Referral from primary care to a physical activity programme: establishing long-term adherence? A randomized controlled trial. Rationale and study design

Background: Declining physical activity is associated with a rising burden of global disease. There is little evidence about effective ways to increase adherence to physical activity. Therefore, interventions are needed that produce sustained increases in adherence to physical activity and are cost-effective. The purpose is to assess the effectiveness of a primary care physical activity intervention in increasing adherence to physical activity in the general population seen in primary care. Method and design: Randomized controlled trial with systematic random sampling. A total of 424 subjects of both sexes will participate; all will be over the age of 18 with a low level of physical activity (according to the International Physical Activity Questionnaire, IPAQ), self-employed and from 9 Primary Healthcare Centres (PHC). They will volunteer to participate in a physical activity programme during 3 months (24 sessions; 2 sessions a week, 60 minutes per session). Participants from each PHC will be randomly allocated to an intervention (IG) and control group (CG). The following parameters will be assessed pre and post intervention in both groups: (1) health-related quality of life (SF-12), (2) physical activity stage of change (Prochaska's stages of change), (3) level of physical activity (IPAQ-short version), (4) change in perception of health (vignettes from the Cooperative World Organization of National Colleges, Academies, and Academic Associations of Family Physicians, COOP/WONCA), (5) level of social support for the physical activity practice (Social Support for Physical Activity Scale, SSPAS), and (6) control based on analysis (HDL, LDL and glycated haemoglobin).Participants' frequency of visits to the PHC will be registered over the six months before and after the programme. There will be a follow up in a face to face interview three, six and twelve months after the programme, with the reduced version of IPAQ, SF-12, SSPAS, and Prochaska's stages. Discussion: The pilot study showed the effectiveness of an enhanced low-cost, evidence-based intervention in increased physical activity and improved social support. If successful in demonstrating long-term improvements, this randomised controlled trial will be the first sustainable physical activity intervention based in primary care in our country to demonstrate longterm adherence to physical activity. Trial Registration: A service of the U.S. National Institutes of Health. Developed by the National Library of Medicine. ClinicalTrials.gov ID: NCT00714831.

Maximum likelihood Linear Programming Data Fusion for Speaker Recognition

Biometric system performance can be improved by means of data fusion. Several kinds of information can be fused in order to obtain a more accurate classification (identification or verification) of an input sample. In this paper we present a method for computing the weights in a weighted sum fusion for score combinations, by means of a likelihood model. The maximum likelihood estimation is set as a linear programming problem. The scores are derived from a GMM classifier working on a different feature extractor. Our experimental results assesed the robustness of the system in front a changes on time (different sessions) and robustness in front a change of microphone. The improvements obtained were significantly better (error bars of two standard deviations) than a uniform weighted sum or a uniform weighted product or the best single classifier. The proposed method scales computationaly with the number of scores to be fussioned as the simplex method for linear programming.

The Effect of a Physical Activity Program on the Total Number of Primary Care Visits in Inactive Patients: A 15-Month Randomized Controlled Trial

Abstract Background: Effective promotion of exercise could result in substantial savings in healthcare cost expenses in terms of direct medical costs, such as the number of medical appointments. However, this is hampered by our limited knowledge of how to achieve sustained increases in physical activity. Objectives: To assess the effectiveness of a Primary Health Care (PHC) based physical activity program in reducing the total number of visits to the healthcare center among inactive patients, over a 15-month period. Research Design: Randomized controlled trial. Subjects: Three hundred and sixty-two (n = 362) inactive patients suffering from at least one chronic condition were included. One hundred and eighty-three patients (n = 183; mean (SD); 68.3 (8.8) years; 118 women) were randomly allocated to the physical activity program (IG). One hundred and seventy-nine patients (n = 179; 67.2 (9.1) years; 106 women) were allocated to the control group (CG). The IG went through a three-month standardized physical activity program led by physical activity specialists and linked to community resources. Measures: The total number of medical appointments to the PHC, during twelve months before and after the program, was registered. Self-reported health status (SF-12 version 2) was assessed at baseline (month 0), at the end of the intervention (month 3), and at 12 months follow-up after the end of the intervention (month 15). Results: The IG had a significantly reduced number of visits during the 12 months after the intervention: 14.8 (8.5). The CG remained about the same: 18.2 (11.1) (P = .002). Conclusions: Our findings indicate that a 3-month physical activity program linked to community resources is a shortduration, effective and sustainable intervention in inactive patients to decrease rates of PHC visits. Trial Registration: ClinicalTrials.gov NCT00714831

