Nutritional Profile, Disease Severity, and Quality of Life of Patients with Inflammatory Bowel Disease: A Case-Control Study.

INTRODUCTION: Diet is thought to play an important role in the clinical course and quality of life (QOL) of patients with inflammatory bowel disease (IBD). However, dietary habits of patients with IBD are still unknown. This case-control study aims to compare the dietary habits of patients with IBD to healthy controls and evaluate differences in disease severity and QOL. MATERIALS AND METHODS: Food frequency, severity scores using the Harvey-Bradshaw and Ulcerative colitis activity index, and QOL were assessed using online questionnaires. Dietary habits were compared for patients with active disease and remission and for those with low QOL (LQOL) and high QOL (HQOL). RESULTS: We recruited 61 patients with IBD and 101 controls. Significance was set at p = 0.05. Controls consumed significantly more daily calories (2546 vs. 1641, p = 0.001). However, patients with IBD consumed a higher percentage of carbohydrates (50% vs. 45%, p = 0.001), more red meat (p = 0.024), and less fiber, sucrose, and lactose (p = 0.001, 0.001, and 0.036). Patients with active disease had higher lipid intake, lower protein intake, and lower QOL (47 vs. 58, p = 0.001). Dietary differences between LQOL and HQOL mirrored those between active disease and remission. CONCLUSION: This study is the first to provide valuable insights into the nutritional profile of Lebanese patients with IBD.

Clinical characteristics of symptomatic young patients with colonic adenomas.

Background: The incidence of colonic adenomas and colorectal cancer has been on the rise among young patients. In this study, we aimed to describe the characteristics of young patients (<50 years) with adenomatous polyps and to characterize those polyps. We also aimed to determine appropriate surveillance intervals for young patients. Methods: We performed a retrospective chart review of patients <50 years of age who had polypectomy of 1 or more adenomatous polyps on colonoscopy between 2008 and 2021. Patient demographics, colonoscopy indication and polyp characteristics were obtained from the chart. Timing and findings on surveillance colonoscopies were recorded. Results: A total of 610 patients were included: mean age 42.9±5.9 years, 61% males, body mass index 27.5±4.7 kg/m2, and over 50% smokers. The most common indications were abdominal pain (23.3%), rectal bleeding (22.3%), and change in bowel habits (17.6%). Almost half of the patients who had adenomas (299) were younger than 45 years. Tubular adenoma was the most frequently encountered type of polyp (571; 93.6%). Mean polyp size was 1.1±0.9 cm. The most common location of adenomas was the sigmoid colon (41%). Of patients with adenomas, 156 (26%) had surveillance colonoscopy within 2.9±2.3 years; 74 patients (47.4%) were found to have new adenomas. Conclusions: Patients aged <50 years with colonic adenomas were mostly males, overweight, and smokers. Further adenomas were found in 47% of surveillance colonoscopies, and most were encountered within 5 years. High rates of recurrent adenomas in people <50 years of age may warrant frequent surveillance.

Efficacy and Safety of Vedolizumab and Tumor Necrosis Factor Inhibitors in the Treatment of Steroid-refractory Microscopic Colitis: A Systematic Review and Meta-analysis.

