Pathways to adverse pregnancy outcomes: exploring the mediating role of intimate partner violence and depression: results from a South African rape cohort study.

Adverse pregnancy outcomes (APOs) are common occurrences that contribute to negative maternal and child health outcomes. Our aim was to test the hypothesis that trauma exposure and depression are drivers of the better-recognised risk factors for miscarriage, abortion and stillbirths. Our comparative cohort study based in Durban, South Africa recruited women who reported a recent rape (n = 852) and those who had never experienced rape (n = 853), with follow-up for 36 months. We explored APOs (miscarriage, abortion or stillbirth) among those having a pregnancy during follow-up (n = 453). Potential mediators were baseline depression, post-traumatic stress symptoms, substance abuse, HbA1C, BMI, hypertension and smoking. A structural equation model (SEM) was used to determine direct and indirect paths to APO. Overall, 26.6% of the women had a pregnancy in the follow-up period and 29.4% ended in an APO, with miscarriage (19.9%) the most common outcome, followed by abortion (6.6%) and stillbirths (2.9%). The SEM showed two direct pathways from exposure to childhood trauma, rape and other trauma, to APO which were ultimately mediated by hypertension and/or BMI, but all paths to BMI were mediated by depression and IPV-mediated pathways from childhood and other trauma to hypertension. Food insecurity mediated a pathway from experiences of trauma in childhood to depression. Our study confirms the important role of trauma exposure, including rape, and depression on APOs, through their impact on hypertension and BMI. It is critical that violence against women and mental health are more systematically addressed in antenatal, pregnancy and postnatal care.

Measured Versus Calculated Small Dense LDL-Cholesterol and Cardiometabolic Traits in a South African Population.

Small-dense low density lipoprotein (sdLDL) is increasingly viewed as a marker for evaluating atherogenic risk, however its clinical uptake is hampered by the cumbersomeness of available methods. Consequently, a number of alternative methods for the estimation of sdLDL have been developed and none have been tested in a population from Africa. We evaluated an equation to estimate sdLDL-C from classic lipid parameters in South Africans. This is a cross-sectional study involving 1550 participants in which direct measurement of sdLDL in 237 participants was performed using a homogeneous enzymatic assay. Their mean age (standard deviation, SD) was 54.2 (14.7) years. 156 (65.8%) were normotolerant, 29 (12.2%) prediabetes, 17 (7.2%) screen detected diabetes and 35 (14.8%) known diabetes. Measured sdLDL values ranged from 0.17 to 3.39 versus-1.85 to 2.52 mmol/L calculated sdLDL. There was a significant positive correlation between the two measurements with a Pearson correlation coefficient of 0.659 (95%CI: 0.581-0.726). In a regression model, the adjusted R2 was 0.440 after adding age, 0.441 after further adding gender, then 0.443 with dysglycemia and lastly 0.447 upon adding body mass index. With the exception of HDL-cholesterol levels that decreased across increasing quintiles of calculated sdLDL, our data showed significant correlations between sdLDL and cardiometabolic risk factors, all p values < 0.0001. In conclusion, this study has shown that calculated sdLDL can be efficiently used to approximate population levels of sdLDL; however the modest correlation indicate that at the individual level, it will poorly approximate true sdLDL levels, with possible implications for risk stratification.

Performance of three glomerular filtration rate estimation equations in a population of sub-Saharan Africans with Type 2 diabetes.

AIM: We evaluated the performance of the Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Cockcroft-Gault (CG) equations against creatinine clearance (CrCl) to estimate glomerular filtration rate (GFR) in 51 patients with Type 2 diabetes. METHODS: The CrCl value was obtained from the average of two consecutive 24-h urine samples. Results were adjusted for body surface area using the Dubois formula. Serum creatinine was measured using the kinetic Jaffe method and was calibrated to standardized levels. Bland-Altman analysis and kappa statistic were used to examine agreement between measured and estimated GFR. RESULTS: Estimates of GFR from the CrCl, MDRD, CKD-EPI and CG equations were similar (overall P = 0.298), and MDRD (r = 0.58; 95% CI: 0.36-0.74), CKD-EPI (r = 0.55; 95% CI: 0.33-0.72) and CG (r = 0.61; 95% CI: 0.39-0.75) showed modest correlation with CrCl (all P < 0.001). Bias was -0.3 for MDRD, 1.7 for CKD-EPI and -5.4 for CG. All three equations showed fair-to-moderate agreement with CrCl (kappa: 0.38-0.51). The c-statistic for all three equations ranged between 0.75 and 0.77 with no significant difference (P = 0.639 for c-statistic comparison). CONCLUSIONS: The MDRD equation seems to have a modest advantage over CKD-EPI and CG in estimating GFR and detecting impaired renal function in sub-Saharan African patients with Type 2 diabetes. The overall relatively modest correlation with CrCl, however, suggests the need for context-specific estimators of GFR or context adaptation of existing estimators.

