Albendazole alone or in combination with microfilaricidal drugs for lymphatic filariasis.

BACKGROUND: The Global Programme to Eliminate Lymphatic Filariasis recommends mass treatment of albendazole co-administered with the microfilaricidal (antifilarial) drugs diethylcarbamazine (DEC) or ivermectin; and recommends albendazole alone in areas where loiasis is endemic. OBJECTIVES: To assess the effects of albendazole alone, and the effects of adding albendazole to DEC or ivermectin, in people and communities with lymphatic filariasis. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials, MEDLINE (PubMed), Embase (OVID), LILACS (BIREME), and reference lists of included trials. We also searched the World Health Organization (WHO) International Clinical Trials Registry Platform and ClinicalTrials.gov to identify ongoing trials. We performed all searches up to 15 January 2018. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and cluster-RCTs that compared albendazole to placebo or no placebo, or compared albendazole combined with a microfilaricidal drug to a microfilaricidal drug alone, given to people known to have lymphatic filariasis or communities where lymphatic filariasis was known to be endemic. We sought data on measures of transmission potential (microfilariae (mf) prevalence and density); markers of adult worm infection (antigenaemia prevalence and density, and adult worm prevalence detected by ultrasound); and data on clinical disease and adverse events. DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed the trials, evaluated the risks of bias, and extracted data. The main analysis examined albendazole overall, whether given alone or added to a microfilaricidal drug. We used data collected from all randomized individuals at time of longest follow-up (up to 12 months) for meta-analysis of outcomes. We evaluated mf density data up to six months and at 12 months follow-up to ensure that we did not miss any subtle temporal effects. We conducted additional analyses for different follow-up periods and whether trials reported on individuals known to be infected or both infected and uninfected. We analysed dichotomous data using the risk ratio (RR) with a 95% confidence interval (CI). We could not meta-analyse data on parasite density outcomes and we summarized them in tables. Where data were missing, we contacted trial authors. We used GRADE to assess the certainty of evidence. MAIN RESULTS: We included 13 trials (12 individually-randomized and one small cluster-randomized trial) with 8713 participants in total. No trials evaluated population-level effects of albendazole in mass drug administration programmes. Seven trials enrolled people with a variety of inclusion criteria related to filarial infection, and six trials enrolled individuals from endemic areas. Outcomes were reported as end or change values. Mf and antigen density data were reported using the geometric mean, log mean and arithmetic mean, and reductions in density were variously calculated. Two trials discounted any increases in mf density in individuals at follow-up by setting any density increase to zero.For mf prevalence over two weeks to 12 months, albendazole alone or added to another microfilaricidal drug makes little or no difference (RR 0.95, 95% CI 0.85 to 1.07; 5027 participants, 12 trials, high-certainty evidence). For mf density there is no trend, with some trials reporting a greater reduction in mf density with albendazole and others a greater reduction with the control group. For mf density up to six months and at 12 months, we do not know if albendazole has an effect (one to six months: 1216 participants, 10 trials, very low-certainty evidence; at 12 months: 1052 participants, 9 trials, very low-certainty evidence).For antigenaemia prevalence between six to 12 months, albendazole alone or added to another microfilaricidal drug makes little or no difference (RR 1.04, 95% CI 0.97 to 1.12; 3774 participants, 7 trials, high-certainty evidence). For antigen density over six to 12 months, the trend shows little or no effect of albendazole; but we do not know if albendazole has an effect on antigen density (1374 participants, 5 trials, very low-certainty evidence). For adult worm prevalence detected by ultrasound at 12 months, albendazole added to a microfilaricidal drug may make little or no difference (RR 1.16, 95% CI 0.72 to 1.86; 165 participants, 3 trials, low-certainty evidence).For people reporting adverse events, albendazole makes little or no difference (RR 0.97, 95% CI 0.84 to 1.13; 2894 participants, 6 trials, high-certainty evidence).We also provide meta-analyses and GRADE tables by drug, as operationally this may be of interest: for albendazole versus placebo (4 trials, 1870 participants); for albendazole with DEC compared to DEC alone (8 trials, 3405 participants); and albendazole with ivermectin compared to ivermectin alone (4 trials, 3438 participants). AUTHORS' CONCLUSIONS: There is good evidence that albendazole makes little difference to clearing microfilaraemia or adult filarial worms in the 12 months post-treatment. This finding is consistent in trials evaluating albendazole alone, or added to DEC or ivermectin. Trials reporting mf density included small numbers of participants, calculated density data variously, and gave inconsistent results.The review raises questions over whether albendazole has any important contribution to the elimination of lymphatic filariasis. To inform policy for areas with loiasis where only albendazole can be used, it may be worth conducting placebo-controlled trials of albendazole alone.

A systematic review of the diagnostic accuracy of automated tests for cognitive impairment.

OBJECTIVE: The aim of this review is to determine whether automated computerised tests accurately identify patients with progressive cognitive impairment and, if so, to investigate their role in monitoring disease progression and/or response to treatment. METHODS: Six electronic databases (Medline, Embase, Cochrane, Institute for Scientific Information, PsycINFO, and ProQuest) were searched from January 2005 to August 2015 to identify papers for inclusion. Studies assessing the diagnostic accuracy of automated computerised tests for mild cognitive impairment (MCI) and early dementia against a reference standard were included. Where possible, sensitivity, specificity, positive predictive value, negative predictive value, and likelihood ratios were calculated. The Quality Assessment of Diagnostic Accuracy Studies tool was used to assess risk of bias. RESULTS: Sixteen studies assessing 11 diagnostic tools for MCI and early dementia were included. No studies were eligible for inclusion in the review of tools for monitoring progressive disease and response to treatment. The overall quality of the studies was good. However, the wide range of tests assessed and the non-standardised reporting of diagnostic accuracy outcomes meant that statistical analysis was not possible. CONCLUSION: Some tests have shown promising results for identifying MCI and early dementia. However, concerns over small sample sizes, lack of replicability of studies, and lack of evidence available make it difficult to make recommendations on the clinical use of the computerised tests for diagnosing, monitoring progression, and treatment response for MCI and early dementia. Research is required to establish stable cut-off points for automated computerised tests used to diagnose patients with MCI or early dementia.

Drugs for treating Buruli ulcer (Mycobacterium ulcerans disease).

BACKGROUND: Buruli ulcer is a necrotizing cutaneous infection caused by infection with Mycobacterium ulcerans bacteria that occurs mainly in tropical and subtropical regions. The infection progresses from nodules under the skin to deep ulcers, often on the upper and lower limbs or on the face. If left undiagnosed and untreated, it can lead to lifelong disfigurement and disabilities. It is often treated with drugs and surgery. OBJECTIVES: To summarize the evidence of drug treatments for treating Buruli ulcer. 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 (PubMed); Embase (Ovid); and LILACS (Latin American and Caribbean Health Sciences Literature; BIREME). We also searched the US National Institutes of Health Ongoing Trials Register (clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en/). All searches were run up to 19 December 2017. We also checked the reference lists of articles identified by the literature search, and contacted leading researchers in this topic area to identify any unpublished data. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that compared antibiotic therapy to placebo or alternative therapy such as surgery, or that compared different antibiotic regimens. We also included prospective observational studies that evaluated different antibiotic regimens with or without surgery. DATA COLLECTION AND ANALYSIS: Two review authors independently applied the inclusion criteria, extracted the data, and assessed methodological quality. We calculated the risk ratio (RR) for dichotomous data with 95% confidence intervals (CI). We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included a total of 18 studies: five RCTs involving a total of 319 participants, ranging from 12 participants to 151 participants, and 13 prospective observational studies, with 1665 participants. Studies evaluated various drugs usually in addition to surgery, and were carried out across eight countries in areas with high Buruli ulcer endemicity in West Africa and Australia. Only one RCT reported adequate methods to minimize bias. Regarding monotherapy, one RCT and one observational study evaluated clofazimine, and one RCT evaluated sulfamethoxazole/trimethoprim. All three studies had small sample sizes, and no treatment effect was demonstrated. The remaining studies examined combination therapy.Rifampicin combined with streptomycinWe found one RCT and six observational studies which evaluated rifampicin combined with streptomycin for different lengths of treatment (2, 4, 8, or 12 weeks) (941 participants). The RCT did not demonstrate a difference between the drugs added to surgery compared with surgery alone for recurrence at 12 months, but was underpowered (RR 0.12, 95% CI 0.01 to 2.51; 21 participants; very low-certainty evidence).An additional five single-arm observational studies with 828 participants using this regimen for eight weeks with surgery (given to either all participants or to a select group) reported healing rates ranging from 84.5% to 100%, assessed between six weeks and one year. Four observational studies reported healing rates for participants who received the regimen alone without surgery, reporting healing rates ranging from 48% to 95% assessed between eight weeks and one year.Rifampicin combined with clarithromycinTwo observational studies administered combined rifampicin and clarithromycin. One study evaluated the regimen alone (no surgery) for eight weeks and reported a healing rate of 50% at 12 months (30 participants). Another study evaluated the regimen administered for various durations (as determined by the clinicians, durations unspecified) with surgery and reported a healing rate of 100% at 12 months (21 participants).Rifampicin with streptomycin initially, changing to rifampicin with clarithromycin in consolidation phaseOne RCT evaluated this regimen (four weeks in each phase) against continuing with rifampicin and streptomycin in the consolidation phase (total eight weeks). All included participants had small lesions, and healing rates were above 90% in both groups without surgery (healing rate at 12 months RR 0.94, 95% CI 0.87 to 1.03; 151 participants; low-certainty evidence). One single-arm observational study evaluating the substitution of streptomycin with clarithromycin in the consolidation phase (6 weeks, total 8 weeks) without surgery given to a select group showed a healing rate of 98% at 12 months (41 participants).Novel combination therapyTwo large prospective studies in Australia evaluated some novel regimens. One study evaluating rifampicin combined with either ciprofloxacin, clarithromycin, or moxifloxacin without surgery reported a healing rate of 76.5% at 12 months (132 participants). Another study evaluating combinations of two to three drugs from rifampicin, ciprofloxacin, clarithromycin, ethambutol, moxifloxacin, or amikacin with surgery reported a healing rate of 100% (90 participants).Adverse effects were reported in only three RCTs (158 participants) and eight prospective observational studies (878 participants), and were consistent with what is already known about the adverse effect profile of these drugs. Paradoxical reactions (clinical deterioration after treatment caused by enhanced immune response to M ulcerans) were evaluated in six prospective observational studies (822 participants), and the incidence of paradoxical reactions ranged from 1.9% to 26%. AUTHORS' CONCLUSIONS: While the antibiotic combination treatments evaluated appear to be effective, we found insufficient evidence showing that any particular drug is more effective than another. How different sizes, lesions, and stages of the disease may contribute to healing and which kind of lesions are in need of surgery are unclear based on the included studies. Guideline development needs to consider these factors in designing practical treatment regimens. Forthcoming trials using clarithromycin with rifampicin and other trials of new regimens that also address these factors will help to identify the best regimens.

