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1.  Preventing malaria in international travellers: an evaluation of published English-language guidelines 
BMC Public Health  2014;14(1):1129.
People intending to travel may seek information on malaria prevention from a range of sources. To ensure the best protection, this information needs to be reliable, up-to-date, consistent, and useful to their decision making. This study appraises current international and national guidelines written in English for malaria prevention in travellers, and whether any recommendations conflict.
We systematically identified national or international English-language guidelines on malaria prevention in travellers to July 2013 using standard and multiple searching methods. We critically appraised guidelines using the AGREE II tool, and report inconsistent recommendations within guidelines.
We identified five sets of English-language guidelines on preventing malaria for travellers. Assessment against AGREE II indicate that all of the guidelines fall short of internationally accepted standards in guideline development: none include a transparent description of methods; only one describes sources of funding or potential conflicts of interest; and only one includes formal presentation of the evidence alongside transparent assessment of the quality of that evidence. There were a number of important discrepancies between guidelines, and some omit information about effectiveness, safety and adverse effects of chemoprophylaxis options.
The methods used for developing guidelines for malaria prevention in travellers lags behind current internationally recognized standards. Healthcare professionals as well as travellers themselves could be better informed if guidelines were more systematic and transparent summaries of the current knowledge on drug interventions in relation to effects, safety, administration and contra-indications.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2458-14-1129) contains supplementary material, which is available to authorized users.
PMCID: PMC4226897  PMID: 25367677
Malaria; Travellers; Chemoprophylaxis; Prevention
2.  Open general medical wards versus specialist psychiatric units for acute psychoses 
As international healthcare policy has moved away from treating people with severe mental illness in large inpatient psychiatric institutions, beds for people with acute psychiatric disorders are being established in specialised psychiatric units in general hospitals. In developing countries, however, limited resources mean that it is not always possible to provide discrete psychiatric units, either in general hospitals or in the community. An alternative model of admission, used in the Caribbean, is to treat the person with acute psychosis in a general hospital ward.
To compare the outcomes for people with acute psychosis who have been admitted to open medical wards with those admitted to conventional psychiatric units.
Search methods
We searched The Cochrane Schizophrenia Group’s study-based register (April 2007). This register is compiled from searches of BIOSIS, CINAHL, The Cochrane Library, EMBASE, LILACS, MEDLINE, PsycINFO, PSYNDEX, Sociofile, and many conference proceedings.
Selection criteria
We would have included all relevant randomised or quasi-randomised trials, allocating anyone thought to be suffering from an acute psychotic episode to either acute management on general medical wards, or acute management in a specialist psychiatric unit. The primary outcomes of interest were length of stay in hospital and relapse.
Data collection and analysis
We extracted data independently. For dichotomous data we would have calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based using a fixed effects model.
Main results
We didnt identify any relevant randomised trials.
Authors’ conclusions
The Caribbean practice of treating people with severe mental illness on general medical wards has been influenced by socio-economic factors rather than evidence from randomised trials. This practice affords an opportunity for a well designed, well conducted and reported randomised trial, now impossible in many other settings.
PMCID: PMC4171961  PMID: 17943786
*Hospital Units; *Patients’ Rooms; Acute Disease; Hospitals, Psychiatric; Psychotic Disorders [* therapy]; Humans
3.  Low Carbohydrate versus Isoenergetic Balanced Diets for Reducing Weight and Cardiovascular Risk: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(7):e100652.
Some popular weight loss diets restricting carbohydrates (CHO) claim to be more effective, and have additional health benefits in preventing cardiovascular disease compared to balanced weight loss diets.
Methods and Findings
We compared the effects of low CHO and isoenergetic balanced weight loss diets in overweight and obese adults assessed in randomised controlled trials (minimum follow-up of 12 weeks), and summarised the effects on weight, as well as cardiovascular and diabetes risk. Dietary criteria were derived from existing macronutrient recommendations. We searched Medline, EMBASE and CENTRAL (19 March 2014). Analysis was stratified by outcomes at 3–6 months and 1–2 years, and participants with diabetes were analysed separately. We evaluated dietary adherence and used GRADE to assess the quality of evidence. We calculated mean differences (MD) and performed random-effects meta-analysis. Nineteen trials were included (n = 3209); 3 had adequate allocation concealment. In non-diabetic participants, our analysis showed little or no difference in mean weight loss in the two groups at 3–6 months (MD 0.74 kg, 95%CI −1.49 to 0.01 kg; I2 = 53%; n = 1745, 14 trials; moderate quality evidence) and 1–2 years (MD 0.48 kg, 95%CI −1.44 kg to 0.49 kg; I2 = 12%; n = 1025; 7 trials, moderate quality evidence). Furthermore, little or no difference was detected at 3–6 months and 1–2 years for blood pressure, LDL, HDL and total cholesterol, triglycerides and fasting blood glucose (>914 participants). In diabetic participants, findings showed a similar pattern.
Trials show weight loss in the short-term irrespective of whether the diet is low CHO or balanced. There is probably little or no difference in weight loss and changes in cardiovascular risk factors up to two years of follow-up when overweight and obese adults, with or without type 2 diabetes, are randomised to low CHO diets and isoenergetic balanced weight loss diets.
PMCID: PMC4090010  PMID: 25007189
4.  Diagnostic accuracy of the WHO clinical staging system for defining eligibility for ART in sub-Saharan Africa: a systematic review and meta-analysis 
The World Health Organization (WHO) recommends that HIV-positive adults with CD4 count ≤500 cells/mm3 initiate antiretroviral therapy (ART). In many countries of sub-Saharan Africa, CD4 count is not widely available or consistently used and instead the WHO clinical staging system is used to determine ART eligibility. However, concerns have been raised regarding its discriminatory ability to identify patients eligible to start ART. We therefore reviewed the accuracy of WHO stage 3 or 4 assessment in identifying ART eligibility according to CD4 count thresholds for ART initiation.