Standard of treatment and outcomes of adults with lupus nephritis in Africa: a systematic review.

BACKGROUND: Lupus nephritis (LN) is a significant cause of mortality and morbidity in patients with systemic lupus erythematosus (SLE) and the severity of disease has been described to be increased in Africans. Observational studies have been conducted; however, the treatment and outcome of African patients with LN has not been rigorously assessed. METHODS: We conducted a systematic review of studies selected from a PubMed search of outcome in Africans with biopsy-proven LN from 1 January 1990 to 30 June 2015. Studies that gave information on histology, treatment and outcome of patients were included. RESULTS: Sixteen studies were selected from a search that yielded 302 papers; half were from North Africa, 2/16 (12.5%) were prospective studies and 2/16 (12.5%) were multi-centre studies. The sample size of reported biopsies in the studies ranged from 22 to 246 patients. Only 3/16 (18.8%) studies used more recent criteria for the classification and reporting of renal histology, and proliferative LN (class III and IV) were reported with increased frequency from the studies. For induction therapy, all the studies reported use of corticosteroids while 15/16 (93.8%) of the studies also used cyclophosphamide (CYC) as an induction agent. Overall mortality rates ranged from 7.9% to 34.9% with increased disease activity, kidney failure and infections cited as common causes of mortality. Five-year renal survival was 48-84% while five-year patient survival was 54%-94%. Survival rates were higher for studies reported from North Africa. CONCLUSION: This analysis highlights diagnostic challenges in LN in Africa and shows that a CYC/glucocorticoid-based regimen remains the standard of treatment for adult patients. The contributions of this therapy to reported outcomes of LN in Africa require further exploration.

Prediction of 10-year vascular risk in patients with diabetes: the AD-ON risk score.

AIMS: To formulate a combined cardiovascular risk score in diabetes that could be useful both to physicians and healthcare funders. METHODS: Data were derived from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation Observational (ADVANCE-ON) study, a randomized controlled trial (mean duration 5 years) with a post-randomization follow-up (mean 4.9 years), that included 11 140 high-risk patients with diabetes. The outcome analysed was the occurrence of either fatal or non-fatal macrovascular or renal disease. A Cox regression model was used to determine weightings in the risk score. The resultant score was recalibrated to each of three major global regions, as covered by the ADVANCE-ON study. RESULTS: Over a median of 9.9 years, 1145 patients experienced at least one component of the combined outcome event. The resultant score, the AD-ON risk score, incorporated 13 demographic or clinical variables. Its discrimination was modest [c-statistic = 0.668 (95% confidence interval 0.651, 0.685)] but its calibration was excellent (predicted and observed risks coincided well, within disparate global regions). In terms of the integrated discrimination improvement index, its performance was marginally superior, over a 10-year risk horizon, to existing risk scores in clinical use, from a restricted version of the same data, for macrovascular and renal disease separately. CONCLUSIONS: The AD-ON risk score has advantages over the existing vascular risk scores in diabetes that used data from the original ADVANCE trial, which treat macrovascular and renal diseases separately. These advantages include its simplicity of use and global application.

Intensification of medication and glycaemic control among patients with type 2 diabetes - the ADVANCE trial.

