Combination of radiotherapy and PD-L1 blockade induces abscopal responses in EGFR-mutated lung cancer through activating CD8+ T cells.

Patients with EGFR-mutated non-small cell lung cancer (NSCLC) respond poorly to immune checkpoint inhibitors (ICIs). It has been reported that the number of CD8+T cells is reduced in EGFR-mutated NSCLC. However, the extent of heterogeneity and effector function of distinct populations of CD8+T cells has not been investigated intensively. In addition, studies investigating whether a combination of radiotherapy and ICIs can improve the efficacy of ICIs in EGFR-mutated lung cancer are lacking. Single-cell RNA sequencing (scRNA-seq) was used to investigate the heterogeneity of CD8+T cell populations in EGFR-mutated NSCLC. The STING pathway was explored after hypofractionated radiation of EGFR-mutated and wild-type cells. Mice bearing LLC-19del and LLC-EGFR tumors were treated with radiotherapy plus anti-PD-L1. The scRNA-seq data showed the percentage of progenitor exhausted CD8+T cells was lower in EGFR-mutated NSCLC. In addition, CD8+T cells in EGFR-mutated NSCLC were enriched in oxidative phosphorylation. In EGFR-mutated and wild-type cells, 8 Gy × 3 increased the expression of chemokines that recruit T cells and activate the cGAS-STING pathway. In the LLC-19del and LLC-EGFR mouse model, the combination of radiation and anti-PD-L1 significantly inhibited the growth of abscopal tumors. The enhanced abscopal effect was associated with systemic CD8+T cell infiltration. This study provided an intensive understanding of the heterogeneity and effector functions of CD8+T cells in EGFR-mutated NSCLC. We showed that the combination of hypofractionated radiation and anti-PD-L1 significantly enhanced the abscopal responses in both EGFR-mutated and wild-type lung cancer by activating CD8+T cells in mice.

The role of immune metabolism in skin cancers: implications for pathogenesis and therapy.

The skin is a complex organ that serves as a critical barrier against external pathogens and environmental impact. Recent advances in immunometabolism have highlighted the intricate link between cellular metabolism and immune function, particularly in the context of skin cancers. This review aims to provide a comprehensive overview of the key metabolic pathways and adaptations that occur in immune cells during homeostasis and activation, and explore how metabolic reprogramming contributes to the pathogenesis of specific skin cancers. We discuss the complex interplay between tumor cells and infiltrating immune cells, which shapes the tumor microenvironment and influences disease outcomes. The review delves into the role of various metabolic pathways, such as glycolysis, oxidative phosphorylation, and lipid metabolism, in the regulation of immune cell function and their impact on the development and progression of skin cancers. Furthermore, we examine the potential of targeting metabolic pathways as a therapeutic strategy in skin cancers and discuss the challenges and future perspectives in this rapidly evolving field. By understanding the metabolic basis of skin immune responses, we can develop novel, personalized therapies for the treatment of skin cancers, ultimately improving patient outcomes and quality of life. The insights gained from this review will contribute to the growing body of knowledge in immunometabolism and its application in the management of skin cancers, paving the way for more effective and targeted interventions in the future.

Facile synthesis of hierarchical core-shell carbon@ZnIn2S4 composite for boosted photothermal-assisted photocatalytic H2 production.

Against the backdrop of energy shortage, hydrogen energy has attracted much attention as a green and clean energy source. In order to explore efficient hydrogen production pathways, we designed a composite photocatalyst with carbon-based core-shell photothermal-assisted photocatalytic system (Carbon@ZnIn2S4, denoted as C@ZIS). The well-designed catalyst C@ZIS composites demonstrated a photocatalytic hydrogen precipitation rate of 2.97 mmol g-1 h-1 even in the absence of the noble metal Pt co-catalyst. The incorporation of carbon-based core-shell photocatalysts into a photocatalytic reaction significantly affects the activity of the reaction by triggering a photothermal effect in the reaction solution. The results of the physicochemical experiments demonstrated that the carbon spheres in C@ZIS composite system could provide a greater number of active sites, thereby accelerating the electron transfer and separation efficiency, and thus enhancing the photocatalytic activity. The study presents an efficacious design concept for the development of efficacious carbon-based core-shell photothermal-assisted photocatalysts, which is anticipated to facilitate the efficient conversion of solar energy to hydrogen energy.

