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Antibacterial resistance (ABR) is a major public health threat. An important accelerating factor is treatment-seeking behaviours, including inappropriate antibiotic (AB) use. In many low- and middle-income countries (LMICs) this includes taking ABs with and without prescription sourced from various providers, including health facilities and community drug sellers. However, investigations of complex treatment-seeking, AB use and drug resistance in LMICs are scarce.The Holistic Approach to Unravel Antibacterial Resistance in East Africa (HATUA) Consortium collected questionnaire and microbiological data from 6,827 adult outpatients with urinary tract infection (UTI)-like symptoms presenting at healthcare facilities in Kenya, Tanzania and Uganda. Among 6,388 patients we analysed patterns of self-reported treatment seeking behaviours (‘patient pathways’) using process mining and single-channel sequence analysis. Of those with microbiologically confirmed UTI (n=1,946), we used logistic regression to assessed the relationship between treatment seeking behaviour, AB use, and likelihood of having a multi-drug resistant (MDR) UTI.The most common treatment pathways for UTI-like symptoms included attending health facilities, rather than other providers (e.g. drug sellers). Patients from the sites sampled in Tanzania and Uganda, where prevalence of MDR UTI was over 50%, were more likely to report treatment failures, and have repeated visits to clinics/other providers, than those from Kenyan sites, where MDR UTI rates were lower (33%). There was no strong or consistent relationship between individual AB use and risk of MDR UTI, after accounting for country context.The results highlight challenges East African patients face in accessing effective UTI treatment. These challenges increase where rates of MDR UTI are higher, suggesting a reinforcing circle of failed treatment attempts and sustained selection for drug resistance. Whilst individual behaviours may contribute to the risk of MDR UTI, our data show that factors related to context are stronger drivers of ABR.

Introduction: The Pan-African Consortium for the Evaluation of Anti-Tuberculosis Antibiotics (PanACEA) was designed to build tuberculosis (TB) trial capacity whilst conducting clinical trials on novel and existing agents to shorten and simplify TB treatment. PanACEA has now established a dynamic network of 11 sub-Saharan clinical trial sites and four European research institutions. Objectives: In 2011, a capacity development program, funded by the European & Developing Countries Clinical Trials Partnership (EDCTP), was launched with four objectives, aiming at strengthening collaborating TB research sites to reach the ultimate goal of becoming self-sustainable institutions: networking; training; conducting clinical trials; and infrastructure scaling-up of sites. Methods: Assessment in six sub-Saharan TB-endemic countries (Gabon, Kenya, South Africa, Tanzania, Uganda and Zambia) were performed through a structured questionnaire, site visits, discussion with the PanACEA consortium, setting of milestones and identification of priorities and followed-up with evaluations of each site. The results of this needs-based assessment was then translated into capacity development measures. Results: In the initial phase, over a four-year period (March 2011 – June 2014), the programme scaled-up six sites; conducted a monitoring training program for 11 participants; funded five MSc and four PhD students, fostering gender balance; conducted four epidemiological studies; supported sites to conduct five Phase II studies and formed a sustainable platform for TB research (panacea-tb.net). Conclusion: Our experience of conducting TB clinical trials within the PanACEA programme environment of mentoring, networking and training has provided a sound platform for establishing future sustainable research centres. Our goal of facilitating emergent clinical TB trial sites to better initiate and lead research activities has been mostly successful.

Funding: UK National Institute for Health Research, UK Medical Research Council, and the Department of Health and Social Care. Background Poverty is a proposed driver of antimicrobial resistance, influencing inappropriate antibiotic use in low-income and middle-income countries (LMICs). However, at subnational levels, studies investigating multidimensional poverty and antibiotic misuse are sparse, and the results are inconsistent. We aimed to investigate the relationship between multidimensional poverty and antibiotic use in patient populations in Kenya, Tanzania, and Uganda. Methods In this mixed-methods study, the Holistic Approach to Unravelling Antimicrobial Resistance (HATUA) Consortium collected data from 6827 outpatients (aged 18 years and older, or aged 14–18 years and pregnant) with urinary tract infection (UTI) symptoms in health-care facilities in Kenya, Tanzania, and Uganda. We used Bayesian hierarchical modelling to investigate the association between multidimensional poverty and self-reported antibiotic self-medication and non-adherence (ie, skipping a dose and not completing the course). We analysed linked qualitative in-depth patient interviews and unlinked focus-group discussions with community members. Findings Between Feb 10, 2019, and Sept 10, 2020, we collected data on 6827 outpatients, of whom 6345 patients had complete data; most individuals were female (5034 [79·2%]), younger than 35 years (3840 [60·5%]), worked in informal employment (2621 [41·3%]), and had primary-level education (2488 [39·2%]). Antibiotic misuse was more common among those least deprived, and lowest among those living in severe multidimensional poverty. Regardless of poverty status, difficulties in affording health care, and more familiarity with antibiotics, were related to more antibiotic misuse. Qualitative data from linked qualitative in-depth patient interviews (n=82) and unlinked focus-group discussions with community members (n=44 groups) suggested that self-medication and treatment non-adherence were driven by perceived inconvenience of the health-care system, financial barriers, and ease of unregulated antibiotic access. Interpretation We should not assume that higher deprivation drives antibiotic misuse. Structural barriers such as inefficiencies in public health care, combined with time and financial constraints, fuel alternative antibiotic access points and treatment non-adherence across all levels of deprivation. In designing interventions to reduce antibiotic misuse and address antimicrobial resistance, greater attention is required to these structural barriers that discourage optimal antibiotic use at all levels of the socioeconomic hierarchy in LMICs. Publisher PDF

