Physical fitness in male adolescents and atherosclerosis in middle age: a population-based cohort study.

OBJECTIVES: To examine the associations between physical fitness in male adolescents and coronary and carotid atherosclerosis in middle age. METHODS: This population-based cohort study linked physical fitness data from the Swedish Military Conscription Register during adolescence to atherosclerosis data from the Swedish CArdioPulmonary bioImage Study in middle age. Cardiorespiratory fitness was assessed using a maximal cycle-ergometer test, and knee extension muscular strength was evaluated through an isometric dynamometer. Coronary atherosclerosis was evaluated via Coronary Computed Tomography Angiography (CCTA) stenosis and Coronary Artery Calcium (CAC) scores, while carotid plaques were evaluated by ultrasound. The associations were analysed using multinomial logistic regression, adjusted (marginal) prevalences and restricted cubic splines. RESULTS: The analysis included 8986 male adolescents (mean age 18.3 years) with a mean follow-up of 38.2 years. Physical fitness showed a reversed J-shaped association with CCTA stenosis and CAC, but no consistent association was observed for carotid plaques. After adjustments, compared with adolescents in the lowest tertile of cardiorespiratory fitness and muscular strength, those in the highest tertile had 22% (OR 0.78; 95% CI 0.61 to 0.99) and 26% (OR 0.74; 95% CI 0.58 to 0.93) lower ORs for severe (≥50%) coronary stenosis, respectively. The highest physical fitness group (high cardiorespiratory fitness and muscular strength) had 33% (OR 0.67; 95% CI 0.52 to 0.87) lower OR for severe coronary stenosis compared with those with the lowest physical fitness. CONCLUSION: This study supports that a combination of high cardiorespiratory fitness and high muscular strength in adolescence is associated with lower coronary atherosclerosis, particularly severe coronary stenosis, almost 40 years later.

Early adulthood exercise capacity, but not muscle strength, associates with subclinical atherosclerosis 40 years later in Swedish men.

AIMS: Poor exercise capacity and muscle strength in early adulthood are risk factors for cardiovascular disease (CVD). However, it is unclear how these factors relate to subclinical atherosclerosis due to a lack of longitudinal studies. This study investigated whether early adulthood exercise capacity and muscle strength associated with later adulthood subclinical atherosclerosis. METHODS AND RESULTS: This study included Swedish men (n = 797) who were eligible for military conscription (at ∼18-years of age) and who participated in the baseline assessment of the visualization of asymptomatic atherosclerotic disease for optimum cardiovascular prevention trial between 2013 and 2016 (at 60 years of age). At conscription, isometric muscle strength (dynamometer) and maximum exercise capacity (maximal load cycle ergometer test) were measured. During later adulthood (at 60 years old), the presence of carotid plaques and intima media thickness were measured by using high-resolution ultrasound. At follow-up, plaques were present in 62% (n = 493) of men. Exercise capacity in early adulthood associated with 19% lower odds of plaques [odds ratio (OR) 0.81, 95% confidence interval (CI) 0.68-0.96], independent of muscle strength. This association was not mediated by any single CVD risk factor. However, the total indirect effect of later, but not early, adulthood CVD risk factors was significant, while the direct effect was non-significant (OR 0.85, 95% CI 0.71-1.02). Associations between muscle strength and subclinical atherosclerosis were non-significant. CONCLUSION: Higher exercise capacity during early adulthood, but not muscle strength, may protect against carotid plaque development during adulthood mediated by the combination rather than a single later adulthood CVD risk factors.

Swedish men who had high fitness at ∼18 years of age (early adulthood) had a lower prevalence of atherosclerotic plaques 40 years later (later adulthood), independent of muscle strength. The underlying mechanism of this protective association of higher fitness on the presence of plaques may be through the combination of later adulthood body mass index, systolic blood pressure, glucose tolerance status, non-HDL cholesterol, and triglycerides instead of through any single risk factor.Muscle strength during early adulthood was not associated with atherosclerosis during later adulthood.

Physical activity attenuates but does not eliminate coronary heart disease risk amongst adults with risk factors: EPIC-CVD case-cohort study.

