Drug Product Development and Case Studies for User Centric Pediatric Protein-Based Therapeutics.

The user of a pediatric drug includes not only the patient, but also their caregiver and healthcare provider, including nurses, doctors, and pharmacists. Therefore, adopting a patient-centric approach that focuses on all users is critical for the development of pediatric drug products. This article outlines the quality target product profile parameters and a patient-centric approach for the development of pediatric proteinbased therapies. The use environment, formulation design, and preparation and in use stability considerations are described. An acceptability profile for the various routes of parenteral administration is described with a focus on pediatric age groups. Furthermore, a risk assessment approach is presented for the selection of excipients to be utilized in pediatric protein-based biopharmaceuticals. Several case studies are included which illustrate the selection of drug product parameters such as formulation, dose volume, and route of administration with the pediatric user in mind.

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

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

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

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

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

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

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

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

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

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

Interventions to prevent spontaneous preterm birth in women with singleton pregnancy who are at high risk: systematic review and network meta-analysis.

OBJECTIVES: To compare the efficacy of bed rest, cervical cerclage (McDonald, Shirodkar, or unspecified type of cerclage), cervical pessary, fish oils or omega fatty acids, nutritional supplements (zinc), progesterone (intramuscular, oral, or vaginal), prophylactic antibiotics, prophylactic tocolytics, combinations of interventions, placebo or no treatment (control) to prevent spontaneous preterm birth in women with a singleton pregnancy and a history of spontaneous preterm birth or short cervical length. DESIGN: Systematic review with bayesian network meta-analysis. DATA SOURCES: The Cochrane Pregnancy and Childbirth Group's Database of Trials, the Cochrane Central Register of Controlled Trials, Medline, Embase, CINAHL, relevant journals, conference proceedings, and registries of ongoing trials. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials of pregnant women who are at high risk of spontaneous preterm birth because of a history of spontaneous preterm birth or short cervical length. No language or date restrictions were applied. OUTCOMES: Seven maternal outcomes and 11 fetal outcomes were analysed in line with published core outcomes for preterm birth research. Relative treatment effects (odds ratios and 95% credible intervals) and certainty of evidence are presented for outcomes of preterm birth <34 weeks and perinatal death. RESULTS: Sixty one trials (17 273 pregnant women) contributed data for the analysis of at least one outcome. For preterm birth <34 weeks (40 trials, 13 310 pregnant women) and with placebo or no treatment as the comparator, vaginal progesterone was associated with fewer women with preterm birth <34 weeks (odds ratio 0.50, 95% credible interval 0.34 to 0.70, high certainty of evidence). Shirodkar cerclage showed the largest effect size (0.06, 0.00 to 0.84), but the certainty of evidence was low. 17OHPC (17α-hydroxyprogesterone caproate; 0.68, 0.43 to 1.02, moderate certainty), vaginal pessary (0.65, 0.39 to 1.08, moderate certainty), and fish oil or omega 3 (0.30, 0.06 to 1.23, moderate certainty) might also reduce preterm birth <34 weeks compared with placebo or no treatment. For the fetal outcome of perinatal death (30 trials, 12 119 pregnant women) and with placebo or no treatment as the comparator, vaginal progesterone was the only treatment that showed clear evidence of benefit for this outcome (0.66, 0.44 to 0.97, moderate certainty). 17OHPC (0.78, 0.50 to 1.21, moderate certainty), McDonald cerclage (0.59, 0.33 to 1.03, moderate certainty), and unspecified cerclage (0.77, 0.53 to 1.11, moderate certainty) might reduce perinatal death rates, but credible intervals could not exclude the possibility of harm. Only progesterone treatments are associated with reduction in neonatal respiratory distress syndrome, neonatal sepsis, necrotising enterocolitis, and admission to neonatal intensive care unit compared with controls. CONCLUSION: Vaginal progesterone should be considered the preventative treatment of choice for women with singleton pregnancy identified to be at risk of spontaneous preterm birth because of a history of spontaneous preterm birth or short cervical length. Future randomised controlled trials should use vaginal progesterone as a comparator to identify better treatments or combination treatments. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020169006.

