Qualitative research to inform hypothesis testing for fidelity-based sub-group analysis in clinical trials : lessons learnt from the process evaluation of a multifaceted podiatry intervention for falls prevention

Background: Ensuring fidelity to complex interventions is a challenge when conducting pragmatic randomised controlled trials. We explore fidelity through a qualitative process evaluation, which was conducted alongside a pragmatic, multicentre, two-arm cohort randomised controlled trial: the REFORM (Reducing Falls with Orthoses and a Multifaceted podiatry intervention) trial. The paper aims, through a qualitative process evaluation, to explore some of the factors that may have affected the delivery of the REFORM intervention and highlight how project-specific fidelity can be assessed using a truly mixed-methods approach when informed by qualitative insights. Design: Semi-structured qualitative interviews carried out as part of a process evaluation. Interviews were analysed thematically. Setting: Seven NHS trusts in the UK and a University podiatry school in Ireland. Interviews were undertaken face-toface or over the telephone. Participants: Twenty-one REFORM trial participants and 14 podiatrists who delivered the REFORM intervention. Results: Factors affecting fidelity included: how similar the intervention was to routine practice; the challenges of delivering a multifaceted intervention to a heterogeneous older population; and practical issues with delivery such as time and training. Trial participants’ views of the intervention, whether falls prevention is a personal priority, their experience of being part of a trial and individual factors such as medical conditions may also have affected intervention fidelity. Conclusions: Our process evaluation highlighted factors that were perceived to have affected the fidelity of the REFORM intervention and in doing so demonstrates the importance of considering fidelity when designing and evaluating pragmatic trials. We propose a number of recommendations of how important project-specific insights from qualitative work can be incorporated into the design of fidelity measurement of future trials, which build on existing conceptual fidelity frameworks. In particular, we encourage adopting a mixed-methods approach whereby qualitative insights can be used to suggest ways to enhance quantitative data collection facilitating integration through hypothesis generation, hypothesis testing and seeking explanation for trial findings. This will provide a framework of enabling measures of fidelity to be incorporated into the understanding of trial results which has been relatively neglected by existing literature. Trial registration: ISRCTN Registry: ISRCTN68240461. Registered on 01/07/2011. Keywords: Process evaluation, Randomised controlled trials, Fidelity, Mixed methods, Falls, Elderly, Ageing, Qualitativ

A Nested Randomised Controlled Trial of a Newsletter and Post-it Note Did not Increase Postal Questionnaire Response Rates in a Falls Prevention Trial

Background: Attrition (i.e. when participants do not return the questionnaires)is a problem for many randomised controlled trials. The resultant loss of dataleads to a reduction in statistical power and can lead to bias. The aim of thisstudy was to assess whether a pre-notification newsletter and/or a handwrittenor printed Post-it® note sticker, as a reminder, increased postal questionnaireresponse rates for participants of randomised controlled trials.Method: This study was a factorial trial embedded within a trial of afalls-prevention intervention among men and women aged ≥65 years underpodiatric care. Participants were randomised into one of six groups: newsletterplus handwritten Post-it®; newsletter plus printed Post-it®; newsletter only;handwritten Post-it® only; printed Post-it® only; or no newsletter or Post-it®.The results were combined with those from previous embedded randomisedcontrolled trials in a meta-analysis.Results: The 12-month response rate was 803/826 (97.2%) (newsletter 95.1%,no newsletter 99.3%, printed Post-it® 97.5%, handwritten Post-it® 97.1%, noPost-it® 97.1%). Pre-notification with a newsletter had a detrimental effect onresponse rates (adjusted odds ratio (OR), 0.14; 95% CI, 0.04 to 0.48; p<0.01)and time to return the questionnaire (adjusted hazard ratio, 0.86; 95% CI, 0.75to 0.99; p=0.04). No other statistically significant differences were observedbetween the intervention groups on response rates, time to response, and theneed for a reminder.Conclusions: Post-it® notes have been shown to be ineffective in threeembedded trials, whereas the evidence for newsletter reminders is stilluncertain.KeywordsRandomised controlled trial; randomisation; embedded trial; newsletter;Post-it® note; response rat

A randomized, embedded trial of pre-notification of trial participation did not increase recruitment rates to a falls prevention trial

