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Urban outdoor play spaces are reported to improve children's health. However, there is little empirical evidence on the impact of outdoor play spaces on childhood mental and behavioral health. To fill this gap, we investigated the associations between residential proximity to outdoor play spaces and the prevalence of diagnosed mental and behavioral disorders. We explored whether these associations differ by individual and area-level socio-economic status (SES). This cross-sectional study included 151 110 children who were 0-12 years old in 2014 and were visited in public primary health care centers in Barcelona (Spain). Each child's demographic and mental and behavioral disorders information was extracted for 2005-2014, including diagnoses on disorders of psychological development together with other four types of mental and behavioral disorders. The pediatrician diagnosed mental and behavioral disorders we explored in this study were: mood/affective; neurotic, stress-related and somatoform; psychological development; behavioral and emotional; and overall mental and behavioral disorders. We assessed 300 m network buffer residential proximity to overall outdoor play spaces (i.e., the overall sum of play spaces of any type), outdoor green play spaces, and to a diversity of outdoor play spaces. We used robust Poisson regression models to investigate the association between proximity to outdoor play spaces indicators and each health outcome. We tested interaction terms for indicators of proximity to outdoor play spaces and individual and area SES. For measures with significant interaction terms, we conducted stratified models. We found residential proximity to outdoor play spaces to be protective of disorders of psychological development. Proximity to overall outdoor play spaces, proximity to outdoor green play spaces and proximity to a greater diversity of outdoor play spaces were associated with a 4% (95% CI: 1,7), 4% (95% CI: 1,7) and 5% (95% CI: 2,9) lower prevalence rates of disorders of psychological development respectively. Most of the associations were found to be in the same direction-although more pronounced-in low SES areas, but in the opposite direction for children living in high SES areas. No differences in these associations were found by individual SES. Residential proximity to outdoor play spaces is protective of children's mental and behavioral health living in low SES areas., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: To characterize the demographics, comorbidities, symptoms, in-hospital treatments, and health outcomes among children and adolescents diagnosed or hospitalized with coronavirus disease 2019 (COVID-19) and to compare them in secondary analyses with patients diagnosed with previous seasonal influenza in 2017-2018., Methods: International network cohort using real-world data from European primary care records (France, Germany, and Spain), South Korean claims and US claims, and hospital databases. We included children and adolescents diagnosed and/or hospitalized with COVID-19 at age <18 between January and June 2020. We described baseline demographics, comorbidities, symptoms, 30-day in-hospital treatments, and outcomes including hospitalization, pneumonia, acute respiratory distress syndrome, multisystem inflammatory syndrome in children, and death., Results: A total of 242 158 children and adolescents diagnosed and 9769 hospitalized with COVID-19 and 2 084 180 diagnosed with influenza were studied. Comorbidities including neurodevelopmental disorders, heart disease, and cancer were more common among those hospitalized with versus diagnosed with COVID-19. Dyspnea, bronchiolitis, anosmia, and gastrointestinal symptoms were more common in COVID-19 than influenza. In-hospital prevalent treatments for COVID-19 included repurposed medications (<10%) and adjunctive therapies: systemic corticosteroids (6.8%-7.6%), famotidine (9.0%-28.1%), and antithrombotics such as aspirin (2.0%-21.4%), heparin (2.2%-18.1%), and enoxaparin (2.8%-14.8%). Hospitalization was observed in 0.3% to 1.3% of the cohort diagnosed with COVID-19, with undetectable ( n < 5 per database) 30-day fatality. Thirty-day outcomes including pneumonia and hypoxemia were more frequent in COVID-19 than influenza., Conclusions: Despite negligible fatality, complications including hospitalization, hypoxemia, and pneumonia were more frequent in children and adolescents with COVID-19 than with influenza. Dyspnea, anosmia, and gastrointestinal symptoms could help differentiate diagnoses. A wide range of medications was used for the inpatient management of pediatric COVID-19., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Purpose: Hydrochlorothiazide (HCTZ) use has been linked to skin cancer in northern European countries. We assessed the association between HCTZ exposure and risk of malignant melanoma (MM) and keratinocyte carcinoma (KC) in a European Mediterranean population., Methods: Two parallel nested case-control studies were conducted in Spain using two electronic primary healthcare databases, each one providing data on both exposure and outcomes: SIDIAP and BIFAP. Cancer cases were matched to 10 controls by age and gender through risk-set sampling. The ORs and 95% CI for MM and KC associated with previous HCTZ use were estimated using conditional logistic regression. In BIFAP, KC cases were further identified as basal cell carcinoma (BCC) or squamous cell carcinoma (SCC)., Results: In adjusted analyses, both ever and cumulative high (≥50,000 mg) use of HCTZ were associated with an increased risk of KC. The risk estimates for high use were 1.30 (1.26-1.34) in SIDIAP and 1.20 (1.12-1.30) in BIFAP, with a lower risk for BCC (1.11 [1.02-1.21]) than for SCC (1.71 [1.45-2.02]). A dose-response relationship was observed between cumulative doses of HCTZ and KC risk. Inconsistent results were found for high use of HCTZ and risk of MM: 1.25 (1.09-1.43) in SIDIAP and 0.85 (0.64-1.13) in BIFAP., Conclusions: In this European Mediterranean population, a high cumulative use of HCTZ was related to an increased risk of KC with a clear dose-response pattern., (© 2021 John Wiley & Sons Ltd.)

Background: Association of type 2 diabetes mellitus (T2D) with subsequent Parkinson's disease (PD) has supported the link between glucose metabolism and PD. We assessed the risk of PD not only in T2D but also in prediabetes., Methods: We conducted a retrospective cohort study of the population attended in primary care centres of the Catalan Health Institute in Catalonia between 2006 and 2018. The data were obtained from the Information System for Research in Primary Care (SIDIAP). We created a cohort of T2D and prediabetes patients (HbA1c ≥ 5.7-6.4% without antidiabetic drugs or previous T2D diagnosis) and compared to a reference cohort. The outcome was PD diagnosis and we excluded PD before or during the first year of follow-up. We used multivariate Cox regression models to calculate hazard ratios (HR) and 95% confidence intervals (95%CI). We excluded subjects with atypical and secondary parkinsonisms., Results: The exposed cohorts comprised of 281.153 patients with T2D and 266.379 with prediabetes and a reference cohort of 2.556.928 subjects. T2D and prediabetes were associated with higher risk of PD (HRadjusted 1.19, 95%CI 1.13-1.25, and 1.07, 1.00-1.14; respectively). In analyses stratified by sex, prediabetes was only associated with PD risk in women (1.12, 1.03-1.22 vs. 1.01, 0.99-1.10 in men). When analysis was stratified by age, T2D and prediabetes were associated with a greater PD risk both in women (2.36, 1.96-2.84 and 2.10, 1.70-2.59 respectively) and men (1.74, 1.52-2.00 and 1.90, 1.57-2.30 respectively) below 65 years-old., Conclusions: We report for the first time that prediabetes increases the odds of subsequent PD and replicate the association with established T2D. Both associations predominate in women and young individuals., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: Concern has been raised in the rheumatology community regarding recent regulatory warnings that HCQ used in the coronavirus disease 2019 pandemic could cause acute psychiatric events. We aimed to study whether there is risk of incident depression, suicidal ideation or psychosis associated with HCQ as used for RA., Methods: We performed a new-user cohort study using claims and electronic medical records from 10 sources and 3 countries (Germany, UK and USA). RA patients ≥18 years of age and initiating HCQ were compared with those initiating SSZ (active comparator) and followed up in the short (30 days) and long term (on treatment). Study outcomes included depression, suicide/suicidal ideation and hospitalization for psychosis. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate database-specific calibrated hazard ratios (HRs), with estimates pooled where I2 <40%., Results: A total of 918 144 and 290 383 users of HCQ and SSZ, respectively, were included. No consistent risk of psychiatric events was observed with short-term HCQ (compared with SSZ) use, with meta-analytic HRs of 0.96 (95% CI 0.79, 1.16) for depression, 0.94 (95% CI 0.49, 1.77) for suicide/suicidal ideation and 1.03 (95% CI 0.66, 1.60) for psychosis. No consistent long-term risk was seen, with meta-analytic HRs of 0.94 (95% CI 0.71, 1.26) for depression, 0.77 (95% CI 0.56, 1.07) for suicide/suicidal ideation and 0.99 (95% CI 0.72, 1.35) for psychosis., Conclusion: HCQ as used to treat RA does not appear to increase the risk of depression, suicide/suicidal ideation or psychosis compared with SSZ. No effects were seen in the short or long term. Use at a higher dose or for different indications needs further investigation., Trial Registration: Registered with EU PAS (reference no. EUPAS34497; http://www.encepp.eu/encepp/viewResource.htm? id=34498). The full study protocol and analysis source code can be found at https://github.com/ohdsi-studies/Covid19EstimationHydroxychloroquine2., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: To quantify the background incidence rates of 15 prespecified adverse events of special interest (AESIs) associated with covid-19 vaccines., Design: Multinational network cohort study., Setting: Electronic health records and health claims data from eight countries: Australia, France, Germany, Japan, the Netherlands, Spain, the United Kingdom, and the United States, mapped to a common data model., Participants: 126 661 070 people observed for at least 365 days before 1 January 2017, 2018, or 2019 from 13 databases., Main Outcome Measures: Events of interests were 15 prespecified AESIs (non-haemorrhagic and haemorrhagic stroke, acute myocardial infarction, deep vein thrombosis, pulmonary embolism, anaphylaxis, Bell's palsy, myocarditis or pericarditis, narcolepsy, appendicitis, immune thrombocytopenia, disseminated intravascular coagulation, encephalomyelitis (including acute disseminated encephalomyelitis), Guillain-Barré syndrome, and transverse myelitis). Incidence rates of AESIs were stratified by age, sex, and database. Rates were pooled across databases using random effects meta-analyses and classified according to the frequency categories of the Council for International Organizations of Medical Sciences., Results: Background rates varied greatly between databases. Deep vein thrombosis ranged from 387 (95% confidence interval 370 to 404) per 100 000 person years in UK CPRD GOLD data to 1443 (1416 to 1470) per 100 000 person years in US IBM MarketScan Multi-State Medicaid data among women aged 65 to 74 years. Some AESIs increased with age. For example, myocardial infarction rates in men increased from 28 (27 to 29) per 100 000 person years among those aged 18-34 years to 1400 (1374 to 1427) per 100 000 person years in those older than 85 years in US Optum electronic health record data. Other AESIs were more common in young people. For example, rates of anaphylaxis among boys and men were 78 (75 to 80) per 100 000 person years in those aged 6-17 years and 8 (6 to 10) per 100 000 person years in those older than 85 years in Optum electronic health record data. Meta-analytic estimates of AESI rates were classified according to age and sex., Conclusion: This study found large variations in the observed rates of AESIs by age group and sex, showing the need for stratification or standardisation before using background rates for safety surveillance. Considerable population level heterogeneity in AESI rates was found between databases., Competing Interests: Competing interests: All authors have completed the ICMJE disclosure form at http://www.icmje.org/disclosure-of-interest/ and declare the following interests: DPA receives funding from the UK National Institute for Health Research (NIHR) in the form of a senior research fellowship and the Oxford NIHR Biomedical Research Centre. XL receives the Clarendon Fund and Brasenose College Scholarship (University of Oxford) to support her DPhil study. DPA’s research group has received research grants from the European Medicines Agency; the Innovative Medicines Initiative; Amgen, Chiesi, and UCB Biopharma; and consultancy or speaker fees from Astellas, Amgen, and UCB Biopharma. GH and AO receive funding from the US National Institutes of Health (NIH) and the US Food and Drug Administration. KV and PR work for a research group that receives/received unconditional research grants from Yamanouchi, Pfizer-Boehringer Ingelheim, Novartis, GSK, Amgen, and Chiesi, none of which relates to the content of this paper. PBR, RM, AS, GR, and AGS are employees of Janssen Research and Development and shareholders in Johnson and Johnson. MAS receives grants and contracts from the FDA and the US Department of Veterans Affairs within the scope of this research, and grants and contracts from NIH, IQVIA, and Private Health Management outside the scope of this research., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Ambient air pollution may play a role in childhood obesity development, but evidence is scarce, and the modifying role of socioeconomic status (SES) is unclear. We aimed to examine the association between exposure to air pollution during early childhood and subsequent risk of developing overweight and obesity, and to evaluate whether SES is a modifier of this association., Methods: This longitudinal study included 416,955 children identified as normal weight between 2-5 years old and registered in an electronic primary healthcare record between 2006 and 2016 in Catalonia (Spain). Children were followed-up until they developed overweight or obesity, reached 15 years of age, died, transferred out, or end of study period (31/12/2018). Overweight and obesity were defined following the WHO reference obtained from height and weight measures. We estimated annual residential census levels of nitrogen dioxide (NO 2 ) and particulate matter <10 μm (PM 10 ), <2.5 μm (PM 2.5 ), and 2.5-10 μm (PM coarse ) at study entry. We estimated the risk of developing overweight and obesity per interquartile range increase in air pollution exposure with Cox proportional hazard models., Results: A total of 142,590 (34.2%) children developed overweight or obesity. Increased exposure to NO 2 , PM 10 , and PM coarse was associated with a 2-3% increased risk of developing overweight and obesity (hazard ratio [HR] per 21.8 μg/m 3 NO 2  = 1.03 [95% CI: 1.02-1.04]; HR per 6.4 μg/m 3 PM 10  = 1.02 [95% CI: 1.02-1.03]; HR per 4.6 µg/m 3 PM coarse  = 1.02, [95% CI: 1.01-1.02]). For all air pollutants, associations were stronger among children living in most compared to least deprived areas., Conclusions: This study suggests that early life exposure to air pollution may be associated with a small increase in the risk of developing overweight and obesity in childhood, and that this association may be exacerbated in the most deprived areas. Even these small associations are of potential global health importance because air pollution exposure is widespread and the long-term health consequences of childhood obesity are clear.

