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Understanding COVID-19 vaccine effectiveness (VE) in healthcare workers (HCWs) is critical to inform vaccination policies. We measured COVID-19 VE against laboratory-confirmed symptomatic infection in HCWs in the country of Georgia from January - June 2022, during a period of Omicron circulation. We conducted a cohort study of HCWs in six hospitals in Georgia. HCWs were enrolled in early 2021. Participants completed weekly symptom questionnaires. Symptomatic HCWs were tested by RT-PCR and/or rapid antigen test (RAT). Participants were also routinely tested, at varying frequencies during the study period, for SARS-CoV-2 by RT-PCR or RAT, regardless of symptoms. Serology was collected quarterly throughout the study and tested by electrochemiluminescence immunoassay for SARS-CoV-2 antibodies. We estimated absolute and relative VE of a first booster dose compared to a primary vaccine series as (1-hazard ratio)*100 using Cox proportional hazards models. Among 1253 HCWs, 141 (11%) received a primary vaccine series (PVS) and a first booster, 855 (68%) received PVS only, and 248 (20%) were unvaccinated. Most boosters were BNT162b2 (Comirnaty original monovalent) vaccine (90%) and BBIBP-CorV vaccine (Sinopharm) (9%). Most PVS were BNT162b2 vaccine (68%) and BBIBP-CorV vaccine (24%). Absolute VE for a first booster was 40% (95% Confidence Interval (CI) -56-77) at 7-29 days following vaccination, -9% (95% CI -104-42) at 30-59 days following vaccination, and -46% (95% CI -156-17) at ≥ 60 days following vaccination. Relative VE of first booster dose compared to PVS was 58% (95% CI 1-82) at 7-29 days following vaccination, 21% (95% CI -33-54) at 30-59 days following vaccination, and -9% (95% CI -82-34) at ≥ 60 days following vaccination. In Georgia, first booster dose VE against symptomatic SARS-CoV-2 infection among HCWs was moderately effective but waned very quickly during Omicron. Increased efforts to vaccinate priority groups in Georgia, such as healthcare workers, prior to periods of anticipated high COVID-19 incidence are essential.

BackgroundThirty per cent of all women experience intimate partner violence (IPV) in their lifetime. The aim of this study was to examine the association between the WHO’s novel R.E.S.P.E.C.T framework and IPV among women in Kenya.MethodsWe used the 2014 Kenya Demographic and Health Survey (KDHS). Only women selected for the domestic violence module and who were married/living with their partner were eligible for this study (n=3737). We created a summary score for the strategies denoted by R.E.S.P.T based on availability of questions addressing these strategies in the KDHS, and a total score that summed responses across all strategies. Each letter was assessed with Cronbach’s alpha. Multiple logistic regression models were used to investigate the relationship between R.E.S.P.T scores and IPV.ResultsAll strategies except for E lowered the odds of IPV. Decision-making (R) was negatively associated with experiencing IPV (OR=0.62 (0.53 to 0.72)). Land and property ownership (E) were positively associated with experiencing IPV (OR=1.25 (1.08 to 1.43)). Access to healthcare (S) was negatively associated with experiencing IPV (OR=0.55 (0.48 to 0.63)). Higher levels of wealth (P) were negatively associated with experiencing IPV (OR=0.47 (0.37 to 0.62)). Not justifying wife-beating in any scenario (T) was negatively associated with experiencing IPV (OR=0.39 (0.29 to 0.53)). After adjusting for demographics, a 1-unit increase in total R.E.S.P.T score was negatively associated with experiencing IPV (AOR=0.63 (0.57 to 0.70)) with a similar finding for IPV in the past 12 months (AOR=0.59 (0.53 to 0.66)). Younger women, higher education and Muslim religion were associated with decreased odds of experiencing IPV while living in a rural location and working were associated with increased odds of experiencing IPV.ConclusionsOur study provides initial evidence that by using the multistrategy R.E.S.P.E.C.T framework, countries can dramatically lower the odds of women experiencing IPV. IPV prevention strategies must have a wide approach. The DHS can be used as a tool to monitor implementation and efficacy of this novel strategy.

