Comparative Effectiveness of Second-Line Antihyperglycemic Agents for Cardiovascular Outcomes: A Multinational, Federated Analysis of LEGEND-T2DM.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, their effectiveness relative to each other and other second-line antihyperglycemic agents is unknown, without any major ongoing head-to-head clinical trials. OBJECTIVES: The aim of this study was to compare the cardiovascular effectiveness of SGLT2is, GLP-1 RAs, dipeptidyl peptidase-4 inhibitors (DPP4is), and clinical sulfonylureas (SUs) as second-line antihyperglycemic agents in T2DM. METHODS: Across the LEGEND-T2DM (Large-Scale Evidence Generation and Evaluation Across a Network of Databases for Type 2 Diabetes Mellitus) network, 10 federated international data sources were included, spanning 1992 to 2021. In total, 1,492,855 patients with T2DM and cardiovascular disease (CVD) on metformin monotherapy were identified who initiated 1 of 4 second-line agents (SGLT2is, GLP-1 RAs, DPP4is, or SUs). Large-scale propensity score models were used to conduct an active-comparator target trial emulation for pairwise comparisons. After evaluating empirical equipoise and population generalizability, on-treatment Cox proportional hazards models were fit for 3-point MACE (myocardial infarction, stroke, and death) and 4-point MACE (3-point MACE plus heart failure hospitalization) risk and HR estimates were combined using random-effects meta-analysis. RESULTS: Over 5.2 million patient-years of follow-up and 489 million patient-days of time at risk, patients experienced 25,982 3-point MACE and 41,447 4-point MACE. SGLT2is and GLP-1 RAs were associated with lower 3-point MACE risk than DPP4is (HR: 0.89 [95% CI: 0.79-1.00] and 0.83 [95% CI: 0.70-0.98]) and SUs (HR: 0.76 [95% CI: 0.65-0.89] and 0.72 [95% CI: 0.58-0.88]). DPP4is were associated with lower 3-point MACE risk than SUs (HR: 0.87; 95% CI: 0.79-0.95). The pattern for 3-point MACE was also observed for the 4-point MACE outcome. There were no significant differences between SGLT2is and GLP-1 RAs for 3-point or 4-point MACE (HR: 1.06 [95% CI: 0.96-1.17] and 1.05 [95% CI: 0.97-1.13]). CONCLUSIONS: In patients with T2DM and CVD, comparable cardiovascular risk reduction was found with SGLT2is and GLP-1 RAs, with both agents more effective than DPP4is, which in turn were more effective than SUs. These findings suggest that the use of SGLT2is and GLP-1 RAs should be prioritized as second-line agents in those with established CVD.

Comparative Effectiveness of Second-line Antihyperglycemic Agents for Cardiovascular Outcomes: A Large-scale, Multinational, Federated Analysis of the LEGEND-T2DM Study.

Background: SGLT2 inhibitors (SGLT2is) and GLP-1 receptor agonists (GLP1-RAs) reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, their effectiveness relative to each other and other second-line antihyperglycemic agents is unknown, without any major ongoing head-to-head trials. Methods: Across the LEGEND-T2DM network, we included ten federated international data sources, spanning 1992-2021. We identified 1,492,855 patients with T2DM and established cardiovascular disease (CVD) on metformin monotherapy who initiated one of four second-line agents (SGLT2is, GLP1-RAs, dipeptidyl peptidase 4 inhibitor [DPP4is], sulfonylureas [SUs]). We used large-scale propensity score models to conduct an active comparator, target trial emulation for pairwise comparisons. After evaluating empirical equipoise and population generalizability, we fit on-treatment Cox proportional hazard models for 3-point MACE (myocardial infarction, stroke, death) and 4-point MACE (3-point MACE + heart failure hospitalization) risk, and combined hazard ratio (HR) estimates in a random-effects meta-analysis. Findings: Across cohorts, 16·4%, 8·3%, 27·7%, and 47·6% of individuals with T2DM initiated SGLT2is, GLP1-RAs, DPP4is, and SUs, respectively. Over 5·2 million patient-years of follow-up and 489 million patient-days of time at-risk, there were 25,982 3-point MACE and 41,447 4-point MACE events. SGLT2is and GLP1-RAs were associated with a lower risk for 3-point MACE compared with DPP4is (HR 0·89 [95% CI, 0·79-1·00] and 0·83 [0·70-0·98]), and SUs (HR 0·76 [0·65-0·89] and 0·71 [0·59-0·86]). DPP4is were associated with a lower 3-point MACE risk versus SUs (HR 0·87 [0·79-0·95]). The pattern was consistent for 4-point MACE for the comparisons above. There were no significant differences between SGLT2is and GLP1-RAs for 3-point or 4-point MACE (HR 1·06 [0·96-1·17] and 1·05 [0·97-1·13]). Interpretation: In patients with T2DM and established CVD, we found comparable cardiovascular risk reduction with SGLT2is and GLP1-RAs, with both agents more effective than DPP4is, which in turn were more effective than SUs. These findings suggest that the use of GLP1-RAs and SGLT2is should be prioritized as second-line agents in those with established CVD. Funding: National Institutes of Health, United States Department of Veterans Affairs.

