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Elevated blood pressure, or hypertension, is the leading cause of preventable deaths globally. Diets high in sodium (predominantly sodium chloride) and low in potassium contribute to elevated blood pressure. The WHO recommends decreasing mean population sodium intake through effective and safe strategies to reduce hypertension and its associated disease burden. Incorporating low-sodium salt substitutes (LSSS) into population strategies has increasingly been recognised as a possible sodium reduction strategy, particularly in populations where a substantial proportion of overall sodium intake comes from discretionary salt. The LSSS contain lower concentrations of sodium through its displacement with potassium predominantly, or other minerals. Potassium-containing LSSS can potentially simultaneously decrease sodium intake and increase potassium intake. Benefits of LSSS include their potential blood pressure-lowering effect and relatively low cost. However, there are concerns about potential adverse effects of LSSS, such as hyperkalaemia, particularly in people at risk, for example, those with chronic kidney disease (CKD) or taking medications that impair potassium excretion.To assess the effects and safety of replacing salt with LSSS to reduce sodium intake on cardiovascular health in adults, pregnant women and children.We searched MEDLINE (PubMed), Embase (Ovid), Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science Core Collection (Clarivate Analytics), Cumulative Index to Nursing and Allied Health Literature (CINAHL, EBSCOhost), ClinicalTrials.gov and WHO International Clinical Trials Registry Platform (ICTRP) up to 18 August 2021, and screened reference lists of included trials and relevant systematic reviews. No language or publication restrictions were applied.We included randomised controlled trials (RCTs) and prospective analytical cohort studies in participants of any age in the general population, from any setting in any country. This included participants with non-communicable diseases and those taking medications that impair potassium excretion. Studies had to compare any type and method of implementation of LSSS with the use of regular salt, or no active intervention, at an individual, household or community level, for any duration.Two review authors independently screened titles, abstracts and full-text articles to determine eligibility; and extracted data, assessed risk of bias (RoB) using the Cochrane RoB tool, and assessed the certainty of the evidence using GRADE. We stratified analyses by adults, children (≤ 18 years) and pregnant women. Primary effectiveness outcomes were change in diastolic and systolic blood pressure (DBP and SBP), hypertension and blood pressure control; cardiovascular events and cardiovascular mortality were additionally assessed as primary effectiveness outcomes in adults. Primary safety outcomes were change in blood potassium, hyperkalaemia and hypokalaemia.We included 26 RCTs, 16 randomising individual participants and 10 randomising clusters (families, households or villages). A total of 34,961 adult participants and 92 children were randomised to either LSSS or regular salt, with the smallest trial including 10 and the largest including 20,995 participants. No studies in pregnant women were identified. Studies included only participants with hypertension (11/26), normal blood pressure (1/26), pre-hypertension (1/26), or participants with and without hypertension (11/26). This was unknown in the remaining studies. The largest study included only participants with an elevated risk of stroke at baseline. Seven studies included adult participants possibly at risk of hyperkalaemia. All 26 trials specifically excluded participants in whom an increased potassium intake is known to be potentially harmful. The majority of trials were conducted in rural or suburban settings, with more than half (14/26) conducted in low- and middle-income countries. The proportion of sodium chloride replacement in the LSSS interventions varied from approximately 3% to 77%. The majority of trials (23/26) investigated LSSS where potassium-containing salts were used to substitute sodium. In most trials, LSSS implementation was discretionary (22/26). Trial duration ranged from two months to nearly five years. We assessed the overall risk of bias as high in six trials and unclear in 12 trials. LSSS compared to regular salt in adults: LSSS compared to regular salt probably reduce DBP on average (mean difference (MD) -2.43 mmHg, 95% confidence interval (CI) -3.50 to -1.36; 20,830 participants, 19 RCTs, moderate-certainty evidence) and SBP (MD -4.76 mmHg, 95% CI -6.01 to -3.50; 21,414 participants, 20 RCTs, moderate-certainty evidence) slightly. On average, LSSS probably reduce non-fatal stroke (absolute effect (AE) 20 fewer/100,000 person-years, 95% CI -40 to 2; 21,250 participants, 3 RCTs, moderate-certainty evidence), non-fatal acute coronary syndrome (AE 150 fewer/100,000 person-years, 95% CI -250 to -30; 20,995 participants, 1 RCT, moderate-certainty evidence) and cardiovascular mortality (AE 180 fewer/100,000 person-years, 95% CI -310 to 0; 23,200 participants, 3 RCTs, moderate-certainty evidence) slightly, and probably increase blood potassium slightly (MD 0.12 mmol/L, 95% CI 0.07 to 0.18; 784 participants, 6 RCTs, moderate-certainty evidence), compared to regular salt. LSSS may result in little to no difference, on average, in hypertension (AE 17 fewer/1000, 