Western Cape Department of Health

Summary Continued uncontrolled transmission of the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) in many parts of the world is creating the conditions for significant virus evolution. Here, we describe a new SARS-CoV-2 lineage (501Y.V2) characterised by eight lineage-defining mutations in the spike protein, including three at important residues in the receptor-binding domain (K417N, E484K and N501Y) that may have functional significance. This lineage emerged in South Africa after the first epidemic wave in a severely affected metropolitan area, Nelson Mandela Bay, located on the coast of the Eastern Cape Province. This lineage spread rapidly, becoming within weeks the dominant lineage in the Eastern Cape and Western Cape Provinces. Whilst the full significance of the mutations is yet to be determined, the genomic data, showing the rapid displacement of other lineages, suggest that this lineage may be associated with increased transmissibility.

BACKGROUND: Historically, women have been attended and supported by other women during labour. However, in hospitals worldwide, continuous support during labour has become the exception rather than the routine. OBJECTIVES: Primary: to assess the effects of continuous, one-to-one intrapartum support compared with usual care. Secondary: to determine whether the effects of continuous support are influenced by: (1) routine practices and policies; (2) the provider's relationship to the hospital and to the woman; and (3) timing of onset. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 June 2012). SELECTION CRITERIA: All published and unpublished randomised controlled trials comparing continuous support during labour with usual care. DATA COLLECTION AND ANALYSIS: We used standard methods of The Cochrane Collaboration Pregnancy and Childbirth Group. Two review authors independently evaluated methodological quality and extracted the data. We sought additional information from the trial authors. We used random-effects analyses for comparisons in which high heterogeneity was present, and we reported results using the average risk ratio (RR) for categorical data and mean difference (MD) for continuous data. MAIN RESULTS: Twenty-two trials involving 15,288 women met inclusion criteria and provided usable outcome data. Results are of random-effects analyses, unless otherwise noted. Women allocated to continuous support were more likely to have a spontaneous vaginal birth (RR 1.08, 95% confidence interval (CI) 1.04 to 1.12) and less likely to have intrapartum analgesia (RR 0.90, 95% CI 0.84 to 0.96) or to report dissatisfaction (RR 0.69, 95% CI 0.59 to 0.79). In addition, their labours were shorter (MD -0.58 hours, 95% CI -0.85 to -0.31), they were less likely to have a caesarean (RR 0.78, 95% CI 0.67 to 0.91) or instrumental vaginal birth (fixed-effect, RR 0.90, 95% CI 0.85 to 0.96), regional analgesia (RR 0.93, 95% CI 0.88 to 0.99), or a baby with a low five-minute Apgar score (fixed-effect, RR 0.69, 95% CI 0.50 to 0.95). There was no apparent impact on other intrapartum interventions, maternal or neonatal complications, or breastfeeding. Subgroup analyses suggested that continuous support was most effective when the provider was neither part of the hospital staff nor the woman's social network, and in settings in which epidural analgesia was not routinely available. No conclusions could be drawn about the timing of onset of continuous support. AUTHORS' CONCLUSIONS: Continuous support during labour has clinically meaningful benefits for women and infants and no known harm. All women should have support throughout labour and birth.

The October 2020 Global TB report reviews TB control strategies and United Nations (UN) targets set in the political declaration at the September 2018 UN General Assembly high-level meeting on TB held in New York. Progress in TB care and prevention has been very slow. In 2019, TB remained the most common cause of death from a single infectious pathogen. Globally, an estimated 10.0 million people developed TB disease in 2019, and there were an estimated 1.2 million TB deaths among HIV-negative people and an additional 208, 000 deaths among people living with HIV. Adults accounted for 88% and children for 12% of people with TB. The WHO regions of South-East Asia (44%), Africa (25%), and the Western Pacific (18%) had the most people with TB. Eight countries accounted for two thirds of the global total: India (26%), Indonesia (8.5%), China (8.4%), the Philippines (6.0%), Pakistan (5.7%), Nigeria (4.4%), Bangladesh (3.6%) and South Africa (3.6%). Only 30% of the 3.5 million five-year target for children treated for TB was met. Major advances have been development of new all oral regimens for MDRTB and new regimens for preventive therapy. In 2020, the COVID-19 pandemic dislodged TB from the top infectious disease cause of mortality globally. Notably, global TB control efforts were not on track even before the advent of the COVID-19 pandemic. Many challenges remain to improve sub-optimal TB treatment and prevention services. Tuberculosis screening and diagnostic test services need to be ramped up. The major drivers of TB remain undernutrition, poverty, diabetes, tobacco smoking, and household air pollution and these need be addressed to achieve the WHO 2035 TB care and prevention targets. National programs need to include interventions for post-tuberculosis holistic wellbeing. From first detection of COVID-19 global coordination and political will with huge financial investments have led to the development of effective vaccines against SARS-CoV2 infection. The world now needs to similarly focus on development of new vaccines for TB utilizing new technological methods.

