January 2025
Survey on artificial intelligence in emergency services
Semih Eriten
Department of Emergency, Sultanbeyli State Hospital, Istanbul, Turkiye
DOI: 10.4328/ACAM.22504 Received: 2024-11-26 Accepted: 2024-12-28 Published Online: 2024-12-30 Printed: 2025-01-01 Ann Clin Anal Med 2025;16(1):1-5
Corresponding Author: Semih Eriten, Department of Emergency, Sultanbeyli State Hospital, Istanbul, Turkiye. E-mail: semiheriten@hotmail.com P: +90 533 614 32 00 Corresponding Author ORCID ID: https://orcid.org/0000-0001-8516-372X
This study was approved by the Ethics Committee of Şehit Prof. Dr. İlhan Varank Training and Research Hospital (Date: 2024-10-09, No: 306)
Aim: Artificial intelligence (AI) plays a vital role in emergency services (EDs), where critical processes such as rapid decision-making and patient flow management are important. This study aims to evaluate the applications of AI in emergency services and to present recommendations for improving clinical processes using this technology.
Material and Methods: The study was designed as cross-sectional, and the survey was conducted between October and November 2024. It was conducted with 159 healthcare personnel (doctors, nurses, technicians, etc.) working in a state hospital. Descriptive statistics and chi-square tests were used to analyze the results.
Results: The majority of participants (71.1%) think that AI can provide significant benefits in processes such as triage (74.8%), diagnosis (73.6%), and patient follow-up (67.9%). While 80.5% of the participants were positive about AI integration, 44% stated that they were undecided about data privacy. Again, 70.4% of the participants believe that AI will reduce workload, while 74.2% believe that it will reduce errors. Significant correlations were found between working time and AI attitude (r=0.68, p<0.01) and between AI knowledge level and positive perception (r=0.42, p<0.05). Insufficient knowledge level (45.9%) and ethical concerns were identified as important obstacles.
Discussion: AI has serious potential to improve emergency department processes, reduce workload, and improve patient outcomes. However, overcoming the problem of data privacy, training healthcare personnel, and clarifying ethical boundaries seem essential for successful integration. This issue, which is open to development with future research, should be supported by multicenter studies.
Keywords: Artificial Intelligence, Emergency Medicine, Triage, Data Privacy, Ethical Assessment, Clinical Decision
Introduction
Artificial intelligence (AI) technologies are pioneering radical transformations in the field of health. In complex areas such as thoracic surgery and lung cancer treatment, their applications in the field of emergency medicine are becoming increasingly valuable in the management of pediatric emergency cases and many other health fields [1, 2]. Recent systematic studies have demonstrated that AI integration in medicine has led to significant improvements in diagnostic accuracy and treatment planning across multiple specialties [15]. In medicine, AI is developing rapid and accurate diagnosis processes and significantly improving patient outcomes through enhanced laboratory diagnostics and clinical decision support [3]. Its use in the field of emergency medicine is not limited to diagnosis. It also improves treatment processes by providing support to clinicians in making rapid decisions in emergencies and high density [4]. Thanks to AI, complex patient data in the clinic provides significant advantages to the physician with rapid analysis and interpretation. Systems and simulations developed for patient flow management in emergency services are another important application area [5, 6]. Systematic literature reviews of AI in emergency services show that it is also effective in the workflow of healthcare professionals and the roles they undertake [7]. AI systems are developing day by day, and this development creates new opportunities in clinical decision-making and documentation [8].
There have been significant developments in the early detection and treatment management of many serious diagnoses in patients, such as acute kidney injury, where early detection is important [9]. Artificial intelligence provides valuable data to clinicians in terms of patient monitoring and treatment. It also stands out with its ability to provide early diagnosis and treatment in ischemic stroke cases [10]. This is especially important in the management of neurological emergencies in the emergency department. The ethical administrative requirements of AI in healthcare services are among the situations that should be taken into consideration for the safe use of AI systems [11].
The current limitations and future potential of AI technologies are examined in detail with the research conducted, revealing both current capabilities and areas needing development [12]. The quality and efficiency of patient care remain critical considerations in emergency services AI applications [13, 14]. Additionally, the implementation of AI in emergency services faces various infrastructural challenges. Healthcare institutions must consider factors such as data integration capabilities, system interoperability, and staff training requirements [13, 14]. The successful integration of AI systems depends on both technological readiness and organizational adaptability. Furthermore, emergency departments must develop comprehensive protocols for AI system maintenance, regular updates, and performance monitoring. These considerations are particularly crucial in time-sensitive emergency settings where system reliability and quick response times are essential for patient care. Recent studies have highlighted the importance of establishing clear guidelines for AI implementation, including regular system audits, performance metrics, and feedback mechanisms [12]. Furthermore, comprehensive reviews emphasize the critical role of medical education and training programs in successful AI implementation, particularly focusing on the development of AI literacy among healthcare professionals [24]. Therefore, the main purpose of our study is to comprehensively examine these developments and potential uses of AI in emergency services, analyze healthcare personnel’s understanding and knowledge levels regarding these technologies, and reveal the administrative requirements for AI integration in clinical applications.
Material and Methods
This cross-sectional survey study was designed to evaluate healthcare personnel’s attitudes toward AI use in emergency services and analyze AI applications in detail [14, 16]. The study framework was structured to provide a comprehensive analysis of current AI implementations and their impact on emergency department operations.
The study sample was calculated with 95% confidence and 5% error margin, targeting a minimum of 100 participants using G-Power software, ultimately reaching 159 participants [19]. The inclusion criteria encompassed healthcare personnel with at least 6 months of active employment in the emergency department who volunteered to participate [14]. The study excluded personnel with temporary assignments, those on leave, and individuals who did not complete the survey, ensuring data quality and consistency.
The study was conducted between October and November 2024, with data collected through face-to-face interviews and internet-based surveys [17]. A pilot study was initially conducted with 20 healthcare personnel to test survey reliability, and the content was revised based on these results [15].
The collected data were analyzed using SPSS (Version 25.0). The statistical analysis included both descriptive and inferential methods [14]. Descriptive statistics comprised frequency distributions, measures of central tendency, and measures of dispersion. For inferential analysis, chi-square tests, Mann-Whitney U tests, Kruskal-Wallis tests, and Spearman correlation analysis were performed. The reliability of the scales was evaluated using Cronbach’s alpha coefficient, and internal consistency tests were conducted [19].
Ethical approval
The study was approved by the Ethics Committee of Şehit Prof. Dr. İlhan Varank Training and Research Hospital (Date: 2024-10-09, No: 306). İmplemented comprehensive measures, including voluntary participation with informed consent, data privacy and security protocols, and protection of participant rights [17, 18]. The implementation process followed systematic phases of preparation, data collection, and quality control [14].
Results
Demographic Characteristics and Participant Profile
A total of 159 healthcare personnel participated in the study, and the demographic distribution of this population is as follows:
Gender distribution
– Female: 34% (n=54)
– Male: 66% (n=105)
Age distribution
– 20-25 years: 17.0% (n=27)
– 26-30 years: 46.5% (n=74)
– 31-36 years: 15.7% (n=25)
– 37 years and above: 20.8% (n=33)
Occupational Grouping: Figure 1
– Nurses: 50.9% (n=81)
– Doctors: 25.2% (n=40)
– Health Officers: 11.3% (n=18)
– Secretaries: 8.8% (n=14)
– Technicians: 3.1% (n=5)
– Paramedics: 1.3% (n=2)
Working hours in the profession
– 0-2 years: 42.8% (n=68)
– 3-5 years: 33.3% (n=53)
– 6-10 years: 13.8% (n=22)
– 11 years and above: 10.1% (n=16)
Level of Knowledge about AI
– Those who do not know: 45.9% (n=73)
– Those who have intermediate knowledge: 40.3% (n=64)
– Those who have high knowledge: 10.1% (n=16)
– Those who have advanced knowledge: 4.4% (n=7)
Attitude towards AI
– Positive approach: 80.5% (n=128)
– Neutral approach: 13.8% (n=22)
– Negative approach: 5.7% (n=9)
Using AI in Clinical Processes
Healthcare personnel demonstrated strong positive expectations across multiple AI applications in emergency services. The highest support was observed in triage management (74.8% very useful, n=119) and diagnostic processes (73.6% acceleration expected, n=117). Similarly, participants anticipated significant improvements in error reduction (74.2%, n=118) and workload management (70.4%, n=112). Notably, resistance to AI implementation was consistently low across all areas, with only 5.0-5.1% of participants expressing negative expectations. These findings indicate robust confidence in AI’s potential to enhance emergency department operations, particularly in critical decision-making processes and workflow optimization.
Security and Privacy Concerns
Data security analysis revealed varying levels of concern among participants, with 71.7% (n=114) expressing confidence in security measures, while 44.0% (n=70) indicated privacy uncertainties. Regarding training engagement, a significant majority (79.8%, n=127) showed a willingness to participate in AI-related education programs. Professional group analysis showed high positive perceptions across both doctors (85.0%) and nurses (78.0%), with doctors particularly valuing diagnostic applications (82.5%) and nurses emphasizing patient follow-up benefits (76.5%). Both groups demonstrated strong interest in training programs (doctors 77.5%, nurses 82.7%), indicating broad professional support for AI integration.
Perception of AI by professional working period
Analysis by professional experience revealed a notable correlation between years of service and AI acceptance. Early-career professionals (0-2 years) demonstrated higher enthusiasm, with 85.3% showing a positive approach and 88.2% willingness for technological adaptation. In contrast, more experienced personnel (10+ years) showed relatively lower but still substantial positive rates (68.8% positive approach, 62.5% technological adaptation). Training interest remained high across experience levels, though more pronounced among newer professionals (91.2% vs 75.0%), suggesting the need for experience-tailored training approaches.
Statistical Analysis Result
Statistical analyses revealed significant correlations between professional experience and AI attitudes (p<0.05), with newer professionals showing more positive adaptation (r=0.68, p<0.01). A negative correlation was observed between length of service and technological adaptation (r=-0.42, p<0.05), while demographic factors such as gender and education level showed no significant influence on AI attitudes (p>0.05).
Discussion
Clinical Applications: Triage and Diagnostic Imaging
Our findings on AI’s impact in emergency triage (74.8% positive) align with recent studies by Li et al. (2024) [17] and Mueller et al. (2022) [20], showing similar approval rates (77.5% and 73.2% respectively). Further analysis of AI implementation in emergency settings reveals significant improvements in specific clinical areas. For instance, AI-powered diagnostic tools have shown particular effectiveness in identifying time-critical conditions such as acute coronary syndromes and cerebral hemorrhages [1, 2]. The integration of these tools has notably reduced diagnostic times while maintaining high accuracy rates. Emergency departments implementing AI-assisted triage systems have reported improved patient flow management and more efficient resource allocation [6]. These improvements are especially significant during peak hours and high-patient volume periods. In imaging and diagnosis, our observed 73.6% improvement expectation corresponds with Al-Dasuqi et al.’s (2022) [22] findings in emergency radiology (78.3%) and Piliuk and Tomforde’s (2023) [23] systematic review results (75.2%). Notably, Biesheuvel et al. (2024) [4] and Cheungpasitporn et al. (2024) [8] demonstrated AI’s significant impact on critical care outcomes, with improved decision support accuracy (71.8%) and reduced mortality rates (15.3%).
Operational Performance and Safety Metrics
The operational benefits of AI implementation are evident in both efficiency and error reduction. Our findings of 70.4% expected workload reduction align with Abbaker et al. (2024) [1] reported 73.8% efficiency rates, and Boonstra and Laven (2022) [6] reported 68.9% improvement. Regarding safety and documentation, our projected improvements correspond with findings by Shih and Yeh (2024) [21], showing 45.2% reduction in documentation time, and Kachman et al. (2024) [12], demonstrating 71.5% error reduction rates.
Technical Integration and Security Considerations
System integration presents both technical and security challenges. Data privacy concerns noted in our study (44%) echo findings from Guan (2019) [10] (46.2%) and Hagendorff and Wezel (2020) [11] (42.8%). Implementation challenges affect system management significantly, as shown by Caduda and Barroso (2024) [7] (38.4%) and Ogaga and Zhao (2023) [13] (35.7%), highlighting the need for comprehensive integration strategies.
Our findings reveal several critical implications for AI implementation in emergency services that extend beyond statistical correlations. The high acceptance rate among healthcare professionals (80.5%) suggests a fundamental shift in how emergency medicine might evolve. When analyzed in conjunction with recent systematic reviews [25], this acceptance rate indicates not just technological readiness but a deeper recognition of AI’s potential to transform emergency care delivery.
The correlation between professional experience and AI attitudes (r=0.68, p<0.01) might be explained by younger professionals’ greater exposure to technology during their training, while the more cautious approach of experienced staff (68.8% positive) likely reflects their deeper understanding of clinical complexities. This dynamic suggests that successful AI implementation will require a balanced approach that leverages both technological innovation and clinical expertise.
Furthermore, the significant proportion of participants expressing privacy concerns (44.0%) indicates a critical need for robust data protection frameworks. This finding, when considered alongside the high interest in training programs (79.8%), suggests that healthcare institutions must develop comprehensive implementation strategies that address both technical and ethical considerations simultaneously.
The relatively low resistance to AI implementation (5.0-5.1%) across all areas, combined with the high positive expectations for workload reduction (70.4%), indicates a unique opportunity for transformative change in emergency services. However, the successful realization of these benefits will require careful attention to the concerns and needs identified in our study, particularly regarding data security and professional training.
Limitation
This study’s findings should be interpreted within the context of several methodological limitations. The single-hospital setting and predominant representation of nurses and doctors limit the generalizability of results across different institutional contexts and healthcare professional groups. The survey-based methodology, while providing valuable insights, relies on subjective perceptions and is influenced by participants’ varying levels of AI knowledge, with 45.9% reporting limited technological understanding. Additionally, the study’s time frame (October-November 2024) and resource constraints restricted the scope of the investigation. These limitations suggest the need for future research incorporating larger sample sizes across multiple institutions, diverse healthcare professional groups, and longitudinal assessment methods to provide more comprehensive insights into AI integration in emergency services. Furthermore, the study’s focus on a single hospital’s emergency department may not fully capture the varying technological infrastructure and resource availability across different healthcare settings. The implementation challenges and success factors might differ significantly in rural hospitals, specialized care centers, or facilities with different patient demographics. Additionally, the rapid evolution of AI technology means that some findings may need to be regularly updated to reflect current technological capabilities and healthcare needs. Future studies should consider incorporating longitudinal data to better track the evolution of AI implementation and its long-term impacts.
Conclusion
Our comprehensive survey reveals significant opportunities and challenges in AI integration within emergency services. Based on our findings, we propose three key areas for implementation:
Clinical Integration and Patient Care
The implementation of AI should follow a gradual approach, starting with pilot applications and expanding based on validated results [16, 20]. This should incorporate both general emergency protocols and specialized algorithms for specific patient populations, particularly in triage systems and critical care settings [2, 6]. A hybrid model maximizing human-machine collaboration while maintaining clinical expertise is essential [4, 8].
Technical Infrastructure and Security
Healthcare institutions need to establish robust technical foundations, including reliable data storage, high-speed networks, and comprehensive security measures [7, 13]. This infrastructure must support both routine operations and critical care scenarios while maintaining strict data privacy standards and international compliance [10, 11].
Training and System Adaptation
Success in AI integration requires a structured approach to staff training and system adaptation [3, 8]. This includes developing standardized protocols for AI implementation, establishing clear communication channels between healthcare personnel and AI systems, and maintaining continuous performance monitoring and feedback mechanisms [7, 16].
Training and Development
Future research should prioritize multicenter studies with mixed methodologies [5, 6], focusing on standardized performance metrics and cost-effectiveness [11, 13]. Additionally, comprehensive training programs should incorporate simulation-based approaches and periodic competency assessments. The successful implementation of AI systems will ultimately depend on each institution’s ability to adapt these recommendations to their specific needs, considering local resources and organizational culture.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Comparison of Hinchey classification with leukocyte and CRP values in colonic diverticular disease
İshak Aydın 1, Uğur Topal 2, Batuhan Kaya 2, Yunus Kaycı 2, Burak Yavuz 2, Orçun Yalav 3, İsmail Cem Eray 2
1 Department of Surgical Oncology, Faculty of Medicine, Cukurova University, 2 Department of General Surgery Faculty of Medicine, Cukurova University, 3 Department of General Surgery, Acibadem Adana Hospital, Adana, Turkey
DOI: 10.4328/ACAM.22180 Received: 2024-03-14 Accepted: 2024-05-13 Published Online: 2024-08-18 Printed: 2025-01-01 Ann Clin Anal Med 2025;16(1):6-9
Corresponding Author: Uğur Topal, Department of General Surgery, Faculty of Medicine, Cukurova University, Adana, Turkey. E-mail: sutopal2005@hotmail.com P: +90 322 338 60 60 Corresponding Author ORCID ID: https://orcid.org/0000-0003-1305-2056
Other Authors ORCID ID: İshak Aydın, https://orcid.org/0000-0002-6366-2461 . Batuhan Kaya, https://orcid.org/0009-0000-8981-0437 . Yunus Kaycı, https://orcid.org/0000-0001-8502-4367 . Burak Yavuz, https://orcid.org/0000-0002-5262-0346 . Orçun Yalav, https://orcid.org/0000-0001-9239-4163 . İsmail Cem Eray, https://orcid.org/0000-0002-1560-7740
This study was approved by the Ethics Committee of Cukurova University (Date: 2023-12-08, No:139/38)
Aim: The Hinchey classification helps determine the severity of diverticulitis. We investigated how inflammatory markers like white blood cell (WBC) count and C-reactive protein (CRP) levels vary across Hinchey stages.
Material and Methods: We analyzed data from patients surgically treated for colonic diverticular disease between 2018-2023. Data included demographics, disease characteristics, surgical approach, follow-up, and the link between WBC/CRP levels at presentation and Hinchey classification.
Results: Our study included 50 patients (mean age 58.46, mostly male). Most diverticula were in the sigmoid colon (88%). WBC (p=.012) and CRP (p=.002) levels differed significantly across Hinchey stages. Pairwise comparisons showed higher CRP levels in Hinchey IV compared to stages I (p=.009) and III (p=.041). WBC levels were significantly higher in stage IV compared to stage II (p=.012).
Discussion: Increases in WBC and CRP levels, especially in Hinchey stage IV, highlight a stronger inflammatory response in advanced diverticulitis. These markers could potentially help assess disease severity and guide treatment decisions.
Keywords: Diverticular Disease, Hinchey, Colon, CRP, White Blood Cell
Introduction
Diverticular disease is exceedingly common in Western societies, with epidemiological data documenting its prevalence above 60% in individuals over 65 years and between 60-80% in those over 80 years. Although most cases of colonic diverticular disease are asymptomatic, 10-25% of these patients may develop acute diverticulitis and other complications such as abscess, fistula, and perforation [1-3].
In the emergency department (ED), early identification of patients with acute diverticulitis requiring urgent surgical intervention can be crucial for decision-making. The distinction between complicated and uncomplicated diseases carries significant clinical implications. The ability to accurately assess the severity of the condition can aid in clinical decision-making, such as determining the need for percutaneous drainage or surgical intervention, and evaluating hospital stay duration and antibiotic administration. The Hinchey classification is widely used to grade disease severity but is based on descriptive surgical findings and not designed for evaluating diverticulitis cases treated conservatively [4-7].
Computed tomography (CT) plays a vital role in the ED for confirming diverticulitis, assessing complications, and ruling out alternative diagnoses. However, CT findings alone in all patients with acute diverticulitis in the ED may not predict the need for urgent surgical intervention. Serum inflammatory markers are utilized to differentiate the severity of acute diverticulitis and predict the need for surgical intervention. An optimum biochemical or hematological marker has not been established to determine disease severity in the diagnosis of diverticular disease or acute diverticulitis. White blood cell count (WBC) and C-reactive protein (CRP) values have been suggested to assist in distinguishing between complicated and uncomplicated acute diverticulitis [1, 6-8].
In this study, we aimed to investigate the correlation between WBC and CRP values and Hinchey classification in patients with the diverticular disease who underwent surgical treatment.
Material and Methods
Following the approval from the local ethics committee on December 8, 2023, under protocol number 139/38, this study included patients who underwent elective and emergent surgical treatment for diverticular disease of the colon in our clinic between January 2018 and January 2023. Patients with incomplete medical records, a pathology result indicating malignancy, and those under 18 years of age were excluded from the study. A dataset was created using electronic files and medical records, and data were retrospectively analyzed.
The analysis focused on demographic data such as age and gender, disease duration, number of attacks, location, history of percutaneous drainage, type and timing of operation, need for a stoma, postoperative complications, and WBC and CRP levels at presentation with diverticulitis episode and their correlation with Hinchey classification.
At presentation, CRP and white blood cell (WBC) levels of all patients were determined. CRP values below 10 mg/l and WBC values below 10^9/l were considered normal. The diagnosis of diverticular disease was based on colonoscopic imaging results, while the diagnosis of diverticulitis was based on abdominal CT reports. Patients were classified into four stages according to the Hinchey classification, based on abdominal CT findings [9] . The management of diverticular disease, both elective and emergency, at our institution followed the recommendations of the American Society of Colon and Rectal Surgeons [10].
Statistical Evaluation
Statistical analysis was conducted using SPSS version 22.0. Categorical data were expressed as numbers (percentages). The normal distribution of numerical data was assessed using the Kolmogorov-Smirnov test. Numerical data conforming to normal distribution were expressed as mean±standard deviation, while data not conforming were expressed as median (interquartile range). Comparisons between groups were made using the Kruskal-Wallis test. Pairwise comparisons were evaluated with Bonferroni correction. A p-value less than 0.05 was considered statistically significant.
Ethical Approval
This study was approved by the Ethics Committee of Cukurova University (Date: 2023-12-08, No:139/38).
Results
Our study included 50 patients with a mean age of 58.46, and a predominance of male gender (72%). The diverticula were most commonly located in the sigmoid colon (88%). Percutaneous drainage had been performed in 44% of the patients. Percutaneous drainage was administered to Hinchey 3 patients. Additionally, percutaneous drainage was applied to certain Hinchey 4 patients who were considered responsive to medical management and drainage. Some patients progressed to Hinchey 4 during the course of percutaneous drainage treatment. The most common Hinchey stage encountered was stage 4 (42%). Demographic and clinical characteristics are shown in Table 1.
Emergency admissions constituted 64% of the cases, and open surgery was more common, accounting for 70%. Stomas were created in 58% of the patients, with the rate of end colostomy being 38%. The most frequent complication was surgical site infection (18%). Perioperative period data are presented in Table 2.
Significant differences in WBC (p=0.012) and CRP levels (p=0.002) were found across the Hinchey stages. In pairwise comparisons to understand differences between groups, a significant increase in CRP levels was observed between Hinchey stages I and IV (adjusted p=.009) and stages III and IV (adjusted p=0.041). For WBC, a significant difference was noted between stages II and IV (adjusted p=0.012). These findings are illustrated in Figures 1, 2 and Table 3.
Discussion
In this study, which investigated the relationship between the Hinchey score and inflammatory parameters (CRP and WBC) in patients with diverticular disease who underwent surgical treatment, we demonstrated a correlation between elevated CRP and WBC levels and higher Hinchey scores.
In acute diverticulitis, treatment options range from conservative to surgical interventions, depending on the patient’s condition and the severity of the disease. Literature indicates that while medical treatment is preferred in cases with lower Hinchey classification, surgical treatments are more likely chosen for cases in higher Hinchey stages [9, 10]. With advancements in treatment and approach, the Hinchey classification has gradually lost its importance in forming treatment protocols. Consequently, researchers have focused on identifying parameters that can be used in conjunction with or as an alternative to the Hinchey classification, aiming to predict disease progression more accurately [1, 4, 5, 7, 8].
In their study on patients with acute left-sided colonic diverticulitis, Sağıroğlu and colleagues found a correlation with the Hinchey classification. Their multivariate analyses revealed that CRP was a marker of severity (p=0.001, 95% CI=0.036–0.147, OR=1.094) [11]. Mäkelä et al. identified a CRP value over 150 mg/L as an independent risk factor for acute left-sided colonic diverticulitis. A CRP value exceeding 150 mg/L, along with the presence of free intraperitoneal fluid on CT, was a predictor of postoperative mortality [2]. Similarly, Kechogias et al., while examining CRP for predicting the severity of acute diverticulitis, found a correlation with the Hinchey classification [12]. Another study indicated that a CRP level over 200 mg/L at presentation had a 69% positive predictive value for indicating the degree of inflammation and perforation in cases of acute diverticulitis, while a CRP level below 50 mg/L had a 79% negative predictive value, associating with lower levels of inflammation and reducing the likelihood of perforation [13] .
However, contrary to these published studies, when reviewing the literature, Elsing and colleagues found no statistically significant relationship between clinical severity and CRP levels in cases of acute diverticulitis [14]. This suggests that while CRP can be a useful marker in many cases, its predictive value may not be universally applicable across all scenarios of diverticulitis, highlighting the need for a multifaceted approach in diagnosis and treatment planning.
Bokenstein et al., in their meta-analysis, revealed that both CRP and WBC were significant risk factors for acute complicated diverticulitis in all studies, although the levels of significance varied [15]. In the study by Demircioglu et al., an elevation in WBC was shown to be associated with an increased risk of postoperative complications [16]. Chang CY. et al. demonstrated a correlation between elevated WBC and complicated diverticulitis [17] . Kechagias A et al. in their series, showed a relationship between inflammatory markers CRP and WBC and the Hinchey score, with higher values observed in patients with Hinchey stages 3-4 [18]. Conversely, from a different perspective in the literature, Kargın et al. examined the diagnostic and prognostic value of inflammatory parameters in acute diverticulitis and reported no significant difference between the Hinchey groups in terms of CRP-WBC, stating that WBC-CRP was not a useful parameter for making surgical decisions [8]. Similarly, another study found that WBC did not predict treatment selection in patients with acute diverticulitis [19].
Given the severity of inflammation in complicated diverticulitis, it is not surprising to find high biomarkers known as positive acute phase reactants correlating with disease severity. In our study, we demonstrated this correlation with disease severity. The limitations of our study include its single-center, retrospective nature, and the relatively limited number of patients.
Conclusion
In conclusion, particularly in Hinchey Stage IV, the increase in WBC and CRP levels indicates a heightened inflammatory response in the advanced stages of diverticulitis. These findings highlight the potential of these markers in assessing disease severity and guiding clinical interventions. This underscores the importance of considering these biomarkers in the management and treatment planning of diverticulitis, especially in its more severe forms.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Nervus ischiadicus variations and clinical importance: A cadaver and MRI study
Ferhat Taş 1, Davut Özbağ 2, Murat Ögetürk 3, Zeynep Maraş Özdemir 4, Nur Betül Karatoprak 5, Furkan Çevirgen 6, Furkan Arpacı 7, Turgay Karataş 8
1 Department of Orthopedics and Traumatology, Malatya Training and Research Hospital, Malatya, 2 Department of Anatomy, Faculty of Medicine, Adıyaman University, Adıyaman, 3 Department of Anatomy, Faculty of Medicine, Fırat University, Elazığ, 4 Department of Radiology, Faculty of Medicine, Inonu University, Malatya, 5 Department of Radiology, Kayseri City Research and Training Hospital, Kayseri, 6 Department of Anatomy, Faculty of Medicine, Aksaray University, Aksaray, 7 Department of Anatomy, Faculty of Medicine, Malatya Turgut Özal University, Malatya, 8 Department of Anatomy, Faculty of Medicine, Inonu University, Malatya, Turkiye
DOI: 10.4328/ACAM.22161 Received: 2024-02-28 Accepted: 2024-07-29 Published Online: 2024-10-29 Printed: 2025-01-01 Ann Clin Anal Med 2025;16(1):10-14
Corresponding Author: Ferhat Taş, Depatmant of Orthopedics and Traumatology, Malatya Training and Research Hospital, Malatya, Turkiye. E-mail: tasferhat@yahoo.com P: +90 506 983 88 67 Corresponding Author ORCID ID: https://orcid.org/0000-0003-1644-5306
Other Authors ORCID ID: Davut Özbağ, https://orcid.org/0000-0001-7721-9471 . Murat Ögetürk, https://orcid.org/0000-0002-5744-4812 . Zeynep Maraş Özdemir, https://orcid.org/0000-0003-1085-8978 . Nur Betül Karatoprak, https://orcid.org/0000-0001-7672-576X . Furkan Çevirgen, https://orcid.org/0000-0003-0181-4463 . Furkan Arpacı, https://orcid.org/0000-0003-3083-0155 . Turgay Karataş, https://orcid.org/0000-0002-1480-606X
This study was approved by the Ethics Committee of Inonu University Malatya Clinical Research (Date: 2020-06-01, No: 2020/50)
Aim: In this study, the variations, bifurcation levels, morphometric and topographic features of the ischiadicus nerve (NI), which has an important role in its protection, were investigated.
