Aetiology and outcomes of sepsis in adults in sub-Saharan Africa: a systematic review and meta-analysis

Background Aetiology and outcomes of sepsis in sub-Saharan Africa (sSA) are poorly described; we performed a systematic review and meta-analysis to summarise the available data. Methods Systematic searches of PubMed and Scopus were undertaken to identify prospective studies recruiting adults (> 13 years) with community-acquired sepsis in sSA post-2000. Random effects meta-analysis of in-hospital and 30-day mortality was undertaken and available aetiology data also summarised by random effects meta-analysis. Results Fifteen studies of 2800 participants were identified. Inclusion criteria were heterogeneous. The majority of patients were HIV-infected, and Mycobacterium tuberculosis was the most common cause of blood stream infection where sought. Pooled in-hospital mortality for Sepsis-2-defined sepsis and severe sepsis was 19% (95% CI 12–29%) and 39% (95% CI 30–47%) respectively, and sepsis mortality was associated with the proportion of HIV-infected participants. Mortality and morbidity data beyond 30 days were absent. Conclusions Sepsis in sSA is dominated by HIV and tuberculosis, with poor outcomes. Optimal antimicrobial strategies, including the role of tuberculosis treatment, are unclear. Long-term outcome data are lacking. Standardised sepsis diagnostic criteria that are easily applied in low-resource settings are needed to establish an evidence base for sepsis management in sSA

rPinecone : Define sub-lineages of a clonal expansion via a phylogenetic tree

The ability to distinguish different circulating pathogen clones from each other is a fundamental requirement to understand the epidemiology of infectious diseases. Phylogenetic analysis of genomic data can provide a powerful platform to identify lineages within bacterial populations, and thus inform outbreak investigation and transmission dynamics. However, resolving differences between pathogens associated with low-variant (LV) populations carrying low median pairwise single nucleotide variant (SNV) distances remains a major challenge. Here we present rPinecone, an R package designed to define sub-lineages within closely related LV populations. rPinecone uses a root-to-tip directional approach to define sub-lineages within a phylogenetic tree according to SNV distance from the ancestral node. The utility of this software was demonstrated using both simulated outbreaks and real genomic data of two LV populations: a hospital outbreak of methicillin-resistant Staphylococcus aureus and endemic Salmonella Typhi from rural Cambodia. rPinecone identified the transmission branches of the hospital outbreak and geographically confined lineages in Cambodia. Sub-lineages identified by rPinecone in both analyses were phylogenetically robust. It is anticipated that rPinecone can be used to discriminate between lineages of bacteria from LV populations where other methods fail, enabling a deeper understanding of infectious disease epidemiology for public health purposes.Peer reviewe

Gut mucosal colonisation with extended-spectrum beta-lactamase producing Enterobacteriaceae in sub-Saharan Africa: a systematic review and meta-analysis.

Background: Extended-spectrum beta-lactamase producing Enterobacteriaceae (ESBL-E) threaten human health; and, in areas of sub-Saharan Africa (sSA) where carbapenems are not available, may render ESBL-E infections untreatable. Gut mucosal colonisation probably occurs before infection, making prevention of colonisation an attractive target for intervention, but the epidemiology of ESBL-E in sSA is poorly described. Objectives: Describe ESBL-E colonisation prevalence in sSA and risk factors associated with colonisation. Methods: Studies included were prospective cross-sectional or cohort studies reporting gut mucosal ESBL-E colonisation in any population in sSA. We searched PubMed and Scopus on 18 December 2018. We summarise the range of prevalence across sites and tabulated risk factors for colonisation. The protocol was registered (Prospero ID CRD42019123559). Results: From 2975 abstracts we identified 32 studies including a total of 8619 participants from a range of countries and settings. Six studies were longitudinal; no longitudinal studies followed patients beyond hospital discharge.  Prevalence varied between 5 and 84% with a median of 31%, with a relationship to setting: pooled ESBL-E colonisation in community studies was 18% (95% CI 12 to 28, 12 studies); in studies recruiting people at admission to hospital colonisation was 32% (95% CI 24 to 41% 8 studies); and for inpatients, colonisation was 55% (95% CI 49 to 60%, 7 studies). Antimicrobial use was associated with increased risk of ESBL-E colonisation, and protected water sources or water treatment by boiling may reduce risk. Conclusions: ESBL-E colonisation is common in sSA, but how people become carriers and why is not well understood. To inform the design of interventions to interrupt transmission in this setting requires longitudinal, community studies

Cryo-EM Structure and Molecular Dynamics Analysis of the Fluoroquinolone Resistant Mutant of the AcrB Transporter from Salmonella.

