Echocardiographic image collection and evaluation in infants with CHD: lessons learned from the imaging core lab for the Residual Lesion Score study.

Many factors affect patient outcome after congenital heart surgery, including the complexity of the heart disease, pre-operative status, patient specific factors (prematurity, nutritional status and/or presence of comorbid conditions or genetic syndromes), and post-operative residual lesions. The Residual Lesion Score is a novel tool for assessing whether specific residual cardiac lesions after surgery have a measurable impact on outcome. The goal is to understand which residual lesions can be tolerated and which should be addressed prior to leaving the operating room. The Residual Lesion Score study is a large multicentre prospective study designed to evaluate the association of Residual Lesion Score to outcomes in infants undergoing surgery for CHD. This Pediatric Heart Network and National Heart, Lung, and Blood Institute-funded study prospectively enrolled 1,149 infants undergoing 5 different congenital cardiac surgical repairs at 17 surgical centres. Given the contribution of echocardiographic measurements in assigning the Residual Lesion Score, the Residual Lesion Score study made use of a centralised core lab in addition to site review of all data. The data collection plan was designed with the added goal of collecting image quality information in a way that would permit us to improve our understanding of the reproducibility, variability, and feasibility of the echocardiographic measurements being made. There were significant challenges along the way, including the coordination, de-identification, storage, and interpretation of very large quantities of imaging data. This necessitated the development of new infrastructure and technology, as well as use of novel statistical methods. The study was successfully completed, but the size and complexity of the population being studied and the data being extracted required more technologic and human resources than expected which impacted the length and cost of conducting the study. This paper outlines the process of designing and executing this complex protocol, some of the barriers to implementation and lessons to be considered in the design of future studies.

A multicentre external quality assessment: A first step to standardise PCR protocols for the diagnosis of histoplasmosis and coccidioidomycosis.

BACKGROUND: In-house real-time PCR (qPCR) is increasingly used to diagnose the so-called endemic mycoses as commercial assays are not widely available. OBJECTIVES: To compare the performance of different molecular diagnostic assays for detecting Histoplasma capsulatum and Coccidioides spp. in five European reference laboratories. METHODS: Two blinded external quality assessment (EQA) panels were sent to each laboratory that performed the analysis with their in-house assays. Both panels included a range of concentrations of H. capsulatum (n = 7) and Coccidioides spp. (n = 6), negative control and DNA from other fungi. Four laboratories used specific qPCRs, and one laboratory a broad-range fungal conventional PCR (cPCR) and a specific cPCR for H. capsulatum with subsequent sequencing. RESULTS: qPCR assays were the most sensitive for the detection of H. capsulatum DNA. The lowest amount of H. capsulatum DNA detected was 1-4 fg, 0.1 pg and 10 pg for qPCRs, specific cPCR and broad-range cPCR, respectively. False positive results occurred with high concentrations of Blastomyces dermatitidis DNA in two laboratories and with Emergomyces spp. in one laboratory. For the Coccidioides panel, the lowest amount of DNA detected was 1-16 fg by qPCRs and 10 pg with the broad-range cPCR. One laboratory reported a false positive result by qPCR with high load of Uncinocarpus DNA. CONCLUSION: All five laboratories were able to correctly detect H. capsulatum and Coccidioides spp. DNA and qPCRs had a better performance than specific cPCR and broad-range cPCR. EQAs may help standardise in-house molecular tests for the so-called endemic mycoses improving patient management.

Harmonization of sensorimotor deficit assessment in a registered multicentre pre-clinical randomized controlled trial using two models of ischemic stroke.

