Impact of exercise-based cardiac rehabilitation in patients with heart failure (ExTraMATCH II) on mortality and hospitalisation:an individual-patient data meta-analysis of randomised trials

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this recordAIMS: To undertake an individual patient data (IPD) meta-analysis to assess the impact of exercise-based cardiac rehabilitation (ExCR) in patients with heart failure (HF) on mortality and hospitalisation, and differential effects of ExCR according to patient characteristics: age, sex, ethnicity, New York Heart Association functional class, ischaemic aetiology, ejection fraction, and exercise capacity. METHODS AND RESULTS: Randomised trials of exercise training for at least 3 weeks compared with no exercise control with 6-month follow-up or longer, providing IPD time to event on mortality or hospitalisation (all-cause or HF-specific). IPD were combined into a single dataset. We used Cox proportional hazards models to investigate the effect of ExCR and the interactions between ExCR and participant characteristics. We used both two-stage random effects and one-stage fixed effect models. IPD were obtained from 18 trials including 3912 patients with HF with reduced ejection fraction. Compared to control, there was no statistically significant difference in pooled time to event estimates in favour of ExCR although confidence intervals (CIs) were wide [all-cause mortality: hazard ratio (HR) 0.83, 95% CI 0.67-1.04; HF-specific mortality: HR 0.84, 95% CI 0.49-1.46; all-cause hospitalisation: HR 0.90, 95% CI 0.76-1.06; and HF-specific hospitalisation: HR 0.98, 95% CI 0.72-1.35]. No strong evidence was found of differential intervention effects across patient characteristics. CONCLUSION: Exercise-based cardiac rehabilitation did not have a significant effect on the risk of mortality and hospitalisation in HF with reduced ejection fraction. However, uncertainty around effect estimates precludes drawing definitive conclusions.This work is supported by UK National Institute for Health Research funding (HTA 15/80/30)

Evidence for Avian Intrathoracic Air Sacs in a New Predatory Dinosaur from Argentina

Background: Living birds possess a unique heterogeneous pulmonary system composed of a rigid, dorsally-anchored lung and several compliant air sacs that operate as bellows, driving inspired air through the lung. Evidence from the fossil record for the origin and evolution of this system is extremely limited, because lungs do not fossilize and because the bellow-like air sacs in living birds only rarely penetrate (pneumatize) skeletal bone and thus leave a record of their presence. Methodology/Principal Findings: We describe a new predatory dinosaur from Upper Cretaceous rocks in Argentina, Aerosteon riocoloradensis gen. et sp. nov., that exhibits extreme pneumatization of skeletal bone, including pneumatic hollowing of the furcula and ilium. In living birds, these two bones are pneumatized by diverticulae of air sacs (clavicular, abdominal) that are involved in pulmonary ventilation. We also describe several pneumatized gastralia (‘‘stomach ribs’’), which suggest that diverticulae of the air sac system were present in surface tissues of the thorax. Conclusions/Significance: We present a four-phase model for the evolution of avian air sacs and costosternal-driven lung ventilation based on the known fossil record of theropod dinosaurs and osteological correlates in extant birds: (1) Phase I—Elaboration of paraxial cervical air sacs in basal theropods no later than the earliest Late Triassic. (2) Phase II—Differentiation of avian ventilatory air sacs, including both cranial (clavicular air sac) and caudal (abdominal air sac) divisions, in basal tetanurans during the Jurassic. A heterogeneous respiratory tract wit

Use of selected complementary and alternative medicine (CAM) treatments in veterans with cancer or chronic pain: a cross-sectional survey

BACKGROUND: Complementary and alternative medicine (CAM) is emerging as an important form of care in the United States. We sought to measure the prevalence of selected CAM use among veterans attending oncology and chronic pain clinics and to describe the characteristics of CAM use in this population. METHODS: The self-administered, mail-in survey included questions on demographics, health beliefs, medical problems and 6 common CAM treatments (herbs, dietary supplements, chiropractic care, massage therapy, acupuncture and homeopathy) use. We used the chi-square test to examine bivariate associations between our predictor variables and CAM use. RESULTS: Seventy-two patients (27.3%) reported CAM use within the past 12 months. CAM use was associated with more education (p = 0.02), higher income (p = 0.006), non-VA insurance (p = 0.003), additional care outside the VA (p = 0.01) and the belief that lifestyle contributes to illness (p = 0.015). The diagnosis of chronic pain versus cancer was not associated with differential CAM use (p = 0.15). Seventy-six percent of CAM non-users reported that they would use it if offered at the VA. CONCLUSION: Use of 6 common CAM treatments among these veterans is lower than among the general population, but still substantial. A large majority of veterans reported interest in using CAM modalities if they were offered at the VA. A national assessment of veteran interest in CAM may assist VA leaders to respond to patients' needs

