Comparison of different statistical models for the analysis of fracture events: findings from the Prevention of Falls Injury Trial (PreFIT).

BACKGROUND: Fractures are rare events and can occur because of a fall. Fracture counts are distinct from other count data in that these data are positively skewed, inflated by excess zero counts, and events can recur over time. Analytical methods used to assess fracture data and account for these characteristics are limited in the literature. METHODS: Commonly used models for count data include Poisson regression, negative binomial regression, hurdle regression, and zero-inflated regression models. In this paper, we compare four alternative statistical models to fit fracture counts using data from a large UK based clinical trial evaluating the clinical and cost-effectiveness of alternative falls prevention interventions in older people (Prevention of Falls Injury Trial; PreFIT). RESULTS: The values of Akaike information criterion and Bayesian information criterion, the goodness-of-fit statistics, were the lowest for negative binomial model. The likelihood ratio test of no dispersion in the data showed strong evidence of dispersion (chi-square = 225.68, p-value < 0.001). This indicates that the negative binomial model fits the data better compared to the Poisson regression model. We also compared the standard negative binomial regression and mixed effects negative binomial models. The LR test showed no gain in fitting the data using mixed effects negative binomial model (chi-square = 1.67, p-value = 0.098) compared to standard negative binomial model. CONCLUSIONS: The negative binomial regression model was the most appropriate and optimal fit model for fracture count analyses. TRIAL REGISTRATION: The PreFIT trial was registered as ISRCTN71002650.

biomArker-guided Duration of Antibiotic treatment in hospitalised Patients with suspecTed Sepsis (ADAPT-Sepsis): A protocol for a multicentre randomised controlled trial.

Aim: To describe the protocol for a multi-centre randomised controlled trial to determine whether treatment protocols monitoring daily CRP (C-reactive protein) or PCT (procalcitonin) safely allow a reduction in duration of antibiotic therapy in hospitalised adult patients with sepsis. Design: Multicentre three-arm randomised controlled trial. Setting: UK NHS hospitals. Target population: Hospitalised critically ill adults who have been commenced on intravenous antibiotics for sepsis. Health technology: Three protocols for guiding antibiotic discontinuation will be compared: (a) standard care; (b) standard care + daily CRP monitoring; (c) standard care + daily PCT monitoring. Standard care will be based on routine sepsis management and antibiotic stewardship. Measurement of outcomes and costs. Outcomes will be assessed to 28 days. The primary outcomes are total duration of antibiotics and safety outcome of all-cause mortality. Secondary outcomes include: escalation of care/re-admission; infection re-lapse/recurrence; antibiotic dose; length and level of critical care stay and length of hospital stay. Ninety-day all-cause mortality rates will also be collected. An assessment of cost effectiveness will be performed. Conclusion: In the setting of routine NHS care, if this trial finds that a treatment protocol based on monitoring CRP or PCT safely allows a reduction in duration of antibiotic therapy, and is cost effective, then this has the potential to change clinical practice for critically ill patients with sepsis. Moreover, if a biomarker-guided protocol is not found to be effective, then it will be important to avoid its use in sepsis and prevent ineffective technology becoming widely adopted in clinical practice.

Landiolol and Organ Failure in Patients With Septic Shock: The STRESS-L Randomized Clinical Trial.

Importance: Patients with septic shock undergo adrenergic stress, which affects cardiac, immune, inflammatory, and metabolic pathways. ß-Blockade may attenuate the adverse effects of catecholamine exposure and has been associated with reduced mortality. Objectives: To assess the efficacy and safety of landiolol in patients with tachycardia and established septic shock requiring prolonged (>24 hours) vasopressor support. Design, Setting, and Participants: An open-label, multicenter, randomized trial involving 126 adults (≥18 years) with tachycardia (heart rate ≥95/min) and established septic shock treated for at least 24 hours with continuous norepinephrine (≥0.1 µg/kg/min) in 40 UK National Health Service intensive care units. The trial ran from April 2018 to December 2021, with early termination in December 2021 due to a signal of possible harm. Intervention: Sixty-three patients were randomized to receive standard care and 63 to receive landiolol infusion. Main Outcomes and Measures: The primary outcome was the mean Sequential Organ Failure Assessment (SOFA) score from randomization through 14 days. Secondary outcomes included mortality at days 28 and 90 and the number of adverse events in each group. Results: The trial was stopped prematurely on the advice of the independent data monitoring committee because it was unlikely to demonstrate benefit and because of possible harm. Of a planned 340 participants, 126 (37%) were enrolled (mean age, 55.6 years [95% CI, 52.7 to 58.5 years]; 58.7% male). The mean (SD) SOFA score in the landiolol group was 8.8 (3.9) compared with 8.1 (3.2) in the standard care group (mean difference [MD], 0.75 [95% CI, -0.49 to 2.0]; P = .24). Mortality at day 28 after randomization in the landiolol group was 37.1% (23 of 62) and 25.4% (16 of 63) in the standard care group (absolute difference, 11.7% [95% CI, -4.4% to 27.8%]; P = .16). Mortality at day 90 after randomization was 43.5% (27 of 62) in the landiolol group and 28.6% (18 of 63) in the standard care group (absolute difference, 15% [95% CI, -1.7% to 31.6%]; P = .08). There were no differences in the number of patients having at least one adverse event. Conclusion and Relevance: Among patients with septic shock with tachycardia and treated with norepinephrine for more than 24 hours, an infusion of landiolol did not reduce organ failure measured by the SOFA score over 14 days from randomization. These results do not support the use of landiolol for managing tachycardia among patients treated with norepinephrine for established septic shock. Trial Registration: EU Clinical Trials Register Eudra CT: 2017-001785-14; isrctn.org Identifier: ISRCTN12600919.

