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Abstract Background Indirect treatment comparison (ITC) and mixed treatment comparisons (MTC) have been increasingly used in network meta-analyses. This simulation study comprehensively investigated statistical properties and performances of commonly used ITC and MTC methods, including simple ITC (the Bucher method), frequentist and Bayesian MTC methods. Methods A simple network of three sets of two-arm trials with a closed loop was simulated. Different simulation scenarios were based on different number of trials, assumed treatment effects, extent of heterogeneity, bias and inconsistency. The performance of the ITC and MTC methods was measured by the type I error, statistical power, observed bias and mean squared error (MSE). Results When there are no biases in primary studies, all ITC and MTC methods investigated are on average unbiased. Depending on the extent and direction of biases in different sets of studies, ITC and MTC methods may be more or less biased than direct treatment comparisons (DTC). Of the methods investigated, the simple ITC method has the largest mean squared error (MSE). The DTC is superior to the ITC in terms of statistical power and MSE. Under the simulated circumstances in which there are no systematic biases and inconsistencies, the performances of MTC methods are generally better than the performance of the corresponding DTC methods. For inconsistency detection in network meta-analysis, the methods evaluated are on average unbiased. The statistical power of commonly used methods for detecting inconsistency is very low. Conclusions The available methods for indirect and mixed treatment comparisons have different advantages and limitations, depending on whether data analysed satisfies underlying assumptions. To choose the most valid statistical methods for research synthesis, an appropriate assessment of primary studies included in evidence network is required.

Abstract Background Task-shifting is promoted widely as a mechanism for expanding antiretroviral treatment (ART) access. However, the evidence for nurse-initiated and managed ART (NIMART) in Africa is limited, and little is known about the key barriers and enablers to implementing NIMART programmes on a large scale. The STRETCH (Streamlining Tasks and Roles to Expand Treatment and Care for HIV) programme was a complex educational and organisational intervention implemented in the Free State Province of South Africa to enable nurses providing primary HIV/AIDS care to expand their roles and include aspects of care and treatment usually provided by physicians. STRETCH used a phased implementation approach and ART treatment guidelines tailored specifically to nurses. The effects of STRETCH on pre-ART mortality, ART provision, and the quality of HIV/ART care were evaluated through a randomised controlled trial. This study was conducted alongside the trial to develop a contextualised understanding of factors affecting the implementation of the programme. Methods This study was a qualitative process evaluation using in-depth interviews and focus group discussions with patients, health workers, health managers, and other key informants as well as observation in clinics. Research questions focused on perceptions of STRETCH, changes in health provider roles, attitudes and patient relationships, and impact of the implementation context on trial outcomes. Data were analysed collaboratively by the research team using thematic analysis. Results NIMART appears to be highly acceptable among nurses, patients, and physicians. Managers and nurses expressed confidence in their ability to deliver ART successfully. This confidence developed slowly and unevenly, through a phased and well-supported approach that guided nurses through training, re-prescription, and initiation. The research also shows that NIMART changes the working and referral relationships between health staff, demands significant training and support, and faces workload and capacity constraints, and logistical and infrastructural challenges. Conclusions Large-scale NIMART appears to be feasible and acceptable in the primary level public sector health services in South Africa. Successful implementation requires a comprehensive approach with: an incremental and well supported approach to implementation; clinical guidelines tailored to nurses; and significant health services reorganisation to accommodate the knock-on effects of shifts in practice. Trial registration ISRCTN46836853

Abstract Background Manual chest physiotherapy (MCP) techniques involving chest percussion, vibration, and shaking have long been used in the treatment of respiratory conditions. However, methodological limitations in existing research have led to a state of clinical equipoise with respect to this treatment. Thus, for patients hospitalised with an exacerbation of Chronic Obstructive Pulmonary Disease (COPD), clinical preference tends to dictate whether MCP is given to assist with sputum clearance. We standardised the delivery of MCP and assessed its effectiveness on disease-specific quality of life. Methods In this randomised, controlled trial powered for equivalence, 526 patients hospitalised with acute COPD exacerbation were enrolled from four centres in the UK. Patients were allocated to receive MCP plus advice on airway clearance or advice on chest clearance alone. The primary outcome was a COPD specific quality of life measure, the Saint Georges Respiratory Questionnaire (SGRQ) at six months post randomisation. Analyses were by intention to treat (ITT). This study was registered, ISRCTN13825248. Results All patients were included in the analyses, of which 372 (71%) provided evaluable data for the primary outcome. An effect size of 0·3 standard deviations in SGRQ score was specified as the threshold for superiority. The ITT analyses showed no significant difference in SGRQ for patients who did, or did not receive MCP (95% CI −0·14 to 0·19). Conclusions These data do not lend support to the routine use of MCP in the management of acute exacerbation of COPD. However, this does not mean that MCP is of no therapeutic value to COPD patients in specific circumstances.

