Improving the Reporting of Pharmacogenetic Studies to Facilitate Evidence Synthesis: Anti-Tuberculosis Drug-Related Toxicity as an Example

Background In pharmacogenetic studies, researchers explore how genetic variants impact individuals’ responses to drugs. Implementation of pharmacogenetic tests in clinical practice can improve treatment efficacy and reduce toxicity. For health service providers to implement pharmacogenetic testing in clinical practice, the pharmacogenetic association of interest must be supported by strong evidence. Performing meta-analyses of pharmacogenetic studies increases sample size and power, and is therefore an indispensable tool to researchers striving to improve the strength of evidence for pharmacogenetic associations. The aim of this thesis is to identify and resolve challenges that reviewers might encounter when synthesising evidence from primary pharmacogenetic studies. Methods We explored methods of evidence synthesis for pharmacogenetic studies and applied them to undertake a systematic review and meta-analysis of associations between genetic variants and anti-tuberculosis drug-related toxicity. We applied both standard methods of meta-analysis, and more complex methods of meta-analysis that account for correlation between related effect sizes for each genetic variant. Conducting this systematic review and meta-analysis enabled us to identify that key information was often poorly reported in the primary pharmacogenetic studies. In order to improve the reporting of pharmacogenetic studies with a view to facilitating the evidence synthesis process, we used consensus methodology to develop a reporting guideline for pharmacogenetic studies, known as the STROPS (Strengthening The Reporting Of Pharmacogenetic Studies) guideline. Results Our systematic review of the association between genetic variants and anti-tuberculosis drug-related toxicity included 70 studies. Slow acetylators are more likely to experience anti-TB drug-induced hepatotoxicity than intermediate/rapid acetylators. We also observed associations between the CYP2E1 RsaI and GSTM1 null polymorphisms and hepatotoxicity. Key information, such as the ethnicity of included patients, methodological quality, and patient cohort overlap, was poorly reported. We also found that improvements in the reporting of outcome data would give systematic reviewers greater freedom in terms of their analysis approach. As part of the development of the STROPS guideline, 52 individuals from key stakeholder groups participated in two rounds of a Delphi survey. A total of eight individuals participated in a consensus meeting, before the 54-item STROPS guideline was finalised. Conclusions Our systematic review showed that pharmacogenetic testing may be useful in clinical practice in terms of risk stratification for hepatotoxicity during TB treatment. More studies are needed to overcome methodological limitations of the existing studies and to assess the feasibility and cost-effectiveness of a stratified medicine approach. It is currently challenging to synthesise pharmacogenetic evidence, due to poor reporting of primary studies. We encourage authors to adhere to the STROPS guideline when publishing pharmacogenetic studies. The STROPS guideline will not only improve the transparency of reporting of pharmacogenetic studies, but will also facilitate the conduct of high-quality systematic reviews and meta-analyses, and thus improve the power to detect pharmacogenetic associations

WHO guidelines for plague management: revised recommendations for the use of rapid diagnostic tests, fluoroquinolones for case management and personal protective equipment for prevention of post-mortem transmission.

Plague has killed millions of people during the past 25 centuries (1), and the disease reappeared in several countries during the 1990s. Consequently, plague was categorized as a re-emerging disease (2). Human plague outbreaks continue to be reported, including an outbreak of pneumonic plague in Madagascar in 2017 (2–4). Plague is an acute bacterial infection caused by Yersinia pestis. Although effective antimicrobials are available, plague still has high mortality because most outbreaks take place in remote places, where proper diagnosis and treatment remain challenging (2). Early identification of the disease is crucial to ensure prompt treatment and better outcomes. Pneumonic plague is highly contagious and of particular concern because of the high risk of triggering epidemics. Thus, plague is both a medical and a public health emergency. These guidelines were developed in accordance with the WHO handbook for guideline development (5). A WHO Steering Group, led by the responsible technical officer, developed the draft scope of the guidelines and the key questions to be addressed. The Steering Group selected the members of the Guideline Development Group (GDG) to ensure diverse areas of expertise were represented, including clinicians, microbiologists, public health professionals, researchers and an anthropologist. The Steering Group also commissioned technical advisers to lead the Evidence Review Team and provide methodological support

