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BackgroundWe examined the association between cannabis use and cardiovascular outcomes among the general population, among never-tobacco smokers, and among younger individuals.Methods and resultsThis is a population-based, cross-sectional study of 2016 to 2020 data from the Behavioral Risk Factor Surveillance Survey from 27 American states and 2 territories. We assessed the association of cannabis use (number of days of cannabis use in the past 30 days) with self-reported cardiovascular outcomes (coronary heart disease, myocardial infarction, stroke, and a composite measure of all 3) in multivariable regression models, adjusting for tobacco use and other characteristics in adults 18 to 74 years old. We repeated this analysis among nontobacco smokers, and among men

All-cause COVID-19 hospitalization ≤ 30 days of infection is a common outcome for severe illness in observational/surveillance studies. Milder COVID-19 disease and COVID-19-specific measurements calls for an evaluation of this endpoint. This was a descriptive, retrospective cohort study of adults ≥ 18 who were established in primary care at Veteran Health Administration (VHA) facilities. The outcome was hospitalization within 30 days of a laboratory-confirmed, symptomatic SARS-CoV-2 infection. Between December 15, 2021 and May 1, 2022, a simple random sample of all VA facilities, excluding Puerto Rico or Philippines, was drawn to identify these hospitalized cases and determine whether hospitalization was due to COVID-19-specific causes. A chart review was conducted to record the inpatient clinical team's diagnosis and whether the inpatient team classified the diagnosis as COVID-19 related or not. These data were used to classify hospitalizations as either due to COVID-19-specific causes (direct manifestations of SARS-CoV-2 infection) or non-COVID-19-specific hospitalizations (incidental SARS-CoV-2 infection), A simple random sample of 9966 (12.3%) all-cause hospitalizations (95% CI: 12.1%, 12.5%) was used to select 300 representative patients. Of these, 226/300 (75.3%) were determined to be COVID-19-specific. COVID-19 pneumonia was most common (147/226, 65.0%). The highest proportion of COVID-19-specific hospitalizations occurred among unvaccinated (85.0%), followed by vaccinated but not boosted (73.7%) and boosted (59.4%) (p

Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.

Patients from historically under-represented racial and ethnic groups are enrolled in cancer clinical trials at disproportionately low rates in the USA1-3. As these patients often have limited English proficiency4-7, we hypothesized that one barrier to their inclusion is the cost to investigators of translating consent documents. To test this hypothesis, we evaluated more than 12,000 consent events at a large cancer centre and assessed whether patients requiring translated consent documents would sign consent documents less frequently in studies lacking industry sponsorship (for which the principal investigator pays the translation costs) than for industry-sponsored studies (for which the translation costs are covered by the sponsor). Here we show that the proportion of consent events for patients with limited English proficiency in studies not sponsored by industry was approximately half of that seen in industry-sponsored studies. We also show that among those signing consent documents, the proportion of consent documents translated into the patient's primary language in studies without industry sponsorship was approximately half of that seen in industry-sponsored studies. The results suggest that the cost of consent document translation in trials not sponsored by industry could be a potentially modifiable barrier to the inclusion of patients with limited English proficiency.

Brain microglia (MG) may serve as a human immunodeficiency virus 1 (HIV) reservoir and ignite rebound viremia following cessation of antiretroviral therapy (ART), but they have yet to be proven to harbor replication-competent HIV. Here, we isolated brain myeloid cells (BrMCs) from nonhuman primates and rapid autopsy of people with HIV (PWH) on ART and sought evidence of persistent viral infection. BrMCs predominantly displayed microglial markers, in which up to 99.9% of the BrMCs were TMEM119+ MG. Total and integrated SIV or HIV DNA was detectable in the MG, with low levels of cell-associated viral RNA. Provirus in MG was highly sensitive to epigenetic inhibition. Outgrowth virus from parietal cortex MG in an individual with HIV productively infected both MG and PBMCs. This inducible, replication-competent virus and virus from basal ganglia proviral DNA were closely related but highly divergent from variants in peripheral compartments. Phenotyping studies characterized brain-derived virus as macrophage tropic based on the ability of the virus to infect cells expressing low levels of CD4. The lack of genetic diversity in virus from the brain suggests that this macrophage-tropic lineage quickly colonized brain regions. These data demonstrate that MG harbor replication-competent HIV and serve as a persistent reservoir in the brain.

Circulating tumor DNA (ctDNA) analysis may improve early-stage breast cancer treatment via non-invasive tumor burden assessment. To investigate subtype-specific differences in the clinical significance and biology of ctDNA shedding, we perform serial personalized ctDNA analysis in hormone receptor (HR)-positive/HER2-negative breast cancer and triple-negative breast cancer (TNBC) patients receiving neoadjuvant chemotherapy (NAC) in the I-SPY2 trial. ctDNA positivity rates before, during, and after NAC are higher in TNBC than in HR-positive/HER2-negative breast cancer patients. Early clearance of ctDNA 3 weeks after treatment initiation predicts a favorable response to NAC in TNBC only. Whereas ctDNA positivity associates with reduced distant recurrence-free survival in both subtypes. Conversely, ctDNA negativity after NAC correlates with improved outcomes, even in patients with extensive residual cancer. Pretreatment tumor mRNA profiling reveals associations between ctDNA shedding and cell cycle and immune-associated signaling. On the basis of these findings, the I-SPY2 trial will prospectively test ctDNA for utility in redirecting therapy to improve response and prognosis.

Prenatal antidepressant exposure has been associated with increased risk for neurodevelopmental disorders in childhood, including autism spectrum disorder (ASD). The current study utilized multi-cohort data from the Environmental influences on Child Health Outcomes (ECHO) program (N = 3129) to test for this association, and determine whether the association remained after adjusting for maternal prenatal depression and other potential confounders. Antidepressants and a subset of selective serotonin reuptake inhibitors (SSRIs) were examined in relation to binary (e.g., diagnostic) and continuous measures of ASD and ASD related traits (e.g., social difficulties, behavior problems) in children 1.5 to 12 years of age. Child sex was tested as an effect modifier. While prenatal antidepressant exposure was associated with ASD related traits in univariate analyses, these associations were statistically non-significant in models that adjusted for prenatal maternal depression and other maternal and child characteristics. Sex assigned at birth was not an effect modifier for the prenatal antidepressant and child ASD relationship. Overall, we found no association between prenatal antidepressant exposures and ASD diagnoses or traits. Discontinuation of antidepressants in pregnancy does not appear to be warranted on the basis of increased risk for offspring ASD.

ObjectivesTo identify incident SARS-CoV-2 infections and inform effective mitigation strategies in university settings, we piloted an integrated symptom and exposure monitoring and testing system among a cohort of university students and employees.DesignProspective cohort study.SettingA public university in California from June to August 2020.Participants2180 university students and 738 university employees.Primary outcome measuresAt baseline and endline, we tested participants for active SARS-CoV-2 infection via quantitative PCR (qPCR) test and collected blood samples for antibody testing. Participants received notifications to complete additional qPCR tests throughout the study if they reported symptoms or exposures in daily surveys or were selected for surveillance testing. Viral whole genome sequencing was performed on positive qPCR samples, and phylogenetic trees were constructed with these genomes and external genomes.ResultsOver the study period, 57 students (2.6%) and 3 employees (0.4%) were diagnosed with SARS-CoV-2 infection via qPCR test. Phylogenetic analyses revealed that a super-spreader event among undergraduates in congregate housing accounted for at least 48% of cases among study participants but did not spread beyond campus. Test positivity was higher among participants who self-reported symptoms (incidence rate ratio (IRR) 12.7; 95% CI 7.4 to 21.8) or had household exposures (IRR 10.3; 95% CI 4.8 to 22.0) that triggered notifications to test. Most (91%) participants with newly identified antibodies at endline had been diagnosed with incident infection via qPCR test during the study.ConclusionsOur findings suggest that integrated monitoring systems can successfully identify and link at-risk students to SARS-CoV-2 testing. As the study took place before the evolution of highly transmissible variants and widespread availability of vaccines and rapid antigen tests, further research is necessary to adapt and evaluate similar systems in the present context.

