Best step-up treatments for children with uncontrolled asthma: a systematic review and network meta-analysis of individual participant data.

BACKGROUND: There is uncertainty about the best treatment option for children/adolescents with uncontrolled asthma despite inhaled corticosteroids (ICS) and international guidelines make different recommendations. We evaluated the pharmacological treatments to reduce asthma exacerbations and symptoms in uncontrolled patients age <18 years on ICS. METHODS: We searched MEDLINE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Embase, Web of Science, National Institute for Health and Care Excellence Technology Appraisals, National Institute for Health and Care Research Health Technology Assessment series, World Health Organization International Clinical Trials Registry, conference abstracts and internal clinical trial registers (1 July 2014 to 5 May 2023) for randomised controlled trials of participants age <18 years with uncontrolled asthma on any ICS dose alone at screening. Studies before July 2014 were retrieved from previous systematic reviews/contact with authors. Patients had to be randomised to any dose of ICS alone or combined with long-acting ß2-agonists (LABA) or combined with leukotriene receptor antagonists (LTRA), LTRA alone, theophylline or placebo. Primary outcomes were exacerbation and asthma control. The interventions evaluated were ICS (low/medium/high dose), ICS+LABA, ICS+LTRA, LTRA alone, theophylline and placebo. RESULTS: Of the 4708 publications identified, 144 trials were eligible. Individual participant data were obtained from 29 trials and aggregate data were obtained from 19 trials. Compared with ICS Low, ICS Medium+LABA was associated with the lowest odds of exacerbation (OR 0.44, 95% credibility interval (95% CrI) 0.19-0.90) and with an increased forced expiratory volume in 1 s (mean difference 0.71, 95% CrI 0.35-1.06). Treatment with LTRA was the least preferred. No apparent differences were found for asthma control. CONCLUSIONS: Uncontrolled children/adolescents on low-dose ICS should be recommended a change to medium-dose ICS+LABA to reduce the risk for exacerbation and improve lung function.

Radiological features characterising indeterminate testes masses: a systematic review and meta-analysis.

CONTEXT: The use of scrotal ultrasonography (SUS) has increased the detection rate of indeterminate testicular masses. Defining radiological characteristics that identify malignancy may reduce the number of men undergoing unnecessary radical orchidectomy. OBJECTIVE: To define which SUS or scrotal magnetic resonance imaging (MRI) characteristics can predict benign or malignant disease in pre- or post-pubertal males with indeterminate testicular masses. EVIDENCE ACQUISITION: This systematic review was conducted in accordance with Cochrane Collaboration guidance. Medline, Embase, Cochrane controlled trials and systematic reviews databases were searched from (1970 to 26 March 2021). Benign and malignant masses were classified using the reported reference test: i.e., histopathology, or 12 months progression-free radiological surveillance. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool (QUADAS-2). EVIDENCE SYNTHESIS: A total of 32 studies were identified, including 1692 masses of which 28 studies and 1550 masses reported SUS features, four studies and 142 masses reported MRI features. Meta-analysis of different SUS (B-mode) values in post-pubertal men demonstrated that a size of ≤0.5 cm had a significantly lower odds ratio (OR) of malignancy compared to masses of >0.5 cm (P < 0.001). Comparison of masses of 0.6-1.0 cm and masses of >1.5 cm also demonstrated a significantly lower OR of malignancy (P = 0.04). There was no significant difference between masses of 0.6-1.0 and 1.1-1.5 cm. SUS in post-pubertal men also had a statistically significantly lower OR of malignancy for heterogenous masses vs homogenous masses (P = 0.04), hyperechogenic vs hypoechogenic masses (P < 0.01), normal vs increased enhancement (P < 0.01), and peripheral vs central vascularity (P < 0.01), respectively. There were limited data on pre-pubertal SUS, pre-pubertal MRI and post-pubertal MRI. CONCLUSIONS: This meta-analysis identifies radiological characteristics that have a lower OR of malignancy and may be of value in the management of the indeterminate testis mass.

Public health deworming programmes for soil-transmitted helminths in children living in endemic areas.

