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Economic and behavioural factors lead to poor outcomes in patients with tuberculosis. We investigated the effects of a package of interventions consisting of pre-test and post-test tuberculosis counselling with conditional cash transfers on patient outcomes in adults undergoing investigation for pulmonary tuberculosis. This pragmatic, open-label, individual randomised controlled trial was done in nine clinics in Johannesburg, South Africa. Participants (aged ≥18 years) undergoing investigation for tuberculosis were randomly assigned (1:1) to the intervention group or control group (standard of care) via permuted block randomisation, stratified by clinic; group assignment was concealed using opaque envelopes. The intervention group received pre-test and post-test tuberculosis counselling, and for participants diagnosed with rifampicin-susceptible tuberculosis, a digital payment (R150; approximately US$10) at treatment initiation and each monthly treatment visit. Payments were contingent on timely attendance: 14 days from initial sputum sample collection and within 7 days on either side of their scheduled monthly appointment. The primary endpoint was successful patient outcome (patients who were cured or completed treatment) or unsuccessful patient outcome (pretreatment loss-to-follow-up, on-treatment loss-to-follow-up, development of rifampicin-resistant tuberculosis while on treatment, treatment failure [ie, smear or culture positive at 5 months or later after commencing treatment], or death). The primary outcome was analysed in the modified intention-to-treat population, defined as all randomly assigned participants with rifampicin-susceptible tuberculosis confirmed before the commencement of tuberculosis treatment. Weighted outcome prevalence, relative risks (RRs), and risk differences were calculated using a multivariable Poisson model with robust standard errors. This trial is registered with the Pan African Clinical Trials Registry (PACTR202410708311054) and is completed. Between Oct 25, 2018, and Dec 9, 2019, 4110 participants were enrolled and randomly assigned, 2059 to the intervention group and 2051 to the control group. 381 (9·3%) participants had microbiologically confirmed rifampicin-susceptible pulmonary tuberculosis (195 [9·5%] of 2059 in the intervention group vs 186 [9·1%] of 2051 in the control group; median age 37 years [IQR 30 to 45], 257 [67·5%] male, 124 [32·5%] female). At study closure, primary outcome data were available for 128 (65·6%) of 195 participants in the intervention group and 139 (74·7%) of 186 participants in the control group. 105 (82·0%) of 128 participants in the intervention group and 93 (66·9%) of 139 participants in the control group had a successful patient outcome; 23 (18·0%) of 128 participants in the intervention group and 46 (33·1%) of 139 participants in the control group had an unsuccessful patient outcome. The weighted regression analysis showed a substantial reduction in the risk of unsuccessful patient outcomes in the intervention group compared with the control group (weighted prevalence 15·9% vs 28·6%; RR in weighted population 0·52, 95% CI 0·33 to 0·82; risk difference in weighted population –14·1 percentage points, 95% CI –23·3 to –4·8). Pretreatment loss to follow-up was lower in the intervention group than in the control group (unweighted population: five [3·9%] of 128 participants vs 22 [15·8%] of 139 participants; risk difference in weighted population –9·6 percentage points, 95% CI –14·9 to –4·2). The package of interventions consisting of pre-test and post-test tuberculosis counselling with conditional cash transfers significantly reduced the risk of unsuccessful tuberculosis patient outcomes, bringing one of the 90–90–90 targets within reach (ie, achieving 90% tuberculosis treatment success). Furthermore, reduction in pretreatment loss to follow-up is expected to reduce transmission and lower incidence of the disease over time. South African Medical Research Council, UK Medical Research Council, and Newton Fund.

