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Objective: To investigate the relationship between self-reported osteoarthritis (OA) and reproductive factors in the Women's Health Initiative (WHI). Method: We used multivariable logistic regression to study the association of self-reported OA and reproductive factors in the WHI Observational Study and Clinical Trial cohorts of 145 965 postmenopausal women, in a retrospective cross-sectional format. Results: In our cohort, we observed no clinically significant associations between reproductive factors and OA given small effect sizes. The following factors were associated with statistically significant increased likelihood of developing OA: younger age at menarche (p < 0.001), history of hysterectomy [adjusted odds ratio (aOR) 1.013, 95% confidence interval (CI) 1.004–1.022, p = 0.04 vs no hysterectomy], history of unilateral oophorectomy (aOR 1.015, 95% CI 1.004–1.026, p < 0.01 vs no oophorectomy), parity (aOR 1.017, 95% CI 1.009–1.026, p < 0.001), ever use of oral contraceptives (aOR 1.008, 95% CI 1.001–1.016, p < 0.01 vs never use), and current use of hormonal therapy (reference current users, aOR 0.951, 95% CI 0.943–0.959 for never users; aOR 0.981, 95% CI 0.972–0.989 for past users; global p < 0.001). Age at menopause, first birth, and pregnancy were not associated with OA. Among parous women, no clear pattern was observed with number of pregnancies, births, or duration of breastfeeding in relation to OA. Conclusion: Our study showed that reproductive factors did not have significant clinical associations with OA after controlling for confounders. This may be due to complex hormonal effects. Additional investigation is warranted in prospective cohort studies. The Women's Health Initiative is registered under ClinicalTrials.gov. Trial registration ID: NCT00000611. [ABSTRACT FROM AUTHOR]

Benchmarks of clinical management are essential for improving the quality of care. However, the lack of established quality metrics for pulmonary arterial hypertension (PAH) contributes to practice heterogeneity. We assessed our center's diagnostic practices, therapeutic practices, and risk-adjusted survival patterns over time for the purpose of establishing quality benchmarks. We analyzed the demographics, clinical characteristics, and diagnostic evaluation of 702 PAH patients enrolled between 1999 and 2019. We examined outcomes in this cohort, including an analysis of risk stratification, therapeutic practice patterns, hospitalizations, organ transplant, and survival. Initial diagnostic workup of incident PAH cases demonstrated excellent completion of echocardiographic (99%) and pulmonary function testing (91%), with improved completion of VQ scanning over the study time period (90% between 2015 and 2019). Right heart catheterization (RHC) was performed in all patients; RHC performed at our center was more likely to include complete hemodynamic data than those performed at referring institutions (55.4% and 30.4% respectively). The average number of PAH-specific medications prescribed increased over time; however, there was no significant increase in the use of parenteral therapy over time, even when stratified by the REVEAL risk score. Survival rates in the cohort were 94% at 1 year, 75% at 5 years, and 60% at 10 years, comparable to those of other PAH cohorts. Analysis of our well-characterized cohort of PAH patients reveals the extent to which guideline-directed diagnostic and therapeutic care is delivered at our specialty center, and the associated outcomes; these data may serve as a benchmark for continued improvements in quality of PAH care., Competing Interests: The authors declare no conflicts of interest., (© 2025 The Author(s). Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Objective: To assess whether conditional bedside alarm triggers can reduce the frequency of nonactionable alarms without compromising patient safety and enhance nursing and family satisfaction., Study Design: Single-center, quality improvement initiative in an acute care cardiac unit and pediatric intensive care unit. Following the 4-week preintervention baseline period, bedside monitors were programmed with hierarchical time delay and conditional alarm triggers. Bedside alarms were tallied for 4 weeks each in the immediate postintervention period and 2-year follow-up. The primary outcome was alarms per monitored patient day. Nurses and families were surveyed preintervention and postintervention., Results: A total of 1509 patients contributed to 2034, 1968, and 2043 monitored patient days which were evaluated in the baseline, follow-up, and 2-year follow-up periods, respectively. The median number of alarms per monitored patient day decreased by 75% in the pediatric intensive care unit (P < .001) and 82% in the acute care cardiac unit (P < .001) with sustained effect at the 2-year follow-up. No increase of rapid response calls, emergent transfers, or code events occurred in either unit. Nursing surveys reported an improved capacity to respond to alarms and fewer perceived nonactionable alarms. Family surveys, however, did not demonstrate improved sleep quality., Conclusions: Implemented changes to bedside monitor alarms decreased total alarm frequency in both the acute care cardiac unit and pediatric intensive care unit, improving the care provider experience without compromising safety., Competing Interests: Declaration of Competing Interest This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors have no conflicts to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The Latinx community faces an increasing amount of mental health challenges and disparities in care. While the contributing factors are complex, there are likely potential barriers related to connecting with mental health support and accessing care that can be addressed., Methods: To investigate barriers in connecting to mental health care, we conducted a cross-sectional survey of mental health service use and barriers in an urban community with a primarily Hispanic/Latinx ethnicity using a modified random walk approach for door-to-door data collection with a two-cluster sampling frame. Survey included questions on socio-demographic, mental health status, desire and attempt to seek care, and the Barriers to Access to Care Evaluation. Shapley additive explanation (SHAP) identified impactful barriers and demographic characteristics. Our primary outcome was the number of respondents who saw a professional in the past 12 months and the key determinants that enabled their successful connection. Secondary outcomes were people with poor mental health who had wanted or tried to seek any source of mental health support., Results: Of the 1004 respondents enrolled, 70.5% were foreign born; 63.4% were women. In the past 12 months, 23.8% of respondents wanted to connect with mental health care; 15.5% tried to connect, and only 11.7% successfully connected to mental health services. The two most cited barriers had the highest SHAP values: concerns about treatments available (65%) and financial costs (62.7%). Additional barriers with high SHAP values: being seen as weak and having no one to help them find care. Of demographic characteristics, age had the highest SHAP values., Conclusion: In a community with a high density of Latinx immigrants, just under half of respondents wanting mental health care successfully connected. Perceived informational, financial, and stigma-related barriers impacted the likelihood to connect with mental health care. These factors should be considered when designing programs and interventions to improve mental health care access and services in the Latinx community., (© 2024. The Author(s).)

Importance: There is an urgent need to identify treatments for postacute sequelae of SARS-CoV-2 infection (PASC)., Objective: To assess the efficacy of a 15-day course of nirmatrelvir-ritonavir in reducing the severity of select PASC symptoms., Design, Setting, and Participants: This was a 15-week blinded, placebo-controlled, randomized clinical trial conducted from November 2022 to September 2023 at Stanford University (California). The participants were adults with moderate to severe PASC symptoms of 3 months or longer duration., Interventions: Participants were randomized 2:1 to treatment with oral nirmatrelvir-ritonavir (NMV/r, 300 mg and 100 mg) or with placebo-ritonavir (PBO/r) twice daily for 15 days., Main Outcomes and Measures: Primary outcome was a pooled severity of 6 PASC symptoms (fatigue, brain fog, shortness of breath, body aches, gastrointestinal symptoms, and cardiovascular symptoms) based on a Likert scale score at 10 weeks. Secondary outcomes included symptom severity at different time points, symptom burden and relief, patient global measures, Patient-Reported Outcomes Measurement Information System (PROMIS) measures, orthostatic vital signs, and sit-to-stand test change from baseline., Results: Of the 155 participants (median [IQR] age, 43 [34-54] years; 92 [59%] females), 102 were randomized to the NMV/r group and 53 to the PBO/r group. Nearly all participants (n = 153) had received the primary series for COVID-19 vaccination. Mean (SD) time between index SARS-CoV-2 infection and randomization was 17.5 (9.1) months. There was no statistically significant difference in the model-derived severity outcome pooled across the 6 core symptoms at 10 weeks between the NMV/r and PBO/r groups. No statistically significant between-group differences were found at 10 weeks in the Patient Global Impression of Severity or Patient Global Impression of Change scores, summative symptom scores, and change from baseline to 10 weeks in PROMIS fatigue, dyspnea, cognitive function, and physical function measures. Adverse event rates were similar in NMV/r and PBO/r groups and mostly of low grade., Conclusions and Relevance: The results of this randomized clinical trial showed that a 15-day course of NMV/r in a population of patients with PASC was generally safe but did not demonstrate a significant benefit for improving select PASC symptoms in a mostly vaccinated cohort with protracted symptom duration. Further studies are needed to determine the role of antivirals in the treatment of PASC., Trial Registration: ClinicalTrials.gov Identifier: NCT05576662.

