Correlation of SOX2 expression with clinicopathologic parameters in larynx squamous cell carcinoma
Elif Gökçe Devecioglu 1, Seyhan Hasçiçek 2, Nazlı Sena Şeker 1, Nurullah Seyhun 3, Fevziye Kabukcuoglu 2
1 Department of Pathology, Gazi Yasargil Research&Training Hospital, Diyarbakır, 2 Department of Pathology, Sisli Hamidiye Etfal Research&Training Hospital, Istanbul, 3 Department of Otorhinolaryngology and Head & Neck Surgery, Şişli Hamidiye Eftal Research&Training Hospital, İstanbul, Turkey
DOI: 10.4328/ACAM.20538 Received: 2021-02-13 Accepted: 2021-06-11 Published Online: 2021-07-20 Printed: 2021-09-01 Ann Clin Anal Med 2021;12(9):958-962
Corresponding Author: Elif Gökçe Devecioğlu, Department of Pathology, Gazi Yasargil Research&Training Hospital,Talaytepe, Üçkuyular District Elazığ Road, Over 10.Km, 21010 Kayapınar / Diyarbakır /Turkey. E-mail: firstname.lastname@example.org P: +90 5058609458 F: +90 4122580060 Corresponding Author ORCID ID: https://orcid.org/0000-0001-6705-3068
Aim: Laryngeal cancers are the most common tumors in the respiratory system after the lung and bronchial system. It is important to identify new biological markers which may also help us to understand the molecular and biological mechanisms of tumor development. SOX2 is a cancer stem cell, that is an indicator of lymph node metastasis, biomarker or potential therapeutic target in some cancer types. The aim of this study is to investigate whether there is a correlation between SOX2 expression and the clinicopathological features of laryngeal squamous cell carcinoma.
Material and Methods: In this retrospective study, we analyzed surgical tissue samples of 61 patients with laryngeal squamous cell carcinoma who had un- dergone total laryngectomy and bilateral cervical lymph node dissection without preoperational radiotherapy and/or chemotherapy between 2012 and 2016. SOX2 expression was evaluated in 61 laryngectomy and cervical lymph node dissection materials using immunohistochemistry and statistically analyzed for its correlation with clinicopathological parameters.
Results: Of the 61 patients, only two were female. The average age of the patients at the time of diagnosis was 60,9 ±8,7 years. SOX2 overexpression was detected in 83,6% of cases. There was a statistically significant correlation between SOX2 overexpression and anatomical location, histological differentia- tion, local cervical lymph node metastasis, perineural invasion and vascular invasion; however, no significant correlation was found between cartilage invasion.
Discussion: SOX2 expression levels in LSCC showed a statistically significant correlation with local cervical lymph node metastasis. Future studies on SOX2 expression levels in preoperational biopsy specimens are warranted to evaluate its potential prognostic parameters, which may guide treatment decisions in patients with LSCC.
Keywords: Laryngeal Cancer; Squamous Carcinoma; SOX2 Expression; Immunohistochemistry
Laryngeal cancers are the most common tumors in the respiratory system after the lung and bronchial system . Almost all laryngeal cancers are squamous cell carcinomas [SCC] . Laryngeal cancers pose a significant risk of morbidity and mortality for patients as the overall 5-year survival rate is 60.3% per SEER Cancer Statistics Review website [accessed on 4/23/2020]. Since tumors in the same location with similar histologic differentiation degree may act differently, new parameters are needed to elucidate the underlying mechanisms of tumor development. New biomarkers, including various immunohistochemical techniques, are needed to determine the prognosis in LSCC and are performed in relation to the correlation of clinicopathology. In studies with cyclin D1 protein  and BCL2L12 and BAX protein  expression, a significant relationship was found with the clinicopathological parameters in LSCC patients.
SOX2 [SRY-related Hmg-box gene 2] encodes a transcription factor that is crucial for maintaining embryonic stem cell pluripotency. SOX2 has also been shown to play a role in proliferation, migration, invasion, and metastasis of cancer cells, as well as the continuation of tumor cells and stem cells, cell programming, apoptosis and development of chemoresistance. Recent studies showed that SOX2 acts as an anti-apoptotic factor in cancer cells [5,6]. Bass et al.  found that SOX2, a transcription factor at chromosome 3q26.33, at a genomic amplification peak, is effective in esophageal and lung squamous cell carcinomas, and concluded that the lung and esophagus can be identified as a lineage-survival oncogene in SCC. They showed that the expression of pluripotency markers is involved in squamous cell differentiation in SOX2-driven tumors . Recent studies have demonstrated that SOX2 plays a role in the development of the normal esophageal squamous cell structure. Similarly, some others studies have reported the induction of pluripotent stem cells, providing both differentiation and proliferation of basal tracheal cells [8,9]. We assumed that SOX2 expression may be critical in LSCC pathogenesis as larynx, lung and esophagus SCC show significant similarity in histomorphological and clinical features.
In this study, we aimed to investigate the tumor behavior of SOX2 expression in laryngeal carcinoma and the correlation with clinicopathological parameters such as differentiation level of the tumor, cartilage invasion, perineural invasion, lymph node metastasis.
Material and Methods
In this study, we included 61 patients, consisting of 59 male and 2 female patients, who were operated due to laryngeal squamous cell carcinoma. In order to compare SOX2 equally with all parameters and to predict the prevalence and correlation of prognostic parameters in general larynx squamous cell cancer, all cases who underwent total laryngectomy and neck dissection operation without preoperational radiotherapy and/ or chemotherapy within 4 years were included in this study. Formalin-fixed, paraffin-embedded tissues [FFPE] of pathological specimens that were stained with Hematoxylin- Eosin were retrieved. Paraffin blocks that contain viable tumor cells were chosen for analysis. The study was approved by the Research Ethics Committee.
After identifying suitable FFPE, an unstained section from each block was retrieved. Three-micron thick sections were taken from paraffin- embedded blocks on positively charged microscope slides for immunohistochemical assays. Immunohistochemical staining of SOX2 [rabbit mab, #SP001, klon: EP103, cell signaling technologies, USA] was performed using the DAP peroxidase method. This procedure was carried out in Leica Bond III device. The immunostaining procedure was performed on a [Leica Bond III] device after slides were incubated at 80°C for 3 hours. Briefly, Bond-Dewak solution was applied for 10 minutes at 60°C, slides were then deparaffinized and rehydrated through graded ethanol solutions. Antibody retrieval was carried out by applying ER1 at 96°C for 20 minutes, followed by H2O2 blocking for 13 minutes at room temperature. The primary antibody [SOX2, rabbit monoclonal antibody, #SP001, klon: EP103, cell signaling technologies, USA, 1:100] was applied for 30 minutes, then it was washed and secondary antibody was applied for 8 minutes at room temperature. DAB was used as a chromogen and hematoxylin was used for counterstaining. Coverslipping followed graded alcohols and xylene.
Evaluation of staining
Immunohistochemical stainings were analyzed under a 20X light microscope. The diencephalon part of fetus human brain was used as a control group. Only cells with nuclear SOX2 staining were accepted as positive staining. Cases were graded according to the intensity of the staining as follows: no staining, weak/yellowish staining, strong/brownish staining (Figure 1). According to the proportion of positively stained tumour cells in 5 high power field: 0 [0-5% stained group], 1+ [6-33% stained group], 2+ [34-66% stained group] and 3+ [67% and over stained group] (Figure 2).
SPSS 22.0 program was used for statistical analysis. Descriptive statistics were given as numbers and percentages for categorical variables; mean, standard deviation, minimum, and maximum for numerical variables. Chi-square analysis was used to compare the ratios between independent groups. Monte Carlo Simulation was used when conditions are not met. P<0.05 was considered statistically significant.
We identified 61 patients who were diagnosed with laryngeal squamous cell carcinoma and underwent total laryngectomy with bilateral neck dissection. Among these patients, 59 [96.7%] were male and 2[3.3%] were female. The mean age of the patients was 60.2 [±]. Histopathologic examination revealed that 26 [42.6%] of tumors were poorly differentiated, 22 [36.1%] were slightly differentiated, and 13 [21.3%] were well differentiated. According to the anatomical location of the tumor, cases were grouped into 6 different groups. The tumor was located in supraglottic region in 25 patients [41.0%], glottic and subglottic in 18 [29.5%], confined to glottis in 11 [18.0%], transglottic in 4 [6.6%], supraglottic and glottic in 2 [3.3%], and confined to subglottis in 1 [1.6%]. In 34 [55.7%] of the patients, thyroid cartilage invasion was present, perineural invasion was seen in 24 [39.3%] patients, vascular invasion was detected in 25 [41,0%] patients, and lymph node metastasis was detected in 21 [34,4%] patients. The relation of tumor differentiation degree with invasion [vascular, perineural, cartilage] and cervical lymph node metastasis is shown in Table 1.
In 10 [16.4%] patients, the tumor was not stained with SOX2 , in 12 patients % 6-33 of the tumor was stained with SOX2 [1+], in 11 patients %34-66 of the tumor was stained with SOX2[2+] and in 28 patients >67% of the tumor was stained with SOX2 [3+]. In cases showing SOX2 expression, 16 [83.6%] had strong staining in 16 and 35 [57.4%] had weak staining. When these groups were compared, significant differences were found regarding location of the tumor, differentiation level of the tumor, perineural and vascular invasion, lymph node metastasis [p=0,002, p<0,001, p=0,023, p=0.021, p=0.037]. In 3+ stained group, the tumors located in supraglottis were statistically higher than in other groups [p=0,002]. The SOX2 staining percentage rate was found to be slightly differentiated in the group with score 3 and well differentiated in the group with a score of 0. It was noted that perineural, vascular invasion, and lymph node metastasis rates were higher in groups with SOX2 staining score 2 and score 3. SOX-2 expression percentage rates are shown in Table 2.
When examining the relationship between SOX2 staining intensity and other parameters, location of the tumor, differentiation degree, perineural and vascular invasion rates, a statistically significant difference was observed between them [p = 0.010, p = 0.026, p = 0.045, p = 0.028].
As the intensity of staining increases, a higher number of supraglottic locations, vascular and perineural invasion, and poorly differentiated tumor were observed (Table 3).
SOX2 is a transcription factor located on chromosome 3p26.33, which is responsible for the regeneration of the pluripotent stem cells. This has been reported to take place in embryologic development, organogenesis and several different neoplastic processes. Overexpression of SOX2 in Hep-2 cells is related to activation of the P13K/Akt/mTOR pathway, which causes overexpression of MMP-2 and results in an increased tumor cell proliferation, migration, and invasion in laryngeal squamous cell carcinoma .
In the literature, there are only a few studies regarding the association of SOX2 overexpression in laryngeal squamous cell carcinomas. In a recent study, SOX2 staining intensity was not found to be associated with the age and gender of the patient, and tumor location in laryngeal squamous cell carcinoma . Similarly, no significant association with the age and gender of patients was found in our study. We found that the location of the tumor was associated with the intensity of SOX staining, which was prominent in supraglottic tumors. This difference might be due to embryologically, the supraglottic area (3rd and 4th branchial arc) and glottic and subglottic area (5th and 6th branchial arc) developed from different embryological structures.
In our study, differentiation of the tumor was also associated with SOX2 expression, as, for example, Gonzalez et al  and Liu et al  reported similar findings. The extensiveness of staining was also found to be associated with differentiation of the tumor. However, Rodriguez et al  did not find any association between tumor differentiation and SOX2 expression in breast cancer, which might be due to the location and histology of the tumor type.
We also confirmed that the intensity and percentage rates of SOX2 staining were significantly associated with lymph node metastasis, vascular and perineural invasion. Lengerke et al  showed that SOX2 overexpression in early-stage breast cancer is an indicator of potential lymph node metastasis. In another study related to tongue SCCs, a significant relationship was shown with lymph node metastasis of SOX-2 expression . Xia-bing et al reported that SOX2 overexpression affects clinical stage, lymph node metastasis and prognosis in laryngeal carcinoma .
Since there is significant connection between sox2 prevalence and lymph node metastasis, cases that have been diagnosed as larinks scc, as a result of first biopsy, taken from the larnyx, lymph node metastasis might be anticipated by means of SOX2 immunohistochemical studies. Therefore, larnyx disection supplementation decision may be included in the surgical procedure. Providing identification of cases that are unlikely to cause lymph node metastasis, it will actually prevent lymph node dissection that is not necessary.
In a study done with 94 patients with precancerous lesions, Rocia et al  found that SOX2 expression was the only significant independent predictor for laryngeal cancer transformation. These findings support the role of SOX2 in early tumor development and the clinical utility of SOX2 expression in predicting the transformation of precancerous lesions to laryngeal cancer in addition to current WHO histopathological classification.
Identification of genetic alterations in the formation of tumorigenesis. It plays a key role in predicting the behavior of the tumor and discovering prognostic biomarkers, as well as in more effective treatments for potential targets . To develop new strategies in diagnosing and treating laryngeal carcinoma, molecular studies about oncogenic transcription factors like SOX-2 are being conducted. In addition, cancer stem cells being effective in tumor formation and cell motility, improve understanding of the resistance mechanism in radiotherapy resistant head and neck cancers, and it is important to develop new therapeutic agents that can also be used in the treatment of these cancers .
It has been found that LSD-1 inhibitors, can stop tumor growth and therefore can be used in targeted therapy in SOX-2 expressing tumors, such as lung SCC . To determine SOX2 expression in larynx biopsies, treatments targeting SOX-2 can also be valuable in the use of larynx SCCs.
In this study, we have shown that SOX2 overexpression has a significant effect on prognostic factors in laryngeal squamous cell carcinoma. These findings will provide insight for future studies about the alternative treatment of laryngeal carcinoma. In this matter, further studies including alternative treatment methods are needed.
SOX2 overexpression shows a statistically significant correlation with cervical lymph node metastasis and clinicopathological parameters. It can be used in the preoperative biopsy specimens with SOX2 expression to guide treatment decisions in laryngeal SCC patients and to evaluate the potential of targeted treatment.
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.
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Download attachments: 10.4328:ACAM.20538
Elif Gökçe Devecioglu, Seyhan Hasçiçek, Nazlı Sena Şeker, Nurullah Seyhun, Fevziye Kabukcuoglu. Correlation of SOX2 expression with clinicopathologic parameters in larynx squamous cell carcinoma. Ann Clin Anal Med 2021;12(9):958-962
The role of magnetic resonance in the staging of Klatskin tumors
Levent Soydan 1, Mehmet Torun 2, Kamil Canpolat 1, Turgay Oner 1, Umut Kına 2, Ismail Ege Subasi 3
1 Department of Radiology, Haydarpasa Numune Training and Research Hospital, 2 Department of General Surgery, Haydarpasa Numune Training and Research Hospital, 3 Department of Gastroenterology, Istanbul Kartal Kosuyolu High Speciality Educational and Research Hospital, Istanbul, Turkey
DOI: 10.4328/ACAM.20542 Received: 2021-02-15 Accepted: 2021-04-01 Published Online: 2021-06-21 Printed: 2021-09-01 Ann Clin Anal Med 2021;12(9):963-968
Corresponding Author: Levent Soydan, Haydarpasa Numune Training and Research Hospital, Selimiye, Tıbbiye street, No:23, 34668 Uskudar/Istanbul, Turkey. E-mail: email@example.com P: +90 5333956490 Corresponding Author ORCID ID: https://orcid.org/0000-0002-8958-5118
Aim: In this study, it was aimed to investigate the diagnostic accuracy of preoperative staging of Klatskin tumors (KT) with Magnetic Resonance (MR) and MR cholangiopancreatography (MRCP) with reference to surgical and histopathological results.
Material and Methods: This study was conducted by retrospectively reviewing preoperative dynamic contrast-enhanced (DCE) MR and MRCP examinations of 25 patients who were operated with the pre-diagnosis of KT and diagnosed as KT by postoperative histopathology at the Haydarpasha Numune Training and Research Hospital between January 1, 2012 and December 31, 2019. Two radiologists evaluated the longitudinal extension of the tumor along the common bile duct and the intrahepatic biliary tract involvement. Consensus was achieved on Bismuth-Corlette (BC) typing and TN staging. The diagnostic performances of the MR/MRCP findings were assessed with reference to surgical exploration and resected specimens.
Results: Among 25 cases evaluated in the study, 12 (48%) were female, 13 (52%) were male, with a mean age of 61.96 ± 8.91 (minimum: 42, maximum: 81) years. The sensitivity of the MRCP in distinguishing between BC Type 3 and T1-Type 2 was 77.78%, the specificity was 78.57%, and the diagnostic was accu- racy 78.26%. The sensitivity of dynamic MRI for T staging was 62.5%, specificity was 86.67% and diagnostic accuracy was 69.26%; In N staging, its sensitivity was 28.57%, specificity was 87.5% and accuracy was 60.57%.
Discussion: MRCP and DCE MR examination can be used for clinical staging of KTs to evaluate biliary extension and operability. In N staging, which is important for prognosis, its accuracy is limited.
Keywords: Diagnostic accuracy; Klatskin tumor; Magnetic resonance; Staging
Klatskin Tumor (KT) is the most common type of cholangiocarcinoma originating from the biliary epithelium at the hepatic duct confluence. The incidence is around 0.3- 6 / 100000 with regional variations . Various classifications based on the extension along bile ducts and vascular invasion have been proposed for KTs to plan an optimal treatment approach and to predict the prognosis .
Currently, the only treatment in KT is R0 surgical resection for resectable tumors to prolong survival . Preoperative imaging identifies non-resectable cases for palliative treatment and enables preoperative assessment of bile duct involvement in resectable cases. An accurate preoperative evaluation of tumor extension, parenchymal involvement and resectability is important for treatment planning. Multislice Computed Tomography (CT), Magnetic Resonance (MR) and endoscopic retrograde cholangiopancreatography (ERCP) are the most commonly used imaging techniques in preoperative staging of KTs [2,3]. MR-Cholangiopancreatography (MRCP) can be used to non-invasively evaluate the presence, degree and level of bile duct obstruction by displaying the biliary tree owing to the heavy T2W-related high contrast between bile ducts and the periphery [3,4]. Dynamic contrast-enhanced (DCE) MR is an alternative to CT in the detection of tumor, parenchymal and distant spread, and evaluation of vascular invasion.
The modified Bismuth-Corlette (BC) classification evaluates tumoral biliary infiltration and is the most widely used classification for KT, while the AJCC-TNM staging classifies patients according to prognosis and allows tailoring an appropriate treatment [5,6]. In addition, Memorial Sloan- Kettering Cancer Centre and Blumgart classifications can be used in the preoperative evaluation of KT by providing information about tumor resectability [6,7]. In this study, we aimed to evaluate the diagnostic performance of KT with MRCP and contrast-enhanced MRI according to TNM staging and BC classification, with reference to surgical and histopathological findings.
Material and Methods
This retrospective study was conducted with 25 patients who were operated with the pre-diagnosis of KT in Haydarpasha Numune Training and Research Hospital between January 1, 2012 and December 31, 2019 and were diagnosed with KT on postsurgical pathology. Ethical approval for this study was obtained from the Ethic Committee of our Institution. Selection of patients
Twenty-five patients who were diagnosed as KT by postoperative histopathology and underwent MRCP and DCE MRI within 20 days before the operation were included in the study. Cases that did not meet these criteria were excluded from the study. MRCP and Contrast-enhanced MRI Technique
All MR scans were performed with a 1.5T GE 760w Optima 4-channel phased-array abdominal coil (GE Healthcare, Milwaukee, USA). In MRCP examination, images were obtained using +/- 300 and 600 T2 weighted (T2W) thick slab turbo spin echo (TSE), breath hold thin slab coronal and axial T2W SSFE (single-shot fast spin echo) sequences in the coronal, oblique coronal and sagittal planes with breath hold. Breath-hold thin-section T2W SSFE MRCP images covered a scan volume of approximately 60 mm3 at a time in 5 minutes. 3D MRCP images were obtained using the ASSET (array of spatial sensitivity technique) technique, respiratory triggering and navigator. These data were transferred to a workstation and 3D images rotating with 100 increments around the z-axis were created with the maximum intensity projection technique.
For DCE images 0.1 mmol/kg gadoteric acid (Dotarem, Guerbet, France) was given intravenously at a rate of 2 ml/ sec and fat-suppressed 3D T1W Gradient Echo (GRE) images (LAVA, GE) at a slice-thickness of 5mm were acquired at 20-35 seconds, 45-60 seconds and 3 minutes for arterial, venous and equilibrium phases images, respectively. The imaging protocol is summarized in Table 1.
All images were reviewed by two radiologists on the PACS workstation (GE Workstation). Two radiologists with 15 and 5 years of experience in abdominal MR imaging evaluated dynamic MR and MRCP images. Both radiologists knew that the patients had been operated, but were blinded to the postoperative results. The MR assessment of each case was reached by consensus of both radiologists.
KT was diagnosed as slightly hyperintense on T2A and hypointense on DCE T1A images. Continuous or segmental enhancement was noted along the involved biliary walls, especially in the arterial phase. In addition, loss of biliary ductal continuity, ductal obstruction, sudden and irregular narrowing of the distal common bile duct, prestenotic dilatation and irregular intraluminal filling defects were accepted as biliary involvement.
Both radiologists evaluated tumor extension along the common bile duct and intrahepatic bile ducts using the BC classification. Dilated bile ducts were correlated with axial/coronal T2W and axial DCE images. The KTs were classified as follows:
– Type I is contained in the common bile duct and does not extend to the biliary confluence (Figures 2),
– Type II involves proximal cystic duct and biliary confluence (Figure 1),
– Type IIIa extends proximally from the junction of cystic duct- common bile duct to the biliary confluence and the right hepatic duct and/or to the right secondary bile ducts,
– Type IIIb extends proximally from the junction of cystic duct- common bile duct to the biliary confluence and the left hepatic duct and/or to the left secondary bile ducts,
– Type IV extends proximal from cystic duct-common bile duct junction to biliary confluence and both hepatic ducts or showing multifocal bile duct involvement.
Axial and coronal DCE images were used for T and N staging and correlated with T2A sections when needed. Accordingly, T1 was defined for a tumor confined in the biliary canal, T2 for invasion of the biliary canal and adjacent hepatic parenchyma, T3 for invasion of the portal vein branch or hepatic artery, and T4 for the involvement of the main portal vein, common hepatic artery or secondary biliary ducts. The diagnosis of venous or arterial invasion was made when KT encased vascular structures > 1800 (Figures 3).
In nodal staging, N1 was defined involvement of 1-3 regional lymph nodes (nodes near the common bile duct, cystic duct,
proper hepatic artery and portal vein), and N2 was defined as > 4 distant nodes. Metastatic involvement was defined in nodes with a short axis > 10 mm, with central necrosis or with hyperenhancement compared to liver parenchyma in the portal phase.
The definitive diagnosis was made in all patients by histopathological examination. The TNM staging was done according to the 8. AJCC criteria. Klatskin typing was done according to the modified BC classification. Hepatobiliary surgical procedures were performed by two surgeons with 17 and 5 years of experience in this field. During the surgery, the biliary confluence was exposed, the vascular involvement was evaluated, and resection was performed in all cases. An intraoperative frozen histological examination of the resection margin was performed to ensure the R0 resection.
Preoperative biliary and nodal involvement were compared with postoperative histopathological findings. Diagnostic performance sensitivity, specificity and diagnostic accuracy were calculated in all patients with radiological TNM staging and Klatskin typing. For statistical analysis, the NCSS (Number Cruncher Statistical System) 2007 (Kaysville, Utah, USA) program was used. Descriptive statistical methods (mean, standard deviation, median, frequency, percentage, minimum, maximum) were used while evaluating the study data. The McNemar test and diagnostic screening tests were used to compare qualitative data. Statistical significance was accepted as p <0.05.
Among 25 patients, 12 (48%) were female, 13 (52%) were male, with a mean age of 61.96 ± 8.91 (range 42-81) years. The mean time between surgery and MRCP/MRI was 7 days. Patient characteristics are given in Table 2. All cases were adenocarcinoma. According to histopathology, 1 patient had type I, 14 patients had type II, 5 patients had type IIIa, and 5 patients had Type IIIb BC KT. The median survival was 841 (21 – 2555) days.
Evaluation of radiological and pathological TNM staging
On DCE/MR enhancement of segments with biliary involvement was observed in the arterial phase in 90% and in the portal phase in 95% of cases.
According to the histopathological T staging, 12% (n = 3) of cases were pT1, 56% (n = 14) were pT2, 28% (n = 7) were pT3 and 4% (n = 1) was pT4. According to MR staging 68% (n = 17) of cases were T2 and 32% (n = 8) was T3. No statistically significant difference was found between histopathology and MR findings (p> 0.05). While there were 34.8% cases pathologically > = T3, there were 30.4% cases with > = T3 on MR. Three of 8 pT3 cases were understaged as T2 by MR (34.8% vs 21.7%).
Nine cases (36%) showed lymph node metastasis on pathology. According to the pathology results, 7 cases (28%) were diagnosed as N1, while radiology evaluated 2 cases (8%) as N1. Extension of the Tumor along Biliary Tract
MRCP images were of sufficient diagnostic quality in all patients. On pathological examination Klatskin classification was as follows; 4% (n = 1) was type 1, 56% (n = 14) were type 2, 20% (n = 5) were type 3a and 20% (n = 5) were type 3b. The MR classification was as follows; 4.3% (n = 1) was type 1, 52.2% (n = 12) were type 2, 17.4% (n = 4) were type 3a and 26.1% (n = 6) were type 3b. No significant difference was found between MR findings and pathology results, (p> 0.05). Nine cases (39.1%) were pathologically classified as Type 3a- 3b and 7 cases (30.4%) as Type 3a-3b on MR. The diagnostic performance of MRCP /MRI in evaluating BC typing and TN stages of KT is shown in Table 3.
In this study, we found that the diagnostic accuracy of preoperative MR/MRCP in distinguishing BC Type 3 patients from Type 1 and Type 2 patients is 78.2%. In addition, the accuracy of the dynamic MR in distinguishing Klatskin T3 from T1 and T2 was 69.2% and the accuracy in differentiating between N1 and N0 was 60.6%. In previous studies, the accuracy of MRCP in detecting biliary tumor extension was reported as 71% -96% and its sensitivity was 92% [8-15]. Our results were consistent with those reported in previously published studies. Zidi et al. and Vogl et al reported that MRCP had an accuracy of 70% and 95% for all BC types, respectively, with ERCP taken as a reference, and that MRCP tended to underdiagnose BC types [9, 10]. Lopera et al. and Lee et al., found that MRCP predicts bile duct involvement with an accuracy of 96% and 87.9%, respectively, using PTK as a reference [14,16]. Similar to our study, Park et al. took surgical and pathological results as a reference and reported that the diagnostic accuracy of combined use of DCE MR and MRCP was 87-90.7% . Similar to other studies, our study also showed that MR tended to understage the BC type. One of the probable explanations for this may be the microscopic tumor infiltration that cannot be discerned on MR due to its low spatial resolution.
Concerning metastatic lymph node involvement, imaging methods have been reported to have low diagnostic accuracy. Noji et al., reported that in lymph nodes with short axis > 16 mm the PPV for metastatic involvement was 56% on CT . In a retrospective study performed by Ruys et al. histopathological examination of lymph nodes from 147 patients revealed that there is no definite threshold value to predict metastatic involvement . To the best of our knowledge, there is no study in the literature that specifically examined nodal involvement in KTs. In our study, the diagnostic accuracy of nodal metastasis was 69%. However, considering the low number of our cases, the generalizability of this result is limited. Therefore, it appears reasonable to suggest that a confirmatory evaluation with PET should be done in cases of suspected nodal involvement, although a PET-negative result will not rule out nodal metastasis .
MRCP imaging has advantages such as being non-invasive compared to invasive ERCP and PTK, panoramic capacity, obviating contrast agent, and visualization of the entire biliary tree. However, MRCP has limitations such as low spatial resolution, inability of showing the complex anatomy of the perihilar bile ducts and superficial spread of the tumor. These limitations are partially offset in 3D MRCP images obtained with isotropic voxels which can be reformatted in every plane with isotropic resolution [14-16]. We used a 3-dimensional GRE (HYPERCUBE / HYPERSENSE, GE) for MRCP imaging which reduces the partial volume effect for better spatial resolution and uses a navigator allowing the patient to breathe freely.
It has been reported that the diagnostic accuracy in BC classification increased with the addition of DCE MR imaging to MRCP . Although an accurate BC classification may inform the surgeon about the extent of surgery, it cannot adequately assess tumor resectability alone as it does not evaluate other inoperability criteria, including vascular invasion, nodal involvement and distant metastasis.
The surgical approach in resectable KTs varies according to the anatomical location of the tumor and its extension in the bile duct. Generally, endoscopic stenting or surgical hilar resection is performed in Type I and Type II tumors, while percutaneous stenting or major hepatectomy is preferred in Type III tumors. Serious complications such as cholangitis due to catheter manipulation may develop especially after percutaneous stenting [20,21]. Antibiotics given after cholangitis may be ineffective in areas that cannot be drained. Apart from some exceptions, Type IV cases are generally not considered resectable. Therefore, an accurate preoperative BC classification enables to plan surgery or stenting and can predict postoperative complications.
In TNM staging, it is important to make stage distinctions as there are significant prognostic differences between T2 = < and => T3, between N1 and N2, and the presence of distant metastasis according to the 8th AJCC staging. Although the diagnostic accuracy of the T stage in our study is high, it may still be insufficient for surgical planning in some cases, as resectability may also depend on anatomical location (eg in T4 tumors).
Even in resectable conditions, the 5-year survival of KT has been reported as 20-42% with the final outcome mostly determined by nodal metastasis [6,22,23]. Studies with meta-analysis reported low diagnostic accuracy rates in the diagnosis of nodal metastasis with current imaging methods [17,18]. In our study, although the accuracy rate of MRI in detecting nodal metastasis was acceptable, its generalizability is limited. Apart from lymph node size, morphological criteria should also be considered in nodal metastasis in CT and MR. Therefore, in daily practice, TNM staging is performed using postoperative histopathology. Nevertheless, we believe that the correct preoperative TNM staging performed with preoperative dynamic MR will help to evaluate resection possibilities. Also, the addition of MR angiography to DCE/MR may help better evaluate vascular invasion . Finally, a preoperative laparoscopic exploration may be attempted to evaluate peritoneal and distant nodal metastasis in cases interpreted as seemingly resectable Type 3 and T4 KT on MRCP .
Our study has several limitations. First, selection bias may be present since only resectable patients were included and unequivocally unresectable patients with high BC type were excluded. Secondly, the retrospective design of the study limited the ability to evaluate parameters that could affect the results. Finally, the study group size is relatively low compared to previous studies.
In conclusion, DCE MRI/MRCP can be used in preoperative staging of KT to assess biliary tumoral extension and can help in the planning of the appropriate surgical approach. However, it should be remembered that the reliability of MR / MRCP imaging alone in terms of resectability is limited due to the possibility of understaging of Klatskin type, tumor infiltration at the level of hepatoduodenal ligament and the possibility of missing metastatic paraaortocaval lymph nodes, caval invasion and peritoneal metastases.
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.
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Levent Soydan, Mehmet Torun, Kamil Canpolat, Turgay Oner, Umut Kına, Ismail Ege Subasi. The role of magnetic resonance in the staging of Klatskin tumors. Ann Clin Anal Med 2021;12(9):963-968
Evaluation of children with disabilities: BMI indicators and difficulties experienced by parents
Yakup Çağ 1, Esra Tunalı 2, Cafer Ataş 3, Ahmet Lütfullah Orhan 4, Mustafa Tunalı 5, Buğra Özen 6
1 Department of Pediatrics, University of Health Sciences, Kartal Dr. Lütfi Kırdar Training and Research Hospital, Istanbul, 2 Department of Orthodontics, University of Health Sciences, Faculty of Dentistry, Istanbul, 3 Department of Pediatric Dentistry, University of Health Sciences, Faculty of Dentistry, Istanbul, 4 Department of Cardiology, University of Health Sciences, Dr. Siyami Ersek Chest and Vascular Surgery Training and Research Hospital, Istanbul, 5 Department of Periodontology, Çanakkale Onsekiz Mart University, Faculty of Dentistry, Çanakkale, 6 Department of Pediatric Dentistry, Altınbas University, Faculty of Dentistry, Istanbul, Turkey
DOI: 10.4328/ACAM.20543 Received: 2021-02-26 Accepted: 2021-04-27 Published Online: 2021-05-05 Printed: 2021-09-01 Ann Clin Anal Med 2021;12(9):969-974
Corresponding Author: Yakup Çağ, Department of Pediatrics, University of Health Sciences, Kartal Dr. Lütfi Kırdar City Hospital, Kartal/Istanbul, Turkey. E-mail: firstname.lastname@example.org P: +90 216 4413900 Corresponding Author ORCID ID: https://orcid.org/0000-0002-3855-7280
Aim: The aim of this study was to analyze the disability categories and sociodemographic characteristics of disabled children to stratify their risks in terms of body mass index (BMI), obesity and underweight, and to identify the problems of affected children and their families.
Material and Methods: A total of 1229 children younger than 7 years of age were identified to be surveyed with home visits by a dedicated team. BMI param- eters were obtained for 330 children. Functional impairment was classified into six groups according to the ICD-10 (International Statistical Classification of Diseases and Related Health Problems) codes.
Results: Children with orthopedic disabilities accounted for 34.9%, with intellectual disability 34.1%, developmental disorders of speech and language 15.6%, autistic disorders 15.5%, hearing loss 8%, and visual disturbances and blindness 0.8%.
According to the BMI percentile curves of the 330 children, 25.8% were considered obese, 5.4% were overweight, and 18.5% were underweight. The risks for obesity and underweight were significantly increased in children with autistic disorders and orthopedic disabilities, respectively (p<0.05).
Discussion: Children with disabilities are at an increased risk for obesity and underweight, which requires the evaluation and close monitoring of nutritional problems and provision of nutritional support.
Keywords: Disability; Children; Body Mass Index
According to the UNICEF’s ‘The State of the World’s Children 2006’ report, there are approximately 150 million disabled children under the age of 18 worldwide (available at: https:// www.unicef.org/reports/state-worlds-children-2006). In a later report by the Turkish Statistical Institute (TSI), ‘’Survey on Problems and Expectations of Disabled People 2010’’, the proportion of disabled individuals for the age bracket of 0 to less than 14 years was 21.1%, with 4.9% falling in the age bracket of 0 to 6 years (available at: https://www.ailevecalisma. gov.tr/media/5602/ozurlulerin-sorun-ve-beklentileri- arastirmasi-2010.pdf). There are genetic, prenatal, natal and postnatal risk factors leading to the disability in children. Among genetic causes, consanguineous marriage represents an increased risk factor for giving birth to a disabled child.  The prevalence of consanguineous marriages in the world is between 20-25% , with a similar Turkish share of 23.2% (available at: https://tuikweb.tuik.gov.tr/HbPrint.do?id=24646). Congenital or acquired disabilities of children adversely affect themselves and their family members in in all aspects of life. Aside from the lack of policies to improve their quality of life, disabled children face many problems that limit their participation in society, including negative attitudes and behaviors towards them, lack of appropriate infrastructure for their living, and difficulties in access to health, education, communication, information and social services, all make it difficult for the child and their families to cope with the situation. [3,4] Moreover, difficulties in raising disabled children and preparing them for future life render family members of these children more susceptible to diseases, especially to mental disorders such as depression. [5,6]
On the other hand, nutrition is of paramount importance to maintain the growth and development of disabled children. Nutritional problems leading to inadequate nourishment are quite common among these children, such as difficulty in eating, chewing and swallowing, prolonged keeping of food particles in the mouth, reflux and vomiting. Thus, comorbidities associated with inadequate and unbalanced nutrition may be inevitable, especially in children with neurological disabilities, such as growth retardation, overweight, micronutrient deficiencies or osteopenia.
The aim of this study was to analyze the disability categories and sociodemographic characteristics of disabled children younger than 7 years of age, and to stratify their risks in terms of body mass index (BMI), obesity and underweight as well as identify the problems of affected children and their families.
Material and Methods
This study was conducted prospectively within the scope of the project implemented by the Istanbul Development Agency, titled ‘Protective and Preventive Measures for Oral and Dental Health in Infants and Children with Disabilities in the 0-6 Age Group’. In the first instance, 2600 eligible children in the 0-6 age group, who received disability reports for various disabilities from community hospitals on the Anatolian side of Istanbul were identified to be surveyed with home visits. Of these, 1229 children were included in the study after obtaining parental consent for home visits. All participants were younger than 7 years of age at the time of home visits that were scheduled from January 1 to December 31, 2017. Home visits were conducted by a team including a dentist, psychologist, social worker, nurse and data entry clerk. A pediatrician was assigned to the project as a director and consultant. The study was approved by the ethics committee of the Kartal Kosuyolu Training and Research Hospital, Health Sciences University (No 2017/18; date 23/02/2017), and was conducted in accordance with the ethical principles of the Helsinki Declaration. Parental written informed consent was obtained for all the children. Data collection
During the visits, a comprehensive survey of demographic characteristics such as age, gender, parental educational status, family economic status, consanguineous marriages, as well as nutritional status and financial, social and psychological needs of the family were carried out. Body mass index was calculated for 330 children whose weight and height measurements were made by the team.
Disability categories of children
Disability status was determined from the present disability reports given by health care institutions and the ICD-10 (International Statistical Classification of Diseases and Related Health Problems) codes assigned based on functional loss and impairment. Children were examined in six categories according to the ICD codes (Figure 1), including intellectual disability ( F70-F79), motor disabilities (specific developmental disorder of motor function F82; primary disorders of muscles G71; myopathies G72; infantile cerebral palsy G80; hemiplegia and hemiparesis G81; paraplegia and quadriplegia G82; abnormalities of gait and mobility R26), developmental disorder of speech and language (F80, F81, R47), autistic disorder (F84), hearing loss (H90, H91), visual disturbances and blindness (H53-H54). In addition, children assigned to multiple ICD codes were identified.
BMI and percentile calculation
BMI was calculated in 330 children as body weight in kilograms divided by height in meters squared, and BMI percentile curves were constructed according to gender and age (in months). National BMI percentile curves were used for reference . Percentile values at <5, 5 to <85, 85 to 95, and >95 were considered indicators of underweight, normal weight, overweight, and obesity, respectively.
The data were processed using NCSS (Number Cruncher Statistical System) 2007 Statistical Software (Kaysville, Utah, USA). Descriptive data were expressed as mean, standard deviation, median, frequency, percentage, and minimum- maximum. Categorical variables were compared using the chi-squared test. A P-value of less than 0.05 was considered statistically significant.
Children with disabilities
Among 1229 participating children, 754 (61.4%) were girls. The mean age of the surveyed population was 4.5±1.5 years. According to the ICD-10 codes, 34.9% (n=429) had motor disabilities, 34.1% (n=419) had intellectual disability, 15.6% (n=192) had developmental disorders of speech and language, 15.5% (n=191) had autistic disorders, 8% (n=98) had hearing loss, and 0.8% (n=10) had visual disturbances and blindness (Fig. 1). Eighty-six and 12 children received two and three categories of disability, respectively.
Means of nutritional intake and BMI indices
While the great majority of children were fed by mouth (96.8%, n=1190), 3.2% (n=39) were fed through a percutaneous endoscopic gastrostomy tube. Nutritional intake was complicated in 36.1% (n=444) due to various problems such as difficulty in swallowing, chewing, prolonged keeping of food particles in the mouth, reflux, and vomiting.
Among the 330 children whose BMI measurements were available, 196 (59.4%) were boys and the median age was 55 months (interquartile range 37-70 months). BMI ranged from 10 to 39 kg/m2, with an average of 16.8±3.6 kg/m2. Eighty children had more than one type of disability, with 75 children falling in two disability categories, and five children in three categories.
According to the percentile curves of the 330 children, 50.3% were within the normal range, while 25.8% were considered obese, 5.4% were overweight, and 18.5% were underweight (Table 1).
The prevalence of obesity was highest (36.9%) among children with autistic disorders, and the prevalence of underweight was highest (27.8%) among children with motor disabilities. Similarly, in each disability category, comparison of children with reference to <5 and >95 percentiles showed that the risk of obesity was highest for autistic disorders (p=0.017), and the risk for underweight was highest for motor disabilities (p=0.001) (Table 2).
Parental socio-demographic characteristics
Levels of educational attainment of mothers vs. fathers were as follows: illiterate 6.9% vs. 2.8%; primary school or less 60.3% vs. 54.8%; high school or less 20.0% vs. 26.3%; and university degree 12.8% vs. 16.1%.
Consanguineous marriage was detected in 29.7% of the parents (n=365).
Self-reported economic profile was poor in 25.1% (n=308), moderate in 71.8% (n=883), and good in 3.1% (n=38).
The need for psychological support was identified in 329 (27%) parents, in particular for mothers, as was the need for financial support for 9.4% of the families.
According to the WHO 2011 report, 0.7% to 5.1% of children aged 0 to 14 years, experience some form of disability (available at: https://www.who.int/disabilities/world_report/2011/report. pdf). TSI survey in 2002 reported the disability rate of 1.54% among children 0 to 9 years of age, with the highest share of motor disabilities (0.64%), followed by developmental speech and language disorders (0.46%), and intellectual disability (0.42%) (available at: http://kutuphane.tuik.gov.tr/pdf/0014899. pdf). In our study, motor disabilities were in first place with 34.9%, followed by intellectual disability with 34.1%, and developmental speech and language disorders with 15.6%. Among genetic factors, consanguineous marriage represents an increased risk factor for giving birth to a disabled child. Among a randomly selected 708 individuals from a small town population in Turkey, the prevalence of disabilities was 23.3%, of which consanguineous marriage was detected in 44.5%.  Another study examined 655 disabled children and found a strikingly high rate of consanguineous marriage with 76.5%.  In our study, the prevalence of consanguineous parents was 29.7% for disabled children. As expected, these results were seen to be higher than the overall average of consanguineous marriages in Turkey. The discrepancies in reported rates of consanguineous marriages may have arisen from regional differences and/or may be due to the fact that our data were obtained about five years after the above-mentioned studies, during which time public awareness of the problem might have increased. In order to prevent genetic diseases arising from consanguineous marriages, it is highly beneficial for prospective spouses to undergo genetic screening before marriage and take precautions for possible risks .
There seems to be a close relationship between disabilities of children and parental education levels. The lower the educational level of the parents, the higher the likelihood that a child will be born with a disability, possibly due to a lack of awareness about the risks associated with consanguineous marriages and about the need for antenatal screening and care. This was evident in our study with an overall low educational level of the parents, with no or only primary school (or less) education in 67.2% of mothers and in 57.6% of fathers. A previous study from Turkey reported similarly low levels of parental education, with 4.6% and 1.7% of children having illiterate mothers and fathers, and 54% and 39.2% of children having mothers and fathers with an education degree of up to the primary level, respectively.  These rates are in striking contrast with the overall rates of maternal and paternal primary education levels, which, according to the TSI 2018 report, are 25% and 17% for women and men, respectively (available at: https://www.tuik.gov.tr). Children with disabilities and their family members are adversely affected by a wide variety of factors, including mental and physical health problems, family relations, employment, and economic problems [11-14]. A previous study from the United Kingdom examined 72 mothers and 42 fathers with disabled children and found that 55.6% of mothers and 64.3% of fathers had mental health problems . Another study from Canada examined 449 parents with disabled children aged 0-19 years and detected mild to severe psychiatric disorders in 42% of the parents . A review from the USA drew attention to chronic stressors faced by parents of children with intellectual and developmental disabilities, particularly when their children are in need of extreme care . Likewise, several studies from Turkey reported highly increased levels of chronic fatigue and depression among mothers of disabled children and emphasized the need for support in addressing these parental problems [6,18,19]. Likewise, in our study, 27% of the parents, especially mothers, were found to be in need of psychological support and were advised to seek help at rehabilitation centers. Unfortunately, only 25.5% of these parents could be integrated into rehabilitation programs, while the majority remained unaided for various reasons on the part of family members, such as having no one to look after their children, transportation difficulties, and time limitations. This shows us that providing psychological support to these families is best done at home rather than at institutional-based settings.
Children with disabilities are at increased risk of morbidity and mortality associated with malnutrition, leading to problems such as growth failure, overweight, micronutrient deficiencies and osteopenia. Therefore, careful evaluation and monitoring of these children for nutritional problems is of the utmost importance [20,21]. In our study, nutritional intake was complicated in a high proportion of children (36.1%) due to problems such as difficulty in swallowing, prolonged keeping of food particles in the mouth, reflux, and vomiting. Nutritional assessments to ensure adequate growth and nutrient intake should be made at least once a year in older children, while younger children and infants need more frequent assessments including length, weight, BMI or weight for height . We used BMI to evaluate these children. Percentile curves of 330 children whose BMI measurements were available showed that a significant proportion of the children were found to be obese (25.8%) or overweight (5.4%), or to lack adequate nutrition (18.5%). The risk for obesity was highest in children with autistic disorders, and underweight was more closely associated with motor disabilities. In a study involving 2,769 children with autistic disorders in the USA, 33.9% were found to be overweight and 18.2% were found to be obese . In the present study, the prevalence of obesity was much higher with 36.9% among children with autistic disorders. Concerning the risk for overweight or obesity associated with motor disabilities, an Australian cohort study examined the BMI Z-scores of 587 children diagnosed with cerebral palsy and found that 19.4% were obese or overweight, and 7% were underweight . Among the 330 children with BMI measurements, 34.9% had motor disabilities, with cerebral palsy being most common, a more pronounced distribution of overweight/obesity and underweight was noted, i.e. 26.1% and 27.8%, respectively. Limitations
Although a considerable number of children with disabilities could be screened through home visits and inquired into a wide range of issues via face-to-face interviews, the study provided no data as to why more than half of the families (1371 of 2600) abstained from giving parental consent for home visits. Another limitation is the limited number of BMI assessments. The weight and height measurements of only 330 children could be made due to various reasons such as insufficient equipment that our visiting teams experienced from time to time, the fact that some children are very agitated and some parents do not want to take measurements. If more children were involved in our BMI measurements, our results on nutritional problems and obesity, as well as the association between BMI variables and disability types, would be more powerful. Another limitation is that our face-to-face interviews were confined to problem- based screening, which could have been combined with some form of referral to prespecified services or centers.
