Search

Daniel Hsiang-Te Tsai,1,2 J Simon Bell,3 Shahab Abtahi,4 Brenda N Baak,5 Marloes T Bazelier,4 Ruth Brauer,6 Adrienne YL Chan,6– 9 Esther W Chan,9– 12 Haoqian Chen,13 Celine SL Chui,9,14,15 Sharon Cook,16 Stephen Crystal,16 Poonam Gandhi,13 Sirpa Hartikainen,17 Frederick K Ho,18 Shao-Ti Hsu,1 Jenni Ilomäki,3 Ju Hwan Kim,19 Olaf H Klungel,4 Marjaana Koponen,17 Wallis CY Lau,6,8,9 Kui Kai Lau,20,21 Terry YS Lum,22 Hao Luo,22 Kenneth KC Man,6,8,9 Jill P Pell,18 Soko Setoguchi,13,23 Shih-Chieh Shao,1,24 Chin-Yao Shen,1 Ju-Young Shin,19,25,26 Patrick C Souverein,4 Anna-Maija Tolppanen,17 Li Wei,6,9 Ian CK Wong,6,8,9,27 Edward Chia-Cheng Lai1 1School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 2Centre for Neonatal and Paediatric Infection, St George’s University of London, London, UK; 3Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Melbourne, Australia; 4Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands; 5PHARMO Institute for Drug Outcomes Research, Utrecht, the Netherlands; 6Research Department of Practice and Policy, UCL School of Pharmacy, London, UK; 7Groningen Research Institute of Pharmacy, Unit of Pharmacotherapy, ‐Epidemiology and ‐Economics, University of Groningen, Groningen, the Netherlands; 8Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 9Laboratory of Data Discovery for Health (D24H), Hong Kong Science Park, Hong Kong, Special Administrative Region, People’s Republic of China; 10Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 11Department of Pharmacy, the University of Hong Kong-Shenzhen Hospital, Shenzhen, People’s Republic of China; 12The University of Hong Kong Shenzhen Institute of Research and Innovation, Shenzhen, People’s Republic of China; 13Center for Pharmacoepidemiology and Treatment Science (PETS), Institute for Health, Rutgers University, New Brunswick, NJ, USA; 14School of Nursing, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 15School of Public Health, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 16Center for Health Services Research, Rutgers University, New Brunswick, NJ, USA; 17Kuopio Research Centre of Geriatric Care and School of Pharmacy, University of Eastern Finland, Kuopio, Finland; 18School of Health and Wellbeing, University of Glasgow, Glasgow, UK; 19School of Pharmacy, Sungkyunkwan University, Suwon, South Korea; 20Division of Neurology, Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 21State Key Laboratory of Brain and Cognitive Sciences, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 22Department of Social Work and Social Administration, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 23Department of Medicine, Rutgers Robert Wood Johnson Medical School and Pharmacoepidemiology and Treatments Science, Institute for Health, Rutgers University, New Brunswick, NJ, USA; 24Department of Pharmacy, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan; 25Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, South Korea; 26Department of Biohealth Regulatory Science, Sungkyunkwan University, Seoul, South Korea; 27Aston Pharmacy School, Aston University, Birmingham, UKCorrespondence: Edward Chia-Cheng Lai, School of Pharmacy and Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Email edward_lai@mail.ncku.edu.twPurpose: To describe and categorize detailed components of databases in the Neurological and Mental Health Global Epidemiology Network (NeuroGEN).Methods: An online 132-item questionnaire was sent to key researchers and data custodians of NeuroGEN in North America, Europe, Asia and Oceania. From the responses, we assessed data characteristics including population coverage, data follow-up, clinical information, validity of diagnoses, medication use and data latency. We also evaluated the possibility of conversion into a common data model (CDM) to implement a federated network approach. Moreover, we used radar charts to visualize the data capacity assessments, based on different perspectives.Results: The results indicated that the 15 databases covered approximately 320 million individuals, included in 7 nationwide claims databases from Australia, Finland, South Korea, Taiwan and the US, 6 population-based electronic health record databases from Hong Kong, Scotland, Taiwan, the Netherlands and the UK, and 2 biomedical databases from Taiwan and the UK.Conclusion: The 15 databases showed good potential for a federated network approach using a common data model. Our study provided publicly accessible information on these databases for those seeking to employ real-world data to facilitate current assessment and future development of treatments for neurological and mental disorders.Keywords: meta-data, data repository, Neurological and Mental Health Global Epidemiology Network, NeuroGEN

Edward Chia-Cheng Lai,1–4 Patrick Ryan,5 Yinghong Zhang,4 Martijn Schuemie,5 N Chantelle Hardy,4 Yukari Kamijima,6 Shinya Kimura,7 Kiyoshi Kubota,6 Kenneth KC Man,8,9 Soo Yeon Cho,10 Rae Woong Park,10 Paul Stang,5 Chien-Chou Su,1,3 Ian CK Wong,8,9 Yea-Huei Yang Kao,1,3 Soko Setoguchi4,11 1School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, National Cheng Kung University, Tainan, Taiwan; 2Department of Pharmacy, National Cheng Kung University Hospital, Tainan, Taiwan; 3Health Outcome Research Center, National Cheng-Kung University, Tainan, Taiwan; 4Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA; 5Janssen Research & Development, LLC, Titusville, NJ, USA; 6NPO Drug Safety Research Unit Japan, Tokyo, Japan; 7Japan Medical Data Center Co.,Ltd, Tokyo, Japan; 8Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, University of Hong Kong, Hong Kong, China; 9Research Department of Practice and Policy, UCL School of Pharmacy, London, UK; 10Department of Biomedical Informatics, School of Medicine, Ajou University, Suwon, Korea; 11Institute for Health, Rutgers University and Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA Objective: The goal of the Asian Pharmacoepidemiology Network is to study the effectiveness and safety of medications commonly used in Asia using databases from individual Asian countries. An efficient infrastructure to support multinational pharmacoepidemiologic studies is critical to this effort. Study design and setting: We converted data from the Japan Medical Data Center database, Taiwan’s National Health Insurance Research Database, Hong Kong’s Clinical Data Analysis and Reporting System, South Korea’s Ajou University School of Medicine database, and the US Medicare 5% sample to the Observational Medical Outcome Partnership common data model (CDM). Results: We completed and documented the process for the CDM conversion. The coordinating center and participating sites reviewed the documents and refined the conversions based on the comments. The time required to convert data to the CDM varied widely across sites and included conversion to standard terminology codes and refinements of the conversion based on reviews. We mapped 97.2%, 86.7%, 92.6%, and 80.1% of domestic drug codes from the USA, Taiwan, Hong Kong, and Korea to RxNorm, respectively. The mapping rate from Japanese domestic drug codes to RxNorm (70.7%) was lower than from other countries, and we mapped remaining unmapped drugs to Anatomical Therapeutic Chemical Classification System codes. Because the native databases used international procedure coding systems for which mapping tables have been established, we were able to map >90% of diagnosis and procedure codes to standard terminology codes. Conclusion: The CDM established the foundation and reinforced collaboration for multinational pharmacoepidemiologic studies in Asia. Mapping of terminology codes was the greatest challenge, because of differences in health systems, cultures, and coding systems. Keywords: clinical coding, computer communication networks, feasibility studies, pharmacoepidemiology, pharmacovigilance

Background: Pain is common during pregnancy yet there are few contemporary studies of opioid utilisation in pregnancy. We aimed to describe prescription analgesic opioid use during pregnancy across four regions: Oceania [New South Wales (Australia), New Zealand], North America [Ontario (Canada), United States (US)], Northern Europe [Denmark, Finland, Iceland, Norway, Sweden, United Kingdom (UK)], and East Asia (Hong Kong, South Korea, Taiwan)., Methods: We applied a common protocol to population-based data to measure analgesic opioid dispensing or prescriptions during pregnancy prior to birth in 2000-2020. Populations captured included those with public and private insurance in the US, a sample of primary care practices in the UK and whole-of-population cohorts in the remainder. We examined prevalence of use, defined as at least one dispensing or prescribing and estimated trends over time. We described use by sociodemographic- and pregnancy characteristics., Results: Among a total of 20,306,228 pregnancies, 1,115,853 (55 per 1000) had at least one analgesic opioid dispensing or prescription, ranging from 4 per 1000 in the UK to 191 per 1000 in the US publicly insured population. We observed the greatest relative decrease in prevalence in Hong Kong (prevalence ratio 0.2; 95% CI 0.1-0.2 between 2005 and 2020) and greatest increase in Iceland (prevalence ratio 4.4; 95% CI 3.7-5.2 between 2004 and 2017). Codeine and tramadol were among the three most prevalent opioids in most populations. In a sensitivity analysis defining opioid use as two or more opioid dispensing or prescribing events, the prevalence of opioid use across populations was 17 per 1000., Conclusions: In this large multinational study, we observed wide global variation in prevalence of analgesic opioid use in pregnancy, yet patterns of use by sociodemographic- and pregnancy characteristics were relatively consistent. Analgesic opioid use remained stable or downward trending over time in most, but not all, countries., (Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc., on behalf of the American Society of Anesthesiologists.)