BACKGROUND: The World Health Organization (WHO) recommends treating all school children at regular intervals with deworming drugs in areas where helminth infection is common. Global advocacy organizations claim routine deworming has substantive health and societal effects beyond the removal of worms. In this update of the 2015 edition we included six new trials, additional data from included trials, and addressed comments and criticisms. OBJECTIVES: To summarize the effects of public health programmes to regularly treat all children with deworming drugs on child growth, haemoglobin, cognition, school attendance, school performance, physical fitness, and mortality. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; Embase; LILACS; the metaRegister of Controlled Trials (mRCT); reference lists; and registers of ongoing and completed trials up to 19 September 2018. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and quasi-RCTs that compared deworming drugs for soil-transmitted helminths (STHs) with placebo or no treatment in children aged 16 years or less, reporting on weight, height, haemoglobin, and formal tests of cognition. We also sought data on other measures of growth, school attendance, school performance, physical fitness, and mortality. DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed the trials for inclusion, risk of bias, and extracted data. We analysed continuous data using the mean difference (MD) with 95% confidence intervals (CIs). Where data were missing, we contacted trial authors. We stratified the analysis based on the background burden of STH infection. We used outcomes at time of longest follow-up. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We identified 51 trials, including 10 cluster-RCTs, that met the inclusion criteria. One trial evaluating mortality included over one million children, and the remaining 50 trials included a total of 84,336 participants. Twenty-four trials were in populations categorized as high burden, including nine trials in children selected because they were helminth-stool positive; 18 with intermediate burden; and nine as low burden.First or single dose of deworming drugsFourteen trials reported on weight after a single dose of deworming drugs (4970 participants, 14 RCTs). The effects were variable. There was little or no effect in studies conducted in low and intermediate worm burden groups. In the high-burden group, there was little or no effect in most studies, except for a large effect detected from one study area in Kenya reported in two trials carried out over 30 years ago. These trials result in qualitative heterogeneity and uncertainty in the meta-analysis across all studies (I2 statistic = 90%), with GRADE assessment assessed as very low-certainty, which means we do not know if a first dose or single dose of deworming impacts on weight.For height, most studies showed little or no effect after a single dose, with one of the two trials in Kenya from 30 years ago showing a large average difference (2621 participants, 10 trials, low-certainty evidence). Single dose probably had no effect on average haemoglobin (MD 0.10 g/dL, 95% CI 0.03 lower to 0.22 higher; 1252 participants, five trials, moderate-certainty evidence), or on average cognition (1596 participants, five trials, low-certainty evidence). The data are insufficient to know if there is an effect on school attendance and performance (304 participants, one trial, low-certainty evidence), or on physical fitness (280 participants, three trials, very low-certainty evidence). No trials reported on mortality.Multiple doses of deworming drugsThe effect of regularly treating children with deworming drugs given every three to six months on weight was reported in 18 trials, with follow-up times of between six months and three years; there was little or no effect on average weight in all but two trials, irrespective of worm prevalence-intensity. The two trials with large average weight gain included one in the high burden area in Kenya carried out over 30 years ago, and one study from India in a low prevalence area where subsequent studies in the same area did not show an effect. This heterogeneity causes uncertainty in any meta-analysis (I2 = 78%). Post-hoc analysis excluding trials published prior to 2000 gave an estimate of average difference in weight gain of 0.02 kg (95%CI from 0.04 kg loss to 0.08 gain, I2 = 0%). Thus we conclude that we do not know if repeated doses of deworming drugs impact on average weight, with a fewer older studies showing large gains, and studies since 2000 showing little or no average gain.Regular treatment probably had little or no effect on the following parameters: average height (MD 0.02 cm higher, 95% CI 0.09 lower to 0.13 cm higher; 13,700 participants, 13 trials, moderate-certainty evidence); average haemoglobin (MD 0.01 g/dL lower; 95% CI 0.05 g/dL lower to 0.07 g/dL higher; 5498 participants, nine trials, moderate-certainty evidence); formal tests of cognition (35,394 participants, 8 trials, moderate-certainty evidence); school performance (34,967 participants, four trials, moderate-certainty evidence). The evidence assessing an effect on school attendance is inconsistent, and at risk of bias (mean attendance 2% higher, 95% CI 5% lower to 8% higher; 20,650 participants, three trials, very low-certainty evidence). No trials reported on physical fitness. No effect was shown on mortality (1,005,135 participants, three trials, low-certainty evidence). AUTHORS' CONCLUSIONS: Public health programmes to regularly treat all children with deworming drugs do not appear to improve height, haemoglobin, cognition, school performance, or mortality. We do not know if there is an effect on school attendance, since the evidence is inconsistent and at risk of bias, and there is insufficient data on physical fitness. Studies conducted in two settings over 20 years ago showed large effects on weight gain, but this is not a finding in more recent, larger studies. We would caution against selecting only the evidence from these older studies as a rationale for contemporary mass treatment programmes as this ignores the recent studies that have not shown benefit.The conclusions of the 2015 edition have not changed in this update.

A systematic review of placebo-controlled trials of topiramate: How useful is a multiple-indications review for evaluating the adverse events of an antiepileptic drug?

OBJECTIVE: Topiramate (TPM) is an antiepileptic drug that is also used for other indications (e.g., migraine). Adverse event (AE) data from epilepsy trials could be supplemented by data from trials in other indications. Combining data across trials and indications is a novel method for evaluating AEs. We conducted a multiple-indications review by systematically reviewing randomized placebo-controlled trials of TPM, to compare the nervous system AEs of TPM in epilepsy with those in other indications. METHODS: Randomized placebo-controlled trials of TPM including patients with any indication were included. We searched Cochrane Central Register of Controlled Trials (Issue 2, 2012) and MEDLINE (1966-February 2012). Two authors assessed eligibility and risk of bias, and extracted data. For each reported nervous system AE, we extracted event rates, applied random-effects inverse-variance meta-analysis (pooling within-indications then across-indications), and assessed within- and across-indication heterogeneity. RESULTS: Ninety trials, including 16 epilepsy trials, were included. A difference was detected between TPM and placebo for three events (i.e., drooling, dysgeusia, and hypoesthesia) that were not reported in epilepsy trials but were reported by other trials. A difference between TPM and placebo was detected for speech disorder using epilepsy trials but not when combining all trials. For two events (i.e., cognitive disorder and "language problems"), no difference was detected between TPM and placebo when using epilepsy trials alone, but a difference was identified using all trials. A difference was detected between TPM and placebo for six events (i.e., ataxia, disturbance in attention, dizziness, memory impairment, paraesthesia, and somnolence) when using epilepsy trials alone, and using all trials. SIGNIFICANCE: Including trials of any indication enabled detection of differences that would have been missed using epilepsy trials alone. Multiple-indications reviews can improve the synthesis of AEs for antiepileptic drugs.

