Genotype-Phenotype Correlations in Syndromic Forms of Hereditary Retinal Diseases

The aim of this thesis is to present a detailed assessment of the phenotypes and genotypes of rare retinal dystrophies with systemic associations (syndromes). Additionally, an in-depth analysis and discussion of two ultra-rare syndromes, Cohen syndrome and Alström syndrome is given. Precise knowledge of genotypes and related phenotypes is important in such rare diseases to allow for correct diagnosis by targeted laboratory and clinical diagnostic procedures. Correct diagnosis of rare hereditary retinal diseases early in life of affected patients also supports the effective use of future therapies that are arriving already in a multitude of clinical trials presently going on in ophthalmology, using gene replacement therapy, CRISPR/Cas9 methods, stem cells and optogenetics

Adhesion Development and the Expression of Endothelial Nitric Oxide Synthase

Objective: This study was conducted to determine whether nitric oxide (NO), a potent vasodilator and inhibitor of thrombus formation, is involved in the formation and maintenance of adhesions. Methods: Skin, subcutaneous tissues, peritoneum and adhesions were collected from surgical patients and total RNA was isolated. Quantitative reverse transcription polymerase chain reaction (QRT-PCR) was performed to quantitate endothelial nitric oxide synthase (eNOS) and β-actin mRNA levels. Results: eNOS mRNA levels for skin, subcutaneous tissue, peritoneum and adhesions were ≤ 3.12 × 10(-4), ≤ 3.12 × 10(-4), 6.24 × 10(-4) and 2.5 × 10(-3) attomoles/μl, respectively. β-actin mRNA levels for all tissues were between 1.25 × 10(-1) and 6.25 × 10(-2) attomoles/μl. Conclusion: eNOS mRNA can be identified in tissue adhesions, and may therefore play a role in adhesion formation and maintenance

Multidisciplinary clinic approach improves overall survival outcomes of patients with metastatic germ-cell tumors

Background To report our experience utilizing a multidisciplinary clinic (MDC) at Indiana University (IU) since the publication of the International Germ Cell Cancer Collaborative Group (IGCCCG), and to compare our overall survival (OS) to that of the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program. Patients and methods We conducted a retrospective analysis of all patients with metastatic germ-cell tumor (GCT) seen at IU from 1998 to 2014. A total of 1611 consecutive patients were identified, of whom 704 patients received an initial evaluation by our MDC (including medical oncology, pathology, urology and thoracic surgery) and started first-line chemotherapy at IU. These 704 patients were eligible for analysis. All patients in this cohort were treated with cisplatin–etoposide-based combination chemotherapy. We compared the progression-free survival (PFS) and OS of patients treated at IU with that of the published IGCCCG cohort. OS of the IU testis cancer primary cohort (n = 622) was further compared with the SEER data of 1283 patients labeled with ‘distant’ disease. The Kaplan–Meier method was used to estimate PFS and OS. Results With a median follow-up of 4.4 years, patients with good, intermediate, and poor risk disease by IGCCCG criteria treated at IU had 5-year PFS of 90%, 84%, and 54% and 5-year OS of 97%, 92%, and 73%, respectively. The 5-year PFS for all patients in the IU cohort was 79% [95% confidence interval (CI) 76% to 82%]. The 5-year OS for the IU cohort was 90% (95% CI 87% to 92%). IU testis cohort had 5-year OS 94% (95% CI 91% to 96%) versus 75% (95% CI 73% to 78%) for the SEER ‘distant’ cohort between 2000 and 2014, P-value <0.0001. Conclusion The MDC approach to GCT at high-volume cancer center associated with improved OS outcomes in this contemporary dataset. OS is significantly higher in the IU cohort compared with the IGCCCG and SEER ‘distant’ cohort

Weak or no association of TCF7L2 variants with Type 2 diabetes risk in an Arab population

<p>Abstract</p> <p>Background</p> <p>The rs7903146 and rs12255372 variants of <it>TCF7L2 </it>have been strongly associated with type 2 diabetes (T2D) risk in most populations studied to date. Meta-analysis of 27 different studies has resulted in a global OR of 1.46 [1.42–1.51] (rs7903146 variant). Thus far, despite a high incidence of T2D, the role of this variant in Arabs has not been established.</p> <p>Methods</p> <p>We performed a case-control association study using 522 Saudi T2D patients (WHO criteria), and 346 controls (age > 60; fasting plasma glucose < 7 mmol/L). Genotyping was performed by pyrosequencing. Statistical analyses were performed using SPSS version 13.0 for Windows (SPSS, Chicago, IL, USA).</p> <p>Results</p> <p>For rs7903146, the T allele frequency of the cases (0.415) was not different from that observed in the controls (0.405). The crude odds ratio (OR) was 1.04 with a 95% CI of 0.86–1.27 (P = 0.675). For rs12255372, the T allele frequency of the cases (0.368) was not different from that observed in the controls (0.355). Retrospective power calculations based upon an OR of 1.46 reported in a comprehensive meta-analysis of <it>TCF7L2 </it>risk, indicated this study was sufficiently powered (96.92%; α = 0.05) to detect an effect of similar magnitude to that reported for rs7903146.</p> <p>Conclusion</p> <p>Our study is consistent with weak or no association of T2D in Arabs with the two <it>TCF7L2 </it>variants, however it cannot rule out an effect of other SNPs in this gene. Future studies in this population are required to confirm our findings and may indicate the presence of yet to be defined genetic risk factors for T2D.</p

