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Background Chronic Obstructive Pulmonary Disease is characterised by declining lung function and a greater oxidative stress burden due to reduced activity of antioxidant enzymes such as Glutathione Peroxidase 1. Objectives The extent to which drugs may contribute to this compromised activity is largely unknown. An integrative drug safety model explores inhibition of Glutathione Peroxidase 1 by drugs and their association with chronic obstructive pulmonary disease adverse drug events. Methods In silico molecular modelling approaches were utilised to predict the interactions that drugs have within the active site of Glutathione Peroxidase 1 in both human and bovine models. Similarities of chemical features between approved drugs and the known inhibitor tiopronin were also investigated. Subsequently the Food and Drug Administration Adverse Event System was searched to uncover adverse drug event signals associated with chronic obstructive pulmonary disease. Results Statistical and molecular modelling analyses confirmed that the use of several registered drugs, including acetylsalicylic acid and atenolol may be associated with inhibition of Glutathione Peroxidase 1 and chronic obstructive pulmonary disease. Conclusion The integration of molecular modelling and pharmacoepidemological data has the potential to advance drug safety science. Ongoing review of medication use and further pharmacoepidemiological and biological analyses are warranted to ensure appropriate use is recommended. Graphical Abstract

BackgroundHealth emergencies disproportionally affect vulnerable populations. Digital tools can help primary care providers find, and reach, the right patients.AimTo evaluate whether digital interventions delivered directly to GPs’ clinical software were more effective at promoting primary care appointments during the COVID-19 pandemic than interventions delivered by post.Design and settingReal-world, non-randomised, interventional study involving GP practices in all Australian states.MethodIntervention material was developed to promote care coordination for vulnerable older veterans during the COVID-19 pandemic, and sent to GPs either digitally to the clinical practice software system or in the post. The intervention material included patient-specific information sent to GPs to support care coordination, and education material sent via post to veterans identified in the administrative claims database. To evaluate the impact of intervention delivery modalities on outcomes, the time to first appointment with the primary GP was measured; a Cox proportional hazards model was used, adjusting for differences and accounting for pre-intervention appointment numbers.ResultsThe intervention took place in April 2020, during the first weeks of COVID-19 social distancing restrictions in Australia. GPs received digital messaging for 51 052 veterans and postal messaging for 26 859 veterans. The digital group was associated with earlier appointments (adjusted hazard ratio 1.38 [1.34 to 1.41]).ConclusionData-driven digital solutions can promote care coordination at scale during national emergencies, opening up new perspectives for precision public-health initiatives.

Background: Aged care residents are vulnerable to the harmful effects of medicines; however, data on the prevalence and preventability of adverse medicine events in aged care residents are scarce. Aim: To determine the prevalence and preventability of adverse medicine events in Australian aged care residents. Methods: A secondary analysis of data from the Reducing Medicine-Induced Deterioration and Adverse Reactions (ReMInDAR) trial was conducted. Potential adverse medicine events were identified and independently screened by two research pharmacists to produce a short-list of potential adverse medicine events. An expert clinical panel reviewed each potential adverse medicine to determine the likelihood that the event was medicine related (based on the Naranjo Probability Scale criteria). The clinical panel assessed preventability of medicine-related events using Schumock-Thornton criteria. Results: There were 583 adverse events due to medicines, involving 154 residents (62% of the 248 study participants). There was a median of three medication-related adverse events (interquartile range [IQR] 1–5) per resident over the 12-month follow-up period. The most common medication-related adverse events were falls (56%), bleeding (18%) and bruising (9%). There were 482 (83%) medication-related adverse events that were preventable, most commonly falls (66% of preventable adverse medicine events), bleeding (12%) and dizziness (8%). Of the 248 residents, 133 (54% of the cohort) had at least one preventable adverse medicine event, with a median of 2 (IQR 1–4) preventable adverse medicine events per resident. Conclusion: In total, 62% of aged care residents in our study had an adverse medicine event and 54% had a preventable adverse medicine event in a 12-month period. Refereed/Peer-reviewed

Introduction: Medicines acting on the central nervous system can increase the risk of postoperative delirium, but the specific medicines associated with greatest risk remain unclear. Objectives: We aimed to examine the risk of individual central nervous system-acting medicines used preoperatively on delirium after hip or knee surgery. Methods: A matched case-control study was conducted using data from the Australian Government Department of Veterans’ Affairs. We included people aged 65 years or older who had knee or hip surgery between 2000 and 2019. People with hip or knee surgery who developed postoperative delirium were cases and controls were people with hip or knee surgery but who did not develop postoperative delirium. Use of medicines including anxiolytics, sedatives, and hypnotics, opioid analgesics and antidepressants prior to surgery was compared between cases and controls. Results: A total of 2614 patient cases with postoperative delirium were matched by same sex, age (±2 years), and year of admission (±2 years) with 7842 controls without postoperative delirium. Cases were more likely to be exposed to nitrazepam (odds ratio [OR] = 1.81, 95% confidence interval [CI] 1.24–2.64), sertraline (OR = 1.50, 95% CI 1.20–1.87), mirtazapine (OR = 1.38, 95% CI 1.11–1.74), venlafaxine (OR = 1.42, 95% CI 1.02–1.98), citalopram (OR = 1.54, 95% CI 1.19–1.99), escitalopram (OR = 1.42, 95% CI 1.06–1.89) or fluvoxamine (OR = 5.01, 95% CI 2.15–11.68) prior to surgery than controls. At the class level, exposure to benzodiazepines (OR = 1.20, 95% CI 1.05–1.37) and antidepressants (OR = 1.64, 95% CI 1.47–1.83) prior to surgery was significantly higher in cases than in controls. The numbers needed to treat to harm for one additional delirium case were 43 for sertraline, 40 for citalopram, 57 for mirtazapine and 26 for nitrazepam. Whereas, the numbers needed to treat to harm were found to be 20 for sertraline, 17 for citalopram, 19 for mirtazapine and 10 for nitrazepam in the 85 years or older age group, indicating that the harmful effect of these medicines is pronounced as age advances. Conclusions: People who developed delirium following hip or knee surgery were more likely to be exposed to nitrazepam, sertraline, mirtazapine, venlafaxine, citalopram, escitalopram or fluvoxamine at the time of admission for surgery. Planning to reduce use of these medicines well prior to surgery may decrease the risk of postoperative delirium. Refereed/Peer-reviewed

Aims The aim of this study was to estimate the 90-day periprosthetic joint infection (PJI) rates following total knee arthroplasty (TKA) and total hip arthroplasty (THA) for osteoarthritis (OA). Methods This was a data linkage study using the New South Wales (NSW) Admitted Patient Data Collection (APDC) and the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR), which collect data from all public and private hospitals in NSW, Australia. Patients who underwent a TKA or THA for OA between 1 January 2002 and 31 December 2017 were included. The main outcome measures were 90-day incidence rates of hospital readmission for: revision arthroplasty for PJI as recorded in the AOANJRR; conservative definition of PJI, defined by T84.5, the PJI diagnosis code in the APDC; and extended definition of PJI, defined by the presence of either T84.5, or combinations of diagnosis and procedure code groups derived from recursive binary partitioning in the APDC. Results The mean 90-day revision rate for infection was 0.1% (0.1% to 0.2%) for TKA and 0.3% (0.1% to 0.5%) for THA. The mean 90-day PJI rates defined by T84.5 were 1.3% (1.1% to 1.7%) for TKA and 1.1% (0.8% to 1.3%) for THA. The mean 90-day PJI rates using the extended definition were 1.9% (1.5% to 2.2%) and 1.5% (1.3% to 1.7%) following TKA and THA, respectively. Conclusion When reporting the revision arthroplasty for infection, the AOANJRR substantially underestimates the rate of PJI at 90 days. Using combinations of infection codes and PJI-related surgical procedure codes in linked hospital administrative databases could be an alternative way to monitor PJI rates. Cite this article: Bone Joint J 2022;104-B(9):1060–1066.