Multicentre preclinical randomized controlled trials (pRCTs) are a valuable tool to improve experimental stroke research, but are challenging and therefore underused. A common challenge regards the standardization of procedures across centres. We here present the harmonization phase for the quantification of sensorimotor deficits by composite neuroscore, which was the primary outcome of two multicentre pRCTs assessing remote ischemic conditioning in rodent models of ischemic stroke. Ischemic stroke was induced by middle cerebral artery occlusion for 30, 45 or 60 min in mice and 50, 75 or 100 min in rats, allowing sufficient variability. Eleven animals per species were video recorded during neurobehavioural tasks and evaluated with neuroscore by eight independent raters, remotely and blindly. We aimed at reaching an intraclass correlation coefficient (ICC) ≥0.60 as satisfactory interrater agreement. After a first remote training we obtained ICC = 0.50 for mice and ICC = 0.49 for rats. Errors were identified in animal handling and test execution. After a second remote training, we reached the target interrater agreement for mice (ICC = 0.64) and rats (ICC = 0.69). In conclusion, a multi-step, online harmonization phase proved to be feasible, easy to implement and highly effective to align each centre's behavioral evaluations before project's interventional phase.

Design and Methodology of a Multi-Centre Clinical Trial of Low Dose Laser Cycloplasty for the Treatment of Malignant Glaucoma in China.

PURPOSE: To summarize the design and methodology of a trial designed to evaluate the efficacy and safety of low dose laser cycloplasty (LCP) in treating malignant glaucoma. METHODS: Prospective, multicentre, non-controlled clinical trial. Subjects were recruited from eight ophthalmic centers in China. The target sample size was 34. Patients aged >18 years with a clinical diagnosis of malignant glaucoma inadequately controlled on medical therapy or malignant glaucoma recurrence after topical cycloplegics withdrawal were enrolled. All patients underwent LCP under retrobulbar anesthesia or sub-Tenon anesthesia. LCP is a treatment adopting few laser points (1100-2000 mW energy, 2000 milliseconds duration) that cauterizes and remodels the ciliary body over two clock hour-positions, which may relieve the ciliary ring block. Follow-up is planned for a period of 12 months. The primary outcome is the resolution of malignant glaucoma which is defined as central anterior chamber deepening after LCP. CONCLUSION: The Malignant Glaucoma Treatment trial (MGTT) will be the first prospective trial providing evidence of a treatment for malignant glaucoma. It intends to provide clinicians an optional, easy and convenient treatment for malignant glaucoma patients. Detailed morphological and biometric information collected during the study period will also help provide experience for the outcomes of malignant glaucoma. TRIAL REGISTRATION NUMBER: ChiCTR1800017960.

Comparison of polyetheretherketone cables and stainless steel wires for sternal fixation after median sternotomy.

OBJECTIVE: To compare the sternal fixation effect of a polyetheretherketone (PEEK) cable product and stainless steel wire after median sternotomy. METHODS: A multicentre retrospective clinical trial was conducted in patients that underwent median sternotomy for a range of surgical reasons. The sternum was fixed using PEEK sternal cables in the experimental group and stainless steel wires in the control group. The general patient state, product manoeuvrability, bone and wound healing state and blood test results were evaluated at seven visits during the preoperative, surgical and follow-up periods. RESULTS: A total of 108 patients (54 in each group) were included in the analysis at the final 180-day follow-up. The sternum was successfully closed using PEEK cables or steel wires in all patients and all healed well. No pathological changes were found on the X-ray imaging. Computed tomography imaging confirmed ideal fracture healing. No significant difference was found between the experimental group and the control group in outcomes. CONCLUSION: PEEK cables are easy to implant and show desirable effectiveness in sternal fixation without any observed side-effects.

A multicentre confirmatory single-arm trial of the safety and efficacy of a transanal drain for prevention of anastomotic leakage after surgery for rectal cancer.