Psychometric sensitivity analyses can identify bias related to measurement properties in trials that use patient-reported outcome measures: a secondary analysis of a clinical trial using the disabilities of the arm, shoulder, and hand questionnaire.

OBJECTIVES: Demonstrate psychometric sensitivity analyses for testing the stability of study findings to assumptions made about patient-reported outcome measures. STUDY DESIGN AND SETTING: We performed secondary analyses of Disability of Arm, Shoulder, and Hand (DASH) data collected within the Prevention of Shoulder Problems clinical trial, which compared upper limb function scores in women who had undergone breast cancer surgery, randomized to either an exercise program or usual care. We repeated the principal trial analyses after grouping DASH items into subscales suggested by factorial analyses in this dataset and applied item response theory to account for unequal item weighting. We checked for measurement invariance by participant age and response shift bias using established techniques. RESULTS: Our analyses suggested that the DASH measured two constructs: motor function and sensory symptoms. The majority of the six-month difference in DASH score was driven by motor function. With item response theory scoring, we found differences in both constructs at 12 months (P = 0.019 and P = 0.007), but in neither construct at 6 months, contrary to the original trial results. We found no differential item function by age or between baseline and 12-month measurements. CONCLUSIONS: Psychometric sensitivity analyses aid in the interpretation of the Prevention of Shoulder Problems trial's results.

Randomised trial of the clinical and cost effectiveness of a supraglottic airway device compared with tracheal intubation for in-hospital cardiac arrest (AIRWAYS-3): Protocol, design and implementation.

Survival from in-hospital cardiac arrest is approximately 18%, but for patients who require advanced airway management survival is lower. Those who do survive are often left with significant disability. Traditionally, resuscitation of cardiac arrest patients has included tracheal intubation, however insertion of a supraglottic airway has gained popularity as an alternative approach to advanced airway management. Evidence from out-of-hospital cardiac arrest suggests no significant differences in mortality or morbidity between these two approaches, but there is no randomised evidence for airway management during in-hospital cardiac arrest. The aim of the AIRWAYS-3 randomised trial, described in this protocol paper, is to determine the clinical and cost effectiveness of a supraglottic airway versus tracheal intubation during in-hospital cardiac arrest. Patients will be allocated randomly to receive either a supraglottic airway or tracheal intubation as the initial advanced airway management. We will also estimate the relative cost-effectiveness of these two approaches. The primary outcome is functional status, measured using the modified Rankin Scale at hospital discharge or 30 days post-randomisation, whichever occurs first. AIRWAYS-3 presents ethical challenges regarding patient consent and data collection. These include the enrolment of unconscious patients without prior consent in a way that avoids methodological bias. Other complexities include the requirement to randomise patients efficiently during a time-critical cardiac arrest. Many of these challenges are encountered in other emergency care research; we discuss our approaches to addressing them. Trial registration: ISRCTN17720457. Prospectively registered on 29/07/2022.

Falls and fracture risk screening in primary care: update and validation of a postal screening tool for community dwelling older adults recruited to UK Prevention of Falls Injury Trial (PreFIT).