We systematically searched PubMed and Global Health databases and conference abstracts using a comprehensive strategy for studies that compared the results of WHO clinical staging with CD4 count thresholds. Studies performed in sub-Saharan Africa and published in English between 1998 and 2013 were eligible for inclusion according to our predefined study protocol. Two authors independently extracted data and assessed methodological quality and risk of bias using the Quality Assessment Tool for Diagnostic Accuracy Studies (QUADAS-2) tool. Summary estimates of sensitivity and specificity were derived for each CD4 count threshold and hierarchical summary receiver operator characteristic curves were plotted.
Fifteen studies met the inclusion criteria, including 25,032 participants from 14 countries. Most studies assessed individuals attending ART clinics prior to treatment initiation. WHO clinical stage 3 or 4 disease had a sensitivity of 60% (95% CI: 45–73%, Q=914.26, p<0.001) and specificity of 73% (95% CI: 60–83%, Q=1439.43, p<0.001) for a CD4 threshold of ≤200 cells/mm3 (11 studies); sensitivity and specificity for a threshold of CD4 count ≤350 cells/mm3 were 45% (95% CI: 26–66%, Q=1607.31, p<0.001) and 85% (95% CI: 69–93%, Q=896.70, p<0.001), respectively (six studies). For the threshold of CD4 count ≤500 cells/mm3 sensitivity was 14% (95% CI: 13–15%) and specificity was 95% (95% CI: 94–96%) (one study).
When used for individual treatment decisions, WHO clinical staging misses a high proportion of individuals who are ART eligible by CD4 count, with sensitivity falling as CD4 count criteria rises. Access to accurate, accessible, robust and affordable CD4 count testing methods will be a pressing need for as long as ART initiation decisions are based on criteria other than seropositivity.
PMCID: PMC4057784  PMID: 24929097
HIV; WHO clinical staging system; antiretroviral therapy; sub-Saharan Africa; systematic reviews; CD4 cell count
5.  Safety of 8-aminoquinolines given to people with G6PD deficiency: protocol for systematic review of prospective studies 
BMJ Open  2014;4(5):e004664.
A single dose or short course of primaquine given to people infected with malaria may reduce transmission of Plasmodium falciparum through its effects on gametocytes. Primaquine is also known to cause haemolysis in people with variants of glucose-6-phosphate dehydrogenase (G6PD) deficiency. The objective of this systematic review was to assess the risk of adverse effects in people with G6PD deficiency given primaquine or other 8-aminoquinoline (8AQ) as a single dose or short course (less than 7 days).
Methods and analysis
We will search the following databases: Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and LILACS. Prospective cohort studies, randomised and quasi-randomised trials that evaluated 8AQs for whatever reason in adults or children with a known G6PD deficiency will be included. Two authors will independently assess each study for eligibility, risk of bias and extract data.
Ethics and dissemination
This systematic review will be published in a peer-reviewed journal. Brief reports of the review findings will be disseminated directly to the appropriate audiences and the WHO Technical Expert Group in Malaria Chemotherapy. As no primary data collection will be undertaken, no additional formal ethical assessment and informed consent are required.
Protocol registration in PROSPERO
The protocol is registered with PROSPERO, registration number CRD42013006518.
PMCID: PMC4024606  PMID: 24833685
Preventive Medicine; Public Health; Infectious Diseases
6.  Immediate fluid management of children with severe febrile illness and signs of impaired circulation in low-income settings: a contextualised systematic review 
BMJ Open  2014;4(4):e004934.
To evaluate the effects of intravenous fluid bolus compared to maintenance intravenous fluids alone as part of immediate emergency care in children with severe febrile illness and signs of impaired circulation in low-income settings.
Systematic review of randomised controlled trials (RCTs), and observational studies, including retrospective analyses, that compare fluid bolus regimens with maintenance fluids alone. The primary outcome measure was predischarge mortality.
Data sources and synthesis
We searched PubMed, The Cochrane Library (to January 2014), with complementary earlier searches on, Google Scholar and Clinical Trial Registries (to March 2013). As studies used different clinical signs to define impaired circulation we classified patients into those with signs of severely impaired circulation, or those with any signs of impaired circulation. The quality of evidence for each outcome was appraised using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Findings are presented as risk ratios (RRs) with 95% CIs.
Six studies were included. Two were RCTs, one large trial (n=3141 children) from a low-income country and a smaller trial from a middle-income country. The remaining studies were from middle-income or high-income settings, observational, and with few participants (34–187 children).
Severely impaired circulation
The large RCT included a small subgroup with severely impaired circulation. There were more deaths in those receiving bolus fluids (20–40 mL/kg/h, saline or albumin) compared to maintenance fluids (2.5–4 mL/kg/h; RR 2.40, 95% CI 0.84 to 6.88, p=0.054, 65 participants, low quality evidence). Three additional observational studies, all at high risk of confounding, found mixed effects on mortality (very low quality evidence).
Any signs of impaired circulation
The large RCT included children with signs of both severely and non-severely impaired circulation. Overall, bolus fluids increased 48 h mortality compared to maintenance fluids with an additional 3 deaths per 100 children treated (RR 1.45, 95% CI 1.13 to 1.86, 3141 participants, high quality evidence). In a second small RCT from India, no difference in 72 h mortality was detected between children who received 20–40 mL/kg Ringers lactate over 15 min and those who received 20 mL over 20 min up to a maximum of 60 mL/kg over 1 h (147 participants, low quality evidence). In one additional observational study, resuscitation consistent with Advanced Paediatric Life Support (APLS) guidelines, including fluids, was not associated with reduced mortality in the small subgroup with septic shock (very low quality evidence).
Signs of impaired circulation, but not severely impaired
Only the large RCT allowed an analysis for children with some signs of impaired circulation who would not meet the criteria for severe impairment. Bolus fluids increased 48 h mortality compared to maintenance alone (RR 1.36, 95% CI 1.05 to 1.76, high quality evidence).
Prior to the publication of the large RCT, the global evidence base for bolus fluid therapy in children with severe febrile illness and signs of impaired circulation was of very low quality. This large study provides robust evidence that in low-income settings fluid boluses increase mortality in children with severe febrile illness and impaired circulation, and this increased risk is consistent across children with severe and less severe circulatory impairment.
