The impact of uninterrupted sitting on central and peripheral cardiovascular function in pre-menopausal and post-menopausal women.

Independently, both prolonged uninterrupted sitting and the onset of menopause negatively impact markers of cardiovascular risk. Whether their combination augment these responses additively remains unknown. This study assessed whether prolonged uninterrupted sitting causes greater central and peripheral cardiovascular dysfunction in post-menopausal women compared to pre-menopausal women. To address this, 23 healthy women (13 pre-menopausal [43.77 ± 4.30 years] and 10 post-menopausal [57.20 ± 8.55 years]) sat uninterrupted for 2-h. Carotid-femoral pulse wave velocity (cf-PWV), pulse wave analysis (PWA), lower limb venous pooling (HHb), and calf circumference were assessed pre-and post-sitting using general linear mixed models, with age as a covariate. Changes in MAP over time (both between and within groups) was assessed using a two-way repeated-measures-ANOVA. There were no significant interactions for any outcome measures. However, for cf-PWV, there was a significant main effect of group (Δ = 0.854 ± 0.354 m s-1; p = 0.026, ηp2 = 0.707). For PWA, only heart rate (HR) and pressure forwards (Pf) showed significant main effects 13 of time [Δ = 6 ± 1 bts-min-1, p < 0.001, ηp2 = 0.861] and group [Δ = 3.893 ± 1.450 mmHg, p = 0.016, ηp2 = 0.271], respectively. Both HHb (Δ = 2.737 ± 0.952, p = 0.009, ηp2 = 0.742) and calf circumference (Δ = 0.812 ± 0.128 cm, p < 0.001, ηp2 = 0.863) significantly increased over time. Whilst post-menopausal women demonstrated greater overall arterial stiffness (increased cf-PWV at baseline), there was no difference in cardiovascular response (central or peripheral) to 2-h of prolonged sitting between the pre- and post-menopausal women.

Localized activity attenuates the combined impact of a high fat meal and prolonged sitting on arterial stiffness: A randomized, controlled cross-over trial.

Exposure to acute prolonged sitting and consumption of a high fat (HF) meal have been shown to independently and additively impair central and peripheral cardiovascular function. This study sought to determine whether localized activity, namely leg fidgeting, offers a protective effect to these deleterious effects. Using a randomized crossover design with three trials, 18 healthy males sat uninterrupted for 180 min following the consumption of a low fat (LF, trial 1) or HF meal (trial 2). The third trial consisted of a HF meal but sitting was interrupted with 1 min of leg fidgeting (isolated bilateral plantar flexion) consisting of -250 taps per min every 5 min for the 180 min duration. Carotid-femoral pulse wave velocity (cfPWV), aortic-femoral stiffness gradient (af-SG), superficial femoral blood flow, shear-rate and PWVß, triglyceride concentrations and lower-limb venous pooling (HHb) were assessed pre and post sitting in all trials. General linear mixed model found that following the uninterrupted HF trial, there was a significant worsening of cfPWV (mean difference (MD) = 0.57 mˑs-1; d = 1.04) and the af-SG (MD = 0.14, d = 0.50), and femoral artery blood flow (MD = 18 mlˑmin-1; d = 0.48) and shear rate (MD = 15 S1; d = 0.67) decreased. However, leg fidgeting was enough to prevent the combined deleterious effects of prolonged sitting following a HF meal. As there were no significant changes in the LF trial, the HF meal maybe the predominant driver when uninterrupted sitting is combined with a HF meal.

'Recruitment, recruitment, recruitment' - the need for more focus on retention: a qualitative study of five trials.

