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Antigenic cartography of immune responses to Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1)

Naturally acquired clinical immunity to Plasmodium falciparum is partly mediated by antibodies directed at parasite-derived antigens expressed on the surface of red blood cells which mediate disease and are extremely diverse. Unlike children, adults recognize a broad range of variant surface antigens (VSAs) and are protected from severe disease. Though crucial to the design and feasibility of an effective malaria vaccine, it is not yet known whether immunity arises through cumulative exposure to each of many antigenic types, cross-reactivity between antigenic types, or some other mechanism. In this study, we measured plasma antibody responses of 36 children with symptomatic malaria to a diverse panel of 36 recombinant proteins comprising part of the DBLalpha domain (the 'DBLalpha-tag') of PfEMP1, a major class of VSAs. We found that although plasma antibody responses were highly specific to individual antigens, serological profiles of responses across antigens fell into one of just two distinct types. One type was found almost exclusively in children that succumbed to severe disease (19 out of 20) while the other occurred in all children with mild disease (16 out of 16). Moreover, children with severe malaria had serological profiles that were narrower in antigen specificity and shorter-lived than those in children with mild malaria. Borrowing a novel technique used in influenza-antigenic cartography-we mapped these dichotomous serological profiles to amino acid sequence variation within a small sub-region of the PfEMP1 DBLalpha domain. By applying our methodology on a larger scale, it should be possible to identify epitopes responsible for eliciting the protective version of serological profiles to PfEMP1 thereby accelerating development of a broadly effective anti-disease malaria vaccine.
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Methodological Issues in Determining the Accuracy of Automated Office Blood Pressure Readings for Diagnosing Hypertension

ABSTRACT JAMA Intern Med Etyang, A. O. Pages:850, Volume:179, Edition:6/4/2019, Date,Jun-01 Link: https://www.ncbi.nlm.nih.gov/pubmed/31157844 Notes:Etyang, Anthony O|eng|Letter|Comment|2019/06/04 06:00|JAMA Intern Med. 2019 Jun 1;179(6):850. doi: 10.1001/jamainternmed.2019.1224. ISBN: 2168-6114 (Electronic)|2168-6106 (Linking) Permanent ID: Accession Number: 31157844 Author Address: Department of Epidemiology and Demography, KEMRI Wellcome Trust Research Programme, Kilifi, Kenya.|Kilifi County Hospital, Kilifi, Kenya. STATISTICS
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Effect of strikes by health workers on mortality between 2010 and 2016 in Kilifi, Kenya: a population-based cohort analysis

BACKGROUND: Health workers' strikes are a global occurrence. Kenya has had several strikes by health workers in recent years but their effect on mortality is unknown. We assessed the effect on mortality of six strikes by health workers that occurred from 2010 to 2016 in Kilifi, Kenya. METHODS: Using daily mortality data obtained from the Kilifi Health and Demographic Surveillance System, we fitted a negative binomial regression model to estimate the change in mortality during strike periods and in the 2 weeks immediately after strikes. We did subgroup analyses by age, cause of death, and strike week. FINDINGS: Between Jan 1, 2010, and Nov 30, 2016, we recorded 1 829 929 person-years of observation, 6396 deaths, and 128 strike days (median duration of strikes, 18.5 days [range 9-42]). In the primary analysis, no change in all-cause mortality was noted during strike periods (adjusted rate ratio [RR] 0.93, 95% CI 0.81-1.08; p=0.34). Weak evidence was recorded of variation in mortality rates by age group, with an apparent decrease among infants aged 1-11 months (adjusted RR 0.58, 95% CI 0.33-1.03; p=0.064) and an increase among children aged 12-59 months (1.75, 1.11-2.76; p=0.016). No change was noted in mortality rates in post-strike periods and for any category of cause of death. INTERPRETATION: The brief strikes by health workers during the period 2010-16 were not associated with obvious changes in overall mortality in Kilifi. The combined effects of private (and some public) health care during strike periods, a high proportion of out-of-hospital deaths, and a low number of events might have led us to underestimate the effect. FUNDING: Wellcome Trust and MRC Tropical Epidemiology Group.
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Effect of strikes by health workers on mortality between 2010 and 2016 in Kilifi, Kenya: a population-based cohort analysis

