Recruitment and retention of participants in UK surgical trials: survey of key issues reported by trial staff.

BACKGROUND: Recruitment and retention of participants in surgical trials is challenging. Knowledge of the most common and problematic issues will aid future trial design. This study aimed to identify trial staff perspectives on the main issues affecting participant recruitment and retention in UK surgical trials. METHODS: An online survey of UK surgical trial staff was performed. Respondents were asked whether or not they had experienced a range of recruitment and retention issues, and, if yes, how relatively problematic these were (no, mild, moderate or serious problem). RESULTS: The survey was completed by 155 respondents including 60 trial managers, 53 research nurses, 20 trial methodologists and 19 chief investigators. The three most common recruitment issues were: patients preferring one treatment over another (81·5 per cent of respondents); clinicians' time constraints (78·1 per cent); and clinicians preferring one treatment over another (76·8 per cent). Seven recruitment issues were rated moderate or serious problems by a majority of respondents, the most problematic being a lack of eligible patients (60·3 per cent). The three most common retention issues were: participants forgetting to return questionnaires (81·4 per cent); participants found to be ineligible for the trial (74·3 per cent); and long follow-up period (70·7 per cent). The most problematic retention issues, rated moderate or serious by the majority of respondents, were participants forgetting to return questionnaires (56·4 per cent) and insufficient research nurse time/funding (53·6 per cent). CONCLUSION: The survey identified a variety of common recruitment and retention issues, several of which were rated moderate or serious problems by the majority of participating UK surgical trial staff. Mitigation of these problems may help boost recruitment and retention in surgical trials.

ANTECEDENTES: El reclutamiento y la retención de participantes en los ensayos quirúrgicos es un desafío. Conocer los problemas más habituales y conflictivos ayudará al diseño de futuros ensayos. Este estudio tuvo como objetivo identificar la percepción de los participantes sobre cuáles son los principales problemas que afectan el reclutamiento y la retención de participantes en los ensayos quirúrgicos del Reino Unido. MÉTODOS: Encuesta electrónica a profesionales de la salud que habían participado en ensayos quirúrgicos del Reino Unido. Se preguntó a los encuestados si habían experimentado o no algún problema en temas de reclutamiento o retención y, en caso afirmativo, qué tan conflictivos fueron (ningún problema/problema leve/moderado/grave). RESULTADOS: Completaron la encuesta 155 participantes, de los que 60 eran directores del ensayo, 53 enfermeras de investigación, 20 metodólogos de ensayos y 19 investigadores principales. Los tres problemas más comunes en el reclutamiento fueron: pacientes que prefieren un tratamiento sobre otro (81,5% de los encuestados), escaso tiempo de dedicación de los médicos (78,1%) y médicos que prefieren un tratamiento sobre otro (76,8%). La mayoría de los encuestados calificaron siete problemas de reclutamiento como "moderados" o "graves", siendo el más conflictivo la falta de pacientes elegibles (60,3%). Los tres problemas de retención más habituales fueron: participantes que olvidaron devolver los cuestionarios (81,4%), participantes que no fueron elegibles para el ensayo (74,3%) y el largo período de seguimiento (70,7%). Los problemas de retención más conflictivos, calificados como "moderados" o "graves" por la mayoría de los encuestados, fueron el olvido de los participantes para devolver los cuestionarios (56,4%) y el escaso tiempo/financiación para la enfermera investigadora (53,6%). CONCLUSIÓN: La encuesta identificó una serie de problemas habituales en el reclutamiento y la retención de los pacientes, muchos ellos calificados como "moderados" o "graves" por la mayoría del personal involucrado en los ensayos quirúrgicos del Reino Unido. Mitigar estos problemas puede ayudar a impulsar el reclutamiento y la retención en los ensayos quirúrgicos.

An emerging framework for fully incorporating public involvement (PI) into patient-reported outcome measures (PROMs).

Patient-reported outcome measures (PROMs) are widely used in the United Kingdom (UK) and internationally to report and monitor patients' subjective assessments of their symptoms and functional status and also their quality of life. Whilst the importance of involving the public in PROM development to increase the quality of the developed PROM has been highlighted this practice is not widespread. There is a lack of guidance on how public involvement (PI) could be embedded in the development of PROMs, where the roles can be more complex than in other types of research. This paper provides a timely review and sets out an emerging framework for fully incorporating PI into PROM development.

