Maternal diabetes and risk of attention-deficit/hyperactivity disorder in offspring in a multinational cohort of 3.6 million mother-child pairs.

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.

Association between prenatal antipsychotic exposure and the risk of attention-deficit/hyperactivity disorder and autism spectrum disorder: a systematic review and meta-analysis.

The paucity of evidence regarding the safety of gestational antipsychotic exposure has led to treatment discontinuation in pregnant women with severe mental health conditions. This systematic review and meta-analysis aimed to summarise the current evidence on the association between gestational antipsychotic exposure and attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in children (Study protocol registered in PROSPERO:CRD42022311354). Five studies included in our meta-analysis with around 8.6 million pregnancy episodes in nine different countries/regions. Results from our meta-analysis indicate that the heightened risks of ASD and ADHD in children gestationally exposed to antipsychotics appear to be attributable to maternal characteristics, rather than having a causal relationship with the antipsychotic exposure during pregnancy. The results underscore the importance of meticulously monitoring the neurodevelopment of children born to mothers with mental illnesses, which can facilitate early interventions and provide requisite support.

Incidence of mental health diagnoses during the COVID-19 pandemic: a multinational network study.

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.

Effect of statin treatment on the risk of cancer in patients with heart failure: A target trial emulation study.

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.

Persistence in risk and effect of COVID-19 vaccination on long-term health consequences after SARS-CoV-2 infection.

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.

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

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

A systematic review of ethnic minority participation in randomised controlled trials of systemic therapies for gynecological cancers.

OBJECTIVE: Randomised controlled trials (RCTs) must include ethnic minority patients to produce generalisable findings and ensure health equity as cancer incidence rises globally. This systematic review examines participation of ethnic minorities in RCTs of licensed systemic anti-cancer therapies (SACT) for gynecological cancers, defining the research population and distribution of research sites to identify disparities in participation on the global scale. METHODS: A systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Phase II and III RCTs of licensed therapies for gynecological cancers published 01/11/2012-01/11/2022 that reported patient race/ethnicity were included. Extracted data included race/ethnicity and research site location. RCT populations were aggregated and participation of groups compared. Global distribution of research sites was described. RESULTS: 26 RCTs met inclusion criteria of 351 publications included in full-text screening, representing 17,041 patients. 79.8% were "Caucasian", 9.1% "East Asian", 3.7% "Black/African American" and 6.1% "Other, Unknown, Not Reported". "Caucasian" patients participated at higher rates than all other groups. Of 5,478 research sites, 80.1% were located in North America, 13.0% in Europe, 3.4% in East Asia, 1.3% in the Middle East, 1.3% in South America and 0.8% in Australasia. CONCLUSIONS: Ethnic minorities formed smaller proportions of RCT cohorts compared to the general population. The majority of sites were located in North America and Europe, with few in other regions, limiting enrollment of South Asian, South-East Asian and African patients in particular. Efforts to recruit more ethnic minority patients should be made in North America and Europe. More sites in underserved regions would promote equitable access to RCTs and ensure findings are generalisable to diverse groups. This review assessed the global population enrolled in contemporary RCTs for novel therapies now routinely given for gynecological cancers, adding novel understanding of the global distribution of research sites.

The Impact of Methylphenidate on Pubertal Maturation and Bone Age in ADHD Children and Adolescents: Results from the ADHD Drugs Use Chronic Effects (ADDUCE) Project.

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.

Methylphenidate and Sleep Difficulties in Children and Adolescents With ADHD: Results From the 2-Year Naturalistic Pharmacovigilance ADDUCE Study.

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.

ADHD medication discontinuation and persistence across the lifespan: a retrospective observational study using population-based databases.