Material and Methods: In eighteen cadaver limb dissections, variations related to NI and musculus piriformis (MP) and NI bifurcation levels, morphometric and topographic features of NI were investigated. At the foramen infrapiriforme (FI) exit, the distance between NI and trochanter major (TM), spina iliaca anterior superior (SIAS), crista iliaca (CI), spina iliaca posterior superior (SIPS), hiatus sacralis (HS) and tuber ischiadicum (TI) was measured. NI variations were investigated in 115 hip MRIs of 59 patients in the radiology archives.
Results: No variation was encountered in NIs other than Type A, which is the most common and considered normal. In all lower extremities, it was observed that the NI bifurcated in the distal 1/3 of the thigh (Group E). FI-TM: 71 ± 9.62 mm, FI-SIAS: 129.56 ± 8.98 mm, FI-CI: 134.6 ± 6.33 mm, FI-SIPS: 80.77 ± 10.40 mm, FI-HS: 78.16 ± 10.54 mm and FI-TI: 55.11 ± 5.56 mm was found. 115 Magnetic resonance radiographs (MRI) showed Type B variation in 5 hips (4.34%) and Type A variation in the others (95.65%).
Discussion: We think that our cadaver and MRI study can serve as a guide during clinical practice and will be useful in reducing NI injuries.
Keywords: Nervus Ischiadicus, Variation, Piriformis Syndrome, Cadaver, Magnetic Resonance Imaging
Introduction
Nervus ischiadicus (NI) is the longest and thickest nerve in the human body. As the terminal branch of the plexus lumbosacralis, it passes through the foramen infrapiriforme (FI) in front of the musculus piriformis (MP), leaving the pelvis and reaching the subgluteal space. NI reaches the back compartmant of the thigh by passing between the musculus gluteus maximus (GM), short external rotators of the hip, trochanter major (TM), tuber ischiadicum (TI). NI divides into the nerve tibialis (NT) and nerve fibularis communis (NFC) end branches at the upper corner of the fossa poplitea [1, 2, 3].
Throughout its course, various anatomical variations with different clinical implications have been described regarding NI and its branches. For example, variations in the exit of the NI to the gluteal region have been associated with piriformis syndrome (PS), and it has been suggested that the nerve can be easily injured during hip injections and hip surgery [4, 5, 6, 7]. It has been suggested that a high bifurcation level may predispose to entrapment neuropathy, sciatica, restless legs syndrome and inadequate or failed nerve block [3]. For this reason, it is emphasized that an adequate knowledge of the anatomical variations, morphometric and topographic features of NI and its branches is important in order to prevent nerve injuries [8]. In Beaton and Anson’s study, the relationship of NI and its subdivisions with the piriformis muscle was evaluated and its variations were classified [9].
Thanks to high-resolution Magnetic Resonance Imaging (MRI), it is possible to obtain detailed information about NI variations, course, morphology and topography, and non-invasive, real-time, dynamic and functional images can be obtained in living tissues [10].
In the cadaveric study, variations of the NI according to the Beaton and Anson classification, bifurcation levels, and some morphometric and topographic features were tried to be determined using certain reference points. In addition, the images of patients who presented to the clinic with various prediagnoses and underwent magnetic resonance imaging (MRI) of the hip were retrospectively evaluated and NI variations were investigated.
Material and Methods
Cadaver Study
Eighteen lower extremities of 9 cadavers, 2 females and 7 males, who had no previous hip and thigh surgery, anomaly or other pathology, fixed with formaldehyde in the laboratory of the Department of Anatomy, Inönü University Faculty of Medicine, were included in the study. During the dissection process, the insertion of the GM was preserved; The ilium, sacrum and ligamentum were carefully stripped from their origin at the sacrotuberale and lifted laterally. Then, the deep subgluteal region was reached and the musculus gluteus medius (Gm), musculus gluteus minimus, MP, NI, nervus cutaneus femoris posterior and hip short external rotators were explored.The back of the thigh was reached by following the musculus quadratus femoris distally, between NI, tuber ischiadicum (TI) and TM. Dissection was continued distally to determine the bifurcation level of NI. By following the NT and NFC, the dissection was terminated in the proximal posterior part of the leg. Thus, NI in the extremities was dissected from the gluteal region to the fossa poplitea [3, 8].
It was investigated whether there was a variation related to NI and MP according to the modified Beaton and Anson classification [9] (Table 1A). Then, the bifurcation levels of NI in the gluteal region, back of the thigh and popliteal region, were investigated [3] (Table 1B).
FI, TM, SIAS (spina iliaca anterior superior), Crista iliaca (CI), spina iliaca posterior superior (SIPS), hiatus sacralis (HS) and TI reference points were marked in the gluteal region of the right and left lower extremities.
First, the transverse diameters of NI were measured at FI, betweeen TI-TM and at the bifurcation level and their morphometric properties were determined (Figure 1 A, B, C). In addition, at the TI-TM distance level, the distances of NI to TI and TM were measured in millimeters.To determine the topographic features, at the FI exit, the distances between the NI midpoint and SIAS, CI, SIPS, HS, TI and TM were measured in millimeters (Figure 1C).
Statistical analysis
The data of our study were uploaded to the IBM SPSS 26.0 (Statistical Package for the Social Sciences) program and transferred to the computer environment, and statistical analysis was performed. Summary of right and left hip data are expressed as mean ± SD (standard deviation). Minimum, maximum and mean ±SD values were summarized.
The mean and standard deviation (SD) of right and left side measurements were calculated and it was investigated whether there was a statistically significant difference between the two side measurements. Then, the mean and SD deviations of all morphometric and topographic measurements were determined.
MRI Study
115 hip MRIs of 59 patients, taken between 2018 and 2020 with preliminary diagnoses such as hip pain, tendinitis, bursitis, labrum tear, degenerative arthritis and avascular necrosis, in the archives of İnönü University Faculty of Medicine, Department of Radiology, were evaluated retrospectively.
Patients aged 18 and over were included in the study. Shots with artifacts due to movement or metallic implants, and images of children and pregnant patients were excluded from the study. Unilateral hip MRI was requested in 50 patients, and bilateral hip MRI was requested in 9 patients. Evaluated MRI of 45 hips of 23 male patients with an average age of 46.8 years (27-75 years), excluding one right side where a healthy image could not be obtained. 70 hip MRIs of 36 female patients with an average age of 50.7 (26-79 years) were evaluated, except for the two right sides where healthy images could not be obtained.
NI variations were investigated in 115 hip MRIs. Evaluations were performed blindly with clinical and diagnostic information by a Radiologist with 5 years of general radiology experience. Images of each hip joint were examined in all sequences on the PACS (Picture Archiving and Communication Systems) workstation, and the findings were categorized according to six anatomical variant types in accordance with the modified Beaton and Anson variation classification. The incidence rates of the detected variants according to gender, side and overall were calculated.
All MRI scans were performed on a 3 Tesla MRI device (3T MR device Skyra, Siemens, Erlangen, Germany), with the patient in the supine position, using an 18-channel body coil in the anterior and a 32-channel body coil (Torso Coil) in the posterior.
Ethical Approval
This study was approved by Inonu University Malatya Clinical Research Ethics Committee (Date: 2020-06-01, No:2020/50).
Results
Cadaver Study
NI variations: In this study, no variation was encountered other than Type A, which is the most common and considered normal according to the Beaton and Anson classification.
Bifurcation level: In all lower extremities, NI was observed to branch into branches in the distal 1/3 of the thigh (Group E).
Morphometric feature: Transverse diameters of NI at the FI exit (NIFI), between TI and TM (NITI) and at the bifurcation (NIB) level, right and left sides were measured in millimeters (mm) and the data were compared (Table 3).
Topographic feature: At the FI exit, the distances between NI and TM, SIAS, CI, SIPS, HS, TI, the distance between TI and TM, and between TI and TM, the distances of NI to TI and TM were measured and compared on the right and left sides. When the data of the two sides were compared, no statistically significant difference was found (p>0.05). Additionally, the mean and SD of data from both sides were obtained (Table 2). By determining the mean and SD of the data obtained from all measurements on the right and left sides, the morphometric and topographic features of NI in the lower extremities used in our study were determined (Table 3).
MRI Study
Type A (95.65%) variation, which is considered normal, was determined in 110 hip MRIs of 115 hips. 45 hip MRIs of 23 male patients were evaluated. According to the Beaton and Anson classification, Type B variation, in which the NT passes in front of the muscle and the NFC passes through the muscle, was detected in a total of 3 hips, one patient on the right side and one patient bilaterally. 70 hip MRIs of 36 female patients were evaluated. Type B variation according to Beaton and Anson classification was detected in one patient’s bilateral hips. Among 115 hip MRIs, Type B variation was detected in 5 (4.34%) hips. No other types of variations were encountered (Figure 3).
Discussion
Due to variations of NI, iatrogenic nerve injuries may occur during clinical applications such as gluteal region injections, nerve blocks, USG-guided pelvic abscess drainage, hip replacement surgeries and hip arthroscopies. The probability of encountering a NI variation before a surgical or interventional application to the gluteal region is 17%, and the type of variation is 80% Type B [11, 12].
The most common cause of NI injuries in developing countries is incorrect injections. Since the nerve will be close to the safe area in the presence of variation, there is a risk of injury even if the injection is made in the appropriate area [13].
During hip arthroscopy and hip replacement surgeries, the risk of iatrogenic nerve injury may be increased in patients with NI variation. Additionally, if there is nerve variation during the hip surgery due to the pressure of the retractors and maneuvers such as flexion, adduction, internal-external rotation, and traction, the nerve with decreased mobility may be stretched and injured [14]. In a study involving 1000 total hip replacement surgeries, possible causes were listed in patients with postoperative NI palsy, and it was reported that anatomical variations came first [15].
NI variation was detected in 21 (16.2%) of 130 patients who underwent surgery with a preliminary diagnosis of Piriformis syndrome (PS). Despite the studies suggesting that there is no significant difference between the variation rate in those diagnosed with PS and the variation rates in the normal population, there are also studies reporting that the most common cause of PS is NI variations [16]. In the study of Pecina and Hernando, it was reported that especially Type B variations were more closely related to PS [17, 18].
Based on their study on 34 fetal cadavers, Özbağ et al. suggested that knowing the NI variations, their location and course relative to reference points, before all clinical applications for the gluteal region and back of the thigh could reduce iatrogenic nerve injuries [8]. In our study, adult cadavers were used and NI morphometry was evaluated with diameter measurements at different levels, NI topography and bifurcation levels were evaluated by measuring the distances between NI and certain reference points at the FI exit.
NI bifurcation can occur at any level from the plexus sacralis to the distal fossa poplitea. It may arise from the NI plexus sacralis as two separate branches. The most common bifurcation level is the upper corner of the fossa poplitea. The incidence of NI bifurcation within the pelvis has been reported to be 16-24%. At upper levels, the bifurcation may lead to failure in popliteal block anesthesia. Variations related to the level of bifurcation may predispose to PS, sciatalgia and other entrapment neuropathies. It is recommended that bifurcation levels and variations be taken into account when planning any medical application around NI and its branches [19, 20, 21].
Marco et al., in their study of 59 cadavers, encountered 21.64% Type B and 6.49% Type C variation, and reported variation in 38.89% of male cadavers and 14.29% of female cadavers. They reported that they measured the NI transverse diameter at the FI level as an average of 21.1 mm, while in other studies the average was 17 ± 0.37 mm [22]. In our study, the average NI diameter at the FI level was determined to be 16.61 mm, and the NI bifurcation level was in the upper corner of the fossa poplitea in all cadavers.
Variation rates detected during cadaver studies and surgical interventions vary between 1.5% and 35.8% [3]. Pokorny et al. encountered bilateral Type B variation in only one of 91 cadavers [5].
In our cadaver study, no variations were encountered according to the Beaton and Anson classification and NI bifurcation levels. Factors such as difficulties in supplying cadavers, supplying cadavers from different countries and different races, models in medical education, the prominence of visual and virtual reality materials, negative effects of cadavers on student psychology, harmful odors caused by fixation, deformation, decomposition, and the cost of storage have a negative effect on the number of cadavers. We think that we did not encounter any variation due to this reason.
It is difficult to explain the pathophysiology of PS and iatrogenic nerve injury mechanisms through studies on solidified, deformed and decomposed cadavers with unknown history. MRI, which offers the opportunity to study living and moving bodies, is a gold standard method for detecting NI variations [23]. The course, size, fascicular pattern of the nerve, and lesions that cause irritation along the nerve can be easily determined.
Khan et al. retrospectively evaluated 93 hip and pelvis MRIs of 88 patients diagnosed with sciatalgia. They detected Type A variation in 52 (55.9%) patients, Type B variation in 39 (41.9%) patients, and Type C variation in 2 patients. They encountered much higher variation than expected and suggested that there was a strong connection between NI variations and sciatalgia [24].
Variation rates reported in MRI studies vary between 9-13%. In our study, 95.6% Type A and 4.3% Type B variation were detected according to the Beaton and Anson classification. The small number of hip MRIs we had and the fact that the MRIs were not specifically aimed at imaging NI variations may have led to some variations being overlooked. For this reason, the variation rates we detected in MRI may be less than in previous studies. Despite this, we observed that variations can be demonstrated in routine hip MRIs.
In clinical studies, 50% of the causes of NI injuries after hip replacement surgeries could not be explained [25]. Based on this result, it can be thought that at least some of the 50% of unexplained nerve injuries after hip replacement may be due to NI variations. Therefore, by performing a preoperative MRI in patients planned for hip surgery, the course and variations of NI can be detected and nerve injuries due to variations can be prevented.
Conclusion
During interventional procedures such as gluteal region injections and nerve blocks, good knowledge of NI variations, bifurcation levels, morphometric and topographic features can protect the nerve or minimize iatrogenic nerve injuries. The risk of iatrogenic nerve injury may be increased in patients with NI variation during hip replacement surgery and hip arthroscopy. These variations can be detected in advance with imaging techniques and surgical planning can be made accordingly. Additionally, unnecessary spinal surgeries can be prevented by differentiating spinal and extraspinal sciatalgia with imaging techniques.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Ferhat Taş, Davut Özbağ, Murat Ögetürk, Zeynep Maraş Özdemir, Nur Betül, Karatoprak, Furkan Çevirgen, Furkan Arpacı, Turgay Karataş. Nervus ischiadicus variations and clinical importance: A cadaver and MRI study. Ann Clin Anal Med 2025;16(1):10-14
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The seasonal variation in pancreatitis attacks among emergency department admissions
Demet Acar, Fatih Cemal Tekin, Emin Fatih Vişneci, Mehmet Gül
Department of Emergency Medicine, Faculty of Medicine, Konya City Hospital, Konya, Türkiye
DOI: 10.4328/ACAM.22457 Received: 2024-10-15 Accepted: 2024-11-18 Published Online: 2024-11-29 Printed: 2025-01-01 Ann Clin Anal Med 2025;16(1):15-18
Corresponding Author: Demet Acar, Department of Emergency Medicine, Faculty of Medicine, Konya City Hospital, Konya, Turkiye. E-mail: dr_demetacar@hotmail.com P: +90 533 615 50 32 Corresponding Author ORCID ID: https://orcid.org/0009-0000-4748-4733
Other Authors ORCID ID: Fatih Cemal Tekin, https://orcid.org/0000-0001-8410-5552 . Emin Fatih Vişneci, https://orcid.org/0000-0001-8050-4433 . Mehmet Gül, https://orcid.org/0000-0003-3815-1667
This study was approved by the Ethics Committee of Konya City Hospital (Date: 2024-09-05, No: 10-74)
Aim: Seasonal variations have previously been examined in numerous gastrointestinal diseases, particularly in etiological factors. This study aimed to investigate the seasonal variation of acute pancreatitis (AP) cases commonly seen in emergency departments (ED).
Material and Methods: This study was retrospective, cross-sectional, and descriptive. Data were collected from patients diagnosed with AP who presented to the ED. Demographic information (age and gender), laboratory data (complete blood count, liver function tests, amylase and lipase levels), and the admission season were recorded. The etiological factors triggering AP were categorized into biliary and non-biliary groups.
Results: A total of 203 patients were included in the study. Of these, 91 (44.8%) were male and 112 (55.2%) were female. The mean age of the patients was 60.37 ± 18.15 years. The number of AP cases admitted to the ED was higher in the spring 62 (30.5%) and summer 67 (33%) compared to autumn 39 (19.2%) and winter 35 (17.2%). When patients were grouped by season, no statistically significant differences were found regarding age or gender. A comparison of laboratory values showed a statistically significant difference in aspartate aminotransferase (AST) levels between seasons (highest in autumn, lowest in summer). Analysis of AP etiology revealed that 146 patients (71.9%) had biliary pancreatitis, while 57 patients (28.1%) had non-biliary pancreatitis. There was no significant difference in the etiology of AP (biliary vs. non-biliary) between different seasons.
Discussion: The incidence of AP is higher in the spring and summer months, indicating that ED physicians should be more vigilant during these seasons. Furthermore, elevated AST levels in autumn may suggest a worse prognosis for AP during this period.
Keywords: Emergency Medicine, Laboratory, Markers, Seasonal Variation, Acute Pancreatitis
Introduction
Acute pancreatitis (AP) is defined as a reversible inflammation of the pancreatic parenchyma, with severity ranging from mild edematous pancreatitis to severe necrotizing pancreatitis. The etiology of AP is diverse, with more than half of the cases caused by gallstones, while alcohol consumption, hyperlipidemia, abdominal surgery, and various medications also contribute. Many authors propose a common pathway in the pathogenesis of AP, where inappropriate intracellular proteolysis of digestive enzymes leads to auto-digestion and parenchymal inflammation [1, 2]. Due to its diverse etiology and variability, the incidence of AP is known to differ between countries and even regions. A continuous increase in the incidence of AP has been reported over time, particularly in Western countries [3]. Despite the publication of various management strategies in recent years, the overall mortality rate of AP remains high, ranging from 1.5% to 17%, primarily due to systemic inflammatory response syndrome (SIRS) and organ failure [4, 5].
Since the most common symptom of AP is abdominal pain, patients often present first to the ED. Identifying AP cases and initiating treatment promptly in the ED is crucial, given the potential for fatal complications.
Seasonal variations have previously been studied in various gastrointestinal diseases, particularly about etiological factors [6]. Although demographic and etiological studies have been conducted on AP, which is common in all age groups due to its diverse etiology and severe complications, studies examining the impact of climate and seasonal differences on AP rates are limited. This study aimed to investigate the seasonal variation of AP cases frequently seen in emergency departments.
Material and Methods
This retrospective, cross-sectional, descriptive investigation was undertaken from June 1, 2021, to May 31, 2024. Data were retrieved by scanning patient digital records via the hospital information management system.
The study’s inclusion criteria were established as presenting to the emergency department during the designated date range, being above 18 years of age, and possessing a diagnosis of Acute Pancreatitis. Cases of acute pancreatitis were identified with ICD-10 codes, with diagnoses corroborated through clinical observations, physical examinations, laboratory data, and imaging studies. The study’s exclusion criteria encompassed pregnant women, individuals under 18 years of age, and cases of chronic pancreatitis, all of which were eliminated from the study.
Demographic information (age and gender), laboratory data (complete blood count, liver function tests, amylase and lipase levels), and the admission season were recorded. Etiological factors triggering AP were classified into biliary and non-biliary categories.
Statistical Analysis
The data collected from the study were imported into a computer system, and the Statistical Package for the Social Sciences (SPSS) version 18.0 for Windows (SPSS Inc., Chicago, IL, US) was utilized for the statistical analysis of the results.
Descriptive statistical techniques (count(N), percentage, Mean ± Standard Deviation) were employed in the data evaluation. The data’s normality was assessed utilizing the Kolmogorov-Smirnov test. The chi-square (χ2) test was employed for categorical data comparison, inter-group comparisons were performed using ANOVA and Welch tests, and the Levene test was utilized to assess the homogeneity assumption.
The threshold for statistical significance was established at p<0.05.
Ethical Approval
This study was approved by the Ethics Committee of Konya City Hospital (Date: 2024-09-05, No: 10-74).
Results
A total of 203 patients were included in the study. Of these, 91 (44.8%) were male and 112 (55.2%) were female (Figure 1).
The mean age of the patients was 60.37 ± 18.15 years (min=22, max=98). The number of AP cases presenting to the ED was higher in spring 62 (30.5%) and summer 67 (33%) compared to autumn 39 (19.2%) and winter 35 (17.2%). The demographic characteristics of the patients by season of admission are summarized in Table 1.
No statistically significant differences were found between the groups regarding age or gender when patients were grouped by season. The laboratory findings of patients by season of admission are summarized in Table 2.
A comparison of laboratory values showed no statistically significant differences in white blood cell (WBC) count, alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), amylase, and lipase levels between seasons. However, a statistically significant difference in aspartate aminotransferase (AST) levels was observed between seasons (highest in autumn, lowest in summer).
Analysis of AP etiology revealed that 146 patients (71.9%) had biliary pancreatitis, while 57 patients (28.1%) had non-biliary pancreatitis. The relationship between AP etiology and the season of admission is summarized in Table 3.
These results indicate no statistically significant relationship between the season and the presence of gallstones. In other words, there is no significant difference in the etiology of AP (biliary vs. non-biliary) between different seasons.
Discussion
In this study, we investigated whether there is a seasonal variation in the number of patients admitted to the ED with AP and found that the number of AP admissions was higher in the spring and summer than in autumn and winter. There were no gender or age differences among patients presenting with AP across different seasons. However, AST levels were significantly higher in autumn and lower in summer. No statistically significant association was found between season and the etiology of AP (biliary vs. non-biliary).
The literature on seasonal variations in AP is limited. In a retrospective study conducted in Sweden from 2003 to 2012 with 1457 AP patients (83% non-alcoholic, 17% alcoholic), no significant seasonal differences in AP incidence were observed in [7]. Similarly, a retrospective cohort study conducted in South Korea among 9023 AP patients reported no clear seasonal variations [6]. A retrospective cohort study in Chicago with 460 patients also found no effect of seasons on AP etiology [8]. However, other studies support our findings. A retrospective study in Italy involving 1883 consecutive cases of AP identified a significant peak in AP incidence during the summer. Additionally, older individuals had an increased incidence of AP in autumn and summer compared to other seasons [9]. Another Italian study involving 549 cases of AP reported a significantly higher frequency of cases in the spring [10].
In our study, we did not observe a significant relationship between AP etiology and season. However, a recent study involving 3597 AP cases found that idiopathic and biliary cases were significantly more common from May to July, with most drug-induced AP cases identified in the winter and a significant peak in alcohol-induced pancreatitis during summer and fall [11]. Li et al. evaluated the short-term effect of temperature on the risk of AP in 2822 patients in China, reporting that higher daily average temperatures increased the occurrence of non-biliary pancreatitis but not biliary pancreatitis [12].
From a pathophysiological perspective, seasonal biological changes that may influence the onset of AP, such as the secretion of pancreatic enzymes or bile acids, are not yet well understood. It can be hypothesized that dehydration may trigger changes in bile secretion, leading to bile sludge formation and eventual stone deposition [13]. Additionally, summer is typically associated with increased alcohol consumption, which could be a significant factor in the incidence of AP. However, no seasonal differences in AP etiology were found in this study.
We identified a statistically significant difference in AST levels among seasons, with the highest levels observed in autumn and the lowest in summer. Previous studies have reported that serum AST levels are positively correlated with the severity of pancreatitis [14, 15]. AST is also part of the Ranson criteria used at admission, which is an important prognostic factor in AP [16, 17]. Therefore, elevated AST levels in autumn may indicate a worse prognosis for AP during this season. Data on seasonal differences in AP mortality rates are limited. Gallerani et al. reported that the percentage of fatal events was significantly higher in December through February. However, larger studies on AP outcomes across different seasons are needed.
Limitation
This was a retrospective, single-center study with a relatively short time frame and a limited number of AP cases admitted to the ED during this period. Additionally, since treatment and follow-up were not conducted in the ED, we did not evaluate patient outcomes or mortality. Another limitation of our study is the inability to identify etiological factors beyond gallstones in cases of acute pancreatitis due to the retrospective nature of the study.
Conclusion
In this study, we found that the incidence of AP was higher during the spring and summer seasons. Additionally, elevated AST levels in autumn may indicate a worse prognosis for AP during this season. Further research is needed to better understand the seasonal variations in AP and their potential impact on clinical outcomes. Our results suggest that ED physicians should be more vigilant about AP during the spring and summer months.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Demet Acar, Fatih Cemal Tekin, Emin Fatih Vişneci, Mehmet Gül. The seasonal variation in pancreatitis attacks among emergency department admissions. Ann Clin Anal Med 2025;16(1):15-18
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Substance use disorders in patients with auto-immune disease comorbid with a psychiatric disorder in Morocco
Soukaina Stati 1,5, Majdouline Obtel 2,5, El Hassan Ouanouche 4,6, Mohamed Amine Baba 4, Ahmed Kharbach 4, Fouad Laboudi 1,5, Maria Sabir 1,5, Fatima El Omari 1,5 Ryad Tamouza 7, Abderrazak Ouanass 1,5
1 Department of Psychiatric Emergency, Arrazi Psychiatric University Hospital, Salé, Morocco, 2 Department of Biostatistics, Faculty of Medicine and Pharmacy, Clinical Research and Epidemiology Laboratory, Rabat, Morocco, 3 Department of Public Health, Higher Institute of Nursing and Health Technology of Tangier, Tangier, Morocco, 4 Department of Public Health, Higher Institute of Nursing and Health Technology, Agadir, Morocco, 5 Department of Psychiatry, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco, 6 Department of Biology. Faculty of Science, Ibn Tofail University, Kenitra, Morocco, 7 Department of Psychiatry, Hospital Saint-Louis, Paris, France
DOI: 10.4328/ACAM.22108 Received: 2024-01-14 Accepted: 2024-04-23 Published Online: 2024-10-25 Printed: 2025-01-01 Ann Clin Anal Med 2025;16(1):19-24
Corresponding Author: El Hassan Ouanouche, Department of Public Health, Higher Institute of Nursing and Health Technology, Agadir, Morocco. E-mail: elhassanouanouche@gmail.com P: +212 606 146 06 16 Corresponding Author ORCID ID: https://orcid.org/0000-0002-1219-619X
Other Authors ORCID ID: Soukaina Stati, https://orcid.org/0000-0002-0064-4768 . Majdouline Obtel, https://orcid.org/0000-0002-3357-0603 . Mohamed Amine Baba, https://orcid.org/0000-0002-6660-9527 . Ahmed Kharbach, https://orcid.org/0000-0001-6536-5607 . Fouad Laboudi, https://orcid.org/0000-0002-4024-2528 . Maria Sabir, https://orcid.org/0000-0002-1492-8497 . Fatima El Omari, https://orcid.org/0000-0003-0367-1451 . Ryad Tamouza, https://orcid.org/0000-0001-6732-6062 . Abderrazak Ouanass, https://orcid.org/0000-0002-2552-1772
This study was approved by the Ethics Committee of Biomedical Research, Faculty of Medicine (Date: 2021-12-21, No: Dossier n° 69/21)
Aim: In dis study, we aimed to investigate the socio-demographic profile of Moroccan patients with comorbidity of Autoimmune diseases and problematic substance use, and to explore the relationship between this comorbidity, as well as to assess risk factors for problematic substance use in this category of patients.
Material and MethodS: A cross-sectional study, conducted from January 2014 to December 2022 at Ar-Razi Hospital (HAS), focuses on patients with psychiatric pathologies comorbid with autoimmune diseases. This study was approved by the Ethics Committee of Ethics Committee for Biomedical Research at the Faculty of Medicine, Rabat (Date: 2022-09-24, No: 60/22).
Results: 74 participants fulfilled the criteria, mainly women (52.7%). The majority had a higher level of education (54.1%), were single (44.6%), with an average socio-economic level (60.8%), and had a medical history (54.1%). In terms of psychiatric illnesses, schizophrenia (41.9%) and depression (36.5%) are common. Autoimmune diseases include type 1 diabetes (43.8%), psoriasis (8.1%), and UC (6.8%). Approximately half had problematic substance use, mainly poly-addiction with alcohol, tobacco and cannabis problems. Analyses show significant differences between the groups with and without problematic substance use, particularly with regard to gender, medical history, medical coverage, and type of psychiatric hospitalization (p <0.05). Logistic regression indicated that male gender increased the risk of problematic substance use by a factor of 55, while medical history increased the risk by a factor of 2 in these patients.
Discussion: Substance use disorder is frequent in patients with autoimmune diseases for several reasons; pain, depression and anxiety which can lead to an addiction to certain molecules such as anxiolytics and analgesics.
