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Efficacy and Safety of Upadacitinib in Patients With Moderate-to-Severe Atopic Dermatitis: Phase 3 Randomized Clinical Trial Results Through 140 Weeks
No full textBACKGROUND: Upadacitinib is an oral selective Janus kinase inhibitor approved to treat moderate-to-severe atopic dermatitis (AD) in adults and adolescents; long-term efficacy and safety data beyond 1 year are needed. OBJECTIVE: The aim was to evaluate the long-term efficacy and safety of upadacitinib treatment through 140 weeks in patients with moderate-to-severe AD. METHODS: Measure Up 1 (MeUp1; NCT03569293), Measure Up 2 (MeUp2; NCT03607422), and AD Up (NCT03568318) are ongoing, phase 3, randomized clinical trials evaluating upadacitinib 15 mg (UPA15) and 30 mg (UPA30) in adults and adolescents with moderate-to-severe AD. This interim analysis evaluated efficacy and safety through week 140. At baseline, patients were randomized 1:1:1 to receive once-daily UPA15, UPA30, or placebo alone (MeUp1/2) or with concomitant topical corticosteroids (AD Up). At week 16, patients initially randomized to placebo were rerandomized 1:1 to UPA15 or UPA30. Skin and itch efficacy assessments included achievement of ≥ 75%/≥ 90%/100% improvement from baseline in Eczema Area and Severity Index (EASI 75/90/100), validated Investigator Global Assessment for AD score of clear/almost clear (vIGA-AD 0/1), and ≥ 4-point improvement from baseline in Worst Pruritus Numerical Rating Scale (∆WP-NRS≥4). Safety assessments included incidence of treatment-emergent adverse events. RESULTS: A total of 2782 patients were randomized in MeUp1/2 or AD Up. Efficacy response rates, including optimal outcomes such as EASI 90 and WP-NRS score of 0/1, were sustained through week 140 in all three studies. At week 140, EASI 75 was achieved by 85.5%/90.5% (UPA15/UPA30; integrated MeUp1/2) and 81.5%/90.0% (UPA15/UPA30; AD Up) of patients, and vIGA-AD 0/1 was achieved by 56.6%/64.4% (UPA15/UPA30; integrated MeUp1/2) and 52.0%/56.8% (UPA15/UPA30; AD Up) of patients. Over 60% of patients across all three studies achieved ∆WP-NRS≥4 at week 140. Pooled safety data across all three studies demonstrated safety profiles consistent with 16-week and 52-week analyses. CONCLUSIONS: UPA15 and UPA30 with and without topical corticosteroids demonstrated robust, durable efficacy and a favorable safety profile through 140 weeks in adults and adolescents with moderate-to-severe AD. TRIAL REGISTRATION: Measure Up 1 (NCT03569293; https://clinicaltrials.gov/study/NCT03569293 ), Measure Up 2 (NCT03607422; https://clinicaltrials.gov/study/NCT03607422 ), and AD Up (NCT03568318; https://clinicaltrials.gov/study/NCT03568318 )
Prematurity, Neonatal Complications, and the Development of Childhood Hypertension
No full textIMPORTANCE: Preterm children face a higher risk of cardiovascular conditions, including hypertension. However, studies have not isolated the associations of prematurity with cardiovascular conditions from the associations of subsequent complications with cardiovascular conditions, especially among those admitted to a neonatal intensive care unit (NICU). OBJECTIVE: To investigate prospective associations of prematurity and NICU complications with childhood hypertension while accounting for prenatal and perinatal factors. DESIGN, SETTING, AND PARTICIPANTS: This cohort study analyzed longitudinal data from the Boston Birth Cohort on 2459 infants (695 preterm, 468 with NICU admission) born between January 1, 1999, and December 31, 2014. Statistical analysis was performed from January 1, 1999, to December 31, 2020. MAIN OUTCOMES AND MEASURES: Children were categorized into 5 subgroups based on preterm birth status, NICU admission, and major complications (sepsis, chronic lung disease, necrotizing enterocolitis, and intraventricular hemorrhage). The primary end point was hypertension (episodic and persistent) per American Academy of Pediatrics guidelines, with elevated blood pressure (BP) and BP percentiles as secondary end points. Modified Poisson and proportional hazards regression were used to determine crude and adjusted relative risks (RRs) and hazard ratios (HRs). Secondary analyses used linear generalized estimating equations to assess repeated BP measurements over time, standardized to population-based BP percentiles. RESULTS: Of the 2459 infants (695 preterm: mean [SD] gestational age, 33.2 [3.5] weeks; 358 boys [51.5%]; and 1764 full term: mean [SD] gestational age, 39.4 [1.3] weeks; 879 