IMPORTANCE:The effect of a short interpregnancy interval (IPI) on pelvic floor disorders is unknown. OBJECTIVES:We investigated the relationship between a short IPI and the development of stress incontinence (SUI), pelvic organ prolapse (POP), and anal incontinence (AI) in the decade after the first delivery. STUDY DESIGN:We performed a secondary analysis of the Mothers' Outcomes After Delivery study-a prospective cohort of women recruited 5-10 years following their first delivery and followed annually between 2008 and 2018. A short IPI was defined as ≤18 months, calculated as the number of months between deliveries minus the length of the second pregnancy. SUI, POP, and AI were identified by annual validated questionnaires, examination, or history of treatment. Data were analyzed in SAS. Variables significant on bivariate analysis were entered into multivariable logistic regression models predicting each outcome using the generalized estimating equations approach for repeated measures. RESULTS:Of 1,127 women, the majority (671, 59%) never had a short IPI, 395 (35%) had 1 short IPI, and 61 (6%) had 2 or more. Within 10-15 years, 219 women (19%) reported SUI, 156 (14%) reported POP, and 251 (22%) reported AI. We found that a short IPI was not associated with SUI ( P =0.69), POP ( P =0.71), or AI ( P =0.95). When restricting the cohort to women with only nonoperative vaginal deliveries (n=440), there remained no difference in the presence of SUI, POP, or AI ( P = 0.88, 0.84, 0.78, respectively). CONCLUSIONS:A short IPI is not associated with pelvic floor disorders in the decade following the first delivery. This should be reassuring to women at risk of PFDs who elect to become pregnant within 18 months of childbirth.

PURPOSE:Cardiac rehabilitation (CR) is an effective but underused secondary prevention strategy. We evaluated where the relative gap in the implementation of CR occurs and characteristics related to CR utilization. METHODS:We analyzed electronic health records from a large academic health system (2017-2019). We included patients aged ≥18 years, hospitalized with a cardiac event, with an indication for CR. We evaluated crude proportions and used mixed-effects logistic regression to examine the association of characteristics with referral, enrollment (≥1 session), and completion (≥36 sessions), accounting for multiple admissions. RESULTS:Among 4084 patient encounters (mean age: 65.3 ± 14.6 years, 45% female, and 42% Black), 25% were referred, 29% of those referred, enrolled, and 21% of those enrolled, completed CR. We identified characteristics associated with lower CR referral, for example, Black patients (OR = 0.64: 95% CI, 0.50-0.80), female patients (OR = 0.68: 95% CI, 0.56-0.83), and discharge from noncardiology services (eg, OR = 0.07: 95% CI, 0.05-0.10 for general medicine). Post-discharge outpatient visits were associated with higher CR referrals (eg, OR = 1.94: 95% CI, 1.56-2.41 for cardiology follow-up visits). The pattern was largely similar for enrollment and completion, except for higher enrollment for cardiac surgery and lower enrollment for lower-income patients. CONCLUSIONS:In the CR care cascade, significant bottlenecks exist at each step, with the narrowest bottleneck noted at the completion stage. We also identified demographic and health system characteristics related to lower CR utilization, which can guide system- and individual-level efforts to promote CR use.

Abstract Background Genetic testing for inherited cardiovascular conditions is recommended by multiple national guidelines to inform medical management. However, access to genetic counseling and testing is often limited particularly in the inpatient setting. Cardiologists cite lack of access to genetic counselors as a reason for not pursuing genetic testing. Genetic test education videos have been successfully implemented in the outpatient setting to increase patient volumes and decrease wait times, but they have not been studied in the inpatient setting. Methods This was a pilot study utilizing a genetic test education video in lieu of a traditional genetics consult for inpatients with a suspected hereditary cardiomyopathy, arrhythmia or familial hypercholesterolemia. Patients completed the cardiovascular multidimensional model of informed choice (MMIC) and SURE scales to assess whether the video provided sufficient information to make an informed decision. Results Over 22 months, 186 adult cardiovascular inpatients at Johns Hopkins Hospital were referred with 112 patients consenting to the study. Implementation of the pre-test videos increased the average number of monthly consults from 1 to 8. After watching the video, 90% (100/111) of patients made an informed choice to proceed with genetic testing using the MMIC scale. Using the SURE scale, 87% (97/112) of patients had no decisional conflict regarding whether or not to proceed with genetic testing. Conclusions These results indicate a pre-test genetic educational video could be considered as a strategy to scale access to genetic counseling and cardiovascular genetic testing, especially in hospital systems where access to genetics is limited in the inpatient setting.