BACKGROUND: Tumor necrosis factor (TNF-α) inhibitors and the α4ß7 integrin antagonist, vedolizumab, have been investigated as treatment options for patients with steroid-refractory microscopic colitis. AIMS: To evaluate the benefit of vedolizumab and TNF-α inhibitors in patients with steroid-refractory microscopic colitis. METHODS: Retrospective studies and case series involving patients with steroid-refractory MC who either received vedolizumab, adalimumab, or infliximab were eligible for inclusion. Pooled proportional meta-analyses were used to calculate the rate of clinical remission at induction, clinical response, maintenance of remission, histologic remission, and overall medication related adverse effects. Statistical analysis was performed in R using the metafor and meta packages. RESULTS: A total of 14 studies involving 164 patients were included. Pooled analysis showed a clinical remission rate of 63.5% [95% CI (0.483; 0.776), I2=43% P=0.08], 57.8% [95% CI (0.3895; 0.7571), I2=0%, P=0.7541], and 39.3% [95% CI (0.0814; 0.7492), I2=66%, P=0.02] for vedolizumab, infliximab, and adalimumab, respectively. The maintenance of remission rates were 65.9% [95% CI (0.389; 0.889), I2=67%, P=0.02], 45.3% [95% CI (0.1479; 0.7747), I2=0%, P=0.36] and 32.5% [95% CI (0.000; 0.8508), I2=53%, P=0.14] in patients who received vedolizumab, infliximab, and adalimumab, respectively. Rate of biological-related adverse events warranting discontinuation of therapy was 12.2%, 32.9%, and 23.0% for the vedolizumab, infliximab, and adalimumab groups, respectively. CONCLUSION: Vedolizumab and anti-TNF-α agents demonstrated a clinical benefit in the treatment of steroid-refractory microscopic colitis and with a tolerable safety profile. Future randomized controlled trials are needed to compare vedolizumab with TNF-α inhibitors and examine treatment effect on patients' quality of life.

Genetics of mirror movements identifies a multifunctional complex required for Netrin-1 guidance and lateralization of motor control.

Mirror movements (MM) disorder is characterized by involuntary movements on one side of the body that mirror intentional movements on the opposite side. We performed genetic characterization of a family with autosomal dominant MM and identified ARHGEF7, a RhoGEF, as a candidate MM gene. We found that Arhgef7 and its partner Git1 bind directly to Dcc. Dcc is the receptor for Netrin-1, an axon guidance cue that attracts commissural axons to the midline, promoting the midline crossing of axon tracts. We show that Arhgef7 and Git1 are required for Netrin-1-mediated axon guidance and act as a multifunctional effector complex. Arhgef7/Git1 activates Rac1 and Cdc42 and inhibits Arf1 downstream of Netrin-1. Furthermore, Arhgef7/Git1, via Arf1, mediates the Netrin-1-induced increase in cell surface Dcc. Mice heterozygous for Arhgef7 have defects in commissural axon trajectories and increased symmetrical paw placements during skilled walking, a MM-like phenotype. Thus, we have delineated how ARHGEF7 mutation causes MM.

Clinical and functional heterogeneity associated with the disruption of retinoic acid receptor beta.

PURPOSE: Dominant variants in the retinoic acid receptor beta (RARB) gene underlie a syndromic form of microphthalmia, known as MCOPS12, which is associated with other birth anomalies and global developmental delay with spasticity and/or dystonia. Here, we report 25 affected individuals with 17 novel pathogenic or likely pathogenic variants in RARB. This study aims to characterize the functional impact of these variants and describe the clinical spectrum of MCOPS12. METHODS: We used in vitro transcriptional assays and in silico structural analysis to assess the functional relevance of RARB variants in affecting the normal response to retinoids. RESULTS: We found that all RARB variants tested in our assays exhibited either a gain-of-function or a loss-of-function activity. Loss-of-function variants disrupted RARB function through a dominant-negative effect, possibly by disrupting ligand binding and/or coactivators' recruitment. By reviewing clinical data from 52 affected individuals, we found that disruption of RARB is associated with a more variable phenotype than initially suspected, with the absence in some individuals of cardinal features of MCOPS12, such as developmental eye anomaly or motor impairment. CONCLUSION: Our study indicates that pathogenic variants in RARB are functionally heterogeneous and associated with extensive clinical heterogeneity.

