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BACKGROUNDCOVID-19 convalescent plasma (CCP) virus-specific antibody levels that translate into recipient posttransfusion antibody levels sufficient to prevent disease progression are not defined.METHODSThis secondary analysis correlated donor and recipient antibody levels to hospitalization risk among unvaccinated, seronegative CCP recipients within the outpatient, double-blind, randomized clinical trial that compared CCP to control plasma. The majority of COVID-19 CCP arm hospitalizations (15/17, 88%) occurred in this unvaccinated, seronegative subgroup. A functional cutoff to delineate recipient high versus low posttransfusion antibody levels was established by 2 methods: (i) analyzing virus neutralization-equivalent anti-Spike receptor-binding domain immunoglobulin G (anti-S-RBD IgG) responses in donors or (ii) receiver operating characteristic (ROC) curve analysis.RESULTSSARS-CoV-2 anti-S-RBD IgG antibody was volume diluted 21.3-fold into posttransfusion seronegative recipients from matched donor units. Virus-specific antibody delivered was approximately 1.2 mg. The high-antibody recipients transfused early (symptom onset within 5 days) had no hospitalizations. A CCP-recipient analysis for antibody thresholds correlated to reduced hospitalizations found a statistical significant association between early transfusion and high antibodies versus all other CCP recipients (or control plasma), with antibody cutoffs established by both methods-donor-based virus neutralization cutoffs in posttransfusion recipients (0/85 [0%] versus 15/276 [5.6%]; P = 0.03) or ROC-based cutoff (0/94 [0%] versus 15/267 [5.4%]; P = 0.01).CONCLUSIONIn unvaccinated, seronegative CCP recipients, early transfusion of plasma units in the upper 30% of study donors antibody levels reduced outpatient hospitalizations. High antibody level plasma units, given early, should be reserved for therapeutic use.TRIAL REGISTRATIONClinicalTrials.gov NCT04373460.FUNDINGDepartment of Defense (W911QY2090012); Defense Health Agency; Bloomberg Philanthropies; the State of Maryland; NIH (3R01AI152078-01S1, U24TR001609-S3, 1K23HL151826NIH); the Mental Wellness Foundation; the Moriah Fund; Octapharma; the Healthnetwork Foundation; the Shear Family Foundation; the NorthShore Research Institute; and the Rice Foundation.

BACKGROUND: Cytokines and chemokines play a critical role in the response to infection and vaccination. We aimed to assess the longitudinal association of COVID-19 vaccination with cytokine and chemokine concentrations and trajectories among people with SARS-CoV-2 infection. METHODS: In this longitudinal, prospective cohort study, blood samples were used from participants enrolled in a multi-centre randomised trial assessing the efficacy of convalescent plasma therapy for ambulatory COVID-19. The trial was conducted in 23 outpatient sites in the USA. In this study, participants (aged ≥18 years) were restricted to those with COVID-19 before vaccination or with breakthrough infections who had blood samples and symptom data collected at screening (pre-transfusion), day 14, and day 90 visits. Associations between COVID-19 vaccination status and concentrations of 21 cytokines and chemokines (measured using multiplexed sandwich immunoassays) were examined using multivariate linear mixed-effects regression models, adjusted for age, sex, BMI, hypertension, diabetes, trial group, and COVID-19 waves (pre-alpha or alpha and delta). FINDINGS: Between June 29, 2020, and Sept 30, 2021, 882 participants recently infected with SARS-CoV-2 were enrolled, of whom 506 (57%) were female and 376 (43%) were male. 688 (78%) of 882 participants were unvaccinated, 55 (6%) were partly vaccinated, and 139 (16%) were fully vaccinated at baseline. After adjusting for confounders, geometric mean concentrations of interleukin (IL)-2RA, IL-7, IL-8, IL-15, IL-29 (interferon-λ), inducible protein-10, monocyte chemoattractant protein-1, and tumour necrosis factor-α were significantly lower among the fully vaccinated group than in the unvaccinated group at screening. On day 90, fully vaccinated participants had approximately 20% lower geometric mean concentrations of IL-7, IL-8, and vascular endothelial growth factor-A than unvaccinated participants. Cytokine and chemokine concentrations decreased over time in the fully and partly vaccinated groups and unvaccinated group. Log10 cytokine and chemokine concentrations decreased faster among participants in the unvaccinated group than in other groups, but their geometric mean concentrations were generally higher than fully vaccinated participants at 90 days. Days since full vaccination and type of vaccine received were not correlated with cytokine and chemokine concentrations. INTERPRETATION: Initially and during recovery from symptomatic COVID-19, fully vaccinated participants had lower concentrations of inflammatory markers than unvaccinated participants suggesting vaccination is associated with short-term and long-term reduction in inflammation, which could in part explain the reduced disease severity and mortality in vaccinated individuals. FUNDING: US Department of Defense, National Institutes of Health, Bloomberg Philanthropies, State of Maryland, Mental Wellness Foundation, Moriah Fund, Octapharma, HealthNetwork Foundation, and the Shear Family Foundation.