Abstract Background Task shifting and the integration of human immunodeficiency virus (HIV) care into primary care services have been identified as possible strategies for improving access to antiretroviral treatment (ART). This paper describes the development and content of an intervention involving these two strategies, as part of the Streamlining Tasks and Roles to Expand Treatment and Care for HIV (STRETCH) pragmatic randomised controlled trial. Methods: Developing the intervention The intervention was developed following discussions with senior management, clinicians, and clinic staff. These discussions revealed that the establishment of separate antiretroviral treatment services for HIV had resulted in problems in accessing care due to the large number of patients at ART clinics. The intervention developed therefore combined the shifting from doctors to nurses of prescriptions of antiretrovirals (ARVs) for uncomplicated patients and the stepwise integration of HIV care into primary care services. Results: Components of the intervention The intervention consisted of regulatory changes, training, and guidelines to support nurse ART prescription, local management teams, an implementation toolkit, and a flexible, phased introduction. Nurse supervisors were equipped to train intervention clinic nurses in ART prescription using outreach education and an integrated primary care guideline. Management teams were set up and a STRETCH coordinator was appointed to oversee the implementation process. Discussion Three important processes were used in developing and implementing this intervention: active participation of clinic staff and local and provincial management, educational outreach to train nurses in intervention sites, and an external facilitator to support all stages of the intervention rollout. The STRETCH trial is registered with Current Control Trials ISRCTN46836853.

Abstract Background Stroke is the third leading cause of death in developed countries and the leading cause of long-term disability worldwide. A series of national stroke audits in the UK highlighted the differences in stroke care between hospitals. The study aims to describe variation in outcomes following stroke and to identify the characteristics of services that are associated with better outcomes, after accounting for case mix differences and individual prognostic factors. Methods/Design We will conduct a cohort study in eight acute NHS trusts within East of England, with at least one year of follow-up after stroke. The study population will be a systematically selected representative sample of patients admitted with stroke during the study period, recruited within each hospital. We will collect individual patient data on prognostic characteristics, health care received, outcomes and costs of care and we will also record relevant characteristics of each provider organisation. The determinants of one year outcome including patient reported outcome will be assessed statistically with proportional hazards regression models. Self (or proxy) completed EuroQol (EQ-5D) questionnaires will measure quality of life at baseline and follow-up for cost utility analyses. Discussion This study will provide observational data about health service factors associated with variations in patient outcomes and health care costs following hospital admission for acute stroke. This will form the basis for future RCTs by identifying promising health service interventions, assessing the feasibility of recruiting and following up trial patients, and provide evidence about frequency and variances in outcomes, and intra-cluster correlation of outcomes, for sample size calculations. The results will inform clinicians, public, service providers, commissioners and policy makers to drive further improvement in health services which will bring direct benefit to the patients.