Introduction and Objective: Conventional thinking suggests that fasting free fatty acids (FFAF) are positively correlated with adiposity. Given adiposity differences by sex and ancestry, we evaluated this relationship in South Asian (SA) adolescents and young adults (AYA) compared with White (W) and African American (AA) peers. Methods: We measured FFAF and total fat mass (FM; Hologic DXA scan) among SA, W, and AA AYA with BMI ≥80%ile (≥23kg/m2 if ≥18y) without diabetes. Ancestry differences in the FFAF-FM association were tested using generalized linear models with interaction analysis between ancestry groups, sex, and FFAF, adjusted for age, pubertal stage, and height2. Results: AYA [51 SA, mean age: 19.8y, 54 W: 18.9y, 49 AA: 18.8y, p=0.02] did not differ by sex, BMI, pubertal stage, or FM [mean: SA 31219g, AA 31964g, W 29733g, p=0.5]. In males, W AYA had a positive relationship between FFAF and FM (β=0.07%, p<0.001), but differed by ancestry: SA vs W, -0.08%, p<0.001; AA vs W, -0.12%, p<0.001 (See Figure). Among females, there were no significant differences. Conclusion: In our cohort, the FFAF -FM relationship varied by sex and ancestry. Among males, FFAF were positive correlated with FM only in the W group. Thus, a positive relationship between FFAF and FM may be specific to W males. Disclosure T. Hitt: None. D. Stefanovski: None. R.J. McCarter: None. L.R. Yanek: None. B.S. Zemel: Consultant; Current; Incyte. Consultant; Ended; Regeneron Pharmaceuticals Inc. A. Kelly: None. S.N. Magge: None. Funding NIH/NDDK (R01DK115648); CTSA(UL1TR001878, UL1TR001079)

Background Heart failure (HF) is increasingly driven by cardiometabolic risk factors such as obesity and insulin resistance. The estimated glucose disposal rate (eGDR) is a validated surrogate marker of insulin resistance. Reduced eGDR, reflecting higher insulin resistance, has been linked to cardiovascular disease, but its associations with myocardial fibrosis and HF remain unclear. Methods The study included 6025 participants in MESA (Multi‐Ethnic Study of Atherosclerosis) free of HF at exam 2 (2002–2004). eGDR was calculated using body mass index, hypertension, and hemoglobin A1c. Cardiac magnetic resonance imaging (2010–2012) assessed left ventricular ejection fraction and myocardial fibrosis by late gadolinium enhancement. Associations of baseline eGDR with incident HF were evaluated using Cox models, stratified by diabetes. Results Over a mean follow‐up of 14±5 years, 404 participants developed HF. eGDR was inversely associated with incident HF (adjusted hazard ratio [HR] per unit decrease, 1.28 [95% CI, 1.22–1.35]), a relationship that persisted regardless of diabetes status and was more pronounced for HF with preserved ejection fraction (n=200; adjusted HR per unit decrease, 1.36 [95% CI, 1.27–1.45]) than HF with reduced ejection fraction (n=168; HR, 1.19 [95% CI, 1.11–1.27]). Lower eGDR was also associated with higher left ventricular ejection fraction (n=2899; β=0.16, [95% CI, 0.03–0.28]) and higher odds of myocardial fibrosis (n=1780; adjusted odds ratio, 1.27 [95% CI, 1.16–1.41]). Conclusions Lower eGDR is independently associated with subclinical myocardial damage and incident HF, highlighting insulin resistance as a key driver of adverse remodeling and a potential marker for early HF risk stratification and prevention.