Top research priorities in healthcare-associated infection in the UK.

BACKGROUND: There is a mismatch between research questions which are considered to be important by patients, carers and healthcare professionals and the research performed in many fields of medicine. No relevant studies which have assessed research priorities in healthcare-associated infection (HCAI) that have involved patients' and carers' opinions were identified in the literature. AIM: The Healthcare-Associated Infections Priority Setting Partnership was established to identify the top research priorities in the prevention, diagnosis and treatment of HCAI in the UK, considering the opinions of all these groups. METHODS: The methods broadly followed the principles of the James Lind Alliance (JLA) priority setting activity. FINDINGS: In total, 259 unique valid research questions were identified from 221 valid responses to a consultation of patients, carers and healthcare professionals after seeking their opinions for research priorities. The steering committee of the priority setting partnership rationalized these to 50 unique questions. A literature review established that for these questions there were no recent high-quality systematic reviews, high-quality systematic reviews which concluded that further studies were necessary, or the steering committee considered that further research was required despite the conclusions of recent systematic reviews. An interim survey ranked the 50 questions, and the 10 main research priorities were identified from the top 32 questions by consensus at a final priority setting workshop of patients, carers and healthcare professionals using group discussions. CONCLUSIONS: A priority setting process using JLA methods and principles involving patients, carers and healthcare professionals was used to identify the top 10 priority areas for research related to HCAI. Basic, translational, clinical and public health research would be required to address these uncertainties.

Lower incidence of inappropriate shock therapy in patients with combined cardiac resynchronisation therapy defibrillators (CRT-D) compared with patients with non-CRT defibrillators (ICDs).

INTRODUCTION: A significant number of patients experience inappropriate shock therapy (IST) from implantable cardioverter-defibrillators (ICD). An increasing number of patients with advanced heart failure receive combined ICD and cardiac resynchronisation therapy devices (CRT-D). The incidence of IST in this group is less well described. We aimed to assess the incidence and predictors of IST in CRT-D patients. METHODS: A retrospective cohort study of prospectively collected data on patients who received an ICD and CRT-D between October 2007 and January 2009 at our institution were studied. The primary outcome measures were the IST event rate and all-cause mortality. RESULTS: A total of 185 patients with ICD/CRT-D (100/85) were included in the analysis. Eighteen patients experienced 35 episodes of IST during the follow-up (21 ± 13 months). There was a significantly lower IST cumulative event rate in the CRT-D vs. ICD group, 5% (CI: 1-13%) vs. 19% (95% CI: 11-30%) by 24 months, (p = 0.017). The majority of the IST was caused by atrial arrhythmias with atrial fibrillation accounting for 28 episodes of IST in nine patients. Multivariate analysis using Cox hazard model including baseline characteristics and coexisting appropriate shock therapy showed that a history of atrial fibrillation/flutter was the strongest independent predictor of IST with a hazard ratio of 3.53 (p = 0.019). CONCLUSION: Patients with CRT-D had a significantly lower incidence of IST compared with patients receiving an ICD. Given that atrial arrhythmia remained the commonest trigger for IST, our finding lends support to the hypothesis that CRT may reduce atrial fibrillation burden in patients receiving CRT-D.

Trends, indications and outcomes of cardiac implantable device system extraction: a single UK centre experience over the last decade.