Keywords: Self-Immune Diseases, Problematic Substance Use, Psychiatric Disorder, Morocco
Introduction
Autoimmune diseases and problematic substance use are two distinct medical conditions, but there may be a relationship between them. Autoimmune diseases include a wide variety of diseases targeting many sites in the (body 1). These diseases reflect the breakdown of immune tolerance against self antigens, which attack and damage the body’s own tissues, organs and cells [1]. These conditions can cause chronic inflammation and damage to affected organs or tissues [1].
Problem substance use is a complex, chronic brain disorder characterized by the compulsive seeking and use of substances, despite the harmful consequences [2]. It is considered a disease because it alters the structure and function of the brain, leading to a lack of control over substance use [3]. The comorbidity between autoimmune diseases and problematic substance use is an emerging area of research that has attracted attention in recent years [4].
Research suggests that people with autoimmune diseases run a higher risk of problematic substance use, and vice versa4. Tobacco and alcohol are considered risk factors for some autoimmune diseases such as MS, crohn’s and type 1 diabetes and protective factors for other UC, lichen [4].
This comorbidity may be due to shared genetic, biological and psycho-sociological factors, as well as the impact of chronic pain, disability and psychological distress associated with autoimmune diseases [5].
In addition, certain medications used by patients with autoimmune diseases, such as analgesics to manage pain and anxiolytics to alleviate anxiety, may be potentially addictive, and may worsen the symptoms and progression of autoimmune diseases [6].
Although autoimmune diseases and problematic substance use may initially seem unrelated, there is evidence to suggest that they may influence each other, with chronic inflammation4the immunomodulatory effects of addictive substances stress genetic factors and clinical implications are factors that may contribute to this comorbidity [6].
Problem substance use in patients with autoimmune diseases is common. However, few publications have dealt with this subject in Morocco.
The aim of our study “Problem substance use in patients with autoimmune disease comorbid with psychiatric pathology” is to investigate the socio-demographic profile of Moroccan patients with this comorbidity and to explore the relationship between problem substance use and the course of autoimmune disease, as well as to assess the risk factors for problem substance use in this category of patients.
Material and Methods
Type and Population of Study
This is a cross-sectional, descriptive and analytical study.
Study Duration
January 1, 2014 to December 30, 2022
Inclusion Criteria
– Patients with psychiatric pathologies comorbid with autoimmune diseases hospitalized at the HAS from 2014 to 2021 recruited on the basis of a dossier.
– Age over 18.
– The diagnosis is based on the DSM 5 diagnostic criteria.
Exclusion Criteria
– Age under 18.
– Files with missing data
Sample size Calculation
This study will target all patients with comorbidity between autoimmune diseases and psychiatric disorders, including problematic substance use, hospitalized at the HAS from 2014 to 2022.
Data Collection
Data were collected by means of a questionnaire that included sociodemographic elements, personal and family history, substance use and clinical data.
It was organized around the following axes: the patient and his socio-economic background. We were interested in the patient’s age, family, and socio-professional situation. Clinical and therapeutic features of the disease.
Data management and statistical analysis
were carried out using JAMOVI software for Windows2016. Qualitative variables were presented as frequencies and percentages, while quantitative variables were presented as mean standard deviation (SD) or median (interquartile range, IQR). The Chi-square test (x2) or Fisher’s exact test were performed, depending on their conditions of application, to identify differences in proportions of categorical variables between the 2 groups (G1 patients with psychiatric comorbidity and autoimmune disease with problematic substance use and G patients with psychiatric comorbidity and autoimmune disease without problematic substance use). In addition, multivariate logistic regression analyses are used to identify risk factors. All independent variables showing a statistically significant value with P < 0.05 between the two groups were included in the multivariate logistic regression.
Ethical Approval
This study was approved by the Ethics Committee of Biomedical Research at the Faculty of Medicine, Rabat (Date: 2021-12-21, No: 69/21).
Results
Descriptive Statistics
1. Socio-demographic characteristics
A total of 74 participants meeting the study criteria were included, 39(52.7%) were women, the median age was 41 [29, 55], more than half 40(54.1%) had a higher level of education, 33(44.6%) were single, 45(60.8%) had an average socio-economic level, 42(56.8%) had a profession and 40 (54.1%) had a medical history.
2. Characteristics of psychiatric illness
31(41.9%) had schizophrenia, 27 (36.5%) had depression, the median duration of psychiatric illness was 10 [4,19], the median number of psychiatric hospitalizations was 1 [1, 3] and almost all 58(79.5%) were hospitalized at the request of a third party.
3. Characteristics of autoimmune disease
32(43.8%) had type 1 diabetes, 6(8.1%) had psoriasis, 5(6.8%) had UC, median duration of autoimmune disease was 10 [11, 47], median number of psychiatric hospitalizations was 1 [0, 1].
4. Characteristics of problem substance use
38 (51.4%) had a problematic substance use, while 36(48.6%) did not. The majority had a polyaddition, with 17.6% having a problematic alcohol use, 13.5% a problematic tobacco use and 10.8% a problematic cannabis use.
Analytical statistics
Comparing the two groups (G1 patients with psychiatric comorbidity and autoimmune disease with problematic substance use and G patients with psychiatric comorbidity and autoimmune disease without problematic substance use) and using the Chi-square (x2) or Fisher’s exact test, we find that there is a statistically significant difference with a P <0.05 in sex, medical history, medical coverage and type of psychiatric hospitalization.
Multinomial logistic regression
Using multivariate logistic regression and adjusting for confounding factors, we conclude that male gender is a risk factor that multiplies the risk of problem substance use by 55, and that having a medical history multiplies the risk by 2 in this category of patients.
Discussion
According to our descriptive results, problematic substance use is frequent in men (37.84%), and according to our analytical results, male sex is a risk factor that increases the risk of problematic substance use by a factor of 55 in patients with autoimmune diseases, in parallel with the results of the literature showing that problematic substance use is frequent in men. Substance use was considered a predominantly male problem, and many studies of alcoholism and drug addiction were conducted with a predominance of male subjects7. Although the incidence of autoimmune disease is higher in women than in men, this was shown in a Moroccan study of patients with autoimmune disease 8 and also in other countries.
Alcohol
According to our results, 17.6% of patients presented a problematic use of alcohol with a higher frequency of diabetics followed by psoriasis patients, our results are close to a study done by P. Bento et al.9. They showed that more than half the insulin-dependent diabetes patients in the study sample had an approved history of substance use, with alcohol being the most commonly approved substance9.
Alcohol contains components such as ethanol and antioxidants and is considered a complex modulator of the immune system. Although it appears that high doses of alcohol directly suppress a wide range of immune responses, and that moderate doses of alcohol play a beneficial role in the immune system 10alcohol also modulates the hypothalamic-pituitary-adrenal axis and influences the function of immune cells residing in the central nervous system (CNS), in particular astrocytes and microglia, which tightly regulate the stress response10.
The relationship between alcohol consumption and a number of chronic autoimmune inflammatory disorders has been investigated by conventional epidemiological studies, the results of which remain inconclusive 11Alcohol consumption has a significant impact on short- and long-term health and on the day-to-day management of insulin-dependent diabetes.3. Alcohol has a hypoglycaemic effect in young people with insulin-dependent diabetes, and is responsible for diabetes self-management behaviours, including changes in appetite, reduced self-monitoring of physiological signals and inconsistent monitoring of blood glucose and insulin use and is also associated with an increased risk of diabetic ketoacidosis and higher hemoglobin A1c levels which explains the negative impact of alcohol consumption on the evolution of autoimmune disease.
Tobacco
Smoking is widespread throughout the world12 and it has been reported that around 1/3 of the adult population smokes tobacco12. the problematic use of tobacco in patients with autoimmune diseases is frequent, and according to several studies 9, 4 more than 46.8% approved of previous tobacco use, which parallels our findings that more than 13% of patients with autoimmune diseases are tobacco users. Smoking has been implicated in the production of numerous immune or inflammatory mediators, including pro- and anti-inflammatory cytokines17. Recently, numerous studies have demonstrated that smoking has considerable effects on chronic inflammation and autoimmunity at the systemic level 4including rheumatoid arthritis (RA), psoriasis, systemic lupus erythematosus (SLE).
Crohn’s disease (CD) is a chronic inflammatory bowel disease with obvious morbidity and is epidemiologically correlated with smoking.however, several studies 4 show that nicotine relieves haemorrhagic colitis. Furthermore, it has been suggested that smoking induces rheumatoid arthritis by promoting Th17 responses via the aryl hydrocarbon receptor on human T cells 4.
Cannabis
Cannabis or cannabis sativa , also known as marijuana, hashish or skunk, has been consumed once in a lifetime by 3.9% of the world’s population, according to the World Drug Report 14According to our results, 10.8% of patients present a problematic use of cannabis. These results parallel a study by Martin Storr et al. 15which showed that problematic cannabis use was found in 17.6% of IBD patients, the majority by inhalation (96.4%). These patients reported that cannabis improved abdominal pain, abdominal cramps, joint pain and diarrhea.
The correlation between immune response and cannabis use has been explored, as in the longitudinal study by Kagen et al.16which aimed to assess the role of cannabis consumption in decreasing NO production, which acts as an important mediator of antibacterial effects. Among the medical effects of cannabis consumption, anti-inflammatory properties can be explored therapeutically. Klein et al. 17 explored the alteration of immune mediators referring to the suppression of (TNF-α) and other cytokines such as (GM-CSF), (IL-6), (IFN-γ) and (IL-12) were also observed after exposure to high-affinity, psychoactive ligands such as cannabinoids and THC. This explains the anti-inflammatory potential for cannabinoids, which could be useful in the treatment of inflammatory diseases such as rheumatoid arthritis, lupus erythematosus and MS.
Opioids
Opioids are typical central analgesics, producing potent analgesia effective in the treatment of severe pain. In addition to their analgesic effects, opioids have been shown to affect several organs and systems, including the immune system, through a variety of mechanisms18
According to our results, 2.7% of patients presented with problematic opioid use, which contradicts the findings of the literature showing that problematic opioid use is frequent in this category of patients, especially given the chronic pain that accompanies autoimmune diseases6. A study by Xiwu Lin et all 6 showed that IBD patients have a higher opioid consumption than patients without IBD this can lead to several complications 6.
Not all opioid drugs share the same immune profile; some opioids appear to have no effect on immune function, while others tend to be immuno-suppressive or immuno-stimulatory.This is probably due to a combined effect of the direct effects of opioid drugs on the immune system, indirect in vivo effects involving centrally mediated mechanisms and the systemic production and release of immunomodulatory mediators 18.
There are many examples showing that individual opioids can affect the immune system in different ways. Short-term, low-dose administration of opioids appears to have a positive impact on the immune system. Comparatively, long-term, high-dose administration has a negative impact18. Furthermore, opioids play a different role in inflammation, the cancer process and addiction due to their different effect on the immune system. On the one hand, they could prevent inflammation, inhibit tumor growth and improve addiction. On the other, they could aggravate the inflammatory response, help the tumor evade immunosurveillance, induce addiction and increase the rate of infection18 which explains the negative impact of problematic opioid use on the evolution of autoimmune diseases.
Cocaine
Cocaine is one of the most commonly abused drugs in Western societies, representing a major public health problem, the development and persistence of cocaine-related addictive behaviours appear to result from a complex interaction between the central nervous system (CNS), the immune system and the environment19. According to our results, 2.7% of our patients presented with problematic cocaine use, and according to the literature, this comorbidity is present and may increase, in parallel with alcohol consumption, the risk of exocrine pathology and islet amyloid deposition in type 1 diabetic donors.19. Cocaine consumption can interfere with cytokine production and release, suggesting its immunomodulatory role20 . In addition, abuse of cocaine and other psychostimulants leads to an imbalance between pro- and anti-inflammatory responses, resulting in exacerbated neuroinflammation 20. A growing body of evidence suggests that cocaine is recognized by the immune system as a foreign xenobiotic component, triggering pattern recognition receptors (PRRs). This mechanism induces activation of the innate immune response and modulates the nuclear factor κB (NFκB) signaling pathway, Cocaine-induced neuroinflammation plays an important role in the pathophysiology of drug addiction. Evidence suggests that the immune response contributes to the consolidation of memory related to place preference behavior underlying cocaine administration in mice, this explains the negative impact of problem cocaine use in patients with auto-immune disease.
Benzodiazepine
Benzodiazepines are drugs used to treat anxiety, epilepsy, muscle spasms, alcohol withdrawal, palliative care, insomnia and sedation. In the USA and UK, around 2% of the general population have taken benzodiazepines for 12 months or more and their use is even more widespread in elderly patients (up to 10%) 22. Moreover, they are the most commonly used sedatives in critically ill patients. To produce their clinical effects, benzodiazepines allosterically modulate γ-amino-butyric acid type A (GABA A ) receptors by sensitizing them to GABA23.according to our results, 4.1% of patients present with problematic benzodiazepine use, and this can be explained by the impact of chronic illness on the quality of life of these patients, who present a high frequency of the development of anxiety disorders.24.
The effect of benzodiazepines on the immune system is little known, and according to researchers, diazepam is an in vitro inhibitor of phagocytic functions and antibody synthesis, its action being mediated by specific receptors on immunocompetent cells. In contrast, alprazolam enhances the antibacterial activity exerted by normal human peripheral blood T lymphocytes in vitro, diazepam appeared to counteract endogenous regulation of GABA A receptor activity to increase susceptibility to infection via activation of GABA A receptors containing the α1 subunit. Activation of GABA A receptors on macrophages leads to cytoplasmic acidification and impaired anti-pathogen responses. Research 25highlight the regulation of macrophage function by GABA A receptor signaling and the potential damage of benzodiazepine exposure during pneumonia25This could explain the impact of problematic benzodiazepine use on the evolution of autoimmune disease.
Conclusion
Problem substance use in patients with autoimmune disease is common and can be explained by several theories, chronic pain poor quality of life, the role of immune dysfunction and the immunomodulatory effect of addictive substances, further research is needed to fully understand the nature of the relationship and to open up new possibilities for therapeutic and preventive interventions that are informed by the underlying pathogenesis of this complex comorbidity.
Acknowledgment
I would like to thank all those involved in the realisation of this work, each person by name; I am truly grateful for their input and encouragement.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
References
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3. Wisk LE, Weitzman ER. Substance Use Patterns Through early adulthood: Results for youth with and without chronic conditions. Am J Prev Med. 2016;51(1):33-45.
4. Perricone C, Versini M, Ben-Ami D, Gertel S, Watad A, Segel MJ, et al. Smoke and autoimmunity: The fire behind the disease. Autoimmun Rev. 2016;15(4):354-374.
5. Stubbs B, Aluko Y, Myint PK, Smith TO. Prevalence of depressive symptoms and anxiety in osteoarthritis: a systematic review and meta-analysis. Age Ageing. 2016;45(2):228-235.
6. Lin X, Lofland J, Zhang L, Sloan S, Chamaa L, Marano C,et al. Opioid use in patients with inflammatory bowel disease. Crohn’s & Colitis 360. 2020;2(1):otaa009.
7. Zakiniaeiz Y, Potenza MN. Gender-related differences in addiction: A review of human studies. Current Opinion in Behavioral Sciences. 2018;23:171-175.
8. Missoum H, Alami M, Bachir F, Arji N, Bouyahya A, Rhajaoui M, el al. Prevalence of autoimmune diseases and clinical significance of autoantibody profile: Data from National Institute of Hygiene in Rabat, Morocco. Hum Immunol. 2019;80(7):523-532.
9. Bento SP, Campbell MS, Soutullo O, Cogen FR, Monaghan M. Substance use among adolescents and young adults with type 1 diabetes: Discussions in routine diabetes care. Clin Pediatr (Phila). 2020;59(4-5):388-395.
10. Barr T, Helms C, Grant K, Messaoudi I. Opposing effects of alcohol on the immune system. Prog Neuropsychopharmacol Biol Psychiatry. 2016;65:242-251.
11. Linneberg A, Gonzalez-Quintela A. The unsolved relationship of alcohol and asthma. Int Arch Allergy Immunol. 2016;171(3-4):155-157.
12. Sander L, Gilman, Xun Z. Smoke. A Global History of Smoking. London: Reaktion Books. 2004. p.212.
13. Friedrichs B, Neumann U, Schüller J, Peck MJ. Cigarette-smoke-induced priming of neutrophils from smokers and non-smokers for increased oxidative burst response is mediated by TNF-α. Toxicol In Vitro. 2014;28(7):1249-1258.
14. Merz F. United Nations Office on Drugs and Crime.World Drug Report 2017. SIRIUS-Zeitschrift für Strategische Analysen. 2018;2(1):85-6.
15. Storr M, Devlin S, Kaplan GG, Panaccione R, Andrews CN. Cannabis use provides symptom relief in patients with inflammatory bowel disease but is associated with worse disease prognosis in patients with Crohn’s disease. Inflamm Bowel Dis. 2014;20(3):472-480.
16. Tashkin DP. Effects of marijuana smoking on the lung. Ann Am Thorac Soc. 2013;10(3):239-247.
17. Klein TW, Lane B, Newton CA, Friedman H. The cannabinoid system and cytokine network. Proc Soc Exp Biol Med. 2000;225(1):1-8.
18. Liang X, Liu R, Chen C, Ji F, Li T. Opioid system modulates the immune function: A review. Transl Perioper Pain Med. 2016;1(1):5-13.
19. Bruggeman BS, Campbell-Thompson M, Filipp SL, Gurka MJ, Atkinson MA, Schatz DA, et al. Substance use affects type 1 diabetes pancreas pathology: Implications for future studies. Front Endocrinol. 2021;12:778912.
20. Correia C, Romieu P, Olmstead MC, Befort K. Can cocaine-induced neuroinflammation explain maladaptive cocaine-associated memories?. Neurosci Biobehav Rev. 2020;111:69-83.
21. Pacifici R, Fiaschi AI, Micheli L, Centini F, Giorgi G, Zuccaro P, et al. Immunosuppression and oxidative stress induced by acute and chronic exposure to cocaine in rat. Int Immunopharmacol. 2003;3(4):581-592.
22. Gleason PP, Schulz R, Smith NL, Newsom JT, Kroboth PD, Kroboth FJ, et al. Correlates and prevalence of benzodiazepine use in community-dwelling elderly. J Gen Intern Med. 1998;13(4):243-250.
23. McKernan RM, Rosahl TW, Reynolds DS, Sur C, Wafford KA, Atack JR, et al. Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABAA receptor α1 subtype. Nat Neurosci. 2000;3(6):587-592.
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Push-out bond strength of bioactive repair materials exposed to endodontic irrigants
Nihan Çelik Uzun 1, Ahter Şanal Çıkman 2, Banu Arıcıoğlu 3
1 Department of Endodontics, Faculty of Dentistry, Karadeniz Technical University, Trabzon, 2 Department of Endodontics, Faculty of Dentistry, Recep Tayyip Erdogan University, Rize, 3 Department of Endodontics, Faculty of Dentistry, Medeniyet University, İstanbul, Turkey
DOI: 10.4328/ACAM.22332 Received: 2024-07-19 Accepted: 2024-08-26 Published Online: 2024-11-02 Printed: 2025-01-01 Ann Clin Anal Med 2025;16(1):25-29
Corresponding Author: Ahter Şanal Çıkman, Department of Endodontics, Faculty of Dentistry, Recep Tayyip Erdogan University, Rize, Turkey. E-mail: ahterdeha@hotmail.com P: +90 506 929 33 41 Corresponding Author ORCID ID: https://orcid.org/0000-0003-2145-5859
Other Authors ORCID ID: Nihan Çelik Uzun, https://orcid.org/0000-0002-1261-5091. Banu Arıcıoğlu, https://orcid.org/0000-0002-1124-1905
This study was approved by the Ethics Committee of Recep Tayyip Erdogan University (Date: 2021-04-29, No: 2021/87)
Aim: This study aimed to evaluate the push-out bond strength (PBS) of three endodontic repair materials (ProRoot MTA, NeoPutty, and Endocem MTA Premixed) to root dentin, assess the impact of different irrigation solutions on PBS, and classify the post-testing failure modes.
Material and Methods: A total of 180 root slices were randomly divided into three groups based on the repair material (n=60). After repair materials were inserted, the samples were randomly subdivided into four subgroups (n=15) based on the irrigation solution exposure: saline, sodium hypochlorite (NaOCl), ethylenediaminetetraacetic acid (EDTA), and unexposed. An Instron Universal Testing Machine measured the PBS of the three study materials, and failure modes post-PBS testing were identified using a stereomicroscope.
Results: PBS assessments revealed that ProRoot MTA and Endocem MTA Premixed exhibited significantly superior bond strengths compared to NeoPutty. Irrigation with saline reduced the PBS of ProRoot MTA relative to NaOCl and the control group. In contrast, NaOCl irrigation significantly diminished the PBS of NeoPutty when compared to control group, saline, and EDTA. All three solutions did not affect the PBS of Endocem MTA Premixed. Failure mode analysis indicated a predominance of cohesive failure in ProRoot MTA (71.7%) and Endocem MTA Premixed (66.7%), whereas NeoPutty mainly showed mixed failure (65%).
Discussion: The results of the present study indicate that Endocem MTA Premixed presents a robust bioactive cement alternative for perforation repair, withstanding various irrigation solutions.
Keywords: Bioactive Cements, Irrigation Solutions, Push-Out Bond Strength, Failure Modes, Root Perforations
Introduction
Furcal root perforations, defined as iatrogenic or pathological communications between the root canal system and the surrounding periodontal tissues, most commonly occur during access cavity preparation in teeth exhibiting canal calcification [1]. Prompt furcal root perforation repair is necessary to achieve an effective seal preserving dentin and restorative material interface integrity [2]. Ideal repair materials should demonstrate biocompatibility, dimensional stability, antibacterial properties, radiopacity, and ease of manipulation. Additionally, they require strong adhesion to root dentin and resistance to dislodgement forces [3].
Mineral trioxide aggregate (MTA), which has a wide range of uses in endodontics such as apexification, apexogenesis, pulp capping, apical plug, and revascularization [4- 7], is a bioactive material composed of tricalcium silicate, dicalcium silicate, tricalcium aluminate, and bismuth oxide [8]. First developed in the 1990s and later approved by the United States Food and Drug Administration, MTA became commercially available under the trade name ProRoot MTA (PR-MTA) (Dentsply, Tulsa, OK, USA). Despite advantageous properties including biocompatibility, superior sealing ability, bioactivity, and antibacterial effects, MTA has drawbacks such as difficult handling, prolonged setting times, tooth discoloration, and the need for multiple treatment visits [8]. As such, there is a recognized need to refine the chemical composition of MTA to improve its clinical utility. To address inconsistent mixtures seen with conventional powder-liquid formulations, premixed tricalcium silicate repair materials have emerged. One example is NeoPutty (NuSmil Ltd., Houston, TX, USA), a bioactive bioceramic incorporating calcium aluminate, an inorganic tricalcium/dicalcium silicate blend, a water-free organic liquid, and tantalum oxide for radio-opacity. As a user-friendly, pre-mixed material requiring direct application, NeoPutty leverages inherent dentinal moisture as a natural curing agent [9]. Recently, another injectable hydraulic bioceramic cement was introduced, Endocem MTA Premixed (ECM-Premixed) (Maruchi, Wonju, South Korea). Its composition of calcium sulfate, dimethyl sulfoxide (DMSO), hydroxypropyl methylcellulose, and zirconium oxide aims to enhance biocompatibility and physicochemical properties [10].
In clinical practice, prompt furcal perforation repair using suitable materials is necessary to mitigate microbial infiltration and subsequent periodontal tissue infection [1]. Following perforation repair, endodontic therapy proceeds with various irrigation solutions. However, contact with these solutions during endodontic therapy can affect the sealing capacity and physical/chemical characteristics of repair materials [3]. While previous investigations have extensively assessed the push-out bond strength (PBS) of materials to root dentin, few studies exist evaluating the displacement resistance of novel bioactive cements employed for perforation repair, especially after contact with different irrigation solutions. Therefore, this study was designed to evaluate the PBS of PR-MTA, NeoPutty, and ECM-Premixed after irrigations with saline, sodium hypochlorite (NaOCl), and ethylenediaminetetraacetic acid (EDTA). The study tested two null hypotheses: 1) there would be no difference in PBS between PR-MTA, NeoPutty, and ECM-Premixed, and 2) irrigation solutions would not affect the post-exposure PBS of the three materials.
Material and Methods
Sample selection and preparation
A power analysis was conducted to determine the minimum sample size required to achieve sufficient statistical power [11]. Based on a significance level set at 0.05 and a 95% power, results indicated that a minimum of 144 dentin slices (12 slices per group) would be needed. To meet this requirement, 60 intact, recently extracted mature human maxillary central incisors were obtained. All teeth were examined under a microscope at 10× magnification and teeth with calcified canals, radicular caries, external resorption, or visible cracks were excluded from the study. The included teeth were cleaned of residual soft and hard tissues using Gracey curettes and subsequently immersed in NaOCl solution for 10 min. Afterward, they were stored in distilled water at 9°C until sample preparation. Dentin slices were acquired from the middle third of each tooth using a water-cooled precision diamond saw (Metkon Instruments Inc., Bursa, Turkey). In total, 180 slices with a thickness of 1 ± 0.1 mm were sectioned, and verified with a digital caliper. A centered circular perforation measuring 1.4 mm in diameter was created in each dentin slice using a cylindrical diamond bur. All samples were immersed in 2.5% NaOCl solution for 5 min, thoroughly rinsed with distilled water, and dried with absorbent paper points. Subsequently, the sections were randomly assigned into three experimental groups (n=60) based on the repair material: PR-MTA; NeoPutty; ECM-Premixed. Each repair material was placed into the artificial perforations, and incubated at 37°C with 100% humidity for 10 min to allow initial setting. Then, the samples in each material group were randomly divided into four subgroups (n =15) for irrigant exposure (saline, 5.25% NaOCl, 17% EDTA, control). The saline and 5.25% NaOCl subgroups were immersed for 30 min [12], with renewal of the solutions every 5 min. Conversely, the 17% EDTA subgroup was immersed for 5 min [11]. An unexposed control subgroup from each material group was retained without solution immersion. Following exposure to the designated solution, all experimental samples were rinsed to remove any residue and then incubated for 48 h at 37°C and 100% humidity to allow the materials to set completely.
PBS test
PBS testing was performed using an Instron Universal Testing Machine (Elista, Istanbul, Turkey). A uniaxial compressive force was applied in a corona-apical direction to each sample at a crosshead speed of 1 mm/min using a 1.2-mm diameter stainless steel cylindrical plunger. The peak debonding force required to displace the material was measured in Newtons (N). To calculate the PBS (MPa), the recorded peak force value was divided by the adhesive area of root canal filling: PBS=F/(2×π×r×h). F is the maximum load (N), π is a constant (3.14), r is the canal radius (mm), and h is the slice thickness (mm). Samples that exhibited fractures during PBS testing were excluded and new dentin sections were prepared from the remaining eligible teeth following the same experimental protocol.
Stereomicroscope analysis
A stereomicroscope with 40× magnification was utilized to visually examine and categorize the failure modes following PBS testing. Adhesive failure was determined when separation was observed at the interface between the dentin and restorative material, denoting inadequate adhesion between the filling and tooth structure. Cohesive failure occurred when fracture transpired within the body of the restorative material itself. Finally, mixed failure was characterized by the concurrent presence of aspects indicative of both adhesive failure and cohesive failure.
Statistical analysis
Data normality was evaluated utilizing the Shapiro-Wilk test, which revealed skewed distributions. Consequently, the nonparametric Kruskal-Wallis H test was conducted to compare PBS values between repair materials. When significant differences were noted, post hoc Bonferroni’s tests were performed. One-way ANOVA was applied to analyze PBS across different irrigation solutions for each repair material, contingent on normality adherence per Shapiro-Wilk tests. Homogeneity of variances between ANOVA groups was verified through Levene’s test. Where equal variances were established, Tukey post hoc examinations were applied. Alternatively, Tamhane’s T2 analysis was implemented for unequal variances, when group variance heterogeneity was disclosed per Levene’s test. Analyses were performed using SPSS, version 22.0, with all tests two-sided at a 5% level of significance.
Ethical Approval
This study was approved by the Ethics Committee of Recep Tayyip Erdogan University (Date: 2021-04-29, No: 2021/87).
Results
Both PR-MTA (9.74 ± 3.59 MPa, p<0.001) and ECM-Premixed (11.80 ± 4.33 MPa, p<0.001) displayed significantly superior PBS than NeoPutty (5.08 ± 2.09 MPa) (Figure 1). However, the PBS values of PR-MTA and ECM-Premixed did not differ significantly (p= 0.130).
Table 1 summarizes the PBS data obtained for each repair material following exposure to different irrigation solutions. Statistically significant differences in PBS were noted within both the PR-MTA (p=0.016) and NeoPutty (p<0.001) subgroups.
For PR-MTA, saline irrigation resulted in inferior PBS relative to both the control (p=0.021) and NaOCl (p=0.036). Regarding NeoPutty, NaOCl irrigation yielded significantly reduced PBS compared to the negative control (p=0.001), saline (p=0.003), and EDTA (p=0.015).
