Associations between postoperative anaemia and unplanned readmission to hospital after major surgery: a retrospective cohort study†.

BACKGROUND: Anaemia following major surgery may be associated with unplanned readmission to hospital. However, the severity-response relationship between the degree of anaemia at discharge and the risk of unplanned readmission is poorly defined. We aimed to describe the severity-response relationship between haemoglobin concentration at the time of discharge and the risk of unplanned readmission in a cohort of patients undergoing different types of major surgery. METHODS: We performed a retrospective cohort study in a single tertiary health service, including all patients who underwent major surgery (orthopaedic, abdominal, cardiac or thoracic) between 1 May 2011 and 1 February 2022. The primary outcome was unplanned readmission to hospital in the 90 days following discharge after the index surgical procedure. These complex, non-linear relationships were modelled with restricted cubic splines. RESULTS: We identified 22,134 patients and included 14,635 in the primary analysis, of whom 1804 (12%) experienced at least one unplanned readmission. The odds of unplanned readmission rose when the discharge haemoglobin concentration was < 100 g.l-1 (p < 0.001). On subgroup analysis, the haemoglobin threshold below which odds of readmission began to increase appeared to be higher in patients undergoing emergency surgery (110 g.l-1; p < 0.001) compared with elective surgery. Declining discharge haemoglobin concentration was associated with increased odds ratios (95%CI) of unplanned readmission in patients undergoing orthopaedic (1.08 (1.01-1.15), p = 0.03), abdominal (1.13 (1.07-1.19), p < 0.001) and thoracic (1.12 (1.01-1.24), p = 0.03) procedures, but not cardiac surgery (1.09 (0.99-1.19), p = 0.07). CONCLUSIONS: Our findings suggest that a haemoglobin concentration < 100 g.l-1 following elective procedures and < 110 g.l-1 following emergency procedures, at the time of hospital discharge after major surgery, was associated with unplanned readmission. Future interventional trials that aim to treat postoperative anaemia and reduce unplanned readmission should include patients with discharge haemoglobin below these thresholds.

Advancing randomized controlled trial methodologies: The place of innovative trial design in eating disorders research.

Randomized controlled trials can be used to generate evidence on the efficacy and safety of new treatments in eating disorders research. Many of the trials previously conducted in this area have been deemed to be of low quality, in part due to a number of practical constraints. This article provides an overview of established and more innovative clinical trial designs, accompanied by pertinent examples, to highlight how design choices can enhance flexibility and improve efficiency of both resource allocation and participant involvement. Trial designs include individually randomized, cluster randomized, and designs with randomizations at multiple time points and/or addressing several research questions (master protocol studies). Design features include the use of adaptations and considerations for pragmatic or registry-based trials. The appropriate choice of trial design, together with rigorous trial conduct, reporting and analysis, can establish high-quality evidence to advance knowledge in the field. It is anticipated that this article will provide a broad and contemporary introduction to trial designs and will help researchers make informed trial design choices for improved testing of new interventions in eating disorders. PUBLIC SIGNIFICANCE: There is a paucity of high quality randomized controlled trials that have been conducted in eating disorders, highlighting the need to identify where efficiency gains in trial design may be possible to advance the eating disorder research field. We provide an overview of some key trial designs and features which may offer solutions to practical constraints and increase trial efficiency.

Handling missing disease information due to death in diseases that need two visits to diagnose.

In studies that assess disease status periodically, time of disease onset is interval censored between visits. Participants who die between two visits may have unknown disease status after their last visit. In this work, we consider an additional scenario where diagnosis requires two consecutive positive tests, such that disease status can also be unknown at the last visit preceding death. We show that this impacts the choice of censoring time for those who die without an observed disease diagnosis. We investigate two classes of models that quantify the effect of risk factors on disease outcome: a Cox proportional hazards model with death as a competing risk and an illness death model that treats disease as a possible intermediate state. We also consider four censoring strategies: participants without observed disease are censored at death (Cox model only), the last visit, the last visit with a negative test, or the second last visit. We evaluate the performance of model and censoring strategy combinations on simulated data with a binary risk factor and illustrate with a real data application. We find that the illness death model with censoring at the second last visit shows the best performance in all simulation settings. Other combinations show bias that varies in magnitude and direction depending on the differential mortality between diseased and disease-free subjects, the gap between visits, and the choice of the censoring time.