BACKGROUND:Changes in ischemic white matter hyperintensity (WMH) volume on magnetic resonance imaging over time are associated with cognitive decline. We investigated whether changes in WMH volume over time exhibit threshold effects of normalized WMH volume on declining cognitive performance and whether these effects on cognition differ between deep WMHs (DWMHs) and periventricular WMHs (PVWMHs). METHODS:We followed 339 participants longitudinally from GeneSTAR (Genetic Study of Atherosclerosis Risk) with brain magnetic resonance imaging and neuropsychological testing at baseline (2009-2013) and at 13-year follow-up (2023 to present; 62% female, and 33% Black; mean baseline age, 49.7±9.6 years). WMHs were classified as PVWMH (within 2 mm of ventricles) or DWMH. Two-segment linear spline regression models using adjusted mixed linear regression identified test-specific thresholds longitudinally beyond which cognitive decline accelerated. Cognitive scores from both timepoints were treated as repeated measures, with WMH included as a time-varying predictor. RESULTS:Declines in motor function and processing speed accelerated beyond thresholds of changing PVWMH and DWMH volumes. For Grooved Pegboard tests, changes in volume were associated with minimal effects below a threshold of changing volume (log-transformed ratio of lesion volume to intracranial volume for PVWMH from -9.42 to -9.29 and DWMH from -11.8 to -11.7). Substantial declines in cognitive performance were observed above thresholds of increases in volume (slope differences: PVWMH: 14.5-15.1 seconds per log-unit; P<0.001; and DWMH: 9.54-10.9; P<0.001). The digit symbol substitution test demonstrated paradoxical positive associations below changing volume thresholds (PVWMH: β=6.68; P=0.001; and DWMH: β=6.98; P<0.001), reversing to decline above thresholds of increase in volume for PVWMH (Δβ=-11.2; P<0.001) and DWMH (Δβ=-9.77; P<0.001). CONCLUSIONS:Changes in WMH volume exhibit nonlinear threshold effects on changes in cognitive performance over time and differ by anatomic region. Minimal cognitive impact occurred below thresholds, with accelerated declines above. PVWMHs demonstrate larger effects on declining cognitive function than DWMH, particularly for motor and processing speed functions, and progress at a faster rate.

Objective To build natural language processing (NLP) strategies to characterize measures of genetic counseling (GC) efficiency and classify measures according to phase of GC (pre- or post-genetic testing).Materials and Methods This study selected and annotated 800 GC notes from 7 clinical specialties in a large academic medical center for NLP model development and validation. The NLP approaches extracted GC efficiency measures, including direct and indirect time and GC phase. The models were then applied to 24 102 GC notes collected from January 2016 through December 2023.Results NLP approaches performed well (F1 scores of 0.95 and 0.90 for direct time in GC and GC phase classification, respectively). Our findings showed median direct time in GC of 50 minutes, with significant differences in direct time distributions observed across clinical specialties, time periods (2016-2019 or 2020-2023), delivery modes (in person or telehealth), and GC phase.Discussion As referrals to GC increase, there is increasing pressure to improve efficiency. Our NLP strategy was used to generate and summarize real-world evidence of GC time for 7 clinical specialties. These approaches enable future research on the impact of interventions intended to improve GC efficiency.Conclusion This work demonstrated the practical value of NLP to provide a useful and scalable strategy to generate real world evidence of GC efficiency. Principles presented in this work may also be valuable for health services research in other practice areas.

Multiple germline and somatic genomic factors are associated with risk of coronary artery disease, but there is no single measure of risk that integrates all information from a DNA sample. To address this gap, we develop an integrated genomic model that includes six germline and somatic genetic drivers for coronary artery disease, including polygenic risk score, genetically-proxied proteomic/metabolomic risk scores, and clonal hematopoiesis of indeterminate potential. We evaluated its predictive power in the UK Biobank (N = 391,536), and validate it using data from the TOPMed program (N = 34,177). The 10-year coronary artery disease risk based on the integrated genomic model profile ranges from 1.1% to 15.5% in the UK Biobank and from 3.8% to 33.0% in TOPMed, with a more pronounced gradient in males than females. The integrated genomic model captures the cumulative effect of multiple genetic drivers, identifying individuals at high risk for coronary artery disease despite lacking any single high-risk genetic factor, as well as individuals at low risk despite carrying known high-risk factors. In middle age, the integrated genomic model augments the performance of the Pooled Cohort Equations, a clinical risk calculator for coronary artery disease. While the integrated genomic model yields only modest incremental predictive value over polygenic risk score at the population level, it identifies approximately 13% of high-risk individuals not detected by polygenic risk score alone.