Insecticide-treated nets for preventing malaria.

BACKGROUND: A previous version of this Cochrane Review identified that insecticide-treated nets (ITNs) are effective at reducing child mortality, parasite prevalence, and uncomplicated and severe malaria episodes. Insecticide-treated nets have since become a core intervention for malaria control and have contributed greatly to the dramatic decline in disease incidence and malaria-related deaths seen since the turn of the millennium. However, this time period has also seen a rise in resistance to pyrethroids (the insecticide used in ITNs), raising questions over whether the evidence from trials conducted before resistance became widespread can be applied to estimate the impact of ITNs on malaria transmission today. OBJECTIVES: The primary objective of this review was to assess the impact of ITNs on mortality and malaria morbidity, incorporating any evidence published since the previous update into new and existing analyses, and assessing the certainty of the resulting evidence using GRADE. 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, the World Health Organization (WHO) International Clinical Trials Registry Platform, ClinicalTrials.gov, and the ISRCTN registry for new trials published since 2004 and up to 18 April 2018. SELECTION CRITERIA: We included individual randomized controlled trials (RCTs) and cluster RCTs comparing bed nets or curtains treated with a synthetic pyrethroid insecticide at a minimum target impregnation dose recommended by the WHO with no nets or untreated nets. DATA COLLECTION AND ANALYSIS: One review author assessed the identified trials for eligibility and risk of bias, and extracted data. We compared intervention and control data using risk ratios (RRs), rate ratios, and mean differences, and presented all results with their associated 95% confidence intervals (CIs). We assessed the certainty of evidence using the GRADE approach. We drew on evidence from a meta-analysis of entomological outcomes stratified by insecticide resistance from 2014 to inform the GRADE assessments. MAIN RESULTS: Our updated search identified three new trials. A total of 23 trials met the inclusion criteria, enrolling more than 275,793 adults and children. The included studies were conducted between 1987 and 2001.ITN versus no netsInsecticide-treated nets reduce child mortality from all causes by 17% compared to no nets (rate ratio 0.83, 95% CI 0.77 to 0.89; 5 trials, 200,833 participants, high-certainty evidence). This corresponds to a saving of 5.6 lives (95% CI 3.6 to 7.6) each year for every 1000 children protected with ITNs. Insecticide-treated nets also reduce the incidence of uncomplicated episodes of Plasmodium falciparum malaria by almost a half (rate ratio 0.55, 95% CI 0.48 to 0.64; 5 trials, 35,551 participants, high-certainty evidence) and probably reduce the incidence of uncomplicated episodes of Plasmodium vivax malaria (risk ratio (RR) 0.61, 95% CI 0.48 to 0.77; 2 trials, 10,967 participants, moderate-certainty evidence).Insecticide-treated nets were also shown to reduce the prevalence of P falciparum malaria by 17% compared to no nets (RR 0.83, 95% CI 0.71 to 0.98; 6 trials, 18,809 participants, high-certainty evidence) but may have little or no effect on the prevalence of P vivax malaria (RR 1.00, 95% CI 0.75 to 1.34; 2 trials, 10,967 participants, low-certainty evidence). A 44% reduction in the incidence of severe malaria episodes was seen in the ITN group (rate ratio 0.56, 95% CI 0.38 to 0.82; 2 trials, 31,173 participants, high-certainty evidence), as well as an increase in mean haemoglobin (expressed as mean packed cell volume) compared to the no-net group (mean difference 1.29, 95% CI 0.42 to 2.16; 5 trials, 11,489 participants, high-certainty evidence).ITN versus untreated netsInsecticide-treated nets probably reduce child mortality from all causes by a third compared to untreated nets (rate ratio 0.67, 95% CI 0.36 to 1.23; 2 trials, 25,389 participants, moderate-certainty evidence). This corresponds to a saving of 3.5 lives (95% CI -2.4 to 6.8) each year for every 1000 children protected with ITNs. Insecticide-treated nets also reduce the incidence of uncomplicated P falciparum malaria episodes (rate ratio 0.58, 95% CI 0.44 to 0.78; 5 trials, 2036 participants, high-certainty evidence) and may also reduce the incidence of uncomplicated P vixax malaria episodes (rate ratio 0.73, 95% CI 0.51 to 1.05; 3 trials, 1535 participants, low-certainty evidence).Use of an ITN probably reduces P falciparum prevalence by one-tenth in comparison to use of untreated nets (RR 0.91, 95% CI 0.78 to 1.05; 3 trials, 2,259 participants, moderate-certainty evidence). However, based on the current evidence it is unclear whether or not ITNs impact on P vivax prevalence (1 trial, 350 participants, very low certainty evidence) or mean packed cell volume (2 trials, 1,909 participants, low certainty evidence). AUTHORS' CONCLUSIONS: Although there is some evidence that insecticide resistance frequency has some effects on mosquito mortality, it is unclear how quantitatively important this is. It appeared insufficient to downgrade the strong evidence of benefit on mortality and malaria illness from the trials conducted earlier.

Early versus delayed antiretroviral treatment in HIV-positive people with cryptococcal meningitis.

BACKGROUND: There remains uncertainty about the optimum timing of antiretroviral therapy (ART) initiation in HIV-positive people with cryptococcal meningitis. This uncertainty is the result of conflicting data on the mortality risk and occurrence of immune reconstitution inflammatory syndrome (IRIS) when ART is initiated less than four weeks after cryptococcal meningitis treatment is commenced. OBJECTIVES: To compare the outcomes of early initiation of ART (less than four weeks after starting antifungal treatment) versus delayed initiation of ART (four weeks or more after starting antifungal treatment) in HIV-positive people with concurrent cryptococcal meningitis. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase for trials published between 1 January 1980 and 7 August 2017. We additionally searched international trial registries, including ClinicalTrials.gov and WHO International Clinical Trials Registry Platform (ICTRP), and conference abstracts from the International AIDS Society (IAS) and the Conference on Retroviruses and Opportunistic Infections (CROI) for ongoing or unpublished studies between 2015 and 2017. We reviewed reference lists of included studies to identify additional studies. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that compared early versus delayed ART initiation in HIV-positive people with cryptococcal meningitis. Children, adults, and adolescents from any setting were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently applied the inclusion criteria and extracted data. We presented dichotomous outcomes as risk ratios (RR) with 95% confidence intervals (CIs). We presented time-to-death data as hazard ratios with 95% CIs. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: Four trials including 294 adult participants met the inclusion criteria of this review. Participants were predominantly from low- and middle-income countries. Two trials treated cryptococcal meningitis with amphotericin B and fluconazole; a third trial used fluconazole monotherapy; and the fourth trial did not specify the antifungal used.Early ART initiation may increase all-cause mortality compared to delayed ART initiation (RR 1.42, 95% CI 1.02 to 1.97; 294 participants, 4 trials; low-certainty evidence). Early ART initiation may reduce relapse of cryptococcal meningitis compared to delayed ART initiation (RR 0.27, 95% CI 0.07 to 1.04; 205 participants, 2 trials, low-certainty evidence). We are uncertain whether early ART initiation increases or reduces cryptococcal IRIS events compared to delayed ART initiation (RR 3.56, 95% CI 0.51 to 25.02; 205 participants, 2 trials; I2 = 54%; very low-certainty evidence). We are uncertain if early ART initiation increases or reduces virological suppression at six months compared to delayed ART initiation (RR 0.93, 95% CI 0.72 to 1.22; 205 participants, 2 trials; I2 statistic = 0%; very low-certainty evidence).We were unable to pool results related to rate of fungal clearance for the two trials that reported this outcome; individual trial results indicated that there was no difference in cerebrospinal fluid fungal clearance between trial arms. Similarly, we were unable to pool results on adverse events for the trials reporting on this outcome; individual trial results indicated no difference in the occurrence of grade 3 to 5 adverse events between trial arms.Three of the four included trials had an overall low or unclear risk of bias related to the primary outcome of all-cause mortality. However, we assessed one trial as at high risk of bias due to selective outcome reporting and other bias. This, in addition to the few clinical events and imprecision of effect estimates, led to downgrading of the evidence to low or very low certainty. AUTHORS' CONCLUSIONS: The results of this review are relevant to HIV-positive adults with cryptococcal meningitis in low- and middle-income countries. These data suggest a higher risk of mortality among people who initiate ART within four weeks of cryptococcal meningitis diagnosis. However, it is unclear if this higher mortality risk is related to cryptococcal meningitis-IRIS.