Rationale: Pulmonary arterial hypertension (PAH) is a life-threatening progressive cardiopulmonary disease associated with high morbidity and mortality. Changes in the six-minute walk test (6MWT) provide prognostic information and help guide treatment decisions for PAH. However, since 6MWT requires in-clinic visits, clinical interventions to address disease progression may be delayed. Wearable technologies could reduce this delay by allowing the performance of 6MWT in the community and delivering data to clinicians remotely., Objectives: To perform a pilot study to determine the safety and feasibility of performing 6MWT in PAH outpatients using a wearable app-based tool., Methods: PAH patients recruited at Stanford University were provided an Apple Watch with an app to perform daily, self-administered 6MWT over 12 weeks. Bland-Altman plots and correlations were used to assess the agreement and reliability of in-clinic vs. app-based 6MWT data at the beginning and end of the 12-week trial., Measurements and Main Results: From 55 PAH participants, we collected 3,139 app-recorded walks during 979.7 patient-weeks of exposure. On average, participants performed 3±2.3 weekly walks. No serious adverse events were reported. App-derived walk distance was highly correlated ( r ≥ 0.9) to the baseline in-clinic 6MWD and showed excellent reliability (ICC=0.9). Correlation and agreement were significantly lower at the 12-week follow-up visit. App-derived metrics beyond 6MWD showed promising associations with disease status., Conclusions: App-based outpatient 6MWT is feasible, safe, reasonably accurate, likely clinically relevant, and reliable in PAH patients but long-term measurement stability may be a concern. App-derived digital measures beyond distance show promise for future applications.

Objective: The purpose of this study was to determine whether sleep characteristics are associated with incidence of treated diabetes in postmenopausal individuals., Methods: Postmenopausal participants ages 50-79 years reported sleep duration, sleep-disordered breathing, or insomnia at baseline and again in a subsample 3 years later. The primary outcome was self-reported new diagnosis of diabetes treated with oral drugs or insulin at any time after baseline. Multivariable Cox proportional hazards models were used., Results: In 135,964 participants followed for 18.1 (± 6.3) years, there was a nonlinear association between sleep duration and risk of treated diabetes. Participants sleeping ≤5 hours at baseline had a 21% increased risk of diabetes compared with those sleeping 7 hours (adjusted hazard ratio [aHR] 1.21; 95% confidence interval [CI], 1.00-1.47). Those who slept for ≥9 hours had a nonsignificant 6% increased risk of diabetes compared with those sleeping 7 hours (aHR 1.06; 95% CI, 0.97-1.16). Participants whose sleep duration had decreased at 3 years had a 9% (aHR 1.09; 95% CI, 1.02-1.16) higher risk of diabetes than participants with unchanged sleep duration. Participants who reported increased sleep duration at 3 years had a risk of diabetes (HR 1.01; 95% CI, 0.95-1.08) similar to those with no sleep duration change. Participants at high risk of sleep-disordered breathing at baseline had a 31% higher risk of diabetes than those without (aHR 1.31; 95% CI, 1.26-1.37). No association was found between self-reported insomnia score and diabetes risk., Conclusions: Sleep-disordered breathing and short or long sleep duration were associated with higher diabetes risk in a postmenopausal population., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Pulmonary arterial hypertension (PAH) is a rare subgroup of pulmonary hypertension (PH). Claims and administrative databases can be particularly important for research in rare diseases; however, there is a lack of validated algorithms to identify PAH patients using administrative codes. We aimed to measure the accuracy of code-based PAH algorithms against the true clinical diagnosis by right heart catheterization (RHC). This study evaluated algorithms in patients who were recorded in two linkable data assets: the Stanford Healthcare administrative electronic health record database and the Stanford Vera Moulton Wall Center clinical PH database (which records each patient's RHC diagnosis). We assessed the sensitivity and specificity achieved by 16 algorithms (six published). In total, 720 PH patients with linked data available were included and 558 (78%) of these were PAH patients. Algorithms consisting solely of a P(A)H-specific diagnostic code classed all or almost all PH patients as PAH (sensitivity >97%, specificity <12%) while multicomponent algorithms with well-defined temporal sequences of procedure, diagnosis and treatment codes achieved a better balance of sensitivity and specificity. Specificity increased and sensitivity decreased with increasing algorithm complexity. The best-performing algorithms, in terms of fewest misclassified patients, included multiple components (e.g., PH diagnosis, PAH treatment, continuous enrollment for ≥6 months before and ≥12 months following index date) and achieved sensitivities and specificities of around 95% and 38%, respectively. Our findings help researchers tailor their choice and design of code-based PAH algorithms to their research question and demonstrate the importance of including well-defined temporal components in the algorithms., Competing Interests: EMD and MB are employees of Janssen Pharmaceutical Companies of Johnson & Johnson and own shares of stock/stock options in Johnson & Johnson. RTZ is a consultant to Morphogen‐IX, Vivus, GossamerBio, and Merck; his institution has received research grant support from United Therapeutics, Janssen Pharmaceutical, Merck, Tenax, and Celtaxsys. HH, DL, and AH have no conflict of interest to declare., (© 2024 The Authors. Pulmonary Circulation published by Wiley Periodicals LLC on behalf of the Pulmonary Vascular Research Institute.)