Multinational patterns of second line antihyperglycaemic drug initiation across cardiovascular risk groups: federated pharmacoepidemiological evaluation in LEGEND-T2DM.

Objective: To assess the uptake of second line antihyperglycaemic drugs among patients with type 2 diabetes mellitus who are receiving metformin. Design: Federated pharmacoepidemiological evaluation in LEGEND-T2DM. Setting: 10 US and seven non-US electronic health record and administrative claims databases in the Observational Health Data Sciences and Informatics network in eight countries from 2011 to the end of 2021. Participants: 4.8 million patients (≥18 years) across US and non-US based databases with type 2 diabetes mellitus who had received metformin monotherapy and had initiated second line treatments. Exposure: The exposure used to evaluate each database was calendar year trends, with the years in the study that were specific to each cohort. Main outcomes measures: The outcome was the incidence of second line antihyperglycaemic drug use (ie, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, dipeptidyl peptidase-4 inhibitors, and sulfonylureas) among individuals who were already receiving treatment with metformin. The relative drug class level uptake across cardiovascular risk groups was also evaluated. Results: 4.6 million patients were identified in US databases, 61 382 from Spain, 32 442 from Germany, 25 173 from the UK, 13 270 from France, 5580 from Scotland, 4614 from Hong Kong, and 2322 from Australia. During 2011-21, the combined proportional initiation of the cardioprotective antihyperglycaemic drugs (glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors) increased across all data sources, with the combined initiation of these drugs as second line drugs in 2021 ranging from 35.2% to 68.2% in the US databases, 15.4% in France, 34.7% in Spain, 50.1% in Germany, and 54.8% in Scotland. From 2016 to 2021, in some US and non-US databases, uptake of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors increased more significantly among populations with no cardiovascular disease compared with patients with established cardiovascular disease. No data source provided evidence of a greater increase in the uptake of these two drug classes in populations with cardiovascular disease compared with no cardiovascular disease. Conclusions: Despite the increase in overall uptake of cardioprotective antihyperglycaemic drugs as second line treatments for type 2 diabetes mellitus, their uptake was lower in patients with cardiovascular disease than in people with no cardiovascular disease over the past decade. A strategy is needed to ensure that medication use is concordant with guideline recommendations to improve outcomes of patients with type 2 diabetes mellitus.

Supporting Pharmacovigilance Signal Validation and Prioritization with Analyses of Routinely Collected Health Data: Lessons Learned from an EHDEN Network Study.

INTRODUCTION: Individual case reports are the main asset in pharmacovigilance signal management. Signal validation is the first stage after signal detection and aims to determine if there is sufficient evidence to justify further assessment. Throughout signal management, a prioritization of signals is continually made. Routinely collected health data can provide relevant contextual information but are primarily used at a later stage in pharmacoepidemiological studies to assess communicated signals. OBJECTIVE: The aim of this study was to examine the feasibility and utility of analysing routine health data from a multinational distributed network to support signal validation and prioritization and to reflect on key user requirements for these analyses to become an integral part of this process. METHODS: Statistical signal detection was performed in VigiBase, the WHO global database of individual case safety reports, targeting generic manufacturer drugs and 16 prespecified adverse events. During a 5-day study-a-thon, signal validation and prioritization were performed using information from VigiBase, regulatory documents and the scientific literature alongside descriptive analyses of routine health data from 10 partners of the European Health Data and Evidence Network (EHDEN). Databases included in the study were from the UK, Spain, Norway, the Netherlands and Serbia, capturing records from primary care and/or hospitals. RESULTS: Ninety-five statistical signals were subjected to signal validation, of which eight were considered for descriptive analyses in the routine health data. Design, execution and interpretation of results from these analyses took up to a few hours for each signal (of which 15-60 minutes were for execution) and informed decisions for five out of eight signals. The impact of insights from the routine health data varied and included possible alternative explanations, potential public health and clinical impact and feasibility of follow-up pharmacoepidemiological studies. Three signals were selected for signal assessment, two of these decisions were supported by insights from the routine health data. Standardization of analytical code, availability of adverse event phenotypes including bridges between different source vocabularies, and governance around the access and use of routine health data were identified as important aspects for future development. CONCLUSIONS: Analyses of routine health data from a distributed network to support signal validation and prioritization are feasible in the given time limits and can inform decision making. The cost-benefit of integrating these analyses at this stage of signal management requires further research.