PMCID: PMC4010848  PMID: 24785400
7.  Osmotic therapies added to antibiotics for acute bacterial meningitis 
Every day children and adults throughout the world die from acute community-acquired bacterial meningitis, particularly in low-income countries. Survivors are at risk of deafness, epilepsy and neurological disabilities. Osmotic therapies have been proposed as an adjunct to improve mortality and morbidity from bacterial meningitis. The theory is that they will attract extra-vascular fluid by osmosis and thus reduce cerebral oedema by moving excess water from the brain into the blood. The intention is to thus reduce death and improve neurological outcomes.
To evaluate the effects on mortality, deafness and neurological disability of osmotic therapies added to antibiotics for acute bacterial meningitis in children and adults.
Search methods
We searched CENTRAL 2012, Issue 11, MEDLINE (1950 to November week 3, 2012), EMBASE (1974 to November 2012), CINAHL (1981 to November 2012), LILACS (1982 to November 2012) and registers of ongoing clinical trials (April 2012). We also searched conference abstracts and contacted researchers in the field.
Selection criteria
Randomised controlled trials testing any osmotic therapy in adults or children with acute bacterial meningitis.
Data collection and analysis
Two review authors independently screened the search results and selected trials for inclusion. We collected data from each study for mortality, deafness, seizures and neurological disabilities. Results are presented using risk ratios (RR) and 95% confidence intervals (CI) and grouped according to whether the participants received steroids or not.
Main results
Four trials were included comprising 1091 participants. All compared glycerol (a water-soluble sugar alcohol) with a control; in three trials this was a placebo, and in one a small amount of 50% dextrose. Three trials included comparators of dexamethasone alone or in combination with glycerol. As dexamethasone appeared to have no modifying effect, we aggregated results across arms where both treatment and control groups received corticosteroids and where both treatment and control groups did not.
Compared to placebo, glycerol may have little or no effect on death in people with bacterial meningitis (RR 1.09, 95% confidence interval (CI) 0.89 to 1.33, 1091 participants, four trials, low-quality evidence); or on death and neurological disability combined (RR 1.04, 95% CI 0.86 to 1.25).
Glycerol may have little or no effect on seizures during treatment for meningitis (RR 1.08, 95% CI 0.90 to 1.30, 909 participants, three trials, low-quality evidence).
Glycerol may reduce the risk of subsequent deafness (RR 0.60, 95% CI 0.38 to 0.93, 741 participants, four trials, low-quality evidence).
Authors’ conclusions
The only osmotic diuretic to have undergone randomised evaluation is glycerol. Data from trials to date have not demonstrated benefit on death, but it may reduce deafness. Osmotic diuretics, including glycerol, should not be given to adults and children with bacterial meningitis unless as part of carefully conducted randomised controlled trial.
PMCID: PMC3996551  PMID: 23543568
Adrenal Cortex Hormones [therapeutic use]; Anti-Bacterial Agents [therapeutic use]; Combined Modality Therapy [methods]; Community-Acquired Infections [complications; metabolism; mortality; therapy]; Deafness [prevention & control]; Dexamethasone [therapeutic use]; Diuretics, Osmotic [*therapeutic use]; Epilepsy [prevention & control]; Glucose [therapeutic use]; Glycerol [*therapeutic use]; Intracranial Pressure [physiology]; Meningitis, Bacterial [complications; metabolism; mortality; *therapy]; Osmosis [physiology]; Osmotic Pressure [physiology]; Randomized Controlled Trials as Topic; Adolescent; Adult; Child; Humans
8.  The Impact of Pyrethroid Resistance on the Efficacy of Insecticide-Treated Bed Nets against African Anopheline Mosquitoes: Systematic Review and Meta-Analysis 
PLoS Medicine  2014;11(3):e1001619.
In a systematic review and meta-analysis, Clare Strode and colleagues assess whether insecticide resistance in African Anopheline mosquitoes affects the efficacy of insecticide-treated bed nets.
Please see later in the article for the Editors' Summary
Pyrethroid insecticide-treated bed nets (ITNs) help contribute to reducing malaria deaths in Africa, but their efficacy is threatened by insecticide resistance in some malaria mosquito vectors. We therefore assessed the evidence that resistance is attenuating the effect of ITNs on entomological outcomes.
Methods and Findings
We included laboratory and field studies of African malaria vectors that measured resistance at the time of the study and used World Health Organization–recommended impregnation regimens. We reported mosquito mortality, blood feeding, induced exophily (premature exit of mosquitoes from the hut), deterrence, time to 50% or 95% knock-down, and percentage knock-down at 60 min. Publications were searched from 1 January 1980 to 31 December 2013 using MEDLINE, Cochrane Central Register of Controlled Trials, Science Citation Index Expanded, Social Sciences Citation Index, African Index Medicus, and CAB Abstracts. We stratified studies into three levels of insecticide resistance, and ITNs were compared with untreated bed nets (UTNs) using the risk difference (RD). Heterogeneity was explored visually and statistically. Included were 36 laboratory and 24 field studies, reported in 25 records. Studies tested and reported resistance inconsistently. Based on the meta-analytic results, the difference in mosquito mortality risk for ITNs compared to UTNs was lower in higher resistance categories. However, mortality risk was significantly higher for ITNs compared to UTNs regardless of resistance. For cone tests: low resistance, risk difference (RD) 0.86 (95% CI 0.72 to 1.01); moderate resistance, RD 0.71 (95% CI 0.53 to 0.88); high resistance, RD 0.56 (95% CI 0.17 to 0.95). For tunnel tests: low resistance, RD 0.74 (95% CI 0.61 to 0.87); moderate resistance, RD 0.50 (95% CI 0.40 to 0.60); high resistance, RD 0.39 (95% CI 0.24 to 0.54). For hut studies: low resistance, RD 0.56 (95% CI 0.43 to 0.68); moderate resistance, RD 0.39 (95% CI 0.16 to 0.61); high resistance, RD 0.35 (95% CI 0.27 to 0.43). However, with the exception of the moderate resistance category for tunnel tests, there was extremely high heterogeneity across studies in each resistance category (chi-squared test, p<0.00001, I2 varied from 95% to 100%).