Isolation of Carbapenem and Colistin Resistant Gram-Negative Bacteria Colonizing Immunocompromised SARS-CoV-2 Patients Admitted to Some Libyan Hospitals.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a devastating effect, globally. We describe, for the first time, the occurrence of carbapenem-resistant bacteria colonizing SARS-CoV-2 patients who developed hospital-associated infections with carbapenemase-producing, Gram-negative bacteria at some isolation centers of SARS-CoV-2 in the eastern part of Libya. In total, at first, 109 samples were collected from 43 patients, with the samples being recovered from oral (n = 35), nasal (n = 45), and rectal (n = 29) cavities. Strain identification was performed via matrix assisted laser desorption ionization-time of flight (MALDI-TOF). Antibiotic susceptibility testing was carried out on Mueller-Hinton agar, using the standard disk diffusion method. MIC determination was confirmed via E-TEST and microdilution standard methods. A molecular study was carried out to characterize the carbapenem and colistin resistance in Gram-negative bacterial strains. All of the positive results were confirmed via sequencing. Klebsiella pneumoniae (n = 32), Citrobacter freundii (n = 21), Escherichia coli (n = 7), and Acinetobacter baumannii (n = 21) were the predominant isolated bacteria. Gram-negative isolates were multidrug-resistant and carried different carbapenem resistance-associated genes, including NDM-1 (56/119; 47.05%), OXA-48 (15/119; 12.60%), OXA-23 (19/119; 15.96%), VIM (10/119; 8.40%), and the colistin resistance mobile gene mcr-1 (4/119; 3.36%). The overuse of antimicrobials, particularly carbapenem antibiotics, during the SARS-CoV-2 pandemic has led to the emergence of multidrug-resistant bacteria, mainly K. pneumoniae, A. baumannii, and colistin-resistant E. coli strains. Increased surveillance as well as the rational use of carbapenem antibiotics and, recently, colistin are required to reduce the propagation of multidrug-resistant strains and to optimally maintain the efficacy of these antibiotics. IMPORTANCE In this work, we describe, for the first time, the occurrence of carbapenem-resistant bacteria colonizing COVID-19 patients who developed hospital-associated infections with carbapenemase-producing, Gram-negative bacteria at some isolation centers of COVID-19 in the eastern part of Libya. Our results confirmed that the overuse of antimicrobials, such as carbapenem antibiotics, during the COVID-19 pandemic has led to the emergence of multidrug-resistant bacteria, mainly K. pneumoniae and A. baumannii, as well as colistin resistance.

Factors Influencing the Length of Hospital Stay Among Pediatric COVID-19 Patients at Queen Rania Al Abdullah Hospital for Children: A Cross-Sectional Study.

Background COVID-19 caused by SARS-CoV-2 is a worldwide epidemic. Children are less commonly infected and have less severe symptoms than adults. However, they are at risk for COVID-19-associated severe sickness and hospitalization. The duration of stay is a major driver of effective health treatment during hospitalization; thus, it is only logical to attempt to comprehend the factors influencing the length of stay (LOS) for these patients, particularly in light of the ongoing pandemic caused by the new SARS-CoV-2 virus. As predictors of hospital LOS, several variables, including age, gender, disease severity, hospital mortality, insurance type, and hospital location, have been discovered. In our study, we focused on the severity of the patient's condition, the presence of comorbidities, and the necessary therapeutic regimen to predict the duration of stay. This study aimed to answer the following questions: If a patient has comorbidity and has COVID-19 requiring hospital treatment, will the patient's comorbidity elongate the duration of stay at the hospital for further management in the pediatric age group? What are the risk factors that play a significant role in the hospital stay duration in pediatrics? Methodology We gathered data from 100 hospitalized children aged up to 14 years who tested positive for COVID-19, which was not specific to variants of SARS-CoV-2, over 24 months (February 2020-February 2022) at Queen Rania Al Abdullah Hospital for Children, one of the Health Care Accreditation Council accredited facilities. Clinical symptoms, signs, oxygen demand, imaging study results, laboratory data, and usage of corticosteroid and antiviral medication were all taken from patients' medical records. There were no limitations in taking the sample of patients. All patients in the duration mentioned were included. Results Clinical data of 100 COVID-19-positive pediatric patients were analyzed; 52% of the patients had associated chronic illnesses, while 48% were medically free. The longest duration of LOS was 28 days, the shortest was one day, the median was eight days, and five days was the most frequent among patients owing to 21% of patients, using mean descriptive statistics. We compared LOS to having or not having comorbidities. The mean LOS of patients with the comorbid disease was 6.15 days, with a maximum of 28 days, while for patients without chronic illnesses, the mean was 4.81 days with a maximum of 14 days. The significance was 0.07. Our results also showed a significant correlation between using steroids and LOS, as it had an advantageous effect by decreasing it with a significance value of 0.04. Having abnormal findings on chest computed tomography (CT) scan was also associated with increased LOS with a significant value of 0.00. Conclusions According to our research, there was no direct association between comorbidity and hospital LOS, which is counterintuitive, as it was influenced by multiplayers of variables such as using steroids, which decreased the LOS, and abnormal findings on chest CT, which resulted in lengthening of the hospital stay. Our findings cannot be proven without further research and a larger patient sample.

