Identifying and managing problematic trials: A research integrity assessment tool for randomized controlled trials in evidence synthesis.

Evidence synthesis findings depend on the assumption that the included studies follow good clinical practice and results are not fabricated or false. Studies which are problematic due to scientific misconduct, poor research practice, or honest error may distort evidence synthesis findings. Authors of evidence synthesis need transparent mechanisms to identify and manage problematic studies to avoid misleading findings. As evidence synthesis authors of the Cochrane COVID-19 review on ivermectin, we identified many problematic studies in terms of research integrity and regulatory compliance. Through iterative discussion, we developed a research integrity assessment (RIA) tool for randomized controlled trials for the update of this Cochrane review. In this paper, we explain the rationale and application of the RIA tool in this case study. RIA assesses six study criteria: study retraction, prospective trial registration, adequate ethics approval, author group, plausibility of methods (e.g., randomization), and plausibility of study results. RIA was used in the Cochrane review as part of the eligibility check during screening of potentially eligible studies. Problematic studies were excluded and studies with open questions were held in awaiting classification until clarified. RIA decisions were made independently by two authors and reported transparently. Using the RIA tool resulted in the exclusion of >40% of studies in the first update of the review. RIA is a complementary tool prior to assessing "Risk of Bias" aiming to establish the integrity and authenticity of studies. RIA provides a platform for urgent development of a standard approach to identifying and managing problematic studies.

Should all pregnant women take calcium supplements in Nepal? GRADE evidence to policy assessment.

BACKGROUND: The WHO recommends oral calcium supplementation (1.5-2.0 g) in pregnant women to reduce the risk of pre-eclampsia living in areas with low dietary calcium intake. Although maternal mortality is high in Nepal and eclampsia causes at least 20% of maternal deaths, implementing WHO recommendations would be a major undertaking. OBJECTIVE: This review aimed to assess whether the current evidence supports the blanket supplementation of calcium to prevent pre-eclampsia among pregnant women in Nepal. METHODS: We used a structured approach to appraise the evidence for calcium supplementation in Nepal. We identified what may influence the impact of calcium supplementation in Nepal and conducted a situation analysis in the country covering maternal mortality, pre-eclampsia occurrence, and existing government policy provisions for supplementation. We also consulted with experts and government officials to explore their perspectives and experience on supplementation. We then used AMSTAR (A MeaSurement Tool to Assess Systematic Reviews) to appraise the Cochrane Systematic Review of calcium supplementation. Finally, we used these data in a GRADE (Grading of Recommendations Assessment, Development and Evaluation)-Evidence to Decision framework to reach a policy recommendation. RESULTS: Our assessment of the Cochrane Review showed that the recommendation made by the WHO is based on weak evidence and trial findings that are not consistent between studies. The Cochrane Review found low certainty of the evidence for benefit (reduction in pre-eclampsia and maternal mortality). Conversely, there is a high certainty of the evidence of undesirable effects (HELLP [haemolysis, elevated liver enzymes and low platelets] syndrome) although this is uncommon. The likely absolute reduction in maternal deaths projected to Nepal was estimated to be low, while the implementation costs were high. Stakeholders also raised several concerns regarding feasibility, acceptability, appropriate dosing, and risk communication. CONCLUSIONS: This review concludes that the blanket supplementation of calcium cannot be recommended in Nepal. A better approach may be to identify high-risk pregnant women and manage their antenatal visits and delivery to prevent mortality from pre-eclampsia.

GRADE guidance 24 optimizing the integration of randomized and non-randomized studies of interventions in evidence syntheses and health guidelines.

BACKGROUND AND OBJECTIVE: This is the 24th in the ongoing series of articles describing the GRADE approach for assessing the certainty of a body of evidence in systematic reviews and health technology assessments and how to move from evidence to recommendations in guidelines. METHODS: Guideline developers and authors of systematic reviews and other evidence syntheses use randomized controlled studies (RCTs) and non-randomized studies of interventions (NRSI) as sources of evidence for questions about health interventions. RCTs with low risk of bias are the most trustworthy source of evidence for estimating relative effects of interventions because of protection against confounding and other biases. However, in several instances, NRSI can still provide valuable information as complementary, sequential, or replacement evidence for RCTs. RESULTS: In this article we offer guidance on the decision regarding when to search for and include either or both types of studies in systematic reviews to inform health recommendations. CONCLUSION: This work aims to help methodologists in review teams, technology assessors, guideline panelists, and anyone conducting evidence syntheses using GRADE.

WHO guidance for refugees in camps: systematic review.

