Clinical, Radiographic, and Molecular Analysis of Patients with X-Linked Hypophosphatemic Rickets: Looking for Phenotype-Genotype Correlation.

Background/objectives: X-linked hypophosphataemic rickets (XLH) represents the most frequent type of rickets from genetic origin, it is caused by mutations on the gene. The main clinical manifestations are short stature and bone deformities. Phenotype variation is observed at the intrafamily and interfamily level.

Host-microbe multiomic profiling identifies distinct COVID-19 immune dysregulation in solid organ transplant recipients.

Coronavirus disease 2019 (COVID-19) poses significant risks for solid organ transplant recipients, who have atypical but poorly characterized immune responses to infection. We aim to understand the host immunologic and microbial features of COVID-19 in transplant recipients by leveraging a prospective multicenter cohort of 86 transplant recipients age- and sex-matched with 172 non-transplant controls. We find that transplant recipients have higher nasal SARS-CoV-2 viral abundance and impaired viral clearance, and lower anti-spike IgG levels.

Neoadjuvant anti-PD-1 alone or in combination with anti-TIGIT or an oncolytic virus in resectable stage IIIB-D melanoma: a phase 1/2 trial.

Neoadjuvant immunotherapies have shown antitumor activity in melanoma. Substudy 02C of the global, rolling-arm, phase 1/2, adaptive-design KEYMAKER-U02 trial is evaluating neoadjuvant pembrolizumab (anti-PD-1) alone or in combination, followed by adjuvant pembrolizumab, for stage IIIB-D melanoma. Here we report results from the first three arms: pembrolizumab plus vibostolimab (anti-TIGIT), pembrolizumab plus gebasaxturev (coxsackievirus A21) and pembrolizumab monotherapy.

Autogene cevumeran with or without atezolizumab in advanced solid tumors: a phase 1 trial.

Effective targeting of somatic cancer mutations to enhance the efficacy of cancer immunotherapy requires an individualized approach. Autogene cevumeran is a uridine messenger RNA lipoplex-based individualized neoantigen-specific immunotherapy designed from tumor-specific somatic mutation data obtained from tumor tissue of each individual patient to stimulate T cell responses against up to 20 neoantigens. This ongoing phase 1 study evaluated autogene cevumeran as monotherapy (n = 30) and in combination with atezolizumab (n = 183) in pretreated patients with advanced solid tumors.

Rapid identification and phenotyping of nonalcoholic fatty liver disease patients using a machine-based approach in diverse healthcare systems.

Nonalcoholic fatty liver disease (NAFLD) is the most common global cause of chronic liver disease and remains under-recognized within healthcare systems. Therapeutic interventions are rapidly advancing for its inflammatory phenotype, nonalcoholic steatohepatitis (NASH) at all stages of disease. Diagnosis codes alone fail to recognize and stratify at-risk patients accurately.

A truncated isoform of Connexin43 caps actin to organize forward delivery of full-length Connexin43.

While membrane proteins such as ion channels continuously turn over and require replacement, the mechanisms of specificity of efficient channel delivery to appropriate membrane subdomains remain poorly understood. GJA1-20k is a truncated Connexin43 (Cx43) isoform arising from translation initiating at an internal start codon within the same parent GJA1 mRNA and is requisite for full-length Cx43 trafficking to cell borders. GJA1-20k does not have a full transmembrane domain, and it is not known how GJA1-20k enables forward delivery of Cx43 hemichannels.

Human AI collaboration for unsupervised categorization of live surgical feedback.

Formative verbal feedback during live surgery is essential for adjusting trainee behavior and accelerating skill acquisition. Despite its importance, understanding optimal feedback is challenging due to the difficulty of capturing and categorizing feedback at scale. We propose a Human-AI Collaborative Refinement Process that uses unsupervised machine learning (Topic Modeling) with human refinement to discover feedback categories from surgical transcripts.

A robust benchmark for detecting low-frequency variants in the HG002 Genome In A Bottle NIST reference material.

Somatic mosaicism is an important cause of disease, but mosaic and somatic variants are often challenging to detect because they exist in only a fraction of cells. To address the need for benchmarking subclonal variants in normal cell populations, we developed a benchmark containing mosaic variants in the Genome in a Bottle Consortium (GIAB) HG002 reference material DNA from a large batch of a normal lymphoblastoid cell line. First, we used a somatic variant caller with high coverage (300x) Illumina whole genome sequencing data from the Ashkenazi Jewish trio to detect variants in HG002 not detected in at least 5% of cells from the combined parental data.

Phase 2A Proof-of-Concept Double-Blind, Randomized, Placebo-Controlled Trial of Nicotinamide in Early Alzheimer Disease.

Background And Objectives: Nicotinamide is a coenzyme involved in cellular oxidation-reduction reactions that can inhibit Class III histone deacetylases (HDACs) or sirtuins. HDAC inhibition can affect numerous therapeutic pathways, including tau phosphorylation. We tested the hypothesis that nicotinamide treatment could reduce tau phosphorylation in early Alzheimer disease (AD).

Effectiveness and Safety of Mechanical Thrombectomy in Large-Vessel-Occlusion Mild Stroke: Insights from the ASSIST Registry.

Background And Purpose: Mechanical thrombectomy (MT) is effective for acute ischemic stroke, yet its indication in mild stroke remains unclear. This study evaluates MT's effectiveness and safety in low NIHSS patients and assesses different MT strategies' impact on procedural success and clinical outcomes.

Materials And Methods: Data from the ASSIST Registry were analyzed, categorizing patients with large vessel occlusion of the anterior circulation into mild (NIHSS≤5) and moderate-severe (NIHSS>5) stroke groups.

Barriers to Medication Adherence in People Living With Epilepsy.