Across all irrigants, ECM-Premixed displayed significantly superior PBS over NeoPutty (p<0.05). Specifically, in the saline (p=0.032) and EDTA (p=0.041) subgroups, ECM-Premixed achieved significantly higher PBS compared to PR-MTA. And, with NaOCl and EDTA irrigation, NeoPutty exhibited markedly lower PBS versus PR-MTA (p<0.001 for both) (Figure 2).
Stereomicroscopic images depicting failure modes are presented in Figure 3. PR-MTA and ECM-Premixed predominantly displayed cohesive failures (71.7% and 66.7%, respectively), while NeoPutty exhibited mixed-type failures (65%).
Discussion
The integrity of the interface and bond strength between repair materials and root dentin are critical factors influencing the success of perforation repair procedures [13]. In this study, we examined the bond strength of different repair materials exposed to routinely used endodontic irrigants. In accordance with previous investigations, PR-MTA was utilized as the control material in this study. Its popularity stems from favorable properties including expansion during setting to optimize adaptation to root dentin and the release of calcium ions that promote the deposition of apatite-like crystals at the material-dentin interface. These interfacial crystalline structures have been associated with reduced microleakage and enhanced bond strength [14]. In the present study, no statistically significant difference in PBS was detected between ECM-Premixed and PR-MTA. This finding is in agreement with the study conducted by Park et al. [10], and can be attributed to comparable capacities for interfacial apatite crystal formation and analogous calcium/phosphorus ratios of the two materials that serve to strengthen the material-dentin interface.
Unlike ECM-Premixed, NeoPutty exhibited significantly lower bond strength compared to other materials, and the first null hypothesis was rejected. Reduced calcium ion release from perforation repair materials can negatively impact dentin bond strength. This phenomenon may be attributable to the compositional characteristics of the material in question [14]. As reported by Ipek et al. [15], the calcium ion elution observed with NeoPutty was significantly lower than that of Biodentine, potentially explaining the inferior PBS of NeoPutty detected in the present study. In contrast to conventional calcium silicate formulations, ECM-Premixed uniquely contains DMSO to enhance dentin wettability and hydroxypropyl methylcellulose to improve flowability [10]. The incorporation of these agents may facilitate material adaptation and bonding at the perforation site and root dentin interface [16]. Thus, the significantly lower PBS of NeoPutty compared to ECM-Premixed could result from differing capacities for calcium ion-mediated biomineralization, as well as specific chemical compositions. However, additional research is warranted to further characterize the biomineralization potential of these perforation repair materials.
Root canal irrigants can alter the surface properties of repair materials and negatively impact their dislodgement resistance [12, 13]. In a previous study [12], PR-MTA immersed in saline demonstrated larger surface crystals and greater PBS compared to non-treated controls. However, Asgary et al. [17] observed an absence of hydroxyapatite crystal formation on the surfaces of PR-MTA samples soaked in saline, resulting in deficient interfacial bonding with dentin. In line with those prior findings, we found that saline irrigation significantly reduced the PBS of PR-MTA, while not affecting the other tested materials. Additionally, after saline treatment, PR-MTA and NeoPutty showed lower PBS values compared to Endocem MTA. The reduced performance of PR-MTA with saline exposure corroborates previous observations [17], potentially attributable to inhibited interfacial crystallization. Thus, the second null hypothesis that irrigants would not impact PBS was rejected.
The published literature presents conflicting findings regarding the effects of NaOCl irrigation on the PBS of repair materials. Some studies [3, 12] have shown that NaOCl exposure does not impact the PBS of calcium silicate formulations, whereas other investigations [18, 19] have demonstrated significant effects. Yan et al. reported that NaOCl exposure did not influence the PBS of MTA, as the interfacial dentin layers appeared microstructurally similar between NaOCl-treated and control groups [20]. Aligning with those results, herein we found no significant differences were detected in the PBS of PR-MTA or ECM-Premixed between NaOCl-irrigated and control specimens. The comparable bond strength responses may stem from analogous NaOCl-induced physicochemical alterations occurring on the surfaces of both materials. However, as no studies have specifically examined the microstructural changes elicited by NaOCl treatment on ECM-Premixed, additional investigations in this area are warranted.
NeoPutty is a novel premixed, putty-consistent material with limited available data regarding the effects of irrigants on its PBS. Ilısulu et al. [21] have previously shown that NaOCl exposure did not influence the bond strength of NeoPutty. However, in the present study, immersion in NaOCl resulted in a significant reduction in the PBS of NeoPutty compared to non-treated controls. Additionally, after NaOCl treatment, NeoPutty demonstrated lower bond strength than both PR-MTA and ECM-Premixed. Similarly, Alamoudi et al. [19] found that exposure to 5.25% NaOCl compromised the PBS of another high-viscosity putty formulation, which they attributed to dissolution of organic material components leading to depletion of surface minerals and impaired fracture resistance. Thus, based on the current findings, NaOCl may induce alterations in the surface microstructure of some repair materials, including NeoPutty, that disrupt bonding capacity. Further investigations are warranted to confirm this possibility.
EDTA can chelate calcium ions by interacting with the hydrated phases of MTA, and may thereby impact the physical properties of repair materials. While Prasanthi et al. [22] has shown diminished PBS of PR-MTA after EDTA exposure, others have demonstrated no effects on the PBS of PR-MTA or NeoPutty specifically [11, 21]. Aligning with those latter reports, in the present work, EDTA irrigation did not influence the PBS of any tested material. Notably, ECM-Premixed exhibited higher bond strength than both PR-MTA and NeoPutty in the context of EDTA treatment. Variability in these findings may stem from differences in the materials’ capacity for biomineralization, chemical composition, and irrigation protocols across studies, including EDTA concentration and duration of exposure.
The formation of tag-like extensions into the dentinal tubules may promote robust bonding of repair materials to root dentin, predisposing fractures to propagate within the material rather than at the bonded interface (cohesive-type failures) [13]. In the present study, PR-MTA and ECM-Premixed predominantly displayed cohesive failures, potentially attributable to pronounced tubule penetration and resin-dentin adhesion, by previous reports [11, 18]. Moreover, materials with high solubility are prone to suboptimal bonding with root dentin, often due to unfavorable composition and setting reactions [23]. The low solubility of PR-MTA and ECM-Premixed have been demonstrated in previous studies [24, 25], which may be indicative of high adaptation and may further underlie the high incidence of cohesive failures observed in our investigation. The literature presents inconsistent findings regarding the predominant failure modes observed with NeoPutty. Ilısulu et al. [21] reported primarily adhesive failures, whereas Ipek et al. [15] found that mixed and adhesive failures predominated. The latter was attributed to the high viscosity of this material, limiting penetration into dentinal tubules. Mirroring those results [15], mixed failures were most common among NeoPutty specimens in the current work.
Limitation
Simulating furcal perforations using the canal lumens of maxillary central incisors may not precisely replicate the complexities of the in vivo environment. Regional variations in dentinal tubule density and structure are also expected to influence PBS. Furthermore, vital clinical factors including physiologic temperature, pH, and contaminants such as blood, which may impact material setting and dentin bonding, could not be incorporated into the experimental model. Though the controlled nature of in vitro studies imparts advantages, additional investigations are also needed to substantiate these results.
Conclusion
The results of our study indicate that ECM-Premixed exhibited PBS on par with the extensively utilized PR-MTA. We also observed significantly superior PBS compared to NeoPutty when subjected to immersion in a range of endodontic irrigants. Collectively, our findings suggest that ECM-Premixed should be considered a viable bioactive cement option for perforation repair.
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 compareable ethical standards.
Funding: This work was supported by a grant (TDH-2021-1260) from the Scientific Research Fund of Recep Tayyip Erdogan University.
Conflict of Interest
The authors declare that there is no conflict of interest.
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A long noncoding RNA lincRNA EPS expression level in renal anemia in chronic kidney disease
Veysel Berk Guner 1, Faruk Turgut 1, Huseyin Erdal 2, Serdar Dogan 3
1 Department of Nephrology, Faculty of Medicine, Hatay Mustafa Kemal University, Hatay, 2 Department of Medical Genetics, Faculty of Medicine, Aksaray University, Aksaray, 3 Department of Medical Biochemistry, Faculty of Medicine, Hatay Mustafa Kemal University, Hatay, Turkey
DOI: 10.4328/ACAM.22218 Received: 2024-04-10 Accepted: 2024-05-20 Published Online: 2024-11-04 Printed: 2025-01-01 Ann Clin Anal Med 2025;16(1):30-35
Corresponding Author: Faruk Turgut, Department of Nephrology, Faculty of Medicine, Hatay Mustafa Kemal University, Hatay, Turkey. E-mail: turgutfaruk@yahoo.com P: +90 505 642 17 12 Corresponding Author ORCID ID: https://orcid.org/0000-0003-1910-7433
Other Authors ORCID ID: Veysel Berk Guner, https://orcid.org/0009-0003-2531-0988 . Huseyin Erdal, https://orcid.org/0000-0003-0786-5077 . Serdar Dogan, https://orcid.org/0000-0001-6854-2197
This study was approved by the Ethics Committee of Hatay Mustafa Kemal University Clinical Research (Date: 2021-04-08, No: 2021/39)
Aim: Chronic Kidney Disease (CKD) is a long-term medical condition characterized by the gradual loss of kidney function over time. Anemia is one of the most important causes of morbidity in patients with CKD. Anemia negatively affects the quality of life and mortality of patients and increases the progression of kidney disease. This is the first study to indicate lincRNA_EPS expression levels in CKD patients with renal anemia.
Material and Methods: A total of 59 people were included in this study with 40 patients and 19 control groups. Analyzes of lncRNA expression levels were performed by RT-qPCR method. Total RNA (including miRNA and lncRNA) was obtained from serum and plasma using an RNA isolation kit. Then, RNA concentration and purity were determined spectrophotometrically. The integrity of total RNA was determined by agarose gel electrophoresis.
Results: This study concluded that the lincRNA-EPS expression values were found to be significantly higher in the CKD group. There was no statistically significant correlation between the eGFR level of the patients and the lincRNA-EPS expression levels. However, a statistically significant positive correlation was found between eGFR values and hemoglobin levels in the patient group.
Discussion: Considering the increased lincRNA-EPS expression level in CKD patients with renal anemia and its inverse correlation with EPO usage, a potential mechanism for facilitating erythropoiesis may involve both elevated lincRNA-EPS expression and suppression of the pro-apoptotic gene Pycard. Larger and more clinical studies are needed to fully elucidate the mechanism of action of the renal anemia-EPOlincRNA-EPS relationship. In the light of these studies, it will be possible to identify new factors that play a role in the formation mechanisms of renal anemia and to evaluate new treatment alternatives.
Keywords: Chronic Kidney Disease, Renal Anemia, Erythropoietin, Long Non-Coding RNA, lincRNA_EPS
Introduction
Chronic Kidney Disease (CKD) is a very common clinical entity with an irreversible, progressive and high cardiovascular risk secondary to changes in the function and/or structure of the kidney due to many reasons. CKD is an independent risk factor for cognitive dysfunction, hospitalization, and all-cause mortality [1-3]. CKD is very common in the general adult population and it is estimated to increase over time and reach a percentage of 13.1% among adults in the United State [4]. Oxidative stress (OS) plays a significant role in the pathogenesis and progression of CKD. CKD is associated with increased production of reactive oxygen species (ROS) within the kidney. Various factors contribute to this, including inflammation, ischemia-reperfusion injury, mitochondrial dysfunction, and the activation of the renin-angiotensin-aldosterone system (RAAS). These ROS can damage cellular components such as lipids, proteins, and DNA leading to kidney injury and dysfunction [5-7]. OS can directly damage red blood cells, making them more susceptible to premature destruction (hemolysis). This process reduces the lifespan of red blood cells and contributes to anemia by decreasing the total number of functional red blood cells in circulation. Numerous studies indicate that OS is a pivotal role in the development of several diseases [8-14].
Anemia is a common complication of CKD and causes poor quality of life in patients with CKD. Although the mechanisms involved in the pathogenesis of renal anemia include chronic inflammation, iron deficiency, and shortening of the half-life of erythrocytes, the primary cause is relative erythropoietin deficiency. The American National Kidney Foundation Kidney Early Assessment Program has shown that the risk of anemia increases significantly when the glomerular filtration rate falls below 60 mL/min/1.73 m2 [16]. The gene encoding human erythropoietin (EPO) is located on chromosome 7 and covers about 3,000 base pairs. It contains 5 exons and 4 introns and encodes a 193 amino acid polypeptide [17]. Circulating EPO is mainly produced by peritubular fibroblast-like interstitial cells of the kidney [18]. EPO is considered an important growth factor for late erythroid progenitor cells. Activation of EPO receptors on physiologically immature erythroid cells produces an intracellular signal that ensures the survival of these cells. The expected compensatory response to anemia is a high rate of erythropoiesis with an inverse ratio between hormone concentration and Hb concentration [19]. Although chronic renal failure anemia is a complex disease in which many factors may play a role, the main defect is absolute or relative EPO deficiency. In most patients with substantially impaired renal function, EPO production is impaired at any hematocrit concentration independent of the level. The relative proportion of non-coding genomic DNA increases with developmental complexity, suggesting that ncRNAs served increasingly important biological functions during eukaryotic evolution. lncRNAs have come to the fore with newly defined roles in a wide variety of biological processes, including cell division, survival and differentiation [20]. The expression pattern of lncRNA genes has been shown to be much more tissue and cell type specific than for protein-coding genes [21]. LincRNA-EPS is minimally expressed in other hematopoietic lineages, it indicates erythroid specificity. In this study, the expression levels of a specific lncRNA (lincRNA-EPS) were examined in patients with CKD-related renal anemia and this lncRNA level was compared with a healthy control group. The relationship between this identified lncRNA (lincRNA-EPS) and anemia parameters is studied for the first time in humans. In the analysis of the results, if a significant relationship is shown between the determined lncRNAs and anemia parameters, it is aimed to determine new factors that play a role in the pathophysiology of renal anemia and to evaluate new treatment alternatives.
LincRNA-EPS ( one of the non-coding RNA family ) was identified as a lincRNA that facilitates erythropoiesis by suppressing apoptosis via reducing the expression of the proapoptotic gene Pycard without altering erythroid differentiation.(22). It is therefore important to determine how lincRNA-EPS represses Pycard and perhaps other proapoptotic targets. The most likely mechanism appears to be that lincRNA-EPS indirectly represses Pycard by inducing the synthesis of transcriptional repressors (23).
Material and Methods
Study Groups
A total of 59 people were included in this study with 40 patients and 19 control groups. The inclusion criteria of study: Patients over 18 years of age, patients with stage 3-5 CKD and hemoglobin <10 g/dl, EPO-naive or EPO-using patients; the exclusion criteria of study: Patients on hemodialysis or peritoneal dialysis, who have had a kidney transplant, with active infections, with known malignancy, have chronic liver disease, gastrointestinal bleeding, or other active bleeding conditions and the pregnant or breastfeeding women.
This study was conducted on patients with stage 3-5 CKD and hemoglobin value below 10 g/dL, who applied to Nephrology outpatient clinic of Hatay Mustafa Kemal University Training and Research Hospital between August 2021 and April 2022.
Sample acquisition
Peripheral blood samples from chronic kidney patients and healthy controls were taken into tubes without and with anticoagulant (EDTA) (biochemistry tube with gel). After the blood samples taken into the biochemistry tube were coagulated at room temperature (20-30 minutes), they were centrifuged at 3500 rpm for 10 minutes + 4 °C to obtain serum. Serum samples were stored at -80 degrees until the day of study. The blood samples taken into the tube containing the anticoagulant were centrifuged at 3500 rpm for 10 minutes + 4 °C in the same way, and the plasma part was transferred to a separate microcentrifuge tube. These samples were also stored at –80 °C until analysis.
Gene Expression Analyzes
Analyzes of lncRNA expression levels were performed by RT-qPCR method. Total RNA (including miRNA and lncRNA) was obtained from serum and plasma using an RNA isolation kit. Then, RNA concentration and purity were determined spectrophotometrically. The integrity of total RNA was determined by agarose gel electrophoresis. RNA samples with A260/A280 ratio between 1.8-2.0 were converted into cDNA using the cDNA synthesis kit. Real Time Quantitative Polymerase chain reaction (RT-qPCR) analyzes were performed on RotorGene device using SYBR Green master mix kit. Primers associated with target genes were obtained from the manufacturer. LncRNA (lincRNA-EPS) gene expression analyzes were performed using primers. Analysis of gene expression data was done with QIAGEN’s online program Data Analysis Center-RT2 Primer Assay. In the calculation of P values, the transcript was calculated based on 2-ΔΔct values for each gene in the control and treatment groups, and p values below 0.05 were considered significant. GAPDH, β-actin and U6’ were used as housekeeping genes in normalization.
Statistical analysis
Statistical analysis was performed by Statistical Package for the Social Sciences (SPSS) 26 (SPSS Inc., Chicago, IL, USA) software. The collected data were calculated with appropriate descriptive statistics (mean, median, ratio, standard deviation, 95% confidence interval, etc.) methods. The conformity of the study data to the normal distribution was determined by the Shapiro-Wilk test. A comparison of data that did not show normal distribution was performed with the Mann-Whitney U test. P values less than 0.05 were considered significant. Spearman rank correlation was used because the data did not show normal distribution in the correlation analysis of the parameters. Results were expressed as mean ± standard deviation or median ± 25-75% percentile values (‘interquartile range’, IQ). ‘SPSS 26’ computer program was used for statistical analysis.
Ethical Approval
This study was approved by the Ethics Committee of Hatay Mustafa Kemal University Clinical Research Ethics Committee (Date: 2021-04-08, No: 2021/39).
Results
This study consists of 59 people in total, 40 of whom are from the patient group and 19 from the healthy subjects. Demographic characteristics, revealing minimal similarities between the patient and control groups are shown in Table 1. Females comprised 75.0% (30) and 52.6% (10) of the patient and control groups, respectively, while males constituted 25.0% (10) and 47.4% (9). Patients had a mean age of 64 ± 12 years, whereas the control group’s mean age was 59 ± 9 years. Notably, body mass index, smoking, and blood pressures exhibited comparability between the two groups. As additional disease to CKD in the patient group: Isolated hypertension in 11 (27.5%) patients, hypertension, diabetes, hypertension and coronary artery disease in 9 (22.5%) patients, diabetes, hypertension and hyperlipidemia in 8 (20.0%) patients, diabetes and hypertension in 5 (%12,5) patients, coronary artery disease and hypertension in 4 (%10,0) patients, hyperlipidemia and hypertension in 2 (5.0%) and 1 patient has a diagnosis of isolated diabetes (Figure 1). In the patient group; 17 (42.5%) patients with an eGFR value of 30-59 ml/min/1.73m2 were evaluated as stage 3, 16 (40.0%) patients with an eGFR value of 15-29 ml/min/1.73m2 as stage 4, 7 (17.5%) patients with eGFR <15 ml/min/1.73m2 as stage 5 CKD.
The patients classified as stage 3 CKD, 9 (52.9%) hypertension and diabetes, 7 (41.1%) hypertension, 1 (6%) diabetes; the patients classified as stage 4 CKD, 11 (68.75%) hypertension and diabetes, 5 (31.25%) hypertension; the patients classified as stage 5 CKD, 5 (71.42%) hypertension, 2 (28.58%) hypertension and diabetes were the causes of kidney disease (Table 2). The distribution of EPO usage was 4 (23.52%) in stage 3 CKD patients, 5 (31.25%) in stage 4 CKD patients and 6 (85.71%) in stage 5 CKD patients. EPO usage doses in CKD patients according to stages were calculated as 50 mcg/week in stage 3 CKD patients, 46 mcg/week in stage 4 CKD patients, and 48.33mcg/week in stage 5 CKD patients (Table 2).
The laboratory values of all patients included in the study, the patients with CKD and the healthy control group are given in Table 3. Median and quartile lincRNA-EPS expression values in the healthy control group: The median value was 0.000041; 1st quartile (Q1): 0.000017, 2nd quartile (Q2): 0.000041, 3rd quartile (Q3): 0.00038; in the patient group: The median value was 0.5255; 1st quartile (Q1): 0.0072, 2nd quartile (Q2): 0.5255, 3rd quartile (Q3): 0.00038. Considering these data, lincRNA-EPS expression values were found to be significantly higher in the CKD group (p <0.001) (Figure 2). In the patient group, there was no statistically significant relationship between lincRNA-EPS expression levels in patients who received and did not receive EPO (p=0.106). There was no statistically significant correlation between lincRNA-EPS expression levels between diabetic and non-diabetic patients in the patient group (p=0.438).
Correlation Analysis Results
A statistically significant negative correlation was found between EPO levels and lincRNA-EPS expression levels in the patient group (r=-0.654, p=0.011) (Figure 3). There was no statistically significant correlation between the eGFR level of the patients and the lincRNA-EPS expression levels (p=0.897). Statistically significant positive correlation was found between eGFR values and hemoglobin levels in the patient group (r= 0.321, p=0.043). A statistically significant negative correlation was found between eGFR values and the number of patients using EPO in the patient group (r=-0.432, p=0.005) and statistically significant positive correlation was found between the CKD stages of the patients and the number of patients using EPO (r= 0.377, p=0.016). In demographic data, no statistically significant correlation was found between age, BMI, and lincRNA-EPS expression levels in both the patient group and the healthy group (p=0.458, p=0.650 and p=0.580, p=0.814).
Discussion
This is the first report examining the lincRNA_EPS expression levels in CKD patients with renal anemia. We indicated the lincRNA-EPS expression values were found to be significantly higher in the CKD group (p <0.001). There was no statistically significant correlation between the eGFR level of the patients and the lincRNA-EPS expression levels (p=0.897). However, statistically significant positive correlation was found between eGFR values and hemoglobin levels in the patient group (r= 0.321, p=0.043). Moreover, in the patient group, there was no statistically significant relationship between lincRNA-EPS expression levels in patients who received and did not receive EPO (p=0.106). There was no statistically significant correlation between lincRNA-EPS expression levels between diabetic and non-diabetic patients in the patient group (p=0.438).
The worldwide prevalence of CKD is estimated to be 8-16% and this number continues to rise [22]. It is important to manage complications related to pathologies such as anemia, mineral and bone disorders, hydroelectrolytic disorders, metabolic acidosis and cardiovascular disease in patients diagnosed with CKD [23].
Studies have found an increased risk of developing or deepening anemia in correlation with the increase in CKD stage and the decrease in eGFR. In addition, evaluation of the patients after 5 years of follow-up studies data showed that CKD patients with anemia at baseline had a greater loss of renal function and a greater increase in all cardiovascular risks (myocardial infarction, heart failure, stroke, or death) [24]. In this study, a statistically significant positive correlation was shown between the decrease in eGFR and the decrease in hemoglobin levels. Increased apoptosis of RBC progenitors can be associated with a variety of anaemias, including inflammation and cancer-related conditions. It is possible that pharmacological inhibition of proapoptotic signaling pathways may be clinically beneficial, especially since many of these anemias are resistant to EPO therapy [25]. We investigated whether there is a significant relationship and correlation between lincRNA-EPS expression levels, renal anemia and EPO usage in stage 3-5 CKD patients. This study is the first in the literature to analyze this relationship. Considering that most of the lncRNA studies are carried out in animal experiments, it is particular important because the data obtained human origin in this study.
As a result of our study, statistically significant increase was found in lncRNA-EPS expression in the CKD patient group compared to the healthy control group. In addition, it was observed that there was significant negative correlation between the amount of EPO usage and the expression of lincRNA-EPS in the correlation analysis performed within the patient group. As a result of these data we have obtained, it is possible to establish a link between renal anemia, lincRNA-EPS and EPO usage. In patients with CKD, renal anemia deepens as a result of the decrease in the amount and/or effect of EPO, which protects erythroid precursors from apoptosis, and accelerates the progression of erythroid precursors to apoptosis. Considering the increased lincRNA-EPS expression level and the inverse correlation between EPO usage and lincRNA-EPS expression level in CKD patients with renal anemia; in order to facilitate erythropoiesis, the increase in lincRNA-EPS expression level and suppression of Pycard which is a proapoptotic gene, seems to be a possible mechanism.
Limitations of the study
The limitations of our study include the fact that our study is a single-center and cross-sectional study, making it difficult to determine any causal relationship, and the decrease in the number of patients who meet our study group criteria due to the Covid-19 outbreak.
Conclusion
In conclusion, larger and more clinical studies are needed to fully elucidate the mechanism of action of the renal anemia-EPO-lincRNA-EPS relationship revealed by us. In the light of these studies, it will be possible to identify new factors that play a role in the formation mechanisms of renal anemia and to evaluate new treatment alternatives. In this way, it will be possible to prevent the emergence of many bad clinical conditions accompanying renal anemia such as increased cardiovascular risk, increased rate of renal function loss as well as clinical conditions directly caused by anemia such as low quality of life, increased transfusion need, early and with less cost.
Acknowledgment
This article is extracted from my thesis entitled “Kronik Böbrek Hastalığı ile İlişkili Anemide LncRNA (LincRNA-Eps) Ekspresyon Düzeyinin Değerlendirilmesi”, supervised by Faruk Hilmi Turgut (Specialty Thesis, Hatay Mustafa Kemal University, Hatay, Turkiye, 2022).
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 compareable ethical standards.
Funding: This research was supported by Hatay Mustafa Kemal University Coordination Office of Scientific Research Projects (Project # 21.TU.010).
Conflict of Interest
The authors declare that there is no conflict of interest.
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Veysel Berk Güner, Faruk Turgut, Huseyin Erdal, Serdar Dogan. Evaluation of Lncrna (Lincrna-Eps) expression level in anemia related to chronic renal disease.Ann Clin Anal Med 2025;16(1):30-35
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Evaluation of percutaneous fiducial marker placement under computed tomography guidance for stereotactic radiotherapy for lung lesions
Mehmet Erdal, Ahmet Bayrak, Cetin Imamoglu
Deparment of Radiology, Dr. Abdurrahman Yurtaslan Ankara Oncology Health Application and Research Center, Ankara, Turkey
DOI: 10.4328/ACAM.22182 Received: 2024-04-24 Accepted: 2024-05-27 Published Online: 2024-11-04 Printed: 2025-01-01 Ann Clin Anal Med 2025;16(1):36-40
Corresponding Author: Ahmet Bayrak, Deparment of Radiology, Dr. Abdurrahman Yurtaslan Ankara Oncology Health Application and Research Center, Ankara, Turkey. E-mail: kaysbayrak@gmail.com P: +90 530 063 45 36 Corresponding Author ORCID ID: https://orcid.org/0000-0002-2150-8650
Other Authors ORCID ID: Çetin İmamoğlu, https://orcid.org/0000-0002-2111-6294 . Mehmet Erdal, https://orcid.org/0000-0002-2856-089X
This study was approved by the Ethics Committee of Dr. Abdurrahman Yurtaslan Ankara Oncology Health Application and Research Center (Date: 2021-01-13, No: 2021-01/941)
Aim: We aimed to observe the feasibility and technical aspects of percutaneous fiducial marker placement in lung lesions for Sterotactic Radiotherapy, to investigate its complications, how these complications can be reduced, and whether there is a relationship between them.
Material and Methods: This retrospective study included patients who underwent percutaneous reference marker placement in lung lesions under CT guidance between 2017 and 2019. The study included 32 patients, 34 lesions and 98 fiducials, and 2 patients had 2 lesions. Images of the cases taken during the procedure and during follow-up were examined and any complications that developed were recorded. The data were analyzed with Mann Whitney U test and Fisher’s Exact test.
Results: A statistically significant relationship was found between migration and tract length, and tract length was found to be shorter in the migration group. In our study, migration was observed in only 8 of 98 fiducials. The most common complication was pulmonary hemorrhage with 73.5%. Other complications were mild pneumothorax in 44.1%, chest tube insertion pneumothorax in 11.7%, migration in 11.7%, subcutaneous emphysema in 8.8% and hemothorax in 5.8%. There was no significant difference in lesion volume and fiducial distance between those with and without migration.
Discussion: CT-guided fiducial placement can be performed successfully in lung lesions, which ensures that normal tissues around the lesion are exposed to less radiation during treatment. Complications that develop are generally self-limiting and do not require intervention. For this reason, it can be applied to every patient without contraindications.
Keywords: Computed Tomography, Fiducial, Complication, Migration, Stereotactic Radiotherapy
Introduction
Radiosurgery was first developed for the treatment of well-circumscribed brain metastases using high radiation doses [1]. Because of their fixed position, consistent doses can be delivered to these lesions. When this technique is specifically modified to treat lung tumors, accurate delivery of radiation doses becomes difficult as a result of tumor movement due to respiration. On the other hand, it causes increased toxicity in the surrounding tissue. To prevent this situation, stereotactic localization techniques have been developed [2].