AIMS: The aim of this study was to assess associations between patient characteristics, intensification of blood glucose-lowering treatment through oral glucose-lowering therapy and/or insulin and effective glycaemic control in type 2 diabetes. METHODS: 11 140 patients from the Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) trial who were randomized to intensive glucose control or standard glucose control and followed up for a median of 5 years were categorized into two groups: effective glycaemic control [haemoglobin A1c (HbA1c) ≤ 7.0% or a proportionate reduction in HbA1c over 10%] or ineffective glycaemic control (HbA1c > 7.0% and a proportionate reduction in HbA1c less than or equal to 10%). Therapeutic intensification was defined as addition of an oral glucose-lowering agent or commencement of insulin. Pooled logistic regression models examined the associations between patient factors, intensification and effective glycaemic control. RESULTS: A total of 7768 patients (69.7%), including 3198 in the standard treatment group achieved effective glycaemic control. Compared to patients with ineffective control, patients with effective glycaemic control had shorter duration of diabetes and lower HbA1c at baseline and at the time of treatment intensification. Treatment intensification with addition of an oral agent or commencement of insulin was associated with a 107% [odds ratio, OR: 2.07 (95% confidence interval, CI: 1.95-2.20)] and 152% [OR: 2.52 (95% CI: 2.30-2.77)] greater chance of achieving effective glycaemic control, respectively. These associations were robust after adjustment for several baseline characteristics and not modified by the number of oral medications taken at the time of treatment intensification. CONCLUSIONS: Effective glycaemic control was associated with treatment intensification at lower HbA1c levels at all stages of the disease course and in both arms of the ADVANCE trial.

Paraoxonase1 genetic polymorphisms in a mixed ancestry African population.

Paraoxonase 1 (PON1) activity is markedly influenced by coding polymorphisms, Q/R at position 192 and M/L at position 55 of the PON1 gene. We investigated the frequencies of these polymorphisms and their effects on PON1 and antioxidant activities in 844 South African mixed ancestry individuals. Genotyping was done using allele-specific TaqMan technology, PON1 activities were measured using paraoxon and phenylacetate, oxidative status was determined by measuring the antioxidant activities of ferric reducing antioxidant power and trolox equivalent antioxidant capacity, and lipid peroxidation markers included malondialdehyde and oxidized LDL. The frequencies of Q192R and L55M were 47.6% and 28.8%, respectively, and the most common corresponding alleles were 192R (60.4%) and 55M (82.6%). The Q192 was significantly associated with 5.8 units' increase in PON1 concentration and 15.4 units' decrease in PONase activity after adjustment for age, sex, BMI, and diabetes, with suggestion of differential effects by diabetes status. The PON1 L55 variant was associated with none of the measured indices. In conclusion, we have shown that the Q192R polymorphism is a determinant of both PON1 concentration and activity and this association appeared to be enhanced in subjects with diabetes.

Differential management and associations of dyslipidaemia and hypertension by glycaemic status in urban South Africans.

BACKGROUND: Dyslipidaemia and hypertension care have not been reported in large samples of community-based participants with known diabetes (KD) nor compared with individuals at high risk for diabetes. OBJECTIVES: To describe the management and associations of dyslipidaemia and hypertension in adults with KD, newly diagnosed diabetes (NDD) and normoglycaemia. METHODS: This urban population-based cross-sectional study comprised participants with KD, NDD and normoglycaemia. Participants at high risk for diabetes but without KD underwent oral glucose tolerance tests; those who were subsequently classified as NDD or normoglycaemic were included in this study. Data collection comprised administered questionnaires, clinical measurements and biochemical analyses. Multivariable logistic regressions determined the associations with hypertension and dyslipidaemia management in separate models. RESULTS: Among 618 participants (82% women), aged median 58 years, there were 339 participants with KD, 70 with NDD and 209 with normoglycaemia. Prevalence of hypertension (BP ≥140/90 mmHg or on treatment) and dyslipidaemia (raised low-density lipoprotein cholesterol >3 mmol/L or on treatment) was highest in KD (89% and 83%) compared with NDD (64% and 74%) and normoglycaemia (66% for both) (p<0.001). Detected or known hypertension was highest in KD (97.4%), followed by NDD (88.9%) and normoglycaemia (80.3%). Among participants with known or detected hypertension, those with KD were most likely to be treated (90.2%) compared with NDD (77.5%) and normoglycaemia (74.5.%). Hypertension control among participants on treatment was highest in KD (69.5%) compared with NDD (51.6%) and normoglycaemia (61.0%). Participants with KD had significantly higher rates of previously detected dyslipidaemia (85.1%) compared with NDD (36.5%) and normoglycaemia (35.5%). KD participants were also more likely to be treated for their previously detected dyslipidaemia (85.4%) and to be controlled when on treatment (56.3%) compared with their counterparts (NDD: 63.2% and 33.3%, normoglycaemia: 61.2% and 43.3%, respectively). Diabetes control was poor; only 20% of those with KD had HbA1c <7%. In the regression models, compared with normoglycaemia, KD was associated with hypertension detection (odds ratio (OR) 6.91, 95% confidence interval (CI) 2.25 - 21.22) and control (OR 2.05, 95% CI 1.04 - 4.02). KD compared with normoglycaemia was associated with dyslipidaemia detection (OR 10.29, 95% CI 5.21 - 20.32) and treatment (OR 3.94, 95% CI 1.68 - 9.27). Sociodemographic and cardiovascular disease risk factors were generally not associated with hypertension or dyslipidaemia management. CONCLUSION: Albeit that diabetes control was poor and required better management, dyslipidaemia and hypertension prevalence were higher and better managed in KD than NDD and normoglycaemia. Different approaches are required to improve glucose control in KD, better identify NDD and monitor and prevent diabetes in high-risk individuals. Also important would be to improve care of hypertension and dyslipidaemia in those without KD.