Co-Regulation of NF-κB and Inflammasome-Mediated Inflammatory Responses by Myxoma Virus Pyrin Domain-Containing Protein M013

NF-κB and inflammasomes both play central roles in orchestrating anti-pathogen responses by rapidly inducing a variety of early-response cytokines and chemokines following infection. Myxoma virus (MYXV), a pathogenic poxvirus of rabbits, encodes a member of the cellular pyrin domain (PYD) superfamily, called M013. The viral M013 protein was previously shown to bind host ASC-1 protein and inhibit the cellular inflammasome complex that regulates the activation and secretion of caspase 1-regulated cytokines such as IL-1β and IL-18. Here, we report that human THP-1 monocytic cells infected with a MYXV construct deleted for the M013L gene (vMyxM013-KO), in stark contrast to the parental MYXV, rapidly induce high levels of secreted pro-inflammatory cytokines like TNF, IL-6, and MCP-1, all of which are regulated by NF-κB. The induction of these NF-κB regulated cytokines following infection with vMyxM013-KO was also confirmed in vivo using THP-1 derived xenografts in NOD-SCID mice. vMyxM013-KO virus infection specifically induced the rapid phosphorylation of IKK and degradation of IκBα, which was followed by nuclear translocation of NF-κB/p65. Even in the absence of virus infection, transiently expressed M013 protein alone inhibited cellular NF-κB-mediated reporter gene expression and nuclear translocation of NF-κB/p65. Using protein/protein interaction analysis, we show that M013 protein also binds directly with cellular NF-κB1, suggesting a direct physical and functional linkage between NF-κB1 and ASC-1. We further demonstrate that inhibition of the inflammasome with a caspase-1 inhibitor did not prevent the induction of NF-κB regulated cytokines following infection with vMyxM013-KO virus, but did block the activation of IL-1β. Thus, the poxviral M013 inhibitor exerts a dual immuno-subversive role in the simultaneous co-regulation of both the cellular inflammasome complex and NF-κB-mediated pro-inflammatory responses

A cluster randomized trial to improve adherence to evidence-based guidelines on diabetes and reduce clinical inertia in primary care physicians in Belgium: study protocol [NTR 1369]

Contains fulltext : 70617.pdf (publisher's version ) (Open Access)ABSTRACT: BACKGROUND: Most quality improvement programs in diabetes care incorporate aspects of clinician education, performance feedback, patient education, care management, and diabetes care teams to support primary care physicians. Few studies have applied all of these dimensions to address clinical inertia. AIM: To evaluate interventions to improve adherence to evidence-based guidelines for diabetes and reduce clinical inertia in primary care physicians. DESIGN: Two-arm cluster randomized controlled trial. PARTICIPANTS: Primary care physicians in Belgium. INTERVENTIONS: Primary care physicians will be randomly allocated to 'Usual' (UQIP) or 'Advanced' (AQIP) Quality Improvement Programs. Physicians in the UQIP will receive interventions addressing the main physician, patient, and office system factors that contribute to clinical inertia. Physicians in the AQIP will receive additional interventions that focus on sustainable behavior changes in patients and providers. OUTCOMES: Primary endpoints are the proportions of patients within targets for three clinical outcomes: 1) glycosylated hemoglobin < 7%; 2) systolic blood pressure differences </=130 mmHg; and 3) low density lipoprotein/cholesterol < 100 mg/dl. Secondary endpoints are individual improvements in 12 validated parameters: glycosylated hemoglobin, low and high density lipoprotein/cholesterol, total cholesterol, systolic blood pressure, diastolic blood pressure, weight, physical exercise, healthy diet, smoking status, and statin and anti-platelet therapy. PRIMARY AND SECONDARY ANALYSIS: Statistical analyses will be performed using an intent-to-treat approach with a multilevel model. Linear and generalized linear mixed models will be used to account for the clustered nature of the data, i.e., patients clustered withinimary care physicians, and repeated assessments clustered within patients. To compare patient characteristics at baseline and between the intervention arms, the generalized estimating equations (GEE) approach will be used, taking the clustered nature of the data within physicians into account. We will also use the GEE approach to test for differences in evolution of the primary and secondary endpoints for all patients, and for patients in the two interventions arms, accounting for within-patient clustering. TRIAL REGISTRATION: number: NTR 1369

