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.

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.

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.

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.

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.

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.

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.

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.

Cardiac rhythm and conduction before and after anatomic correction of transposition of the great arteries.

To assess pre- and postoperative arrhythmias associated with anatomic correction of transposition of the great arteries, 34 patients had 145 standard electrocardiograms (ECGs) and 24 of these patients had 46 24-hour ECGs from 11 months before to 54 months after anatomic repair. Twenty-two patients underwent balloon atrial septostomy and 7 surgical atrial septectomy before the initial 24-hour ECG. Anatomic correction included repair of a large ventricular septal defect in 16 patients and an aortopulmonary window in 1 patient. The preoperative standard ECG showed sinus rhythm in every patient. Preoperative 24-hour tapes revealed sinus arrhythmias in 2, sinus bradycardia at a rate of less than or equal to 50 beats/min in 1, junctional rhythm in 1 and rare premature ventricular contractions (PVCs) in 1. The postoperative 24-hour ECG showed atrioventricular dissociation in 1 patient, rare premature atrial contractions in 7, rare PVCs in 8 and sinus bradycardia with junctional escape in 1. Eight patients had PVCs on the postoperative ECG that were not noted on preoperative tapes. No patient had prolonged bradycardia (less than or equal to 50 beats/min), life-threatening arrhythmias or sudden death. Except for 1 patient with atrioventricular dissociation believed to be secondary to a preventable cause, 34 patients followed for 890 patient-months after anatomic correction for transposition of the great arteries had no significant arrhythmias.

The 24-hour heart rate behavior in long-term survivors of cardiac transplantation.

A detailed computerized analysis of heart rate (HR) behavior during ambulatory monitoring was performed in 19 long-term survivors of cardiac transplantation (12 orthotopic, 7 heterotopic) and in 10 normal volunteers. Compared with normal hearts, the transplanted denervated and the recipient innervated hearts in the heterotopic group showed higher average HRs over the whole 24 hours, the waking and sleeping periods. The rates of the denervated and the recipient hearts did not differ significantly. The maximal HR was similar in all 3 groups, but the minimal HR was lower in the normal hearts than in denervated and recipient hearts. The 24-hour RR interval variability was greatly reduced in the denervated hearts (60 +/- 22 ms) compared with the recipient (89 +/- 26 ms) and normal (151 +/- 38 ms) hearts. During arousal from sleep, the magnitude, time and rate of the HR change were significantly reduced in the denervated hearts compared with the innervated hearts and in the recipient compared with the normal hearts. These findings demonstrate that denervated hearts can show significant variations in HR during the 24-hour period, but to a lesser extent than normal hearts. The widest deviation from normal occurs during sleep, when the denervated heart shows minimal slowing probably due to lack of parasympathetic innervation. In heterotopic transplant recipients, the patients' own HR responses also are significantly blunted.

Iatrogenic atrioventricular bypass tract following a Fontan operation for tricuspid atresia.

A 16 year old female with tricuspid atresia had undergone a Fontan operation at four years of age. Two years later she first presented with a narrow complex tachycardia which could only be partially controlled on flecainide in high doses. On electrophysiological study, the tachycardia was found to be due to atrioventricular re-entry within the surgical right atrial to right ventricular outflow tract anastomosis. Radiofrequency ablation at this site abolished the arrhythmia and she is now symptom-free on no medication.

Unguarded tricuspid orifice with pulmonary atresia: successful radiofrequency ablation of an accessory pathway in an infant.

A male infant with the rare lesion of unguarded tricuspid orifice in the setting of pulmonary valve atresia, intact ventricular septum, and a hypoplastic right ventricle is described. The patient presented with cyanosis at 1 day old; transcutaneous oxygen saturations were between 20% and 30% in room air, and 60% in 100% inspired oxygen. Pre-excitation was found incidentally on the ECG and the potential for rapid antegrade conduction of atrial tachyarrhythmias, after eventual extended palliation with the Fontan procedure, was demonstrated at electrophysiological study. By 11 months old the patient was becoming increasingly cyanosed and interim palliation with a bidirectional cavopulmonary shunt was proposed. Successful radiofrequency ablation of the accessory pathway was performed before bidirectional cavopulmonary shunt, which would have prevented access to the heart via the superior vena cava. Difficulty with femoral venous access because of previous occlusion of a femoral vein was overcome by the use of 2 F pacing electrodes and a 5 F ablation catheter.

Laparoscopic sterilization with spring-loaded clips: double-puncture technique.

The application of a spring-loaded clip to each fallopian tube using a second-incision clip applicator is a safe and effective method of laparoscopic sterilization. The operation is quick and easy to perform and is suitable for use with local anesthesia. The method avoids the dangers of hemorrhage, for the clip only alters 3 mm of the fallopian tube and does not transect the tube or mesosalpinx. No pregnancies have followed the sterilization procedure. An intrauterine pregnancy has occurred after a reversal procedure in one patient.

PIP: 533 women undergoing laparoscopic sterilization were studied in an effort to determine the feasibility and safety of a second-puncture clip applicator. The operation was done on an outpatient or overnight basis and a choice of general or local anesthesia was offered. Results indicated that 97.7% of the cases were uncomplicated while 1.2% resulted in bowel perforation; .4% in hematoma and .7% in tubal ligation. None of the complications were due to clip or applicator design. 85% of the cases had no complaints while 5% of the patients experienced abdominal discomfort lasting 48 to 72 hours. This was the only side effect related to the procedure with a spring-loaded clip. No pregnancies occurred at the 6-month follow-up and 1 reanastomosis occurred supporting existing evidence about successful reversal after sterilization with a spring-loaded clip.

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.