N-terminal pro-B-type natriuretic peptide concentrations and long-term outcome after cardiac surgery: a prospective cohort study.

BACKGROUND: N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations predict cardiovascular outcome in many settings. There are very few data assessing the utility of NT-proBNP concentrations in the prediction of long-term outcome after cardiac surgery. We assessed the ability of NT-proBNP to predict 3 yr mortality compared with validated clinical risk prediction tools. METHODS: A secondary analysis of a prospectively recruited patient cohort of 1010 patients undergoing cardiac surgery. Baseline clinical details were obtained including EuroSCORE. Multi-variable modelling, area under the receiver operating characteristic curves (AUCs), and net reclassification improvement were utilized. RESULTS: NT-proBNP was a univariable predictor of 3 yr mortality but was no longer a significant predictor in a multivariable model (hazard ratio 1.00 per 250 ng litre(-1), 95% confidence interval 0.98-1.02, P=0.80). The relative and additive predictive values of the preoperative EuroSCORE (both additive and logistic versions) and NT-proBNP concentrations were compared. All were predictive of 3 yr mortality (P<0.001) with almost identical AUCs (0.71 for EuroSCORE, 0.70 for NT-proBNP). When either the EuroSCORE or NT-proBNP concentrations are known, the addition of the other does not improve the ability to predict 3 yr mortality. CONCLUSIONS: Preoperative NT-proBNP concentrations and the EuroSCORE have equivalent, and moderate, predictive accuracy for mortality 3 yr after cardiac surgery. EuroSCORE uses clinical data but is not routinely used for individual clinical risk prediction. NT-proBNP measurement would incur additional costs but can be measured quickly and objectively. With such similar predictive accuracy, factors such as the ease of calculation and cost will likely determine their use in clinical practice.

Leveraging the South African Diabetes Prevention Programme to screen for chronic kidney disease: an observational study.

OBJECTIVE: To evaluate the viability of leveraging an existing screening programme (the South African Diabetes Prevention Programme (SA-DPP)) to screen for chronic kidney disease (CKD), by assessing the yield of CKD cases among those participating in the programme. DESIGN: Observational study conducted between 2017 and 2019. SETTING: 16 resource-poor communities in Cape Town, South Africa. PARTICIPANTS: 690 participants, aged between 25 and 65 years, identified as at high risk for type 2 diabetes mellitus (T2DM) by the African Diabetes Risk Score. PRIMARY OUTCOME MEASURE: The prevalence of CKD among those participating in the SA-DPP. RESULTS: Of the 2173 individuals screened in the community, 690 participants underwent further testing. Of these participants, 9.6% (n=66) and 18.1% (n=125) had screen-detected T2DM and CKD (defined as an estimated glomerular filtration rate (eGFR) of<60 mL/min/1.73 m2 and/or albumin-to-creatinine ratio >3 mg/mmol), respectively. Of those with CKD, 73.6% (n=92), 17.6% (n=22) and 8.8% (n=11) presented with stages 1, 2 and 3, respectively. Of the participants with an eGFR <60 mL/min/1.73 m2, 36.4% had no albuminuria and of those with normal kidney function (eGFR ≥90 mL/min/1.73 m2), 10.2% and 3.8% had albuminuria stages 2 and 3, respectively. Of those with T2DM and hypertension, 22.7% and 19.8% had CKD, respectively. CONCLUSION: The fact that almost one in five participants identified as high risk for T2DM had CKD underscores the value of including markers of kidney function in an existing screening programme. By using an opportunistic approach to screen high-risk individuals, those with CKD can be identified and appropriately treated to reduce disease progression.

