Diagnostic implications of pitfalls in causal variant identification based on 4577 molecularly characterized families

Despite large sequencing and data sharing efforts, previously characterized pathogenic variants only account for a fraction of Mendelian disease patients, which highlights the need for accurate identification and interpretation of novel variants. In a large Mendelian cohort of 4577 molecularly characterized families, numerous scenarios in which variant identification and interpretation can be challenging are encountered. We describe categories of challenges that cover the phenotype (e.g. novel allelic disorders), pedigree structure (e.g. imprinting disorders masquerading as autosomal recessive phenotypes), positional mapping (e.g. double recombination events abrogating candidate autozygous intervals), gene (e.g. novel gene-disease assertion) and variant (e.g. complex compound inheritance). Overall, we estimate a probability of 34.3% for encountering at least one of these challenges. Importantly, our data show that by only addressing non-sequencing-based challenges, around 71% increase in the diagnostic yield can be expected. Indeed, by applying these lessons to a cohort of 314 cases with negative clinical exome or genome reports, we could identify the likely causal variant in 54.5%. Our work highlights the need to have a thorough approach to undiagnosed diseases by considering a wide range of challenges rather than a narrow focus on sequencing technologies. It is hoped that by sharing this experience, the yield of undiagnosed disease programs globally can be improved

A Multi-Branch Convolutional Neural Network with Squeeze-and-Excitation Attention Blocks for EEG-Based Motor Imagery Signals Classification

Electroencephalography-based motor imagery (EEG-MI) classification is a critical component of the brain-computer interface (BCI), which enables people with physical limitations to communicate with the outside world via assistive technology. Regrettably, EEG decoding is challenging because of the complexity, dynamic nature, and low signal-to-noise ratio of the EEG signal. Developing an end-to-end architecture capable of correctly extracting EEG data’s high-level features remains a difficulty. This study introduces a new model for decoding MI known as a Multi-Branch EEGNet with squeeze-and-excitation blocks (MBEEGSE). By clearly specifying channel interdependencies, a multi-branch CNN model with attention blocks is employed to adaptively change channel-wise feature responses. When compared to existing state-of-the-art EEG motor imagery classification models, the suggested model achieves good accuracy (82.87%) with reduced parameters in the BCI-IV2a motor imagery dataset and (96.15%) in the high gamma dataset

Short-and long-term outcomes of coronavirus disease 2019 patients presenting with diarrhea

Gastrointestinal (GI) manifestations of the coronavirus disease 2019 (COVID-19) pandemic are frequently observed in SARS-CoV-2-infected individuals at distinct time intervals after the initial diagnosis. Psychological distress in the form of anxiety, burnout, and depression is regarded as a common complication of COVID-19, but also as a risk factor for the development and exacerbation of irritable bowel syndrome (IBS), which is highly prevalent among COVID-19 patients and the general population. The pathophysiological mechanisms culminating in the diagnosis of IBS are yet to be fully understood, however, factors including gut–brain interaction, COVID-19-related intestinal damage, and other external influences might play a role in this process. While long-term GI complications of COVID-19 such as IBS are speculated to develop as a result of a multifaceted interaction between the virus itself with the host, in addition to the effects of psychological distress, further research on this topic is warranted. The purpose of this study was to explore possible factors correlating with the development of IBS and depression during the follow-up period post-COVID-19 infection

Subcutaneous versus intraperitoneal insulin for patients with diabetes mellitus on continuous ambulatory peritoneal dialysis: Meta-analysis of non-randomized clinical trials.

Background: Diabetes mellitus is one of the leading causes of end stage renal disease. Use of intraperitoneal (IP) nsulin in diabetic patients on peritoneal dialysis (PD) can restore glucose control to near normal values. The safety and efficacy of this method is unclear. Methods: We performed a meta-analysis to study the safety and efficacy of IP insulin administration in diabetic patients on PD. The primary outcome measures is glycemic control: secondary outcome measures were plasma lipids, insulin dose requirement/day and the risk of peritonitis and hepatic subcapsular steatosis. Medline, EMBASE, Cochrane Central Register of Controlled Trials, and reference lists of eligible studies were searched. Eligible studies included randomized and non-randomized controlled trials that allocated adult PD diabetic patients to IP insulin and subcutaneous (SC) insulin. Results: Twenty one citations were identified and three met the eligibility criteria. Glycemic control with IP insulin, as assessed with HbA1C, was equal to or better than that obtained with SC insulin: weighted mean difference was −1.49 % (95% CI: -2.17 to - 0.27, p=0.0001). The insulin dose required was more than two-fold higher in the IP treatment. Serum HDL-cholesterol decreased during IP insulin therapy while serum triglyceride (TG) concentration tended to increase, in comparison with levels seen in patients treated with SC insulin. Conclusions: Use of IP insulin provides adequate glycemic control, which appears superior to that seen following treatment with conventional SC insulin. The plasma lipids are adversely affected by IP insulin, possibly contributing to increased cardiovascular risk. Data are limited and further studies are needed to assess for the long-term safety of this approach

