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Hepatitis B and Hepatitis C are viral causes of Hepatitis that lead to significant worldwide mortality and morbidity through the sequelae of fibrosis and hepatocellular carcinoma. In this review, we have summarized recent studies that have examined the effects of antiviral therapy on the regression of fibrosis and the reduction in mortalities associated with the viruses. Antiviral therapy significantly decreases mortality and induces the regression of fibrosis.

Pulsar timing arrays perform Bayesian posterior inference with expensive Markov chain Monte Carlo (MCMC) methods. Given a dataset of ∼10-100 pulsars and O(10^{3}) timing residuals each, producing a posterior distribution for the stochastic gravitational wave background (SGWB) can take days to a week. The computational bottleneck arises because the likelihood evaluation required for MCMC is extremely costly when considering the dimensionality of the search space. Fortunately, generating simulated data is fast, so modern simulation-based inference techniques can be brought to bear on the problem. In this Letter, we demonstrate how conditional normalizing flows trained on simulated data can be used for extremely fast and accurate estimation of the SGWB posteriors, reducing the sampling time from weeks to a matter of seconds.

Machine learning-based anomaly detection (AD) methods are promising tools for extending the coverage of searches for physics beyond the Standard Model (BSM). One class of AD methods that has received significant attention is resonant anomaly detection, where the BSM physics is assumed to be localized in at least one known variable. While there have been many methods proposed to identify such a BSM signal that make use of simulated or detected data in different ways, there has not yet been a study of the methods' complementarity. To this end, we address two questions. First, in the absence of any signal, do different methods pick the same events as signal-like? If not, then we can significantly reduce the false-positive rate by comparing different methods on the same dataset. Second, if there is a signal, are different methods fully correlated? Even if their maximum performance is the same, since we do not know how much signal is present, it may be beneficial to combine approaches. Using the Large Hadron Collider (LHC) Olympics dataset, we provide quantitative answers to these questions. We find that there are significant gains possible by combining multiple methods, which will strengthen the search program at the LHC and beyond., (© The Author(s) 2024.)

Purpose: ATHENA (ClinicalTrials.gov identifier: NCT03522246) was designed to evaluate rucaparib first-line maintenance treatment in a broad patient population, including those without BRCA1 or BRCA2 (BRCA) mutations or other evidence of homologous recombination deficiency (HRD), or high-risk clinical characteristics such as residual disease. We report the results from the ATHENA-MONO comparison of rucaparib versus placebo., Methods: Patients with stage III-IV high-grade ovarian cancer undergoing surgical cytoreduction (R0/complete resection permitted) and responding to first-line platinum-doublet chemotherapy were randomly assigned 4:1 to oral rucaparib 600 mg twice a day or placebo. Stratification factors were HRD test status, residual disease after chemotherapy, and timing of surgery. The primary end point of investigator-assessed progression-free survival was assessed in a step-down procedure, first in the HRD population (BRCA-mutant or BRCA wild-type/loss of heterozygosity high tumor), and then in the intent-to-treat population., Results: As of March 23, 2022 (data cutoff), 427 and 111 patients were randomly assigned to rucaparib or placebo, respectively (HRD population: 185 v 49). Median progression-free survival (95% CI) was 28.7 months (23.0 to not reached) with rucaparib versus 11.3 months (9.1 to 22.1) with placebo in the HRD population (log-rank P = .0004; hazard ratio [HR], 0.47; 95% CI, 0.31 to 0.72); 20.2 months (15.2 to 24.7) versus 9.2 months (8.3 to 12.2) in the intent-to-treat population (log-rank P < .0001; HR, 0.52; 95% CI, 0.40 to 0.68); and 12.1 months (11.1 to 17.7) versus 9.1 months (4.0 to 12.2) in the HRD-negative population (HR, 0.65; 95% CI, 0.45 to 0.95). The most common grade ≥ 3 treatment-emergent adverse events were anemia (rucaparib, 28.7% v placebo, 0%) and neutropenia (14.6% v 0.9%)., Conclusion: Rucaparib monotherapy is effective as first-line maintenance, conferring significant benefit versus placebo in patients with advanced ovarian cancer with and without HRD.

