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OBJECTIVES: To describe the methods for the in-person assessment of the RISE FOR HEALTH (RISE) study, a population-based multicenter prospective cohort study designed to identify factors that promote bladder health and/or prevent lower urinary tract symptoms in adult women, conducted by the Prevention of Lower Urinary Tract Symptoms Research Consortium (PLUS). METHODS AND RESULTS: A subset of RISE participants who express interest in the in-person assessment will be screened to ensure eligibility (planned n = 525). Eligible consenting participants are asked to complete 15 physical assessments in addition to height and weight, to assess pelvic floor muscle function, musculoskeletal (MSK) status, and pain, and to provide urogenital microbiome samples. Pelvic floor muscle assessments include presence of prolapse, strength, levator attachment integrity (tear) and myofascial pain. MSK tests evaluate core stability, lumbar spine, pelvic girdle and hip pain and function. Participants are asked to complete the Short Physical Performance Battery to measure balance, lower extremity strength, and functional capacity. All participants are asked to provide a voided urine sample and a vaginal swab for microbiome analyses; a subset of 100 are asked to contribute additional samples for feasibility and validation of a home collection of urinary, vaginal, and fecal biospecimens. RESULTS: Online and in-person training sessions were used to certify research staff at each clinical center before the start of RISE in-person assessments. Standardized protocols and data collection methods are employed uniformly across sites. CONCLUSIONS: The RISE in-person assessment is an integral portion of the overall population-based RISE study and represents an innovative approach to assessing factors hypothesized to promote bladder health and/or prevent lower urinary tract symptoms. Data collected from this assessment will be used to prioritize future research questions and prevention strategies and interventions. This description of the assessment methods is intended to provide methodologic transparency and inform other researchers who join efforts to understand and improve bladder health.

BACKGROUND: The ultrasmall, superparamagnetic iron oxide (USPIO) nanoparticle ferumoxytol has unique applications in cardiac, vascular, and body magnetic resonance imaging (MRI) due to its long intravascular half-life and suitability as a blood pool agent. However, limited availability and high cost have hindered its clinical adoption. A new ferumoxytol generic, and the emergence of MoldayION as an alternative USPIO, represent opportunities to expand the use of USPIO-enhanced MRI techniques. PURPOSE: To compare in vitro and in vivo MRI relaxometry and enhancement of Feraheme, generic ferumoxytol, and MoldayION. STUDY TYPE: Prospective. ANIMAL MODEL: Ten healthy swine and six swine with artificially induced coronary narrowing underwent cardiac MRI. FIELD STRENGTH/SEQUENCE: 3.0 T; T1-weighted (4D-MUSIC, 3D-VIBE, 2D-MOLLI) and T2-weighted (2D-HASTE) sequences pre- and post-contrast. ASSESSMENT: We compared the MRI relaxometry of Feraheme, generic ferumoxytol, and MoldayION using saline, plasma, and whole blood MRI phantoms with contrast concentrations from 0.26 mM to 2.10 mM. In-vivo contrast effects on T1- and T2-weighted sequences and fractional intravascular contrast distribution volume in myocardium, liver, and spleen were evaluated. STATISTICAL TESTS: Analysis of variance and covariance were used for group comparisons. A P value

ObjectiveFood insecurity is defined as lack of consistent access to adequate food for healthy living. The objective of this study was to determine the associations between food insecurity and binge-eating disorder in a national cohort of 9- to 14-year-old children.MethodWe analyzed prospective cohort data from the Adolescent Brain Cognitive Development (ABCD) Study (N = 10,035, 2016-2020). Logistic regression analyses estimated the associations between food insecurity at baseline, year 1, or year 2 (exposure) and binge eating, subclinical binge-eating disorder (Other Specified Feeding and Eating Disorder-Binge-Eating Disorder [OSFED-BED]), and binge-eating disorder (BED) (outcome) based on the Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS-5) at 2-year follow-up.ResultsThe prevalence of food insecurity in the study was 15.8%. At 2-year follow-up, 1.71% of the sample received a diagnosis of BED or OSFED-BED, while 6.62% reported binge eating. Food insecurity was associated with 1.67 higher odds of BED or OSFED-BED (95% CI 1.04-2.69) and 1.31 higher odds of binge-eating symptoms (95% CI 1.01-1.71).DiscussionFood insecurity in early adolescence is associated with higher odds of developing future binge-eating and BED or OSFED-BED. Clinicians may consider assessing for binge eating in adolescents with food insecurity and provide support in accessing appropriate food resources.Public significancePrior research has shown that food insecurity is associated with disordered eating behaviors, including binge eating in adulthood. This study explored whether food insecurity in early adolescence increases risk for developing binge-eating disorder (BED). Targeted screening for BED in adolescents experiencing FI, and vice versa, may be warranted.

INTRODUCTION: To evaluate the clinical characteristics as well as the postoperative course of urolithiasis patients undergoing a ureteroscopy (URS) without stent placement. MATERIALS AND METHODS: This was a prospective case cohort study utilizing data collected in the Registry for Stones of the Kidney and Ureter (ReSKU) from a single institution between October 2015 and December 2020. We identified all consecutive patients undergoing URS for stone disease and analyzed data encompassing demographics, medical history, intra and postoperative characteristics, including complications and postoperative symptoms. Univariate and multivariate logistic regression analyses were performed based on the presence or absence of an indwelling ureteral stent. RESULTS: A total of 470 patients were included for analysis, 92 patients in the stentless group (19.5%). Factors associated with stentless ureteroscopy were a lower stone burden (p < 0.001), the pre-existence of a ureteral stent (37.4% vs. 27.9% p = 0.011), absence of an access sheath (14.6% vs. 69.5% p < 0.001), and a shorter operative time (31 vs. 58 min p < 0.001). Postoperative gross hematuria and lower urinary tract symptoms (LUTS) were reported less frequently in stentless patients (p = 0.02, p = 0.01, respectively). There was no difference in postoperative complications between both groups (15.2% vs. 12.0%, p = 0.385). On multivariate analysis, the risk of postoperative complications was associated with obesity, stone burden ≥ 1 cm, and positive preoperative urine culture. There was no patient who required emergent stent placement in the stentless group. CONCLUSION: Our data show that, in well selected patients, omitting ureteral stent placement after URS can decrease postoperative gross hematuria and LUTS without increasing postoperative complications.

STUDY OBJECTIVES: Sleep fellowship program websites likely serve as a preliminary source of information for prospective fellows. Arguably, applicants have likely become even more reliant on program websites during the COVID-19 pandemic due to travel restrictions and social-distancing measures limiting in-person interviews. In this study, we evaluated the content and comprehensiveness of sleep medicine fellowship websites to identify areas of improvement. METHODS: A list of sleep medicine fellowship programs in the United States participating in the 2021 match cycle was compiled using the Electronic Residency Application Service (ERAS) and Fellowship and Residency Electronic Interactive database (FREIDA) websites. Twenty-two prespecified content criteria related to education, recruitment, and compensation were used to evaluate each program website. Sleep programs website comprehensiveness were compared based on US location, type, matching status, core specialty, and size of programs. RESULTS: Seventy-eight US sleep fellowship program websites were evaluated. Most program websites had a working hyperlink on ERAS or FREIDA. There was considerable variability in content reported across program websites, with a mean of 56.8% of content items reported per program. There was a greater educational website content comprehensiveness for internal medicine compared with other specialty-based sleep programs. There was no difference in sleep programs website comprehensiveness based on US location, type, matching status, or size of programs. CONCLUSIONS: Website content comprehensiveness among sleep fellowship programs is variable. There is opportunity for all sleep fellowship programs to improve their websites to better inform prospective trainees. CITATION: Shenoy S, Akberzie W, Landeo-Gutierrez JS, Leon Guerrero CR, Karroum EG. Evaluation of sleep medicine fellowship program websites. J Clin Sleep Med. 2023;19(6):1083-1088.

BACKGROUND: Venetoclax is frequently used as salvage treatment in pediatric, adolescent, and young adult (AYA) patients with advanced hematologic malignancies. However, more data are needed from real-world studies to guide the safe and appropriate use of venetoclax in this population. PROCEDURE: We retrospectively reviewed the medical records of all patients diagnosed with hematologic malignancies less than 30 years of age treated with venetoclax outside of clinical trials at the University of California San Francisco Benioff Childrens Hospitals from 2016 to 2022. RESULTS: We identified 13 patients (acute myeloid leukemia, n = 8; B-acute lymphoblastic leukemia, n = 3; myelodysplastic syndrome, n = 2) aged 4 months to 27 years. A median of 3 prior lines of therapy weregiven (range 0-5). All patients received venetoclax in combination with either a hypomethylating agent or conventional chemotherapy. Three (23%) patients achieved complete remission (CR); two (15%) achieved partial remission (PR); 3 (23%) had stable disease (SD), and five (42%) had progressive disease. Median survival and time to progression from venetoclax initiation was 9 months (range 2.5-52 months) and 3 months (range 2 weeks to 7.5 months), respectively. Six patients (46%) developed grade 3 or higher infections while receiving venetoclax, including bacteremia due to atypical organisms, invasive pulmonary infections with Aspergillus, cytomegalovirus (CMV) viremia, skin infections, and encephalitis with bacterial brain abscesses. CONCLUSIONS: Venetoclax in combination with hypomethylating agents or cytotoxic chemotherapy was effective in a subset of pediatric/AYA patients with advanced hematologic malignancies, but multiple severe infections were observed, particularly among patients who received venetoclax in combination with chemotherapy. Prospective studies will be required to determine the optimal dose and duration of venetoclax in this population.