House modifications for preventing malaria

Background Malaria remains an important public health problem. Research in 1900 suggested house modifications may reduce malaria transmission. A previous version of this review concluded that house screening may be effective in reducing malaria. This update includes data from five new studies. Objectives To assess the effects of house modifications that aim to reduce exposure to mosquitoes on malaria disease and transmission. Search methods We searched the Cochrane Infectious Diseases Group Specialized Register; Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE (PubMed); Embase (OVID); Centre for Agriculture and Bioscience International (CAB) Abstracts (Web of Science); and the Latin American and Caribbean Health Science Information database (LILACS) up to 25 May 2022. We also searched the World Health Organization International Clinical Trials Registry Platform, ClinicalTrials.gov, and the ISRCTN registry to identify ongoing trials up to 25 May 2022. Selection criteria Randomized controlled trials, including cluster‐randomized controlled trials (cRCTs), cross‐over studies, and stepped‐wedge designs were eligible, as were quasi‐experimental trials, including controlled before‐and‐after studies, controlled interrupted time series, and non‐randomized cross‐over studies. We sought studies investigating primary construction and house modifications to existing homes reporting epidemiological outcomes (malaria case incidence, malaria infection incidence or parasite prevalence). We extracted any entomological outcomes that were also reported in these studies. Data collection and analysis Two review authors independently selected eligible studies, extracted data, and assessed the risk of bias. We used risk ratios (RR) to compare the effect of the intervention with the control for dichotomous data. For continuous data, we presented the mean difference; and for count and rate data, we used rate ratios. We presented all results with 95% confidence intervals (CIs). We assessed the certainty of evidence using the GRADE approach. Main results One RCT and six cRCTs met our inclusion criteria, with an additional six ongoing RCTs. We did not identify any eligible non‐randomized studies. All included trials were conducted in sub‐Saharan Africa since 2009; two randomized by household and four at the block or village level. All trials assessed screening of windows, doors, eaves, ceilings, or any combination of these; this was either alone, or in combination with roof modification or eave tube installation (an insecticidal "lure and kill" device that reduces mosquito entry whilst maintaining some airflow). In one trial, the screening material was treated with 2% permethrin insecticide. In five trials, the researchers implemented the interventions. A community‐based approach was adopted in the other trial. Overall, the implementation of house modifications probably reduced malaria parasite prevalence (RR 0.68, 95% CI 0.57 to 0.82; 5 trials, 5183 participants; moderate‐certainty evidence), although an inconsistent effect was observed in a subpopulation of children in one study. House modifications reduced moderate to severe anaemia prevalence (RR 0.70, 95% CI 0.55 to 0.89; 3 trials, 3643 participants; high‐certainty evidence). There was no consistent effect on clinical malaria incidence, with rate ratios ranging from 0.38 to 1.62 (3 trials, 3365 participants, 4126.6 person‐years). House modifications may reduce indoor mosquito density (rate ratio 0.63, 95% CI 0.30 to 1.30; 4 trials, 9894 household‐nights; low‐certainty evidence), although two studies showed little effect on this parameter. Authors' conclusions House modifications – largely screening, sometimes combined with insecticide and lure and kill devices – were associated with a reduction in malaria parasite prevalence and a reduction in people with anaemia. Findings on malaria incidence were mixed. Modifications were also associated with lower indoor adult mosquito density, but this effect was not present in some studies

Funny walking : the rise, fall and rise of the Anglo-American comic eccentric dancer

This article will attempt to reposition comic eccentric dance as a metamorphic form that still, surprisingly, exists, and is to be found with reasonable ubiquity, in renewed incarna-tions within twenty first century media. Tracing the origins of comic eccentric dance through examples of earlier comedy performance, and drawing from Bergson’s comic theory of body misalliance, this article will dis-cuss this particularly ludic fusion of music and comedy. Further changes to the form affected by modernist preoccupations during the new Jazz Age at the turn of the twentieth century will be suggested. Finally, ways in which the formulation lives on in twenty-first century in-carnations in the comedy work of, for instance, Jimmy Fallon and Ricky Gervase, and in popular television shows such as Strictly Come Dancing (BBC 2004 - ) and Britain’s Got Talent (ITV 2006 - ) will be posited