Background When analyzing the outcomes of joint arthroplasty, an important factor to consider is patient comorbidities. The presence of multiple comorbidities has been associated with longer hospital stays, more postoperative complications, and increased mortality. The American Society of Anesthesiologists (ASA) physical status classification system score is a measure of a patient's overall health and has been shown to be associated with complications and mortality after joint arthroplasty. The Rx-Risk score is another measure for determining the number of different health conditions for which an individual is treated, with a possible score ranging from 0 to 47. Questions/purposes For patients undergoing THA or TKA, we asked: (1) Which metric, the Rx-Risk score or the ASA score, correlates more closely with 30- and 90-day mortality after TKA or THA? (2) Is the Rx-Risk score correlated with the ASA score? Methods This was a retrospective analysis of the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) database linked to two other national databases, the National Death Index (NDI) database and the Pharmaceutical Benefits Scheme (PBS), a dispensing database. Linkage to the NDI provided outcome information on patient death, including the fact of and date of death. Linkage to the PBS was performed to obtain records of all medicines dispensed to patients undergoing a joint replacement procedure. Patients were included if they had undergone either a THA (119,076 patients, 131,336 procedures) or TKA (182,445 patients, 215,712 procedures) with a primary diagnosis of osteoarthritis, performed between 2013 and 2017. We excluded patients with missing ASA information (THA: 3% [3055 of 119,076]; TKA: 2% [4095 of 182,445]). This left 127,761 primary THA procedures performed in 116,021 patients (53% [68,037 of 127,761] were women, mean age 68 ± 11 years) and 210,501 TKA procedures performed in 178,350 patients (56% [117,337 of 210,501] were women, mean age 68 ± 9 years) included in this study. Logistic regression models were used to determine the concordance of the ASA and Rx-Risk scores and 30-day and 90-day postoperative mortality. The Spearman correlation coefficient (r) was used to estimate the correlation between the ASA score and Rx-Risk score. All analyses were performed separately for THAs and TKAs. Results We found both the ASA and Rx-Risk scores had high concordance with 30-day mortality after THA (ASA: c-statistic 0.83 [95% CI 0.79 to 0.86]; Rx-Risk: c-statistic 0.82 [95% CI 0.79 to 0.86]) and TKA (ASA: c-statistic 0.73 [95% CI 0.69 to 0.78]; Rx-Risk: c-statistic 0.74 [95% CI 0.70 to 0.79]). Although both scores were strongly associated with death, their correlation was moderate for patients undergoing THA (r = 0.45) and weak for TKA (r = 0.38). However, the median Rx-Risk score did increase with increasing ASA score. For example, for THAs, the median Rx-Risk score was 1, 3, 5, and 7 for ASA scores 1, 2, 3, and 4, respectively. For TKAs, the median Rx-Risk score was 2, 4, 5, and 7 for ASA scores 1, 2, 3, and 4, respectively. Conclusion The ASA physical status and RxRisk were associated with 30-day and 90-day mortality; however, the scores were only weakly to moderately correlated with each other. This suggests that although both scores capture a similar level of patient illness, each score may be capturing different aspects of health. The Rx-Risk may be used as a complementary measure to the ASA score. Level of evidence Level III, therapeutic study.

Infection is a major complication following joint replacement (JR) surgery. However, little data exist regarding antibiotic utilisation following primary JR and how use changes with subsequent revision surgery. This study aimed to examine variation in antibiotic utilisation rates before and after hip replacement surgery in those revised for infection, revised for other reasons and those without revision.This retrospective cohort analysis used linked data from the Australian Orthopaedic Association National Joint Replacement Registry and Australian Government Pharmaceutical Benefits Scheme. Patients were included if undergoing total hip replacement (THR) for osteoarthritis in private hospitals between 2002 and 2017. Three groups were examined: primary THR with no subsequent revision (n = 102 577), primary THR with a subsequent revision for reasons other than periprosthetic joint infection (PJI) (n = 3156) and primary THR with a subsequent revision for PJI (n = 520). Monthly antibiotic utilisation rates and prevalence rate ratios (PRRs) with 95% confidence intervals (CIs) were calculated in the 2 years pre- and post-THR.Prior to primary THR antibiotic utilisation was 9%-10%. After primary THR, antibiotic utilisation rates were higher among patients revised for PJI (PRR 1.69, 95% CI 1.60-1.79) compared to non-revised patients, while the utilisation rate was lower in patients revised for reasons other than infection (PRR 0.96, 95% CI 0.93-0.98). For those revised for infection, antibiotic utilisation post-revision surgery was two times higher than those revised for other reasons (PRR 2.16, 95% CI 2.08-2.23). Utilisation of injectable antibiotics including, vancomycin, flucloxacillin and cephazolin was higher in those revised for PJI patients 0-2 weeks following surgery but not in those revised for other reasons compared to the non-revised group.Ongoing antibiotic utilisation after primary surgery may be an early signal of problems with the THR and should be a prompt for primary care physicians to refer patients to specialists for further appropriate investigations and management.

Evidence for the effectiveness and safety of the third-generation beta-blockers other than atenolol in hypertension remains scarce. We assessed the effectiveness and safety of beta-blockers as first-line treatment for hypertension using three databases in the United States: two administrative claim databases and one electronic health record-based database from 2001 to 2018. In each database, comparative effectiveness of beta-blockers for the risks of acute myocardial infarction, stroke, and hospitalization for heart failure was assessed, using large-scale propensity adjustment and empirical calibration. Estimates were combined across databases using random-effects meta-analyses. Overall, 118,133 and 267,891 patients initiated third-generation beta-blockers (carvedilol and nebivolol) or atenolol, respectively. The pooled hazard ratios of acute myocardial infarction, stroke, hospitalization for heart failure, and most metabolic complications were not different between the third-generation beta-blockers versus atenolol after propensity score matching and empirical calibration (hazard ratio 1.07, 95% CI 0.74 to 1.55 for acute myocardial infarction; hazard ratio 1.06, 95% CI 0.87 to 1.31 for stroke; hazard ratio 1.46, 95% CI 0.99 to 2.24 for hospitalized heart failure). Third-generation beta-blockers were associated with significantly higher risk of stroke than angiotensin-converting enzyme inhibitors (hazard ratio 1.29, 95% CI 1.03 to 1.72), and thiazide diuretics (hazard ratio 1.56, 95% CI 1.17 to 2.20). In conclusion, this study found many patients with first-line beta-blocker monotherapy for hypertension and no statistically significant differences in the effectiveness and safety comparing atenolol with third-generation beta-blockers. Patients on third-generation beta-blockers had a higher risk of stroke than those on angiotensin-converting enzyme inhibitors and thiazide diuretics.