BACKGROUND/OBJECTIVES: Tablet-based perimetry could be used to test for glaucomatous visual field defects in settings without easy access to perimeters, although few studies have assessed diagnostic accuracy of tablet-based tests. The goal of this study was to determine the diagnostic accuracy of iPad perimetry using the visualFields Easy application. SUBJECTS/METHODS: This was a prospective, cross-sectional study of patients undergoing their first Humphrey Field Analyser (HFA) visual field test at a glaucoma clinic in India. Participants underwent 24-2 SITA Standard HFA testing and iPad-based perimetry with the visualFields Easy application. Reference standards for both visual field loss and suspected glaucoma were determined by ophthalmologist review of HFA results and optic disc photographs. Receiver operating characteristic curves were constructed to assess diagnostic accuracy at various test thresholds. RESULTS: 203 eyes from 115 participants were included, with 82 eyes classified as moderate or worse glaucoma. iPad perimetry had an area under the receiver operating characteristic (AUROC) curve of 0.64 (95% CI 0.57 to 0.71) for detection of any visual field defect relative to HFA and an AUROC of 0.68 (0.59 to 0.76) for detection of moderate or worse glaucoma relative to ophthalmologist examination. At a set specificity of 90%, the sensitivity of iPad perimetry for detection of moderate or worse glaucoma was 35% (22-48%). CONCLUSIONS: iPad perimetry using the visualFields Easy application had inadequate diagnostic accuracy to be used as a screening tool for glaucoma in this South Indian population.

PurposeTo evaluate disease progression using static perimetry (SP) in patients with USH2A-related retinal degeneration, including Usher syndrome type 2 (USH2) and nonsyndromic autosomal recessive retinitis pigmentosa.DesignProspective, observational cohort study.MethodsA total of 102 patients with biallelic disease-causing sequence variants in USH2A with baseline best-corrected visual acuity (BCVA) letter score ≥54 were recruited from 16 clinical sites in Europe and North America. SP, BCVA, full-field stimulus thresholds, spectral domain optical coherence tomography macular scans, and fundus-guided mesopic microperimetry were performed at baseline and annually. The main outcome measures were total hill of vision (VTOT), hill of vision in the central 30° (V30), VTOT minus V30 (VPERIPH), and mean sensitivity.ResultsThe average decline (95% CI) was 2.05 (1.40, 2.70) decibel-steradian (dB-sr)/y for VTOT, 0.48 (0.32, 0.65) dB-sr/y for V30, 1.53 (0.97, 2.08) dB-sr/y for VPERIPH, and 0.55 (0.40, 0.71) dB/y for mean sensitivity. Average percentage decline per year was 8.3 (5.5, 11.1) for VTOT, 5.2 (3.0, 7.4) for V30, 16.0 (9.5, 22.0) for VPERIPH, and 5.1 (3.5, 6.7) for mean sensitivity. Changes from baseline to year 2 in all SP measures were highly correlated (r's ranging from 0.52 [V30 vs VPERIPH] to 0.98 [VTOT vs VPERIPH]).ConclusionsQuantitative measures of SP declined significantly over 2 years in USH2A-related retinal degeneration. The annual percentage rate of change was greatest for VTOT and VPERIPH, whereas V30 and mean sensitivity changed least, reflecting earlier and more severe peripheral degeneration compared with central loss.

OBJECTIVES: To describe the methods for the in-person musculoskeletal (MSK) assessment of the RISE FOR HEALTH (RISE) study, a population-based multicenter prospective cohort study designed to identify factors associated with bladder health (BH) conducted by the Prevention of Lower Urinary Tract Symptoms Research Consortium (PLUS). METHODS: A subset of RISE participants who express interest in the in-person assessment are screened to ensure eligibility (planned n = 525). Eligible consenting participants are asked to complete a standardized MSK assessment to evaluate core stability (four component core stability test, lumbar spine pain (seated slump test), pelvic girdle pain, (sacroiliac joint, anterior superior iliac spine, pubic symphysis tenderness, and pelvic girdle pain provocation test), hip pain (flexion, abduction, internal rotation and flexion, adduction and external rotation) and pelvic girdle function (active straight leg raise). Participants are also asked to complete the Short Physical Performance Battery to measure balance, gait speed, lower extremity strength, and functional capacity. RESULTS: Detailed online and in-person MSK training sessions led by physical therapy were used to certify research staff at each clinical center before the start of RISE in-person assessments. All evaluators exceeded the pre-specified pass rates. CONCLUSIONS: The RISE in-person MSK assessment will provide further insight into the role of general body MSK health and dysfunction and the spectrum of BH.

INTRODUCTION: The spectrum of bladder health and the factors that promote bladder health and prevent lower urinary tract symptoms (LUTS) among women are not well understood. This manuscript describes the rationale, aims, study design, sampling strategy, and data collection for the RISE FOR HEALTH (RISE) study, a novel study of bladder health in women conducted by the Prevention of Lower Urinary Tract Symptom (PLUS) Research Consortium. METHODS AND RESULTS: RISE is a population-based, multicenter, prospective longitudinal cohort study of community-dwelling, English- and Spanish-speaking adult women based in the United States. Its goal is to inform the distribution of bladder health and the individual factors (biologic, behavioral, and psychosocial) and multilevel factors (interpersonal, institutional, community, and societal) that promote bladder health and/or prevent LUTS in women across the life course. Key study development activities included the: (1) development of a conceptual framework and philosophy to guide subsequent activities, (2) creation of a study design and sampling strategy, prioritizing diversity, equity, and inclusion, and (3) selection and development of data collection components. Community members and cross-cultural experts shaped and ensured the appropriateness of all study procedures and materials. RISE participants will be selected by simple random sampling of individuals identified by a marketing database who reside in the 50 counties surrounding nine PLUS clinical research centers. Participants will complete self-administered surveys at baseline (mailed paper or electronic) to capture bladder health and LUTS, knowledge about bladder health, and factors hypothesized to promote bladder health and prevent LUTS. A subset of participants will complete an in-person assessment to augment data with objective measures including urogenital microbiome specimens. Initial longitudinal follow-up is planned at 1 year. DISCUSSION: Findings from RISE will begin to build the necessary evidence base to support much-needed, new bladder health promotion and LUTS prevention interventions in women.

BACKGROUND: Atopic disease may be influenced by prenatal and early life exposure to endocrine disrupting chemicals, including bisphenols, but results from epidemiological studies have been mixed. This study aimed to extend the epidemiological literature, hypothesizing that children with higher prenatal bisphenol exposure are more likely to have childhood atopic disease. METHODS: Urinary bisphenol A (BPA) and S (BPS) concentrations were measured in each trimester from 501 pregnant women in a multi-center, prospective pregnancy cohort. Ever asthma, current asthma, wheeze, and food allergy) were assessed at age six via standardized ISAAC questionnaire. We constructed generalized estimating equations to examine BPA and BPS exposure jointly at each trimester for each atopy phenotype. BPA was modeled as a log-transformed continuous variable, whereas BPS was modeled as detected versus not detected. We also modeled pregnancy-averaged BPA values and a categorical indicator for number of detectable BPS values over pregnancy (0-3) in logistic regression models. RESULTS: First trimester BPA was associated with inverse odds of food allergy among the entire study sample (OR = 0.78, 95% CI = 0.64-0.95, p = 0.01) and females only (OR = 0.69, 95% CI = 0.52-0.90, p = 0.006). The inverse relationship persisted in pregnancy-averaged models of BPA among females (OR = 0.56, 95% CI = 0.35-0.90, p = 0.006). Second trimester BPA was associated with greater odds of food allergy in the entire sample (OR = 1.27, 95% CI = 1.02-1.58, p = 0.03) and among males only (OR = 1.48, 95% CI = 1.02-2.14, p = 0.04). Odds of current asthma increased among males in the pregnancy-averaged BPS models (OR = 1.65, 95% CI = 1.01-2.69, p = 0.045). CONCLUSION: We saw opposite effects of BPA on food allergy that were trimester- and sex-specific. These divergent associations warrant further investigation. There is some evidence to suggest that prenatal BPS is associated with asthma among males, but further research is required in cohorts with a greater proportion of prenatal urine samples with detectable BPS to validate these results.

PURPOSE: While immune checkpoint inhibitors (ICI) have had success with various malignancies, their efficacy in brain cancer is still unclear. Retrospective and prospective studies using PD-1 inhibitors for recurrent glioblastoma (GBM) have not established survival benefit. This study evaluated if ICI may be effective for select patients with recurrent GBM. METHODS: This was a single-center retrospective study of adult patients diagnosed with first recurrence GBM and received pembrolizumab or nivolumab with or without concurrent bevacizumab. Archival tissue was used for immunohistochemistry (IHC) and targeted DNA next-generation sequencing (NGS) analysis. RESULTS: Median overall survival (mOS) from initial diagnosis was 24.5 months (range 10-42). mOS from onset of ICI was 10 months (range 1-31) with 75% surviving > 6 months and 46% > 12 months. Additional IHC analysis on tumors from eight patients demonstrated a trend of longer survival after ICI for those with elevated PD-L1 expression. NGS of samples from 15 patients identified EGFR amplification at initial diagnosis and at any time point to be associated with worse survival after ICI (HR 12.2, 95% CI 1.37-108, p = 0.025 and HR 3.92, 95% CI 1.03-14.9, p = 0.045, respectively). This significance was corroborated with previously tested EGFR amplification via in situ hybridization. CONCLUSION: ICI did not extend overall survival for recurrent GBM. However, molecular sequencing identified EGFR amplification as associated with worse survival. Prospective studies can validate if EGFR amplification is a biomarker of ICI resistance and determine if its use can stratify responders from non-responders.