Efficacy and safety of avatrombopag in combination with immunosuppressive therapy in treatment-naïve and relapsed/refractory severe aplastic anaemia: protocol for the DIAAMOND-Ava-FIRST and DIAAMOND-Ava-NEXT Bayesian Optimal Phase II trials.

INTRODUCTION: Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and ciclosporin is standard of care for patients with severe aplastic anaemia (sAA) not eligible or suitable for allogeneic stem cell transplant. While patients respond to IST, few achieve complete responses and a significant proportion are refractory or relapse. The addition of eltrombopag, a thrombopoietin-receptor agonist (TPO-A), to IST has been shown to improve haematological responses in sAA. Avatrombopag is a second-generation TPO-A with potential advantages over eltrombopag. However, to date avatrombopag has not been studied in sAA. METHODS AND ANALYSIS: Investigator-initiated, single-arm registry-based Bayesian Optimal Phase II trial of avatrombopag conducted in two cohorts, patients with untreated sAA (FIRST cohort) and in patients with sAA that has relapsed or is refractory to IST (NEXT cohort). In the FIRST cohort, participants receive IST (equine ATG and ciclosporin) plus avatrombopag from day 1 until day 180 at 60 mg oral daily, with dose adjusted according to platelet count. Participants in the NEXT cohort receive avatrombopag at 60 mg oral daily from day 1 until day 180, with or without additional IST at the discretion of the treating clinician.For each cohort, two primary endpoints (haematological response and acquired clonal evolution) are jointly monitored and the trial reviewed at each interim analysis where a 'go/no-go' decision is made by evaluating the posterior probability of the events of interests. ETHICS AND DISSEMINATION: The trial has received ethics approval (Monash Health RES-18-0000707A). The trial conduct will comply with ICH-GCP and all applicable regulatory requirements. The results of the trial will be submitted to a peer-review journal for publication. TRIAL REGISTRATION NUMBER: ACTRN12619001042134, ACTRN12619001043123.

Metformin for knee osteoarthritis with obesity: study protocol for a randomised, double-blind, placebo-controlled trial.

INTRODUCTION: Over half of the populations with knee osteoarthritis (OA) have obesity. These individuals have many other shared metabolic risk factors. Metformin is a safe, inexpensive, well-tolerated drug that has pleiotropic effects, including structural protection, anti-inflammatory and analgesic effects in OA, specifically the knee. The aim of this randomised, double-blind, placebo-controlled trial is to determine whether metformin reduces knee pain over 6 months in individuals with symptomatic knee OA who are overweight or obese. METHODS AND ANALYSIS: One hundred and two participants with symptomatic knee OA and overweight or obesity will be recruited from the community in Melbourne, Australia, and randomly allocated in a 1:1 ratio to receive either metformin 2 g or identical placebo daily for 6 months. The primary outcome is reduction of knee pain [assessed by 100 mm Visual Analogue Scale (VAS)] at 6 months. The secondary outcomes are OMERACT-OARSI (Outcome Measures in Rheumatology-Osteoarthritis Research Society International) responder criteria [Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, function and participant's global assessment (VAS)] at 6 months; change in knee pain, stiffness, function using WOMAC at 6 months and quality of life at 6 months. Adverse events will be recorded. The primary analysis will be by intention to treat, including all participants in their randomised groups. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the Alfred Hospital Ethics Committee (708/20) and Monash University Human Research Ethics Committee (28498). Written informed consent will be obtained from all the participants. The findings will be disseminated through peer-review publications and conference presentations. TRIAL REGISTRATION NUMBER: ACTRN12621000710820 .