A Nomenclature for Vertebral Fossae in Sauropods and Other Saurischian Dinosaurs

The axial skeleton of extinct saurischian dinosaurs (i.e., theropods, sauropodomorphs), like living birds, was pneumatized by epithelial outpocketings of the respiratory system. Pneumatic signatures in the vertebral column of fossil saurischians include complex branching chambers within the bone (internal pneumaticity) and large chambers visible externally that are bounded by neural arch laminae (external pneumaticity). Although general aspects of internal pneumaticity are synapomorphic for saurischian subgroups, the individual internal pneumatic spaces cannot be homologized across species or even along the vertebral column, due to their variability and absence of topographical landmarks. External pneumatic structures, in contrast, are defined by ready topological landmarks (vertebral laminae), but no consistent nomenclatural system exists. This deficiency has fostered confusion and limited their use as character data in phylogenetic analysis.We present a simple system for naming external neural arch fossae that parallels the one developed for the vertebral laminae that bound them. The nomenclatural system identifies fossae by pointing to reference landmarks (e.g., neural spine, centrum, costal articulations, zygapophyses). We standardize the naming process by creating tripartite names from “primary landmarks,” which form the zygodiapophyseal table, “secondary landmarks,” which orient with respect to that table, and “tertiary landmarks,” which further delineate a given fossa.The proposed nomenclatural system for lamina-bounded fossae adds clarity to descriptions of complex vertebrae and allows these structures to be sourced as character data for phylogenetic analyses. These anatomical terms denote potentially homologous pneumatic structures within Saurischia, but they could be applied to any vertebrate with vertebral laminae that enclose spaces, regardless of their developmental origin or phylogenetic distribution

Interdisciplinary diabetes care teams operating on the interface between primary and specialty care are associated with improved outcomes of care: findings from the Leuven Diabetes Project

<p>Abstract</p> <p>Background</p> <p>Type 2 diabetes mellitus is a complex, progressive disease which requires a variety of quality improvement strategies. Limited information is available on the feasibility and effectiveness of interdisciplinary diabetes care teams (IDCT) operating on the interface between primary and specialty care. A first study hypothesis was that the implementation of an IDCT is feasible in a health care setting with limited tradition in shared care. A second hypothesis was that patients who make use of an IDCT would have significantly better outcomes compared to non-users of the IDCT after an 18-month intervention period. A third hypothesis was that patients who used the IDCT in an Advanced quality Improvement Program (AQIP) would have significantly better outcomes compared to users of a Usual Quality Improvement Program (UQIP).</p> <p>Methods</p> <p>This investigation comprised a two-arm cluster randomized trial conducted in a primary care setting in Belgium. Primary care physicians (PCPs, n = 120) and their patients with type 2 diabetes mellitus (n = 2495) were included and subjects were randomly assigned to the intervention arms. The IDCT acted as a cornerstone to both the intervention arms, but the number, type and intensity of IDCT related interventions varied depending upon the intervention arm.</p> <p>Results</p> <p>Final registration included 67 PCPs and 1577 patients in the AQIP and 53 PCPs and 918 patients in the UQIP. 84% of the PCPs made use of the IDCT. The expected participation rate in patients (30%) was not attained, with 12,5% of the patients using the IDCT. When comparing users and non-users of the IDCT (irrespective of the intervention arm) and after 18 months of intervention the use of the IDCT was significantly associated with improvements in HbA1c, LDL-cholesterol, an increase in statins and anti-platelet therapy as well as the number of targets that were reached. When comparing users of the IDCT in the two intervention arms no significant differences were noted, except for anti-platelet therapy.</p> <p>Conclusion</p> <p>IDCT's operating on the interface between primary and specialty care are associated with improved outcomes of care. More research is required on what team and program characteristics contribute to improvements in diabetes care.</p> <p>Trial registration</p> <p>NTR 1369.</p