Updates: This is the fourteenth version (thirteenth update) of the living guideline, replacing earlier versions (available as data supplements). New recommendations will be published as updates to this guideline. Clinical question: What is the role of drugs in the treatment of patients with covid-19? Context: The evidence base for therapeutics for covid-19 is evolving with numerous randomised controlled trials (RCTs) recently completed and underway. Emerging SARS-CoV-2 variants and subvariants are changing the role of therapeutics. What is new?: The guideline development group (GDG) defined 1.5% as a new threshold for an important reduction in risk of hospitalisation in patients with non-severe covid-19. Combined with updated baseline risk estimates, this resulted in stratification into patients at low, moderate, and high risk for hospitalisation. New recommendations were added for moderate risk of hospitalisation for nirmatrelvir/ritonavir, and for moderate and low risk of hospitalisation for molnupiravir and remdesivir. New pharmacokinetic evidence was included for nirmatrelvir/ritonavir and molnupiravir, supporting existing recommendations for patients at high risk of hospitalisation. The recommendation for ivermectin in patients with non-severe illness was updated in light of additional trial evidence which reduced the high degree of uncertainty informing previous guidance. A new recommendation was made against the antiviral agent VV116 for patients with non-severe and with severe or critical illness outside of randomised clinical trials based on one RCT comparing the drug with nirmatrelvir/ritonavir. The structure of the guideline publication has also been changed; recommendations are now ordered by severity of covid-19. About this guideline: This living guideline from the World Health Organization (WHO) incorporates new evidence to dynamically update recommendations for covid-19 therapeutics. The GDG typically evaluates a therapy when the WHO judges sufficient evidence is available to make a recommendation. While the GDG takes an individual patient perspective in making recommendations, it also considers resource implications, acceptability, feasibility, equity, and human rights. This guideline was developed according to standards and methods for trustworthy guidelines, making use of an innovative process to achieve efficiency in dynamic updating of recommendations. The methods are aligned with the WHO Handbook for Guideline Development and according to a pre-approved protocol (planning proposal) by the Guideline Review Committee (GRC). A box at the end of the article outlines key methodological aspects of the guideline process. MAGIC Evidence Ecosystem Foundation provides methodological support, including the coordination of living systematic reviews with network meta-analyses to inform the recommendations. The full version of the guideline is available online in MAGICapp and in PDF on the WHO website, with a summary version here in The BMJ. These formats should facilitate adaptation, which is strongly encouraged by WHO to contextualise recommendations in a healthcare system to maximise impact. Future recommendations: Recommendations on anticoagulation are planned for the next update to this guideline. Updated data regarding systemic corticosteroids, azithromycin, favipiravir and umefenovir for non-severe illness, and convalescent plasma and statin therapy for severe or critical illness, are planned for review in upcoming guideline iterations.

BACKGROUND: Pre-eclampsia and eclampsia are common causes of serious morbidity and death. Calcium supplementation may reduce the risk of pre-eclampsia, and may help to prevent preterm birth. This is an update of a review last published in 2014. OBJECTIVES: To assess the effects of calcium supplementation during pregnancy on hypertensive disorders of pregnancy and related maternal and child outcomes. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (18 September 2017), and reference lists of retrieved studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs), including cluster-randomised trials, comparing high-dose calcium supplementation (at least 1 g daily of calcium) during pregnancy with placebo. For low-dose calcium we included quasi-randomised trials, trials without placebo, trials with cointerventions and dose comparison trials. DATA COLLECTION AND ANALYSIS: Two researchers independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. Two researchers assessed the evidence using the GRADE approach. MAIN RESULTS: We included 27 studies (18,064 women). We assessed the included studies as being at low risk of bias, although bias was frequently difficult to assess due to poor reporting and inadequate information on methods.High-dose calcium supplementation (≥ 1 g/day) versus placeboFourteen studies examined this comparison, however one study contributed no data. The 13 studies contributed data from 15,730 women to our meta-analyses. The average risk of high blood pressure (BP) was reduced with calcium supplementation compared with placebo (12 trials, 15,470 women: risk ratio (RR) 0.65, 95% confidence interval (CI) 0.53 to 0.81; I² = 74%). There was also a reduction in the risk of pre-eclampsia associated with calcium supplementation (13 trials, 15,730 women: average RR 0.45, 95% CI 0.31 to 0.65; I² = 70%; low-quality evidence). This effect was clear for women with low calcium diets (eight trials, 10,678 women: average RR 0.36, 95% CI 0.20 to 0.65; I² = 76%) but not those with adequate calcium diets. The effect appeared to be greater for women at higher risk of pre-eclampsia, though this may be due to small-study effects (five trials, 587 women: average RR 0.22, 95% CI 0.12 to 0.42). These data should be interpreted with caution because of the possibility of small-study effects or publication bias. In the largest trial, the reduction in pre-eclampsia was modest (8%) and the CI included the possibility of no effect.The composite outcome maternal death or serious morbidity was reduced with calcium supplementation (four trials, 9732 women; RR 0.80, 95% CI 0.66 to 0.98). Maternal deaths were no different (one trial of 8312 women: one death in the calcium group versus six in the placebo group). There was an anomalous increase in the risk of HELLP syndrome in the calcium group (two trials, 12,901 women: RR 2.67, 95% CI 1.05 to 6.82, high-quality evidence), however, the absolute number of events was low (16 versus six).The average risk of preterm birth was reduced in the calcium supplementation group (11 trials, 15,275 women: RR 0.76, 95% CI 0.60 to 0.97; I² = 60%; low-quality evidence); this reduction was greatest amongst women at higher risk of developing pre-eclampsia (four trials, 568 women: average RR 0.45, 95% CI 0.24 to 0.83; I² = 60%). Again, these data should be interpreted with caution because of the possibility of small-study effects or publication bias. There was no clear effect on admission to neonatal intensive care. There was also no clear effect on the risk of stillbirth or infant death before discharge from hospital (11 trials, 15,665 babies: RR 0.90, 95% CI 0.74 to 1.09).One study showed a reduction in childhood systolic BP greater than 95th percentile among children exposed to calcium supplementation in utero (514 children: RR 0.59, 95% CI 0.39 to 0.91). In a subset of these children, dental caries at 12 years old was also reduced (195 children, RR 0.73, 95% CI 0.62 to 0.87).Low-dose calcium supplementation (< 1 g/day) versus placebo or no treatmentTwelve trials (2334 women) evaluated low-dose (usually 500 mg daily) supplementation with calcium alone (four trials) or in association with vitamin D (five trials), linoleic acid (two trials), or antioxidants (one trial). Most studies recruited women at high risk for pre-eclampsia, and were at high risk of bias, thus the results should be interpreted with caution. Supplementation with low doses of calcium reduced the risk of pre-eclampsia (nine trials, 2234 women: RR 0.38, 95% CI 0.28 to 0.52). There was also a reduction in high BP (five trials, 665 women: RR 0.53, 95% CI 0.38 to 0.74), admission to neonatal intensive care unit (one trial, 422 women, RR 0.44, 95% CI 0.20 to 0.99), but not preterm birth (six trials, 1290 women, average RR 0.83, 95% CI 0.34 to 2.03), or stillbirth or death before discharge (five trials, 1025 babies, RR 0.48, 95% CI 0.14 to 1.67).High-dose (=/> 1 g) versus low-dose (< 1 g) calcium supplementationWe included one trial with 262 women, the results of which should be interpreted with caution due to unclear risk of bias. Risk of pre-eclampsia appeared to be reduced in the high-dose group (RR 0.42, 95% CI 0.18 to 0.96). No other differences were found (preterm birth: RR 0.31, 95% CI 0.09 to 1.08; eclampsia: RR 0.32, 95% CI 0.07 to 1.53; stillbirth: RR 0.48, 95% CI 0.13 to 1.83). AUTHORS' CONCLUSIONS: High-dose calcium supplementation (≥ 1 g/day) may reduce the risk of pre-eclampsia and preterm birth, particularly for women with low calcium diets (low-quality evidence). The treatment effect may be overestimated due to small-study effects or publication bias. It reduces the occurrence of the composite outcome 'maternal death or serious morbidity', but not stillbirth or neonatal high care admission. There was an increased risk of HELLP syndrome with calcium supplementation, which was small in absolute numbers.The limited evidence on low-dose calcium supplementation suggests a reduction in pre-eclampsia, hypertension and admission to neonatal high care, but needs to be confirmed by larger, high-quality trials.