Abstract Background Children aged under five years with severe acute malnutrition (SAM) in Africa and Asia have high mortality rates without effective treatment. Primary care-based treatment of SAM can have good outcomes but its cost effectiveness is largely unknown. Method This study estimated the cost effectiveness of community-based therapeutic care (CTC) for children with severe acute malnutrition in government primary health care centres in Lusaka, Zambia, compared to no care. A decision tree model compared the costs (in year 2008 international dollars) and outcomes of CTC to a hypothetical 'do-nothing' alternative. The primary outcomes were mortality within one year, and disability adjusted life years (DALYs) after surviving one year. Outcomes and health service costs of CTC were obtained from the CTC programme, local health services and World Health Organization (WHO) estimates of unit costs. Outcomes of doing nothing were estimated from published African cohort studies. Probabilistic and deterministic sensitivity analyses were done. Results The mean cost of CTC per child was $203 (95% confidence interval (CI) $139–$274), of which ready to use therapeutic food (RUTF) cost 36%, health centre visits cost 13%, hospital admissions cost 17% and technical support while establishing the programme cost 34%. Expected death rates within one year of presentation were 9.2% with CTC and 20.8% with no treatment (risk difference 11.5% (95% CI 0.4–23.0%). CTC cost $1760 (95% CI $592–$10142) per life saved and $ 53 (95% CI $18–$306) per DALY gained. CTC was at least 80% likely to be cost effective if society was willing to pay at least $88 per DALY gained. Analyses were most sensitive to assumptions about mortality rates with no treatment, weeks of CTC per child and costs of purchasing RUTF. Conclusion CTC is relatively cost effective compared to other priority health care interventions in developing countries, for a wide range of assumptions.

Abstract Background A major barrier to accessing free government-provided antiretroviral treatment (ART) in South Africa is the shortage of suitably skilled health professionals. Current South African guidelines recommend that only doctors should prescribe ART, even though most primary care is provided by nurses. We have developed an effective method of educational outreach to primary care nurses in South Africa. Evidence is needed as to whether primary care nurses, with suitable training and managerial support, can initiate and continue to prescribe and monitor ART in the majority of ART-eligible adults. Methods/design This is a protocol for a pragmatic cluster randomised trial to evaluate the effectiveness of a complex intervention based on and supporting nurse-led antiretroviral treatment (ART) for South African patients with HIV/AIDS, compared to current practice in which doctors are responsible for initiating ART and continuing prescribing. We will randomly allocate 31 primary care clinics in the Free State province to nurse-led or doctor-led ART. Two groups of patients aged 16 years and over will be included: a) 7400 registering with the programme with CD4 counts of ≤ 350 cells/mL (mainly to evaluate treatment initiation) and b) 4900 already receiving ART (to evaluate ongoing treatment and monitoring). The primary outcomes will be time to death (in the first group) and viral suppression (in the second group). Patients' survival, viral load and health status indicators will be measured at least 6-monthly for at least one year and up to 2 years, using an existing province-wide clinical database linked to the national death register. Trial registration Controlled Clinical Trials ISRCTN46836853

Abstract Background Health Related Quality of Life (HRQoL) is an important outcome in times of Highly Active Antiretroviral Treatment (HAART). We compared the HRQoL of HIV positive patients receiving HAART with those awaiting treatment in public sector facilities in the Free State province in South Africa. Methods A stratified random sample of 371 patients receiving or awaiting HAART were interviewed and the EuroQol-profile, EuroQol-index and Visual Analogue Scale (VAS) were compared. Independent associations between these outcomes and HAART, socio-demographic, clinical and health service variables were estimated using linear and ordinal logistic regression, adjusted for intra-clinic clustering of outcomes. Results Patients receiving HAART reported better HRQoL for 3 of the 5 EuroQol-dimensions, for the VAS score and for the EuroQol index in bivariable analysis. They had a higher mean EuroQol index (0.11 difference, 95% confidence interval [CI] 0.04; 0.23), and were more likely to have a higher index (odds ratio 1.9, 95% CI 1.1; 1.3), compared to those awaiting HAART, in multivariate analysis. Higher mean VAS scores were reported for patients who were receiving HAART (6.5 difference, 95% CI 1.3; 11.7), were employed (9.1, 95% CI 4.3; 13.7) or were female (4.7, 95% CI 0.79; 8.5). Conclusion HAART was associated with improved HRQoL in patients enrolled in a public sector treatment program in South Africa. Our finding that the EuroQol instrument was sensitive to HAART supports its use in future evaluation of HIV/AIDS care in South Africa. Longitudinal studies are needed to evaluate changes in individuals' HRQoL.

