“Rationale and Background
During the evaluation of the safety results of a clinical trial in patients with severe asthma, differences in rates of serious adverse events were observed in the experimental treatment arm compared to the control arm. In order to contextualise these differences, a non-interventional study was required to generate background rates of selected health outcomes in patients with severe asthma, with a disease definition that follows recently conducted clinical trials. The results of this study may inform future drug-related safety assessments in the same population.
The present study is to produce background information on the occurrence of the health outcomes in adolescent and adult patients with severe asthma using recent data.
Research Methods
Study design
Retrospective cohort studies will be conducted using routinely-collected health data from 5 databases.
The incidence rate of mortality and the outcomes of interest will be assessed using Population Level Disease Epidemiology analytical pipelines from the DARWIN EU Complete Catalogue of Standard Data Analyses.
Population
All individuals present in the database in the period between 01/01/2015 and 31/12/2021, with at least 1 year of prior history, being diagnosed with severe asthma and fulfilling inclusion and exclusion criteria.
Variables
Variables of interest will consist of outcomes, comorbidity, lifestyle factors, measurements and drug exposure data.
Data sources
1. Integrated Primary Care Information Project (IPCI), The Netherlands
2. Sistema d’Informació per al Desenvolupament de la Investigació en Atenció Primària (SIDIAP), Spain
3. Clinical Practice Research Datalink GOLD (CPRD GOLD), United Kingdom
4. Parc Salut Mar Barcelona (PSMAR), Hospital del Mar (IMIM) (hospital database), Spain
5. University of Tartu – Estonian Biobank, Estonia”

This project is part of Andrea Pistillo’s PhD thesis project. A part of the project has received funds from Ajuntament de Barcelona “Subvencions extraordinàries per a projectes de recerca i innovació en col·laboració amb la Fundació La Caixa, 2022”. We lead the project from IDIAPJGol and other two institution are partners: ISGlobal and ICTA-BCNUEJ.

Environmental exposures may affect people’s lives. In particular heatwaves and peaks in air pollution had been associated with more mortality and hospitalizations, and a worst life quality. In Barcelona and its metropolitan area, these two types of exposures affect the neighbourhoods in a different way, both for geographic reasons (neighbourhoods nearer to the sea had a milder temperature during daytime) and sociodemographics ones (older population, energy poverty, areas with less green spaces, low education). Higher temperature and air pollution had been linked to respiratory, cardiovascular, mental, perinatal problems and infectious diseases. So far, this problems had been studied in hospital settings and a comprehensive study in primary care is needed to understand both the prevalence of the problems due to these environmental exposures and the burden of this on the primary care system. In this project we aim to analyze the relationship among temperature and air pollution on the health of the citizens of Barcelona and its metropolitan area. We will perform a quantitative study using the newest methodologies (case time series), and we will link daily environmental exposures with three types of health indicators (diagnosis, medications registered in primary care and sick leaves). The focus will be on neighborhoods and will take into account gender perspective and multidisciplinarity, justified with the synergy of the three institutions involved. An important part of the project will be dissemination of results, indeed we will publicly publish a risk map with the results in which citizens and policy makers will be able to interactively visualize the results of the project (at a neighborhood scale).

“Background
The current COVID-19 vaccines include mRNA vaccines, non-replicating viral vector vaccines and traditional inactivated whole virus vaccines. All of them have demonstrated their effectiveness against confirmed COVID-19 infection in previous and ongoing clinical trials However, vulnerable populations, such as pregnant women, children, individuals living in nursing homes, those with cancer, autoimmune diseases, immunodeficiencies or organ transplant recipients were systematically excluded from these trials, limiting the available evidence regarding the efficacy of the COVID-19 vaccines on these patients to retrospective observational studies, and small non-randomized trials with surrogate endpoints (e.g. antibody levels).

