomethacin has been shown to enhance adipogenic differentiation via multiple prostaglandin-dependent and independent mechanisms, in addition to PPARg induction [15,16]. Indomethacin also increases PPARg2 protein to levels that are higher than those observed with rosiglitazone, suggesting an effect of indomethacin on PPARg2 through post- transcriptional mechanisms .
Ueki I et al studied the pathways for taurine synthesis in 3T3- L1 cells during their adipogenic conversion. It was noted that CDO mRNA levels increased during adipogenic differentiation in response to cysteine or cysteamine treatment in adipocytes and were accompanied by increased taurine production , which suggests a role of taurine in adipogenesis. In the present study, primary human SVF including preadipocytes were cultured under limiting cystine concentrations with or without 30 μM taurine supplementation. The concentration of taurine was chosen to be similar to that reported in human plasma . Our data showed no significant effect of taurine supplementation on lipid accumulation, as assessed by quantification of total area stained and mean lipid droplet size. Taurine supplementation in the culture medium also had no significant effect on the mRNA expression of PPARG during adipogenesis. In support of our findings, Hou et al showed that, although the taurine transporter played an important role in the differentiation of human adipose-derived stem cells into adipocytes, alongside its substrates, hypotaurine and β-alanine, taurine failed to enhance adipogenesis in the same model .
The effect of taurine supplementation on CDO expression deserves further investigations. In our study, a non-significant trend for increased CDO gene expression was observed following taurine supplementation. The reason for this is unclear. Studies showed that adding taurine to cells grown in a taurine-free medium has little direct effect on CDO gene transcript levels. In contrast, taurine supplementation reduces transcript levels of the taurine transporter, TauT . CDO is also known to be regulated post-transcriptionally in response to changes in intracellular cysteine concentration via changes in the rate of CDO ubiquitination and degradation , the possibility of a similar post- transcriptional regulation by taurine warrants investigations.
The association between taurine and adiposity in animal and human studies is complex. While numerous studies have noted an anti-obesity effects of taurine in rodents, the evidence in humans is less clear. An early study on genetically obese mice, showed that twenty-week supplementation of taurine in genetically obese/hyperglycemic KK mice reduced body weight gain and abdominal fat compared with control KK mice . Moreover, Tsuboyama-Kasaoka et al demonstrated that dietary taurine supplementation prevented high-fat diet-induced obesity and increased resting energy expenditure in mice . Taurine was also shown to prevent obesity and to improve glucose tolerance in weaned mice fed a high-fat diet for 8 weeks . Additionally, taurine supplementation for 14 weeks significantly reduced body weight gain and weight of the white adipose tissues in mice fed a high-fat diet, and reduced the infiltration of macrophages and the production of inflammatory cytokines . Taken together, these observations suggest a possible role of taurine in the prevention of diet-induced obesity. Human studies, however, have failed to collectively document a clear anti-obesity effect of taurine supplementation. An early cross-sectional study in 60 populations across 25 countries worldwide found that 24-hour urinary taurine excretion, which is considered a marker for dietary taurine intake, was inversely associated with BMI and other markers of cardiometabolic risk . However, this finding may be explained by confounding, since the intake of at least one taurine-rich food, namely fish, is itself inversely associated with BMI . Indeed, a meta-analysis of 12 randomized controlled trials of taurine supplementation for durations ranging from 15 days to 6 months concluded that taurine has no significant effect on body mass index (BMI) , at doses ranging from 0.5 to 6 g/d. This conclusion is in line with our observation that taurine did not significantly influence human adipogenesis in the present study.
The main strength of the study is that primary preadipocytes were derived from volunteers of similar age, sex, BMI and ethnicity. The tested extracellular taurine concentration was physiologic, and in line with reported taurine levels in plasma . The study was designed primarily for proof of concept and more work is needed for elucidation of downstream mediators. Furthermore, while taurine had no significant effect on adipogenesis in our in vitro model, it cannot be determined conclusively that the same occurs in vivo, where metabolic, endocrine, and paracrine stimuli could modify its effects on preadipocytes.
In conclusion, taurine supplementation at concentrations similar to those observed in human plasma did not stimulate adipogenic differentiation in preadipocytes cultured at limiting cysteine concentrations. This suggests that previously reported effects of extracellular cystine on adipogenesis in 3T3L1 cells  may be independent of its catabolic product, taurine. The mechanistic effects of different sulfur containing compounds on human adipogenesis deserve further investigations.
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Conflict of interest
1. Townsend DM, Tew KD, Tapiero H. Sulfur containing amino acids and human disease. Biomed Pharmacother. 2004; 58(1):47-55. DOI:10.1016/j. biopha.2003.11.005
2. Ueki I, Stipanuk MH. 3T3-L1 adipocytes and rat adipose tissue have a high capacity for taurine synthesis by the cysteine dioxygenase/cysteinesulfinate decarboxylase and cysteamine dioxygenase pathways. J Nutr. 2009; 139(2):207- 14. DOI:10.3945/jn.108.099085
3. Elshorbagy AK, Kozich V, Smith AD, Refsum H. Cysteine and obesity: consistency of the evidence across epidemiologic, animal and cellular studies. Curr Opin Clin Nutr Metab Care. 2012; 15(1):49-57. DOI:10.1097/MCO.0b013e32834d199f
4. Elshorbagy AK, Church C, Valdivia-Garcia M, Smith AD, Refsum H, Cox R. Dietary cystine level affects metabolic rate and glycaemic control in adult mice. J Nutr Biochem. 2012; 23(4):332-40. DOI:10.1016/j.jnutbio.2010.12.009
5. Haj-Yasein NN, Berg O, Jernerén F, Refsum H, Nebb HI, Dalen KT. Cysteine deprivation prevents induction of peroxisome proliferator-activated receptor gamma-2 and adipose differentiation of 3T3-L1 cells. Biochim Biophys Acta Mol Cell Biol Lipids. 2017; 1862(6):623-35. DOI:10.1016/j.bbalip.2017.02.009
6. Lin S, Hirai S, Yamaguchi Y, Goto T, Takahashi N, Tani F, et al. Taurine improves obesity-induced inflammatory responses and modulates the unbalanced phenotype of adipose tissue macrophages. Mol Nutr Food Res. 2013; 57(12):2155- 65. DOI:10.1002/mnfr.201300150
7. Tsuboyama-Kasaoka N, Shozawa C, Sano K, Kamei Y, Kasaoka S, Hosokawa Y, et al. Taurine (2-Aminoethanesulfonic Acid) Deficiency Creates a Vicious Circle Promoting Obesity. Endocrinology. 2006; 147(7):3276-84. DOI:10.1210/en.2005- 1007
8. Murakami S. Role of taurine in the pathogenesis of obesity. Mol Nutr Food Res. 2015; 59:1353-63. DOI:10.1002/mnfr.201500067
9. Stipanuk MH, Ueki I, Dominy JE, Simmons CR, Hirschberger LL. Cysteine dioxygenase: A robust system for regulation of cellular cysteine levels. Amino Acids. 2009; 37(1):55-63. DOI:10.1007/s00726-008-0202-y
10. Deng P, Chen Y, Ji N, Lin Y, Yuan Q, Ye L, et al. Cysteine dioxygenase type 1 promotes adipogenesis via interaction with peroxisome proliferator- activated receptor gamma. Biochem Biophys Res Commun. 2015; 458(1):123-7. DOI:10.1016/j.bbrc.2015.01.080
11. Laplante M, Sell H, MacNaul KL, Richard D, Berger JP, Deshaies Y. PPAR-γ activation mediates adipose depot-specific effects on gene expression and lipoprotein lipase activity: Mechanisms for modulation of postprandial lipemia and differential adipose accretion. Diabetes. 2003; 52(2):291-9. DOI:10.2337/ diabetes.52.2.291
12. Meyer J, Salamon A, Herzmann N, Adam S, Kleine H-D, Matthiesen I, Ueberreiter K, et al. Isolation and differentiation potential of human mesenchymal stem cells from adipose tissue harvested by water jet-assisted liposuction. Aesthetic Surg J. 2015; 35(8):1030-9. DOI:10.1093/asj/sjv075
13. Bunnell BA, Estes BT, Guilak F, Gimble JM. Differentiation of adipose stem cells. Methods Mol Biol. 2008; 456:155-71. DOI:10.1007/978-1-59745-245-8_12
14. Ramírez-Zacarías JL, Castro-Muñozledo F, Kuri-Harcuch W. Quantitation of adipose conversion and triglycerides by staining intracytoplasmic lipids with Oil red O. Histochemistry. 1992; 97(6):493-7. DOI:10.1007/bf00316069
15. Styner M, Sen B, Xie Z, Case N, Rubin J. Indomethacin Promotes Adipogenesis of Mesenchymal Stem Cells Through a Cyclooxygenase Independent Mechanism. J Cell Biochem. 2010; 111(4):1042-50. DOI:10.1002/jcb.22793
16. Lehmann JM, Lenhard JM, Oliver BB, Ringold GM, Kliewer SA. Peroxisome proliferator-activated receptors α and γ are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J Biol Chem. 1997; 272(6):3406-10. DOI:10.1074/jbc.272.6.3406
17. Elshorbagy A, Jernerén F, Basta M, Basta C, Turner C, Khaled M, et al. Amino acid changes during transition to a vegan diet supplemented with fish in healthy humans. Eur J Nutr. 2017; 56(5):1953-62. DOI:10.1007/s00394-016-1237-6
18. Hou X, Wang Z, He Y, Ding F, Wang P, Liu X, et al. Taurine Transporter Regulates Adipogenic Differentiation of Human Adipose-Derived Stem Cells through Affecting Wnt/β-catenin Signaling Pathway. Int J Biol Sci. 2019; 15(5):1104-12. DOI:10.7150/ijbs.31794
19. Liu CL, Watson AM, Place AR, Jagus R. Taurine biosynthesis in a fish liver cell line (ZFL) adapted to a serum-free medium. Mar Drugs. 2017; 15(6):147. DOI:10.3390/md15060147
20. Stipanuk MH, Dominy JE, Lee JI, Coloso RM. Mammalian cysteine metabolism: New insights into regulation of cysteine metabolism. J Nutr. 2006; 136(Suppl.6):S1652S-9. DOI:10.1093/jn/136.6.1652s
21. Fujihira E, Takahashi H, Nakazawa M. Effect of Long-Term Feeding of Taurine in Hereditary Hyperglycemic Obese Mice. Chem Pharm Bull. 1970; 18(8):1636-42. DOI:10.1248/cpb.18.1636
22. Batista TM, Ribeiro RA, da Silva PMR, Camargo RL, Lollo PCB, Boschero AC, et al. Taurine supplementation improves liver glucose control in normal protein and malnourished mice fed a high-fat diet. Mol Nutr Food Res. 2013; 57(3):423- 34. DOI:10.1002/mnfr.201200345
23. Yamori Y, Liu L, Ikeda K, Miura A, Mizushima S, Miki T, et al. Distribution of twenty-four hour urinary taurine excretion and association with ischemic heart disease mortality in 24 populations of 16 countries: Results from the WHO- CARDIAC Study. Hypertens Res. 2001; 24(4):453-7. DOI:10.1291/hypres.24.453
24. Liaset B, Øyen J, Jacques H, Kristiansen K, Madsen L. Seafood intake and the development of obesity, insulin resistance and type 2 diabetes. Nutr Res Rev. 2019; 32(1):146-67. DOI:10.1017/S0954422418000240
25. Guan L, Miao P. The effects of taurine supplementation on obesity, blood pressure and lipid profile: A meta-analysis of randomized controlled trials. Eur J Pharmacol. 2020; 885:173533. DOI:10.1016/j.ejphar.2020.173533
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Hagar Elkafrawy, Radwa Mehanna, Fayrouz Ali, Ayman Barghash, Iman Dessouky, Amany Elshorbagy. A study of the possible role of taurine, a cystine catabolic product, on adipogenesis in vitro. Ann Clin Anal Med 2021;12(10):1141-1146
The effect of serum Magnesium levels on prognosis and mortality in patients with spontaneus intracranial hemorrhage
Rezan Karaali, Zeynep Karakaya
Department of Emergency, Katip Çelebi University Atatürk Training and Research Hospital, Izmir, Turkey
DOI: 10.4328/ACAM.20676 Received: 2021-05-05 Accepted: 2021-07-20 Published Online: 2021-08-09 Printed: 2021-10-01 Ann Clin Anal Med 2021;12(10):1147-1151
Corresponding Author: Rezan Karaali, Emergency Department, İzmir Katip Çelebi University, Atatürk Training and Research Hospital, Basın sitesi, Gazeteci Hasan Tahsin Caddesi, Karabağlar, 35150, İzmir, Turkey. E-mail: email@example.com P: +90 232 243 43 43 Corresponding Author ORCID ID: https://orcid.org/0000-0003-1831-2566
Aim: Non-traumatic intracranial hemorrhages are subarachnoid (SAH), intracerebral (ICH) and subdural (SH) events with a high risk of mortality and morbidity. Magnesium (Mg) plays neuroprotective and coagulation cascade roles. We tested the relationship between serum Mg levels at admission and severity scores and mortality in intracranial hemorrhages.
Material and Methods: Demographic, clinical, laboratory, and radiographic data were analyzed in this single-center prospective observational study. SAH patients were classified as mFisher score≥3 and mFisher score≤2, and ICH and SH patients were classified as ICHscore≥3 and ICHscore≤2. Blood Mg levels, severity scores and mortality were compared.
Results: One hundred ninety-five patients were enrolled, of which 35.4% were women and 64/6% were men. The median age was 70 years in ICH patients, 55 in SAH patients, and 68 in SH patients. Mg levels in cases with ICH score ≤2 were statistically significantly higher than in those with ICH score ≥3 (p<0.05). In the SAH group, Mg values in cases with mFisher scores ≤2 were statistically significantly higher than those in cases with mFisher scores ≥3 (p<0.05) ROC analysis was applied to determine Mg values identifying exitus patients. At a cut-off value of 1.83 (AUC: 0.775), the sensitivity was 89.87% (95%CI 81- 95.5) and the specificity 58.62% (95%CI 49.1-67.7) (p<0.05).
Discussion: Mg levels at admission time are associated with severity scores and mortality in patients with intracranial hemorrhages.
Keywords: Emergency; Intracerebral hemorrhage; Subarachnoid hemorrhage; Subdural hemorrhage; Magnesium
Non-traumatic intracranial hemorrhages are subarachnoid, intraparenchymal and subdural events with a severe risk of mortality and morbidity . Spontaneous intracerebral hemorrhage is responsible for 10-30% of acute cerebrovascular diseases. It is the most fatal form of stroke, affecting more than 1 million people worldwide. The most important factor determining 30-day mortality is hematoma volume and expansion [2-4].
Subarachnoid hemorrhage (SAH) refers to bleeding between the pia mater and the arachnoid mater and constitutes approximately 5% of all stroke cases . It frequently occurs as a result of intracranial aneurysm rupture. SAH is more common in women over 50, and one-month mortality rate is 45% . Cerebral arterial vasospasm is the most important complication of SAH. Blood flow to the arteries decreases as a result of cerebral arterial vasospasm, leading to delayed cerebral ischemia (DCI). Delayed cerebral ischemic infarction (DCII) can even occur due to DCI. DCI is also responsible for mortality and morbidity in SAH patients [7, 8].
Subdural hemorrhage (SH) refers to bleeding into the space between the dura mater and subarachnoid mater. Since it frequently occurs as a result of trauma, it is seen in only approximately 5% of all strokes. Spontaneous SH generally occurs in elderly patients due to cortical artery hemorrhage, vascular anomalies, coagulopathy, malignancy, arachnoid cyst, and cocaine use. Diagnosis may be delayed since it is not immediately suspected in patients with no history of trauma, and the prognosis is, therefore, poor .
Magnesium (Mg) is an intracellular cation, 60% of which is stored in bone, with important physiological functions. It prevents the release of catecholamines by inhibiting N-methyl- D-aspartate glutamate (NMDA) receptors in the central nervous system. Thus, it produces dilatation in the cerebral arteries [6, 10]. It also produces activation of factor X in the coagulation cascade through the mediation of factor VII. The resulting structural changes in factor X trigger platelet activation. Levels of the antithrombotic proteins S and C decrease. Thus, Mg exhibits a hemostatic effect .
The purpose of this study was to investigate the value of blood Mg levels at the time of presentation in determining the severity of hemorrhage and 30-day mortality in patients with SAH, ICH, and spontaneous SH.
Material and Methods
This prospective study involved patients presenting to a tertiary emergency department with SAH, ICH, and/or SH determined at cerebral tomography (CT) performed due to clinical suspicion following physical examination and evaluations, and confirmed either verbally or in writing by a specialist radiologist. The study commenced with patients capable of giving consent after receipt of the approval of the ethics committee (17.05.2018 no:61). All stages of the study were performed in compliance with the Declaration of Helsinki.
After obtaining ethical approval, five hundred eighty-five patients who presented to our hospital emergency department due to spontaneous intracranial hemorrhage within a one-year period (20.05.2018-20.05.2019) were included in the study. Patients with a history or findings of trauma, pregnant women, those using anticoagulant medication and patients with a history or findings of malignancy were excluded. Patients aged over the age of 18 who were capable of giving consent were included. Due to the prospective nature of the study, the study included patients personally encountered by the principal and other authors and whose examination and tests were followed- up under their supervision. Patients from whom consent could not be obtained were excluded.
Patients’ age, sex, Glasgow coma scale scores and blood pressure were recorded on a specially produced form. Laboratory parameters studied from blood specimens, such as Mg levels, platelet count and international normalized ratio (INR) values were recorded from the computer database system.
ICH volume, a parameter required in order to calculate the intracerebral hemorrhage score in patients with ICH and SH identified at tomography, was calculated by a specialist radiologist using the ABC/2 formula.
Volume of Hemorrhage = A × B × C × Slices/Hemorrhage Shape. A = Largest diameter of the hemorrhage on CT, B = Largest diameter 90° to A on the same CT slice, C = Number of CT slices on which hemorrhage is visible multiplied by the slice thickness (Slice with ≥75% Area of Hemorrhage: Counts as 1 slice; Slice with 25-75% Area of Hemorrhage: Counts as 0.5 slices; Slice with <25% Area of Hemorrhage: Counts as 0 slices), hemorrhage shape = If Round/Ellipsoid: 2; Otherwise: 3. This is a recognized scoring system used in estimating the severity of disease and 30-day survival in patients with ICH and SH. ICH ≥3 indicates an increased risk of mortality (26% in ICH≤2, but 74% in ICH≥3) . Patients were therefore classified as ICH score ≤ 2 and ICH score ≥ 3.
Modified Fisher (mFisher) scores of SAH cases were also calculated by a specialist radiologist. Grade 1=focal or diffuse, thin SAH, no IVH, Grade 2= focal or diffuse, thin SAH, with IVH, Grade 3 = focal or diffuse, thick SAH, no IVH, Grade 4 = focal or diffuse, thick, SAH, with IVH. The mFisher scale is a risk classification showing vasospasm in SAH. The risk of vasospasm development is 6% in mFisher 1, 15% in mFisher 2, 35% in mFisher 3, and 34% in mFisher 4 [13,14]. Patients were therefore classified as mFisher ≥3 and mFisher ≤2. The Mg levels in the groups were subjected to comparative analysis. Patients were also followed up for a 30-day mortality rate. Statistical Analysis
Statistical analysis was performed on IBM SPSS Statistics Version 24 software. Descriptive data were summarized as patient number (n) and %. Pearson’s chi-square and Fisher’s exact tests, and chi-square trend analyses were used to compare categorical data between groups. The normality of the distribution of continuous data was evaluated using the Kolmogorov-Smirnov test. The data were found not to exhibit normal distribution (p<0.05). Continuous data were expressed as median (IQR) values. The Mann Whitney U test was therefore applied to compare data between the two groups, and the Kruskal-Wallis H test (post hoc Bonferroni corrected Mann- Whitney U test) was used to compare data between more than two groups. The relationship between ICH and mFisher scores and laboratory values were analyzed using Spearman’s correlation analysis, and ROC analysis was performed to calculate optimal cut-off values for laboratory findings. P values <0.05 were considered statistically significant.
Women constituted 35.4% of the 195 patients enrolled, and men 64.6%. The mean age was 70 years in ICH patients (16), 55 in SAH (23.5) and 68 in SH (21). Mg levels from laboratory values by type of hemorrhage were 1.77 mg/dl for ICH (0.35), 1.77 mg/dl for SAH (0.27), and 1.73 mg/dl for SH (0.25) (Table1). Mann Whitney U analysis applied to ICH and SH group cases revealed that Mg levels in cases with ICH scores ≤2 were statistically significantly higher than in those with ICH scores ≥3 (p<0.05). In the SAH group cases, Mg values in cases with Fisher scores ≤2 were statistically significantly higher than those in cases with Fisher scores ≥3 (p<0.05) (Table 2).
The mortality from all hemorrhages was 40.5%. The highest mortality rate, at 44.7%, was determined in ICH. Examination of mean age and clinical characteristics, mFisher, and ICH scores by exitus status revealed a statistically significant difference in mortality between the groups based on ICH score grouping (p<0.05). The age and INR values were significantly lower in surviving cases than in fatal cases (p<0.05). Mg and platelet values were significantly higher in surviving cases than in fatal cases (p<0.05), while hematoma volume was lower. No statistically significant difference was observed in terms of other variables (Table 3). Multivariate logistic regression analysis was applied to identify independent factors predicting mortality. Age, Mg, ICH score, platelet count, hematoma volume and INR emerged as independent risk factors in determining mortality (p<0.05). ROC analysis was applied to determine Mg values in identifying exitus patients. At the cut-off value of 1.83 mg/dl (AUC: 0.775), sensitivity was 89.87% (95%CI 81-95.5), the specificity was 58.62% (95%CI 49.1-67.7) (p<0.05). (Figure 1).
The basic pathology in SAH, which is especially important among intracranial hemorrhages, since it particularly affects the young population, involves the impairment of cerebral circulation due to intracranial pressure increasing under the effect of the hemorrhage. The resulting DCI determines the course of the disease. The prevention of DCI will also improve the prognosis. Due to its cerebral vasodilatation and neuroprotective effects, the role and effects of Mg in intracranial hemorrhages have been investigated in several studies.
Can et al. reported that Mg levels during the follow-up of patients with cerebral aneurysms differed from levels at the time the hemorrhage (SAH) developed. However, the levels the day prior to rupture were the same. The authors concluded that Mg does not play any role in aneurysm rupture, but that blood levels decrease in patients with developing SAH . However, that study did not investigate the effect of this decrease in Mg levels on prognosis. We investigated the relationship between Mg values at time of presentation and mFisher scores. SAH was identified in 57 of the 195 patients enrolled in this study. Mg levels were significantly higher in patients with mFisher scores ≥3. A decrease in Mg values had an adverse impact on prognosis. Liotta et al examined the relationship between hemorrhage thickness and Mg levels in SAH. They observed that every 1 mg/dl increase in blood Mg values reduced the severity of hemorrhage. Since SAH patients with hemorrhage exceeding 1 mm in size were classified as mFisher 3 and 4, they reported that low Mg levels were indirectly related to prognosis . However, they did not compare variations in Mg levels and mFisher scores. Ours is the first study to compare Mg levels and mFisher scores. An increased mFisher score is an important marker of intracranial vasoconstriction and therefore of DCI. We predict that a decrease in Mg levels worsens the prognosis. In addition, IMASH, MASH II and Sommer et al. investigated the effects of Mg therapy on neurological outcomes in SAH patients. They applied varying doses of Mg, and no difference was observed in neurological outcomes compared with placebo [17-19]. However, treatment was not planned based on Mg levels and severity scores at the time of admission. The relationship between Mg levels and prognosis could not therefore be clearly established. We evaluated patient prognosis in terms of Mg levels and mFisher scores, and observed that a decrease in Mg levels affected prognosis. We, therefore, think that treatment should be planned based on Mg levels in the period between the onset of hemorrhage and the occurrence of DCI.