boys [49.7%]) in this study, 468 (19.0%) were admitted to the NICU. The incidence of persistent hypertension was higher among children born preterm compared with those born at full term (25.2% [175 of 695] vs 15.8% [278 of 1764]). Preterm infants and infants admitted to the NICU had a greater risk of developing persistent hypertension compared with full term-born children without NICU admission or neonatal complications, independent of pertinent maternal and infant characteristics. Preterm infants with an NICU stay, both with (adjusted RR, 1.87 [95% CI, 1.19-2.94]) and without (adjusted RR, 1.62 [95% CI, 1.27-2.07]) a neonatal complication, had the greatest risk for persistent hypertension. Cox proportional hazards regression analysis identified preterm infants with an NICU stay, particularly those with a complication, as having the highest risk of developing persistent hypertension (adjusted HR, 2.37 [95% CI, 1.44-3.89]). On average, infants born prematurely without an NICU admission or complication (β, 2.74 percentile points [95% CI, 0.38-5.10 percentile points]) and those born prematurely with an NICU admission but no complications (β, 4.06 percentile points [95% CI, 2.11-6.02 percentile points]) had higher systolic BP percentiles and those born prematurely with an NICU admission but no complications had higher diastolic BP percentiles (β, 4.01 percentile points [95% CI, 2.52-5.49 percentile points]) during follow-up up to 18 years of age. CONCLUSIONS AND RELEVANCE: This prospective cohort study found incrementally stronger associations for NICU admission, prematurity, and prematurity-related complications with the risk of developing persistent hypertension in childhood. These findings support the need for hypertension screening, coordinated primary and specialist care, and cardiovascular health promotion among children born preterm
Mediation Analysis of Internalized Homophobia, Self-esteem and Mental Health in Adolescent Sexual Minority Men: A Repeated Measures Study
No full textInternalized homophobia (IH) negatively impacts the mental health of adolescent sexual minority men (ASMM), while self-esteem is posited to bolster their mental health. In a repeated-measures study with 599 ASMM (Mean age = 16.2 [SD = 1.3]; 75.6% racial and ethnic minorities), longitudinal structural equation models investigated the relationships among IH, self-esteem, and mental health (depression and anxiety), as well as the mediating role of self-esteem. Higher self-esteem at earlier time points was significantly associated with lower anxiety and depressive symptoms. The hypothesized mediation pathways were not statistically significant. Subgroup analyses revealed that the protective effect of self-esteem against anxiety was significant for racial and ethnic minority ASMM but not for their non-Hispanic White counterparts. These findings highlight the need for tailored interventions that address the unique experiences of ASMM from diverse racial and ethnic backgrounds
Global, regional and national estimates of the burden of childhood asthma attributable to NO exposure for 204 countries and territories from 1990 to 2023: a Global Burden of Disease study 2023
No full textBACKGROUND: Asthma, a chronic lung condition characterised by inflammation and airway constriction, has been associated with nitrogen dioxide (NO) exposure, an association that particularly impacts children. Our study rigorously assessed this relationship and estimated the global burden of childhood asthma attributable to NO exposure in 204 countries and territories from 1990 to 2023. METHODS: We systematically reviewed epidemiological studies evaluating NO\u27s long-term impact on childhood asthma. Using burden of proof meta-regression methods that account for bias by adjusting for study-design covariates and quantify remaining unexplained between-study heterogeneity to incorporate into uncertainty, we estimated the relative risk of childhood asthma occurring as a function of NO exposure. From this, we computed global and country-specific population attributable fractions (PAFs) - i.e., the proportional change in asthma risk that would occur if NO exposure were reduced to a theoretical minimum exposure level range of 4.6-6.2 ppb. We applied PAFs to data from the 2023 Global Burden of Disease Study (GBD) to derive the asthma burden attributable to NO exposure in children and youths under 20 years old. Burden of proof methods allowed us to further compute risk-outcome metrics quantifying the magnitude