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Sterile inflammation after myocardial infarction is classically credited to myeloid cells interacting with dead cell debris in the infarct zone1,2. Here we show that cardiomyocytes are the dominant initiators of a previously undescribed type I interferon response in the infarct borderzone. Using spatial transcriptomics analysis in mice and humans, we find that myocardial infarction induces colonies of interferon-induced cells (IFNICs) expressing interferon-stimulated genes decorating the borderzone, where cardiomyocytes experience mechanical stress, nuclear rupture and escape of chromosomal DNA. Cardiomyocyte-selective deletion of Irf3 abrogated IFNIC colonies, whereas mice lacking Irf3 in fibroblasts, macrophages, neutrophils or endothelial cells, Ccr2-deficient mice or plasmacytoid-dendritic-cell-depleted mice did not. Interferons blunted the protective matricellular programs and contractile function of borderzone fibroblasts, and increased vulnerability to pathological remodelling. In mice that died after myocardial infarction, IFNIC colonies were immediately adjacent to sites of ventricular rupture, while mice lacking IFNICs were protected from rupture and exhibited improved survival3. Together, these results reveal a pathological borderzone niche characterized by a cardiomyocyte-initiated innate immune response. We suggest that selective inhibition of IRF3 activation in non-immune cells could limit ischaemic cardiomyopathy while avoiding broad immunosuppression.

BACKGROUND: To interrupt residual malaria transmission and achieve successful elimination of Plasmodium falciparum in low-transmission settings, the World Health Organization (WHO) recommends the administration of a single dose of 0.25 mg/kg (or 15 mg/kg for adults) primaquine (PQ) combined with artemisinin-based combination therapy (ACT), without glucose-6-phosphate dehydrogenase (G6PD) testing. However, due to the risk of haemolysis in patients with G6PD deficiency (G6PDd), PQ use is uncommon. Thus, this study aimed to assess the safety of a single low dose of PQ administered to patients with G6PD deficiency. METHODS: An observational cohort study was conducted with patients treated for uncomplicated P. falciparum malaria with either single-dose PQ (0.25 mg/kg) (SLD PQ) + ACT or ACT alone. Microscopy-confirmed uncomplicated P. falciparum malaria patients visiting public health facilities in Arjo Didessa, Southwest Ethiopia, were enrolled in the study from September 2019 to November 2022. Patients with uncomplicated P. falciparum malaria were followed up for 28 days through clinical and laboratory diagnosis, such as measurements of G6PD levels and haemoglobin (Hb) concentrations. G6PD levels were measured by a quantiative CareSTART™ POCT S1 biosensor machine. Patient interviews were also conducted, and the type and frequency of clinical complaints were recorded. Hb data were taken on days (D) 7, 14, 21, and 28 following treatment with SLD-PQ + ACT or ACT alone. RESULTS: A total of 249 patients with uncomplicated P. falciparum malaria were enrolled in this study. Of these, 83 (33.3%) patients received ACT alone, and 166 (66.7%) received ACT combined with SLD-PQ treatment. The median age of the patients was 20 (IQR 28-15) years. G6PD deficiency was found in 17 (6.8%) patients, 14 males and 3 females. There were 6 (7.2%) and 11 (6.6%) phenotypic G6PD-deficient patients in the ACT alone and ACT + SLD-PQ arms, respectively. The mean Hb levels in patients treated with ACT + SLD-PQ were reduced by an average of 0.45 g/dl (95% CI = 0.39 to 0.52) in the posttreatment phase (D7) compared to a reduction of 0.30 g/dl (95% CI = 0.14 to - 0.47) in patients treated with ACT alone (P = 0.157). A greater mean Hb reduction was observed on day 7 in the G6PDd ACT + SLD-PQ group (- 0.60 g/dL) than in the G6PDd ACT alone group (- 0.48 g/dL); however, there was no statistically significant difference (P = 0.465). Overall, D14 losses were 0.10 g/dl (95% CI = - 0.00 to 0.20) and 0.05 g/dl (95% CI = - 0.123 to 0.22) in patients with and without SLD-PQ, respectively (P = 0.412). CONCLUSIONS: This studys findings indicate that using SLD-PQ in combination with ACT is safe for uncomplicated P. falciparum malaria regardless of the patients G6PD status in Ethiopian settings. Caution should be taken in extrapolating this finding in other settings with diverse G6DP phenotypes.

ObjectivePatients with relapsed or metastatic head and neck squamous cell carcinoma (HNSCC) after primary local therapy have low response rates with cetuximab, systemic chemotherapy or check point inhibitor therapy. Novel combination therapies with the potential to improve outcomes for patients with HNSCC is an area of high unmet need.MethodsThis is a phase II single-arm clinical trial of locally advanced or metastatic HNSCC patients treated with a combination of soluble EphB4-human serum albumin (sEphB4-HSA) fusion protein and pembrolizumab after platinum-based chemotherapy with up to 2 prior lines of treatment. The primary endpoints were safety and tolerability and the primary efficacy endpoint was overall response rate (ORR). Secondary endpoints included progression free survival (PFS) and overall survival (OS). HPV status and EphrinB2 expression were evaluated for outcome.ResultsTwenty-five patients were enrolled. Median follow up was 40.4 months (range 9.8 - 40.4). There were 6 responders (ORR 24%). There were 5 responders in the 11 HPV-negative and EphrinB2 positive patients, (ORR 45%) with 2 of these patients achieving a complete response (CR). The median PFS in HPV-negative/EphrinB2 positive patients was 3.2 months (95% CI 1.1, 7.3). Median OS in HPV-negative/EphrinB2 positive patients was 10.9 months (95% CI 2.0, 13.7). Hypertension, transaminitis and fatigue were the most common toxicities.DiscussionThe combination of sEphB4-HSA and pembrolizumab has a favorable toxicity profile and favorable activity particularly among HPV-negative EphrinB2 positive patients with HNSCC.

Although the cerebellum contributes to higher-order cognitive and emotional functions relevant to posttraumatic stress disorder (PTSD), prior research on cerebellar volume in PTSD is scant, particularly when considering subregions that differentially map on to motor, cognitive, and affective functions. In a sample of 4215 adults (PTSD n = 1642; Control n = 2573) across 40 sites from the ENIGMA-PGC PTSD working group, we employed a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation to obtain volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum volumes in PTSD compared to healthy controls (88% trauma-exposed). PTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume, as well as reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), vermis (VI, VIII), flocculonodular lobe (lobule X), and corpus medullare (all p-FDR

BackgroundPrior research suggests that physicians' personal experience with breastfeeding may influence their attitudes toward breastfeeding. This phenomenon has not been explored in well-newborn care physician leaders, whose administrative responsibilities often include drafting and approval of hospital breastfeeding and formula supplementation policies.MethodsWe conducted a mixed-methods study, surveying physicians in the Better Outcomes through Research for Newborns (BORN) network. We examined physician attitudes toward recommending breastfeeding and their breastfeeding experience. Qualitative analysis was conducted on responses to the question: "How do you think your breastfeeding experience influences your clinical practice?"ResultsOf 71 participants, most (92%) had a very positive attitude toward breastfeeding with 75% of respondents reporting personal experience with breastfeeding. Of these, 68% had a very positive experience, 25% had a somewhat positive experience, and 6% had a neutral experience. Four themes emerged with respect to the effect of breastfeeding experience on practice: (1) empathy with breastfeeding struggles, (2) increased knowledge and skills, (3) passion for breastfeeding benefits, and (4) application of personal experience in lieu of evidence-based medicine, particularly among those who struggled with breastfeeding.ConclusionsWell-newborn care physician leaders reported positive attitudes about breastfeeding, increased support toward breastfeeding persons, and a perception of improved clinical lactation skills. Those who struggled with breastfeeding reported increased comfort with recommending formula supplementation to their own patients. Medical education about evidence-based breastfeeding support practices and provision of lactation support to physicians has the potential to affect public health through improved care for the patients they serve.

