Prevention of overweight and hypertension through cardiorespiratory fitness and extracurricular sport participation among South African schoolchildren

Hypertension and overweight are growing public health concerns in school-aged children. We examined whether cardiorespiratory fitness and sport participation contribute to the prevention of hypertension and overweight. We conducted a cluster-randomized controlled trial with 853 children aged 8-13 years in eight primary schools in Port Elizabeth, South Africa. Cardiorespiratory fitness, sport participation, body mass index, and blood pressure were assessed at baseline and after a physical activity intervention, which took place at two time-points (July-September 2015 and February-April 2016) for 10 weeks each. Mixed logistic regressions were employed to analyze the data. At baseline, 18.8% of the children were classified as overweight/obese and 13.5% as hypertensive. High cardiorespiratory fitness and high sport participation were negatively associated with overweight/obesity, while high sport participation was associated with lower risk for hypertension. Longitudinally, normal weight children who initially had higher cardiorespiratory fitness showed less decrease in this variable, while those who participated in the physical activity intervention were less likely to become overweight/obese. High cardiorespiratory fitness and sport participation are linked with children's weight status. Children who are fit and participate regularly in sport outside school hours are less likely to be hypertensive. Our findings highlight the importance of regular extracurricular physical activity and maintaining cardiorespiratory fitness levels

Evaluation of in vitro Assays to Assess the Modulation of Dendritic Cells Functions by Therapeutic Antibodies and Aggregates

Therapeutic antibodies have the potential to induce immunogenicity leading to the development of anti-drug antibodies (ADA) that consequently may result in reduced serum drug concentrations, a loss of efficacy or potential hypersensitivity reactions. Among other factors, aggregated antibodies have been suggested to promote immunogenicity, thus enhancing ADA production. Dendritic cells (DC) are the most efficient antigen-presenting cell population and are crucial for the initiation of T cell responses and the subsequent generation of an adaptive immune response. This work focuses on the development of predictive in vitro assays that can monitor DC maturation, in order to determine whether drug products have direct DC stimulatory capabilities. To this end, four independent laboratories aligned a common protocol to differentiate human monocyte-derived DC (moDC) that were treated with either native or aggregated preparations of infliximab, natalizumab, adalimumab, or rituximab. These drug products were subjected to different forms of physical stress, heat and shear, resulting in aggregation and the formation of subvisible particles. Each partner developed and optimized assays to monitor diverse end-points of moDC maturation: measuring the upregulation of DC activation markers via flow cytometry, analyzing cytokine, and chemokine production via mRNA and protein quantification and identifying cell signaling pathways via quantification of protein phosphorylation. These study results indicated that infliximab, with the highest propensity to form aggregates when heat-stressed, induced a marked activation of moDC as measured by an increase in CD83 and CD86 surface expression, IL-1β, IL-6, IL-8, IL-12, TNFα, CCL3, and CCL4 transcript upregulation and release of respective proteins, and phosphorylation of the intracellular signaling proteins Syk, ERK1/2, and Akt. In contrast, natalizumab, which does not aggregate under these stress conditions, induced no DC activation in any assay system, whereas adalimumab or rituximab aggregates induced only slight parameter variation. Importantly, the data generated in the different assay systems by each partner site correlated and supported the use of these assays to monitor drug-intrinsic propensities to drive maturation of DC. This moDC assay is also a valuable tool as an in vitro model to assess the intracellular mechanisms that drive DC activation by aggregated therapeutic proteins

The long-term impact of the leprosy post-exposure prophylaxis (Lpep) program on leprosy incidence:a modelling study

Background The Leprosy Post-Exposure Prophylaxis (LPEP) program explored the feasibility and impact of contact tracing and the provision of single dose rifampicin (SDR) to eligible contacts of newly diagnosed leprosy patients in Brazil, India, Indonesia, Myanmar, Nepal, Sri Lanka and Tanzania. As the impact of the programme is difficult to establish in the short term, we apply mathematical modelling to predict its long-term impact on the leprosy incidence. Methodology The individual-based model SIMCOLEP was calibrated and validated to the historic leprosy incidence data in the study areas. For each area, we assessed two scenarios: 1) continua-tion of existing routine activities as in 2014; and 2) routine activities combined with LPEP starting in 2015. The number of contacts per index patient screened varied from 1 to 36 between areas. Projections were made until 2040. Principal findings In all areas, the LPEP program increased the number of detected cases in the first year(s) of the programme as compared to the routine programme, followed by a faster reduction after-wards with increasing benefit over time. LPEP could accelerate the reduction of the leprosy incidence by up to six years as compared to the routine programme. The impact of LPEP varied by area due to differences in the number of contacts per index patient included and differences in leprosy epidemiology and routine control programme. Conclusions The LPEP program contributes significantly to the reduction of the leprosy incidence and could potentially accelerate the interruption of transmission. It would be advisable to include contact tracing/screening and SDR in routine leprosy programmes.</p

