Associations of HIV and prevalent type 2 diabetes mellitus in the context of obesity in South Africa.

It is unclear how rising obesity among people with HIV (PWH) in sub-Saharan Africa (SSA) impacts their risk of type 2 diabetes mellitus (diabetes). Using a South African national cross-sectional sample of adult PWH and their peers without HIV (PWOH), we examined the associations between HIV and prevalent diabetes across the spectrum of body mass index (BMI), waist circumference (WC) and waist-to-height ratio (WtHR). Analyses were sex stratified, and adjusted for age, sociodemographic and behavioral factors. The prevalence of diabetes among males was similar between PWH and PWOH, overall and at all levels of adiposity. In contrast, overall diabetes prevalence was higher among female PWOH than female PWH. However, there were differences according to adiposity such that, compared to female PWOH, relative diabetes prevalence in female PWH was reduced with obesity but accentuated with leanness. These differences in the relationship between adiposity and diabetes by HIV serostatus call for better mechanistic understanding of sex-specific adipose tissue biology in HIV in South Africa, and possibly in other HIV endemic settings in SSA.

Insulin resistance, and not ß-cell impairment, mediates association between Mycobacterium tuberculosis sensitization and type II diabetes mellitus among US adults.

Type 2 diabetes mellitus (T2DM) may be a long-term sequela of infection with Mycobacterium tuberculosis (M.tb) by mechanisms that remain to be fully explained. We evaluated association between M.tb sensitization and T2DM among U.S adults and, via formal mediation analysis, the extent to which this association is mediated by insulin resistance and/or ß-cell failure. These evaluations accounted for demographic, socio-economic, behavioral and clinical characteristics. T2DM was assessed by fasting plasma glucose, 2-hour oral glucose tolerance testing and HbA1c; homoeostasis model assessment 2 (HOMA2) was used to estimate ß-cell dysfunction (HOMA2-B) and insulin resistance (HOMA2-IR); while M.tb sensitization status was ascertained by tuberculin skin testing (TST). Exposure to M.tb was associated with increased risk for T2DM, likely driven by an increase in insulin resistance. Definitive prospective studies examining incident T2DM following tuberculosis are warranted. Research in Context: What is already known about this subject?: Accumulating evidence suggests that pre-diabetes and new-onset type 2 diabetes mellitus (T2DM) may be a long-term complication of exposure to Mycobacterium tuberculosis ( M.tb ) via mechanisms that remain to be unraveled What is the key question?: To what extent do insulin resistance and ß-cell failure mediate the association between M.tb sensitization with T2DM among US adults? What are the new findings?: M.tb sensitization is characterized by distinct glucose metabolic disturbances manifesting as increased risk of T2DM and isolated impaired fasting glucose (IFG) Insulin resistance, and not ß-cell impairment, likely independently mediate the observed diabetogenic effects of M.tb sensitization How might this impact on clinical and/or public health practice in the foreseeable future?: If corroborated by prospective studies, both TB programs and individual clinical care must incorporate monitoring of serum glucose and long-term metabolic outcomesThis will be particularly urgent in sub-Saharan Africa and South-East Asia where scarce health resources coincide with overlapping endemic TB and epidemic T2DM.

C-terminal citrullinated peptide alters antigen-specific APC:T cell interactions leading to breach of immune tolerance.

In rheumatoid arthritis, the emergence of anti-citrullinated autoimmunity is associated with HLA-antigen-T cell receptor complexes. The precise mechanisms underpinning this breach of tolerance are not well understood. Porphyromonas gingivalis expresses an enzyme capable of non-endogenous C-terminal citrullination with potential to generate citrullinated autoantigens. Here we document how C-terminal citrullination of ovalbumin peptide323-339 alters the interaction between antigen-presenting cells and OTII T cells to induce functional changes in responding T cells. These data reveal that C-terminal citrullination is sufficient to breach T cell peripheral tolerance in vivo and reveal the potential of C-terminal citrullination to lower the threshold for T cell activation. Finally, we demonstrate a role for the IL-2/STAT5/CD25 signalling axis in breach of tolerance. Together, our data identify a tractable mechanism and targetable pathways underpinning breach of tolerance in rheumatoid arthritis and provide new conceptual insight into the origins of anti-citrullinated autoimmunity.