Objective: To evaluate whether prophylactic administration of 1 g of intravenous calcium chloride after cord clamping reduces blood loss from uterine atony during intrapartum cesarean delivery., Methods: This single-center, block-randomized, placebo-controlled, double-blind superiority trial compared the effects of 1 g intravenous calcium chloride with those of saline placebo control on blood loss at cesarean delivery. Parturients at 34 or more weeks of gestation requiring intrapartum cesarean delivery after oxytocin exposure in labor were enrolled. Calcium or saline placebo was infused over 10 minutes beginning 1 minute after umbilical cord clamping in addition to standard care with oxytocin. The primary outcome was quantitative blood loss, analyzed by inverse Gaussian regression. Planned subgroup analysis excluded nonatonic bleeding, such as hysterotomy extension, arterial bleeding, and occult placenta accreta. We planned to enroll 120 patients to show a 200-mL reduction in quantitative blood loss in planned subgroup analysis, assuming up to 40% incidence of nonatonic bleeding (80% power, α<0.05)., Results: From April 2022 through March 2023, 828 laboring parturients provided consent and 120 participants were enrolled. Median blood loss was 840 mL in patients allocated to calcium chloride (n=60) and 1,051 mL in patients allocated to placebo (n=60), which was not statistically different (mean reduction 211 mL, 95% CI -33 to 410). In the planned subgroup analysis (n=39 calcium and n=40 placebo), excluding cases of surgeon-documented nonatonic bleeding, calcium reduced quantitative blood loss by 356 mL (95% CI 159-515). Rates of reported side effects were similar between the two groups (38% calcium vs 42% placebo)., Conclusion: Prophylactic intravenous calcium chloride administered during intrapartum cesarean delivery after umbilical cord clamping did not significantly reduce blood loss in the primary analysis. However, in the planned subgroup analysis, calcium infusion significantly reduced blood loss by approximately 350 mL. These data suggest that this inexpensive and shelf-stable medication warrants future study as a novel treatment strategy to decrease postpartum hemorrhage, the leading global cause of maternal morbidity and mortality., Clinical Trial Registration: ClinicalTrials.gov , NCT05027048., Competing Interests: Financial Disclosure Deirdre Lyell reports financial relationships with National Institutes of Health (NIH), the Society for Maternal-Fetal Medicine (SMFM), and UC San Francisco. Lyell is a stock owner in ZenFlow, unrelated to this work, and a consultant for stock options for Bloomlife, also unrelated to this work. The other authors did not report any potential conflicts of interest., (Copyright © 2023 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Clinical trials provide the "gold standard" evidence for advancing the practice of medicine, even as they evolve to integrate real-world data sources. Modern clinical trials are increasingly incorporating real-world data sources - data not intended for research and often collected in free-living contexts. We refer to trials that incorporate real-world data sources as real-world trials. Such trials may have the potential to enhance the generalizability of findings, facilitate pragmatic study designs, and evaluate real-world effectiveness. However, key differences in the design, conduct, and implementation of real-world vs traditional trials have ramifications in data management that can threaten their desired rigor., Methods: Three examples of real-world trials that leverage different types of data sources - wearables, medical devices, and electronic health records are described. Key insights applicable to all three trials in their relationship to Data and Safety Monitoring Boards (DSMBs) are derived., Results: Insight and recommendations are given on four topic areas: A. Charge of the DSMB; B. Composition of the DSMB; C. Pre-launch Activities; and D. Post-launch Activities. We recommend stronger and additional focus on data integrity., Conclusions: Clinical trials can benefit from incorporating real-world data sources, potentially increasing the generalizability of findings and overall trial scale and efficiency. The data, however, present a level of informatic complexity that relies heavily on a robust data science infrastructure. The nature of monitoring the data and safety must evolve to adapt to new trial scenarios to protect the rigor of clinical trials., Competing Interests: BJB, HH, JDC, JOF, AG, RJ, JL, KOO, MP, KR, HS, MT, & MD have no disclosures. JHC has received research grant support from NIH/National Institute on Drug Abuse Clinical Trials Network (UG1DA015815 - CTN-0136), Stanford Artificial Intelligence in Medicine and Imaging - Human-Centered Artificial Intelligence (AIMI-HAI) Partnership Grant, Doris Duke Charitable Foundation - Covid-19 Fund to Retain Clinical Scientists (20211260), Google, Inc. Research collaboration Co-I to leverage EHR data to predict a range of clinical outcomes, and American Heart Association - Strategically Focused Research Network - Diversity in Clinical Trials. JHC discloses: Co-founder of Reaction Explorer LLC that develops and licenses organic chemistry education software & Paid consulting fees from Sutton Pierce and Younker Hyde MacFarlane PLLC as a medical expert witness. EF is supported in part by AFOSR Grant FA9550-21-1-0397, ONR Grant N00014-22-1-2110, and the Stanford Institute for Human-Centered Artificial Intelligence (HAI). EBF is a Chan Zuckerberg Biohub – San Francisco Investigator. AGo has received research funding from the National Heart, Lung, and Blood Institute; National Institute of Diabetes, Digestive, and Kidney Diseases; and the National Institute on Aging. He has also received research grants through his institution from Novartis, Bristol Myers Squibb, Pfizer, Janssen Research & Development, CSL Behring, iRhythm Technologies, and Amarin Pharmaceuticals. RJ was partially supported by the National Science Foundation under grant 2205084, and by the Stanford Maternal and Child Health Research Institute under the Transdisciplinary Initiatives Program. DMM has had research support from the NIH, JDRF, NSF, and the Helmsley Charitable Trust and his institution has had research support from Medtronic, Dexcom, Insulet, Bigfoot Biomedical, Tandem, and Roche. Dr Maahs has consulted for Abbott, Aditxt, the Helmsley Charitable Trust, Lifescan, Mannkind, Sanofi, Novo Nordisk, Eli Lilly, Medtronic, Insulet, Dompe, Biospex, Provention Bio, and Bayer. DS discloses advising Carta Healthcare. MPT has received grants or personal fees from American Heart Association, Apple, Bayer, Bristol Myers Squibb, FDA, Gilead Sciences, Johnson & Johnson, Medtronic Inc., Myokardia, Pfizer, and Sanofi, is a shareholder of AliveCor, Connect America, Evidently, Forward, iRhythm, and PocketRN, and is an employee of iRhythm Technologies, Inc. KWM’s financial disclosures can be viewed at http://med.stanford.edu/profiles/kenneth-mahaffey., (© The Author(s) 2023.)

Background: The vast majority of coronavirus disease 2019 (COVID-19) disease occurs in outpatients where treatment is limited to antivirals for high-risk subgroups. Acebilustat, a leukotriene B4 inhibitor, has potential to reduce inflammation and symptom duration., Methods: In a single-center trial spanning Delta and Omicron variants, outpatients were randomized to 100 mg/d of oral acebilustat or placebo for 28 days. Patients reported daily symptoms via electronic query through day 28 with phone follow-up on day 120 and collected nasal swab samples on days 1-10. The primary outcome was sustained symptom resolution to day 28. Secondary 28-day outcomes included time to first symptom resolution, area under the curve (AUC) for longitudinal daily symptom scores, duration of viral shedding through day 10, and symptoms on day 120., Results: Sixty participants were randomized to each study arm. At enrollment, the median duration was 4 days (interquartile range, 3-5 days), and the median number of symptoms was 9 (7-11). Most patients (90%) were vaccinated, with 73% having neutralizing antibodies. A minority of participants (44%; 35% in the acebilustat arm and 53% in placebo) had sustained symptom resolution at day 28 (hazard ratio, 0.6 [95% confidence interval, .34-1.04]; P = .07 favoring placebo). There was no difference in the mean AUC for symptom scores over 28 days (difference in mean AUC, 9.4 [95% confidence interval, -42.1 to 60.9]; P = .72). Acebilustat did not affect viral shedding or symptoms at day 120., Conclusions: Sustained symptoms through day 28 were common in this low-risk population. Despite this, leukotriene B4 antagonism with acebilustat did not shorten symptom duration in outpatients with COVID-19. Clinical Trials Registration. NCT04662060., Competing Interests: Potential conflicts of interest . J. E. L., M. D., and A. J. R. report receipt of study drugs without cost, supplied by Celltaxis. E. H. and E. S are consultants for Celltaxis. R. B. M. reports consulting fees from 4D Molecular Therapeutics, Aridid Pharmaceuticals, Mayne Pharma, Zambon, and Pumatrix; participation on an advisory board for Nob Hill Therapeutics; and stock or stock options in Regneron, Pfizer, Amgen, Gilead, Johnson & Johnson, and Vertex. J. P. reports grants or contracts from Ono Pharmaceuticals for a clinical trial of camostat treatment of coronavirus disease 2019. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Pulmonary arterial hypertension (PAH) is characterised by loss of microvessels. The Wnt pathways control pulmonary angiogenesis but their role in PAH is incompletely understood. We hypothesised that Wnt activation in pulmonary microvascular endothelial cells (PMVECs) is required for pulmonary angiogenesis, and its loss contributes to PAH., Methods: Lung tissue and PMVECs from healthy and PAH patients were screened for Wnt production. Global and endothelial-specific Wnt7a -/- mice were generated and exposed to chronic hypoxia and Sugen-hypoxia (SuHx)., Results: Healthy PMVECs demonstrated >6-fold Wnt7a expression during angiogenesis that was absent in PAH PMVECs and lungs. Wnt7a expression correlated with the formation of tip cells, a migratory endothelial phenotype critical for angiogenesis. PAH PMVECs demonstrated reduced vascular endothelial growth factor (VEGF)-induced tip cell formation as evidenced by reduced filopodia formation and motility, which was partially rescued by recombinant Wnt7a. We discovered that Wnt7a promotes VEGF signalling by facilitating Y1175 tyrosine phosphorylation in vascular endothelial growth factor receptor 2 (VEGFR2) through receptor tyrosine kinase-like orphan receptor 2 (ROR2), a Wnt-specific receptor. We found that ROR2 knockdown mimics Wnt7a insufficiency and prevents recovery of tip cell formation with Wnt7a stimulation. While there was no difference between wild-type and endothelial-specific Wnt7a -/- mice under either chronic hypoxia or SuHx, global Wnt7a +/- mice in hypoxia demonstrated higher pulmonary pressures and severe right ventricular and lung vascular remodelling. Similar to PAH, Wnt7a +/- PMVECs exhibited an insufficient angiogenic response to VEGF-A that improved with Wnt7a., Conclusions: Wnt7a promotes VEGF signalling in lung PMVECs and its loss is associated with an insufficient VEGF-A angiogenic response. We propose that Wnt7a deficiency contributes to progressive small vessel loss in PAH., Competing Interests: Conflict of interest: V.A. de Jesus Perez reports support for the present manuscript from the National Institutes of Health National Heart, Lung, and Blood Institute; and outside the submitted work, holds a leadership position as AHA Chair of Diversity subcommittee. All other authors have nothing to disclose., (Copyright ©The authors 2023.)

