Evaluation of Drug Interactions in Patients Treated with DAAs for Hepatitis C Therapy with Comorbidities and Cardiovascular Issues—A Delphi Consensus Project

Orally administered direct-acting antivirals (DAAs) have dramatically changed the possibility of curing HCV (hepatitis C virus) infection, with the two principal HCV regimens based on the combination of glecaprevir + pibrentasvir (GLE-PIB) and sofosbuvir + velpatasvir (SOF-VEL). A combination of drugs containing NS3/4A protease inhibitors, as well as the fact that almost all HCV patients can be treated at present, may expose patients to a higher rate of drug–drug interactions (DDIs). The hepatitis C treatment recommendations from the EASL (European Association for the Study of the Liver) state that, prior to starting treatment with a DAA, a detailed drug history should be taken; yet, the decision on managing the potential DDIs is not always clear. For this reason, a group of Italian cardiologists and hepatologists promoted a survey among colleagues to assess the controversial issues when treating patients with chronic hepatitis C taking concomitant cardiovascular drugs, aiming to reach a consensus on the best practice to apply when treating a patient with chronic hepatitis C who is taking concomitant drugs for cardiovascular diseases. Two consecutive questionnaires were proposed between June and July 2022 to a qualitative Expert Panel (EP) of 14 gastroenterologists, infectologists, hepatologists, and internists, with statistical analyses performed on 100% of the responses for both questionnaires. Agreement among experts was assessed following the Delphi method as developed by the RAND Corporation. The interviewed experts consider DDIs a critical clinical problem to be evaluated in HCV patients. Therefore, dose changes, drug substitution, and discontinuation of concomitant cardiovascular drugs should be discouraged, even if planned for a relatively short period. Since oral DAAs have different DDIs profiles, hepatologists should prefer the antiviral DAA combination presenting the lowest instance of potential interactions

Primer informe de Aelurostrongylus abstrusus en el caracol de tierra Rumina decollata, en la Ciudad Autónoma de Buenos Aires

Aelurostrongylus abstrusus (Railliet, 1898) is a worldwide distributed lungworm that affects wild and domestic cats, causing bronchopneumonia of varying intensity. Cats became infected by eating slugs and snails with third infective stage larvae (L3). The aim of the study was to describe the presence of A. abstrusus in R. decollate snails. R. decollata specimens and samples of cats’ faeces were collected from the open spaces of a public institution of Buenos Aires city, inhabited by a stray cat population. Cats’ faeces were processed by Baermman´s technique and snails were digested in pool, by artificial digestion method. First stage larvae of A. abstrusus were recovered from 35.30 % (6/17) of the sampled faeces. An 80 % (20/25) snails pools were positive for the second and third larval stages. Mean value of total larvae recovered per pool was 150.64 and mean value of L3/pool was 93.89. This is the first report of the development of A. abstrusus infective larvae in R. decollate snail as intermediate host, since the relationship between high levels of infection in snails and in cats’ faeces could be demonstrated in cats’ habitat.Aelurostrongylus abstrusus (Railliet, 1898) es un helminto pulmonar mundialmente distribuido que afecta a los gatos, causando bronconeumonias de variada intensidad. La infección se produce por ingestión de babosas y caracoles terrestres con larvas infectantes (L3). El objetivo del estudio fue describir la presencia de A. abstrusus en el caracol R. decollata. Se recolectaron muestras de heces felinas y caracoles presentes en una institución pública de la Ciudad Autónoma de Buenos Aires, habitada por una población de gatos sin propietario. Las heces fueron procesadas mediante la técnica de Baermman y los caracoles fueron digeridos en pool por digestión artificial enzimática. Larvas de primer estadio (L1) de A. abstrusus fueron recuperadas en el 35,30% (6/17) de las heces. El 80% (20/25) de los pooles de caracoles presentó larvas de segundo y tercer estadio. El promedio de larvas totales recuperado por pool fue de 150,64 y el valor medio de L3/pool fue de 93.89. Este es el primer hallazgo del desarrollo de larvas infectivas de A. abstrusus en el caracol doméstico R. decollata. Los altos niveles de infección encontrados en los caracoles y en las heces de los gatos demuestran el potencial de R. decollata como hospedador intermediario de A. abstrusus.Fil: Cardillo, Natalia Marina. Universidad de Buenos Aires. Facultad de Cs.veterinarias. Area de Parasitología y Enfermedades Parasitarias; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Clemente, A.. Universidad de Buenos Aires. Facultad de Cs.veterinarias. Area de Parasitología y Enfermedades Parasitarias; ArgentinaFil: Pasqualetti, M.. Universidad de Buenos Aires. Facultad de Cs.veterinarias. Area de Parasitología y Enfermedades Parasitarias; ArgentinaFil: Borrás, P.. Universidad de Buenos Aires. Facultad de Cs.veterinarias. Area de Parasitología y Enfermedades Parasitarias; ArgentinaFil: Rosa, A.. Universidad de Buenos Aires. Facultad de Cs.veterinarias. Area de Parasitología y Enfermedades Parasitarias; ArgentinaFil: Ribicich, M.. Universidad de Buenos Aires. Facultad de Cs.veterinarias. Area de Parasitología y Enfermedades Parasitarias; Argentin

