Exploring synaptic pathways in traumatic brain injury: a cross-phenotype genomics approach.

Traumatic brain injury (TBI), a global leading cause of mortality and disability, lacks effective treatments to enhance recovery. Synaptic remodeling has been postulated as one mechanism that influences outcomes after TBI. We sought to investigate whether common mechanisms affecting synapse maintenance are shared between TBI and other neuropsychiatric conditions using pathway enrichment tools and genome-wide genotype data, with the goal of highlighting novel treatment targets. We leveraged an integrative approach, combining data from Genome-Wide Association Studies (GWAS) with pathway and gene-set enrichment analyses. Literature review-based and Reactome database-driven approaches were combined to identify synapse-related pathways of interest in TBI outcome, and to assess for shared associations with conditions in which synapse-related pathobiological mechanisms have been implicated, including Alzheimer's disease (AD), schizophrenia (SCZ), major depressive disorder (MDD), post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Gene and pathway-level enrichment analyses were conducted using MAGMA and its extensions, e- and H-MAGMA, followed by Mendelian Randomization (MR) to investigate potential causal associations. Of the 98 pathways tested, 32 were significantly enriched in the included conditions. In TBI outcome, we identified significant enrichment in five pathways: "Serotonin clearance from the synaptic cleft" (p-value = 0.0001), "Presynaptic nicotinic acetylcholine receptors" (p-value = 0.0003), "Postsynaptic nicotinic acetylcholine receptors" (p-value = 0.0003), "Highly sodium permeable postsynaptic acetylcholine nicotinic receptors" (p-value = 0.0001), and "Acetylcholine binding and downstream events" pathways (p-value = 0.0003). These associations highlight potential involvement of the cholinergic and serotonergic systems in post-TBI recovery. Three of those pathways were shared between TBI and schizophrenia, suggesting possible pathophysiologic commonalities. In this study we utilize comparative and integrative genomic approaches across brain conditions that share synaptic mechanisms to explore the pathophysiology of TBI outcome. Our results implicate associations between TBI outcome and synaptic pathways as well as pathobiologic overlap with other neuropsychiatric diseases.

Agroecosystem's contributions to people: how ranchers and specialists perceive threatened Espinal forests used for cattle-grazing.

Scientists and managers seek to implement more inclusive and effective conservation strategies by incorporating plural valuations of nature and nature's contributions to people (NCP) into research and decision-making. For Argentina's threatened Espinal ecoregion, this need is particularly acute. In Entre Ríos province, practically all of these forests are devoted to production, and the expanding agricultural frontier increases their conversion to crops. We surveyed family ranchers and agricultural/environmental specialists, two key stakeholders for managing Espinal forests used for cattle grazing. Employing a sociocultural valuation, we determined i) stakeholder recognition of the Espinal's NCP and its support for quality of life, ii) similarity between stakeholder valuations (importance: 0 = none; 4 = very) of NCP and dimensions of well-being derived from the Espinal, and iii) relationship between ecological (e.g., forest degradation) and social (e.g., place of residence) factors and perceptions of the forest. Ranchers recognized more NCP and quality-of-life aspects, and the importance to their well-being tended to be greater than specialists. Both groups valued regulating and non-material NCP above material contributions and considered that forests are very important for physical and mental health. Finally, only rancher perceptions varied with tested variables, depending on degradation levels of forests with which they have the most contact and/or carry out their activities, the number of uses and recreational activities they carry out in forests, their knowledge of forests, and their place of residence. This study illustrates common ground upon which to promote synergies between production and conservation in Espinal-cattle agroecosystems.

Advancements in Understanding and Managing Radiation Cystitis: A Comprehensive Review.

PURPOSE OF REVIEW: This manuscript aims to provide a comprehensive overview of the pathophysiology, risk factors, prevention strategies, and management options for radiation cystitis. RECENT FINDINGS: Recent studies have shed light on the pathophysiology of radiation cystitis, highlighting the role of inflammation, fibrosis, and vascular damage. Emerging preventive measures like stem cell therapy offer promise, alongside novel treatments such as amniotic bladder therapy and hyperbaric oxygen therapy. This review outlines the latest research on radiation cystitis, covering its pathophysiology, risk factors, prevention, and management. Major findings include insights into the mechanisms of RC development, promising preventive and therapeutic approaches, and the importance of standardized treatment pathways. Future research should focus on identifying genetic risk factors, improving treatment efficacy, and enhancing patient outcomes. This review offers valuable insights for clinicians and researchers, guiding future investigations into radiation cystitis management.