Background: There is limited and conflicting evidence on the comparative cardiometabolic safety and effectiveness of aripiprazole in the management of severe mental illness. We investigated the hypothesis that aripiprazole has a favourable cardiometabolic profile, but similar effectiveness when compared to olanzapine, quetiapine, and risperidone., Methods and Findings: We conducted an observational emulation of a head-to-head trial of aripiprazole versus olanzapine, quetiapine, and risperidone in UK primary care using data from the Clinical Practice Research Datalink. We included adults diagnosed with severe mental illness (i.e., bipolar disorder, schizophrenia, and other non-organic psychoses) who were prescribed a new antipsychotic between 2005 and 2017, with a 2-year follow-up to 2019. The primary outcome was total cholesterol at 1 year (cardiometabolic safety). The main secondary outcome was psychiatric hospitalisation (effectiveness). Other outcomes included body weight, blood pressure, all-cause discontinuation, and mortality. Analyses adjusted for baseline confounders, including sociodemographics, diagnoses, concomitant medications, and cardiometabolic parameters. We included 26,537 patients (aripiprazole, n = 3,573, olanzapine, n = 8,554, quetiapine, n = 8,289, risperidone, n = 6,121). Median (IQR) age was 53 (42-67) years, 55.4% were female, 82.3% White, and 18.0% were diagnosed with schizophrenia. Patients prescribed aripiprazole had similar total cholesterol levels after 1 year to those prescribed olanzapine (adjusted mean difference [aMD], -0.03, 95% CI, -0.09 to 0.02, p = 0.261), quetiapine (aMD, -0.03, 95% CI, -0.09 to 0.03, p = 0.324), and risperidone (aMD, -0.01, 95% CI, -0.08 to 0.05, p = 0.707). However, there was evidence that patients prescribed aripiprazole had better outcomes on other cardiometabolic parameters, such as body weight and blood pressure, especially compared to olanzapine. After additional adjustment for prior hospitalisation, patients prescribed aripiprazole had similar rates of psychiatric hospitalisation as those prescribed olanzapine (adjusted hazard ratio [aHR], 0.91, 95% CI, 0.82 to 1.01, p = 0.078), quetiapine (aHR, 0.94, 95% CI, 0.85 to 1.04, p = 0.230), or risperidone (aHR, 1.01, 95% CI, 0.91 to 1.12, p = 0.854)., Conclusions: Data from our large, powered, diverse, real-world target trial emulation sample, followed over 2 years, suggest that adults diagnosed with severe mental illness prescribed aripiprazole have similar total cholesterol 1 year after first prescription compared to those prescribed olanzapine, quetiapine, and risperidone. However, patients prescribed aripiprazole had better outcomes on some other cardiometabolic parameters, and there was little evidence of differences in effectiveness. Our findings inform a common clinical dilemma and contribute to the evidence base for real-world clinical decision-making on antipsychotic choice for patients diagnosed with severe mental illness., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: JFH has received consultancy fees from Wellcome Trust and funding grants from juli Health unrelated to the results of the current study. All other authors declare no competing interests., (Copyright: © 2025 Richards-Belle et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: Barcode medication administration (BCMA) systems may improve patient safety with successful integration and use. This study aimed to explore the barriers and enablers for the successful use of a BCMA system by examining the patterns of medication and patient scanning over time and potential safety implications., Methods: Retrospective longitudinal study informed by prospective clinical observations using data extracted from five hospital wards over the first 16 months after implementation to determine trends in medication and patient scanning rates, reasons for non-compliance and scanning mismatch alerts. Regression models were applied to explore factors influencing medication scanning rates across wards of different specialties., Results: Electronic data on 613 868 medication administrations showed overall medication scanning rates per ward ranged from 5.6% to 67% and patient scanning rates from 4.6% to 89%. Reported reasons for not scanning medications were 'barcode not readable' and 'unavailability of scanners'. Scanning rates declined over time and the pattern of reason codes for not scanning also changed. Factors associated with higher scanning rates included a locally led quality improvement (QI) initiative, the medication administration time and the medication formulation, for example, tablets and liquids. Overall, 37% of scanning alerts resulted in a change in user action. Staff tried to comply with the BCMA system workflow, but workarounds were observed., Discussion: Compliance with BCMA systems varied across wards and changed over time. QI initiatives hold promise to ensure sustained use of BCMA systems., Conclusions: BCMA systems may help to improve medication safety, but further research is needed to confirm sustained safety benefits., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Importance: Elevated body mass index (BMI) and type 2 diabetes are prevalent in asthma and are associated with an increase in the risk of asthma attacks. In experimental studies, the diabetes medications metformin and glucagon-like peptide-1 receptor agonists (GLP-1RA) have mitigated airway inflammation, hyperresponsiveness, and remodeling. However, epidemiological evidence is limited., Objective: To estimate the association of metformin and add-on antidiabetic medications (GLP-1RA, dipeptidyl peptidase-4 inhibitors, sulphonylureas, sodium-glucose cotransporter-2 inhibitors, and insulin) with asthma attacks., Design, Setting, and Participants: The study used data from the UK Clinical Practice Research Datalink (CPRD) Aurum linked hospital admissions and mortality data from 2004 to 2020. A triangulation approach was used that applied 2 distinct approaches to enhance robustness: a self-controlled case series (SCCS) and a metformin new user cohort with inverse probability of treatment weighting (IPTW). Eligible participants were new users of metformin with type 2 diabetes. To evaluate the association between metabolic phenotypes (BMI, glycemic control) and asthma phenotypes (type 2 inflammation, asthma severity), interaction analyses were conducted. Negative control analyses were conducted to assess for bias., Exposure: The primary exposure was metformin; secondary exposures included add-on antidiabetic medications., Main Outcomes: The primary outcome was first asthma exacerbation (short course of oral corticosteroids, unscheduled asthma-related hospital attendance, or death) during 12-month follow-up. Incidence rate ratios (IRRs) with 95% CIs were estimated using fixed-effect conditional Poisson models in the SCCS, and hazard ratios (HRs) were estimated using weighted Cox proportional hazards models in the cohort., Results: Of more than 2 million adults with asthma, 4278 patients (2617 women [61.2%]; mean [SD] age, 52.9 [13.6] years) were identified for the SCCS and 8424 patients (4690 women [55.7%]; unexposed: mean [SD] age, 61.6 [13.2] years; exposed: mean [SD] age, 59.7 [13.7] years) for the IPTW cohort. Metformin was found to be associated with fewer asthma attacks of similar magnitude in both approaches (SCCS: IRR, 0.68; 95% CI, 0.62-0.75; IPTW: HR, 0.76; 95% CI, 0.67-0.85). Negative control analyses did not find evidence of significant bias. Hemoglobin A1c levels, BMI, blood eosinophil cell counts, and asthma severity did not modify the association. The only add-on antidiabetic medication to have an additive association was GLP-1RA (SCCS: IRR, 0.60; 95% CI, 0.49-0.73)., Conclusions and Relevance: The results of this cohort study suggest that metformin was associated with a lower rate of asthma attacks, with further reductions with the use of GLP-1RA. This appeared to be associated with mechanisms other than through glycemic control or weight loss and occurred across asthma phenotypes.

Background: Contemporary data relating to antipsychotic prescribing in UK primary care for patients diagnosed with severe mental illness (SMI) are lacking., Aims: To describe contemporary patterns of antipsychotic prescribing in UK primary care for patients diagnosed with SMI., Method: Cohort study of patients with an SMI diagnosis (i.e. schizophrenia, bipolar disorder, other non-organic psychoses) first recorded in primary care between 2000 and 2017 derived from Clinical Practice Research Datalink. Patients were considered exposed to antipsychotics if prescribed at least one antipsychotic in primary care between 2000 and 2019. We compared characteristics of patients prescribed and not prescribed antipsychotics; calculated annual prevalence rates for antipsychotic prescribing; and computed average daily antipsychotic doses stratified by patient characteristics., Results: Of 309 378 patients first diagnosed with an SMI in primary care between 2000 and 2017, 212,618 (68.7%) were prescribed an antipsychotic between 2000 and 2019. Antipsychotic prescribing prevalence was 426 (95% CI, 420-433) per 1000 patients in the year 2000, reaching a peak of 550 (547-553) in 2016, decreasing to 470 (468-473) in 2019. The proportion prescribed antipsychotics was higher among patients diagnosed with schizophrenia (81.0%) than with bipolar disorder (64.6%) and other non-organic psychoses (65.7%). Olanzapine, quetiapine, risperidone and aripiprazole accounted for 78.8% of all antipsychotic prescriptions. Higher mean olanzapine equivalent total daily doses were prescribed to patients with the following characteristics: schizophrenia diagnosis, ethnic minority status, male gender, younger age and greater relative deprivation., Conclusions: Antipsychotic prescribing is dominated by olanzapine, quetiapine, risperidone and aripiprazole. We identified potential disparities in both the receipt and prescribed doses of antipsychotics across subgroups. To inform efforts to optimise prescribing and ensure equity of care, further research is needed to understand why certain groups are prescribed higher doses and are more likely to be treated with long-acting injectable antipsychotics compared with others.

Importance: In pregnancy, the benefits of lithium treatment for relapse prevention in psychiatric conditions must be weighed against potential teratogenic effects. Currently, there is a paucity of information on how and when lithium is used by pregnant women., Objective: To examine lithium use in the perinatal period., Design, Setting, and Participants: This cohort study used individual-level data of pregnancies from January 1, 2000, to December 31, 2021, in Australia, Denmark, Finland, Germany, Hong Kong, Iceland, Israel, New Zealand, Norway, South Korea, Sweden, Taiwan, the UK, and 2 cohorts in the US. Analyses were performed from September 1 to November 30, 2023., Exposures: The prevalence of lithium use as the proportion of pregnancies with at least 1 prescription fill or prescription within 3 months before pregnancy until childbirth was estimated using a common protocol. Lithium use during pregnancy by trimester and in the 3 months before and after pregnancy was examined., Main Outcomes and Measures: Comparison of prevalence between the first and last 3-year periods of available data., Results: Among 21 659 454 pregnancies from all collaborating sites, the prevalence of lithium use ranged from 0.07 per 1000 pregnancies in Hong Kong to 1.56 per 1000 in the US publicly insured population. Lithium use increased per 1000 pregnancies in 10 populations (Australia [0.60 to 0.74], Denmark [0.09 to 0.51], Finland [0.10 to 0.29], Iceland [0.24 to 0.99], Israel [0.25 to 0.37], Norway [0.24 to 0.47], South Korea [0.30 to 0.44], Sweden [0.42 to 1.07], the UK [0.07 to 0.10], and Taiwan [0.15 to 0.19]), remained stable in 4 populations (Germany [0.17 to 0.16], Hong Kong [0.06 to 0.06], and the publicly [1.50 to 1.34] and commercially [0.38 to 0.36] insured US populations), and decreased in 1 population (New Zealand [0.54 to 0.39]). Use of lithium decreased with each trimester of pregnancy, while prevalence of postpartum use was similar to prepregnancy levels. The proportion of lithium use in the second trimester compared with the prepregnancy period ranged from 2% in South Korea to 80% in Denmark., Conclusions and Relevance: Prevalence of lithium use in pregnant women over the past 2 decades varied markedly between populations. Patterns of use before, during, and after pregnancy suggest that many women discontinued lithium use during pregnancy and reinitiated treatment after childbirth, with large variations between countries. These findings underscore the need for internationally harmonized guidelines, specifically for psychiatric conditions among pregnant women that may benefit from lithium treatment.

Introduction: Chemotherapy forms the cornerstone of systemic treatment for advanced ovarian cancer, extending overall survival; however, drug-related toxicity can lead to treatment delays, potentially diminishing treatment efficacy. This study evaluated the impact of treatment delays on all-cause mortality of patients with ovarian cancer, to better inform decisions on patient management., Methods: This retrospective, population-based cohort study included 1517 women with advanced-stage ovarian cancer, receiving first-line adjuvant or neoadjuvant chemotherapy in 2014 and 2015. The frequency of inter-cycle delays >7 days was calculated using drug administration dates. Kaplan-Meier estimates were used to compare 2-year overall survival (OS) between patients who were delayed and those treated to schedule. Cox proportional hazards regression was used to investigate the impact of treatment delay on all-cause mortality. Inverse probability of treatment weighting propensity scores were used to adjust for confounding variables., Results: Delays >7 days occurred in 35.3% of patients. Two-year OS probability was 62.7% in patients who experienced treatment delays >7 days (95% CI, 58.7-66.9) compared to 69.1% in those treated to schedule (95% CI, 66.2-72.0). Delays were not significantly associated with all-cause mortality when adjusted for confounders (HR 1.00 95% CI, 0.83-1.20, P = .9)., Conclusions: Delays to chemotherapy treatment were not significantly associated with worsened survival in patients with advanced-stage ovarian cancer. These results can inform clinical decision making that prioritize toxicity management and quality of life for those treated with chemotherapy., (© The Author(s) 2024. Published by Oxford University Press.)