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. As the intervention is often claimed to have important health, nutrition, and societal effects beyond the removal of worms, we critically evaluated the evidence on benefits. OBJECTIVES: To summarize the effects of giving deworming drugs to children to treat soil-transmitted helminths on weight, haemoglobin, and cognition; and the evidence of impact on physical well-being, school attendance, school performance, and mortality. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register (14 April 2015); Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library (2015, Issue 4); MEDLINE (2000 to 14 April 2015); EMBASE (2000 to 14 April 2015); LILACS (2000 to 14 April 2015); the metaRegister of Controlled Trials (mRCT); and reference lists, and registers of ongoing and completed trials up to 14 April 2015. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and quasi-RCTs comparing deworming drugs for soil-transmitted helminths with placebo or no treatment in children aged 16 years or less, reporting on weight, haemoglobin, and formal tests of intellectual development. We also sought data on school attendance, school performance, and mortality. We included trials that combined health education with deworming programmes. DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed the trials, evaluated risk of bias, and extracted data. We analysed continuous data using the mean difference (MD) with 95% confidence intervals (CIs). Where data were missing, we contacted trial authors. We used outcomes at time of longest follow-up. The evidence quality was assessed using GRADE. This edition of the Cochrane Review adds the DEVTA trial from India, and draws on an independent analytical replication of a trial from Kenya. MAIN RESULTS: We identified 45 trials, including nine cluster-RCTs, that met the inclusion criteria. One trial evaluating mortality included over one million children, and the remaining 44 trials included a total of 67,672 participants. Eight trials were in children known to be infected, and 37 trials were carried out in endemic areas, including areas of high (15 trials), moderate (12 trials), and low prevalence (10 trials). Treating children known to be infectedTreating children known to be infected with a single dose of deworming drugs (selected by screening, or living in areas where all children are infected) may increase weight gain over the next one to six months (627 participants, five trials, low quality evidence). The effect size varied across trials from an additional 0.2 kg gain to 1.3 kg. There is currently insufficient evidence to know whether treatment has additional effects on haemoglobin (247 participants, two trials, very low quality evidence); school attendance (0 trials); cognitive functioning (103 participants, two trials, very low quality evidence), or physical well-being (280 participants, three trials, very low quality evidence). Community deworming programmesTreating all children living in endemic areas with a dose of deworming drugs probably has little or no effect on average weight gain (MD 0.04 kg less, 95% CI 0.11 kg less to 0.04 kg more; trials 2719 participants, seven trials, moderate quality evidence), even in settings with high prevalence of infection (290 participants, two trials). A single dose also probably has no effect on average haemoglobin (MD 0.06 g/dL, 95% CI -0.05 lower to 0.17 higher; 1005 participants, three trials, moderate quality evidence), or average cognition (1361 participants, two trials, low quality evidence).Similiarly, regularly treating all children in endemic areas with deworming drugs, given every three to six months, may have little or no effect on average weight gain (MD 0.08 kg, 95% CI 0.11 kg less to 0.27 kg more; 38,392 participants, 10 trials, low quality evidence). The effects were variable across trials; one trial from a low prevalence setting carried out in 1995 found an increase in weight, but nine trials carried out since then found no effect, including five from moderate and high prevalence areas.There is also reasonable evidence that regular treatment probably has no effect on average height (MD 0.02 cm higher, 95% CI 0.14 lower to 0.17 cm higher; 7057 participants, seven trials, moderate quality evidence); average haemoglobin (MD 0.02 g/dL lower; 95% CI 0.08 g/dL lower to 0.04 g/dL higher; 3595 participants, seven trials, low quality evidence); formal tests of cognition (32,486 participants, five trials, moderate quality evidence); exam performance (32,659 participants, two trials, moderate quality evidence); or mortality (1,005,135 participants, three trials, low quality evidence). There is very limited evidence assessing an effect on school attendance and the findings are inconsistent, and at risk of bias (mean attendance 2% higher, 95% CI 4% lower to 8% higher; 20,243 participants, two trials, very low quality evidence).In a sensitivity analysis that only included trials with adequate allocation concealment, there was no evidence of any effect for the main outcomes. AUTHORS' CONCLUSIONS: Treating children known to have worm infection may have some nutritional benefits for the individual. However, in mass treatment of all children in endemic areas, there is now substantial evidence that this does not improve average nutritional status, haemoglobin, cognition, school performance, or survival.

The impact of pyrethroid resistance on the efficacy of insecticide-treated bed nets against African anopheline mosquitoes: systematic review and meta-analysis.

BACKGROUND: 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%). CONCLUSIONS: 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.

Dihydroartemisinin-piperaquine for treating uncomplicated Plasmodium falciparum malaria.

BACKGROUND: The World Health Organization (WHO) recommends Artemisinin-based Combination Therapy (ACT) for treating uncomplicated Plasmodium falciparum malaria. This review aims to assist the decision-making of malaria control programmes by providing an overview of the relative effects of dihydroartemisinin-piperaquine (DHA-P) versus other recommended ACTs. OBJECTIVES: To evaluate the effectiveness and safety of DHA-P compared to other ACTs for treating uncomplicated P. falciparum malaria in adults and children. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL) published in The Cochrane Library; MEDLINE; EMBASE; LILACS, and the metaRegister of Controlled Trials (mRCT) up to July 2013. SELECTION CRITERIA: Randomized controlled trials comparing a three-day course of DHA-P to a three-day course of an alternative WHO recommended ACT in uncomplicated P. falciparum malaria. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trials for eligibility and risk of bias, and extracted data. We analysed primary outcomes in line with the WHO 'Protocol for assessing and monitoring antimalarial drug efficacy' and compared drugs using risk ratios (RR) and 95% confidence intervals (CI). Secondary outcomes were effects on gametocytes, haemoglobin, and adverse events. We assessed the quality of evidence using the GRADE approach. MAIN RESULTS: We included 27 trials, enrolling 16,382 adults and children, and conducted between 2002 and 2010. Most trials excluded infants aged less than six months and pregnant women. DHA-P versus artemether-lumefantrineIn Africa, over 28 days follow-up, DHA-P is superior to artemether-lumefantrine at preventing further parasitaemia (PCR-unadjusted treatment failure: RR 0.34, 95% CI 0.30 to 0.39, nine trials, 6200 participants, high quality evidence), and although PCR-adjusted treatment failure was below 5% for both ACTs, it was consistently lower with DHA-P (PCR-adjusted treatment failure: RR 0.42, 95% CI 0.29 to 0.62, nine trials, 5417 participants, high quality evidence). DHA-P has a longer prophylactic effect on new infections which may last for up to 63 days (PCR-unadjusted treatment failure: RR 0.71, 95% CI 0.65 to 0.78, two trials, 3200 participants, high quality evidence).In Asia and Oceania, no differences have been shown at day 28 (four trials, 1143 participants, moderate quality evidence), or day 63 (one trial, 323 participants, low quality evidence).Compared to artemether-lumefantrine, no difference was seen in prolonged QTc (low quality evidence), and no cardiac arrhythmias were reported. The frequency of other adverse events is probably similar with both combinations (moderate quality evidence). DHA-P versus artesunate plus mefloquineIn Asia, over 28 days follow-up, DHA-P is as effective as artesunate plus mefloquine at preventing further parasitaemia (PCR-unadjusted treatment failure: eight trials, 3487 participants, high quality evidence). Once adjusted by PCR to exclude new infections, treatment failure at day 28 was below 5% for both ACTs in all eight trials, but lower with DHA-P in two trials (PCR-adjusted treatment failure: RR 0.41 95% CI 0.21 to 0.80, eight trials, 3482 participants, high quality evidence). Both combinations contain partner drugs with very long half-lives and no consistent benefit in preventing new infections has been seen over 63 days follow-up (PCR-unadjusted treatment failure: five trials, 2715 participants, moderate quality evidence).In the only trial from South America, there were fewer recurrent parastaemias over 63 days with artesunate plus mefloquine (PCR-unadjusted treatment failure: RR 6.19, 95% CI 1.40 to 27.35, one trial, 445 participants, low quality evidence), but no differences were seen once adjusted for new infections (PCR-adjusted treatment failure: one trial, 435 participants, low quality evidence).DHA-P is associated with less nausea, vomiting, dizziness, sleeplessness, and palpitations compared to artesunate plus mefloquine (moderate quality evidence). DHA-P was associated with more frequent prolongation of the QTc interval (low quality evidence), but no cardiac arrhythmias were reported. AUTHORS' CONCLUSIONS: In Africa, dihydroartemisinin-piperaquine reduces overall treatment failure compared to artemether-lumefantrine, although both drugs have PCR-adjusted failure rates of less than 5%. In Asia, dihydroartemisinin-piperaquine is as effective as artesunate plus mefloquine, and is better tolerated.