A Cross-Linguistic Study of the Relationship between Grammar & Lexical Development

The relationship between grammatical and lexical development was compared in 233 English and 233 Italian children aged between 1;6 and 2;6, matched for age, gender, and vocabulary size on the MacArthur Communicative Development Inventories (CDI). Four different measures of Mean Length of Utterance were applied to the three longest utterances reported by parents, and to corrected/expanded versions representing the 'target' for each utterance. Italians had longer MLUs on most measures, but the ratio of actual to target MLUs did not differ between languages. Age and vocabulary both contributed significant variance to MLU, but the contribution of vocabulary was much larger, suggesting that vocabulary size may provide a better basis for crosslinguistic comparisons of grammatical development. The relationship between MLU and vocabulary size was non-linear in English but linear in Italian, suggesting that grammar 'gets off the ground' earlier in a richly inflected language. A possible mechanism to account for this difference is discussed

Probing transport and slow relaxation in the mass-imbalanced Fermi-Hubbard model

Constraints in the dynamics of quantum many-body systems can dramatically alter transport properties and relaxation time scales even in the absence of static disorder. Here, we report on the observation of such constrained dynamics arising from the distinct mobility of two species in the one-dimensional mass-imbalanced Fermi-Hubbard model, realized with ultracold ytterbium atoms in a state-dependent optical lattice. By displacing the trap potential and monitoring the dynamical response of the system, we identify suppressed transport and slow relaxation with a strong dependence on the mass imbalance and interspecies interaction strength, suggesting eventual thermalization for long times. Our observations are supported by numerical simulations and pave the way to study metastability arising from dynamical constraints in other quantum many-body systems

Decipher the glioblastoma microenvironment: The first milestone for new groundbreaking therapeutic strategies

Glioblastoma (GBM) is the most common primary malignant brain tumour in adults. Despite the combination of novel therapeutical approaches, it remains a deadly malignancy with an abysmal prognosis. GBM is a polymorphic tumour from both molecular and histological points of view. It consists of different malignant cells and various stromal cells, contributing to tumour initiation, progression, and treatment response. GBM’s microenvironment is multifaceted and is made up of soluble factors, extracellular matrix components, tissue-resident cell types (e.g., neurons, astrocytes, endothelial cells, pericytes, and fibroblasts) together with resident (e.g., microglia) or recruited (e.g., bone marrow-derived macrophages) immune cells. These latter constitute the so-called immune microenvironment, accounting for a substantial GBM’s tumour volume. Despite the abundance of immune cells, an intense state of tumour immunosuppression is promoted and developed; this represents the significant challenge for cancer cells’ immune-mediated destruction. Though literature data suggest that distinct GBM’s subtypes harbour differences in their microenvironment, its role in treatment response remains obscure. However, an in-depth investigation of GBM’s microenvironment may lead to novel therapeutic opportunities to improve patients’ outcomes. This review will elucidate the GBM’s microenvironment composition, highlighting the current state of the art in immunotherapy approaches. We will focus on novel strategies of active and passive immunotherapies, including vaccination, gene therapy, checkpoint blockade, and adoptive T-cell therapies

Comparative pharmacokinetic and pharmacodynamic evaluation of branded and generic formulations of meloxicam in healthy male volunteers

PURPOSE: The primary aim of the present study was to assess the pharmacokinetic bioequivalence between a generic formulation of meloxicam 15 mg tablets (Meloxicam Hexal) and its respective brand product (Mobic), in order to verify whether the generic product conforms to the regulatory standards of bioequivalence in the postmarketing setting. As a secondary exploratory aim, the pharmacodynamic effects of the two formulations were also evaluated by means of rating scales following hyperalgesia induced by cutaneous freeze injury. SUBJECTS AND METHODS: A single 15 mg dose of generic or branded meloxicam tablets was administered to 24 healthy male volunteers in a crossover fashion. Plasma samples, collected for 24 hours after dosing, were assayed for meloxicam concentration by a validated highperformance liquid chromatography method. RESULTS: THE ANALYSIS OF PHARMACOKINETIC PARAMETERS DID NOT SHOW ANY SIGNIFICANT DIFFERENCE BETWEEN THE TWO MELOXICAM FORMULATIONS: the 90% confidence intervals fell within the acceptance range of 80%-125% (0.84-1.16 for area under the curve [0-24], and 0.89-1.23 for peak concentration). No difference in the pharmacodynamic end point was observed between the two groups. CONCLUSION: The pharmacokinetic profiles of the two meloxicam formulations confirm the regulatory criteria for bioequivalence; pharmacodynamic data indicate a similar antihyperalgesic effect. The two formulations can be used interchangeably in the clinical setting