95% CI -58 to 17; 2566 participants, 1 RCT, low-certainty evidence) and hyperkalaemia (AE 4 more/100,000, 95% CI -47 to 121; 22,849 participants, 5 RCTs, moderate-certainty evidence) compared to regular salt. The evidence is very uncertain about the effects of LSSS on blood pressure control, various cardiovascular events, stroke mortality, hypokalaemia, and other adverse events (very-low certainty evidence). LSSS compared to regular salt in children: The evidence is very uncertain about the effects of LSSS on DBP and SBP in children. We found no evidence about the effects of LSSS on hypertension, blood pressure control, blood potassium, hyperkalaemia and hypokalaemia in children.When compared to regular salt, LSSS probably reduce blood pressure, non-fatal cardiovascular events and cardiovascular mortality slightly in adults. However, LSSS also probably increase blood potassium slightly in adults. These small effects may be important when LSSS interventions are implemented at the population level. Evidence is limited for adults without elevated blood pressure, and there is a lack of evidence in pregnant women and people in whom an increased potassium intake is known to be potentially harmful, limiting conclusions on the safety of LSSS in the general population. We also cannot draw firm conclusions about effects of non-discretionary LSSS implementations. The evidence is very uncertain about the effects of LSSS on blood pressure in children.

Background After decades of decline since 2005, the global prevalence of undernourishment reverted and since 2015 has increased to levels seen in 2010 to 2011. The prevalence is highest in low- and middle-income countries (LMICs), especially Africa and Asia. Food insecurity and associated undernutrition detrimentally affect health and socioeconomic development in the short and long term, for individuals, including children, and societies. Physical and economic access to food is crucial to ensure food security. Community-level interventions could be important to increase access to food in LMICs. Objectives To determine the effects of community-level interventions that aim to improve access to nutritious food in LMICs, for both the whole community and for disadvantaged or at-risk individuals or groups within a community, such as infants, children and women; elderly, poor or unemployed people; or minority groups. Search methods We searched for relevant studies in 16 electronic databases, including trial registries, from 1980 to September 2019, and updated the searches in six key databases in February 2020. We applied no language or publication status limits. Selection criteria We included randomised controlled trials (RCTs), cluster randomised controlled trials (cRCTs) and prospective controlled studies (PCS). All population groups, adults and children, living in communities in LMICs exposed to community-level interventions aiming to improve food access were eligible for inclusion. We excluded studies that only included participants with specific diseases or conditions (e.g. severely malnourished children). Eligible interventions were broadly categorised into those that improved buying power (e.g. create income-generation opportunities, cash transfer schemes); addressed food prices (e.g. vouchers and subsidies); addressed infrastructure and transport that affected physical access to food outlets; addressed the social environment and provided social support (e.g. social support from family, neighbours or government). Data collection and analysis Two authors independently screened titles and abstracts, and full texts of potentially eligible records, against the inclusion criteria. Disagreements were resolved through discussion or arbitration by a third author, if necessary. For each included study, two authors independently extracted data and a third author arbitrated disagreements. However, the outcome data were extracted by one author and checked by a biostatistician. We assessed risk of bias for all studies using the Effective Practice and Organization of Care (EPOC) risk of bias tool for studies with a separate control group. We conducted meta-analyses if there was a minimum of two studies for interventions within the same category, reporting the same outcome measure and these were sufficiently homogeneous. Where we were able to meta-analyse, we used the random-effects model to incorporate any existing heterogeneity. Where we were unable to conduct meta-analyses, we synthesised using vote counting based on effect direction. Main results We included 59 studies, including 214 to 169,485 participants, and 300 to 124, 644 households, mostly from Africa and Latin America, addressing the following six intervention types (three studies assessed two different types of interventions). Interventions that improved buying power: Unconditional cash transfers (UCTs) (16 cRCTs, two RCTs, three PCSs): we found high-certainty evidence that UCTs improve food security and make little or no difference to cognitive function and development and low-certainty evidence that UCTs may increase dietary diversity and may reduce stunting. The evidence was very uncertain about the effects of UCTs on the proportion of household expenditure on food, and on wasting. Regarding adverse outcomes, evidence from one trial indicates that UCTs reduce the proportion of infants who are overweight. Conditional cash transfers (CCTs) (nine cRCTs, five PCSs): we found high-certainty evidence that CCTs result in little to no difference