The diagnostic accuracy of the GenoType(®) MTBDRsl assay for the detection of resistance to second-line anti-tuberculosis drugs.

BACKGROUND: Accurate and rapid tests for tuberculosis (TB) drug resistance are critical for improving patient care and decreasing the transmission of drug-resistant TB. Genotype(®)MTBDRsl (MTBDRsl) is the only commercially-available molecular test for detecting resistance in TB to the fluoroquinolones (FQs; ofloxacin, moxifloxacin and levofloxacin) and the second-line injectable drugs (SLIDs; amikacin, kanamycin and capreomycin), which are used to treat patients with multidrug-resistant (MDR-)TB. OBJECTIVES: To obtain summary estimates of the diagnostic accuracy of MTBDRsl for FQ resistance, SLID resistance and extensively drug-resistant TB (XDR-TB; defined as MDR-TB plus resistance to a FQ and a SLID) when performed (1) indirectly (ie on culture isolates confirmed as TB positive) and (2) directly (ie on smear-positive sputum specimens).To compare summary estimates of the diagnostic accuracy of MTBDRsl for FQ resistance, SLID resistance and XDR-TB by type of testing (indirect versus direct testing).The populations of interest were adults with drug-susceptible TB or drug-resistant TB. The settings of interest were intermediate and central laboratories. SEARCH METHODS: We searched the following databases without any language restriction up to 30 January 2014: Cochrane Infectious Diseases Group Specialized Register; MEDLINE; EMBASE; ISI Web of Knowledge; MEDION; LILACS; BIOSIS; SCOPUS; the metaRegister of Controlled Trials; the search portal of the World Health Organization International Clinical Trials Registry Platform; and ProQuest Dissertations & Theses A&I. SELECTION CRITERIA: We included all studies that determined MTBDRsl accuracy against a defined reference standard (culture-based drug susceptibility testing (DST), genetic testing or both). We included cross-sectional and diagnostic case-control studies. We excluded unpublished data and conference proceedings. DATA COLLECTION AND ANALYSIS: For each study, two review authors independently extracted data using a standardized form and assessed study quality using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. We performed meta-analyses to estimate the pooled sensitivity and specificity of MTBDRsl for FQ resistance, SLID resistance, and XDR-TB. We explored the influence of different reference standards. We performed the majority of analyses using a bivariate random-effects model against culture-based DST as the reference standard. MAIN RESULTS: We included 21 unique studies: 14 studies reported the accuracy of MTBDRsl when done directly, five studies when done indirectly and two studies that did both. Of the 21 studies, 15 studies (71%) were cross-sectional and 11 studies (58%) were located in low-income or middle-income countries. All studies but two were written in English. Nine (43%) of the 21 included studies had a high risk of bias for patient selection. At least half of the studies had low risk of bias for the other QUADAS-2 domains.As a test for FQ resistance measured against culture-based DST, the pooled sensitivity of MTBDRsl when performed indirectly was 83.1% (95% confidence interval (CI) 78.7% to 86.7%) and the pooled specificity was 97.7% (95% CI 94.3% to 99.1%), respectively (16 studies, 1766 participants; 610 confirmed cases of FQ-resistant TB; moderate quality evidence). When performed directly, the pooled sensitivity was 85.1% (95% CI 71.9% to 92.7%) and the pooled specificity was 98.2% (95% CI 96.8% to 99.0%), respectively (seven studies, 1033 participants; 230 confirmed cases of FQ-resistant TB; moderate quality evidence). For indirect testing for FQ resistance, four (0.2%) of 1766 MTBDRsl results were indeterminate, whereas for direct testing 20 (1.9%) of 1033 were MTBDRsl indeterminate (P < 0.001).As a test for SLID resistance measured against culture-based DST, the pooled sensitivity of MTBDRsl when performed indirectly was 76.9% (95% CI 61.1% to 87.6%) and the pooled specificity was 99.5% (95% CI 97.1% to 99.9%), respectively (14 studies, 1637 participants; 414 confirmed cases of SLID-resistant TB; moderate quality evidence). For amikacin resistance, the pooled sensitivity and specificity were 87.9% (95% CI 82.1% to 92.0%) and 99.5% (95% CI 97.5% to 99.9%), respectively. For kanamycin resistance, the pooled sensitivity and specificity were 66.9% (95% CI 44.1% to 83.8%) and 98.6% (95% CI 96.1% to 99.5%), respectively. For capreomycin resistance, the pooled sensitivity and specificity were 79.5% (95% CI 58.3% to 91.4%) and 95.8% (95% CI 93.4% to 97.3%), respectively. When performed directly, the pooled sensitivity for SLID resistance was 94.4% (95% CI 25.2% to 99.9%) and the pooled specificity was 98.2% (95% CI 88.9% to 99.7%), respectively (six studies, 947 participants; 207 confirmed cases of SLID-resistant TB, 740 SLID susceptible cases of TB; very low quality evidence). For indirect testing for SLID resistance, three (0.4%) of 774 MTBDRsl results were indeterminate, whereas for direct testing 53 (6.1%) of 873 were MTBDRsl indeterminate (P < 0.001).As a test for XDR-TB measured against culture-based DST, the pooled sensitivity of MTBDRsl when performed indirectly was 70.9% (95% CI 42.9% to 88.8%) and the pooled specificity was 98.8% (95% CI 96.1% to 99.6%), respectively (eight studies, 880 participants; 173 confirmed cases of XDR-TB; low quality evidence). AUTHORS' CONCLUSIONS: In adults with TB, a positive MTBDRsl result for FQ resistance, SLID resistance, or XDR-TB can be treated with confidence. However, MTBDRsl does not detect approximately one in five cases of FQ-resistant TB, and does not detect approximately one in four cases of SLID-resistant TB. Of the three SLIDs, MTBDRsl has the poorest sensitivity for kanamycin resistance. MTBDRsl will miss between one in four and one in three cases of XDR-TB. The diagnostic accuracy of MTBDRsl is similar when done using either culture isolates or smear-positive sputum. As the location of the resistance causing mutations can vary on a strain-by-strain basis, further research is required on test accuracy in different settings and, if genetic sequencing is used as a reference standard, it should examine all resistance-determining regions. Given the confidence one can have in a positive result, and the ability of the test to provide results within a matter of days, MTBDRsl may be used as an initial test for second-line drug resistance. However, when the test reports a negative result, clinicians may still wish to carry out conventional testing.

