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.

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.

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.

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.

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.

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.

Viewpoint: scaling up testing services for non-communicable diseases in Africa: priorities for implementation research.

The burden of non-communicable diseases in Africa is rising rapidly and implementation of evidence-based control strategies is needed urgently. Testing people for hypertension and diabetes will be an important component in the fight against these diseases, as voluntary counselling and testing was for HIV-infection. We discuss the below the areas where we believe evidence is needed to inform policy.

AMP-activated protein kinase regulates glucagon secretion from mouse pancreatic alpha cells.

AIM/HYPOTHESIS: AMP-activated protein kinase (AMPK), encoded by Prkaa genes, is emerging as a key regulator of overall energy homeostasis and the control of insulin secretion and action. We sought here to investigate the role of AMPK in controlling glucagon secretion from pancreatic islet alpha cells. METHODS: AMPK activity was modulated in vitro in clonal alphaTC1-9 cells and isolated mouse pancreatic islets using pharmacological agents and adenoviruses encoding constitutively active or dominant negative forms of AMPK. Glucagon secretion was measured during static incubation by radioimmunoassay. AMPK activity was assessed by both direct phosphotransfer assay and by western (immuno-)blotting of the phosphorylated AMPK α subunits and the downstream target acetyl-CoA carboxylase 1. Intracellular free [Ca²(+)] was measured using Fura-Red. RESULTS: Increasing glucose concentrations strongly inhibited AMPK activity in clonal pancreatic alpha cells. Forced increases in AMPK activity in alphaTC1-9 cells, achieved through the use of pharmacological agents including metformin, phenformin and A-769662, or via adenoviral transduction, resulted in stimulation of glucagon secretion at both low and high glucose concentrations, whereas AMPK inactivation inhibited both [Ca²(+)](i) increases and glucagon secretion at low glucose. Transduction of isolated mouse islets with an adenovirus encoding AMPK-CA under the control of the preproglucagon promoter increased glucagon secretion selectively at elevated glucose concentrations. CONCLUSIONS/INTERPRETATION: AMPK is strongly regulated by glucose in pancreatic alpha cells, and increases in AMPK activity are sufficient and necessary for the stimulation of glucagon release in vitro. Modulation of AMPK activity in alpha cells may therefore provide a novel approach to controlling blood glucose concentrations.

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.

Translating global health research aims into action: the example of the ALPHA network.

There is increasing consensus on the importance of strengthening global health research to meet health and development goals. Three key global health research aims are to ensure that research (i) addresses priority health needs, (ii) contributes to policy development, and (iii) adds value to investments in developing countries through South-South collaboration and capacity-strengthening in the South. The ALPHA network (Analysing Longitudinal Population-based HIV/AIDS data on Africa) is an illustrative example of how these global health research aims can be translated into action. The network facilitates additional collaborative HIV epidemiological research among six independent research projects in Africa studying population-based cohorts. Under the first of the earlier mentioned aims, the network addresses key epidemiology research issues in HIV/AIDS which are crucial to making progress and monitoring progress in the response against HIV/AIDS. Under the second aim, the network's scientific programme of research has contributed to strengthening the evidence base on HIV epidemiology in Africa and has informed policy development in areas such as targeted HIV prevention, social support, monitoring epidemic response and epidemic forecasting. Under the third aim, investment in the network has added value to the research investment in the individual projects through capacity development among African researchers as well as through the collaborative research outputs of the individual projects. Lessons from the network are relevant to collaborations facing similar challenges in other areas of global health research. These include the importance of establishing transparent and efficient governance for research collaborations, developing advance consensus on data sharing, ensuring effective communication for networking and demonstrating the added value of research investment in South-South collaborations.

Perspectives of normal child development in rural Malawi - a qualitative analysis to create a more culturally appropriate developmental assessment tool.