BACKGROUND: Postal screening has not previously been validated as a method for identifying fall and fracture risk in community-dwelling populations. We examined prognostic performance of a postal risk screener used in the UK Prevention of Falls Injury Trial (PreFIT; ISRCTN71002650), to predict any fall, recurrent falls, and fractures over 12 months. We tested whether adding variables would improve screener performance. METHODS: Nine thousand eight hundred and eight community-dwelling participants, aged 70 years and older, and 63 general practices in the UK National Health Service (NHS) were included in a large, pragmatic cluster randomised trial comparing screen and treat fall prevention interventions. The short postal screener was sent to all participants in the trial intervention arms as an A4 sheet to be completed and returned to the GP (n = 6,580). The postal screener items were embedded in the baseline pre-randomisation postal questionnaire for all arms of the trial (n = 9,808). We assessed discrimination and calibration using area under the curve (AUC). We identified additional predictors using data from the control arm and applied these coefficients to internal validation models in the intervention arm participants. We used logistic regression to identify additional predictor variables. FINDINGS: A total of 10,743 falls and 307 fractures were reported over 12 months. Over one third of participants 3,349/8,136 (41%) fell at least once over 12 month follow up. Response to the postal screener was high (5,779/6,580; 88%). Prediction models showed similar discriminatory ability in both control and intervention arms, with discrimination values for any fall AUC 0.67 (95% CI 0.65 to 0.68), and recurrent falls (AUC 0.71; 95% CI 0.69, 0.72) but poorer discrimination for fractures (AUC 0.60; 95% CI 0.56, 0.64). Additional predictor variables improved prediction of falls but had modest effect on fracture, where AUC rose to 0.71 (95% CI 0.67 to 0.74). Calibration slopes were very close to 1. CONCLUSION: A short fall risk postal screener was acceptable for use in primary care but fall prediction was limited, although consistent with other tools. Fracture and fall prediction were only partially reliant on fall risk although were improved with the additional variables.

Feedback of Antibiotic Prescribing in Primary Care (FAPPC) trial: results of a real-world cluster randomized controlled trial in Scotland, UK.

OBJECTIVES: To evaluate the effect of general practice-level prescribing feedback on antibiotic prescribing in a real-world pragmatic cluster randomized controlled trial. METHODS: Three hundred and forty general practices in four territorial Health Boards in NHS Scotland were randomized in Quarter 1, 2016 to receive four quarterly antibiotic-prescribing feedback reports or not, from Quarter 2, 2016 to Quarter 1, 2017. Reports included different clinical topics, benchmarking against national and health board rates, and behavioural messaging with improvement actions. The primary outcome was total antibiotic prescribing rate. There were 16 secondary prescribing outcomes and 5 hospital admission outcomes (potential adverse effects of reduced prescribing). The main evaluation timepoint was 1 year after the final report (Quarter 1, 2018), with an additional evaluation in the quarter after the final report (Quarter 2, 2017). Routine administrative NHS data were used to generate the feedback reports and analyse the effects. RESULTS: Total antibiotic prescribing rates were lower at the main evaluation timepoint in both intervention (1.83 versus baseline 1.93 prescriptions/1000 patients/day) and control (1.90 versus baseline 1.98) practices, with no evidence of intervention effect [adjusted rate ratio (ARR) 0.98 (95% CI 0.94-1.02; P = 0.35)]. At the additional timepoint, adjusted total antibiotic prescribing rates were 1.67 and 1.73 prescriptions/1000 patients/day, with evidence of a small intervention effect, ARR 0.99 (0.98-1.00; P = 0.03). CONCLUSIONS: This well-designed, practice-level antibiotic-prescribing feedback had limited evidence of additional effects in the context of decreasing antibiotic prescribing and an established national stewardship programme.

Exercise to prevent shoulder problems after breast cancer surgery: the PROSPER RCT.