Background: Crohn's disease (CD) patients demonstrate distinct intestinal microbial compositions and metabolic characteristics compared to unaffected controls. However, the impact of inflammation and underlying genetic risk on these microbial profiles and their relationship to disease phenotype are unclear. We used lavage sampling to characterize the colonic mucosal-luminal interface (MLI) microbiome of CD patients in endoscopic remission and unaffected controls relative to obesity, disease genetics, and phenotype., Methods: Cecum and sigmoid colon were sampled from 110 non-CD controls undergoing screening colonoscopy who were stratified by body mass index and 88 CD patients in endoscopic remission (396 total samples). CD polygenic risk score (GRS) was calculated using 186 known CD variants. MLI pellets were analyzed by 16S ribosomal RNA gene sequencing, and supernatants by untargeted liquid chromatography-mass spectrometry., Results: CD and obesity were each associated with decreased cecal and sigmoid MLI bacterial diversity and distinct bacterial composition compared to controls, including expansion of Escherichia/Shigella. Cecal and sigmoid dysbiosis indices for CD were significantly greater in obese controls than non-overweight controls. CD, but not obesity, was characterized by altered biogeographic relationship between the sigmoid and cecum. GRS was associated with select taxonomic shifts that overlapped with changes seen in CD compared to controls including Fusobacterium enrichment. Stricturing or penetrating Crohn's disease behavior was characterized by lower MLI bacterial diversity and altered composition, including reduced Faecalibacterium, compared to uncomplicated CD. Taxonomic profiles including reduced Parasutterella were associated with clinical disease progression over a mean follow-up of 3.7 years. Random forest classifiers using MLI bacterial abundances could distinguish disease state (area under the curve (AUC) 0.93), stricturing or penetrating Crohn's disease behavior (AUC 0.82), and future clinical disease progression (AUC 0.74). CD patients showed alterations in the MLI metabolome including increased cholate:deoxycholate ratio compared to controls., Conclusions: Obesity, CD in endoscopic remission, and high CD genetic risk have overlapping colonic mucosal-luminal interface (MLI) microbiome features, suggesting a shared microbiome contribution to CD and obesity which may be influenced by genetic factors. Microbial profiling during endoscopic remission predicted Crohn's disease behavior and progression, supporting that MLI sampling could offer unique insight into CD pathogenesis and provide novel prognostic biomarkers., (© 2022. The Author(s).)

Objective: To conduct a meta-analysis to compare different dosing scalars of sugammadex in a morbidly obese population for reversal of neuromuscular blockade (NMB)., Methods: PubMed®, ClinicalTrials.gov, Cochrane Central Register of Controlled Trials (CENTRAL) and Google Scholar were searched for relevant randomized controlled trials (RCTs) comparing lower-dose sugammadex using ideal body weight (IBW) or corrected body weight (CBW) as dosing scalars with standard-dose sugammadex based on total body weight (TBW) among morbidly obese people after NMB. Mean difference with SD was used to estimate the results., Results: The analysis included five RCT with a total of 444 morbidly obese patients. The reversal time was significantly longer in patients receiving sugammadex with dosing scalar based on IBW than in patients receiving sugammadex with dosing scalar based on TBW (mean difference 55.77 s, 95% confidence interval [CI] 32.01, 79.53 s), but it was not significantly different between patients receiving sugammadex with dosing scalars based on CBW versus TBW (mean difference 2.28 s, 95% CI -10.34, 14.89 s)., Conclusion: Compared with standard-dose sugammadex based on TBW, lower-dose sugammadex based on IBW had 56 s longer reversal time whereas lower-dose sugammadex based on CBW had a comparable reversal time.

A new paradigm for data-driven, model-agnostic new physics searches at colliders is emerging, and aims to leverage recent breakthroughs in anomaly detection and machine learning. In order to develop and benchmark new anomaly detection methods within this framework, it is essential to have standard datasets. To this end, we have created the LHC Olympics 2020, a community challenge accompanied by a set of simulated collider events. Participants in these Olympics have developed their methods using an R&D dataset and then tested them on black boxes: datasets with an unknown anomaly (or not). Methods made use of modern machine learning tools and were based on unsupervised learning (autoencoders, generative adversarial networks, normalizing flows), weakly supervised learning, and semi-supervised learning. This paper will review the LHC Olympics 2020 challenge, including an overview of the competition, a description of methods deployed in the competition, lessons learned from the experience, and implications for data analyses with future datasets as well as future colliders., (© 2021 IOP Publishing Ltd.)