Objectives
To estimate coverage and the effectiveness of COVID-19 vaccines against COVID-19-related outcomes in vulnerable populations, overall and by sex, age, baseline comorbidities, and socioeconomic status, using electronic health records from Catalonia, Spain.
1- To provide periodic estimates of vaccine coverage in predefined subgroups of population at risk of being excluded from the general vaccine campaigns (i.e individuals with mental disorder), stratified by vaccine type/brand, vaccine dose, sex, age groups, socioeconomic status, and nationality.
2- To assess the effectiveness of COVID-19 vaccines in vulnerable population against COVID-19 related outcomes (COVID-19 infection, hospitalisation, intensive care admission, or death) in:
2.1- pregnant women and infants up to 12 months of age;
2.2- children and adolescents from the age of 5 to 19 years;
2.3- persons living with immunodeficient conditions, namely cancer, autoimmune conditions, primary immunodeficiencies, people living with HIV infection, organ transplant recipients or people taking immunosuppressive drugs;
2.4- persons living in nursing homes.

Methods
We will conduct a population-based matched cohort study using individual-level routinely-collected electronic health records (EHR) data from the Information System for Research in Primary Care (SIDIAP; www.sidiap.org) database in Catalonia mapped to the OMOP-CDM.

Study population
We will include all women with a pregnancy episode during the study period (mother-child linkage), children and adolescents, as well as those with history of cancer, immunodeficient conditions (HIV, autoimmune diseases, organ transplant recipients) and/or use of immunosuppressive drugs (including high chronic use of corticosteroids, biological and non-biological disease modifying drugs, antineoplastic drugs), persons living in nurse home residencies or persons with mental health conditions of any age, registered for at least 365 days in the SIDIAP database prior to the 27th of December 2020 (date of initiation of the vaccination in Spain) and up to December 2022 and December 2023.

Exposures
Four COVID-19 vaccines will be included: ChAdOx1-S, BNT162b2, mRNA-1273, and Ad26.COV2.S.

Outcomes
The main outcomes to evaluate effectiveness of COVID-19 vaccination will include: 1.SARS-CoV-2 infection will be defined as any confirmed infection identified by diagnostic codes and/or a positive RT-PCR or antigen test result, 2.COVID-19-related hospitalisation will be defined as a hospital admission (at least one night) where the individual had a positive RT-PCR test result or a clinical diagnosis of COVID-19 over the 21 days prior to their admission up to the end of their hospital stay,3. COVID-19-related intensive care unit (ICU) admission in those with COVID-19 related hospitalisation, 4.COVID-19-related death will be defined as death (any cause) registered after a COVID-19-related hospitalisation or 28 days after a SARS-CoV-2 infection.

Covariates
Covariates to be considered in the analyses will include demographics, socioeconomic status, nationality and diagnosis of mental health condition (only for coverage), BMI, pre-existing comorbid conditions, history of COVID-19 infection (6 months previous), period of predominant SARS-CoV-2 variants, number of GP visits per year, pregnancy variables (gestational age at vaccination, parity, breastfeeding, maternal lifestyle behaviour factors (when available).

Follow-up
For individuals from the age of 5 and above follow up will be from their index date to occurrence of an event, end of pregnancy (for pregnancy cohort), death, or loss of visibility in the database (e.g., person leaving the practice in electronic health records data). For cohorts that had received a first vaccine dose, we also censored follow-up if a second dose was observed before 21 days for BNT162b2 and before 27 days for mRNA-1273 and ChAdOx1-S.
The index date for exposed children (up to 12 months of age) will be the date of maternal vaccination. Children will be followed from the index date until occurrence of an event of interest, exit from the database, death, end of pre-defined follow-up time (12 months after birth), or end of data availability, whichever comes first.