Hydroxyurea reduces sickle cell disease (SCD) complications, but medication adherence is low. We tested 2 mobile health (mHealth) interventions targeting determinants of low adherence among patients (InCharge Health) and low prescribing among providers (HU Toolbox) in a multi-center, non-randomized trial of individuals with SCD ages 15-45. We compared the percentage of days covered (PDC), labs, healthcare utilization, and self-reported pain over 24 weeks of intervention and 12 weeks post-study with a 24-week preintervention interval. We enrolled 293 patients (51% male; median age 27.5 years, 86.8% HbSS/HbSβ0-thalassemia). The mean change in PDC among 235 evaluable subjects increased (39.7% to 56.0%; P < 0.001) and sustained (39.7% to 51.4%, P < 0.001). Mean HbF increased (10.95% to 12.78%; P = 0.03). Self-reported pain frequency reduced (3.54 to 3.35 events/year; P = 0.041). InCharge Health was used ≥1 day by 199 of 235 participants (84.7% implementation; median usage: 17% study days; IQR: 4.8-45.8%). For individuals with ≥1 baseline admission for pain, admissions per 24 weeks declined from baseline through 24 weeks (1.97 to 1.48 events/patient, P = 0.0045) and weeks 25-36 (1.25 events/patient, P = 0.0015). PDC increased with app use (P < 0.001), with the greatest effect in those with private insurance (P = 0.0078), older subjects (P = 0.033), and those with lower pain interference (P = 0.0012). Of the 89 providers (49 hematologists, 36 advanced care providers, 4 unreported), only 11.2% used HU Toolbox ≥1/month on average. This use did not affect change in PDC. Tailoring mHealth solutions to address barriers to hydroxyurea adherence can potentially improve adherence and provide clinical benefits. A definitive randomized study is warranted. This trial was registered at www.clinicaltrials.gov as #NCT04080167.

BackgroundStatins lower circulating low-density lipoprotein cholesterol (LDLC) levels and reduce cardiovascular disease risk. Though highly efficacious in general, there is considerable inter-individual variation in statin efficacy that remains largely unexplained.MethodsTo identify novel genes that may modulate statin-induced LDLC lowering, we used RNA-sequencing data from 426 control- and 2 µM simvastatin-treated lymphoblastoid cell lines (LCLs) derived from European and African American ancestry participants of the Cholesterol and Pharmacogenetics (CAP) 40 mg/day 6-week simvastatin clinical trial (ClinicalTrials.gov Identifier: NCT00451828). We correlated statin-induced changes in LCL gene expression with plasma LDLC statin response in the corresponding CAP participants. For the most correlated gene identified (ZNF335), we followed up in vivo by comparing plasma cholesterol levels, lipoprotein profiles, and lipid statin response between wild-type mice and carriers of a hypomorphic (partial loss of function) missense mutation in Zfp335 (the mouse homolog of ZNF335).ResultsThe statin-induced expression changes of 147 human LCL genes were significantly correlated to the plasma LDLC statin responses of the corresponding CAP participants in vivo (FDR = 5%). The two genes with the strongest correlations were zinc finger protein 335 (ZNF335 aka NIF-1, rho = 0.237, FDR-adj p = 0.0085) and CCR4-NOT transcription complex subunit 3 (CNOT3, rho = 0.233, FDR-adj p = 0.0085). Chow-fed mice carrying a hypomorphic missense (R1092W; aka bloto) mutation in Zfp335 had significantly lower non-HDL cholesterol levels than wild-type C57BL/6J mice in a sex combined model (p = 0.04). Furthermore, male (but not female) mice carrying the Zfp335R1092W allele had significantly lower total and HDL cholesterol levels than wild-type mice. In a separate experiment, wild-type mice fed a control diet for 4 weeks and a matched simvastatin diet for an additional 4 weeks had significant statin-induced reductions in non-HDLC (-43 ± 18% and -23 ± 19% for males and females, respectively). Wild-type male (but not female) mice experienced significant reductions in plasma LDL particle concentrations, while male mice carrying Zfp335R1092W allele(s) exhibited a significantly blunted LDL statin response.ConclusionsOur in vitro and in vivo studies identified ZNF335 as a novel modulator of plasma cholesterol levels and statin response, suggesting that variation in ZNF335 activity could contribute to inter-individual differences in statin clinical efficacy.

This protocol outlines a proposed scoping review to characterize evidence on implementation and quality improvement (QI) strategies that aim to improve equitable, evidence-informed care delivery for pregnant and birthing people with substance use disorder (SUD) in acute care. Untreated SUD during pregnancy is associated with an increased risk of overdose and severe maternal morbidity. Acute care settings are one important place to deliver equitable, evidence-informed clinical care. While clinical practice guidelines for substance use treatment and care of pregnant and birthing people with SUD exist, there are gaps in implementation. Our population of interest is pregnant and birthing people with SUD in an acute care setting. We will include US-based studies that describe or evaluate implementation or QI strategies, including experimental, observational, and descriptive studies published from 2016 to 2023. The proposed scoping review will be conducted in accordance with JBI methodology for scoping reviews and registered at OSF (registration number: BC4VZ). We will search MEDLINE (PubMed), CINAHL Complete (EBSCO), Scopus (Elsevier), and APA PsychInfo (Ovid) for published studies. Conference proceedings and Perinatal Quality Collaborative websites will be searched for grey literature. Two reviewers will independently screen then extract studies that meet inclusion criteria using a data extraction tool. The completion of this scoping review will help illuminate strengths and gaps in research and practice that aim to inform substance use treatment and care in acute care settings for pregnant and birthing people with SUD.

We report on the identification of extracellular miRNA (ex-miRNA) biomarkers for early diagnosis and prognosis of preeclampsia (PE). Small RNA sequencing of maternal serum prospectively collected from participants undergoing evaluation for suspected PE revealed distinct patterns of ex-miRNA expression among different categories of hypertensive disorders in pregnancy. Applying an iterative machine learning method identified three bivariate miRNA biomarkers (miR-522-3p/miR-4732-5p, miR-516a-5p/miR-144-3p, and miR-27b-3p/let-7b-5p) that, when applied serially, distinguished between PE cases of different severity and differentiated cases from controls with a sensitivity of 93%, specificity of 79%, positive predictive value (PPV) of 55%, and negative predictive value (NPV) of 89%. In a small independent validation cohort, these ex-miRNA biomarkers had a sensitivity of 91% and specificity of 57%. Combining these ex-miRNA biomarkers with the established sFlt1:PlGF protein biomarker ratio performed better than either set of biomarkers alone (sensitivity of 89.4%, specificity of 91.3%, PPV of 95.5%, and NPV of 80.8%).

Despite great progress in understanding lipoprotein physiology, there is still much to be learned about the genetic drivers of lipoprotein abundance, composition, and function. We used ion mobility spectrometry to survey 16 plasma lipoprotein subfractions in 500 Diversity Outbred mice maintained on a Western-style diet. We identified 21 quantitative trait loci (QTL) affecting lipoprotein abundance. To refine the QTL and link them to disease risk in humans, we asked if the human homologs of genes located at each QTL were associated with lipid traits in human genome-wide association studies. Integration of mouse QTL with human genome-wide association studies yielded candidate gene drivers for 18 of the 21 QTL. This approach enabled us to nominate the gene encoding the neutral ceramidase, Asah2, as a novel candidate driver at a QTL on chromosome 19 for large HDL particles (HDL-2b). To experimentally validate Asah2, we surveyed lipoproteins in Asah2-/- mice. Compared to wild-type mice, female Asah2-/- mice showed an increase in several lipoproteins, including HDL. Our results provide insights into the genetic regulation of circulating lipoproteins, as well as mechanisms by which lipoprotein subfractions may affect cardiovascular disease risk in humans.

IntroductionUnhealthy alcohol use significantly contributes to viral non-suppression among persons with HIV (PWH). It is unknown whether brief behavioural interventions to reduce alcohol use can improve viral suppression among PWH with unhealthy alcohol use in sub-Saharan Africa (SSA).MethodsAs part of the SEARCH study (NCT04810650), we conducted an individually randomized trial in Kenya and Uganda of a brief, skills-based alcohol intervention among PWH with self-reported unhealthy alcohol use (Alcohol Use Disorders Identification Test-Consumption [AUDIT-C], prior 3 months, ≥3/female; ≥4/male) and at risk of viral non-suppression, defined as either recent HIV viral non-suppression (≥400 copies/ml), missed visits, out of care or new diagnosis. The intervention included baseline and 3-month in-person counselling sessions with interim booster phone calls every 3 weeks. The primary outcome was HIV viral suppression (200 ng/ml (RR 0.97, 95% CI: 0.92-1.02).ConclusionsIn a randomized trial of 401 PWH with unhealthy alcohol use and risk for viral non-suppression, a brief alcohol intervention reduced unhealthy alcohol use but did not affect viral suppression at 24 weeks. Brief alcohol interventions have the potential to improve the health of PWH in SSA by reducing alcohol use, a significant driver of HIV-associated co-morbidities.

