The weighted cumulative exposure method and its application to pharmacoepidemiology: A narrative review.

PURPOSE: The weighted cumulative exposure (WCE) method has been used in a number of fields including pharmacoepidemiology where it can account for intensity, duration and timing of exposures on the risk of an outcome. The method uses a data driven approach with flexible cubic B-splines to assign weights to past doses and select an aetiologically appropriate time window. Predictions of risk are possible for common exposure patterns encountered in real-world studies. The purpose of this study was to describe applications of the WCE method to pharmacoepidemiology and assess the strengths and limitations of the method. METHOD: A literature search was undertaken to find studies applying the WCE method to the study of medicines. Articles published in PubMed using the search term 'weighted cumulative exposure' and articles citing Sylvestre et al. (2009) in Google Scholar or Scopus up to March 2023 were subsequently reviewed. Articles were selected based on title and review of abstracts. RESULTS: Seventeen clinical applications using the data-driven WCE method with flexible cubic splines were identified in the review. These included 3 case-control studies and 14 cohort studies, of which 12 were analysed with Cox proportional hazards models and 2 with logistic regression. Thirteen studies used time windows of 1 year or longer. Of 11 studies which compared conventional models with the WCE method, 10 (91%) studies found a better fit with WCE models while one had an equivalent fit. The freely available 'WCE' software package has facilitated the applications of the WCE method with flexible cubic splines. CONCLUSIONS: The WCE method allows additional insights into the effect of cumulative exposure on outcomes, including the timing and intensity (dose) of the exposure on the risk. The flexibility of the method is particularly well suited to studies with long-term exposures that vary over time or where the current risk of an event is affected by how far the exposure is in the past, which is difficult to model with conventional definitions of exposure. Interpretation of the results can be more complex than for conventional models and would be facilitated by a standardised reporting framework.

Medicine utilization studies in Australian individual-level dispensing data: A blinded, multi-center replicated analysis.

PURPOSE: Medicine dispensing data require extensive preparation when used for research and decisions during this process may lead to results that do not replicate between independent studies. We conducted an experiment to examine the impact of these decisions on results of a study measuring discontinuation, intensification, and switching in a cohort of patients initiating metformin. METHODS: Four Australian sites independently developed a HARmonized Protocol template to Enhance Reproducibility (HARPER) protocol and executed their analyses using the Australian Pharmaceutical Benefits Scheme 10% sample dataset. Each site calculated cohort size and demographics and measured treatment events including discontinuation, switch to another diabetes medicine, and intensification (addition of another diabetes medicine). Time to event and hazard ratios for associations between cohort characteristics and each event were also calculated. Concordance was assessed by measuring deviations from the calculated median of each value across the sites. RESULTS: Good agreement was found across sites for the number of initiators (median: 53 127, range: 51 848-55 273), gender (56.9% female, range: 56.8%-57.1%) and age group. Each site employed different methods for estimating days supply and used different operational definitions for the treatment events. Consequently, poor agreement was found for incidence of discontinuation (median 55%, range: 34%-67%), switching (median 3.5%, range: 1%-7%), intensification (median 8%, range: 5%-12%), time to event estimates and hazard ratios. CONCLUSIONS: Differences in analytical decisions when deriving exposure from dispensing data affect replicability. Detailed analytical protocols, such as HARPER, are critical for transparency of operational definitions and interpretations of key study parameters.

Association between routine cell salvage use for lower segment caesarean section and post-operative iron infusion and anemia.

PURPOSE: Intraoperative cell salvage is central to Patient Blood Management including for lower segment caesarean section. Prior to April 2020, we initiated intraoperative cell salvage during caesarean section based on risk assessment for hemorrhage and patient factors. As the pandemic broadened, we mandated intraoperative cell salvage to prevent peri-partum anemia and potentially reduce blood product usage. We examined the association of routine intraoperative cell salvage on maternal outcomes. METHODS: We conducted a single-center non-overlapping before-after study of obstetric patients undergoing lower segment caesarean section in the 2 months prior to a change in practice ('usual care = selective intraoperative cell salvage', n = 203) and the 2 months following ('mandated intraoperative cell salvage', n = 228). Recovered blood was processed when a minimal autologous reinfusion volume of 100 ml was expected. Post-operative iron infusion and length of stay were modelled using logistic or linear regression, using inverse probability weighting to account for confounding. RESULTS: More emergency lower-segment caesarean sections occurred in the Usual Care group. Compared to the Usual Care group, post-operative hemoglobin was higher and anemia cases fewer in the Mandated intraoperative cell salvage group. Rates of post-partum iron infusion were significantly lower in the Mandated intraoperative cell salvage group (OR = 0.31, 95% CI = 0.12 to 0.80, P = 0.016). No difference was found for length of stay. CONCLUSION: Routine cell salvage provision during lower segment caesarean section was associated with a significant reduction in post-partum iron infusions, increased post-operative hemoglobin and reduced anemia prevalence.