Introduction: Information regarding availability of electronic healthcare databases in the Asia-Pacific region is critical for planning vaccine safety assessments particularly, as COVID-19 vaccines are introduced. This study aimed to identify data sources in the region, potentially suitable for vaccine safety surveillance. This manuscript is endorsed by the International Society for Pharmacoepidemiology (ISPE). Methods: Nineteen countries targeted for database reporting were identified using published country lists and review articles. Surveillance capacity was assessed using two surveys: a 9-item introductory survey and a 51-item full survey. Survey questions related to database characteristics, covariate and health outcome variables, vaccine exposure characteristics, access and governance, and dataset linkage capability. Other questions collated research/regulatory applications of the data and local publications detailing database use for research. Results: Eleven databases containing vaccine-specific information were identified across 8 countries. Databases were largely national in coverage (8/11, 73%), encompassed all ages (9/11, 82%) with population size from 1.4 to 52 million persons. Vaccine exposure information varied particularly for standardized vaccine codes (5/11, 46%), brand (7/11, 64%) and manufacturer (5/11, 46%). Outcome data were integrated with vaccine data in 6 (55%) databases and available via linkage in 5 (46%) databases. Data approval processes varied, impacting on timeliness of data access. Conclusions: Variation in vaccine data availability, complexities in data access including, governance and data release approval procedures, together with requirement for data linkage for outcome information, all contribute to the challenges in building a distributed network for vaccine safety assessment in the Asia-Pacific and globally. Common data models (CDMs) may help expedite vaccine safety research across the region. Refereed/Peer-reviewed

BackgroundMany countries have high opioid use among people with chronic non-cancer pain. Knowledge about effective interventions that could be implemented at scale is limited. We designed a national intervention that included audit and feedback, deprescribing guidance, information on catastrophising assessment, pain neuroscience education and a cognitive tool for use by patients with their healthcare providers.MethodWe used a single-arm time series with segmented regression to assess rates of people using opioids before (January 2015 to September 2017), at the time of (October 2017) and after the intervention (November 2017 to August 2019). We used a cohort with historical comparison group and log binomial regression to examine the rate of psychologist claims in opioid users not using psychologist services prior to the intervention.Results13 968 patients using opioids, 8568 general practitioners, 8370 pharmacies and accredited pharmacists and 689 psychologists were targeted. The estimated difference in opioid use was −0.51 persons per 1000 persons per month (95% CI −0.69, –0.34; pConclusionsOur intervention addressed the cognitive, affective and sensory factors that contribute to pain and consequent opioid use, demonstrating it could be implemented at scale and was associated with a reduction in opioid use and increasing utilisation of psychologist services.

BackgroundThe use of health services is likely to vary among veterans with an accepted disability of post-traumatic stress disorder (PTSD), however, the extent of variation is not known. We aimed to determine the extent and type of health services used by veterans with an accepted disability of PTSD.MethodsThe cohort included veterans who served post 1975, were eligible for all Australian Government Department of Veterans’ Affairs funded health services, had PTSD as an accepted disability prior to July 2015 and were alive at the 30 June 2016. Veterans were assigned to groups based on their use of health services using K-means cluster analysis.ResultsThe cohort comprised five clusters involving 2286 veterans. The largest cluster (43%) were a younger, general practitioner (GP) managed cluster who saw their GP quarterly and the psychiatrist twice a year. The second GP cluster (30%) had higher levels of physical comorbidity. The psychiatrist managed cluster (14%) had a mean of 12 psychiatrist visits and one PTSD hospitalisation in the year. The remaining two clusters involved GP and allied healthcare, but no psychologist care. High levels of antidepressant use occurred in all clusters, ranging from 44% up to 69%. The psychiatrist managed cluster had 47% on antipsychotics and 58% on anxiolytics.ConclusionOur study highlights the heterogeneity in health service use. These results identify the significant health utilisation required for up to one-sixth of veterans with PTSD and the significant role of primary care physicians in supporting veterans with PTSD.

Background Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have been postulated to affect susceptibility to COVID-19. Observational studies so far have lacked rigorous ascertainment adjustment and international generalisability. We aimed to determine whether use of ACEIs or ARBs is associated with an increased susceptibility to COVID-19 in patients with hypertension. Methods In this international, open science, cohort analysis, we used electronic health records from Spain (Information Systems for Research in Primary Care [SIDIAP]) and the USA (Columbia University Irving Medical Center data warehouse [CUIMC] and Department of Veterans Affairs Observational Medical Outcomes Partnership [VA-OMOP]) to identify patients aged 18 years or older with at least one prescription for ACEIs and ARBs (target cohort) or calcium channel blockers (CCBs) and thiazide or thiazide-like diuretics (THZs; comparator cohort) between Nov 1, 2019, and Jan 31, 2020. Users were defined separately as receiving either monotherapy with these four drug classes, or monotherapy or combination therapy (combination use) with other antihypertensive medications. We assessed four outcomes: COVID-19 diagnosis; hospital admission with COVID-19; hospital admission with pneumonia; and hospital admission with pneumonia, acute respiratory distress syndrome, acute kidney injury, or sepsis. We built large-scale propensity score methods derived through a data-driven approach and negative control experiments across ten pairwise comparisons, with results meta-analysed to generate 1280 study effects. For each study effect, we did negative control outcome experiments using a possible 123 controls identified through a data-rich algorithm. This process used a set of predefined baseline patient characteristics to provide the most accurate prediction of treatment and balance among patient cohorts across characteristics. The study is registered with the EU Post-Authorisation Studies register, EUPAS35296. Findings Among 1 355 349 antihypertensive users (363 785 ACEI or ARB monotherapy users, 248 915 CCB or THZ monotherapy users, 711 799 ACEI or ARB combination users, and 473 076 CCB or THZ combination users) included in analyses, no association was observed between COVID-19 diagnosis and exposure to ACEI or ARB monotherapy versus CCB or THZ monotherapy (calibrated hazard ratio [HR] 0·98, 95% CI 0·84–1·14) or combination use exposure (1·01, 0·90–1·15). ACEIs alone similarly showed no relative risk difference when compared with CCB or THZ monotherapy (HR 0·91, 95% CI 0·68–1·21; with heterogeneity of >40%) or combination use (0·95, 0·83–1·07). Directly comparing ACEIs with ARBs demonstrated a moderately lower risk with ACEIs, which was significant with combination use (HR 0·88, 95% CI 0·79–0·99) and non-significant for monotherapy (0·85, 0·69–1·05). We observed no significant difference between drug classes for risk of hospital admission with COVID-19, hospital admission with pneumonia, or hospital admission with pneumonia, acute respiratory distress syndrome, acute kidney injury, or sepsis across all comparisons. Interpretation No clinically significant increased risk of COVID-19 diagnosis or hospital admission-related outcomes associated with ACEI or ARB use was observed, suggesting users should not discontinue or change their treatment to decrease their risk of COVID-19.

Refereed/Peer-reviewed Background and objective: Increasing age, male sex and various chronic conditions have been identified as important risk factors for poor outcomes from COVID-19. The aim of this study was to examine the prevalence of risk factors for poor outcomes due to COVID-19 infection in an older population. Methods: The proportion of the population with one or more risk factors and the prevalence of individual risk factors and multiple risk factors were calculated among Department of Veterans' Affairs (DVA) clients aged >= 70 years. Results: There were 103,422 DVA clients included. Of these, 79% in the community and 82% in residential aged care had at least one risk factor for poor outcomes from COVID-19. Hypertension was most prevalent, followed by chronic heart and airways disease. Over half had >= 2 risk factors, and one in five had >= 3 risk factors across multiple body systems. Discussion: A substantial proportion of older Australians are at risk of poor outcomes from COVID-19 because of their multimorbid risk profile. These patients should be prioritised for proactive monitoring to avoid unintentional harm due to potential omission of care during the pandemic.

Evidence derived from existing health-care data, such as administrative claims and electronic health records, can fill evidence gaps in medicine. However, many claim such data cannot be used to estimate causal treatment effects because of the potential for observational study bias; for example, due to residual confounding. Other concerns include P hacking and publication bias. In response, the Observational Health Data Sciences and Informatics international collaborative launched the Large-scale Evidence Generation and Evaluation across a Network of Databases (LEGEND) research initiative. Its mission is to generate evidence on the effects of medical interventions using observational health-care databases while addressing the aforementioned concerns by following a recently proposed paradigm. We define 10 principles of LEGEND that enshrine this new paradigm, prescribing the generation and dissemination of evidence on many research questions at once; for example, comparing all treatments for a disease for many outcomes, thus preventing publication bias. These questions are answered using a prespecified and systematic approach, avoiding P hacking. Best-practice statistical methods address measured confounding, and control questions (research questions where the answer is known) quantify potential residual bias. Finally, the evidence is generated in a network of databases to assess consistency by sharing open-source analytics code to enhance transparency and reproducibility, but without sharing patient-level information. Here we detail the LEGEND principles and provide a generic overview of a LEGEND study. Our companion paper highlights an example study on the effects of hypertension treatments, and evaluates the internal and external validity of the evidence we generate.

