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Objectives: To assess the mental health and wellbeing of health and aged care workers in Australia during the second and third years of the coronavirus disease 2019 (COVID-19) pandemic, overall and by occupation group., Design, Setting, Participants: Longitudinal cohort study of health and aged care workers (ambulance, hospitals, primary care, residential aged care) in Victoria: May-July 2021 (survey 1), October-December 2021 (survey 2), and May-June 2022 (survey 3)., Main Outcome Measures: Proportions of respondents (adjusted for age, gender, socio-economic status) reporting moderate to severe symptoms of depression (Patient Health Questionnaire-9, PHQ-9), anxiety (Generalized Anxiety Disorder scale, GAD-7), or post-traumatic stress (Impact of Event Scale-6, IES-6), burnout (abbreviated Maslach Burnout Inventory, aMBI), or high optimism (10-point visual analogue scale); mean scores (adjusted for age, gender, socio-economic status) for wellbeing (Personal Wellbeing Index-Adult, PWI-A) and resilience (Connor Davidson Resilience Scale 2, CD-RISC-2)., Results: A total of 1667 people responded to at least one survey (survey 1, 989; survey 2, 1153; survey 3, 993; response rate, 3.3%). Overall, 1211 survey responses were from women (72.6%); most respondents were hospital workers (1289, 77.3%) or ambulance staff (315, 18.9%). The adjusted proportions of respondents who reported moderate to severe symptoms of depression (survey 1, 16.4%; survey 2, 22.6%; survey 3, 19.2%), anxiety (survey 1, 8.8%; survey 2, 16.0%; survey 3, 11.0%), or post-traumatic stress (survey 1, 14.6%; survey 2, 35.1%; survey 3, 14.9%) were each largest for survey 2. The adjusted proportions of participants who reported moderate to severe symptoms of burnout were higher in surveys 2 and 3 than in survey 1, and the proportions who reported high optimism were smaller in surveys 2 and 3 than in survey 1. Adjusted mean scores for wellbeing and resilience were similar at surveys 2 and 3 and lower than at survey 1. The magnitude but not the patterns of change differed by occupation group., Conclusion: Burnout was more frequently reported and mean wellbeing and resilience scores were lower in mid-2022 than in mid-2021 for Victorian health and aged care workers who participated in our study. Evidence-based mental health and wellbeing programs for workers in health care organisations are needed., Trial Registration: Australian New Zealand Clinical Trials Registry: ACTRN12621000533897 (observational study; retrospective)., (© 2023 The Authors. Medical Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of AMPCo Pty Ltd.)

Objective: Populations with knee osteoarthritis (KOA) are at increased risk of cardiovascular disease, due to higher prevalence of risk factors including dyslipidaemia, where statins are commonly prescribed. However, the effect of statins on muscles and symptoms in this population is unknown. Thus, this study examined the effect of atorvastatin on muscle properties in patients with symptomatic KOA., Design: Post-hoc analysis of a 2-year multicentre randomised, double-blind, placebo-controlled trial., Setting: Australian community., Participants: Participants aged 40-70 years (mean age 55.7 years, 55.6% female) with KOA who met the American College of Rheumatology clinical criteria received atorvastatin 40 mg daily ( n = 151) or placebo ( n = 153)., Main Outcome Measures: Levels of creatinine kinase (CK), aspartate transaminase (AST), and alanine transaminase (ALT) at 1, 6, 12, and 24 months; muscle strength (by dynamometry) at 12 and 24 months; vastus medialis cross-sectional area (CSA) on magnetic resonance imaging at 24 months; and self-reported myalgia., Results: There were no significant between-group differences in CK and AST at all timespoints. The atorvastatin group had higher ALT than placebo group at 1 (median 26 vs. 21, p = 0.004) and 6 (25 vs. 22, p = 0.007) months without significant between-group differences at 12 and 24 months. Muscle strength increased in both groups at 24 months without between-group differences [mean 8.2 (95% CI 3.5, 12.9) vs. 5.9 (1.3, 10.4), p = 0.49]. Change in vastus medialis CSA at 24 months favoured the atorvastatin group [0.11 (-0.10, 0.31) vs. -0.23 (-0.43, -0.03), p = 0.02] but of uncertain clinical significance. There was a trend for more myalgia in the atorvastatin group (8/151 vs. 2/153, p = 0.06) over 2 years, mostly occurring within 6 months (7/151 vs. 1/153, p = 0.04)., Conclusions: In those with symptomatic KOA, despite a trend for more myalgia, there was no clear evidence of an adverse effect of atorvastatin on muscles, including those most relevant to knee joint health., Competing Interests: GJ received honoraria for talks from BMS, Roche, AbbVie, Amgen, Lilly, Novartis, and Janssen, and grant for a clinical trial from Covance. AT received honoraria for lectures from Pfizer, honoraria for lectures and advisory board participation from Amgen, honoraria for data and safety monitoring board participation from Merck, and honoraria for data and safety monitoring board participation from Novartis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lim, Cicuttini, Wluka, Jones, Hill, Forbes, Tonkin, Berezovskaya, Tan, Ding and Wang.)