Preterm birth has been associated with insulin resistance and beta-cell dysfunction, a hallmark characteristic of type 2 diabetes. However, studies investigating the relationship between a personal history of being born preterm and type 2 diabetes are sparse. We sought to investigate the potential association between a personal history of being born preterm and risk for type 2 diabetes in a racially and ethnically diverse population. Baseline and incident data (>16 years of follow-up) from the Womens Health Initiative (n = 85,356) were used to examine the association between personal history of being born preterm (born 1910-1940s) and prevalent (baseline enrollment; cross-sectional) or incident (prospective cohort) cases of type 2 diabetes. Logistic and Cox proportional hazards regression models were used to estimate odds and hazards ratios. Being born preterm was significantly, positively associated with odds for prevalent type 2 diabetes at enrollment (adjOR = 1.79, 95% CI 1.43-2.24; P < 0.0001). Stratified regression models suggested the positive associations at baseline were consistent across race and ethnicity groups. However, being born preterm was not significantly associated with risk for incident type 2 diabetes. Regression models stratified by age at enrollment suggest the relationship between being born preterm and type 2 diabetes persists only among younger age groups. Preterm birth was associated with higher risk of type 2 diabetes but only in those diagnosed with type 2 diabetes prior to study enrollment, suggesting the association between preterm birth and type 2 diabetes may exist at earlier age of diagnosis but wane over time.

INTRODUCTION: The impact of COVID-19 on low-resource surgical systems is concerning but there are limited studies examining the effect in low- and middle-income countries. This study assesses changes in surgical capacity during the COVID-19 pandemic at Soroti Regional Referral Hospital, a tertiary healthcare facility in Soroti, Uganda. METHODS: Patients from a prospective general surgery registry at SRRH were divided into cohorts admitted prior to the pandemic (January 2017 to February 2020) and during the pandemic (March 2020 to May 2021). Demographics, pre-hospital characteristics, in-hospital characteristics, provider-reported delays in care, and adverse events were compared between cohorts. RESULTS: Of the 1547 general surgery patients, 1159 were admitted prior to the pandemic and 388 were admitted during the pandemic. There was no difference in the median number of elective (24.5 vs. 20.0, p value = 0.16) or emergent (6.0 vs. 6.0, p value = 0.36) surgeries per month. Patients were more likely to have a delay in surgical care during the pandemic (22.6% vs. 46.6%, p

Exposure to traumatic events during pregnancy may influence pregnancy and birth outcomes. Growing evidence suggests that exposure to traumatic events well before pregnancy, such as childhood maltreatment (CM), also may influence the course of pregnancy and risk of adverse birth outcomes. We aimed to estimate associations between maternal CM exposure and small-for-gestational-age birth (SGA) and preterm birth (PTB) in a diverse US sample, and to examine whether common CM-associated health and behavioral sequelae either moderate or mediate these associations. The Measurement of Maternal Stress (MOMS) Study was a prospective cohort study that enrolled 744 healthy English-speaking participants ≥ 18 years with a singleton pregnancy, who were

BackgroundThe rate of open tibia fractures is rapidly increasing across the globe due to a recent rise in road traffic accidents, predominantly in low- and low-middle-income countries. These injuries are orthopedic emergencies associated with infection rates as high as 40% despite the use of systemic antibiotics and surgical debridement. The use of local antibiotics has shown some promise in reducing the burden of infection in these injuries due to increasing local tissue availability; however, no trial has yet been appropriately powered to evaluate for definitive evidence and the majority of current studies have taken place in a high-resource countries where resources and the bio-burden may be different.MethodsThis is a prospective randomized, masked, placebo-controlled superiority trial designed to evaluate the efficacy of locally administered gentamicin versus placebo in the prevention of fracture-related infection in adults (age > 18 years) with primarily closeable Gustillo-Anderson class I, II, and IIIA open tibia fractures. Eight hundred ninety patients will be randomized to receive an injection of either gentamicin (treatment group) or saline (control group) at the site of their primarily closed open fracture. The primary outcome will be the occurrence of a fracture-related infection occurring during the course of the 12-month follow-up.DiscussionThis study will definitively assess the effectiveness of local gentamicin for the prevention of fracture-related infections in adults with open tibia fractures in Tanzania. The results of this study have the potential to demonstrate a low-cost, widely available intervention for the reduction of infection in open tibia fractures.Trial registrationClinicaltrials.gov NCT05157126. Registered on December 14, 2021.

The quality department used adaptive leadership and the plan-do-study-act cycle to decrease pressure injury (PI) rates. After identifying gaps, the pressure injury prevention bundle was developed and implemented to bring evidence-based nursing practice to frontline nurses. Organisational rates of PI was followed for 4 years (2019-2022) and a smaller subset of 88 patients were followed in the prospective arm. Using statistical analysis, the decrease in PI rates (90%) and severity is significant (p

BackgroundGestational per- and polyfluoroalkyl substances (PFAS) exposure may be associated with adiposity and increased risk of obesity among children and adolescents. However, results from epidemiological studies evaluating these associations are inconsistent.ObjectivesWe estimated the associations of pregnancy PFAS concentrations with child body mass index (BMI) z-scores and risk of overweight/obesity in eight U.S. cohorts.MethodsWe used data from 1,391 mother-child pairs who enrolled in eight Environmental influences on Child Health Outcomes (ECHO) cohorts (enrolled: 1999-2019). We quantified concentrations of seven PFAS in maternal plasma or serum in pregnancy. We measured child weight and height between the ages of 2 and 5 y and calculated age- and sex-specific BMI z-scores; 19.6% children had more than one BMI measurement. We estimated covariate-adjusted associations of individual PFAS and their mixture with child BMI z-scores and risk of overweight/obesity using linear mixed models, modified Poisson regression models, and Bayesian approaches for mixtures. We explored whether child sex modified these associations.ResultsWe observed a pattern of subtle positive associations of PFAS concentrations in pregnancy with BMI z-scores and risk of overweight/obesity. For instance, each doubling in perfluorohexane sulfonic acid concentrations was associated with higher BMI z-scores (β=0.07; 95% CI: 0.01, 0.12). Each doubling in perfluroundecanoic acid [relative risk (RR)=1.10; 95% CI: 1.04, 1.16] and N-methyl perfluorooctane sulfonamido acetic acid (RR=1.06; 95% CI: 1.00, 1.12) was associated with increased risk of overweight/obesity, with some evidence of a monotonic dose-response relation. We observed weaker and more imprecise associations of the PFAS mixture with BMI or risk of overweight/obesity. Associations did not differ by child sex.DiscussionIn eight U.S.-based prospective cohorts, gestational exposure to higher levels of PFAS were associated with slightly higher childhood BMI z-score and risk of overweight or obesity. Future studies should examine associations of gestational exposure to PFAS with adiposity and related cardiometabolic consequences in older children. https://doi.org/10.1289/EHP11545.

PurposeWe sought to determine whether adherence to the American Cancer Society (ACS) Nutrition and Physical Activity Guidelines was associated with better bowel function among colon cancer survivors.MethodsThis prospective cohort study included patients surgically treated for stage I-IV colon cancer enrolled in the Lifestyle and Outcomes after Gastrointestinal Cancer (LOGIC) study between February 2017 and May 2021. Participants were assigned an ACS score (0-6 points) at enrollment. Stool frequency (SF) was assessed every 6 months using the EORTC QLQ-CR29. Higher SF is an indication of bowel function impairment. ACS score at enrollment was examined in relation to SF at enrollment and over a 3-year period. Secondarily, we examined associations between the ACS score components (body mass index, dietary factors, and physical activity) and SF. Multivariable models were adjusted for demographic and surgical characteristics.ResultsA total of 112 people with colon cancer (59% women, mean age 59.5 years) were included. Cross-sectionally, for every point increase in ACS score at enrollment, the odds of having frequent stools at enrollment decreased by 43% (CI 0.42-0.79; p

BackgroundPrevious studies have analyzed the relationship between screen time and cardiometabolic disease risk factors among adolescents, but few have examined the longitudinal effects of screen time on cardiometabolic health into adulthood using nationally representative data.ObjectiveTo determine prospective associations between screen time and later cardiometabolic disease over a 24-year period using a nationally representative adolescent cohort.DesignLongitudinal prospective cohort data from the National Longitudinal Study of Adolescent to Adult Health (Add Health) collected from 1994 to 2018.ParticipantsAdolescents aged 11-18 years old at baseline (1994-1995) followed for 24 years.Main measuresPredictors: screen time (five repeated measures of self-reported television and video watching from adolescence to adulthood).OutcomesFive repeated measures of body mass index (BMI); two repeated measures of waist circumference, hypertension, hyperlipidemia, and diabetes collected at 15- and 24-year follow-up exams.Key resultsFor the 7105 adolescents in the sample (49.7% female, 35.0% non-white), the baseline adolescent average screen time per day was 2.86 ± 0.08 hours per day, which generally declined through 24-year follow-up. Average BMI at baseline was 22.57 ± 0.13 kg/m2, which increased to 30.27 ± 0.18 kg/m2 through follow-up. By 24-year follow-up, 43.4% of participants had obesity, 8.4% had diabetes, 31.8% had hypertension, and 14.9% had hyperlipidemia. In mixed-effects generalized linear models, each additional hour of screen time per day was associated with 0.06 (95% CI 0.04-0.09) within-person increase in BMI. Each additional hour of screen time per day was associated with higher within-person odds of high waist circumference (AOR 1.17, 95% CI 1.09-1.26), obesity (AOR 1.09, 95% CI 1.03-1.15), and diabetes (AOR 1.17, 95% CI 1.07-1.28). Screen time was not significantly associated with hypertension or hyperlipidemia.ConclusionsIn this prospective cohort study, higher screen time in adolescence was associated with higher odds of select indicators of cardiometabolic disease in adulthood.

