A multicenter, randomized, controlled trial on short-term feasibility and impact on functional capacity, symptoms and neurohumoral activation

RE-START is a multicenter, randomized, prospective, open, controlled trial aiming to evaluate the feasibility and the short- and medium-term effects of an earlystart AET program on functional capacity, symptoms and neurohormonal activation in chronic heart failure (CHF) patients with recent acute hemodynamic decompensation. Study endpoints will be: 1) safety of and compliance to AET; 2) effects of AET on i) functional capacity, ii) patient- reported symptoms and iii) AET-induced changes in beta-adrenergic receptor signaling and circulating angiogenetic and inflammatory markers. Two-hundred patients, randomized 1:1 to training (TR) or control (C), will be enrolled. Inclusion criteria: 1) history of systolic CHF for at least 6 months, with ongoing acute decompensation with need of intravenous diuretic and/or vasodilator therapy; 2) proBNP >1000 pg/ml at admission. Exclusion criteria: 1) ongoing cardiogenic shock; 2) need of intravenous inotropic therapy; 3) creatinine >2.5 mg/dl at admission. After a 72-hour run-in period, TR will undergo the following 12-day early-start AET protocol: days 1-2: active/passive mobilization (2 sessions/day, each 30 minutes duration); days 3-4: as days 1-2 + unloaded bedside cycle ergometer (3 sessions/day, each 5-10 minutes duration); days 5-8: as days 1-2 + unloaded bedside cycle ergometer (3 sessions/day, each 15-20 minutes duration); days 9-12: as days 1-2 + bedside cycle ergometer at 10-20 W (3 sessions/day, each 15-20 minutes duration). During the same period, C will undergo the same activity protocol as in days 1-2 for TR. All patients will undergo a 6- minWT at day 1, 6, 12 and 30 and echocardiogram, patient- reported symptoms on 7-point Likert scale and measurement of lymphocyte G protein coupled receptor kinase, VEGF, angiopoietin, TNF alfa, IL-1, IL-6 and eNOS levels at day 1, 12 and 30

Acquired myasthenia gravis with concurrent polymyositis and myocarditis secondary to a thymoma in a dog

Background: Canine thymomas are associated with multiple paraneoplastic syndromes, among which myasthenia gravis (MG) is the most common. Acquired MG is an autoimmune disease characterized by the presence of antibodies against acetylcholine receptors (ACHRs). ACHRs antibodies are the most commonly formed, but the production of antistriational antibodies binding to skeletal and cardiac muscle proteins has also been recorded both in humans and dogs. An association between the occurrence of antistriational antibodies and a severe form of myocarditis, giant cell myocarditis, has been described in humans.Case Description: A 4-year-old mixed-breed dog was referred because of 1 month history of exercise-induced weakness, hypersalivation, and regurgitation. The neurologic examination was indicative of a neuromuscular junction disease, and MG was suspected. A computed tomographic scan examination showed the presence of a megaoesophagus and a thymic mass. Serum antibodies against ACHRs confirmed the diagnosis of MG. Treatment with pyridostigmine was started, and the thymic mass was surgically excised, and a diagnosis of thymoma was confirmed by histology. 24 hours after surgery, the dog developed a third-degree atrioventricular block. Severe arrhythmia and increased troponin serum levels suggested myocarditis which rapidly led to cardiopulmonary arrest. Histopathologic examination of the heart, esophagus and diaphragm revealed a lymphocytic and macrophagic infiltration, consistent with myocarditis and polymyositis. Scattered rare giant multinucleated cells were also detected in the myocardium.Conclusion: To the author’s knowledge, this is the first report of thymoma-associated MG with concurrent polymyositis and giant cell-like myocarditis in a dog

Hyperbranched Anatase TiO2 Nanocrystals: Nonaqueous Synthesis, Growth Mechanism, and Exploitation in Dye-Sensitized Solar Cells

