Randomized Cluster Crossover Trials for Reliable,Efficient, Comparative Effectiveness Testing: Design of the Prevention of Arrhythmia Device Infection Trial (PADIT)

Randomized clinical trials are a major advance in clinical research methodology. However, there are myriad important questions about the effectiveness of treatments used in daily practice that are not informed by the results of randomized trials. This is in part because of important limitations inherent in the methodology of randomized efficacy trials which are performed with tight control of inclusion, exclusion, treatment, and follow-up. This approach enhances evaluation of clinical efficacy (performance in controlled situations) but increases complexity and is not well suited to test clinical effectiveness (performance under conditions of actual use). The cluster crossover trial is a new concept for efficient comparative effectiveness testing. Deep tissue infection occurs in 2% of patients after arrhythmia device implantation, usually requires system extraction, and increases mortality. There is variation in antibiotic prophylaxis used to reduce implanted device infections. To efficiently evaluate the comparative effectiveness of antibiotic strategies now in use, we designed a cluster crossover clinical trial, which randomized implanting centres to 1 of 2 prophylactic antibiotic strategies, which became the standard care at the centre for 6 months, followed by crossover to the other strategy, rerandomization, and second crossover. This method greatly reduces trial complexity because it aligns study procedures with usual clinical care and increases generalizability. Pilot studies have tested the feasibility and an 10,800-patient trial, funded by the Canadian Institutes of Health Research, is now under way. The cluster crossover randomized trial design is well suited to efficiently test comparative effectiveness of existing treatments where there is variability of practice, clinical equipoise, and minimal risk.     

Palytoxins and cytoskeleton: An overview

Cytoskeleton is a dynamic structure essential for a wide variety of normal cellular processes, including the maintenance of cell shape and morphology, volume regulation, membrane dynamics and signal transduction. Cytoskeleton is organized into microtubules, actin meshwork and intermediate filaments. Actin has been identified as a major target for destruction during apoptosis and is also important under pathological conditions such as cancers.Several natural compounds actively modulate actin organization by specific signaling cascades being useful tools to study cytoskeleton dynamics.Palytoxin is a large bioactive compound, first isolated from zoanthids, with a complex structure and different analogs such as ostreocin-D or ovatoxin-a. This toxin has been identified as a potent tumor promoter and cytotoxic molecule, which leads to actin filament distortion and triggers cell death or apoptosis. In this review we report the findings on the involvement of palytoxin and analogues modulating the actin cytoskeleton within different cellular models.     

Device to Provide Intuitive Assistance in Laparoscope Holding

This work proposes a new navigation device which autonomously handles the laparoscope, with a view to reducing latency and adjusting optics in real time. The system designed is an intuitive mechatronic device with three degrees of freedom and a sole active articulation. The device uses the point of insertion as the invariant point for navigation and has a work space that closely resembles an inverted cone.     

Long-term results of two consecutive trials in childhood acute lymphoblastic leukaemia performed by the Spanish Cooperative Group for Childhood Acute Lymphoblastic Leukemia Group (SHOP) from 1989 to 1998

INTRODUCTION: The first multi-centric protocol for childhood acute lymphoblastic leukaemia (ALL) treatment in Spain started in 1989 and was conducted by the Spanish Pediatric Hematology and Oncology Societies. MATERIALS AND METHODS: A total of 673 patients were included in two consecutive trials, SHOP-89 (1989-1993) and SHOP- 94 (1994-1998). Approximately 67% of the children diagnosed with ALL in Spain during this period were enrolled in these trials. The 250 eligible patients enrolled in the SHOP- 89 study were stratified to either a standard or a high-risk group. Therapy schedule was based on the central nervous system (CNS) therapy designed by St Jude CRH and the Children's Cancer Group, and the post-induction intensification developed by the BFM group. In the SHOP-94 study, a further high-risk group was included in the stratification of the 423 enrolled patients. The therapeutic protocol was characterised by intensification of systemic chemotherapy and the administration of cranial radiotherapy only to patients at high risk of relapse or with CNS involvement at diagnosis. RESULTS: Event-free survival (EFS) increased from 0.57+/- 0.03 at 15 years in SHOP-89, to 0.68+/-0.03 at 11 years in SHOP-94 (p=0.01). Relapse rate decreased from SHOP-89 to SHOP-94: 0.38 vs. 0.25 (p=0.01). CNS relapse rate was 9.1% in SHOP-89 and 4.6% in SHOP-94 (p=0.001). EFS in patients with T-immunophenotype was 0.40+/-0.08 in SHOP-89 and 0.44+/-0.06 in SHOP-94 (p=ns). CONCLUSIONS: Our therapeutic results evidence a significant improvement in EFS and systemic and CNS relapse rates among the two consecutive trials after modification of patient stratification and intensification of systemic chemotherapy.     

