Evolution of irreversible differentiation under stage-dependent cell differentiation.

The specialization of cells is a hallmark of complex multicellularity. Cell differentiation enables the emergence of specialized cell types that carry out separate functions previously executed by a multifunctional ancestor cell. One view about the origin of cell differentiation is that it first occurred randomly in genetically identical cells exposed to the same life history environment.

Tracking HIV persistence across T cell lineages during early ART-treated HIV-1-infection using a reservoir-marking humanized mouse model.

Human immunodeficiency virus (HIV) infection depletes CD4 T-cells, and long-term persistence of latent virus prevents full clearance of HIV even in the presence of effective antiretroviral therapy (ART), Here we present the HIV-1-induced lineage tracing (HILT) system, a model that irreversibly marks infected cells within a humanized mouse model, which detects rare latently infected cells. Immunodeficient mice transplanted with genetically modified hematopoietic stem cells develop a human immune system, in which CD4 T-cells contain a genetic switch that permanently labels cells infected by HIV-1 expressing cre-recombinase. Through single-cell RNA sequencing of HILT-marked cells during acute infection and post-ART treatment, we identify distinct CD4+ T-cell transcriptional lineages enriched in either active or latent infections.

Recent genetic drift in the co-diversified gut bacterial symbionts of laboratory mice.

Laboratory mice (Mus musculus domesticus) harbor gut bacterial strains that are distinct from those of wild mice but whose evolutionary histories are unclear. Here, we show that laboratory mice have retained gut bacterial lineages that diversified in parallel (co-diversified) with rodent species for > 25 million years, but that laboratory-mouse gut microbiota (LGM) strains of these ancestral symbionts have experienced accelerated accumulation of genetic load during the past ~ 120 years of captivity. Compared to closely related wild-mouse gut microbiota (WGM) strains, co-diversified LGM strains displayed significantly faster genome-wide rates of nonsynonymous substitutions, indicating elevated genetic drift-a difference that was absent in non-co-diversified symbiont clades.

Short-term outcomes of transcatheter aortic valve implantation in patients with concomitant mitral or tricuspid regurgitation.

Mitral regurgitation (MR) or tricuspid regurgitation (TR) is often an indicator of poor prognosis in patients with aortic stenosis (AS). Our study aims to compare transcatheter aortic valve implantation (TAVI) outcomes in patients with and without concomitant MR or isolated TR. Using the national readmission database (2016-2020), we identified patients with severe AS undergoing TAVI.

Early CABG with intraoperative hemoadsorption in patients on ticagrelor: Real world data from the international Safe and Timely Antithrombotic Removal (STAR) registry.

Objectives: Severe perioperative bleeding occurs in over 30 % of patients on ticagrelor undergoing isolated coronary artery bypass grafting (i-CABG) before completing the recommended 3-day washout. Intraoperative ticagrelor removal with a polymer bead hemoadsorption device is an approved therapy that may reduce perioperative bleeding.

Methods: The current analysis from the international Safe and Timely Antithrombotic Removal (STAR) registry reports outcomes with intraoperative hemoadsorption in patients on ticagrelor undergoing i-CABG before completing the recommended washout.

Advances in the Treatment of the Partially Edentulous Patient.

Advancements in digital technologies over the past decade have revolutionized dentistry, particularly with the integration of digital workflows in removable partial dentures (RPDs). Key innovations include digital data capture and computer-aided design and manufacturing, which enhance patient comfort, streamline workflows, and reduce treatment time and costs. Initially embraced by fixed restorations, these technologies are now transforming RPDs, previously reliant on analog methods.

Uses of ulipristal acetate beyond emergency contraception: a narrative review.

Objectives: Ulipristal acetate (UPA) is a selective progesterone receptor modulator and the most effective oral EC method available in the United States (US). The aim of this review is to identify and describe uses of UPA beyond EC and to further discuss the concerns regarding the possible off-target liver effects.