Body mass index and incident cardiometabolic conditions in relation to obesity-related cancer risk: A population-based cohort study in Catalonia, Spain.

BACKGROUND: We investigated the association between body mass index (BMI) and obesity-related cancer risk among individuals with/without incident hypertension (HTN), type 2 diabetes mellitus (T2DM), and cardiovascular disease (CVD) and the joint associations of overweight/obesity (BMI ≥25 kg/m2 ) and each cardiometabolic condition with obesity-related cancer risk METHODS: We conducted a population-based cohort (n = 1,774,904 individuals aged ≥40 years and free of cancer and cardiometabolic conditions at baseline) study between 2010 and 2018 with electronic health records from Spain. Our main outcome measures were hazard ratios (HRs) for incident obesity-related cancers and relative excess risk due to interaction (RERI). RESULTS: A total of 38,082 individuals developed obesity-related cancers after a median of 8 years of follow-up. The positive association between BMI and obesity-related cancer risk was similar among individuals free of cardiometabolic conditions (hazard ratio, HR per 5 kg/m2 : 1.08, 95% confidence interval, CI: 1.06-1.10) and with incident HTN (1.05, 1.01-1.08). The association among those with incident T2DM was null (0.98, 0.93-1.03). There was a positive additive interaction between overweight/obesity and CVD (relative excess risk due to interaction [RERI]: 0.19 [0.09, 0.30]), meaning that the combined association was 0.19 more than the sum of the individual associations. In contrast, a RERI of -0.24 (-0.28, -0.20) was observed for the combined association between overweight/obesity and T2DM. CONCLUSIONS: Public health strategies to reduce overweight can help prevent cancer cases among the general population and individuals with incident HTN/CVD. Further, weight-loss interventions seem to lead to a greater cancer risk reduction among individuals with CVD.

Transforming the Information System for Research in Primary Care (SIDIAP) in Catalonia to the OMOP Common Data Model and Its Use for COVID-19 Research.

Purpose: The primary aim of this work was to convert the Information System for Research in Primary Care (SIDIAP) from Catalonia, Spain, to the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). Our second aim was to provide a descriptive analysis of COVID-19-related outcomes among the general population. Patients and Methods: We mapped patient-level data from SIDIAP to the OMOP CDM and we performed more than 3,400 data quality checks to assess its readiness for research. We established a general population cohort as of the 1st March 2020 and identified outpatient COVID-19 diagnoses or tested positive for, hospitalised with, admitted to intensive care units (ICU) with, died with, or vaccinated against COVID-19 up to 30th June 2022. Results: After verifying the high quality of the transformed dataset, we included 5,870,274 individuals in the general population cohort. Of those, 604,472 had either an outpatient COVID-19 diagnosis or positive test result, 58,991 had a hospitalisation, 5,642 had an ICU admission, and 11,233 died with COVID-19. A total of 4,584,515 received a COVID-19 vaccine. People who were hospitalised or died were more commonly older, male, and with more comorbidities. Those admitted to ICU with COVID-19 were generally younger and more often male than those hospitalised and those who died. Conclusion: We successfully transformed SIDIAP to the OMOP CDM. From this dataset, a general population cohort of 5.9 million individuals was identified and their COVID-19-related outcomes over time were described. The transformed SIDIAP database is a valuable resource that can enable distributed network research in COVID-19 and beyond.

Changes in air pollution exposure after residential relocation and body mass index in children and adolescents: A natural experiment study.