PURPOSE: Compared with people living without HIV (PWOH), people living with HIV (PWH) and cancer have traditionally been excluded from immune checkpoint inhibitor (ICI) trials. Furthermore, there is a paucity of real-world data on the use of ICIs in PWH and cancer. METHODS: This retrospective study included PWH treated with anti-PD-1- or anti-PD-L1-based therapies for advanced cancers. Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Objective response rates (ORRs) were measured per RECIST 1.1 or other tumor-specific criteria, whenever feasible. Restricted mean survival time (RMST) was used to compare OS and PFS between matched PWH and PWOH with metastatic NSCLC (mNSCLC). RESULTS: Among 390 PWH, median age was 58 years, 85% (n = 331) were males, 36% (n = 138) were Black; 70% (n = 274) received anti-PD-1/anti-PD-L1 monotherapy. Most common cancers were NSCLC (28%, n = 111), hepatocellular carcinoma ([HCC]; 11%, n = 44), and head and neck squamous cell carcinoma (HNSCC; 10%, n = 39). Seventy percent (152/216) had CD4+ T cell counts ≥200 cells/µL, and 94% (179/190) had HIV viral load

Adolescent girls and young women (AGYW; ages 15-24) in sub-Saharan Africa face many barriers to accessing preventive sexual and reproductive health (SRH) services. We drew upon the strengths of two complementary approaches, human-centered design and behavioral economics, to craft a holistic, highly-tailored, and empathetic intervention to motivate AGYW to seek contraception and HIV self-test kits at community drug shops. To encourage engagement, we embedded "nudge" strategies at different opportunity points (uncovered during our design research) along the care-seeking and service delivery journey. Our Malkia Klabu intervention is a loyalty program designed to enhance drug shops' role as SRH providers through which AGYW earned punches for shop purchases redeemable for small prizes; free SRH products could be requested at any time. From our 4-month pilot in Shinyanga, Tanzania, we assess the extent to which different behavioral nudge strategies motivated behaviors as predicted by synthesizing findings from (1) in-depth interviews with AGYW and shopkeepers, (2) shop program records, (3) shop observations, and (4) customer exit surveys. Overall, we find that AGYW and shopkeepers were motivated by many intervention features as intended and consistent with hypothesized mechanisms. We found strong evidence of social norms for helping to spread awareness of Malkia Klabu among peers, prize incentives for drawing AGYW back to shops, and the opt-out default membership gift of an HIV self-test kit for encouraging testing uptake and exploration of contraceptives. Shopkeepers in both arms noted increased community status from distributing HIV self-testing kits (ego). Malkia Klabu shopkeepers experienced increased customer traffic and business revenues (incentives), which reduced shopkeepers' gatekeeping tendencies and earned them additional recognition as champions of AGYW well-being. Integrating human-centered design and behavioral economics was effective for developing an innovative and effective intervention that simultaneously met the different needs of economic actors in support of public health priorities.

