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Randy M Stalter,1 Vidya Atluri,2 Fan Xia,1 Katherine K Thomas,3 Kristine F Lan,2 Alexander L Greninger,4 Rena C Patel2 1Department of Epidemiology, University of Washington, Seattle, WA, USA; 2Department of Medicine, University of Washington, Seattle, WA, USA; 3Department of Global Health, University of Washington, Seattle, WA, USA; 4Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USACorrespondence: Randy M StalterDepartment of Epidemiology, University of Washington, UW Box 359927 325 Ninth Avenue, Seattle, WA, 98104, USA, Tel +1-412-760-8134, Email rstalter@uw.eduPurpose: To examine associations between male sex and SARS-CoV-2 test positivity, severe COVID-19 disease, and death in a single-site cohort, and assess whether male sex impacts risk for severe COVID-19 disease through socioeconomic status (SES), comorbidities, or inflammation.Materials and Methods: We conducted a retrospective cohort study with data collected from University of Washington Medicine EMR from March 1 to September 29, 2020. All persons, regardless of age, were included if they had a conclusive diagnostic COVID-19 PCR test result. Our exposure was sex assigned at birth. We used Poisson regression to assess associations between sex and COVID-19 test positivity, disease severity and COVID-19 related death, and linear regression to compare viral cycle threshold at the first positive test. We conducted mediation analyses to assess interventional indirect effects of male sex on severe COVID-19 risk through socioeconomic status (SES, based on area deprivation and insurance type), comorbidities, and inflammation status. Models controlled for age and race/ethnicity.Results: Of 32,919 males and 34,733 females included, 1469 (4.5%) and 1372 (4.0%) tested positive for SARS-CoV-2, respectively. Males were 14% more likely to test positive (RR = 1.14; 95% CI: 1.06– 1.23), had 80% higher risk for severe COVID-19 disease (RR = 1.80; 95% CI: 1.39– 2.33) and had 58% higher risk for death (RR = 1.58; 95% CI: 1.10– 2.26) compared to females after adjusting for age and race/ethnicity. Mediation analyses indicated non-significant interventional indirect effects of male sex on severe COVID-19 disease through elevated inflammatory markers, SES and comorbidities, but the greatest effect was through the inflammation pathway.Conclusion: Males appear to be at higher risk at all steps of the continuum of COVID-19 illness. The strongest mediating signal, albeit non-significant, is with inflammatory pathways. Further elucidation of causal pathways linking sex and COVID-19 severity is needed in larger cohorts.Keywords: SARS-CoV-2, disease severity, mediation, sex-based differences

© 2015 Hagey JM et al.Introduction: Avoiding unintended pregnancies is important for the health of adolescents living with HIV and has the additional benefit of preventing potential vertical HIV transmission. Health facility providers represent an untapped

© 2015 Elsevier Ltd. All rights reserved.BACKGROUND: Concerns have been raised about efavirenz reducing the effectiveness of contraceptive implants. We aimed to establish whether pregnancy rates differ between HIV-positive women who use various contracepti

Variants in the PRKRA gene, which encodes PACT, cause the early-onset primary dystonia DYT-PRKRA, a movement disorder associated with disruption of coordinated muscle movements. PACT and its murine homolog RAX activate protein kinase R (PKR; also known as EIF2AK2) by a direct interaction in response to cellular stressors to mediate phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α). Mice homozygous for a naturally arisen, recessively inherited frameshift mutation, Prkralear-5J, exhibit progressive dystonia. In the present study, we investigated the biochemical and developmental consequences of the Prkralear-5J mutation. Our results indicated that the truncated PACT/RAX protein retains its ability to interact with PKR but inhibits PKR activation. Mice homozygous for the mutation showed abnormalities in cerebellar development as well as a severe lack of dendritic arborization of Purkinje neurons. Additionally, reduced eIF2α phosphorylation was noted in the cerebellum and Purkinje neurons of the homozygous Prkralear-5J mice. These findings indicate that PACT/RAX-mediated regulation of PKR activity and eIF2α phosphorylation plays a role in cerebellar development and contributes to the dystonia phenotype resulting from the Prkralear-5J mutation., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Potential associations between periconception dolutegravir (DTG) exposure and neural tube defects (NTDs) reported in 2018 caused shifting international and national antiretroviral treatment (ART) guidelines. They sometimes required women to use contraception prior to initiating DTG. To better understand the tensions between ART and family planning (FP) choices, and explore the decision-making processes of women living with HIV (WLHIV) and their healthcare providers (HCPs) employed, we conducted interviews with WLHIV exposed to DTG and their providers in western Kenya from July 2019 to August 2020. For the interviews with WLHIV, we sampled women at varying ages who either continued using DTG, switched to a different ART, or became pregnant while using DTG. We utilized inductive coding and thematic analysis. We conducted 44 interviews with WLHIV and 10 with providers. We found four dominant themes: (1) a range of attitudes about birth defects, (2) nuanced knowledge of DTG and its potential risk of birth defects, (3) significant tensions at the intersection of DTG and FP use with varying priorities amongst WLHIV and their providers for navigating the tensions, and (4) WLHIV desiring autonomy, and provider support for this, in such decision-making. Variations in beliefs were noted between WLHIV and HCPs. WLHIV highlighted the impact of community and social beliefs when discussing their attitudes while HCPs generally reported more medicalized views towards DTG utilization, potential adverse outcomes, and FP selection. Decisions pertaining to ART and FP selection are complex, and HIV treatment guidelines need to better support women's agency and reproductive health justice., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Annually, about 4000 US children undergo a tracheostomy procedure to provide a functional, safe airway. In the hospital, qualified staff monitor and address problems, but post-discharge this responsibility shifts entirely to caregivers. The stress and constant demands of caregiving for a child with a tracheostomy with or without ventilator negatively affect caregivers. The aims of the study are to relieve the burden and stress experienced by caregivers at home, improve safety and outcomes for children post-discharge, and identify facilitators and barriers to implementation of comprehensive pediatric discharge programs., Methods: The Boosting REsources and cAregiver empowerment for Tracheostomy care at HomE (BREATHE Study) is a pragmatic two-arm, randomized trial with six sites across the US. Caregivers of a child with a tracheostomy are randomized to comparator ("Trach Me Home") or intervention ("Trach Plus"). The Comparator arm is the current gold standard focusing on caregiver education, technical skill building, and case management. The Intervention arm contains all elements of the Comparator plus educational resources, social support and communication with the outpatient pediatrician. Caregivers will complete three surveys: baseline (pre-discharge), 4-week and 6-month post-discharge. Outpatient pediatricians will complete a survey to assess self-confidence in caring for a child with tracheostomy and satisfaction with discharge communication. Interviews with clinicians and staff will identify facilitators and barriers to implementation. The study will examine whether the Intervention arm leads to lower caregiver burden, lower readmission rates and higher pediatrician satisfaction than Comparator arm., Discussion: The BREATHE Study will advance our understanding of how hospitals can support caregivers with a child with a tracheostomy as they resume life, work, and family activities after discharge., Trial Registration: Registered on clinicaltrials.gov (NCT06283953). February 28, 2024., (© 2024. The Author(s).)