AIM: Recent reports have described the use and efficacy of several types of transanal tube (TAT) for preventing anastomotic leakage by reducing intraluminal pressure. The aim of this study was to evaluate the safety and efficacy of a newly developed TAT for the prevention of anastomotic leakage after low anterior resection (LAR) for rectal cancer. METHOD: A multicentre confirmatory single-arm trial was designed to evaluate the safety and efficacy of a new TAT after LAR for rectal cancer. A total of 115 patients were registered in the trial at several cancer centres and other hospitals. All patients initially received reconstruction with a stapled anastomosis, but 18 then underwent creation of a diverting stoma. Of the remaining 97 patients, the first 96 were included in the protocol-defined primary analysis set. The primary outcome was the incidence of symptomatic leakage and the secondary endpoint was the incidence of complications associated with use of the TAT. The TAT was placed during LAR without creating a covering stoma and the drain was removed 4 or 5 days postoperatively. RESULTS: The rate of symptomatic leakage was 5.2% (95% confidence interval 1.7-11.7), which was significantly lower than the predetermined threshold value of 15.8% (one-sided p-value 0.0013). Only one patient had Grade 3 rectal bleeding that might have been related to use of the TAT. CONCLUSION: This nonrandomized study shows that the TAT appears to be safe and results in lower rates of anastomotic leakage in LAR compared with previous studies.

Recommendations for Multicentre Clinical Trials Involving Dosimetry for Molecular Radiotherapy.

Multicentre clinical trials involving a dosimetry component are becoming more prevalent in molecular radiotherapy and are essential to generate the evidence to support individualised approaches to treatment planning and to ensure that sufficient patients are recruited to achieve the statistical significance required. Quality assurance programmes should be considered to support the standardisation required to achieve meaningful results. Trials should be designed to ensure that dosimetry results from image acquisition systems across centres are comparable by incorporating steps to standardise the methodologies used for the quantification of images and dosimetry. Furthermore, it is essential to assess the expertise and resources available at each participating site prior to trial commencement. A quality assurance plan should be drawn up and training provided if necessary. Standardisation of quantification and dosimetry methodologies used in a trial are essential to ensure that results from different centres may be collated. In addition, appropriate uncertainty analysis should be carried out to correct for differences in methodologies between centres. Recommendations are provided to support dosimetry studies based on the experience of several previous and ongoing multicentre trials.

Serum hepatitis B surface antigen correlates with fibrosis and necroinflammation: A multicentre perspective in China.

The kinetics of serum hepatitis B surface antigen (HBsAg) during the natural history of hepatitis B virus (HBV) infection has been studied, but the factors affecting them remain unclear. We aimed to investigate the factors affecting HBsAg titres, using data from multicentre, large-sized clinical trials in China. The baseline data of 1795 patients in 3 multicentre trials were studied, and the patients were classified into 3 groups: hepatitis B early antigen (HBeAg)-positive chronic HBV infection (n = 588), HBeAg-positive chronic hepatitis B (n = 596), and HBeAg-negative chronic hepatitis B (n = 611). HBsAg titres in the different phases were compared, and multiple linear progression analyses were performed to investigate the implicated factors. HBsAg titres varied significantly in different phases (P = .000), with the highest (4.60 log10 IU/mL [10%-90% confidence interval: 3.52 log10 IU/mL-4.99 log10 IU/mL]) in patients with HBeAg-positive chronic HBV infection. In all phases, age and HBV DNA were correlated with serum HBsAg level. In HBeAg-positive chronic hepatitis B patients, a negative correlation between HBsAg titres and fibrosis stage was observed. Alanine amonitransferase or necroinflammatory activity was also correlated with HBsAg titres in HBeAg-negative chronic hepatitis B patients. In conclusion, decreased HBsAg titres may be associated with advancing fibrosis in HBeAg-positive chronic hepatitis B patients or increased necroinflammation in those with HBeAg-negative chronic hepatitis B. Our findings may help clinicians better understand the kinetics of HBsAg and provide useful insights into the management of this disease.

Cardiac Function Improvement and Bone Marrow Response -: Outcome Analysis of the Randomized PERFECT Phase III Clinical Trial of Intramyocardial CD133+ Application After Myocardial Infarction.

