BACKGROUND:Real-world data studies suggest that the vaccine effectiveness (VE) of a fourth mRNA vaccine dose against SARS-CoV2 infection related hospitalisation wanes after a few months, potentially warranting consideration of additional booster doses. METHODS:A multi-data source cohort study was conducted through the Data Analysis and Real World Interrogation Network (DARWIN EU®) using routinely collected electronic health records from the UK (CPRD GOLD), the Netherlands (IPCI), and Spain (SIDIAP) from January 2021 to June 2023. The study included individuals aged 12 and above, vaccinated with at least three doses. We matched fourth-dose to third-dose vaccinated individuals using a weekly sequential approach, defining the date of the last dose received by the exposed individual as the index date. Primary outcomes were SARS-CoV2 infection related death and hospitalisation. Hazard ratios (HR) were estimated using Cox proportional hazard models, with VE defined as the percentage of 1 minus HR. Waning of VE was assessed at monthly intervals. FINDINGS:A total number of 975,496 matched pairs were identified from the three data sources, with a median age of 63-78. The pooled VE of a fourth vaccine dose against SARS-CoV2 infection related death compared to three vaccine doses was 30% (95%CI 9 to 46, I2=0). VE against SARS-CoV2 infection related hospitalisation was 26% (19% to 33%) in Spain (SIDIAP, median follow-up 8 weeks), and 46% (15% to 66%), in the Netherlands (IPCI, median follow-up 21 weeks) respectively. VE of a fourth dose started waning at 4-8 weeks after vaccination. INTERPRETATION:A fourth dose of a mRNA COVID-19 vaccination was effective against SARS-CoV2 infection related death and hospitalisation. However, effectiveness waned over time. Periodic revaccination should be considered, with recommendations regarding booster timing taking into account circulating variants, patterns of viral transmission, and population uptake. FUNDING:European Medicines Agency.

To evaluate secular trends of incidence and prevalence of Parkinson's Disease (PD), Vascular Parkinsonism (VP), and Drug-induced Parkinsonism from 2007 to 2021 in the UK. We used primary care data, Clinical Practice Research Datalink GOLD, from the UK. Individuals were included if they were registered from January 2007 to December 2021 with at least one year of prior observation. Age-standardized and crude incidence and prevalence were calculated annually; age-standardized rates were stratified by sex, and crude rates by age and sex. From 2007 to 2019, the age-standardized incidence of PD decreased from 35.61 (95% confidence interval: 33.97-37.30) to 31.27 (29.27-33.37) per 100 000 person-years. The prevalence of PD increased from 0.21% (0.21%-0.22%) in 2007, peaking in 2016 at 0.23% (0.23%-0.24%). The number of VP diagnoses has increased since 2010, whereas the incidence and prevalence of DIP remained stable. Incidence and prevalence increased with age and were generally higher in males, except for DIP, which was slightly higher in females. Crude rates showed similar trends. Though Parkinson Disease incidence has declined, prevalence has risen, suggesting improved survival. VP rates have increased, possibly due to improvements in diagnostic screening. Drug-induced Parkinsonism rates remained stable. With an aging UK population, Parkinsonism subtypes pose a growing burden.

Purpose To develop and describe DrugUtilisation, an open-source R package that facilitates drug utilisation studies using data mapped to the OMOP Common Data Model (CDM).Methods Core functionalities include creating drug user cohorts, identifying and summarising indications, describing the duration and dose of medication/s and assessing treatment adherence. The package works with packages developed within the DARWIN EU initiative to support study-specific workflows. We show the package's workflow by analysing the use of simvastatin in three European real-world databases.Results This paper outlines the DrugUtilisation package's functions and demonstrates their application with a clinical example of simvastatin use in databases from the United Kingdom, Estonia and the Netherlands. We generated results including cohort counts, indication summaries, measures of dose and duration, as well as publication-ready tables and figures. We implemented comprehensive unit tests and standardised output format, which ensured consistency across databases and minimised coding errors.Conclusion The development of this software allows for researchers to quickly perform common drug utilisation analyses, while also providing the foundation for additional, bespoke study-specific analyses.