Background: Long COVID, also known as post-acute sequelae of COVID-19 (PASC), is a poorly understood condition with symptoms across a range of biological domains that often have debilitating consequences. Some have recently suggested that lingering SARS-CoV-2 virus particles in the gut may impede serotonin production and that low serotonin may drive many Long COVID symptoms across a range of biological systems. Therefore, selective serotonin reuptake inhibitors (SSRIs), which increase synaptic serotonin availability, may be used to prevent or treat Long COVID. SSRIs are commonly prescribed for depression, therefore restricting a study sample to only include patients with depression can reduce the concern of confounding by indication., Methods: In an observational sample of electronic health records from patients in the National COVID Cohort Collaborative (N3C) with a COVID-19 diagnosis between September 1, 2021, and December 1, 2022, and a comorbid depressive disorder, the leading indication for SSRI use, we evaluated the relationship between SSRI use during acute COVID-19 and subsequent 12-month risk of Long COVID (defined by ICD-10 code U09.9). We defined SSRI use as a prescription for SSRI medication beginning at least 30 days before acute COVID-19 and not ending before SARS-CoV-2 infection. To minimize bias, we estimated relationships using nonparametric targeted maximum likelihood estimation to aggressively adjust for high-dimensional covariates., Results: We analyzed a sample (n = 302,626) of patients with a diagnosis of a depressive condition before COVID-19 diagnosis, where 100,803 (33%) were using an SSRI. We found that SSRI users had a significantly lower risk of Long COVID compared to nonusers (adjusted causal relative risk 0.92, 95% CI (0.86, 0.99)) and we found a similar relationship comparing new SSRI users (first SSRI prescription 1 to 4 months before acute COVID-19 with no prior history of SSRI use) to nonusers (adjusted causal relative risk 0.89, 95% CI (0.80, 0.98))., Conclusions: These findings suggest that SSRI use during acute COVID-19 may be protective against Long COVID, supporting the hypothesis that serotonin may be a key mechanistic biomarker of Long COVID., (© 2024. The Author(s).)

Postpartum depression (PPD) is a mood disorder affecting one in seven women after childbirth that is often under-screened and under-detected. If not diagnosed and treated, PPD is associated with long-term developmental challenges in the child and maternal morbidity. Wearable technologies, such as smartwatches and fitness trackers (e.g., Fitbit), offer continuous and longitudinal digital phenotyping for mood disorder diagnosis and monitoring, with device wear time being an important yet understudied aspect. Using the All of Us Research Program (AoURP) dataset, we assessed the percentage of days women with PPD wore Fitbit devices across pre-pregnancy, pregnancy, postpartum, and PPD periods, as determined by electronic health records. Wear time was compared in women with and without PPD using linear regression models. Results showed a strong trend that women in the PPD cohort wore their Fitbits more those without PPD during the postpartum (PPD: mean=72.9%, SE=13.8%; non-PPD: mean=58.9%, SE=12.2%, P -value=0.09) and PPD time periods (PPD: mean=70.7%, SE=14.5%; non-PPD: mean=55.6%, SE=12.9%, P -value=0.08). We hypothesize this may be attributed to hypervigilance, given the common co-occurrence of anxiety symptoms among women with PPD. Future studies should assess the link between PPD, hypervigilance, and wear time patterns. We envision that device wear patterns with digital biomarkers like sleep and physical activity could enhance early PPD detection using machine learning by alerting clinicians to potential concerns facilitating timely screenings, which may have implications for other mental health disorders., Competing Interests: Competing interests MAH is a founder of Alamya Health.

The articles in this special issue of AIDS and Behavior focus on the collision between HIV/AIDS and COVID-19 as intersecting pandemics that profoundly impacted communities globally. This editorial highlights the complex interplay between these two public health crises. The pandemic disrupted access to HIV prevention, testing, and treatment services, potentially jeopardizing decades of progress. Mental health challenges and social vulnerability among people living with HIV (PWH) were exacerbated, with preexisting health disparities amplified, disproportionately affecting marginalized populations. However, despite these challenges, the pandemic also spurred innovation and adaptation in HIV prevention and care, with increased use of telehealth and other modalities. The enduring and actionable lessons learned from the collision of HIV and COVID-19 pandemics can prepare us for the next public health challenge with two calls for action. First, we call for integrated and equitable responses that address the multifaceted challenges faced by individuals and communities affected by HIV in the post-COVID-19 era. Second, we call for a strengthened commitment to building resilient health systems and community-engaged interventions that can withstand future challenges., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Individually, the COVID-19 and HIV pandemics have differentially impacted minoritized groups due to the role of social determinants of health (SDoH) in the U.S. Little is known how the collision of these two pandemics may have exacerbated adverse health outcomes. We evaluated county-level SDoH and associations with hospitalization after a COVID-19 diagnosis among people with (PWH) and without HIV (PWOH) by racial/ethnic groups. We used the U.S. National COVID Cohort Collaborative (January 2020-November 2023), a nationally-sampled electronic health record repository, to identify adults who were diagnosed with COVID-19 with HIV (n = 22,491) and without HIV (n = 2,220,660). We aggregated SDoH measures at the county-level and categorized racial/ethnic groups as Non-Hispanic (NH) White, NH-Black, Hispanic/Latinx, NH-Asian and Pacific Islander (AAPI), and NH-American Indian or Alaskan Native (AIAN). To estimate associations of county-level SDoH with hospitalization after a COVID-19 diagnosis, we used multilevel, multivariable logistic regressions, calculating adjusted relative risks (aRR) with 95% confidence intervals (95% CI). COVID-19 related hospitalization occurred among 11% of PWH and 7% of PWOH, with the highest proportion among NH-Black PWH (15%). In evaluating county-level SDoH among PWH, we found higher average household size was associated with lower risk of COVID-19 related hospitalization across racial/ethnic groups. Higher mean commute time (aRR: 1.76; 95% CI 1.10-2.62) and higher proportion of adults without health insurance (aRR: 1.40; 95% CI 1.04-1.84) was associated with a higher risk of COVID-19 hospitalization among NH-Black PWH, however, NH-Black PWOH did not demonstrate these associations. Differences by race and ethnicity exist in associations of adverse county-level SDoH with COVID-19 outcomes among people with and without HIV in the U.S., (© 2024. The Author(s).)