ICH score is used to estimate the severity of disease in ICH patients. Behrouz et al. reported that Mg values at the time of presentation of 1.7 mg/dl or below were correlated with ICH scores ≥3 . We also found that Mg values were statistically significant in ICH patients at time of admission ICH scores ≥3. Liotta et al. compared hematoma volume and changes in Mg levels at time of presentation and after 24 hours in ICH patients. A large hematoma volume was determined in patients with low Mg levels on arrival. That study also investigated patients’ three-month outcomes and observed correlations between hematoma expansion and Mg levels, also between functional outcomes . Similarly, Goyal et al. reported lower ICH Score and hematoma volume in ICH patients with high Mg levels at the time of admission, and reported that Mg level on admission was an important factor . The essential parameter in both scoring systems determining disease severity is hematoma volume. Liotta et al. found an inverse correlation between Mg levels and the size of hemorrhage in SAH, while Goyal et al. identified Mg levels as an independent risk factor affecting hematoma volume [6, 16]. Our results are consistent with these findings, showing that Mg levels at time of admission are associated with the severity of disease for both SAH and
Twenty-five cases in the present study were diagnosed as spontaneous SH. The only research of the effects of Mg therapy in SH in the literature was Heat et al.’s study involving experimentally induced traumatic SH in mice receiving i.v. Mg and saline solution as placebo. Mg was described as a factor exacerbating neurological status in the presence of SH . However, Heat et al.’s study involved traumatic animals. In the present study, we determined a statistically significant but poor relationship between ICH score and Mg levels. Further studies with larger patient numbers are now required for SH patients. The effect of Mg on mortality was only investigated in the IMASH study; the mortality rate in SAH patients given Mg was 10%, compared to 12% in the placebo group . In our study, mortality rates also increased in cases with Mg values less than 1.83 mg/dl among our entire patient group (ICH, SAH, and SH). When the effect of other variables on mortality was examined, we found that mortality increased with hematoma volume, INR, ICH score and age, and as platelet counts decreased. The administration of platelets to patients with thrombocytopenia, and of cofactor or TDP to patients with high INR is recommended in the approach to intracranial hemorrhages. However, the role of Mg in the treatment of intracranial hemorrhages is still unclear.
There are a number of limitations to this study. Since the patient group consisted of individuals with intracranial hemorrhage, who were largely unconscious, obtaining consent from these was problematic. Patients whose relatives’ consent was received were included in the study. Therefore, the number of our patients was low.
Non-traumatic intracranial hemorrhages involve a high risk of mortality and morbidity. Mg levels at the time of presentation are associated with mortality independently of scoring systems employed to predict prognosis. Determining the role of Mg in hemorrhage control through further studies with larger patient numbers will make a major contribution to emergency approach.
The authors are grateful to the study participants, nurses and other emergency department workers. The authors would also like to thank Dr. Olcay KARAKAYA, a radiologist who calculated patients’ hematoma volumes, ICH scores and mFisher scores.
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Animal and human rights statement
Conflict of interest
1. Maysam A, Masoud S, Fariba A, Zohreh D, Mohamad S, Abbas A. Impact of electrolyte imbalances on the outcome of aneurysmal subarachnoid hemorrhage: a prospective study. Asian J Neurosurg 2016; 11(1):29-33.
2. Behrouz R, Hafeez S, Mutgi SA, Zakaria A, Miller CM, Hypomagnesemia in ıntracerebral hemorrhage. World Neurosurg. 2015; 84(6):1929-32.
3. Jafaria M, Di Napolib M, Lattanzic S, Mayerd AS, Bachoure S, Bershad ME. Serum magnesium level and hematoma expansion in patients with intracerebral hemorrhage. J Neurol Sci. 2019; 398:39–44.
4. Gross BA, Jankowitz BT, Friedlander RM. Cerebral intraparenchymal hemorrhage a review. JAMA. 2019; 321(13):1295-303.
5. Grasso G, Alafaci C, Macdonald RL. Management of aneurysmal subarachnoid hemorrhage: State of the art and future perspectives. Surg Neurol Int. 2017; 8:11.
6. Goyal N, Tsivgoulis G, Malhotra K, Houck LA, Khorchid YM, Abhi Pandhi A et al. Serum Magnesium Levels and Outcomes in Patients With Acute Spontaneous Intracerebral Hemorrhage. J Am Heart Assoc 2018; 7(8). DOI: 10.1161/ JAHA.118.008698.
7. Yarad EA, Hammond NE. Intravenous magnesium therapy in adult patients with an aneurysmal subarachnoid haemorrhage: A systematic review and meta- analysis. Aust Crit Care. 2013; 26(3):105-17.
8. Muroi C, Burkhardt JK, Hugelshofer M, Seule M, Mishima K, Keller E. Magnesium and the inflammatory response: potential pathophysiological implications in the management of patients with aneurysmal subarachnoid hemorrhage? Magnes Res. 2012; 25(2):64-71.
9. Heat DL, Vink R. Subdural hematoma following traumatic brain ınjury causes a secondary decline in brain free magnesium concentration. J Neurotrauma. 2001; 18(4):465-9.
10. Herroeder S, Schönherr ME, De Hert SG, Hollmann MW. Magnesium— Essentials for Anesthesiologists. Anesthesiology. 2011; 114(4):971-93.
11. Golan E, Vasquez DN, Ferguson DNM, Adhikari NKJ, Scales DC. Prophylactic magnesium for improving neurologic outcome after aneurysmal subarachnoid hemorrhage: Systematic review and meta-analysis. J Crit Care. 2013; 28(2):173– 81.
12. Hemphill JC, Bonovich DC, Besmertis L, Manley GT, Johnston SC. The ICH Score a simple, reliable grading scale for ıntracerebral hemorrhage. Stroke. 2001; 32(4):891-7.
13. Kramer AH, el Hehir M, Nathan B, Gress D, Dumont AS, Kassell NF, et al. A comparison of 3 radiographic scales for the prediction of delayed ischemia and prognosis following subarachnoid hemorrhage. J Neurosurg. 2008; 109(2):199- 207.
14. Jiménez-Roldán L, Alén JF, Gómez PA, Lobato RD, Ramos A, Munarr PM. Volumetric analysis of subarachnoid hemorrhage: assessment of the reliability of two computerized methods and their comparison with other radiographic scales. J Neurosurg. 2013; 118(1):84-93.
15. Can A, Rudy RF, Castro VM, Dligach D, Finan S, Yu S. Low Serum Calcium and Magnesium Levels and Rupture of Intracranial Aneurysms. Stroke. 2018; 49(7):1747-50.
16. Liotta EM, Karmarkar A, Batra A, Kim M, Prabhakaran S, Naidech AM, et al. Magnesium and hemorrhage volume in patients with aneurysmal subarachnoid hemorrhage. Crit Care Med. 2020; 48(1):104-10.
17. Wong CKG, Poon WS, Chan MTV, Boet R, Gin T, Stephanie CP, et al. Intravenous Magnesium Sulphate for Aneurysmal Subarachnoid Hemorrhage (IMASH). Stroke. 2010; 41(5):921-6.
18. Mees DSM, Algra A, Vandertop WP, van Kooten F, Kuijsten HA, Boiten J, et al. Magnesium for aneurysmal subarachnoid haemorrhage (MASH-2): a randomised placebo-controlled trial. Lancet. 2012; 380(9836):44-9.
19. Sommer B, Weidinger CS, Wolf D, Buchfelder M, Schmitt H. Intraoperative continuous cerebral microcirculation measurement in patients with aneurysmal subarachnoid hemorrhage: preliminary data on the early administration of magnesium sulfate. BMC Anesthesiol. 2017; 17(1):143.
20. Liotta EM, Prabhakaran S, Sangha RS, Bush RA, Long AE, Trevick SA.. Magnesium, hemostasis and outcomes in patients with intracerebral hemorrhage. Neurology. 2017; 89(8):813-9.
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Rezan Karaali, Zeynep Karakaya. The effect of serum Magnesium levels on prognosis and mortality in patients with spontaneus intracranial hemorrhage. Ann Clin Anal Med 2021;12(10):1147-1151
The predictive value of the Patient Health Questionnaire-9 score for measuring the severity of coronary artery disease
Songül Usalp 1, Ramazan Gündüz 2, Belma Yaman 1, Levent Cerit 1, Hamza Duygu 1
1 Department of Cardiology, Near East University Faculty of Medicine, Nicosia, Cyprus, 2 Department of Cardiology, Manisa City Hospital, Manisa, Turkey
DOI: 10.4328/ACAM.20679 Received: 2021-04-29 Accepted: 2021-08-14 Published Online: 2021-08-15 Printed: 2021-10-01 Ann Clin Anal Med 2021;12(10):1152-1156
Corresponding Author: Songül Usalp, Near East Hospital University Hospital, Near East Boulevard, 99138, Nicosia, Cyprus. E-mail: firstname.lastname@example.org P: +90 392 675 10 00 F: +90 392 223 64 61 Corresponding Author ORCID ID: https://orcid.org/0000-0001-9572-5431
Aim: It is known that the prevalence of depression increases in patients with coronary artery disease (CAD). However, it is not clear whether patients’ symp- toms of depression worsen as the severity of CAD increases. The aim of this study is to investigate whether there is a relationship between the Patient Health Questionnaire-9 (PHQ) score and the severity of CAD.
Material and Methods: A total of 168 patients, diagnosed with stable and unstable angina, acute myocardial infarction, were included in the study. The patients were divided into two groups as mild (n=133) and severe CAD (n=35) according to the SYNTAX score (SS) results. All patients completed PHQ-9 questionnaires, reflecting their mood up to 2 weeks before the heart attack. Patients with a previous diagnosis of depression, coronary artery disease, using psychiatric drugs, severe heart and kidney failure were excluded from the study.
Results: The PHQ-9 score was higher in severe CAD (6.7±4.5 vs 12.5±15.0 p<0.000). Correlation analyses showed a strong association between PHQ-9 and SS (r=0.724, p<0.000) and heart rate (r=0.381, p<0.000). However, regression analysis showed that only SS [OR: 7.8, 95% CI (0.214-0.358), p<0.000] significantly increased the risk of depression. Receiver operating characteristics curve analyses presented that the optimal cut-off PHQ-9 score was ≥ 8 with 71.4 % sen- sitivity, 68.4 % specificity, and the area under the curve of 0.79, p < 0.000.
Discussion: PHQ-9 was higher in patients with severe CAD, and there was a strong link between PHQ-9 score and heart rate.
Keywords: Coronary artery disease; Patient health questionnaire; Depression
The prevalence of depression is almost twice in patients with coronary artery disease (CAD) compared to the general population . A sedentary life, smoking, alcohol consumption, stressful personality, which are among the risk factors for coronary artery disease, increase the tendency to depression. Conversely, depressed people have a stressful lifestyle that leads to more smoking, alcohol consumption, and CAD. It is known that compliance with medical treatment is poor in depressed patients and associated with unfavorable cardiovascular outcomes [2,3]. Therefore, the American Heart Association recommends routine screening for depression in patients with CAD and the European Society of Cardiology recommends the assessment of psychosocial risk factors with standardized questionnaires or clinical interviews in patients with CAD [4,5]. The Patient Health Questionnaire-9 (PHQ-9) scoring system is one of the approved questionnaires developed in the Diagnostic and Statistical Manual of Mental Disorders (DSM V) criteria for the diagnosis of depression in patients with coronary artery disease. This scoring is based on the patient’s symptoms in the past 2 weeks. Each question is scored between 0 and 3, and if the total score is 10 or more, it can be considered depression . To measure the severity of CAD, a different scoring system was developed. The SYNTAX score (SS) defines coronary artery dominance, lesion severity, the complexity, and the location. The SS is also used to predict cardiac outcomes after percutaneous coronary intervention (PCI) .
The aim of this study is to investigate whether there is a relationship between the PHQ score and the severity of CAD.
Material and Methods
A total of 168 patients diagnosed with stable and unstable angina, acute myocardial infarction were included in the study. BMI was calculated by taking height, weight, and waist circumference was measured from the midpoint of the distance between the archus costarum and the spina iliaca anterior superior. Biochemical and hematological blood parameters were obtained from the medical records of the patients. SS was calculated by monitoring angiography images. The patients were interviewed and informed about the PHQ-9 questionnaire, and completed the questionnaires themselves. The questionnaires were completed before the patient was discharged from the hospital.
SYNTAX score and Severity of CAD
Coronary angiographies (CAG) were performed using the Judkins technique, and all lesions ≥ 1.5 mm in diameter and causing 50 % stenosis in the coronary artery were included in the SS calculation . After CAG, website software (http:// www.SYNTAXscore.com) was used for the calculation of SYNTAX score. The SYNTAX score was calculated for following points: Coronary dominance, number of lesions, segment per lesion, total occlusion, bifurcation, trifurcation, aortic-osteal lesion, severe tortuosity, calcification, thrombus, diffuse/small vessel disease and lesion length > 20 mm. SS was calculated separately by two interventional cardiologists who did not know the study protocol and patient characteristics. Patients were divided into two groups according to SYNTAX scores as severe CAD (> 23) and mild CAD (≥ 22) .
Patients with severe aortic and mitral valve stenosis, permanent cardiac pacemaker, advanced heart failure, chronic kidney failure, previous myocardial infarction, and patients having the psychiatric disease were excluded from the study.
This survey is a depression component of the Patient Health Questionnaire developed according to the diagnostic criteria for major depressive disorders (DSM-V) [9,10]. PHQ -9 is a self-reporting tool that can help an intense clinician easily scan, diagnose, monitor, and correctly measure the severity of depression .
PHQ -9 is a survey that includes 9 questions, evaluating the symptoms of depression during the last two weeks. The time required to complete the questionnaire is usually 3-5 minutes. Each question is answered with one of four possible numbers between 0-3 (0 = Not at all, 1 = Several days, 2 = More than half of days, and 3 = Almost every day). Total scores in PHQ-9 can range from 0 to 27’ scoring: 1 to 4 points = minimal depression, 5 to 9 points = mild depression, 10 to 14 points = moderate depression, 15 to 19 points = moderately severe depression, 20 to 27 points = severe depression. A score of 10 or higher suggests possible depression and indicates the need for further investigation [10,11].
Statistical analysis was performed using SPSS 20.0 (IBM Corporation, Armonk, NY, USA). The baseline characteristics of the CAD patients were compared using Student’s t-test for continuous variables, and the χ2 Pearson’s test was used for categorical variables. Pearson’s correlation coefficient (r) and multivariable regression analyses were used to evaluate the strength of the relation between PHQ-9 score, SYNTAX score and heart rate. Then the receiver operating characteristics curve analysis (ROC) was used to evaluate the optimal cut-off the PHQ-9 score prediction model for high SS was applied to identify the optimal cut-off point. For all statistics, a p-value below 0.05 was considered significant.
Ethics Committee approval (decision no: YDU/2019/69-836, date: 30.05.2019) was obtained from the Non-Interventional Clinical Research Ethics Committee of Near East University, before the initiation of the study. The Declaration of Helsinki was followed in the application of ethical rules of the study. All subjects gave informed consent for participation.
A total of 168 patients who were diagnosed with CAD by coronary angiography and who responded to the PHQ-9 questionnaire were included in the study. Thirty-five of these patients were severe CAD [mean age 59.3±11.2 years, 56 (81.2%) were males] and 133 of them were mild CAD [mean age 61.5±13.1 years, 75 (75.8%) were males].
There was no significant difference between LSS and HSS patients in terms of age, BMI, gender, waist circumference, systolic blood pressure, diastolic blood pressure, smoking and alcohol use, family history, before CAD history, ejection fraction values and medical treatment (p>0.05) (Table 1).
There was a significant difference in terms of PHQ-9 score (6.7 ± 4.5 vs 12.5 ± 5.2, p<0.000). However, serum creatinine
levels (0.8±0.1 vs 0.8±0.3 mg/dl, p=0.301), serum aspartate transaminase (24.7±11.6 vs 54.6±82.9 U/L, p=0.003), alanine transaminase (27.0 ± 16.0 vs 33.7± 59.0 U/L, p=0.356), vitamin D (19.8 ± 23.0 vs 18.1 ± 12.1 ng/ml, p=0.567), vitamin B12 (419.7 ± 197.4 vs 361.3 ± 193.2 pg/ml, p=0.195), total cholesterol (200.6 ± 48.8 vs 187.0 ± 41.4 mg/dl, p=0.088), LDL (125.2 ± 29.0 vs 121.7 ± 34.0 mg/dl, p=0.426), triglycerides (173.0 ± 153.6 vs 167.0 ± 113.0 mg/dl, p=0.078), HDL(43.6 ± 15.1 vs 40.9 ± 14.0 mg/dl, p=0.236), glucose (133.1 ± 65.1 vs 132.7 ± 69.9 mg/dl, p=0.973), HbA1c (6.1 ± 1.4 vs 6.3 ± 1.5, p=436), thyroid-stimulating hormone (1.6 ± 1.0 vs 1.7 ± 1.4 mIU/L, p=0.402), serum hemoglobin (13.7 ± 1.8 vs 13.2 ± 1.8 g/ dl, p=0.122), platelet levels (244.8 ± 61.5 vs 242.3 ± 64.1 x103 u/L, p=0.806), white blood cells (8.6±2.0 vs 8.7±3.1 x103 u/L, p=0.512) levels were similarly in two groups (Table 2). Correlation analyses showed a strong association between PHQ-9 score and SS (r = 0.724, p < 0.000) and heart rate (r = 0.381, p < 0.000) (Figure 1).
Multivariable regression analysis showed that only SS [OR: 7.8, 95 % CI (0.214 – 0.358), (p<0.000)] were an independent risk factor for depression. No association was found between heart rate [OR: 1.3, 95 % CI (0.011-0.107), p=0.175], age [OR: -0.7, 95 % CI (0.073-0.308), p=0.483], and gender [OR: 0.1, 95 % CI (0.065-0.138), p=0.340] and PHQ-9 score (Table 3).
The ROC curve for PHQ-9 score to predict the coronary artery severity showed AUC = 0.79 (95% CI 0.723–0.874, p < 0.000), cut-off value was PHQ-9 = 8, with sensitivity 71.4 % and specificity 68.4 % (Figure 2).
In our study, we found that the PHQ-9 score was higher in severe CAD, and there was a strong link between the PHQ- 9 score and heart rate. To our knowledge so far, have not encountered a study on any link between severity of CAD and PHQ-9 questionnaire.
The pathophysiological process between depression and CAD begins with a change in the hypothalamic-pituitary gland axis and an increase in endocrine and inflammatory markers (C-reactive protein, interleukin-6, intercellular adhesion molecule-1 and increased fibrinogen). Changes in autonomic functions (activation of the sympathetic system and suppression of the activity of the parasympathetic system), leads to impaired endothelial and myocardial functions and the onset of hemostatic, inflammatory processes [12,13]. Increased catecholamines can also cause platelet activation with a procoagulant effect. Depression may increase coronary events both by accelerating the atherosclerotic process and by predisposition to thrombus. In our study, we found that patients with coronary artery disease had depressive symptoms 2 weeks before diagnosis, and patients with higher PHQ-9 scores had a higher severity of coronary artery stenosis.
Patient Health Questionnaire-9 (PHQ-9) is a nine-item questionnaire designed to identify depression in primary care and other medical settings. It has been shown in previous studies that the most appropriate method for diagnosing depression in coronary artery patients is the PHQ-9 score . The PHQ-9 questionnaire standard cutoff score of 10 or greater maximizes the combined sensitivity and specificity for general and subgroups . The strength of the PHQ-9 scores to predict depression in CAD has been tested in many studies. Haddad et al. in their study found that cut- points of PHQ-9 at ≥ 8 provide optimal test characteristics in CAD populations: a combination of test values (sensitivity = 94%; specificity = 84%; Youden Index 0.78), supports the selection of this breakpoint . In our study, we found that a PHQ-9 score of ≥ 8 was significant for severe CAD.
Our study was a single-center, retrospective and subjectively conducted study based on the responses of patients to the PHQ-9 questionnaire. The number of patients was limited because we were able to enroll patients participating with their consent. In future studies, we believe that the relationship between depression and severity of CAD can be examined in different populations and scoring systems. Since such a study has not been conducted before, it was difficult to reflect the differences in our study and make comparisons.
In our study, we found that the PHQ-9 score was higher in patients having serious CAD. Therefore, we believe it is important to explore patients with high SS for the likelihood of depression.
Depression is a general problem associated with high mortality and reduced quality of life in patients with CAD. Depression complicates the treatment of CAD by worsening cardiovascular risk factors, decreasing compliance with treatment and reducing adherence to a healthy lifestyle. In our study, we found that depression increased in patients with severe coronary artery disease. Therefore, in severe CAD, depression should be thoroughly investigated and treated.
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Conflict of interest
1. Davidson KW. Depression and coronary heart disease. ISRN Cardiol. 2012; 2012:743813.
2. Vitinius F, Escherich S, Deter HC, Hellmich M, Jünger J, Petrowski K, et al. Somatic and sociodemographic predictors of depression outcome among depressed patients with coronary artery disease – a secondary analysis of the SPIRR-CAD study. BMC Psychiatry. 2019; 19:57.
3. Albus C, Waller C, Fritzsche K, Gunold H, Haass M, Hamann B, et al. Significance of psychosocial factors in cardiology: update 2018: Position paper of the German Cardiac Society. Clin Res Cardiol. 2019; 108(11):1175-96.
4. Elderon L, Smolderen KG, Na B, Whooley MA. Accuracy and prognostic value of American Heart Association: recommended depression screening in patients with coronary heart disease: data from the Heart and Soul Study. Circ Cardiovasc Qual Outcomes. 2011; 4(5):533-40.
5. Pogosova N, Kotseva K, De Bacquer D, von Känel R, De Smedt D, Bruthans J, et al. EUROASPIRE Investigators. Psychosocial risk factors in relation to other cardiovascular risk factors in coronary heart disease: Results from the EUROASPIRE IV survey. A registry from the European Society of Cardiology. Eur J Prev Cardiol. 2017; 24(13):1371-80.
6. Maurer DM, Raymond TJ, Davis BN. Depression: Screening and Diagnosis. Am Fam Physician. 2018; 98:508-15.
7. Judkins MP. Selective coronary arteriography. I. A percutaneous transfemoral technic. Radiology. 1967; 89(5):815-24.
8. Bundhun PK, Sookharee Y, Bholee A, Huang F. Application of the SYNTAX score in interventional cardiology: A systematic review and meta-analysis. Medicine (Baltimore). 2017; 96:e7410.
9. Head SJ, Davierwala PM, Serruys PW, Redwood SR, Colombo A, Mack MJ, et al. Coronary artery bypass grafting vs. percutaneous coronary intervention for patients with three-vessel disease: final five-year follow-up of the SYNTAX trial. Eur Heart J. 2014; 35(40):2821-30.
10. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001; 16(9):606-13.
11. U.S. Preventive Services Task Force. Screening for Depression: Recommendation and rationale. Ann Intern Med. 2002; 136(10):760-4.
12. Vaccarino V, L Badimon, Bremner JD, Cenko E, Cubedo J, Dorobantu M, et al. Depression and coronary heart disease: 2018 position paper of the ESC working group on coronary pathophysiology and microcirculation. Eur Heart J. 2020; 41(17):1687-96.
13. RC Veith, N Lewis, OA Linares, Barnes RF, Raskind MA, Villacres EC, et al. Sympathetic Nervous System Activity in Major Depression. Basal and Desipramine-Induced Alterations in Plasma Norepinephrine Kinetics. Arch Gen Psychiatry. 1994; 51(5):411-22.
14. Haddad M, Walters P, Philips R, Tsakok J, Williams P, Mann A, et al. Detecting Depression in patients with Coronary Heart Disease: a Diagnostic Evaluation of the PHQ-9 and HADS-D in Primary Care Findings From the UPBEAT-UK Study. PLoS One. 2013; 8(10):e78493.
15. Levis B, Benedetti A, Thombs BD; DEPRESsion Screening Data (DEPRESSD) Collaboration Accuracy of Patient Health Questionnaire-9 (PHQ-9) for screening to detect major depression: individual participant data meta-analysis. BMJ. 2019; 365:l1476.
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Songül Usalp, Ramazan Gündüz, Belma Yaman, Levent Cerit, Hamza Duygu. The predictive value of the Patient Health Questionnaire-9 score for measuring the severity of coronary artery disease. Ann Clin Anal Med 2021;12(10):1152-1156
Assessment of the shape and dimensions of sella turcica using cone-beam computed tomography
Ceren Özeren Keşkek 1, Emre Aytuğar 2
1 Oral and Maxillofacial Radiologist, Izmir Training Dental Hospital, 2 Department of Oral and Maxillofacial Radiology, Faculty of Dentistry, Izmir Katip Celebi University, Izmir, Turkey
DOI: 10.4328/ACAM.20680 Received: 2021-04-30 Accepted: 2021-06-28 Published Online: 2021-07-20 Printed: 2021-10-01 Ann Clin Anal Med 2021;12(10):1157-1161
Corresponding Author: Ceren Özeren Keşkek, Izmir Training Dental Hospital, Fevzipasa Boulevard, Akinci district, No.172/2, Konak, Izmir, Turkey. E-mail: email@example.com P: +90 232 441 81 81 F: +90 232 489 35 48 Corresponding Author ORCID ID: https://orcid.org/0000-0002-1758-0852
Aim: This study aimed to evaluate the shape and dimensions of sella turcica in the Turkish population using cone-beam computed tomography (CBCT).
Material and methods: CBCT records of 798 individuals aged 9-78 years were examined retrospectively. The depth, diameter and length of sella turcica were measured. The shapes of sella turcica were examined and classified as round, oval and flat. The obtained findings were compared according to gender and age groups. The data obtained were analyzed statistically.
Results: The most common shape of sella turcica was round (46.1%). There was a statistically significant difference in all dimensions of sella turcica accord- ing to age groups (p<0.0001). The length and depth of sella turcica showed a statistically significant difference according to gender (p<0.0001). A significant positive correlation was found between age and the dimensions of sella turcica (p<0.0001).