Background: As large-scale immunization programs against COVID-19 proceed around the world, safety signals will emerge that need rapid evaluation. We report population-based, age- and sex-specific background incidence rates of potential adverse events of special interest (AESI) in eight countries using thirteen databases., Methods: This multi-national network cohort study included eight electronic medical record and five administrative claims databases from Australia, France, Germany, Japan, Netherlands, Spain, the United Kingdom, and the United States, mapped to a common data model. People observed for at least 365 days before 1 January 2017, 2018, or 2019 were included. We based study outcomes on lists published by regulators: acute myocardial infarction, anaphylaxis, appendicitis, Bell's palsy, deep vein thrombosis, disseminated intravascular coagulation, encephalomyelitis, Guillain-Barre syndrome, hemorrhagic and non-hemorrhagic stroke, immune thrombocytopenia, myocarditis/pericarditis, narcolepsy, pulmonary embolism, and transverse myelitis. We calculated incidence rates stratified by age, sex, and database. We pooled rates across databases using random effects meta-analyses. We classified meta-analytic estimates into Council of International Organizations of Medical Sciences categories: very common, common, uncommon, rare, or very rare., Findings: We analysed 126,661,070 people. Rates varied greatly between databases and by age and sex. Some AESI (e.g., myocardial infarction, Guillain-Barre syndrome) increased with age, while others (e.g., anaphylaxis, appendicitis) were more common in young people. As a result, AESI were classified differently according to age. For example, myocardial infarction was very rare in children, rare in women aged 35-54 years, uncommon in men and women aged 55-84 years, and common in those aged ≥85 years., Interpretation: We report robust baseline rates of prioritised AESI across 13 databases. Age, sex, and variation between databases should be considered if background AESI rates are compared to event rates observed with COVID-19 vaccines., Competing Interests: Declaration of interests DPA’s research group has received research grants from the European Medicines Agency, from the Innovative Medicines Initiative, from Amgen, Chiesi, and from UCB Biopharma; and consultancy or speaker fees from Astellas, Amgen and UCB Biopharma. GH and AO receive funding from the US National Institutes of Health and the US Food and Drug Administration. KV and PR work for a research group who receives/received unconditional research grants from Yamanouchi, Pfizer-Boehringer Ingelheim, Novartis, GSK, Amgen, Chiesi none of which relates to the content of this paper. PBR, RM, AS, GR, AGS are employee of Janssen Research and Development, and shareholder in Johnson & Johnson. MAS receives grants and contracts from the US Food & Drug Administration and the US Department of Veterans Affairs within the scope of this research, and grants and contracts from the US National Institutes of Health, IQVIA and Private Health Management outside the scope of this research. Funders had no role in the conceptualization, design, data collection, analysis, decision to publish nor preparation of the manuscript. TDS has no conflicts of interest to declare. EM has no conflicts of interest to declare.

Background: SARS-CoV-2 is straining health care systems globally. The burden on hospitals during the pandemic could be reduced by implementing prediction models that can discriminate patients who require hospitalization from those who do not. The COVID-19 vulnerability (C-19) index, a model that predicts which patients will be admitted to hospital for treatment of pneumonia or pneumonia proxies, has been developed and proposed as a valuable tool for decision-making during the pandemic. However, the model is at high risk of bias according to the "prediction model risk of bias assessment" criteria, and it has not been externally validated., Objective: The aim of this study was to externally validate the C-19 index across a range of health care settings to determine how well it broadly predicts hospitalization due to pneumonia in COVID-19 cases., Methods: We followed the Observational Health Data Sciences and Informatics (OHDSI) framework for external validation to assess the reliability of the C-19 index. We evaluated the model on two different target populations, 41,381 patients who presented with SARS-CoV-2 at an outpatient or emergency department visit and 9,429,285 patients who presented with influenza or related symptoms during an outpatient or emergency department visit, to predict their risk of hospitalization with pneumonia during the following 0-30 days. In total, we validated the model across a network of 14 databases spanning the United States, Europe, Australia, and Asia., Results: The internal validation performance of the C-19 index had a C statistic of 0.73, and the calibration was not reported by the authors. When we externally validated it by transporting it to SARS-CoV-2 data, the model obtained C statistics of 0.36, 0.53 (0.473-0.584) and 0.56 (0.488-0.636) on Spanish, US, and South Korean data sets, respectively. The calibration was poor, with the model underestimating risk. When validated on 12 data sets containing influenza patients across the OHDSI network, the C statistics ranged between 0.40 and 0.68., Conclusions: Our results show that the discriminative performance of the C-19 index model is low for influenza cohorts and even worse among patients with COVID-19 in the United States, Spain, and South Korea. These results suggest that C-19 should not be used to aid decision-making during the COVID-19 pandemic. Our findings highlight the importance of performing external validation across a range of settings, especially when a prediction model is being extrapolated to a different population. In the field of prediction, extensive validation is required to create appropriate trust in a model., (©Jenna M Reps, Chungsoo Kim, Ross D Williams, Aniek F Markus, Cynthia Yang, Talita Duarte-Salles, Thomas Falconer, Jitendra Jonnagaddala, Andrew Williams, Sergio Fernández-Bertolín, Scott L DuVall, Kristin Kostka, Gowtham Rao, Azza Shoaibi, Anna Ostropolets, Matthew E Spotnitz, Lin Zhang, Paula Casajust, Ewout W Steyerberg, Fredrik Nyberg, Benjamin Skov Kaas-Hansen, Young Hwa Choi, Daniel Morales, Siaw-Teng Liaw, Maria Tereza Fernandes Abrahão, Carlos Areia, Michael E Matheny, Kristine E Lynch, María Aragón, Rae Woong Park, George Hripcsak, Christian G Reich, Marc A Suchard, Seng Chan You, Patrick B Ryan, Daniel Prieto-Alhambra, Peter R Rijnbeek. Originally published in JMIR Medical Informatics (http://medinform.jmir.org), 05.04.2021.)

Alpha-1 blockers, often used to treat benign prostate hyperplasia (BPH), have been hypothesized to prevent COVID-19 complications by minimising cytokine storms release. We conducted a prevalent-user active-comparator cohort study to assess association between alpha-1 blocker use and risks of three COVID-19 outcomes: diagnosis, hospitalization, and hospitalization requiring intensive services. Our study included 2.6 and 0.46 million users of alpha-1 blockers and of alternative BPH therapy during the period between November 2019 and January 2020, found in electronic health records from Spain (SIDIAP) and the United States (Department of Veterans Affairs, Columbia University Irving Medical Center, IQVIA OpenClaims, Optum DOD, Optum EHR). We estimated hazard ratios using state-of-the-art techniques to minimize potential confounding, including large-scale propensity score matching/stratification and negative control calibration. We found no differential risk for any of COVID-19 outcome, pointing to the need for further research on potential COVID-19 therapies.

Background: Routinely collected real world data (RWD) have great utility in aiding the novel coronavirus disease (COVID-19) pandemic response [1,2]. Here we present the international Observational Health Data Sciences and Informatics (OHDSI) [3] Characterizing Health Associated Risks, and Your Baseline Disease In SARS-COV-2 (CHARYBDIS) framework for standardisation and analysis of COVID-19 RWD. Methods: We conducted a descriptive cohort 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 11 th June 2020 and are iteratively updated via GitHub [4]. Findings: 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 . All comorbidities, symptoms, medications, and outcomes are described by cohort in aggregate counts, and are available in an interactive website: https://data.ohdsi.org/Covid19CharacterizationCharybdis/. Interpretation: CHARYBDIS findings provide benchmarks that contribute to our understanding of COVID-19 progression, management and evolution over time. This can enable timely assessment of real-world outcomes of preventative and therapeutic options as they are introduced in clinical practice.

Objective: To estimate the proportion of patients hospitalized with COVID-19 who undergo dialysis, tracheostomy, and extracorporeal membrane oxygenation (ECMO)., Design: A network cohort study., Setting: Seven databases from the United States containing routinely-collected patient data: HealthVerity, Premier, IQVIA Hospital CDM, IQVIA Open Claims, Optum EHR, Optum SES, and VA-OMOP., Patients: Patients hospitalized with a clinical diagnosis or a positive test result for COVID-19., Interventions: Dialysis, tracheostomy, and ECMO., Measurements and Main Results: 842,928 patients hospitalized with COVID-19 were included (22,887 from HealthVerity, 77,853 from IQVIA Hospital CDM, 533,997 from IQVIA Open Claims, 36,717 from Optum EHR, 4,336 from OPTUM SES, 156,187 from Premier, and 10,951 from VA-OMOP). Across the six databases, 35,192 (4.17% [95% CI: 4.13% to 4.22%]) patients received dialysis, 6,950 (0.82% [0.81% to 0.84%]) had a tracheostomy, and 1,568 (0.19% [95% CI: 0.18% to 0.20%]) patients underwent ECMO over the 30 days following hospitalization. Use of ECMO was more common among patients who were younger, male, and with fewer comorbidities. Tracheostomy was broadly used for a similar proportion of patients regardless of age, sex, or comorbidity. While dialysis was generally used for a similar proportion among younger and older patients, it was more frequent among male patients and among those with chronic kidney disease., Conclusion: Use of dialysis among those hospitalized with COVID-19 is high at around 4%. Although less than one percent of patients undergo tracheostomy and ECMO, the absolute numbers of patients who have undergone these interventions is substantial., Competing Interests: Competing interests All authors have completed the ICMJE uniform disclosure form, with the following declarations made: AS reports personal fees from Janssen Research & Development, during the conduct of the study; personal fees from Janssen Research & Development, outside the submitted work. AS is a full time employee of Janssen and shareholder of Johnson & Johnson. SDV reports grants from Anolinx, LLC, grants from Astellas Pharma, Inc, grants from AstraZeneca Pharmaceuticals LP, grants from Boehringer Ingelheim International GmbH, grants from Celgene Corporation, grants from Eli Lilly and Company, grants from Genentech Inc., , grants from Genomic Health, Inc., grants from Gilead Sciences Inc., grants from GlaxoSmithKline PLC, grants from Innocrin Pharmaceuticals Inc., grants from Janssen Pharmaceuticals, Inc., grants from Kantar Health, grants from Myriad Genetic Laboratories, Inc., grants from Novartis International AG, grants from Parexel International Corporation through the University of Utah or Western Institute for Biomedical Research outside the submitted work. MEM has nothing to disclose. CR is an employee of IQVIA. CB reports other from Janssen, Research and Development, outside the submitted work; and full time employee of Janssen R&D and Johnson & Johnson shareholder. AA reports other from Janssen, Research and Development, outside the submitted work; and full time employee of Janssen R&D and Johnson & Johnson shareholder. SF reports other from Janssen, outside the submitted work. AG reports personal fees from Regeneron Pharmaceuticals, outside the submitted work. She is a full-time employee at Regeneron Pharmaceuticals. This work was not conducted at Regeneron Pharmaceuticals. DM is supported by a Wellcome Trust Clinical Research Development Fellowship (Grant 214588/Z/18/Z) and reports grants from Chief Scientist Office (CSO), grants from Health Data Research UK (HDR-UK), grants from Tenovus, grants from National Institute of Health Research (NIHR), outside the submitted work. PR reports grants from Innovative Medicines Initiative, grants from Janssen Research and Development, during the conduct of the study. VS reports grants from National Science Foundation, grants from State of Arizona; Arizona Board of Regents, grants from Agency for Healthcare Research and Quality, outside the submitted work. DV reports personal fees from Bayer, outside the submitted work; and he is a full-time employee at a pharmaceutical company. GH reports grants from US NIH National Library of Medicine, during the conduct of the study; grants from Janssen Research, outside the submitted work. MAS reports grants from US National Science Foundation, grants from US National Institutes of Health, grants from IQVIA, personal fees from Janssen Research and Development, during the conduct of the study .PR reports and is employee of Janssen Research and Development and shareholder of Johnson & Johnson. DPA reports grants and other from AMGEN, grants, non-financial support and other from UCB Biopharma, grants from Les Laboratoires Servier, outside the submitted work; and Janssen, on behalf of IMI-funded EHDEN and EMIF consortiums, and Synapse Management Partners have supported training programmes organised by DPA’s department and open for external participants. KK reports she is an employee of IQVIA. All other authors declare no competing interests.