Calls-to-action in health research have described a need to improve research on race, ethnicity, and structural racism. Well-established cohort studies typically lack access to novel structural and social determinants of health (SSDOH) or precise race and ethnicity categorization, contributing to a loss of rigor to conduct informative analyses and a gap in prospective evidence on the role of structural racism in health outcomes. We propose and implement methods that prospective cohort studies can use to begin to rectify this, using the Women's Health Initiative (WHI) cohort as a case study. To do so, we evaluated the quality, precision, and representativeness of race, ethnicity, and SSDOH data compared with the target US population and operationalized methods to quantify structural determinants in cohort studies. Harmonizing racial and ethnic categorization to the current standards set by the Office of Management and Budget improved measurement precision, aligned with published recommendations, disaggregated groups, decreased missing data, and decreased participants reporting "some other race". Disaggregation revealed sub-group disparities in SSDOH, including a greater proportion of Black-Latina (35.2%) and AIAN-Latina (33.3%) WHI participants with income below the US median compared with White-Latina (42.5%) participants. We found similarities in the racial and ethnic patterning of SSDOH disparities between WHI and US women but less disparity overall in WHI. Despite higher individual-level advantage in WHI, racial disparities in neighborhood resources were similar to the US, reflecting structural racism. Median neighborhood income was comparable between Black WHI ($39,000) and US ($34,700) women. WHI SSDOH-associated outcomes may be generalizable on the basis of comparing across race and ethnicity but may quantitatively (but not qualitatively) underestimate US effect sizes. This paper takes steps towards data justice by implementing methods to make visible hidden health disparity groups and operationalizing structural-level determinants in prospective cohort studies, a first step to establishing causality in health disparities research., Competing Interests: Electra Paskett is multiple PI on grants to the institution from Merck Foundation, Pfizer, and Genentech not related to this work. There is no other financial nor personal interest or belief that could affect their objectivity., (© 2023 The Authors. Published by Elsevier Ltd.)

An app-based clinical trial enrolment process can contribute to duplicated records, carrying data management implications. Our objective was to identify duplicated records in real time in the Apple Heart Study (AHS). We leveraged personal identifiable information (PII) to develop a dissimilarity score (DS) using the Damerau-Levenshtein distance. For computational efficiency, we focused on four types of records at the highest risk of duplication. We used the receiver operating curve (ROC) and resampling methods to derive and validate a decision rule to classify duplicated records. We identified 16,398 (4%) duplicated participants, resulting in 419,297 unique participants out of a total of 438,435 possible. Our decision rule yielded a high positive predictive value (96%) with negligible impact on the trial's original findings. Our findings provide principled solutions for future digital trials. When establishing deduplication procedures for digital trials, we recommend collecting device identifiers in addition to participant identifiers; collecting and ensuring secure access to PII; conducting a pilot study to identify reasons for duplicated records; establishing an initial deduplication algorithm that can be refined; creating a data quality plan that informs refinement; and embedding the initial deduplication algorithm in the enrolment platform to ensure unique enrolment and linkage to previous records., (© 2022 The Authors. Stat published by John Wiley & Sons Ltd.)

Importance: The efficacy of physical activity interventions among individuals with type 2 diabetes has been established; however, practical approaches to translate and extend these findings into community settings have not been well explored., Objective: To test the effectiveness of providing varying frequencies of weekly structured exercise sessions to improve diabetes control., Design, Setting, and Participants: The IMPACT (Initiate and Maintain Physical Activity in Communities Trial) study was a controlled randomized clinical trial (randomization occurred from October 2016 to April 2019) that included a 6-month, structured exercise intervention either once or thrice weekly vs usual care (UC; advice only). The exercise intervention was conducted at community-based fitness centers. Follow-up visits were conducted in a university research clinic. Participants included adults with type 2 diabetes (hemoglobin A1c [HbA1c] 6.5%-13.0%, not taking insulin, and no precluding health issues). Data analysis was performed from January to April 2022., Interventions: A once-weekly structured exercise group, a thrice-weekly structured exercise group, or UC., Main Outcomes and Measures: The primary outcome was HbA1c at 6 months., Results: A total of 357 participants (143 women [40.1%]) with a mean (SD) age of 57.4 (11.1) years were randomized (119 each to the UC, once-weekly exercise, and thrice-weekly exercise groups). There was no significant difference in HbA1c change by study group in the intention-to-treat analysis at 6 months. Specifically, HbA1c changed by -0.23% (95% CI, -0.48% to 0.01%) in the thrice-weekly exercise group and by -0.16% (95% CI, -0.41% to 0.09%) in the once-weekly exercise group. A total of 62 participants (52.1%) in the once-weekly exercise group and 56 participants (47.1%) in the thrice-weekly exercise group were at least 50% adherent to the assigned structured exercise regimen and were included in the per-protocol analysis. Per-protocol analysis showed that HbA1c changed by -0.35% (95% CI, -0.60% to -0.10%; P = .005) at 3 months and by -0.38% (95% CI, -0.65% to -0.12%; P = .005) at 6 months in the thrice-weekly exercise group compared with UC. There was no significant decrease in HbA1c in the once-weekly exercise group. The exercise intervention was effective in improving self-reported minutes of metabolic equivalent tasks per week for participants in the thrice-weekly exercise group (both overall and per protocol)., Conclusions and Relevance: Although the intervention was not effective in the intention-to-treat analysis, participants in the thrice-weekly exercise group who attended at least 50% of the sessions during the 6-month exercise intervention program improved HbA1c levels at 6 months. Future efforts should focus on improving adherence to thrice-weekly structured exercise programs to meet exercise guidelines., Trial Registration: ClinicalTrials.gov Identifier: NCT02061579.