In the U.S., inequities by race/ethnicity in health outcomes, such as in the HIV epidemic, are long standing but have come to the forefront during the COVID-19 pandemic. There is growing recognition of the role of structural racism in racialized health inequities, yet the conceptualization and operationalization of structural racism in HIV research lags. We conducted a scoping review of existing published literature, between 1999-April 2024, conceptualizing and measuring structural racism's impact among people living with or at risk for HIV in the U.S. Our initial search yielded 236 unique articles, which after title and abstract screening yielded ten articles meeting full text review criteria. We then extracted key parameters, such as conceptualization, method of measurement of structural racism, study aims, design, and findings. Three of the articles were qualitative studies that conceptualized structural racism using (1) the social network model, (2) individual and structural intersectionality and (3) critical race theory. Operationalization of structural racism within the seven quantitative studies fell into three categories: (1) structural level, (2) a scale of experiences of racism, including structural racism, and (3) using explanatory demographic factors as downstream measures of the effects of structural racism. The variance in the conceptualization and operationalization of structural racism highlights the different interpretations of structural racism in its applications to the field of HIV research. Given the vast racial/ethnic inequities in HIV, we propose three overarching suggestions for next steps in improving the conduct of research on structural racism in HIV: (1) we must prioritize measuring racism past the individual and interpersonal levels to consider systemic factors at a societal level that manifest as structural racism to improve HIV outcomes in the U.S., (2) consider intergenerational effects of structural racism through the use of longitudinal data, and (3) broaden the agenda of structural racism to incorporate other systems of oppression. Additionally, broadening the scope of funding and inclusion of more researchers and individuals with lived experiences to support structural racism research to drive the scientific agenda and design of structural-level interventions will not only bolster achieving the U.S. Ending the HIV Epidemic goals but will do so by addressing inequities., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Pharmacovigilance (PV), or the ongoing safety monitoring after a medication has been licensed, plays a crucial role in pregnancy, as clinical trials often exclude pregnant people. It is important to understand how pregnancy PV projects operate in low- and middle-income countries (LMICs), where there is a disproportionate lack of PV data yet a high burden of adverse pregnancy outcomes. We conducted a scoping review to assess how exposures and outcomes were measured in recently published pregnancy PV projects in LMICs., Methods: We utilized a search string, secondary review, and team knowledge to review publications focusing on therapeutic or vaccine exposures among pregnant people in LMICs. We screened abstracts for relevance before conducting a full text review, and documented measurements of exposures and outcomes (categorized as maternal, birth, or neonatal/infant) among other factors, including study topic, setting, and design, comparator groups, and funding sources., Results: We identified 31 PV publications spanning at least 24 LMICs, all focusing on therapeutics or vaccines for infectious diseases, including HIV (n = 17), tuberculosis (TB; n = 9), malaria (n = 7), pertussis, tetanus, and diphtheria (n = 1), and influenza (n = 3). As for outcomes, n = 15, n = 31, and n = 20 of the publications covered maternal, birth, and neonatal/infant outcomes, respectively. Among HIV-specific publications, the primary exposure-outcome relationship of focus was exposure to maternal antiretroviral therapy and adverse outcomes. For TB-specific publications, the main exposures of interest were second-line drug-resistant TB and isoniazid-based prevention therapeutics for pregnant people living with HIV. For malaria-specific publications, the primary exposure-outcome relationship of interest was antimalarial medication exposure during pregnancy and adverse outcomes. Among vaccine-focused publications, the exposure was assessed during a specific time during pregnancy, with an overall interest in vaccine safety and/or efficacy. The study settings were frequently from Africa, designs varied from cohort or cross-sectional studies to clinical trials, and funding sources were largely from high-income countries., Conclusion: The published pregnancy PV projects were largely centered in Africa and concerned with infectious diseases. This may reflect the disease burden in LMICs but also funding priorities from high-income countries. As the prevalence of non-communicable diseases increases in LMICs, PV projects will have to broaden their scope. Birth and neonatal/infant outcomes were most reported, with fewer reporting on maternal outcomes and none on longer-term child outcomes; additionally, heterogeneity existed in definitions and ascertainment of specific measures. Notably, almost all projects covered a single therapeutic exposure, missing an opportunity to leverage their projects to cover additional exposures, add scientific rigor, create uniformity across health services, and bolster existing health systems. For many publications, the timing of exposure, specifically by trimester, was crucial to maternal and neonatal safety. While currently published pregnancy PV literature offer insights into the PV landscape in LMICs, further work is needed to standardize definitions and measurements, integrate PV projects across health services, and establish longer-term monitoring., (© 2024. The Author(s).)

