Isotopic Grand Unification with the Inclusion of Gravity (revised version)

We introduce a dual lifting of unified gauge theories, the first characterized by the isotopies, which are axiom- preserving maps into broader structures with positive-definite generalized units used for the representation of matter under the isotopies of the Poincare' symmetry, and the second characterized by the isodualities, which are anti-isomorphic maps with negative-definite generalized units used for the representation of antimatter under the isodualities of the Poincare' symmetry. We then submit, apparently for the first time, a novel grand unification with the inclusion of gravity for matter embedded in the generalized positive-definite units of unified gauge theories while gravity for antimatter is embedded in the isodual isounit. We then show that the proposed grand unification provides realistic possibilities for a resolution of the axiomatic incompatibilities between gravitation and electroweak interactions due to curvature, antimatter and the fundamental space-time symmetries.Comment: 20 pages, Latex, revised in various details and with added reference

Invariant variational principle for Hamiltonian mechanics

It is shown that the action for Hamiltonian equations of motion can be brought into invariant symplectic form. In other words, it can be formulated directly in terms of the symplectic structure $\omega$ without any need to choose some 1-form $\gamma$, such that $\omega= d \gamma$, which is not unique and does not even generally exist in a global sense.Comment: final version; to appear in J.Phys.A; 17 pages, 2 figure

The Inverse Variational Problem for Autoparallels

We study the problem of the existence of a local quantum scalar field theory in a general affine metric space that in the semiclassical approximation would lead to the autoparallel motion of wave packets, thus providing a deviation of the spinless particle trajectory from the geodesics in the presence of torsion. The problem is shown to be equivalent to the inverse problem of the calculus of variations for the autoparallel motion with additional conditions that the action (if it exists) has to be invariant under time reparametrizations and general coordinate transformations, while depending analytically on the torsion tensor. The problem is proved to have no solution for a generic torsion in four-dimensional spacetime. A solution exists only if the contracted torsion tensor is a gradient of a scalar field. The corresponding field theory describes coupling of matter to the dilaton field.Comment: 13 pages, plain Latex, no figure

Canonical quantization of so-called non-Lagrangian systems

We present an approach to the canonical quantization of systems with equations of motion that are historically called non-Lagrangian equations. Our viewpoint of this problem is the following: despite the fact that a set of differential equations cannot be directly identified with a set of Euler-Lagrange equations, one can reformulate such a set in an equivalent first-order form which can always be treated as the Euler-Lagrange equations of a certain action. We construct such an action explicitly. It turns out that in the general case the hamiltonization and canonical quantization of such an action are non-trivial problems, since the theory involves time-dependent constraints. We adopt the general approach of hamiltonization and canonical quantization for such theories (Gitman, Tyutin, 1990) to the case under consideration. There exists an ambiguity (not reduced to a total time derivative) in associating a Lagrange function with a given set of equations. We present a complete description of this ambiguity. The proposed scheme is applied to the quantization of a general quadratic theory. In addition, we consider the quantization of a damped oscillator and of a radiating point-like charge.Comment: 13 page

Longitudinal Analysis of Quality of Life, Clinical, Radiographic, Echocardiographic, and Laboratory Variables in Dogs with Preclinical Myxomatous Mitral Valve Disease Receiving Pimobendan or Placebo: The EPIC Study

Background: Changes in clinical variables associated with the administration of pimobendan to dogs with preclinical myxomatous mitral valve disease (MMVD) and cardiomegaly have not been described. Objectives: To investigate the effect of pimobendan on clinical variables and the relationship between a change in heart size and the time to congestive heart failure (CHF) or cardiac-related death (CRD) in dogs with MMVD and cardiomegaly. To determine whether pimobendan-treated dogs differ from dogs receiving placebo at onset of CHF. Animals: Three hundred and fifty-four dogs with MMVD and cardiomegaly. Materials and Methods: Prospective, blinded study with dogs randomized (ratio 1:1) to pimobendan (0.4-0.6 mg/kg/d) or placebo. Clinical, laboratory, and heart-size variables in both groups were measured and compared at different time points (day 35 and onset of CHF) and over the study duration. Relationships between short-term changes in echocardiographic variables and time to CHF or CRD were explored. Results: At day 35, heart size had reduced in the pimobendan group:median change in (Delta) LVIDDN -0.06 (IQR:-0.15 to + 0.02), P < 0.0001, and LA:Ao -0.08 (IQR:-0.23 to + 0.03), P < 0.0001. Reduction in heart size was associated with increased time to CHF or CRD. Hazard ratio for a 0.1 increase in Delta LVIDDN was 1.26, P = 0.0003. Hazard ratio for a 0.1 increase in Delta LA:Ao was 1.14, P = 0.0002. At onset of CHF, groups were similar. Conclusions and Clinical Importance: Pimobendan treatment reduces heart size. Reduced heart size is associated with improved outcome. At the onset of CHF, dogs treated with pimobendan were indistinguishable from those receiving placebo