Depression and post-traumatic stress symptoms two years post-rape and the role of early counselling: Rape Impact Cohort Evaluation (RICE) study.

Background: Survivors of sexual violence are at higher risk of adverse mental health outcomes compared to those exposed to other interpersonal traumas.Objective: To examine the trajectory of both post-traumatic stress disorder (PTSD) and depression as well as the role of early counselling over 24 months among rape survivors.Method: The South African Rape Impact Cohort Evaluation (RICE) study enrolled women aged 16-40 years attending post-rape care services within 20 days of a rape incident (n = 734), and a comparison group (n = 786) was recruited from primary health care. Women were followed for 24 months; the main study outcomes were depression and PTSD. Reports of early supportive counselling by the exposed group were also included. The analysis included an adjusted joint mixed model with linear splines to account for correlated observations between the outcomes.Results: At 24 months, 45.2% of the rape-exposed women met the cut-off for depression and 32.7% for PTSD. This was significantly higher than levels found among the unexposed. Although a decline in depression and PTSD was seen at 3 months among the women who reported a rape, mean scores remained stable thereafter. At 24 months mean depression scores remained above the depression cut-off (17.1) while mean PTSD scores declined below the PTSD cut-off (14.5). Early counselling was not associated with the trajectory of either depression or PTSD scores over the two years in rape-exposed women with both depression and PTSD persisting regardless of early counselling.Conclusion: The study findings highlight the importance to find and provide effective mental health interventions post-rape in South Africa.

Association between dietary scores and 13-year weight change and obesity risk in a French prospective cohort.

BACKGROUND/OBJECTIVES: The relationship between diet quality and development of obesity is complex and unresolved. The aim of this study was to assess and compare the predictive value of six different dietary scores on both relative weight change and the risk of obesity after 13 years of follow-up in adults aged 45 years and older. SUBJECTS/METHODS: Six scores reflecting adherence to different nutritional recommendations (the French Programme National Nutrition Santé-Guideline Score (PNNS-GS), the Dietary Guidelines for Americans Index (DGAI), the Diet Quality Index-International (DQI-I), the Mediterranean Diet Scale (MDS), the relative Mediterranean Diet Score (rMED) and the Mediterranean Style Dietary Pattern Score (MSDPS)) were estimated in 3151 participants in the French SU.VI.MAX (SUpplémentation en VItamines et Minéraux AntioXydants) study. Associations of dietary scores with 13-year weight change were assessed through multivariate linear regression models, and obesity risk was analyzed with logistic regression, providing odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Except for the MSDPS, higher scores, that is, better adherence to nutritional guidelines or to a Mediterranean diet, were associated with lower weight gain in men (all P-value for trend <0.05). In addition, among men, ORs for becoming obese after 13 years associated with a 1 s.d. increase in dietary scores ranged from 0.63, 95% CI: 0.51, 0.78 for DGAI to 0.72, 95% CI: 0.59, 0.88 for MDS. These associations were weaker or not statistically significant in women. CONCLUSION: Overall, the six dietary scores predicted obesity risk equally well. Among French adults, strong adherence to dietary guidelines appears to be protective with regard to weight gain and obesity, especially in men.

Would sickle cell trait influence the metabolic control in sub-Saharan individuals with type 2 diabetes?

AIMS: To determine the prevalence and effects of sickle cell trait on metabolic control in a Cameroonian diabetic population in a tertiary care setup. METHODS: This was a cross-sectional study involving 73 consecutive outpatients with Type 2 diabetes recruited from the Yaounde National Diabetes and Obesity Centre. Sickle cell trait status was based on haemoglobin electrophoresis. Metabolic control was assessed by plasma glucose and HbA(1c), and comparisons made between participants with and without sickle cell trait, with adjustment for confounders through linear regressions models. RESULTS: The prevalence of sickle cell trait was 19%, without sex difference, and comparable with figures in individuals without diabetes in this setting. Participants with diabetes and sickle cell trait were older than the non-trait participants (66 vs. 58 years, P = 0.02). Otherwise, clinical and biological profile including indicators of metabolic control were similarly distributed between trait and non-trait participants (all P >0.08). After adjustment for confounders, sickle cell trait was unrelated to fasting glucose (ß = 0.02; 95% confidence interval -37.68-43.30) and HbA(1c) (ß = -0.03, 95% confidence interval -1.18-0.93), and did not affect the relationship between the two markers of diabetes control (ß = -0.03, 95% confidence interval -1.18-0.89). CONCLUSIONS: Sickle cell trait was as frequent in this subgroup of patients with Type 2 diabetes as in the general population, suggesting no specific association with diabetes. It does not affect the metabolic control of diabetes. However, how this translates into long-term outcome needs to be fully elucidated in this setting, with an increasing population with both sickle cell trait and diabetes mellitus.