Air pollution exposure may affect child weight gain, but observational studies provide inconsistent evidence. Residential relocation can be leveraged as a natural experiment by studying changes in health outcomes after a sudden change in exposure within an individual. We aimed to evaluate whether changes in air pollution exposure due to residential relocation are associated with changes in body mass index (BMI) in children and adolescents in a natural experiment study. This population-based study included children and adolescents, between 2 and 17 years, who moved during 2011-2018 and were registered in the primary healthcare in Catalonia, Spain (N = 46,644). Outdoor air pollutants (nitrogen dioxides (NO2), particulate matter <10 µm (PM10) and <2.5 µm (PM2.5)) were estimated at residential census tract level before and after relocation; tertile cut-offs were used to define changes in exposure. Routinely measured weight and height were used to calculate age-sex-specific BMI z-scores. A minimum of 180 days after moving was considered to observe zBMI changes according to changes in exposure using linear fixed effects regression. The majority of participants (60-67% depending on the pollutant) moved to areas with similar levels of air pollution, 15-49% to less polluted, and 14-31% to more polluted areas. Moving to areas with more air pollution was associated with zBMI increases for all air pollutants (ß NO2 = 0.10(95%CI 0.09; 0.12), ß PM2.5 0.06(0.04; 0.07), ß PM10 0.08(0.06; 0.10)). Moving to similar air pollution areas was associated with decreases in zBMI for all pollutants. No associations were found for those moving to less polluted areas. Associations with moving to more polluted areas were stronger in preschool- and primary school-ages. Associations did not differ by area deprivation strata. This large, natural experiment study suggests that increases in outdoor air pollution may be associated with child weight gain, supporting ongoing efforts to lower air pollution levels.

Longitudinal body mass index and cancer risk: a cohort study of 2.6 million Catalan adults.

Single body mass index (BMI) measurements have been associated with increased risk of 13 cancers. Whether life course adiposity-related exposures are more relevant cancer risk factors than baseline BMI (ie, at start of follow-up for disease outcome) remains unclear. We conducted a cohort study from 2009 until 2018 with population-based electronic health records in Catalonia, Spain. We included 2,645,885 individuals aged ≥40 years and free of cancer in 2009. After 9 years of follow-up, 225,396 participants were diagnosed with cancer. This study shows that longer duration, greater degree, and younger age of onset of overweight and obesity during early adulthood are positively associated with risk of 18 cancers, including leukemia, non-Hodgkin lymphoma, and among never-smokers, head and neck, and bladder cancers which are not yet considered as obesity-related cancers in the literature. Our findings support public health strategies for cancer prevention focussing on preventing and reducing early overweight and obesity.

Time trends in the incidence of cardiovascular disease, hypertension and diabetes by sex and socioeconomic status in Catalonia, Spain: a population-based cohort study.

OBJECTIVE: We aimed to estimate how longitudinal trends in cardiovascular disease, hypertension and type 2 diabetes mellitus incidence in Catalonia, Spain from 2009 to 2018 may differ by age, sex and socioeconomic deprivation. DESIGN: Cohort study using prospectively collected data. SETTING: Electronic health records from primary healthcare centres in Catalonia, Spain. PARTICIPANTS: 3 247 244 adults (≥40 years). OUTCOME MEASURES: We calculated the annual incidence (per 1000 persons-year) and incidence rate ratios (IRR) between three time periods of cardiovascular disease, hypertension and type 2 diabetes mellitus to measure trends and changes in incidence during the study period. RESULTS: In 2016-2018 compared with 2009-2012, cardiovascular disease incidence increased in the 40-54 (eg, IRR=1.61, 95% CI: 1.52 to 1.69 in women) and 55-69 age groups. There was no change in cardiovascular disease incidence in women aged 70+ years, and a slight decrease in men aged 70+ years (0.93, 0.90 to 0.95). Hypertension incidence decreased in all age groups for both sexes. Type 2 diabetes mellitus incidence decreased in all age groups for both sexes (eg, 0.72, 0.70 to 0.73 in women aged 55-69 years), except for the 40-54 year age group (eg, 1.09, 1.06 to 1.13 in women). Higher incidence levels were found in the most deprived areas, especially in the 40-54 and 55-69 groups. CONCLUSIONS: Overall cardiovascular disease incidence has increased while hypertension and type 2 diabetes mellitus incidence have decreased in the last years in Catalonia, Spain, with differences in trends by age group and socioeconomic deprivation.

Contextualising adverse events of special interest to characterise the baseline incidence rates in 24 million patients with COVID-19 across 26 databases: a multinational retrospective cohort study.