The natural history of coronavirus disease 2019 (COVID-19) has yet to be fully described. Here, we use patient-level data from the Information System for Research in Primary Care (SIDIAP) to summarise COVID-19 outcomes in Catalonia, Spain. We included 5,586,521 individuals from the general population. Of these, 102,002 had an outpatient diagnosis of COVID-19, 16,901 were hospitalised with COVID-19, and 5273 died after either being diagnosed or hospitalised with COVID-19 between 1st March and 6th May 2020. Older age, being male, and having comorbidities were all generally associated with worse outcomes. These findings demonstrate the continued need to protect those at high risk of poor outcomes, particularly older people, from COVID-19 and provide appropriate care for those who develop symptomatic disease. While risks of hospitalisation and death were lower for younger populations, there is a need to limit their role in community transmission.

Hepatocellular carcinoma (HCC) development entails changes in liver metabolism. Current knowledge on metabolic perturbations in HCC is derived mostly from case-control designs, with sparse information from prospective cohorts. Our objective was to apply comprehensive metabolite profiling to detect metabolites whose serum concentrations are associated with HCC development, using biological samples from within the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (>520 000 participants), where we identified 129 HCC cases matched 1:1 to controls. We conducted high-resolution untargeted liquid chromatography-mass spectrometry-based metabolomics on serum samples collected at recruitment prior to cancer diagnosis. Multivariable conditional logistic regression was applied controlling for dietary habits, alcohol consumption, smoking, body size, hepatitis infection and liver dysfunction. Corrections for multiple comparisons were applied. Of 9206 molecular features detected, 220 discriminated HCC cases from controls. Detailed feature annotation revealed 92 metabolites associated with HCC risk, of which 14 were unambiguously identified using pure reference standards. Positive HCC-risk associations were observed for N1-acetylspermidine, isatin, p-hydroxyphenyllactic acid, tyrosine, sphingosine, l,l-cyclo(leucylprolyl), glycochenodeoxycholic acid, glycocholic acid and 7-methylguanine. Inverse risk associations were observed for retinol, dehydroepiandrosterone sulfate, glycerophosphocholine, γ-carboxyethyl hydroxychroman and creatine. Discernible differences for these metabolites were observed between cases and controls up to 10 years prior to diagnosis. Our observations highlight the diversity of metabolic perturbations involved in HCC development and replicate previous observations (metabolism of bile acids, amino acids and phospholipids) made in Asian and Scandinavian populations. These findings emphasize the role of metabolic pathways associated with steroid metabolism and immunity and specific dietary and environmental exposures in HCC development., (© 2020 UICC.)

Background: Currently, there is a missing link in the natural history of COVID-19, from first (usually milder) symptoms to hospitalization and/or death. To fill in this gap, we characterized COVID-19 patients at the time at which they were diagnosed in outpatient settings and estimated 30-day hospital admission and fatality rates., Methods: This was a population-based cohort study., Data were obtained from Information System for Research in Primary Care (SIDIAP)-a primary-care records database covering >6 million people (>80% of the population of Catalonia), linked to COVID-19 reverse transcriptase polymerase chain reaction (RT-PCR) tests and hospital emergency, inpatient and mortality registers. We included all patients in the database who were ≥15 years old and diagnosed with COVID-19 in outpatient settings between 15 March and 24 April 2020 (10 April for outcome studies). Baseline characteristics included socio-demographics, co-morbidity and previous drug use at the time of diagnosis, and polymerase chain reaction (PCR) testing and results., Study outcomes included 30-day hospitalization for COVID-19 and all-cause fatality., Results: We identified 118 150 and 95 467 COVID-19 patients for characterization and outcome studies, respectively. Most were women (58.7%) and young-to-middle-aged (e.g. 21.1% were 45-54 years old). Of the 44 575 who were tested with PCR, 32 723 (73.4%) tested positive. In the month after diagnosis, 14.8% (14.6-15.0) were hospitalized, with a greater proportion of men and older people, peaking at age 75-84 years. Thirty-day fatality was 3.5% (95% confidence interval: 3.4% to 3.6%), higher in men, increasing with age and highest in those residing in nursing homes [24.5% (23.4% to 25.6%)]., Conclusion: COVID-19 infections were widespread in the community, including all age-sex strata. However, severe forms of the disease clustered in older men and nursing-home residents. Although initially managed in outpatient settings, 15% of cases required hospitalization and 4% died within a month of first symptoms. These data are instrumental for designing deconfinement strategies and will inform healthcare planning and hospital-bed allocation in current and future COVID-19 outbreaks., (© The Author(s) 2020. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: A high body mass index (BMI) has been associated with increased risk of several cancers; however, whether BMI is related to a larger number of cancers than currently recognized is unclear. Moreover, whether waist circumference (WC) is more strongly associated with specific cancers than BMI is not well established. We aimed to investigate the associations between BMI and 26 cancers accounting for non-linearity and residual confounding by smoking status as well as to compare cancer risk estimates between BMI and WC., Methods: Prospective cohort study with population-based electronic health records from Catalonia, Spain. We included 3,658,417 adults aged ≥ 18 years and free of cancer at baseline between 2006 and 2017. Our main outcome measures were cause-specific hazard ratios (HRs) with 99% confidence intervals (CIs) for incident cancer at 26 anatomical sites., Results: After a median follow-up time of 8.3 years, 202,837 participants were diagnosed with cancer. A higher BMI was positively associated with risk of nine cancers (corpus uteri, kidney, gallbladder, thyroid, colorectal, breast post-menopausal, multiple myeloma, leukemia, non-Hodgkin lymphoma) and was positively associated with three additional cancers among never smokers (head and neck, brain and central nervous system, Hodgkin lymphoma). The respective HRs (per 5 kg/m 2 increment) ranged from 1.04 (99%CI 1.01 to 1.08) for non-Hodgkin lymphoma to 1.49 (1.45 to 1.53) for corpus uteri cancer. While BMI was negatively associated to five cancer types in the linear analyses of the overall population, accounting for non-linearity revealed that BMI was associated to prostate cancer in a U-shaped manner and to head and neck, esophagus, larynx, and trachea, bronchus and lung cancers in an L-shaped fashion, suggesting that low BMIs are an approximation of heavy smoking. Of the 291,305 participants with a WC measurement, 27,837 were diagnosed with cancer. The 99%CIs of the BMI and WC point estimates (per 1 standard deviation increment) overlapped for all cancers., Conclusions: In this large Southern European study, a higher BMI was associated with increased risk of twelve cancers, including four hematological and head and neck (only among never smokers) cancers. Furthermore, BMI and WC showed comparable estimates of cancer risk associated with adiposity.