Study Design: We conducted a literature search in August 2024, using Embase, Medline (PubMed), and Cochrane, utilizing a combination of MeSH and keywords for UPA, excluding animal studies, and limiting to English language publications.

State Preemption Repeal: A Pathway to Broader Smoke-Free Indoor Air Policies in the U.S.

Introduction: Public health advocates have expressed concern about state preemption laws limiting local government's ability to regulate tobacco smoking. However, empirical evidence on these laws' impact is scarce. This study examines how repealing such laws impacts policies covering smoke-free indoor air.

Allogeneic Stem Cell Transplantation in Participants With Hematologic Malignancies Following Pembrolizumab Therapy.

Background: The safety and efficacy of allogeneic stem cell transplantation (allo-SCT) following anti-programmed cell death protein 1 (PD-1) therapy in participants with hematologic malignances is of high clinical interest.

Objective: To present outcomes in participants enrolled in 4 clinical trials who underwent allo-SCT within 2 years of their last dose of pembrolizumab therapy.

Study Design: This analysis included participants from the phase 1b KEYNOTE-013 study (n = 20), the phase 2 KEYNOTE-087 study (n = 31), the phase 2 KEYNOTE-170 study (n = 5), and the phase 3 KEYNOTE-204 study (n = 14).

Multiomics reveal key inflammatory drivers of severe obesity: IL4R, LILRA5, and OSM.

Polygenic severe obesity (body mass index [BMI] ≥40 kg/m) has increased, especially in Hispanic/Latino populations, yet we know little about the underlying mechanistic pathways. We analyzed whole-blood multiomics data to identify genes differentially regulated in severe obesity in Mexican Americans from the Cameron County Hispanic Cohort. Our RNA sequencing analysis identified 124 genes significantly differentially expressed between severe obesity cases (BMI ≥40 kg/m) and controls (BMI <25 kg/m); 33% replicated in an independent sample from the same population.

Cross-kingdom-mediated detection of intestinal protozoa through NLRP6.

Intestinal protists are detected by the host innate immune system through mechanisms that remain poorly understood. Here, we demonstrate that Tritrichomonas protozoa induce thickening of the colonic mucus in an NLRP6-, ASC-, and caspase-11-dependent manner, consistent with the activation of sentinel goblet cells. Mucus growth is recapitulated with cecal extracts from Tritrichomonas-infected mice but not purified protozoa, suggesting that NLRP6 may detect infection-induced microbial dysbiosis.

A cellular and molecular basis of leptin resistance.

Similar to most humans with obesity, diet-induced obese (DIO) mice have high leptin levels and fail to respond to the exogenous hormone, suggesting that their obesity is caused by leptin resistance, the pathogenesis of which is unknown. We found that leptin treatment reduced plasma levels of leucine and methionine, mTOR-activating ligands, leading us to hypothesize that chronic mTOR activation might reduce leptin signaling. Rapamycin, an mTOR inhibitor, reduced fat mass and increased leptin sensitivity in DIO mice but not in mice with defects in leptin signaling.

Laboratory validation of a simplified model for estimating equilibrium PFAS mass leaching from unsaturated soils.

Modelling per- and polyfluoroalkyl substance (PFAS) fate and transport in the vadose zone is inherently more complex than in the saturated zone due to the highly transient nature and the wetting phase saturation dependent hydraulic flux associated with the vadose zone. The chemical complexity of PFAS impart multiple partitioning processes which complicate the evaluation of PFAS transport in the vadose zone. To date, simplified screening models describing PFAS leaching have been developed to determine PFAS soil cleanup criteria in the vadose zone.

Guideline-directed medical therapies (GDMTs) for chronic kidney disease with type 2 diabetes (CKD + T2D): Translation of lessons learned from the management of heart failure.

Although guideline-directed medical therapy (GDMT) is an evidence-based, proven approach to manage chronic kidney disease and type 2 diabetes (CKD + T2DM), adherence is low and multifactorial. Opportunities exist to improve care delivery, thus delaying disease progression, avoiding unnecessary costs, and potentially improving quality of life for patients both diagnosed and yet to be diagnosed.