Weight changes and their predictors amongst 11 140 patients with type 2 diabetes in the ADVANCE trial.

AIMS: To determine the baseline characteristics and glucose-lowering therapies associated with weight change among patients with type 2 diabetes. METHODS: Eleven thousand one hundred and forty participants in the ADVANCE trial were randomly assigned to an intensive [aiming for a haemoglobin A1c (HbA1c) ≤6.5%] or a standard blood glucose-control strategy. Weight was measured at baseline and every 6 months over a median follow-up of 5 years. Multivariable linear regression and linear-mixed effect models were used to examine predictors of weight change. RESULTS: The mean difference in weight between the intensive and standard glucose-control arm during follow-up was 0.75 kg (95% CI: 0.56-0.94), p-value <0.001. The mean weight decreased by 0.70 kg (95% CI: 0.53-0.87), p < 0.001 by the end of follow-up in the standard arm but remained stable in the intensive arm, with a non-significant gain of 0.16 kg (95% CI: -0.02 to 0.34), p = 0.075. Baseline factors associated with weight gain were younger age, higher HbA1c, Caucasian ethnicity and number of glucose-lowering medications. Treatment combinations including insulin [3.22 kg (95% CI: 2.92-3.52)] and thiazolidinediones [3.06 kg (95% CI: 2.69-3.43)] were associated with the greatest weight gain while treatment combinations including sulphonylureas were associated with less weight gain [0.71 kg (95%CI: 0.39-1.03)]. CONCLUSIONS: Intensive glucose-control regimens are not necessarily associated with substantial weight gain. Patient characteristic associated with weight change were age, ethnicity, smoking and HbA1c. The main treatment strategies predicting weight gain were the use of insulin and thiazolidinediones.

MicroRNAs associated with chronic kidney disease in the general population and high-risk subgroups: protocol for a systematic review and meta-analysis.

INTRODUCTION: Chronic kidney disease (CKD) is a significant health and economic burden, owing to its ever-increasing global prevalence. Due to the limitations in the current diagnostic methods, CKD is frequently diagnosed at advanced stages, where there is an increased risk of cardiovascular complications and end-stage kidney disease. As such, there has been considerable interest in microRNAs (miRNAs) as potential markers for CKD detection. This review seeks to identify all miRNAs associated with CKD and/or markers of kidney function or kidney damage in the general population and high-risk subgroups, and explore their expression profiles in these populations. METHODS AND ANALYSIS: A systematic search of published literature will be conducted for observational studies that report on miRNAs associated with CKD or kidney function or kidney damage markers (serum creatinine and cystatin C, estimated glomerular filtration rate and urinary albumin excretion) in adult humans. The electronic database search will be restricted to English and French publications up to 31 October 2021. Two investigators will independently screen and identify studies for inclusion, as well as extract data from eligible studies. Risk-of-bias and methodological quality will be assessed by the Newcastle-Ottawa Quality Assessment Scale for observational studies and Grading of Recommendations Assessment, Development and Evaluation tools. Appropriate meta-analytic techniques will be used to pool estimates from studies with similar miRNAs, overall and by major characteristics, including by country or region, sample size, gender and risk-of-bias score. Heterogeneity of the estimates across studies will be quantified and publication bias investigated. This protocol is reported according to Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 guidelines. ETHICS AND DISSEMINATION: This study design does not require formal ethical clearance and findings will be published in a peer-reviewed journal. CONCLUSION: This review will provide the expression pattern of miRNAs associated with CKD. This will allow for further research into the identified miRNAs, which could later be used as biomarkers for prediction and early detection of CKD, monitoring of disease progression to advanced stages and as potential therapeutic targets. PROSPERO REGISTRATION NUMBER: CRD42021270028.