Our study provided instrumental data about the main characteristics and risk factors for disabilities seen in children in the 0-7 age group: motor disabilities and intellectual disability as the two most common impairments; high prevalence of consanguineous marriages among parents, and low educational level of the parents. Disabilities themselves, in particular motor disabilities and autistic disorders, predispose these children to an increased risk for the development of obesity and underweight, which requires close monitoring and the provision of appropriate nutritional support. Besides having a child with a disability and inherent problems, a significant number of parents experience psychosocial problems, for which access to psychological support services is unavailable or limited.
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.
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8. Akbaba M, Uludağ Kis S, Nazlıcan E, Gündüz E. Adana Havutlu Beldesinde özürlülük sıklığı ve özürlülerde akraba evliliği sıklığının araştırılması (Investigation of the frequency of disability and the frequency of consanguineous marriages in disabled people in Adana Havutlu Town). TAF Preventive Medicine Bulletin. 2012;11:725-30.
9. Şimşek İE, Erel S, Şimşek TT, Atasavun Uysal S, Yakut H, Yakut Y, et al. Factors related to the impact of chronically disabled children on their families. Pediatr Neurol. 2014;50(3):255-61.
10. Verdonk P, Metselaar S, Storms O, Bartels E. Reproductive choices: a qualitative study of Dutch Moroccan and Turkish consanguineously married women’s perspectives on preconception carrier screening. BMC Women’s Health. 2018;18:79.
11. Whiting M. Children with disability and complex health needs: the impact on family life. Nurs Child Young People. 2014;26(3):26-30.
12. Schoen C, Osborn R, Squires D, Doty M, Pierson R, Applebaum S. New 2011 survey of patients with complex care needs in eleven countries finds that care is often poorly coordinated. Health Aff. 2011;30(12):2437–48.
13. Elias ER, Murphy NA, Council on Children with Disabilities. Home care of children and youth with complex health care needs and technology dependencies. Pediatrics. 2012;129(5):996–1005.
14. Thornicroft G, Rose D, Kassam A. Discrimination in health care against people with mental illness. Int Rev Psychiatry. 2007;19(2):113–22.
15. While AE, Citrone C, Cornish J. A study of the needs and provisions for families caring for children with life-limiting incurable disorders. London: King’s College Department of Nursing Studies; 1996.
16. Thurston S, Paul L, Loney P, Ye C, Wong M, Browne G. Associations and costs of parental symptoms of psychiatric distress in a multi-diagnosis group of children with special needs. J Intellect Disabil Res. 2011;55(3):263-80.
17. Miodrag N, Hodapp RM. Chronic stress and health among parents of children with intellectual and developmental disabilities. Curr Opin Psychiatry. 2010;23(5):407-11.
18. Garip Y, Ozel S, Tuncer OB, Kilinc G, Seckin F, Arasil T. Fatigue in the mothers of children with cerebral palsy. Disabil Rehabil. 2017;39(8):757-62.
19. Yıldırım A, Aşılar RH, Karakurt P. Engelli çocukların annelerinin ruhsal durumlarının belirlenmesi (Determining the mental state of the mothers of disabled children). Florence Nightingale J Nurs. 2013;20:200-9.
20. Marchand V, Motil KJ, NASPGHAN Committee on Nutrition. Nutrition support for neurologically impaired children: a clinical report of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr. 2006;43(1):123-35.
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23. Pascoe J, Thomason P, Graham HK, Reddihough D, Sabin MA. Body mass index in ambulatory children with cerebral palsy: a cohort study. J Paediatr Child Health. 2016;52(4):417-21.
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Yakup Çağ, Esra Tunalı, Cafer Ataş, Ahmet Lütfullah Orhan, Mustafa Tunalı, Buğra Özen. Evaluation of children with disabilities: BMI indicators and difficulties experienced by parents. Ann Clin Anal Med 2021;12(9):969-974
A bibliometric analysis of the 50 most cited articles on Parkinson’s disease
Department of Neurology, Çanakkale Onsekiz Mart University, Faculty of Medicine, Çanakkale, Turkey
DOI: 10.4328/ACAM.20545 Received: 2021-02-19 Accepted: 2021-04-13 Published Online: 2021-04-21 Printed: 2021-09-01 Ann Clin Anal Med 2021;12(9):975-979
Corresponding Author: Özgül Ocak, Department of Neurology, Çanakkale Onsekiz Mart University, Çanakkale, Turkey. E-mail: email@example.com P: +90 5058320631 Corresponding Author ORCID ID: https://orcid.org/0000-0001-8276-0174
Aim: Parkinson’s disease is a chronic progressive degenerative disease that restricts people’s daily life activities and impairs their quality of life. The aim of this study was to evaluate the features of the most cited articles on Parkinson’s disease in the literature.
Material and Methods: In the study, a bibliometric analysis of articles in the field of Parkinson’s disease indexed in the Thomson ISI Web of Science® was performed. The publications that received the most citations were listed by writing “Parkinson’s disease” as a keyword with the “topic” option in the search criteria. The publications cover the years 1991-2015 and include only articles in the English language. In the research, the first 50 articles that received the most citations out of 62861 articles meeting these criteria were examined.
Results: The total number of citations of the first 50 articles with the highest number of citations was 92903 (minimum 1040 – maximum 6578). The most cited publication year was 1998 (8 publications), and the most cited source country was the United States of America. The journals in which the most cited articles were published were the “New England Journal of Medicine” and “Science”.
Discussion: In the study, the most cited publications were identified in order to guide authors dealing with Parkinson’s disease. The most common research topics on Parkinson’s disease were laboratory studies.
Keywords: Parkinson’s disease; Bibliometric analysis; Citation
Parkinson’s disease (PD) is the most common cause of parkinsonism and is the most common clinical picture among movement disorders after essential tremor. Although PD generally presents with motor system symptoms (resting tremor, bradykinesia, imbalance, rigidity, etc.), besides these, it is a complex disease in which non-motor (autonomic, depression, anxiety, such as behavioral, cognitive and sensory) symptoms are common [1,2].
Variation in the symptoms of PD sometimes makes diagnosis difficult in the early period of the disease and causes a delay in treatment. PD usually occurs in middle and advanced ages, starts at the age of 50-60 years on average, and progresses for approximately 10-20 years. Although different results have been obtained in studies conducted in different countries, it is known that the annual incidence of parkinsonism is between 4.5-21/100000 [3,4]. The prevalence of PD in Eskisehir, Turkey, was reported to be111/100000 .
Many articles are published every year on PD, which is a very important field of neurology, and these publications are used and cited by other scientists. The number of citations of an article shows how many times that article has been cited in other scientific articles. It is an important parameter that shows how much attention this article has attracted . However, in order to measure the impact of an article with the help of the number of citations, it is necessary to wait for a certain time after the article is published.
With the help of bibliometric analysis, all research on a subject can be scientifically reviewed . Many features of the research made can be determined with the bibliometric analysis. The country in which the studies were conducted, the journals in which they were published in and their authors can be determined. In the Web of Science Core Collection, more than 20,000 peer-reviewed, high-quality scientific journals, books, articles that are globally accepted,archived and create a very large database for bibliometric analysis (Web of Science2020. Available at: http://www.webofknowledge.com). PD, which we see frequently in neurology, limits the quality of life and creates an important economic burden on the healthcare system. This is why the analysis of research on PD is valuable. The aim of this study was to analyze the 50 most cited articles on PD in the literature and to identify the most interesting scientific topics in recent years.
Material and Methods
In our study, a search was made using the topic option with the keyword “Parkinson’s disease” in the search section of the Web of Science database. Only articles with PD as the main research subject and written in English were included in the study. All articles were reviewed by a neurologist, and those without the main topic of PD were excluded. A bibliometric analysis of indexed articles about PD has been performed.
Selected publications were analyzed and attributed to one of six subgroups according to the research area (clinical, animal study, treatment, genetics, laboratory, review). The publication year of the articles, the name of the first author, the country and the institution of the first author were evaluated in the study.
This study was conducted in accordance with the ethical standards of the institutional and/or national research committee and the Helsinki Declaration of 1964 and subsequent amendments until 2004.
A search in the ISI Web of Science database was performed on July 11, 2020 by writing ‘’Parkinson’s disease ‘’ in the search section. Fifty articles with the highest number of citations selected according to inclusion criteria were evaluated among 62,861 articles.
Each of the selected articles was reviewed and the data of article, including the title, journal, publication year and country of origin of the first author were extracted. After the data were digitalized and organized, they were analyzed using the SPSS 26.0 package statistics program. The results were expressed as frequency and percentage in discrete variables, mean, standard deviation, minimum and maximum values in continuous variables. To evaluate the relative impact of an article, the citation density (number of citations/years since publication) was calculated.
Fifty articles selected for the study were divided into six subgroups according to their content, classified as clinical studies, animal studies, treatment (medical and surgical), genetic studies, laboratory studies (molecular and cell biology, neuropathology) and reviews. There were 3 review articles, 3 animal studies, 4 clinical studies, 8 articles on treatment (3 surgical studies, 5 medical studies), 12 genetic studies, 20 laboratory studies (6 cellular and molecular biology studies, 14 neuropathology studies) (Table 1). The 10 most cited papers according to citation density are shown in Table 2.
The total number of citations for the 50 selected articles was 92903, and the number of citations per article was 1858.1 ± 1136.9 (min. 1040 – max. 6578). The citation number of 13 articles was higher than 2000.
When analyzed according to 6 subgroups, the number of citations per article was 1456.3 ± 431.1 (min. 1052 – max. 1910) for clinical studies, 1522.8 ± 576.0 (min. 1172 – max. 2376) for animal studies, 1328.4 ± 263.4 (min. 1040 – max. 1871) for treatment studies, 1734.4 ± 716.1 (min. 1064 – max. 3382) for genetic studies, 2285.1 ± 1598,3(min. 1071 – max. 6578) for laboratory studies, 1767.0 ± 367.2 (min. 1361 – max. 2076) for reviews.
The most cited article was titled ‘Accuracy of clinical diagnosis of idiopathic Parkinson’s disease – a clinicopathological study of 100 cases’ by Hughes A.J. published in the ‘Journal Of Neurology Neurosurgery and Psychiatry’ in 1992 (total citations: 6578). The least cited article was titled ‘The Sydney multicenter study of Parkinson’s disease: the inevitability of dementia at 20 years’ by Hely M.A, published in the “Movement Disorders” journal in 1992 (total citations: 1052).
The last article was published by Kalia, LV in the ‘Lancet’ journal in 2015, and titled ‘Parkinson’s disease ‘.
One of the studies was on autosomal recessive juvenile parkinsonism (AR-JP), one was about the Ala30Pro mutation, one was about PINK1 (PTEN-induced kinase 1) gene mutation, one was about DJ-1 (PARK7) gene mutation, three were about alpha-synuclein gene mutation, one was about LRRK2 (leucine rich repeat kinase 2) variant as risk factors in Parkinson’s patients, two were related to the pink1 and parkin gene, and two were related to the PARK 8 gene mutation.
In one of the studies, cytoplasmic inclusions containing ubiquitin and alpha-synuclein were examined in nigral neurons in rats treated with rotenone, in one alpha-synuclein in transgenic mice and in the last one, locomotor findings were investigated in mice negative for alpha-synuclein.
A total of 20 articles were divided into cellular and molecular biology and neuropathology studies.
It was observed that 10 out of 14 studies on neuropathology were articles on Lewy bodies alpha-synucleinopathy, 1 on striatonigral degeneration, 1 on complex I activity, oxidative stress and alpha-synuclein aggregation, 1 on the ubiquitin pathway, and 1 on hyaline inclusions and neurofilaments. Among 6 studies on cellular and molecular biology, 2 were related to mitochondrial dysfunction and oxidative stress, 1 to free oxygen radicals and oxidative stress, 2 to embryonic stem cells, 1 to mitochondrial damage, ubiquitylation and autophagy. Treatment studies
Three out of 8 studies were related to surgery and 5 were related to medical treatment.
Two of the 5 studies about medical treatment were related to levodopa treatment, 1 to Unified Parkinson’s Disease Rating Scale, part III (UPDRS-III) scoring in patients who did not receive treatment, 1 to ropinirole and levodopa treatment, 1 to dopamine therapy and learning.
It was observed that 2 of the 3 surgical treatment studies were related to bilateral stimulation of the subthalamic nucleus, and 1 to deep-brain stimulation.
The studies were related to the evaluation of the MDS-UPDRS scale (1), dementia in Parkinson’s patients (1), and non-motor and motor symptoms in the follow-up of treatment response (2) Reviews
There was 1 article on Medline search results for “Parkinson’s disease”, “diagnosis” and “signs and symptoms”; 1 article was on the treatment of non-motor symptoms, and 1 article was on non-genetic risk factors and prognosis forPD.
The 50 most cited publications were published between 1991 and 2015. It was seen that the year with the most citations was 1998 (8 publications). When analyzed according to decades, 13 publications between 1990-1999 had an average citation number of 2480.5 ± 1751.5 (min. 1071 – max. 6578), 33 publications between 2000-2009 had 1649.8 ± 780.7 (min. 1040 – max. 4945) and 4 publications between 2010 -2019 had 1553.5 ± 246.4 (min. 1279 – max. 1871) (Figure 1).
According to the first author’s country, the most cited articles were published in the United States (13, 26%), United Kingdom (9, 18%) and Germany (5, 10%). According to the journals, the most cited articles were published in the New England Journal of Medicine (7, 14%) and Science (7,14%).
Parkinson’s disease differs from other causes of parkinsonism in terms of its pathology, clinical presentation and response to dopaminergic therapy. It is very important to diagnose and treat Parkinson’s disease because it has the best response to medical treatment among neurodegenerative diseases. The motor signs of PD are characterized by asymmetric-onset resting tremor, rigidity, bradykinesia, akinesia, and postural abnormalities [8,9]. The gold standard in the diagnosis of PD is still neurological examination. Although PD is diagnosed with motor findings, it is a complex disease that includes motor and nonmotor findings. Due to the wide variety of clinical findings, it can be difficult to diagnose the disease at the initial stage of the disease, which can cause a delay in treatment.
In a study conducted in the Netherlands, it was observed that 26% of Parkinson’s patients used inappropriate drugs and 33% had complications . In another study, treatment errors were detected in 39% of Parkinson’s patients, and an approximately 5 points worsening in UPDRS scores at discharge was found compared to UPDRS before hospitalization .
The fifty most cited articles out of 62,861 on Parkinson’s disease were selected for analysis. The total number of citations of the articles was 92903 and ranged from a minimum of 1040 to a maximum of 6578 per article. The year 1998 was in the first place among the publication years of the most cited articles. In terms of citation density, articles published in the 1990s and 2000s were at the forefront.
Laboratory studies were included in the list of 50 articles with the highest number of articles (20) and constituted the most cited group with 2285 citations per article. The largest group of laboratory studies was nephropathology, which showed that this area was more researched, aroused clinical attention, and the effect on researchers was more prominent.
Review articles, the second most frequently cited group. This shows that general knowledge about PD has been used by researchers in a comprehensive way, as well as the results of current researches.
According to the countries of the first authors of most cited articles, the United States of America (USA) was the first. This has revealed that the USA is the leader in the scientific field about Parkinson’s disease, with studies that attract more attention.
High citation can give a good estimate of the impact of a journal. The most frequently cited journals were the New England Journal of Medicine (7, 14%) and Science (7, 14%), which showed that these journals are important sources of information about Parkinson’s disease.
Although not a perfect method, citation analysis can largely reflect the impact of articles on a topic. In this study, articles on PD, which has a high prevalence, were examined, and the
number of citations of these publications was evaluated, and the characteristics of the fifty most cited publications were determined and analyzed. Data were presented on issues that have attracted attention and the popular journals about PD. This research will help us understand the evidence base for clinical decision-making in the field of PD.
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Conflict of interest
1. McDonald WM, Richard IH, DeLong MR. Prevalence, etiology, and treatment of depression in Parkinson’s disease. Biol Psychiatry. 2003;54(3):363–75.
2. Carod-Artal FJ, Ziomkowski S, MesquitaHM, Martinez-Martin P. Anxiety and depression: Main determinants of health-related quality of life in Brazilian patients with Parkinson’s disease. Parkinsonism Relat Disord. 2008;14(2):102–8.
3. Rajput AH, Birdi S. Epidemiology of Parkinson’s Disease. Parkinsonism Relat Disord. 1997;3(4):175-86.
4. Tanner CM, Hubble JP, Chan P. Epidemiology and genetics of Parkinson’s disease. In: Watts RL, Koller WC, editors. Movement Disorders: Neurologic Principles and Practice. New York: McGraw-Hill; 1997. p.137-52.
5. Torun Ş, Uysal M, Gücüyener D, Özdemir G. Parkinson’s disease in Eskişehir, Turkey. Eur J Neurol. 1995; 2(Suppl. 1):44-5.
6. Beel J, Gipp B. Google Scholar’s ranking algorithm: an introductory overview. In: Larsen B, Leta J, editors. Proceedings of the 12th International Conference on Scientometrics and Informetrics (ISSI’09). São Paulo : BIREME/PANO/WHO; 2009. p.230–41.
7. Kurutkan MN, Orhan F. Analysis of Health Policy Issue with Science Mapping Techniques. Turkey: İKSAD Yayınları; 2018. [Turkish].
8. Hou I-GG, Lai EC. Non-motor symptoms of Parkinson’s disease. International Journal of Gerontology. 2007;1:53-64.
9. Jankovic J. Parkinson’s disease: clinical features and diagnosis. J Neurol. Neurosurg Psychiatry.2008;79(4):368–76.
10. Gerlach OH, Broen MP, Domburg PH, Vermeij AJ, Weber WE. Deterioration of Parkinson’s disease during hospitalization: survey of 684 patients. BMC Neurol. 2012; 8:12-3.
11. Gerlach OH, Broen MP, Weber WE. Motor outcomes during hospitalization in Parkinson’s disease patients: a prospective study. Parkinsonism Relat Disord. 2013;19(8):737-41.
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Özgül Ocak. A bibliometric analysis of the 50 most cited articles on Parkinson’s disease. Ann Clin Anal Med 2021;12(9):975-979
Molecular docking study reveals naringenin and hesperetin from desert truffles as promising potential inhibitors for coronavirus (COVID-19)
Ghassab M. Al-Mazaideh 1, Farhan K Al-Swailmi 2, Mujeeb Ur Rehman Parrey 3
1 Department of Pharmaceutical Chemistry, College of Pharmacy, University of Hafr Al-Batin, Hafr Al-Batin, 2 Department of Pharmacy Practice, College of Pharmacy, University of Hafr Al-Batin, Hafr Al-Batin, 3 Department of Surgery, Faculty of Medicine Northern Border University, Arar, Saudi Arabia
DOI: 10.4328/ACAM.20546 Received: 2021-02-20 Accepted: 2021-04-13 Published Online: 2021-04-26 Printed: 2021-09-01 Ann Clin Anal Med 2021;12(9):980-985
Corresponding Author: Ghassab M. Al-Mazaideh, Department of Pharmaceutical Chemistry, College of Pharmacy, University of Hafr Al-Batin Hafr Al-Batin, Saudi Arabia. E-mail: firstname.lastname@example.org P: +966556753883 Corresponding Author ORCID ID: https://orcid.org/0000-0003-4494-4284
Aim: In silico methods such as network analysis and screening have been commonly used to investigate the pharmacological functions of typical medicinal plants. The aim of the current research is to use pharmacological and binding affinity methods to test desert truffle compounds as bioactive constituents’ inhibitors for COVID-19.
Material and Methods: Forty-four compounds, as well as lopinavir and indinavir, were examined for molecular docking and pharmacokinetics (ADMET) against the 3CLpro and Nsp15 proteins of COVID-19.
Results: Ten compounds out of 44 phytoconstituents (homogentisic acid, catechin hydrate, caffeic acid, syringic acid, epicatechin, trans-cinnamic acid, luteolin, quercetin, naringenin and hesperetin) demonstrated outstanding pharmacokinetics (ADMET) and drug-like properties as HIV inhibitors Lopinavir and Indinavir. Interestingly, the Swiss ADME prediction BOILED-Egg model showed that only three compounds (catechin hydrate, naringenin and hesperetin) were able, like the controls, to bind to the P-glycoprotein substrate
Discussion: The pharmacokinetic prediction analysis has already shown that catechin hydrate, naringenin, and hesperetin have excellent inhibitor-like profiles. Naringenin and hesperetin were able to form strong H-bonds with the main amino acids (residues that may be responsible for destroying protein activity) HIS41 and/or CYS145 of 3CLpro and THR341 of Nsp15, as well as the HIV-inhibitors, which gives hope to be novel coronavirus inhibitors.
Keywords: Deseret truffles; COVID-19; ADMET screening; Naringenin; Hesperetin
In 2019, the novel Covid Disease (COVID-19) arose spontaneously as the causative specialist of Extreme and Acute Respiratory Syndrome (SARS-CoV-2) Researchers in China rapidly sequenced the viral genome and made it unreservedly available to all. Sixty-seven druggable human proteins or hosts have been identified and used as a focal point for 69 current FDA-confirmed drugs, drugs in clinical trials as well as preclinical mixtures. In either case, using the COVID- 19 genomic grouping, researchers have distinguished novel, helpful drugs against COVID -19 [1-3].
Medicinal mushrooms are a rich source of polysaccharides with antitumor, antibacterial and immunostimulating-like medicinal benefits. Recent studies related to hypogeous fungi and the so-called desert truffles have been carried out in addition to the traditional studies of epigenous higher basidiomycetes . A possible drug target named (Nsp15 and Mpro) was recently determined in SARS-CoV-2 . These enzymes have played a significant role to play in the production of translated polyproteins. This protein is 89% indistinguishable from the previous SARS-CoV flare-up protein . Nsp15 obstruction has been reported to reduce viral replication .
Various therapeutic protocols, including anti-HIV, anti-influenza, and antimalarial drugs in a single or in combination regimens, have been adopted by the researchers to fight against COVID-19. These drugs, however, cannot respond to the sophisticated coronaviral attacks continuously. Phytochemicals were reported in the literature to have potent antiviral activity, which could be recruited to suppress the high rate of coronavirus replication process [7-10].
In vivo, it has been found that antagonistic reaction to protein or enzyme inhibitors does not promise that the inhibitor is suitable as a potential drug. In drug discovery, the pharmacokinetic profile (absorption, distribution, metabolism, and excretion) of the inhibitor including drug-likeness analyses is important to determine whether the inhibitor can be administered to a biological system. Poor pharmacokinetics properties of candidate inhibitors with highly toxic effects on cells are the major cause to stop the continuation of the clinical phases. The number of atoms (20-70), including heteroatoms, and molar refractivity between 40-130, is an important factor in the success of an inhibitor [11-17].
Accordingly, the present study attempted to screen and evaluate the possible inhibitory effect of desert truffles derived compounds against SARS-CoV-2 (3CLpro and Nsp15), which would in turn provide the possibility to know new compounds against the novel pandemic coronavirus disease (COVID-19).
Material and Methods
This study was conducted at the Pharmacy college in Hafr Al- Batin University, Hafr Al-Batin, Saudi Arabia in December 2020. Pharmacokinetics prediction by Swiss-ADME
In the current study, we used the Swiss-ADME free web tool to predict the pharmacokinetics and the drug-likeness of the small molecules that are important to know before turning to clinical trials . The 2D structures (SDF format) of the compounds were imported and turned into a SMILES format, then the docking process was run.
Molecular docking simulation
This part was achieved using the AutoDock 4.2 software (Forli W, Halliday S, Belew R, Olson A. AutoDock Version 4.2. Citeseer. 2012) for selected bioactive compounds of desert truffles and two inhibitors against 3CLpro enzyme (PDB ID: 6LU7) and the non-structural endoribonuclease protein Nsp15 (PDB ID: 6VWW). 3Clpro and Nsp15 to predict their potential activity in halting the viral replications . All rotatable bonds of the selected compounds were set randomized as completely flexible during the simulation process. Grid box size was set to 40*40*40 for the active binding sites, coordinates (as x, y, z respectively). The binding site of the 3Clpro was -10.2439, 17.966, 66.5084 and it was -94.65, 19.58, and -28.99 for Nsp15 . A maximum number of 100 runs were chosen for each independent Lamarckian genetic algorithm. The rest of parameters were kept as default. 2D and 3D models of interactions were visualized and analyzed by the Biovia Discovery Studio Visualizer 19, to easily observe hydrogen bonds and the hydrophobic interactions.
In silico ADMET /Pharmacokinetic Predictions
The ADME properties of the bioactive compounds of desert truffles and two FDA-approved HIV inhibitors are presented in Table 1 to illustrate and identify the good pharmacokinetic properties of the promising candidates from the desert truffles. In addition, hepatotoxicity, AMES toxicity, inhibition of hERG, and skin sensitization have been predicted in order to identify the toxic effects of the inhibitors. These criteria have been measured and tested for conformity with their normal ranges. Furthermore, the drug-likeness properties of the bioactive compounds with their bioavailability scores have been investigated in Table 1 to identify which of these molecules have properties close to those of known HIV-inhibitors. Subsequently, the pharmacokinetic properties of the truffle phytoconstituents were analyzed using the BOILED-Egg model, which enables an intuitive assessment of passive gastrointestinal absorption (GIA) and blood brain barrier (BBB) penetration according to the molecular position in the LOG P vs. TPSA (Figure 1).
The white area has a high probability of passive absorption by the gastrointestinal tract, and the yellow area has a high probability of BBB permeability. A blue dot indicates that the drug is not able to inhibit the P-gp substrate, while the red is its inhibitor.
Recent literature reported that the key amino acids in the active binding site of 3CLpro were HIS41 and CYS145, as well as THR341 in Nsp15 [21-23]. Accordingly, there is broad consensus among researchers that promising new antiviral activity drugs need to interact with these enzymes, which may help to stop protein activity in viral replication.
In our study, the molecular docking analysis was carried to evaluate the interaction of desert truffle-derived compounds with the two target SARS-CoV-2 proteins (3CLpro and Nsp15). Then, the best binding affinity of the interacting compounds to the active site residues (CYS145 and HIS 41) of 3CLpro and THR341 of Nsp15 were also calculated. Two commonly used anti-viral medications lopinavir and indinavir were also docked for further comparisons. Table 2 and Figure 2 display the computed docking scores between SARS-CoV-2 proteins (3CLpro and Nsp15) and the 44 phytoconstituents compounds of truffles (ligands), as well the HIV-inhibitors (Lopinavir and indinavir).
Truffle phytoconstituents have good pharmacological properties, as do the HIV inhibitors (Lopinavir and Indinavir) All of these compounds have high water solubility and gastrointestinal absorption. They smoothly excrete from the body without bounding with the renal OCT2 substrate, and also cannot cross the BBB. In addition, the toxicity profiles of these phytoconstituents revealed there are no undesirable characteristics, and all of them appear to be almost identical to the inhibitors (controls). Interestingly, the BOILED-Egg model (Figure 1) showed that, like lopinavir and indinavir, the compounds catechin hydrate, naringenin and hesperetin only have the ability to bind to the P-GP substrate, suggesting that these compounds may be promising and safer for COVID-19. In silico, pharmacokinetic tools along with the drug-likeness prediction, provide an array of opportunities to accelerate the discovery of new potential compounds with predicted biological activity.
The docking simulation was carried out for all the selected ligands with two COVID-19 proteins (Table 2 and Figures 2 and 3). The findings of this study showed that some phytoconstituent compounds tend to enzyme more than others. The free binding energies of drugs containing more negative values than -6.5 kcal/mol are assumed to show strong interactions and may significantly impair enzymatic activities. Six compounds showed a more negative binding affinity than – 6.50 Kcal/mol for the main protease (3CLpro) and endoribonuclease (Nsp15). Lopinavir and indinavir  revealed strong binding affinity for both proteins, and the scores were close to the most negative compounds. However, the analysis also showed violations of drug-like properties by rutin, while luteolin and apigenin had good pharmacological predictive values. Therefore, the docked structures of catechin hydrate, naringenin, hesperetin and control complexes of HIV-inhibitors (Lopinavir and indinavir) with main protease (PDB: 6LU7) and endoribonuclease (PDB: 6VWW) of SARS CoV-2 were presented in Figure 2 and Figure 3, respectively, to recognize key amino acid interactions in the pockets and evaluate inhibitory effects on viral replications.
Strikingly, the findings exhibited the ability of naringenin and hesperetin to form strong H-bonds with key amino acids of the main protease (CYS145) from the hydroxy group of naringenin and hesperetin at the distances of 1.98A and 2.47A, respectively, and also, H-bonds with the key residue THR341of the Nsp15 at distances of 2.77A and 1.99A, respectively. This indicates that both may be potent drugs to inhibit the viral replication of COVID-19 by halting the activity of the two essential proteins. Conclusion
The results of the ADMET and drug-like properties have shown that the truffle phytoconstituents (catechin hydrate, naringenin and hesperetin) have excellent properties like inability to cross the BBB and high GI absorption when taken orally. They are expected to be safe and have a strong bioavailability score. In addition, the free binding energy (Molecular Docking) of all compounds on the active site of 3CLpro and Nsp15 was measured to confirm their affinity to interact and to classify potential lead drugs according to their affinity and pharmacological properties. Docking scores revealed that catechin hydrate, rutin, luteolin, naringenin, apigenin and hesperetin have more negative free binding energy than -6.50 kcal/mol for both proteins. The analysis of the interactions of catechin hydrate, naringenin and hesperetin with the key amino acids in 3CLpro (HIS41 and/or CYS145) and Nsp15 (THR341) showed that naringenin and hesperetin are able to form strong H-bonds with proteins, which provide potential compounds to be novel inhibitors to COVID-19. In order to confirm the computational findings, the findings of this study need further in vitro and in vivo investigations.
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Animal and human rights statement
Funding: The authors extend their appreciation to the Deanship of Scientific Research, University of Hafr Al Batin for funding this work through the research group project No. G-113-2020.
Conflict of interest
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Ghassab M. Al-Mazaideh, Farhan K Al-Swailmi, Mujeeb Ur Rehman Parrey. Molecular docking study reveals naringenin and hesperetin from desert truffles as promising potential inhibitors for coronavirus (COVID-19). Ann Clin Anal Med 2021;12(9):980-985
Association between peripheral perfusion index and five vital signs in patients admitted to the emergency department
Banu Arslan 1, Gulcim Saracoglu 2, Hakan Topacoglu 3
1 Department of Emergency Medicine, Basaksehir Cam ve Sakura City Hospital, Istanbul, 2 Department of Emergency Medicine, Mugla Research and Training Hospital, Muğla, 3 Department of Emergency Medicine, Duzce University, Duzce, Turkey
DOI: 10.4328/ACAM.20547 Received: 2021-02-21 Accepted: 2021-05-12 Published Online: 2021-05-17 Printed: 2021-09-01 Ann Clin Anal Med 2021;12(9):986-990
Corresponding Author: Banu Arslan, Department of Emergency Medicine, Basaksehir Cam ve Sakura City Hospital, 34480, Istanbul, Turkey. E-mail: email@example.com P: +90 (212) 9096000 Corresponding Author ORCID ID: https://orcid.org/0000-0003-0982-5351
Aim: Mental status, skin temperature and color, urine output, mean arterial pressure, lactate levels, and capillary refill time are widely used in the evaluation of peripheral perfusion. However, reliable, simple, and objective tests are needed. The peripheral perfusion index (PI), derived from the pulse oximeter signal, has been lately suggested for providing fast, continuous, bedside, and affordable clinical data. This study aimed to investigate the association between the perfusion index and five vital parameters in a large emergency medicine patient population.
Material and Methods: A single-center, prospective, cross-sectional study was carried out on 2330 adult patients who were admitted to the emergency de- partment during five consecutive days. Patients who required emergency operation and cardiopulmonary resuscitation, and were unable to communicate with were excluded from the study. PI was measured at the 4th finger of the non-dominant hand by using Masimo RDS-7 pulse oximeter. Simultaneously, vital signs were taken.
Results: The mean PI, independent of diagnosis and the severity of a disease, was calculated as 3.71±2,83. The mean PI was found to be significantly higher in males than females, respectively 4,03±3,04 and 3,36±2,56 (p<0.001). A significant difference in the mean PI levels was detected across four age groups. PI was positively correlated with SBP, DBP, and MAP. Moreover, it correlated negatively with heart rate and body temperature (p<0,001). The correlation between the PI and respiratory rate and oxygen saturation was not statistically significant.
Discussion: Even though PI cannot replace clinical assessment in assessing peripheral perfusion, it has great potential to be a useful tool in recognizing poor peripheral perfusion at the triage level and lead to improved outcomes of emergency department patients.
Keywords: Perfusion Index, Emergency Medicine, Vital Signs, Blood Pressure, Peripheral Perfusion
Sufficient tissue perfusion and oxygenation are vital for the continuity of metabolic processes in cells, healing process, and resistance to infections . It is well known that the early recognition of tissue hypoxia with adequate oxygen supply can decrease mortality and morbidity in critical patients .
In the clinical assessment of peripheral tissue perfusion, many subjective parameters can be used such as mental status, skin temperature and color, urine output, pulse volume, mean arterial pressure, and capillary refill time . However, these parameters may be seen as normal at the early stages of a shock . Tissue oxygen status can be directly monitored by invasive electrodes or non-invasively using light absorbance (pulse oximetry (SpO2)). Pulse oximetry may be more useful in emergency medicine practice compared to invasive perfusion measurement methods in terms of the ability to provide fast, continuous, real-time, bedside, and inexpensive data.
Perfusion Index (PI) is the ratio of the pulsatile blood flow to non- pulsatile static blood flow in peripheral tissue that is measured by a pulse oximeter. PI is calculated by dividing the pulsatile signal (during arterial inflow) by the non-pulsatile signal, both of which are derived from the amount of infrared (940 nm) light absorbed, times 100 (available at: https://www.masimo.co.uk/ siteassets/uk/documents/pdf/clinical-evidence/whitepapers/ lab3410f_whitepapers_perfusion_index.pdf). It is expressed as a percentage ranging from 0.02% (very weak pulse strength) to 20% (very strong pulse strength) .
PI= (Pulsatile infrared light signals / Non-pulsatile infrared light signals) x100
The objective of this study to assess the variation of PFI in adult emergency patients and its relationship between 5 vital parameters including blood pressure, heart rate, respiratory rate, body temperature, and oxygen saturation.
Material and Methods
The present study was designed as a single-center, prospective, and cross-sectional study. It was conducted with adult patients who were admitted to the Emergency Medicine department of Istanbul Research and Training Hospital for five consecutive days, after obtaining approval from the research ethics committee of the hospital. Patients with cardiac arrest during the initial admission, requiring emergency surgery, and unable to communicate with were excluded from the study.
All PI measurements were performed within 5 minutes of admission to the emergency department at the triage area except for patients with red triage tags or brought by an ambulance. Patients with red triage tags or brought in by an ambulance were enrolled in the study at the bedside. After getting written informed consent for participation in the study from patients or their next-of-kin, hemodynamic monitoring included systolic blood pressure (SBP), diastolic blood pressure (DBP) mean arterial pressure (MAP), heart rate (HR), respiratory rate (RR), body temperature and oxygen saturation (SpO2) were done using Carescape V100 Vital Signs Monitor by General Electric by the nurses who trained for the study. Simultaneously, PI was monitored for over 60 seconds at the 4th finger of the non-dominant hand by using Masimo RDS7 pulse oximeter (Massimo Corp, Irvine, CA) [Figure 1]. The PI level was calculated as the average of the value measured at 15 seconds, 30 seconds, 45 seconds, and 60 seconds.
Statistical data analysis was performed with SPSS Statistics software version 25.0. Categorical variables were expressed as percentages and numerical values were expressed as mean, median, standard deviation, minimum and maximum. Comparisons between the two independent groups were made using the Mann-Whitney U test, since the numerical variables did not meet the normal distribution condition. Relationships between numerical variables were examined by Spearman’s correlation analysis, since parameter test conditions were not met. The factors determining the numerical variable were examined using the Linear Regression Analysis Backward method. The statistical significance level sought was p <0.05.
Recruitment and Enrollment
Daily emergency visits ranged between 500 and 600 patients per day, and a total of 2,880 patients were admitted to the emergency department during the entire study period. Among them, 244 patients did not meet the inclusion criteria. One hundred forty-two patients were excluded from the study due to missing clinical data such as RR, SpO2, or body temperature. One hundred seventy patients were excluded for lack of written consent. Finally, 2330 patients who were screened, confirmed eligible, agreed to participate, and completed in-person consent were studied (Figure 2).
This study involved 1236 female (53%) and 1094 male (47%) patients with a wide variety of complaints, disorders, and diseases. Participants’ ages ranged from 18 years to 101 years. The mean age was 43.1(±17,83) years.
Peripheral Perfusion Index and Hemodynamic Data
Our study was designed to cover every single patient who admitted to our emergency department, regardless of diagnosis and severity of diseases. Since our subjects had a variety of complaints, diseases and disorders, our hemodynamics data exhibited a wide distribution [Table 1]. For example, our subjects’ SBP ranged between 49 mmHg to 258 mmHg. Similarly, HR ranged between 36 bpm to 207.
The mean PI of 2330 study subjects was identified as 3,71±2,83 (Table1). The mean PI of female patients was 3,36±2,56 and of male subjects was 4,03±3,04. The PI value was found to be significantly higher in male subjects (p<0.001). The patients were also divided into four age groups as follows; Group 1: 18- 44 years old (58%), Group 2: 45-64 years old (27%), Group 3: 65-84 years old (13.5%), and Group 4: 85 years old and older (1.5%). The mean PI was 3,46±2,73 in Group 1, 4,22±3 in Groups 2, 3,83±2,85 in Group 3, and 3,02±1,79 in Group 4. A significant difference between age groups was detected (p<0.0001).
Our findings revealed that PI was positively correlated with SBP, DBP, and MAP (p<0.001) and negatively correlated with body temperature and heart rate (p<0.001). In addition, no correlation was detected with RR and SpO2 (p=0,368 p=0,348) (Table2).
According to multivariable linear regression analysis DBP MAP, HR, and body temperature are the most important parameters in terms of affecting PI.
Rapid identification of critical patients and recognizing shock early, even before it occurs, are associated with improved outcomes in emergency departments. Traditional vital signs are poor indicators of shock, especially in the geriatric population . During the early stages of uncomplicated shock, blood pressure may be normal, because hypotension occurs once the compensatory mechanisms are overwhelmed. In order to recognize compromised peripheral perfusion early, clinicians should assess the perfusion of less vital organs such as skin and subcutaneous tissue. Clinical features of circulatory failure involve decreased urinary output, confusion, sluggish capillary return, widen central-to-toe temperature difference, lactatemia, tachypnea, and cold, pale, clammy, and mottled skin. However, these findings can be normal in the early stages of shock . Besides, assessing them consumes time and requires a clinical experience. Therefore, simple and objective tests are needed to assess peripheral perfusion. Lately, the pulse oximetry signal has been suggested to assess peripheral perfusion for non-invasiveness, continuity, speed, availability, and ease of use without the need for advanced skills. However, studies indicating variances based on age, gender, and specific patient groups are still limited.
We studied the variation of PI in a large population of adult emergency patients and its relationship between five vital parameters including SBP, DBP, MAP, HR, RR, SpO2, and body temperature. In simple terms, PI is the strength of the peripheral pulse. It is measured by the ratio of pulsatile and non-pulsatile componentsofthebloodflowatthesensorsite.Limaetall reported normal values in adults range from 0.3 to 10.0% with a median of 1.4% . Several studies have used 1.4 as a cut-off point in identifying abnormal peripheral perfusion.
Although there is a limited number of studies in the previous literature reporting the mean PI values of emergency patients, reference PI values based on ages, gender, and specific patient groups have not yet been evaluated. From this perspective, the current study reporting the mean PI value of a significant number of adult emergency patients, adds great value to the medical literature. Previously, Yeniocak et al. reported the mean PI of patients with synthetic cannabinoid use as 3.16 ± 3.26 , Ozakin et al. reported PI levels of adult multi-trauma patients as 4.1 ± 2.2 , and Acar N. et al. reported PI levels of critically ill patients who need blood glucose check as 4.56±3.59 . Our subject’s PI values ranged from 0.1% to 20%. The mean PI value, independent from diagnosis and the severity of a disease, was reported as 3,71±2,83.
Our results revealed that there was a statistically significant difference in the PI levels between female (3,36±2,56) and male (4,03±3,04) emergency patients. PI was found to be higher in male subjects (p<0.001). In agreement with the current study, in a study investigating the age-related and sex-related changes in perfusion index in response to pain, it was demonstrated that baseline PI values were significantly different between male and female groups, respectively 4.99±0.459 and 3.56±0.312 (p<0.05) . Similarly, the study conducted with diabetic patients who have a high peripheral arterial occlusive disease risk revealed that PI was higher in men than in women (p<0.0001) .
In the present study, we detected a significant difference in the PI levels across four age groups (p<0.0001). After age 64, the mean PI decreased. We can attribute this decline to the increasing prevalence of chronic medical conditions such as peripheral arterial diseases or severe medical conditions such as septic shock in the elderly population. However, further research with large elderly population is needed in this area. Another significant result we reached was that PI had a positive correlation with SBP, DBP, and MAP. Peripheral PI is mainly affected by cardiac output and peripheral resistance. It is well known that in a case of shock peripheral organ perfusion compromises simply due to decreased CO in hypovolemic, cardiogenic, and obstructive shock and decreased peripheral resistance in distributive shock . Højlund J. et al. demonstrated that PI can immediately reflect changes in central hemodynamics with a high degree of correlation R=0.9, P<0.001 . In our study, we found a positive correlation between PI and SBP, DBP, and MAP. Similarly, Ozakin and his colleagues reported a positive correlation between PI and SBP and DBP in emergency multi-trauma patients . Sivaprasath P. et al. also reported a good correlation with pulse pressure and SBP . However, further research involving cardiac output (CO) and invasive blood pressure monitoring should be done to confirm or refute the explanations and further refine the knowledge above.
On the other hand, there was a negative correlation between PI and heart rate. The cardiovascular system responds to circulatory failure by increasing the heart rate, increasing myocardial contractility, and constricting peripheral blood vessels . Peripheral vasoconstriction mainly reduces the pulsatile component of the light that reaches the detector of pulse oximeter, hence decreases the PI . In agreement with the present study, van Genderen ME et al. demonstrated a negative correlation between HR and PI in the study investigating changes in PI induced by changes in circulating volume. In that study, applying -60 mmHg lower body negative pressure increased the subjects’ heart rate from 63 ±1.8 to 83 ±2.0, whereas decreased PI from 2.2 (1.6-3.3) to 1.3 (0.9-1.7) .
The relationship between body temperature and PI levels is quite controversial. In case of circulatory failure, organ blood flow will be shifted away from the skin, non-exercising skeletal muscles and splanchnic viscera in order to optimize CO and maintain adequate perfusion to coronary arteries, brain, and kidneys . As a result, skin looks cold, pale, clammy, and mottled. Additionally, during advance stages of hypovolemic shock, spontaneous hypothermia can occur due to depleted energy stores  and is usually associated with worse outcomes . Moreover, removing clothes, cold iv fluid and blood product administrations and the use of anesthetic agents contribute to hypothermia. Therefore, low body temperatures with low PI levels can be seen together in hypovolemic shock. On the other hand, septic shock is often accompanied by fever. High body temperature with low PI levels can be seen together in septic shock. In the current study, we detected a weak negative correlation between PI and body temperature. However, a great number of our subjects had normal body temperature. Studies involving a large number of hypothermia and hyperthermia patients are needed in this area.
In the current study, we reported a significant difference in PI across age groups. Our results revealed that patients over 64 years old had lower PI levels. However, the age of our subjects did not show the homogeneous distribution and it created bias here. For example, we had 1355 patients in group 1, whereas there were only 34 patients in Group 4.
Another important limitation in this study is that a great number of our patients had normal body temperature. We had only 26 patients with hypothermia and 192 patients with hyperthermia. This dissimilarity could have led to negative results. A large- scale study including more patients with hypothermia and hyperthermia is needed to explore the relationship between PI and body temperature.
Lastly, there are several factors influencing PI such as emotional stress and pain. In the present study, these factors were ignored. Conclusion
Monitoring of tissue perfusion is an essential step in the management of acute circulatory failure. In emergency situations, assessing capillary refill time and measuring central- to-toe temperature gradient are usually found time consuming. Recognizing the clinical signs of poor peripheral perfusion requires clinical experience. On the other hand, the PI derived from pulse oximeter has many advantages; it is fast, easy to operate, simple, inexpensive, and it provides a simple numerical value. Even though PI cannot replace clinical assessment in recognizing poor tissue perfusion, we believe that PI has high potential to become a useful tool in triage and help clinicians to monitor tissue perfusion continuously, which may lead to improved outcomes in emergency patients. However, we need more studies done in a large patient population. Cut-off values for the geriatric population should be redefined.
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Animal and human rights statement
Conflict of interest
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Banu Arslan, Gulcim Saracoglu, Hakan Topacoglu. Association between peripheral perfusion index and five vital signs in patients admitted to the emergency department. Ann Clin Anal Med 2021;12(9):986-990
Is it possible that antidepressants protect against COVID-19?
Ejder Saylav Bora 1, Cüneyt Arıkan 1, Güner Yurtsever 1, Hüseyin Acar 1, Dursun Hakan Delibaş 2, Fatih Esad Topal 1
1 Department of Emergency Medicine, Izmir Katip Çelebi University Atatürk Training and Research Hospital, 2 Department of Psychiatry İzmir Bozyaka Training and Research Hospital, Izmir, Turkey
DOI: 10.4328/ACAM.20549 Received: 2021-02-24 Accepted: 2021-04-01 Published Online: 2021-04-12 Printed: 2021-09-01 Ann Clin Anal Med 2021;12(9):991-994
Corresponding Author: Ejder Saylav Bora, Department of Emergency Medicine, Izmir Katip Çelebi University Atatürk Training and Research Hospital, Izmir, Turkey. E-mail: firstname.lastname@example.org P: +90 (532) 450 78 55 Corresponding Author ORCID ID: https://orcid.org/0000-0002-2448-2337
Aim: The neuroinflammatory hypothesis suggests that proinflammatory cytokines or the immune system may play a role in the etiopathogenesis of depression. COVID-19 affects older people the most because their immune systems are weakened. In this study, we aimed to examine the effect of using antidepressant use on mortality in patients infected with COVID-19.