Digital messaging to support control for type 2 diabetes (StAR2D): a multicentre randomised controlled trial.

BACKGROUND: Failure to take medicines for diabetes as prescribed contributes to poor outcomes from the condition. Mobile phones are ubiquitous and short message service (SMS) texts have shown promise as a low-cost intervention. We tested the effectiveness of SMS-text messaging in improving outcomes in adults with type 2 diabetes. METHODS: StAR2D was a 12-month two-arm randomised trial of SMS-text messaging and usual care in Cape Town, South Africa and Lilongwe, Malawi. Messages used behaviour change theory and were developed with patients and staff. The intervention group received four messages each week. The primary outcome was change in HbA1c. Secondary outcomes were the proportion of patients who collected > 80% medication and changes in systolic blood pressure, lipids, cardiovascular risk, and the proportion of the participants reaching treatment goals. RESULTS: The trial took place between 1 October, 2016 and 1 October 2018, 1186 participants were randomised to intervention (593) and control (593) groups. 91% of participants completed follow-up. There was a reduction in HbA1c (DCCT) in both groups but not in mean change (95% CI) between groups (- 0.08% (- 0.31 to 0.16) (IFCC - 0.82 mmol/mol (- 3.44 to 1.79). There was a small but not significant increase in the proportions of participants likely to have collected 80% or more of medication (Relative risk 1.11 (0.84 to 1.47; P = 0.47). There was a significant difference between groups in change in systolic blood pressure from baseline of 3.46 mmHg (1.48 to 5.44, P = 0.001) in favour of the intervention group. The between group difference in change in 10-year risk of coronary heart disease was - 0.71% (- 1.46 to 0.04, P = 0.064). The proportion of participants meeting treatment goals in the intervention group was 36.0% and in the control group 26.8% (Relative risk 1.36 (1.13 to 1.63, P = 0.001). Participants reported many challenges to adherence despite finding messages acceptable and useful. CONCLUSIONS: Whilst SMS text messages do not lead to improved glycaemia in these low-resource settings there appeared to be an impact on blood pressure and achievement of treatment goals but the mechanisms for this are unclear. Text messages alone, may be unsuccessful unless accompanied by health system strengthening and other forms of self-management support for type 2 diabetes. TRIAL REGISTRATION: Trial registration: ISRCTN, ISRCTN70768808. Registered 1 July 2015, http://www.isrctn.com/I ISRCTN70768808.

In depth analysis of patients with severe SARS-CoV-2 in sub-Saharan Africa demonstrates distinct clinical and immunological profiles.

Although the COVID-19 pandemic has left no country untouched there has been limited research to understand clinical and immunological responses in African populations. Here we comprehensively characterise patients hospitalised with suspected or confirmed COVID-19, and healthy community controls. PCR-confirmed COVID-19 participants were more likely to receive dexamethasone and a beta-lactam antibiotic, and survive to hospital discharge than PCR-/IgG+ and PCR-/IgG-participants. PCR-/IgG+ participants exhibited a nasal and systemic cytokine signature analogous to PCR-confirmed COVID-19 participants, but increased propensity for Staphylococcus aureus and Streptococcus pneumoniae colonisation. We did not find evidence that HIV co-infection in COVID-19 participants was associated with mortality or altered cytokine responses. The nasal immune signature in PCR-/IgG+ and PCR-confirmed COVID-19 participants was distinct and predominated by chemokines and neutrophils. In addition, PCR-/IgG+ individuals with high COVID-19 clinical suspicion had inflammatory profiles analogous to PCR-confirmed disease and potentially represent a target population for COVID-19 treatment strategies.

The effect of TB treatment on health-related quality of life for people with advanced HIV.