Salmonella is an important genus of Gram-negative pathogens, treatment of which has become problematic due to increases in antimicrobial resistance. This is partly attributable to the overexpression of tripartite efflux pumps, particularly the constitutively expressed AcrAB-TolC. Despite its clinical importance, the structure of the Salmonella AcrB transporter remained unknown to-date, with much of our structural understanding coming from the Escherichia coli orthologue. Here, by taking advantage of the styrene maleic acid (SMA) technology to isolate membrane proteins with closely associated lipids, we report the very first experimental structure of Salmonella AcrB transporter. Furthermore, this novel structure provides additional insight into mechanisms of drug efflux as it bears the mutation (G288D), originating from a clinical isolate of Salmonella Typhimurium presenting an increased resistance to fluoroquinolones. Experimental data are complemented by state-of-the-art molecular dynamics (MD) simulations on both the wild type and G288D variant of Salmonella AcrB. Together, these reveal several important differences with respect to the E. coli protein, providing insights into the role of the G288D mutation in increasing drug efflux and extending our understanding of the mechanisms underlying antibiotic resistance

Sequential Acquisition of T Cells and Antibodies to Nontyphoidal Salmonella in Malawian Children

Background Salmonella Typhimurium (STm) remain a prominent cause of bacteremia in sub-Saharan Africa. Complement-fixing antibodies to STm develop by 2 years of age. We hypothesized that STm-specific CD4+ T cells develop alongside this process. Methods Eighty healthy Malawian children aged 0–60 months were recruited. STm-specific CD4+ T cells producing interferon γ, tumor necrosis factor α, and interleukin 2 were quantified using intracellular cytokine staining. Antibodies to STm were measured by serum bactericidal activity (SBA) assay, and anti-STm immunoglobulin G antibodies by enzyme-linked immunosorbent assay. Results Between 2006 and 2011, STm bacteremias were detected in 449 children <5 years old. STm-specific CD4+ T cells were acquired in infancy, peaked at 14 months, and then declined. STm-specific SBA was detectable in newborns, declined in the first 8 months, and then increased to a peak at age 35 months. Acquisition of SBA correlated with acquisition of anti–STm–lipopolysaccharide (LPS) immunoglobulin G (r = 0.329 [95% confidence interval, .552–.062]; P = .01) but not anti–STm–outer membrane protein or anti–STm-flagellar protein (FliC). Conclusions Acquisition of STm-specific CD4+ T cells in early childhood is consistent with early exposure to STm or cross-reactive protein antigens priming this T-cell development. STm-specific CD4+ T cells seem insufficient to protect against invasive nontyphoidal Salmonella disease, but sequential acquisition of SBA to STm LPS is associated with a decline in its incidence

Cryo-EM structure and molecular dynamics analysis of the fluoroquinolone resistant mutant of the AcrB transporter from salmonella

Salmonella is an important genus of Gram-negative pathogens, treatment of which has become problematic due to increases in antimicrobial resistance. This is partly attributable to the overexpression of tripartite efflux pumps, particularly the constitutively expressed AcrAB-TolC. Despite its clinical importance, the structure of the Salmonella AcrB transporter remained unknown to-date, with much of our structural understanding coming from the Escherichia coli orthologue. Here, by taking advantage of the styrene maleic acid (SMA) technology to isolate membrane proteins with closely associated lipids, we report the very first experimental structure of Salmonella AcrB transporter. Furthermore, this novel structure provides additional insight into mechanisms of drug efflux as it bears the mutation (G288D), originating from a clinical isolate of Salmonella Typhimurium presenting an increased resistance to fluoroquinolones. Experimental data are complemented by state-of-the-art molecular dynamics (MD) simulations on both the wild type and G288D variant of Salmonella AcrB. Together, these reveal several important differences with respect to the E. coli protein, providing insights into the role of the G288D mutation in increasing drug efflux and extending our understanding of the mechanisms underlying antibiotic resistance

Public health surveillance in the UK revolutionises our understanding of the invasive Salmonella Typhimurium epidemic in Africa

Background:The ST313 sequence type ofSalmonellaTyphimurium causes invasive non-typhoidal salmonellosis and wasthought to be confined to sub-Saharan Africa. Two distinct phylogenetic lineages of African ST313 have been identified.Methods:We analysed the whole genome sequences ofS. Typhimurium isolates from UK patients that weregenerated following the introduction of routine whole-genome sequencing (WGS) ofSalmonella entericabyPublic Health England in 2014.Results:We found that 2.7% (84/3147) ofS. Typhimurium from patients in England and Wales were ST313 and wereassociated with gastrointestinal infection. Phylogenetic analysis revealed novel diversity of ST313 that distinguishedUK-linked gastrointestinal isolates from African-associated extra-intestinal isolates. The majority of genome degradationof African ST313 lineage 2 was conserved in the UK-ST313, but the African lineages carried a characteristic prophageand antibiotic resistance gene repertoire. These findings suggest that a strong selection pressure exists for certainhorizontally acquired genetic elements in the African setting. One UK-isolated lineage 2 strain that probably originatedin Kenya carried a chromosomally locatedblaCTX-M-15, demonstrating the continual evolution of this sequence type inAfrica in response to widespread antibiotic usage.Conclusions:The discovery of ST313 isolates responsible for gastroenteritis in the UK reveals new diversity in thisimportant sequence type. This study highlights thepower of routine WGS by public health agencies to makeepidemiologically significant deductions that would be missed by conventional microbiological methods. Wespeculate that the niche specialisation of sub-Saharan African ST313 lineages is driven in part by the acquisitionof accessory genome elements