Bias Due to Within-Subject Exposure Dependency With or Without Bias Due to Lack of Pairwise Exchangeability When Exposure Is Chronic in Case-Crossover and Case-Time-Control Studies: A Simulation Study.

The case-crossover study design has been proposed as a suitable design for use when a brief exposure causes a transient change in risk of an acute-onset disease. In pharmacoepidemiology, the condition of "brief exposure" is rarely satisfied because medication use is often chronic or successive, which may result in bias due to within-subject exposure dependency. Here we describe a simulation of a case-crossover study conducted within a cohort, where patients successively used a drug for 60 or more days and the rate ratio for the outcome occurrence was 4.0. Standard conditional logistic regression for the analysis produced overestimated odds ratios ranging up to 7.8. This bias due to within-subject exposure dependency from chronic use can be removed by the Mantel-Haenszel method or by our recently proposed weighting method. We also show that when some patients are censored after switching to another drug, a lack of pairwise exchangeability causes bias which is similar to bias due to an exposure time trend. This bias can be removed by using the case-time-control study design. We show that bias due to within-subject exposure dependency and lack of pairwise exchangeability occur independently and can occur separately or simultaneously, and we demonstrate how to detect and remove them.

Cerebrovascular Complications of COVID-19 on Venovenous Extracorporeal Membrane Oxygenation.

OBJECTIVES: Evidence of cerebrovascular complications in COVID-19 requiring venovenous extracorporeal membrane oxygenation (ECMO) is limited. Our study aims to characterize the prevalence and risk factors of stroke secondary to COVID-19 in patients on venovenous ECMO. DESIGN: We analyzed prospectively collected observational data, using univariable and multivariable survival modeling to identify risk factors for stroke. Cox proportional hazards and Fine-Gray models were used, with death and discharge treated as competing risks. SETTING: Three hundred eighty institutions in 53 countries in the COVID-19 Critical Care Consortium (COVID Critical) registry. PATIENTS: Adult COVID-19 patients who were supported by venovenous ECMO. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Five hundred ninety-five patients (median age [interquartile range], 51 yr [42-59 yr]; male: 70.8%) had venovenous ECMO support. Forty-three patients (7.2%) suffered strokes, 83.7% of which were hemorrhagic. In multivariable survival analysis, obesity (adjusted hazard ratio [aHR], 2.19; 95% CI, 1.05-4.59) and use of vasopressors before ECMO (aHR, 2.37; 95% CI, 1.08-5.22) were associated with an increased risk of stroke. Forty-eight-hour post-ECMO Pa co2 -pre-ECMO Pa co2 /pre-ECMO Pa co2 (relative ΔPa co2 ) of negative 26% and 48-hour post-ECMO Pa o2 -pre-ECMO Pa o2 /pre-ECMO Pa o2 (relative ΔPa o2 ) of positive 24% at 48 hours of ECMO initiation were observed in stroke patients in comparison to relative ΔPa co2 of negative 17% and relative ΔPa o2 of positive 7% in the nonstroke group. Patients with acute stroke had a 79% in-hospital mortality compared with 45% mortality for stroke-free patients. CONCLUSIONS: Our study highlights the association of obesity and pre-ECMO vasopressor use with the development of stroke in COVID-19 patients on venovenous ECMO. Also, the importance of relative decrease in Pa co2 and moderate hyperoxia within 48 hours after ECMO initiation were additional risk factors.

Testing equivalence of two doses of intravenous iron to treat iron deficiency in pregnancy: A randomised controlled trial.