Introduction and aims: Mental health disorders and substance abuse are risk factors that both precede and follow chronic opioid use. We predicted that incident opioid users would have lower rates of mental health comorbidities than chronic opioid users, but that incident chronic opioid users would have lower rates of mental health comorbidities than prevalent chronic users.Design and methods: We used administrative health claims data to evaluate differences in lifetime mental health and substance abuse comorbidity profiles of people who were prevalent and incident chronic opioid users, as well as those who used opioids acutely. Results were stratified by age.Results: Over 5,188 people were prevalent chronic opioid users at study entry. Of the 10,079 people who initiated opioids, 10.2 percent had a subsequent chronic episode (incident chronic) and the remainder stopped within 90 days (incident acute). In prevalent chronic users compared to incident chronic users, rates of depression and anxiety were higher across all age groups (odds ratio (OR) across age groups range from = 1.60, 95 percent confidence interval (CI) = 1.35,1.89, to OR = 6.66, 95 percent CI = 3.02, 14.69) and prevalence of alcohol abuse was higher in those aged 55 to 74 years (OR = 5.11, 95 percent CI = 1.83, 14.24, p = 0.002). Acute users were less likely than incident chronic users to have depression and anxiety in those aged over 74 years (depression OR = 0.82, 95 percent CI = 0.70, 0.95; anxiety OR = 0.82, 95% CI 0.70, 0.98).Conclusions: Mental health morbidities commonly associated with chronic opioid use increase in prevalence as chronic use continues. Refereed/Peer-reviewed

Background: Poor recognition of medicine‐induced dry mouth can have a number of adverse effects, including difficulties with speech, chewing and swallowing dry foods, gum disease, dental caries and oral candidosis. This study examined the prevalence of use of medicines that cause dry mouth and claims for dental services funded by the Department of Veterans’ Affairs (DVA) in an Australian cohort. Methods: We used the DVA administrative health claims data to identify persons using medicines that can cause dry mouth at 1st of September 2016 and determine their DVA dental claims in the subsequent year. Results were stratified by gender, residence in community or residential aged cared facility, and number of medicines. Results: We identified 50,679 persons using medicines known to cause dry mouth. Of these, 72.6% were taking only one medicine that may cause dry mouth, and 21.6% were taking two. Less than half (46.2%) of all people taking at least one of these medicines had a dental claim in the following year. A smaller proportion of women (35.9%) made claims than men (56.9%), χ2 = 2248.77, p

Background There is increasing interest in the development and use of clinical prediction models, but a lack of evidence-supported guidance on the merits of different modelling approaches. This is especially true for time-to-event outcomes, where limited studies have compared the vast number of modelling approaches available. This study compares prediction accuracy and variable importance measures for four modelling approaches in prediction of time-to-revision surgery following total knee arthroplasty (TKA) and total hip arthroplasty (THA). Methods The study included 321,945 TKA and 151,113 THA procedures performed between 1 January 2003 and 31 December 2017. Accuracy of the Cox model, Weibull parametric model, flexible parametric model, and random survival forest were compared, with patient age, sex, comorbidities, and prosthesis characteristics considered as predictors. Prediction accuracy was assessed using the Index of Prediction Accuracy (IPA), c-index, and smoothed calibration curves. Variable importance rankings from the Cox model and random survival forest were also compared. Results Overall, the Cox and flexible parametric survival models performed best for prediction of both TKA (integrated IPA 0.056 (95% CI [0.054, 0.057]) compared to 0.054 (95% CI [0.053, 0.056]) for the Weibull parametric model), and THA revision. (0.029 95% CI [0.027, 0.030] compared to 0.027 (95% CI [0.025, 0.028]) for the random survival forest). The c-index showed broadly similar discrimination between all modelling approaches. Models were generally well calibrated, but random survival forest underfitted the predicted risk of TKA revision compared to regression approaches. The most important predictors of revision were similar in the Cox model and random survival forest for TKA (age, opioid use, and patella resurfacing) and THA (femoral cement, depression, and opioid use). Conclusion The Cox and flexible parametric models had superior overall performance, although all approaches performed similarly. Notably, this study showed no benefit of a tuned random survival forest over regression models in this setting.

Refereed/Peer-reviewed Objective: We aimed to assess whether the introduction of the first infliximab biosimilar was associated with changes in overall infliximab consumption (originator and biosimilars) and price changes to the originator infliximab. Methods: An interrupted time series analysis using infliximab sales data from 2010 to 2020 from the IQVIA Multinational Integrated Data Analysis System for eight selected regions: Australia, Canada, Hong Kong, Korea, India, Japan, the UK, and the USA. Quarterly measures of infliximab consumption and list prices were respectively defined as the number of standard units (SU)/1000 inhabitants and as 2020 USA dollars (USD)/SU. Results: Following the introduction of infliximab biosimilars, overall infliximab consumption increased in Australia [immediate change: 0.145 SU/1000 inhabitants (P = 0.014); long-term change: 0.022 SU/1000 inhabitants per quarter (P < 0.001)], Canada [immediate change 0.415 (P = 0.008)], the UK [long-term change 0.024 (P < 0.001)], and Hong Kong [immediate change: 0.042 (P < 0.001)]. The list price of originator infliximab also decreased following biosimilar introduction in Australia [immediate change: − 187.84 USD/SU (P < 0.001); long-term change − 6.46 USD/SU per quarter (P = 0.043)], Canada [immediate change: − 145.58 (P < 0.001)], the UK [immediate change: − 34.95 (P = 0.010); long-term change: − 4.77 (P < 0.001)], and Hong Kong [long-term change: − 4.065 (P = 0.046)]. Consumption and price changes were inconsistent in India, Japan, Korea, and the USA. Conclusions: Introduction of the first infliximab biosimilar was not consistently associated with increased consumption across regions. Additional policy and healthcare system interventions to support biosimilar infliximab adoption are needed.

Background Digital technologies can enable rapid targeted delivery of audit and feedback interventions at scale. Few studies have evaluated how mode of delivery affects clinical professional behavior change and none have assessed the feasibility of such an initiative at a national scale. Objective The aim of this study was to develop and evaluate the effect of audit and feedback by digital versus postal (letter) mode of delivery on primary care physician behavior. Methods This study was developed as part of the Veterans’ Medicines Advice and Therapeutics Education Services (MATES) program, an intervention funded by the Australian Government Department of Veterans’ Affairs that provides targeted education and patient-specific audit with feedback to Australian general practitioners, as well as educational material to veterans and other health professionals. We performed a cluster randomized controlled trial of a multifaceted intervention to reduce inappropriate gabapentinoid prescription, comparing digital and postal mode of delivery. All veteran patients targeted also received an educational intervention (postal delivery). Efficacy was measured using a linear mixed-effects model as the average number of gabapentinoid prescriptions standardized by defined daily dose (individual level), and number of veterans visiting a psychologist in the 6 and 12 months following the intervention. Results The trial involved 2552 general practitioners in Australia and took place in March 2020. Both intervention groups had a significant reduction in total gabapentinoid prescription by the end of the study period (digital: mean reduction of 11.2%, P=.004; postal: mean reduction of 11.2%, P=.001). We found no difference between digital and postal mode of delivery in reduction of gabapentinoid prescriptions at 12 months (digital: –0.058, postal: –0.058, P=.98). Digital delivery increased initiations to psychologists at 12 months (digital: 3.8%, postal: 2.0%, P=.02). Conclusions Our digitally delivered professional behavior change intervention was feasible, had comparable effectiveness to the postal intervention with regard to changes in medicine use, and had increased effectiveness with regard to referrals to a psychologist. Given the logistical benefits of digital delivery in nationwide programs, the results encourage exploration of this mode in future interventions.