Few studies assessed the performance of population-based phasing combined with parental genotypes to infer recombination on whole genome sequence (WGS) data. In this study, our objective was to evaluate whether Shapeit2 duoHMM, a Hidden Markov Model using parental genotypes, infers recombination events reliably on WGS and with narrower intervals than SNP arrays. We based our analysis on the overlap between recombination events inferred by Merlin on SNP genotypes and Shapeit2 on WGS and SNP genotypes. We used a sample of 61 extended families from the GeneSTAR study with TopMED freeze 8 WGS on 580 sequenced subjects (60% of sample). Shapeit2 was run with a window size of 500 kilobases and 200 states on WGS. To mimic a SNP array, we extracted genotypes of 355,112 autosomal markers on the Illumina OmniExpress array. The number of recombination events per meiosis inferred by Shapeit2 on the WGS data (36.8) was aligned with the expected numbers over autosomes (35.7), although Merlin overestimated this number (115.0). 73% of Shapeit2 recombination events on WGS were detected by Merlin, a proportion rising to 91% when restricting to events also inferred by Shapeit2 on OmniExpress genotypes. Furthermore, Shapeit2 recombination intervals were narrower on WGS than OmniExpress genotypes (median of 4,530 bp vs. 49,458 bp). This suggests that Shapeit2 on WGS is a reliable and accurate method for inferring recombination events.

Large-scale multiancestry genome-wide association studies have identified hundreds of loci associated with type 2 diabetes (T2D) and glycemic traits, yet imputed genotyping arrays limit the detection of low-frequency and rare variants. Whole-genome sequencing (WGS) offers a more complete view of genetic variation, especially across diverse populations. We analyzed high-coverage (38×) WGS data from 21,913 T2D case subjects, 61,036 control subjects, and up to 50,011 individuals with no diabetes with fasting glucose, fasting insulin, and HbA1c from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine Program. We performed single-variant association testing, conditional analysis, fine-mapping, and Bayesian colocalization to identify genetic signals and assess regulatory relevance in diabetes-related tissues. We identified 76 distinct association signals across 34 loci, including novel variants at DUSP9 for T2D, and ROBO1, NDN, and MYT1 for HbA1c. Fine-mapping narrowed credible sets and improved causal variant resolution. Colocalization highlighted 80 expression signals in diabetes-related tissues, linking genetic associations to functional regulatory mechanisms. Our findings demonstrate the utility of WGS to uncover novel variants in diverse populations, enhance locus resolution, and link regulatory variation to disease-relevant tissues. This work refines the genetic architecture of T2D and glycemic traits and supports precision medicine efforts targeting diverse populations. ARTICLE HIGHLIGHTS:We aimed to improve understanding of the genetic architecture of type 2 diabetes and glycemic traits by leveraging whole-genome sequencing in diverse populations. Our goal was to identify novel variants, refine known loci, and link genetic signals to regulatory mechanisms through colocalization with expression quantitative trait loci. We discovered novel variants, significantly improved fine-mapping resolution, and identified 80 regulatory colocalization signals in diabetes-relevant tissues. These findings support precision medicine approaches by connecting genetic variation to functional biology in type 2 diabetes.

