A Conserved Noncoding Locus Regulates Random Monoallelic Xist Expression across a Topological Boundary.

cis-Regulatory communication is crucial in mammalian development and is thought to be restricted by the spatial partitioning of the genome in topologically associating domains (TADs). Here, we discovered that the Xist locus is regulated by sequences in the neighboring TAD. In particular, the promoter of the noncoding RNA Linx (LinxP) acts as a long-range silencer and influences the choice of X chromosome to be inactivated. This is independent of Linx transcription and independent of any effect on Tsix, the antisense regulator of Xist that shares the same TAD as Linx. Unlike Tsix, LinxP is well conserved across mammals, suggesting an ancestral mechanism for random monoallelic Xist regulation. When introduced in the same TAD as Xist, LinxP switches from a silencer to an enhancer. Our study uncovers an unsuspected regulatory axis for X chromosome inactivation and a class of cis-regulatory effects that may exploit TAD partitioning to modulate developmental decisions.

Routine Emergency Department Screening to Decrease Subsequent Physical Abuse.

STUDY OBJECTIVE: Emergency department (ED) screening for child physical abuse has been widely implemented, with uncertain effects on child abuse identification. Our goal was to determine the effect of screening on referrals to child protective services (CPS) identifying abuse. METHODS: We performed a retrospective cohort study of children younger than 6 years old with an ED encounter at 1 of 2 large health care systems, one of which implemented routine child abuse screening. The main outcome was initial (<2 days) or subsequent (3 to 180 days) referral to CPS identifying child abuse using linked records. We compared outcomes for the 2-year period after screening was implemented to the preperiod and nonscreening EDs using generalized estimating equations to adjust for sex, age, race/ethnicity, payor and prior ED encounters and clustered by center. RESULTS: Of the 331,120 ED encounters, 41,589 (12.6%) occurred at screening EDs during the screening period. Screening was completed in 34,272 (82%) and was positive in 188 (0.45%). Overall, 7,623 encounters (2.3%) had a subsequent referral, of which 589 (0.2%) identified moderate or severe abuse. ED screening did not change initial (adjusted odds ratio [aOR]=1.01, 95% confidence interval [CI] 0.89 to 1.15) or subsequent referral to CPS when compared to the prescreening period (aOR=1.05, 95% CI 0.9 to 1.18) or to the nonscreening EDs (aOR=1.06, 95% CI 0.92 to 1.21). CONCLUSION: Routine screening did not affect initial or subsequent referrals to CPS.

Food-related inhibitory control training reduces food liking but not snacking frequency or weight in a large healthy adult sample.

Inhibitory control training has recently been used as an intervention to aid healthy eating and encourage weight loss. The aim of this pre-registered study was to explore the effects of training on food liking, food consumption and weight loss in a large (n = 366), predominantly healthy-weight sample. Participants received four training sessions within a week, in which they had to inhibit their responses to either energy-dense foods (active group) or non-food images (control group). Subjective food ratings, food consumption frequency and weight were measured pre- and post-training. At two-weeks post-training, the active group reported a greater reduction in liking for energy-dense foods, compared to the control group. Active participants also reported a significantly greater increase in healthy food liking, immediately post-training, relative to the control group. There was no statistically significant difference between groups for the change in consumption of trained foods or for weight loss. These findings are partially consistent with previous research conducted in smaller, more overweight samples. Exploratory analyses suggest that some effects of training may be driven by awareness effects. Methodological differences across findings and avenues for future investigation are discussed.

Barriers to eating are associated with poor physical function in older women.

Older adults have physical and social barriers to eating but whether this affects functional status is unknown. We examined associations between eating barriers and physical function in the Women's Health Initiative (WHI). In 2012-14, a subset of alive and participating women (n = 5910) completed an in-home examination including the Short Physical Performance Battery (SPPB) (grip strength, balance, timed walking speed, chair stand). WHI participants complete annual mailed questionnaires; the 2013-14 questionnaire included items on eating alone, eating < two meals/day, dentition problems affecting eating, physical difficulties with cooking/shopping and monetary resources for food. Linear regression tested associations of these eating barriers with SPPB, adjusting for BMI, age, race/ethnicity, and medical multimorbidities. Over half (56.8%) of participants were ≥ 75 years, 98.8% had a BMI ≥ 25.0 kg/m2 and 66% had multimorbidities. Eating barriers, excluding eating alone, were associated with significantly lower total (all p < .001) and component-specific, multivariate-adjusted SPPB scores (all p < .05). Compared to no barriers, eating < two meals/day (7.83 vs. 8.38, p < .0002), dentition problems (7.69 vs. 8.38, p < .0001), inability to shop/prepare meals (7.74 vs. 8.38, p < .0001) and insufficient resources (7.84 vs. 8.37 p < .001) were significantly associated with multivariate-adjusted mean SPPB score < 8. Models additionally adjusting for Healthy Eating Index-2010 had little influence on scores. As barriers increased, scores declined further for grip strength (16.10 kg for 4-5 barriers, p = .001), timed walk (0.58 m/s for 4-5 barriers, p = .001) and total SPPB (7.27 for 4-5 barriers, p < .0001). In conclusion, in this WHI subset, eating barriers were associated with poor SPPB scores.