It is known that younger patients treated with antipsychotics are at increased risk of metabolic events; however, it is unknown how this risk varies according to ethnicity, the class of antipsychotic and the specific product used, and by age group. We conducted a multinational sequence symmetry study in Asian populations (Hong Kong, Japan, Korea, Taiwan and Thailand) and non-Asian populations (Australia and Denmark) to evaluate the metabolic events associated with antipsychotics in both Asian and non-Asian populations, for typical and atypical antipsychotics, and by the subgroups of children and adolescents, and young adults. Patients aged 6–30 years newly initiating oral antipsychotic drugs were included. We defined a composite outcome for metabolic events which included dyslipidemia, hypertension and hyperglycemia. We calculated the sequence ratio (SR) by dividing the number of people for whom a medicine for one of the outcome events was initiated within a 12-month period after antipsychotic initiation by the number before antipsychotic initiation. This study included 346,904 antipsychotic initiators across seven countries. Antipsychotic use was associated with an increased risk of composite metabolic events with a pooled adjusted SR (ASR) of 1.22 (95% CI 1.00–1.50). Pooled ASRs were similar between Asian (ASR, 1.22; 95% CI 0.88–1.70) and non-Asian populations (ASR, 1.22; 95% CI 1.04–1.43). The pooled ASR for typical and atypical antipsychotics was 0.98 (95% CI 0.85–1.12) and 1.24 (95% CI 0.97–1.59), respectively. No difference was observed in the relative effect in children and adolescents compared to young adults. The risk of metabolic events associated with antipsychotics use was similar in magnitude in Asian and non-Asian populations despite the marked difference in drug utilization patterns Refereed/Peer-reviewed

Objective To assess the effectiveness of a pharmacist-led intervention using validated tools to reduce medicine-induced deterioration and adverse reactions. Design and setting Multicenter, open-label parallel randomised controlled trial involving 39 Australian aged-care facilities. Participants Residents on ≥4 medicines or ≥1 anticholinergic or sedative medicine. Intervention Pharmacist-led intervention using validated tools to detect signs and symptoms of medicine-induced deterioration which occurred every 8 weeks over 12 months. Comparator Usual care (Residential Medication Management Review) provided by accredited pharmacists. Outcomes Primary outcome was change in Frailty Index at 12 months. Secondary outcomes included changes in cognition, 24-hour movement behaviour by accelerometry, grip strength, weight, adverse events and quality of life. Results 248 persons (median age 87 years) completed the study; 120 in the interventionand, 128 in control arms. In total 575 pharmacist, sessions were undertaken in the intervention arm. There was no statistically significant difference for change in frailty between groups (mean difference: 0.009, 95% CI: −0.028, 0.009, P = 0.320). A significant difference for cognition was observed, with a mean difference of 1.36 point change at 12 months (95% CI: 0.01, 2.72, P = 0.048). Changes in 24-hour movement behaviour, grip strength, adverse events and quality of life were not significantly different between groups. Point estimates favoured the intervention arm at 12 months for frailty, 24-hour movement behaviour and grip strength. Conclusions The use of validated tools by pharmacists to detect signs of medicine-induced deterioration is a model of practice that requires further research, with promising results from this trial, particularly with regards to improved cognition.

Background In elderly populations, paracetamol may be used regularly for conditions such as osteoarthritis. Paracetamol has been associated with respiratory disease through a proposed mechanism of glutathione depletion and oxidative stress. Given that chronic obstructive pulmonary disease (COPD) is frequently co-morbid with osteoarthritis, this study investigated whether the dose and timing of paracetamol exposure may induce COPD exacerbations. Methods The study population was 3523 Australian Government Department of Veterans’ Affairs full entitlement holders who had existing COPD on 1 January 2011, who were dispensed at least one prescription of paracetamol between 1 January 2011 and 30 September 2015, and had no paracetamol dispensed in the 6 months prior to 1 January 2011. The outcome was time to first hospitalisation for COPD exacerbation after initiation of paracetamol. A weighted cumulative exposure approach was used. Results The association between paracetamol exposure and COPD exacerbation was protective or harmful depending on the dose, duration, and recency of exposure. Compared to non-use, current use at the maximum dose of 4 g daily for 7 days was associated with a lower risk (HR = 0.78, 95% CI = 0.67–0.92) and a higher risk after 30 days (HR = 1.27, 95% CI = 1.06–1.52). Risk declined to baseline after 2 months. For past use, there was a short-term increase in risk on discontinuation depending of dose, duration and time since stopping. Conclusions Patients and doctors should be aware of the possible risk of COPD exacerbation with higher dose paracetamol 1 to 6 weeks after initiation or discontinuation, but no increased risk after 2 months.

Medicines acting on the central nervous system can increase the risk of postoperative delirium, but the specific medicines associated with greatest risk remain unclear.We aimed to examine the risk of individual central nervous system-acting medicines used preoperatively on delirium after hip or knee surgery.A matched case-control study was conducted using data from the Australian Government Department of Veterans' Affairs. We included people aged 65 years or older who had knee or hip surgery between 2000 and 2019. People with hip or knee surgery who developed postoperative delirium were cases and controls were people with hip or knee surgery but who did not develop postoperative delirium. Use of medicines including anxiolytics, sedatives, and hypnotics, opioid analgesics and antidepressants prior to surgery was compared between cases and controls.A total of 2614 patient cases with postoperative delirium were matched by same sex, age (±2 years), and year of admission (±2 years) with 7842 controls without postoperative delirium. Cases were more likely to be exposed to nitrazepam (odds ratio [OR] = 1.81, 95% confidence interval [CI] 1.24-2.64), sertraline (OR = 1.50, 95% CI 1.20-1.87), mirtazapine (OR = 1.38, 95% CI 1.11-1.74), venlafaxine (OR = 1.42, 95% CI 1.02-1.98), citalopram (OR = 1.54, 95% CI 1.19-1.99), escitalopram (OR = 1.42, 95% CI 1.06-1.89) or fluvoxamine (OR = 5.01, 95% CI 2.15-11.68) prior to surgery than controls. At the class level, exposure to benzodiazepines (OR = 1.20, 95% CI 1.05-1.37) and antidepressants (OR = 1.64, 95% CI 1.47-1.83) prior to surgery was significantly higher in cases than in controls. The numbers needed to treat to harm for one additional delirium case were 43 for sertraline, 40 for citalopram, 57 for mirtazapine and 26 for nitrazepam. Whereas, the numbers needed to treat to harm were found to be 20 for sertraline, 17 for citalopram, 19 for mirtazapine and 10 for nitrazepam in the 85 years or older age group, indicating that the harmful effect of these medicines is pronounced as age advances.People who developed delirium following hip or knee surgery were more likely to be exposed to nitrazepam, sertraline, mirtazapine, venlafaxine, citalopram, escitalopram or fluvoxamine at the time of admission for surgery. Planning to reduce use of these medicines well prior to surgery may decrease the risk of postoperative delirium.

For self-controlled studies of medication-related effects, time-varying confounding by indication can occur if the indication varies over time. We describe how active comparators might mitigate such bias, using an empirical example. Approaches to using active comparators are described for case-crossover design, case-time-control design, self-controlled case-series, and sequence symmetry analyses. In the empirical example, we used Danish data from 1996–2018 to study the association between penicillin and venous thromboembolism (VTE), using roxithromycin, a macrolide antibiotic, as comparator. Upper respiratory infection is a transient risk factor for VTE, thus representing time-dependent confounding by indication. Odds ratios for case-crossover analysis were 3.35 (95% confidence interval: 3.23, 3.49) for penicillin and 3.56 (95% confidence interval: 3.30, 3.83) for roxithromycin. We used a Wald-based method or an interaction term to estimate the odds ratio for penicillin with roxithromycin as comparator. These 2 estimates were 0.94 (95% confidence interval: 0.87, 1.03) and 1.03 (95% confidence interval: 0.95, 1.13). Results were similar for the case-time-control analysis, but both the self-controlled case-series and sequence symmetry analysis suggested a weak protective effect of penicillin, seemingly explained by VTE affecting future exposure exclusively for penicillin. The strong association of antibiotics with VTE suggests presence of confounding by indication. Such confounding can be mitigated by using an active comparator.