ABSTRACT Background Pretest genetic counseling (GC) is recommended in conjunction with genetic testing (GT) for cardiovascular (CV) indications, yet access to CVGC is limited leading to delayed GT. Posttest GC could increase GC and GT access but requires efficient pretest education that supports both informed GT decision-making and robust GT uptake. Methods We developed four indication-tailored online CV genetics education videos and deployed them in a 3-arm randomized trial comparing pretest vs. posttest outpatient CVGC (RESEQUENCE-GC, NCT05422573 ). Participants were 1:1:1 randomized to pretest video education plus an optional (efficiency arm) or required (flipped arm) phone call with a genetic counselor and planned posttest CVGC or to standard pretest CVGC (SOC arm). Questionnaires administered at baseline and post-education included the CV Multidimensional Model of Informed Choice [MMIC] to quantify GT knowledge and informed GT choice. Results 389/767 (50.7%) adults aged 18-80 (mean 51.2±14.9 years) scheduling a first CVGC appointment consented to RESEQUENCE-GC and completed the baseline questionnaire. Efficiency arm participants (video education + optional phone call) were most likely to complete pretest education (134, 97.4% efficiency; 107, 85.6% flipped; 111, 87.4% SOC, p=0.0012) and elect GT (131, 95.6% efficiency; 105, 84.0% flipped; 107, 84.2% SOC, p=0.0036). Few (4, 2.9%) efficiency arm participants requested an optional pretest phone call. Most flipped arm participants (90, 84.1%) had no post-video questions, consistent with the 97 second [IQR: 65s-145s] median call duration. CV genetics knowledge was high post-education (median 8 [IQR 7,8]/8 MMIC items correct). Only video-based pretest education was associated with a significant increase in knowledge (p<0.0001). Nearly all participants made an informed GT choice with no difference between intervention (95.6%) and SOC (90.4%) arms (p=0.074). Conclusions Tailored, online video pretest education can enhance CV GT uptake, support informed GT decision-making, and be integrated into efficient pretest workflows, suggesting utility in scalable posttest CVGC.

Sex-specific genetic effects on platelet aggregation may contribute to differences in thrombotic risk between women and men, yet the underlying genetic mechanisms remain poorly defined. We performed whole-genome sequencing-based genome-wide association studies (GWAS) of 19 harmonized platelet aggregation phenotypes in response to ADP, epinephrine (EPI), and collagen across three independent cohorts: GeneSTAR, the Framingham Heart Study and the Old Order Amish. Our meta-analysis identified a cluster of low-frequency variants within a 20 kb region on chromosome 10 showing strong sex-specific associations with platelet aggregation in response to low-dose EPI. The lead variant, rs116725046, exhibited a genome-wide significant sex interaction (p = 5.2 × 10-9), with opposite phenotypic effects in women and men. Female carriers demonstrated substantially increased platelet aggregation, whereas male carriers showed decreased aggregation, consistent across cohorts. Several additional variants in tight linkage disequilibrium yielded comparable interaction signals for low-dose EPI, including five SNPs driving the lowest meta-analysis p-value (p = 8.3 × 10-9). The associated variants reside within an intronic region of the long noncoding gene LINC00702, with FUMA annotations indicating regulatory chromatin states. Megakaryocyte epigenome data also indicates potential regulatory activity in platelet precursor cells near the lead variants. eQTL analyses suggested sex-differentiated genetic regulation of LINC00702 in multiple tissues, with reduced expression in male heterozygotes only. An ARE motif was identified upstream of LINC00702, supporting a potential hormone-responsive regulatory mechanism. Together, these findings identify a novel sex-specific regulatory locus influencing platelet reactivity and highlight LINC00702 as a biologically plausible mediator of sexually dimorphic platelet responses.