To exploratorily test (1) the impact of HIV and aging process among PLWH on COVID-19 outcomes; and (2) whether the effects of HIV on COVID-19 outcomes differed by immunity level. The data used in this study was retrieved from the COVID-19 positive cohort in National COVID Cohort Collaborative (N3C). Multivariable logistic regression models were conducted on populations that were matched using either exact matching or propensity score matching (PSM) with varying age difference between PLWH and non-PLWH to examine the impact of HIV and aging process on all-cause mortality and hospitalization among COVID-19 patients. Subgroup analyses by CD4 counts and viral load (VL) levels were conducted using similar approaches. Among the 2,422,864 adults with a COVID-19 diagnosis, 15,188 were PLWH. PLWH had a significantly higher odds of death compared to non-PLWH until age difference reached 6 years or more, while PLWH were still at an elevated risk of hospitalization across all matched cohorts. The odds of both severe outcomes were persistently higher among PLWH with CD4 < 200 cells/mm 3 . VL ≥ 200 copies/ml was only associated with higher hospitalization, regardless of the predefined age differences. Age advancement in HIV might significantly contribute to the higher risk of COVID-19 mortality and HIV infection may still impact COVID-19 hospitalization independent of the age advancement in HIV., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Autoimmune or inflammatory rheumatic diseases (AIRDs) increase the risk for poor COVID-19 outcomes. Although rurality is associated with higher post-COVID-19 mortality in the general population, whether rurality elevates this risk among people with AIRD is unknown. We assessed associations between rurality and post-COVID-19 all-cause mortality, up to two years post infection, among people with AIRD using a large nationally sampled US cohort., Methods: This retrospective study used the National COVID Cohort Collaborative, a medical records repository containing COVID-19 patient data. We included adults with two or more AIRD diagnostic codes and a COVID-19 diagnosis documented between April 2020 and March 2023. Rural residency was categorized using patient residential zip codes. We adjusted for AIRD medications and glucocorticoid prescription, age, sex, race and ethnicity, tobacco or substance use, comorbid burden, and SARS-CoV-2 variant-dominant periods. Multivariable Cox proportional hazards with inverse probability treatment weighting assessed associations between rurality and two-year all-cause mortality., Results: Among the 86,467 SARS-CoV-2-infected persons with AIRD, we observed a higher risk for two-year post-COVID-19 mortality in rural versus urban dwellers. Rural-residing persons with AIRD had higher two-year all-cause mortality risk (adjusted hazard ratio 1.24, 95% confidence interval 1.19-1.29). Glucocorticoid, immunosuppressive, and rituximab prescriptions were associated with a higher risk for two-year post-COVID-19 mortality, whereas risk with nonbiologic or biologic disease-modifying antirheumatic drugs was lower., Conclusion: Rural residence in people with AIRD was independently associated with higher two-year post-COVID-19 mortality in a large US cohort after adjusting for background risk factors. Policymakers and health care providers should consider these findings when designing interventions to improve outcomes in people with AIRD following SARS-CoV-2 infection, especially among high-risk rural residents., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Postacute sequelae of COVID-19 (PASC), also known as long COVID, is a broad grouping of a range of long-term symptoms following acute COVID-19. These symptoms can occur across a range of biological systems, leading to challenges in determining risk factors for PASC and the causal etiology of this disorder. An understanding of characteristics that are predictive of future PASC is valuable, as this can inform the identification of high-risk individuals and future preventative efforts. However, current knowledge regarding PASC risk factors is limited., Objective: Using a sample of 55,257 patients (at a ratio of 1 patient with PASC to 4 matched controls) from the National COVID Cohort Collaborative, as part of the National Institutes of Health Long COVID Computational Challenge, we sought to predict individual risk of PASC diagnosis from a curated set of clinically informed covariates. The National COVID Cohort Collaborative includes electronic health records for more than 22 million patients from 84 sites across the United States., Methods: We predicted individual PASC status, given covariate information, using Super Learner (an ensemble machine learning algorithm also known as stacking) to learn the optimal combination of gradient boosting and random forest algorithms to maximize the area under the receiver operator curve. We evaluated variable importance (Shapley values) based on 3 levels: individual features, temporal windows, and clinical domains. We externally validated these findings using a holdout set of randomly selected study sites., Results: We were able to predict individual PASC diagnoses accurately (area under the curve 0.874). The individual features of the length of observation period, number of health care interactions during acute COVID-19, and viral lower respiratory infection were the most predictive of subsequent PASC diagnosis. Temporally, we found that baseline characteristics were the most predictive of future PASC diagnosis, compared with characteristics immediately before, during, or after acute COVID-19. We found that the clinical domains of health care use, demographics or anthropometry, and respiratory factors were the most predictive of PASC diagnosis., Conclusions: The methods outlined here provide an open-source, applied example of using Super Learner to predict PASC status using electronic health record data, which can be replicated across a variety of settings. Across individual predictors and clinical domains, we consistently found that factors related to health care use were the strongest predictors of PASC diagnosis. This indicates that any observational studies using PASC diagnosis as a primary outcome must rigorously account for heterogeneous health care use. Our temporal findings support the hypothesis that clinicians may be able to accurately assess the risk of PASC in patients before acute COVID-19 diagnosis, which could improve early interventions and preventive care. Our findings also highlight the importance of respiratory characteristics in PASC risk assessment., International Registered Report Identifier (irrid): RR2-10.1101/2023.07.27.23293272., (©Zachary Butzin-Dozier, Yunwen Ji, Haodong Li, Jeremy Coyle, Junming Shi, Rachael V Phillips, Andrew N Mertens, Romain Pirracchio, Mark J van der Laan, Rena C Patel, John M Colford, Alan E Hubbard, The National COVID Cohort Collaborative (N3C) Consortium. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 15.08.2024.)

Background: Levonorgestrel implant is a highly effective hormonal contraceptive, but its efficacy may be compromised when used with cytochrome enzyme inducers such as efavirenz. The primary aim of this study was to evaluate methods of mitigating the drug interaction. Methods: Using a physiologically-based pharmacokinetic (PBPK) model for levonorgestrel that we developed within the Simcyp ® program, we evaluated a higher dose of levonorgestrel implant, a lower dose of efavirenz, and the combination of both, as possible methods to mitigate the interaction. In addition, we investigated the impact on levonorgestrel total and unbound concentrations of other events likely to be associated with efavirenz coadministration: changes in plasma protein binding of levonorgestrel (as with displacement) and high variability of efavirenz exposure (as with genetic polymorphism of its metabolism). The range of fraction unbound tested was 0.6% to 2.6%, and the range of efavirenz exposure ranged from the equivalent of 200 mg to 4800 mg doses. Results: Levonorgestrel plasma concentrations at any given time with a standard 150 mg implant dose are predicted to be approximately 68% of those of control when given with efavirenz 600 mg and 72% of control with efavirenz 400 mg. With double-dose levonorgestrel, the predictions are 136% and 145% of control, respectively. A decrease in levonorgestrel plasma protein binding is predicted to primarily decrease total levonorgestrel plasma concentrations, whereas higher efavirenz exposure is predicted to decrease total and unbound concentrations. Conclusions: Simulations suggest that doubling the dose of levonorgestrel, particularly in combination with 400 mg daily efavirenz, may mitigate the drug interaction. Changes in levonorgestrel plasma protein binding and efavirenz genetic polymorphism may help explain differences between model predictions and clinical data but need to be studied further.