The SIN3A histone deacetylase complex is required for a complete transcriptional response to hypoxia.

Cells adapt to environmental changes, including fluctuations in oxygen levels, through the induction of specific gene expression programs. To identify genes regulated by hypoxia at the transcriptional level, we pulse-labeled HUVEC cells with 4-thiouridine and sequenced nascent transcripts. Then, we searched genome-wide binding profiles from the ENCODE project for factors that correlated with changes in transcription and identified binding of several components of the Sin3A co-repressor complex, including SIN3A, SAP30 and HDAC1/2, proximal to genes repressed by hypoxia. SIN3A interference revealed that it participates in the downregulation of 75% of the hypoxia-repressed genes in endothelial cells. Unexpectedly, it also blunted the induction of 47% of the upregulated genes, suggesting a role for this corepressor in gene induction. In agreement, ChIP-seq experiments showed that SIN3A preferentially localizes to the promoter region of actively transcribed genes and that SIN3A signal was enriched in hypoxia-repressed genes, prior exposure to the stimulus. Importantly, SINA3 occupancy was not altered by hypoxia in spite of changes in H3K27ac signal. In summary, our results reveal a prominent role for SIN3A in the transcriptional response to hypoxia and suggest a model where modulation of the associated histone deacetylase activity, rather than its recruitment, determines the transcriptional output.

JASPAR 2016: a major expansion and update of the open-access database of transcription factor binding profiles.

JASPAR (http://jaspar.genereg.net) is an open-access database storing curated, non-redundant transcription factor (TF) binding profiles representing transcription factor binding preferences as position frequency matrices for multiple species in six taxonomic groups. For this 2016 release, we expanded the JASPAR CORE collection with 494 new TF binding profiles (315 in vertebrates, 11 in nematodes, 3 in insects, 1 in fungi and 164 in plants) and updated 59 profiles (58 in vertebrates and 1 in fungi). The introduced profiles represent an 83% expansion and 10% update when compared to the previous release. We updated the structural annotation of the TF DNA binding domains (DBDs) following a published hierarchical structural classification. In addition, we introduced 130 transcription factor flexible models trained on ChIP-seq data for vertebrates, which capture dinucleotide dependencies within TF binding sites. This new JASPAR release is accompanied by a new web tool to infer JASPAR TF binding profiles recognized by a given TF protein sequence. Moreover, we provide the users with a Ruby module complementing the JASPAR API to ease programmatic access and use of the JASPAR collection of profiles. Finally, we provide the JASPAR2016 R/Bioconductor data package with the data of this release.

JASPAR 2014: an extensively expanded and updated open-access database of transcription factor binding profiles.

JASPAR (http://jaspar.genereg.net) is the largest open-access database of matrix-based nucleotide profiles describing the binding preference of transcription factors from multiple species. The fifth major release greatly expands the heart of JASPAR-the JASPAR CORE subcollection, which contains curated, non-redundant profiles-with 135 new curated profiles (74 in vertebrates, 8 in Drosophila melanogaster, 10 in Caenorhabditis elegans and 43 in Arabidopsis thaliana; a 30% increase in total) and 43 older updated profiles (36 in vertebrates, 3 in D. melanogaster and 4 in A. thaliana; a 9% update in total). The new and updated profiles are mainly derived from published chromatin immunoprecipitation-seq experimental datasets. In addition, the web interface has been enhanced with advanced capabilities in browsing, searching and subsetting. Finally, the new JASPAR release is accompanied by a new BioPython package, a new R tool package and a new R/Bioconductor data package to facilitate access for both manual and automated methods.