BackgroundMost research on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants focuses on initial symptomatology with limited longer-term data. We characterized prevalences of prolonged symptoms 3 months post-SARS-CoV-2 infection across 3 variant time-periods (pre-Delta, Delta, and Omicron).MethodsThis multicenter prospective cohort study of adults with acute illness tested for SARS-CoV-2 compared fatigue severity, fatigue symptoms, organ system-based symptoms, and ≥3 symptoms across variants among participants with a positive ("COVID-positive") or negative SARS-CoV-2 test ("COVID-negative") at 3 months after SARS-CoV-2 testing. Variant periods were defined by dates with ≥50% dominant strain. We performed multivariable logistic regression modeling to estimate independent effects of variants adjusting for sociodemographics, baseline health, and vaccine status.ResultsThe study included 2402 COVID-positive and 821 COVID-negative participants. Among COVID-positives, 463 (19.3%) were pre-Delta, 1198 (49.9%) Delta, and 741 (30.8%) Omicron. The pre-Delta COVID-positive cohort exhibited more prolonged severe fatigue (16.7% vs 11.5% vs 12.3%; P = .017) and presence of ≥3 prolonged symptoms (28.4% vs 21.7% vs 16.0%; P < .001) compared with the Delta and Omicron cohorts. No differences were seen in the COVID-negatives across time-periods. In multivariable models adjusted for vaccination, severe fatigue and odds of having ≥3 symptoms were no longer significant across variants.ConclusionsProlonged symptoms following SARS-CoV-2 infection were more common among participants infected during pre-Delta than with Delta and Omicron; however, these differences were no longer significant after adjusting for vaccination status, suggesting a beneficial effect of vaccination on risk of long-term symptoms. Clinical Trials Registration. NCT04610515.

BackgroundDonor-derived cell-free DNA (dd-cfDNA) testing is an emerging screening modality for noninvasive detection of acute rejection (AR). This study compared the testing accuracy for AR of two commercially available dd-cfDNA and gene-expression profiling (GEP) testing in heart transplant (HTx) recipients.MethodsThis is a retrospective, observational study of HTx only patients who underwent standard and expanded single nucleotide polymorphism (SNP) dd-cfDNA between October 2020 to January 2022. Comparison with GEP was also performed. Assays were compared for correlation, accurate classification, and prediction for AR.ResultsA total of 428 samples from 112 unique HTx patients were used for the study. A positive standard SNP correlated with the expanded SNP assay (p

BackgroundMusculoskeletal pain, a possible marker of central sensitization, is associated with higher prevalence of lower urinary tract symptoms (LUTS) among older men. We investigated whether musculoskeletal pain is associated with LUTS progression.MethodsParticipants were 5 569 men age ≥65 years enrolled in the prospective, multicenter Osteoporotic Fractures in Men (MrOS) Study. Self-reported musculoskeletal pain within 12 months before baseline was categorized as any pain and multilocation pain. Pain interference within 4 weeks of baseline was assessed with the SF-12 questionnaire. LUTS were assessed repeatedly with the American Urological Association Symptom Index (AUA-SI). Men with severe LUTS at baseline were excluded. LUTS progression was defined as the first occurrence of a ≥4-point AUA-SI increase during a 2-year follow-up interval. Incidence rate ratios (IRR) and 95% confidence intervals (CI) were estimated using multivariable pooled logistic regression.ResultsLUTS progression was 37% higher among men with any musculoskeletal pain compared with men without pain (IRR 1.37, 95% CI: 1.21, 1.54). Positive associations were also observed between LUTS progression and pain at 1 (IRR 1.31, 95% CI: 1.13, 1.48) and ≥2 locations (IRR 1.42, 95% CI: 1.24, 1.60). Compared with men without pain interference, men with quite a bit/extreme pain interference were most likely to experience LUTS progression (minimal interference IRR 1.15, 95% CI: 1.03, 1.26; moderate interference IRR 1.28, 95% CI: 1.11, 1.45; quite a bit/extreme interference IRR 1.47, 95% CI: 1.22, 1.71).ConclusionsAmong men initially without severe LUTS, musculoskeletal pain is associated with an increased risk of LUTS progression. Studies using validated measures of central sensitization and LUTS progression among men are warranted.

The human soluble epoxide hydrolase (sEH) is a bifunctional enzyme that modulates the levels of regulatory epoxy lipids. The hydrolase activity is carried out by a catalytic triad located at the center of a wide L-shaped binding site, which contains two hydrophobic subpockets at both sides. On the basis of these structural features, it can be assumed that desolvation is a major factor in determining the maximal achievable affinity that can be attained for this pocket. Accordingly, hydrophobic descriptors may be better suited to the search of novel hits targeting this enzyme. This study examines the suitability of quantum mechanically derived hydrophobic descriptors in the discovery of novel sEH inhibitors. To this end, three-dimensional quantitative structure-activity relationship (3D-QSAR) pharmacophores were generated by combining electrostatic and steric or alternatively hydrophobic and hydrogen-bond parameters in conjunction with a tailored list of 76 known sEH inhibitors. The pharmacophore models were then validated by using two external sets chosen (i) to rank the potency of four distinct series of compounds and (ii) to discriminate actives from decoys, using in both cases datasets taken from the literature. Finally, a prospective study was performed including a virtual screening of two chemical libraries to identify new potential hits, which were subsequently experimentally tested for their inhibitory activity on human, rat, and mouse sEH. The use of hydrophobic-based descriptors led to the identification of six compounds as inhibitors of the human enzyme with IC50 < 20 nM, including two with IC50 values of 0.4 and 0.7 nM. The results support the use of hydrophobic descriptors as a valuable tool in the search of novel scaffolds that encode a proper hydrophilic/hydrophobic distribution complementary to the target's binding site.

BACKGROUND: Long-term symptoms following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are a major concern, yet their prevalence is poorly understood. METHODS: We conducted a prospective cohort study comparing adults with SARS-CoV-2 infection (coronavirus disease-positive [COVID+]) with adults who tested negative (COVID-), enrolled within 28 days of a Food and Drug Administration (FDA)-approved SARS-CoV-2 test result for active symptoms. Sociodemographic characteristics, symptoms of SARS-CoV-2 infection (assessed with the Centers for Disease Control and Prevention [CDC] Person Under Investigation Symptom List), and symptoms of post-infectious syndromes (ie, fatigue, sleep quality, muscle/joint pains, unrefreshing sleep, and dizziness/fainting, assessed with CDC Short Symptom Screener for myalgic encephalomyelitis/chronic fatigue syndrome) were assessed at baseline and 3 months via electronic surveys sent via text or email. RESULTS: Among the first 1000 participants, 722 were COVID+ and 278 were COVID-. Mean age was 41.5 (SD 15.2); 66.3% were female, 13.4% were Black, and 15.3% were Hispanic. At baseline, SARS-CoV-2 symptoms were more common in the COVID+ group than the COVID- group. At 3 months, SARS-CoV-2 symptoms declined in both groups, although were more prevalent in the COVID+ group: upper respiratory symptoms/head/eyes/ears/nose/throat (HEENT; 37.3% vs 20.9%), constitutional (28.8% vs 19.4%), musculoskeletal (19.5% vs 14.7%), pulmonary (17.6% vs 12.2%), cardiovascular (10.0% vs 7.2%), and gastrointestinal (8.7% vs 8.3%); only 50.2% and 73.3% reported no symptoms at all. Symptoms of post-infectious syndromes were similarly prevalent among the COVID+ and COVID- groups at 3 months. CONCLUSIONS: Approximately half of COVID+ participants, as compared with one-quarter of COVID- participants, had at least 1 SARS-CoV-2 symptom at 3 months, highlighting the need for future work to distinguish long COVID. CLINICAL TRIALS REGISTRATION: NCT04610515.