There are no drugs as effective as isotretinoin for acne. Deciphering the changes in the microbiome induced by isotretinoin in the pilosebaceous follicle of successfully treated patients can pave the way to identify novel therapeutic alternatives. We determined how the follicular microbiome changes with isotretinoin and identified which alterations correlate with a successful treatment response. Whole genome sequencing was done on casts from facial follicles of acne patients sampled before, during and after isotretinoin treatment. Alterations in the microbiome were assessed and correlated with treatment response at 20 weeks as defined as a 2-grade improvement in global assessment score. We investigated the α-diversity, β-diversity, relative abundance of individual taxa, Cutibacterium acnes strain composition and bacterial metabolic profiles with a computational approach. We found that increased β-diversity of the microbiome coincides with a successful treatment response to isotretinoin at 20 weeks. Isotretinoin selectively altered C. acnes strain diversity in SLST A and D clusters, with increased diversity in D1 strains correlating with a successful clinical response. Isotretinoin significantly decreased the prevalence of KEGG Ontology (KO) terms associated with four distinct metabolic pathways inferring that follicular microbes may have limited capacity for growth or survival following treatment. Importantly, these alterations in microbial composition or metabolic profiles were not observed in patients that failed to achieve a successful response at 20 weeks. Alternative approaches to recapitulate this shift in the balance of C. acnes strains and microbiome metabolic function within the follicle may be beneficial in the future treatment of acne.

BackgroundDecades of research have transformed hemophilia from severely limiting children's lives to a manageable disorder compatible with a full, active life, for many in high-income countries. The direction of future research will determine whether exciting developments truly advance health equity for all people with hemophilia (PWH). National Hemophilia Foundation (NHF) and American Thrombosis and Hemostasis Network conducted extensive inclusive all-stakeholder consultations to identify the priorities of people with inherited bleeding disorders and those who care for them.Research design and methodsWorking group (WG) 1 of the NHF State of the Science Research Summit distilled the community-identified priorities for hemophilia A and B into concrete research questions and scored their feasibility, impact, and risk.ResultsWG1 defined 63 top priority research questions concerning arthropathy/pain/bone health, inhibitors, diagnostics, gene therapy, the pediatric to adult transition of care, disparities faced by the community, and cardiovascular disease. This research has the potential to empower PWH to thrive despite lifelong comorbidities and achieve new standards of wellbeing, including psychosocial.ConclusionsCollaborative research and care delivery will be key to capitalizing on current and horizon treatments and harnessing technical advances to improve diagnostics and testing, to advance health equity for all PWH.

Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention.

BackgroundThe efficacy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) convalescent plasma (CCP) for preventing infection in exposed, uninfected individuals is unknown. CCP might prevent infection when administered before symptoms or laboratory evidence of infection.MethodsThis double-blinded, phase 2 randomized, controlled trial (RCT) compared the efficacy and safety of prophylactic high titer (≥1:320 by Euroimmun ELISA) CCP with standard plasma. Asymptomatic participants aged ≥18 years with close contact exposure to a person with confirmed coronavirus disease 2019 (COVID-19) in the previous 120 hours and negative SARS-CoV-2 test within 24 hours before transfusion were eligible. The primary outcome was new SARS-CoV-2 infection.ResultsIn total, 180 participants were enrolled; 87 were assigned to CCP and 93 to control plasma, and 170 transfused at 19 sites across the United States from June 2020 to March 2021. Two were excluded for screening SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) positivity. Of the remaining 168 participants, 12/81 (14.8%) CCP and 13/87 (14.9%) control recipients developed SARS-CoV-2 infection; 6 (7.4%) CCP and 7 (8%) control recipients developed COVID-19 (infection with symptoms). There were no COVID-19-related hospitalizations in CCP and 2 in control recipients. Efficacy by restricted mean infection free time (RMIFT) by 28 days for all SARS-CoV-2 infections (25.3 vs 25.2 days; P = .49) and COVID-19 (26.3 vs 25.9 days; P = .35) was similar for both groups.ConclusionsAdministration of high-titer CCP as post-exposure prophylaxis, although appearing safe, did not prevent SARS-CoV-2 infection.Clinical trials registrationNCT04323800.

BackgroundAdjuvant immune checkpoint blockade (ICB) following chemoradiotherapy and adding ICB to chemotherapy have been key advances for stages III-IV non-small cell lung cancer (NSCLC) treatment. However, known biomarkers like PD-L1 are not consistently indicative of ICB response. Other markers within the tumor immune microenvironment (TIME) may better reflect ICB response and/or resistance mechanisms, but an understanding of how TIMEs differ between stage III and IV NSCLC has not been explored.MethodsReal-world data from unresectable, stage III-IV, non-squamous, pretreatment NSCLCs (stage III n = 106, stage IV n = 285) were retrospectively analyzed. PD-L1 immunohistochemistry (IHC) was compared to CD274 gene expression. Then, differential gene expression levels, pathway enrichment, and immune infiltrate between stages were calculated from whole-transcriptome RNA-seq. Analyses were stratified by EGFR status.ResultsPD-L1 IHC and CD274 expression in tumor cells were highly correlated (n = 295, P

BackgroundCannabis is marketed as a treatment for pain. There is limited data on the prevalence of cannabis use and its correlates among Veterans prescribed opioids.ObjectiveTo examine the prevalence and correlates of cannabis use among Veterans prescribed opioids.DesignCross-sectional study.ParticipantsVeterans with a urine drug test (UDT) from Primary Care 2014-2018, in 50 states, Washington, D.C., and Puerto Rico. A total of 1,182,779 patients were identified with an opioid prescription within 90 days prior to UDT.Main measuresAnnual prevalence of cannabis positive UDT by state. We used multivariable logistic regression to assess associations of demographic factors, mental health conditions, substance use disorders, and pain diagnoses with cannabis positive UDT.ResultsAnnual prevalence of cannabis positive UDT ranged from 8.5% to 9.7% during the study period, and in 2018 was 18.15% in Washington, D.C. and 10 states with legalized medical and recreational cannabis, 6.1% in Puerto Rico and 25 states with legalized medical cannabis, and 4.5% in non-legal states. Younger age, male sex, being unmarried, and marginal housing were associated with use (p

BackgroundThe composition of the skin microbiome varies from infancy to adulthood and becomes most stable in adulthood. Adult acne patients harbour an 'acne microbiome' dominated by specific strains of Cutibacterium acnes. However, the precise timing of skin microbiome evolution, the development of the acne microbiome, and the shift to virulent C. acnes strain composition during puberty is unknown.ObjectivesWe performed a cross-sectional pilot study in a paediatric population to understand how and when the skin microbiome composition transitions during puberty and whether a distinct 'acne microbiome' emerges in paediatric subjects.MethodsForty-eight volunteers including males and females, ages 7-17 years, with and without acne were enrolled and evaluated for pubertal development using the Tanner staging criteria. Sebum levels were measured, and skin microbiota were collected by sterile swab on the subject's forehead. DNA was sequenced by whole genome shotgun sequencing.ResultsA significant shift in microbial diversity emerged between early (T1-T2) and late (T3-T5) stages of puberty, coinciding with increased sebum production on the face. The overall relative abundance of C. acnes in both normal and acne skin increased during puberty and individual C. acnes strains were uniquely affected by pubertal stage and the presence of acne. Further, an acne microbiome signature associated with unique C. acnes strain composition and metabolic activity emerges in late puberty in those with acne. This unique C. acnes strain composition is predicted to have increased porphyrin production, which may contribute to skin inflammation.ConclusionsOur data suggest that the stage of pubertal development influences skin microbiome composition. As children mature, a distinct acne microbiome composition emerges in those with acne. Understanding how both puberty and acne influence the microbiome may support novel therapeutic strategies to combat acne in the paediatric population.