BACKGROUND: Health workers' strikes are a global occurrence. Kenya has had several strikes by health workers in recent years but their effect on mortality is unknown. We assessed the effect on mortality of six strikes by health workers that occurred from 2010 to 2016 in Kilifi, Kenya. METHODS: Using daily mortality data obtained from the Kilifi Health and Demographic Surveillance System, we fitted a negative binomial regression model to estimate the change in mortality during strike periods and in the 2 weeks immediately after strikes. We did subgroup analyses by age, cause of death, and strike week. FINDINGS: Between Jan 1, 2010, and Nov 30, 2016, we recorded 1 829 929 person-years of observation, 6396 deaths, and 128 strike days (median duration of strikes, 18.5 days [range 9-42]). In the primary analysis, no change in all-cause mortality was noted during strike periods (adjusted rate ratio [RR] 0.93, 95% CI 0.81-1.08; p=0.34). Weak evidence was recorded of variation in mortality rates by age group, with an apparent decrease among infants aged 1-11 months (adjusted RR 0.58, 95% CI 0.33-1.03; p=0.064) and an increase among children aged 12-59 months (1.75, 1.11-2.76; p=0.016). No change was noted in mortality rates in post-strike periods and for any category of cause of death. INTERPRETATION: The brief strikes by health workers during the period 2010-16 were not associated with obvious changes in overall mortality in Kilifi. The combined effects of private (and some public) health care during strike periods, a high proportion of out-of-hospital deaths, and a low number of events might have led us to underestimate the effect. FUNDING: Wellcome Trust and MRC Tropical Epidemiology Group.
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The effects of exposures to mycotoxins on immunity in children: A systematic review

The majority of childhood deaths occur in low-income countries, with vaccine-preventable infections contributing greatly. Of the many possible environmental factors that could hamper a child's immune response, mycotoxins rank among the least studied in spite of the high exposure in vulnerable populations. Aflatoxin crosses the placenta, is secreted in breast milk and is consumed widely in weaning diets by children with developing organ systems. This review describes the effects of mycotoxin exposure on immunity in children that may contribute to sub-optimal vaccine effectiveness. We searched electronic databases and references of identified articles for relevant studies on the effects of mycotoxins on the immune system in children. Geographical location, publication year, study design, sample selection, sample size, mean age, route of exposure were extracted on a standard template. Quality was assessed using Joanna Briggs Institute tool for appraisal of systematic reviews for prevalence studies. Our analyses and reporting were conducted in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Out of 806 articles screened, 5 observational studies met criteria for inclusion for review. The definition of exposures to mycotoxins and outcomes varied across the studies. Exposure to mycotoxins was positively associated with low birth weight and concentration of antibodies to asexual malaria parasites and hepatitis B surface antigen, and negatively associated with death and sIgA, antibodies to pneumococcal antigen 23. Despite the far-reaching clinical and public health effects of mycotoxin exposure among children, studies on the effects of mycotoxin exposure on immunity in children were few, small and mostly of low quality. There is an urgent need for carefully designed prospective studies in this neglected field to inform policy interventions for child health in settings where exposure to mycotoxins is high.
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The effects of aflatoxin exposure on Hepatitis B-vaccine induced immunity in Kenyan children

BACKGROUND: Globally, approximately three million children die each year from vaccine preventable infectious diseases mainly in developing countries. Despite the success of the expanded immunization program, not all infants and children around the world develop the same protective immune response to the same vaccine. A vaccine must induce a response over the basal immune response that may be driven by population-specific, environmental or socio-economic factors. Mycotoxins like aflatoxins are immune suppressants that are confirmed to interfere with both cell-mediated and acquired immunity. The mechanism of aflatoxin toxicity is through the binding of the bio-activated AFB1-8, 9-epoxide to cellular macromolecules. METHODS: We studied Hepatitis B surface antibodies [anti-HBs] levels to explore the immune modulation effects of dietary exposure to aflatoxins in children aged between one and fourteen years in Kenya. Hepatitis B vaccine was introduced for routine administration for Kenyan infants in November 2001. To assess the effects of aflatoxin on immunogenicity of childhood vaccines Aflatoxin B1-lysine in blood serum samples were determined using High Performance Liquid Chromatography with Fluorescence detection while anti-HBs were measured using Bio-ELISA anti-HBs kit. RESULTS: The mean +/- SD of AFB1-lysine adducts in our study population was 45.38 +/- 87.03 pg/mg of albumin while the geometric mean was 20.40 pg/mg. The distribution of AFB1-lysine adducts was skewed to the right. Only 98/205 (47.8%) of the study population tested positive for Hepatitis B surface antibodies. From regression analysis, we noted that for every unit rise in serum aflatoxin level, anti-HBs dropped by 0.91 mIU/ml (-0.9110038; 95% C.I -1.604948, -0.21706). CONCLUSION: Despite high coverage of routine immunization, less than half of the study population had developed immunity to HepB. Exposure to aflatoxin was high and weakly associated with low anti-HBs antibodies. These findings highlight a potentially significant role for environmental factors that may contribute to vaccine effectiveness warranting further research.
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Airway response to respiratory syncytial virus has incidental antibacterial effects