Abstract Patients with earlier SARS-CoV-2 variants are at increased risk of venous and arterial thromboembolic (VTE, ATE) events. Here we aimed to contextualise the incidence of thromboembolic events among patients with COVID-19 during the Omicron period. We conducted a population-based cohort study using electronic health records from the UK (CPRD GOLD), the Netherlands (IPCI), and Spain (SIDIAP) within the DARWIN EU ® network. Two cohorts were included: a pre-pandemic population (2017–2019) and individuals infected with SARS-CoV-2 during the Omicron-dominant period. We estimated incidence rates (IRs) of VTE, ATE, and other cardiovascular events at 30-, 60-, 90-, and 180-days post-infection. Crude incidence rate ratios (IRRs) and age-sex standardized incidence ratios (SIRs) were calculated relative to the pre-pandemic cohort. Analyses were stratified by prior infection, vaccination status, and immunocompromised status. In total, we included over 7.6 million individuals (CPRD GOLD: 5.28 M; IPCI: 1.59 M; SIDIAP: 0.75 M) in the general population cohort, and about 0.8 million individuals (CPRD GOLD: 248,847; IPCI: 330,200; SIDIAP: 200,563) in the COVID-19 Omicron cohort. Crude IRs varied by outcome and data source. For VTE, IRs per 100,000 person-years were 136 [95%CI 131–141] in SIDIAP, 167 [164–169] in CPRD GOLD, and 264 [259–270] in IPCI. Elevated SIRs for VTE and ATE were observed following SARS-CoV-2 infection, highest within 30 days and persisting up to 180 days. In CPRD GOLD, the VTE SIR was 3.61 [2.45–5.53] at 30 days, decreasing to 1.88 [1.52–2.34] at 180 days. Higher SIRs were observed among immunocompromised individuals and those without prior infection. Our findings indicate that among individuals diagnosed with SARS-CoV-2 infection during the Omicron-dominant period, observed rates of thromboembolic events exceeded expected background incidence, particularly in the early post-infection period.

Objectives We aimed to assess the risk of incident autoimmune and inflammatory conditions during the post-acute period of COVID-19.Design Descriptive network cohort study.Setting Electronic health records from the UK and Dutch primary care, Norwegian linked health registry, hospital records of specialist centres in Spain, France and Korea and healthcare claims from Estonia and the USA.Participants We followed individuals between September 2020 and the latest available data from day 91 after a SARS-CoV-2 negative test (comparator) or a COVID-19 record (exposed patients, ie assessing patients during the post-acute phase). We further established a reinfection cohort (any further COVID-19 record among the exposed patients). We followed patients until an outcome, end of study period, death, day 365 or an infection (comparator only) or reinfection (exposed patients only).Main outcome measures We assessed postural orthostatic tachycardia syndrome (POTS) diagnoses/symptoms, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) diagnoses/symptoms, multi-inflammatory syndrome (MIS) and several autoimmune diseases (rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD) and type 1 diabetes mellitus (T1DM)).Meta-analysed crude incidence rate ratios (IRRs) of outcomes after COVID-19 versus negative testing and after reinfection versus a previous COVID-19 record yield the ratios of respective absolute risks of each assessed outcome. We performed subgroup analyses by age, sex and predominant variant periods.Results We included 2 521 812 individuals with a first COVID-19 record, 4 233 145 with a first negative test and 135 551 with a reinfection. Age and sex were largely comparable between exposure groups with a shorter follow-up for the reinfection cohorts. After COVID-19 compared with test-negative patients and equally after reinfection compared with previous COVID-19 patients, we did not observe increased rates for all outcomes and all subgroup analyses. Counts of MIS and JIA were too small for meta-analyses.Conclusions In our descriptive meta-analyses of crude IRRs among databases from various countries and settings, we did not observe increased rates of incident POTS, ME/CFS, RA, IBD, SLE and T1DM in COVID-19 versus test-negative or reinfection versus COVID-19 during the first 9 months of the post-acute phase of COVID-19 or reinfection (>90 days postinfection until month 12). Since causal interpretation cannot be made from this study, further causal research is warranted.