OBJECTIVES: The circumstances of people living in refugee camps means that they have distinct medical care requirements. Our objective is to describe clinical guidance in published WHO guidelines that refer to people living in refugee camps; and how evidence and context are used and reported in making recommendations. DESIGN: Systematic review and analysis of WHO guidelines approved by the organisation's quality oversight body and published between 2007 and 2018. We sought for key terms related to camps and humanitarian settings, and identified text that included guidance. We compared this to Mèdecins Sans Frontièrs (MSF) guidelines. RESULTS: No WHO guideline published in the last 10 years focused exclusively on clinical guidance for healthcare in camp settings. Seven guidelines contained guidance about camps; three made recommendations for camps-but only two used formal evidence summaries. We did not find any structured consideration of the situation in camps used in the decision-making process. We examined seven WHO guidelines and six chapters within guidelines that concerned humanitarian settings: none of these documents contained recommendations based on formal evidence summaries for camp settings. One of the eight MSF guidelines was devoted to clinical care in refugees and the authors had clearly linked the health problems and recommendations to the setting, but this guideline is now >20 years old. CONCLUSIONS: There is an absence of up-to-date, evidence-based medical treatment guidelines from WHO and MSF that comprehensively address the clinical needs for people living in camps; and there is no common framework to help guideline groups formulate recommendations in these settings. WHO may wish to consider context of special populations more formally in the evidence to decision-making approach for clinical guidelines relevant to primary care.

Series: Clinical Epidemiology in South Africa. Paper 1: Evidence-based health care and policy in Africa: past, present, and future.

Africa has high disease burden and health system challenges but is making progress in recognizing, accepting, and adopting evidence-based health care (EBHC). In this article, we reflect on the developments of the past 2 decades and consider further steps that will help with the translation of reliable research results into the decision making process. There has been a rapid growth in various initiatives to promote EBHC in the African region. These include the conduct and reporting of primary and secondary research, research capacity development and supportive initiatives, access to information, and work with decision makers in getting research into clinical guidelines and health policies. Much, however, still needs to be done to improve the impact on health in the region. A multipronged approach consisting of regionally relevant well-conducted research addressing priority health problems, increased uptake of research in health care policy and practice, dedicated capacity development initiatives to support the conduct as well as use of research, facilitated by wider collaboration, and equitable partnerships will be important. Working together in mutually supporting partnerships is key to advancing both evidence-informed health care practices and better health.

Subsidising artemisinin-based combination therapy in the private retail sector.

BACKGROUND: Malaria causes ill health and death in Africa. Treating illness promptly with artemisinin-based combination therapy (ACT) is likely to cure people and avoid the disease progressing to more severe forms and death. In many countries, ACT use remains low. Part of the problem is that most people seek treatment from the retail sector where ACTs are expensive; this expense is a barrier to their use.The Global Fund and other international organisations are subsidising the cost of ACTs for private retail providers to improve access to ACTs. The subsidy was initially organised through a stand-alone initiative, called the Affordable Medicines Facility-malaria (AMFm), but has since been integrated into the Global Fund core grant management and financial processes. OBJECTIVES: To assess the effect of programmes that include ACT price subsidies for private retailers on ACT use, availability, price and market share. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 1, The Cochrane Library, including the Cochrane Effective Practice and Organisation of Care (EPOC) Group Specialised Register); MEDLINE (OvidSP), EMBASE (OvidSP), CINAHL (EbscoHost), EconLit (ProQuest), Global Health (OvidSP), Regional Indexes (Global Health Library, WHO), LILACS (Global Health Library, WHO), Science Citation Index and Social Sciences Citation Index (ISI Web of Science) and Health Management (ProQuest). All databases were searched February 2015, except for Health Management which was searched November 2013, without any date, language or publication status restrictions. We also searched the International Clinical Trials Registry Platform (ICTRP; WHO), ClinicalTrials.gov (NIH) and various grey literature sources. We also conducted a cited reference search for all included studies in ISI Web of Knowledge, checked references of identified articles and contacted authors to identify additional studies. SELECTION CRITERIA: Randomised trials, non-randomised trials, controlled before-after studies and interrupted-time-series studies that compared the effects of ACT price subsidies for private retailers to no subsidies or alternative ACT financing mechanisms were eligible for inclusion. Two authors independently screened and selected studies for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data, assessed study risk of bias and confidence in effect estimates (certainty of evidence) using Grading of Recommendations, Assessment, Development and Evaluation (GRADE). MAIN RESULTS: We included four trials (two cluster-randomised trials reported in three articles and two non-randomised cluster trials). Three trials assessed retail sector ACT subsidies combined with supportive interventions (retail outlet provider training, community awareness and mass media campaigns). One trial assessed vouchers provided to households to purchase subsidised ACTs. Price subsidies ranged from 80% to 95%. One trial enrolled children under five years of age; the other three trials studied people of all age groups. The studies were done in rural districts in East Africa (Kenya, Uganda and Tanzania).In this East Africa setting, these ACT subsidy programmes increased the percentage of children under five years of age receiving ACTs on the day, or following day, of fever onset by 25 percentage points (95% confidence interval (CI) 14.1 to 35.9 percentage points; 1 study, high certainty evidence). This suggests that in practice, among febrile children under five years of age with an ACT usage rate of 5% without a subsidy, subsidy programmes would increase usage by between 19% and 41% over a one year period.The ACT subsidy programmes increased the percentage of retail outlets stocking ACTs for children under five years of age by 31.9 percentage points (95% CI 26.3 to 37.5 percentage points; 1 study, high certainty evidence). Effects on ACT stocking for patients of any age is unknown because the certainty of evidence was very low.The ACT subsidy programmes decreased the median cost of ACTs for children under five years of age by US$ 0.84 (median cost per ACT course without subsidy: US$ 1.08 versus with subsidy: US$ 0.24; 1 study, high certainty evidence).The ACT subsidy programmes increased the market share of ACTs for children under five years of age by between 23.6 and 63.0 percentage points (1 study, high certainty evidence).The ACT subsidy programmes decreased the use of older antimalarial drugs (such as amodiaquine and sulphadoxine-pyrimethamine) among children under five years of age by 10.4 percentage points (95% CI 3.9 to 16.9 percentage points; 1 study, high certainty evidence).None of the three studies of ACT subsidies reported the number of patients treated who had confirmed malaria.Vouchers increased the likelihood that an illness is treated with an ACT by 16 to 23 percentage points; however, vouchers were associated with a high rate of over-treatment of malaria (only 56% of patients taking ACTs from the drug shop tested positive for malaria under the 92% subsidy; 1 study, high certainty evidence). AUTHORS' CONCLUSIONS: Programmes that include substantive subsidies for private sector retailers combined with training of providers and social marketing improved use and availability of ACTs for children under five years of age with suspected malaria in research studies from three countries in East Africa. These programmes also reduced prices of ACTs, improved market share of ACTs and reduced the use of older antimalarial drugs among febrile children under five years of age. The research evaluates drug delivery but does not assess whether the patients had confirmed (parasite-diagnosed) malaria. None of the included studies assessed patient outcomes; it is therefore not known whether the effects seen in the studies would translate to an impact on health.