RSV infection is typically associated with secondary bacterial infection. We hypothesise that the local airway immune response to RSV has incidental antibacterial effects. Using coordinated proteomics and metagenomics analysis we simultaneously analysed the microbiota and proteomes of the upper airway and determined direct antibacterial activity in airway secretions of RSV-infected children. Here, we report that the airway abundance of Streptococcus was higher in samples collected at the time of RSV infection compared with samples collected one month later. RSV infection is associated with neutrophil influx into the airway and degranulation and is marked by overexpression of proteins with known antibacterial activity including BPI, EPX, MPO and AZU1. Airway secretions of children infected with RSV, have significantly greater antibacterial activity compared to RSV-negative controls. This RSV-associated, neutrophil-mediated antibacterial response in the airway appears to act as a regulatory mechanism that modulates bacterial growth in the airways of RSV-infected children.
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Optimizing observer performance of clinic blood pressure measurement: a position statement from the Lancet Commission on Hypertension Group

: High blood pressure (BP) is a highly prevalent modifiable cause of cardiovascular disease, stroke, and death. Accurate BP measurement is critical, given that a 5-mmHg measurement error may lead to incorrect hypertension status classification in 84 million individuals worldwide. This position statement summarizes procedures for optimizing observer performance in clinic BP measurement, with special attention given to low-to-middle-income settings, where resource limitations, heavy workloads, time constraints, and lack of electrical power make measurement more challenging. Many measurement errors can be minimized by appropriate patient preparation and standardized techniques. Validated semi-automated/automated upper arm cuff devices should be used instead of auscultation to simplify measurement and prevent observer error. Task sharing, creating a dedicated measurement workstation, and using semi-automated or solar-charged devices may help. Ensuring observer training, and periodic re-training, is critical. Low-cost, easily accessible certification programs should be considered to facilitate best BP measurement practice.
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Population-Based Estimate of Melioidosis, Kenya

Melioidosis is thought to be endemic, although underdiagnosed, in Africa. We identified 5 autochthonous cases of Burkholderia pseudomallei infection in a case series in Kenya. Incidence of B. pseudomallei bacteremia in Kenya's Kilifi County is low, at 1.5 cases per million person-years, but this result might be an underestimate.
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Effect of ten-valent pneumococcal conjugate vaccine on invasive pneumococcal disease and nasopharyngeal carriage in Kenya: a longitudinal surveillance study

BACKGROUND: Ten-valent pneumococcal conjugate vaccine (PCV10), delivered at 6, 10, and 14 weeks of age was introduced in Kenya in January, 2011, accompanied by a catch-up campaign in Kilifi County for children aged younger than 5 years. Coverage with at least two PCV10 doses in children aged 2-11 months was 80% in 2011 and 84% in 2016; coverage with at least one dose in children aged 12-59 months was 66% in 2011 and 87% in 2016. We aimed to assess PCV10 effect against nasopharyngeal carriage and invasive pneumococcal disease (IPD) in children and adults in Kilifi County. METHODS: This study was done at the KEMRI-Wellcome Trust Research Programme among residents of the Kilifi Health and Demographic Surveillance System, a rural community on the Kenyan coast covering an area of 891 km(2). We linked clinical and microbiological surveillance for IPD among admissions of all ages at Kilifi County Hospital, Kenya, which serves the community, to the Kilifi Health and Demographic Surveillance System from 1999 to 2016. We calculated the incidence rate ratio (IRR) comparing the prevaccine (Jan 1, 1999-Dec 31, 2010) and postvaccine (Jan 1, 2012-Dec 31, 2016) eras, adjusted for confounding, and reported percentage reduction in IPD as 1 minus IRR. Annual cross-sectional surveys of nasopharyngeal carriage were done from 2009 to 2016. FINDINGS: Surveillance identified 667 cases of IPD in 3 211 403 person-years of observation. Yearly IPD incidence in children younger than 5 years reduced sharply in 2011 following vaccine introduction and remained low (PCV10-type IPD: 60.8 cases per 100 000 in the prevaccine era vs 3.2 per 100 000 in the postvaccine era [adjusted IRR 0.08, 95% CI 0.03-0.22]; IPD caused by any serotype: 81.6 per 100 000 vs 15.3 per 100 000 [0.32, 0.17-0.60]). PCV10-type IPD also declined in the post-vaccination era in unvaccinated age groups (<2 months [no cases in the postvaccine era], 5-14 years [adjusted IRR 0.26, 95% CI 0.11-0.59], and >/=15 years [0.19, 0.07-0.51]). Incidence of non-PCV10-type IPD did not differ between eras. In children younger than 5 years, PCV10-type carriage declined between eras (age-standardised adjusted prevalence ratio 0.26, 95% CI 0.19-0.35) and non-PCV10-type carriage increased (1.71, 1.47-1.99). INTERPRETATION: Introduction of PCV10 in Kenya, accompanied by a catch-up campaign, resulted in a substantial reduction in PCV10-type IPD in children and adults without significant replacement disease. Although the catch-up campaign is likely to have brought forward the benefits by several years, the study suggests that routine infant PCV10 immunisation programmes will provide substantial direct and indirect protection in low-income settings in tropical Africa. FUNDING: Gavi, The Vaccine Alliance and The Wellcome Trust of Great Britain.
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