PurposeWe hypothesized that an intervention designed to create girl-friendly drug shops would increase access to sexual and reproductive health products and services among adolescent girls and young women (AGYW) (ages 15-24 years) in Tanzania.MethodsWe conducted a four-month randomized trial at 20 drug shops in Shinyanga, Tanzania from August-December 2019 to determine if the Malkia Klabu ("Queen Club") intervention increased AGYW patronage and the provision of HIV self-testing (HIVST), contraception, and health facility referrals to AGYW (primary outcomes). Drug shops were randomized 1:1 to the intervention or comparison arm. All shops were provided with OraQuick HIVST kits to give to AGYW for free. Intervention shops implemented Malkia Klabu, a loyalty program for AGYW created using human-centered design through which AGYW could also access free contraception. We compared outcomes in intention-to-treat analyses using shop observations and shopkeeper records.ResultsBy endline, shops implementing Malkia Klabu had higher AGYW patronage than comparison shops (rate ratio: 4.4; 95% confidence interval: 2.0, 9.8). Intervention shops distributed more HIVST kits (median per shop: 130.5 vs. 58.5, P = .02) and contraceptives (325.5 vs. 7.0, P < .01) to AGYW and provided more referrals for HIV, family planning, or pregnancy services combined (3.5 vs. 0.5, P = .02) than comparison shops.DiscussionThe Malkia Klabu intervention increased AGYW patronage and the provision of HIVST kits, contraception, and referrals to AGYW at drug shops, despite HIVST kits being freely available at all participating shops. Enhancing drug shops with girl-friendly services may be an effective strategy to reach AGYW with sexual and reproductive health services.

The social worlds of young children primarily revolve around parents and caregivers, who play a key role in guiding childrens social and cognitive development. However, a hallmark of adolescence is a shift in orientation toward nonfamilial social targets, an adaptive process that prepares adolescents for their independence. Little is known regarding neurobiological signatures underlying changes in adolescents social orientation. Using functional brain imaging of human voice processing in children and adolescents (ages 7-16), we demonstrate distinct neural signatures for mothers voice and nonfamilial voices across child and adolescent development in reward and social valuation systems, instantiated in nucleus accumbens and ventromedial prefrontal cortex. While younger children showed greater activity in these brain systems for mothers voice compared with nonfamilial voices, older adolescents showed the opposite effect with increased activity for nonfamilial compared with mothers voice. Findings uncover a critical role for reward and social valuative brain systems in the pronounced changes in adolescents orientation toward nonfamilial social targets. Our approach provides a template for examining developmental shifts in social reward and motivation in individuals with pronounced social impairments, including adolescents with autism.SIGNIFICANCE STATEMENT Childrens social worlds undergo a transformation during adolescence. While socialization in young children revolves around parents and caregivers, adolescence is characterized by a shift in social orientation toward nonfamilial social partners. Here we show that this shift is reflected in neural activity measured from reward processing regions in response to brief vocal samples. When younger children hear their mothers voice, reward processing regions show greater activity compared with when they hear nonfamilial, unfamiliar voices. Strikingly, older adolescents show the opposite effect, with increased activity for nonfamilial compared with mothers voice. Findings identify the brain basis of adolescents switch in social orientation toward nonfamilial social partners and provides a template for understanding neurodevelopment in clinical populations with social and communication difficulties.

The novel severe acute respiratory syndrome (SARS) coronavirus, SARS-CoV-2, is responsible for the global COVID-19 pandemic. Effective interventions are urgently needed to mitigate the effects of COVID-19 and likely require multiple strategies. Egg-extracted antibody therapies are a low-cost and scalable strategy to protect at-risk individuals from SARS-CoV-2 infection. Commercial laying hens were hyperimmunized against the SARS-CoV-2 S1 protein using three different S1 recombinant proteins and three different doses. Sera and egg yolk were collected at three and six weeks after the second immunization for enzyme-linked immunosorbent assay and plaque-reduction neutralization assay to determine antigen-specific antibody titers and neutralizing antibody titers, respectively. In this study we demonstrate that hens hyperimmunized against the SARS-CoV-2 recombinant S1 and receptor binding domain (RBD) proteins produced neutralizing antibodies against SARS-CoV-2. We further demonstrate that antibody production was dependent on the dose and type of antigen administered. Our data suggests that antibodies purified from the egg yolk of hyperimmunized hens can be used as immunoprophylaxis in humans at risk of exposure to SARS-CoV-2.