Discussion: It was observed that the dimensions of sella turcica increased with increasing age and these dimensions were larger in males. This study with a large sample size can help determine the standard sella turcica sizes. Besides, CBCT can be useful in examining sella turcica and its surrounding anatomical structures.
Keywords: Anatomy; Cone-Beam Computed Tomography; Morphology; Pituitary Gland; Sella Turcica
Sella turcica is located in the sphenoid bone and is a saddle- shaped depression area. It is also known as the pituitary fossa. The boundaries of the sella turcica are formed by the tuberculum sella anteriorly, the dorsum sella posteriorly, and the roof of the sphenoid sinus inferiorly . Sella turcica is located close to vital structures such as optic chiasma, cavernous sinus, hypothalamus, and sphenoid sinus . The pituitary gland is located in sella turcica . The pituitary gland is very substantial in growth and development as it is responsible for most of the endocrine functions. Since the pituitary gland is formed before sella turcica is formed, the development of the sella is associated with the pituitary gland. Changes in the development of the pituitary gland may cause differences in the dimensions and morphology of sella turcica. Sella turcica differs from its normal size, which may raise suspicion of a lurking disease [4, 5]. For example, an increase in the dimensions of sella turcica may indicate acromegaly, turner syndrome, empty sella syndrome and adenomas, while at decrease in size may indicate Williams syndrome, Sheehan’s syndrome, type I diabetes, or unilateral cleft lip and palate [6, 7].
Sella turcica is one of the reference points in the analysis of cephalometric radiographs in orthodontics and is frequently used in the evaluation of craniofacial development and facial- skeletal pattern [8, 9]. By examining the morphology of sella turcica, early diagnosis of skeletal malocclusions can be achieved and less complicated treatments can be performed instead of complex treatment methods to be applied in the future .
Various methods such as lateral cephalometric radiograms (LCR) [10-12], computed tomography (CT) [1, 5, 13], and cone- beam computed tomography (CBCT)[2, 3, 9, 14] were used to evaluate the normal morphology of sella turcica. The LCR provides a two-dimensional view and the two-sided structures overlap. Therefore, it can be difficult to examine sella turcica with LCR . Three-dimensional imaging techniques such as CT or CBCT can provide clearer information about the anatomy of the sella turcica. CBCT has advantages such as lower-priced equipment, shorter scanning time, and lower radiation dose compared to CT . The evaluation of sella turcica with CBCT is important for examining craniofacial defects, evaluating orthodontic treatment, determining the abnormal structures of sella turcica and establishing standard norms .
The dimensions and shape of sella turcica may vary depending on genetic and racial factors, syndromes, and congenital disorders . To detect an abnormality in the sizes and morphology of sella turcica, it is necessary to know the normal morphology and dimensions first. Establishing normal standards is very useful in identifying any abnormality . For this reason, we aimed to determine the shape and morphometric dimensions of sella turcica with a large sample size using CBCT and to investigate the effect of gender and age on sella turcica and contribute to the creation of standard norms in the literature.
Material and Methods
CBCT records of 1000 patients taken for various reasons in the Department of Oral and Maxillofacial Radiology were evaluated. Images of 202 patients were excluded from the study according to the exclusion criteria. The exclusion criteria were the presence of craniofacial deformity or syndrome, cleft lip-palate, history of pathology or surgical procedure in the pituitary region, and poor-quality images. Radiological measurements were made on images of 798 individuals. The dimensions of sella turcica were measured in mid-sagittal sections, but the first evaluation of the relevant region and examination of the suitability of images for the study were carried out in three sections.
All images used in the study were obtained using the CBCT (NewTom 5G, Quantitative Radiology, Verona, Italy) device operating at 110 kVp. Images with 15 × 12 cm FOV range and 0.200 mm voxel size were used. Images were analyzed by an oral and maxillofacial radiologist under dim light using NNT (NNT Software Version 9.1; NewTom; Italy) computer software. The study followed the Helsinki declaration and was conducted with the permission of the Izmir Katip Celebi University Non- Interventional Clinical Studies Ethics Committee (02.07.2020, IRB:835).
In the mid-sagittal section, the following distances were measured: the length from the dorsum sella (DS) to the tuberculum sella (TS); the depth from the middle of the length to the deepest part of the sella; the diameter as the longest distance on the posteroinferior direction between the TS and the pituitary fossa (Figure. 1). The shapes of sella turcica were classified as oval, round and flat (Figure. 2). The depth of the oval-shaped sella turcica was greater than its length, but this shape was not as symmetrical as the round one. The shape of sella turcica, whose depth was less than its length, and whose angles between its base and its anterior and posterior surfaces were close to vertical, was called flat.
Linear measurements were repeated 4 weeks later by the same observer on 160 randomly selected images (20% of images) to determine intraobserver consistency. The intra- observer reliability was evaluated for all variables using the intraclass correlation coefficient, and the intraclass correlation coefficients were between 0.85 and 0.93.
IBM SPSS Version 26 was used for statistical analysis. Descriptive statistical methods (mean, frequency, percentage) were used. Data distribution was determined by the Kolmogorov-Smirnov test. The Mann-Whitney U test was used for differences between means of two independent groups. The Kruskal-Wallis test was used for differences between the means of more than two independent groups. Spearman’s rho correlation test was used to evaluate the correlation between measurements and age. A chi-square test was used to compare categorical variables. The level of significance (p-value) was accepted as 0.05.
The study population consisted of 458 women (Mean age=40.3) and 340 (Mean age=42.9) men. The mean sizes of the sella turcica according to gender and age groups are presented in Table 1. There was a statistically significant difference in the length and depth according to both gender and age groups (p<0.0001). While no significant difference was observed in the diameter by gender (p=0.464), a significant difference was observed according to age groups (p<0.0001).
Among the sella turcica shapes, the most common shape was round (46.1%), followed by an oval (41.5%) and flat (12.4%). There was a statistically significant difference between sella turcica shapes and gender (p<0.0001). Round-shaped sella turcica (52%) was the most common in females, followed by an oval (40.6%) and flat (7.4%). Oval-shaped sella turcica (42.6%)
was the most common in males, followed by round (38.2%) and flat (19.2%).
Differences in the sizes of sella turcica according to their shapes were investigated. The flat-shaped sella turcica had a mean length of 10.9 mm, a mean depth of 6.8 mm, and a mean diameter of 12.5 mm. The oval-shaped sella turcica had a mean length of 9.9 mm, a mean depth of 8.4 mm, and a mean diameter of 12.5 mm. The round-shaped sella turcica had a mean length of 9.3 mm, a mean depth of 8.3 mm, and a mean diameter of 11.7 mm. There was a statistically significant difference between the shapes of sella turcica and their length, depth and diameter (p<0.0001). The mean lengths of the three shapes of the sella turcica were statistically significantly different from each other. The mean depths of oval and round- shaped sella turcica were similar, while the depth of flat- shaped sella turcica was statistically different from the others. The mean diameters of oval and flat-shaped sella turcica were similar, while the diameter of round-shaped sella turcica was statistically different from the others.
Also, it was investigated whether age affects dimensions. A significant positive correlation was found between age and the length, depth and diameter (p<0.0001) (Table 2).
Understanding the morphology of sella turcica is important for examining the pathologies in the pituitary gland and cephalometric analysis. Abnormal situations in the form of sella turcica can provide information about underlying diseases or syndromes . LCR was used in the studies to evaluate sella turcica [12, 18-21]. Although useful data have been obtained with studies performed with LCR, it should be kept in mind that sella turcica cannot be fully examined without using three- dimensional imaging . CT and CBCT are used to obtain more accurate information without magnification and distortion. CBCT enables similar hard tissue images to be acquired with lower radiation dose compared to CT. It also ensures reliable measurements of bone structures without superposition . For these reasons, images obtained with CBCT were used and evaluated in our study.
Researchers have examined the dimensions and anatomical variations of sella turcica according to gender and chronological age [3, 9, 12, 13, 23, 24]. However, there are not many studies with large sample sizes to determine the standard dimensions in the Turkish population [2, 11, 14, 25]. Determining the size of sella turcica is very valuable as it can be a mark of a pathology or a disease in the pituitary gland. For these reasons, in this study, the normal sizes of sella turcica and its relationship with age and gender in the Turkish population were investigated using CBCT images of 798 patients with a wide age range (9- 78 years).
The age-related increase in the dimensions of sella turcica is thought to be associated with the increase in the size of the pituitary gland and this increase continues until the age of 16- 18 . Choi et al.  reported that the dimensions of sella turcica increased by the age of 25, but there was no significant increase after the age of 26. Magat and Ozcan Sener  evaluated the sella turcica in subjects between the ages of 9 and 21 and reported that the diameter and depth of sella turcica in the 15-21 age group were greater than in the 9-14 age group. Muhammed et al.  examined the sizes of sella turcica in subjects aged 8-28, consisting of Bosnian and Iraqi populations and reported that the diameter, depth and length of sella turcica in the 15-28 age group were greater than the 8-14 age group. Yasa et al.  found that sella turcica sizes showed statistically significant differences according to age groups in their study on individuals aged between 11-73 years. Silveira et al.  reported that there is no significant correlation between age and dimensions of sella turcica. Gargi et al.  determined that there was no correlation between the diameter and length of sella turcica and age, but they found a positive correlation between the depth and age. We also examined whether there was a correlation between age and dimensions of sella turcica and detected a positive correlation between the depth, diameter and length of sella turcica and age. According to the results we obtained, the dimensions of sella may change developmentally throughout life. In this study, we have presented that the sizes of sella turcica increase with increasing age without pathology. In studies, there was no statistically significant difference between the dimensions of sella turcica and gender [1, 2, 5, 12, 14]. Magat and Ozcan Sener  and Silveira et al.  reported that the mean values of length and depth did not differ significantly according to gender, but the diameter showed a statistically significant difference according to gender and was greater in women. In our study, unlike other studies, a significant difference was observed in mean length and depth according to gender, but there was no statistically significant difference between diameter and gender. The difference between previous studies and this study may be due to the difference in sample size.
Islam et al.  reported the prevalence of the basic shape of sella turcica as ovoid (48.2%), flat (28.3%) and circle (23.4%), respectively. Usman et al.  determined it as round (56.6%), oval (32%) and flat (11.4%). Yasa et al.  found the most common round (69.5%) shaped sella turcica, flat (16.4%) and oval (14%), respectively, and reported that there was no statistically significant difference between gender and sella turcica shapes. In our study, most frequently round (46.1%), then oval (41.5%) and flat (12.4%) were observed, and a statistically significant difference was found between sella turcica shapes and gender.
The normal morphology and dimensions of sella turcica may show ethnic differences and it is important to determine the normal anatomical structure with large sample groups for the detection of pathological conditions. We compared the findings we obtained in the study with the results of other studies in the literature (Table 3). It may be useful to compare the sizes of sella turcica with other studies. In this study, we believe that the dimensions of sella turcica obtained in the Turkish population using CBCT will guide clinicians and these measurements can be used in the detection of pathologies in the sellar region.
In conclusion, it was observed that the sizes of sella turcica increased with age, and the depth and length of sella turcica were greater in males. The results of this study carried out with a large sample size, can be used as reference standards in determining the dimensions of sella turcica in the Turkish population and can contribute to further studies. Besides, sella turcica and surrounding bone structures can be examined in detail using CBCT.
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Conflict of interest
1. Islam M, Alam M, Yusof A, Kato I, Kubo K, Honda Y, et al. 3D CT Study of Morphological Shape and Size of Sella Turcica in Bangladeshi Population. Journal of Hard Tissue Biology. 2017; 26(1):1-6.
2. Yasa Y, Ocak A, Bayrakdar IS, Duman SB, Gumussoy I. Morphometric Analysis of Sella Turcica Using Cone Beam Computed Tomography. J Craniofac Surg. 2017; 28(1):e70-4.
3. Gargi V, Ravi Prakash SM, Nagaraju K, Malik S, Goel S, Gupta S. Radiological analysis of the sella turcica and its correlations with body mass index in a North Indian population. Oral Radiol. 2019; 35(2):184-8.
4. Yalcin ED. Morphometric Analysis of Sella Turcica Using Cone-Beam Computed Tomography in Patients With Cleft Lip and Palate. J Craniofac Surg. 2020; 31(1):306-9.
5. Ogunnaike P, Sunday yinka O, Joshua O, Ginigeme A, Olanrewaju J. An Assessment of the Size of Sella Turcica Among Adult Nigerians Resident in Lagos. International Journal of Medical Imaging. 2016; 4(3):12-16.
6. Sundareswaran S, Vijayan R, Nair P, Vadakkepediyakkal L, Sathyanadhan S. Cephalometric Appraisal of the Sella Turcica- A Literature Review. Iranian Journal of Orthodontics. 2019; DOI:10.5812/ijo.55972
7. Tassoker M, Ozcan S. Clinical And Radiological Significance of Sella Turcica: A Literature Review. IOSR Journal of Dental and Medical Sciences. 2016; 15(8):108- 113.
8. Muhammed FK, Abdullah AO, Liu Y. Morphology, Incidence of Bridging, Dimensions of Sella Turcica, and Cephalometric Standards in Three Different Racial Groups. J Craniofac Surg. 2019; 30(7):2076-81.
9. Silveira BT, Fernandes KS, Trivino T, Dos Santos LYF, de Freitas CF. Assessment of the relationship between size, shape and volume of the sella turcica in class II and III patients prior to orthognathic surgery. Surg Radiol Anat. 2020; 42(5):577- 82.
10. Afzal E, Fida M. Association Between Variations In Sella Turcica Dimensions And Morphology And Skeletal Malocclusions. J Ayub Med Coll Abbottabad. 2019; 31(2):172-7.
11. Magat G, Ozcan Sener S. Morphometric analysis of the sella turcica in Turkish individuals with different dentofacial skeletal patterns. Folia Morphol (Warsz). 2018; 77(3):543-50.
12. Nagaraj T, Shruthi R, James L, Keerthi I, Balraj L, Goswami R. The size and morphology of sella turcica: A lateral cephalometric study. Journal of Medicine, Radiology, Pathology and Surgery. 2015; 1:3-7.
13. Usman Z, Zagga A, Yunusa G, Abubakar U, Bello A, Usman JD, et al. Shapes and Sizes of Sella Turcica Using Computerized Tomography (CT) from Tertiary Hospital in Sokoto, Nigeria. Asian Journal of Medicine and Health. 2020; 8-15.
14. Taner L, Deniz Uzuner F, Demirel O, Güngor K. Volumetric and three- dimensional examination of sella turcica by cone-beam computed tomography: reference data for guidance to pathologic pituitary morphology. Folia Morphol (Warsz). 2019; 78(3):517-23.
15. Yasa Y, Bayrakdar IS, Ocak A, Duman SB, Dedeoglu N. Evaluation of Sella Turcica Shape and Dimensions in Cleft Subjects Using Cone-Beam Computed Tomography. Med Princ Pract. 2017; 26(3):280-5.
16. Akay G, Eren I, Karadag O, Gungor K. Three-dimensional assessment of the sella turcica: comparison between cleft lip and palate patients and skeletal malocclusion classes. Surg Radiol Anat. 2020; 42(9):977-83.
17. Isman O, Kayar S, Murat Aktan A. Cone beam computed tomography evaluation of variations in the sella turcica in a Turkish population. Folia Morphol (Warsz). 2020; 79(1):46-50.
18. Alkofide EA. Sella turcica morphology and dimensions in cleft subjects. Cleft Palate Craniofac J. 2008; 45(6):647-53.
19. Sato D, Endo T. Size and bridging of the sella turcica in Japanese orthodontic patients with tooth agenesis. Odontology. 2020;108(4):730-7.
20. Alam MK, Alfawzan AA. Evaluation of Sella Turcica Bridging and Morphology in Different Types of Cleft Patients. Front Cell Dev Biol. 2020; 8:656.
21. Chauhan P, Kalra S, Mongia S, Ali S, Anurag A. Morphometric analysis of sella turcica in North Indian population: a radiological study. International Journal of Research in Medical Sciences. 2014; 2:521.
22. Kucia A, Jankowski T, Siewniak M, Janiszewska-Olszowska J, Grocholewicz K, Szych Z, et al. Sella turcica anomalies on lateral cephalometric radiographs of Polish children. Dentomaxillofac Radiol. 2014; 43(8):20140165.
23. Choi WJ, Hwang EH, Lee SR. The study of shape and size of normal sella turcica in cephalometric radiographs. Korean Journal of Oral and Maxillofacial Radiology. 2001; 31(1):43-9.
24. Axelsson S, Storhaug K, Kjaer I. Post-natal size and morphology of the sella turcica. Longitudinal cephalometric standards for Norwegians between 6 and 21 years of age. Eur J Orthod. 2004; 26(6):597-604.
25. Turamanlar O, Öztürk K, Horata E, Beker-Acay M. Morphometric assessment of sella turcica using CT scan. Anatomy. 2017; 11:6-11.
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Ceren Özeren Keşkek, Emre Aytuğar. Assessment of the shape and dimensions of sella turcica using cone-beam computed tomography. Ann Clin Anal Med 2021;12(10):1157-1161
Evaluation of symptom severity and life quality of cancer patients in palliative care unit
Zülfünaz Özer 1, Rukiye Pınar Bölüktaş 1, Ayşe Nefise Bahçecik 1, Gülistan Şakar 2
1 Department of Nursing, Faculty of Health Sciences, Istanbul Sabahattin Zaim University, 2 Beylikdüzü State Hospital, Istanbul, Turkey
DOI: 10.4328/ACAM.20687 Received: 2021-05-04 Accepted: 2021-07-19 Published Online: 2021-08-01 Printed: 2021-10-01 Ann Clin Anal Med 2021;12(10):1162-1166
Corresponding Author: Zülfünaz Özer, Department of Nursing, Faculty of Health Sciences, Istanbul Sabahattin Zaim University, Istanbul, Turkey. E-mail: firstname.lastname@example.org P: +90 212 692 89 78 Corresponding Author ORCID ID: https://orcid.org/0000-0002-2431-2346
Aim: This cross-sectional and descriptive study was conducted to evaluate the symptom severity and quality of life levels of cancer patients hospitalized in palliative care units, and the effect of symptom severity on quality of life.
Material and Methods: This study included 100 cancer patients hospitalized in palliative care units between November and December 2019, who accepted to participate in the study. Data were collected through face-to-face interview and Patient Information Form, Edmonton Symptom Assessment Scale (ESAS) and Functional Assessment of Chronic Illness Therapy-Palliative Care (FACIT-Pal) Scale through face-to-face interview.
Results: The mean age of the participants was 66.4 years; 51% were females and 77% of the patients received care help from their spouses. Lung cancer was diagnosed in 30% of the patients, 98% were at the fourth stage of the disease, and 66% received chemotherapy. Most severely experienced symptoms were as follows in order: lack of appetite, dyspnea, fatigue, changes in skin and nails, anxiety, pain, and drowsiness. Life quality mean scores were 9.5±3.06 for physical well-being, 12.5±4.41 for social life/family well-being, 8.9±3.19 for emotional well-being, 4.8±3.08 for functional well-being, 29.7±8.09 for other concerns, and 65.3±14.50 for total FACIT-Pal.
Discussion: It was determined that the patients had high symptom severity and low life quality; besides as the severity of the symptoms increase, life quality decreased.
Keywords: Palliative care; Life quality; Symptom severity
Palliative care is an approach that increases the life quality of a patient, together with and his/her family, who has experienced a life-threatening serious disease, by early diagnosis, evaluation and treatment of physical (primarily pain), psychosocial and spiritual problems. WHO declares that patients with cancer, cardiovascular diseases, chronic respiratory diseases, and chronic renal failure require palliative care . Cancer patients in palliative care units are reported to experience many physiological and psychological symptoms like pain, fatigue, asthenia, respiratory distress, nausea, vomiting, mucositis, constipation, lack of appetite, weight loss, anxiety, and depression [2,3]. It is also determined that problems experienced due to these symptoms negatively affect the functionality and life quality of patients [2-4].
Life quality is defined as how individuals perceive themselves concerning expectations from life, purposes, interests, and standards within the context of their own culture and values. Many factors like physical, psychological status and performance of the individual, relationship with family members, environmental events, belief status, chronic terminal diseases, and the support level affect the life quality of an individual . The symptoms of palliative care patients with life-threatening chronic diseases (pain, dyspnea, anxiety, nausea, vomiting, etc.) have a particularly negative effect on the life quality of individuals .
The purpose of palliative care is to improve functional capacity and relieve pain and improve life quality by controlling the symptoms while acting responsibly for the cultural and local values, beliefs, and applications of the beliefs of individuals . It has been reported that usually attention is focused on the management of a single symptom in cancer patients experiencing multiple symptoms . When focusing on only one symptom, other symptoms may escape attention, treatment falls short and this negatively affects the life quality of the patient . When the disease and symptoms arising from therapy are not brought under control, patients may give up therapy, the dosage of therapy may have to be reduced or the therapy may be discontinued. Controlling the symptoms is crucial for the patient and family in coping with the therapy [7,8]. Systematic evaluation of all the symptoms of the patient would provide information on disease prognosis and would help in clinical decisions on how to increase the life quality of the patient .
Systematic and regular evaluation of symptoms is important for effective symptom management and maintaining and sustaining the life quality of the patients . Nurses must define the symptoms of their patients through comprehensive symptom evaluation and evaluate the life quality of their patients in palliative care. Patients should receive holistic care according to symptom management and their life quality should be improved [6,10,11]. Besides, correct measurement of patient’s life quality is necessary for evaluation of service provision and testing the efficacy of the intervention . In light of this information, this cross-sectional and descriptive study was conducted to evaluate the symptom severity and quality of life levels of cancer patients hospitalized in palliative care units and the effect of symptom severity on quality of life.
Material and Methods
This study is a cross-sectional descriptive study.
Universe and Sample of the Study
This study was done between November and December 2019, in the palliative care units of three hospitals in Istanbul. The universe of the study was composed of 120 patients hospitalized in these hospitals during the indicated period. The sample of the study included 100 patients that were over 18 years of age, conscious, able to communicate verbally, and accepted to participate in the study.
Data Collection Tools
Research data were collected through face-to-face interviews with the patients. Data were collected using the “Patient Information Form”, “Edmonton Symptom Assessment Scale (ESAS)” and “Functional Assessment of Chronic Illness Therapy- Palliative Care (FACIT-Pal) Scale”.
Patient Information Form: This form was developed by the researchers and included questions about patients’ age, gender, marital status, whether they had children, education status, spouse, employment status, unemployment reason, income, the person responsible for the care, diagnosis, metastasis status, chemotherapy status, radiotherapy status, surgical therapy status, other chronic disease status and the stage of the disease.
Edmonton Symptom Assessment Scale (ESAS)
Edmonton Symptom Assessment Scale (ESAS) evaluates the symptoms like pain, fatigue, nausea, sadness, anxiety, drowsiness, lack of appetite, feeling unwell, dyspnea, changes in skin and nails, mouth sores, and paresthesia in hands, which are commonly observed in cancer patients, with a score between 0 and 10. Zero indicates no symptom, while 10 indicates a very severe symptom. This scale was developed by Bruera et.al. (1991) and the validity and reliability of the Turkish version of the scale were done by Sadırlı and Ünsar (2009). Chronbach’s alpha value for the scale was calculated as 0.76 . In this study, Chronbach’s alpha value of the scale was found as 0.79. Functional Assessment of Chronic Illness Therapy- Palliative Care (FACIT-Pal) Scale
Functional Assessment of Chronic Illness Therapy- Palliative Care (FACIT-Pal) Scale is one of the life quality scales of Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System that is widely used in clinical research. The validity and reliability of the Turkish version of the scale was done by Bagcivan et.al. (2019). This scale is used to evaluate the life quality associated with palliative care. The scale is composed of 45 items (26 items for FACIT-G and 19 newly added items on additional concerns/palliative care) with 5- point Likert type questions (0: None-4: Very Much). FACIT-Pal (0-180 point) is composed of five subscales: physical well-being (0-28 points), social/family well- being (0-24 points), emotional well-being (0-24 points), functional well-being (0-28 points) and additional concerns (0-76 points). Higher scores from subscales and total scale indicate higher life quality. Chronbach’s alpha value for FACIT-Pal total scale is 0.93 and Chronbach’s alpha values calculated for subscales are between 0.73 and 0.86 . In this study, Chronbach’s alpha value was calculated as 0.82 for the total FACIT-Pal scale, and it was found to be between 0.70 and 0.75 for subscales.
SPSS version 25.00 statistical package program was used for data analysis. Percentage, mean, standard deviation, and multiple regression analysis were used for descriptive statistics. The significance level was accepted as p<0.05. Ethical Aspects of The Study
The approval (31.07.2019 date and 2019/07 numbered) was obtained from the Directorate of the Ethics Committee of one university. Oral consent was obtained from patients included in the study, after informing them about the aim and application method of the study. This study was done following the ethical standards of the Helsinki Declaration. Voluntary participants were included in the study and personal identifying information was kept confidential.