Rapid diagnostic tests for diagnosing uncomplicated non-falciparum or Plasmodium vivax malaria in endemic countries.

BACKGROUND: In settings where both Plasmodium vivax and Plasmodium falciparum infection cause malaria, rapid diagnostic tests (RDTs) need to distinguish which species is causing the patients' symptoms, as different treatments are required. Older RDTs incorporated two test lines to distinguish malaria due to P. falciparum, from malaria due to any other Plasmodium species (non-falciparum). These RDTs can be classified according to which antibodies they use: Type 2 RDTs use HRP-2 (for P. falciparum) and aldolase (all species); Type 3 RDTs use HRP-2 (for P. falciparum) and pLDH (all species); Type 4 use pLDH (fromP. falciparum) and pLDH (all species).More recently, RDTs have been developed to distinguish P. vivax parasitaemia by utilizing a pLDH antibody specific to P. vivax. OBJECTIVES: To assess the diagnostic accuracy of RDTs for detecting non-falciparum or P. vivax parasitaemia in people living in malaria-endemic areas who present to ambulatory healthcare facilities with symptoms suggestive of malaria, and to identify which types and brands of commercial test best detect non-falciparum and P. vivax malaria. SEARCH METHODS: We undertook a comprehensive search of the following databases up to 31 December 2013: Cochrane Infectious Diseases Group Specialized Register; MEDLINE; EMBASE; MEDION; Science Citation Index; Web of Knowledge; African Index Medicus; LILACS; and IndMED. SELECTION CRITERIA: Studies comparing RDTs with a reference standard (microscopy or polymerase chain reaction) in blood samples from a random or consecutive series of patients attending ambulatory health facilities with symptoms suggestive of malaria in non-falciparum endemic areas. DATA COLLECTION AND ANALYSIS: For each study, two review authors independently extracted a standard set of data using a tailored data extraction form. We grouped comparisons by type of RDT (defined by the combinations of antibodies used), and combined in meta-analysis where appropriate. Average sensitivities and specificities are presented alongside 95% confidence intervals (95% CI). MAIN RESULTS: We included 47 studies enrolling 22,862 participants. Patient characteristics, sampling methods and reference standard methods were poorly reported in most studies. RDTs detecting 'non-falciparum' parasitaemiaEleven studies evaluated Type 2 tests compared with microscopy, 25 evaluated Type 3 tests, and 11 evaluated Type 4 tests. In meta-analyses, average sensitivities and specificities were 78% (95% CI 73% to 82%) and 99% (95% CI 97% to 99%) for Type 2 tests, 78% (95% CI 69% to 84%) and 99% (95% CI 98% to 99%) for Type 3 tests, and 89% (95% CI 79% to 95%) and 98% (95% CI 97% to 99%) for Type 4 tests, respectively. Type 4 tests were more sensitive than both Type 2 (P = 0.01) and Type 3 tests (P = 0.03).Five studies compared Type 3 tests with PCR; in meta-analysis, the average sensitivity and specificity were 81% (95% CI 72% to 88%) and 99% (95% CI 97% to 99%) respectively. RDTs detecting P.vivax parasitaemiaEight studies compared pLDH tests to microscopy; the average sensitivity and specificity were 95% (95% CI 86% to 99%) and 99% (95% CI 99% to 100%), respectively. AUTHORS' CONCLUSIONS: RDTs designed to detect P. vivax specifically, whether alone or as part of a mixed infection, appear to be more accurate than older tests designed to distinguish P. falciparum malaria from non-falciparum malaria. Compared to microscopy, these tests fail to detect around 5% ofP. vivax cases. This Cochrane Review, in combination with other published information about in vitro test performance and stability in the field, can assist policy-makers to choose between the available RDTs.

Rapid diagnostic tests versus clinical diagnosis for managing people with fever in malaria endemic settings.

BACKGROUND: In 2010, the World Health Organization recommended that all patients with suspected malaria are tested for malaria before treatment. In rural African settings light microscopy is often unavailable. Diagnosis has relied on detecting fever, and most people were given antimalarial drugs presumptively. Rapid diagnostic tests (RDTs) provide a point-of-care test that may improve management, particularly of people for whom the RDT excludes the diagnosis of malaria. OBJECTIVES: To evaluate whether introducing RDTs into algorithms for diagnosing and treating people with fever improves health outcomes, reduces antimalarial prescribing, and is safe, compared to algorithms using clinical diagnosis. SEARCH METHODS: We searched the Cochrane Infectious Disease Group Specialized Register; CENTRAL (The Cochrane Library); MEDLINE; EMBASE; CINAHL; LILACS; and the metaRegister of Controlled Trials for eligible trials up to 10 January 2014. We contacted researchers in the field and reviewed the reference lists of all included trials to identify any additional trials. SELECTION CRITERIA: Individual or cluster randomized trials (RCTs) comparing RDT-supported algorithms and algorithms using clinical diagnosis alone for diagnosing and treating people with fever living in malaria-endemic settings. DATA COLLECTION AND ANALYSIS: Two authors independently applied the inclusion criteria and extracted data. We combined data from individually and cluster RCTs using the generic inverse variance method. We presented all outcomes as risk ratios (RR) with 95% confidence intervals (CIs), and assessed the quality of evidence using the GRADE approach. MAIN RESULTS: We included seven trials, enrolling 17,505 people with fever or reported history of fever in this review; two individually randomized trials and five cluster randomized trials. All trials were conducted in rural African settings.In most trials the health workers diagnosing and treating malaria were nurses or clinical officers with less than one week of training in RDT supported diagnosis. Health worker prescribing adherence to RDT results was highly variable: the number of participants with a negative RDT result who received antimalarials ranged from 0% to 81%.Overall, RDT supported diagnosis had little or no effect on the number of participants remaining unwell at four to seven days after treatment (6990 participants, five trials, low quality evidence); but using RDTs reduced prescribing of antimalarials by up to three-quarters (17,287 participants, seven trials, moderate quality evidence). As would be expected, the reduction in antimalarial prescriptions was highest where health workers adherence to the RDT result was high, and where the true prevalence of malaria was lower.Using RDTs to support diagnosis did not have a consistent effect on the prescription of antibiotics, with some trials showing higher antibiotic prescribing and some showing lower prescribing in the RDT group (13,573 participants, five trials, very low quality evidence).One trial reported malaria microscopy on all enrolled patients in an area of moderate endemicity, so we could compare the number of patients in the RDT and clinical diagnosis groups that actually had microscopy confirmed malaria infection but did not receive antimalarials. No difference was detected between the two diagnostic strategies (1280 participants, one trial, low quality evidence). AUTHORS' CONCLUSIONS: Algorithms incorporating RDTs can substantially reduce antimalarial prescribing if health workers adhere to the test results. Introducing RDTs has not been shown to improve health outcomes for patients, but adherence to the test result does not seem to result in worse clinical outcomes than presumptive treatment.Concentrating on improving the care of RDT negative patients could improve health outcomes in febrile children.