Statistical analysis
Vaccination uptake rate will be calculated as the number of persons receiving any COVID-19 vaccines in a certain population subgroup divided by all individuals eligible for vaccination in that group.
We will conduct a new user cohort study, to compare the effectiveness of COVID-19 vaccines against COVID-19-related outcomes. We will use propensity score (PS) matching to minimise the risk of confounding. Vaccinated individuals will be matched in a 1:3 ratio (if sample size allows) with eligible non-vaccinated individuals with no prior history of COVID-19 infection in the past 3 months. Matching will be done taking into account age group, sex, calendar time, baseline comorbidities associated with increased risks of severe COVID-19 (e.g., obesity, diabetes, immunosuppression), and smoking. We will also use a large-scale, data-driven approach to identify additional potential confounders to be included in the PS.

Rationale and Background
The WHO 2021 AWaRe classification (who.int) of antibiotics for evaluation and monitoring of use classifies 258 antibiotics into 3 categories (Access/Watch/Reserve) according to their impact on antimicrobial resistance. The Watch list includes antibiotic classes that have higher resistance potential and includes most of the highest priority agents among the Critically Important Antimicrobials for Human Medicine and/or antibiotics that are at relatively high risk of selection of bacterial resistance. These medicines should be prioritized as key targets of stewardship programs and monitoring. This study will improve our understanding of the use of antibiotics in the Watch category in routine health care delivery, including indication, treatment duration and trends over time. The results will contribute to the EU efforts to monitor use of antibiotics as part of the global fight against antimicrobial resistance.
Research question and Objectives
The objectives of this study are (i) To investigate the incidence and prevalence of use of antibiotics (from the WHO Watch list) stratified by calendar year, age, sex and country/database during the study period 2012-2021. (ii) To explore duration of antibiotic use as well as indication for antibiotic prescribing/dispensing.
Research Methods
Study design: ? Population level cohort study (Objective 1, Population-level drug utilisation study on antibiotics) ? New drug user cohort study (Objective 2, Patient-level drug utilisation analysis with regard to duration and indication of antibiotic use)
Population
Population-level utilisation of antibiotics: All individuals present in the database in the period between 01/01/2012 and 31/12/2021 will be included in the analysis after 365 days of database history. For this population, incidence of use of antibiotics will be explored.
Patient-level antibiotic utilisation: All new users of antibiotics after not using the antibiotic of interest for 30 days in the period between 01/01/2012 and 31/12/2021, with at least 365 days of visibility prior to the date of their first antibiotic prescription.
Variables
Drug of interest: All antibiotics from the WHO Watch list (see also section 9.3.1 – exposure)
Data sources
1. Integrated Primary Care Information Project (IPCI), The Netherlands 2. Bordeaux University Hospital France 3. Sistema d’Informació per al Desenvolupament de la Investigació en Atenció Primària (SIDIAP)-OMOP, Spain 4. Parc Salut Mar Barcelona, Hospital del Mar (IMIM) (hospital database), Spain 5. IQVIA Disease Analyzer Germany (IQVIA DA Germany), Germany, 6. Clinical Practice Research Datalink GOLD (CPRD GOLD), United Kingdom
For all analyses a minimum cell count of 5 will be used when reporting results, with any smaller counts obscured.

Background
Growth reference charts are useful tools to monitor infants growth and development. In Catalonia, national and WHO growth charts are widely used despite not being representative of the general population visited in primary care.
Objectives
To generate new growth curves for children and adolescents living in Catalonia based on data collected routinely in primary care electronic health records.
Methods
We will conduct a population-based cohort study using individual-level routinely-collected electronic health records (EHR) from primary care in Catalonia. We will include a population from 0 to 18 years of age with at least one valid weight and length/height measurement registered in their EHR between 2006 to 2019. Growth references for head circumference, weight, length/height, weight-for-length/height, and body mass index (BMI) for age will be fitted using generalized additive models for location, scale, and shape (GAMLSS). BMI percentile curves passing through BMIs 30, 25, 18.5, 17, and 16 kg/m 2 at the age of 18 years will be calculated to define limits for obesity, overweight, and various grades of thinness.
Impact
The new growth charts could be incorporated into the electronic health records system of primary care centers in Catalonia in order to facilitate the monitoring of growth and development of children and adolescents in clinical practice.