BACKGROUND: Growing recognition of racism perpetuated within academic institutions has given rise to anti-racism efforts in these settings. In June 2020, the university-based California Preterm Birth Initiative (PTBi) committed to an Anti-Racism Action Plan outlining an approach to address anti-Blackness. This case study assessed perspectives on PTBis anti-racism efforts to support continued growth toward racial equity within the initiative. METHODS: This mixed methods case study included an online survey with multiple choice and open-ended survey items (n = 27) and key informant interviews (n = 8) of leadership, faculty, staff, and trainees working within the initiative. Survey and interview questions focused on perspectives about individual and organizational anti-racism competencies, perceived areas of initiative success, and opportunities for improvement. Qualitative interview and survey data were coded and organized into common themes within assessment domains. RESULTS: Most survey respondents reported they felt competent in all the assessed anti-racism skills, including foundational knowledge and responding to workplace racism. They also felt confident in PTBis commitment to address anti-Blackness. Fewer respondents were clear on strategic plans, resources allocated, and how the anti-racism agenda was being implemented. Suggestions from both data sources included further operationalizing and communicating commitments, integrating an anti-racism lens across all activities, ensuring accountability including staffing and funding consistent with anti-racist approaches, persistence in hiring Black faculty, providing professional development and support for Black staff, and addressing unintentional interpersonal harms to Black individuals. CONCLUSIONS: This case study contributes key lessons which move beyond individual-level and theoretical approaches towards transparency and accountability in academic institutions aiming to address anti-Black racism. Even with PTBis strong commitment and efforts towards racial equity, these case study findings illustrate that actions must have sustained support by the broader institution and include leadership commitment, capacity-building via ongoing coaching and training, broad incorporation of anti-racism practices and procedures, continuous learning, and ongoing accountability for both short- and longer-term sustainable impact.

BACKGROUND: Zinc-biofortified potatoes have considerable potential to reduce zinc deficiency because of their low levels of phytate, an inhibitor of zinc absorption, and their high consumption, especially in the Andean region of Peru. OBJECTIVES: The purpose of this study was to measure fractional and total zinc absorption from a test meal of biofortified compared with regular potatoes. METHODS: We undertook a single-blinded randomized crossover study (using 67Zn and 70Zn stable isotopes) in which 37 women consumed 500-g biofortified or regular potatoes twice a day. Urine samples were collected to determine fractional and total zinc absorption. RESULTS: The zinc content of the biofortified potato and regular potato was 0.48 (standard deviation [SD]: 0.02) and 0.32 (SD: 0.03) mg/100 g fresh weight, respectively. Mean fractional zinc absorption (FZA) from the biofortified potatoes was lower than from the regular potatoes, 20.8% (SD: 5.4%) and 25.5% (SD: 7.0%), respectively (P < 0.01). However, total zinc absorbed was significantly higher (0.49; SD: 0.13 and 0.40; SD: 0.11 mg/500 g, P < 0.01, respectively). CONCLUSIONS: The results of this study demonstrate that biofortified potatoes provide more absorbable zinc than regular potatoes. Zinc-biofortified potatoes could contribute toward reducing zinc deficiency in populations where potatoes are a staple food. This trial was registered at clinicaltrials.gov as NCT05154500.

PURPOSE: The Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007 and updated in 2021 (STEEP 2.0), provide standardized definitions of adjuvant breast cancer (BC) end points. STEEP 2.0 identified a need to separately address end points for neoadjuvant clinical trials. The multidisciplinary NeoSTEEP working group of experts was convened to critically evaluate and align neoadjuvant BC trial end points. METHODS: The NeoSTEEP working group concentrated on neoadjuvant systemic therapy end points in clinical trials with efficacy outcomes-both pathologic and time-to-event survival end points-particularly for registrational intent. Special considerations for subtypes and therapeutic approaches, imaging, nodal staging at surgery, bilateral and multifocal diseases, correlative tissue collection, and US Food and Drug Administration regulatory considerations were contemplated. RESULTS: The working group recommends a preferred definition of pathologic complete response (pCR) as the absence of residual invasive cancer in the complete resected breast specimen and all sampled regional lymph nodes (ypT0/Tis ypN0 per AJCC staging). Residual cancer burden should be a secondary end point to facilitate future assessment of its utility. Alternative end points are needed for hormone receptor-positive disease. Time-to-event survival end point definitions should pay particular attention to the measurement starting point. Trials should include end points originating at random assignment (event-free survival and overall survival) to capture presurgery progression and deaths as events. Secondary end points adapted from STEEP 2.0, which are defined from starting at curative-intent surgery, may also be appropriate. Specification and standardization of biopsy protocols, imaging, and pathologic nodal evaluation are also crucial. CONCLUSION: End points in addition to pCR should be selected on the basis of clinical and biologic aspects of the tumor and the therapeutic agent investigated. Consistent prespecified definitions and interventions are paramount for clinically meaningful trial results and cross-trial comparison.

Non-alcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome, and is estimated to affect one billion individuals worldwide. An increased intake of a high-fat diet (HFD) and sugar-sweetened beverages are risk-factors for NAFLD development, but how their combined intake promotes progression to a more severe form of liver injury is unknown. Here we show that fructose metabolism via ketohexokinase (KHK) C isoform leads to unresolved endoplasmic reticulum (ER) stress when coupled with a HFD intake. Conversely, a liver-specific knockdown of KHK in mice consuming fructose on a HFD is adequate to improve the NAFLD activity score and exert a profound effect on the hepatic transcriptome. Overexpression of KHK-C in cultured hepatocytes is sufficient to induce ER stress in fructose free media. Upregulation of KHK-C is also observed in mice with genetically induced obesity or metabolic dysfunction, whereas KHK knockdown in these mice improves metabolic function. Additionally, in over 100 inbred strains of male or female mice hepatic KHK expression correlates positively with adiposity, insulin resistance, and liver triglycerides. Similarly, in 241 human subjects and their controls, hepatic Khk expression is upregulated in early, but not late stages of NAFLD. In summary, we describe a novel role of KHK-C in triggering ER stress, which offers a mechanistic understanding of how the combined intake of fructose and a HFD propagates the development of metabolic complications.

Background & aimsMost patients in the immunotolerant (IT) phase of chronic hepatitis B (CHB) transition to the immune active (IA-hepatitis B surface antigen [HBeAg]+) phase by early adulthood. We examined characteristics of adults in the IT vs IA-HBeAg+ phase and rate of transition from IT to other phases of CHB, with a focus on those ≥40 years.MethodsDemographic, clinical, and virologic characteristics of participants in the Hepatitis B Research Network adult cohort study with IT CHB (alanine aminotransferase ≤1.5 × upper limit of normal, hepatitis B virus DNA >107 IU/mL) were compared by age category, and to those with IA-HBeAg+ CHB in cross-sectional analysis. This study received institutional review board approval at all participating centers.ResultsOf 107 adult IT participants, 52 (48%) were

PurposeThe "rapid-onset gender dysphoria" (ROGD) hypothesis theorized, based on a parent-report survey, a distinct and more transient form of gender dysphoria in which individuals purportedly come to understand themselves as transgender and/or gender diverse (TGD) suddenly during adolescence. This study evaluated components of ROGD by (1) estimating the prevalence among TGD adults of first realizing one's TGD identity after childhood (i.e., after the onset of puberty), and (2) assessing the median time between realizing one's gender identity and disclosing this to someone else.MethodsWe conducted a secondary analysis of the 2015 US Transgender Survey, a survey of 27,715 TGD adults in the United States. Participants were asked the age at which they first realized their gender identity was different than societal expectations based on their sex assigned at birth and grouped by "childhood realization" (ages ≤ 10 years) and "later realization" (ages > 10). They were also asked the age at which they first shared their gender identity with another person.ResultsOf 27,497 participants, 40.8% reported "later realization" of TGD identities. Within the "childhood realization" group, the median age of sharing one's gender identity with another person was 20. In this group, the median time between realization of one's gender identity and sharing this with another person was 14 years.DiscussionA substantial proportion of TGD adults reported realizing their gender identity was different from societal expectations based on their sex assigned at birth during adolescence or later. Several years typically elapsed between participants' TGD identity realization and sharing this with another person. The results of this study do not support the ROGD hypothesis.

Spontaneous coronary artery dissection (SCAD) is an understudied cause of myocardial infarction primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Here we present a genome-wide association meta-analysis (1,917 cases and 9,292 controls) identifying 16 risk loci for SCAD. Integrative functional annotations prioritized genes that are likely to be regulated in vascular smooth muscle cells and artery fibroblasts and implicated in extracellular matrix biology. One locus containing the tissue factor gene F3, which is involved in blood coagulation cascade initiation, appears to be specific for SCAD risk. Several associated variants have diametrically opposite associations with CAD, suggesting that shared biological processes contribute to both diseases, but through different mechanisms. We also infer a causal role for high blood pressure in SCAD. Our findings provide novel pathophysiological insights involving arterial integrity and tissue-mediated coagulation in SCAD and set the stage for future specific therapeutics and preventions.