This meta-analysis found that ITNs are more effective than UTNs regardless of resistance. There appears to be a relationship between resistance and the RD for mosquito mortality in laboratory and field studies. However, the substantive heterogeneity in the studies' results and design may mask the true relationship between resistance and the RD, and the results need to be interpreted with caution. Our analysis suggests the potential for cumulative meta-analysis in entomological trials, but further field research in this area will require specialists in the field to work together to improve the quality of trials, and to standardise designs, assessment, and reporting of both resistance and entomological outcomes.
Please see later in the article for the Editors' Summary
Editors' Summary
Every year more than 200 million cases of malaria occur worldwide, and more than 600,000 people, mostly children living in sub-Saharan Africa, die from this parasitic infection. Malaria is transmitted to people through the bites of night-flying mosquitoes. Soon after entering the human body, the parasite begins to replicate in red blood cells, bursting out every 2–3 days and infecting more red blood cells. The presence of the parasite in the bloodstream causes malaria's recurring flu-like symptoms, which need to be treated promptly with antimalarial drugs to prevent anemia (a reduction in red blood cell numbers) and life-threatening organ damage. Malaria can be prevented by using insecticides to control the mosquitoes (vectors) that spread the parasite and by sleeping under insecticide-treated bed nets (ITNs) to avoid mosquito bites. High levels of ITN use reduce malaria-related deaths among children by about 20%. Consequently, the widespread provision of ITNs is a mainstay of global efforts to control malaria.
Why Was This Study Done?
About 50% of African households now possess an ITN. However, the emergence of resistance to pyrethroid insecticides—the insecticide class recommended by the World Health Organization for use in ITNs—in some mosquitoes potentially threatens the efficacy of ITNs. Pyrethroids kill Anopheles mosquitoes (the main malaria vectors in sub-Saharan Africa) but also prevent mosquitoes entering houses (deterrence), disrupt feeding, and encourage mosquitoes to leave homes prematurely (“induced exophily”; Anopheles mosquitoes usually rest inside for a while after feeding). Worryingly, 27 countries in sub-Saharan Africa have already reported resistance to pyrethroids in Anopheles mosquitoes. In this systematic review and meta-analysis, the researchers assess the impact of pyrethroid resistance on the efficacy of ITNs against African anopheline mosquitoes in terms of entomological outcomes. A systematic review identifies all the research on a given topic using predefined criteria, meta-analysis uses statistical methods to combine the results of several studies, and entomological outcomes are measures of mosquito behavior and survival.
What Did the Researchers Do and Find?
The researchers identified 25 reports of laboratory and field studies of the impact of ITNs on African malaria vectors that measured the mosquitoes' resistance to pyrethroid insecticides at the time of the study. The laboratory studies used two assays to measure entomological outcomes. The cone test measured mosquito mortality (death), percent of mosquitoes knocked down (immobilized) after 60 minutes, and the time to knock down 50% or 95% of the mosquitoes after brief exposure to an ITN or untreated bed net (UTN). In the tunnel test, mosquitoes had to pass through a holed ITN or UTN to reach animal baits; counts of live and dead mosquitoes, and fed and unfed mosquitoes on both sides of the net measured deterrence, blood feeding, and mosquito mortality. In the field studies, volunteers slept under an ITN or UTN in an experimental hut. Subsequent counts of live and dead mosquitoes and fed and unfed mosquitoes inside the huts and in exit traps measured deterrence, blood feeding, mosquito mortality, and induced exophily. The researchers report that the measurement of insecticide resistance was inconsistent across the identified studies. Nevertheless, their analysis found that ITNs are more effective than UTNs in relation to mosquito mortality, regardless of resistance. There was a relationship between resistance and the risk difference for mosquito mortality in laboratory and field studies, but the substantive variation between studies means that the findings should be interpreted with caution.
What Do These Findings Mean?
These findings show that pyrethroid resistance clearly affects entomological outcomes in laboratory studies, and suggests that this pattern may also be observed in field trials. However, ITNs remained at least somewhat effective despite insecticide resistance in terms of personal protection. The researchers note that there was considerable variability (heterogeneity) among the results obtained in the field trials and suggest that poorly standardized methods and reporting might have masked the true relationship between insecticide resistance and ITN efficacy in these studies. Thus, although ITNs continue to have a substantive effect in many laboratory studies in the face of insecticide resistance, whether ITNs are likely to remain effective against insecticide-resistant mosquitoes in the real world cannot be definitively concluded. Malaria experts and vector biologists need to work together to improve the quality of field trials and to standardize the measurement of insecticide resistance and entomological outcomes, suggest the researchers. Such collaborations, they conclude, are essential to provide the data that policy makers need to plan malaria control strategies.
Additional Information
Please access these websites via the online version of this summary at
Information is available from the World Health Organization on malaria (in several languages); the World Malaria Report 2013 provides details of the current global malaria situation
Information is available from the World Health Organization on a call for action to tackle the growing threat of insecticide resistance and to facilitate the development of innovative vector control tools and strategies (in English, French and Spanish)
The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish) and on insecticide-treated bed nets; it also provides a selection of personal stories about malaria
Information is available from the Roll Back Malaria Partnership on the global control of malaria and on the Global Malaria Action Plan (in English and French); its website includes fact sheets about malaria in Africa and about insecticide-treated bed nets
MedlinePlus provides links to additional information on malaria (in English and Spanish)
PMCID: PMC3958359  PMID: 24642791
9.  Artemisinin Combination Therapy: A Good Antimalarial, but Is the Dose Right? 
PLoS Medicine  2013;10(12):e1001565.
In an accompanying Perspective, Paul Garner further discusses dosing issues for artemisinin combination therapy.
Please see later in the article for the Editors' Summary
PMCID: PMC3861545  PMID: 24348204
10.  Translating Cochrane Reviews to Ensure that Healthcare Decision-Making is Informed by High-Quality Research Evidence 
PLoS Medicine  2013;10(9):e1001516.