Background and objectivesPrevious studies suggest that lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer disease (AD) and AD-related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults.MethodsWe included dementia-free participants from 9 diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within ±5 years (i.e., cross-sectional analyses) or 5-20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (

BACKGROUND: Although trust is central to successful physician-family relationships in ICUs, little is known about how to promote surrogates trust of ICU physicians in this setting. RESEARCH QUESTION: Does the conduct of family conferences and physicians use of shared decision-making (SDM) within family conferences impact surrogates trust in the physician? STUDY DESIGN AND METHODS: A mixed-methods secondary analysis was done of a multicenter prospective cohort study of 369 surrogate decision-makers of 204 decisionally incapacitated patients at high risk of death or severe functional impairment within 13 ICUs at six US medical centers between 2008 and 2012. Surrogates completed the Abbreviated Wake Forest Physician Trust Scale (range, 5-25) before and after an audio-recorded family conference conducted within 5 days of ICU admission. We qualitatively coded transcribed conferences to determine physicians use of five SDM behaviors: discussing surrogates role, explaining medical condition and prognosis, providing emotional support, assessing understanding, and eliciting patients values and preferences. Using multivariable linear regression with adjustment for clustering, we assessed whether surrogates trust in the physician increased after the family meeting; we also examined whether the number of SDM behaviors used by physicians during the family meeting impacted trust scores. RESULTS: In adjusted models, conduct of a family meeting was associated with increased trust (average change, pre- to post family meeting: 0.91 point [95% CI, 0.4-1.4; P < .01]). Every additional element of SDM used during the family meeting, including discussing surrogates role, providing emotional support, assessing understanding, and eliciting patients values and preferences, was associated with a 0.37-point increase in trust (95% CI, 0.08-0.67; P = .01). If all four elements were used, trust increased by 1.48 points. Explaining medical condition or prognosis was observed in nearly every conference (98.5%) and was excluded from the final model. INTERPRETATION: The conduct of family meetings and physicians use of SDM behaviors during meetings were both associated with increases in surrogates trust in the treating physician.

We assessed whether neighborhood socioeconomic disadvantage, as measured by the Area Deprivation Index (ADI), was associated with an increased risk of postpartum readmission. This is a secondary analysis from nuMoM2b (Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-To-Be), a prospective cohort of nulliparous pregnant individuals from 2010 to 2013. The exposure was the ADI in quartiles, and the outcome was postpartum readmission; Poisson regression was used. Among 9,061 assessed individuals, 154 (1.7%) were readmitted postpartum within 2 weeks of delivery. Individuals living with the most neighborhood deprivation (ADI quartile 4) were at increased risk of postpartum readmission compared with those living with the lowest neighborhood deprivation (ADI quartile 1) (adjusted risk ratio 1.80, 95% CI 1.11-2.93). Measures of community-level adverse social determinants of health, such as the ADI, may inform postpartum care after delivery discharge.

Allogeneic Hematopoietic Cell Transplantation (HCT) offers children with life-threatening diseases a chance at survival. Complications from graft-versus-host disease (GVHD, Stages 0-4) represent a significant cause of morbidity and mortality which has been recently associated with gut dysbiosis the adult HCT population. Here, our objective was to conduct a prospective, longitudinal cohort study in nine pediatric allogeneic HCT participants by collecting longitudinally post-HCT stool specimens up to 1 year. Stool microbiota analyses showed that allogeneic HCT and antibiotic therapy lead to acute shifts in the diversity of the gut microbiota with those experiencing stages 3-4 gut GVHD having significantly greater microbiota variation over time when compared to control participants (p = 0.007). Pre-HCT microbiota diversity trended towards an inverse relationship with gut microbiota stability over time, however, this did not reach statistical significance (p = 0.05). Future large prospective studies are necessary to elucidate the mechanisms underlying these dynamic changes in the gut microbiota following pediatric allogeneic HCT.

ObjectivesWe investigated the prospective association between (a) ADHD symptom dimensions, including their persistence and (b) adult sleep quality in a female sample, covarying adult depressive symptoms.MethodsParticipants comprised four persistence groups (persisters, partials, desisters, and comparison) based on overall ADHD diagnosis and separate dimensions of inattention and hyperactivity/impulsivity (HI) in childhood, late adolescence, and early adulthood, featuring girls with (n = 140) and without (n = 88) carefully diagnosed ADHD.ResultsOnly persistence of inattention predicted lower adult sleep quality when covarying young-adult depression, which was also a significant predictor. When additionally covarying stimulant medication use in adulthood, inattention persistence lost significance, although depression maintained significance, with medication use predicting worse sleep quality.ConclusionsPersistence of inattentive (but not HI) symptoms was significantly related to adult sleep quality in the context of concurrent depression. Sleep quality is an important outcome for research on and treatment for ADHD.

BACKGROUND: Little is known about specific obsessive-compulsive clinical features associated with lifetime history of suicide attempt in individuals with obsessive-compulsive disorder (OCD) and major depression. METHODS: The study sample included 515 adults with OCD and a history of major depression. In exploratory analyses, we compared the distributions of demographic characteristics and clinical features in those with and without a history of attempted suicide and used logistic regression to evaluate the association between specific obsessive-compulsive clinical features and lifetime suicide attempt. RESULTS: Sixty-four (12%) of the participants reported a lifetime history of suicide attempt. Those who had attempted suicide were more likely to report having experienced violent or horrific images (52% vs. 30%; p

BackgroundAdiposity amplifies the genetic risk of non-alcoholic fatty liver disease (NAFLD).AimWe evaluated the association between overweight-years, a cumulative exposure based on the product of the duration and severity of excess body weight (body mass index (BMI) ≥ 25 kg/m2 ), and genetic risk on liver fat and fibrosis.MethodsThis is a longitudinal analysis derived from a prospective cohort of adults in the Framingham Heart Study who underwent genotyping and vibration-controlled-transient-elastography with controlled attenuation parameter. Univariable and multivariable linear and logistic regression analyses were used to assess the association between overweight-years and liver fat and fibrosis. The association between genetic variants of liver fat (PNPLA3, TM6SF2, GCKR) and fibrosis (PNPLA3, TM6SF2, HSD17B13) was also assessed using a polygenic risk score.ResultsOur sample included 2478 participants (54% women) with mean age and BMI of 40 (±8.5) years and 26.5(±5.1) kg/m2 , respectively. The mean follow-up was 14(±0.9) years, and each participant underwent three study visits. The prevalence of NAFLD was 28.3% (n = 700), and 207 (8.4%) had clinically significant fibrosis. In age-, sex- and diabetes-adjusted multivariable analyses, overweight-years (per SD) had a strong association with NAFLD (aOR 3.53 [95% CI: 3.10-4.02], p

BackgroundCancer patients and survivors often experience acute cognitive impairments; however, the long-term cognitive impact remains unclear particularly among Hispanics/Latinos. We examined the association between cancer history and neurocognitive test performance among middle-aged and older Hispanic/Latinos.MethodsParticipants included 9639 Hispanic/Latino adults from the community-based and prospective Hispanic Community Health Study/Study of Latinos. At baseline (2008-2011; V1), participants self-reported their cancer history. At V1 and again at a 7-year follow-up (2015-2018; V2), trained technicians administered neurocognitive tests including the Brief-Spanish English Verbal Learning Test (B-SEVLT), Word Fluency Test (WF), and Digit Symbol Substitution Test (DSS). We used survey linear regression to estimate the overall, sex-specific, and cancer site-specific [i.e., cervix, breast, uterus, and prostate] adjusted associations between cancer history and neurocognitive test performance at V1 and changes from V1 to V2.ResultsAt V1, a history of cancer (6.4%) versus no history of cancer (93.6%) was associated with higher WF scores (β = 0.14, SE = 0.06; p = 0.03) and global cognition (β = 0.09, SE = 0.04; p = 0.04). Among women, a history of cervical cancer predicted decreases in SEVLT-Recall scores (β = -0.31, SE = 0.13; p = 0.02) from V1 to V2, and among men, a history of prostate cancer was associated with higher V1 WF scores (β = 0.29, SE = 0.12; p = 0.02) and predicted increases in SEVLT-Sum (β = 0.46, SE = 0.22; p = 0.04) from V1 to V2.ConclusionAmong women, a history of cervical cancer was associated with 7-year memory decline, which may reflect the impacts of systemic cancer therapies. Among men, however, a history of prostate cancer was associated with improvements in cognitive performance, perhaps due in part to engaging in health promoting behaviors following cancer.

PURPOSE: To elucidate which swept-source optical coherence tomography (OCT)-derived optic nerve head (ONH) parameters are associated with longer axial length (AXL) in healthy myopic eyes. DESIGN: Prospective cross-sectional observational study. METHODS: Two hundred eleven healthy eyes of 140 participants (96 emmetropic-mild myopic [AXL: 22.2-24.5 mm], 83 moderately myopic [24.5-26.0 mm], and 32 highly myopic [26.0-27.4 mm] eyes) were enrolled. Bruch membrane opening (BMO), anterior scleral canal opening (ASCO) area and ovality, minimum rim width, parameters defining misalignment between the BMO and ASCO planes, OCT-defined region of perineural canal retinal epithelium atrophy and externally oblique choroidal border tissue, circumpapillary retinal nerve fiber layer thickness (cpRNFLT), circumpapillary choroidal thickness (cpChT), lamina cribrosa parameters, and peripapillary scleral (PPS) angle were calculated from BMO-centered radial scans reconstructed from 3D raster scans. Multivariate linear mixed models were used to elucidate ONH parameters that are independently associated with AXL. RESULTS: Longer AXL was associated with a greater misalignment between ASCO and BMO planes, larger region of externally oblique choroidal border tissue, thinner cpChT, larger PPS angle, larger ASCO area, and thicker cpRNFLT (all P < .040 after Bonferronis correction for number of included explanatory variables). CONCLUSIONS: A greater misalignment between BMO and ASCO planes, thinner choroid, a more posteriorly bowed PPS, an enlargement of ASCO, and thicker cpRNFLT were each associated with longer AXL. An enhanced understanding of these AXL-associated configurations should provide essential information to improve our ability to detect glaucoma-induced ONH morphology in myopic eyes.