Background: Favipiravir, an oral, RNA-dependent RNA polymerase inhibitor, has in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite limited data, favipiravir is administered to patients with coronavirus disease 2019 (COVID-19) in several countries., Methods: We conducted a phase 2, double-blind, randomized controlled outpatient trial of favipiravir in asymptomatic or mildly symptomatic adults with a positive SARS-CoV-2 reverse-transcription polymerase chain reaction assay (RT-PCR) within 72 hours of enrollment. Participants were randomized to receive placebo or favipiravir (1800 mg twice daily [BID] day 1, 800 mg BID days 2-10). The primary outcome was SARS-CoV-2 shedding cessation in a modified intention-to-treat (mITT) cohort of participants with positive enrollment RT-PCRs. Using SARS-CoV-2 amplicon-based sequencing, we assessed favipiravir's impact on mutagenesis., Results: We randomized 149 participants with 116 included in the mITT cohort. The participants' mean age was 43 years (standard deviation, 12.5 years) and 57 (49%) were women. We found no difference in time to shedding cessation overall (hazard ratio [HR], 0.76 favoring placebo [95% confidence interval {CI}, .48-1.20]) or in subgroups (age, sex, high-risk comorbidities, seropositivity, or symptom duration at enrollment). We detected no difference in time to symptom resolution (initial: HR, 0.84 [95% CI, .54-1.29]; sustained: HR, 0.87 [95% CI, .52-1.45]) and no difference in transition mutation accumulation in the viral genome during treatment., Conclusions: Our data do not support favipiravir at commonly used doses in outpatients with uncomplicated COVID-19. Further research is needed to ascertain if higher favipiravir doses are effective and safe for patients with COVID-19., Clinical Trials Registration: NCT04346628., Competing Interests: Potential conflicts of interest. M. H. reports payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from UpToDate. A. S. reports grants from Gilead Sciences, Regeneron Pharma, and Janssen Pharma. H. H. reports salary support from anonymous donors to Stanford University and grant support from the NIH (UL1 TR003142). C. E. reports financial support for the present manuscript from Fujifilm Pharmaceuticals USA (payments made to author’s consulting LLC). P. J. reports research support from anonymous donors to Stanford University to support clinical work. R. H. K. is currently the Chief Medical Officer for AiPharma Global Holdings LLC; is an unpaid consultant to Fujifilm Toyama Chemical Co Ltd and the Anti Viral Drug Development Alliance; and reports support for attending conferences and stock options from AiPharma Global Holdings LLC. J. P. reports grants from Heluna Health (seroepidemiological studies of SARS-CoV-2), Gauss Surgical (testing of an antigen test for SARS-CoV-2) and Ono Pharmaceuticals (clinical trial of Camostat for SARS-CoV-2). J. R. A. reports research support from anonymous donors to Stanford University. C. K. reports licenses from Clear Creek Bio and a patent assigned to Stanford University (“Use of a dihydroorotate dehydrogenase (DHODH) inhibitor in combination with an inhibitor of pyrimidine salvage,” US patent number 10,736,911; 2020). Y. M. reports grants from the NIH (U54 MD010724, U54 MD010724-05S1, R21AI148810, P30AG059307, 000522211-022), Pfizer (C3671008, C4591007), the Bill & Melinda Gates Foundation (OPP1113682), and the Chan Zuckerberg Foundation (12089sc); has received payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from the American Academy of Pediatrics for the National Conference; and is on a Pfizer DSMB (non–COVID-19 vaccine trial). All other authors report no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

Positive associations between well-being and a single contemplative practice (e.g., mindfulness meditation) are well documented, yet prior work may have underestimated the strength of the association by omitting consideration of multiple and/or alternative contemplative practices. Moreover, little is known about how contemplative practice behavior (CPB) impacts different dimensions of well-being. This study investigates the relationship of CPB, consisting of four discrete practices (embodied somatic-observing, non-reactive mindfulness, self-compassion, and compassion for others), with multiple dimensions of well-being. As with other canonical lifestyle behaviors, multiple contemplative practices can be integrated into one's daily routine. Thus, it is critical to holistically consider these behaviors, extending them beyond a simple uni-dimensional measure (e.g., daily mindfulness meditation practice). We developed an integrative measure of four types of contemplative practice and found it to be significantly associated with a multi-dimensional measure of well-being. Importantly, our findings were from three large global multi-regional cohorts and compared against better-understood lifestyle behaviors (physical activity). Data were drawn from California/San Francisco Bay Area, ( n = 6442), Hangzhou City ( n = 10,268), and New Taipei City ( n = 3033). In all three cohorts, we found statistically significant ( p < 0.05) positive associations between CPB and well-being, both overall and with all of the constituent domains of well-being, comparable to or stronger than the relationship with physical activity across most well-being outcomes. These findings provide robust and cross-cultural evidence for a positive association between CPB and well-being, illuminate dimensions of well-being that could be most influenced by CPB, and suggest CPB may be useful to include as part of fundamental lifestyle recommendations for health and well-being., Competing Interests: The authors have no conflicts of interest to declare.

Background: The great majority of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infections are mild and uncomplicated, but some individuals with initially mild COVID-19 progressively develop more severe symptoms. Furthermore, there is substantial heterogeneity in SARS-CoV-2-specific memory immune responses following infection. There remains a critical need to identify host immune biomarkers predictive of clinical and immunological outcomes in SARS-CoV-2-infected patients., Methods: Leveraging longitudinal samples and data from a clinical trial (N=108) in SARS-CoV-2-infected outpatients, we used host proteomics and transcriptomics to characterize the trajectory of the immune response in COVID-19 patients. We characterized the association between early immune markers and subsequent disease progression, control of viral shedding, and SARS-CoV-2-specific T cell and antibody responses measured up to 7 months after enrollment. We further compared associations between early immune markers and subsequent T cell and antibody responses following natural infection with those following mRNA vaccination. We developed machine-learning models to predict patient outcomes and validated the predictive model using data from 54 individuals enrolled in an independent clinical trial., Results: We identify early immune signatures, including plasma RIG-I levels, early IFN signaling, and related cytokines (CXCL10, MCP1, MCP-2, and MCP-3) associated with subsequent disease progression, control of viral shedding, and the SARS-CoV-2-specific T cell and antibody response measured up to 7 months after enrollment. We found that several biomarkers for immunological outcomes are shared between individuals receiving BNT162b2 (Pfizer-BioNTech) vaccine and COVID-19 patients. Finally, we demonstrate that machine-learning models using 2-7 plasma protein markers measured early within the course of infection are able to accurately predict disease progression, T cell memory, and the antibody response post-infection in a second, independent dataset., Conclusions: Early immune signatures following infection can accurately predict clinical and immunological outcomes in outpatients with COVID-19 using validated machine-learning models., Funding: Support for the study was provided from National Institute of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID) (U01 AI150741-01S1 and T32-AI052073), the Stanford's Innovative Medicines Accelerator, National Institutes of Health/National Institute on Drug Abuse (NIH/NIDA) DP1DA046089, and anonymous donors to Stanford University. Peginterferon lambda provided by Eiger BioPharmaceuticals., Competing Interests: ZH, Kv, SC, PA, DM, KJ, HB, JP, JA, MH, AS, CK, YM, HH, Ld, KP, MT, GT, CB, ST, BG, AB, US, BP, TW, PJ No competing interests declared, IR Reviewing editor, eLife, (© 2022, Hu et al.)