A Study of Characteristics of work of the school teacher for every place of work -What should be know with the staff of mental health support？-

学校教師の仕事は非常に複雑で難しく、教師は非常に多忙である。そのため、教師のメンタルヘルスは次第に悪化し、休職者も増える傾向である。ところが精神科医やカウンセラーなどの教師を支援する立場にある専門家の中には、「教師の仕事は楽である」という誤解をしているものもいる。それでは十分な支援ができるはずもない。筆者は、支援にあたる者が、教師の業務の特性や学校組織の特徴を知りことが重要であると考えた。そこで小学校、中学校、高等学校ごとに、その職場の特性や人間関係の特徴を列記し、不調の背景要因を整理した。The school teachers' works are very complicated and difficult, and most of teachers are very busy. Therefore, the state of teachers' mental health is in a very bad tendency. However, among the specialists in the position which supports teachers, such as a psychiatrist and counselor, there are those who have misunderstanding, saying "A teacher's work is easy". The writer thought it important that a psychiatrist and counselor got to know the characteristic of a teacher's work and culture peculiar to school. So, in thia paper, the writer summarized the characteristic of the work for every elementary school, junior high school, and high school, and described the factor to which a school teacher becomes out of condition mentally

Bacterial Meningitis in Malawian Adults, Adolescents, and Children During the Era of Antiretroviral Scale-up and Haemophilus influenzae Type b Vaccination, 2000-2012

Background We documented bacterial meningitis trends among adults and children presenting to a large teaching hospital in Malawi during introduction of Haemophilus influenzae type b (Hib) vaccination and the rollout of antiretroviral therapy (ART). Methods We analyzed data from 51 000 consecutive cerebrospinal fluid (CSF) samples obtained from adults, adolescents, and children with suspected meningitis admitted to the Queen Elizabeth Central Hospital, Blantyre, Malawi, between 2000 and 2012. Results There was a significant decline in the total number of CSF isolates over 12 years (incident rate ratio [IRR], 0.93; 95% CI, .92–.94; P < .001). This decline was entirely in children aged <5 years (IRR, 0.87; 95% CI, .85–.88; P < .001) and coincided with the introduction of Hib vaccination. The number of adult isolates has remained unchanged (IRR, 0.99; 95% CI, .97–1.0; P = .135) despite rapid scale-up of ART provision. In children aged <5 years, Streptococcus pneumoniae, nontyphoidal salmonellae (NTS), and Hib were the most frequently isolated pathogens, and have declined over this time period. Streptococcus pneumoniae was the most frequently isolated pathogen in older children and adults. Estimated incidence of bacterial meningitis in 2012 was 20 per 100 000 cases in children aged <14 years, 6 per 100 000 adolescents, and 10 per 100 000 adults. Conclusions Rates of bacterial meningitis have declined in children, but not adults, coinciding with the introduction of Hib vaccination. The highly successful rollout of ART has not yet resulted in a reduction in the incidence in adults where the burden remains high. Long-term surveillance of bacterial meningitis outside of the epidemic “meningitis belt” in Africa is essential

Young people's uses of celebrity: Class, gender and 'improper' celebrity

This is an Author's Accepted Manuscript of an article published in Discourse: Studies in the Cultural Politics of Education, 34(1), 2013, copyright Taylor & Francis, available online at: http://www.tandfonline.com/10.1080/01596306.2012.698865.In this article, we explore the question of how celebrity operates in young people's everyday lives, thus contributing to the urgent need to address celebrity's social function. Drawing on data from three studies in England on young people's perspectives on their educational and work futures, we show how celebrity operates as a classed and gendered discursive device within young people's identity work. We illustrate how young people draw upon class and gender distinctions that circulate within celebrity discourses (proper/improper, deserving/undeserving, talented/talentless and respectable/tacky) as they construct their own identities in relation to notions of work, aspiration and achievement. We argue that these distinctions operate as part of neoliberal demands to produce oneself as a ‘subject of value’. However, some participants produced readings that show ambivalence and even resistance to these dominant discourses. Young people's responses to celebrity are shown to relate to their own class and gender position.The Arts and Humanities Research Council, the British Academy, the Economic and Social Research Council, and the UK Resource Centre for Women in Science Engineering and Technology