Improving analysis of transcription factor binding sites within ChIP-Seq data based on topological motif enrichment.

BACKGROUND: Chromatin immunoprecipitation (ChIP) coupled to high-throughput sequencing (ChIP-Seq) techniques can reveal DNA regions bound by transcription factors (TF). Analysis of the ChIP-Seq regions is now a central component in gene regulation studies. The need remains strong for methods to improve the interpretation of ChIP-Seq data and the study of specific TF binding sites (TFBS). RESULTS: We introduce a set of methods to improve the interpretation of ChIP-Seq data, including the inference of mediating TFs based on TFBS motif over-representation analysis and the subsequent study of spatial distribution of TFBSs. TFBS over-representation analysis applied to ChIP-Seq data is used to detect which TFBSs arise more frequently than expected by chance. Visualization of over-representation analysis results with new composition-bias plots reveals systematic bias in over-representation scores. We introduce the BiasAway background generating software to resolve the problem. A heuristic procedure based on topological motif enrichment relative to the ChIP-Seq peaks' local maximums highlights peaks likely to be directly bound by a TF of interest. The results suggest that on average two-thirds of a ChIP-Seq dataset's peaks are bound by the ChIP'd TF; the origin of the remaining peaks remaining undetermined. Additional visualization methods allow for the study of both inter-TFBS spatial relationships and motif-flanking sequence properties, as demonstrated in case studies for TBP and ZNF143/THAP11. CONCLUSIONS: Topological properties of TFBS within ChIP-Seq datasets can be harnessed to better interpret regulatory sequences. Using GC content corrected TFBS over-representation analysis, combined with visualization techniques and analysis of the topological distribution of TFBS, we can distinguish peaks likely to be directly bound by a TF. The new methods will empower researchers for exploration of gene regulation and TF binding.

Medicare Part D low-income subsidies expanded in January 2024, but more needs to be done to ensure that eligible beneficiaries enroll.

BACKGROUND: The Inflation Reduction Act of 2022 extended full low-income subsidies (LIS) to a small group of Medicare Part D recipients with limited assets and incomes between 135% and 150% of the Federal Poverty Level beginning in January 2024. This policy may result in small enrollment gains among beneficiaries eligible for the new benefits, but the biggest problem with the current LIS program is underenrollment across all eligibility groups. Prior research has shown that underenrollment has been a persistent problem since the LIS program began in 2006, yet little has been done to correct the situation. OBJECTIVE: To identify individual-level factors associated with failure to enroll among low-income beneficiaries eligible for both full subsidies and partial subsidies under the LIS program. METHODS: We used 2019 Medicare Current Beneficiary Survey data for the study. The Medicare Current Beneficiary Survey is uniquely suited for this work because it contains administrative data on LIS enrollment plus extensive survey information on financial resources necessary to establish program eligibility. We conducted descriptive and multivariate analyses to identify factors associated with failure to enroll when eligible for either full or partial subsidies. Explanatory variables included sociodemographic characteristics, economic resources, work status, health variables, and source of prescription coverage (for nonsubsidized beneficiaries). RESULTS: In 2019, 73% of beneficiaries eligible for full subsidies under pre-Inflation Reduction Act LIS provisions were enrolled, compared with only 25% eligible for partial subsidies. The number of those estimated to be eligible for full subsidies but not enrolled (N = 3.9 million) was more than double that of those eligible but not enrolled for partial subsidies (N = 1.5 million). Factors associated with failure to enroll (older age, male sex, White race, married, higher education, higher income and assets, and excellent/very good health status) were similar for both groups. In multivariate analyses, the single strongest predictor of failure to enroll was receipt of income from work (odds ratio = 5.50; P < 0.001). Among the nonenrolled, 64% eligible for full subsidies and 75% eligible for partial subsidies maintained unsubsidized Part D coverage. CONCLUSIONS: Significant numbers of low-income Medicare beneficiaries are eligible for Part D subsidies but fail to enroll. Common characteristics distinguishing nonenrollees from enrollees include older age with higher proportions of White individuals, married individuals, higher income and assets, and better overall health. Two promising targets for increasing LIS enrollment are evidence of work income and unsubsidized Part D coverage.

Life-course trajectories of children through the U. S foster care system.