BACKGROUND: Although the burden of disease in sub-Saharan Africa continues to be dominated by infectious diseases, countries in this region are undergoing a demographic transition leading to increasing prevalence of non-communicable diseases (NCDs). To inform health system responses to these changing patterns of disease, we aimed to assess changes in the burden of NCDs in sub-Saharan Africa from 1990 to 2017. METHODS: We used data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 to analyse the burden of NCDs in sub-Saharan Africa in terms of disability-adjusted life-years (DALYs)-with crude counts as well as all-age and age-standardised rates per 100 000 population-with 95% uncertainty intervals (UIs). We examined changes in burden between 1990 and 2017, and differences across age, sex, and regions. We also compared the observed NCD burden across countries with the expected values based on a country's Socio-demographic Index. FINDINGS: All-age total DALYs due to NCDs increased by 67·0% between 1990 (90·6 million [95% UI 81·0-101·9]) and 2017 (151·3 million [133·4-171·8]), reflecting an increase in the proportion of total DALYs attributable to NCDs (from 18·6% [95% UI 17·1-20·4] to 29·8% [27·6-32·0] of the total burden). Although most of this increase can be explained by population growth and ageing, the age-standardised DALY rate (per 100 000 population) due to NCDs in 2017 (21 757·7 DALYs [95% UI 19 377·1-24 380·7]) was almost equivalent to that of communicable, maternal, neonatal, and nutritional diseases (26 491·6 DALYs [25 165·2-28 129·8]). Cardiovascular diseases were the second leading cause of NCD burden in 2017, resulting in 22·9 million (21·5-24·3) DALYs (15·1% of the total NCD burden), after the group of disorders categorised as other NCDs (28·8 million [25·1-33·0] DALYs, 19·1%). These categories were followed by neoplasms, mental disorders, and digestive diseases. Although crude DALY rates for all NCDs have decreased slightly across sub-Saharan Africa, age-standardised rates are on the rise in some countries (particularly those in southern sub-Saharan Africa) and for some NCDs (such as diabetes and some cancers, including breast and prostate cancer). INTERPRETATION: NCDs in sub-Saharan Africa are posing an increasing challenge for health systems, which have to date largely focused on tackling infectious diseases and maternal, neonatal, and child deaths. To effectively address these changing needs, countries in sub-Saharan Africa require detailed epidemiological data on NCDs. FUNDING: Bill & Melinda Gates Foundation, National Health and Medical Research Centre (Australia).