Effect of Pimobendan in Dogs with Preclinical Myxomatous Mitral Valve Disease and Cardiomegaly: The EPIC Study - A Randomized Clinical Trial

Background: Pimobendan is effective in treatment of dogs with congestive heart failure (CHF) secondary to myxomatous mitral valve disease (MMVD). Its effect on dogs before the onset of CHF is unknown. Hypothesis/Objectives: Administration of pimobendan (0.4-0.6 mg/kg/d in divided doses) to dogs with increased heart size secondary to preclinical MMVD, not receiving other cardiovascular medications, will delay the onset of signs of CHF, cardiac-related death, or euthanasia. Animals: 360 client-owned dogs with MMVD with left atrial-to-aortic ratio >= 1.6, normalized left ventricular internal diameter in diastole >= 1.7, and vertebral heart sum >10.5. Methods: Prospective, randomized, placebo-controlled, blinded, multicenter clinical trial. Primary outcome variable was time to a composite of the onset of CHF, cardiac-related death, or euthanasia. Results: Median time to primary endpoint was 1228 days (95% CI: 856-NA) in the pimobendan group and 766 days (95% CI: 667-875) in the placebo group (P = .0038). Hazard ratio for the pimobendan group was 0.64 (95% CI: 0.47-0.87) compared with the placebo group. The benefit persisted after adjustment for other variables. Adverse events were not different between treatment groups. Dogs in the pimobendan group lived longer (median survival time was 1059 days (95% CI: 952-NA) in the pimobendan group and 902 days (95% CI: 747-1061) in the placebo group) (P = .012). Conclusions and Clinical Importance: Administration of pimobendan to dogs with MMVD and echocardiographic and radiographic evidence of cardiomegaly results in prolongation of preclinical period and is safe and well tolerated. Prolongation of preclinical period by approximately 15 months represents substantial clinical benefit

Preclinical Optimization and Safety Studies of a New Lentiviral Gene Therapy for p47phox-Deficient Chronic Granulomatous Disease

Chronic granulomatous disease (CGD) is an inherited blood disorder that renders patients susceptible to infections and inflammation. A recent clinical trial of lentiviral gene therapy for the most frequent form of CGD, X-linked, has demonstrated stable correction over time, with no adverse events related to the gene therapy procedure. We have recently developed a parallel lentiviral vector for p47-deficient CGD (p47phoxCGD), the second most common form of this disease. Using this vector, we have observed biochemical correction of CGD in a mouse model of the disease. In preparation for clinical trial approval, we have performed standardised pre-clinical studies following Good Laboratory Practice (GLP) principles, to assess the safety of the gene therapy procedure. We report no evidence of adverse events, including mutagenesis and tumourigenesis, in human haematopoietic stem cells transduced with the lentiviral vector. Biodistribution studies of transduced human CD34+ cells indicate that the homing properties or engraftment ability of the stem cells is not negatively affected. CD34+ cells derived from a p47phoxCGD patient were subjected to an optimised transduction protocol and transplanted into immunocompromised mice. After the procedure, patient-derived neutrophils resumed NADPH oxidase production in vivo, suggesting that gene correction was successful. These studies pave the way to a first-in-man clinical trial of lentiviral gene therapy for the treatment of p47phoxCGD

Eight-year retention rate of first-line tumor necrosis factor inhibitors in spondyloarthritis : A multi-center retrospective analysis