The mean age of the patients was 66.43±10.14 years; 51% were female, 87% were married, 88% had children, 58% were primary school graduates, 56% lived with their spouse and children, 99% did not work, 58% were retired and 67% had moderate-income (Table 1). Among the patients, 35% had no other chronic diseases, and spouses provided care for 77%. Lung cancer was diagnosed in 30% of the patients, 37% had metastasis, 66% received chemotherapy, 10% received radiotherapy, 4% received surgical therapy; almost all of the patients (98%) were at stage 4 (Table 1).
The severity of patients’ symptoms is presented in Table 2.
The most severe symptoms were appetite (8.0±1.86), dyspnea (7.8±1.53), fatigue (7.7±2.27), anxiety (7.40±1.94), pain (7.40±2.30), changes in skin and nails (7.30±2.08), feeling unwell (7.30±1.98), sadness (7.24±2.22) and nausea (6.20±2.48).
Life Quality scores of patients were 9.5±3.06 for physical well-being, 12.5±4.41 for social/family well-being, 8.9±3.19 for emotional well-being, 4.8±3.08 for functional well-being, 29.7±8.09 for additional concerns, and 65.3±14.50 for total FACIT-Pal.
When Table 3 was evaluated, multiple linear regression analysis done to determine the effect of independent variables on FACIT- Pal turned out to be statistically significant (F(5.94)=20.961, p<0.001). Independent variables in the model accounted for 52.7% of the total variance in FACT-Pal (R2=0.527, p<0.001). When regression coefficients were analyzed, it was found that nausea β=-0.348, p<0.001), sadness (β=-0.552, p<0.001), anxiety (β=-0.371, p<0.001), feeling unwell (β=-0.299, p<0.001) and dyspnea (β=-0.175, p<0.001) variables had a negative and significant effect on FACIT-Pal.
Physical, psychosocial, and spiritual symptoms, experienced by palliative care patients, restraint their lives, result in the feeling of loss of control over life, and negatively affect their life quality . This study was conducted to evaluate the symptom severity and quality of life levels of cancer patients hospitalized in palliative care units and the effect of symptom severity on quality of life. The findings of this study are discussed according to the literature.
The most severe symptoms of patients are lack of appetite, dyspnea, fatigue, anxiety, pain, changes in skin and nails, feeling unwell, sadness and nausea, in the order of severity. Saygılı and Çelik (2020) reported that patients in palliative care units experienced fatigue, feeling unwell, lack of appetite, anxiety, sadness, and pain symptoms most frequently. Various studies also determined palliative care patients experience fatigue, lack of appetite, feeling unwell symptoms . Omran et.al. (2017) stated the most frequent symptoms of patients as lack of energy, pain, mouth dryness, lack of appetite, drowsiness, and dyspnea. Another study on palliative care patients determined the most commonly experienced symptoms, including pain, fatigue, dyspnea, nausea, and cough . A review on the subject listed the most frequent symptoms as pain, dyspnea, fatigue, lack of appetite, nausea, and vomiting, constipation, anxiety, and depression . Radiotherapy receiving palliative care patients were reported to experience fatigue, drowsiness, feeling unwell, pain, nausea, lack of appetite, and dyspnea most frequently . The findings of our study reveal a different ranking of symptom frequency, compared to the literature. A possible reason for this difference could be the inclusion of different patient groups.
It has also been stated that symptom experience is dynamic and therefore results in different symptoms being experienced among patients .
In this study, patients’ physical well-being, emotional well- being, functional well-being states, additional concerns, and FACIT-Pal total life quality scores were found to be low. A study on palliative patients also found low physical and emotional functionality and total life quality score . Another study on palliative patients determined the life quality of the patients (including physical functionality, role functioning, emotional functionality, cognitive functionality, and social functionality subscales) was low . A systemic review on the life quality of palliative care patients also determined a low life quality score . Another study by Soares Cruz (2019) also found low life quality among patients . There are various studies in the literature reporting low life quality scores among palliative care patients [2,11,22]. Our findings are consistent with the literature, pointing out that the physical, functional, and emotional losses of palliative care patients affect life quality negatively.
Patients’ sadness, nausea, anxiety, feeling unwell and dyspnea symptoms are the variables that negatively affect life quality, in our study. Bužgová and Sikorová (2015) reported pain, dyspnea, lack of sleep, and lack of appetite as symptoms negatively affecting life quality and stated that life qualities of palliative care patients were related to good symptom management and high-quality nursing care . A meta-analysis by Kassianos et al. (2018) stated that improvement in pain, nausea, fatigue symptoms affected life quality positively . It has also been found that as the severity of fatigue, lack of appetite, and feeling unwell symptoms increased, life quality was negatively affected . Emotional problems and fatigue-pain symptoms were stated to negatively affect the life quality and general health of patients . Also, physical, gastrointestinal, respiratory, and psychological symptoms experienced by patients negatively affected life quality . Our findings were similar to those in the literature. Symptom severity of patients negatively affected life quality. Symptoms of patients must be periodically evaluated and controlled to improve life quality.
Limitations of the Study
This study has several limitations. First, the findings of this study are valid for the patients included in the study; therefore, it cannot be generalized to all palliative patients. Second, the reliability of the data is limited by the trueness of the answers of patients who participated in the study.
It was determined that the patients had high symptom severity and low life quality; an increase in symptom severity (sadness, nausea, anxiety, feeling unwell, and dyspnea) decreased life quality. Each symptom of palliative care patients must be addressed separately and evaluated periodically. It is suggested that life quality should be evaluated from all aspects, and the life quality of patients at the last stage of their disease should be improved with appropriate interventions. The presence of other potential variables decreasing the life quality of palliative care patients should also be investigated.
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Animal and human rights statement
Conflict of interest
1.Kaur S, Kaur H, Komal K, Kaur P, Kaur D, Jariyal VL, et al. Need of palliative care services in rural area of Northern India. Indian J Palliat Care. 2020; 26(4):528-30
2.Omran S, Khader Y, McMillan S. Symptom clusters and quality of life in hospice patients with cancer. Asian Pac J Cancer Prev. 2017; 18(9):2387.
3.Stapleton SJ, Holden J, Epstein J, Wilkie DJ. Symptom clusters in patients with cancer in the hospice/palliative care setting. Support Care Cancer. 2016; 24(9):3863-71.
4.Digel-Vandyk A, Harrison MB, Macartney G, Ross-White A Stacey D. Emergency department visits for symptoms experienced by oncology patients: A systematic review. Support Care Cancer. 2012; 20(8):1589-99.
5.Boylu AA, Paçacıoğlu B. Yaşam kalitesi ve göstergeleri (Quality of life and its indicators). Akademik Araştırmalar ve Çalışmalar Dergisi (AKAD)/ Journal of Academic Research and Studies. 2016; 8(15):137-50.
6.Dong ST, Butow PN, Costa DS, Lovell MR, Agar M. Symptom clusters in patients with advanced cancer: A systematic review of observational studies. J Pain Symptom Manage. 2014; 48(3):411–50.
7.Alves M, Abril R, Neto IG. Symptomatic control in end-of-life patients. Acta Medica Portuguesa. 2017; 30(1):61-8.
8.Levy M, Smith T, Alvarez-Perez A, Back A, Baker JN, Beck AC, et al. Palliative care version 1.2016. J Natl Compr Canc Netw. 2016; 14(1):82-113.
9.Ganesh V, Zhang L, Chan S, Wan BA, Drost L, Tsao M, et al. An update in symptom clusters using the Edmonton Symptom Assessment System in a palliative radiotherapy clinic. Support Care Cancer. 2017; 25(11):3321-27.
10.Lynch MT. Palliative care at the end of life. Semin Oncol Nurs. 2014; 30 (4):268-79.
11.Silva LDS, Lenhani BE, Tomim DH, Guimarães PRB, Kalinke LP. Quality of life of patients with advanced cancer in palliative therapy and in palliative care. Aquichan. 2019; 19(3):e1937. DOI: 10.5294/aqui.2019.19.3.7
12.Siegert R, Selman L, Higginson IJ, Ali Z, Powell RA, Namisango E, et al. A psychometric evaluation of the functional assessment of chronic illness therapy- palliative care (FACIT-Pal) scale with palliative care samples in three African countries. J Pain Symptom Manage. 2014; 48(5):983-91.
13.Bruera E, Kuehn N, Miller MJ, Selmser P, Macmillan K. The Edmonton Symptom Assessment System (ESAS): a simple method for the assessment of palliative care patients. J Palliat Care. 1991; 7(2):6-9.
14.Sadırlı SK, Ünsar S. Kanserli Hastalarda Edmonton Semptom Tanılama Ölçeği (ESTÖ): Türkçe Geçerlilik ve Güvenirlik Çalışması (Edmonton Symptom Assessment System (ESAS): A Turkish Validity and Reliability Study). Fırat Saglık Hizmetleri Dergisi/ Fırat Journal of Health Services. 2009;4 (11):79-95.
15.Bagcivan G, Bredle J, Bakitas M, Dogan BG. Reliability and validity of the Turkish Version of the FACIT-PAL Quality of Life Instrument. J Pain Symptom Manage. 2019; 58(2):297-305.
16.Saygılı M, Çelik Y. Kanser tanılı hastalarda palyatif bakım hizmetlerinin etkisinin değerlendirilmesi: Semptom düzeyi ve bakım memnuniyeti açısından bir karşılaştırma (Evaluation of the effect of palliative care services in cancer patients: A comparison in terms of symptom level and care satisfaction). Ağri/ Pain. 2020; 32(2):61–71. DOI: 0.14744/agri.2019.95770
17.Uysal N, Şenel G, Karaca Ş, Kadıoğulları N, Koçak N, Oğuz G. Palyatif bakım kliniğinde yatan hastalarda görülen semptomlar ve palyatif bakımın semptom kontrolüne etkisi (Symptoms seen in patients hospitalized in the palliative care clinic and the effect of palliative care on symptom control). Ağrı/ Pain. 2015; 27(2):104-10.
18.Leppert W, Majkowicz M, Forycka M, Mess E, Zdun-Ryzewska A. Quality of life assessment in advanced cancer patients treated at home, an inpatient unit, and a day care center. Onco Targets Ther. 2014; 7:687-95. DOI: 10.2147/OTT.S57338
19.Bužgová R, Sikorová L. Association between quality of life, demographic characteristics, physical symptoms, and unmet needs in inpatients receiving end- of-life care: A Cross-sectional Study. Journal of Hospice & Palliative Nursing. 2015; 17(4):325-32.
20.Lenhani BE, Tomim DH, dos Santos Silva L, de Alcântara Nogueira L, Kalinke LP. Life quality assessment of patients in palliative chemotherapy and palliative care: Scoping review. Cienc Cuid Saude. 2019; 18(1):e43078.
21.Soares Cruz FC, Maria Borges F, da Silva EHE, das Graças Pena G. Are the nutritional status and tube feeding associated with quality of life in oncologic patients on palliative care? Demetra: Food, Nutrition & Health/Alimentação, Nutrição & Saúde. 2019; 14:e38198
22.Figueiredo JF, Souza VM, Coelho HV, Souza RS. Qualidade de vida de pacientes oncológicos em cuidados paliativos (Quality of life of cancer patients in palliative care). Rev Enferm do Centro-Oeste Min. 2018; 8:e2638. DOI: 10.19175/recom. v8i0.2638
23.Kassianos AP, Ioannou M, Koutsantoni M, Charalambous H. The impact of specialized palliative care on cancer patients’ health-related quality of life: a systematic review and meta-analysis. Support Care Cancer. 2018; 26(1):61-79. DOI:10.1007/s00520-017-3895-1
24.Dong ST, Costa DSJ, Butow PN, Lovell MR, Agar M, Velikova G, et al. Symptom clusters in advanced cancer patients: an empirical comparison of statistical methods and impact on quality of life. J Pain Symptom Manage. 2016; 51(1):88– 98.
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Zülfünaz Özer, Rukiye Pınar Bölüktaş, Ayşe Nefise Bahçecik, Gülistan Şakar. Evaluation of symptom severity and life quality of cancer patients in palliative care unit. Ann Clin Anal Med 2021;12(10):1162-1166
The impact of COVID-19 on traumatic hand injuries: A Turkish survey
Sezgin Bahadır Tekin 1, Mehmet Vakıf Keskinbıçkı 2
1 Department of Orthopedic Surgery, 25 Aralık State Hospital, 2 Department of Hand Surgery, Dr. Ersin Arslan Education and Research Hospital, Gaziantep, Turkey
DOI: 10.4328/ACAM.20688 Received: 2021-05-04 Accepted: 2021-07-17 Published Online: 2021-07-30 Printed: 2021-10-01 Ann Clin Anal Med 2021;12(10):1167-1170
Corresponding Author: Sezgin Bahadır Tekin, 25 Aralık State Hospital, Department of Orthopedic Surgery, Gaziantep, Turkey. E-mail: email@example.com P: +90 531 791 66 86 Corresponding Author ORCID ID: https://orcid.org/0000-0003-4740-9949
Aim: Our aim in the study is to perform a comparative analysis of traumatic hand injuries during the quarantine period of the COVID-19 pandemic with data of the previous year and to research the effect of quarantine on hand injuries.
Material and Methods: We retrospectively analyzed patients who presented to the emergency department with traumatic hand injuries between 16.03.2020 and 01.06.2020 and within the same period of 2019. Patients’ age, gender, injury mechanism, length of hospitalization, ethnic origin, presence of major and digital nerve injuries, presence of bone injury, emergency or elective surgery data were recorded. The data were analyzed statistically in comparison with the previous year.
Results: A total of 301 patients participated in the study. There were 117 patients in 2020, and 184 patients in 2019. When patients of both years were exam- ined in terms of age, gender and length of hospitalization, there was no statistically significant difference between the patients who were operated for hand injuries between 2020 and 2019 (p>0.05). When patients who were operated due to hand injuries were examined in terms of differences in ethnic origin, opera- tion under emergency conditions and accompanying bone injury between both groups, a statistically significant difference was found between them (p<0.05).
Discussion: A decrease was observed in the number of traumatic hand injuries admitted to the emergency department during the COVID-19 pandemic; how- ever, there were no changes in etiology. These reference data can help healthcare systems prepare for future outbreaks and similar restrictions.
Keywords: Hand; Injury; COVID; Pandemic; Trauma
As it is known, the COVID-19 virus, which emerged in China- Wuhan in December 2019, has spread rapidly all over the world. After this rapidly spreading pandemic, patients with respiratory complaints began to present to hospitals day by day, placing a serious burden on the health system . Even though daily life is restricted during this period, trauma patients continue to present to the hospital. It is also known that hand injuries, in general, constitute about 29% of the injuries treated in hospital, and they represent a considerable percentage . Therefore, emergency and hand surgery departments are constantly dealing with hand injuries. Due to the pandemic, the management of both virus-related and trauma patients has gained significance in this period. Our aim in the study is to investigate the effects of the pandemic and quarantine period on hand injuries by analyzing patients who presented to the hand surgery department in the period since the COVID-19 outbreak compared to the previous year, and to have an idea about what might happen in similar cases in the future. Considering this situation, the issue of how traumatic hand injuries are managed will be an example for similar cases in the future besides the increasing health system burden [2-3].
Material and Methods
The study was designed retrospectively; the data of patients between 16.03.2020 and 01.06.2020 and the data of patients who had been hospitalized and had traumatic hand injuries within the same period a year ago were examined and analyzed. The digital archive of the hospital was used while obtaining the data. Patients with problems other than hand injuries, conservatively treated patients, and patients who had hand operations due to non-traumatic reasons were excluded from the study. Patients who received inpatient treatment and operated due to hand injuries, according to the hospital registry archive, were included in the study. All patients’ age, gender, ethnic origin, injury mechanism, presence of accompanying major nerve injury, presence of accompanying digital nerve injury, presence of accompanying bone injury, whether they were operated in emergency or elective conditions, and duration of hospitalization were recorded. The same data were also recorded within the same date range for the previous year. Differences within each year were statistically analyzed. The study was approved by local ethic committee (decision no:2020/425).
In the descriptive statistics of the variables examined in the study, continuous variables (age, length of hospitalization (days)) were expressed as mean ± standard deviation, median (minimum-maximum), and nominal variables as n (%). The statistical significance of nominal variables between two years was tested with the chi-square test, and continuous variables with the Mann-Whitney U test. In all statistical analyses, the significance level was accepted as p<0.05, and the IBM SPSS 22.0 (IBM Corp, Armonk, NY, USA) software was used.
A total of 301 patients participated in the study (Table 1). While 263 (87.4%) of the patients who participated in the study were
Turkish citizens, 38 (12.6%) were Syrian refugees. According to years, 108 were Turkish citizens and 9 were Syrian citizens in 2020, whereas 155 were Turkish citizens and 29 were Syrian refugees in 2019. Among the injury mechanisms, most of the injuries were caused by accidents resulting from glass incision (Table 2).
When the major nerve injuries accompanying the injuries were analyzed, a total of 258 patients had no accompanying nerve injuries, whereas 43 patients had major ulnar, radial, and median nerve injuries. Median nerve injury was found in 24 patients, ulnar nerve injury in 11 patients, and radial nerve injury in 8 patients. While this number was characterized bynerve injuries in 26 (10 median, 10 ulnar, 6 radial) patients in 2020, major nerve injuries were observed in 17 (9 median, 6 ulnar, 2 radial) patients in 2019. On the other hand, when the digital nerve injuries accompanying the injuries were analyzed, 93 patients had no digital nerve injuries, whereas 24 patients had digital nerve injuries in 2020. In 2019, 163 patients had no digital nerve injuries, whereas 21 patients had digital nerve injuries.
When both groups were analyzed for the presence of accompanying bone injuries, 49 patients had accompanying bone injuries and 68 patients did not in 2020. In 2019, on the other hand, 49 patients had bone injuries, whereas 135 patients had no accompanying bone injuries.
Among the patients who participated in the study, 224 were operated under emergency conditions.
Length of hospitalization was analyzed in both groups. The average length of hospitalization was 0 days in both groups. Length of hospitalization varied between 0 and 35 for 2019 and between 0 and 13 for 2020.
When the patients of both years were examined in respect for age, gender and length of hospitalization, there was no statistically significant difference between the patients who were operated for hand injuries between 2020 and 2019 (p>0.05) (Table 3).
When the patients operated for hand injuries were examined in respect of differences in ethnic origin, operation under emergency conditions and accompanying bone injury between the two groups, a statistically significant difference was detected between them (p<0.05) (Table 3).
The study includes a comparative analysis of the patients who presented with traumatic hand injuries in our country, where partial quarantine is implemented during the COVID-19 pandemic, with the previous year. When evaluated economically in terms of both loss of job and treatment costs, hand injuries are significant and constitute 29% of the injuries in emergency departments .
In the literature, there are publications that have examined hand injuries during the COVID-19 pandemic before [5-7]. In these studies, it was highlighted that the etiology and management of hand injuries changed during the lockdown period.
In our study, it was concluded that the most common type of injury during lockdown occurred in occupational accidents involving glass incisions. However, no change was observed in the injury mechanism in the previous year. This situation may indicate that the working life and the intensity of work brought by industry and production did not change so much when compared to the period before the pandemic.
It has been demonstrated that orthopedic practice has also been affected during the COVID-19 pandemic . It is assumed that reducing human mobility to lessen the spread of the virus will decrease trauma-related injuries. When evaluated in respect of hand injuries, the number of patients dropped compared to the previous year. However, no obvious decrease was felt even though the number of patients decreased. This situation may be attributed to the lack of a complete quarantine implementation in our country.
It has been reported that lockdown periods have led to changes in people’s behavior and habits . Even though it was thought that behavioural changes might influence hand injuries, there was no significant difference between the two groups in terms of injury mechanism.
In several parts of the world, different precautions have been taken by hand surgeons during the COVID-19 pandemic [7-10]. In many clinics, the number of beds and operating rooms has been decreased. The purpose of this action was to make room for COVID-19 patients . Also, in our clinic, the number of beds has dropped from 40 to 20 during the pandemic period. However, as the study examined patients with hand injuries and patients exposed to trauma for both years, no problems were encountered regarding accommodation for patients with hand injuries. Meanwhile, it was observed that there was no significant difference in the length of hospitalization of the patients in both years.
In our study, patients who presented to the emergency department for hand injuries and their demographic analyses were examined. Hand injuries, which were admitted to the emergency department and did not require hospitalization were not included in the study. This enabled us to more clearly conduct a comparative analysis of both years.
Unlike other studies, refugee patients are also provided with a lot of health services because of the geographic location in which we live. When both groups were analyzed, a significant difference was identified between the ethnic origins of patients with hand injuries. This may show that during the lockdown period, refugees are either less exposed to hand injuries or cannot access health services as easily as others. On the other hand, the accompanying bone injuries were found to be significantly different between the two groups, and even the accompanying bone injuries were proportionally higher in the pandemic period. Even though it is predicted that the pandemic will reduce mobility in the streets and reduce high-energy traumas, our data exclude this prediction.
The study has some limitations. First, this is a retrospective study. This is a limitation. Besides, the patients were analyzed in line with the data obtained from the digital archive of the hospital. In such cases, though rare, a few things may be overlooked due to the problems in the recording system. Conclusion
With the COVID-19 pandemic, it is observed that the mechanism of hand injuries, age, gender, length of hospitalization and the process do not change so much for our country. The pandemic period changes habits; however, we cannot determine how much hand injuries will be influenced unless there is a complete quarantine application.
Scientific Responsibility Statement
Animal and human rights statement
Conflict of interest
1. Paules CI, Marston HD, Fauci AS. Coronavirus infections—more than just the common cold. JAMA. 2020; 323(8):707–8. DOI: 10.1001/jama.2020.0757.
2. de Putter CE, Selles RW, Polinder S, Panneman MJM, Hovius SER, van Beeck EF. Economic impact of hand and wrist injuries: health-care costs and productivity costs in a population-based study. J Bone Joint Surg Am. 2012; 94:e56–61.
3. Fontanarosa PB, Bauchner H. COVID-19-looking beyond tomorrow for health care and society. JAMA. 2020; 323:1907–8.
4. Larsen CF, Mulder S, Johansen AMT, Stam C. The epidemiology of hand injuries in the Netherlands and Denmark. Eur J Epidemiol. 2004; 19(4):323–7.
5. Pichard R, Kopel L, Lejeune Q, Masmoudi R, Masmejean EH. Impact of the Coronavirus Disease 2019 lockdown on hand and upper limb emergencies: experience of a referred university trauma hand centre in Paris, France. Int Orthop. 2020; 44(8):1497–501.
6. Ducournau F, Arianni M, Awwad S, Baur EM, Beaulieu JY, et al. COVID-19: initial experience of an international group of hand surgeons. Hand Surg Rehabil. 2020; 39(3):159–66.
7. Facchin F, Messana F, Sonda R, Faccio D, Tiengo C, Bassetto F. COVID-19: initial experience of hand surgeons in Northern Italy. Hand Surg Rehabil. 2020; 39(4):332-3.
8. Bram JT, Johnson MA, Magee LC, et al. Where have all the fractures gone? The epidemiology of pediatric fractures during the COVID-19 pandemic. J Pediatr Orthop. 2020; 40(8):373-9. DOI: 10.1097/ BPO.0000000000001600.
9. Brooks SK, Webster RK, Smith LE, Woodland L, Wessely S, Greenberg N, et al. The psychological impact of quarantine and how to reduce it: rapid review of the evidence. Lancet. 2020; 14(395):912–20.
10. Hwee J, Chiew J, Sechachalam S. The impact of coronavirus disease 2019 (COVID-19) on the practice of hand surgery in Singapore. J Hand Surg. 2020; 45(6):536-41.
11. Mauffrey C, Trompeter A. Lead the way or leave the way: leading a Department of Orthopedics through the COVID-19 pandemic. Eur J Orthop Surg Traumatol. 2020; 30(4):555–7.
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Sezgin Bahadır Tekin, Mehmet Vakıf Keskinbıçkı. The impact of COVID-19 on traumatic hand injuries: A Turkish survey. Ann Clin Anal Med 2021;12(10):1167- 1170
Evaluation of the relationship between amitriptyline dose ingested and ADORA criteria in amitriptyline intoxication: A retrospective observational study
Abdullah Algın, Serdar Özdemir, Hatice Şeyma Akça, İbrahim Altunok
Department of Emergency Medicine, University of Health Sciences, Umraniye Training and Research Hospital, Istanbul, Turkey
DOI: 10.4328/ACAM.20739 Received: 2021-06-08 Accepted: 2021-08-19 Published Online: 2021-09-13 Printed: 2021-10-01 Ann Clin Anal Med 2021;12(10):1171-1174
Corresponding Author: Serdar Özdemir, Department of Emergency Medicine, University of Health Sciences, Umraniye Training and Research Hospital, Istanbul, Turkey. E-mail: firstname.lastname@example.org P: +90 505 267 32 92 Corresponding Author ORCID ID: https://orcid.org/0000-0002-6186-6110
Aim: Amitriptyline exerts its effects on the central nervous system by inhibiting the reuptake of norepinephrine, dopamine, and serotonin. Amitriptyline’s toxic effects occur 30 min after the ingestion of an excessive dose and peak within 2-6 h. While amitriptyline has a primarily anticholinergic effect at low doses, at high doses, it produces a potent depressive effect on the central nervous system, accompanied by cardiotoxicity, seizures, and hypotensive symptoms. The Antidepressant Overdose Risk Assessment (ADORA) criteria are used to evaluate clinical symptoms. In this study, we investigated the relationship between certain clinical and demographic parameters and the ADORA criteria in patients presenting to the emergency department with tricyclic antidepressant agent poisoning.