Background: The Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) is a public-private collaboration aiming to develop and test a system for rapid benefit-risk (B/R) monitoring of vaccines using electronic health record (eHR) databases in Europe. Proof-of-concept studies were designed to assess the proposed processes and system for generating the required evidence to perform B/R assessment and near-real time monitoring of vaccines. We aimed to test B/R methodologies for vaccines, using the comparison of the B/R profiles of whole-cell (wP) and acellular pertussis (aP) vaccine formulations in children as an example., Methods: We used multi-criteria decision analysis (MCDA) to structure the B/R assessment combined with individual-level state transition modelling to build the B/R effects table. In the state transition model, we simulated the number of events in two hypothetical cohorts of 1 million children followed from first pertussis dose till pre-school-entry booster (or six years of age, whichever occurred first), with one cohort receiving wP, and the other aP. The benefits were reductions in pertussis incidence and complications. The risks were increased incidences of febrile convulsions, fever, hypotonic-hyporesponsive episodes, injection-site reactions and persistent crying. Most model parameters were informed by estimates (coverage, background incidences, relative risks) from eHR databases from Denmark (SSI), Spain (BIFAP and SIDIAP), Italy (Pedianet) and the UK (RCGP-RSC and THIN). Preferences were elicited from clinical and epidemiological experts., Results: Using state transition modelling to build the B/R effects table facilitated the comparison of different vaccine effects (e.g. immediate vaccine risks vs long-term vaccine benefits). Estimates from eHR databases could be used to inform the simulation model. The model results could be easily combined with preference weights to obtain B/R scores., Conclusion: Existing B/R methodology, modelling and estimates from eHR databases can be successfully used for B/R assessment of vaccines., Competing Interests: Declaration of Competing Interest Tom de Smedt, Hanne-Dorthe Emborg, Giorgia Danieli, Talita Duarte-Salles, Consuelo Huerta, Elisa Martin-Merino, Gino Picelli and Lara Tramontan declared no potential conflicts of interest. Kaatje Bollaerts and Daniel Weibel received consultancy fees from GSK for work unrelated to the submitted work. Miriam Sturkenboom declared that she has received grants from Novartis, CDC and Bill & Melinda Gates Foundation, for work unrelated to the submitted work. Edouard Ledent and Vincent Bauchau declared that he is employed by GSK and holds company shares., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) is a public-private partnership aiming to develop and test a system for rapid benefit-risk (B/R) monitoring of vaccines using European electronic health record (eHR) databases. This proof-of-concept study aimed to test the feasibility of near real-time (NRT) monitoring of vaccination coverage, benefits and risks based on multiple European eHR databases, using acellular pertussis vaccination in children aged <6 years as test case., Methods: A qualitative feasibility assessment on NRT monitoring was carried out using a survey and face-to-face discussion with ADVANCE data partners. Subsequently, a dynamic cohort study was conducted containing two distinct observation periods: a first period to establish a baseline (Jan 2014 to Mar 2018) and a subsequent 3-month period to test the actual feasibility of weekly NRT monitoring, based on which data latencies were calculated. An interactive web-application was additionally developed to facilitate the visual monitoring of vaccination coverage, the vaccine preventable disease incidence rates (benefits) and the incidence rates of adverse events (risks)., Results: Nine databases from four countries (Denmark, Italy, Spain and UK) participated in the qualitative feasibility assessment. Of them, five databases took part in the dynamic cohort study, with 5 databases providing baseline data and 3 databases participating to the NRT monitoring, providing data extractions on an almost weekly basis. The median data latency (time between event date and data release date) was between 1 and 2 weeks except for the benefit and risk events in one of the databases (latency 16 weeks)., Conclusion: Three European eHR databases successfully demonstrated the feasibility of providing data for weekly NRT monitoring, with short data latencies of 1-2 weeks for most events., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tom de Smedt, Chris McGee, Hanne-Dorthe Emborg, Marco Villa, Talita Duarte-Salles, declared no potential conflicts of interest. Kaatje Bollaerts and Maria Alexandridou received consultancy fees from GSK for work unrelated to the submitted work. Rosa Gini declared that her institution is participating in studies funded by Novartis, Eli Lilly, and Daiichi outside the scope of this project. Claudia Bartolini declared she has received grants from PHARMO Institute for work outside the submitted work. Simon de Lusignan declared he has received funding through his University to conduct enhanced surveillance of influenza vaccine (GSK), and is a member Seqirus and Sanofi Pasteur advisory boards for which he received personal payment within the limits defined by his university. Myint TinTin Htar declared that she is employed by Pfizer and holds company shares. Miriam Sturkenboom declared that she has received grants from Novartis, CDC and Bill & Melinda Gates Foundation, for work unrelated to the submitted work. Lina Titievsky declared that she is employed by Pfizer and holds company stocks/shares. Vincent Bauchau declared that he is employed by GSK and holds company shares., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The Accelerated Development of VAccine benefit-risk Collaboration in Europe (ADVANCE), a public-private consortium, implemented and tested a distributed network system for the generation of evidence on the benefits-risks of marketed vaccines in Europe. We tested the system by estimating the incidence rate (IR) of pertussis and pertussis-related complications in children vaccinated with acellular (aP) and whole-cell (wP) pertussis vaccine. Data from seven electronic databases from four countries (Denmark: AUH and SSI, Spain: SIDIAP and BIFAP, UK: THIN and RCGP RSC and Italy: Pedianet) were included in a retrospective cohort analysis. Exposure was defined as any pertussis vaccination (aP or wP). The follow-up time started 14 days after the first dose. Children who had received any pertussis vaccine from January 1990 to December 2015 were included (those who switched type, or had unknown type were excluded). The outcomes of interest were confirmed or suspected pertussis and pertussis-related pneumonia and generalised convulsions within one month of pertussis diagnosis and death within three months of pertussis diagnosis. The cohort comprised 2,886,367 children ≤5 years of age. Data on wP and aP vaccination were available in three and seven databases, respectively. The IRs (per 100,000 person-years) for pertussis varied largely and ranged between 0.15 (95% CI: 0.12; 0.19) and 1.15 (95% CI: 1.07; 1.23), and the trends over time was consistent with those observed from national surveillance databases for confirmed pertussis. The pertussis IRs decreased as the number of wP and aP vaccine doses increased. Pertussis-related complications were rare (89 pneumonia, 7 generalised convulsions and no deaths) and their relative risk (vs. non-pertussis) could not be reliably estimated. The study demonstrated the feasibility of the ADVANCE system to estimate the change in pertussis IRs following pertussis vaccination. Larger sample sizes would provide additional power to compare the risk for complications between children with and without pertussis. The feasibility of vaccine-type specific effectiveness studies may be considered in the future., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Maria de Ridder, Toon Braeye, Ana Correa, Chris McGee, Talita Duarte-Salles, Consuelo Huerta, Elisa Martín-Merino, Lara Tramontan, Giorgia Danieli, Gino Picelli, Nicoline van der Maas, Klara Berensci, Hanne-Dorthe Emborg, Daniel Weibel and Kaat Bollaerts declared no conflicts of interest. Myint Tin Tin Htar is employed by Pfizer and holds company shares/stock options. Simon de Lusignan declared he has received funding through his University to conduct enhanced surveillance of influenza vaccine (GSK), and is a member Seqirus and Sanofi Pasteur advisory boards for which he received personal payment within the limits defined by his university. Lisen Arnheim-Dahlström declared that her organisation has received funding from SPMSD, MSD and GSK for population-based, observational studies that she has conducted and that she is currently employed by Celgene AB. Ulrich Heininger declared that he is a member of the Global Pertussis Initiative (GPI) Steering Committee, which is funded by an educational grant from Sanofi Pasteur. Miriam Sturkenboom declared that she has received grants from Novartis, CDC and Bill & Melinda Gates Foundation, for work unrelated to the submitted work., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) is a public-private collaboration aiming to develop and test a system for rapid vaccine benefit-risk monitoring using existing European healthcare databases. Incidence rate (IR) estimates of vaccination-associated adverse events that are needed to model vaccination risks can be calculated from existing healthcare databases when vaccination (exposure) data are available. We assessed different methods to derive IRs in risk periods following vaccination when exposure data are missing in one database, using estimated IRs and IRRs from other databases for febrile seizures, fever and persistent crying. IRs were estimated for children aged 0-5 years in outcome-specific risk and non-risk periods following the first dose of acellular pertussis (aP) vaccination in four primary care databases and one hospital database. We compared derived and observed IRs in each database using three methods: 1) multiplication of non-risk period IR for database i by IR ratio (IRR) obtained from meta-analysis of IRRs estimated using the self-controlled case-series method, from databases other than i; 2) same method as 1, but multiplying with background IR; and 3) meta-analyses of observed IRs from databases other than i. IRs for febrile seizures were lower in primary care databases than the hospital database. The derived IR for febrile seizures using data from primary care databases was lower than that observed in the hospital database, and using data from the hospital database gave a higher derived IR than that observed in the primary care database. For fever and persistent crying the opposite was observed. We demonstrated that missing IRs for a post-vaccination period can be derived but that the type of database and the method of event data capture can have an impact on potential bias. We recommend IRs are derived using data from similar database types (hospital or primary care) with caution as even this can give heterogeneous results., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Caitlin Dodd, Maria de Ridder, Tom de Smedt, Chris McGee, Talita Duarte-Salles, Hanne-Dorthe Emborg, Consuelo Huerta, Elisa Martín-Merino, Gino Picelli, Klara Berencsi, Giorgia Danieli declared that they have no potential conflicts of interest. Daniel Weibel declared that he has received personal fees from GSK for work unrelated to the submitted work. Olivia Mahaux and Francois Haguinet declared that they are employed by GSK and hold company shares. Simon de Lusignan declared that he has received grants from GSK, Takeda, and Seqirus / JSS, and also personal fees from Sequirus and Sanofi, for work unrelated to the submitted work. Miriam Sturkenboom declared that she has received grants from Novartis, CDC and Bill & Melinda Gates Foundation, for work unrelated to the submitted work]., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) is a public-private collaboration aiming to develop and test a system for rapid benefit-risk (B/R) monitoring of vaccines using European healthcare databases. Event misclassification can result in biased estimates. Using different algorithms for identifying cases of Bordetella pertussis (BorPer) infection as a test case, we aimed to describe a strategy to quantify event misclassification, when manual chart review is not feasible., Methods: Four participating databases retrieved data from primary care (PC) setting: BIFAP: (Spain), THIN and RCGP RSC (UK) and PEDIANET (Italy); SIDIAP (Spain) retrieved data from both PC and hospital settings. BorPer algorithms were defined by healthcare setting, data domain (diagnoses, drugs, or laboratory tests) and concept sets (specific or unspecified pertussis). Algorithm- and database-specific BorPer incidence rates (IRs) were estimated in children aged 0-14 years enrolled in 2012 and 2014 and followed up until the end of each calendar year and compared with IRs of confirmed pertussis from the ECDC surveillance system (TESSy). Novel formulas were used to approximate validity indices, based on a small set of assumptions. They were applied to approximately estimate positive predictive value (PPV) and sensitivity in SIDIAP., Results: The number of cases and the estimated BorPer IRs per 100,000 person-years in PC, using data representing 3,173,268 person-years, were 0 (IR = 0.0), 21 (IR = 4.3), 21 (IR = 5.1), 79 (IR = 5.7), and 2 (IR = 2.3) in BIFAP, SIDIAP, THIN, RCGP RSC and PEDIANET respectively. The IRs for combined specific/unspecified pertussis were higher than TESSy, suggesting that some false positives had been included. In SIDIAP the estimated IR was 45.0 when discharge diagnoses were included. The sensitivity and PPV of combined PC specific and unspecific diagnoses for BorPer cases in SIDIAP were approximately 85% and 72%, respectively., Conclusion: Retrieving BorPer cases using only specific concepts has low sensitivity in PC databases, while including cases retrieved by unspecified concepts introduces false positives, which were approximately estimated to be 28% in one database. The share of cases that cannot be retrieved from a PC database because they are only seen in hospital was approximately estimated to be 15% in one database. This study demonstrated that quantifying the impact of different event-finding algorithms across databases and benchmarking with disease surveillance data can provide approximate estimates of algorithm validity., Competing Interests: Declaration of Competing Interest Caitlin Dodd, Kaatje Bollaerts, Claudia Bartolini, Giuseppe Roberto, Consuelo Huerta-Alvarez, Elisa Martín-Merino, Talita Duarte-Salles, Gino Picelli, Lara Tramontan, Giorgia Danieli, Ana Correa, Chris McGee, Benedikt Becker, Charlotte Switzer, Jorgen Bauwens, Nicoline van der Maas, Gianfranco Spiteri, Emmanouela Sdona declared no conflicts of interest. Rosa Gini declared that her institution participates in studies funded by Novartis, Eli Lilly, Daiichi Sankyo, compliant with the ENCePP Code of Conduct. Sonja Gandhi-Banga declared that she works for Sanofi Pasteur and holds company shares. Daniel Weibel declared that he has received personal fees from GSK for work unrelated to the submitted work. Miriam Sturkenboom declared that she has received grants from Novartis, CDC and Bill & Melinda Gates Foundation for work unrelated to the submitted work., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The Accelerated Development of Vaccine benefit-risk Collaboration in Europe (ADVANCE) public-private collaboration, aimed to develop and test a system for rapid benefit-risk monitoring of vaccines using healthcare databases in Europe. The objective of this proof-of-concept (POC) study was to test the feasibility of the ADVANCE system to generate incidence rates (IRs) per 1000 person-years and incidence rate ratios (IRRs) for risks associated with whole cell- (wP) and acellular- (aP) pertussis vaccines, occurring in event-specific risk windows in children prior to their pre-school-entry booster., Methods: The study population comprised almost 5.1 million children aged 1 month to <6 years vaccinated with wP or aP vaccines during the study period from 1 January 1990 to 31 December 2015. Data from two Danish hospital (H) databases (AUH and SSI) and five primary care (PC) databases from, UK (THIN and RCGP RSC), Spain (SIDIAP and BIFAP) and Italy (Pedianet) were analysed. Database-specific IRRs between risk vs. non-risk periods were estimated in a self-controlled case series study and pooled using random-effects meta-analyses., Results: The overall IRs were: fever, 58.2 (95% CI: 58.1; 58.3), 96.9 (96.7; 97.1) for PC DBs and 8.56 (8.5; 8.6) for H DBs; convulsions, 7.6 (95% CI: 7.6; 7.7), 3.55 (3.5; 3.6) for PC and 12.87 (12.8; 13) for H; persistent crying, 3.9 (95% CI: 3.8; 3.9) for PC, injection-site reactions, 2.2 (95% CI 2.1; 2.2) for PC, hypotonic hypo-responsive episode (HHE), 0.4 (95% CI: 0.4; 0.4), 0.6 (0.6; 0.6) for PC and 0.2 (0.2; 0.3) for H; and somnolence: 0.3 (95% CI: 0.3; 0.3) for PC. The pooled IRRs for persistent crying, fever, and ISR, adjusted for age and healthy vaccinee period were higher after wP vs. aP vaccination, and lower for convulsions, for all doses. The IRR for HHE was slightly lower for wP than aP, while wP was associated with somnolence only for dose 1 and dose 3 compared with aP., Conclusions: The estimated IRs and IRRs were comparable with published data, therefore demonstrating that the ADVANCE system was able to combine several European healthcare databases to assess vaccine safety data for wP and aP vaccination., Competing Interests: Declaration of Competing Interest Caitlin Dodd, Talita Duarte-Salles, Gino Picelli, Lara Tramontan, Giorgia Danieli, Ana Correa, Chris McGee, Elisa Martín-Merino, Consuelo Huerta, Hanne-Dorthe Emborg, Kaatje Bollaerts, Klara Berencsi declared no conflicts of interest. Daniel Weibel declared personal fees from GSK outside the submitted work. Olivia Mahaux, Francois Haguinet and Vincent Bauchau declared that they are employed by GSK and hold shares from GSK. Lina Titievsky declared that she is employed Pfizer and holds stocks from Pfizer. Miriam Sturkenboom declared that she has received grants from Novartis, CDC and the Bill & Melinda Gates Foundation outside the submitted work., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The public-private ADVANCE consortium (Accelerated development of vaccine benefit-risk collaboration in Europe) aimed to assess if electronic healthcare databases can provide fit-for purpose data for collaborative, distributed studies and monitoring of vaccine coverage, benefits and risks of vaccines., Objective: To evaluate if European healthcare databases can be used to estimate vaccine coverage, benefit and/or risk using pertussis-containing vaccines as an example., Methods: Characterisation was conducted using open-source Java-based (Jerboa) software and R scripts. We obtained: (i) The general characteristics of the database and data source (meta-data) and (ii) a detailed description of the database population (size, representatively of age/sex of national population, rounding of birth dates, delay between birth and database entry), vaccinations (number of vaccine doses, recording of doses, pattern of doses by age and coverage) and events of interest (diagnosis codes, incidence rates). A total of nine databases (primary care, regional/national record linkage) provided data on events (pertussis, pneumonia, death, fever, convulsions, injection site reactions, hypotonic hypo-responsive episode, persistent crying) and vaccines (acellular pertussis and whole cell pertussis) related to the pertussis proof of concept studies., Results: The databases contained data for a total population of 44 million individuals. Seven databases had recorded doses of vaccines. The pertussis coverage estimates were similar to those reported by the World Health Organisation (WHO). Incidence rates of events were comparable in magnitude and age-distribution between databases with the same characteristics. Several conditions (persistent crying and somnolence) were not captured by the databases for which outcomes were restricted to hospital discharge diagnoses., Conclusion: The database characterisation programs and workflows allowed for an efficient, transparent and standardised description and verification of electronic healthcare databases which may participate in pertussis vaccine coverage, benefit and risk studies. This approach is ready to be used for other vaccines/events to create readiness for participation in other vaccine related studies., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Toon Braeye, Lieke van der Aa, Giorgia Danieli, Caitlin Dodd, Talita Duarte-Salles, Hanne- Dorthe Emborg, Marius Gheorge, Consuelo Huerta, Elisa Martín-Merino, Chris McGee, Gino Picelli Giuseppe Roberto, Lara Tramontan, Marco Villa and Daniel Weibel declared no potential conflicts of interest. Miriam Sturkenboom, declared that she has received grants from Novartis, CDC and Bill & Melinda Gates Foundation, for work unrelated to the submitted work. Johnny Kahlert declared that he is employed at Department of Clinical Epidemiology, Aarhus University Hospital, which is involved in studies with research grants from various companies that are administered by Aarhus University; he does not receive fees, honoraria, grants or consultancies personally. Simon de Lusignan declared that he is Director of RCGP RSC that he has received funding through his University for vaccine-related studies from GSK and Seqirus and he is also a member of advisory groups for Seqirus and Sanofi. Lina Titievsky declared that she is employed by Pfizer and holds company stocks/shares. Rosa Gini's institution is involved in studies funded by Novartis, Eli Lilly, and Daiichi, compliant with the ENCePP CoC“., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)