Background: Adverse events of special interest (AESIs) were pre-specified to be monitored for the COVID-19 vaccines. Some AESIs are not only associated with the vaccines, but with COVID-19. Our aim was to characterise the incidence rates of AESIs following SARS-CoV-2 infection in patients and compare these to historical rates in the general population. Methods: A multi-national cohort study with data from primary care, electronic health records, and insurance claims mapped to a common data model. This study's evidence was collected between Jan 1, 2017 and the conclusion of each database (which ranged from Jul 2020 to May 2022). The 16 pre-specified prevalent AESIs were: acute myocardial infarction, anaphylaxis, appendicitis, Bell's palsy, deep vein thrombosis, disseminated intravascular coagulation, encephalomyelitis, Guillain- Barré syndrome, haemorrhagic stroke, non-haemorrhagic stroke, immune thrombocytopenia, myocarditis/pericarditis, narcolepsy, pulmonary embolism, transverse myelitis, and thrombosis with thrombocytopenia. Age-sex standardised incidence rate ratios (SIR) were estimated to compare post-COVID-19 to pre-pandemic rates in each of the databases. Findings: Substantial heterogeneity by age was seen for AESI rates, with some clearly increasing with age but others following the opposite trend. Similarly, differences were also observed across databases for same health outcome and age-sex strata. All studied AESIs appeared consistently more common in the post-COVID-19 compared to the historical cohorts, with related meta-analytic SIRs ranging from 1.32 (1.05 to 1.66) for narcolepsy to 11.70 (10.10 to 13.70) for pulmonary embolism. Interpretation: Our findings suggest all AESIs are more common after COVID-19 than in the general population. Thromboembolic events were particularly common, and over 10-fold more so. More research is needed to contextualise post-COVID-19 complications in the longer term. Funding: None.

Impact of the COVID-19 pandemic on eating disorders diagnoses among adolescents and young adults in Catalonia: A population-based cohort study.

OBJECTIVE: To describe the impact of the COVID-19 pandemic on trends in incidence rates (IR) of diagnoses of eating disorders (ED) among adolescents and young adults. METHODS: Population-based cohort study using primary care records of people aged 10-24 years between January, 2016 and December, 2021 in Catalonia, Spain. IRs were calculated monthly and grouped by the different stages of the COVID-19 pandemic in Catalonia: (1) the pre-lockdown (January, 2016-February, 2020), (2) lockdown (March-June, 2020) and, (3) post-lockdown (July, 2020-December, 2021) periods. Incidence rate ratios (IRR) relative to the corresponding periods in 2018-2019 were calculated. RESULTS: A total of 1,179,009 individuals were included. The IR was 9.2 per 100,000 person-months (95% confidence intervals [CI]: 8.9-9.5) during the pre-lockdown period. It decreased during the lockdown period (6.3 per 100,000 person-months [5.5-7.3]), but substantially increased during the following period (19.4. per 100,000 person-months [18.7-20.1]). While large reductions in IRs were observed for both sexes during the lockdown period (IRR 95% CI: 0.65 [0.54-0.78] in females and 0.46 [0.29-0.71] in males), substantial increases during the post-lockdown period were limited to females, and were particularly pronounced among those aged 10-14 and 15-19 years (2.50 [2.23-2.80] and 2.29 [2.07-2.54], respectively). DISCUSSION: The COVID-19 pandemic has resulted in a substantial increase in ED diagnoses, primarily driven by higher rates among adolescent females. PUBLIC SIGNIFICANCE: This population-based cohort study demonstrated a substantial increase in incidence rates of eating disorders in primary care following the end of lockdown in Catalonia, Spain, with adolescent girls seen to be most affected.

Thrombosis and thrombocytopenia after vaccination against and infection with SARS-CoV-2 in Catalonia, Spain.

