Fluoroquinolones and rifampin combination in the backdrop of heteroresistant tuberculosis.

The impact of heteroresistance on tuberculosis (TB) treatment outcomes is unclear, as is the role of different rifampin and isoniazid exposures on developing resistance mutations. Hollow fiber system model of TB (HFS-TB) units were inoculated with drug-susceptible () and treated with isoniazid and rifampin exposure identified in a clinical trial as leading to treatment failure and acquired drug resistance. Systems were sampled for drug concentration measurements, estimation of total and drug-resistant , and small molecule overlapping reads (SMOR) analysis for the detection of heteroresistance.

INSIGHT: A Tool for Fit-for-Purpose Evaluation and Quality Assessment of Standardized Observational Data Sources for Real World Evidence on Medicine and Vaccine Safety.

Purpose: To describe the development of INSIGHT, a real-world data quality tool to assess completeness, consistency, and fitness-for-purpose of observational health data sources.

Methods: We designed a three-level pipeline with data quality assessments (DQAs) to be performed in ConcePTION Common Data Model (CDM) instances. The pipeline has been coded using R.

Safety, Efficacy and Pharmacokinetics of daily optimised doses of Rifampicin for the Treatment of Tuberculosis: A Systematic Review and Bayesian Network Meta-Analysis.

Background: Higher than standard doses of rifampicin could improve the treatment outcome of drug-susceptible tuberculosis without compromising the safety of patients.

Methods: We performed a systematic review of prospective clinical studies including adults with pulmonary and extrapulmonary TB receiving rifampicin doses above 10mg/kg/day. We extracted the data on overall adverse events (AE), hepatic AE, sputum culture conversion (SCC) at week 8, recurrence, mortality, and pharmacokinetics.

Real-World Evidence BRIDGE: A Tool to Connect Protocol With Code Programming.

Objective: To enhance documentation on programming decisions in Real World Evidence (RWE) studies.

Materials And Methods: We analyzed several statistical analysis plans (SAP) within the Vaccine Monitoring Collaboration for Europe (VAC4EU) to identify study design sections and specifications for programming RWE studies. We designed a machine-readable metadata schema containing study sections, codelists, and time anchoring definitions specified in the SAPs with adaptability and user-friendliness.

Incidence of severe and non-severe SARS-CoV-2 infections in children and adolescents: a population-based cohort study using six healthcare databases from Italy, Spain, and Norway.

Unlabelled: We aim to estimate the incidence rates (IRs) of SARS-CoV-2 infections stratified by disease severity and comorbidities in pediatric population and to describe the COVID-19 vaccination coverage in children with and without comorbidities. A population-based cohort study was conducted in 6 electronic healthcare records databases from Italy, Spain, and Norway. The study lasted from 1 January 2020 to the latest databases' available data in each site, i.

Safety of COVID-19 Vaccines among People with History of Allergy: A European Active Surveillance Study.

Conventional vaccines rarely cause severe allergic reactions. However, the rapid development and approval of COVID-19 vaccines left limited initial data on their adverse reactions, particularly in individuals with a history of allergy. The aim of this study was to assess and compare the safety profile of different doses and brands of COVID-19 vaccines in subjects with a history of allergy vs.

Metadata for Data dIscoverability aNd Study rEplicability in obseRVAtional Studies (MINERVA): Development and Pilot of a Metadata List and Catalogue in Europe.

Purpose: Metadata for data dIscoverability aNd study rEplicability in obseRVAtional studies (MINERVA), a European Medicines Agency-funded project (EUPAS39322), defined a set of metadata to describe real-world data sources (RWDSs) and piloted metadata collection in a prototype catalogue to assist investigators from data source discoverability through study conduct.

Methods: A list of metadata was created from a review of existing metadata catalogues and recommendations, structured interviews, a stakeholder survey, and a technical workshop. The prototype was designed to comply with the FAIR principles (findable, accessible, interoperable, reusable), using MOLGENIS software.

Safety of high-dose amikacin in the first week of all-oral rifampicin-resistant tuberculosis treatment for the prevention of acquired resistance (STAKE): protocol for a single-arm clinical trial.

Introduction: An effective rifampicin-resistant tuberculosis (RR-TB) treatment regimen should include prevention of resistance amplification. While bedaquiline (BDQ) has been recommended in all-oral RR-TB treatment regimen since 2019, resistance is rising at alarming rates. This may be due to BDQ's delayed bactericidal effect, which increases the risk of selecting for resistance to fluoroquinolones and/or BDQ in the first week of treatment when the bacterial load is highest.

An ethics framework for the transition to an operational learning healthcare system.