Background Human Papillomavirus (HPV) vaccines prevent HPV infection and related disease. 15 years after the first HPV vaccination programmes were launched in Europe, their long-term effectiveness can now start to be assessed. We designed a target trial emulation study to estimate the effectiveness of HPV vaccination in preventing invasive cervical cancer and high-grade precancerous lesions using three primary care databases. Methods In this target trial emulation study, we analysed primary care records from the UK (Clinical Practice Research Datalink; data from Sept 9, 1987 to Dec 15, 2023), primary care records linked to hospital records from Catalonia, Spain (Sistema d’Informació per al Desenvolupament de la Investigació en Atenció Primària; Jan 1, 2006 to June 30, 2023), and nationwide linked health registry (including primary care, secondary care, and other health data) in Norway (Norwegian Linked Health Registry; Jan 1, 2018 to Dec 31, 2023), all standardised to the Observational Medical Outcomes Partnership common data model. We included women aged 15 years or younger in 2008, coinciding with the start of public vaccination programmes. Exposure was defined as receiving one or more HPV vaccine doses by age 15 years. The main outcomes included high-grade cervical intraepithelial neoplasia (CIN2+), invasive cervical cancer, and conisation (as a proxy for CIN2+ diagnosis). Vaccinated and unvaccinated cohorts were sequentially matched on an annual basis by year of birth, location, and propensity scores, with up to five vaccinated people matched to an unvaccinated individual. Vaccine effectiveness, based on incidence rate ratios after 15 years of follow-up, were calculated using Poisson regression. Results across databases were meta-analysed using fixed-effects. The specified primary analysis in the original protocol was designed to assess exposure by HPV brand versus unvaccinated populations; however, due to the low number of events by brand, the study was underpowered and the primary analysis was amended to assess HPV vaccination exposure overall (any brand) versus unvaccinated. Findings After two-step matching, our analysis included 81 863 vaccinated and 46 357 unvaccinated women from the UK; 148 214 vaccinated and 39 952 unvaccinated from Spain; and 14 885 vaccinated and 4073 unvaccinated from Norway. Fewer than five cervical cancers were observed per cohort, precluding vaccine effectiveness estimation for this outcome. Meta-analytic vaccine effectiveness at 15 years was 42% (95% CI 6–64) against CIN2+ and 58% (6–82) against conisation. Interpretation Our estimates of vaccine effectiveness against CIN2+ and conisation in Europe align with estimates from previous systematic reviews of randomised controlled trials. We also observed an increased health-seeking behaviour among vaccinated individuals, suggesting that our study might have underestimated vaccine effectiveness. Further studies with longer follow-up are needed to estimate vaccine effectiveness against cervical cancer. Funding European Medicines Agency.

Describing cohort characterisation ensures comparability and reproducibility in multi-database observational studies. To address this need, we developed CohortCharacteristics, an open-source R package that facilitates standardised cohort characterisation in datasets mapped to the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). This study aims to explain the development of the package and demonstrate its core functionality. We developed CohortCharacteristics, an open-source R package that can perform cohort characterisation for various types of databases. To demonstrate its functionality, we then used CohortCharacteristics to generate descriptive statistics on demographics, comorbidities, medication exposures, cohort overlap, and timing of cohort entries. The study included data from CPRD GOLD (UK), DK-DHR (Denmark), IPCI (Netherlands), IQVIA Longitudinal Patient Database Belgium (IQVIA LPD Belgium), IQVIA DA Germany, NAJS (Croatia), and SIDIAP (Spain), all mapped to the OMOP CDM. The CohortCharacteristics R package is freely available on CRAN with detailed vignettes and documentation on its functionality. Cohort characteristics were generally consistent across databases, with similar age distributions and female representation. CPRD GOLD, NAJS, and SIDIAP exhibited higher prescribing rates for respiratory, cardiovascular, and nervous system medications, while IQVIA databases and DK-DHR reported lower rates. Timing analysis showed that dementia diagnoses typically followed insomnia diagnoses in several databases, supporting existing literature. Antipsychotic prescriptions often occurred after dementia diagnosis, reflecting prescribing practices aligned with clinical guidelines. CohortCharacteristics enables consistent cohort characterisation across a network of data mapped to the OMOP CDM, thereby improving transparency in multi-database research. The package’s functionality, demonstrated in this study, illustrates its applicability in observational studies with OMOP CDM data.