Objectives: To design and evaluate the effectiveness of a pre-notification leaflet about research to increase recruitment to a randomised controlled trial (RCT). Methods: A methodological, two arm, randomised controlled trial was conducted, embedded within an existing cohort RCT (REFORM). Participants were randomised for the embedded trial, using a 1:2 (intervention:control) allocation ratio, prior to being randomised for the REFORM RCT. Controls received a trial recruitment pack. The intervention group received an additional pre-notification leaflet 2 to 3 weeks before the recruitment pack. Primary and secondary analyses were conducted using relative risk, the Cox Proportional Hazards Model and Incremental Cost Effectiveness Ratios. Results: Of the 1,436 intervention group participants, 73 (5.1%) were randomised into the REFORM trial compared to 126 (4.4%) of the 2,878 control group participants. The associated relative risk (1.16) was not statistically significant (95% CI 0.88 - 1.56). The leaflet did not significantly increase return rate (RR 1.10, 95% CI 0.92 -1.28) or decrease time to return (Hazard Ratio: 1.11, 95% CI 0.93 -1.33). Incremental Cost Effectiveness Ratios indicated that the intervention may be cost-effective if the true estimate of effect were close to the upper bound of the associated 95% CI. Conclusion: A pre-notification leaflet to potential trial participants demonstrated a small difference in favour of the intervention with regards randomisation (0.7% difference) and return rates (1.1% difference).Results should however be interpreted with caution as confidence intervals for these estimates cross the point of no effect. Nevertheless, this research enhances existing evidence for pre-notification to increase recruitment rates, with further development and assessment of this potentially cost-effective intervention being recommended

Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: A systematic analysis for the Global Burden of Disease Study 2017

Background: The Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017) includes a comprehensive assessment of incidence, prevalence, and years lived with disability (YLDs) for 354 causes in 195 countries and territories from 1990 to 2017. Previous GBD studies have shown how the decline of mortality rates from 1990 to 2016 has led to an increase in life expectancy, an ageing global population, and an expansion of the non-fatal burden of disease and injury. These studies have also shown how a substantial portion of the world's population experiences non-fatal health loss with considerable heterogeneity among different causes, locations, ages, and sexes. Ongoing objectives of the GBD study include increasing the level of estimation detail, improving analytical strategies, and increasing the amount of high-quality data. Methods: We estimated incidence and prevalence for 354 diseases and injuries and 3484 sequelae. We used an updated and extensive body of literature studies, survey data, surveillance data, inpatient admission records, outpatient visit records, and health insurance claims, and additionally used results from cause of death models to inform estimates using a total of 68 781 data sources. Newly available clinical data from India, Iran, Japan, Jordan, Nepal, China, Brazil, Norway, and Italy were incorporated, as well as updated claims data from the USA and new claims data from Taiwan (province of China) and Singapore. We used DisMod-MR 2.1, a Bayesian meta-regression tool, as the main method of estimation, ensuring consistency between rates of incidence, prevalence, remission, and cause of death for each condition. YLDs were estimated as the product of a prevalence estimate and a disability weight for health states of each mutually exclusive sequela, adjusted for comorbidity. We updated the Socio-demographic Index (SDI), a summary development indicator of income per capita, years of schooling, and total fertility rate. Additionally, we calculated differences between male and female YLDs to identify divergent trends across sexes. GBD 2017 complies with the Guidelines for Accurate and Transparent Health Estimates Reporting. Findings: Globally, for females, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and haemoglobinopathies and haemolytic anaemias in both 1990 and 2017. For males, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and tuberculosis including latent tuberculosis infection in both 1990 and 2017. In terms of YLDs, low back pain, headache disorders, and dietary iron deficiency were the leading Level 3 causes of YLD counts in 1990, whereas low back pain, headache disorders, and depressive disorders were the leading causes in 2017 for both sexes combined. All-cause age-standardised YLD rates decreased by 3·9% (95% uncertainty interval [UI] 3·1-4·6) from 1990 to 2017; however, the all-age YLD rate increased by 7·2% (6·0-8·4) while the total sum of global YLDs increased from 562 million (421-723) to 853 million (642-1100). The increases for males and females were similar, with increases in all-age YLD rates of 7·9% (6·6-9·2) for males and 6·5% (5·4-7·7) for females. We found significant differences between males and females in terms of age-standardised prevalence estimates for multiple causes. The causes with the greatest relative differences between sexes in 2017 included substance use disorders (3018 cases [95% UI 2782-3252] per 100 000 in males vs 1400 [1279-1524] per 100 000 in females), transport injuries (3322 [3082-3583] vs 2336 [2154-2535]), and self-harm and interpersonal violence (3265 [2943-3630] vs 5643 [5057-6302]). Interpretation: Global all-cause age-standardised YLD rates have improved only slightly over a period spanning nearly three decades. However, the magnitude of the non-fatal disease burden has expanded globally, with increasing numbers of people who have a wide spectrum of conditions. A subset of conditions has remained globally pervasive since 1990, whereas other conditions have displayed more dynamic trends, with different ages, sexes, and geographies across the globe experiencing varying burdens and trends of health loss. This study emphasises how global improvements in premature mortality for select conditions have led to older populations with complex and potentially expensive diseases, yet also highlights global achievements in certain domains of disease and injury