Rationale: There is a noticeable underrepresentation of minorities in clinical trials and registries in pulmonary arterial hypertension (PAH). Prior studies evaluating the association between Hispanic ethnicity and clinical outcomes in patients with PAH have not assessed the socioeconomic profile of Hispanic individuals or the significance of social determinants of health in clinical outcomes. Objectives: To determine the association between Hispanic ethnicity, social determinants of health, and clinical outcomes in PAH. Methods: This was a prospective cohort study of adult participants with PAH enrolled in the Pulmonary Hypertension Association Registry, a multicenter U.S.-based registry of patients treated at pulmonary hypertension care centers. Participants were classified as Hispanics and non-Hispanic White individuals, based on self-reported ethnicity. A comparison of baseline clinical and sociodemographic characteristics between groups was performed as well using absolute standardized differences (ASD). The primary outcome of the study was to assess transplant-free survival between Hispanics and non-Hispanic White individuals. A Cox proportional hazards model was used for the multivariable analysis after adjusting for age, sex, PAH etiology, annual income, education level, and health insurance. Results: A total of 683 individuals were included, 98 (14.3%) of Hispanic ethnicity. Hispanic patients had impaired access to health care (31.6% vs. 12.9% Medicaid/uninsured; ASD, 0.35), lower education level (72.6% vs. 94.0% high school graduates or higher; ASD, 0.60), and lower annual income (32.0% vs. 17.4% with income <20,000 U.S. dollars; ASD, 0.47), compared with non-Hispanic White individuals. Hispanic patients had a higher frequency of emergency room visits and a higher number of hospitalizations, despite having similar disease severity (incidence rate ratio, 1.452; 95% confidence interval [CI], 1.326-1.590; and 1.428; 95% CI, 1.292-1.577, respectively). Although the unadjusted analysis showed a lower transplant/death hazard ratio for Hispanics (hazard ratio, 0.47; 95% CI, 0.24-0.94; P  = 0.032), there was no association between Hispanic ethnicity and outcome in the multivariable model after adjusting for social determinants of health and other covariates (HR, 0.76; 95% CI, 0.35-1.62; P  = 0.474). Conclusions: Hispanic ethnicity was not associated with differences in survival after adjusting for social determinants of health and other factors. Social determinants of health are important to consider when assessing the association between ethnicity and outcomes in PAH.

Background: COVID-19 manifests with respiratory, systemic, and gastrointestinal (GI) symptoms. 1 , SARS-CoV-2 RNA is detected in respiratory and fecal samples, and recent reports demonstrate viral replication in both the lung and intestinal tissue.2, 3, 4 Although much is known about early fecal RNA shedding, little is known about long-term shedding, especially in those with mild COVID-19. Furthermore, most reports of fecal RNA shedding do not correlate these findings with GI symptoms. 5 ., Methods: We analyzed the dynamics of fecal RNA shedding up to 10 months after COVID-19 diagnosis in 113 individuals with mild to moderate disease. We also correlated shedding with disease symptoms., Findings: Fecal SARS-CoV-2 RNA is detected in 49.2% [95% confidence interval, 38.2%-60.3%] of participants within the first week after diagnosis. Whereas there was no ongoing oropharyngeal SARS-CoV-2 RNA shedding in subjects at 4 months, 12.7% [8.5%-18.4%] of participants continued to shed SARS-CoV-2 RNA in the feces at 4 months after diagnosis and 3.8% [2.0%-7.3%] shed at 7 months. Finally, we found that GI symptoms (abdominal pain, nausea, vomiting) are associated with fecal shedding of SARS-CoV-2 RNA., Conclusions: The extended presence of viral RNA in feces, but not in respiratory samples, along with the association of fecal viral RNA shedding with GI symptoms suggest that SARS-CoV-2 infects the GI tract and that this infection can be prolonged in a subset of individuals with COVID-19., Funding: This research was supported by a Stanford ChemH-IMA grant; fellowships from the AACR and NSF; and NIH R01-AI148623, R01-AI143757, and UL1TR003142., Competing Interests: The authors declare no competing interests., (© 2022 Elsevier Inc.)

Introduction : Resilience-which we define as the "ability to bounce back from stress"-can foster successful aging among older, racially and ethnically diverse women. This study investigated the association between psychological resilience in the Women's Health Initiative Extension Study (WHI-ES) and three constructs defined by Staudinger's 2015 model of resilience and aging: (1) perceived stress, (2) non-psychological resources, and (3) psychological resources. We further examined whether the relationship between resilience and key resources differed by race/ethnicity. Methods : We conducted a secondary analysis on 77,395 women aged 62+ (4475 Black or African American; 69,448 non-Hispanic White; 1891 Hispanic/Latina; and 1581 Asian or Pacific Islanders) who enrolled in the WHI-ES, which was conducted in the United States. Participants completed a short version of the Brief Resilience Scale one-time in 2011. Guided by Staudinger's model, we used linear regression analysis to examine the relationships between resilience and resources, adjusting for age, race/ethnicity, and stressful life events. To identify the most significant associations, we applied elastic net regularization to our linear regression models. Findings : On average, women who reported higher resilience were younger, had fewer stressful life events, and reported access to more resources. Black or African American women reported the highest resilience, followed by Hispanic/Latina, non-Hispanic White, and Asian or Pacific Islander women. The most important resilience-related resources were psychological, including control of beliefs, energy, personal growth, mild-to-no forgetfulness, and experiencing a sense of purpose. Race/ethnicity significantly modified the relationship between resilience and energy (overall interaction p = 0.0017). Conclusion : Increasing resilience among older women may require culturally informed stress reduction techniques and resource-building strategies, including empowerment to control the important things in life and exercises to boost energy levels.

Background: Long-term survival after lung transplantation (LTx) is limited by chronic lung allograft dysfunction (CLAD)., Methods: We report an analysis of cytokine profiles in bronchoalveolar lavage samples collected during a prospective multicenter non-interventional trial primarily designed to determine the impact of community-acquired respiratory viral infections (CARV) in outcomes after pediatric LTx. In this analysis, we identify potential biomarkers of auto-inflammation and auto-immunity associated with survival and risk of bronchiolitis obliterans (BOS) after LTx with cytokine analysis of bronchoalveolar lavage fluid (BALF) from 61 pediatric recipients., Results: Higher IL-23 (p = .048) and IL-31 (p = .035) levels were associated with the risk of BOS, and lower levels of epithelial growth factor (EGF) (p = .041) and eotaxin (EOX) (p = .017) were associated with BOS. Analysis using conditional inference trees to evaluate cytokines at each visit associated with survival identified soluble CD30 (p < .001), pro-inflammatory cytokine IL-23 (p = .02), and sTNFRI (p = .01) below cutoff levels as associated with BOS-free survival., Conclusions: Our results indicate that post-LTx survival in children may be linked to activation of alternate pathways of the immune system that affect airway remodeling in addition to activation of "classical" pathways that have been described in adult LTx recipients. These may indicate pathways to target for intervention., (© 2022 Wiley Periodicals LLC.)

The digital clinical trial is fast emerging as a pragmatic trial that can improve a trial's design including recruitment and retention, data collection and analytics. To that end, digital platforms such as electronic health records or wearable technologies that enable passive data collection can be leveraged, alleviating burden from the participant and study coordinator. However, there are challenges. For example, many of these data sources not originally intended for research may be noisier than traditionally obtained measures. Further, the secure flow of passively collected data and their integration for analysis is non-trivial. The Apple Heart Study was a prospective, single-arm, site-less digital trial designed to evaluate the ability of an app to detect atrial fibrillation. The study was designed with pragmatic features, such as an app for enrollment, a wearable device (the Apple Watch) for data collection, and electronic surveys for participant-reported outcomes that enabled a high volume of patient enrollment and accompanying data. These elements led to challenges including identifying the number of unique participants, maintaining participant-level linkage of multiple complex data streams, and participant adherence and engagement. Novel solutions were derived that inform future designs with an emphasis on data management. We build upon the excellent framework of the Clinical Trials Transformation Initiative to provide a comprehensive set of guidelines for data management of the digital clinical trial that include an increased role of collaborative data scientists in the design and conduct of the modern digital trial.