Background:Real-world evidence provides valuable insights into cancer burden, presentation, and care variations. Through a large-scale federated approach, this study aims to explore patient characteristics and overall survival for eight cancers using data from 11 electronic health records and cancer registries from eight European countries, mapped to the Observational Medical Outcomes Partnership Common Data Model (OMOP-CDM). Methods:Patients aged 18 years or older with a primary cancer diagnosis between 2000 and 2019 were included. Patients were followed from cancer diagnosis until death, database exit, or study end. Mortality data was sourced from linked national or subnational death registries for most databases. Patient characteristics, including comorbidities, and medication use, were summarised. Age-standardised overall survival (OS) at one, five, and ten years were calculated using the Kaplan-Meier method and stratified by cancer type, age group and sex. Findings:There were 1,796,278 eligible cancer patients included with most diagnoses in individuals aged 60-79 years. Top comorbidities and medications were relatively consistent across databases, with certain variations observed by cancer type, possibly indicative of early cancer signs and risk factors. For instance, anaemia was frequent in colorectal (9% [HUS]-23% [IMASIS]; 791/8395-730/3141 individuals) and stomach cancers (10% [HUS]-34% [IMASIS]; 130/1277-225/670), while chronic obstructive pulmonary disease (18% [SIDIAP]-34% [HUVM], 5310/29,009-1039/3063) and pneumonia (5% [CPRD GOLD]-33% [UTARTU], 1904/34,990-1001/3063) were common in lung cancer patients. Breast and prostate cancers had the highest one, five and ten-year overall survival, with 5-year OS ranging from 76% [ECi]-85% [IMASIS] and 75% [HUVM]-83% [SIDIAP], respectively. Pancreatic cancer showed the lowest survival ranging from 3% [NCR]-25% [IMASIS] 5-year OS. Variations in cancer survival estimates were observed across data sources and countries. Interpretation:Federated analysis of diverse European real-world databases, standardised to OMOP-CDM, offer a valuable benchmark for future cancer research, particularly in understanding prodromes and risk factors, often recorded in routinely collected healthcare data prior to cancer onset. Funding:The European Health Data & Evidence Network has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 806968. The JU receives support from the European Union's Horizon 2020 research and innovation programme and the European Federation of Pharmaceutical Industries and Associations partners.

AbstractQuestion addressed by the studyA radiological index capable of quantifying pulmonary tuberculosis (TB) disease progression on standard Chest X-Ray (CXR) could enhance clinical management and inform therapeutic decision-making. Our objectives were: to develop a radiological index that quantitatively assesses the progression of pulmonary TB in patients over the course of treatment and follow-up, to evaluate its usefulness by using CXRs from a cohort of TB patients, and to validate it with CXRs from an independent cohort of TB patients.Materials/patients and methodsAn index was developed to identify and classify patterns of radiological findings of both active and inactive pulmonary TB. This index was evaluated in a first cohort comprising a pseudonymized sample of serial CXRs from 21 TB patients at the Perinatal HIV Research Unit (PHRU) in South Africa and validated in a second, larger, independent cohort comprising 50 treated TB patients from the National Institute of Allergy and Infectious Diseases (NIAID) TB Data Portals. The relationship between index values for activity markers and patients’ clinical characteristics was also analysed.ResultsA radiological index, the RUTI-TB Evolution Score (RTBES), was created and validated in two cohorts, achieving 95.96% interobserver agreement (±2 points). In both cohorts, RTBES for active TB signs decreased over follow-up. Higher baseline RTBES correlated with male sex, higher bacterial loads, and extensive pulmonary involvement (including cavitation and pleural effusions). Baseline RTBES≥2 predicted unfavourable outcomes; 80% of failures/deaths occurred above this threshold.Answer to the questionRTBES effectively quantified pulmonary TB severity and tracked treatment evolution on standard CXRs, showing promise as a prognostic tool to inform clinical decision-making.