Introduction: The Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) is a public-private collaboration aiming to develop and test a system for rapid benefit-risk (B/R) monitoring of vaccines, using existing healthcare databases in Europe. The objective of this paper was to assess the feasibility of using electronic healthcare databases to estimate dose-specific acellular pertussis (aP) and whole cell pertussis (wP) vaccine coverage., Methods: Seven electronic healthcare databases in four European countries (Denmark (n = 2), UK (n = 2), Spain (n = 2) and Italy (n = 1)) participated in this study. Children were included from birth and followed up to age six years. Vaccination exposure was obtained from the databases and classified by type (aP or wP), and dose 1, 2 or 3. Coverage was estimated using period prevalence. For the 2006 birth cohort, two estimation methods for pertussis vaccine coverage, period prevalence and cumulative incidence were compared for each database., Results: The majority of the 2,575,576 children included had been vaccinated at the country-specific recommended ages. Overall, the estimated dose 3 coverage was 88-97% in Denmark (birth cohorts from 2003 to 2014), 96-100% in the UK (2003-2014), 95-98% in Spain (2004-2014) and 94% in Italy (2006-2007). The estimated dose 3 coverage per birth cohort in Denmark and the UK differed by 1-6% compared with national estimates, with our estimates mostly higher. The estimated dose 3 coverage in Spain differed by 0-2% with no consistent over- or underestimation. In Italy, the estimates were 3% lower compared with the national estimates. Except for Italy, for which the two coverage estimation methods generated the same results, the estimated cumulative incidence coverages were consistently 1-10% lower than period prevalence estimates., Conclusion: This study showed that it was possible to provide consistent estimates of pertussis immunisation coverage from the electronic healthcare databases included, and that the estimates were comparable with the national estimates., Competing Interests: Declaration of Competing Interest Hanne-Dorthe Emborg, Toon Braeye, Jorgen Bauwens, Kaatje Bollaerts, Giorgia Danieli, Talita Duarte-Salles, Consuelo Huerta Elisa Martin, Chris McGee, Ana Correa and Lara Tramontan declared no conflicts of interest. Johnny Kahlert declared that although he does not personally receive fees, honoraria, or grants he is employed at Department of Clinical Epidemiology, Aarhus University Hospital that receives research grants from various pharmaceutical companies administered by Aarhus University. Steffen Glismann is employed by the GSK group of companies and holds company shares. Simon de Lusignan declared he has received funding through his University to conduct enhanced surveillance of influenza vaccine (GSK), and is a member of Seqirus and Sanofi Pasteur advisory boards for which he received personal payment within the limits defined by his university. Daniel Weibel declared that he has received consultancy fees from GSK unrelated to the submitted work. Miriam Sturkenboom declared that she has received grants from Novartis, CDC and Bill & Melinda Gates Foundation, for work unrelated to the submitted work., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Patients with autoimmune diseases were advised to shield to avoid COVID-19, but information on their prognosis is lacking. We characterised 30-day outcomes and mortality after hospitalisation with COVID-19 among patients with prevalent autoimmune diseases, and compared outcomes after hospital admissions among similar patients with seasonal influenza., Design: Multinational network cohort study., Setting: Electronic health records data from Columbia University Irving Medical Center (CUIMC) (NYC, United States [US]), Optum [US], Department of Veterans Affairs (VA) (US), Information System for Research in Primary Care-Hospitalisation Linked Data (SIDIAP-H) (Spain), and claims data from IQVIA Open Claims (US) and Health Insurance and Review Assessment (HIRA) (South Korea)., Participants: All patients with prevalent autoimmune diseases, diagnosed and/or hospitalised between January and June 2020 with COVID-19, and similar patients hospitalised with influenza in 2017-2018 were included., Main Outcome Measures: 30-day complications during hospitalisation and death., Results: We studied 133,589 patients diagnosed and 48,418 hospitalised with COVID-19 with prevalent autoimmune diseases. The majority of participants were female (60.5% to 65.9%) and aged ≥50 years. The most prevalent autoimmune conditions were psoriasis (3.5 to 32.5%), rheumatoid arthritis (3.9 to 18.9%), and vasculitis (3.3 to 17.6%). Amongst hospitalised patients, Type 1 diabetes was the most common autoimmune condition (4.8% to 7.5%) in US databases, rheumatoid arthritis in HIRA (18.9%), and psoriasis in SIDIAP-H (26.4%).Compared to 70,660 hospitalised with influenza, those admitted with COVID-19 had more respiratory complications including pneumonia and acute respiratory distress syndrome, and higher 30-day mortality (2.2% to 4.3% versus 6.3% to 24.6%)., Conclusions: Patients with autoimmune diseases had high rates of respiratory complications and 30-day mortality following a hospitalization with COVID-19. Compared to influenza, COVID-19 is a more severe disease, leading to more complications and higher mortality. Future studies should investigate predictors of poor outcomes in COVID-19 patients with autoimmune diseases., What Is Already Known About This Topic: Patients with autoimmune conditions may be at increased risk of COVID-19 infection andcomplications.There is a paucity of evidence characterising the outcomes of hospitalised COVID-19 patients with prevalent autoimmune conditions., What This Study Adds: Most people with autoimmune diseases who required hospitalisation for COVID-19 were women, aged 50 years or older, and had substantial previous comorbidities.Patients who were hospitalised with COVID-19 and had prevalent autoimmune diseases had higher prevalence of hypertension, chronic kidney disease, heart disease, and Type 2 diabetes as compared to those with prevalent autoimmune diseases who were diagnosed with COVID-19.A variable proportion of 6% to 25% across data sources died within one month of hospitalisation with COVID-19 and prevalent autoimmune diseases.For people with autoimmune diseases, COVID-19 hospitalisation was associated with worse outcomes and 30-day mortality compared to admission with influenza in the 2017-2018 season.

Objective: Lockdown has impacts on people's living conditions and mental health. The study aims to assess the relations between social impact and mental health among adults living in Spain during COVID-19 lockdown measures, taking a gender-based approach into account., Design, Setting and Participants: We conducted a cross-sectional study among adults living in Spain during the lockdown of COVID-19 with an online survey from 8 April to 28 May 2020. The main variable was mental health measured by Generalized Anxiety Disorder Scale for anxiety and the Patient Health Questionnaire for depression. Sex-stratified multivariate ordinal logistic regression models were constructed to assess the association between social impact variables, anxiety and depression., Results: A total of 7053 people completed this survey. A total of 31.2% of women and 17.7% of men reported anxiety. Depression levels were reported in 28.5% of women and 16.7% of men. A higher proportion of anxiety and depression levels was found in the younger population (18-35 years), especially in women. Poorer mental health was mainly related to fear of COVID-19 infection, with higher anxiety levels especially in women (adjusted ordinal OR (aOR): 4.23, 95% CI 3.68 to 4.87) and worsened economy with higher levels of depression in women (aOR: 1.51, 95% CI 1.24 to 1.84), and perceived inadequate housing to cope with lockdown was especially associated with anxiety in men (aOR: 2.53, 95% CI 1.93 to 3.44)., Conclusion: The social impact of the lockdown is related to gender, age and socioeconomic conditions. Women and young people had worse mental health outcomes during lockdown. It is urgent to establish strategies for public health emergencies that include mental health and its determinants, taking a gender-based approach into account, in order to reduce health inequities., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The objective of the study is to compare body mass index (BMI), systolic/diastolic blood pressure (SBP/DBP) and serum total cholesterol levels between dementia cases and controls at multiple time intervals prior to dementia onset, and to test time interval as a modifying factor for these associations., Design: Case-control study., Setting: Six European electronic health records databases., Participants: 291 780 cases at the date of first-recorded dementia diagnosis, compared with 29 170 549 controls randomly selected from the same databases, age matched and sex matched at this index date., Exposure: The following measures were extracted whenever recorded within each dataset: BMI (kg/m 2 ), SBP and DBP (mm Hg) and serum total cholesterol (mmol/L). Levels for each of these variables were defined within six 2-year time intervals over the 12 years prior to the index date., Main Outcomes: Case-control differences in exposures of interest were modelled for each time period and adjusted for demographic and clinical factors (ischaemic/unspecified stroke, type 2 diabetes mellitus, acute myocardial infarction, hypertension diagnosis, antihypertensive medication, cholesterol-lowering medication). Coefficients and interactions with time period were meta-analysed across the six databases., Results: Mean BMI (coefficient -1.16 kg/m 2 ; 95% CI -1.38 to 0.93) and SBP (-2.83 mm Hg; 95% CI -4.49 to -1.16) were lower in cases at diagnosis, and case-control differences were greater in more recent time periods, as indicated by significant case-x-time interaction and case-x-time-squared interaction terms. Time variations in coefficients for cholesterol levels were less consistent between databases and those for DBP were largely not significant., Conclusion: Routine clinical data show emerging divergence in levels of BMI and SBP prior to the diagnosis of dementia but less evidence for DBP or total cholesterol levels. These divergences should receive at least some consideration in routine dementia risk screening, although underlying mechanisms still require further investigation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: Hydroxychloroquine, a drug commonly used in the treatment of rheumatoid arthritis, has received much negative publicity for adverse events associated with its authorisation for emergency use to treat patients with COVID-19 pneumonia. We studied the safety of hydroxychloroquine, alone and in combination with azithromycin, to determine the risk associated with its use in routine care in patients with rheumatoid arthritis., Methods: In this multinational, retrospective study, new user cohort studies in patients with rheumatoid arthritis aged 18 years or older and initiating hydroxychloroquine were compared with those initiating sulfasalazine and followed up over 30 days, with 16 severe adverse events studied. Self-controlled case series were done to further establish safety in wider populations, and included all users of hydroxychloroquine regardless of rheumatoid arthritis status or indication. Separately, severe adverse events associated with hydroxychloroquine plus azithromycin (compared with hydroxychloroquine plus amoxicillin) were studied. Data comprised 14 sources of claims data or electronic medical records from Germany, Japan, the Netherlands, Spain, the UK, and the USA. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate calibrated hazard ratios (HRs) according to drug use. Estimates were pooled where the I 2 value was less than 0·4., Findings: The study included 956 374 users of hydroxychloroquine, 310 350 users of sulfasalazine, 323 122 users of hydroxychloroquine plus azithromycin, and 351 956 users of hydroxychloroquine plus amoxicillin. No excess risk of severe adverse events was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. Self-controlled case series confirmed these findings. However, long-term use of hydroxychloroquine appeared to be associated with increased cardiovascular mortality (calibrated HR 1·65 [95% CI 1·12-2·44]). Addition of azithromycin appeared to be associated with an increased risk of 30-day cardiovascular mortality (calibrated HR 2·19 [95% CI 1·22-3·95]), chest pain or angina (1·15 [1·05-1·26]), and heart failure (1·22 [1·02-1·45])., Interpretation: Hydroxychloroquine treatment appears to have no increased risk in the short term among patients with rheumatoid arthritis, but in the long term it appears to be associated with excess cardiovascular mortality. The addition of azithromycin increases the risk of heart failure and cardiovascular mortality even in the short term. We call for careful consideration of the benefit-risk trade-off when counselling those on hydroxychloroquine treatment., Funding: National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, NIHR Senior Research Fellowship programme, US National Institutes of Health, US Department of Veterans Affairs, Janssen Research and Development, IQVIA, Korea Health Industry Development Institute through the Ministry of Health and Welfare Republic of Korea, Versus Arthritis, UK Medical Research Council Doctoral Training Partnership, Foundation Alfonso Martin Escudero, Innovation Fund Denmark, Novo Nordisk Foundation, Singapore Ministry of Health's National Medical Research Council Open Fund Large Collaborative Grant, VINCI, Innovative Medicines Initiative 2 Joint Undertaking, EU's Horizon 2020 research and innovation programme, and European Federation of Pharmaceutical Industries and Associations., (© 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.)