Bi-allelic variants in WNT7B disrupt the development of multiple organs in humans.

BACKGROUND: Pulmonary hypoplasia, Diaphragmatic anomalies, Anophthalmia/microphthalmia and Cardiac defects delineate the PDAC syndrome. We aim to identify the cause of PDAC syndrome in patients who do not carry pathogenic variants in RARB and STRA6, which have been previously associated with this disorder. METHODS: We sequenced the exome of patients with unexplained PDAC syndrome and performed functional validation of candidate variants. RESULTS: We identified bi-allelic variants in WNT7B in fetuses with PDAC syndrome from two unrelated families. In one family, the fetus was homozygous for the c.292C>T (p.(Arg98*)) variant whereas the fetuses from the other family were compound heterozygous for the variants c.225C>G (p.(Tyr75*)) and c.562G>A (p.(Gly188Ser)). Finally, a molecular autopsy by proxy in a consanguineous couple that lost two babies due to lung hypoplasia revealed that both parents carry the p.(Arg98*) variant. Using a WNT signalling canonical luciferase assay, we demonstrated that the identified variants are deleterious. In addition, we found that wnt7bb mutant zebrafish display a defect of the swimbladder, an air-filled organ that is a structural homolog of the mammalian lung, suggesting that the function of WNT7B has been conserved during evolution for the development of these structures. CONCLUSION: Our findings indicate that defective WNT7B function underlies a form of lung hypoplasia that is associated with the PDAC syndrome, and provide evidence for involvement of the WNT-ß-catenin pathway in human lung, tracheal, ocular, cardiac, and renal development.

Efficacy of Fecal Microbiota Transplantation in the Treatment of Active Ulcerative Colitis: A Systematic Review and Meta-Analysis of Double-Blind Randomized Controlled Trials.

BACKGROUND: Fecal microbiota transplantation (FMT) has been investigated as a treatment option for patients with inflammatory bowel disease with controversial results.We sought to perform a systematic review and meta-analysis to evaluate the benefit of FMT in patients with ulcerative colitis. METHODS: Double-blind randomized controlled trials (RCTs) including adult patients with active ulcerative colitis who received either FMT or placebo were eligible for inclusion. Outcomes of interest included the rate of combined clinical and endoscopic remission, endoscopic remission or response, clinical remission or response, and specific adverse events. The results were pooled together using Reviewer Manager 5.4 software. Publication bias was assessed using the Egger's test. RESULTS: Six RCTs involving 324 patients were included. Our findings demonstrate that compared with placebo, FMT has significant benefit in inducing combined clinical and endoscopic remission (odds ratio, 4.11; 95% confidence interval, 2.19-7.72; P < .0001). Subgroup analyses of influencing factors showed no differences between pooled or single stool donors (P = .71), fresh or frozen FMT (P = .35), and different routes or frequencies of delivery (P = .80 and .48, respectively). Pre-FMT antibiotics, bowel lavage, concomitant biologic therapy, and topical rectal therapy did not affect combined remission rates (P values of .47, .38, .28, and .40, respectively). Clinical remission or response and endoscopic remission or response were significantly higher in patients who received FMT compared with placebo (P < .05) without any differences in serious or specific adverse events. CONCLUSIONS: FMT demonstrated a clinical and endoscopic benefit in the short-term treatment of active ulcerative colitis, with a comparable safety profile to placebo. Future RCTs are required to standardize study protocols and examine data on maintenance therapy.