BACKGROUND: Upper limb problems are common after breast cancer treatment. OBJECTIVES: To investigate the clinical effectiveness and cost-effectiveness of a structured exercise programme compared with usual care on upper limb function, health-related outcomes and costs in women undergoing breast cancer surgery. DESIGN: This was a two-arm, pragmatic, randomised controlled trial with embedded qualitative research, process evaluation and parallel economic analysis; the unit of randomisation was the individual (allocated ratio 1 : 1). SETTING: Breast cancer centres, secondary care. PARTICIPANTS: Women aged ≥ 18 years who had been diagnosed with breast cancer and were at higher risk of developing shoulder problems. Women were screened to identify their risk status. INTERVENTIONS: All participants received usual-care information leaflets. Those randomised to exercise were referred to physiotherapy for an early, structured exercise programme (three to six face-to-face appointments that included strengthening, physical activity and behavioural change strategies). MAIN OUTCOME MEASURES: The primary outcome was upper limb function at 12 months as assessed using the Disabilities of Arm, Hand and Shoulder questionnaire. Secondary outcomes were function (Disabilities of Arm, Hand and Shoulder questionnaire subscales), pain, complications (e.g. wound-related complications, lymphoedema), health-related quality of life (e.g. EuroQol-5 Dimensions, five-level version; Short Form questionnaire-12 items), physical activity and health service resource use. The economic evaluation was expressed in terms of incremental cost per quality-adjusted life-year and incremental net monetary benefit gained from an NHS and Personal Social Services perspective. Participants and physiotherapists were not blinded to group assignment, but data collectors were blinded. RESULTS: Between 2016 and 2017, we randomised 392 participants from 17 breast cancer centres across England: 196 (50%) to the usual-care group and 196 (50%) to the exercise group. Ten participants (10/392; 3%) were withdrawn at randomisation and 32 (8%) did not provide complete baseline data. A total of 175 participants (89%) from each treatment group provided baseline data. Participants' mean age was 58.1 years (standard deviation 12.1 years; range 28-88 years). Most participants had undergone axillary node clearance surgery (327/392; 83%) and 317 (81%) had received radiotherapy. Uptake of the exercise treatment was high, with 181 out of 196 (92%) participants attending at least one physiotherapy appointment. Compliance with exercise was good: 143 out of 196 (73%) participants completed three or more physiotherapy sessions. At 12 months, 274 out of 392 (70%) participants returned questionnaires. Improvement in arm function was greater in the exercise group [mean Disabilities of Arm, Hand and Shoulder questionnaire score of 16.3 (standard deviation 17.6)] than in the usual-care group [mean Disabilities of Arm, Hand and Shoulder questionnaire score of 23.7 (standard deviation 22.9)] at 12 months for intention-to-treat (adjusted mean difference Disabilities of Arm, Hand and Shoulder questionnaire score of -7.81, 95% confidence interval -12.44 to -3.17; p = 0.001) and complier-average causal effect analyses (adjusted mean difference -8.74, 95% confidence interval -13.71 to -3.77; p ≤ 0.001). At 12 months, pain scores were lower and physical health-related quality of life was higher in the exercise group than in the usual-care group (Short Form questionnaire-12 items, mean difference 4.39, 95% confidence interval 1.74 to 7.04; p = 0.001). We found no differences in the rate of adverse events or lymphoedema over 12 months. The qualitative findings suggested that women found the exercise programme beneficial and enjoyable. Exercise accrued lower costs (-£387, 95% CI -£2491 to £1718) and generated more quality-adjusted life years (0.029, 95% CI 0.001 to 0.056) than usual care over 12 months. The cost-effectiveness analysis indicated that exercise was more cost-effective and that the results were robust to sensitivity analyses. Exercise was relatively cheap to implement (£129 per participant) and associated with lower health-care costs than usual care and improved health-related quality of life. Benefits may accrue beyond the end of the trial. LIMITATIONS: Postal follow-up was lower than estimated; however, the study was adequately powered. No serious adverse events directly related to the intervention were reported. CONCLUSIONS: This trial provided robust evidence that referral for early, supported exercise after breast cancer surgery improved shoulder function in those at risk of shoulder problems and was associated with lower health-care costs than usual care and improved health-related quality of life. FUTURE WORK: Future work should focus on the implementation of exercise programmes in clinical practice for those at highest risk of shoulder problems. TRIAL REGISTRATION: This trial is registered as ISRCTN35358984. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 15. See the NIHR Journals Library website for further project information.

WHAT IS THE PROBLEM?: Breast cancer is the most common cancer affecting women. Women now live longer because the detection and treatment of cancer has improved over the last 40 years. The side effects of breast cancer treatments can lead to complications, such as difficulties with arm movements, arm swelling (lymphoedema), pain and poor quality of life. These problems can last for many years after the cancer has been treated. Usual care after breast cancer surgery is to give patients an information leaflet explaining arm exercises that they can undertake after their operation. Offering exercise support from a physiotherapist may be a better way to help those at risk of developing shoulder problems after breast cancer treatment than providing a leaflet only. WHAT DID WE DO?: We compared two strategies to prevent shoulder problems in women having breast cancer treatment: information leaflets and an exercise programme. We invited women with a new diagnosis of breast cancer who were at higher risk of developing shoulder problems than other women with a new diagnosis of breast cancer. We recruited 392 women aged 28­88 years from 17 breast cancer units across England. Women were allocated to one of two groups by chance using a computer. Everyone was given information leaflets that explained what type of exercises to do after surgery. Half of the women (n = 196) were then invited to take part in an exercise programme, supported by a trained physiotherapist. These women followed a programme of shoulder mobility, stretching and strengthening exercises for up to 1 year. We measured changes in arm function, pain, arm swelling (lymphoedema) and physical and mental quality of life, and the cost of treatments during the whole first year of recovery, in everyone. We also spoke to the women and physiotherapists to find out whether or not these treatment strategies were acceptable to them. WHAT DID WE FIND OUT?: Women doing the exercise programme had better arm function, less pain and better quality of life than the women given an information leaflet only. Women said that the exercise programme helped with their recovery during cancer treatment. Exercise was cheap to deliver (£129 per person) and led to improved overall quality of life at 1 year after breast cancer surgery.