Global, regional, and national age-sex-specific mortality and life expectancy, 1950-2017: a systematic analysis for the Global Burden of Disease Study 2017

Background: Assessments of age-specific mortality and life expectancy have been done by the UN Population Division, Department of Economics and Social Affairs (UNPOP), the United States Census Bureau, WHO, and as part of previous iterations of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD). Previous iterations of the GBD used population estimates from UNPOP, which were not derived in a way that was internally consistent with the estimates of the numbers of deaths in the GBD. The present iteration of the GBD, GBD 2017, improves on previous assessments and provides timely estimates of the mortality experience of populations globally. Methods: The GBD uses all available data to produce estimates of mortality rates between 1950 and 2017 for 23 age groups, both sexes, and 918 locations, including 195 countries and territories and subnational locations for 16 countries. Data used include vital registration systems, sample registration systems, household surveys (complete birth histories, summary birth histories, sibling histories), censuses (summary birth histories, household deaths), and Demographic Surveillance Sites. In total, this analysis used 8259 data sources. Estimates of the probability of death between birth and the age of 5 years and between ages 15 and 60 years are generated and then input into a model life table system to produce complete life tables for all locations and years. Fatal discontinuities and mortality due to HIV/AIDS are analysed separately and then incorporated into the estimation. We analyse the relationship between age-specific mortality and development status using the Socio-demographic Index, a composite measure based on fertility under the age of 25 years, education, and income. There are four main methodological improvements in GBD 2017 compared with GBD 2016: 622 additional data sources have been incorporated; new estimates of population, generated by the GBD study, are used; statistical methods used in different components of the analysis have been further standardised and improved; and the analysis has been extended backwards in time by two decades to start in 1950. Findings: Globally, 18·7% (95% uncertainty interval 18·4–19·0) of deaths were registered in 1950 and that proportion has been steadily increasing since, with 58·8% (58·2–59·3) of all deaths being registered in 2015. At the global level, between 1950 and 2017, life expectancy increased from 48·1 years (46·5–49·6) to 70·5 years (70·1–70·8) for men and from 52·9 years (51·7–54·0) to 75·6 years (75·3–75·9) for women. Despite this overall progress, there remains substantial variation in life expectancy at birth in 2017, which ranges from 49·1 years (46·5–51·7) for men in the Central African Republic to 87·6 years (86·9–88·1) among women in Singapore. The greatest progress across age groups was for children younger than 5 years; under-5 mortality dropped from 216·0 deaths (196·3–238·1) per 1000 livebirths in 1950 to 38·9 deaths (35·6–42·83) per 1000 livebirths in 2017, with huge reductions across countries. Nevertheless, there were still 5·4 million (5·2–5·6) deaths among children younger than 5 years in the world in 2017. Progress has been less pronounced and more variable for adults, especially for adult males, who had stagnant or increasing mortality rates in several countries. The gap between male and female life expectancy between 1950 and 2017, while relatively stable at the global level, shows distinctive patterns across super-regions and has consistently been the largest in central Europe, eastern Europe, and central Asia, and smallest in south Asia. Performance was also variable across countries and time in observed mortality rates compared with those expected on the basis of development. Interpretation: This analysis of age-sex-specific mortality shows that there are remarkably complex patterns in population mortality across countries. The findings of this study highlight global successes, such as the large decline in under-5 mortality, which reflects significant local, national, and global commitment and investment over several decades. However, they also bring attention to mortality patterns that are a cause for concern, particularly among adult men and, to a lesser extent, women, whose mortality rates have stagnated in many countries over the time period of this study, and in some cases are increasing

Home environmental assessments and modification delivered by occupational therapists to reduce falls in people aged 65 years and over : the OTIS RCT