Artificial intelligence prediction of In-Hospital mortality in patients with dementia: A multi-center study.

BACKGROUND: Prediction of mortality is very important for care planning in hospitalized patients with dementia and artificial intelligence has the potential to serve as a solution; however, this issue remains unclear. Thus, this study was conducted to elucidate this matter. METHODS: We identified 10,573 hospitalized patients aged ≥ 45 years with dementia from three hospitals between 2010 and 2020 for this study. Utilizing 44 feature variables extracted from electronic medical records, an artificial intelligence (AI) model was constructed to predict death during hospitalization. The data was randomly separated into 70 % training set and 30 % testing set. We compared predictive accuracy among six algorithms including logistic regression, random forest, extreme gradient boosting (XGBoost), Light Gradient Boosting Machine (LightGBM), multilayer perceptron (MLP), and support vector machine (SVM). Additionally, another set of data collected in 2021 was used as the validation set to assess the performance of six algorithms. RESULTS: The average age was 79.8 years, with females constituting 54.5 % of the sample. The in-hospital mortality rate was 6.7 %. LightGBM exhibited the highest area under the curve (0.991) for predicting mortality compared to other algorithms (XGBoost: 0.987, random forest: 0.985, logistic regression: 0.918, MLP: 0.898, SVM: 0.897). The accuracy, sensitivity, positive predictive value, and negative predictive value of LightGBM were 0.943, 0.944, 0.943, 0.542, and 0.996, respectively. Among the features in LightGBM, the three most important variables were the Glasgow Coma Scale, respiratory rate, and blood urea nitrogen. In the validation set, the area under the curve of LightGBM reached 0.753. CONCLUSIONS: The AI prediction model demonstrates strong accuracy in predicting in-hospital mortality among patients with dementia, suggesting its potential implementation to enhance future care quality.

Encapsulating CoNi nanoparticles into nitrogen-doped carbon nanotube arrays as bifunctional oxygen electrocatalyst for rechargeable zinc-air batteries.

The high theoretical specific energy and environmental friendliness of zinc-air batteries (ZABs) have garnered significant attention. However, the practical application of ZABs requires overcoming the sluggish kinetics associated with oxygen reduction reaction (ORR) and oxygen evolution reaction (OER). Herein, 3D self-supported nitrogen-doped carbon nanotubes (N-CNTs) arrays encapsulated by CoNi nanoparticles on carbon fiber cloth (CoNi@N-CNTs/CFC) are synthesized as bifunctional catalysts for OER and ORR. The 3D interconnected N-CNTs arrays not only improve the electrical conductivity, the permeation and gas escape capabilities of the electrode, but also enhance the corrosion resistance of CoNi metals. DFT calculations reveal that the co-existence of Co and Ni synergistically reduces the energy barrier for OOH conversion to OH, thereby optimizing the Gibbs free energy of the catalysts. Additionally, analysis of the change in energy barrier during the rate-determining step suggests that the primary catalytic active center is Ni site for OER. As a result, CoNi@N-CNTs/CFC exhibits superior catalytic activity with an overpotential of 240 mV at 10 mA cm-2 toward OER, and the onset potential of 0.92 V for ORR. Moreover, utilization of CoNi@N-CNTs/CFC in liquid and solid-state ZABs exhibited exceptional stability, manifesting a consistent cycling operation lasting for 100 and 15 h, respectively.

Fate of emerging antibiotics in soil-plant systems: A case on fluoroquinolones.

