Mutations in hnRNP A1 drive neurodegeneration and alternative RNA splicing of neuronal gene targets.

RNA binding protein dysfunction is a pathogenic feature of multiple neurological diseases, including multiple sclerosis (MS). Neurodegeneration (the loss of, or damage to neurons and axons) is the primary driver of disease progression in MS. Herein, we utilized a novel, neuron-specific model of neurodegeneration by transducing primary mouse neurons with mutant forms of the RNA binding protein heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) identified from MS patients, including one within the M9-nuclear localization sequence of hnRNP A1 (A1(P275S)) and a second in the prion-like domain of hnRNP A1 (A1(F263S)) to test the hypothesis that neuronal hnRNP A1 dysfunction drives neurodegeneration in MS.

Nivolumab plus ipilimumab versus nivolumab in microsatellite instability-high metastatic colorectal cancer (CheckMate 8HW): a randomised, open-label, phase 3 trial.

Background: CheckMate 8HW prespecified dual primary endpoints, assessed in patients with centrally confirmed microsatellite instability-high or mismatch repair-deficient status: progression-free survival with nivolumab plus ipilimumab compared with chemotherapy as first-line therapy and progression-free survival with nivolumab plus ipilimumab compared with nivolumab alone, regardless of previous systemic treatment for metastatic disease. In our previous report, nivolumab plus ipilimumab showed superior progression-free survival versus chemotherapy in first-line microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer in the CheckMate 8HW trial. Here, we report results from the prespecified interim analysis for the other primary endpoint of progression-free survival for nivolumab plus ipilimumab versus nivolumab across all treatment lines.

Topography of putative bi-directional interaction between hippocampal sharp-wave ripples and neocortical slow oscillations.

Systems consolidation relies on coordination between hippocampal sharp-wave ripples (SWRs) and neocortical UP/DOWN states during sleep. However, whether this coupling exists across the neocortex and the mechanisms enabling it remains unknown. By combining electrophysiology in mouse hippocampus (HPC) and retrosplenial cortex (RSC) with wide-field imaging of the dorsal neocortex, we found spatially and temporally precise bi-directional hippocampo-neocortical interaction.

"It's Allowing Space for Vulnerability": Exploring Athletes' Experiences With Trust in Interdependent Sport.

Despite trust being associated with a range of favorable outcomes across high-performing team contexts (e.g., enhanced satisfaction, performance), efforts to investigate the meaning of trust in sport remain limited.

Toward cognitive models of misophonia.

Misophonia is a disorder in which specific common sounds such as another person breathing or chewing, or the ticking of a clock, cause an atypical negative emotional response. Affected individuals may experience anger, irritability, annoyance, disgust, and anxiety, as well as physiological autonomic responses, and may find everyday environments and contexts to be unbearable in which their 'misophonic stimuli' (often called 'trigger sounds') are present. Misophonia is gradually being recognized as a genuine problem that causes significant distress and has negative consequences for individuals and their families.

Has the documentation of chest injuries and the development of systemic complications in patients with long bone fractures changed over time?-A systematic literature review and meta-analysis by the IMPACT expert group.

Introduction: Blunt chest trauma represents a major risk factor for complications in polytrauma patients. Various scoring systems have emerged, but their impact is not fully appreciated. This review evaluates changes in chest trauma scoring over time and potential shifts in complication rates linked to modified surgical approaches in long bone fractures.

Radiofrequency-thermocoagulation in pediatric epilepsy surgery: A systematic review and pooled analysis of cases.

Objective: To conduct a systematic review on radiofrequency thermocoagulation (RF-TC) in pediatric epilepsy surgery. In addition, due to the low number of dedicated pediatric series, to conduct a pooled analysis of cases published in the literature.

Methods: We conducted a literature search using PUBMED and EMBASE which produced 432 results.

Natural history progression of MRI brain volumetrics in type II late-infantile and juvenile GM1 gangliosidosis patients.