Exercise versus usual care after non-reconstructive breast cancer surgery (UK PROSPER): multicentre randomised controlled trial and economic evaluation.

OBJECTIVE: To evaluate whether a structured exercise programme improved functional and health related quality of life outcomes compared with usual care for women at high risk of upper limb disability after breast cancer surgery. DESIGN: Multicentre, pragmatic, superiority, randomised controlled trial with economic evaluation. SETTING: 17 UK National Health Service cancer centres. PARTICIPANTS: 392 women undergoing breast cancer surgery, at risk of postoperative upper limb morbidity, randomised (1:1) to usual care with structured exercise (n=196) or usual care alone (n=196). INTERVENTIONS: Usual care (information leaflets) only or usual care plus a physiotherapy led exercise programme, incorporating stretching, strengthening, physical activity, and behavioural change techniques to support adherence to exercise, introduced at 7-10 days postoperatively, with two further appointments at one and three months. MAIN OUTCOME MEASURES: Disability of Arm, Hand and Shoulder (DASH) questionnaire at 12 months, analysed by intention to treat. Secondary outcomes included DASH subscales, pain, complications, health related quality of life, and resource use, from a health and personal social services perspective. RESULTS: Between 26 January 2016 and 31 July 2017, 951 patients were screened and 392 (mean age 58.1 years) were randomly allocated, with 382 (97%) eligible for intention to treat analysis. 181 (95%) of 191 participants allocated to exercise attended at least one appointment. Upper limb function improved after exercise compared with usual care (mean DASH 16.3 (SD 17.6) for exercise (n=132); 23.7 (22.9) usual care (n=138); adjusted mean difference 7.81, 95% confidence interval 3.17 to 12.44; P=0.001). Secondary outcomes favoured exercise over usual care, with lower pain intensity at 12 months (adjusted mean difference on numerical rating scale -0.68, -1.23 to -0.12; P=0.02) and fewer arm disability symptoms at 12 months (adjusted mean difference on Functional Assessment of Cancer Therapy-Breast+4 (FACT-B+4) -2.02, -3.11 to -0.93; P=0.001). No increase in complications, lymphoedema, or adverse events was noted in participants allocated to exercise. Exercise accrued lower costs per patient (on average -£387 (€457; $533) (95% confidence interval -£2491 to £1718; 2015 pricing) and was cost effective compared with usual care. CONCLUSIONS: The PROSPER exercise programme was clinically effective and cost effective and reduced upper limb disability one year after breast cancer treatment in patients at risk of treatment related postoperative complications. TRIAL REGISTRATION: ISRCTN Registry ISRCTN35358984.

Fall prevention interventions in primary care to reduce fractures and falls in people aged 70 years and over: the PreFIT three-arm cluster RCT.