Neoadjuvant androgen deprivation therapy with or without Fc-enhanced non-fucosylated anti-CTLA-4 (BMS-986218) in high risk localized prostate cancer: a randomized phase 1 trial.

Men with high-risk localized prostate cancer exhibit high rates of post-surgical recurrence. In these patients, androgen deprivation therapy (ADT) is immunomodulatory, however increased infiltration of regulatory T cells (Tregs) may limit the antitumor immune effects of ADT. We designed a neoadjuvant clinical trial to test whether BMS-986218 - a next-generation non-fucosylated anti-CTLA-4 antibody engineered for enhanced antibody-dependent cellular cytotoxicity or phagocytosis (ADCC/P) - depletes intratumoral Tregs and augments the response to ADT. In this single-center, two-arm, open-label study, 24 men with high-risk localized prostate cancer were randomized to receive a single dose of ADT with or without two pre-operative doses of BMS-986218 (anti-CTLA4-NF) prior to radical prostatectomy. Treatment was well tolerated and feasible in the neoadjuvant setting. A secondary clinical outcome was the rate of disease recurrence, which was lower than predicted in both arms. Mechanistically, anti-CTLA4-NF reduced ADT-induced Treg accumulation through engagement of CD16a/ FCGR3A on tumor macrophages, and depth of Treg depletion was quantitatively associated with clinical outcome. Increased intratumoral dendritic cell (DC) frequencies also associated with lack of recurrence, and pre-clinical data suggest ADCC/P-competent anti-CTLA-4 antibodies elicit activation and expansion of tumor DCs. Patients receiving anti-CTLA4-NF also exhibited phenotypic signatures of enhanced antitumor T cell priming. In total, this study provides the first-in-human evidence of Treg depletion by glycoengineered antibodies targeting CTLA-4 in humans and their potential in combination with ADT in prostate cancer patients with high-risk of recurrence.

Age- and Sex-Specific Analysis of Stroke Hospitalization Rates, Risk Factors, and Outcomes From German Nationwide Data.

BACKGROUND: Significant age and sex differences have been reported at each stage of the stroke pathway, from risk factors to outcomes. However, there is some uncertainty in previous studies with regard to the role of potential confounders and selection bias. Therefore, using German nationwide administrative data, we aimed to determine the magnitude and direction of trends in age- or sex-specific differences with respect to admission rates, risk factors, and acute treatments of ischemic and hemorrhagic stroke. METHODS: We obtained and analyzed data from the Research Data Centres of the Federal Statistical Office for the years 2010 to 2020 with regard to all acute stroke hospitalizations, risk factors, treatments, and in-hospital mortality, stratified by sex and stroke subtype. This database provides a complete national-level census of stroke hospitalizations combined with population census counts. All hospitalized patients ≥15 years with an acute stroke (diagnosis code: I60-64) were included in the analysis. RESULTS: Over the 11-year study period, there were 3 375 157 stroke events; 51.2% (n=1 728 954) occurred in men. There were higher rates of stroke admissions in men compared with women for both ischemic (378.1 versus 346.7/100 000 population) and hemorrhagic subtypes (75.6 versus 65.5/100 000 population) across all age groups. The incidence of ischemic stroke admissions peaked in 2016 among women (354.0/100 000 population) and in 2017 among men (395.8/100 000 population), followed by a consistent decline from 2018 onward. There was a recent decline in hemorrhagic stroke admissions observed for both sexes, reaching its nadir in 2020 (68.9/100 000 for men; 59.5/100 000 for women). Female sex was associated with in-hospital mortality for both ischemic (adjusted odds ratio, 1.11 [1.09-1.12]; P<0.001) and hemorrhagic stroke (adjusted odds ratio, 1.18 [95% CI, 1.16-1.20]; P<0.001). CONCLUSIONS: Despite improvements in stroke prevention and treatment pathways in the past decade, sex-specific differences remain with regard to hospitalization rates, risk factors, and mortality. Better understanding the mechanisms for these differences may allow us to develop a sex-stratified approach to stroke care.

