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Abstract An effective HIV-1 vaccine remains a critical unmet need for ending the AIDS epidemic. Vaccine trials conducted to date have suggested the need to increase the durability and functionality of vaccine-elicited antibodies to improve efficacy. We hypothesized that a conjugate vaccine based on the learned response to immunization with hepatitis B virus could be utilized to expand T cell help and improve antibody production against HIV-1. To test this, we developed an innovative conjugate vaccine regimen that used a modified vaccinia virus Ankara (MVA) co-expressing HIV-1 envelope (Env) and the hepatitis B virus surface antigen (HBsAg) as a prime, followed by two Env–HBsAg conjugate protein boosts. We compared the immunogenicity of this conjugate regimen to matched HIV-1 Env-only vaccines in two groups of 5 juvenile rhesus macaques previously immunized with hepatitis B vaccines in infancy. We found expansion of both HIV-1 and HBsAg-specific circulating T follicular helper cells and elevated serum levels of CXCL13, a marker for germinal center activity, after boosting with HBsAg–Env conjugate antigens in comparison to Env alone. The conjugate vaccine elicited higher levels of antibodies binding to select HIV Env antigens, but we did not observe significant improvement in antibody functionality, durability, maturation, or B cell clonal expansion. These data suggests that conjugate vaccination can engage both HIV-1 Env and HBsAg specific T cell help and modify antibody responses at early time points, but more research is needed to understand how to leverage this strategy to improve the durability and efficacy of next-generation HIV vaccines.

[Objetivo] El objetivo fue determinar cuál de las dos especies de hidras (Hydra attenuata o Hydra viridis) resultaba más sensible a dos plaguicidas, para luego usarla como parte de la batería de organismos de prueba del Laboratorio de Estudios Ecotoxicológicos (ECOTOX). [Metodología] Para esto se utilizaron diluciones de dos de los plaguicidas más comúnmente usados en el cultivo de piña en Costa Rica y detectados en muestras de agua: el herbicida diuron y el insecticida etoprofos. Se realizaron bioensayos de toxicidad con cada una de estas sustancias y con una mezcla de estas. Se registró el estado morfológico de las hidras. Además, se evaluaron la concentración de efecto medio (EC50), la concentración letal media (LC50), y las interacciones de toxicidad según tres posibilidades: antagónica, aditiva o sinérgica. [Resultados] La H. attenuata fue la especie más sensible a ambos plaguicidas, con LC50s de 16,84 mg/L y 103,01 mg/L; y EC50s de 4,24 mg/L y 23,74 mg/L para diuron y etoprofos, respectivamente. Mientras tanto la H. viridis tuvo LC50s de 36,94 mg/L y 103,01 mg/L, con EC50s de 13,64 mg/L y 53,12 mg/L, también para diuron y etoprofos, respectivamente. La exposición a la mezcla de plaguicidas solo causó mortalidad a la H. viridis y tuvo efecto sinérgico en ambas especies. [Conclusiones] Estos resultados sugieren que la H. attenuata es la especie más apropiada para la evaluación de efectos de plaguicidas, pero se deben realizar más estudios sobre las interacciones de los contaminantes en mezclas, porque estas pueden modificar su toxicidad para diferentes especies.

Rhesus macaques (RMs) are a common pre-clinical model used to test HIV vaccine efficacy and passive immunization strategies. Yet, it remains unclear to what extent the Fc-Fc receptor (FcR) interactions impacting antiviral activities of antibodies in RMs recapitulate those in humans. Here, we evaluated the FcR-related functionality of natural killer cells (NKs) from peripheral blood of uninfected humans and RMs to identify intra- and inter-species variation. NKs were screened for FcγRIIIa (human) and FcγRIII (RM) genotypes (FcγRIII(a)), receptor signaling, and antibody-dependent cellular cytotoxicity (ADCC), the latter mediated by a cocktail of monoclonal IgG1 antibodies with human or RM Fc. FcγRIII(a) genetic polymorphisms alone did not explain differences in NK effector functionality in either species cohort. Using the same parameters, hierarchical clustering separated each species into two clusters. Importantly, in principal components analyses, ADCC magnitude, NK contribution to ADCC, FcγRIII(a) cell-surface expression, and frequency of phosphorylated CD3ζ NK cells all contributed similarly to the first principal component within each species, demonstrating the importance of measuring multiple facets of NK cell function. Although ADCC potency was similar between species, we detected significant differences in frequencies of NK cells and pCD3ζ+ cells, level of cell-surface FcγRIII(a) expression, and NK-mediated ADCC (P

