Injectable, reversibly thermoresponsive captopril-laden hydrogel for the local treatment of sensory loss in diabetic neuropathy.

A major and irreversible complication of diabetes is diabetic peripheral neuropathy (DPN), which can lead to significant disability and decreased quality of life. Prior work demonstrates the peptide hormone Angiotensin II (Ang II) is released locally in neuropathy and drives inflammation and impaired endoneurial blood flow. Therefore, we proposed that by utilizing a local thermoresponsive hydrogel injection, we could deliver inhibitors of angiotensin-converting enzyme (ACE) to suppress Ang II production and reduce nerve dysfunction in DPN through local drug release. The ACE inhibitor captopril was encapsulated into a micelle, which was then embedded into a reversibly thermoresponsive pluronics-based hydrogel matrix. Drug-free and captopril-loaded hydrogels demonstrated excellent product stability and sterility. Rheology testing confirmed sol properties with low viscosity at ambient temperature and increased viscosity and gelation at 37 °C. Captopril-loaded hydrogels significantly inhibited Ang II production in comparison to drug-free hydrogels. DPN mice treated with captopril-loaded hydrogels displayed normalized mechanical sensitivity and reduced inflammation, without side-effects associated with systemic exposure. Our data demonstrate the feasibility of repurposing ACE inhibitors as locally delivered anti-inflammatories for the treatment of sensory deficits in DPN. To the best of our knowledge, this is the first example of a locally delivered ACE inhibitor for the treatment of DPN.

Lung cancer mortality trends and disparities: A cross-sectional analysis 1999-2020.

BACKGROUND: Lung cancer remains a leading cause of morbidity and mortality in the United States. Given the importance of epidemiological insight on lung cancer outcomes as the foundation for targeted interventions, we aimed to examine lung cancer death trends in the United States in the recent 22-year period, exploring demographic disparities and yearly mortality shifts. METHODS: Mortality information was obtained from the CDC Wide-ranging Online Data for Epidemiologic Research database from the years 1999-2020. Demographic information included age, sex, race or ethnicity, and area of residence. We performed log-linear regression models to assess temporal mortality shifts and calculated average annual percentage change (AAPC) and compared age-adjusted mortality rates (AAMR) across demographic subpopulations. RESULTS: A total of 3,380,830 lung cancer deaths were identified. The AAMR decreased from 55.4 in 1999-31.8 in 2020 (p<0.001). Males (AAMR 57.6) and non-Hispanic (NH) (AAMR 47.5) populations were disproportionately impacted compared to females (AAMR 36.0) and Hispanic (AAMR 19.1) populations, respectively. NH Black populations had the highest AAMR (48.5) despite an overall reduction in lung cancer deaths (AAPC -3.3 %) over the study period. Although non-metropolitan regions were affected by higher mortality rates, the annual decrease in mortality among metropolitan regions (AAPC -2.8 %, p<0.001) was greater compared to non-metropolitan regions (AAPC -1.7 %, p<0.001). Individuals living in the Western US (AAPC -3.4 %, p<0.001) experienced the greatest decline in lung cancer mortality compared to other US census regions. CONCLUSIONS: Our findings revealed lung cancer mortality inequalities in the US. By contextualizing these mortality shifts, we provide a larger framework of data-driven initiatives for societal and health policy changes for improving access to care, minimizing healthcare inequalities, and improving outcomes.

Dual vs triple antithrombotic therapy in atrial fibrillation and acute coronary syndrome: An updated meta-analysis of randomized controlled trials.