Rationale and design of a randomised controlled trial evaluating the effectiveness of an exercise program to improve the quality of life of patients with heart failure in primary care : the EFICAR study protocol

Background: Quality of life (QoL) decreases as heart failure worsens, which is one of the greatest worries of these patients. Physical exercise has been shown to be safe for people with heart failure. Previous studies have tested heterogeneous exercise programs using different QoL instruments and reported inconsistent effects on QoL. The aim of this study is to evaluate the effectiveness of a new exercise program for people with heart failure (EFICAR), additional to the recommended optimal treatment in primary care, to improve QoL, functional capacity and control of cardiovascular risk factors. Methods/Design: Multicenter clinical trial in which 600 patients with heart failure in NYHA class II-IV will be randomized to two parallel groups: EFICAR and control. After being recruited, through the reference cardiology services, in six health centres from the Spanish Primary Care Prevention and Health Promotion Research Network (redIAPP), patients are followed for 1 year after the beginning of the intervention. Both groups receive the optimized treatment according to the European Society of Cardiology guidelines. In addition, the EFICAR group performs a 3 month supervised progressive exercise program with an aerobic (high-intensity intervals) and a strength component; and the programme continues linked with community resources for 9 months. The main outcome measure is the change in health-related QoL measured by the SF-36 and the Minnesota Living with Heart Failure Questionnaires at baseline, 3, 6 and 12 months. Secondary outcomes considered are changes in functional capacity measured by the 6-Minute Walking Test, cardiac structure (B-type natriuretic peptides), muscle strength and body composition. Both groups will be compared on an intention to treat basis, using multi-level longitudinal mixed models. Sex, age, social class, co-morbidity and cardiovascular risk factors will be considered as potential confounding and predictor variables. Discussion: A key challenges of this study is to guarantee the safety of the patients; however, the current scientific evidence supports the notion of there being no increase in the risk of decompensation, cardiac events, hospitalizations and deaths associated with exercise, but rather the opposite. Safety assurance will be based on an optimized standardised pharmacological therapy and health education for all the participants

The Antidiabetic Drug Ciglitazone Induces High Grade Bladder Cancer Cells Apoptosis through the Up-Regulation of TRAIL

International audienceBACKGROUND: Ciglitazone belongs to the thiazolidinediones class of antidiabetic drug family and is a high-affinity ligand for the Peroxisome Proliferator-Activated Receptor γ (PPARγ). Apart from its antidiabetic activity, this molecule shows antineoplastic effectiveness in numerous cancer cell lines. METHODOLOGY/PRINCIPAL FINDINGS: Using RT4 (derived from a well differentiated grade I papillary tumor) and T24 (derived from an undifferentiated grade III carcinoma) bladder cancer cells, we investigated the potential of ciglitazone to induce apoptotic cell death and characterized the molecular mechanisms involved. In RT4 cells, the drug induced G2/M cell cycle arrest characterized by an overexpression of p53, p21(waf1/CIP1) and p27(Kip1) in concomitance with a decrease of cyclin B1. On the contrary, in T24 cells, it triggered apoptosis via extrinsic and intrinsic pathways. Cell cycle arrest and induction of apoptosis occurred at high concentrations through PPARγ activation-independent pathways. We show that in vivo treatment of nude mice by ciglitazone inhibits high grade bladder cancer xenograft development. We identified a novel mechanism by which ciglitazone kills cancer cells. Ciglitazone up-regulated soluble and membrane-bound TRAIL and let TRAIL-resistant T24 cells to respond to TRAIL through caspase activation, death receptor signalling pathway and Bid cleavage. We provided evidence that TRAIL-induced apoptosis is partially driven by ciglitazone-mediated down-regulation of c-FLIP and survivin protein levels through a proteasome-dependent degradation mechanism. CONCLUSIONS/SIGNIFICANCE: Therefore, ciglitazone could be clinically relevant as chemopreventive or therapeutic agent for the treatment of TRAIL-refractory high grade urothelial cancers