Background Opioid overprescribing is commonplace after total hip (THA) and total knee arthroplasty (TKA). Preliminary data demonstrated that approximately 32% of the opioids prescribed at discharge from our hospital following THA and TKA remain unused. This is a concern given that unused prescribed opioids are available for diversion and may result in misuse and abuse.Methods Pre-intervention data were collected between 1 November 2018 and 10 December 2018. An intervention bundle was then introduced, including education of patients and providers, a standardised pain management algorithm and an autopopulated discharge prescription. The aim of this quality improvement initiative was to reduce the amount of opioid (average oral morphine equivalents (OME)) dispensed (based on the discharge prescription provided) following THA and TKA at our institution by 15% by 1 April 2019.Design Using an interrupted time series design, the outcome measure was the amount of opioid (OME) dispensed from the discharge prescription provided. Process measures included the percentage of autopopulated discharge prescriptions, the percentage of patients receiving education at discharge and the percentage of nurses and residents receiving standardised education. Balancing measures included patient satisfaction with postoperative pain management, and the percentage of patients filling the second half of the part-fill or requiring a subsequent opioid prescription.Results With 600 patients identified, mean OME dispensed at discharge was reduced by 26.3% (from 522.2 to 384.9 mg) after our interventions started. Utilisation of autopopulated part-fill prescriptions was 95.8%. There was no change in patient satisfaction nor in the proportion of patients requiring an additional opioid prescription post-intervention. Only 39% of patients filled the second half of the part-fill prescription post-intervention.Conclusions Mean OME dispensed at discharge per patient was reduced with no change in patient satisfaction after introduction of the intervention bundle.

Abstract Introduction To understand when knowledge objects in a computable biomedical knowledge library are likely to be subject to regulation as a medical device in the United Kingdom. Methods A briefing paper was circulated to a multi‐disciplinary group of 25 including regulators, lawyers and others with insights into device regulation. A 1‐day workshop was convened to discuss questions relating to our aim. A discussion paper was drafted by lead authors and circulated to other authors for their comments and contributions. Results This article reports on those deliberations and describes how UK device regulators are likely to treat the different kinds of knowledge objects that may be stored in computable biomedical knowledge libraries. While our focus is the likely approach of UK regulators, our analogies and analysis will also be relevant to the approaches taken by regulators elsewhere. We include a table examining the implications for each of the four knowledge levels described by Boxwala in 2011 and propose an additional level. Conclusions If a knowledge object is described as directly executable for a medical purpose to provide decision support, it will generally be in scope of UK regulation as “software as a medical device.” However, if the knowledge object consists of an algorithm, a ruleset, pseudocode or some other representation that is not directly executable and whose developers make no claim that it can be used for a medical purpose, it is not likely to be subject to regulation. We expect similar reasoning to be applied by regulators in other countries.

Abstract Background Residual malaria transmission is the result of adaptive mosquito behavior that allows malaria vectors to thrive and sustain transmission in the presence of good access to bed nets or insecticide residual spraying. These behaviors include crepuscular and outdoor feeding as well as intermittent feeding upon livestock. Ivermectin is a broadly used antiparasitic drug that kills mosquitoes feeding on a treated subject for a dose-dependent period. Mass drug administration with ivermectin has been proposed as a complementary strategy to reduce malaria transmission. Methods A cluster randomized, parallel arm, superiority trial conducted in two settings with distinct eco-epidemiological conditions in East and Southern Africa. There will be three groups: human intervention, consisting of a dose of ivermectin (400 mcg/kg) administered monthly for 3 months to all the eligible population in the cluster (>15 kg, non-pregnant and no medical contraindication); human and livestock intervention, consisting human treatment as above plus treatment of livestock in the area with a single dose of injectable ivermectin (200 mcg/kg) monthly for 3 months; and controls, consisting of a dose of albendazole (400 mg) monthly for 3 months. The main outcome measure will be malaria incidence in a cohort of children under five living in the core of each cluster followed prospectively with monthly RDTs Discussion The second site for the implementation of this protocol has changed from Tanzania to Kenya. This summary presents the Mozambique-specific protocol while the updated master protocol and the adapted Kenya-specific protocol undergo national approval in Kenya. BOHEMIA will be the first large-scale trial evaluating the impact of ivermectin-only mass drug administration to humans or humans and cattle on local malaria transmission Trial registration ClinicalTrials.gov NCT04966702 . Registered on July 19, 2021. Pan African Clinical Trials Registry PACTR202106695877303.