Antithrombotic treatment in patients with atrial fibrillation (AF) and acute coronary syndrome (ACS) poses a dilemma. We compared outcomes of dual antithrombotic therapy (DAT) (direct oral anticoagulants (DOACs)/warfarin + antiplatelets) vs triple antithrombotic therapy (TAT) (DOACs/warfarin, aspirin, and P2Y12 inhibitor) in this population. Multiple databases were searched from inception to December 17, 2023 to identify randomized controlled trials (RCTs) comparing DAT vs TAT in patients with AF and ACS. Outcomes included major adverse cardiac events (MACE), bleeding events, stroke, stent thrombosis, and myocardial infarction (MI). Relative risk and 95% confidence intervals were estimated with a random-effects model using the inverse-variance technique. We assigned I2 > 50% as an indicator of statistical heterogeneity. p-Value <0.05 was considered significant. Ten RCTs comprising 6186 patients on TAT (female 26%, mean age 71 ± 9 years) and 6800 patients on DAT (female 27%, mean age 71 ± 9 years) were included. Patients receiving DAT experienced lower rates of bleeding events compared to those receiving TAT, with relative risks of 0.69 [0.55-0.87] (p < 0.001), 0.65 [0.40-1.06] (p = 0.09), and 0.62 [0.46-0.84] (p < 0.001) for TAT durations of 3, 6, and 12 months, respectively. No difference was seen in the occurrence of MACE, MI, stroke, or stent thrombosis between DAT and TAT across all three durations of TAT. This is the largest pooled analysis comparing TAT to DAT stratified by the duration of antithrombotic therapy. Our results revealed that DAT was associated with reduced bleeding risk despite no difference in other outcomes.

Social Vulnerability Index and Cardiovascular Disease Care Continuum: A Scoping Review.

Background: Social vulnerability index (SVI) estimates the vulnerability of communities to disasters, encompassing 4 separate domains (socioeconomic, household composition and disability, minority status and language, and housing and transportation). The SVI has been linked with risk and outcomes of cardiovascular disease (CVD). Objectives: This scoping review explored the literature between the SVI and CVD continuum, with a goal to identify gaps in understanding the impact of the SVI on CVD and to elucidate future research opportunities. Methods: We systematically searched 7 databases from inception to May 19, 2023, for articles that explored the relationship between the SVI and CVD care continuum, including prevention, diagnosis and prevalence, treatment, and health outcomes. Extracted data included SVI ranking type, populations, outcomes, and quality of studies. Results: Twelve studies evaluated the impact of SVI on the CVD continuum. Five studies explored mortality outcomes, 3 studies explored CVD risk factor prevalence, 4 studies explored CVD prevalence, 1 study explored access to health care in those with CVD, 1 study explored the use of cardiac rehabilitation services, and 1 study explored heart failure readmission rates, all of which revealed statistically significant associations with SVI. All studies included the SVI aggregate percentile ranking, while 5 studies focused on individual thematic components. We identified gaps in understanding the SVI's impact on CVD care continuum, particularly regarding CVD prevention and early detection. Conclusions: This review provides a comprehensive understanding of the SVI's application in assessing various aspects of the CVD care continuum and highlights potential avenues for future research.

Social Phenotyping for Cardiovascular Risk Stratification in Electronic Health Registries.

PURPOSE OF REVIEW: Evaluation of social influences on cardiovascular care requires a comprehensive analysis encompassing economic, societal, and environmental factors. The increased utilization of electronic health registries provides a foundation for social phenotyping, yet standardization in methodology remains lacking. This review aimed to elucidate the primary approaches to social phenotyping for cardiovascular risk stratification through electronic health registries. RECENT FINDINGS: Social phenotyping in the context of cardiovascular risk stratification within electronic health registries can be separated into four principal approaches: place-based metrics, questionnaires, ICD Z-coding, and natural language processing. These methodologies vary in their complexity, advantages and limitations, and intended outcomes. Place-based metrics often rely on geospatial data to infer socioeconomic influences, while questionnaires may directly gather individual-level behavioral and social factors. Z-coding, a relatively new approach, can capture data directly related to social determinant of health domains in the clinical context. Natural language processing has been increasingly utilized to extract social influences from unstructured clinical narratives-offering nuanced insights for risk prediction models. Each method plays an important role in our understanding and approach to using social determinants data for improving population cardiovascular health. These four principal approaches to social phenotyping contribute to a more structured approach to social determinant of health research via electronic health registries, with a focus on cardiovascular risk stratification. Social phenotyping related research should prioritize refining predictive models for cardiovascular diseases and advancing health equity by integrating applied implementation science into public health strategies.