of the NO-asthma association and its strength of supporting evidence. FINDINGS: We identified a total of 27 cohort studies, spanning 12 countries, primarily in Europe and high-income North America, with some studies from Asia (China and Japan). A meta-regression log-linear risk curve of these studies produced a summary RR of 1.05 (95% UI 0.99-1.12) per 5 ppb NO and Egger\u27s regression indicated significant publication bias. We estimated a global PAF of 4.67% (95% uncertainty interval [UI]: -3.75 to 20.6; all UIs reported in this study are inclusive of between-study heterogeneity except where noted), yielding 233,000 (-250,000-956,000) years lived with disability (YLDs) attributable to NO globally in 2023. GBD 2023 ranked NO seventh among environmental risk factors contributing to YLDs in children for all causes and third for childhood asthma YLDs. Attributable burden estimates and trends varied significantly by GBD super-region. While NO-attributable childhood asthma burden has declined substantially since 1990 in the high-income and central Europe, eastern Europe, and central Asia super-regions, NO remains a prominent environmental risk factor in these two super-regions, ranked third in both super-regions for paediatric asthma YLDs in 2023, contributing 57,100 (-63 600 to 242,000) and 6570 (-7050 to 30,200) YLDs, respectively. In South Asia, NO ranks second as risk factor for pediatric asthma contributing to 20,100 (-17 600, 105,000) YLDs in 2023. INTERPRETATION: NO pollution remains a top environmental risk for paediatric health, necessitating policy interventions targeting NO pollution, especially in high-income locations and urban areas. FUNDING: The research described in this article was conducted in part under contract with the Health Effects Institute (HEI), an organization jointly funded by the United States Environmental Protection Agency (EPA) and certain motor vehicle and engine manufacturers, grant number 4977/20-11. The contents of this article do not necessarily reflect the views of HEI or its sponsors, nor do they necessarily reflect the views and policies of the EPA or motor vehicle and engine manufacturers. Additional funding for this study was received by the Gates foundation, grant no. OPP1152504 for MB, KB, and SW. SA, DG, AM and GHK were supported by NASA grant no. 80NSSC21K0511 and SA and GHK NIH grant no. P20ES036775
The influence of nutritional status, the home environment, and schooling on behavioral outcomes of hyperactivity and inattention among grade-school children in rural Nepal
No full textAttention-deficit/hyperactivity disorder (ADHD) in children is characterized by frequent inattention and/or hyperactivity that can affect child development, including learning, social adaptation, and mental health. Despite the impact of these behaviors, data on the prevalence and risk factors of child behavioral and neurodevelopmental disorders in low- and middle-income countries are limited. This paper aims to identify maternal, child and environmental risk factors associated with ADHD-related behaviors (hyperactivity/ oppositionality, and inattention) in a cohort of 7- to 9-year-old children born between 1999-2001 (n = 1,927), whose mothers participated in a cluster randomized trial of prenatal micronutrient supplementation, and who were subsequently enrolled in a preschool micronutrient supplementation trial. Behaviors were assessed using the Conners\u27 Parent and Teacher Rating Scales-Revised (CPRS-R, CTRS-R). T-scores are reported and dichotomized at the upper tertile, defining the presence of behavioral difficulties. Multivariable logistic regression models were conducted to assess the association between behavioral outcomes and maternal characteristics (anemia, education, and intelligence using the Raven\u27s Coloured Progressive Matrices), child nutritional status (anemia, height-for age, body mass index z-scores (HAZ, BMIZ)), child schooling history and the home environment, using the Middle Childhood Home Observation Measurement of the Environment (MC-HOME). Boys (50.2%) and girls (49.8%) were evenly distributed, with a mean age of 8.38 (SD 0.66) years and parent and teacher behavioral assessments were available for 1,808 and 1,374 children, respectively. Mean t-scores for parent-reported inattention and hyperactivity/oppositionality and teacher-reported inattention and hyperactivity were 62.9 (SD 6.29), 62.1 (SD 5.84), 62.2 (SD 8.07) and 62.2 (SD 8.43), respectively. In adjusted logistic regression models, a higher