Background And Objectives: Epilepsy affects approximately 1.2% of the US population, resulting in 3.4 million Americans with active epilepsy.

Twice-Yearly Lenacapavir for HIV Prevention in Men and Gender-Diverse Persons.

Background: Twice-yearly subcutaneous lenacapavir has been shown to be efficacious for prevention of HIV infection in cisgender women. The efficacy of lenacapavir for preexposure prophylaxis (PrEP) in cisgender men, transgender women, transgender men, and gender-nonbinary persons is unclear.

Methods: In this phase 3, double-blind, randomized, active-controlled trial, we randomly assigned participants in a 2:1 ratio to receive subcutaneous lenacapavir every 26 weeks or daily oral emtricitabine-tenofovir disoproxil fumarate (F/TDF).

Ictal Involvement of the Pulvinar and the Anterior Nucleus of the Thalamus in Patients With Refractory Epilepsy.

Background And Objectives: Deep brain stimulation (DBS) targeting the anterior nucleus of the thalamus (ANT) has been shown to be effective in treating some patients with medically refractory epilepsy. However, it remains unknown how seizures spread through the ANT relative to other thalamic nuclei. This study aimed to investigate, through simultaneous recordings from both ANT and pulvinar (PLV) nucleus, their roles in seizure propagation.

Scalable log-ratio lasso regression for enhanced microbial feature selection with FLORAL.

Identifying predictive biomarkers of patient outcomes from high-throughput microbiome data is of high interest, while existing computational methods do not satisfactorily account for complex survival endpoints, longitudinal samples, and taxa-specific sequencing biases. We present FLORAL, an open-source tool to perform scalable log-ratio lasso regression and microbial feature selection for continuous, binary, time-to-event, and competing risk outcomes, with compatibility for longitudinal microbiome data as time-dependent covariates. The proposed method adapts the augmented Lagrangian algorithm for a zero-sum constraint optimization problem while enabling a two-stage screening process for enhanced false-positive control.

Care Quality and Outcomes of Ischemic Stroke in Patients With Premorbid Dementia: Get With The Guidelines-Stroke Registry.

Background: Patients with premorbid dementia have been generally excluded from trials of stroke therapies, and their dementia diagnosis may affect the care received. There are few data on the quality of stroke care and outcomes in these patients.

Methods: We compared the quality of care and outcomes for acute ischemic stroke patients with versus without premorbid dementia using national data from the Get With The Guidelines-Stroke registry between July 1, 2020, and December 31, 2021.

Polygenic Risk of Epilepsy and Poststroke Epilepsy.

Background: Epilepsy is highly heritable, with numerous known genetic risk loci. However, the genetic predisposition's role in poststroke epilepsy (PSE) remains understudied. This study assesses whether a higher genetic predisposition to epilepsy raises poststroke survivor's risk of PSE.

Transcatheter Aortic-Valve Replacement for Asymptomatic Severe Aortic Stenosis.

Background: For patients with asymptomatic severe aortic stenosis and preserved left ventricular ejection fraction, current guidelines recommend routine clinical surveillance every 6 to 12 months. Data from randomized trials examining whether early intervention with transcatheter aortic-valve replacement (TAVR) will improve outcomes in these patients are lacking.

Methods: At 75 centers in the United States and Canada, we randomly assigned, in a 1:1 ratio, patients with asymptomatic severe aortic stenosis to undergo early TAVR with transfemoral placement of a balloon-expandable valve or clinical surveillance.

The Dunning‒Kruger effect in resident predicted and actual performance on the American Board of Emergency Medicine in-training examination.

Objectives: The Dunning-Kruger effect (DKE) is a cognitive bias wherein individuals who are unskilled overestimate their abilities, while those who are skilled tend to underestimate their capabilities. The purpose of this investigation is to determine if the DKE exists among American Board of Emergency Medicine (ABEM) in-training examination (ITE) participants.

Methods: This is a prospective, cross-sectional survey of residents in Accreditation Council for Graduate Medical Education (ACGME)-accredited emergency medicine (EM) residency programs.

Rapid and Robust Identification of Sepsis Using SeptiCyte RAPID in a Heterogeneous Patient Population.

SeptiCyte RAPID is a transcriptional host response assay that discriminates between sepsis and non-infectious systemic inflammation (SIRS) with a one-hour turnaround time. The overall performance of this test in a cohort of 419 patients has recently been described [Balk et al., J Clin Med 2024, 13, 1194].

Observation-first versus angioembolization-first approach in stable patients with blunt liver trauma: A WTA multicenter study.

Background: Prior studies evaluating observation versus angioembolization (AE) for blunt liver injuries (BLT) with contrast extravasation (CE) on computed tomography imaging have yielded inconsistent conclusions, primarily due to limitations in single-center and/or retrospective study design. Therefore, this multicenter study aims to compare an observation versus AE-first approach for BLT, hypothesizing decreased liver-related complications (LRCs) with observation.

Methods: We conducted a post hoc analysis of a multicenter, prospective observational study (2019-2021) across 23 centers.

Twenty Years of Sustained Improvement in Quality of Care and Outcomes for Patients Hospitalized With Stroke or Transient Ischemic Attack: Data From The Get With The Guidelines-Stroke Program.

Background: The Get With The Guidelines-Stroke program is a quality improvement initiative designed to enhance adherence to evidence-based stroke care. Since its inception in 2003, over 2800 hospitals in the United States have participated in the program.

Methods: We examined patient characteristics, adherence to performance measures, and in-hospital outcomes in patients hospitalized for acute ischemic stroke, subarachnoid hemorrhage, intracerebral hemorrhage, and transient ischemic attack in The Get With The Guidelines-Stroke hospitals from 2003 through 2022.