Geometric approach to the Hamilton-Jacobi equation and global parametrices for the Schr\"odinger propagator

We construct a family of Fourier Integral Operators, defined for arbitrary large times, representing a global parametrix for the Schr\"odinger propagator when the potential is quadratic at infinity. This construction is based on the geometric approach to the corresponding Hamilton-Jacobi equation and thus sidesteps the problem of the caustics generated by the classical flow. Moreover, a detailed study of the real phase function allows us to recover a WKB semiclassical approximation which necessarily involves the multivaluedness of the graph of the Hamiltonian flow past the caustics

On the determination of constitutive parametersin a hyperelastic model for a soft tissue

The aim of this paper is to study a model of hyperelastic materials and itsapplications into soft tissue mechanics. In particular, we first determine an unbounded domain of the constitutive parameters of the model making our smoothstrain energy function to be polyconvex and hence satisfying the Legendre–Hadamard condition. Thus, physically reasonable material behaviour are described by our model with these parameters and a plently of tissues can betreated. Furthermore, we localize bounded subsets of constitutive parameters in fixed physical and very general bounds and then introduce a family of descrete stress–strain curves. Whence, various classes of tissues are characterized. Ourgeneral approach is based on a detailed analytical study of the first Piola–Kirchhoff stress tensor through its dependence on the invariants and on the constitutive parameters. The uniqueness of parameters for one tissue is discussed by introducing the notion of manifold of constitutive parameters, whichis locally represented by possibly different physical quantities. The advantage of our study is that we show a possible way to improve of the usual approachesshown in the literature which are mainly based on the minimization of a costfunction as the difference between experimental and model results

Use of Miltefosine in a Patient With Mucosal Leishmaniasis and HIV-coinfection: A Challenge in Long-Term Management

The management of mucosal leishmaniasis in immunocompromised patients is not standardized and limited data are available on the use of miltefosine for treatment and secondary prophylaxis. We describe a case of mucosal leishmaniasis in an HIV-coinfected patient treated with miltefosine due to a severe allergic reaction to liposomal amphotericin B

Interactions of airborne graphene oxides with the sexual reproduction of a model plant: When production impurities matter

The increasing use of graphene-related materials (GRMs) in everyday-life products raises concerns for their possible release into the environment and consequent impact on organisms. GRMs have widely varying effects on plants and, according to recent evidences, graphene oxide (GO) has the potential to interfere with the sexual reproduction owing to its acidic properties and production residues. Here, stigmas of the model plant Cucurbita pepo (summer squash) were subjected to simulated dry depositions of GO and GO purified from production residues (PGO). Stigmas were then hand-pollinated and GRM deposition was checked by ESEM and confocal microscopy. Analysis of stigma integrity, pH homeostasis and pollen-stigma interactions did not reveal negative effects. Fruit and seed production were not affected, but GO depositions of 22.1 ± 7.2 ng mm-2 affected the normal development of seeds, decreasing seed dimensions, seed germination and germination speed. The elemental analysis revealed that GO has significant quantities of production residues, such as strong acids and oxidants, while PGO has only traces, which justifies the differences observed in the effects caused by the two materials. Our results show that GO depositions of up to 11.1 ± 3.6 ng mm-2, which fall within the variation range of total dry particulate matter depositions reported in the literature, are safe for reproduction of C. pepo. This is the first "safety" limit ever recorded for depositions of "out-of-the-box" GO concerning the reproduction of a seed plant. If confirmed for wind-pollinated species, it might be considered for policymaking of GRMs emissions in the air

On the dynamics of WKB wave functions whose phase are weak KAM solutions of H-J equation

In the framework of toroidal Pseudodifferential operators on the flat torus $\Bbb T^n := (\Bbb R / 2\pi \Bbb Z)^n$ we begin by proving the closure under composition for the class of Weyl operators $\mathrm{Op}^w_\hbar(b)$ with simbols $b \in S^m (\mathbb{T}^n \times \mathbb{R}^n)$. Subsequently, we consider $\mathrm{Op}^w_\hbar(H)$ when $H=\frac{1}{2} |\eta|^2 + V(x)$ where $V \in C^\infty (\Bbb T^n;\Bbb R)$ and we exhibit the toroidal version of the equation for the Wigner transform of the solution of the Schr\"odinger equation. Moreover, we prove the convergence (in a weak sense) of the Wigner transform of the solution of the Schr\"odinger equation to the solution of the Liouville equation on $\Bbb T^n \times \Bbb R^n$ written in the measure sense. These results are applied to the study of some WKB type wave functions in the Sobolev space $H^{1} (\mathbb{T}^n; \Bbb C)$ with phase functions in the class of Lipschitz continuous weak KAM solutions (of positive and negative type) of the Hamilton-Jacobi equation $\frac{1}{2} |P+ \nabla_x v_\pm (P,x)|^2 + V(x) = \bar{H}(P)$ for $P \in \ell \Bbb Z^n$ with $\ell >0$, and to the study of the backward and forward time propagation of the related Wigner measures supported on the graph of $P+ \nabla_x v_\pm$

Prevalence of resistance-associated substitutions to NS3, NS5A and NS5B inhibitors at DAA-failure in hepatitis C virus in Italy from 2015 to 2019