STAREE-Mind Imaging Study: a randomised placebo-controlled trial of atorvastatin for prevention of cerebrovascular decline and neurodegeneration in older individuals.

Introduction: Cerebrovascular disease and neurodegeneration are causes of cognitive decline and dementia, for which primary prevention options are currently lacking. Statins are well-tolerated and widely available medications that potentially have neuroprotective effects. The STAREE-Mind Imaging Study is a randomised, double-blind, placebo-controlled clinical trial that will investigate the impact of atorvastatin on markers of neurovascular health and brain atrophy in a healthy, older population using MRI. This is a nested substudy of the 'Statins for Reducing Events in the Elderly' (STAREE) primary prevention trial. Methods: Participants aged 70 years or older (n=340) will be randomised to atorvastatin or placebo. Comprehensive brain MRI assessment will be undertaken at baseline and up to 4 years follow-up, including structural, diffusion, perfusion and susceptibility imaging. The primary outcome measures will be change in brain free water fraction (a composite marker of vascular leakage, neuroinflammation and neurodegeneration) and white matter hyperintensity volume (small vessel disease). Secondary outcomes will include change in perivascular space volume (glymphatic drainage), cortical thickness, hippocampal volume, microbleeds and lacunae, prefrontal cerebral perfusion and white matter microstructure. Ethics and dissemination: Academic publications from this work will address the current uncertainty regarding the impact of statins on brain structure and vascular integrity. This study will inform the utility of repurposing these well-tolerated, inexpensive and widely available drugs for primary prevention of neurological outcomes in older individuals. Ethics approval was given by Monash University Human Research Ethics Committee, Protocol 12206. Trial registration number: ClinicalTrials.gov Identifier: NCT05586750.

Negative back beliefs are associated with increased odds of low back pain and disability: a 10-year cohort study in men.

OBJECTIVE: Although negative back beliefs are associated with high-intensity low back pain (LBP)/disability, whether they influence incident high-intensity LBP/high-disability over the long-term is unknown. This study aimed to investigate whether negative back beliefs were associated with developing high-intensity LBP and/or high-disability over 10 years in men. METHODS: Men with no or low-intensity LBP and/or disability attending the Geelong Osteoporosis Study between 2006-2010 were included. Data on age, body mass index, mobility, education, back beliefs (Back Beliefs Questionnaire), LBP and disability (Graded Chronic Pain Scale) were collected between 2006-2010. Beliefs, LBP and disability were re-assessed in 2016-2021. Binary logistic regression was used to examine the association between negative back beliefs and incident high-intensity pain and/or high-disability, adjusting for age, body mass index, mobility, and education. RESULTS: At baseline, 705 participants (mean age 53.8 years) had no or low LBP and no or low-disability; 441 (62.6%) participants completed a 10-year follow-up. Of these, 37 (8.4%) developed high-intensity pain and/or high-disability. In multivariate analyses, participants with more negative back beliefs at baseline were more likely to develop high-intensity pain and/or high-disability (Odds ratio 1.05, 95% CI 1.00-1.11). Developing more negative back beliefs was also associated with incident high-intensity pain and/or high-disability (Odds Ratio 1.20, 95% CI 1.12-1.30). CONCLUSION: In a male community-based population, negative beliefs regarding the consequences of LBP were associated with an increased likelihood of developing high-intensity pain and/or high-disability. Addressing negative back beliefs in the community may reduce the incidence of high-intensity pain and/or high-disability over 10 years in men.

Effect of 6-week treatment with topical betamethasone dipropionate in patients with symptomatic hand osteoarthritis: A randomized double-blind, placebo-controlled trial.