Optimal CD8 T cell responsiveness is controlled within a defined TCR affinity window

Protective immune responses relyon TCR-mediated recognition of antigenspresented by MHC molecules. Tcells directed against tumor antigensare thought to express TCRs of loweraffinity/avidity than pathogen-specificT lymphocytes. An attractivestrategy to improve anti-tumor T cellresponses is to adoptively transferCD8+ T cells engineered with TCRsof optimized affinity. However, themechanisms that control optimal Tcell activation and responsiveness remainpoorly defined. We aim at characterizingTCR-pMHC binding parametersand downstream signalingevents that regulate T cell functionalityby using an in silico designedpanel of tumor antigen-specific TCRsof incremental affinity for pMHC(Kd100 M- 15 nM).We found that optimalT cell responses (cytokine secretionand target cell killing) occurredwithin a well-defined window ofTCR-pMHC binding affinity (5 M-1 M), while drastic functional declinewas detected in T cells expressingvery low and very high TCRaffinities,which was not caused by any increasein apoptosis. Whole-genomemicroarray analysis revealed that Tcells with optimal TCR affinitieshighly up-regulated transcription ofgenes typical of T cell activation (i.e.IFN-, NF-B and TNFR), while reducedexpression was detected in Tcells of very low or very high TCR affinity.Strikingly, hierarchical clusteringshowed that the latter two variantsclustered together with the un-stimulatedcontrol Tcells.Yet, despite commonclustering, several genes seemedto be differentially expressed, suggestingthat the mechanisms involvedin this "unresponsiveness state" maydiffer between those two variants. Finally,calcium influx assays also demonstratedattenuated responses in Tcells of very high TCR affinity. Ourresults indicate that optimal T cellfunction is tightly controlled within adefinedTCRaffinity window throughvery proximal TCR-mediated mechanisms,possibly at the TCR-pMHCbinding interface. Uncovering themechanisms regulating optimal/maximalT cell function is essential to understandand promote therapeutic designlike adoptive T cell therapy.

A randomised controlled clinical trial and gait analysis of fixed- and mobile-bearing total knee replacements with a five-year follow-up.

This study compared the outcome of total knee replacement (TKR) in adult patients with fixed- and mobile-bearing prostheses during the first post-operative year and at five years' follow-up, using gait parameters as a new objective measure. This double-blind randomised controlled clinical trial included 55 patients with mobile-bearing (n = 26) and fixed-bearing (n = 29) prostheses of the same design, evaluated pre-operatively and post-operatively at six weeks, three months, six months, one year and five years. Each participant undertook two walking trials of 30 m and completed the EuroQol questionnaire, Western Ontario and McMaster Universities osteoarthritis index, Knee Society score, and visual analogue scales for pain and stiffness. Gait analysis was performed using five miniature angular rate sensors mounted on the trunk (sacrum), each thigh and calf. The study population was divided into two groups according to age (≤ 70 years versus > 70 years). Improvements in most gait parameters at five years' follow-up were greater for fixed-bearing TKRs in older patients (> 70 years), and greater for mobile-bearing TKRs in younger patients (≤ 70 years). These findings should be confirmed by an extended age controlled study, as the ideal choice of prosthesis might depend on the age of the patient at the time of surgery.

A randomised controlled pilot study comparing Mepitel(®) and SurfaSoft(®) on paediatric donor sites treated with Recell(®).