Interstitial Lung Disease Mortality Disparities Along the US-Mexico Border, 1999-2020.

BACKGROUND: Optimal diagnosis and management of interstitial lung diseases (ILDs) needs access to specialized centers, frequent monitoring, and complex therapeutic options. In underprivileged areas, these necessities can often lead to barriers in delivering care. RESEARCH QUESTION: What are the ILD mortality disparities in the regions along the US-Mexico (US-MX) border? STUDY DESIGN AND METHODS: We obtained ILD mortality information through death certificate queries from the Centers for Disease Control and Prevention repository. Death data were adjusted for age and stratified by US-MX border regions and nonborder regions in the United States. Log-linear regression models were used to analyze mortality trends in the period from 1999 to 2020 followed by calculation of annual percentage changes (APCs). Age-adjusted mortality rates (AAMRs) were compared across cumulative and subdemographic populations. RESULTS: ILD-related mortality among border regions (AAMR, 5.31) was higher than nonborder regions (AAMR, 4.86). Mortality within border regions remained unchanged from 1999 to 2020 (APC, 0.3; P = .269). Nonborder regions experienced a significant rise in mortality rates (APC, 2.6; P = .017) from 1999 to 2005 and remained unchanged from 2005 to 2020. Mortality was higher within both men (AAMR, 6.57) and women (AAMR, 4.36) populations among border regions compared with their nonborder counterparts (AAMR, 6.27 and 3.87, respectively). Hispanic populations among the border regions experienced higher mortality rates (AAMR, 6.15) than Hispanic populations within nonborder regions (AAMR, 5.44). Non-Hispanic populations encountered similar mortality rates between the two regions. Mortality rates among Hispanic (APC, 0.0; P = .938) and non-Hispanic (APC, 0.2; P = .531) populations in the border regions remained unchanged from 1999 to 2020. INTERPRETATION: These results revealed ILD-related mortality disparities among the US-MX border regions, emphasizing the importance of public health measures to increase access to equitable medical care and implement targeted interventions among these vulnerable populations.

Neuromuscular Polytrauma Pain is Resolved by Macrophage COX-2 Nanoimmunomodulation.

Soft tissue injuries often involve muscle and peripheral nerves and are qualitatively distinct from single-tissue injuries. Prior research suggests that damaged innervation compromises wound healing. To test this in a traumatic injury context, we developed a novel mouse model of nerve and lower limb polytrauma, which features greater pain hypersensitivity and more sustained macrophage infiltration than either injury in isolation. We also show that macrophages are crucial mediators of pain hypersensitivity in this model by delivering macrophage-targeted nanoemulsions laden with the cyclooxygenase-2 (COX-2) inhibitor celecoxib. This treatment was more effective in males than females, and more effective when delivered 3 days post-injury than 7 days post-injury. The COX-2 inhibiting nanoemulsion drove widespread anti-inflammatory changes in cytokine expression in polytrauma-affected peripheral nerves. Our data shed new light on the modulation of inflammation by injured nerve input and demonstrate macrophage-targeted nanoimmunomodulation can produce rapid and sustained pain relief following complex injuries.

Improving Micro-EDM Machining Efficiency for Titanium Alloy Fabrication with Advanced Coated Electrodes.