Background
Growth reference charts are useful tools to monitor infants growth and development. In Catalonia, national and WHO growth charts are widely used despite not being representative of the general population visited in primary care.
Objectives
To generate new growth curves for children and adolescents living in Catalonia based on data collected routinely in primary care electronic health records.
Methods
We will conduct a population-based cohort study using individual-level routinely-collected electronic health records (EHR) from primary care in Catalonia. We will include a population from 0 to 18 years of age with at least one valid weight and length/height measurement registered in their EHR between 2006 to 2019. Growth references for head circumference, weight, length/height, weight-for-length/height, and body mass index (BMI) for age will be fitted using generalized additive models for location, scale, and shape (GAMLSS). BMI percentile curves passing through BMIs 30, 25, 18.5, 17, and 16 kg/m 2 at the age of 18 years will be calculated to define limits for obesity, overweight, and various grades of thinness.
Impact
The new growth charts could be incorporated into the electronic health records system of primary care centers in Catalonia in order to facilitate the monitoring of growth and development of children and adolescents in clinical practice.

Multiple myeloma is a rare type of blood cancer with an estimated overall crude incidence rate of 3.9 cases per 100,000 and an estimated prevalence of 3 per 100,000 in 2020 in Europe. Survival rates have improved due to the better management of the disease and the development in recent years of new medicines such as immunomodulatory agents, proteasome inhibitors and monoclonal antibodies. However, there is still unmeet need for new medicines for patients who do not respond to existing therapies. The rarity of multiple myeloma makes it challenging to have a clear picture across Europe of the characteristics of these patients at the time of diagnosis, the lines of therapy they receive and their overall survival. The goal of this study is to inform these aspects, which are important from a regulatory point of view to provide context and help understand how new medicines may add value for patients.
The overall objective of this study is to characterise patients with multiple myeloma diagnosed in the period 2012-2022. The specific objectives of this study are: i) to describe demographic and clinical characteristics of patients with multiple myeloma at the time of diagnosis; ii) to describe multiple myeloma treatments; iii) to describe multiple myeloma treatment sequences; iv) to estimate the overall 1-, 5-, and 10-year survival of incident multiple myeloma cases during the study period (2012-2022).
This population-based cohort study will include all individuals identified in the database between 01/01/2012 and date of the latest data available in each database. Participants with a diagnosis of cancer (any, excluding non-melanoma skin cancer) any time prior to the diagnosis of multiple myeloma or prior to the start of the study period will be excluded. Additional eligibility criteria will be applied for each study objective. Two main outcomes of interest will be studied: treatment/s initiated at index date, 1 to 30, 1 to 90, and/or 1 to 365 days post index date, and death. For the former, a pre-specified list of multiple myeloma treatments will be generated (objectives 2-3). Overall survival in patients with multiple myeloma will also be identified based on the registered date of birth. All co-morbidities and co-medications will be used for large-scale patient characterisation, identified as concept/code and descendants. A list of pre-specified co-morbidities and co-medications will also be described. Several data sources will participate in the present study: IQVIA Diseases Analyzer Germany (IQVIA-DA Germany), Sistema d’Informació per al Desenvolupament de la Investigació en Atenció Primària (SIDIAP), Institut Municipal Assistencia Sanitaria Information System (IMASIS), Estonian Biobank, Auria Clinical Informatics (ACI), Clinical Data Warehouse of Bordeaux University Hospital (CDWBordeaux) and Netherlands Cancer Registry (IKNL). We will conduct a large-scale patient-level characterisation (objective 1). Age and sex at time of multiple myeloma diagnosis will be described. Medical history will be assessed for anytime – and up 366 days before index date, for 365 to 31 days before index date, for 30 to 1 day before index date, and at index date. Medication use history will be reported for 365 to 31 days before index date, for 30 to 1 day before index date, and at index date. We will also report medication use for 1 to 30, 1 to 90, and 1 to 365 days post index date. The number and % of patients receiving each of a pre-specified list of multiple myeloma treatments and treatment combinations (objective 2) will be described at index date, 1 to 30, 1 to 90 and 1 to 365 days post index date. When available, treatment regimen types will also be described. Additionally, sunburst plots and Sankey diagrams will be used to describe treatments patterns and sequences over time (objective 3). Overall, as well as 1-, 5-, and 10-year survival (objective 4) will be estimated as the probability of survival from any cause of death and will be reported using Kaplan-Meier plots. This analysis will be conducted only for databases with complete information on mortality. For all analyses n and % will be reported. A minimum cell counts of 5 will be used when reporting results, with many smaller counts obscured. When possible, all analyses will be stratified by age groups and sex, and data source/country. Additionally, in order to capture treatments availability and survival changes over time, sunburst plots, Sankey diagrams and KM curves will be further stratified by study periods (2012-2017 and 2018-2022).