BackgroundAlopecia areata is characterised by non-scarring loss of scalp, face, or body hair. We investigated the efficacy and safety of ritlecitinib, an oral, selective dual JAK3/TEC family kinase inhibitor, in patients with alopecia areata.MethodsIn this randomised, double-blind, multicentre, phase 2b-3 trial done at 118 sites in 18 countries, patients aged 12 years and older with alopecia areata and at least 50% scalp hair loss were randomly assigned to oral ritlecitinib or placebo once-daily for 24 weeks, with or without a 4-week loading dose (50 mg, 30 mg, 10 mg, 200 mg loading dose followed by 50 mg, or 200 mg loading dose followed by 30 mg), followed by a 24-week extension period during which ritlecitinib groups continued their assigned doses and patients initially assigned to placebo switched to ritlecitinib 50 mg or 200 mg loading dose followed by 50 mg. Randomisation was done by use of an interactive response system and was stratified by baseline disease severity and age. The sponsor, patients, and investigators were masked to treatment, and all patients received the same number of tablets to maintain masking. The primary endpoint was Severity of Alopecia Tool (SALT) score 20 or less at week 24. The primary endpoint was assessed in all assigned patients, regardless of whether they received treatment. This study was registered with ClinicalTrials.gov, NCT03732807.FindingsBetween Dec 3, 2018, and June 24, 2021, 1097 patients were screened and 718 were randomly assigned to receive ritlecitinib 200 mg + 50 mg (n=132), 200 mg + 30 mg (n=130), 50 mg (n=130), 30 mg (n=132), 10 mg (n=63), placebo to 50 mg (n=66), or placebo to 200 mg + 50 mg (n=65). 446 (62%) of 718 patients were female and 272 (38%) were male. 488 (68%) were White, 186 (26%) were Asian, and 27 (4%) were Black or African American. Of 718 patients randomly assigned, 104 patients discontinued treatment (34 withdrew, 19 adverse events [AEs], 12 physician decision, 12 lack of efficacy, 13 lost to follow up, five rolled over to long-term study transfer, four pregnancies, two protocol deviations, one declined to attend follow-up due to COVID-19, one attended last visit very late due to COVID-19, and one non-compliance). At week 24, 38 (31%) of 124 patients in the ritlecitinib 200 mg + 50 mg group, 27 (22%) of 121 patients in the 200 mg + 30 mg group, 29 (23%) of 124 patients in the 50 mg group, 17 (14%) of 119 patients in the 30 mg group, and two (2%) of 130 patients in the placebo group had a response based on SALT score 20 or less. The difference in response rate based on SALT score 20 or less between the placebo and the ritlecitinib 200 mg + 50 mg group was 29·1% (95% CI 21·2-37·9; p

ImportancePain related to sickle cell disease (SCD) is complex and associated with social determinants of health. Emotional and stress-related effects of SCD impact daily quality of life and the frequency and severity of pain.ObjectiveTo explore the association of educational attainment, employment status, and mental health with pain episode frequency and severity among individuals with SCD.Design, setting, and participantsThis is a cross-sectional analysis of patient registry data collected at baseline (2017-2018) from patients treated at 8 sites of the US Sickle Cell Disease Implementation Consortium. Data analysis was performed from September 2020 to March 2022.Main outcomes and measuresElectronic medical record abstraction and a participant survey provided demographic data, mental health diagnosis, and Adult Sickle Cell Quality of Life Measurement Information System pain scores. Multivariable regression was used to examine the associations of education, employment, and mental health with the main outcomes (pain frequency and pain severity).ResultsThe study enrolled a total of 2264 participants aged 15 to 45 years (mean [SD] age, 27.9 [7.9] years; 1272 female participants [56.2%]) with SCD. Nearly one-half of the participant sample reported taking daily pain medication (1057 participants [47.0%]) and/or hydroxyurea use (1091 participants [49.2%]), 627 participants (28.0%) received regular blood transfusion, 457 (20.0%) had a depression diagnosis confirmed by medical record abstraction, 1789 (79.8%) reported severe pain (rated most recent pain crises as ≥7 out of 10), and 1078 (47.8%) reported more than 4 pain episodes in the prior 12 months. The mean (SD) pain frequency and severity t scores for the sample were 48.6 (11.4) and 50.3 (10.1), respectively. Educational attainment and income were not associated with increased pain frequency or severity. Unemployment (β, 2.13; 95% CI, 0.99 to 3.23; P

People who are in close relationships tend to do and like the same things, a phenomenon termed the "homophily principle." The present research probed for evidence of the homophily principle in 4- to 6-year-old children. Across two experiments, participants (N = 327; 166 girls, 161 boys; located in the Midwestern United States) were asked to predict the closeness of two people based on their preferences. Participants in Experiment 1 indicated that people with a shared preference or a shared dispreference were more closely affiliated than people whose preferences diverged, suggesting inferences of homophily. Furthermore, children were not only relying on the emotional valences expressed: They expected people with a shared preference to be closer than people who expressed positive emotions about different items and expected people with a shared dispreference to be closer than people who expressed negative emotions about different items. Experiment 2 replicated and extended the main findings of Experiment 1 with more naturalistic stimuli. The present studies provide strong evidence that young children apply the homophily principle to their reasoning about social relationships. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

BACKGROUND AND OBJECTIVES: Previous studies have identified racial-ethnic differences in the diagnostic patterns and recurrence outcomes of women with phyllodes tumors (PT). However, these studies are generally limited in size and generalizability. We therefore sought to explore racial-ethnic differences in age, tumor size, subtype, and recurrence in a large US cohort of women with PT. METHODS: We performed an 11-institution retrospective review of women with PT from 2007 to 2017. Differences in age at diagnosis, tumor size and subtype, and recurrence-free survival according to race-ethnicity. RESULTS: Women of non-White race or Hispanic ethnicity were younger at the time of diagnosis with phyllodes tumor. Non-Hispanic Other women had a larger proportion of malignant PT. There were no differences in recurrence-free survival in our cohort. CONCLUSIONS: Differences in age, tumor size, and subtype were small. Therefore, the workup of young women with breast masses and the treatment of women with PT should not differ according to race-ethnicity. These conclusions are supported by our finding that there were no differences in recurrence-free survival.

PURPOSE: To test the efficacy of two interventions to reduce alcohol use and increase viral suppression compared to a control in persons with HIV (PWH). METHODS: In a three-arm (1:1:1) randomized controlled trial (N = 269), we compared in-person counselling (45-70 minutes, two sessions over three months) with interim monthly booster phone calls (live call arm) or twice-weekly automated booster sessions (technology arm) to a brief advice control arm. We enrolled PWH self-reporting unhealthy alcohol use (Alcohol Use Disorders Identification Test - Consumption, prior three months, women ≥3, men ≥4). Primary outcomes were number of self-reported drinking days (NDD) in the prior 21 and biomarker phosphatidylethanol (PEth) at six and nine months and viral suppression (

Extant research on the gender pay gap suggests that men and women who do the same work for the same employer receive similar pay, so that processes sorting people into jobs are thought to account for the vast majority of the pay gap. Data that can identify women and men who do the same work for the same employer are rare, and research informing this crucial aspect of gender differences in pay is several decades old and from a limited number of countries. Here, using recent linked employer-employee data from 15 countries, we show that the processes sorting people into different jobs account for substantially less of the gender pay differences than was previously believed and that within-job pay differences remain consequential.

OBJECTIVE: Tenofovir disoproxil fumarate (TDF) is a common component of antiretroviral therapy in hepatitis B virus (HBV)-HIV co-infected adults but few studies have evaluated worsening renal function and bone turnover, known effects of TDF. METHODS: Adults from eight North American sites were enrolled in this cohort study. Research assessments were conducted at entry and every 24 weeks for ≤192 weeks. Bone markers were tested at baseline, week 96 and week 192 from stored serum. We evaluated changes in markers of renal function and bone turnover over time and potential contributing factors. RESULTS: A total of 115 patients were prospectively followed; median age 49 years, 91% male and 52% non-Hispanic Black. Duration of HIV was 20.5 years. TDF use ranged from 80% to 92% throughout follow-up. Estimated glomerular filtration rate (eGFR) (ml/min/1.73m2 ) decreased from 87.1 to 79.9 over 192 weeks (p

BackgroundIn recognition of the interconnected nature of complex challenges such as COVID-19, a collaborative, multisectoral, and transdisciplinary approach, referred to as One Health, has been employed to address sustainable development and strengthen global health security. Although significant investments have been made to build global health capacity, characterization of the One Health is absent from the literature.Methods and findingsWe collected and analyzed perspectives from students, graduates, workers, and employers in One Health through a multinational online survey across health disciplines and sectors. Respondents were recruited through professional networks. A total of 828 respondents from 66 countries participated, representing governmental and academic institutions and students, among others; 57% were female, and 56% had completed professional health degrees. Interpersonal communication, communication with non-scientific audiences, and the ability to work in transdisciplinary teams were valued in the workplace and were considered essential competencies to build an interdisciplinary health workforce. Employers indicated difficulty recruiting workers, while workers indicated limited availability of positions. Employers identified limited funding and ill-defined career pathways as prominent challenges for retaining One Health workers.ConclusionsSuccessful One Health workers use interpersonal skills and scientific knowledge to address complex health challenges. Aligning the definition of One Health will likely improve the matching of job seekers and employers. Encouraging the employment of the One Health approach for a diverse range of positions, even if they do not explicitly include "One Health" in the job title, and clarifying the expectations, roles and responsibilities within a transdisciplinary team will lead to building a stronger workforce. As One Health has evolved to address food insecurity, emerging diseases, and antimicrobial resistance, it holds promise for supporting an interdisciplinary global health workforce that can make substantial progress on Sustainable Development Goals and improve global health security for all.