Improving GRADE evidence tables part 3: detailed guidance for explanatory footnotes supports creating and understanding GRADE certainty in the evidence judgments.

BACKGROUND: The Grading of Recommendations Assessment, Development and Evaluation (GRADE) is widely used and reliable and accurate for assessing the certainty in the body of health evidence. The GRADE working group has provided detailed guidance for assessing the certainty in the body of evidence in systematic reviews and health technology assessments (HTAs) and how to grade the strength of health recommendations. However, there is limited advice regarding how to maximize transparency of these judgments, in particular through explanatory footnotes or explanations in Summary of Findings tables and Evidence Profiles (GRADE evidence tables). METHODS: We conducted this study to define the essential attributes of useful explanations and to develop specific guidance for explanations associated with GRADE evidence tables. We used a sample of explanations according to their complexity, type of judgment involved, and appropriateness from a database of published GRADE evidence tables in Cochrane reviews and World Health Organization guidelines. We used an iterative process and group consensus to determine the attributes and develop guidance. RESULTS: Explanations in GRADE evidence tables should be concise, informative, relevant, easy to understand, and accurate. We provide general and domain-specific guidance to assist authors with achieving these desirable attributes in their explanations associated with GRADE evidence tables. CONCLUSIONS: Adhering to the general and GRADE domain-specific guidance should improve the quality of explanations associated with GRADE evidence tables, assist authors of systematic reviews, HTA reports, or guidelines with information that they can use in other parts of their evidence synthesis. This guidance will also support editorial evaluation of evidence syntheses using GRADE and provide a minimum quality standard of judgments across tables.

The impact of mass deworming programmes on schooling and economic development: an appraisal of long-term studies.

Background: Documents from advocacy and fund-raising organizations for child mass deworming programmes in low- and middle-income countries cite unpublished economic studies claiming long-term effects on health, schooling and economic development. Methods: To summarize and appraise these studies, we searched for and included all long-term follow-up studies based on cluster-randomized trials included in a 2015 Cochrane review on deworming. We used Cochrane methods to assess risk of bias, and appraised the credibility of the main findings. Where necessary we contacted study authors for clarifications. Results: We identified three studies (Baird 2016, Ozier 2016 and Croke 2014) evaluating effects more than 9 years after cluster-randomized trials in Kenya and Uganda. Baird and Croke evaluate short additional exposures to deworming programmes in settings where all children were dewormed multiple times. Ozier evaluates potential spin-off effects to infants living in areas with school-based deworming. None of the studies used pre-planned protocols nor blinded the analysis to treatment allocation. Conclusions: In the context of reliable epidemiological methods, all three studies are at risk of substantial methodological bias. They therefore help in generating hypotheses, but should not be considered to provide reliable evidence of effects.

Strategies for expanding health insurance coverage in vulnerable populations.