Healthcare workers (HCWs) have suffered considerable morbidity and mortality during the COVID-19 pandemic. Few data on COVID-19 vaccine effectiveness (VE) are available from middle-income countries in the WHO European Region. We evaluated primary series COVID-19 VE against laboratory-confirmed COVID-19 among HCWs in Georgia. HCWs in six hospitals in Georgia were invited to enroll in a prospective cohort study conducted during March 19-December 5, 2021. Participants completed weekly symptom questionnaires. Symptomatic HCWs were tested by RT-PCR and/or rapid antigen test (RAT), and participants were routinely tested for SARS-CoV-2 by RT-PCR or RAT, regardless of symptoms. Serology was collected at enrolment, and quarterly thereafter, and tested by electrochemiluminescence immunoassay for SARS-CoV-2 antibodies. We defined primary series vaccination as two doses of COVID-19 vaccine received ≥14 days before symptom onset. We estimated VE as (1-hazard ratio)*100 using a Cox proportional hazards model with vaccination status as a time-varying covariate. Estimates were adjusted by potential confounders that changed the VE estimate by more than 5%, according to the change-in-estimate approach. Overall, 1561/3849 (41%) eligible HCWs enrolled and were included in the analysis. The median age was 40 (IQR: 30-53), 1318 (84%) were female, and 1003 (64%) had laboratory evidence of prior SARS-Cov-2 infection. At enrolment, 1300 (83%) were unvaccinated; By study end, 1082 (62%) had completed a primary vaccine series (69% BNT162b2 (Pfizer-BioNTech); 22% BBIBP-CorV (Sinopharm); 9% other). During the study period, 191(12%) participants had a new PCR- or RAT-confirmed symptomatic SARS-CoV-2 infection. VE against PCR- or RAT- confirmed symptomatic SARS-CoV-2 infection was 58% (95%CI: 41; 70) for all primary series vaccinations, 68% (95%CI: 51; 79) for BNT162b2, and 40% (95%CI: 1; 64) for BBIBP-CorV vaccines. Among previously infected HCWs, VE was 58% (95%CI: 11; 80). VE against medically attended COVID-19 was 52% (95%CI: 28; 68), and VE against hospitalization was 69% (95% CI: 36; 85). During the period of predominant Delta variant circulation (July-December 2021), VE against symptomatic COVID-19 was 52% (95%CI: 30; 66). Primary series vaccination with BNT162b2 and BBIBP-CorV was effective at preventing COVID-19 among HCWs, most of whom had previous infection, during a period of mainly Delta circulation. Our results support the utility of COVID-19 primary vaccine series, and the importance of increasing coverage, even among previously infected individuals.

Rapid demographic, epidemiological, and nutritional transitons have brought a pressing need to track progress in adolescent health. Here, we present country-level estimates of 12 headline indicators from the Lancet Commission on adolescent health and wellbeing, from 1990 to 2016. Indicators included those of health outcomes (disability-adjusted life-years [DALYs] due to communicable, maternal, and nutritional diseases; injuries; and non-communicable diseases); health risks (tobacco smoking, binge drinking, overweight, and anaemia); and social determinants of health (adolescent fertility; completion of secondary education; not in education, employment, or training [NEET]; child marriage; and demand for contraception satisfied with modern methods). We drew data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016, International Labour Organisation, household surveys, and the Barro-Lee education dataset. From 1990 to 2016, remarkable shifts in adolescent health occurred. A decrease in disease burden in many countries has been offset by population growth in countries with the poorest adolescent health profiles. Compared with 1990, an additional 250 million adolescents were living in multi-burden countries in 2016, where they face a heavy and complex burden of disease. The rapidity of nutritional transition is evident from the 324·1 million (18%) of 1·8 billion adolescents globally who were overweight or obese in 2016, an increase of 176·9 million compared with 1990, and the 430·7 million (24%) who had anaemia in 2016, an increase of 74·2 million compared with 1990. Child marriage remains common, with an estimated 66 million women aged 20–24 years married before age 18 years. Although gender-parity in secondary school completion exists globally, prevalence of NEET remains high for young women in multi-burden countries, suggesting few opportunities to enter the workforce in these settings. Although disease burden has fallen in many settings, demographic shifts have heightened global inequalities. Global disease burden has changed little since 1990 and the prevalence of many adolescent health risks have increased. Health, education, and legal systems have not kept pace with shifting adolescent needs and demographic changes. Gender inequity remains a powerful driver of poor adolescent health in many countries. Australian National Health and Medical Research Council, and the Bill & Melinda Gates Foundation.