Effects of a school-based health intervention program in marginalized communities of Port Elizabeth, South Africa (the KaziBantu Study): protocol for a randomized controlled trial

The burden of poverty-related infectious diseases remains high in low- and middle-income countries, while noncommunicable diseases (NCDs) are rapidly gaining importance. To address this dual disease burden, the KaziBantu project aims at improving and promoting health literacy as a means for a healthy and active lifestyle. The project implements a school-based health intervention package consisting of physical education, moving-to-music, and specific health and nutrition education lessons from the KaziKidz toolkit. It is complemented by the KaziHealth workplace health intervention program for teachers.; The aim of the KaziBantu project is to assess the effect of a school-based health intervention package on risk factors for NCDs, health behaviors, and psychosocial health in primary school children in disadvantaged communities in Port Elizabeth, South Africa. In addition, we aim to test a workplace health intervention for teachers.; A randomized controlled trial (RCT) will be conducted in 8 schools. Approximately 1000 grade 4 to grade 6 school children, aged 9 to 13 years, and approximately 60 teachers will be recruited during a baseline survey in early 2019. For school children, the study is designed as a 36-week, cluster RCT (KaziKidz intervention), whereas for teachers, a 24-week intervention phase (KaziHealth intervention) is planned. The intervention program consists of 3 main components; namely, (1) KaziKidz and KaziHealth teaching material, (2) workshops, and (3) teacher coaches. After randomization, 4 of the 8 schools will receive the education program, whereas the other schools will serve as the control group. Intervention schools will be further randomized to the different combinations of 2 additional intervention components: teacher workshops and teacher coaching.; This study builds on previous experience and will generate new evidence on health intervention responses to NCD risk factors in school settings as a decision tool for future controlled studies that will enable comparisons among marginalized communities between South African and other African settings.; The KaziKidz teaching material is a holistic educational and instructional tool designed for primary school teachers in low-resource settings, which is in line with South Africa's Curriculum and Assessment Policy Statement. The ready-to-use lessons and assessments within KaziKidz should facilitate the use and implementation of the teaching material. Furthermore, the KaziHealth interventions should empower teachers to take care of their health through knowledge gains regarding disease risk factors, physical activity, fitness, psychosocial health, and nutrition indicators. Teachers as role models will be able to promote better health behaviors and encourage a healthy and active lifestyle for children at school. We conjecture that improved health and well-being increase teachers' productivity with trickle-down effects on the children they teach and train.; International Standard Randomized Controlled Trial Number (ISRCTN): 18485542; http://www.isrctn.com/ISRCTN18485542.; DERR1-10.2196/14097

Study protocol for a cluster randomised controlled factorial design trial to assess the effectiveness and feasibility of reactive focal mass drug administration and vector control to reduce malaria transmission in the low endemic setting of Namibia.

INTRODUCTION: To interrupt malaria transmission, strategies must target the parasite reservoir in both humans and mosquitos. Testing of community members linked to an index case, termed reactive case detection (RACD), is commonly implemented in low transmission areas, though its impact may be limited by the sensitivity of current diagnostics. Indoor residual spraying (IRS) before malaria season is a cornerstone of vector control efforts. Despite their implementation in Namibia, a country approaching elimination, these methods have been met with recent plateaus in transmission reduction. This study evaluates the effectiveness and feasibility of two new targeted strategies, reactive focal mass drug administration (rfMDA) and reactive focal vector control (RAVC) in Namibia. METHODS AND ANALYSIS: This is an open-label cluster randomised controlled trial with 2×2 factorial design. The interventions include: rfMDA (presumptive treatment with artemether-lumefantrine (AL)) versus RACD (rapid diagnostic testing and treatment using AL) and RAVC (IRS with Acellic 300CS) versus no RAVC. Factorial design also enables comparison of the combined rfMDA+RAVC intervention to RACD. Participants living in 56 enumeration areas will be randomised to one of four arms: rfMDA, rfMDA+RAVC, RACD or RACD+RAVC. These interventions, triggered by index cases detected at health facilities, will be targeted to individuals residing within 500 m of an index. The primary outcome is cumulative incidence of locally acquired malaria detected at health facilities over 1 year. Secondary outcomes include seroprevalence, infection prevalence, intervention coverage, safety, acceptability, adherence, cost and cost-effectiveness. ETHICS AND DISSEMINATION: Findings will be reported on clinicaltrials.gov, in peer-reviewed publications and through stakeholder meetings with MoHSS and community leaders in Namibia. TRIAL REGISTRATION NUMBER: NCT02610400; Pre-results