Distinct cell death pathways induced by granzymes collectively protect against intestinal Salmonella infection.

Intestinal intraepithelial T lymphocytes (IEL) constitutively express high amounts of the cytotoxic proteases Granzymes (Gzm) A and B and are therefore thought to protect the intestinal epithelium against infection by killing infected epithelial cells. However, the role of IEL granzymes in a protective immune response has yet to be demonstrated. We show that GzmA and GzmB are required to protect mice against oral, but not intravenous, infection with Salmonella enterica serovar Typhimurium, consistent with an intestine-specific role. IEL-intrinsic granzymes mediate the protective effects by controlling intracellular bacterial growth and aiding in cell-intrinsic pyroptotic cell death of epithelial cells. Surprisingly, we found that both granzymes play non-redundant roles. GzmB-/- mice carried significantly lower burdens of Salmonella, as predominant GzmA-mediated cell death effectively reduced bacterial translocation across the intestinal barrier. Conversely, in GzmA-/- mice, GzmB-driven apoptosis favored luminal Salmonella growth by providing nutrients, while still reducing translocation across the epithelial barrier. Together, the concerted actions of both GzmA and GzmB balance cell death mechanisms at the intestinal epithelium to provide optimal control that Salmonella cannot subvert.

Genetically proxied HTRA1 protease activity and circulating levels independently predict risk of ischemic stroke and coronary artery disease.

Genetic variants in HTRA1 are associated with stroke risk. However, the mechanisms mediating this remain largely unknown, as does the full spectrum of phenotypes associated with genetic variation in HTRA1. Here we show that rare HTRA1 variants are linked to ischemic stroke in the UK Biobank and BioBank Japan. Integrating data from biochemical experiments, we next show that variants causing loss of protease function associated with ischemic stroke, coronary artery disease and skeletal traits in the UK Biobank and MyCode cohorts. Moreover, a common variant modulating circulating HTRA1 mRNA and protein levels enhances the risk of ischemic stroke and coronary artery disease while lowering the risk of migraine and macular dystrophy in genome-wide association study, UK Biobank, MyCode and BioBank Japan data. We found no interaction between proxied HTRA1 activity and levels. Our findings demonstrate the role of HTRA1 for cardiovascular diseases and identify two mechanisms as potential targets for therapeutic interventions.

Metabolite-based inter-kingdom communication controls intestinal tissue recovery following chemotherapeutic injury.

Cytotoxic chemotherapies have devastating side effects, particularly within the gastrointestinal tract. Gastrointestinal toxicity includes the death and damage of the epithelium and an imbalance in the intestinal microbiota, otherwise known as dysbiosis. Whether dysbiosis is a direct contributor to tissue toxicity is a key area of focus. Here, from both mammalian and bacterial perspectives, we uncover an intestinal epithelial cell death-Enterobacteriaceae signaling axis that fuels dysbiosis. Specifically, our data demonstrate that chemotherapy-induced epithelial cell apoptosis and the purine-containing metabolites released from dying cells drive the inter-kingdom transcriptional re-wiring of the Enterobacteriaceae, including fundamental shifts in bacterial respiration and promotion of purine utilization-dependent expansion, which in turn delays the recovery of the intestinal tract. Inhibition of epithelial cell death or restriction of the Enterobacteriaceae to homeostatic levels reverses dysbiosis and improves intestinal recovery. These findings suggest that supportive therapies that maintain homeostatic levels of Enterobacteriaceae may be useful in resolving intestinal disease.

Collagen IV deficiency causes hypertrophic remodeling and endothelium-dependent hyperpolarization in small vessel disease with intracerebral hemorrhage.

