Jacobs Institute of Women's Health
George Washington University: Health Sciences Research Commons (HSRC)Not a member yet
51297 research outputs found
Sort by
The nonsteroidal MR antagonist finerenone reverses Western diet-induced kidney disease by regulating mitochondrial and lipid metabolism and inflammation
No full textMineralocorticoid receptor (MR) overactivation plays a crucial role in the pathogenesis of chronic kidney disease, as well as several cardiovascular and arterial diseases. Current studies determined the mechanisms of the beneficial kidney effects of the nonsteroidal MR antagonist finerenone (FN) in a mouse model of Western diet-induced obesity and insulin resistance. Ten-week-old male C57BL/6J mice were fed a low-fat (LF) or a Western diet (WD) for 12 weeks followed by treatment with either vehicle or FN for another 14 weeks (intervention studies) until they were 36 weeks old. Finerenone treatment prevented 1) the increased albuminuria and kidney injury molecule 1 (KIM1); 2) the expanded extracellular mesangial matrix and synaptopodin coverage; 3) fibronectin, collagen IV, CD45, and CD68 immunostaining; 4) glomerular basement membrane disruption, podocyte foot processes effacement, and mitochondrial structural abnormalities; 5) the proinflammatory cytokines [monocyte chemoattractant protein-1 (MCP-1)], innate immunity pathways [Toll-like receptor-2 (TLR2), stimulator of interferon genes (STING), signal transducer and activator of transcription 3 (STAT3)], and fibrosis markers fibronectin, transforming growth factor-β (TGFβ), and plasminogen activator inhibitor-1 (Pail); and 6) the increased kidney cholesterol levels. There was also reduced expression of nuclear receptor estrogen-related receptor-γ (ERRγ) without changes in ERRα in WD-fed mice, whereas both ERRα and ERRγ expression levels increased after finerenone treatment. NADH lifetime analysis showed decreased bound NADH, compatible with decreased mitochondrial oxidative phosphorylation (OXPHOS) in the kidneys of WD-fed mice compared to controls, which was prevented by finerenone treatment. In conclusion, finerenone treatment exhibits a renal protective role and prevents the progression of kidney disease by regulating mitochondrial function, most likely via ERRγ, and reducing lipid accumulation and inflammation. Finerenone, a nonsteroidal mineralocorticoid receptor (MR) antagonist, has shown promise in protecting against kidney damage in obese, insulin-resistant mice. It effectively prevents albuminuria, inflammation, fibrosis, and mitochondrial dysfunction, while also restoring estrogen-related receptor-γ (ERRγ) expression. These results suggest that finerenone could play a key role in halting the progression of kidney disease by enhancing mitochondrial function and reducing harmful lipid accumulation, offering a potential therapeutic strategy for managing kidney complications in metabolic disorders
Healthcare worker perspectives on system-level barriers to hepatitis B birth dose vaccination: An analysis in five urban U.S. hospitals
No full textDespite three decades of recommendations, hepatitis B birth dose vaccination coverage remains suboptimal at 81.5% nationally, falling short of other routine immunizations and public health targets. This study examined implementation practices across five Washington, DC birthing hospitals through semi-structured interviews with 36 healthcare workers representing professional roles. While providers demonstrated strong support for vaccination, with 94% routinely recommending the birth dose for newborns, significant system-level barriers emerged that impede optimal delivery. Only 69% consistently recommended vaccination for premature infants, revealing concerning practice variability and knowledge gaps regarding weight-based guidelines. Critical infrastructure deficiencies included widespread unawareness of vaccination tracking systems (64% uncertain), complete absence of designated vaccine champions, minimal leadership engagement, and severely limited provider training - with only 19% receiving regular education on birth dose importance and 86% lacking training to address vaccine hesitancy. Electronic reminder systems were absent (17% utilization), despite proven effectiveness. Although parent education showed better implementation with literacy-appropriate materials and multi-modal communication strategies, the disconnect between robust provider support and weak institutional systems represents a fundamental implementation failure. Addressing these modifiable barriers through systematic quality improvement initiatives, enhanced monitoring infrastructure, and comprehensive workforce development could substantially improve vaccination coverage and advance perinatal hepatitis B elimination goals
Antenatal Prediction of Early Cord Clamping among Infants Born Extremely Preterm