BACKGROUND: Health insurance has the potential to improve access to health care and protect people from the financial risks of diseases. However, health insurance coverage is often low, particularly for people most in need of protection, including children and other vulnerable populations. OBJECTIVES: To assess the effectiveness of strategies for expanding health insurance coverage in vulnerable populations. SEARCH METHODS: We searched Cochrane Central Register of Controlled Trials (CENTRAL), part of The Cochrane Library. www.thecochranelibrary.com (searched 2 November 2012), PubMed (searched 1 November 2012), EMBASE (searched 6 July 2012), Global Health (searched 6 July 2012), IBSS (searched 6 July 2012), WHO Library Database (WHOLIS) (searched 1 November 2012), IDEAS (searched 1 November 2012), ISI-Proceedings (searched 1 November 2012),OpenGrey (changed from OpenSIGLE) (searched 1 November 2012), African Index Medicus (searched 1 November 2012), BLDS (searched 1 November 2012), Econlit (searched 1 November 2012), ELDIS (searched 1 November 2012), ERIC (searched 1 November 2012), HERDIN NeON Database (searched 1 November 2012), IndMED (searched 1 November 2012), JSTOR (searched 1 November 2012), LILACS(searched 1 November 2012), NTIS (searched 1 November 2012), PAIS (searched 6 July 2012), Popline (searched 1 November 2012), ProQuest Dissertation &Theses Database (searched 1 November 2012), PsycINFO (searched 6 July 2012), SSRN (searched 1 November 2012), Thai Index Medicus (searched 1 November 2012), World Bank (searched 2 November 2012), WanFang (searched 3 November 2012), China National Knowledge Infrastructure (CHKD-CNKI) (searched 2 November 2012).In addition, we searched the reference lists of included studies and carried out a citation search for the included studies via Web of Science to find other potentially relevant studies. SELECTION CRITERIA: Randomised controlled trials (RCTs), non-randomised controlled trials (NRCTs), controlled before-after (CBA) studies and Interrupted time series (ITS) studies that evaluated the effects of strategies on increasing health insurance coverage for vulnerable populations. We defined strategies as measures to improve the enrolment of vulnerable populations into health insurance schemes. Two categories and six specified strategies were identified as the interventions. DATA COLLECTION AND ANALYSIS: At least two review authors independently extracted data and assessed the risk of bias. We undertook a structured synthesis. MAIN RESULTS: We included two studies, both from the United States. People offered health insurance information and application support by community-based case managers were probably more likely to enrol their children into health insurance programmes (risk ratio (RR) 1.68, 95% confidence interval (CI) 1.44 to 1.96, moderate quality evidence) and were probably more likely to continue insuring their children (RR 2.59, 95% CI 1.95 to 3.44, moderate quality evidence). Of all the children that were insured, those in the intervention group may have been insured quicker (47.3 fewer days, 95% CI 20.6 to 74.0 fewer days, low quality evidence) and parents may have been more satisfied on average (satisfaction score average difference 1.07, 95% CI 0.72 to 1.42, low quality evidence).In the second study applications were handed out in emergency departments at hospitals, compared to not handing out applications, and may have had an effect on enrolment (RR 1.5, 95% CI 1.03 to 2.18, low quality evidence). AUTHORS' CONCLUSIONS: Community-based case managers who provide health insurance information, application support, and negotiate with the insurer probably increase enrolment of children in health insurance schemes. However, the transferability of this intervention to other populations or other settings is uncertain. Handing out insurance application materials in hospital emergency departments may help increase the enrolment of children in health insurance schemes. Further studies evaluating the effectiveness of different strategies for expanding health insurance coverage in vulnerable population are needed in different settings, with careful attention given to study design.

Deworming drugs for soil-transmitted intestinal worms in children: effects on nutritional indicators, haemoglobin and school performance.