BACKGROUND: Child development in developing countries is often evaluated using assessment tools created for 'Western' settings. Recent work has demonstrated that, for certain developmental milestones, 'Western' tools may be inaccurate as they include items unfamiliar to children of different cultural settings. METHODS: We used qualitative methods to gather information about normal development in an African setting. Ten village and two professional focus group discussions (FGDs) were conducted. We used purposive sampling methods to recruit groups of mothers, grandmothers and men in four areas of Southern Malawi for village FGDs. Separate FGDs were carried out with professionals working in areas relating to child development. A thematic content analysis established main patterns and themes and dissemination of results and continued feedback allowed for respondent validation and reflection of results. The information then gathered was used to create questions for a revised Malawian developmental assessment tool. RESULTS: Social and gross motor milestones were the main focus of interest for village and professional FGDs with the latter creating new language and fine motor concepts. Social milestones highlighted included 'duties and chores', 'sharing' and 'taking up leadership roles'. Language milestones included 'reporting events' and 'shrugging to indicate no' and fine motor milestones included 'peeling bananas', 'sorting maize' and 'making patterns with bottle tops'. Intelligence was described in relation to social and community integrity rather than 'Western' concepts of numeracy and literacy. CONCLUSIONS: Concepts, ideas and language relating to normal development in a sub-Saharan African setting have been gathered in this study. These have been used to create items for a more culturally appropriate developmental assessment tool.

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.

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.

Age at first sex in rural South Africa.

OBJECTIVES: To identify factors associated with sexual debut and early age at first sex (AFS) among young men and women (12-25 years) in a population with a high prevalence and incidence of HIV in rural South Africa. METHODS: Longitudinal data from four rounds (2003-7) of a prospective population-based HIV and sexual behaviour survey in rural KwaZulu-Natal were used to investigate the distribution and predictors of earlier first sex. Survival analyses were used, and each analysis considered men and women separately. RESULTS: Among the 4724 women and 4029 men who were virgins at the beginning of the period, the median AFS was 18.5 and 19.2 years, respectively. In multivariable models, factors associated with earlier AFS across gender were periurban residence (vs rural), ever use of alcohol and knowing at least one person who had HIV, while school attendance had a significant protective effect. Other factors were important for one gender only. Maternal death was significantly associated with earlier AFS for women, in the same way that paternal death was for young men, while mother's membership of the same household significantly delayed AFS of young men. The analysis of early first sex confirmed the same factors to be important as in the overall analyses for men and women. CONCLUSION: Given the association of individual, household and community level factors with sexual debut, a multisectorial approach to prevention and targeting in youth programmes is recommended.

Trends in marriage and time spent single in sub-Saharan Africa: a comparative analysis of six population-based cohort studies and nine Demographic and Health Surveys.

OBJECTIVES: To describe trends in age at first sex (AFS), age at first marriage (AFM) and time spent single between events and to compare age-specific trends in marital status in six cohort studies. METHODS: Cohort data from Uganda, Tanzania, South Africa, Zimbabwe and Malawi and Demographic and Health Survey (DHS) data from Uganda, Tanzania and Zimbabwe were analysed. Life table methods were used to calculate median AFS, AFM and time spent single. In each study, two surveys were chosen to compare marital status by age and identify changes over time. RESULTS: Median AFM was much higher in South Africa than in the other sites. Between the other populations there were considerable differences in median AFS and AFM (AFS 17-19 years for men and 16-19 years for women, AFM 21-24 years and 18-19 years, respectively, for the 1970-9 birth cohort). In all surveys, men reported a longer time spent single than women (median 4-7 years for men and 0-2 years for women). Median years spent single for women has increased, apart from in Manicaland. For men in Rakai it has decreased slightly over time but increased in Kisesa and Masaka. The DHS data showed similar trends to those in the cohort data. The age-specific proportion of married individuals has changed little over time. CONCLUSIONS: Median AFS, AFM and time spent single vary considerably among these populations. These three measures are underlying determinants of sexual risk and HIV infection, and they may partially explain the variation in HIV prevalence levels between these populations.

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.