Radiomics-Based Inter-Lesion Relation Network to Describe [18F]FMCH PET/CT Imaging Phenotypes in Prostate Cancer

Advanced image analysis, specifically radiomics, has been recognized as a potential source of biomarkers for cancers. However, there are challenges to its application in the clinic, such as proper description of diseases where multiple lesions coexist. In this study, we aimed to characterize the intra-tumor heterogeneity of metastatic prostate cancer using an innovative approach. This approach consisted of a transformation method to build a radiomic profile of lesions extracted from [18F]FMCH PET/CT images, a qualitative assessment of intra-tumor heterogeneity of patients, and a quantitative representation of the intra-tumor heterogeneity of patients in terms of the relationship between their lesions’ profiles. We found that metastatic prostate cancer patients had lesions with different radiomic profiles that exhibited intra-tumor radiomic heterogeneity and that the presence of many radiomic profiles within the same patient impacted the outcome

Early management of COPD: Where are we now and where do we go from here? a delphi consensus project

Purpose: There is a lack of consensus on the most appropriate early diagnostic strategy, criteria for early access to treatment and follow-up approach for patients with COPD.Materials and methods: A Delphi consensus project investigated the early management of COPD. We formulated two questionnaires for completion by pneumologists in Italy.Results: A total of 207 specialists completed questionnaire 1 and 184 of them questionnaire 2, between November 2016 and October 2017. Early diagnosis of COPD was considered uncommon for 93.2% of the expert panel. Regardless of the definition of "early diagnosis" - a diagnosis made before the clinical manifestation of the disease for most responders (60.4%) - experts were confident of the positive effects of early disease management, which they consider is effective in modifying the natural history of the disease. Lack of awareness of the disease was considered the first limiting factor to early COPD management for 78% of respondents. The most effective steps to reduce functional decline were considered to be smoking cessation, followed by long-acting beta 2-agonist (LABA)/long-acting muscarinic antagonist (LAMA), LAMA, LABA, and finally inhaled corticosteroid/LABA (P<0.01 for each paired comparison). Specialists considered it "inappropriate" for general practitioners to perform both the early diagnosis and therapy of COPD without the involvement of a specialist.Conclusion: Early management of COPD is uncommon, and although data on the effects of early disease management on long-term outcomes are limited, Italian experts are confident of the clinical efficacy of this approach

Mitochondrial enzyme GLUD2 plays a critical role in glioblastoma progression

Background: Glioblastoma (GBM) is the most frequent and malignant primary brain tumor in adults and despite the progress in surgical procedures and therapy options, the overall survival remains very poor. Glutamate and α-KG are fundamental elements necessary to support the growth and proliferation of GBM cells. Glutamate oxidative deamination, catalyzed by GLUD2, is the predominant pathway for the production of α-KG. Methods: GLUD2 emerged from the RNA-seq analysis of 13 GBM patients, performed in our laboratory and a microarray analysis of 77 high-grade gliomas available on the Geo database. Thereafter, we investigated GLUD2 relevance in cancer cell behavior by GLUD2 overexpression and silencing in two different human GBM cell lines. Finally, we overexpressed GLUD2 in-vivo by using zebrafish embryos and monitored the developing central nervous system. Findings: GLUD2 expression was found associated to the histopathological classification, prognosis and survival of GBM patients. Moreover, through in-vitro functional studies, we showed that differences in GLUD2 expression level affected cell proliferation, migration, invasion, colony formation abilities, cell cycle phases, mitochondrial function and ROS production. In support of these findings, we also demonstrated, with in-vivo studies, that GLUD2 overexpression affects glial cell proliferation without affecting neuronal development in zebrafish embryos. Interpretation: We concluded that GLUD2 overexpression inhibited GBM cell growth suggesting a novel potential drug target for control of GBM progression. The possibility to enhance GLUD2 activity in GBM could result in a blocked/reduced proliferation of GBM cells without affecting the survival of the surrounding neurons