South Africa has the highest incidence of tuberculosis in the world, largely resulting from a high population prevalence of HIV infection. We investigated the incidence of microbiologically confirmed pulmonary tuberculosis, and new cases of pulmonary tuberculosis registered for treatment, nationally and provincially in South Africa from 2004 to 2012, during which time there were changes in antiretroviral therapy (ART) coverage among individuals with HIV infection. We identified cases of microbiologically confirmed pulmonary tuberculosis from 2004 to 2012 from the National Health Laboratory Service Corporate Data Warehouse. New cases registered for treatment were identified from National Department of Health electronic registries. A time series analysis, using autoregressive models, was undertaken on incidence of microbiologically confirmed pulmonary disease nationally and provincially; this trend was also examined relative to ART coverage of adults with HIV infection. During the 9-year period, 3 523 371 cases of microbiologically confirmed pulmonary tuberculosis were recorded nationally. Annual incidence (per 100 000 population) increased from 650 (95% CI 648–652) in 2004 to 848 (845–850) in 2008, declining to 774 (771–776) by 2012 (9% decrease from 2008 to 2012). Incidence varied by age-group, sex, and province. There was an inverse association between incidence of microbiologically confirmed disease and ART coverage among HIV-infected individuals nationally and provincially. Trends in incidence of tuberculosis cases registered for treatment mirrored those of microbiologically confirmed cases nationally and provincially; however, incidence of microbiologically confirmed cases was consistently higher than cases registered for treatment nationally and in seven of nine provinces. Since its peak in 2008, the incidence of microbiologically confirmed pulmonary tuberculosis in South Africa had declined by 2012; this decline is associated with an increase in ART coverage. Future integration of registries for microbiologically confirmed cases and new cases registered for treatment would improve the assessment of the burden of pulmonary tuberculosis in South Africa. National Institute for Communicable Diseases: Division of the National Health Laboratory Service, South Africa.

Background Group B Streptococcus (GBS) infections are a major cause of invasive disease (IGbsD) in young infants and cause miscarriage and stillbirths. Immunization of pregnant women against GBS in addition to intrapartum antibiotic prophylaxis could prevent disease. Establishing accurate serological markers of protection against IGbsD could enable use of efficient clinical trial designs for vaccine development and licensure, without needing to undertake efficacy trials in prohibitively large number of mother-infant dyads. The association of maternal naturally acquired serotype-specific anti-capsular antibodies (IgG) against serotype-specific IGbsD in their infants has been studied in case-control studies. The statistical models used so far to estimate IGbsD risk from these case-control studies assumed that the antibody concentrations measured sharing the same disease status are sampled from the same population, not allowing for differences between mothers colonised by GBS and mothers also potentially infected (e.g urinary tract infection or chorioamnionitis) by GBS during pregnancy. This distinction is relevant as infants born from infected mothers with occult medical illness may be exposed to GBS prior to the mother developing antibodies measured in maternal or infant sera. Methods Unsupervised mixture model averaging (MMA) is proposed and applied here to accurately estimate infant IGbsD risk from case-control study data in presence or absence of antibody concentration subgroups potentially associated to maternal GBS carriage or infection. MMA estimators are compared to non-parametric disease risk estimators in simulation studies and by analysis of two published GBS case-control studies. Results MMA provides more accurate relative risk estimates under a broad range of data simulation scenarios and more accurate absolute disease risk estimates when the proportion of IGbsD cases with high antibody levels is not ignorable. MMA estimates of the relative and absolute disease risk curves are more amenable to clinical interpretation compared to non-parametric estimates with no detectable overfitting of the data. Antibody concentration thresholds predictive of protection from infant IGbsD estimated by MMA from maternal and infant sera are consistent with non-parametric estimates. Conclusions MMA is a flexible and robust method for design, accurate analysis and clinical interpretation of case-control studies estimating relative and absolute IGbsD risk from antibody concentrations measured at or after birth.

Background. The public health impact of rotavirus vaccination in African settings with a high human immunodeficiency virus (HIV) infection prevalence is yet to be established. We evaluated trends in all-cause diarrheal hospitalizations in Soweto, Johannesburg, before and after the introduction of rotavirus vaccine into South Africa's national immunization program in August 2009. Methods. Hospitalizations in children <5 years of age with a diagnosis of diarrhea, defined by International Classification of Diseases, Tenth Revision codes A00–A05, A06.0–A06.3, A06.9, A07.0–A07.2, A07.9, and A08–A09, were identified at the Chris Hani Baragwanath Academic Hospital from 1 January 2006 to 31 December 2014. The median annual prevaccine (2006–2008) hospitalization incidence was compared to that of the vaccine era (2010–2014), and stratified by age group and HIV infection status. Results. Incidence reductions (per 1000 population) were greatest in children aged <12 months: 54.4 in the prevaccine era vs 30.0, 23.6, 20.0, 18.8, and 18.9 in the postvaccine years 2010–2014, respectively (a 44.9%–65.4% reduction). Lower incidence reductions (39.8%–49.4%) were observed among children aged 12–24 months from the second year post–vaccine introduction onward. Reductions were observed in both HIV-infected and HIV-uninfected children. There was a change in the seasonal pattern of diarrheal hospitalizations post–vaccine introduction, with flattening of the autumn–winter peaks seen in the prevaccine years. Conclusions. An accelerated and sustained decline in all-cause diarrheal hospitalizations, temporally associated with rotavirus vaccine introduction, was observed in children <2 years of age. However, the impact of other interventions such as improved sanitation and changes in HIV management cannot be discounted.