Combining individual patient data and aggregate data in mixed treatment comparison meta-analysis: Individual patient data may be beneficial if only for a subset of trials.

BACKGROUND: Individual patient data (IPD) meta-analysis is the gold standard. Aggregate data (AD) and IPD can be combined using conventional pairwise meta-analysis when IPD cannot be obtained for all relevant studies. We extend the methodology to combine IPD and AD in a mixed treatment comparison (MTC) meta-analysis. METHODS: The proposed random-effects MTC models combine IPD and AD for a dichotomous outcome. We study the benefits of acquiring IPD for a subset of trials when assessing the underlying consistency assumption by including treatment-by-covariate interactions in the model. We describe three different model specifications that make increasingly stronger assumptions regarding the interactions. We illustrate the methodology through application to real data sets to compare drugs for treating malaria by using the outcome unadjusted treatment success at day 28. We compare results from AD alone, IPD alone and all data. RESULTS: When IPD contributed (i.e. either using IPD alone or combining IPD and AD), the chains converged, and we identified statistically significant regression coefficients for the interactions. Using IPD alone, we were able to compare only three of the six treatments of interest. When models were fitted to AD, the treatment effects and regression coefficients for the interactions were far more imprecise, and the chains did not converge. CONCLUSIONS: The models combining IPD and AD encapsulated all available evidence. When exploring interactions, it can be beneficial to obtain IPD for a subset of trials and to combine IPD with additional AD.

Drugs for treating Schistosoma mansoni infection.

BACKGROUND: Schistosoma mansoni is a parasitic infection common in the tropics and sub-tropics. Chronic and advanced disease includes abdominal pain, diarrhoea, blood in the stool, liver cirrhosis, portal hypertension, and premature death. OBJECTIVES: To evaluate the effects of antischistosomal drugs, used alone or in combination, for treating S. mansoni infection. SEARCH METHODS: We searched MEDLINE, EMBASE and LILACS from inception to October 2012, with no language restrictions. We also searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2012) and mRCT. The reference lists of articles were reviewed and experts were contacted for unpublished studies. SELECTION CRITERIA: Randomized controlled trials of antischistosomal drugs, used alone or in combination, versus placebo, different antischistosomal drugs, or different doses of the same antischistosomal drug for treating S. mansoni infection. DATA COLLECTION AND ANALYSIS: One author extracted data and assessed eligibility and risk of bias in the included studies, which were independently checked by a second author. We combined dichotomous outcomes using risk ratio (RR) and continuous data weighted mean difference (WMD); we presented both with 95% confidence intervals (CI). We assessed the quality of evidence using the GRADE approach. MAIN RESULTS: Fifty-two trials enrolling 10,269 participants were included. The evidence was of moderate or low quality due to the trial methods and small numbers of included participants.Praziquantel: Compared to placebo, praziquantel 40 mg/kg probably reduces parasitological treatment failure at one month post-treatment (RR 3.13, 95% CI 1.03 to 9.53, two trials, 414 participants, moderate quality evidence). Compared to this standard dose, lower doses may be inferior (30 mg/kg: RR 1.52, 95% CI 1.15 to 2.01, three trials, 521 participants, low quality evidence; 20 mg/kg: RR 2.23, 95% CI 1.64 to 3.02, two trials, 341 participants, low quality evidence); and higher doses, up to 60 mg/kg, do not appear to show any advantage (four trials, 783 participants, moderate quality evidence).The absolute parasitological cure rate at one month with praziquantel 40 mg/kg varied substantially across studies, ranging from 52% in Senegal in 1993 to 92% in Brazil in 2006/2007. Oxamniquine: Compared to placebo, oxamniquine 40 mg/kg probably reduces parasitological treatment failure at three months (RR 8.74, 95% CI 3.74 to 20.43, two trials, 82 participants, moderate quality evidence). Lower doses than 40 mg/kg may be inferior at one month (30 mg/kg: RR 1.78, 95% CI 1.15 to 2.75, four trials, 268 participants, low quality evidence; 20 mg/kg: RR 3.78, 95% CI 2.05 to 6.99, two trials, 190 participants, low quality evidence), and higher doses, such as 60 mg/kg, do not show a consistent benefit (four trials, 317 participants, low quality evidence).These trials are now over 20 years old and only limited information was provided on the study designs and methods. Praziquantel versus oxamniquine: Only one small study directly compared praziquantel 40 mg/kg with oxamniquine 40 mg/kg and we are uncertain which treatment is more effective in reducing parasitological failure (one trial, 33 participants, very low quality evidence). A further 10 trials compared oxamniquine at 20, 30 and 60 mg/kg with praziquantel 40 mg/kg and did not show any marked differences in failure rate or percent egg reduction.Combination treatments: We are uncertain whether combining praziquantel with artesunate reduces failures compared to praziquantel alone at one month (one trial, 75 participants, very low quality evidence).Two trials also compared combinations of praziquantel and oxamniquine in different doses, but did not find statistically significant differences in failure (two trials, 87 participants). Other outcomes and analyses: In trials reporting clinical improvement evaluating lower doses (20 mg/kg and 30 mg/kg) against the standard 40 mg/kg for both praziquantel or oxamniquine, no dose effect was demonstrable in resolving abdominal pain, diarrhoea, blood in stool, hepatomegaly, and splenomegaly (follow up at one, three, six, 12, and 24 months; three trials, 655 participants).Adverse events were not well-reported but were mostly described as minor and transient.In an additional analysis of treatment failure in the treatment arm of individual studies stratified by age, failure rates with 40 mg/kg of both praziquantel and oxamniquine were higher in children. AUTHORS' CONCLUSIONS: Praziquantel 40 mg/kg as the standard treatment for S. mansoni infection is consistent with the evidence. Oxamniquine, a largely discarded alternative, also appears effective.Further research will help find the optimal dosing regimen of both these drugs in children.Combination therapy, ideally with drugs with unrelated mechanisms of action and targeting the different developmental stages of the schistosomes in the human host should be pursued as an area for future research.