Abstract Background The 2013 WHO guidelines for nutritional rehabilitation of malnourished infants under six months (u6m) focus on inpatient re-establishment of exclusive breastfeeding and recommends discharge when infant is gaining weight on breastmilk alone. Guided by a breastfeeding support tool, breastfeeding peer supporters (BFPS) can support implementation of these guideline by providing continuous individualised breastfeeding counselling to mothers of malnourished infants u6m. Recording and sharing information plays an important role in shaping in-patient care but little is known about recording practices for inpatient nutrition rehabilitation of infants u6m or how such practices affect care. We set out to explore introduction of BFPS into hospitals, and how it shaped the recording and practices of care for acutely malnourished infants u6m. Methods We applied a descriptive, exploratory design involving a pre and during intervention audit of the infant u6m inpatient records in two hospitals in Kenya, as well as pre- and post-intervention in-depth interviews with health workers involved in the care of admitted infants u6m. We developed an audit tool and used it to extract routine data on patient information from hospital records. Data were entered into a REDCap database and analyzed using STATA 17.0 software. We conducted thirty in-depth interviews with health workers exploring their care practices and their perceived effect of the presence of the BFPS on health workers treatment practices. We analysed interview data using thematic framework approach. Results A total of 170 and 65 inpatient files were available for the audit during the pre- and post-intervention period respectively. The presence of the BFPS seemed to have encouraged the recording of (i) breastfeeding status upon admission, (ii) breastfeeding management plan and (iii) reporting of its implementation and progress during treatment. The breastfeeding peer support intervention had a positive impact on breastfeeding recording and reporting practices. Health workers reported that the BFPS facilitated the recording of observed breastfeeding data and how their records influenced final inputs of breastfeeding support provided in the inpatient file. Conclusions Guideline implementation tools facilitate effective application of guidelines and should accompany any guideline formulation process and have their effectiveness at recording and monitoring progress evaluated.

Abstract Background The housing stock of rural sub-Saharan Africa is changing rapidly. With millions of new homes required over the coming decades, there is an opportunity to protect residents by screening homes from malaria mosquitoes. This study, undertaken in the Upper River Region of The Gambia, explores local perceptions of what a good house should provide for its inhabitants and responses to living in a house that has been modified as part of a randomized control trial designed to assess whether improved housing provided additional protection against clinical malaria in children (the RooPfs trial). Methods This descriptive, exploratory study was undertaken over 22 months using mixed-methods (informal conversations, observations, focus group discussions, photovoice, and a questionnaire survey) in a parallel convergent design. Analysis was conducted across the data sets using a framework approach. Following coding, the textual data were charted by a priori and emerging themes. These themes were compared with the quantitative survey results. The nature and range of views about housing and the RooPfs study modifications and the relationships among them were identified and described. Results The data were derived from a total of 35 sets of observations and informal conversations in 10 villages, 12 discussions with the photovoice photographers, 26 focus group discussions (across 13 villages) and 391 completed questionnaires. The study participants described a ‘good house’ as one with a corrugate-metal roof, cement walls (preferably cement block, but mud block covered with cement plaster was also an acceptable and cheaper substitute) and well-fitting doors. These features align with local perceptions of a modern house that provides social status and protection from physical harms. The RooPfs modifications were largely appreciated, although poor workmanship caused concerns that houses had become insecure. However, the long-term trusting relationship with the implementing institution and the actions taken to rectify problems provided reassurance and enhanced acceptability. Conclusion In developing housing to address population needs in Africa, attention should be paid to local perceptions of what is required to make a house secure for its inhabitants, as well as providing a healthy environment.