Omidubicel is an umbilical cord blood (UCB)-derived ex vivo-expanded cellular therapy product that has demonstrated faster engraftment and fewer infections compared with unmanipulated UCB in allogeneic hematopoietic cell transplantation. Although the early benefits of omidubicel have been established, long-term outcomes remain unknown. We report on a planned pooled analysis of 5 multicenter clinical trials including 105 patients with hematologic malignancies or sickle cell hemoglobinopathy who underwent omidubicel transplantation at 26 academic transplantation centers worldwide. With a median follow-up of 22 months (range, .3 to 122 months), the 3-year estimated overall survival and disease-free survival were 62.5% and 54.0%, respectively. With up to 10 years of follow-up, omidubicel showed durable trilineage hematopoiesis. Serial quantitative assessments of CD3+, CD4+, CD8+, CD19+, CD116+CD56+, and CD123+ immune subsets revealed median counts remaining within normal ranges through up to 8 years of follow-up. Secondary graft failure occurred in 5 patients (5%) in the first year, with no late cases reported. One case of donor-derived myeloid neoplasm was reported at 40 months post-transplantation. This was also observed in a control arm patient who received only unmanipulated UCB. Overall, omidubicel demonstrated stable trilineage hematopoiesis, immune competence, and graft durability in extended follow-up.

BackgroundEpidemiological studies suggest that maternal immune activation (MIA) is a significant risk factor for future neurodevelopmental disorders, including schizophrenia (SZ), in offspring. Consistent with findings in SZ research and work in rodent systems, preliminary cross-sectional findings in nonhuman primates suggest that MIA is associated with dopaminergic hyperfunction in young adult offspring.MethodsIn this unique prospective longitudinal study, we used [18F]fluoro-l-m-tyrosine positron emission tomography to examine the developmental time course of striatal presynaptic dopamine synthesis in male rhesus monkeys born to dams (n = 13) injected with a modified form of the inflammatory viral mimic, polyinosinic:polycytidylic acid [poly(I:C)], in the late first trimester. Striatal (caudate, putamen, and nucleus accumbens) dopamine from these animals was compared with that of control offspring born to dams that received saline (n = 10) or no injection (n = 4). Dopamine was measured at 15, 26, 38, and 48 months of age. Prior work with this cohort found decreased prefrontal gray matter volume in MIA offspring versus controls between 6 and 45 months of age. Based on theories of the etiology and development of SZ-related pathology, we hypothesized that there would be a delayed (relative to the gray matter decrease) increase in striatal fluoro-l-m-tyrosine signal in the MIA group versus controls.Results[18F]fluoro-l-m-tyrosine signal showed developmental increases in both groups in the caudate and putamen. Group comparisons revealed significantly greater caudate dopaminergic signal in the MIA group at 26 months.ConclusionsThese findings are highly relevant to the known pathophysiology of SZ and highlight the translational relevance of the MIA model in understanding mechanisms by which MIA during pregnancy increases risk for later illness in offspring.

PurposeTo determine the prevalence of fast global and central visual field (VF) progression in individuals with glaucoma under routine care.DesignObservational study.ParticipantsSix hundred ninety-three eyes of 461 individuals with glaucoma followed up over a median of 4.5 years.MethodsThis study included (1) patients at a private ophthalmology clinic in Melbourne, Australia, and (2) individuals in 2 prospective longitudinal observational studies across 3 sites in the United States. All individuals had a diagnosis of glaucoma and were under routine care, and had performed 5 or more reliable 24-2 VF tests over a 1- to 5-year period. Ordinary least squares regression analyses were used to calculate the rate of global mean deviation (MD) change over time and the rate of the mean total deviation values of the 12 test locations within the central 10° region (MTD10) for each eye.Main outcome measuresPrevalence of progression based on the rate of MD and the MTD10 change across various fixed cutoffs and cutoffs based on the estimated normal distribution (from the positive slopes).ResultsBased on the MD and the MTD10, 12.5% and 11.7% of the eyes, respectively, exhibited a rate of change that was less than -1.0 dB/year (being a rate that typically is defined as "fast progression" for MD values), and 29.0% of the eyes showed a change of less than -0.5 dB/year on MTD10. Furthermore, 12.7% and 9.1% of the eyes exhibited a rate of change that exceeded the 1% cutoff of the estimated normal distribution MD and the MTD10 values, respectively.ConclusionsThis study found that approximately 1 in 8 eyes with glaucoma receiving routine care showed fast progression based on global MD values (< -1.0 dB/year) and that nearly 1 in 3 eyes showed a < -0.5 dB/year decline centrally. These findings highlight the clinical importance of assessing progressive central VF loss and reinforce the need for new therapies to prevent functional disability in a notable proportion of individuals who continue to exhibit fast progression.Financial disclosure(s)Proprietary or commercial disclosure may be found after the references.

Background & aimsAlcohol is one of the leading causes of hepatocellular carcinoma (HCC). However, pooled estimates of HCC incidence in alcohol-associated cirrhosis have not been evaluated systematically. We performed a pooled analysis of time-to-event data to provide robust estimates for the incidence of HCC in alcohol-associated cirrhosis.MethodsMedline, Embase, Cochrane Central Register, Scopus, and Web of Science were searched from inception to August 2021. Individual patient data were reconstructed from published Kaplan-Meier curves, and a pooled analysis of cumulative HCC incidence was performed using a random-effects model.ResultsWe screened 5022 articles and included 18 studies (148,333 patients). In the pooled analysis, the cumulative incidence of HCC in alcohol-associated cirrhosis at 1, 5, and 10 years among studies that accounted for the competing risk of death without HCC was 1%, 3%, and 9%, respectively. A secondary analysis by traditional meta-analysis determined that the HCC incidence rate was higher in cohorts enrolled in a HCC surveillance program (18.6 vs 4.8 per 1000 person-years; P = .001) vs those who were not enrolled in a surveillance program. Meta-regression showed that diabetes, smoking, variceal bleeding, and hepatic decompensation were associated with a higher risk of HCC.ConclusionsOur analysis determined that the 5- and 10- year cumulative risk of HCC in alcohol-associated cirrhosis was 3% and 9%, respectively, with a higher incidence in cohorts that were enrolled in a HCC surveillance program. These data should be validated further in large prospective studies, and may have important implications for HCC screening and surveillance among patients with alcohol-associated cirrhosis.

BackgroundAutomated segmentation of the placenta by MRI in early pregnancy may help predict normal and aberrant placenta function, which could improve the efficiency of placental assessment and the prediction of pregnancy outcomes. An automated segmentation method that works at one gestational age may not transfer effectively to other gestational ages.PurposeTo evaluate a spatial attentive deep learning method (SADL) for automated placental segmentation on longitudinal placental MRI scans.Study typeProspective, single-center.SubjectsA total of 154 pregnant women who underwent MRI scans at both 14-18 weeks of gestation and at 19-24 weeks of gestation, divided into training (N = 108), validation (N = 15), and independent testing datasets (N = 31).Field strength/sequenceA 3 T, T2-weighted half Fourier single-shot turbo spin-echo (T2-HASTE) sequence.AssessmentThe reference standard of placental segmentation was manual delineation on T2-HASTE by a third-year neonatology clinical fellow (B.L.) under the supervision of an experienced maternal-fetal medicine specialist (C.J. with 20 years of experience) and an MRI scientist (K.S. with 19 years of experience).Statistical testsThe three-dimensional Dice similarity coefficient (DSC) was used to measure the automated segmentation performance compared to the manual placental segmentation. A paired t-test was used to compare the DSCs between SADL and U-Net methods. A Bland-Altman plot was used to analyze the agreement between manual and automated placental volume measurements. A P value

PurposeLimited data exist to help surgeons decide between active surveillance (AS) versus treatment for men with favorable intermediate risk (FIR) prostate cancer. To estimate the theoretical excess risk of prostate cancer-specific mortality (PCSM) with AS versus radical prostatectomy (RP), we determined the risk of PCSM in FIR men undergoing RP and modeled the PCSM risk for AS using a range of increased PSCM scenarios ranging from 1.25x to 2x higher relative to RP.Materials and methodsWe retrospectively reviewed data from men undergoing RP from 1988 to 2017 at 8 Veterans Affairs hospitals within the SEARCH cohort. Men with FIR PC were identified using the NCCN risk criteria. Risk of PCSM at 5, 10, and 15 years after RP was estimated. Using these estimates, PCSM was then modeled for AS using a range of increased risk of PCSM relative to RP ranging from 1.25x to 2x higher.ResultsFor the 920 FIR men identified, 5-, 10-, and 15-year survival estimates for PCSM after RP were 99.9%, 99.0%, and 97.8%, respectively. If the risk of PCSM on AS were 1.25-2x greater than RP, there would be 0.54%-2.17% excess risk of PCSM at 15 years.ConclusionsThe risk of death for FIR after RP is very low. Assuming even modestly increased PCSM with AS versus RP, the excess risk of death for AS in FIR is low even up to 15 years. These data support the consideration of AS as a relatively safe alternative to RP in FIR men, though prospective randomized trials are needed to validate these findings.