Urban environments are characterized by multiple exposures that may influence body mass index (BMI) growth in early life. Previous studies are few, with inconsistent results and no evaluation of simultaneous exposures. Thus, this study aimed to assess the associations between exposure to air pollution, green spaces and built environment characteristics, and BMI growth trajectories from 0 to 5 years. This longitudinal study used data from an electronic primary care health record database in Catalonia (Spain), including 79,992 children born between January 01, 2011 and December 31, 2012 in urban areas and followed until 5 years of age. Height and weight were measured frequently during childhood and BMI (kg/m 2 ) was calculated. Urban exposures were estimated at census tract level and included: air pollution (nitrogen dioxide (NO 2 ), particulate matter <10 μm (PM 10 ) and <2.5 μm (PM 2.5) ), green spaces (Normalized Difference Vegetation Index (NDVI) and % green space) and built environment (population density, street connectivity, land use mix, walkability index). Individual BMI trajectories were estimated using linear spline multilevel models with several knot points. In single exposure models, NO 2, PM 10, PM 2.5, and population density were associated with small increases in BMI growth (e.g. β per IQR PM 10 increase = 0.023 kg/m 2 , 95%CI: 0.013, 0.033), and NDVI, % of green spaces and land use mix with small reductions in BMI growth (e.g. β per IQR % green spaces increase = -0.015 kg/m 2, 95%CI: -0.026, -0.005). These associations were strongest during the first two months of life. In multiple exposure models, most associations were attenuated, with only those for PM 10 and land use mix remaining statistically significant. This large longitudinal study suggests that early life exposure to air pollution, green space and built environment characteristics may be associated with small changes in BMI growth trajectories during the first years of life, and that it is important to account for multiple exposures in urban settings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives To characterize the demographics, comorbidities, symptoms, in-hospital treatments, and health outcomes among children/adolescents diagnosed or hospitalized with COVID-19. Secondly, to describe health outcomes amongst children/adolescents diagnosed with previous seasonal influenza. Design International network cohort. Setting Real-world data from European primary care records (France/Germany/Spain), South Korean claims and US claims and hospital databases. Participants Diagnosed and/or hospitalized children/adolescents with COVID-19 at age <18 between January and June 2020; diagnosed with influenza in 2017-2018. Main outcome measures Baseline demographics and comorbidities, symptoms, 30-day in-hospital treatments and outcomes including hospitalization, pneumonia, acute respiratory distress syndrome (ARDS), multi-system inflammatory syndrome (MIS-C), and death. Results A total of 55,270 children/adolescents diagnosed and 3,693 hospitalized with COVID-19 and 1,952,693 diagnosed with influenza were studied. Comorbidities including neurodevelopmental disorders, heart disease, and cancer were all more common among those hospitalized vs diagnosed with COVID-19. The most common COVID-19 symptom was fever. Dyspnea, bronchiolitis, anosmia and gastrointestinal symptoms were more common in COVID-19 than influenza. In-hospital treatments for COVID-19 included repurposed medications (<10%), and adjunctive therapies: systemic corticosteroids (6.8% to 37.6%), famotidine (9.0% to 28.1%), and antithrombotics such as aspirin (2.0% to 21.4%), heparin (2.2% to 18.1%), and enoxaparin (2.8% to 14.8%). Hospitalization was observed in 0.3% to 1.3% of the COVID-19 diagnosed cohort, with undetectable (N<5 per database) 30-day fatality. Thirty-day outcomes including pneumonia, ARDS, and MIS-C were more frequent in COVID-19 than influenza. Conclusions Despite negligible fatality, complications including pneumonia, ARDS and MIS-C were more frequent in children/adolescents with COVID-19 than with influenza. Dyspnea, anosmia and gastrointestinal symptoms could help differential diagnosis. A wide range of medications were used for the inpatient management of pediatric COVID-19.

Early identification of symptoms and comorbidities most predictive of COVID-19 is critical to identify infection, guide policies to effectively contain the pandemic, and improve health systems' response. Here, we characterised socio-demographics and comorbidity in 3,316,107persons tested and 219,072 persons tested positive for SARS-CoV-2 since January 2020, and their key health outcomes in the month following the first positive test. Routine care data from primary care electronic health records (EHR) from Spain, hospital EHR from the United States (US), and claims data from South Korea and the US were used. The majority of study participants were women aged 18-65 years old. Positive/tested ratio varied greatly geographically (2.2:100 to 31.2:100) and over time (from 50:100 in February-April to 6.8:100 in May-June). Fever, cough and dyspnoea were the most common symptoms at presentation. Between 4%-38% required admission and 1-10.5% died within a month from their first positive test. Observed disparity in testing practices led to variable baseline characteristics and outcomes, both nationally (US) and internationally. Our findings highlight the importance of large scale characterization of COVID-19 international cohorts to inform planning and resource allocation including testing as countries face a second wave., Competing Interests: COMPETING INTEREST STATEMENT All authors have completed the ICMJE uniform disclosure form, with the following declarations made: DPA reports grants from Amgen, grants and other from UCB Biopharma, grants from Johnson and Johnson, outside the submitted work. DM is supported by a Wellcome Trust Clinical Research Development Fellowship (Grant 214588/Z/18/Z) and reports grants from Chief Scientist Office (CSO), grants from Health Data Research UK (HDR-UK), grants from National Institute of Health Research (NIHR), and Tenovus outside the submitted work. SCY reports grants from Korean Ministry of Health & Welfare, grants from Korean Ministry of Trade, Industry & Energy, during the conduct of the study. AG reports personal fees from Regeneron Pharmaceuticals, outside the submitted work; and she is a full-time employee at Regeneron Pharmaceuticals. This work was not conducted at Regeneron Pharmaceuticals. Dr. Lane reports grants from Versus Arthritis, grants from Medical Research Council, outside the submitted work. MS reports grants from US National Science Foundation, grants from US National Institutes of Health, grants from IQVIA, personal fees from Janssen Research and Development, during the conduct of the study. HA reports personal fees from Eli Lilly and Company, outside the submitted work. AS reports personal fees from Janssen Research & Development, during the conduct of the study; personal fees from Janssen Research & Development, outside the submitted work. AS is a full-time employee of Janssen and shareholder of Johnson & Johnson. FD reports personal fees from Janssen Research & Development, during the conduct of the study; personal fees from Janssen Research & Development, outside the submitted work. KK reports she is an employee of IQVIA. CR reports he is an employee of IQVIA. FN was an employee of AstraZeneca until 2019 and holds some AstraZeneca shares. SF is an employee of Janssen Research and Development, a subsidiary of Johnson and Johnson. VS reports grant funding from the National Science Foundation, Agency for Healthcare Research and Quality, and the Arizona Board of Regents outside of the submitted work. The views expressed are those of the authors and do not necessarily represent the views or policy of the Department of Veterans Affairs or the United States Government. PR reports and is employee of Janssen Research and Development and shareholder of Johnson & Johnson. No other relationships or activities that could appear to have influenced the submitted work.

Comorbid conditions appear to be common among individuals hospitalised with coronavirus disease 2019 (COVID-19) but estimates of prevalence vary and little is known about the prior medication use of patients. Here, we describe the characteristics of adults hospitalised with COVID-19 and compare them with influenza patients. We include 34,128 (US: 8362, South Korea: 7341, Spain: 18,425) COVID-19 patients, summarising between 4811 and 11,643 unique aggregate characteristics. COVID-19 patients have been majority male in the US and Spain, but predominantly female in South Korea. Age profiles vary across data sources. Compared to 84,585 individuals hospitalised with influenza in 2014-19, COVID-19 patients have more typically been male, younger, and with fewer comorbidities and lower medication use. While protecting groups vulnerable to influenza is likely a useful starting point in the response to COVID-19, strategies will likely need to be broadened to reflect the particular characteristics of individuals being hospitalised with COVID-19.

Extensive multiple-age cohort human papillomavirus (HPV) vaccination has proved to be highly effective. We aimed to determine the 8-year population impact of a female single-age cohort HPV vaccination programme on the incidence of anogenital warts (AGW). In 2008, Catalonia initiated a school-based quadrivalent HPV vaccination programme targeting 11-year-old girls, achieving coverage over 80%. Data on diagnoses of AGW and genital herpes were obtained from a population-based database of electronic health records covering 74% of the population. The annual incidence rates from 2009 to 2016 were calculated, stratified by age and sex using Joinpoint regression to estimate trends and annual percentage changes (APC). Among women aged 16-19 years, the AGW incidence decreased by 61% from 2012 to 2016 (APC -19.4%; 95% CI: -30.0 to -7.3). In contrast, the incidence of genital herpes in same-aged women increased throughout the study period (APC 11.1%; 95% CI: 7.2-15.2). Among men aged 20-22 years, the increasing incidence of AGW shifted to a downward trend in 2013 (APC 2009-2013: 17.0%; 95% CI: 8.2-26.5; and APC 2013-2016: -4.5%; 95% CI: -14.6 to 6.9). A similar pattern was observed among men aged 23-25 years (APC 2009-2014: 16.0%; 95% CI: 12.0-20.2; and APC 2014-2016: -6.0%; 95% CI: -18.4 to 8.3). In contrast to AGW, among men aged 20-25 years, the incidence of genital herpes increased over this period. Our study strongly suggests that a single-cohort HPV vaccination strategy with high vaccine uptake not only provides direct benefit in the vaccinated cohorts but also extends protection through a herd effect to unvaccinated men., Competing Interests: Declaration of competing interest F. Xavier Bosch has received scientific advisory board fees, speaker's fees, or travel grants from GlaxoSmithKline, Merck and Co., Inc. and IMS Health and unrestricted institutional research grants from GlaxoSmithKline and Merck and Co., Inc. The Cancer Epidemiology Research Programme (with which Maria Brotons, Laura Monfil, Esther Roura, F. Xavier Bosch, Silvia de Sanjosé and Laia Bruni are affiliated) has received sponsorship for grants from Merck and Co., Inc. and GSK. The rest of the authors declare no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background In this study we phenotyped individuals hospitalised with coronavirus disease 2019 (COVID-19) in depth, summarising entire medical histories, including medications, as captured in routinely collected data drawn from databases across three continents. We then compared individuals hospitalised with COVID-19 to those previously hospitalised with influenza. Methods We report demographics, previously recorded conditions and medication use of patients hospitalised with COVID-19 in the US (Columbia University Irving Medical Center [CUIMC], Premier Healthcare Database [PHD], UCHealth System Health Data Compass Database [UC HDC], and the Department of Veterans Affairs [VA OMOP]), in South Korea (Health Insurance Review & Assessment [HIRA]), and Spain (The Information System for Research in Primary Care [SIDIAP] and HM Hospitales [HM]). These patients were then compared with patients hospitalised with influenza in 2014-19. Results 34,128 (US: 8,362, South Korea: 7,341, Spain: 18,425) individuals hospitalised with COVID-19 were included. Between 4,811 (HM) and 11,643 (CUIMC) unique aggregate characteristics were extracted per patient, with all summarised in an accompanying interactive website (http://evidence.ohdsi.org/Covid19CharacterizationHospitalization/). Patients were majority male in the US (CUIMC: 52%, PHD: 52%, UC HDC: 54%, VA OMOP: 94%,) and Spain (SIDIAP: 54%, HM: 60%), but were predominantly female in South Korea (HIRA: 60%). Age profiles varied across data sources. Prevalence of asthma ranged from 4% to 15%, diabetes from 13% to 43%, and hypertensive disorder from 24% to 70% across data sources. Between 14% and 33% were taking drugs acting on the renin-angiotensin system in the 30 days prior to hospitalisation. Compared to 81,596 individuals hospitalised with influenza in 2014-19, patients admitted with COVID-19 were more typically male, younger, and healthier, with fewer comorbidities and lower medication use. Conclusions We provide a detailed characterisation of patients hospitalised with COVID-19. Protecting groups known to be vulnerable to influenza is a useful starting point to minimize the number of hospital admissions needed for COVID-19. However, such strategies will also likely need to be broadened so as to reflect the particular characteristics of individuals hospitalised with COVID-19.

Introduction: Angiotensin converting enzyme inhibitors (ACEs) and angiotensin receptor blockers (ARBs) could influence infection risk of coronavirus disease (COVID-19). Observational studies to date lack pre-specification, transparency, rigorous ascertainment adjustment and international generalizability, with contradictory results., Methods: Using electronic health records from Spain (SIDIAP) and the United States (Columbia University Irving Medical Center and Department of Veterans Affairs), we conducted a systematic cohort study with prevalent ACE, ARB, calcium channel blocker (CCB) and thiazide diuretic (THZ) use to determine relative risk of COVID-19 diagnosis and related hospitalization outcomes. The study addressed confounding through large-scale propensity score adjustment and negative control experiments., Results: Following over 1.1 million antihypertensive users identified between November 2019 and January 2020, we observed no significant difference in relative COVID-19 diagnosis risk comparing ACE/ARB vs CCB/THZ monotherapy (hazard ratio: 0.98; 95% CI 0.84 - 1.14), nor any difference for mono/combination use (1.01; 0.90 - 1.15). ACE alone and ARB alone similarly showed no relative risk difference when compared to CCB/THZ monotherapy or mono/combination use. Directly comparing ACE vs. ARB demonstrated a moderately lower risk with ACE, non-significant for monotherapy (0.85; 0.69 - 1.05) and marginally significant for mono/combination users (0.88; 0.79 - 0.99). We observed, however, no significant difference between drug- classes for COVID-19 hospitalization or pneumonia risk across all comparisons., Conclusion: There is no clinically significant increased risk of COVID-19 diagnosis or hospitalization with ACE or ARB use. Users should not discontinue or change their treatment to avoid COVID-19.