Background: People with mental health conditions were potentially more vulnerable than others to the neuropsychiatric effects of the COVID-19 pandemic and the global efforts taken to contain it. The aim of this multinational study was to examine the changes in psychotropic drug prescribing during the pandemic among people with depressive and anxiety disorders., Methods: This study included electronic medical records and claims data from nine databases in six countries (France, Germany, Italy, the UK, South Korea, and the USA) of patients with a diagnosis of depressive or anxiety disorders between 2016 and 2021. The outcomes were monthly prevalence rates of antidepressant, antipsychotic, and anxiolytic drug prescribing. The associations between the pandemic and psychotropic drug prescribing were examined with interrupted time series analyses for the total sample and stratified by sex and age group. People with lived experience were not involved in the research and writing process., Findings: Between Jan 1, 2016 and Dec 31, 2020, an average of 16 567 914 patients with depressive disorders (10 820 956 females [65·31%] and 5 746 958 males [34·69%]) and 15 988 451 patients with anxiety disorders (10 688 788 females [66·85%] and 5 299 663 males [33·15%]) were identified annually. Most patients with depressive disorders and anxiety disorders were aged 45-64 years. Ethnicity data were not available. Two distinct trends in prescribing rates were identified. The first pattern shows an initial surge at the start of the pandemic (eg, antipsychotics among patients with depressive disorders in MDCD_US (rate ratio [RR] 1·077, 95% CI 1·055-1·100), followed by a gradual decline towards the counterfactual level (RR 0·990, 95% CI 0·988-0·992). The second pattern, observed in four databases for anxiolytics among patients with depressive disorders and two for antipsychotics among patients with anxiety disorders, shows an immediate increase (eg, antipsychotics among patients with anxiety disorders in IQVIA_UK: RR 1·467, 95% CI 1·282-1·675) without a subsequent change in slope (RR 0·985, 95% CI 0·969-1·003). In MDCD_US and IQVIA_US, the anxiolytic prescribing rate continued to increase among patients younger than 25 years for both disorders., Interpretation: The study reveals persistently elevated rates of psychotropic drug prescriptions beyond the initial phase of the pandemic. These findings underscore the importance of enhanced mental health support and emphasise the need for regular review of psychotropic drug use among this patient group in the post-pandemic era., Funding: University Grants Committee, Research Grants Council, The Government of the Hong Kong Special Administrative Region., Competing Interests: Declaration of interests HL reports grants from Research Grants Council of Hong Kong, outside the submitted work. WCYL reports research grants from AIR@InnoHK administered by Innovation and Technology Commission, outside the submitted work. JH reports grants from UKRI, Consultancy Fees from Wellcome Trust and Juli Health, and patents pending and stock from Juli Health, outside the submitted work. COT reports stock or stock options and other financial or non-financial interests from Roche Pharmaceutical as an employee, outside the submitted work. XL reports grants from IQVIA, outside the submitted work. SF and DMK report stock or stock options and other financial or non-financial interests from Johnson and Johnson as employees, outside the submitted work. JL reports stock or stock options and other financial or non-financial interests from IQVIA as an employee, outside the submitted work. KKCM reports grants from the CW Maplethorpe Fellowship, National Institute of Health Research, UK, Hong Kong Research Grant Council, and the European Commission Horizon 2020 Framework, outside the submitted work. ICKW reports grants from Amgen, Bristol-Myers Squibb, Pfizer, Janssen, Bayer, GSK and Novartis, the Hong Kong RGC, and the Hong Kong Health and Medical Research Fund, National Institute for Health Research in England, European Commission, and National Health and Medical Research Council in Australia, consulting fees from IQVIA, payment for expert testimony and a role as an independent non-executive director of Jacobson Medical, Hong Kong, outside of the submitted work. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Socioeconomic inequality in infant mortality in the UK is rising. This study aims to identify contributory maternal and pregnancy factors that can explain the known association between area deprivation and infant mortality., Methods: A cohort study was conducted using Clinical Practice Research Datalink (CPRD) primary care data between 2004 and 2019 linked to the Index of Multiple Deprivation (IMD), and infant mortality from the Office for National Statistics death data. Potential maternal and pregnancy contributory factors included: maternal age, prior maternal health conditions, pregnancy lifestyle factors and complications, use of medications during pregnancy, and characteristics of birth. Counterfactual-based decomposition analysis was used to quantify the relative importance of equalising these factors to reduce inequalities in infant mortality., Findings: A total of 392,606 mother-child dyads were included in this study. The overall risk of infant mortality was greatest for individuals in the most deprived quintile (risk ratio 2.13 [95% CI 1.58-2.90]; risk difference 6.6 [3.8-8.8] per 10,000 live births) compared with the least deprived. Four contributory factors were identified as potentially important: preterm birth (Proportion eliminated [PE] 15.25% [95% CI 9.44-24.12%]), smoking during pregnancy (PE 13.61% [95% CI 3.96-80.97%]), maternal age <20 years at childbirth (PE 10.52% [95% CI 2.93-21.35%]) and maternal depression (PE 9.13% [95% CI 4.47-14.93%]). These collectively accounted for more than one-third of the socioeconomic inequality in mortality., Interpretation: Multifactorial interventions targeting maternal mental health, smoking, teenage pregnancy and preterm birth may mitigate a proportion of the effects of socioeconomic inequality but targeting these, alone, will not stem the rise in infant mortality. Structural efforts to reduce socioeconomic inequalities will also be required to prevent these excess infant deaths., Funding: UK Medical Research Council, Scottish Chief Scientist Office, Wellcome Trust., Competing Interests: FH received research funding from Glasgow Children Hospital Charity, Biotechnology and Biological Sciences Research Council, Understanding Children's Trust, and The Swedish Child Neuropsychiatry Science Foundation, consulting fee from the Chinese University of Hong Kong, and personal honorarium from Sage Publications. KM received research funding from CW Maplethorpe Fellowship, European Commission Horizon 2020, National Institute for Health and Care Research UK, Hong Kong Research Grant Council. JC received research funding from Bristol Myers Squibb, CSL-Vifor, British Heart Foundation, and Pharmacosmos, consulting fee from Pharmacosmos, CSL-Vifor, and Biopeutics, personal honorarium from Pharmacosmos and ABBOTT, travel support from Pharmacosmos, participated on advisory boards of Medtronic, ADAPT-CRT, CMR-Guide, PROTECT-HF, and have stocks or stock options in HeartFelt (non-invasive monitoring), Viscardia (synchronous diaphragmatic pacing). CD received research funding from Wellcome Trust. PI received research funding from Hong Kong Health and Medical Research Fund and Hong Kong General Research Fund. ICKW received research grants from Amgen, Janssen, GSK, Novartis, Pfizer, Bayer and Bristol-Myers Squibb and Takeda, Institute for Health Research in England, European Commission, National Health and Medical Research Council in Australia, The European Union's Seventh Framework Programme for research, technological development, Research Grants Council Hong Kong and Health and Medical Research Fund Hong Kong; consulting fees from IQVIA and World Health Organization; payment for expert testimony for Appeal Court in Hong Kong; serves on advisory committees for Member of Pharmacy and Poisons Board; is a member of the Expert Committee on Clinical Events Assessment Following COVID-19 Immunization; is a member of the Advisory Panel on COVID-19 Vaccines of the Hong Kong Government; is the non-executive director of Jacobson Medical in Hong Kong; and is the founder and director of Therakind Limited (UK), Advance Data Analytics for Medical Science (ADAMS) Limited (HK), Asia Medicine Regulatory Affairs (AMERA) Services Limited and OCUS Innovation Limited (HK, Ireland and UK). PW received research funding from Boehringer Ingelheim, Astrazeneca, Roche diagnostics, Novartis, personal honorarium from Novo Nordisk and Raisio. AP received research funding from Wellcome Trust, MRC, CSO, NIHR, Obesity Action Scotland, Health Foundation, and UKPRP., (© 2024 The Author(s).)

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, their effectiveness relative to each other and other second-line antihyperglycemic agents is unknown, without any major ongoing head-to-head clinical trials., Objectives: The aim of this study was to compare the cardiovascular effectiveness of SGLT2is, GLP-1 RAs, dipeptidyl peptidase-4 inhibitors (DPP4is), and clinical sulfonylureas (SUs) as second-line antihyperglycemic agents in T2DM., Methods: Across the LEGEND-T2DM (Large-Scale Evidence Generation and Evaluation Across a Network of Databases for Type 2 Diabetes Mellitus) network, 10 federated international data sources were included, spanning 1992 to 2021. In total, 1,492,855 patients with T2DM and cardiovascular disease (CVD) on metformin monotherapy were identified who initiated 1 of 4 second-line agents (SGLT2is, GLP-1 RAs, DPP4is, or SUs). Large-scale propensity score models were used to conduct an active-comparator target trial emulation for pairwise comparisons. After evaluating empirical equipoise and population generalizability, on-treatment Cox proportional hazards models were fit for 3-point MACE (myocardial infarction, stroke, and death) and 4-point MACE (3-point MACE plus heart failure hospitalization) risk and HR estimates were combined using random-effects meta-analysis., Results: Over 5.2 million patient-years of follow-up and 489 million patient-days of time at risk, patients experienced 25,982 3-point MACE and 41,447 4-point MACE. SGLT2is and GLP-1 RAs were associated with lower 3-point MACE risk than DPP4is (HR: 0.89 [95% CI: 0.79-1.00] and 0.83 [95% CI: 0.70-0.98]) and SUs (HR: 0.76 [95% CI: 0.65-0.89] and 0.72 [95% CI: 0.58-0.88]). DPP4is were associated with lower 3-point MACE risk than SUs (HR: 0.87; 95% CI: 0.79-0.95). The pattern for 3-point MACE was also observed for the 4-point MACE outcome. There were no significant differences between SGLT2is and GLP-1 RAs for 3-point or 4-point MACE (HR: 1.06 [95% CI: 0.96-1.17] and 1.05 [95% CI: 0.97-1.13])., Conclusions: In patients with T2DM and CVD, comparable cardiovascular risk reduction was found with SGLT2is and GLP-1 RAs, with both agents more effective than DPP4is, which in turn were more effective than SUs. These findings suggest that the use of SGLT2is and GLP-1 RAs should be prioritized as second-line agents in those with established CVD., Competing Interests: Funding Support and Author Disclosures This study was partially funded through National Institutes of Health grants R01 HL167858, K23 HL153775, R01 LM006910, R01 HG006139, and R01 HL169954 and the U.S. Department of Veterans Affairs under the research priority to “Put VA Data to Work for Veterans” (VA ORD 22-D4V). The funders had no role in the design and conduct of the protocol; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Dr Khera is an associate editor at JAMA; and has received support from the National Heart, Lung, and Blood Institute of the National Institutes of Health (awards R01 HL167858 and K23 HL153775) and the Doris Duke Charitable Foundation (award 2022060); has received research support, through Yale University, from Bristol Myers Squibb, Novo Nordisk, and BridgeBio; is a coinventor of U.S. provisional patent applications WO2023230345A1, US20220336048A1, 63/346,610, 63/428,569, 63/484,426, 63/508,315, 63/580,137, 63/606,203, 63/619,241, and 63/562,335, unrelated to the present work; and is a cofounder of Evidence2Health and Ensight-AI, precision health platforms to improve evidence-based cardiovascular care and cardiovascular diagnostics. Dr DuVall has received grants from Alnylam Pharmaceuticals, AstraZeneca Pharmaceuticals, Biodesix, Celgene, Cerner Enviza, GlaxoSmithKline, Janssen Pharmaceuticals, Novartis International, and Parexel International through the University of Utah or the Western Institute for Veteran Research (outside the submitted work). Dr Man has received support from the C.W. Maplethorpe Fellowship, the National Institute of Health Research, European Commission Framework Horizon 2020, the Hong Kong Research Grant Council, and the Innovation and Technology Commission of the Hong Kong Special Administration Region Government outside the submitted work). Dr Morales is supported by a Wellcome Trust Clinical Research Fellowship (214588/Z/18/Z). In the past 3 years, Dr Krumholz has received expenses and/or personal fees from UnitedHealth, Element Science, Aetna, Reality Labs, Tesseract/4Catalyst, F-Prime, the Siegfried and Jensen Law Firm, the Arnold and Porter Law Firm, and the Martin/Baughman Law Firm; is a cofounder of Refactor Health, HugoHealth, and Ensight-AI; and is associated with contracts, through Yale New Haven Hospital, from the Centers for Medicare and Medicaid Services and, through Yale University, from Johnson & Johnson. Dr You is chief technology officer of PHI Digital Healthcare. Dr Ross has received research support through Yale University from Johnson & Johnson to develop methods of clinical trial data sharing, from the Food and Drug Administration for the Yale-Mayo Clinic Center for Excellence in Regulatory Science and Innovation program (grant U01 FD005938), from the Agency for Healthcare Research and Quality (grant R01 HS022882), and from Arnold Ventures; has received research support from the Medical Device Innovation Consortium as part of the National Evaluation System for Health Technology and from the National Heart, Lung, and Blood Institute of the National Institutes of Health (grants R01 HS025164 and R01 HL144644); and was an expert witness at the request of the relator’s attorneys, the Greene Law Firm, in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen that was settled September 2022. Dr Thangaraj is a coinventor on provisional patent 63/606,203, unrelated to the present work, and is funded by grant 5T32 HL155000-03. Ms Blacketer, Dr Ostropolets, and Dr Ryan are employees of Johnson & Johnson. Dr Schuemie is an employee and shareholder of Johnson & Johnson. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. All rights reserved.)