BACKGROUND: Study A5274 was an open-label trial of people with HIV (PLHIV) with CD4 cell count <50 cells/µL who were randomized to empirical TB treatment vs. isoniazid preventive therapy (IPT) in addition to antiretroviral therapy (ART). We evaluated health-related quality of life (HRQoL) by study arm, changes over time, and association with sociodemographic and clinical factors.METHODS: Participants aged >13 years were enrolled from outpatient clinics in 10 countries. HRQoL was assessed at Weeks 0, 8, 24 and 96 with questions about daily activity, hospital or emergency room visits, and general health status. We used logistic regression to examine HRQoL by arm and association with sociodemographic and clinical factors.RESULTS: Among 850 participants (424 empiric arm, 426 IPT arm), HRQoL improved over time with no difference between arms. At baseline and Week 24, participants with WHO Stage 3 or 4 events, or those who had Grade 3 or 4 signs/symptoms, were significantly more likely to report poor HRQoL using the composite of four HRQoL measures.CONCLUSION: HRQoL improved substantially in both arms during the study period. These findings show that ART, TB screening, and IPT can not only reduce mortality, but also improve HRQoL in PLHIV with advanced disease.

Comparison of oral glucose tolerance test and ambulatory glycaemic profiles in pregnant women in Uganda with gestational diabetes using the FreeStyle Libre flash glucose monitoring system.

BACKGROUND: The diagnosis of hyperglycaemia in sub-Saharan Africa (SSA) is challenging. Blood glucose levels obtained during oral glucose tolerance test (OGTT) may not reflect home glycaemic profiles. We compare OGTT results with home glycaemic profiles obtained using the FreeStyle Libre continuous glucose monitoring device (FSL-CGM). METHODS: Twenty-eight women (20 with gestational diabetes [GDM], 8 controls) were recruited following OGTT between 24 and 28 weeks of gestation. All women wore the FSL-CGM device for 48-96 h at home in early third trimester, and recorded a meal diary. OGTT was repeated on the final day of FSL-CGM recording. OGTT results were compared with ambulatory glycaemic variables, and repeat OGTT was undertaken whilst wearing FSL-CGM to determine accuracy of the device. RESULTS: FSL-CGM results were available for 27/28 women with mean data capture 92.8%. There were significant differences in the ambulatory fasting, post-prandial peaks, and mean glucose between controls in whom both primary and secondary OGTT was normal (n = 6) and those with two abnormal OGTTs or "true" GDM (n = 7). There was no difference in ambulatory mean glucose between these controls and the 13 women who had an abnormal primary OGTT and normal repeat OGTT. These participants had significantly lower body mass index (BMI) than the true GDM group (29.0 Vs 36.3 kg/m2, p-value 0.014). Paired OGTT/FSL-CGM readings revealed a Mean Absolute difference (MAD) -0.58 mmol/L and Mean Absolute Relative Difference (MARD) -11.9%. Bland-Altman plot suggests FSL-CGM underestimated blood glucose by approximately 0.78 mmol/L. CONCLUSION: Diagnosis of GDM on a single OGTT identifies a proportion of women who do not have a significantly higher home glucose levels than controls. This raises questions about factors which may affect the reproducibility of OGTT in this population, including food insecurity and atypical phenotypes of diabetes. More investigation is needed to understand the suitability of the OGTT as a diagnostic test in sub-Saharan Africa.

Adolescent girls and young women: Policy-to-implementation gaps for addressing sexual and reproductive health needs in South Africa.

Sexual and reproductive health (SRH) services for adolescent girls and young women (AGYW) remain inadequate - both globally and in South Africa (SA). We systematically scoped the available policies and guidelines for SRH-related policy for AGYW in SA. We found many available policies and guidelines to address issues of family planning, HIV prevention and care and antenatal and maternal care. Despite the wealth of guidance, SA's high rates of pregnancy and HIV transmission continue unabated. Our policy review and analysis identified issues for researchers and policymakers to consider when developing and implementing programmes to improve SRH services. We suggest that considering national policies alongside evidence of what is effective, as well as contextual barriers to and enablers of strategies to address AGYW needs for SRH, are among the key steps to addressing the policy-to-implementation gap.

Appraisal of water quality indices for service reservoirs in water distribution networks.