Background: Falls and fall-related fractures in older people are highly prevalent and a major contributor to morbidity and cost to individuals and society. There is only one small pilot trial evaluating the effectiveness of a home hazard assessment and environmental modification in the UK. This trial reported a reduction in falls as a secondary outcome; no economic evaluation was undertaken. The results therefore need confirming and a cost-effectiveness analysis undertaking. Objectives: To determine the clinical and cost-effectiveness of a home hazard assessment and environmental modification delivered by occupational therapists for preventing falls in community-dwelling people aged over 65 at risk of falling, relative to usual care. Design: A pragmatic, multicentre, modified cohort randomised controlled trial with an economic evaluation and qualitative study. Setting: Eight NHS trusts in primary and secondary care in England. Participants: In total, 1331 participants were randomised (intervention, n=430; usual care group, n=901) via a secure, remote service. Blinding was not possible. Interventions: All participants received a falls prevention leaflet and routine care from their General Practitioner. The intervention group were additionally offered one home environmental assessment and modifications recommended or provided to identify and manage personal fall-related hazards, delivered by an occupational therapist. Main outcome measures: The primary outcome was the number of falls per participant over the 12 months from randomisation. The secondary outcomes were the proportion of fallers and multiple fallers, time to fall, fear of falling, fracture rate, health-related quality of life and cost-effectiveness. Results: The primary analysis included all 1331 randomised participants and indicated weak evidence of a difference in fall rate between the two groups, with an increase in the intervention group relative to usual care (adjusted incidence rate ratio 1.17, 95% CI 0.99 to 1.38; p=0.07). A similar proportion of participants in the intervention group (57.0%) and the usual care group (56.2%) reported at least one fall over 12 months. There were no differences in any of the secondary outcomes. The base case cost-effectiveness analysis from an NHS and personal social services perspective found that, on average per participant, the intervention was associated with additional costs (£18.78, 95% CI £16.33 to £21.24), but was less effective (mean QALY loss -0.0042, 95% CI -0.0041 to -0.0043). Sensitivity analyses demonstrated uncertainty in these findings. No serious, related adverse events were reported. The intervention was largely delivered as intended but recommendations were followed to a varying degree. Limitations: Outcome data were participant self-reported, which may have led to inaccuracies in the reported falls data. Conclusions: We found no evidence that an occupational therapist-delivered home assessment and modification reduced falls in this population of over 65 year old, community-dwelling participants deemed at risk of falling. The intervention was more expensive and less effective than usual care, therefore does not provide a cost-effective alternative. Future work: Evaluation of falls prevention advice in a higher risk population, perhaps those previously hospitalised for a fall, or given by other professional staff could be justified. Trial registration: ISRCTN2220213

Analysis of trends in the chemical composition of the troposphere during the last 40 years (RETRO) simulated with the MOZECH model

Background: Most incisions following surgery heal by primary intention, with the edges of the wound apposed with sutures or clips. However, some wounds may break open or be left to heal from the bottom up (i.e. healing by secondary intention). Surgical Wounds Healing by Secondary Intention (SWHSI) are often more complex to manage, and require additional treatments during the course of healing. There is significant uncertainty regarding the best treatment for these complex wounds, with limited robust evidence regarding the clinical and cost-effectiveness of different dressings and treatments; one such treatment is Negative Pressure Wound Therapy (NPWT) which is frequently used in the management of SWHSI. Previous randomised controlled trials (RCTs) of NPWT have failed to recruit to time and target, thus we aimed to conduct a pilot RCT to assess the feasibility of conducting a future, full-scale RCT. Methods: This pilot RCT will test the methods and feasibility of recruiting, randomising, and retaining participants into a larger trial of NPWT verses usual care for patients with SWHSI. Participants will be randomised to receive either NPWT or usual care (no NPWT) and will be followed up for 3 months. Discussion: This study will provide a full assessment of methods for, and feasibility of, recruiting, randomising, and retaining patients with SWHSI in a trial of NPWT versus usual care. On the basis of this pilot trial, a full trial may be proposed in the future which will provide additional, robust evidence on the clinical and cost-effectiveness of NPWT in the management of SWHSI. Trial registration: Clinical Trial Registry: ISRCTN12761776, registered on 10 December 2015 – retrospective registration

Home hazard assessment and environmental modification to prevent falls in older people : the OTIS trial