in the proportion of household expenditure on food and that they slightly improve cognitive function in children; moderate-certainty evidence that CCTs probably slightly improve dietary diversity and low-certainty evidence that they may make little to no difference to stunting or wasting. Evidence on adverse outcomes (two PCSs) shows that CCTs make no difference to the proportion of overweight children. Income generation interventions (six cRCTs, 11 PCSs): we found moderate-certainty evidence that income generation interventions probably make little or no difference to stunting or wasting; and low-certainty evidence that they may result in little to no difference to food security or that they may improve dietary diversity in children, but not for households. Interventions that addressed food prices: Food vouchers (three cRCTs, one RCT): we found moderate-certainty evidence that food vouchers probably reduce stunting; and low-certainty evidence that that they may improve dietary diversity slightly, and may result in little to no difference in wasting. Food and nutrition subsidies (one cRCT, three PCSs): we found low-certainty evidence that food and nutrition subsidies may improve dietary diversity among school children. The evidence is very uncertain about the effects on household expenditure on healthy foods as a proportion of total expenditure on food (very low-certainty evidence). Interventions that addressed the social environment: Social support interventions (one cRCT, one PCS): we found moderate-certainty evidence that community grants probably make little or no difference to wasting; low-certainty evidence that they may make little or no difference to stunting. The evidence is very uncertain about the effects of village savings and loans on food security and dietary diversity. None of the included studies addressed the intervention category of infrastructure changes. In addition, none of the studies reported on one of the primary outcomes of this review, namely prevalence of undernourishment. Authors' conclusions The body of evidence indicates that UCTs can improve food security. Income generation interventions do not seem to make a difference for food security, but the evidence is unclear for the other interventions. CCTs, UCTs, interventions that help generate income, interventions that help minimise impact of food prices through food vouchers and subsidies can potentially improve dietary diversity. UCTs and food vouchers may have a potential impact on reducing stunting, but CCTs, income generation interventions or social environment interventions do not seem to make a difference on wasting or stunting. CCTs seem to positively impact cognitive function and development, but not UCTs, which may be due to school attendance, healthcare visits and other conditionalities associated with CCTs.

BACKGROUND: Aflatoxins are carcinogenic mycotoxins that contaminate many food crops. Maize and groundnuts are prone to aflatoxin contamination, and are the major sources of human exposure to aflatoxins, due to their high intake as staple foods, particularly in low‐ and middle‐income countries (LMICs). Observational studies suggest an association between dietary exposure to aflatoxins during pregnancy and early childhood and linear growth in infants and young children. OBJECTIVES: To assess the effects on pre‐ and postnatal growth outcomes when agricultural and nutritional education interventions during the post‐harvest period that aim to reduce aflatoxin exposure are compared to usual support or no intervention. We assessed this in infants, children, and pregnant and lactating women at the household or community level in LMICs. SEARCH METHODS: In July and August 2019, we searched: CENTRAL, MEDLINE, Embase, CINAHL, Web of Science Core Collection, Africa‐Wide, LILACS, CAB Abstracts, Agricola, and two trials registers. We also checked the bibliographies of the included studies and contacted relevant mycotoxin organisations and researchers for additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and cluster‐RCTs of agricultural education and nutritional education interventions of any duration, at the household or community level, aimed at reducing aflatoxin intake by infants, children, and pregnant and lactating women, in LMICs during the post‐harvest period, compared to no intervention or usual support. We excluded studies that followed participants for less than four weeks. We assessed prespecified prenatal (at birth) and postnatal growth outcomes (during infancy, childhood, and adolescence), with linear growth (as the primary outcome), infectious disease morbidity, and unintended consequences. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study eligibility using prespecified criteria, extracted data, and assessed risk of bias of included RCTs. We evaluated the certainty of the evidence using GRADE, and presented the main results in a 'Summary of findings' table. MAIN RESULTS: We included three recent cluster‐RCTs reporting the effects of agricultural education plus post‐harvest technologies, compared to usual agricultural support or no intervention. The participants were pregnant women and their children, lactating women and their infants (< 6 months), women of childbearing age, and young children (< 59 months), from rural, subsistence maize‐farming communities in Kenya, Zimbabwe, and Tanzania. Two trials randomised villages to the intervention and control groups, including a total of at least 979 mother‐child pairs from 