Although the vast majority of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infections are uncomplicated, our understanding of predictors of symptom resolution and viral shedding cessation remains limited. We characterized symptom trajectories and oropharyngeal viral shedding among 120 outpatients with uncomplicated Coronavirus Disease of 2019 (COVID-19) enrolled in a clinical trial of Peginterferon Lambda, which demonstrated no clinical or virologic benefit compared with placebo. In the combined trial cohort, objective fever was uncommon, inflammatory symptoms (myalgias, fatigue) peaked at 4 to 5 days postsymptom onset, and cough peaked at 9 days. The median time to symptom resolution from earliest symptom onset was 17 days (95% confidence interval 14-18). SARS-CoV-2 IgG seropositivity at enrollment was associated with hastened resolution of viral shedding (hazard ratio 1.80, 95% confidence interval 1.05-3.1, P = 0.03), but not with symptom resolution. Inflammatory symptoms were associated with a significantly greater odds of oropharyngeal SARS-CoV-2 RNA detection; respiratory symptoms were not. These findings have important implications for COVID-19 screening approaches and trial design., Competing Interests: Declaration of competing interest The authors have no conflicts of interests to declare., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: We describe the design of a longitudinal cohort study to determine SARS-CoV-2 incidence and prevalence among a population-based sample of adults living in six San Francisco Bay Area counties., Methods: Using an address-based sample, we stratified households by county and by census-tract risk. Risk strata were determined by using regression models to predict infections by geographic area using census-level sociodemographic and health characteristics. We disproportionately sampled high and medium risk strata, which had smaller population sizes, to improve precision of estimates, and calculated a desired sample size of 3400. Participants were primarily recruited by mail and were followed monthly with PCR testing of nasopharyngeal swabs, testing of venous blood samples for antibodies to SARS-CoV-2 spike and nucleocapsid antigens, and testing of the presence of neutralizing antibodies, with completion of questionnaires about socio-demographics and behavior. Estimates of incidence and prevalence will be weighted by county, risk strata and sociodemographic characteristics of non-responders, and will take into account laboratory test performance., Results: We enrolled 3842 adults from August to December 2020, and completed follow-up March 31, 2021. We reached target sample sizes within most strata., Conclusions: Our stratified random sampling design will allow us to recruit a robust general population cohort of adults to determine the incidence of SARS-CoV-2 infection. Identifying risk strata was unique to the design and will help ensure precise estimates, and high-performance testing for presence of virus and antibodies will enable accurate ascertainment of infections., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The great majority of SARS-CoV-2 infections are mild and uncomplicated, but some individuals with initially mild COVID-19 progressively develop more severe symptoms. Furthermore, there is substantial heterogeneity in SARS-CoV-2-specific memory immune responses following infection. There remains a critical need to identify host immune biomarkers predictive of clinical and immunologic outcomes in SARS-CoV-2-infected patients. Leveraging longitudinal samples and data from a clinical trial in SARS-CoV-2 infected outpatients, we used host proteomics and transcriptomics to characterize the trajectory of the immune response in COVID-19 patients within the first 2 weeks of symptom onset. We identify early immune signatures, including plasma RIG-I levels, early interferon signaling, and related cytokines (CXCL10, MCP1, MCP-2 and MCP-3) associated with subsequent disease progression, control of viral shedding, and the SARS-CoV-2 specific T cell and antibody response measured up to 7 months after enrollment. We found that several biomarkers for immunological outcomes are shared between individuals receiving BNT162b2 (Pfizer-BioNTech) vaccine and COVID-19 patients. Finally, we demonstrate that machine learning models using 7-10 plasma protein markers measured early within the course of infection are able to accurately predict disease progression, T cell memory, and the antibody response post-infection in a second, independent dataset.

Background: Urinary incontinence affects >40% of women in the United States, with an annual societal cost of >$12 billion and demonstrated associations with depressive symptoms, social isolation, and loss of work productivity. Weight has been established as an exposure that increases urinary incontinence risk and certain dietary components have been associated with urinary incontinence symptoms. We hypothesized that diet plays a key role in the association between weight and urinary incontinence in US women., Objective: This study aimed to examine the effect of a low-fat diet on urinary incontinence in postmenopausal women as a post hoc analysis of a randomized controlled trial of diet modification., Study Design: This was a post hoc analysis of the Women's Health Initiative Dietary Modification randomized controlled trial of 48,835 postmenopausal women from 40 US centers assigned to a dietary intervention (20% energy from fat, 5 fruits or vegetable servings, and 6 whole grain servings daily and an intensive behavioral modification program) or to the usual diet comparison group. The outcome was urinary incontinence at 1 year., Results: Of the participants, 60% were randomized to the usual diet comparison group and 40% to the dietary modification intervention. After adjusting for weight change, women assigned to the dietary modification intervention were less likely to report urinary incontinence (odds ratio, 0.94; 95% confidence interval, 0.90-0.98; P =.003), more likely to report urinary incontinence resolution (odds ratio, 1.11; 95% confidence interval, 1.03-1.19; P =.01), and less likely to develop urinary incontinence (odds ratio, 0.92; 95% confidence interval, 0.87-0.98; P =.01) in adjusted models., Conclusion: Dietary modification may be a reasonable treatment for postmenopausal women with incontinence and also a urinary incontinence prevention strategy for continent women. Our results provide evidence to support a randomized clinical trial to determine whether a reduced fat-intake dietary modification is an effective intervention for the prevention and treatment of urinary incontinence. In addition to providing further insights into mechanisms of lower urinary tract symptoms, these findings may have a substantial impact on public health based on the evidence that diet seems to be a modifiable risk factor for urinary incontinence., (© 2021 The Authors.)

Background: Pulmonary hypertension is a complication of chronic lung diseases (PH-CLD) associated with significant morbidity and mortality. Management guidelines for PH-CLD emphasize the treatment of the underlying lung disease, but the role of PH-targeted therapy remains controversial. We hypothesized that treatment approaches for PH-CLD would be variable across physicians depending on the type of CLD and the severity of PH. Methods and Results: Between May and July 2020, we conducted an online survey of PH experts asking for their preferred treatment approach in seven hypothetical cases of PH-CLD of varying severity. We assessed agreement amongst clinicians for initial therapy choice using Fleiss' kappa calculations. Over 90% of respondents agreed that they would treat cases of severe PH in the context of mild lung disease with some form of PH-targeted therapy. For cases of severe PH in the context of severe lung disease, over 70% of respondents agreed to use PH-targeted therapy. For mild PH and mild lung disease cases, <50% of respondents chose to start PH-specific therapy. There was overall poor agreement between respondents in the choice to use mono-, double or triple combination therapy with PH-specific agents in all cases. Conclusion: Although management guidelines discourage the routine use of PH-targeted therapies to treat PH-CLD patients, most physicians choose to treat patients with some form of PH-targeted therapy. The choice of therapy and treatment approach are variable and appear to be influenced by the severity of the PH and the underlying lung disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Thomas, Lee, Bernardo, Anderson, Glinskii, Sung, Kudelko, Hedlin, Sweatt, Kawut, Raj, Zamanian and de Jesus Perez.)