The COVID-19 pandemic accelerated the adoption of digital health solutions, including patient portals, which offer secure access to medical records, communication with providers, and appointment management. Despite their benefits, disparities in adoption persist across demographic and socioeconomic groups. This observational cohort study examined patient portal enrollment trends before and during the pandemic at Johns Hopkins Medicine, analyzing differences by race and socioeconomic status. We categorized patients as prior enrollees, new enrollees, or non-enrollees across three periods: pre-pandemic (March 2019 – March 2020), first-year pandemic (March 2020 – March 2021), and second-year pandemic (March 2021 – March 2022).Using electronic health record data, we assessed enrollment rates and applied logistic regression to evaluate associations with demographic and social determinants of health. The cohort included 68,738 patients, observed throughout all study periods. Analysis revealed an increase in patient portal enrollment incidence rates from 22.9 per 100 patients eligible to enroll pre-pandemic to 35.2 per 100 in the first year of the pandemic, followed by a decreased enrollment incidence rate to 13.0 per 100 in the second year of the pandemic. This trend suggests an association between the onset of the COVID-19 pandemic and the initial surge in patient portal enrollment. Comparisons between the pre-pandemic and second year of the pandemic showed statistically significant differences in enrollment rates across most demographic subgroups.Higher odds of enrollment were observed among patients aged 18–44, White, and non-Hispanic individuals, while Black, Hispanic, male, and socioeconomically disadvantaged patients exhibited lower enrollment rates. These findings highlight disparities in digital health engagement and underscore the need for targeted strategies to promote equitable access to patient portals.

BACKGROUND: Genome-wide association studies have identified several hundred susceptibility single nucleotide variants for coronary artery disease (CAD). Despite single nucleotide variant-based genome-wide association studies improving our understanding of the genetics of CAD, the contribution of structural variants (SVs) to the risk of CAD remains largely unclear. METHOD AND RESULTS: We leveraged SVs detected from high-coverage whole genome sequencing data in a diverse group of participants from the National Heart Lung and Blood Institute's Trans-Omics for Precision Medicine program. Single variant tests were performed on 58 706 SVs in a study sample of 11 556 CAD cases and 42 907 controls. Additionally, aggregate tests using sliding windows were performed to examine rare SVs. One genome-wide significant association was identified for a common biallelic intergenic duplication on chromosome 6q21 (P=1.54E-09, odds ratio=1.34). The sliding window-based aggregate tests found 1 region on chromosome 17q25.3, overlapping USP36, to be significantly associated with coronary artery disease (P=1.03E-10). USP36 is highly expressed in arterial and adipose tissues while broadly affecting several cardiometabolic traits. CONCLUSIONS: Our results suggest that SVs, both common and rare, may influence the risk of coronary artery disease.

Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals (P < 5 × 10-9). Notably, we identified and replicated a novel low frequency single nucleotide polymorphism (SNP) in MTMR3 that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpointed two likely causal variants in the POC5 and DMD loci. Our work demonstrates the benefits of combining WGS and diverse cohorts in expanding current catalog of variants and genes confer risk for obesity, bringing us one step closer to personalized medicine.

BACKGROUND:Heart failure with preserved ejection fraction (HFpEF) is a systemic process with contributions from peripheral factors, including skeletal muscle (SM). Age-associated SM loss and impaired energy metabolism occur without heart failure, but the relative importance of changes in SM quantity versus metabolic quality in patients with HFpEF for exercise intolerance (EI) or outcomes has not been studied. We hypothesized that EI and subsequent clinical outcomes across the adult lifespan in patients with HFpEF are related to impaired SM energy metabolism rather than age-associated SM loss. METHODS:Patients with HFpEF (n=64; aged 34-86 years) with left ventricular ejection fraction ≥50% were stratified by age in a prospective study. They underwent 3T magnetic resonance imaging to measure calf muscle quantity and 31P magnetic resonance spectroscopy to measure muscle high-energy phosphate metabolism during plantar flexion exercise. RESULTS:Older patients with HFpEF exhibited more severe EI, less calf muscle, faster exercise-induced high-energy phosphate decline, and worse SM energetics at fatigue than younger patients. EI correlated closely with muscle metabolic quality, not quantity. Neither magnetic resonance imaging exercise time, 6-minute walk distance, nor peak oxygen uptake at cardiopulmonary exercise testing on cardiopulmonary bicycle exercise testing correlated with calf SM area. In contrast, the 6-minute walk distance or peak oxygen uptake at cardiopulmonary exercise testing were inversely related to rapid exercise-induced high-energy phosphate decline and worse SM energetic profile at fatigue. Rapid exercise-induced high-energy phosphate decline and lower ATP at fatigue were associated with increased cardiovascular death or heart failure hospitalizations in univariate analysis over a median of 39.3 months. CONCLUSIONS:EI in older patients with HFpEF is closely linked to age-associated abnormalities in SM energy metabolism, namely, rapid exercise-induced energetic decline and worse energetic profile at fatigue, and not SM quantity. Abnormal SM energy metabolism is associated with worse outcomes in patients with HFpEF in unadjusted analysis. These findings support SM energy metabolism as a barometer of systemic HFpEF severity and the pursuit of new SM metabolic modulators to reduce disabling EI and possibly adverse outcomes in patients with HFpEF.