AIMS: This study aimed to evaluate the association between physical activity and the incidence of coronary heart disease (CHD) in individuals with and without CHD risk factors. METHODS AND RESULTS: EPIC-CVD is a case-cohort study of 29 333 participants that included 13 582 incident CHD cases and a randomly selected sub-cohort nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Self-reported physical activity was summarized using the Cambridge physical activity index (inactive, moderately inactive, moderately active, and active). Participants were categorized into sub-groups based on the presence or the absence of the following risk factors: obesity (body mass index ≥30 kg/m2), hypercholesterolaemia (total cholesterol ≥6.2 mmol/L), history of diabetes, hypertension (self-reported or ≥140/90 mmHg), and current smoking. Prentice-weighted Cox regression was used to assess the association between physical activity and incident CHD events (non-fatal and fatal).Compared to inactive participants without the respective CHD risk factor (referent), excess CHD risk was highest in physically inactive and lowest in moderately active participants with CHD risk factors. Corresponding excess CHD risk estimates amongst those with obesity were 47% [95% confidence interval (CI) 32-64%] and 21% (95%CI 2-44%), with hypercholesterolaemia were 80% (95%CI 55-108%) and 48% (95%CI 22-81%), with hypertension were 80% (95%CI 65-96%) and 49% (95%CI 28-74%), with diabetes were 142% (95%CI 63-260%), and 100% (95%CI 32-204%), and amongst smokers were 152% (95%CI 122-186%) and 109% (95%CI 74-150%). CONCLUSIONS: In people with CHD risk factors, moderate physical activity, equivalent to 40 mins of walking per day, attenuates but does not completely offset CHD risk.

ß-cell function in black South African women: exploratory associations with insulin clearance, visceral and ectopic fat.

The role of ectopic fat, insulin secretion and clearance in the preservation ofß-cell function in black African women with obesity who typically present with hyperinsulinaemia is not clear. We aim to examine the associations between disposition index (DI, an estimate of ß-cell function), insulin secretion and clearance and ectopic fat deposition. This is a cross-sectional study of 43 black South African women (age 20-35 years) with obesity (BMI 30-40 kg/m2) and without type 2 diabetes that measured the following: DI, insulin sensitivity (SI), acute insulin response (AIRg), insulin secretion rate (ISR), hepatic insulin extraction and peripheral insulin clearance (frequently sampled i.v. glucose tolerance test); pancreatic and hepatic fat, visceral adipose tissue (VAT) and abdominal s.c. adipose tissue (aSAT) volume (MRI), intra-myocellular (IMCL) and extra-myocellular fat content (EMCL) (magnetic resonance spectroscopy). DI correlated positively with peripheral insulin clearance (ß 55.80, P = 0.002). Higher DI was associated with lower VAT, pancreatic fat and soleus fat, but VAT explained most of the variance in DI (32%). Additionally, higher first phase ISR (P = 0.033) and lower hepatic insulin extraction (P = 0.022) were associated with lower VAT, independent from SI, rather than with ectopic fat. In conclusion, peripheral insulin clearance emerged as an important correlate of DI. However, VAT was the main determinant of a lower DI above ectopic fat depots. Importantly, VAT, but not ectopic fat, is associated with both lower insulin secretion and higher hepatic insulin extraction. Prevention of VAT accumulation in young black African women should, therefore, be an important target for beta cell preservation.

Exercise training improves mitochondrial respiration and is associated with an altered intramuscular phospholipid signature in women with obesity.