IntroductionChildren who are HIV-exposed uninfected (HEU), that is, children who do not acquire HIV infection despite being born to mothers with HIV, have a higher risk of mortality, infectious morbidity and growth deficits than children who are HIV-unexposed uninfected (HUU). Prior research has focused on breast feeding and has pointed to changes in human milk oligosaccharides (HMOs) associated with maternal HIV that may influence the infant microbiome and thereby lead to these adverse outcomes. However, to our knowledge, no study has attempted to intervene along this pathway to reduce the occurrence of the adverse outcomes in children HEU. We will conduct a double-blind, randomised trial of a synbiotic intervention, which combines an HMO and probiotic, in breastfed infants HEU in South Africa to evaluate whether this intervention has promise to reduce excess infectious morbidity and growth faltering compared with controls.Methods and analysisOne hundred and forty-four breastfed infants HEU, aged 4 weeks, will be 1:1 randomised to receive either a daily synbiotic or an identical-looking placebo through age 24 weeks. Infants will be followed until age 48 weeks and outcomes of infectious morbidity, growth and biological measurements (eg, microbiota, inflammation and metabolome) will be assessed. Analyses will follow intention-to-treat principles comparing the cohorts as randomised. Infants HEU will be compared across arms with respect to the occurrence of infectious morbidity and growth outcomes through 4-24 weeks and 4-48 weeks using appropriate parametric and non-parametric statistical tests. Additionally, an observational cohort of 40 breastfed infants HUU will be recruited as a comparator group with no intervention.Ethics and disseminationEthical approval for this study has been obtained from the ethics committees at Columbia University and Stellenbosch University. The findings will be disseminated in publications.Trial registration numberClinicalTrials.gov Identifier: NCT05282485. SANCTR ID number: DOH-27-122021-6543.

The coronavirus disease 2019 (COVID-19) pandemic has created a global health crisis, with disproportionate effects on vulnerable sociodemographic groups. Although the pandemic is showing potential to increase suicide ideation (SI), we know little about which sociodemographic characteristics or COVID-19 experiences are associated with SI. Our United States-based sample (n = 837 adults [mean age = 37.1 years]) completed an online survey during August-September 2020. The study utilized an online convenience sample from a prior study, which was enriched for exposure to trauma and experiences of posttraumatic stress symptoms. We assessed SI using the Beck Depression Inventory-II. Traditional (i.e., logistic regression) and machine learning (i.e., LASSO, random forest) methods evaluated associations of 148 self-reported COVID-19 factors and sociodemographic characteristics with current SI. 234 participants (28.0%) reported SI. Twenty items were significantly associated with SI from logistic regression. Of these 20 items, LASSO identified seven sociodemographic characteristics (younger age, lower income, single relationship status, sexual orientation other than heterosexual as well as specifically identifying as bisexual, non-full-time employment, and living in a town) and six COVID-19 factors (not engaging in protective COVID-19 behaviors, receiving mental health treatment (medication and/or psychotherapy) due to the COVID-19 pandemic, socializing during the pandemic, losing one's job due to COVID-19, having a friend with COVID-19, and having an acquaintance with COVID-19) associated with SI. Random forest findings were largely consistent with LASSO. These findings may inform multidisciplinary research and intervention work focused on understanding and preventing adverse mental health outcomes such as SI during and in the aftermath of the pandemic.

BackgroundDuring the COVID-19 pandemic within the United States, much of the responsibility for diagnostic testing and epidemiologic response has relied on the action of county-level departments of public health. Here we describe the integration of genomic surveillance into epidemiologic response within Humboldt County, a rural county in northwest California.MethodsThrough a collaborative effort, 853 whole SARS-CoV-2 genomes were generated, representing ~58% of the 1,449 SARS-CoV-2-positive cases detected in Humboldt County as of March 12, 2021. Phylogenetic analysis of these data was used to develop a comprehensive understanding of SARS-CoV-2 introductions to the county and to support contact tracing and epidemiologic investigations of all large outbreaks in the county.ResultsIn the case of an outbreak on a commercial farm, viral genomic data were used to validate reported epidemiologic links and link additional cases within the community who did not report a farm exposure to the outbreak. During a separate outbreak within a skilled nursing facility, genomic surveillance data were used to rule out the putative index case, detect the emergence of an independent Spike:N501Y substitution, and verify that the outbreak had been brought under control.ConclusionsThese use cases demonstrate how developing genomic surveillance capacity within local public health departments can support timely and responsive deployment of genomic epidemiology for surveillance and outbreak response based on local needs and priorities.

BackgroundRecent studies have reignited the tinderbox of debate surrounding the use of race and ancestry in medicine. These controversial studies have argued for a strong correlation between genetic ancestry and race, justifying continued use of genetic ancestry measures in studies of disease. These studies contend that increased use of continental ancestry estimates can inform clinical risk assessments and management. Further, recent studies of racial corrections used in clinical algorithms, such as those used to estimate 'normal' lung function, also advocate for use of genetic ancestry in place of race for refining risk algorithms.Main bodyThese positions are misleading, harmful, and reflect superficial interpretations of population genetics. In this Perspective, we argue that continental genetic ancestry, often proxied by race, serves as a poor indicator of disease risk, and reinforces racialized inequities.ConclusionInstead, we endorse that racial disparities in disease should be investigated by rigorous measures of structural racism alongside careful measures of genetic factors in relevant disease pathways, rather than relying on genetic ancestry or race as a crude proxy for disease-causing alleles.

Over the course of human life, health care decision-making is often interdependent. In this article, we use "interdependence" to refer to patients' engagement of nonclinicians-for example, family members or trusted friends-to reach health care decisions. Interdependence, we suggest, is common for patients in all stages of life, from early childhood to late adulthood. This view contrasts with the common bioethical assumption that medical decisions are either wholly independent or dependent and that independence or dependence is tightly coupled with a person's decision-making capacity. In this article, we array various approaches to decision-making along a continuum of interdependence. An appreciation of this continuum can empower patients and elucidate ethical challenges that arise when people transition between different kinds of interdependence across the life span.