Objective: To examine the efficacy and safety of topical corticosteroid over 6 weeks in patients with symptomatic hand osteoarthritis. Design: In a randomized, double-blind, placebo-controlled trial, community-based participants with hand osteoarthritis were randomly assigned (1:1) to topical Diprosone OV (betamethasone dipropionate 0.5 â€‹mg/g in optimised vehicle, n=54) or placebo (plain paraffin, n=52) ointment to painful joints 3 times daily for 6 weeks. Primary outcome was pain reduction [assessed by 100 â€‹mm visual analogue scale (VAS)] at 6 weeks. Secondary outcomes included changes in pain and function using the Australian Canadian Osteoarthritis Hand Index (AUSCAN), Functional Index for Hand Osteoarthritis (FIHOA), and Michigan Hand Outcomes Questionnaire (MHQ) at 6 weeks. Adverse events were recorded. Results: Of 106 participants (mean age 64.2 years, 85.9% female), 103 (97.2%) completed the study. Change in VAS at 6 weeks was similar in the Diprosone OV and placebo groups (-19.9 vs. -20.9, adjusted difference 0.6, 95% CI -8.9 to 10.2). There were no significant between-group differences in change in AUSCAN pain [adjusted difference 25.8 (-16.0 to 67.5)], AUSCAN function [21.2 (-55.0 to 97.4)], FIHOA [-0.1 (-1.7 to 1.5)], or MHQ [-1.2 (-6.0 to 3.6)]. Incidence of adverse events was 16.7% in Diprosone OV and 19.2% in placebo group. Conclusions: Topical Diprosone OV ointment, although well-tolerated, was no better than placebo in improving pain or function over 6 weeks in patient with symptomatic hand osteoarthritis. Future studies should consider examining joints with synovitis and whether delivery approaches enhancing transdermal penetration of corticosteroids into joints are effective in hand osteoarthritis. Trial registration: ACTRN 12620000599976. Registered May 22, 2020.

High levels of back disability, not back pain, are associated with reduced physical activity across key activity domains.

BACKGROUND: Although remaining physically active is the cornerstone of management for low back pain, our understanding of the physical activity performed by those with back pain is limited. OBJECTIVES: To examine the physical activity reported by individuals with different levels of low back pain and disability across key activity domains. DESIGN: Community-based, cross-sectional study. METHODS: 542 women were recruited from a research database formed from an electoral roll and completed validated, self-report questionnaires. The amount and intensity of physical activity was reported using the International Physical Activity Questionnaire. Low back pain and disability were examined using the Graded Chronic Pain Scale. Participants were categorised into no, low or high pain and disability groups. RESULTS: Individuals who reported high disability performed 55% of the physical activity of those without disability (MET(hours/week):median(95%CI) = 27.1(13.2-41.0); 48.8(37.8-59.9),p = 0.01), including less moderate (18.0(10.4-25.6); 31.0(24.0-38.1),p = 0.007), and domestic and gardening activity (14.7(7.2-22.3); 25.7(19.8-31.7),p = 0.001). Fewer women with high disability performed vigorous (OR(95%CI) = 0.29(0.13-0.65),p = 0.002) and leisure activities (0.17(0.04-0.75),p = 0.02) compared to those with no disability. Those with low disability reported less leisure activity ((0.55(0.35-0.88),p = 0.01), but more work-related activities and active transport than individuals without disability (1.65(1.01-2.7),p = 0.04; 1.6(1.04-2.6),p = 0.03). There were no differences in activity between pain groups, with the exception of those with low intensity pain performing less leisure activity (0.51(0.30-0.88),p = 0.01). CONCLUSIONS: Individuals who reported high back disability, not back pain, were found to perform reduced physical activity, including less total, moderate, vigorous, and discretionary activity. These findings highlight the altered activity levels of people with back disability and the need to examine its impact on their health and wellbeing.

A Systematic Review of Joint Spatial and Spatiotemporal Models in Health Research.