BACKGROUND: The World Health Organization (WHO) recommends treating all school children at regular intervals with deworming drugs in areas where helminth infection is common. The WHO state this will improve nutritional status, haemoglobin, and cognition and thus will improve health, intellect, and school attendance. Consequently, it is claimed that school performance will improve, child mortality will decline, and economic productivity will increase. Given the important health and societal benefits attributed to this intervention, we sought to determine whether they are based on reliable evidence. OBJECTIVES: To summarize the effects of giving deworming drugs to children to treat soil-transmitted intestinal worms (nematode geohelminths) on weight, haemoglobin, and cognition; and the evidence of impact on physical well being, school attendance, school performance, and mortality. SEARCH METHODS: In February 2012, we searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, EMBASE, LILACS, mRCT, and reference lists, and registers of ongoing and completed trials. SELECTION CRITERIA: We selected randomized controlled trials (RCTs) and quasi-RCTs comparing deworming drugs for geohelminth worms with placebo or no treatment in children aged 16 years or less, reporting on weight, haemoglobin, and formal test of intellectual development. In cluster-RCTs treating communities or schools, we also sought data on school attendance, school performance, and mortality. We included trials that included health education with deworming. DATA COLLECTION AND ANALYSIS: At least two authors independently assessed the trials, evaluated risk of bias, and extracted data. Continuous data were analysed using the mean difference (MD) with 95% confidence intervals (CI). Where data were missing, we contacted trial authors. We used GRADE to assess evidence quality, and this is reflected in the wording we used: high quality ("deworming improves...."); moderate quality ("deworming probably improves..."); low quality ("deworming may improve...."); and very low quality ("we don't know if deworming improves...."). MAIN RESULTS: We identified 42 trials, including eight cluster trials, that met the inclusion criteria. Excluding one trial where data are awaited, the 41 trials include 65,168 participants.Screening then treatingFor children known to be infected with worms (by screening), a single dose of deworming drugs may increase weight (0.58 kg, 95% CI 0.40 to 0.76, three trials, 139 participants; low quality evidence) and may increase haemoglobin (0.37 g/dL, 95% CI 0.1 to 0.64, two trials, 108 participants; low quality evidence), but we do not know if there is an effect on cognitive functioning (two trials, very low quality evidence).Single dose deworming for all childrenIn trials treating all children, a single dose of deworming drugs gave mixed effects on weight, with no effects evident in seven trials, but large effects in two (nine trials, 3058 participants, very low quality evidence). The two trials with a positive effect were from the same very high prevalence setting and may not be easily generalised elsewhere. Single dose deworming probably made little or no effect on haemoglobin (mean difference (MD) 0.06 g/dL, 95% CI -0.06 to 0.17, three trials, 1005 participants; moderate evidence), and may have little or no effect on cognition (two trials, low quality evidence).Mulitple dose deworming for all childrenOver the first year of follow up, multiple doses of deworming drugs given to all children may have little or no effect on weight (MD 0.06 kg, 95% CI -0.17 to 0.30; seven trials, 2460 participants; low quality evidence); haemoglobin, (mean 0.01 g/dL lower; 95% CI 0.14 lower to 0.13 higher; four trials, 807 participants; low quality evidence); cognition (three trials, 30,571 participants, low quality evidence); or school attendance (4% higher attendance; 95% CI -6 to 14; two trials, 30,243 participants; low quality evidence);For time periods beyond a year, there were five trials with weight measures. One cluster-RCT of 3712 children in a low prevalence area showed a large effect (average gain of 0.98 kg), whilst the other four trials did not show an effect, including a cluster-RCT of 27,995 children in a moderate prevalence area (five trials, 37,306 participants; low quality evidence). For height, we are uncertain whether there is an effect of deworming (-0.26 cm; 95% CI -0.84 to 0.31, three trials, 6652 participants; very low quality evidence). Deworming may have little or no effect on haemoglobin (0.00 g/dL, 95%CI -0.08 to 0.08, two trials, 1365 participants, low quality evidence); cognition (two trials, 3720 participants; moderate quality evidence). For school attendance, we are uncertain if there is an effect (mean attendance 5% higher, 95% CI -0.5 to 10.5, approximately 20,000 participants, very low quality evidence).Stratified analysis to seek subgroup effects into low, medium and high helminth endemicity areas did not demonstrate any pattern of effect. In a sensitivity analysis that only included trials with adequate allocation concealment, we detected no significant effects for any primary outcomes.One million children were randomized in a deworming trial from India with mortality as the primary outcome. This was completed in 2005 but the authors have not published the results. AUTHORS' CONCLUSIONS: Screening children for intestinal helminths and then treating infected children appears promising, but the evidence base is small. Routine deworming drugs given to school children has been more extensively investigated, and has not shown benefit on weight in most studies, except for substantial weight changes in three trials conducted 15 years ago or more. Two of these trials were carried out in the same high prevalence setting. For haemoglobin and cognition, community deworming seems to have little or no effect, and the evidence in relation to school attendance, and school performance is generally poor, with no obvious or consistent effect. Our interpretation of this data is that it is probably misleading to justify contemporary deworming programmes based on evidence of consistent benefit on nutrition, haemoglobin, school attendance or school performance as there is simply insufficient reliable information to know whether this is so.

Deworming drugs for soil-transmitted intestinal worms in children: effects on nutritional indicators, haemoglobin and school performance.