AIMS/HYPOTHESIS: We sought to determine putative relationships among improved mitochondrial respiration, insulin sensitivity and altered skeletal muscle lipids and metabolite signature in response to combined aerobic and resistance training in women with obesity. METHODS: This study reports a secondary analysis of a randomised controlled trial including additional measures of mitochondrial respiration, skeletal muscle lipidomics, metabolomics and protein content. Women with obesity were randomised into 12 weeks of combined aerobic and resistance exercise training (n = 20) or control (n = 15) groups. Pre- and post-intervention testing included peak oxygen consumption, whole-body insulin sensitivity (intravenous glucose tolerance test), skeletal muscle mitochondrial respiration (high-resolution respirometry), lipidomics and metabolomics (mass spectrometry) and lipid content (magnetic resonance imaging and spectroscopy). Proteins involved in glucose transport (i.e. GLUT4) and lipid turnover (i.e. sphingomyelin synthase 1 and 2) were assessed by western blotting. RESULTS: The original randomised controlled trial showed that exercise training increased insulin sensitivity (median [IQR]; 3.4 [2.0-4.6] to 3.6 [2.4-6.2] x10-5 pmol l-1 min-1), peak oxygen consumption (mean ± SD; 24.9 ± 2.4 to 27.6 ± 3.4 ml kg-1 min-1), and decreased body weight (84.1 ± 8.7 to 83.3 ± 9.7 kg), with an increase in weight (pre intervention, 87.8± 10.9 to post intervention 88.8 ± 11.0 kg) in the control group (interaction p < 0.05). The current study shows an increase in mitochondrial respiration and content in response to exercise training (interaction p < 0.05). The metabolite and lipid signature at baseline were significantly associated with mitochondrial respiratory capacity (p < 0.05) but were not associated with whole-body insulin sensitivity or GLUT4 protein content. Exercise training significantly altered the skeletal muscle lipid profile, increasing specific diacylglycerol(32:2) and ceramide(d18:1/24:0) levels, without changes in other intermediates or total content of diacylglycerol and ceramide. The total content of cardiolipin, phosphatidylcholine (PC) and phosphatidylethanolamine (PE) increased with exercise training with a decrease in the PC:PE ratios containing 22:5 and 20:4 fatty acids. These changes were associated with content-driven increases in mitochondrial respiration (p < 0.05), but not with the increase in whole-body insulin sensitivity or GLUT4 protein content. Exercise training increased sphingomyelin synthase 1 (p < 0.05), with no change in plasma-membrane-located sphingomyelin synthase 2. CONCLUSIONS/INTERPRETATION: The major findings of our study were that exercise training altered specific intramuscular lipid intermediates, associated with content-driven increases in mitochondrial respiration but not whole-body insulin sensitivity. This highlights the benefits of exercise training and presents putative target pathways for preventing lipotoxicity in skeletal muscle, which is typically associated with the development of type 2 diabetes.

Improved Sleep Quality and Depressive Symptoms With Exercise Training in Obese Women From a Low Socioeconomic Community: A Randomized Controlled Trial.

BACKGROUND: Improving sleep quality and reducing depressive symptoms may be target mechanisms for intervention-based research aimed at reducing cardiometabolic risk in low-income communities. This study assessed the effects of exercise training on depressive symptoms and sleep in obese women for a low socioeconomic community. The secondary aim explored associations between changes in depressive symptoms and sleep with changes in cardiorespiratory fitness and cardiometabolic risk factors. METHODS: Participants were randomized into exercise (n = 20) or control (n = 15) groups. The exercise group completed 12 weeks of combined resistance and aerobic training (40-60 min, 4 d/wk), and the control group maintained habitual diet and activity. Preintervention and postintervention testing included questionnaires on symptoms of depression, psychological distress, and sleep quality. Sedentary time, peak oxygen consumption, body mass index, and insulin sensitivity were measured objectively. Sleep duration (accelerometry) was assessed at preintervention and weeks 4, 8, and 12. RESULTS: Exercise training reduced depressive symptoms (P = .002) and improved sleep quality (P < .001) and sleep efficiency (P = .005). Reduced depressive symptoms were associated with improved peak oxygen consumption (rho = -.600, P < .001), and improved sleep quality correlated with reduced sedentary time (rho = .415, P = .018). CONCLUSION: These results highlight the potential for community-based exercise interventions to simultaneously address multiple comorbidities in a low-income setting.

Exercise Training Alters Red Blood Cell Fatty Acid Desaturase Indices and Adipose Tissue Fatty Acid Profile in African Women with Obesity.