With the advancement of spatial analysis approaches, methodological research addressing the technical and statistical issues related to joint spatial and spatiotemporal models has increased. Despite the benefits of spatial modelling of several interrelated outcomes simultaneously, there has been no published systematic review on this topic, specifically when such models would be useful. This systematic review therefore aimed at reviewing health research published using joint spatial and spatiotemporal models. A systematic search of published studies that applied joint spatial and spatiotemporal models was performed using six electronic databases without geographic restriction. A search with the developed search terms yielded 4077 studies, from which 43 studies were included for the systematic review, including 15 studies focused on infectious diseases and 11 on cancer. Most of the studies (81.40%) were performed based on the Bayesian framework. Different joint spatial and spatiotemporal models were applied based on the nature of the data, population size, the incidence of outcomes, and assumptions. This review found that when the outcome is rare or the population is small, joint spatial and spatiotemporal models provide better performance by borrowing strength from related health outcomes which have a higher prevalence. A framework for the design, analysis, and reporting of such studies is also needed.

Use of a novel smartphone-based application tool for enrolment and randomisation in pre-hospital clinical trials.

The effective recruitment and randomisation of patients in pre-hospital clinical trials presents unique challenges. Owing to the time critical nature of many pre-hospital emergencies and limited resourcing, the use of traditional methods of randomisation that may include centralised telephone or web-based systems are often not practicable or feasible. Previous technological limitations have necessitated that pre-hospital trialists strike a compromise between implementing pragmatic, deliverable study designs, with robust enrolment and randomisation methodologies. In this commentary piece, we present a novel smartphone-based solution that has the potential to align pre-hospital clinical trial recruitment processes to that of best-in-practice in-hospital and ambulatory care based studies.

Platform trials for anaesthesia and perioperative medicine: a narrative review.

Large randomised trials provide the most reliable evidence of effectiveness of new treatments in clinical practice. However, the time and resources required to complete such trials can be daunting. An overarching clinical trial platform focused on a single condition or type of surgery, aiming to compare several treatments, with an option to stop any or add in new treatment options, can provide greater efficiency. This has the potential to accelerate knowledge acquisition and identify effective, ineffective, or harmful treatments faster. The master protocol of the platform defines the study population(s) and standardised procedures. Ineffective or harmful treatments can be discarded or study drug dose modified during the life cycle of the trial. Other adaptive elements that can be modified include eligibility criteria, required sample size for any comparison(s), randomisation assignment ratio, and the addition of other promising treatment options. There are excellent opportunities for anaesthetists to establish platform trials in perioperative medicine. Platform trials are highly efficient, with the potential to provide quicker answers to important clinical questions that lead to improved patient care.

A protocol for a prospective, multicentre observational study to determine if nonanaemic iron deficiency worsens postoperative outcome in patients undergoing elective surgery for resection of colorectal cancer: The NATO study.

BACKGROUND: Preoperative absolute and functional iron deficiency anaemia is associated with poor postoperative outcomes in patients undergoing surgery for colorectal cancer. It is biologically plausible that "early", or "nonanaemic" iron deficiency may also be associated with worse postoperative outcomes in similar cohorts, albeit at lesser severity than that seen for anaemia. The evidence supporting this assertion is of low quality. METHODS: We have designed a prospective, observational study to delineate associations between preoperative non-anaemic iron deficiency and postoperative outcomes after surgery for colorectal cancer. Patients without anaemia, undergoing elective surgery for colorectal cancer will be allocated to an iron replete or an iron deficient group based on preoperative transferrin saturation. The primary outcome is days alive and at home on postoperative day 90. Secondary outcomes include days alive and at home on postoperative day 30, length of hospital stay, readmission to acute care, postoperative complications, health-related quality of life scores, quality of postoperative recovery, and requirement for allogeneic blood transfusion. The planned sample size is 422 patients, which has 80% power to detect a two-day difference in the primary outcome. The study commenced in May 2019. CONCLUSION: The results of this study will provide patients and clinicians with high-quality evidence concerning associations between nonanaemic iron deficiency and patient-centred outcomes after surgery for colorectal cancer. The study will be conducted in multiple urban and rural centres across Australia and New Zealand. The results will be highly generalisable to contemporary surgical practice and should be rapidly translated.

