Fluoroquinolones, are broad spectrum antibiotics that are active against both Gram-negative and Gram-positive bacteria and are indicated in the management of certain bacterial infections. The use of Fluoroquinolones has been associated with the risk of some serious adverse events, which involve the peripheral and central nervous system as well as tendons, muscles and joints. The concerns of the persistence of side effects resulted in the European Medicines Agency (EMA) conducting a pharmacovigilance referral procedure focused on assessing the severity and persistence of long lasting, disabling and potentially irreversible adverse drug reactions, and the benefit-risk balance of Fluoroquinolones for systemic and inhalational use. In November 2018, the EMA concluded that serious adverse reactions including tendon, muscle and joint disorders, neurologic and psychiatric disorders listed in the product information of different fluoroquinolones could in rare cases become long-lasting, and recommended cessation of prescriptions for milder, non-severe or self-limiting infections, and restrictions for other indications.

The overall aim of this study is to evaluate the impact of the regulatory actions taken for fluoroquinolone containing medicinal products following the 2018 referral procedure. The study objectives are:
1. To determine the drug utilisation and prescription patterns of fluoroquinolone containing medicinal products over the period 2016 and 2020 by
a) estimating monthly incident drug use, stratified by on label indications (which includes first line and last line indications) and off label indications (mild infections for which fluoroquinolones are not indicated for).
b) Estimation of early discontinuation proportion (prescribed courses that were discontinued prior to intended treatment end date)
2. Evaluate the impact of regulatory interventions on fluoroquinolone prescribing patterns using time series analysis.
3. To determine prescribers’ compliance with warnings as described in fluoroquinolones SmPC section 4.4, in particular on tendinitis and tendon rupture as well as on aortic aneurysm/dissection specifically by calculation of monthly incident prescription rates in the subgroups at risk:
a) risk groups for tendinitis and tendon rupture
b) risk groups for aortic aneurysm/dissection
c) patients with recent (within 30 days prior) or concomitant prescribing of systemic corticosteroids
4. To determine monthly incident prescription rates for alternative antibiotics prescribed in patients where systemic or inhalation use fluoroquinolones have previously been prescribed and discontinued

In contrast to declining incidence and mortality rates for older men and women, since the mid-1980s, rates of early-onset colorectal cancer (EOCRC, diagnosed before age 50 years) have increased in many high-income countries. Increasing trends in EOCRC are unexplained but may reflect secular changes that began in the 1960s and 1970s in exposure to putative risk factors including obesity, diabetes, metabolic dysfunction, and use of certain medications (including antibiotics). Few epidemiological studies have adequately examined the etiology of EOCRC. Most prior evidence is from case-control studies or small-scale cohort analyses (<150 EOCRC cases). We propose to leverage data from electronic primary care records in the Information System for Research in Primary Care (SIDIAP database; www.sidiap.org) to examine the role of obesity, diabetes and metabolic factors, aspirin/NSAID use, statin use, oral antibiotics, and tobacco smoking in EOCRC development. Hazard ratios (HR) and 95% confidence intervals (CI) for the risk factors and colorectal cancer (CRC) will be estimated using multivariable adjusted flexible parametric survival models. Risk factor associations for EOCRC will also be compared with those for CRC diagnoses at older ages (50-64 and >=65 years at diagnosis) using interaction terms. We expect to robustly identify a selection of modifiable risk factors associated with EOCRC development. Such evidence informs on the etiology of EOCRC, sheds light on possible lifestyle behaviours that can be intervened upon, and could be used by clinicians to risk stratify young-adults presenting with non-specific CRC symptoms for early screening.

Childhood overweight and obesity is an unprecedented public health challenge with immediate and adulthood effects. Findings on the relationship between playspace and overweight and obesity are mixed and studies limited, as mainly are cross-sectional and focused on green spaces. Some studies have explored how individual or area-based characteristics moderate the relationship between playspaces and overweight and obesity, finding lower effects for girls or younger children and mixed effects by race. Also, higher playspaces exposure has been linked to lower body mass index for low socioeconomic families, but higher outcome for high socioeconomic ones. Differential effects by area characteristics have been less explored, despite links between deprivation and higher risk of overweight and playspaces only benefiting privileged residents in gentrifying neighborhoods.
This study aims to assess the associations between the exposure of playspaces and overweight and obesity incidences and explore the role of individual and area-level characteristics. We will use a retrospective open longitudinal study with children aged between 2 and 5, identified as normal weight and registered in a primary healthcare record (SIDIAP database) between 2011 and 2018 in Barcelona (Spain). Overweight and obesity will be defined following the international reference and based on height and weight measures. We will estimate residential proximity to playspaces based on a local data from 2014.
We will estimate the risk of developing overweight and obesity per playspace exposure with Cox proportional hazard models by sex. To explore effect modification, interactions will be tested for individual and area-level characteristics, and stratification will be conducted for significant interaction.