Our systematic review of double-blind randomized controlled trials demonstrates that fecal microbiota transplantation is effective in inducing short-term clinical and endoscopic remission in adult patients with active ulcerative colitis and with a similar safety profile as compared with placebo.

Outcomes and Cost-Analysis of Open Versus Endovascular Abdominal Aortic Aneurysm Repair in a Developing Country: A 15-year Experience at a Tertiary Medical Center.

BACKGROUND: Endovascular aortic aneurysm repair (EVAR) has become the most common procedure for treating abdominal aortic aneurysms based on multiple studies conducted in the western world. The implication of such findings in developing countries is not well demonstrated. The objective of this study was to compare medical outcomes and costs of EVAR and open surgical repair (OSR) in a developing country. METHODS: This is a retrospective study of all patients undergoing elective abdominal aortic aneurysm repair between 2005 and 2020 at a tertiary medical center in a developing country. Medical records were used to retrieve demographics, comorbidities, and perioperative complications. Medical records were also used to provide data on the need of reintervention, date of last follow-up, and mortality. RESULTS: The study included a total of 164 patients. Median follow-up time was 41 months. The mean age was 69.9 +/- 7.84 years and 90.24% (n = 148) of patients were males. Regarding long-term mortality outcomes, no significant difference was detected between both groups; OSR patients had a survival rate of 91.38% and 74.86% at 5 and 10 years, compared to 77.29% and 56.52% in the EVAR group (P value = 0.10). Both groups had comparable long-term reintervention rates (P value = 0.334). The OSR group was charged significantly less than the EVAR group ($27,666.35 vs. $44,528.04, P value = 0.008). CONCLUSIONS: OSR and EVAR have comparable survival and reintervention outcomes. Unlike what was reported in developed countries, patients undergoing OSR in countries with low hospital stay costs incur lower treatment costs.

Congenital heart disease research landscape in the Arab world: a 25-year bibliometric review.

Background: While research on congenital heart disease has been extensively conducted worldwide, comprehensive studies from developing countries and the Arab world remain scarce. Aim: This study aims to perform a bibliometric review of research on congenital heart disease in the Arab world from 1997 to 2022. Methods: We analyzed data from the Web of Science, encompassing various aspects such as topics, countries, research output, citations, authors, collaborations, and affiliations. This comprehensive science mapping analysis was done using the R statistical software's Bibliometrix Package. Results: The research output from Arab countries over the 25 years showed an average annual growth rate of 11.5%. However, Arab countries exhibited lower research productivity than the United States and Europe, with a 24-fold difference. There was substantial variation in research output among 22 Arab countries, with five countries contributing to 78% of the total publications. Most of the published research was clinical, with limited innovative contributions and a preference for regional journals. High-income Arab countries displayed higher research productivity and citation rates than their low-income developing counterparts. Despite being categorized as upper-middle-income, post-conflict countries exhibited low research productivity. About one-quarter of the published articles (26%) resulted from collaborative efforts among multiple countries, with the United States being the most frequent collaborator. Enhanced research productivity and impact output were strongly associated with increased international cooperation. Conclusion: Research productivity in the Arab region closely correlates with a country's GDP. Success hinges on governmental support, funding, international collaboration, and a clear research vision. These findings offer valuable insights for policymakers, educational institutions, and governments to strengthen research programs and nurture a research culture.

An Expert Opinion/Approach: Clinical Presentations, Diagnostic Considerations, and Therapeutic Options for Gastrointestinal Manifestations of Common Variable Immune Deficiency.