Lithium is considered to be the most effective mood stabilizer for bipolar disorder. Evolving evidence suggested lithium can also regulate bone metabolism which may reduce the risk of fractures. While there are concerns about fractures for antipsychotics and mood stabilizing antiepileptics, very little is known about the overall risk of fractures associated with specific treatments. This study aimed to compare the risk of fractures in patients with bipolar disorder prescribed lithium, antipsychotics or mood stabilizing antiepileptics (valproate, lamotrigine, carbamazepine). Among 40,697 patients with bipolar disorder from 1993 to 2019 identified from a primary care electronic health record database in the UK, 13,385 were new users of mood stabilizing agents (lithium:2339; non-lithium: 11,046). Lithium was associated with a lower risk of fractures compared with non-lithium treatments (HR 0.66, 95 % CI 0.44-0.98). The results were similar when comparing lithium with prolactin raising and sparing antipsychotics, and individual antiepileptics. Lithium use may lower fracture risk, a benefit that is particularly relevant for patients with serious mental illness who are more prone to falls due to their behaviors. Our findings could help inform better treatment decisions for bipolar disorder, and lithium's potential to prevent fractures should be considered for patients at high risk of fractures., Competing Interests: Declaration of competing interest Esther W. Chan has received grants from Research Grants Council (RGC, Hong Kong), Research Fund Secretariat of the Food and Health Bureau, National Natural Science Fund of China, Bayer, Bristol-Myers Squibb, Pfizer, Janssen, Novartis, Amgen, AstraZeneca, Takeda, the RGA Reinsurance Company, Narcotics Division of the Security Bureau of the Hong Kong Special Administrative Region, the National Health and Medical Research Council Australia; consulting fees from AstraZeneca, Pfizer and Novartis; and honorarium from the Hospital Authority Hong Kong, outside the submitted work. Joseph F. Hayes has received consultancy fees from Wellcome Trust and juli Health. Kenneth K.C. Man received the CW Maplethorpe Fellowship, grants from the National Institute for Health Research (United Kingdom), the European Union Horizon 2020 Framework, Innovation and Technology Commission of the Hong Kong Special Administration Region Government, and Hong Kong Research Grant Council and personal fees from IQVIA Holdings, Inc., unrelated to this work. Ian C.K.Wong received research grants from Amgen, Janssen, GSK, Novartis, Pfizer, Bayer and Bristol-Myers Squibb and Takeda, Institute for Health Research in England, European Commission, National Health and Medical Research Council in Australia, The European Union's Seventh Framework Programme for research, technological development, Research Grants Council Hong Kong and Health and Medical Research Fund Hong Kong; consulting fee from IQVIA and WHO; payment for expert testimony for Appeal Court in Hong Kong; serves on advisory committees for Member of Pharmacy and Poisons Board; Member of the Expert Committee on Clinical Events Assessment Following COVID-19 Immunization; Member of the Advisory Panel on COVID-19 Vaccines of the Hong Kong Government; is the non-executive director of Jacobson Medical in Hong Kong; is the Founder and Director of Therakind Limited (UK), Advance Data Analytics for Medical Science (ADAMS) Limited (HK), Asia Medicine Regulatory Affairs (AMERA) Services Limited and OCUS Innovation Limited (HK, Ireland and UK). Ching-Lung Cheung received research grants and the honorarium from Amgen, research grant support from HMRF, and the honorarium from Abbott. Wallis C.Y. Lau reports grant from Diabetes UK, AIR@InnoHK administered by Innovation and Technology Commission, outside the submitted work. Vanessa W.S. Ng, Miriam T.Y. Leung, and David P.J. Osborn declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aims: Women with atrial fibrillation (AF) are under-represented in randomised controlled trials (RCTs) of direct oral anticoagulants (DOACs). This systematic review and meta-analysis of RCTs and observational studies examined sex-specific outcomes of DOACs in AF., Methods: PubMed, Embase, Web of Science and Cochrane Library were searched from January 2008 to November 2022. Sex-specific comparative outcomes of stroke/systemic embolism (SE), major bleeding, intracranial haemorrhage (ICH) and gastrointestinal bleeding (GIB) between oral anticoagulants were pooled using random effects models. P values for interaction were calculated to examine differences in results between sexes. RCTs and observational studies were meta-analysed separately., Results: 5 RCTs and 33 observational studies were included, totalling 1 085 931 women and 1 387 123 men. Meta-analyses showed that for both sexes, DOAC versus warfarin was generally associated with lower risk of stroke/SE, major bleeding and ICH; in DOAC-DOAC comparisons, rivaroxaban versus dabigatran had higher GIB risk. The only sex-specific difference observed was that when compared with warfarin, women had higher GIB risk with rivaroxaban (women: pooled risk ratio (pRR)=1.34, 95% CI=1.18 to 1.51; men: pRR=0.97, 95% CI=0.85 to 1.10; p value for interaction (p for interaction)<0.001) and possibly dabigatran (women: pRR=1.25, 95% CI=0.92 to 1.70; men: pRR=0.83, 95% CI=0.72 to 0.97; p-for-interaction=0.02). The sex difference in GIB remained for rivaroxaban when a Bonferroni-corrected significance level was used (α=0.003). No sex-specific GIB data for apixaban and edoxaban was available for the meta-analysis., Conclusions: For both sexes, DOACs generally demonstrated favourable effectiveness and safety over warfarin. However, observational data suggested that women may have higher GIB risk with rivaroxaban and possibly dabigatran than warfarin. Further studies are warranted to verify our findings and elucidate sex-specific GIB risk with apixaban and edoxaban, of which the data is currently lacking., Prospero Registration Number: CRD42022325027., Competing Interests: Competing interests: ZW’s current post is partly supported by the AIR@InnoHK administered by Innovation and Technology Commission. KKCM was supported by the CW Maplethorpe Fellowship and received research funding from the National Institute of Health Research, UK, European Commission Horizon 2020 framework and Hong Kong Research Grants Council and personal fee from IQVIA, outside the scope of the submitted work. GYHL is consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, Anthos and Daiichi-Sankyo, no fees was received personally. ICKW has received research funding from the National Institute of Health Research, UK, European Commission Horizon 2020 framework, the Hong Kong Research Grants Council, the Hong Kong Health and Medical Research Fund, Amgen, Janssen, Novartis and GSK for medication safety research, outside the scope of the submitted work. He also received funding from Bristol-Myers Squibb, Pfizer and Bayer on DOACs research but it is not associated with the current study. His current post is partly funded by the AIR@InnoHK administered by Innovation and Technology Commission. WL reported research funding from the AIR@InnoHK administered by Innovation and Technology Commission, outside the scope of the submitted work. There are no other relationships or activities to disclose., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Previous studies report an association between maternal diabetes mellitus (MDM) and attention-deficit/hyperactivity disorder (ADHD), often overlooking unmeasured confounders such as shared genetics and environmental factors. We therefore conducted a multinational cohort study with linked mother-child pairs data in Hong Kong, New Zealand, Taiwan, Finland, Iceland, Norway and Sweden to evaluate associations between different MDM (any MDM, gestational diabetes mellitus (GDM) and pregestational diabetes mellitus (PGDM)) and ADHD using Cox proportional hazards regression. We included over 3.6 million mother-child pairs between 2001 and 2014 with follow-up until 2020. Children who were born to mothers with any type of diabetes during pregnancy had a higher risk of ADHD than unexposed children (pooled hazard ratio (HR) = 1.16, 95% confidence interval (CI) = 1.08-1.24). Higher risks of ADHD were also observed for both GDM (pooled HR = 1.10, 95% CI = 1.04-1.17) and PGDM (pooled HR = 1.39, 95% CI = 1.25-1.55). However, siblings with discordant exposure to GDM in pregnancy had similar risks of ADHD (pooled HR = 1.05, 95% CI = 0.94-1.17), suggesting potential confounding by unmeasured, shared familial factors. Our findings indicate that there is a small-to-moderate association between MDM and ADHD, whereas the association between GDM and ADHD is unlikely to be causal. This finding contrast with previous studies, which reported substantially higher risk estimates, and underscores the need to reevaluate the precise roles of hyperglycemia and genetic factors in the relationship between MDM and ADHD., (© 2024. The Author(s).)

Aims: Population-wide restrictions during the COVID-19 pandemic may create barriers to mental health diagnosis. This study aims to examine changes in the number of incident cases and the incidence rates of mental health diagnoses during the COVID-19 pandemic., Methods: By using electronic health records from France, Germany, Italy, South Korea and the UK and claims data from the US, this study conducted interrupted time-series analyses to compare the monthly incident cases and the incidence of depressive disorders, anxiety disorders, alcohol misuse or dependence, substance misuse or dependence, bipolar disorders, personality disorders and psychoses diagnoses before (January 2017 to February 2020) and after (April 2020 to the latest available date of each database [up to November 2021]) the introduction of COVID-related restrictions., Results: A total of 629,712,954 individuals were enrolled across nine databases. Following the introduction of restrictions, an immediate decline was observed in the number of incident cases of all mental health diagnoses in the US (rate ratios (RRs) ranged from 0.005 to 0.677) and in the incidence of all conditions in France, Germany, Italy and the US (RRs ranged from 0.002 to 0.422). In the UK, significant reductions were only observed in common mental illnesses. The number of incident cases and the incidence began to return to or exceed pre-pandemic levels in most countries from mid-2020 through 2021., Conclusions: Healthcare providers should be prepared to deliver service adaptations to mitigate burdens directly or indirectly caused by delays in the diagnosis and treatment of mental health conditions.

