Inhibitors of the Hepatitis C Virus Polymerase; Mode of Action and Resistance

The hepatitis C virus (HCV) is a pandemic human pathogen posing a substantial health and economic burden in both developing and developed countries. Controlling the spread of HCV through behavioural prevention strategies has met with limited success and vaccine development remains slow. The development of antiviral therapeutic agents has also been challenging, primarily due to the lack of efficient cell culture and animal models for all HCV genotypes, as well as the large genetic diversity between HCV strains. On the other hand, the use of interferon-α-based treatments in combination with the guanosine analogue, ribavirin, achieved limited success, and widespread use of these therapies has been hampered by prevalent side effects. For more than a decade, the HCV RNA-dependent RNA polymerase (RdRp) has been targeted for antiviral development. Direct acting antivirals (DAA) have been identified which bind to one of at least six RdRp inhibitor-binding sites, and are now becoming a mainstay of highly effective and well tolerated antiviral treatment for HCV infection. Here we review the different classes of RdRp inhibitors and their mode of action against HCV. Furthermore, the mechanism of antiviral resistance to each class is described, including naturally occurring resistance-associated variants (RAVs) in different viral strains and genotypes. Finally, we review the impact of these RAVs on treatment outcomes with the newly developed regimens.     

Nicotine-induced dopamine plasticity: a gateway to neurotransmitter replacement?

Nicotine,the principal neuroactive component of tobacco,acts on the reward systems of smokers,inducing addiction.Experimental evidence indicates that nicotine-induced addiction alters the activity of dopaminergic neurons within reward-processing brain centers.The effect of developmental nicotine exposure on neuroplasticity of identified reward neurocircuitry in the adult is finally emerging and begins to be understood at the molecular,cellular,and behavioral level(Romoli et al.,2019).     

Cardiopulmonary exercise testing for personalized job reintegration after acute cardiovascular attacks: a pilot cross-sectional study

Background:Cardiovascular diseases (CVD), particularly the ischemic heart disease, are a growing public health issue. In addition, the return to work after an acute cardiovascular attack represents a complex challenge.Objectives:To evaluate utility and safety of cardiopulmonary exercise testing (CPET), particularly performed “on site”, to promote a return to work in line with the residual working capacity.Methods:Fifty-nine workers affected by a major cardiovascular event, aged 18-63 years, have been enrolled between 2015 and 2018. All the patients underwent a CPET in outpatient clinic. Eleven workers also underwent the “on site” CPET, recorded during their working activities.Results:Outpatient clinic CPET outcomes (i.e. normal, mild impairment or moderate/severe impairment of cardiopulmonary function) were associated with the subjective perception of workers’ health status after returning to work. The “on site” CPET was found to be safe and reliable to promote a personalized return to work of patients. In 7 out of 11 patients, the values of O₂ consumption (VO₂) during the working activity were higher than 40% of VO₂ max as obtained from laboratory CPET.Conclusions:This study provides evidence for safety and usefulness of “on site” CPET for a personalized statement of fitness for work. This may facilitate the job retention of patients characterized by a high risk of unnecessary job loss. The use of CPET represents a first step of energy expenditure evaluation associated with specific working tasks.Key words: Acute coronary syndrome, cardiopulmonary exercise testing, return to work     

Sensitivity and specificity of a self-administered questionnaire for familial screening of adult-onset dystonia.

We developed a self-administered questionnaire for screening the most common adult-onset dystonias. It was tested in 90 first-degree relatives of 22 adult-onset dystonia patients, yielding 79% sensitivity and 94% specificity. Simulation of a case-finding procedure based on serial application of the questionnaire and clinical examination of both subjects screening positive and subjects screening negative who had < 8 years of schooling increased sensitivity to 95% and specificity to 100%. This questionnaire may be an important screening resource for familial aggregation studies to be used in the context of a complex case-finding procedure.     

3D FEA of cemented steel, glass and carbon posts in a maxillary incisor.

OBJECTIVES: A comparative study on the stress distribution in the dentine and cement layer of an endodontically treated maxillary incisor has been carried out by using Finite Element Analysis (FEA). The role of post and cement rigidity on reliability of endodontic restorations is discussed. METHODS: A 3D FEM model (13,272 elements and 15,152 nodes) of a central maxillary incisor is presented. A chewing static force of 10 N was applied at 125 degree angle with the tooth longitudinal axis at the palatal surface of the crown. Steel, carbon and glass fiber posts have been considered. The differences in occlusal load transfer ability when steel, carbon and glass posts, fixed to root canal using luting cements of different elastic moduli (7.0 and 18.7 GPa) are discussed. RESULTS AND SIGNIFICANCE: The more stiff systems (steel and carbon posts) have been evaluated to work against the natural function of the tooth. Maximum Von Mises equivalent stress values ranging from 7.5 (steel) to 5.4 and 3.6 MPa (respectively, for carbon posts fixed with high and low cement moduli) and to 2.2 MPa (either for glass posts fixed with high and low cement moduli) have been observed under a static masticatory load of 10 N. A very stiff post works against the natural function of the tooth creating zones of tension and shear both in the dentine and at the interfaces of the luting cement and the post. Stresses in static loading do not reach material (dentine and cement) failure limits, however, they significantly differ leading to different abilities of the restored systems to sustain fatigue loading. The influence of the cement layer elasticity in redistributing the stresses has been observed to be less relevant as the post flexibility is increased.     

An exceptional postoperative gastric tube bleeding after esophageal resection for cancer

A case of gastric tube bleeding after an Ivor-Lewis esophagectomy with gastroesophageal anastomosis is reported. During the early postoperative course, the patient had a gastric tube stasis that improved progressively. The subsequent onset of a serious and intermittent hematemesis, which was endoscopically deemed to be the result of a hemorrhagic gastritis, required multiple blood transfusions. The evolution to a severe hemodynamic instability obliged us to reoperate on the patient. During surgery, a band-related obstruction of the first jejunal loop with local signs of vascular hypertension was noted. As soon as the obstruction was solved, the gastric bleeding stopped. The authors discuss the clinical aspects and physiopathology of the gastric tube bleeding and, in particular, they evaluate the influence of the intestinal obstruction with vascular involvement on the development of this exceptional and severe complication.