OBJECTIVE: Foster care is surprisingly commonplace in the United States, with more than one in twenty children experiencing placement in their lifetimes. Due to the complexity of foster care (e.g. age at contact, length of stay), we still lack a clear idea of how children move through the child welfare system. We pose the question, "do distinct typologies of system trajectories exist that may be used to inform policy analyses?" METHODS: We used child maltreatment reports and foster care case records for all U.S. children born in FY2006 and placed in care between birth and age 15. Using sequence analysis, we classified child-level system trajectories into distinct clusters. Then, we employed multilevel multinomial regression to explore child and system characteristics associated with each. RESULTS: Three typologies were identified: 1) early-entry-exit, 2) school-age-entry, and 3) late-entry. Early-entry-exit cases typically entered and left foster care before turning three, were frequently adopted, and had little ongoing system contact. School-age-entry children typically entered between ages 5-10, were in care for the shortest amount of time, and mostly exited to reunification. Late-entry children typically entered between ages 9-11, entered with substantial CPS history and remained in care into mid-adolescence. CONCLUSIONS: Our findings provide the first description of foster care trajectories in the US. Both practice and policy formulation can benefit from these empirically supported descriptions. Using such trajectory typologies, researchers can now explore how trajectories may predict wellbeing outcomes. We discuss how the differences among the typologies may inform identification of service needs and outcomes.

An Equity-Focused Assessment of Evidence-Based Parenting Intervention Research.

Evidence-based parenting interventions (EBPI) support children and families to promote resilience, address emotional and behavioral concerns, and prevent or address issues related to child maltreatment. Critiques of EBPIs include concerns about their relevance and effectiveness for diverse populations when they are implemented at population scale. Research methods that center racial equity and include community-based participatory approaches have the potential to address some of these concerns. The purpose of the present review was to document the extent to which methods associated with promoting racial equity in research have been used in studies that contribute to the evidence base for programs that meet evidentiary standards for a clearinghouse that was developed to support the Family First Prevention Services Act in the United States. We developed a coding system largely based on the Culturally Responsive Evaluation model. A sample of 47 papers that are part of the evidence base for ten in-home parent skill-based programs were reviewed and coded. Only three of 28 possible codes were observed to occur in over half of the studies (including race/ethnicity demographic characteristics, conducting measure reliability for the study sample, and including information on socioeconomic status). Although the overall presence of equity-informed methods was low, a positive trend was observed over time. This review highlights ways in which rigorous research can incorporate racial equity into the planning, design, execution, and interpretation and dissemination of programs of study. We posit that doing so improves the external validity of studies while maintaining high-quality research that can contribute to an evidence base.

Induced topological changes in DNA complexes: influence of DNA sequences and small molecule structures.

Heterocyclic diamidines are compounds with antiparasitic properties that target the minor groove of kinetoplast DNA. The mechanism of action of these compounds is unknown, but topological changes to DNA structures are likely to be involved. In this study, we have developed a polyacrylamide gel electrophoresis-based screening method to determine topological effects of heterocyclic diamidines on four minor groove target sequences: AAAAA, TTTAA, AAATT and ATATA. The AAAAA and AAATT sequences have the largest intrinsic bend, whereas the TTTAA and ATATA sequences are relatively straight. The changes caused by binding of the compounds are sequence dependent, but generally the topological effects on AAAAA and AAATT are similar as are the effects on TTTAA and ATATA. A total of 13 compounds with a variety of structural differences were evaluated for topological changes to DNA. All compounds decrease the mobility of the ATATA sequence that is consistent with decreased minor groove width and bending of the relatively straight DNA into the minor groove. Similar, but generally smaller, effects are seen with TTTAA. The intrinsically bent AAAAA and AAATT sequences, which have more narrow minor grooves, have smaller mobility changes on binding that are consistent with increased or decreased bending depending on compound structure.

Young Adults with Lived Foster Care Experience Who Later Experience Houselessness: an Exploratory Latent Class Analysis.

