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Rift Valley fever is a viral epidemic illness prevalent in Africa that can be fatal or result in debilitating sequelae in humans. No vaccines are available for human use. We aimed to evaluate the safety and immunogenicity of a non-replicating simian adenovirus-vectored Rift Valley fever (ChAdOx1 RVF) vaccine in humans. We conducted a phase 1, first-in-human, open-label, dose-escalation trial in healthy adults aged 18–50 years at the Centre for Clinical Vaccinology and Tropical Medicine, Oxford, UK. Participants were required to have no serious comorbidities or previous history of receiving an adenovirus-based vaccine before enrolment. Participants were non-randomly allocated to receive a single ChAdOx1 RVF dose of either 5 × 109 virus particles (vp), 2·5 × 1010 vp, or 5 × 1010 vp administered intramuscularly into the deltoid of their non-dominant arm; enrolment was sequential and administration was staggered to allow for safety to be assessed before progression to the next dose. Primary outcome measures were assessment of adverse events and secondary outcome measures were Rift Valley fever neutralising antibody titres, Rift Valley fever GnGc-binding antibody titres (ELISA), and cellular response (ELISpot), analysed in all participants who received a vaccine. This trial is registered with ClinicalTrials.gov (NCT04754776). Between June 11, 2021, and Jan 13, 2022, 15 volunteers received a single dose of either 5 × 109 vp (n=3), 2·5 × 1010 vp (n=6), or 5 × 1010 vp (n=6) ChAdOx1 RVF. Nine participants were female and six were male. 14 (93%) of 15 participants reported solicited local adverse reactions; injection-site pain was the most frequent (13 [87%] of 15). Ten (67%) of 15 participants (from the 2·5 × 1010 vp and 5 × 1010 vp groups only) reported systemic symptoms, which were mostly mild in intensity, the most common being headache (nine [60%] of 15) and fatigue (seven [47%]). All unsolicited adverse events reported within 28 days were either mild or moderate in severity; gastrointestinal symptoms were the most common reaction (at least possibly related to vaccination), occurring in four (27%) of 15 participants. Transient decreases in total white cell, lymphocyte, or neutrophil counts occurred at day 2 in some participants in the intermediate-dose and high-dose groups. Lymphopenia graded as severe occurred in two participants in the 5 × 1010 vp group at a single timepoint, but resolved at the subsequent follow-up visit. No serious adverse events occurred. Rift Valley fever neutralising antibodies were detectable across all dose groups, with all participants in the 5 × 1010 vp dose group having high neutralising antibody titres that peaked at day 28 after vaccination and persisted through the 3-month follow-up. High titres of binding IgG targeting Gc glycoprotein were detected whereas those targeting Gn were comparatively low. IFNγ cellular responses against Rift Valley fever Gn and Gc glycoproteins were observed in all participants except one in the 5 × 1010 vp dose group. These IFNγ responses peaked at 2 weeks after vaccination, were highest in the 5 × 1010 vp dose group, and tended to be more frequent against the Gn glycoprotein. ChAdOx1 RVF was safe, well tolerated, and immunogenic when administered as a single dose in this study population. The data support further clinical development of ChAdOx1 RVF for human use. UK Department of Health and Social Care through the UK Vaccines Network, Oak Foundation, and the Wellcome Trust. For the Swahili translation of the abstract see Supplementary Materials section.

Clinical immunity to malaria can lead to asymptomatic infection, but the underlying mechanisms remain unclear. To examine the development of clinical immunity, we conducted a multi-cohort, repeat controlled human malaria infection (CHMI) study with Plasmodium vivax , and a heterologous rechallenge with P. falciparum (ClinicalTrials.gov NCT03797989). Malaria-naïve adults underwent CHMI up to three times, by administration of red blood cells infected with P. vivax PvW1 clone or P. falciparum 3D7 clone. Nineteen participants underwent primary CHMI with P. vivax , 12 returned for secondary homologous CHMI and 2 for tertiary homologous CHMI. Six participants who had completed P. vivax CHMI then underwent heterologous rechallenge with P. falciparum . We find that clinical immunity to P. vivax develops rapidly after a single CHMI, protecting participants against fever and laboratory abnormalities. This is underpinned by the attenuation of inflammatory cytokines and chemokines, as well as reduced coagulation and endothelium activation. In contrast, there is no evidence of anti-parasite immunity, suggesting that mechanisms of clinical immunity can operate independently of pathogen load to reduce the damage caused by malaria infection. In addition, we show that clinical immunity to P. vivax is parasite species-specific and provides no protection against CHMI with P. falciparum . Understanding the mechanisms behind clinical immunity to malaria is crucial for developing effective interventions. Here, the authors demonstrate that clinical immunity to Plasmodium vivax develops rapidly after a single controlled human malaria infection, reducing inflammatory responses and protecting against symptoms, while not significantly affecting parasite load.