Discovery of mutations predictive of survival benefit from immunotherapy in first-line NSCLC: A retrospective machine learning study of IMpower150 liquid biopsy data.

Predictive biomarker identification in cancer treatment has traditionally relied on pre-defined analyses, limiting discoveries to expected biomarkers and potentially overlooking novel ones predictive of therapy response. In this work, we develop a novel machine-learning approach capable of exploring full landscape of mutations and combinations and identify potentially new predictive biomarkers for chemoimmunotherapy. Utilizing the liquid biopsy dataset from 313 non-small cell lung cancer (NSCLC) patients in the Phase 3 Impower150 trial (NCT02366143), we developed the HRdiffRF algorithm with a novel hazard ratio-splitting criterion.

Pembrolizumab Plus Docetaxel Versus Docetaxel for Previously Treated Metastatic Castration-Resistant Prostate Cancer: The Randomized, Double-Blind, Phase III KEYNOTE-921 Trial.

Purpose: The standard of care for metastatic castration-resistant prostate cancer (mCRPC) after second-generation androgen receptor pathway inhibitor (ARPI) therapy is still docetaxel. The randomized, double-blind, phase III KEYNOTE-921 trial (Clinicaltrials.gov identifier: NCT03834506) evaluated the efficacy and safety of pembrolizumab or placebo plus docetaxel for previously treated mCRPC.

Culturally Adapting an Occupational Therapy Intervention for Black American Autistic Communities.

Importance: Ayres Sensory Integration® is an evidence-based intervention for autistic children, but there is no culturally responsive adaptation to support Black American autistic children and their families.

Objective: To culturally adapt an occupational therapy intervention for Black American families.

Design: Qualitative study involving focus groups and interviews, using researcher triangulation and member-checking surveys for the trustworthiness of findings.

The role of non-operative management for high-grade renal injuries.

Purpose: This study aimed to investigate the long-term outcomes of non-operative, operative, and minimally invasive surgery management of high-grade renal injuries (Grades III-V) in an underserved population at a high-volume trauma center.

Methods: We conducted a retrospective chart review of 93 patients who sustained high-grade renal trauma and presented to University Hospital, a Level 1 trauma center, between 2017 and 2022. The patients were categorized by initial management strategy: non-operative, operative, or minimally invasive surgery (endoscopic urologic and interventional radiologic procedures).

Shared decision making in routine oncology appointments with Black patients with lung cancer.

Purpose: Poor clinician-patient communication may contribute to racialized inequities in cancer symptom burden. Shared decision-making (SDM) enhances clinician-patient communication, and could contribute to health equity for Black patients with cancer. However, research on SDM is limited for Black patients with cancer.

Scaling new heights: a prospective survey of rock climbing's impact on mental health.

Background: Sport climbing, officially added to the 2020 Summer Olympics, has grown rapidly, with U.S. climbing gyms increasing from 310 in 2013 to 591 in 2021.

The Intersectional Influence of Experienced Stigma on Clinically Significant Depressive Symptoms Among Gay, Bisexual, and Other Men Who Have Sex with Men.

We sought to determine how intersectional stigma, operationalized by interactions of perceived stigma experiences in adulthood attributed to various social identities/characteristics (age, gender, race, ethnicity/nationality, religion, height/weight, other aspect of appearance [unrelated to the identities/characteristics listed-e.g. height/weight/race/gender], physical disability, sexual orientation, and HIV status), associates with clinically significant depressive symptoms (DS).

Predicting Postprandial Glycemic Responses With Limited Data in Type 1 and Type 2 Diabetes.

Background: A core challenge in managing diabetes is predicting glycemic responses to meals. Prior work identified significant interindividual variation in responses and developed personalized forecasts. However, intraindividual variation is still not well understood, and the most accurate approaches require invasive microbiome data.