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Background The World Health Organization (WHO) recommends systematic symptom screening for tuberculosis (TB). However, TB prevalence surveys suggest that this strategy does not identify millions of TB patients, globally. Undiagnosed or delayed diagnosis of TB contribute to TB transmission and exacerbate morbidity and mortality. We conducted a cluster-randomized trial of large urban and rural primary healthcare clinics in 3 provinces of South Africa to evaluate whether a novel intervention of targeted universal testing for TB (TUTT) in high-risk groups diagnosed more patients with TB per month compared to current standard of care (SoC) symptom-directed TB testing. Methods and findings Sixty-two clinics were randomized; with initiation of the intervention clinics over 6 months from March 2019. The study was prematurely stopped in March 2020 due to clinics restricting access to patients, and then a week later due to the Coronavirus Disease 2019 (COVID-19) national lockdown; by then, we had accrued a similar number of TB diagnoses to that of the power estimates and permanently stopped the trial. In intervention clinics, attendees living with HIV, those self-reporting a recent close contact with TB, or a prior episode of TB were all offered a sputum test for TB, irrespective of whether they reported symptoms of TB. We analyzed data abstracted from the national public sector laboratory database using Poisson regression models and compared the mean number of TB patients diagnosed per clinic per month between the study arms. Intervention clinics diagnosed 6,777 patients with TB, 20.7 patients with TB per clinic month (95% CI 16.7, 24.8) versus 6,750, 18.8 patients with TB per clinic month (95% CI 15.3, 22.2) in control clinics during study months. A direct comparison, adjusting for province and clinic TB case volume strata, did not show a significant difference in the number of TB cases between the 2 arms, incidence rate ratio (IRR) 1.14 (95% CI 0.94, 1.38, p = 0.46). However, prespecified difference-in-differences analyses showed that while the rate of TB diagnoses in control clinics decreased over time, intervention clinics had a 17% relative increase in TB patients diagnosed per month compared to the prior year, interaction IRR 1.17 (95% CI 1.14, 1.19, p < 0.001). Trial limitations were the premature stop due to COVID-19 lockdowns and the absence of between-arm comparisons of initiation and outcomes of TB treatment in those diagnosed with TB. Conclusions Our trial suggests that the implementation of TUTT in these 3 groups at extreme risk of TB identified more TB patients than SoC and could assist in reducing undiagnosed TB patients in settings of high TB prevalence. Trial registration South African National Clinical Trials Registry DOH-27-092021-4901., Author(s): Neil A. Martinson 1,2,*, Bareng A. S. Nonyane 3, Leisha P. Genade 1, Rebecca H. Berhanu 4, Pren Naidoo 5, Zameer Brey 6, Anthony Kinghorn 1, Sipho Nyathi 7, [...]

Background There is a dearth of comparative effectiveness research examining the implementation of different strategies for active tuberculosis (TB) case finding, particularly in rural settings, which represent 60% of the population of sub-Saharan Africa. Methods and findings We conducted a pragmatic, cluster-randomized comparative effectiveness trial of two TB case finding strategies (facility-based screening and contact tracing) in 56 public primary care clinics in two largely rural districts of Limpopo Province, South Africa. In the facility-based screening arm, sputum Xpert MTB/RIF was performed on all patients presenting (for any reason) with TB symptoms to 28 study clinics, and no contact tracing was performed. In the contact-tracing arm, contacts of patients with active TB were identified (via household tracing in 14 clinics and using small monetary incentives in the other 14 clinics), screened for TB symptoms, and offered Xpert MTB/RIF testing. The primary outcome was the number of newly identified patients with TB started on treatment. The analysis used multivariable Poisson regression adjusted for historical clinic-level TB case volumes and district. The trial was registered with ClinicalTrials.gov (NCT02808507). From July 18, 2017, to January 17, 2019, a total of 3,755 individuals started TB treatment across 56 study clinics in the 18-month period. Clinic characteristics and clinic-level averages of patient characteristics were similar across the two arms: 40/56 (71%) clinics were in a rural location, 2,136/3,655 (58%) patients were male, and 2,243 (61%) were HIV positive. The treatment initiation ratio comparing the yield of TB patients started on treatment in the facility-based arm compared to that from the contact-tracing arm was 1.04 (95% confidence interval [CI] 0.83-1.30, p = 0. 73). In the contact-tracing arm, 1,677 contacts of 788 new TB index patients were screened, yielding 12 new patients with TB. Prespecified subgroup analyses resulted in similar results, with estimated treatment initiation ratios of 0.96 (95% CI 0.64-1.27; p = 0.78) and 1.23 (95% CI 0.87-1.59; p = 0.29) among historically smaller and historically larger clinics, respectively. This ratio was 1.02 (95% CI 0.66-1.37; p = 0.93) and 1.08 (95% CI 0.74-1.42; p = 0.68) in the Vhembe and Waterberg districts, respectively. The estimated treatment initiation ratio was unchanged in sensitivity analyses excluding 24 records whose TB registration numbers could not be verified (1.03, 95% CI 0.82-1.29; p = 0.78) and excluding transfers-in (1.02, 95% CI 0.80-1.29; p = 0.71). Study limitations include the possibility of imbalance on cluster size owing to changes in catchment population over time and the inability to distinguish the independent effects of the two contact investigation strategies. Conclusions Contact tracing based on symptom screening and Xpert MTB/RIF testing did not increase the rate of treatment initiation for TB relative to the less resource-intensive approach of facility-based screening in this rural sub-Saharan setting. Trial registration ClinicalTrials.gov NCT02808507., Author(s): Colleen F. Hanrahan 1,*, Bareng A. S. Nonyane 2, Lesego Mmolawa 3, Nora S. West 2, Tsundzukani Siwelana 3, Limakatso Lebina 3, Neil Martinson 3, David W. Dowdy 1 [...]