RationaleGABAA receptors containing the α5 subunit (i.e., α5GABAA receptors) appear to be critically involved in the reinforcing and subjective effects of alcohol. Their role in alcohol relapse remains unknown.ObjectivesPharmacological approaches were used to probe the role of α5GABAA receptors in alcohol seeking induced by re-exposure to a sweetened alcohol-paired cue, as well as in alcohol + sucrose vs. sucrose self-administration.MethodsFor reinstatement studies, rats were trained to self-administer alcohol under a fixed-ratio schedule in which responding was maintained by alcohol + sucrose deliveries and an alcohol-paired stimulus. Sweetened alcohol seeking was extinguished by eliminating solution deliveries and the sweetened alcohol-paired stimulus. During reinstatement tests, animals received pretreatments of an α5GABAA inverse agonist (L-655,708) or an agonist (QH-ii-066) prior to sessions in which presentation of the sweetened alcohol-paired stimulus was restored, but no solution was delivered. For self-administration studies, rats were trained to self-administer alcohol + sucrose or sucrose under a fixed-ratio schedule. Once stable, animals received pretreatments of QH-ii-066, L-655,708, the inverse agonist RY-023, or naltrexone.ResultsL-655,708 attenuated reinstatement of sweetened alcohol seeking by alcohol + sucrose-paired cues; whereas sweetened alcohol-seeking behavior was augmented by QH-ii-066, albeit at different doses in different rats. Both L-655,708 and RY-023 selectively reduced alcohol + sucrose vs. sucrose self-administration. In contrast, naltrexone reduced both alcohol + sucrose and sucrose self-administration; whereas QH-ii-066 enhanced sucrose self-administration only.Conclusionsα5GABAA receptors play a key role in the modulation of sweetened alcohol cue-induced reinstatement, as well as in alcohol + sucrose but not sucrose self-administration. Inverse agonist activity at α5GABAA receptors may offer a novel strategy for both the reduction of problematic drinking and the prevention of relapse.

Little is known about the experiences of parents who are in receipt of in-patient psychiatric care or about what interventions are employed to support them in their parenting role. The objective of the current study is to review two complementary areas of research: (a) research examining interventions developed to support the parent-child relationship within these settings; and (b) research focused on the experience of parents in in-patient settings. For studies reporting on parents' experience, qualitative accounts of past or present psychiatric in-patients (child aged 1-18 years) were included. For intervention studies, the intervention had to focus on supporting the parenting role and/or the parent-child dyad of parents (child aged 1-18 years) in current receipt of in-patient care. Four bibliographic databases (PubMed, SCOPOS, Web of Science and PsychINFO) were searched for relevant published and unpublished literature from 1 January 1980 to 26 July 2022. Intervention studies were appraised using the Mixed Methods Appraisal Tool. Qualitative papers were assessed using the Critical Appraisal Skills Programme tool. Data were extracted using tools designed for the study. Qualitative data were synthesised using thematic analysis. The protocol was registered with the International Prospective Register of Systematic Reviews (reference CRD42022309065). Twenty-four papers (eight intervention studies and 16 studies examining parent experience) were included in the review. In-patient parents commonly reported hospital admission as having a negative impact on their parenting. Very few robust reports of interventions designed to support parents in receipt of psychiatric in-patient care were found. Despite the identified need for support by parents who are receiving in-patient care, there is currently no intervention of this nature running in the UK health service.

Abstract Routine data on vaccine uptake are not disaggregated by lesbian, gay, bisexual, transgender, queer, and other sexual identities (LGBTQ+) populations, despite higher risk of infection and severe disease. We found comparable vaccination uptake patterns among 1032 LGBTQ+ New Yorkers and the general population. We identified critical socioeconomic factors that were associated with vaccine hesitancy in this economically vulnerable population.

Background Warfarin is an anticoagulant effective in preventing stroke, but it has a narrow therapeutic range requiring optimal adherence to achieve the most favorable effects. Purpose The goal of this study was to examine specific patient factors that might help explain warfarin non-adherence at outpatient anticoagulation clinics. Method In a prospective cohort study of 156 adults, we utilized logistic regression analyses to examine the relationship between the five Treatment Prognostics scales from the Millon Behavioral Medicine Diagnostic (MBMD), as well as three additional MBMD scales (Depression, Future Pessimism, and Social Isolation), and daily warfarin non-adherence assessed using electronic medication event monitoring systems caps over a median of 139 days. Results Four of the five Treatment Prognostic scales and greater social isolation were associated with warfarin non-adherence. When controlling for pertinent demographic and medical variables, the Information Discomfort scale remained significantly associated with warfarin non-adherence over time. Conclusion Although several factors were related to warfarin non-adherence, patients reporting a lack of receptivity to details regarding their medical illness seemed most at risk for warfarin non-adherence. This information might aid in the development of interventions to enhance warfarin adherence and perhaps reduce adverse medical events.

The story of one particular family's involvement in these networks provides fine-grained, intimate details of education practices in late Tokugawa Shinano, from the critical role played by personal relationships to the pattern of the school day and year.