A colloidal crystal-splitting growth regime was used in which TiO2 nanocrystals, selectively trapped in the metastable anatase phase, can evolve to anisotropic shapes with tunable hyper-branched topologies over a broad size interval. The synthetic strategy relies on a nonaq. sol-gel route involving programmed activation of aminolysis and pyrolysis of Ti carboxylate complexes in hot surfactant media via a simple multi-injection reactant delivery technique. Detailed studies indicate that the branched objects initially formed upon the aminolysis reaction, possess a strained monocryst. skeleton, and their corresponding larger derivs. grown in the subsequent pyrolysis stage accommodate addnl. arms crystallog. decoupled from the lattice underneath. The complex evolution of the nano-architectures is rationalized within the frame of complementary mechanistic arguments. Thermodn. pathways, detd. by the shape-directing effect of the anatase structure and free-energy changes accompanying branching and anisotropic development, are considered to interplay with kinetic processes, related to diffusion-limited, spatially inhomogeneous monomer fluxes, lattice symmetry breaking at transient Ti5O5 domains, and surfactant-induced stabilization. Finally, as a proof of functionality, the fabrication of dye-sensitized solar cells based on thin-film photoelectrodes that incorporate networked branched nanocrystals with intact crystal structure and geometric features is demonstrated. An energy conversion efficiency of 6.2% was achieved with std. device configuration, which exceeds the best performance with prototypes of split TiO2 nanostructures. Anal. of the relevant photovoltaic parameters reveals that the used branched building blocks indeed offer light-harvesting and charge-collecting properties that can overwhelm detrimental electron losses due to recombination and trapping events

High-quality photoelectrodes based on shape-tailored TiO2 nanocrystals for dye-sensitized solar cells

We demonstrate a general approach by which colloidal anatase TiO2 nanocrystals with anisotropically tailored linear and branched shapes can safely be processed into high-quality mesoporous photoelectrodes for dye-sensitized solar cells. A detailed study has been carried out to elucidate how the nanoscale architecture underlying the photoelectrodes impacts their ultimate performances. From the anal. of the most relevant electrochem. parameters, an intrinsic correlation between the photovoltaic performances and the structure of the nanocrystal building blocks has been deduced and explained on the basis of relative contributions of the electron transport and light-harvesting properties of the photoelectrodes. Depending on the nanocrystals incorporated, these devices can exhibit an energy conversion efficiency of 5.2-7.8%, which ranks 38-53% higher than that achievable with corresponding cells based on ref. spherical nanoparticles. It has been ascertained that dye-sensitized solar cells based on high aspect-ratio linear nanorods allow for a remarkable improvement in the charge-collection efficiency due to minimization of detrimental charge-recombination processes at the photoelectrode/electrolyte interface. On the other hand, dye-sensitized solar cells fabricated from branched nanocrystals with a peculiar bundle-like configuration are characterized by a drastic redn. of undesired charge-trapping phenomena. These findings can be useful in the design and fabrication of future generations of high-performing dye-sensitized solar cells based on colloidal nanocrystals with properly engineered size and shape parameters

Predicting outcome in dogs with diffuse large B-cell lymphoma with a novel immune landscape signature

: Canine diffuse large B-cell lymphoma (cDLBCL) is characterized by high mortality and clinical heterogeneity. Although chemo-immunotherapy improves outcome, treatment response remains mainly unpredictable. To identify a set of immune-related genes aberrantly regulated and impacting the prognosis, we explored the immune landscape of cDLBCL by NanoString. The immune gene expression profile of 48 fully clinically characterized cDLBCLs treated with chemo-immunotherapy was analyzed with the NanoString nCounter Canine IO Panel using RNA extracted from tumor tissue paraffin blocks. A Cox proportional-hazards model was used to design a prognostic gene signature. The Cox model identified a 6-gene signature (IL2RB, BCL6, TXK, C2, CDKN2B, ITK) strongly associated with lymphoma-specific survival, from which a risk score was calculated. Dogs were assigned to high-risk or low-risk groups according to the median score. Thirty-nine genes were differentially expressed between the 2 groups. Gene set analysis highlighted an upregulation of genes involved in complement activation, cytotoxicity, and antigen processing in low-risk dogs compared with high-risk dogs, whereas genes associated with cell cycle were downregulated in dogs with a lower risk. In line with these results, cell type profiling suggested the abundance of natural killer and CD8+ cells in low-risk dogs compared with high-risk dogs. Furthermore, the prognostic power of the risk score was validated in an independent cohort of cDLBCL. In conclusion, the 6-gene-derived risk score represents a robust biomarker in predicting the prognosis in cDLBCL. Moreover, our results suggest that enhanced tumor antigen recognition and cytotoxic activity are crucial in achieving a more effective response to chemo-immunotherapy

The genomic landscape of canine diffuse large B-cell lymphoma identifies distinct subtypes with clinical and therapeutic implications