Vaccines for preventing typhoid fever.

BACKGROUND: Typhoid fever and paratyphoid fever continue to be important causes of illness and death, particularly among children and adolescents in south-central and southeast Asia. Two typhoid vaccines are widely available, Ty21a (oral) and Vi polysaccharide (parenteral). Newer typhoid conjugate vaccines are at varying stages of development and use. The World Health Organization has recently recommended a Vi tetanus toxoid (Vi-TT) conjugate vaccine, Typbar-TCV, as the preferred vaccine for all ages. OBJECTIVES: To assess the effects of vaccines for preventing typhoid fever. SEARCH METHODS: In February 2018, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE, Embase, LILACS, and mRCT. We also searched the reference lists of all included trials. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials (RCTs) comparing typhoid fever vaccines with other typhoid fever vaccines or with an inactive agent (placebo or vaccine for a different disease) in adults and children. Human challenge studies were not eligible. DATA COLLECTION AND ANALYSIS: Two review authors independently applied inclusion criteria and extracted data, and assessed the certainty of the evidence using the GRADE approach. We computed vaccine efficacy per year of follow-up and cumulative three-year efficacy, stratifying for vaccine type and dose. The outcome addressed was typhoid fever, defined as isolation of Salmonella enterica serovar Typhi in blood. We calculated risk ratios (RRs) and efficacy (1 - RR as a percentage) with 95% confidence intervals (CIs). MAIN RESULTS: In total, 18 RCTs contributed to the quantitative analysis in this review: 13 evaluated efficacy (Ty21a: 5 trials; Vi polysaccharide: 6 trials; Vi-rEPA: 1 trial; Vi-TT: 1 trial), and 9 reported on adverse events. All trials but one took place in typhoid-endemic countries. There was no information on vaccination in adults aged over 55 years of age, pregnant women, or travellers. Only one trial included data on children under two years of age.Ty21a vaccine (oral vaccine, three doses)A three-dose schedule of Ty21a vaccine probably prevents around half of typhoid cases during the first three years after vaccination (cumulative efficacy 2.5 to 3 years: 50%, 95% CI 35% to 61%, 4 trials, 235,239 participants, moderate-certainty evidence). These data include patients aged 3 to 44 years.Compared with placebo, this vaccine probably does not cause more vomiting, diarrhoea, nausea or abdominal pain (2 trials, 2066 participants; moderate-certainty evidence), headache, or rash (1 trial, 1190 participants; moderate-certainty evidence); however, fever (2 trials, 2066 participants; moderate-certainty evidence) is probably more common following vaccination.Vi polysaccharide vaccine (injection, one dose)A single dose of Vi polysaccharide vaccine prevents around two-thirds of typhoid cases in the first year after vaccination (year 1: 69%, 95% CI 63% to 74%; 3 trials, 99,979 participants; high-certainty evidence). In year 2, trial results were more variable, with the vaccine probably preventing between 45% and 69% of typhoid cases (year 2: 59%, 95% CI 45% to 69%; 4 trials, 194,969 participants; moderate-certainty evidence). These data included participants aged 2 to 55 years of age.The three-year cumulative efficacy of the vaccine may be around 55% (95% CI 30% to 70%; 11,384 participants, 1 trial; low-certainty evidence). These data came from a single trial conducted in South Africa in the 1980s in participants aged 5 to 15 years.Compared with placebo, this vaccine probably did not increase the incidence of fever (3 trials, 132,261 participants; moderate-certainty evidence) or erythema (3 trials, 132,261 participants; low-certainty evidence); however, swelling (3 trials, 1767 participants; moderate-certainty evidence) and pain at the injection site (1 trial, 667 participants; moderate-certainty evidence) were more common in the vaccine group.Vi-rEPA vaccine (two doses)Administration of two doses of the Vi-rEPA vaccine probably prevents between 50% and 96% of typhoid cases during the first two years after vaccination (year 1: 94%, 95% CI 75% to 99%; year 2: 87%, 95% CI 56% to 96%, 1 trial, 12,008 participants; moderate-certainty evidence). These data came from a single trial with children two to five years of age conducted in Vietnam.Compared with placebo, both the first and the second dose of this vaccine increased the risk of fever (1 trial, 12,008 and 11,091 participants, low-certainty evidence) and the second dose increase the incidence of swelling at the injection site (one trial, 11,091 participants, moderate-certainty evidence).Vi-TT vaccine (two doses)We are uncertain of the efficacy of administration of two doses of Vi-TT (PedaTyph) in typhoid cases in children during the first year after vaccination (year 1: 94%, 95% CI -1% to 100%, 1 trial, 1625 participants; very low-certainty evidence). These data come from a single cluster-randomized trial in children aged six months to 12 years and conducted in India. For single dose Vi-TT (Typbar-TCV), we found no efficacy trials evaluating the vaccine with natural exposure.There were no reported serious adverse effects in RCTs of any of the vaccines studied. AUTHORS' CONCLUSIONS: The licensed Ty21a and Vi polysaccharide vaccines are efficacious in adults and children older than two years in endemic countries. The Vi-rEPA vaccine is just as efficacious, although data is only available for children. The new Vi-TT vaccine (PedaTyph) requires further evaluation to determine if it provides protection against typhoid fever. At the time of writing, there were only efficacy data from a human challenge setting in adults on the Vi-TT vaccine (Tybar), which clearly justify the ongoing field trials to evaluate vaccine efficacy.

Piperonyl butoxide (PBO) combined with pyrethroids in insecticide-treated nets to prevent malaria in Africa.

