Early administration of tecovirimat shortens the time to mpox clearance in a model of human infection.

Despite use of tecovirimat since the beginning of the 2022 outbreak, few data have been published on its antiviral effect in humans. We here predict tecovirimat efficacy using a unique set of data in nonhuman primates (NHPs) and humans. We analyzed tecovirimat antiviral activity on viral kinetics in NHP to characterize its concentration-effect relationship in vivo. Next, we used a pharmacological model developed in healthy volunteers to project its antiviral efficacy in humans. Finally, a viral dynamic model was applied to characterize mpox kinetics in skin lesions from 54 untreated patients, and we used this modeling framework to predict the impact of tecovirimat on viral clearance in skin lesions. At human-recommended doses, tecovirimat could inhibit viral replication from infected cells by more than 90% after 3 to 5 days of drug administration and achieved over 97% efficacy at drug steady state. With an estimated mpox within-host basic reproduction number, R0, equal to 5.6, tecovirimat could therefore shorten the time to viral clearance if given before viral peak. We predicted that initiating treatment at symptom onset, which on average occurred 2 days before viral peak, could reduce the time to viral clearance by about 6 days. Immediate postexposure prophylaxis could not only reduce time to clearance but also lower peak viral load by more than 1.0 log10 copies/mL and shorten the duration of positive viral culture by about 7 to 10 days. These findings support the early administration of tecovirimat against mpox infection, ideally starting from the infection day as a postexposure prophylaxis.

Total RNA sequencing reveals gene expression and microbial alterations shared by oral pre-malignant lesions and cancer.

Head and neck cancers are a complex malignancy comprising multiple anatomical sites, with cancer of the oral cavity ranking among the deadliest and the most disfiguring cancers globally. Oral cancer (OC) constitutes a subset of head and neck cancer cases, presenting primarily as tobacco- and alcohol-associated oral squamous cell carcinoma (OSCC), with a 5-year survival rate of ~ 65%, partly due to the lack of early detection and effective treatments. OSCC arises from premalignant lesions (PMLs) in the oral cavity through a multi-step series of clinical and histopathological stages, including varying degrees of epithelial dysplasia. To gain insights into the molecular mechanisms associated with the progression of PMLs to OSCC, we profiled the whole transcriptome of 66 human PMLs comprising leukoplakia with dysplasia and hyperkeratosis non-reactive (HkNR) pathologies, alongside healthy controls and OSCC. Our data revealed that PMLs were enriched in gene signatures associated with cellular plasticity, such as partial EMT (p-EMT) phenotypes, and with immune response. Integrated analyses of the host transcriptome and microbiome further highlighted a significant association between differential microbial abundance and PML pathway activity, suggesting a contribution of the oral microbiome toward PML evolution to OSCC. Collectively, this study reveals molecular processes associated with PML progression that may help early diagnosis and disease interception at an early stage.

Modifying the trajectory of epicardial leads can substantially reduce MRI-induced RF heating in pediatric patients with a cardiac implantable electronic device at 1.5T.

PURPOSE: After epicardial cardiac implantable electronic devices are implanted in pediatric patients, they become ineligible to receive MRI exams due to an elevated risk of RF heating. We investigated whether simple modifications in the trajectories of epicardial leads could substantially and reliably reduce RF heating during MRI at 1.5 T, with benefits extending to abandoned leads. METHODS: Electromagnetic simulations were performed to assess RF heating of two common 35-cm epicardial lead trajectories exhibiting different degrees of coupling with MRI incident electric fields. Experiments in anthropomorphic phantoms implanted with commercial cardiac implantable electronic devices confirmed the findings. Both electromagnetic simulations and experimental measurements were performed using head-first and feet-first positioning and various landmarks. Transfer function approach was used to assess the performance of suggested modifications in realistic body models. RESULTS: Simulations (head-first, chest landmark) of a 35-cm epicardial lead with a trajectory where the excess length of the lead was looped and placed on the inferior surface of the heart showed an 87-fold reduction in the 0.1 g-averaged specific absorption rate compared with the lead where the excess length was looped on the anterior surface. Repeated experiments with a commercial epicardial device confirmed this. For fully implanted systems following low-specific absorption rate trajectories, there was a 16-fold reduction in the average temperature rise and a 28-fold reduction for abandoned leads. The transfer function method predicted a 7-fold reduction in the RF heating in 336 realistic scenarios. CONCLUSION: Surgical modification of epicardial lead trajectory can substantially reduce RF heating at 1.5 T, with benefits extending to abandoned leads.

