Quality of outcome reporting in phase II studies in pulmonary tuberculosis

Tuberculosis (TB) remains a major killer amongst the infectious diseases. Current treatment involves a four-drug regimen for at least 6 months. New drugs and regimens are required to shorten treatment duration, reduce toxicity and combat drug resistance, but the optimal methodology to define the critical path for novel regimens is not well defined. We undertook a systematic review to summarise outcomes reported in Phase II trials of patients with newly diagnosed pulmonary TB to assess the need for a core outcome set. A systematic search of databases (PubMed, MEDLINE, EMBASE and LILACs) was conducted on 1 May 2015 to retrieve relevant peer-reviewed articles. Reference lists of included studies were also searched. This systematic review considered all reported outcomes. Risk of bias was considered via sequence generation, allocation concealment, blinding, reasons for exclusions, and selective reporting. Of 55 included studies, 20 were Phase IIB studies based on culture conversion, 32 were Phase IIA studies based on quantitative bacteriology, and three considered alternative outcomes. Large variation in reported outcomes and trial characteristics was observed across the included studies. Bacteriological results were as often expressed in terms of positivity as negativity, with varying definitions of culture conversion. Variation in reporting was particularly marked for Phase IIA studies, where multiple time intervals were typically selected for analysis and sometimes resulted in differing interpretations of the efficacy of drugs or regimens. Within both Phase IIA and IIB studies, there was variation in the time points at which the study participants were sampled, as well as in the bacteriological media and methods used. For successful future meta-analysis of early-phase studies, the findings of this review suggest that development of a core outcome set would be desirable. This would enable trial results to be more easily compared and combined, potentially leading to more effective development of new treatment strategies for patients with TB. Pending development of, and agreement on, such a core outcome set, we suggest some interim recommendations for reporting of future phase II studies of pulmonary tuberculosis

Biased sampling activity: an investigation to promote discussion.

The statistical concept of sampling is often given little direct attention, typically reduced to the mantra "take a random sample". This low resource and adaptable activity demonstrates sampling and explores issues that arise due to biased sampling

Prognostic factors for epilepsy

Introduction and Aims: Epilepsy is a neurological disorder and is a heterogeneous condition both in terms of cause and prognosis. Prognostic factors identify patients at varying degrees of risk for specific outcomes which facilitates treatment choice and aids patient counselling. Few prognostic models based on prospective cohorts or randomised controlled trial data have been published in epilepsy. Patients with epilepsy can be loosely categorised as having had a first seizure, being newly diagnosed with epilepsy, having established epilepsy or frequent unremitting seizures despite optimum treatment. This thesis concerns modelling prognostic factors for these patient groups, for outcomes including seizure recurrence, seizure remission and treatment failure. Methods: Methods for modelling prognostic factors are discussed and applied to several examples including eligibility to drive following a first seizure and following withdrawal of treatment after a period of remission from seizures. Internal and external model validation techniques are reviewed. The latter is investigated further in a simulation study, the results of which are demonstrated in a motivating example. Mixture modelling is introduced and assessed to better predict whether a patient would achieve remission from seizures immediately, at a later time point, or whether they may never achieve remission. Results: Multivariable models identified a number of significant factors. Future risk of a seizure was therefore obtained for various patient subgroups. The models identified that the chance of a second seizure was below the risk threshold for driving, set by the DVLA, after six months, and the risk of a seizure following treatment withdrawal after a period of remission from seizures was below the risk threshold after three months. Selected models were found to be internally valid and the simulation study indicated that concordance and a variety of imputation methods for handling covariates missing from the validation dataset were useful approaches for external validation of prognostic models. Assessing these methods for a selected model indicated that the model was valid in independent datasets. Mixture modelling techniques begin to show an improved prognostic model for the frequently reported outcome time to 12-month remission. Conclusions: The models described within this thesis can be used to predict outcome for patients with first seizures or epilepsy aiding individual patient risk stratification and the design and analysis of future epilepsy trials. Prognostic models are not commonly externally validated. A method of external validation in the presence of a missing covariate has been proposed and may facilitate validation of prognostic models making the evidence base more transparent and reliable and instil confidence in any significant findings

Is infant exposure to antiretroviral drugs during breastfeeding quantitatively important? A systematic review and meta-analysis of pharmacokinetic studies

Objectives The objectives of this study were to summarize antiretroviral drug concentrations in breast milk (BM) and exposure of breast-fed infants. Methods This was a systematic review of pharmacokinetic studies of HIV-positive women taking antiretrovirals that measured drugs in BM. The quality of pharmacokinetic and laboratory methods was assessed using pre-defined criteria. Pooled ratios and 95% CIs were calculated using the generalized inverse variance method and heterogeneity was estimated by the I2 statistic. PubMed Central, SCOPUS and LactMed databases were searched. No date or language restrictions were applied. Searches were conducted up to 10 November 2014. Clinical relevance was estimated by comparing ingested dose with the recommended therapeutic dose for each drug. Results Twenty-four studies were included. There was substantial variability in the clinical and laboratory methods used and in reported results. Relative to maternal plasma (MP), NRTIs accumulate in BM, with BM : MP ratios (95% CI estimates) from 0.89 to 1.21 (14 studies, 1159 paired BM and MP samples). NNRTI estimates were from 0.71 to 0.94 (17 studies, 965 paired samples) and PI estimates were from 0.17 to 0.21 (8 studies, 477 paired samples). Relative to the recommended paediatric doses, a breast-fed infant may ingest 8.4% (95% CI 1.9–15.0), 12.5% (95% CI 2.6–22.3) and 1.1% (95% CI 0–3.6) of lamivudine, nevirapine and efavirenz, respectively, via BM. Conclusions Transfer to untreated infants appears quantitatively important for some NRTIs and NNRTIs. The pharmacokinetic methods varied widely and we propose standards for the design, analysis and reporting of future pharmacokinetic studies of drug transfer during breastfeeding