Giannuzzi et al. present an integrated analysis of clinical features and exome and RNA sequencing data in a cohort of dogs with diffuse large B-cell lymphoma to better define the genetic landscape of this tumor and identify multiple mutations associated with the outcome.Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid neoplasm in dogs and in humans. It is characterized by a remarkable degree of clinical heterogeneity that is not completely elucidated by molecular data. This poses a major barrier to understanding the disease and its response to therapy, or when treating dogs with DLBCL within clinical trials. We performed an integrated analysis of exome (n = 77) and RNA sequencing (n = 43) data in a cohort of canine DLBCL to define the genetic landscape of this tumor. A wide range of signaling pathways and cellular processes were found in common with human DLBCL, but the frequencies of the most recurrently mutated genes (TRAF3, SETD2, POT1, TP53, MYC, FBXW7, DDX3X and TBL1XR1) differed. We developed a prognostic model integrating exonic variants and clinical and transcriptomic features to predict the outcome in dogs with DLBCL. These results comprehensively define the genetic drivers of canine DLBCL and can be prospectively utilized to identify new therapeutic opportunities

Renal function and peak exercise oxygen consumption in chronic heart failure with reduced left ventricular ejection fraction

Background: Chronic kidney disease is associated with sympathetic activation and muscle abnormalities, which may contribute to decreased exercise capacity. We investigated the correlation of renal function with peak exercise oxygen consumption (V˙O2) in heart failure (HF) patients. Methods and Results: We recruited 2,938 systolic HF patients who underwent clinical, laboratory, echocardiographic and cardiopulmonary exercise testing. The patients were stratified according to estimated glomerular filtration rate (eGFR). Mean follow-up was 3.7 years. The primary outcome was a composite of cardiovascular death and urgent heart transplantation at 3 years. On multivariable regression, eGFR was predictor of peakV˙O2 (P<0.0001). Other predictors were age, sex, body mass index, HF etiology, NYHA class, atrial fibrillation, resting heart rate, Btype natriuretic peptide, hemoglobin, and treatment. After adjusting for significant covariates, the hazard ratio for primary outcome associated with peakVO2 <12 ml ・ kg−1 ・ min−1 was 1.75 (95% confidence interval (CI): 1.06–2.91; P=0.0292) in patients with eGFR ≥60, 1.77 (0.87–3.61; P=0.1141) in those with eGFR of 45–59, and 2.72 (1.01– 7.37; P=0.0489) in those with eGFR <45 ml ・ min−1 ・ 1.73 m−2. The area under the receiver-operating characteristic curve for peakV˙O2 <12 ml ・ kg−1 ・ min−1 was 0.63 (95% CI: 0.54–0.71), 0.67 (0.56–0.78), and 0.57 (0.47–0.69), respectively. Testing for interaction was not significant. Conclusions: Renal dysfunction is correlated with peakV O2. A peakV O2 cutoff of 12 ml ・ kg–1 ・ min–1 offers limited prognostic information in HF patients with more severely impaired renal function

Metabolic exercise test data combined with cardiac and kidney indexes, the MECKI score: A multiparametric approach to heart failure prognosis

Objectives: We built and validated a new heart failure (HF) prognostic model which integrates cardiopulmonary exercise test (CPET) parameters with easy-to-obtain clinical, laboratory, and echocardiographic variables. Background: HF prognostication is a challenging medical judgment, constrained by a magnitude of uncertainty. Methods: Our risk model was derived from a cohort of 2716 systolic HF patients followed in 13 Italian centers. Median follow up was 1041 days (range 4-5185). Cox proportional hazard regression analysis with stepwise selection of variables was used, followed by cross-validation procedure. The study end-point was a composite of cardiovascular death and urgent heart transplant. Results: Six variables (hemoglobin, Na+, kidney function by means of MDRD, left ventricle ejection fraction [echocardiography], peak oxygen consumption [% pred] and VE/VCO2 slope) out of the several evaluated resulted independently related to prognosis. A score was built from Metabolic Exercise Cardiac Kidney Indexes, the MECKI score, which identified the risk of study end-point with AUC values of 0.804 (0.754-0.852) at 1 year, 0.789 (0.750-0.828) at 2 years, 0.762 (0.726-0.799) at 3 years and 0.760 (0.724-0.796) at 4 years. Conclusions: This is the first large-scale multicenter study where a prognostic score, the MECKI score, has been built for systolic HF patients considering CPET data combined with clinical, laboratory and echocardiographic measurements. In the present population, the MECKI score has been successfully validated, performing very high AUC. © 2012 Elsevier Ireland Ltd

Metabolic exercise data combined with cardiac and kidney indexes: MECKI score. Predictive role in cardiopulmonary exercise testing with low respiratory exchange ratio in heart failure

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