Examining evidence of time-dependent treatment effects: an illustration using regression methods.

BACKGROUND: For the design and analysis of clinical trials with time-to-event outcomes, the Cox proportional hazards model and the logrank test have been the cornerstone methods for many decades. Increasingly, the key assumption of proportionality-or time-fixed effects-that underpins these methods has been called into question. The availability of novel therapies with new mechanisms of action and clinical trials of longer duration mean that non-proportional hazards are now more frequently encountered. METHODS: We compared several regression-based methods to model time-dependent treatment effects. For illustration purposes, we used selected endpoints from a large, community-based clinical trial of low dose daily aspirin in older persons. Relative and absolute estimands were defined, and analyses were conducted in all participants. Additional exploratory analyses were undertaken by selected subgroups of interest using interaction terms in the regression models. DISCUSSION: In the trial with median 4.7 years follow-up, we found evidence for non-proportionality and a time-dependent treatment effect of aspirin on cancer mortality not previously reported in trial findings. We also found some evidence of time-dependence to an aspirin by age interaction for major adverse cardiovascular events. For other endpoints, time-fixed treatment effect estimates were confirmed as appropriate. CONCLUSIONS: The consideration of treatment effects using both absolute and relative estimands enhanced clinical insights into potential dynamic treatment effects. We recommend these analytical approaches as an adjunct to primary analyses to fully explore findings from clinical trials.

Bayesian adaptive clinical trial designs for respiratory medicine.

The use of Bayesian adaptive designs for clinical trials has increased in recent years, particularly during the COVID-19 pandemic. Bayesian adaptive designs offer a flexible and efficient framework for conducting clinical trials and may provide results that are more useful and natural to interpret for clinicians, compared to traditional approaches. In this review, we provide an introduction to Bayesian adaptive designs and discuss its use in recent clinical trials conducted in respiratory medicine. We illustrate this approach by constructing a Bayesian adaptive design for a multi-arm trial that compares two non-invasive ventilation treatments to standard oxygen therapy for patients with acute cardiogenic pulmonary oedema. We highlight the benefits and some of the challenges involved in designing and implementing Bayesian adaptive trials.

Hospital costs and factors associated with days alive and at home after surgery (DAH30 ).

OBJECTIVE: To assess the relationships of patient and surgical factors and hospital costs with the number of days alive and at home during the 30 days following surgery (DAH30 ). DESIGN: Retrospective cohort study; analysis of Medibank Private health insurance hospital claims data, Australia, 1 January 2016 - 31 December 2017. SETTING, PARTICIPANTS: Admissions of adults (18 years or older) to hospitals for elective or emergency inpatient surgery with anaesthesia covered by private health insurance, Australia, 1 January 2016 - 31 December 2017. MAIN OUTCOME MEASURES: Associations between DAH30 and total hospital costs, and between DAH30 and surgery risk factors. RESULTS: Complete data were available for 126 788 of 181 281 eligible patients (69.9%); their median age was 62 years (IQR, 47-73 years), 72 872 were women (57%), and 115 117 had undergone elective surgery (91%). The median DAH30 was 27.1 days (IQR, 24.2-28.8 days), the median hospital cost per patient was $10 358 (IQR, $6624-20 174). The association between DAH30 and total hospital costs was moderate (Spearman ρ = -0.60; P < 0.001). Median DAH30 declined with age, comorbidity score, ASA physical status score, and surgical severity and duration, and was also lower for women. CONCLUSIONS: DAH30 is a validated, patient-centred outcome measure of post-surgical outcomes; higher values reflect shorter hospital stays and fewer serious complications, re-admissions, and deaths. DAH30 can be used to benchmark quality of surgical care and to monitor quality improvement programs for reducing the costs of surgical and other peri-operative care.