Rationale and Background
Opioid overdoses are the primary cause of mortality among problematic drug users globally. Naloxone, an opioid antagonist, can avert such fatalities by rapidly counteracting opioid effects. To address the frequent untreated overdoses due to the lack of recognition, fear of legal consequences, and lack of naloxone access, Take-Home Naloxone (THN) programs have been established, providing naloxone to potential bystanders in 12 European countries. This study will investigate the trend of naloxone use, particularly THN, across Europe, and elucidate user profiles to augment aggregated data from existing THN programs, thereby aiding the monitoring of naloxone use and informing regulatory decisions.

Research question and Objectives
The objectives of this study are
(i) To investigate the incidence and prevalence of THN use in (1) the general population and (2) among people with a recorded history of opioid use disorder during the study period 2012-2022. Analyses will be stratified by age, sex, calendar year and country/database.
(ii) To provide summary baseline characteristics of “new” THN users including demographics and history of opioid use, overdose
(iii) To study the use of THN in ”new” users including summary statistics of number of THN packages prescribed at index date for each “new” user (e.g. mean (SD), median, q25 and q75)
Research Methods
Study design
• Population level cohort study (Objective 1, Population-level drug utilization study on THN)
• New drug user cohort study (Objective 2+3, Patient-level drug utilization analyses with regard to number of THN prescriptions and summary patient characteristics incl. history of opioid use, overdose)
Population
Population-level utilization of THN: All individuals present in the database in the period between 01/01/2012 and 31/12/2022 will be included in the analysis after 365 days of database history. Therefore, children aged <1year will be excluded. Patient-level THN utilization: All “new” users of THN in the period between 01/01/2012 and 31/12/2022, with “new” users being defined as all people with a prescription THN within the study period, with at least 365 days of visibility prior to the date of their THN prescription and no prescription of THN in the last 7 days. Therefore, the same person can be a “new” user multiple times during the study period. Variables Drug of interest: Take-Home Naloxone Data sources 1. IQVIA Disease Analyzer Germany (IQVIA DA Germany), Germany 2. IQVIA LBD Belgium, Belgium 3. Clinical Practice Research Datalink GOLD (CPRD GOLD), United Kingdom 4. The Information System for Research in Primary Care (SIDIAP), Spain Sample size No sample size has been calculated. Data analyses Population-level THN use: Annual period prevalence of THN use and annual incidence rates per 100,000 person years in (1) the general population and (2) among people with a recorded history of opioid use disorder (OUD), as described in section 9.7.5.1 – Population-level drug utilization study. Patient-level THN use: Summary baseline characteristics of “new” users incl. demographics and history of opioid use, overdose will be conducted. Index date will be the date of the respective prescription of THN for each person. Number of THN prescriptions/packages per “new” user at index date will be summarised and mean (SD), median, p25 and p75 provided. See for further description section 9.7.5.2 – Patient-level drug utilization study. For all analyses a minimum cell count of 5 will be used when reporting results, with any smaller counts obscured.