Erik von Elm and colleagues discuss plans to increase access and global reach of Cochrane Reviews through translations into other languages.
Please see later in the article for the Editors' Summary
PMCID: PMC3775718  PMID: 24068897
11.  Correction: World Health Organization Guideline Development: An Evaluation 
PLoS ONE  2013;8(9):10.1371/annotation/fd04e7c6-0d40-4d2c-a382-c5ad10074c99.
PMCID: PMC3779259
12.  Has the NTD Community Neglected Evidence-Based Policy? 
PMCID: PMC3708801  PMID: 23875030
13.  World Health Organization Guideline Development: An Evaluation 
PLoS ONE  2013;8(5):e63715.
Research in 2007 showed that World Health Organization (WHO) recommendations were largely based on expert opinion, rarely used systematic evidence-based methods, and did not follow the organization's own “Guidelines for Guidelines”. In response, the WHO established a “Guidelines Review Committee” (GRC) to implement and oversee internationally recognized standards. We examined the impact of these changes on WHO guideline documents and explored senior staff's perceptions of the new procedures.
Methods and Findings
We used the AGREE II guideline appraisal tool to appraise ten GRC-approved guidelines from nine WHO departments, and ten pre-GRC guidelines matched by department and topic. We interviewed 20 senior staff across 16 departments and analyzed the transcripts using the framework approach. Average AGREE II scores for GRC-approved guidelines were higher across all six AGREE domains compared with pre-GRC guidelines. The biggest changes were noted for “Rigour of Development” (up 37.6%, from 30.7% to 68.3%) and “Editorial Independence” (up 52.7%, from 20.9% to 73.6%). Four main themes emerged from the interviews: (1) high standards were widely recognized as essential for WHO credibility, particularly with regard to conflicts of interest; (2) views were mixed on whether WHO needed a single quality assurance mechanism, with some departments purposefully bypassing the procedures; (3) staff expressed some uncertainties in applying the GRADE approach, with departmental staff concentrating on technicalities while the GRC remained concerned the underlying principles were not fully institutionalized; (4) the capacity to implement the new standards varied widely, with many departments looking to an overstretched GRC for technical support.
Since 2007, WHO guideline development methods have become more systematic and transparent. However, some departments are bypassing the procedures, and as yet neither the GRC, nor the quality assurance standards they have set, are fully embedded within the organization.
PMCID: PMC3669321  PMID: 23741299
14.  Integrating Global and National Knowledge to Select Medicines for Children: The Ghana National Drugs Programme 
PLoS Medicine  2013;10(5):e1001449.
David Sinclair and colleagues discuss their experience at the Ghana National Drugs Programme reviewing the international evidence base for five priority pediatric medicines and report that applying the global recommendations to Ghana was not straightforward for any of the five medicines.
Please see later in the article for the Editors' Summary
PMCID: PMC3660441  PMID: 23704834
15.  Incidence, Clinical Features and Impact on Anti-Tuberculosis Treatment of Anti-Tuberculosis Drug Induced Liver Injury (ATLI) in China 
PLoS ONE  2011;6(7):e21836.
Anti-tuberculosis drug induced liver injury (ATLI) is emerging as a significant threat to tuberculosis control in China, though limited data is available about the burden of ATLI at population level. This study aimed to estimate the incidence of ATLI, to better understand its clinical features, and to evaluate its impact on anti-tuberculosis (TB) treatment in China.
Methodology/Principal Findings
In a population-based prospective study, we monitored 4,304 TB patients receiving directly observed treatment strategy (DOTS) treatment, and found that 106 patients developed ATLI with a cumulative incidence of 2.55% (95% Confidence Interval [CI], 2.04%–3.06%). Nausea, vomiting and anorexia were the top three most frequently observed symptoms. There were 35 (33.02%) ATLI patients with no symptoms, including 8 with severe hepatotoxicity. Regarding the prognosis of ATLI, 84 cases (79.25%) recovered, 18 (16.98%) improved, 2 (1.89%) failed to respond to the treatment with continued elevation of serum alanine aminotransferase, and 2 (1.89%) died as result of ATLI. Of all the ATLI cases, 74 (69.81%) cases changed their anti-TB treatment, including 4 (3.77%) cases with medication administration change, 21 (19.81%) cases with drugs replacement, 54 (50.94%) cases with therapy interruption, and 12 (11.32%) cases who discontinued therapy. In terms of treatment outcomes, 53 (51.46%) cases had TB cured in time, 48 (46.60%) cases had therapy prolonged, and 2 (1.94%) cases died. Compared with non-ATLI patients, ATLI patients had a 9.25-fold (95%CI, 5.69–15.05) risk of unsuccessful anti-TB treatment outcomes and a 2.11-fold (95%CI,1.23–3.60) risk of prolonged intensive treatment phase.
ATLI could considerably impact the outcomes of anti-TB treatment. Given the incidence of ATLI and the size of TB population in China, the negative impact is substantial. Therefore, more research and efforts are warranted in order to enhance the diagnosis and the prevention of ATLI.
PMCID: PMC3130045  PMID: 21750735
16.  Do existing research summaries on health systems match immunisation managers' needs in middle- and low-income countries? Analysis of GAVI health systems strengthening support 
BMC Public Health  2011;11:449.
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.
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.
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.
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.
PMCID: PMC3125377  PMID: 21651793
17.  Patient medical costs for tuberculosis treatment and impact on adherence in China: a systematic review 
BMC Public Health  2011;11:393.
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.
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.
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.
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.
PMCID: PMC3125370  PMID: 21615930
18.  Tuberculosis (HIV-negative people) 
Clinical Evidence  2009;2009:0904.