Using individual participant data to improve network meta-analysis projects.

A network meta-analysis combines the evidence from existing randomised trials about the comparative efficacy of multiple treatments. It allows direct and indirect evidence about each comparison to be included in the same analysis, and provides a coherent framework to compare and rank treatments. A traditional network meta-analysis uses aggregate data (eg, treatment effect estimates and standard errors) obtained from publications or trial investigators. An alternative approach is to obtain, check, harmonise and meta-analyse the individual participant data (IPD) from each trial. In this article, we describe potential advantages of IPD for network meta-analysis projects, emphasising five key benefits: (1) improving the quality and scope of information available for inclusion in the meta-analysis, (2) examining and plotting distributions of covariates across trials (eg, for potential effect modifiers), (3) standardising and improving the analysis of each trial, (4) adjusting for prognostic factors to allow a network meta-analysis of conditional treatment effects and (5) including treatment-covariate interactions (effect modifiers) to allow relative treatment effects to vary by participant-level covariate values (eg, age, baseline depression score). A running theme of all these benefits is that they help examine and reduce heterogeneity (differences in the true treatment effect between trials) and inconsistency (differences in the true treatment effect between direct and indirect evidence) in the network. As a consequence, an IPD network meta-analysis has the potential for more precise, reliable and informative results for clinical practice and even allows treatment comparisons to be made for individual patients and targeted populations conditional on their particular characteristics.

Assessing the consistency assumption by exploring treatment by covariate interactions in mixed treatment comparison meta-analysis: individual patient-level covariates versus aggregate trial-level covariates.

Mixed treatment comparison (MTC) meta-analysis allows several treatments to be compared in a single analysis while utilising direct and indirect evidence. Treatment by covariate interactions can be included in MTC models to explore how the covariate modifies the treatment effects. If interactions exist, the assumptions underlying MTCs may be invalidated. For conventional pair-wise meta-analysis, important benefits regarding the investigation of such interactions, gained from using individual patient data (IPD) rather than aggregate data (AD), have been described. We aim to compare IPD MTC models including patient-level covariates with AD MTC models including study-level covariates. IPD and AD random-effects MTC models for dichotomous outcomes are specified. Three assumptions are made regarding the interactions (i.e. independent, exchangeable and common interactions). The models are applied to a dataset to compare four drugs for treating malaria (i.e. amodiaquine-artesunate, dihydroartemisinin-piperaquine (DHAPQ), artemether-lumefantrine and chlorproguanil-dapsone plus artesunate) using the outcome unadjusted treatment success at day 28. The treatment effects and regression coefficients for interactions from the IPD models were more precise than those from AD models. Using IPD, assuming independent or exchangeable interactions, the regression coefficient for chlorproguanil-dapsone plus artesunate versus DHAPQ was statistically significant and assuming common interactions, the common coefficient was significant; whereas using AD, no coefficients were significant. Using IPD, DHAPQ was the best drug; whereas using AD, the best drug varied. Using AD models, there was no evidence that the consistency assumption was invalid; whereas, the assumption was questionable based on the IPD models. The AD analyses were misleading.

Artesunate versus quinine for treating severe malaria.

BACKGROUND: Severe malaria results in over a million deaths every year, most of them in children aged under five years and living in sub-Saharan Africa. This review examines whether treatment with artesunate, instead of the standard treatment quinine, would result in fewer deaths and better treatment outcomes. OBJECTIVES: To compare artesunate with quinine for treating severe malaria. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library), MEDLINE, EMBASE, LILACS, ISI Web of Science, the metaRegister of Controlled trials (mRCT), conference proceedings, and reference lists of articles to November 2010. SELECTION CRITERIA: Randomized controlled trials comparing intravenous, intramuscular, or rectal artesunate with intravenous or intramuscular quinine for treating adults and children with severe malaria who are unable to take medication by mouth. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the eligibility and risk of bias of trials, and extracted and analysed data. The primary outcome was all-cause death. Dichotomous outcomes were summarized using risk ratios (RR) and continuous outcomes by mean differences (MD). Where appropriate, we combined data in meta-analyses. MAIN RESULTS: Eight trials enrolling 1664 adults and 5765 children are included in this review.Treatment with artesunate significantly reduced the risk of death both in adults (RR 0.61, 95% Confidence Interval (CI) 0.50 to 0.75; 1664 participants, five trials) and children (RR 0.76, 95% CI 0.65 to 0.90; 5765 participants, four trials)In children, treatment with artesunate increased the incidence of neurological sequelae at the time of hospital discharge. The majority of these sequelae were transient and no significant difference between treatments was seen at later follow up. AUTHORS' CONCLUSIONS: The evidence clearly supports the superiority of parenteral artesunate over quinine for the treatment of severe malaria in both adults and children and in different regions of the world.

Intermittent preventive treatment for malaria in children living in areas with seasonal transmission.