This study aimed to determine if having an overweight or obese range body mass index (BMI) at time of beginning school is associated with increased fracture incidence in childhood. A dynamic cohort was created from children presenting for routine preschool primary care screening, collected in the Information System for Research in Primary Care (SIDIAP) platform in Catalonia, Spain. Data were collected from 296 primary care centers representing 74% of the regional pediatric population. A total of 466,997 children (48.6% female) with a validated weight and height measurement within routine health care screening at age 4 years (±6 months) between 2006 and 2013 were included, and followed up to the age of 15, migration out of region, death, or until December 31, 2016. BMI was calculated at age 4 years and classified using WHO growth tables, and fractures were identified using previously validated ICD10 codes in electronic primary care records, divided by anatomical location. Actuarial lifetables were used to calculate cumulative incidence. Cox regression was used to investigate the association of BMI category and fracture risk with adjustment for socioeconomic status, age, sex, and nationality. Median follow-up was 4.90 years (interquartile range [IQR] 2.50 to 7.61). Cumulative incidence of any fracture during childhood was 9.20% (95% confidence interval [CI] 3.79% to 14.61%) for underweight, 10.06% (9.82% to 10.29%) for normal weight, 11.28% (10.22% to 12.35%) for overweight children, and 13.05% (10.69% to 15.41%) for children with obesity. Compared with children of normal range weight, having an overweight and obese range BMI was associated with an excess risk of lower limb fracture (adjusted hazard ratio [HR] = 1.42 [1.26 to 1.59]; 1.74 [1.46 to 2.06], respectively) and upper limb fracture (adjusted HR = 1.10 [1.03 to 1.17]; 1.19 [1.07 to 1.31]). Overall, preschool children with an overweight or obese range BMI had increased incidence of upper and lower limb fractures in childhood compared with contemporaries of normal weight. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research., (© 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.)

Background: Inflammatory processes have been shown to play a role in dementia. To understand this role, we selected two anti-inflammatory drugs (methotrexate and sulfasalazine) to study their association with dementia risk., Methods: A retrospective matched case-control study of patients over 50 with rheumatoid arthritis (486 dementia cases and 641 controls) who were identified from electronic health records in the UK, Spain, Denmark and the Netherlands. Conditional logistic regression models were fitted to estimate the risk of dementia., Results: Prior methotrexate use was associated with a lower risk of dementia (OR 0.71, 95% CI 0.52-0.98). Furthermore, methotrexate use with therapy longer than 4 years had the lowest risk of dementia (odds ratio 0.37, 95% CI 0.17-0.79). Sulfasalazine use was not associated with dementia (odds ratio 0.88, 95% CI 0.57-1.37)., Conclusions: Further studies are still required to clarify the relationship between prior methotrexate use and duration as well as biological treatments with dementia risk.

Background: The Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) is a public-private collaboration aiming to develop and test a system for rapid benefit-risk monitoring of vaccines using existing healthcare databases in Europe. We estimated vaccine coverage from electronic healthcare databases as part of a fit-for-purpose assessment for vaccine benefit-risk studies., Methods: A retrospective dynamic cohort study was conducted through a distributed network approach. Coverage with measles-vaccine for birth year 2006, human papillomavirus (HPV)-vaccine for birth years 1990-2000 and influenza-vaccine for birth years 1920-1950 was estimated using period-prevalence and inverse probability weighting methods. Seven databases from four countries participated: Italy (Pedianet, Val Padana), Spain (BIFAP, SIDIAP), UK (RCGP-RSC, THIN), Denmark (SSI/AUH). Database access providers extracted the data, transformed it into a common structure and ran an R-script locally. The created output tables were shared and pooled at a central server., Results: The total study population comprised 274,616 persons for measles-vaccine, 2,011,666 persons for HPV-vaccine and 14,904,033 persons for influenza-vaccine. Measles-vaccine coverage varied from 84.3% (Denmark) to 96.5% (Italy, Val Padana) for the first dose and from 82.8% (Italy, Val Padana) to 90.9% (UK) for the second dose at the age of 7 years. The HPV-vaccine coverage, aggregated over birth years 1997-2000, ranged from 60% (UK) to 88.3% (Denmark) at the age of 15 years. The influenza-vaccine coverage for the influenza seasons from 2009 to 2015 for persons aged 65 years and more was roughly stable around 43% in Denmark and around 68% in the UK while a decrease from 58 to 50% was observed in Catalonia (Spain)., Conclusions: We obtained detailed, age-specific coverage estimates though a common procedure. We discussed between database comparability and comparability to published national estimates., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Toon Braeye, Hanne-Dorthe Emborg, Ana Llorente-García, Consuelo Huerta, Elisa Martín-Merino, Talita Duarte-Salles, Giorgia Danieli, Lara Tramontan, Daniel Weibel, Chris McGee, Marco Villa, Matti Lehtinen declared no potential conflicts of interest. Miriam Sturkenboom, declared that she has received grants from Novartis, CDC and Bill & Melinda Gates Foundation, for work unrelated to the submitted work. Lina Titievsky declared that she is employed by Pfizer and holds company stocks/shares. Rosa Gini's institution is involved in studies funded by Novartis, Eli Lilly, and Daiichi, compliant with the ENCePP CoC., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Importance: Time-trend studies of overweight and obesity in childhood by sociodemographic factors are important for prioritizing public health initiatives. However, little is known about these trends in Spain, where high levels of obesity are found and where important demographic changes have occurred during the last 2 decades., Objective: To examine how time trends in the prevalence and incidence of overweight and obesity among children and adolescents differ by age, sex, socioeconomic status, urban/rural residence, and nationality., Design, Setting, and Participants: This cohort study included 1.1 million children and adolescents (aged 2-17 years) with at least 1 measure of height and weight in Catalonia, Spain, from 2006 to 2016. Electronic health records were accessed from the Information System for Research in Primary Care. Data analysis was conducted from January to December 2018., Main Outcomes and Measures: Prevalence and incidence rates and trends of overweight/obesity and obesity (overweight/obesity defined as having of BMI z score greater than 2.0 among children aged <5 years and greater than 1.0 among children aged ≥5 years; obesity defined as having of BMI z score greater than 3.0 among children aged <5 years and greater than 2.0 among children aged ≥5 years) between 2006 and 2016 were calculated and stratified by sociodemographic characteristics (ie, age, sex, deprivation index, urban/rural residence, and nationality)., Results: The study population included 1 166 609 children and adolescents (570 982 [48.9%] girls; median [interquartile range] age at entry to electronic health record system, 2.4 [0-7.7] years; 1 006 892 [86.3%] with Spanish nationality). Of 941 041 children (80.7%) who lived in urban areas, 197 427 (20.7%) lived in the most deprived areas. Overall, the prevalence of overweight/obesity and obesity decreased between 2006 and 2016 in all sex and age groups; for example, among boys and girls aged 6 to 11 years, overweight/obesity prevalence decreased from 41.9% (95% CI, 41.5%-42.2%) to 39.9% (95% CI, 39.6%-40.3%) and from 39.7% (95% CI, 39.3%-40.2%) to 37.6% (95% CI, 37.3%-38.0%), respectively. Incidence rates of overweight/obesity and obesity were highest among children aged 6 to 7 years (overweight/obesity among boys: 11.9 [95% CI, 11.8-12.0] new cases per 100 person-years; obesity among boys: 4.9 [95% CI, 4.8-4.9] new cases per 100 person-years). Prevalence and incidence rates were highest in the most deprived areas, in urban areas, and among children with North, Central, or South American nationalities. Between 2006 and 2016, prevalence increased in the most deprived areas in almost all sex and age groups. Among girls aged 6 to 11 years living in the most deprived areas, the obesity prevalence ratio increased from 1.59 (95% CI, 1.46-1.74) to 2.03 (95% CI, 1.88-2.19) compared with those living in the least deprived areas. Furthermore, during this period, prevalence increased among children with non-Spanish nationalities, especially in the African and Asian nationality groups (eg, boys aged 6-11 years with Asian nationality compared with Spanish nationality, 2006: prevalence rate, 0.78 [95% CI, 0.60-1.01]; 2016: prevalence rate, 1.27 [95% CI, 1.15-1.39]). Incidence rates decreased among younger groups (eg, ≤7 years: incidence rate ratio for January 1, 2006, to June 30, 2011, vs July 1, 2011, to December 31, 2016: 0.94; 95% CI, 0.91-0.98) but remained stable in older groups., Conclusions and Relevance: In this study, the overall prevalence and incidence rates of childhood overweight/obesity and obesity slightly decreased during the last decade. However, increased deprivation disparities in childhood obesity were found, given that the prevalence increased among children living in deprived areas and with non-Spanish nationalities.

Background: Electronic health records are becoming an increasingly valuable resource for epidemiology but their data quality needs to be quantified. We aimed to validate twenty-five types of incident cancer cases in the Information System for Research in Primary Care (SIDIAP) in Catalonia with the population-based cancer registries of Girona and Tarragona as the gold-standard., Methods: We calculated the sensitivity, positive predictive values (PPV), and the time-difference between the date of diagnosis entered into the SIDIAP and into the registries. We added hospital discharge cancer diagnoses to the SIDIAP to assess sensitivity changes., Results: We identified 27,046 incident cancer diagnoses in the SIDIAP from 2009-2015 among the 949,841 residents of Girona and Tarragona. The cancer types with the highest sensitivity were breast (89%, 95% CI: 88-90%), colorectal (81%, 95% CI: 80-82%), and prostate (81%, 95% CI: 80-83%). Trachea, bronchus and lung cancers had the highest PPV (76%, 95% CI: 74%-78%) followed by stomach (72%, 95% CI: 68-75%) and pancreas (71%, 95% CI: 67-75%). Most cancer diagnoses were reported with less than three months of difference between the SIDIAP and the registries. More cases were registered first in the registries than in the SIDIAP. By adding cancer diagnoses based on hospital discharge data, sensitivity increased for all cancers, especially for gallbladder and biliary tract for which the sensitivity increased by 21%., Conclusion: The SIDIAP includes 76% of the cancer diagnoses in the cancer registries but includes a considerable number of cases that are not in the registries. The SIDIAP reports most of the cancer diagnoses within a three-month period difference from the date of diagnosis in the cancer registries. Our results support the use of the SIDIAP cancer diagnoses for epidemiological research when cancer is the outcome of interest. We recommend adding hospital discharge data to the SIDIAP to increase data quality, particularly for less frequent cancer types., Competing Interests: The authors report no conflicts of interest in this work., (© 2019 Recalde et al.)

