From Theory to Therapy: Unlocking the Potential of Muscarinic Receptor Activation in Schizophrenia With the Dual M1/M4 Muscarinic Receptor Agonist Xanomeline and Trospium Chloride and Insights From Clinical Trials.

Since the 1950s, understanding of antipsychotic activity in schizophrenia has been largely grounded in the dopamine hypothesis. Most antipsychotics approved for schizophrenia interact with D2 dopamine receptors as an important part of their mechanism of action. While antipsychotics blocking D2 dopamine receptors can be effective for positive symptoms of schizophrenia, none are approved by regulatory authorities for predominant negative or cognitive symptoms.

Emerging, novel gene-modulating therapies for transthyretin amyloid cardiomyopathy.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, life-threatening disease caused by the pathological deposition of misfolded transthyretin (TTR) protein in the myocardium, leading to restrictive cardiomyopathy and heart failure. While TTR stabilizers such as tafamidis and acoramidis are the only FDA-approved treatments, novel gene-modulating therapies are emerging as transformative approaches. Small interfering RNA (siRNA) and antisense oligonucleotide (ASO) therapies effectively reduce TTR production and have demonstrated promising clinical outcomes, though their use in cardiac amyloidosis remains investigational.

An Evaluation of Time Spent Completing Electronically Collected Patient-Reported Outcomes in Clinical Trials.

Objectives: Patient-reported outcomes (PROs) are important measures of efficacy in the context of clinical trials but are sometimes identified as time and resource intensive to study participants and site personnel. The objective of this research was to evaluate the amount of time that participants spend completing PROs via an electronic device in phase 2 and 3 clinical trials across several disease areas.

Methods: The electronic Clinical Outcome Assessment (eCOA) data were obtained from Johnson & Johnson clinical trials across various disease areas from 2016 to 2023.

Comprehensive identification of hub mRNAs and lncRNAs in colorectal cancer using galaxy: an in silico transcriptome analysis.

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality. Using the Galaxy platform, the present study aimed to assess the differentially expressed genes (DEGs) in CRC patients. The expression data was obtained from the Gene Expression Omnibus database (GSE137327).

Applications of reflectance confocal microscopy in photoaging and aesthetic conditions: skin characterization and treatment monitoring.

Reflectance confocal microscopy (RCM) is an in-vivo, non-invasive imaging modality that provides a high-resolution image of the epidermis and upper dermis. RCM has been utilized as a diagnostic aid for several inflammatory, infectious, and malignant skin conditions; however, its use for clinical and aesthetic skin purposes has not been well established. The purpose of this review is to describe the landscape of RCM utilization for the application of aesthetic skin conditions.

Guidance for stem cell therapy for juvenile systemic sclerosis patients.

Introduction: Autologous stem cell transplantation (ASCT) and cellular therapies (CTs) are emerging therapeutic options for both adult and juvenile-onset systemic sclerosis (jSSc) patients. However, most efficacy data are derived from adult studies, and it remains unclear whether adult stem cell transplant criteria are fully applicable to pediatric patients with jSSc. Given pediatric patients' unique potential for recovery and tissue remodeling, the stringent criteria used in adults need adaptation for children.

Chaperone-mediated autophagy regulates the metastatic state of mesenchymal tumors.

Tumors often recapitulate programs to acquire invasive and dissemination abilities, during which pro-metastatic proteins are distinctively stabilized in cancer cells to drive further progression. Whether failed protein degradation affects the metastatic programs of cancer remains unknown. Here, we show that the human cancer cell-specific knockout (KO) of LAMP-2A, a limiting protein for chaperone-mediated autophagy (CMA), promotes the aggressiveness of mesenchymal tumors.

A unified acoustic-to-speech-to-language embedding space captures the neural basis of natural language processing in everyday conversations.

This study introduces a unified computational framework connecting acoustic, speech and word-level linguistic structures to study the neural basis of everyday conversations in the human brain. We used electrocorticography to record neural signals across 100 h of speech production and comprehension as participants engaged in open-ended real-life conversations. We extracted low-level acoustic, mid-level speech and contextual word embeddings from a multimodal speech-to-text model (Whisper).

Nivolumab plus chemotherapy or ipilimumab in gastroesophageal cancer: exploratory biomarker analyses of a randomized phase 3 trial.

First-line nivolumab-plus-chemotherapy demonstrated superior overall survival (OS) and progression-free survival versus chemotherapy for advanced gastroesophageal adenocarcinoma with programmed death ligand 1 combined positive score ≥ 5, meeting both primary end points of the randomized phase 3 CheckMate 649 trial. Nivolumab-plus-ipilimumab provided durable responses and higher survival rates versus chemotherapy; however, the prespecified OS significance boundary was not met. To identify biomarkers predictive of differential efficacy outcomes, post hoc exploratory analyses were performed using whole-exome sequencing and RNA sequencing.

Integrated multi-omic characterizations of the synapse reveal RNA processing factors and ubiquitin ligases associated with neurodevelopmental disorders.

The molecular composition of the excitatory synapse is incompletely defined due to its dynamic nature across developmental stages and neuronal populations. To address this gap, we apply proteomic mass spectrometry to characterize the synapse in multiple biological models, including the fetal human brain and human induced pluripotent stem cell (hiPSC)-derived neurons. To prioritize the identified proteins, we develop an orthogonal multi-omic screen of genomic, transcriptomic, interactomic, and structural data.

The relationship between mean arterial pressure and terlipressin in hepatorenal syndrome-acute kidney injury reversal: a post hoc analysis.

Background And Aims: Terlipressin reverses hepatorenal syndrome-acute kidney injury (HRS-AKI) by increasing mean arterial pressure (MAP). To further characterize the relationship between terlipressin and MAP and their impact on HRS-AKI reversal, we used patient-level data from Phase 3 clinical trials REVERSE and CONFIRM.