Rates of suicide and unintended overdose death are high among midlife and older women, yet there is paucity of data identifying women at greatest risk. Psychoactive medications, commonly prescribed and co-prescribed in this population, may serve as salient indicators of risk for these outcomes. To determine whether long-term psychoactive medications and psychoactive polypharmacy predict risk of suicide and unintended overdose death among midlife and older women Veterans above and beyond other recognized factors. Longitudinal cohort study PARTICIPANTS: Women Veterans aged ≥ 50 with at least one Veterans Health Administration (VHA) clinical encounter in FY2012-2013. Long-term psychoactive medications (opioids, benzodiazepines, sedative-hypnotics, antidepressants, antipsychotics, and antiepileptics, prescribed for ≥ 90/180 days) and psychoactive polypharmacy (overlapping for ≥ 1 day) from VHA pharmacy records; suicide and unintended overdose death through December 31, 2018. In this national sample of 154,558 midlife and older women Veterans (mean age 63.4, SD 9.3 years), 130 died by suicide and 175 died from unintentional overdose over an average of 5.6 years. In fully adjusted models, long-term opioids (hazard ratio (HR) 2.01, 95% CI 1.21-3.35) and benzodiazepines (HR 2.99, 95% CI 1.82-4.91) were associated with death by suicide; opioids (HR 3.62, 95% CI 2.46-5.34), benzodiazepines (HR 2.77, 95% CI 1.73-4.42), sedative-hypnotics (HR 1.87, 95% CI 1.06-3.29), antidepressants (HR 1.47, 95% CI 1.03-2.12), antipsychotics (HR 1.81, 95% CI 1.02-3.22), and antiepileptics (HR 2.17, 95% CI 1.48-3.19) were associated with unintended overdose death. Women who were co-prescribed ≥ 3 psychoactive medications had over 2-fold increased risk of suicide (HR 2.83, 95% CI 1.65-4.84) and unintended overdose death (HR 2.60, 95% CI 1.72-3.94). Long-term psychoactive medications and psychoactive medication polypharmacy were important indicators of risk for death by suicide and death by unintended overdose among midlife and older women Veterans, even after accounting for psychiatric and substance use disorders.

The COVID pandemic has put a spotlight on laboratory medicine, showcasing how vital diagnostic testing is for society and the health care system. It has also brought to light and accelerated the critical shortage of trained and experienced laboratory personnel that has been felt for decades. The need for laboratory professionals is expected to grow by 11% between 2020 and 2030, a higher rate of growth than the overall average for all other health care occupations. Here, the background to this workforce shortage is reviewed. Some proposed actions to help address the issue are put forth, including increasing awareness of the medical laboratory science profession along with bolstering training opportunities and awareness of alternate routes to obtaining certification as a medical laboratory scientist. In addition, recent survey data specifically related to the employee shortages in microbiology are presented which demonstrate that 80% of microbiology laboratories have vacant positions and that filling these positions is challenging for a number of reasons, including a lack of qualified applicants.

Alzheimer's disease and related dementias (ADRD) are progressive illnesses characterized by decline in cognitive function that impairs performing daily activities. People with ADRD are at an increased risk of suicide, especially those who have comorbid mental health conditions, have specific types of ADRD, or have been recently diagnosed. The coronavirus disease 2019 (COVID-19) pandemic has increased the distress of people with ADRD, a population also at increased risk of contracting the COVID-19 virus. In this article, we draw on a case study and use the Interpersonal Theory of Suicide to help describe the association between ADRD and suicide risk. Secondly, we call for new strategies to mitigate suicide risk in people living with ADRD during and beyond the current pandemic by using lessons learned from cancer care. Our goal is not to dictate solutions but rather to start the conversation by outlining a framework for future research aimed at preventing death by suicide in people with ADRD. Specifically, we draw on the updated Framework for Developing and Evaluating Complex Interventions to reflect on the complexity of the issue and to break it down into achievable parts to reduce the risk of suicidal behavior (ideation, plans, attempts) in those living with ADRD.

ObjectiveRacial/ethnic disparities in menopause symptoms and hormone therapy management remain understudied among women served by the Veteran's Health Administration, despite the unique racial/ethnic diversity of this population. Thus, we determined racial/ethnic disparities in medical record-documented menopause symptoms and prescribed menopausal hormone therapy among women veterans.MethodsWe conducted cross-sectional analyses of national Veteran's Health Administration electronic health record data from 2014 to 2015. We used logistic regression models to compare medical-record documented menopause symptoms and treatment (eg, vaginal estrogen or systemic hormone therapy) by self-identified race/ethnicity, adjusting for age, body mass index, and depression. Models examining hormone treatment were adjusted for menopause symptoms.ResultsAmong 200,901 women veterans (mean age 54.3, SD 5.4 y; 58% non-Hispanic/Latinx White, 33% non-Hispanic/Latinx Black, 4% Hispanic/Latinx, and 4% other), 5% had documented menopause symptoms, 5% were prescribed vaginal estrogen, and 5% were prescribed systemic hormone therapy. In fully adjusted multivariable models, non-Hispanic/Latinx Black women veterans had lower odds of documented menopause symptoms relative to non-Hispanic/Latinx White women (OR 0.82, 95% CI: 0.78-0.86). Moreover, non-Hispanic/Latinx Black women (OR 0.74, 95% CI: 0.70-0.77), as well as Hispanic/Latinx women (OR 0.68, 95% CI: 0.61-0.77), had lower likelihood of systemic hormone therapy prescription. Hispanic/Latinx women had higher odds of vaginal estrogen prescription (OR 1.12 95% CI: 1.02-1.24) than non-Hispanic/Latinx White women. Non-Hispanic/Latinx Black women had lower likelihood of estrogen use (OR 0.78 95% CI: 0.74-0.81) than non-Hispanic/Latinx White women.ConclusionDespite evidence suggesting higher menopause symptom burden among Black women in community samples, documented menopause symptoms and hormone therapy were less common among Black, compared with White, women veterans. Additionally, Hispanic/Latinx women veterans had lower odds of prescribed systemic menopause therapy and yet higher odds of prescribed vaginal estrogen, despite no difference in documented symptoms. These findings may signal important disparities in symptom reporting, documentation, and/or treatment for minority women veterans.

BackgroundPrevious research has revealed links between air pollution exposure and metabolic syndrome in adults; however, these associations are less explored in children.ObjectiveThis study aims to investigate the association between traffic-related air pollutants (TRAP) and biomarkers of metabolic dysregulation, oxidative stress, and lung epithelial damage in children.MethodsWe conducted cross-sectional analyses in a sample of predominantly Latinx, low-income children (n = 218) to examine associations between air pollutants (nitrogen dioxide (NO2), nitrogen oxides (NOx), elemental carbon, polycyclic aromatic hydrocarbons, carbon monoxide (CO), fine particulates (PM2.5)) and biomarkers of metabolic function (high-density lipoprotein (HDL), hemoglobin A1c (HbA1c), oxidative stress (8-isoprostane), and lung epithelial damage (club cell protein 16 (CC16)).ResultsHDL cholesterol showed an inverse association with NO2 and NOx, with the strongest relationship between HDL and 3-month exposure to NO2 (-15.4 mg/dL per IQR increase in 3-month NO2, 95% CI = -27.4, -3.4). 8-isoprostane showed a consistent pattern of increasing values with 1-day and 1-week exposure across all pollutants. Non-significant increases in % HbA1c were found during 1-month time frames and decreasing CC16 in 3-month exposure time frames.ConclusionOur results suggest that TRAP is significantly associated with decreased HDL cholesterol in longer-term time frames and elevated 8-isoprostane in shorter-term time frames. TRAP could have the potential to influence lifelong metabolic patterns, through metabolic effects in childhood.