Background Providing incentives to screen close contacts for tuberculosis (TB) is an alternative to household-based contact investigation. We aimed to characterize patients and contexts where this incentive-based strategy might be preferred. Methods This is a secondary analysis of a cluster randomized trial of TB contact investigation in Limpopo District, South Africa, conducted between 2016 and 2020. Twenty-eight clinics were randomly allocated to household-based vs incentive-based contact investigation. In the incentive-based arm, index participants and contacts received transport reimbursement and incentives for TB screening and microbiological diagnosis of contacts. We estimated differences in mean number of contacts per index participant with household-based vs incentive-based contact investigation overall and within subgroups of index participants. Results A total of 3776 contacts (1903 in the incentive-based and 1873 in the household-based arm) were referred by 2501 index participants. A higher proportion of contacts in the incentive-based than household-based arm were adults (72% vs 59%), reported chronic TB symptoms (25% vs 16%) or ever smoking (23% vs 11%). Index participants who walked or bicycled to a clinic referred 1.03 more contacts per index (95% confidence interval [CI],.48 to 1.57) through incentive-based than household-based investigation. Index participants living with >5 household members referred 0.48 more contacts per index (95% CI,.03 to.94) through household-based than incentive-based investigation. Conclusions Relative to household-based investigation, incentive-based investigation identifies contacts likely at higher risk for active TB. Incentive-based investigation may be more appropriate for index participants who can easily access clinics, versus household-based investigation for patients with large households. Clinical Trials Registration. NCT02808507. [ABSTRACT FROM AUTHOR]

Background: Many individuals at risk for HIV may be reached through active TB case finding interventions in areas with highly prevalent co-epidemics of TB/HIV. Methods: We analyzed data from a cluster-randomized trial of 2 TB case finding strategies: facility-based screening and contact investigation of newly identified TB cases. In both arms, on-site rapid HIV testing was offered to all contacts older than 18 months who did not self-report HIV-positive status. Those who were HIV infected were referred appropriately. All contacts 15 years and older were included in this analysis. Results: Among 2179 contacts identified, 50% (1092) accepted HIV testing and counselling, of whom 6.3% (68) tested HIV-positive. Contacts who were unemployed [adjusted prevalence ratio (aPR) 1.14, 95% confidence interval (CI): 1.04 to 1.25], had not been to a clinic (aPR 1.09, 95% CI: 1.02 to 1.18) or HIV tested (aPR 1.25, 95% CI: 1.14 to 1.39) 6 months before, and those reporting gastrointestinal symptoms (aPR 1.22, 95% CI: 0.98 to 1.52) and genitourinary symptoms (aPR 1.30, 95% CI: 1.17 to 1.45) were significantly associated with accepting HIV testing. Women [adjusted odds ratio (aOR) 2.19, 95% CI: 1.26 to 3.81], individuals with a past history of tuberculosis (aOR 1.96, 95% CI: 0.93 to 4.14), and those not HIV tested 6 months before (aOR 2.20, 95% CI: 1.28 to 3.79) were significantly associated with testing HIV-positive. Conclusion: Offering HIV testing in the context of active tuberculosis case finding represents an opportunity to identify a large proportion of previously undiagnosed individuals with HIV in a population that might otherwise not seek testing. [ABSTRACT FROM AUTHOR]