Fluoroquinolones (FQs), a class of broad-spectrum antibiotics widely used to treat human and animal diseases globally, have limited adsorption and are often excreted unchanged or as metabolites. These compounds enter the soil environment through feces, urban wastewater, or discharge of biological solids. The fluorine atoms in FQs impart high electronegativity, chemical stability, and resistance to microbial degradation, allowing them to potentially enter food chains. The persistence of FQs in soils raises questions about their impacts on plant growth, an aspect not yet conclusively determined. We reviewed whether, like other organic compounds, FQs are actively absorbed by plants, resulting in bioaccumulation and posing threats to human health. The influx of FQs has led to antibiotic resistance in soil microbes by exerting selective pressure and contributing to multidrug-resistant bacteria. Therefore, the environmental risks of FQs warrant further attention. This work provides a comprehensive review of the fate and behavior of FQs at the plant-environment interface, their migration and transport from the environment into plants, and associated toxicity. Current limitations in research are discussed and prospects for future investigations outlined. Thus, understanding antibiotic behavior in plants and translocation within tissues is not only crucial for ecosystem health (plant health), but also assessing potential human health risks. In addition, it can offer insights into the fate of emerging soil pollutants in plant-soil systems.

Ventricular arrhythmias originating from different portions of the communicating vein of the left ventricular summit: electrocardiographic characteristics and catheter ablation.

BACKGROUND: Idiopathic ventricular arrhythmias (IVAs) arising from different portions of the communicating vein of the left ventricular summit (summit-CV) are not a rare phenomenon. Whereas its electrocardiographic (ECG) and electrophysiological characteristics are not fully investigated. OBJECTIVE: This study aimed to identify distinct ECG and electrophysiological features of IVAs originating from different portions of summit-CV. METHODS: Nineteen patients confirmed arising from summit-CV were included in this study. RESULTS: The 19 patients were divided into proximal and distal portion groups based on their target sites in summit-CV. In the proximal portion group, 100% (11/11) VAs showed dominant negative (rs or QS) waves in lead I, while in the distal portion group, 87.5% (7/8) showed dominant positive waves (R, Rs or r) (p < 0.000). In lead V1, 100% (11/11) of the proximal portion group showed dominant positive waves (R or Rs), while 62.50% (5/8) of the distal portion group showed positive and negative bidirectional or negative waves (RS or rS) (p < 0.005). RI>4mV, SI<3.5mV, RV1<13mV, SV1>3.5mV, RI/SI>0.83, and RV1/SV1< 2.6 indicated a distal portion of summit-CV with the predictive value of 0.909, 1.000, 0.653, 0.972, 0.903, 0.966, respectively. A more positive wave in lead I and a more negative wave in lead V1 indicated more distal origin in summit-CV. Target sites in proximal and distal summit-CV groups showed similar electrophysiological characteristics during mapping. CONCLUSIONS: There were significant differences in ECG characteristics of VAs at different portions of summit-CV, which could aid pre-procedure planning and facilitate radiofrequency catheter ablation (RFCA) procedures.

Wedging crystals to fabricate crystalline framework nanosheets via mechanochemistry.

Mechanochemistry studies the effect of mechanical force on chemical bonds, bringing opportunities for synthesizing alloys, ceramics, organics, polymers, and biomaterials. A vital issue of applying macro-scale mechanical force to manipulate crystal structures is finding ways to precisely adjust the force directions to break micro-scale target chemical bonds. Inspired by a common technique of driving a wedge into the wood to make wood chopping much easier, a wedging strategy of splitting three-dimensional structured crystalline frameworks and then converting them to nanosheets was proposed, where specific molecules were wedged into crystalline frameworks to drive the directional transmission of mechanical force to break chemical bonds. As a result, various crystalline framework nanosheets including metal-organic framework nanosheets, covalent organic framework nanosheets, and coordination polymer nanosheets were fabricated. This wedging crystal strategy exhibits advantages of operability, flexibility and designability, and furthermore, it is expected to expand mechanochemistry applications in material preparation.