BackgroundAccumulating evidence indicates that behaviors in Alzheimer's disease and related dementias could result in incarceration. Yet, the proportion of persons diagnosed with dementia and mild cognitive impairment (MCI) before they were incarcerated is largely unknown. By leveraging a national sample of mid- to late-life adults who were incarcerated, we determined the prevalence of dementia and MCI before their incarceration.MethodsIn this current study, participants were Medicare-eligible U.S. veterans who transitioned from incarceration to the community in mid- to late-life from October 1, 2012, to September 30, 2018, after having been incarcerated for ≤10 consecutive years (N = 17,962). Medical claims data were used to determine clinical diagnoses of dementia and MCI up to three years before incarceration. Demographics, comorbidities, and duration of incarceration among those with dementia and MCI were compared to those with neither diagnosis.ResultsParticipants were >97% male, 65% non-Hispanic white, 30% non-Hispanic black, and 3.3% had a diagnosis of either dementia (2.5%) or MCI (0.8%) before their most recent incarceration. Individuals with MCI or dementia diagnoses were older, were more likely to be non-Hispanic white, had more medical and psychiatric comorbidities, and experienced homelessness and traumatic brain injury at higher rates than those with neither diagnosis. Average duration of incarceration was significantly shorter among those with MCI (201.8 [±248.0] days) or dementia (312.8 [±548.3] days), as compared to those with neither diagnosis (497.0 [±692.7] days) (p

To determine whether the association between perceived social support or strain in close relationships and sleep outcomes varies by gender. Participants were selected from the Biomarker projects of either the MIDUS II or MIDUS Refresher study if they were in a married-or married-like relationship and shared a bed with their partner (N = 989). A subsample also participated in a seven-day sleep study (n = 282). Perceived social support and strain from partner, family, and friends were examined by self-report questionnaires. We used the Pittsburgh Sleep Quality Index, sleep daily diary, and actigraphy to measure both subjective and objective sleep. Social support and strain were both associated with sleep outcomes. Specifically, higher social support was associated with fewer daily reports of light sleep and feeling more rested in the morning, while higher social strain was associated with higher clinical sleep disturbance. For women, but not men, social support was significantly associated with lower daily sleep disturbance while perceived social strain was significantly associated with higher daily sleep disturbance, lighter sleep, feeling less rested in the morning, lower sleep efficiency, and longer sleep onset latency. Mainly among women, social support and strain are associated with an important transdiagnostic health outcome-sleep-which may have implications for a wide range of health disparities. Interpersonal stressors may increase health risks differently for women compared to men and one mechanism that may link social relationships to long-term health outcomes is sleep.

BackgroundThe interaction between cancer diagnoses and COVID-19 infection and outcomes is unclear. We leveraged a state-wide, multi-institutional database to assess cancer-related risk factors for poor COVID-19 outcomes.MethodsWe conducted a retrospective cohort study using the University of California Health COVID Research Dataset, which includes electronic health data of patients tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at 17 California medical centers. We identified adults tested for SARS-CoV-2 from 2/1/2020-12/31/2020 and selected a cohort of patients with cancer. We obtained demographic, clinical, cancer type, and antineoplastic therapy data. The primary outcome was hospitalization within 30d after the first positive SARS-CoV-2 test. Secondary outcomes were SARS-CoV-2 positivity and severe COVID-19 (intensive care, mechanical ventilation, or death within 30d after the first positive test). We used multivariable logistic regression to identify cancer-related factors associated with outcomes.ResultsWe identified 409,462 patients undergoing SARS-CoV-2 testing. Of 49,918 patients with cancer, 1781 (3.6%) tested positive. Patients with cancer were less likely to test positive (RR 0.70, 95% CI: 0.67-0.74, p

IntroductionThe COVID-19 pandemic brought an urgent need to discover novel effective therapeutics for patients hospitalised with severe COVID-19. The Investigation of Serial studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis (ISPY COVID-19 trial) was designed and implemented in early 2020 to evaluate investigational agents rapidly and simultaneously on a phase 2 adaptive platform. This manuscript outlines the design, rationale, implementation and challenges of the ISPY COVID-19 trial during the first phase of trial activity from April 2020 until December 2021.Methods and analysisThe ISPY COVID-19 Trial is a multicentre open-label phase 2 platform trial in the USA designed to evaluate therapeutics that may have a large effect on improving outcomes from severe COVID-19. The ISPY COVID-19 Trial network includes academic and community hospitals with significant geographical diversity across the country. Enrolled patients are randomised to receive one of up to four investigational agents or a control and are evaluated for a family of two primary outcomes-time to recovery and mortality. The statistical design uses a Bayesian model with 'stopping' and 'graduation' criteria designed to efficiently discard ineffective therapies and graduate promising agents for definitive efficacy trials. Each investigational agent arm enrols to a maximum of 125 patients per arm and is compared with concurrent controls. As of December 2021, 11 investigational agent arms had been activated, and 8 arms were complete. Enrolment and adaptation of the trial design are ongoing.Ethics and disseminationISPY COVID-19 operates under a central institutional review board via Wake Forest School of Medicine IRB00066805. Data generated from this trial will be reported in peer-reviewed medical journals.Trial registration numberNCT04488081.

BackgroundPolyclonal convalescent plasma may be obtained from donors who have recovered from coronavirus disease 2019 (Covid-19). The efficacy of this plasma in preventing serious complications in outpatients with recent-onset Covid-19 is uncertain.MethodsIn this multicenter, double-blind, randomized, controlled trial, we evaluated the efficacy and safety of Covid-19 convalescent plasma, as compared with control plasma, in symptomatic adults (≥18 years of age) who had tested positive for severe acute respiratory syndrome coronavirus 2, regardless of their risk factors for disease progression or vaccination status. Participants were enrolled within 8 days after symptom onset and received a transfusion within 1 day after randomization. The primary outcome was Covid-19-related hospitalization within 28 days after transfusion.ResultsParticipants were enrolled from June 3, 2020, through October 1, 2021. A total of 1225 participants underwent randomization, and 1181 received a transfusion. In the prespecified modified intention-to-treat analysis that included only participants who received a transfusion, the primary outcome occurred in 17 of 592 participants (2.9%) who received convalescent plasma and 37 of 589 participants (6.3%) who received control plasma (absolute risk reduction, 3.4 percentage points; 95% confidence interval, 1.0 to 5.8; P = 0.005), which corresponded to a relative risk reduction of 54%. Evidence of efficacy in vaccinated participants cannot be inferred from these data because 53 of the 54 participants with Covid-19 who were hospitalized were unvaccinated and 1 participant was partially vaccinated. A total of 16 grade 3 or 4 adverse events (7 in the convalescent-plasma group and 9 in the control-plasma group) occurred in participants who were not hospitalized.ConclusionsIn participants with Covid-19, most of whom were unvaccinated, the administration of convalescent plasma within 9 days after the onset of symptoms reduced the risk of disease progression leading to hospitalization. (Funded by the Department of Defense and others; CSSC-004 ClinicalTrials.gov number, NCT04373460.).

BackgroundChildren with isolated cleft of the lip and/or palate (iCL/P) are at a higher risk for language and reading issues. The current pilot study evaluated concurrent writing skills of children with iCL/P compared to unaffected participants with average (uAR) and impaired (uIR) reading. It was hypothesized that children with iCL/P would perform lower than age-expectations.MethodsTwenty-three males, aged 8-11 years old, were recruited through clinics, local advertisements, and state dyslexia groups (iCL/P = 7, uAR = 8, uIR = 8). Group differences on measures of cognitive processes and writing were evaluated using ANCOVA. Relationships between these measures were compared for each group through Pearson correlations.ResultsParticipants with iCL/P performed within the average range across all measures; group differences were only found for the uIR group. For those with iCL/P, writing was correlated to global cognitive skills rather than more specific skills.ConclusionsWhile this small sample of children with iCL/P demonstrated average writing skills, patterns suggest performance is related to global cognitive reasoning rather than specific cognitive processes as found in unaffected children with impaired reading. Further research is needed to better understand writing in iCL/P and the relationship to reading and cognitive processes.ImpactResearch in children with isolated cleft of the lip and/or palate (iCL/P) has demonstrated higher rates of language and reading disorders. No work has assessed written expression in children with iCL/P in over 40 years. This study is the first to evaluate elements of written expression and associated cognitive processes among children with iCL/P in comparison to unaffected children with either average or impaired reading skills. Measures of writing were within the average range for children with iCL/P and demonstrated correlation to global cognitive reasoning rather than to specific cognitive processes as found in unaffected children with impaired reading.