Objective. To evaluate the 8-year survival of the first TNF inhibitor (TNFi) in patients with axial spondyloarthritis (axSpA) or psoriatic arthritis (PsA), identify the predictive factors for withdrawal, and compare the discontinuation rates for infliximab, etanercept, and adalimumab. Methods. We evaluated PsA and axSpA patients treated with a first-line TNFi between 2005 and 2015 at four Italian tertiary centres. 8-year drug survival was calculated by Kaplan-Meier method and risk for discontinuation among treatment groups compared by stratified log-rank test. Univariate and multivariate Cox proportional hazard models were developed to examine predictors of withdrawal. Results. Out of 614 patients (316 axSpA, 298 PsA), 203 received adalimumab, 131 etanercept, and 280 infliximab, with similar frequencies in axSpA and PsA subgroups. The cumulative 8-year retention rate in the whole population was 55.1% (57.2 and 51.9% and for axSpA and PsA, respectively; p=NS). No significant differences were observed in drug persistence among individual TNFi in either group. Male sex (HR 0.595, 95% CI 0.405-0.875; p=0.008) and concomitant methotrexate use (HR 0.648, 95% CI 0.426-0.985; p=0.042) were associated with a lower risk of withdrawal in PsA and high baseline BASDAI (HR 0.9842 95% CI 0.9708-0.9980; p=0.028) in axSpA. No difference was found in the comparative analysis of reasons for discontinuation between PsA and axSpA. Conclusion. We reported that the real-life 8-year retention rate of the first TNFi in axSpA and PsA is over 50%, with no significant differences between axSpA and PsA and irrespective of the individual TNFi

Eight-year retention rate of first-line tumor necrosis factor inhibitors in spondyloarthritis : A multi-center retrospective analysis

Objective. To evaluate the 8-year survival of the first TNF inhibitor (TNFi) in patients with axial spondyloarthritis (axSpA) or psoriatic arthritis (PsA), identify the predictive factors for withdrawal, and compare the discontinuation rates for infliximab, etanercept, and adalimumab. Methods. We evaluated PsA and axSpA patients treated with a first-line TNFi between 2005 and 2015 at four Italian tertiary centres. 8-year drug survival was calculated by Kaplan-Meier method and risk for discontinuation among treatment groups compared by stratified log-rank test. Univariate and multivariate Cox proportional hazard models were developed to examine predictors of withdrawal. Results. Out of 614 patients (316 axSpA, 298 PsA), 203 received adalimumab, 131 etanercept, and 280 infliximab, with similar frequencies in axSpA and PsA subgroups. The cumulative 8-year retention rate in the whole population was 55.1% (57.2 and 51.9% and for axSpA and PsA, respectively; p=NS). No significant differences were observed in drug persistence among individual TNFi in either group. Male sex (HR 0.595, 95% CI 0.405-0.875; p=0.008) and concomitant methotrexate use (HR 0.648, 95% CI 0.426-0.985; p=0.042) were associated with a lower risk of withdrawal in PsA and high baseline BASDAI (HR 0.9842 95% CI 0.9708-0.9980; p=0.028) in axSpA. No difference was found in the comparative analysis of reasons for discontinuation between PsA and axSpA. Conclusion. We reported that the real-life 8-year retention rate of the first TNFi in axSpA and PsA is over 50%, with no significant differences between axSpA and PsA and irrespective of the individual TNFi

Progress in Classical and Quantum Variational Principles

We review the development and practical uses of a generalized Maupertuis least action principle in classical mechanics, in which the action is varied under the constraint of fixed mean energy for the trial trajectory. The original Maupertuis (Euler-Lagrange) principle constrains the energy at every point along the trajectory. The generalized Maupertuis principle is equivalent to Hamilton's principle. Reciprocal principles are also derived for both the generalized Maupertuis and the Hamilton principles. The Reciprocal Maupertuis Principle is the classical limit of Schr\"{o}dinger's variational principle of wave mechanics, and is also very useful to solve practical problems in both classical and semiclassical mechanics, in complete analogy with the quantum Rayleigh-Ritz method. Classical, semiclassical and quantum variational calculations are carried out for a number of systems, and the results are compared. Pedagogical as well as research problems are used as examples, which include nonconservative as well as relativistic systems