Epigenomic features associated with body temperature stabilize tissues during cold exposure in cold-resistant pigs.

Cold stress in low-temperature environments can trigger changes in gene expression, but epigenomics regulation of temperature stability in vital tissues, including the fat and diencephalon, is still unclear. Here, we explore the cold-induced changes in epigenomic features in the diencephalon and fat tissues of two cold-resistant Chinese pig breeds, Min and Enshi black (ES) pigs, utilizing H3K27ac CUT&Tag, RNA-seq, and selective signature analysis. Our results show significant alterations in H3K27ac modifications in the diencephalon of Min pigs and the fat of ES pigs after cold exposure. Dramatic changes in H3K27ac modifications in the diencephalon of Min pig are primarily associated with genes involved in energy metabolism and hormone regulation, whereas those in the fat of ES pig are primarily associated with immunity-related genes. Moreover, transcription factors PRDM1 and HSF1, which show evidence of selection, are enriched in genomic regions presenting cold-responsive alterations in H3K27ac modification in the Min pig diencephalon and ES pig fat, respectively. Our results indicate the diversity of epigenomic response mechanisms to cold exposure between Min and ES pigs, providing unique epigenetic resources for studies of low-temperature adaptation in large mammals.

Joint effect of atrial fibrillation and obesity on mortality in critically ill patients.

BACKGROUND: The interplay between atrial fibrillation (AF) and obesity on mortality in critically ill patients warrants detailed exploration, given their individual impacts on patient prognosis. This study aimed to assess the associations between AF, obesity, and 1-year mortality in a critically ill population. METHODS: Utilizing data from the Medical Information Mart for Intensive Care (MIMIC)-IV database, we conducted a retrospective analysis of adult patients admitted to the intensive care unit. The primary endpoint was 1-year mortality, analyzed through Cox regression with hazard ratio (HR) and Kaplan-Meier survival methods. RESULTS: The study included 25,654 patients (median age 67.0 years, 40.6% female), with 39.0% having AF and 36.1% being obese. Multivariate COX regression analysis revealed that AF was associated with a 14.7% increase in the risk of 1-year mortality (p < 0.001), while obesity was linked to a 13.9% reduction in mortality risk (p < 0.001). The protective effect of obesity on mortality was similar in patients with (HR = 0.85) and without AF (HR = 0.86). AF led to a slightly higher risk of mortality in patients without obesity (HR = 1.16) compared to those with obesity (HR = 1.13). Kaplan-Meier survival curves highlighted that non-obese patients with AF had the lowest survival rate, whereas the highest survival was observed in obese patients without AF. CONCLUSIONS: AF significantly increased 1-year mortality risk in critically ill patients, whereas obesity was associated with a decreased mortality risk. The most adverse survival outcomes were identified in non-obese patients with AF.

Clinical and pathological characteristics of OPDM4 patients in advanced disease.

INTRODUCTION/AIMS: Oculopharyngodistal myopathy type 4 (OPDM4) arises from a CGG repeat expansion in the 5' UTR of the RILPL1 gene. Reported cases of OPDM4 have been limited. The aim of this study was to investigate the clinical and myopathological characteristics of OPDM4 patients with advanced disease. METHODS: We assessed a total of 8 affected and 12 unaffected individuals in an OPDM4 family with autosomal dominant inheritance. Muscle biopsy tissue from the proband underwent histological, enzyme histochemical, and immunohistochemical stains, and electron microscopy analysis. Whole exome sequencing and repeat primer PCR (RP-PCR) were conducted to investigate underlying variants. RESULTS: OPDM4 patients displayed a progressive disease course. Most experienced lower limb weakness and diminished walking ability in their 20s and 30s, followed by ptosis, ophthalmoplegia, swallowing difficulties, and dysarthria in their 30s to 50s, By their 50s to 70s, they became non-ambulatory. Muscle magnetic resonance imaging (MRI) of the proband in advanced disease revealed severe fatty infiltration of pelvic girdle and lower limb muscles. Biopsied muscle tissue exhibited advanced changes typified by adipose connective tissue replacement and the presence of multiple eosinophilic and p62-positive intranuclear inclusions. Immunopositivity for the intranuclear inclusions was observed with anti-glycine antibody and laboratory-made polyA-R1 antibody. RP-PCR unveiled an abnormal CGG repeat expansion in the 5' UTR of the RILPL1 gene. DISCUSSION: The clinical and radiological features in this family broaden the phenotypic spectrum of OPDM4. The presence of intranuclear inclusions in the proliferative adipose connective tissues of muscle biopsy specimens holds diagnostic significance for OPDM4 in advanced disease.