OBJECTIVE: To test the equivalence of two doses of intravenous iron (ferric carboxymaltose) in pregnancy. DESIGN: Parallel, two-arm equivalence randomised controlled trial with an equivalence margin of 5%. SETTING: Single centre in Australia. POPULATION: 278 pregnant women with iron deficiency. METHODS: Participants received either 500 mg (n = 152) or 1000 mg (n = 126) of intravenous ferric carboxymaltose in the second or third trimester. MAIN OUTCOME MEASURES: The proportion of participants requiring additional intravenous iron (500 mg) to achieve and maintain ferritin >30 microg/L (diagnostic threshold for iron deficiency) at 4 weeks post-infusion, and at 6 weeks, and 3-, 6- and 12-months postpartum. Secondary endpoints included repeat infusion rate, iron status, birth and safety outcomes. RESULTS: The two doses were not equivalent within a 5% margin at any time point. At 4 weeks post infusion, 26/73 (36%) participants required a repeat infusion in the 500-mg group compared with 5/67 (8%) in the 1000-mg group: difference in proportions, 0.283 (95% confidence interval [CI] 0.177-0.389). Overall, participants in the 500-mg arm received twice the repeat infusion rate (0.81 [SD = 0.824] versus 0.40 [SD = 0.69], rate ratio 2.05, 95% CI 1.45-2.91). CONCLUSIONS: Administration of 1000 mg ferric carboxymaltose in pregnancy maintains iron stores and reduces the need for repeat infusions. A 500- mg dose requires ongoing monitoring to ensure adequate iron stores are reached and sustained.

Implementation of the South Australian Regional Telestroke service is associated with improved care quality and lower stroke mortality: A retrospective cohort study.

INTRODUCTION: Stroke in Regional Australia may have worse outcomes due to difficulties accessing optimal care. The South Australian Regional Telestroke service aimed to improve telestroke neurologist access, supported by improved ambulance triage. OBJECTIVE: To assess stroke care quality and patient mortality pre- and postimplementation of a vascular neurologist-led Telestroke service. DESIGN: Historically controlled mixed methods cohort study comparing key quality indicators and patient mortality (6 months pre- vs. 18 months postimplementation date [4 June 2018]) at the three major South Australian regional stroke centres. The primary outcome was 13 care quality indicators as a combined composite risk-adjusted score, and the secondary outcome was risk-adjusted mortality at 12-month postadmission. FINDINGS: On an annualised basis, of 189 patients with stroke, more were admitted postintervention to the regional stroke centres than in the control period (158 [annualised rate 105.3, 95% CI 86.2-127.4] vs. 31 [annualised rate 62.0, 95% CI 47.5-79.5]) Baseline patient characteristics were similar in both periods. Post-implementation, median last-known-well time to presentation (3.5 h [IQR 1.6-17] vs. 2.0 [IQR 1-14]; p = 0.46) and door to needle times (121 min [IQR 97-144] vs. 90 [IQR 75-138]; p = 0.65) were not significantly lower but an improvement in the combined composite quality score was observed (0.069 [95% CI 0.004-0.134; p = 0.04]), reflecting individual improvements in some quality indicators. Mortality at 12-month postimplementation was substantially lower postimplementation (prechange 23% vs. postchange 13% [hazard ratio 0.58 (95% CI 0.44-0.76; p < 0.001)]). CONCLUSION: Implementation of a South Australian Regional Telestroke service was associated with improved care metrics and lower mortality.

The association between exacerbation of chronic obstructive pulmonary disease and timing of paracetamol use: a cohort study in elderly Australians.

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.

Effect of an ongoing pharmacist service to reduce medicine-induced deterioration and adverse reactions in aged-care facilities (nursing homes): a multicentre, randomised controlled trial (the ReMInDAR trial).

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.

The impact of withholding nitrous oxide in labour during the COVID-19 pandemic on maternal and neonatal outcomes.

Nitrous oxide is commonly used in Australia for labour analgesia. Its use in labour is potentially associated with aerosol generation. During the first wave of the COVID-19 pandemic of 2020, nitrous oxide was suspended on many birthing units to reduce the risk of transmission. We aimed to determine the impact of withholding nitrous oxide for labour analgesia, during the COVID-19 pandemic, on epidural rates, opioid analgesia use, and maternal and neonatal outcomes. Withholding nitrous oxide for labour analgesia did not alter epidural rates but did significantly increase opioid analgesia use. Caesarean section rates, post-partum blood loss and neonatal APGAR scores did not change.

