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er study protocol experienced at least a 4-step DR severity improvement on the DRSS, accompanied by meaningful improvements in BCVA.Sexual selection and divergent selection are among the major driving forces of reproductive isolation, which could eventually result in speciation. A magic trait is defined such that a single trait is subject to both divergent selection and mate choice through phenotype-based assortative mating. We are here interested in the evolutionary behavior of alleles at a genetic locus responsible for a magic trait in a finite population. We assume that, in a pair of homogeneous subpopulations, a mutant allele arises at the magic trait locus, and theoretically obtain the probability that the new allele establishes in the population, or the establishment probability. We also show an analytical expression for the trajectory of allele frequency along the establishment, from which the time required for the establishment is obtained, or the establishment time. Under this model, divergent selection simply favors the new allele to fix where it is beneficial, whereas assortative mating works against rare alleles. It is theoretically demonstrated that the fate of the new allele is determined by the relative contributions of the two selective forces, divergent selection and assortative mating, when the allele is rare so that the two selective forces counteract. Our theoretical results for the establishment probability and time allow us to understand the relative role of random genetic drift in the establishment process of a magic trait allele in a finite population.Treatment adaptation after hepatitis B virus (HBV) treatment failure relies on genotypic resistance testing. However, the results of such tests are not always consistent with treatment response. These discrepancies may be due to differences in resistance levels between isolates with the same genotypic resistance testing profiles. We explored this hypothesis by investigating six cases of entecavir treatment failure with an integrative strategy combining genotypic and phenotypic resistance testing, medical record review and therapeutic drug monitoring. Among isolates with genotypic reduced susceptibility to entecavir, one displayed a higher level of resistance to entecavir (mean fold change in entecavir IC50 of 1 508 ± 531 vs. 318 ± 53, p = 0.008). This isolate harbored a substitution (rt250L) at a position reported to be associated with resistance (rt250V). Reversion to wild-type amino acid at this position partially restored susceptibility to entecavir, confirming that the rt250L mutation was responsible for the high level of resistance to entecavir. This is the first description of entecavir treatment failure associated with selection of the rt250L mutation without other entecavir resistance mutations. One isolate with genotypic resistance to entecavir, harboring the rt173L mutation, displayed a lower level of resistance than the other, harboring the rt202G mutation (mean fold change of 323 ± 124 vs. read more 6 036 ± 2 100, p = 0.20). These results suggest that isolates harboring the rt250L mutations should be considered resistant to entecavir, whereas isolates harboring the rt173L mutations should be considered to display reduced susceptibility to entecavir. An integrative approach to antiviral drug resistance in HBV would provide a more accurate assessment of entecavir treatment failures and help to improve the accuracy of genotypic testing algorithms.Based on genome-scale loss-of-function screens we discovered that Topoisomerase III-β (TOP3B), a human topoisomerase that acts on DNA and RNA, is required for yellow fever virus and dengue virus-2 replication. Remarkably, we found that TOP3B is required for efficient replication of all positive-sense-single stranded RNA viruses tested, including SARS-CoV-2. While there are no drugs that specifically inhibit this topoisomerase, we posit that TOP3B is an attractive anti-viral target.

Despite numerous studies assessing the natural history of patients with hypertrophic cardiomyopathy (HCM), there is lack of data regarding the burden of hospitalization. Aim of this study was to describe prevalence, causes and predictors of cardiovascular hospitalization in patients with HCM.

We retrospectively included 253 patients with HCM undergoing first evaluation at our center. Enrolment criteria included cardiac magnetic resonance imaging (CMRI) at baseline and>1-year follow-up. All hospital admissions were recorded during follow-up and adjudicated as acute vs elective and cardiovascular (CV) vs non-cardiovascular (non-CV).

During 6.4±4.0years there were 187 hospitalizations in 92 patients (36%, at a rate of 5.7%/year). Most were CV-related (158/187,84.5%; 4.8%/year) while non-CV admissions were 29/187 (15.5%, 0.88%/year). There was a slight predominance of elective (n=96, 58%, 2.8%/year) vs acute (n=62, 41.8%, 2.0%/year) CV hospitalizations. Independent predictors of CV hospitalization were breventing hospitalizations are an important target to reduce the burden of disease in HCM patients.Indirect and direct approaches to assess sympathetic neural function in man have shown that congestive heart failure is characterized by a marked adrenergic overdrive. Although compensatory in the initial phases of the disease, with time the sympathetic overactivity exerts adverse cardiovascular effects, favoring the disease progression and promoting the occurrence of non-fatal and fatal cardiovascular events. This explains why the adrenergic overactivity has become an important target of the therapeutic interventions adopted in the managementof the disease. The present paper will examine the impact of therapeutic approaches, used in the management of heart failure, on the sympathetic activation characterizing the disease. After a brief mention of the sympathetic effects of non-pharmacological interventions and procedural approches, particular emphasis will be given to the effects of pharmacological interventions and device treatments (renal denervation and carotid baroreceptor stimulation), which became in recent years a promising tool for the management of the disease. The clinical implications as well as the unsolved aspects related to the sympathomodulatory interventions in heart failure management will be finally discussed.