Cervical cancer is a malignant tumour that occurs in the cervix and is classified into two histological types, adenocarcinoma and squamous cell carcinoma (SCC); SCC is more common and accounts for 70% of all cases. In 2018 there were ~569,000 new cases of cervical cancer diagnosed worldwide and ~311,000 deaths were attributed to cervical cancer. Of these, between 84 and 90% occurred in low- and middle-income countries (LMICs) such as South Africa, India, China and Brazil. The most common cause of cervical cancer is persistent infection caused by the sexually transmitted human papilloma virus. Other factors that contribute to the incidence of cervical cancer include geography, traditional practices and beliefs, the screening levels, socioeconomic status, healthcare access, public awareness, use of oral contraceptives, smoking and co-infection with HIV. An estimated 11 million women from LMICs will be diagnosed with cervical cancer in the next 10-20 years. The aim of this review was to explore various types of genetic and epigenetic factors that influence the development, progression or suppression of cervical cancer.

Humans exhibit remarkable interindividual and interpopulation immune response variability upon microbial challenges. Cytokines play a vital role in regulating inflammation and immune responses, but dysregulation of cytokine responses has been implicated in different disease states. Host genetic factors were previously shown to significantly impact cytokine response heterogeneity mainly in European-based studies, but it is unclear whether these findings are transferable to non-European individuals. Here, we aimed to identify genetic variants modulating cytokine responses in healthy adults of East African ancestry from Tanzania. We leveraged both cytokine and genetic data and performed genome-wide cytokine quantitative trait loci (cQTLs) mapping. The results were compared with another cohort of healthy adults of Western European ancestry via direct overlap and functional enrichment analyses. We also performed meta-analyses to identify cQTLs with congruent effect direction in both populations. In the Tanzanians, cQTL mapping identified 80 independent suggestive loci and one genome-wide significant locus (TBC1D22A) at chromosome 22; SNP rs12169244 was associated with IL-1b release after Salmonella enteritidis stimulation. Remarkably, the identified cQTLs varied significantly when compared to the European cohort, and there was a very limited percentage of overlap (1.6% to 1.9%). We further observed ancestry-specific pathways regulating induced cytokine responses, and there was significant enrichment of the interferon pathway specifically in the Tanzanians. Furthermore, contrary to the Europeans, genetic variants in the TLR10-TLR1-TLR6 locus showed no effect on cytokine response. Our data reveal both ancestry-specific effects of genetic variants and pathways on cytokine response heterogeneity, hence arguing for the importance of initiatives to include diverse populations into genomics research.

Contains fulltext : 251902.pdf (Publisher’s version ) (Open Access) BACKGROUND: Geographic variability in coagulation across populations and their determinants are poorly understood. OBJECTIVE: To compare thrombin (TG) and plasmin (PG) generation parameters between healthy Tanzanian and Dutch individuals, and to study associations with inflammation and different genetic, host and environmental factors. METHODS: TG and PG parameters were measured in 313 Tanzanians of African descent living in Tanzania and 392 Dutch of European descent living in the Netherlands and related to results of a dietary questionnaire, circulating inflammatory markers, genotyping, and plasma metabolomics. RESULTS: Tanzanians exhibited an enhanced TG and PG capacity, compared to Dutch participants. A higher proportion of Tanzanians had a TG value in the upper quartile with a PG value in the lower/middle quartile, suggesting a relative pro-coagulant state. Tanzanians also displayed an increased normalized thrombomodulin sensitivity ratio, suggesting reduced sensitivity to protein C. In Tanzanians, PG parameters (lag time and TTP) were associated with seasonality and food-derived plasma metabolites. The Tanzanians had higher concentrations of pro-inflammatory cytokines, which correlated strongly with TG and PG parameters. There was limited overlap in genetic variation associated with TG and PG parameters between the two cohorts. Pathway analysis of genetic variants in the Tanzanian cohort revealed multiple immune pathways that were enriched with TG and PG traits, confirming the importance of co-regulation between coagulation and inflammation. CONCLUSIONS: Tanzanians have an enhanced TG and PG potential compared to Dutch individuals, which may relate to differences in inflammation, genetics and diet. These observations highlight the importance of better understanding of the geographic variability in coagulation across populations.