BACKGROUND: The World Health Organization (WHO) recommends treating all school children at regular intervals with deworming drugs in areas where helminth infection is common. The WHO state this will improve nutritional status, haemoglobin, and cognition and thus will improve health, intellect, and school attendance. Consequently, it is claimed that school performance will improve, child mortality will decline, and economic productivity will increase. Given the important health and societal benefits attributed to this intervention, we sought to determine whether they are based on reliable evidence. OBJECTIVES: To summarize the effects of giving deworming drugs to children to treat soil-transmitted intestinal worms (nematode geohelminths) on weight, haemoglobin, and cognition; and the evidence of impact on physical well being, school attendance, school performance, and mortality. SEARCH METHODS: In February 2012, we searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, EMBASE, LILACS, mRCT, and reference lists, and registers of ongoing and completed trials. SELECTION CRITERIA: We selected randomized controlled trials (RCTs) and quasi-RCTs comparing deworming drugs for geohelminth worms with placebo or no treatment in children aged 16 years or less, reporting on weight, haemoglobin, and formal test of intellectual development. In cluster-RCTs treating communities or schools, we also sought data on school attendance, school performance, and mortality. We included trials that included health education with deworming. DATA COLLECTION AND ANALYSIS: At least two authors independently assessed the trials, evaluated risk of bias, and extracted data. Continuous data were analysed using the mean difference (MD) with 95% confidence intervals (CI). Where data were missing, we contacted trial authors. We used GRADE to assess evidence quality, and this is reflected in the wording we used: high quality ("deworming improves...."); moderate quality ("deworming probably improves..."); low quality ("deworming may improve...."); and very low quality ("we don't know if deworming improves...."). MAIN RESULTS: We identified 42 trials, including eight cluster trials, that met the inclusion criteria. Excluding one trial where data are awaited, the 41 trials include 65,168 participants.For programmes that treat only children detected as infected (by screening), a single dose of deworming drugs probably increased weight (0.58 kg, 95% CI 0.40 to 0.76, three trials, 139 participants; moderate quality evidence) and may have increased haemoglobin (0.37 g/dL, 95% CI 0.1 to 0.64, two trials, 108 participants; low quality evidence), but we do not know if there is an effect on cognitive functioning (two trials, very low quality evidence).For a single dose of deworming drugs given to all children in endemic areas, there were mixed effects on weight, with no effects evident in seven trials, but large effects in two. Overall our analysis indicated that we are uncertain whether there was an effect on weight (nine trials, 3058 participants; very low quality evidence). For haemoglobin, deworming made little or no difference (0.02 g/dL, 95% CI -0.05 to 0.09, four trials, 1992 participants; low quality evidence), and we don't know if it improves cognition (one trial, very low quality evidence).For multiple doses of deworming drugs with follow up for up to one year given to all children in endemic areas, we are uncertain if there is an effect on weight (0.06 kg, 95% CI -0.17 to 0.30; seven trials, 2460 participants; very low quality evidence); cognition (three trials, very low quality evidence); or school attendance (4% higher attendance; 95% CI -6 to 14; two trials, 75 clusters and 143 individually randomized participants, very low quality evidence). For haemoglobin, the intervention may have little or no effect (mean 0.01 g/dL lower; 95% CI 0.14 lower to 0.13 higher; four trials, 807 participants; low quality evidence).For multiple doses of deworming drugs with follow up beyond one year given to all children in endemic areas there were five trials with weight measures. One cluster-RCT of 3712 children in a low prevalence area showed a large effect (average gain of 0.98kg), whilst the other four trials did not show an effect, including a cluster-RCT of 27,995 children in a moderate prevalence area. Overall, we are uncertain if there is an effect for weight (five trials, 302 clusters and 1045 individually randomized participants; very low quality evidence). For other outcomes, we are uncertain whether deworming affects height (-0.26 cm; 95%CI -0.84 to 0.31, three trials, 1219 participants); haemoglobin (0.02 g/dL, 95%CI 0.3 to 0.27, two trials, 1365 participants); cognition (two trials), or school attendance (mean attendance 5% higher, 95% CI -0.5 to 10.5, one trial, 50 clusters).Stratified analysis to seek subgroup effects into low, medium and high helminth endemicity areas did not demonstrate any pattern of effect. We did not detect any significant effects for any primary outcomes in a sensitivity analysis only including trials with adequate allocation concealment.One million children were randomized in a deworming trial from India with mortality as the primary outcome. This was completed in 2005 but the authors have not published the results. AUTHORS' CONCLUSIONS: Screening children for intestinal helminths and then treating infected children appears promising, but the evidence base is small. Routine deworming drugs given to school children has been more extensively investigated, and has not shown benefit on weight in most studies, except for substantial weight changes in three trials conducted 15 years ago or more. Two of these trials were carried out in the same high prevalence setting. For haemoglobin, community deworming seems to have little or no effect, and the evidence in relation to cognition, school attendance, and school performance is generally poor, with no obvious or consistent effect. Our interpretation of this data is that it is probably misleading to justify contemporary deworming programmes based on evidence of consistent benefit on nutrition, haemoglobin, school attendance or school performance as there is simply insufficient reliable information to know whether this is so.

Strategies for integrating primary health services in low- and middle-income countries at the point of delivery.

