Centre selection for clinical trials and the generalisability of results: a mixed methods study.

BACKGROUND: The rationale for centre selection in randomised controlled trials (RCTs) is often unclear but may have important implications for the generalisability of trial results. The aims of this study were to evaluate the factors which currently influence centre selection in RCTs and consider how generalisability considerations inform current and optimal practice. METHODS AND FINDINGS: Mixed methods approach consisting of a systematic review and meta-summary of centre selection criteria reported in RCT protocols funded by the UK National Institute of Health Research (NIHR) initiated between January 2005-January 2012; and an online survey on the topic of current and optimal centre selection, distributed to professionals in the 48 UK Clinical Trials Units and 10 NIHR Research Design Services. The survey design was informed by the systematic review and by two focus groups conducted with trialists at the Birmingham Centre for Clinical Trials. 129 trial protocols were included in the systematic review, with a total target sample size in excess of 317,000 participants. The meta-summary identified 53 unique centre selection criteria. 78 protocols (60%) provided at least one criterion for centre selection, but only 31 (24%) protocols explicitly acknowledged generalisability. This is consistent with the survey findings (n = 70), where less than a third of participants reported generalisability as a key driver of centre selection in current practice. This contrasts with trialists' views on optimal practice, where generalisability in terms of clinical practice, population characteristics and economic results were prime considerations for 60% (n = 42), 57% (n = 40) and 46% (n = 32) of respondents, respectively. CONCLUSIONS: Centres are rarely enrolled in RCTs with an explicit view to external validity, although trialists acknowledge that incorporating generalisability in centre selection should ideally be more prominent. There is a need to operationalize 'generalisability' and incorporate it at the design stage of RCTs so that results are readily transferable to 'real world' practice

Designing high-quality implementation research: development, application, feasibility and preliminary evaluation of the implementation science research development (ImpRes) tool and guide

Background:  Designing implementation research can be a complex and daunting task, especially for applied health researchers who have not received specialist training in implementation science. We developed the Implementation Science Research Development (ImpRes) tool and supplementary guide to address this challenge and provide researchers with a systematic approach to designing implementation research. Methods:  A multi-method and multi-stage approach was employed. An international, multidisciplinary expert panel engaged in an iterative brainstorming and consensus-building process to generate core domains of the ImpRes tool, representing core implementation science principles and concepts that researchers should consider when designing implementation research. Simultaneously, an iterative process of reviewing the literature and expert input informed the development and content of the tool. Once consensus had been reached, specialist expert input was sought on involving and engaging patients/service users; and economic evaluation. ImpRes was then applied to 15 implementation and improvement science projects across the National Institute of Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) South London, a research organisation in London, UK. Researchers who applied the ImpRes tool completed an 11-item questionnaire evaluating its structure, content and usefulness. Results:  Consensus was reached on ten implementation science domains to be considered when designing implementation research. These include implementation theories, frameworks and models, determinants of implementation, implementation strategies, implementation outcomes and unintended consequences. Researchers who used the ImpRes tool found it useful for identifying project areas where implementation science is lacking (median 5/5, IQR 4–5) and for improving the quality of implementation research (median 4/5, IQR 4–5) and agreed that it contained the key components that should be considered when designing implementation research (median 4/5, IQR 4–4). Qualitative feedback from researchers who applied the ImpRes tool indicated that a supplementary guide was needed to facilitate use of the tool. Conclusions:  We have developed a feasible and acceptable tool, and supplementary guide, to facilitate consideration and incorporation of core principles and concepts of implementation science in applied health implementation research. Future research is needed to establish whether application of the tool and guide has an effect on the quality of implementation research

Histological Evaluation of Corneal Scar Formation in Pseudophakic Bullous Keratopathy

PURPOSE: To evaluate histological changes in the corneal stroma in pseudophakic bullous keratopathy. METHODS: Twenty-eight patients (28 eyes) with pseudophakic bullous keratopathy underwent therapeutic penetrating keratoplasty at Shandong Eye Institute between January 2006 and November 2011. The patients were divided into two groups according to the duration of bullous keratopathy (<1.0 year group or >1.0 year group), and three buttons from enucleated eyes with choroidal melanoma served as a control. In vivo confocal microscopy examination, hematoxylin-eosin, Masson's trichrome stain and Van Gieson staining were used for microscopic examination. The histological evaluation and scoring of the buttons for morphological changes, including the degree of stromal scars, neovascularization and inflammatory cells within the corneal buttons, were compared. To study the underlying mechanism, connective tissue growth factor (CTGF) and TGF-β immunohistochemistry were performed. RESULTS: Confocal microscopy examination and histological evaluation and scoring of the buttons showed that compared with the <1.0 year group, stromal scars, neovascularization and inflammatory cells were more severe in the >1.0 year group (P<0.05). There was an increase in CTGF- and TGF-β1-positive stromal cells in the >1.0 year group. CONCLUSIONS: During the progression of pseudophakic bullous keratopathy, stromal scars occurred more often in the patients that had a longer duration of disease. Cytokines such as CTGF and TGF-β1 may play a role in this pathological process and deserve further investigation