Objective: The short-term safety of methylphenidate (MPH) has been widely demonstrated; however the long-term safety is less clear. The aim of this study was to investigate the safety of MPH in relation to pubertal maturation and to explore the monitoring of bone age., Method: Participants from ADDUCE, a two-year observational longitudinal study with three parallel cohorts (MPH group, no-MPH group, and a non-ADHD control group), were compared with respect to Tanner staging. An Italian subsample of medicated-ADHD was further assessed by the monitoring of bone age., Results: The medicated and unmedicated ADHD groups did not differ in Tanner stages indicating no higher risk of sexual maturational delay in the MPH-treated patients. The medicated subsample monitored for bone age showed a slight acceleration of the bone maturation after 24 months, however their predicted adult height remained stable., Conclusion: Our results do not suggest safety concerns on long-term treatment with MPH in relation to pubertal maturation and growth., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: SC reports collaboration on projects from the EU Seventh Framework Program and on clinical trials sponsored by Lundbeck, Otsuka, Janssen-Cilag, Angelini and Acadia. KKCM reports grants from the CW Maplethorpe Fellowship, the UK National Institute for Health and Care Research (NIHR), the EU Horizon 2020 Framework, and the Hong Kong Research Grant Council, and personal fees from IQVIA Holdings, outside the submitted work. CB reports collaboration on projects from the EU Seventh Framework Program and on clinical trials sponsored by Otsuka, Janssen-Cilag, Angelini and Acadia. JB has been in the past 3 years a consultant to / member of advisory board of / and/or speaker for Takeda, Medice, Angelini, Janssen, Boehringer-Ingelheim, and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, royalties. MD has received research funding from Takeda–Shire, outside the submitted work. RWD—For the past 3 years, he has no conflicts of interest to report. As a former company employee, he has been a stockholder of Eli Lilly & Co. FD reports collaboration as sub-investigator in clinical trials sponsored by Lundbeck as an independent rater in clinical trials sponsored by Servier and Acadia. BF has been a consultant or speaker for Abbvie, Actelion, Allergan, Almirall, Alnylam, Amgen, Astellas, Astrazeneca, Bayer, Biogen, Biopecs, Bioproject, Biotronik, BMS,Boehringer, Celgène, Daiichi-Sankyio, Ethypharm, Forestlab, Genevrier, Genzyme, Gilead, Grünenthal, GSK, Idorsia, IMS, Indivior, IQVIA, JNJ, Léo, Lilly, Lundbeck, Menarini, MSD, Novartis, Novonordisk, Otsuka, Pfizer, Pierre-Frabre, Recordati, Roche, SANOFI, Servier, Takeda, UCB, ViiV, and Wellmera. AH has received compensation for serving as consultant or speaker for Shire–Takeda and Medice, unrelated to this work. KKCM reports grants from the CW Maplethorpe Fellowship, the UK National Institute for Health and Care Research (NIHR), the EU Horizon 2020 Framework, and the Hong Kong Research Grant Council, and personal fees from IQVIA Holdings, outside the submitted work. CH reports research funding from the NIHR including the Health Technology Assessment SATURN trial (grant ref: NIHR128472) comparing methylpheidate with guanfacine for children and young people with ADHD and tics. CH was chair of the NICE Guideline (CG155) for psychosis and schizophrenia in children and young people; member of the NICE ADHD Guideline Update committee (NG87) and is a member of Eunethydis and the Europhean ADHD Guideline Group. SM reports speaker’s fee, travel support, and research support from Shire, outside the submitted work. AN reports research funding from the EU, the German Ministry of Health, and the German Federal Joint Committee, outside the submitted work. PN has been a consultant or speaker for Medice, Servier, and Egis Pharmaceuticals, outside the submitted work. ER received speaker’s fee and travel support from Shire, outside the submitted work. PN has been a consultant or speaker for Medice, Servier, and Egis Pharmaceuticals, outside the submitted work. ER received speaker’s fee and travel support from Shire, outside the submitted work. ESB has received in the last 3 years speakers fees from Takeda and Medice and research support from QBTech. AZ served in an advisory or consultancy role for Angelini, EduPharma, Servier; received conference support or speaker’s fee from Angelini and Janssen; participated in clinical trials conducted by Angelini, Janssen, Lundbeck, Otsuka, Roche, Sevier, and Shire; and received royalties from Giunti OS and Oxford University Press. ICKW reports research and educational funding from Amgen, Bristol Myers Squibb, Pfizer, Janssen, Bayer, GSK, Novartis, Takeda, the Hong Kong Research Grants Council, the Hong Kong Health and Medical Research Fund, the Hong Kong Innovation and Technology Commission, the NIHR, the EU, and the Australian National Health and Medical Research Council, and the expert testimony payment from the Hong Kong Court of Final Appeal; outside the submitted work. TB served in an advisory or consultancy role for eye level, Infectopharm, Medice, Neurim Pharmaceuticals, Oberberg GmbH and Takeda. He received conference support or speaker’s fee by Janssen, Medice and Takeda. He received royalities from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press; the present work is unrelated to these relationships. DC reports, in the past 3 years, a consultant, member of advisory board, or speaker role for Takeda–Shire, Medice, Novartis, and Servier. He has received royalties from Oxford University Press and Cambridge University Press; research support from the Australian National Health and Medical Research Council and the Royal Children’s Hospital Foundation; and funding for the current study from the European Commission. All other authors declare no competing interests.

Objective: Short-term RCTs have demonstrated that MPH-treatment significantly reduces ADHD-symptoms, but is also associated with adverse events, including sleep problems. However, data on long-term effects of MPH on sleep remain limited., Methods: We performed a 2-year naturalistic prospective pharmacovigilance multicentre study. Participants were recruited into three groups: ADHD patients intending to start MPH-treatment (MPH-group), those not intending to use ADHD-medication (no-MPH-group), and a non-ADHD control-group. Sleep problems were assessed with the Children's-Sleep-Habits-Questionnaire (CSHQ)., Results: 1,410 participants were enrolled. Baseline mean CSHQ-total-sleep-scores could be considered clinically significant for the MPH-group and the no-MPH-group, but not for controls. The only group to show a significant increase in any aspect of sleep from baseline to 24-months was the control-group. Comparing the MPH- to the no-MPH-group no differences in total-sleep-score changes were found., Conclusion: Our findings support that sleep-problems are common in ADHD, but don't suggest significant negative long-term effects of MPH on sleep., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AH has received compensation for serving as consultant or speaker for Shire–Takeda and Medice, unrelated to this work. KKCM reports grants from the CW Maplethorpe Fellowship, the UK National Institute for Health and Care Research (NIHR), the EU Horizon 2020 Framework, and the Hong Kong Research Grant Council, and personal fees from IQVIA Holdings, outside the submitted work. JB has been in the past 3 years a consultant, member of advisory board, or speaker for Takeda–Shire, Roche, Medice, Angelini, Janssen, and Servier. SC reports collaboration on projects from the EU Seventh Framework Programme and on clinical trials sponsored by Shire Pharmaceutical Company, Lundbeck, Otsuka, Janssen-Cilag, and Angelini. MD has received research funding from Takeda–Shire, outside the submitted work. RWD—For the past 3 years, he has no conflicts of interest to report. As a former company employee, he has been a stock holder of Eli Lilly & Co. BF has been a consultant or speaker for Abbvie, Actelion, Allergan, Almirall, Alnylam, Amgen, Astellas, Astrazeneca, Bayer, Biogen, Biopecs, Bioproject, Biotronik, BMS, Boehringer, Celgène, Daiichi-Sankyio, Ethypharm, Forestlab, Genevrier, Genzyme, Gilead, Grünenthal, GSK, Idorsia, IMS, Indivior, IQVIA, JNJ, Léo, Lilly, Lundbeck, Menarini, MSD, Novartis, Novonordisk, Otsuka, Pfizer, Pierre-Frabre, Recordati, Roche, SANOFI, Servier, Takeda, UCB, ViiV, and Wellmera. CH reports research funding from the NIHR including the Health Technology Assessment SATURN trial (grant ref: NIHR128472) comparing MPH with guanfacine for children and young people with ADHD and tics. CH was chair of the NICE Guideline (CG155) for psychosis and schizophrenia in children and young people; member of the NICE ADHD Guideline Update committee (NG87) and is a member of Eunethydis and the European ADHD Guideline Group. SM reports speaker’s fee, travel support, and research support from Shire, outside the submitted work. AN reports research funding from the EU, the German Ministry of Health, and the German Federal Joint Committee, outside the submitted work. PN has been a consultant or speaker for Medice, Servier, and Egis Pharmaceuticals, outside the submitted work. ER received speaker’s fee and travel support from Shire, outside the submitted work. ESB has received in the last 3 years speakers fees from Takeda and Medice and research support from QBTech. AZ served in an advisory or consultancy role for Angelini, EduPharma, Servier; received conference support or speaker’s fee from Angelini and Janssen; participated in clinical trials conducted by Angelini, Janssen, Lundbeck, Otsuka, Roche, Servier, and Shire; and received royalties from Giunti OS and Oxford University Press. ICKW reports research and educational funding from Amgen, Bristol Myers Squibb, Pfizer, Janssen, Bayer, GSK, Novartis, Takeda, the Hong Kong Research Grants Council, the Hong Kong Health and Medical Research Fund, the Hong Kong Innovation and Technology Commission, the NIHR, the EU, and the Australian National Health and Medical Research Council, and the expert testimony payment from the Hong Kong Court of Final Appeal; outside the submitted work. DC reports, in the past 3 years, a consultant, member of advisory board, or speaker role for Takeda–Shire, Medice, Novartis, and Servier. He has received royalties from Oxford University Press and Cambridge University Press; research support from the Australian National Health and Medical Research Council and the Royal Children’s Hospital Foundation; and funding for the current study from the European Commission. All other authors declare no competing interests. TB served in an advisory or consultancy role for Eyelevel, Infectopharm, Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg, Roche, and Takeda; received conference support or speaker’s fee from Jansen, Medice, and Takeda; and royalities from Hogrefe, Kohlhammer, CIP Medien, and Oxford University Press; outside the submitted work.

Purpose: A recent observational study suggested statins could reduce cancer diagnosis in patients with heart failure (HF). The findings need to be validated using robust epidemiological methods. This study aimed to evaluate the effect of statin treatment on the risk of cancer in patients with HF., Methods: We conducted two target trial emulations using primary care data from IQVIA Medical Research Database-UK (2000 to 2019) with a clone-censor-weight design. The first emulated trial addressed the treatment initiation effect: initiating within 1 year versus not initiating a statin after the HF diagnosis. The second emulated trial addressed the cumulative exposure effect: continuing a statin for ≤3 years, 3-6 years, and >6 years after initiation. The study outcomes were any incident cancer and site-specific cancer diagnoses. Weighted pooled logistic regression models were used to estimate 10-year risk ratios (RR). 95% confidence intervals (CIs) were estimated using non-parametric bootstrapping., Results: The first emulated trial showed that, compared to no statin, statins did not reduce the cancer risk in patients with HF (RR, 1.05; 95% CI, 0.94-1.15). The second emulated trial showed that, compared to treatment ≤3 years, statins with longer durations did not reduce the cancer risk (3-6 years: RR, 0.94; 95% CI, 0.70-1.33. >6 years: RR, 0.97; 95% CI, 0.79-1.26). No significant risk difference was observed on any site-specific cancer diagnoses., Conclusions: The results from the target trial emulations suggest that statin treatment is not associated with cancer risk in patients with HF., (© 2024 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

The persisting risk of long-term health consequences of SARS-CoV-2 infection and the protection against such risk conferred by COVID-19 vaccination remains unclear. Here we conducted a retrospective territory-wide cohort study on 1,175,277 patients with SARS-CoV-2 infection stratified by their vaccination status and non-infected controls to evaluate the risk of clinical sequelae, cardiovascular and all-cause mortality using a territory-wide public healthcare database with population-based vaccination records in Hong Kong. A progressive reduction in risk of all-cause mortality was observed over one year between patients with SARS-CoV-2 infection and controls. Patients with complete vaccination or have received booster dose incurred a lower risk of health consequences including major cardiovascular diseases, and all-cause mortality than unvaccinated or patients with incomplete vaccination 30-90 days after infection. Completely vaccinated and patients with booster dose of vaccines did not incur significant higher risk of health consequences from 271 and 91 days of infection onwards, respectively, whilst un-vaccinated and incompletely vaccinated patients continued to incur a greater risk of clinical sequelae for up to a year following SARS-CoV-2 infection. This study provided real-world evidence supporting the effectiveness of COVID-19 vaccines in reducing the risk of long-term health consequences of SARS-CoV-2 infection and its persistence following infection., (© 2024. The Author(s).)

Aim: To assess the risk of amputation associated with sodium-glucose co-transporter-2 inhibitors (SGLT2is) among patients with type 2 diabetes, across categories of baseline cardiovascular disease (CVD) and diuretic use (DU)., Materials and Methods: We conducted an active comparator, new-user cohort study using Korea's nationwide claims data (2015-2020). The study cohort consisted of patients with type 2 diabetes who initiated SGLT2is or dipeptidyl peptidase-4 inhibitors (DPP4is). Cohort entry was defined by first prescription date. We then classified patients into four discrete subcohorts based on their baseline status of CVD and DU as (1) CVD+/DU+, (2) CVD+/DU-, (3) CVD-/DU+ and (4) CVD-/DU-. We performed 1:1 propensity score (PS) matching within each cohort and estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for the risk of amputation with SGLT2is versus DPP4is using Cox models., Results: We identified 219 900 PS-matched pairs of SGLT2is and DPP4is (CVD+/DU+, n = 11 719; CVD+/DU-, n = 26 092; CVD-/DU+, n = 26 894; and CVD-/DU-, n = 155 195), with well-balanced baseline covariates across all cohorts. Significantly lower risks of amputation with SGLT2is versus DPP4is were found in CVD+/DU+ (HR 0.36, 95% CI 0.14-0.90), CVD+/DU- (0.45, 0.21-0.99) and CVD-/DU- (0.48, 0.33-0.70), but not in CVD-/DU+ (0.54, 0.26-1.12). Consistent trends in estimates were found across various sensitivity analyses., Conclusions: Initiating SGLT2is against DPP4is did not increase the risk of amputation across patient populations of varying vulnerability. These findings based on routine practice will reassure clinicians of the safety of SGLT2is with regard to amputation risk in selected high-risk patients with type 2 diabetes., (© 2023 John Wiley & Sons Ltd.)