This randomized controlled pilot study examined the effects of a silicone net dressing (Mepitel(®)) and a monofilament polyamide woven dressing (SurfaSoft(®)) on the rate of epithelialisation and epidermal maturation, pain, and ease of dressing removal on paediatric donor sites treated with epithelial cell suspension (ReCell(®)). Fifteen children (1-15 years) admitted for acute or reconstructive burns procedures in a tertiary referral hospital in Australia were randomly assigned to the experimental group, Mepitel(®) (n=8) and to the control group, SurfaSoft(®) (n=7). All donor sites were treated with ReCell(®) and covered with the assigned dressing. Measurements of rate of epithelialisation and epidermal maturation, pain, and ease of dressing removal were recorded every two days until the wound was healed. Results showed that there was no difference in the rate of epidermal maturation between the two groups. Less pain and force to remove the dressing was shown in the Mepitel(®) group when compared to SurfaSoft(®). The rate of epithelialisation was found to be an unreliable measure. Although additional research is required to support the results of this study, these results suggest that Mepitel's(®) pliable, self-adhesive and atraumatic properties may improve healing of ReCell(®) treated donor sites with less pain at dressing changes. This pilot study provides a strong base for further research in this area.

Efficacy and safety of a phospholipid emulsion (GR270773) in Gram-negative severe sepsis: results of a phase II multicenter, randomized, placebo-controlled, dose-finding clinical trial.

OBJECTIVE: To assess the survival benefit and safety profile of low-dose (850 mg/kg) and high-dose (1350 mg/kg) phospholipid emulsion vs. placebo administered as a continuous 3-day infusion in patients with confirmed or suspected Gram-negative severe sepsis. Preclinical and ex vivo studies show that lipoproteins bind and neutralize endotoxin, and experimental animal studies demonstrate protection from septic death when lipoproteins are administered. Endotoxin neutralization correlates with the amount of phospholipid in the lipoprotein particles. DESIGN: A three-arm, randomized, blinded, placebo-controlled trial. SETTING: Conducted at 235 centers worldwide between September 2004 and April 2006. PATIENTS: A total of 1379 patients participated in the study, 598 patients received low-dose phospholipid emulsion, and 599 patients received placebo. The high-dose phospholipid emulsion arm was stopped, on the recommendation of the Independent Data Monitoring Committee, due to an increase in life-threatening serious adverse events at the fourth interim analysis and included 182 patients. MEASUREMENTS AND MAIN RESULTS: A 28-day all-cause mortality and new-onset organ failure. There was no significant treatment benefit for low- or high-dose phospholipid emulsion vs. placebo for 28-day all-cause mortality, with rates of 25.8% (p = .329), 31.3% (p = .879), and 26.9%, respectively. The rate of new-onset organ failure was not statistically different among groups at 26.3%, 31.3%, 20.4% with low- and high-dose phospholipid emulsion, and placebo, respectively (one-sided p = .992, low vs. placebo; p = .999, high vs. placebo). Of the subjects treated, 45% had microbiologically confirmed Gram-negative infections. Maximal changes in mean hemoglobin levels were reached on day 10 (-1.04 g/dL) and day 5 (-1.36 g/dL) with low- and high-dose phospholipid emulsion, respectively, and on day 14 (-0.82 g/dL) with placebo. CONCLUSIONS: Treatment with phospholipid emulsion did not reduce 28-day all-cause mortality, or reduce the onset of new organ failure in patients with suspected or confirmed Gram-negative severe sepsis.

Disc degeneration: current surgical options.

Chronic low back pain attributed to lumbar disc degeneration poses a serious challenge to physicians. Surgery may be indicated in selected cases following failure of appropriate conservative treatment. For decades, the only surgical option has been spinal fusion, but its results have been inconsistent. Some prospective trials show superiority over usual conservative measures while others fail to demonstrate its advantages. In an effort to improve results of fusion and to decrease the incidence of adjacent segment degeneration, total disc replacement techniques have been introduced and studied extensively. Short-term results have shown superiority over some fusion techniques. Mid-term results however tend to show that this approach yields results equivalent to those of spinal fusion. Nucleus replacement has gained some popularity initially, but evidence on its efficacy is scarce. Dynamic stabilisation, a technique involving less rigid implants than in spinal fusion and performed without the need for bone grafting, represents another surgical option. Evidence again is lacking on its superiority over other surgical strategies and conservative measures. Insertion of interspinous devices posteriorly, aiming at redistributing loads and relieving pain, has been used as an adjunct to disc removal surgery for disc herniation. To date however, there is no clear evidence on their efficacy. Minimally invasive intradiscal thermocoagulation techniques have also been tried, but evidence of their effectiveness is questioned. Surgery using novel biological solutions may be the future of discogenic pain treatment. Collaboration between clinicians and basic scientists in this multidisciplinary field will undoubtedly shape the future of treating symptomatic disc degeneration.