Background: The optimal treatment strategy for women with newly diagnosed ovarian cancer has yet to be determined. Poly(ADP-ribose) polymerase (PARP) inhibitors have demonstrated substantial improvement in progression-free survival as monotherapy maintenance treatment in the frontline setting versus active surveillance. Furthermore, preclinical and early clinical studies have shown that PARP inhibitors and immune checkpoint inhibitors have synergistic antitumor activity and may provide an additional therapeutic option for patients in this population., Primary Objectives: In women with newly diagnosed ovarian, fallopian tube, or peritoneal cancer, we wish to assess the efficacy of frontline maintenance treatment with the PARP inhibitor rucaparib versus placebo following response to platinum-based chemotherapy (ATHENA-MONO), and to assess the combination of rucaparib plus nivolumab (a programmed death receptor 1 (PD-1)-blocking monoclonal antibody) versus rucaparib alone (ATHENA-COMBO)., Study Hypothesis: (1) Maintenance therapy with rucaparib monotherapy may extend progression-free survival following standard treatment for ovarian cancer in the frontline setting. (2) The combination of nivolumab plus rucaparib may extend progression-free survival following standard treatment for ovarian cancer in the frontline setting compared with rucaparib alone., Trial Design: ATHENA is an international, randomized, double-blind, phase III trial consisting of two independent comparisons (ATHENA-MONO and ATHENA-COMBO) in patients with newly diagnosed platinum-sensitive ovarian cancer. Patients are randomized 4:4:1:1 to the following: oral rucaparib+ intravenous nivolumab (arm A); oral rucaparib + intravenous placebo (arm B); oral placebo+ intravenous nivolumab (arm C); and oral placebo + intravenous placebo (arm D). The starting dose of rucaparib is 600 mg orally twice a day and nivolumab 480 mg intravenously every 4 weeks. ATHENA-MONO compares arm B with arm D to evaluate rucaparib monotherapy versus placebo, and ATHENA-COMBO evaluates arm A versus arm B to investigate the effects of rucaparib and nivolumab in combination versus rucaparib monotherapy. ATHENA-MONO and ATHENA-COMBO share a common treatment arm (arm B) but each comparison is independently powered., Major Inclusion/exclusion Criteria: Patients ≥18 years of age with newly diagnosed advanced, high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancer who have achieved a response after completion of cytoreductive surgery and initial platinum-based chemotherapy are enrolled. No other prior treatment for ovarian cancer, other than the frontline platinum regimen, is permitted., Primary Endpoint: The primary endpoint is investigator-assessed progression-free survival by Response Evaluation Criteria in Solid Tumors v1.1., Sample Size: Approximately 1000 patients have been enrolled and randomized., Estimated Dates for Completing Accrual and Presenting Results: The trial completed accrual in 2020. While dependent on event rates, primary results of ATHENA-MONO are anticipated in early 2022 and results of ATHENA-COMBO are anticipated to mature at a later date., Trial Registration: This trial is registered at clinicaltrials.gov (NCT03522246)., Competing Interests: Competing interests: BJM has served as a consultant and received honoraria from Clovis Oncology, Aravive, AstraZeneca, Easai, Elevar, Genetics, Genmab/Seattle, GOG Foundation, Gradalis, ImmunoGen, Karyopharm, McKesson, Merck, Mersana, Myriad, Novocure, Pfizer, Roche/Genentech, Sorrento, Tesaro/GSK, and VBL outside the submitted work. RLC reports grants from Clovis Oncology, AstraZeneca, Genmab, Janssen, Merck, and Roche/Genentech; and has served as a consultant for Clovis Oncology, Agenus, AstraZeneca, Genmab, GSK, Janssen, OncoQuest, Roche/Genentech, and Regeneron outside the submitted work. KF has received institutional funding from Clovis Oncology during the conduct of the study; and received traveling support from Clovis Oncology outside the submitted work. AMO has received an institutional grant from AstraZeneca; served on data safety monitoring boards or advisory boards (uncompensated) for AstraZeneca and GSK; served on steering committees (uncompensated) for Clovis Oncology and AstraZeneca; and served as a principal investigator on investigator-initiated trials for Clovis Oncology, AstraZeneca, and GSK. DMO has served as a consultant for Clovis Oncology, Abbvie, Agenus, Ambry, Amgen, Arquer