Background: There is uncertainty around whether to use unicompartmental knee replacement (UKR) or total knee replacement (TKR) for individuals with osteoarthritis confined to a single compartment of the knee. We aimed to emulate the design of the Total or Partial Knee Arthroplasty Trial (TOPKAT) using routinely collected data to assess whether the efficacy results reported in the trial translate into effectiveness in routine practice, and to assess comparative safety., Methods: We did a population-based network study using data from four US and one UK health-care database, part of the Observational Health Data Sciences and Informatics network. The inclusion criteria were the same as those for TOPKAT; briefly, we identified patients aged at least 40 years with osteoarthritis who had undergone UKR or TKR and who had available data for at least one year prior to surgery. Patients were excluded if they had evidence of previous knee arthroplasty, knee fracture, knee surgery (except diagnostic), rheumatoid arthritis, infammatory arthropathies, or septic arthritis. Opioid use from 91-365 days after surgery, as a proxy for persistent pain, was assessed for all participants in all databases. Postoperative complications (ie, venous thromboembolism, infection, readmission, and mortality) were assessed over the 60 days after surgery and implant survival (as measured by revision procedures) was assessed over the 5 years after surgery. Outcomes were assessed in all databases, except for readmission, which was assessed in three of the databases, and mortality, which was assessed in two of the databases. Propensity score matched Cox proportional hazards models were fitted for each outcome. Calibrated hazard ratios (cHRs) were generated for each database to account for observed differences in control outcomes, and cHRs were then combined using meta-analysis., Findings: 33 867 individuals who received UKR and 557 831 individuals who received TKR between Jan 1, 2005, and April 30, 2018, were eligible for matching. 32 379 with UKR and 250 377 with TKR were propensity score matched and informed the analyses. UKR was associated with a reduced risk of postoperative opioid use (cHR from meta-analysis 0·81, 95% CI 0·73-0·90) and a reduced risk of venous thromboembolism (0·62, 0·36-0·95), whereas no difference was seen for infection (0·85, 0·51-1·37) and readmission (0·79, 0·47-1·25). Evidence was insufficient to conclude whether there was a reduction in risk of mortality. UKR was also associated with an increased risk of revision (1·64, 1·40-1·94)., Interpretation: UKR was associated with a reduced risk of postoperative opioid use compared with TKR, which might indicate a reduced risk of persistent pain after surgery. UKR was associated with a lower risk of venous thromboembolism but an increased risk of revision compared with TKR. These findings can help to inform shared decision making for individuals eligible for knee replacement surgery., Funding: EU/European Federation of Pharmaceutical Industries and Associations Innovative Medicines Initiative (2) Joint Undertaking (EHDEN)., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: Prenatal exposure to organochlorine compounds (OCs) can increase the risk of reported respiratory symptoms in children. It remains unclear whether these compounds can also impact on lung function. We assessed the association between prenatal exposure to OCs and lung function during childhood., Methods: We included 1308 mother-child pairs enrolled in a prospective cohort study. Prenatal concentrations of p,p'-dichlorodiphenyltrichloroethane [p,p'-DDT], p,p'-dichlorodiphenyldichloroethylene [p,p'-DDE], hexachlorobenzene [HCB], and seven polychlorinated biphenyls [PCBs] were measured in cord blood. Spirometry was performed in the offspring at ages 4 (n = 636) and 7 years (n = 1192)., Results: More than 80% of samples presented quantifiable levels of p,p'-DDE, HCB, PCB-138, PCB-153, and PCB-180; p,p'-DDE was the compound with the highest median concentrations. At 4 years, prenatal p,p'-DDE exposure was associated with a decrease in forced expiratory volume in 1 s (FEV 1 ) in all quartiles of exposure (e.g., third quartile [0.23-0.34 ng/mL]: β for FEV 1 -53.61 mL, 95% CI -89.87, -17.35, vs. the lowest). Prenatal p,p'-DDE levels also decreased forced vital capacity (FVC) and FEV 1 /FVC, but associations did not reach statistical significance in most exposure quartiles. At 7 years, p,p'-DDE was associated with a decrease in FVC and FEV 1 in only the second quartile of exposure (e.g. β for FEV 1 -36.96 mL, 95% CI -66.22, -7.70, vs. the lowest). Prenatal exposure to HCB was associated with decreased FVC and FEV 1 , but in only the second quartile and at 7 years (e.g. [0.07-0.14 ng/mL]: β for FEV 1 -25.79 mL, 95% CI -55.98, 4.39, vs. the lowest). PCBs were not consistently associated with lung function., Conclusion: Prenatal exposure to p,p'-DDE may decrease lung function during childhood, especially FEV 1 and at medium levels of exposure. Further and deeper knowledge on the impact of environmental chemicals during pregnancy on lung development is needed., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Metabolic syndrome (MS) is defined by the clustering of specific metabolic disorders in one subject. MS is highly prevalent globally and currently considered a growing public health concern. MS comprises obesity, hypertension, dyslipidaemia and insulin resistance. Mechanisms linking MS with cancer are poorly understood, and it is as yet unknown if MS confers a greater risk than the risk entailed by each of its separate components. The main objective of this study is to compare the association between MS and 14 site-specific cancer against the association between one or two individual components of MS and cancer. The secondary objective is to evaluate the time elapsed since the diagnosis of MS and the subsequent onset of cancer within the 2006-2017 period by sex., Methods and Analysis: A case-control study will be conducted for the main objective and a cohort of patients with MS will be followed for the evaluation of the second objective. Incident cases of fourteen types of cancer in patients ≥40 years of age diagnosed prospectively will be selected from electronic primary care records in the Information System for Research in Primary Care (SIDIAP database; www.sidiap.org). The SIDIAP database includes anonymous data from 6 million people (80% of the Catalan population) registered in 286 primary healthcare centres. Each matched control (four controls for each case) will have the same inclusion date, the same sex and age (±1 year) than the paired case. Logistic regression and a descriptive analysis and Kaplan-Meier analysis will be performed, in accordance with the objectives., Ethics and Dissemination: The protocol of the study was approved by the IDIAP Jordi Gol Clinical Research Ethics Committee (protocol P17/212). The study's findings will be published in a peer-reviewed journal and disseminated at national and international conferences and oral presentations to researchers, clinicians and policy makers., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Non-alcoholic fatty liver disease (NAFLD) is a common condition that progresses in some patients to steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). Here we used healthcare records of 18 million adults to estimate risk of acquiring advanced liver disease diagnoses in patients with NAFLD or NASH compared to individually matched controls., Methods: Data were extracted from four European primary care databases representing the UK, Netherlands, Italy and Spain. Patients with a recorded diagnosis of NAFLD or NASH (NAFLD/NASH) were followed up for incident cirrhosis and HCC diagnoses. Each coded NAFLD/NASH patient was matched to up to 100 "non-NAFLD" patients by practice site, gender, age ± 5 years and visit recorded within ± 6 months. Hazard ratios (HR) were estimated using Cox models adjusted for age and smoking status and pooled across databases by random effects meta-analyses., Results: Out of 18,782,281 adults, we identified 136,703 patients with coded NAFLD/NASH. Coded NAFLD/NASH patients were more likely to have diabetes, hypertension and obesity than matched controls. HR for cirrhosis in patients compared to controls was 4.73 (95% CI 2.43-9.19) and for HCC, 3.51 (95% CI 1.72-7.16). HR for either outcome was higher in patients with NASH and those with high-risk Fib-4 scores. The strongest independent predictor of a diagnosis of HCC or cirrhosis was baseline diagnosis of diabetes., Conclusions: Real-world population data show that recorded diagnosis of NAFLD/NASH increases risk of life-threatening liver outcomes. Diabetes is an independent predictor of advanced liver disease diagnosis, emphasising the need to identify specific groups of patients at highest risk.

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide. It affects an estimated 20% of the general population, based on cohort studies of varying size and heterogeneous selection. However, the prevalence and incidence of recorded NAFLD diagnoses in unselected real-world health-care records is unknown. We harmonised health records from four major European territories and assessed age- and sex-specific point prevalence and incidence of NAFLD over the past decade., Methods: Data were extracted from The Health Improvement Network (UK), Health Search Database (Italy), Information System for Research in Primary Care (Spain) and Integrated Primary Care Information (Netherlands). Each database uses a different coding system. Prevalence and incidence estimates were pooled across databases by random-effects meta-analysis after a log-transformation., Results: Data were available for 17,669,973 adults, of which 176,114 had a recorded diagnosis of NAFLD. Pooled prevalence trebled from 0.60% in 2007 (95% confidence interval: 0.41-0.79) to 1.85% (0.91-2.79) in 2014. Incidence doubled from 1.32 (0.83-1.82) to 2.35 (1.29-3.40) per 1000 person-years. The FIB-4 non-invasive estimate of liver fibrosis could be calculated in 40.6% of patients, of whom 29.6-35.7% had indeterminate or high-risk scores., Conclusions: In the largest primary-care record study of its kind to date, rates of recorded NAFLD are much lower than expected suggesting under-diagnosis and under-recording. Despite this, we have identified rising incidence and prevalence of the diagnosis. Improved recognition of NAFLD may identify people who will benefit from risk factor modification or emerging therapies to prevent progression to cardiometabolic and hepatic complications.

We previously identified osteopontin (OPN) as a promising marker for the early detection of hepatocellular carcinoma (HCC). In this study, we investigated the association between prediagnostic circulating OPN levels and HCC incidence in a large population-based cohort. A nested case-control study was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. During a mean follow-up of 4.8 years, 100 HCC cases were identified. Each case was matched to two controls and OPN levels were measured in baseline plasma samples. Viral hepatitis, liver function, and α-fetoprotein (AFP) tests were also conducted. Conditional logistic regression models were used to calculate multivariable odds ratio (OR) and 95% confidence intervals (95% CI) for OPN levels in relation to HCC. Receiver operating characteristics curves were constructed to determine the discriminatory accuracy of OPN alone or in combination with other liver biomarkers in the prediction of HCC. OPN levels were positively associated with HCC risk (per 10% increment, ORmultivariable = 1.30; 95% CI, 1.14-1.48). The association was stronger among cases diagnosed within 2 years of follow-up. Adding liver function tests to OPN improved the discriminatory performance for subjects who developed HCC (AUC = 0.86). For cases diagnosed within 2 years, the combination of OPN and AFP was best able to predict HCC risk (AUC = 0.88). The best predictive model for HCC in this low-risk population is OPN in combination with liver function tests. Within 2 years of diagnosis, the combination of OPN and AFP best predicted HCC development, suggesting that measuring OPN and AFP could identify high-risk groups independently of a liver disease diagnosis. Cancer Prev Res; 9(9); 758-65. ©2016 AACR., Competing Interests: Conflicts of Interest: None declared., (©2016 American Association for Cancer Research.)

Background: Selenium status is suboptimal in many Europeans and may be a risk factor for the development of various cancers, including those of the liver and biliary tract., Objective: We wished to examine whether selenium status in advance of cancer onset is associated with hepatobiliary cancers in the EPIC (European Prospective Investigation into Cancer and Nutrition) study., Design: We assessed prediagnostic selenium status by measuring serum concentrations of selenium and selenoprotein P (SePP; the major circulating selenium transfer protein) and examined the association with hepatocellular carcinoma (HCC; n = 121), gallbladder and biliary tract cancers (GBTCs; n = 100), and intrahepatic bile duct cancer (IHBC; n = 40) risk in a nested case-control design within the EPIC study. Selenium was measured by total reflection X-ray fluorescence, and SePP was determined by a colorimetric sandwich ELISA. Multivariable ORs and 95% CIs were calculated by using conditional logistic regression., Results: HCC and GBTC cases, but not IHBC cases, showed significantly lower circulating selenium and SePP concentrations than their matched controls. Higher circulating selenium was associated with a significantly lower HCC risk (OR per 20-μg/L increase: 0.41; 95% CI: 0.23, 0.72) but not with the risk of GBTC or IHBC. Similarly, higher SePP concentrations were associated with lowered HCC risk only in both the categorical and continuous analyses (HCC: P-trend ≤ 0.0001; OR per 1.5-mg/L increase: 0.37; 95% CI: 0.21, 0.63)., Conclusion: These findings from a large prospective cohort provide evidence that suboptimal selenium status in Europeans may be associated with an appreciably increased risk of HCC development., (© 2016 American Society for Nutrition.)

Introduction: Serum liver biomarkers (gamma-glutamyl transferase, GGT; alanine aminotransferase, ALT; aspartate aminotransferase, AST; alkaline phosphatase, ALP; total bilirubin) are used as indicators of liver disease, but there is currently little data on their prospective association with risk of hepatobiliary cancers., Methods: A nested-case control study was conducted within the prospective EPIC cohort (>520,000 participants, 10 European countries). After a mean 7.5 mean years of follow-up, 121 hepatocellular carcinoma (HCC), 34 intrahepatic bile duct (IHBC) and 131 gallbladder and biliary tract (GBTC) cases were identified and matched to 2 controls each. Circulating biomarkers were measured in serum taken at recruitment into the cohort, prior to cancer diagnosis. Multivariable adjusted conditional logistic regression was used to calculate odds ratios and 95% confidence intervals (OR; 95%CI)., Results: In multivariable models, 1SD increase of each log-transformed biomarker was positively associated with HCC risk (OR(GGT)=4.23, 95%CI:2.72-6.59; OR(ALP)=3.43, 95%CI:2.31-5.10;OR(AST)=3.00, 95%CI:2.04-4.42; OR(ALT)=2.69, 95%CI:1.89-3.84; OR(Bilirubin)=2.25, 95%CI:1.58-3.20). Each liver enzyme (OR(GGT)=4.98; 95%CI:1.75-14.17; OR(AST)=3.10, 95%CI:1.04-9.30; OR(ALT)=2.86, 95%CI:1.26-6.48, OR(ALP)=2.31, 95%CI:1.10-4.86) but not bilirubin (OR(Bilirubin)=1.46,95%CI:0.85-2.51) showed a significant association with IHBC. Only ALP was significantly associated with GBTC risk (OR(ALP)=1.59, 95%CI:1.20-2.09)., Conclusion: This study shows positive associations between circulating liver biomarkers in sera collected prior to cancer diagnoses and the risks of developing HCC or IHBC, but not GBTC., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: The aim of the study was to assess associations between intake of combined soft drinks (sugar sweetened and artificially sweetened) and fruit and vegetable juices and the risk of hepatocellular carcinoma (HCC), intrahepatic bile duct (IHBC) and biliary tract cancers (GBTC) using data from the European Prospective Investigation into Cancer and Nutrition cohort of 477,206 participants from 10 European countries., Methods: After 11.4 years of follow-up, 191 HCC, 66 IHBC and 236 GBTC cases were identified. Hazard ratios and 95% confidence intervals (HR; 95% CI) were estimated with Cox regression models with multivariable adjustment (baseline total energy intake, alcohol consumption and intake pattern, body mass index, physical activity, level of educational attainment and self-reported diabetes status)., Results: No risk associations were observed for IHBC or GBTC. Combined soft drinks consumption of >6 servings/week was positively associated with HCC risk: HR 1.83; 95% CI 1.11-3.02, p trend = 0.01 versus non-consumers. In sub-group analyses available for 91% of the cohort artificially sweetened soft drinks increased HCC risk by 6% per 1 serving increment (HR 1.06, 95% CI 1.03-1.09, n cases = 101); for sugar-sweetened soft drinks, this association was null (HR 1.00, 95% CI 0.95-1.06; n cases = 127, p heterogeneity = 0.07). Juice consumption was not associated with HCC risk, except at very low intakes (<1 serving/week: HR 0.60; 95% CI 0.38-0.95; p trend = 0.02 vs. non-consumers)., Conclusions: Daily intake of combined soft drinks is positively associated with HCC, but a differential association between sugar and artificially sweetened cannot be discounted. This study provides some insight into possible associations of HCC with sugary drinks intake. Further exploration in other settings is required.