The landscape of family medicine in India - A cross-sectional survey study.

Family medicine was recognized as a distinct specialty in India in the early 1980s, but it is at an early stage of implementation. There are few training programs, and little is known about family physicians' training, perceptions, and current practices. This paper describes the findings from the first national survey of family medicine in India.

Comparative Improvement in Health-Related Quality of Life with Advanced Therapies for Moderate-to-Severe Crohn's Disease: A Network Meta-Analysis.

Background And Aims: The comparative efficacy of advanced therapies to improve health-related quality of life (HR-QoL) in Crohn's disease (CD) is unknown. We aimed to compare the impact of approved advanced therapies for moderate-to-severe CD on HR-QoL.

Methods: We searched MEDLINE, Embase, and Cochrane CENTRAL from inception to December 2023.

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.

The role of circular RNAs in autoimmune diseases: Potential diagnostic biomarkers and therapeutic targets.

With the emergence of high-quality sequencing technologies, further research on transcriptomes has become possible. Circular RNA (circRNA), a novel type of endogenous RNA molecule with a covalently closed circular structure through "back-splicing," is reported to be widely present in eukaryotic cells and participates mainly in regulating gene and protein expression in various ways. It is becoming a research hotspot in the non-coding RNA field.

The BLM-TOP3A-RMI1-RMI2 proximity map reveals that RAD54L2 suppresses sister chromatid exchanges.

Homologous recombination is a largely error-free DNA repair mechanism conserved across all domains of life and is essential for the maintenance of genome integrity. Not only are the mutations in homologous recombination repair genes probable cancer drivers, some also cause genetic disorders. In particular, mutations in the Bloom (BLM) helicase cause Bloom Syndrome, a rare autosomal recessive disorder characterized by increased sister chromatid exchanges and predisposition to a variety of cancers.

HERC1 E3 Ubiquitin Ligase Is Necessary for Autophagy Processes and for the Maintenance and Homeostasis of Vesicles in Motor Nerve Terminals, but Not for Proteasomal Activity.

The ubiquitin proteasome system (UPS) is implicated in protein homeostasis. One of the proteins involved in this system is HERC1 E3 ubiquitin ligase, which was associated with several processes including the normal development and neurotransmission at the neuromuscular junction (NMJ), autophagy in projection neurons, myelination of the peripheral nervous system, among others. The tambaleante (tbl) mouse model carries the spontaneous mutation Gly483Glu substitution in the HERC1 E3 protein.

TRIM28-dependent developmental heterogeneity determines cancer susceptibility through distinct epigenetic states.

Mutations in cancer risk genes increase susceptibility, but not all carriers develop cancer. Indeed, while DNA mutations are necessary drivers of cancer, only a small subset of mutated cells go on to cause the disease. To date, the mechanisms underlying individual cancer susceptibility remain unclear.

Placental Hypoxia-Induced Ferroptosis Drives Vascular Damage in Preeclampsia.

Background: Iron is an essential micronutrient for cell survival and growth; however, excess of this metal drives ferroptosis. Although maternal iron imbalance and placental hypoxia are independent contributors to the pathogenesis of preeclampsia, a hypertensive disorder of pregnancy, the mechanisms by which their interaction impinge on maternal and placental health remain elusive.

Methods: We used placentae from normotensive and preeclampsia pregnancy cohorts, human H9 embryonic stem cells differentiated into cytotrophoblast-like cells, and placenta-specific preeclamptic mice.

The association between pain, analgesia, and delirium among critically ill adults: a systematic review and meta-analysis.

Purpose: We performed a systematic review with meta-analysis examining the relationship between pain or pain medications and delirium occurence, duration, and severity.

Methods: We searched MEDLINE, EMBASE, CINAHL and the Cochrane Central Register of Controlled Trials from inception to May 15, 2023. We included randomised or observational studies among critically ill adults, that reported data on pain or exposure to analgesics, and reported delirium presence, duration, or severity with no language or region restrictions.

Systematic ocular phenotyping of 8,707 knockout mouse lines identifies genes associated with abnormal corneal phenotypes.

Purpose: Corneal dysmorphologies (CDs) are typically classified as either regressive degenerative corneal dystrophies (CDtrs) or defective growth and differentiation-driven corneal dysplasias (CDyps). Both eye disorders have multifactorial etiologies. While previous work has elucidated many aspects of CDs, such as presenting symptoms, epidemiology, and pathophysiology, the genetic mechanisms remain incompletely understood.

Low-dose aspirin versus placebo in postpartum venous thromboembolism: a multi-national, pilot, randomised, placebo-controlled trial.

Background: Despite the morbidity and mortality of venous thromboembolism, there is little evidence to guide postpartum thromboprophylaxis in patients at moderate risk. We aimed to assess the feasibility of conducting a double-blind, randomised trial of aspirin versus placebo in postpartum individuals with two or more venous thromboembolism risk factors, mild-to-moderate thrombophilia, or both.

Methods: The pilot PARTUM trial, a multi-national, randomised, double-blind, placebo-controlled trial, was conducted in seven centres across Canada, France, Ireland, and the Netherlands.

Claudin 18.2 Expression in 1,404 Digestive Tract Adenocarcinomas including 1,175 Colorectal Carcinomas: Distinct Colorectal Carcinoma Subtypes are Claudin 18.2 Positive.

Claudin 18.2 (CLDN18.2) immunohistochemical expression can be used to select patients with gastric/gastroesophageal junction adenocarcinomas for zolbetuximab (IMAB362) therapy, a monoclonal antibody targeting CLDN18.

Substrate stiffness dictates unique doxorubicin-induced senescence-associated secretory phenotypes and transcriptomic signatures in human pulmonary fibroblasts.