BACKGROUND: The rising number of device implantation has seen a parallel in the rising numbers of lead extraction. Herein we have analysed our experience in cardiac device and lead extraction in a single tertiary centre over the last decade. METHOD: Retrospective analysis of all consecutive patients undergoing lead extractions performed between 2001 and 2010. Procedural success and complications as defined by the Heart Rhythm Society policy. RESULTS: A total of 745 leads were extracted with a procedural success of 98.9% [382 cases; partial success in 6.9% (26) cases] and failure in 1.1% (4). Major complication rate was 1% (four cases) and minor complication rate was 3.6%. By both univariate and multivariate analysis only duration of lead implantation was an indicator for success (p < 0.0001). The mean implantation time for failed lead extraction was 203 ± 64 months compared with 71.8 ± 16.5 months in the successful cohort (p < 0.0001). Laser-assisted extraction was required in 176 cases. With regard to extraction indication, lead malfunction/recall showed a significant increase during the study period (p = 0.03). On time trend analysis the rise in coronary sinus (CS) lead extraction over time was significant. (p = 0.02) Despite a trend for increased laser use over time this did not achieve statistical significance, p = 0.06. CONCLUSIONS: A decade's experience of percutaneous lead extraction suggests that a high procedural success rate with a low complication rate is achieved in a high-volume centre. During this time, an increase in both defibrillator and CS lead explantation and a rising trend in laser assistance with almost 50% of cases needing laser usage were observed.

Biophysical modeling to simulate the response to multisite left ventricular stimulation using a quadripolar pacing lead.

BACKGROUND: Response to cardiac resynchronization therapy (CRT) is reduced in patients with posterolateral scar. Multipolar pacing leads offer the ability to select desirable pacing sites and/or stimulate from multiple pacing sites concurrently using a single lead position. Despite this potential, the clinical evaluation and identification of metrics for optimization of multisite CRT (MCRT) has not been performed. METHODS: The efficacy of MCRT via a quadripolar lead with two left ventricular (LV) pacing sites in conjunction with right ventricular pacing was compared with single-site LV pacing using a coupled electromechanical biophysical model of the human heart with no, mild, or severe scar in the LV posterolateral wall. RESULT: The maximum dP/dt(max) improvement from baseline was 21%, 23%, and 21% for standard CRT versus 22%, 24%, and 25% for MCRT for no, mild, and severe scar, respectively. In the presence of severe scar, there was an incremental benefit of multisite versus standard CRT (25% vs 21%, 19% relative improvement in response). Minimizing total activation time (analogous to QRS duration) or minimizing the activation time of short-axis slices of the heart did not correlate with CRT response. The peak electrical activation wave area in the LV corresponded with CRT response with an R(2) value between 0.42 and 0.75. CONCLUSION: Biophysical modeling predicts that in the presence of posterolateral scar MCRT offers an improved response over conventional CRT. Maximizing the activation wave area in the LV had the most consistent correlation with CRT response, independent of pacing protocol, scar size, or lead location.

Male gender and chronic obstructive pulmonary disease predict a poor clinical response in patients undergoing cardiac resynchronisation therapy.

AIMS: Current guidelines advocate cardiac resynchronisation therapy (CRT) in patients with class III/IV New York Heart Association (NYHA) heart failure, depressed left ventricular function and a broad QRS. However, a significant proportion of patients do not derive any benefit from CRT. The aim of this study was to identify clinical, electrocardiographic and echocardiographic predictors of response to CRT. METHODS: A retrospective analysis of patients undergoing CRT in our institution was performed. A favourable clinical response to CRT was defined as an improvement in NYHA Heart failure class of ≥ 1 and lack of hospitalisation with heart failure. Comparisons were made between responders and non-responders in terms of baseline characteristics and potential predictors of CRT response (QRS width, presence of left bundle branch block, atrial fibrillation, evidence of mechanical dyssynchrony on echocardiography and LV lead position). RESULTS: A total of 164 patients had full follow-up data. The mean follow-up was 293 days. Of patients undergoing CRT, 90 (58.9%) had a favourable clinical response to CRT. Predictors of a lack of clinical response to CRT were male gender (p = 0.012) and chronic obstructive pulmonary disease (COPD) (0.008). Pre-implant echocardiographic dyssynchrony assessment appeared not to predict response to CRT (p = 0.87); however, there was a trend towards a positive response in those patients with significant dyssynchrony (p = 0.09) defined as interventricular delay > 40 ms or maximal LV delay of > 80 ms. CONCLUSION: Male gender and coexisting COPD were shown to be independent predictors of non-response to CRT in this cohort of patients fulfilling current criteria for CRT.

Increased mutability of Pseudomonas aeruginosa in biofilms.