BACKGROUND: Public health strategies that target mosquito vectors, particularly pyrethroid long-lasting insecticidal nets (LLINs), have been largely responsible for the substantial reduction in the number of people in Africa developing malaria. The spread of insecticide resistance in Anopheles mosquitoes threatens these impacts. One way to control insecticide-resistant populations is by using insecticide synergists. Piperonyl butoxide (PBO) is a synergist that inhibits specific metabolic enzymes within mosquitoes and has been incorporated into pyrethroid-LLINs to form pyrethroid-PBO nets. Pyrethroid-PBO nets are currently produced by four LLIN manufacturers and, following a recommendation from the World Health Organization (WHO) in 2017, are being included in distribution campaigns in countries. This review examines epidemiological and entomological evidence on whether the addition of PBO to LLINs improves their efficacy. OBJECTIVES: 1. Evaluate whether adding PBO to pyrethroid LLINs increases the epidemiological and entomological effectiveness of the nets.2. Compare the effects of pyrethroid-PBO nets currently in commercial development or on the market with their non-PBO equivalent in relation to:a. malaria infection (prevalence or incidence);b. entomological outcomes. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group (CIDG) Specialized Register; CENTRAL, MEDLINE, Embase, Web of Science, CAB Abstracts, and two clinical trial registers (ClinicalTrials.gov and WHO International Clinical Trials Registry Platform) up to 24 August 2018. We contacted organizations for unpublished data. We checked the reference lists of trials identified by the above methods. SELECTION CRITERIA: We included laboratory trials, experimental hut trials, village trials, and randomized clinical trials with mosquitoes from the Anopheles gambiae complex or Anopheles funestus group. DATA COLLECTION AND ANALYSIS: Two review authors assessed each trial for eligibility, extracted data, and determined the risk of bias for included trials. We resolved disagreements through discussion with a third review author. We analysed the data using Review Manager 5 and assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: Fifteen trials met the inclusion criteria: two laboratory trials, eight experimental hut trials, and five cluster-randomized controlled village trials.One village trial examined the effect of pyrethroid-PBO nets on malaria infection prevalence in an area with highly pyrethroid-resistant mosquitoes. The latest endpoint at 21 months post-intervention showed that malaria prevalence probably decreased in the intervention arm (OR 0.40, 95% CI 0.20 to 0.80; 1 trial, 1 comparison, moderate-certainty evidence).In highly pyrethroid-resistant areas (< 30% mosquito mortality), in comparisons of unwashed pyrethroid-PBO nets to unwashed standard-LLINs, PBO nets resulted in higher mosquito mortality (risk ratio (RR) 1.84, 95% CI 1.60 to 2.11; 14,620 mosquitoes, 5 trials, 9 comparisons, high-certainty evidence) and lower blood feeding success (RR 0.60, 95% CI 0.50 to 0.71; 14,000 mosquitoes, 4 trials, 8 comparisons, high-certainty evidence). However, in comparisons of washed pyrethroid-PBO nets to washed LLINs we do not know if PBO nets have a greater effect on mosquito mortality (RR 1.20, 95% CI 0.88 to 1.63; 10,268 mosquitoes, 4 trials, 5 comparisons, very low-certainty evidence), although the washed pyrethroid-PBO nets do decrease blood feeding success compared to standard-LLINs (RR 0.81, 95% CI 0.72 to 0.92; 9674 mosquitoes, 3 trials, 4 comparisons, high-certainty evidence).In areas where pyrethroid resistance is considered moderate (31% to 60% mosquito mortality), there may be little or no difference in effects of unwashed pyrethroid-PBO nets compared to unwashed standard-LLINs on mosquito mortality (RR 1.16, 95% CI 0.88 to 1.54; 242 mosquitoes, 1 trial, 1 comparison, low-certainty evidence), and there may be little or no difference in the effects on blood feeding success (RR 0.87, 95% CI 0.67 to 1.13; 242 mosquitoes, 1 trial, 1 comparison, low-certainty evidence). The same pattern is apparent for washed pyrethroid-PBO nets compared to washed standard-LLINs (mortality: RR 1.07, 95% CI 0.74 to 1.54; 329 mosquitoes, 1 trial, 1 comparison, low-certainty evidence; blood feeding success: RR 0.91, 95% CI 0.74 to 1.13; 329 mosquitoes, 1 trial, 1 comparison, low-certainty evidence).In areas where pyrethroid resistance is low (61% to 90% mosquito mortality), there is probably little or no difference in the effect of unwashed pyrethroid-PBO nets compared to unwashed standard-LLINs on mosquito mortality (RR 1.10, 95% CI 1.05 to 1.16; 708 mosquitoes, 1 trial, 2 comparisons, moderate-certainty evidence), but there is no evidence for an effect on blood feeding success (RR 0.67, 95% CI 0.06 to 7.37; 708 mosquitoes, 1 trial, 2 comparisons, very low-certainty evidence). For washed pyrethroid-PBO nets compared to washed standard-LLINs we do not know if there is any difference in mosquito mortality (RR 1.16, 96% CI 0.83 to 1.63; 878 mosquitoes, 1 trial, 2 comparisons, very low-certainty evidence), but blood feeding may decrease (RR 1.50, 95% CI 0.89 to 2.54; 878 mosquitoes, 1 trial, 2 comparisons, low-certainty evidence).In areas were mosquito populations are susceptible to insecticides (> 90% mosquito mortality), there may be little or no difference in the effect of unwashed pyrethroid-PBO nets compared to unwashed standard-LLINs on mosquito mortality (RR 1.20, 95% CI 0.64 to 2.26; 2791 mosquitoes, 2 trials, 2 comparisons, low-certainty evidence). This is similar for washed nets (RR 1.07, 95% CI 0.92 to 1.25; 2644 mosquitoes, 2 trials, 2 comparisons, low-certainty evidence). We do not know if unwashed pyrethroid-PBO nets have any effect on blood feeding success of susceptible mosquitoes (RR 0.50, 95% CI 0.11 to 2.32; 2791 mosquitoes, 2 trials, 2 comparisons, very low-certainty evidence). The same applies to washed nets (RR 1.28, 95% CI 0.81 to 2.04; 2644 mosquitoes, 2 trials, 2 comparisons, low-certainty evidence).In village trials comparing pyrethroid-PBO nets to LLINs, there was no difference in sporozoite rate (4 trials, 5 comparison) and mosquito parity (3 trials, 4 comparisons). AUTHORS' CONCLUSIONS: In areas of high insecticide resistance, pyrethroid-PBO nets reduce mosquito mortality and blood feeding rates, and results from a single clinical trial demonstrate that this leads to lower malaria prevalence. Questions remain about the durability of PBO on nets, as the impact of pyrethroid-PBO LLINs on mosquito mortality was not sustained over 20 washes in experimental hut trials. There is little evidence to support higher entomological efficacy of pyrethroid-PBO nets in areas where the mosquitoes show lower levels of resistance to pyrethroids.

Insecticide space spraying for preventing malaria transmission.

BACKGROUND: Space spraying is the dispersal of a liquid fog of insecticide into an outdoor area to kill adult insects. It has been regularly used in public health and pest control programmes, including use as an emergency response to malaria epidemics. This Cochrane Review aims to assist the decision-making of malaria vector control programmes by summarizing the evidence of the impact of space spraying on malaria transmission. OBJECTIVES: The review's primary objective was to evaluate the impact of space spraying on malaria transmission, or the incremental impact when applied in combination with other malaria control methods, in comparison to equivalent conditions with no space spraying intervention.To guide future evaluations of space spraying, a secondary objective was to identify and summarize the range of space spraying strategies that have been trialled, those which were promising and warrant further evaluation, and those which appear unlikely to warrant further evaluation (for example, if they were not feasible to implement, or were unacceptable to the population). SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; PubMed (MEDLINE); Embase (OVID), CAB Abstracts (Web of Science), LILACS (BIREME), the World Health Organization (WHO) International Clinical Trials Registry Platform, and ClinicalTrials.gov up to 18 April 2018. We contacted organizations for ongoing and unpublished trials, and checked the reference lists of all included studies for relevant studies. SELECTION CRITERIA: We included cluster-randomized controlled trials, interrupted time series (ITS) studies, randomized cross-over studies, and controlled before-and-after (CBA) studies comparing space spraying with no space spraying that met the inclusion criteria for the review. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for eligibility and risk of bias, and extracted the data. For ITS studies, we present findings graphically, and estimated the effect of space spraying on the step change and the slope change. We assessed the certainty of evidence using the GRADE approach. MAIN RESULTS: Two ITS studies, conducted between 1972 and 1984, met our inclusion criteria for the primary objective, and one study contributed to the quantitative analysis. This study was conducted in India, reported the incidence of malaria in four separate sites, and covered a total population of 18,460 people. In the pooled analysis across sites, there was no step effect for the incidence of uncomplicated malaria (step rate ratio 1.00, 95% confidence interval (CI) 0.51 to 1.92). There was an effect on the slope: the number of cases was reduced by 15% per month (slope rate ratio 0.85, 95% CI 0.79 to 0.91). Using these ratios, we estimated the effect of 12 months of space spraying on malaria incidence to be a reduction from 6 cases to 1 case per month per 1000 population (95% CI 0 to 2 cases, very low-certainty evidence). The second study reported the impact of space spraying on malaria incidence and adult mosquito density in a population of 15,106 in Haiti, but it did not provide data from previous years. Thus, we could not estimate an effect of space spraying that was independent from temporal trends.For the review's secondary objective, we identified a further two studies in addition to the two ITS studies; both used a CBA design and were conducted between 1973 and 2000. The four studies used a range of delivery methods including handheld, vehicle-mounted, and aircraft-mounted spraying equipment. A variety of insecticides, doses, and spraying times were also used, with methods typically determined based on environmental factors and vector profiles. AUTHORS' CONCLUSIONS: Evidence from one state in India conducted over 30 years ago suggests an effect of space spraying on the incidence of malaria, but the certainty of the evidence is very low. Reliable research in a variety of settings will help establish whether and when this intervention may be worthwhile.

Mosquito repellents for malaria prevention.

BACKGROUND: Malaria is an important cause of illness and death across endemic regions. Considerable success against malaria has been achieved within the past decade mainly through long-lasting insecticide-treated nets (LLINs). However, elimination of the disease is proving difficult as current control methods do not protect against mosquitoes biting outdoors and when people are active. Repellents may provide a personal protection solution during these times. OBJECTIVES: To assess the impact of topical repellents, insecticide-treated clothing, and spatial repellents on malaria transmission. SEARCH METHODS: We searched the following databases up to 26 June 2017: the Cochrane Infectious Diseases Group Specialized Register; the Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE; Embase; US AFPMB; CAB Abstracts; and LILACS. We also searched trial registration platforms and conference proceedings; and contacted organizations and companies for ongoing and unpublished trials. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and cluster-randomized controlled trials of topical repellents proven to repel mosquitoes; permethrin-treated clothing; and spatial repellents such as mosquito coils. We included trials that investigated the use of repellents with or without LLINs, referred to as insecticide-treated nets. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed trials for inclusion, extracted the data, and assessed the risk of bias. A third review author resolved any discrepancies. We analysed data by conducting meta-analysis and stratified by whether the trials had included LLINs. We combined results from cRCTs with individually RCTs by adjusting for clustering and presented results using forest plots. We used GRADE to assess the certainty of the evidence. MAIN RESULTS: Eight cRCTs and two RCTs met the inclusion criteria. Six trials investigated topical repellents, two trials investigated insecticide-treated clothing, and two trials investigated spatial repellents.Topical repellentsSix RCTS, five of them cluster-randomized, investigated topical repellents involving residents of malaria-endemic regions. Four trials used topical repellents in combination with nets, but two trials undertaken in displaced populations used topical repellents alone. It is unclear if topical repellents can prevent clinical malaria (RR 0.65, 95% CI 0.4 to 1.07, very low certainty evidence) or malaria infection (RR 0.84, 95% CI 0.64 to 1.12, low-certainty evidence) caused by P. falciparum. It is also unclear if there is any protection against clinical cases of P. vivax (RR 1.32, 95% CI 0.99 to 1.76, low-certainty evidence) or incidence of infections (RR 1.07, 95% CI 0.80 to 1.41, low-certainty evidence). Subgroup analysis of trials including insecticide-treated nets did not show a protective effect of topical repellents against malaria. Only two studies did not include insecticide-treated nets, and they measured different outcomes; one reported a protective effect against clinical cases of P. falciparum (RR 0.40, 95% CI 0.23 to 0.71); but the other study measured no protective effect against malaria infection incidence caused by either P. falciparum or P. vivax.Insecticide-treated clothingInsecticide-treated clothing were investigated in trials conducted in refugee camps in Pakistan and amongst military based in the Colombian Amazon. Neither study provided participants with insecticide-treated nets. In the absence of nets, treated clothing may reduce the incidence of clinical malaria caused by P. falciparum by approximately 50% (RR 0.49, 95% CI 0.29 to 0.83, low-certainty evidence) and P. vivax (RR 0.64, 95% CI 0.40 to 1.01, low-certainty evidence).Spatial repellentsTwo cluster-randomized RCTs investigated mosquito coils for malaria prevention. We do not know the effect of spatial repellents on malaria prevention (RR 0.24, 95% CI 0.03 to 1.72, very low certainty evidence). There was large heterogeneity between studies and one study had high risk of bias. AUTHORS' CONCLUSIONS: There is insufficient evidence to conclude topical or spatial repellents can prevent malaria. There is a need for better designed trials to generate higher certainty of evidence before well-informed recommendations can be made. Adherence to daily compliance remains a major limitation. Insecticide-treated clothing may reduce risk of malaria infection in the absence of insecticide-treated nets; further studies on insecticide-treated clothing in the general population should be done to broaden the applicability of the results.