Introduction: Chronic hepatitis B virus (HBV) infection is associated with significant global morbidity and mortality. Low treatment rates are observed in patients living with HBV; the reasons for this are unclear. This study sought to describe patients' demographic, clinical and biochemical characteristics across three continents and their associated treatment need., Methods: This retrospective cross-sectional post hoc analysis of real-world data used four large electronic databases from the United States, United Kingdom and China (specifically Hong Kong and Fuzhou). Patients were identified by first evidence of chronic HBV infection in a given year (their index date) and characterized. An algorithm was designed and applied, wherein patients were categorized as treated, untreated but indicated for treatment and untreated and not indicated for treatment based on treatment status and demographic, clinical, biochemical and virological characteristics (age; evidence of fibrosis/cirrhosis; alanine aminotransferase [ALT] levels, HCV/HIV coinfection and HBV virology markers)., Results: In total, 12,614 US patients, 503 UK patients, 34,135 patients from Hong Kong and 21,614 from Fuzhou were included. Adults (99.4%) and males (59.0%) predominated. Overall, 34.5% of patients were treated at index (range 15.9-49.6%), with nucleos(t)ide analogue monotherapy most commonly prescribed. The proportion of untreated-but-indicated patients ranged from 12.9% in Hong Kong to 18.2% in the UK; almost two-thirds of these patients (range 61.3-66.7%) had evidence of fibrosis/cirrhosis. A quarter (25.3%) of untreated-but-indicated patients were aged ≥ 65 years., Conclusion: This large real-world dataset demonstrates that chronic hepatitis B infection remains a global health concern; despite the availability of effective suppressive therapy, a considerable proportion of predominantly adult patients apparently indicated for treatment are currently untreated, including many patients with fibrosis/cirrhosis. Causes of disparity in treatment status warrant further investigation., (© 2023. GSK.)

Introduction and Objective: The risk of seizure in offspring following prenatal exposure to levothyroxine is not well investigated. This study aimed to evaluate the association between levothyroxine treatment among pregnant women and the risk of seizure in their offspring., Methods: This population-based cohort study included all pregnant women who delivered a live birth between January 2001 to January 2018, with a follow-up to December 2020, using data from the Hong Kong Clinical Data Analysis and Reporting System. Propensity score fine-stratification weighted hazard ratios (wHR) with 95% confidence intervals (CIs) were presented to assess the association between maternal levothyroxine use during pregnancy and seizures in children., Results: Among 528,343 included mother-child pairs, 3044 children were prenatally exposed to levothyroxine at any time during the pregnancy period. A significantly increased risk of seizure was observed in children of the prenatally exposed group compared with the prenatally unexposed group (wHR 1.12, 95% CI 1.02-1.22). An increased risk of seizure was observed when comparing the prenatally exposed group with euthyroid mothers who had no history of thyroid-related diagnosis or prescriptions (wHR 1.12, 95% CI 1.02-1.23). However, no significant difference was observed between the prenatally exposed group and those previously exposed to levothyroxine but had stopped during pregnancy (wHR 0.97, 95% CI 0.66-1.44). No significant difference was observed in the sibling-matched analysis either (wHR 1.23, 95% CI 0.76-2.01)., Conclusion: The observed increased risk of seizure in children born from mothers exposed to levothyroxine during pregnancy might be due to residual confounding by maternal thyroid disease. The findings support the current guidelines on the safe use of levothyroxine treatment during pregnancy., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: In response to the unprecedented challenges posed by the COVID-19 pandemic, conventional recruitment approaches were halted, causing the suspension of numerous clinical trials. Previously, Facebook (Meta Platforms, Inc) has emerged as a promising tool for augmenting participant recruitment. While previous research has explored the use of Facebook for surveys and qualitative studies, its potential for recruiting participants into randomized controlled trials (RCTs) remains underexplored., Objective: This study aimed to comprehensively examine the effectiveness of using Facebook groups and pages to facilitate participant recruitment during the COVID-19 pandemic for an RCT on the effectiveness of a remote parenting program, 1-2-3 Magic, in families who have children with attention-deficit/hyperactivity disorder (ADHD) in the United Kingdom., Methods: We disseminated 5 Facebook posts with an attached digital flyer across 4 prominent ADHD UK support groups and pages run by the National Attention Deficit Disorder Information and Support Services, reaching an audience of around 16,000 individuals over 2 months (January 7 to March 4, 2022). Eligibility criteria mandated participants to be parents or caregivers of a child with diagnosed ADHD aged 12 years or younger, be residing in the United Kingdom, have access to stable internet, and have a device with the Zoom (Zoom Video Communications) app. Participants were required to have never attended 1-2-3 Magic training previously. Prospective participants expressed their interest through Microsoft Forms (Microsoft Corporation). The trial aimed to recruit 84 parents. It is important to note that the term "parent" or "caregiver" in the RCT and in this study within a trial refers to anybody who has legal responsibility for the child., Results: Overall, 478 individuals registered their interest through Microsoft Forms within the stipulated 2-month window. After the eligibility check, 135 participants were contacted for a baseline meeting through Zoom. The first 84 participants who attended a baseline meeting and returned a completed consent form were enrolled. Subsequently, another 16 participants were added, resulting in a final sample of 100 participants. This recruitment strategy incurred negligible expenses and demanded minimal human resources. The approach yielded favorable outcomes by efficiently attracting eligible participants in a condensed time frame, transcending geographical barriers throughout the United Kingdom, which would have been tedious to achieve through traditional recruitment methods., Conclusions: Our experience demonstrated that digital flyers posted in the targeted Facebook groups were a cost-effective and quick method for recruiting for an RCT, which opened during the COVID-19 pandemic when lockdown restrictions were in place in the United Kingdom. Trialists should consider this low-cost recruitment intervention for trials going forward, and in the case of a global pandemic, this novel recruitment method enabled the trial to continue where many have failed., Trial Registration: International Standard Randomized Controlled Trial Number (ISRCTN) 15281572; https://www.isrctn.com/ISRCTN15281572., (©Kirstie H T W Wong, Wallis C Y Lau, Kenneth K C Man, Andrea Bilbow, Patrick Ip, Li Wei. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 17.10.2023.)

Study Objectives: To investigate the trends in the consumption of benzodiazepines (BZDs) and Z-drugs at global, regional, and national levels from 2008 to 2018, across 67 countries and regions., Methods: This cross-sectional descriptive study investigated the consumption of BZDs and Z-drugs analyzed by global pharmaceutical sales data from the IQVIA-Multinational Integrated Data Analysis System database between 2008 and 2018. Consumption was measured in defined daily dose (DDD) per 1000 inhabitants per day (DDD/TID). The global, regional, and national trends were estimated using linear mixed models. Additional analyses were conducted by grouping countries by income level. The association between consumption and Gross Domestic Product (GDP) and the prevalence of different medical conditions was explored in univariable linear models., Results: BZD consumption decreased annually by -1.88% (95% CI: -2.27%, -1.48%), and Z-drugs increased by + 3.28% (+2.55%, +4.01%). In 2008, the top ten countries for BZD and Z-drug consumption were all European, ranging from 63.69 to 128.24 DDD/TID. Very low levels were found in Russia, Kuwait, United Arab Emirates, Saudi Arabia, French West Africa, and the Philippines, with DDD/TID < 1. The consumption in high-income countries was much higher than in middle-income countries. The results showed that increased consumption of BZDs and Z-drugs was statistically associated (p < 0.05) with higher GDP and increased prevalence of anxiety, self-harm, neurological disorders, chronic respiratory diseases, cardiovascular diseases, and cancers., Conclusions: Distinct differences in consumption and trends of BZDs and Z-drugs were found across different countries and regions. Further exploration is needed to understand the association and safety of the use of BZDs and Z-drugs in patients with comorbidities., (© The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Recent studies raised concerns about the increasing use of gabapentinoids in different countries. With their potential for misuse and addiction, understanding the global consumption of gabapentinoids will offer us a platform to examine the need for any interventional policies. This longitudinal trend study utilised pharmaceutical sales data from 65 countries and regions across the world to evaluate the global trends in gabapentinoid consumption between 2008-2018. The multinational average annual percentage change of gabapentinoid consumption was +17.20%, increased from 4.17 defined daily dose per ten thousand inhabitants per day (DDD/TID) in 2008 to 18.26 DDD/TID in 2018. High-income countries had the highest pooled gabapentinoid consumption rate (39.92 DDD/TID) in 2018, which was more than six times higher than the lower-middle income countries (6.11 DDD/TID). The study shows that despite differences in healthcare system and culture, a consistent increase in gabapentinoid consumption is observed worldwide, with high-income countries remaining the largest consumers., (© 2023. Springer Nature Limited.)

Background: There is no real-world evidence regarding the association between beta-blocker use and mortality or cardiovascular outcomes in patients with obstructive sleep apnoea (OSA). We aimed to investigate the impact of beta-blocker use on all-cause mortality and cardiovascular diseases (CVDs) in patients with OSA., Methods: We conducted a target trial emulation study of 37,581 patients with newly diagnosed OSA from 1st January 2000 to 30th November 2021 using the IMRD-UK database (formerly known as the THIN database). We compared the treatment strategies of initiating beta-blocker treatment within one year versus non-beta-blocker treatment through the method of clone-censor-weight. Covariates, including patients' demographics, lifestyle, comorbidities, and recent medications, were measured and controlled. Patients were followed up for all-cause mortality or composite CVD outcomes (angina, myocardial infarction, stroke/transient ischaemic attack, heart failure, or atrial fibrillation). We estimated the five-year absolute risks, risk differences and risk ratio with 95% confidence intervals (CIs) with standardised, weighted pooled logistic regression, which is a discrete-time hazard model for survival analysis. Several sensitivity analyses were performed, including multiple imputation addressing the missing data., Findings: The median follow-up time was 4.1 (interquartile range, 1.9-7.8) years. The five-year absolute risk of all-cause mortality and CVD outcomes were 4.9% (95% CI, 3.8-6.0) and 13.0% (95% CI, 11.4-15.0) among beta-blocker users, and 4.0% (95% CI, 3.8-4.2) and 9.4% (95% CI, 9.1-9.7) among non-beta-blocker users, respectively. The five-year absolute risk difference and risk ratio between the two groups for all-cause mortality and CVD outcomes were 0.9% (95% CI, -0.2 to 2.1) and 1.22 (95% CI, 0.96-1.54), and 3.5% (95% CI, 2.1-5.5) and 1.37 (95% CI, 1.22-1.62), respectively. Findings were consistent across the sensitivity analyses., Interpretation: Beta-blocker treatment was associated with an increased risk of CVD and a trend for an increased risk of mortality among patients with OSA. Further studies are needed to confirm our findings., Funding: Innovation and Technology Commission of the Hong Kong Special Administration Region Government., Competing Interests: All authors have completed the ICMJE uniform disclosure form at https://www.thelancet.com/for-authors/forms?section=icmje-coi. ISM reports research grant income to her institution from Menarini, EMA, Sanofi, HDR UK, British Heart Foundation, NIHR HTA and IMI outside the submitted work, institutional consultancy income from AstraZeneca outside the submitted work and personal income from AstraZeneca, Amgen and Amarin outside the submitted work. TMM reports grants from the British Heart Foundation, The National Institute for Health Research Health Technology Assessment (NIHR HTA), Menarini, MSD. Personal income from AstraZeneca (advice on patient/public involvement), Novartis (steering committee), Viatris (lecture fees), Novartis (DSMB), he also served on the HEAT study DSMB (NIHR HTA funded) and he is a trustee of the Scottish Heart Arterial Risk Prevention (SHARP) organisation. KKCM reported receiving grants from the C W Maplethorpe Fellowship, European Union Horizon 2020, National Institute for Health and Care Research (NIHR), and the Innovation and Technology Commission of the Government of the Hong Kong Special Administration Region, and the Hong Kong Research Grants Council (RGC) and receiving personal fees from IQVIA Ltd outside the submitted work. AC, CJ, ADS and LW declare no competing interests., (© 2023 The Author(s).)