OBJECTIVES: Isolates of Pseudomonas aeruginosa from cystic fibrosis (CF) patients are frequently hypermutable due to selection of mutants with defects in DNA repair genes such as mutS. Since P. aeruginosa grows as a biofilm within the infected CF lung, it is possible that this mode of growth enhances the mutability of the organism thereby increasing the opportunity to derive permanent hypermutators through mutation in DNA repair genes. We have now conducted experiments to examine this possibility. METHODS: Using established procedures, we examined the mutability of P. aeruginosa PA01 in planktonic cultures and in biofilm cultures generated by growth in a Sorbarod system. Transcriptional profiling by DNA microarray was used to compare gene expression in planktonic and biofilm cells. RESULTS: Mutation frequency determinations for resistance to rifampicin and ciprofloxacin demonstrated that biofilm cultures of P. aeruginosa displayed up to a 105-fold increase in mutability compared with planktonic cultures. Several genes (ahpC, katA, sodB and PA3529, a probable peroxidase) that encode enzymes conferring protection against oxidative DNA damage were down-regulated in biofilm cells. In particular, katA, which encodes the major pseudomonal antioxidant catalase, was down-regulated 7.7-fold. CONCLUSIONS: Down-regulation of antioxidant enzymes in P. aeruginosa biofilms may enhance the rate of mutagenic events due to the accumulation of DNA damage. Since P. aeruginosa forms biofilms in the CF lung, this mode of growth may enhance the direct selection of antibiotic-resistant organisms in CF patients and also increase the opportunity to derive permanent hypermutators thereby providing a further source of antibiotic-resistant mutants in the CF lung.

A DHA14 drug efflux gene from Xanthomonas albilineans confers high-level albicidin antibiotic resistance in Escherichia coli.

AIMS: Identification of a gene for self-protection from the antibiotic-producing plant pathogen Xanthomonas albilineans, and functional testing by heterologous expression. METHODS AND RESULTS: Albicidin antibiotics and phytotoxins are potent inhibitors of prokaryote DNA replication. A resistance gene (albF) isolated by shotgun cloning from the X. albilineans albicidin-biosynthesis region encodes a protein with typical features of DHA14 drug efflux pumps. Low-level expression of albF in Escherichia coli increased the MIC of albicidin 3000-fold, without affecting tsx-mediated albicidin uptake into the periplasm or resistance to other tested antibiotics. Bioinformatic analysis indicates more similarity to proteins involved in self-protection in polyketide-antibiotic-producing actinomycetes than to multi-drug resistance pumps in other gram-negative bacteria. A complex promoter region may co-regulate albF with genes for hydrolases likely to be involved in albicidin activation or self-protection. CONCLUSIONS: AlbF is the first apparent single-component antibiotic-specific efflux pump from a gram-negative antibiotic producer. It shows extraordinary efficiency as measured by resistance level conferred upon heterologous expression. SIGNIFICANCE AND IMPACT OF THE STUDY: Development of the clinical potential of albicidins as potent bactericidial antibiotics against diverse bacteria has been limited because of low yields in culture. Expression of albF with recently described albicidin-biosynthesis genes may enable large-scale production. Because albicidins are X. albilineans pathogenicity factors, interference with AlbF function is also an opportunity for control of the associated plant disease.

Metformin reduces C-reactive protein but not complement factor C3 in overweight patients with Type 2 diabetes mellitus.