Adolescent and young adult women in sub-Saharan Africa experience barriers to sexual and reproductive health (SRH) services that elevate their risk of human immunodeficiency virus (HIV) acquisition and unintended pregnancy. Community drug shops may be effective distribution points to connect young women with SRH products. Thus, we used human-centred design (HCD) to create drug shops where young women could access HIV self-testing and contraception in Shinyanga, Tanzania. Enhancing the HCD process with behavioural science, we collected diverse data (i.e. 18 in-depth interviews, 9 'shadowing' interviews, 6 shop observations, 6 focus groups) to understand the latent needs and motivations of young women and drug shopkeepers, brainstormed creative solutions and iteratively refined and tested solutions for acceptability, feasibility and cultural fit. We found a widespread moral imperative to control young women's behaviour via misinformation about SRH, community gossip and financial control. Young women often engaged in mundane shopping at the behest of others. At drug shops, few SRH products were deemed appropriate for unmarried women, and many reactively sought SRH products only after engaging in higher risk behaviours. In response to these insights, we designed the 'Malkia Klabu' ('Queen Club') loyalty programme through which young women could earn mystery prizes by shopping at drug shops and discreetly request free SRH products, including HIV self-test kits, by pointing at symbols on loyalty cards. Our HCD approach increases the likelihood that the intervention will address the specific needs and preferences of both drug shopkeepers and young women. We will evaluate its effectiveness in a randomized trial.

Genetic factors underlying coronary artery disease (CAD) have been widely studied using genome-wide association studies (GWASs). However, the functional understanding of the CAD loci has been limited by the fact that a majority of GWAS variants are located within non-coding regions with no functional role. High cholesterol and dysregulation of the liver metabolism such as non-alcoholic fatty liver disease confer an increased risk of CAD. Here, we studied the function of non-coding single-nucleotide polymorphisms in CAD GWAS loci located within liver-specific enhancer elements by identifying their potential target genes using liver cis-eQTL analysis and promoter Capture Hi-C in HepG2 cells. Altogether, 734 target genes were identified of which 121 exhibited correlations to liver-related traits. To identify potentially causal regulatory SNPs, the allele-specific enhancer activity was analyzed by (1) sequence-based computational predictions, (2) quantification of allele-specific transcription factor binding, and (3) STARR-seq massively parallel reporter assay. Altogether, our analysis identified 1,277 unique SNPs that display allele-specific regulatory activity. Among these, susceptibility enhancers near important cholesterol homeostasis genes (APOB, APOC1, APOE, and LIPA) were identified, suggesting that altered gene regulatory activity could represent another way by which genetic variation regulates serum lipoprotein levels. Using CRISPR-based perturbation, we demonstrate how the deletion/activation of a single enhancer leads to changes in the expression of many target genes located in a shared chromatin interaction domain. Our integrative genomics approach represents a comprehensive effort in identifying putative causal regulatory regions and target genes that could predispose to clinical manifestation of CAD by affecting liver function.

BackgroundRepresentation trends of women, older adults, and ethnic/racial minorities in randomized controlled trials (RCTs) of atrial fibrillation (AF) are uncertain.MethodsWe systematically reviewed 134 AF related RCTs (phase II and III) encompassing 149,162 participants using Medline and ClinicalTrials.gov through April 2019 to determine representation trends of women, older patients (≥75 years), and ethnic/racial minorities. Weighted data on the prevalence of AF from epidemiological studies were used to compare the representation of the studied groups of interest in AF RCTs to their expected burden of the disease.ResultsOnly 18.7% of the RCTs reported proportion of older patients, and 12.7% RCTs reported ethnic/racial minorities. The proportions of women in RCTs versus general population were 35.2% and 35.1%, of Hispanics were 11.9% and 5.2%, of Blacks were 1.2% and 5.7%, of American Indian/Alaskans were 0.2% and 0.2%, of Asians were 14.2% and 2.4%, of native Hawaiian/Pacific Islanders were 0.05% and 0.1% and of non-Whites were 19.5% and 22.5%, respectively. The weighted mean age (SD) across the trials was 65.3 (3.2) years which was less than the corresponding weighted mean age of 71.1 (4.5) years in the comparative epidemiological data.ConclusionThe reporting of older patients and ethnic/racial minorities was poor in RCTs of AF. The representation of women and American Indian/Alaskan natives matched their expected population share of disease burden. Hispanics and Asians were over-represented and Blacks, native Hawaiian/Pacific Islanders and non-Whites were under-represented in RCTs of AF.