Importance Patients deciding between advanced therapies for overactive bladder syndrome may be interested to know the likelihood of treatment crossover after sacral neuromodulation, intradetrusor OnabotulinumtoxinA, or percutaneous tibial nerve stimulation. Treatment crossover was defined as a switch from one advanced therapy to another. Objectives The aim of this study was to estimate the rate of treatment crossover after each advanced therapy for nonneurogenic overactive bladder syndrome. Our secondary objective was to compare medication use after each advanced therapy. Study Design Using claims data from the MarketScan database, privately insured women 18-65 years old with overactive bladder syndrome were identified for this retrospective cohort study. For all patients who received an advanced therapy between 2013 and 2019, we calculated the proportion who subsequently crossed over to a different advanced treatment. For each advanced therapy, we also calculated the proportion who subsequently utilized overactive bladder medication. Results We identified 7,231 adult women who underwent index advanced therapy for overactive bladder syndrome between 2013 and 2019. Treatment crossover occurred in 309 women (4.3%) and was significantly more likely following percutaneous tibial nerve stimulation (8.0%) compared to sacral neuromodulation (4.2%) or intradetrusor OnabotulinumtoxinA (2.6%, P < 0.01). Treatment crossover was also more likely following sacral neuromodulation compared to intradetrusor OnabotulinumtoxinA (P < 0.01). Medication use after advanced therapy was more common after percutaneous tibial nerve stimulation (29.2%) compared to intradetrusor OnabotulinumtoxinA (20.4%) or sacral neuromodulation (18.8%, P < 0.01). Conclusions Treatment crossover following advanced therapy for overactive bladder syndrome was uncommon but was significantly more likely after percutaneous tibial nerve stimulation. Medication use following advanced treatment occurred in a substantial minority in all cohorts.

Introduction: Blood-brain barrier (BBB) dysfunction is increasingly recognized as a key factor in the pathogenesis of cerebral small vessel disease (cSVD). Typical brain Magnetic Resonance Imaging (MRI) findings of cSVD include white matter hyperintensities (WMH). Based on their anatomical locations, WMH can be classified as Periventricular WMH (PVWMH), which are immediately adjacent to the ventricles, or deep WMH (DWMH), which are subcortical. This study aimed to investigate the relationship between BBB permeability as measured by Dynamic Susceptibility Contrast (DSC) MRI, and changes in total WMH, PVWMH, and DWMH volume over 10-13 years in asymptomatic individuals enriched for vascular risk factors. Hypothesis: Higher K2 measurements, which reflect leakage of contrast due to increased BBB permeability, derived from second MRI will corelate with increases in WMH, DWMH, and PVWMH volume that occurred over the previous decade. Methods: We included 100 volunteers from GeneSTAR, an ongoing family-based study of families enriched for vascular risk factors and cardiovascular disease, age = 63.3 ± 9.5 years, 60% females, 63% Hypertension, 22% African Americans. Two MRI’s were obtained 10-13 years apart using 3T scanners. At each visit total WMH, PVWMH and DWMH volumes were determined using automated software with consistent co-registration (Figure 1). K2 was measured for each individual by averaging the highest 100 voxels (hotspots) within the regions of interest in each individual lesion using a gadolinium-based DSC-MRI at the second visit (Figure 2). Linear regression models used to analyze the relationship between K2 and volume changes in total WMH, PVWMH, and DWMH, adjusting for age, systolic blood pressure, race, sex, and education. Results: Positive correlations between K2 at time point two and changes in volume were statistically significant for total WMH (R-squared = 0.497, p = 0.006), PVWMH (R-squared = 0.461, p = 0.0085), but did not reach significance for DWMH (R-squared = 0.394, p = 0.08) (Figure 3). Conclusion: The robust correlation between K2 and overall WMH volume change underscores the potential of K2 as a biomarker for monitoring ongoing disease activity for subclinical cerebrovascular changes in at-risk populations.