Estimating the changing burden of disease attributable to high fasting plasma glucose in South Africa for 2000, 2006 and 2012.

BACKGROUND: Worldwide, higher-than-optimal fasting plasma glucose (FPG) is among the leading modifiable risk factors associated with all- cause mortality and disability-adjusted life years (DALYs) due to the direct sequelae of diabetes and the increased risk for cardiovascular and chronic kidney disease. OBJECTIVES: To report deaths and DALYs of health outcomes attributable to high FPG by age and sex for South Africa (SA) for 2000, 2006 and 2012. METHODS: Comparative risk assessment methodology was used to estimate the burden attributable to high FPG. A meta-regression analysis was performed using data from national and small-area studies to estimate the population distribution of FPG and diabetes prevalence. Attributable fractions were calculated for selected health outcomes and applied to local burden estimates from the second South African National Burden of Disease Study (SANBD2). Age-standardised rates were calculated using World Health Organization world standard population weights. RESULTS: We estimated a 5% increase in mean FPG from 5.31 (95% confidence interval (CI) 5.18 - 5.43) mmol/L to 5.57 (95% CI 5.41 - 5.72) mmol/L and a 75% increase in diabetes prevalence from 7.3% (95% CI 6.7 - 8.3) to 12.8% (95% CI 11.9 - 14.0) between 2000 and 2012. The age-standardised attributable death rate increased from 153.7 (95% CI 126.9 - 192.7) per 100 000 population in 2000 to 203.5 (95% CI 172.2 - 240.8) per 100 000 population in 2012, i.e. a 32.4% increase. During the same period, age-standardised attributable DALY rates increased by 43.8%, from 3 000 (95% CI 2 564 - 3 602) per 100 000 population in 2000 to 4 312 (95% CI 3 798 - 4 916) per 100 000 population in 2012. In each year, females had similar attributable death rates to males but higher DALY rates. A notable exception was tuberculosis, with an age-standardised attributable death rate in males double that in females in 2000 (14.3 v. 7.0 per 100 000 population) and 2.2 times higher in 2012 (18.4 v. 8.5 per 100 000 population). Similarly, attributable DALY rates were higher in males, 1.7 times higher in 2000 (323 v. 186 per 100 000 population) and 1.6 times higher in 2012 (502 v. 321 per 100 000 population). Between 2000 and 2012, the age-standardised death rate for chronic kidney disease increased by 98.3% (from 11.7 to 23.1 per 100 000 population) and the DALY rate increased by 116.9% (from 266 to 578 per 100 000 population). CONCLUSION: High FPG is emerging as a public health crisis, with an attributable burden doubling between 2000 and 2012. The consequences are costly in terms of quality of life, ability to earn an income, and the economic and emotional burden on individuals and their families. Urgent action is needed to curb the increase and reduce the burden associated with this risk factor. National data on FPG distribution are scant, and efforts are warranted to ensure adequate monitoring of the effectiveness of the interventions.

Building knowledge, optimising physical and mental health and setting up healthier life trajectories in South African women (Bukhali): a preconception randomised control trial part of the Healthy Life Trajectories Initiative (HeLTI).

INTRODUCTION: South Africa's evolving burden of disease is challenging due to a persistent infectious disease, burgeoning obesity, most notably among women and rising rates of non-communicable diseases (NCDs). With two thirds of women presenting at their first antenatal visit either overweight or obese in urban South Africa (SA), the preconception period is an opportunity to optimise health and offset transgenerational risk of both obesity and NCDs. METHODS AND ANALYSIS: Bukhali is the first individual randomised controlled trial in Africa to test the efficacy of a complex continuum of care intervention and forms part of the Healthy Life Trajectories Initiative (HeLTI) consortium implementing harmonised trials in Canada, China, India and SA. Starting preconception and continuing through pregnancy, infancy and childhood, the intervention is designed to improve nutrition, physical and mental health and health behaviours of South African women to offset obesity-risk (adiposity) in their offspring. Women aged 18-28 years (n=6800) will be recruited from Soweto, an urban-poor area of Johannesburg. The primary outcome is dual-energy X-ray absorptiometry derived fat mass index (fat mass divided by height2) in the offspring at age 5 years. Community health workers will deliver the intervention randomly to half the cohort by providing health literacy material, dispensing a multimicronutrient supplement, providing health services and feedback, and facilitating behaviour change support sessions to optimise: (1) nutrition, (2) physical and mental health and (3) lay the foundations for healthier pregnancies and early child development. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Human Ethics Research Committee University of the Witwatersrand, Johannesburg, South Africa (M1811111), the University of Toronto, Canada (19-0066-E) and the WHO Ethics Committee (ERC.0003328). Data and biological sample sharing policies are consistent with the governance policy of the HeLTI Consortium (https://helti.org) and South African government legislation (POPIA). The recruitment and research team will obtain informed consent. TRIAL REGISTRATION: This trial is registered with the Pan African Clinical Trials Registry (https://pactr.samrc.ac.za) on 25 March 2019 (identifier: PACTR201903750173871). PROTOCOL VERSION: 20 March 2022 (version #4). Any protocol amendments will be communicated to investigators, Institutional Review Board (IRB)s, trial participants and trial registries.

