Efficacy and safety of ensitrelvir in patients with mild-to-moderate COVID-19: the phase 2b part of a randomized, placebo-controlled, phase 2/3 study

alexandrossfakianakis shared this article with you from Inoreader Efficacy and safety of ensitrelvir in patients with mild-to-moderate COVID-19: the phase 2b part of a randomized, placebo-controlled, phase 2/3 study via Clinical Infectious Diseases Advance Access Abstract Background This phase 2b part of a randomized phase 2/3 study assessed the efficacy and safety of ensitrelvir for mild-to-moderate coronavirus disease 2019 (COVID-19) during the Omicron epidemic. Methods Patients were randomized (1:1:1) to orally receive ensitrelvir fumaric acid 125 mg (375 mg on day 1) or 250 mg (750 mg on day 1) or placebo once daily for 5 days. The co-primary endpoints were the change from baseline in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) titer on day 4 and time-weighted average change from baseline up to 120 hours in the total score of predefined 12 COVID-19 symptoms. Safety was assessed through adverse events. Results A total of 341 patients (ensitrelvir 125 mg group, 114; ensitrelvir 250 mg group, 116; and placebo group, 111; male, 53.5%–64.9%; mean age, 35.3–37.3 years) were included in the efficacy analyses. The change from baseline in the SARS-CoV-2 titer on da y 4 was significantly greater with both ensitrelvir doses than with placebo (differences from placebo: -0.41 log10 50% tissue-culture infectious dose/mL, P < 0.0001 for both). The total score of the 12 COVID-19 symptoms did not show a significant difference between the ensitrelvir groups and placebo group. The time-weighted average change from baseline up to 120 hours was significantly greater with ensitrelvir versus placebo in several subtotal scores, including acute symptoms and respiratory symptoms. Most adverse events were mild in severity. Conclusions Ensitrelvir treatment demonstrated a favorable antiviral efficacy and potential clinical benefit with an acceptable safety profile. View on Web

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Helicobacter pyhlori regulated microRNA map of human gastric cells

alexandrossfakianakis shared this article with you from Inoreader Helicobacter pyhlori regulated microRNA map of human gastric cells via Helicobacter Abstract Background Helicobacter pylori is an infection of concern for its chronic colonization leading to peptic ulcers and gastric cancer. In recent times, microRNAs have been extensively studied to understand their role in the pathogenesis of this bacteria in diverse contexts of gastric diseases. The current analysis reports the microRNA-mRNA interactions that are associated with effective survival and virulence of this pathogen. Materials and Methods We convened differentially regulated human microRNAs responsive to H. pylori infection (HP-hDEmiRs) at different multiplicity of infection and time points in human gastric cell lines through retrospective data mining of experimental studies. In view of the molecular disparity of clinical samples and animal models, data from tissue, serum/plasma, urine, and ascites were excluded. Further, we utilized diverse bioinformatics approaches to retrieve experimentally validated, high-confidence targets of the HP-hDEmiRs to analyze the microRNA-mRNA interactions that are relevant to H. pylori pathogenesis. Results A total of 39 HP-hDEmiRs that showed unidirectional expression of either overexpression or downregulation were identified to modulate 23 targets explicitly studied under this infection. We also identified 476 experimentally validated targets regulated by at least 4 of the HP-hDEmiRs. In addition to the pathways prior-associated with H. pylori infection, the microRNA-mRNA interactome analysis identified several cellular processes and pathways highly associated with cell cycle, cell division, migration, and carcinogenesis. Conclusion This study generated a platform to study the mechanisms utilized by this pathogen using microRNAs as surrogate. View on Web

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Traditional versus conservative endodontic access impact on fracture resistance of chairside CAD‐CAM lithium disilicate anterior crowns: An in vitro study