Background: Falls in older people are a major cause of morbidity and mortality. There is some evidence to suggest that home hazard assessment and environmental modification delivered by an occupational therapist may reduce falls. The objective of this study was to evaluate the effectiveness of this intervention, relative to usual care. Methods: A pragmatic, two-arm modified cohort randomised controlled trial in eight NHS trusts in primary and secondary care in England. In total 1331 community-dwelling adults aged 65 years and over with a history of falls or fear of falling were randomised in a 2:1 allocation to either usual care plus a falls prevention leaflet (n=901) or to receive the home hazard assessment and environmental modification intervention, plus usual care and a falls prevention leaflet (n=430). The primary outcome was the number of falls per participant over the 12 months from randomization. Secondary outcomes included: proportion of fallers and multiple fallers, time to fall, and fear of falling. Results: All 1331 randomised participants (mean age 80 years, 872 [65.5%] female) were included in the primary analysis. There was a small increase in the rate of falls in the intervention group relative to usual care (adjusted incidence rate ratio 1.17, 95% CI 0.99 to 1.38; p=0.07). A similar proportion of participants in the intervention (57.0%) and usual care group (56.2%) reported at least one fall over 12 months. There were no differences in any of the other secondary outcomes and no serious, related adverse events were reported. Conclusions: Home hazard assessment and environmental modification delivered by an occupational therapist did not reduce falls in community-dwelling older people deemed at higher risk of falling recruited to this trial. ISRCTN registry: ISRCTN22202133 Key words: home hazard assessment and environmental modification, falls prevention, older adults, modified cohort randomized controlled tria

Effect of Noninvasive Respiratory Strategies on Intubation or Mortality Among Patients With Acute Hypoxemic Respiratory Failure and COVID-19: The RECOVERY-RS Randomized Clinical Trial.

Importance Continuous positive airway pressure (CPAP) and high-flow nasal oxygen (HFNO) have been recommended for acute hypoxemic respiratory failure in patients with COVID-19. Uncertainty exists regarding the effectiveness and safety of these noninvasive respiratory strategies. Objective To determine whether either CPAP or HFNO, compared with conventional oxygen therapy, improves clinical outcomes in hospitalized patients with COVID-19-related acute hypoxemic respiratory failure. Design, Setting, and Participants A parallel group, adaptive, randomized clinical trial of 1273 hospitalized adults with COVID-19-related acute hypoxemic respiratory failure. The trial was conducted between April 6, 2020, and May 3, 2021, across 48 acute care hospitals in the UK and Jersey. Final follow-up occurred on June 20, 2021. Interventions Adult patients were randomized to receive CPAP (n = 380), HFNO (n = 418), or conventional oxygen therapy (n = 475). Main Outcomes and Measures The primary outcome was a composite of tracheal intubation or mortality within 30 days. Results The trial was stopped prematurely due to declining COVID-19 case numbers in the UK and the end of the funded recruitment period. Of the 1273 randomized patients (mean age, 57.4 [95% CI, 56.7 to 58.1] years; 66% male; 65% White race), primary outcome data were available for 1260. Crossover between interventions occurred in 17.1% of participants (15.3% in the CPAP group, 11.5% in the HFNO group, and 23.6% in the conventional oxygen therapy group). The requirement for tracheal intubation or mortality within 30 days was significantly lower with CPAP (36.3%; 137 of 377 participants) vs conventional oxygen therapy (44.4%; 158 of 356 participants) (absolute difference, -8% [95% CI, -15% to -1%], P = .03), but was not significantly different with HFNO (44.3%; 184 of 415 participants) vs conventional oxygen therapy (45.1%; 166 of 368 participants) (absolute difference, -1% [95% CI, -8% to 6%], P = .83). Adverse events occurred in 34.2% (130/380) of participants in the CPAP group, 20.6% (86/418) in the HFNO group, and 13.9% (66/475) in the conventional oxygen therapy group. Conclusions and Relevance Among patients with acute hypoxemic respiratory failure due to COVID-19, an initial strategy of CPAP significantly reduced the risk of tracheal intubation or mortality compared with conventional oxygen therapy, but there was no significant difference between an initial strategy of HFNO compared with conventional oxygen therapy. The study may have been underpowered for the comparison of HFNO vs conventional oxygen therapy, and early study termination and crossover among the groups should be considered when interpreting the findings. Trial Registration isrctn.org Identifier: ISRCTN16912075