Different PD-L1 Assays Reveal Distinct Immunobiology and Clinical Outcomes in Urothelial Cancer.

Testing for PD-L1 expression by immunohistochemistry (IHC) is used to predict immune checkpoint blockade (ICB) benefit but has performed inconsistently in urothelial cancer (UC) clinical trials. Different approaches are used for PD-L1 IHC. We analyzed paired PD-L1 IHC data on UC samples using the SP142 and 22C3 assays from the phase 3 IMvigor130 trial and found discordant findings summarized by four phenotypes: PD-L1 positive by both assays (PD-L1 double positive; PD-L1DP), PD-L1 positive by the SP142 assay only (SP142 single positive; SP142SP), PD-L1 positive by the 22C3 assay only (22C3 single positive; 22C3SP), and PD-L1 negative by both assays double negative (PD-L1 double negative; PD-L1DN).

Predictive signatures of immune response to vaccination and implications of the immune setpoint remodeling.

In 2020, I featured two articles in the "mSphere of Influence" commentary series that had profound implications for the field of immunology and helped shape my research perspective. These articles were "Global Analyses of Human Immune Variation Reveal Baseline Predictors of Postvaccination Responses" by Tsang et al. (Cell 157:499-513, 2014, https://doi.

Internal Tremor in Long COVID May Be a Symptom of Dysautonomia and Small Fiber Neuropathy.

Internal tremor (IT) is often reported by patients with post-acute sequelae of SARS-CoV-2, also known as Long COVID, as a distressing and disabling symptom. Similarly, physicians are typically perplexed by the nature and etiology of IT and find it extremely challenging to manage. We describe a patient with Long COVID who experienced IT as part of post-COVID postural orthostatic tachycardia syndrome (POTS) and small fiber neuropathy (SFN) and review the limited literature available on this topic.

Visual-textual integration in LLMs for medical diagnosis: A preliminary quantitative analysis.

Background And Aim: Visual data from images is essential for many medical diagnoses. This study evaluates the performance of multimodal Large Language Models (LLMs) in integrating textual and visual information for diagnostic purposes.

Methods: We tested GPT-4o and Claude Sonnet 3.

Factors predicting manipulation under anaesthesia after total knee replacement.

Introduction: Manipulation under anesthesia (MUA) is a standard and effective treatment to correct stiffness and improve range of motion (ROM) following total knee arthroplasty (TKA). Delayed MUA has been associated with increased rates of revision surgeries and infections. Early MUA has been shown to double the mean gain in flexion compared to delayed interventions.

Effects of aortic valve calcification on transcatheter aortic valve replacement for low-flow, low-gradient aortic stenosis.

Background: Patients with low-flow, low-gradient (LFLG) aortic stenosis (AS) have precarious hemodynamics and are a fragile population for intervention. Quantification of aortic valve calcification (AVC) severity is a critical component of the evaluation for transcatheter aortic valve replacement (TAVR); this study aims to further clarify its utility for risk stratification in LFLG AS.

Methods: This retrospective study evaluated 467 patients with LFLG AS undergoing TAVR at a large quaternary-care hospital from January 2019 to December 2021.

A new Mediterranean Lifestyle Pyramid for children and youth: a critical lifestyle tool for preventing obesity and associated cardiometabolic diseases in a sustainable context.

Cardiovascular risk factors begin in childhood and track into adulthood, increasing the possibility of impaired cardiometabolic health. Adopting healthy dietary patterns can help curb childhood obesity, a worrisome epidemic problem at present. In the era of personalized nutrition, dietary recommendations should be adapted to different stages of life, including children (older than 3 years) and adolescents.

Lysosomal dysfunction and inflammatory sterol metabolism in pulmonary arterial hypertension.

Vascular inflammation regulates endothelial pathophenotypes, particularly in pulmonary arterial hypertension (PAH). Dysregulated lysosomal activity and cholesterol metabolism activate pathogenic inflammation, but their relevance to PAH is unclear. Nuclear receptor coactivator 7 () deficiency in endothelium produced an oxysterol and bile acid signature through lysosomal dysregulation, promoting endothelial pathophenotypes.

Orismilast, a PDE4B/D inhibitor, in moderate-to-severe atopic dermatitis: Efficacy and safety from a multicenter, randomized, placebo-controlled, phase 2b dose-ranging study (ADESOS).

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease, characterized by eczematous skin lesions and pruritus. There is an unmet need for effective first-line systemic therapies with good safety profiles, particularly oral medications. Orismilast is a novel first-in-class oral phosphodiesterase-4 (PDE4) B/D inhibitor under investigation for the treatment of moderate-to-severe AD.

Distinct changes to hippocampal and medial entorhinal circuits emerge across the progression of cognitive deficits in epilepsy.

Temporal lobe epilepsy (TLE) causes pervasive and progressive memory impairments, yet the specific circuit changes that drive these deficits remain unclear. To investigate how hippocampal-entorhinal dysfunction contributes to progressive memory deficits in epilepsy, we performed simultaneous in vivo electrophysiology in the hippocampus (HPC) and medial entorhinal cortex (MEC) of control and epileptic mice 3 or 8 weeks after pilocarpine-induced status epilepticus (Pilo-SE). We found that HPC synchronization deficits (including reduced theta power, coherence, and altered interneuron spike timing) emerged within 3 weeks of Pilo-SE, aligning with early-onset, relatively subtle memory deficits.

A Narrative Review of Cardiometabolic Profiles among U.S. Adults: Temporal Trends and Implications.

Purpose Of Review: To provide a narrative overview of trends and disparities in the cardiometabolic profiles of U.S. adults by synthesizing findings from nationally representative studies conducted between 1999 and 2020.