Material and Methods: Our study was developed as a retrospective examination of unique central patient records. In our study, the diagnosis of COVID-19 diagnostics (U07.3) was between the ICD-10 classification (U07.3) and the diagnosis of depressive emotional state disorders (F31, F32, F33, F34) and patients with the diagnosis of COVID 19 confirmed by the test result were included.
Results: Considering the relationship between the use of antidepressants and mortality in COVID-19 patients, it was seen that the mortality rate was signifi- cantly lower in those using antidepressants (p <0.05). The presence of chronic disease was found to be significantly associated with mortality in COVID-19. The mortality rates of patients with chronic diseases were found to be higher (p <0.01).
Discussion: In our study, we found that antidepressants did not have any superiority over each other in terms of mortality in COVID-19 patients.However, when all anti depressants were evaluated in our study, we observed that drug use had a positive effect on statistically significant mortality (p <0.05). More enlighten- ing results will emerge in larger case series.
Keywords: Antidepressant; COVID-19; Pneumonia; Mortality
Research in the field of psychoneuroimmunology shows that there is a mutual relationship between the immune system and the central nervous system.  The immune system has congenital and adaptive parts. Both sections have cellular and humoral components from which different cytokines are excreted. The cytokines produced by the non-specific immune system include interleukin (IL) -1, IL-6, tumor cornea factor (TNF) -A, Interferon (IFN) -A. The cytokines generated by the specific immune system are IL-2, IFN-γ, IL-4, IL-10. They can be classified as “cytokines”. Proinflammatory cytokines are IL- 1, IL-2, IL-6, TNF-α, Inf-gamma; Anti-inflammatory cytokines (inhibitors of cytokine synthesis) are IL-4, IL-10, IL-12, IL-13, since cytokines like IL-13 have pro-inflammatory and anti- inflammatory functions [2,3].
Proinflammatory cytokines can be presented in response to exciting development, tissue damage, or psychosocial factors and transmitted between the immune system and the brain . The rise in pro-inflammatory cytokines is generally adaptive, transient, and regulated by anti-inflammatory mechanisms. The neuroinflammatory hypothesis suggests that proinflammatory cytokines or the immune system may play a role in the etiopathogenesis of depression [3,5].
COVID-19 has caused the Chinese pandemic process in Wuhan, and around the world, and it affects older people the most because their immune systems are weakened.It is not known exactly if it was symptomatic in humans . COVID-19 pneumonia is a disease that can be spread rapidly in the lungs and cause acute breathing syndrome (ARD). The main cause of morbidity and mortality in patients with COVID-19 in the hospital is acute viral pneumonia that causes ARDS [7-9]. The average mortality in patients with COVID-19 with ARDS in all countries is 39% (World Health Organization. Clinical management of severe acute respiratory infection when novel coronavirus (nCoV) infection is suspected: Interim guidance. January 28, 2020.).
In this study, we aimed to examine the effect of antidepressant use on mortality in patients embedded by COVID-19.
Material and Methods
The experimental methods and analyses used in this study were examined by the Institutional Review Board of Izmir Katip Çelebi University Non-interventional Clinical Studies, where the study was conducted considered appropriate to be performed (21.01.2021/0007).
Study Design and Population
Our study was developed as a retrospective examination of unique central patient records. It takes place in Izmir Katip Çelebi University Ataturk Emergency Medical Clinic, with a single center in Izmir city center, with an annual number of patient applications. The emergency department of approximately 200,000. The duration of our research was between 01.10.2020-01.01.2021.
Data Collection and Processing
In our study, the diagnosis of COVID-19 diagnostics (U07.3) was between the ICD-10 classification (U07.3) and the diagnosis of depressive emotional state disorders (F31, F32, F33, F34) and patients with the diagnosis of COVID-19 confirmed by the test results were included.
The active ingredients of the drugs used by our patients included in our study are “Duloxetine, escitalopram, fluoxetine, fluvoxamine, mirtazapine, paroxetine, sertraline, venlafaxine. There are tricyclic antidepressants, double-action antidepressants and serotonin reuptake inhibitors, and there is no limit to the types of these medications.
Patients under the age of 18, COVID-19 diagnosis code (U07.3), entered in the COVID-19 diagnosis code (U07.3) as diagnosis/ pre-diagnosis code (U07.3), with missing data were excluded from the study. The patient’s medical records are verified through the hospital data processing database. The patient’s demographic data, such as age, sex, vital signs, medical history and the results of the patient’s physical examination, chronic medical history, medications used in the laboratory and image tests, and the rate of mortality rate from the disease were analyzed statistically.
The data obtained were analyzed using the SPSS software for Windows version 21.0 (SPSS Inc., Chicago, USA. UU). Frequency distributions for categorical variables, means and standard deviation values were given as descriptive measures for numerical variables. Pearson’s Chi-Square test was used as a categorical variable when comparing two independent groups. Any p-value of less than 0.05 was considered statistically significant.
A total of 1051 patients were included in the study. The mean age of the patients was 47.65 ± 17.46 years. Four hundred ninety (46.6%) of the patients were female and 561 (53.4%) were male. There was no significant difference between gender and mortality (p = 0.931). The mean age of the deceased patients was 68.23 ± 15.69 years and the average age of the survivors was 45.34 ± 16.08 years. Considering the relationship between the use of antidepressants and mortality in COVID-19 patients, it was seen that the mortality rate was significantly lower in those using antidepressants (p <0.05) (Table 1).
The presence of chronic disease was found to be significantly associated with mortality in COVID-19. The mortality rates of patients with chronic diseases were found to be higher (p <0.01) (Table 2). When the mortality rates were compared according to the antidepressant drugs used by the patients, it was observed that there was no significant difference (p = 0.65) (Table 1).
It is generally accepted that psychiatric diseases such as depression, schizophrenia, panic, and bipolar disorder derive directly from the dysfunction of the nerve cells, the working system disorder. In recent years, another hypothesis, called the “neuroinflammation hypothesis” has emerged. According to this hypothesis,these diseases occur due to the negative effect of the immune system cells on nervous system cells and inflammatory events in neurons. In summary, we can say that antidepressants directly and indirectly strengthen the immune system, and people who use these drugs have a somewhat more protective shield than other people .
As it is known, stress mainly affects the functions of the Hypothalamus-pituitary-adrenal axis (HPA) axis. Under stress, corticotropin-releasing hormone (CRH) is released from the hypothalamus, adrenocorticotropic hormone (ACTH) release is stimulated by the pituitary, and glucocorticoids release from the adrenal cortex increases [1,10]. The functioning of this system is regulated by the negative feedback mechanism. Cytokines cause desensitization of glucocorticoid receptors and prevent the functioning of negative feedback mechanism in the HPA axis. This results in a strong stimulation of HPA axis activity. Acute stress response occurs with activation of the HPA axis, but long-term problems arise when stress becomes chronic [10- 12].
Antidepressants normalize by reducing pre-treatment high serum proinflammatory cytokine levels (IL-1β, IL-2, IL-6, TNF-α and INF–) . In a meta-analysis evaluating publications investigating the effects of antidepressants on TNF-α, IL-6 and IL-1β, it was determined that depressive symptoms decreased after treatment, TNF-α levels did not change, but IL-1β and IL-6 levels decreased, and oxidative stress decrease .
It has been determined that SSRIs reduce IL-6 and TNF-α levels, but other antidepressants do not cause a decrease in cytokine levels. It was emphasized that while depression is improving, cytokine levels normalize, cytokines contribute to the development of depressive symptoms, and antidepressants reduce cytokine levels, which may contribute to the recovery fromdepression.  The results of our study support this hypothesis. Cytokine reduction and suppression of Ils and TNF alpha cause a decrease in inflammatory response. Accordingly, we think that the progression of ARDS in patients using antidepressants may be slower than in patients who do not use antidepressants.
Although it is not known exactly how the immunomodulatory effects of antidepressants emerge, the possible mechanisms are as follows: hypotheses such as regulation of central glucocorticoid receptor expression, reestablishment of glucocorticoid-mediated feedback mechanism, that is, improvement of glucocorticoid receptor sensitivity, adaptive modification of central monoaminergic neurotransmission, down-regulation of the receptors on which cytokines and reduction of NO and PDE2 synthesis mediating central effects of cytokines [13,15,16]. Based on these hypotheses, we evaluated 8 different antidepressant drugs (duloxetine, escitalopram, fluoxetine, fluvoxamine, mirtazapine, paroxetine, sertraline and venlafaxine). Based on the antioxidant effect of reboxetine, in a study published in the literature, a significant relationship with mortality was found. However, in our study, we found that antidepressant drugs did not have any superiority over each other in terms of mortality in patients with COVID-19. However, when all antidepressants were evaluated in our study, we observed that drug use had a statistically significant positive effect on mortality (p <0.05). More enlightening results will emerge in larger case series.
It is considered that using antidepressantss protects against COVID-19 Pneumonie and decreases mortality by diminishing stress hormones and probably supports immunity in a good way.
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Animal and human rights statement
Conflict of interest
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Download attachments: 10.4328:ACAM.20549
Ejder Saylav Bora, Cüneyt Arıkan, Güner Yurtsever, Hüseyin Acar, Dursun Hakan Delibaş, Fatih Esad Topal. Is it possible that antidepressants protect against COVID-19? Ann Clin Anal Med 2021;12(9):991-994
Endoscopic ultrasound versus computed tomography for preoperative evaluation of primary ampullary tumors
Yusuf Uzum 1, Hakan Camyar 2, Ugur Bayram Korkmaz 1, Zeynep Zehra Gumus 1, Emrah Alper 3
1 Department of Internal Medicine, Katip Celebi University, Ataturk Training and Research Hospital, Izmir, 2 Department of Gastroenterology, Katip Celebi University, Ataturk Training and Research Hospital, Izmir, 3 Department of Gastroenterology, Koc University Hospital, Istanbul, Turkey
DOI: 10.4328/ACAM.20550 Received: 2021-02-24 Accepted: 2021-04-17 Published Online: 2021-05-04 Printed: 2021-09-01 Ann Clin Anal Med 2021;12(9):995-999
Corresponding Author: Yusuf Uzum, Department of Internal Medicine, Katip Celebi University, Ataturk Training and Research Hospital, Izmir, Turkey. E-mail: email@example.com P: +902322444444 , +905366658786 Corresponding Author ORCID ID: https://orcid.org/0000-0001-5027-1827
Aim: The study aimed to compare the efficacy of endoscopic ultrasound (EUS) and computed tomography (CT) in detecting primary tumor and evaluating preoperative vascular and peripheral invasion in histopathologically proven malignant ampullar tumors.
Material and Methods: Fifty-two patients who underwent surgery or endoscopic ampullectomy for the primary ampullary tumors between 2014 and 2016 were evaluated. The demographic data and EUS, CT, pathology results of all patients were recorded. The efficacy of EUS and CT in detecting tumor, peripheral tissue invasion, and vascular tissue invasion was evaluated and compared with pathology results.
Results: Forty-nine patients had the Whipple procedure and 3 patients underwent endoscopic ampullectomy. In pathology results, all patients had adenocar- cinoma histology, and the mean tumor diameter was 20.12 mm. The rate of peripheral tissue invasion and vascular invasion was 86.5%, 5.8% respectively. Ampullary mass was detected in 41 (78.8%) patients by EUS, in 35 (67.3%) by CT (p=0.002). Three patients had a vascular invasion in pathology. The sensitiv- ity and specificity of EUS in detecting vascular invasion were 66% and 100%, respectively. CT failed to demonstrate vascular invasion in these 3 patients.
Discussion: The results showed that EUS was superior to CT in detecting a mass, peripheral tissue invasion, and vascular invasion. Although EUS is superior to CT, CT plays an important role in the evaluation of distant metastases, and therefore CT and EUS are two important complementary radiological tests in the evaluation of these patients.
Keywords: Endoscopic Ultrasound; Ampullary tumors; Preoperative evaluation
Tumors of the Ampulla of Vater account for only 0.2% of gastrointestinal tract tumors and often manifest with jaundice, abdominal pain, and anemia [1,2]. Patients with tumors of the major ampulla have a better prognosis compared to other periampullary malignancies because symptoms tend to manifest relatively early when the disease is still localized. Thus, accurate preoperative staging of ampullary tumors is critical for surgical planning and predicting the patient’s prognosis.
There are different diagnostic modalities available for delineating stages of the tumor with examination of tumor invasion (T) and nodal involvement (N). These include magnetic resonance imaging (MRI), computed tomography (CT), endoscopic ultrasound (EUS), and transpapillary intraductal ultrasound (IDUS). Although having conflicting results, CT and EUS are the most commonly used methods for staging cancer [3,4]. Nevertheless, there is no consensus on the role of EUS in the locoregional staging of ampullary tumors .
CT is commonly performed on patients with symptoms of the biliary tract due to its widespread availability. It is often considered an acceptable imaging test for metastatic spread, tumor, and nodal staging, especially if an EUS expert is not readily available .
Some studies have shown that EUS is more effective than CT to demonstrate the ampulla, closely related anatomical structures (lymph nodes, bile duct, pancreatic duct) and the interface between the duodenal wall and pancreas [6-9]. EUS can visualize the local extent of tumors, and the status of regional lymph nodes and the detection of malignant stenosis of the distal bile duct with a sensitivity of up to 96% . EUS can be a technically challenging procedure, and although it is widely available, it is very much operator-dependent . The most effective method to demonstrate the efficacy of CT and EUS is to compare them with histopathological results. These studies have compared the preoperative evaluation of T- and N-staging of CT and EUS with the histopathological staging of the resected specimen, and EUS has been suggested as the best modality of choice in the locoregional stage of the ampullary lesion . The majority of these studies were limited to a small number of ampullary tumors and had different ampullary diseases such as benign ampullary adenoma.
This study aims to investigate the efficacy of EUS and CT in the detection of primary tumor and evaluation of preoperative vascular and peripheral invasion in histopathologically confirmed malignant ampullary tumors.
Material and Methods
In this study, we retrospectively evaluated patients who underwent surgery (pancreaticoduodenectomy) or endoscopic ampullectomy for the primary ampullary tumor in our hospital between 2004 and 2016. Patients who had been preoperatively evaluated with both EUS and CT were included in the study. The demographic data (age, gender) and the results of EUS, CT, pathology of all patients were recorded. Peripheral tissue invasion was defined as the direct extension and penetration by the tumor into the duodenum, pancreatic head. Vascular invasion was defined as the direct extension and penetration by cancer into the portal vein (PV), superior mesenteric vein (SMV), superior mesenteric artery (SMA), and branches. The efficacy of EUS and CT in detecting tumor, peripheral tissue invasion, and vascular invasion were evaluated and compared with the pathology results of patients.
All analyzes were performed using the Statistical Package for the Social Sciences software version 20.0 (SPSS Inc, USA) program. The normality of the distribution was checked for all continuous variables using the Kolmogorov-Smirnov Test. Categorical variables were shown as frequencies and percentages; numeric variables were described by means and standard deviations or medians and interquartile ranges. The percentage of sensitivity, specificity, and accuracy of invasion detection was calculated for EUS and CT. A p-value less than .05 was accepted as a statistically significant difference.
Fifty-two patients diagnosed with primary ampullary tumors were included in the study. The mean age of the patients was 61.9±10.2 years, and two-thirds of the patients were male (59.6%). Forty-nine (94.2%) patients underwent the Whipple procedure, and 3 (5.8%) patients underwent endoscopic ampullectomy.
When the pathology results of the patients were examined, it was seen that half of the cancers were attributable to moderately differentiated adenocarcinoma histology. The mean tumor diameter was 20.12±1.16 mm in the pathology specimens. It was found that 86.5% of the patients had peripheral tissue invasion, and 5.8% had vascular invasion (Table 1).
Ampullary mass was detected in 41 (78.8%) patients using EUS, in 35 (67.3%) patients using CT. There was a significant difference between EUS and CT in detecting ampullary mass (p<0.001). The mean diameter of EUS-detected ampullary tumors was 20.5 mm. The mean diameter of CT-detected ampullary tumors was 24 mm (Table 2).
Peripheral tissue invasion was detected in 20 (38.5%) patients by using EUS, in 8 (15.4%) patients by using CT (Table 2). For detection of peripheral tissue invasion, the specificity of EUS and CT was 100%, and sensitivity was 44.44% for EUS and 17.77% for CT (Table 3). There was a significant difference between EUS and CT in detecting peripheral tissue invasion (p=0.002) (Table 2).
Three patients had vascular invasion in pathology, and EUS detected 2 of them. CT failed to demonstrate vascular invasion in these three patients. Forty-nine patients had no vascular invasion in pathology. CT and EUS showed no invasion in all of these patients without pathological vascular invasion (Table 3).
In the literature, the number of studies covering only ampullary tumors is limited, and the number of patients with primary ampullary tumors involved in the periampullary tumors studies is low. In our study, CT and EUS were compared with pathology in 52 patients with primary ampullary tumors.
In the literature, primary ampullary cancers are frequently seen in patients with more than 50 years of age, especially between the ages of 60 to 70, and are mostly detected in men. In our study, the mean age of 52 patients was 61.9 years, and 59.6% of the patients were male. However, despite the same anatomical structure and similar risk factors, the reason for the frequent occurrence in men has not been found yet. This may be due to smoking that is more common in men.
In our study, CT was able to identify 67.3% of the tumor mass, and this was consistent with the literature. In a multicenter study by Bakkevold et al., 472 pancreatic and ampullary tumor patients were investigated, and the rate of mass detection of CT was found to be 58% in 30 patients with ampullary carcinoma .
In our study, an ampullary mass was detected in 78.8% of patients with EUS. The rate of detection of mass in EUS was found to be between 74-90% in nine comprehensive studies [2-4,12-17].
In our study, it was determined that the EUS technique was superior to CT in detecting the primary tumor. Maluf-Filho F, et al. reported a total of 61 patients with periampullary tumors, and only 10 of them had an ampullary tumor. In this study, it was shown that EUS was superior to CT in detecting primary tumors, but it was not statistically significant. It was reported that small tumors in the ampullary region could not be seen due to low CT resolution . In another study, when 21 patients with periampullary tumors had been examined, EUS was found to be more sensitive in detecting the tumor compared to CT (100% and 67%, respectively) . In the study by Chien-Hua Chen et al., 41 patients had been diagnosed with an ampullary tumor. In this study, the primary tumor detection rate using EUS was 97.6%, and CT was 28.6%. This difference was found to be statistically significant .
Ampullary tumors usually grow into the lumen of the duodenum, and ampullary area in the duodenal lumen contains too much air and luminal content. Ampullary tumors are generally small tumors at the time of diagnosis. The diagnostic effectiveness of CT is low due to the location and size of the mass. The lack of air and content artifact during endosonographic evaluation and the easy identification of diverticula provide high diagnostic efficacy to EUS.
According to the TNM classification of primary ampullary tumors, T1 stage is defined as tumors limited to the ampulla, T2 stage is defined as tumors invading the duodenal invasion, T3 stage is defined as tumors invading the pancreas (less than 2 cm), T4 stage is defined as invading pancreas (more than 2 cm) and adjacent organs. In our study, 7 (13%) patients were T1 stage, 21 (40%) patients were T2 stage, 21 (40%) patients were T3 stage, and 3 (7%) patients were T4 stage in the pathology results.
In our study, peripheral tissue invasion (stage T2 and T3) and vascular invasion (stage T4) were found in 45 patients according to the pathology results. EUS was found to be superior to CT in determining the peripheral tissue invasion. The sensitivity for demonstrating peripheral tissue invasion was also superior to the CT. As in our study, Everson et al. also looked at peripheral tissue invasion in ampullary tumors. The sensitivity of EUS and CT was found to be 85% and 35%, respectively .
In the study by Artifon et al., the sensitivity of CT in T2 and T3 stages with ampullary cancer has been found to be 35% and 75%, respectively . In a study of 41 patients with ampullary cancer, the rate of CT detection of peripheral tissue invasion was 26.1% . In our research, it was determined as 17.7%.
In our study, the rate of detection of peripheral tissue invasion by EUS was 44.4%. According to the pathology results, EUS was compatible with pathology in 6 (85%) of 7 T1 tumor patients, in 6 (28%) of 21 T2 tumor patients, in 11 (52%) of 21 T3 tumor patients and 2 (66.6%) of 3 T4 tumor patients. According to these results, the compatibility of EUS with the pathology result is higher in tumors that are in the very early stage (stage T1) and in later stages (stage from T2 to T4).
In the study by Ito et al., endoscopic ultrasonography determined 45% of patients with duodenal wall invasion . In our research, pathology results of patients in whom EUS could not detect duodenal invasion were examined, and it was seen that most of them were microscopic invasions.
Primary ampullary tumors can invade the surrounding vascular structures SMV, SMA, PV. However, the frequent growth of these tumors to the intraluminal area and being away from large vascular structures leads to a low risk of vascular invasion in the early stages.
In the preoperative evaluation of 52 patients with EUS and CT, CT showed no vascular invasion in any patients, whereas EUS revealed that two patients had vascular invasion. Although EUS detected vascular invasion in 2 patients, these two patients were operated on because of the negative CT results. According to the pathology result, the vascular invasion was seen in 3 patients, and EUS was able to show vascular invasion preoperatively in 2 of them. The rate of detection of EUS in patients with vascular invasion in the histopathological examination was found to be 66.6 %. In the literature, we could not find a study investigating the efficacy of EUS in detecting vascular invasions of primary ampullary tumors. Both EUS and CT had high specificity in the preoperative evaluation of vascular invasion.
In the study of Rösch T. et al., 46 patients with pancreatic cancer and 14 patients with ampullary tumors were examined. The rate of CT to detect invasion of vascular structures, such as SMV and PV, was found to be 75% . However, in this study, pancreatic and ampullary tumors were evaluated together for vascular invasion, and no separate subgroup analysis of primary ampullary tumors was performed.
There are few studies in the literature on the sensitivity of vascular invasion of EUS in periampullary tumors. In the study by Rösch T. et al. with 75 patients with periampullary tumors, the sensitivity and specificity of the EUS procedure for demonstrating vascular invasion were 43% and 91%, respectively . In another study, the sensitivity and specificity of EUS detecting vascular invasion in 37 patients with periampullary tumors were 20% and 100%, respectively . In our study, the sensitivity of EUS in demonstrating vascular invasion was found to be compatible with the literature.
There are some limitations to our study. It was not considered to what extent the use of invasive interventions such as Percutaneous Transhepatic Cholangiography (PTC) and endoscopic retrograde cholangiopancreatography (ERCP) for bile duct drainage affects efficacy before radiological and endoscopic examinations such as EUS and CT. In our clinical experience, we think that previous invasive procedures might decrease the effectiveness of CT and EUS in tumor evaluation. Although the EUS was made by a single operator, the CT was evaluated by different radiologists. Due to the small number of patients with vascular invasion in pathology, the statistical analysis of the comparison of CT and EUS in terms of vascular invasion was not sufficient.
In conclusion, radiological and endoscopic examinations are essential in the early diagnosis, staging, and treatment of ampullary tumors. In our study, we aimed to compare CT and EUS in terms of their contribution to early diagnosis and staging of ampullary tumors. The results showed that EUS was superior in detecting mass, peripheral tissue invasion, and vascular invasion than CT. In the literature, it has been reported that EUS should be the first choice in patients in whom ampullary tumors cannot be detected by CT and in patients with insufficient information for vascular and peripheral tissue invasion by CT. Our results also support this approach. Moreover, the results support the realization of EUS in patients who are considered to have ampullary tumors due to their current superiority, regardless of CT.
EUS appears to be superior to CT, but EUS is an operator- dependent procedure and can only work well in experienced hands. CT and EUS are two important complementary examinations in the evaluation of these patients.
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Animal and human rights statement
Conflict of interest
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21. Rösch T, Dittler HJ, Strobel K, Meining A, Schusdziarra V, Lorenz R, et al. Endoscopic ultrasound criteria for vascular invasion in the staging of cancer of the head of the pancreas: a blind reevaluation of videotapes. Gastrointestinal Endoscopy. 2000; 52(4): 469-77.
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Yusuf Uzum, Hakan Camyar, Ugur Bayram Korkmaz, Zeynep Zehra Gumus, Emrah Alper. Endoscopic ultrasound versus computed tomography for preoperative evaluation of primary ampullary tumors. Ann Clin Anal Med 2021;12(9):995-999
The risk factors of chronic kidney disease progression in AA amyloidosis
Refika Büberci, Ayşe Zeynep Bal, Murat Duranay
Department of Nephrology, Ankara Training and Research Hospital, Ankara, Turkey
DOI: 10.4328/ACAM.20554 Received: 2021-02-27 Accepted: 2021-08-06 Published Online: 2021-08-15 Printed: 2021-09-01 Ann Clin Anal Med 2021;12(9):1000-1004
Corresponding Author: Refika Büberci, Department of Nephrology, Ankara Training and Research Hospital, Ankara, Turkey. E-mail: firstname.lastname@example.org P: +90 5052990707 Corresponding Author ORCID ID: https://orcid.org/0000-0003-4737-6681
Aim: AA amyloidosis is a disease characterized by the accumulation of protofilaments in the extracellular space as a result of chronic inflammatory disease. The kidneys are the most affected organ. Although the prevalence has decreased due to the advances in treatments, the progression rate to end-stage renal disease (ESRD) is still high. The aim of this study was to determine the risk factors for the progression of chronic kidney disease (CKD) progression in patients with AA amyloidosis.
Material and Methods: Fifty-six patients who were diagnosed with AA amyloidosis as a result of kidney biopsy were included in the study. Demographic fea- tures, laboratory data were recorded. Etiological reasons were noted as Familial Mediterranean Fever (FMF) and non-FMF disease. Patients were divided into two groups according to the annual decline of eGFR. Group I consisted of patients whose annual eGFR decline was more than 1ml/min/1,73m2
Results: The mean age of the patients was 51.12±14.5 years. The mean follow-up time was 3.72±3.57years. No difference was found between the two groups in terms of comorbid diseases, age, gender, mean blood pressure. eGFR at baseline was similar. In Group-I, non-FMF diseases were more, proteinuria in 24-hour urinalysis and CRP levels were high, and albumin was low. In regression analysis etiology, proteinuria, LDL-c/HDL-c ratio, platelet-lymphocyte ratio (PLR) are independent risk factors for the annual decline of eGFR.
Discussion: Proteinuria, inflammation and dyslipidemia are important risk factors for CKD progression in AA amyloidosis. PLR is a simple and easy test that reflects inflammation in AA amyloidosis. It is beneficial to closely follow up amyloidosis cases caused by non-FMF disease, such as amyloidosis cases caused by FMF.
Keywords: AA amyloidosis; Dyslipidemia; Inflammation; LDL-c/HDL-c ratio; Proteinuria; Platelet-Lymphocyte ratio
AA amyloidosis is a systemic disease characterized by the storage of amorphous, water-insoluble, proteolysis-resistant protofilaments in the extracellular environment. It occurs as a result of complications of diseases that cause chronic inflammation. Protofilaments originate from the amyloid precursor serum amyloid A (SAA). SAA is an important acute phase reactant biosynthesized in the liver against pro- inflammatory cytokines such as IL-1, IL-6, and TNF-α . While the plasma concentration is 3 mg/l in a normal healthy individual, it may increase up to 1000 mg/l as an acute phase response .
The kidneys are the most affected organ in AA amyloidosis. The clinical picture generally starts as proteinuria and over time turns into nephrotic syndrome and end-stage renal disease (ESRD). However, the rate of developing end-stage renal disease is different for each patient. The aim of this study was to determine the risk factors for the progression of chronic kidney disease (CKD) in patients with AA amyloidosis.
Material and Methods
Patients and study design
Fifty-six patients followed between 2010 and 2020 were included in the study. The protocol for the research project has been approved by a suitably constituted Ethics Committee of the institution within which the work was undertaken (Approval number: 15.06.2020/202). All patients had undergone renal biopsy and had been confirmed to have AA amyloidosis. The renal biopsy specimens were stained with hematoxylin and eosin, periodic acid-Schiff, silver methenamine and Masson trichrome for evaluation of glomerular, interstitial, vascular and other pathological changes using light microscopy. Congo- red staining of renal tissue specimens was performed for histopathological diagnosis, and green birefringence was considered to indicate the presence of amyloid deposits. These deposits were confirmed as the AA types of amyloid using immunohistochemical analysis. Patients with primary amyloidosis or NHYA class III and IV heart failure or non- regular follow-up, patients taking anti-coagulant medication, active malignancy and infection, patients who are unwilling to participate in the study were excluded from the study. The endpoints of the study were renal replacement therapy requirement and death in the course of follow-up. The demographic characteristics of the patients, (comorbid diseases (diabetes, hypertension) age, gender, follow-up time) were recorded. Hypertension was determined by physician diagnosis, systolic blood pressure (BP) ≥ 140 mm Hg or diastolic BP ≥ 90 mmHg, or treatment with antihypertensive drugs. Diabetes was determined by physician diagnosis, fasting glucose ≥ 126 mg/dL, or treatment with insulin or oral antidiabetic drugs. Etiological reasons were noted as Familial Mediterranean Fever (FMF) and non-FMF diseases. The diagnosis of FMF was established in accordance with the Tel Hashomer Criteria. Laboratory analyses
All laboratory data were measured using automated systems and standardized methods. Urea, creatinine, estimated glomerular filtration rate (eGFR), proteinuria level in 24-hour urine at first and last admission to hospital, C-reactive protein (CRP), albumin, uric acid, cholesterol parameters, and complete blood count at first admission to hospital were recorded. On first admission, the patient underwent a kidney biopsy. The last admission was the last outpatient clinic control of patients who did not receive renal replacement treatment and came for regular follow-up, regardless of the CKD stage. CRP, neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) parameters were used to evaluate the inflammation status of the patients. NLR was obtained by dividing the absolute neutrophil count by the absolute number of lymphocytes, while the PLR was obtained by dividing the absolute number of platelets by the absolute number of lymphocytes. eGFR was calculated according to the CKD-EPI (CKD Epidemiology Collaboration) equation. The average annual decrease in eGFR was calculated as follow-up times were not the same. It was estimated by the difference between baseline eGFR and the latest available eGFR divided by the time interval in a year. Patients were classified according to the annual change of eGFR as Groups I and II. Group I consisted of patients whose annual decline of eGFR was more than 1ml/ min/1,73m2.
All data were first checked for normal distribution using the Kolmogorov-Smirnov and the Shapiro-Wilk test. Normally distributed data are presented as the mean± standard deviation. Non-normally distributed data are represented as median (inter-quartile range). Independent samples T-test was used to compare parametric continuous variables between groups. The Mann-Whitney U test was employed for the comparison of non-parametric variables. Pearson’s X2 or Fisher’s exact were used for categorical variables. Univariate and multivariate Cox regression analyzes were performed to find causes that may affect the annual decline in eGFR. Correlation analysis was used to understand the mechanism of the effects of significant parameters. P <0.05 was considered a significant difference. Analyses were conducted using SPSS Statistics for Windows (version 22.0; IBM Corp, Armonk [NY], United States).
The mean age of the patients was 51.12 ± 14.5 years, and 32 patients were male. The mean follow-up time was 3.72 ± 3.57 years. Familial Mediterranean Fever (FMF) was the most common cause of AA amyloidosis with a frequency of 50%. Non-FMF diseases include infections (14.3%), cancer (10.7%), unidentified factors (10.7%), rheumatoid arthritis (7.1%), inflammatory bowel disease (3.6%), and ankylosing spondylitis (3.6%), respectively. The etiology of cancer patients were head and neck cancer (n:2), colon carcinoma (n:2), basal cell carcinoma (n:2). In these patients, chemotheropathic agents that affect eGFR were not used. At first admission the number of CKD patients with stage 1, 2, 3, 4, 5 are 17, 15, 15, 6, 3, respectively. At the last admission, these numbers changed to 13, 9, 10, 12, 12, respectively. In other words, stage 4 CKD patients increased by 100 %, stage 5 CKD patients increased by 300 % numerically. There were no differences between the two groups in terms of comorbid diseases such as diabetes mellitus (DM) and hypertension (HT), or in terms of age, gender and mean blood pressure (MBP). Baseline levels of urea, creatinine, eGFR at the start of the study was also similar. However, after follow-up, urea and creatinine levels were were significantly higher, and eGFR was significantly lower in Group 1. The annual decline in eGFR was also significantly higher in Group 1. Non- FMF diseases were more, albumin level was low, proteinuria in 24-hour urinalysis at first and last admission, and CRP levels were high in Group I. Cholesterol parameters, cholesterol ratios, and complete blood count parameters were similar between groups (Table-1). In multivariate regression analyses, we found that PLR, etiology (non-FMF diseases), proteinuria at first admission and LDL/HDL ratio are independent risk factors of annual decline of eGFR. (HR:1,05, HR:0,287, HR:1, HR:1,293, respectively) (Table-2). To understand the effect of PLR on annual decline of eGFR, we performed correlation analysis. A positive correlation between PLR and proteinuria at first admission, CRP and NLR was found (r:0.319, p:0.016; r:0.461, p<0.001; r:0.560, p<0.001, respectively). We classified patients into two groups as FMF and non-FMF according to their etiology. Proteinuria at first admission, CRP and PLR levels were high in the non-FMF group compared to the FMF group (Table-3).
AA amyloidosis is a systemic disease resulting from complications of diseases that cause chronic inflammation. The prevalence has decreased from 8.5% to 1.3% due to the advances in treatments [3,4]. However, the progression rate to ESRD is still high. According to the biopsy registry data of the Japan Nephrology Association, 26 (9.2%) of 281 renal amyloidosis patients had stage 5 CKD at the time of diagnosis . According to the 2019 registry of the Turkish Society of Nephrology, amyloidosis is involved in the etiology in 1.89% of hemodialysis (HD) and 1.79% of peritoneal dialysis (PD) patients . In the current study, four of the 56 patients had stage 5 CKD at the time of first admission, this number increased to 14 after 3,7 years of follow-up. Seven patients had begun dialysis. In the regression analysis, it was found that inflammation, proteinuria, dyslipidemia, and non-FMF diseases are independent risk factors affecting the annual decline of eGFR.
Inflammation during renal progression in patients with amyloidosis has both direct and indirect effects. Circulating pro-inflammatory cytokines directly stimulate endothelial and leukocyte cells in the kidney. Reactive oxygen radicals and new pro-inflammatory mediators are released. These substances disrupt the endothelial structure in the kidney and activate the coagulation system. Subsequently, the microvascular response created by the kidney against changes in circulation is disrupted and damage occurs in the nephrons . Indirectly, increased pro-inflammatory cytokines, especially IL-6, accelerate the accumulation in the kidney by increasing serum amyloid-A (amyloid precursor) production . In particular, the deposition in the glomeruli leads to the disruption of the glomerular filtration barrier, and the progression of proteinuria ultimately results in acceleration of renal fibrosis .
Another feature of the increased IL-6 in AA amyloidosis is that it increases the platelet level by increasing the production of thrombopoietin in the liver . Previous publications reported that elevated platelet and PLR were independently associated with all-cause mortality risk in cancer patients , patients with heart failure , pulmonary embolism , hemodialysis and peritoneal dialysis patients [12,13]. There is a limited number of studies investigating the effect of PLR on CKD progression. In a study conducted with stage 3-5 non-dialysis, 165 geriatric CKD patients, the effect of PLR on renal progression was not found . However, Binnetoglu E et al. demonstrated a significant correlation between PLR and proteinuria in patients with stage 3-4 CKD . In the current study, it was determined that PLR affects the annual decline in eGFR in both univariate and multivariate Cox regression analysis. Correlation analysis also showed that this effect was due to both inflammation and proteinuria.
Dyslipidemia plays a role in the development of CKD by causing not only atherosclerosis in the microcirculation, but also direct inflammation. Excessive accumulation of free fatty acids (FFA) in tubule cells causes lipoproteins to undergo structural changes, which eventually trigger apoptosis. The SLC27A2 gene is known to play a role in this mechanism . In addition, tubule cells require ATP for reabsorption. The highest level of ATP is produced during the breakdown of fatty acids in the mitochondria. However, excessive breakdown of these fatty acids leads to the production of reactive oxygen radicals and subsequent renal damage . Decreased HDL-c levels and diminished cholesterol efflux capacity are the underlying reasons for the excessive accumulation of FFAs and lipoproteins in the kidneys of CKD patients . LDL, especially oxidized LDL levels, also play a role in the pathogenesis by increasing IL-6 release from macrophages and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) production . Activation of this receptor induces production of adhesion molecules, cytokines and the release of reactive oxygen species via NADPH oxidase. Besides experimental studies, clinical studies reported the effect of lipid parameters on CKD progression. In a study conducted with 48054 participants, total cholesterol, triglyceride, non-HDL-c, triglyceride/HDL-c ratio, LDL-c/HDL-c ratio were higher in CKD group compared to control group. Regression analysis revealed that triglyceride/HDL-c ratio and non-HDL-c/HDL-c ratio play a role in CKD progression (OR1,21;1,14, respectively) . In a meta-analysis, high intensity statins were found to improve decline in eGFR in populations with CKD not requiring dialysis compared to controls . The current study found that the LDL-c/ HDL-c ratio affects the annual decline of eGFR (HR:1.29) Proteinuria has been established as a marker of kidney damage in experimental studies and has been widely reported to be a predictor of long-term disease progression at all stages of kidney disease. Guidelines for the evaluation and management of CKD have already emphasized the importance of assessing albuminuria and proteinuria, in addition to the use of estimated GFR, for disease classification and risk stratification . Similar to our study, the correlation between proteinuria and an annual decline in eGFR has been shown in various studies, and meta-analyses. Astor B C et al. found a strong graded association between proteinuria and risk of ESRD, and an 8-fold higher proteinuria was significantly associated with ESRD (HR 3.42, 95% CI 1.84–6.37) . In a meta-analysis, it was reported that more than 1 gr/day proteinuria had an effect on the progression of stage 3-5 CKD patients to ESRD (HR:1,64 (1,01-2,66) .
Finally, in our study, we determined that non-FMF diseases play a role in the progression of CKD. Proteinuria and inflammation, which were higher in the non-FMF group compared to the FMF group, are important underlying reasons.
The limitations of our study are that it is a retrospective study, the sample size is small and IL-6 and SAA levels were not measured. Drugs and drugs compliance were not evaluated.
In conclusion, proteinuria, inflammation and dyslipidemia play an important role in the progression of CKD in AA amyloidosis patients. PLR and LDL-c/ HDL-c ratio are simple and easily applied tests that reflect CKD progression in AA amyloidosis. It is beneficial to closely follow up amyloidosis cases caused by non-FMF disease, such as amyloidosis cases caused by FMF.
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Conflict of interest
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Refika Büberci, Ayşe Zeynep Bal, Murat Duranay. The risk factors of chronic kidney disease progression in AA amyloidosis. Ann Clin Anal Med 2021;12(9):1000-1004
The comparison of narrow and regular platform dental implants placed in posterior regions: A retrospective, longitudinal study
Berceste Güler 1, Banu Çukurluöz Bayındır 2
1 Department of Periodontology, Kütahya Health Sciences University, Faculty of Dentistry, Kütahya, 2 Department of Prosthetic Rehabilitation, Kütahya Health Sciences University, Faculty of Dentistry, Kütahya, Turkey
DOI: 10.4328/ACAM.20556 Received: 2021-02-27 Accepted: 2021-05-18 Published Online: 2021-06-06 Printed: 2021-09-01 Ann Clin Anal Med 2021;12(9):1005-1010
Corresponding Author: Berceste Güler, Kütahya Health Sciences University, Faculty of Dentistry, Department of Periodontology, Kütahya, Turkey. E-mail: email@example.com P: +90 (274) 265 20 31 F: +90 (274) 265 20 13 Corresponding Author ORCID ID: https://orcid.org/0000-0003-2440-6884
Aim: The present study aimed to evaluate the clinical measurements and radiographic marginal bone loss of narrow and regular platform dental implants with the TiUnite surface placed in the posterior jaws.
Material and Methods: The study was designed as a retrospective, parallel, longitudinal pilot trial. Twenty-eight patients (mean age: 48.34 ± 6.06) and 66 TiUnite surfaces bone level dental implants (Nobel Biocare Parallel Conical Connection) were included in the study. The implants were divided into two differ- ent groups according to the narrow platform implants (NPIs) (n=32) and regular platform implants(RPIs) (n=26). The mean implant lengths, plaque index (PI), gingival index (GI), periodontal pocket depth (PD), gingival recession (GR), keratinized gingival width (KGW) and bleeding on probing (BOP) values were recorded. Mean marginal bone level (MBL) values were evaluated, in which the distance between the bone-implant contact and the implant shoulder reference points was assessed on digital periapical radiographs via a software program (Mediadent Software). The Student’s t-test was used for between-group comparison. Trial registration: NCT04572490. Retrospectively registered, (available at: https://clinicaltrials.gov/ct2/show/NCT04572490).
Results: The mean MBL value was 0.84±0.81 mm in the NPIs group and 0.44±0.65 mm in the RPIs group. Regarding the radiological evaluations, there was a statistically significant difference between the groups in the mean MBL (p<0.05). F(3)+6.56, p<0.001 and the GR value of 41% of the variance in the dependent variable predict mean MBL positively and significantly in the NPI group.
Discussion: Within the limitations, in this study group, narrow-platform TiUnite surface conical connection dental implants showed a higher rate of gingival recession and, consequently, marginal bone loss was observed at a higher rate in the long follow-up period.
Keywords: Dental Implants; Alveolar Bone Loss; Periodontal Pocket; Peri-Implantitis; Narrow Platform
The increasing use of dental implants as a treatment option for edentulous areas, the option of dental implants in different diameters, lengths, and designs, which can be applied in various clinical cases . Many factors, such as the implant diameter, buccolingual thickness of the residual alveolar bone, the implant platform, the occlusion type, and the mesiodistal dimension for prosthetic restoration, are important in implant design and commercial brand selection .
In such cases, horizontal augmentation or narrow diameter implant placement is considered two different surgical techniques [3,4]. Al-Johany et al. have shown that the diameter was classified as narrow when the implant diameter was less than 3.75 mm; however, the definition of NPIs in the studies in the literature varies according to manufacturer . The use of narrow platform implants (NPIs) to avoid bone augmentation is preferable, particularly in the posterior jaws, because of its high success rate and cost-effectiveness . The narrow diameter of the implant leads to a decrease in the osseointegrated surface area; therefore, the possible complications increase depending on the mechanical stress on the screw and abutment parts of the implant . Because of the direct connection between dental implants and alveolar bone and the absence of a periodontal ligament, repetitive and excessive mechanical stress on the implant may cause resorption of alveolar marginal bone . Dittmer et al. have conducted static load tests with the same geometry setup and reported that the load-bearing capacity was higher in TiUnite surface implants than sandblasted, large grit, acid-etched (SLA) surface implants . Song et al. have mentioned that the reduced implant diameter and the implant neck showed lower fatigue strength in terms of suprastructure failure compared to the standard diameter implant . Albrektsson et al. have reported that a mean 2 mm peri-implant marginal bone loss (MBL) was acceptable in the first year of implant treatment, and then 0.2 mm MBL each year would generally be within physiological limits . De Souza et al. concluded that there is no statistically significant difference in terms of radiographic MBL of narrow platform implants (NPIs) and regular platform implants (RPIs) placed in posterior regions . Zweers et al. evaluated NPIs for implant-supported overdenture prostheses, and reported higher MBL compared to RPIs . In addition, there was more alveolar bone loss in the molar region than implants placed in the premolar region; and there is no difference in terms of MBL in splinted or single implant-supported fixed prostheses [12,13].
The hypothesis of this study is that there is no difference with regards to MBL and prosthetic complications in NPI and RPI implants with TiUnite surface in implants placed in the posterior region. This study aimed to compare the long-term radiographically peri-implant MBL, clinical measurements, and prosthetic complications of NPIs and RPIs placed in posterior jaws after functional loading.
Material and Methods
The study was designed as a retrospective, nonequivalent control group, parallel, two-year longitudinal pilot trial and evaluated implant-supported fixed prostheses placed in the posterior jaws of patients who received implant treatment at the Faculty of Dentistry at Kütahya Health Sciences University between 2016 December and 2018 October. Non-Interventional Clinical Ethics Committee of Kütahya Health Sciences University approved the study (Decision No: 2019/07-4 Date: 27.06.2019) and it is registered at ClinicalTrials.gov ((NCT04572490) 01.10.2020). All data were collected between July 2019 and September 2019 and all patients signed informed consent.
Inclusion criteria were as follows: the presence of a dental implant treated with fixed prosthetic restoration placed in the posterior jaw, followed for at least one year after functional loading, no active periodontal disease, no history of penicillin allergy, no radiotherapy to the head and neck region, smoking less than ten cigarettes per day, no bone augmentation surgery before or during dental implant surgery, age>18, no mesial or distal additional crown restoration, no use of medications that affect bone metabolism, and no pregnancy or lactation. Exclusion criteria
The implants placed in the anterior region, immediate placing and loading, or augmented before or using a graft membrane with surgery were excluded from the study
Patient Selection and Assignment
Fifteen male and 13 female patients and 66 dental implants were included in the study. This observational retrospective study was designed according to the STROBE Statement guidelines . A study flow chart of this study was shown in Figure 1.
The assignment was performed according to the dental implant diameters to include cases in the NPI and RPI which are the test and control groups. All dental implants involved are the Nobel Biocare Parallel CC brand (Nobel Biocare, Gothenburg, Sweden) with a TiUnite surface, and it defined a regular diameter of 4.3 mm and narrow diameter of 3.75 mm. Dental implants were divided into two groups according to implant diameter, the NPI group comprised 3.75 mm diameter (NP, Ø= 3.75 mm) implants, and the RPI group comprised 4.3 mm diameter (RP, Ø= 4.3mm) implants (implant lengths: 10 mm-13 mm).