BACKGROUND Digital technologies can enable rapid targeted delivery of audit and feedback interventions at scale. Few studies have evaluated how mode of delivery affects clinical professional behavior change and none have assessed the feasibility of such an initiative at a national scale. OBJECTIVE The aim of this study was to develop and evaluate the effect of audit and feedback by digital versus postal (letter) mode of delivery on primary care physician behavior. METHODS This study was developed as part of the Veterans’ Medicines Advice and Therapeutics Education Services (MATES) program, an intervention funded by the Australian Government Department of Veterans’ Affairs that provides targeted education and patient-specific audit with feedback to Australian general practitioners, as well as educational material to veterans and other health professionals. We performed a cluster randomized controlled trial of a multifaceted intervention to reduce inappropriate gabapentinoid prescription, comparing digital and postal mode of delivery. All veteran patients targeted also received an educational intervention (postal delivery). Efficacy was measured using a linear mixed-effects model as the average number of gabapentinoid prescriptions standardized by defined daily dose (individual level), and number of veterans visiting a psychologist in the 6 and 12 months following the intervention. RESULTS The trial involved 2552 general practitioners in Australia and took place in March 2020. Both intervention groups had a significant reduction in total gabapentinoid prescription by the end of the study period (digital: mean reduction of 11.2%, P=.004; postal: mean reduction of 11.2%, P=.001). We found no difference between digital and postal mode of delivery in reduction of gabapentinoid prescriptions at 12 months (digital: –0.058, postal: –0.058, P=.98). Digital delivery increased initiations to psychologists at 12 months (digital: 3.8%, postal: 2.0%, P=.02). CONCLUSIONS Our digitally delivered professional behavior change intervention was feasible, had comparable effectiveness to the postal intervention with regard to changes in medicine use, and had increased effectiveness with regard to referrals to a psychologist. Given the logistical benefits of digital delivery in nationwide programs, the results encourage exploration of this mode in future interventions.

Background: Emergencies disproportionally affect vulnerable populations. The COVID-19 pandemic affected older patients with co-morbidities both directly due to more severe infection and indirectly by affecting care provision. To promote continuity of care, public health professionals require tools to quickly and precisely coordinate with primary care providers. This study evaluated whether digital interventions powered by current existing infrastructure are more effective than conventional interventions in promoting primary care appointments during the COVID-19 pandemic. Methods: We developed a digital intervention delivered by secure messaging and compared it to a post delivered intervention to promote continuity of care for vulnerable veterans during COVID-19 in a real world, non-randomised, interventional study. The study was implemented as part of the Veterans’ MATES program, an Australian Government Department of Veterans’ Affairs program to promote improvements in health care for veterans. The intervention provided patient specific information to general practitioners (GPs) to support continuity of care, alongside mailed education to veterans. The intervention key messages were to maintain regular contact with care providers and to continue to adhere to health plans. The intervention took place in April 2020, during the first weeks of COVID-19 social distancing rules in Australia. The main outcome was time to first appointment with the primary general practitioner (GP) measured using a Cox proportional hazards model.Results: GPs received digital messaging for 51,052 veterans and post messaging for 26,859 veterans. The proportion of patients seeing their primary GP during the three months following intervention was higher in the digital group (77.8%) than the post group (61.5%) (pConclusion: Current infrastructure coupled with innovative solutions is effective in promoting care coordination at scale during national emergencies, opening up new perspectives for precision public health initiatives.

Renal function testing should be performed prior to initiating medicines that require dose adjustment in renal impairment, with ongoing monitoring in continued use, particularly in older people. There is little evidence regarding the extent to which renal function monitoring is performed in older Australians dispensed medicines requiring renal function monitoring.The aim of this study was to determine the extent of renal function testing in older people dispensed medicines requiring renal function monitoring.A retrospective analysis of administrative claims data from the Australian Government Department of Veterans' Affairs was conducted for people aged 65 years or older who were dispensed one or more medicines requiring renal function monitoring, from 1 June 2019 to 30 September 2019, to investigate the proportion of people with a claim for a pathology test that included creatinine levels in the 6-12 months before or after dispensing of a medicine requiring renal function monitoring.There were 100,113 people who were dispensed at least one medicine requiring renal function monitoring during the study period, of whom 15% had a history of renal impairment and 16% had diabetes mellitus. Sixty-one percent had a claim for a test in the prior 6 months; this increased to 80% of participants with a claim for a test in the prior 12 months. The rate of claims for testing was lower in aged care facility residents compared with people living in the community (54% vs 62% in the previous 6 months; p 0.001), and was higher in people with diabetes (75% vs 58%; p 0.001), history of renal impairment (91% vs 59%; p 0.001) or heart failure (77% vs 60%; p 0.001) compared with those without these conditions.Medicines that require renal function monitoring are commonly used in older Australians, and while the majority have claims for tests that include renal function, some are missing out.

What is known and objective: Proton pump inhibitors (PPIs), used to treat and prevent gastro-oesophageal conditions, are well-tolerated but have been associated with risk including pneumonia. The extent to which initiation of PPIs can contribute to other respiratory conditions such as chronic obstructive pulmonary disease (COPD)is largely unknown. Methods: A sequence symmetry analysis (SSA) approach was applied to the Australian Department of Human Services, Pharmaceutical Benefits Scheme 10% extract. Participants were aged 45 years and older and were dispensed PPIs (ATC CodesA02BC01, A02BC02, A02BC03, A02BC04 and A02BC05) and long-acting bronchodilators (LABDs) for COPD (ATC Codes R03BB04 (PBS Item Code 10509D and 08626B),R03BB05, R03BB06, R03BB07 and R03AC18 (PBS Item Code 05137J and 05134F))between 2013 and 2019. The analysis included patients initiated on an LABD within12 months before or after their first prescription of a PPI. The crude sequence ratio(cSR) was calculated as the number of patients prescribed their first LABD after starting a PPI divided by the number of patients prescribed their first LABD before starting a PPI. Calculation of the adjusted sequence ratio (aSR) accounted for prescribing trends over time in initiation of each of the medicines. A signal was identified where the aSR lower 95% confidence interval (CI) was greater than one. Results and discussion: Initiation of omeprazole was associated with a 29% increased risk of initiating a LABD (ASR = 1.29 95% CI 1.22–1.36). Initiation of esomeprazole, rabeprazole, pantoprazole or lansoprazole was associated with 25%, 15%, 8% and 8%increased risk, respectively. What is new and conclusion: There is an established association between gastrooesophageal reflux disease and COPD which has been confirmed by implementation of a sequence symmetry-based approach which demonstrated that PPI initiation is potentially associated with progression or exacerbation of COPD. The impact PPI use has directly on this association requires further investigation. Refereed/Peer-reviewed