Material and Methods: The study included 18 patients admitted to the hospital between January 2016 and December 2019 following attempted suicide by amitriptyline overdose. Clinical and demographic data, ADORA risk classification, and ingested doses were recorded on a case-by-case basis. The relationship between ADORA risk classification, ingested dose, and other clinical parameters was analyzed.
Results: Of the patients included in the study, two were male (10.5%) and 16 were female (84.2%). The minimum ingested dose was 100 mg, maximum 525 mg, and median 300 mg. According to the ADORA criteria, 12 cases (66.7%) were classified as low-risk and six cases (33.3%) as high-risk. All the high-risk patients were hospitalized and treated (p<0.0001). The relationship between the amitriptyline dose ingested and ADORA classification was statistically significant (p=0.02). The sensitivity and specificity of this classification system for amitriptyline dose ingested were 100% and 60%, respectively, at a cut-off value of 285 mg and 60% and 100%, respectively, at a cut-off value of 350 mg.
Discussion: The ADORA risk classification system positively correlated with the hospitalization rate. Patients having ingested ≥350 mg of amitriptyline were classified as high-risk by the ADORA system with high specificity.
Keywords: Amitriptyline, Tricyclic Antidepressants, Antidepressants, Adrenergic Uptake Inhibitors, Prognosis
Amitriptyline (AMT) is a tricyclic antidepressant agent (TCA). Compounds containing AMT, imipramine, and other V-dimethyl derivatives came into use as antidepressants in the 1960s . These agents act by inhibiting the reuptake of norepinephrine, dopamine, and serotonin from synapses in the central nervous system. Tricyclics are well absorbed from the gastrointestinal tract, transported through binding to plasma proteins, and eliminated by the hepatic metabolism .
Toxic effects start within 30 min following the excessive intake of TCA and peak in 2-6 h. Anticholinergic effects are dominant at low doses, while high doses of TCA produce significant depression in the central nervous system, accompanied by cardiotoxicity, seizures, and hypotensive symptoms . Cardiotoxicities are associated with ventricular tachyarrhythmias, atrioventricular block, delays, bradycardia, and decreased cardiac output. Widening of the QRS complex is associated with increased cardiac arrhythmias and seizures . The Antidepressant Overdose Risk Assessment (ADORA) criteria are used to evaluate clinical findings . These criteria include QRS prolongation, arrhythmias, mental status changes, seizures, respiratory depression, and hypotension. Patients who do not meet any of these criteria at the time of admission to the emergency department (ED) within the first 6 h following TCA intake or those for whom the time of drug intake is not precisely known are classified as low-risk, while those meeting at least one of these criteria are classified as high-risk . The current study aimed to determine the relationship between the clinical and demographic characteristics of patients who presented to the ED due to AMT intoxication and evaluate the relationship between the AMT dose ingested and the ADORA criteria.
Material and Methods
This retrospective descriptive study was conducted at University of Health Sciences Ümraniye Training and Research Hospital, a 682-bed tertiary academic education hospital with an annual ED census of 356,000 during the study period. We retrospectively collected the data of patients who presented to our ED with a history of AMT ingestion for suicidal purposes between January 1, 2016 and January 1, 2020. The flowchart of the study including the inclusion and exclusion criteria is shown in Figure 1.
The clinical data of the patients, such as age, gender, pregnancy and lactation status, comorbidities, multiple drug use for suicidal purposes, initial ECG abnormalities, emergency service outcome, length of stay in the ED, treatment methods applied, necessity of inotrope use, mechanical ventilation requirement, and number of suicide attempts were recorded. The time from drug intake to admission to ED, dose of AMT taken, vital parameters, and Glasgow Coma Scale scores were documented. Vital parameters recorded were systolic and diastolic blood pressure, peripheral oxygen saturation, and pulse rate. From the laboratory parameters, the lactate level was noted. The ADORA criteria were evaluated by the researchers for each patient and their scores were calculated.
Categorical data were expressed as numbers and percentages and numerical data were expressed as minimum, maximum, and median values. IBM SPSS Statistics 27.0 for Mac (IBM Corp., Armonk, NY, USA) was used for statistical analysis. The Mann-Whitney U test was used to compare ADORA scores with numerical data and Fisher’s exact test was used to compare them with categorical data. In addition, receiver operating characteristic (ROC) curve analysis was performed between the drug dose used and the presence of ADORA criteria, and the cut-off value of this classification system was calculated. Results with a p-value below 0.05 were considered statistically significant.
Ethical approval for the study was obtained from the Clinic Research Ethics Committee of University of Health Sciences Ümraniye Training and Research Hospital (approval number: 188; date: 06.17.2021). We retrospectively reviewed secondary data recorded from the computer-based system of the hospital. Informed consent was waived due to the documented clinical data not including any personal identifiable information.
Of the total 18 cases included in the study (Figure 1), two patients (10.5%) were male and 16 (88.8%) were female. There were no pregnant women in our study population, and there was one lactating woman. According to the evaluation of the disease history and comorbidities of the patients, schizophrenia was present in one patient (5.5%), major depression in two patients (11.1%), diabetes in one patient (5.5%), and migraine in one patient (5.5%). Half of the patients had taken multiple drugs. The minimum age was 22 years, maximum 52 years, and median 32 years. The clinical characteristics of the patients are shown in Table 1.
Detoxification by gastric lavage and repeated administration of activated charcoal were performed for 16 (88.8%) patients. Three of the patients (33.3%) were treated with lipid emulsion. None of the patients required inotropes in the ED. Two patients (11.1%) were mechanically ventilated. When initial ECG abnormalities were evaluated, sinus tachycardia was observed in three (16.6%) patients and QT prolongation in one (5.5%) patient.
According to the ADORA criteria, 12 cases (66.7%) were classified as low-risk and six (33.3%) as high-risk. There was no statistically significant correlation between ADORA and age, gender, systolic and diastolic blood pressure, pulse rate, peripheral oxygen saturation, multiple drug intake, ECG findings, lactate level at admission, treatment methods applied in the ED, mechanical ventilation requirement, time from drug intake to admission to ED, or length of ED stay (p>0.05). Three-quarters of the low-risk patients were discharged, while the remaining one-quarter refused treatment and left the hospital. All high-risk patients were treated as inpatients (p<0.0001). The relationship between the AMT dose ingested and ADORA classification was also statistically significant (p=0.02). The ADORA criteria had sensitivity and specificity of 100% and 60%, respectively, at the cut-off value of 285 mg and 60% and 100%, respectively, at the cut-off value of 350 mg (Figure 2).
In this study, the relationship between AMT level and ADORA criteria was investigated in patients with AMT poisoning admitted to our clinic. The results revealed that the AMT level was correlated with the ADORA criteria.
The ADORA criteria are used to evaluate the clinical findings of patients with antidepressant intoxication [5-8]. These criteria can distinguish serious toxicities in cases of antidepressant intoxication, allowing for daily follow-up and treatment plans to be carried out systematically. In addition, this classification can provide information on the differentiation of severe poisoning findings and possible clinical outcomes . In a retrospective study conducted with 110 patients, Güllüoğlu et al. reported a correlation between the ADORA criteria and the dose of ingested AMT . They showed a high level of correlation between AMT ingestion of greater than 500 mg and the ADORA criteria. In contrast, in our study with a similar methodology, we used the cut-off values of 285 mg and 350 mg for AMT and determined the sensitivity as 100% and 60%, respectively, and specificity as 60% and 100%, respectively. Although we evaluated a smaller population, our findings being in agreement with those of Güllüoğlu et al. support the clinical validity of our data. Both studies can be considered clinically important since the serum AMT level mostly cannot be tested in emergency services in Turkey, as is the case in many other parts of the world, or the patient cannot or does not provide medical history. According to the results of these two similar studies, the ADORA criteria can be used in clinical decision-making in cases where clinicians need to make treatment decisions according to the patient’s clinical state.
Intravenous lipid emulsion therapy was first used in 2006 by Rossenbalt et al. in the treatment of asystole due to bupivacaine, a local anesthetic . Lipid emulsion therapy is defined as the intravenous use of lipid emulsions to reduce the bioavailability and toxicity of circulating lipophilic toxic substances . This method, which is generally preferred for the treatment of systemic toxicity, aims to rapidly lower the content of lipid- soluble compounds in the blood through an initial high-dose bolus administration followed by a constant-rate infusion. In the current literature, it is suggested that lipid emulsion therapy can be used in cases of AMT intoxication [10, 11]. Bora et al. investigated the effectiveness of MgSO4, metoprolol, and lipid emulsion treatments in preventing the cardiac toxicity of AMT overdose in an experimental study and reported that all three treatment options were effective in rats with elongated QTc associated with AMT overdose . In an experimental study on guinea pigs, Tsujikawa et al. suggested that lipid emulsion was a superior first-line therapy method for TCA-induced cardiotoxicity compared to alkalinization therapy . There may be several logical explanations for this positive effect of lipid therapy. One possibility is that emulsified oil droplets form a lipid compartment in the plasma and AMT is drawn into this compartment, thus moving away from areas with high blood flow, such as the heart, kidneys, and brain, where lipophilic substances are present in high concentrations [10-13]. Another mechanism could be the direct inotropic effect of lipids on cardiac work [10-13]. In our cohort, three patients received lipid emulsion therapy and all achieved clinical improvement. Suicidal drug use is a more common behavior among women than men worldwide [12,13]. In our sample, about four-fifths of the patients were female. Among the reasons for this are gender-related characteristics, cultural and social pressure, and not being able to meet societal expectations of the female gender [14-16].
A quarter of our low-risk patient population withdrew from treatment and did not fully attend the recommended close follow-up. In clinical practice, the legal guardians of suicidal patients who have withdrawn from treatment are also asked to confirm this decision; however, certain legal problems may still arise for clinicians . Withdrawal from treatment is an important problem in cases of intoxication . The treatment of especially high-risk patients should be enforced with legal arrangements. It is also important to improve health literacy to ensure compliance with current scientific treatment by patients and their relatives .
The main limitation of this study is its retrospective design. Less biased results can be obtained with prospective studies. Due to the retrospective design, we were not able to access the data of 22 patients, which limited our cohort. Secondly, our study was conducted in a single center with an observational design; therefore, the results cannot be generalized to other healthcare institutions. Thirdly, in this study, we evaluated the intoxication and dose of a specific drug, which further limited the number of cases. This is a general problem of studies conducted in the field of toxicology, especially for specific drugs. A plausible explanation for this may be that clinicians prefer selective serotonin reuptake inhibitor group antidepressants over AMT because selective serotonin reuptake inhibitors have a wide margin of safety and less danger of producing toxic effects with a high therapeutic index. Finally, the generalizability of our study should be increased with larger populations and multicenter studies.
The ADORA risk classification system positively correlated with the hospitalization rate. Patients having ingested ≥350 mg of AMT were classified as high-risk by the ADORA system with high specificity. However, the generalizability of this finding should be increased by further studies with larger populations and multicenter designs.
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1. Baldessarini RJ. Antidepressants. In: Goodman LS, Gilman A, Hardman JG, eds. The Pharmacological Basis of Therapeutics. 10th edition. New York: McGraw-Hill, 2001:451e67.
2. Linden CH, Frederick HH. Poisoning and drug overdosage. In: Fauci AS, Braunwald E, Isselbacher KJ, eds. Harrison’s Principles of Internal Medicine. 14th edn. New York: McGraw-Hill, 1998:2539e42.
3. Mills KC. Tricyclic antidepressants. In: Tintinalli JE, Kelen GD, Stapczynski JS, eds. Emergency Medicine: A Comprehensive Study Guide. 6th edition. New York: McGraw-Hill, 2004:1025e33.
4. Foulke GE. Identifying toxicity risk early after antidepressant overdose. Am J Emerg Med 1995;13:123e6.
5. Tayfur I, Senel A, Colak S, Ibrahim A, Afacan MA, Saritas A. Does determination of drug level in intoxicated patients offer an advantage in diagnosis, treatment, and reducing complications? J Pak Med Assoc. 2020 May;70(5):825-9.
6. Unverir P, Atilla R, Karcioglu O, Topacoglu H, Demiral Y, Tuncok Y. A retrospective analysis of antidepressant poisonings in the emergency department: 11-year experience. Hum Exp Toxicol. 2006 Oct;25(10):605-12.
7. Güloglu C, Orak M, Ustündag M, Altunci YA. Analysis of amitriptyline overdose in emergency medicine. EMJ. 2011 Apr;28(4):296-9.
8. Aydın M, Yardan T, Baydın A, Genç S. Trisiklik Antidepresan Zehirlenmelerinde Adora Risk Skorlaması. Konuralp Medical Journal. 2018; 10(2): 218-21.
9. Bigwood B, Galler D, Amir N, Smith W. Brugada syndrome following tricyclic antidepressant overdose. Anaesth Intensive Care.2005;33:266-70.
10. Gülen M. Trisiklik Antidepresanlarla Zehirlenme ve Güncel Tedaviler. Aktd. 2016; 25(4): 608-17.
11. Arici A, Demirci Ö, Kaplan Y, Tunçok Y. Antidepressant Poisonings Reported to The Dokuz Eylul University Drug and Poison Information Center. Eurasian J Emerg Med 2008;7:23-9.
12. Bora S, Erdoğan MA, Yiğittürk G, Erbaş O, Parlak İ. The Effects of Lipid Emulsion, Magnesium Sulphate and Metoprolol in Amitriptyline-Induced Cardiovascular Toxicity in Rats. Cardiovasc Toxicol. 2018 Dec;18(6):547-56.
13. Tsujikawa S, Matsuura T, Hori K, Mori T, Kuno M, Nishikawa K. Superior Efficacy of Lipid Emulsion Infusion Over Serum Alkalinization in Reversing Amitriptyline- Induced Cardiotoxicity in Guinea Pig. Anesth Analg. 2018 Apr;126(4):1159-69.
14. Akça H, Ozdemir S, Kokulu K, Algın A, Eroğlu S. Psychiatric Evaluation of Suicidal Drug Intake in the Emergency Department. Eurasian J Tox. 2019; 1(3): 91-6.
15. Erensoy H, Aytaç HM, Berkol TD, Tav AŞ. İlaç İçerek İntihar Girişiminde Bulunanlarda Eksen-I Tanı Sıklığı ve Klinik Özellikler. Genel Tıp Derg 2020;30(4):224-34.
16. Ocal O, Ozdemir S, Demir H, Eroglu SE, Onur OE, Ozturk TC. Evaluation of domestic violence against women admitted to the emergency room. Turk J Emerg Med. 2013;13:133-7.
17. Young RJ, King A. Legal aspects of withdrawal of therapy. Anaesth Intensive Care. 2003 Oct;31(5):501-8.
18. Ozdemir S, Kokulu K, Algın A, Akça H. Demographic and Clinical Characteristics of Applications to the Emergency Service with Mushroom Intoxication. Eurasian J Tox. 2019; 1(2): 49-52.
19. Ozdemir S, Akça HŞ, Algın A, Kokulu K. Health Literacy in The Emergency Department: A Cross-sectional Descriptive Study. Eurasian J Emerg Med 2020;19(2):94-7.
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Abdullah Algın, Serdar Özdemir, Hatice Şeyma Akça, İbrahim Altunok. Evaluation of the relationship between amitriptyline dose ingested and ADORA criteria in amitriptyline intoxication: A retrospective observational study. Ann Clin Anal Med 2021;12(10):1171-1174
Current concepts in physiotherapy and rehabilitation protocol for arthrogryposis multiplex congenita: An unusual case report
Elisa Calisgan 1, Betül Akyol 2
1 Department of Physical Therapy and Rehabilitation, Faculty of Health Science, Kahramanmaras Sutcu Imam University, Kahramanmaras, 2 Department of Physical Education and Sports, Faculty of Sport Science, Inonu University, Malatya, Turkey
DOI: 10.4328/ACAM.20596 Received: 2021-03-17 Accepted: 2021-05-24 Published Online: 2021-06-10 Printed: 2021-10-01 Ann Clin Anal Med 2021;12(10):1175-1179
Corresponding Author: Elisa Calisgan, Department of Physical Therapy and Rehabilitation, Faculty of Health Science, Kahramanmaras Sutcu Imam University, Kahramanmaras, Turkey. E-mail: email@example.com P: +90 534 246 24 71 Corresponding Author ORCID ID: https://orcid.org/0000-0003-4710-9540
Arthrogryposis multiplex congenita is a non-progressive syndrome characterized by multiple congenital joint contractures. This case is a six-year-old child with arthrogryposis multiplex congenita who presented at Inonu University Orthopedic Clinic with complaints of weakness and atrophy of m. flexor and extensor carpi radialis and ulnaris, m.flexor and extensor digitorum superficialis, biceps, triceps muscles in the bilateral arms. The tendon transfer was performed in the attachment of the triceps muscle due to the absence of brachialis. This case report presents information on differential diagnosis, detailed symptoms, and physical therapy management of a six- year- old patient with arthrogryposis multiplex congenita.
An early approach to physical therapy decreases complications such as flexor contracture of the wrist and elbow, muscle weakness and atrophy following arthrogryposis multiplex congenita. Physical therapy interventions can improve rigid contracture and muscle atrophy and prolong the need for surgical opera- tion in childhood.
Keywords: Physical Rehabilitation; Arthrogryposis; Atrophy; Children
Arthrogryposis multiplex congenita (AMC) is a non-progressive syndrome characterized by multiple congenital joint contractures . It depends on a multifactorial etiology, and there are autosomal recessive, autosomal dominant, X-linked (more observed in males) or mitochondrial inheritance. 1/3000 of the detected arthrogryposis multiplex congenita is also called amyoplasia congenita or multiple congenital articular rigidity. It may occur due to joint limitation during fetal development because of the mother’s narrow uterus. The disease is divided into two main types due to neurological or myopathic disorders, and neurological symptoms are observed in most patients. Also, in children diagnosed with AMC, the incidence of scoliosis is between 30% and 67% in childhood and the curves generally progress by 6.50 per year [1, 2]. AMC occurs because of intrinsic or fetal anomalies and extrinsic causes. As fetal abnormalities, congenital myopathy and muscular dystrophies are noticed on account of connective tissue disorders such as amyoplasia, peripheral or central nervous system anomalies, diastrophic dysplasia, connective tissue diseases, ligamentous and bone anomalies, dermopathies, osteochondroplasia. Extrinsic causes may occur owing to maternal infection (rubella, Coxsackie), uterine abnormalities or tumours, multiple pregnancies, intrauterine vascular problems and traumas . In AMC cases, the extremities are generally weakened, and the muscles appear fusiform. Sensory perception is normal, but a decrease or loss of the deep tendon reflex is observed. . Amyoplasia is the most common form of AMC and constitutes 1/3 of all cases. Symmetrical contractures are usually detected in 85% of children diagnosed with amyoplasia, and generally, all extremities are affected. Very few of them have genital abnormalities, congenital hernia, amniotic band, congenital heart disease and respiratory problems. Generally, in AMC cases, internal rotation, adduction in the shoulders, extension in the elbow, and flexion position in the wrist are observed. There are internal rotation, adduction in the shoulder, extension in the elbow and flexor contracture in the wrist. In severe cases, the hand may be fully flexed, and the finger joints in rigid flexion [2, 3]. Rigid flexor contracture in the interphalangeal joint was not detected in this case. Dysplasia of the hip joint of the affected lower extremity is often observed. The leg joints are more affected than the arm joints. The affected extremities are soft tube-shaped and hypoplasic . However, in this case, the lower extremity has completed its normal development, and walking symmetry, speed, cadence and duration are expected. Other joints involved are elbow, knee, wrist, ankle, fingers and hip joints. In this case, rigid elbow extension contracture and flexion limitation due to arthrodesis in the elbow joint were observed. The objects given due to 600 flexor contractures in the right wrist cannot be taken bilaterally and brought to the opposite shoulder or mouth.
Based on the ICF (International Classification of Functioning, Disability and Health) criteria and treatment guidelines for physiotherapists, physical therapy management for patients with AMC may include gentle joint manipulation and massage application consisting of stroking, kneading, picking up and rolling applications, removable splint management for knees and feet to help allow regular muscle movement . Also, orthosis management can aid walking and independence for children with AMC [3, 4], by maintaining muscle tension and strengthening the patient’s muscles, especially the hip extensors, quadriceps and deltoid anterior, middle, and posterior part, rotator cuff muscles, trapezius and serratus anterior muscles [2, 4]. It helps to encourage active muscle use to prevent immobilization, stretching of joint and muscle contractures, and initiates a neck, pectoral, elbow, wrist and finger flexor muscle stretching program for the family to do at home. It is recommended to stretch 3-5 times a day, 3-5 repetitions per set, holding each stretch for 20-30 seconds . Aquatherapy, hippotherapy, training in the use of assistive devices such as a gait instructor, walker, crutches, orthosis, dynamic strengthening of the trunk, ambulation independently or with an assistive device are other treatment methods in the physical therapy for children with AMC [4, 5].
This study aimed to provide information about the duration and frequency of physical therapy to be applied to children with AMC in play age and create an appropriate rehabilitation protocol to provide information on its content.
To conduct this study, informed consent was obtained from the patients’ family. In this case, anencephaly, meningomyelocele, and holoprosencephaly were not observed. There was no fetal immobility due to these reasons. Besides, the mother had no history of multiple pregnancy or oligohydramnios. There was no central nervous system (CNS) anomaly in this case, and the tendon reflex was normal. Cognition and mental health were in line with their peers. Joint stiffness, column vertebral, and flexor contracture in the distal and proximal joints were detected. Hypoplasia and aplasia were noticed in m. flexor and extensor carpi radialis and ulnaris, m.flexor and extensor digitorum superficialis, biceps, triceps and deltoid muscles. Lower extremity muscle tone, which was evaluated with resistance during passive motion, was expected in the range of motion. Adduction and internal rotation in the shoulders, forearm pronation, flexion contracture on the left and right sides of the wrist and ulnar deviation were observed. There was no hip dislocation, unilateral or bilateral hip flexion contracture in the lower extremity. Extension contracture of the knees or standing pes calcaneus, talipes equinovarus was not observed. Blood glucose, urea and electrode levels were normal.
Description of the Evaluation Outcomes
This case was six years old, and there was an active contraction of the right flexor carpi radialis. The tendon transfer was performed in the attachment of the triceps muscle due to the absence of brachialis. Shoulder flexion was bilaterally 700, shoulder abduction 600, and tends to compensate, especially shoulder flexion with neck flexion (Figure 1). Elbow flexion was limited at 900, wrists were restrained in extension at 200, and both hips and knees had normal joint movement in all directions. In short, a decrease in range of motion was observed in the extremities and neck. Throughout the passive movement, there was an increase in pain, asymmetrical posture, a reduction in comfort in the prone position, difficulties in participating in the social environment, and a decrease in the movements required for daily life activities and playing games. The cylindrical grip fails due to flexor contracture in the wrist. There was a decrease in the fingers’ muscle strength, and the elbow’s skin piles have disappeared. Both elbows have webbing. Diaphragmatic dwarfism was present. Also, there was hypoplasia in the pectoral muscles (Figure 2). Abdominal breathing was dominant in the patient, and chest respiration was restricted. Mental retardation was not detected in our patient. Cleft lip and palate were not observed.
Sitting balance was full, and kyphosis occurred in sitting and standing position. Muscle strength (according to the Modified Oxford Scale): Global 3-4 / 5 in the upper extremities, global 5/5 in the lower extremities, and walking was natural. The evaluation made according to the ICF model is given in Table 1. Description of Intervention
The AMC treatment in this study aims to increase the passive range of motion and strengthen active movement. The experimental stage has been reached by stabilizing the joints and loosening the contractures with surgery. If there were flexion or extension contractures in the shoulders and elbows, stretches were given to reduce this. Passive exercises, bandaging, and corrective plastering were essential for the treatment. Wrist flexor contracture and thumb adductor orientation were reduced with serial casts applied for six weeks. As a superficial heating agent in joints with contractures before exercise, a hot pack for 15 minutes, and as a deep heating agent to increase connective tissue elasticity in joints with arthrodesis, ultrasound (1,5 w/cm2) was applied for 5 minutes. It is possible to open contractures with thermoplastic splints. A wrist flexor contracture with a night splint was used for 6-9 weeks. The wrist was left in 200 extension, the metacarpophalangeal joint at 250 flexion, and in semiflexion due to absence of flexor contracture in the fingers. Besides, since the abdominal and pectoral muscles were weak, pulmonary exercises combined with aerobic exercise were studied. Strengthening exercises were performed with active assistive and resistive (theraband, 0.5 kg or 1 kg dumbbells, sandbags) exercises. Additionally, electrical stimulation was given to the relevant muscles for 15 minutes in the strengthening program. The exercise program applied during these 12 weeks was done at least 3-4 times a week, 3-5 times a day, 45 minutes, 20-30 repetitions of each movement, and the splint was attached immediately thereafter to preserve the obtained angle.