Intensive glucose control and risk of cancer in patients with type 2 diabetes.

AIMS/HYPOTHESIS: Type 2 diabetes has been associated with an increased risk of cancer. This study examines the effect of more vs less intensive glucose control on the risk of cancer in patients with type 2 diabetes. METHODS: All 11,140 participants from the Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE) trial (ClinicalTrials.gov NCT00145925) were studied. Cancer incidence and cancer mortality was compared in groups randomised to intensive or standard glucose control. Information on events during follow-up was obtained from serious adverse event reports and death certificates. HRs (95% CI) were calculated for all cancers, all solid cancers, cancer deaths and site-specific cancers. RESULTS: After a median follow-up of 5 years, 363 and 337 cancer events were reported in the intensive and standard control groups, respectively (incidence 1.39/100 person-years [PY] and 1.28/100 PY; HR 1.08 [95% CI 0.93-1.26]). The incidences of all solid cancers and cancer deaths were 1.25/100 PY and 0.55/100 PY in the intensive group and 1.15/100 PY and 0.63/100 PY in the standard group (HR 1.09[95% CI 0.93­1.27] for solid cancers, and 0.88 [0.71­1.10] for cancer death) [corrected].Across all the major organ systems studied, no significant differences in the cancer incidences were observed in the intensive and standard control groups. CONCLUSIONS/INTERPRETATIONS: More intensive glucose control achieved with a regimen that included greater use of gliclazide, insulin, metformin and other agents, did not affect the risk of cancer events or death in patients with type 2 diabetes.

Metabolic sequelae of ß-blocker therapy: weighing in on the obesity epidemic?

BACKGROUND: Sympathetic activation is an important metabolic adaptation limiting weight gain. Propensity of weight gain associated with ß-blocker therapy in the obese modern population is unknown. OBJECTIVE: To determine whether chronic ß-blocker therapy reduces energy expenditure (EE) and increases body weight. METHODS: We undertook (i) a mechanistic study comparing EE, diet-induced thermogenesis and habitual activity between healthy volunteers (n=11) with uncomplicated hypertension treated with a ß-blocker and anthropometrically matched controls (n=19) and (ii) three cross-sectional studies comparing body weight, body mass index (BMI) and waist circumference between ß-blocker treated and untreated patients from ambulatory patients attending (a) diabetes outpatient clinic (n=214), (b) hypertension outpatient (n=84) and (c) participants in a multi-centre type 2 diabetes trial (ADVANCE) (n=11140). RESULTS: Among weight-matched ß-blocker users, diet-induced thermogenesis, fat oxidation rate and weekly habitual activity were lower by 50% (P<0.01), 32% (P=0.04) and 30% (P<0.01), respectively, compared with controls. In ß-blocker treated patients, the adjusted mean body weight was 9.2 ± 1.2 kg (P=0.0002) higher among those attending the diabetes clinic, 17.2 ± 3.2 kg (P=0.004) higher among those attending the hypertension clinic and 5.2 ± 0.7 kg (P=0.0003) higher at baseline among participants in the ADVANCE trial compared with patients not treated with ß-blockers. BMI displayed a similar difference. CONCLUSIONS: EE is reduced and body weight increased in chronic ß-blocker users. We hypothesise that chronic ß-blockade causes obesity by blunting EE.