Safety of primaquine given to people with G6PD deficiency: systematic review of prospective studies.

BACKGROUND: Haemolysis risk with single dose or short course primaquine was evaluated in glucose-6-phosphate dehydrogenase (G6PD) deficient people. METHODS: Major electronic databases (to August 2016) were searched for single or short course 8-aminoquinolines (8-AQ) in (1) randomized comparisons against placebo in G6PD deficient people; and (2) observational comparisons in G6PD deficient compared to replete people. Two authors independently assessed eligibility, risk-of-bias, and extracted data. RESULTS: Five randomized controlled trials and four controlled observational cohorts were included. In G6PD deficient individuals, high-dose (0.75 mg/kg) PQ resulted in lower average haemoglobin levels at 7 days (mean difference [MD] -1.45 g/dl, 95% CI -2.17 to -0.74, 2 trials) and larger percentage fall from baseline to day 7 (MD -10.31%, 95% CI -17.69 to -2.92, 3 trials) compared to placebo. In G6PD deficient compared to replete people, average haemoglobin was lower at 7 days (MD -1.19 g/dl, 95% CI -1.94 to -0.44, 2 trials) and haemoglobin change from baseline to day 7 was greater (MD -9.10%, 95% CI -12.55 to -5.65, 5 trials). One small trial evaluated mid-range PQ dose (0.4-0.5 mg/kg) in G6PD deficient people, with no difference detected in average haemoglobin at day 7 compared to placebo. In one cohort comparing G6PD deficient and replete people there was a greater fall with G6PD deficiency (MD -4.99%, 95% CI -9.96 to -0.02). For low-dose PQ (0.1-0.25 mg/kg) in G6PD deficient people, haemoglobin change from baseline was similar to the placebo group (MD 1.72%, 95% CI -1.89 to 5.34, 2 trials). Comparing low dose PQ in G6PD deficient with replete people, the average haemoglobin was lower in the G6PD deficient group at 7 days (-0.57 g (95% CI -0.97 to -0.17, 1 trial)); although change from baseline was similar (MD -1.45%, 95% CI -5.69 to 2.78, 3 trials). CONCLUSIONS: Falls in average haemoglobin are less marked with the 0.1 to 0.25 mg/kg PQ than with the 0.75 mg/kg dose, and severe haemolytic events are not common. However, data were limited and the evidence GRADE was low or very low certainty.

Pharmacological treatment of acute agitation associated with psychotic and bipolar disorder: a systematic review and meta-analysis.

OBJECTIVES: We used systematic review methodology to identify and evaluate short-term pharmacological interventions for agitation associated with schizophrenia or bipolar disorder. METHOD: We searched electronic databases for randomised controlled trials involving comparisons between current treatments for agitation, benzodiazepines, antipsychotics and placebo. The patient population was adults with agitation associated with psychotic or bipolar disorder treated in specialist mental health services. The outcome of interest was change in agitation measured by accepted standard scales. Paired meta-analyses and network meta-analyses are presented. RESULTS: Seventeen randomised controlled trials were identified (n = 3841). Treatments included haloperidol, olanzapine, aripiprazole, risperidone and lorazepam. The primary outcome was change in Positive and Negative Syndrome Scale Excited Component scores. Pair-wise comparisons suggest that after 60 min, olanzapine is superior to haloperidol; no other treatment was more effective than any other. At 120 min, loxapine 10 mg is more effective than loxapine 5 mg, and olanzapine is more effective than lorazepam. In the network meta-analyses, no treatment was superior to any other. CONCLUSION: Because of limitations of available research, firm conclusions could not be drawn regarding the efficacy and safety of any identified intervention. Based on our results, there is no evidence that one drug is more effective or preferred over any other and treatment decisions could be made based on individual patient needs or costs. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

GenoType® MTBDRsl assay for resistance to second-line anti-tuberculosis drugs.

BACKGROUND: Genotype® MTBDRsl (MTBDRsl) is a rapid DNA-based test for detecting specific mutations associated with resistance to fluoroquinolones and second-line injectable drugs (SLIDs) in Mycobacterium tuberculosis complex. MTBDRsl version 2.0 (released in 2015) identifies the mutations detected by version 1.0, as well as additional mutations. The test may be performed on a culture isolate or a patient specimen, which eliminates delays associated with culture. Version 1.0 requires a smear-positive specimen, while version 2.0 may use a smear-positive or -negative specimen. We performed this updated review as part of a World Health Organization process to develop updated guidelines for using MTBDRsl. OBJECTIVES: To assess and compare the diagnostic accuracy of MTBDRsl for: 1. fluoroquinolone resistance, 2. SLID resistance, and 3. extensively drug-resistant tuberculosis, indirectly on a M. tuberculosis isolate grown from culture or directly on a patient specimen. Participants were people with rifampicin-resistant or multidrug-resistant tuberculosis. The role of MTBDRsl would be as the initial test, replacing culture-based drug susceptibility testing (DST), for detecting second-line drug resistance. SEARCH METHODS: We searched the following databases without language restrictions up to 21 September 2015: the Cochrane Infectious Diseases Group Specialized Register; MEDLINE; Embase OVID; Science Citation Index Expanded, Conference Proceedings Citation Index-Science, and BIOSIS Previews (all three from Web of Science); LILACS; and SCOPUS; registers for ongoing trials; and ProQuest Dissertations & Theses A&I. We reviewed references from included studies and contacted specialists in the field. SELECTION CRITERIA: We included cross-sectional and case-control studies that determined MTBDRsl accuracy against a defined reference standard (culture-based DST, genetic sequencing, or both). DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed quality using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. We synthesized data for versions 1.0 and 2.0 separately. We estimated MTBDRsl sensitivity and specificity for fluoroquinolone resistance, SLID resistance, and extensively drug-resistant tuberculosis when the test was performed indirectly or directly (smear-positive specimen for version 1.0, smear-positive or -negative specimen for version 2.0). We explored the influence on accuracy estimates of individual drugs within a drug class and of different reference standards. We performed most analyses using a bivariate random-effects model with culture-based DST as reference standard. MAIN RESULTS: We included 27 studies. Twenty-six studies evaluated version 1.0, and one study version 2.0. Of 26 studies stating specimen country origin, 15 studies (58%) evaluated patients from low- or middle-income countries. Overall, we considered the studies to be of high methodological quality. However, only three studies (11%) had low risk of bias for the reference standard; these studies used World Health Organization (WHO)-recommended critical concentrations for all drugs in the culture-based DST reference standard. MTBDRsl version 1.0 Fluoroquinolone resistance: indirect testing, MTBDRsl pooled sensitivity and specificity (95% confidence interval (CI)) were 85.6% (79.2% to 90.4%) and 98.5% (95.7% to 99.5%), (19 studies, 2223 participants); direct testing (smear-positive specimen), pooled sensitivity and specificity were 86.2% (74.6% to 93.0%) and 98.6% (96.9% to 99.4%), (nine studies, 1771 participants, moderate quality evidence). SLID resistance: indirect testing, MTBDRsl pooled sensitivity and specificity were 76.5% (63.3% to 86.0%) and 99.1% (97.3% to 99.7%), (16 studies, 1921 participants); direct testing (smear-positive specimen), pooled sensitivity and specificity were 87.0% (38.1% to 98.6%) and 99.5% (93.6% to 100.0%), (eight studies, 1639 participants, low quality evidence). Extensively drug-resistant tuberculosis: indirect testing, MTBDRsl pooled sensitivity and specificity were 70.9% (42.9% to 88.8%) and 98.8% (96.1% to 99.6%), (eight studies, 880 participants); direct testing (smear-positive specimen), pooled sensitivity and specificity were 69.4% (38.8% to 89.0%) and 99.4% (95.0% to 99.3%), (six studies, 1420 participants, low quality evidence).Similar to the original Cochrane review, we found no evidence of a significant difference in MTBDRsl version 1.0 accuracy between indirect and direct testing for fluoroquinolone resistance, SLID resistance, and extensively drug-resistant tuberculosis. MTBDRsl version 2.0 Fluoroquinolone resistance: direct testing, MTBDRsl sensitivity and specificity were 97% (83% to 100%) and 98% (93% to 100%), smear-positive specimen; 80% (28% to 99%) and 100% (40% to 100%), smear-negative specimen. SLID resistance: direct testing, MTBDRsl sensitivity and specificity were 89% (72% to 98%) and 90% (84% to 95%), smear-positive specimen; 80% (28% to 99%) and 100% (40% to 100%), smear-negative specimen. Extensively drug-resistant tuberculosis: direct testing, MTBDRsl sensitivity and specificity were 79% (49% to 95%) and 97% (93% to 99%), smear-positive specimen; 50% (1% to 99%) and 100% (59% to 100%), smear-negative specimen.We had insufficient data to estimate summary sensitivity and specificity of version 2.0 (smear-positive and -negative specimens) or to compare accuracy of the two versions.A limitation was that most included studies did not consistently use the World Health Organization (WHO)-recommended concentrations for drugs in the culture-based DST reference standard. AUTHORS' CONCLUSIONS: In people with rifampicin-resistant or multidrug-resistant tuberculosis, MTBDRsl performed on a culture isolate or smear-positive specimen may be useful in detecting second-line drug resistance. MTBDRsl (smear-positive specimen) correctly classified around six in seven people as having fluoroquinolone or SLID resistance, although the sensitivity estimates for SLID resistance varied. The test rarely gave a positive result for people without drug resistance. However, when second-line drug resistance is not detected (MTBDRsl result is negative), conventional DST can still be used to evaluate patients for resistance to the fluoroquinolones or SLIDs.We recommend that future work evaluate MTBDRsl version 2.0, in particular on smear-negative specimens and in different settings to account for different resistance-causing mutations that may vary by strain. Researchers should also consider incorporating WHO-recommended critical concentrations into their culture-based reference standards.