Age-related neurodegenerative disorders are characterized by a slow, persistent accumulation of aggregated proteins. Although cells can elicit physiological responses to enhance cellular clearance and counteract accumulation, it is unclear how pathogenic proteins evade this process in disease. We find that Parkinson's disease α-synuclein perturbs the physiological response to lysosomal stress by impeding the SNARE protein ykt6. Cytosolic ykt6 is normally autoinhibited by a unique farnesyl-mediated regulatory mechanism; however, during lysosomal stress, it activates and redistributes into membranes to preferentially promote hydrolase trafficking and enhance cellular clearance. α-Synuclein aberrantly binds and deactivates ykt6 in patient-derived neurons, thereby disabling the lysosomal stress response and facilitating protein accumulation. Activating ykt6 by small-molecule farnesyltransferase inhibitors restores lysosomal activity and reduces α-synuclein in patient-derived neurons and mice. Our findings indicate that α-synuclein creates a permissive environment for aggregate persistence by inhibiting regulated cellular clearance and provide a therapeutic strategy to restore protein homeostasis by harnessing SNARE activity.

UNLABELLED: Engaging with vocal sounds is critical for childrens social-emotional learning, and children with autism spectrum disorder (ASD) often tune out voices in their environment. Little is known regarding the neurobiological basis of voice processing and its link to social impairments in ASD. Here, we perform the first comprehensive brain network analysis of voice processing in children with ASD. We examined neural responses elicited by unfamiliar voices and mothers voice, a biologically salient voice for social learning, and identified a striking relationship between social communication abilities in children with ASD and activation in key structures of reward and salience processing regions. Functional connectivity between voice-selective and reward regions during voice processing predicted social communication in children with ASD and distinguished them from typically developing children. Results support the Social Motivation Theory of ASD by showing reward system deficits associated with the processing of a critical social stimulus, mothers voice, in children with ASD. EDITORIAL NOTE: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editors assessment is that minor issues remain unresolved (see decision letter).

BackgroundInterventions incorporating constructs from behavioral economics and psychology have the potential to enhance HIV 'treatment as prevention' (TasP) strategies. To test this hypothesis, we evaluated an intervention to improve antiretroviral therapy (ART) adherence based on the concepts of social norms and priming.MethodsWe used tools from marketing research and patient-centered design to develop a combination intervention that included visual feedback about clinic-level retention in care, a self-relevant prime, and useful take-home items with the priming image. The intervention was implemented at two HIV primary clinics in Shinyanga, Tanzania in 2-week intervals for six months. We conducted a quasi-experimental pilot study with a random sample of exposed and unexposed adult patients living with HIV infection (PLHIV) to compare retention and the proportion of patients with medication possession ratio (MPR) ≥95% after six months. Intervention acceptability was determined with a convenience sample of 405 PLHIV at baseline (n = 189) and endline (n = 216).ResultsMedical records were reviewed for 438 PLHIV (320 intervention, 118 standard of care). In adjusted analyses, PLHIV exposed to the intervention were significantly more likely to be in care after 6 months (87% vs. 79%, adjusted odds ratio (ORa) = 1.73, 95% CI: 1.08, 2.78, p

BackgroundInterventions incorporating constructs from behavioral economics and psychology have the potential to enhance HIV 'treatment as prevention' (TasP) strategies. To test this hypothesis, we evaluated an intervention to improve antiretroviral therapy (ART) adherence based on the concepts of social norms and priming.MethodsWe used tools from marketing research and patient-centered design to develop a combination intervention that included visual feedback about clinic-level retention in care, a self-relevant prime, and useful take-home items with the priming image. The intervention was implemented at two HIV primary clinics in Shinyanga, Tanzania in 2-week intervals for six months. We conducted a quasi-experimental pilot study with a random sample of exposed and unexposed adult patients living with HIV infection (PLHIV) to compare retention and the proportion of patients with medication possession ratio (MPR) ≥95% after six months. Intervention acceptability was determined with a convenience sample of 405 PLHIV at baseline (n = 189) and endline (n = 216).ResultsMedical records were reviewed for 438 PLHIV (320 intervention, 118 standard of care). In adjusted analyses, PLHIV exposed to the intervention were significantly more likely to be in care after 6 months (87% vs. 79%, adjusted odds ratio (ORa) = 1.73, 95% CI: 1.08, 2.78, p