Abstract Background Undernourished children in low- and middle-income countries remain at elevated risk of death following hospital discharge, even when treated during hospitalisation using World Health Organisation recommended guidelines. The role of community health workers (CHWs) in supporting post-discharge recovery to improve outcomes has not been adequately explored. Methods This paper draws on qualitative research conducted as part of the Childhood Acute Illnesses and Nutrition (CHAIN) Network in Bangladesh and Kenya. We interviewed family members of 64 acutely ill children admitted across four hospitals (a rural and urban hospital in each country). 27 children had severe wasting or kwashiorkor on admission. Family members were interviewed in their homes soon after discharge, and up to three further times over the following six to fourteen months. These data were supplemented by observations in facilities and homes, key informant interviews with CHWs and policy makers, and a review of relevant guidelines. Results Guidelines suggest that CHWs could play a role in supporting recovery of undernourished children post-discharge, but the mechanisms to link CHWs into post-discharge support processes are not specified. Few families we interviewed reported any interactions with CHWs post-discharge, especially in Kenya, despite our data suggesting that opportunities for CHWs to assist families post-discharge include providing context sensitive information and education, identification of danger signs, and supporting linkages with community-based services and interventions. Although CHWs are generally present in communities, challenges they face in conducting their roles include unmanageable workloads, few incentives, lack of equipment and supplies and inadequate support from supervisors and some community members. Conclusion A multi-pronged approach before or on discharge is needed to strengthen linkages between CHWs and children vulnerable to poor outcomes, supported by clear guidance. To encourage scale-ability and cost-effectiveness of interventions, the most vulnerable, high-risk children, should be targeted, including undernourished children. Intervention designs must also take into account existing health worker shortages and training levels, including for CHWs, and how any new tasks or personnel are incorporated into hospital and broader health system hierarchies and systems. Any such interventions will need to be evaluated in carefully designed studies, including tracking for unintended consequences.

Characterizing older adult engagement is important to determine the effectiveness of interventions. Engagement refers to the occupying of oneself in external stimuli and is observable across multiple dimensions of behavior. Engagement of older adults is commonly investigated using a single behavioral dimension. There is a dearth of analytical methods that can simultaneously quantify both verbal and non-verbal forms of communication as proxies for engagement. In this article, we present a multidimensional technique to measure engagement of older adults using techniques appropriate for people with varying degrees of dementia. The new analytical approach measures facial movement, lexical use, and prosodic patterns of speech as indices of affective and behavioral outcomes of engagement. Contexts for engagement included a dyadic reminiscence therapy interview and a 12-week technology-driven group reminiscence therapy. Illustrative examples of the technique are described by two participants from two different groups in a naturalistic setting. Application of these analytical techniques can enhance measurement precision and further develop the science and evidence base, especially for, but not confined to, non-pharmacological interventions.

BackgroundThe growing ethical requirement to engage communities with health research has yielded diversification in approaches and targeted audiences. Conventional approaches like community “town-hall meetings,” laboratory open-days and focus group discussions, have evolved into new methods and audiences such as community drama and school engagement with health research (SEHR) involving learning interactions between researchers and school students. While engagement practices are diversifying, evaluations of these initiatives are rare in Low- and Middle-Income Countries (LMIC). This article focuses on the use of Participatory Video (PV) to explore the influence of the KEMRI-Wellcome Trust Research Programme's (KWTRP) School Engagement Programme (SEP) on the views and understandings of science and research among Kenyan state secondary school students.MethodsTwelve male and twelve female students from four coeducational schools were provided with film-making kits (1 per school), and a one-day PV training workshop. They prepared 22 short films over 8 weeks depicting their experiences and views of research and engagement and conveying their career aspirations. Schools were selected based on prior SEP participation; two schools having experienced different engagement approaches, and the others with no prior school engagement. Study data comprised footage and participant observation notes.ResultsPV provided an opportunity to simultaneously engage and evaluate to inform practice. Through student-led filmmaking, PV stimulated conversations with students about research and engagement, enabling them to share their views in a way they felt was appropriate. These interactions offered an understanding of student gains from engagement, the depth of interaction required to address perceptions held about research and the potential unintended consequences of engagement. PV also provided insights into the context and complexity of life in which engagement is situated. Understanding this context is important because of its potential influence on participation in engagement activities. We draw on these insights to make two recommendations for school engagement practice. First is that PV can provide an enjoyable and insightful means of combining engagement with evaluation. Second, given that time for SEHR is competed for against other important curricular and extracurricular activities, SEHR practitioners must ensure that activities are as beneficial and enjoyable as possible to students.