Adrenal adenomatoid tumor in a patient with human immunodeficiency virus

We present the clinical course of a patient with human immunodeficiency virus and an adrenal adenomatoid tumor (AAT). We describe the clinical course and laboratory, radiographic, and microscopic findings of a patient with human immunodeficiency virus (HIV) and an adenomatoid tumor of the right adrenal gland. A review of the literature was also done via electronic searches through PubMed for articles from 1965 to 2008 that contained the following search terms, adenomatoid tumor limited to the English language only. A 22 year-old African-American male with HIV was incidentally found to have a hypermetabolic right adrenal mass. The patient underwent laparoscopic adrenalectomy and the mass had morphological and immunohistochemical features that were consistent with an AAT. A review of the medical literature reveals that almost all cases of AAT were in male patients (96%) with a mean age of 41±11 years (range=22–64) with no significant difference in laterality (right side=46%, left side=50%, unknown=4%). AAT have an average size of 4.2±3.5 cm (range=0.5–14.3 cm). Pre-operative imaging studies do not appear to be able to reliably distinguish AAT from other types of adrenocortical tumors. For reasons that require further research, AAT typically occur in male patients and may be associated with immunosuppression. AAT can be safely removed laparoscopically with no evidence of long-term recurrence even with tumor extension beyond the adrenal capsule

Process factors explaining the ineffectiveness of a multidisciplinary fall prevention programme: A process evaluation

<p>Abstract</p> <p>Background</p> <p>Falls are a major health threat to older community-living people, and initiatives to prevent falls should be a public health priority. We evaluated a Dutch version of a successful British fall prevention programme. Results of this Dutch study showed no effects on falls or daily functioning. In parallel to the effect evaluation, we carried out a detailed process evaluation to assess the feasibility of our multidisciplinary fall prevention programme. The present study reports on the results of this process evaluation.</p> <p>Methods</p> <p>Our fall prevention programme comprised a medical and occupational-therapy assessment, resulting in recommendations and/or referrals to other services if indicated. We used self-administered questionnaires, structured telephone interviews, structured recording forms, structured face-to-face interviews and a plenary group discussion to collect data from participants allocated to the intervention group (n = 166) and from all practitioners who performed the assessments (n = 8). The following outcomes were assessed: the extent to which the multidisciplinary fall prevention programme was performed according to protocol, the nature of the recommendations and referrals provided to the participants, participants' self-reported compliance and participants' and practitioners' opinions about the programme.</p> <p>Results</p> <p>Both participants and practitioners judged the programme to be feasible. The programme was largely performed according to protocol. The number of referrals and recommendations ensuing from the medical assessment was relatively small. Participants' self-reported compliance as regards contacting their GP to be informed of the recommendations and/or referrals was low to moderate. However, self-reported compliance with such referrals and recommendations was reasonable to good. A large majority of participants reported they had benefited from the programme.</p> <p>Conclusion</p> <p>The results of the present study show that the programme was feasible for both practitioners and participants. Main factors that seem to be responsible for the lack of effectiveness are the relatively low number of referrals and recommendations ensuing from the medical assessments and participants' low compliance as regards contacting their GP about the results of the medical assessment. We do not recommend implementing the programme in its present form in regular care.</p> <p>Trial registration</p> <p>ISRCTN64716113</p

Results from the dissemination of an evidence-based telephone-delivered intervention for healthy lifestyle and weight loss: the Optimal Health Program

Despite proven efficacy, there are few published evaluations of telephone-delivered interventions targeting physical activity, healthy eating, and weight loss in community dissemination contexts. This study aims to evaluate participant and program outcomes from the Optimal Health Program, a telephone-delivered healthy lifestyle and weight loss program provided by a primary health care organization. Dissemination study used a single-group, repeated measures design; outcomes were assessed at 6-month (mid-program; n = 166) and 12-month (end of program; n = 88) using paired analyses. The program reached a representative sample of at-risk, primary care patients, with 56 % withdrawing before program completion. Among completers, a statistically significant improvement between baseline and end of program was observed for weight [mean change (SE) −5.4 (7.0) kg] and waist circumference [−4.8 (9.7) cm], underpinned by significant physical activity and dietary change. Findings suggest that telephone-delivered weight loss and healthy lifestyle programs can provide an effective model for use in primary care settings, but participant retention remains a challenge

The feasibility of an exercise intervention in males at risk of oesophageal adenocarcinoma: a randomized controlled trial

Objective: To investigate the feasibility and safety of a 24-week exercise intervention, compared to control, in males with Barrett's oesophagus, and to estimate the effect of the intervention, compared to control, on risk factors associated with oesophageal adenocarcinoma development. Methods: A randomized controlled trial of an exercise intervention (60 minutes moderate-intensity aerobic and resistance exercise five days/week over 24 weeks; one supervised and four unsupervised sessions) versus attention control (45 minutes stretching five days/week over 24 weeks; one supervised and four unsupervised sessions) in inactive, overweight/obese (25.0-34.9 kg/m2) males with Barrett's oesophagus, aged 18-70 years. Primary outcomes were obesity-associated hormones relevant to oesophageal adenocarcinoma risk (circulating concentrations of leptin, adiponectin, interleukin-6, tumour necrosis factor-alpha, C-reactive protein, and insulin resistance HOMA). Secondary outcomes included waist circumference, body composition, fitness, strength and gastro-oesophageal reflux symptoms. Outcomes were measured at baseline and 24-weeks. Intervention effects were analysed using generalised linear models, adjusting for baseline value. Results: Recruitment was difficult in this population with a total of 33 participants recruited (target sample size: n = 80); 97% retention at 24-weeks. Adherence to the exercise protocol was moderate. No serious adverse events were reported. A statistically significant intervention effect (exercise minus control) was observed for waist circumference (-4.5 95%CI -7.5, -1.4 cm; p &lt; 0.01). Effects on primary outcomes were not statistically significant. Conclusion: This small, exploratory trial provides important information to inform future trial development including recruitment rates and estimates of effect sizes on outcomes related to oesophageal adenocarcinoma risk. Future trials should investigate a combined dietary and exercise intervention to achieve greater weight loss in this population and relax inclusion criteria to maximize recruitment. Trial Registration: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12609000401257. © 2015 Winzer et al