Ontology of the apelinergic system in mouse pancreas during pregnancy and relationship with ß-cell mass.

The apelin receptor (Aplnr) and its ligands, Apelin and Apela, contribute to metabolic control. The insulin resistance associated with pregnancy is accommodated by an expansion of pancreatic ß-cell mass (BCM) and increased insulin secretion, involving the proliferation of insulin-expressing, glucose transporter 2-low (Ins+Glut2LO) progenitor cells. We examined changes in the apelinergic system during normal mouse pregnancy and in pregnancies complicated by glucose intolerance with reduced BCM. Expression of Aplnr, Apelin and Apela was quantified in Ins+Glut2LO cells isolated from mouse pancreata and found to be significantly higher than in mature ß-cells by DNA microarray and qPCR. Apelin was localized to most ß-cells by immunohistochemistry although Aplnr was predominantly associated with Ins+Glut2LO cells. Aplnr-staining cells increased three- to four-fold during pregnancy being maximal at gestational days (GD) 9-12 but were significantly reduced in glucose intolerant mice. Apelin-13 increased ß-cell proliferation in isolated mouse islets and INS1E cells, but not glucose-stimulated insulin secretion. Glucose intolerant pregnant mice had significantly elevated serum Apelin levels at GD 9 associated with an increased presence of placental IL-6. Placental expression of the apelinergic axis remained unaltered, however. Results show that the apelinergic system is highly expressed in pancreatic ß-cell progenitors and may contribute to ß-cell proliferation in pregnancy.

EstablishINg the best STEp-up treatments for children with uncontrolled asthma despite INhaled corticosteroids (EINSTEIN): protocol for a systematic review, network meta-analysis and cost-effectiveness analysis using individual participant data (IPD).

INTRODUCTION: Asthma affects millions of children worldwide-1.1 million children in the UK. Asthma symptoms cannot be cured but can be controlled with low-dose inhaled corticosteroids (ICSs) in the majority of individuals. Treatment with a low-dose ICS, however, fails to control asthma symptoms in around 10%-15% of children and this places the individual at increased risk for an asthma attack. At present, there is no clear preferred treatment option for a child whose asthma is not controlled by low-dose ICS and international guidelines currently recommend at least three treatment options. Herein, we propose a systematic review and individual participant data network meta-analysis (IPD-NMA) aiming to synthesise all available published and unpublished evidence from randomised controlled trials (RCTs) to establish the clinical effectiveness of pharmacological treatments in children and adolescents with uncontrolled asthma on ICS and help to make evidence-informed treatment choices. This will be used to parameterise a Markov-based economic model to assess the cost-effectiveness of alternative treatment options in order to inform decisions in the context of drug formularies and clinical guidelines. METHODS AND ANALYSIS: We will search in MEDLINE, the Cochrane Library, the Cochrane Central Register of Controlled Trials (CENTRAL), Embase, NICE Technology Appraisals and the National Institute for Health Research (NIHR) Health Technology Assessment series for RCTs of interventions in patients with uncontrolled asthma on ICS. All studies where children and adolescents were eligible for inclusion will be considered, and authors or sponsors will be contacted to request IPD on patients aged <18. The reference lists of existing clinical guidelines, along with included studies and relevant reviews, will be checked to identify further relevant studies. Unpublished studies will be located by searching across a range of clinical trial registries, including internal trial registers for pharmaceutical companies. All studies will be appraised for inclusion against predefined inclusion and exclusion criteria by two independent reviewers with disagreements resolved through discussion with a third reviewer. We will perform an IPD-NMA-eventually supplemented with aggregate data for the RCTs without IPD-to establish both the probability that a treatment is best and the probability that a particular treatment is most likely to be effective for a specific profile of the patient. The IPD-NMA will be performed for each outcome variable within a Bayesian framework, using the WinBUGS software. Also, potential patient-level characteristics that may modify treatment effects will be explored, which represents one of the strengths of this study. ETHICS AND DISSEMINATION: The Committee on Research Ethics, University of Liverpool, has confirmed that ethics review is not required. The dissemination plan consists of publishing the results in an open-access medical journal, a plain-language summary available for parents and children, dissemination via local, national and international meetings and conferences and the press offices of our Higher Education Institutions (HEIs). A synopsis of results will be disseminated to NICE and British Thoracic Society/Scottish Intercollegiate Guidelines Network (SIGN) as highly relevant to future clinical guideline updates. PROSPERO REGISTRATION NUMBER: CRD42019127599.