BACKGROUND: Genetic variants in COL4A1 and COL4A2 (encoding collagen IV alpha chain 1/2) occur in genetic and sporadic forms of cerebral small vessel disease (CSVD), a leading cause of stroke, dementia and intracerebral haemorrhage (ICH). However, the molecular mechanisms of CSVD with ICH and COL4A1/COL4A2 variants remain obscure. METHODS: Vascular function and molecular investigations in mice with a Col4a1 missense mutation and heterozygous Col4a2 knock-out mice were combined with analysis of human brain endothelial cells harboring COL4A1/COL4A2 mutations, and brain tissue of patients with sporadic CSVD with ICH. FINDINGS: Col4a1 missense mutations cause early-onset CSVD independent of hypertension, with enhanced vasodilation of small arteries due to endothelial dysfunction, vascular wall thickening and reduced stiffness. Mechanistically, the early-onset dysregulated endothelium-dependent hyperpolarization (EDH) is due to reduced collagen IV levels with elevated activity and levels of endothelial Ca2+-sensitive K+ channels. This results in vasodilation via the Na/K pump in vascular smooth muscle cells. Our data support this endothelial dysfunction preceding development of CSVD-associated ICH is due to increased cytoplasmic Ca2+ levels in endothelial cells. Moreover, cerebral blood vessels of patients with sporadic CSVD show genotype-dependent mechanisms with wall thickening and lower collagen IV levels in those harboring common non-coding COL4A1/COL4A2 risk alleles. INTERPRETATION: COL4A1/COL4A2 variants act in genetic and sporadic CSVD with ICH via dysregulated EDH, and altered vascular wall thickness and biomechanics due to lower collagen IV levels and/or mutant collagen IV secretion. These data highlight EDH and collagen IV levels as potential treatment targets. FUNDING: MRC, Wellcome Trust, BHF.

The predictive validity of a Brain Care Score for late-life depression and a composite outcome of dementia, stroke, and late-life depression: data from the UK Biobank cohort.

Introduction: The 21-point Brain Care Score (BCS) is a novel tool designed to motivate individuals and care providers to take action to reduce the risk of stroke and dementia by encouraging lifestyle changes. Given that late-life depression is increasingly recognized to share risk factors with stroke and dementia, and is an important clinical endpoint for brain health, we tested the hypothesis that a higher BCS is associated with a reduced incidence of future depression. Additionally, we examined its association with a brain health composite outcome comprising stroke, dementia, and late-life depression. Methods: The BCS was derived from the United Kingdom Biobank baseline evaluation in participants with complete data on BCS items. Associations of BCS with the risk of subsequent incident late-life depression and the composite brain health outcome were estimated using multivariable Cox proportional hazard models. These models were adjusted for age at baseline and sex assigned at birth. Results: A total of 363,323 participants were included in this analysis, with a median BCS at baseline of 12 (IQR: 11-14). There were 6,628 incident cases of late-life depression during a median follow-up period of 13 years. Each five-point increase in baseline BCS was associated with a 33% lower risk of incident late-life depression (95% CI: 29%-36%) and a 27% lower risk of the incident composite outcome (95% CI: 24%-30%). Discussion: These data further demonstrate the shared risk factors across depression, dementia, and stroke. The findings suggest that a higher BCS, indicative of healthier lifestyle choices, is significantly associated with a lower incidence of late-life depression and a composite brain health outcome. Additional validation of the BCS is warranted to assess the weighting of its components, its motivational aspects, and its acceptability and adaptability in routine clinical care worldwide.

Broad-spectrum antibiotics disrupt homeostatic efferocytosis.

The clearance of apoptotic cells, termed efferocytosis, is essential for tissue homeostasis and prevention of autoimmunity1. Although past studies have elucidated local molecular signals that regulate homeostatic efferocytosis in a tissue2,3, whether signals arising distally also regulate homeostatic efferocytosis remains elusive. Here, we show that large peritoneal macrophage (LPM) display impairs efferocytosis in broad-spectrum antibiotics (ABX)-treated, vancomycin-treated and germ-free mice in vivo, all of which have a depleted gut microbiota. Mechanistically, the microbiota-derived short-chain fatty acid butyrate directly boosts efferocytosis efficiency and capacity in mouse and human macrophages, and rescues ABX-induced LPM efferocytosis defects in vivo. Bulk messenger RNA sequencing of butyrate-treated macrophages in vitro and single-cell messenger RNA sequencing of LPMs isolated from ABX-treated and butyrate-rescued mice reveals regulation of efferocytosis-supportive transcriptional programmes. Specifically, we find that the efferocytosis receptor T cell immunoglobulin and mucin domain containing 4 (TIM-4, Timd4) is downregulated in LPMs of ABX-treated mice but rescued by oral butyrate. We show that TIM-4 is required for the butyrate-induced enhancement of LPM efferocytosis capacity and that LPM efferocytosis is impaired beyond withdrawal of ABX. ABX-treated mice exhibit significantly worse disease in a mouse model of lupus. Our results demonstrate that homeostatic efferocytosis relies on distal metabolic signals and suggest that defective homeostatic efferocytosis may explain the link between ABX use and inflammatory disease4-7.