Associations between non-anaemic iron deficiency and outcomes following elective cardiac surgery (IDOCS): a prospective cohort study.

BACKGROUND: One in two adults undergoing cardiac surgery are iron deficient, best practice guidelines and consensus statements recommend routine investigation and treatment of iron deficiency before elective cardiac surgery, even in the absence of anaemia; however, it is not clear if non-anaemic iron deficiency is associated with worse outcomes in this patient population. We hypothesised that iron deficiency would be associated with worse postoperative outcomes than an iron replete state in adults without anaemia undergoing elective cardiac surgery. METHODS: We performed a prospective, cohort study at two hospitals in Australia. We recruited adults (ie, people 18 years and older) undergoing elective cardiac surgery without anaemia (defined as a haemoglobin of less than 130 g/L for men and less than 120 g/L for women), concomitant haemoglobinopathy, bone marrow pathology, haemochromatosis, or end-stage renal failure requiring dialysis. Participants were stratified as iron deficient or iron replete on the basis of preoperative testing. Iron deficiency was defined as a serum ferritin of less than 100 µg/L or 100-300 µg/L if transferrin saturation was less than 20% or C-reactive protein was more than 5 mg/L. The primary endpoint was days alive and at home at postoperative day 30. The primary analysis included all patients with data available for the primary endpoint and was adjusted for risk measured using EuroSCORE-II and body surface area. The study was prospectively registered with the Australian and New Zealand Clinical Trials Registry, ACTRN12618000185268. FINDINGS: We conducted the study between Feb 21, 2018, and May 7, 2021. We assessed 1171 patients for eligibility and 691 were ineligible; therefore, we enrolled and followed up 480 participants. 240 (50%) were iron deficient and 240 (50%) were iron replete, 95 (20%) were women, 385 (80%) were men, and 453 (94%) were White. Complete data was available for 479 individuals (240 in the iron deficient group and 239 in the iron replete group) for the primary endpoint. The iron deficient group had a median of 22·87 days (IQR 20·65 to 24·06) alive and at home at postoperative day 30, and the iron replete group had a median of 23·18 days (IQR 20·69 to 24·70). The unadjusted difference in medians between the groups was -0·18 days (95% CI -0·73 to 0·36; p=0·51) and the adjusted difference in medians between the groups was -0·11 days (95% CI -0·66 to 0·45; p=0·70). INTERPRETATION: In non-anaemic adults undergoing elective cardiac surgery, our findings suggest that patients with iron deficiency do not have a reduction in days alive and at home at postoperative day 30 compared with patients who have a normal iron status. Routine preoperative investigation for iron deficiency in patients without anaemia undergoing elective cardiac surgery using the definitions we tested might be low-value care. FUNDING: Australian and New Zealand College of Anaesthetists Foundation.

Evaluating the performance of Bayesian and restricted maximum likelihood estimation for stepped wedge cluster randomized trials with a small number of clusters.

BACKGROUND: Stepped wedge trials are an appealing and potentially powerful cluster randomized trial design. However, they are frequently implemented with a small number of clusters. Standard analysis methods for these trials such as a linear mixed model with estimation via maximum likelihood or restricted maximum likelihood (REML) rely on asymptotic properties and have been shown to yield inflated type I error when applied to studies with a small number of clusters. Small-sample methods such as the Kenward-Roger approximation in combination with REML can potentially improve estimation of the fixed effects such as the treatment effect. A Bayesian approach may also be promising for such multilevel models but has not yet seen much application in cluster randomized trials. METHODS: We conducted a simulation study comparing the performance of REML with and without a Kenward-Roger approximation to a Bayesian approach using weakly informative prior distributions on the intracluster correlation parameters. We considered a continuous outcome and a range of stepped wedge trial configurations with between 4 and 40 clusters. To assess method performance we calculated bias and mean squared error for the treatment effect and correlation parameters and the coverage of 95% confidence/credible intervals and relative percent error in model-based standard error for the treatment effect. RESULTS: Both REML with a Kenward-Roger standard error and degrees of freedom correction and the Bayesian method performed similarly well for the estimation of the treatment effect, while intracluster correlation parameter estimates obtained via the Bayesian method were less variable than REML estimates with different relative levels of bias. CONCLUSIONS: The use of REML with a Kenward-Roger approximation may be sufficient for the analysis of stepped wedge cluster randomized trials with a small number of clusters. However, a Bayesian approach with weakly informative prior distributions on the intracluster correlation parameters offers a viable alternative, particularly when there is interest in the probability-based inferences permitted within this paradigm.