Safety of prolonged use of metoclopramide and domperidone as treatment for chronic gastrointestinal dysmotility disorders in patients with systemic sclerosis

Background: Metoclopramide and domperidone are prokinetic agents commonly used to treat gastrointestinal dysmotility disorders. This study aimed to evaluate the safety and associated side effects of prolonged-use metoclopramide and domperidone as treatment for chronic gastrointestinal dysmotility disorders in patients with systemic sclerosis (SSc). Methods: A quantitative observational survey was conducted by interview questionnaire in rheumatology outpatients at a tertiary teaching hospital in Riyadh, Saudi Arabia. The study included all patients aged 25–80 years diagnosed with SSc. All patients were on metoclopramide or domperidone for the treatment of chronic gastrointestinal dysmotility symptoms over at least 12 weeks. Results: Eighteen eligible patients were included. Most study participants were diagnosed with SSc complicated by interstitial lung disease (n = 13; 72.2 %). The most frequently reported side effect that occurred while taking prokinetic drugs was shortness of breath (n = 12; 66.7 %). None of the participants reported experiencing depression, galactorrhea, or syncope. CNS side effects were reported in 5.6 %. There were no differences in side effects based on the type and dosage of prokinetic drug used. Conclusions: Use of metoclopramide and domperidone for the treatment of chronic gastrointestinal dysmotility in SSc patients for 12 weeks or longer was not associated with any troublesome side effects. Further studies with more participants are needed to confirm our findings

Development of the global inflammatory bowel disease visualization of epidemiology studies in the 21st century (GIVES-21)

Abstract Background There is a rapid increase in the incidence of inflammatory bowel diseases (IBD) in newly industrialized countries, yet epidemiological data is incomplete. We herein report the methodology adopted to study the incidence of IBD in newly industrialized countries and to evaluate the effect of environmental factors including diet on IBD development. Methods Global IBD Visualization of Epidemiology Studies in the 21st Century (GIVES-21) is a population-based cohort of newly diagnosed persons with Crohn’s disease and ulcerative colitis in Asia, Africa, and Latin America to be followed prospectively for 12 months. New cases were ascertained from multiple sources and were entered into a secured online system. Cases were confirmed using standard diagnostic criteria. In addition, endoscopy, pathology and pharmacy records from each local site were searched to ensure completeness of case capture. Validated environmental and dietary questionnaires were used to determine exposure in incident cases prior to diagnosis. Results Through November 2022, 106 hospitals from 24 regions (16 Asia; 6 Latin America; 2 Africa) have joined the GIVES-21 Consortium. To date, over 290 incident cases have been reported. All patients have demographic data, clinical disease characteristics, and disease course data including healthcare utilization, medication history and environmental and dietary exposures data collected. We have established a comprehensive platform and infrastructure required to examine disease incidence, risk factors and disease course of IBD in the real-world setting. Conclusions The GIVES-21 consortium offers a unique opportunity to investigate the epidemiology of IBD and explores new clinical research questions on the association between environmental and dietary factors and IBD development in newly industrialized countries

Global Hospitalization Trends for Crohn’s Disease and Ulcerative Colitis in the 21st Century: A Systematic Review With Temporal Analyses