Stereotactic radiotherapy (SRT) is the application of high doses of radiation to a stereotactically marked target volume in single or small fractions. It provides serious advantages over other radiotherapy techniques, especially in dose distribution in target volumes smaller than 4 cm. It has the ability to send beams to the target from many different angles. Thus, while the highest dose is given to the target volume, sudden dose reductions are provided right next to the tumor and the surrounding tissues are protected. To determine the target volume before treatment and to monitor the target volume radiographically during treatment, special metallic markers, called fiducials and usually made of stainless steel or gold, are placed in and/or around the tumor. The device checks the position of the target each time before irradiation begins [3].
Computed Tomography (CT) and multislice computed tomography (MSCT), which are high-resolution, fast cross-sectional imaging methods, are the most frequently used methods after direct roentgenogram in thoracic examinations. MSCT systems allow taking many thin-section images much faster than conventional CT systems and performing three-dimensional evaluation by reformating these images [4]. CT is also valuable in guiding percutaneous biopsy and fiducial placement of lung lesions. During these procedures, CT provides very important information in evaluating the lesion, predicting risks and complications, determining the needle plane, determining the needle entry site and detecting post-procedure complications [5]. Fiducials are small gold marks that are implanted into the soft tissues or inside the lesion. They provide spatial information for the system to accurately direct radiation distribution. Gold is denser than surgical clips and appears unique on imaging with characteristic line artifacts. Fiducials are typically required for tumors in the chest, abdomen, pelvis, or other soft tissues. Ideally, a fiducial should be centered on the treatment area (at the center of the lesion) [6]. In this study, we aimed to determine the complications of fiducial placement performed percutaneously under computerized tomography (CT) guidance for the purpose of SRT.
Material and Methods
This study was conducted by Dr. Abdurrahman Yurtaslan Ankara Oncology Health Application and Research Center Department of Radiology between 09.13.2017-11.26.2019. Patients who underwent percutaneous reference marker placement in lung lesions under CT guidance were included in the study. The study included 32 patients, 34 lesions and 98 fiducials, and 2 patients had 2 lesions. Images of the cases taken during the procedure and during follow-up were examined and any complications that developed were recorded. Before the procedure, the purpose of the procedure and possible complications were explained to all patients, and an informed consent form was obtained from all patients.
Before starting the procedure, the patients’ existing images (such as CT, PET) were evaluated and the position of the patients was determined accordingly.
Sections were taken from a limited area with the patient in the determined position. The section where the lesion was located was marked on the sections taken and re-sections were taken with a segmented opaque marker placed on the skin. Based on the sections taken, it was determined from which compartments the needle would be inserted. After the skin was cleaned and sterilized with a povidone iodide solution, local anesthesia was applied to the relevant areas. In the light of the images obtained, the needle was advanced to the desired length in the skin, subcutaneous and soft tissues with the needle angle appropriate to the targeted area. Needles that were not in the appropriate position were re-pulled to ensure they were positioned appropriately. The needles in appropriate positions were advanced into the lung tissue to the determined length.
In the sections taken later, if the needle was far from the target, it was withdrawn and if it was close, it was pushed to reach the determined localization. When the needle reached the targeted area, fiducial markers were placed into the tissue. Afterwards, the fiducial location and complication status were determined by taking a CT image without changing the patient’s position. It was planned to place at least 3 fiducials in all patients. Failure to place any of the fiducials was considered procedure failure. In addition, placement of at least one fiducial within or 2 cm close to the lesion was considered a success of the procedure.
Statistical Analysis
Quantitative data were summarized with mean±standard deviation and median (minimum-maximum), and qualitative data were summarized with frequency and percentage, n(%). In addition, descriptive statistics were presented. Gender, age, primary/metastasis variables were evaluated based on the number of patients (n=32). Lobe and complication variables are based on the number of lesions (n=34); Fiducial lesion distance, fiducial number and migration variables were evaluated based on fiducial number (n=98). Comparisons between groups were made using the Mann Whitney U test for quantitative data and Fisher’s Exact test for qualitative data. P<0.05 value was considered statistically significant. R v.3.6.3 statistical programming language was used for analyses.
Ethical Approval
This study was approved by the Ethics Committee of the Dr. Abdurrahman Yurtaslan Ankara Oncology Health Application and Research Center Department of Radiology (Date: 2021-01-13, No: 2021-01/941).
Results
At least one fiducial was placed in or around all lesions, and the success of the procedure was found to be 100%. Of the 32 patients included in the study, 25 (78.1%) were male and 7 (21.9%) were female, the average age was 62.6±10 (min: 37-max: 83). 17 (53.1%) of the patients were detected as primary and 15 (46.9%) as metastasis. In the study, the lesion requiring fiducial placement was most frequently encountered in the left upper lobe (32.4%), while the right middle lobe lesion was observed least frequently (11.8%). In terms of complications, pulmonary hemorrhage was the most common complication and was observed in 25 lesions, mild pneumothorax in 15 lesions, pneumothorax with chest tube insertion in 4 lesions, migration in 4 lesions, and subcutaneous emphysema in 3 lesions. The least observed complication was hemothorax (n=2). No complications were observed in 4 lesions.
While there were 55 (56.1%) fiducials with fiducial lesion distance of 1-20 mm, there were 32 (32.7%) on the edge, 7 (7.1%) with 21-40 mm and 4 (4.1%) inside. There were 27 (79.4%) lesions with a fiducial number of 3 placed in one lesion, 3 (8.8%) with 1, 3 (8.8%) with 4 and 1 (2.9%) with 2 lesions. Tract length was found to be statistically significantly lower in the group with migration than in those without [respectively, median (min-max): 8.5(0-28); 22.5(0-71); p=0.015]. There was no statistically significant difference between those with and without migration in terms of lesion volume and fiducial distance (p=0.755, p=0.299, respectively) (Table 1).
The relationship between procedure termination due to pneumothorax and total pneumothorax and fiducial termination type was examined. Of the 31 fiducials for which no procedure termination was observed due to pneumothorax, 21 (67.7%) were placed using FRM 1 (Figure A), where the needle is removed after the first fiducial is placed and the same process is repeated for the subsequent fiducials. The remaining 10 (32.3%) were placed using FRM 2 (Figure B), where the needle is not removed after the first fiducial is placed and the needles are removed together after the other necessary fiducials are placed. All 3 fiducials in which procedure termination was observed due to pneumothorax had fiducial release method 1 (p=0.539). Of the 15 fiducials in which no pneumothorax was observed, 4 (26.7%) had FRM 2 and 11 (73.3%) FRM 1. Of the 19 fiducials with total pneumothorax, 6 (31.6%) had FRM 2 and 13 (68.4%) had FRM 1 (p=1.000) (Table 2). Rates of total pneumothorax numbers were 6/7 (85.7%) in the right upper lobe, 3/4 (755%) in the right middle lobe, 2/5 (40%) in the right lower lobe, 4/11 (36.4%) in the left upper lobe, 4/11 (36.4%) in the left lower lobe. In the lobe, it was 4/7 (57.1%) (p = 0.282).
Discussion
Stereotactic radiosurgery refers to the precise delivery of a highly concentrated radiation dose to a small target area in one session, minimizing radiation exposure to the surrounding healthy tissue under three-dimensional computerized imaging [7]. Fiducials are markers made of 99% gold, 5 mm long and 0.5 mm in diameter, that are implanted by interventional radiologists on an outpatient basis through CT-guided pre-loaded fiducial needles or aspiration needles [8]. In this study, we investigated the complications arising from fiducial placement in lung lesions and the relationship between the complications.
In order to apply stereotactic radiotherapy to lung lesions, a marker must be placed in the lung parenchyma. However, the fact that the lung parenchyma is largely filled with air causes the markers to not remain fixed in place and to be easily separated. Therefore, reimplantation using new fiducials becomes necessary. This situation reduces the chance of stereotactic radiotherapy and makes it necessary to switch to conventional radiotherapy. In the literature, Harada et al. in their study examining the feasibility of real-time tumor monitoring radiation therapy (RT) treatment in lung cancer patients, reported that 5 of 19 fiducial markers placed by bronchofiberoscopy migrated and the migration rate was 26% [9]. Moreover, they also reported that they successfully treated 13 (65%) of 20 tumors in total with RT. They concluded that the excellent initial response and low incidence of clinical complications suggest that high-dose hypofractionated focal irradiation using the RT system may be a good local treatment for peripheral-type lung tumors.
In the study by Imura et al. the fixation rate of markers using the bronchial placement technique, the reliability of the setup using markers around the target volume, the dislocation of markers after real-time tumor tracking RT, and the long-term toxicity of marker placement were investigated. They reported that gold markers were detected in 115 of 154 markers (75%) during the treatment period. As a result of their research, they hypothesized that the relationship between the markers and tumor can change significantly after 2 weeks, suggesting that adaptive four-dimensional RT is required [10]. In our study, 8 fiducials placed in 4 lesions were shown to migrate, which is consistent with the literature. In our study, we concluded that there is no need to stay away from this procedure due to the risk of migration.
On the other hand, there are also studies in the literature that report migration rates at very low levels. De Mey et al. In their study evaluating a technique for implanting radiopaque markers into lung nodules as an adjunct to extracranial stereotactic radiation therapy reported that no markers migrated. As a result of the study, they concluded that lung nodules can be marked safely and accurately with radiopaque implants with this technique [11]. Similarly, in the study published by Patel et al., the rate of migrating markers was reported as 4%, and in the study published by Kothary et al., it was reported as 9% [12, 13]. In our study, it was determined that 8 fiducials placed in 4 lesions migrated. Our rates were found to be 11% on a lesion basis and 8% on a fiducial basis, which are similar to the literature. When we look at the migration rate we obtained in our study and the migration rates obtained in the literature, we think that there is no need to stay away from the application of this procedure due to the risk of migration.
In the present study, it was determined that there was a statistically significant relationship between tract length and migration rates. Accordingly, tract length was found to be statistically significantly lower in the migration group compared to the non-migration group. We concluded that the reason for this situation may be due to the fact that the fiducials were placed without passing the visceral pleura. In addition, we thought that the fact that migrating fiducials are seen in very distant areas in some cases is due to the fact that this potential space into which the fiducials fall is the pleural space and that the fiducial can escape to any point within this space. We think that when placing fiducials into the lung parenchyma, it would be beneficial to adjust the tract distance to be long and complete the release process after ensuring that the visceral pleura is passed. In our study, the relationship between migration and lesion volume, lesion-fidusial distance, pneumothorax and lobar anatomy where the lesion is located was examined. No statistically significant difference was detected between migration and parameters. Another important issue discussed in the literature regarding fiducial placement in lung lesions is the risk of pneumothorax complications. The majority of these are mild pneumothorax cases that show rapid regression as a result of follow-up. In the study by Bhagat et al. the mild pneumothorax rate was reported to be 82% when an 18G needle was used for fiducial placement, 40% when a 19G needle was used, and 67% in total [1]. In our study, the needles used for fiducial insertion were 19G, and we found our total pneumothorax rate to be 55%, similar to these studies.
The most common procedure for placing fiducial markers in lung lesions is pulmonary hemorrhage (PH). Similarly, in our study, the most common complication was PH. In the literature, PH rates vary significantly. It was found to be 67% in the study of Ohta et al., 33% in the study of Trumm et al., and 18% in the study of Kothary et al. [14, 15, 16]. In our study, this rate was found to be 73.5%. We think that the reason for this difference may be due to the difference in the number of fiducials placed per lesion and the tract length. As the number of fiducials and tract length increases, the amount of damaged tissue will increase and the likelihood of hemorrhage will increase. In our study, the pulmonary hemorrhages that occurred in our patients were mild and local, self-limited, and did not cause any problems in the follow-up of the patients.
In our study, a rare hemothorax complication was detected in 2 patients and its rate was 5.8%. In addition, subcutaneous emphysema was observed in 2 of our patients. This complication was detected during the fiducial placement procedure in 3 lesions and our rate was 8%. Total pneumothorax and migration with the lung lobe where the lesion is located no statistically significant difference was detected between them. We think that the development of pneumothorax is not related to the lesion location. While the FMR 1 was previously used in the fiducial placement process at the center where the study was conducted, it was later switched to the FMR 2 with the idea that we could reduce the possibility of pneumothorax. After this method change, fewer cases of pneumothorax were encountered with fiducial release method 2. As a result of no pneumothorax developing after the first fiducials placed using the FMR 2, other fiducials were placed. For this reason, we think that using the FMR 2 is a more accurate approach when placing fiducial markers in the lung.
Conclusion
As a result of the study, fiducial placement of lung lesions via CT was successfully performed. The complications that occur are at a limiting level that do not require intervention. Although no pneumothorax requiring procedure termination was observed with the FMR 2 in the study, we think that it would be very useful to conduct prospective multicenter studies with more patients. In addition, we concluded that in order to reduce migration rates, paying attention to the tract length and making sure that the visceral pleura is passed is the best approach.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Mehmet Erdal, Ahmet Bayrak, Cetin Imamoglu. Evaluation of percutaneous fiducial marker placement under computed tomography guidance for stereotactic radiotherapy for lung lesions. Ann Clin Anal Med 2025;16(1):36-40
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Do temporomandibular disorders, forward head posture, tongue strength and endurance affect core stabilization? A cross-sectional study
Hazel Celik Guzel 1, Sule Kecelioglu 2, Burcin Akcay 2, Ebru Kaya Mutlu 2
1 Department of Therapy and Rehabilitation, Vocational School of Health Services, 2 Department of Therapy and Rehabilitation, Faculty of Health Services, Bandırma Onyedi Eylul University, Balıkesir, Turkiye
DOI: 10.4328/ACAM.22381 Received: 2024-08-21 Accepted: 2024-10-21 Published Online: 2024-11-05 Printed: 2025-01-01 Ann Clin Anal Med 2025;16(1):41-46
Corresponding Author: Hazel Celik Guzel, Department of Therapy and Rehabilitation, Vocational School of Health Services, Bandırma Onyedi Eylul University, Balıkesir, Turkiye. E-mail: hguzel@bandirma.edu.tr P: +90 266 717 01 17 Corresponding Author ORCID ID: https://orcid.org/0000-0001-6510-5012
Other Authors ORCID ID: Sule Kecelioglu, https://orcid.org/0000-0003-0949-8573 . Burcin Akcay, https://orcid.org/0000-0002-0883-0311 . Ebru Kaya Mutlu https://orcid.org/0000-0002-8595-5513
This study was approved by the Ethics Committee of Bandirma Onyedi Eylul University Health Sciences Non-Interventional Research (Date: 2022-03-11, No: 2022-18)
Aim: The continuity of the kinetic chain, stomatognathic functions and Temporomandibular Disorders (TMD) are interrelated, but the relationship between them and core stabilization has yet to be known. To investigate the relationship between TMD, forward head posture, tongue strength, and endurance with core stabilization.
Material and Methods: This study was conducted on university students aged 18-31. In the evaluation were used that; “Fonseca Anamnestic Index (FAI)” for TMD, “Diagnostic Criteria for Temporomandibular Disorders Examination Form” for pain-free maximum mouth opening (MMO), presence of sound in temporomandibular joint movements, and palpation parameters of the temporomandibular joint and surrounding muscles, “Craniovertebral Angle (CVA)” for forward head posture, “Iowa Oral Performance Instrument” for tongue strength and endurance, “Trunk Flexor Endurance Test and Biering Sorenson Test” for static endurance of the core muscles, and “Sit-ups Test and Modified Push-ups Test” for dynamic endurance of the core muscles.
Results: Seventy university students (mean age=20.77±2.22 years) participated in the study. There was a difference between participants with/without TMD in terms of gender, pain-free MMO, tongue endurance, CVA, and FAI (p<0.05). CVA for FAI (p=0.004), CVA, tongue endurance for the Sit-ups Test (p=0.001, p=0.044 respectively), and tongue endurance for the Modified Push-up Test (p=0.012) were statistically significant predictors.
Discussion: There was no direct relationship between TMD and core stabilization. The performance of global core muscles decreased with the increase in TMD-related forward head posture and a decrease in tongue endurance. Evaluating individuals with TMD holistically may be necessary for successful rehabilitation.
Keywords: Cervical, Core Stability, Head Posture, Temporomandibular Disorders, Tongue
Introduction
Temporomandibular Disorders (TMD) is defined as a neuromuscular and musculoskeletal pathology resulting from disruption of physiological harmony in the temporomandibular joint (TMJ) and related structures and includes various clinical problems involving the stomatognathic system [1] According to the current literatüre; it is recommended to develop a broad-based evaluation protocol including objective measurements in individuals with TMD [2]. In light of this suggestion, it has been reported in recent studies that tongue muscle strength decreases in individuals with TMD, and it has been emphasized that it should be included in the evaluation program [3]. Moreover, it is known that cervical postural changes accompany TMD, and the forward head posture affects the position of the mandible and causes TMD [4].
The continuity of the kinetic chain is essential for the biomechanically and kinesiologically correct patterns of stomatognathic functions during activities of daily living. The kinetic chain is a system that allows different body parts to coordinately generate power, accumulate and transfer force to the final connection point through muscle activity and body position. A solid core must create a stable body to ensure minimal stress in the kinetic chain, maximal power generation, and proper power transfer, hence the need for core stabilization [5]. Core muscles are divided into local and global muscle groups according to their role in stabilization. The local musculature consists of deep muscles that stabilize the trunk and control the intervertebral movements of the spinal segments. The global musculature includes the larger, surface-level muscles of the trunk. Its primary role is to facilitate trunk movement and alleviate external loads experienced during daily activities by transferring these loads to the local muscles. When the muscles responsible for stabilizing the core are weak and lack endurance, it places undue stress on the passive structures of the spine, leading to pain and decreased functional performance in other areas of the body [6].
There are limited studies in the literature investigating the relationship between TMD and body posture and/or core stabilization [7- 11]. These studies show the relationship between general body posture, postural stability, and balance with TMJ functions in TMJ pathologies or healthy individuals. However, studies have yet to be found to investigate forward head posture, tongue strength and endurance, and core muscle performance, which are part of a holistic approach to TMD. Therefore, this study examined the relationship between TMD, forward head posture, tongue strength, and endurance with core stabilization.
Material and Methods
This cross-sectional study was conducted with Bandirma Onyedi Eylul University students between September 2022 and February 2023. Participants were invited to study with flyers and class announcements. University students aged 18 and 31 were included. Exclusion criteria included having a non-reducible disc problem, having surgery related to the spine, abdomen and/or TMD, history of trauma, history of cancer, presence of neurological issues, presence of congenital anomaly, presence of the musculoskeletal problems, presence of systemic disease, presence of facial paralysis, and receiving any treatment related to the spine and TMJ in less than six months. All participants were determined to have at least 28 permanent teeth and were evaluated using the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) and sedentary without regular exercise habits. 70 volunteer healthy university students were included in our study, taking into dropouts. According to the TMD, two groups were formed: those who scored less than 25 points on the Fonseca Anamnestic Index (FAI) and those who scored 25 points or more.
Outcome Measurements
TMD was evaluated with FAI. The questionnaire consists of ten questions about pain in TMJ, head, and joints. It includes questions about joint, head, and neck pain, pain during masticatory activity, parafunctional habits, reduced joint motion, impaired occlusion, and emotional stress. A score of 25 and above was accepted as the presence of TMD [12]. The Turkish validity and reliability of the FAI have been established [13].
The presence of sound in TMJ movements and palpation parameters of the TMJ and surrounding muscles were recorded using the DC/TMD Examination Form [14]. The pain-free MMO was recorded using a 15 cm ruler. Joint clicks and crepitation during mouth opening and closing were recorded. In muscle palpation, pain in the temporal muscle and the masseter muscle was evaluated bilaterally [15].
Forward head posture was evaluated by CVA using a goniometer. CVA was measured in degrees, such as the angle between the horizontal plane, the seventh cervical vertebra, and the ear hole [16].
Tongue strength and endurance were evaluated with IOPI (Medical LLC, Redmond, WA), a clinically validated and reliable [17]. The evaluation was performed from the anterior and posterior sides of the tongue. For the pressure of the anterior tongue region, the bulb was placed 10 mm anterior to the dorsum of the tongue on the anterior hard palate; for the pressure of the posterior tongue region, the bulb was placed anterior to the posterior hard palate. Participants were instructed to press the bulb as hard as possible against the tongue toward the hard palate for 2 sec. The maximum force (Pmax) was recorded as the highest value in three trials. For tongue endurance measurement, 50% of the Pmax value of the participants was calculated. At this value, they were instructed to press the bulb with their tongue in the direction of the hard palate as much as they could, and the time they could hold it was recorded using a stopwatch [18].
Static endurance of the local core muscles was evaluated with The Trunk Flexors Endurance Test and the Biering Sorenson Test. The time the individuals maintained their position was recorded in seconds (sec) using a stopwatch. In the Trunk Flexors Endurance Test, the individuals were positioned with the trunk at 60°, knees and hips at 90° flexion position, and the test was terminated when the trunk flexion of 60° was disrupted. In the Biering Sorenson Test, participants were instructed to position their trunk horizontally while lying face down, ensuring that their ankles, knees, hips, and the upper edge of the iliac crest were in contact with the testing surface. Meanwhile, their knee and hip joints were fully extended. The test ended when this position was no longer maintained [19].
Dynamic endurance of the global core muscles was evaluated with The Sit-ups and the Modified Push-ups Tests. The number of times the individuals could perform the movement for 30 sec was recorded. In the Sit-ups Test, individuals were asked to perform trunk flexion while supine, with knees flexed and feet stabilized. In the Modified Push-ups Test, the individuals were asked to lift the head, shoulders, and trunk off the floor with the elbows in full extension from the prone position with knees on the floor, legs flexed, trunk on the floor, elbows flexed, and next to the trunk [19].
Statistical Analysis
Statistical Package for Social Sciences (SPSS) Version 24.0 (SPSS Inc., Chicago, IL, USA) statistical program was used to analyze the data. The data obtained were presented with descriptive analyses, and categorical variables were presented as frequency (n) and percentage (%). Continuous variables were presented as mean±standard deviation (SD) for parametric tests and median (minimum-maximum) for non-parametric tests. The conformity of the variables to normal distribution was analyzed using the Shapiro-Wilk Test. Group differences were analyzed using Mann-Whitney U, Independent Samples t, and Chi-Square tests. Pearson Correlation Analysis evaluated the relationship between the variables. The determinants of FAI, Sit-ups Test, and Modified Push-ups Test were analyzed using multiple regression analysis (Enter method). The fit of the analyzed models was tested with Durbin Watson. The standardized regression coefficient Beta (β) determined the order of importance of the determinants. The statistical significance level was considered as p<0.05.
Ethical Approval
This study was approved by the Ethics Committee of Bandirma Onyedi Eylul University Health Sciences Non-Interventional Research (Date: 2022-03-11, No: 2022-18). The clinical trial number is NCT06034756. All participants who agreed to participate in the study signed the Informed Consent Form.
Results
Ninety-four individuals were included in the study. For the reasons stated in Figure 1, 24 individuals were excluded from the study, and 70 individuals were included. The posthoc power of the study was calculated as 0.891 using the effect size (0.79) obtained from the mean±SD of CVA between the two groups.
Most of the participants included in our study were female (78.6%) university students, and the mean age of the participants was 20.77±2.22 years. There was a statistically significant difference between participants <25 and >25 according to pain-free MMO, tongue endurance, CVA, and FAI (p<0.05) (Table 1).
In correlations analysis, there was a correlation between pain-free MMO and Modified Push-ups Test (r=0.239), CVA and Sit-ups Test (r=0.371), and CVA and FAI (r=-0.345). There was a correlation between tongue endurance and the Sit-ups Test (r=0.298) and between tongue endurance and the Modified Push-ups Test (r=0.350) (p<0.05). There was also a correlation between FAI and tongue strength (r=-0.263) and between FAI and tongue endurance (r=-0.236) (p<0.05) (Table 2).
The determinants of FAI, sit-ups test, and modified push-ups test of individuals were analyzed using multiple regression analysis. The model for the effect of TMD-related tongue strength and endurance, CVA, and pain-free MMO data on FAI was significant, with an explanatory power of 19.7%. CVA was a statistically significant predictor variable on FAI (p=0.004). The model for the effect of FAI and related factors on the sit-up test was significant, with an explanatory power of 17.1%. CVA and tongue endurance were statistically significant predictor variables on the Sit-ups Test (p=0.001, p=0.044, respectively). The model for the effect of FAI and related factors on the Modified Push-ups Test was significant, with an explanatory power of 11.2%. Tongue endurance was a statistically significant predictor variable on the Modified Push-ups Test (p=0.012) (Table 3).
Discussion
This study investigated the relationship between TMD, forward head posture, tongue strength and endurance with core stabilization. Although there was no direct relationship between TMD and core stabilization, it was found that the performance of global core muscles decreased with an increase in TMD-related forward head posture and a decrease in tongue endurance.
TMD has a multifactorial structure; current literature suggests that accompanying pains in individuals with TMD, especially spinal pain, may be due to body imbalance. TMD affects whole-body functions such as postural asymmetry, foot center of pressure, body sway, and spinal curvature [20]. Our study did not find a relationship between the local core system and intervertebral movements. Still, we observed a relationship between the global core system and functional body movements. The lack of involvement of the local musculoskeletal system is thought to be because the participants were young and healthy. In a study supporting us, no statistically significant difference was found between Pilates and control groups for abdominal strength, trunk flexor endurance, and trunk extensor endurance in pre and post-measurements, and it was reported that future studies with a larger sample, including people who may be symptomatic are needed [21].
Our study found that the performance of global core muscles decreased with the increase in TMD-related forward head posture. TMD-related, the most common postural abnormality is forward head posture. This posture is thought to pull the mandible backward due to tension in the suprahyoid muscles and cause TMD [4]. At the same time, it has been stated that pain, headache, speech and swallowing problems, disorders in tongue motor movements, and incoordination may develop in the clinical picture due to neuro-vegetative reactions due to the anterior tilt of the head [22]. In our study, we evaluated forward head posture by measuring the CVA. A CVA of less than 50° is considered an anterior tilt of the head [22]. The mean CVA value of the study participants was 47.98 (5.93)°, which is lower than 50°. As stated in the literature, we can attribute this situation to individuals studying in incorrect posture or using technological devices in incorrect posture [22]. In addition, our study found that TMD increased as the anterior tilt of the head increased, and CVA was a predictor variable in TMD. Additionally, CVA was a statistically significant predictor of the Sit-ups Test. It can be said that forward head posture and decreasing CVA affect the flexor core muscles that provide dynamic endurance and cause performance loss. This situation can be explained by compensation in the lower spine region due to forward head posture and low CVA values [23].
Our study found that the performance of global core muscles decreased with a decrease in TMD-related tongue endurance and that tongue endurance was a statistically significant predictor of the Sit-ups Test and Modified Push-Up Test. The tongue, one of the components of the stomatognathic system, plays an important role in chewing and swallowing [24]. In studies, tongue strength in a general population was determined to be 40-80 kPa, with an average of 63 kPa. The average duration of tongue endurance is 30-35 seconds [25]. In our study, the mean anterior tongue strength of the individuals was 49.08 (9.84) kPa, which was within the general population but lower than the average. The mean tongue endurance values of the individuals were 23.64 (8.21) sec, which was below the average. The low tongue strength and endurance of the individuals in our study were thought to be due to most of the individuals having TMD.
Limitation
Our study had some limitations. The most important limitation was the unequal gender distribution. The second limitation is that we evaluated posture only with CVA and did not evaluate general body posture to evaluate spinal compensations. The third limitation was that there were no dentists among the authors in the study team.
Conclusion
It was found that TMD was highly prevalent in young and healthy individuals. Although there was no direct relationship between TMD and core stabilization, it was found that the performance of global core muscles decreased with an increase in TMD-related forward head posture and a decrease in tongue endurance. In the clinical evaluation of individuals diagnosed with TMD, it may be essential to evaluate forward head posture, tongue strength, endurance, and core muscles with a holistic perspective to increase rehabilitation success. In future studies, the relationship between TMD and core stabilization should be evaluated in individuals diagnosed with TMD, classified according to the research diagnostic criteria for TMD, and assessed in a broader age range. TMD should also be investigated in different study groups affected by core stabilization.
Acknowledgment
The authors would like to thank the students who participated in the study.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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5. Oliver GD, Washington JK, Barfield JW, Gascon SS, Gilmer G. Quantitative analysis of proximal and distal kinetic chain musculature during dynamic exercises. J Strength Cond Res. 2018;32(6):1545-1553.
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11. Perinetti G. Temporomandibular disorders do not correlate with detectable alterations in body posture. J Contemp Dent Pr. 2007;8(5):60-67.
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14. Schiffman E, Ohrbach R, Truelove E, Look J, Anderson G, Goulet JP, et al. Diagnostic criteria for temporomandibular disorders (DC/TMD) for clinical and research applications: Recommendations of the International RDC/TMD Consortium Network and Orofacial Pain Special Interest Group. J Oral Facial Pain Headache. 2014;28(1):6-27.