The clinical measurements were recorded during subsequent sessions using a periodontal probe that was calibrated in 1 mm increments. The clinical measurements were as follows: 1) plaque index (PI); 2) gingival index (GI); 3) probing depth (PD); 4) clinical attachment level (CAL); 5) bleeding on probing (BOP); 6) keratinized gingival width (KGW); 7) gingival recession (GR). The same researcher performed all clinical measurements. The calibration protocol was applied to the reliability of the measurements. PI, GI, PD, CAL, GR, KGW measurements were assessed in five patients and ten peri-implant values. The calibration was accepted when measurements were 90% similar. All clinical measurements were recorded for four sites (mesiobuccal, distobuccal, mid-buccal, mesiopalatal, midpalatal, and distopalatal) per peri-implant region. PD and PI measurements are reliable in peri-implantitis diagnosis. Prosthetic complications of patients were also evaluated clinically. Veneer ceramic chipping, abutment screw loosening or fracture, implant fracture, loss of retention were recorded.
Studies have shown that periapical radiographs obtained using the parallel technique are reliable in detecting the MBL changes at different follow-ups. Digital periapical radiographs of the posterior region were obtained using a parallel method at follow-up sessions. MBL measurements were provided on periapical radiographs using a software program (Mediadent Software, The Dental Imaging Company, London, England). Ten radiographic measurements of MBL around the peri-implant were performed twice with an interval of 3 weeks, and the researcher’s calibration was accepted when the measurements were similar as %90. Measurements were performed separately from the mesial and distal parts and also the average of the two measurements. The reference points for assessment are the implant shoulder and the most apical end-point of the bone- implant contact point. The vertical distance between these two points is defined as MBL (Figure 2).
Primary and Secondary Outcome Variables
Mean MBL and prosthetic complications were assessed as the primary outcome variables. Also, clinical measurements such as PD, GR, and KGW and those related with mean MBL, were evaluated as secondary outcome measurements.
Surgical Treatment and Prosthetic Rehabilitation
All surgical treatments were performed with the same surgical protocol by the same surgeon. Antimicrobial prophylaxis with amoxicillin-clavulanate (2 x 1000 mg per day) was started one day before surgery. Local anesthesia was applied to the surgical site, and the full-thickness flap was raised. Dental implants were placed with a 35 Ncm2 insertion torque. All dental implants were placed crestally and the flap was closed primarily; a two-stage surgical technique was applied.
As a postoperative recommendation, the patients have been prescribed amoxicillin-clavulanate 1000 mg per day for seven days. Diclofenac potassium 50 mg as an analgesic and 0.012% chlorhexidine mouthwash were recommended for all patients until the sutures were removed one week later. All prosthetic rehabilitation was planned as veneer, and cemented fixed- suprastructures, and was delivered to the patient.
Data analysis was performed using a software program (SPSS Statistics for Windows, version 20.0, Chicago, IL, USA). All clinical and radiological measurements showed a normal distribution in the study; Student’s t-test was used to compare NPIs and RPIs groups . Descriptive data presented as percentages, and clinical and radiological data presented as mean±SD. A p-value of less than 0.05 was accepted as statistically significant. De Souza et al reported that the sample was determined as 22 for each group to detect MBL with 80% power and α = 0.05.  According to the results, the required number of implants was determined with power analysis (G Power, Brunsbüttel, Germany) to be 30 for each group. In order to evaluate the effect on mean MBL, a multivariate regression analysis test was applied for PD, GR and KGW independent variables.
Twenty-eight patients (mean age: 48.34 ± 6.06 years) with 66 TiUnite surfaces dental were included in the study. The dental
implant survival rate was 100%. The mean follow-up time was 2.39 ± 0.62 years in the NPI group and 2.10±0.63 years in the RPI group. The mean length of the implants was found 10.33±1.19 mm in NPI group and 10.38±1.29 mm in RPI group. Dental implant localizations, history of periodontitis, smoking and single or splinted crowns values are shown in Table 1.
The mean MBL value was 0.84±0.81 mm in the NPIs group and 0.44±0.65 mm in the RPIs group. Regarding the radiological evaluations, there was a statistically significant difference between the groups in the mean MBL (p<0.05) (Table 2). When prosthetic complications were examined, abutment screw loosening occurred in solely one RPIs single-crown fixed prosthetic restoration.
There was no statistically significant difference between the NPIs and RPIs groups in terms of all clinical measurements. KGW values were 2.46 ± 1.62 mm and 2.60 ± 1.5 mm in the NPIs and RPIs groups, respectively. PD levels were 2.25 ± 0.57 mm in the NPIs group and 2.29 ± 0.48 mm in the RPIs, and the GR values were 0.08 ± 0.35 mm in the NPIs group and 0.02 ± 0.12 mm in the RPIs group, respectively (Table 2).
As a result of the multivariate regression analysis, a significant regression model was obtained in the NPI group, but no significant model was obtained in the RPI group. F (3) +6.56, p <0.001 and the GR value of 41% of the variance in the dependent variable predict the mean MBL positively and significantly in the NPI group. As a result of the analysis, it was found that the effect of PD and KGW on mean MBL was not found in both study groups (Table 3).
Recently, studies comparing the placed NPIs and RPIs in the posterior region on variable patient populations have increased. [11,15] The hypothesis that “there is no difference with regards to MBL and prosthetic complications in NPI and RPI implants with TiUnite surface in implants placed in the posterior region” is rejected for MBL and prosthetic complications in this study population. This study has shown that radiographically MBL changes were increased in the NPI group comparing to the RPI group in the long-term, and gingival recession was related to increased mean MBL.
Galindo-Moreno et al. have concluded that MBL rates were significantly affected by connection type, bone substratum, and smoking.  However, Hingsammer et al. reported that age, gender, insertion torque, implant surface area, location, position, bone quality, and insertion torque did not influence peri-implant bone loss after one year of loading for short-splinted dental implants . The mean peri-implant MBL would be higher with narrow implants due to decreased implant surface area exposed to excessive occlusal force and the accumulation of mechanical stress on the implant shoulder . However, De Souza et al. have mentioned that no statistically significant difference was found in terms of MBL in SLA surface NPIs and RPIs in posterior jaws in a randomized controlled clinical study . Grandi et al. have shown that one-year follow-up clinical and radiological evaluations were performed after splinted fixed NPIs supported fixed prosthetic restorations in the posterior mandible, and the mean MBL was reported 0.48 mm in the first year . The mean 10-year follow-up of NPIs placed in the posterior region revealed that the mesial MBL was 1.16 mm, and the distal MBL was 1.21 mm; 1.10 mm in single crowns and 1.22 mm in splinted restorations. Also, it has been mentioned that SLA surface implants placed in the premolar region to NPIs have higher MBL than those placed in the molar region . Hingsammer et al. reported that factors affecting MBL in short and NPIs were evaluated. Thus, the MBL around short implants measured 0.71 mm ± 0.74 mm and has been found to have a strong correlation with the calculated crown-to-implant ratio . In our study, the lengths of the dental implants were recorded, but crown-implant ratios were not evaluated. The assessment of the effect of dental implants on crown-to implant ratio and MBL by calibrating on radiographs may be necessary for clarifying the factors that will affect MBL in NPIs. Shi et al. have shown that the risk of prosthetic complications with SLA surface NPIs was significantly higher than with splinted restorations of single crowns . In a review, the most common complications in single crown restorations are loss of retention, screw loosening, or veneer chipping . De Souza et al. reported that two RPIs and one NPI had screw loosening, and one RPI had veneer chipping . Also, Al-Aali at al. evaluated technical complications on NPIs splinted and a single crown fixed prosthetic restoration, they reported that significantly more complications were observed in single crowns . Controversial results in the studies may be due to different implant systems, different abutment torque application force, different implant placement techniques, the bone structure of the implant placing region, or the experience of the dentist who performed the prosthetic restoration. In this study, abutment screw loosening was found solely in one single-crown RPI implant placed in the maxilla.
The studies have reported that smoking is a risk factor for peri- implantitis and causes a higher rate of both periodontal and peri-implant destruction [20, 21]. Alasqah et al. showed that MBL was higher in smokers, however, no differences were found between the NPI and RPI groups in a 3-year retrospective study of SLA surface NPIs and RPIs . Arisan et al. found that 81 Friadent Plus surface implants with 3.4 diameters and sandblasted, large-grit, acid-etched (SLA) surface implants were evaluated clinically and radiographically in a 5-year follow- up study; in terms of MBL, there was more bone destruction in the posterior jaws compared to the anterior region and in smokers compared to non-smokers . In our study, although there were a higher number of implants exposed to smoke in the RPI group, a lower rate of MBL was confirmed in the RPI group than the NPI group.
Gingival recession was evaluated in a single study comparing NPIs and RPIs. Ghazal et al. reported that there was no statistically significant difference regarding gingival recession between the NPI and RPI groups . In this study, there were no statistically significant differences between the groups in GR values, however, in regression analysis, an increased gingival recession affected mean MBL in NPI groups.
De Souza et al. reported that MBL was 0.58 ± 0.39 mm for NPIs and 0.53 ± 0.46 mm for RPIs, however, there is no information on implant placement in bone level crestally or subcrestally . In a long-term study of subcrestally and crestally placed dental implants, the mean MBL value was 1.2 ± 0.2 mm for the 2 mm subcrestally placed implant and 1.4 ± 0.2 mm for the crestally placed implant . In this study, all dental implants were placed crestally according to the manufacturer’s recommendations. One of the limitations of this study is the evaluation of splinted and single crowns in a pool. The present study did not evaluate whether the opposite occlusion was tooth-supported or removable prosthesis-supported. Since this study was evaluated prospectively, however, patient-related operational data could not be assessed. An important limitation in this study is that the implant placement area, the amount of buccal alveolar bone remaining after implant placement, and the biological width, which are factors that will affect the peri-implant MBL, are not evaluated.
Conclusion: In terms of clinical peri-implant measurements and prosthetic complications, there was significant difference was found between the NPI and RPI groups at the 2-year follow- up. Within the limitations, in this study group, narrow-platform implants showed a higher rate of gingival recession and, consequently, marginal bone loss was observed at a higher rate in the long follow-up period. Studies with a larger data set are needed.
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Berceste Güler, Banu Çukurluöz Bayındır. The comparison of narrow and regular platform dental implants placed in posterior regions: A retrospective, longitudinal study. Ann Clin Anal Med 2021;12(9):1005-1010
Does muscle strength decrease on the unaffected side in stroke patients?
Aziz Dengiz, Emre Baskan
School of Physical Therapy and Rehabilitation, Pamukkale University, Denizli, Turkey
DOI: 10.4328/ACAM.20559 Received: 2021-03-02 Accepted: 2021-04-24 Published Online: 2021-05-05 Printed: 2021-09-01 Ann Clin Anal Med 2021;12(9):1011-1015
Corresponding Author: Emre Baskan, School of Physical Therapy and Rehabilitation, Pamukkale University, 20100, Denizli, Turkey. E-mail: firstname.lastname@example.org P: +90 258 296 42 99/ 009 Corresponding Author ORCID ID: https://orcid.org/0000-0001-7069-0658
Aim: Muscle strength is necessary to overcome the resistance encountered during activity in stroke individuals. The present study aims to determine total muscle strength and muscle strength loss of unaffected side in stroke individuals.
Material and Methods: In this study, muscle strength and grip strength were evaluated using the Power Track II Commander dynamometer and Jamar Hand dynamometer, respectively. Thirty-three stroke individuals and 33 healthy individuals were compared to determine the total muscle strength. The total muscle strength of healthy individuals was calculated by summing the muscle strength of the trunk, lower and upper extremities. In addition, muscle strength of the trunk, unaffected upper and lower extremities was summed to calculate the total muscle strength of stroke patients. Twenty-seven stroke individuals and 33 healthy individuals were analyzed to compare muscle strength of unaffected sides between groups.
Results: The total muscle strength of stroke individuals and healthy individuals was 49909.5 N and 182375 N, respectively. The difference between groups was measured as 132465.5 N. The loss of total muscle strength in stroke patients was 72.63%. When comparing total muscle strength on the unaffected side, a significant difference was found in favor of healthy individuals (p = 0.0001).
Discussion: Loss of muscle strength on the unaffected side affects the patient’s functionality. Therefore, this must be taken into consideration in physiotherapy programs.
Keywords: Muscle strength; Stroke rehabilitation; Unaffected side
Stroke is the most common neurological disorder in the world and the third cause of mortality in the United States and European countries . After stroke, motor deficits are probably the most recognized impairments . It was reported that stroke patients experience these deficits between 89.1% and 61.0% in the first 6 months period after stroke and may continue throughout life. Motor deficits can take various forms, but the muscle strength (MS) loss (maximum voluntary force or torque) is probably the most obvious clinical presentation . MS loss is one of the important factors that affect recovery after stroke. The loss in MS obstacles proper posture and the come out of the functional movement . MS must overcome the resistance encountered during the activity . Therefore, loss in MS is one of the barriers to reach full independence in activities of daily living (ADL) in stroke individuals (SI) .
It has been shown that MS loss occurs generally on the contralateral (affected) side of the cerebral lesion in SI . However, many studies are showing that MS loss, balance disturbances, coordination, somatosensory, perception, and executive function impairments are not only characterized in the contralateral side, but also in the ipsilateral (unaffected) side [7,8]. Although MS loss and motor impairments are shown to be bilaterally in SI, the amount of this loss was not objectively demonstrated. Besides, previous studies have only focused on specific muscle groups and did not examine the total MS loss. Determining the loss of total and unaffected side MS is important because of the muscle strength effect on functionality, daily living activity and balance . This study aims to investigate the unaffected side MS and total MS loss in the SI.
Material and Methods
As a result of the power analysis, 66 people (33 for each group) were included in the study, with a power of 90% could be obtained with a confidence level of 95%. This study was included chronic phase (patients diagnosed with a stroke at least 6 months ago) SI between the ages of 30-65 who were treated in the department of the neurological rehabilitation unit of the university hospital. Also, individuals with ischemic stroke were included in the study. Individuals with additional to stroke neurological disease and individuals with orthopedic, mental and communication impairments that may affect assessment were excluded. In addition, SI who scored more than 3 points for the Modified Rankin Scale were excluded (Figure 1).
Individuals with orthopedic, metabolic, rheumatologic, mental and communication problems and active sporting life were excluded (Figure 1).
All procedures were in accordance with the Declaration of Helsinki. This study was approved by the Ethics and Human Research committee of Pamukkale University Hospital (Denizli, Turkey). IRB approval was obtained with the number of 60116787-020/8882. Each patient gave written informed consent.
After demographic characteristics including age, body mass index (BMI), and medical status of participants (affected and
dominant side) were recorded, MS was measured using a Power Track II Commander dynamometer and recorded in Newton. Measurements were performed on both limbs and trunk muscles of the unaffected side in SI and on both side extremity and trunk muscles in HI. The upper extremity, lower extremity, and trunk muscles of SI and HI were evaluated in the muscle test position defined for the dynamometer, and isometric maximum resistance was recorded . HI and SI had to generate maximum muscle force against a stationary dynamometer held by the therapist, and the muscle strength was measured in newton from the maximum reflection. The measurements were made three times with rest intervals and recorded by taking the average of all .
In both groups, the lower extremity total muscle strength was calculated by summing the strength of the hip flexor, extensor, internal rotator, external rotator, abductor, adductor, knee flexor, extensor, ankle plantar flexor, evertor, invertor muscles. Also, to calculate the upper extremity total muscle strength, the strength of shoulder flexor, extensor, abductor, adductor, horizontal abduction and adduction, external and internal rotator, scapular adductor, scapular adductor and down rotator, scapular depression and adductor, scapular elevation, elbow flexor extensor, wrist flexor, extension were summed; and, trunk extensor muscles were summed.
The Jamar Hand dynamometer was used to measure the grip strength. Measurements were done in a sitting position on a chair without arm support, with the shoulder in the adduction and neutral position, with the elbow at 90 degrees flexion, and the forearm and wrist in a neutral position. The measurements were made three times with rest intervals and recorded by taking the average of all .
The total MS was calculated by summing upper extremity total MS, lower extremity total MS, trunk extensor MS and grip strength of unaffected side in SI and both upper extremity total MS, lower extremity total MS, grip strength and trunk extensor strength in HI.
When comparing the unaffected side of SI, HI with right-side dominant and SI with right-side dominant and unaffected were matched. The data obtained from the right side of the HI group and the unaffected side of the SI group were compared. Statistical analysis
The statistical package SPSS 21.00 for Windows (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. Continuous variables were expressed as mean ± standard deviation, median (minimum and maximum values) and categorical variables as numbers and percentages. All continuous variables were evaluated for normality using the Shapiro- Wilk test. Significant differences in quantitative demographics between groups were analyzed using an independent sample test (when the data are normally distributed), Mann–Whitney U test (when the data are non-normally distributed). Significant differences in qualitative demographics between groups were analyzed using the Chi- square test. The total MS of the upper extremity, the total MS of the lower extremity, grip strength data of groups were compared with the “Mann–Whitney U test” because of the non- normal distribution. Since Trunk extensor MS of groups were normally distributed, Trunk extensor MS were compared with the “Independent sample t-test”. The MS data of the groups were compared with the “Independent sample t-test” because of normal distribution. The level of significance was set at p<0.05.
This study was conducted in 33 SI [11 (33.3%) females, 22 (66.6%) males] and 33 HI [13 (39.4%) females, 20 (60.6%) males]. All stroke patients were in the chronic phase and had an ischemic stroke. In addition, the average duration of stroke from the onset was 1.23±0,60 years. The average age was 56.33 ± 8.92 years in the SI group and 52.3 ± 8.52 years in the HI group. The body mass index (BMI) average was 27.23 ± 3.62 kg/m2 in the SI group and 28.17 ± 4.56 kg/m2 in the HI group. The dominant side of all SI was the right hand, the affected side (AS) of 27 SI was left and in the other 6 was right. There was no statistically significant difference between the groups in terms of gender, BMI (p>0.05) (Table 1). There was a significant difference in favor of the SI group in terms of average age (p<0.05) (Table 1).
Thirty-three HI with right-side dominant and 27 SI with right-side dominant and unaffected were matched. The data obtained from the right side of the HI group and the unaffected side of the SI group were compared. There were significant differences found in favor of HI in all values (upper extremity total MS, lower extremity total MS, Trunk extensor MS and grip strength) (Table 2).
The total upper extremity MS of the SI was 28202,5 N, and the total upper extremity MS of the HI was 115119 N. The difference between the total upper extremity MS of the HI and SI was 86916.5 N. On a percentage basis, the loss of MS was 75.50% in SI (Table 3).
The total lower extremity MS of the SI was 18989 N, and the total lower extremity MS of the HI was 75334 N. The difference between the total lower extremity MS HI, and SI was 56345 N. On a percentage basis, the loss MS was 77.79% in SI (Table 3).
The MS of trunk extensor of the SI was 2718 N and the MS of the trunk extensor of HI was 4090 N. The difference between the MS of trunk extensor of the HI and SI was 1372 N. On a percentage basis, the loss of MS was 33.55% in SI (Table 3). The grip strength of the SI was 1484 N, and the grip strength of HI was 5083 N. The difference between the grip strength of HI and SI was 3599 N. On a percentage basis, the loss in grip strength was 70.80 in SI (Table 3).
The total MS of the SI was 49909.5 N and the total MS of the HI was 182375 N. The difference between the total MS of the healthy and SI was 132465.5 N. On a percentage basis, the loss in total MS was found 72.63% in SI (Table 3).
The aim of this study was to investigate unaffected side MS and total MS loss in the SI. The results of this study showed that unaffected side MS (upper extremıty total MS, lower extremity total MS, grip strength, trunk extensor MS) of SI decreased dramatically compared to HI, and the total MS of SI decreased 72.63%.
The studies about MS, as one of the most important factors in preventing disability during stroke rehabilitation, are generally focused on the affected side of SI. But it may be hard to initiate and improve movement because of muscle weakness and spasticity. This situation may limit proper neuroplasticity response and cause maladaptive plasticity . On the other hand, studies have shown that the findings in the cerebral cortex lesions are bilateral . These results strengthen the idea that the unaffected side extremities may be affected. In accordance with all these studies, in our study, we found that the individuals with stroke have significantly decreased MS compared to HI. Therefore, we believe that it is necessary to improve MS of the unaffected side through the chronic stage to ensure full independence in ADL of SI.
Muscle mass, power and strength begin to decrease in the 3rd decade of life. Between 30 and 50 years of age, the reported decreases in muscle mass, power and strength are small. Pronounced decreases with the aging process occur after 50th year of life with more than 15% strength loss per decade . In our study, we found that the average age of the stroke group was significantly higher than in the healthy group. The difference between the average age of the groups was 4 years. This may affect our result negatively. However, when we look at the MS values, we can see that this difference may not affect the results sharply.
The grip strength is robustly associated with mobility outcomes and is a relatively simple and inexpensive proxy of overall MS . Grip strength is an important parameter of self-care ability and quality-of-life, and grip strength loss is associated with a reduction in self-care ability and quality-of-life; therefore, grip strength is important for the maintenance of ADL while eating, bathing or others . But stroke patients have difficulty in performing these tasks due to strength insufficiency and spasticity. Therefore, the grip strength of the unaffected side plays an important role in performing these tasks. In accordance with our study, it was also stated in a few previous studies that the grip strength was affected in the unaffected side . Additionally, our study revealed the rate of this loss as a percentage and showed how this problem is great. On the other hand, unilateral grip strength training improves the grip power bilaterally, and it is stated that such training may be used in neurological diseases like stroke to improve neuroplasticity .
SI has a motor impairment between 50%-75% in the affected upper extremity, and about 30% of this impairment cannot be fully recovered. The motor impairment of the ipsilesional side, also known as the unaffected side, has been investigated less and this impairment has not been elucidated yet. In a study, proximal and distal muscle strength of unaffected upper extremities of 72 SI was assessed from an early period. It was concluded that, although MS recovery reached a maximum level within 1 month, the weakness did not completely disappear. Moreover, it was suggested that the proximal and distal upper extremity weakness in the unaffected side after stroke was not a transient event . In another study, it was demonstrated that movement (especially in ADL), speed-related kinematic and movement quality are impaired clearly in unaffected side upper extremity in SI . Our results, closely supported by the abovementioned studies, suggest that the unaffected side of MS should be improved through the chronic stage in patient with stroke to improve daily tasks such as drinking water, brushing teeth.
Although the weakness of the trunk MS in SI has been already mentioned, studies on the strength of the trunk muscles is scarce. Muscle weakness is observed more prominently in upper and lower extremities, because approximately 80% of them are innervated only by one hemisphere . Since the nerves that innervate the trunk are controlled by both hemispheres of the brain, the muscle weakness in the trunk is seen less than the extremities . The recovery of the trunk muscles starts from the early period. Although the weakness of trunk muscles is evident in the acute and subacute phases, it should be kept in mind that it can continue in the chronic phase . In addition, the weakness of the trunk muscles not only covers the anterior trunk flexors, but also the trunk extensors and rotators. All trunk muscles play a very important role in protecting the body against gravity and providing proximal stabilization during functional activities. Adequate function of these muscles is very important for balance, transfer, walking, other functional activities and respiratory sufficiency [5,23]. Due to important functions of the trunk muscles, it is mandatory to evaluate and improve trunk MS of SI . In our study, the decrease in trunk extensor MS was found to be less than the decrease in MS of extremities. In addition to the previous studies, our study revealed this loss as a percentage and clarified the importance of this topic. We think that clinicians, working in this field, should improve trunk MS from the early period and through chronic phase of the rehabilitation process to get better results rapidly.
Stroke is the main cause of disability in adults. The MS loss of lower limb is one of the main impairments that can be encountered after stroke . It is also associated with a limited ability to perform activities of daily living such as walking . In a systematic review including 5 studies, the MS of hip flexor, knee extensor and ankle dorsiflexor were examined. According to this review, all of the included studies found that MS of the unaffected side significantly decreased, with the exception of one study. As a result of this review, it was concluded that the MS of the US was decreased in SI, and this reduction was reported to be at least 10-13.4% (28). In the light of literature and our study, lower extremity MS, which forms the basis of ADL, should be improved on the affected and unaffected side. It was shown that the strength of wrist flexor muscle, wrist extension muscle, grip, finger flexion muscle, thumb flexion muscle, thumb extension muscle, elbow flexion muscle, elbow extension muscle, shoulder abduction muscle and shoulder adduction muscle were decreased by 68%, 57%, 66%, 64%, 59%, 58%, 53%, 47%, 43% and 37%, respectively in SI. In our study, we found that the loss of total MS in the upper extremity was 75.50% and in grip strength was 70.80%. This dramatic loss of total MS has clearly demonstrated the negative impact of stroke on patients.
According to the results of our study, lower extremity MS decreased by 74.79%, trunk extensor MS by 33.55% and total MS by 72.63%. We could not find any study examining the percentage of loss of the lower extremity, trunk and total MS. These findings have been examined for the first time in the literature. Thus, our study is prominent in this field, and it is important to support it with new studies.
One limitation of our study was that the hands, toes and neck muscles strength could not be evaluated because the dynamometer was not compatible. Another limitation of the current study was that the MS of the AS was not measured in terms of muscle spasticity. However, in some individuals, little MS on the AS was observed. Examination of the muscle strength of AS by eliminating spasticity is important to obtain more objective results. In addition, studies to be conducted by increasing the sample group and using golden standard instrument methods will shed more light on this issue. Despite the limitations, our study objectively demonstrated the loss in total MS. In addition, our study showed that the muscle strength of the US reduced significantly.
In conclusion, our study showed that MS of unaffected side and total MS decreased dramatically in SI. As a result of our study, MS should be improved on both the affected and US in SI. In addition, we think that it may be more appropriate to use the term ‘less AS’ instead of the unaffected side.
The authors would like to thank all participants for their support.
Scientific Responsibility Statement
Animal and human rights statement
Conflict of interest
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Aziz Dengiz, Emre Baskan. Does muscle strength decrease on the unaffected side in stroke patients? Ann Clin Anal Med 2021;12(9):1011-1015
The role of circulating miR-200 family members in differentiating prostate cancer from benign prostatic hyperplasia
Semanur Özseven 1, Kuyaş Hekimler Öztürk 2, Alper Özorak 3
1 Department of Bioengineering, Science Institute, 2 Department of Medical Genetics, Faculty of Medicine, 3 Department of Urology, Faculty of Medicine, Süleyman Demirel University, Isparta, Turkey
DOI: 10.4328/ACAM.20562 Received: 2021-03-01 Accepted: 2021-05-12 Published Online: 2021-05-25 Printed: 2021-09-01 Ann Clin Anal Med 2021;12(9):1016-1020
Corresponding Author: Kuyaş Hekimler Öztürk, Süleyman Demirel University, Faculty of Medicine, Department of Medical Genetics, Isparta, Turkey. E-mail: email@example.com P: +90 246 211 2759 F: +90 246 237 1165 Corresponding Author ORCID ID: https://orcid.org/0000-0002-7075-8875
Aim: Although prostate-specific antigen (PSA) is one of the best-known tumor markers used in the early diagnosis of prostate cancer, it may be insufficient in differentiating benign prostatic hyperplasia (BPH) from prostate cancer (PCa). In this study, in cases where the diagnostic power of PSA is insufficient, it was aimed to evaluate the possible diagnostic and prognostic roles of the miR-200 family (miR-200a, miR-200b, miR-200c, miR-141), which has been proven to be associated with cancer by many studies.
Material and Methods: Thirty-one untreated PCa patients were included in the study as the case group and 29 untreated BPH patients as a control group. PSA levels of all patient samples were measured. miRNAs expression levels were determined from total RNA isolated from plasma samples by the qRT-PCR method. The relationship between miRNAs and clinicopathological data was evaluated using statistical tests.
Results: The relative expression levels of the examined miRNAs, although not statistically significant, tended to decrease in the PCa group compared to the BPH group. The ability of miR-200 family members to differentiate PCa from BPH was found to be weaker than serum PSA, and no significant relationship was found between clinicopathological parameters and these miRNAs (p>0.05).
Discussion: Regardless of serum PSA, the potential of the circulating miR-200 family members to differentiate PCa from BPH is weak. Although our findings are guiding for future functional studies, it is thought that further studies should be done in larger patient groups.
Keywords: Prostate Cancer; Benign Prostate Hyperplasia; microRNA; microRNA-200 Family
Prostate cancer (PCa) is the most common malignancy of the male reproductive system worldwide . The pathogenesis of PCa is still not fully understood; however, it is known to be a multifactorial disease involving genetic predisposition, hormonal changes and various environmental factors . Although the most widely used biomarker that can correlate with the risk and prognosis of PCa is the prostate-specific antigen (PSA), benign prostatic hyperplasia (BPH), prostatitis, or the use of certain drugs can increase the PSA level and cause misdiagnosis in terms of PCa . Therefore, non-invasive markers with higher sensitivity and specificity are needed in the early diagnosis of PCa. Recently, circulating microRNAs (miRNAs) have been proposed as potential new biomarkers for the diagnosis and prognosis of PCa .
Circulating miRNAs are known as promising diagnostic and prognostic biomarkers in various cancers, including PCa, due to their increased stability, tissue specificity, ease of detection, and frequent dysregulation during tumorigenesis [5, 6]. MiRNAs are short RNAs of 20-24 nucleotides that play a significant role in almost all biological processes in mammalian species . While miRNAs can play the role of an oncogene when they target tumor suppressor genes, and similarly, when they target oncogenes, they can play a tumor suppressor role. Therefore, miRNA profiling has been a powerful tool to identify predictive miRNA signatures associated with the early diagnosis and progression of various cancers .
It has been determined that the miR-200 family (consisting of 5 miRNAs: miR-141/200a/200b/200c/429), which is a member of a certain microRNA family, plays a very significant role in tumor formation . The role of miR-200 family members in cancer is considered mainly as tumor suppression . Studies show that the miR-200 family plays a significant role in epithelial- mesenchymal transition (EMT), migration, apoptosis, tumor cell adhesion, and regulation of angiogenesis [9, 10]. However, the available data suggest that the biological functions of the miR-200 family may differ depending on the stage of tumor progression and metastasis, and the nuclear or cytoplasmic localization of the interacting targets .
In our study, it was aimed to reveal the power of expression levels of miR-200 family members in the differential diagnosis of PCa and BPH in cases where serum PSA was insufficient, and to determine their roles in the pathogenesis and severity of the disease. Besides, in this study, which aims to determine their role as a non-invasive biomarker in the development and progression of PCa, their relationship with clinicopathological parameters was also examined.
Material and Methods
Study design and samples collection
The research protocol was created following the Declaration of Helsinki, and it was reviewed, approved and registered by the Ethics Committee of Süleyman Demirel University Faculty of Medicine (dated 29.03.2018, with the decision no. 2018/65). All patients were evaluated in the Urology policlinic of the SDU hospital. The study included 31 untreated PCa and 29 BPH patients. All patients provided written informed consent. Patients with different malignancies, chronic diseases and inflammatory diseases other than PCa and BPH were excluded from the study. A healthy control group was randomly selected from individuals without any systemic disease and drug use. All medical histories of the patients were questioned and recorded. PCa patients were subjected to clinical evaluation to determine the stage of prostate cancer. The stage of PCa was evaluated by the tumor node metastasis (TNM) system according to the American Joint Committee on Cancer. PCa grading was made according to the Gleason score. If PSA<10 ng/mL and GS<7 were considered as low risk, if PSA is 10-20 ng/mL and GS=7 as a medium risk, if PSA>20 ng/mL and GS>7 as high risk. Venous blood (4cc) was drawn into EDTA tubes from the patients. The collected blood was centrifuged for 10 minutes at 15,000 rpm in 1 hour in a cooled centrifuge and the plasma samples were stored at -80°C. The chemiluminescence immunochemical method (Beckman Coulter) was used to determine serum concentrations of total specific antigen (tPSA) and free PSA (fPSA).
Selection of candidate miRNAs and primer sequences
Candidate miRNAs, assumed to target genes associated with PCa, were selected using insilico tools. TargetScan Release 7.2 (http://www.targetscan.org/vert_72/) and miRDB (http://mirdb. org/index.html) algorithms were used for this purpose. The primer sequences of the miRNAs we researched are given in Table 1.
RNA isolation and cDNA synthesis
Total miRNA was isolated using the Hybrid-RTM miRNA Isolation Kit (GeneAll Biotechnology, Korea) following the manufacturer’s instructions. miRNA samples with a sufficient quantity and high quality were used. Measurements of the isolated total miRNAs were made with the Thermo Fisher NanoDropTM spectrophotometer device. Samples with an A260/280 ratio below 1.8 or A260/230 ratio below 2.0 were not included in the study. From the obtained total miRNA, using the WizScriptTM cDNA Synthesis Kit, cDNA was obtained using the stem-loop primer separately for each miRNA to be studied. Reverse transcription was performed using SimpliAmp Thermal Cycler (Thermo Fisher Scientific, US). cDNA samples were stored at -80oC until Real-Time PCR analysis was performed.
Quantitative PCR analysis
The quantitation of miRNA molecules was performed using the StepOnePlus Real-Time PCR Detection System (Thermo Fisher Scientific, US). RT-PCR steps were performed according to the manufacturer’s instructions. The expression of the selected miRNAs in the blood was normalized to the expression of U6 small nuclear RNA (RNU6B). Each experiment was performed at least in duplicate.
Statistical analysis was performed using PASW (Predictive Analytics SoftWare) version 19 program. Continuous variables were expressed as mean ±SD, and the level of significance was defined as p<0.05. Normality test was done using the Kolmogorov-Smirnov test. It is compared using an independent sample t-test for normally distributed data and a Mann- Whitney U test for non-normally distributed data. Comparison of categorical data was made using the chi-square test. Specificity and sensitivity were combined in receiver operating characteristic (ROC) curve analysis and reported in areas under
The quantitation of miRNA molecules was performed using the StepOnePlus R the curves (AUCs). Fold change analysis between groups was performed using the Relative Expression Software Tool (REST 2009, version 1, released 22).
Demographic data of the study subjects
The patient’s clinical and demographic data are listed in Table 2. The mean age of the PCa patients was 68.13±7.88 years, while the mean age of BPH patients was 65.48±7.61 years; there was no significant difference between the studied groups regarding the age (p=0.192), so the two groups were well matched in terms of age. Serum PSA levels were significantly higher in the PCa group (p=0.000). It was found that 38.7% of the patients had GS<7, 19.4% of them had GS=7, and 41.9% of them had GS>7. According to clinical staging, T1c was determined as 3.2%, T2a was determined as 16.1%, T2b was determined as 6.5%, T2c was determined as 12.9%, T3a was determined as 16.1% and metastasis status was determined as 45.2%.
Plasma expressions of miRNAs
MiRNA expression was determined in plasma samples of PCa and BPH patients using qPCR relative to the endogenous control RNU6B. Values were expressed as relative median fold change in gene expression. Target miRNAs and RNU6B established reliable Ct values in plasma samples of PC and BPH patients. The expression of miRNAs showed a downward trend in the PCa group compared to the BPH group, although it was not statistically significant. The fold changes of miR-200a, miR- 200b, miR-200c and miR-141 in the PCa group, compared to the BPH group were 0.816, 0.615, 0.434 and 0.737, respectively. Fold changes and expression distributions between groups are given in Table 3 and Figure 1.
Relationship Between miRNA Levels and Clinical Data
In our study, the relationship of features such as serum PSA, Gleason score, and clinical staging with miRNA expression levels was researched. There was no significant correlation between serum PSA and miR200a, miR200b, miR200c or miR141 expression levels (r=0.109, p=0.406; r=-0.24, p=0.857; r=-0.27, p=0.836, r=-0.58, p=0.658 respectively.). In addition, there was no significant difference between the Gleason score and clinical staging or miRNA expression levels (p=0.829, p=0.268, p=0.827, p=0.767, respectively).
miRNAs and serum PSA as diagnostic markers
ROC analyzes were performed to evaluate the value of circulating miRNAs as a diagnostic marker for PCa. ROC curves are given in Figure 2. The area under curve (AUCs) value, which was used to distinguish prostate cancer from the BPH group, was found as 0.505 for miR-200a, 0.548 for miR-200b, 0.509 for miR-200c, 0.465 for miR-141, and 0.890 for PSA. The sensitivity and specificity of these miRNAs, were determined as 54.8% and 48.3% for miR-200a, 54.8% and 51.7% for miR- 200b, 54.8% and 65.5% for miR-200c, 41.9% and 51.7% for miR-141, 87.1% and 72.4% for PSA, respectively. The power of miRNAs to differentiate PCa from BPH was not statistically significant. However, the diagnostic power, sensitivity and specificity values of serum PSA were significant.
Prostate cancer is among the most common cancers in the world and the leading cause of cancer death in men. BPH, which is common in men, affects about 70% of men over the age of 70 . Unfortunately, BPH is often misdiagnosed, thus leading to invasive prostate biopsies for differential diagnosis when not needed . Therefore, alternative non-invasive biomarkers have become important to help in the early diagnosis of PCa, as well as to differentiate patients with malignant and benign prostates and reduce the need for invasive biopsies . miRNAs play an important role in tumor development due to their ability as regulators of tumor suppressor genes and to act as oncogenes . With the discovery of these features, miRNAs have been considered ideal non-invasive biomarkers in many types of cancer .
This study aimed to determine the circulating miRNAs that differentiate PCa from BPH in the patient population with increased PSA levels. Besides, it was aimed to determine the roles of the circulating miR-200 family in the pathogenesis of PCa and BPH, and to evaluate their diagnostic and prognostic roles. In our study, the relative expression levels of miRNAs showed a downward trend in the PCa group compared to the BPH group, although it was not statistically significant. No significant difference was found between other clinicopathological parameters and miRNA expression levels. Besides, the ROC analysis, which evaluated the diagnostic powers for the differentiation of BPH and PCa, did not find miRNA with a higher diagnostic power than PSA was detected. Studies have shown that miR-200 family members are abnormally expressed in many human malignancies, and these miRNAs play a role in tumor pathogenesis during the carcinogenesis process. It is known that miR-200 family members are downregulated during the tumor progression process . Additionally, the miR-200 family is a tumor suppressor microRNA family that plays critical roles in suppressing EMT .
miR-200a and miR-141 are known to inhibit migration, invasion, proliferation and drug resistance in various forms of cancer . miR-141 is dysregulated in malignant tumors and plays an important role in tumor development and progression . Agaoglu et al., in their study, to differentiate PCa patients that have metastasis from those who have locally advanced disease, reported that miR-141 was the strongest differentiator of metastatic PCa in clinical practice, supporting PSA testing . Zhang et al. suggested that the miR-141 expression level increased in the serum of patients with bone- metastatic prostate cancer and positively correlated with bone lesions . In the study conducted by Brase et al., high levels of circulating miR-141 were found to be associated with high- risk (Gleason score≥8) tumors, while low levels of miR-200a were found to correlate with recurrence in prostate cancer . While Barron et al. pointed out that measuring miR-200a on its own in patients with prostate cancer would not have sufficient sensitivity and specificity to be useful for predicting recurrence, they stated that miR-200a could be a part of a panel of biomarkers with other family members . Akbayır et al. researched miRNA expression values in order to increase the diagnostic power of the grey zone PSA in PCa and BPH patients, and they found no significant difference between the groups in terms of miR-141 expression . In our study, compatible with Akbayır et al., miR-141 and miR-200a expressions were found to be downregulated in the cancer group, although this was not statistically significant (FC=0.737, p=0.754, FC=0.816, p=0.776, respectively). We think that this downregulation can facilitate cancer progression by inducing EMT, the first step of metastasis, similar to the study of Du et al. . However, the weakness of miR-141 and miR-200a in differential diagnosis compared to serum PSA (AUC = 0.465, AUC = 0.505, respectively) made us think that these miRNAs could not help to improve the diagnostic prediction.
miR-200b and miR-200c are important regulators of epithelial- mesenchymal transformation. In addition to its role in normal cell phenotypic transformation, miR-200b/200c is differentially expressed in many cancer cells. However, there are few studies in the literature regarding miR-200b/200c and PCa, and it is unclear whether they regulate PCa . Zhang et al. found that the tumor suppressor miR200b is overexpressed in human prostate tumors . Vrba et al. showed that miR-200c is less expressed in normal prostate tissues compared to cancerous tissues . Yu et al. found that miR-200b expression was significantly downregulated in PCa tissues compared to BPH tissue samples . In our study, we found that the expression levels of miR-200b and miR-200c decreased in the cancer group, although it was not statistically significant (FC=0.615, p=0.442, FC=0.434, p=0.297, respectively). Our findings suggest that these downregulated miRNAs may play a vital role as a potential tumor suppressor in PCa tumor development and progression. However, the weakness of miR-200b and miR- 200c in differential diagnosis compared to serum PSA (AUC = 0.548, AUC = 0.509, respectively) showed us that these miRNAs cannot be independent biomarkers.
In miRNA expression profiling studies carried out to differentiate prostate cancer from BPH, there may be contradictions due to many reasons, such as the use of different samples (such as tissue, plasma, urine, serum), the inclusion of populations of different sizes in the study, the difference in expression profiling methods, the selection of patients with BPH or healthy volunteers as a control group. Although our findings serve as a guide for future functional studies, they are limited due to their small population and the evaluation of a small number of miRNAs.
As a result, plasma expression levels of the miR-200 family tended to decrease in the group with PCa compared to the group with BPH. Independently of serum PSA, these molecules did not have sufficient sensitivity and specificity to be useful for distinguishing PCa from BPH. It is thought that the present study should be conducted in a larger population in a multicenter group to evaluate the roles, potential diagnostic and prognostic roles of circulating miR-200 family expressions in carcinogenesis as non-invasive biomarkers for PCa.
This study was supported by the Agen Biotechnology Company.
Scientific Responsibility Statement
Animal and human rights statement
Funding: This study was supported by Süleyman Demirel University Scientific Research Projects Coordination Unit (Project Number: TYL-2018-6723).
Conflict of interest
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23. Mongroo PS, Rustgi AK. The role of the miR-200 family in epithelial- mesenchymal transition. Cancer Biol Ther. 2010; 10(3):219-22. DOI: 10.4161/ cbt.10.3.12548.
24. Zhang Z, Lanz RB, Xiao L, Wang L, Hartig SM, Ittmann MM, et al. The tumour suppressive miR- 200b subfamily is an ERG target gene in human prostate tumours. Oncotarget. 2016; 7(25):37993–38003. DOI: 10.18632/ oncotarget.9366.
25. Vrba L, Jensen TJ, Garbe JC, Heimark RL, Cress AE, Dickinson S, et al. Role for DNA methylation in the regulation of miR-200c and miR-141 expression in normal and cancer cells. PLoS One. 2010; 5(1):e8697. DOI: 10.1371/journal. pone.0008697.
Download attachments: 10.4328:ACAM.20562
Semanur Özseven, Kuyaş Hekimler Öztürk, Alper Özorak. The role of circulating mir-200 family members in differentiating prostate cancer from benign prostatic hyperplasia. Ann Clin Anal Med 2021;12(9):1016-1020
Epiretinal membrane surgery challenges and results in patients with premium intraocular lens
Berkay Akmaz 1, Ugur Unsal 2
1 Department of Ophthalmology, Manisa City Hospital, Manisa, 2 Department of Ophthalmology, Batigoz Eye Health Center, Izmir, Turkey
DOI: 10.4328/ACAM.20565 Received: 2021-03-02 Accepted: 2021-08-14 Published Online: 2021-08-17 Printed: 2021-09-01 Ann Clin Anal Med 2021;12(9):1021-1025
Corresponding Author: Berkay Akmaz, Department of Ophthalmology, Manisa City Hospital, Manisa, Turkey. E-mail: firstname.lastname@example.org P: +90 506 917 11 37 Corresponding Author ORCID ID: https://orcid.org/0000-0003-1852-9474
Aim: In this study, it was aimed to evaluate the epiretinal membrane surgery challenges and results in patients with premium intraocular lens performed by an experienced surgeon in our clinic and compare with the current literature.
Material and Methods: In this retrospective study, 75 patients who underwent vitrectomy by a single surgeon were included. All patients had previously under- gone phaco + iol implantation. Patients were divided into three groups according to the types of intraocular lens (Group 1: monofocal, group 2: bifocal, and group: 3 trifocal). Surgery time, retinal nipping, best-corrected visual acuity (BCVA) and Central macular thickness (CMT) were analyzed among three groups (Pre-op Post-op 6th month and Post-op 1st year).
Results: Compared to the group of monofocal IOLs, surgery time and the number of retinal nipping were significantly increased in groups of bifocal and trifo- cal IOLs (p<0.001). In addition, there was a significant positive correlation between surgery time and retinal nipping (p<0.001, r: 0.371**). When the Pre-op, Post-op 6th month and Post-op 1st year logMAR visual acuity values in the groups were compared, it was found that the logMAR (Logarithm of the minimum angle of resolution or recognition) visual acuity values in Post-op 6th month and Post-op 1st year increased statistically significantly compared to Pre-op logMAR (p<0.001).
Discussion: Premium lenses prolong the surgery time during vitreoretinal surgery. Since premium iols negatively affect visual acuity, it should not be recom- mended to patients with retinal disease. However, with careful preoperative planning, proactive familiarity with these premium IOLs, and proper contact with patients, retinal surgeons do not need to fear these sophisticated lenses.
Keywords: Cataract; Vitrectomy; Epiretinal membrane surgery; Premium intraocular lenses
Cataracts are the first cause of blindness in underdeveloped countries. After cataract surgery, vision is corrected by removing the lens and replacing it with an intraocular lens (IOL).
The majority of implanted IOLs in the world are monofocal IOLs that are designed to change lens dioptric power to a single focal point and can provide only satisfying far vision, but require glasses for close vision . Therefore, a wide variety of designs and optical properties have been developed to overcome this obstacle. Multifocal IOLs that have developed over the past 20 years can now supply high levels of uncorrected vision for both close visual tasks and distance. Modern multifocal IOLs provide independence from spectacles for most patients with refractive lens exchange (RLE) and cataracts. Patients were very pleased with the release of new generation lenses. However, since there are some disadvantages of the new generation lenses besides its advantages, one of these disadvantages is that when it is necessary for patients who will have a premium lens in the future, vitreoretinal surgery will be required.