BACKGROUND: In some low- and middle-income countries, separate vertical programmes deliver specific life-saving interventions but can fragment services. Strategies to integrate services aim to bring together inputs, organisation, and delivery of particular functions to increase efficiency and people's access. We examined the evidence on the effectiveness of integration strategies at the point of delivery (sometimes termed 'linkages'), including integrated delivery of tuberculosis (TB), HIV/AIDS and reproductive health programmes. OBJECTIVES: To assess the effects of strategies to integrate primary health care services on healthcare delivery and health status in low- and middle-income countries. SEARCH STRATEGY: We searched The Cochrane Central Register of Controlled Trials (CENTRAL) 2010, Issue 3, part of the The Cochrane Library. www.thecochranelibrary.com, including the Cochrane Effective Practice and Organisation of Care Group Specialised Register (searched 15 September  2010); MEDLINE, Ovid (1950 to August Week 5 2010) (searched 10 September  2010); EMBASE, Ovid (1980 to 2010 Week 35) (searched 10 September  2010); CINAHL, EBSCO (1980 to present) (searched 20 September 2010); Sociological Abstracts, CSA Illumina (1952 to current) (searched 10 September  2010); Social Services Abstracts, CSA Illumina (1979 to current) (searched 10 September  2010); POPLINE (1970 to current) (searched 10 September  2010); International Bibliography of the Social Sciences, Webspirs (1951 to current) (searched 01 July 2008); HealthStar (1975 to September 2005), Cab Health (1972 to 1999), and reference lists of articles. We also searched the World Health Organization (WHOLIS) library database, handsearched relevant WHO publications, and contacted experts in the field. SELECTION CRITERIA: Randomised controlled trials, non-randomised controlled trials, controlled before and after studies, and interrupted time series analyses of integration strategies, including strengthening linkages, in primary health care services. Health services in high-income countries, private public partnerships, and hospital inpatient care were excluded as were programmes promoting the integrated management of childhood illnesses. The main outcomes were indicators of healthcare delivery, user views, and health status. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed the risk of bias. The statistical results of individual studies are reported and summarised. MAIN RESULTS: Five randomised trials and four controlled before and after studies were included. The interventions were complex.Five studies added an additional component, or linked a new component, to an existing service, for example, adding family planning or HIV counselling and testing to routine services. The evidence from these studies indicated that adding on services probably increases service utilisation but probably does not improve health status outcomes, such as incident pregnancies.Four studies compared integrated services to single, special services. Based on the included studies, fully integrating sexually transmitted infection (STI) and family planning, and maternal and child health services into routine care as opposed to delivering them as special 'vertical' services may decrease utilisation, client knowledge of and satisfaction with the services and may not result in any difference in health outcomes, such as child survival. Integrating HIV prevention and control at facility and community level improved the effectiveness of certain services (STI treatment in males) but resulted in no difference in health seeking behaviour, STI incidence, or HIV incidence in the population. AUTHORS' CONCLUSIONS: There is some evidence that 'adding on' services (or linkages) may improve the utilisation and outputs of healthcare delivery. However, there is no evidence to date that a fuller form of integration improves healthcare delivery or health status. Available evidence suggests that full integration probably decreases the knowledge and utilisation of specific services and may not result in any improvements in health status. More rigorous studies of different strategies to promote integration over a wider range of services and settings are needed. These studies should include economic evaluation and the views of clients as clients' views will influence the uptake of integration strategies at the point of delivery and the effectiveness on community health of these strategies.

Do existing research summaries on health systems match immunisation managers' needs in middle- and low-income countries? Analysis of GAVI health systems strengthening support.

BACKGROUND: The GAVI Alliance was created in 2000 to increase access to vaccines. More recently, GAVI has supported evidence-based health systems strengthening to overcome barriers to vaccination. Our objectives were: to explore countries' priorities for health systems strengthening; to describe published research summaries for each priority area in relation to their number, quality and relevance; and to describe the use of national data from surveys in identifying barriers to immunisation. METHODS: From 44 health systems strengthening proposals submitted to GAVI in 2007 and 2008, we analysed the topics identified, the coverage of these topics by existing systematic reviews and the use of nation-wide surveys with vaccination data to justify the needs identified in the proposals. RESULTS: Thirty topics were identified and grouped into three thematic areas: health workforce (10 topics); organisation and management (14); and supply, distribution and maintenance (6). We found 51 potentially relevant systematic reviews, although for the topic that appeared most frequently in the proposals ('Health information systems') no review was identified. Thematic and geographic relevance were generally categorised as "high" in 33 (65%) and 25 (49%) reviews, respectively, but few reviews were categorised as "highly relevant for policy" (7 reviews, 14%). With regard to methodological quality, 14 reviews (27%) were categorised as "high".The number of topics that were addressed by at least one high quality systematic review was: seven of the 10 topics in the 'health workforce' thematic area; six of the 14 topics in the area of 'organisation and management'; and none of the topics in the thematic area of 'supply, distribution and maintenance'. Only twelve of the 39 countries with available national surveys referred to them in their proposals. CONCLUSION: Relevant, high quality research summaries were found for few of the topics identified by managers. Few proposals used national surveys evidence to identify barriers to vaccination. Researchers generating or adapting evidence about health systems need to be more responsive to managers' needs. Use of available evidence from local or national surveys should be strongly encouraged.

Patient medical costs for tuberculosis treatment and impact on adherence in China: a systematic review.

BACKGROUND: Charging for tuberculosis (TB) treatment could reduce completion rates, particularly in the poor. We identified and synthesised studies that measure costs of TB treatment, estimates of adherence and the potential impact of charging on treatment completion in China. METHODS: Inclusion criteria were primary research studies, including surveys and studies using qualitative methods, conducted in mainland China. We searched MEDLINE, PUBMED, EMBASE, Science Direct, HEED, CNKI to June 2010; and web pages of relevant Chinese and international organisations. Cost estimates were extracted, transformed, and expressed in absolute values and as a percentage of household income. RESULTS: Low income patients, defined at household or district level, pay a total of US$ 149 to 724 (RMB 1241 to 5228) for medical costs for a treatment course; as a percentage of annual household income, estimates range from 42% to 119%. One national survey showed 73% of TB patients at the time of the survey had interrupted or suspended treatment, and estimates from 9 smaller more recent studies showed that the proportion of patients at the time of the survey who had run out of drugs or were not taking them ranged from 3 to 25%. Synthesis of surveys and qualitative research indicate that cost is the most cited reason for default. CONCLUSIONS: Despite a policy of free drug treatment for TB in China, health services charge all income groups, and costs are high. Adherence measured in cross sectional surveys is often low, and the cumulative failure to adhere is likely to be much higher. These findings may be relevant to those concerned with the development and spread of multi-drug resistant TB. New strategies need to take this into account and ensure patient adherence.