Klebsiella pneumoniae (KPn) colonizes multiple anatomical sites and is a leading cause of invasive disease and death in African children; however, there is no comparative genomic analysis between colonizing and invasive strains. This study investigated the genomic relatedness of KPn colonizing and invasive isolates in South African infants; and evaluated the relative invasiveness of KPn isolates based on sequence types (ST), capsular (KL), and lipopolysaccharide (O) loci by calculating case-carrier ratios (CCRs). There was less genomic diversity amongst invasive (22 ST, 17 K-loci) than colonizing isolates (31 ST, 29 K-loci), with invasive isolates being 8.59-fold and 3.49-fold more likely to harbour genes encoding for multi-drug resistance and yersiniabactin production compared with colonizing isolates. The CCRs for KL102 and O1/O2v2 were > 1, and < 1 for KL8, ST1414, and O1O2v1. Identifying high-risk strains, including KL102 and O1O2v2, that may have a higher potential to cause invasive disease, could enhance risk assessment and management strategies in vulnerable populations.

ObjectiveWe evaluated the association between early-onset sepsis and neonatal encephalopathy in a low-middle-income setting.MethodsWe undertook a retrospective study in newborns with gestational age ≥35 weeks and/or birth weight ≥2500 grams, diagnosed with neonatal encephalopathy. Early-onset sepsis was defined as culture-confirmed sepsis or probable sepsis.ResultsOf 10,182 hospitalised newborns, 1027 (10.1%) were diagnosed with neonatal encephalopathy, of whom 52 (5.1%) had culture-confirmed and 129 (12.5%) probable sepsis. The case fatality rate for culture-confirmed sepsis associated neonatal encephalopathy was threefold higher compared to neonatal encephalopathy without sepsis (30.8% vs. 10.5%, p < 0.001). Predictors of mortality for culture-confirmed sepsis associated neonatal encephalopathy included severe neonatal encephalopathy (aOR 6.51, 95%CI: 1.03–41.44) and seizures (aOR 10.64, 95%CI: 1.05–107.39).ConclusionIn this setting, 5% of neonatal encephalopathy cases was associated with culture-confirmed sepsis and a high case fatality rate.

SARS-CoV-2 cell-mediated immunity remains understudied during pregnancy in unvaccinated Black African women living with HIV (WLWH) from low- and middle-income countries. We investigated SARS-CoV-2-specific T-cell responses 1 month following infection in 24 HIV-uninfected women and 15 WLWH at any stage during pregnancy or postpartum. The full-length spike (FLS) glycoprotein and nucleocapsid (N) protein of wild-type (WT) SARS-CoV-2, as well as mutated spike protein regions found in the Omicron variant (B.1.1.529) were targeted by flow cytometry. WT-specific CD4 + and CD8 + T cells elicited similar FLS- and N-specific responses in HIV-uninfected women and WLWH. SARS-CoV-2-specific T-lymphocytes were predominantly TNF-α monofunctional in pregnant and postpartum women living with and without HIV, with fever cells producing either IFN-γ or IL-2. Furthermore, T-cell responses were unaffected by Omicron-specific spike mutations as similar responses between Omicron and the ancestral virus were detected for CD4 + and CD8 + T cells. Our results collectively demonstrate comparable T-cell responses between WLWH on antiretroviral therapy and HIV-uninfected pregnant and postpartum women who were naïve to Covid-19 vaccination. Additionally, we show that T cells from women infected with the ancestral virus, Beta variant (B.1.351), or Delta variant (B.1.617.2) can cross-recognize Omicron, suggesting an overall preservation of T-cell immunity.