Altered pancreas remodeling following glucose intolerance in pregnancy in mice.

Gestational diabetes mellitus increases the risk of dysglycemia postpartum, in part, due to pancreatic ß-cell dysfunction. However, no histological evidence exists comparing endocrine pancreas after healthy and glucose-intolerant pregnancies. This study sought to address this knowledge gap, in addition to exploring the contribution of an inflammatory environment to changes in endocrine pancreas after parturition. We used a previously established mouse model of gestational glucose intolerance induced by dietary low protein insult from conception until weaning. Pancreas and adipose samples were collected at 7, 30 and 90 days postpartum for histomorphometric and cytokine analyses, respectively. Glucose tolerance tests were performed prior to euthanasia and blood was collected via cardiac puncture. Pregnant female mice born to dams fed a low protein diet previously shown to develop glucose intolerance at late gestation relative to controls continued to be glucose intolerant until 1 month postpartum. However, glucose tolerance normalized by 3 months postpartum. Glucose intolerance at 7 days postpartum was associated with lower beta- and alpha-cell fractional areas and higher adipose levels of pro-inflammatory cytokine, interleukin-6. By 3 months postpartum, a compensatory increase in the number of small islets and a higher insulin to glucagon ratio likely enabled euglycemia to be attained in the previously glucose-intolerant mice. The results show that impairments in endocrine pancreas compensation in hyperglycemic pregnancy persist after parturition and contribute to prolonged glucose intolerance. These impairments may increase the susceptibility to development of future type 2 diabetes.

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

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

Assessing the consistency assumptions underlying network meta-regression using aggregate data.

When numerous treatments exist for a disease (Treatments 1, 2, 3, etc), network meta-regression (NMR) examines whether each relative treatment effect (eg, mean difference for 2 vs 1, 3 vs 1, and 3 vs 2) differs according to a covariate (eg, disease severity). Two consistency assumptions underlie NMR: consistency of the treatment effects at the covariate value 0 and consistency of the regression coefficients for the treatment by covariate interaction. The NMR results may be unreliable when the assumptions do not hold. Furthermore, interactions may exist but are not found because inconsistency of the coefficients is masking them, for example, when the treatment effect increases as the covariate increases using direct evidence but the effect decreases with the increasing covariate using indirect evidence. We outline existing NMR models that incorporate different types of treatment by covariate interaction. We then introduce models that can be used to assess the consistency assumptions underlying NMR for aggregate data. We extend existing node-splitting models, the unrelated mean effects inconsistency model, and the design by treatment inconsistency model to incorporate covariate interactions. We propose models for assessing both consistency assumptions simultaneously and models for assessing each of the assumptions in turn to gain a more thorough understanding of consistency. We apply the methods in a Bayesian framework to trial-level data comparing antimalarial treatments using the covariate average age and to four fabricated data sets to demonstrate key scenarios. We discuss the pros and cons of the methods and important considerations when applying models to aggregated data.

Graphs of study contributions and covariate distributions for network meta-regression.