One of the conditions requiring vitreoretinal surgery is the formation of epiretinal membrane (ERM), which can be seen mostly in elderly patients. ERM has an avascular, fibrocellular structure formed by proliferation on the inner surface of the Internal Limit Membrane (ILM) and causes varying levels of visual impairment . ERMs that develop in normal eyes, other than the detection of a posterior vitreous detachment, are called idiopathic . The mean age of ERM diagnosis is 65 years old. The incidence of idiopathic ERM is 5.8%. Its incidence is equal in men and women, and it is bilateral in 20% -30% of cases [2, 3]. In the literature, it has been reported that multifocal IOLs cause imaging difficulties during vitrectomy for retinal detachment and the epiretinal membrane (ERM) peeling . On the other hand, normal imaging with multifocal IOLs during PPV has also been reported . In patients with a premium intraocular lens during ERM peeling surgery, problems such as focusing on the membrane and defocus occur when the lens of the lens coincides with the optic axis of the surgeon. There are a limited number of studies in the literature evaluating visual outcomes related to ERM surgery in patients with multifocal IOLs and other macular diseases [6, 7]. However, there are very limited human studies in the literature evaluating visual results related to ERM surgery in patients with premium intraocular lenses. In this respect, our study is very important in terms of contributing to the literature.
In this study, it was aimed to evaluate the epiretinal membrane surgery challenges and results in patients with premium intraocular lens performed by an experienced surgeon in our clinic and compare with the current literature.
Material and Methods
This study was conducted at Katip Celebi University Ataturk Education and Research Hospital with the permission of the Ethics Committee of the Department of Ophthalmology. The medical files of 75 patients, all of whom were pseudophakic and underwent vitreoretinal surgery at the West Eye Institute ambulatory surgery center from March 2014 to July 2018, were analyzed retrospectively. Informed consent was obtained from all participants included in the study.
Patients and data selection
The electronic medical data of patients who had previously undergone uncomplicated phaco + iol implantation and who underwent PPV + ERM + ILM peeling surgery due to idiopathic erm at our center were scanned retrospectively. Inclusion criteria for files were as follows: a comprehensive ophthalmological examination (pre-op and post-op, written iol features, follow-up year), ERM surgery duration recorded, those with complete OCT images, and those who had a post op follow-up for at least 1 year. Inclusion criteria for iols were as follows: Alcon SA (mono), Zeiss AT LISA (Bi) or Alcon panOptix (Tri) patients. Exclusion criteria were those with ocular surface defects, those with corneal pathology, those with pupil and pathology affecting the anterior segment (pupil dysfunction), those with posterior capsulotomy and those with posterior capsular opacity, those with vitreous disorder (asteroid hyaloids), those with secondary ERM (trauma, diabetic ERM), those with optic neuropathy, those with systemic diseases (DM, HT, hyperlipidemia).
The patients were divided into three groups according to the types of intraocular lenses already inserted (Group 1: monofocal, Group 2: bifocal, Group: 3 trifocal). Age, gender, type of IOLs applied, surgery time, number of retinal nipping, logMAR (Logarithm of the minimum angle of resolution or recognition) (Pre-op/Post-op 6th month and Post-op 1st year) and CMT (Central macular thickness) (Pre-op/Post-op 6th month and Post-op 1st year) values were recorded.
All surgeries were performed under subtenon local anesthesia using the Möller-Wedel microscope. Before the surgery, the periorbital skin and eyelids were cleaned using a 5% povidone- iodine solution, and the eyelid was carefully closed to avoid the surgery area. Sclerotomy areas were carefully performed between 1 and 2 o’clock positions of the endoillumination probe and 10 to 11 o’clock positions of the vitrectomy probe. The infusion was carefully placed between 8-9 hours for the right eyes and 3-4 hours for the left eyes. After the conjunctiva displaced about 2 mm, the sclera penetrated the limbus with a 3.5 mm posterior trocar to the limbus at an angle of 25 ° to 30 ° with the 25-G one-step Kit (Alcon Laboratories, Inc, TX, USA). All vitrectomy transactions were applied utilizing a Constellation Alcon Vision System, and a noncontact lens (Eibos 90 [90D] and SPXL [132 D], Möller-Wedel, Wedel, Germany) was utilized for imaging of the posterior segment throughout the surgery. The SPXL lens was utilized during core vitrectomy and peripheral retinal control, and the 90 D lens was peeling erm during macular surgery. The working distance of the SPXL lens was 4 mm from the cornea, while the 90 D macular lens was 7 mm from the cornea. The posterior hyaloid was removed in all cases by core vitrectomy triamcinolone after standard trocars with 25 gauges. MembraneBlue-Dual (DORC International, Zuidland, the Netherlands) was used under the liquid to stain the ERM and ILM membranes. The epiretinal membrane was peeled with pinch and peel technique using a 25-G intraocular forceps (Dorc Int., Netherlands). ILM was stained again with dual dye and peeled off with the same technique. Retinal nipping was defined as involuntarily pinching of the neurosensory retina with forceps during the peeling of the ERM and ILM membranes. Scleral indentation and retinal circumference were carefully examined, and any refraction in the retina was repaired with laser retinopexy. Air liquid change was made (30-50%). Injection of 20% sf6 gas was made. Trocars were removed. Gas leakage control was done and surgery was terminated. For surgery time, the beginning was the entering of the trocars and the end was the end of the leakage check.
IOLs used in patients are monofocal (Alcon SA or alcon iQ model) (Constellation; Alcon, Fort Worth, TX), bifocal Zeiss AT LISA 809 and diffractive aspherical trifocal alcon Panoptix iol (AcrySof- PanOptixTM, Alcon Laboratories, Inc., TX, USA). The AcrySof SA60AT IOL is monofocal, anterior asymmetric biconvex, one- piece IOL with a square edge of 6 mm. The AT-LISA-809 (Carl Zeiss) is an aspheric diffractive (bifocal biconvex) IOL. This lens is a single-piece IOL with an overall diameter of 11.0 mm and an optic diameter of 6.0 mm. The surface is divided into phase zonesand main zones; the phase zones take on the function of the steps of the main zones’ diffractive power. The close vision add of this lens is +3.75 D over the distance power. The AcrySof® IQ PanOptix® Trifocal intraocular lenses (IOLs) are ultraviolet absorbing and foldable multifocal IOLs (blue light filtering). Each IOL model is a single-piece design with a central optic and two open-loop haptics. The optical diffractive structure is in the central optic portion of 4.5 mm and divides the incoming light to create a +3.25 D near and a +2.17 D intermediate add power at the IOL plane.
The data were unified and statistical analysis was supplied with SPSS v25 (SPSS Inc., USA). The Snellen value was used for visual acuity and afterwards turned to logMAR scale for analysis. The Chi-square or Kruskal-Wallis variance analysis test (post-hoc Bonferroni test) were used for comparison between groups. Paired t-test analysis was used to determine changes before and after changes in outcome variables. The p-values <0.05 were considered statistically significant.
The records of 190 patients were screened retrospectively. A total of 125 patients were excluded from the study since 32 patients had undetectable iol subtypes, 5 patients had traumatic erm, 5 corneal pathologies, 23 patients had laser capsulotomy, and 60 patients had systemic diseases, lack of sufficient VA and OCT data, and lack of sufficient follow-up time.
Demographic characteristics of patients
The sociodemographic comparison of patients is shown in Table 1. There was no statistically significant difference between the groups in terms of mean age and gender (p = 0.770 and p = 0.299, respectively) (Table 1).
ERM surgery time and number of retinal nipping among iol subtypes
Comparison of patients with monofocal and multifocal (bifocal, trifocal) IOLs in terms of surgery time and the number retinal nipping is shown in Table 2. Compared to the group using monofocal IOLs, surgery time was found to be statistically significantly increased in the groups using bifocal IOLs and trifocal IOLs (p<0.001). Compared to the group using monofocal IOLs, it was found that the number of retinal nipping increased statistically significantly in groups using bifocal IOLs and trifocal IOLs (p<0.001) (Table 2). In addition, there was a significant positive correlation between surgery time and retinal nipping (p=0.001, r: 0.371**).
OCT measurements among iol subtypes
Comparison of patients with monofocal and multifocal (bifocal, trifocal) IOL in terms of logMAR and CMT is shown in Table 3. There was a statistically significant difference between the groups in terms of Pre-op, Post-op 6th month and Post- op 1st year logMAR values (p= 0.043, p=0.031, and p=0.016, respectively). In terms of Pre-op, Post-op 6th month and Post- op 1st year logMAR values, there was a statistically significant increase in group bifocal and trifocal compared to group monofocal (p=0.034, p=0.012, and p=0.008, respectively).
In addition, when the pre-op, post-op 6th month and post-op 1st year logMAR values in the groups were compared, it was found that the logMAR values in Post-op 6th month and Post-op 1st year decreased statistically significantly compared to Pre- op logMAR (p<0.001). In other words, the median visual acuity improved at post-operative month 6 and post-operative year 1 in all 3 groups. Final visual acuity (at post-operative year 1) was significantly worse in patients with multifocal lenses when compared to patients with monofocal lenses.
There was no statistically significant difference between the groups in terms of pre-op, post-op 6th month and post- op 1st year CMT values (p = 0.886, p = 0.215 and p = 0.361, respectively). In addition, when comparing the Pre-op, Post-op 6th month and Post-op 1st year CMT values in the groups, it was found that CMT values in Post-op 6th month and Post-op 1st year decreased statistically significantly compared to Pre- op CMT (p<0.001) (Table 3).
In our study, we compared our epiretinal membrane surgery results in patients who had previously undergone phacoemulsification with different types of iol implantations. To the best of our knowledge, this is the first study in the published literature. We showed that surgery time increased statistically significantly in groups using bifocal and trifocal IOLs. It was also found that the number of retinal nipping increased statistically significantly in groups using bifocal and trifocal IOLs, and there was a significant positive correlation between surgery time and retinal nipping. Furthermore, BCVA was better in monofocal compared to multifocal in logMAR at all times.
A curious question about presbyopia correction is whether IOLs block imaging for retinal work. In general, lenses that can provoke problems are multi-focused, as they have diffraction or optical zones with changing power. However, various studies have reported that the posterior pole imaging is comparable to monofocal IOLs , while other studies have objected . A study of nine retinal surgeons in the first author’s study reported that a few have had macular visualization problems with current multifocal lenses. In the case of smaller optical designs, such as crystalline optics, the environment may be more difficult due to the rapid alteration in optical power encountered when the lens crosses the optical edge . In our study, the total retinal nipping count was calculated as 17 in the Monofocal iol group, 25 in the bifocal iol group, and 24 in the trifocal iol group, and compared to the group monofocal IOLs, it was found that the number of retinal nipping increased statistically in groups bifocal and trifocal IOLs. In addition, there was a significant positive correlation between surgery time and retinal nipping. Integrated phacovitrectomy has represented efficacy, and the argumentation of lens options (eg. monofocal, bifocal, trifocal) is an accepted standard of care for all patients undergoing cataract extraction . A study by Hadayer et al and other researchers have reported that applying PPV potential difficulty through a multi-focal IOL (bifocal and trifocal) because of impaired fundus visualization and intraoperative difficulties (additional effort needed to focus on the retinal vessels and peripheral retina, decreased stereopsis, and weaken view after fluid–air exchange) . Yoshino et al. and Kawamura et al. showed that imaging difficulties during vitrectomy for ERM peeling are caused by retinal detachment and diffractive IOLs . Otherwise, Marques et al. showed standard imaging with diffractive IOL during PPV . In our study, while patients with trifocal IOLs did not have a focal problem in imaging the peripheral retina (similar to monofocal), focusing problems were experienced during peripheral retinal control with bifocal IOLs. However, the number of retinal nipping was found to be increased in patients with trifocal and bifocal IOLs.
Different strategies have been applied to achieve independence from eyeglasses and better visual acuity after cataract surgery, and there are many options related to intraocular lenses (IOL). In many studies in the literature, it was stated that, although there is uncertainty as to the size of the effect, multifocal IOLs are potent at improving near vision relative to monofocal IOLs [16, 17]. However, some studies reported similar logMAR values in both groups . One study reported lightly preferable logMAR values in the monofocal group and one study reported substantially better logMAR values in the multifocal group . Only two studies assessed the visual outcome of MIOLs in patients with concurrent retinal diseases. Kamath et al. showed that patients with concurrent eye diseases, including diabetic retinopathy, glaucoma, or age-related macular degeneration, benefited from a multifocal IOL and distance visual acuities were similar in the monofocal IOL and multifocal IOL groups . Gayton et al. reported that in cataractous eyes with age- related macular degeneration and corrected distance, visual acuity was worse in the MIOL group . In our study, in terms of Pre-op, Post-op 6th month and Post-op 1st year logMAR values, there was a statistically significantly increase in the bifocal and trifocal group compared to the monofocal group. In addition, when the Pre-op, Post-op 6th month and Post-op 1st year logMAR values in the groups were compared, it was found that the logMAR values in Post-op 6th month and Post-op 1st year decreased statistically significantly compared to Pre-op logMAR. In other words, median visual acuity improved at post- operative month 6 and post-operative year 1 in all 3 groups. Final visual acuity (at post-operative year 1) was significantly worse in patients with multifocal lenses compared to patients with monofocal lenses.
The drawbacks associated with multifocal IOLs design are loss of contrast sensitivity, an increase in higher-order aberrations, and night-time glare and halos [18, 19]. In a few studies in the literature, the authors found no differences in retinal macula thickness, retinal volume, or fundoscopic photographs between monofocal and multifocal iols [18, 19]. Aychoua et al. showed a relevant reduction in visual sensitivity in patients with multifocal IOLs . Another study reported wavy horizontal artifacts on OCT line scanning ophthalmoscopy images in patients with multifocal IOLs . In a study by Lee et al., central macular thickness significantly decreased in patients with monofocal lens after surgical removal of the idiopathic macular epiretinal membrane . In our study, when comparing the Pre-op, Post- op 6th month and Post-op 1st year CMT values in the groups, it was found that CMT values in Post-op 6th month and Post- op 1st year decreased statistically significantly compared to Pre-op CMT. However, there was no statistically significant difference between the groups in terms of pre-op, post-op 6th month and post-op 1st year CMT (Central macular thickness) values.
The study has some limitations. This study was carried out only by a surgeon in a center and without a control group and was a retrospective study. Second, post-op near vision could not be observed because it was retrospective. However, it should be accepted that it is difficult to find a patient who has a Premium lens and underwent retinal surgery. Therefore, although it is retrospective, we think that it is a strong study in terms of the number of patients and it can be evaluated as a preliminary pilot study for future studies.
Premium lenses prolong surgery time during vitreoretinal surgery. Since premium iols negatively affect visual acuity, it should not be recommended for patients with retinal disease. However, with careful preoperative planning, proactive familiarity with these premium IOLs, and proper contact with patients, retinal surgeons do not need to fear these sophisticated lenses.
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Animal and human rights statement
Conflict of interest
1. de Vries NE, Nuijts RM. Multifocal intraocular lenses in cataract surgery: literature review of benefits and side effects. J Cataract Refract Surg. 2013; 39(2):268-78.
2. Diaz-Valverde A, Wu L. To Peel or Not to Peel the Internal Limiting Membrane in Idiopathic Epiretinal Membranes. Retina. 2018; 38(Suppl 1.):S5-11.
3. Bae JH, Song SJ, Lee MY. Five-Year Incidence and Risk Factors for Idiopathic Epiretinal Membranes. Retina. 2019; 39(4):753-60.
4. Yoshino M, Inoue M, Kitamura N, Bissen-Miyajima H. Diffractive multifocal intraocular lens interferes with intraoperative view. Clin Ophthalmol. 2010; 4:467.
5. Marques EF, Ferreira TB, Castanheira-Dinis A. Visualization of the macula during elective pars plana vitrectomy in the presence of a dual-optic accommodating intraocular lens. J Cataract Refract Surg. 2014; 40(5):836-9.
6. Gayton JL, Mackool RJ, Ernest PH, Seabolt RA, Dumont S. Implantation of multifocal intraocular lenses using a magnification strategy in cataractous eyes with age-related macular degeneration. J Cataract Refract Surg. 2012; 38(3):415-8.
7. Kamath GG, Prasad S, Danson A, Phillips RP. Visual outcome with the array multifocal intraocular lens in patients with concurrent eye disease. J Cataract Refract Surg. 2000; 26(4):576-81.
8. Behndig A, Montan P, Stenevi U, Kugelberg M, Zetterström C, Lundström M. Aiming for emmetropia after cataract surgery: Swedish National Cataract Register study. J Cataract Refract Surg. 2012; 38(7):1181-6.
9. Westin O, Koskela T, Behndig A. Epidemiology and outcomes in refractive lens exchange surgery. Acta Ophthalmol. 2015; 93(1):41-5.
10. Negishi K, Ohnuma K, Ikeda T, Noda T. Visual simulation of retinal images through a decentered monofocal and a refractive multifocal intraocular lens. Jpn J Ophthalmol. 2005; 49(4):281-6.
11. Bhavsar AR, Hardten D, Gilbert HD, Lindstrom RL. Vitrectomy and membrane dissection surgery. Ophthalmology. 2001; 108(9):1513.
12. Tewari A, Shah GK. Presbyopia-correcting intraocular lenses: what retinal surgeons should know. Retina. 2008; 28(4):535-7.
13. Ahmad BU, Shah GK, Hardten DR. Presbyopia-correcting intraocular lenses and corneal refractive procedures: a review for retinal surgeons. Retina. 2014; 34(6):1046-54.
14. Patel SB, Snyder ME, Riemann CD, Foster RE, Sisk RAJCO. Short-term outcomes of combined pars plana vitrectomy for epiretinal membrane and phacoemulsification surgery with multifocal intraocular lens implantation. Clin Ophthalmol. 2019; 13:723-30.
15. Hadayer A, Jusufbegovic D, Schaal S. Retinal detachment repair through multifocal intraocular lens-overcoming visualization challenge of the peripheral retina. Int J Ophthalmol. 2017;10(6):1008-10.
16. Grzybowski A, Kanclerz P, Tuuminen R. Multifocal intraocular lenses and retinal diseases. Graefes Arch Clin Exp Ophthalmol. 2020; 258(4):805-13.
17. Rasp M, Bachernegg A, Seyeddain O, Ruckhofer J, Emesz M, Stoiber J, et al. Bilateral reading performance of 4 multifocal intraocular lens models and a monofocal intraocular lens under bright lighting conditions. J Cataract Refract Surg. 2012; 38(11):1950-61.
18. Inoue M, Bissen-Miyajima H, Yoshino M, Suzuki T. Wavy horizontal artifacts on optical coherence tomography line-scanning images caused by diffractive multifocal intraocular lenses. J Cataract Refract Surg. 2009; 35(7):1239-43.
19. Aychoua N, Junoy Montolio FG, Jansonius NM. Influence of multifocal intraocular lenses on standard automated perimetry test results. JAMA Ophthalmol. 2013; 131(4):481-5.
20. Lee PY, Cheng KC, Wu WC. Anatomic and functional outcome after surgical removal of idiopathic macular epiretinal membrane. Kaohsiung J Med Sci. 2011; 27(7):268-75.
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Berkay Akmaz, Ugur Unsal. Epiretinal membrane surgery challenges and results in patients with premium intraocular lens. Ann Clin Anal Med 2021;12(9):1021- 1025
Methicillin resistance of S. aureus bloodstream infections: The data of 15 years
Fatma Zehra Oztek Celebi 1, Asuman Samli 2, Husniye Yucel 1, Saliha Senel 1
1 Department of Pediatrics and Adolescent Medicine, University of Health Sciences, Dr. Sami Ulus Obstetrics and Gynecology and Pediatrics Training and Research Hospital, 2 Department of Microbiology, University of Health Sciences, Dr. Sami Ulus Obstetrics and Gynecology and Pediatrics Training and Research Hospital, Ankara, Turkey
DOI: 10.4328/ACAM.20568 Received: 2021-03-04 Accepted: 2021-05-22 Published Online: 2021-06-10 Printed: 2021-09-01 Ann Clin Anal Med 2021;12(9):1026-1030
Corresponding Author: Fatma Zehra Oztek Celebi, Department of Pediatrics, Universith of Health Sciences, Dr. Sami Ulus Maternity and Children’s Health and Diseases Training and Research Hospital, Babür Caddesi No:44, Altındağ, Ankara, Turkey. E-mail: email@example.com P: +90 312 3056198 Corresponding Author ORCID ID: https://orcid.org/0000-0002-2203-5904
Aim: The aim of this study is to determine the annual changes in the frequency of methicillin resistance in the S. aureus strains isolated from blood cultures in our hospital and to find the resistance rate of S. aureus strains against other antimicrobial agents.
Material and Methods: S. aureus strains isolated from blood cultures of the hospitalized children between 2004 and 2018 were retrospectively analyzed. Pa- tients’ age, gender, complex chronic conditions (CCC) and the number of positive S. aureus blood cultures were investigated. The study period, 15 years, was classified in 3 periods of 5 years.
Results: Four hundred eleven blood cultures of 337 patients (157 girls, 180 boys) were positive for S. aureus. There were 100 MRSA (100/411, 24%) bacteremia in total. Twenty-eight of them were community-acquired (CA-MRSA). One hundred thirty-five patients (%40) had CCC. MRSA bacteremia was significantly higher in patients with CCC compared to patients without CCC (35% to 11%). The highest MRSA rate was detected in the period 2014-2018 among all positive S. aureus blood cultures. Clindamycin, erythromycin, gentamicin, trimethoprim/sulfamethoxazole and ciprofloxacin resistance were higher in the MRSA group. Hospital-acquired MRSA strains have a statistically higher rate of clindamycin, erythromycin, gentamicin, and ciprofloxacin resistance than CA-MRSA strains.
Discussion: The frequency of MRSA bacteremia has been increasing in our center in recent years due to the spread in the number of patients with chronic conditions. More attention should be paid to rational antibiotic use in children with CCC.
Keywords: Bacteremia; Complex Chronic Condition; Methicillin- Resistant S. aureus
Bloodstream infections are clinical conditions associated with high mortality and morbidity. Its mortality rates are reduced when it is diagnosed and treated early. S. aureus, which is one of the most common agents of Gram-positive bacteremia, causes numerous serious infections such as skin and soft tissue infections, surgical site infections, pneumonia, empyema, osteomyelitis, septic arthritis, and endocarditis [1-3].
While S. aureus related infections were successfully treated with penicillin G in the early 1940s, S. aureus developed resistance to penicillin, especially in hospital-acquired (HA) infections. Resistance of S. aureus to erythromycin and tetracycline was observed in the 1950s, then methicillin- resistant S. aureus (MRSA) was emerged in 1961 . MRSA strains cause serious problems with treatment, thus increase treatment costs. The multidrug resistance of these strains is the most important treatment problem. A significant part of MRSA strains has a decreased susceptibility to macrolides, clindamycin, chloramphenicol, aminoglycosides and antiseptics . In studies from our country, the rate of MRSA strains among all S. aureus strains was found to be 32-61% [1, 6, 7].
The frequency of methicillin-resistant strains has been increasing all over the world until recent years, but it has been reported that the frequency of MRSA has decreased in some centers [8, 9]. A study of a pediatric cohort from our country that evaluated microorganisms isolated from blood cultures between 2000 and 2011 found MRSA strains decreased over the years, and MRSA rate was found to be 0% in 2011 .
The antimicrobial resistance status of S. aureus strains is extremely important both to determine the treatment protocol and to make epidemiological evaluations. The aims of this study are to assess the prevalence of MRSA, as well as determining the annual frequency of methicillin resistance in the S. aureus strains isolated from blood cultures in our hospital over the 15 years, and to evaluate antimicrobial susceptibility patterns of S. aureus strains to other common antibiotics.
Material and Methods
S. aureus strains isolated from blood cultures of hospitalized children at Dr. Sami Ulus Obstetrics and Gynecology and Pediatrics Training and Research Hospital, between 2004 and 2018 were retrospectively analyzed. Cultures from patients older than 18 years of age and cultures with more than one strain were excluded from the study. Patients’ age, gender, complex chronic conditions (CCC) and the number of positive S. aureus blood cultures were investigated. A complex chronic condition was defined as ‘any medical condition that are expected to last for at least 12 months (unless death intervenes), and that affects more than one organ system, or that severely affects a system, requiring specialized paediatric care and possibly requiring hospitalization at a tertiary care centre’ . Patients were divided into two groups according to the unit where they were hospitalized: patients who were hospitalized in intensive care (pediatric, neonatal and cardiovascular) units and in other services. The rate of MRSA infections was compared with the rate of methicillin-sensitive S. aureus (MSSA) infections according to patients’ place of hospitalization, CCC and their age. The length of hospital stay after S. aureus bacteremia and the mortality status of the patients were examined. The study period, 15 years, was classified in 3 periods of 5 years (2004- 2008, 2009-2013 and 2014-2018) to determine the change in MRSA epidemiology obviously.
S. aureus blood cultures obtained within the first 3 days of admission were considered to originate from Community- Acquired (CA) infections ; those obtained after the 3rd calendar day of admission were considered to originate from Hospital-Acquired (HA) infections. Blood cultures were performed in BACTEC Vacutainer Culture Systems. To diagnose S. aureus strains, presumptive isolates were inoculated onto Blood agar base with a 5% sheep blood medium (Oxoid, England). Microorganisms were evaluated according to colony morphologies, Gram staining properties, the status of beta hemolysis on blood agar and Catalase and Coagulase tests. Both tube and slide coagulase tests were performed. Strains that were positive for beta hemolysis on blood agar Catalase and Coagulase tests (both tube and slide) were identified as S. aureus. Methicillin resistance was determined by Cefoxitin disc diffusion test considering the recommendations of the Clinical and Laboratory Standards Institute (CLSI) (Wayne PA. Clinical and laboratory standards institute. Performance standards for antimicrobial susceptibility testing 2011;100-21). Antimicrobial susceptibility analyzes were conducted with the first positive S. aureus strains of recurrent positive S. aureus blood cultures. The study was conducted in accordance with the principles of the Declaration of Helsinki. The institutional review board of Dr. Sami Ulus Maternity and Children’s Health and Diseases Training and Research Hospital approved the study (Decision No: 2019-12-18). Statistical analysis was performed in SPSS for Windows 15.0 (SPSS Inc., Chicago, IL, USA). Descriptive statistics were given as median and interquartile range for continuous variables and frequency, the percentage for categorical variables. Comparisons were performed using the Mann-Whitney u test and Chi-square test, where p< 0.05 was considered statistically significant.
Four hundred-eleven positive blood cultures for S. aureus were detected in 337 patients (157 girls, 180 boys). Demographic variables of the patients are shown in Table 1. Forty percent (n=135) of the patients had an underlying CCC. The most common CCC was cardiovascular diseases (n = 32). This was followed by renal (n=24), neurological (n=19), and metabolic (n=17) conditions. Forty-five percent (n=151) of patients had CA S. aureus bacteremia.
During the years 2004-2018, there were 100 MRSA (100/411, 24%) and 311 MSSA bacteremia in total. Table 2 shows important variables about S. aureus positive blood cultures. The MRSA rates of intensive care units and other services were comparable. There was more CA bacteremia in the MSSA group. MRSA bacteremia was significantly higher in patients with CCC compared to patients without CCC. Patients who were older than 12 months of age had significantly higher rates of MRSA bacteremia (Table 2). The number of positive blood cultures for S. aureus in each year is demonstrated in Figure 1. Most of the S. aureus bacteremia took place between 2015 and 2018. When all S. aureus positive blood cultures were examined in 3 periods, the highest MRSA rate was detected in the period 2014-2018. In the 2004-2008 years, 26%, of all positive S. aureus infections were MRSA, in the 2009-2013 years- 9% and 31% in 2014- 2018 years (p <0.01) (Figure 2). Among patients with S. aureus bacteremia, there were significantly more patients with a CCC in the period 2014-2018 years. The rates of patients with a CCC were 31% in the period 2004-2008, 31% in the period 2009-2013, and 50% in the period 2014-2018 (p <0.01).
The antibiotic resistance of all first positive S. aureus strains as well as MRSA and MSSA strains is shown in Table 3. Resistance to penicillin G, clindamycin, erythromycin, gentamicin, trimethoprim/sulfamethoxazole and ciprofloxacin was higher in the MRSA group than in the MSSA group (Table 3). There were no vancomycin, teicoplanin and linezolid resistant strains in both groups. Compared to CA-MRSA strains, HA-MRSA strains had statistically significantly higher rates of resistance to clindamycin (55.1% to 21.1%; p=0.01), erythromycin (81.6% to 37.5%; p<0.01), gentamicin (45.7% to 15.0%; p=0.02), and ciprofloxacin (46.5% to 10.5%; p<0.01).
The median length of hospital stay (LOS) after S. aureus bacteremia was 18 (IQR: 16) days in the MRSA group, while it was 9.5 (IQR: 8) days in the MSSA group (p <0.01). In the 15- year period, 13 patients (4%) died. Six of the 13 patients had MRSA and seven MSSA bacteremia. All 13 patients had CCC.
S. aureus bacteremia is associated with severe morbidity and mortality. In this study, we determined that the methicillin resistance of S. aureus strains isolated from blood cultures decreased in the period 2008-2012, but increased in the period 2013-2018. In addition, MRSA strains isolated from blood cultures had higher resistance to clindamycin, erythromycin, gentamicin, trimethoprim/sulfamethoxazole and ciprofloxacin compared to MSSA strains. The HA-MRSA strains had higher rates of resistance to clindamycin, erythromycin, gentamicin and ciprofloxacin compared to CA-MRSAs.
According to EARS-Net data, which is a surveillance study involving European countries, the methicillin resistance rates of S. aureus strains reduced in Europe . In Norway, the frequency of MRSA was 0.2% in 2002, and 0.8% in 2014, while in EU countries, this rate was 25.6% in 2007 and 18% in 2013 . Low MRSA rates in Scandinavian countries are considered to be associated with low and rational antibiotic use in these countries . In a study from our country, MRSA rates gradually decreased to 0 in 2011 . We observed a decrease in the total number of S. aureus bacteremia in the 2009- 2013 years in our hospital. Nevertheless, the total number of S. aureus bacteremia increased significantly after 2015. A possible explanation of this fact could be an increase in the number of hospital beds, including intensive care beds, after 2015 in our hospital. However, regardless of the increase in the number of hospital beds, MRSA rates were increased to 31% in the 2014-2018 years. The spread in the number of hospitalized patients with CCC and their increased antibiotic use might be the reason for this challenge in recent years. The higher rate of MRSA bacteremia in patients with CCC in this study supports this explanation as well.
Resistance to antibiotics is directly associated with the overuse of antibiotics . Turkey has the highest rate of total antibiotic consumption among European countries . Therefore, the ministry of health in Turkey carefully follows rational antibiotic use policies . In studies conducted in adults in our country, MRSA rates were reported as 50.2% . Although the frequency of MRSA infections among all S. aureus bacteremia was 24% in our hospital, the increase of MRSA rates in recent years suggested that infection control measures and restriction programs in antibiotic consumption should be adhered carefully .
In our study, no resistance to vancomycin, teicoplanin and linezolid was detected. However, clindamycin resistance was found by 7% in MSSA strains and 40% in MRSA strains. In an Afghan study, the clindamycin resistance rate was found 0% in MSSA and 8.5% in MRSA strains . In a large cohort from US, the clindamycin resistance rate was reported approximately 15% in MSSA and 10% in MRSA strains . Clindamycin is a common antibiotic that could be used for S. aureus infections in non-toxic children whose clinic is stable. However, the high clindamycin resistance in MRSA strains in our study made the use of clindamycin in S. aureus infections questionable.
The epidemiology of MRSA infections changed significantly. From 1961 to the 1990s MRSA infections were assumed as hospital- acquired infections . Today MRSA infections are increasingly common in the community. Defined risk factors for CA-MRSA infections are intravenous drug use, prior antibiotic use, and prior hospitalizations . Since patients with CA-MRSA bacteremia do not have classical risk factors such as dialysis catheters or central lines, it is difficult to predict whether these patients are at risk of having an MRSA infection. The choice of empirical therapy for serious infections where S. aureus is a possible agent could be a great challenge with the evidence that inappropriate initial antibiotic treatment leads to higher mortality . On the other hand, increased consumption of anti-MRSA antibiotics such as vancomycin could cause further resistant strains such as vancomycin-resistant S. aureus . In our study, the rate of CA MRSA bacteremia was 28%. In some centers, CA-MRSA reached 86% among MRSA bacteremia . Consistent with the literature, CA-MRSA strains have lower rates of clindamycin, erythromycin, gentamicin and ciprofloxacin resistance compared to HA-MRSA bacteremia in this study [24, 25]. Due to the fact that HA-MRSA strains have higher rates of resistance against antibiotics, more caution is needed in the choice of antibiotics in HA-MRSA infections.
In conclusion, the frequency of MRSA bacteremia has been increasing in our center in recent years due to the spread of patients with CCC and their possibly increased consumption of antibiotics. Multicenter studies are needed to examine this increase. More attention should be paid to the rational antibiotic use in children with CCC.
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Conflict of interest
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Fatma Zehra Oztek Celebi, Asuman Samli, Husniye Yucel, Saliha Senel. Methicillin resistance of S. Aureus bloodstream infections: The data of 15 years. Ann Clin Anal Med 2021;12(9):1026-1030
QTc interval and electrocardiographic findings of COVID-19 patients
Mehmet Oguzhan Ay 1, Nalan Kozaci 2, Ozlem Oymak Ay 3, Halil Kaya 1, Mehtap Bulut 1, Melih Yuksel 1, Ebru Adali 1, Enad Kenan 1, Ebru Cetin 1
1 Department of Emergency Medicine, University of Health Sciences, Bursa Yuksek Ihtisas Training and Research Hospital, Bursa, 2 Department of Emergency Medicine, University of Alanya Alaaddin Keykubat, Training and Research Hospital, Antalya, 3 Department of Otolaryngology, University of Health Sciences, Bursa City Hospital, Bursa, Turkey
DOI: 10.4328/ACAM.20574 Received: 2021-03-08 Accepted: 2021-05-05 Published Online: 2021-05-15 Printed: 2021-09-01 Ann Clin Anal Med 2021;12(9):1031-1036
Corresponding Author: Mehmet Oguzhan Ay, University of Health Sciences, Bursa Yuksek Ihtisas Training and Research Hospital, Department of Emergency Medicine, 16290, Bursa, Turkey. E-mail: firstname.lastname@example.org P: +90 5053893239 Corresponding Author ORCID ID: https://orcid.org/0000-0003-1061-5327
Aim: This study aimed to investigate the effectiveness of using the QTc interval and electrocardiographic (ECG) findings to predict 28-day all-cause mortality in patients with COVID-19.
Material and Methods: Patients aged 18 or older who visited ED with complaints of fever, cough and shortness of breath were tested using real-time reverse- transcriptase polymerase chain reaction, were imaged with CCT, underwent ECG, and consequently, diagnosed with COVID-19 were included in this study.
Results: A total of 276 patients were included in the study. When at least one comorbid disease, reduced oxygen saturation, ECG findings of prolonged QTc interval, ventricular tachycardia/fibrillation, left bundle branch block and ST segment elevation/depression or severe lung involvement (four or five lobes) on CCT scans were detected, patients had a higher 28-day all-cause mortality rate. Compared to surviving individuals, deceased patients had approximately 4.5-fold increased D-dimer levels, and approximately 5-fold increased C-reactive protein and troponin T levels. Among the deceased patients, 40% had sinus tachycardia.
Discussion: Usage of comorbidities, ECG, laboratory tests and CCT together is useful for predicting 28-day all-cause mortality rate in patients diagnosed with COVID-19.
Keywords: COVID-19; Electrocardiography; Mortality; Chest computed tomography; Laboratory tests
In December 2019, a pandemic named COVID-19 pneumonia, which is caused by the novel coronavirus (SARS-nCoV-2), emerged in the city of Hubei, Wuhan, China . Among the first published cohort from the Wuhan Jinyintan Hospital, which consisted of 41 patients with COVID-19 pneumonia, six (14.6%) patients’ medical conditions deteriorated rapidly, leading to death from multiple organ failure . When the cohort size reached 99 cases, 11 (11.1%) patients died . In another Wuhan cohort comprised of patients hospitalized due to COVID-19 pneumonia, general mortality rate was reported as 4.3% (6/138) . These studies have suggested that advanced age and underlying comorbidities are associated with disease severity and mortality rate in patients with COVID-19 pneumonia [2-4].
COVID-19 continues to spread rapidly throughout the world. The number of patients is growing each day, and these patients constitute the majority of cases who visit emergency departments (ED). This exceeding volume of patients hinders routine operations at ED. Establishing markers for the early and accurate diagnosis of COVID-19 and anticipating patients at risk of mortality would reduce rates of morbidity and mortality. This study aimed to investigate the effectiveness of using the QTc interval and electrocardiographic (ECG) findings to predict 28-day all-cause mortality in patients with COVID-19.
Material and Methods
This study was initiated following approval from the COVID-19 Scientific Research Review Commission (under the General Directorate of Health Services, the Ministry of Health) and the Hospital Ethical Committee (2011-KAEK-25 2020/07-18). Study population
Patients aged 18 or older who visited ED between 15.03.2020 and 30.06.2020 with complaints of fever, cough and shortness of breath, underwent ECG, were tested with real-time reverse- transcriptase polymerase chain reaction (rRT-PCR), were imaged with chest computed tomography (CCT), and consequently, diagnosed with COVID-19 were included in the study.
Patient information was gathered from the hospital automation system and patient files. The assessment of CCT scans of the participating patients was based on official reports on the hospital automation system made by Radiology Specialist. The assessment of ECGs was made by two experienced Emergency Medicine Specialists. The exclusion criteria were as follows: absence of ECG, rRT-PCR or CCT results, age below 18, transfer of the patient from ED or from hospitalized clinic to another facility, and lacking patient information.
A standard data form was prepared for the study. File number, age, gender, initial complaints, existing disorders (hypertension, diabetes mellitus, coronary artery disease, chronic obstructive pulmonary disease/asthma, chronic renal failure, history of cerebrovascular accident, malignancy), ECG findings (QTc interval, heart rate, heart rhythm, bundle branch block, axis deviation, negative T wave, ST elevation or depression, pathological Q wave), laboratory findings, CCT assessment (pneumonic infiltration, localization, number of involved lobe), clinical outcome (admission to a hospital ward, admission to the intensive care unit, death) and the 28-day all-cause mortality condition of the patients were recorded in these forms. Statistical Analysis
The data obtained were analyzed using the IBM SPSS Statistics version 21.0 software package (SPSS Inc., Chicago, IL, USA). The normality of the distribution of numeric data was evaluated with the Kolmogorov-Smirnov test. Numeric data without normal distribution, a comparison of which was made using the Mann-Whitney U test, were shown as the median and interquartile range (IQR 25-75). Normally distributed data were given as mean and standard deviation and were assessed with the independent samples Student’s t-test. Categorical variables were shown as number and percentage (%). Relations between categorical variables were analyzed using the chi-squared test and Fisher’s exact test. A p- value of <0.05 was considered statistically significant.
A total of 276 patients were included in the study. One hundred fifty (54.3%) patients were male and 126 (45.7%) were female. The mean age of the study group was 68 (60-79) years.
The most common initial complaints were shortness of breath (n=145; 52.5%), cough (n=124; 44.9%), fever (n=107; 38.8%) and tiredness (n=72; 26.1%). One hundred ninety-three (69.9%) patients had a history of comorbid diseases. The most frequent comorbidities were hypertension (n=125; 45.3%), coronary artery disease (n=83; 30.1%), diabetes mellitus (n=74; 26.8%) and chronic lung disease (n=64; 23.2%) (Table 1).
Thirty (10.9%) patients in the study lost their lives within 28 days. No statistically significant relation was observed between the 28-day all-cause mortality rate, and age, gender or symptoms at the time of ED visit. There was a statistically significant increase in the 28-day all-cause mortality rate in the presence of at least one comorbidity (p<0.001), hypertension (p<0.001), coronary artery disease (p<0.001), diabetes mellitus (p<0.001), chronic renal failure (p=0.03) and malignancy (p=0.001). The deceased patients had an elevated pulse and respiration rate, and reduced oxygen saturation compared to surviving patients (Table 1).
The median of QTc interval on study patients’ initial ECGs was 390 (360-428) ms. The inspection of the rhythm on the ECGs of patient revealed that while sinus rhythm was prevalent (n=152; 55.1%), sinus tachycardia (n=75; 27.2%), atrial fibrillation (n=25; 9.1%), supraventricular tachycardia (n=22; 8.0%) and ventricular tachycardia/fibrillation (n=2; 0.7%) were also present. Among the deceased patients, 40% had sinus tachycardia. Thirty-seven (13.4%) patients exhibited negative T waves, 9 (3.3%) had elevated/depressed ST segments and 8 (2.9%) had pathological Q waves. In the presence of QTc interval prolongation (p<0.001), ventricular tachycardia/fibrillation (p<0.001), left bundle branch block (p=0.001) and ST segment elevation/depression (p<0.001), 28-day all-cause mortality rate was significantly increased (Table 2).
Involvement consistent with COVID-19 was observed on CCT scans of 173 (62.7%) patients. Distribution of pulmonary infiltrates was mostly peripheral (n=165; 59.8%) or bilateral (n=113; 40.9%). The most frequent findings on CCT scans of the patients were ground-glass opacities (n=142; 51.4%) (Figure 1), consolidation (n=51; 18.5%), pleural fluid (n=47; 17.0%) and multifocal nodules (n=22; 8.0%). The increase in 28-day all-cause mortality rate was statistically significant in the presence of severe (four or five lobes) (p<0.001), peripheral (p<0.001) and bilateral (p<0.001) lung involvement, ground-glass opacities (p<0.001), consolidation (p<0.001), pleural fluid (p<0.001), and vascular enlargement (p<0.001) on patient CCT scans (Table 2).
Compared to surviving individuals, deceased patients had higher levels of aspartate transaminase (AST) (p=0.022), lactate dehydrogenase (LDH) (p=0.003), blood urea nitrogen (BUN) (p<0.001), creatinine (p=0.003), D-dimer (p<0.001), troponin T (p<0.001), C-reactive protein (CRP) (p<0.001) and ferritin (p=0.002), white blood cell (WBC) count (p=0.025), neutrophil count (p=0.009), and mean platelet volume (MPV) (p=0.033), whereas lower lymphocyte count (p<0.001) and hemoglobin levels (p=0.003). The most pronounced increases were in the levels of D-dimer, CRP and troponin T. Deceased patients had approximately 4.5-fold higher D-dimer levels, and approximately 5-fold higher CRP and troponin T levels compared to those in surviving patients (Table 3).
An assessment of clinical outcomes following ED visit revealed that 192 (69.6%) of the study patients were admitted to a hospital ward, 19 (6.9%) were admitted to the intensive care unit, 63 (22.8%) were discharged and 2 (0.7%) lost their lives. Among the 211 hospitalized patients, 183 (66.3%) were discharged and 28 (10.1%) died during their hospital stay (Table 3).
Determining disease severity, along with the COVID-19 diagnosis of patients visiting ED, is crucial for making the decision between discharge, admission to a ward and admission to the intensive care unit. Various studies have explored initial complaints, comorbidities, clinical findings, ECG findings, CCT imaging and laboratory results in order to distinguish high- riskCOVID-19patients.Inonesuchstudy,advancedage,high number of affected lung lobes, elevated CRP levels at the time of the visit, chest pain/shortness of breath and a history of smoking were identified as independent risk factors for fatality . Another study has found that age over 65, elevated cardiac troponin I levels, cerebrovascular disease and cardiovascular disease led to higher mortality rates. Among all the variables examined in the same study, a PaO2 value of ≥80 mmHg was the only factor linked with survival . Findings of another study have indicated a strong association between the mortality rate and the presence of hypoxemia necessitating oxygen support within three hours of presentation . In a study involving COVID-19 patients in severe condition, male gender, SpO2≤89%, respiratory rate of >30/min and a diastolic pressure of ≤80 mmHg, were found to be related to significantly higher mortality rates . In our study, 10.9% of the patients lost their lives within 28 days. There was no statistically significant difference between deceased and surviving patients in terms of age, gender or symptoms at the time of emergency department visit. Nonetheless, the 28-day all-cause mortality rate was significantly elevated in patients with at least one comorbid disease. Comparison of the initial vital signs of the study group noted at ED revealed that patients that died within 28 days had a higher pulse and respiratory rate, whereas oxygen saturation was lower than in surviving patients.