No full textOBJECTIVE: To identify prenatal risk factors associated with early cord clamping (ECC) in extremely infants born extremely preterm (22-28 weeks) and to use these factors to predict which infants have the highest risk of ECC. STUDY DESIGN: Stepwise logistic regression and classification and regression tree (CART) analysis was performed to identify variables most associated with ECC and to build a parsimonious model to identify infants born preterm who are at the highest risk of ECC. RESULTS: There were 12,622 infants eligible for analysis, (ECC, N=8465 vs deferred cord clamping (DCC), N=4157). In the CART model, center, lack of antenatal magnesium, cesarean delivery, lower gestational age, and antenatal hemorrhage, in that rank order, were the factors that contributed most to identifying which infants received ECC. Several additional factors were also statistically significant, including time to delivery after admission to the hospital as well as maternal race and ethnicity. CONCLUSIONS: Our results suggest that there are multiple factors among extremely preterm pregnancies, including center, lack of antenatal magnesium, cesarean delivery, lower gestational age, and antenatal hemorrhage, that are associated with infants who are more likely to miss DCC. There are also differences in rates by maternal race and ethnicity in who receives DCC compared with ECC. Identifying these factors now can inform future research and encourage local and larger-scale quality improvement practice changes
Pathophysiological mechanisms linking osteoarthritis and neurodegenerative disease risk
No full textOBJECTIVE: This review aims to assess the existing evidence that connects osteoarthritis (OA) with neurodegenerative diseases, specifically Alzheimer\u27s disease (AD) and Parkinson\u27s disease (PD), and to elucidate shared mechanisms that may contribute to the development of innovative therapeutic approaches. METHOD: We present a narrative review of prior epidemiological, genetic, and mechanistic studies that describe overlapping risk factors and convergent pathological pathways linking OA and neurodegenerative diseases. Key focus areas include metabolic and hormonal influences, inflammatory cytokine signaling, and mitochondrial dysfunction that arise in both OA and neurodegenerative diseases. RESULTS: Emerging evidence indicates that OA and neurodegenerative diseases share core drivers-advanced age, obesity, metabolic syndrome, and genetic susceptibility. Central to both are chronic inflammation, mediated by tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β), as well as mitochondrial dysfunction, which promote both cartilage degradation and neuronal death. Genetic data reveal consistent activation of NF-κB and JAK/STAT signaling, with contributions from MAPK, TGF-β, and WNT signaling pathways. Preclinical models demonstrate that OA-induced peripheral inflammation can amplify neuroinflammation and accelerate AD-like pathology, underscoring a potential bidirectional link. Despite these associations, causal relationships have not been concretely established. CONCLUSION: OA may contribute to neurodegenerative risk through shared inflammatory and metabolic mechanisms, representing an underrecognized intersection between musculoskeletal and neurological diseases. Targeting these convergent pathways offers a promising avenue for dual-purpose interventions. Establishing causality through longitudinal and mechanistic studies could enable early identification of at-risk patients and guide the development of therapies that mitigate both joint degeneration and neurodegeneration
Pre- and post-move exposure to air pollution and neighborhood socioeconomic status
No full textINTRODUCTION: Nearly 10 % of the U.S. population moves in a given year. We aimed to examine differences in neighborhood socioeconomic status (nSES) and ambient air pollution concentrations before and after a residential move, whether change varies by distance of the move, and whether moving is a potential source of bias in estimating relationships between contextual exposures and outcomes. METHODS: We used data from participants in the Atherosclerosis Risk in Communities (ARIC) Study with geocoded addresses at Visit 2 (Visit 2; 1990-1992) and Visit 3 (Visit 3; 1993-1995). We quantified nSES using the 1990 census and estimated concentrations of fine particulate matter (PM), ozone (O) and nitrogen dioxide (NO). We defined short-distance and long-distance movers as having moved less and more than the median move distance of 4.3 miles, respectively. We quantified Visits 2 to 3 change in nSES and air pollution for short and long-distance movers, examined change in air pollution after accounting for temporal trends, and conducted a quantitative bias analysis to estimate the bias introduced by not accounting for moving in example studies of PM and health. RESULTS: On average, compared to non-movers, short-distance movers relocated to neighborhoods with better nSES and similar air pollution concentrations, while long-distance movers relocated to neighborhoods with worse nSES but lower exposure to air pollution. The quantitative bias analysis suggested there was little to no bias in the PM-health relationship from not accounting for relocation, likely due to relatively little overall difference in PM exposures observed with relocation. CONCLUSIONS: Change in nSES and air pollution with a residential move differs by move distance. However, not accounting for relocation may not lead to significant bias in the relationship with the health outcome. Understanding the extent to which contextual exposures change after a move can clarify whether accounting for bias due to relocation is necessary