Nirmatrelvir with ritonavir (Paxlovid) is indicated for patients with Coronavirus Disease 2019 (COVID-19) who are at risk for progression to severe disease due to the presence of one or more risk factors. Millions of treatment courses have been prescribed in the United States alone. Paxlovid was highly effective at preventing hospitalization and death in clinical trials. Several studies have found a protective association in real-world data, but they variously used less recent study periods, correlational methods, and small, local cohorts. Their estimates also varied widely. The real-world effectiveness of Paxlovid remains uncertain, and it is unknown whether its effect is homogeneous across demographic strata. This study leverages electronic health record data in the National COVID Cohort Collaborative's (N3C) repository to investigate disparities in Paxlovid treatment and to emulate a target trial assessing its effectiveness in reducing severe COVID-19 outcomes. This target trial emulation used a cohort of 703,647 patients with COVID-19 seen at 34 clinical sites across the United States between April 1, 2022 and August 28, 2023. Treatment was defined as receipt of a Paxlovid prescription within 5 days of the patient's COVID-19 index date (positive test or diagnosis). To emulate randomization, we used the clone-censor-weight technique with inverse probability of censoring weights to balance a set of covariates including sex, age, race and ethnicity, comorbidities, community well-being index (CWBI), prior healthcare utilization, month of COVID-19 index, and site of care provision. The primary outcome was hospitalization; death was a secondary outcome. We estimated that Paxlovid reduced the risk of hospitalization by 39% (95% confidence interval (CI) [36%, 41%]; p < 0.001), with an absolute risk reduction of 0.9 percentage points (95% CI [0.9, 1.0]; p < 0.001), and reduced the risk of death by 61% (95% CI [55%, 67%]; p < 0.001), with an absolute risk reduction of 0.2 percentage points (95% CI [0.1, 0.2]; p < 0.001). We also conducted stratified analyses by vaccination status and age group. Absolute risk reduction for hospitalization was similar among patients that were vaccinated and unvaccinate, but was much greater among patients aged 65+ years than among younger patients. We observed disparities in Paxlovid treatment, with lower rates among black and Hispanic or Latino patients, and within socially vulnerable communities. This study's main limitation is that it estimates causal effects using observational data and could be biased by unmeasured confounding. In this study of Paxlovid's real-world effectiveness, we observed that Paxlovid is effective at preventing hospitalization and death, including among vaccinated patients, and particularly among older patients. This remains true in the era of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Omicron subvariants. However, disparities in Paxlovid treatment rates imply that the benefit of Paxlovid's effectiveness is not equitably distributed.

North America's scoter species are poorly monitored relative to other waterfowl. Black Melanitta americana, surf M. perspicillata, and white‐winged M. deglandi scoter abundance and trend estimates are thus uncertain in many parts of these species' ranges. The most extensive source of waterfowl abundance and distribution data in North America is the Waterfowl breeding population and habitat survey (WBPHS). Although the WBPHS effectively monitors most species, both its timing and geographic coverage may preclude accurate scoter monitoring. Therefore, our goal was to better define when and where scoters breed to help interpret survey results and optimize potential supplemental survey efforts for scoters. We integrated satellite telemetry tracking data from scoters marked at multiple molting, staging, breeding, and wintering areas along the Atlantic and Pacific coasts to quantify continent‐wide breeding chronology and distribution. We also examined possible drivers of variation in timing of arrival, length of stay, and departure at nesting locations. We documented a northwest to southeast distribution of estimated breeding sites across Alaska and Canada. On average, scoters arrived at nest sites on 1 June. Surf scoters and Pacific black scoters arrived earliest and departed earliest. Pacific‐wintering black and white‐winged scoters began breeding earlier than Atlantic‐wintering birds. Additionally, birds arrived at nesting locations earlier in years with earlier snowmelt, and later snowmelt reduced lengths of stay for males. Breeding chronology also varied by age group, with adults arriving earlier than subadults. Our study is the first to comprehensively describe spatial variation in timing of breeding of both Atlantic and Pacific populations of all three scoter species across North America. Our results increase our understanding of how current surveys enumerate scoters and will inform possible supplemental efforts to improve continental monitoring of scoter populations.