A phase 1, randomized, double-blind, placebo-controlled, dose escalation study to evaluate the safety, tolerability, pharmacokinetics and immunogenicity of SHR-1905, a long-acting anti-thymic stromal lymphopoietin antibody, in healthy subjects.

Introduction: Thymic stromal lymphopoietin (TSLP) is integral to inducing innate and T helper two cell inflammation that leads to clinical symptoms of asthma. SHR-1905 is a humanized immunoglobulin G1 kappa monoclonal antibody that inhibits TSLP bioactivity, developed for the treatment of severe uncontrolled asthma. This phase 1, randomized, double-blind, placebo-controlled single ascending dose study assessed the safety, tolerability, pharmacokinetics (PK), and immunogenicity of subcutaneous SHR-1905 in healthy subjects. Methods: Five dose cohorts were planned (50, 100, 200, 400, and 600 mg) and subjects were randomized (8:2) in each cohort to receive SHR-1905 or placebo with a follow-up period up to Day 253. Results: The majority of treatment-emergent adverse events (TEAEs) were mild and the incidence of TEAEs was comparable between the SHR-1905 and the placebo groups. The maximum serum concentration was reached 7.0-17.6 days after injection. The serum concentration of SHR-1905 increased with increasing dose level, and SHR-1905 exposure exhibited in a slightly greater-than-dose-proportional manner from 50 to 600 mg. SHR-1905 had a prolonged serum half-life around 80 days supporting every 6-month dosing. In SHR-1905 treated subjects, 15% tested positive for anti-drug antibodies post-dose with no apparent effect on corresponding PK profiles or safety. Conclusion: SHR-1905 demonstrated a good safety and tolerability profile with a long half-life in healthy subjects after a single administration in the dose range of 50-600 mg. Clinical Trial Registration: clinicaltrials.gov, identifier NCT04800263.

Transforming Cell-Drug Interaction through Granular Hydrogel-Mediated Delivery of Polyplex Nanoparticles for Enhanced Safety and Extended Efficacy in Gene Therapy.

The utilization of hydrogels for DNA/cationic polymer polyplex nanoparticle (polyplex) delivery has significantly advanced gene therapy in tissue regeneration and cancer treatment. However, persistent challenges related to the efficacy and safety of encapsulated polyplexes, stemming from issues such as aggregation, degradation, or difficulties in controlled release during or postintegration with hydrogel scaffolds, necessitate further exploration. Here, we introduce an injectable gene therapy gel achieved by incorporating concentrated polyplexes onto densely packed hydrogel microparticles (HMPs). Polyplexes, when uniformly adhered to the gene therapy gel through reversible electrostatic interactions, can detach from the HMP surface in a controlled manner, contrasting with free polyplexes, and thereby reducing dose-dependent toxicity during transfection. Additionally, the integration of RGD cell adhesion peptides enhances the scaffolding characteristics of the gel, facilitating cell adhesion, migration, and further minimizing toxicity during gene drug administration. Notably, despite the overall transfection efficiency showing average performance, utilizing confocal microscopy to meticulously observe and analyze the cellular states infiltrating into various depths of the gene therapy gel resulted in the groundbreaking discovery of significantly enhanced local transfection efficiency, with primary cell transfection approaching 80%. This phenomenon could be potentially attributed to the granular hydrogel-mediated delivery of polyplex nanoparticles, which revolutionizes the spatial and temporal distribution and thus the "encounter" mode between polyplexes and cells. Moreover, the gene therapy gel's intrinsic injectability and self-healing properties offer ease of administration, making it a highly promising candidate as a novel gene transfection gel dressing with significant potential across various fields, including regenerative medicine and innovative living materials.