OBJECTIVE: This study assessed the changes in red blood cell total phospholipid (RBC-TPL) and subcutaneous adipose tissue (SAT) fatty acid (FA) composition in response to 12 weeks of exercise training in South African women with obesity and the associations with changes in cardiometabolic risk factors. METHODS: Previously sedentary women were randomized into control (n = 15) or exercise (n = 20) groups. RBC-TPL and SAT FA profiles, SAT gene expression, systemic inflammatory markers, liver fat, and insulin sensitivity (SI ) were measured before and after the intervention. RESULTS: Compared with control, exercise training induced decreases in RBC-TPL dihomo-γ-linolenic acid content and stearoyl-CoA desaturase-1 and increased delta-5 desaturase-estimated activity (P < 0.05). In the combined group, these changes correlated with changes in circulating leptin and TNFα (P < 0.05), as well as lower liver fat (P < 0.01). Exercise training decreased saturated FA (lauric and myristic acids) and increased polyunsaturated FA (eicosadienoic and adrenic acids) (P < 0.05) in abdominal SAT, whereas γ-linolenic acid decreased (P < 0.01) in gluteal SAT. These changes in RBC-TPL and SAT FA compositions were not associated with changes in SAT gene expression and SI . CONCLUSIONS: Exercise training alters RBC-TPL desaturase activities, which correlate with lower liver fat and systemic inflammation but not with the improvement of SI .

Effect of exercise training on insulin sensitivity, hyperinsulinemia and ectopic fat in black South African women: a randomized controlled trial.

OBJECTIVE: We investigated the effects of a 12-week exercise intervention on insulin sensitivity (SI) and hyperinsulinemia and associated changes in regional and ectopic fat. RESEARCH DESIGN AND METHODS: Healthy, black South African women with obesity (mean age 23 ± 3.5 years) and of isiXhosa ancestry were randomised into a 12-week aerobic and resistance exercise training group (n = 23) and a no exercise group (control, n = 22). Pre and post-intervention testing included assessment of SI, insulin response to glucose (AIRg), insulin secretion rate (ISR), hepatic insulin extraction (FEL) and disposition index (DI) (AIRg × SI) (frequently sampled i.v. glucose tolerance test); fat mass and regional adiposity (dual-energy X-ray absorptiometry); hepatic, pancreatic and skeletal muscle fat content and abdominal s.c. and visceral adipose tissue volumes (MRI). RESULTS: Exercise training increased VO2peak (mean ± s.d.: 24.9 ± 2.42 to 27.6 ± 3.39 mL/kg/min, P < 0.001), SI (2.0 (1.2-2.8) to 2.2 (1.5-3.7) (mU/l)-1 min-1, P = 0.005) and DI (median (interquartile range): 6.1 (3.6-7.1) to 6.5 (5.6-9.2) × 103 arbitrary units, P = 0.028), and decreased gynoid fat mass (18.5 ± 1.7 to 18.2 ± 1.6%, P < 0.001) and body weight (84.1 ± 8.7 to 83.3 ± .9.7 kg, P = 0.038). None of these changes were observed in the control group, but body weight increased (P = 0.030). AIRg, ISR and FEL, VAT, SAT and ectopic fat were unaltered after exercise training. The increase in SI and DI were not associated with changes in regional or ectopic fat. CONCLUSION: Exercise training increased SI independent from changes in hyperinsulinemia and ectopic fat, suggesting that ectopic fat might not be a principal determinant of insulin resistance in this cohort.

Exercise training results in depot-specific adaptations to adipose tissue mitochondrial function.

We assessed differences in mitochondrial function in gluteal (gSAT) and abdominal subcutaneous adipose tissue (aSAT) at baseline and in response to 12-weeks of exercise training; and examined depot-specific associations with body fat distribution and insulin sensitivity (SI). Obese, black South African women (n = 45) were randomized into exercise (n = 23) or control (n = 22) groups. Exercise group completed 12-weeks of aerobic and resistance training (n = 20), while the control group (n = 15) continued usual behaviours. Mitochondrial function (high-resolution respirometry and fluorometry) in gSAT and aSAT, SI (frequently sampled intravenous glucose tolerance test), body composition (dual-energy X-ray absorptiometry), and ectopic fat (MRI) were assessed pre- and post-intervention. At baseline, gSAT had higher mitochondrial respiratory capacity and hydrogen peroxide (H2O2) production than aSAT (p < 0.05). Higher gSAT respiration was associated with higher gynoid fat (p < 0.05). Higher gSAT H2O2 production and lower aSAT mitochondrial respiration were independently associated with lower SI (p < 0.05). In response to training, SI improved and gynoid fat decreased (p < 0.05), while H2O2 production reduced in both depots, and mtDNA decreased in gSAT (p < 0.05). Mitochondrial respiration increased in aSAT and correlated with a decrease in body fat and an increase in soleus and hepatic fat content (p < 0.05). This study highlights the importance of understanding the differences in mitochondrial function in multiple SAT depots when investigating the pathophysiology of insulin resistance and associated risk factors such as body fat distribution and ectopic lipid deposition. Furthermore, we highlight the benefits of exercise training in stimulating positive adaptations in mitochondrial function in gluteal and abdominal SAT depots.