Population-based studies can provide important evidence on the safety of COVID-19 vaccines. Here we compare rates of thrombosis and thrombocytopenia following vaccination against SARS-CoV-2 with the background (expected) rates in the general population. In addition, we compare the rates of the same adverse events among persons infected with SARS-CoV-2 with background rates. Primary care and linked hospital data from Catalonia, Spain informed the study, with participants vaccinated with BNT162b2 or ChAdOx1 (27/12/2020-23/06/2021), COVID-19 cases (01/09/2020-23/06/2021) or present in the database as of 01/01/2017. We included 2,021,366 BNT162b2 (1,327,031 with 2 doses), 592,408 ChAdOx1, 174,556 COVID-19 cases, and 4,573,494 background participants. Standardised incidence ratios for venous thromboembolism were 1.18 (95% CI 1.06-1.32) and 0.92 (0.81-1.05) after first- and second dose BNT162b2, and 0.92 (0.71-1.18) after first dose ChAdOx1. The standardised incidence ratio for venous thromboembolism in COVID-19 was 10.19 (9.43-11.02). Standardised incidence ratios for arterial thromboembolism were 1.02 (0.95-1.09) and 1.04 (0.97-1.12) after first- and second dose BNT162b2, 1.06 (0.91-1.23) after first-dose ChAdOx1 and 4.13 (3.83-4.45) for COVID-19. Standardised incidence ratios for thrombocytopenia were 1.49 (1.43-1.54) and 1.40 (1.35-1.45) after first- and second dose BNT162b2, 1.28 (1.19-1.38) after first-dose ChAdOx1 and 4.59 (4.41- 4.77) for COVID-19. While rates of thrombosis with thrombocytopenia were generally similar to background rates, the standardised incidence ratio for pulmonary embolism with thrombocytopenia after first-dose BNT162b2 was 1.70 (1.11-2.61). These findings suggest that the safety profiles of BNT162b2 and ChAdOx1 are similar, with rates of adverse events seen after vaccination typically similar to background rates. Meanwhile, rates of adverse events are much increased for COVID-19 cases further underlining the importance of vaccination.

Socioeconomic Inequalities in COVID-19 Vaccination and Infection in Adults, Catalonia, Spain.

Evidence on the impact of the COVID-19 vaccine rollout on socioeconomic COVID-19-related inequalities is scarce. We analyzed associations between socioeconomic deprivation index (SDI) and COVID-19 vaccination, infection, and hospitalization before and after vaccine rollout in Catalonia, Spain. We conducted a population-based cohort study during September 2020-June 2021 that comprised 2,297,146 adults >40 years of age. We estimated odds ratio of nonvaccination and hazard ratios (HRs) of infection and hospitalization by SDI quintile relative to the least deprived quintile, Q1. Six months after rollout, vaccination coverage differed by SDI quintile in working-age (40-64 years) persons: 81% for Q1, 71% for Q5. Before rollout, we found a pattern of increased HR of infection and hospitalization with deprivation among working-age and retirement-age (>65 years) persons. After rollout, infection inequalities decreased in both age groups, whereas hospitalization inequalities decreased among retirement-age persons. Our findings suggest that mass vaccination reduced socioeconomic COVID-19-related inequalities.

Residential Proximity to Urban Play Spaces and Childhood Overweight and Obesity in Barcelona, Spain: A Population-Based Longitudinal Study.

Findings on the relationship between play spaces and childhood overweight and obesity are mixed and scarce. This study aimed to investigate the associations between residential proximity to play spaces and the risk of childhood overweight or obesity and potential effect modifiers. This longitudinal study included children living in the city of Barcelona identified in an electronic primary healthcare record database between 2011 and 2018 (N = 75,608). Overweight and obesity were defined according to the WHO standards and we used 300 m network buffers to assess residential proximity to play spaces. We calculated the risk of developing overweight or obesity using Cox proportional hazard models. A share of 29.4% of the study population developed overweight or obesity, but we did not find consistent associations between play space indicators and overweight or obesity. We did not find any consistent sign of effect modification by sex, and only some indications of the modifying role of area socioeconomic status and level of exposure. Although it is not possible to draw clear conclusions from our study, we call for cities to continue increasing and improving urban play spaces with an equitable, healthy, and child-friendly perspective.

Endometriosis prevalence and incidence trends in a large population-based study in Catalonia (Spain) from 2009 to 2018.

OBJECTIVE: Endometriosis greatly impacts women's health and quality of life. However, research on the prevalence and incidence of endometriosis remains inconclusive. This study assesses time trends in the prevalence and incidence of endometriosis diagnoses in Catalonia (Spain) from 2009 to 2018, considering differences by age and socioeconomic status. METHODS: Population-based cohort study using data from the Information System for Research in Primary Care (SIDIAP) database. Data were included from over 2.4 million women aged 15-55 years between 1 January 2006 and 31 December 2018. RESULTS: A total of 2,337,717 women were selected as the incident population; 0.7% had an endometriosis diagnosis. Median (interquartile range) age at diagnosis was 37 (32-43) years. Most women were European (92.3%) and lived in urban areas (73.6%). Overall prevalence of endometriosis consistently increased during the 2009-2018 period, and it was 1.24% in 2018. Trends were the highest for women with less socioeconomic deprivation and for the 35-44 years age group. Median incidence rates were 94.9 (92.6-102.9) per 100,000 women-years, being the highest in women aged 35-44 years throughout the whole study period. Overall, incidence increased between 2015 and 2017, and plateaued or decreased in 2018. Incidence rates in women from the most deprived and rural areas were lower, although incidence time trends by socioeconomic status were unclear. CONCLUSION: Healthcare services and public health strategies need to be strengthened to ensure timely endometriosis diagnosis and treatment. Special attention should be given to the most affected populations and the social inequities of health.