Young adults with lived experience in out-of-home care during childhood report later experiences of housing instability as common. Existing literature identifies a host of factors compounding an individual's risk of experiencing houselessness, but research has yet to explore constellations of characteristics which describe youth formerly in care who later become unhoused. This exploratory study leverages a public-private data linkage collaborative to integrate and de-identify child welfare data extracted from a Rocky Mountain state's administrative database and houselessness service utilization data from a regional provider in a large metro area of the state. Linkage and sampling yielded a final sample of 285 youth (ages 18 to 24) formerly in foster care who accessed houselessness services between December 2018 and March 2020 and who had signed required consents. A 22-measure latent class analysis identified three characteristic groups: intensive youth corrections involvement and emancipation from the child welfare system (32% of sample); family-based challenges, neglect, and more moderate youth corrections involvement (41% of sample); and youth behavior and substance use challenges along with family reunification before accessing houselessness services (26%). We found that young women and Black, Indigenous, and people of color were disproportionately represented in the sample compared to the state's population of youth in out-of-home care. Youth with long histories of child welfare placement were a majority of the sample. Implications are discussed. Data-sharing barriers must be addressed to facilitate further research aimed at understanding houselessness within this population.

Cardiovascular Disease and Mortality in Black Women Carrying the Amyloidogenic V122I Transthyretin Gene Variant.

BACKGROUND: Long-term data on cardiovascular disease (CVD) and mortality in female carriers of the transthyretin (TTR) V122I (pV142I) variant, one of the most common variants of hereditary transthyretin cardiac amyloidosis, are sparse and the effects of blood pressure, heart rate, body mass index, and physical activity on CVD outcomes remain largely unknown. OBJECTIVES: The aim was to first examine the relationship of TTR V122I (pV142I) carrier status with CVD and mortality and second to investigate the effects of blood pressure, heart rate, body mass index, and physical activity in a large cohort of postmenopausal women. METHODS: The study population consisted of 9,862 non-Hispanic Black/African American women, 9,529 noncarriers and 333 TTR V122I carriers, enrolled in the Women's Health Initiative at 40 centers in the United States. Women were generally healthy and postmenopausal at the time of enrollment (1993-1998). CVD was defined as a composite endpoint consisting of coronary heart disease, stroke, acute heart failure or CVD death, and all-cause mortality. CVD cases were based on self-reported annual mailed health updates. All information was centrally adjudicated by trained physicians. HRs and 95% CIs were obtained from adjusted Cox proportional hazards models. RESULTS: Among 9,862 Black female participants (mean age: 62 years [IQR: 56-67 years]), the population frequency of the TTR V122I variant was 3.4% (333 variant carriers and 9,529 noncarriers). During a mean follow-up of 16.1 years (IQR: 9.7-22.2 years), incident CVD occurred in 2,229 noncarriers and 96 carriers, whereas 2,689 noncarriers and 108 carriers died. In adjusted models including demographic, lifestyle, and medical history covariates, TTR V122I carriers were at higher risk of the composite endpoint CVD (HR: 1.52; 95% CI: 1.22-1.88), acute heart failure (HR: 2.21; 95% CI: 1.53-3.18), coronary heart disease (HR: 1.80; 95% CI: 1.30-2.47), CVD death (HR: 1.70; 95% CI: 1.26-2.30), and all-cause mortality (HR: 1.28; 95% CI: 1.04-1.56). The authors found a significant interaction by age but not by blood pressure, heart rate, body mass index, or physical activity. CONCLUSIONS: Black female TTR V122I (pV142I) carriers have a higher CVD and all-cause mortality risk compared to noncarriers. In case of clinical suspicion of amyloidosis, they should be screened for TTR V122I (pV142I) carrier status to ensure early treatment onset.

Racial and Ethnic Differences in Self-Reported COVID-19 Exposure Risks, Concerns, and Behaviors Among Diverse Participants in the Women's Health Initiative Study.

BACKGROUND: Racial and ethnic disparities in coronavirus disease 2019 (COVID-19) risk are well-documented; however, few studies in older adults have examined multiple factors related to COVID-19 exposure, concerns, and behaviors or conducted race- and ethnicity-stratified analyses. The Women's Health Initiative (WHI) provides a unique opportunity to address those gaps. METHODS: We conducted a secondary analysis of WHI data from a supplemental survey of 48 492 older adults (mean age 84 years). In multivariable-adjusted modified Poisson regression analyses, we examined predisposing factors and COVID-19 exposure risk, concerns, and behaviors. We hypothesized that women from minoritized racial or ethnic groups, compared to non-Hispanic White women, would be more likely to report: exposure to COVID-19, a family or friend dying from COVID-19, difficulty getting routine medical care or deciding to forego care to avoid COVID-19 exposure, and having concerns about the COVID-19 pandemic. RESULTS: Asian women and non-Hispanic Black/African American women had a higher risk of being somewhat/very concerned about risk of getting COVID-19 compared to non-Hispanic White women and each was significantly more likely than non-Hispanic White women to report forgoing medical care to avoid COVID-19 exposure. However, Asian women were 35% less likely than non-Hispanic White women to report difficulty getting routine medical care since March 2020 (adjusted relative risk 0.65; 95% confidence interval 0.57, 0.75). CONCLUSIONS: We documented COVID-related racial and ethnic disparities in COVID-19 exposure risk, concerns, and care-related behaviors that disfavored minoritized racial and ethnic groups, particularly non-Hispanic Black/African American women.