BACKGROUND:von Willebrand disease (VWD) is a common inherited bleeding disorder caused by low levels or activity of circulating von Willebrand factor (VWF). Genetic susceptibility to VWF antigen (VWF:Ag) below normal (≤ 50 IU/dL) in the general population is underexplored. OBJECTIVES:To identify genetic variants influencing VWF:Ag levels ≤ 50 IU/dL. METHODS:We performed a genome-wide association study in 926 cases with VWF:Ag levels ≤ 50 IU/dL and 12 846 controls from 7 studies from the Trans-Omics for Precision Medicine program. We then examined whether significant genome-wide findings were also associated with clinical diagnosis of VWD in 5 biobanks with 708 VWD cases and 1 286 069 controls, and with 6 bleeding and thrombotic disorders in FinnGen. RESULTS:Variants at 2 loci were associated (P < 5 × 10-9) with VWF:Ag levels ≤ 50 IU/dL: ABO and VWF. The VWF index variant, p.Tyr1584Cys, is a rare (0.22%) missense variant with odds ratio (OR) of 78.58, while the ABO index variant is a common intronic variant with a smaller effect (OR = 2.52). Notably, both VWF (OR = 7.16) and ABO (OR = 1.57) variants were also associated (P < .025) with diagnosed VWD. Among p.Tyr1584Cys heterozygotes, the penetrance of VWF:Ag levels ≤ 50 IU/dL was 24.2% and the penetrance of diagnosed VWD was 0.3%. p.Tyr1584Cys was associated (P < .0042) with increased odds of heavy menstrual bleeding (OR = 1.27), iron deficiency anemia (OR = 1.55), and intrapartum hemorrhage (OR = 2.20), but decreased odds of deep vein thrombosis (OR = 0.54). CONCLUSIONS:Although there are currently conflicting interpretations of pathogenicity p.Tyr1584Cys, our results suggest that it is a low penetrance pathogenic variant that contributes to VWF:Ag levels ≤ 50 IU/dL, bleeding, and VWD.

Importance Patients with urgency urinary incontinence are often recommended to avoid bladder irritants, but there is a lack of evidence for this. Objective The aim of the study was to compare consumption of purported bladder irritants between women with and without urgency urinary incontinence. Study Design We performed a case-control study of nonpregnant females aged ≥20 years using the National Health and Nutrition Examination Survey, 2007–2020. Cases were defined as participants with moderate, severe, or very severe urgency urinary incontinence without stress urinary incontinence, measured with the Sandvik Incontinence Severity Index. Controls were defined as those without urgency urinary incontinence. The exposures of interest were 6 bladder irritants listed by the National Institute of Diabetes and Digestive and Kidney Diseases: (1) alcohol; (2) spicy foods; (3) chocolate; (4) artificial sweeteners; (5) caffeinated, carbonated, and citrus beverages; and (6) high-acid foods. Weighted multivariable logistic regression analysis was used to determine independent associations between each irritant and urgency urinary incontinence. Results Overall, this study included 651 cases with urgency urinary incontinence (6.8%) and 8,890 controls (93.2%). More cases reported consuming caffeinated, carbonated, and citrus beverages (53.8% vs 47.1%, P = 0.01) and high-acid foods (50.3% vs 44.3%, P = 0.02). In multivariable analysis, the odds of urgency urinary incontinence were increased significantly with intake of caffeinated, carbonated, and citrus beverages (odds ratio 1.37, 95% confidence interval 1.09–1.73) and high-acid foods (odds ratio 1.29, 95% confidence interval 1.03–1.62). Conclusions In this case-control study of community-dwelling adult females, urgency urinary incontinence was associated with consumption of caffeinated, carbonated, and citrus beverages and high-acid foods. Adequately powered prospective trials are needed to further investigate the effects of these foods and beverages on urgency urinary incontinence to guide clinical practice.