Some people remain healthier throughout life than others but the underlying reasons are poorly understood. Here we hypothesize this advantage is attributable in part to optimal immune resilience (IR), defined as the capacity to preserve and/or rapidly restore immune functions that promote disease resistance (immunocompetence) and control inflammation in infectious diseases as well as other causes of inflammatory stress. We gauge IR levels with two distinct peripheral blood metrics that quantify the balance between (i) CD8+ and CD4+ T-cell levels and (ii) gene expression signatures tracking longevity-associated immunocompetence and mortality-associated inflammation. Profiles of IR metrics in ~48,500 individuals collectively indicate that some persons resist degradation of IR both during aging and when challenged with varied inflammatory stressors. With this resistance, preservation of optimal IR tracked (i) a lower risk of HIV acquisition, AIDS development, symptomatic influenza infection, and recurrent skin cancer; (ii) survival during COVID-19 and sepsis; and (iii) longevity. IR degradation is potentially reversible by decreasing inflammatory stress. Overall, we show that optimal IR is a trait observed across the age spectrum, more common in females, and aligned with a specific immunocompetence-inflammation balance linked to favorable immunity-dependent health outcomes. IR metrics and mechanisms have utility both as biomarkers for measuring immune health and for improving health outcomes.

We examined parents' COVID-19 vaccination intentions for their children, reasons for not vaccinating, and the potential impact of a school/daycare vaccination requirement or pediatrician's recommendation on vaccination intentions. Two online surveys were conducted in June-July and September-October 2021, before pediatric COVID-19 vaccines were authorized for emergency use in children age

BackgroundPre-treatment HIV drug resistance is a threat to elimination of mother to child HIV transmission and could lead to virological failure among HIV-positive pregnant women. We analysed genotypic HIV drug resistance (HIVDR) of baseline samples of participants enrolled in the Option B+ clinical trial in Uganda.MethodsHIV-infected pregnant women attending antenatal care were enrolled from Uganda's National Referral Hospital (Mulago) and Mityana District general hospital and surrounding health centers (HCs). Genotypic HIV testing was performed on blood samples from the first 135 enrolled women out of a subset of 136 participants (25%) who had a baseline VL>1000 copies/mL as one sample failed to amplify.Results159/540 (29.4%) had a VL < 1000 copies/ml and 381/540 (70.6%) had a VL >1,000 copies/ml. Of the women with VL>1000 copies/ml, 32 (23.7%) had resistance mutations including 29/135 (21.5%) NNRTI mutations, 6/135 (4.4%) NRTI mutations and 3/135 (2.2%) had both NNRTI and NRTI mutations. The most common NNRTI resistance mutations were: K103KN (5), K103N (5), V179T (4) and E138A (4).ConclusionsOne quarter of the HIV-infected pregnant women in this trial at baseline had NNRTI genotypic resistance mutations. Our findings support new WHO guidelines for first-line ART that were changed to dolutegravir-based regimens.

BackgroundRecent calls to action have been made for Implementation Science to attend to health inequities at the intersections of race, gender, and social injustice in the United States. Transgender people, particularly Black and Latina transgender women, experience a range of health inequities and social injustices. In this study, we compared two processes of transgender community engagement in Los Angeles and in Chicago as an implementation strategy to address inequitable access to care; we adapted and extended the Exploration Planning Implementation and Sustainment (EPIS) framework for transgender health equity.MethodsA comparative case method and the EPIS framework were used to examine parallel implementation strategies of transgender community engagement to expand access to care. To foster conceptual development and adaptation of EPIS for trans health equity, the comparative case method required detailed description, exploration, and analyses of the community-engagement processes that led to different interventions to expand access. In both cities, the unit of analysis was a steering committee made up of local transgender and cisgender stakeholders.ResultsBoth steering committees initiated their exploration processes with World Café-style, transgender community-engaged events in order to assess community needs and structural barriers to healthcare. The steering committees curated activities that amplified the voices of transgender community members among stakeholders, encouraging more effective and collaborative ways to advance transgender health equity. Based on analysis and findings from the Los Angeles town hall, the steering committee worked with a local medical school, extending the transgender medicine curriculum, and incorporating elements of transgender community-engagement. The Chicago steering committee determined from their findings that the most impactful intervention on structural racism and barriers to healthcare access would be to design and pilot an employment program for Black and Latina transgender women.ConclusionIn Los Angeles and Chicago, transgender community engagement guided implementation processes and led to critical insights regarding specific, local barriers to healthcare. The steering committee itself represented an important vehicle for individual-, organizational-, and community-level relationship and capacity building. This comparative case study highlights key adaptations of EPIS toward the formation of an implementation science framework for transgender health equity.

BackgroundIt is unknown if football players with femoroacetabular impingement (FAI) syndrome report worse burden than those with other causes of hip/groin pain, and to what extent this is mediated by cartilage defects and labral tears.HypothesisFootball players with FAI syndrome would report worse burden than other symptomatic players, with the effect partially mediated by cartilage defects and/or labral tears.Study designCross-sectional study.Level of evidenceLevel 4.MethodsFootball (soccer and Australian football) players (n = 165; 35 women) with hip/groin pain (≥6 months and positive flexion-adduction-internal rotation test) were recruited. Participants completed 2 patient-reported outcome measures (PROMs; the International Hip Outcome Tool-33 [iHOT-33] and Copenhagen Hip and Groin Outcome Score [HAGOS]) and underwent hip radiographs and magnetic resonance imaging (MRI). FAI syndrome was determined to be present when cam and/or pincer morphology were present. Cartilage defects and labral tears were graded as present or absent using MRI. Linear regression models investigated relationships between FAI syndrome (dichotomous independent variable) and PROM scores (dependent variables). Mediation analyses investigated the effect of cartilage defects and labral tears on these relationships.ResultsFAI syndrome was not related to PROM scores (unadjusted b values ranged from -4.693 (P = 0.23) to 0.337 (P = 0.93)) and cartilage defects and/or labral tears did not mediate its effect (P = 0.22-0.97).ConclusionFootball players with FAI syndrome did not report worse burden than those with other causes of hip/groin pain. Cartilage defects and/or labral tears did not explain the effect of FAI syndrome on reported burden.Clinical relevanceFAI syndrome, cartilage defects, and labral tears were prevalent but unrelated to reported burden in symptomatic football players.

Target identification remains a critical challenge in inorganic drug discovery to deconvolute potential polypharmacology. Herein, we describe an improved approach to prioritize candidate protein targets based on a combination of dose-dependent chemoproteomics and treatment effects in living cancer cells for the rhenium tricarbonyl compound TRIP. Chemoproteomics revealed 89 distinct dose-dependent targets with concentrations of competitive saturation between 0.1 and 32 μM despite the broad proteotoxic effects of TRIP. Target-response networks revealed two highly probable targets of which the Fe-S cluster biogenesis factor NUBP2 was competitively saturated by free TRIP at nanomolar concentrations. Importantly, TRIP treatment led to a down-regulation of Fe-S cluster containing proteins and upregulated ferritin. Fe-S cluster depletion was further verified by assessing mitochondrial bioenergetics. Consequently, TRIP emerges as a first-in-class modulator of the scaffold protein NUBP2, which disturbs Fe-S cluster biogenesis at sub-cytotoxic concentrations in ovarian cancer cells.