Approach And Results: In this post hoc analysis we employed a linear mixed-effects model to assess terlipressin's impact on MAP, exploring the relationship between MAP, treatment group, and time, incorporating a random intercept for individual patients.

Social Media as a Platform for Cancer Care Decision-Making Among Women: Internet Survey-Based Study on Trust, Engagement, and Preferences.

Background: Decision aids improve patient and clinician decision-making but are underused and often restricted to clinical settings.

Objective: Given limited studies analyzing the feasibility of disseminating decision aids through social media, this study aimed to evaluate the acceptability, trust, and engagement of women with social media as a tool to deliver online decision aids for cancer treatment.

Methods: To prepare for potential dissemination of a breast cancer decision aid via social media, a cross-sectional survey in February 2023 was conducted via Prime Panels, an online market research platform, of women aged 35-75 years in the United States.

Current Landscape and Future Directions for Mental Health Conversational Agents for Youth: Scoping Review.

Background: Conversational agents (CAs; chatbots) are systems with the ability to interact with users using natural human dialogue. They are increasingly used to support interactive knowledge discovery of sensitive topics such as mental health topics. While much of the research on CAs for mental health has focused on adult populations, the insights from such research may not apply to CAs for youth.

Pembrolizumab in combination with binimetinib in patients with unresectable locally advanced or metastatic triple-negative breast cancer.

Purpose: Activation of the RAS/MAPK pathway is associated with reduced tumor-infiltrating lymphocytes and poor outcomes in triple-negative breast cancer (TNBC). Previous studies demonstrated that inhibition of the MAPK pathway with a MEK inhibitor is synergistic with immune checkpoint inhibitors.

Experimental Design: We conducted a phase I/II trial of pembrolizumab and binimetinib in patients with metastatic TNBC with ≤ 3 prior lines of therapy.

Rewilding catalyzes maturation of the humoral immune system.

Inbred mice used for biomedical research display an underdeveloped immune system compared with adult humans, which is attributed in part to the artificial laboratory environment. Despite representing a central component of adaptive immunity, the impact of the laboratory environment on the B cell compartment has not been investigated in detail. Here, we performed an in-depth examination of B cells following rewilding, the controlled release of inbred laboratory mice into an outdoor enclosure.

Earth orbital rhythms links timing of Deccan trap volcanism phases and global climate change.

At the end of the Cretaceous, the massive Deccan trap (DT) volcanic eruptions are regarded as the primary driver of global climate deterioration. Accurate age models are key to unravel the sequence of events related to DT volcanism onset and effects on the global climate system. We establish a direct geochemical link between DT volcanism as recorded in marine osmium isotopic data and global climate change documented in benthic foraminifera carbon and oxygen isotope records.

Candidate transmission survival genome of .

(Mtb), a leading cause of death from infection, completes its life cycle entirely in humans except for transmission through the air. To begin to understand how Mtb survives aerosolization, we mimicked liquid and atmospheric conditions experienced by Mtb before and after exhalation using a model aerosol fluid (MAF) based on the water-soluble, lipidic, and cellular constituents of necrotic tuberculosis lesions. MAF induced drug tolerance in Mtb, remodeled its transcriptome, and protected Mtb from dying in microdroplets desiccating in air.

Plectin-mediated cytoskeletal crosstalk as a target for inhibition of hepatocellular carcinoma growth and metastasis.

The most common primary malignancy of the liver, hepatocellular carcinoma (HCC), is a heterogeneous tumor entity with high metastatic potential and complex pathophysiology. Increasing evidence suggests that tissue mechanics plays a critical role in tumor onset and progression. Here, we show that plectin, a major cytoskeletal crosslinker protein, plays a crucial role in mechanical homeostasis and mechanosensitive oncogenic signaling that drives hepatocarcinogenesis.

Association of Conjunctival Cell HLA-DR Expression with the Severity of Signs and Symptoms of Dry Eye Disease at Baseline in the NORTHERN LIGHTS Phase 2 Trial.

Purpose: To assess the association of HLA-DR on ocular surface conjunctival cells with the severity of signs and symptoms of dry eye disease (DED) in patients enrolled in the NORTHERN LIGHTS phase 2 trial.

Methods: Patients with moderate to severe DED were recruited from 10 different countries in Europe. Symptoms of DED were assessed using the visual analog scale (VAS) global discomfort score, and signs corneal fluorescein staining (CFS), lissamine green staining, Schirmer's test, and tear osmolarity.

Harnessing the Plasma Proteome to Predict Mortality in Heart Failure Subpopulations.

Background: We derived and validated proteomic risk scores (PRSs) for heart failure (HF) prognosis that provide absolute risk estimates for all-cause mortality within 1 year.

Methods: Plasma samples from individuals with HF with reduced ejection fraction (HFrEF; ejection fraction <40%; training/validation n=1247/762) and preserved ejection fraction (HFpEF; ejection fraction ≥50%; training/validation n=725/785) from 3 independent studies were run on the SomaScan Assay measuring ≈5000 proteins. Machine learning techniques resulted in unique 17- and 14-protein models for HFrEF and HFpEF that predict 1-year mortality.

Genicular Nerve Radiofrequency Ablation for Chronic Knee Joint Pain Using a V-Shaped Active Tip Needle: A Single-Center Retrospective Observational Study.

Background: Chronic knee pain from osteoarthritis (OA) affects a significant proportion of adults over 40. Total knee arthroplasty (TKA) remains the standard for advanced OA, yet up to 20% of patients experience chronic postsurgical pain (CPSP). Genicular nerve radiofrequency ablation (GNRFA) can alleviate pain in those unresponsive to conservative treatments or TKA.