Protease inhibitors-based therapy induces acquired spherocytic-like anemia and ineffective erythropoiesis in chronic HCV patients

Background & Aims: The addition of protease inhibitors, boceprevir (BOC)or telaprevir (TRV), to peg-interferon and ribavirin (PR) increases the incidenceof anaemia in patients with chronic hepatitis C virus (HCV) infection.Although genetic variants in inosine triphosphatase (ITPA) gene have beenlinked to the haemolytic anaemia induced by PR, the mechanism sustainingsevere anaemia during triple therapy is still unknown. This study aims to elucidatethe molecular mechanisms underlying anaemia in chronic HCVpatients with combined therapy. Methods: We studied 59 patients withchronic HCV genotype-1: 29 treated with TRV/PR and 30 with BOC/PR. Weevaluated biochemical and haematological parameters, red cell index at baseline,4, 12, 16 and 24 weeks of treatment; in a subgroup, we performed functionalstudies: osmotic fragility, red cell membrane protein separation, massspectrometry analysis, quantification of erythroid microparticles release.IL28B and ITPA polymorphisms were also evaluated. Results: We foundearly acute normochromic normocytic haemolytic anaemia (4\u20138 weeks) followedby a late macrocytic hypo-regenerative anaemia with inappropriatelow reticulocyte count (12\u201324 weeks). Studies on red cells revealed: (i) presenceof spherocytes; (ii) increased osmotic fragility; (iii) abnormalities in redcell membrane protein composition; (iv) reduced membrane-cytoskeletonstability; (v) increased release of erythroid microparticles. ITPA polymorphismsimpacted only the early phase of anaemia. Conclusions: The bimodalpattern of anaemia in chronic HCV patients on triple therapy might bebecause of acquired spherocytic-like anaemia in the early phase, followed byhyporegenerative anaemia, most likely related to the combined effects of PRand TRV or BOC on erythropoiesis

Metal-organic framework glasses with permanent accessible porosity.

To date, only several microporous, and even fewer nanoporous, glasses have been produced, always via post synthesis acid treatment of phase separated dense materials, e.g. Vycor glass. In contrast, high internal surface areas are readily achieved in crystalline materials, such as metal-organic frameworks (MOFs). It has recently been discovered that a new family of melt quenched glasses can be produced from MOFs, though they have thus far lacked the accessible and intrinsic porosity of their crystalline precursors. Here, we report the first glasses that are permanently and reversibly porous toward incoming gases, without post-synthetic treatment. We characterize the structure of these glasses using a range of experimental techniques, and demonstrate pores in the range of 4 - 8 Å. The discovery of MOF glasses with permanent accessible porosity reveals a new category of porous glass materials that are elevated beyond conventional inorganic and organic porous glasses by their diversity and tunability

Real-life data on potential drug-drug interactions in patients with chronic hepatitis C viral infection undergoing antiviral therapy with interferon-free DAAs in the PITER Cohort Study

Background There are few real-life data on the potential drug-drug interactions (DDIs) between anti-HCV direct-acting antivirals (DAAs) and the comedications used. Aim To assess the potential DDIs of DAAs in HCV-infected outpatients, according to the severity of liver disease and comedication used in a prospective multicentric study. Methods Data from patients in 15 clinical centers who had started a DAA regimen and were receiving comedications during March 2015 to March 2016 were prospectively evaluated. The DDIs for each regimen and comedication were assigned according to HepC Drug Interactions (www.hep-druginteractions.org). Results Of the 449 patients evaluated, 86 had mild liver disease and 363 had moderate-to-severe disease. The use of a single comedication was more frequent among patients with mild liver disease (p = 0.03), whereas utilization of more than three drugs among those with moderate-to-severe disease (p = 0.05). Of the 142 comedications used in 86 patients with mild disease, 27 (20%) may require dose adjustment/closer monitoring, none was contraindicated. Of the 322 comedications used in 363 patients with moderate-to-severe liver disease, 82 (25%) were classified with potential DDIs that required only monitoring and dose adjustments; 10 (3%) were contraindicated in severe liver disease. In patients with mild liver disease 30% (26/86) used at least one drug with a potential DDI whereas of the 363 patients with moderate-to-severe liver disease, 161 (44%) were at risk for one or more DDI. Conclusions Based on these results, we can estimate that 30-44% of patients undergoing DAA and taking comedications are at risk of a clinically significant DDI. This data indicates the need for increased awareness of potential DDI during DAA therapy, especially in patients with moderate-to-severe liver disease. For several drugs, the recommendation related to the DDI changes from "dose adjustment/closer monitoring" in mild to moderate liver disease, to "the use is contraindicated" in severe liver disease

Tracing compilation by abstract interpretation

Tracing just-in-time compilation is a popular compilation schema for the efficient implementation of dynamic languages, which is commonly used for JavaScript, Python, and PHP. It relies on two key ideas. First, it monitors the execution of the program to detect so-called hot paths, i.e., the most frequently executed paths. Then, it uses some store information available at runtime to optimize hot paths. The result is a residual program where the optimized hot paths are guarded by sufficient conditions ensuring the equivalence of the optimized path and the original program. The residual program is persistently mutated during its execution, e.g., to add new optimized paths or to merge existing paths. Tracing compilation is thus fundamentally different than traditional static compilation. Nevertheless, despite the remarkable practical success of tracing compilation, very little is known about its theoretical foundations. We formalize tracing compilation of programs using abstract interpretation. The monitoring (viz., hot path detection) phase corresponds to an abstraction of the trace semantics that captures the most frequent occurrences of sequences of program points together with an abstraction of their corresponding stores, e.g., a type environment. The optimization (viz., residual program generation) phase corresponds to a transform of the original program that preserves its trace semantics up to a given observation as modeled by some abstraction. We provide a generic framework to express dynamic optimizations and to prove them correct. We instantiate it to prove the correctness of dynamic type specialization. We show that our framework is more general than a recent model of tracing compilation introduced in POPL 2011 by Guo and Palsberg (based on operational bisimulations). In our model we can naturally express hot path reentrance and common optimizations like deadstore elimination, which are either excluded or unsound in Guo and Palsberg's framework

Monitoring of immunosuppressive therapy in renal transplanted patients

The regulation of the immunosuppressive therapy after kidney transplantation is the most complex aspect of the management of transplanted patients. Every day the transplant clinician is challenged by need to provide a sufficient immunosuppression to avoid or reduce the risk of rejection without exposing the patient to the risk of developing opportunistic infections or malignancy or toxic side effects. The safety and efficacy profile Of immunosuppressive therapy is limited within a narrow therapeutic window whose borders are represented by two clinical Conditions Such as rejection and drug-related toxicity. The availability of several different drugs allows the clinicians to make multiple choices to individualize treatments according to the specific needs of a single patient. Pharmacokinetic monitoring of the immunosuppressive drugs is an important element in the management of these patients but cannot be considered as the unique driving factor and must be integrated with a careful Surveillance and evaluation of all drug-related side effects

TCAD study of the Holding-Voltage Modulation in Irradiated SCR-LDMOS for HV ESD Protection

This paper investigates a method to increase the holding voltage in a conventional Silicon Controlled Rectifier (SCR) for ESD power clamping. Specifically, a SCR-LDMOS device with 150 V trigger voltage and 9 V holding voltage is investigated assuming the application of high-energy electron irradiation. Based on previous experimental and TCAD investigations, the most relevant kind of defects is accounted for at different irradiation levels clearly showing an increase of the holding voltage up to 16 V without any other significant change in the TLP characteristics. The role of trapped charges in the holding regime has been addressed up to the thermal runaway through extensive numerical investigations