BACKGROUND: The SARS-CoV-2 omicron variant of concern was identified in South Africa in November, 2021, and was associated with an increase in COVID-19 cases. We aimed to assess the clinical severity of infections with the omicron variant using S gene target failure (SGTF) on the Thermo Fisher Scientific TaqPath COVID-19 PCR test as a proxy. METHODS: We did data linkages for national, South African COVID-19 case data, SARS-CoV-2 laboratory test data, SARS-CoV-2 genome data, and COVID-19 hospital admissions data. For individuals diagnosed with COVID-19 via TaqPath PCR tests, infections were designated as either SGTF or non-SGTF. The delta variant was identified by genome sequencing. Using multivariable logistic regression models, we assessed disease severity and hospitalisations by comparing individuals with SGTF versus non-SGTF infections diagnosed between Oct 1 and Nov 30, 2021, and we further assessed disease severity by comparing SGTF-infected individuals diagnosed between Oct 1 and Nov 30, 2021, with delta variant-infected individuals diagnosed between April 1 and Nov 9, 2021. FINDINGS: From Oct 1 (week 39), 2021, to Dec 6 (week 49), 2021, 161 328 cases of COVID-19 were reported in South Africa. 38 282 people were diagnosed via TaqPath PCR tests and 29 721 SGTF infections and 1412 non-SGTF infections were identified. The proportion of SGTF infections increased from two (3·2%) of 63 in week 39 to 21 978 (97·9%) of 22 455 in week 48. After controlling for factors associated with hospitalisation, individuals with SGTF infections had significantly lower odds of admission than did those with non-SGTF infections (256 [2·4%] of 10 547 vs 121 [12·8%] of 948; adjusted odds ratio [aOR] 0·2, 95% CI 0·1-0·3). After controlling for factors associated with disease severity, the odds of severe disease were similar between hospitalised individuals with SGTF versus non-SGTF infections (42 [21%] of 204 vs 45 [40%] of 113; aOR 0·7, 95% CI 0·3-1·4). Compared with individuals with earlier delta variant infections, SGTF-infected individuals had a significantly lower odds of severe disease (496 [62·5%] of 793 vs 57 [23·4%] of 244; aOR 0·3, 95% CI 0·2-0·5), after controlling for factors associated with disease severity. INTERPRETATION: Our early analyses suggest a significantly reduced odds of hospitalisation among individuals with SGTF versus non-SGTF infections diagnosed during the same time period. SGTF-infected individuals had a significantly reduced odds of severe disease compared with individuals infected earlier with the delta variant. Some of this reduced severity is probably a result of previous immunity. FUNDING: The South African Medical Research Council, the South African National Department of Health, US Centers for Disease Control and Prevention, the African Society of Laboratory Medicine, Africa Centers for Disease Control and Prevention, the Bill & Melinda Gates Foundation, the Wellcome Trust, and the Fleming Fund.

defined by trial authors.....

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.

BACKGROUND: Risk factors for coronavirus disease 2019 (COVID-19) death in sub-Saharan Africa and the effects of human immunodeficiency virus (HIV) and tuberculosis on COVID-19 outcomes are unknown. METHODS: We conducted a population cohort study using linked data from adults attending public-sector health facilities in the Western Cape, South Africa. We used Cox proportional hazards models, adjusted for age, sex, location, and comorbidities, to examine the associations between HIV, tuberculosis, and COVID-19 death from 1 March to 9 June 2020 among (1) public-sector "active patients" (≥1 visit in the 3 years before March 2020); (2) laboratory-diagnosed COVID-19 cases; and (3) hospitalized COVID-19 cases. We calculated the standardized mortality ratio (SMR) for COVID-19, comparing adults living with and without HIV using modeled population estimates. RESULTS: Among 3 460 932 patients (16% living with HIV), 22 308 were diagnosed with COVID-19, of whom 625 died. COVID-19 death was associated with male sex, increasing age, diabetes, hypertension, and chronic kidney disease. HIV was associated with COVID-19 mortality (adjusted hazard ratio [aHR], 2.14; 95% confidence interval [CI], 1.70-2.70), with similar risks across strata of viral loads and immunosuppression. Current and previous diagnoses of tuberculosis were associated with COVID-19 death (aHR, 2.70 [95% CI, 1.81-4.04] and 1.51 [95% CI, 1.18-1.93], respectively). The SMR for COVID-19 death associated with HIV was 2.39 (95% CI, 1.96-2.86); population attributable fraction 8.5% (95% CI, 6.1-11.1). CONCLUSIONS: While our findings may overestimate HIV- and tuberculosis-associated COVID-19 mortality risks due to residual confounding, both living with HIV and having current tuberculosis were independently associated with increased COVID-19 mortality. The associations between age, sex, and other comorbidities and COVID-19 mortality were similar to those in other settings.