Effect of Aspirin vs Enoxaparin on Symptomatic Venous Thromboembolism in Patients Undergoing Hip or Knee Arthroplasty: The CRISTAL Randomized Trial.

Importance: There remains a lack of randomized trials investigating aspirin monotherapy for symptomatic venous thromboembolism (VTE) prophylaxis following total hip arthroplasty (THA) or total knee arthroplasty (TKA). Objective: To determine whether aspirin was noninferior to enoxaparin in preventing symptomatic VTE after THA or TKA. Design, Setting, and Participants: Cluster-randomized, crossover, registry-nested trial across 31 hospitals in Australia. Clusters were hospitals performing greater than 250 THA or TKA procedures annually. Patients (aged ≥18 years) undergoing hip or knee arthroplasty procedures were enrolled at each hospital. Patients receiving preoperative anticoagulation or who had a medical contraindication to either study drug were excluded. A total of 9711 eligible patients were enrolled (5675 in the aspirin group and 4036 in the enoxaparin group) between April 20, 2019, and December 18, 2020. Final follow-up occurred on August 14, 2021. Interventions: Hospitals were randomized to administer aspirin (100 mg/d) or enoxaparin (40 mg/d) for 35 days after THA and for 14 days after TKA. Crossover occurred after the patient enrollment target had been met for the first group. All 31 hospitals were initially randomized and 16 crossed over prior to trial cessation. Main Outcomes and Measures: The primary outcome was symptomatic VTE within 90 days, including pulmonary embolism and deep venous thrombosis (DVT) (above or below the knee). The noninferiority margin was 1%. Six secondary outcomes are reported, including death and major bleeding within 90 days. Analyses were performed by randomization group. Results: Enrollment was stopped after an interim analysis determined the stopping rule was met, with 9711 patients (median age, 68 years; 56.8% female) of the prespecified 15 562 enrolled (62%). Of these, 9203 (95%) completed the trial. Within 90 days of surgery, symptomatic VTE occurred in 256 patients, including pulmonary embolism (79 cases), above-knee DVT (18 cases), and below-knee DVT (174 cases). The symptomatic VTE rate in the aspirin group was 3.45% and in the enoxaparin group was 1.82% (estimated difference, 1.97%; 95% CI, 0.54%-3.41%). This failed to meet the criterion for noninferiority for aspirin and was significantly superior for enoxaparin (P = .007). Of 6 secondary outcomes, none were significantly better in the enoxaparin group compared with the aspirin group. Conclusions and Relevance: Among patients undergoing hip or knee arthroplasty for osteoarthritis, aspirin compared with enoxaparin resulted in a significantly higher rate of symptomatic VTE within 90 days, defined as below- or above-knee DVT or pulmonary embolism. These findings may be informed by a cost-effectiveness analysis. Trial Registration: ANZCTR Identifier: ACTRN12618001879257.

A novel weighting method to remove bias from within-subject exposure dependency in case-crossover studies.

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.

Is the Survivorship of Birmingham Hip Resurfacing Better Than Selected Conventional Hip Arthroplasties in Men Younger Than 65 Years of Age? A Study from the Australian Orthopaedic Association National Joint Replacement Registry.