Background: Most children with steroid-sensitive nephrotic syndrome have relapses that are triggered by upper respiratory tract infections. Four small trials, mostly in children already taking maintenance corticosteroid in countries of different upper respiratory tract infection epidemiology, showed that giving daily low-dose prednisone/prednisolone for 5–7 days during an upper respiratory tract infection reduces the risk of relapse. Objectives: To determine if these findings were replicated in a large UK population of children with relapsing steroid-sensitive nephrotic syndrome on different background medication or none. Design: A randomised double-blind placebo-controlled trial, including a cost-effectiveness analysis. Setting: A total of 122 UK paediatric departments, of which 91 recruited patients. Participants: A total of 365 children with relapsing steroid-sensitive nephrotic syndrome (mean age 7.6 ± 3.5 years) were randomised (1 : 1) according to a minimisation algorithm based on background treatment. Eighty children completed 12 months of follow-up without an upper respiratory tract infection. Thirty-two children were withdrawn from the trial (14 prior to an upper respiratory tract infection), leaving a modified intention-to-treat analysis population of 271 children (134 and 137 children in the prednisolone and placebo arms, respectively). Interventions: At the start of an upper respiratory tract infection, children received 6 days of prednisolone (15 mg/m2) or an equivalent dose of placebo. Main outcome measures: The primary outcome was the incidence of first upper respiratory tract infection-related relapse following any upper respiratory tract infection over 12 months. The secondary outcomes were the overall rate of relapse, changes in background treatment, cumulative dose of prednisolone, rates of serious adverse events, incidence of corticosteroid adverse effects, change in Achenbach Child Behaviour Checklist score and quality of life. Analysis was by intention-to-treat principle. The cost-effectiveness analysis used trial data and a decision-analytic model to estimate quality-adjusted life-years and costs at 1 year, which were then extrapolated over 16 years. Results: There were 384 upper respiratory tract infections and 82 upper respiratory tract infection-related relapses in the prednisolone arm, and 407 upper respiratory tract infections and 82 upper respiratory tract infection-related relapses in the placebo arm. The number of patients experiencing an upper respiratory tract infection-related relapse was 56 (42.7%) and 58 (44.3%) in the prednisolone and placebo arms, respectively (adjusted risk difference –0.024, 95% confidence interval –0.14 to 0.09; p = 0.70). There was no evidence that the treatment effect differed when data were analysed according to background treatment. There were no significant differences in secondary outcomes between treatment arms. Giving daily prednisolone at the time of an upper respiratory tract infection was associated with increased quality-adjusted life-years (0.9427 vs. 0.9424) and decreased average costs (£252 vs. £254), when compared with standard care. The cost saving was driven by background therapy and hospitalisations after relapse. The finding was robust to sensitivity analysis. Limitations: A larger number of children than expected did not have an upper respiratory tract infection and the sample size attrition rate was adjusted accordingly during the trial. Conclusions: The clinical analysis indicated that giving 6 days of daily low-dose prednisolone at the time of an upper respiratory tract infection does not reduce the risk of relapse of steroid-sensitive nephrotic syndrome in UK children. However, there was an economic benefit from costs associated with background therapy and relapse, and the health-related quality-of-life impact of having a relapse. Future work: Further work is needed to investigate the clinical and health economic impact of relapses, interethnic differences in treatment response, the effect of different corticosteroid regimens in treating relapses, and the pathogenesis of individual viral infections and their effect on steroid-sensitive nephrotic syndrome. Trial registration: Current Controlled Trials ISRCTN10900733 and EudraCT 2012-003476-39. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 3. See the NIHR Journals Library website for further project information.