Objective: GM1 gangliosidosis is a rare lysosomal storage disorder characterized by the accumulation of GM1 gangliosides in neuronal cells, resulting in severe neurodegeneration. Currently, limited data exists on the brain volumetric changes associated with this disease. This study focuses on the late-infantile and juvenile subtypes of type II GM1 gangliosidosis, aiming to quantify brain volumetric characteristics to track disease progression.

Housing matters: The long-term impact of stable housing on mortality among people with HIV in British Columbia, Canada.

Aim: For several decades, British Columbia (BC), Canada, has been experiencing a housing crisis marked by a shortage of safe and affordable housing, which coincides with a severe drug poisoning epidemic in the region. We explore the impact of housing instability on mortality (all-cause, drug-related) among a cohort of people with HIV (PWH) in BC.

Methods: Data are from the Longitudinal Investigation into Supportive and Ancillary Health Services (LISA) study (n = 997).

Musculoskeletal model predictions sensitivity to upper body mass scaling during gait.

Musculoskeletal modeling based on inverse dynamics provides a cost-effective non-invasive means for calculating intersegmental joint reaction forces and moments, solely relying on kinematic data, easily obtained from smart wearables. On the other hand, the accuracy and precision of such models strongly hinge upon the selected scaling methodology tailored to subject-specific data. This study investigates the impact of upper body mass distribution on internal and external kinetics computed using a comprehensive musculoskeletal model during level walking in both normal weight and obese individuals.

Towards contrast-agnostic soft segmentation of the spinal cord.

Spinal cord segmentation is clinically relevant and is notably used to compute spinal cord cross-sectional area (CSA) for the diagnosis and monitoring of cord compression or neurodegenerative diseases such as multiple sclerosis. While several semi and automatic methods exist, one key limitation remains: the segmentation depends on the MRI contrast, resulting in different CSA across contrasts. This is partly due to the varying appearance of the boundary between the spinal cord and the cerebrospinal fluid that depends on the sequence and acquisition parameters.

Diagnostic accuracy of an automated classifier for the detection of pleural effusions in patients undergoing lung ultrasound.

Rationale: Lung ultrasound, the most precise diagnostic tool for pleural effusions, is underutilized due to healthcare providers' limited proficiency. To address this, deep learning models can be trained to recognize pleural effusions. However, current models lack the ability to diagnose effusions in diverse clinical contexts, which presents significant challenges.

Brain microenvironment-remodeling nanomedicine improves cerebral glucose metabolism, mitochondrial activity and synaptic function in a mouse model of Alzheimer's disease.

The development of disease-modifying therapeutics for Alzheimer's disease remains challenging due to the complex pathology and the presence of the blood-brain barrier. Previously we have described the investigation of a brain-penetrating multifunctional bioreactive nanoparticle system capable of remodeling the hypoxic and inflammatory brain microenvironment and reducing beta-amyloid plaques improving cognitive function in a mouse model of Alzheimer's disease. Despite the linkage of hypoxia and inflammation to metabolic alteration, the effects of this system on modulating cerebral glucose metabolism, mitochondrial activity and synaptic function remained to be elucidated.

Web Visualization for Spatiotemporal Genomic Epidemiology, Annotation, and Mutation Dynamics of Orthohantavirus hantanense Using Nextstrain.

The phylogeographic inference approach aims to connect genomic data with epidemiology to understand the spread and evolution of pathogens using visualization of spatiotemporal reconstructions. Orthohantavirus hantanense (HTNV), the causative agent of hemorrhagic fever with renal syndrome (HFRS), represents a significant global public health concern. Here, we introduce a localized Nextstrain platform for HTNV, offering a comprehensive resource for facilitating spatiotemporal genomic surveillance and the study of evolutionary dynamics of viral genomes.

An exploratory survey assessing the determinants of heat stress and heat strain in the Canadian mining industry from the worker's perspective.

With mines extending deeper and rising surface temperatures, workers are exposed to hotter environments. This study aimed to characterize heat stress and strain in the Canadian mining industry and evaluate the utility of the Heat Strain Score Index (HSSI), combined with additional self-reported adverse health outcomes. An exploratory web-based survey was conducted among workers ( = 119) in the Canadian mining industry.