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency. It is characterized by impaired B-cell differentiation. Although patients can be diagnosed with CVID anytime during their lifetime, most patients have symptoms for 5-9 years before their diagnosis. The diagnosis of CVID starts with a detailed history focusing on the infectious and noninfectious manifestations of the disease. In patients who are suspected to experience CVID, quantitative immunoglobulins (Ig) should be checked to confirm the diagnosis. IgG should be at least 2 times less than the age-specific SD along with either a low IgA or IgM and with evidence of impaired vaccine response. CVID is usually associated with infectious and/or noninfectious conditions, the latter of which can be inflammatory, autoimmune, lymphoproliferative, or malignant, among other manifestations. Ig therapy has positively affected the disease course of patients with infectious complications but has limited effect on the noninfectious manifestations because the noninfectious complications are related to immune dysregulation involving B cells and T cells rather than primarily due to antibody deficiency. When the gastrointestinal (GI) system is involved, patients with CVID may display signs and symptoms that mimic several GI conditions such as celiac disease, pernicious anemia, or inflammatory bowel diseases. The inflammatory bowel disease-like condition is usually treated with steroids, 5-aminosalicylates, thiopurines, or biologic agents to control the inflammation. In this review, the clinical presentations, diagnostic considerations, and therapeutic options for GI manifestations of CVID will be discussed to facilitate the individualized management of these often-complex patients.

Significance of granulomas in the outcomes of Crohn's disease patients.

Background: The presence of granulomas in the gastrointestinal (GI) tract is one of the characteristic histologic features of Crohn's disease (CD). The clinical significance of granulomas remains unclear. In this study, we aimed to determine whether the presence of granulomas on endoscopic pinch biopsy or surgical resection from the upper or lower GI tract is associated with worse outcomes among patients with CD. Methods: This was a retrospective chart review of patients with CD evaluated at a tertiary care center between 1996 and 2019. Patients were divided into 2 groups based on the presence or absence of granulomas on GI histology. Clinical and laboratory data, and outcomes of interest, were obtained from the electronic medical records. Patients' characteristics and outcomes were compared between the 2 groups. Results: A total of 237 patients were included in our study; 41 (17.3%) had granulomas on their biopsy/resection specimen. The presence of granulomas in the GI tract was significantly associated with the development of intra-abdominal abscesses and/or fistulas (P=0.037), greater utilization of immunomodulators (P=0.029), and greater use of immunosuppressive medications (immunomodulator and/or biologic therapy) (P=0.015). No significant differences were found between the 2 groups in terms of number of hospitalizations, presence of perianal disease, intestinal resection, mean age, mean age at initial diagnosis of CD, duration of disease, sex, or smoking history. Conclusions: The presence of granulomas in the GI tract of CD patients may serve as a prognostic biomarker of worse disease severity. Larger studies are needed to better validate this finding.

Eyelash Trichomegaly: Unusual Feature Associated with Systemic Lupus Erythematosus Patient.

Eyelash trichomegaly is a rare disorder in which normal features of eyelashes such as length, color, thickness, or curling changes. It may occur due to many causes, such as the presence of other disorders such as HIV infection, congenital anomalies like oculocutaneous albinism, or Oliver-McFarlane syndrome. It may be linked to the use of certain drugs and can also be present as an isolated trait by birth. Here, we report a rare case of eyelash trichomegaly in a 19-year-old female having diffused alopecia, diagnosed with systemic lupus erythematosus.

Assessment of burden and segregation profiles of CNVs in patients with epilepsy.

OBJECTIVE: Microdeletions are associated with different forms of epilepsy but show incomplete penetrance, which is not well understood. We aimed to assess whether unmasked variants or double CNVs could explain incomplete penetrance. METHODS: We analyzed copy number variants (CNVs) in 603 patients with four different subgroups of epilepsy and 945 controls. CNVs were called from genotypes and validated on whole-genome (WGS) or whole-exome sequences (WES). CNV burden difference between patients and controls was obtained by fitting a logistic regression. CNV burden was assessed for small and large (>1 Mb) deletions and duplications and for deletions overlapping different gene sets. RESULTS: Large deletions were enriched in genetic generalized epilepsies (GGE) compared to controls. We also found enrichment of deletions in epilepsy genes and hotspots for GGE. We did not find truncating or functional variants that could have been unmasked by the deletions. We observed a double CNV hit in two patients. One patient also carried a de novo deletion in the 22q11.2 hotspot. INTERPRETATION: We could corroborate previous findings of an enrichment of large microdeletions and deletions in epilepsy genes in GGE. We could also replicate that microdeletions show incomplete penetrance. However, we could not validate the hypothesis of unmasked variants nor the hypothesis of double CNVs to explain the incomplete penetrance. We found a de novo CNV on 22q11.2 that could be of interest. We also observed GGE families carrying a deletion on 15q13.3 hotspot that could be investigated in the Quebec founder population.