BackgroundGut microbial dysbiosis contributes to colorectal cancer (CRC) pathogenesis, possibly mediated in part by increased intestinal permeability to endotoxin lipopolysaccharide (LPS), microbial translocation, and subsequent endotoxemia and inflammation. However, epidemiologic evidence linking circulating markers of microbial translocation with CRC risk is limited.MethodsWe conducted a prospective, nested case-control study of 261 incident CRC cases and 261 controls (matched on age and time of blood draw) among 18,159 men with pre-diagnostic blood specimens in the Health Professionals Follow-Up Study (1993-2009). We examined three complementary markers of microbial translocation and host response to bacteria, including LPS-binding protein (LBP), soluble CD14 (sCD14), and endotoxincore antibody (EndoCAb) immunoglobulin M (IgM), with subsequent risk of CRC. Unconditional logistic regressions were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs).FindingsPre-diagnostic circulating levels of sCD14 were associated with a higher risk of incident CRC. Compared to men in the lowest quartile, the multivariable OR was 1.90 (95% CI, 1.13-3.22) for men in the highest quartile (OR per standard deviation [SD] increase, 1.28; 95%CI 1.06-1.53; Ptrend = 0.01). This positive association remained similar after adjusting for C-reactive protein, interleukin-6, and soluble tumor necrosis factor receptor-2, and within strata of putative CRC risk factors. We also observed a suggestive inverse association between EndoCAb IgM and risk of CRC (OR per SD increase, 0.84; 95%CI 0.69-1.02; Ptrend = 0.09).InterpretationMicrobial translocation and host response to bacteria, as reflected by sCD14, is associated with risk of incident CRC in men.FundingUS National Institutes of Health.

BackgroundLymphoplasmacytic enteritis (LPE) and low-grade intestinal T cell lymphoma (LGITL) are common diseases in older cats, but their diagnosis and differentiation remain challenging.ObjectivesTo summarize the current literature on etiopathogenesis and diagnosis of LPE and LGITL in cats and provide guidance on the differentiation between LPE and LGITL in cats. To provide statements established using evidence-based approaches or where such evidence is lacking, statements based on consensus of experts in the field.AnimalsNone.MethodsA panel of 6 experts in the field (2 internists, 1 radiologist, 1 anatomic pathologist, 1 clonality expert, 1 oncologist) with the support of a human medical immunologist, was formed to assess and summarize evidence in the peer-reviewed literature and complement it with consensus recommendations.ResultsDespite increasing interest on the topic for clinicians and pathologists, few prospective studies were available, and interpretation of the pertinent literature often was challenging because of the heterogeneity of the cases. Most recommendations by the panel were supported by a moderate or low level of evidence. Several understudied areas were identified, including cellular markers using immunohistochemistry, genomics, and transcriptomic studies.Conclusions and clinical importanceTo date, no single diagnostic criterion or known biomarker reliably differentiates inflammatory lesions from neoplastic lymphoproliferations in the intestinal tract of cats and a diagnosis currently is established by integrating all available clinical and diagnostic data. Histopathology remains the mainstay to better differentiate LPE from LGITL in cats with chronic enteropathy.

BACKGROUNDLongitudinal investigations of murine acute kidney injury (AKI) suggest that injury and inflammation may persist long after the initial insult. However, the evolution of these processes and their prognostic values are unknown in patients with AKI.METHODSIn a prospective cohort of 656 participants hospitalized with AKI, we measured 7 urine and 2 plasma biomarkers of kidney injury, inflammation, and tubular health at multiple time points from the diagnosis to 12 months after AKI. We used linear mixed-effect models to estimate biomarker changes over time, and we used Cox proportional hazard regressions to determine their associations with a composite outcome of chronic kidney disease (CKD) incidence and progression. We compared the gene expression kinetics of biomarkers in murine models of repair and atrophy after ischemic reperfusion injury (IRI).RESULTSAfter 4.3 years, 106 and 52 participants developed incident CKD and CKD progression, respectively. Each SD increase in the change of urine KIM-1, MCP-1, and plasma TNFR1 from baseline to 12 months was associated with 2- to 3-fold increased risk for CKD, while the increase in urine uromodulin was associated with 40% reduced risk for CKD. The trajectories of these biological processes were associated with progression to kidney atrophy in mice after IRI.CONCLUSIONSustained tissue injury and inflammation, and slower restoration of tubular health, are associated with higher risk of kidney disease progression. Further investigation into these ongoing biological processes may help researchers understand and prevent the AKI-to-CKD transition.FUNDINGNIH and NIDDK (grants U01DK082223, U01DK082185, U01DK082192, U01DK082183, R01DK098233, R01DK101507, R01DK114014, K23DK100468, R03DK111881, K01DK120783, and R01DK093771).

PurposeWe compared ganglion cell layer (GCL) and inner plexiform layer (IPL) rates of change (RoC) in patients with glaucoma suspect (GS) and established glaucoma (EG) to test the hypothesis that IPL thickness changes would occur earlier than GCL changes in eyes with early damage.DesignProspective, cohort study.MethodsA total of 64 GS eyes (46 patients) and 112 EG eyes (112 patients) with ≥2 years of follow-up and ≥3 macular optical coherence tomography scans were included. GCL and IPL superpixel thickness measurements were exported. A Bayesian hierarchical model with random intercepts/slopes and random residual variances was fitted to estimate RoC in individual superpixels. Normalized RoC and proportions of superpixels with significantly negative and positive GCL and IPL RoC were compared within the groups.ResultsThe average (SD) follow-up time and number of scans were 3.5 (0.7) years and 4.2 (1.0), respectively, in the GS group and 3.6 (0.4) years and 7.3 (1.1) in the EG group. Mean (SD) normalized RoC was faster for GCL than IPL (-0.69 [0.05] vs -0.33 [0.04]) in the GS group, whereas it was faster for IPL (-0.47 [0.03] vs -0.28 [0.02]) in EG eyes. GCL RoC were significantly negative in 24 of 36 superpixels compared with 8 of 36 for IPL (P < .001) in GS eyes. In the EG group, 23 of 36 superpixels had significant negative IPL RoC compared with 13 of 36 superpixels for GCL (P = .006).ConclusionsGCL thickness is more likely to demonstrate change over time compared with IPL in glaucoma suspects. There is no evidence of preferential IPL thinning in eyes with suspected early glaucoma damage.

IntroductionCongenital diaphragmatic hernia (CDH) repair is an area of active research. Large defects requiring patches have a hernia recurrence rate of up to 50%. We designed a biodegradable polyurethane (PU)-based elastic patch that matches the mechanical properties of native diaphragm muscle. We compared the PU patch to a non-biodegradable Gore-Tex™ (polytetrafluoroethylene) patch.MethodsThe biodegradable polyurethane was synthesized from polycaprolactone, hexadiisocyanate and putrescine, and then processed into fibrous PU patches by electrospinning. Rats underwent 4 mm diaphragmatic hernia (DH) creation via laparotomy followed by immediate repair with Gore-Tex™ (n = 6) or PU (n = 6) patches. Six rats underwent sham laparotomy without DH creation/repair. Diaphragm function was evaluated by fluoroscopy at 1 and 4 weeks. At 4 weeks, animals underwent gross inspection for recurrence and histologic evaluation for inflammatory reaction to the patch materials.ResultsThere were no hernia recurrences in either cohort. Gore-Tex™ had limited diaphragm rise compared to sham at 4 weeks (1.3 mm vs 2.9 mm, p = 0.003), but no difference was found between PU and sham (1.7 mm vs 2.9 mm, p = 0.09). There were no differences between PU and Gore-Tex™ at any time point. Both patches formed an inflammatory capsule, with similar thicknesses between cohorts on the abdominal (Gore-Tex™ 0.07 mm vs. PU 0.13 mm, p = 0.39) and thoracic (Gore-Tex™ 0.3 mm vs. PU 0.6 mm, p = 0.09) sides.ConclusionThe biodegradable PU patch allowed for similar diaphragmatic excursion compared to control animals. There were similar inflammatory responses to both patches. Further work is needed to evaluate long-term functional outcomes and further optimize the properties of the novel PU patch in vitro and in vivo.Level of evidenceLevel II, Prospective Comparative Study.

BackgroundThe ability to detect bacteriuria in dogs with a point-of-care test might improve medical care and antimicrobial stewardship.Hypothesis and objectiveA rapid immunoassay (RIA; RapidBac) will provide acceptable sensitivity and specificity for diagnosis of bacteriuria.AnimalsForty-four client-owned dogs with a clinical indication for urinalysis and aerobic bacterial urine culture.MethodsProspective study. Urine, collected by cystocentesis, was submitted for urinalysis and culture at a diagnostic laboratory. Owners completed an enrollment questionnaire regarding their dogs' clinical signs. The RIA was performed according to the manufacturer's guidelines. Results were compared to culture.ResultsForty-four urine specimens were evaluated from 44 dogs. The sensitivity and specificity of the RIA test to detect bacteriuria compared to urine culture were 81.8% (95% CI, 65.7%-97.9%) and 95.5% (95% CI, 86.8%-99.9%), respectively. For cultures yielding ≥103  CFU/mL, sensitivity increased to 90.0% (95% CI, 76.9%-100%) and specificity was similar at 95.2% (95% CI, 86.1%-99.9%). Malodorous urine, bacteriuria, and pyuria were more likely to be present in dogs with positive RIA or urine culture results compared to dogs with negative results.Conclusions and clinical importanceThe RIA was easy to perform and had good sensitivity and excellent specificity in this group of dogs. The RIA might be a useful screening test for decision-making regarding antimicrobial therapy in dogs with a clinical indication for urine culture. Consideration could be given to amending the International Society for Companion Animal Infectious Disease definition of bacterial cystitis as the presence of signs of lower urinary tract disease together with positive culture or a positive RIA.