Intention‐to‐treat analyses and missing outcome data: A tutorial

This tutorial focuses on “intention-to-treat” analyses and missing outcome data in systematic reviews. There is a lack of consensus on the definition of the ITT approach. We will explain the principles of an intention-to-treat analysis, and outline the key issues you need to consider when planning, conducting and writing up your systematic review

Wolbachia ‐carrying Aedes mosquitoes for preventing dengue infection

Background Dengue is a global health problem of high significance, with 3.9 billion people at risk of infection. The geographic expansion of dengue virus (DENV) infection has resulted in increased frequency and severity of the disease, and the number of deaths has increased in recent years. Wolbachia, an intracellular bacterial endosymbiont, has been under investigation for several years as a novel dengue‐control strategy. Some dengue vectors (Aedes mosquitoes) can be transinfected with specific strains of Wolbachia, which decreases their fitness (ability to survive and mate) and their ability to reproduce, inhibiting the replication of dengue. Both laboratory and field studies have demonstrated the potential effect of Wolbachia deployments on reducing dengue transmission, and modelling studies have suggested that this may be a self‐sustaining strategy for dengue prevention, although long‐term effects are yet to be elucidated. Objectives To assess the efficacy of Wolbachia‐carrying Aedes species deployments (specifically wMel‐, wMelPop‐, and wAlbB‐ strains of Wolbachia) for preventing dengue virus infection. Search methods We searched CENTRAL, MEDLINE, Embase, four other databases, and two trial registries up to 24 January 2024. Selection criteria Randomized controlled trials (RCTs), including cluster‐randomized controlled trials (cRCTs), conducted in dengue endemic or epidemic‐prone settings were eligible. We sought studies that investigated the impact of Wolbachia‐carrying Aedes deployments on epidemiological or entomological dengue‐related outcomes, utilizing either the population replacement or population suppression strategy. Data collection and analysis Two review authors independently selected eligible studies, extracted data, and assessed the risk of bias using the Cochrane RoB 2 tool. We used odds ratios (OR) with the corresponding 95% confidence intervals (CI) as the effect measure for dichotomous outcomes. For count/rate outcomes, we planned to use the rate ratio with 95% CI as the effect measure. We used adjusted measures of effect for cRCTs. We assessed the certainty of evidence using GRADE. Main results One completed cRCT met our inclusion criteria, and we identified two further ongoing cRCTs. The included trial was conducted in an urban setting in Yogyakarta, Indonesia. It utilized a nested test‐negative study design, whereby all participants aged three to 45 years who presented at healthcare centres with a fever were enrolled in the study provided they had resided in the study area for the previous 10 nights. The trial showed that wMel‐Wolbachia infected Ae aegypti deployments probably reduce the odds of contracting virologically confirmed dengue by 77% (OR 0.23, 95% CI 0.15 to 0.35; 1 trial, 6306 participants; moderate‐certainty evidence). The cluster‐level prevalence of wMel Wolbachia‐carrying mosquitoes remained high over two years in the intervention arm of the trial, reported as 95.8% (interquartile range 91.5 to 97.8) across 27 months in clusters receiving wMel‐Wolbachia Ae aegypti deployments, but there were no reliable comparative data for this outcome. Other primary outcomes were the incidence of virologically confirmed dengue, the prevalence of dengue ribonucleic acid in the mosquito population, and mosquito density, but there were no data for these outcomes. Additionally, there were no data on adverse events. Authors' conclusions The included trial demonstrates the potential significant impact of wMel‐Wolbachia‐carrying Ae aegypti mosquitoes on preventing dengue infection in an endemic setting, and supports evidence reported in non‐randomized and uncontrolled studies. Further trials across a greater diversity of settings are required to confirm whether these findings apply to other locations and country settings, and greater reporting of acceptability and cost are important