Health Differs by Foster Care Eligibility: A Nine-Year Retrospective Observational Study Among Medicaid-Enrolled Children.

OBJECTIVE: This study sought to determine the prevalence and rates of physical, behavioral, and chronic health conditions among Medicaid-enrolled Colorado children by foster care eligibility codes over 9 years. METHODS: This retrospective, population-based study used Colorado's Medicaid administrative data for all enrolled children, aged <19 years old, from July 2011 to August 2020 to determine the period prevalence and rates of physical, behavioral, and chronic health conditions. We identified children in foster care by Medicaid eligibility codes and used the Pediatric Medical Complexity Algorithm version 3.0 to describe health condition outcomes. We report frequencies and percentages by foster care eligibility status, birth year cohort, and sex. RESULTS: Among 1,084,026 children, we identified 34,971 children in the foster cohort. Rates of physical (1105.0 per 100,000 person-months (PMs)) and behavioral health conditions (583.6 per 100,000 PMs) were two to threefold higher among the foster cohort than peers (physical 685.1 per 100,000 PMs; behavioral 212.2 per 100,000 PMs). By birth cohort, rates of behavioral health conditions among children in foster care were up to 8 times greater than peers. The foster cohort had greater prevalence of chronic conditions with (55.2%) and without (38.6%) behavioral health inclusion. CONCLUSIONS: This study provides a broader health assessment among Medicaid-enrolled children and finds condition disparities concentrated among youth in foster care. A more complete understanding of health problems among children in foster care is critical for health, child welfare, and Medicaid systems to improve health outcomes through coordinated and evidence-based interventions, programs, and policies.

Effects of Environmental Enrichment on Dog Behaviour: Pilot Study.

Environmental enrichment (EE) can be used to enhance the environment of various animals. The aim of this pilot study was to determine the effects of seven EE activities (Bonding, Bubble machine, Conspecific play, Interactive toy, Playhouse, Stuffed food toy and Tug play) on dog behaviour, pre- and post-EE for dogs housed in an office environment during training as part of an assistance dog training programme. EE activities resulted in a significant increase in the frequency of relaxation behaviours (p < 0.01) and a significant reduction in alert (p < 0.01) and stress behaviours (p = 0.02). Results suggest various benefits of the different activities with Conspecific Play and Playhouse activities having the greatest overall positive behaviour change when compared to the other activities. The food-based EE activities (Interactive toy and Stuffed food toy) had the least behaviour change of all the activities provided. Findings will be of interest to pet owners, animal rescue centres, dog trainers and working dog organisations.

Blood Pressure Variability and Heart Failure Hospitalization: Results From the Women's Health Initiative.

INTRODUCTION: Little is known about the relationships between annual visit-to-visit blood pressure variability and heart failure subphenotypes. The aim of this analysis was to examine the association between blood pressure variability and incident heart failure with preserved and reduced ejection fraction. METHODS: Data from 23,918 postmenopausal women enrolled in the Women's Health Initiative Hormone Therapy Trials were analyzed. Blood pressure was measured at baseline (1993‒1998) and then annually through 2005. Variability was defined as the SD of the mean blood pressure across visits or the SD of the participant's regression line for blood pressure across visits. The outcome was the first heart failure hospitalization. Heart failure ascertainment and adjudications were through March 31, 2018. RESULTS: During a mean follow-up of 15.8 years, 913 incident cases of heart failure with preserved ejection fraction and 421 cases of heart failure with reduced ejection fraction were identified. In fully adjusted models, including mean longitudinal systolic and diastolic blood pressure and time-varying coronary events interim to heart failure hospitalization, women in the highest versus in the lowest quartile of SD of the mean systolic blood pressure were at a statistically significantly higher risk of heart failure with preserved ejection fraction (hazard ratio [95% CI]=1.61 [1.12, 2.31]) but not of heart failure with reduced ejection fraction (1.18 [0.70,1.96]). Conversely, the hazard ratio (95% CI) for the highest versus lowest quartile of SD of the mean diastolic blood pressure was 1.56 (0.89, 2.74) for heart failure with reduced ejection fraction and 1.19 (0.85,1.65) for heart failure with preserved ejection fraction. Results attenuated for SD of the participant's regression line when additionally adjusted for the temporal trend of systolic and diastolic blood pressure. CONCLUSIONS: Greater systolic blood pressure variability was associated with a higher risk of heart failure with preserved ejection fraction independent of mean blood pressure and coronary events interim to heart failure hospitalization.