Objectives: To evaluate the effectiveness of COVID-19 vaccinations (initial and booster) during pre-Delta, Delta, and Omicron dominant periods among pregnant people via (1) COVID-19 incident and severe infections among pregnant people who were vaccinated vs. unvaccinated and (2) post-COVID-19 vaccination breakthrough infections and severe infections among vaccinated females who were pregnant vs. non-pregnant., Design: Retrospective cohort study using nationally sampled electronic health records data from the National COVID Cohort Collaborative (N3C), December 10, 2020, to June 07, 2022., Participants: Cohort 1 included pregnant people (15-55 years), and Cohort 2 included vaccinated females of reproductive age (15-55 years)., Exposures: (1) COVID-19 vaccination and (2) pregnancy., Main Outcome Measures: Adjusted hazard ratios (aHRs) for COVID-19 incident or breakthrough infections and severe infections (i.e., COVID-19 infections with related hospitalizations)., Results: In Cohort 1, 301,107 pregnant people were included. Compared to unvaccinated pregnant people, the aHRs for pregnant people with initial vaccinations during pregnancy of incident COVID-19 were 0.77 (95% CI: 0.62, 0.96) and 0.88 (95%CI: 0.73, 1.07) and aHRs of severe COVID-19 infections were 0.65 (95% CI: 0.47, 0.90) and 0.79 (95% CI: 0.51, 1.21) during the Delta and Omicron periods, respectively. Compared to pregnant people with full initial vaccinations, the aHR of incident COVID-19 for pregnant people with booster vaccinations was 0.64 (95% CI: 0.58, 0.71) during the Omicron period. In Cohort 2, 934,337 vaccinated people were included. Compared to vaccinated non-pregnant females, the aHRs of severe COVID-19 infections for people with initial vaccinations during pregnancy was 2.71 (95% CI: 1.31, 5.60) during the Omicron periods., Conclusions: Pregnant people with initial and booster vaccinations during pregnancy had a lower risk of incident and severe COVID-19 infections compared to unvaccinated pregnant people across the pandemic stages. However, vaccinated pregnant people still had a higher risk of severe infections compared to non-pregnant females., Competing Interests: Conflicts of Interest and Disclaimers APC helped to conceptualize this study while at Vanderbilt University. Following this contribution, APC joined the staff of AstraZeneca Pharmaceuticals, LP (“AZ”), which markets a COVID-19 vaccine in direct competition to other products considered in this manuscript. After joining AZ, APC did not participate in the conduct of this research, with his subsequent contributions limited to ad hoc consultation on methods for real-world data management, as part of routine meetings of the N3C Pregnancy Domain Team for which he is an advisor. APC did not provide any guidance on product-specific or advocacy topics. Similarly, AZ did not provide any data, funding, or scientific input towards the results herein. The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health, AZ, or the N3C program.

Routine HIV viral load testing is important for evaluating HIV treatment outcomes, but conventional viral load testing has many barriers including expensive laboratory equipment and lengthy results return times to patients. A point-of-care viral load testing technology, such as GeneXpert HIV-1 quantification assay, could reduce these barriers by decreasing cost and turnaround time, however real-world performance is limited. We conducted a secondary analysis using 900 samples collected from participants in two studies to examine the performance of GeneXpert as point-of-care viral load compared to standard-of-care testing (which was conducted with two centralized laboratories using traditional HIV-1 RNA PCR quantification assays). The two studies, Opt4Kids (n = 704 participants) and Opt4Mamas (n = 820 participants), were conducted in western Kenya from 2019-2021 to evaluate the effectiveness of a combined intervention strategy, which included point-of-care viral load testing. Paired viral load results were compared using four different thresholds for virological non-suppression, namely ≥50, ≥200, ≥400, ≥1000 copies/ml. At a threshold of ≥1000 copies/mL, paired samples collected on the same day: demonstrated sensitivities of 90.0% (95% confidence interval [CI] 68.3, 98.8) and 66.7% (9.4, 99.2), specificities of 98.4% (95.5, 99.7) and 100% (96.5, 100), and percent agreements of 97.7% (94.6, 99.2) and 99.1% (95.0, 100) in Opt4Kids and Opt4Mamas studies, respectively. When lower viral load thresholds were used and the paired samples were collected an increasing number of days apart, sensitivity, specificity, and percent agreement generally decreased. While specificity and percent agreement were uniformly high, sensitivity was lower than expected. Non-specificity of the standard of care testing may have been responsible for the sensitivity values. Nonetheless, our results demonstrate that GeneXpert may be used reliably to monitor HIV treatment in low- and middle- income countries to attain UNAID's 95-95-95 HIV goals., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Giang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Mutations in Prkra gene, which encodes PACT/RAX cause early onset primary dystonia DYT-PRKRA, a movement disorder that disrupts coordinated muscle movements. PACT/RAX activates protein kinase R (PKR, aka EIF2AK2) by a direct interaction in response to cellular stressors to mediate phosphorylation of the α subunit of the eukaryotic translation initiation factor 2 (eIF2α). Mice homozygous for a naturally arisen, recessively inherited frameshift mutation, Prkra lear-5J exhibit progressive dystonia. In the present study, we investigate the biochemical and developmental consequences of the Prkra lear-5J mutation. Our results indicate that the truncated PACT/RAX protein retains its ability to interact with PKR, however, it inhibits PKR activation. Furthermore, mice homozygous for the mutation have abnormalities in the cerebellar development as well as a severe lack of dendritic arborization of Purkinje neurons. Additionally, reduced eIF2α phosphorylation is noted in the cerebellums and Purkinje neurons of the homozygous Prkra lear-5J mice. These results indicate that PACT/RAX mediated regulation of PKR activity and eIF2α phosphorylation plays a role in cerebellar development and contributes to the dystonia phenotype resulting from this mutation., Competing Interests: Financial Disclosure/Conflict of Interest: The authors declare no financial disclosures or conflicts of interest.

Background: Leveraging the National COVID-19 Cohort Collaborative (N3C), a nationally sampled electronic health records repository, we explored associations between individual-level social determinants of health (SDoH) and COVID-19-related hospitalizations among racialized minority people with human immunodeficiency virus (HIV) (PWH), who have been historically adversely affected by SDoH., Methods: We retrospectively studied PWH and people without HIV (PWoH) using N3C data from January 2020 to November 2023. We evaluated SDoH variables across three domains in the Healthy People 2030 framework: (1) healthcare access, (2) economic stability, and (3) social cohesion with our primary outcome, COVID-19-related hospitalization. We conducted hierarchically nested additive and adjusted mixed-effects logistic regression models, stratifying by HIV status and race/ethnicity groups, accounting for age, sex, comorbidities, and data partners., Results: Our analytic sample included 280,441 individuals from 24 data partner sites, where 3,291 (1.17%) were PWH, with racialized minority PWH having higher proportions of adverse SDoH exposures than racialized minority PWoH. COVID-19-related hospitalizations occurred in 11.23% of all individuals (9.17% among PWH, 11.26% among PWoH). In our initial additive modeling, we observed that all three SDoH domains were significantly associated with hospitalizations, even with progressive adjustments (adjusted odds ratios [aOR] range 1.36-1.97). Subsequently, our HIV-stratified analyses indicated economic instability was associated with hospitalization in both PWH and PWoH (aOR range 1.35-1.48). Lastly, our fully adjusted, race/ethnicity-stratified analysis, indicated access to healthcare issues was associated with hospitalization across various racialized groups (aOR range 1.36-2.00)., Conclusion: Our study underscores the importance of assessing individual-level SDoH variables to unravel the complex interplay of these factors for racialized minority groups., Competing Interests: All authors declare no conflicts of interest., (© The Author(s) 2024.)