: Despite the high efficacy of direct-acting antivirals (DAAs), the selection of resistance-associated substitutions (RASs) after virological failure of hepatitis C virus (HCV) DAAs can impair the cure of chronic HCV. The aim of the study was to characterize RASs after virological failure of DAAs in Italy over the years. Within the Italian network VIRONET-C, the change in prevalence of NS3/4A-NS5A-NS5B RASs was retrospectively evaluated in patients who failed a DAA regimen over the years 2015-2019. NS3, NS5A and NS5B Sanger sequencing was performed using homemade protocols and the geno2pheno system was used to define HCV-genotype/subtype and predict drug resistance. The changes in the prevalence of RASs over time were evaluated using the chi-square test for trend. Predictors of RASs at failure were analysed by logistic regression. Among 468 HCV-infected patients, HCV genotype 1 was the most prevalent (1b in 154, 33% and 1a in 109, 23%). DAA regimens were: ledipasvir (LDV)/sofosbuvir (SOF) in 131 patients (28%), daclatasvir (DCV)/SOF in 109 (23%), ombitasvir/paritaprevir/ritonavir+dasabuvir (3D) in 89 (19%), elbasvir (EBR)/grazoprevir (GRZ) in 52 (10.5%), velpatasvir (VEL)/SOF in 53 (11%), glecaprevir (GLE)/pibrentasvir (PIB) in 27 (6%) and ombitasvir/paritaprevir/ritonavir (2D) in 7 (1.5%); ribavirin was administered in 133 (28%). The NS5A fasta sequence was available for all patients, NS5B and NS3/4A both for 93%. The prevalence of NS5A and NS3/4A RASs significantly declined from 2015 to 2019; NS5B RAS remained stable. Independent predictors of any RASs included older age and genotype 1a (vs G2 and vs G4). Notably, at least partial susceptibility to all the agents included in the GLE/PIB and VEL/SOF/Voxilaprevir (VOX) combinations was predicted in >95% of cases. As RASs remain common at the failure of DAAs, their identification could play a crucial role in optimizing re-treatment strategies. In Italy RAS prevalence has been decreasing over the years and susceptibility to the latest developed drug combinations is maintained in most cases

DECLINE OF PREVALENCE OF RESISTANCE ASSOCIATED SUBSTITUTIONS TO NS3 AND NS5A INHIBITORS AT DAA- FAILURE IN HEPATITIS C VIRUS IN ITALY OVER THE YEARS 2015 TO 2018

Background: A minority of patients fails to eliminate HCV and resistance-associated substitutions (RASs) are commonly detected at failure of interferon-free DAA regimens . Methods: Within the Italian network VIRONET-C, the prevalence of NS3/NS5A/NS5B RASs was retrospectively evaluated in patients who failed an EASL recommended DAA-regimen in 2015-2018 . The geno2pheno system and Sorbo MC et al. Drug Resistance Updates 2018 were used to infer HCV- genotype/subtype and predict drug resistance . The changes in prevalence of RASs over time were evaluated by chi-square test for trend, predictors of RASs at failure were analysed by logistic regression . Results: We included 386 HCV infected patients: 75% males, median age was 56 years (IQR 52-61), metavir fibrosis stage F4 in 76%; 106 (28%) were treatment- experienced: 91 (86%) with IFN-based treatments, 26 (25%) with DAAs. Patients with HIV and HBV coinfection were 10% (33/317) and 8% (6/72), respectively. HCV genotype was 1b in 122 pts (32%), 3 in 109 (28%), 1a in 97 (25%), 4 in 37 (10%), 2 in 21 (5%). DAA regimens were: LDV/SOF in 115 (30%), DCV/SOF in 103 (27%), 3D in 83 (21%), EBR/GRZ in 32 (8%), VEL/SOF in 29 (7%), GLE/PIB in 18 (5%) and 2D in 6 (2%); ribavirin was administered in 123 (32%) . The NS5A fasta-sequence was available for all patients, NS5B for 361 (94%), NS3 for 365 (95%) . According to the DAA failed the prevalence of any RASs was 90%, namely 80/135 (59%) in NS3, 313/359 (87%) in NS5A, 114/286 (40%) in NS5B . The prevalence of any RASs significantly declined from 2015 to 2018 (93% vs 70%, p=0.004): NS5A RASs from 90% to 72% (p=0 .29), NS3 RASs from 74% to 18% (p<0 .001), while NS5B RASs remained stable . Independent predictors of any RASs included advanced fibrosis (AOR 6.1, CI 95% 1.8-20.3, p=0 .004) and genotype (G2 vs G1a AOR 0 .03, CI 95% 0 .002- 0 .31, p=0 .004; G3 vs G1a AOR 0 .08, CI 95% 0 .01-0 .62, p=0 .02; G4 vs G1a AOR 0 .05, CI 95% 0 .006-0 .46, p=0 .008), after adjusting for age, previous HCV treatment and year of genotype . Notably, full activity was predicted for GLE/PIB in 75% of cases and for at least two components of VEL/SOF/VOX in 53% of cases, no case with full-resistance to either regimen was found . Conclusion: Despite decreasing prevalence over the years, RASs remain common at virological failure of DAA treatment, particularly in patients with the highest grade of liver fibrosis. The identification of RASs after failure could play a crucial role in optimizing retreatment strategies

The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males

The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired macroautophagy/autophagy and reduced TNF/TNFα production was demonstrated in HEK293 cells transfected with TLR3L412F-encoding plasmid and stimulated with specific agonist poly(I:C). A statistically significant reduced survival at 28 days was shown in L412F COVID-19 patients treated with the autophagy-inhibitor hydroxychloroquine (p = 0.038). An increased frequency of autoimmune disorders such as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways. Abbreviations: AP: autophagosome; AUC: area under the curve; BafA1: bafilomycin A1; COVID-19: coronavirus disease-2019; HCQ: hydroxychloroquine; RAP: rapamycin; ROC: receiver operating characteristic; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLR: toll like receptor; TNF/TNF-α: tumor necrosis factor