Explore the vast range of titles available.

The high-sensitivity cardiac troponin on presentation to rule out myocardial infarction (HiSTORIC) study was a stepped-wedge cluster randomised trial with long before-and-after periods, involving seven hospitals across Scotland. Results were divergent for the binary safety endpoint (type 1 or type 4b myocardial infarction or cardiac death) across certain pre-specified analyses, which warranted further investigation. In particular, the calendar-matched analysis produced an odds ratio in the opposite direction to the primary logistic mixed-effects model analysis. Several post-hoc statistical models were fitted to each of the co-primary outcomes of length of hospital stay and safety events, which included adjusting for exposure time, incorporating splines, and fitting a random time effect. We improved control of patient characteristics over time by adjusting for multiple additional covariates using different methods: direct inclusion, regression adjustment for propensity score, and weighting. A data augmentation approach was also conducted aiming to reduce the effect of sparse data bias. Finally, the raw data was examined. The new statistical models confirmed the results of the pre-specified trial analysis. In particular, the observed divergence between the calendar-matched and other analyses remained, even after performing the covariate adjustment methods, and after using data augmentation. Divergence was particularly acute for the safety endpoint, which had an event rate of 0.36% overall. Examining the raw data was particularly helpful to assess the sensitivity of the results to small changes in event rates and identify patterns in the data. Our experience reveals the importance of conducting multiple pre-specified sensitivity analyses and examining the raw data, particularly for stepped wedge trials with low event rates or with a small number of sites. Before-and-after analytical approaches that adjust for differences in patient populations but avoid direct modelling of the time trend should be considered in future stepped wedge trials with similar designs.

IntroductionOsteogenesis imperfecta (OI) is a rare genetic disease associated with multiple fractures throughout life. It is often treated with osteoporosis medications but their effectiveness at preventing fractures is unknown. The Treatment of Osteogenesis Imperfecta with Parathyroid Hormone and Zoledronic Acid trial will determine if therapy with teriparatide (TPTD) followed by zoledronic acid (ZA) can reduce the risk of clinical fractures in OI.Methods and analysisIndividuals aged ≥18 years with a clinical diagnosis of OI are eligible to take part. At baseline, participants will undergo a spine X-ray, and have bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) at the spine and hip. Information on previous fractures and previous bone targeted treatments will be collected. Questionnaires will be completed to assess pain and other aspects of health-related quality of life (HRQoL). Participants will be randomised to receive a 2-year course of TPTD injections 20 µg daily followed by a single intravenous infusion of 5 mg ZA, or to receive standard care, which will exclude the use of bone anabolic drugs. Participants will be followed up annually, have a repeat DXA at 2 years and at the end of study. Spine X-rays will be repeated at the end of study. The duration of follow-up will range between 2 and 8 years. The primary endpoint will be new clinical fractures confirmed by X-ray or other imaging. Secondary endpoints will include participant reported fractures, BMD and changes in pain and HRQoL.Ethics and disseminationThe study received ethical approval in December 2016. Following completion of the trial, a manuscript will be submitted to a peer-reviewed journal. The results will inform clinical practice by determining if TPTD/ZA can reduce the risk of fractures in OI compared with standard care.Trial registration numberISRCTN15313991.

Background There is an increasing demand by non-commercial funders that trialists should provide access to trial data once the primary analysis is completed. This has to take into account concerns about identifying individual trial participants, and the legal and regulatory requirements. Methods Using the good practice guideline laid out by the work funded by the Medical Research Council Hubs for Trials Methodology Research (MRC HTMR), we anonymised a dataset from a recently completed trial. Using this example, we present practical guidance on how to anonymise a dataset, and describe rules that could be used on other trial datasets. We describe how these might differ if the trial was to be made freely available to all, or if the data could only be accessed with specific permission and data usage agreements in place. Results Following the good practice guidelines, we successfully created a controlled access model for trial data sharing. The data were assessed on a case-by-case basis classifying variables as direct, indirect and superfluous identifiers with differing methods of anonymisation assigned depending on the type of identifier. A final dataset was created and checks of the anonymised dataset were applied. Lastly, a procedure for release of the data was implemented to complete the process. Conclusions We have implemented a practical solution to the data anonymisation process resulting in a bespoke anonymised dataset for a recently completed trial. We have gained useful learnings in terms of efficiency of the process going forward, the need to balance anonymity with data utilisation and future work that should be undertaken.