Objectives: Interrupted Time Series (ITS) are a type of nonrandomized design commonly used to evaluate public health policy interventions, and the impact of exposures, at the population level. Meta-analysis may be used to combine results from ITS across studies (in the context of systematic reviews) or across sites within the same study. We aimed to examine the statistical approaches, methods, and completeness of reporting in reviews that meta-analyze results from ITS., Study Design and Settings: Eight electronic databases were searched to identify reviews (published 2000-2019) that meta-analyzed at least two ITS. Characteristics of the included reviews, the statistical methods used to analyze the ITS and meta-analyze their results, effect measures, and risk of bias assessment tools were extracted., Results: Of the 4213 identified records, 54 reviews were included. Nearly all reviews (94%) used two-stage meta-analysis, most commonly fitting a random effects model (69%). Among the 41 reviews that re-analyzed the ITS, linear regression (39%) and ARIMA (20%) were most commonly used; 38% adjusted for autocorrelation. The most common effect measure meta-analyzed was an immediate level-change (46/54). Reporting of the statistical methods and ITS characteristics was often incomplete., Conclusion: Improvement is needed in the conduct and reporting of reviews that meta-analyze results from ITS., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

In cluster-randomized trials, sometimes the effect of the intervention being studied differs between clusters, commonly referred to as treatment effect heterogeneity. In the analysis of stepped wedge and cluster-randomized crossover trials, it is possible to include terms in outcome regression models to allow for such treatment effect heterogeneity yet this is not frequently considered. Outside of some simulation studies of specific cases where the outcome is binary, the impact of failing to include terms for treatment effect heterogeneity on the variance of the treatment effect estimator is unknown. We analytically examine the impact of failing to include terms for treatment effect heterogeneity on the variance of the treatment effect estimator, when outcomes are continuous. Using analysis of variance and feasible generalized least squares we provide expressions for this variance. For both the cluster-randomized crossover design and the stepped wedge design, our analytic derivations indicate that failing to include treatment effect heterogeneity results in the estimates for variance of the treatment effect that are too small, leading to inflation of type I error rates. We therefore recommend assessing the sensitivity of sample size calculations and conclusions drawn from the analysis of cluster randomized trials to the inclusion of treatment effect heterogeneity.

Background: Interrupted time series (ITS) studies are frequently used to evaluate the effects of population-level interventions or exposures. However, examination of the performance of statistical methods for this design has received relatively little attention., Methods: We simulated continuous data to compare the performance of a set of statistical methods under a range of scenarios which included different level and slope changes, varying lengths of series and magnitudes of lag-1 autocorrelation. We also examined the performance of the Durbin-Watson (DW) test for detecting autocorrelation., Results: All methods yielded unbiased estimates of the level and slope changes over all scenarios. The magnitude of autocorrelation was underestimated by all methods, however, restricted maximum likelihood (REML) yielded the least biased estimates. Underestimation of autocorrelation led to standard errors that were too small and coverage less than the nominal 95%. All methods performed better with longer time series, except for ordinary least squares (OLS) in the presence of autocorrelation and Newey-West for high values of autocorrelation. The DW test for the presence of autocorrelation performed poorly except for long series and large autocorrelation., Conclusions: From the methods evaluated, OLS was the preferred method in series with fewer than 12 points, while in longer series, REML was preferred. The DW test should not be relied upon to detect autocorrelation, except when the series is long. Care is needed when interpreting results from all methods, given confidence intervals will generally be too narrow. Further research is required to develop better performing methods for ITS, especially for short series., (© 2021. The Author(s).)