Patients may also develop cardiovascular complications associated with COVID-19. Fatal cardiovascular complications seen in such patients include acute myocardial infarction, myocarditis, dysrhythmia, heart failure, cardiomyopathy, cardiogenic shock and venous thromboembolism . Due to complications, ECG findings of these patients may include ST segment abnormalities, QT prolongation, conduction abnormalities and ventricular arrhythmias. Accordingly, patients that exhibit cardiac symptoms and ECG abnormalities should be carefully examined with regards to COVID-19 related cardiac complications . Patients with severe COVID-19 had a higher risk of arrhythmia complications . One study has shown that patients had higher mortality rates if their ECG findings included one or more atrial premature contractions, right bundle branch block or intraventricular block, ischemic T-wave inversion, and nonspecific repolarization. ST elevation has been found to be rare at the time of the initial hospital visit . Another study has reported the presence of sinus tachycardia and ventricular arrhythmia on the ECG as independent risk factors for fatality . Among our study group, 40% of the deceased patients had sinus tachycardia. The 28-day all-cause mortality rate was significantly elevated in the presence of QTc interval prolongation, ventricular tachycardia/fibrillation, left bundle branch block and ST segment elevation/depression. rRT-PCR testing has become a standard tool for the diagnosis of COVID-19. However, no difference has been observed in viral load between symptomatic and asymptomatic patients. The effectiveness of the rRT-PCR test for COVID-19 diagnosis at ED is limited due to its low positivity rate and long procedure time [12,13]. CCT imaging is a favorable diagnostic tool, as it is readily accessible, and yields fast and robust results. The typical radiological features of COVID-19 include bilateral, multifocal, and multilobar ground- glass opacification with patchy consolidation, a peripheral/subpleural or posterior distribution (or both), mainly in the lower lobes. The combination of CCT and repeated Reverse Transcription-Polymerase Chain Reaction (RT-PCR) testing may be beneficial for the diagnosis of COVID-19 in the setting of strong clinical suspicion . In a cohort of 1,014 patients with a 71% rRT-PCR positivity rate, 98% of the patients that tested positive exhibited CCT findings indicative of COVID-19 lung involvement (bilateral ground-glass opacities and consolidations distributed peripherally especially in lower lobes) . Another study has shown that 86% of the patients with positive rRT-PCR results had bilateral ground- glass opacities on their CCT scans . While early-stage patients’ CCT scans show small plaque shadows and interstitial changes, severe cases display multiple ground-glass opacities, infiltration and consolidation . Another study has reported that a higher number of involved lobes (5 involved lobes) within the first week of disease onset were associated with elevated mortality rates . In spite of its high sensitivity, CCT imaging may not be always useful for diagnosis or exclusion of COVID-19. Especially in asymptomatic patients, in those with mild symptoms and in those without pneumonia, CCT is not an effective diagnostic tool. Further disadvantages of CCT include high radiation emission, unavailability in smaller hospitals and requirement for radiologist interpretation [12,13,17]. In our study, CCT scans of 62.7% of the patients exhibited lung involvement concordant with COVID-19. The most common CCT findings were ground-glass opacities, consolidation, pleural fluid and multifocal nodules. Severe (4 or 5 lobes), peripheric and bilateral involvement of lobes, ground-glass opacities, consolidation, and vascular enlargement on CCT scans were associated with rise in 28-day all-cause mortality rates. Laboratory tests are nonspecific for the diagnosis of COVID-19. The most frequent laboratory findings in COVID-19 patients are normal/low lymphocyte count, coagulopathy, and increased levels of CRP, erythrocyte sedimentation rate, LDH, aminotransferase and ferritin. Conversely, procalcitonin levels are typically normal. Elevated levels of D-dimer, troponin I, ferritin, LDH and IL-6, as well as low basal lymphocyte count have been found to be related to worse prognosis [12,13,18- 20]. According to another study, a four-fold increase in D-dimer levels compared to the time of admission could be used as an effective predictor of in-hospital fatality . In agreement with the literature, our study showed that deceased patients had higher levels of AST, LDH, BUN, creatinine, D-dimer, troponin T, CRP, ferritin, WBC, neutrophil and MPV, and lower levels of lymphocyte and hemoglobin than those in surviving patients. The most significant increases were in the levels of D-dimer, CRP and troponin T. Compared to survivors, the deceased patients had 4.5-fold higher D-dimer levels, as well as 5-fold higher CRP and troponin T levels.
In conclusion, diagnosing and determining the severity of COVID-19 at ED can be achieved by evaluating vital signs, comorbidities, and findings of ECG, laboratory tests and CCT. At the time of ED visit, the presence of at least one comorbidity, high pulse and respiratory rate, reduced oxygen saturation, ECG findings of sinus tachycardia, QTc interval prolongation, ventricular tachycardia/fibrillation, left bundle branch block and ST segment elevation/depression, CCT findings of severe lung involvement (four or five lobes), peripheric/bilateral lobe involvement, ground-glass opacities, consolidation, pleural fluid and vascular enlargement, elevated levels of D-dimer, CRP and troponin T were associated with higher 28-day all-cause mortality rates.
Scientific Responsibility Statement
Animal and human rights statement
Conflict of interest
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Download attachments: 10.4328:ACAM.20574
Mehmet Oguzhan Ay, Nalan Kozaci, Ozlem Oymak Ay, Halil Kaya, Mehtap Bulut, Melih Yuksel, Ebru Adali, Enad Kenan, Ebru Cetin. QTc interval and electrocardiographic findings of COVID-19 patients. Ann Clin Anal Med 2021; 12(9):1031-1036
The evaluation of the newly defined CHA2DS2-VASc-HSF score in the severity of coronary artery disease and short-term prognosis
Sara Cetin Sanlialp 1, Gokay Nar 2
1 Department of Cardiology, Servergazi State Hospital, 2 Department of Cardiology, Faculty of Medicine, Pamukkale University, Denizli, Turkey
DOI: 10.4328/ACAM.20575 Received: 2021-03-08 Accepted: 2021-04-21 Published Online: 2021-05-03 Printed: 2021-09-01 Ann Clin Anal Med 2021;12(9):1037-1042
Corresponding Author: Sara Cetin Sanlialp, Servergazi State Hospital, Department of Cardiology, Bereketler No: 1, 20000, Merkezefendi, Denizli, Turkey. E-mail: email@example.com P: +90 5468574067 Corresponding Author ORCID ID: https://orcid.org/0000-0001-9328-9197
Aim: In this study, we aimed to evaluate the ability of the CHA2DS2-VASc-HSF score to predict short-term prognosis in acute coronary syndrome (ACS) patients.
Material and Methods: A total of 167 patients who underwent coronary angiography were included in this retrospective study. The patients were divided into two groups according to CHA2DS2-VASc-HSF: the low-score group (≤ 4 points) and the high score group (> 4 points). Primary and secondary endpoints were defined. CHA2DS2-VASc and GRACE scores were calculated, and the severity of coronary artery disease (CAD) was evaluated using SYNTAX I score (SSI).
Results: Patients in the high score group had increased CHA2DS2-VASc, GRACE scores and SSI. Also, in-hospital death and MACE within 30 days were more common in this group. There was a strong correlation between the CHA2DS2-VASc-HSF score and SSI (r=0.825, p<0.001). In the ROC analysis, CHA2DS2- VASc-HSF predicted in-hospital death and MACE within 30 days with cut off value 5.5 and 4.5, respectively (AUC= 0.803, p<0.001; AUC= 0.877, p<0.001). In multivariate binary logistic regression analysis, CHA2DS2-VASc-HSF, CHA2DS2-VASc, GRACE and age were independent predictors of short-term prognosis.
Discussion: We evaluated the role of the CHA2DS2-VASc-HSF score in CAD severity and short-prognosis, and we agree that this new score can be used to predict CAD severity and short-term prognosis in patients presenting with ACS.
Keywords: Cardiovascular disease; CHA2DS2-VASc-HSF Score; GRACE; Prognosis; SYNTAX I
Acute coronary syndrome (ACS) including unstable angina (UA), ST-elevation myocardial infarction (STEMI) and non-ST- elevation myocardial infarction (NSTEMI), is closely associated with morbidity and mortality . Early risk stratification in ACS may be useful in predicting prognosis or in determining appropriate therapy options. Various risk scores have been developed to identify patients who may need more aggressive treatment and who may be at high risk for major adverse cardiovascular events (MACE). For risk stratification, the Global Registry of Acute Coronary Events (GRACE) or thrombolysis in myocardial infarction (TIMI) are generally preferred in clinical practice [2,3].
CHADS2 and CHA2DS2-VASc are clinical scores used in evaluating the risk of cardiac thromboembolism and in the decision of antithrombotic therapy in patients with non- valvular atrial fibrillation (NVAF). Also, these scores include traditional cardiovascular risk factors predisposing to coronary artery disease (CAD) [4,5]. Several studies have shown that these scores may predict the severity of CAD, peripheral artery disease (PAD) and the adverse cardiovascular outcomes in CAD patients [6,7]. In addition, Cetin et al. reported that a newly defined CHA2DS2-VASc-HS score, such as CHADS2, CHA2DS2- VASc, may indicate the CAD severity . Recently, a new scoring has been developed by adding hyperlipidemia, smoking, family history and, male gender instead of the female gender to the CHA2DS2-VASc score and has been shown its association with CAD severity and complexity [9,10]. In addition, Kalyoncuoglu et al. showed that the performance of this score was successful in showing the long-term prognosis, similar to GRACE score, in NSTEMI patients . However, to our knowledge, no studies have been reported on the relationship between CHA2DS2- VASc-HSF score and short-term prognosis, including in-hospital death and MACE within 30 days. Thus, in this study, we aimed to evaluate the role of the CHA2DS2-VASc-HSF score in determining CAD severity and short-term prognosis in patients with ACS.
Material and Methods
In this retrospective observational study, medical records of 167 ACS patients who underwent coronary angiography with or without percutaneous coronary intervention (PCI) from January 2020 to July 2020 were analyzed using the hospital database. Malignancy, active infection, autoimmune disease, connective tissue disease, end-stage renal disease, coronary ectasia, myocardial bridging or vasospastic angina, severe liver disease and missing data in the analysis were determined as exclusion criteria. This study was approved by the Pamukkale University Faculty of Medicine Hospital Ethics Review Board in accordance with the Declaration of Helsinki, and all patients gave informed consent before enrolling in the study. (12/2020-24, protocol no: 10.150.1.90 /020-11760)
Data Analysis and Definitions
Each patient’s medical history, family pre-mature CAD history were reviewed. The physical examination, electrocardiographic findings, echocardiographic and laboratory data were analyzed. Medical history consisted of hypertension, diabetes, smoking history, chronic heart failure, stroke or transient ischemic attack (TIA), previous MI or CAD and PAD. The diagnosis of ACS was made in accordance with current clinical practice guidelines based on symptoms, electrocardiographic and imaging methods [12,13].
HT was defined as systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg or under medical treatment. Diabetes was defined as fasting blood glucose ≥126 mg/dL or blood glucose at any time ≥200 mg/dL or antidiabetic drug use. Hyperlipidemia was defined as increased LDL-C level or lipid- lowering drug use according to the recommendations of the National Cholesterol Education Program-3. Family history was defined as the presence of a diagnosis of CAD in the first degree relativeofapatientbeforeage65yearsinwomenand55years in men. The ischemic cerebrovascular event was defined as TIA or ischemic stroke. Vascular disease was defined as a history of revascularization or MI, amputation or angiographic evidence of PAD. Chronic heart failure (HF) was defined as verification of identified signs and symptoms of HF using objective evidence of cardiac dysfunction. Current smoking was defined as >10 cigarettes per day for at least 1 year without any cessation attempt.
Risk Scoring and the evaluation of CAD severity
The patients were evaluated in terms of GRACE, CHA2DS2-VASc and CHA2DS2-VASc-HSF scores. The GRACE score, consisting of age, heart rate, systolic blood pressure, creatinine level, Killip class, ST deviation, cardiac biomarker, and cardiac arrest was measured for each patient. The CHA2DS2-Vasc score was the sum of 1 point each for chronic HF, hypertension, diabetes, and vascular disease, 1 point for 65-74 years old, 2 points for >75 years old and prior stroke or TIA, and 1 point for the female gender. Compared to the CHA2DS2-VASc score, hyperlipidemia, smoking, family history of CAD and, male gender instead of female in the gender category were added to the newly defined CHA2DS2-VASc-HSF score, and these risk factors were scored as 1 point. Then the patients were divided into two groups as CHA2DS2-VASc-HSF score >4 points and score ≤4 points. Diagnostic angiogram views, previously recorded on digital media, were analyzed by experienced clinicians who were blind to the patients’ clinical and laboratory data. Significant CAD was defined as>50% narrowing of the lumen diameter in any of the main epicardial coronary arteries. CAD severity was evaluated using the SYNTAX I score (SSI). To calculate SSI, the online calculator (www.syntaxscore.com) was used for each lesion with ≥ 50% diameter stenosis in vessels ≥ 1.5 mm in diameter .
The primary endpoint of the study was in-hospital death and the secondary endpoint was MACE, including all-cause mortality, objective findings of coronary ischemia, recurrent MI, or unplanned revascularization in 30 days.
SPSS v.17.0 for Windows (SPSS, Inc., Chicago, Ill., USA) was used for data analysis. Qualitative variables were shown as percentages (numbers), and quantitative variables were presented as mean ± SD. The Kolmogorov-Smirnov test was used to determine the normal distribution. Variables were evaluated based on normality distribution using Student’s t-test or Mann-Whitney U test. Categorical variables were compared using the χ2 test. The relationship between the variables was analyzed using the Pearson or Spearman correlation. Receiver operating characteristic (ROC) curves were used to assess the sensitivity and specificity of the CHA2DS2-VASc-HSF score in predicting in-hospital mortality and MACE within 30 days. Multivariate binary logistic regression analysis was used to examine independent factors for clinical endpoints, and p<0.05 was considered statistically significant.
The study population consisted of 118 patients with low scores (≤ 4) and 49 patients with high scores (>4) according to the CHA2DS2-VASc-HSF scoring model. Baseline characteristics and the clinical data, including laboratory, echocardiographic and angiographic parameters of the patients are listed in Table 1. Patients in the high score group were older and involved a higher percentage of the male gender, compared with the patients in the low-score group (for all p<0.05). Hypertension, diabetes, dyslipidemia, smoking, a history of any vascular disease, stroke or TIA, and heart failure were more common in the patients with high scores (for all p<0.05). However, the type of ACS did not differ between the groups.
In laboratory parameters, patients with a high score showed significantly increased levels of fasting glucose, creatinine and hemoglobin, however there were no significant differences in lipid parameters and white blood cell counts between the groups. LVEF was significantly lower in patients with high scores (p=0.008).
The medians of CHA2DS2-VASc and CHA2DS2-VASc- HSF in the patients with low and high scores were 2 vs 4 and 3.5 vs 6, respectively (for all p<0.001). In addition, there was a significant difference in the GRACE scores in the groups (110 vs 151, p<0.001). Hospital deaths occurred in 2% of patients with low score and in 14% of patients with high score (p<0.001). MACE within 30 days occurred in 3% and 22% of the patients with low and high scores, respectively (p<0.001). In the ROC analysis, the cut-off value for in-hospital death was 5.5 with 88 % specificity and 66% sensitivity, and the cut-off value for MACE within 30 days was 4.5 with 83% specificity and 80% sensitivity (AUC = 0.803, p<0.001; AUC= 0.877, p<0.001) (Figure 1).
The CAD severity was evaluated using SSI, and SSI more increased in the patients with CHA2DS2-VASc-HSF>4 (20.24±12.38 vs 28.46±9.67, p<0.001). When the patients were divided into three groups according to SSI; CHA2DS2-VASc- HSF, CHA2DS2-VASc and GRACE scores differed between low and intermediate tertile and low and high tertile. However, all scores were similar between intermediate and high tertile (Table 2, Figure 2). In addition, there was a strong correlation between CHA2DS2-VASc-HSF and SSI (r= 0.825, p<0.001) (Figure 2). In a binary multivariate logistic regression analysis, CHA2DS2-VASc-HSF, CHA2DS2-VASc, GRACE, age were found to be independent predictors for primary and secondary clinical endpoints (for all p<0.05). However, SSI score and LVEF were only independent predictors for in-hospital death (Table 3)
The main findings of our study were as follows: (1) Patients with CHA2DS2-VASc-HSF score >4 had more common cardiovascular risk factors or a history of CVD. Also, LVEF was lower and CHA2DS2-VASc, GRACE scores were higher in this group; (2) CHA2DS2-VASc-HSF was strongly correlated with CAD severity identified by SSI; (3) Patients in the high CHA2DS2-VASc-HSF group showed a significant increase in in- hospital death and MACE within 30 days; (4) The cut-off values of CHA2DS2-VASc-HSF were 5.5 and 4.5 in hospital deaths and MACE within 30 days, respectively; (5) In a binary multivariate logistic regression analysis, CHA2DS2-VASc-HSF score was an independent predictor of in-hospital death and MACE within 30 days.
ACS may be fatal if undiagnosed early and is associated with a poor prognosis. Although coronary angiography is the gold standard to diagnose, unfortunately, the lack of angiography units in developing countries makes it difficult to access patients. Hence, easy-to-use and inexpensive assessment tools are needed in clinical practice to determine cardiovascular risk profiles in the patients and to modify risk factors [15,16]. The CHA2DS2-VASc score, which is used to stratify the risk for stroke in NVAF patients, includes risk factors that trigger atherosclerosis, such as hypertension, diabetes, and increasing age . Studies have reported that increased CHA2DS2- VASc score may indicate the severity of CAD and may be associated with acute stent thrombosis [17,18]. Recently, CHA2D2DS2-VASc-HS and CHA2D2DS2-VASc-HSF scores, including hyperlipidemia, smoking, female gender instead of male gender and family story have been developed for more reliable determination of the severity of CAD . In a study involving 2976 people in Northern India, CHADS2, CHA2DS2- VASc, CHA2DS2-VASc-HS and CHA2DS2-VASc-HSF scores were associated with increased GENSINI score and number of diseased vessels. In another study, there was a significant relationship between SSI with CHA2DS2-VASc and CHA2DS2- VASc-HSF in patients with STEMI [9,20]. In our study, patients with CHA2DS2VASc-HSF score>4 had a high SSI score and had a strong correlation with the severity of CAD as assessed by SSI similar to these studies. Especially, when patients were divided into three groups according to SSI, there was a remarkable difference in CHADS2-VASc and CHADS2-VASc-HSF among those with medium and high SSI and those with low SSI.
The prognostic value of CHA2DS2-VASc has been evaluated in several studies in patients with CAD. Rozenbaum et al. showed that the increase of CHA2DS2-VASc was associated with in -hospital death, MACE within 30 days and increased 1-year all-cause mortality . In another study, Bozbay et al. showed more in-hospital death occurred in patients with high CHA2DS2-VASc score, and CHA2DS2-VASc was an independent predictor of long-term cardiovascular mortality . To our knowledge, the relationship between the CHA2DS2-VASc-HSF score and the short-term prognosis has not been previously evaluated. Similar to these studies, increased CHA2DS2-VASc and CHA2DS2-VASc-HSF scores were associated with in- hospital mortality and MACE in the first 30 days in our study, and this relationship remained after multivariate regression analysis. Recently Kalyoncuoğlu et al. reported that in-hospital death, one-year mortality and one-year adverse cardiovascular outcomes were significantly higher in patients with a CHA2DS2-VASc-HSF score> 4 compared to low-risk patients in NSTEMI . In addition, the high-risk patients in this study showed an increased GRACE score similar to our study. But they emphasized that in-hospital mortality results were not certain due to the small number of patient deaths, and did not provide information about the first 30-days prognosis in this study. Moreover, they showed that one-year mortality and adverse cardiovascular events were higher in patients with high SSI.
Although we found that high SSI was an independent predictor for in-hospital death, a significant correlation was not observed between SSI and MACE within 30 days, unlike this study. The difference between the study results may be due to the type of ACS, the characteristics of the study population, the number of patients treated with PCI, the heterogeneity in aggressive treatment options, and duration of follow-up. However, in a study in which NSTEMI patients were evaluated with CHA2DS2- VASc-HS, demonstrating severe CAD and an increase of in- hospital mortality in patients with high scores supports our study .
There were several limitations in this study, such as a retrospective single-center design and a relatively small sample. However, the real-world unselected population was evaluated. Visual X-ray coronary angiogram was performed for SSI calculation based on luminal stenosis, and advanced imaging methods enabling a more detailed evaluation of CAD were not used. In addition, we aimed to investigate the short-term prognostic significance of the CHA2DS2-VASc-HSF score, so we could not determine its role on long-term clinical outcomes.
The CHA2DS2-VASc-HSF score was correlated with CAD severity and may be used to predict short-term prognosis. Using the CHAD2DS2VASc-HSF score, patients at high risk can be identified and more aggressive treatment strategies can be followed to reduce death and adverse cardiovascular events. In addition, multi-center prospective large-scale studies should be performed to clearly demonstrate the prognostic significance of the CHA2DS2-VASc-HSF score.
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9. Modi R, Patted SV, Halkati PC, Porwal S, Ambar S, Mr P, et al. CHA2 DS2 -VASc- HSF score-New predictor of severity of coronary artery disease in 2976 patients. Int J Cardiol. 2017;228:1002-6.
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12. Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, et al. ESC Scientific Document Group. 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J. 2016;37(3):267-331.
13. Steg G, James SK, Atar D, Badano LP, Blo ̈mstrom-Lundqvist C, Borger MA, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012;33(20):2569-619.
14. Sianos G, Morel MA, Kappetein AP, Morice MC, Colombo A, Dawkins K, et al. The SYNTAX Score: an angiographic tool grading the complexity of coronary artery disease. EuroIntervention. 2005;1(2):219-27.
15. Lloyd-Jones DM, Larson MG, Beiser A, Levy D. Lifetime risk of developing coronary heart disease. Lancet. 1999;353(9147):89-92.
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17. Bozbay M, Uyarel H, Cicek G, Oz A, Keskin M, Murat A, et al. CHA2DS2- VASc score predicts in-hospital and long-term clinical outcomes in patients with ST-segment elevation myocardial infarction who were undergoing primary percutaneous coronary intervention. Clin Appl Thromb Hemost. 2017;23(2):132- 8.
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Sara Cetin Sanlialp, Gokay Nar. The evaluation of the newly defined CHA2DS2- VASc-HSF score in the severity of coronary artery disease and short-term prognosis. Ann Clin Anal Med 2021;12(9):1037-1042
Can C-reactive protein-to-albumin ratio be a predictor of short-term mortality in community-acquired pneumonia?
Serdar Özdemir, Hatice Şeyma Akça, Abdullah Algın, Serkan Emre Eroğlu
Department of Emergency Medicine, University of Health Sciences Umraniye Training and Research Hospital, Istanbul, Turkey
DOI: 10.4328/ACAM.20576 Received: 2021-03-08 Accepted: 2021-05-06 Published Online: 2021-05-15 Printed: 2021-09-01 Ann Clin Anal Med 2021;12(9):1043-1048
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) 2673292 Corresponding Author ORCID ID: https://orcid.org/0000-0002-6186-6110
Aim: This study aimed to investigate the predictive ability of the C-reactive protein (CRP)-to-albumin ratio for short-term mortality in patients presenting to the emergency department with community-acquired pneumonia.
Material and Methods: This retrospective study was conducted with patients admitted to our clinic with community-acquired pneumonia diagnosed based on computed tomography findings and clinical findings between March 2018 and February 2020. Baseline characteristics, comorbid diseases, laboratory findings, CRP and albumin concentrations and their ratios, clinical outcomes for the first 24 hours, and 30-day all-cause mortality data were recorded. The relationship between the CRP-to-albumin ratio and short-term mortality was evaluated.
Results: A total of 958 patients with community-acquired pneumonia were included in the study for analyses. The rates of outpatient treatment, need for hospitalization in other hospital services, need for intensive care, death in the emergency department and 30-day mortality were 33.4%, 35.3%, 30.2%, 1.1% and 30.1%, respectively. Significant differences were observed in albumin, CRP, CRP-to-albumin ratio, and neutrophil-to-lymphocyte ratio (NLR) between the non-survivor and survivor groups (p<0.001 for all). The cut-off value for the CRP-to-albumin ratio was 2.72 (sensitivity: 62.5%, specificity: 59.55%), area under the curve (AUC) was 0.651 (95% confidence interval 0,613 – 0,688). The AUC of the CRP-to-albumin ratio was similar to that of NLR (p=0.534).
Discussion: The CRP-to-albumin ratio can be useful in determining the short-term mortality from community-acquired pneumonia in patients presenting to the emergency department.
Keywords: C-reactive Proteins; Albumins; Prognosis; Community-Acquired Pneumonia; Pneumonia
Acute infections, especially community-acquired pneumonia (CAP), are the most common cause of hospitalization, morbidity, and mortality. In patients hospitalized with CAP, the 30-day mortality rate is 7.3-13.3% . Scoring systems, such as SMART-COP, SCAP, ATS 2001, ATS/IDSA 2007, PSI, CURB, CRB-65, and CURB-65 are used to predict mortality and severe complications in hospital admissions due to CAP [2-4]. Similarly, various biomarkers, such as procalcitonin, cytokines, pro- vasopressin, pro-adrenomedullin, and C-reactive protein (CRP) are used for diagnostic and prognostic purposes in CAP. Among these, CRP and procalcitonin are the most frequently studied biomarkers [5-8].
CRP is an acute-phase protein used as a prognostic and follow- up test in patients with infection. Studies have concluded that CRP is useful for the diagnosis and follow-up of CAP [9-11]. Albumin is an acute-phase protein, and hypoalbuminemia correlates with the inflammatory response in patients with infection [12, 13]. Recent studies have shown that the CRP-to- albumin ratio predicts mortality in critically ill patients or those with malignancies, infection or sepsis that require intensive care [14-19]. In light of this knowledge, we speculated that the CRP-to-albumin ratio could predict mortality in the emergency department (ED) in patients with CAP. This study aimed to investigate the predictive ability of this ratio for short-term mortality in patients presenting to ED with CAP.
Material and Methods
This study was designed retrospectively and conducted at University of Health Sciences Umraniye Training and Research Hospital, a tertiary academic healthcare center with an annual ED visits of 438,000 patients and a capacity of 672 beds. We retrospectively recorded data of the patients admitted to the ED with CAP between March 2018 and February 2020.
The study population consisted of patients presenting to our ED with CAP, diagnosed based on radiographic and clinical findings between March 2018 and February 2020. Computed tomography (CT) was used for radiological evaluation. Chest CT images, demonstrating new infiltrates consistent with a diagnosis of pneumonia were assessed by a radiologist. The patients had acute-onset clinical symptoms suggestive of pneumonia. Eligible patients with the diagnosis of CAP who were hospitalized or treated in the outpatient setting were included. If clinic or intensive care beds were unavailable, the patients requiring hospitalization were transferred to another hospital or held in the ED until a bed became available. Patients younger than 18 years, those with no data of CRP or albumin levels within the first 24 hours of ED admission, those discharged from the hospital within 10 days, those using immunosuppressive agents, chronically immunosuppressed patients, and cases with a history of pneumonia within the past 30 days were excluded.
The data extracted from the computer-based system of our hospital included baseline characteristics, comorbid diseases, laboratory findings, CRP and albumin concentrations and
their ratio, and clinical outcomes for the first 24 hours. Comorbid diseases were recorded as congestive heart failure, cerebrovascular disease, history of malignancy, chronic kidney disease, and chronic liver disease. Clinical outcomes within the first 24 hours of ED admission were recorded as discharge, need for hospitalization in other hospital services, need for intensive care, and death in the ED. Initial laboratory data analyzed within the first 24 hours of ED visit consisted of hematocrit, hemoglobin, platelet count, neutrophil count, lymphocyte count, white blood cell count, CRP, albumin, sodium, serum creatinine, blood urea nitrogen, lactate and glucose levels. The CRP-to-albumin ratio, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) were calculated. A 30-day all-cause mortality of the patients was also noted.
The primary outcome of this study was short-term mortality after ED admission. The secondary outcomes were the need for hospitalization in other hospital services or intensive care units (ICU), vasopressor requirement in ED, and mechanical ventilation use in ED.
IBM SPSS Statistics for Mac, Version 27.0. Armonk, NY, IBM Corp was used to perform statistical analyses. The Kolmogorov-Smirnov test was conducted for the evaluation of the conformance of variables to a normal distribution. The data that matched a normal distribution were presented with mean and standard deviation and values, and the remaining data were expressed as interquartile range and median values. Categorical data were presented with the number of cases and percentages. For the comparison of quantitative and qualitative data between two groups, the chi-square and Mann-Whitney U tests were used. We also formed a receiver-operating characteristic curve (ROC) for 30-day mortality and obtained the area under the curve (AUC) for individual variables. The AUC values of the parameters were calculated and tested mutually for significance with the DeLong equality test. A p- value lower than 0.05 was considered statistically significant in all analyses. Ethics
Ethical approval for the study was obtained from the Ethics Committee of Clinical Research of Umraniye Training and Research Hospital with the approval number B.10.1. TKH.4.34. H.GP.0.01/73. We retrospectively reviewed the data extracted from the computer-based hospital information management system. The extracted data were solely clinical, and did not include any personal, identifiable information. Therefore, the need for informed consent was waived.
A total of 845,050 patients presented to ED during the study period, and 1,202 were diagnosed with pneumonia. We excluded 153 patients because they were younger than 18 years or had no data of CRP or albumin levels measured within the first 24 hours of ED admission. Next 91 patients were excluded since they were discharged within 10 days of hospitalization, had a history of pneumonia within the past 30 days, used immunosuppressive agents, or were chronically immunosuppressed. Therefore, for the final analysis, 958 patients were included. The flowchart of the study is presented in Figure 1.
The median age and interquartile range of the patients was 76 (66 – 83) years, and 491 patients (51.3%) were male. A total of 288 patients died within 30 days of ED admission. The rates of discharge, hospitalization in other hospital services, requirement of intensive care, death in ED, and 30- day mortality were 33.4%, 35.3%, 30.2%, 1.1% and 30.1%, respectively. The patient characteristics according to age and gender, comorbidities, and laboratory findings, including the CRP-to-albumin ratio, NLR, and PLR are shown in Table 1.
Laboratory values and Outcomes
The comparisons of the demographic characteristics of the non- survivor and survivor groups are shown in Table 1. Significant differences were observed between the non-survivor and survivor groups in terms of age [75 (64–82) versus 78 (69.5- 85) years, p = 0.009], clinical outcome within the first 24 hours, albumin levels [3.59 (3.13–3.90) versus 2.94 (2.60 – 3.35) g/dL], CRP levels [6.95 (2.40–13.80) versus 10.35 (5.00-17.50) mg/L], neutrophil count [8.60 (6.07–12.53) versus 10.36 (6.96–14.62)], lymphocyte count [1.31 (0.86–1.93) versus 1.04 (0.69-1.67)], NLR [6.95 (4.11–12.56) versus 8.98 (5.18–16.06)], PLR [186.27 (122.76–292.21) versus 211.19 (117.28-368.44)] (p < 0.001 for all). The CRP-to-albumin ratio was significantly lower in the survivor patient group than in the non-survivor group [3.64 (1.61-6.80) versus 2.00 (0.63–4.33), p < 0.001] (Table 1).
The results of the ROC curve analysis for the prediction of 30- day all-cause mortality after ED admission are shown in Figure 2. The cut-off and AUC (95% confidence interval) values of CRP, albumin, CRP-to-albumin ratio, and NLR are given in Figure 2 and Table 3. The cut-off value of the CRP-to-albumin ratio was 2.72 (sensitivity: 62.5%, specificity: 59.55%), and the AUC value was 0.651 (95% confidence interval 0.613–0.688). The AUC value of the CRP-to-albumin ratio was significantly higher than that of CRP and NLR (DeLong equality test, p < 0.001 and p = 0.003, respectively).
Data on hospitalization requirements according to age and gender are presented in Table 3. The ROC curve analysis for the prediction of the requirement for hospitalization revealed that the AUC was 0.640 (0.603-0.677) for the CRP-to-albumin ratio, 0.626 (0.589-0.663) for NLR, and 0.569 (0.532-0.607) for PLR. The AUC value of the CRP-to-albumin ratio was similar to that of NLR (p = 0.534), but significantly higher compared to the PLR (p = 0.004).
Significant differences were observed between the hospitalized and outpatient groups in terms of CRP [9.25 (3.70–15.80) versus 5.60 (1.70–11.85) mg/L, p < 0.001], and CRP-to-albumin ratio [3.00 (1.08–3.54) versus 1.60 (0.46–3.55), p < 0.001].
There were significant differences between the mechanically ventilated in ED and not-mechanically ventilated in ED groups in terms of CRP [10.10 (5.60–15.80) versus 7.50 (2.60–14.60) mg/L, p = 0.001], and CRP-to-albumin ratio [3.43 (1.54–6.07) versus 2.23 (0.73–4.80), p < 0.001]. Significant differences were detected between the vasopressor used and not used in ED groups in terms of CRP [11.50 (6.40–18.00) versus 7.50 (2.60–14.40) mg/L, p < 0.001], and CRP-to-albumin ratio [3.93 (2.15–6.37) versus 2.22 (0.70–4.75), p < 0.001].
The results of this retrospective study with 958 patients showed that the CRP-to-albumin ratio was associated with short- term mortality, which was especially remarkable in patients with a CRP-to-albumin ratio greater than 2.72. Moreover, the CRP-to-albumin ratio had a higher AUC value than CRP in predicting short-term mortality in patients with CAP. The rates of requirement for hospitalization, hospitalization in other hospital services or ICU, vasopressor requirement in ED, and mechanical ventilation use in ED were also affected by the CRP- to-albumin ratio.
Several studies have investigated the prognostic importance of the CRP-to-albumin ratio in septic or critically ill patients, and most were based on the data of hospitalized patients [15,17- 19]. In light of the current literature, our study is the first to demonstrate the relationship between short-term mortality and the CRP-to-albumin ratio in patients with CAP. Another difference of our study from previous studies is that it revealed the differences between the inpatients and outpatients with CAP in terms of the CRP-to-albumin ratio.
CRP expression increases during inflammatory conditions, some cardiovascular diseases, and infection [13-15]. Chalmers et al. and Lee et al. showed that the CRP could predict the severity of CAP at the time of hospital admission in their prospective studies with 570 and 424 patients, respectively [20,21]. In contrast, in a study conducted with a total of 391 patients with a median age of 80 years, Thiem et al. reported that CRP could not predict mortality in patients with CAP . In our study, similar to Chalmers et al. and Lee et al., we determined that the CPR levels were associated with mortality, requirement of hospitalization, mechanical ventilation use, and vasopressor requirement in patients with CAP.
The CRP-to-albumin ratio has been studied as a biological prognostic marker in critically ill patients, as well as those with septic shock, severe sepsis, and other diseases [14-19]. Park et al. showed that the CRP-to-albumin ratio could be a predictor of prognosis in critically ill patients . In that study, the cut-off value for the CRP-to-albumin ratio in predicting 28 day-mortality after ICU admission was reported to be 34.3 in critically ill patients, and the AUC for this ratio was significantly higher than that of CRP (0.594 versus 0.567, p < 0.001) . In a study evaluating patients with septic shock or severe sepsis treated with early gold-directed therapy, the cut-off value for the CRP-to-albumin ratio for the prediction of 180-day all- cause mortality after ICU admission was 5.09, and the AUC of this ratio was significantly higher than that of CRP (0.621 versus 0.562, p < 0.001) . In another study, Ranzani et al. suggested that the CRP-to-albumin ratio could be used as a long-term prognostic indicator instead of standard CRP values alone . Oh et al. showed that the CRP-to-albumin ratio could predict 30-day and 1-year mortality in patients admitted to ICU postoperatively . In the same study, the cut-off value for the CRP-to-albumin ratio was 1,75 and 1,58 for the prediction of 30-day and 1-year mortality, respectively. In the current study, the CRP-to-albumin ratio had greater precision than CRP alone in the prediction of 30-day mortality among the patients that presented to our ED with CAP. Our results are consistent with those of previous studies.
Kaya et al. reported that the NLR of patients with CAP was significantly higher among those receiving inpatient care than those requiring intensive care . In a study conducted with pediatric patients, Kartal et al. showed that the mean NLR and PLR levels of the patients with CAP were significantly higher than in the control group, but there was no statistically significant difference between the inpatient and outpatient groups . In our study, the NLR and CRP-to-albumin ratio levels of the patients with CAP were significantly lower in the outpatient group than in the inpatient group, and the CRP-to- albumin ratio had greater accuracy than NLR in predicting the requirement of hospitalization.
The main limitation of our study was its retrospective nature. Secondly, we could not include patients with CAP who were not tested for CRP and albumin. Lastly, our study had a single- center observational design, and therefore the results cannot be generalized to other healthcare institutions.
In this study, we concluded that the CRP-to-albumin ratio was associated with short-term mortality, requirement of hospitalization, vasopressor requirement in ED, and mechanical ventilation use in ED in patients with CAP. In these patients, the predictive power of the CRP-to-albumin ratio for short-term mortality after ED admission was higher than that of CRP alone.
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Conflict of interest
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Serdar Özdemir, Hatice Şeyma Akça, Abdullah Algın, Serkan Emre Eroğlu. Can C-reactive protein-to-albumin ratio be a predictor of short-term mortality in community-acquired pneumonia? Ann Clin Anal Med 2021;12(9):1043-1048
Quality of life of families and mothers of children with cerebral palsy, with or without epilepsy
Hamza Sucuoglu 1, 2
1 Istanbul Gelisim University, School of Health Sciences, 2 Physical Medicine and Rehabilitation, Private Nisa Hospital, Istanbul, Turkey
DOI: 10.4328/ACAM.20585 Received: 2021-03-13 Accepted: 2021-04-28 Published Online: 2021-05-08 Printed: 2021-09-01 Ann Clin Anal Med 2021;12(9):1049-1054
Corresponding Author: Hamza Sucuoglu, Istanbul Gelisim University, School of Health Sciences, Cihangir quarter Şehit Jandarma Komando Er Hakan Öner Street. No:1, Postcode:34310, Avcılar, Istanbul, Turkey. E-mail: email@example.com P: +90 5056297688 F: +902124227401 Corresponding Author ORCID ID: https://orcid.org/0000-0002-8539-1834
Aim: The effects of the presence of epilepsy in Cerebral palsy (CP) on the quality of life (QOL) of mothers and their families are not clear. In this regard, our study aimed to evaluate the effects of the presence of epilepsy in CP on the QOL of mothers and families.
Material and Methods: The study was conducted with 61 mothers whose children had CP, and 25 mothers with healthy children as the control group. Mothers whose children had CP were divided into two groups: children with epilepsy (n = 22) and children without epilepsy (n = 39). All mothers assessed their QOL using the Short Form-36 (SF-36) questionnaire, and their family life qualities were assessed with the Beach Center Family Quality of Life (BC-FQOL) scale.
Results: Despite the fact that mothers of children with CP had the lowest scores on the SF-36 for the physical component summary (PCS) and for the mental component summary (MCS) scores compared with the epilepsy group, there was no significant difference between the groups (p> 0.05). In the BC-FQOL, emotional well-being and disability-related support scores were significantly lower in the epilepsy group (p <0.05).
Discussion: Mothers of epileptic children with CP have a worse QOL tendency in both physical and mental health, but there is no significant difference com- pared to the other mothers.
Keywords: Cerebral palsy; Rehabilitation; Epilepsy; Quality of life; Family; Mother
Cerebral palsy (CP) is a non-progressive persistent movement and postural disorder that occurs as a result of the development of static lesion in the central nervous system (CNS) . Functional inadequacies due to the clinical problems in children with CP can negatively affect children with CP and their families. The nature of this disease and the accompanying conditions affecting the quality of life (QOL), and the QOL of the mother and the family, as well as child, have been the subject of research in recent years .
A child with CP can be perceived as a big disappointment in the family, may be considered as a reason why the family suffers more, and can increase anxiety levels of parents. This greatly affects the psychological, social, economic and cultural life of the family [3,4]. It has been suggested that stress associated with coping with chronic illnesses is a primary risk factor for the development of psychosocial problems for both the affected child and the family . The influence of CP on the daily life of the family and caregiver depends on various factors, such as the type and severity of CP, the presence of additional clinical problems such as epilepsy, the level of family and community support, family economic structure, socio-cultural level, and the educational status [2,5].
CP is not a specific disease, but a collection of symptoms. In addition to behavioral and cognitive problems, as well as motor dysfunction in CP, epilepsy accompanies this disease [5,6]. The prevalence of epilepsy reported in patients with CP is between 15% and 55%, and it is critical for the identification of child and family needs in terms of health . Epilepsy has serious effects on the child’s health status and the QOL and it also has negative effects on families and parents . The physical and psychosocial burden of the illness on families and mothers as primary caregivers who have to look after their disabled children all day and for many years can negatively affect the QOL . It is also considered that by addressing the problems that will arise, effective solutions can be produced, and parents can have more comprehensive care with their children. This will help set the right rehabilitation goals for these patients. In the treatment of children with CP, the concept of family-based care has become the recent trend, and the positive caregiver role and interest can improve the QOL of the child. Thus, the psychosocial consequences for these children and their families can be more positively affected .
In this study, we aim to determine the likely effects of epilepsy in children with CP on the life quality of the mother and family and how psychological, economic, social and cultural situation of the child, the mother and the family will be affected.
Material and Methods
Setting and Participants
This study was conducted between September 2016 and October 2017 at the Private Aktif Medicine Central Physical Therapy and Rehabilitation clinic. The study was initiated following the approval of Istanbul University Cerrahpaşa Faculty of Medicine, Clinical Research Ethics Committee (number: 83045809/604.01/02-280029, date: 04.09.2015).
A prospective study was conducted with three groups (CP with epilepsy, CP without epilepsy, and a healthy control group) of children between the ages of 2 and 18, as well as mothers and a control group of mothers with healthy children. According to the GMFCS, which can express fear or discomfort, non-disabled literate mothers of children of all levels and all types of CP were included in the study. The exclusion criteria in the study were as follows: significant changes in the social, health or economic conditions of the family or of mother during the last three months (which may have changed the perception of QOL); the primary caregiver of a child with CP is someone other than the mother; mother and father are separated; a child with CP does not live with the family; a child with CP or a mother has aggressive or self-harmful behavior; a mother being pregnant, diagnosed with severe psychiatric disorder or chronic systemic disease, or a mother having a disability.
Evaluation and Outcome Measures
The clinical and demographic characteristics (gender, age, age at diagnosis, previous and current treatments (antiepileptic or antispastic medications and botulinum toxin-A injection), history of operations (orthopedic musculoskeletal surgery), and the etiology of CP (premature, intrauterine hypoxia, asphyxia, postnatal hemorrhage, meningitis or the other postnatal factors and idiopathic) of all CP cases were questioned.
Gross motor function classification system (GMFCS) , and Manual Ability Classification System (MACS) , staging of patients with CP were performed. These measures and classifications are tools that assess the severity of movement disorders in children with CP and allow measurement of their skills and limitations. The GMFCS level sets lower extremity walking functions and the MACS level sets the hand skill levels between I and V.
36-item Short Form Health Survey
The mother’s QOL was assessed using the 36-item Short Form Health Survey (SF-36). The SF-36 physical component summary (PCS) and mental component summary (MCS) subscales were calculated. The SF-36 is a short but comprehensive, easily applicable and widely used QOL scale with validity and reliability . Scores between 0 and 100 were obtained on the subscales, and higher scores indicate better QOL.
Beach Center Family Quality of Life
The QOL of the family was assessed by the Beach Center Family Quality of Life (BC-FQOL) scale. The BC-FQOL, which was completed by Mothers was developed in 2006 by the University of Kansas . It is a measurement implemented to determine the QOL of developmentally impaired children with validity and reliability in Turkish . BC-FQOL is the data collection tool consisting of quintile rating type answers of 25 questions; Five sub-domains (Family Interaction (FI), Parenting (P), Emotional Well-being (EW-b), Physical/Material Well-being (P/MW-b), Disability-Related Support (D-RS)). The highest score on the entire BC-FQOL scale is 125 (25×5) and the lowest score is 25 (25×1). High scores on the scale with no negative substance indicate a high level of family life quality perception. The family life quality perception can be calculated according to the total scores from the scale, as well as dividing the total score obtained by the number of items. In this study, the five sub-area scales and the total score were evaluated based on the ratio divided by the number of items (Total ratio = TR). Disability-Related Support (D-RS) was not calculated since the control group did not have a child with developmental disability and the total ratio (TR) value calculation in this group was determined by dividing the total score by 21.
Basic statistical analyses were performed using the SPSS software (ver. 22.0; SPSS, Inc., Chicago, IL). The normality of the data was assessed using the Shapiro–Wilk test. The statistical analysis of our data was performed using a parametric test (independent samples test and one-way ANOVA). The non- parametric Mann–Whitney U-test was used since the variables were not normally distributed. Categorical variables were evaluated using the Chi- Square test. The post hoc analysis test used in the one-way ANOVA was the Bonferroni test. For all the analyses, P-values of <0.05 were considered statistically significant. The total sample size, effect size (f=0.34), and actual power (0.80) of the study were calculated using the G power statistic program (Heinrich-Heine-University. Dusseldorf, Germany).
Among the 110 individuals evaluated for the study, 85 were mothers of patients with CP, and 25 were mothers with healthy children, which constituted the control group. The study was completed with 86 individuals and analyzed in three groups. There were 39 mothers in the “without epilepsy” group, 22 mothers in the “with epilepsy” group, and 25 mothers in the control group (Figure 1).
The mean age of the patients with CP (mean ± SD) was 7.39 ± 4.16 (years), and the age of diagnosis (mean ± SD) was 15.34 ± 12.45 months. There was no significant difference between the groups (p> 0.05). There were significant differences between the groups in terms of etiology, medication history, CP type, MACS and GMFCS levels (p<0.05). These differences showed changes in the groups of “with” or “without epilepsy”. Сlinical and demographic characteristics of children with CP are displayed in detail in Table 1.
The mean age of the mothers in the control group, without epilepsy and with epilepsy groups were (mean ± SD) 36.36 ± 6.81, 33.72 ± 6.97, and 36.27 ± 5.68 years, respectively. There was no significant difference between the groups (p> 0.05). The level of education of 53 (61.6%) of the mothers was primary school and 60 (69.7%) of them were housewives (Table 2). Although the SF-36 PCS and SF-36 MCS scores were highest in the control group and lowest in the epilepsy group, there was no significant difference between the groups (p> 0.05) (Figure 2). When the BC-FQOL subscales, evaluating the QOL of the families were examined, the Emotional Well-being scores (EW- b) were the lowest in the epilepsy group, and children who had CP with epilepsy had significantly lower emotional competence than the control group (p = 0.001). With regard to the Disability- Related Support (D-RS) scores, the “with epilepsy” group had the lowest score and it was significantly different from families with children who had CP without epilepsy (p = 0.045). In the other BC-FQOL subscales, there was no significant difference between the groups (p> 0.05) (Figure 2).
The families lived in the same neighborhood with low socioeconomic status. Among the factors that could affect the FQOL: the socioeconomic status of the families and the age and profession of the mother possessed similar features between the age and genders of children groups with CP (Table 1, 2).