BACKGROUND: In malaria endemic areas, pre-school children are at high risk of severe and repeated malaria illness. One possible public health strategy, known as Intermittent Preventive Treatment in children (IPTc), is to treat all children for malaria at regular intervals during the transmission season, regardless of whether they are infected or not. OBJECTIVES: To evaluate the effects of IPTc to prevent malaria in preschool children living in endemic areas with seasonal malaria transmission. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register (July 2011), CENTRAL (The Cochrane Library 2011, Issue 6), MEDLINE (1966 to July 2011), EMBASE (1974 to July 2011), LILACS (1982 to July 2011), mRCT (July 2011), and reference lists of identified trials. We also contacted researchers working in the field for unpublished and ongoing trials. SELECTION CRITERIA: Individually randomized and cluster-randomized controlled trials of full therapeutic dose of antimalarial or antimalarial drug combinations given at regular intervals compared with placebo or no preventive treatment in children aged six years or less living in an area with seasonal malaria transmission. DATA COLLECTION AND ANALYSIS: Two authors independently assessed eligibility, extracted data and assessed the risk of bias in the trials. Data were meta-analysed and measures of effects (ie rate ratio, risk ratio and mean difference) are presented with 95% confidence intervals (CIs). The quality of evidence was assessed using the GRADE methods. MAIN RESULTS: Seven trials (12,589 participants), including one cluster-randomized trial, met the inclusion criteria. All were conducted in West Africa, and six of seven trials were restricted to children aged less than 5 years.IPTc prevents approximately three quarters of all clinical malaria episodes (rate ratio 0.26; 95% CI 0.17 to 0.38; 9321 participants, six trials, high quality evidence), and a similar proportion of severe malaria episodes (rate ratio 0.27, 95% CI 0.10 to 0.76; 5964 participants, two trials, high quality evidence). These effects remain present even where insecticide treated net (ITN) usage is high (two trials, 5964 participants, high quality evidence).IPTc probably produces a small reduction in all-cause mortality consistent with the effect on severe malaria, but the trials were underpowered to reach statistical significance (risk ratio 0.66, 95% CI 0.31 to 1.39, moderate quality evidence).The effect on anaemia varied between studies, but the risk of moderately severe anaemia is probably lower with IPTc (risk ratio 0.71, 95% CI 0.52 to 0.98; 8805 participants, five trials, moderate quality evidence).Serious drug-related adverse events, if they occur, are probably rare, with none reported in the six trials (9533 participants, six trials, moderate quality evidence). Amodiaquine plus sulphadoxine-pyrimethamine is the most studied drug combination for seasonal chemoprevention. Although effective, it causes increased vomiting in this age-group (risk ratio 2.78, 95% CI 2.31 to 3.35; two trials, 3544 participants, high quality evidence).When antimalarial IPTc was stopped, no rebound increase in malaria was observed in the three trials which continued follow-up for one season after IPTc. AUTHORS' CONCLUSIONS: In areas with seasonal malaria transmission, giving antimalarial drugs to preschool children (age < 6 years) as IPTc during the malaria transmission season markedly reduces episodes of clinical malaria, including severe malaria. This benefit occurs even in areas where insecticide treated net usage is high.

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.

The management of anticoagulants in patients with atrial fibrillation and history of falls or risk of falls: protocol for a systematic review and meta-analysis.

BACKGROUND: Atrial fibrillation affects an estimated 33 million individuals worldwide and is a major cause of stroke, heart failure, and death. Anticoagulants substantially reduce the risk of stroke but are also associated with an increased risk of bleeding and especially intracranial hemorrhage which is the most concerning complication. Because of this, many patients are not offered anticoagulants, particularly patients at risk of falls or with a history of falls. It is unclear what anticoagulant treatment these patients should be offered. The Liverpool AF-Falls project aims to investigate this area, and this protocol for a systematic review and meta-analysis aims to define what is the most appropriate anticoagulant treatment option for the management of atrial fibrillation patients at risk of falls or with a history of falls. METHODS: This systematic review and meta-analysis will include randomized and non-randomized studies evaluating the safety and efficacy of different anticoagulant treatments (vitamin K antagonist and non-vitamin K antagonist oral anti-coagulant). Bibliographic databases (Cochrane Central Register of Controlled Trials, CINAHL, ClinicalTrials.gov , Embase, MEDLINE, Scopus and Web of Science) will be searched according to a pre-specified search strategy. Titles, abstracts, and full texts will be assessed by two independent reviewers and disagreements resolved with a third independent reviewer. The Cochrane Risk of Bias tool 2 (RoB 2) will be used to assess the risk of bias in randomized trials, and the Risk Of Bias In Non-randomized Studies - of Interventions (ROBINS-I) tool will be used for non-randomized studies. A pairwise meta-analysis based on the fixed and random-effects models will be conducted. Publication bias will be evaluated with a funnel plot and Egger's test. Heterogeneity will be assessed with the I2 statistic. If conditions for indirect comparison are met and sufficient data are available, a network meta-analysis will be conducted using frequentist and Bayesian methodologies. DISCUSSION: This review will be the first to summarize direct and indirect evidence on the safety and efficacy of anticoagulant treatments in atrial fibrillation patients at risk of falls or with a history of falls. The findings will be important to patients, clinicians, and health policy-makers to inform best practices in the use of these treatments. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registry number: CRD42020201086.

Efficacy and Safety of Anticoagulants in Patients with Atrial Fibrillation and History of Falls or Risk of Falls: A Systematic Review and Multilevel Meta-Analysis.

INTRODUCTION: Atrial fibrillation (AF) is a major cause of stroke. Anticoagulants substantially reduce risk of stroke but are also associated with an increased risk of bleeding. Because of that, many patients do not receive anticoagulants, particularly patients at risk of falls. This systematic review and meta-analysis aims to compare anticoagulant treatment options for the management of atrial fibrillation patients at risk of falls or with a history of falls. METHODS: We conducted a PRISMA systematic review (until March 2022), including studies evaluating safety and efficacy of different anticoagulants (vitamin K antagonist [VKA] versus non-vitamin K antagonist oral anticoagulant [NOAC]). Outcomes were ischemic stroke, major bleeding, intracranial hemorrhage, hemorrhagic stroke, myocardial infarction, gastrointestinal bleeding, cardiovascular and all-cause mortality. A multilevel meta-analysis was conducted adjusting for clustering effects within studies examining more than one effect size. RESULTS: A total of 919 articles were identified, 848 after removing duplicates. The full text of 155 were screened and 10 articles were retained for final quantitative synthesis. Risk of bias was moderate to serious for the included studies. In meta-analysis, NOACs were associated with superior effectiveness compared with VKA for ischemic stroke/systemic embolism (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.69-0.98; p < 0.05) and safety (HR 0.53, 95% CI 0.40-0.71; p < 0.05) for intracranial hemorrhage. There were no differences in other outcomes. CONCLUSION: NOACs were associated with less intracranial hemorrhages and ischemic strokes/systemic embolisms than VKAs in AF patients at risk of falls. These findings suggesting preferred use of NOACs over VKAs have clinical implications for physicians, patients and policy makers.