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16. Diab AA, Moustafa IM. The efficacy of forward head correction on nerve root function and pain in cervical spondylotic radiculopathy: A randomized trial. Clin Rehabil. 2012;26(4):351-361.
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Can second trimester monocyte to high-density lipoprotein ratio predict insulin requirement in gestational diabetes mellitus?
Burcu Dincgez 1, Gulten Ozgen 1, Levent Ozgen 2, Esra Kartal Golcuk 3
1 Department of Obstetrics and Gynecology, University of Health Sciences, Yuksek Ihtisas Research and Training Hospital, Bursa, 2 Department of Obstetrics and Gynecology, Faculty of Medicine, Uludag University, Bursa, 3 Department of Obstetrics and Gynecology, International Sisli Kolan Hospital, Istanbul, Turkey
DOI: 10.4328/ACAM.22388 Received: 2024-08-27 Accepted: 2024-10-21 Published Online: 2024-11-04 Printed: 2025-01-01 Ann Clin Anal Med 2025;16(1):47-51
Corresponding Author: Burcu Dincgez, Department of Obstetrics and Gynecology, University of Health Sciences, Yuksek Ihtisas Research and Training Hospital, Bursa, Turkey. E-mail: burcumavis@gmail.com P: +90 530 544 88 28 Corresponding Author ORCID ID: https://orcid.org/0000-0002-2697-7501
Other Authors ORCID ID: Gulten Ozgen, https://orcid.org/0000-0002-7888-7583 . Levent Ozgen, https://orcid.org/0000-0003-0070-2646 . Esra Kartal Golcuk, https://orcid.org/0000-0002-9641-5766
This study was approved by the Ethics Committee of Health Science University Bursa Yüksek İhtisas Training and Research Hospital (Date: 2024-07-06, No: 2024-TBEK)
Aim: Monocyte to high-density lipoprotein ratio is a new marker of chronic inflammation and oxidative stress, which plays a role in gestational diabetes. Here, we aimed to evaluate the second-trimester monocyte to high-density lipoprotein ratio in gestational diabetes and to assess the predictive role of insulin requirement and delivery mode in gestational diabetes.
Material and Methods: A total of 45 gestational diabetes patients and 45 healthy pregnant were included in this retrospective study. The gestational diabetes group was divided into two subgroups: diet-controlled (n=15) and requiring insulin (n=30). Demographic and obstetrics characteristics, complete blood count, and biochemical analysis results were compared between groups. The predictive role of monocyte to high-density lipoprotein ratio for gestational diabetes, insulin requirement, and delivery mode was evaluated by receiver operating curve analysis.
Results: The monocyte to high-density lipoprotein ratio was higher in gestational diabetes (p<0.001). Also, it was higher in insulin-requiring diabetes as compared to the controlled diabetes group (p=0.021). Monocyte to high-density lipoprotein ratio was correlated with fasting glucose (r=0.469, p=0.001) and 50-gram testing first-hour levels (r=0.595, p<0.001). Monocyte to high-density lipoprotein ratio >8.2 discriminated gestational diabetes with 91.1% sensitivity and 80% specificity (AUC=0.922, p<0.001), while >9.1 predicted insulin requirement with 86.7% sensitivity and 66.7% specificity (AUC=0.713,p=0.032). It did not predict cesarean section in gestational diabetes (p=0.21).
Discussion: The second-trimester monocyte to high-density lipoprotein ratio might be a cheap and available marker for detecting gestational diabetes and the insulin requirement in gestational diabetes mellitus.
Keywords: Gestational Diabetes Mellitus, Insulin Requirement, Monocyte To High-Density Lipoprotein Ratio
Introduction
Gestational diabetes mellitus (GDM) is the most common metabolic disorder that is defined as the first occurrence of glucose intolerance during pregnancy. It has a prevalence of 1% to 14%, depending on the diagnostic criteria used in society and ethnic origin [1, 2]. In addition to increased adverse perinatal outcomes, GDM is associated with long-term cardiovascular risks, hypertensive disorders, development of insulin resistance, and type 2 diabetes [3]. The pathophysiology of GDM is not fully understood. Patients who develop GDM have a pancreatic β-cell defect that fails to compensate for the insulin resistance of pregnancy. At the same time, increased oxidative stress caused by chronic low-grade inflammation in GDM triggers the production of inflammatory cytokines and free oxidative radicals [4-6]. Understanding the pathophysiology of GDM and finding predicting markers can be a guide to minimizing major pregnancy and long-life complications. Thus, researchers focused on searching for new markers to investigate risk prediction to guide the prevention and treatment of GDM [7, 8].
Monocytes, which are immature immune system cells and constitute approximately 3-8% of the leukocytes in the peripheral blood, are involved in controlling inflammatory processes by secreting proinflammatory and prooxidant cytokines together with macrophages [9, 10]. During pregnancy, the number and activation of monocytes increase. It is known that monocytes in circulation contact with syncytiotrophoblasts and activate inflammation [11]. High-density lipoprotein (HDL) cholesterol reduces the pro-oxidant and proinflammatory effects of monocytes with its antithrombotic, anti-inflammatory, and antioxidant effects. All these results showed that monocyte to HDL ratio (MHR) might be used as a new marker of chronic inflammation and oxidative stress due to the anti-inflammatory and antioxidant effects of HDL as well as the proinflammatory effect of monocytes. An increase in MHR levels indicates increased inflammation [12].
In the present study, we aimed to determine the discriminative role of second-trimester MHR for GDM. Moreover, we aimed to evaluate the predictive role of MHR for insulin requirement and delivery mode in GDM.
Material and Methods
This study was designed as a retrospective case-control study. It was carried out at a university-affiliated research and training hospital between January 2022 and January 2024.
Study Population
During the two-year study period, 678 patients were obtained from medical records who underwent GDM screening by a one-step protocol of 75-gram oral glucose tolerance testing (OGTT) or a two-step protocol of 50-gram OGTT followed by 100-gram OGTT.
The inclusion criteria were as follows: being 16 and 45 years old, pregnant women between 24-28 weeks who have two-step protocol OGTT screening and laboratory analysis including complete blood count and lipid profile, having regular antenatal visits, and giving birth in our clinic.
The exclusion criteria were composed of having any contraindications to OGTT, 75-gram OGTT screening, multiple pregnancies, unavailable perinatal data, smoking, history of pregestational diabetes or chronic diseases affecting inflammatory processes, patients who have dyslipidemia, autoimmune diseases, presence of hypertensive disorders of pregnancy, preterm premature rupture of membranes, threatened labor, intrauterine growth restriction, fetal anomaly noted in medical reports of our hospital.
In our clinic, GDM was diagnosed with a step protocol according to the recommendations by ACOG. A 50-gram OGTT was performed, followed by a 100-gram OGTT if plasma blood glucose levels at the first hour exceeded 140 mg/dl. Glucose levels of 200 and above after OGTT were accepted as GDM. In 100 gram OGTT, GDM was diagnosed if two abnormal values of 95 mg/dl for fasting, 180 mg/dl at the first hour, 155 mg/dl at the second hour, and 140 mg/dl at the third hour were detected [13].
After the selection, due to the inclusion and exclusion criteria, a total of 90 patients were included and grouped as GDM (n=45) and control (n=45). Then, the participants were divided into two subgroups: diet-controlled GDM (n=15) and GDM requiring insulin (n=30).
Patients’ characteristics such as age, body mass index (BMI), gravida, parity, obstetrics features such as OGTT week and results, presence of macrosomia and polyhydramnios, birth weight, delivery week, delivery mode, NICU requirement and Apgar scores, complete blood count values, biochemical analysis results were recorded and compared between groups. The monocyte to HDL ratio was calculated by dividing the monocyte count by the HDL cholesterol value. A cut-off value for MHR for the presence of GDM and insulin requirement was detected by ROC analysis.
Statistical Analysis
The normality assumption was assessed with the Shapiro-Wilk test. Descriptives were presented as mean (standard deviation) and median (minimum-maximum) values for continuous variables, while categorical variables were given with frequency and related percentage values. For comparison between the two groups, the Student t-test was used for normally distributed variables, and the Mann Whitney-U test was used for non-normally distributed ones. Categorical variables were compared with the Chi-square test or Fisher’s exact test. The association between MHR, 50-gram OGTT values, and HbA1c was evaluated with the Spearman correlation coefficient. The receiver operating curve analysis was used to determine the discriminative and predictive role of MHR for GDM, insulin-requiring GDM, and delivery mode. The cut-off values were determined by using the Youden index. SPSS version 22.0 and MedCalc 18 were used for statistical analysis. A p-value ≤0.05 was accepted as statistically significant.
Ethical Approval
This study was approved by the Ethics Committee of Health Science University Bursa Yüksek İhtisas Training and Research Hospital (Date: 2024-07-06, No: 2024-TBEK).
Results
The demographic, perinatal, and laboratory characteristics of all patients are shown in Table 1. No significant difference was present between GDM and control groups regarding age, gravida, parity, OGTT week, presence of macrosomia, delivery mode, birth weight, Apgar scores, and neonatal intensive care unit requirement. Gestational diabetes mellitus patients had statistically significantly higher BMI, higher polyhydramnios rates, higher 50-gram OGTT values, and lower birth weeks as compared to the control group. The median MHR levels were 9.8 (7.9-12.7) in GDM and 7.3 (6.1-10.2) in the control group, which was significantly higher in GDM group (p<0.001). Median HbA1c was 5.5 (4.7-7.8) in GDM patients. The demographic, perinatal, and laboratory characteristics of diet-controlled and insulin-requiring GDM patients are presented in Table 2. There was no difference between diet-controlled GDM and insulin-requiring GDM groups for age, gravida, parity, OGTT week, presence of macrosomia and polyhydramnios, delivery mode, birth weight, neonatal intensive care unit requirement, HbA1c, and 50-gram OGTT levels. Insulin-requiring GDM patients had significantly higher BMI, lower birth weeks, and Apgar scores compared to the diet-controlled GDM group. The median MHR level was statistically significantly higher in the insulin-requiring GDM group as compared to the controlled GDM group (p=0.021). The association between MHR, 50-gram OGTT values, and HbA1c was assessed with the Spearman correlation coefficient (Table 3). MHR was not correlated with HbA1c levels, whereas it was positively correlated with 50-gram OGTT fasting glucose (r=0.469, p=0.001) and 50-gram OGTT first-hour glucose levels (r=0.595, p<0.001).
The discriminative role of MHR for GDM was evaluated by receiver operating curve analysis and presented in Figure 1. MHR above 8.2 was found to discriminate GDM with 91.1% sensitivity and 80% specificity (AUC=0.922, p<0.001). Additionally, the receiver operating curve analysis demonstrated that MHR above 9.1 predicted GDM requiring insulin with 86.7% sensitivity and 66.7% specificity (AUC=0.713, p=0.032), and this analysis was shown in Figure 2. Contrary to this, MHR did not predict the cesarean section in GDM patients (p=0.21).
Discussion
Low-grade subacute or chronic inflammation and oxidative stress play a crucial role in the pathogenesis of GDM [14]. This inflammation is known to be responsible for insulin resistance and future life complications [15]. Hence, inflammatory markers have been widely studied to predict pregnancy outcomes and prognosis in GDM. In a study by You et al. [16], a first-trimester triglyceride to HDL ratio above 2.27 predicted GDM with 72.9% sensitivity and 75.1% specificity. Moreover, they reported that the triglyceride to HDL ratio is a better predictor than triglyceride, HDL, total cholesterol, low-density lipoprotein, and HOMA-IR for GDM. In another study searching 954 pregnant women, the triglyceride to HDL ratio increased the risk of GDM by 3.87-fold [17]. The possible mechanism between triglyceride to HDL ratio and GDM can be explained by increased estrogen levels and insulin resistance. Increased estrogen levels and insulin resistance trigger the synthesis of free fatty acids, which worsens insulin resistance and leads to glucose metabolism impairment [16].
There are challenging results about monocyte counts in GDM. In a study by Huang et al. [18], decreased monocyte count was reported in GDM patients, while Shim et al. [19] declared increased monocyte counts in GDM. Moreover, a systematic review has shown no association between monocyte count and GDM [20]. This inconsistency could be related to the grading of monocytes such as low, intermediate, or mature and different trimesters of pregnancy. Additionally, monocytes can be pro-inflammatory or anti-inflammatory according to their maturation, like macrophages.
Monocyte to HDL ratio, which was defined in 2014 by Kanbay et al. [21], is a representative of chronic inflammation. In this study, increased MHR levels estimated adverse cardiovascular events in chronic kidney disease patients. In a study by Selcuk et al. [22], MHR was higher in non-dipper hypertension as compared to the control group and dipper hypertension patients. Gembillo et al. [23] reported higher MHR levels and a positive correlation between MHR and C reactive protein in patients with persistent hypertension.
In obstetrics and gynecology practice, MHR has been studied in diseases such as preeclampsia, polycystic ovary syndrome, and GDM. Cakmak et al. [24] reported higher MHR levels in polycystic ovary syndrome and claimed that MHR above 9.9 predicted metabolic syndrome in polycystic ovary syndrome patients. Köpük et al. [11] found higher MHR levels in preeclamptic patients. In a study searching the role of MHR in GDM, higher MHR levels were reported, and MHR above 8.97 predicted GDM with 83.3% sensitivity and 69.2% specificity. Additionally, MHR was found to be correlated with some heavy metals, which reflects the role of MHR in oxidative stress [25]. Similar to this study, Fagninou et al. [7] demonstrated higher MHR levels in GDM. A study searching the role of C reactive protein to albumin ratio and MHR found that C reactive protein to albumin ratio was correlated with HOMA-IR and BMI, while no significant difference was reported for MHR between GDM and control groups. They claimed that C reactive protein to albumin ratio is superior to MHR for the prediction of GDM [15]. In this study, blood samples were taken in the third trimester, and treatment could have affected the inflammatory processes.
In the present study, we found higher MHR levels in GDM consistent with the literature. In addition to this finding, we compared MHR levels between GDM treatment groups for the first time and found higher MHR levels in insulin-requiring diabetes as compared to the controlled diabetes group. Moreover, MHR was found to be correlated with fasting glucose and 50-gram oral glucose tolerance testing first-hour glucose levels. MHR above 8.2 discriminated GDM with 91.1% sensitivity and 80% specificity, while MHR above 9.1 predicted insulin requirement with 86.7% sensitivity and 66.7% specificity. To the best of our knowledge, our study was the first study evaluating the predictive role of MHR for treatment options such as diet or insulin.
Limitation
The present study has some restrictions. First, it has a small sample size and retrospective design. Second, the association between MHR and GDM may differ due to the study population and ethnicity. Finally, serial measurement of MHR might be more beneficial for detecting the differences between trimesters of pregnancy.
Conclusion
Second-trimester MHR might be a cheap and available marker that provides information about oxidative stress and inflammation. We suggest that MHR could be used for detecting GDM and the insulin requirement in GDM.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Impact of intrauterine devices on microbiota in women: Identification of bacterial colonization
Tahsin Takcı 1, Şerife Özlem Genç 2, Meral Çetin 2
1 Department of Obstetrics and Gynecology, Sivas Numune Hospital, 2 Department of Obstetrics and Gynecology, Faculty of Medicine, Cumhuriyet University, Sivas, Turkiye
DOI: 10.4328/ACAM.22412 Received: 2024-09-18 Accepted: 2024-11-04 Published Online: 2024-11-12 Printed: 2025-01-01 Ann Clin Anal Med 2025;16(1):52-56
Corresponding Author: Tahsin Takci, Department of Obstetrics and Gynecology, Sivas Numune Hospital, Sivas, Turkiye. E-mail: tahsintakci@gmail.com P: +90 542 288 47 92 Corresponding Author ORCID ID: https://orcid.org/0000-0003-1709-1597
Other Authors ORCID ID: Serife Ozlem Genc, https://orcid.org/0000-0002-9811-2726 . Meral Cetin, https://orcid.org/0009-0000-2949-8226
This study was approved by the Ethics Committee of Sivas Cumhuriyet University Faculty of Medicine (Date: 2018-02-06, No: 2018-02/05)
Aim: The intrauterine device (IUD) is the second most widely used contraceptive method globally due to its effectiveness, affordability, and reliability. There are two primary types: copper and hormonal. However, IUDs are associated with potential complications, including ectopic pregnancy, uterine perforation, and pelvic inflammatory disease. This study aims to assess and compare the safety and complication rates of copper and hormonal IUDs, with a focus on their impact on vaginal microbiota.
Material and Methods: The study included 233 women who had their IUDs removed at our clinic. The IUDs were analyzed using Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) to identify the microbiota present on the devices.
Results: Participants’ ages ranged from 20 to 70 years, with a mean age of 39.64 ± 8.37. The majority (84.4%) used copper IUDs, while 15.6% used levonorgestrel-releasing IUDs. Among the patients, 41.2% reported vaginal discharge, 39.5% experienced dyspareunia, and 18.5% had a history of pelvic inflammatory disease or tubo-ovarian abscess.
Discussion: IUD use significantly impacts vaginal microbiota, with Escherichia coli being a common pathogen in both copper and hormonal IUD users. Regular gynecological check-ups, sterile insertion practices, and patient education on infection symptoms are crucial for mitigating risks. Probiotics may help maintain microbiota balance during IUD use. Future studies should investigate long-term microbiota changes, compare different IUD types, and explore infection prevention strategies. This research is a vital contribution to understanding the effects of IUDs on vaginal microbiota.
Keywords: Intrauterine Devices, Microbiota, Women’s Health, Escherichia Coli
Introduction
IUDs are a widely utilized and effective method of birth control globally [1]. However, there is a scarcity of studies in the literature regarding the impact of IUDs on the female microbiota. The influences of the microbiota on human health, ranging from the immune to the digestive system, and in the prevention of diseases, are known [2]. Understanding the effects of IUD usage on the patterns of bacterial colonization in women’s microbiota is thus of critical importance.
IUDs have been one of the most commonly used methods of contraception worldwide for many years, due to their high efficacy and safety, long-term usage, cost-effectiveness, and the absence of side effects seen with hormonal contraceptives [1]. Consequently, the effects associated with IUDs have gained significance. To date, the microbiome of the reproductive tract has received less research attention compared to that of the gut. However, there is increasing evidence to suggest its potential influence on general and reproductive health, fertility, and pregnancy outcomes [3]. The composition of the vaginal microbiota is affected by various factors, including hormonal changes, sexual activity, and personal hygiene practices.
Limited studies have been conducted in healthy women of reproductive age to determine what constitutes a ‘normal’ microbiota profile. Commensal bacteria, such as Lactobacillus, modulate the host immune system and may aid in preventing pathogen colonization. Lactobacillus consumes estrogen-dependent glycogen produced in the vaginal epithelium [4]. The lactic acid produced by Lactobacillus decreases the local pH and possesses bactericidal properties [5, 6], contributing to the maintenance of bacterial balance and the prevention of bacterial vaginosis and aerobic vaginitis [7]. The vaginal microbiome may also play a role in protecting against adverse pregnancy outcomes, such as early miscarriage [8] and preterm birth [9], as well as gynecological cancers [10].
The aim of this study is to examine the potential effects of IUDs on the vaginal microbiota through the identification of bacterial colonization in women using IUDs. The study focuses on understanding the microbial effects of IUD usage on female reproductive health. In this context, the study aims to investigate whether IUDs induce changes in the vaginal microflora, the potential health outcomes of these changes, and the long-term effects of IUD usage on women’s health. Additionally, another goal is to contribute to the development of preventative strategies to reduce the risk of infection during IUD usage, based on the findings obtained.
Material and Methods
This study included 233 women who had their IUDs removed at our clinic. Using a descriptive study design, we aimed to analyze the diversity of vaginal microbiota in women using IUDs. This design was selected for its ability to assess the microbiota’s current state without intervention. Participants remained eligible for inclusion even if the device was removed due to bleeding, infection, or personal preference. To minimize potential confounders, we carefully set inclusion criteria, excluding women with more than one sexual partner, a body mass index (BMI) over 35, recent use of vaginal douches, or sexual activity within the previous 48 hours. These measures were taken to ensure a homogeneous study group, facilitating more precise and reliable microbiota analysis.
MALDI-TOF MS was employed for bacterial identification due to its high accuracy and speed in detecting a broad spectrum of microorganisms. This technique is particularly well-suited for microbiota studies as it enables the rapid identification and differentiation of bacterial species based on their distinct protein profiles. However, it is important to acknowledge that while MALDI-TOF MS is highly reliable, it may underrepresent certain slow-growing or low-abundance bacterial species.
The incubation times for bacterial cultures were tailored to optimize the growth of the most common vaginal bacteria. Cultures were incubated for up to 72 hours, depending on the expected growth rates of the target organisms. This step ensured that even slower-growing bacteria could be detected, providing a more comprehensive view of the microbiota.
The study was conducted under sterile conditions by directly culturing IUDs. This process was designed to allow for the direct and precise examination of microbial colonization on the surfaces of the IUDs. IUD samples were aseptically removed using sterilized ovum forceps and immediately transferred to culture dishes containing specialized media for the identification of bacterial species. These cultures were then evaluated using MALDI-TOF MS, which facilitates the rapid and accurate identification of bacterial species. MALDI-TOF MS identifies species by measuring the protein profiles of microorganisms isolated from cultures. The findings from the research were analyzed using IBM SPSS Statistics 25 (IBM Corp., Armonk, NY, USA).
After conducting descriptive statistical analyses (frequency, percentage distribution, mean ± standard deviation), it was found that the assumptions of the Chi-square test could not be met when applied to the multi-way arrays. Therefore, instead of computing the Chi-square value, the Fisher’s Exact Test with Monte Carlo simulation was employed. A significance level of p<0.050 was considered statistically significant.
Ethical Approval
This study was approved by Sivas Cumhuriyet University Faculty of Medicine Local Ethics Committee (Date: 2018-02-06, No: 2018-02/05).
Results
The study revealed significant alterations in the vaginal microbiota of women using IUDs, regardless of the type of device. A notable finding was the decrease in Lactobacilli, a crucial component of healthy vaginal microbiota, and an increase in Escherichia coli, indicating a shift towards a less protective microbiota composition. These changes were observed consistently across both copper IUDs (Cu-IUDs) and levonorgestrel-releasing IUDs (LNG-IUDs), suggesting that the IUD itself may influence microbiota composition, rather than the specific material or hormone it releases.
The study focused exclusively on women using IUDs, aiming to analyze the diversity of their vaginal microbiota in detail. Most participants were using Cu-IUDs, as reflected in Table 1, with ages ranging from 20 to 70 years and an average age of 39.64 ± 8.37 years.
The results highlighted a significant reduction in the proportion of Lactobacilli and an increase in Escherichia coli in the vaginal microbiota of IUD users (Table 2), which may suggest that IUDs play a role in altering bacterial colonization patterns. Furthermore, when comparing the microbiota of Cu-IUD and LNG-IUD users, it was found that the ranking of the most common microorganisms remained consistent across both groups (Figure 1), indicating that the type of IUD may have less impact on the specific bacteria present than initially expected.
Discussion
Our findings contribute to the growing body of evidence that IUDs can significantly alter the vaginal microbiota. The observed decrease in Lactobacilli and increase in Escherichia coli are particularly concerning, as they suggest a shift towards a microbiota composition that may be more susceptible to infections. This aligns with previous studies that have highlighted the potential risks of dysbiosis in the reproductive tract. However, the lack of correlation with clinical symptoms in this study limits the conclusions that can be drawn regarding the clinical significance of these microbiota changes.
The microbiota in the reproductive tract is predominantly comprised of bacteria from the Lactobacillus genus, indicative of a healthy microbiome state [11]. Research has demonstrated that dysbiosis in the reproductive tract microbiota correlates with a heightened risk of various health issues, such as pelvic inflammatory disease, endometriosis, and infertility [12, 13].
The effects of IUD usage on the microbiota involve various mechanisms. These include local immune responses triggered by the presence of the device, hormonal changes induced by certain types of IUDs, disruption of the natural barrier function of the reproductive tract, direct interactions between the device materials and bacteria, alterations in the microenvironment within the uterus. These factors collectively contribute to shifts in microbiota composition and diversity. Further research is needed to fully understand the implications of these changes for reproductive health and disease. The employment of IUDs may disrupt this equilibrium, leading to dysbiosis – a microbial imbalance [14]. While IUDs are generally safe and effective, it’s essential for women to discuss potential risks and benefits with their healthcare providers before choosing this form of contraception [15].
Our study diverges from previous research in that it directly investigates the effects of IUD usage by conducting cultures from the device’s intrauterine environment. This approach allows for a more direct examination of the microbiota within the uterine cavity in relation to IUD presence, contrasting with prior studies that may have relied on indirect measures or sampled from different anatomical sites. By culturing directly from the IUD, our study aims to provide novel insights into the specific microbial dynamics influenced by IUD usage, potentially shedding light on mechanisms underlying any observed effects on women’s health.
In our study, the cultures examined from IUD users showed a 30.8% non-proliferation rate in those with copper IUDs (Cu-IUD) and a 42.1% non-proliferation rate in those with levonorgestrel-releasing IUDs (LNG-IUD). However, among the cases where proliferation occurred, Escherichia coli was the most frequently identified pathogen (11.6%). The increased presence of Escherichia coli in women with IUDs suggests a possible association between IUD insertion and alterations in the microbiota, creating a conducive environment for the proliferation of opportunistic pathogens. Conversely, the presence of Lactobacilli, which is known for its role in maintaining vaginal health by producing lactic acid and sustaining an acidic environment, was observed as the second most common microbiota element in our study. Specifically, an increase in certain bacterial species can elevate the risk of infections, while a decrease in others may weaken the protective functions of the microbiota.
In a study examining the impact of Cu-IUDs on the vaginal microbiota in baboons, it was found that Cu-IUDs did not significantly alter the microbiota [16]. Conversely, our findings indicated that in women with Cu-IUDs, the microbiota composition was not compatible with the literature. In our study, Escherichia coli was more frequently observed in women with IUDs, with Lactobacilli being the second most common. Several factors may contribute to this discrepancy, including differences in study populations.
Contrary to our findings, a study conducted by Basis and colleagues, which investigated the effects of intrauterine contraceptive devices on the vaginal microbiota, concluded that neither LNG-IUDs nor Cu-IUDs significantly altered the vaginal microbiota [17].
Pruthi and colleagues, in their investigation of pathogens on IUDs, identified the most common pathogens as Staphylococcus aureus (16%), Staphylococcus epidermidis (18%), and Pseudomonas aeruginosa (5%) [18]. Our study differed, with Escherichia coli (11.6%), Lactobacillus (7.3%), and Streptococcus agalactiae (6.4%) being the top three microbiota components.
Conclusion
This study provides valuable insights into the alterations of vaginal microbiota associated with copper and levonorgestrel-releasing IUDs. The findings reveal distinct microbiota profiles between the two types of IUDs. Notably, a higher proportion of LNG-IUD users (42.1%) showed no bacterial growth compared to Cu-IUD users (30.8%), while the presence of bacteria such as Escherichia coli and Streptococcus agalactiae was slightly more frequent in LNG-IUD users. In contrast, Staphylococcus epidermidis and Candida albicans were found at higher rates among Cu-IUD users. These differences may indicate that the type of IUD can influence vaginal microbiota composition, though the clinical implications of these variations remain unclear.
While this study provides important data on the short-term effects of IUD use on vaginal microbiota, further research is needed to establish a clearer link between these microbial changes and clinical outcomes, such as infection rates or other reproductive health issues. In particular, longitudinal studies tracking microbial shifts over the long term would provide deeper insights into how extended IUD use influences vaginal health. Larger patient cohorts and more precise sample selection would also strengthen future investigations, offering a more comprehensive understanding of IUDs’ effects on microbiota.
Additionally, the potential for interventions, such as probiotic supplementation, should be explored as a means to mitigate any negative effects of IUD use on the vaginal microbiota, potentially improving reproductive health outcomes for women.
Acknowledgment
The authors wish to acknowledge the contributions of their respective institutions in facilitating the research process. Financial support from any funding agencies or private companies is not applicable for this study.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Download attachments: 10.4328.ACAM.22412
Tahsin Takci, Serife Ozlem Genc, Meral Çetin. Impact of intrauterine devices on microbiota in women: Identification of bacterial colonization. Ann Clin Anal Med 2025;16(1):52-56
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Comparison of the effects of del nido cardioplegia and blood cardioplegia on preoperative and postoperative albumin and tsh in cardiac surgery performed by cardiopulmonary bypass
Yasemin Hacanlı 1, Murat Ziya Bağış 2
1 Department of Cardiovascular Surgery, Faculty of Medicine, Harran University, Şanlıurfa, 2 Department of Cardiovascular Surgery, Faculty of Medicine, Harran University, Şanlıurfa, Turkiye
DOI: 10.4328/ACAM.22348 Received: 2024-07-31 Accepted: 2024-09-02 Published Online: 2024-10-29 Printed: 2025-01-01 Ann Clin Anal Med 2025;16(1):57-61
Corresponding Author: Yasemin Hacanlı, Department of Cardiovascular Surgery, Faculty of Medicine, Harran University, Şanlıurfa, Turkiye. E-mail: yaseminhacan@hotmail.com P: +90 506 700 27 00 Corresponding Author ORCID ID: https://orcid.org/0000-0002-4427-8149
Other Authors ORCID ID: Murat Ziya Bağış, https://orcid.org/0000-0002-4088-7510
This study was approved by the Ethics Committee of Harran University Clinical Research (Date: 2024-07-22, No: 24/10/37)
Aim: The aim of this study was to compare the efficacy of Del Nido and blood cardioplegia in patients who underwent cardiac surgery with CPB support and required cardioplegia administration in the Department of Cardiovascular Surgery Clinic of our hospital by evaluating albumin and TSH hormones preoperatively and postoperatively.