About a third of the world's population has latent tuberculosis. In 2004, over 14 million people had active tuberculosis. Approximately 1.7 million people died from the infection. Over 80% of new cases diagnosed in 2004 were in people in Africa, South-East Asia, and Western Pacific regions.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent tuberculosis in people without HIV infection at high risk of developing tuberculosis? What are the effects of interventions to prevent tuberculosis in people without HIV infection at high risk of developing multidrug-resistant tuberculosis? What are the effects of different drug regimens in people with newly diagnosed pulmonary tuberculosis without HIV infection? What are the effects of different drug regimens in people with multidrug-resistant tuberculosis without HIV infection? What are the effects of low-level laser therapy in people with tuberculosis without HIV infection? Which interventions improve adherence to treatment in people with tuberculosis without HIV infection? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 31 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding pyrazinamide in chemotherapy regimens lasting up to 6 months; adding rifampicin to isoniazid regimens; benefits of different regimens; chemotherapy for less than 6 months; daily chemotherapy; direct observation treatment; intermittent chemotherapy for 6 months or longer; isoniazid; low-level laser therapy for pulmonary tuberculosis; regimens containing quinolones; rifampicin plus isoniazid; substituting rifampicin with ethambutol in the continuous phase; and support mechanisms for directly observed treatment.
Key Points
About a third of the world's population has latent tuberculosis. Over 14 million people had active tuberculosis in 2004, many of whom also had HIV. Approximately 1.7 million people died from the infection.Over 80% of new cases diagnosed in 2004 were in people in Africa, South-East Asia, and Western Pacific regions.
Most people who inhale Mycobacterium tuberculosis clear the infection and become skin-test positive. Active infection is more likely in people affected by social factors, such as poverty, overcrowding, homelessness, and inadequate health care, or with reduced immune function — such as with HIV infection.Some people develop latent infection — persistent bacterial presence which is asymptomatic and not infectious.
Drug treatments can reduce the risk of active tuberculosis in people at high risk of infection. Prophylactic isoniazid for 6 months can reduce the risk of tuberculosis infection in high-risk people without HIV, but increases the risk of hepatotoxicity. Rifampicin plus isoniazid for 3-4 months, or isoniazid for 6-12 months, may be equally effective at reducing active infection rates in people with latent tuberculosis.
Treatment requires chemotherapy with combination regimens. Adding rifampicin to isoniazid is more effective than isoniazid treatment alone, and more effective than ethambutol plus isoniazid regimens.Regimens including pyrazinamide improve short-term sputum clearance, but long-term effects are unclear. Quinolones, such as ciprofloxacin, ofloxacin, and moxifloxacin, have not been shown to improve outcomes compared with ethambutol, isoniazid, and pyrazinamide regimens, but the evidence is sparse.
The optimal length of treatment seems to be 6 months, but evidence is not robust. Relapse rates are the same after 6 months' treatment compared with longer regimens. Intermittent chemotherapy, taken 2−3 times a week, may be as effective as daily treatment for 6 months or more, but the evidence is weak.
Current practice in multidrug-resistant tuberculosis is to use at least three drugs to which the particular strain is sensitive.
Direct observation of treatment (DOT) does not seem to increase cure rates compared with self-administered treatment. We don't know how different types of support mechanisms for DOT compare with each other.
PMCID: PMC2907790  PMID: 19445749
19.  Quality of Private and Public Ambulatory Health Care in Low and Middle Income Countries: Systematic Review of Comparative Studies 
PLoS Medicine  2011;8(4):e1000433.
Paul Garner and colleagues conducted a systematic review of 80 studies to compare the quality of private versus public ambulatory health care in low- and middle-income countries.
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.
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.
Please see later in the article for the Editors' Summary
Editors' Summary
The provision of private (“for-profit” hospitals and self-employed practitioners, and “not-for-profit” non-government providers, including faith-based organizations) versus public health care services in low and middle income countries raises considerable ideological debate. Ideological arguments aside—which can be very passionate on both sides—there is general agreement that improving the quality of both public and private health care could have a major impact on improved health outcomes, especially as the private sector is so widely used in low and middle income countries. For example, almost three quarters and half of children from the poorest households of South Asia and sub-Saharan Africa, respectively, seek health care from a private provider when they are ill. Private providers are also increasingly responsible for outpatient care for non-communicable diseases.
As a result of the mixed health care system in many low and middle income countries, adequate oversight and stewardship of the mixed system from the national government is essential yet often missing.
Why Was This Study Done?
An understanding of how quality and performance in the private sector compares with that in the public sector would help governments to prioritize where they need to concentrate their efforts. So, for example, if the private sector is generally providing poorer quality care than the public sector, then there is an imperative to improve the quality and outcomes; on the other hand, if the quality of care offered by the private sector is good, the policy priority is to influence the market to further improve access to such health care for low income groups.
In order to help with this comparison, the researchers wanted to systematically identify and summarize the results of studies that directly compared the quality of care offered by public providers with the one offered by “formal” private providers (recognized by law) and “informal” private providers (providers that are not legally recognized, such as lay health workers and shop keepers). For the purposes of this study the researchers focused their comparison on the private and public provision of outpatient care in low and middle income countries.
What Did the Researchers Do and Find?
In their literature review, the researchers searched for relevant studies reported in English, French, or German and published between January 1970 and April 2009. Only studies that compared private and public outpatient medical services in the same country, at the same time, using the same methods, and which met particular quality criteria, were included in the analysis. The researchers also had strict criteria for including qualitative studies, and they retrieved the full text of articles, contacted study authors where appropriate, and verified with a second researcher most (80%) of the extracted study data. In order to evaluate and compare the studies, the researchers converted study values to a linear 100% scale, calculated differences between providers within studies, and summarized the median values of the differences across studies.
The researchers identified a total of 8,812 relevant titles and abstracts and found 80 studies that included direct quantitative comparisons of public and private formal providers. Ten studies included qualitative data. Most studies were conducted after 1990, and mainly in sub-Saharan Africa (n = 39) and Asia and the Pacific (n = 23). Most studies did not report socio-economic status of public and private service users, and only five studies presented data by different income groups. No study compared the same individual providers working in public and private care settings. Only two studies compared public providers and private informal providers, so the authors excluded these from subsequent analysis.