Serious adverse drug reactions at two children's hospitals in South Africa.

BACKGROUND: The high HIV prevalence in South Africa may potentially be shaping the local adverse drug reaction (ADR) burden. We aimed to describe the prevalence and characteristics of serious ADRs at admission, and during admission, to two South African children's hospitals. METHODS: We reviewed the folders of children admitted over sequential 30-day periods in 2015 to the medical wards and intensive care units of each hospital. We identified potential ADRs using a trigger tool developed for this study. A multidisciplinary team assessed ADR causality, type, seriousness, and preventability through consensus discussion. We used multivariate logistic regression to explore associations with serious ADRs. RESULTS: Among 1050 patients (median age 11 months, 56% male, 2.8% HIV-infected) with 1106 admissions we found 40 serious ADRs (3.8 per 100 drug-exposed admissions), including 9/40 (23%) preventable serious ADRs, and 8/40 (20%) fatal or near-fatal serious ADRs. Antibacterials, corticosteroids, psycholeptics, immunosuppressants, and antivirals were the most commonly implicated drug classes. Preterm neonates and children in middle childhood (6 to 11 years) were at increased risk of serious ADRs compared to infants (under 1 year) and term neonates: adjusted odds ratio (aOR) 5.97 (95% confidence interval 1.30 to 27.3) and aOR 3.63 (1.24 to 10.6) respectively. Other risk factors for serious ADRs were HIV infection (aOR 3.87 (1.14 to 13.2) versus HIV-negative) and increasing drug count (aOR 1.08 (1.04 to 1.12) per additional drug). CONCLUSIONS: Serious ADR prevalence in our survey was similar to the prevalence found elsewhere. In our setting, serious ADRs were associated with HIV-infection and the antiviral drug class was one of the most commonly implicated. Similar to other sub-Saharan African studies, a large proportion of serious ADRs were fatal or near-fatal. Many serious ADRs were preventable.

An Exercise Intervention to Unravel the Mechanisms Underlying Insulin Resistance in a Cohort of Black South African Women: Protocol for a Randomized Controlled Trial and Baseline Characteristics of Participants.

BACKGROUND: The pathogenesis of type 2 diabetes (T2D) in black African women is complex and differs from that in their white counterparts. However, earlier studies have been cross-sectional and provide little insight into the causal pathways. Exercise training is consistently used as a model to examine the mechanisms underlying insulin resistance and risk for T2D. OBJECTIVE: The objective of the study was to examine the mechanisms underlying the changes in insulin sensitivity and secretion in response to a 12-week exercise intervention in obese black South African (SA) women. METHODS: A total of 45 obese (body mass index, BMI: 30-40 kg/m2) black SA women were randomized into a control (n=22) or experimental (exercise; n=23) group. The exercise group completed 12 weeks of supervised combined aerobic and resistance training (40-60 min, 4 days/week), while the control group maintained their typical physical activity patterns, and both groups were requested not to change their dietary patterns. Before and following the 12-week intervention period, insulin sensitivity and secretion (frequently sampled intravenous glucose tolerance test) and its primary and secondary determinants were measured. Dietary intake, sleep quality and quantity, physical activity, and sedentary behaviors were measured every 4 weeks. RESULTS: The final sample included 20 exercise and 15 control participants. Baseline sociodemographics, cardiorespiratory fitness, anthropometry, cardiometabolic risk factors, physical activity, and diet did not differ between the groups (P>.05). CONCLUSIONS: The study describes a research protocol for an exercise intervention to understand the mechanisms underlying insulin sensitivity and secretion in obese black SA women and aims to identify causal pathways underlying the high prevalence of insulin resistance and risk for T2D in black SA women, targeting specific areas for therapeutic intervention. TRIAL REGISTRATION: Pan African Clinical Trial Registry PACTR201711002789113; http://www.pactr.org/ATMWeb/ appmanager/atm/atmregistry?_nfpb=true&_pageLabel=portals_app_atmregistry_portal_page_13 (Archived by WebCite at http://www.webcitation.org/6xLEFqKr0).