Background: The neonatal mortality rate (NMR) in Malawi has remained stagnant at around 27 per 1000 live births over the last 15 years, despite an increase in the uptake of targeted health care interventions. We used the nationally representative 2015/16 Demographic Health Survey data set to evaluate the effect of two types of maternal exposures, namely, lack of access to maternal or intra-partum care services and birth history factors, on the risk of neonatal mortality.Methods: A causal inference approach was used to estimate a population attributable risk parameter for each exposure, adjusting for co-exposures and household, maternal and child-specific covariates. The maternal exposures evaluated were unmet family planning needs, less than 4+ antenatal care visits, lack of institutional delivery or skilled birth attendance, having prior neonatal mortality, short (8-24 months) birth interval preceding the index birth, first pregnancy, and two or more pregnancy outcomes within the preceding five years of the survey interview.Results: We included 9553 women and their most recent live birth within 3 years of the survey. The sample's overall neonatal mortality rate was 18.5 per 1000 live births. The adjusted population attributable risk for first pregnancies was 3.9/1000 (P < 0.001), while non-institutional deliveries and the shortest preceding birth interval (8-24 months) each had an attributable risk of 1.3/1000 (Ps = 0.01). Having 2 or more pregnancy outcomes within the last 5 years had an attributable risk of 3/1000 (P = 0.006). Attending less than 4 ANC visits had, a relatively large attributable risk (2.1/1,000), and it was not statistically significant at alpha level 0.05.Conclusions: Our analysis addresses the gap in the literature on evaluating the effect of these exposures on neonatal mortality in Malawi. It also helps inform programs and current efforts such as the Every Newborn Action 2020 Plan. Increasing access to maternal care interventions has an important role to play in changing the trajectory of neonatal mortality, and women who are at an increased risk may not be receiving adequate care. Recent studies indicate an urgent need to assess gaps in service readiness and quality of care at the antenatal and obstetric care facilities. [ABSTRACT FROM AUTHOR]

Background: We conducted a social and verbal autopsy study to determine cultural-, social- and health system-related factors that were associated with the delay in formal care seeking in Sylhet district, Bangladesh.Methods: Verbal and social autopsy interviews were conducted with mothers who experienced a neonatal death between October 2007 and May 2011. We fitted a semi-parametric regression model of the cumulative incidence of seeking formal care first, accounting for competing events of death or seeking informal care first.Results: Three hundred and thirty-one neonatal deaths were included in the analysis and of these, 91(27.5%) sought formal care first; 26 (7.9%) sought informal care first; 59 (17.8%) sought informal care only, and 155 (46.8%) did not seek any type of care. There was lower cumulative incidence of seeking formal care first for preterm neonates (sub-hazard ratio SHR 0.61, P = 0.025), and those who delivered at home (SHR 0.52, P = 0.010); and higher cumulative incidence for those who reported less than normal activity (SHR 1.95, P = 0.048). The main barriers to seeking formal care reported by 165 mothers included cost (n = 98, 59.4%), believing the neonate was going to die anyway (n = 29, 17.7%), and believing traditional care was more appropriate (n = 26, 15.8%).Conclusions: The majority of neonates died before formal care could be sought, but formal care was more likely to be sought than informal care. There were economic and social belief barriers to care-seeking. There is a need for programs that educate caregivers about well-recognized danger signs requiring timely care-seeking, particularly for preterm neonates and those who deliver at home. [ABSTRACT FROM AUTHOR]

Community-based maternal and newborn care interventions have been shown to improve neonatal survival and other key health indicators. It is important to evaluate whether the improvement in health indicators is accompanied by a parallel increase in the equitable distribution of the intervention activities, and the uptake of healthy newborn care practices. We present an analysis of equity improvements after the implementation of a Community Based Newborn Care Package (CB-NCP) in the Bardiya district of Nepal. The package was implemented alongside other programs that were already in place within the district. We present changes in concentration indices (CIndices) as measures of changes in equity, as well as percentage changes in coverage, between baseline and endline. The CIndices were derived from wealth scores that were based on household assets, and they were compared usingt-tests. We observed statistically significant improvements in equity for facility delivery [CIndex: -0.15 (-0.24, -0.06)], knowledge of at least three newborn danger signs [-0.026(-0.06, -0.003)], breastfeeding within 1 h [-0.05(-0.11, -0.0001)], at least one antenatal visit with a skilled provider [-0.25(-0.04, -0.01)], at least four antenatal visits from any provider [-0.15(-0.19, -0.10)] and birth preparedness [-0.09(-0.12, -0.06)]. The largest increases in practices were observed for facility delivery (50%), immediate drying (34%) and delayed bathing (29%). These results and those of similar studies are evidence that community-based interventions delivered by female community health volunteers can be instrumental in improving equity in levels of facility delivery and other newborn care behaviours. We recommend that equity be evaluated in other similar settings within Nepal in order to determine if similar results are observed. [ABSTRACT FROM AUTHOR]

Background: The term vitamin E describes a family of 8 vitamers, 1 of which is α-tocopherol, that is essential for human health. Vitamin E status remains largely unknown in low-income countries because of the complexity and cost of measurement. Quantitative proteomics may offer an approach for identifying plasma proteins for assessing vitamin E status in these populations.Objective: To improve options for vitamin E status assessment, we sought to detect and quantify a set of plasma proteins associated with α- and γ-tocopherol concentrations in a cohort of 500 rural Nepalese children aged 6-8 y and, based on nutrient-protein associations, to predict the prevalence of vitamin E deficiency (α-tocopherol <12 μmol/L).Methods: Study children were born to mothers enrolled in an earlier antenatal micronutrient trial in Sarlahi District, Nepal. Plasma α- and γ-tocopherol concentrations were measured by high-performance liquid chromatography. Plasma aliquots were depleted of 6 high-abundance proteins, digested with trypsin, labeled with isobaric mass tags, and assessed for relative protein abundance by tandem mass spectrometry. Linear mixed-effects models were used to evaluate the association between α-tocopherol status and relative protein abundance and to predict deficiency.Results: We quantified 982 plasma proteins in >10% of all child samples, of which 119 correlated with α-tocopherol (false discovery rate, q < 0.10). Proteins were primarily involved in lipid transport, coagulation, repair, innate host defenses, neural function, and homeostasis. Six proteins [apolipoprotein (apo)C-III; apoB; pyruvate kinase, muscle; forkhead box 04; unc5 homolog C; and regulator of G-protein signaling 8] explained 71% of the variability in plasma α-tocopherol, predicting an in-sample population prevalence of vitamin E deficiency of 51.4% (95% CI: 46.4%, 56.3%) compared with a measured prevalence of 54.8%. Plasma γ-tocopherol was associated with 12 proteins (q < 0.10), 2 of which (apoC-III and Misato 1) explained 20% of its variability.Conclusions: In this undernourished population of children in South Asia, quantitative proteomics identified a large plasma α-tocopherome from which 6 proteins predicted the prevalence of vitamin E deficiency. The findings illustrate that protein biomarkers, once absolutely quantified, can potentially predict micronutrient deficiencies in populations. The maternal micronutrient supplementation trial from which data were derived as a follow-up activity was registered with clinicaltrials.gov as NCT00115271. [ABSTRACT FROM AUTHOR]

Objectives: The incidence of intestinal failure–associated liver disease (IFALD) varies following intestinal surgical intervention in infants, ranging from 25% to 60%. Although IFALD resolves in some infants, 40% of infants who require long-term parenteral nutrition (PN) progress to liver failure. The purpose of this study was to investigate the incidence of IFALD at our center among infants requiring intestinal procedures and to assess postoperative feeding practices. Methods: We performed a retrospective review of infants with intestinal surgical procedures before 6 months of age from 2007 to 2012. Infants with preexisting liver disease, other than IFALD, were excluded. The primary outcome was incidence of IFALD during the initial hospitalization. Timing of IFALD development and median time to reach enteral nutrition goals were investigated. Results: The overall incidence of IFALD was 66% (54/82), and among infants requiring >60 days of PN, the incidence was 90% (27/30). Median direct bilirubin of those with IFALD was 7.5 mg/dL. Infants with IFALD were more likely to be premature (29 vs 38 weeks, P < .001), have necrotizing enterocolitis (54% vs 17%, P = .002), and have culture-positive infection (42% vs 7%, P = .001). Among the most recent 24 infants, the median time to introduce enteral nutrition postoperatively was 19 days (interquartile range = 9-27), and the median time to reach 50% of calories from enteral nutrition was 34 days (interquartile range = 23-50). Conclusions: The risk of IFALD is common at our center. Multidisciplinary preventive and therapeutic strategies need to be investigated. Future investigation will focus on the time to reach enteral nutrition goals as a modifiable risk factor. [ABSTRACT FROM PUBLISHER]

Background Inequities in both health status and coverage of health services are considered important barriers to achieving Millennium Development Goal 4. Community-based health promotion is a strategy that is believed to reduce inequities in rural low-income settings. This paper examines the contributions of community-based programming to improving the equity of newborn health in three districts in Malawi. Methods This study is a before-and-after evaluation of Malawi's Community-Based Maternal and Newborn Care (CBMNC) program, a package of facility and community-based interventions to improve newborn health. Health Surveillance Assistants (HSAs) within the catchment area of 14 health facilities were trained to make pregnancy and postnatal home visits to promote healthy behaviors and assess women and newborns for danger signs requiring referral to a facility. "Core groups" of community volunteers were also trained to raise awareness about recommended newborn care practices. Baseline and endline household surveys measured the coverage of the intervention and targeted health behaviors for this before-and-after evaluation. Wealth indices were constructed using household asset data and concentration indices were compared between baseline and endline for each indicator. Results The HSAs trained in the intervention reached 36.7% of women with a pregnancy home visit and 10.9% of women with a postnatal home visit within three days of delivery. Coverage of the intervention was slightly inequitable, with richer households more likely to receive one or two pregnancy home visits (concentration indices (CI) of 0.0786 and 0.0960), but not significantly more likely to receive a postnatal visit or know of a core group. Despite modest coverage levels for the intervention, health equity improved significantly over the study period for several indicators. Greater improvements in inequities were observed for knowledge indicators than for coverage of routine health services. At endline, a greater proportion of women from the poorest quintile knew three or more danger signs for pregnancy, delivery, and postpartum mothers than did women from the least poor quintile (change in CI: -0.1704, -0.2464, and -0.4166, respectively; p < 0.05). Equity also significantly improved for coverage of some health behaviors, including delivery at a health facility (change in CI: -0.0591), breastfeeding within the first hour (-0.0379), and delayed bathing (-0.0405). Conclusions Although these results indicate promising improvements for newborn health in Malawi, the extent to which the CBMNC program contributed to these improvements in coverage and equity are not known. The strategies through which community-based programs are implemented likely play an important role in their ability to improve equity, and further research and program monitoring are needed to ensure that the poorest households are reached by community-based health programs. [ABSTRACT FROM AUTHOR]

Background: Pneumococcal pneumonia causes significant morbidity and mortality among adults. Given limitations of diagnostic tests for non-bacteremic pneumococcal pneumonia, most studies report the incidence of bacteremic or invasive pneumococcal disease (IPD), and thus, grossly underestimate the pneumococcal pneumonia burden. We aimed to develop a conceptual and quantitative strategy to estimate the non-bacteremic disease burden among adults with community-acquired pneumonia (CAP) using systematic study methods and the availability of a urine antigen assay. Methods and Findings: We performed a systematic literature review of studies providing information on the relative yield of various diagnostic assays (BinaxNOW® S. pneumoniae urine antigen test (UAT) with blood and/or sputum culture) in diagnosing pneumococcal pneumonia. We estimated the proportion of pneumococcal pneumonia that is bacteremic, the proportion of CAP attributable to pneumococcus, and the additional contribution of the Binax UAT beyond conventional diagnostic techniques, using random effects meta-analytic methods and bootstrapping. We included 35 studies in the analysis, predominantly from developed countries. The estimated proportion of pneumococcal pneumonia that is bacteremic was 24.8% (95% CI: 21.3%, 28.9%). The estimated proportion of CAP attributable to pneumococcus was 27.3% (95% CI: 23.9%, 31.1%). The Binax UAT diagnosed an additional 11.4% (95% CI: 9.6, 13.6%) of CAP beyond conventional techniques. We were limited by the fact that not all patients underwent all diagnostic tests and by the sensitivity and specificity of the diagnostic tests themselves. We address these resulting biases and provide a range of plausible values in order to estimate the burden of pneumococcal pneumonia among adults. Conclusions: Estimating the adult burden of pneumococcal disease from bacteremic pneumococcal pneumonia data alone significantly underestimates the true burden of disease in adults. For every case of bacteremic pneumococcal pneumonia, we estimate that there are at least 3 additional cases of non-bacteremic pneumococcal pneumonia. [ABSTRACT FROM AUTHOR]