Enhancing the operational efficacy of electrical discharge machining (EDM) is crucial for achieving optimal results in various engineering materials. This study introduces an innovative solution-the use of coated electrodes-representing a significant advancement over current limitations. The choice of coating material is critical for micro-EDM performance, necessitating a thorough investigation of its impact. This research explores the application of different coating materials (AlCrN, TiN, and Carbon) on WC electrodes in micro-EDM processes specifically designed for Ti-6Al-4V. A comprehensive assessment was conducted, focusing on key quality indicators such as depth of cut (Z), tool wear rate (TWR), overcut (OVC), and post-machining surface quality. Through rigorous experimental methods, the study demonstrates substantial improvements in these quality parameters with coated electrodes. The results show significant enhancements, including increased Z, reduced TWR and OVC, and improved surface quality. This evidence underscores the effectiveness of coated electrodes in enhancing micro-EDM performance, marking a notable advancement in the precision and quality of Ti-6Al-4V machining processes. Among the evaluated coatings, AlCrN-coated electrodes exhibited the greatest increase in Z, the most significant reduction in TWR, and the best OVC performance compared to other coatings and the uncoated counterpart.

Synthesis of a 3D Flower-Like BiOCl/Bi-MOF Heterostructure for High-Performance Removal of Rhodamine B and Tetracycline Hydrochloride.

Semiconductor materials based on bismuth metal have been extensively explored for their potential in photocatalytic applications owing to their distinctive crystal structure. Herein, we present the development of a hybrid photocatalyst, CAU-17/BiOCl, featuring a flower-like nanosheet morphology tailored for the photocatalytic degradation of organic contaminants such as rhodamine B (RhB) and tetracycline hydrochloride (TCH). The composite material is obtained by growing thin CAU-17 layers directly onto the host flower-like BiOCl nanosheets under solvothermal conditions. The optimized CAU-17/BiOCl composite possesses excellent photocatalytic performance, achieving a notable 96.0% removal rate for RhB and 78.4% for TCH after 60 and 90 min of LED light irradiation, respectively. This boosted activity is attributed to the heightened absorption of visible light caused by BiOCl and the provision of additional reaction sites due to the thin CAU-17 layers. Furthermore, the establishment of an S-scheme heterojunction mechanism enables efficient charge separation between CAU-17 and BiOCl, facilitating the separation of photoinduced electrons (e-) and holes (h+). Analysis of the degradation mechanism of RhB and TCH reveals the predominant role of superoxide radicals (•O2-), e-, and h+ in the photocatalytic degradation process. Moreover, the removal efficiency of TCH can reach approximately 64.5% after four cycles of recycling of CAU-17/BiOCl. Our work provides a facile, effective solution and a theoretically explained approach for the effective degradation of pollutants using heterojunction photocatalysts.

Pharmacological Management of Transthyretin Amyloid Cardiomyopathy: A scoping review.

AIMS: Transthyretin amyloid cardiomyopathy (ATTR-CM) is characterized by the accumulation of transthyretin (TTR) protein in the myocardium. The aim of this scoping review is to provide a descriptive summary of the clinical trials and observational studies that evaluated the clinical efficacy and safety of various agents used in ATTR-CM, with a goal of identifying the contemporary gaps in literature and to reveal future research opportunities. METHODS AND RESULTS: The search was performed in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A literature search using several databases for observational and clinical trials investigating the treatment modalities for ATTR-CM was undertaken. We extracted data including study characteristics, primary endpoints, and adverse events from each study. A total of 19 studies were included in our scoping review. 8 were clinical trials and 11 were observational analyses. The drugs evaluated included tafamadis, acoramidis, revusiran, TUDCA and doxycycline, diflusinil, inotersan, eplontersen, and patisiran. Tafamidis has shown to be efficacious in the management of ATTR-CM, particularly when initiated at earlier stages. RNA interference and antisense oligonucleotide drugs have shown promising impacts on quality of life. Additionally, this review identified gaps in the literature, particularly among long-term outcomes, comparative effectiveness, and the translation of research into economic contexts. CONCLUSIONS: Multiple pharmacological options are potential disease-modifying therapies for ATTR-CM. However, many gaps exist in the understanding of these various drug therapies, warranting further research. The future directions for management of ATTR-CM are promising in regard to improving prognostic implications.