Further Understanding the Roles of Solvent, Brønsted Acids, and Hydrogen Bonding in Iron Porphyrin-Mediated Carbon Dioxide Reduction.

Improving our understanding of how molecules and materials mediate the electrochemical reduction of carbon dioxide (CO2) to upgraded products is of great interest as a means to address climate change. A leading class of molecules that can facilitate the electrochemical conversion of CO2 to carbon monoxide (CO) is iron porphyrins. These molecules can have high rate constants for CO2-to-CO conversion; they are robust, and they rely on abundant and inexpensive synthetic building blocks. Important foundational work has been conducted using chloroiron 5,10,15,20-tetraphenylporphyrin (FeTPPCl) in N,N-dimethylformamide (DMF) solvent. A related and recent report points out that the corresponding perchlorate complex, FeTPPClO4, can have superior function due to its solubility in other organic solvents. However, the importance of hydrogen bonding and solvent effects was not discussed. Herein, we present a detailed kinetic study of the triflate (CF3SO3-) complex of FeTPP in DMF and in MeCN using a range of phenol Brønsted acid additives. We also detected the formation of Fe(III)TPP-phenolate complexes using cyclic voltammetry experiments. Importantly, our new analysis of apparent rate constants with different added phenols allows for a modification to the established mechanistic model for CO2-to-CO conversion. Critically, our improved model accounts for hydrogen bonding and solvent effects by using simple hydrogen bond acidity and basicity descriptors. We use this augmented model to rationalize function in other reported porphyrin systems and to make predictions about operational conditions that can enhance the CO2 reduction chemistry.

High-Valent Ni and Cu Complexes of a Tetraanionic Bis(amidateanilido) Ligand.

High-valent metal species are often invoked as intermediates during enzymatic and synthetic catalytic cycles. Anionic donors are often required to stabilize such high-valent states by forming strong bonds with the Lewis acidic metal centers while decreasing their oxidation potentials. In this report, we discuss the synthesis of two high-valent metal complexes [ML]+ in which the NiIII and CuIII centers are ligated by a new tetradentate, tetraanionic bis(amidateanilido) ligand. [ML]+, obtained via chemical oxidation of ML, exhibits UV-vis-NIR, EPR, and XANES spectra characteristic of square planar, high-valent MIII species, suggesting the locus of oxidation for both [ML]+ is predominantly metal-based. This is supported by theoretical analyses, which also support the observed visible transitions as ligand-to-metal charge transfer transitions characteristic of square planar, high-valent MIII species. Notably, [ML]+ can also be obtained via O2 oxidation of ML due to its remarkably negative oxidation potentials (CuL/[CuL]+: -1.16 V, NiL/[NiL]+: -1.01 V vs Fc/Fc+ in MeCN). This demonstrates the exceptionally strong donating nature of the tetraanionic bis(amidateanilido) ligation and its ability to stabilize high-valent metal centers..

Arteriovenous fistula creation by nephrologist and its outcomes: a prospective cohort study from Vietnam.