PURPOSE: The purpose of this study was to analyze the results of the modified Latarjet procedure for shoulder instability associated with an inverted-pear glenoid (bone loss of at least 25% of the width of the inferior glenoid) or an engaging Hill-Sachs lesion. METHODS: From March 1996 to December 2002, 102 patients underwent an open Latarjet procedure for shoulder instability with an inverted-pear glenoid, with or without an associated engaging Hill-Sachs lesion, by the 2 senior authors (S.S.B. and J.F.D.), and 47 of them were available for follow-up physical examination. The remaining 55 patients were contacted by telephone or letter to see if they had had recurrent dislocation or subluxation. The mean age of the patients was 26.5 +/- 6.6 years (range, 16 to 41 years). There were 46 male patients and 1 female patient. Preoperatively, mean forward elevation was 177.2 degrees +/- 13.6 degrees (range, 90 degrees to 180 degrees) and mean external rotation with the arm at the side was 55.3 degrees +/- 16.1 degrees (range, 0 degrees to 80 degrees). All patients had a positive apprehension sign preoperatively. The median number of dislocations before surgery was 6, with 20 patients having had more than 15 dislocations preoperatively. RESULTS: The mean follow-up time for the 47 patients who were personally examined was 59.0 +/- 18.5 months (range, 32 to 108 months). Postoperatively, mean forward elevation was 179.6 degrees +/- 2.0 degrees (range, 170 degrees to 180 degrees; gain of 2.4 degrees) and external rotation with the arm at the side was 50.2 degrees +/- 12.6 degrees (range, 22 degrees to 78 degrees; loss of 5.1 degrees). As for postoperative functional scores, the mean Constant score was 94.4 and the mean Walch-Duplay score was 91.7. None of these 47 patients showed any further dislocation, and 1 of them still had a positive apprehension sign (2.2%) indicating subluxation. However, 4 patients out of the total 102 who underwent the modified Latarjet procedure had a recurrence. With 4 recurrent dislocations and 1 recurrent subluxation, there was a 4.9% recurrence rate. The 4 patients with recurrent dislocations were not among the 47 who returned for personal follow-up evaluation. CONCLUSIONS: The 2 senior authors (S.S.B. and J.F.D.) have previously reported an unacceptably high recurrence rate (67%) for arthroscopic Bankart repair in the presence of an inverted-pear glenoid with or without an engaging Hill-Sachs lesion. They have recommended an open modified Latarjet procedure in such patients. The present study confirms the validity of that recommendation, because the same 2 surgeons have had only a 4.9% recurrence rate in that same category of patient at a mean follow-up of 59 months. Furthermore, the results of this study show the efficacy of the modified Latarjet procedure in the extremely challenging category of patients who present with such dramatic bone loss that soft-tissue reconstruction, either open or arthroscopic, is not a reasonable option. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

BACKGROUND: For centuries, there has been controversy around whether being upright (sitting, birthing stools, chairs, squatting, kneeling) or lying down (lateral (Sim's) position, semi-recumbent, lithotomy position, Trendelenburg's position) have advantages for women giving birth to their babies. This is an update of a review previously published in 2012, 2004 and 1999. OBJECTIVES: To determine the possible benefits and risks of the use of different birth positions during the second stage of labour without epidural anaesthesia, on maternal, fetal, neonatal and caregiver outcomes. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register (30 November 2016) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised, quasi-randomised or cluster-randomised controlled trials of any upright position assumed by pregnant women during the second stage of labour compared with supine or lithotomy positions. Secondary comparisons include comparison of different upright positions and the supine position. Trials in abstract form were included. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and assessed trial quality. At least two review authors extracted the data. Data were checked for accuracy. The quality of the evidence was assessed using the GRADE approach. MAIN RESULTS: Results should be interpreted with caution because risk of bias of the included trials was variable. We included eleven new trials for this update; there are now 32 included studies, and one trial is ongoing. Thirty trials involving 9015 women contributed to the analysis. Comparisons include any upright position, birth or squat stool, birth cushion, and birth chair versus supine positions.In all women studied (primigravid and multigravid), when compared with supine positions, the upright position was associated with a reduction in duration of second stage in the upright group (MD -6.16 minutes, 95% CI -9.74 to -2.59 minutes; 19 trials; 5811 women; P = 0.0007; random-effects; I² = 91%; very low-quality evidence); however, this result should be interpreted with caution due to large differences in size and direction of effect in individual studies. Upright positions were also associated with no clear difference in the rates of caesarean section (RR 1.22, 95% CI 0.81 to 1.81; 16 trials; 5439 women; low-quality evidence), a reduction in assisted deliveries (RR 0.75, 95% CI 0.66 to 0.86; 21 trials; 6481 women; moderate-quality evidence), a reduction in episiotomies (average RR 0.75, 95% CI 0.61 to 0.92; 17 trials; 6148 women; random-effects; I² = 88%), a possible increase in second degree perineal tears (RR 1.20, 95% CI 1.00 to 1.44; 18 trials; 6715 women; I² = 43%; low-quality evidence), no clear difference in the number of third or fourth degree perineal tears (RR 0.72, 95% CI 0.32 to 1.65; 6 trials; 1840 women; very low-quality evidence), increased estimated blood loss greater than 500 mL (RR 1.48, 95% CI 1.10 to 1.98; 15 trials; 5615 women; I² = 33%; moderate-quality evidence), fewer abnormal fetal heart rate patterns (RR 0.46, 95% CI 0.22 to 0.93; 2 trials; 617 women), no clear difference in the number of babies admitted to neonatal intensive care (RR 0.79, 95% CI 0.51 to 1.21; 4 trials; 2565 infants; low-quality evidence). On sensitivity analysis excluding trials with high risk of bias, these findings were unchanged except that there was no longer a clear difference in duration of second stage of labour (MD -4.34, 95% CI -9.00 to 0.32; 21 trials; 2499 women; I² = 85%).The main reasons for downgrading of GRADE assessment was that several studies had design limitations (inadequate randomisation and allocation concealment) with high heterogeneity and wide CIs. AUTHORS' CONCLUSIONS: The findings of this review suggest several possible benefits for upright posture in women without epidural anaesthesia, such as a very small reduction in the duration of second stage of labour (mainly from the primigravid group), reduction in episiotomy rates and assisted deliveries. However, there is an increased risk blood loss greater than 500 mL and there may be an increased risk of second degree tears, though we cannot be certain of this. In view of the variable risk of bias of the trials reviewed, further trials using well-designed protocols are needed to ascertain the true benefits and risks of various birth positions.