BACKGROUND: The Birmingham Hip Resurfacing (BHR) prosthesis is the most commonly used metal-on-metal hip resurfacing arthroplasty device. The current manufacturer-recommended target demographic for the BHR is male patients, younger than 65 years requiring a femoral head size of ≥ 50 mm. Female patients, older patients, and individuals with smaller femoral-head diameter (≤ 50 mm) are known to have higher revision rates. Prior studies suggest that the survivorship of the BHR when used in the target demographic is comparable with that of primary conventional THA, but comparing survivorship of the most durable hip resurfacing arthroplasty device to the survivorship of all conventional THA prostheses is not ideal because the THA group comprises a large number of different types of prostheses that have considerable variation in prosthesis survival. A more informative comparison would be with the THA implants with the best survivorship, as this might help address the question of whether survivorship in the BHR target population can be improved by using a well-performing conventional THA. QUESTIONS/PURPOSES: We compared the difference in cumulative percent revision, reasons for revision and types of revision for procedures reported to the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) using the BHR prosthesis (femoral-head size > 50 mm) and three conventional THA prostheses identified as having the lowest 10-year cumulative percent revision in the currently recommended BHR target population to ask: (1) Does the BHR have a lower cumulative revision rate than the group of three conventional THA prostheses? (2) Is there a difference in the revision diagnosis between the BHR and the three best conventional THA prostheses? (3) What is the difference in the components used for a revision of a BHR compared with the three best conventional THA prostheses? METHODS: Data reported to the AOANJRR between September 1, 1999 and December 31, 2018 was used for this analysis. This study period includes almost the entire use of the BHR in Australia. The AOANJRR is a large national joint registry with almost 100% completeness, high accuracy, rigorous validation, and little to no loss to follow-up. The study population included males younger than 65 years that had received one hip replacement procedure for osteoarthritis. All patients with bilateral procedures, no matter the time interval between hips, were excluded. Only BHR prostheses with a femoral-head size ≥ 50 mm and conventional THA prostheses with femoral head sizes ≥ 32 mm and either ceramic-on-ceramic or metal, ceramic, ceramicized metal-on-crosslinked polyethylene (XLPE) bearings were included. These femoral head sizes and bearings were selected because they reflect modern conventional THA practice. There is no difference in the revision rate of these bearings in the AOANJRR. There were 4790 BHR procedures and 2696 conventional THA procedures in the study group. The mean (± SD) age for BHR procedures was 52 ± 7.8 years and 56 ± 7.1 years for conventional THA procedures. All comparative analyses were adjusted for age. Other demographics data including American Society Anesthesiologists (ASA) score and BMI were only included in AOANJRR data collection since 2012 and 2015, respectively, and have not been included in this analysis because of the low use of BHR in Australia since that time. The maximum follow-up was 18.7 years for both groups and mean follow-up of 11.9 years for the BHR and 9.3 years for the conventional THA group. Revision rates were determined using Kaplan-Meier estimates of survivorship to describe the time to the first revision, with censoring at the time of death or closure of the database at the time of analysis. A revision was defined as removal, replacement or addition of any component of a joint replacement. Revisions can be further classified as major revisions (removal of a component articulating with bone-usually the stem and/or the shell) or minor revisions (removal of other components-usually the head and/or the liner). The unadjusted cumulative percent revision after the primary arthroplasty (with 95% confidence intervals) was calculated and compared using Cox proportional hazard models adjusted for age. RESULTS: The BHR prosthesis had a statistically higher rate of all-cause revision at 17 years than the selected conventional THA prostheses (HR 2.77 [95% CI 1.78 to 4.32]; p < 0.001). The revision diagnoses differed between the groups, with the BHR demonstrating a higher revision rate for loosening after 2 years than the conventional THA protheses (HR 4.64 [95% CI 1.66 to 12.97]; p = 0.003), as well as a higher fracture rate during the entire period (HR 2.57 [95% CI 1.24 to 5.33]; p = 0.01). There was a lower revision rate for infection for the BHR compared with the THA group in the first 5 years, with no difference between the two groups after this time. All revisions of the BHR were major revisions (such as, removal or exchange of the femoral and/or acetabular components) and this occurred in 4.5% of the primary BHR procedures. Major revision was the most common type of revision for primary THA accounting for 1.7% of all primary THA procedures. Minor revisions (head, inset or both) were undertaken in a further 0.6% of primary THA procedures. CONCLUSIONS: Given the increasing revision risk of the BHR compared with better-performing conventional THA prostheses in the target population, we recommend that patients be counseled about this risk. We suggest that a THA with proven low revision rates might be the better choice, particularly for patients who are concerned about implant durability. Well-controlled prospective studies that show appreciable clinically important differences in patient-reported outcomes and functional results favoring the BHR over conventional THA prostheses using modern bearings are needed to justify the use of the BHR in view of this revision risk. LEVEL OF EVIDENCE: Level III, therapeutic study.

Human growth hormone for poor responders: a randomized placebo-controlled trial provides no evidence for improved live birth rate.