HOME score was associated with a reduced risk of parent-reported inattention (RR 0.97, 95% CI 0.96, 0.99), whereas higher maternal Raven\u27s score (RR 0.99, 95% CI 0.97, 1.00), a higher HOME score (RR 0.98, 95% CI 0.97, 1.00) and child pre-primary, late and continuous schooling compared to no schooling (RR 0.75, 95% CI 0.57, 0.98; RR 0.66, 95% CI 0.52, 0.85; RR 0.68, 95% CI 0.48, 0.98) were associated with a reduced risk of parent-reported hyperactivity/oppositionality. Higher child HAZ was associated with a reduced risk of teacher-reported hyperactivity (RR 0.87, 95% CI 0.80, 0.96) after adjustment. The home psychosocial environment, and child schooling and height were the strongest predictors of inattention and hyperactivity/oppositionality in school-age children in rural Nepal
Age and Sex-Specific Percentiles of 30-Year Cardiovascular Disease Risk Based on the PREVENT Equations
No full textBACKGROUND: Current primary prevention guidelines recommend estimation of long-term cardiovascular disease (CVD) risk among younger adults to enable preventive efforts earlier in the life course. However, conceptualizing absolute risk estimates over this time horizon is challenging for both clinicians and patients. Framing risk relative to peers (ie, population-based percentiles ) as complementary information may have utility for risk communication. OBJECTIVES: We sought to develop population-based age- and sex-specific percentiles of 30-year absolute risk estimates for CVD, atherosclerotic cardiovascular disease (ASCVD), and heart failure (HF) with the PREVENT (Predicting Risk of CVD EVENTs) equations. METHODS: We used data from a nationally representative sample of U.S. adults aged 30 to 59 years without prevalent CVD in the National Health and Nutrition Examination Survey (NHANES) 2011 to March 2020. We calculated 30-year risk estimates with PREVENT for eligible participants and derived age- and sex-specific percentiles at each age (using rolling windows of ±5 years) for each outcome of CVD, ASCVD, and HF. RESULTS: Among 8,686 NHANES participants, representing approximately 91 million U.S. adults aged 30 to 59 years in the final sample, mean age was 44.8 ± 0.2 years among female participants and 44.2 ± 0.2 years among male participants. The median 30-year absolute CVD risk in the overall sample was 13.1%. Then, corresponding percentile values were developed and evaluated for each age among women and men aged 30 to 59 years for 30-year risk of CVD, ASCVD, and HF. For example, at age 45 years, the 50th percentile of 30-year CVD risk for was 9.9% for women and 16.2% for men, and the 75th percentile was 14.7% for women and 21.2% for men at that age. Similar patterns were observed for ASCVD and HF, with higher 30-year absolute risk in men compared with women. An online tool was developed to present risk percentiles alongside absolute 30-year risk for CVD, ASCVD, and HF. CONCLUSIONS: Population-based age- and sex-specific percentiles for 30-year CVD risk with PREVENT may offer a complementary tool for clinicians and patients in addition to communicating absolute CVD risk estimates. Prospective studies should test whether this approach improves risk perception or decision-making in younger adults
A patient-centric paradigm and tool for clinical research: the DOOR is open
No full textRandomized clinical trials are the gold standard for evaluating the benefits and harms of interventions and yet may not provide the evidence needed to inform medical decision-making, an ultimate goal for clinical research. Commonly used design and analysis approaches are often not suited to answer the most important questions to inform clinical practice, specifically how do resulting patient experiences, when comprehensively considering benefits and harms, compare between therapeutic alternatives? The standard approach of siloed analysis of one outcome at a time: (i) does not incorporate associations between multiple outcomes; (ii) does not recognize the cumulative nature of multiple outcomes in individual patients or recognize important gradations of global patient response; (iii) suffers from competing risk complexities during interpretation of individual outcomes; (iv) provides for ambiguous generalizability with respect to benefit:risk since efficacy and safety analyses are often conducted on different populations. Evaluation of treatment effect heterogeneity to identify subgroups for treatment or avoidance of treatment is typically evaluated based on a single efficacy or safety