The development of appropriate integrated and scalable information systems in the health sector in developing countries has been difficult to achieve, and is likely to remain elusive in the face of continued fragmented funding of health programs, particularly related to the HIV/AIDS epidemic. In this article, we propose a strategy for developing information infrastructures in general and in particular for the health care sector in developing countries. We use complexity science to explain the challenges that need to be addressed, in particular the need for standards that can adapt to a changing health care environment, and propose the concept of flexible standards as a key element in a sustainable infrastructure development strategy. Drawing on case material from a number of developing countries, a case is built around the use of flexible standards as attractors, arguing that if they are well defined and simple, they will be able to adapt to the frequent changes that are experienced in the complex health environment. A number of paradoxes are highlighted as useful strategies, integrated independence being one that encourages experimentation and heterogeneity to develop and share innovative solutions while still conforming to simple standards. The article provides theoretical concepts to support standardization processes in complex systems, and to suggest an approach to implement health standards in developing country settings that is sensitive to the local context, allows change to occur through small steps, and provides a mechanism for scaling information systems.

OBJECTIVE: Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a frequent complication of antiretroviral therapy in resource-limited countries. We aimed to assess whether a 4-week course of prednisone would reduce morbidity in patients with paradoxical TB-IRIS without excess adverse events. DESIGN: A randomized, double-blind, placebo-controlled trial of prednisone (1.5 mg/kg per day for 2 weeks then 0.75 mg/kg per day for 2 weeks). Patients with immediately life-threatening TB-IRIS manifestations were excluded. METHODS: The primary combined endpoint was days of hospitalization and outpatient therapeutic procedures, which were counted as one hospital day. RESULTS: One hundred and ten participants were enrolled (55 to each arm). The primary combined endpoint was more frequent in the placebo than the prednisone arm {median hospital days 3 [interquartile range (IQR) 0-9] and 0 (IQR 0-3), respectively; P = 0.04}. There were significantly greater improvements in symptoms, Karnofsky score, and quality of life (MOS-HIV) in the prednisone vs. the placebo arm at 2 and 4 weeks, but not at later time points. Chest radiographs improved significantly more in the prednisone arm at weeks 2 (P = 0.002) and 4 (P = 0.02). Infections on study medication occurred in more participants in prednisone than in placebo arm (27 vs. 17, respectively; P = 0.05), but there was no difference in severe infections (2 vs. 4, respectively; P = 0.40). Isolates from 10 participants were found to be resistant to rifampicin after enrolment. CONCLUSION: Prednisone reduced the need for hospitalization and therapeutic procedures and hastened improvements in symptoms, performance, and quality of life. It is important to investigate for drug-resistant tuberculosis and other causes for deterioration before administering glucocorticoids.

BACKGROUND: Historically, women have been attended and supported by other women during labour. However, in hospitals worldwide, continuous support during labour has become the exception rather than the routine. OBJECTIVES: Primary: to assess the effects of continuous, one-to-one intrapartum support compared with usual care. Secondary: to determine whether the effects of continuous support are influenced by: (1) routine practices and policies; (2) the provider's relationship to the hospital and to the woman; and (3) timing of onset. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 May 2013). SELECTION CRITERIA: All published and unpublished randomised controlled trials comparing continuous support during labour with usual care. DATA COLLECTION AND ANALYSIS: We used standard methods of The Cochrane Collaboration Pregnancy and Childbirth Group. Two review authors independently evaluated methodological quality and extracted the data. We sought additional information from the trial authors. We used random-effects analyses for comparisons in which high heterogeneity was present, and we reported results using the average risk ratio (RR) for categorical data and mean difference (MD) for continuous data. MAIN RESULTS: Twenty-two trials involving 15,288 women met inclusion criteria and provided usable outcome data. Results are of random-effects analyses, unless otherwise noted. Women allocated to continuous support were more likely to have a spontaneous vaginal birth (RR 1.08, 95% confidence interval (CI) 1.04 to 1.12) and less likely to have intrapartum analgesia (RR 0.90, 95% CI 0.84 to 0.96) or to report dissatisfaction (RR 0.69, 95% CI 0.59 to 0.79). In addition, their labours were shorter (MD -0.58 hours, 95% CI -0.85 to -0.31), they were less likely to have a caesarean (RR 0.78, 95% CI 0.67 to 0.91) or instrumental vaginal birth (fixed-effect, RR 0.90, 95% CI 0.85 to 0.96), regional analgesia (RR 0.93, 95% CI 0.88 to 0.99), or a baby with a low five-minute Apgar score (fixed-effect, RR 0.69, 95% CI 0.50 to 0.95). There was no apparent impact on other intrapartum interventions, maternal or neonatal complications, or breastfeeding. Subgroup analyses suggested that continuous support was most effective when the provider was neither part of the hospital staff nor the woman's social network, and in settings in which epidural analgesia was not routinely available. No conclusions could be drawn about the timing of onset of continuous support. AUTHORS' CONCLUSIONS: Continuous support during labour has clinically meaningful benefits for women and infants and no known harm. All women should have support throughout labour and birth.