BACKGROUND: Falls and fractures are a major problem. OBJECTIVES: To investigate the clinical effectiveness and cost-effectiveness of alternative falls prevention interventions. DESIGN: Three-arm, pragmatic, cluster randomised controlled trial with parallel economic analysis. The unit of randomisation was the general practice. SETTING: Primary care. PARTICIPANTS: People aged ≥ 70 years. INTERVENTIONS: All practices posted an advice leaflet to each participant. Practices randomised to active intervention arms (exercise and multifactorial falls prevention) screened participants for falls risk using a postal questionnaire. Active treatments were delivered to participants at higher risk of falling. MAIN OUTCOME MEASURES: The primary outcome was fracture rate over 18 months, captured from Hospital Episode Statistics, general practice records and self-report. Secondary outcomes were falls rate, health-related quality of life, mortality, frailty and health service resource use. Economic evaluation was expressed in terms of incremental cost per quality-adjusted life-year and incremental net monetary benefit. RESULTS: Between 2011 and 2014, we randomised 63 general practices (9803 participants): 21 practices (3223 participants) to advice only, 21 practices (3279 participants) to exercise and 21 practices (3301 participants) to multifactorial falls prevention. In the active intervention arms, 5779 out of 6580 (87.8%) participants responded to the postal fall risk screener, of whom 2153 (37.3%) were classed as being at higher risk of falling and invited for treatment. The rate of intervention uptake was 65% (697 out of 1079) in the exercise arm and 71% (762 out of 1074) in the multifactorial falls prevention arm. Overall, 379 out of 9803 (3.9%) participants sustained a fracture. There was no difference in the fracture rate between the advice and exercise arms (rate ratio 1.20, 95% confidence interval 0.91 to 1.59) or between the advice and multifactorial falls prevention arms (rate ratio 1.30, 95% confidence interval 0.99 to 1.71). There was no difference in falls rate over 18 months (exercise arm: rate ratio 0.99, 95% confidence interval 0.86 to 1.14; multifactorial falls prevention arm: rate ratio 1.13, 95% confidence interval 0.98 to 1.30). A lower rate of falls was observed in the exercise arm at 8 months (rate ratio 0.78, 95% confidence interval 0.64 to 0.96), but not at other time points. There were 289 (2.9%) deaths, with no differences by treatment arm. There was no evidence of effects in prespecified subgroup comparisons, nor in nested intention-to-treat analyses that considered only those at higher risk of falling. Exercise provided the highest expected quality-adjusted life-years (1.120), followed by advice and multifactorial falls prevention, with 1.106 and 1.114 quality-adjusted life-years, respectively. NHS costs associated with exercise (£3720) were lower than the costs of advice (£3737) or of multifactorial falls prevention (£3941). Although incremental differences between treatment arms were small, exercise dominated advice, which in turn dominated multifactorial falls prevention. The incremental net monetary benefit of exercise relative to treatment valued at £30,000 per quality-adjusted life-year is modest, at £191, and for multifactorial falls prevention is £613. Exercise is the most cost-effective treatment. No serious adverse events were reported. LIMITATIONS: The rate of fractures was lower than anticipated. CONCLUSIONS: Screen-and-treat falls prevention strategies in primary care did not reduce fractures. Exercise resulted in a short-term reduction in falls and was cost-effective. FUTURE WORK: Exercise is the most promising intervention for primary care. Work is needed to ensure adequate uptake and sustained effects. TRIAL REGISTRATION: Current Controlled Trials ISRCTN71002650. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 34. See the NIHR Journals Library website for further project information.

WHAT IS THE PROBLEM?: Falls are a major problem for older people. Current practice is to give people advice leaflets. Another approach is exercise, especially balance and strength training. A third alternative is to invite older people to attend a falls assessment with a health-care professional, either a doctor or a trained nurse. This usually involves a careful check of prescribed tablets, blood pressure, eyesight and other problems that might cause falls. WHAT DID WE DO?: We compared three strategies. We recruited 9803 people aged 70­101 years from 63 general practices across England. We randomly allocated practices in clusters into three treatment groups. The participants in one group were given a Staying Steady advice leaflet (Age UK. Staying Steady. London: Age UK; 2009). Participants in the second group received the same leaflet and were assessed to see if they were at higher risk of falling. Those participants identified as being at higher risk (about 1000 people) were invited to take part in an exercise programme, supported by an exercise therapist. These people did balance and strength training at home for up to 6 months. In the third group, we again identified participants who were at higher risk of falling (about 1000 people) and invited them for a detailed falls assessment with a trained nurse or doctor. This last group of participants were referred for other treatments if any health problems were found. In all groups we counted fractures and falls and measured changes in quality of life, frailty and the cost of the treatments over 18 months of follow-up. WHAT DID WE FIND OUT?: We found no difference in the number of fractures over 18 months between the different treatments. The exercise programme reduced falls in the short term but not over the longer term. The exercise programme was cheaper and led to a slightly better overall quality of life.

Monitoring COVID-19 Vaccine Acceptance in Kuwait During the Pandemic: Results from a National Serial Study.