Introduction: While Learning Healthcare Systems (LHSs) have received increasing attention in health care and research, the amount of operational LHSs remains limited. Given the investment of resources in these projects, a moral responsibility to pursue the transition toward an LHS falls on projects and their participating stakeholders. This paper provides an ethics framework for projects that have taken steps toward building an LHS and are in the position to transition to an operational LHS.

Applying two approaches to detect unmeasured confounding due to time-varying variables in a self-controlled risk interval design evaluating COVID-19 vaccine safety signals, using myocarditis as a case example.

We test the robustness of the self-controlled risk interval (SCRI) design in a setting where time between doses may introduce time-varying confounding, using both negative control outcomes (NCOs) and quantitative bias analysis (QBA). All vaccinated cases identified from 5 European databases between September 1, 2020, and end of data availability were included. Exposures were doses 1-3 of the Pfizer, Moderna, AstraZeneca, and Janssen COVID-19 vaccines; outcomes were myocarditis and, as the NCO, otitis externa.

Measurement of isoniazid in tuberculosis patients using finger sweat with creatinine normalisation: A controlled administration study.

Background: Insufficient exposure and poor compliance with anti-tuberculosis (TB) medications are risk factors for treatment failure and the development of drug resistance. Measurement of drugs in biological samples, such as blood and saliva, can be used to assess adherence and make dose adjustments by therapeutic drug monitoring (TDM). Finger sweat testing is a convenient and non-invasive method to monitor patients.

Respiratory syncytial virus vaccination during pregnancy for improving infant outcomes.

Background: Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections (LRTIs) in infants. Maternal RSV vaccination is a preventive strategy of great interest, as it could have a substantial impact on infant RSV disease burden. In recent years, the clinical development of maternal RSV vaccines has advanced rapidly.

Ten-year results of an international external quality control programme for measurement of anti-tuberculosis drug concentrations.

Objectives: Participation in an external (interlaboratory) quality control (QC) programme is an essential part of quality assurance as it provides laboratories with valuable insights into their analytical performance. We describe the 10 year results of an international QC programme for the measurement of anti-tuberculosis (TB) drugs.

Methods: Each year, two rounds were organized in which serum (or plasma) samples, spiked with known concentrations of anti-TB drugs, were provided to participating laboratories for analysis.

Frequency and timing of adverse reactions to COVID-19 vaccines; A multi-country cohort event monitoring study.

Introduction: During the COVID-19 pandemic, EMA set-up a large-scale cohort event monitoring (CEM) system to estimate incidence rates of patient-reported adverse drug reactions (ADRs) of different COVID-19 vaccines across the participating countries. This study aims to give an up to date and in-depth analysis of the frequency of patient-reported ADRs after the 1st, 2nd, and booster vaccination, to identify potential predictors in developing ADRs and to describe time-to-onset (TTO) and time-to-recovery (TTR) of ADRs.

Methods: A CEM study was rolled out in a period ranging from February 2021 to February 2023 across multiple European countries; The Netherlands, Belgium, France, the United Kingdom, Italy, Portugal, Romania, Slovakia and Spain.

COVID-19 and pregnancy: A European study on pre- and post-infection medication use.

Purpose: The COVID-19 pandemic has impacted medication needs and prescribing practices, including those affecting pregnant women. Our goal was to investigate patterns of medication use among pregnant women with COVID-19, focusing on variations by trimester of infection and location.

Methods: We conducted an observational study using six electronic healthcare databases from six European regions (Aragon/Spain; France; Norway; Tuscany, Italy; Valencia/Spain; and Wales/UK).

Building a Sustainable Learning Health Care System for Pregnant and Lactating People: Interview Study Among Data Access Providers.

Background: In many areas of health care, learning health care systems (LHSs) are seen as promising ways to accelerate research and outcomes for patients by reusing health and research data. For example, considering pregnant and lactating people, for whom there is still a poor evidence base for medication safety and efficacy, an LHS presents an interesting way forward. Combining unique data sources across Europe in an LHS could help clarify how medications affect pregnancy outcomes and lactation exposures.

Derivation and Clinical Utility of Safety Targets for Linezolid-Related Adverse Events in Drug-Resistant Tuberculosis Treatment.

Long-term usage of linezolid can result in adverse events such as peripheral neuropathy, anemia and thrombocytopenia. Therapeutic drug monitoring data from 75 drug-resistant tuberculosis patients treated with linezolid were analyzed using a time-to-event (TTE) approach for peripheral neuropathy and anemia and indirect response modelling for thrombocytopenia. Different time-varying linezolid pharmacokinetic exposure indices (AUC, C, C and C) and patient characteristics were investigated as risk factors.