BACKGROUND: Loss to follow-up (attrition) is a frequent problem in clinical trials and can introduce bias or reduce power. So, understanding retention issues and strategies to address these are important. As part of a multi-method project, this qualitative study aimed to explore retention strategies used by trial teams and factors which may influence strategy adoption. METHOD: A purposive sample of active trials was selected from the UK NIHR HTA portfolio of ongoing trials in 2014/2015. Semi-structured interviews with several trial team members from each trial and supplementary interviews with experienced trial managers explored strategies in collecting clinical outcome data and retaining participants. Interview data were analysed thematically using techniques of constant comparison. RESULTS: Twenty-two semi-structured interviews with trial team members including chief investigators, trial managers, nurses and research administrators revealed strategies used to enhance retention. Some were recognised methods and planned from trial outset whilst others were implemented more responsively. Interviewees placed great value on fostering positive relationships with trial participants to enhance retention. However, these strategies took time which was not always appreciated by the wider trial team or funding bodies. The national focus on recruitment targets in networks posed a challenge to staff and was deemed detrimental to retention. The 'moral compass' of individual researchers relied on their own beliefs and values and research experience and the factors affected their confidence to pursue participant data during follow-up. CONCLUSION: The role of trial staff and their underlying behaviours influence retention practices and, combined with emphasis on recruitment targets, can be detrimental to motivation and retention activities. There is a need to consider how to train and support trial staff involved in retention practices and recognition of retention from funding bodies and oversight organisations.

Reducing attrition within clinical trials: The communication of retention and withdrawal within patient information leaflets.

BACKGROUND: The recruitment and retention of patients are significant methodological challenges for trials. Whilst research has focussed on recruitment, the failure to retain recruited patients and collect outcome data can lead to additional problems and potentially biased results. Research to identify effective retention strategies has focussed on influencing patient behaviour through incentives, reminders and alleviating patient burden, but has not sought to improve patient understanding of the importance of retention. Our aim is to assess how withdrawal, retention and the value of outcome data collection is described within the Patient Information Leaflets (PIL) used during consent. METHODS: Fifty adult or parent PIL from a cohort of trials starting between 2009-2012 and funded by the NIHR Health Technology Assessment programme were obtained from protocols, websites or by contacting trialists. A checklist of PIL content based on Health Research Authority (HRA) and ICH GCP Guidelines was supplemented with retention specific questions. Corresponding protocols were also evaluated to cross reference trial specific procedures with information communicated to patients. RESULTS: PIL frequently reiterated the patient's right to withdraw at any time (n = 49, 98%), without having to give a reason and without penalty (n = 45, 90%). However, few informed patients they may be asked to give a withdrawal reason where willing (n = 6, 12%). Statements about the value of retention were infrequent (n = 8, 16%). Consent documents failed to include key content that might mitigate withdrawals, such as the need for treatment equipoise (n = 3, 6%). Nearly half the trials in the cohort (n = 23, 46%) wanted to continue to collect outcome data if patients withdraw. However, in 70% of PIL using prospective consent, withdrawal was described in generic terms leaving patients unaware of the difference between stopping treatment and all trial involvement. Nineteen (38%) trials offered withdrawing patients the option to delete existing data. CONCLUSIONS: Withdrawal and retention is poorly described within PIL and addressing this might positively impact levels of patient attrition, reducing missing data. Consent information is unbalanced, focussing on patient's rights to withdraw without accompanying information that promotes robust consent and sustained participation. With many citing altruistic reasons for participation it is essential that PIL include more information on retention and clarify withdrawal terminology so patients are aware of how they can make a valuable contribution to clinical studies. There is a need to determine how retention can be described to patients to avoid concerns of coercion. Future research is needed to explore whether the absence of information about retention at the time of consent is impacting attrition.

'We all want to succeed, but we've also got to be realistic about what is happening': an ethnographic study of relationships in trial oversight and their impact.