BackgroundDietary methyl donors (e.g., choline) support the activity of the phosphatidylethanolamine N-methyltransferase (PEMT) pathway, which generates phosphatidylcholine (PC) molecules enriched in DHA that are exported from the liver and made available to extrahepatic tissues.ObjectivesThis study investigated the effect of prenatal choline supplementation on biomarkers of DHA status among pregnant participants consuming supplemental DHA.MethodsPregnant participants (n = 30) were randomly assigned to receive supplemental choline intakes of 550 mg/d [500 mg/d d0-choline + 50 mg/d deuterium-labeled choline (d9-choline); intervention] or 25 mg/d (25 mg/d d9-choline; control) from gestational week (GW) 12-16 until delivery. All participants received a daily 200-mg DHA supplement and consumed self-selected diets. Fasting blood samples were obtained at baseline, GW 20-24, and GW 28-32; maternal/cord blood was obtained at delivery. Mixed-effects linear models were used to assess the impact of prenatal choline supplementation on maternal and newborn DHA status.ResultsCholine supplementation (550 vs. 25 mg/d) did not achieve a statistically significant intervention × time interaction for RBC PC-DHA (P = 0.11); a significant interaction was observed for plasma PC-DHA and RBC total DHA, with choline supplementation yielding higher levels (+32-38% and +8-11%, respectively) at GW 28-32 (P

Undermining is thought to improve wound outcomes; however, randomized controlled data regarding its efficacy are lacking in humans. The objective of this randomized clinical trial was to determine whether undermining low to moderate tension wounds improves scar cosmesis compared to wound closure without undermining. Fifty-four patients, 18 years or older, undergoing primary linear closure of a cutaneous defect with predicted postoperative closure length of ≥ 3 cm on any anatomic site were screened. Four patients were excluded, 50 patients were enrolled, and 48 patients were seen in follow-up. Wounds were divided in half and one side was randomized to receive either no undermining or 2 cm of undermining. The other side received the unselected intervention. Three months, patients and 2 masked observers evaluated each scar using the Patient and Observer Scar Assessment Scale (POSAS). A total of 50 patients [mean (SD) age, 67.6 (11.5) years; 31 (64.6%) male; 48 (100%) white] were enrolled in the study. The mean (SD) sum of the POSAS observer component scores was 12.0 (6.05) for the undermined side and 11.1 (4.68) for the non-undermined side (P = .60). No statistically significant difference was found in the mean (SD) sum of the patient component for the POSAS score between the undermined side [15.9 (9.07)] and the non-undermined side [13.33 (6.20)] at 3 months. For wounds under low to moderate perceived tension, no statistically significant differences in scar outcome or total complications were noted between undermined wound halves and non-undermined halves.Trail Registry: Clinical trials.gov Identifier NCT02289859. https://clinicaltrials.gov/ct2/show/NCT02289859 .

BackgroundMorphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life.MethodsInterregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 individuals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed.ResultsAcross the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre/perinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth.ConclusionsOur findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from typical brain development during pregnancy.

COVID-19 mRNA vaccines (BNT162b2 [Pfizer-BioNTech] and mRNA-1273 [Moderna]) provide protection against infection with SARS-CoV-2, the virus that causes COVID-19, and are highly effective against COVID-19-associated hospitalization among eligible persons who receive 2 doses (1,2). However, vaccine effectiveness (VE) among persons with immunocompromising conditions* is lower than that among immunocompetent persons (2), and VE declines after several months among all persons (3). On August 12, 2021, the Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for a third mRNA vaccine dose as part of a primary series ≥28 days after dose 2 for persons aged ≥12 years with immunocompromising conditions, and, on November 19, 2021, as a booster dose for all adults aged ≥18 years at least 6 months after dose 2, changed to ≥5 months after dose 2 on January 3, 2022 (4,5,6). Among 2,952 adults (including 1,385 COVID-19 case-patients and 1,567 COVID-19-negative controls) hospitalized at 21 U.S. hospitals during August 19-December 15, 2021, effectiveness of mRNA vaccines against COVID-19-associated hospitalization was compared between adults eligible for but who had not received a third vaccine dose (1,251) and vaccine-eligible adults who received a third dose ≥7 days before illness onset (312). Among 1,875 adults without immunocompromising conditions (including 1,065 [57%] unvaccinated, 679 [36%] 2-dose recipients, and 131 [7%] 3-dose [booster] recipients), VE against COVID-19 hospitalization was higher among those who received a booster dose (97%; 95% CI = 95%-99%) compared with that among 2-dose recipients (82%; 95% CI = 77%-86%) (p

ObjectiveUganda is HIV-endemic with a prevalence of 5.7%. Lack of epidemic control has been attributed to low engagement with HIV testing. Collaborating with informal healthcare providers, such as traditional healers, has been proposed as a strategy to increase testing uptake. We explored acceptability and implementation of an HIV testing program where traditional healers delivered point-of-care testing and counseling to adults of unknown serostatus (clinicaltrials.gov NCT#03718871).MethodsThis study was conducted in rural, southwestern Uganda. We interviewed participating traditional healers ( N  = 17) and a purposive sample of trial participants ( N  = 107). Healers were practicing within 10 km of Mbarara township, and 18+ years old. Participants were 18+ years old; sexually active; had received care from participating healers; self-reported not receiving an HIV test in prior 12 months; and not previously diagnosed with HIV infection. Interviews explored perceptions of a healer-delivered HIV testing model and were analyzed following a content-analysis approach.ResultsMost participants were female individuals ( N  = 68, 55%). Healer-delivered HIV testing overcame structural barriers, such as underlying poverty and rural locations that limited use, as transportation was costly and often prohibitive. Additionally, healers were located in villages and communities, which made services more accessible compared with facility-based testing. Participants also considered healers trustworthy and 'confidential'. These qualities explain some preference for healer-delivered HIV testing, in contrast to 'stigmatizing' biomedical settings.ConclusionTraditional healer-delivered HIV testing was considered more confidential and easily accessible compared with clinic-based testing. Offering services through traditional healers may improve uptake of HIV testing services in rural, medically pluralistic communities.

BackgroundDexamethasone decreases mortality in coronavirus disease 2019 (COVID-19) patients on intensive respiratory support (IRS) but is of uncertain benefit if less severely ill. We determined whether early (within 48 h) dexamethasone was associated with mortality in patients hospitalised with COVID-19 not on IRS.MethodsWe included patients admitted to US Veterans Affairs hospitals between 7 June 2020 and 31 May 2021 within 14 days after a positive test for severe acute respiratory syndrome coronavirus 2. Exclusions included recent prior corticosteroids and IRS within 48 h. We used inverse probability of treatment weighting (IPTW) to balance exposed and unexposed groups, and Cox proportional hazards models to determine 90-day all-cause mortality.ResultsOf 19 973 total patients (95% men, median age 71 years, 27% black), 15 404 (77%) were without IRS within 48 h. Of these, 3514 out of 9450 (34%) patients on no oxygen received dexamethasone and 1042 (11%) died; 4472 out of 5954 (75%) patients on low-flow nasal cannula (NC) only received dexamethasone and 857 (14%) died. In IPTW stratified models, patients on no oxygen who received dexamethasone experienced 76% increased risk for 90-day mortality (hazard ratio (HR) 1.76, 95% CI 1.47-2.12); there was no association with mortality among patients on NC only (HR 1.08, 95% CI 0.86-1.36).ConclusionsIn patients hospitalised with COVID-19, early initiation of dexamethasone was common and was associated with no mortality benefit among those on no oxygen or NC only in the first 48 h; instead, we found evidence of potential harm. These real-world findings do not support the use of early dexamethasone in hospitalised COVID-19 patients without IRS.

BACKGROUND: Fatty liver disease (FLD) and hepatitis B virus (HBV) infection occur commonly in human immunodeficiency virus (HIV). FLD resolution is associated with improvement in lipoproteins in HIV-uninfected patients. We evaluated changes in FLD in an HBV/HIV-coinfected cohort. METHODS: One hundred eight HBV/HIV-coinfected adults with baseline liver biopsies were followed every 24 weeks (median, 166 weeks) and 60 had follow-up biopsies. Baseline FLD categories (none, ≥5% steatosis, steatohepatitis), their change, and relationships with clinical and lipid/lipoprotein parameters were explored using multivariable modeling. RESULTS: Median age was 50 years, and 93% were male. At baseline 30% had FLD. With control for lipid-lowering medications and body mass index, low-density lipoprotein (LDL) cholesterol (LDL-C), LDL particle concentration (LDL-P), and apolipoprotein B (apoB) decreased and adiponectin increased over time (all P < .05); On follow-up (vs baseline), there was no significant difference in FLD category (P = .85); 60% remained without FLD, 17% had unchanged, 12% worsening, and 12% improved FLD. Baseline low-density lipoproteins (LDL-C, LDL-P, small LDL-P) and apoB appeared highest in those with unchanged FLD status (all P < .05). No associations between changes in FLD across follow-up (worsening/improvement vs unchanged) and lipid/lipoproteins changes were identified. CONCLUSIONS: In this cohort, there was no significant change in FLD prevalence over a relatively short timeframe. Baseline atherogenic lipids appeared highest in those with persistent steatosis or steatohepatitis, suggesting potentially increased cardiovascular risk in this group, but an independent relationship between individual-level change in FLD status and lipid/lipoprotein levels across follow-up was not observed.