The use of water quality indices to aggregate pollution loads in rivers has been widely studied, with researchers using various sub-indices and aggregation methods. These have been used to combine various quality variables at a sampling point in a river into an overall water quality index to compare the state of water quality in different river reaches. Service reservoirs in a water distribution network, like rivers, have complex mixing mechanisms, are subjected to various water quality variables and are variably sized and sited. Water quality indices and the relevant sub-indices are formulated here and applied to service reservoirs within a water distribution network. This is in an attempt to compare holistically the performance of service reservoirs in solutions of optimisation algorithms with regards to water quality.

First social impact bond for the SAMRC: A novel financing strategy to address the health and social challenges facing adolescent girls and young women in South Africa.

A social impact bond (SIB) is an innovative financing mechanism to attract investors to social programmes traditionally funded by governments. In this article, in celebration of the 50th anniversary of the South African Medical Research Council (SAMRC), the authors describe the SAMRC's first foray into this new world of financing through a SIB to improve the health and quality of life of adolescent girls and young women (AGYW). The AGYW SIB is in its preparatory phase and is scheduled for implementation in 2020. The authors describe the mechanism, including financial flows and the process of customising the SIB to meet the needs of AGYW, focusing on HIV prevention and treatment and the prevention and management of unintended pregnancies in schoolgoing AGYW. The authors outline an approach to designing the package of interventions, the metrics associated with such a programme and the business model. It is hypothesised that the proposed approach will lead to an improvement in programmatic outcomes, monitoring and evaluation tools and cost-effectiveness, and will develop key learning data for the future use of SIBs in health service delivery.

Essential medicines for emergency care in Africa.

OBJECTIVES: Essential medicines lists (EMLs) are efficient means to ensure access to safe and effective medications. The WHO has led this initiative, generating a biannual EML since 1977. Nearly all countries have implemented national EMLs based on the WHO EML. Although EMLs have given careful consideration to many public health priorities, they have yet to comprehensively address the importance of medicines for treating acute illness and injury. METHODS: We undertook a multi-step consensus process to establish an EML for emergency care in Africa. After a review of existing literature and international EMLs, we generated a candidate list for emergency care. This list was reviewed by expert clinicians who ranked the medicines for overall inclusion and strength of recommendation. These medications and recommendations were then evaluated by an expert group. Medications that reached consensus in both the online survey and expert review were included in a draft emergency care EML, which underwent a final in-person consensus process. RESULTS: The final emergency care EML included 213 medicines, 25 of which are not in the 2017 WHO EML but were deemed essential for clinical practice by regional emergency providers. The final EML has associated recommendations of desirable or essential, and is subdivided by facility level. Thirty-nine medicines were recommended for basic facilities, an additional 96 for intermediate facilities (e.g. district hospitals), and an additional 78 for advanced facilities (e.g. tertiary centres). CONCLUSION: The 25 novel medications not currently on the WHO EML should be considered by planners when making rational formularies for developing emergency care systems. It is our hope that these resource-stratified lists will allow for easier implementation, and will be a useful tool for practical expansion of emergency care delivery in Africa.

Good correlation between the Afinion AS100 analyser and the ABX Pentra 400 analyser for the measurement of glycosylated haemoglobin and lipid levels in older adults in Durban, South Africa.

BACKGROUND: The Afinion AS100 analyser is a small bench-top, multi-assay, point-of-care (POC) analyser that is able to measure glycated haemoglobin (HbA1c) and lipid levels. OBJECTIVE: To assess performance of the Afinion analyser compared with a reference laboratory test for the measurement of HbA1c and lipid levels. METHOD: The study involved men and women enrolled in a cross-sectional study, Sexual health, HIV infection and comorbidity with non-communicable diseases among Older Persons (SHIOP), which was conducted from February to May 2016. Whole blood was drawn aseptically by a trained study nurse into a serum separator gel tube and an ethylenediaminetetra-acetic acid (EDTA) tube. The EDTA whole blood was used to measure HbA1c levels, and serum to measure total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglyceride levels. Lin's correlation coefficient was used to assess the agreement between the Afinion and ABX Pentra 400 analysers for each marker. RESULTS: A total of 435 older individuals were included in the study. The proportion of HbA1c results that were correctly classified by the Afinion analyser was 92.2%. Bland-Altman analysis and linear regression analysis showed a very good agreement (correlation concordance 0.89) between the two analysers for the measurement of HbA1c. The two-way scatter plot for TC showed a substantial correlation (0.80). However, a total of 69 cholesterol results that were within the normal range on the Pentra were misclassified as abnormal on the Afinion. The readings obtained for HDL-C levels with the Afinion were shown to be slightly overestimated when compared with the Pentra. However, correlation for HDL-C on the two analysers was 0.93, indicating an almost perfect agreement. Seventy-four LDL-C results were erroneously classified as abnormal on the Afinion but were within the normal range on the Pentra, resulting in a substantial correlation of 0.75. An excellent agreement was observed between triglyceride measurements (0.99). CONCLUSION: This study supports the use of the Afinion AS100 analyser in POC testing for the measurement of HbA1c, triglycerides and HDL-C in a South African setting.