60 villages. The third trial randomised 420 households, including 189 mother‐child pairs and 231 women of childbearing age. Duration of the intervention and follow‐up ranged between five and nine months. Due to risk of attrition bias, the overall risk of bias was unclear in one trial, and high in the other two trials. None of the included studies addressed the effects of nutritional education on pre‐ and postnatal growth. One trial reported outcomes not prespecified in our review, and we were unable to obtain unpublished growth data from the second trial, even after contacting the authors. The third trial, in lactating women and their infants in Tanzania, reported on the infants' weight‐for‐age z‐score (WAZ) after six months. This trial found that providing agricultural education aimed at changing farmers' post‐harvest practices to reduce aflatoxin exposure, by using demonstrations (e.g. handsorting, de‐hulling of maize, drying sheets, and insecticides), may improve WAZ in infants from these farmers' households, on average, by 0.57 (95% confidence interval (CI) 0.16 to 0.98; 1 study; 249 participants; very low‐certainty evidence), compared to infants from households where the farmers received routine agricultural extension services. Another way of reporting the effect on WAZ is to compare the proportion of underweight infants (WAZ > 2 SD below the reference median value) per group. This trial found that the intervention may reduce the proportion of underweight infants in the intervention households by 6.7% (95% CI ‐12.6 to ‐1.4; 249 participants; very low‐certainty evidence) compared to control households. No studies reported on unintended effects of agricultural and nutritional education. AUTHORS' CONCLUSIONS: Evidence on the effects on child growth in LMICs of agricultural or nutritional education interventions that reduce aflatoxin exposure was very limited; no included study reported on linear growth. Very low‐certainty evidence suggested that agricultural education aimed at changing farmers' post‐harvest practices to reduce aflatoxin exposure by using demonstrations, may result in an increase in WAZ, when compared to usual or no education.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effects of agricultural and nutritional educational interventions that aim to reduce the intake of aflatoxins in infants, children, and pregnant and lactating women at the household or community level in low‐ and middle‐income countries (LMIC), on prenatal and postnatal growth.

BACKGROUND: As part of efforts to prevent childhood overweight and obesity, we need to understand the relationship between total fat intake and body fatness in generally healthy children. OBJECTIVES: To assess the effects and associations of total fat intake on measures of weight and body fatness in children and young people not aiming to lose weight. SEARCH METHODS: For this update we revised the previous search strategy and ran it over all years in the Cochrane Library, MEDLINE (Ovid), MEDLINE (PubMed), and Embase (Ovid) (current to 23 May 2017). No language and publication status limits were applied. We searched the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov for ongoing and unpublished studies (5 June 2017). SELECTION CRITERIA: We included randomised controlled trials (RCTs) in children aged 24 months to 18 years, with or without risk factors for cardiovascular disease, randomised to a lower fat (30% or less of total energy (TE)) versus usual or moderate‐fat diet (greater than 30%TE), without the intention to reduce weight, and assessed a measure of weight or body fatness after at least six months. We included prospective cohort studies if they related baseline total fat intake to weight or body fatness at least 12 months later. DATA COLLECTION AND ANALYSIS: We extracted data on participants, interventions or exposures, controls and outcomes, and trial or cohort quality characteristics, as well as data on potential effect modifiers, and assessed risk of bias for all included studies. We extracted body weight and blood lipid levels outcomes at six months, six to 12 months, one to two years, two to five years and more than five years for RCTs; and for cohort studies, at baseline to one year, one to two years, two to five years, five to 10 years and more than 10 years. We planned to perform random‐effects meta‐analyses with relevant subgrouping, and sensitivity and funnel plot analyses where data allowed. MAIN RESULTS: We included 24 studies comprising three parallel‐group RCTs (n = 1054 randomised) and 21 prospective analytical cohort studies (about 25,059 children completed). Twenty‐three studies were conducted in high‐income countries. No meta‐analyses were possible, since only one RCT reported the same outcome at each time point range for all outcomes, and cohort studies were too heterogeneous to combine. Effects of dietary counselling to reduce total fat intake from RCTs Two studies recruited children aged between 4 and 11 years and a third recruited children aged 12 to 13 years. Interventions were combinations of individual and group counselling, and education sessions in clinics, schools and homes, delivered by dieticians, nutritionists, behaviourists or trained, supervised teachers. Concerns about imprecision and poor reporting limited our confidence in our findings. In addition, the inclusion of hypercholesteraemic children in two trials raised concerns about applicability. One study of dietary counselling to lower total fat intake found that