OBJECTIVE: To determine the prevalence of uterine rupture worldwide. DESIGN: Systematic review of all available data since 1990. SETTING: Community-based and facility-based reports from urban and rural studies worldwide. Sample Eighty-three reports of uterine rupture rates are included in the systematic review. Most are facility based using cross-sectional study designs. METHODS: Following a pre-defined protocol an extensive search was conducted of 10 electronic databases as well as other sources. Articles were evaluated according to specified inclusion criteria. Uterine rupture data were collected along with information on the quality of reporting including definitions and identification of cases. Data were entered into a database and tabulated using SAS software. MAIN OUTCOME MEASURES: Prevalence of uterine rupture by country, period, study design, setting, participants, facility type and data source. RESULTS: Prevalence figures for uterine rupture were available for 86 groups of women. For unselected pregnant women, the prevalence of uterine rupture reported was considerably lower for community-based (median 0.053, range 0.016-0.30%) than for facility-based studies (0.31, 0.012-2.9%). The prevalence tended to be lower for countries defined by the United Nations as developed than the less or least developed countries. For women with previous caesarean section, the prevalence of uterine rupture reported was in the region of 1%. Only one report gave a prevalence for women without previous caesarean section, from a developed country, and this was extremely low (0.006%). CONCLUSION: In less and least developed countries, uterine rupture is more prevalent than in developed countries. In developed countries most uterine ruptures follow caesarean section. Future research on the prevalence of uterine rupture should differentiate between uterine rupture with and without previous caesarean section.

BACKGROUND: Poor outcomes after breech birth might be the result of underlying conditions causing breech presentation or due to factors associated with the delivery. OBJECTIVES: To assess the effects of planned caesarean section for singleton breech presentation at term on measures of pregnancy outcome. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 March 2015). SELECTION CRITERIA: Randomised trials comparing planned caesarean section for singleton breech presentation at term with planned vaginal birth. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. MAIN RESULTS: Three trials (2396 participants) were included in the review. Caesarean delivery occurred in 550/1227 (45%) of those women allocated to a vaginal delivery protocol and 1060/1169 (91%) of those women allocated to planned caesarean section (average risk ratio (RR) random-effects, 1.88, 95% confidence interval (CI) 1.60 to 2.20; three studies, 2396 women, evidence graded low quality). Perinatal or neonatal death (excluding fatal anomalies) or severe neonatal morbidity was reduced with a policy of planned caesarean section in settings with a low national perinatal mortality rate (RR 0.07, 95% CI 0.02 to 0.29, one study, 1025 women, evidence graded moderate quality), but not in settings with a high national perinatal mortality rate (RR 0.66, 95% CI 0.35 to 1.24, one study, 1053 women, evidence graded low quality). The difference between subgroups was significant (Test for subgroup differences: Chi² = 8.01, df = 1 (P = 0.005), I² = 87.5%). Due to this significant heterogeneity, a random-effects analysis was performed. The average overall effect was not statistically significant (RR 0.23, 95% CI 0.02 to 2.44, one study, 2078 infants). Perinatal or neonatal death (excluding fatal anomalies) was reduced with planned caesarean section (RR 0.29, 95% CI 0.10 to 0.86, three studies, 2388 women). The proportional reductions were similar for countries with low and high national perinatal mortality rates.The numbers studied were too small to satisfactorily address reductions in birth trauma and brachial plexus injury with planned caesarean section. Neither of these outcomes reached statistical significance (birth trauma: RR 0.42, 95% CI 0.16 to 1.10, one study, 2062 infants (20 events),evidence graded low quality; brachial plexus injury: RR 0.35, 95% CI 0.08 to 1.47, three studies, 2375 infants (nine events)).Planned caesarean section was associated with modestly increased short-term maternal morbidity (RR 1.29, 95% CI 1.03 to 1.61, three studies, 2396 women,low quality evidence). At three months after delivery, women allocated to the planned caesarean section group reported less urinary incontinence (RR 0.62, 95% CI 0.41 to 0.93, one study, 1595 women); no difference in 'any pain' (RR 1.09, 95% CI 0.93 to 1.29, one study, 1593 women,low quality evidence); more abdominal pain (RR 1.89, 95% CI 1.29 to 2.79, one study, 1593 women); and less perineal pain (RR 0.32, 95% CI 0.18 to 0.58, one study, 1593 women).At two years, there were no differences in the combined outcome 'death or neurodevelopmental delay' (RR 1.09, 95% CI 0.52 to 2.30, one study, 920 children,evidence graded low quality); more infants who had been allocated to planned caesarean delivery had medical problems at two years (RR 1.41, 95% CI 1.05 to 1.89, one study, 843 children). Maternal outcomes at two years were also similar. In countries with low perinatal mortality rates, the protocol of planned caesarean section was associated with lower healthcare costs, expressed in 2002 Canadian dollars (mean difference -$877.00, 95% CI -894.89 to -859.11, one study, 1027 women).All of the trials included in this review had design limitations, and the GRADE level of evidence was mostly low. No studies attempted to blind the intervention, and the process of random allocation was suboptimal in two studies. Two of the three trials had serious design limitations, however these studies contributed to fewer outcomes than the large multi-centre trial with lower risk of bias. AUTHORS' CONCLUSIONS: Planned caesarean section compared with planned vaginal birth reduced perinatal or neonatal death as well as the composite outcome death or serious neonatal morbidity, at the expense of somewhat increased maternal morbidity. In a subset with 2-year follow up, infant medical problems were increased following planned caesarean section and no difference in long-term neurodevelopmental delay or the outcome "death or neurodevelopmental delay" was found, though the numbers were too small to exclude the possibility of an important difference in either direction.The benefits need to be weighed against factors such as the mother's preference for vaginal birth and risks such as future pregnancy complications in the woman's specific healthcare setting. The option of external cephalic version is dealt with in separate reviews. The data from this review cannot be generalised to settings where caesarean section is not readily available, or to methods of breech delivery that differ materially from the clinical delivery protocols used in the trials reviewed. The review will help to inform individualised decision-making regarding breech delivery. Research on strategies to improve the safety of breech delivery and to further investigate the possible association of caesarean section with infant medical problems is needed.