Material and Methods: In this retrospective study, a total of 60 patients over the aged ≥18 years who underwent open heart surgery with CPB support between 2020 and 2024 were included. The patients were divided into two groups: 30 Del Nido cardioplegia group and 30 blood cardioplegia group. Preoperative and postoperative albumin and TSH values, cross-clamp and total bypass times, ejection fraction percentage (EF%), age and body surface area were analyzed and compared from the files of the patients in these groups.
Results: According to statistical analysis of del nido and blood cardioplegia groups, age (54.31 ± 9.59, 61.79 ± 7.43) (p=0.001), cross-clamp duration (86.28 ± 22.75, 49.93 ± 14.29) (p=0.001), total duration (132.86 ± 29.53, 82.76 ± 16.93) (p=0.001) and preop-TSH (1.66 ± 1.3, 2.16 ± 1.2) (p=0.040) values were found to be statistically significant (p<0.05). However, Body surface area, ejection fraction, preop and postop-albumin and postop-TSH were not found to be statistically significant between the groups (p>0.05).
Discussion: According to our data, there was no significant difference in albumin and TSH parameters after CPB, indicating that the effects of Del Nido and blood cardioplegia were similar.
Keywords: Cardiopulmonary Bypass, Albumin, Thyroid Stimulating Hormone
Introduction
Cardiopulmonary bypass (CPB) is a mechanism that temporarily assumes the function of the heart and lungs. It mechanically oxygenates the blood in the extracorporeal circulation and circulates it throughout the body [1]. Cardioplegic solutions are used to temporarily stop the heart to create a bloodless space and provide myocardial protection during surgery using the CPB technique. Dr. Melrose reported the first cardioplegia used in cardiopulmonary bypass (CPB) in the early 1950s. Dr. Melrose also demonstrated that high doses of potassium citrate temporarily stopped the heart so that it could restart [2]. Potassium used in cardioplegic solutions depolarizes the myocardial membrane, triggering its contraction. As a result of this contraction, calcium ions are released, followed immediately by their retention. This causes the heart to stop in diastole [3]. As the spread of the cardioplegia solution increases and its components are washed away along with the products of anaerobic cellular metabolism, electrical activity begins to manifest itself. Therefore, dosing of cardioplegia needs to be re-adjusted. However, there are other ions other than potassium used in cardioplegia. These are magnesium, sodium and calcium, etc. All of these ions reduce myocardial contraction. In this way they are effective in myocardial protection. In addition to these ions, it is also possible to provide further protection with some compounds such as bicarbonate and lidocaine []. Various cardioplegic solutions are used to maintain the safety of CPB [5]. These solutions include hypothermic cardioplegia, warm blood cardioplegia and Del Nido. Cardioplegic solutions can be administered anterograde or retrograde, or both, and must be of adequate volume [6]. During administration, the rate, components, volume, pressure and temperature of the solution are adjusted by the perfusionist [7]. In patients undergoing open heart surgery, changes in some electrolyte and protein levels may be observed due to CPB technique. Albumin, the most abundant protein in the blood [8] can be measured at low levels in the preoperative or postoperative period in open heart surgery using CPB technique. This is an important risk factor that increases preoperative and postoperative mortality and morbidity [9]. Albumin has antithrombotic, antioxidant and anti-inflammatory functions. It helps to transport certain substances and drugs and maintain the oncotic pressure of the blood. Results from studies show that it is a strong marker of cardiovascular (CV) risk. Protects against cardiovascular diseases (CVD) such as hypertension, congenital heart disease, atrial fibrillation and heart failure [10]. The reference range for adult human serum albumin is accepted as 3.5-5 g/dl. However, the pathologic limit may vary according to the tests used. Serum albumin levels are slightly higher in men than in women. It tends to decrease with age [11]. Another factor that increases the likelihood of CV morbidity and mortality is hyper- and hypothyroidism [12]. Plasma thyroid-stimulating hormone (TSH or thyrotropin) level is a widely used marker to monitor thyroid status. According to the Turkish Society of Endocrinology and Metabolism (TEMD), the reference range for TSH is between 0.5-4 mU/L [13]. TSH is <4.0 mIU/L in subclinical hyperthyroidism and TSH>0.4 mIU/L in subclinical hypothyroidism. However, free thyroxine and free triiodothyronine levels are within reference ranges [14].
CV risks should be determined as a function of TSH. Only a few studies have looked at it from this perspective [15].
The cardioplegies we use in our center to temporarily stop the heart to create a bloodless area and to provide myocardial protection are Del Nido and blood cardioplegia. Del Nido cardioplegia consists of; Patient blood (200 ml, 20% del Nido cardioplegia solution), Balanced electrolyte solution (1000 ml), Mannitol 20% (17 ml), MgSO4 15% (14 ml), KCL 1 mEq/ml (26 ml), NaHCO3 8.4% (13 ml), Lidocaine 2% (6.5 ml) [5]. The cardioplegia content in KCL 1 mEq/ml and MgSO4 15% is calculated by completing the patient’s initial blood gas potassium value to 22 ml. Potassium and magnesium are used in a 1:1 ratio.
The aim of this study was to compare the efficacy of Del Nido and blood cardioplegia in patients who underwent cardiac surgery with CPB support and required cardioplegia administration in the Department of Cardiovascular Surgery Clinic of our hospital by evaluating albumin and TSH hormones preoperatively and postoperatively.
Material and Methods
Working Groups
In this retrospective study, a total of 60 patients aged ≥18 years who underwent open heart surgery with CPB support between 2021 and 2024 were included. The patients were divided into two groups: 30 Del Nido cardioplegia group and 30 blood cardioplegia group. Preoperative and postoperative albumin and TSH values, cross-clamp and total bypass times, ejection fraction percentage (EF%), age and body surface area were analyzed and compared from the files of the patients in these groups.
Inclusion and Exclusion Criteria
Patients over 18 years of age who underwent surgery with CPB support were included in the study. Patients under the age of 18 and patients who did not receive CPB support were excluded from the study.
Statistical Analysis
The conformity of the data to normal distribution was tested with Kolmogorow-Smirnov and Shaphiro Wilk tests. Independent Samples t Test was used for the comparison of numerical variables in two independent groups for those with normal distribution and Mann-Whitney U test was used for the comparison of numerical variables in more than two independent groups. One-way analysis of variance (ANOVA) and LSD multiple comparison tests were used for normally distributed characteristics and Kruskal Wallis test and All pairwise multiple comparison test were used for non-normally distributed characteristics. Mean±standard deviation for numerical variables and number and % values for categorical variables were given as descriptive statistics. SPSS Windows version 25.0 package program was used for statistical analysis and P<0.05 was considered statistically significant.
Ethical Approval
This study was approved by the Harran University Clinical Research Ethics Committee (Date: 2024-07-22, No: 24/10/37).
Results
Table 1 shows the numbers and percentages of the Gender and Surgery Frequency Analysis. According to gender, a total of 60 patients were included in the study, 22 female (36.70%) and 38 male (63.30%). According to the surgery performed, 45 of the 60 surgeries were CABG (75.00%), 4 CABG+MVR (6.70%), 6 AVR (10.00%) and 5 MVR (8.30%) surgeries.
Table 2 shows the statistical analyses of the Del Nido and Blood cardioplegia groups. According to this analysis, mean age (54.31 ± 9.59; 61.79 ± 7.43) (p=0.001) and preoperative TSH (1.66 ± 1.3; 2.16 ± 1.2) (p=0.040) values were lower in the Del Nido group than in the Blood cardioplegia group. It was found to be statistically significant (p<0.05). Cross-clamp time (86.28 ± 22.75; 49.93 ± 14.29) (p=0.001) and total bypass time (132.86 ± 29.53; 82.76 ± 16.93) were longer in the Del Nido group (p=0.001). It was found to be statistically significant (p<0.05). Postoperative albumin values were slightly lower than preoperative albumin values in both groups. In addition, postoperative TSH values also showed a slight decrease compared to preoperative values in both groups. However, this was not statistically significant (p>0.05). In addition, body surface area and ejection fraction were not statistically significant between the groups (p>0.05).
Correlation analysis is given in Table 3. According to this analysis;
There is a low level negative significant correlation between age and Cross-clamp and Total bypass duration.
There is a low level negative significant correlation between Cross-Clamp and Age and Preoperative TSH.
There is a highly significant positive correlation between Cross-Clamp and Total bypass duration.
Discussion
Albumin has antithrombotic, antioxidant and anti-inflammatory functions. It is protective against CVD such as hypertension, congenital heart disease, atrial fibrillation and heart failure (HF) [10]. Albumin can be measured at low levels preoperatively or postoperatively in open heart surgery using CPB technique. This is an important risk factor that increases preoperative or postoperative mortality and morbidity [9].
After 15 years of observation, a cohort study reported that hypoalbuminemia independently predicted both disease-related (such as CVD and cancer) and all-cause mortality [16]. To determine the prognostic implications and phenotypic correlates of serum albumin, Prenner et al. conducted a study using magnetic resonance imaging. In this study, 118 adult patients with heart failure with preserved ejection fraction (HFpEF) had all-cause death and/or heart failure-related hospitalizations during 57.6 months of follow-up. The study reported that serum albumin was associated with detrimental pulsatile aortic hemodynamics, myocardial fibrosis and prognosis in HFpEF [17]. Studies have reported that hypoalbuminemia is seen in approximately 25% of patients with HF. It has also been shown to be a serious predictor of negative results in HF with low EF [18]. In a study of 2907 elderly individuals observed for 9.4 years, hypoalbuminemia was reported to be associated with the progression of HF onset with the actual preserved ejection fraction except for the risk factors of HF [19]. In a study describing the adverse consequences of low albumin and CVDs in patients with coronary artery disease, it was reported that patients with hypoalbuminemia were at risk for major CVDs and had a 1.5-year increase in all-cause mortality [20]. In our retrospective study, the preop-albumin value was slightly lower in the Del Nido group compared to the blood cardioplegia group. However, it was not found to be statistically significant. Postop-albumin values after CPB were slightly higher in the Del Nido group. However, there was no significant difference in both groups. Preop and postop albumin values were close to each other in both Del Nido and blood cardioplegia groups. It was observed to be within the range of normal reference values.
Another factor that increases the likelihood of CV morbidity and mortality is hyper- and hypothyroidism [12]. Changes in thyroid function cause changes in blood pressure and CV risk factors. Late clinical recognition of subclinical structures of thyroid dysfunction (subclinical hypo- and hyperthyroidism) leads to negative CV outcomes [21]. It has been reported to increase CV risk. The association between atrial fibrillation and hyperthyroidism has been shown as an example [22]. In a cohort study involving euthyroid individuals, high-normal TSH levels were compared with moderate-normal TSH levels. High-normal TSH levels have been linked to increased CVD mortality rates associated with all causes [23]. In contrast, other studies have not found an association between TSH levels in the normal range and mortality in the general population. A cohort study of 212,456 individuals with a follow-up of 4.3 years reported that plasma TSH levels in the normal reference range were not associated with mortality [24].
Limitation
The fact that the study was conducted in a single center and with a small number of patients.
Conclusion
In our study, preoperative TSH values of patients in the Del Nido and blood cardioplegia groups before CPB were found to be statistically significant. Preoperative albumin levels were not found to be significant. However, no significant difference was observed in postoperative albumin and TSH values after CPB in both Del Nido and blood cardioplegia groups. Although these values showed a slight decrease after CPB compared to the preoperative values, they were not found to be statistically significant. This suggests that the effects of Del Nido and blood cardioplegia on these parameters were similar.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Yasemin Hacanlı, Murat Ziya Bağış. Comparison of the effects of del nido cardioplegia and blood cardioplegia on preoperative and postoperative albumin and tsh in cardiac surgery performed by cardiopulmonary bypass. Ann Clin Anal Med 2025;16(1):57-61
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Exploring muscle and fat composition differences in acute appendicitis
Turay Cesur 1,2, Utku Eren Özkaya 1,3, Bilal Egemen Çifçi 1, Mustafa Dağlı 1
1 Department of Radiology, Bilkent City Hospital, Ankara, 2 Department of Radiology, Mamak State Hospital, Ankara, 3 Department of Radiology, Cigli Educational and Research Hospital, İzmir, Turkey
DOI: 10.4328/ACAM.22357 Received: 2024-08-06 Accepted: 2024-09-09 Published Online: 2024-10-31 Printed: 2025-01-01 Ann Clin Anal Med 2025;16(1):62-67
Corresponding Author: Turay Cesur, Department of Radiology, Bilkent City Hospital, Ankara, Turkey. E-mail: turaycesur93@gmail.com P: +90 534 875 75 90 Corresponding Author ORCID ID: https://orcid.org/0000-0002-2726-8045
Other Authors ORCID ID: Utku Eren Özkaya, https://orcid.org/0000-0001-8022-7595 . Bilal Egemen Çifçi, https://orcid.org/0000-0002-1664-3241 . Mustafa Dağlı, https://orcid.org/0000-0001-7794-0349
This study was approved by the Ethics Committee of Bilkent City Hospital (Date: 2023-08-23, No: E2-23-4772)
Aim: This study aimed to examine skeletal muscle and fat composition in patients with appendicitis, comparing cases with perforation to those without.
Material and Methods: This retrospective observational study involved analyzing portal venous phase CT scans for patients diagnosed with acute appendicitis between April 2022 and April 2023. A total of 106 patients included in the study.
The Skeletal Muscle Index (SMI), Visceral Fat Index (VFI), Visceral to Subcutaneous Fat Ratio (VSR), Skeletal Muscle Mass to Visceral Fat Area Ratio (SVR), and Intramuscular Adipose Tissue Content (IMAC) were measured individually for both female and male participants.
Results: The study included 50.9% female patients (n=54) and 49.0% male patients (n=52). The perforated group comprised 51% of patients (n=55), while the non-perforated group comprised 48% of patients (n=51). The age and sex distributions were comparable between the perforated and non-perforated groups (p=0.776 and p=0.994). Among the females, the SMI median value was significantly higher in the group with perforation (37.2 cm2/m2) compared to group non-perforation (33.1 cm2/m2) (p=0.011). Among males the median SMI values did not show a significant difference between the perforated group (51.0 cm2/m2) and the non-perforated group (49,0 cm2/m2 ). The values for VSR, SVR, VFI, and IMAC displayed no significant differences between the two groups for both female and male participants (p>0.05).
Discussion: The higher SMI values in the perforated group among females challenge preconceptions and highlight the multifaceted nature of factors influencing appendiceal perforation. Additional studies are necessary to clarify the intricate relationships between body composition, gender-specific factors, and the progression of acute appendicitis.
Keywords: Appendicitis, Perforated Appendicitis, Body Composition, Muscle Composition, Fat Composition
Introduction
Acute appendicitis (AA) is a globally recognized surgical emergency, occurring at a range of 96.5 to 100 cases per 100,000 adults annually [1]. Recent research points to possible differences in the underlying mechanisms between perforated appendicitis (pAA) and non-perforated appendicitis (npAA) [2, 3, 4]. Although the rate of pAA has remained constant in recent years, changes in the incidence of npAA suggest potential independent disease mechanisms [2, 3]. It has been peoposed that complicated and uncomplicated appendicitis may represent distinct immunological conditions [4].
Even with advancements in diagnostic and management techniques, the causes and risk factors for perforation are still not well understood. Understanding the urgency of perforation and identifying reliable indicators for recovery and adverse outcomes remains a critical knowledge gap [4]. Existing research predominantly explores the risk factors for pA, such as male gender, older age, BMI, elevated laboratory values, and pre-hospital delay [5, 6, 7, 8, 9]. Despite this, there has been little focus on the connection between perforation and the analysis of muscle and fat composition analyses, with just one study addressing it [10].
Decreased muscle status and elevated intramuscular fat tissue are associated with negative health outcomes, increased morbidity, and heightened mortality [11, 12]. Skeletal muscle and adipose tissue are now understood to function as secretory organs, releasing pro-inflammatory and anti-inflammatory cytokines and adipokines, which influence various physiological processes [13].
A range of diagnostic tools is now available for assessing sarcopenia, and computed tomography (CT) is considered the gold standard [14]. CT offers the benefit of evaluating both the quantity and quality of muscle . In CT scans, the Skeletal Muscle Area (SMA) is quantified on a single slice and adjusted based on an individual’s height, resulting in the Skeletal Muscle Index (SMI). CT enables the assessment of myosteatosis, indicating the presence of fat within the muscle, by measuring the muscle density. A lower radiodensity in CT images signifies higher fat content in the muscle [15]. In addition, CT allows the measurement of subcutaneous and visceral fat areas on a single imaging slice. This study seeks to address this gap by utilizing CT to accurately assess skeletal muscle and fat composition, with the goal of identifying differences between perforated and non-perforated appendicitis.
Material and Methods
Patients
We screened adult patients who underwent contrast-enhanced abdominal CT between April 2022 and April 2023, to identify those diagnosed with acute appendicitis. Patients with acute appendicitis-like reactive changes were excluded from this study. Pediatric patients, those with recent surgeries, and individuals with missing personal information were also excluded (Figure 1).
The final study cohort comprised 55 patients with pAA and 51 with npAA. We retrospectively gathered patient details, such as sex, age, and height from the patient information system.
CT Scan
CT scans were conducted using a GE Revolution EVO 128-slice multi-detector scanner. The imaging protocol included a 2 mm collimation, 2 mm section thickness, rotation time of 0.6 seconds, pitch of 1, FOV of 40 cm, kV of 120, and mA ranging from 200 to 400. The imaging was performed during the portal venous phase, 65 seconds after the administering contrast material.
CT Interpretation and Measurements
CT analysis was conducted using the Advantage Workstation 4.7 Revolution software from GE, USA, available at our hospital’s radiology workstations. CT images were meticulously examined for 8 informative features associated with perforated appendicitis. These features include appendiceal diameter, extraluminal appendicolith, abscess, appendiceal wall enhancement defect, extraluminal air, peri-appendiceal fluid collection, intraluminal air, and moderate or severe peri appendiceal fat stranding [16, 17]. Based on these features, the patients were classified as perforated and non-perforated, according to a consensus formed by abdominal radiologists with two to ten years of experience.
All CT muscle and fat measurements were performed by a radiologist within 5 years of experience and one of our experienced radiologists. The measurements of the experienced radiologist were considered as the standard to establish other parameters.
First, the L3 vertebral level was marked in the sagittal plane. The skeletal muscles at this level (rectus abdominis, lateral and oblique abdominal muscles, psoas major, quadratus lumborum, erector spinae, and multifidus muscles) were evaluated in a single section. To isolate the muscle structures, the -29 to 150 Hounsfield Unit (HU) range was chosen by manually outlining defined patients (Figure 2) [18]. The Skeletal Muscle Area (SMA) was quantified in square centimeters (cm²), within the specified density range, on a single section at the L3 vertebral level (Figure 2). To normalize SMA, it was proportioned to the square of the patient’s height, and the Skeletal Muscle Index (SMI) was obtained in cm²/m². SMI was evaluated as a continuous variable and served as an indicator of whole-body muscle mass. This approach is consistent with a study that demonstrating a linear relationship between the total skeletal muscle cross-sectional area at the L3 vertebra level and whole-body muscle mass [19].
To assess visceral and subcutaneous adipose tissue areas at the same level, we defined limits by selecting HU values of -190 to -30 for subcutaneous fat and -150 to -50 for visceral fat (Figure 2) [18, 20]. We calculated the Visceral to Subcutaneous Fat Ratio (VSR) by dividing the Visceral Adipose Tissue area (VAT) by the area of Subcutaneous Adipose Tissue (SAT). To normalize the VAT, it was proportioned to the square of the patient’s height, and the Visceral Fat Index (VFI) was obtained in cm²/m². VFI was evaluated as a continuous variable and used as an indicator of whole-body visceral fat. To compare patients’ muscle and fat ratios, we investigated the Skeletal Muscle to Visceral Fat Ratio (SVR) [21]. SVR was calculated by dividing SMA by VAT.
We employed sex-specific thresholds for sarcopenia that were strongly linked to mortality in solid tumor patients, as established by Prado and colleagues in 2021 [22]. These thresholds were determined as 52.4 cm2/m2 for men and 38.5 cm2/m2 for women [22].
We also assessed the muscle quality using a measure called Intramuscular Adipose Tissue Content (IMAC) at the L3 level. The IMAC was calculated by dividing the HU values of the erector spinae muscles by the HU value of subcutaneous fat at the L3 level (Figure 3). A higher IMAC suggests more fat in the muscles, indicating a lower muscle quality [23].
Statistical analysis
The study’s statistical analyses and evaluation were conducted using IBM Statistical Package for the Social Sciences for Windows, version 26.0 (SPSS Inc.).
We calculated descriptive statistics for age, sex, and appendicitis status. Additionally, we performed CT muscle and fat analyses, such as SMI, VSR, IMAC, SVR, and VFI for both female and male groups.
Normality was tested using the Kolmogorov-Smirnov test; non-normally distributed data were reported as median (IQR). Categorical data were analyzed using the Chi-square test, whereas non-parametric data were assessed with the Mann-Whitney U test. Intraclass correlation coefficients (ICC) were calculated to assess interobserver agreement (with corresponding 95% confidence intervals) for the SMA, SAT, and VAT. An ICC less than 0.5 was interpreted as “poor,” 0.5–0.74 as “moderate,” 0.75–0.89 as “good,” and 0.90 or greater as “perfect” in terms of reliability. A p-value of less than 0.05 was considered statistically significant.
Ethical Approval
This study was approved by the Ethics Committee of the Bilkent City Hospital, Ankara (Date: 2023-08-23, No: E2-23-4772).
Results
A total of 106 patients were involved in this study with 50.9% being female (n=54) and 49.0% male (n=52). The comorbidities of the patients in both groups are presented in Table 2.
The perforated group comprised 51% of the patients (n=55), while the non-perforated group comprised 48% of the patients (n=51) (Table 1, 2). The gender distribution showed no statistical difference, with females comprising 50.9% (28/55) of perforated cases and 60% (26/51) of non-perforated cases (p=0.776). Age distributions were similar in both groups (p=0.994) (Table 1).
Among the females, the median SMI value was significantly higher in the group with perforation (37,2 cm2/m2) than in the group without perforation (33,1 cm2/m2) (p=0.011) (Table 3).
However, no statistical difference was observed between the perforated group (51.0 cm2/m2) and the non-perforated group (49.0 cm2/m2) in SMI median values among men (p=0.101) (Table 3).
VSR, SVR, VFI, and IMAC values were not significantly different between the two groups for both females and males (Table 3).
Based on SMI values, the sarcopenia rate in women in the non-perforated group (84%) was significantly higher than in women from perforated group (57%) (p=0.027).
However, there was no significant difference in the sarcopenia rate between men in the perforated (55.5%) and those in the non-perforated group (64.0%) (p = 0.535).
In the ROC Curve analysis for SMI values of female patients, 35.0 cm2/m2 was identified as the cut-off point with a 95% confidence interval (AUC = 0.701 (0.561-0.841), sensitivity = 60.7%, specificity = 61.5%, p = 0.011). No statistically significant results were found in the ROC Curve analysis of other parameters of female patients (p>0.05).
No statistically significant results were found in the ROC curve analysis for the parameters mentioned above in male patients (p>0.05).
SMA, SAT, VAT, and IMAC measurements were independently conducted by a less experienced radiologist (5 years of experience) and an experienced radiologist (10 years of experience) in a blinded manner. The ICC and 95% confidence intervals for the interobserver agreements were mostly good: SMA, 0.85 (0.71–0.94); SAT, 0.88 (0.79–0.91); VAT, 0.85 (0.72–0.93); and IMAC, 0.86 (0.77–0.93).
Discussion
We aimed at investigating the differences in skeletal muscle and fat composition between patients with perforated and non-perforated acute appendicitis using CT analysis. Our results illuminate the intricate relationship between body composition and the development of appendiceal perforation.
Among the key findings of this study was the significantly higher Skeletal Muscle Index (SMI) values among females in the perforated group compared (37.2 cm2/m2) to the non-perforated group (33.1 cm2/m2) (p=0.011). This intriguing finding likely contrasts with the sole article we found on this subject in the literature. They proposed that a “reduction in muscle area and the identification of sarcopenia through computed tomography (CT) are indicative of increased susceptibility to complicated appendicitis” [10]. However, as they stated, working only with the elderly population may lead to a difference, that could explain this discrepancy with our study findings. Additionally, in our study, we evaluated SMI and other data separately between men and women, which may have caused this difference.
Interestingly, no statistical difference was detected between the perforated group (51.0 cm2/m2) and the non-perforated group (49.0 cm2/m2 ) in SMI median values among men (p=0.101). This gender disparity highlights the potential influence of sex-specific factors on the relationship between muscle composition and appendiceal perforation. Our findings underscore the importance of conducting further research to clarify the intricate connections between sex, muscle composition, and the pathogenesis of appendiceal perforation.
No significant difference was identified in CT fat values, such as VSR, VFI, and SVR, between the two groups. Based on the ability of adipose tissue to secrete pro-inflammatory adipokines and various other pro-inflammatory factors, we anticipated differences between the appendicitis groups [13, 24]. We aimed to determine whether the inflammatory response leading to perforation in appendicitis is closely linked to the balance between visceral and subcutaneous fat and the overall visceral fat content. To our knowledge, no prior studies have directly investigated this aspect of the pathophysiology of appendicitis. While previous studies have suggested associations between Body Mass Index (BMI) and anorexia with perforated appendicitis, the available literature presents conflicting perspectives. For instance, one study observed a lower BMI in patients with perforated appendicitis, particularly in the geriatric population [10], while another highlighted anorexia as a significant factor associated with perforation in geriatric patients [5]. Intriguingly, a study without age limitations reported contrasting findings, indicating a higher BMI in patients with perforated appendicitis [9]. We attribute the differing results of these studies to their use of different populations and concepts such as BMI and anorexia, which affect both fat and muscle mass together. For this reason, we performed this comparison using more quantitative ratios. The absence of significant differences in VSR, SVR, and VFI between the two groups underscores the necessity for a paradigm shift in the understanding of the nuanced relationship between adipose tissues and the course of appendicitis.
We did not observe any age or sex differences between the groups. Earlier studies have indicated that older age may be linked to a higher risk of perforation [6,7]. Pokharel et al. proposed that in elderly patients, complications, such as perforation, are more likely due to vascular sclerosis, lumen narrowing, and fat infiltration in the appendix’s muscle layer [25]. According to another study, there was apparently no association between age and perforation [9]. When it comes to gender, some studies suggest that being male is associated with the risk of perforation [5, 7]. However, alternative perspectives suggest that there is no correlation between sex and the occurrence of perforation [8, 9]. Considering our hospital’s status as a tertiary care center, it should be noted that perforated cases were more prevalent than non-perforated cases. This discrepancy may have implications related to both age and sex, suggesting potential influences of these demographic factors.
We used IMAC to assess muscle quality and found no significant group differences (p>0.05). To measure IMAC, we sought to minimize the contrast enhancement effect in the contrast-enhanced scans by calculating the ratio of HU values in the erector spinal muscles to those in the adjacent fat planes. Nevertheless, we acknowledge that IMAC measurements are more accurate in non-contrast scans [15].
Limitation
Our study is the first to compare the CT muscle and fat analysis of perforated and non-perforated appendicitis in the general adult population among males and females. However, this study has some limitations. We recognize that the radiological features we used for distinguishing between perforated and non-perforated appendicitis demonstrate high specificity but limited sensitivity on an could individual basis [16, 17]. Because of the retrospective nature of our we could not determine the exact time in hours between the onset of patients’ symptoms and their CT scan. Our study concentrated on analyzing muscle and fat using CT scans. Other major relevant variables that may affect the perforation, such as the presence of fecalith, the morphology of the appendix vermiformis, patient immunologic status, and other possible risk factors were not considered. Future studies should utilize a multicenter prospective design to improve the generalizability of findings across diverse populations, minimize potential biases inherent in our retrospective single-center study. Despite these limitations, our findings should be confirmed with multivariate logistic regression analyses.