OBJECTIVE: The phase III clinical trial PERFECT was designed to assess clinical safety and efficacy of intramyocardial CD133+ bone marrow stem cell treatment combined with CABG for induction of cardiac repair. DESIGN: Multicentre, double-blinded, randomised placebo controlled trial. SETTING: The study was conducted across six centres in Germany October 2009 through March 2016 and stopped due slow recruitment after positive interim analysis in March 2015. PARTICIPANTS: Post-infarction patients with chronic ischemia and reduced LVEF (25-50%). INTERVENTIONS: Eighty-two patients were randomised to two groups receiving intramyocardial application of 5ml placebo or a suspension of 0.5-5×106 CD133+. OUTCOME: Primary endpoint was delta (∆) LVEF at 180days (d) compared to baseline measured in MRI. FINDINGS (PRESPECIFIED): Safety (n=77): 180d survival was 100%, MACE n=2, SAE n=49, without difference between placebo and CD133+. Efficacy (n=58): The LVEF improved from baseline LVEF 33.5% by +9.6% at 180d, p=0.001 (n=58). Treatment groups were not different in ∆LVEF (ANCOVA: Placebo +8.8% vs. CD133+ +10.4%, ∆CD133+vs placebo +2.6%, p=0.4). FINDINGS (POST HOC): Responders (R) classified by ∆LVEF≥5% after 180d were 60% of the patients (35/58) in both treatment groups. ∆LVEF in ANCOVA was +17.1% in (R) vs. non-responders (NR) (∆LVEF 0%, n=23). NR were characterized by a preoperative response signature in peripheral blood with reduced CD133+ EPC (RvsNR: p=0.005) and thrombocytes (p=0.004) in contrast to increased Erythropoeitin (p=0.02), and SH2B3 mRNA expression (p=0.073). Actuarial computed mean survival time was 76.9±3.32months (R) vs. +72.3±5.0months (NR), HR 0.3 [Cl 0.07-1.2]; p=0.067.Using a machine learning 20 biomarker response parameters were identified allowing preoperative discrimination with an accuracy of 80% (R) and 84% (NR) after 10-fold cross-validation. INTERPRETATION: The PERFECT trial analysis demonstrates that the regulation of induced cardiac repair is linked to the circulating pool of CD133+ EPC and thrombocytes, associated with SH2B3 gene expression. Based on these findings, responders to cardiac functional improvement may be identified by a peripheral blood biomarker signature. TRIAL REGISTRATION: ClinicalTrials.govNCT00950274.

North American trial results at 1 year with the Sorin Freedom SOLO pericardial aortic valve.

OBJECTIVES: A North American prospective, 15-centre Food and Drug Administration (FDA) valve trial was designed to assess the safety and effectiveness of the Freedom SOLO stentless pericardial aortic valve in the treatment of surgical aortic valve disease. METHODS: Beginning in 2010, 251 patients (mean: 74.7 ± 7.5 years), were recruited in the Freedom SOLO aortic valve trial. One hundred eighty-nine patients have been followed for at least 1 year and are the basis for this review. Preoperatively, 54% of patients had NYHA functional class III or IV symptoms, and the majority of patients had a normal ejection fraction (EF) (median EF = 61%). Concomitant procedures were performed in 61.9% of patients, with coronary artery bypass grafting (CABG) (48.7%) being the most common followed by a MAZE procedure (13.7%). Reoperations were performed in 8.5% of patients in the study. RESULTS: The entire cohort of 251 patients enrolled had 7 deaths prior to 30 days, 2 of which were valve-related (aspiration pneumonia and sudden death) and 5 were not valve-related. There were 11 deaths after 30 days, 1 valve-related (unknown cardiac death) and 10 not valve-related. Five valves were explanted, 3 early (endocarditis, acute insufficiency and possible root dissection) and 2 late (endocarditis). Thirty-day adverse events include arrhythmias requiring permanent pacemaker (4.2%), thromboembolic events (3.7%) and thrombocytopenia (7.4%). One-year follow-up of all 189 patients demonstrated mean gradients for valve sizes 19, 21, 23, 25 and 27 mm of 11.7, 7.8, 6.3, 4.6 and 5.0 mmHg, respectively. Effective orifice areas for the same valve sizes were 1.2, 1.3, 1.6, 1.8 and 1.9 cm(2), respectively. Ninety-six percent of patients (181/189) were in NYHA class I or II at the 1-year follow-up. CONCLUSIONS: The Freedom SOLO stentless pericardial aortic valve demonstrated excellent haemodynamics and a good safety profile out to the 1 year of follow-up.