Background: Over one billion adults have hypertension globally, of whom 70% cannot achieve hypertension control goal with monotherapy alone. Data are lacking on patterns of dual combination therapies prescribed to patients who escalate from monotherapy. Methods: Using eleven electronic health record databases that 118 million patients across eight countries/regions, we characterized the initiation of antihypertensive dual combination therapies for patients with hypertension. In each database, we first constructed cohorts of patients who newly initiate dual combination therapy of the four most commonly used antihypertensive drug classes (angiotensin-converting enzyme inhibitor [ACEi] or angiotensin receptor blocker [ARB]; calcium channel blocker [CCB]; beta-blocker; and thiazide diuretic) after escalating from monotherapy, and then described treatment utilization using these cohorts. Findings: We identified 980,648 patients with hypertension who newly initiated dual combination therapy: 12,541 from Australia, 6,980 from South Korea, 2,096 from Singapore, 7,008 from China, 16,663 from Taiwan, 103,994 from France, 76,082 from Italy, and 754,137 from the United States (US). Significant variations in treatment utilization existed across databases and patient subgroups. In Australia and Singapore databases, starting an ACEi/ARB monotherapy followed by a CCB was most common while in South Korea, China and Taiwan databases, starting a CCB monotherapy followed by an ACEi/ARB was most common. In Italy, France, and US databases, sequential use of an ACEi/ARB monotherapy followed by a diuretic was most common. Younger patients were more likely to be prescribed ACEi/ARB then a CCB or a diuretic compared with older patients. Women were more likely to be prescribed diuretics then an ACEi/ARB or a CCB compared with men. Interpretation: Large variation in the transition between monotherapy and dual combination therapy for hypertension was observed across countries and by demographic groups. These results highlight the need for future research to identify which dual combination therapy is most effective in practice. Funding: This study was supported by the National Research Foundation Singapore under its AI Singapore Programme (Award Number: AISG-GC-2019-002), National Medical Research Council (NMRC) under the Open Fund - Large Collaborative Grant (OF-LCG) - NMRC/OFLCG/001/2017 and Center Grant (CG) schemes - NMRC/CG/C016/2017, the Bio Industrial Strategic Technology Development Program (20003883, 20005021), the Ministry of Trade, Industry & Energy (MOTIE, Korea), a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), the Ministry of Health &Welfare, Republic of Korea (grant number: HR16C0001), the Australian Government National Health and Medical Research Council (NHMRC Grant Number: APP1192469). Declaration of Interest: JL, XW, CR MVZ are employees of IQVIA. YL reports grants from the National Heart, Lung, and Blood Institute (K12HL138037) and the Yale Center for Implementation Science. She was a recipient of a research agreement, through Yale University, from the Shenzhen Center for Health Information for work to advance intelligent disease prevention and health promotion. HMK received expenses and/or personal fees from UnitedHealth, IBM Watson Health, Element Science, Aetna, Facebook, the Siegfried and Jensen Law Firm, Arnold and Porter Law Firm, Martin/Baughman Law Firm, F-Prime, and the National Center for Cardiovascular Diseases in Beijing. He was a co-founder of Refactor Health and HugoHealth and had grants and/or contracts from the Centers for Medicare & Medicaid Services, Medtronic, the U.S. Food and Drug Administration, Johnson & Johnson, and the Shenzhen Center for Health Information. MAS reports grants from US National Science Foundation, grants from US National Institutes of Health, grants from the US Department of Veterans Affairs, grants from IQVIA, and personal fees from Janssen Research & Development and Private Health Management. SCY reports grants from Korean Ministry of Health & Welfare, grants from Korean Ministry of Trade, Industry & Energy. RWP reports grants from Korean Ministry of Health & Welfare, grants from Korean Ministry of Trade, Industry & Energy. The other co-authors report no potential competing interests. Ethical Approval: Use of TMUCRD data has been approved by theTMU-Joint Institutional Review Board (Project number: TMU-JIRB N202011003).

Objective: To determine the prevalence of medication- related hospitalisations pre-ceded by potentially suboptimal processes of care in aged care residents Method: We conducted a retrospective analysis of administrative claims data from the Australian Government Department of Veterans’ Affairs (DVA). We identified all hospital admissions for aged care residents between 1 July 2014 and 30 June 2019. The proportion of hospital admissions preceded by potentially suboptimal medication- related processes of care was determined Results: A total of 18874 hospitalisations were included, and 46% were preceded by potentially suboptimal medication- related care. One- quarter of fracture admissions occurred in residents at risk of fracture who were not using a medicine to prevent fracture, and 87% occurred in residents using falls- risk medicines. Thirty per cent of heart failure admissions occurred in patients who were not using an angiotensin- converting enzyme inhibitor or angiotensin receptor blocker Conclusion: Nearly half of hospital admissions were preceded by potentially sub-optimal medication- related processes of care. Interventions to improve use of medi-cines for aged care residents in these areas are warranted. Refereed/Peer-reviewed

Purpose The purpose of this paper is to provide guidance on the evaluation of data linkage quality through the development of a checklist for reporting key elements of the linkage process. Methods Responding to a call for manuscripts from the International Society for Pharmacoepidemiology (ISPE), a working group including international representation from the academic, industry, and contract research, and regulatory sectors was formed to develop a checklist for evaluation of data linkage performance and reporting data linkage specifically for pharmacoepidemiologic research. This checklist expands on the reporting of studies conducted using observational routinely collected health data specific to pharmacoepidemiology (RECORD-PE) guidelines. Results A key aspect of data linkage evaluation for pharmacoepidemiology is to articulate how a linkage process was performed and its accuracy in terms of validation and verification of the resulting linked data. This study generates a checklist, which covers domains including data sources, linkage variables, linkage methods, linkage results, and linkage evaluation. For each domain, specific recommendations provide a clear and transparent assessment of the linkage process. Conclusions Linking data sources can help to enrich analytic databases to more accurately define study populations, enable adjustment for confounding, and improve the capture of health outcomes. Clear and transparent reporting of data linkage processes will help to increase confidence in the evidence generated from these data by allowing researchers and end users to critically assess the potential for bias owing to the data linkage process.

Objective: To provide insights into complexities of seeking access to state and federal crossjurisdictional data for linkage with the Australian Childhood Immunisation Register (ACIR). We provide recommendations for improving access and receipt of linked datasets involving Australian Government-administered data. Methods: We describe requirements for linking eleven federal and state data sources to establish a national linked dataset for safety evaluation of vaccines. The required data linkage methodology for integrating cross-jurisdictional data sources is also described. Results: Extensive negotiation was required with 18 different agencies for 21 separate authorisations and 12 ethics approvals. Three variations of the 'best practice' linkage model were implemented. Australian Government approval requests spanned nearly four years from initial request for data, with a further year before ACIR data transfer to the linkage agency. Conclusions: Integration of immunisation registers with other data collections is achievable in Australia but infeasible for routine and rapid identification of vaccine safety concerns. Lengthy authorisation requirements, convoluted disparate application processes and inconsistencies in data supplied all contribute to delayed data availability. Implications for public health: Delayed data access for safety surveillance prevents timely epidemiological reviews. Poor responsiveness to safety concerns may erode public confidence, compromising effectiveness of vaccination programs through reduced participation. Refereed/Peer-reviewed

Older people might be embarrassed to talk about falling as they worry this may be judged as a loss of their ability to live independently. Ask older patients, at least yearly, if they ever feel unsteady on their feet or if they have fallen Consider whether medicines may be contributing to feelings of unsteadiness or falling. Drugs such as benzodiazepines and selective serotonin reuptake inhibitors, particularly if taken together, are associated with a risk of falling and hip fracture Review the patient’s treatment regimen to see if there are drugs that are no longer required. Psychotropic drugs should usually be tapered gradually so that adverse effects can be minimised Involve a range of health professionals to identify and manage the risk of falls. Help patients stay physically active, independent and socially connected Keywords: antipsychotics, benzodiazepines, deprescribing, opioids, selective serotonin reuptake inhibitors Introduction In Australia, an estimated 30% of people aged over 65 years living in the community and 50% of residents of aged-care facilities fall at least once a year.1,2 The resultant harm is significant. In 2018, the estimated number of Australians aged 50 years and over who were hospitalised for a hip fracture was 28,000.3 An estimated 5% of those who sustain a hip fracture die in hospital, and more than 10% are discharged from hospital to an aged-care facility. More than 50% experience a persistent mobility-related disability one year after their injury.4 Falls typically result from multiple interacting factors. The more factors present, the more likely the person is to fall.1 Medicines are a modifiable risk factor. Adverse effects such as drowsiness, dizziness, blurred vision, confusion or postural hypotension may all contribute to falls.5,6 The association between psychotropic drugs and the increased risk of hip fracture is well recognised.7,8 This is likely to be even greater when psychotropic drugs are used in combination.