alexandrossfakianakis shared this article with you from Inoreader Traditional versus conservative endodontic access impact on fracture resistance of chairside CAD‐CAM lithium disilicate anterior crowns: An in vitro study via Journal of Prosthodontics Abstract Purpose To evaluate the effect of traditional and conservative endodontic access hole preparation on fracture resistance of chairside computer-aided design and computer-aided manufacturing (CAD-CAM) lithium disilicate maxillary right central incisor crowns. Materials and Methods Fifty-seven milled lithium disilicate maxillary right central incisor crowns were designed and fabricated with a chairside CAD-CAM system (Planmeca Romexis, Planmeca). The abutment preparation had a 1.0 mm incisal reduction and 1.0 mm chamfer finish. The restorations were bonded with resin cement to printed resin dies (n = 19 per group) and were treated and divided into three groups, 1) no endodontic access, 2) traditional triangular endodontic access, and 3) conservative ovoidal endodontic access. The endodontic access of the crowns was sealed with flowable resin composite. Restorations were subjected to 10,000 cycles of thermal cycling between 5° and 55°C. Then, restorations were loaded and exposed to compressive loading force, and the crack initiation (CI) and complete fracture (CF) were recorded. SEM micrographs of broken specimens on the printed dies were captured. ANOVA test and Bonferroni's correction were used for statistical comparison. Results The fracture resistance among the three groups varied. Crowns with no endodontic access displayed significantly (p < 0.001) higher resistance [CI: 1025 (121) N; CF 1134 (127) N], followed by crowns with conservative ovoidal endodontic access [CI: 924 (60) N; CF: 1000 (72) N. Crowns with traditional triangular endodontic access showed the significantly (p < 0.001) lowest fracture resistance [CI: 635 (82) N; CF: 709 (75) N]. Conclusion The fracture resistance of chairside CAD-CAM lithium disilicate maxillary anterior crowns is influenced by the type of endodontic access provided. Conservative ovoidal endodontic access provides crowns with higher fracture resistance than traditional triangular endodontic access. Crowns with no endodontic access provided the highest resistance than other types of endodontic access. This article is protected by copyright. All rights reserved View on Web

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Trotabresib, an oral potent bromodomain and extraterminal inhibitor, in patients with high-grade gliomas: a phase I, “windowofopportunity” study

alexandrossfakianakis shared this article with you from Inoreader Trotabresib, an oral potent bromodomain and extraterminal inhibitor, in patients with high-grade gliomas: a phase I, "windowofopportunity" study via Neuro-Oncology Advance Access Abstract Background The bromodomain and extraterminal protein (BET) inhibitor trotabresib has demonstrated antitumor activity in patients with advanced solid tumors, including high-grade gliomas. CC-90010-GBM-001 (NCT04047303) is a phase I study investigating the pharmacokinetics, pharmacodynamics, and CNS penetration of trotabresib in patients with recurrent high-grade gliomas scheduled for salvage resection. Methods Patients received trotabresib 30 mg/day on days 1–4 before surgery, followed by maintenance trotabresib 45 mg/day 4 days on/24 days off after surgery. Primary endpoints were plasma pharmacokinetics and trotabresib concentrations in resected tissue. Secondary and exploratory endpoints included safety, pharmacodynamics, and antitumor activity. Results Twenty patients received preoperative trotabresib and underwent resection with no delays or cancellations of surgery; 16 patients received maintenance trot abresib after recovery from surgery. Trotabresib plasma pharmacokinetics were consistent with previous data. Mean trotabresib brain tumor tissue:plasma ratio was 0.84 (estimated unbound partition coefficient [KPUU] 0.37), and modulation of pharmacodynamic markers was observed in blood and brain tumor tissue. Trotabresib was well tolerated; the most frequent grade 3/4 treatment-related adverse event during maintenance treatment was thrombocytopenia (5/16 patients). Sixmonth progression-free survival was 12%. Two patients remain on treatment with stable disease at cycles 25 and 30. Conclusions Trotabresib penetrates the blood–brain-tumor barrier in patients with recurrent high-grade glioma and demonstrates target engagement in resected tumor tissue. Plasma pharmacokinetics, blood pharmacodynamics, and safety were comparable with previous results for trotabresib in patients with advanced solid tumors. Investigation of adjuvant trotabresib + temozolomide and concom itant trotabresib + temozolomide + radiotherapy in patients with newly diagnosed glioblastoma is ongoing (NCT04324840). View on Web