Background: Postpartum depression (PPD) poses a significant maternal health challenge. The current approach to detecting PPD relies on in-person postpartum visits, which contributes to underdiagnosis. Furthermore, recognizing PPD symptoms can be challenging. Therefore, we explored the potential of using digital biomarkers from consumer wearables for PPD recognition., Objective: The main goal of this study was to showcase the viability of using machine learning (ML) and digital biomarkers related to heart rate, physical activity, and energy expenditure derived from consumer-grade wearables for the recognition of PPD., Methods: Using the All of Us Research Program Registered Tier v6 data set, we performed computational phenotyping of women with and without PPD following childbirth. Intraindividual ML models were developed using digital biomarkers from Fitbit to discern between prepregnancy, pregnancy, postpartum without depression, and postpartum with depression (ie, PPD diagnosis) periods. Models were built using generalized linear models, random forest, support vector machine, and k-nearest neighbor algorithms and evaluated using the κ statistic and multiclass area under the receiver operating characteristic curve (mAUC) to determine the algorithm with the best performance. The specificity of our individualized ML approach was confirmed in a cohort of women who gave birth and did not experience PPD. Moreover, we assessed the impact of a previous history of depression on model performance. We determined the variable importance for predicting the PPD period using Shapley additive explanations and confirmed the results using a permutation approach. Finally, we compared our individualized ML methodology against a traditional cohort-based ML model for PPD recognition and compared model performance using sensitivity, specificity, precision, recall, and F 1 -score., Results: Patient cohorts of women with valid Fitbit data who gave birth included <20 with PPD and 39 without PPD. Our results demonstrated that intraindividual models using digital biomarkers discerned among prepregnancy, pregnancy, postpartum without depression, and postpartum with depression (ie, PPD diagnosis) periods, with random forest (mAUC=0.85; κ=0.80) models outperforming generalized linear models (mAUC=0.82; κ=0.74), support vector machine (mAUC=0.75; κ=0.72), and k-nearest neighbor (mAUC=0.74; κ=0.62). Model performance decreased in women without PPD, illustrating the method's specificity. Previous depression history did not impact the efficacy of the model for PPD recognition. Moreover, we found that the most predictive biomarker of PPD was calories burned during the basal metabolic rate. Finally, individualized models surpassed the performance of a conventional cohort-based model for PPD detection., Conclusions: This research establishes consumer wearables as a promising tool for PPD identification and highlights personalized ML approaches, which could transform early disease detection strategies., (©Eric Hurwitz, Zachary Butzin-Dozier, Hiral Master, Shawn T O'Neil, Anita Walden, Michelle Holko, Rena C Patel, Melissa A Haendel. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 02.05.2024.)

Background: HIV drug resistance (DR) is a growing threat to the durability of current and future HIV treatment success. DR testing (DRT) technologies are very expensive and specialised, relying on centralised laboratories in most low and middle-income countries. Modelling for laboratory network with point-of-care (POC) DRT assays to minimise turnaround time (TAT), is urgently needed to meet the growing demand., Methods: We developed a model with user-friendly interface using integer programming and queueing theory to improve the DRT system in Kisumu County, Kenya. We estimated DRT demand based on both current and idealised scenarios and evaluated a centralised laboratory-only network and an optimised POC DRT network. A one-way sensitivity analysis of key user inputs was conducted., Results: In a centralised laboratory-only network, the mean TAT ranged from 8.52 to 8.55 working days, and the system could not handle a demand proportion exceeding 1.6%. In contrast, the mean TAT for POC DRT network ranged from 1.13 to 2.11 working days, with demand proportion up to 4.8%. Sensitivity analyses showed that expanding DRT hubs reduces mean TAT substantially while increasing the processing rate at national labs had minimal effect. For instance, doubling the current service rate at national labs reduced the mean TAT by only 0.0%-1.9% in various tested scenarios, whereas doubling the current service rate at DRT hubs reduced the mean TAT by 37.5%-49.8%. In addition, faster batching modes and transportation were important factors influencing the mean TAT., Conclusions: Our model offers decision-makers an informed framework for improving the DRT system using POC in Kenya. POC DRT networks substantially reduce mean TAT and can handle a higher demand proportion than a centralised laboratory-only network, especially for children and pregnant women living with HIV, where there is an immediate push to use DRT results for patient case management., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

COVID-19 vaccines have been shown to be effective in preventing severe illness, including among pregnant persons. The vaccines appear to be safe in pregnancy, supporting a continuously favorable overall risk/benefit profile, though supportive data for the U.S. over different periods of variant predominance are lacking. We sought to analyze the association of adverse pregnancy outcomes with COVID-19 vaccinations in the pre-Delta, Delta, and Omicron SARS-CoV-2 variants' dominant periods (constituting 50% or more of each pregnancy) for pregnant persons in a large, nationally sampled electronic health record repository in the U.S. Our overall analysis included 311,057 pregnant persons from December 2020 to October 2023 at a time when there were approximately 3.6 million births per year. We compared rates of preterm births and stillbirths among pregnant persons who were vaccinated before or during pregnancy to persons vaccinated after pregnancy or those who were not vaccinated. We performed a multivariable Poisson regression with generalized estimated equations to address data site heterogeneity for preterm births and unadjusted exact models for stillbirths, stratified by the dominant variant period. We found lower rates of preterm birth in the majority of modeled periods (adjusted incidence rate ratio [aIRR] range: 0.42 to 0.85; p -value range: <0.001 to 0.06) and lower rates of stillbirth (IRR range: 0.53 to 1.82; p -value range: <0.001 to 0.976) in most periods among those who were vaccinated before or during pregnancy compared to those who were vaccinated after pregnancy or not vaccinated. We largely found no adverse associations between COVID-19 vaccination and preterm birth or stillbirth; these findings reinforce the safety of COVID-19 vaccination during pregnancy and bolster confidence for pregnant persons, providers, and policymakers in the importance of COVID-19 vaccination for this group despite the end of the public health emergency.