JARID2 is a direct target of the PAX3-FOXO1 fusion protein and inhibits myogenic differentiation of rhabdomyosarcoma cells.

Rhabdomyosarcomas (RMS) are the most frequent soft-tissue sarcoma in children and characteristically show features of developing skeletal muscle. The alveolar subtype is frequently associated with a PAX3-FOXO1 fusion protein that is known to contribute to the undifferentiated myogenic phenotype of RMS cells. Histone methylation of lysine residues controls developmental processes in both normal and malignant cell contexts. Here we show that JARID2, which encodes a protein known to recruit various complexes with histone-methylating activity to their target genes, is significantly overexpressed in RMS with PAX3-FOXO1 compared with the fusion gene-negative RMS (t-test; P < 0.0001). Multivariate analyses showed that higher JARID2 levels are also associated with metastases at diagnosis, independent of fusion gene status and RMS subtype (n = 120; P = 0.039). JARID2 levels were altered by silencing or overexpressing PAX3-FOXO1 in RMS cell lines with and without the fusion gene, respectively. Consistent with this, we demonstrated that JARID2 is a direct transcriptional target of the PAX3-FOXO1 fusion protein. Silencing JARID2 resulted in reduced cell proliferation coupled with myogenic differentiation, including increased expression of Myogenin (MYOG) and Myosin Light Chain (MYL1) in RMS cell lines representative of both the alveolar and embryonal subtypes. Induced myogenic differentiation was associated with a decrease in JARID2 levels and this phenotype could be rescued by overexpressing JARID2. Furthermore, we that showed JARID2 binds to and alters the methylation status of histone H3 lysine 27 in the promoter regions of MYOG and MYL1 and that the interaction of JARID2 at these promoters is dependent on EED, a core component of the polycomb repressive complex 2 (PRC2). Therefore, JARID2 is a downstream effector of PAX3-FOXO1 that maintains an undifferentiated myogenic phenotype that is characteristic of RMS. JARID2 and other components of PRC2 may represent novel therapeutic targets for treating RMS patients.

SWIVIT - Swiss video-intubation trial evaluating video-laryngoscopes in a simulated difficult airway scenario: study protocol for a multicenter prospective randomized controlled trial in Switzerland.

BACKGROUND: Video-laryngoscopes are marketed for intubation in difficult airway management. They provide a better view of the larynx and may facilitate tracheal intubation, but there is no adequately powered study comparing different types of video-laryngoscopes in a difficult airway scenario or in a simulated difficult airway situation. METHODS/DESIGN: The objective of this trial is to evaluate and to compare the clinical performance of three video-laryngoscopes with a guiding channel for intubation (Airtraq?, A. P. Advance?, King Vision?) and three video-laryngoscopes without an integrated tracheal tube guidance (C-MAC?, GlideScope?, McGrath?) in a simulated difficult airway situation in surgical patients. The working hypothesis is that each video-laryngoscope provides at least a 90% first intubation success rate (lower limit of the 95% confidence interval >0.9). It is a prospective, patient-blinded, multicenter, randomized controlled trial in 720 patients who are scheduled for elective surgery under general anesthesia, requiring tracheal intubation at one of the three participating hospitals. A difficult airway will be created using an extrication collar and taping the patients' head on the operating table to substantially reduce mouth opening and to minimize neck movement. Tracheal intubation will be performed with the help of one of the six devices according to randomization. Insertion success, time necessary for intubation, Cormack-Lehane grade and percentage of glottic opening (POGO) score at laryngoscopy, optimization maneuvers required to aid tracheal intubation, adverse events and technical problems will be recorded. Primary outcome is intubation success at first attempt. DISCUSSION: We will simulate the difficult airway and evaluate different video-laryngoscopes in this highly realistic and clinically challenging scenario, independently from manufacturers of the devices. Because of the sufficiently powered multicenter design this study will deliver important and cutting-edge results that will help clinicians decide which device to use for intubation of the expected and unexpected difficult airway. TRIAL REGISTRATION: NCT01692535.