Objectives: Interrupted time series (ITS) designs are frequently used in public health to examine whether an intervention or exposure has influenced health outcomes. Few reviews have been undertaken to examine the design characteristics, statistical methods, and completeness of reporting of published ITS studies., Study Design and Setting: We used stratified random sampling to identify 200 ITS studies that evaluated public health interventions or exposures from PubMed (2013-2017). Study characteristics, details of statistical models and estimation methods used, effect metrics, and parameter estimates were extracted. From the 200 studies, 230 time series were examined., Results: Common statistical methods used were linear regression (31%, 72/230) and autoregressive integrated moving average (19%, 43/230). In 17% (40/230) of the series, we could not determine the statistical method used. Autocorrelation was acknowledged in 63% (145/230) of the series. An estimate of the autocorrelation coefficient was given for only 1% of the series (3/230). Measures of precision were reported for 63% of effect measures (541/852)., Conclusion: Many aspects of the design, methods, analysis, and reporting of ITS studies can be improved, particularly description of the statistical methods and approaches to adjust for and estimate autocorrelation. More guidance on the conduct and reporting of ITS studies is needed to improve this study design., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Stepped wedge and other multiple-period cluster randomized trials, which collect data from multiple clusters across multiple time periods, are being conducted with increasing frequency; statistical research into these designs has not kept apace. In particular, some stepped wedge designs with missing cluster-period "cells" have been proposed without any formal justification. Indeed there are no general guidelines regarding which cells of a stepped wedge design contribute the least information toward estimation of the treatment effect, and correspondingly which may be preferentially omitted. In this article, we define a metric of the information content of cluster-period cells, entire treatment sequences, and entire periods of the standard stepped wedge design as the increase in variance of the estimator of the treatment effect when that cell, sequence, or period is omitted. We show that the most information-rich cells are those that occur immediately before or after treatment switches, but also that there are additional cells that contribute almost as much to the estimation of the treatment effect. However, the information content patterns depend on the assumed correlation structure for the repeated measurements within a cluster., (© 2018, The International Biometric Society.)

Objective: The cluster randomised crossover (CRXO) design provides an opportunity to conduct randomised controlled trials to evaluate low risk interventions in the intensive care setting. Our aim is to provide a tutorial on how to perform a sample size calculation for a CRXO trial, focusing on the meaning of the elements required for the calculations, with application to intensive care trials., Data Sources: We use all-cause in-hospital mortality from the Australian and New Zealand Intensive Care Society Adult Patient Database clinical registry to illustrate the sample size calculations., Methods: We show sample size calculations for a two-intervention, two 12-month period, cross-sectional CRXO trial. We provide the formulae, and examples of their use, to determine the number of intensive care units required to detect a risk ratio (RR) with a designated level of power between two interventions for trials in which the elements required for sample size calculations remain constant across all ICUs (unstratified design); and in which there are distinct groups (strata) of ICUs that differ importantly in the elements required for sample size calculations (stratified design)., Results: The CRXO design markedly reduces the sample size requirement compared with the parallel-group, cluster randomised design for the example cases. The stratified design further reduces the sample size requirement compared with the unstratified design., Conclusions: The CRXO design enables the evaluation of routinely used interventions that can bring about small, but important, improvements in patient care in the intensive care setting.

Background: Sedation strategy in critically ill patients who are mechanically ventilated is influenced by patient-related factors, choice of sedative agent and the intensity or depth of sedation prescribed. The impact of sedation strategy on outcome, in particular when delivered early after initiation of mechanical ventilation, is uncertain., Objectives: To present the protocol and analysis plan of a large randomised clinical trial investigating the effect of a sedation strategy, in critically ill patients who are mechanically ventilated, based on a protocol targeting light sedation using dexmedetomidine as the primary sedative, termed "early goal-directed sedation", compared with usual practice., Methods: This is a multinational randomised clinical trial in adult intensive care patients expected to require mechanical ventilation for longer than 24 hours. The main exclusion criteria include suspected or proven primary brain pathology or having already been intubated or sedated in an intensive care unit for longer than 12 hours. Randomisation occurs via a secured website with baseline stratification by site and suspected or proven sepsis. The primary outcome is 90-day all-cause mortality. Secondary outcomes include death, institutional dependency, cognitive function and health-related quality of life 180 days after randomisation, as well as deliriumfree, coma-free and ventilation-free days at 28 days after randomisation. A predefined subgroup analysis will also be conducted. Analyses will be on an intention-to-treat basis and in accordance with this pre-specified analysis plan., Conclusion: SPICE III is an ongoing large scale clinical trial. Once completed, it will inform sedation practice in critically ill patients who are ventilated.