First-line antiretroviral drug discontinuations in children.

INTRODUCTION: There are a limited number of paediatric antiretroviral drug options. Characterising the long term safety and durability of different antiretrovirals in children is important to optimise management of HIV infected children and to determine the estimated need for alternative drugs in paediatric regimens. We describe first-line antiretroviral therapy (ART) durability and reasons for discontinuations in children at two South African ART programmes, where lopinavir/ritonavir has been recommended for children <3 years old since 2004, and abacavir replaced stavudine as the preferred nucleoside reverse transcriptase inhibitor in 2010. METHODS: We included children (<16 years at ART initiation) who initiated ≥3 antiretrovirals between 2004-2014 with ≥1 follow-up visit on ART. We estimated the incidence of first antiretroviral discontinuation using Kaplan-Meier analysis. We determined the reasons for antiretroviral discontinuations using competing risks analysis. We used Cox regression to identify factors associated with treatment-limiting toxicity. RESULTS: We included 3579 children with median follow-up duration of 41 months (IQR 14-72). At ART initiation, median age was 44 months (IQR 13-89) and median CD4 percent was 15% (IQR 9-21%). At three and five years on ART, 72% and 26% of children respectively remained on their initial regimen. By five years on ART, the most common reasons for discontinuations were toxicity (32%), treatment failure (18%), treatment simplification (5%), drug interactions (3%), and other or unspecified reasons (18%). The incidences of treatment limiting toxicity were 50.6 (95% CI 46.2-55.4), 1.6 (0.5-4.8), 2.0 (1.2-3.3), and 1.3 (0.6-2.8) per 1000 patient years for stavudine, abacavir, efavirenz and lopinavir/ritonavir respectively. CONCLUSIONS: While stavudine was associated with a high risk of treatment-limiting toxicity, abacavir, lopinavir/ritonavir and efavirenz were well-tolerated. This supports the World Health Organization recommendation to replace stavudine with abacavir or zidovudine in paediatric first-line ART regimens in order to improve paediatric first-line ART durability.

Prevalence and Hospital Management of Amphotericin B Deoxycholate-Related Toxicities during Treatment of HIV-Associated Cryptococcal Meningitis in South Africa.

BACKGROUND: We aimed to establish the prevalence of amphotericin B deoxycholate (AmBd)-related toxicities among South African patients with cryptococcosis and determine adherence to international recommendations to prevent, monitor and manage AmBd-related toxicities. METHODS: Clinical data were collected from cases of laboratory-confirmed cryptococcosis at 25 hospitals, October 2012 -February 2013. Anemia was defined as hemoglobin (Hb) concentration <10 g/dl, hypokalemia as serum potassium (K) <3.4 mEq/L and nephrotoxicity as an increase in serum creatinine (Cr) to >1.1 times the upper limit of normal. To determine adherence to toxicity prevention recommendations, we documented whether baseline Hb, K and Cr tests were performed, whether pre-emptive hydration and IV potassium chloride (KCl) was administered prior to 80% and 60% of AmBd doses and whether daily oral KCl supplementation was given ≥60% of the time. To determine adherence to monitoring recommendations, we ascertained whether a daily fluid chart was completed, Hb was monitored weekly and K or Cr were monitored bi-weekly. RESULTS: Of 846 patients, clinical data were available for 76% (642/846), 82% (524/642) of whom received AmBd. Sixty-four per cent (n = 333) had documented baseline laboratory tests, 40% (n = 211) were given pre-emptive hydration and 14% (n = 72) and 19% (n = 101) received intravenous and oral KCl. While on AmBd, 88% (n = 452) had fluid monitoring; 27% (n = 142), 45% (n = 235) and 44% (n = 232) had Hb, K and Cr levels monitored. Toxicities developed frequently during treatment: anemia, 16% (86/524); hypokalemia, 43% (226/524) and nephrotoxicity, 32% (169/524). CONCLUSION: AmBd-related toxicities occurred frequently but were potentially preventable with adequate monitoring, supplemental fluid and electrolyte therapies.