Diagnostics, AstraZeneca, Eisai, Elevar, Genentech/Roche, GOG Foundation, Immunogen, InxMed, Iovance Biotherapeutics, Janssen/J&J, Merck, Mersana, Myriad Genetics, Novartis, Novocure, Regeneron, Roche Diagnostics MSA, Rubis, SDP Oncology (BBI), SeaGen, Sorrento, Takeda, Tarveda, Tesaro/GSK, and Toray; and has received research support from Clovis Oncology, Abbvie, Agenus, Ajinomoto, Amgen, Array Biopharma, AstraZeneca, Bristol-Myers Squibb, Cerulean Pharma, Eisai, EMD Serono, Ergomed, Genentech/Roche, GenMab, GOG Foundation, Immunogen, INC Research, inVentiv Health Clinical, Iovance Biotherapeutics, Janssen/J&J, Ludwig Cancer Research, Merck, Mersana, New Mexico Cancer Care Alliance, Novocure, PRA International, Regeneron, SDP Oncology (BBI), SeaGen, Serono, Stemcentrx, Tesaro/GSK, TRACON Pharmaceuticals, VentiRx, and Yale University outside the submitted work. DL has received institutional funding for trial development from Clovis Oncology during the conduct of the study; and has received research grants from Clovis Oncology; served on advisory boards for Clovis Oncology, AstraZeneca, GSK, Merck Sharp & Dohme, and PharmaMar outside the submitted work. SNW has received institutional funding and served as a consultant for Clovis Oncology during the conduct of the study; received institutional funding from Clovis Oncology, AstraZeneca, Bayer, Bio-Path, Cotinga Pharmaceuticals, GSK/Tesaro, Mereo, NIH, Novartis, and Roche/Genentech; served as a consultant for Clovis Oncology, Agenus, AstraZeneca, Eisai, GSK/Tesaro, Merck, Novartis, Pfizer, Roche/Genentech, and Zentalis; and is involved in an unpaid leadership or fiduciary role for GOG Foundation Board of Directors, Houston Gynecology and Obstetrical Society, NOCC – National Ovarian Cancer Coalition Advisory Board, OVARCOME Leadership Council, and Society of Gynecologic Oncology Board of Directors outside the submitted work. TJH has served on advisory boards for Clovis Oncology, Aravive, AstraZeneca, Caris, Elsai, GSK, Johnson & Johnson, Merck, and Roche Genentech; and has served as a consultant for Abbvie outside the submitted work. FM reports personal fees from Amgen, AstraZeneca, Celegene, CureVac, Eisai, GenomicHealth, Gilead/Immunomedics, GSK, Janssen-Cilag, MSD, Myriad, Novartis, Pfizer, Pierre-Fabre, PharmaMar, Roche, Tesaro, and Seagen outside the submitted work. RNE has served as a consultant for Clovis Oncology, AstraZeneca, Daiich Sankyo, Eisai, GSK, Merck, and Seagen; and received honoraria from AstraZeneca and Myriad outside the submitted work. IAM has served on advisory boards for Clovis Oncology, AstraZeneca, Roche, Takeda, and Tesaro; and received institutional funding from AstraZeneca outside the submitted work. RSK has served on data safety monitoring boards or advisory boards for Clovis Oncology, Basilea, Eisai, GSK, iTeos Therapeutics, Roche, Sotio, and Tesaro; and is involved in a leadership or fiduciary role for MHRA OHEAG. KKL, DS, SG, NG, SH, and LM are employees of Clovis Oncology and may own stock or have stock options in that company. All authors received writing support from Clovis Oncology during the conduct of the study., (© IGCS and ESGO 2021. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Perampanel is a novel antiepileptic drug, which antagonises AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) glutamate receptor. We describe perampanel as an adjunctive treatment for FIRES (febrile infection-related epilepsy syndrome) and other drug-resistant epilepsies. A single-centre, observational, retrospective study involving 20 pediatric patients was conducted. Perampanel was started for three patients with FIRES, achieving seizure cessation in two patients within a day and on days 19 and 32 of illness. Doses used ranged from 4 to 12 mg/day, without any adverse effects reported or discontinuation of therapy. Responder-rate for other drug-resistant epilepsies is 25%. Median time to achieve ≥50% seizure reduction was 80 days (range: 26-326 days). Adverse effect reported in 47% of the patients includes central nervous system-related, and thrombocytopenia. Eight patients discontinued perampanel, because of ineffectiveness or adverse effects. The median time on perampanel before discontinuation was 179 days (range: 94-345 days). Perampanel may be of benefit in pediatrics FIRES and is of utility in other drug-resistant epilepsies., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)