Multiomics dissection of human RAG deficiency reveals distinctive patterns of immune dysregulation but a common inflammatory signature.

Human recombination-activating gene (RAG) deficiency can manifest with distinct clinical and immunological phenotypes. By applying a multiomics approach to a large group of -mutated patients, we aimed at characterizing the immunopathology associated with each phenotype. Although defective T and B cell development is common to all phenotypes, patients with hypomorphic variants can generate T and B cells with signatures of immune dysregulation and produce autoantibodies to a broad range of self-antigens, including type I interferons.

Long-Term Safety and Efficacy with Roflumilast Cream 0.15% in Patients Aged ≥6 Years with Atopic Dermatitis: A Phase 3 Open-Label Extension Trial.

Safety and efficacy of roflumilast cream 0.15% for atopic dermatitis (AD) were demonstrated in two 4-week phase 3 trials. Evaluate long-term safety, tolerability, and efficacy of roflumilast cream 0.

What is the Surgical Burden of Treatment for High-Energy Lower Extremity Trauma? A Secondary Analysis of the OUTLET Study.

Objectives: To describe and enumerate surgeries for patients who underwent reconstruction or amputation after severe distal tibia, ankle, and mid to hindfoot injuries.

Methods: Design: Secondary analysis of a multicenter prospective observational study.

Setting: 31 U.

Non-Genetic Biomarkers in Merkel Cell Carcinoma: Prognostic Implications and Predictive Utility for Response to Anti-PD-(L)1 Immune Checkpoint Inhibitors.

Merkel cell carcinoma (MCC) is a skin cancer that arises due to either Merkel cell polyomavirus infection (MCPyV) or ultraviolet (UV) radiation exposure, presenting primarily in the head and neck region of fair-skinned males. The recent success of PD-(L)1 immune checkpoint inhibitors (ICIs) in locally advanced/metastatic MCC, with an objective response rate (ORR) around 50% and improved survival, as a first-line treatment has moved ICIs to the forefront of therapy for MCC and generated interest in identifying biomarkers to predict clinical response. The MCC tumour microenvironment (TME) contains various components of the adaptive and innate immune system.

The Comparative Sufficiency of ChatGPT, Google Bard, and Bing AI in Answering Diagnosis, Treatment, and Prognosis Questions About Common Dermatological Diagnoses.

Our team explored the utility of unpaid versions of 3 artificial intelligence chatbots in offering patient-facing responses to questions about 5 common dermatological diagnoses, and highlighted the strengths and limitations of different artificial intelligence chatbots, while demonstrating how chatbots presented the most potential in tandem with dermatologists' diagnosis.

State of Lung Cancer in Egypt: Moving Towards Improved Guidelines for Prevention, Screening, Treatment, and Clinical Care Programs.

Lung cancer remains a leading cause of cancer-related mortality globally and presents significant challenges in Egypt. In 2023, the first annual meeting of the Thoracic Oncology Multidisciplinary Faculty, organized by the Egyptian Cancer Research Network and the Egyptian Society of Respiratory Neoplasms, was held in Cairo, Egypt. The meeting aimed to address gaps in lung cancer management across Egypt and the broader Middle East and North Africa region.

Modified Technique for Difficult Secondary Tracheoesophageal Puncture.

Tracheoesophageal puncture (TEP) with voice prosthesis (VP) placement is commonly used to restore voice in laryngectomy patients. The conventional procedure utilizes a rigid esophagoscope to open and visualize the pharyngeal inlet. However, this approach is challenging in patients with postradiation changes, reduced neck extension, or trismus.

The anti-melanoma roles and mechanisms of tricholoma isoflavone derivative CA028.

As a form of skin cancer, melanoma's incidence rate is continuing to rise globally. Therefore, there is an urgent need to find new agents to improve survival in melanoma patients. Isoflavones, a class of phytoestrogens, are primarily found in soy and other legumes.

Neoadjuvant or concurrent atezolizumab with chemoradiation for locally advanced cervical cancer: a randomized phase I trial.

Combined immune checkpoint blockade (ICB) and chemoradiation (CRT) is approved in patients with locally advanced cervical cancer (LACC) but optimal sequencing of CRT and ICB is unknown. NRG-GY017 (NCT03738228) was a randomized phase I trial of atezolizumab (anti-PD-L1) neoadjuvant and concurrent with CRT (Arm A) vs. concurrent with CRT (Arm B) in patients with high-risk node-positive LACC.

LGR4 is essential for maintaining β-cell homeostasis through suppression of RANK.

Objective: Loss of functional β-cell mass is a major cause of diabetes. Thus, identifying regulators of β-cell health is crucial for treating this disease. The Leucine-rich repeat-containing G-protein-coupled receptor (GPCR) 4 (LGR4) is expressed in β-cells and is the fourth most abundant GPCR in human islets.

Repurposing of a gill gene regulatory program for outer ear evolution.

How novel structures emerge during evolution has long fascinated biologists. A dramatic example is how the diminutive bones of the mammalian middle ear arose from ancestral fish jawbones. In contrast, the evolutionary origin of the outer ear, another mammalian innovation, remains a mystery, in part because it is supported by non-mineralized elastic cartilage rarely recovered in fossils.

Evaluating ADHD medication trial representativeness: a Swedish population-based study comparing hypothetically trial-eligible and trial-ineligible individuals.