Genome-wide association studies (GWAS) of psychiatric phenotypes have tended to focus on categorical diagnoses, but to understand the biology of mental illness it may be more useful to study traits which cut across traditional boundaries. Here, we report the results of a GWAS of mood instability as a trait in a large population cohort (UK Biobank, n = 363,705). We also assess the clinical and biological relevance of the findings, including whether genetic associations show enrichment for nervous system pathways. Forty six unique loci associated with mood instability were identified with a SNP heritability estimate of 9%. Linkage Disequilibrium Score Regression (LDSR) analyses identified genetic correlations with Major Depressive Disorder (MDD), Bipolar Disorder (BD), Schizophrenia, anxiety, and Post Traumatic Stress Disorder (PTSD). Gene-level and gene set analyses identified 244 significant genes and 6 enriched gene sets. Tissue expression analysis of the SNP-level data found enrichment in multiple brain regions, and eQTL analyses highlighted an inversion on chromosome 17 plus two brain-specific eQTLs. In addition, we used a Phenotype Linkage Network (PLN) analysis and community analysis to assess for enrichment of nervous system gene sets using mouse orthologue databases. The PLN analysis found enrichment in nervous system PLNs for a community containing serotonin and melatonin receptors. In summary, this work has identified novel loci, tissues and gene sets contributing to mood instability. These findings may be relevant for the identification of novel trans-diagnostic drug targets and could help to inform future stratified medicine innovations in mental health.

The interplay between host genetics, immunity, and microbiota is central to the pathogenesis of inflammatory bowel disease. Previous population-based studies suggested a link between antibiotic use and increased inflammatory bowel disease risk, but the mechanisms are unknown. The purpose of this study was to determine the long-term effects of antibiotic administration on microbiota composition, innate immunity, and susceptibility to colitis, as well as the mechanism by which antibiotics alter host colitogenicity.MethodsWild-type mice were given broad-spectrum antibiotics or no antibiotics for 2 weeks, and subsequent immunophenotyping and 16S rRNA gene sequencing–based analysis of the fecal microbiome were performed 6 weeks later. In a separate experiment, control and antibiotic-treated mice were given 7 days of dextran sulfate sodium, 6 weeks after completing antibiotic treatment, and the severity of colitis scored histologically. Fecal transfer was performed from control or antibiotic-treated mice to recipient mice whose endogenous microbiota had been cleared with antibiotics, and the susceptibility of the recipients to dextran sulfate sodium–induced colitis was analyzed. Naive CD4+ T cells were transferred from control and antibiotic-treated mice to immunodeficient Rag-1−/− recipients and the severity of colitis compared.ResultsAntibiotics led to sustained dysbiosis and changes in T-cell subpopulations, including reductions in colonic lamina propria total T cells and CD4+ T cells. Antibiotics conferred protection against dextran sulfate sodium colitis, and this effect was transferable by fecal transplant but not by naive T cells.ConclusionsAntibiotic exposure protects against colitis, and this effect is transferable with fecal microbiota from antibiotic-treated mice, supporting a protective effect of the microbial community.

Seizures are one of the most common reasons for emergency medical services (EMS) activation for children, and current EMS practice results in underdosing and delayed delivery of anti-seizure medication. A prehospital evidence-based guideline recommends using intranasal or intramuscular midazolam as first-line treatment for pediatric seizures. Despite attempts to implement these guidelines, one-third of children having a paramedic-witnessed seizure have ongoing seizures on emergency department (ED) arrival; this may be due to inadequate or delayed midazolam dosing. Replacing the error-prone, sequential calculations with age-based midazolam dosing may be simpler, faster, and more effective without compromising safety. The objective of this manuscript is to describe the methodology of the Pediatric Dose Optimization for Seizures in EMS (PediDOSE) study, a clinical trial designed to compare the effectiveness and safety of an EMS protocol with four age-based categories for midazolam dosing relative to the current weight-based dosing. We are conducting a large EMS-based stepped wedge trial in the Pediatric Emergency Care Applied Research Network (PECARN) by implementing midazolam dosing based on four age categories in seizure protocols in EMS systems in 20 cities. We believe that this implementation will stop more seizures before ED arrival without increasing respiratory failure rates. The primary aim of this study is to compare the effectiveness of age-based EMS midazolam dosing compared to the current weight-based dosing on seizure cessation upon ED arrival. The secondary aim is to determine the frequency of respiratory failure in children after the implementation of EMS midazolam dosing based on these age categories. If this study demonstrates that an EMS patient care protocol with age-based midazolam dosing is safe and more effective than current practice, the potential impact of this study is a paradigm shift in the treatment of pediatric seizures that can be easily implemented in EMS systems across the country. Beyond seizures, the concept of age-based dosing may also be applicable to other commonly encountered pediatric prehospital conditions for which medication may be indicated.