KCNV2-associated retinopathy: genotype–phenotype correlations – KCNV2 study group report 3

BACKGROUND/AIMS: To investigate genotype–phenotype associations in patients withKCNV2retinopathy. METHODS: Review of clinical notes, best-corrected visual acuity (BCVA), molecular variants, electroretinography (ERG) and retinal imaging. Subjects were grouped according to the combination ofKCNV2variants—two loss-of-function (TLOF), two missense (TM) or one of each (MLOF)—and parameters were compared. RESULTS: Ninety-two patients were included. The mean age of onset (mean±SD) in TLOF (n=55), TM (n=23) and MLOF (n=14) groups was 3.51±0.58, 4.07±2.76 and 5.54±3.38 years, respectively. The mean LogMAR BCVA (±SD) at baseline in TLOF, TM and MLOF groups was 0.89±0.25, 0.67±0.38 and 0.81±0.35 for right, and 0.88±0.26, 0.69±0.33 and 0.78±0.33 for left eyes, respectively. The difference in BCVA between groups at baseline was significant in right (p=0.03) and left eyes (p=0.035). Mean outer nuclear layer thickness (±SD) at baseline in TLOF, MLOF and TM groups was 37.07±15.20 µm, 40.67±12.53 and 40.38±18.67, respectively, which was not significantly different (p=0.85). The mean ellipsoid zone width (EZW) loss (±SD) was 2051 µm (±1318) for patients in the TLOF, and 1314 µm (±965) for MLOF. Only one patient in the TM group had EZW loss at presentation. There was considerable overlap in ERG findings, although the largest DA 10 ERG b-waves were associated with TLOF and the smallest with TM variants. CONCLUSIONS: Patients with missense alterations had better BCVA and greater structural integrity. This is important for patient prognostication and counselling, as well as stratification for future gene therapy trials

Burnout among surgeons before and during the SARS-CoV-2 pandemic: an international survey

Background: SARS-CoV-2 pandemic has had many significant impacts within the surgical realm, and surgeons have been obligated to reconsider almost every aspect of daily clinical practice. Methods: This is a cross-sectional study reported in compliance with the CHERRIES guidelines and conducted through an online platform from June 14th to July 15th, 2020. The primary outcome was the burden of burnout during the pandemic indicated by the validated Shirom-Melamed Burnout Measure. Results: Nine hundred fifty-four surgeons completed the survey. The median length of practice was 10&nbsp;years; 78.2% included were male with a median age of 37&nbsp;years old, 39.5% were consultants, 68.9% were general surgeons, and 55.7% were affiliated with an academic institution. Overall, there was a significant increase in the mean burnout score during the pandemic; longer years of practice and older age were significantly associated with less burnout. There were significant reductions in the median number of outpatient visits, operated cases, on-call hours, emergency visits, and research work, so, 48.2% of respondents felt that the training resources were insufficient. The majority (81.3%) of respondents reported that their hospitals were included in the management of COVID-19, 66.5% felt their roles had been minimized; 41% were asked to assist in non-surgical medical practices, and 37.6% of respondents were included in COVID-19 management. Conclusions: There was a significant burnout among trainees. Almost all aspects of clinical and research activities were affected with a significant reduction in the volume of research, outpatient clinic visits, surgical procedures, on-call hours, and emergency cases hindering the training. Trial registration: The study was registered on clicaltrials.gov "NCT04433286" on 16/06/2020

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

العلاقة بين زاوية القاعدة القحفية والأنواع المختلفة من سوء الإطباق الهيكلي في المستوى السهمي لدى عينة من مرضى تقويم الأسنان السوريين باستخدام ال CBCT (دراسة استرجاعية)

الهدف: هدفت هذه الدراسة إلى تقييم العلاقة بين قاعدة الجمجمة وقاعدة الفك في عينة من المرضى السوريين البالغين. المواد والطرق: صممت هذه الدراسة على شكل دراسة استرجاعية Retrospective Study على عينة مؤلفة من 60 مريضا تم اختيارهم من أرشيف قسم تقويم الاسنان والفكين في كلية طب الاسنان –جامعة تشرين. وتم توزيعهم على ثلاث مجموعات (صنف اول هيكلي – صنف ثاني هيكلي – صنف ثالث هيكلي) وفقا لقيمة الزاوية ANB وكانت المتغيرات الشعاعية المدروسة في هذه الدراسة هي (NSBa، N-S، S-Ba، N-Ba) صنف اول: الزاوية ANB (2-5) درجة صنف ثاني: الزاوية ANB  أكبر من (5) درجات صنف ثالث: الزاوية ANB أقل من (2) النتائج: لم تظهر زاوية القاعدة القحفية وأطوال القاعدة القحفية فروق ذات دلالة إحصائية بين الفئات الرئيسية لسوء الإطباق المدروسة. كما انه لم تشاهد أي فروقات ذات دلالة إحصائية بين اطوال قاعدة القحف والزاوية القحفية والزاوية ANB ضمن كل صنف على حدا من اصناف سوء الاطباق. الاستنتاجات: زوايا القاعدة القحفية وأطوالها ليس لها دور رئيسي في تطور سوء الإطباق. أيضًا، لم تُلاحظ فروق ذات دلالة إحصائية بين أطوال وزاويا قاعدة الجمجمة والزاوية ANB داخل كل نوع من أنواع سوء الإطباق