Background and objectivesSuccessful clinical integration of genomic sequencing (GS) requires evidence of its utility. While GS potentially has benefits (utilities) or harms (disutilities) across multiple domains of life for both patients and their families, there is as yet no empirically informed conceptual model of these effects. Our objective was to develop an empirically informed conceptual model of perceived utility of GS that captures utilities and disutilities for patients and their families across diverse backgrounds.MethodsWe took a patient-centered approach, in which we began with a review of existing literature followed by collection of primary interview data. We conducted semi-structured interviews to explore types of utility in a clinically and sociopolitically diverse sample of 60 adults from seven Clinical Sequencing Evidence-Generating Research (CSER) consortium projects. Interviewees had either personally received, or were parents of a child who had received, GS results. Qualitative data were analyzed using thematic analysis. Findings from interviews were integrated with existing literature on clinical and personal utility to form the basis of an initial conceptual model that was refined based on expert review and feedback.ResultsFive key utility types that have been previously identified in qualitative literature held up as primary domains of utility and disutility in our diverse sample. Interview data were used to specify and organize subdomains of an initial conceptual model. After expert refinement, the five primary domains included in the final model are clinical, emotional, behavioral, cognitive, and social, and several subdomains are specified within each.ConclusionWe present an empirically informed conceptual model of perceived utility of GS. This model can be used to guide development of instruments for patient-centered outcome measurement that capture the range of relevant utilities and disutilities and inform clinical implementation of GS.

The objective is to determine patients' utilization rate of radiology image viewing through an online patient portal and to understand its impact on radiologists. IRB approval was waived. In this two-part, multi-institutional study, patients' image viewing rate was retrospectively assessed, and radiologists were anonymously surveyed for the impact of patient imaging access on their workflow. Patient access to web-based image viewing via electronic patient portals was enabled at 3 institutions (all had open radiology reports) within the past 5 years. The number of exams viewed online was compared against the total number of viewable imaging studies. An anonymized survey was distributed to radiologists at the 3 institutions, and responses were collected over 2 months. Patients viewed 14.2% of available exams - monthly open rate varied from 7.3 to 41.0%. A total of 254 radiologists responded to the survey (response rate 32.8%); 204 were aware that patients could view images. The majority (155/204; 76.0%) felt no impact on their role as radiologists; 11.8% felt negative and 9.3% positive. The majority (63.8%) were never approached by patients. Of the 86 who were contacted, 46.5% were contacted once or twice, 46.5% 3-4 times a year, and 4.7% 3-4 times a month. Free text comments included support for healthcare transparency (71), concern for patient confusion and anxiety (45), and need for attention to radiology reports and image annotations (15). A small proportion of patients viewed their radiology images. Overall, patients' image viewing had minimal impact on radiologists. Radiologists were seldom contacted by patients. While many radiologists feel supportive, some are concerned about causing patient confusion and suggest minor workflow modifications.

Pandemic mitigation measures may lead to excess weight gain in children. Our objective was to assess weight gain during the COVID-19 pandemic in children of ages 4-12 years with overweight and obesity in San Francisco, CA. Children with BMI ≥85th percentile measured at a clinic visit from January to March 2020 were recruited. Follow-up BMI measurements were obtained between October 2020 and March 2021 from the electronic medical record or through a video study visit. Pre- and post-BMI measurements were obtained on n = 91 participants. The majority were Latino (85%) and publicly insured (91%). Mean monthly weight gain was 0.73 kg [standard deviation (SD) 0.47], equivalent to yearly weight gain of 8.8 kg. Mean monthly change in BMI z-score was 0.02 (SD 0.04) equivalent to yearly increase in BMI-z of 0.24. Weight gain among children in San Francisco with overweight and obesity during the COVID-19 pandemic far exceeded healthy weight gain for this age group.

BackgroundDuring the COVID-19 pandemic, federal and state governments removed the scope of practice restrictions on nurse practitioners (NPs), allowing them to deliver care to patients without restrictions.PurposeTo support policy makers' efforts to grant full practice authority to NPs beyond the COVID-19 pandemic, this manuscript summarizes the existing evidence on the benefits of permanently removing state-level scope of practice barriers and outline recommendations for policy, practice, and research.MethodsWe have conducted a thorough review of the existing literature.FindingsNP full scope of practice improves access and quality of care and leads to better patient outcomes. It also has the potential to reduce health care cost.DiscussionThe changes to support full practice authority enacted to address COVID-19 are temporary. NP full practice authority could be part of a longer-term plan to address healthcare inequities and deficiencies rather than merely a crisis measure.

IntroductionCancer is the second leading cause of death among women in the United States. Previous studies demonstrate a higher prevalence of cancer among female orthopaedic surgeons. This study aimed to provide an updated prevalence of breast and all-cause cancer among female orthopaedic surgeons using a larger and more current study population.MethodsWe distributed surveys to female orthopaedic surgeons in national orthopaedic specialty societies. Six hundred seventy-two survey responses were collected. We calculated standardized prevalence ratios (SPRs) and 95% confidence intervals (CIs) based on gender-specific, race-specific, and age-specific cancer prevalence statistics in the US population. We compared the distribution of breast cancer risk factors with that of women in the 2018 and 2009 California Health Interview Survey.ResultsFifty-one of the 672 surveyed surgeons reported a diagnosis of invasive cancer. Twenty reported breast cancer with a prevalence higher among female orthopaedic surgeons compared with the US female population (SPR: 2.89, 95% CI: 2.16 to 3.81, P < 0.001). The breast cancer prevalence was also higher among orthopaedic surgeons compared with the US female population (SPR: 3.97, 95% CI: 2.43 to 6.14, P = 0.003).DiscussionThe increased prevalence of breast and all-cause cancer among a larger and more diverse cohort of female orthopaedic surgeons confirms previous studies and provides an update regarding a concerning public health issue within this specialty.

BackgroundPrevious research has found that social risk factors are associated with an increased risk of 30-day readmission. We aimed to assess the association of 5 social risk factors (living alone, lack of social support, marginal housing, substance abuse, and low income) with 30-day Heart Failure (HF) hospital readmissions within the Veterans Health Affairs (VA) and the impact of their inclusion on hospital readmission model performance.MethodsWe performed a retrospective cohort study using chart review and VA and Centers for Medicare and Medicaid Services (CMS) administrative data from a random sample of 1,500 elderly (≥ 65 years) Veterans hospitalized for HF in 2012. Using logistic regression, we examined whether any of the social risk factors were associated with 30-day readmission after adjusting for age alone and clinical variables used by CMS in its 30-day risk stratified readmission model. The impact of these five social risk factors on readmission model performance was assessed by comparing c-statistics, likelihood ratio tests, and the Hosmer-Lemeshow goodness-of-fit statistic.ResultsThe prevalence varied among the 5 risk factors; low income (47 % vs. 47 %), lives alone (18 % vs. 19 %), substance abuse (14 % vs. 16 %), lacks social support (2 % vs.