BackgroundChimeric antigen receptor (CAR) T-cell therapy has demonstrated clinical efficacy in hematologic malignancies1; however, implementation of these therapies in solid tumors has been challenging due to a lack of tumor-specific targets that discriminate cancer from normal cells. Previous studies using carcinoembryonic antigen (CEA) T-cell receptors and T-cell engagers have resulted in dose-limiting, on-target, off-tumor toxicities.2 3 EVEREST-1 (NCT05736731) is a seamless, phase 1/2, open-label, nonrandomized study to evaluate the safety and efficacy of A2B530, a logic-gated CEA-targeting Tmod CAR T-cell therapy, in adult patients. Tmod CAR T-cell therapy addresses challenges of on-target, off-tumor toxicity by combining a CAR-activating receptor with a blocking receptor to discriminate tumor from normal cells (figure 1).4 5 The activator receptor recognizes CEA on the surface of both tumor and normal cells. CEA is normally widely expressed in epithelial cells, particularly of the gastrointestinal (GI) system and can be upregulated in GI and lung tumors. Specificity for tumor cells is provided by a blocker that recognizes human leukocyte antigen (HLA) A*02, which is absent on tumor cells with HLA-A*02 LOH.6 LOH for HLA-A*02 is observed in solid tumor malignancies and can be detected using the Tempus next-generation sequencing testing. With this definitive discriminator target, A2B530 can potentially provide a therapeutic window to treat patients with CEA-expressing solid tumors exhibiting HLA LOH.MethodsPatients are enrolled through BASECAMP-1 (NCT04981119), a master prescreening study that identifies patients with HLA LOH at any time in the course of their disease. BASECAMP-1 eligible patients undergo leukapheresis and, when clinically appropriate, their banked T cells are manufactured for the EVEREST-1 study (figure 2). The key inclusion criteria include histologically confirmed recurrent, unresectable, locally advanced, or metastatic cancers that are associated with CEA expression: non-small cell lung (NSCLC), colorectal (CRC), or pancreatic (PANC) cancers. Patients should have received ≥1 line of prior therapy (eg, checkpoint inhibitor, molecular-targeted, or chemotherapy). The primary objective of phase 1 is to evaluate the safety and tolerability of A2B530 in patients with NSCLC, CRC, and PANC, and to identify the maximum tolerated dose and recommended phase 2 dose (RP2D). The dose-expansion phase will confirm RP2D and collect biomarker data to further characterize A2B530.Trial RegistrationNCT05736731References1. Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640–654.2. Parkhurst MR, Yang JC, Langan RC, et al. T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol Ther. 2011;19:620–626.3. Tabernero JT, Melero I, Ros W, et al. Phase Ia and Ib studies of the novel carcinoembryonic antigen (CEA) T-cell bispecific (CEA CD3 TCB) antibody as a single agent and in combination with atezolizumab: Preliminary efficacy and safety in patients with metastatic colorectal cancer (mCRC). J Clin Oncol. 2017;35(15_Suppl):3002.4. Hamburger AE, DiAndreth B, Cui J, et al. Engineered T cells directed at tumors with defined allelic loss. Mol Immunol. 2020;128:298–310.5. DiAndreth B, Hamburger A, Xu H, Kamb A. The Tmod cellular logic gate as a solution for tumor-selective immunotherapy. Clin Immunol. 2022;241:109030.6. Sandberg ML, Wang X, Martin AD, et al. A carcinoembryonic antigen-specific cell therapy selectively targets tumor cells with HLA loss of heterozygosity in vitro and in vivo. Sci Transl Med. 2022;14:eabm0306.Ethics ApprovalThis study was approved by site IRBs.Abstract 634 Figure 1CEA CAR Tmod Single Vector ConstructAbstract 634 Figure 2Everest-1 Study Design