the intervention may make little or no difference to weight compared with usual diet at 12 months (mean difference (MD) ‐0.50 kg, 95% confidence interval (CI) ‐1.78 to 0.78; n = 620; low‐quality evidence) and at three years (MD ‐0.60 kg, 95% CI ‐2.39 to 1.19; n = 612; low‐quality evidence). Education delivered as a classroom curriculum probably decreased BMI in children at 17 months (MD ‐1.5 kg/m(2), 95% CI ‐2.45 to ‐0.55; 1 RCT; n = 191; moderate‐quality evidence). The effects were smaller at longer term follow‐up (five years: MD 0 kg/m(2), 95% CI ‐0.63 to 0.63; n = 541; seven years; MD ‐0.10 kg/m(2), 95% CI ‐0.75 to 0.55; n = 576; low‐quality evidence). Dietary counselling probably slightly reduced total cholesterol at 12 months compared to controls (MD ‐0.15 mmol/L, 95% CI ‐0.24 to ‐0.06; 1 RCT; n = 618; moderate‐quality evidence), but may make little or no difference over longer time periods. Dietary counselling probably slightly decreased low‐density lipoprotein (LDL) cholesterol at 12 months (MD ‐0.12 mmol/L, 95% CI ‐0.20 to ‐0.04; 1 RCT; n = 618, moderate‐quality evidence) and at five years (MD ‐0.09, 95% CI ‐0.17 to ‐0.01; 1 RCT; n = 623; moderate‐quality evidence), compared to controls. Dietary counselling probably made little or no difference to HDL‐C at 12 months (MD ‐0.03 mmol/L, 95% CI ‐0.08 to 0.02; 1 RCT; n = 618; moderate‐quality evidence), and at five years (MD ‐0.01 mmol/L, 95% CI ‐0.06 to 0.04; 1 RCT; n = 522; moderate‐quality evidence). Likewise, counselling probably made little or no difference to triglycerides in children at 12 months (MD ‐0.01 mmol/L, 95% CI ‐0.08 to 0.06; 1 RCT; n = 618; moderate‐quality evidence). Lower versus usual or modified fat intake may make little or no difference to height at seven years (MD ‐0.60 cm, 95% CI ‐2.06 to 0.86; 1 RCT; n = 577; low‐quality evidence). Associations between total fat intake, weight and body fatness from cohort studies Over half the cohort analyses that reported on primary outcomes suggested that as total fat intake increases, body fatness measures may move in the same direction. However, heterogeneous methods and reporting across cohort studies, and predominantly very low‐quality evidence, made it difficult to draw firm conclusions and true relationships may be substantially different. AUTHORS' CONCLUSIONS: We were unable to reach firm conclusions. Limited evidence from three trials that randomised children to dietary counselling or education to lower total fat intake (30% or less TE) versus usual or modified fat intake, but with no intention to reduce weight, showed small reductions in body mass index, total‐ and LDL‐cholesterol at some time points with lower fat intake compared to controls. There were no consistent effects on weight, high‐density lipoprotein (HDL) cholesterol or height. Associations in cohort studies that related total fat intake to later measures of body fatness in children were inconsistent and the quality of this evidence was mostly very low. Most studies were conducted in high‐income countries, and may not be applicable in low‐ and middle‐income settings. High‐quality, longer‐term studies are needed, that include low‐ and middle‐income settings to look at both possible benefits and harms.

The relationships between antituberculosis drug exposure and treatment effects on humans receiving multidrug therapy are complex and nonlinear. In patients on treatment, an analysis of the rate of decline in the sputum bacillary burden reveals two slopes. The first is the α-slope, which is thought to reflect bactericidal effect, followed by a β-slope, which is thought to reflect sterilizing activity. We sought to characterize the effects of standard first-line treatment on sterilizing activity. Fifty-four patients receiving combination therapy for pulmonary tuberculosis in a clinical trial had drug concentrations measured and Mycobacterium tuberculosis isolates available for MIC identification. Sputum sample cultures were performed at baseline and weekly for 8 weeks. A time-to-event model based on the days to positivity in the liquid cultures was used to estimate the β-slope. The pharmacokinetic parameters of rifampin, isoniazid, ethambutol, and pyrazinamide were determined for each patient. Multivariate adaptive regression splines analyses, which simultaneously perform linear and nonlinear analyses, were used to identify the relationships between the predictors and the β-slope. The potential predictors examined included HIV status, lung cavitation, 24-h area under the concentration-time curve (AUC), peak drug concentration ( C max ), AUC/MIC ratio, C max /MIC ratio, and the time that that concentration persisted above MIC. A rifampin C max of >8.2 mg/liter and a pyrazinamide AUC/MIC of >11.3 were key predictors of the β-slope and interacted positively to increase the β-slope. In patients with a rifampin AUC of C max /MIC increased the β-slope, while increasing isoniazid C max decreased it, suggesting isoniazid antagonism. Antibiotic concentrations and MICs interact in a nonlinear fashion as the main drivers of a sterilizing effect. The results suggest that faster speeds of sterilizing effect might be achieved by omitting isoniazid and by increasing rifampin, pyrazinamide, and ethambutol exposures. However, isoniazid and ethambutol exposures may only be of importance when rifampin exposure is low. These findings need confirmation in larger studies. (This study has been registered at controlled-trials.com under registration no. ISRCTN80852505.)