Prescriptions (Rx) for Prevention: Clinical Tools for Integrating Environmental Health into Pediatric Clinical Care.

The integration of environmental health (EH) into routine clinical care for children is in its early stages. The vision of pediatric EH is that all clinicians caring for children are aware of and able to help connect families to needed resources to reduce harmful environmental exposures and increase health-enhancing ones. Environmental exposures include air pollution, substandard housing, lead, mercury, pesticides, consumer products chemicals, drinking water contaminants, industrial facility emissions and, increasingly, climate change-related extreme weather and heat events.

Tendon Inversion Improves Tendon-to-Bone Healing in a Rat Bicep Tenodesis Model.

Purpose: Tendon-to-bone repair remains a surgical challenge. Although bone tunnel fixation is a common surgical technique whereby soft tissue is expected to heal against a bone tunnel interface, contemporary methods have yet to recapitulate biomechanical similarity to the native enthesis. In this study, we aimed to understand how inside-out longitudinal tendon inversion affects bone tunnel healing with the hypothesis that inversion removes the gliding epitenon surface to facilitate interface healing.

Directed Acyclic Graphs in Decision-Analytic Modeling: Bridging Causal Inference and Effective Model Design in Medical Decision Making.

Our commentary proposes the application of directed acyclic graphs (DAGs) in the design of decision-analytic models, offering researchers a valuable and structured tool to enhance transparency and accuracy by bridging the gap between causal inference and model design in medical decision making.The practical examples in this article showcase the transformative effect DAGs can have on model structure, parameter selection, and the resulting conclusions on effectiveness and cost-effectiveness.This methodological article invites a broader conversation on decision-modeling choices grounded in causal assumptions.

Immunotherapy-based neoadjuvant treatment and complication rates after radical cystectomy.

Objective: To assess 30- and 90-day postoperative complication rates in patients who underwent robot-assisted radical cystectomy (RARC) after receiving novel immunotherapy-based neoadjuvant treatment.

Methods: A bi-centre analysis was conducted in patients who underwent RARC with intracorporeal urinary diversion and who received an immunotherapy-based neoadjuvant regimen between 2017 and 2023. Complications were classified using the Clavien-Dindo system.

Elective hand surgery and concomitant corticosteroid injection: Confirming increased infection risk using A national dataset.

Background: Recent studies demonstrate a link between corticosteroid injection and surgical complications when procedures occur shortly after steroid administration. These publications focus on single procedures like carpal tunnel release. This study seeks to demonstrate how surgical site infection risk changes across thirteen common elective hand procedures when steroid injection is performed contemporaneously.

Cryopreservation of brain cell structure: a review.

Cryopreservation, the preservation of tissues at subzero temperatures, is a mainstay of brain banking that allows for the storage of brain tissue without the use of chemical fixatives. This is particularly important for molecular studies that are incompatible with tissue fixation. However, brain tissue is vulnerable to various forms of damage during the cryopreservation process, in particular due to the phase transition of water from a liquid to a solid state with the formation of ice crystals, which can disrupt cellular morphology.

Antibody-drug conjugates in urothelial carcinoma: current status and future.

Purpose Of Review: Antibody-drug conjugates (ADCs) are quickly becoming frontline standard of care in many tumor types, including urothelial carcinoma. This review summarizes recent clinical investigations into the use of ADCs targeting nectin-4, trophoblast cell surface antigen-2 (Trop-2), human epidermal growth factor receptor 2 (HER-2), and other antigens in urothelial carcinoma.

Recent Findings: This review covers efficacy and toxicity data of ADCs alone and in combination with immunotherapy; mechanisms of resistance; and preclinical studies that provide biological basis for clinical approaches.

Multi-omics analysis reveals novel causal pathways in psoriasis pathogenesis.

Background: To elucidate the genetic and molecular mechanisms underlying psoriasis by employing an integrative multi-omics approach, using summary-data-based Mendelian randomization (SMR) to infer causal relationships among DNA methylation, gene expression, and protein levels in relation to psoriasis risk.

Methods: We conducted SMR analyses integrating genome-wide association study (GWAS) summary statistics with methylation quantitative trait loci (mQTL), expression quantitative trait loci (eQTL), and protein quantitative trait loci (pQTL) data. Publicly available datasets were utilized, including psoriasis GWAS data from the European Molecular Biology Laboratory-European Bioinformatics Institute and the UK Biobank.

Microglia modulate the cerebrovascular reactivity through ectonucleotidase CD39.

Microglia and the border-associated macrophages contribute to the modulation of cerebral blood flow, but the mechanisms have remained uncertain. Here, we show that microglia regulate the cerebral blood flow baseline and the responses to whisker stimulation or intra-cisternal magna injection of adenosine triphosphate, but not intra-cisternal magna injection of adenosine in mice model. Notably, microglia repopulation corrects these cerebral blood flow anomalies.

Hemoglobin Decrements are Associated with Ischemic Brain Lesions and Poor Outcomes in Patients with Intracerebral Hemorrhage.

Background: Acute ischemic lesions seen on brain magnetic resonance imaging (MRI) are associated with poor intracerebral hemorrhage (ICH) outcomes, but drivers for these lesions are unknown. Rapid hemoglobin decrements occur in the initial days after ICH and may impair brain oxygen delivery. We investigated whether acute hemoglobin decrements after ICH are associated with MRI ischemic lesions and poor long-term ICH outcomes.

Genomics yields biological and phenotypic insights into bipolar disorder.

Bipolar disorder is a leading contributor to the global burden of disease. Despite high heritability (60-80%), the majority of the underlying genetic determinants remain unknown. We analysed data from participants of European, East Asian, African American and Latino ancestries (n = 158,036 cases with bipolar disorder, 2.