endpoint and rarely evaluated based on the overall benefit:risk. Methods that quantify and compare the patient experience are needed. The desirability of outcome ranking (DOOR) is a paradigm for the design, monitoring, analysis, interpretation, and reporting of clinical trials and other research studies based on patient-centric benefit:risk evaluation, developed to address these issues and advance clinical trial science. Aligning the clinical research strategy with the relevant question for clinical practice will enhance research applicability. Careful design and comprehensive analyses are critical for DOOR paradigm application. We provide a recommended statistical analysis plan for research studies implementing DOOR, describe its elements, and illustrate analysis application using examples. A freely available online tool for the recommended analyses and the design of studies implementing the DOOR paradigm is provided.ClinicalTrials.gov ID: NCT05641298
Impact of breast MRI on the surgical management of young women with breast cancer
No full textOBJECTIVE: This study evaluates the impact of preoperative breast MRI on surgical management in young women diagnosed with breast cancer. METHODS: A retrospective chart review identified 125 women aged 40 years or younger diagnosed with breast cancer at a university academic practice between January 2015 and December 2020. Twenty-three patients were excluded due to loss of follow-up, resulting in a final sample of 102 patients. Patients were included regardless of surgical plan. Variables analyzed included demographic data, breast cancer risk factors, imaging findings, and subsequent surgical outcomes. Chi-square and Fisher\u27s exact test were used for bivariate analyses. Univariate and multivariate logistic regression were used to assess the association between MRI findings and surgical management. RESULTS: Preoperative MRI detected additional findings or lesions warranting biopsy in 53.9 % of cases, with 45.5 % of these lesions confirmed as malignant. Of the confirmed malignancies, 24 were ipsilateral and 1 was contralateral. The detection of additional carcinoma was associated with a 6.34-fold increased likelihood of undergoing mastectomy (aOR: 6.34, 95 % CI: 1.85-29.82). MRI was particularly effective in detecting additional ipsilateral disease, supporting its role in preoperative planning. CONCLUSION: Preoperative MRI in women aged 40 years and younger increases the detection of additional malignancies, influencing surgical decisions and supporting its integration into routine preoperative evaluation for improved patient outcomes
Long-term effect of multivitamin supplementation on incident self-reported hypertension and blood pressure changes in the COSMOS trial
No full textBACKGROUNDS: Multivitamin-multimineral (MVM) supplements have been associated with lower blood pressure (BP) in several small trials. We investigated the effects of a MVM on incident hypertension and BP in a secondary analysis of the COcoa Supplement and Multivitamin Outcomes Study (COSMOS). METHODS: COSMOS is a 2X2 factorial, double-blinded RCT testing effects of cocoa extract and MVM supplementation among women aged ≥65y and men aged ≥60y. Among 8905 COSMOS participants free from hypertension, effects of MVM supplementation on incident hypertension were investigated. Hypertension diagnosis was ascertained through self-reports. Additionally, in two substudies with BP measurements (N = 529 at clinic by research staff and 994 at home by technician), we evaluated the effects on 2-year BP changes. RESULTS: Incident hypertension was observed in N = 1034 (22.9%) in MVM arm and N = 1039 (23.6%) in placebo arm over a median of 3.4 years (IQR: 3.0, 3.9) of follow-up, with hazard ratio (HR) 0.98 [95% CI: 0.90, 1.06]. Effects differed according to baseline diet quality, with HRs of incident hypertension 0.81 [0.70, 0.95] and 1.14 [1.01, 1.28] among participants with lower and higher Alternate Mediterranean Diet score, respectively (p-interaction = 0.001). There was no effect of MVM on 2-year changes in systolic BP (4.4mmHg in MVM; 4.5mmHg in placebo), while pronounced effects were observed for baseline normal BP (p-interaction = 0.004). CONCLUSION: MVM supplementation versus placebo did not reduce hypertension incidence or lower BP overall. Exploratory analyses showed greater reduction in hypertension risk and BP changes among those with lower dietary quality and normal BP at baseline, respectively. CLINICALTRIALS.GOV REGISTRATION: NCT02422745