Point-of-Care Diagnostics for Infection and Antimicrobial Resistance in Sub-Saharan Africa - A Narrative Review.

INTRODUCTION Sub-Saharan African (SSA) countries are severely impacted by antimicrobial resistance (AMR). Due to gaps in access to diagnostics in SSA the true extent of AMR remains unknown. This diagnostic gap affects patient management and leads to significant antimicrobial overuse. This review explores how point-of-care (POC) testing for pathogen identification and AMR may be used to close the diagnostic gap in SSA countries. METHODS A narrative review exploring current clinical practice and novel developments in the field of point-of-care (POC) testing for infectious diseases and AMR. FINDINGS POC assays for identification of various pathogens have been successfully rolled out in SSA countries. While implementation studies have mostly highlighted impressive test performance of POC assays, there is limited data on effect of implementation on clinical outcomes and cost-effectiveness. We did not encounter local studies of host-directed POC assays relevant to AMR. Novel POC assays using real-time PCR, isothermal amplification, microfluidics and other technologies are in various stages of development. DISCUSSION Available literature shows that POC testing for AMR applications is implementable in SSA and holds the potential to reduce the diagnostic gap. Implementation will require effective regulatory pathways, incorporation of POC testing in clinical and laboratory guidelines, and adequate value capture in existing health financing models

Editorial: Neuromechanics in Movement and Disease With Physiological and Pathophysiological Implications: From Fundamental Experiments to Bio-Inspired Technologies.

SCOPUS: ed.jinfo:eu-repo/semantics/publishe

Sentinel seroprevalence of SARS-CoV-2 in Gauteng Province, South Africa, August - October 2020

Background. Estimates of prevalence of anti-SARS-CoV-2 antibody positivity (seroprevalence) for tracking the COVID-19 epidemic are lacking for most African countries.Objectives. To determine the prevalence of antibodies against SARS-CoV-2 in a sentinel cohort of patient samples received for routine testing at tertiary laboratories in Johannesburg, South Africa.Methods. This sentinel study was conducted using remnant serum samples received at three National Health Laboratory Service laboratories in the City of Johannesburg (CoJ) district. Collection was from 1 August to 31 October 2020. We extracted accompanying laboratory results for glycated haemoglobin (HbA1c), creatinine, HIV, viral load and CD4 T-cell count. An anti-SARS-CoV-2 targeting the nucleocapsid (N) protein of the coronavirus with higher affinity for IgM and IgG antibodies was used. We reported crude as well as population-weighted and test-adjusted seroprevalence. Multivariate logistic regression analysis was used to determine whether age, sex, HIV and diabetic status were associated with increased risk for seropositivity.Results. A total of 6 477 samples were analysed, the majority (n=5 290) from the CoJ region. After excluding samples with no age or sex stated, the model population-weighted and test-adjusted seroprevalence for the CoJ (n=4 393) was 27.0% (95% confidence interval (CI) 25.4 - 28.6). Seroprevalence was highest in those aged 45 - 49 years (29.8%; 95% CI 25.5 - 35.0) and in those from the most densely populated areas of the CoJ. Risk for seropositivity was highest in those aged 18 - 49 years (adjusted odds ratio (aOR) 1.52; 95% CI 1.13 - 2.13; p=0.0005) and in samples from diabetics (aOR 1.36; 95% CI 1.13 - 1.63; p=0.001).Conclusions. Our study conducted between the first and second waves of the pandemic shows high levels of current infection among patients attending public health facilities in Gauteng Province

Diagnostic accuracy of a three-gene Mycobacterium tuberculosis host response cartridge using fingerstick blood for childhood tuberculosis: a multicentre prospective study in low-income and middle-income countries

BACKGROUND: Childhood tuberculosis remains a major cause of morbidity and mortality in part due to missed diagnosis. Diagnostic methods with enhanced sensitivity using easy-to-obtain specimens are needed. We aimed to assess the diagnostic accuracy of the Cepheid Mycobacterium tuberculosis Host Response prototype cartridge (MTB-HR), a candidate test measuring a three-gene transcriptomic signature from fingerstick blood, in children with presumptive tuberculosis disease. METHODS: RaPaed-TB was a prospective diagnostic accuracy study conducted at four sites in African countries (Malawi, Mozambique, South Africa, and Tanzania) and one site in India. Children younger than 15 years with presumptive pulmonary or extrapulmonary tuberculosis were enrolled between Jan 21, 2019, and June 30, 2021. MTB-HR was performed at baseline and at 1 month in all children and was repeated at 3 months and 6 months in children on tuberculosis treatment. Accuracy was compared with tuberculosis status based on standardised microbiological, radiological, and clinical data. FINDINGS: 5313 potentially eligible children were screened, of whom 975 were eligible. 784 children had MTB-HR test results, of whom 639 had a diagnostic classification and were included in the analysis. MTB-HR differentiated children with culture-confirmed tuberculosis from those with unlikely tuberculosis with a sensitivity of 59·8% (95% CI 50·8–68·4). Using any microbiological confirmation (culture, Xpert MTB/RIF Ultra, or both), sensitivity was 41·6% (34·7–48·7), and using a composite clinical reference standard, sensitivity was 29·6% (25·4–34·2). Specificity for all three reference standards was 90·3% (95% CI 85·5–94·0). Performance was similar in different age groups and by malnutrition status. Among children living with HIV, accuracy against the strict reference standard tended to be lower (sensitivity 50·0%, 15·7–84·3) compared with those without HIV (61·0%, 51·6–69·9), although the difference did not reach statistical significance. Combining baseline MTB-HR result with one Ultra result identified 71·2% of children with microbiologically confirmed tuberculosis. INTERPRETATION: MTB-HR showed promising diagnostic accuracy for culture-confirmed tuberculosis in this large, geographically diverse, paediatric cohort and hard-to-diagnose subgroups. FUNDING: European and Developing Countries Clinical Trials Partnership, UK Medical Research Council, Swedish International Development Cooperation Agency, Bundesministerium für Bildung und Forschung; German Center for Infection Research (DZIF)