ObjectiveTo investigate a possible link between breast and thyroid cancer.MethodsA multicenter retrospective review of patients in the electronic medical records of six Accrual to Clinical Trial (ACT) institutions with both breast cancer and thyroid carcinoma. Each center queried its data using a predefined data dictionary. Information on thyroid and breast cancer included dates of diagnosis, histology, and patient demographics.ResultsA random-effects model was used. There were 4.24 million women's records screened, 44 605 with breast cancer and 11 846 with thyroid cancer. The relative risks observed at each institution ranged from 0.49 to 13.47. The combined risk ratio (RR) estimate was 1.77 (95% confidence interval: 0.50-5.18).ConclusionThere was no association between the risk of developing thyroid cancer and being a breast cancer survivor compared to no history of breast cancer, but the range of relative risks among the participating institutions was wide. Our findings warrant further study of more institutions with larger sample size. Additionally, further analysis of the significance of regional RR differences may be enlightening.

Hydroxyurea reduces pain crises, acute chest syndrome, and blood transfusions in sickle cell disease (SCD), but potential detrimental effects on fertility and birth outcomes impede its use. Data on the effects of hydroxyurea taken for SCD during conception and pregnancy are scarce. The Sickle Cell Disease Implementation Consortium collected self-reported pregnancy history, corresponding hydroxyurea use, and pregnancy outcomes in women with SCD in the clinical setting. Among 1285 women 18-45 years of age, 737 (57.4%) reported 1788 pregnancies (1079 live births, 394 miscarriages, 40 stillbirths, 207 abortions, 48 current pregnancies, and 20 missing outcomes) of which 241 (15.9%) live births, miscarriages or stillbirths were conceived while on hydroxyurea. In univariate analyses, pregnancy number more than three, severe sickle genotype, history of stillbirth or miscarriage, and chronic kidney disease at enrollment were covariates significantly associated with a pregnancy ending in miscarriage or stillbirth. After adjustment for covariates and additional SCD severity markers in multivariate analyses, hydroxyurea use during conception and pregnancy, but not during conception only, was associated with an increase in the odds ratio (OR) of miscarriage or stillbirth (OR 2.21, 95% confidence interval [CI] 1.40-3.47). In analyses of live birth outcomes, hydroxyurea use during conception and pregnancy was associated with birth weight

BackgroundThe content validity (appropriateness and acceptability) of patient-reported outcome (PRO) measures for scalp hair loss, eyebrow loss, eyelash loss, nail damage and eye irritation has been demonstrated in adults with alopecia areata (AA) but not adolescents.ObjectivesTo explore the content validity of the suite of AA PRO measures and accompanying photoguides in an adolescent sample.MethodsSemi-structured, 90-min, combined concept elicitation and cognitive interviews were conducted face-to-face with adolescents who experienced ≥ 50% AA-related scalp hair loss. Transcripts underwent thematic and framework analysis.ResultsEleven adolescents (aged 12-17 years, 55% female, 45% nonwhite) diagnosed with AA for 5·9 years (mean) participated. Participants had 69·6% scalp hair (mean) and current eyebrow (82%) and/or eyelash loss (82%) and/or nail involvement (36%). Adolescents reported scalp, eyebrow and eyelash hair loss as their top three most bothersome signs/symptoms. Despite mostly accepting their AA, impacts related to visible areas of hair loss were prominent. Participants demonstrated good understanding and appropriate use of the PRO measures, and advocated including hair loss percentages alongside descriptive categories in the Scalp Hair Assessment PRO™. Results confirmed treatment success thresholds established with adults: achievement of ≤ 20% scalp hair loss, no/minimal eyebrow and eyelash loss, no/a little nail damage and eye irritation (PRO measure categories 0 or 1).ConclusionsThe Scalp Hair Assessment PRO™, PRO Measure for Eyebrows™, PRO Measure for Eyelashes™, PRO Measure for Nail Appearance™ and PRO Measure for Eye Irritation™ and accompanying photoguides are fit-for-purpose self-reported measures of AA signs/symptoms that are impactful to adolescents with AA.

BACKGROUND: Excessive gestational weight gain has been associated with increased total body fat (TBF), metabolic syndrome, and abdominal obesity. However, little is known about the relationship of gestational weight gain with changes in metabolically active visceral or ectopic (hepatic and skeletal muscle) lipid stores. OBJECTIVES: In a prospective study of 50 healthy, pregnant women, we assessed whether changes in weight were associated with changes in total, visceral, and ectopic lipid stores. METHODS: Participants (ages 19-39) were primarily White (84%). The mean preconception BMI was 25.8 kg/m2 (SD, 4.5 kg/m2; min-max, 17.1-35.9 kg/m2). Measurements were completed at visits 1 and 2 at means of 16 and 34 weeks gestation, respectively, and included TBF using BOD POD; abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) using MRI; and intrahepatic lipids (IHL), intramyocellular lipids (IMCL), and extramyocellular lipids (EMCL) using magnetic resonance spectroscopy. We used paired t-tests to examine changes in adipose tissue and Pearsons correlation to examine associations of adipose tissue changes and weight changes. We also examined whether changes in adipose tissue stores differed by preconception BMI (normal, overweight, and obese), using 1-way ANOVA. RESULTS: The TBF (mean change, +3.5 kg; 95% CI: 2.4-4.6 kg), SAT (mean change, +701 cm3; 95% CI: 421-981 cm3), VAT (mean change, +275 cm3; 95% CI: 170-379 cm3), and IHL (percentage water peak; median, +0.15; IQR = -0.01 to 0.32) values increased significantly; the IMCL and EMCL values did not change. Changes varied by BMI strata, with the least increase (or, for SAT, net loss) among women with obesity. Weight change was positively correlated with changes in TBF (r = 0.83; P

ImportanceSocial isolation and loneliness are increasing public health concerns and have been associated with increased risk of cardiovascular disease (CVD) among older adults.ObjectiveTo examine the associations of social isolation and loneliness with incident CVD in a large cohort of postmenopausal women and whether social support moderated these associations.Design, setting, and participantsThis prospective cohort study, conducted from March 2011 through March 2019, included community-living US women aged 65 to 99 years from the Women's Health Initiative Extension Study II who had no history of myocardial infarction, stroke, or coronary heart disease.ExposuresSocial isolation and loneliness were ascertained using validated questionnaires.Main outcomes and measuresThe main outcome was major CVD, which was physician adjudicated using medical records and included coronary heart disease, stroke, and death from CVD. Continuous scores of social isolation and loneliness were analyzed. Hazard ratios (HRs) and 95% CIs for CVD were calculated for women with high social isolation and loneliness scores (midpoint of the upper half of the distribution) vs those with low scores (midpoint of the lower half of the distribution) using multivariable Cox proportional hazards regression models adjusting for age, race and ethnicity, educational level, and depression and then adding relevant health behavior and health status variables. Questionnaire-assessed social support was tested as a potential effect modifier.ResultsAmong 57 825 women (mean [SD] age, 79.0 [6.1] years; 89.1% White), 1599 major CVD events occurred over 186 762 person-years. The HR for the association of high vs low social isolation scores with CVD was 1.18 (95% CI, 1.13-1.23), and the HR for the association of high vs low loneliness scores with CVD was 1.14 (95% CI, 1.10-1.18). The HRs after additional adjustment for health behaviors and health status were 1.08 (95% CI, 1.03-1.12; 8.0% higher risk) for social isolation and 1.05 (95% CI, 1.01-1.09; 5.0% higher risk) for loneliness. Women with both high social isolation and high loneliness scores had a 13.0% to 27.0% higher risk of incident CVD than did women with low social isolation and low loneliness scores. Social support was not a significant effect modifier of the associations (social isolation × social support: r, -0.18; P = .86; loneliness × social support: r, 0.78; P = .48).Conclusions and relevanceIn this cohort study, social isolation and loneliness were independently associated with modestly higher risk of CVD among postmenopausal women in the US, and women with both social isolation and loneliness had greater CVD risk than did those with either exposure alone. The findings suggest that these prevalent psychosocial processes merit increased attention for prevention of CVD in older women, particularly in the era of COVID-19.