RESEARCH QUESTION: Does the addition of human growth hormone (HGH) to an IVF cycle improve the live birth rate in previously documented poor responders to FSH? DESIGN: Double-blind, placebo-controlled, randomized clinical trial comparing HGH to placebo in maximal stimulation in an IVF cycle. The study was stopped after 4 years. Women receiving ovarian stimulation in one IVF cycle, having failed to produce more than 5 eggs in a previous cycle with more than 250 IU/day of FSH were included. Basal FSH was ≤15 IU/l, body mass index <33 kg/m2, age <41 years. HGH or placebo were added from the start of the cycle in a double-blinded manner. The primary outcome was live birth rate. MAIN RESULTS: The live birth rates following an IVF cycle were 9/62 (14.5%) for growth hormone and 7/51 (13.7%) for the placebo group (risk difference 0.8%, 95% confidence interval [CI] -12.1 to 13.7%; odds ratio [OR] 1.07, 95% CI 0.37-3.10). There was a greater odds of oocyte retrieval with growth hormone (OR 5.67, 95% CI 1.54-20.80) but no better chance of embryo transfer (OR 1.42, 95% CI 0.50-4.00). Birth weights were comparable. CONCLUSIONS: Planned participant numbers were not reached. It was not possible to demonstrate an increase in live birth rate from the addition of growth hormone in women with a previous poor ovarian response to IVF.

A note on sample size calculations for cluster randomised crossover trials with a fixed number of clusters.

Girardeau, Ravaud and Donner in 2008 presented a formula for sample size calculations for cluster randomised crossover trials, when the intracluster correlation coefficient, interperiod correlation coefficient and mean cluster size are specified in advance. However, in many randomised trials, the number of clusters is constrained in some way, but the mean cluster size is not. We present a version of the Girardeau formula for sample size calculations for cluster randomised crossover trials when the number of clusters is fixed. Formulae are given for the minimum number of clusters, the maximum cluster size and the relationship between the correlation coefficients when there are constraints on both the number of clusters and the cluster size. Our version of the formula may aid the efficient planning and design of cluster randomised crossover trials.

Revision joint replacement surgeries of the hip and knee across geographic region and socioeconomic status in the western region of Victoria: a cross-sectional multilevel analysis of registry data.

BACKGROUND: Residents of rural and regional areas, compared to those in urban regions, are more likely to experience geographical difficulties in accessing healthcare, particularly specialist services. We investigated associations between region of residence, socioeconomic status (SES) and utilisation of all-cause revision hip replacement or revision knee replacement surgeries. METHODS: Conducted in western Victoria, Australia, as part of the Ageing, Chronic Disease and Injury study, data from the Australian Orthopaedic Association National Joint Replacement Registry (2011-2013) for adults who underwent a revision hip replacement (n = 542; 54% female) or revision knee replacement (n = 353; 54% female) were extracted. We cross-matched residential addresses with 2011 census data from the Australian Bureau of Statistics (ABS), and using an ABS-derived composite index, classified region of residence according to local government areas (LGAs), and area-level SES into quintiles. For analyses, the control population (n = 591,265; 51% female) was ABS-determined and excluded adults already identified as cases. Mixed-effects logistic regression was performed. RESULTS: We observed that 77% of revision hip surgeries and 83% of revision knee surgeries were performed for residents in the three most socially disadvantaged quintiles. In adjusted multilevel models, total variances contributed by the variance in LGAs for revisions of the hip or knee joint were only 1% (SD random effects ±0.01) and 3% (SD ± 0.02), respectively. No differences across SES or sex were observed. CONCLUSIONS: No differences in utilisation were identified between SES groups in the provision of revision surgeries of the hip or knee, independent of small between-LGA differences.

Temporal trends in medical device implant procedures in Australia 2008-22: evidence from the Australian Institute of Health and Welfare National Hospital Morbidity database.

ObjectiveExamine the temporal trends in medical device implant procedures in the Australian population.MethodsWe used data from the Australian Institute of Health and Welfare from the financial years 2007-08 to 2021-22 and chose the most frequently performed medical device implant procedures. We estimated the annual change in volume of procedures and age-standardised rates by calculating the compound annual growth rate (CAGR), and used regression with the Newey-West robust variance estimator to examine whether there was a linear trend in the age-standardised rates for each procedure.ResultsFor procedures including cardiac pacemakers, heart valves, hip and knee arthroplasties, and intraocular lenses, the crude CAGR was over 3%. For the age-standardised rates, the CAGR was largest for cardiac pacemaker, followed by heart valve replacement and hip arthroplasty procedures. For some procedures, the growth was more than in the Australian population, including cardiac pacemakers (ß=1.00; 95% CI: 0.14-1.86), heart valve replacements (ß=0.41; 95% CI: 0.28-0.54), hip arthroplasty (ß=3.50; 95% CI: 1.61-5.38), and knee arthroplasty (ß=4.31; 95% CI: 0.54-8.09) procedures. The trend of standardised rates of procedures, including incisional hernia with mesh, breast implants, coronary stents, and cardiac defibrillators, grew at the same rate as the population, whereas the rate for gastric banding procedures decreased (ß=-3.14; 95% CI: -4.92 to -1.34).ConclusionThe findings from the current study, showing a large increase in medical device implant procedures, will assist in future healthcare planning and efforts in post-market surveillance of safety of medical devices.