Navigating the liver landscape: upcoming pharmacotherapies for primary sclerosing cholangitis.

INTRODUCTION: Primary sclerosing cholangitis (PSC) is a bile duct disorder characterized by ductular reaction, hepatic inflammation, and liver fibrosis. The pathogenesis of PSC is still undefined, and treatment options for patients are limited. Previous clinical trials evaluated drug candidates targeting various cellular functions and pathways, such as bile acid signaling and absorption, gut bacteria and permeability, and lipid metabolisms. However, most of phase III clinical trials for PSC were disappointing, except vancomycin therapy, and there are still no established medications for PSC with efficacy and safety confirmed by phase IV clinical trials. AREAS COVERED: This review summarizes the currently ongoing or completed clinical studies for PSC, which are phase II or further, and discusses therapeutic targets and strategies, limitations, and future directions and possibilities of PSC treatments. A literature search was conducted in PubMed and ClinicalTrials.gov utilizing the combination of the searched term 'primary sclerosing cholangitis' with other keywords, such as 'clinical trials,' 'antibiotics,' or drug names. Clinical trials at phase II or further were included for consideration. EXPERT OPINION: Only vancomycin demonstrated promising therapeutic effects in the phase III clinical trial. Other drug candidates showed futility or inconsistent results, and the search for novel PSC treatments is still ongoing.

Rural-urban stroke mortality gaps in the United States.

INTRODUCTION: Disparities in stroke outcomes, influenced by the use of systemic thrombolysis, endovascular therapies, and rehabilitation services, have been identified. Our study assesses these disparities in mortality after stroke between rural and urban areas across the United States (US). METHODS: We analyzed the CDC data on deaths attributed to cerebrovascular disease from 1999 to 2020. Data was categorized into rural and urban regions for comparative purposes. Age-adjusted mortality rates (AAMR) were computed using the direct method, allowing us to examine the ratios of rural to urban deaths for the cumulative population and among demographic subpopulations. Linear regression models were used to assess temporal changes in mortality ratios over the study period, yielding beta-coefficients (ß). RESULTS: There was a total of 628,309 stroke deaths in rural regions and 2,556,293 stroke deaths within urban regions. There were 1.13 rural deaths for each one urban death per 100,000 population in 1999 and 1.07 in 2020 (ß = -0.001, ptrend = 0.41). The rural-urban mortality ratio in Hispanic populations decreased from 1.32 rural deaths for each urban death per 100,000 population in 1999 to 0.85 in 2020 (ß = -0.011, ptrend < 0.001). For non-Hispanic populations, mortality remained stagnant with 1.12 rural deaths for each urban death per 100,000 population in 1999 and 1.07 in 2020 (ß = -0.001, ptrend = 0.543). Regionally, the Southern US exhibited the highest disparity with a urban-rural mortality ratio of 1.19, followed by the Northeast (1.13), Midwest (1.04), and West (1.01). CONCLUSIONS: Our findings depict marked disparities in stroke mortality between rural and urban regions, emphasizing the importance of targeted interventions to mitigate stroke-related disparities.

A Longitudinal Analysis of Mortality Related to Chronic Viral Hepatitis and Hepatocellular Carcinoma in the United States.