Adverse Drug Reactions Causing Admission to Medical Wards: A Cross-Sectional Survey at 4 Hospitals in South Africa.

Limited data exist on the burden of serious adverse drug reactions (ADRs) in sub-Saharan Africa, which has high HIV and tuberculosis prevalence. We determined the proportion of adult admissions attributable to ADRs at 4 hospitals in South Africa. We characterized drugs implicated in, risk factors for, and the preventability of ADR-related admissions.We prospectively followed patients admitted to 4 hospitals' medical wards over sequential 30-day periods in 2013 and identified suspected ADRs with the aid of a trigger tool. A multidisciplinary team performed causality, preventability, and severity assessment using published criteria. We categorized an admission as ADR-related if the ADR was the primary reason for admission.There were 1951 admissions involving 1904 patients: median age was 50 years (interquartile range 34-65), 1057 of 1904 (56%) were female, 559 of 1904 (29%) were HIV-infected, and 183 of 1904 (10%) were on antituberculosis therapy (ATT). There were 164 of 1951 (8.4%) ADR-related admissions. After adjustment for age and ATT, ADR-related admission was independently associated (P ≤ 0.02) with female sex (adjusted odds ratio [aOR] 1.51, 95% confidence interval [95% CI] 1.06-2.14), increasing drug count (aOR 1.14 per additional drug, 95% CI 1.09-1.20), increasing comorbidity score (aOR 1.23 per additional point, 95% CI 1.07-1.41), and use of antiretroviral therapy (ART) if HIV-infected (aOR 1.92 compared with HIV-negative/unknown, 95% CI 1.17-3.14). The most common ADRs were renal impairment, hypoglycemia, liver injury, and hemorrhage. Tenofovir disoproxil fumarate, insulin, rifampicin, and warfarin were most commonly implicated, respectively, in these 4 ADRs. ART, ATT, and/or co-trimoxazole were implicated in 56 of 164 (34%) ADR-related admissions. Seventy-three of 164 (45%) ADRs were assessed as preventable.In our survey, approximately 1 in 12 admissions was because of an ADR. The range of ADRs and implicated drugs reflect South Africa's high HIV and tuberculosis burden. Identification and management of these ADRs should be considered in HIV and tuberculosis care and treatment programs and should be emphasized in health care worker training programmes.

Staphylococcus aureus bacteraemia in Gauteng academic hospitals, South Africa.

INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) infections are responsible for longer hospital stays, increased hospital costs, and poorer outcomes compared to methicillin-sensitive S. aureus (MSSA) infections. We aimed to describe the epidemiology of S. aureus bacteraemia (SAB) and to determine factors associated with MRSA infection in South Africa. METHODS: Cases of SAB were reported from September 2012 to September 2013 from three sentinel sites. A case was defined as the isolation of S. aureus from a blood culture during a 21-day period. Detailed clinical information was collected. Multivariable logistic regression was done to determine factors associated with MRSA infection and mortality. RESULTS: There were 442 cases of SAB reported; antimicrobial susceptibility testing was performed on 240 isolates (54%). Thirty-six percent (86/240) of cases had an MRSA infection. A longer hospital stay before positive specimen collection (odds ratio (OR) 1.08, 95% confidence interval (CI) 1.02-1.13, p=0.004), hospitalization in the last year (OR 15.7, 95% CI 2.5-99.5, p=0.003), HIV infection (OR 4.9, 95% CI 1.05-22.90, p=0.044), and antibiotic use in the previous 2 months (OR 0.1, 95% CI 0.01-0.68, p=0.022) were independent predictors of MRSA. Older age, and in particular age 25-44 years (OR 22.2, 95% CI 2.7-185.5, p=0.004, compared to those aged<5 years), was the only independent predictor of mortality amongst cases with SAB. MRSA isolates were non-susceptible to more antimicrobial agents compared to MSSA isolates. CONCLUSIONS: HIV infection was an independent risk factor for MRSA infection. The selection of appropriate empirical antimicrobial treatment is essential in patients with MRSA infections because of non-susceptibility to many other antimicrobial classes.