Impact of the COVID-19 pandemic on diagnoses of common mental health disorders in adults in Catalonia, Spain: a population-based cohort study.

OBJECTIVE: To investigate how trends in incidence of anxiety and depressive disorders have been affected by the COVID-19 pandemic. DESIGN: Population-based cohort study. SETTING: Retrospective cohort study from 2018 to 2021 using the Information System for Research in Primary Care (SIDIAP) database in Catalonia, Spain. PARTICIPANTS: 3 640 204 individuals aged 18 or older in SIDIAP on 1 March 2018 with no history of anxiety and depressive disorders. PRIMARY AND SECONDARY OUTCOMES MEASURES: The incidence of anxiety and depressive disorders during the prelockdown period (March 2018-February 2020), lockdown period (March-June 2020) and postlockdown period (July 2020-March 2021) was calculated. Forecasted rates over the COVID-19 periods were estimated using negative binomial regression models based on prelockdown data. The percentage of reduction was estimated by comparing forecasted versus observed events, overall and by sex, age and socioeconomic status. RESULTS: The incidence rates per 100 000 person-months of anxiety and depressive disorders were 151.1 (95% CI 150.3 to 152.0) and 32.3 (31.9 to 32.6), respectively, during the prelockdown period. We observed an increase of 37.1% (95% prediction interval 25.5 to 50.2) in incident anxiety diagnoses compared with the expected in March 2020, followed by a reduction of 15.8% (7.3 to 23.5) during the postlockdown period. A reduction in incident depressive disorders occurred during the lockdown and postlockdown periods (45.6% (39.2 to 51.0) and 22.0% (12.6 to 30.1), respectively). Reductions were higher among women during the lockdown period, adults aged 18-34 years and individuals living in the most deprived areas. CONCLUSIONS: The COVID-19 pandemic in Catalonia was associated with an initial increase in anxiety disorders diagnosed in primary care but a reduction in cases as the pandemic continued. Diagnoses of depressive disorders were lower than expected throughout the pandemic.

Unraveling COVID-19: A Large-Scale Characterization of 4.5 Million COVID-19 Cases Using CHARYBDIS.

Purpose: Routinely collected real world data (RWD) have great utility in aiding the novel coronavirus disease (COVID-19) pandemic response. Here we present the international Observational Health Data Sciences and Informatics (OHDSI) Characterizing Health Associated Risks and Your Baseline Disease In SARS-COV-2 (CHARYBDIS) framework for standardisation and analysis of COVID-19 RWD. Patients and Methods: We conducted a descriptive retrospective database study using a federated network of data partners in the United States, Europe (the Netherlands, Spain, the UK, Germany, France and Italy) and Asia (South Korea and China). The study protocol and analytical package were released on 11th June 2020 and are iteratively updated via GitHub. We identified three non-mutually exclusive cohorts of 4,537,153 individuals with a clinical COVID-19 diagnosis or positive test, 886,193 hospitalized with COVID-19, and 113,627 hospitalized with COVID-19 requiring intensive services. Results: We aggregated over 22,000 unique characteristics describing patients with COVID-19. All comorbidities, symptoms, medications, and outcomes are described by cohort in aggregate counts and are readily available online. Globally, we observed similarities in the USA and Europe: more women diagnosed than men but more men hospitalized than women, most diagnosed cases between 25 and 60 years of age versus most hospitalized cases between 60 and 80 years of age. South Korea differed with more women than men hospitalized. Common comorbidities included type 2 diabetes, hypertension, chronic kidney disease and heart disease. Common presenting symptoms were dyspnea, cough and fever. Symptom data availability was more common in hospitalized cohorts than diagnosed. Conclusion: We constructed a global, multi-centre view to describe trends in COVID-19 progression, management and evolution over time. By characterising baseline variability in patients and geography, our work provides critical context that may otherwise be misconstrued as data quality issues. This is important as we perform studies on adverse events of special interest in COVID-19 vaccine surveillance.

Association between covid-19 vaccination, SARS-CoV-2 infection, and risk of immune mediated neurological events: population based cohort and self-controlled case series analysis.