The evolving epidemiologic patterns of inflammatory bowel disease (IBD) throughout the world, in conjunction with advances in therapeutic treatments, may influence hospitalization rates of IBD. We performed a systematic review with temporal analysis of hospitalization rates for IBD across the world in the 21st century. We systematically reviewed Medline and Embase for population-based studies reporting hospitalization rates for IBD, Crohn’s disease (CD), or ulcerative colitis (UC) in the 21st century. Log-linear models were used to calculate the average annual percentage change (AAPC) with associated 95% CIs. Random-effects meta-analysis pooled country-level AAPCs. Data were stratified by the epidemiologic stage of a region: compounding prevalence (stage 3) in North America, Western Europe, and Oceania vs acceleration of incidence (stage 2) in Asia, Eastern Europe, and Latin America vs emergence (stage 1) in developing countries. Hospitalization rates for a primary diagnosis of IBD were stable in countries in stage 3 (AAPC, −0.13%; 95% CI, −0.72 to 0.97), CD (AAPC, 0.20%; 95% CI, −1.78 to 2.17), and UC (AAPC, 0.02%; 95% CI, −0.91 to 0.94). In contrast, hospitalization rates for a primary diagnosis were increasing in countries in stage 2 for IBD (AAPC, 4.44%; 95% CI, 2.75–6.14), CD (AAPC, 8.34%; 95% CI, 4.38–12.29), and UC (AAPC, 3.90; 95% CI, 1.29–6.52). No population-based studies were available for developing regions in stage 1 (emergence). Hospitalization rates for IBD are stabilizing in countries in stage 3, whereas newly industrialized countries in stage 2 have rapidly increasing hospitalization rates, contributing to an increasing burden on global health care systems. [Display omitted

TRENDS IN INFLAMMATORY BOWEL DISEASE INCIDENCE AND PREVALENCE ACROSS EPIDEMIOLOGIC STAGES: A GLOBAL SYSTEMATIC REVIEW WITH META-ANALYSIS

Abstract BACKGROUND Rising incidence and prevalence of inflammatory bowel disease (IBD) observed historically in early-industrialized regions now also appear in newly-industrialized and emerging regions. The epidemiology of IBD has been proposed to progress across epidemiologic stages: 1. Emergence (low incidence and prevalence); 2. Acceleration in Incidence (rapid rising incidence); and 3. Compounding Prevalence (stabilizing incidence, rapid rising prevalence). AIM To gather real-world data on the incidence and prevalence of IBD and characterize global regions in each epidemiologic stage by meta-analyses. METHODS Two previous systematic reviews (database inception–2010; 2010–2016) were updated with a search of MEDLINE, Embase, PubMed, and Web of Science (2017–2023) to identify all population-based studies reporting the incidence or prevalence of Crohn’s disease (CD) or ulcerative colitis (UC). International partners provided a secondary review of the included studies from their local regions. Incidence and prevalence rates (per 100,000 population), stratified by epidemiologic stage, were meta-analyzed to determine pooled rates with associated 95% confidence intervals (95%CI). A Cochrane Q test was used to investigate differences between epidemiologic stages for both CD and UC. RESULTS After assessing 1,250 manuscripts, a total of 491 studies (439 incidence, 228 prevalence) from 80 global regions spanning 1920-2022 were identified by the systematic review (Figure 1). All data identified with our search strategy are available to view in an open-access, online interactive data repository (https://gives21.shinyapps.io/dashboard/) created with Shiny for R. The pooled incidence of CD and UC per 100,000 person-years rose from 0.28 (95%CI: 0.21, 0.36) and 0.57 (95%CI: 0.47, 0.69) in Stage 1 to 2.13 (95%CI: 1.88, 2.42) and 4.05 (95%CI: 3.65, 4.50) in Stage 2 to 9.34 (95%CI: 8.73, 9.99) and 14.07 (95%CI: 13.09, 15.12) in Stage 3 (Table 1). Similarly, the pooled prevalence of CD and UC per 100,000 persons rose from 1.96 (95%CI: 1.41, 2.74) and 6.35 (95%CI: 4.45, 9.07) in Stage 1 to 22.18 (95%CI: 17.96, 27.38) and 45.36 (95%CI: 37.84, 54.38) in Stage 2 to 186.18 (95%CI: 163.18, 212.42) and 255.92 (95%CI: 230.60, 284.02) in Stage 3 (Table 1). Subgroup analysis confirmed differences in both incidence and prevalence for CD and UC between epidemiologic stages (p<0.001). DISCUSSION This is the most comprehensive systematic review on the incidence and prevalence of IBD. The amalgamated real-world data from this study highlight the rising global burden of IBD across three distinct epidemiologic stages: 1. Emergence, 2. Acceleration in Incidence, and 3. Compounding Prevalence. Figure 1 Systematic review study selection flowchart including a brief overview of two previous systematic reviews: Molodecky, N.A. et al. Gastroenterology. 2012;142(1):46-54 and Ng, S.C. et al. Lancet. 2017;390(10114):2769-78. Table 1 Pooled incidence and prevalence rates per 100,000 population for Crohn’s disease and ulcerative colitis. Cochrane Q subgroup analysis for difference in estimates between epidemiologic stages. † Represents the number of study-subregion groups used in the calculation of pooled rates and their 95% confidence intervals