Quality of private and public ambulatory health care in low and middle income countries: systematic review of comparative studies.

BACKGROUND: In developing countries, the private sector provides a substantial proportion of primary health care to low income groups for communicable and non-communicable diseases. These providers are therefore central to improving health outcomes. We need to know how their services compare to those of the public sector to inform policy options. METHODS AND FINDINGS: We summarised reliable research comparing the quality of formal private versus public ambulatory health care in low and middle income countries. We selected studies against inclusion criteria following a comprehensive search, yielding 80 studies. We compared quality under standard categories, converted values to a linear 100% scale, calculated differences between providers within studies, and summarised median values of the differences across studies. As the results for for-profit and not-for-profit providers were similar, we combined them. Overall, median values indicated that many services, irrespective of whether public or private, scored low on infrastructure, clinical competence, and practice. Overall, the private sector performed better in relation to drug supply, responsiveness, and effort. No difference between provider groups was detected for patient satisfaction or competence. Synthesis of qualitative components indicates the private sector is more client centred. CONCLUSIONS: Although data are limited, quality in both provider groups seems poor, with the private sector performing better in drug availability and aspects of delivery of care, including responsiveness and effort, and possibly being more client orientated. Strategies seeking to influence quality in both groups are needed to improve care delivery and outcomes for the poor, including managing the increasing burden of non-communicable diseases.

Expanding health insurance coverage in vulnerable groups: a systematic review of options.

Vulnerable groups are often not covered by health insurance schemes. Strategies to extend coverage in these groups will help to address inequity. We used the existing literature to summarize the options for expanding health insurance coverage, describe which countries have tried these strategies, and identify and describe evaluation studies. We included any report of a policy or strategy to expand health insurance coverage and any evaluation and economic modelling studies. Vulnerable populations were defined as children, the elderly, women, low-income individuals, rural population, racial or ethnic minorities, immigrants, and those with disability or chronic diseases. Forty-five databases were searched for relevant documents. The authors applied inclusion criteria, and extracted data using pre-coded forms, on contents of health insurance schemes or programmes, and used the framework approach to establish categories. Of the 21,528 articles screened, 86 documents were finally included. Descriptions about the USA dominated (72), with only five from Africa, six from Asia and two from South America. We identified six main categories: (1) changing eligibility criteria of health insurance; (2) increasing public awareness; (3) making the premium more affordable; (4) innovative enrollment strategies; (5) improving health care delivery; and (6) improving management and organization of the insurance schemes. All six categories were found in the literature about schemes in the USA, and schemes often included components from each category. Strategies in developing countries were much more limited in their scope. Evaluation studies numbered 25, of which the majority were of time series design. All studies found that the expansion strategies were effective, as assessed by the author(s). In countries expanding coverage, the categories identified from the literature can help policy makers consider their options, implement strategies where it is common sense to do so and establish appropriate implementation monitoring.

Outreach strategies for expanding health insurance coverage in children.

BACKGROUND: Health insurance has the potential to improve access to health care and protect people from healthcare costs when they are ill. However, coverage is often low, particularly in people most in need of protection. OBJECTIVES: To assess the effectiveness of outreach strategies for expanding insurance coverage of children who are eligible for health insurance schemes. SEARCH STRATEGY: We searched the Cochrane Effective Practice and Organisation of Care Group (EPOC) Specialised Register (The Cochrane Library 2009, Issue 2), PubMed (January 1951 to January 2010), EMBASE (January 1966 to April 2009), PsycINFO (January 1967 to April 2009) and other relevant databases and websites. In addition, we searched the reference lists of included studies and relevant reviews, and carried out a citation search for included studies to find more potentially relevant studies. SELECTION CRITERIA: Randomised controlled trials, controlled clinical trials, controlled before-after studies and interrupted time series which evaluated the effects of outreach strategies on increasing health insurance coverage for children. We defined outreach strategies as measures to improve the implementation of existing health insurance to enrol more eligible populations. This included increasing awareness of schemes, modifying enrolment, improving management and organis ation of insurance schemes, and mixed strategies. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the risk of bias . We narratively summari sed the data. MAIN RESULTS: We included two studies, both from the United States. One randomised controlled trial study with a low risk of bias showed that community- based case managers who provided health insurance information, application support, and negotiated with the insurer were effective in enrolling and maintaining enrolment of Latino American children into health insurance schemes (n = 257). The second quasi-randomised controlled trial, with an unclear risk of bias (n = 223), indicated that handing out insurance application materials in hospital emergenc y departments can increase enrolment of children into health insurance. AUTHORS' CONCLUSIONS: The two studies included in this review provide evidence that in the US providing health insurance information and application assistance, and handing out application materials in hospital emergency departments can probably both improve insurance coverage of children. Further studies evaluating the effectiveness of different outreach strategies for expanding health insurance coverage of children in different countries are needed, with careful attention given to study design.