BACKGROUND: With COVD-19 cases on the rise globally and two approved vaccines, determining vaccine acceptance is imperative to avoid low inoculation rates. The aim of this study was to evaluate the changes and determinants of vaccine acceptance among citizens and non-citizens, over time during the pandemic in Kuwait. METHODS: Data were obtained from the COVID-19 Snapshot Monitoring (COSMO Kuwait) study that was implemented according to the WHO tool for behavioral insights on COVID-19. Data was collected online, every two weeks throughout the pandemic. Individuals living in Kuwait during the pandemic were surveyed, representing an independent sample of the population during each data collection wave. RESULTS: A total of 7241 adults living in Kuwait participated. Sixty-seven percent of those participating agreed to take a vaccine if it was available and recommended. However, the proportion of vaccine acceptance drastically dropped overtime as COVID-19 related restrictions were eased, among citizens (73 to 47%) and noncitizens (80 to 60%). Some factors associated with increased odds of agreeing to take the COVID-19 vaccine, among citizens and non-citizens, included increased frequency of informing oneself about the virus (OR, 1.34-1.83; 95% confidence interval 1.16-2.55), having high versus low confidence in doctors (OR, 1.79-2.11; CI 1.17-3.80), increased agreement with containment policies (OR, 1.11-1.27; CI 1.05-1.41), expressing more fears and worries (OR, 1.05-1.12; 1.01-1.24), and the increased perceived likelihood of getting infected with influenza (OR, 1.3-1.4; CI 1.03-1.84). Decreased odds of agreement were associated with increased age (OR, 0.37-0.61; CI 0.26-0.95), being female (OR, 0.56-0.62; CI 0.43-0.73), and not taking the influenza vaccine in 2019 (OR, 0.61; CI 0.43-0.87). CONCLUSION: Vaccine acceptance was multifactorial, heterogenous among citizens and non-citizens, and changed over time. While acceptance was relatively high, it decreased throughout the pandemic and as restrictions in the country loosened. This increase in vaccine hesitancy reveals a challenge in achieving high inoculation levels, and the need for effective vaccine-promotion campaigns and increased health education in the country.

Screening and Intervention to Prevent Falls and Fractures in Older People.

BACKGROUND: Community screening and therapeutic prevention strategies may reduce the incidence of falls in older people. The effects of these measures on the incidence of fractures, the use of health resources, and health-related quality of life are unknown. METHODS: In a pragmatic, three-group, cluster-randomized, controlled trial, we estimated the effect of advice sent by mail, risk screening for falls, and targeted interventions (multifactorial fall prevention or exercise for people at increased risk for falls) as compared with advice by mail only. The primary outcome was the rate of fractures per 100 person-years over 18 months. Secondary outcomes were falls, health-related quality of life, frailty, and a parallel economic evaluation. RESULTS: We randomly selected 9803 persons 70 years of age or older from 63 general practices across England: 3223 were assigned to advice by mail alone, 3279 to falls-risk screening and targeted exercise in addition to advice by mail, and 3301 to falls-risk screening and targeted multifactorial fall prevention in addition to advice by mail. A falls-risk screening questionnaire was sent to persons assigned to the exercise and multifactorial fall-prevention groups. Completed screening questionnaires were returned by 2925 of the 3279 participants (89%) in the exercise group and by 2854 of the 3301 participants (87%) in the multifactorial fall-prevention group. Of the 5779 participants from both these groups who returned questionnaires, 2153 (37%) were considered to be at increased risk for falls and were invited to receive the intervention. Fracture data were available for 9802 of the 9803 participants. Screening and targeted intervention did not result in lower fracture rates; the rate ratio for fracture with exercise as compared with advice by mail was 1.20 (95% confidence interval [CI], 0.91 to 1.59), and the rate ratio with multifactorial fall prevention as compared with advice by mail was 1.30 (95% CI, 0.99 to 1.71). The exercise strategy was associated with small gains in health-related quality of life and the lowest overall costs. There were three adverse events (one episode of angina, one fall during a multifactorial fall-prevention assessment, and one hip fracture) during the trial period. CONCLUSIONS: Advice by mail, screening for fall risk, and a targeted exercise or multifactorial intervention to prevent falls did not result in fewer fractures than advice by mail alone. (Funded by the National Institute of Health Research; ISRCTN number, ISRCTN71002650.).

Cost-effectiveness of adrenaline for out-of-hospital cardiac arrest.

BACKGROUND: The 'Prehospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug Administration In Cardiac Arrest' (PARAMEDIC2) trial showed that adrenaline improves overall survival, but not neurological outcomes. We sought to determine the within-trial and lifetime health and social care costs and benefits associated with adrenaline, including secondary benefits from organ donation. METHODS: We estimated the costs, benefits (quality-adjusted life years (QALYs)) and incremental cost-effectiveness ratios (ICERs) associated with adrenaline during the 6-month trial follow-up. Model-based analyses explored how results altered when the time horizon was extended beyond 6 months and the scope extended to include recipients of donated organs. RESULTS: The within-trial (6 months) and lifetime horizon economic evaluations focussed on the trial population produced ICERs of £1,693,003 (€1,946,953) and £81,070 (€93,231) per QALY gained in 2017 prices, respectively, reflecting significantly higher mean costs and only marginally higher mean QALYs in the adrenaline group. The probability that adrenaline is cost-effective was less than 1% across a range of cost-effectiveness thresholds. Combined direct economic effects over the lifetimes of survivors and indirect economic effects in organ recipients produced an ICER of £16,086 (€18,499) per QALY gained for adrenaline with the probability that adrenaline is cost-effective increasing to 90% at a £30,000 (€34,500) per QALY cost-effectiveness threshold. CONCLUSIONS: Adrenaline was not cost-effective when only directly related costs and consequences are considered. However, incorporating the indirect economic effects associated with transplanted organs substantially alters cost-effectiveness, suggesting decision-makers should consider the complexity of direct and indirect economic impacts of adrenaline. TRIAL REGISTRATION: ISRCTN73485024 . Registered on 13 March 2014.