In chronic spontaneous urticaria, increased Galectin-9 expression on basophils and eosinophils is linked to high disease activity, endotype-specific markers, and response to omalizumab treatment.

BACKGROUND: Galectin-9 (Gal-9) has been implicated in allergic and autoimmune diseases, but its role and relevance in chronic spontaneous urticaria (CSU) are unclear. OBJECTIVES: To characterize the role and relevance of Gal-9 in the pathogenesis of CSU. METHODS: We assessed 60 CSU patients for their expression of Gal-9 on circulating eosinophils and basophils as well as T cell expression of the Gal-9 receptor TIM-3, compared them with 26 healthy controls (HCs), and explored possible links with disease features including disease activity (urticaria activity score, UAS), total IgE, basophil activation test (BAT), and response to omalizumab treatment. We also investigated potential drivers of Gal-9 expression by eosinophils and basophils. RESULTS: Our CSU patients had markedly increased rates of circulating Gal-9+ eosinophils and basophils and high numbers of lesional Gal-9+ cells. High rates of blood Gal-9+ eosinophils/basophils were linked to high disease activity, IgE levels, and BAT negativity. Serum levels of TNF-α were positively correlated with circulating Gal-9+ eosinophils/basophils, and TNF-α markedly upregulated Gal-9 on eosinophils. CSU patients who responded to omalizumab treatment had more Gal-9+ eosinophils/basophils than non-responders, and omalizumab reduced blood levels of Gal-9+ eosinophils/basophils in responders. Gal-9+ eosinophils/basophils were negatively correlated with TIM-3+TH17 cells. CONCLUSION: Our findings demonstrate a previously unrecognized involvement of the Gal-9/TIM-3 pathway in the pathogenesis CSU and call for studies that explore its relevance.

PD-L2 mediates tobacco smoking-induced recruitment of regulatory T cells via the RGMB/NFκB/CCL20 cascade.

Programmed cell death ligand 2 (PD-L2), a ligand for the receptor programmed cell death 1 (PD-1), has an identity of 34% with its twin ligand PD-L1 and exhibits higher binding affinity with PD-1 than PD-L1. However, the role of PD-L2 in non-small cell lung cancer (NSCLC) progression, especially tobacco-induced cancer progression, has not been fully understood. Here, we found that PD-L2 promoted tumor growth in murine models with recruitment of regulatory T cells (Tregs). In patients with NSCLC, PD-L2 expression level in tumor samples was higher than in counterpart normal controls and was positively associated with patients' response to anti-PD-1 treatment. Mechanismly, PD-L2 bound its receptor Repulsive guidance molecule B (RGMB) on cancer cells and activated extracellular signal-regulated kinase (Erk) and nuclear factor κB (NFκB), leading to increased production of chemokine CCL20, which recruited Tregs and contributed to NSCLC progression. Consistently, knockdown of RGMB or NFκB p65 inhibited PD-L2-induced CCL20 production, and silencing of PD-L2 repressed Treg recruitment by NSCLC cells. Furthermore, cigarette smoke and carcinogen benzo(a)pyrene (BaP) upregulated PD-L2 in lung epithelial cells via aryl hydrocarbon receptor (AhR)-mediated transcription activation, whose deficiency markedly suppressed BaP-induced PD-L2 upregulation. These results suggest that PD-L2 mediates tobacco-induced recruitment of Tregs via the RGMB/NFκB/CCL20 cascade, and targeting this pathway might have therapeutic potentials in NSCLC.