Effectiveness of hexaminolevulinate fluorescence cystoscopy for the diagnosis of non-muscle-invasive bladder cancer in daily clinical practice: a Spanish multicentre observational study.

OBJECTIVE: To assess the sensitivity and specificity of blue-light cystoscopy (BLC) with hexaminolevulinate as an adjunct to white-light cystoscopy (WLC) vs WLC alone for the detection of non-muscle-invasive bladder cancer (NMIBC), in routine clinical practice in Spain. PATIENTS AND METHOD: An intra-patient comparative, multicentre, prospective, observational study. Adults with suspected or documented primary or recurrent NMIBC at eight Spanish centres were included in the study. All patients were examined with WLC followed by BLC with hexaminolevulinate. We evaluated the detection rate of bladder cancer lesions by WLC and BLC with hexaminolevulinate, overall and by tumour stage and compared with histological examination of the biopsied lesions. Sensitivity and specificity was calculated. RESULTS: In all, 1,569 lesions were identified from 283 patients: 621 were tumour lesions according to histology and 948 were false-positives. Of the 621 tumour lesions, 475 were detected by WLC (sensitivity 76.5%, 95% confidence interval [CI] 73.2-79.8) and 579 were detected by BLC (sensitivity 93.2%, 95% CI 91.0-95.1; P < 0.001). There was a significant improvement in the sensitivity in the detection of all types of NMIBC lesions with BLC compared with WLC. Of 219 patients with tumours, 188 had NMIBC [highest grade: carcinoma in situ (CIS), n = 36; Ta, n = 87; T1, n = 65). CIS lesions were identified more with BLC (n = 27) than with WLC [n = 19; sensitivity: BLC 75.0% (95% CI 57.8-87.9) vs WLC 52.8% (95% CI 35.5-69.6); P = 0.021]. Results varied across centres. CONCLUSIONS: This study shows that improvement in diagnosis of NMIBC, mainly CIS and Ta tumours, obtained with BLC with hexaminolevulinate as an adjunct to WLC vs WLC alone can be shown in routine clinical practice.

A multicentre randomized trial of combined individual and telephone counselling for smoking cessation.

OBJECTIVE: The present study assessed the effectiveness of smoking cessation programs combining individual and telephone counselling, compared to individual or telephone counselling alone. METHOD: A randomized, multicentre, open-label trial was performed between January 2009 and July 2011 at six smoking cessation clinics in Spain. Of 772 smokers assessed for eligibility, 600 (77%) met inclusion criteria and were randomized. Smokers were randomized to receive individual counselling, combined telephone and individual counselling, or telephone counselling. The primary outcome was biochemically validated continuous abstinence at 52 weeks. RESULTS: The 52-week abstinence rate was significantly lower in the telephone group compared to the combined group (20.1% vs. 29.0%; OR, 1.32; 95% CI, 1.1-2.7) and to the individual counselling group (20.1% vs. 27.9%; OR, 1.37; 95% CI, 1.0-2.8). The 52-week abstinence rates were not significantly higher in the combined group than the individual group (OR, 0.97; 95% CI, 0.7-1.4). CONCLUSION: Individual counselling and combined individual and telephone counselling were associated with higher 52-week abstinence rates than telephone counselling alone. A combined approach may be highly useful in the clinical treatment of smokers, as it involves less clinic visits than individual counselling alone, thus reducing the program cost, and it increases patient compliance compared to telephone counselling alone.