Obesity and other health determinants across Europe: the EURALIM project

STUDY OBJECTIVE: EURALIM (EURope ALIMentation), a European collaborative study, aimed to determine and describe the extent to which European data on risk factor distributions from different populations could be pooled and harmonised in a common database for international comparisons. SETTING: Seven independent population-based surveys from six European countries (France, Italy, Northern Ireland/United Kingdom, Spain, Switzerland, the Netherlands). METHODS: Data for 18 381 women and 12 908 men aged 40-59 were pooled in a common database. Central statistical analyses on major cardiovascular risk factors were conducted with careful consideration of methodological issues, including differences in study designs, data assessment tools, and analytic techniques used. MAIN RESULTS: Because of the detected variability among methods used, direct comparisons of risk factor distributions and prevalences between studies were problematic. None the less, comparisons of within population contrasts by sex, age group, and other health determinants were considered to be meaningful and apt, as illustrated here for obesity. Results were targeted and disseminated to both the general public and public health professionals and framed in the context of a European information campaign. CONCLUSIONS: International and national comparisons between existing locally run studies are feasible and useful, but harmonisation methods need improvement. Development of an international risk factor surveillance programme based on decentralised data collection is warranted. In the meantime, risk factor contrasts across populations can be used as a basis for targeting needed public health intervention programmes.     

Dietary patterns in six european populations: results from EURALIM, a collaborative European data harmonization and information campaign

OBJECTIVE: To determine and describe the extent to which European dietary data collected in disparate surveys can be meaningfully compared. DESIGN: Seven independent population-based surveys from six European countries were initially included. Differences in study designs and methodological approaches were examined. Risk factor data for 31,289 adults aged 40-59 y were harmonized and pooled in a common, centralized database. RESULTS: Direct comparisons of dietary measures across studies were not deemed appropriate due to methodological heterogeneity. Nonetheless, comparisons of intra-population contrasts by gender across sites were considered valid. Women consumed fruit and vegetables more often than men. Age-standardized gender differences in the prevalence of low fruit and vegetable consumption ranged from 7 to 18% and 5 to 15%, respectively. Data on energy intake showed good agreement across study populations. The proportion of total energy from macronutrients was similar for women and men. Gender differences for relative intakes of saturated fatty acids (percentage energy) were small and only in France were they significant. Dietary fibre density was significantly higher in women than in men. Overall, the participating Southern European populations from Italy and Spain exhibited more healthful food composition patterns. CONCLUSIONS: Contrasts in dietary patterns by gender across populations may provide the basis for health promotion campaigns. The most favourable patterns observed may serve as attainable goals for other populations. An international risk factor surveillance programme based upon locally run, good quality studies has the potential to provide the needed data. SPONSORSHIP: European Community (DG V), project 96CVVF3-446-0; Swiss Federal Office for Education and Science, OFES 96.0089.     

Surface coil magnetic resonance imaging of the normal larynx

The use of specialized surface coils has made it possible to obtain high-signal, high-resolution magnetic resonance (MR) images of the neck. We describe the normal anatomy of the larynx imaged with surface coils and a technique adapted from respiratory gating to reduce motion from swallowing and coughing. Compared with computed tomography, MR has superior discrimination of tissues that on computed tomography appear to be of similar density. The intrinsic laryngeal muscles and carotid sheath are well seen. Multiplanar imaging capability allows easy distinction of false and true cords and optimal evaluation of the preepiglottic and paralaryngeal spaces. Computed tomography is easier to perform than MR and is superior to MR in depicting the laryngeal cartilages. However, with improved technology, MR may become the imaging modality of choice in evaluation of the larynx and adjacent hypopharynx and subglottic regions.     

Autonomic microganglia of the nasal mucosa and their relation to vasomotor rhinitis

The classical concept of the autonomic innervation of the nasal mucosa states that the postganglionic sympathetic neurones lie in the superior cervical ganglion and those of the postganglionic parasympathetic neurones are in the pterygopalatine ganglion. We have carried out a study of the fine structure of the respiratory nasal mucosa in man and in the cat using the techniques described by Jabonero, Champy Maillet and Koelle-Friedenwald. The most striking finding was the presence of microganglia deep within the mucosa of the inferior turbinate close to the glands. These microganglia were cholinergic in nature since they demonstrated a positive reaction to anticholinesterase. From this we deduce that the nasal parasympathetic pathway has its postganglionic neurones not only in the pterygopalatine ganglion but also in these microganglia of the inferior turbinate. Each of four groups of cats were submitted to different techniques, including administration of neostigmine, inferior turbinectomy and Vidian neurectomy. Resection of the microganglia by means of turbinectomy reduced the hypersecretion caused by neostigmine and this was most noticeable when a Vidian neurectomy was carried out in addition.     

HIV-1 subtype J recombinant viruses in Spain

Genetic characterization of HIV-1 was carried out in two women who originated in Cameroon and Equatorial Guinea, respectively, and who were diagnosed more recently as HIV-1 seropositive in Madrid, Spain. Phylogenetic studies showed that the protease-encoding gene from both individuals clustered with subtype J sequences with a high bootstrap. However, env sequences clustered with subtypes A and C, respectively. This work represents the first characterization of HIV-1 containing subtype J-like genomic regions in Spain.