Exploring the Efficacy of Group Music and Game Therapy on the Well-Being of Institutionalized Elderly.

This study aims to explore the efficacy of group music and game therapy in enhancing the well-being of the institutionalised elderly. The implementation of group music and game therapy have significantly improved the well-being of the participating elderly residents in Long-Term Care Facilities. These participants demonstrated increased engagement and achieved interpersonal interaction objectives during the sessions.

Stimulation of mouse hair regrowth by exosomes derived from human umbilical cord mesenchymal stem cells.

BACKGROUND: There is an urgent need for new treatments to solve hair loss problem. As mesenchymal stem cells were proved to have effects on promoting tissue repair and regeneration, in which the exosome plays a vital role, we aim to investigate the influence of umbilical cord mesenchymal stem cells exosome (UCMSC-Exos) on hair growth and its mechanism. METHODS: The hUCMSC-Exos were extracted by ultracentrifugation. Primary fibroblasts were cultured with or without hUCMSC-Exos and cell proliferation was evaluated by CCK-8 assay. C57BL/6 mice model of depilation-induced hair regrowth was treated with either hUCMSC-Exos (200 µg/mL) or PBS on one side of the dorsal back. Real time quantitative PCR, flow cytometry analysis, immunohistochemistry and Immunofluorescent staining were used to analyze the regulative effect of hUCMSC-Exos on hair follicle stem/progenitor cells and Wnt/ß-catenin pathway. RESULTS: The proliferation of fibroblasts incubated with hUCMSC-Exos at the concentration of 200 µg/mL was greater than other groups. Treatment with hUCMSC-Exos resulted in rapid reentry into anagen. Hair follicle stem/progenitor cell markers (K15, Lgr5, Lgr6, CD34 and Lrig1) and Wnt/ß-catenin pathway related factors (Wnt5, Lef1, Lrp5 and ß-catenin) were increased in hUCMSC-Exos-injected region. CONCLUSION: hUCMSC-Exos promote fibroblasts proliferation and accelerate mouse hair regrowth by upregulating hair follicle stem/progenitor cell and Wnt/ß-catenin pathway, which suggests potential therapeutic approaches for hair loss disorders.

Provision of Stroke Care Services by Community Disadvantage Status in the US, 2009-2022.

Importance: Stroke center certification is granted to facilities that demonstrate distinct capabilities for treating patients with stroke. A thorough understanding of structural discrimination in the provision of stroke centers is critical for identifying and implementing effective interventions to improve health inequities for socioeconomically disadvantaged populations. Objective: To determine whether (1) hospitals in socioeconomically disadvantaged communities (defined using the Area Deprivation Index) are less likely to adopt any stroke certification and (2) adoption rates differ between entry-level (acute stroke-ready hospitals) and higher-level certifications (primary, thrombectomy capable, and comprehensive) by community disadvantage status. Design, Setting, and Participants: This cohort study used newly collected stroke center data merged with data from the American Hospital Association, Healthcare Cost Report Information datasets, and the US Census. All general acute hospitals in the continental US between January 1, 2009, and December 31, 2022, were included. Data analysis was conducted from July 2023 to May 2024. Main Outcomes and Measures: The primary outcome was the likelihood of hospitals adopting stroke care certification. Cox proportional hazard and competing risk models were used to estimate the likelihood of a hospital becoming stroke certified based on the socioeconomic disadvantage status of the community. Results: Among the 5055 hospitals studied from 2009 to 2022, 2415 (47.8%) never achieved stroke certification, 602 (11.9%) were certified as acute stroke-ready hospitals, and 2038 (40.3%) were certified as primary stroke centers or higher. When compared with mixed-advantage communities, adoption of any stroke certification was most likely to occur near the most advantaged communities (hazard ratio [HR], 1.24; 95% CI, 1.07-1.44) and least likely near the most disadvantaged communities (HR, 0.43; 95% CI, 0.34-0.55). Adoption of acute stroke-ready certification was most likely in mixed-advantage communities, while adoption of higher-level certification was more likely in the most advantaged communities (HR,1.41; 95% CI, 1.22-1.62) and less likely for the most disadvantaged communities (HR, 0.31; 95% CI, 0.21-0.45). After adjusting for population size and hospital capacity, compared with mixed-advantage communities, stroke certification adoption hazard was still 20% lower for relatively disadvantaged communities (adjusted HR, 0.80; 95% CI, 0.73-0.87) and 42% lower for the most disadvantaged communities (adjusted HR, 0.58; 95% CI, 0.45-0.74). Conclusions and Relevance: In this cohort study examining hospital adoption of stroke services, when compared with mixed-advantage communities, hospitals located in the most disadvantaged communities had a 42% lower hazard of adopting any stroke certification and relatively disadvantaged communities had a 20% lower hazard of adopting any stroke certification. These findings suggest that there is a need to support hospitals in disadvantaged communities to obtain stroke certification as a way to reduce stroke disparities.