Design and baseline characteristics of participants in the COcoa Supplement and Multivitamin Outcomes Study (COSMOS).

Background Cocoa extract and multivitamins have been proposed to reduce the risk of cardiovascular disease (CVD) and cancer, respectively. However, few randomized clinical trials have tested their long-term effects on these outcomes. Methods The COcoa Supplement and Multivitamin Outcomes Study (COSMOS) is a randomized, double-blind, placebo-controlled, 2 × 2 factorial trial of a cocoa extract supplement and a multivitamin supplement to reduce the risk of CVD and cancer. Here we describe the pragmatic, hybrid design of the trial and baseline characteristics of the trial participants. Results The nationwide study population includes 21,442 U.S. women aged ≥65 years and men aged ≥60 years without baseline myocardial infarction (MI), stroke, or a recent (within the past 2 years) cancer diagnosis. Participants were randomized in a 2 × 2 factorial design to one of four groups: (1) cocoa extract (containing 500 mg/d flavanols, including 80 mg (-)-epicatechin) and a multivitamin (Centrum Silver©); (2) cocoa extract and multivitamin placebo; (3) multivitamin and cocoa extract placebo; or (4) both placebos. Randomization successfully distributed baseline demographic, clinical, behavioral, and dietary characteristics across treatment groups. Baseline biospecimens were collected from 6867 participants, with at least one follow-up biospecimen from 2142 participants. The primary outcome for the cocoa extract intervention is total CVD (a composite of MI, stroke, cardiovascular mortality, coronary revascularization, unstable angina requiring hospitalization, carotid artery surgery, and peripheral artery surgery); the primary outcome for the multivitamin intervention is total invasive cancer. Conclusion COSMOS will provide important information on the health effects of cocoa extract and multivitamin supplementation in older U.S. adults. Clinical Trials Registration: clinicaltrials.gov #NCT02422745.

After the initial fracture in postmenopausal women, where do subsequent fractures occur?

BACKGROUND: The locations of subsequent fractures after initial fracture in postmenopausal women are poorly characterized. METHODS: We conducted a prospective analysis of subsequent fractures after initial fracture in Women's Health Initiative (1993-2018) participants who provided follow-up (mean 15.4 years, SD 6.2 years) data (n = 157,282 participants; baseline age 50-79; 47,458 participants with incident fracture). Cox proportional hazards models were adjusted for age, race/ethnicity, body mass index, and other covariates. FINDINGS: The risk of each type of subsequent fracture was increased after each type of initial fracture. Incident lower arm/wrist fracture was associated with significantly elevated risks of subsequent fractures at the upper arm/shoulder, upper leg, knee, lower leg/ankle, hip/pelvis, and spine (adjusted hazard ratios [aHRs] ranging 2·63-5·68). The risk of hip fracture was increased after initial lower arm or wrist fracture (aHR 4·80, 95% CI 4·29-5·36), initial upper arm or shoulder fracture (aHR 5·06, 95% CI 4·39-5·82), initial upper leg fracture (aHR 5·11, 95% CI 3·91-6·67), initial knee fracture (aHR 5·03, 95% CI 4·20-6·03), initial lower leg/ankle fracture (aHR 4·10, 95% CI 3·58-4·68), and initial spine fracture (aHR 6·69, 95% CI 5·95-7·53). Associations were significant in all age groups, even women aged 50-59 years. Risks of subsequent fracture were more pronounced among non-Hispanic Black, Hispanic/Latina, and Asian/Pacific Islander than among non-Hispanic White women. INTERPRETATION: Increased risk of subsequent fracture is observed for all fracture types across all ages. Women who experience any of these fractures should be targeted for interventions to prevent subsequent fractures. FUNDING: National Institutes of Health HHSN268201600018C,HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C.