Cells are subjected to dynamic mechanical environments which impart forces and induce cellular responses. In age-related conditions like pulmonary fibrosis, there is both an increase in tissue stiffness and an accumulation of senescent cells. While senescent cells produce a senescence-associated secretory phenotype (SASP), the impact of physical stimuli on both cellular senescence and the SASP is not well understood.

Endocrinologists' Acceptability and Implementation of Hemoglobin A1c Targets among Adults with Type 1 Diabetes.

Aims: Attainment of the A1C target of ≤7.0% is consistently low among those living with type 1 diabetes (T1D). We evaluated endocrinologists' acceptability and implementation of A1C targets.

Longitudinal association of statin treatment with insulin sensitivity and beta-cell function in the PROMISE cohort.

Context: Statin treatment lowers low-density lipoprotein (LDL) cholesterol thereby reducing cardiovascular risk. Meta-analyses of clinical trials report a higher risk of new-onset type 2 diabetes with statins. Current clinical evidence regarding effects of statins on insulin sensitivity and beta-cell function is limited.

What does cancer screening have to do with tomato growing?

Cancer screening is considered to be a major strategy for combatting cancer. The United States Preventive Services Task Force (USPSTF) recommends screening for five cancers, but the strength of evidence about the effectiveness of screening is limited. To gain insights into the efficacy of early detection requires prospective, blinded, placebo-controlled clinical trials with decades of follow-up and inclusion of millions of participants.

LINE1 elements at distal junctions of rDNA repeats regulate nucleolar organization in human embryonic stem cells.

The nucleolus is a major subnuclear compartment where ribosomal DNA (rDNA) is transcribed and ribosomes are assembled. In addition, recent studies have shown that the nucleolus is a dynamic organizer of chromatin architecture that modulates developmental gene expression. rDNA gene units are assembled into arrays located in the p-arms of five human acrocentric chromosomes.

Adenomas from individuals with pathogenic biallelic variants in the MUTYH and NTHL1 genes demonstrate base excision repair tumour mutational signature profiles similar to colorectal cancers, expanding potential diagnostic and variant classification applications.

Background: Colorectal cancers (CRCs) from people with biallelic germline likely pathogenic/pathogenic variants in MUTYH or NTHL1 exhibit specific single base substitution (SBS) mutational signatures, namely combined SBS18 and SBS36 (SBS18+SBS36), and SBS30, respectively. The aim was to determine if adenomas from biallelic cases demonstrated these mutational signatures at diagnostic levels.

Methods: Whole-exome sequencing of FFPE tissue and matched blood-derived DNA was performed on 9 adenomas and 15 CRCs from 13 biallelic MUTYH cases, on 7 adenomas and 2 CRCs from 5 biallelic NTHL1 cases and on 27 adenomas and 26 CRCs from 46 non-hereditary (sporadic) participants.

Small Extracellular Vesicles Promote Axon Outgrowth by Engaging the Wnt-Planar Cell Polarity Pathway.

In neurons, the acquisition of a polarized morphology is achieved upon the outgrowth of a single axon from one of several neurites. Small extracellular vesicles (sEVs), such as exosomes, from diverse sources are known to promote neurite outgrowth and thus may have therapeutic potential. However, the effect of fibroblast-derived exosomes on axon elongation in neurons of the central nervous system under growth-permissive conditions remains unclear.

The canine blood-brain barrier in health and disease: focus on brain protection.

This review examines the role of the canine blood-brain barrier (BBB) in health and disease, focusing on the impact of the multidrug resistance (MDR) transporter P-glycoprotein (P-gp) encoded by the gene. The BBB is critical in maintaining central nervous system homeostasis and brain protection against xenobiotics and environmental drugs that may be circulating in the blood stream. We revise key anatomical, histological and functional aspects of the canine BBB and examine the role of the gene mutation in specific dog breeds that exhibit reduced P-gp activity and disrupted drug brain pharmacokinetics.

A bivalent COVID-19 mRNA vaccine elicited broad immune responses and protection against Omicron subvariants infection.

Continuously emerging SARS-CoV-2 Omicron subvariants pose a threat thwarting the effectiveness of approved COVID-19 vaccines. Especially, the protection breadth and degree of these vaccines against antigenically distant Omicron subvariants is unclear. Here, we report the immunogenicity and efficacy of a bivalent mRNA vaccine, PTX-COVID19-M1.

Switching Drivers: Epigenetic Rewiring to Genetic Progression in Glioma.

IDH-mutant low-grade gliomas (LGGs) are slow-growing brain tumors that frequently progress to aggressive high-grade gliomas that have dismal outcomes. In a recent study, Wu and colleagues provide critical insights into the mechanisms underlying malignant progression by analyzing single-cell gene expression and chromatin accessibility across different tumor grades. Their findings support a two-phase model: in early stages, tumors are primarily driven by oligodendrocyte precursor-like cells and epigenetic alterations that silence tumor suppressors like CDKN2A and activate oncogenes such as PDGFRA.

Breast Cancer Susceptibility Gene Sequence Variations and Development of Contralateral Breast Cancer.

Importance: Heterogeneity in development of estrogen receptor (ER)-specific first primary breast cancer exists due to deleterious germline variants in moderate- to high-penetrance breast cancer susceptibility genes, but it is unknown if these associations occur in ER-specific CBC.

Objective: To determine the association of deleterious germline variants in breast cancer susceptibility genes with ER-specific CBC development and whether ER status of the first primary breast cancer modifies these associations.

Design, Setting, And Participants: This case-control study included CBC cases and matched unilateral breast cancer controls from The Women's Environment, Cancer, and Radiation Epidemiology (WECARE) Study, a population-based case-control study.