For the formal sector, since the results for “for-profit” and “not-for-profit” providers were similar, the researchers decided to combine the results. Overall, the researchers found that the median values indicated that many services, irrespective of whether public or private, scored low (less than 50%) on infrastructure, clinical competence, and practice. Generally, the private sector performed better in relation to drug supply, responsiveness, and effort, but there was no detectable difference between provider groups for patient satisfaction. Furthermore, a synthesis of qualitative data suggested that the private sector may be more client-centered.
What Do These Findings Mean?
Based on the findings of this review, there is a clear need to consider the quality of primary health services in both the public and private sector in order to improve health outcomes in low and middle income countries. These findings also indicate that, for some aspects of care, on average the private sector provided better quality services. The overall low quality of care in both the formal private and public sector found in this review is worrying, and calls for the governments of low and middle income countries to find and implement effective strategies to improve the quality in both sectors. This is particularly important given the increasing volume of conditions that require relatively sophisticated, long-term ambulatory medical care, such as non-communicable diseases.
Additional Information
Please access these Web sites via the online version of this summary at
This study is further discussed in a PLoS Medicine Perspective by Jishnu Das
WHO has more information on health service delivery in low- and middle-income countries
WHO has more information on noncommunicable diseases
The World Bank's World Development Report for 2004 addresses health care for poor people
PMCID: PMC3075233  PMID: 21532746
20.  Priorities for tuberculosis research: a systematic review 
The Lancet Infectious Diseases  2010;10(12):889-892.
Reliable and relevant research can help to improve tuberculosis control worldwide. In recent years, various organisations have assessed research needs and proposed priorities for tuberculosis. We summarise existing priority statements and assess the rigour of the methods used to generate them. We found 33 documents that specifically outline priorities in tuberculosis research. The top priority areas were drug development (28 articles), diagnosis and diagnostic tests (27), epidemiology (20), health services research (16), basic research (13), and vaccine development and use (13). The most focused questions were on the treatment and prevention of multidrug-resistant tuberculosis in people co-infected with HIV. Methods used to identify these priorities were varied. Improvements can be made to ensure the process is more rigorous and transparent, and to use existing research or systematic reviews more often. WHO, Stop TB Partnership, and other organisations could adopt an incremental process of priority development, building on the existing knowledge base.
PMCID: PMC2992175  PMID: 21050822
21.  Ribavirin for Crimean-Congo hemorrhagic fever: systematic review and meta-analysis 
BMC Infectious Diseases  2010;10:207.
Crimean-Congo hemorrhagic fever epidemics often occur in areas where health services are limited, and result in high case fatality rates. Besides intensive care, ribavirin is often recommended. A solid evidence base for the use of this drug will help justify assuring access to the drug in areas where epidemics are common.
We carried out a systematic review of observational and experimental studies of people with suspected or confirmed Crimean-Congo hemorrhagic fever that included comparisons between patients given ribavirin and those not. We extracted data on mortality, hospital stay, and adverse events. Risk of bias was assessed using a standard checklist, and data were presented in meta-analytical graphs, stratified by study design, and GRADE tables presented. The risk of bias was summarised using the GRADE method.
21 unique studies, including one randomised controlled trial of ribavirin, were included. Quality of the evidence was very low, with a Down and Black median score of 4 (maximum possible 33). Ribavirin treatment was not shown to be superior to no ribavirin treatment for mortality rate in a single RCT (RR: 1.13, 95%CI: 0.29 to 4.32, 136 participants, GRADE=low quality evidence); but ribavirin was associated with reduced mortality by 44% when compared to no ribavirin treatment in the pooled observational studies (RR: 0.56, 95%CI: 0.35 to 0.90, 955 participants; GRADE=very low quality evidence). Adverse events were more common with the ribavirin patients, but no severe adverse events were reported. No difference in length of hospital stay was reported.
No clear message of benefit is available from the current data on ribavirin as observational data are heavily confounded, and the one trial carried out has limited power. However, ribavirin could potentially have benefits in this condition and these results clearly indicate a pragmatic, randomised controlled trial in the context of good quality supportive care, is urgently needed and ethically justified.
PMCID: PMC2912908  PMID: 20626907
22.  Occupational injury history and universal precautions awareness: a survey in Kabul hospital staff 
Health staff in Afghanistan may be at high risk of needle stick injury and occupational infection with blood borne pathogens, but we have not found any published or unpublished data.
Our aim was to measure the percentage of healthcare staff reporting sharps injuries in the preceding 12 months, and to explore what they knew about universal precautions. In five randomly selected government hospitals in Kabul a total of 950 staff participated in the study. Data were analyzed with Epi Info 3.
Seventy three percent of staff (72.6%, 491/676) reported sharps injury in the preceding 12 months, with remarkably similar levels between hospitals and staff cadres in the 676 (71.1%) people responding. Most at risk were gynaecologist/obstetricians (96.1%) followed by surgeons (91.1%), nurses (80.2%), dentists (75.4%), midwives (62.0%), technicians (50.0%), and internist/paediatricians (47.5%). Of the injuries reported, the commonest were from hollow-bore needles (46.3%, n = 361/780), usually during recapping. Almost a quarter (27.9%) of respondents had not been vaccinated against hepatitis B. Basic knowledge about universal precautions were found insufficient across all hospitals and cadres.
Occupational health policies for universal precautions need to be implemented in Afghani hospitals. Staff vaccination against hepatitis B is recommended.
PMCID: PMC2835705  PMID: 20113517
23.  Malaria: uncomplicated, caused by Plasmodium falciparum  
Clinical Evidence  2008;2008:0919.
Malaria is a major health problem in the tropics, with 300 to 500 million new clinical cases annually, most of them cases of uncomplicated malaria. An estimated 1.1 to 2.7 million deaths occur annually as a result of severe falciparum malaria. Uncomplicated malaria can progress to severe malaria, become chronic, or resolve, depending on host immunity and prompt access to appropriate treatment.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: Are artemisinin combination treatments more effective than non-artemisinin combination treatments in people living in endemic areas (excluding South-East Asia)? Which artemisinin combination treatment is most effective in people living in endemic areas? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2007 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 25 systematic reviews, RCTs, or observational studies that met our inclusion criteria.