Bacterial killing in TB-patients with relapse was compared to patients achieving cure, measured by TB-molecular bacterial load assay(TB-MBLA) or MGIT time to positivity(TTP). TB-MBLA in 4 relapsed patients was significantly different compared to 132 cured patients after 2 weeks of treatment; MGIT TTP showed a significant difference from week 8.

Background: Poverty is a proposed driver of antimicrobial resistance (AMR), influencing inappropriate antibiotic (AB) use in low and middle-income countries (LMICs). However, at sub-national levels, studies investigating poverty and AB use are sparse and the results inconsistent. Methods: The Holistic Approach to Unravelling Antimicrobial Resistance (HATUA) Consortium collected data from 6,827 patients presenting with urinary tract infection (UTI) symptoms in Kenya, Uganda, and Tanzania. Using Bayesian hierarchical modelling, we investigated the association between multidimensional poverty and self-reported AB self-medication and treatment non-adherence (skipping a dose and not completing the course). We also analysed linked qualitative in-depth patient interviews (IDIs) (n = 82) and unlinked focus group discussions (FGDs) with community members (n = 44 groups). Findings: AB self-medication and non-adherence to treatment courses was significantly more common in the least deprived group compared with those in severe poverty. Adjustment for AB ‘knowledge’, attitudes and socio-demographics diminished the association with self-medication, but not non-adherence. IDIs and FGDs suggested that self-medication and non-adherence are driven by perceived inconvenience of the healthcare system, financial barriers, and ease of unregulated AB access. Interpretation: Structural barriers to optimal AB use exist at all levels of the socioeconomic hierarchy. Inefficiencies in public healthcare may be fuelling alternative antibiotic access points, for those who can afford it. In designing interventions to tackle AMR and reduce AB misuse, the behaviours and needs of wealthier population groups should not be neglected. Funding Information: UK National Institute for Health Research, Medical Research Council and the Department of Health and Social Care. Declaration of Interests: None. Ethics Approval Statement: Ethical approval for this project was obtained from the University of St Andrews, UK (No. MD14548, 10/09/19); National Institute for Medical Research, Tanzania (No. 2831, updated 26/07/19), CUHAS/BMC research ethics and review committee (No. CREC/266/2018, updated on 02/2019), Mbeya Medical Research and Ethics Committee (No. SZEC-2439/R. A/V.1/303030), Kilimanjaro Christian Medical College, Tanzania (No. 2293, updated 14/08/19). Uganda National Council for Science and Technology (number HS2406, 18/06/18); Makerere University, Uganda (number 514, 25/04/18); and Kenya Medical Research Institute (04/06/19, Scientific and Ethics Review Committee (SERU) number KEMRI/SERU/CMR/P00112/3865 V.1.2). For Uganda, administrative letters of support were obtained from the district health officers to allow the research to be conducted in the respective hospitals and health centres.

Oesophageal cancer (OC) is an aggressive neoplasm that manifests in the gastrointestinal tract and is the result of numerous factors that can contribute to the development of the disease. These may include old age, nutritional deficiencies, oesophageal obstruction and food ingestion difficulties. Environmental factors serve a large role in increasing the risk of developing OC. Two factors that serve an increasing risk of developing OC are the use of tobacco and the consumption of alcohol. Genetic factors also exhibit a large effect on the risk of developing OC, for example, the causative genes in Black Africans differ from other races. OC is 3–4 times more common among men than women. OC has been previously reported in >450 000 individuals worldwide, and its incidence is increasing. The current review compares OC in low to middle-income countries with developed countries. The incidence of OC, particularly squamous cell carcinoma (SCC) is high in low and middle-income countries. In developed countries, the incidence of SCC is low compared with adenocarcinoma. The majority of OC cases are diagnosed in the late stages of the disease, leading to high mortality rates. The current review aimed to discuss factors that contribute to the development of this disease in different geographical areas and genetic mechanisms governing these findings. The current review also aims to discuss the preventative treatment options for the disease, and also discusses the diagnosis and surveillance in five LMICs, including South Africa, China, Tanzania, India and Brazil.