IntroductionThyroid dysfunction is the most frequent endocrine immune related adverse event (irAE) in non-small cell lung cancer (NSCLC), typically arising 3-6 months into immune checkpoint inhibitor (ICI) therapy, but arising after ICI cessation, in some cases. Due to limited post-treatment adverse event reporting requirements on ICI trials, the incidence of ICI-induced thyroid dysfunction arising after therapy is unclear. We investigated ICI-induced thyroid dysfunction in a cohort of 294 NSCLC patients, with a specific focus on the post-treatment setting.MethodsRetrospective analysis of ICI-induced thyroid dysfunction (clinically acted upon or laboratory only) was performed in 294 UCLA NSCLC patients treated 2012-2018. Clinically acted upon thyroid dysfunction was defined as thyroid diagnosis documentation and/or thyroid medication administration. Laboratory only dysfunction was defined as abnormal thyroid labs in the absence of clinical action. Timing of thyroid dysfunction relative to ICI treatment and thyroid monitoring patterns were also assessed.Results82% (241/294) of ICI treated NSCLC patients had thyroid labs during treatment. Of these 241 patients, 13% (31/241) had clinically acted upon thyroid dysfunction prior to, 8% (18/241) during, and 4% (9/241) after ICI. Most patients, 66% (159/241), did not have thyroid labs after ICI, but in the 53 patients with labs and no prior clinical dysfunction, 17% (9/53) developed clinical dysfunction after ICI. In these 9 patients, median time from ICI initiation to dysfunction was 253 days. Two patients with post-treatment laboratory only dysfunction were observed.ConclusionsICI-induced thyroid dysfunction arising post-treatment appears more common than previously appreciated, warranting additional evaluation.

Prior to integration into clinical care, a novel medical innovation is typically assessed in terms of its balance of benefits and risks, often referred to as utility. Members of multidisciplinary research teams may conceptualize and assess utility in different ways, which has implications within the translational genomics community and for the evidence base upon which clinical guidelines groups and healthcare payers make decisions. Ambiguity in the conceptualization of utility in translational genomics research can lead to communication challenges within research teams and to study designs that do not meet stakeholder needs. We seek to address the ambiguity challenge by describing the conceptual understanding of utility and use of the term by scholars in the fields of philosophy, medicine, and the social sciences of decision psychology and health economics. We illustrate applications of each field's orientation to translational genomics research by using examples from the Clinical Sequencing Evidence-Generating Research (CSER) consortium, and we provide recommendations for increasing clarity and cohesion in future research. Given that different understandings of utility will align to a greater or lesser degree with important stakeholders' views, more precise use of the term can help researchers to better integrate multidisciplinary investigations and communicate with stakeholders.

ObjectiveTo understand the impact of the coronavirus disease 2019 (COVID-19) pandemic on parental perceptions of health behaviors and food insecurity among children with overweight and obesity living in San Francisco and to assess the relationship between food insecurity and dietary intake during the pandemic.MethodsParents of children ages 4 to 12 in San Francisco with body mass index ≥85th percentile measured at a clinic visit at a Federally Qualified Health Center or academic practice from January 1st to March 15th, 2020 were eligible to participate. Parents completed a survey reporting on child health behaviors and household food insecurity prior to and since the start of the pandemic. Survey items were abstracted from validated surveys with adaptations. Regression models evaluated associations between food insecurity and dietary intake variables.ResultsMost participants (n = 145) were publicly insured (90%), Latino (77%), and spoke Spanish at home (70%). Parents perceived that child mean daily nonacademic screen time was higher during the pandemic compared to before (3.8 hours vs 1.6 hours). Mean daily physical activity was reported to be lower compared to prior to the pandemic (1 hour vs 1.8 hours). On average, reported bedtime shifted 1.6 hours later. Food insecurity increased significantly but was not associated with intake of fruits, vegetables, sugar-sweetened beverages, or foods with added sugar during the pandemic.ConclusionsParents of children with overweight or obesity in San Francisco perceive increased child screen time, decreased physical activity and later bedtimes during the COVID-19 pandemic. Findings suggest a need for policies that support healthy lifestyle behaviors among low-income children during the pandemic.

The development of the National Institutes of Health (NIH) COVID-19 Treatment Guidelines began in March 2020 in response to a request from the White House Coronavirus Task Force. Within 4 days of the request, the NIH COVID-19 Treatment Guidelines Panel was established and the first meeting took place (virtually-as did subsequent meetings). The Panel comprises 57 individuals representing 6 governmental agencies, 11 professional societies, and 33 medical centers, plus 2 community members, who have worked together to create and frequently update the guidelines on the basis of evidence from the most recent clinical studies available. The initial version of the guidelines was completed within 2 weeks and posted online on 21 April 2020. Initially, sparse evidence was available to guide COVID-19 treatment recommendations. However, treatment data rapidly accrued based on results from clinical studies that used various study designs and evaluated different therapeutic agents and approaches. Data have continued to evolve at a rapid pace, leading to 24 revisions and updates of the guidelines in the first year. This process has provided important lessons for responding to an unprecedented public health emergency: Providers and stakeholders are eager to access credible, current treatment guidelines; governmental agencies, professional societies, and health care leaders can work together effectively and expeditiously; panelists from various disciplines, including biostatistics, are important for quickly developing well-informed recommendations; well-powered randomized clinical trials continue to provide the most compelling evidence to guide treatment recommendations; treatment recommendations need to be developed in a confidential setting free from external pressures; development of a user-friendly, web-based format for communicating with health care providers requires substantial administrative support; and frequent updates are necessary as clinical evidence rapidly emerges.

The pioneer transcription factor (TF) PU.1 controls hematopoietic cell fate by decompacting stem cell heterochromatin and allowing nonpioneer TFs to enter otherwise inaccessible genomic sites. PU.1 deficiency fatally arrests lymphopoiesis and myelopoiesis in mice, but human congenital PU.1 disorders have not previously been described. We studied six unrelated agammaglobulinemic patients, each harboring a heterozygous mutation (four de novo, two unphased) of SPI1, the gene encoding PU.1. Affected patients lacked circulating B cells and possessed few conventional dendritic cells. Introducing disease-similar SPI1 mutations into human hematopoietic stem and progenitor cells impaired early in vitro B cell and myeloid cell differentiation. Patient SPI1 mutations encoded destabilized PU.1 proteins unable to nuclear localize or bind target DNA. In PU.1-haploinsufficient pro-B cell lines, euchromatin was less accessible to nonpioneer TFs critical for B cell development, and gene expression patterns associated with the pro- to pre-B cell transition were undermined. Our findings molecularly describe a novel form of agammaglobulinemia and underscore PU.1's critical, dose-dependent role as a hematopoietic euchromatin gatekeeper.

IntroductionLatino adolescents experience high rates of obesity and physical activity can protect against obesity and obesity comorbidities. Health interventions to promote physical activity are more likely to be successful if they take into account the experiences and perspectives of their target population. Our study objective was to explore barriers and facilitators to physical activity among Latino adolescents with the goal of informing future interventions for this population.MethodSemistructured interviews were conducted with (n = 30) low-income, Latino adolescents. The interviews were analyzed using inductive methods and the Capability-Opportunity-Motivation model of behavior.ResultsAdolescents described capability gaps including lacking skills for preferred activities. School physical education and parks provided opportunities for adolescents to be physically active. Adolescents also described opportunity challenges, including age limits, not being able to afford preferred classes, and safety concerns. Families provided role modeling but rarely engaged in activities with adolescents. Adolescents were motivated to engage in physical activity but often lacked the necessary resources.ConclusionsInterventions to increase physical activity among urban Latino adolescents should offer tailored programming, incorporate families, enhance physical education, and improve the safety and appeal of recreational facilities.