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: amodiaquine plus sulfadoxine-pyrimethamine; artemether-lumefantrine; artesunate plus mefloquine; artesunate plus amodiaquine; and artesunate plus sulfadoxine-pyrimethamine.
Key Points
Uncomplicated malaria is where the person has symptomatic infection with malaria parasites, but no signs of vital organ disturbance. Uncomplicated malaria can progress to severe malaria, become chronic, or resolve, depending on host immunity and prompt access to appropriate treatment.Severe malaria is more likely to develop in people with no prior immunity, and accounts for over one million deaths worldwide each year.The choice between treatment regimens depends partly on background drug-resistance patterns in the relevant country or region.
In most RCTs, artemether-lumefantrine was more effective than amodiaquine plus sulfadoxine-pyrimethamine. However, it was not more effective in all RCTs.
Artesunate plus amodiaquine is more effective at curing a current infection than amodiaquine plus sulfadoxine-pyrimethamine, but, in terms of people being parasite free at day 28, there is little to choose between them, since the risk of new infections appears greater with artesunate plus amodiaquine.
Amodiaquine plus sulfadoxine-pyrimethamine achieved higher cure rates than artesunate plus sulfadoxine-pyrimethamine. Gametocyte clearance was better with artesunate plus sulfadoxine-pyrimethamine.
Evidence suggests that a six-dose regimen of artemether-lumefantrine is more effective than a four-dose regimen.
Both artemether-lumefantrine (6 doses) and artesunate plus amodiaquine were effective, but artemether-lumefantrine (6 doses) was superior in some trials.
Artesunate plus mefloquine performs better than artemether-lumefantrine in terms of cure in some areas where this has been studied.
The choice between artesunate plus amodiaquine and artesunate plus sulfadoxine-pyrimethamine depends on background drug-resistance patterns in the relevant country or region.
We found insufficient evidence on the effects of artemer-lumefantrine (6 doses) versus artesunate plus sulfadoxine-pyrimethamine, artesunate plus mefloquine versus artesunate plus amodiaquine, or artesunate plus mefloquine versus artesunate plus sulfadoxine-pyrimethamine.
PMCID: PMC2907983  PMID: 19450360
24.  Malaria: severe, life-threatening 
Clinical Evidence  2007;2007:0913.
Severe malaria mainly affects children under 5 years old, non-immune travellers, migrants to malarial areas, and people living in areas with unstable or seasonal malaria. Cerebral malaria, causing encephalopathy and coma, is fatal in around 20% of children and adults, and neurological sequelae may occur in some survivors. Severe malarial anaemia may have a mortality rate of over 13%.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of antimalarial treatments; and adjunctive treatment for complicated falciparum malaria in non-pregnant people? We searched: Medline, Embase, The Cochrane Library and other important databases up to December 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 31 systematic reviews, RCTs, or observational studies that met our inclusion criteria.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: dexamethasone, exchange blood transfusion, initial blood transfusion, intramuscular artemether, intravenous artesunate,
Key Points
Severe malaria mainly affects children under 5 years old, non-immune travellers, migrants to malarial areas, and people living in areas with unstable or seasonal malaria. Cerebral malaria, causing encephalopathy and coma, is fatal in around 20% of children and adults, and neurological sequelae may occur in some survivors.Severe malarial anaemia may have a mortality rate of over 13%.
International consensus has historically regarded quinine as standard treatment for severe falciparum malaria. Controlled trials will generally compare new treatments against this standard. We found no clear evidence on the best quinine treatment regimen or route of administration to use, although high initial dose quinine clears parasites more rapidly compared with lower-dose quinine, but increases the risk of adverse effects. Intravenous artesunate is probably more effective than quinine in reducing mortality from severe malaria. Intramuscular artemether and rectal artemisinin, artemether, artesunate, and dihydroartemisinin may be as effective as quinine in reducing mortality from severe malaria.We don't know how intramuscular arteether compares with quinine.Routine use of phenobarbitone in cerebral malaria may reduce convulsions compared with placebo, but can increase mortality. Dexamethasone has not been shown to reduce mortality from severe malaria, and it increases the risk of gastrointestinal bleeding and seizures.
We don't know whether initial blood transfusion or exchange blood transfusion reduce mortality from severe malaria as no adequate-quality studies have been found. Blood transfusion is associated with adverse effects, but is clinically essential in some circumstances.
PMCID: PMC2943816  PMID: 19454095
25.  Pathogens associated with persistent diarrhoea in children in low and middle income countries: systematic review 
Persistent diarrhoea in children is a common problem in low and middle income countries. To help target appropriate treatment for specific pathogens in the absence of diagnostic tests, we systematically reviewed pathogens most commonly associated with persistent diarrhoea in children.
We sought all descriptive studies of pathogens in the stool of children with diarrhoea of over 14 days duration in low and middle income countries with a comprehensive search of the MEDLINE, EMBASE, LILACS and WEB OF SCIENCE databases. We described the study designs and populations, assessed the quality of the laboratory tests, and extracted and summarised data on pathogens. For Escherichia coli, we calculated high and low prevalence estimates of all enteropathic types combined. Results across studies were compared for geographical patterns.
Nineteen studies were included. Some used episodes of diarrhoea as the unit of analysis, others used children. The quality of reporting of laboratory procedures varied, and pathogens (particularly E. coli types) were classified in different ways. As there were no apparent regional differences in pathogen prevalence, we aggregated data between studies to give a guide to overall prevalence. Enteropathic E. coli types were commonly found in children with persistent diarrhoea (up to 63%). Various other organisms, including viruses, bacteria and parasites, were detected but across all studies their prevalence was under 10%. However, these pathogens were also found in similar frequencies in children without diarrhoea.
A number of pathogens are commonly associated with persistent diarrhoea in children, but in children without diarrhoea the pathogens are found with similar frequencies. New research with carefully selected controls and standardised laboratory investigations across countries will help map causes and help explore effective options for presumptive treatment.
PMCID: PMC2709113  PMID: 19515227

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