The importance of different frailty domains in a population based sample in England.

BACKGROUND: The aim was to estimate the prevalence of frailty and relative contribution of physical/balance, nutritive, cognitive and sensory frailty to important adverse health states (falls, physical activity levels, outdoor mobility, problems in self-care or usual activities, and lack of energy or accomplishment) in an English cohort by age and sex. METHODS: Analysis of baseline data from a cohort of 9803 community-dwelling participants in a clinical trial. The sample was drawn from a random selection of all people aged 70 or more registered with 63 general practices across England. Data were collected by postal questionnaire. Frailty was measured with the Strawbridge questionnaire. We used cross sectional, multivariate logistic regression to estimate the association between frailty domains and known correlates and adjusted for age. Some models were stratified by sex. RESULTS: Mean age of participants was 78 years (sd 5.7), range 70 to 101 and 47.5% (4653/9803) were men. The prevalence of overall frailty was 20.7% (2005/9671) and there was no difference in prevalence by sex (Odds Ratio 0.98; 95% Confidence Interval 0.89 to 1.08). Sensory frailty was the most common and this was reported by more men (1823/4586) than women (1469/5056; Odds Ratio for sensory frailty 0.62, 95% Confidence Interval 0.57 to 0.68). Men were less likely than women to have physical or nutritive frailty. Physical frailty had the strongest independent associations with adverse health states. However, sensory frailty was independently associated with falls, less frequent walking, problems in self-care and usual activities, lack of energy and accomplishment. CONCLUSIONS: Physical frailty was more strongly associated with adverse health states, but sensory frailty was much more common. The health gain from intervention for sensory frailty in England is likely to be substantial, particularly for older men. Sensory frailty should be explored further as an important target of intervention to improve health outcomes for older people both at clinical and population level. TRIAL REGISTRATION: ISRCTN71002650.

Missing binary outcomes under covariate-dependent missingness in cluster randomised trials.

Missing outcomes are a commonly occurring problem for cluster randomised trials, which can lead to biased and inefficient inference if ignored or handled inappropriately. Two approaches for analysing such trials are cluster-level analysis and individual-level analysis. In this study, we assessed the performance of unadjusted cluster-level analysis, baseline covariate-adjusted cluster-level analysis, random effects logistic regression and generalised estimating equations when binary outcomes are missing under a baseline covariate-dependent missingness mechanism. Missing outcomes were handled using complete records analysis and multilevel multiple imputation. We analytically show that cluster-level analyses for estimating risk ratio using complete records are valid if the true data generating model has log link and the intervention groups have the same missingness mechanism and the same covariate effect in the outcome model. We performed a simulation study considering four different scenarios, depending on whether the missingness mechanisms are the same or different between the intervention groups and whether there is an interaction between intervention group and baseline covariate in the outcome model. On the basis of the simulation study and analytical results, we give guidance on the conditions under which each approach is valid. © 2017 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

Missing continuous outcomes under covariate dependent missingness in cluster randomised trials.

Attrition is a common occurrence in cluster randomised trials which leads to missing outcome data. Two approaches for analysing such trials are cluster-level analysis and individual-level analysis. This paper compares the performance of unadjusted cluster-level analysis, baseline covariate adjusted cluster-level analysis and linear mixed model analysis, under baseline covariate dependent missingness in continuous outcomes, in terms of bias, average estimated standard error and coverage probability. The methods of complete records analysis and multiple imputation are used to handle the missing outcome data. We considered four scenarios, with the missingness mechanism and baseline covariate effect on outcome either the same or different between intervention groups. We show that both unadjusted cluster-level analysis and baseline covariate adjusted cluster-level analysis give unbiased estimates of the intervention effect only if both intervention groups have the same missingness mechanisms and there is no interaction between baseline covariate and intervention group. Linear mixed model and multiple imputation give unbiased estimates under all four considered scenarios, provided that an interaction of intervention and baseline covariate is included in the model when appropriate. Cluster mean imputation has been proposed as a valid approach for handling missing outcomes in cluster randomised trials. We show that cluster mean imputation only gives unbiased estimates when missingness mechanism is the same between the intervention groups and there is no interaction between baseline covariate and intervention group. Multiple imputation shows overcoverage for small number of clusters in each intervention group.