BACKGROUND: The oversight and conduct of a randomised controlled trial involves several stakeholders, including a Trial Steering Committee (TSC), Trial Management Group (TMG), Data Monitoring Committee (DMC), funder and sponsor. We aimed to examine how the relationships between these stakeholders affect the trial oversight process and its rigour, to inform future revision of Good Clinical Practice guidelines. METHODS: Using an ethnographic study design, we observed the oversight processes of eight trials and conducted semi-structured interviews with members of the trials' TSCs and TMGs, plus other relevant informants, including sponsors and funders of trials. Data were analysed thematically, and findings triangulated and integrated to give a multi-perspective account of current oversight practices in the UK. RESULTS: Eight TSC and six TMG meetings from eight trials were observed and audio-recorded, and 66 semi-structured interviews conducted with 52 purposively sampled key informants. Five themes are presented: (1) Collaboration within the TMG and role of the CTU; (2) Collaboration and conflict between oversight committees; (3) Priorities; (4) Communication between trial oversight groups and (5) Power and accountability. There was evidence of collaborative relationships, based on mutual respect, between CTUs, TMGs and TSCs, but also evidence of conflict. Relationships between trial oversight committees were influenced by stakeholders' priorities, both organisational and individual. Good communication following specific, recognised routes played a central role in ensuring that relationships were productive and trial oversight efficient. Participants described the possession of power over trials as a shifting political landscape, and there was lack of clarity regarding the roles and accountability of each committee, the sponsor and funder. Stakeholders' perceptions of their own power over a trial, and the power of others, influenced relationships between those involved in trial oversight. CONCLUSIONS: Recent developments in trial design and conduct have been accompanied by changes in roles and relationships between trial oversight groups. Recognising and respecting the value of differing priorities among those involved in running trials is key to successful relationships between committees, funders and sponsors. Clarity regarding appropriate lines of communication, roles and accountability is needed. We present 10 evidence-based recommendations to inform updates to international trial guidance, particularly the Medical Research Council guidelines.

Identifying research priorities for effective retention strategies in clinical trials.

BACKGROUND: The failure to retain patients or collect primary-outcome data is a common challenge for trials and reduces the statistical power and potentially introduces bias into the analysis. Identifying strategies to minimise missing data was the second highest methodological research priority in a Delphi survey of the Directors of UK Clinical Trial Units (CTUs) and is important to minimise waste in research. Our aim was to assess the current retention practices within the UK and priorities for future research to evaluate the effectiveness of strategies to reduce attrition. METHODS: Seventy-five chief investigators of NIHR Health Technology Assessment (HTA)-funded trials starting between 2009 and 2012 were surveyed to elicit their awareness about causes of missing data within their trial and recommended practices for improving retention. Forty-seven CTUs registered within the UKCRC network were surveyed separately to identify approaches and strategies being used to mitigate missing data across trials. Responses from the current practice surveys were used to inform a subsequent two-round Delphi survey with registered CTUs. A consensus list of retention research strategies was produced and ranked by priority. RESULTS: Fifty out of seventy-five (67%) chief investigators and 33/47 (70%) registered CTUs completed the current practice surveys. Seventy-eight percent of trialists were aware of retention challenges and implemented strategies at trial design. Patient-initiated withdrawal was the most common cause of missing data. Registered CTUs routinely used newsletters, timeline of participant visits, and telephone reminders to mitigate missing data. Whilst 36 out of 59 strategies presented had been formally or informally evaluated, some frequently used strategies, such as site initiation training, have had no research to inform practice. Thirty-five registered CTUs (74%) participated in the Delphi survey. Research into the effectiveness of site initiation training, frequency of patient contact during a trial, the use of routinely collected data, the frequency and timing of reminders, triggered site training and the time needed to complete questionnaires was deemed critical. Research into the effectiveness of Christmas cards for site staff was not of critical importance. CONCLUSION: The surveys of current practices demonstrates that a variety of strategies are being used to mitigate missing data but with little evidence to support their use. Six retention strategies were deemed critically important within the Delphi survey and should be a primary focus of future retention research.

What are the roles and valued attributes of a Trial Steering Committee? Ethnographic study of eight clinical trials facing challenges.