Genetically proxied IL-6 signaling and risk of Alzheimer's disease and lobar intracerebral hemorrhage: A drug target Mendelian randomization study.

INTRODUCTION: Evidence suggests that higher C-reactive protein (CRP) is associated with lower risk of Alzheimer's disease (AD) and lobar intracerebral hemorrhage (ICH). Whether interleukin (IL)-6 signaling, an active pharmacological target upstream of CRP, is associated with these amyloid-related pathologies remains unknown. METHODS: We used 26 CRP-lowering variants near the IL-6 receptor gene to perform Mendelian randomization analyses for AD (111,326 cases, 677,663 controls) and ICH (1545 cases, 1481 controls). We explored the effect of genetically proxied IL-6 signaling on serum, cerebrospinal fluid (CSF), and brain proteome (971 individuals). RESULTS: Genetically upregulated IL-6 receptor-mediated signaling was associated with lower risk of AD (OR per increment in serum logCRP levels: 0.87, 95% CI: 0.79-0.95) and lobar ICH (OR: 0.27, 95% CI: 0.09-0.89). We also found associations with 312, 77, and 79 brain, CSF, and plasma proteins, respectively, some of which were previously implicated in amyloid-clearing mechanisms. DISCUSSION: Genetic data support that CRP-lowering through variation in the gene encoding IL-6 receptor may be associated with amyloid-related outcomes. Highlights: Genetic variants proxying IL-6 inhibition are associated with AD and lobar ICH risk.The variants are also associated with amyloid clearing-related proteomic changes.Whether pharmacologic IL-6 inhibition is linked to AD or lobar ICH merits further study.

The role of the gluteofemoral adipose tissue in cerebrovascular disease risk: evidence from a mendelian randomization and mediation analysis.

Objective: To explore causal associations between BMI-independent body fat distribution profiles and cerebrovascular disease risk, and to investigate potential mediators underlying these associations. Methods: Leveraging data from genome wide association studies of BMI-independent gluteofemoral (GFAT), abdominal subcutaneous (ASAT), and visceral (VAT) adipose tissue volumes in UK Biobank, we selected variants associated with each trait, and performed univariable and multivariable mendelian randomization (MR) analyses on ischemic stroke and subtypes (large artery (LAS), cardioembolic (CES), small vessel (SVS)). We used coronary artery disease (CAD), carotid intima media thickness (cIMT), and an MRI-confirmed lacunar stroke as positive controls. For significant associations, we explored the mediatory role of four possible mediator categories in mediation MR analyses. Results: Higher genetically proxied, BMI-independent GFAT volume was associated with decreased risk of ischemic stroke (FDR-p=0.0084), LAS (FDR-p=0.019), SVS (FDR-p<0.001), CAD (FDR-p<0.001), MRI-confirmed lacunar stroke (FDR-p=0.0053), and lower mean cIMT (FDR-p=0.0023), but not CES (FDR-p=0.749). Associations were largely consistent in pleiotropy- and sample structure-robust analyses. No association was observed between genetically proxied ASAT or VAT volumes and ischemic stroke/subtypes risk. In multivariable MR analyses, GFAT showed the most consistent independent association with ischemic stroke, LAS, and SVS. Common vascular risk factors were the predominant mediators in the GFAT-cerebrovascular disease axis, while adipose-tissue-specific adiponectin and leptin mediated a proportion of ischemic stroke and CAD risk. Interpretation: Genetically proxied, BMI-independent higher GFAT volume is associated with reduced cerebrovascular disease risk. Although this is largely mediated by common vascular risk factor modification, targeting adipose-tissue specific pathways may provide additional cardiovascular benefit.