Background. Millions of people are infected with hepatitis C virus (HCV) worldwide and 30% spontaneously clear the infection. Reasons for HCV clearance without antiviral treatment are not well understood. Methods. Blood was collected for DNA analysis from patients with chronic HCV infection or evidence of spontaneous clearance. To overcome anticipated limitations of small sample size, primary analyses consisted of a candidate gene analysis of 12 preselected genes based on known association with host immunologic response to HCV infection. To further reduce the impact of multiple testing on power, a single likelihood ratio test was conducted for each gene using all associated SNPs assayed on the Illumina Quad 610/660W chip. Step-down permutation methods were used to adjust for multiple testing in all analyses. Results. Ninety-five and 62 patients with HCV chronic infection or spontaneous clearance, respectively, were included for analysis. HLA-DQB1 (p = 1.76⁎10(-5)) and IL-6 (p = 0.0007) genes were significantly associated with spontaneous HCV clearance. IL-28B was not significantly associated with spontaneous clearance (p = 0.17). Conclusion. Our whole-gene analytic strategy identified a previously unreported association of IL-6 with spontaneous clearance of HCV infection. We also confirmed the finding that HLA-DQB1 is associated with spontaneous resolution of HCV infection.

Background. Millions of people are infected with hepatitis C virus (HCV) worldwide and 30% spontaneously clear the infection. Reasons for HCV clearance without antiviral treatment are not well understood. Methods. Blood was collected for DNA analysis from patients with chronic HCV infection or evidence of spontaneous clearance. To overcome anticipated limitations of small sample size, primary analyses consisted of a candidate gene analysis of 12 preselected genes based on known association with host immunologic response to HCV infection. To further reduce the impact of multiple testing on power, a single likelihood ratio test was conducted for each gene using all associated SNPs assayed on the Illumina Quad 610/660W chip. Step-down permutation methods were used to adjust for multiple testing in all analyses. Results. Ninety-five and 62 patients with HCV chronic infection or spontaneous clearance, respectively, were included for analysis. HLA-DQB1 (p = 1.76⁎10(-5)) and IL-6 (p = 0.0007) genes were significantly associated with spontaneous HCV clearance. IL-28B was not significantly associated with spontaneous clearance (p = 0.17). Conclusion. Our whole-gene analytic strategy identified a previously unreported association of IL-6 with spontaneous clearance of HCV infection. We also confirmed the finding that HLA-DQB1 is associated with spontaneous resolution of HCV infection.

Sclerostin is a potent inhibitor of bone formation but has been shown to correlate positively with areal bone mineral density (aBMD). Little is known about its relationship to parameters of bone strength and volumetric BMD (vBMD) as measured by peripheral quantitative computed tomography (pQCT). We measured both serum sclerostin and parameters of tibial bone size and strength by pQCT to characterize this relationship. Our study population consisted of 223 white and 35 African American women (mean age 87 years) from the Study of Osteoporotic Fractures (SOF) cohort, who had usable pQCT scans of the tibia at sites 4% (T4%), 33% (T33%), and 66% (T66%) from the ankle. Analysis of covariance was used to test for differences in age-adjusted means of aBMD, pQCT variables, and serum biomarkers across sclerostin quartiles. African American women had significantly lower median sclerostin (34.3 pmol/L) than white women (48.5 pmol/L) (p = 0.05). Women in the highest sclerostin quartile had 7% to 14.5% higher hip aBMD and pQCT parameters of vBMD and bone size than those in the lowest quartile in multivariate models adjusting for age, race, weight, height, and diabetes status. The association of sclerostin with parameters of bone strength differed dramatically between T33% and T66% sites. At T66%, women in the highest sclerostin quartile had pQCT strength parameters 9.4% to 15.3% greater than the lowest quartile, whereas no trend was found for the T33% site. Our results suggest paradoxical associations between circulating sclerostin and bone size, density, and strength.