BACKGROUND: Clinical trials oversight by a Trial Steering Committee (TSC) is mandated by Good Clinical Practice. This study used qualitative methods to explore the role and valued attributes of the TSC to inform planned updates of Medical Research Council guidance and TSC terms of reference. METHODS: An ethnographic study was conducted during 2013-2014. TSC and Trial Management Group meetings from eight trials were observed and audio-recorded, and semi-structured interviews conducted with purposively sampled key informants: independent and non-independent TSC members, trial sponsor representatives, funder representatives and chief investigators. The selected trials were currently recruiting and dealing with challenging scenarios. Data were analysed thematically and findings triangulated and integrated to give a multi-perspective account of the role and valued attributes of a TSC. RESULTS: Eight TSC meetings and six Trial Management Group meetings were observed. Sixty-five interviews were conducted with 51 informants. The two main roles played by the TSC were quality assurance and patient advocacy. Quality assurance involved being a 'critical friend' or a provider of 'tough love'. Factors influencing the ability of the TSC to fulfil this role included the TSC Chair, other independent TSC members and the model of the TSC and its fit with the trial subject. The role of the TSC as an advocate for patient well-being was perceived as paramount. Two attributes of TSC members emerged as critical: experience (of running a trial, trial oversight or in a clinical/methodological area) and independence. While independence was valued for giving impartiality, the lack of consensus about its definition and strict requirements of some funders made it difficult to operationalise. CONCLUSIONS: We found tensions and ambiguities in the roles expected of TSCs and the attributes valued of TSC members. In particular, the requirements of independence and experience could conflict, impacting the TSCs' quality assurance role. Concerns were raised regarding whose interests are served by funders' criteria of independence; in particular, funders' selection of TSC members was thought to potentially inhibit TSCs' ability to fulfil their patient advocacy role. These findings should be incorporated in revising guidance and terms of reference for TSCs.

Pilot study of an exercise intervention suitable for older heart failure patients with left ventricular systolic dysfunction.

BACKGROUND: Most studies of exercise training for heart failure have been conducted on relatively young patients with little comorbidity. Such programmes are unsuitable for the majority of older frail heart failure patients. AIMS: To test the acceptability and tolerability of an outpatient exercise programme in older heart failure patients with comorbid disease. METHODS: 17 patients aged 70 years and over with left ventricular systolic dysfunction attended twice weekly group exercise classes for 12 weeks, focussing on endurance exercise and everyday functional tasks. Outcome measures were proportion of sessions attended; adverse events and reasons for non-attendance; six-minute walk, accelerometry, hospital depression and anxiety score, Guyatt quality of life scale, carer strain and satisfaction scores. RESULTS: 83% of sessions were attended; 80% of subjects attended at least 80% of allocated sessions. One adverse incident occurred in 324 person-sessions. Encouraging improvements were seen in six minute walk test (+19 m, p=0.14) and in Functional Limitation Profile score (-82 points, p=0.02). 50% of informal carers attended at least one session. No increase in carer strain was noted. CONCLUSIONS: Twice-weekly group exercise focussing on aerobic endurance and everyday functional tasks was acceptable and well-tolerated in this patient group.

Physiotherapists' pain beliefs and their influence on the management of patients with chronic low back pain.

PURPOSE: Little is known about physiotherapists' pain beliefs and whether they influence behavior within therapeutic encounters with patients. This qualitative study explored physiotherapists' pain beliefs with the purpose of highlighting the nature of their beliefs and the role they played within their management of chronic low back pain. METHODS: Six physiotherapists were purposefully sampled along with 12 of their patients with chronic low back pain (two patients each). A qualitative exploration of physiotherapists' pain beliefs within the context of a clinical situation was carried out using semistructured interviews and observations at designated stages throughout therapeutic encounters with their patients. The data were prepared and analyzed according to a grounded theory approach. RESULTS: The themes that emerged from the data indicated that the pain beliefs of physiotherapists in this study were determined by a number of perspectives including their beliefs regarding the development of craft knowledge needed to manage chronic low back pain, beliefs regarding the clinical characteristics of patients with chronic low back pain they considered to be "good" to treat and the challenge of patients who were "difficult" to treat, and pain beliefs within the therapeutic encounter. A tentative theory was developed which proposed that the physiotherapists' biomedically oriented pain beliefs influenced their clinical reasoning processes including the explanations given to the patients. CONCLUSIONS: The findings suggest that in order to maximize the rehabilitation potential of patients with chronic low back pain, physiotherapists need to be aware that their pain beliefs may influence their management of these patients.