Protocol for a systematic review of prognostic models for recurrent events in chronic conditions.

Background:Prognostic models for repeated events of the same type are highly useful in predicting when a patient may have a recurrence of a chronic disease or illness. Whilst methods are currently available for analysing recurrent event data in prognostic models, to our knowledge, most are not widely known or applied in a medical setting. As a result, often only the first recurrence is analysed meaning valuable information for multiple recurrences is discarded. Therefore, the aim of this review is to systemically review models for repeated medical events of the same type, to determine what modelling techniques are available and how they are applied. Methods:MEDLINE will be used as the primary method to search sources. Various databases from the Cochrane Library and EMBASE will also be searched. Trial registries such as Clinicaltrials.gov.uk will be searched, as will registered trials that are ongoing and not yet published. Abstracts submitted to conferences will also be searched, and non-English sources will also be considered. Studies to be included in the review will be decided based on PICO guidelines, where the study population and outcomes correspond to this study's aims and target population. The prognostic models used in each study chosen for inclusion in the review will be summarised qualitatively. Discussion:As recurrent event data is not widely analysed in prognostic models, the results from this systematic review will identify which methods are available and which are commonly used. It is also unknown if certain methods which will be identified in the review perform better given certain conditions. Therefore, if included studies assess predictive performance, the results of this review could also provide evidence to determine if certain models are better fitting dependant on the event rate of the chronic condition. The results will be used to determine if model selection varies across disease area. The review will also provide an insight into the development of any new methods used for analysing recurrent events. Trial registration:The review has been registered on PROSPERO (CRD42019116031)

A systematic review of interventions to increase physical activity and reduce sedentary behaviour following bariatric surgery.

BACKGROUND: Bariatric surgery promotes weight loss and improves co-morbid conditions, with patients who are more physically active having better outcomes. However, levels of physical activity and sedentary behaviour often remain unchanged following surgery. OBJECTIVES: To identify interventions and components thereof that are able to facilitate changes in physical activity and sedentary behaviour. ELIGIBILITY: Physical activity and/or sedentary behaviour must have been measured, pre and post intervention, in patients who have undergone bariatric surgery. STUDY APPRAISAL AND SYNTHESIS METHODS: : Four databases were searched with key-words. Two researchers conducted paper screening, data extraction and risk-of-bias assessment. RESULTS: Twelve studies were included; eleven were randomised. Two were delivered presurgery and ten postsurgery; five found positive effect. Moderate to vigorous physical activity increased in three studies, two of which also found a significant increase in step count. The fourth found a significant increase in strenuous activity and the fifth a significant increase in metabolic equivalent of task/day and reduced time spent watching television. LIMITATIONS: Meta-analysis could not be conducted due to heterogeneity of outcomes and the tools used. CONCLUSION AND IMPLICATIONS OF KEY FINDINGS: This review has identified interventions and components thereof that were able to provoke positive effect. However, intervention and control conditions were not always well described particularly in terms of behaviour change techniques and the rationale for their use. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO (CRD42019121372

Amoxicillin is associated with a lower risk of further antibiotic prescriptions for lower respiratory tract infections in primary care - A database analysis spanning over 30 years.

Antibiotic prescriptions for lower respiratory tract infections occur commonly in primary care but there is uncertainty about the most effective initial treatment strategy. Both increasing antimicrobial resistance and awareness of preventable harm from medicines make resolving this uncertainty a priority. Pragmatic, real-life epidemiological investigations are needed to inform future interventional studies. In this cross-sectional database study we analysed antibiotic prescriptions for non-pneumonic, lower respiratory tract infections (LRTI) in primary care as captured in the Optimum Care Database from 1984 to 2017. The primary outcome was a second antibiotic prescription for a LRTI code within 14 days of index prescription, the secondary outcome further antibiotic prescription for any indication. Only individuals without chronic respiratory diseases were included. We conducted univariable analysis to identify factors associated with repeat prescriptions and generate hypotheses for forthcoming projects. We analysed 367,188 index prescriptions for LRTI. Amoxicillin was the commonest used index drug (65.1%). In 6% a second antibiotic course coded for a further LRTI was prescribed (11.2% without this coding restriction). Further antibiotic prescriptions for LRTI were significantly associated with older age, previous smoking, seven day index courses and not using amoxicillin initially. The largest effect size was seen when amoxicillin was not used as index drug (odds ratio (OR) 1.15, p < 0.001). This would support current prescribing practice for amoxicillin as index drug in those without respiratory disease. Prospective studies are needed to explore the observed differences