A protocol for prospective observational study to determine if non-anaemic iron deficiency worsens postoperative outcome in adult patients undergoing elective cardiac surgery: the IDOCS study.

BACKGROUND: Pre-operative anaemia has been associated independently with worse outcomes after cardiac surgery in adults and is often caused by absolute or functional iron deficiency. Iron deficiency is a continuum ending with anaemia, and therefore it is plausible that pre-operative early or 'non-anaemic' iron deficiency may also be associated with worse outcomes in patients undergoing cardiac surgery. METHODS: We have designed a prospective, observational study to determine if there is an association between non-anaemic iron deficiency and worse outcomes after cardiac surgery in adults. Patients without anaemia undergoing elective cardiac surgery will be allocated to an iron-deficient and an iron-replete group based on standard pre-operative blood tests (ferritin, transferrin saturation and C-reactive protein). The primary outcome is days alive and at home on postoperative day 30. The key secondary outcomes are days alive and at home on postoperative day 90 and readmission to acute care. Other secondary outcomes include health-related quality of life questionnaires, quality of postoperative recovery, postoperative complications, changes in haemoglobin concentration, and requirement for allogeneic blood products. The planned study sample size is 240 patients per group, which has 83% power to detect a median difference of 1.25 days in the primary outcome. The study commenced in March 2018, and recently completed recruitment, with data audit and cleaning ongoing. DISCUSSION: This study will be conducted using a rigorous, prospective observational design; it will provide peak bodies and clinicians with high-quality evidence concerning the associations between non-anaemic iron deficiency and patient-centred outcomes after elective cardiac surgery. Our primary and key secondary outcomes are known to have great importance to clinicians and patients alike and align with the recommendations of the StEP-COMPAC group for outcomes in prospective peri-operative research. The definition used for iron deficiency accounts for both absolute and functional iron deficiency and make use of standard pre-operative blood tests to make this determination, easing the transition of results into clinical practice. The study will be conducted in two relatively high-volume centres in a single high-income country. This limits the generalisability of study results to similar centres. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ( ACTRN12618000185268 ). Registered 5 February 2018.

Penalized likelihood estimation of the proportional hazards model for survival data with interval censoring.

This paper considers the problem of semi-parametric proportional hazards model fitting where observed survival times contain event times and also interval, left and right censoring times. Although this is not a new topic, many existing methods suffer from poor computational performance. In this paper, we adopt a more versatile penalized likelihood method to estimate the baseline hazard and the regression coefficients simultaneously. The baseline hazard is approximated using basis functions such as M-splines. A penalty is introduced to regularize the baseline hazard estimate and also to ease dependence of the estimates on the knots of the basis functions. We propose a Newton-MI (multiplicative iterative) algorithm to fit this model. We also present novel asymptotic properties of our estimates, allowing for the possibility that some parameters of the approximate baseline hazard may lie on the parameter space boundary. Comparisons of our method against other similar approaches are made through an intensive simulation study. Results demonstrate that our method is very stable and encounters virtually no numerical issues. A real data application involving melanoma recurrence is presented and an R package 'survivalMPL' implementing the method is available on R CRAN.