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Perceived legitimacy can moderate the effect of proscriptive vs. prescriptive injunctions on intentions to comply with UK government COVID‐19 guidelines and reactance

alexandrossfakianakis shared this article with you from Inoreader Perceived legitimacy can moderate the effect of proscriptive vs. prescriptive injunctions on intentions to comply with UK government COVID‐19 guidelines and reactance via Journal of Applied Social Psychology Abstract Proscriptive injunctions (i.e., telling people what they should not do) have been found in research to elicit greater perceptions of a threat to freedom, and greater reactance (anger, irritation and annoyance), than prescriptive injunctions (i.e., telling people what they should do), across several health and social behaviours. The current research investigated the effects of Injunction Type (proscriptive vs. prescriptive) and perceived legitimacy of the injunction, on intentions to comply with UK government behavioural guidelines during the COVID-19 pandemic, and on reactance. In two online experimental studies (Study 1: N = 142; Study 2: N = 307), UK participants were presented with information about UK government COVID-19 guidelines that included either a proscriptive injunction or prescriptive injunction and reported their perceptions of the legitimacy of the injunction, their intentions to comply with government guidelines, a nd their reactance. In both Study 1 and Study 2, the effect of Injunction Type on intentions to comply and reactance was moderated by perceived legitimacy. In both studies, when perceived legitimacy was low, participants exposed to the proscriptive injunction indicated lower intentions to comply with UK government COVID 19 guidelines than did participants exposed to the prescriptive injunction, The findings imply that using a prescriptive injunction frame can elicit greater intentions to comply than using a proscriptive injunction frame when people perceive the injunction to be unreasonable. The results are discussed in relation to the role of legitimacy in determining the effectiveness of different types of injunctions on compliance with rules and guidelines. This article is protected by copyright. All rights reserved. View on Web

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International variations in carcinoma and melanoma incidence in children and adolescents

alexandrossfakianakis shared this article with you from Inoreader International variations in carcinoma and melanoma incidence in children and adolescents via Japanese Journal of Clinical Oncology - current issue In order to compare the subtype distribution of carcinoma and melanoma in children and adolescents between Japan and other countries, we extracted information on cancer incidence in children and adolescents from the third volume of the International Incidence of Childhood Cancer series (IICC-3) (1). The IICC-3 reports the number or incidence rates of cancers diagnosed in childhood and adolescence, from cancer registries (regional or national) worldwide. We analysed carcinoma and melanoma incidence in four countries in Asia (Japan, China, the Republic of Korea and Thailand), two countries in Africa (Egypt and Uganda), four countries in the Americas (North: The United States of America and Canada, Latin and Caribbean: Brazil and Colombia), three countries in Europe (the United Kingdom [UK], France and Germany) and two countries in Oceania (Australia and New Z ealand). Information from the Republic of Korea, USA, UK, Australia and New Zealand was obtained at the national level, and that from the other countries was extracted from one or multiple regional cancer registries. The years of incidence included in the analyses varied from country to country, ranging from 1990 to 2014, with the shortest being 12 years (Egypt: 1999–2010, UK: 2000–2011) and the longest being 24 years (Japan and China: both 1990–2013). In this study, we compared the incidence and proportional distribution of carcinoma and melanoma subtypes in children (0–14 years old) and adolescents (15–19 years old) between these countries. View on Web

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In-utero Exposure to Maternal Diabetes and the Risk of Cerebral Palsy: A Population-based Cohort Study

alexandrossfakianakis shared this article with you from Inoreader In-utero Exposure to Maternal Diabetes and the Risk of Cerebral Palsy: A Population-based Cohort Study via Epidemiology - Published Ahead-of-Print Background: Evidence on the effects of in utero exposure to maternal diabetes on cerebral palsy in offspring is limited. We aimed to examine the effects of pre-gestational (PGDM) and gestational diabetes (GDM) separately on CP risk and the mediating role of increased fetal size. Methods: In a population-based study, we included all live births in Ontario, Canada, between 2002–2017 followed up through 2018 (n=2,110,177). Using administrative health data, we estimated crude and adjusted associations between PGDM or GDM and CP using Cox proportional hazards models to account for unequal follow-up in children. For the mediation analysis, we used marginal structural models to estimate the controlled direct effect of PGDM (and GDM) on the risk of CP not mediated by large-for-gestational age (LGA). Results: During the study period, 5,317 children were diagnosed with CP (187 exposed to PGDM and 171 exposed to GDM). Children of mothers with PGDM showed an increased risk {hazard ratio [HR]: 1.84 [95% confidence interval (CI): 1.59, 2.14]} after adjusting for maternal sociodemographic and clinical factors. We found no associations between GDM and CP (adjusted HR: 0.91 (0.77, 1.06)). Our mediation analysis estimated that LGA explained 14% of the PDGM–CP association. Conclusions: In this population-based birth cohort study, maternal pre-gestational diabetes was associated with increased risk of CP, and the increased risk was not substantially mediated by the increased fetal size. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved. View on Web

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