The role of common genetic variation in presumed monogenic epilepsies.

BACKGROUND: The developmental and epileptic encephalopathies (DEEs) are the most severe group of epilepsies which co-present with developmental delay and intellectual disability (ID). DEEs usually occur in people without a family history of epilepsy and have emerged as primarily monogenic, with damaging rare mutations found in 50% of patients. Little is known about the genetic architecture of patients with DEEs in whom no pathogenic variant is identified. Polygenic risk scoring (PRS) is a method that measures a person's common genetic burden for a trait or condition. Here, we used PRS to test whether genetic burden for epilepsy is relevant in individuals with DEEs, and other forms of epilepsy with ID. METHODS: Genetic data on 2,759 cases with DEEs, or epilepsy with ID presumed to have a monogenic basis, and 447,760 population-matched controls were analysed. We compared PRS for 'all epilepsy', 'focal epilepsy', and 'genetic generalised epilepsy' (GGE) between cases and controls. We performed pairwise comparisons between cases stratified for identifiable rare deleterious genetic variants and controls. FINDINGS: Cases of presumed monogenic severe epilepsy had an increased PRS for 'all epilepsy' (p<0.0001), 'focal epilepsy' (p<0.0001), and 'GGE' (p=0.0002) relative to controls, which explain between 0.08% and 3.3% of phenotypic variance. PRS was increased in cases both with and without an identified deleterious variant of major effect, and there was no significant difference in PRS between the two groups. INTERPRETATION: We provide evidence that common genetic variation contributes to the aetiology of DEEs and other forms of epilepsy with ID, even when there is a known pathogenic variant of major effect. These results provide insight into the genetic underpinnings of the severe epilepsies and warrant a shift in our understanding of the aetiology of the DEEs as complex, rather than monogenic, disorders. FUNDING: Science foundation Ireland, Human Genome Research Institute; National Heart, Lung, and Blood Institute; German Research Foundation.

Cardiac manifestations and short-term outcomes of multisystem inflammatory syndrome in Middle Eastern children during the COVID-19 pandemic: a case series.

We herein report on a series of four patients presented to our tertiary care centre with features of multisystem inflammatory syndrome in children and cardiac involvement. Two of our patients had recent exposure to a COVID-19-positive patient, one had recent documented infection, and another had no known positive contact. All the patients were tested positive for severe acute respiratory syndrome coronavirus 2 immunoglobulin G antibody at the time of presentation. All of them fulfilled the diagnostic criteria according to the World Health Organization Centers for Disease Control or the British guidelines for MIS-C (fever for ≥3 days, multisystem involvement (at least two), elevated markers of inflammation, and no other alternative diagnosis).Cardiac involvement was variable ranging from isolated ectasia of the coronary arteries to full-blown pancarditis such as severe biventricular dysfunction, multi-valvar involvement, and pericardial effusion.All our patients received intravenous immunoglobulin (2 g/kg), methylprednisolone, and aspirin and some required inotropic support and ICU admission.Remarkably, all our patients showed significant improvement in their cardiac disease within a few days as evident on serial echocardiographic evaluation. However, we stress the need for long-term follow-up as one of our patients demonstrated mild LV myocardial scarring as evident by gadolinium late enhancement on a cardiac MRI.

De novo DHDDS variants cause a neurodevelopmental and neurodegenerative disorder with myoclonus.