Although surgical site infection (SSI) risk after hand trauma surgery is around 5%, the severity of these infections is not known. The risk of superficial SSI in a cohort study was evaluated using NHS UK-wide primary care records ( n = 641,223), using the Clinical Practice Research Datalink GOLD database. Within this cohort, a subcohort of those who had undergone a hand surgery operation for trauma were identified ( n = 3,088). Antibiotic and analgesic prescriptions were analysed at 30 and 90 days postoperatively. By 30 days, 6.2% had been prescribed antibiotics appropriate for SSI, rising to 14.4% (CI [13.2 to 15.8]) by 90 days. By 30 days, 10% had been prescribed opioid analgaesia and by 90 days this had increased to 13.8%. Antibiotics prescriptions for SSI in primary care are substantially higher than the NICE estimate for SSI overall and the expected risk in hand trauma. The implications of this study are that many patients are receiving treatment for SSI in primary care and may be in more pain, for longer, than we expect. Further exploration of this is warranted and future research in hand trauma surgery should capture adverse events occurring outside of the hospital environment. Level of evidence: II

Background:The opioid crisis has been a serious public health challenge in North America for decades, despite numerous efforts to mitigate its devastating consequences. As concerns grow about a similar situation developing in Europe, we evaluated the trends in opioid use and characterized prescribing indications across seven European countries. Methods:We conducted a multinational cohort study using electronic health records from various healthcare settings: primary care [Clinical Practice Research Datalink (CPRD) GOLD (United Kingdom), Sistema d'Informació per al Desenvolupament de la Investigació en Atenció Primària (SIDIAP, Spain), and Integrated Primary Care Information Project (IPCI, the Netherlands)]; primary and outpatient specialist care [IQVIA Disease Analyzer (DA) Germany and IQVIA Longitudinal Patient Database (LPD) Belgium]; hospital care [Clinical Data Warehouse of Bordeaux University Hospital (CHUBX, France)]; and the Estonian Biobank (EBB). All data were mapped to the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). All people registered in a contributing database for ≥365 days between 2012 and 2022 were included. Annual period prevalence and incidence rates of opioid prescriptions were estimated, and long-term trends were quantified as the percent change from 2012 to 2019. New opioid users were characterized, including potential prescribing indications. Results:Between 2012 and 2019, the incidence of opioid prescriptions in primary care decreased by -50·7% (CPRD GOLD) and -2·0% (SIDIAP), while it increased in EBB (+52·8%) and CHUBX (+25·3%) data. The incidence of codeine and tramadol use decreased in most databases. However, the prevalence of oxycodone, morphine, and fentanyl increased. Opioid use was highest among older age groups, and the majority of prescriptions were for oral formulations. Respiratory and pain-related conditions were the most common indications for new opioid users in outpatient settings. Conclusion:Despite a decrease in new opioid prescriptions in many European countries, the prevalence of opioid use remained largely stable over the last decade. More data are needed to monitor evolving opioid prescription patterns in Europe, particularly in the post-pandemic era.