Objectives To identify the pyrazinamide MIC above which standard combination therapy fails. Methods MICs of pyrazinamide were determined for Mycobacterium tuberculosis isolates, cultured from 58 patients in a previous randomized clinical trial in Cape Town, South Africa. The MICs were determined using BACTEC MGIT 960 for isolates that were collected before standard treatment with isoniazid, rifampicin, pyrazinamide and ethambutol commenced. Weekly sputum collections were subsequently made for 8 weeks in order to culture M. tuberculosis in Middlebrook broth medium. Classification and regression tree (CART) analysis was utilized to identify the pyrazinamide MIC predictive of sputum culture results at the end of pyrazinamide therapy. The machine learning-derived susceptibility breakpoints were then confirmed using standard association statistics that took into account confounders of 2 month sputum conversion. Results The pyrazinamide MIC range was 12.5 to >100 mg/L for the isolates prior to therapy. The epidemiological 95% cut-off value was >100 mg/L. The 2 month sputum conversion rate in liquid cultures was 26% by stringent criteria and 48% by less stringent criteria. CART analysis identified an MIC breakpoint of 50 mg/L, above which patients had poor sputum conversion rates. The relative risk of poor sputum conversion was 1.5 (95% CI: 1.2–1.8) for an MIC >50 mg/L compared with an MIC ≤50 mg/L. Conclusions We propose a pyrazinamide susceptibility breakpoint of 50 mg/L for clinical decision making and for development of rapid susceptibility assays. This breakpoint is identical to that identified using computer-aided simulations of hollow fibre system output.

Days to positivity in automated liquid mycobacterial culture have been shown to correlate with mycobacterial load and have been proposed as a useful biomarker for treatment responses in tuberculosis. However, there is currently no quantitative method or model to analyze the change in days to positivity with time on treatment. The objectives of this study were to describe the decline in numbers of mycobacteria in sputum collected once weekly for 8 weeks from patients on treatment for tuberculosis using days to positivity in liquid culture. One hundred forty-four patients with smear-positive pulmonary tuberculosis were recruited from a tuberculosis clinic in Cape Town, South Africa. A nonlinear mixed-effects repeated-time-to-event modeling approach was used to analyze the time-to-positivity data. A biexponential model described the decline in the estimated number of bacteria in patients' sputum samples, while a logistic model with a lag time described the growth of the bacteria in liquid culture. At baseline, the estimated number of rapidly killed bacteria is typically 41 times higher than that of those that are killed slowly. The time to kill half of the rapidly killed bacteria was about 1.8 days, while it was 39 days for slowly killed bacteria. Patients with lung cavitation had higher bacterial loads than patients without lung cavitation. The model successfully described the increase in days to positivity as treatment progressed, differentiating between bacteria that are killed rapidly and those that are killed slowly. Our model can be used to analyze similar data from studies testing new drug regimens.

Among patients with tuberculosis, rifampin plasma concentrations and sputum conversion rates have been reported to be lower in Africans. Rifampin is a substrate of P-glycoprotein (coded for by the ABCB1 gene) and organic anion-transporting polypeptide 1B1 (coded for by SLCO1B1 ). The objectives were to identify genetic polymorphisms of drug transporters and the transcriptional regulators pregnane X receptor (PXR) and constitutive androstane receptor (CAR) with an impact on rifampin pharmacokinetics in South Africans. Fifty-seven patients with tuberculosis from Cape Town underwent pharmacokinetic sampling during treatment with rifampin, pyrazinamide, isoniazid, and ethambutol. DNA was genotyped for ABCB1 , SLCO1B1 , PXR , and CAR polymorphisms by using real-time PCR. NONMEM was used for data analysis. The allele frequency of the SLCO1B1 rs4149032 polymorphism was 0.70. Patients heterozygous and homozygous for this polymorphism had reductions in the bioavailability (and, thus, the area under the curve [AUC]) of rifampin of 18% and 28%, respectively. Simulations showed that increasing the daily rifampin dose by 150 mg in patients with the polymorphism would result in plasma concentrations similar to those of wild-type individuals and reduce the percentage of patients with peak plasma concentrations ( C max ) below 8 mg/liter from 63% to 31%. ABCB1 , PXR , and CAR polymorphisms were not associated with differences in rifampin pharmacokinetics. SLCO1B1 rs4149032 was present in most patients and was associated with substantially reduced rifampin exposure. These data suggest that the standard recommended dose of rifampin should be reconsidered for South Africans.

