John Walley

Clinical diagnosis of smear-negative pulmonary tuberculosis in low-income countries: the current evidence.

Sputum smear examination for acid-fast bacilli (AFB) can diagnose up to 50-60% of cases of pulmonary tuberculosis in well-equipped laboratories. In low-income countries, poor access to high-quality microscopy services contributes to even lower rates of AFB detection. Furthermore, in countries with high prevalence of both pulmonary tuberculosis and HIV infection, the detection rate is even lower owing to the paucibacillary nature of pulmonary tuberculosis in patients with HIV infection. In the absence of positive sputum smears for AFB, at primary care level, most cases of pulmonary tuberculosis are diagnosed on the basis of clinical and radiological indicators. This review aims to evaluate various criteria, algorithms, scoring systems, and clinical indicators used in low-income countries in the diagnosis of pulmonary tuberculosis in people with suspected tuberculosis but repeated negative sputum smears. Several algorithms and clinical scoring systems based on local epidemiology have been developed to predict smear-negative tuberculosis. Few of these have been validated within the local context. However, in areas where smear-negative tuberculosis poses a major public-health problem, these algorithms may be useful to national tuberculosis programmes by providing a starting point for development their own context-specific diagnostic guidelines.

Effectiveness of the direct observation component of DOTS for tuberculosis: a randomised controlled trial in Pakistan

BACKGROUND DOTS is the control strategy for tuberculosis promoted by WHO. Pakistan is currently developing its National Tuberculosis Programme, and requires guidance on types of direct observation of treatment appropriate for the local conditions. We did a randomised trial to assess the effectiveness of different packages for tuberculosis treatment under operational conditions in Pakistan. METHODS We enrolled 497 adults with new sputum-positive tuberculosis. 170 were assigned DOTS with direct observation of treatment by health workers; 165 were assigned DOTS with direct observation of treatment by family members; and 162 were assigned self-administered treatment. The trial was done at three sites that provide tuberculosis services strengthened according to WHO guidelines for the purposes of the research, with a standard daily short-course drugs regimen (2 months of isoniazid, rifampicin, pyrazinamide, and ethambutol, followed by 6 months of isoniazid and ethambutol). The main outcome measures were cure, and cure or treatment completion. Analysis was by intention to treat. FINDINGS Within the strengthened tuberculosis services, the health-worker DOTS, family-member DOTS, and self-administered treatment strategies gave very similar outcomes, with cure rates of 64%, 55%, and 62%, respectively, and cure or treatment-completed rates of 67%, 62%, and 65%, respectively. INTERPRETATION None of the three strategies tested was shown to be superior to the others, and direct observation of treatment did not give any additional improvement in cure rates. The effectiveness of direct observation of treatment remains unclear, and further operational research is needed.

Delayed consultation among pulmonary tuberculosis patients: a cross sectional study of 10 DOTS districts of Ethiopia.

BackgroundDelays seeking care increase transmission of pulmonary tuberculosis and hence the burden of tuberculosis, which remains high in developing countries. This study investigates patterns of health seeking behavior and determines risk factors for delayed patient consultation at public health facilities in 10 districts of Ethiopia.MethodsNew pulmonary TB patients ≥ 15 years old were recruited at 18 diagnostic centres. Patients were asked about their health care seeking behaviour and the time from onset of symptoms to first consultation at a public health facility. First consultation at a public health facility 30 days or longer after onset of symptoms was regarded as prolonged patient delay.ResultsInterviews were held with 924 pulmonary patients. Of these, 537 (58%) were smear positive and 387 (42%) were smear negative; 413 (45%) were female; 451 (49%) were rural residents; and the median age was 34 years. Prior to their first consultation at a public health facility, patients received treatment from a variety of informal sources: the Orthodox Church, where they were treated with holy water (24%); private practitioners (13%); rural drug vendors (7%); and traditional healers (3%). The overall median patient delay was 30 days (mean = 60 days). Fifty three percent [95% Confidence Intervals (CI) (50%, 56%)] of patients had delayed their first consultation for ≥ 30 days. Patient delay for women was 54%; 95% CI (54%, 58%) and men 51%; 95% CI (47%, 55%). The delay was higher for patients who used informal treatment (median 31 days) than those who did not (15 days). Prolonged patient delay (≥ 30 days) was significantly associated with both patient-related and treatment-related factors. Significant patient-related factors were smear positive pulmonary disease [Adjusted Odds Ratio (AOR) 1.4; 95% CI (1.1 to 1.9)], rural residence [AOR 1.4; 95% CI (1.1 to 1.9)], illiteracy [AOR 1.7; 95% CI (1.2 to 2.4)], and lack of awareness/misperceptions of causes of pulmonary TB. Significant informal treatment-related factors were prior treatment with holy water [AOR 3.5; 95% CI (2.4 to 5)], treatment by private practitioners [AOR 1.7; 95% CI (1.1 to 2.6)] and treatment by drug vendors [AOR 1.9; 95% CI (1.1 to 3.5)].ConclusionNearly half of pulmonary tuberculosis patients delayed seeking health care at a public health facility while getting treatment from informal sources. The involvement of religious institutions and private practitioners in early referral of patients with pulmonary symptoms and creating public awareness about tuberculosis could help reduce delays in starting modern treatment.