Evaluating the Association of the Increase in the WIC Cash Value Benefit on the Diversity of MyPlate Fruits and Vegetables Redeemed and Consumed By Children in Low-Income Households.

Background: Fruits and vegetables (FV) are a critical source of nutrients, yet children in the United States are not meeting the Dietary Guidelines for Americans (DGA). The monthly FV cash value benefit (CVB) included in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC)'s food package to support child FV intake (FVI) received a substantial increase for economic relief during the COVID-19 pandemic. Objectives: To evaluate how an expansion of the monthly WIC CVB to purchase FV for WIC children ages 1-4 y is associated with diversity in FV redeemed, and how changes in redeemed FV are related to FVI. Methods: Caregivers representing 1463 WIC-participating children recruited from Los Angeles County, California, completed surveys during the CVB augmentation (T1: CVB = $9/mo; T2 = $35/mo; T3 = $24/mo). Redeemed price look-up codes (PLUs), corresponding to a food item, were assigned to its corresponding MyPlate FV group. Multivariable generalized estimating equation regression models assessed changes in amount and diversity of FV redemption across MyPlate groups and associations between changes in FV diversity and changes in FVI. Results: Slightly over half of all households were food insecure (55%), half of the children were female (52%), and most were Hispanic (78%). Compared with T1, significant increases in the number of PLUs and dollars redeemed were observed in most MyPlate FV groups. From T1 to T2, significant increases in diversity scores were observed for total fruit (ß: 1.6 pts; 95% confidence interval [CI]: 1.4, 1.7), total vegetable (ß: 3.6 pts; 95%CI: 3.4, 3.9), and total FV (ß:7.8 pts; 95%CI: 7.4, 8.2). Similarly, increases in diversity score were observed at T3 compared with T1. Changes in FV diversity redeemed were not associated with changes in FVI. Conclusions: During the CVB augmentation, WIC participants redeemed a greater amount and variety of FV according to DGA MyPlate recommendations, supporting its permanent increase.

Radiographic Findings Associated With Mild Hip Dysplasia in 3869 Patients Using a Deep Learning Measurement Tool.

Background: Hip dysplasia is considered one of the leading etiologies contributing to hip degeneration and the eventual need for total hip arthroplasty (THA). We validated a deep learning (DL) algorithm to measure angles relevant to hip dysplasia and applied this algorithm to determine the prevalence of dysplasia in a large population based on incremental radiographic cutoffs. Methods: Patients from the Osteoarthritis Initiative with anteroposterior pelvis radiographs and without previous THAs were included. A DL algorithm automated 3 angles associated with hip dysplasia: modified lateral center-edge angle (LCEA), Tönnis angle, and modified Sharp angle. The algorithm was validated against manual measurements, and all angles were measured in a cohort of 3869 patients (61.2 ± 9.2 years, 57.1% female). The percentile distributions and prevalence of dysplastic hips were analyzed using each angle. Results: The algorithm had no significant difference (P > .05) in measurements (paired difference: 0.3°-0.7°) against readers and had excellent agreement for dysplasia classification (kappa = 0.78-0.88). In 140 minutes, 23,214 measurements were automated for 3869 patients. LCEA and Sharp angles were higher and the Tönnis angle was lower (P < .01) in females. The dysplastic hip prevalence varied from 2.5% to 20% utilizing the following cutoffs: 17.3°-25.5° (LCEA), 9.4°-15.6° (Tönnis), and 41.3°-45.9° (Sharp). Conclusions: A DL algorithm was developed to measure and classify hips with mild hip dysplasia. The reported prevalence of dysplasia in a large patient cohort was dependent on both the measurement and threshold, with 12.4% of patients having dysplasia radiographic indices indicative of higher THA risk.

Brain Care Score and Neuroimaging Markers of Brain Health in Asymptomatic Middle-Age Persons.