Background: Mortality after THA and TKA is lower than expected for several years after surgery when compared with age- A nd sex-adjusted population data. With long-term followup (beyond approximately 10 years), some evidence has suggested that this trend reverses, such that postsurgical mortality is higher than expected as more time passes. However, the degree to which this may be the case has not been clearly established.Questions/purposes: In this large-registry study, we asked: What is the long-term mortality after THA and TKA compared with the expected mortality, adjusted for age, sex, and calendar year. Methods: Using data on 243,057 THAs and 363,355 TKAs performed for osteoarthritis from the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) from 2003 to 2016, and life tables from the Australian Bureau of Statistics the Standardised Mortality Ratio (SMR), relative mortality and excess mortality (relative to the expected mortality for people of the same sex and age in the same country) was calculated separately for hips and knees. The AOANJRR contains near-complete (98%-100%) data from all hospitals in Australia performing arthroplasty but does not include followup data on people who have left the country. Followup was from the date of surgery to 13 years, mean 5.8 years. Results: We found a lower-than-expected mortality for THA and TKA in the early years after surgery. This association diminished over time and the mortality became higher than expected after 12 years for both THA and TKA. For THA, the excess mortality (per thousand people) increased from 11 fewer deaths (95% CI, 10-11 fewer) after 1 year to four more deaths (95% CI, 0-9 more) in the 13th year, and the SMR increased from 0.50 (95% CI, 0.48-0.52) after 1 year to 1.07 (95% CI, 0.99-1.14) in the 13th year. For TKA, the excess mortality (per thousand people) increased from 12 fewer deaths (95% CI, 12-13 fewer) after 1 year to five more deaths (95% CI 2-9 more) in the 13th year, and the SMR increased from 0.39 (95% CI, 0.37-0.40) after 1 year to 1.09 (95% CI, 1.03-1.15) in the 13th year. Conclusions: Mortality after hip and knee arthroplasty is lower than expected (based on population norms) in the first 8 years to 9 years but gradually increases over time, becoming higher than expected after 12 years. The lower-than-expected mortality in the early years after surgery is likely the result of patient selection with patients undergoing primary arthroplasty having better health at the time of surgery than that of the age- A nd sex-matched population. The increasing mortality over time cannot be regression to the mean, as late mortality is higher than expected, moving beyond the mean. It is important to understand if there are modifiable factors associated with this increased mortality. The reasons for the change are uncertain. Factors to consider in future research include determining the effect of different patient factors on late mortality. Some of these included higher obesity rates for joint replacement patients and the association or causal impact of osteoarthritis and/or its treatment to increase late mortality in a similar manner to other forms of arthritis. There is also a possibility that the arthroplasty device itself may affect late mortality. Refereed/Peer-reviewed

Objective To determine whether differences in combination DTaP vaccine types at 2, 4 and 6 months of age were associated with mortality (all-cause or non-specific), within 30 days of vaccination. Design Observational nationwide cohort study. Setting Linked population data from the Australian Childhood Immunisation Register and National Death Index. Participants Australian infants administered a combination trivalent, quadrivalent or hexavalent DTaP vaccine (DTaP types) between January 1999 and December 2010 at 2, 4 and 6 months as part of the primary vaccination series. The study population included 2.9, 2.6, & 2.3 million children in the 2, 4 and 6 month vaccine cohorts, respectively. Main outcome measures Infants were evaluated for the primary outcome of all-cause mortality within 30 days. A secondary outcome was non-specific mortality (unknown cause of death) within 30 days of vaccination. Non-specific mortality was defined as underlying or other cause of death codes, R95 ‘Sudden infant death syndrome’, R96 ‘Other sudden death, cause unknown’, R98 ‘Unattended death’, R99 ‘Other ill-defined and unspecified cause of mortality’ or where no cause of death was recorded. Results The rate of 30 day all-cause mortality was low and declined from 127.4 to 59.3 deaths per 100,000 person-years between 2 and 6 month cohorts. When compared with trivalent DTaP vaccines, no elevated risk in all-cause or non-specific mortality was seen with any quadrivalent or hexavalent DTaP vaccines, for any cohort. Conclusion Use of routine DTaP combination vaccines with differing disease antigens administered during the first six months of life is not associated with infant mortality.

Objectives: Adverse drug events (ADEs) are among the top causes of hospitalization and death. Social media is a promising open data source for the timely detection of potential ADEs. In this paper, we study the problem of detecting signals of ADEs from social media. Methods: Detecting ADEs whose drug and AE may be reported in different posts of a user leads to major concerns regarding the content authenticity and user credibility, which have not been addressed in previous studies. Content authenticity concerns whether a post mentions drugs or adverse events that are actually consumed or experienced by the writer. User credibility indicates the degree to which chronological evidence from a user's sequence of posts should be trusted in the ADE detection. We propose AC-SPASM, a Bayesian model for the authenticity and credibility aware detection of ADEs from social media. The model exploits the interaction between content authenticity, user credibility and ADE signal quality. In particular, we argue that the credibility of a user correlates with the user's consistency in reporting authentic content. Results: We conduct experiments on a real-world Twitter dataset containing 1.2 million posts from 13,178 users. Our benchmark set contains 22 drugs and 8089 AEs. AC-SPASM recognizes authentic posts with F1 - the harmonic mean of precision and recall of 80%, and estimates user credibility with precision@10 = 90% and NDCG@10 - a measure for top-10 ranking quality of 96%. Upon validation against known ADEs, AC-SPASM achieves F1 = 91%, outperforming state-of-the-art baseline models by 32% (p

Background Case-crossover studies have been widely used in various fields including pharmacoepidemiology. Vines and Farrington indicated in 2001 that when within-subject exposure dependency exists, conditional logistic regression can be biased. However, this bias has not been well studied. Methods We have extended findings by Vines and Farrington to develop a weighting method for the case-crossover study which removes bias from within-subject exposure dependency. Our method calculates the exposure probability at the case period in the case-crossover study which is used to weight the likelihood formulae presented by Greenland in 1999. We simulated data for the population with a disease where most patients receive a cyclic treatment pattern with within-subject exposure dependency but no time trends while some patients stop and start treatment. Finally, the method was applied to real-world data from Japan to study the association between celecoxib and peripheral edema and to study the association between selective serotonin reuptake inhibitor (SSRI) and hip fracture in Australia. Results When the simulated rate ratio of the outcome was 4.0 in a case-crossover study with no time-varying confounder, the proposed weighting method and the Mantel-Haenszel odds ratio reproduced the true rate ratio. When a time-varying confounder existed, the Mantel-Haenszel method was biased but the weighting method was not. When more than one control period was used, standard conditional logistic regression was biased either with or without time-varying confounding and the bias increased (up to 8.7) when the study period was extended. In real-world analysis with a binary exposure variable in Japan and Australia, the point estimate of the odds ratio (around 2.5 for the association between celecoxib and peripheral edema and around 1.6 between SSRI and hip fracture) by our weighting method was equal to the Mantel-Haenszel odds ratio and stable compared with standard conditional logistic regression. Conclusion Case-crossover studies may be biased from within-subject exposure dependency, even without exposure time trends. This bias can be identified by comparing the odds ratio by the Mantel-Haenszel method and that by standard conditional logistic regression. We recommend using our proposed method which removes bias from within-subject exposure dependency and can account for time-varying confounders.

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