The present functional deficits and cognitive problems of children with CP can create an important physical and psychological burden for the family, especially for the caregiver mother [3,4]. This situation has negative effects on the QOL, which is a subjective concept and assesses one’s life problems according to their own perceptions [6,14]. This effect can be seen in the QOL of the patient, the mother and the family [2,5]. In the literature, studies investigating the QOL of CP or epileptic children and their mothers and the factors affecting them (such as motor function levels) are frequently encountered [5,14]. In addition, studies examining the family life qualities of this group are also seen, but less frequently [2,15,16]. However, no study has been found in the literature on combined work to evaluate the effects of the presence of epilepsy in children with CP on the QOL of mothers and families. Studies in the literature have reported that childhood epilepsy has serious effects on the QOL and psychological health of parents and that the control of epileptic seizures is associated with an improvement in parental QOL . In a review by Puka et al. it was reported that childhood epilepsy disrupted the QOL of the parents, that the family environment and child/parent health had two-way interactions in epilepsy, and that family interventions should be aimed for the treatment . For this reason, our study is important in terms of examining the interactions of the QOL of mothers and their families with children with both epilepsy and CP.
In another study, after 10 years of follow-up of epileptic children, Puka et al. evaluated their mothers’ QOL in the SF-36 mental and physical health sub-headings . It was observed that these mothers had similar mental health subscale scores compared to the normal population, and had better scores on physical health subscale scores. It is argued that a mother who has to look after a physically disabled child throughout the day is more likely to have psychiatric and physical health problems.  In a study by Mobarak et al., 41.8% of mothers of children with CP were found to have a risk of psychiatric morbidity . In a study where they evaluated the quality of life of 424 mothers with children with CP, Dehghan et al. determined the PCS and MCS scores of 39.21 and 41.23, respectively . This indicated that the mothers had low level of QOL. For this reason, QOL has been of particular concern for mothers with children who have CP, and rehabilitation specialists have suggested that strategies should be developed to support the QOL of the mothers. In the recent study, the QOL of mothers was assessed with SF-36 MCS and PCS, and general maternal QOLs were found to be low, similar to the scores in the study conducted by Dehghan et al. There was no significant difference in the QOL between mothers of children with CP without epilepsy and mothers of children with CP with epilepsy . However, it was observed that mothers of children with CP with epilepsy had a worse QOL tendency in both physical and mental health domains. A similar situation was observed in the study by Terra et al., and the low QOL in mothers of children with CP with epilepsy was not significant compared to the group without epilepsy and the control groups .
The QOL of a child with a disability is affected by the QOL of the family as well as that of the caregiver . These children bring a burden to the family, both in terms of health and economics . In order to determine the needs of the child with CP, the whole family should be included in the education, treatment planning and implementation processes . Working together with family members on this issue can better meet the needs of children with disabilities . In this respect, the recognition of the characteristics of the family that are important in families with children with disabilities further improved the FQOL concept .
Although FQOL data have been studied in many cohorts, the literature specifically examining the effects of CP characteristics on children with FQOL is limited, and the results show differences [14,24].
Magill-Evans et al. reported that families with young adolescents with CP and families with an adolescent without any disabilities had more similarities than differences in terms of QOL . They stated that the child with CP may be a challenge for the parents, but the conclusion of the study emphasized that the existence of a disabled family member may not always reduce the QOL. Dobhal et al. reported that the QOL was severely affected in three-quarters of 100 children with CP and their families . They stated that QOL’s physical independence, mobility and social integration dimensions were affected more than the clinical burden, economic burden and schooling dimensions. They also commented on the more significant presence of low QOL in patients with quadriplegic CPs and their families, explaining that comorbidities such as epilepsy were more common in this group . Davis and Gavidia-Payne reported that FQOL satisfaction and disability severity were not associated with children with disabilities, but said that FQOL was positively associated with the family income, caregiver training, family support and good family-centered service . In the recent study, children with epileptic CP generally tended to have a lower FQOL. In this group, emotional well-being and disability related support scores were significantly lower. There was no difference in the FQOL scores of family interaction, parenting, physical/material well-being, and total rate between children with CP with or without epilepsy.
Emotional well-being refers to the presence of individuals and institutions through which individuals can talk and share personal problems and special issues . The observation of a low perception of emotional competence can be attributed to the lack of families with adequate emotional support . In the recent study, this may be due to the fact that if a child with CP also has epilepsy, mothers think that they are not receiving the psychological and emotional support they expect from other family members or social circles, and that they cannot spare time for themselves.
Disability-related support is the support that a disabled individual needs to achieve his/her goals in an environment such as home, school, work-place or therapy center . The low level of disability-related support in the group with epileptic CP shows that mothers consider the presence of epilepsy in their children with CP as the reason why their children are not sufficiently supported to achieve their goals in such environments.
Several possible limitations should be considered when interpreting the results of this study. The main limitation is that the number of studies on the subject is small, and clinical populations have similar socio-economic characteristics living in the same region. For this reason, the results may not reflect the findings of mothers of children with CP and their families in the country as a whole, since they only represent the population participating in the study.
Another limitation is that it is not known what the status of the families’ living quarters is before the child has CP, because the study is a time-limited cross-sectional study. However, despite all these limitations, the results between the groups were comparable due to the presence of a healthy control group in the study and the similarity in the socio-demographic data of the study population.
CP has a negative impact on the QOL of the child, mother and family. The effects of the presence of epilepsy in CP on the QOL of mothers and their families are not clear. In this study, it was observed that mothers of children with epileptic CP had a worse QOL tendency in both mental and physical health, but there was no significant difference between them and other mothers. The FQOL perception of mothers tended to be lower in families with epileptic CP, and emotional well-being and disability-related support levels were found to be significantly worse than in other families.
As a result, the mother as the primary caregiver and the family as the main support center should indispensably have a good QOL, so that the needs of the CP child, with or without epilepsy, can be fulfilled and treatment is effective and sustainable.
We thank physiotherapists Nihat Bakırcı, Zeynep Zengin, Özge Büyükdoğan and Çağkan Çağlar who contributed to the evaluation of patients. We thank Dr. Murat Uludağ for his consultative role.
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Conflict of interest
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9. Hanna SE, Bartlett DJ, Rivard LM, Russell DJ. Reference curves for the Gross Motor Function Measure: percentiles for clinical description and tracking over time among children with cerebral palsy. Phys Ther. 2008;88:596-607.
10. Eliasson AC, Krumlinde Sundholm L, Rösblad B, Beckung E, Arner M, et al. The Manual Ability Classification System (MACS) for children with cerebral palsy: scale development and evidence of validity and reliability. Dev Med Child Neurol. 2006;48(7):549-54.
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Hamza Sucuoglu. Quality of life of families and mothers of children with cerebral palsy, with or without epilepsy. Ann Clin Anal Med 2021;12(9):1049-1054
Transdiscal screw fixation in L5-S1 spondylolysis: A biomechanical study
Murat Aydin 1, Tugrul Bulut 2, Mustafa Guden 3, Nuri Erel 4
1 Department of Neurosurgery, Hand and Microsurgery, Orthopaedics and Traumatology (EMOT) Hospital, 2 Department of Orthopaedics and Traumatology, Izmir Katip Celebi University, Ataturk Training and Research Hospital, 3 Department of Mechanical Engineering, Izmir Institute of Technology, 4 Department of Orthopaedics and Traumatology, Hand and Microsurgery, Orthopaedics and Traumatology (EMOT) Hospital, Izmir, Turkey
DOI: 10.4328/ACAM.20586 Received: 2021-03-14 Accepted: 2021-05-08 Published Online: 2021-05-24 Printed: 2021-09-01 Ann Clin Anal Med 2021;12(9):1055-1057
Corresponding Author: Tugrul Bulut, Izmir Katip Celebi University, Ataturk Training and Research Hospital, Department of Orthopaedics and Traumatology, Basin Sitesi, 35360 Izmir/Turkey. E-mail: firstname.lastname@example.org P: +90 505 259 56 94 F: +90 232 243 15 30 Corresponding Author ORCID ID: https://orcid.org/0000-0002-7075-0873
Aim: This study aimed to investigate whether the L5-S1 transdiscal screw fixation is biomechanically sufficient against axial loads and the resulting shear forces.
Material and Methods: Eighteen fresh calf spines under 1 year of age were used in this study. Two randomly selected spines were used as test materials. The inferior facet and ligamentum flavum were removed in 7 randomly selected spines. In these spines (transdiscal screw group), two transdiscal screws were placed bilaterally between L5 and S1. Tests were performed on the remaining 9 spines, while the spines were initially intact (intact group) and after creating a listhesis model (injury group). The extent of displacement occurring as a result of axial loading was noted in all groups in order to calculate the load-displacement curves.
Results: The mean displacement as a result of successive axial loadings of 5000 N was as follows: 3 mm (range: 2.4 – 4 mm) in the intact group, 3.5 mm (range: 3 – 4.5 mm) in the transdiscal screw group and 4.5 mm (range: 3.9 – 5 mm) in the group with injury. The difference was statistically significant (p<0.05). None of the samples exhibited broken screws, screw deformation or dislocation, even in failure tests, in the transdiscal screw group.
Discussion: These findings have shown that transdiscal screw fixation can be biomechanically sufficient against the shear forces occurring as a result of axial loading. We believe that this technique can be a good alternative as a fixation method for the L5-S1 spondylolisthesis.
Keywords: Biomechanics; Spondylolisthesis; Transdiscal Screw
The surgical fixation technique to be employed in spondylolisthesis remains controversial due to the challenges in achieving reliable fixation. Spinal fusion has long been used for the stabilization of vertebral segments with abnormal mobility . The posterolateral fusion technique employed without instrumentation is known to be associated with high rates of pseudoarthrosis in the surgical treatment of spondylolisthesis, particularly at the L5-S1 level. As the severity of listhesis increases, it becomes more difficult to achieve fusion, which leads to higher rates of failure and pseudoarthrosis [2,3]. Significantly increased fusion rates were observed with segment instrumentation that prevents movement [1,4].
The pursuit in this field is still ongoing, although pedicle screws constitute an important step considering the history of segment fixation techniques. The transpedicular screw fixation technique was first described by Harrington and Tullos in 1969 . This technique is still considered the gold standard by some authors, due to its biomechanical advantages and high fusion rates. Abdu et al. described the transdiscal screw fixation technique in 1994 and used transdiscal screws in combination with pedicle screws . The biomechanical and clinical advantages of this combined technique were later demonstrated by numerous authors [3,7,8]. Grob et al. published a case series of 16 patients in which they used transdiscal screws alone in 1996. In the mentioned study, fusion was achieved in all patients according to the radiologic assessment, and it was stated that the transdiscal screw fixation technique alone was both simple and minimally traumatic with highly successful clinical outcomes .
A fixation method should be able to provide resistance against the strong mechanical forces that will be endured until the achievement of fusion in order to be suitable or ideal for the surgical treatment of spondylolisthesis. Therefore, biomechanical testing of the said method is of utmost importance for determining the suitability of a fixation technique.
This study aimed to investigate whether the L5-S1 transdiscal screws are biomechanically sufficient against axial loading and the resulting shear forces.
Material and Methods
Eighteen fresh calf spines under 1 year of age were used in this study. The spines were kept at -20° until testing. Biomechanical tests were conducted on the sacrum and on the vertebra that is adjacent and superior to the sacrum. Two randomly selected models were used as test materials. These two spines were observed in terms of deformation under various loads. As a result of these tests, the upper limit of loading and test speed were determined to be 5000 N and 5 mm/min, respectively.
Of the remaining 16 fresh frozen calf spines, 9 randomly selected spines were initially tested while they were intact. The test results of this group were documented as results of the intact group. This was followed by creating a defect at the lamina and isthmus by removing the inferior facet and ligamentum flavum in these 9 spines. This group was subjected to testing once more, after creating an L5-S1 lysis model. The test results of this group were documented as results of the group with injury. A lysis model was initially created in the third group, i.e. the remaining 7 spines. Titanium screws with a diameter of 7 mm were bilaterally inserted from the lateral aspect of the first sacral foramina posteriorly, in the caudal to cranial and lateral to medial direction in a manner to pass through 3 cortical surfaces, i.e. the posterior wall of the sacrum, sacral endplate and L5 endplate, respectively. This group, in which two transdiscal screws were placed bilaterally between L5 and S1, was subjected to testing as the transdiscal screw group. This group was tested once more by removing the upper loading limit of 5000 N. The test was continued until the samples exhibited failure. All tests were performed with a Schimadzu compression testing machine.
The extent of displacement resulting from axial loading was noted in all groups (the group with injury, intact group and the transdiscal screw group) in order to calculate the load- displacement curves. The non-parametric Wilcoxon Test was used to compare the extent of displacement between the groups. P<0.05 was considered statistically significant.
The mean displacement resulting from successive axial loadings of 5000 N were as follows: 3.07 ± 0.53 mm (range: 2.4 – 4 mm) in the intact group, 3.5 ± 0.52 mm (range: 3 – 4.5 mm) in the transdiscal screw group and 4.5 ± 0.34 mm (range: 3.9 – 5 mm) in the group with injury. The difference was statistically significant (p = 0.007, 0.018, 0.034) (p<0.05). None of the samples exhibited broken screws, screw deformation or dislocation, even in the failure tests performed by removing the upper loading limit of 5000 N, in the transdiscal screw group. In this group, all failures were observed at the L5 level.
Spondylolisthesis is a dynamic condition that leads to symptoms such as neurogenic claudication, lower back and leg pain, which have been studied by spinal surgeons for a long time. Patients with severe listhesis who do not benefit from nonsurgical treatment are candidates for surgical treatment. The main goal of surgical treatment is to obtain rigid fusion. Pseudoarthrosis rates up to 40% have been reported in fusion procedures performed without internal fixation [2,3]. On the other hand, internal fixation has led to a significant increase in fusion rates [1,4]. Although the relevant scientific evidence is scarce, decompression, instrumentation and posterolateral fusion are considered the gold standards, particularly in the treatment of isthmic spondylolisthesis . However, posterior fusion fails to suffice with increased degree of slippage, thereby leading to higher rates of pseudoarthrosis, especially in high- grade spondylolisthesis [2,3,8,11]. This causes overloading of the instruments, which, in turn, leads to instrument failure . Therefore, spinal surgeons began seeking ways of achieving more rigid fixation.
Lehman et al. demonstrated that tricortical screw fixation provided higher biomechanical strength compared to bicortical screw fixation . In this study, the transdiscal screws were placed in a manner to grip three cortices consisting of the posterior wall of the sacrum, S1 endplate and L5 endplate. Therefore, we believe that these screws are highly resistant to detachment forces.
Solid fusion is essential to obtain good outcomes in surgeries for spondylolisthesis . Moreover, a good fusion requires rigid internal fixation until fusion is achieved. In traditional pedicle screw, fixation performed in high-grade L5-S1 spondylolisthesis, shear forces occurring as a result of axial loads on the anterior column lead to failure, thereby causing slip progression (increase in the extent of slippage). This brings up the necessity of additional anterior support. Beringer et al. reported that the use of a transvertebral interbody cage provided sufficient anterior support against the shear forces in high-grade spondylolisthesis .
Highly satisfactory clinical outcomes have been reported in studies employing a combination of pedicle and transdiscal screws [6,11]. Minamide et al. performed biomechanical tests on transdiscal screws used in combination with pedicle screws, and reported that transdiscal screws led to 1.8-fold increase in system strength .
We believe that transdiscal screws act like a cage and support the anterior column, which makes them highly sufficient from the biomechanical aspect. This stems from the fact that the location of these screws is very close to the site where interbody cages should be placed. In addition, these screws are placed almost perpendicular to the shear forces resulting from axial loading. This constitutes a biomechanical advantage, which also explains the high resistance to these shear forces.
In conclusion, we are of the opinion that transdiscal screws are biomechanically sufficient against the shear forces resulting from axial loading, and therefore transdiscal screw fixation can be a good alternative as a fixation method for achieving fusion in patients with spondylolisthesis.
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Animal and human rights statement
Conflict of interest
1. El Masry MA, McAllen CJ, Weatherley CR. Lumbosacral fusion using the Boucher technique in combination with a posterolateral bone graft. Eur Spine J. 2003;12(4):408-12.
2. Roca J, Ubierna MT, Cáceres E, Iborra M. One-stage decompression and posterolateral and interbody fusion for severe spondylolisthesis. An analysis of 14 patients. Spine (Phila Pa 1976). 1999;24(7):709-14.
3. Minamide A, Akamaru T, Yoon ST, Tamaki T, Rhee JM, Hutton WC. Transdiscal L5-S1 screws for the fixation of isthmic spondylolisthesis: a biomechanical evaluation. J Spinal Disord Tech. 2003;16(2):144-9.
4. Fritzell P, Hägg O, Wessberg P, Nordwall A, Swedish Lumbar Spine Study Group. Chronic low back pain and fusion: a comparison of three surgical techniques: a prospective multicenter randomized study from the Swedish lumbar spine study group. Spine (Phila Pa 1976). 2002;27(11):1131-41.
5. Harrington PR, Tullos HS. Reduction of severe spondylolisthesis in children. South Med J. 1969;62(1):1-7.
6. Abdu WA, Wilber RG, Emery SE. Pedicular transvertebral screw fixation of the lumbosacral spine in spondylolisthesis. A new technique for stabilization. Spine (Phila Pa 1976). 1994;19(6):710-5.
7. Beringer WF, Mobasser JP, Karahalios D, Potts EA. Anterior transvertebral interbody cage with posterior transdiscal pedicle screw instrumentation for high- grade spondylolisthesis. Technical note. Neurosurg Focus. 2006;20(3):E7.
8. Bartolozzi P, Sandri A, Cassini M, Ricci M. One-stage posterior decompression- stabilization and trans-sacral interbody fusion after partial reduction for severe L5-S1 spondylolisthesis. Spine (Phila Pa 1976). 2003;28(11):1135-41.
9. Grob D, Humke T, Dvorak J. Direct pediculo-body fixation in cases of spondylolisthesis with advanced intervertebral disc degeneration. Eur Spine J. 1996;5(4):281-5.
10. Jacobs WC, Vreeling A, De Kleuver M. Fusion for low-grade adult isthmic spondylolisthesis: a systematic review of the literature. Eur Spine J. 2006;15(4):391-402.
11. François J, Lauweryns P, Fabry G. Treatment of high-grade spondylolisthesis by posterior lumbosacral transfixation with transdiscal screws: surgical technique and preliminary results in four cases. Acta Orthop Belg. 2005;71(3):334-41.
12. Lehman RA Jr, Kuklo TR, Belmont PJ Jr, Andersen RC, Polly DW Jr. Advantage of pedicle screw fixation directed into the apex of the sacral promontory over bicortical fixation: a biomechanical analysis. Spine (Phila Pa 1976). 2002;27(8):806-11.
13. Sasso RC, Shively KD, Reilly TM. Transvertebral transsacral strut grafting for high-grade isthmic spondylolisthesis L5-S1 with fibular allograft. J Spinal Disord Tech. 2008;21(5):328-33.
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Murat Aydin, Tugrul Bulut, Mustafa Guden, Nuri Erel. Transdiscal screw fixation in L5-S1 spondylolysis: A biomechanical study. Ann Clin Anal Med 2021;12(9):1055- 1057
Brief emergency department patient satisfaction scale (BEPSS): Turkish validity and reliability study
Hüseyin Acar 1, Kadriye Acar 2, Pınar Yeşim Akyol 1, Fatih Esad Topal 1, Adnan Yamanoğlu 1, Adem Çakır 3
1 Department of Emergency Medicine, Izmir Katip Çelebi University Atatürk Training and Research Hospital, İzmir, 2 Operating room, Izmir Katip Çelebi University, Atatürk Training and Research Hospital, İzmir, 3 Department of Emergency Medicine, Başakşehir Çam and Sakura City Hospital, İstanbul, Turkey
DOI: 10.4328/ACAM.20587 Received: 2021-03-14 Accepted: 2021-06-07 Published Online: 2021-06-19 Printed: 2021-09-01 Ann Clin Anal Med 2021;12(9):1058-1062
Corresponding Author: Hüseyin Acar, Department of Emergency Medicine, Izmir Katip Çelebi University Atatürk Training and Research Hospital, İzmir, TURKEY. E-mail: email@example.com P: +90 (532) 500 90 29 Corresponding Author ORCID ID: https://orcid.org/0000-0002-1905-7133
Aim: Evaluation of patient satisfaction constitutes an important step in improving the quality of care. Because of difficulties in evaluating patient satisfaction in the Emergency department, a practical method specific to the emergency department is needed. In this study, the Turkish validity and reliability trial of BEPSS, which evaluates patient satisfaction in the emergency department, was carried out.
Material and Methods: This is a scale validity and reliability study. First, BEPPS was translated into Turkish. The scale was then tested on 200 patients. Based on the data obtained, the construct validity, criterion validity and the reliability of the scale were evaluated.
Results: The average total score of BEPSS was 73.50±10.345. In the explanatory factor analysis for construct validity, the eigenvalue of a factor was found to be 5.282, and the total variance was 75.46%. According to the Cronbach alpha coefficient used in the reliability analysis, the internal consistency of the scale was 0.79. In the correlation matrix, it was seen that there was a positive and average correlation between the items of the scale.
Discussion: In the study, it was found that the Turkish version of BEPSS was appropriate in terms of criterion validity, structural validity, and reliability.
Keywords: Patient Satisfaction; Emergency Department; Validity; Reliability; Scale
Patient satisfaction is a concept directly related to the quality of the healthcare provided to patients . The increase in the value given to the patient and the quality of healthcare affect patient satisfaction positively . Due to the increasing competition in the health sector, patient satisfaction and health service quality have become increasingly important in recent years . There are many different factors that affect patient satisfaction . Factors affecting patient satisfaction include the number of healthcare professionals in the hospital, bed capacity of the hospital , patient s age, communication between the patient and the healthcare provider , waiting time of the patients, mutual empathy, respect for patients and their relatives, and patient privacy .
Patient satisfaction surveys used to evaluate the level of patient satisfaction often focus on the hospital environment, the health care provided to the patient, and the attitude of hospital staff . However, features such as Emergency department crowding , the urgency of the patient’s condition, long waiting times, and anxiety of patients or their companions, which distinguish the emergency department from other departments, can directly affect patient satisfaction . For this reason, it will be appropriate to use a specialized patient satisfaction survey for the emergency department. Atari et al. developed the “Brief Emergency Department Patient Satisfaction Scale (BEPSS)”, which evaluates patient satisfaction in different aspects for the emergency department. BEPSS is a patient satisfaction questionnaire specific to the emergency department, as it is prepared based on emergency department-specific problems. This scale, prepared in English, questions the satisfaction level of the patients through 20 questions under 5 subgroups . This study aimed to translate BEPSS into Turkish and conduct the validity and reliability study of BEPSS for Turkish society.
Material and Methods
Study Design and Ethics
This study is a scale validity and reliability study carried out prospectively. Study was approved by the local ethics committee (2019-GOKAE-1096).
This study was conducted in the ED of a training and research hospital with 350,000 annual ED visits.
Patients aged 18 and over who presented to the emergency department and volunteered to participate were included in the study. Patients with a history of alcohol or drug use within the last 48 hours, patients who were unconscious or intubated, patients who refused to participate in the study, and patients who did not complete the questionnaire were excluded from the study (Figure 1)
A single questionnaire including the Brief Emergency Department Patient Satisfaction Scale (BEPSS), demographic dataofthepatientsandtheNumericRatingScale(NRS)that measures the patient’s satisfaction level was used to collect the data. BEPSS consists of 5 subgroups and a total of 20 questions evaluating patient satisfaction in the ED. The subgroups of the scale are emergency department staff (EDS) consisting of 6 questions, emergency department environment (EDE) consisting of 3 questions, physician care satisfaction (PCS) consisting of 4 questions, general patient satisfaction (GPS) consisting of 5 questions and patient’s family satisfaction (PFS) consisting of 2 questions. BEPSS is a Likert-type scale with each question scored between 1 and 4. Among the points given in response to the questions, 1 point means completely disagree, 2 points mildly disagree, 3 points mildly agree, and 4 points completely agree. By collecting the points given by the patient to each item, the patient’s emergency satisfaction score is obtained. While the minimum score that can be obtained from the whole scale is 20, the maximum score is 80. While a score of 20 points taken from the scale indicates complete dissatisfaction of the patient, a score of 80 points indicates complete satisfaction. The demographic data collection form includes age, gender, time for presentation to the emergency department, waiting time before seeing the doctor, patient’s triage category, hospitalization status of the patient (outpatient/hospitalization/ intensive care), previous medical history, educational status, and smoking information. The Numeric Rating Scale (NRS), which measures the level of satisfaction in order to compare with BEPSS, is scored between 0 and 10, while “0” means complete dissatisfaction, “10” means complete satisfaction . Verbal consent was obtained from all patients before the questionnaires were filled. The questionnaire was completed by the patients themselves. For elderly or visually impaired patients, the questionnaire form was read out loudly by the researcher, and the patient’s responses were written on the form by the researcher. However, in conditions where it was not possible for the patient to complete the questionnaire for any reason, one of the patient’s relatives was asked to complete it. The questionnaire was completed just before the patient left the ED. For any patient who needed immediate treatment for a life-threatening condition, after the patient’s treatment was completed, one of the relatives of the patient was politely asked to complete the questionnaire form.
Preparation of the Turkish Version of the Scale
Firstly, in order to prepare the Turkish adaptation of the scale, permission to use the scale was obtained by e-mail from Mohammad Atari, the developer of the original version of BEPSS. Turkish adaptation of the scale, completed in 6 steps, was prepared based on the guideline developed by Beaton et al. .
First step: The scale was translated into Turkish separately by an emergency medicine specialist who knew the concept of the study, whose native language was Turkish and who could speak English well, as well as an English foreign language lecturer who was not familiar with the concept and whose native language was English.
Second step: Both the Turkish translations of the scale and the original English version of the scale were synthesized by two translators, accompanied by an observer, and a single Turkish version was created.
Third step: The Turkish version of the scale has been retranslated into English by two translators whose native language was English and who spoke Turkish well and were blinded to the original version of the scale.
Fourth step: This is the step where the translations were evaluated by a committee and the Turkish version of the scale was finalized. In this step, the meaning compatibility between the Turkish version of the scale and the original English version was evaluated. The committee included an emergency medicine specialist and an English lecturer who were translators of the original scale into Turkish, and two translators who retranslated the scale back to English.
Fifth step: In this step, the Turkish version of the scale, approved by the committee, was evaluated for clarity in a pilot study of 30 participants. The volunteers who filled the questionnaire were asked to evaluate each item on the scale for clarity. In this pilot study, it was determined that there was no item that could not be understood by the patients.
Sixth step: In this step, the version of the scale retranslated from Turkish to English and the final Turkish version of the scale were sent to Mohammad Atari, the developer of the scale, and his approval was obtained.
After the 6-step stage in which the Turkish version of the scale was prepared, the validity and reliability study of the Turkish version of BEPSS was performed. In this study, patients presented to the emergency department were asked to fill in the questionnaire after verbal consent was obtained. The research was terminated when the targeted 200 participants were reached. The Turkish validity and reliability of BEPSS were investigated as described in the statistical analysis section. Sample Size
It is stated in the literature that a sample of 10 times the number of items on the scale is ideal for scale validity and reliability studies . Since there were 20 items on this scale, the sample size was determined as 200.
The data obtained in the study were analyzed using the SPSS 20.0 package program for Windows (IBM Corporation, Armonk, New York, USA). While evaluating the study data, the frequency distribution (number, percentage) for categorical variables and descriptive statistics (mean, standard deviation) for numerical variables were used. In statistical analysis, Type-1 error was taken as α = 0.05 for statistical significance. The Cronbach Alpha Reliability Coefficient, which is one of the internal consistency methods, was used in the reliability study. The Kaiser-Meyer-Olkin (KMO) coefficient and Barlett tests were used to evaluate the feasibility of factor analysis, and factor analysis is used to evaluate the suitability of the construct validity of the scale. For criterion validity, BEPSS’s correlation with the NRS satisfaction scale was examined. The relation between subgroups of the scale was examined using the Spearman Correlation analysis.
Socio-Demographic Characteristics of Patients
A total of 200 patients participated in the study. The average age of the patients was 46 ± 20.92 years, and 46% were women. The triage category of 102 (51%) patients was green, 70 (35%) were yellow and 28 (14%) were red. One hundred fifty-seven (78.5%) of the patients included in the study were discharged from the emergency department, 133 (16.5%) were hospitalized and 10 (5%) were admitted to the intensive care unit.
The average total BEPSS score was 73.50 ± 10.345 and the average NRS satisfaction score was 8.84 ± 1.75. Looking at the average scores of the BEPSS subgroups, average EDS score was 21.80 ± 4.030, average EDE score was 10.50 ± 2.110, average PCS score was 15.41 ± 1.821, the GPS scale score was 18.40 ±3.129 and average PFS score was 7.28 ±1.466. When the relationship between NRS satisfaction score and BEPSS subgroup scores were examined one by one, there was a positive and significant relationship between them (p=0.0001). In addition, when the patients’ responses to the scale were evaluated using the Spearman Correlation analysis, it was calculated that the subgroups had a positive relationship with each other, as shown in Table 1 (p=0.00001).
Cronbach’s alpha coefficient was used in the reliability analysis where the internal consistency of BEPSS was evaluated. When the correlation between subgroup items and the correlation of BEPSS with subgroup items were evaluated, the correlation coefficients were found to be in the range of 0.56-0.80 (p=0.0001), and the internal consistency of the scale was 0.79. Validity Analysis
The Kaiser-Meyer-Olkin (KMO) coefficient, which evaluates the adequacy of the sample size, was found to be 0.64 and the Bartlett Test (x2 = 1782.42, SD = 12, p=0.00001), in which the suitability of the scale was evaluated was found to be significant. In the explanatory factor analysis for construct validity, the eigenvalue of a factor was found to be 5.282, and the total variance was 75.46% as shown in Table 2.
When the relationship between the items of the scale was examined in the correlation matrix, it is seen that there is a positive and average relationship, as shown in Table 3. Since it is the only factor, Varimax rotation cannot be done.
In this study, the Turkish version of BEPSS developed by Atari et al. evaluating patient satisfaction in the emergency department was prepared, and its validity and reliability study was performed. Within the scope of the study, firstly, Turkish version of the scale was prepared and then criterion validity, construct validity, internal consistency and explanatory factor analysis were evaluated. It was seen that the scale was valid and reliable and it was appropriate to be used inTurkish society. Validity Analysis
The purpose of the validity analysis is to examine whether the items of the scale represent the area or behavior desired to be measured, and to form an entirety of meaningful items by a group of experts [14,15]. The only condition for measuring criterion validity is that there is a suitable and valid criterion to compare. The aim is to establish the relationship between the valid measurement tool and another measurement tool . In this study, concurrent validity was used to measure criterion validity. In concurrent validity, the score obtained from the scale to be tested is compared with the score obtained from another scale, measuring the same or similar behavior. The tests to be compared should be carried out simultaneously or within a close time . In this study, NRS satisfaction and BEPSS were performed simultaneously. A positive correlation was found between BEPSS and NRS satisfaction. According to these results, the criteria validity of BEPSS has been confirmed. The Kaiser-Meyer-Olkin (KMO) coefficient and Barlett tests are used to evaluate the feasibility of factor analysis . The KMO coefficient must be over 0.50 for factor analysis. In addition, the interpretation of the KMO coefficient between 0.70 and 0.80 is moderate, between 0.80 and 0.90 is good, and above 0.90 is excellent sampling . The Bartlett test is used to evaluate the suitability of items on the scale for the factor analysis of the correlation matrix . In this study, the KMO coefficient was determined as 0.64 and the Bartlett test was significant. In the light of these findings, it was concluded that the sample size for the study was sufficient and feasible for factor analysis. Factor analysis is used to evaluate the suitability of the construct validity of a scale. When conducting exploratory factor analysis, it is necessary to take into account whether the scale has a single or multi-factor structure. In single-factor scales, the scale is expected to explain at least 30% of the total variance, while in multi-factor scales this value should be even higher (20). In the exploratory factor analysis evaluating BEPSS, when the items of the scale were compared through factor analysis, it was found that the initial eigenvalue of one factor was 5,282 and the total variance was 75,46%. Since this value explains the variance of the scale, the scale can be explained using a single factor. According to these results, it can be said that the structural validity of the scale was confirmed.
Reliability analysis means that the scale can reflect the structure it measures consistently. In reliability studies, Cronbach’s alpha value is used while evaluating internal consistency, which shows that the scale items are consistent with each other and contribute to the scale in the same direction. In order to say that the scale is reliable, Cronbach’s alpha value must be above 0.70 . In this study, Cronbach’s alpha value was found to be 0.79 in the internal consistency analysis for BEPSS. According to this result, it can be said that the Turkish version of BEPSS is reliable.
This study shows that the Turkish version of BEPSS is an easy-to-use, reliable and valid instrument that can be used to evaluate patient satisfaction in the emergency department. Patient satisfaction assessments that will be performed in the emergency department using BEPSS will enable the identification of problems specific to the emergency department and the improvement of health care provided to the patients.
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Conflict of interest
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Download attachments: 10.4328:ACAM.20587
Hüseyin Acar, Kadriye Acar, Pınar Yeşim Akyol, Fatih Esad Topal, Adnan Yamanoğlu, Adem Çakır. Brief emergency department patient satisfaction scale (BEPSS): Turkish validity and reliability study. Ann Clin Anal Med 2021;12(9):1058-1062
The utility of computed tomography and transfontanelle ultrasonography in various intracranial lesions in the newborns and infants
Mehmet Ercüment Döğen 1, Ümit Yaşar Ayaz 1, Ö. Meriç Tüzün 2, Hasan Ali Durmaz 2, Baki Hekimoğlu 2
1 Department of Radiology, Mersin City Training and Research Hospital, Mersin, 2 Department of Radiology, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara, Turkey
DOI: 10.4328/ACAM.20588 Received: 2021-03-14 Accepted: 2021-05-12 Published Online: 2021-06-21 Printed: 2021-09-01 Ann Clin Anal Med 2021;12(9):1063-1067
Corresponding Author: Mehmet Ercüment Döğen, Mersin City Training and Research Hospital, Department of Radiology, Mersin, Turkey. E-mail: firstname.lastname@example.org P: +90 324 2251000 GSM: +90 506 5341161 F: +90 324 2251017 Corresponding Author ORCID ID: https://orcid.org/0000-0002-5414-2771
Aim: We aimed to diagnose intracranial lesions in infants by performing transfontanel ultrasonography (US) and computed tomography (CT), and to evaluate the efficacy of both methods with respect to each other.
Material and Methods: In this retrospective study, 111 infants were included between 2007-2011. The mean age of the participants was 2.2 months (range, 1 d-24 mo) and 42 (37.8%) of them were females, 69 (62.1%) of them were males. Both US and CT were used in 34.2 % of cases (n=38/111). Only US was used in 52.2% of cases (n=58/111) and only CT was used in 13.5% of cases (n=15/111).
Results: Intracranial hemorrhage was demonstrated in 39.6% of the infants (n=19/48) Congenital malformations were shown in 22.9% of the patients (n=11/48). Communicating and non-communicating hydrocephalus in 20.9% of the patients (n=23/111), periventricular leukomalacia in 9% of the patients (n=10/111), diffuse cerebral edema in 5.4% of the patients (n=6/111), central nervous system infections in 4.5% of the patients (n=5/111), acute ischemic infarct in 1.8% of the patients (n=2/111), and metabolic disease in 0.9% of the patients (n=1/111), were demonstrated.
Discussion: Intracranial hemorrhage was the leading finding, followed by congenital malformations and hydrocephalus in the present study. US and/or CT can be used effectively and interchangeably for the earlier diagnosis of infantile intracranial pathologies especially in cases where MRI is not available.
Keywords: Tomography; Ultrasonography; Infant; Intracranial Hemorrhage
Early and correct diagnosis of infantile intracranial pathologies is essential for their correct and efficient treatment by pediatricians. Radiological methods such as plain radiographs, transfontanelle ultrasonography (US) and computed tomography (CT) are practical and less time-consuming diagnostic tools . The US can provide real-time information about the anatomic location, size, and shape of lesions as well as their mass effect on adjacent structures . However, the differential diagnosis can be difficult with US findings only . Understanding the spectrum of appearances of the various intracranial lesions on both CT and US improves the diagnostic yield, enables one to understand their pathogenesis, and facilitates patient care . In this study, we aimed to diagnose intracranial lesions in infants by performing transfontanelle US and CT, and to evaluate the efficacy of both methods with respect to each other.
Material and Methods
Our study population included 232 newborns and infants who were clinically suspected to have various types of intracranial pathologies and who underwent transfontanelle US and/or cranial CT between 2007−2011, in the first selection. A total of 121 subjects were excluded because of normal US and/or CT findings. Finally, 111 consecutive newborns and infants with positive transfontanelle US and/or cranial CT findings were included in this retrospective study. The study was conducted in accordance with the current Helsinki Declaration and the ethics granted by the institution. The parents or closest relatives of all the patients were informed about US and CT studies. Although the radiologist’s opinion was asked about which method to choose for some patients, the clinician usually decided which radiological imaging method to choose. Accessing medical records between two dates in the past, two experienced radiologists have re-evaluated the radiological images. Our study was approved by the Ethics Committee of Mersin University Medical Research Ethics Committee with the board decision dated 19.12.2018 and numbered 2018/507. The mean age of the participants was 2.2 months (range, 1 d-24 mo), and 42 (37.8%) of them were females, 69 (62.1%) were males. Both US and CT were used in 34.2 % of cases (n=38/111). Only US was used in 52.2% of cases (n=58/111) and only CT was used in 13.5% of cases (n=15/111). The cranial US examinations of infants were performed with 3.5-3.75 MHz convex transducers, 3.75-7.5 MHz sector/microconvex transducers and 7.5-8.0 MHz linear transducers by using anterior and posterior fontanelles as acoustic windows (transfontanel approach) in every case and additionally through temporal bone (transtemporal approach) in case of need. Intravenous contrast material was administered when necessary during CT examinations. US examinations were performed by two experienced radiologists together, and CT images were interpreted by two experienced radiologists in consensus. The findings were verified by clinical results and/or cranial magnetic resonance imaging (MRI) and/or follow-up US and CT examinations.
The frequencies (percentage, n) of the patients according to the type of the lesions were obtained. All analyses were done with SPSS software (version 16.0; SPSS Inc; Chicago, IL, USA).
Using US and/or CT, intracranial hemorrhage (Figures 1, 2) was demonstrated in 39% of the infants (n=43/111). Congenital intracranial malformations (Dandy-Walker malformations, lissencephaly-pachygyria, schizencephaly, semilobar holoprosencephaly, occipital meningocele, choroid plexus cysts, mega cisterna magna formations) were shown in 19.8% of the patients (n=22/111). Communicating and non-communicating hydrocephalus (postinfectious and posthemorrhagic hydrocephalus (Figure 3), congenital hydrocephalus due to achondroplasia and Dandy-Walker malformation, hydrocephalus due to glial tumour in the posterior fossa) in 20.9% of the patients (n=23/111), periventricular leukomalacia in 9% of the patients (n=10/111), diffuse cerebral edema in 5.4% of the patients (n=6/111), central nervous system infections in 4.5% of the patients (n=5/111), acute ischemic infarct in 1.8% of the patients (n=2/111), and metabolic disease in 0.9% of the patients (n=1/111), were demonstrated.
On US, intracranial acute hemorrhage is seen as highly echogenic and relatively homogeneous mass , as in the cases of the present study. By the time, intracranial (intracerebral, intraventricular, subdural, epidural etc.) hematoma becomes more hypoechoic and in about eight weeks it is readily seen as a cystic structure on US . On CT, intracranial hematoma is seen hyperdense for a period of about one week, as it was in our study, then becomes isodense . US is very important for the diagnosis of neonatal and infantile cranial hemorrhages and for their follow-up . Germinal matrix has a rich vascular supply, its fragile vessel walls can get damaged after metabolic and blood pressure changes. In turn, subependymal, intraventricular, intraparenchymal hemorrhages may occur and porencephalic cysts besides hydrocephalus can develop after these hemorrhages [2, 7]. Intracerebral hemorrhages are commonly seen in frontal and parietal lobes of the cerebral hemispheres. Compared with CT and magnetic resonance imaging (MRI), US is less sensitive to detect subdural and epidural hemorrhages , though in one of our cases we were able to demonstrate a large epidural hematoma easily with US. Compared with other types of intracranial hemorrhages, US has the least efficacy in the detection of subarachnoid hemorrhages. As indirect findings, enlarged fissures and sulci and their increased echogenicity may raise suspicion for subarachnoid hemorrhage [1-5]. Regarding the congenital intracranial malformations that could be detected in the present study, lissencephaly (agyria-pachygyria complex) is a congenital migration anomaly of gray matter of brain that is characterized by the lack or few sulci, shallowing of the present sulci, thickened appearance of the gray matter and decreased amount of white matter . We could effectively demonstrate all the above-mentioned findings related to lissencephaly (agyria-pachygyria complex) on transfontanelle US of one case in our study. Schizencephaly is a full-thickness cerebrospinal fluid-filled parenchymal cleft lined by gray matter extending from subarachnoid space to subependyma of lateral ventricles . Dandy-Walker malformation is characterized by an enlarged posterior fossa, a cystic lesion in the posterior fossa, which is in communication with the fourth ventricle, vermian aplasia or hypoplasia, and cerebellar hypoplasia [11- 13]. We could be able to demonstrate all these findings on CT images of the related cases in the present study. Hydrocephalus (ventriculomegaly) also associates this malformation due to congenital atresia of the foramina of Luschka and Magendie. CT is superior to US in assessing the enlargement of posterior fossa shapes of bony structures, sizes of cerebellum and vermis compared to other intracranial structures [11-13]. CT provides the view of the whole cranium in the same field of view, which is quite helpful to make a comparison . This is less satisfactory for US, but allows dynamic examination  and unlike CT, we are able to make examinations in every plane in which acoustic windows are suitable. Choroid plexus cysts are non-neoplastic cystic structures that may be unilateral or bilateral . They can be diagnosed in utero, in the infantile period or even in young adults coincidentally . They are often larger than 3 mm and can reach a diameter of 25 mm. But they have an average diameter of 4.5 mm. If the cyst is large enough, hydrocephalus may develop as a complication [15-17]. Choroid plexus cysts, besides other congenital malformations such as semilobar holoprosencephaly, occipital meningocele, mega cisterna magna formations, were also well depicted on US examinations of the cases in the present study. Hydrocephalus may result from obstruction of cerebrospinal fluid (CSF) flow, inadequate absorption or overproduction of CSF . Hydrocephalus may be communicated or non- communicated . Non-communicated hydrocephalus may develop as a result of some of the infections, hemorrhages, tumors, cysts and congenital anomalies . Communicated hydrocephalus may develop as a result of subarachnoid hemorrhages, meningeal carcinomatosis or infections [18, 19]. Regarding one of the infants in the present study, US could be able to demonstrate advanced hydrocephalus, which developed within one month after the onset of meningitis. Moreover, the CT which was obtained after US was in total accordance with US findings.
Periventricular leukomalacia is periventricular white matter necrosis due to hypoxia and ischemia. Sonographically, in the early period, periventricular white matter echogenicity increases [20, 21]. But in the later stages, cystic changes occur. Different degrees of cerebral atrophy and ventricular dilatation develop eventually. In the very early periods, CT is not as effective as expected. About 12 hours after the onset of infarct, hypodense areas are apparent with CT . In later periods, periventricular hypodensity becomes much more apparent (20-21). During the subacute stage, pathologic contrast enhancement, especially in the periphery of the infarct, can be detected with CT . Regarding acute cerebral infarcts in infants, US shows echogenic parenchyma, lack of arterial blood flow signals in Doppler imaging, mass effect due to edema, effacement of gyri and sulci . In our relevant cases, both US and CT could be able to demonstrate the above-mentioned changes. Congenital intracranial infections are toxoplasmosis, Herpes simplex type 2 infections, Rubella and Cytomegalovirus infections. In almost all of these so-called TORCH group infections, intracerebral calcifications occur, which can be demonstrated both on US and CT, as we did in the present study. Acquired infections are meningitis, ventriculitis, encephalitis, abscesses and extracerebral infections (subdural empyema etc.) [22-24]. In ventriculitis, US examination can detect hydrocephalus, echogenic structures within ventricles, increased echogenicity of the ventricle walls and fibrous septations within the ependymal lining . US can not help in the diagnosis of uncomplicated meningitis, though in some cases increased echogenicity and thickening of the sulci may be noticed [22- 24]. On US, intracerebral abscesses are hyperechogenic in the early periods, but gain mixed echogenicity later on. US is not as effective as CT in the detection of extracerebral abscesses and empyemas [22, 23]. Especially, contrast enhancement of meningeal structures and the walls of infectious lesions and collections helps us to identify abscesses, meningitis, ventriculitis, subdural and epidural empyemas easily with CT . On contrast-enhanced CT images of our relevant cases, subdural and epidural empyemas and associated hydrocephalus could clearly be depicted. However, we couldn’t reveal subdural and epidural empyemas clearly with US, but could demonstrate ventricular dilatation.
On US, cerebral edema may be seen as blurred parenchymal images, diffuse and increased parenchymal echogenicity, though it is sometimes subjective to evaluate the echogenicity of the parenchyma [3-5]. On CT, cerebral edema can be seen as decreased density of cerebral parenchyma, loss of distinction between gray and white matter, the shift of midline structures and compression of the ventricles . In one of our cases, we could clearly demonstrate diffuse cerebral edema associated with intracranial hematoma in a traumatized infant. Intracranial tumors are rare in infants . On US, most tumors are seen as hyperechoic lesions, though some may have mixed echogenicity . In very few cases they may be anechoic . Intratumoral calcifications are seen as echogenic foci [18, 19]. Craniopharyngioma, dermoid tumor, pinealoma, astrocytoma, papilloma of choroid plexus, ependymoma, primitive neuroectodermal tumors are among the intracranial tumors of the infantile period . CT is very helpful in diagnosis, assessing the contrast enhancement pattern, extension and complications of tumors, evaluation of the bony structures of the skull, detection of intratumoral calcification [2-6]. In two of our cases with glial tumors in the posterior fossa, CT was helpful not only in demonstrating the tumor, but associating hydrocephalus as well. US was helpful in revealing obstructive hydrocephalus in these cases, however, we consider that small tumors, particularly in the posterior fossa, can be overlooked with US.
