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STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti-IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder.

The detection of evolutionary transitions in influenza A (H3N2) viruses' antigenicity is a major obstacle to effective vaccine design and development. In this study, we describe Novel Influenza Virus A Detector (NIAViD), an unsupervised machine learning tool, adept at identifying these transitions, using the HA1 sequence and associated physico-chemical properties. NIAViD performed with 88.9% (95% CI, 56.5–98.0%) and 72.7% (95% CI, 43.4–90.3%) sensitivity in training and validation, respectively, outperforming the uncalibrated null model—33.3% (95% CI, 12.1–64.6%) and does not require potentially biased, time-consuming and costly laboratory assays. The pivotal role of the Boman's index, indicative of the virus's cell surface binding potential, is underscored, enhancing the precision of detecting antigenic transitions. NIAViD's efficacy is not only in identifying influenza isolates that belong to novel antigenic clusters, but also in pinpointing potential sites driving significant antigenic changes, without the reliance on explicit modelling of haemagglutinin inhibition titres. We believe this approach holds promise to augment existing surveillance networks, offering timely insights for the development of updated, effective influenza vaccines. Consequently, NIAViD, in conjunction with other resources, could be used to support surveillance efforts and inform the development of updated influenza vaccines. [ABSTRACT FROM AUTHOR]

Patients with very early-onset inflammatory bowel disease (VEO-IBD) may present because of underlying monogenic inborn errors of immunity (IEI). Strong differences have been observed in the causes of monogenic IBD among ethnic populations. This multicenter study was carried out on 16 Iranian patients with VEO-IBD. We reviewed clinical and basic immunologic evaluation including flow cytometry and immunoglobulin levels. All patients underwent clinical whole exome sequencing (WES). Sixteen patients (8 females and 8 males) with a median age of 43.5 months were enrolled. The median age at the onset of symptoms was 4 months. Most patients (12, 75%) had consanguineous parents. Chronic non-bloody diarrhea (13, 81.3%) and perianal diseases including perianal abscess (6, 37.5%), anal fissure (6, 37.5%), or anal fistula (2, 12.5%) were the most common manifestations. WES identified a spectrum of genetic variants in 13 patients (81.3%): IL10RB (6, 37.5%), MVK (3, 18.8%), and CASP8, SLC35C1, G6PC3, and IKBKB in 1 patient, respectively. In 3 patients (18.7%), no variant was identified. Flow cytometry identified a spectrum of abnormalities that helped to assess the evidence of genetic diagnosis. At the end of the survey, 3 (18.8%) patients were deceased. This high rate of monogenic defects with a broad spectrum of genes reiterates the importance of investigating IEI in patients with infantile-onset IBD. Patients with very early-onset inflammatory bowel disease (VEO-IBD) may present because of underlying monogenic inborn errors of immunity (IEI). Strong differences have been observed in the causes of monogenic IBD among ethnic populations. The high rate of monogenic defects with a broad spectrum of genes reiterates the importance of investigating IEI in patients with infantile-onset IBD. Graphical Abstract [ABSTRACT FROM AUTHOR]

Background: Overall, there is conflicting evidence regarding the beneficial effects of optimal lifestyle modification, particularly weight loss interventions, with nonalcoholic fatty liver disease (non‐alcoholic fatty liver disease (NAFLD)). Therefore, this study investigated the effects of weight loss interventions on laboratory and clinical parameters in children and adolescents with NAFLD. Methods: Original databases (PubMed/MEDLINE, Web of Science, SCOPUS, and Embase) were searched using standard keywords to identify all controlled trials investigating the effects of weight loss interventions among NAFLD children and adolescents. Pooled weighted mean difference and 95% confidence intervals were achieved by random‐effects model analysis. Results: Eighteen eligible clinical trials were included in this systematic review and meta‐analysis. The pooled findings showed that especially more intense weight loss interventions significantly reduced the glucose (p = 0.007), insulin (p = 0.002), homeostatic model assessment‐insulin resistance (HOMA‐IR) (p = 0.003), weight (p = 0.025), body mass index (BMI) (p = 0.003), BMI z‐score (p < 0.001), waist circumference (WC) (p = 0.013), triglyceride (TG) (p = 0.001), and aspartate transaminase (AST) (p = 0.027). However, no significant changes were found in total cholesterol, low‐density lipoprotein cholesterol (LDL‐C), high‐density lipoprotein cholesterol (HDL‐C), alanine transaminase (ALT), and hepatic steatosis grades (all p > 0.05) following weight loss interventions. Conclusions: Weight loss interventions had significant effects on NAFLD‐related parameters including glucose, insulin, HOMA‐IR, weight, BMI, BMI z‐score, WC, TG, and AST. [ABSTRACT FROM AUTHOR]

Background: Considering the conflicting effects of bupropion on parameters related to metabolic syndrome including glucose metabolism and lipid profile, in this meta‐analysis study, we investigated the effects of this drug alone or in combination with naltrexone on glucose metabolism and lipid profile. Methods: Scopus, PubMed/Medline, Web of Science and Embase databases were searched using standard keywords to identify all controlled trials investigating effects of bupropion alone and combined with naltrexone on the glucose and lipid profile. Pooled weighted mean difference and 95% confidence intervals were achieved by random‐effects model. Results: Twelve studies with 5152 participants' were included in this article. The pooled findings showed that bupropion alone or in combination with naltrexone would significantly reduce glucose (weighted mean difference (WMD): −2.25 mg/dL, 95% confidence interval (CI): −4.10, −0.40), insulin (WMD: −4.06 μU/mL, 95% CI: −6.09, −2.03), homeostatic model assessment for insulin resistance (HOMA‐IR) (WMD: −0.58, 95% CI: −0.98, −0.19), triglyceride (TG) (WMD: −11.78 mg/dL, 95% CI: −14.48 to −9.08) and increase high‐density lipoprotein (HDL) (WMD: 2.68 mg/dL, 95% CI: 2.13 to 3.24). A Greater reduction in glucose levels was observed with duration >26 weeks. Dose of bupropion intake ≤360 mg and intervention for more than 26 weeks decreased insulin level significantly. With regard to lipid profile, reduction of triglycerides is more significant with dose of bupropion greater than 360 mg and a shorter intervention length equal to 26 weeks. Conclusions: The addition of combination therapies such as bupropion and naltrexone to lifestyle modification can significantly improve glucose metabolism and some lipid parameters. [ABSTRACT FROM AUTHOR]

Fisheries and aquaculture provide food and economic security, especially in the developing world, but both face challenges from infectious disease. Here, we consider management of disease issues from a structured decision‐making perspective to examine how infectious disease can threaten seafood production and influence management decisions. For both wild fisheries and aquaculture, disease‐management objectives generally aim to mitigate the severity and economic burden of outbreaks. General management strategies include manipulating host densities, reducing system connectivity, conserving or improving habitat, and implementing direct treatments or some other biological interventions. To inform decisions, mathematical models can be used to explore disease dynamics and to forecast the potential effectiveness of alternative management actions. Developing and implementing disease‐management strategies also involve considering uncertainties and balancing competing stakeholder interests and risk tolerances. We conclude by outlining several steps for applying structured decision making that are broadly useful to decision makers facing issues related to disease. [ABSTRACT FROM AUTHOR]