One prominent social-cognitive model of internalized stigma by Corrigan and his colleagues (2012; 2002) proposes that individuals are exposed to societal stereotypes about mental illness, at least tacitly agree with them, and may apply them to oneself, engendering harmful self-beliefs. There is limited empirical support for this model in serious mental illness. Moreover, it is not clearly established how internalized stigma and its associated factors impact recovery in this population. The current study uses structural equation modeling (SEM) to assess the social-cognitive model's goodness of fit in a sample of Veterans with serious mental illness (Veteran sample, n = 248), and then validates the model in a second and independent sample of individuals receiving community-based psychiatric rehabilitation services (community sample, n = 267). Participants completed the Self-Stigma of Mental Illness Scale (SSMIS; Corrigan et al., 2006) and measures of self-esteem, self-efficacy, and recovery attitudes. Consistent with Corrigan and colleagues' formulation of internalized stigma, SEM analyses showed a significant indirect pathway from stereotype awareness, to stereotype agreement, to application to self, to self-esteem decrement, to poorer recovery attitudes. Additionally, there was a significant direct effect from stereotype awareness to self-esteem. This study shows that individuals with serious mental illness experience psychological harm from stigma in two ways: (1) through perceived public prejudice and bias, and (2) through internalizing these negative messages. In particular, stigma harms individuals' self-esteem, which then reduces their recovery attitudes.

Cystic fibrosis (CF) is a lethal autosomal recessive disorder that afflicts more than 70,000 people. People with CF experience multi-organ dysfunction resulting from aberrant electrolyte transport across polarized epithelia due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CF-related lung disease is by far the most important determinant of morbidity and mortality. Here we report results from a multi-institute consortium in which single-cell transcriptomics were applied to define disease-related changes by comparing the proximal airway of CF donors (n = 19) undergoing transplantation for end-stage lung disease with that of previously healthy lung donors (n = 19). Disease-dependent differences observed include an overabundance of epithelial cells transitioning to specialized ciliated and secretory cell subsets coupled with an unexpected decrease in cycling basal cells. Our study yields a molecular atlas of the proximal airway epithelium that will provide insights for the development of new targeted therapies for CF airway disease.

Advising patients before air travel is a frequently overlooked, but important, role of the physician, particularly primary care providers and pulmonary specialists. Although physiologic changes occur in all individuals during air travel, those with underlying pulmonary disease are at increased risk of serious complications and require a specific approach to risk stratification. We discuss the available tools for assessment of preflight risk and strategies to minimize potential harm. We also present a case discussion to illustrate our approach to assessing patients for air travel and discuss the specific conditions that should prompt a more thorough preflight workup.

BackgroundWe examined the prognostic significance of circulating tumor cell (CTC) dynamics during treatment in metastatic breast cancer (MBC) patients receiving first-line chemotherapy.MethodsSerial CTC data from 469 patients (2202 samples) were used to build a novel latent mixture model to identify groups with similar CTC trajectory (tCTC) patterns during the course of treatment. Cox regression was used to estimate hazard ratios for progression-free survival (PFS) and overall survival (OS) in groups based on baseline CTCs, combined CTC status at baseline to the end of cycle 1, and tCTC. Akaike information criterion was used to select the model that best predicted PFS and OS.ResultsLatent mixture modeling revealed 4 distinct tCTC patterns: undetectable CTCs (56.9% ), low (23.7%), intermediate (14.5%), or high (4.9%). Patients with low, intermediate, and high tCTC patterns had statistically significant inferior PFS and OS compared with those with undetectable CTCs (P < .001). Akaike Information Criterion indicated that the tCTC model best predicted PFS and OS compared with baseline CTCs and combined CTC status at baseline to the end of cycle 1 models. Validation studies in an independent cohort of 1856 MBC patients confirmed these findings. Further validation using only a single pretreatment CTC measurement confirmed prognostic performance of the tCTC model.ConclusionsWe identified 4 novel prognostic groups in MBC based on similarities in tCTC patterns during chemotherapy. Prognostic groups included patients with very poor outcome (intermediate + high CTCs, 19.4%) who could benefit from more effective treatment. Our novel prognostic classification approach may be used for fine-tuning of CTC-based risk stratification strategies to guide future prospective clinical trials in MBC.

ObjectiveTo explore multi-clinician perspectives on intensive care early mobility, monitoring and to assess the perceived value of technology-generated mobility metrics to provide user feedback to inform research, practice improvement, and technology development.MethodsWe performed a qualitative descriptive study. Three focus groups were conducted with critical care clinicians, including nurses (n = 10), physical therapists (n = 8) and physicians (n = 8) at an academic medical centre that implemented an intensive care early mobility programme in 2012. Qualitative thematic analysis was used to code transcripts and identify overarching themes.FindingsAlong with reaffirming the value of performing early mobility interventions, four themes for improving mobility monitoring emerged, including the need for: 1) standardised indicators for documenting mobility; 2) inclusion of both quantitative and qualitative metrics to measure mobility 3) a balance between quantity and quality of data; and 4) trending mobility metrics over time.ConclusionIntensive care mobility monitoring should be standardised and data generated should be high quality, capable of supporting trend analysis, and meaningful. By improving measurement and monitoring of mobility, future researchers can examine the arc of activity that patients in the intensive care unit undergo and develop models to understand factors that influence successful implementation.

ObjectiveTo test the hypothesis that veterans with traumatic brain injury (TBI) have an increased subsequent risk of sleep disorders, we studied the longitudinal association between TBI and incident sleep disorders in nearly 200,000 veterans.MethodsWe performed a cohort study of all patients diagnosed with a TBI in the Veterans Health Administration system from October 1, 2001, to September 30, 2015, who were age-matched 1:1 to veterans without TBI. Veterans with prevalent sleep disorders at baseline were excluded. Development of sleep disorders was defined as any inpatient or outpatient diagnosis of sleep apnea, hypersomnia, insomnia, or sleep-related movement disorders based on ICD-9 codes after the first TBI diagnosis or the random selection date for those without TBI. We restricted the analysis to those with at least 1 year of follow-up. We used Cox proportional hazards models to examine the association between TBI and subsequent risk of sleep disorders.ResultsThe study included 98,709 veterans with TBI and 98,709 age-matched veterans without TBI (age 49 ± 20 years). After an average follow-up of 5 (1-14) years, 23,127 (19.6%) veterans developed sleep disorders. After adjustment for demographics, education, income, and medical and psychiatric conditions, those who had TBI compared to those without TBI were 41% more likely to develop any sleep disorders (hazard ratio 1.41 [95% confidence interval 1.37-1.44]), including sleep apnea (1.28 [1.24-1.32]), insomnia (1.50 [1.45-1.55]), hypersomnia (1.50 [1.39-1.61]), and sleep-related movement disorders (1.33 [1.16-1.52]). The association was stronger for mild TBIs, did not differ appreciably by presence of posttraumatic stress disorder, and remained after a 2-year time lag.ConclusionIn 197,418 veterans without sleep disorders, those with diagnosed TBI had an increased risk of incident sleep disorders over 14 years. Improved prevention and long-term management strategies for sleep are needed for veterans with TBI.