Leprosy post-exposure prophylaxis with single-dose rifampicin

_Objective:_ Leprosy post-exposure prophylaxis with single-dose rifampicin (SDRPEP) has proven effective and feasible, and is recommended by WHO since 2018. This SDR-PEP toolkit was developed through the experience of the leprosy postexposure prophylaxis (LPEP) programme. It has been designed to facilitate and standardise the implementation of contact tracing and SDR-PEP administration in regions and countries that start the intervention. _Results:_ Four tools were developed, incorporating the current evidence for SDRPEP and the methods and learnings from the LPEP project in eight countries. (1) th

Evaluation of in vitro assays to assess the modulation of dendritic cells functions by therapeutic antibodies and aggregates

Therapeutic antibodies have the potential to induce immunogenicity leading to the development of anti-drug antibodies (ADA) that consequently may result in reduced serum drug concentrations, a loss of efficacy or potential hypersensitivity reactions. Among other factors, aggregated antibodies have been suggested to promote immunogenicity, thus enhancing ADA production. Dendritic cells (DC) are the most efficient antigen-presenting cell population and are crucial for the initiation of T cell responses and the subsequent generation of an adaptive immune response. This work focuses on the development of predictive in vitro assays that can monitor DC maturation, in order to determine whether drug products have direct DC stimulatory capabilities. To this end, four independent laboratories aligned a common protocol to obtain human monocyte-derived DC (moDC) that were treated with either native or aggregated preparations of infliximab, natalizumab, adalimumab or rituximab. These drug products were subjected to different forms of physical stress, heat and shear, resulting in aggregation and the formation of subvisible particles. Each partner developed and optimized assays to monitor diverse end-points of moDC maturation: measuring the upregulation of DC activation markers via flow cytometry, analysing cytokine and chemokine production via mRNA and protein quantification, and identifying cell signalling pathways via protein phosphorylation. These study results indicated that infliximab, with the highest propensity to form aggregates when heat-stressed, induced a marked activation of moDC as measured by an increase in CD83 and CD86 surface expression, IL-1β, IL-6, IL-8, IL-12, TNFα, CCL3 and CCL4 transcript upregulation and release of respective proteins, and phosphorylation of the intracellular signalling proteins Syk, ERK1/2 and Akt. In contrast, natalizumab, which does not aggregate under these stress conditions, induced no DC activation in any assay system, whereas adalimumab or rituximab aggregates induced only slight parameter variation. Importantly, the data generated in the different assay systems by each partner site correlated and supported the use of these assays to monitor drug-intrinsic propensities to drive maturation of DC. This moDC assay is also a valuable tool as an in vitro model to assess the intracellular mechanisms that drive DC activation by aggregated therapeutic proteins

A whole blood in vitro cytokine release assay with aqueous monoclonal antibody presentation for the prediction of therapeutic protein induced cytokine release syndrome in humans

The administration of several monoclonal antibodies (mAbs) to humans has been associated with acute adverse events characterized by clinically significant release of cytokines in the blood. The limited predictive value of toxicology species in this field has triggered intensive research to establish human in vitro assays using peripheral blood mononuclear cells or blood to predict cytokine release in humans. A thorough characterization of these assays is required to understand their predictive value for hazard identification and risk assessment in an optimal manner, and to highlight potential limitations of individual assay formats. We have characterized a whole human blood cytokine release assay with only minimal dilution by the test antibodies (95% v/v blood) in aqueous presentation format, an assay which so far received less attention in the scientific world with respect to evaluation of its suitability to predict cytokine release in humans. This format was compared with a human PBMC assay with immobilized mAbs presentation already well-characterized by others. The test mAbs were anti-CD28 superagonist TGN1412-like material (TGN1412L), another anti-CD28 superagonistic mAb (ANC28.1), a T-cell depleting mAb (Orthoclone™), and a TGN1412 isotype-matched control (Tysabri™) not associated with clinically-relevant cytokine release. The whole blood assay was found suitable for hazard identification due to the production of the expected clinical cytokine signature for the tested mAbs and showed markedly lower assay background and cytokine release with the isotype-matched control mAb Tysabri™. However, lower donor response rates to TGN1412L for most tested cytokines were observed when compared to the PBMC assay. Importantly, quantitative and qualitative differences in the relative cytokine responses to the individual mAbs, in the concentration-response relationships and the prominent cytokine signatures for individual mAbs in the two formats reflect diverging mechanisms of cytokine release and different levels of dependency on high density coating even for two anti-CD28 superagonistic antibodies. These results clearly show that one generic approach to assessment of cytokine release using in vitro assays is not sufficient, but rather the assay format needs to be optimized considering the target characteristics and the mechanistic features of the therapeutic mAbs being evaluated