IntroductionElectronic health records can be used to understand the diverse presentation of post-acute and long-term health outcomes following COVID-19 infection. In England, the UK Health Security Agency, in collaboration with the University of Oxford, has created the Evaluation of post-acute COVID-19 Health Outcomes (ECHOES) dataset to monitor how an initial SARS-CoV-2 infection episode is associated with changes in the risk of health outcomes that are recorded in routinely collected health data.MethodsThe ECHOES dataset is a national-level dataset combining national-level surveillance, administrative, and healthcare data. Entity resolution and data linkage methods are used to create a cohort of individuals who have tested positive and negative for SARS-CoV-2 in England throughout the COVID-19 pandemic, alongside information on a range of health outcomes, including diagnosed clinical conditions, mortality, and risk factor information.ResultsThe dataset contains comprehensive COVID-19 testing data and demographic, socio-economic, and health-related information for 44 million individuals who tested for SARS-CoV-2 between March 2020 and April 2022, representing 15,720,286 individuals who tested positive and 42,351,016 individuals who tested negative.DiscussionWith the application of epidemiological and statistical methods, this dataset allows a range of clinical outcomes to be investigated, including pre-specified health conditions and mortality. Furthermore, understanding potential determinants of health outcomes can be gained, including pre-existing health conditions, acute disease characteristics, SARS-CoV-2 vaccination status, and genomic variants.

Background: Real-world data are valuable for detecting adverse drug events, and Sequence Symmetry Analysis (SSA) is a simple yet effective method frequently used for this purpose. However, heterogeneous implementations across studies limit reproducibility and scalability. To address this, we developed an open-source R package that standardises SSA analytics using data mapped to the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). Methods: We developed CohortSymmetry, an R package that implements SSA for OMOP CDM data. The package was validated through unit testing and evaluated empirically by estimating adjusted sequence ratios (ASRs) with 95% confidence intervals (CIs) for 23 positive and 10 negative controls across six European databases, including CPRD GOLD (UK) and THIN (Belgium, Italy, Romania, Spain, UK). Sensitivity and specificity were defined as the proportions of positive and negative controls correctly identified by SSA. Sensitivity analyses varied key parameters, including the washout period. Results: CohortSymmetry passed high-coverage unit tests. Of 33 eligible controls, four showed results consistent with expectations across all databases; for example, the amiodarone-levothyroxine pair had a lower 95% CI bound >1 in each. Sensitivity was moderate, whereas specificity was high in the primary analyses. Parameter variation influenced outcomes; a 365-day prior observation requirement reduced specificity in CPRD GOLD from 75% to 38%. Conclusions: CohortSymmetry enables reproducible SSA using OMOP CDM data. Differences across databases likely reflect heterogeneity in data capture and prescribing patterns. Limitations include residual data variability and SSA's susceptibility to time-varying confounding, underscoring the need for tailored analytic design in pharmacovigilance studies. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The author(s) declare that financial support was received for the research, authorship, and/or publication of this work. This research was partially funded by the European Health Data and Evidence Network (EHDEN). This activity under the EHDEN has received funding from the Innovative Medicines Initiative 2 (IMI2) Joint Undertaking under grant agreement No 806968. IMI2 receives support from the European Union's Horizon 2020 research and innovation program and European Federation of Pharmaceutical Industries and Associations (EFPIA). The sponsors of the study did not have any involvement in the writing of the manuscript or the decision to submit it for publication. Additionally, there was partial support from the Oxford NIHR Biomedical Research Centre. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The use of CPRD GOLD for this study was approved through CPRD's Research Data Governance (RDG) Process (Protocol number: 22\_002351). Individual consent was not necessary, as the CPRD GOLD data are de-identified and approved for research use by the UK Health Research Authority and the NHS Health and Social Care Research Ethics Committee. The use of the THIN databases for this study was approved by THIN EuroBoard under protocol 2024\_10 and provided by Cegedim. The data are available from Cegedim upon request for researchers who meet the criteria for access to confidential data. THIN databases contain de‐identified data provided by patients as part of their routine care; therefore, no informed consent was required as well. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript.