Robust analysis of stepped wedge trials using cluster-level summaries within periods.

In stepped-wedge trials (SWTs), the intervention is rolled out in a random order over more than 1 time-period. SWTs are often analysed using mixed-effects models that require strong assumptions and may be inappropriate when the number of clusters is small. We propose a non-parametric within-period method to analyse SWTs. This method estimates the intervention effect by comparing intervention and control conditions in a given period using cluster-level data corresponding to exposure. The within-period intervention effects are combined with an inverse-variance-weighted average, and permutation tests are used. We present an example and, using simulated data, compared the method to (1) a parametric cluster-level within-period method, (2) the most commonly used mixed-effects model, and (3) a more flexible mixed-effects model. We simulated scenarios where period effects were common to all clusters, and when they varied according to a distribution informed by routinely collected health data. The non-parametric within-period method provided unbiased intervention effect estimates with correct confidence-interval coverage for all scenarios. The parametric within-period method produced confidence intervals with low coverage for most scenarios. The mixed-effects models' confidence intervals had low coverage when period effects varied between clusters but had greater power than the non-parametric within-period method when period effects were common to all clusters. The non-parametric within-period method is a robust method for analysing SWT. The method could be used by trial statisticians who want to emphasise that the SWT is a randomised trial, in the common position of being uncertain about whether data will meet the assumptions necessary for mixed-effect models.

Secondary analysis of tuberculosis stigma data from a cluster randomised trial in Zambia and South Africa (ZAMSTAR).

SETTING: Zambian and South African TB and HIV Reduction (ZAMSTAR) cluster-randomised trial (CRT) communities, 2006-2009. OBJECTIVES: To develop TB stigma items, and evaluate changes in them in response to a household intervention aimed at reducing TB transmission and prevalence but not tailored to reduce stigma. DESIGN: TB stigma was measured at baseline and 18 months later among 1826 recently diagnosed TB patients and 1235 adult members of their households across 24 communities; 12 of 24 communities were randomised to receive the household intervention. We estimated the impact of the household intervention on TB stigma using standard CRT analytical methods. RESULTS: Among household members, prevalence of blame and belief in transmission myths fell in both study arms over time: adjusted prevalence ratios (aPRs) comparing the household intervention with the non-household intervention arm were respectively 0.61 (95%CI 0.26-1.44) and 0.77 (95%CI 0.48-1.25) at 18-month follow-up. Among TB patients, at baseline a low percentage experienced social exclusion and poor treatment by health staff and a relatively high percentage reported 'being made fun of', with little change over time. Disclosure of TB status increased over time in both study arms. Internalised stigma was less prevalent in the household arm at both baseline and follow-up, with an aPR of 0.85 (95%CI 0.41-1.76). Variability in stigma levels between countries and across communities was large. CONCLUSION: Robust TB stigma items were developed. TB stigma was not significantly reduced by the household intervention, although confidence intervals for estimated intervention effects were wide. We suggest that stigma-specific interventions are required to effectively address TB stigma.

Overlapping HIV and sex-work stigma among female sex workers recruited to 14 respondent-driven sampling surveys across Zimbabwe, 2013.

HIV stigma can inhibit uptake of HIV testing and antiretroviral therapy as well as negatively affect mental health. Efforts to reduce discrimination against people living with HIV (LWH) have contributed to greater acceptance of the infection. Female sex workers (FSW) LWH may experience overlapping stigma due to both their work and HIV status, although this is poorly understood. We examined HIV and sex-work stigma experienced by FSW LWH in Zimbabwe. Using the SAPPH-IRe cluster-randomised trial baseline survey, we analysed the data from 1039 FSW self-reporting HIV. The women were recruited in 14 sites using respondent-driven sampling. We asked five questions to assess internalised and experienced stigma related to working as a sex worker, and the same questions were asked in reference to HIV. Among all FSW, 91% reported some form of sex-work stigma. This was not associated with sociodemographic or sex-work characteristics. Rates of sex-work stigma were higher than those of HIV-related stigma. For example, 38% reported being "talked badly about" for LWH compared with 77% for their involvement in sex work. Those who reported any sex-work stigma also reported experiencing more HIV stigma compared to those who did not report sex-work stigma, suggesting a layering effect. FSW in Zimbabwe experience stigma for their role as "immoral" women and this appears more prevalent than HIV stigma. As HIV stigma attenuates, other forms of social stigma associated with the disease may persist and continue to pose barriers to effective care.

Is the wealth index a proxy for consumption expenditure? A systematic review.

BACKGROUND: Many epidemiological studies require a measure of socioeconomic position. The monetary measure preferred by economists is consumption expenditure; the wealth index has been proposed as a reliable, simple alternative to expenditure and is extensively used. METHODS: A systematic review was conducted of the agreement between wealth indices and consumption expenditure, summarising the agreement and exploring factors affecting agreement. RESULTS: Seventeen studies using 36 datasets met the inclusion criteria. Of these, 22 demonstrated weak agreement, 10 moderate agreement, and four strong agreement. There was some evidence that agreement is higher: in middle-income settings; in urban areas; for wealth indices with a greater number of indicators; and for wealth indices including a wider range of indicators. CONCLUSIONS: The wealth index is mostly a poor proxy for consumption expenditure.

The association between school attendance, HIV infection and sexual behaviour among young people in rural South Africa.

OBJECTIVES: To investigate whether the prevalence of HIV infection among young people, and sexual behaviours associated with increased HIV risk, are differentially distributed between students and those not attending school or college. DESIGN: A random population sample of unmarried young people (916 males, 1003 females) aged 14-25 years from rural South Africa in 2001. METHODS: Data on school attendance and HIV risk characteristics came from structured face-to-face interviews. HIV serostatus was assessed by oral fluid ELISA. Logistic regression models specified HIV serostatus and high-risk behaviours as outcome variables. The primary exposure was school attendance. Models were adjusted for potential confounders. RESULTS: HIV knowledge, communication about sex and HIV testing were similarly distributed among students and non-students. The lifetime number of partners was lower for students of both sexes (adjusted odds ratio (aOR) for more than three partners for men 0.67; 95% CI 0.44 to 1.00; aOR for more than two partners for women 0.69; 95% CI 0.46 to 1.04). Among young women, fewer students reported having partners more than three years older than themselves (aOR 0.58; 95% CI 0.37 to 0.92), having sex more than five times with a partner (aOR 0.57; 95% CI 0.37 to 0.87) and unprotected intercourse during the past year (aOR 0.60; 95% CI 0.40 to 0.91). Male students were less likely to be HIV positive than non-students (aOR 0.21; 95% CI 0.06 to 0.71). CONCLUSIONS: Attending school was associated with lower-risk sexual behaviours and, among young men, lower HIV prevalence. Secondary school attendance may influence the structure of sexual networks and reduce HIV risk. Maximising school attendance may reduce HIV transmission among young people.

Adherence to TB preventive therapy for HIV-positive patients in rural South Africa: implications for antiretroviral delivery in resource-poor settings?

OBJECTIVES: To explore patient and health worker perspectives on adherence to tuberculosis preventive therapy (TBPT), and to derive lessons for improving access to care amongst human immunodeficiency virus (HIV) infected individuals in resource-poor settings. DESIGN: Both quantitative and qualitative methods were employed. Patient records were reviewed for HIV-positive individuals attending a hospital-based HIV clinic between January 2000 and March 2002. Eighteen patients and two health care workers underwent in-depth interviews exploring perspectives around adherence. RESULTS: Of 229 HIV-positive clinic attendees, 94 (41.0%) were eligible for TBPT. Of 87 patients initiating a 6-month TBPT course of isoniazid 300 mg daily, 41 (47.1%) completed TBPT. Of the 46 interrupters, 16 (34.7%) did not return to the clinic after receiving their first dose of TBPT. Barriers to adherence included fear of stigmatization, lack of money for food and transport, the belief that HIV is incurable, competition between Western and traditional medicine, and a reluctance to take medication in the absence of symptoms. Disclosure of HIV status, social and family support, and a supportive clinic environment positively influenced adherence. CONCLUSION: Interventions to improve the accessibility and quality of the care delivery system have the potential to support adherence to TBPT and other HIV care regimens, including antiretroviral therapy.

Production of leucinostatins and nematicidal activity of Australian isolates of Paecilomyces lilacinus (Thom) Samson.

AIMS: To evaluate the relationship between leucinostatin production by Paecilomyces lilacinus isolates and their biological activities. METHODS AND RESULTS: The nematicidal, parasitic and enzymatic activity of Australian P. lilacinus isolates were investigated. Nematicidal activities of culture filtrates were measured by mortality and inhibition of reproduction of Caenorhabditis elegans, whereas egg-parasitic activity was measured by colonization on Meloidogyne javanica. Enzymatic activities (protease and chitinase) were assayed on solid media. The results suggest that leucinostatins in P. lilacinus are indicators of nematicidal activity, whereas chitinase activity might be related to parasitism. CONCLUSIONS: Nematicidal activity of culture filtrates of Paecilomyces lilacinus strains related to their ability to produce leucinostatins. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study describing the leucinostatins as nematicides.

Undiagnosed pulmonary tuberculosis deaths in rural South Africa.

This research explores death from pulmonary tuberculosis (PTB) using a verbal autopsy (VA) tool within the established Agincourt Health and Demographic Surveillance System site in South Africa's rural northeast. Previous work on active case finding in the area highlighted a modest burden of undiagnosed PTB in the community. This VA research confirms the existence of undiagnosed PTB deaths, with 13 (46%) of 28 PTB deaths among the permanent adult population (n = 38,251) going undetected by the health service. There was a median duration of coughing in the community of 16 weeks among these undiagnosed PTB deaths. As most undiagnosed cases present to the health service at some point during their illness, intervention strategies to support early diagnosis at this level can only be re-emphasised by this work.

Introduction of voluntary counselling and rapid testing for HIV in rural South Africa: from theory to practice.

Expanding access to voluntary counselling and testing (VCT) for HIV is an important first step in the development of a comprehensive package of HIV services. This article describes the introduction of VCT among five primary health care (PHC) facilities in a rural South African setting, alongside a multidimensional impact assessment as part of a national pilot programme. A baseline review of services demonstrated low levels of VCT, which were predominantly hospital-based. Twenty health workers in five PHC facilities were trained to provide VCT using rapid-testing assays. The feasibility of VCT introduction and its overall acceptability to clients and providers were evaluated using clinic testing registers, semi-structured interviews with counsellors and mock client encounters. One year after its introduction, a major increase in the quantity of HIV testing, the proportion of clients who receive their results, and the proportion who present voluntarily was observed. The majority of those presenting were women, and 20-40 year olds predominated. There was a high level of acceptance among health workers, and the quality of VCT was rated very good in mock client encounters. This work demonstrates one effective model for improving access to VCT through existing primary health care services in a rural South African context.

Active case finding: understanding the burden of tuberculosis in rural South Africa.

SETTING: The Agincourt demographic and health surveillance site in South Africa's rural Northern Province. OBJECTIVES: To accurately assess the true burden of tuberculosis in a rural sub-district with a known high prevalence of human immunodeficiency virus. DESIGN: Data on hospital registrations of tuberculosis were combined with data from an ongoing demographic health and surveillance system to accurately describe the burden of tuberculosis in a well-defined community. Undiagnosed active cases of sputum-positive disease in the community were detected among chronic coughers identified by heads of household during a single-pass census interview. RESULTS: The incidence of hospitalised tuberculosis among the permanently resident population (n = 56 566) was 212/100,000 person-years during 1999. The average point prevalence of detected tuberculosis (all forms) among patients aged over 10 years was 133/100,000, and 81/100,000 for sputum-positive pulmonary disease. This compares with a point prevalence of 16/100,000 cases of sputum-positive disease detected through active case finding. CONCLUSION: For every nine cases of sputum positive pulmonary tuberculosis being treated at any one time, there are two cases of undiagnosed disease in the community. This study demonstrates a modest burden of undiagnosed tuberculosis among residents in a rural sub-district in South Africa.

Assessing health seeking behaviour among tuberculosis patients in rural South Africa.

SETTING: South Africa's rural Northern Province. OBJECTIVES: To examine patterns of health seeking behaviour among hospitalised tuberculosis patients. DESIGN: Information on personal characteristics, health seeking behaviour and delays to presentation and hospitalisation was collected from hospitalised TB patients. Analysis of rates was used to investigate factors associated with delay. RESULTS: Among 298 patients, median total delay to hospitalisation was 10 weeks, with patient delay contributing a greater proportion than service provider delay. Patients more often presented initially to public hospitals (41%) or clinics (31 %) than to spiritual/traditional healers (15%) or private GPs (13%). Total delay was shorter amongst those presenting to hospitals than those presenting to clinics (rate ratio 1.33, 95%CI 1.13-1.85), with a significantly smaller proportion of the total delay attributable to the health service provider (18% vs. 42%). Those exhibiting a conventional risk profile for TB (migrants, alcohol drinkers, history of TB) were diagnosed most quickly by health services, while women remained undiagnosed for longer. CONCLUSION: Considerable delay exists between symptom onset and treatment initiation among pulmonary tuberculosis patients. While a substantial delay was attributable to late patient presentation, an important, preventable period of infectiousness was caused by the failure of recognised clinical services to diagnose tuberculosis among symptomatic individuals.

Low molecular weight heparin for treatment of acute myocardial infarction (FAMI): Fragmin (dalteparin sodium) in acute myocardial infarction.

The benefit of using subcutaneous low molecular weight heparin for the treatment of acute myocardial infarction is not known. The aim of this study was to determine the efficacy of a low molecular weight heparin (dalteparin sodium) for the treatment of acute myocardial infarction in patients not treated with thrombolytic therapy. Twenty-nine cardiological centres from leading hospitals in India participated in this prospective, multicentre, double-blind, placebo-controlled study in two phases which included 1128 patients with acute myocardial infarction. In the acute phase (between day 1 and 3 of admission) all the patients received a weight-adjusted dose of subcutaneous dalteparin (120 IU/kg twice daily). In the second, double-blind phase of acute myocardial infarction, patients were randomised to receive a fixed dose of dalteparin (7,500 IU) or an identical placebo injection for 30 days. A composite primary endpoint of death, reinfarction, recurrence of angina and emergency revascularisation was used. All the 1128 patients with acute myocardial infarction were included in the trial. In the acute phase, the composite primary endpoint was observed in 58 (5.1%) patients. Of 1037 paients who were randomly assigned to receive a fixed dose of dalteparin (n=519) or placebo (n=518), the composite primary event rate was 6.7 percent and 7.0 percent, respectively (RR 0.97; 95% CI 0.62-1.52; p=0.90). To conclude, treatment with dalteparin administered subcutaneously in a weight-adjusted dose of 120 IU/kg twice daily resulted in a lower than expected mortality during the acute phase of myocardial infarction. A lower fixed once daily dose of 7,500 IU during the chronic phase did not confer additional protection.