Microstructural evolution of primary crystallization in diffusion-controlled grain growth

A model has been developed for evaluating grain size distributions in primary crystallizations where the grain growth is diffusion controlled. The body of the model is grounded in a recently presented mean-field integration of the nucleation and growth kinetic equations, modified conveniently in order to take into account a radius-dependent growth rate, as occurs in diffusion-controlled growth. The classical diffusion theory is considered, and a modification of this is proposed to take into account interference of the diffusion profiles between neighbor grains. The potentiality of the mean-field model to give detailed information on the grain size distribution and transformed volume fraction for transformations driven by nucleation and either interface- or diffusion-controlled growth processes is demonstrated. The model is evaluated for the primary crystallization of an amorphous alloy, giving an excellent agreement with experimental data. Grain size distributions are computed, and their properties are discussed.

The V-ATPase proteolipid cylinder promotes the lipid-mixing stage of SNARE-dependent fusion of yeast vacuoles.

The V-ATPase V(0) sector associates with the peripheral V(1) sector to form a proton pump. V(0) alone has an additional function, facilitating membrane fusion in the endocytic and late exocytic pathways. V(0) contains a hexameric proteolipid cylinder, which might support fusion as proposed in proteinaceous pore models. To test this, we randomly mutagenized proteolipids. We recovered alleles that preserve proton translocation, normal SNARE activation and trans-SNARE pairing but that impair lipid and content mixing. Critical residues were found in all subunits of the proteolipid ring. They concentrate within the bilayer, close to the ring subunit interfaces. The fusion-impairing proteolipid substitutions stabilize the interaction of V(0) with V(1). Deletion of the vacuolar v-SNARE Nyv1 has the same effect, suggesting that both types of mutations similarly alter the conformation of V(0). Also covalent linkage of subunits in the proteolipid cylinder blocks vacuole fusion. We propose that a SNARE-dependent conformational change in V(0) proteolipids might stimulate fusion by creating a hydrophobic crevice that promotes lipid reorientation and formation of a lipidic fusion pore.

Randomized controlled study demonstrating failure of LPV/r monotherapy in HIV: the role of compartment and CD4-nadir.

BACKGROUND: Long-term side-effects and cost of HIV treatment motivate the development of simplified maintenance. Monotherapy with ritonavir-boosted lopinavir (LPV/r-MT) is the most widely studied strategy. However, efficacy of LPV/r-MT in compartments remains to be shown. METHODS: Randomized controlled open-label trial comparing LPV/r-MT with continued treatment for 48 weeks in treated patients with fully suppressed viral load. The primary endpoint was treatment failure in the central nervous system [cerebrospinal fluid (CSF)] and/or genital tract. Treatment failure in blood was defined as two consecutive HIV RNA levels more than 400 copies/ml. RESULTS: The trial was prematurely stopped when six patients on monotherapy (none in continued treatment-arm) demonstrated a viral failure in blood. At study termination, 60 patients were included, 29 randomized to monotherapy and 13 additional patients switched from continued treatment to monotherapy after 48 weeks. All failures occurred in patients with a nadir CD4 cell count below 200/microl and within the first 24 weeks of monotherapy. Among failing patients, all five patients with a lumbar puncture had an elevated HIV RNA load in CSF and four of six had neurological symptoms. Viral load was fully resuppressed in all failing patients after resumption of the original combination therapy. No drug resistant virus was found. The only predictor of failure was low nadir CD4 cell count (P < 0.02). CONCLUSION: Maintenance of HIV therapy with LPV/r alone should not be recommended as a standard strategy; particularly not in patients with a CD4 cell count nadir less than 200/microl. Further studies are warranted to elucidate the role of the central nervous system compartment in monotherapy-failure.

Landmark detection for fusion of fundus and MRI toward a patient-specific multimodal eye model.

Ophthalmologists typically acquire different image modalities to diagnose eye pathologies. They comprise, e.g., Fundus photography, optical coherence tomography, computed tomography, and magnetic resonance imaging (MRI). Yet, these images are often complementary and do express the same pathologies in a different way. Some pathologies are only visible in a particular modality. Thus, it is beneficial for the ophthalmologist to have these modalities fused into a single patient-specific model. The goal of this paper is a fusion of Fundus photography with segmented MRI volumes. This adds information to MRI that was not visible before like vessels and the macula. This paper contributions include automatic detection of the optic disc, the fovea, the optic axis, and an automatic segmentation of the vitreous humor of the eye.