Contaminant-Associated Disruption of the Skin Transcriptome in the Endangered St. Lawrence Estuary Beluga.

The St. Lawrence Estuary (SLE) beluga () population in Canada is Endangered, and endocrine disrupting contaminants, such as polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and other halogenated flame retardants, have been identified as a threat to the recovery of this population. Here, potential impacts of these contaminants on SLE beluga were evaluated by comparing skin transcriptome profiles and biological pathways between this population and a population less exposed to contaminants (Eastern Beaufort Sea) used as a reference.

Examining the Biophysical Properties of the Inner Membrane of Gram-Negative ESKAPE Pathogens.

The World Health Organization has identified multidrug-resistant bacteria as a serious global health threat. Gram-negative bacteria are particularly prone to antibiotic resistance, and their high rate of antibiotic resistance has been suggested to be related to the complex structure of their cell membrane. The outer membrane of Gram-negative bacteria contains lipopolysaccharides that protect the bacteria against threats such as antibiotics, while the inner membrane houses 20-30% of the bacterial cellular proteins.

Speech-Language Pathology Preservice Preparation for Working in School-Age Literacy: International Perspectives.

Purpose: This narrative review of preservice training of speech-language pathologists (SLPs) to work in school-age literacy contexts examines (a) studies regarding SLPs' perceptions of their preservice training and (b) accreditation requirements for preservice training in selected nations.

Method: A review of the literature examining (a) SLPs' perspectives about their preservice training; (b) SLPs' beliefs, confidence, and self-efficacy; and (c) speech-language pathology preservice program content was conducted via analysis of studies published after the year 2010. Policy documents and websites outlining accreditation requirements in the United States, Canada, the United Kingdom, Australia, and New Zealand were reviewed.

The Lanthanide Contraction: What is an Abnormal and Why?

The lanthanide contraction is a widely known phenomenon in which the ionic radii of the Ln ions decrease across the series from La to Lu. As a result, the distance (Ln-Y), where Y is a ligand donor atom, decreases across the series. As shown previously, the decrease normally has a linear dependence on the number of 4f Ln electrons, , and the net change, Δ', is between 0.

Multidimensional scaling improves distance-based clustering for microbiome data.

Motivation: Clustering patients into subgroups based on their microbial compositions can greatly enhance our understanding of the role of microbes in human health and disease etiology. Distance-based clustering methods, such as partitioning around medoids (PAM), are popular due to their computational efficiency and absence of distributional assumptions. However, the performance of these methods can be suboptimal when true cluster memberships are driven by differences in the abundance of only a few microbes, a situation known as the sparse signal scenario.

Prion Protein Endoproteolysis: Cleavage Sites, Mechanisms and Connections to Prion Disease.

Highly abundant in neurons, the cellular prion protein (PrP) is an obligatory precursor to the disease-associated misfolded isoform denoted PrP that accumulates in the rare neurodegenerative disorders referred to either as transmissible spongiform encephalopathies (TSEs) or as prion diseases. The ability of PrP to serve as a substrate for this template-mediated conversion process depends on several criteria but importantly includes the presence or absence of certain endoproteolytic events performed at the cell surface or in acidic endolysosomal compartments. The major endoproteolytic events affecting PrP are referred to as α- and β-cleavages, and in this review we outline the sites within PrP at which the cleavages occur, the mechanisms potentially responsible and their relevance to pathology.

Pyoderma Gangrenosum Improved with Dapsone and Prednisone: A Case Report.

Pyoderma gangrenosum is a rare ulcerative condition that poses diagnostic and therapeutic challenges. Diagnosis and appropriate management are often delayed due to its rarity and the presence of numerous clinical variants. In this case report, the authors present the case of a 36-year-old man who had long-standing and nonhealing ulcers that did not respond to multiple antibiotics and serial wound debridement.