and allied fusarioid genera (www.fusarium.org).

BACKGROUND: In the Global Burden of Disease Study 2013 (GBD 2013), knowledge about health and its determinants has been integrated into a comparable framework to inform health policy. Outputs of this analysis are relevant to current policy questions in England and elsewhere, particularly on health inequalities. We use GBD 2013 data on mortality and causes of death, and disease and injury incidence and prevalence to analyse the burden of disease and injury in England as a whole, in English regions, and within each English region by deprivation quintile. We also assess disease and injury burden in England attributable to potentially preventable risk factors. England and the English regions are compared with the remaining constituent countries of the UK and with comparable countries in the European Union (EU) and beyond. METHODS: We extracted data from the GBD 2013 to compare mortality, causes of death, years of life lost (YLLs), years lived with a disability (YLDs), and disability-adjusted life-years (DALYs) in England, the UK, and 18 other countries (the first 15 EU members [apart from the UK] and Australia, Canada, Norway, and the USA [EU15+]). We extended elements of the analysis to English regions, and subregional areas defined by deprivation quintile (deprivation areas). We used data split by the nine English regions (corresponding to the European boundaries of the Nomenclature for Territorial Statistics level 1 [NUTS 1] regions), and by quintile groups within each English region according to deprivation, thereby making 45 regional deprivation areas. Deprivation quintiles were defined by area of residence ranked at national level by Index of Multiple Deprivation score, 2010. Burden due to various risk factors is described for England using new GBD methodology to estimate independent and overlapping attributable risk for five tiers of behavioural, metabolic, and environmental risk factors. We present results for 306 causes and 2337 sequelae, and 79 risks or risk clusters. FINDINGS: Between 1990 and 2013, life expectancy from birth in England increased by 5·4 years (95% uncertainty interval 5·0-5·8) from 75·9 years (75·9-76·0) to 81·3 years (80·9-81·7); gains were greater for men than for women. Rates of age-standardised YLLs reduced by 41·1% (38·3-43·6), whereas DALYs were reduced by 23·8% (20·9-27·1), and YLDs by 1·4% (0·1-2·8). For these measures, England ranked better than the UK and the EU15+ means. Between 1990 and 2013, the range in life expectancy among 45 regional deprivation areas remained 8·2 years for men and decreased from 7·2 years in 1990 to 6·9 years in 2013 for women. In 2013, the leading cause of YLLs was ischaemic heart disease, and the leading cause of DALYs was low back and neck pain. Known risk factors accounted for 39·6% (37·7-41·7) of DALYs; leading behavioural risk factors were suboptimal diet (10·8% [9·1-12·7]) and tobacco (10·7% [9·4-12·0]). INTERPRETATION: Health in England is improving although substantial opportunities exist for further reductions in the burden of preventable disease. The gap in mortality rates between men and women has reduced, but marked health inequalities between the least deprived and most deprived areas remain. Declines in mortality have not been matched by similar declines in morbidity, resulting in people living longer with diseases. Health policies must therefore address the causes of ill health as well as those of premature mortality. Systematic action locally and nationally is needed to reduce risk exposures, support healthy behaviours, alleviate the severity of chronic disabling disorders, and mitigate the effects of socioeconomic deprivation. FUNDING: Bill & Melinda Gates Foundation and Public Health England.

We aimed to estimate the global occurrence of zoonotic tuberculosis (TB) caused by Mycobacterium bovis or M. caprae infections in humans by performing a multilingual, systematic review and analysis of relevant scientific literature of the last 2 decades. Although information from many parts of the world was not available, data from 61 countries suggested a low global disease incidence. In regions outside Africa included in this study, overall median proportions of zoonotic TB of ≤1.4% in connection with overall TB incidence rates ≤71/100,000 population/year suggested low incidence rates. For countries of Africa included in the study, we multiplied the observed median proportion of zoonotic TB cases of 2.8% with the continental average overall TB incidence rate of 264/100,000 population/year, which resulted in a crude estimate of 7 zoonotic TB cases/100,000 population/year. These generally low incidence rates notwithstanding, available data indicated substantial consequences of this disease for some population groups and settings.