IntroductionThe aim of the STOPPIT-3 study is to determine the clinical and cost effectiveness of antenatal corticosteroids (ACS) prior to planned birth of twins in a multicentre placebo-controlled trial with internal pilot.Methods and analysisThis study will comprise a multicentre, double-blinded, randomised, placebo-controlled trial in at least 50 UK obstetric units. The target population is 1552 women with a twin pregnancy and a planned birth between 35 and 38+6 weeks’ gestation recruited from antenatal clinics. Women will be randomised to Dexamethasone Phosphate (24 mg) or saline administered via two intramuscular injections 24 hours apart, 24–120 hours prior to scheduled birth.OutcomesThe primary outcome is need for respiratory support within 72 hours of birth. Secondary and safety outcomes will be included. Cognitive and language development at age 2 years will be assessed in a subset of participants using the Parent report of Children’s Abilities-Revised questionnaire. We will also determine the cost effectiveness of the treatment with ACS compared with placebo.Ethics and disseminationSTOPPIT-3 has been funded and approved by the National Institute of Healthcare Research. It has been approved by the West Midlands Research Ethics Committee (22/WM/0018). The results will be disseminated via publication in peer-reviewed journals and conference presentation and will also be communicated to the public via links with charity partners and social media.Trial sponsorThe University of Edinburgh and Lothian Health Board ACCORD, The Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ.Trial registration numberISRCTN59959611.

IntroductionFractures of the odontoid process frequently result from low impact falls in frail or older adults. These are increasing in incidence and importance as the population ages. In the UK, odontoid fractures in older adults are usually managed in hard collars to immobilise the fracture and promote bony healing. However, bony healing does not always occur in older adults, and bony healing is not associated with quality of life, functional, or pain outcomes. Further, hard collars can cause complications such as skin pressure ulcers, swallowing difficulties and difficulties with personal care. We hypothesise that management with no immobilisation may be superior to management in a hard collar for older or frail adults with odontoid fractures.Methods and analysesThis is the protocol for the Duration of External Neck Stabilisation (DENS) trial—a non-blinded randomised controlled trial comparing management in a hard collar with management without a collar for older (≥65 years) or frail (Rockwood Clinical Frailty Scale ≥5) adults with a new odontoid fracture. 887 neurologically intact participants with any odontoid process fracture type will be randomised to continuing with a hard collar (standard care) or removal of the collar (intervention). The primary outcome is quality of life measured using the EQ-5D-5L at 12 weeks. Secondary outcomes include pain scores, neck disability index, health and social care use and costs, and mortality.Ethics and disseminationInformed consent for participation will be sought from those able to provide it. We will also include those who lack capacity to ensure representativeness of frail and acutely unwell older adults. Results will be disseminated via scientific publication, lay summary, and visual abstract. The DENS trial received a favourable ethical opinion from the Scotland A Research Ethics Committee (21/SS/0036) and the Leeds West Research Ethics Committee (21/YH/0141).Trial registration numberNCT04895644.

Background The majority of patients with suspected acute coronary syndrome presenting to the emergency department will be discharged once myocardial infarction has been ruled out, although a proportion will have unrecognised coronary artery disease. In this setting, high-sensitivity cardiac troponin identifies those at increased risk of future cardiac events. In patients with intermediate cardiac troponin concentrations in whom myocardial infarction has been ruled out, this trial aims to investigate whether outpatient computed tomography coronary angiography (CTCA) reduces subsequent myocardial infarction or cardiac death. Methods TARGET-CTCA is a multicentre prospective randomised open label with blinded endpoint parallel group event driven trial. After myocardial infarction and clear alternative diagnoses have been ruled out, participants with intermediate cardiac troponin concentrations (5 ng/L to 99th centile upper reference limit) will be randomised 1:1 to outpatient CTCA plus standard of care or standard of care alone. The primary endpoint is myocardial infarction or cardiac death. Secondary endpoints include clinical, patient-centred, process and cost-effectiveness. Recruitment of 2270 patients will give 90% power with a two-sided P value of 0.05 to detect a 40% relative risk reduction in the primary endpoint. Follow-up will continue until 97 primary outcome events have been accrued in the standard care arm with an estimated median follow-up of 36 months. Discussion This randomised controlled trial will determine whether high-sensitivity cardiac troponin-guided CTCA can improve outcomes and reduce subsequent major adverse cardiac events in patients presenting to the emergency department who do not have myocardial infarction. Trial registration ClinicalTrials.gov Identifier: NCT03952351. Registered on May 16, 2019.

AbstractObjectiveProtocols to evaluate for myocardial infarction (MI) using high‐sensitivity cardiac troponin (hs‐cTn) have the potential to drive costs upward due to the added sensitivity. We performed an economic evaluation of an accelerated protocol (AP) to evaluate for MI using hs‐cTn to identify changes in costs of treatment and length of stay compared with conventional testing. MethodsWe performed a planned secondary economic analysis of a large, cluster randomized trial across nine emergency departments (EDs) from July 2020 to April 2021. Patients were included if they were 18 years or older with clinical suspicion for MI. In the AP, patients could be discharged without further testing at 0 h if they had a hs‐cTnI < 4 ng/L and at 1 h if the initial value were 4 ng/L and the 1‐h value ≤7 ng/L. Patients in the standard of care (SC) protocol used conventional cTn testing at 0 and 3 h. The primary outcome was the total cost of treatment, and the secondary outcome was ED length of stay. ResultsAmong 32,450 included patients, an AP had no significant differences in cost (+$89, CI: −$714, $893 hospital cost, +$362, CI: −$414, $1138 health system cost) or ED length of stay (+46, CI: −28, 120 min) compared with the SC protocol. In lower acuity, free‐standing EDs, patients under the AP experienced shorter length of stay (−37 min, CI: −62, 12 min) and reduced health system cost (−$112, CI: −$250, $25). ConclusionOverall, the implementation of AP using hs‐cTn does not result in higher costs.