The need for an integrated approach for chronic disease research and care in Africa.

With the changing distribution of infectious diseases, and an increase in the burden of non-communicable diseases, low- and middle-income countries, including those in Africa, will need to expand their health care capacities to effectively respond to these epidemiological transitions. The interrelated risk factors for chronic infectious and non-communicable diseases and the need for long-term disease management, argue for combined strategies to understand their underlying causes and to design strategies for effective prevention and long-term care. Through multidisciplinary research and implementation partnerships, we advocate an integrated approach for research and healthcare for chronic diseases in Africa.

H3Africa multi-centre study of the prevalence and environmental and genetic determinants of type 2 diabetes in sub-Saharan Africa: study protocol.

The burden and aetiology of type 2 diabetes (T2D) and its microvascular complications may be influenced by varying behavioural and lifestyle environments as well as by genetic susceptibility. These aspects of the epidemiology of T2D have not been reliably clarified in sub-Saharan Africa (SSA), highlighting the need for context-specific epidemiological studies with the statistical resolution to inform potential preventative and therapeutic strategies. Therefore, as part of the Human Heredity and Health in Africa (H3Africa) initiative, we designed a multi-site study comprising case collections and population-based surveys at 11 sites in eight countries across SSA. The goal is to recruit up to 6000 T2D participants and 6000 control participants. We will collect questionnaire data, biophysical measurements and biological samples for chronic disease traits, risk factors and genetic data on all study participants. Through integrating epidemiological and genomic techniques, the study provides a framework for assessing the burden, spectrum and environmental and genetic risk factors for T2D and its complications across SSA. With established mechanisms for fieldwork, data and sample collection and management, data-sharing and consent for re-approaching participants, the study will be a resource for future research studies, including longitudinal studies, prospective case ascertainment of incident disease and interventional studies.

Role of cytokines in Trypanosoma brucei-induced anaemia: A review of the literature.

BACKGROUND: Anaemia is an important complication of trypanosomiasis. The mechanisms through which trypanosomal infection leads to anaemia are poorly defined. A number of studies have implicated inflammatory cytokines, but these data are limited and inconsistent. In this article, we reviewed the published literature on cytokines associated with Trypanosoma brucei infections and their role in the immunopathology leading to anaemia. METHODOLOGY: Articles were searched in PubMed through screening of titles and abstracts with no limitation on date of publishing and study design. Articles in English were searched using keywords "African trypanosomiasis", "sleeping sickness", "Trypanosoma brucei", in all possible combinations with "anaemia" and/or "cytokines". RESULTS: Twelve articles examining cytokines and their role in trypanosomeinduced anaemia were identified out of 1095 originally retrieved from PubMed. None of the articles identified were from human-based studies. A total of eight cytokines were implicated, with four cytokines (IFN-γ, IL-10, TNF-α, IL-12) showing an association with anaemia. These articles reported that mice lacking TNF-α were able to control anaemia, and that IFN-γ was linked to severe anaemia given its capacity to suppress erythropoiesis, while IL-10 was shown to regulate IFN-γ and TNF-α, providing a balance that was associated with severity of anaemia. IFN-γ and TNF-α have also been reported to work in concert with other factors such as nitric oxide and iron in order to induce anaemia. CONCLUSION: IFN-γ, IL-10, and TNF-α were the three major cytokines identified to be heavily involved in anaemia caused by Trypanosoma brucei infection. The anti-inflammatory cytokine, IL-10, was shown to counter the effects of proinflammatory cytokines in order to balance the severity of anaemia. The mechanism of anaemia is multifactorial and therefore requires further, more elaborate research. Data from human subjects would also shed more light.

