IVIg-exposure and thromboembolic event risk: findings from the UK Biobank.

BACKGROUND: Arterial and venous thromboembolic events (TEEs) have been associated with intravenous Ig use, but the risk has been poorly quantified. We aimed to calculate the risk of TEEs associated with exposure to intravenous Ig. METHODS: We included participants from UK Biobank recruited over 3 years, data extracted September 2020.The study endpoints were incidence of myocardial infarction, other acute ischaemic heart disease, stroke, pulmonary embolism and other venous embolism and thrombosis.Predictors included known TEE risk factors: age, sex, hypertension, smoking status, type 2 diabetes mellitus, hypercholesterolaemia, cancer and past history of TEE. Intravenous Ig and six other predictors were added in the sensitivity analysis.Information from participants was collected prospectively, while data from linked resources, including death, cancer, hospital admissions and primary care records were collected retrospectively and prospectively.  FINDINGS: 14 794 of 502 492 individuals had an incident TEE during the study period. The rate of incident events was threefold higher in those with prior history of TEE (8 .7%) than those without previous history of TEE (3.0%).In the prior TEE category, intravenous Ig exposure was independently associated with increased risk of incident TEE (OR=3.69 (95% CI 1.15 to 11.92), p=0.03) on multivariate analysis. The number needed to harm by exposure to intravenous Ig in those with a history of TEE was 5.8 (95% CI 2.3 to 88.3).Intravenous Ig exposure did not increase risk of TEE in those with no previous history of TEE. INTERPRETATION: Intravenous Ig is associated with increased risk of further TEE in individuals with prior history of an event with one further TEE for every six people exposed. In practice, this will influence how clinicians consent for and manage overall TEE risk on intravenous Ig exposure.

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 I(2) 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.

Observational cohort study with internal and external validation of a predictive tool for identification of children in need of hospital admission from the emergency department: the Paediatric Admission Guidance in the Emergency Department (PAGE) score.

OBJECTIVES: To devise an assessment tool to aid discharge and admission decision-making in relation to children and young people in hospital urgent and emergency care facilities, and thereby improve the quality of care that patients receive, using a clinical prediction modelling approach. DESIGN: Observational cohort study with internal and external validation of a predictive tool. SETTING: Two general emergency departments (EDs) and an urgent care centre in the North of England. PARTICIPANTS: The eligibility criteria were children and young people 0-16 years of age who attended one of the three hospital sites within one National Health Service (NHS) organisation. Children were excluded if they opted out of the study, were brought to the ED following their death in the community or arrived in cardiac arrest when the heart rate and respiratory rate would be unmeasurable. MAIN OUTCOME MEASURES: Admission or discharge. A participant was defined as being admitted to hospital if they left the ED to enter the hospital for further assessment, (including being admitted to an observation and assessment unit or hospital ward), either on first presentation or with the same complaint within 7 days. Those who were not admitted were defined as having been discharged. RESULTS: The study collected data on 36 365 participants. 15 328 participants were included in the final analysis cohort (21 045 observations) and 17 710 participants were included in the validation cohort (23 262 observations). There were 14 variables entered into the regression analysis. Of the 13 that remained in the final model, 10 were present in all 500 bootstraps. The resulting Paediatric Admission Guidance in the Emergency Department (PAGE) score demonstrated good internal validity. The C-index (area under the ROC) was 0.779 (95% CI 0.772 to 0.786). CONCLUSIONS: For units without the immediate availability of paediatricians the PAGE score can assist staff to determine risk of admission. Cut-off values will need to be adjusted to local circumstance. STUDY PROTOCOL: The study protocol has been published in an open access journal: Riaz et al Refining and testing the diagnostic accuracy of an assessment tool (Pennine Acute Hospitals NHS Trust-Paediatric Observation Priority Score) to predict admission and discharge of children and young people who attend an ED: protocol for an observational study. BMC Pediatr 18, 303 (2018). https://doi.org/10.1186/s12887-018-1268-7. TRIAL REGISTRATION NUMBER: The protocol has been published and the study registered (NIHR RfPB Grant: PB-PG-0815-20034; ClinicalTrials.gov:213469).

Quality of reporting of outcomes in phase III studies of pulmonary tuberculosis: a systematic review.

BACKGROUND: Despite more than 60 years of clinical trials, tuberculosis (TB) still causes a high global burden of mortality and morbidity. Treatment currently requires multiple drugs in combination, taken over a prolonged period. New drugs are needed to shorten treatment duration, prevent resistance and reduce adverse events. However, to improve on current methodology in drug development, a more complete understanding of the existing clinical evidence base is required. METHODS: A systematic review was undertaken to summarise outcomes reported in phase III trials of patients with newly diagnosed pulmonary TB. A systematic search of databases (PubMed, MEDLINE, EMBASE, CENTRAL and LILACs) was conducted on 30 November 2017 to retrieve relevant peer-reviewed articles. Reference lists of included studies were also searched. This systematic review considered all reported outcomes. RESULTS: Of 248 included studies, 229 considered "on-treatment" outcomes whilst 148 reported "off-treatment" outcomes. There was wide variation and ambiguity in the definition of reported outcomes, including their relationship to treatment and in the time points evaluated. Additional challenges were observed regarding the analysis approach taken (per protocol versus intention to treat) and the varying durations of "intensive" and "continuation" phases of treatment. Bacteriological outcomes were most frequently reported but radiological and clinical data were often included as an implicit or explicit component of the overall definition of outcome. CONCLUSIONS: Terminology used to define long-term outcomes in phase III trials is inconsistent, reflecting evolving differences in protocols and practices. For successful future cumulative meta-analysis, the findings of this review suggest that greater availability of individual patient data and the development of a core outcome set would be desirable. In the meantime, we propose a simple and logical approach which should facilitate combination of key evidence and inform improvements in the methodology of TB drug development and clinical trials.

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.

External validation of a prognostic model for seizure recurrence following a first unprovoked seizure and implications for driving.

OBJECTIVE: In the United Kingdom and other European Union countries guidelines for driving following a first unprovoked seizure require the risk of another seizure in the next year to be less than 20%. Using data from one clinical trial, we previously developed a prognostic model to inform driving guidelines. The objective of this work is to externally validate our published model and demonstrate its generalisability. METHODS: A cohort of 620 people with a first unprovoked seizure was used to develop the original model which included variables for aetiology, first degree relative with epilepsy, seizures only while asleep, electroencephalogram, computed tomography or magnetic resonance scan result, and treatment policy. The validation cohorts consisted of 274 (United Kingdom), 305 (Italy), and 847 (Australia) people. The model was evaluated using discrimination and calibration methods. A covariate, missing from the Italian dataset, was handled via five imputation methods. Following external validation, the model was fitted to a pooled population comprising all validation datasets and the development dataset. The model was stratified by dataset. RESULTS: The model generalised relatively well. All methods of imputation performed fairly similarly. At six months, the risk of a seizure recurrence following a first ever seizure, based on the pooled datasets, is 15% (95% CI: (12% to 18%)) for patients who are treated immediately and 18% (95% CI: (15 to 21%)) otherwise. Individuals can be reliably stratified into risk groups according to the clinical factors included in the model. SIGNIFICANCE: Our prognostic model, used to inform driving regulations, has been validated and consequently has been proven as a valuable tool for predicting risk of seizure recurrence following a first seizure in people with various combinations of risk factors. Additionally, there is evidence to support one worldwide overall prognostic model for risk of second seizure following a first.