To treat the wrist contracture, both wrists were stretched, and the sensory input was provided by approaching the shoulder joint capsule by weight transfer. To prevent kyphotic posture, prone positioning on the hands and elbows was recommended for most of the day, except for one hour after each meal. Pectoral stretches and back muscles stimulation were performed in the supine position on the physioball.
In our case patient, after rehabilitation, an increase in the range of motion of the upper extremity (Table 2), the muscle strength measured before physical therapy (according to the Modified Oxford Scale) was generally 3-4 / 5 in the upper extremities, and 5/5 in the lower extremities, after treatment, the upper and lower extremities were 5/5 when measuring; Muscle tone, which was evaluated with resistance during passive movement, was found to be expected in the range of motion. Pinching grip strength was measured as 2.33 before treatment on the right side, 3.66 after treatment, and 1.33 before treatment on the left side, and 2.66 after treatment. While the coarse grip was 9.33 before the treatment in the right hand, it was measured as 10.66 after the treatment; It was 8.66 before treatment in the left hand, and 9.66 after treatment. After rehabilitation, our patient has become able to perform fine motor skills such as holding objects, holding a cylinder and palmar, releasing an object, and button fastening. With the stretching of the pectoral muscle, the increase in back extensor and trapezius muscle strength, kyphotic posture was prevented and sitting in an upright position was achieved.
Arthrogryposis multiplex congenita is a rare and heterogeneous disease. Children diagnosed with AMC should be handled with an interdisciplinary problem-solving approach. It has been found that there is little literature on rehabilitation strategies for treating children with AMC, which makes rehabilitation professionals more anxious when treating children with AMC. This case report provides information on rehabilitation sessions and specific treatment strategies for a growing play-age child with AMC.
Physical therapy for children with AMC plays an essential role in their independence. A recent review of AMC studies shows that the detailed description of a specific therapy session is not clearly stated in any literature. In this report, we tried to convey the duration, frequency (frequency) and treatment methods used in the treatment of a play-age boy with AMC.
Studies have been recommended for patients with AMC diagnosis, physical therapy and occupational therapy to increase postural muscle strength and maximal mobilization and the motor ability for age-appropriate activities. If a patient diagnosed with AMC cannot hold objects, cannot provide personal care, and has eating problems, compensated devices (splints, adaptive equipment) are required. As soon as infants diagnosed with AMC are born, passive ROM is used to assess muscle strength by muscle contraction palpation, functional mobility and motor evaluations, the Alberta Infant Motor Scale, and The Bayley Scale Infant Developmental III or Peabody Developmental Motor Scale-II (PDMS-2). The PDMS-2 scale is used to assess fine and gross motor skills in newborn-71- month-old children.
In the study conducted by Azbell et al., they evaluated the efficacy of serial casting and physical therapy applied for clubfoot in the lower extremity in a 9-month-old patient with arthrogryposis multiplex congenita, whose initial evaluation was 11 days. Hip dysplasia was suspected due to the 50-100 restriction as a result of hip abduction with the hip flexed at 900. Passive ROM (shoulder flexion, abduction, shoulder internal and external rotation, elbow, wrist, finger flexion and extension, hip, knee extension and flexion, and ankle flexion), muscle strength assessment, FLACC pain scale was used to assess the amount of pain during passive motion and after ROM in the 4-5 minutes. It was aimed to reduce knee and hip flexor contracture with two repetitions of 30-second stretching on each contracted joint, neck stretching, night splint for the wrist, a dynamic splint for elbow, prone positioning . In the cases reported by Azbell et al., elbow flexion restriction was due to extension contracture. They also used Mitchell shoes for clubfoot treatment . Since our case had tendon transfer due to the absence of brachialis, active 900 elbow flexion took place. We preferred to use a dynamic splint to maintain active elbow flexion. Besides, in our study, family training was provided as a physical therapy practice to slow down the progression by stretching, muscle strengthening, motor ability facilitation, reduction in pain that restricts daily activity and using a splint in play, and prevention of secondary scoliosis. However, the locomotion abilities in PDMS-2 (Peabody Developmental Motor Scale) were not examined because our case was an ambulatory patient.
Patel et al. published a case report in which they shared the duration, frequency and effects of physical therapy for a girl with AMC in infancy, starting from 15 days and continuing until the age of 11 months. In evaluations using the ICF model, they have ensured to increase ROM patency in physical therapy, to preserve muscle tension, and to improve neuro-sensory motor development . In our case study, the evaluation was made according to the ICF model. Fine and gross motor development was contributed by physical therapy, range of motion, muscle tension, and neuro-sensory motor facilitation.
Shinde et al. observed in their case study that a neurological and myopathic abnormality caused AMC. The neurological form is more common than the myopathic form. AMC’s symptoms are micrognathia, wide flat nose, low ear, high arched plaque, and hypoplastic diaphragm/lungs . In our case, hypoplastic diaphragm/lung and atrophic pectoral muscles were observed as symptoms.
An early physical therapy approach reduces complications such as arthrogryposis multiplex delivery, elbow extension contracture, wrist flexor contracture, muscle weakness and atrophy. It has an important place in increasing the range of motion of the upper extremity.
Physical therapy interventions can help improve rigid contracture and muscle atrophy and prolong the need for surgical operations in children’s younger ages.
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Conflict of interest
1. Glinska AB, Rek AS, Bakula S, Wierzba J, Prewek K, Kowalski IM, et al. Arthrogryposis in infancy, multidisciplinary approach: Case report. BMC Pediatrics. 2013; 13(1):1-6.
2. Greggi T, Martikos K, Pipitone E, Lolli F, Vommaro F, Maredi E. Surgical treatment of scoliosis in a rare disease: arthrogryposis. Scoliosis. 2010; 5:24.
3. Lake AL, Oishi SN. Hand therapy following elbow release for passive elbow flexion and long head of the triceps transfer for active elbow flexion in children with amyoplasia. J Hand Ther. 2015; 28(2): 222–7.
4. Bartonek Å. The use of orthoses and gait analysis in children with AMC. J Child Orthop. 2015; 9(6):437-47.
5. Campbell SK, Palisano RJ, Orlin MN. Physical therapy for children. 4th ed. St. Louis, MO: Elsevier/Saunders; 2012. p. 313–32.
6. Azbell K, Dannemiller L. A Case Report of an Infant with Arthrogryposis. Pediatr Phys Ther. 2015; 27(3): 293–301.
7. Patel V. Role of Early Rehabilitation in An Infant with Arthrogryposis Multiplex Congenita: A Case Report with 11 Months of Follow up. Indian Journal of Physiotherapy and Occupational Therapy. 2021;15(1):134-40.
8. Shinde A, Mhaske SN, Bhate SN. Arthrogryposis Multiplex Congenita: A Rare Case Report. VIMS Health Science Journal. 2020; 7(3):85-6.
Download attachments: 10.4328:ACAM.20596
Elisa Calisgan, Betül Akyol. Current concepts in physiotherapy and rehabilitation protocol for arthrogryposis multiplex congenita: An unusual case report. Ann Clin Anal Med 2021;12(10):1175-1179
Nicolau syndrome after Thiocolchicoside injection
Nuray Yılmaz Cakmak 1, Emin Gemcıoglu 1, Salih Baser 2
1 Department of Internal Medicine, Ankara City Hospital, 2 Department of Internal Medicine, Yıldırım Beyazıt University, Ankara City Hospital, Ankara, Turkey
DOI: 10.4328/ACAM.20609 Received: 2021-03-20 Accepted: 2021-07-01 Published Online: 2021-08-06 Printed: 2021-10-01 Ann Clin Anal Med 2021;12(10):1180-1181
Corresponding Author: Emin Gemcioglu, Ankara City Hospital, Department of Internal Medicine, Ankara, 06100, Turkey. E-mail: firstname.lastname@example.org P: +90 505 936 91 41 F: +90 312 310 01 94 Corresponding Author ORCID ID: https://orcid.org/0000-0001-9751-8452
A 48 -year-old male was admitted to the hospital with chief complaints of pain around the left buttock and a skin wound on the same area. One week before the current admission, he was treated with an intramuscular thiocolchicoside injection. Pain, significant edema and spasm occurred within 60 minutes of the injection. There was hyperemia on gluteal skin after the first day of injection and necrotic skin patch after six days, as described by the patient. The patient was referred to our hospital after 7 days after the onset of symptoms. Blood count, erythrocyte sedimentation rate and C-reactive protein values were within normal limits. Bacteriological culture was negative. Color Doppler sonography revealed no impairment in the lower extremity flow. The patient recovered with surgical debridement.
Keywords: Livedo Dermatitis; Cutis Medicamentosa; Intramuscular Injections
Tissue necrosis associated with intramuscular drug injection occurs due to phenylbutazone, local anesthetics, antihistaminics, anti-inflammatory agents, corticosteroids, and penicillins. Typically, necrosis develops following hyperemia, skin discoloration, livedoid and hemorrhagic patch formation at the injection site. This clinical profile is termed ‘livedoid dermatitis’, or ‘embolia cutis medicamentosa’, or ‘Nicolau Syndrome’. In this study, we presented a case of Nicolau Syndrome developed after thiocolchicoside injection.
A 48- year-old male patient presented to our hospital with the complaint of pain around the left buttock and a skin wound on the same area. Intramuscular thiocolchicoside injection was made by a general practitioner to the left upper and outer gluteal region at the emergency room for lumbalgia one week ago. He said that immediately after injection, he felt intensive pain at the site of injection. In the history, there was hyperemia on gluteal skin after the first day of injection and a necrotic skin patch after six days, as described by the patient. Seven days after injection, when he presented to our hospital, the examination revealed a 15×7 cm necrotic skin lesion with ulceration in the left gluteal region (Figure 1). Blood count, erythrocyte sedimentation rate and C-reactive protein values were within normal limits. Bacteriological culture was negative. The patient was given oral non-steroidal anti-inflammatory medication, and a total of four surgical debridements were performed. After six weeks, a significant improvement was detected in the wound.
Nicolau syndrome, embolia cutis medicamentosa or livedo- like dermatitis is a rare adverse reaction of the site of intramuscular, intraarticular subcutaneous injection of particular drugs such as diclofenac, corticosteroid, local anesthetics, penicillin, vitamin B12, vitamin K . The exact NS pathogenesis is uncertain but the most accepted hypothesis is direct trauma or irritation of the vascular structures with compression by the arterial embolism . Pain around necrosis, may be due to the acute local vasospasm during the period of the skin necrosis develops. Differential diagnosis of NS includes cutaneus cholesterol embolia vasculitis, but it is a disease of the elderly and atherosclerotic individuals . Our patient was young and has no atherosclerotic history, so the differential diagnosis was easily made. There is no spesific treatment for NS. Additional treatment includes antibiotics, skin graft, and flap reconstruction if needed. The Z-track injection is a method of intramuscular injection that can minimize or prevent the Nicolau syndrome . We report one such case for the first time with intramuscular injection of thiocolchicoside.
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1. Khopkar UP. Nicolau syndrome. In: Valia RG, editor. What is new in dermatology, sexually transmitted diseases and leprosy. Bombay: KM Varghese & Co; 2000. p.22-30.
2. Senel E. Nicolau Syndrome as an avoidable complication. J Family Community Med. 2012; 19(1):52-3.
3. Masthan SD, Salome, Madhav, Reddy KC, Sridevi, Lakshmi, et al. Nicolau syndrome. Indian J Dermatol Venereol Leprol. 2002; 68(1):45-6.
4. Senel E, Ada S, Gulec AT, Caglar B. Nicolau sydrome aggravated by cold application after i.m. diclofenac. J Dermatol. 2008; 35(1):18-20
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Nuray Yılmaz Cakmak, Emin Gemcıoglu, Salih Baser. Nicolau syndrome after Thiocolchicoside injection. Ann Clin Anal Med 2021;12(10):1180-1181
A case report of umbilical cord torsion with a favorable outcome
Yunus Çavuş 1, Mehmet Şah İpek 2
1 Department of Obstetrics and Gynecology, 2 Department of Paediatrics, Division of Neonatology, Memorial Dicle Hospital, Diyarbakir, Turkey
DOI: 10.4328/ACAM.20610 Received: 2021-03-22 Accepted: 2021-07-10 Published Online: 2021-07-29 Printed: 2021-10-01 Ann Clin Anal Med 2021;12(10):1182-1184
Corresponding Author: Mehmet Sah İpek, Division of Neonatology, Department of Pediatrics, Memorial Dicle Hospital, Urfa Road 3rd km, No:150, Kayapinar, Diyarbakir, Turkey. E-mail: email@example.com P: +90 412 315 66 66 / +90 412 315 15 19 F: +90 412 315 66 15 Corresponding Author ORCID ID: https://orcid.org/0000-0002-1472-9199
Umbilical cord torsion is a rare form of cord accidents, which is an important cause of stillbirth. Due to the fact that it is difficult to diagnose cord torsion prenatally, the majority of cases are associated with intrauterine fetal demise. Here we report a case of pregnancy acutely complicated by umbilical cord tor- sion with the favorable outcome.
Keywords: Umbilical Cord; Torsion of Cord; Wharton’s Jelly; Outcome
Umbilical cord accidents are an important cause of stillbirth and account for over 10% of cases . Cord abnormalities related to morphology, coiling, placental insertion, number of vessels, length, diameter, Wharton’s jelly content and blood flow pattern can contribute to perinatal complications . Umbilical cord torsion is a rare form of cord constriction, and is defined as excessive twisting of the cord at any site along the length of the umbilical cord . It can either lead to chronic hypoxia with critically reduced blood flow, oligohydramnios and fetal growth retardation, or severely obstruct fetal–placental circulation with subsequent death [3,4]. Although advances in imaging studies have made it possible to identify an umbilical cord accident, it can be difficult to diagnose cord torsion prenatally . The majority of cases diagnosed with umbilical cord torsion, upon postnatal examination were associated with intrauterine fetal demise [4,5]. Here we report a case of pregnancy acutely complicated by umbilical cord torsion.
A 26- year-old woman with gravida 1, para 0 at 33 weeks of gestation was admitted to the hospital after noticing the loss of sensation of fetal movements for at least 24 hours. Until then, she had regular follow-up, and her pregnancy had been progressing without complication. She had no history of trauma, vaginal bleeding, infection, or medication. At the last visit three days ago, ultrasound examinations, including fetal biometry measures and Doppler flow examinations were normal. On examination, her vitals were normal. Examination of the abdomen revealed 33 weeks pregnant uterus and cephalic presentation. There were no any signs of labor. Laboratory tests, including hematological and biochemical ones, were within normal limits. The fetal heart rate monitoring showed a rate of 150 beats per minute with absent variability. Obstetric ultrasound showed a single cephalic fetus of 34 gestational weeks weighing 2040 grams with the absence of fetal body and respiratory movements. The amniotic fluid index was 14 centimeters. The placenta was situated at the fundus and there was no demonstrable fetal or placental abnormality. The layer of Wharton jelly overlying the umbilical cord near where it enters the anterior wall of the fetal abdomen was thick. Doppler velocimetry on the umbilical artery showed that the pulsatility index value was 0.32 (normal range: 0.86–1.19 at 34 weeks of gestation), and that the peak systolic to end-diastolic (S/D) flow velocity ratio was 1.38 (normal range: 2.52–3.58) at the cord’s initial section (Figure 1A). On the rest of umbilical cord, including middle section and the section in the placenta, Doppler flow analysis could not be calculated due to absent systolic blood flow. Due to the presence of the above-mentioned findings, a female neonate weighing 2000 grams was delivered by cesarean section. The delivery was attended by the neonatal resuscitation team, and resuscitation was performed in a standard manner. She was intubated within few minutes for poor respiratory effort. The Apgar scores were 5 and 8 at 1 and 5 minutes of life, respectively. The umbilical cord, with 45 cm of length, was twisted at the fetal insertion site (Figure 1B). Umbilical cord arterial gas values were as follows; pH: 7.16, pCO2:69 mmHg, pO2:34 mmHg, HCO3:18.4 mmol/L, and base excess: -3.4 mmol/L. Following delivery room stabilization, she was admitted to the neonatal intensive care unit, and received routine care with empirical antibiotics, parenteral nutrition, and ventilation support. After three hours she was extubated, and received supplemental oxygen for up to four days. Thereafter, she presented good postnatal evolution and was discharged from the hospital on the 26th day of life. The family was fully informed of the risk of subsequent pregnancies. One year later, she was doing well without any signs of neurodevelopmental disabilities. Informed consent was obtained from the parents to publish this case.
Umbilical cord torsion can occur at any time during pregnancy, but is more common during the second and third trimesters . Although it is considered to be a sporadic event, recent reports have shown familial clustering, which suggests a genetic predisposition in some cases . Risk factors such as absence of Wharton jelly, increased fetal mobility, excessively long and hypercoiled umbilical cord, twin gestations and invasive procedures are believed to play a role in the development of umbilical cord torsions [2,5]. Wharton jelly is known to protect the umbilical vessels by providing elasticity and partial rigidity, serving as a supportive layer, so the lack or abnormality of Wharton jelly may cause weakness in the cord and predispose it to torsion and resultant vascular compromise. The site of torsion is usually the area where the umbilical cord enters the fetal abdomen. Edema may be present in the distal portion of the affected area or areas . Torsion may be associated with a pronounced spiraling or intensively twisted umbilical cord . In the case presented here, it seemed that the excessive thickness of Wharton jelly near the fetal insertion site led the thinner cord section just above there to coiling and twisting excessively. The presence of adverse fetal and placental changes related to cord torsion, prior to fetal demise, may raise suspicion and make it possible to identify cord torsion prenatally using ultrasonography. It is suggested that decreasing blood flow through the area of torsion may lead to serious consequences for fetus, and the most reported of them are heart failure, non- immune hydrops, intrauterine growth retardation, placental insufficiency and oligohydramnios [6,7]. If cord torsion develops acutely or the above-mentioned changes are not recognized timely, intrauterine fetal death may be the first clinically apparent manifestation, even in pregnant on regular follow- up [4,7]. As in the case presented here, a decrease in fetal movements may be the only symptom, so prompt recognition followed by an early intervention is essential to prevent complications and spare fetal death. It has been reported that identifying marked spiraling cord by prenatal ultrasound measurements may predict fetuses with risk for cord torsion. A distance between helixes (the vein-to-vein pitch) less than 2 cm, or a pitch value of the cord below 2.0 and a ratio of the systolic maximum blood flow velocity of the umbilical artery to the end-diastolic blood flow velocity (S/D) greater than 3.0 may help predict cord torsion, and it is recommended that these fetuses should be closely monitored to identify relevant complications [7,8]. In the case presented, the distance between helixes reduced in the initial section of the umbilical cord, where the torsion happened, but not in the rest of the sections. Additionally, the cord blood flow S/D ratio could not be measured due to the absence of typical flow velocities. Since cord torsion in this case was formed by a different mechanism, it was difficult to predict using the previously reported methods. It developed acutely and diminished cord blood flow that was severe enough to cause fetal distress. Fortunately, a favorable outcome was achieved by prompt intervention.
In conclusion, this case report showed that umbilical cord torsion can occur unexpectedly despite the regular antenatal visits and having no risk factors, emphasizing the importance of umbilical cord imaging as part of the fetal evaluation.
However, optimal measurements, which may predict the risk of fetal cord torsion are not available, and require prospective comprehensive researches.
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1. Collins JH. Umbilical cord accidents and legal implications. Semin Fetal Neonatal Med. 2014; 19(5):285-9.
2. Moshiri M, Zaidi SF, Robinson TJ, Bhargava P, Siebert JR, Dubinsky TJ, et al. Comprehensive imaging review of abnormalities of the umbilical cord. Radiographics. 2014; 34(1):179-96.
3. Fleisch MC, Hoehn T. Intrauterine fetal death after multiple umbilical cord torsion-complication of a twin pregnancy following assisted reproduction. J Assist Reprod Genet. 2008; 25(6):277-9.
4. Hallak M, Pryde PG, Qureshi F, Johnson MP, Jacques SM, Evans MI. Constriction of the umbilical cord leading to fetal death. A report of three cases. J Reprod Med. 1994; 39(7):561-5.
5. Bakotic BW, Boyd T, Poppiti R, Pflueger S. Recurrent umbilical cord torsion leading to fetal death in 3 subsequent pregnancies: a case report and review of the literature. Arch Pathol Lab Med. 2000; 124(9):1352-5.
6. Ben-Arie A, Weissman A, Steinberg Y, Levy R, Hagay Z. Oligohydramnios, intrauterine growth retardation and fetal death due to umbilical cord torsion. Arch Gynecol Obstet. 1995; 256(3):159-61.
7. Collins JH. Prenatal observation of umbilical cord torsion with subsequent premature labor and delivery of a 31-week infant with mild nonimmune hydrops. Am J Obstet Gynecol. 1995; 172(3):1048-9.
8. Tian CF, Kang MH, Wu W, Fu LJ. Relationship between pitch value or S/D ratio of torsion of cord and fetal outcome. Prenat Diagn. 2010; 30(5):454-8.
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Yunus Çavuş, Mehmet Şah İpek. A case report of umbilical cord torsion with a favorable outcome. Ann Clin Anal Med 2021;12(10):1182-1184
Accessory cervical rib in palpable supraclavicular mass
Ahmet N. Şanlı 1, Deniz E.T. Şanlı 2, 3, Ergin Erginöz 1
1 Department of General Surgery, Istanbul University Cerrahpasa, Cerrahpasa School of Medicine, 2 Department of Medical Imaging Techniques, Vocational School of Health Services, Istanbul Rumeli University, 3 Department of Radiology, Acibadem Kozyatagi Hospital, Istanbul, Turkey
DOI: 10.4328/ACAM.20659 Received: 2021-04-16 Accepted: 2021-06-08 Published Online: 2021-06-24 Printed: 2021-10-01 Ann Clin Anal Med 2021;12(10):1185-1187
Corresponding Author: Ahmet Necati Şanlı, Medical Doctor, General surgery resident, Istanbul University Cerrahpasa – Cerrahpasa School of Medicine, Cerrahpaşa Mah. Kocamustafapaşa Cad. No:34/E, Fatih, Istanbul, Turkey. E-mail: firstname.lastname@example.org P: +90 541 923 97 27 Corresponding Author ORCID ID: https://orcid.org/0000-0002-1483-8176
Swelling in the supraclavicular region often raises suspicion and requires prompt diagnosis in order to rule out malignancy or infection. When neither are pres- ent, however, the differential diagnosis can be broad. The cervical accessory rib is generally asymptomatic, but it can also present with symptoms related to neurovascular impingement. In this report, we clinically and radiologically present a case of newly identified stiffness and asymmetrical swelling in the neck that presented to our clinic.
Keywords: Accessory Cervical Rib, Supraclavicular Mass, Swelling
Swelling in the supraclavicular fossa often raises suspicion in the clinical setting as it is usually a finding secondary to an underlying disease. Pathologies to be considered include lymphadenopathy due to underlying infection, branchial cleft cysts, thoracic duct cyst, and tumors that are benign or malignant in nature . An accessory cervical rib may also present with a supraclavicular swelling in a clinical setting and should be included in the differential diagnosis. A thorough physical examination and a proper radiological evaluation are necessary to diagnose accessory cervical ribs.
A 45-year-old male patient presented to our clinic with a newly identified left supraclavicular mass (Figure 1). In the physical examination, asymmetric fullness and non-pulsatile palpable mass were observed in the left supraclavicular region compared with the right side. The rest of the physical examination was unremarkable. Cervical lymphadenopathy was not palpable.
The preliminary diagnosis, in this case, was malignant lymphadenopathy, given the nature of the supraclavicular mass as being non-mobile, hard consistency, and new in occurrence. The laboratory work-up was within normal limits. An ultrasound of the neck did not show any nodules in the thyroid or any other thyroid pathology. However, a linear osseous structure with a sonographic characteristic of posterior acoustic shadowing was observed in the posterosuperior region left clavicle extending towards the medial side. Aside from this, no other pathology was observed in the bilateral cervical lymph nodes. A cervical spine X-ray was taken due to the calcified nature of the lesion. An antero-posterior (AP) X-ray view of the cervical spine showed a left accessory cervical rib (Figure 2).
No other calcified lesion was detected in the neck region. Given the clinical and radiological features, this supraclavicular swelling was diagnosed as an accessory cervical rib. The case did not include any other symptom besides swelling in the left supraclavicular region, therefore, no treatment was offered and follow-up was recommended.