BACKGROUND: Micronutrient deficiencies are widespread and compound the effects of HIV disease in children especially in poor communities. Micronutrient supplements may be effective and safe in reducing the burden of HIV disease. This review is an update of an earlier Cochrane review of micronutrient supplementation in children and adults which found that vitamin A and zinc are beneficial and safe in children exposed to HIV and living with HIV infection (Irlam 2010). OBJECTIVES: To assess whether micronutrient supplements are effective and safe in reducing mortality and morbidity in children with HIV infection. SEARCH METHODS: The CENTRAL EMBASE and PubMed databases were searched for randomized controlled trials of micronutrient supplements (vitamins trace elements and combinations of these) using the search methods of the Cochrane HIV/AIDS Group. SELECTION CRITERIA: Randomized controlled trials were selected that compared the effects of micronutrient supplements with other supplements or placebo or no treatment on the primary outcomes of mortality morbidity and HIV-related hospitalizations. Indicators of HIV disease progession anthropometric measures and any adverse effects of supplementation were secondary outcomes. DATA COLLECTION AND ANALYSIS: Two reviewers independently screened and selected trials for inclusion assessed the risk of bias using standardized criteria and extracted data. Review Manager 5.1 was used to calculate the risk ratio (RR) for dichotomous data and the weighted mean difference (WMD) for continuous data and to perform random effects meta-analysis where appropriate. MAIN RESULTS: We included three new studies in addition to the eight studies in the earlier version of the review (Irlam 2010). Eleven studies with a total of 2412 participants were therefore included: five trials of vitamin A one trial of vitamin D two trials of zinc and three trials of multiple micronutrient supplements. All except one trial were conducted in African children.Vitamin A halved all-cause mortality in a meta-analysis of three trials in African children had inconsistent impacts on diarrheal and respiratory morbidity and improved short-term growth in a Tanzanian trial. No significant adverse effects were reported.A single small trial of vitamin D in North American adolescents and children demonstrated safety but no clinical benefits. Zinc supplements reduced diarrheal morbidity and had no adverse effects on disease progression in one small South African trial. Another trial in South African children with and without HIV infection did not show benefit from the the prophylactic use of zinc or multiple supplements versus vitamin A in the small subgroup of children with HIV infection. Multiple micronutrient supplements at twice the RDA did not alter mortality growth or CD4 counts at 12 months in Ugandan children aged one to five years. Short-term supplementation until hospital discharge significantly reduced the duration of all hospital admissions in poorly nourished South African children and supplementation for six months after discharge improved appetite and nutritional indicators. AUTHORS CONCLUSIONS: Vitamin A supplementation is beneficial and safe in children with HIV infection. Zinc is safe and appears to have similar benefits on diarrheal morbidity in children with HIV as in children without HIV infection. Multiple micronutrient supplements have some clinical benefit in poorly nourished children with HIV infection. Further trials of single supplements (vitamin D zinc and selenium) are required to build the evidence base. The long-term effects and optimal composition and dosing of multiple micronutrient supplements require further investigation in children with diverse HIV disease status.