AIMS: To determine the influence of metformin treatment on plasma C-reactive protein (CRP) and complement factor C3. METHODS: A double-blind, placebo-controlled trial of metformin in patients with poorly controlled Type 2 diabetes mellitus and body mass index > 25 kg/m2. CRP and C3 were analysed in stored plasma samples by in-house ELISAs. Patients attended two baseline visits before randomization and subsequently attended at 3, 6, 12 and 24 weeks post randomization. All patients gave informed consent according to a protocol approved by the Leeds Teaching Hospitals Research Ethics Committee. RESULTS: Baseline CRP in the patients randomized to placebo [1.33 (0.79, 2.25) mg/l] and metformin [1.24 (0.89, 1.71) mg/l] were similar (P = 0.8). Baseline CRP correlated with baseline C3 (r = 0.366) and HbA1c (r = 0.327). The difference in ratios of CRP levels at each visit to baseline between placebo- (n = 16) and metformin-treated (n = 26) subjects was significantly different at the 12-week (P = 0.002) and 24-week (P = 0.03) visits. The difference in CRP ratios between the two treatment groups remained significant after accounting for glycaemic control at both visits (P = 0.001 and P = 0.003, respectively). Baseline C3 was correlated with CRP. Baseline C3 was lower in the placebo-treated group [0.97 (0.88, 1.05) mg/ml] compared with the metformin-treated group [1.09 (1.02, 1.17) mg/ml, P = 0.03]. There was no difference in the mean change in C3 at any visit from baseline between placebo- and metformin-treated groups. CONCLUSION: Metformin may have a specific interaction with mechanisms involved in CRP synthesis or secretion, not directly related to improved insulin sensitivity and dampening of chronic inflammation.

Antimicrobial activity and mechanisms of resistance to cephalosporin P1, an antibiotic related to fusidic acid.

The antimicrobial properties of cephalosporin P1, an antibiotic structurally related to fusidic acid, were examined. Cephalosporin P1 exhibited potent activity against methicillin-sensitive Staphylococcus aureus, methicillin-resistant S. aureus and vancomycin-intermediate S. aureus. Mutants of S. aureus resistant to cephalosporin P1 arose with a frequency of 1.6 x 10(-6) for selections at 4 x MIC, a frequency similar to that for fusidic acid. The mutations conferred cross-resistance to fusidic acid and mapped in fusA, the gene encoding elongation factor G. Cross-resistance between cephalosporin P1 and fusidic acid also occurred for S. aureus fusA mutants selected with fusidic acid, and in fusidic acid-resistant clinical isolates. Plasmid pUB101, which mediates resistance to fusidic acid in S. aureus, also conferred resistance to cephalosporin P1. Escherichia coli was intrinsically resistant to both fusidic acid and cephalosporin P1, but deletion of the AcrAB efflux pump resulted in susceptibility to both antibiotics. Although complete cross-resistance between fusidic acid and cephalosporin P1 was demonstrated, the nature and location of fusA mutations in S. aureus when cephalosporin P1 was the selective agent frequently differed from those selected with fusidic acid. This may reflect differences in the interaction of the two antibiotics with the translational apparatus, which results in the selection of separate mutation classes for each antibiotic. Furthermore, in three of 14 mutants selected with fusidic acid, resistance was attributed to mutations lying outside fusA. In contrast, mutations in 10 mutants selected with cephalosporin P1 were all located in fusA.

Atrial flutter ablation: efficacy and cost-effectiveness of a single decapolar electrode to demonstrate bidirectional isthmus block.

AIMS: To evaluate whether a single decapolar electrode is a reliable and cost-effective substitute for the 'Halo' catheter to map the circuit and detect bidirectional isthmus block during atrial flutter (AFL) ablation. METHODS AND RESULTS: Twenty-four patients underwent AFL ablation by using the decapolar electrode in the infero-lateral wall of right atrium (group A) while a 'Halo' catheter was used in 11 patients (group B). Both groups had similar clinical characteristics. Anti-clockwise rotation (20 patients), clockwise (3 patients) or both forms of AFL (1 patient) were detected in group A. All patients in group B had anti-clockwise AFL. Bidirectional isthmus block was completed in 22 patients of group A and in 9 of group B (P=NS) while incomplete isthmus block was detected in 2 patients in each group (P=NS). Mean fluoroscopy and procedure time was 27 +/- 47 min, 107 +/- 36 min in group A and 14 +/- 19 min, 114 +/- 65 min in group B (P=NS). AFL relapsed in 3 patients of group A (follow-up 7 +/- 4 months) and in 2 of group B (4 +/- 2 months). CONCLUSION: A single decapolar electrode is a reliable method to map the circuit and demonstrate bidirectional isthmus block during AFL ablation. The cost of the decapolar electrode is a quarter of that of the 'Halo' catheter. This represents a significant saving particularly for centres with a substantial number of AFL ablations.