Integrated management of childhood illness (IMCI) strategy for children under five.

BACKGROUND: More than 7.5 million children younger than age five living in low- and middle-income countries die every year. The World Health Organization (WHO) developed the integrated management of childhood illness (IMCI) strategy to reduce mortality and morbidity and to improve quality of care by improving the delivery of a variety of curative and preventive medical and behavioral interventions at health facilities, at home, and in the community. OBJECTIVES: To evaluate the effects of programs that implement the IMCI strategy in terms of death, nutritional status, quality of care, coverage with IMCI deliverables, and satisfaction of beneficiaries. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 3), including the Cochrane Effective Practice and Organisation of Care (EPOC) Group Specialised Register; MEDLINE; EMBASE, Ovid; the Cumulative Index to Nursing and Allied Health Literature (CINAHL), EbscoHost; the Latin American Caribbean Health Sciences Literature (LILACS), Virtual Health Library (VHL); the WHO Library & Information Networks for Knowledge Database (WHOLIS); the Science Citation Index and Social Sciences Citation Index, Institute for Scientific Information (ISI) Web of Science; Population Information Online (POPLINE); the WHO International Clinical Trials Registry Platform (WHO ICTRP); and the Global Health, Ovid and Health Management, ProQuest database. We performed searches until 30 June 2015 and supplemented these by searching revised bibliographies and by contacting experts to identify ongoing and unpublished studies. SELECTION CRITERIA: We sought to include randomised controlled trials (RCTs) and controlled before-after (CBA) studies with at least two intervention and two control sites evaluating the generic IMCI strategy or its adaptation in children younger than age five, and including at minimum efforts to improve health care worker skills for case management. We excluded studies in which IMCI was accompanied by other interventions including conditional cash transfers, food supplementation, and employment. The comparison group received usual health services without provision of IMCI. DATA COLLECTION AND ANALYSIS: Two review authors independently screened searches, selected trials, and extracted, analysed and tabulated data. We used inverse variance for cluster trials and an intracluster co-efficient of 0.01 when adjustment had not been made in the primary study. We used the GRADE (Grades of Recommendation, Assessment, Development and Evaluation Working Group) approach to assess the certainty of evidence. MAIN RESULTS: Two cluster-randomised trials (India and Bangladesh) and two controlled before-after studies (Tanzania and India) met our inclusion criteria. Strategies included training of health care staff, management strengthening of health care systems (all four studies), and home visiting (two studies). The two studies from India included care packages targeting the neonatal period.One trial in Bangladesh estimated that child mortality may be 13% lower with IMCI, but the confidence interval (CI) included no effect (risk ratio (RR) 0.87, 95% CI 0.68 to 1.10; 5090 participants; low-certainty evidence). One CBA study in Tanzania gave almost identical estimates (RR 0.87, 95% CI 0.72 to 1.05; 1932 participants).One trial in India examined infant and neonatal mortality by implementing the integrated management of neonatal and childhood illness (IMNCI) strategy including post-natal home visits. Neonatal and infant mortality may be lower in the IMNCI group compared with the control group (infant mortality hazard ratio (HR) 0.85, 95% CI 0.77 to 0.94; neonatal mortality HR 0.91, 95% CI 0.80 to 1.03; one trial, 60,480 participants; low-certainty evidence).We estimated the effect of IMCI on any mortality measured by combining infant and child mortality in the one IMCI and the one IMNCI trial. Mortality may be reduced by IMCI (RR 0.85, 95% CI 0.78 to 0.93; two trials, 65,570 participants; low-certainty evidence).Two trials (India, Bangladesh) evaluated nutritional status and noted that there may be little or no effect on stunting (RR 0.94, 95% CI 0.84 to 1.06; 5242 participants, two trials; low-certainty evidence) and there is probably little or no effect on wasting (RR 1.04, 95% CI 0.87 to 1.25; two trials, 4288 participants; moderate-certainty evidence).The Tanzania CBA study showed similar results.Investigators measured quality of care by observing prescribing for common illnesses at health facilities (727 observations, two studies; very low-certainty evidence) and by observing prescribing by lay health care workers (1051 observations, three studies; very low-certainty evidence). We could not confirm a consistent effect on prescribing at health facilities or by lay health care workers, as certainty of the evidence was very low.For coverage of IMCI deliverables, we examined vaccine and vitamin A coverage, appropriate care seeking, and exclusive breast feeding. Two trials (India, Bangladesh) estimated vaccine coverage for measles and reported that there is probably little or no effect on measles vaccine coverage (RR 0.92, 95% CI 0.80 to 1.05; two trials, 4895 participants; moderate-certainty evidence), with similar effects seen in the Tanzania CBA study. Two studies measured the third dose of diphtheria, pertussis, and tetanus vaccine; and two measured vitamin A coverage, all providing little or no evidence of increased coverage with IMCI.Four studies (2 from India, and 1 each from Tanzania and Bangladesh) reported appropriate care seeking and derived information from careful questioning of mothers about recent illness. Some studies on effects of IMCI may report better care seeking behavior, but others do not report this.All four studies recorded maternal responses on exclusive breast feeding. They provided mixed results and very low-certainty evidence. Therefore, we do not know whether IMCI impacts exclusive breast feeding.No studies reported on the satisfaction of mothers and service users. AUTHORS' CONCLUSIONS: The mix of interventions examined in research studies evaluating the IMCI strategy varies, and some studies include specific inputs to improve neonatal health. Most studies were conducted in South Asia. Implementing the integrated management of childhood illness strategy may reduce child mortality, and packages that include interventions for the neonatal period may reduce infant mortality. IMCI may have little or no effect on nutritional status and probably has little or no effect on vaccine coverage. Maternal care seeking behavior may be more appropriate with IMCI, but study results have been mixed, providing evidence of very low certainty about whether IMCI has effects on adherence to exclusive breast feeding.

Health system and community level interventions for improving antenatal care coverage and health outcomes.