Subcellular membrane systems are highly enriched in dolichol, whose role in organelle homeostasis and endosomal-lysosomal pathway remains largely unclear besides being involved in protein glycosylation. DHDDS encodes for the catalytic subunit (DHDDS) of the enzyme cis-prenyltransferase (cis-PTase), involved in dolichol biosynthesis and dolichol-dependent protein glycosylation in the endoplasmic reticulum. An autosomal recessive form of retinitis pigmentosa (retinitis pigmentosa 59) has been associated with a recurrent DHDDS variant. Moreover, two recurring de novo substitutions were detected in a few cases presenting with neurodevelopmental disorder, epilepsy and movement disorder. We evaluated a large cohort of patients (n = 25) with de novo pathogenic variants in DHDDS and provided the first systematic description of the clinical features and long-term outcome of this new neurodevelopmental and neurodegenerative disorder. The functional impact of the identified variants was explored by yeast complementation system and enzymatic assay. Patients presented during infancy or childhood with a variable association of neurodevelopmental disorder, generalized epilepsy, action myoclonus/cortical tremor and ataxia. Later in the disease course, they experienced a slow neurological decline with the emergence of hyperkinetic and/or hypokinetic movement disorder, cognitive deterioration and psychiatric disturbances. Storage of lipidic material and altered lysosomes were detected in myelinated fibres and fibroblasts, suggesting a dysfunction of the lysosomal enzymatic scavenger machinery. Serum glycoprotein hypoglycosylation was not detected and, in contrast to retinitis pigmentosa and other congenital disorders of glycosylation involving dolichol metabolism, the urinary dolichol D18/D19 ratio was normal. Mapping the disease-causing variants into the protein structure revealed that most of them clustered around the active site of the DHDDS subunit. Functional studies using yeast complementation assay and in vitro activity measurements confirmed that these changes affected the catalytic activity of the cis-PTase and showed growth defect in yeast complementation system as compared with the wild-type enzyme and retinitis pigmentosa-associated protein. In conclusion, we characterized a distinctive neurodegenerative disorder due to de novo DHDDS variants, which clinically belongs to the spectrum of genetic progressive encephalopathies with myoclonus. Clinical and biochemical data from this cohort depicted a condition at the intersection of congenital disorders of glycosylation and inherited storage diseases with several features akin to of progressive myoclonus epilepsy such as neuronal ceroid lipofuscinosis and other lysosomal disorders.

De novo coding variants in the AGO1 gene cause a neurodevelopmental disorder with intellectual disability.

BACKGROUND: High-impact pathogenic variants in more than a thousand genes are involved in Mendelian forms of neurodevelopmental disorders (NDD). METHODS: This study describes the molecular and clinical characterisation of 28 probands with NDD harbouring heterozygous AGO1 coding variants, occurring de novo for all those whose transmission could have been verified (26/28). RESULTS: A total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in-frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues. Recurrently identified variants were present in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del). AGO1 encodes the Argonaute 1 protein, which functions in gene-silencing pathways mediated by small non-coding RNAs. Three-dimensional protein structure predictions suggest that these variants might alter the flexibility of the AGO1 linker domains, which likely would impair its function in mRNA processing. Affected individuals present with intellectual disability of varying severity, as well as speech and motor delay, autistic behaviour and additional behavioural manifestations. CONCLUSION: Our study establishes that de novo coding variants in AGO1 are involved in a novel monogenic form of NDD, highly similar to the recently reported AGO2-related NDD.

An Unusual Gastric Polyp: Brunneroma.

Brunneromas or polypoid hamartomas are benign lesions arising from Brunner glands. They are usually benign lesions with low potential for malignancy. They are usually located in the duodenum and manifest with different unspecific symptoms, such as abdominal pain, nausea, or bloating. Other more serious manifestations are also reported in the literature that are related to the size of the lesion. Usually, they are treated with endoscopic resection, with some lesions requiring surgical intervention. We present a case of a gastric antral polypoid lesion that was consistent with Brunneroma on histology.