Objective: To investigate whether dual-energy x-ray absorptiometry (DXA) estimates of adiposity improve risk prediction for cardiometabolic diseases over traditional surrogates, body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) in older women., Patients and Methods: We analyzed up to 9744 postmenopausal women aged 50 to 79 years participating in the Women's Health Initiative who underwent a DXA scan and were free of cardiovascular disease and diabetes at baseline (October 1993 to December 1998) and followed through September 2015. Baseline BMI, WC, WHR, and DXA-derived percent total-body and trunk fat (%TrF) were incorporated into multivariable Cox proportional hazards models to estimate the risk of incident diabetes, atherosclerosis-related cardiovascular diseases (ASCVDs), heart failure, and death. Concordance probability estimates assessed the relative discriminatory value between pairs of adiposity measures., Results: A total of 1327 diabetes cases, 1266 atherosclerotic cardiovascular disease (ASCVD) cases, 292 heart failure cases, and 1811 deaths from any cause accrued during a median follow-up of up to 17.2 years. The largest hazard ratio observed per 1 standard deviation increase of an adiposity measure was for %TrF and diabetes (1.77; 95% CI, 1.66-1.88) followed by %TrF and broadly defined ASCVD (1.22; 95% CI, 1.15-1.30). These hazard ratios remained significant for both diabetes (1.47; 95% CI, 1.37-1.57) and ASCVD (1.22; 95% CI, 1.14-1.31) even after adjusting for the best traditional surrogate measure of adiposity, WC. Percentage of trunk fat was also the only adiposity measure to demonstrate statistically significant improved concordance probability estimates over BMI, WC, and WHR for diabetes and ASCVD (all P<0.05)., Conclusion: DXA-derived estimates of abdominal adiposity in postmenopausal women may allow for substantially improved risk prediction of diabetes over standard clinical risk models. Larger DXA studies with complete lipid biomarker profiles and clinical trials are needed before firm conclusions can be made., (Copyright © 2021 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Alterations of the gut microbiota after allogeneic hematopoietic cell transplantation (allo-HCT) are a key factor in the development of transplant-related complications such as graft-versus-host disease (GVHD). Interventions that preserve the gut microbiome hold promise to improve HCT-associated morbidity and mortality. Murine models demonstrate that prebiotics such as fructo-oligosaccharides (FOSs) may increase gut levels of short-chain fatty acids (SCFAs) such as butyrate and consequently induce proliferation of immunomodulatory FOXP3 + CD4 + regulatory T cells (Tregs), which impact GVHD risk. We conducted a pilot phase I trial to investigate the maximum tolerated dose of FOS in patients undergoing reduced-intensity allo-HCT (n = 15) compared with concurrent controls (n = 16). We administered the FOS starting at pretransplant conditioning and continuing for a total of 21 days. We characterized the gut microbiome using shotgun metagenomic sequencing, measured stool short-chain fatty acids (SCFAs) using liquid chromatography-mass spectrometry, and determined peripheral T cell concentrations using cytometry by time-of-flight. We found that FOS was safe and well-tolerated at 10 g/d without significant adverse effects in patients undergoing allo-HCT. Community-level gut microbiota composition differed significantly on the day of transplant (day 0) between patients receiving FOS and concurrent controls; however, FOS-associated alterations of the gut microbiota were not sustained after transplant. Although the impact of FOS was fleeting, transplantation itself impacted a substantial number of taxa over time. In our small pilot trial, no significant differences were observed in gut microbial metabolic pathways, stool SCFAs, or peripheral Tregs, although Tregs trended higher in those patients who received FOS. A marker of CD4 + T cell activation (namely, CTLA4 + ) was significantly higher in patients receiving FOS, whereas a non-significant trend existed for FOP3 + CD4 + Treg cells, which were higher in those receiving FOS compared with controls. FOS is well tolerated at 10 g/d in patients undergoing reduced-intensity allo-HCT. Although the alterations in gut microbiota and peripheral immune cell composition in those receiving FOS are intriguing, additional studies are required to investigate the use of prebiotics in HCT recipients., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

[Figure: see text].

More than 3000 clinical trials related to COVID-19 have been registered through clinicaltrials.gov. With so many trials, there is a risk that many will be inconclusive due to being underpowered or due to an inability to recruit patients. At academic medical centers, multiple trials are competing for the same resources; the success of one may come at the expense of another. The COVID-19 Outpatient Pragmatic Protocol Study (COPPS) is a flexible phase 2, multi-site, randomized, blinded trial based at Stanford University designed to overcome these issues by simultaneously evaluating multiple COVID-19 treatments in the outpatient setting in one common platform with shared controls. This approach reduces the overall number of patients required for statistical power, while improving the likelihood that any enrolled patient receives active treatment. The platform study has two main domains designed to evaluate COVID-19 treatments by assessing their ability to reduce viral shedding (Viral Domain), measured with self-collected nasal swabs, or improve clinical outcomes (Clinical Domain), measured through self-reported symptomology data. Data are collected on both domains for all participants enrolled. Participants are followed over a 28-day period. COPPS has the advantage of pragmatism created around its workflow that is also appealing to potential participants because of a lower probability of inactive treatment. At the conclusion of this clinical trial we expect to have identified potentially effective therapeutic strategy/ies for treating COVID-19 in the outpatient setting, which will have a transformative impact on medicine and public health., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Clinical trials, conducted efficiently and with the utmost integrity, are a key component in identifying effective vaccines, therapies, and other interventions urgently needed to solve the COVID-19 crisis. Yet launching and implementing trials with the rigor necessary to produce convincing results is a complicated and time-consuming process. Balancing rigor and efficiency involves relying on designs that employ flexible features to respond to a fast-changing landscape, measuring valid endpoints that result in translational actions and disseminating findings in a timely manner. We describe the challenges involved in creating infrastructure with potential utility for shared learning., Methods: We have established a shared infrastructure that borrows strength across multiple trials. The infrastructure includes an endpoint registry to aid in selecting appropriate endpoints, a registry to facilitate establishing a Data & Safety Monitoring Board, common data collection instruments, a COVID-19 dedicated design and analysis team, and a pragmatic platform protocol, among other elements., Results: The authors have relied on the shared infrastructure for six clinical trials for which they serve as the Data Coordinating Center and have a design and analysis team comprising 15 members who are dedicated to COVID-19. The authors established a pragmatic platform to simultaneously investigate multiple treatments for the outpatient with adaptive features to add or drop treatment arms., Conclusion: The shared infrastructure provides appealing opportunities to evaluate disease in a more robust manner with fewer resources and is especially valued during a pandemic where efficiency in time and resources is crucial. The most important element of the shared infrastructure is the pragmatic platform. While it may be the most challenging of the elements to establish, it may provide the greatest benefit to both patients and researchers.

Objective: To compare the pregnancy outcomes of lesbian women undergoing donor sperm intrauterine insemination (IUI) with that of heterosexual women undergoing IUI using partner or donor sperm., Design: Retrospective cohort analysis., Setting: Two academic fertility practices., Patients: All IUI cycles between 2007 and 2016., Interventions: None., Main Outcome Measures: Primary outcomes included clinical pregnancy (CP) rates and live birth/ongoing pregnancy (LB) rates. The baseline characteristics and cycle characteristics were compared between the two groups using absolute standardized differences (ASDs). To account for the correlation between cycles per patient, a generalized estimating equation method for multivariable logistic regression was used., Results: A total of 11,870 IUI cycles were included, of which 393 were in lesbian women using donor sperm and 11,477 were in heterosexual women with infertility using either partner or donor sperm. The CP rates were similar between the lesbian and heterosexual groups (13.2% vs. 11.1%, respectively, ASD = 0.06). In addition, the LB rates were similar between the two groups (10.4% vs. 8.3%, respectively, ASD = 0.10). After implementing the generalized estimating equation in a multivariable logistic regression, the lesbian group had an overall higher odds of CP (adjusted odds ratio 1.40, 95% confidence interval: [1.04-1.88]) and LB (adjusted odds ratio 1.59, 95% confidence interval [1.15-2.20]) compared with the heterosexual group. The clinical miscarriage rate was higher in the heterosexual group compared with that in the lesbian group (23.8% vs. 15.4%, respectively, ASD = 0.21)., Conclusion: Although the unadjusted rates were similar between the two groups, the adjusted CP and LB odds were significantly higher for lesbian women undergoing IUI for procreative management than those for heterosexual women undergoing IUI for infertility., (© 2021 The Author(s).)