BACKGROUND: The World Health Organization (WHO) recommends at least four antenatal care (ANC) visits for all pregnant women. Almost half of pregnant women worldwide, and especially in developing countries do not receive this amount of care. Poor attendance of ANC is associated with delivery of low birthweight babies and more neonatal deaths. ANC may include education on nutrition, potential problems with pregnancy or childbirth, child care and prevention or detection of disease during pregnancy.This review focused on community-based interventions and health systems-related interventions. OBJECTIVES: To assess the effects of health system and community interventions for improving coverage of antenatal care and other perinatal health outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (7 June 2015) and reference lists of retrieved studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs), quasi-randomised trials and cluster-randomised trials. Trials of any interventions to improve ANC coverage were eligible for inclusion. Trials were also eligible if they targeted specific and related outcomes, such as maternal or perinatal death, but also reported ANC coverage. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. MAIN RESULTS: We included 34 trials involving approximately 400,000 women. Some trials tested community-based interventions to improve uptake of antenatal care (media campaigns, education or financial incentives for pregnant women), while other trials looked at health systems interventions (home visits for pregnant women or equipment for clinics). Most trials took place in low- and middle-income countries, and 29 of the 34 trials used a cluster-randomised design. We assessed 30 of the 34 trials as of low or unclear overall risk of bias. Comparison 1: One intervention versus no interventionWe found marginal improvements in ANC coverage of at least four visits (average odds ratio (OR) 1.11, 95% confidence interval (CI) 1.01 to 1.22; participants = 45,022; studies = 10; Heterogeneity: Tau² = 0.01; I² = 52%; high quality evidence). Sensitivity analysis with a more conservative intra-cluster correlation co-efficient (ICC) gave similar marginal results. Excluding one study at high risk of bias shifted the marginal pooled estimate towards no effect. There was no effect on pregnancy-related deaths (average OR 0.69, 95% CI 0.45 to 1.08; participants = 114,930; studies = 10; Heterogeneity: Tau² = 0.00; I² = 0%; low quality evidence), perinatal mortality (average OR 0.98, 95% CI 0.90 to 1.07; studies = 15; Heterogeneity: Tau² = 0.01; I² = 58%; moderate quality evidence) or low birthweight (average OR 0.94, 95% CI 0.82 to 1.06; studies = five; Heterogeneity: Tau² = 0.00; I² = 5%; high quality evidence). Single interventions led to marginal improvements in the number of women who delivered in health facilities (average OR 1.08, 95% CI 1.02 to 1.15; studies = 10; Heterogeneity: Tau² = 0.00; I² = 0%; high quality evidence), and in the proportion of women who had at least one ANC visit (average OR 1.68, 95% CI 1.02 to 2.79; studies = six; Heterogeneity: Tau² = 0.24; I² = 76%; moderate quality evidence). Results for ANC coverage (at least four and at least one visit) and for perinatal mortality had substantial statistical heterogeneity. Single interventions did not improve the proportion of women receiving tetanus protection (average OR 1.03, 95% CI 0.92 to 1.15; studies = 8; Heterogeneity: Tau² = 0.01; I² = 57%). No study reported onintermittent prophylactic treatment for malaria. Comparison 2: Two or more interventions versus no interventionWe found no improvements in ANC coverage of four or more visits (average OR 1.48, 95% CI 0.99 to 2.21; participants = 7840; studies = six; Heterogeneity: Tau² = 0.10; I² = 48%; low quality evidence) or pregnancy-related deaths (average OR 0.70, 95% CI 0.39 to 1.26; participants = 13,756; studies = three; Heterogeneity: Tau² = 0.00; I² = 0%; moderate quality evidence). However, combined interventions led to improvements in ANC coverage of at least one visit (average OR 1.79, 95% CI 1.47 to 2.17; studies = five; Heterogeneity: Tau² = 0.00; I² = 0%; moderate quality evidence), perinatal mortality (average OR 0.74, 95% CI 0.57 to 0.95; studies = five; Heterogeneity: Tau² = 0.06; I² = 83%; moderate quality evidence) and low birthweight (average OR 0.61, 95% CI 0.46 to 0.80; studies = two; Heterogeneity: Tau² = 0.00; I² = 0%; moderate quality evidence). Meta-analyses for both ANC coverage four or more visits and perinatal mortality had substantial statistical heterogeneity. Combined interventions improved the proportion of women who had tetanus protection (average OR 1.48, 95% CI 1.18 to 1.87; studies = 3; Heterogeneity: Tau² = 0.01; I² = 33%). No trial in this comparison reported on intermittent prophylactic treatment for malaria. Comparison 3: Two interventions compared head to head. No trials found. Comparison 4: One intervention versus a combination of interventionsThere was no difference in ANC coverage (four or more visits and at least one visit), pregnancy-related deaths, deliveries in a health facility or perinatal mortality. No trials in this comparison reported on low birthweight orintermittent prophylactic treatment of malaria. AUTHORS' CONCLUSIONS: Implications for practice - Single interventions may improve ANC coverage (at least one visit and four or more visits) and deliveries in health facilities. Combined interventions may improve ANC coverage (at least one visit), reduce perinatal mortality and reduce the occurrence of low birthweight. The effects of the interventions are unrelated to whether they are community or health system interventions. Implications for research - More details should be provided in reporting numbers of events, group totals and the ICCs used to adjust for cluster effects. Outcomes should be reported uniformly so that they are comparable to commonly-used population indicators. We recommend further cluster-RCTs of pregnant women and women in their reproductive years, using combinations of interventions and looking at outcomes that are important to pregnant women, such as maternal and perinatal morbidity and mortality, alongside the explanatory outcomes along the pathway of care: ANC coverage, the services provided during ANC and deliveries in health facilities.

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.

Lenvatinib and sorafenib for differentiated thyroid cancer after radioactive iodine: a systematic review and economic evaluation.

BACKGROUND: Thyroid cancer is a rare cancer, accounting for only 1% of all malignancies in England and Wales. Differentiated thyroid cancer (DTC) accounts for ≈94% of all thyroid cancers. Patients with DTC often require treatment with radioactive iodine. Treatment for DTC that is refractory to radioactive iodine [radioactive iodine-refractory DTC (RR-DTC)] is often limited to best supportive care (BSC). OBJECTIVES: We aimed to assess the clinical effectiveness and cost-effectiveness of lenvatinib (Lenvima®; Eisai Ltd, Hertfordshire, UK) and sorafenib (Nexar®; Bayer HealthCare, Leverkusen, Germany) for the treatment of patients with RR-DTC. DATA SOURCES: EMBASE, MEDLINE, PubMed, The Cochrane Library and EconLit were searched (date range 1999 to 10 January 2017; searched on 10 January 2017). The bibliographies of retrieved citations were also examined. REVIEW METHODS: We searched for randomised controlled trials (RCTs), systematic reviews, prospective observational studies and economic evaluations of lenvatinib or sorafenib. In the absence of relevant economic evaluations, we constructed a de novo economic model to compare the cost-effectiveness of lenvatinib and sorafenib with that of BSC. RESULTS: Two RCTs were identified: SELECT (Study of [E7080] LEnvatinib in 131I-refractory differentiated Cancer of the Thyroid) and DECISION (StuDy of sorafEnib in loCally advanced or metastatIc patientS with radioactive Iodine-refractory thyrOid caNcer). Lenvatinib and sorafenib were both reported to improve median progression-free survival (PFS) compared with placebo: 18.3 months (lenvatinib) vs. 3.6 months (placebo) and 10.8 months (sorafenib) vs. 5.8 months (placebo). Patient crossover was high (≥ 75%) in both trials, confounding estimates of overall survival (OS). Using OS data adjusted for crossover, trial authors reported a statistically significant improvement in OS for patients treated with lenvatinib compared with those given placebo (SELECT) but not for patients treated with sorafenib compared with those given placebo (DECISION). Both lenvatinib and sorafenib increased the incidence of adverse events (AEs), and dose reductions were required (for > 60% of patients). The results from nine prospective observational studies and 13 systematic reviews of lenvatinib or sorafenib were broadly comparable to those from the RCTs. Health-related quality-of-life (HRQoL) data were collected only in DECISION. We considered the feasibility of comparing lenvatinib with sorafenib via an indirect comparison but concluded that this would not be appropriate because of differences in trial and participant characteristics, risk profiles of the participants in the placebo arms and because the proportional hazard assumption was violated for five of the six survival outcomes available from the trials. In the base-case economic analysis, using list prices only, the cost-effectiveness comparison of lenvatinib versus BSC yields an incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) gained of £65,872, and the comparison of sorafenib versus BSC yields an ICER of £85,644 per QALY gained. The deterministic sensitivity analyses show that none of the variations lowered the base-case ICERs to < £50,000 per QALY gained. LIMITATIONS: We consider that it is not possible to compare the clinical effectiveness or cost-effectiveness of lenvatinib and sorafenib. CONCLUSIONS: Compared with placebo/BSC, treatment with lenvatinib or sorafenib results in an improvement in PFS, objective tumour response rate and possibly OS, but dose modifications were required to treat AEs. Both treatments exhibit estimated ICERs of > £50,000 per QALY gained. Further research should include examination of the effects of lenvatinib, sorafenib and BSC (including HRQoL) for both symptomatic and asymptomatic patients, and the positioning of treatments in the treatment pathway. STUDY REGISTRATION: This study is registered as PROSPERO CRD42017055516. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

WHAT WAS THE PROBLEM?: Differentiated thyroid cancer is a common type of thyroid cancer. For many patients, radioactive iodine is an effective treatment; however, for some patients, the treatment stops working or becomes unsafe. Two new drugs, lenvatinib (Lenvima®; Eisai Ltd, Hertfordshire, UK) and sorafenib (Nexar®; Bayer HealthCare, Leverkusen, Germany), may be new treatment options. WHAT DID WE DO?: We reviewed the clinical evidence of lenvatinib and sorafenib. We also estimated the costs and benefits of treatment. WHAT DID WE FIND?: Compared with no treatment, treatment with lenvatinib or sorafenib may increase the time that people live with thyroid cancer before their disease gets worse; however, both drugs are expensive and may have unpleasant side effects. WHAT DOES THIS MEAN?: At their published (undiscounted) prices, lenvatinib or sorafenib may not be considered to provide good value for money to the NHS.

Lead-I ECG for detecting atrial fibrillation in patients with an irregular pulse using single time point testing: a systematic review and economic evaluation.