Validation studies are often used to obtain more reliable information in settings with error-prone data. Validated data on a subsample of subjects can be used together with error-prone data on all subjects to improve estimation. In practice, more than one round of data validation may be required, and direct application of standard approaches for combining validation data into analyses may lead to inefficient estimators since the information available from intermediate validation steps is only partially considered or even completely ignored. In this paper, we present two novel extensions of multiple imputation and generalized raking estimators that make full use of all available data. We show through simulations that incorporating information from intermediate steps can lead to substantial gains in efficiency. This work is motivated by and illustrated in a study of contraceptive effectiveness among 83 671 women living with HIV, whose data were originally extracted from electronic medical records, of whom 4732 had their charts reviewed, and a subsequent 1210 also had a telephone interview to validate key study variables., (© 2023 John Wiley & Sons Ltd.)

Background: Real-world evidence of coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) booster effectiveness among patients with immune dysfunction are limited., Methods: We included data from patients in the United States National COVID Cohort Collaborative (N3C) who completed ≥2 doses of mRNA vaccination between 10 December 2020 and 27 May 2022. Immune dysfunction conditions included human immunodeficiency virus infection, solid organ or bone marrow transplant, autoimmune diseases, and cancer. We defined incident COVID-19 BTI as positive results from laboratory tests or diagnostic codes 14 days after at least 2 doses of mRNA vaccination; and severe COVID-19 BTI as hospitalization, invasive cardiopulmonary support, and/or death. We used propensity scores to match boosted versus nonboosted patients and evaluated hazards of incident and severe COVID-19 BTI using Cox regression after matching., Results: Among patients without immune dysfunction, the relative effectiveness of booster (3 doses) after 6 months from the primary (2 doses) vaccination against BTI ranged from 69% to 81% during the Delta-predominant period and from 33% to 39% during the Omicron-predominant period. Relative effectiveness against BTI was lower among patients with immune dysfunction but remained statistically significant in both periods. Boosted patients had lower risk of COVID-19-related hospitalization (hazard ratios [HR] ranged from 0.5 [95% confidence interval {CI}, .48-.53] to 0.63 [95% CI, .56-.70]), invasive cardiopulmonary support, or death (HRs ranged from 0.46 [95% CI, .41-.52] to 0.63 [95% CI, .50-.79]) during both periods., Conclusions: Booster vaccines remain effective against severe COVID-19 BTI throughout the Delta- and Omicron-predominant periods, regardless of patients' immune status., Competing Interests: Potential conflicts of interest. J. Y. I. reports receiving consulting fees from Flatiron Health. D. S. reports receiving honoraria from Sanofi, Novartis, Veloxis, Mallinckrodt, Jazz Pharmaceuticals, CSL Behring, Thermo Fisher Scientific, Caredx, Transmedics, Kamada, MediGO, Regeneron, AstraZeneca, Takeda, and Bridge to Life. R. B. M. reports receiving honoraria from Vitaeris and Olaris and grant support from VericiDx. J. A. S. reports receiving personal fees from Crealta/Horizon, Medisys, Fidia, PK Med, Two Labs Inc, Adept Field, Solutions, Clinical Care Options, ClearView, Healthcare Partners, Putnam Associates, Focus Forward, Navigant, Spherix, MedIQ, Jupiter Life, Science, UBM LLC, Trio Health, Medscape, WebMD, Practice Point Communications, National Institutes of Health, American College of Rheumatology, and Simply Speaking; and holds stock options from TPT Global Tech, Vaxart, Atyu Biopharma, and Charlotte's Web Holdings, outside the submitted work. All other authors report no potential conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objectives: To describe the use of customized and custom tracheostomies at our institution, and to identify trends in patient presentation and tracheostomy design., Methods: A retrospective review was conducted for patients at our institution for whom a customized or custom tracheostomy tube was ordered between January 2011 and July 2021. Customized tracheostomy tubes allow for a small selection of alterations to trach design, such as cuff length and flange type. Custom tracheostomies have a unique design created by tracheostomy tube engineers in collaboration with the clinical provider, and are built specifically for a single patient., Results: A total of 235 patients were included, of whom 220 (93%) received customized tracheostomies and 15 custom (7%). The most common indications for customized tracheostomy were tracheal or stomal breakdown on a standard tracheostomy (n = 73, 33%) and ventilation difficulties (n = 61, 27%). The most frequent customization was shaft length (n = 126, 57%). The most common indication for custom tracheostomies was a persistent air leak on a standard or customized trach (n = 9) and the most frequent designs were custom cuffs (n = 8), flanges (n = 4), and anteriorly curved shafts (n = 4). Patients treated with a customized tracheostomy had a 5-year overall survival of 75.3%, compared to 51.4% for custom., Conclusion: These are the first cohorts of pediatric patients with customized and custom tracheostomies to be described. Modifications to tracheostomies, in particular shaft length and cuff design, can address common complications of extended tracheostomy, and may help improve ventilation in the most challenging cases., Level of Evidence: 4 Laryngoscope, 134:452-458, 2024., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)

Introduction: Lack of viral suppression (VS) among pregnant and breastfeeding women living with HIV poses challenges for maternal and infant health, and viral load (VL) monitoring via centralized laboratory systems faces many barriers. We aimed to determine the impact of point-of-care (POC) VL and targeted drug resistance mutation (DRM) testing in improving VS among pregnant and postpartum women on antiretroviral therapy., Methods: We conducted a pre/post-intervention prospective cohort study among 820 pregnant women accessing HIV care at five public-sector facilities in western Kenya from 2019 to 2022. The pre-intervention or "control" group consisted of standard-of-care (SOC) centralized VL testing every 6 months and the post-intervention or "intervention" group consisted of a combined strategy of POC VL every 3 months, targeted DRM testing, and clinical management support. The primary outcome was VS (VL ≤1000 copies/ml) at 6 months postpartum; secondary outcomes included uptake and turnaround times for VL testing and sustained VS., Results: At 6 months postpartum, 321/328 (98%) of participants in the intervention group and 339/347 (98%) in the control group achieved VS (aRR 1.00, 95% confidence interval [CI] 0.98, 1.02). When assessing VS using a threshold of <40 copies/ml, VS proportions were lower overall (90-91%) but remained similar between groups. Among women with viraemia (VL>1000 copies/ml) who underwent successful DRM testing in the intervention group, all (46/46, 100%) had some DRMs and 20 (43%) had major DRMs (of which 80% were nucleos(t)ide reverse transcriptase inhibitor mutations). POC VL testing uptake was high (>89%) throughout pregnancy, delivery, and postpartum periods, with a median turnaround time of 1 day (IQR 1, 4) for POC VL in the intervention group and 7 days (IQR 5, 9) for SOC VL in the control group. Sustained VS throughout follow-up was similar between groups with either POC or SOC VL testing (90-91% for <1000 copies/ml, 62-70% for <40 copies/ml)., Conclusions: Our combined strategy markedly decreased turnaround time but did not increase VS rates, which were already very high, or sustained VS among pregnant and postpartum women living with HIV. Further research on how best to utilize POC VL and DRM testing is needed to optimize sustained VS among this population., (© 2023 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