The cervical accessory rib is usually a clinical situation when the transverse process of the C7 vertebrae elongates. Even though it has an incidence of 0.5-2.5% in the population, it is usually asymptomatic . It has a higher tendency to be bilateral, although it can be unilateral like in our case. Patients usually present with symptoms due to the impingement of neurovascular structures (as observed in thoracic outlet syndrome), and these include, ipsilateral upper extremity sensory loss, tingling sensation, numbness, and loss of strength. However, they can also present with a newly identified, non- pulsatile, stiff, non-mobile swelling similar to that observed in our case. In this case, malignancy must be ruled out, especially in the elderly. In this case report, we hypothesized a malignant supraclavicular lymphadenopathy and after going through a thorough laboratory and radiological evaluation, we came to a conclusion of an accessory cervical rib finding.
When diagnosing an accessory cervical rib, radiological tests are an important aspect to consider aside from clinical evaluation and physical examination. Diagnosis can be established with a simple AP X-ray of the cervical spine [3,4]. In symptomatic patients, medical and surgical treatment can be administered according to the severity of the symptoms. No treatment is necessary in asymptomatic cases. Those with minor symptoms can benefit from non-steroidal anti-inflammatory drugs (NSAIDs). Severe symptoms may require surgical decompression through transaxillary, supraclavicular, and posterior subscapular routes .
After ruling out a malignant lymphadenopathy, the accessory cervical rib should be included in the differential diagnosis in patients with unilateral, non-mobile, asymmetric, stiff swelling. Treatment modalities differ according to the severity of the symptoms, but the definitive treatment is surgical excision.
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1. Moesgaard L, Baerentzen S, Mirz F. Cervical thoracic duct cyst: a differential diagnosis of left supraclavicular swelling. Eur Arch Otorhinolaryngol. 2007;264(7):797-9.
2. Haroun HSW. Cervical rib and thoracic outlet syndrome. MOJ Anat Physiol. 2016;2(5):138–43.
3. Spadliński Ł, Cecot T, Majos A, Stefańczyk L, Pietruszewska W, Wysiadecki G, et al. The Epidemiological, Morphological, and Clinical Aspects of the Cervical Ribs in Humans. Biomed Res Int. 2016;2016:8034613.
4. Wise R. Seventh cervical rib associated with subclavian artery occlusion and multiple infarcts. J Neurosci Nurs. 2008;40(3):169-72.
5. Chandak S, Kumar A. Usefulness of 3D CT in Diagnosis of Cervical Rib Presenting as Supraclavicular Swelling of Short Duration. J Clin Diagn Res. 2014;8(5):RD01-2.
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Ahmet N. Şanlı, Deniz E.T. Şanlı, Ergin Erginöz. Accessory cervical rib in palpable supraclavicular mass. Ann Clin Anal Med 2021;12(10):1185-1187
A case of neurobrucellosis detected during brucella treatment
Pınar Korkmaz 1, Irem Yıldırım 2, Fatma Akkoyun Arıkan 3, Halil Aslan 1, Duru Mıstanoğlu Özatağ 1, Özlem Genç 4, Mehmet Karaman 5
1 Infectious Diseases Clinic, 2 Neurology Clinic, 3 Neurology Diseases Clinic, 4 Microbiology Laboratory, 5 Internal Medicine Clinic, KSBÜ Evliya Çelebi Training and Research Hospital, Kutahya, Turkey
DOI: 10.4328/ACAM.20698 Received: 2021-05-10 Accepted: 2021-07-13 Published Online: 2021-08-01 Printed: 2021-10-01 Ann Clin Anal Med 2021;12(10):1188-1190
Corresponding Author: Pınar Korkmaz, KSBÜ Evliya Çelebi Training and Research Hospital, Infectious Diseases Clinic, İstiklal Cad. Okmeydanı Cd. 43040, Kütahya, Turkey. E-mail: email@example.com P: +90 505-5502260 Corresponding Author ORCID ID: https://orcid.org/0000-0001-5035-5895
Brucellosis is a systemic zoonotic infectious disease caused by the gram-negative Brucella bacteria that can be transmitted from infected animals to humans. Neurobrucellosis occurs when the central nervous system is directly or indirectly affected by Brucella spp. Clinical meningoencephalitis in neurobrucellosis includes meningovascular involvement, parenchymal dysfunction, peripheral neuropathy/radiculopathy, and various degrees of behavioral abnormalities. At the admission of our case, psychiatry was consulted considering psychosis due to decreased speech and agitation, there were no signs of meningeal irritation in physical examination, and no cells were seen in the first CSF examination. In the presence of unexplained neurological and psychiatric symptoms, especially in endemic areas, neurobrucellosis should be considered in the differential diagnosis, and necessary blood and CSF tests should performed.
Keywords: Meningoencephalitis; Brucellosis; Neurobrucellosis
Brucellosis is a systemic zoonotic infectious disease caused by the gram-negative Brucella bacteria that can be transmitted from infected animals to humans. It is the most common zoonotic disease in the world and is an important public health problem in many developing countries. Brucella can affect any organ or system, and the disease manifests in many different clinical forms. Neurobrucellosis occurs when the Central Nervous System (CNS) is directly or indirectly affected by Brucella spp. (available at: https://www.uptodate.com/contents/brucellosis- epidemiology-microbiology-clinical-manifestations-and diag nosis?search=brucella&source=search_result&selectedTitle= 1~104&usage_type=default&display_rank=1.) Neurological involvement rate can be seen in 0-25% of brucellosis cases . The clinical spectrum of neurobrucellosis is very heterogeneous. Neurological manifestations in neurobrucellosis can be seen in the acute or late stages of the disease. In the clinic, it can be seen as acute/chronic meningitis, meningoencephalitis, brain abscess, myelitis, radiculitis and/or neuritis (cranial or peripheral nerve involvement). Although the incidence of CNS involvement is not high, it may result in serious morbidity . Neurobrucellosis may present with different clinical presentations and its diagnosis may be difficult. Therefore, we aimed to draw attention to this complication with our case.
A nineteen-year-old male patient was brought to the emergency room by his relatives with complaints of sudden onset of vomiting, meaningless speech, and decreased speech, was evaluated by a psychiatrist in the emergency room and no psychiatric illness was considered. Although demyelinating and vasculitic diseases were considered in the differential diagnosis in the patient evaluated by a neurologist, consultation with an infectious diseases specialist was recommended in terms of central nervous system infection. The patient was evaluated in the emergency room, and it was learned that he had complaints of sudden onset of vomiting and impaired speech. It was learned that the patient applied to the urology outpatient clinic 8 months ago due to fever and unilateral orchitis, and that the brucella tube test was negative at that time, brucella was not considered, but the patient was diagnosed with brucellosis 5 months later, as complaints of fatigue and joint pain continued. It was learned that the patient had been using rifampicin 1×600 mg tb and doxycycline 2×100 mg tb for 3 months. It was found that the patient regularly used his drugs. From the history of the patient, it was found that he lived in the village and was engaged in animal husbandry.
On physical examination, he was conscious, partially cooperative, and disoriented. His speech was reduced, his interest in the environment was low, his attention was reduced, he had meaningless speech and aggression. There were no signs of meningeal irritation. Other system reviews were normal. There were no signs of acute bleeding or edema in the cranial tomography. Cranial diffusion magnetic resonance imaging (MRI) did not show signs of acute ischemia, and cranial MRI findings showed plaque appearances consistent with bilateral demyelinating/vasculitic lesions in the white matter (Figures 1, 2). The patient underwent lumbar puncture (LP) in the emergency. No leukocytes were seen in the cerebrospinal fluid (CSF) examination. CSF protein was 295 mg / dL (15-45), CSF glucose was 2.5 (45-80 mg / dL), concurrent blood glucose (sour blood sugar) was 111 mg / dL.
The patient was started with ceftriaxone 2×2 gr IV, vancomycin 2×1 gr IV, acyclovir 3×750 mg iv with the diagnosis of meningoencephalitis, and she was taken to the neurology intensive care unit. No features were found in the CSF Gram and ARB staining of the patient. CSF mycobacterium polymerase chain reaction (PCR) was negative, there was no growth in mycobacterial culture. Herpes simplex virus 1 and 2, human parechovirus, enterovirus, mumps and varicella zoster virus were found negative in the CSF viral meningitis panel. There was no reproduction in the CSF and blood culture. In brucella agglutination tests in CSF fluid and blood, neurobrucellosis was considered in the patient because of positive findings in CSF with a titer of 1/640 and above and a titer of 1/320 in the blood. Treatment was continued with ceftriaxone, rifampicin and doxycycline. The cooperation and orientation of the patient improved with the treatment. It was detected in 40 cells/mm3 in LP performed on the 21st day of treatment, it was 75% lymphocytes. CSF protein was found to be 124 mg/ dL, CSF glucose 32, and concurrent blood glucose 103 mg/dL. Ceftriaxone treatment was completed within 1 month, and the patient was discharged with rifampicin and doxycycline treatment. At the end of the first month of the follow-up, the patient had no complaints, his physical examination was normal. The treatment of the patient was completed for 6 months.
Clinical meningoencephalitis in neurobrucellosis includes meningovascular involvement, parenchymal dysfunction, peripheral neuropathy/radiculopathy and various degrees of behavioral abnormalities . It can be confused with chronic central nervous system infections or with migraine, convulsion, hemiplegia, temporary parkinsonism, tremor, general rigidity, psychosis and neurosis . Several behavioral and neuropsychiatric diseases, sleep disorders, epilepsy, agitation and depression have been detected in patients with neurobrucellosis. The recovery of cognitive and mood disorders in brucellosis without treatment with antidepressant and/ or antipsychotic distinguishes the disease from functional psychiatric diseases [4,5]. Similarly, in our case, psychiatry was consulted, considering it psychosis due to decreased speech at admission, lack of interest and attention to the environment, meaningless speech and aggression, and an increase in anxiety in the last 3 months.
It was stated that the clinical picture of neurobrucellosis can be variable, and the findings are not specific, therefore, CSF examination can be more helpful in making the diagnosis [1,4]. The diagnosis of neurobrucellosis can be made with the presence of a neurological picture that cannot be explained by another neurological disease, isolation of bacteria in the CSF or blood culture, or positivity in serological tests, abnormal CSF findings (low CSF glucose, increased CSF protein, lymphocytic pleocytosis) [3-5]. The low bacterial isolation rate in the CSF (5- 30%) necessitates the use of serological diagnostic methods in most of the patients [1,4]. Similarly, in our patient, serologically positive blood and CSF were detected, but bacteria could not be isolated in the CSF and blood culture.
There are four imaging findings in the radiological diagnosis of neurobrucellosis: normal, inflammation (meningeal enhancement), white matter changes and vascular changes. In a study conducted in Turkey, 263 neurobrucellosis cases were evaluated, 54.3% had normal MRI findings, the most common changes were leptomeningeal (n = 44) and basal meningeal involvement (n = 30), white matter involvement with demyelinating lesions (n = 32), chronic cerebral ischemic changes are vascular involvement (n = 37) and brain edema (n = 40) .
There is no consensus on antibiotic choice, dose and duration in the treatment of neurobrucellosis. Double or triple combination therapy with doxycycline, rifampicin, trimethoprim- sulfamethoxazole, streptomycin or ceftriaxone is recommended . In a study conducted in Turkey, it is recommended to continue with ceftriaxone, doxycycline and rifampicin after 1 month of treatment, and doxycycline and rifampicin, treatment with ceftriaxone was found to be more successful in terms of relapse and treatment failure compared to other treatment options, and it was shown that the treatment duration was shorter compared to oral treatments . Clinical response and normalization of CSF findings are the main factors that determine the duration of treatment . Our patient received treatment for uncomplicated brucellosis, used his medications regularly, but the disease was complicated with neurobrucellosis, so no response was obtained with the current treatment. Following the addition of ceftriaxone for neurobrucellosis, a clinical response was obtained, while doxycycline and rifampicin treatment was extended for 6 months.
As a result, the clinical spectrum of neurobrucellosis is highly variable. At the admission of our case, psychiatry was consulted considering psychosis due to decreased speech and agitation, there were no signs of meningeal irritation in physical examination, no cells were seen in the first CSF examination. In the presence of unexplained neurological and psychiatric symptoms, especially in endemic areas, neurobrucellosis should be considered in the differential diagnosis, and the necessary blood and CSF tests should be performed.
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1. Yetkin MA, Bulut C, Erdinç FŞ, Oral B, Tulek N. Evaluation of the clinical presentations in neurobrucellosis. Int J Infect Dis. 2006; 10(6):446-52.
2. Erdem H, Ulu-Kilic A, Kilic S, Karahocagil M, Shehata G, Eren-Tulek N, et al. Efficacy and tolerability of antibiotic combinations in neurobrucellosis: results of the Istanbul study. Antimicrob Agents Chemother. 2012; 56(3):1523-8.
3. Ural O, Güler S. Nörobruselloz: Bir Olgu Nedeniyle (Neurobrucellosis: Due to a Case). Flora Dergisi. 2007; 12(4):208-10.
4. Gul HC, Erdem H, Bek S. Overview of neurobrucellosis: pooled analysis of 187 cases. Int J Infect Dis. 2009; 13(6): e339-43.
5. Guven T, Ugurlu K, Ergonul O, Kocagul Celikbas A, Eren Gok S, Comoglu S, et al. Neurobrucellosis: clinical and diagnostic features. Clin Infect Dis. 2013; 56(10):1407-12.
6. Erdem H, Senbayrak S, Meriç K, Batirel A, Karahocagil MK, Hasbun R, et al. Cranial Imaging Findings in Neurobrucellosis: Results of Istanbul-3 Study. Infection. 2016; 44(5):623-31.
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Pınar Korkmaz, Irem Yıldırım, Fatma Akkoyun Arıkan, Halil Aslan, Duru Mıstanoğlu Özatağ, Özlem Genç, Mehmet Karaman. A case of neurobrucellosis detected during brucella treatment. Ann Clin Anal Med 2021;12(10):1188-1190
COVID-19 epidemiology and laboratory findings
Abdullah Sivrikaya 1, Fatma Zehra Erbayram 2, Esma Menevse 1
1 Department of Medical Biochemistry, Medicine Faculty, Selcuk University, 2 Department of Medical Biochemistry, Medicine Faculty, KTO Karatay University, Konya, Turkey
DOI: 10.4328/ACAM.20614 Received: 2021-03-26 Accepted: 2021-06-23 Published Online: 2021-07-20 Printed: 2021-10-01 Ann Clin Anal Med 2021;12(10):1191-1197
Corresponding Author: Fatma Zehra Erbayram, KTO karatay University, Medicine Faculty, Department of Medical Biochemistry, Akabe Mah., Alaaddin Kap Cad., No:130, 42020, Karatay, Konya, Turkey. E-mail: firstname.lastname@example.org P: +90 507 411 06 38 Corresponding Author ORCID ID: https://orcid.org/0000-0002-9305-4782
In the last days of 2019, the World Health Organization (WHO) Country Office reported cases of pneumonia of unknown etiology in Wuhan City, Hubei Province, China. The causative agent was isolated on January 7, 2020 and identified as a new type of coronavirus. A novel coronavirus outbreak known as SARS-CoV-2 was announced by the WHO as an urgent public health problem of international concern on January 31, 2020. The recent pandemic caused by a novel corona- virus, which occurs in humans in the form of severe acute respiratory syndrome and called SARS-CoV-2, has not only had a great impact on the health system and economy in all countries, but also has led to changes in habits and lifestyles. In this review, attention was drawn to the relationship between SARS-CoV-2, which is the cause of the current pandemic, and coronaviruses observed in animals, and its effect on humans. The new coronavirus and what we have learned about the pandemic, the situation in Turkey and current approaches in diagnosis and treatment were discussed.
Keywords: COVID-19; Virus; Laboratory Findings
In the last 20 years, the swine flu, SARS, MERS, Zika, Ebola pandemics, and finally COVID-19 that emerged in Wuhan, China in December 2019 affected the entire world in a short time, are seen to be effective at a global level. In a review published in 2005, which was about the viruses that affect the lower and upper respiratory tract and cause clinical symptoms such as severe acute respiratory syndrome in children were described and many members of the coronavirus family were identified. Furthermore, the people are likely to be exposed to the other viruses belonging to this family, but have not been yet specified . Therefore, it has been known for a long time that coronavirus family act on the respiratory tract and causes serious clinical features. Even so far, it is clearly known that viruses, which are members of this family can cause serious epidemics on a global scale, as the examples of SARS (Severe Acute Respiratory Syndrome) identified in February 2003, and Middle East Respiratory Syndrome (MERS) identified in September 2012 , (available at: https://www.who.int/ emergencies/diseases/ novel-coronavirus-2019).
The relationship between human health and animals was first pointed out by Rudolf Virchow, a pathologist of German origin, and the term “zoonosis” was introduced by this researcher in 1880 [3, 4]. It is noteworthy that in the last two decades, newly emerging and fatal zoonotic viruses, including the coronavirus infections mentioned above, are expected to originate from bats. Many studies have revealed that bats are exceptional mammals in their ability to be a natural reservoir of viruses and accommodate a wide variety of viruses to other animal species [5-8]. Though many studies have been conducted in recent years on the biological mechanisms underlying these determinations, it is considered certain that in the coming years the world will witness epidemics caused by bat-borne viruses [9, 10].
In 1937, Beaudette and Hudson identified the first coronavirus that cause respiratory infection in chickens . The first case of human coronavirus (HCoV) infection was reported in 1960 in a patient suffering from the common cold . These coronavirusesaredividedintotwodifferentantigenicclasses: HCoV 229E and HCoV OC43 . HCoV NL-63 was defined in 2004 and HCoV HKU1 in 2005. In many studies, it has been determined that especially HCoV NL-63 causes respiratory system infections in children [14-17].
Started on December 31, 2019, a case of pneumonia that could not be determined with the existing tests in Wuhan city in China’s Hubei province, revealed on January 7, 2020 that the agent was a new coronavirus, causing infections in humans (available at: https://www.who.int/ emergencies/diseases/novel- coronavirus-2019), (available at: https://www.ecdc.europa. Eu/en/ covid-19/latest-evidence/coronaviruses), (available at: https://hsgm.saglik.Gov.tr/tr/covid19 ), [18-20]. It has been named as SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) by the International Committee for Taxonomy of Viruses. It has been identified as the seventh CoV that causes disease in humans, and the third CoV that has passed from animals to humans since 2003 and has been associated with severe respiratory diseases . The causative agent virus has been defined as 2019-nCoV (2019-novel coronavirus) and the disease was defined as COVID-19 (coronavirus disease-2019) by WHO (available at: https://www.who.int/emergencis/ diseases/ novel-coronavirus-2019).
The causative agent of the virus
Coronaviruses are single-stranded, positive-polarity enveloped RNA viruses in the Coronavirinae subfamily of the Coronaviridae family of the Nidovirales. These viruses are named as “coronavirus”, based on the word “corona”, which means “crown” in Latin, due to the rod-shaped extensions on their surfaces. Coronavirinae is divided into four subgroups as alpha coronaviruses, beta coronaviruses, gamma coronaviruses, and delta coronaviruses. Grouping, which was previously done using a serology-based approach, is now identified by phylogenetic analysis (available at: https://www.ecdc.europa.Eu/en/covid-19/ latest-evidence/coronaviruses), [19, 22]. Only alpha CoV and betaCoV are known to infect humans. Coronaviruses are the largest RNA virus detected so far in terms of genome size and genetic complex structure. The large genome makes the virus less host-dependent during replication. Its replication occurs in the cytoplasm of respiratory and gastrointestinal epithelial cells . Coronaviruses are capable of replicating their own genome without integrating into the host-genome. Due to the RdRp gene, these viruses can replicate their genomes in the host’s cytoplasm. COVID-19, like other coronaviruses, is sensitive to UV light and heat and can be inactivated with lipid solvents (except chlorhexidine) such as ether (75%), ethanol, chlorine- containing disinfectant, peroxyacetic acid and chloroform . Four structural proteins in coronaviruses are involved in the formation of mature virus particles (virions) and the occurrence of infection. These are S (Spike) protein, E (Envelope) protein, M (Membrane) protein, and N (Nucleocapsid) protein [19, 25]. The S protein enables the formation of spikes on the viral surface, and they are responsible for attachment to host receptors. It also provides the major antigenic feature of the virus . S proteins bind to the virion membrane via their C-terminal transmembrane regions and interact with M proteins . Another structural viral protein, M protein, with its three different transmembrane regions, provides the formation of the virion, the curvature of the virus-cell membrane, and binds to the nucleocapsid . M proteins are glycosylated in the Golgi apparatus. This modification of the M protein is important in the virion’s fusion into the cell, and the protein gaining antigenic properties. The M protein plays a key role in regenerating virions in the cell . The N protein forms a complex by binding to genomic RNA, and then the M protein interacts with this complex in the endoplasmic reticulum-Golgi device intermediate compartment (ERGIC), trigger the formation of virions. This protein is important in the sensitization of the host cell by the virus, enabling activation of the Interferon- beta (IFN-beta) pathway via a Toll-like receptor-dependent mechanism . The N protein also acts as an interferon antagonist, thus attempts to destroy the virus by the immune system are also inhibited . The E protein plays a role in viral pathogenesis by packaging and releasing the virus . It has been found that even though there is no E protein in the virus, the viral load in the host is lower .
It binds to the ACE-2 receptor on the host cell surface via the Virion S protein and enters into the cell and releases its genomic RNA to the cytoplasm. Initially, two viral replicase polyproteins are synthesized. These two large proteases result in 16 non- structural proteins (nsp). These 16 nsp form double-membrane vesicles (DMV) and replication and transcription complex (RTC). These newly formed structural proteins and genomic RNA are combined in the ERGIC to create new virions. The formed virions exit the cell via exosomes .
Serological tests are usually designed against S proteins, as receptor binding constitutes the initiation process of infection [29,30].
Although the source of the agent has not yet been precisely defined, the first cases were reported epidemiologically associated with the Huanan Seafood Wholesale Market, a livestock and seafood market in Wuhan. As there are predictions that the disease is transmitted from bats to humans, it has also been suggested that there is an intermediate host between bat and humans, and this intermediate host is an anteater (pangolin), and the new coronavirus may have originated from the recombination of bats and pangolin coronaviruses [31,32]. Although the disease is considered to be of zoonotic origin, human-to-human transmission has also been identified and has become the main route of transmission. In a short time, there was a significant increase in the number of cases, and the disease spread globally [18,33,34]. Although incubation begins 1-2 days before the symptomatic period and ends with the disappearance of symptoms, there are also opinions that viral spread may take longer depending on the severity of the disease (available at: https://hsgm.saglik.gov.tr/tr/covid19), (available at: https://www.uptodate.com/contents/corona virus-disease-2019-covid-19-epidemiology-virology-clinical- features-diagnosis-and-prevention). While the highest rates of infected people and deaths were reported from China in the first two months, the number of cases and deaths in China has decreased since the first week of March 2020, but the number of infected people and deaths has gradually increased in all regions where human life is located, except for Antarctica.
There are three zones on the epidemic curve: Increasing, plateau, and decreasing phases.
The period of increasing phase is affected by the country’s demography, age distribution, the health system’s preparedness, implementing some preventive measures, the reaction time of the country to the pandemic, and the reaction of the society to the new implementation rules. This period is usually 3 or 4 weeks for COVID-19 .
Plateau phase: The incidence of the disease is stable at this stage. For COVID-19, this phase lasts 2 or 3 weeks, depending on the daily data of the country .
Decreasing stage: Today, only China is at this stage, and disease activity can be detected at very low levels 2 or 3 weeks later .
The basic reproduction number (R0) is the estimated value expressed as the average number of individuals infected in a susceptible population during the period when an infected person was contagious (number of secondary cases) [31,36]. If R0<1, the infection will decrease and disappear over time and if R0>1, a pandemic is expected . With the initial data, the basic reproduction number for COVID-19 caused by SARS- CoV-2 was estimated to be between 2.24 and 3.58, and a higher pandemic potential was predicted compared to SARS [ 18,31,37].
Characteristics of clinical features
As the pandemic continues, the distribution of clinical features commonly detected in patients with infection may change over time. In a recently published review, approximately 83- 98% of cases complained of fever, cough in 76-82%, muscle pains, weakness, fatigue in 11-44%, headache, and it has been reported that sore throat, abdominal pain and diarrhea may accompany the clinical picture . Furthermore, pneumonia is the most common serious state in the infection. Definitions regarding the severity of the disease are not yet clear and different classifications can be made , (available at: https:// hsgm.saglik.gov.tr/tr/covid19), (available at: http://www. uptodate.com/ contents/coronavirus-disease-2019-covid- 19-epidemiology-virology-clinical-features-diagnosis-and- prevention-clinical-features-diagnosis-and-prevention).
Whole blood count findings may vary in COVID-19 cases. While lymphopenia is detected in most of the cases, varying degrees of leukopenia or leukocytosis can be seen. In the biochemical analysis, it is generally stated that lactate dehydrogenase (LDH) and ferritin levels are high, and as well as aminotransferase levels can be detected to a high degree. It has been reported that serum procalcitonin levels were within normal limits in most cases with pneumonia at the beginning, but these levels could be found to be increased if intensive care is needed. High D-dimer levels and the presence of lymphopenia have been associated with mortality (Tables 1 and 2) [31,39-41] (available at: http://www.uptodate.com/contents/coronavirus- disease-2019-covid-19-epidemiology-virology-clinical- features-diagnosis-and-prevention-clinical-features-diagnosis- and-prevention). In some cases of COVID-19, persistent fever progresses with high levels of inflammatory markers such as D-dimer, ferritin and proinflammatory cytokines. It has been reported in studies that an excessive or uncontrolled inflammatory response, similar to the situation defined as cytokine release syndrome or cytokine storm, and the presence of these laboratory findings is associated with the severity of the disease (available at: http://www.Uptodate.com/ contents/ coronavirus-disease-2019-covid-19-epidemiology-virology- clinical-features-diagnosis-and-prevention-clinical-features- diagnosis-and-prevent ion), .