BACKGROUND: Atrial fibrillation (AF) is the most common type of cardiac arrhythmia and is associated with an increased risk of stroke and congestive heart failure. Lead-I electrocardiogram (ECG) devices are handheld instruments that can be used to detect AF at a single time point in people who present with relevant signs or symptoms. OBJECTIVE: To assess the diagnostic test accuracy, clinical impact and cost-effectiveness of using single time point lead-I ECG devices for the detection of AF in people presenting to primary care with relevant signs or symptoms, and who have an irregular pulse compared with using manual pulse palpation (MPP) followed by a 12-lead ECG in primary or secondary care. DATA SOURCES: MEDLINE, MEDLINE Epub Ahead of Print and MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, PubMed, Cochrane Databases of Systematic Reviews, Cochrane Central Database of Controlled Trials, Database of Abstracts of Reviews of Effects and the Health Technology Assessment Database. METHODS: The systematic review methods followed published guidance. Two reviewers screened the search results (database inception to April 2018), extracted data and assessed the quality of the included studies. Summary estimates of diagnostic accuracy were calculated using bivariate models. An economic model consisting of a decision tree and two cohort Markov models was developed to evaluate the cost-effectiveness of lead-I ECG devices. RESULTS: No studies were identified that evaluated the use of lead-I ECG devices for patients with signs or symptoms of AF. Therefore, the diagnostic accuracy and clinical impact results presented are derived from an asymptomatic population (used as a proxy for people with signs or symptoms of AF). The summary sensitivity of lead-I ECG devices was 93.9% [95% confidence interval (CI) 86.2% to 97.4%] and summary specificity was 96.5% (95% CI 90.4% to 98.8%). One study reported limited clinical outcome data. Acceptability of lead-I ECG devices was reported in four studies, with generally positive views. The de novo economic model yielded incremental cost-effectiveness ratios (ICERs) per quality-adjusted life-year (QALY) gained. The results of the pairwise analysis show that all lead-I ECG devices generated ICERs per QALY gained below the £20,000-30,000 threshold. Kardia Mobile (AliveCor Ltd, Mountain View, CA, USA) is the most cost-effective option in a full incremental analysis. LIMITATIONS: No published data evaluating the diagnostic accuracy, clinical impact or cost-effectiveness of lead-I ECG devices for the population of interest are available. CONCLUSIONS: Single time point lead-I ECG devices for the detection of AF in people with signs or symptoms of AF and an irregular pulse appear to be a cost-effective use of NHS resources compared with MPP followed by a 12-lead ECG in primary or secondary care, given the assumptions used in the base-case model. FUTURE WORK: Studies assessing how the use of lead-I ECG devices in this population affects the number of people diagnosed with AF when compared with current practice would be useful. STUDY REGISTRATION: This study is registered as PROSPERO CRD42018090375. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Atrial fibrillation (AF) is the most common type of abnormal heart rhythm. People with AF are more likely to have a serious stroke or die than people without the condition. Many people go to their general practitioner (GP) with the signs or symptoms commonly linked to AF, such as feeling dizzy, being short of breath, feeling tired and having heart palpitations. GPs check for AF by taking the patient's pulse by hand. If the GP thinks that the patient might have AF, a 12-lead electrocardiogram (ECG) test is arranged. Lead-I (i.e. one lead) ECGs are handheld electronic devices that could detect AF more accurately than a manual pulse check. If GPs were to routinely use lead-I ECG devices, people with suspected AF could receive treatment while waiting for the AF diagnosis to be confirmed by a 12-lead ECG. This study aimed to assess whether or not the use of lead-I ECGs in GP surgeries could benefit these patients and offer good value for money to the NHS. All studies that examined how well lead-I ECGs identified people with AF were reviewed, and the economic value of using these devices was assessed. No evidence was found that examined the use of lead-I ECGs for people with signs or symptoms of AF. As an alternative, evidence for the use of lead-I ECGs for people with no symptoms of AF was searched for and these data were used to assess value for money. The study found that using a manual pulse check followed by a lead-I ECG offers value for money when compared with a manual pulse check followed by a 12-lead ECG. This is mostly because patients with AF can begin treatment earlier when a GP has access to a lead-I ECG device.

Protocol for the development of the STrengthening the Reporting Of Pharmacogenetic Studies (STROPS) guideline: checklist of items for reporting pharmacogenetic studies.

INTRODUCTION: Large sample sizes are often required to detect statistically significant associations between pharmacogenetic markers and treatment response. Meta-analysis may be performed to synthesise data from several studies, increasing sample size and consequently power to detect significant genetic effects. However, performing robust synthesis of data from pharmacogenetic studies is often challenging due to poor reporting of key data in study reports. There is currently no guideline for the reporting of pharmacogenetic studies. The aim of this project is to develop the STrengthening the Reporting Of Pharmacogenetic Studies (STROPS) guideline. The STROPS guideline will facilitate the conduct of high-quality meta-analyses and thus improve the power to detect genetic associations. METHODS AND ANALYSIS: We will establish a preliminary checklist of reporting items to be considered for inclusion in the guideline. We will then conduct a Delphi survey of key stakeholder groups to gain consensus opinion on which reporting items to include in the final guideline. The Delphi survey will consist of two rounds: the first round will invite participants to score items from the preliminary checklist and to suggest additional relevant items; the second round will provide feedback from the previous round and invite participants to re-score the items. Following the second round, we will summarise the distribution of scores for each item, stratified by stakeholder group. The Steering Committee for the project and representatives from the key stakeholder groups will meet to consider the results of the Delphi survey and to finalise the list of reporting items. We will then draft, pilot-test and publish the STROPS reporting guideline and accompanying explanatory document. ETHICS AND DISSEMINATION: The University of Liverpool Ethics Committee has confirmed ethical approval for this study (reference: 3586). Dissemination activities will include presenting the reporting guideline at conferences relevant to pharmacogenetic research.

Eribulin for Treating Locally Advanced or Metastatic Breast Cancer After One Chemotherapy Regimen: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

Eribulin is a recommended treatment option for locally advanced or metastatic breast cancer (LABC/MBC) in adults whose disease has progressed after at least two chemotherapy regimens. The National Institute for Health and Care Excellence (NICE) invited the manufacturer of eribulin (Halaven®; Eisai Ltd) to submit evidence for the clinical and cost effectiveness of eribulin for treating LABC/MBC after one chemotherapy regimen in accordance with the institute's Single Technology Appraisal (STA) process. This article presents a summary of the company's evidence, Evidence Review Group (ERG) review and resulting NICE guidance (TA515), issued 28 March 2018. Clinical evidence for eribulin versus capecitabine in LABC/MBC was derived from a subgroup of 392 patients with human epidermal growth factor receptor (HER2)-negative disease which had progressed after only one prior chemotherapy regimen for LABC/MBC in the phase III, randomised, controlled Study 301 (n = 1102). Overall survival (OS) but not progression-free survival (PFS) was improved for patients treated with eribulin versus capecitabine in this subgroup. Using the discounted patient access scheme price for eribulin, the company developed a de novo economic model. In the base case, the incremental cost-effectiveness ratio (ICER) for eribulin versus capecitabine was £36,244 per quality-adjusted life year (QALY) gained. However, the ERG identified several problematic issues relating to modelling OS and PFS, drug costing and utility values, and made ten revisions to the company model. The overall impact of all ten revisions was to increase the ICER per QALY gained by £46,499. The Appraisal Committee (AC) accepted all changes made by the ERG except for the change to utility values; the AC considered that the value should be mid-way between the company's and the ERG's preferred values. A modified model was submitted by the company that included this utility value, but maintained some elements of the base case that the AC had been critical of (differential PFS between treatment arms and application of treatment cap). The new model also included a 'blended' comparator (capecitabine and vinorelbine). The AC noted there was no evidence to support a 'blended' comparator, differential PFS between treatment arms or a treatment cap. The AC therefore concluded that the most plausible ICER was likely to be £69,843 per QALY gained (derived from an ERG sensitivity analysis using the AC's preferred utility value, no differential PFS and no treatment cap). Therefore, eribulin was not recommended for treating LABC/MBC in adults who have had only one chemotherapy regimen.

Lead-I ECG for detecting atrial fibrillation in patients attending primary care with an irregular pulse using single-time point testing: A systematic review and economic evaluation.

BACKGROUND: Atrial fibrillation (AF) is the most common type of cardiac arrhythmia and is associated with increased risk of stroke and congestive heart failure. Lead-I electrocardiogram (ECG) devices are handheld instruments that can detect AF at a single-time point. PURPOSE: To assess the diagnostic test accuracy, clinical impact and cost effectiveness of single-time point lead-I ECG devices compared with manual pulse palpation (MPP) followed by a 12-lead ECG for the detection of AF in symptomatic primary care patients with an irregular pulse. METHODS: Electronic databases (MEDLINE, MEDLINE Epub Ahead of Print and MEDLINE In-Process, EMBASE, PubMed and Cochrane Databases of Systematic Reviews, Cochrane Central Database of Controlled Trials, Database of Abstracts of Reviews of Effects, Health Technology Assessment Database) were searched to March 2018. Two reviewers screened the search results, extracted data and assessed study quality. Summary estimates of diagnostic accuracy were calculated using bivariate models. Cost-effectiveness was evaluated using an economic model consisting of a decision tree and two cohort Markov models. RESULTS: Diagnostic accuracy The diagnostic accuracy (13 publications reporting on nine studies) and clinical impact (24 publications reporting on 19 studies) results are derived from an asymptomatic population (used as a proxy for people with signs or symptoms of AF). The summary sensitivity of lead-I ECG devices was 93.9% (95% confidence interval [CI]: 86.2% to 97.4%) and summary specificity was 96.5% (95% CI: 90.4% to 98.8%). Cost effectiveness The de novo economic model yielded incremental cost effectiveness ratios (ICERs) per quality adjusted life year (QALY) gained. The results of the pairwise analysis show that all lead-I ECG devices generate ICERs per QALY gained below the £20,000-£30,000 threshold. Kardia Mobile is the most cost effective option in a full incremental analysis. Lead-I ECG tests may identify more AF cases than the standard diagnostic pathway. This comes at a higher cost but with greater patient benefit in terms of mortality and quality of life. LIMITATIONS: No published data evaluating the diagnostic accuracy, clinical impact or cost effectiveness of lead-I ECG devices for the target population are available. CONCLUSIONS: The use of single-time point lead-I ECG devices in primary care for the detection of AF in people with signs or symptoms of AF and an irregular pulse appears to be a cost effective use of NHS resources compared with MPP followed by a 12-lead ECG, given the assumptions used in the base case model. REGISTRATION: The protocol for this review is registered on PROSPERO as CRD42018090375.