Despite approximately 2.6 million stillbirths occurring annually, there is a paucity of systematic biological investigation and consequently knowledge on the causes of these deaths in low- and middle-income countries (LMICs). We investigated the utility of minimally invasive tissue sampling (MITS), placental examination, and clinical history, in attributing the causes of stillbirth in a South African LMIC setting. This prospective, observational pilot study undertook sampling of brain, lung, and liver tissue using core biopsy needles, blood and cerebrospinal fluid collection, and placental examination. Testing included microbial culture and/or molecular testing and tissue histological examination. The cause of death was determined for each case by an international panel of medical specialists and categorized using the World Health Organization's International Classification of Diseases, Tenth Revision application to perinatal deaths. A cause of stillbirth was identifiable for 117 of 129 (90.7%) stillbirths, including an underlying maternal cause in 63.4% (n = 83) and an immediate fetal cause in 79.1% (n = 102) of cases. The leading underlying causes of stillbirth were maternal hypertensive disorders (16.3%), placental separation and hemorrhage (14.0%), and chorioamnionitis (10.9%). The leading immediate causes of fetal death were antepartum hypoxia (35.7%) and fetal infection (37.2%), including due to Escherichia coli (16.3%), Enterococcus species (3.9%), and group B Streptococcus (3.1%). In this pilot, proof-of-concept study, focused investigation of stillbirth provided granular detail on the causes thereof in an LMIC setting, including provisionally highlighting the largely underrecognized role of fetal sepsis as a dominant cause.

We conducted an epidemiologic survey to determine the seroprevalence of SARS-CoV-2 anti-nucleocapsid (anti-N) and anti-spike (anti-S) protein IgG from 1 March to 11 April 2022 after the BA.1-dominant wave had subsided in South Africa and prior to another wave dominated by the BA.4 and BA.5 (BA.4/BA.5) sub-lineages. We also analysed epidemiologic trends in Gauteng Province for cases, hospitalizations, recorded deaths, and excess deaths were evaluated from the inception of the pandemic through 17 November 2022. Despite only 26.7% (1995/7470) of individuals having received a COVID-19 vaccine, the overall seropositivity for SARS-CoV-2 was 90.9% (95% confidence interval (CI), 90.2 to 91.5) at the end of the BA.1 wave, and 64% (95% CI, 61.8 to 65.9) of individuals were infected during the BA.1-dominant wave. The SARS-CoV-2 infection fatality risk was 16.5–22.3 times lower in the BA.1-dominant wave compared with the pre-BA.1 waves for recorded deaths (0.02% vs. 0.33%) and estimated excess mortality (0.03% vs. 0.67%). Although there are ongoing cases of COVID-19 infections, hospitalization and death, there has not been any meaningful resurgence of COVID-19 since the BA.1-dominant wave despite only 37.8% coverage by at least a single dose of COVID-19 vaccine in Gauteng, South Africa.

There is a paucity of longitudinal data on the serotype-specific burden of invasive group B Streptococcus (GBS) disease from low-middle income countries, which could inform selection of vaccine epitopes. From 2005 to 2014, infants less than 90 days of age with invasive GBS disease were identified through sentinel laboratory and hospital admission surveillance at Chris Hani Baragwanath Academic Hospital in Soweto, South Africa. We identified 820 cases of invasive GBS disease, including 55% among newborns <7 days age (i.e. early-onset disease; EOD). The overall incidence (per 1,000 live births) of invasive GBS disease was 2.59 (95% CI: 2.42-2.77), including 1.41 (95% CI: 1.28-1.55) for EOD and 1.18 (95% CI: 1.06-1.30) in infants 7-89 days age (late-onset disease). Year-on-year, from 2005 to 2014, we observed a 9.4% increase in incidence of serotype Ia invasive disease (RR: 1.09; 95% CI: 1.04-1.15; p<0.001), and a 7.4% decline in serotype III invasive disease (RR: 0.93; 95% CI: 0.90-0.96; p<0.001). Overall, serotypes Ia (28.2%), III (55.4%) and V (7.9%) were the commonest disease causing serotypes. The incidence of invasive GBS disease has remained persistently high in our setting, with some changes in serotype distribution, albeit mainly involving the same group of dominant serotypes.