Who cares? Implications of care-giving and -receiving by HIV-infected or -affected older people on functional disability and emotional wellbeing.

This paper examines how care-giving to adults and/or children and care-receiving is associated with the health and wellbeing of older people aged 50+ in rural South Africa. Data used are from a cross-sectional survey adapted from World Health Organization's Study on Global Ageing and Adult Health (SAGE) conducted in 2009/10 in rural South Africa. Bivariate statistics and multivariate logistical regression were used to assess the relationship between care-giving and/or care-receiving with functional disability, quality of life or emotional wellbeing, and self-rated health status, adjusted for socio-demographic factors. Sixty-three per cent of 422 older people were care-givers to at least one young adult or child; 27 per cent of older people were care-givers due to HIV-related reasons in young adults; 84 per cent of participants were care-recipients mainly from adult children, grandchildren and spouse. In logistic regressions adjusting for sex, age, marital status, education, receipt of grants, household headship, household wealth and HIV status, care-giving was statistically significantly associated with good functional ability as measured by ability to perform activities of daily living. This relationship was stronger for older people providing care-giving to adults than to children. In contrast, care-givers were less likely to report good emotional wellbeing; again the relationship was stronger for care-givers to adults than children. Simultaneous care-giving and -receiving was likewise associated with good functional ability, but about a 47 per cent lower chance of good emotional wellbeing. Participants who were HIV-infected were more likely to be in better health but less likely to be receiving care than those who were HIV-affected. Our findings suggest a strong relationship between care-giving and poor emotional wellbeing via an economic or psychological stressor pathway. Interventions that improve older people's socio-economic circumstances and reduce financial hardship as well as those that provide social support would go some way towards mitigating this relationship.

Renal and metabolic toxicities following initiation of HIV-1 treatment regimen in a diverse, multinational setting: a focused safety analysis of ACTG PEARLS (A5175).

BACKGROUND: Convenient dosing, potency, and low toxicity support use of tenofovir disoproxil fumarate (TDF) as preferred nucleotide reverse transcriptase inhibitor (NRTI) for HIV-1 treatment. However, renal and metabolic safety of TDF compared to other NRTIs has not been well described in resource-limited settings. METHODS: This was a secondary analysis examining the occurrence of renal abnormalities (RAs) and renal and metabolic serious non-AIDS-defining events (SNADEs) through study follow-up between participants randomized to zidovudine (ZDV)/lamivudine/ efavirenz and TDF/emtricitabine/efavirenz treatment arms within A5175/PEARLS trial. Exact logistic regression explored associations between baseline covariates and RAs. Response profile longitudinal analysis compared creatinine clearance (CrCl) over time between NRTI groups. RESULTS: Twenty-one of 1,045 participants developed RAs through 192 weeks follow-up; there were 15 out of 21 in the TDF arm (P = .08). Age 41 years or older (odds ratio [OR], 3.35; 95% CI, 1.1-13.1), his- tory of diabetes (OR, 10.7; 95% CI, 2.1-55), and lower baseline CrCl (OR, 3.1 per 25 mL/min decline; 95% CI, 1.7-5.8) were associated with development of RAs. Renal SNADEs occurred in 42 participants; 33 were urinary tract infections and 4 were renal failure/insufficiency; one event was attributed to TDF. Significantly lower CrCl values were maintained among patients receiving TDF compared to ZDV (repeated measures analysis, P = .05), however worsening CrCl from baseline was not observed with TDF exposure over time. Metabolic SNADEs were rare, but were higher in the ZDV arm (20 vs 3; P < .001). CONCLUSIONS: TDF is associated with lower serious metabolic toxicities but not higher risk of RAs, serious renal events, or worsening CrCl over time compared to ZDV in this randomized multinational study.