Cervical cancer is a malignant tumour that occurs in the cervix and is classified into two histological types, adenocarcinoma and squamous cell carcinoma (SCC); SCC is more common and accounts for 70% of all cases. In 2018 there were ~569,000 new cases of cervical cancer diagnosed worldwide and ~311,000 deaths were attributed to cervical cancer. Of these, between 84 and 90% occurred in low- and middle-income countries (LMICs) such as South Africa, India, China and Brazil. The most common cause of cervical cancer is persistent infection caused by the sexually transmitted human papilloma virus. Other factors that contribute to the incidence of cervical cancer include geography, traditional practices and beliefs, the screening levels, socioeconomic status, healthcare access, public awareness, use of oral contraceptives, smoking and co-infection with HIV. An estimated 11 million women from LMICs will be diagnosed with cervical cancer in the next 10–20 years. The aim of this review was to explore various types of genetic and epigenetic factors that influence the development, progression or suppression of cervical cancer.

Expected responses for knowledge assessments on molecular diagnostics; XpertMTB/RIF/GenotypeMTB/RIF for MDR-TB diagnosis. (Knowledge on molecular diagnostics). (DOCX 50 kb)

Background Limited information regarding the clonality of circulating E. coli strains in tertiary care hospitals in low and middle-income countries is available. The purpose of this study was to determine the serotypes, antimicrobial resistance and virulence genes. Further, we carried out a phylogenetic tree reconstruction to determine relatedness of E. coli isolated from patients in a tertiary care hospital in Tanzania. Methods E. coli isolates from inpatients admitted at Kilimanjaro Christian Medical Centre between August 2013 and August 2015 were fully genome-sequenced at KCMC hospital. Sequence analysis was done for identification of resistance genes, Multi-Locus Sequence Typing, serotyping, and virulence genes. Phylogeny reconstruction using CSI Phylogeny was done to ascertain E. coli relatedness. Stata 13 (College Station, Texas 77,845 USA) was used to determine Cohen’s kappa coefficient of agreement between the phenotypically tested and whole genome sequence predicted antimicrobial resistance. Results Out of 38 E. coli isolates, 21 different sequence types (ST) were observed. Eight (21.1%) isolates belonged to ST131; of which 7 (87.5.%) were serotype O25:H4. Ten (18.4%) isolates belonged to ST10 clonal complex; of these, four (40.0%) were ST617 with serotype O89:H10. Twenty-eight (73.7%) isolates carried genes encoding beta-lactam resistance enzymes. On average, agreement across all drugs tested was 83.9%. Trimethoprim/sulphamethoxazole (co-trimoxazole) showed moderate agreement: 45.8%, kappa =15% and p = 0.08. Amoxicillin-clavulanate showed strongest agreement: 87.5%, kappa = 74% and p = 0.0001. Twenty-two (57.9%) isolates carried virulence factors for host cells adherence and 25 (65.7%) for factors that promote E. coli immune evasion by increasing survival in serum. The phylogeny analysis showed that ST131 clustering close together whereas ST10 clonal complex had a very clear segregation of the ST617 and a mix of the rest STs. Conclusion There is a high diversity of E. coli isolated from patients admitted to a tertiary care hospital in Tanzania. This underscores the necessity to routinely screen all bacterial isolates of clinical importance in tertiary health care facilities. WGS use for laboratory-based surveillance can be an effective early warning system for emerging pathogens and resistance mechanisms in LMICs. Electronic supplementary material The online version of this article (10.1186/s13756-018-0361-x) contains supplementary material, which is available to authorized users.

Objective To determine molecular epidemiology of methicillin-resistant S. aureus in Tanzania using whole genome sequencing. Methods DNA from 33 Staphylococcus species was recovered from subcultured archived Staphylococcus isolates. Whole genome sequencing was performed on Illumina Miseq using paired-end 2 × 250 bp protocol. Raw sequence data were analyzed using online tools. Results Full susceptibility to vancomycin and chloramphenicol was observed. Thirteen isolates (43.3%) resisted cefoxitin and other antimicrobials tested. Multilocus sequence typing revealed 13 different sequence types among the 30 S. aureus isolates, with ST-8 (n = seven, 23%) being the most common. Gene detection in S. aureus stains were as follows: mecA, 10 (33.3%); pvl, 5 (16.7%); tst, 2 (6.7%). The SNP difference among the six Tanzanian ST-8 MRSA isolates ranged from 24 to 196 SNPs and from 16 to 446 SNPs when using the USA300_FPR3757 or the USA500_2395 as a reference, respectively. The mutation rate was 1.38 × 10−11 SNPs/site/year or 1.4 × 10−6 SNPs/site/year as estimated by USA300_FPR3757 or the USA500_2395, respectively. Conclusion S. aureus isolates causing infections in hospitalized patients in Moshi are highly diverse and epidemiologically unrelated. Temporal phylogenetic analysis provided better resolution on transmission and introduction of MRSA and it may be important to include this in future routines.

Additional file 2: Table S2. Bacteria isolated in different types of wound infection.

The PRISMA checklist. (DOC 62Â kb)