Zero-dose children, or children who have not received any routine vaccination, are a priority population for global health policy makers as these children are at high risk of mortality from vaccine-preventable illnesses. We conducted a narrative review to identify potential interventions, both within and outside of the health sector, to reach zero-dose children. We reviewed the peer-reviewed and grey literature and identified 27 relevant resources. Additionally, we interviewed six key informants to enhance the synthesis of our findings. Data were organized into three priority settings: (1) urban slums, (2) remote or rural communities, and (3) conflict settings. We found that zero-dose children in the three priority settings face differing barriers to vaccination and, therefore, require context-specific interventions, such as leveraging slum health committees for urban slums or integrating with existing humanitarian response services for conflict settings. Three predominant themes emerged for grouping the various interventions: (1) community engagement, (2) health systems' strengthening and integration, and (3) technological innovations. The barriers to reaching zero-dose children are multifaceted and nuanced to each setting, therefore, no one intervention is enough. Technological interventions especially must be coupled with community engagement and health systems' strengthening efforts. Evaluations of the suggested interventions are needed to guide scale-up, as the evidence base around these interventions is relatively small.

Increasing HIV drug resistance (DR) among children with HIV (CHIV) on antiretroviral treatment (ART) is concerning. CHIV ages 1-14 years enrolled from March 2019 to December 2020 from five facilities in Kisumu County, Kenya, were included. Children were randomized 1:1 to control (standard-of-care) or intervention (point-of-care viral load (POC VL) testing every three months with targeted genotypic drug resistance testing (DRT) for virologic failure (VF) (≥1000 copies/mL)). A multidisciplinary committee reviewed CHIV with DRT results and offered treatment recommendations. We describe DR mutations and present logistic regression models to identify factors associated with clinically significant DR. We enrolled 704 children in the study; the median age was 9 years (interquartile range (IQR) 7, 12), 344 (49%) were female, and the median time on ART was 5 years (IQR 3, 8). During the study period, 106 (15%) children had DRT results (84 intervention and 22 control). DRT detected mutations associated with DR in all participants tested, with 93 (88%) having major mutations, including 51 (54%) with dual-class resistance. A history of VF in the prior 2 years (adjusted odds ratio (aOR) 11.1; 95% confidence interval (CI) 6.3, 20.0) and less than 2 years on ART at enrollment (aOR 2.2; 95% CI 1.1, 4.4) were associated with increased odds of major DR. DR is highly prevalent among CHIV on ART with VF in Kenya. Factors associated with drug resistance may be used to determine which children should be prioritized for DRT.

Background: Pregnant women and children living with HIV in Kenya achieve viral suppression (VS) at lower rates than other adults. While many factors contribute to these low rates, the acquisition and development of HIV drug resistance mutations (DRMs) are a contributing factor. Recognizing the significance of DRMs in treatment decisions, resource-limited settings are scaling up national DRM testing programs. From provider and patient perspectives, however, optimal ways to operationalize and scale-up DRM testing in such settings remain unclear., Methods: Our mixed methods study evaluates the attitudes towards, facilitators to, and barriers to DRM testing approaches among children and pregnant women on antiretroviral therapy (ART) in five HIV treatment facilities in Kenya. We conducted 68 key informant interviews (KIIs) from December 2019 to December 2020 with adolescents, caregivers, pregnant women newly initiating ART or with a high viral load, and providers, laboratory/facility leadership, and policy makers. Our KII guides covered the following domains: (1) DRM testing experiences in routine care and through our intervention and (2) barriers and facilitators to routine and point-of-care DRM testing scale-up. We used inductive coding and thematic analysis to identify dominant themes with convergent and divergent subthemes., Results: The following themes emerged from our analysis: (1) DRM testing and counseling were valuable to clinical decision-making and reassuring to patients, with timely results allowing providers to change patient ART regimens faster; (2) providers and policymakers desired an amended and potentially decentralized DRM testing process that incorporates quicker sample-to-results turn-around-time, less burdensome procedures, and greater patient and provider "empowerment" to increase comfort with testing protocols; (3) facility-level delays, deriving from overworked facilities and sample tracking difficulties, were highlighted as areas for improvement., Conclusions: DRM testing has the potential to considerably improve patient health outcomes. Key informants recognized several obstacles to implementation and desired a more simplified, time-efficient, and potentially decentralized DRM testing process that builds provider comfort and confidence with DRM testing protocols. Further investigating the implementation, endurance, and effectiveness of DRM testing training is critical to addressing the barriers and areas of improvement highlighted in our study., Trial Registration: NCT03820323., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objectives: To define pregnancy episodes and estimate gestational age within electronic health record (EHR) data from the National COVID Cohort Collaborative (N3C)., Materials and Methods: We developed a comprehensive approach, named Hierarchy and rule-based pregnancy episode Inference integrated with Pregnancy Progression Signatures (HIPPS), and applied it to EHR data in the N3C (January 1, 2018-April 7, 2022). HIPPS combines: (1) an extension of a previously published pregnancy episode algorithm, (2) a novel algorithm to detect gestational age-specific signatures of a progressing pregnancy for further episode support, and (3) pregnancy start date inference. Clinicians performed validation of HIPPS on a subset of episodes. We then generated pregnancy cohorts based on gestational age precision and pregnancy outcomes for assessment of accuracy and comparison of COVID-19 and other characteristics., Results: We identified 628 165 pregnant persons with 816 471 pregnancy episodes, of which 52.3% were live births, 24.4% were other outcomes (stillbirth, ectopic pregnancy, abortions), and 23.3% had unknown outcomes. Clinician validation agreed 98.8% with HIPPS-identified episodes. We were able to estimate start dates within 1 week of precision for 475 433 (58.2%) episodes. 62 540 (7.7%) episodes had incident COVID-19 during pregnancy., Discussion: HIPPS provides measures of support for pregnancy-related variables such as gestational age and pregnancy outcomes based on N3C data. Gestational age precision allows researchers to find time to events with reasonable confidence., Conclusion: We have developed a novel and robust approach for inferring pregnancy episodes and gestational age that addresses data inconsistency and missingness in EHR data., Competing Interests: K.R.B. and S.L. are employees of Palantir Technologies. Y.K. and L.L. are employees of Sema4. M.N.L. is Managing Director of IPQ Analytics, LLC., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Competing Interests: None