Objective: To compare health service utilization and disability claims among military personnel with multisymptom illness (MSI) (but no chronic diseases), those with chronic disease(s) and those without MSI or chronic diseases. MSI is also known as Gulf War illness., Design: Cohort study., Setting: Australia., Participants: In total, 1288 participants of a Gulf War veterans' study conducted in 2000-2003 (Wave-1) were followed up in 2011-2012 (Wave-2), aged on average 40 years. About 160 had MSI, 217 had chronic disease(s) and 911 had neither chronic disease(s) nor MSI., Methods: At Wave-2, the cohort was linked to the national Medicare and Department of Veterans' Affairs (DVA) databases to obtain health service utilization and disability claims data recorded between 2001 and 2012., Results: The likelihood of visiting a general practitioner (GP) (risk ratio [RR] = 1.04, 95% confidence interval [CI] = 0.92, 1.19) or visiting a specialist medical doctor (RR = 0.83; 95% CI = 0.54, 1.28) or hospitalizations (RR = 0.89; 95% CI = 0.61, 1.29) or) in the 12 months preceding Wave-2 or successfully claiming for DVA disability compensation (RR = 1.13; 95% CI = 0.86, 1.47) was similar for personnel with MSI and those with chronic disease(s). However, GP consultations, hospitalizations, specialist doctor consultations and disability claims were significantly higher among those with MSI than those without MSI/chronic diseases., Conclusions: Health service use and disability claims by personnel with MSI were comparable to those with chronic disease(s), but were in excess of those without MSI/chronic diseases. Hence recognition of the high health service use by personnel with MSI is important to ensure adequate provision of health services., (© Commonwealth of Australia 2017. Published by Oxford University Press in association with the International Society for Quality in Health Care. For permissions, please e-mail: journals.permissions@oup.com)

The development of anthelmintic resistance by helminths can be slowed by maintaining refugia on pasture or in untreated hosts. Targeted selective treatments (TST) may achieve this through the treatment only of individuals that would benefit most from anthelmintic, according to certain criteria. However TST consequences on cattle are uncertain, mainly due to difficulties of comparison between alternative strategies. We developed a mathematical model to compare: 1) the most 'beneficial' indicator for treatment selection and 2) the method of selection of calves exposed to Ostertagia ostertagi, i.e. treating a fixed percentage of the population with the lowest (or highest) indicator values versus treating individuals who exceed (or are below) a given indicator threshold. The indicators evaluated were average daily gain (ADG), faecal egg counts (FEC), plasma pepsinogen, combined FEC and plasma pepsinogen, versus random selection of individuals. Treatment success was assessed in terms of benefit per R (BPR), the ratio of average benefit in weight gain to change in frequency of resistance alleles R (relative to an untreated population). The optimal indicator in terms of BPR for fixed percentages of calves treated was plasma pepsinogen and the worst ADG; in the latter case treatment was applied to some individuals who were not in need of treatment. The reverse was found when calves were treated according to threshold criteria, with ADG being the best target indicator for treatment. This was also the most beneficial strategy overall, with a significantly higher BPR value than any other strategy, but its degree of success depended on the chosen threshold of the indicator. The study shows strong support for TST, with all strategies showing improvements on calves treated selectively, compared with whole-herd treatment at 3, 8, 13 weeks post-turnout. The developed model appeared capable of assessing the consequences of other TST strategies on calf populations., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: The aim of this study was to conduct a systematic review and meta-analysis of multisymptom illness (MSI) in 1990 to 1991 Gulf/Afghanistan/Iraq War veterans., Methods: Electronic databases were searched from January 1990, June 2014 for studies on MSI prevalence in Gulf/Afghanistan/Iraq War veterans, based on the Centers for Disease Control and Prevention MSI case definition, and which included a military comparison group., Results: Seven studies were identified among US, UK, and Australian Gulf War veterans; no studies were identified in Afghanistan/Iraq War veterans. MSI prevalence in Gulf War veterans and comparison groups ranged from 26 to 65% and from 12 to 37%, respectively. More recent studies were larger, with improved designs. The pooled odds ratio comparing Gulf War veterans to other military groups was 2.74 (95% confidence interval 2.15 to 3.51)., Conclusion: The systematic review showed that MSI was most prevalent in Gulf War veterans, emphasizing the health burden of MSI in this veteran population.