BACKGROUND: Meta-regression results must be interpreted taking into account the range of covariate values of the contributing studies. Results based on interpolation or extrapolation may be unreliable. In network meta-regression (NMR) models, which include covariates in network meta-analyses, results are estimated using direct and indirect evidence; therefore, it may be unclear which studies and covariate values contribute to which result. We propose graphs to help understand which trials and covariate values contribute to each NMR result and to highlight extrapolation or interpolation. METHODS: We introduce methods to calculate the contribution that each trial and covariate value makes to each result and compare them with existing methods. We show how to construct graphs including a network covariate distribution diagram, covariate-contribution plot, heat plot, contribution-NMR plot, and heat-NMR plot. We demonstrate the methods using a dataset with treatments for malaria using the covariate average age and a dataset of topical fluoride interventions for preventing dental caries using the covariate randomisation year. RESULTS: For the malaria dataset, no contributing trials had an average age between 7-25 years and therefore results were interpolated within this range. For the fluoride dataset, there are no contributing trials randomised between 1954-1959 for most comparisons therefore, within this range, results would be extrapolated. CONCLUSIONS: Even in a fully connected network, an NMR result may be estimated from trials with a narrower covariate range than the range of the whole dataset. Calculating contributions and graphically displaying them aids interpretation of NMR result by highlighting extrapolated or interpolated results.

Network meta-analysis including treatment by covariate interactions: Consistency can vary across covariate values.

BACKGROUND: Many reviews aim to compare numerous treatments and report results stratified by subgroups (eg, by disease severity). In such cases, a network meta-analysis model including treatment by covariate interactions can estimate the relative effects of all treatment pairings for each subgroup of patients. Two key assumptions underlie such models: consistency of treatment effects and consistency of the regression coefficients for the interactions. Consistency may differ depending on the covariate value at which consistency is assessed. For valid inference, we need to be confident of consistency for the relevant range of covariate values. In this paper, we demonstrate how to assess consistency of treatment effects from direct and indirect evidence at various covariate values. METHODS: Consistency is assessed using visual inspection, inconsistency estimates, and probabilities. The method is applied to an individual patient dataset comparing artemisinin combination therapies for treating uncomplicated malaria in children using the covariate age. RESULTS: The magnitude of the inconsistency appears to be decreasing with increasing age for each comparison. For one comparison, direct and indirect evidence differ for age 1 (P = .05), and this brings results for age 1 for all comparisons into question. CONCLUSION: When fitting models including interactions, the consistency of direct and indirect evidence must be assessed across the range of covariates included in the trials. Clinical inferences are only valid for covariate values for which results are consistent.

Is Dengue Vector Control Deficient in Effectiveness or Evidence?: Systematic Review and Meta-analysis.

BACKGROUND: Although a vaccine could be available as early as 2016, vector control remains the primary approach used to prevent dengue, the most common and widespread arbovirus of humans worldwide. We reviewed the evidence for effectiveness of vector control methods in reducing its transmission. METHODOLOGY/PRINCIPAL FINDINGS: Studies of any design published since 1980 were included if they evaluated method(s) targeting Aedes aegypti or Ae. albopictus for at least 3 months. Primary outcome was dengue incidence. Following Cochrane and PRISMA Group guidelines, database searches yielded 960 reports, and 41 were eligible for inclusion, with 19 providing data for meta-analysis. Study duration ranged from 5 months to 10 years. Studies evaluating multiple tools/approaches (23 records) were more common than single methods, while environmental management was the most common method (19 studies). Only 9/41 reports were randomized controlled trials (RCTs). Two out of 19 studies evaluating dengue incidence were RCTs, and neither reported any statistically significant impact. No RCTs evaluated effectiveness of insecticide space-spraying (fogging) against dengue. Based on meta-analyses, house screening significantly reduced dengue risk, OR 0.22 (95% CI 0.05-0.93, p = 0.04), as did combining community-based environmental management and water container covers, OR 0.22 (95% CI 0.15-0.32, p<0.0001). Indoor residual spraying (IRS) did not impact significantly on infection risk (OR 0.67; 95% CI 0.22-2.11; p = 0.50). Skin repellents, insecticide-treated bed nets or traps had no effect (p>0.5), but insecticide aerosols (OR 2.03; 95% CI 1.44-2.86) and mosquito coils (OR 1.44; 95% CI 1.09-1.91) were associated with higher dengue risk (p = 0.01). Although 23/41 studies examined the impact of insecticide-based tools, only 9 evaluated the insecticide susceptibility status of the target vector population during the study. CONCLUSIONS/SIGNIFICANCE: This review and meta-analysis demonstrate the remarkable paucity of reliable evidence for the effectiveness of any dengue vector control method. Standardised studies of higher quality to evaluate and compare methods must be prioritised to optimise cost-effective dengue prevention.