OBJECTIVES: To investigate associations between health-related behaviors as measured using the Brain Care Score (BCS) and neuroimaging markers of white matter injury. METHODS: This prospective cohort study in the UK Biobank assessed the BCS, a novel tool designed to empower patients to address 12 dementia and stroke risk factors. The BCS ranges from 0 to 21, with higher scores suggesting better brain care. Outcomes included white matter hyperintensities (WMH) volume, fractional anisotropy (FA), and mean diffusivity (MD) obtained during 2 imaging assessments, as well as their progression between assessments, using multivariable linear regression adjusted for age and sex. RESULTS: We included 34,509 participants (average age 55 years, 53% female) with no stroke or dementia history. At first and repeat imaging assessments, every 5-point increase in baseline BCS was linked to significantly lower WMH volumes (25% 95% CI [23%-27%] first, 33% [27%-39%] repeat) and higher FA (18% [16%-20%] first, 22% [15%-28%] repeat), with a decrease in MD (9% [7%-11%] first, 10% [4%-16%] repeat). In addition, a higher baseline BCS was associated with a 10% [3%-17%] reduction in WMH progression and FA decline over time. DISCUSSION: This study extends the impact of the BCS to neuroimaging markers of clinically silent cerebrovascular disease. Our results suggest that improving one's BCS could be a valuable intervention to prevent early brain health decline.

Gamma amplitude-envelope correlations are strongly elevated within hyperexcitable networks in focal epilepsy.

Methods to quantify cortical hyperexcitability are of enormous interest for mapping epileptic networks in patients with focal epilepsy. We hypothesize that, in the resting state, cortical hyperexcitability increases firing-rate correlations between neuronal populations within seizure onset zones (SOZs). This hypothesis predicts that in the gamma frequency band (40-200 Hz), amplitude envelope correlations (AECs), a relatively straightforward measure of functional connectivity, should be elevated within SOZs compared to other areas. To test this prediction, we analyzed archived samples of interictal electrocorticographic (ECoG) signals recorded from patients who became seizure-free after surgery targeting SOZs identified by multiday intracranial recordings. We show that in the gamma band, AECs between nodes within SOZs are markedly elevated relative to those elsewhere. AEC-based node strength, eigencentrality, and clustering coefficient are also robustly increased within the SOZ with maxima in the low-gamma band (permutation test Z-scores > 8) and yield moderate discriminability of the SOZ using ROC analysis (maximal mean AUC ~ 0.73). By contrast to AECs, phase locking values (PLVs), a measure of narrow-band phase coupling across sites, and PLV-based graph metrics discriminate the seizure onset nodes weakly. Our results suggest that gamma band AECs may provide a clinically useful marker of cortical hyperexcitability in focal epilepsy.

The Impact of American Board of Urology Certification on Postoperative Outcomes for Patients in New York State.

INTRODUCTION: Our goal was to determine if board certification status was associated with improved postoperative outcomes for certain urologic oncology operations. METHODS: We performed a retrospective cohort study of patients aged 65 and over having radical prostatectomy (RP), radical cystectomy (RC), and radical or partial nephrectomy (RPN) by surgeons with New York State licenses from 2015 to 2021 using the Medicare limited dataset. Our primary exposure was surgeon American Board of Urology certification determined by the New York State Physician Profile. All surgeons were in practice for at least 5 years. Our primary outcomes were 90-day mortality, 30-day unplanned readmission, and hospital length of stay (LOS). We used multivariable linear and logistic regression adjusted for surgeon, hospital, and patient characteristics. We performed the analysis in R, and 2-sided P values < .05 were considered statistically significant. RESULTS: We identified 12,601 patients who had a procedure performed. At the time of the procedure, a minority of procedures (1.3%) were performed by nonboard-certified (NBC) urologists. Among the patient cohort, there were 262 and 1419 mortality and readmission events, respectively; median LOS was 2 days (interquartile range 1155). Patients operated on by NBC urologists tended to have lower-volume surgeons who were less likely to be fellowship trained and to have surgery at smaller hospitals. Patients treated by NBC urologists were more likely to have RP, and less likely to have RC and RPN. On multivariate analysis, board certification was protective against readmission for RP (P < .001) and RC (P = .02), longer LOS for RC (P = .001), and mortality for RPN (P = .008). CONCLUSIONS: Urology board certification was associated with fewer readmissions after RP and RC, a shorter LOS after RC, and a lower risk of mortality after RPN. Given low event numbers, these findings require validation with a larger dataset.