Background: Patients with bipolar disorder (BPD) are prone to engage in risk-taking behaviours and self-harm, contributing to higher risk of traumatic injuries requiring medical attention at the emergency room (ER).We hypothesize that pharmacological treatment of BPD could reduce the risk of traumatic injuries by alleviating symptoms but evidence remains unclear. This study aimed to examine the association between pharmacological treatment and the risk of ER admissions due to traumatic injuries., Methods: Individuals with BPD who received mood stabilizers and/or antipsychotics were identified using a population-based electronic healthcare records database in Hong Kong (2001-2019). A self-controlled case series design was applied to control for time-invariant confounders., Results: A total of 5040 out of 14 021 adults with BPD who received pharmacological treatment and had incident ER admissions due to traumatic injuries from 2001 to 2019 were included. An increased risk of traumatic injuries was found 30 days before treatment [incidence rate ratio (IRR) 4.44 (3.71-5.31), p < 0.0001]. After treatment initiation, the risk remained increased with a smaller magnitude, before returning to baseline [IRR 0.97 (0.88-1.06), p = 0.50] during maintenance treatment. The direct comparison of the risk during treatment to that before and after treatment showed a significant decrease. After treatment cessation, the risk was increased [IRR 1.34 (1.09-1.66), p = 0.006]., Conclusions: This study supports the hypothesis that pharmacological treatment of BPD was associated with a lower risk of ER admissions due to traumatic injuries but an increased risk after treatment cessation. Close monitoring of symptoms relapse is recommended to clinicians and patients if treatment cessation is warranted.

Aims: Animal studies suggest that methylphenidate treatment for around 3 months may lead to less mineralized and weaker appendicular bones. A systematic review was conducted to summarize the evidence from observational studies, and a self-controlled case series study was used to compare the risk before and after treatment initiation., Methods: Literature search was conducted using PubMed, Embase and the Cochrane Library to identify observational studies on methylphenidate and fractures. We also conducted a self-controlled case series study with individuals aged 5-24 years who received methylphenidate treatment and experienced fractures from 2001 to 2020 in Hong Kong. Incidence rate ratios and 95% confidence intervals were calculated by comparing the incidence rate in the methylphenidate-exposed period compared with nonexposed period., Results: Six cohort studies and 2 case-control studies were included in the systematic review. For all-cause fractures, studies found a 39-74% lower risk in treated-attention deficit hyperactivity disorder (ADHD) group compared with untreated ADHD but no difference between stimulants and nonstimulants. Differences between sexes and treatment duration were also found-significant results were shown in males and those with longer treatment duration. Among 43 841 individuals with ADHD medication before the year 2020, 2023 were included in the self-controlled case series analysis. The risks of fractures were lower by 32-41% in different treatment periods when compared with 6 months before treatment initiation., Conclusion: Methylphenidate treatment may lower the risk of all-cause fractures from both study designs; however, further evidence is needed about the treatment duration and sex effect. Conclusions on stress fractures are not yet established, and further research is required., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Bipolar disorder (BPD) is associated with high rates of suicide attempts but the anti-suicidal effect of mood stabilizing agents remains unclear. This study aimed to examine the association between mood stabilizing agents (lithium, valproate, lamotrigine, carbamazepine or antipsychotics) and risk of suicide attempts in patients with BPD using self-controlled case series study design. Among 14,087 patients with BPD who received mood stabilizing agents from 2001 to 2020 in Hong Kong, 1316 patients had at least one suicide attempts during the observation period. An increased risk of suicide attempts was observed 14 days before treatment initiation compared to non-exposed period. Following treatment initiation, an increased risk with smaller magnitude was found with the use of mood stabilizing agents. A lower risk was observed with lithium and antiepileptics while the risk remained attenuated with decreasing magnitude with antipsychotics. During 30-day post-treatment period, the risk was elevated. Therefore, this study suggests that use of mood stabilizing agents is not causally associated with an increased risk of suicide attempts. Indeed, there are potential protective effects of lithium and antiepileptics against suicide attempts. Assiduous monitoring of symptoms relapse and warning signs of suicide should be part of the management plan and discussed between clinicians, caregivers and patients., Competing Interests: Declaration of Competing Interest Esther W. Chan has received grants from Research Grants Council (RGC, Hong Kong), Research Fund Secretariat of the Food and Health Bureau, National Natural Science Fund of China, Bayer, Bristol-Myers Squibb, Pfizer, Janssen, Novartis, Amgen, AstraZeneca, Takeda, the RGA Reinsurance Company, Narcotics Division of the Security Bureau of the Hong Kong Special Administrative Region, the National Health and Medical Research Council Australia; consulting fees from AstraZeneca, Pfizer and Novartis; and honorarium from the Hospital Authority Hong Kong, outside the submitted work. Joseph F. Hayes has received consultancy fees from Wellcome Trust and juli Health.Yun Kwok Wing has received honorarium from Eisai Hong Kong and consultation fees from Eisai Co., Ltd, grants from Research Grants Council (RGC, Hong Kong). Wallis C.Y. Lau reports grant from AIR@InnoHK administered by Innovation and Technology Commission, outside the submitted work. Kenneth K.C. Man received the CW Maplethorpe Fellowship, grants from the National Institute for Health Research, United Kingdom; the European Union Horizon 2020 Framework; Hong Kong Research Grant Council and personal fees from IQVIA Holdings, Inc., unrelated to this work. Ian C.K. Wong has received grants from the Research Grants Council (RGC, Hong Kong), the National Institute for Health Research, United Kingdom, National Health and Medical Research Council in Australia, Innovative Medicines Initiative (IMI), Shire, Janssen-Cilag, Eli-Lily, Pfizer, Bayer, Bristol-Myers Squibb, Takeda, Amgen, AstraZeneca and the European Union FP7 program. He is a member of the National Institute for Health and Clinical Excellence (NICE) ADHD Guideline Group, the British Association for Psychopharmacology ADHD guideline group and an advisor to Shire. He also receives personal fee from IQVIA and Jacobson Pharmaceutical and speaker fees from Janssen and Medice in the previous 3 years. Vanessa W.S. Ng, Miriam T.Y. Leung, Edwin H.M. Lee, and David P.J. Osborn, declare no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Background: Evidence on post-acute sequelae of SARS-CoV-2 (PASC) has shown inconsistent findings. This study aimed to generate coherent evidence on the post-acute sequelae of COVID-19 infection using electronic healthcare records across two regions., Methods: In this retrospective, multi-database cohort study, patients with COVID-19 aged 18 or above between April 1st 2020 and May 31st 2022 from the Hong Kong Hospital Authority (HKHA) and March 16th 2020 and May 31st 2021 from the UK Biobank (UKB) databases and their matched controls were followed for up to 28 and 17 months, respectively. Covariates between patients with COVID-19 and non-COVID-19 controls were adjusted using propensity score-based inverse probability treatment weighting. Cox proportional regression was used to estimate the hazard ratio (HR) of clinical sequelae, cardiovascular, and all-cause mortality 21 days after COVID-19 infection., Findings: A total of 535,186 and 16,400 patients were diagnosed with COVID-19 from HKHA and UKB, of whom 253,872 (47.4%) and 7613 (46.4%) were male, with a mean age (±SD) of 53.6 (17.8) years and 65.0 (8.5) years, respectively. Patients with COVID-19 incurred greater risk of heart failure (HR 1.82; 95% CI 1.65, 2.01), atrial fibrillation (1.31; 1.16, 1.48), coronary artery disease (1.32; 1.07, 1.63), deep vein thrombosis (1.74; 1.27, 2.37), chronic pulmonary disease (1.61; 1.40, 1.85), acute respiratory distress syndrome (1.89; 1.04, 3.43), interstitial lung disease (3.91; 2.36, 6.50), seizure (2.32; 1.12, 4.79), anxiety disorder (1.65; 1.29, 2.09), post-traumatic stress disorder (1.52; 1.23, 1.87), end-stage renal disease (1.76; 1.31, 2.38), acute kidney injury (2.14; 1.69, 2.71), pancreatitis (1.42; 1.10, 1.83), cardiovascular (2.86; 1.25, 6.51) and all-cause mortality (4.16; 2.11, 8.21) mortality during their post-acute phase of infection., Interpretation: The consistent greater risk of PASC highlighted the need for sustained multi-disciplinary care for COVID-19 survivors., Funding: Health Bureau, The Government of the Hong Kong Special Administrative Region, Collaborative Research Fund, The Government of the Hong Kong Special Administrative Region and AIR@InnoHK, administered by the Innovation and Technology Commission, The Government of the Hong Kong Special Administrative Region., Competing Interests: CKHW reports receipt of research funding from the EuroQoL Group Research Foundation, the Hong Kong Research Grants Council, and the Hong Kong Health and Medical Research Fund; CSLC has received grants from the Health Bureau of the Hong Kong Government, Hong Kong Research Grant Council, Hong Kong Innovation and Technology Commission, Pfizer, IQVIA, MSD, and Amgen, personal fee from Primevigilance Ltd., outside the submitted work; FTTL has been supported by the RGC Postdoctoral Fellowship under the Hong Kong Research Grants Council; XL has received research grants from the Health Bureau of the Government of the Hong Kong SAR, research and educational grants from Janssen and Pfizer, internal funding from University of Hong Kong, consultancy fee from Merck Sharp & Dohme, speaker fee from Pfizer, unrelated to this work; KKCM reports grants from the CW Maplethorpe Fellowship, National Institute of Health Research, UK, Hong Kong Research Grant Council and the European Commission Horizon 2020 Framework, personal fees from IQVIA, and grants from Amgen and GlaxoSmithKline, outside this work. EWYC has received grants from Research Grants Council of the Hong Kong SAR, Research Fund Secretariat of the Health Bureau of the Hong Kong SAR, National Natural Science Fund of China, Bayer, Bristol-Myers Squibb, Pfizer, Janssen, Novartis, Amgen, AstraZeneca, Takeda, the RGA Reinsurance Company, Narcotics Division of the Security Bureau of the Hong Kong SAR, and the National Health and Medical Research Council Australia; consulting fees from AstraZeneca, Pfizer and Novartis; and honorarium from the Hospital Authority of the Hong Kong SAR and serve as the president of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR), Hong Kong Regional Chapter, outside the submitted work.; BMYC reports research funding outside the submitted work from Guangdong-Hong Kong Technology Cooperation Funding Scheme; SCWT reports research funding outside the submitted work from the Hong Kong RGC, and the Hong Kong Health and Medical Research Fund, and National Natural Science Fund of China; ICKW reports research funding from Amgen, Bristol Myers Squibb, Pfizer, Janssen, Bayer, GSK, Novartis, the Hong Kong Research Grants Council, the Hong Kong Health and Medical Research Fund, the National Institute for Health Research in England, the European Commission, and the National Health and Medical Research Council in Australia, outside the submitted work; and is a non-executive director of Jacobson Medical in Hong Kong and a consultant to IQVIA and World Health Organization; and serve as a member of the Pharmacy and Poisons Board, Hong Kong SAR, Expert Committee on Clinical Events Assessment Following COVID-19 Immunization and Advisory Panel on COVID-19 Vaccines of the Hong Kong Government; EYFW received research grants from the Health Bureau of the Government of the Hong Kong SAR, and the Hong Kong Research Grants Council, outside the submitted work. All other authors report no disclosures relevant to the manuscript., (© 2023 The Author(s).)