Key summary points Aim To investigate performance of the Months of the Year Backwards (MOTYB) test in older hospitalised patients with delirium, dementia, and no cognitive impairment. Findings Half of the patients with delirium (46%) could not engage with MOTYB compared to only 11% of patients with dementia without delirium. In patients able to give responses, those with delirium or dementia performed significantly worse than those without cognitive impairment. Message Our findings show the potential value of analysing response patterns, especially initial engagement, self-correction, and ability to continue to do the task in addition to considering exclusively the capacity to correctly recite the months until July, June or January. Purpose To investigate performance of the Months of the Year Backwards (MOTYB) test in older hospitalised patients with delirium, dementia, and no cognitive impairment. Methods Secondary analysis of data from a case–control study of 149 hospitalised patients aged ≥ 65 years with delirium [with or without dementia ( N  = 50)], dementia [without delirium ( N  = 46)], and no cognitive impairment ( N  = 53). Verbatim transcripts of MOTYB audio recordings were analysed to determine group differences in response patterns. Results In the total sample [median age 85y (IQR 80–88), 82% female], patients with delirium were more often unable to recite months backward to November (36/50 = 72%) than patients with dementia (21/46 = 46%; p  < 0.01) and both differed significantly from patients without cognitive impairment (2/53 = 4%; p ’s < 0.001). 121/149 (81%) of patients were able to engage with the test. Patients with delirium were more often unable to engage with MOTYB (23/50 = 46%; e.g., due to reduced arousal) than patients with dementia (5/46 = 11%; p  < 0.001); both groups differed significantly ( p ’s < 0.001) from patients without cognitive impairment (0/53 = 0%). There was no statistically significant difference between patients with delirium (2/27 = 7%) and patients with dementia (8/41 = 20%) in completing MOTYB to January, but performance in both groups differed ( p  < 0.001 and p  < 0.02, respectively) from patients without cognitive impairment (35/53 = 66%). Conclusion Delirium was associated with inability to engage with MOTYB and low rates of completion. In patients able to engage with the test, error-free completion rates were low in delirium and dementia. Recording of engagement and patterns of errors may add useful information to MOTYB scoring.

Background Patients’ pre-operative health and physical function is known to influence their post-operative outcomes. In patients with knee osteoarthritis, pharmacological and non-pharmacological options are often not optimised prior to joint replacement. This results in some patients undergoing surgery when they are not as fit as they could be. The aim of this study is to assess the feasibility and acceptability of a pre-operative package of non-operative care versus standard care prior to joint replacement. Methods/design This is a multicentre, randomised controlled feasibility trial of patients undergoing primary total knee replacement for osteoarthritis. Sixty patients will be recruited and randomised (2:1) to intervention or standard care arms. Data will be collected at baseline (before the start of the intervention), around the end of the intervention period and a minimum of 90 days after the planned date of surgery. Adherence will be reviewed each week during the intervention period (by telephone or in person). Participants will be randomised to a pre-operative package of non-operative care or standard care. The non-operative care will consist of (1) a weight-loss programme, (2) a set of exercises, (3) provision of advice on analgesia use and (4) provision of insoles. The intervention will be started as soon as possible after patients have been added to the waiting list for joint replacement surgery to take advantage of the incentive for behavioural change that this will create. The primary outcomes of this study are feasibility outcomes which will indicate whether the intervention and study protocol is feasible and acceptable and whether a full-scale effectiveness trial is warranted. The following will be measured and used to inform study feasibility: rate of recruitment, rate of retention at 90-day follow-up review after planned surgery date, and adherence to the intervention estimated through review questionnaires and weight change (for those receiving the weight-loss aspect of intervention). In addition the following information will be assessed qualitatively: analysis of qualitative interviews exploring acceptability, feasibility, adherence and possible barriers to implementing the intervention, and acceptability of the different outcome measures. Discussion The aims of the study specifically relate to testing the feasibility and acceptability of the proposed effectiveness trial intervention and the feasibility of the trial methods. This study forms the important first step in developing and assessing whether the intervention has the potential to be assessed in a future fully powered effectiveness trial. The findings will also be used to refine the design of the effectiveness trial. Trial registration ISRCTN registry, ID: ISRCTN96684272 . Registered on 18 April 2018.

After publication of our article [1] we have been notified that two of the author names have been mistakenly removed from the authorship list: Colin R. Howie and Nicholas D. Clement.After publication of our article [1] we have been notified that two of the author names have been mistakenly removed from the authorship list: Colin R. Howie and Nicholas D. Clement.