Getting access to CT and preparing an infant for a CT scan is easier than using MRI . CT provides faster examination (literally seconds for a brain examination) with better monitoring (particularly in unstable neonates) and has fewer equipment-related contraindications than MRI . In MRI, the need for sedation in infants is an important and ongoing problem [6-8]. We consider that modality decisions should be based on available resources and patient status, in addition to diagnostic yield.
Ultrasonography is a non-invasive and non-ionizing imaging modality. Unlike CT, it provides real-time images in all planes.
Sedation is not required. The bed-side examination is possible for the patients that are attached to monitors and life-support units. We concluded that US was useful to demonstrate most of the infantile intracranial lesions, especially the ones that need periodic evaluation. CT is found superior to US in demonstrating extraaxial fluid collections such as subdural empyemas and subdural, subarachnoid hemorrhages. CT helps to evaluate the whole intracranial structures within that field of view and compare them with each other. The contrast enhancement patterns of the lesions help a lot for differentiation of them with CT. Calcifications can easily be detected with CT, and bony structures are evaluated more accurately.
The present study had some limitations mostly because of its retrospective design. Firstly, our sample size was not large enough to divide the patients into subgroups according to different pathologies, which would help us better see and check the efficacy of both US and CT in different pathological situations and conditions. Secondly, we could not take each patient to CT scanning after US to avoid unnecessary ionizing radiation. This is also true for some patients who underwent CT but could not be evaluated by US because of their critical and unfavorable clinical status. Thirdly, due to patient-related factors and/or because it is unnecessary from the point of making the diagnosis, we could not correlate our findings with the MRI in every case, which would also be helpful in providing more detailed information about the intracranial lesions of the patients. However, we consider that our results proved the usefulness and practicality of both US and CT in our patient groups. We could not correlate our findings with MRI.
In conclusion, intracranial hemorrhage was the leading finding, followed by congenital malformations and hydrocephalus in the present study. US and/or CT can be used effectively and interchangeably for earlier diagnosis of infantile intracranial pathologies, especially in cases where MRI is not available.
We are grateful to the pediatricians Dr. Durmuş Zaimoğlu and Prof. Dr. Erdal Taşkın for their kind contributions.
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Conflict of interest
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Mehmet Ercüment Döğen, Ümit Yaşar Ayaz, Ö. Meriç Tüzün, Hasan Ali Durmaz, Baki Hekimoğlu. The utility of computed tomography and transfontanelle ultrasonography in various intracranial lesions in the newborns and infants. Ann Clin Anal Med 2021;12(9):1063-1067
The Turkish adaptation of the emergency medical services resilience scale
Hulya Saray Kilic 1, Sevinc Mersin 1, Ozlem Ibrahimoglu 2, Burcu Ozkan 3
1 Department of Nursing, Bilecik Seyh Edebali University, Health Sciences Faculty, Bilecik, 2 Department of Nursing, Istanbul Medeniyet University, Health Sciences Faculty, Istanbul, 3 Department of Nursing, Istanbul Kent, Health Sciences Faculty, Istanbul University, Istanbul, Turkey
DOI: 10.4328/ACAM.20589 Received: 2021-03-14 Accepted: 2021-05-22 Published Online:2021-06-10 Printed: 2021-09-01 Ann Clin Anal Med 2021;12(9):1068-1072
Corresponding Author: Hulya Saray Kilic, Faculty Member, Bilecik Seyh Edebali University, Health Sciences Faculty, Nursing Department, 11210, Bilecik/TURKEY. E-mail: email@example.com P: +90 530 558 11 51 / +90 228 214 17 93 Corresponding Author ORCID ID: https://orcid.org/0000-0001-8165-2577
Aim: In this study, we aimed to determine the psychometric properties of the Turkish version of the Emergency Medical Services Resilience Scale.
Material and Methods: This study was methodological and cross-sectional. It was conducted in emergency medical services of five education and research hospitals in Turkey between July-September 2019 with 244 emergency medical service personnel. Data were collected with Sociodemographic Form, the Emer- gency Medical Services Resilience Scale, and the Cognitive Flexibility Inventory. In the evaluation of the data, explanatory factor analysis, reliability analysis and correlation between scales were tested.
Results: Explanatory factor analysis showed that there are 31 items with a five-factor structure, explaining 47.5% of the variance in the Turkish version of the scale. Cronbach’s alpha coefficient was calculated as 0.82.
Discussion: The Emergency Medical Services Resilience Scale is a valid and reliable measurement tool in Turkish culture. It can enable early intervention attempts to be used, especially by managers, to determine the resilience level of emergency medical service personnel in the emergency medical services.
Keywords: Emergency Medical Services; Resilience; Reliability; Validity
Emergency medical services (EMS) are places where emergency medical service personnel work under high levels of stress with unexpected incidents, life-threatening situations and patient deaths. In these overcrowding services, every patient and their families want to feel more important and they have high level of anxiety about their lives [1,2]. EMS personnel help patients and their families in lots of critical conditions. Life-threatening conditions and forcing patients to survive can create stress in EMS personnel, as well as inadequate number of employees, excessive workload, critical patient events and communication deficiencies . This may be more likely to increase the likelihood of stress, distress, anxiety, depression, posttraumatic stress disorder, burnout and dissatisfaction in EMS [2-5]. Khan et al.  stated that paramedics had stress (32.0%), depression (31.0%), anxiety (26.0%), insomnia (20.0%), and obstructive sleep apnea (8.0%). DeLucia et al.  stated that in their study, which examined the prevalence of posttraumatic stress disorder in emergency physicians in the USA, 15.8% of the participants observed symptoms of posttraumatic stress disorder. Moss et al.,  on the other hand, reported that mental health is negatively affected because EMS personnel often experience life-threatening cases. Cocker and Joss  reported that compassionate fatigue had negative physical and psychological effects on EMS personnel together with general healthcare professionals. They have also proposed new studies to prevent this compassion fatigue, to protect and improve the health of healthcare professionals.
Resilience is the ability of an individual to regain their health and well-being safely and efficiently in expected or unexpected situations . In recent years, being resilience has gained importance to protect and improve the psychosocial health of healthcare professionals. This can lead to adaptive behaviors, new solutions, coping with difficulties, psychological well-being, self-confidence, job satisfaction and leave of job among health professionals. Therefore, resilience may cause positive patient outcomes [4, 11].
Resilience is an important factor for EMS personnel because of challenges in workplaces, psychological problems, insomnia, fatigue, physical and psychosocial difficulties associated with decision-making, conflicts at work, high level of stress, heavy workloads . Resilience is related to recovery from adversity, overcoming setbacks . In different studies conducted with health professionals, there was an inverse relationship between resilience and stress, psychosocial problems, carelessness, and burnout [14,15]. Resilience can make it easier for EMS personnel to maintain their emotional balance with their job, to cope with stressful life events by reducing burnout . Therefore, individuals with high levels of resilience are preferred in the EMS. It is aimed to evaluate and increase resilience levels in places. Culture, behavior patterns, social support systems and individual resilience are effective for EMS personnel . Therefore, due to the need for a standard measurement tool, the resilience scale has been developed in the EMS . Determining the resilience levels of EMS personnel is important and necessary. When the literature is examined, it is seen that the measure of resilience in EMS in Turkey does not have any instrument. In this study, it was aimed to determine the psychometric properties and transcultural adaptation of the Turkish version of the Emergency Medical Services Resilience Scale (EMSRS).
Material and Methods
Participant and Setting
This study was methodological and cross-sectional. It was conducted in EMS of five education and research hospitals in Turkey between July-September 2019. These hospitals admit about 3500 – 15000 patients per year. The study was conducted with 244 EMS personnel working as physicians, nurses, emergency medical technicians, technicians and health officers on the 31-item scale by considering the number of scale items. For validity and reliability studies, the sample size for each scale item should be 5-10 people. Although the sample size was at least 155 people, the study was completed with 244 participants. Participants who had more than one year of work experience in EMS were included in the study. Also, the EMS personnel with serious mental and physical health problems were excluded from the research. The participants were given a data collection form and asked to complete it. It took 10- 15 minutes to complete the data collection form. To evaluate the reliability of the scale, 106 participants were re-tested two weeks after the data collection.
To adapt the scale to Turkish, the translation-back translation method was used. The original version of the EMSRS was translated from English to Turkish by two independent language experts for language validity. In order to evaluate the scale, translated into Turkish as grammar, the opinions of three experts in their fields were taken into account. A common Turkish text was created with expert opinions. It was re-translated from Turkish to English. After the translation was completed, the original scale and translated version of the Turkish to English scale were evaluated in terms of similarities or inconsistencies. After the evaluation, both scales were found to be similar and psychometric analyses was started.
Data collection tools
The Sociodemographic Form, the Emergency Medical Services Resilience Scale, and the Cognitive Flexibility Inventory were used for data collection.
Sociodemographic Form: It consists of questions prepared by researchers that evaluate the participants’ characteristics, work experience in the emergency medical services (in years), and total work experience in the profession (in years). Emergency Medical Services Resilience Scale: It was developed in 2019 by Ebadi et al. . The tool was designed to identify the resilience of the EMS personnel. It is a 5-point Likert- type scale with a total of 31 items. The minimum and maximum score range is 31-155. A high score indicates high resilience. Cronbach’s alpha for the original scale was calculated as 0.91. Cognitive Flexibility Inventory (CFI): It was developed by Dennis and Vander Wal  and adapted to Turkish by Gülüm and Dağ . It is designed to produce alternative, harmonious, appropriate and balanced thoughts for people in difficult situations. It was used for evaluating criteria validity. Cronbach’s alpha coefficient for the original scale and Turkish version were calculated as 0.91 and 0.94, respectively.
Permission was obtained from the developer of the EMSRS by e-mail in order to use the scale in the study. In order to carry out the study, ethics committee approval was obtained from the local ethics committee (2019/0075; 27.02.2019) and permission was received from the study hospitals. EMS personnel were informed about the study. The personnel who agreed to participate in the study were asked to fill in the data collection forms with their written consent. Participants were told that participation in the study was voluntary, personal information would be kept confidential, and they could be withdrawn at any stage of the study. The study was performed in accordance with the Declaration of Helsinki.
SPSS 21.0 (SPSS, Inc., Chicago, IL, USA) was used to analyze the data. To define the participants’ characteristics, number, percentage, mean and standard deviation values were used. Content and language validity were evaluated for adaptation of the scale. To determine the factor structure of the Turkish form of the EMSRS, explanatory factor analysis (EFA) with varimax rotation was evaluated. The Kaiser-Meyer-Olkin (KMO) and Bartlett’s sphericity tests were used to investigate the sample size adequacy. Cronbach’s alpha coefficient was used to examine the internal consistency of scale items. The CFI and the EMSRS were compared for criterion validity. For reliability analysis, internal consistency and test-retest measurements were evaluated. To determine the compatibility between the test and re-test, paired sample t- test was used.
The average age of 244 participants was 28.67±6.17 years, and 58.2% (n=142) were women; 61.1% (n=149) of the participants worked as nurses and 23.4% (n=57) worked as physicians, 57.4% had undergraduate education level, 34.8% (n=85) were married and 20.5% (n=50) had children. The average work experiences in EMS and in the profession were determined as 4.19±4.51 and 6.14±6.16 years, respectively.
The Kaiser-Meyer-Olkin (KMO) coefficient and Bartlett’s sphericity test were used to determine the suitability of the data for explanatory factor analysis (EFA). The KMO’s higher than 0.60 and the significance of the Bartlett Sphericity test show that the data are suitable for factor analysis . In this study, it was determined that the KMO coefficient was 0.792 and Bartlett’s sphericity test was 2692.366 (p<0.001). The results of the KMO coefficient and Bartlett’s sphericity test showed that the data are suitable for factor analysis.
To evaluate the construct validity of the EMSRS, EFA was used. The analysis with varimax rotation showed that five factors had values higher than one. The scale explained 47.512% of the total variance. Factor loads of the items on the scale ranged from 0.376-0.809. Factor structure and the factor loads of EMSRS are shown in Table 2. The first factor contained nine items. These items were related to work motivation. The six items related to self-management were created the second factor. The third factor was related to remaining calm at the scene of an accident and contained five items. The fourth factor contained five items related to communication challenges. The fifth factor contained six items related to the consequences of stress.
Cronbach’s alpha coefficient was calculated for the reliability of the scale and internal consistency was evaluated. Cronbach’s alpha coefficients for test and re-test were 0.825 and 0.859, respectively. According to the paired-samples t- test, there was no difference between test and re-test values of the EMSRS (t=1.430; p=0.156).
Correlations Between Scales
The EMSRS was applied to EMS personnel with the CFI to evaluate criteria validity. As a result of the correlation analysis, a strong positive correlation was determined between the scales (r=0.554, p<0.001).
In this study, the psychometric analyses of the Turkish version of EMSRS, which was developed to evaluate the resilience of EMS personnel, were tested.
Before performing factor analysis, it is recommended to examine KMO and Bartlett’s test in the literature . When the explanatory factor analysis results of EMSRS were examined, the factor loads of the items were determined between 0.376- 0.809, and no item was removed from the scale since there was no factor load below 0.30. . The factor loads determined in this study are similar to the original scale . According to the data obtained from this study, it can be said that the factor load values of the scale are high for EMS personnel. As a result of factor analysis, although the original scale was specified as a six- factors structure, in this study, five-factor structures were obtained. Factor structures in the original scale were work motivation (1st, 2nd, 3rd, 4th, 5th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, and 18th items), self-management (6th, 7th, 8th, 9th, and 29th items), remaining calm at the scene of an accident (10th, 23rd, 24th, 30th, and 33rd items), communication challenges (20th, 21st, and 22nd items), social support (25th, and 26th items) and the consequence of stress (36th, 37th, and 38th items), and it explains 51.8% of the variance . The factor structures of this study were determined as work motivation (2nd, 14th, 15th, 16th, 17th, 18th, 20th, 26th, and 28th items), self-management (4th, 5th, 6th, 7th, 8th, and 9th items), remaining calm (22nd, 23rd, 24th, 25th, and 27th items), communication challenges (1st, 10th, 11th, 12th, and 13th items) and consequence of stress (3rd, 19th, 21st, 29th, 30th, and 31st items). When the two items of the social support factor in the original scale were evaluated in terms of factor loads and semantic integrity, they were evaluated in the remaining calm factor in this study. Due to the five-factor structure of the scale, the items applied to professionals cover 47.512% of the total variance. In the validity and reliability analysis, the factor analysis is the most common method used to test the construct validity , and it is recommended that the variance described in the literature should be between 40-60% . In this study, it was found that the construct validity of the scale was provided with its five-factor structure in Turkish culture.
Internal consistency of items was evaluated with Cronbach’s alpha of the reliability of the scale. In the literature, it was stated that the acceptable value of Cronbach’s alpha for internal consistency should be over 0.70. [21,22]. In this study, Cronbach’s alpha was determined as 0.82. It was found as 0.91 on the original scale .
Since it was suggested in the literature that the test should be used again with the same group at two-six weeks interval in order to evaluate the stability of the scales against time , in this study, re-test was performed two weeks later, and Cronbach’s alpha coefficient was determined as 0.85 in re-test. When the test and re-test results are compared, it was seen that the results were similar, and the reliability of the scale was provided with the current version.
In the literature, it was stated that the correlation of the scales should be at least 0.30 for criterion validity . In this study, the CFI was used to evaluate the criterion validity of the scale. The correlation between EMSRS and CFI was calculated and the accuracy of the scale was tested. It was found that there was a statistically significant strong correlation between EMSRS and CFI and a value above 0.30, therefore, the criterion validity of the scale is provided.
There are different measurement tools in the literature for measuring resilience . Their general characteristics are based on answers given by the individuals. Therefore, resilience is affected by cultural differences . Although, in this study, the measurement of resilience for emergency medical services personnel was self-reported, the results were similar with the original scale.
This study has some limitations. Psychological factors that may affect EMC personnel’s’ flexibility have not been investigated. The scale, whose validity and reliability was completed with this study, is valid only for Turkish society.
The data obtained from this study showed that EMSRS can be used to determine the resilience levels of EMS personnel. The results of this study were relative with the original scale. Cronbach’s alpha internal consistency coefficient, test-retest analysis, and equivalent form analysis showed reliability.
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Animal and human rights statement
Conflict of interest
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Hulya Saray Kilic, Sevinc Mersin, Ozlem Ibrahimoglu, Burcu Ozkan. The Turkish adaptation of the emergency medical services resilience scale. Ann Clin Anal Med 2021;12(9):1068-1072
Incarcerated Morgagni hernia in an elderly patient: A case report
Department of Gastroenterology Surgery, Erzurum City Hospital, Erzurum, Turkey
DOI: 10.4328/ACAM.20539 Received: 2021-02-13 Accepted: 2021-05-12 Published Online: 2021-05-17 Printed: 2021-09-01 Ann Clin Anal Med 2021;12(9):1073-1075
Corresponding Author: Deniz Ocal, Department of Gastroenterology Surgery, Erzurum City Hospital, Çat yolu street. No:2, 25240, 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
Congenital diaphragmatic hernias are Bochdalek, Morgagni and Esophagialhernias.
An anterior medial localization defect occurs in the Morgagni hernia diaphragm.
It can be clinically asymptomatic in adults, or may present with serious life-threatening conditions. It is more common in women than men in adults. In this case, we aimed to present the 87-year-old patient who was operated on to achieve a Morgagni hernia.
Keywords: Morgagni; Hernia; Adult patient
It is reported that the incidence of Morgagni hernias among all diaphragmatic hernias is between 3-4%. It is the rarest diaphragmatic defect. Morgagni hernia is located in the anterior diaphragm and is seen bilaterally in 90-100% on the right, 8% on the left and 2% on the left.  As it may be asymptomatic, the most common signs of obstruction are blunt abdominal pain, constipation, and obstruction if the herniated organ is incarcerated. 
Radiological examinations are highly successful in diagnosis. A solid or air-fluid density is observed adjacent to the heart, usually on the right, in the retrosternal area. With computed tomography, a definite diagnosis can be made between 83- 100% of a Morgagni hernia. 
In the treatment of Morgagni hernia, according to the experience of the surgeon, the thoracic or abdominal route can be preferred, surgery is performed by choosing one of the laparoscopic, thoracoscopic or open surgical procedures.
This study presents a patient who was diagnosed with Morgagni hernia in our clinic and whose treatment was completed surgically.
An 87-year-old female patient applied to our clinic with complaints of nausea, vomiting, inability to eat, abdominal pain, and respiratory distress that became evident with effort for the last week. His medical history included hypertension, diabetes mellitus, and chronic obstructive pulmonary disease. The patient had stated that he had intermittent constipation and colic-style pain for years. On physical examination, the abdomen was natural, and there was tenderness in the epigastrium and right upper quadrant by palpation. Respiratory sounds were greatly reduced, and bowel sounds were heard in the right thorax upon listening. Routine blood values were as follows: WBC: 10.41, HB: 13.5, PLT: 236, glucose: 165, urea: 61, creatinine: 1.4, AST: 18, ALT: 9, Na: 146, K: 3.4, CRP: 16, INR: 1.21. In the chest radiography, diaphragm elevation on the right, blunting in costophrenic and cardiophrenic angles and air-fluid level in the paracardiac area on the right were observed.
In tomography examination, Morgagni hernia, 6×8 cm in size, extending from the anterior paracardiac area to the thorax was detected on the right. The pouch filled the stomach, omentum and transverse colon. The preoperative preparations were completed as ASAIII. She was operated with a transabdominal approach with mini laparotomy. During the surgery, it was observed that the corpus of the stomach, antrum, duodenum, omentum, and transverse colon were herniated into the thorax in the right and hernia sac. Organs were rejected in the abdomen, there was widespread edema in the incarcerated organs, and mild ischemic discoloration of the duodenal stomach antrum, no necrosis. The hernia defect was closed with 1 no prolenile separate suture. He was discharged on the 3rd day without any complications.
Giovanni Battista Morgagni found that during autopsy, the diaphragm defect at the sternocostal junction and colon with gangrene in this region caused the patient’s death.  Although Morgagni hernia is frequently encountered in childhood, it is rarely encountered in adulthood. Adult Morgagni hernia is more common in women and obese people.  Morgagni hernia in adults can be diagnosed with a delay because it may be asymptomatic. Symptoms often result from strangulation of the organ within the hernia sac. In our case, the hernia of the patient was detected in the early youth, but the surgery was delayed because it was not symptomatic and the patient was afraid of the operation. Radiological studies were carried out to reveal the cause of ileus, while an appropriate fluid-electrolyte replacement was performed for the patient who could not take orals and was dehydrated due to vomiting. Straight posterior anterior and lateral chest radiographs are extremely valuable in diagnosis.  The most valuable diagnostic tool is computed tomography.  In cases that are asymptomatic or detected incidentally, surgery should be recommended considering possible gastrointestinal obstructions, organ necrosis and severe complications.
The surgeon’s experience is important in choosing a thoracic or abdominal approach. It is stated that thoracic approaches provide a wide field of view and allow reduction with easy access to the contents of the hernia, and are frequently preferred by thoracic surgeons.  Abdominal approaches provide advantages in the repair of bilateral hernias.  It is preferred by general surgeons, stating that organ resections and anastomoses can be performed more easily if necessary. In addition, since 1992, Morgagni hernia has been performed laparoscopically with the advantages of minimally invasive surgery.  Laparoscopic surgery could not be performed in our patient due to his accompanying diseases. The surgery was initiated with a mini laparotomy, and the operation was completed without enlarging the incision, since organ necrosis was not observed in the hernia sac. It should be known that pericardial and pleural perforations may develop during the removal of the hernia sac.  In the literature, it was stated that no problem was encountered in the follow-up of cases whose hernia sac was not resected.  The hernia sac was easily removed in our case because it did not cause serious adhesions. No 1 prolene defect was repaired with individual stitches. In recent years, the safe use of prolene patches has increased.
As a result, Morgagni hernias, although rarely seen, can cause serious morbidity and mortality. After the diagnosis, they should be operated under elective conditions.
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1. Doğusoy I. Diagnosis and Treatment of Morgagni Hernias. J Thor Surg-Special Topics 2010; 3 (1):23-6
2. Eren S, Çiriş F. Diaphragmatic hernia: Diagnostic approaches with review of the literature. Eur J Radiol. 2005; 54 (3):448-59.
3. Kılıç D, Nadir A, Döner E, Kavukçu S, Akal M, Özdemir N, et al. Transthoracic approach in the surgical treatment of Morgagni hernia. Eur J Cardiothorac Surg. 2001; 20:1016-19.
4. Minneci PC, Deans KJ, Kim P, Mathisen DJ. Foramen of Morgagni hernia: changes in diagnosis and treatment. Ann Thorac Surg. 2004;77(6):1956-9.
5. Sirmali M, Türüt H, Gezer S, Findik G, Kaya S, Tastepe Y, et al. Clinical and radiological evaluation of foramen of Morgagni hernias and the transthoracic approach. World J Surg. 2005; 29:1520-4.
6. Loong TPF, Kocher HM. Clinical presentation and operative repair of hernia of Morgagni. Postgrad Med J. 2005;81(951):41-4.
7. Kuster GG, Kline LE, Garzo G. Diaphragmatic hernia through the foramen of Morgagni: laparoscopic repair case report. J Laparoendoscopic Surg. 1992; 2(2):93-100.
8. Golden J, Barry WE, Jang G, Nguyen N, Bliss D. Pediatric Morgagni Diaphragmatic Hernia: A Descriptive Study. Pediatr Surg Int. 2017;33(7):771-5.
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Deniz Ocal. Incarcerated Morgagni hernia in an elderly patient: A case report. Ann Clin Anal Med 2021;12(9):1073-1075
Lung cancer and Lambert-Eaton syndrome concealed by COVID-19
Selçuk Akan 1, Baran Balca 2
1 Department of Internal Medicine, Ankara City Hospital, Ankara, 2 Department of Chest Disease, Marmara University Faculty of Medicine, Istanbul, Turkey
DOI: 10.4328/ACAM.20563 Received: 2021-03-01 Accepted: 2021-04-30 Published Online: 2021-05-08 Printed: 2021-09-01 Ann Clin Anal Med 2021;12(9):1076-1079
Corresponding Author: Selçuk Akan, Ankara City Hospital, Internal Medicine department, Bilkent, Ankara, Turkey. E-mail: email@example.com P: +90 546 4745678 Corresponding Author ORCID ID: https://orcid.org/0000-0002-5053-6896
COVID-19, which infects millions of people worldwide, can affect many organs and systems, mainly the lungs, heart, brain, kidneys, vascular endothelium and bone marrow. As a result, it causes a wide range of complications such as ARDS, acute coronary syndrome, delirium, pancytopenia, DIC, kidney damage. There- fore, in the presence of COVID-19, some diseases that progress rapidly and which can cause similar complications may be concealed. In our article, we aimed to describe a patient who was missed due to the adverse effects of the pandemic period and because the COVID-19 infection may cause similar findings, although he admitted to emergency clinic twice before. In a pancytopenic patient suffering from intermittent fever, exhaustion, myalgia and arthralgia for several months, the diagnosis of small cell lung cancer, bone marrow metastasis and Lambert Eaton Myasthenic Syndrome (LEMS) was delayed due to the presence of COVID-19 infection. Therefore, the patient died in a short time. It was presented because it is a rare case and can lead to serious consequences if not imagined.
Keywords: COVID-19; Lung cancer; Lambert-Eaton Myasthenic syndrome
The coronavirus pandemic negatively impacted healthcare access and healthcare provision. Most of the hospitals were used for patients affected by the pandemia, and medical teams were assigned to follow up and treat these patients. The number of active outpatient clinics and patients was reduced in all branches. However, avoiding medical assistance due to curfews and fear of COVID-19 also prevented early diagnosis of serious diseases such as cancer.
Cancer patients are relatively elderly, in poor physical condition, often with more than one underlying disease and poor lung function. In patients with lung cancer, there are tumor symptoms, including cough, sputum, dyspnea and even fever, and all of these symptoms can be also seen in lung infections. Therefore, COVID-19, which can cause rapid and widespread lung involvement in lung cancer cases that have not yet been diagnosed, may mask cancer clinically and radiologically and may delay diagnosis. On the other hand, symptoms of COVID-19 infection in patients with cancer are more severe and can quickly worsen the clinic .
Lung cancers are the most common tumors associated with paraneoplastic syndromes. Lambert-Eaton Myasthenic Syndrome (LEMS) is the most common neurological paraneoplastic syndrome. Small cell lung cancer was detected in 60% of all patients presenting with LEMS .
Small cell lung cancer has the feature of doubling time, high growth fraction and early metastasis, hematogenous metastasis is present in 2/3 of the cases during diagnosis . As a matter of fact, the patient, who was admitted to the emergency department with various complaints for a few months and was treated on an outpatient basis due to COVID-19 infection, was hospitalized to our internal medicine clinic due to COVID-19 pneumonia and pancytopenia as his complaints worsen. In addition to COVID infection, small cell lung carcinoma bone marrow metastasis and LEMS were detected in further examinations. It was presented to raise awareness, as it is a rare situation in the adverse conditions of the pandemic period and has fatal consequences when overlooked.
A 53-year-old male patient without known systemic disease, admitted to the emergency service 2 months ago with weakness, back pain and mild weakness in the legs. In his examinations, Hb: 11.3 g/dl, Plt: 135000 /mm3, CRP: 15 mg /L. Oral iron preparation and non-steroidal anti-inflammatory drug were prescribed to the patient. The patient whose complaints continued to increase despite the medications, had an intermittent fever and admitted to the emergency department 15 days ago with these complaints. Here, favipiravir and paracetamol were administered to the patient, whose COVID test was positive and mild involvement in the lower lobes was detected on chest X-ray, as O2 saturation was normal. Despite the medication, the patient’s complaints continued and dyspnea started. The patient referred to our internal medicine outpatient clinic with complaints of increasing back and lumbar pain, progressive muscle weakness and fever for 2 months. The patient had a smoking history of 40 packs/year. There was no feature in his family history.
WBC: 3.400 /mcL, Hb: 9.8 g/dl, Plt: 81.000 /mm3, sedimentation: 80 mm/hour, CRP: 60 mg/L, Na: 132 mEq/L, K: 3.6 mEq/L, ALP: 112 U/L, AST: 97 U/L, ALT: 62 U/L, LDH: 885 U/L, GGT: 121 U/L, D-dimer 0.40 μg/mL, COVID-19 PCR (+) was detected in blood analysis. The chest X-ray showed low-density pneumonia focuses, which mostly involved bilateral middle and lower zones (Figure 1). The patient was admitted to the internal medicine clinic for the investigation of COVID-19 pneumonia and pancytopenia. Positive pressure oxygen, erythrocyte suspension replacement, methylprednisolone, enoxaparin sodium, Plaquenil (previously taken favipiravir) treatment was initiated in the patient whose saturation was measured as 85% in room air.
In the peripheral blood smear examination, 55% PNL, 25% lymphocyte, 4% monocyte, 2% eosinophil, 9% normoblast, 1% myelocyte, 2% metamyelocyte, 2% myeloblast were seen. A bone marrow biopsy was performed on the patient, who was consulted to the hematology clinic.
In the follow-up, the patient’s muscle enzymes CK: 1166 mcg/L, CKMB: 92 mcg/L were found to be higher, with progressive loss of strength in the left arm and both legs. Electroneuromyography (ENMG) was performed to the patient, who was consulted to the neurology clinic. In ENMG, a decrease in muscle activity was detected as a result of repetitive nerve impulses to the biceps brachia, quadriceps and tibialis anterior muscles. Combined Muscle Action Potential amplitudes (CMAP) were detected at normal and lower limits in the nerve conduction study. In the needle EMG, more prominent myogenic motor unit potentials (MUP) were observed in the proximal muscles. In the Repetitive Stimulation (RS) test performed with 3 and 5 Hz, 34% decrement response was observed, and 178 % increment response was observed in RS performed with 50 Hz. It was stated that EMG findings were compatible with LEMS and malignancy screening was recommended.
In bone marrow biopsy, tumoral cells with round oval nuclei infiltrating the marrow, narrow cytoplasm and vesicular nucleus were observed and interpreted as bone marrow metastasis ofsmallcelllungcancer(Figure2).Inthethoraxtomography, amasswithasofttissuedensityof25x23mmintheleft middle lobe of the lung and multiple patch-like ground glass- like densities in both lungs were observed. The progression in the lung findings was observed on the patient’s subsequent tomography one week later. (Figure 1). Considering the patient’s biopsy result and EMG findings, diagnoses of small cell lung cancer, bone marrow metastasis, LEMS and COVID-19 pneumoniaweremade.Inthepatientwhowasgivenantiviral therapy, oxygen support and erythrocyte suspension, dyspnea increased and O2 saturations decreased within 1 week. The intubated patient was transferred to the intensive care unit and died 2 days later.
Severe acute respiratory syndrome coronavirus (SARS-CoV)-2, a novel RNA coronavirus in the same family as SARS-CoV, was identified in December 2019 as the cause of a pneumonia outbreak affecting Wuhan, China . It worldwide infected 98 million people and killed more than 2.122.000 people up to February 2021 (available at: https://www.worldometers. info/coronavirus/). COVID-19 mostly affects the lungs, heart, brain, kidneys, vascular endothelium, and bone marrow and can causes complications in patients such as ARDS, acute coronary syndrome, delirium, pancytopenia, DIC, and kidney injury . The COVID-19 may present with symptoms ranging from asymptomatic to severe respiratory failure and may differ from person to person . Fever, dyspnea, cough, sputum, sore throat, headache, diarrhea, nausea-vomiting, muscle-joint pain and weakness are the most common symptoms in patients . Our patient had similar symptoms.
Smoking, hypertension, chronic kidney disease, cardiac disorder, age older than 65 years and cancer have been identified as risk factors for hospitalization and severe respiratory disease in COVID-19 . Our patient had been smoking 1 pack/day for 40 years and had undiagnosed lung cancer.
Typical thorax CT findings in individuals with COVID-19 were ground-glass opacities, particularly on the peripheral and lower lobes, nontypical CT findings included pleural effusion (only about 5%), masses, cavitations and lymphadenopathies [6,8]. Similar radiological findings were present in our patient. Since the radiological findings were compatible with COVID-19 and there was no dyspnea and the O2 saturation was normal, the patient did not have thorax tomography at the emergency admission. Lung cancer was not considered in the preliminary diagnosis, as chest radiography findings can also be seen in COVID-19.
Lung cancer had metastasized to the bone marrow in the 2-months period from the onset of the complaints, and LEMS developed as a paraneoplastic syndrome in the patient with the effect of released mediators and/or autoimmune mechanisms . Since all clinical and laboratory findings, including pancytopenia, can be seen in COVID-19, only antiviral treatment was given to the patient. The patient, whose complaints increased despite antiviral therapy and his laboratory findings worsened, was hospitalized at internal medicine admission. LEMS is a rare neuromuscular junction disease characterized by proximal muscle weakness, decrease or loss of reflexes, moderate ocular and autonomic findings with antibody development to presynaptic voltage-dependent calcium channels. It can be paraneoplastic or autoimmune . LEMS is a rare neuromuscular conduction disorder and malignancy can be detected in 50-60% of the cases. In our case, it was associated with small cell lung cancer. Neuromuscular symptoms may occur for a few weeks or months before lung cancer is diagnosed.
Clinically; pelvic and thigh muscles fatigue, dry mouth, dysarthria, dysphagia and muscle pain can be seen. In physical examination; ptosis, ocular muscle weakness, reduction and/ or loss of deep tendon reflexes can be detected . In our case, before the diagnosis of malignancy, there was a loss of strength in arms and legs.
COVID-19 delayed the diagnosis of cancer and led to rapid deterioration in the clinical condition in the patient with lung cancer, bone marrow metastasis and LEMS. As a result, in some diseases, clinical and laboratory findings may mask more serious diseases similar to them and delay their diagnosis. Therefore, it should be kept in mind that a more serious underlying pathology may be present in patients whose complaints continue for a long time and/or do not respond to treatment. In addition, it should be kept in mind that malignancy may accompany the disease in LEMS cases, and symptoms may be observed even if the tumor is very small.
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1. Yan X, Hongsheng L, Ke H, Mengzhao W. Clinical Management of Lung Cancer Patients during the Outbreak of 2019 Novel Coronavirus Disease (COVID-19). CJLC. 2020; 23(3):136-41. DOI: 10.3779/j.issn.1009-3419.2020.03.02.
2. Block JB. Paraneoplastic syndromes. In: Haksel CM, editors. Cancer Treatment. 4th ed. Philadelphia: WB Saunders; 1995. p. 245-6.
3. Yılmaz Ü. Treatment Approaches in Lung Cancer. Nucl Med Semin. 2018; 4: 32-8. DOI: 10.4274/nts.2018.005.
4. Jain U. Effect of COVID-19 on the organs. Cureus. 2020; 12(8): e9540. DOI:10.7759/cureus.9540.
5. He F, Deng Y, Li W. Coronavirus disease 2019 (COVID-19): What we know? J Med Virol. 2020; 92(7):719-25. DOI: 10.1002/jmv.25766.
6. Giuseppe P, Alessandro S, Chiara P, Federica B, Romualdo DB, Fabio C, et al. COVID-19 diagnosis and management: a comprehensive review. J Intern Med. 2020; 288(2):192-206. DOI: 10.1111/joim.13091.
7. Robilotti EV, Babady NE, Mead PA, Rolling T, Perez-Johnston R, Bernardes M, et al. Determinants of COVID-19 disease severity in patients with cancer. Nat Med. 2020; 26(8):1218–23. DOI: 10.1038/s41591-020-0979-0.
8. Adhikari SP, Meng S, Wu YJ, Mao YP, Ye RX, Wang ZQ, et al. Epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (COVID-19) during the early outbreak period: a scoping review. Infect Dis Poverty. 2020; 9(1):29. DOI: 10.1186/s40249-020-00646-x.
9. Hersby DS, Do TH, Gang AO, Nielsen TH. COVID-19-associated pancytopenia can be self-limiting and does not necessarily warrant bone marrow biopsy for the purposes of SARS-CoV-2 diagnostics. Ann Oncol. 2021; 32(1):121-3. DOI: 10.1016/j.annonc.2020.09.020.
10. Say B, Ergün U, Karaca G. Case with atrophy and proximal muscle weakness: seronegative Lambert Eaton Myasthenic Syndrome. Pam Med J. 2019; 12:181-3. Doi: 10.31362/patd.453646.
11. Gül Ş, Çetinkaya E, Özgül G, Gençoğlu A, Çam E. Small Cell Lung Cancer With Lambert-Eaton Myastenic Syndrome: A Case Report. Göğüs Hastanesi Dergisi. 2010; 24(1):45-8.
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Selçuk Akan, Baran Balca. Lung cancer and Lambert-Eaton syndrome concealed by COVID-19. Ann Clin Anal Med 2021;12(9):1076-1079
Asymmetric ocular manifestations in a premature infant with Candidemia
Ayşegül Arman 1, İkbal Seza Petriçli 2, Caner Kara 2, Ayşen Sumru Kavurt 3
1 Department of Ophthalmology, Bilkent City Hospital, 2 Department of Ophthalmology, Etlik Zübeyde Hanim Women’s Health Education and Research Hospital, 3 Department of Neonatology, Etlik Zübeyde Hanim Women’s Health Education and Research Hospital, Ankara, Turkey
DOI: 10.4328/ACAM.20569 Received: 2021-03-08 Accepted: 2021-04-17 Published Online: 2021-05-11 Printed: 2021-09-01 Ann Clin Anal Med 2021;12(9):1080-1082
Corresponding Author: Caner Kara, Etlik Zübeyde Hanim Women’s Health Education and Research Hospital, Department of Ophthalmology, Yeni Etlik Caddesi No: 55, 06010, Etlik, Keçiören, Ankara, Turkey. E-mail: firstname.lastname@example.org P: +90 (312) 567-4679 F: +90 (312) 322-0184 Corresponding Author ORCID ID: https://orcid.org/0000-0002-3628-547X
Candidemia can cause candida chorioretinitis, candida endophthalmitis, and, rarely, candida lens abscess in premature infants. Here, we describe a case of a premature infant with leukocoria and chorioretinitis, presumed to be caused by candidemia. The patient was diagnosed with systemic candidiasis after the growth of C albicans in the blood culture done for septic work up because of a deterioration of his general condition. Ophthalmological evaluation revealed minimal ciliary injection, lens abscess and shallow anterior chamber in the left eye, and chorioretinitis in the right eye at 3rd week of life. The infant developed multiorgan failure and died on the 28th day of life. A dilated ophthalmological examination should be performed in all patients with candidemia within the first week of treatment. Although rarely seen, candida lens abscess should be kept in mind in the differential diagnosis of lens opacities in premature infants.
Keywords: Abscess; Candida; Chorioretinitis; Endophthalmitis; Lens
Candida species are important nosocomial pathogens in neonatal intensive care units (NICU). Preterm infants with gestational age ≤ 32 weeks and birth weights ≤1000g are especially at risk of systemic candidiasis. Common practices in NICU’s, indwelling catheters and endotracheal tubes put the preterm infant at risk of invasive candidiasis . Other risk factors are sepsis, abdominal surgeries, malnutrition, treatment with broad spectrum and multiple antibiotics and total parenteral nutrition . Colonization of the skin and gastrointestinal tract is the first step in the pathogenesis with the adherence of candida to mucosal and dermal epithelial cells, and hematogenous spread is the second step . Infection of the eye results from hematogenous seeding during candidemia and may result in chorioretinitis, endophthalmitis, and, rarely, lens abscess.
Here, we report a premature infant with late onset candidemia and asymmetric ocular involvement at 3rd week of life.
The 975-g male infant was consulted at the NICU of Etlik Zübeyde Hanım Woman Health Training and Research Hospital at 28 weeks postmenstrual age to be evaluated for a fungal eye infection. The infant was born at 254/7 weeks of gestation to a 34-year-old mother by cesarean section due to preterm labor and previous cesarean delivery. Apgar scores were four and eight in the first and fifth minutes, respectively. The patient was intubated in the delivery room and admitted to the NICU. He received two doses of surfactant for respiratory distress syndrome. On the first day, a central venous catheter (CVC) was inserted through which penicillin and gentamicin were administered for three days. Parenteral nutrition was started. Gradually, respiratory distress improved and the baby was weaned from continuous positive airway pressure (CPAP) on the fifth postnatal day. On the eighth day of life, the baby had recurrent episodes of prolonged apnea with desaturation and was evaluated for suspected sepsis. Empiric antibiotherapy with cefotaxime and amikacin was given. However, he deteriorated gradually, and was started on invasive ventilation because of poor respiratory efforts prompting another septic work up including a new blood culture. At the 48th hour, the blood culture yielded growth of Candida albicans, and fluconazole was started. The CVC was removed as the source of infection. The cerebrospinal fluid (CSF) analysis was normal and the culture of CSF was sterile. Cranial ultrasound examination reported hyperechogenic lesions, and fluconazole was changed to amphotericin B. Echocardiogram, abdominal and renal ultrasound examination revealed no vegetation.
On hand-held biomicroscopic examination of the right eye, the cornea was clear, the conjunctiva was white and quiet, the anterior chamber depth was normal without hypopyon, and the lens was clear. There was not any definite sign of inflammation. On indirect ophthalmoscopic evaluation after pupillary dilation, a persistent tunica vasculosa lentis (TVL) and minimal vitreous haze with two yellow-white creamy chorioretinal lesions, half of the optic disc diameter with ill-defined margins were detected in the temporal mid-periphery (Figure 1). Retina was immature and avascular in Zone 2 and Zone 3. On the hand-held biomicroscopic evaluation of the left eye, the cornea was clear, the conjunctiva was hyperemic with minimal ciliary injection, the anterior chamber was shallow without hypopyon and the lens was swollen with a total creamy white lens opacity (Figure 1). Complete fluffy opacification of the lens with signs of ocular inflammation and shallowing of the anterior chamber was considered as lens abscess. The pupillary red reflex was absent, and after pupillary dilation, retina could not be visualized. Intraocular pressure was 15mmHg for the right eye and 31mmHg for the left eye. B-scan ultrasonographic (USG) evaluation of the left eye revealed an enlarged lens extending into the anterior vitreous and no definitive retinal detachment (Figure 2). B-scan USG evaluation of the right eye revealed a normal lens and an attached retina. The initial diagnosis was persistent TVL with presumed candida lens abscess of the left eye and candida chorioretinitis of the right eye. During antifungal therapy, C. albicans was identified in the second blood culture, and amphotericin B treatment was switched to micafungin.
We planned to refer the infant for an intravitreal injection of micafungin into the left eye, but the infant’s condition deteriorated gradually. Supportive treatment as packed cell transfusion for anemia and platelet transfusion for thrombocytopenia was done. The infant gradually developed generalized sclerema, oliguria and despite the intense treatment, the patient died on the 28 day of life due to multiorgan failure. Written informed consent for the publication of this case report has been obtained from a parent of the infant.
Candidemia is the most common cause of endogenous endophthalmitis and can cause candida chorioretinitis with choroidal and retinal lesions, and candida endophthalmitis characterized by chorioretinitis with vitritis [4-6]. Lens involvement is very rare [7,8]. A dilated ophthalmologic examination should be performed on all patients with candidemia according to the Infectious Disease Society of America guidelines . This case is a late-onset endogenous candida eye infection detected at the 3rd week of life after the initiation of treatment for candidemia in an extremely premature infant. This infant had multiple risk factors for systemic candidiasis, including severe prematurity, low birth weight, intravenous catheter, endotracheal tube, total parenteral nutrition, and broad-spectrum antibiotherapy. During embryologic development, the lens is supplied with blood from the hyaloid artery, which approaches the lens from the posterior and supplies a network of vessels called tunica vasculosa lentis (TVL). The hyaloid artery regresses later in gestation followed by the regression of TVL. Birnholz et al.  found that patent hyaloid artery was not seen beyond 29.9 weeks of gestation. These findings were corroborated with a power Doppler US study by Achiron et al. ; they showed that HA regression is a gradual process, and beyond 29 weeks of gestation, HA could not be detected. Patent hyaloid artery system in a preterm infant may allow the fungus to be sequestered in the lens during candidemia. We supposed that the lens opacity in the left eye was caused by the invasion of fungi through the patent HA system. The chorioretinitis in the right eye is caused by the invasion of fungi through the developing retinal and choroidal vasculature. The infant had asymmetric involvement of the eyes, which may be due to the difference in the proximity of the eyes to direct arterial blood flow and patency of the HA system. Although candida lens abscess is a very rare complication of systemic candidiasis, we thought that the growth of less-sensitive fungal strains in serial blood cultures, despite fluconazole and amphotericin-B treatment allowed fungi to be sequestered in the lens and to progress into total lens abscess. In addition, the swollen lens had led to shallowing of the anterior chamber and an increase of the intraocular pressure.
Candida species are a frequent cause of sepsis in premature infants. Dilated eye examinations should be performed within the first week of antifungal treatment. In the presence of candidemia, all cases of neonatal endophthalmitis should be accepted as candidal in etiology. In addition, candidal lens abscess should be kept in mind in the differential diagnosis of lens opacities in premature infants.
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2. Narang A, Agrawal PB, Chakrabarti A, Kumar P. Epidemiology of systemic candidiasis in a tertiary care neonatal unit. J Trop Pediatr. 1998;44(2):104-8.
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9. Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, et al. Executive Summary: Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):409-17.
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11. Achiron R, Kreiser D, Achiron A. Axial growth of the fetal eye and evaluation of the hyaloid artery: in utero ultrasonographic study. Prenat Diagn. 2000;20(11):894-9.
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Ayşegül Arman, İkbal Seza Petriçli, Caner Kara, Ayşen Sumru Kavurt. Asymmetric ocular manifestations in a premature infant with Candidemia. Ann Clin Anal Med 2021;12(9):1080-1082