Direct observation of treatment for tuberculosis: a randomized controlled trial of community health workers versus family members

We implemented community‐based direct observation of treatment, short course (DOTS), including a randomized controlled trial of direct observation either by community health workers (CHWs) or family members, under operational conditions in a region of Swaziland. There was a high death rate of 15%, due to the high HIV rates in the region. There was no significant difference in the cure and completion rate between direct observation of treatment by CHWs and family members [2% difference (95% CI −3% to 7%), exact P = 0.52]. A before‐and‐after comparison of outcomes demonstrated that the cure and treatment completion rate improved from a baseline of 27–67% following implementation of community‐based DOTS. We conclude that community‐based tuberculosis DOTS can improve successful outcomes of treatment. However, direct observation can be undertaken effectively using either daily family or CHW supervision. The choice of treatment supporter should be based on access, patient preference and availability of CHW resource.

Ferritin levels and risk of type 2 diabetes mellitus: an updated systematic review and meta-analysis of prospective evidence.

Emerging evidence suggests that a strong link that exists between elevated baseline body iron stores and high risk of incident type 2 diabetes mellitus (T2DM) in general populations, but the precise magnitude of the associations remains uncertain.

Liver Aminotransferases and Risk of Incident Type 2 Diabetes: A Systematic Review and Meta-Analysis

We evaluated the associations of liver aminotransferases with risk of type 2 diabetes (T2D) in general populations by conducting a systematic review and meta-analysis of published prospective studies. Studies were identified in a literature search of PubMed, EMBASE, and Web of Science from 1950 through October 2012. Of the 2,729 studies reviewed, 17 studies involving 60,359 participants and 3,890 incident T2D events were included. All of the studies assessed associations between alanine aminotransferase (ALT) level and T2D, with heterogeneous findings (I(2) = 88%, 95% confidence interval (CI): 82, 92; P < 0.001). The pooled fully adjusted relative risk of T2D was 1.26 (95% CI: 1.14, 1.41) per 1-standard-deviation change in log baseline ALT level. This association became nonsignificant after trim-and-fill correction for publication bias. Nine studies evaluated associations between aspartate aminotransferase (AST) levels and T2D risk, with a corresponding relative risk of 1.02 (95% CI: 0.99, 1.04). The relative risk of T2D per 5-IU/L increase in ALT level was 1.16 (95% CI: 1.08, 1.25). Available data indicate moderate associations of ALT with risk of T2D events, which may be attributable to publication bias. There was no evidence for an increased risk of T2D with AST. Large prospective studies may still be needed to establish the magnitude and nature of these associations.

Barriers to TB care for rural-to-urban migrant TB patients in Shanghai: a qualitative study

Objective  To understand barriers to tuberculosis (TB) care among migrant TB patients in Shanghai after the introduction of the TB‐free treatment policy which has applied to migrants since 2003, and to provide policy recommendations to improve TB control in migrant populations in big cities.

Liver enzymes and risk of all-cause mortality in general populations: a systematic review and meta-analysis