Background: The overwhelming numbers of COVID-19 infections have led to an unprecedented crisis for healthcare systems worldwide. Understanding the impact of this pandemic on health is an urgent priority.
Objectives: UNCOVER aims to unravel the mid- and long-term effects of the pandemic on COVID-19 and non-COVID-19 morbidity and mortality through the use of large real-world databases from Catalonia and the UK.
Methods: UNCOVER will conduct a cohort study using longitudinal electronic health records from Catalonia (SIDIAP) and the UK (CPRD). These databases have been transformed to an international common data model (CDM), and when possible, the study will be replicated in other databases around the world. COVID-19 testing, diagnosis in primary care, hospitalisations, and deaths will be identified from March 1st 2020. Study periods will be defined as pre-COVID-19, COVID-19-pre-vaccine, and COVID-19-vaccination. Different periods will be defined for the study of non-pharmaceutical interventions by country. Mid- and long-term symptoms and outcomes will be identified. Time-series and multi-state models will be used for data analyses.
Expected results: UNCOVER will provide novel scientific knowledge aimed at helping decision-makers and clinicians in the control and management of the pandemic on a national and international level, whilst improving populations’ health and quality of life.

The use of healthcare data, generated through the delivery of normal clinical care is increasingly being proposed as a source of evidence to support not only drug development and regulatory decision-making but also to understand the physiology and pathogenesis of diseases.
Use of multiple electronic health care databases is important not only to increase sample size but also to investigate country specific differences, differences by type of databases (e.g. primary vs. secondary care) or to replicate findings. One of the challenges however are the differences between the databases with regard to the underlying structures and semantic mapping. A common data model could help harmonise healthcare data across multiple data sets and provide a mechanism to allow the conduct of multi-database, international studies.
The European Health Data and Evidence Network (EHDEN) project (https://www.ehden.eu/) is an international project supported by the Innovative Medicines Initiative (IMI) aiming to standardize health care data to the Observational Medical Outcomes Partnership Common Data Model (OMOP CDM) and to develop and implement tools to facilitate research on large electronic health care databases.
One of the objectives of the EHDEN project is to test existing methodologies but also to develop new methodologies and analytical tools to conduct (pharmaco)epidemiological research using electronic health care databases mapped to the OMOP CDM. To investigate the validity and functionality of this approach, we want to conduct a drug-utilisation study using EHR data. As proof of concept study we want to conduct a drug utilisation studies on respiratory drug use in patients with asthma and chronic obstructive pulmonary disease (COPD). This research is important and relevant as asthma and COPD are prevalent conditions, primarily treated in primary care.

This is a study protocol for an observational health data analysis, submitted as a preprint to facilitate transparency and open science. Watchful waiting (WW) represents a deferred treatment option for prostate cancer (PCa) patients when curative treatment seems overtreatment right from the outset. Patients are ‘watched’ for the development of local or systemic progression with disease-related symptoms, at which stage they are then treated palliatively according to their symptoms, in order to maintain quality of life. When choosing WW, it is important to adequately assess life expectancy of patients. Although previous studies reported the outcomes of PCa patients managed with WW, which is the impact of individual patient characteristics and comorbidities on long-term outcomes is still largely unknown. The PIONEER, which is a novel project of the Innovative Medicine Initiative’s (IMI’s) “”Big Data for Better Outcomes”” program
with the mission to transform PCa care with particular focus on improving cancer related outcomes, health system efficiency and the quality of health and social care across Europe, aims at assessing which are the long-term outcomes of PCa patients undergoing WW overall and after stratification according to disease characteristics, comorbidities and life expectancy. This topic emerged as the second one with the
highest agreement score among different stakeholders after an international consensus to identify and prioritize the most important questions in the field of PCa. This study aims to describe demographics, clinical characteristics and estimate outcomes of PCa patients under WW across a network of databases in the overall
population and subgroups of patients identified by individual disease characteristics, demographics and comorbidities. The study will rely on large observational data, namely population-based registries, electronic health records and insurance claims data. The study will be an observational cohort study based on routinely collected health care data which has been mapped to the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM).

*In SIDIAP, the study will be performed in the data mapped to OMOP. Not all the objectives presented in the protocol will be studies in SIDIAP, data availability will be taken into account. For example, cause-specific survival or cancer treatment are not available in SIDIAP and therefore will not be investigated.