Cluster Randomised Trials in Cochrane Reviews: Evaluation of Methodological and Reporting Practice.

OBJECTIVE: Systematic reviews can include cluster-randomised controlled trials (C-RCTs), which require different analysis compared with standard individual-randomised controlled trials. However, it is not known whether review authors follow the methodological and reporting guidance when including these trials. The aim of this study was to assess the methodological and reporting practice of Cochrane reviews that included C-RCTs against criteria developed from existing guidance. METHODS: Criteria were developed, based on methodological literature and personal experience supervising review production and quality. Criteria were grouped into four themes: identifying, reporting, assessing risk of bias, and analysing C-RCTs. The Cochrane Database of Systematic Reviews was searched (2nd December 2013), and the 50 most recent reviews that included C-RCTs were retrieved. Each review was then assessed using the criteria. RESULTS: The 50 reviews we identified were published by 26 Cochrane Review Groups between June 2013 and November 2013. For identifying C-RCTs, only 56% identified that C-RCTs were eligible for inclusion in the review in the eligibility criteria. For reporting C-RCTs, only eight (24%) of the 33 reviews reported the method of cluster adjustment for their included C-RCTs. For assessing risk of bias, only one review assessed all five C-RCT-specific risk-of-bias criteria. For analysing C-RCTs, of the 27 reviews that presented unadjusted data, only nine (33%) provided a warning that confidence intervals may be artificially narrow. Of the 34 reviews that reported data from unadjusted C-RCTs, only 13 (38%) excluded the unadjusted results from the meta-analyses. CONCLUSIONS: The methodological and reporting practices in Cochrane reviews incorporating C-RCTs could be greatly improved, particularly with regard to analyses. Criteria developed as part of the current study could be used by review authors or editors to identify errors and improve the quality of published systematic reviews incorporating C-RCTs.

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

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

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

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

Exploring treatment by covariate interactions using subgroup analysis and meta-regression in cochrane reviews: a review of recent practice.

BACKGROUND: Treatment by covariate interactions can be explored in reviews using interaction analyses (e.g., subgroup analysis). Such analyses can provide information on how the covariate modifies the treatment effect and is an important methodological approach for personalising medicine. Guidance exists regarding how to apply such analyses but little is known about whether authors follow the guidance. METHODS: Using published recommendations, we developed criteria to assess how well interaction analyses were designed, applied, interpreted, and reported. The Cochrane Database of Systematic Reviews was searched (8th August 2013). We applied the criteria to the most recently published review, with an accessible protocol, for each Cochrane Review Group. We excluded review updates, diagnostic test accuracy reviews, withdrawn reviews, and overviews of reviews. Data were summarised regarding reviews, covariates, and analyses. RESULTS: Each of the 52 included reviews planned or did interaction analyses; 51 reviews (98%) planned analyses and 33 reviews (63%) applied analyses. The type of analysis planned and the type subsequently applied (e.g., sensitivity or subgroup analysis) was discrepant in 24 reviews (46%). No review reported how or why each covariate had been chosen; 22 reviews (42%) did state each covariate a priori in the protocol but no review identified each post-hoc covariate as such. Eleven reviews (21%) mentioned five covariates or less. One review reported planning to use a method to detect interactions (i.e., interaction test) for each covariate; another review reported applying the method for each covariate. Regarding interpretation, only one review reported whether an interaction was detected for each covariate and no review discussed the importance, or plausibility, of the results, or the possibility of confounding for each covariate. CONCLUSIONS: Interaction analyses in Cochrane Reviews can be substantially improved. The proposed criteria can be used to help guide the reporting and conduct of analyses.

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

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