Abstract Background Measurement of individuals' costs and outcomes in randomized trials allows uncertainty about cost effectiveness to be quantified. Uncertainty is expressed as probabilities that an intervention is cost effective, and confidence intervals of incremental cost effectiveness ratios. Randomizing clusters instead of individuals tends to increase uncertainty but such data are often analysed incorrectly in published studies. Methods We used data from a cluster randomized trial to demonstrate five appropriate analytic methods: 1) joint modeling of costs and effects with two-stage non-parametric bootstrap sampling of clusters then individuals, 2) joint modeling of costs and effects with Bayesian hierarchical models and 3) linear regression of net benefits at different willingness to pay levels using a) least squares regression with Huber-White robust adjustment of errors, b) a least squares hierarchical model and c) a Bayesian hierarchical model. Results All five methods produced similar results, with greater uncertainty than if cluster randomization was not accounted for. Conclusion Cost effectiveness analyses alongside cluster randomized trials need to account for study design. Several theoretically coherent methods can be implemented with common statistical software.

Abstract Background To evaluate the diagnostic accuracy of the integrated Practical Approach to Lung Health in South Africa (PALSA) guideline in identifying patients requiring bacteriological screening for tuberculosis (TB), and to determine which clinical features best predict suspected and bacteriologically-confirmed tuberculosis among patients with respiratory symptoms. Methods A prospective, cross-sectional study in which 1392 adult patients with cough and/or difficult breathing, attending a primary care facility in Cape Town, South Africa, were evaluated by a nurse using the guideline. The accuracy of a nurse using the guideline to identify TB suspects was compared to that of primary care physicians' diagnoses of (1) suspected TB, and (2) proven TB supported by clinical information and chest radiographs. Results The nurse using the guideline identified 516 patients as TB suspects compared with 365 by the primary care physicians, representing a sensitivity of 76% (95% confidence interval (CI) 71%–79%), specificity of 77% (95% CI 74%–79%), positive predictive value of 53% (95% CI 49%–58%), negative predictive value of 90% (95% CI 88%–92%), and area under the receiver operating characteristic curve (ARUC) of 0.76 (95% CI 0.74–0.79). Sputum results were obtained in 320 of the 365 primary care physicians TB suspects (88%); 40 (13%) of these were positive for TB. Only 4 cases were not identified by the nurse using the guideline. The primary care physicians diagnostic accuracy in diagnosing bacteriologically-confirmed TB (n = 320) was as follows: sensitivity 90% (95% CI 76%–97%), specificity 65% (95% CI 63%–68%), negative predictive value 7% (95% CI 5%–10%), positive predictive value 99.5% (95% CI 98.8%–99.8%), and ARUC 0.78 (95% CI 0.73–0.82). Weight loss, pleuritic pain, and night sweats were independently associated with the diagnosis of bacteriologically-confirmed tuberculosis (positive likelihood ratio if all three present = 16.7, 95% CI 5.9–29.4). Conclusion The PALSA guideline is an effective screening tool for identifying patients requiring bacteriological screening for pulmonary tuberculosis in this primary care setting. This supports the randomized trial finding that use of the guideline increased TB case detection.

Abstract Background South African households are severely affected by human immunodeficiency virus / acquired immunodeficiency syndrome (HIV/AIDS) but health and economic impacts have not been quantified in controlled cohort studies. Methods We compared households with an HIV-infected member, and unaffected neighbouring households, in one rural and one urban area in Free State province, South Africa. Interviews were conducted with one key informant in each household, at baseline and six months later. We studied 1913 members of 404 households, with 94% and 96% follow up, respectively. Household and individual level analyses were done. Results Members of affected households, compared to members of unaffected households, were independently more likely to be continuously ill (adjusted odds ratio (OR) 2.1, 95% CI 1.3–3.4 at follow up), and to die (adjusted OR 3.4, 95% CI 1.0–11), mainly due to infectious diseases. Government clinics and hospitals were the main sources of health care. Affected households were poorer than unaffected households at baseline (relative income per person 0.61, 95% CI 0.49–0.76). Over six months expenditure and income decreased more rapidly in affected than in unaffected households (baseline-adjusted relative expenditure 0.86, 95% CI 0.75–0.99 and income 0.89, 95% CI 0.75–1.05). Baseline morbidity was independently associated with lower income and expenditure at baseline but not with changes over six months. Conclusions HIV/AIDS affects the health and wealth of households as well as infected individuals, aggravating pre-existing poverty.