Boundary work: becoming middle class in suburban Dar es Salaam

Suburban space provides a useful window onto contemporary class practices in Africa, where it is difficult to identify social classes on the basis of income or occupation. In this article I argue that the middle classes and the suburbs are mutually constitutive in the Tanzanian city of Dar es Salaam. Using interviews with residents and local government officials in the city's northern suburbs, I discuss the material and representational practices of middle-class boundary work in relation to land and landscape. If the middle classes do not presently constitute a coherent political-economic force, they are nevertheless transforming the city's former northern peri-urban zones into desirable suburban residential neighbourhoods

Developmental regulation of MURF E3 ubiquitin ligases in skeletal muscle

The striated muscle-specific tripartite motif (TRIM) proteins TRIM63/MURF1, TRIM55/MURF2 and TRIM54/MURF3 can function as E3 ubiquitin ligases in ubiquitin-mediated muscle protein turnover. Despite the well-characterised role of MURF1 in skeletal muscle atrophy, the dynamics of MURF isogene expression in the development and early postnatal adaptation of skeletal muscle is unknown. Here, we show that MURF2 is the isogene most highly expressed in embryonic skeletal muscle at E15.5, with the 50 kDa A isoform predominantly expressed. MURF1 and MURF3 are upregulated only postnatally. Knockdown of MURF2 p50A by isoform-specific siRNA results in delayed myogenic differentiation and myotube formation in vitro, with perturbation of the stable, glutamylated microtubule population. This underscores that MURF2 plays an important role in the earliest stages of skeletal muscle differentiation and myofibrillogenesis. During further development, there is a shift towards the 60 kDa A isoform, which dominates postnatally. Analysis of the fibre-type expression shows that MURF2 A isoforms are predominantly slow-fibre associated, whilst MURF1 is largely excluded from these fibres, and MURF3 is ubiquitously distributed in both type I and II fibres

Conformation-regulated mechanosensory control via titin domains in cardiac muscle

The giant filamentous protein titin is ideally positioned in the muscle sarcomere to sense mechanical stimuli and transform them into biochemical signals, such as those triggering cardiac hypertrophy. In this review, we ponder the evidence for signaling hotspots along the titin filament involved in mechanosensory control mechanisms. On the way, we distinguish between stress and strain as triggers of mechanical signaling events at the cardiac sarcomere. Whereas the Z-disk and M-band regions of titin may be prominently involved in sensing mechanical stress, signaling hotspots within the elastic I-band titin segment may respond primarily to mechanical strain. Common to both stress and strain sensor elements is their regulation by conformational changes in protein domains

Signatures of Environmental Genetic Adaptation Pinpoint Pathogens as the Main Selective Pressure through Human Evolution

Previous genome-wide scans of positive natural selection in humans have identified a number of non-neutrally evolving genes that play important roles in skin pigmentation, metabolism, or immune function. Recent studies have also shown that a genome-wide pattern of local adaptation can be detected by identifying correlations between patterns of allele frequencies and environmental variables. Despite these observations, the degree to which natural selection is primarily driven by adaptation to local environments, and the role of pathogens or other ecological factors as selective agents, is still under debate. To address this issue, we correlated the spatial allele frequency distribution of a large sample of SNPs from 55 distinct human populations to a set of environmental factors that describe local geographical features such as climate, diet regimes, and pathogen loads. In concordance with previous studies, we detected a significant enrichment of genic SNPs, and particularly non-synonymous SNPs associated with local adaptation. Furthermore, we show that the diversity of the local pathogenic environment is the predominant driver of local adaptation, and that climate, at least as measured here, only plays a relatively minor role. While background demography by far makes the strongest contribution in explaining the genetic variance among populations, we detected about 100 genes which show an unexpectedly strong correlation between allele frequencies and pathogenic environment, after correcting for demography. Conversely, for diet regimes and climatic conditions, no genes show a similar correlation between the environmental factor and allele frequencies. This result is validated using low-coverage sequencing data for multiple populations. Among the loci targeted by pathogen-driven selection, we found an enrichment of genes associated to autoimmune diseases, such as celiac disease, type 1 diabetes, and multiples sclerosis, which lends credence to the hypothesis that some susceptibility alleles for autoimmune diseases may be maintained in human population due to past selective processes