Stroke in critically ill patients with respiratory failure due to COVID-19: Disparities between low-middle and high-income countries.

PURPOSE: We aimed to compare the incidence of stroke in low-and middle-income countries (LMICs) versus high-income countries (HICs) in critically ill patients with COVID-19 and its impact on in-hospital mortality. METHODS: International observational study conducted in 43 countries. Stroke and mortality incidence rates and rate ratios (IRR) were calculated per admitted days using Poisson regression. Inverse probability weighting (IPW) was used to address the HICs vs. LMICs imbalance for confounders. RESULTS: 23,738 patients [20,511(86.4 %) HICs vs. 3,227(13.6 %) LMICs] were included. The incidence stroke/1000 admitted-days was 35.7 (95 %CI = 28.4-44.9) LMICs and 17.6 (95 %CI = 15.8-19.7) HICs; ischemic 9.47 (95 %CI = 6.57-13.7) LMICs, 1.97 (95 %CI = 1.53, 2.55) HICs; hemorrhagic, 7.18 (95 %CI = 4.73-10.9) LMICs, and 2.52 (95 %CI = 2.00-3.16) HICs; unspecified stroke type 11.6 (95 %CI = 7.75-17.3) LMICs, 8.99 (95 %CI = 7.70-10.5) HICs. In regression with IPW, LMICs vs. HICs had IRR = 1.78 (95 %CI = 1.31-2.42, p < 0.001). Patients from LMICs were more likely to die than those from HICs [43.6% vs 29.2 %; Relative Risk (RR) = 2.59 (95 %CI = 2.29-2.93), p < 0.001)]. Patients with stroke were more likely to die than those without stroke [RR = 1.43 (95 %CI = 1.19-1.72), p < 0.001)]. CONCLUSIONS: Stroke incidence was low in HICs and LMICs although the stroke risk was higher in LMICs. Both LMIC status and stroke increased the risk of death. Improving early diagnosis of stroke and redistribution of healthcare resources should be a priority. TRIAL REGISTRATION: ACTRN12620000421932 registered on 30/03/2020.

Wrist accelerometer temporal analysis as a prognostic tool for aged care residents: A sub-study of the ReMInDAR trial.

BACKGROUND: Objective measures for screening, prioritizing, and planning care for frail individuals are essential for appropriate aged care provision. This study evaluates metrics derived from actigraphy measures (captured by wrist accelerometer) as a digital biomarker to identify frail individuals at risk of adverse outcomes, including death, hospitalization, and cognitive decline. METHODS: This was a secondary study using data from a randomized controlled trial assessing the effectiveness of an ongoing pharmacist service in residential aged care facilities. Three metrics are studied and compared: the Frailty Index, the daily time spent in light time activity, and the temporal correlation of the actigraphy signal, measured by detrended fluctuation analysis. The association between actigraphy-derived metrics at baseline and adverse events within 12 months (death, cognitive decline, and hospitalizations) was assessed using logistic regression. RESULTS: Actigraphy records were available for 213 participants living in aged-care, median age of 85 years. Individuals with higher temporal correlation (activity is less random) were at lower risk of death (Standardized OR: 0.49; 95% CI 0.34, 0.7, p < 0.001) and hospitalization (Standardized OR: 0.57; 95% CI 0.42, 0.77, p < 0.001) in 12 months, but there was no difference in cognitive decline (Standardized OR: 1; 95% CI 0.74, 1.35, p = 0.98). The predictive model that included temporal correlation had an area under the curve of 0.70 (CI 0.60-0.80) for death and 0.64 (CI 0.54-0.72) for hospitalization. CONCLUSION: Temporal correlation of the actigraphy signal from aged care residents was strongly associated with death and hospitalization, but not cognitive decline. Digital biomarkers may have a place as an objective, accurate, and low-cost patient metric to support risk stratification and clinical planning.