(1) Background: Hepatocellular carcinoma (HCC) contributes to the significant burden of cancer mortality in the United States (US). Despite highly efficacious antivirals, chronic viral hepatitis (CVH) remains an important cause of HCC. With advancements in therapeutic modalities, along with the aging of the population, we aimed to assess the contribution of CVH in HCC-related mortality in the US between 1999-2020. (2) Methods: We queried all deaths related to CVH and HCC in the multiple-causes-of-death files from the CDC Wide-ranging Online Data for Epidemiologic Research (WONDER) database between 1999-2020. Using the direct method of standardization, we adjusted all mortality information for age and compared the age-adjusted mortality rates (AAMRs) across demographic populations and by percentile rankings of social vulnerability. Temporal shifts in mortality were quantified using log-linear regression models. (3) Results: A total of 35,030 deaths were identified between 1999-2020. The overall crude mortality increased from 0.27 in 1999 to 8.32 in 2016, followed by a slight reduction to 7.04 in 2020. The cumulative AAMR during the study period was 4.43 (95% CI, 4.39-4.48). Males (AAMR 7.70) had higher mortality rates compared to females (AAMR 1.44). Mortality was higher among Hispanic populations (AAMR 6.72) compared to non-Hispanic populations (AAMR 4.18). Higher mortality was observed in US counties categorized as the most socially vulnerable (AAMR 5.20) compared to counties that are the least socially vulnerable (AAMR 2.53), with social vulnerability accounting for 2.67 excess deaths per 1,000,000 person-years. (4) Conclusions: Our epidemiological analysis revealed an overall increase in CVH-related HCC mortality between 1999-2008, followed by a stagnation period until 2020. CVH-related HCC mortality disproportionately affected males, Hispanic populations, and Black/African American populations, Western US regions, and socially vulnerable counties. These insights can help aid in the development of strategies to target vulnerable patients, focus on preventive efforts, and allocate resources to decrease HCC-related mortality.

Deconvolution analysis identified altered hepatic cell landscape in primary sclerosing cholangitis and primary biliary cholangitis.

Introduction: Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are characterized by ductular reaction, hepatic inflammation, and liver fibrosis. Hepatic cells are heterogeneous, and functional roles of different hepatic cell phenotypes are still not defined in the pathophysiology of cholangiopathies. Cell deconvolution analysis estimates cell fractions of different cell phenotypes in bulk transcriptome data, and CIBERSORTx is a powerful deconvolution method to estimate cell composition in microarray data. CIBERSORTx performs estimation based on the reference file, which is referred to as signature matrix, and allows users to create custom signature matrix to identify specific phenotypes. In the current study, we created two custom signature matrices using two single cell RNA sequencing data of hepatic cells and performed deconvolution for bulk microarray data of liver tissues including PSC and PBC patients. Methods: Custom signature matrix files were created using single-cell RNA sequencing data downloaded from GSE185477 and GSE115469. Custom signature matrices were validated for their deconvolution performance using validation data sets. Cell composition of each hepatic cell phenotype in the liver, which was identified in custom signature matrices, was calculated by CIBERSORTx and bulk RNA sequencing data of GSE159676. Deconvolution results were validated by analyzing marker expression for the cell phenotype in GSE159676 data. Results: CIBERSORTx and custom signature matrices showed comprehensive performance in estimation of population of various hepatic cell phenotypes. We identified increased population of large cholangiocytes in PSC and PBC livers, which is in agreement with previous studies referred to as ductular reaction, supporting the effectiveness and reliability of deconvolution analysis in this study. Interestingly, we identified decreased population of small cholangiocytes, periportal hepatocytes, and interzonal hepatocytes in PSC and PBC liver tissues compared to healthy livers. Discussion: Although further studies are required to elucidate the roles of these hepatic cell phenotypes in cholestatic liver injury, our approach provides important implications that cell functions may differ depending on phenotypes, even in the same cell type during liver injury. Deconvolution analysis using CIBERSORTx could provide a novel approach for studies of specific hepatic cell phenotypes in liver diseases.

Radiological Features of Herpetic Encephalitis in Children.