Urbanization is one of the leading global trends of the 21st century. Childhood obesity is a key health outcome in childhood and for lifelong health. World-wide childhood obesity rates are alarmingly high. The urban environment provides important opportunities for interventions aimed at alleviating the childhood obesity epidemic. It is increasingly recognized that the urban environment may affect childhood growth and obesity and that it provides important opportunities for community-level prevention.
The aim of UrbanKids is to evaluate how changes in the urban and social environment affect weight gain and obesity in children. For this we will use a large longitudinal cohort of 1 million children and adolescents (aged 0-18 years) in Catalonia, with repeat measures of height and weight, registered in the electronic health records (EHRs) from primary care data between 2011 and 2019. The moving2health approach will focus on children who changed address and who thus provide a unique natural experiment design by changing their neighbourhood environment from one day to the next.
The UrbanKids will tackle key societal changes regarding childhood obesity by identifying which urban exposures could be modified to reduce the obesity epidemic, and by identifying how socioeconomic status may drive environmental health disparities.

Ranitidine is a competitive and reversible inhibitor of the action of histamine and indicated for the management of peptic ulceration (with or without Helicobacter Pylori), Gastro-Esophageal Reflux Disease (GERD), reflux oesophagitis and Zollinger-Ellison syndrome. In 2019, results of a preliminary laboratory analysis have shown the presence of NNitrosodimethylamine (NDMA), a human carcinogen, in ranitidine.
The European Commission triggered on 12 September 2019 a referral procedure to evaluate the relevance of these findings, the potential root causes and their impact on the benefit-risk balance of medicinal products containing ranitidine. Based on this evaluation, in April 2020 EMA’s Committee for Medicinal Products for Human Use (CHMP) has recommended the suspension of all ranitidine-containing medicines in the
EU due to the presence of low levels of NDMA impurities.
Many ranitidine-containing medicines have not been available in the EU for several months since the initiation of the referral, because national competent authorities have recalled them either due to levels of NDMA found in the products or as a precaution while the EMA review is ongoing. Healthcare professionals have been asked to advise patients on alternative medicines. In addition, in some Member States the outcome of the referral was communicated at national level through media campaigns,
involving learned societies and medical associations to inform prescribing physicians and health care organisations about these changes.
The unavailability of ranitidine-containing medicines is expected to cause patients to switch treatment to alternative medicines or alternative treatment strategies. The extent of switches to alternative medicines remains unknown as well as the rate of patients permanently discontinuing treatment following unavailability of ranitidine-containing medicines.

The overall aim of this study is to evaluate the impact of the regulatory actions taken for ranitidine containing medicinal products following the 2019 referral procedure, using healthcare databases of six European countries.

Background and Significance: Type 2 diabetes mellitus (T2DM) is a major cause of morbidity and mortality globally and is associated with an elevated risk of cardiovascular events. Therapeutic options for T2DM have expanded over the last decade with the emergence of sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP1) receptor agonists, which reduced the risk of major cardiovascular events in randomized controlled trials (RCTs). Cardiovascular evidence for older second-line agents, such as sulfonylureas, and direct head-to-head comparisons, including with dipeptidyl peptidase 4 (DPP4) inhibitors, are lacking, leaving a critical gap in our understanding of the relative effects of T2DM agents on cardiovascular risk and on patient-centered safety outcomes.

Study Aims: To determine real-world comparative effectiveness and safety of traditionally second-line T2DM agents using health information encompassing millions of patients with T2DM, with a focus on individuals at moderate cardiovascular risk and other key subgroups.
Study Description: We will conduct three large-scale, systematic, observational studies to make pairwise comparisons of all SGLT2 inhibitor, GLP1 receptor agonist, DPP4 inhibitor and sulfonylurea agents at the drug-, class- and population subgroup-level within our proposed Large-Scale Evidence Generations Across a Network of Databases for T2DM (LEGEND-T2DM) initiative. LEGEND-T2DM will leverage the ObservationalHealth Data Science and Informatics (OHDSI) community that provides access to a standing global network of administrative claims and electronic health record (EHR) data sources. The 13 data sources already committed to LEGEND-T2DM cover > 190 million patients in the US and about 50 million internationally, and include two academic medical centers, IBM MarketScan and Optum databases, and the US Department of Veterans Affairs. LEGEND-T2DM will study invite other OHDSI data custodians around the world to participate in the study.

Population: Adult, T2DM patients who newly initiate a traditionally second-line T2DM agent, including individuals with and without established cardiovascular disease.

Our systematic framework will address residual confounding, publication bias and ?-hacking using data-driven, large-scale propensity adjustment for measured confounding, a large set of negative control outcome experiments to address unmeasured and systematic bias, prespecification and full disclosure of hypotheses tested and their results. These approaches capitalize on mature OHDSI open source resources and a large body of clinical and quantitative research that the LEGEND-T2DM investigators originated and continue to drive. Finally, LEGEND-T2DM is dedicated to open science and transparency and will publicly share all our analytic code from reproducible cohort definitions through turn-key software, enabling other research groups to leverage our methods, data, and results in order to verify and extend our findings.