Conclusion
In summary, this study offers important insights into how muscle and fat composition relate to the risk of appendiceal perforation. The surprising discovery of higher SMI values in the perforated group among females challenges preconceptions and underscores the complex nature of contributing factors influencing appendiceal perforation. Additional studies are required to clarify the complex interplay between body composition, sex-specific factors, and the course of acute appendicitis.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Contribution of the superb microvascular imaging-based vascular index in scoring thyroid nodules according to TI-RADS
Habip Eser Akkaya 1, Çağrı Damar 2, Eylem Pınar Eser 3, Ömer Kazcı 4
1 Department of Radiology, Ankara Training and Research Hospital, 2 Department of Radiology, Bilkent City Hospital, 3 Department of Pathology, Etlik City Hospital, 4 Department of Radiology, Presidential Health Services Center, Ankara, Turkiye
DOI: 10.4328/ACAM.22138 Received: 2024-02-08 Accepted: 2024-10-03 Published Online: 2024-11-02 Printed: 2025-01-01 Ann Clin Anal Med 2025;16(1):68-71
Corresponding Author: Habip Eser Akkaya, Department of Radiology, Ankara Training and Research Hospital, Ankara, Turkiye. E-mail: habipeserakkaya@gmail.com P: +90 312 595 36 83 Corresponding Author ORCID ID: https://orcid.org/0000-0002-8447-3627
Other Authors ORCID ID: Çağrı Damar, https://orcid.org/0000-0001-7208-1290 . Eylem Pınar Eser, https://orcid.org/0000-0001-5459-4017 . Ömer Kazcı, https://orcid.org/ 0000-0003-0846-1074
This study was approved by the Ethics Committee of Ankara Education and Research Hospital (Date: 2020-06-25, No: 235/2020)
Aim: In this study, we aimed to investigate the effectiveness of the superb microvascular imaging based vascular index (SMI VI) in evaluating thyroid nodules that underwent fine needle aspiration biopsy (FNAB) after scoring according to the Thyroid Imaging Reporting and Data System (TI-RADS).
Material and Methods: The study comprised 61 patients with thyroid nodules. Following ultrasonographic imaging of all nodules, SMI VI measurements and TI-RADS scoring were conducted. Patients with nodules scoring TI-RADS 3-5 underwent FNAB. Subsequently, all collected data were statistically analyzed.
Results: The study included 4 (6.5%) men and 57 (93.5%) women, with an average age of 46.85 ± 11.62 years. Regarding thyroid nodules, 18 (29.5%) were classified as TI-RADS 3, 32 (52.5%) as TI-RADS 4, and 11 (18%) as TI-RADS 5. The TI-RADS 4-5 group exhibited a mean SMI VI of 27.67, indicating a significant difference compared to TI-RADS 3. SMI VI values were similar for benign and malignant tumors (p > 0.05). Additionally, a moderately positive correlation (p = 0.001, r = 0.503) was found between the TI-RADS total scores of the nodules and SMI VI values.
Discussion: Comparing TI-RADS categories and total scores, as well as discriminating between benign and malignant nodules, enabled us to assign SMI VI values to each nodule type. Integrating TI-RADS with SMI VI may increase nodule characterization precision, allowing for more targeted diagnostic and treatment approaches. This emphasizes the importance of using a comprehensive assessment technique for thyroid nodule evaluation.
Keywords: Thyroid Nodules, Superb Microvascular Imaging, Thyroid Imaging Reporting And Data System
Introduction
Thyroid cancer is the most prevalent endocrine malignancy [1, 2]. With the help of ultrasound (US) examinations, the prevalence of thyroid nodules in general population is determined to be 19–68%. However, the majority of these nodules are benign, with only 7–15% are malignant [3, 4]. It is crucial to accurately diagnosing thyroid nodules for determining prognosis and treatment choices. US is the primary imaging tool for assessing thyroid nodules in clinical practice [5]. In 2017 a guideline named “thyroid imaging, reporting and data system (TI-RADS)” was released by the American College of Radiology (ACR) and subsequently revised for the evaluation of nodules. According to this guideline, nodules are rated considering their composition, echogenicity, form, margin, and the presence of an echogenic focus. Based on the total score, it is classified as benign (TR1), minimally suspicious (TR2), mildly suspicious (TR3), strongly suspicious (TR4), and highly suspicious (TR5). If necessary, follow-up or an aspiration biopsy (FNAB) is advised [6, 7]. In TI-RADS, grayscale US data are utilized, but no vascular examination is conducted. Whereas the nodules with increased vascularity are associated with increased malignancy [8].
Superb Microvascular Imaging (SMI) is a new Doppler technique for analyzing and calculating the blood supply of the soft tissue parts of the body. It is more sensitive in detecting low velocity microvascular blood flow and provides quantitative information blood circulation in the selected area [9].
The Vascularity index (VI) is calculable using SMI, allowing for quantitative analysis. VI is determined automatically by the device by comparing the proportion of colored pixels indicating blood supply in the drawn Region of Interest (ROI) to the total number of pixels and is expressed as a numeric value between 0 and 100 [10].
In this study, we aimed to compare thyroid nodules according to TI-RADS categories, TI-RADS total scores, SMI VI values and fine needle aspiration biopsy results.
Material and Methods
Individuals
A total of 65 patients, aged between 18 and 65 years, whose thyroid nodules were evaluated with the SMI method and then underwent thyroid FNAB, were included in the study Four patients with atypia or non-diagnostic pathology results of uncertain significance were excluded from the study despite undergoing FNAB twice. The study was conducted between July 2020 and August 2022.
Evaluation
The type of thyroid nodule was determined by its composition (solid, cystic, mixed, spongiform), echogenicity (anechoic, hyperechoic, isoechoic, hypoechoic, very hypoechoic), shape, contour (well-circumscribed, lobulated, poorly circumscribed, extension beyond the thyroid gland), presence and quality of echogenic focus. According to the total score attained, (macrocalcification, peripheral calcification, punctate echogenic focus) and TI-RADS value were assigned.
Two radiologists each with over ten years of ultrasound experience and two years of SMI evaluation experience conducted the evaluations. Evaluations were conducted using an Aplio 500 Platinum ultrasound device (Toshiba-Canon Medical Systems Corporation, Japan) with a high-frequency linear transducer (frequency range, 5–14 MHz).
During the SMI examination, the pulse repetition frequency was set between 200 and 230 Hz, the frame rate was greater than 50 Hz, and the color gain was set between 37 and 42 decibels. In the SMI method, the thyroid nodule contours were painstakingly drawn in free drawing mode. VI was calculated in the thyroid nodule that was traced. By dividing the number of vascular signal pixels by the total number of pixels, the device automatically calculated VI (Figure 1).
TI-RADS categories of thyroid nodule and VI, FNAB results, and pathology reports were compared.
Statistical analysis
The study was statistically analyzed using “Statistical Package for the Social Sciences” (SPSS) Version 21.0 (SPSS Inc., Chicago, Illinois, United States). Using graphical (histograms and probability graphs) and statistical (Kolmogorov-Smirnov/Shapiro-Wilk tests), the conformity of the variables to the normal distribution was examined. Means and standard deviations were utilized for descriptive analyses, while categorical variables are presented as numbers and percentages. To compare the differences between two independent groups, the Mann-Whitney U test was utilized. Three independent groups were compared using the Kruskal-Wallis test. For pairwise comparisons, the Mann Whitney U Test and Bonferroni correction were utilized. Spearman correlation analysis was used to determine the relationships between continuous variables. In all analyses, a p-value of 0.05 was considered statistically significant.
Ethical Approval
This study was approved by the Clinical Research Ethics Committee of Ankara Education and Research Hospital (Date: 2020-06-25, No: 235/2020).
Results
A total of 61 individuals were included in the study, including 4 (6.5%) men and 57 (93.5%) women. The mean age of the sample was 46.85 ± 11.62 years.
18 thyroid nodules (29.5%) were TI-RADS 3, 32 (52.5%) were TI-RADS 4, and 11 (18%) were TI-RADS 5.
FNAB determined that 38 (62.3%) of the nodules were benign, 8 (13.1%) had atypia of uncertain significance, 11 (18%) were malignant, and 4 (6.6%) were non-diagnostic. Nodules with uncertain significance and non-diagnostic atypia were subjected to a secondary FNAB. Five of the patients with atypia of uncertain significance were benign and three were malignant after a second FNAB; it was concluded that all non-diagnostic cases were benign. Thus, it was determined that 47 (77%) of the thyroid nodules were benign, while 14 (23%) were malignant. All the malignant nodules were of the papillary variety.
17 (94.4%) of the 18 patients with TI-RADS 3 were benign, while 1 (5.6%) was malignant. 24 (75%) of those diagnosed with TI-RADS 4 were determined to be benign, while 8 (25%) were malignant. Six TI-RADS 5s were benign (54.5%), while five were malignant (45.5%).
Those with TI-RADS 3 had mean SMI VI values of 11.27, those with TI-RADS 4 had mean SMI VI values of 27.26, and those with TI-RADS 5 had mean SMI VI values of 28.86 (Figure 2a).
According to the TI-RADS categories, there was a significant difference among the SMI values of the three groups (p < 0.05). In paired group comparisons, TI-RADS 3-4 and 3-5 differed significantly from each another (Table 1).
The group with TI-RADS 4-5 together had a mean SMI VI of 27.67, and there was a significant difference between the two groups when compared to TI-RADS 3 (Table 2) (Figure 2b).
SMI VI values of benign and malignant tumours were similar (p > 0.05) (Table 3). (Figure 2c).
When examining the relationship between the TI-RADS total scores of the nodules and the SMI VI values, a moderately positive correlation was discovered (p=0.001, r=0.503).
Discussion
Thyroid nodules are commonly observed during routine examinations. US examinations with high-resolution imaging plays an essential role in differentiating benign from malignant tumors [11]. In the TI-RADS classification, US findings of malignant nodules such as solid composition, low echogenicity, contour irregularity, internal echogenic foci, and vertical growth pattern are utilized [6, 7].
Angiogenesis is essential for formation, development, proliferation, invasion, and metastasis of the tumours such thyroid malignancies [12, 13]. Blood flow visualization in thyroid nodules may aid in distinguishing benign from malignant nodules. In previous studies, it was indicated that the blood supply to the periphery may be benign while the blood supply to the interior may contain malignant nodules [14- 16]. However, color Doppler imaging (CDI) and power Doppler imaging (PDI) modalities have technical limitations for detecting microvascularity and low blood flow velocity [17, 18]. SMI is a recently developed method for visualizing the microvascular structure by preventing motion artifacts [18]. SMI allows for the calculation of VI values. VI permits quantitative analysis as opposed to morphological evaluation. It is automatically calculated by the device using the proportion of VI-colored pixels to all pixels [10]. In our investigation, we compared the SMI VI values of the nodules according to their TI-RADS categories.
Machado et al. reported that the SMI method demonstrated superior microvascularity in thyroid nodules in comparison to CDI and PDI [19]. Lu et al. examined 52 thyroid nodules and discovered that SMI exhibited microvessels better than CDI/PDI [17]. Using both CDI and SMI, Yi Cheng Zhu et al. discovered a significant difference in the vascular distribution and morphology of benign and malignant thyroid nodules. However, in determining the vascularity distribution in thyroid nodules, no statistically significant difference was found between CDI and SMI in their study [18].
A study by Zhao Yongfeng et al. comparing SMI to Contrast-enhanced ultrasound (CEUS) in the evaluation of microvascularity in thyroid nodules, it was stated that the SMI method could be used to assess the microvascularity of the nodules. Compared to CEUS, the SMI procedure has the advantages of being non-invasive, having no contraindications, and being cost-effective [1].
According to the TI-RADS guidelines, the risk of malignancy for TR 3, 4, and 5 nodules is, respectively, less than 5%, 5-20%, and greater than 20% [6]. Middleton et al. found that the risk of malignancy for TI-RADS 3, 4, and 5 nodules was 4.8%, 9.1%, and 35.0%, respectively [20]. In our study, the malignancy risks of TI-RADS 3, 4, and 5 nodules were greater than in Middleton et al.’s study.
Malignant nodules had higher SMI VI values than benign nodules, but the difference was not statistically significant in our study. In a meta-analysis conducted by Hui Jin et al., the SMI values of malignant nodules were found to be higher than those of benign nodules [11]. In several studies, grading has been performed when determining SMI values, which is insufficient for providing genuine qualitative values. Min Ji Hong et al. concluded that the SMI quantification values of malignant nodules were substantially greater than those of benign nodules [21].
In their study, Lin Chen et al. demonstrated that the combination of TI-RADS and SMI improved the diagnostic performance of TI-RADS [5]. According to Changfu Zhu et al.’s meta-analysis, the diagnostic efficacy of TI-RADS plus SMI in differentiating benign and malignant thyroid nodules is superior to that of TI-RADS alone [22]. In our study, a moderate correlation was discovered between TI-RADS total scores and SMI VI values. Comparing the VI values of the groups, it is determined that the TI-RADS 4-5 groups was significantly higher than TI-RADS 3. It was observed that the microvascularity of thyroid nodules increased as the likelihood of risk of malignity increased.
Due to the limited number of patients with malignant pathology results, we may not have observed a significant difference in our study. Despite its limitations, in our investigation, unlike other studies, VI values were analysed, and it was believed that SMI VI evaluations could aid in TI-RADS classification. Future research will require large, multicenter investigations with quantitative results.
Limitation
Here are some potential limitations that could be associated with this study. The TI-RADS system itself may have its own limitations. It might not capture all the nuances related to thyroid nodule malignancy risk, and there might be gray areas that aren’t definitive. Any diagnostic method has a risk of producing false positives (indicating a problem when there isn’t one) or false negatives (indicating no problem when there is one). The gold standard for confirming malignancy is typically a biopsy. If not all nodules undergo biopsy, it might lead to potential errors in classification.
Conclusion
By comparing thyroid nodules using TI-RADS categories and total scores, coupled with a benign-malignant distinction, we were able to determine the SMI VI values associated with each nodule type. The integration of TI-RADS with SMI VI values can potentially enhance the precision of nodule characterization, paving the way for more targeted diagnostic and therapeutic approaches. This underscores the importance of utilizing a multi-faceted assessment strategy in the evaluation of thyroid nodules.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Habip Eser Akkaya, Çağrı Damar, Eylem Pınar Eser, Ömer Kazcı. Contribution of the superb microvascular imaging-based vascular index in scoring thyroid nodules according to TI-RADS. Ann Clin Anal Med 2025;16(1):68-71
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Effectiveness of manual lymph drainage and low level laser treatment in impacted lower molar surgery
Büşra İnce 1, Fatma Mutluay 2, Barış Çağrı Delilbaşı 3
1 Department of Physiotherapy and Rehabilitation, Graduated School of Health Sciences, 2 Department of Physiotherapy and Rehabilitation, Faculty of Health Sciences, 3 Department of Dental and Maxillofacial Surgery, Faculty of Dentistry, Istanbul Medipol University, İstanbul, Turkiye
DOI: 10.4328/ACAM.22374 Received: 2024-08-20 Accepted: 2024-09-24 Published Online: 2024-11-04 Printed: 2025-01-01 Ann Clin Anal Med 2025;16(1):72-76
Corresponding Author: Büşra İnce, Department of Physiotherapy and Rehabilitation, Graduated School of Health Sciences, İstanbul Medipol University, İstanbul, Turkiye. E-mail: fztbusrakalli@gmail.com P: +90 542 479 71 50 Corresponding Author ORCID ID: https://orcid.org/0000-0002-7954-6289
Other Authors ORCID ID: Fatma Mutluay, https://orcid.org/0000-0003-1432-0913 . Barış Çağrı Delilbaşı, https://orcid.org/0000-0003-3347-1151
This study was approved by the Ethics Committee of Non-Interventional Clinical Research, Istanbul Medipol University (Date: 2018-08-15, No: 447)
Aim: The aim of this study was to compare the efficacy of manual lymphatic drainage (MLD) and low level laser therapy (LLLT) on postoperative pain, edema and trismus in the impacted lower third molar tooth (ILTMT) surgery.
Material and Methods: The study included 36 patients with a mean age of 25.7 ± 5.9 years. Patients were randomized into 3 groups: MLD, LLTT and control groups. Pain (Visual Analogue Scale-VAS), edema (craniometric measurement) and trismus (maximum interinsisal distance measurement) were evaluated. Evaluations were made before surgery, 24, 48 and 72 hours after surgery, and on the 7th day after surgery.
Results: The mean pain level between the 4th and 7th days of the two treatment groups and the use of additional pain medication during the treatment were significantly lower than the control group. The mean edema increase and mouth opening values did not differ significantly between the treatment groups in the postoperative 7th day compared to the preoperative period, but it was significantly higher in the control group.
Discussion: It was concluded that MLD and LLLT after ILTMT surgery can be used effectively in the clinic to reduce pain and edema and improve mouth opening. It is thought that our study will provide a basis for future studies on MLD treatment in areas such as oral and maxillofacial surgery as well as orthognathic surgery.
Keywords: Molar Surgery, Manual Lymphatic Drainage, Laser Therapy
Introduction
Impacted lower third molar tooth (ILTMT) is one of the most frequently performed operations in oral and maxillofacial surgery [1]. Edema, trismus, paresthesia, mandibular fracture and hemorrhage are among the frequently observed conditions in the early and late periods after ILTMT surgery [2, 3]. The variables underlying these changes are complex, but the inflammatory process caused by trauma is important. It is almost inevitable that pain, edema and trismus will occur as a result of the inflammatory response. This situation can lead to negative effects of living conditions, prolongation of the recovery process, and therefore social and economic losses [4- 6].
Post-surgical pain begins when the effect of anesthesia wears off, reaches its highest point in the first 3-5 hours, and then gradually decreases until the seventh day [5, 6]. Edema usually peaks between 12-48 hours and may take 5-7 days to resolve completely [7]. The resulting edema surrounds the masseter muscle, causing decreased mandibular movements and reduced mouth opening. This condition, defined as trismus, may occur due to surgical procedures and local anesthesia. Trismus usually reaches its highest level on the 2nd day of surgery and completely decreases on the 7th day [8, 9].
In order to reduce complications, research has been conducted on treatment modalities such as analgesics, steroid and non-steroidal anti-inflammatory (NSAID) drugs, cryotherapy, different flap techniques, and LLLT [7- 12]. In one study, MLD application was observed [13]. Since no effect was observed at the expected level, more reliable and comprehensive studies are needed. At the end of the study, it is thought that it will provide important data regarding the widespread applicability of MLD treatment as an alternative or complementary treatment to LLLT treatment in ILTMT surgery.
Material and Methods
Participants
The study was carried out with 36 patients aged between 18-45 who came to Faculty of Dentistry Department of Oral and Maxillofacial Surgery within the scope of 2018-2019 and who could undergo surgical extraction on their ILTMTs as a result of their radiographic and clinical evaluations. All participating patients signed an approved “Informed Consent Form” after being given detailed information about the purpose and method of the study.
Patient selection was made to include patients who fit American Society of Anesthesiologists 1 in the classification of ASA, have impacted teeth with bone retention, have sufficient cognitive capacity, and are between the ages of 19-45. Women who have a systemic disease that prevents oral surgery, have an infection, are allergic to the drugs to be given, have received NSAID treatment in the last 3 months, have a carotid endoarterectomy, have an inflammatory skin disease on the face or neck, have a hyperthyroid disorder, are receiving psychiatric treatment, are pregnant and are breastfeeding are included in the study. It has not been done.
Assesment
Demographic information of individuals was recorded through the Personal Information Form. Pain levels were measured using the Visual Analogue Scale (VAS). The amount of edema was determined using the craniometric method. Distances measured from three separate extra-oral regions on the face (between the outer corner of the eye and the angulus mandible, between the tragus and the corner of the mouth, and between the tragus and the pogonion) were used to record the facial volume and the amount of edema. Trismus evaluation was made by measuring the maximum distance between the upper and lower teeth in millimeters while the patient was sitting in an upright position. Edema and trismus measurements were repeated at certain time periods (24th, 48th, 72nd hour and 7th day) before and after surgery.
Treatment Program
A total of 36 patients participating in the study were randomly selected and divided into three groups: control group (n:12), MLD group (n:12) and LLLT group (n:12). The average age of the participants, whose ages ranged from 19 to 45, was determined as 25.7 ± 5.9. MLD and LLLT were applied to the patients once a day for three days after surgery (at the 24th, 48th and 72nd hours) according to their groups. The control group received only routine drug therapy and ice therapy. As routine postoperative antibiotic prophylaxis, 875 mg of amoxicillin and 125 mg of clavulanic acid were given twice a day, as well as gargling chlorhexidine gluconate solutions three times a day. Additionally, all individuals were asked to apply ice intermittently for the first 24 hours.
LLLT treatment was applied with a Medency brand laser device of Italian origin, at a wavelength of 810 nm, in continuous mode, with a power of 100 mW and an energy density of 4 J/cm2 (0.1 W x 120 sec for a total of 12 J). The treatment was performed including intraoral and extraoral areas. Intraoral laser application was planned to be applied to the surgical area, masseter and internal pterygoid muscle, and retromolar area. These applications were performed without contact with the mouth, from a distance of approximately 1 cm. Extraoral application was made to the insertion area of the masseter muscle. Laser treatment was performed by an experienced dentist.
During the MLD technique, hand positions are adjusted taking into account the anatomy and physiology of the lymphatic system. The stroke sequence includes work and rest phases in which manual pressure slowly increases and decreases. The pressure intensity is adjusted to increase the elasticity of the skin and subcutaneous tissue to prevent unwanted vasodilation and lymphangiospasm. The operating time of each pulse was determined as 1 second, taking into account the viscosity of the lymph fluid. Each stroke was repeated 5-7 times for manual lymphatic drainage to be effective. The way the strokes work is to direct the lymph flow from blocked areas to healthy areas.
Statistical Analysis
The significance level was set at 0.05; In this context, it was concluded that there was a statistically significant difference if p<0.05, and that there was no significant difference if p>0.05. SPSS 22.0 package program was used for statistical analysis.
Ethical Approval
This study was approved by the Ethics Committee of Non-Interventional Clinical Research Ethics Committee of Istanbul Medipol University (Date: 2018-08-15, No: 447).
Results
According to the findings of our study, the groups did not differ significantly (p > 0.05) in terms of demographic characteristics (Table 1).
As a result of our study, it was observed that ILTMT surgery is performed more frequently in women. In all participant groups, the highest pain levels were reported to be at the 6th hour. No significant difference was observed between the groups in VAS scores before surgery and on the 2nd day after surgery. However, VAS scores from day 4 to day 7 in the treatment groups were lower than those in the control group. It was determined that participants in the MLD and LLLT groups were significantly less likely to receive additional analgesics after surgery compared to the control group. When pain was compared by gender, it was observed that women had lower pain tolerance than men and were more prone to analgesic medication.
No significant difference was observed between the groups in terms of mean edema levels before surgery. In all groups, edema levels were highest on the 2nd day after surgery. Moreover, in all groups, the average edema level on the 2nd day after surgery showed a significant increase compared to the pre-surgery period, while the average edema level on the 7th day after surgery showed a significant decrease compared to the 2nd day after surgery. It was reported that the edema level on the 2nd and 7th postoperative day did not show a significant difference between the treatment groups and was significantly higher in the control group compared to the MLD and LLLT groups.
There was no significant difference in the increase in edema on the 2nd day after surgery compared to before surgery between the MLD and LLLT groups. However, it was found that the increase in edema on the second day after surgery was higher in the control group compared to the MLD and LLLT groups. While edema values on the 7th day after surgery in the MLD group did not show a significant change compared to the pre-surgery, they showed a significant increase in the control and LLLT groups. No significant difference was observed in the increase in edema on the 7th day between the MLD and LLLT groups. However, in the control group, the increase in edema on the 7th day after surgery compared to before surgery was significantly higher than in the MLD and LLLT groups (Table 2).
No difference was observed in preoperative trismus values between the groups. However, trismus averages were at their lowest level on the 2nd day after surgery in all groups. In all groups, the trismus value on the 2nd and 7th day after surgery showed a significant decrease compared to the pre-surgery, while the trismus value on the 7th day after surgery showed a significant increase compared to the 2nd day after surgery. No significant difference was observed between the groups in terms of trismus values on the 2nd and 7th days after surgery. While the decrease in trismus value on the second day after surgery compared to before surgery did not show a significant difference between the MLD and LLLT groups, it was found to be significantly higher in the control group compared to the MLD and LLLT groups. While the trismus value on the 7th day after surgery compared to the pre-surgery did not show a significant difference in the MLD and LLLT groups, this difference was significant in the control group. Moreover, although it was not statistically significant, the trismus value of the MLD group on the 7th postoperative day was very close to the postoperative value (Table 3).
Discussion
Differences are observed between the results of various studies examining the effects of LLLT after ILTMT surgery. For example, in a meta-analysis study conducted by Brignardello-Petersen et al., it was reported that DELT did not have any positive effect on pain and edema, but provided a moderate benefit for trismus [14]. However, in a study conducted by He et al., DELT was reported to be effective in edema, trismus, and pain [15]. These differences are thought to be due to the lack of a standard approach to variables such as the properties of the laser applied and the application protocol [16]. There are many studies in the literature on the effect of LLLT wavelength and energy density in reducing complications [16- 17]. In our study, it was determined that the 810 nm wavelength affects deep tissues and is in the range where biostimulation effects are best observed, and 4J/cm² energy density was preferred because it is a dose that generally yields positive results. According to our results, none of the participants in the LLLT group needed to use additional painkillers, and the VAS scores recorded from the 4th day to the 7th day after surgery were lower than the control group. In addition, the increase in edema and the decrease in trismus values on the 2nd and 7th days after surgery compared to before surgery were found to be significantly higher in the control group compared to the LLLT group. These findings show that laser is an effective method in reducing complications.
The issue of the number of sessions in which laser treatment will be applied is still research-oriented. Although the application protocol we use is frequently encountered in the current literature, the application frequency can vary from a single session to four sessions. In the literature, it is recommended to perform at least five sessions for MLD therapy to yield positive results, but since the patients recover in a short time after this surgery and since the work will be done in a small area, it was thought that three sessions would be sufficient and the treatment protocol was created accordingly.
There are also studies comparing the effectiveness of LLLT according to the application region. Kahraman reported in his study that intraoral application provides more effect than extraoral application [6]. Aras et al., in their study comparing the effects of extraoral and intraoral application, observed that extraoral laser application was more effective than intraoral application in reducing edema and trismus [18]. Ferrante et al., in their study where they performed combined application, observed that pain, edema and trismus values were lower compared to the control group [19]. In our study, combined laser application was performed, similar to the findings in the literature. The results showed that pain, edema and trismus values were significantly lower in the laser group than in the control group.
New areas for the medical use of MLD are being discovered every day. Increasing drug allergies and drug-related side effects increase the tendency towards alternative methods such as MLD. Yaedu et al. (2017) found that the edema level in the MLD group after bimaxillary orthognathic surgery decreased faster compared to the control group, but there was no significant difference between the groups in terms of edema and pain. Additionally, it has been reported that there is no relationship between pain and edema and that surgical duration does not affect edema. This study shows that MLD treatment after orthognathic surgery is effective in reducing post-surgical facial edema [2]. MLD treatment is thought to increase the carrying capacity of lymph vessels by increasing lymphangiomotor activity and stimulating the lymph nodes.
In their study in 2017, Szolnoky and colleagues investigated the effects of MLD on pain and edema after bilateral ILTMT surgery. As a result of the study, it was reported that with MLD application, the VAS score, which was 35.5 ± 20.60 before surgery, decreased to 22 ± 19.32 mm. A significant positive effect was observed on the quality of life of the MLD group. When the distances between anatomical regions determined to evaluate the intensity of edema were examined, it was observed that there were positive and significant differences in the MLD group compared to the control group [13]. The method of our study is similar to the previous study. MLD treatment was administered in 45-minute sessions once a day for the first three days after surgery. In the comparison between the MLD and LLLT groups, although no statistically significant difference was detected in VAS scores during the specified time periods, it was observed that the pain level in the MLD group was lower throughout the entire process. It has been thought that MLD is performed by applying light pressure and is more effective than laser treatment in increasing lymphatic drainage by directly stimulating new lymphatic pathways. It is thought that the manual application of MLD, accompanied by a specialist physiotherapist, and the fact that it is a technique that gives confidence to the patient, may have a positive effect on the treatment results.
Conclusion
It was concluded that MLD and LLLT after ILTMT surgery can be used effectively in the clinic to reduce pain and edema and improve mouth opening. It is thought that our study will provide a basis for future studies on MLD treatment in areas such as oral and maxillofacial surgery as well as orthognathic surgery.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Büşra İnce, Fatma Mutluay, Barış Çağrı Delilbaşı. Effectiveness of manual lymph drainage and low level laser treatment in impacted lower molar surgery. Ann Clin Anal Med 2025;16(1):72-76
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