BACKGROUND: Nonspecific clinical manifestations and unclear radiological features may delay treatment initiation in pediatric patients with Herpes simplex encephalitis (HSE). The aim of this study is to analyze the clinical and radiological features of the disease. METHODS: Clinical, laboratory, and magnetic resonance imaging (MRI) data were obtained retrospectively from a group of 37 hospitalized pediatric patients older than two months and with a polymerase chain reaction-confirmed HSE diagnosis. Clinical severity (i.e., mechanical ventilatory support) and outcome at discharge (i.e., pediatric modified Rankin Scale [ped-mRS]) were also assessed. RESULTS: Median age was 14 months (interquartile range: 10-36). All patients survived, 15 (41%) had complete recovery (i.e., ped-mRS = 0), and 10 (27%) had significant residual disability at discharge (i.e., ped-mRS ≥3). Brain MRI was obtained in 31 patients. T2-hyperintense lesions were usually bilateral (28, 90%) and multifocal (30, 97%). Hemorrhage and mass effect were observed in 13 (42%) and 15 (48%) patients, respectively. Parenchymal lesions involved the temporal lobes (94%), insula (90%), parietal lobes (84%), and frontal lobes (61%). Occipital lesions were rare. In multivariable binary logistic regression models the presence of altered consciousness was associated with mechanical ventilation (odds ratio [OR] = 8.2, Nagelkerke R2 = 0.22), whereas the involvement of the occipital lobes (OR = 7.8) and the administration of vasopressors (OR = 12.1) were independent predictors of poor outcome (Nagelkerke R2 = 0.41). CONCLUSIONS: Brain MRI is useful for diagnosis and outcome assessment in pediatric HSE. Radiological patterns with common frontotemporal involvement overlap adults, but multifocal and parietal lobe abnormalities are observed as well.

Influence of social vulnerability index on Medicare beneficiaries' expenditures upon discharge.

Medicare beneficiaries' healthcare spending varies across geographical regions, influenced by availability of medical resources and institutional efficiency. We aimed to evaluate whether social vulnerability influences healthcare costs among Medicare beneficiaries. Multivariable regression analyses were conducted to determine whether the social vulnerability index (SVI), released by the Centers for Disease Control and Prevention (CDC), was associated with average submitted covered charges, total payment amounts, or total covered days upon hospital discharge among Medicare beneficiaries. We used information from discharged Medicare beneficiaries from hospitals participating in the Inpatient Prospective Payment System. Covariate adjustment included demographic information consisting of age groups, race/ethnicity, and Hierarchical Condition Category risk score. The regressions were performed with weights proportioned to the number of discharges. Average submitted covered charges significantly correlated with SVI (ß = 0.50, p < 0.001) in the unadjusted model and remained significant in the covariates-adjusted model (ß = 0.25, p = 0.039). The SVI was not significantly associated with the total payment amounts (ß = -0.07, p = 0.238) or the total covered days (ß = 0.00, p = 0.953) in the adjusted model. Regional variations in Medicare beneficiaries' healthcare spending exist and are influenced by levels of social vulnerability. Further research is warranted to fully comprehend the impact of social determinants on healthcare costs.

Loss-of-function mutation in PRMT9 causes abnormal synapse development by dysregulation of RNA alternative splicing.

Protein arginine methyltransferase 9 (PRMT9) is a recently identified member of the PRMT family, yet its biological function remains largely unknown. Here, by characterizing an intellectual disability associated PRMT9 mutation (G189R) and establishing a Prmt9 conditional knockout (cKO) mouse model, we uncover an important function of PRMT9 in neuronal development. The G189R mutation abolishes PRMT9 methyltransferase activity and reduces its protein stability. Knockout of Prmt9 in hippocampal neurons causes alternative splicing of ~1900 genes, which likely accounts for the aberrant synapse development and impaired learning and memory in the Prmt9 cKO mice. Mechanistically, we discover a methylation-sensitive protein-RNA interaction between the arginine 508 (R508) of the splicing factor 3B subunit 2 (SF3B2), the site that is exclusively methylated by PRMT9, and the pre-mRNA anchoring site, a cis-regulatory element that is critical for RNA splicing. Additionally, using human and mouse cell lines, as well as an SF3B2 arginine methylation-deficient mouse model, we provide strong evidence that SF3B2 is the primary methylation substrate of PRMT9, thus highlighting the conserved function of the PRMT9/SF3B2 axis in regulating pre-mRNA splicing.