BACKGROUND Gamma glutamyltransferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP), commonly used as markers of liver dysfunction, have been implicated with risk of all-cause mortality. The prospective evidence on the associations in general populations has not been reliably quantified. METHODS We conducted a systematic review and meta-analysis of published prospective cohort studies evaluating the associations of baseline levels of these enzymes with all-cause mortality in general populations. Relevant studies were identified in a literature search of MEDLINE, EMBASE and Web of Science up to March 2013. Authors of unpublished studies provided data on request. RESULTS Nineteen unique cohort studies with aggregate data on over 9.24 million participants and 242 953 all-cause mortality outcomes were included. In a comparison of extreme thirds of baseline GGT and ALP levels, relative risks (RRs) (95% confidence intervals) for all-cause mortality were 1.60 (1.42-1.80) and 1.38 (1.17-1.63), respectively. The corresponding RRs for ALT were 0.82 (0.78-0.86) and 1.43 (1.08-1.90) in North American and Asian populations, respectively. There was no strong evidence of an association of AST with all-cause mortality: RR 1.23 (0.80-1.88). The pooled RRs per 5 U/l increment in GGT and ALP levels were 1.07 (1.04-1.10) and 1.03 (1.01-1.06), respectively. CONCLUSIONS Available data indicate positive independent associations of baseline levels of GGT and ALP with all-cause mortality, consistent with linear dose-response relationships. There were geographical variations in the association of ALT with all-cause mortality which require further investigation. The potential incremental prognostic values of GGT and ALP in mortality risk assessment need evaluation.

Ferritin levels and risk of type 2 diabetes mellitus

Emerging evidence suggests that a strong link that exists between elevated baseline body iron stores and high risk of incident type 2 diabetes mellitus (T2DM) in general populations, but the precise magnitude of the associations remains uncertain.

How to get research into practice : first get practice into research

Discovering ways to increase access to and delivery of interventions is a major challenge. Typically research is divorced from implementation, which has led to a growing literature about how to get research into practice. However, operational research is best prioritized, designed, implemented and replicated from within national programmes. The current model for most international health service research is based on the assumption that the research community “discovers” solutions and then tries to market them to busy decision-makers and practitioners. The problem of failing to get research into policy and practice is well known. Much debate focuses on the effectiveness of different approaches to dissemination and behaviour change.1–4 This is a significant issue when trying to influence individual practitioners. Another focus is on developing the capacity of research institutions in developing countries, with the expectation that this will increase the relevance and local ownership of results.5 We argue that these two approaches are necessary but not sufficient. The aim should not be to perfect techniques of feeding results to decision-makers, but to start from the perspective of the decision-makers even before devising the questions. This means “getting practice into research”. This approach is not appropriate for research into new and untried treatments where efficacy has not been established, but should become the norm for operational research, by which we understand research into how an intervention is implemented. It is an approach that is gaining ground in the developed north, but which has even greater application in resource-constrained settings. Here, based on our experience in China, Pakistan and elsewhere, are some key considerations: Operational research should be embedded in local programmes. Operational research should emerge out of an ongoing partnership with a national programme. This includes the process of prioritizing, developing, conducting and disseminating research, and is part of national expansion of services. Operational research should focus on local opportunities for going to scale. The first stage is to explore the options that are under consideration for implementation and then design research to inform the choice of how that implementation should best be carried out. For maximum effect, it is often useful to focus attention on situations where there are resources available from international or national agencies, but where some technical or organizational block has prevented them from being used effectively. The research questions may be based on an understanding of the barriers to large-scale access.6 Then trials and social and economic studies can be embedded within programme sites, and provide knowledge on how to overcome these barriers and deliver effective interventions, as in Pakistan.7–9 Because these operational issues are commonly relevant to other high-burden countries, the publication of the results should have international as well as national influence. Interventions to be evaluated should be realistic, given the resource constraints in that setting. Trial designs will vary according to the circumstances, but the key point is that the intervention is not implemented according to some kind of international ideal, relying on additional resources, but is integrated into existing health systems and is carried out using the resources which will be available for eventual scale-up. Unless the resource expectations are realistic, there will be no follow-up to research. The national programme should implement the intervention, while researchers facilitate. Researchers can act as a catalyst for action, and participate within national programme working groups to design the intervention and draft the guidelines and materials required for implementation. They can conduct the research together with the national programme and advise on the national scale-up. The main point is that the national programme implements both the existing service and the intervention being tested (as they will replicate nationally if it is found effective). Researchers can carry out any data-gathering that is over and above the routine (e.g. structured interviews or collection of cost data). Research and programme development should be linked. The development components should run alongside the research, with technical assistance being provided on programme frameworks and operational plans. The intervention research guidelines and training materials should also be adapted and used for successful expansion of whichever modality is supported by the operational research results. By focusing on specific obstacles, embedded research improves resource use and hence resource availability. Done well, operations research not only helps make effective use of existing internal and external resources, but also assists programme managers to mobilize further support once successful implementation has been demonstrated. Supporting programmes to conduct research is the best way to build capacity. The embedded research approach should also build local research capacity. A track record of successful country research helps local research teams to bid for further funding. Health programme managers in developing countries are increasingly recognizing the value of research and are setting up their own research teams. ■