Objective: To assess the design and statistical methods used in cluster-randomized crossover (CRXO) trials., Study Design and Setting: We undertook a systematic review of CRXO trials. Searches of MEDLINE, EMBASE, and CINAHL Plus; and citation searches of CRXO methodological articles were conducted to December 2014. We extracted data on design characteristics and statistical methods for sample size, data analysis, and handling of missing data., Results: Ninety-one trials including 139 end point analyses met the inclusion criteria. Trials had a median of nine clusters [interquartile range (IQR), 4-21] and median cluster-period size of 30 individuals (IQR, 14-77); 58 (69%) trials had two periods, and 27 trials (30%) included the same individuals in all periods. A rationale for the design was reported in only 25 trials (27%). A sample size justification was provided in 53 (58%) trials. Only nine (10%) trials accounted appropriately for the design in their sample size calculation. Ten of the 12 cluster-level analyses used a method that accounted for the clustering and multiple-period aspects of the design. In contrast, only 4 of the 127 individual-level analyses used a potentially appropriate method., Conclusions: There is a need for improved application of appropriate analysis and sample size methods, and reporting, in CRXO trials., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Following the 1990-1991 Gulf War, Gulf War veterans (veterans) reported health symptoms more commonly than non-deployed groups. This article examines symptom persistence, incidence and prevalence 20 years on., Methods: In 2000-2003 and 2011-2012, a 63-item symptom checklist was administered to 697 veterans and 659 comparison group. Symptomatology was compared using log-binomial regression., Results: Both veterans and comparison group reported significantly increased prevalence (3-52%) over time in more than half the symptoms, with a similar overall rate of increase. Half the symptoms had higher incidence (risk-ratios ranged 1.43-1.50) and a quarter were more persistent (risk-ratios ranged 1.12-1.20) in veterans than the comparison group., Conclusions: Symptomatology increased in both groups over time, but persisted to a similar extent and had higher incidence among veterans than the comparison group. The gap in symptom prevalence between the two groups remained unchanged. These findings suggest enduring health consequences of Gulf War service., (© 2015 Commonwealth of Australia. American Journal of Industrial Medicine © 2015 Wiley Periodicals, Inc.)

Lectin binding to carbohydrates on parasite surfaces has been investigated as a method of distinguishing adult worms, eggs and sheathed and exsheathed L3 of Teladorsagia circumcincta and Haemonchus contortus, economically important abomasal parasites in temperate climates. Both species were maintained as pure laboratory cultures of field isolates from New Zealand. Each of the four life cycle stages could be distinguished by the binding of at least one lectin: adult worms by Sambucus nigra agglutinin (SNA); eggs by peanut agglutinin (PNA), ConcavalinA and Lens culinaris agglutinin (LCA); exsheathed L3 by Griffonia simplicifolia-I lectin (GSL-I) and Lotus tetragonolobus lectin (LTL) and sheathed L3 by Aleuria aurantia lectin (AAL). The whole surface of both adult T. circumcincta and H. contortus strongly bound lectins specific for N-acetylglucosamine (GlcNAc), N-acetylgalactosamine (GalNAc), mannose and fucose, but the two species could be distinguished by SNA binding only to T. circumcincta. Eggs could be distinguished by the binding of mannose-specific PNA to H. contortus and GalNAc-specific LCA and PSA to T. circumcincta eggs. GalNAc, GlcNAc and mannose lectins bound to the cuticle and over the excretory pores of a large proportion of sheathed L3 of both species, but only the H. contortus surface had exposed fucose or sialic acid complexes. The distinguishing lectin for sheathed L3 was AAL, which did not bind to T. circumcincta, but bound weakly to the head region of all fresh H. contortus and to 50-90% after 3 months storage. The cuticle of exsheathed L3 was unresponsive to all 19 lectins, and any binding was restricted to the head and tail regions. L3 exsheathed after 2-4 months storage could be distinguished by the binding of GSL-I and LTL to H. contortus but not to T. circumcincta. Lectin binding could be a useful adjunct in identifying L3, but lacked the consistency to be definitive, whereas it could be further developed as a practical method of distinguishing parasitic nematodes at other stages in the life cycle, particularly the eggs.