Increased levels of interleukin-6 (IL-6) were found to correlate with increased fibrinogen levels in a study by Ranucci et al. . Tang et al. also found a significant correlation between disease severity and mortality risk with some hemostasis tests such as increased D-dimer level, fibrin degradation products, and prolonged prothrombin time (PT), and reported a significant difference between laboratory results in death patients and survived. Also, deceased patients showed a statistically significant increase in their D-dimer, PT prolongation, and a decrease in fibrinogen and antithrombin levels at the findings of 10-14 days . In another study involving ninety-four patients with COVID-19, PT prolongation, and low fibrinogen were found to be significant in predicting severe disease . In a retrospective study conducted by Seyit et al. with 233 patients, the CRP, LDH, PLR and NLR levels remained significantly higher in patients with positive COVID-19 PCR test result. In contrast, eosinophil, lymphocyte, platelet levels were calculated to be significantly higher in COVID-19 negative patients. Laboratory results are presented in Table 3. Among 110 COVID-19 positive patients, 75 were hospitalized in different clinics, whereas 35 were monitored with self-isolation at home .
In a retrospective study conducted by Gormez et al. with 247 adult patients (154 males, 93 females; mean age: 51.3±14.2 years) hospitalized due to COVID-19, 48 of this patients were treated in the intensive care unit. The median length of stay in intensive care was 13 days, 4 patients died . Shao et al. indicated that 18 patients of 155 individuals died; 80% of deaths occurred within the first three weeks. The deceased are reported to suffer from other underlying chronic diseases such as hepatitis, HIV, diabetes, and hypertension, and are elderly (73.5 years) accompanying COVID-19 . In a retrospective study by Masetti et al., 229 individuals with a mild form of the disease out of 370 COVID-19 positive patients were included in the study; 196 of these individuals were discharged from the hospital within 9 days on average, 33 people (14%) died from respiratory failure . Liu et al. determined that the total mortality rate was 13.47% .
Altıntaş et al. in a retrospective study conducted on the data of 56 patients (30 men, 26 women) who were positive for COVID-19, the most common laboratory findings were determined as lymphopenia (30.3%) and high CRP (62.5%). The findings of 23 patients were normal, and 25 patients were reported to have chronic diseases .
Ok et al. examined retrospectively 139 patients who were positive for COVID-19 by categorizing them into three groups according to the severity of the disease (medium: 85, severe: 34 and critical: 20). A total of 13 individuals from the severe group died (9.4%) . The severity of COVID-19 can vary from patient to patient. According to the results of a retrospective study, advanced age, the presence of an underlying disease and the immune system can be considered as the main risk factors affecting the severity and survival time of the disease.
Diagnostic tests and screening
People who need to be screened for SARS-CoV-2 and the decision on which people apply to diagnostic tests may vary according to national and local health policies. In addition, decisions on this issue are updated according to the changes in the distribution of incidence and mortality in the country. Currently, there are 2 currently valid test methods for the diagnosis of COVID-19 .
1. Tests to detect viral antigens/viral RNA 2. Serological tests
1. Viral RNA tests
The first method of choice for diagnosing COVID-19 is the detection of viral nucleic acid using reverse transcription- polymerase chain reaction (RT-PCR) . Its sensitivity has been reported to be moderate, within the range of 63–78% on average .
Another broad category of tests in the diagnosis of COVID-19 is serological blood tests that detect IgM, IgA, IgG, and total antibodies. The development of an antibody response to infection depends on host immunity and requires a period . Treatment
There is currently a certain treatment for COVID-19. Treatment is supportive and symptomatic. The first step is to provide adequate isolation to prevent contamination of other contacts, patients, and healthcare workers. General principles are to maintain hydration and nutrition and to control fever and cough . Numerous clinical trials are ongoing to define new agents and drugs that will be more effective in treatment , (available at: https://www.uptodate.com/contents/ coronavirus- disease-2019-covid-19-epidemiology-virology-clinical- features-diagnosis-and-prevention).
Antiviral drugs used in the early stages of COVID-19 constitute the basis of the treatments. Among these antivirals, two drugs have shown their efficacy in inhibition of SARS-CoV-2 replication in cell culture: ”Remdesivir (GS-5734)”, an experimental drug developed for the treatment of Ebola virus infection; and ‘’’Chloroquine (CQ)”’ which is used in the treatment of malaria and autoimmune diseases. A summary of candidate antivirals and their mechanisms, according to the highlight of the current publications, is given below .
– Mechanism to prevent cell entry by inhibiting TMPRSS2: “Camostat mesylate”
– By inhibiting membrane fusion via targeting to the S protein/ ACE: “Arbidol”
– Preventing the entry of the virus into the cell by endocytosis: “Hydroxychloroquine”
– By the action of a protease inhibitor: “Lopinavir, darunavir”
– With RNA-dependent RNA polymerase inhibition: “Ribavirin, remdesivir, favipiravir” .
SARS-CoV-2 is an RNA virus, and when it enters a cell, it performs protein synthesis with its RNA polymerase. Since it has a large RNA genome and has many repetitive parts, blocking the virus is one of the most limiting aspects of treatment. In addition, it is thought that different species use different receptors and use different pathways to enter the cell, therefore this state reduces the effect of antivirals .
Some drugs interact with antiplatelet or anticoagulant drugs, and a few can cause thrombotic events or thrombocytopenia. For example, dose adjustment of vitamin K antagonists, apixaban, and betrixaban may be required while using lopinavir/ritonavir. Lopinavir/ritonavir should not be used in combination with edoxaban or rivaroxaban. Among parenteral anticoagulants and research drugs, a major drug interaction has not been detected. Further studies are needed on this subject as well [57,58].
One of the other drug active substances discussed for patients with COVID-19 is the non-steroidal anti-inflammatory group drug, Ibuprofen; Ibuprofen has analgesic, anti-inflammatory, and antipyretic effects. The hypothetical information about Ibuprofen can increase the expression of ACE-2 , as well as the statements of the French Minister of Health, about the anti-inflammatory drugs such as ibuprofen and corticosteroids may worsen the infection by suppressing the immune system in COVID-19 patients have been the source of aforementioned debate [60,61].
It was pointed out that prostaglandins such as PGE2, PGD2, PGI2 are factors that both support and restrain inflammation, and the use of ibuprofen and other non-steroidal anti-inflammatory drugs, which inhibit the synthesis of prostaglandins through cyclooxygenase (COX) inhibition, may increase the severity of the disease in COVID-19 cases. Therefore, it has been stated that it may be contradictory [62,63]. Furthermore, it was shown in 2003 that SARS-CoV viruses, causing the SARS outbreak, lead to an increase COX-2 expression by direct binding to the COX- 2 promoter . It has been reported that the COX inhibitor, Indomethacin, exerts a potent antiviral effect by inhibiting the RNA synthesis of the SARS-CoV virus. It has been stated that antiviral activity of indomethacin occurs independently from COX inhibition . In this context, it has been suggested that Indomethacin can be useful in the treatment of SARS infections with both its anti-inflammatory activity mediated by COX-2 inhibition and its antiviral activity independent of COX-2 . Remdesivir is not recommended in patients with an alanine aminotransferase (ALT) values greater than or equal to ten times the upper limit of normal, and it is stated that it should be discontinued if ALT reaches the specified values during treatment or in the presence of any evidence of liver damage (available at: https://www.uptodate.com/ contents/coronavirus-disease- 2019-covid-19-management-in hospitalized-adults),WHO has initiated a multinational study to evaluate the efficacy of remdesivir, chloroquine, and hydroxychloroquine, and lopinavir/ ritonavir with or without interferon-beta (available at: https:// www.uptodate.com/ contents/coronavirus-disease-2019-covid- 19-management-in hospitalized-adults), (available at: https:// www.sciencemag.org/ news/2020/03/who-launches-global- megatrial-four-most-promising-coronavirus-treatments).
The RNA polymerase inhibitor favipiravir, which is used in the treatment of influenza in Japan, has also been approved in China to be used in the experimental treatment of COVID-19 and has been used in treatment protocols in Turkey (available at: https://www.uptodate.com/contents/ coronavirus-disease- 2019-covid-19-management-in-hospitalized-adults), (available at: https:// hsgm.saglik.gov.tr/tr/covid19) .
Among the cytokines that are reported to be increased during hypercytokinemia, the most important one is IL-6. In COVID- 19-associated Macrophage activation syndrome (MAS), inflammation appears to be more lung-centered than multi- organ, so the argument for the involvement of IL-6 comes from changes in biochemical parameters, including ferritin, and reports of anti-IL6R efficacy. The timing of anti-IL-6R, if too early, may adversely affect viral clearance, which should be evaluated in trials. If blocking IL-6R early in COVID pneumonia MAS-like disease appears to have a detrimental effect on type- 2 pneumocyte antiviral immunity, then local enhancement of IL-6 may be considered. There are concerns that its early use may be harmful due to Antibody-dependent enhancement (ADE) .
Recent studies have focused on the importance of viral load in COVID-19 pneumonia. Therefore, it is very important to find an effective antiviral drug and include it in the early treatment plan . Other recommended drugs for treatment are arbidol (an antiviral drug available in Russia and China), intravenous immunoglobulin, interferons, anticoagulants, and plasma treatment .
Vaccines are the most effective strategy for preventing infectious disease because they are less costly than treatment protocols and reduce morbidity and mortality without long-term effects. In the last two decades, three human coronaviruses (SARS-CoV, MERS-CoV, and SARS-CoV-2) have emerged worldwide and pose a significant threat to global health. However, there are still no approved vaccines for human coronaviruses [18,68,69].
SARS-CoV-2, from the coronavirus family, is an RNA virus thought to originate from bats and started in China, affected the whole world and brought social and economic life to a stop. The frequent occurrence of zoonotic viruses such as Sars, Mers and finally SARS-CoV-2 from animals to humans reveals that issues such as the investigation, control and prevention of outbreaks are important issues that need to be carefully considered. Although it is thought that protease inhibitors may affect viral S proteins and viral RNA polymerases, there is no effective drug therapy developed and approved against coronavirus infections. Many drug or vaccination studies are being carried out intensively. Until a solution is reached, measures to prevent the spread of the epidemic should be strictly complied with, and a stable attitude should be shown in compliance with these measures taken by the health authorities of the society in combating the pandemic.
Laboratory findings have become much more important in combating this newly defined disease as its effects on the lockdown of health systems are observed. The main role of clinical laboratories in this pandemic has gone beyond the etiological diagnosis of COVID-19. In COVID-19 positive patients, especially hypoalbuminemia, lymphopenia and thrombocytopenia, and increases in aminotransferases, total bilirubin, D-dimer, CRP, erythrocyte sedimentation rate, cardiac troponins, creatinine, prothrombin time and procalcitonin levels should be monitored as markers for both the severity of the infection and the prognosis. It is critical to monitor the levels of these parameters in the process leading to multiple organ failure and death. In addition laboratory parameters still used in the clinical practice of COVID-19, researches continue searchingforpotentiallyusefulandpracticalnewbiochemical parameters in screening, clinical management of COVID-19, as well as many studies on drugs or vaccines continues intensively. It is considered that in cases, laboratory tests (D-Dimer, CRP, AST, ALT, Ferritin, Fibrinogen, Neutrophil, Lymphocyte), which can help clinicians to identify and monitor patients with high risk of COVID-19, also guide the pathophysiology of the disease.
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1. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in China, 2019. New England Journal of Medicine. 2020; 382:727-33
2. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020; 323(13):1239-42.
3. Walter E, Scott M. The life and work of Rudolf Virchow 1821–1902:“Cell theory, thrombosis and the sausage duel”. J Intensive Care Soc. 2017; 18(3):234-5.
4. Schultz M. Rudolf virchow. Emerging infectious diseases. 2008; 14(9):1480.
5. Li W, Shi Z, Yu M, Ren W, Smith C, Epstein JH, et al. Bats are natural reservoirs of SARS-like coronaviruses. Science. 2005; 310(5748):676-9.
6. Ge X-Y, Li J-L, Yang X-L, Chmura AA, Zhu G, Epstein JH, et al. Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. Nature. 2013;503(7477):535-8.
7. Yang L, Wu Z, Ren X, Yang F, He G, Zhang J, et al. Novel SARS-like betacoronaviruses in bats, China, 2011. Emerg Infect Dis. 2013;19(6):989.
8. Hu B, Zeng L-P, Yang X-L, Ge X-Y, Zhang W, Li B, et al. Discovery of a rich gene pool of bat SARS-related coronaviruses provides new insights into the origin of SARS coronavirus. PLoS Pathog. 2017; 13(11):e1006698.
9. Cui J, Li F, Shi Z-L. Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol. 2019;17(3):181-92.
10. Fan Y, Zhao K, Shi Z-L, Zhou P. Bat coronaviruses in China. Viruses. 2019; 11(3):210.
11. Fabricant J. The early history of infectious bronchitis. Avian Dis. 1998;42(4):648-50.
12. Hamre D, Procknow JJ. A new virus isolated from the human respiratory tract. Proc Soc Exp Biol Med. 1966; 121(1):190-3.
13. Mäkelä MJ, Puhakka T, Ruuskanen O, Leinonen M, Saikku P, Kimpimäki M, et al. Viruses and bacteria in the etiology of the common cold. J Clin Microbiol. 1998; 36(2):539-42.
14. Chiu SS, Hung Chan K, Wing Chu K, Kwan SW, Guan Y, Man Poon LL, et al. Human coronavirus NL63 infection and other coronavirus infections in children hospitalized with acute respiratory disease in Hong Kong, China. Clini Infect Dis. 2005;40(12):1721-9.
15.Moës E, Vijgen L, Keyaerts E, Zlateva K, Li S, Maes P, et al. A novel pancoronavirus RT-PCR assay: frequent detection of human coronavirus NL63 in children hospitalized with respiratory tract infections in Belgium. BMC Infect Dis. 2005; 5(1):6.
16. Ebihara T, Endo R, Ma X, Ishiguro N, Kikuta H. Detection of human coronavirus NL63 in young children with bronchiolitis. J Med Virol. 2005; 75(3):463-5.
17. Boivin G, Baz M, Côté S, Gilca R, Deffrasnes C, Leblanc É, et al. Infections by human coronavirus-NL in hospitalized children. Pediatr Infect Dis J. 2005; 24(12):1045-8.
18. Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J Autoimmun. 2020; 109:102433.
19. Chen Y, Liu Q, Guo D. Emerging coronaviruses: genome structure, replication, and pathogenesis. J Med Virol. 2020; 92(4):418-23.
20. Lu H, Stratton CW, Tang YW. Outbreak of pneumonia of unknown etiology in Wuhan, China: The mystery and the miracle. J Med Virol. 2020; 92(4):401-2.
21. Peeri NC, Shrestha N, Rahman MS, Zaki R, Tan Z, Bibi S, et al. The SARS, MERS and novel coronavirus (COVID-19) epidemics, the newest and biggest global health threats: what lessons have we learned? Int J Epidemiol. 2020; 49(3):717-26
22. Fehr AR, Perlman S. Coronaviruses: an overview of their replication and pathogenesis. Methods Mol Biol. 2015; 1282:1-23.
23. King A, Adams M, Carstens E, Lefkowitz E. Order-Caudovirales. Virus Taxonomy: Ninth Report of the International Committee on Taxonomy of Viruses. Amsterdam: Elsevier; 2012. p.39-45.
24. Lai C-C, Shih T-P, Ko W-C, Tang H-J, Hsueh P-R. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and corona virus disease-2019 (COVID-19): the epidemic and the challenges. Int J Antimicrob Agents. 2020; 55(3):105924.
25. Neuman BW, Kiss G, Kunding AH, Bhella D, Baksh MF, Connelly S, et al. A structural analysis of M protein in coronavirus assembly and morphology. Journal of structural biology. 2011; 174(1):11-22.
26. Kopecky-Bromberg SA, Martínez-Sobrido L, Frieman M, Baric RA, Palese P. Severe acute respiratory syndrome coronavirus open reading frame (ORF) 3b, ORF 6, and nucleocapsid proteins function as interferon antagonists. J Virol. 2007; 81(2):548-57.
27. Schoeman D, Fielding BC. Coronavirus envelope protein: current knowledge. Virol J. 2019; 16(1):1-22.
28. Ulasli M, Bayraktar R, Bozgeyik I. Replication of coronavirus. Gaziantep Medical Journal. 2013; 19(3):141-8.
29. Loeffelholz MJ, Tang Y-W. Laboratory diagnosis of emerging human coronavirus infections–the state of the art. Emerg Microbes Infect. 2020; 9(1):747-56.
30. Ou X, Liu Y, Lei X, Li P, Mi D, Ren L, et al. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat Commun. 2020; 11(1):1-12.
31. Del Rio C, Malani PN. COVID-19—new insights on a rapidly changing epidemic. Jama. 2020; 323(14):1339-40.
32. Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med. 2020; 46(4):586-90.
33. Carlos WG, Dela CC, Cao B, Pasnick S, Jamil S. Novel Wuhan (2019-nCoV) Coronavirus. Am J Respir Crit Care Med. 2020; 201(4):P7-8.
34. Wu P, Hao X, Lau EH, Wong JY, Leung KS, Wu JT, et al. Real-time tentative assessment of the epidemiological characteristics of novel coronavirus infections in Wuhan, China, as at 22 January 2020. Eurosurveillance. 2020; 25(3):2000044.
35. Bulut C, Kato Y. Epidemiology of COVID-19. Turk J Med Sci. 2020; 50(SI- 1):563-70.
36. Li Y, Campbell H, Kulkarni D, Harpur A, Nundy M, Wang X, et al. The temporal association of introducing and lifting non-pharmaceutical interventions with the time-varying reproduction number (R) of SARS-CoV-2: a modelling study across 131 countries. The Lancet Infectious Diseases. 2020; 21(2):193-202.
37. Zhao S, Lin Q, Ran J, Musa SS, Yang G, Wang W, et al. Preliminary estimation of the basic reproduction number of novel coronavirus (2019-nCoV) in China, from 2019 to 2020: A data-driven analysis in the early phase of the outbreak. Int J Infect Dis. 2020; 92:214-7.
38. Chang D, Lin M, Wei L, Xie L, Zhu G, Cruz CSD, et al. Epidemiologic and clinical characteristics of novel coronavirus infections involving 13 patients outside Wuhan, China. Jama. 2020; 323(11):1092-3.
39. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. The Lancet. 2020; 395(10223):507-13.
40. Shao L, Li X, Zhou Y, Yu Y, Liu Y, Liu M, et al. Novel Insights Into Illness Progression and Risk Profiles for Mortality in Non-survivors of COVID-19. Front Med. 2020; 7:246.
41. Masetti C, Generali E, Colapietro F, Voza A, Cecconi M, Messina A, et al. High mortality in COVID-19 patients with mild respiratory disease. Eur J Clin Invest. 2020; e13314.
42. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet. 2020; 395(10223):497-506.
43. Ranucci M, Ballotta A, Di Dedda U, Bayshnikova E, Dei Poli M, Resta M, et al. The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome. J Thromb Haemost. 2020; 18(7):1747-51.
44. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020; 18(4):844-7.
45. Han H, Yang L, Liu R, Liu F, Wu K-l, Li J, et al. Prominent changes in blood coagulation of patients with SARS-CoV-2 infection. Clin Chem Lab Med. 2020; 58(7):1116-20.
46. Ok F, Erdogan O, Durmus E, Carkci S, Canik A. Predictive values of blood urea nitrogen/creatinine ratio and other routine blood parameters on disease severity and survival of COVID-19 patients. J Med Virol. 2020; 93(2):786-93.
47. Seyit M, Avci E, Nar R, Senol H, Yilmaz A, Ozen M, et al. Neutrophil to lymphocyte ratio, lymphocyte to monocyte ratio and platelet to lymphocyte ratio to predict the severity of COVID-19. Am J Emerg Med. 2021; 40:110-14.
48. Gormez S, Ekicibasi E, Degirmencioglu A, Paudel A, Erdim R, Gumusel HK, et al. Association between renin–angiotensin–aldosterone system inhibitor treatment, neutrophil–lymphocyte ratio, D-Dimer and clinical severity of COVID-19 in hospitalized patients: a multicenter, observational study. J Hum Hypertens. 2020; 1-10.
49. Liu Y, Du X, Chen J, Jin Y, Peng L, Wang HH, et al. Neutrophil-to-lymphocyte ratio as an independent risk factor for mortality in hospitalized patients with COVID-19. J Infect. 2020; 81(1):e6-e12.
50. Altintas M, Akdeniz G, Gurbuz B, Kara Y, Celbis O. Demographic and clinical features of Covid-19 cases in Serik, Turkey. Medicine. 2020; 9(3):657-61.
51. Patel R, Babady E, Theel ES, Storch GA, Pinsky BA, George KS, et al. Report from the American Society for Microbiology COVID-19 international summit, 23 march 2020: value of diagnostic testing for SARS–CoV-2/COVID-19. Am Soc Microbiol. 2020; 11(2): e00722-20
52. Li D, Wang D, Dong J, Wang N, Huang H, Xu H, et al. False-negative results of real-time reverse-transcriptase polymerase chain reaction for severe acute respiratory syndrome coronavirus 2: role of deep-learning-based CT diagnosis and insights from two cases. Korean J Radiol. 2020; 21(4):505-8.
53. Zitek T. The appropriate use of testing for COVID-19. West J Emerg Med. 2020; 21(3):470-2.
54. Li Z, Yi Y, Luo X, Xiong N, Liu Y, Li S, et al. Development and clinical application of a rapid IgM-IgG combined antibody test for SARS- CoV- 2 infection diagnosis. J Med Virol. 2020; 92(9):1518-24.
55. Jin Y-H, Cai L, Cheng Z-S, Cheng H, Deng T, Fan Y-P, et al. A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version). Mil Med Res. 2020; 7(1):4.
56. Yanartaş MS, Törün SH. COVID-19 ve Çocuk (COVID-19 and Child). Sağlık Bilimlerinde İleri Araştırmalar Dergisi/ Journal of Advanced Studies in Health Sciences. 3(S1):40-8.
57. Bikdeli B, Madhavan MV, Jimenez D, Chuich T, Dreyfus I, Driggin E, et al. COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020; 75(23):2950-73.
58. Cannegieter SC, Klok FA. COVID-19 associated coagulopathy and thromboembolic disease: Commentary on an interim expert guidance. Res Pract Thromb Haemost. 2020; 4(4):439-45.
59. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? The Lancet. Respiratory Medicine. 2020; 8(4):e21.
60. Day M. Covid-19: ibuprofen should not be used for managing symptoms, say doctors and scientists. BMJ. 2020; 368:m1086.
61. Willsher K. Anti-inflammatories may aggravate Covid-19, France advises. The Guardian. 2020;
62. FitzGerald GA. Misguided drug advice for COVID-19. Science. 2020; 367(6485):1434.
63. Vijay R, Fehr AR, Janowski AM, Athmer J, Wheeler DL, Grunewald M, et al. Virus-induced inflammasome activation is suppressed by prostaglandin D2/ DP1 signaling. Proceedings of the National Academy of Sciences. 2017;114 (27):E5444-53.
64. Yan X, Hao Q, Mu Y, Timani KA, Ye L, Zhu Y, et al. Nucleocapsid protein of SARS-CoV activates the expression of cyclooxygenase-2 by binding directly to regulatory elements for nuclear factor-kappa B and CCAAT/enhancer binding protein. Int J Biochem Cell Biol. 2006; 38(8):1417-28.
65. Amici C, Di Coro A, Ciucci A, Chiappa L, Castilletti C, Martella V, et al. Indomethacin has a potent antiviral activity against SARS coronavirus. Antiviral Ther. 2006; 11(8):1021.
66. McGonagle D, Sharif K, O’Regan A, Bridgewood C. Interleukin-6 use in COVID-19 pneumonia related macrophage activation syndrome. Autoimmun Rev. 2020; 102537.
67. Zhang L, Liu Y. Potential interventions for novel coronavirus in China: A systematic review. J Med Virol. 2020; 92(5):479-90.
68. Ahn D-G, Shin H-J, Kim M-H, Lee S, Kim H-S, Myoung J, et al. Current status of epidemiology, diagnosis, therapeutics, and vaccines for novel coronavirus disease 2019 (COVID-19). J Microbiol Biotechnol. 2020; 30(3):313-24.
69. Guarner J. Three emerging coronaviruses in two decades: the story of SARS, MERS, and now COVID-19. Oxford University Press US. 2020; 153( 4):420–1.
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