BACKGROUND: Although often intended for long-term treatment, discontinuation of medication for ADHD is common. However, cross-national estimates of discontinuation are missing due to the absence of standardised measures. The aim of this study was to determine the rate of ADHD treatment discontinuation across the lifespan and to describe similarities and differences across countries to guide clinical practice. METHODS: We did a retrospective, observational study using population-based databases from eight countries and one Special Administrative Region (Australia, Denmark, Hong Kong, Iceland, the Netherlands, Norway, Sweden, the UK, and the USA). We used a common analytical protocol approach and extracted prescription data to identify new users of ADHD medication. Eligible individuals were aged 3 years or older who had initiated ADHD medication between 2010 and 2020. We estimated treatment discontinuation and persistence in the 5 years after treatment initiation, stratified by age at initiation (children [age 4-11 years], adolescents [age 12-17 years], young adults [age 18-24 years], and adults [age ≥25 years]) and sex. Ethnicity data were not available. FINDINGS: 1 229 972 individuals (735 503 [60%] males, 494 469 females [40%]; median age 8-21 years) were included in the study. Across countries, treatment discontinuation 1-5 years after initiation was lowest in children, and highest in young adults and adolescents. Within 1 year of initiation, 65% (95% CI 60-70) of children, 47% (43-51) of adolescents, 39% (36-42) of young adults, and 48% (44-52) of adults remained on treatment. The proportion of patients discontinuing was highest between age 18 and 19 years. Treatment persistence for up to 5 years was higher across countries when accounting for reinitiation of medication; at 5 years of follow-up, 50-60% of children and 30-40% of adolescents and adults were covered by treatment in most countries. Patterns were similar across sex. INTERPRETATION: Early medication discontinuation is prevalent in ADHD treatment, particularly among young adults. Although reinitiation of medication is common, treatment persistence in adolescents and young adults is lower than expected based on previous estimates of ADHD symptom persistence in these age groups. This study highlights the scope of medication treatment discontinuation and persistence in ADHD across the lifespan and provides new knowledge about long-term ADHD medication use. FUNDING: European Union Horizon 2020 Research and Innovation Programme.

Cross-Regional Data Initiative for the Assessment and Development of Treatment for Neurological and Mental Disorders.

Purpose: 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.

Impact of ACEIs and ARBs-related adverse drug reaction on patients' clinical outcomes: a cohort study in UK primary care.

BACKGROUND: Adverse drug reaction (ADR) related to angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may negatively affect patients' treatment outcomes. AIM: To investigate the impact of ACEIs/ARBs-related ADR consultation on cardiovascular disease (CVD) events and all-cause mortality. DESIGN AND SETTING: Propensity score-matched cohort study of ACEIs/ARBs between 2004 and 2019 using UK IQVIA medical research data. METHOD: ADR consultations were identified using standardised designated codes. Propensity scores were calculated based on comorbidities, concomitant medications, frailty, and polypharmacy. Cox's proportional hazard regression model was used to compare the outcomes between patients in ADR and non-ADR groups. In the secondary analysis, treatment- pattern changes following the ADR were examined and the subsequent outcomes were compared. RESULTS: Among 1 471 906 eligible users of ACEIs/ARBs, 13 652 (0.93%) patients had ACEIs/ARBs- related ADR consultation in primary care. Patients with ACEIs/ARBs-related ADR consultation had an increased risk of subsequent CVD events and all- cause mortality in both primary prevention (CVD events: adjusted hazard ratio [aHR] 1.22, 95% confidence interval [CI] = 1.05 to 1.43; all-cause mortality: aHR 1.14, 95% CI = 1.01 to 1.27) and secondary prevention cohorts (CVD events: aHR 1.13, 95% CI = 1.05 to 1.21; all-cause mortality: aHR 1.15, 95% CI = 1.09 to 1.21). Half (50.19%) of patients with ADR continued to use ACEIs/ARBs, and these patients had a reduced risk of mortality (aHR 0.88, 95% CI = 0.82 to 0.95) compared with those who discontinued using ACEIs/ARBs. CONCLUSION: This study provides information on the burden of ADR on patients and the health system. The findings call for additional monitoring and treatment strategies for patients affected by ADR to mitigate the risks of adverse clinical outcomes.

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

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

Levothyroxine Treatment Among Pregnant Women and Risk of Seizure in Children: A Population-Based Cohort Study.

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.

Effectiveness of Facebook Groups and Pages on Participant Recruitment Into a Randomized Controlled Trial During the COVID-19 Pandemic: Descriptive Study.

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.

Impact of beta-blockers on mortality and cardiovascular disease outcomes in patients with obstructive sleep apnoea: a population-based cohort study in target trial emulation framework.

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.

Gabapentinoid consumption in 65 countries and regions from 2008 to 2018: a longitudinal trend study.

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.