ObjectiveTo evaluate heavy menstrual bleeding treatment outcomes with levonorgestrel 52-mg intrauterine device (IUD) use in participants without body mass index (BMI) or parity restrictions.MethodsInvestigators included participants aged 18-50 years with no pelvic or systemic pathology causing heavy menstrual bleeding at 29 U.S. centers in a prospective trial. Participants had up to three screening cycles with menstrual product collection for alkaline hematin blood-loss measurements. Investigators enrolled those with two menses with blood loss of 80 mL or more (values averaged for baseline blood loss), placed the IUD, and followed participants for up to six 28-day cycles. Participants collected any menstrual products used during cycles 3 and 6 for blood-loss measurement. We evaluated outcomes in participants with at least one follow-up assessment for the primary outcome of median absolute blood-loss change and, secondarily, treatment success , defined as the proportion with a final measured blood loss less than 80 mL and at least 50% reduction from baseline. We evaluated exploratory outcomes of differences in blood-loss changes by BMI and parity using Wilcoxon rank sum test.ResultsOf 105 enrolled participants, 47 (44.8%) had obesity (BMI 30.0 or higher) and 29 (27.6%) were nulliparous. Baseline mean blood loss ranged from 73 to 520 mL (median 143 mL, interquartile range 112-196 mL). Eighty-nine (84.8%) had at least one evaluable follow-up evaluation. Participants had median (interquartile range) absolute blood-loss decreases at cycles 3 (n=86) and 6 (n=81) of 93.3% (86.1-97.7%) and 97.6% (90.4-100%), respectively. At cycle 6, participants without obesity (n=43) and with obesity (n=38) had similar median [interquartile range] decreases (97.6% [91.8-100%] and 97.5% [90.3-100%], respectively; P =.89), with comparable findings for nulliparous (n=25) and parous (n=56) participants (97.0% [91.7-99.1%] and 98.1% [89.9-100%], respectively; P =.43). Treatment success occurred in 81.8% (95% CI 74.2-89.4%) of 99 participants, excluding those with no outcomes due to lost to follow-up or consent withdrawal, and did not vary by BMI or parity. The most common adverse events leading to discontinuation were bleeding or cramping (n=6 [5.7%]) and expulsion (n=5 [4.8%]).ConclusionThis levonorgestrel 52-mg IUD reduces blood loss by more than 90% over 6 months compared with baseline for most users with heavy menstrual bleeding.Funding sourceMedicines360.Clinical trial registrationClinicalTrials.gov , NCT03642210.

BACKGROUND AND OBJECTIVES: In spinocerebellar ataxia, ataxia onset can be preceded by mild clinical manifestation, cerebellar and/or brainstem alterations, or biomarker modifications. READISCA is a prospective, longitudinal observational study of patients with spinocerebellar ataxia type 1 (SCA1) and 3 (SCA3) to provide essential markers for therapeutic interventions. We looked for clinical, imaging, or biological markers that are present at an early stage of the disease. METHODS: We enrolled carriers of a pathologic ATXN1 or ATXN3 expansion and controls from 18 US and 2 European ataxia referral centers. Clinical, cognitive, quantitative motor, neuropsychological measures and plasma neurofilament light chain (NfL) measurements were compared between expansion carriers with and without ataxia and controls. RESULTS: We enrolled 200 participants: 45 carriers of a pathologic ATXN1 expansion (31 patients with ataxia [median Scale for the Assessment and Rating of Ataxia: 9; 7-10] and 14 expansion carriers without ataxia [1; 0-2]) and 116 carriers of a pathologic ATXN3 expansion (80 patients with ataxia [7; 6-9] and 36 expansion carriers without ataxia [1; 0-2]). In addition, we enrolled 39 controls who did not carry a pathologic expansion in ATXN1 or ATXN3. Plasma NfL levels were significantly higher in expansion carriers without ataxia than controls, despite similar mean age (controls: 5.7 pg/mL, SCA1: 18.0 pg/mL [p < 0.0001], SCA3: 19.8 pg/mL [p < 0.0001]). Expansion carriers without ataxia differed from controls by significantly more upper motor signs (SCA1 p = 0.0003, SCA3 p = 0.003) and by the presence of sensor impairment and diplopia in SCA3 (p = 0.0448 and 0.0445, respectively). Functional scales, fatigue and depression scores, swallowing difficulties, and cognitive impairment were worse in expansion carriers with ataxia than those without ataxia. Ataxic SCA3 participants showed extrapyramidal signs, urinary dysfunction, and lower motor neuron signs significantly more often than expansion carriers without ataxia. DISCUSSION: READISCA showed the feasibility of harmonized data acquisition in a multinational network. NfL alterations, early sensory ataxia, and corticospinal signs were quantifiable between preataxic participants and controls. Patients with ataxia differed in many parameters from controls and expansion carriers without ataxia, with a graded increase of abnormal measures from control to preataxic to ataxic cohorts. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT03487367.

Glioblastoma is characterized by diffuse infiltration into the surrounding tissue along white matter tracts. Identifying the invisible tumour invasion beyond focal lesion promises more effective treatment, which remains a significant challenge. It is increasingly accepted that glioblastoma could widely affect brain structure and function, and further lead to reorganization of neural connectivity. Quantifying neural connectivity in glioblastoma may provide a valuable tool for identifying tumour invasion. Here we propose an approach to systematically identify tumour invasion by quantifying the structural connectome in glioblastoma patients. We first recruit two independent prospective glioblastoma cohorts: the discovery cohort with 117 patients and validation cohort with 42 patients. Next, we use diffusion MRI of healthy subjects to construct tractography templates indicating white matter connection pathways between brain regions. Next, we construct fractional anisotropy skeletons from diffusion MRI using an improved voxel projection approach based on the tract-based spatial statistics, where the strengths of white matter connection and brain regions are estimated. To quantify the disrupted connectome, we calculate the deviation of the connectome strengths of patients from that of the age-matched healthy controls. We then categorize the disruption into regional disruptions on the basis of the relative location of connectome to focal lesions. We also characterize the topological properties of the patient connectome based on the graph theory. Finally, we investigate the clinical, cognitive and prognostic significance of connectome metrics using Pearson correlation test, mediation test and survival models. Our results show that the connectome disruptions in glioblastoma patients are widespread in the normal-appearing brain beyond focal lesions, associated with lower preoperative performance (P < 0.001), impaired cognitive function (P < 0.001) and worse survival (overall survival: hazard ratio = 1.46, P = 0.049; progression-free survival: hazard ratio = 1.49, P = 0.019). Additionally, these distant disruptions mediate the effect on topological alterations of the connectome (mediation effect: clustering coefficient -0.017, P < 0.001, characteristic path length 0.17, P = 0.008). Further, the preserved connectome in the normal-appearing brain demonstrates evidence of connectivity reorganization, where the increased neural connectivity is associated with better overall survival (log-rank P = 0.005). In conclusion, our connectome approach could reveal and quantify the glioblastoma invasion distant from the focal lesion and invisible on the conventional MRI. The structural disruptions in the normal-appearing brain were associated with the topological alteration of the brain and could indicate treatment target. Our approach promises to aid more accurate patient stratification and more precise treatment planning.

Background and objectivesTo understand the role of premature (defined as ≤ 60 years) cardiovascular disease (CVD) in brain health earlier in life, we examined the associations of premature CVD with midlife cognition and white matter health.MethodsWe studied a prospective cohort in the Coronary Artery Risk Development in Young Adults study, who were 18-30 years at baseline (1985-1986) and followed up to 30 years when 5 cognitive tests measuring different domains were administered. A subset (656 participants) had brain MRI measures of white matter hyperintensity (WMH) and white matter integrity. A premature CVD event was adjudicated based on medical records of coronary heart disease, stroke/TIA, congestive heart failure, carotid artery disease, and peripheral artery disease. We conducted linear regression to determine the associations of nonfatal premature CVD with cognitive performance (z-standardized), cognitive decline, and MRI measures.ResultsAmong 3,146 participants, the mean age (57% women and 48% Black) was 55.1 ± 3.6 years, with 5% (n = 147) having premature CVD. Adjusting for demographics, education, literacy, income, depressive symptoms, physical activity, diet, and APOE, premature CVD was associated with lower cognition in 4 of 5 domains: global cognition (-0.22, 95% CI -0.37 to -0.08), verbal memory (-0.28, 95% CI -0.44 to -0.12), processing speed (-0.46, 95% CI -0.62 to -0.31), and executive function (-0.38, 95% CI -0.55 to -0.22). Premature CVD was associated with greater WMH (total, temporal, and parietal lobes) and higher white matter mean diffusivity (total and temporal lobes) after adjustment for covariates. These associations remained significant after adjusting for cardiovascular risk factors (CVRFs) and excluding those with stroke/TIA. Premature CVD was also associated with accelerated cognitive decline over 5 years (adjusted OR 3.07, 95% CI 1.65-5.71).DiscussionPremature CVD is associated with worse midlife cognition and white matter health, which is not entirely driven by stroke/TIA and even independent of CVRFs. Preventing CVD in early adulthood may delay the onset of cognitive decline and promote brain health over the life course.