In a previous study with LSL-LITE layers (-23 to 30-week-old), isoleucine at 0.72% and 0.84% produced values for FCR at 1.45 and 1.44, respectively and shared significance with 0.78% isoleucine (1.49). Considering that FCR is an important standard in the poultry industry due to the cost for adding feed ingredients such as synthetic amino acids and the low FCR of 1.45, 0.72% isoleucine was chosen for further study with LSL-LITE layers (n = 490 at 33- to 40-week-old) to determine effects on production and egg quality. The study included 7 diets (2730 Kcal kg metabolizable energy and constant isoleucine at 0.72%) containing varying quantities of valine [0.72 (Control), 0.75, 0.78, 0.81, 0.84, 0.87 or 0.90%] x 7 replicates x 10 hens/replicate. Significance at P ≤ 0.05 and P < 0.10 was determined. Level and week were significant for feed intake, egg production, and FCR; the interaction of level x week (L*W) was significant for feed intake and FCR. An isoleucine:valine of 1.233 corresponding to 0.72% isoleucine and 0.87% valine produced the lowest FCR of 1.30 (a 2.26% decrease compared to the Control at 1.33 ± 0.04). All measurements for external egg quality, except shape index and eggshell thickness, were significant for level. Week was significant for all parameters except shell thickness; L*W was significant for external quality measurements except shape index and shell thickness. Level, week, and L*W were significant for internal egg quality measurements. Serum protein and H1 titer were significant for level. Various production, egg quality, and biochemical measurements were significantly different from the control (0.72% isoleucine and 0.72% valine) at 0.81 to 0.87% valine. Findings of this study will aid researchers and commercial producers in narrowing the range of isoleucine, valine, and leucine needed for effects on particular parameters. Knowledge gained from this and others studies will eventually lead to an understanding of synergistic and antagonistic effects of branched chain amino acids in feed for various genetic types of layers throughout their productive lifetime.

BackgroundIn populations at high risk of HIV infection, rates of depression can be elevated with far-reaching effects on overall well-being. There is limited research on depression among young women engaged in high-risk sexual behaviour in low and middle-income settings. We investigated the prevalence, correlates and factors associated with mean HSCL depression score among young women at high risk (aged 15-24 years old) in Kampala, Uganda.MethodsWe conducted a baseline analysis of a randomized controlled trial. Probable depression was measured using the 15-item Hopkins Symptoms Checklist for depression (HSCL). This checklist has been validated in Ugandan populations, and our reliability test gave a Cronbach alpha coefficient of 0.89. The test was administered to all the participants. Participants whose HSCL mean score was greater than 1.75 were categorized as having probable depression. Socio-demographics and behaviour data were collected and factors associated with mean HSCL depression score were analysed using multiple linear regression.ResultsData was available for 600 participants, mean age 20.4 (SD±2.44) years. The prevalence of probable depression was 56% (95% CI, 52%-60%). Probable depression symptoms were most prevalent among those who reported ever-experiencing violence from a sexual partner (64.7%), those aged between 20-24 years (58.2%) and those who reported more than 10 sexual exposures in the month prior to the interview (56.8%). At the adjusted analysis level, condom use during their last sexual intercourse prior to the survey decreased probable depression symptoms by 0.147 units compared to those who never used condoms (β = -0.147, 95% CI -0.266-0.027). Having experienced physical violence by a sexual partners increased mean HSCL depression score by 0.183 units compared to those who have never experienced violence (β = 0.183, 95% CI 0.068-0.300). Participants who reported ever using drugs of addiction had their mean HSCL depression scoreincrease by 0.20 units compared to those who have never used (β = 0.20,95% CI 0.083-0.317).ConclusionsProbable depression is high in this population and increased mean HSCL depression score is related to violence. Periodic screening for depression and interventions targeting depression, partner violence and risky sexual behaviours are recommended.

BackgroundDespite being a priority population for COVID-19 vaccination, limited data are available regarding acceptability of COVID-19 vaccines among people living with HIV (PLWH) in Sub-Saharan Africa. We described COVID-19 vaccine acceptability and factors associated with vaccine acceptability among PLWH in Uganda.MethodsThis was a cross-sectional study conducted among PLWH, aged ≥18 years, enrolled participants who were seeking HIV care from six purposely selected accredited ART clinics in Kampala. We obtained data on vaccine acceptability defined as willingness to accept any of the available COVID-19 vaccines using interviewer-administered questionnaires. In addition, we assessed vaccination status, complacency regarding COVID-19 disease, vaccine confidence, and vaccine convenience. Factors associated with COVID-19 vaccine acceptability were evaluated using modified Poisson regression with robust standard errors.ResultsWe enrolled 767 participants of whom 485 (63%) were women. The median age was 33 years [interquartile range (IQR) 28-40] for women and 40 years [IQR], (34-47) for men. Of the respondents 534 (69.6%,95% confidence interval [CI]: 66.3%-72.8%) reported receiving at least one vaccine dose, with women significantly more likely than men to have been vaccinated (73% vs. 63%; p = 0.003). Among the unvaccinated 169 (72.7%, 95% CI: 66.6%-78.0%) were willing to accept vaccination, had greater vaccine confidence (85.9% had strong belief that the vaccines were effective; 81.9% that they were beneficial and 71% safe for PLWH; 90.5% had trust in health care professionals or 77.4% top government officials), and believed that it would be easy to obtain a vaccine if one decided to be vaccinated (83.6%). Vaccine acceptability was positively associated with greater vaccine confidence (adjusted prevalence ratio [aPR] 1.44; 95% CI: 1.08-1.90), and positive perception that it would be easy to obtain a vaccine (aPR 1.57; 95% CI: 1.26-1.96).Conclusionvaccine acceptance was high among this cohort of PLWH, and was positively associated with greater vaccine confidence, and perceived easiness (convince) to obtained the vaccine. Building vaccine confidence and making vaccines easily accessible should be a priority for vaccination programs targeting PLWH.

Main objectiveThere is limited information on how patient outcomes have changed during the COVID-19 pandemic. This study characterizes changes in mortality, intubation, and ICU admission rates during the first 20 months of the pandemic.Study design and methodsUniversity of Wisconsin researchers collected and harmonized electronic health record data from 1.1 million COVID-19 patients across 21 United States health systems from February 2020 through September 2021. The analysis comprised data from 104,590 adult hospitalized COVID-19 patients. Inclusion criteria for the analysis were: (1) age 18 years or older; (2) COVID-19 ICD-10 diagnosis during hospitalization and/or a positive COVID-19 PCR test in a 14-day window (+/- 7 days of hospital admission); and (3) health system contact prior to COVID-19 hospitalization. Outcomes assessed were: (1) mortality (primary), (2) endotracheal intubation, and (3) ICU admission.Results and significanceThe 104,590 hospitalized participants had a mean age of 61.7 years and were 50.4% female, 24% Black, and 56.8% White. Overall risk-standardized mortality (adjusted for age, sex, race, ethnicity, body mass index, insurance status and medical comorbidities) declined from 16% of hospitalized COVID-19 patients (95% CI: 16% to 17%) early in the pandemic (February-April 2020) to 9% (CI: 9% to 10%) later (July-September 2021). Among subpopulations, males (vs. females), those on Medicare (vs. those on commercial insurance), the severely obese (vs. normal weight), and those aged 60 and older (vs. younger individuals) had especially high mortality rates both early and late in the pandemic. ICU admission and intubation rates also declined across these 20 months.ConclusionsMortality, intubation, and ICU admission rates improved markedly over the first 20 months of the pandemic among adult hospitalized COVID-19 patients although gains varied by subpopulation. These data provide important information on the course of COVID-19 and identify hospitalized patient groups at heightened risk for negative outcomes.Trial registrationClinicalTrials.gov Identifier: NCT04506528 (https://clinicaltrials.gov/ct2/show/NCT04506528).

Despite recent advances in therapeutic approaches, patients with MLL-rearranged leukemia still have poor outcomes. Here, we find that the RNA-binding protein IGF2BP3, which is overexpressed in MLL-translocated leukemia, strongly amplifies MLL-Af4-mediated leukemogenesis. Deletion of Igf2bp3 significantly increases the survival of mice with MLL-Af4-driven leukemia and greatly attenuates disease, with a minimal impact on baseline hematopoiesis. At the cellular level, MLL-Af4 leukemia-initiating cells require Igf2bp3 for their function in leukemogenesis. At the molecular level, IGF2BP3 regulates a complex posttranscriptional operon governing leukemia cell survival and proliferation. IGF2BP3-targeted mRNA transcripts include important MLL-Af4-induced genes, such as those in the Hoxa locus, and the Ras signaling pathway. Targeting of transcripts by IGF2BP3 regulates both steady-state mRNA levels and, unexpectedly, pre-mRNA splicing. Together, our findings show that IGF2BP3 represents an attractive therapeutic target in this disease, providing important insights into mechanisms of posttranscriptional regulation in leukemia.

BackgroundThis study was conducted to determine the level and feasibility of use of information and communication technology (ICT) and social media for research and service delivery among young female sex workers (YFSWs) in Kampala, Uganda.MethodsWe analysed baseline data from 234 YFSWs in Kampala ages 15-24 y participating in a randomized controlled trial testing a cognitive behavioural human immunodeficiency virus prevention intervention.ResultsMobile phone ownership (68.3%) and short message service use (64.9%) were moderate and significantly lower in the 15- to 19-y age group. Computer use experience and internet access were low.ConclusionsWe believe that the feasibility of ICT and social media-driven interventions among YFSWs is limited.