Cerebellar tDCS modulates cortico-cortical functional networks in a regionally specific manner
No full textWith extensive anatomical interconnections with the cerebral cortex, the cerebellum is well-positioned to coordinate communication between cortical regions. Because different cerebellar subregions interconnect with distinct cortical networks, the impact of regional cerebellar activity should be network-specific. However, it is unclear whether or how cerebellar modulation impacts the functional connectivity of human cerebral cortical networks. To test this, young adults (n=33, 21.2±3.1 years, 22M/11F) were randomly assigned to receive 20min of 1.5mA transcranial direct current stimulation (tDCS) targeting either the posterior midline (n=17) or right posterolateral cerebellum (n=16). Each participant received anodal (excitatory), cathodal (inhibitory) or sham tDCS during separate MRI sessions. We analyzed post-tDCS resting-state fMRI data to determine whether modulating different cerebellar subregions impacted resting-state functional connectivity (FC) of distinct cortical networks. Multivariate Pattern Analyses revealed that posterior midline tDCS primarily modulated FC in the default mode network (DMN), while posterolateral cerebellar tDCS altered FC in the frontoparietal network (FPN). Seed-based connectivity analyses confirmed that posterior midline modulation increased within-network DMN FC while decreasing FC between DMN, visual, and somatomotor networks. In contrast, posterolateral cerebellar tDCS strengthened frontoparietal and attentional network FC while decoupling FPN-DMN and FPN-visual networks. These results support the hypothesis that the cerebellum modulates cortico-cortical connectivity and further suggest that the posterior midline modulates the DMN while the posterolateral cerebellum shifts the brain toward a task-ready cognitive state. These findings provide insight into how the cerebellum influences the cerebral cortex and have clinical implications for targeted interventions for a range of neurological and psychiatric conditions. The cerebellum is extensively interconnected with the cerebral cortex, and it has been proposed that the cerebellum modulates cortico-cortical functional interactions. Confirming this, transcranial direct current stimulation (tDCS) targeting two cerebellar subregions modulated functional connectivity in different cortico-cortical networks. TDCS targeting the posterior cerebellar midline altered functional connectivity in regions of the default mode network. Right posterolateral cerebellar tDCS primarily impacted the functional connectivity of the fronto-parietal network. These data confirm that the cerebellum modulates interactions between cortical networks in a topographically-specific manner and could inform therapeutic interventions using cerebellar neuromodulation for a range of neurological and psychiatric conditions
The Data Distillery: A Graph Framework for Semantic Integration and Querying of Biomedical Data
No full textThe Data Distillery Knowledge Graph (DDKG) is a framework for semantic integration and querying of biomedical data across domains. Built for the NIH Common Fund Data Ecosystem, it supports translational research by linking clinical and experimental datasets in a unified graph model. Clinical standards such as ICD-10, SNOMED, and DrugBank are integrated through UMLS, while genomics and basic science data are structured using ontologies and standards such as HPO, GENCODE, Ensembl, STRING, and ClinVar. The DDKG uses a property graph architecture based on the UBKG infrastructure and supports ontology-based ingestion, identifier normalization, and graph-native querying. The system is modular and can be extended with new datasets or schema modules. We demonstrate its utility for informatics queries across eight use cases, including regulatory variant analysis, tissue-specific expression, biomarker discovery, and cross-species variant prioritization. The DDKG is accessible via a public interface, a programmatic API, and downloadable builds for local use
Impact of Comprehensive Lifestyle Interventions on Plasma Branched-Chain Amino Acid Concentrations: A Randomized Trial