Background Adequate nutrition is important for optimal immune and metabolic function. Dietary support may, therefore, improve clinical outcomes in HIV-infected individuals by reducing the incidence of HIV-associated complications and attenuating progression of HIV disease, improving quality of life and ultimately reducing disease-related mortality. Objectives To evaluate the effectiveness of various macronutrient interventions, given orally, in reducing morbidity and mortality in adults and children living with HIV infection. Search methods We searched CENTRAL (up to August 2011), MEDLINE (1966 to August 2011), EMBASE (1988 to August 2011), LILACS (up to February 2012), and Gateway (March 2006-February 2010). We also scanned reference lists of articles and contacted authors of relevant studies and other researchers. Selection criteria Randomised controlled trials evaluating the effectiveness of macronutrient interventions compared with no nutritional supplements or placebo in the management of adults and children infected with HIV. Data collection and analysis Three reviewers independently applied study selection criteria, assessed study quality, and extracted data. Effects were assessed using mean difference and 95% confidence intervals. Homogenous studies were combined wherever it was clinically meaningful to do so and a meta-analysis using the random effects model was conducted. Main results Fourteen trials (including 1725 HIV positive adults and 271 HIV positive children), were included in this review. Neither supplementary food nor daily supplement of Spirulina significantly altered the risk of death compared with no supplement or placebo in malnourished, ART naive adult participants in the two studies which reported on this outcome. A nutritional supplement enhanced with protein did not significantly alter the risk of death compared to standard nutritional care in children with prolonged diarrhoea. Supplementation with macronutrient formulas given to provide protein and/or energy and fortified with micronutrients, in conjunction with nutrition counselling, significantly improved energy intake (3 trials; n=131; MD 393.57 kcal/day; 95% CI: 224.66 to 562.47;p

Background Micronutrient deficiencies are widespread and compound the effects of HIV disease; micronutrient supplements may be effective and safe in reducing this burden. Objectives To assess whether micronutrient supplements are effective and safe in reducing mortality and morbidity in pregnant and lactating women with HIV infection and their infants. Search methods The review has been updated three times since publication in 2005. In reviews prior to this update (2011), we searched the CENTRAL, EMBASE, PubMed, and GATEWAY databases to identify randomised controlled trials of micronutrient supplements using the search methods of the Cochrane HIV/AIDS Group. In the 2011 review the PubMed, EMBASE, and CENTRAL databases were searched in July 2011. As the GATEWAY database does not include conference abstracts after 2006, we also searched the AIDS-specific conference database, www.aegis.org, and contacted researchers and organisations active in the field of research to identify additional unpublished trials. Selection criteria Randomised controlled trials were selected that compared the effects of micronutrient supplements (vitamins, trace elements, and combinations of these) with other supplements, placebo or no treatment on mortality, morbidity, pregnancy outcomes, immunologic indicators, and anthropometric measures in HIV-positive pregnant and lactating women. Any adverse effects of supplementation were recorded. Data collection and analysis Two reviewer authors independently selected trials, appraised trial quality for risk of bias using standardised criteria, and extracted data using standardised forms. Where disagreements arose, a third author, acted as arbiter. Main results One additional trial is included in this update in addition to the three trials included in the 2010 update of the initial Cochrane review. Four relatively large, well-conducted randomised controlled trials of the benefits of micronutrient supplementation have been conducted in pregnant and lactating women infected with HIV. Each of the trials evaluated a different micronutrient supplement and no direct comparisons or analyses can be made across the four trials. The four trials were conducted between 1995 and 2006. The trials have all been conducted by the same research team in Dar es Salaam in Tanzania, in an urban setting in hospital-based antenatal clinics. Pregnant women were recruited with gestational age ranging from 12 to 27 weeks in each of the trials. Sample sizes range from 400 to 1129 with a median of 1000 participants. Three of the trials were placebo-controlled. Different interventions have been evaluated in each trial, viz.:Vitamin A versus Vitamin A and multivitamins versus Multivitamins versus placebo; Selenium versus placebo; Zinc versus placebo; and Multiple RDA multivitamins versus Single RDA multivitamins. None of the women were receiving antiretrovrial therapy (ART). Multiple micronutrient supplements conferred multiple clinical benefits to pregnant women and their offspring. No significant adverse effects were reported. No significant clinical benefits were found from zinc supplementation of pregnant Tanzanian women. Selenium supplements given during and after pregnancy did not delay maternal HIV disease progression or improve pregnancy outcomes, but may improve child survival and decrease maternal diarrhoeal morbidity. There were no differences in maternal and infant outcomes when women received single RDA multivitamins or multiple RDA multivitamin supplementation. The evidence is lacking for the effects of micronutrient supplementation given concomitantly to pregnant women already initiated on antiretroviral therapy for treatment purposes. GRADE assessments were conducted on outcomes for each trial and included reviewing the data and the potential biases in each trial before grading the level of evidence. None of the trials were graded as providing high quality evidence primarily because there was no replication of results in other trials in other settings. Authors' conclusions In keeping with previous World Health Organization (WHO) recommendations everything possible should be done to promote and support adequate dietary intake of micronutrients, while recognising that this may not be sufficient to correct specific micronutrient deficiencies in all HIV-infected individuals. Specific recommendations for pregnant and lactating women infected with HIV would be to include the provision of multivitamin supplements in single RDA formulations during the antenatal period and at least for 6 weeks post-partum, especially for women who are breast-feeding. There is no conclusive evidence to provide stand-alone zinc or selenium supplementation to HIV-infected pregnant and lactating women. Micronutrient supplementation should not be used as a substitute for provision of recommended antiretroviral medication for preventing mother-to-child transmission of HIV and treating maternal HIV infection when this is recommended. Further trials of single supplements are required to build the evidence base. The long-term clinical benefits, adverse effects, and optimal formulation of multiple micronutrient supplements require further investigation in pregnant women at different stages of HIV infection.