Rationale and Background
Prescription opioids, while effective for managing severe pain, have led to a public health crisis due to misuse, addiction, and overdose, particularly in the US. Recently, concerns have been growing in Europe due to increasing opioid use and related mortality. Factors such as chronic pain, mental health disorders, and advanced age can exacerbate misuse and the development of dependence. Given the potential for global spread of this issue, enhanced surveillance and in-depth research into opioid utilization patterns are imperative. A drug utilization study using the Common Data Model (CDM) is a promising approach to supplement European opioid monitoring systems, providing more granular data to inform evidence-based decisions on this complex problem.

Research question and Objectives
The objectives of this study are
(i) To investigate the annual incidence and annual period prevalence of use of opioids (overall, active drug substance, strength (weak/strong opioids) and route (oral, transdermal or parenteral)), stratified by calendar year, age, sex and country/database during the study period 2012-2022.
(ii) To determine duration of prescription opioid use, as well as characteristics of new users and indication for opioid prescribing/dispensing, all stratified by country/database.
Research Methods
Study design
• Population level cohort study (Objective 1, Population-level drug utilization study on opioids)
• New drug user cohort study (Objective 2, Patient-level drug utilization analyses regarding summary characterisation, duration, and indication of opioid use)
Population
Population-level utilization of opioids: All people registered in the respective databases on 1st of January of each year in the period 2012-2022 (or the latest available), with at least 1 year of data availability, will participate in the population-level analysis (period prevalence calculation in Objective 1). Therefore, children aged <1year will be excluded. New users of opioids in the period between 1/1/2012 and 31/12/2022 (or latest date available), with at least 1 year of data visibility, and no use of the respective opioid in the previous 6 months or 12 months, will be included for incidence rate calculations in Objective 1. Patient-level drug utilization: New users of opioids in the period between 1/1/2012 and 31/12/2022 (or latest date available), with at least 1 year of data visibility, and no use of the respective opioid in the previous 6 months or 12 months, will be included for patient-level drug utilisation analyses. Variables Drug of interest: Opioids (substances listed in ATC classes N01AH, N02A and R05DA) incl. naloxone and fixed naloxone-opioid combinations. (further details see section 9.3.1) Data sources 1. Estonian Biobank (EBB), Estonia 2. IQVIA Disease Analyzer Germany (IQVIA DA Germany), Germany 3. IQVIA LBD Belgium, Belgium 4. Integrated Primary Care Information Project (IPCI), The Netherlands 5. The Information System for Research in Primary Care (SIDIAP), Spain 6. Clinical Data Warehouse of Bordeaux University Hospital (CHUBX), France 7. Auria Clinical Informatics VARHA (ACI Varha), Finland Sample size No sample size has been calculated. Data analyses Population-level drug utilisation will be conducted in all databases, with ACI VARHA not contributing to the prevalence analyses. Patient-level DUS analyses will be conducted in all databases, with ACI VARHA not contributing to the analysis of duration of opioid prescriptions. Population-level opioid use: Annual period prevalence of opioid use and annual incidence rates per 100,000 person years will be estimated as described in section 9.7.5.1 – Population-level drug utilization study. Patient-level opioid use: Large-scale patient-level characterization will be conducted. Index date will be the date of the first prescription of the specific opioid for each person. Frequency of indication at index date, and in the immediate time before will be assessed. Cumulative treatment duration will be estimated for the first treatment era and the minimum, p25, median, p75, and maximum will be provided. See for further description section 9.7.5.2 – Patient-level drug utilization study. For all analyses a minimum cell count of 5 will be used when reporting results, with any smaller counts obscured.