Introduction: The number of poisoning cases involving attention deficit hyperactivity disorder (ADHD) medications has reportedly risen with their increased use. However, there is limited relevant evidence from Asia. We analysed the characteristics of poisoning events involving these medications in Hong Kong., Methods: We retrieved data regarding ADHD medication-related poisoning cases from the Hong Kong Poison Information Centre and conducted a descriptive analysis of the demographic information and poisoning information including sources of cases, exposure reason, exposure location, and outcome. The HKPIC data were linked with the Hospital Authority Clinical Data Analysis and Reporting System (CDARS) via de-identified Accident and Emergency numbers of public hospitals to investigate clinical characteristics. We also retrieved ADHD medication prescription records from the CDARS, then compared trends between poisoning cases and ADHD medication use., Results: We identified 72 poisoning cases involving ADHD medications between 2009 and 2019, of which approximately 70% occurred in the affected individual's residence; most were intentional poisoning events (65.3%). No statistically significant association was observed between ADHD medication prescription trends and poisoning events involving ADHD medications. Of the 66 cases (91.7%) successfully linked to CDARS, 40 (60.6%) occurred in individuals with ADHD (median age: 14 years); 26 (39.4%) occurred in individuals who lacked ADHD (median age: 33 years) but displayed higher rates of other mental disorders including depression and anxiety., Conclusion: No significant correlation was evident between ADHD medication prescriptions and poisoning events involving ADHD medications. However, medication management and caregiver education must be emphasised to prevent potential poisoning events., Competing Interests: L Gao, ATY Chow, ML Tse and KHTW Wong declare no conflict of interest. KKC Man is a recipient of the CW Maplethorpe Fellowship and reports grants from the National Institute for Health Research of the United Kingdom, Research Grants Council (RGC) of Hong Kong, Horizon 2020 Framework of the European Commission, and personal fees from IQVIA Ltd, outside the submitted work. EW Chan reports honorarium from the Hospital Authority, grants from RGC, the Research Fund Secretariat of the Health Bureau (formerly Food and Health Bureau) and the Narcotics Division of the Security Bureau of the Hong Kong SAR Government, the National Natural Science Fund of China, the Wellcome Trust, Bayer, Bristol Myers Squibb, Pfizer, Janssen, Amgen, and Takeda, outside the submitted work. CSL Chui reports grants from Pfizer and personal fees from PrimeVigilance, outside the submitted work. D Coghill reports grants and personal fees from Shire/Takeda, and personal fees from Medice, Servier and Oxford University Press, outside the submitted work. As an editor of the journal, KL Hon was not involved in the peer review process. P Ip reports research grants from the RGC and the Health and Medical Research Fund (HMRF) of the Hong Kong SAR Government, outside the submitted work. ICK Wong reports research funding outside the submitted work from Amgen, Bristol Myers Squibb, Pfizer, Janssen, Bayer, GSK, Novartis, the RGC, the HMRF, the National Institute for Health Research of the United Kingdom, the European Commission and the National Health and Medical Research Council in Australia, as well as speaker fees from Janssen and Medice in the previous 3 years.

Background: Methylphenidate is the most frequently prescribed medication for the treatment of ADHD in children and adolescents in many countries. Although many randomised controlled trials support short-term efficacy, tolerability, and safety, data on long-term safety and tolerability are scarce. The aim of this study was to investigate the safety of methylphenidate over a 2-year period in relation to growth and development, psychiatric health, neurological health, and cardiovascular function in children and adolescents., Methods: We conducted a naturalistic, longitudinal, controlled study as part of the ADDUCE research programme in 27 European child and adolescent mental health centres in the UK, Germany, Switzerland, Italy, and Hungary. Participants aged 6-17 years were recruited into three cohorts: medication-naive ADHD patients who intended to start methylphenidate treatment (methylphenidate group), medication-naive ADHD patients who did not intend to start any ADHD medication (no-methylphenidate group), and a control group without ADHD. Children with ADHD diagnosed by a qualified clinician according to the DSM-IV criteria and, in the control group, children who scored less than 1·5 on average on the Swanson, Nolan, and Pelham IV rating scale for ADHD items, and whose hyperactivity score on the parent-rated Strengths and Difficulties Questionnaire was within the normal range (<6) were eligible for inclusion. Participants were excluded if they had previously taken any ADHD medications but remained eligible if they had previously taken or were currently taking other psychotropic drugs. The primary outcome was height velocity (height velocity SD score; estimated from at least two consecutive height measurements, and normalised with reference to the mean and SD of a population of the same age and sex)., Findings: Between Feb 01, 2012, and Jan 31, 2016, 1410 participants were enrolled (756 in methylphenidate group, 391 in no-methylphenidate group, and 263 in control group). 1070 (76·3%) participants were male, 332 (23·7%) were female, and for eight gender was unknown. The average age for the cohort was 9·28 years (SD 2·78; IQR 7-11). 1312 (93·0%) of 1410 participants were White. The methylphenidate and no-methylphenidate groups differed in ADHD symptom severity and other characteristics. After controlling for the effects of these variables using propensity scores, there was little evidence of an effect on growth (24 months height velocity SD score difference -0·07 (95% CI -0·18 to 0·04; p=0·20) or increased risk of psychiatric or neurological adverse events in the methylphenidate group compared with the no-methylphenidate group. Pulse rate and systolic and diastolic blood pressure were higher in the methylphenidate group compared with the no-methylphenidate group after 24 months of treatment. No serious adverse events were reported during the study., Interpretation: Our results suggest that long-term treatment with methylphenidate for 2 years is safe. There was no evidence to support the hypothesis that methylphenidate treatment leads to reductions in growth. Methylphenidate-related pulse and blood pressure changes, although relatively small, require regular monitoring., Funding: EU Seventh Framework Programme., Competing Interests: Declaration of interests KKCM reports grants from the CW Maplethorpe Fellowship, the UK National Institute for Health and Care Research (NIHR), the EU Horizon 2020 Framework, and the Hong Kong Research Grant Council, and personal fees from IQVIA Holdings, outside the submitted work. AH has received compensation for serving as consultant or speaker for Shire–Takeda and Medice, unrelated to this work. TB served in an advisory or consultancy role for Eyelevel, Infectopharm, Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg, Roche, and Takeda; received conference support or speaker's fee from Jansen, Medice, and Takeda; and royalities from Hogrefe, Kohlhammer, CIP Medien, and Oxford University Press; outside the submitted work. JB has been in the past 3 years a consultant, member of advisory board, or speaker for Takeda–Shire, Roche, Medice, Angelini, Janssen, and Servier. SC reports collaboration on projects from the EU Seventh Framework Programme and on clinical trials sponsored by Shire Pharmaceutical Company, Lundbeck, Otsuka, Janssen-Cilag, and Angelini. MD has received research funding from Takeda–Shire, outside the submitted work. RWD has received compensation for serving as consultant or speaker, or he or the institution he works for have received research support or royalties from: EU Seventh Framework Programme, US National Institute of Mental Health (NIMH), German Federal Ministry of Health–Regulatory Agency, German Federal Ministry of Education and Research, German Research Foundation, Volkswagen Foundation; Boehringer Ingelheim, Ferring, Janssen-Cilag, Lilly, Lundbeck, Otsuka, Servier, Shire, Sunovion–Takeda, and Theravance. He was a former employee in clinical CNS research of Eli Lilly until Aug 2008, and owns Eli Lilly stock (small part of the respective annual salary). BF has been a consultant or speaker for Abbvie, Actelion, Allergan, Almirall, Alnylam, Amgen, Astellas, Astrazeneca, Bayer, Biogen, Biopecs, Bioproject, Biotronik, BMS, Boehringer, Celgène, Daiichi-Sankyio, Ethypharm, Forestlab, Genevrier, Genzyme, Gilead, Grünenthal, GSK, Idorsia, IMS, Indivior, IQVIA, JNJ, Léo, Lilly, Lundbeck, Menarini, MSD, Novartis, Novonordisk, Otsuka, Pfizer, Pierre-Frabre, Recordati, Roche, SANOFI, Servier, Takeda, UCB, ViiV, and Wellmera. CH reports research funding from the NIHR including the Health Technology Assessment SATURN trial (grant ref: NIHR128472) comparing methylpheidate with guanfacine for children and young people with ADHD and tics. CH was chair of the NICE Guideline (CG155) for psychosis and schizophrenia in children and young people; member of the NICE ADHD Guideline Update committee (NG87) and is a member of Eunethydis and the Europhean ADHD Guideline Group. SM reports speaker's fee, travel support, and research support from Shire, outside the submitted work. AN reports research funding from the EU, the German Ministry of Health, and the German Federal Joint Committee, outside the submitted work. PN has been a consultant or speaker for Medice, Servier, and Egis Pharmaceuticals, outside the submitted work. ER received speaker's fee and travel support from Shire, outside the submitted work. ESB has received in the last 3 years speakers fees from Takeda and Medice and research support from QBTech. AZ served in an advisory or consultancy role for Angelini, EduPharma, Servier; received conference support or speaker's fee from Angelini and Janssen; participated in clinical trials conducted by Angelini, Janssen, Lundbeck, Otsuka, Roche, Sevier, and Shire; and received royalties from Giunti OS and Oxford University Press. ICKW reports research and educational funding from Amgen, Bristol Myers Squibb, Pfizer, Janssen, Bayer, GSK, Novartis, Takeda, the Hong Kong Research Grants Council, the Hong Kong Health and Medical Research Fund, the Hong Kong Innovation and Technology Commission, the NIHR, the EU, and the Australian National Health and Medical Research Council, and the expert testimony payment from the Hong Kong Court of Final Appeal; outside the submitted work. DC reports, in the past 3 years, a consultant, member of advisory board, or speaker role for Takeda–Shire, Medice, Novartis, and Servier. He has received royalties from Oxford University Press and Cambridge University Press; research support from the Australian National Health and Medical Research Council and the Royal Children's Hospital Foundation; and funding for the current study from the European Commission. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Preterm birth (PTB) is the leading cause of infant mortality worldwide. Changes in PTB rates, ranging from -90% to +30%, were reported in many countries following early COVID-19 pandemic response measures ('lockdowns'). It is unclear whether this variation reflects real differences in lockdown impacts, or perhaps differences in stillbirth rates and/or study designs. Here we present interrupted time series and meta-analyses using harmonized data from 52 million births in 26 countries, 18 of which had representative population-based data, with overall PTB rates ranging from 6% to 12% and stillbirth ranging from 2.5 to 10.5 per 1,000 births. We show small reductions in PTB in the first (odds ratio 0.96, 95% confidence interval 0.95-0.98, P value <0.0001), second (0.96, 0.92-0.99, 0.03) and third (0.97, 0.94-1.00, 0.09) months of lockdown, but not in the fourth month of lockdown (0.99, 0.96-1.01, 0.34), although there were some between-country differences after the first month. For high-income countries in this study, we did not observe an association between lockdown and stillbirths in the second (1.00, 0.88-1.14, 0.98), third (0.99, 0.88-1.12, 0.89) and fourth (1.01, 0.87-1.18, 0.86) months of lockdown, although we have imprecise estimates due to stillbirths being a relatively rare event. We did, however, find evidence of increased risk of stillbirth in the first month of lockdown in high-income countries (1.14, 1.02-1.29, 0.02) and, in Brazil, we found evidence for an association between lockdown and stillbirth in the second (1.09, 1.03-1.15, 0.002), third (1.10, 1.03-1.17, 0.003) and fourth (1.12, 1.05-1.19, <0.001) months of lockdown. With an estimated 14.8 million PTB annually worldwide, the modest reductions observed during early pandemic lockdowns translate into large numbers of PTB averted globally and warrant further research into causal pathways., (© 2023. The Author(s).)