OBJECTIVE: To study the association between covid-19 vaccines, SARS-CoV-2 infection, and risk of immune mediated neurological events. DESIGN: Population based historical rate comparison study and self-controlled case series analysis. SETTING: Primary care records from the United Kingdom, and primary care records from Spain linked to hospital data. PARTICIPANTS: 8 330 497 people who received at least one dose of covid-19 vaccines ChAdOx1 nCoV-19, BNT162b2, mRNA-1273, or Ad.26.COV2.S between the rollout of the vaccination campaigns and end of data availability (UK: 9 May 2021; Spain: 30 June 2021). The study sample also comprised a cohort of 735 870 unvaccinated individuals with a first positive reverse transcription polymerase chain reaction test result for SARS-CoV-2 from 1 September 2020, and 14 330 080 participants from the general population. MAIN OUTCOME MEASURES: Outcomes were incidence of Bell's palsy, encephalomyelitis, Guillain-Barré syndrome, and transverse myelitis. Incidence rates were estimated in the 21 days after the first vaccine dose, 90 days after a positive test result for SARS-CoV-2, and between 2017 and 2019 for background rates in the general population cohort. Indirectly standardised incidence ratios were estimated. Adjusted incidence rate ratios were estimated from the self-controlled case series. RESULTS: The study included 4 376 535 people who received ChAdOx1 nCoV-19, 3 588 318 who received BNT162b2, 244 913 who received mRNA-1273, and 120 731 who received Ad26.CoV.2; 735 870 people with SARS-CoV-2 infection; and 14 330 080 people from the general population. Overall, post-vaccine rates were consistent with expected (background) rates for Bell's palsy, encephalomyelitis, and Guillain-Barré syndrome. Self-controlled case series was conducted only for Bell's palsy, given limited statistical power, but with no safety signal seen for those vaccinated. Rates were, however, higher than expected after SARS-CoV-2 infection. For example, in the data from the UK, the standardised incidence ratio for Bell's palsy was 1.33 (1.02 to 1.74), for encephalomyelitis was 6.89 (3.82 to 12.44), and for Guillain-Barré syndrome was 3.53 (1.83 to 6.77). Transverse myelitis was rare (<5 events in all vaccinated cohorts) and could not be analysed. CONCLUSIONS: No safety signal was observed between covid-19 vaccines and the immune mediated neurological events of Bell's palsy, encephalomyelitis, Guillain-Barré syndrome, and transverse myelitis. An increased risk of Bell's palsy, encephalomyelitis, and Guillain-Barré syndrome was, however, observed for people with SARS-CoV-2 infection.

Flecainide and risk of skin neoplasms: Results of a large nested case-control study in Spain and Denmark.

Background: A previous study in Denmark suggested an increased melanoma risk associated with the use of flecainide. Objective: To study the association between flecainide use and the risk of melanoma and non-melanoma skin cancer in Spain and Denmark. Methods: We conducted a multi-database case-control study in (database/study period) Spain (SIDIAP/2005-2017 and BIFAP/2007-2017) and Denmark (Danish registries/2001-2018). We included incident cases of melanoma or non-melanoma skin cancer (NMSC) aged ≥18 with ≥2 years of previous data (≥10 years for Denmark) before the skin cancer and matched them to controls (10:1 by age and sex). We excluded persons with immunosuppression or previous cancer. We defined ever-use as any prescription fill and high-use as a cumulative dose of at least 200 g (reference: never-use). We categorized a cumulative dose for a dose-response assessment. We used conditional logistic regression to compute ORs (95% CI) adjusted for photosensitizing, anti-neoplastic, disease-specific drugs and comorbidities. Results: The total numbers of melanoma/NMSC cases included were 7,809/64,230 in SIDIAP, 4,661/31,063 in BIFAP, and 27,978/152,821 in Denmark. In Denmark, high-use of flecainide was associated with increased adjusted ORs of skin cancer compared with never-use [melanoma: OR 1.97 (1.38-2.81); NMSC: OR 1.34 (1.15-1.56)]. In Spain, an association between high-use of flecainide and NMSC was also observed [BIFAP: OR 1.42 (1.04-1.93); SIDIAP: OR 1.19 (0.95-1.48)]. There was a non-significant dose-response pattern for melanoma in Denmark and no apparent dose-response pattern for NMSC in any of the three databases. We found similar results for ever-use of flecainide. Conclusion: Flecainide use was associated with an increased risk of melanoma (Denmark only) and NMSC (Denmark and Spain) but without substantial evidence of dose-response patterns. Further studies are needed to assess for possible unmeasured confounders.