Autism-associated neuroligin-3 deficiency in medial septum causes social deficits and sleep loss in mice.

Patients with autism spectrum disorder (ASD) frequently experience sleep disturbance. Genetic mutations in Neuroligin-3 (NLG3) genes are highly correlative with ASD and sleep disturbance. However, the cellular and neural circuit bases of this correlation remain elusive. Here, we find the conditional knockout of NLG3 (NLG3-CKO) in the medial septum (MS) impairs social memory and reduces sleep. NLG3 knockout in MS causes hyperactivity of MS-GABA neurons during social avoidance and wakefulness. Activation of MSGABA neurons induces social memory deficits and sleep loss in C57BL/6 mice. In contrast, inactivation of these neurons ameliorates social memory deficits and sleep loss in NLG3-CKO mice. Sleep deprivation leads to social memory deficits, while social isolation causes sleep loss, both resulting in a reduction of NLG3 expression and an increase in activity of GABAergic neurons in MS from C57BL/6 mice. Furthermore, MS-GABA-innervated CA2 neurons specifically regulate social memory without impacting sleep, whereas MSGABA-innervating neurons in the preoptic area selectively control sleep without affecting social behavior. Together, these findings demonstrate that the hyperactive MS-GABA neurons impair social memory and disrupt sleep resulting from NLG3 knockout in MS, and achieve the modality specificity through their divergent downstream targets.

Structural Inequities In The Adoption Of Percutaneous Coronary Intervention Services By US Hospitals, 2000-20.

Percutaneous coronary intervention (PCI) is a procedure that opens blocked arteries and restores blood flow to the heart. Timely access to hospitals offering PCI services can be a matter of life or death for patients experiencing a heart attack; however, hospitals' adoption of PCI services may vary between communities, posing potential barriers to critical care. Our cohort study of US general acute hospitals during the period 2000-20 examined PCI service adoption across communities stratified by race, ethnicity, income, and rurality and further classified as segregated or integrated. Of 5,260 hospitals, 1,621 offered PCI services in 2020 or before, 630 added PCI services between 2001 and 2010, and 225 added PCI services between 2011 and 2020. Hospitals serving Black, racially segregated communities were 48 percent less likely to adopt PCI services compared with hospitals serving non-Black, racially segregated communities, and hospitals serving Hispanic, ethnically segregated communities were 41 percent less likely to do so than those serving non-Hispanic, ethnically segregated communities. Hospitals in high-income, economically integrated communities were 1.8 times more likely to adopt PCI services than those in high-income, economically segregated communities, and rural hospitals were less likely to do so than urban hospitals. Understanding where services are expanding in relation to community need may aid in successful policy interventions.