Background: Randomised controlled trials (RCTs) evaluating ADHD medications often use strict eligibility criteria, potentially limiting generalisability to patients in real-world clinical settings. We aimed to identify the proportion of individuals with ADHD who would be ineligible for medication RCTs and evaluate differences in treatment patterns and clinical and functional outcomes between RCT-eligible and RCT-ineligible individuals.

Methods: We used multiple Swedish national registries to identify individuals with ADHD, aged at least 4 years at the age of diagnosis, initiating pharmacological treatment between Jan 1, 2007, and Dec 31, 2019, with follow-up up to Dec 31, 2020.

Sex disparities in outcome of medication-assisted therapy of opioid use disorder: Nationally representative outpatient clinic data.

Question: The opioid epidemic causes massive morbidity, and males have substantially greater overdose mortality rates than females. It is unclear whether there are sex-related disparities at different stages in the trajectory of opioid use disorders (OUD), from large samples in the community.

Goal: To determine sex disparities in non-medical opioid use (NMOU) at the end of treatment with medications for opioid use disorder (MOUD), using national data.

Increased medication utilization precedes incidentally diagnosed inflammatory bowel disease: a multicenter, case-control study.

This study investigates whether subclinical inflammation in asymptomatic inflammatory bowel disease (IBD) patients leads to increased medication use. In a multicenter, retrospective analysis of patients diagnosed with incidental ulcerative colitis or Crohn's disease during colorectal cancer screening (2010-2021), medication use was compared with symptomatic patients and healthy non-IBD controls. Asymptomatic patients showed a higher use of cardiovascular, antiparasitic, musculoskeletal, respiratory, and sensory organ medications up to five years before diagnosis.

Children's executive functioning and health behaviors across pediatric life stages and ecological contexts.

Executive functioning (EF) has been linked to chronic disease risk in children. Health behaviors are thought to partially explain this association. The current cross-sectional study evaluated specific domains of EF and varied health behaviors in three pediatric life stages.

CAGI6 ID panel challenge: assessment of phenotype and variant predictions in 415 children with neurodevelopmental disorders (NDDs).

The Genetics of Neurodevelopmental Disorders Lab in Padua provided a new intellectual disability (ID) Panel challenge for computational methods to predict patient phenotypes and their causal variants in the context of the Critical Assessment of the Genome Interpretation, 6th edition (CAGI6). Eight research teams submitted a total of 30 models to predict phenotypes based on the sequences of 74 genes (VCF format) in 415 pediatric patients affected by Neurodevelopmental Disorders (NDDs). NDDs are clinically and genetically heterogeneous conditions, with onset in infant age.

Survey of Urogynecology Fellows on the Care of Patients with Differences in Sex Development/Intersex Traits.

Introduction And Hypothesis: Patients with differences in sex development or intersex traits (DSD/I) struggle to find clinically competent care in adulthood. We sought to describe the surgical exposure of Urogynecology and Reconstructive Pelvic Surgery (URPS) fellows who had previously trained in ObGyn (URPS-Gyn) to patients with DSD/I and their interest in performing 18 relevant procedures. We hypothesized that most graduating fellows would not have had exposure to many of the surgeries.

Predictive Methods and Probabilistic Mapping of Subcortical Brain Components in Fossil Carnivora.

Paleoneurology reconstructs the evolutionary history of nervous systems through direct observations from the fossil record and comparative data from extant species. Although this approach can provide direct evidence of phylogenetic links among species, it is constrained by the availability and quality of data that can be gleaned from the fossil record. Here, we sought to translate brain component relationships in a sample of extant Carnivora to make inferences about brain structure in fossil species.

Automated Detection of Isolated REM Sleep Behavior Disorder Using Computer Vision.

Objective: Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is, in most cases, an early stage of Parkinson's disease or related disorders. Diagnosis requires an overnight video-polysomnogram (vPSG), however, even for sleep experts, interpreting vPSG data is challenging. Using a 3D camera, automated analysis of movements has yielded high accuracy.

Racism and Postpartum Blood Pressure in a Multiethnic Prospective Cohort.

Background: Postpartum hypertension is a key factor in racial-ethnic inequities in maternal mortality. Emerging evidence suggests that experiences of racism, both structural and interpersonal, may contribute to disparities. We examined associations between gendered racial microaggressions (GRMs) during obstetric care with postpartum blood pressure (BP).

evoke and evoke+: design of two large-scale, double-blind, placebo-controlled, phase 3 studies evaluating efficacy, safety, and tolerability of semaglutide in early-stage symptomatic Alzheimer's disease.

Background: Disease-modifying therapies targeting the diverse pathophysiology of Alzheimer's disease (AD), including neuroinflammation, represent potentially important and novel approaches. The glucagon-like peptide-1 receptor agonist semaglutide is approved for the treatment of type 2 diabetes and obesity and has an established safety profile. Semaglutide may have a disease-modifying, neuroprotective effect in AD through multimodal mechanisms including neuroinflammatory, vascular, and other AD-related processes.

Bidirectional histone monoaminylation dynamics regulate neural rhythmicity.

Histone H3 monoaminylations at Gln5 represent an important family of epigenetic marks in brain that have critical roles in permissive gene expression. We previously demonstrated that serotonylation and dopaminylation of Gln5 of histone H3 (H3Q5ser and H3Q5dop, respectively) are catalysed by transglutaminase 2 (TG2), and alter both local and global chromatin states. Here we found that TG2 additionally functions as an eraser and exchanger of H3 monoaminylations, including H3Q5 histaminylation (H3Q5his), which displays diurnally rhythmic expression in brain and contributes to circadian gene expression and behaviour.