No full textBACKGROUND: Elevated plasma branched-chain amino acid (BCAA) concentrations are associated with a higher risk of type 2 diabetes and cardiovascular diseases. Lifestyle interventions have been proposed as a strategy to manage plasma BCAA concentrations, but evidence of their effectiveness is limited. OBJECTIVE: We investigated the effects of comprehensive lifestyle interventions on plasma BCAA concentrations over six months and associations between changes in Body Mass Index (BMI), physical fitness, and dietary factors and plasma BCAA changes METHODS: The PREMIER study was a randomized trial of the effects of behavioral lifestyle interventions. The interventions included counseling on diet, exercise, and weight loss (\u27Established\u27), a similar intervention with additional guidance to follow Dietary Approaches to Stop Hypertension (\u27Established plus DASH\u27), and an advice-only control group. We analyzed data from 713 male and female adult participants during the 6-month intervention period. Data and biospecimens were obtained through the NHLBI BioLINCC repository, and plasma BCAA concentrations were measured using NMR spectroscopy. Multiple linear regression was used to assess the association between intervention groups and BCAA concentrations. RESULTS: The Established (-7.19 μmol/L; 95% CI 17.45, 3.08) and Established plus DASH (-8.70 μmol/L; 95% CI -18.95, 1.55) interventions were associated with non-significant decreases in BCAA concentrations compared with the control group. Changes in BMI were correlated with changes in BCAA concentrations during the trial (partial Pearson r=0.24, p\u3c0.001). Although changes in fitness and fiber intake were also significantly correlated with changes in BCAA concentrations, adjustment for BMI attenuated these correlations. Changes in the DASH and healthy plant-based diet indices and BCAA and protein intakes were not significantly correlated with plasma BCAA changes. CONCLUSION: Weight loss resulting from lifestyle interventions was associated with reductions in plasma BCAA concentrations. Improvements in fitness and diet composition were not associated with changes in BCAA concentrations independent of weight loss. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT00000616)
Heart Rate Variability Biofeedback and Mental Stress Myocardial Flow Reserve: A Randomized Clinical Trial
No full textIMPORTANCE: Heart rate variability biofeedback (HRVB) is a self-regulation intervention that targets autonomic nervous system activity through guided breathing and visualization. Investigating its effects on cardiovascular responses to psychological stress may clarify its therapeutic potential for patients with coronary artery disease (CAD). OBJECTIVE: To examine the effects of HRVB on myocardial blood flow (MBF) changes during a mental stress challenge in individuals with CAD. DESIGN, SETTING, AND PARTICIPANTS: This single-center pilot randomized clinical trial included participants aged 30 to 79 years with CAD recruited in a university hospital setting and enrolled from March 30 to November 9, 2016 (data were analyzed from January to August 2025 for final reporting). Participants were followed up for 2 months. INTERVENTION: Six weeks of HRVB training and prescribed daily practice vs usual care (standard medical care with the intervention received after study completion). MAIN OUTCOMES AND MEASURES: Myocardial blood flow changes after an arithmetic mental stress challenge, as measured by rubidium-82 positron emission tomography at baseline and again after 8 weeks. Linear mixed models examined the effects of HRVB on mental stress myocardial flow reserve (MFR), which is the ratio of MBF with mental stress to MBF at rest, while adjusting for baseline flow levels. RESULTS: Data were analyzed from 21 participants (12 HRVB, 9 usual care) with mean (SD) age of 65 (6) years; 13 (61.9%) were male. In the HRVB group, the mean MFR with mental stress at baseline was 1.07 (95% CI, 0.94-1.22) and after the intervention was 1.16 (95% CI, 1.06-1.26). In the usual care group, the mean MFR with mental stress at baseline was 1.20 (95% CI, 1.05-1.38) and at the follow-up visit was 1.15 (95% CI, 0.94-1.40). While the within-group changes were not statistically significant, between-group difference in change from baseline to follow-up was significant. Specifically, the change in MFR in the HRVB group was 0.10 (95% CI, 0.01-0.19) units greater than the change in the usual care group (P = .03). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of participants with CAD, HRVB resulted in an increased MFR with mental stress compared with usual care. These results suggest potential benefits of HRVB during periods of mental stress and support the need for larger clinical trials to further investigate the efficacy of HRVB in cardiovascular disease prevention. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02657382