BACKGROUND: Arteriovenous fistula (AVF) is the gold standard vascular access for effective hemodialysis. There is a growing interest in AVF creations performed by nephrologists to help reduce vascular surgeons' workload and enhance the timely treatment of patients with end-stage renal disease (ESRD). However, little is known about the feasibility and effectiveness of this approach in the low-resource settings. We examined the AVF surgical success and failure rates and associated predictors as well as early complications of AVF creations by a trained nephrologist with supports from vascular surgeons in Vietnam. METHODS: A prospective cohort study was conducted on all adult ESRD patients at the Hemodialysis Department of Thong Nhat Hospital between April 2018 and October 2020. Information on demographic characteristics, comorbidities, and AVF creations was collected using a standardized questionnaire. All patients were followed up until 18 weeks post-surgery. RESULTS: Among 100 patients with a mean age of 61.22 ± 17.11 years old, male accounted for 54%. Common causes of ESRD included hypertension (57%) and diabetes (32%). Just more than half (52%) of them reported having an AVF creation prior to ESRD. The successful first-time AVF creation rate was 98% (13/99, 95%CI: 8.74-21.18%). The primary and secondary AVF failure rates were 13.13% (13/99, 95%CI: 8.74-21.18%) and 16.87% (14/83, 95%CI: 10.32-26.25%), respectively. Early complications included bleeding (1%) and early thrombosis of the anastomosis (2%). There was a statistically significant association between age and primary AVF failure (P = 0.005) and between operation time and secondary AVF failure (P = 0.038). CONCLUSIONS: AVF creations performed by well-trained and skilled interventional nephrologists with supports from vascular surgeons can result in favorable short- and long-term outcomes. It is important to follow up older patients and those with a long operation time to detect AVF failures. A standardized AVF creation training program and practice for nephrologists is needed to increase successful rates.

Safety of MRI in patients with retained cardiac leads.

PURPOSE: To evaluate the safety of MRI in patients with fragmented retained leads (FRLs) through numerical simulation and phantom experiments. METHODS: Electromagnetic and thermal simulations were performed to determine the worst-case RF heating of 10 patient-derived FRL models during MRI at 1.5 T and 3 T and at imaging landmarks corresponding to head, chest, and abdomen. RF heating measurements were performed in phantoms implanted with reconstructed FRL models that produced highest heating in numerical simulations. The potential for unintended tissue stimulation was assessed through a conservative estimation of the electric field induced in the tissue due to gradient-induced voltages developed along the length of FRLs. RESULTS: In simulations under conservative approach, RF exposure at B1+ ≤ 2 µT generated cumulative equivalent minutes (CEM)43 < 40 at all imaging landmarks at both 1.5 T and 3 T, indicating no thermal damage for acquisition times (TAs) < 10 min. In experiments, the maximum temperature rise when FRLs were positioned at the location of maximum electric field exposure was measured to be 2.4°C at 3 T and 2.1°C at 1.5 T. Electric fields induced in the tissue due to gradient-induced voltages remained below the threshold for cardiac tissue stimulation in all cases. CONCLUSIONS: Simulation and experimental results indicate that patients with FRLs can be scanned safely at both 1.5 T and 3 T with most clinical pulse sequences.

Loss of the aryl hydrocarbon receptor increases tumorigenesis in p53-deficient mice.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates cell fate via activation of a diverse set of genes. There are conflicting reports describing the role of AhR in cancer. AhR-knockout mice do not develop tumors spontaneously, yet the AhR can act as a tumor suppressor in certain contexts. Loss of tumor suppression by p53 is common in human cancer. To investigate AhR function in the absence of p53, we generated mice lacking both AhR and p53. Mice deficient for AhR and p53 had shortened lifespan, increased tumorigenesis, and an altered tumor spectrum relative to control mice lacking only p53. In addition, knockout of both AhR and p53 resulted in reduced embryonic survival and neonatal fitness. We also examined the consequences of loss of AhR in p53-heterozygous mice and observed a significantly reduced lifespan and enhanced tumor burden. These findings reveal an important role for the AhR as a tumor suppressor in the absence of p53 signaling and support the development of anti-cancer therapeutics that would promote the tumor suppressive actions of the AhR.

Quality of life assessment in patients on chronic dialysis: Comparison between haemodialysis and peritoneal dialysis at a national hospital in Vietnam.

OBJECTIVES: End-stage renal disease (ESRD) is a chronic disease that can adversely affect the patient's quality of life (QoL) in terms of functional limitation and cognitive impairment. This study aimed to identify the factors associated with QoL in patients with ESRD undergoing dialysis at a national hospital in Vietnam. METHODS: A descriptive cross-sectional study was conducted among outpatients aged ≥18 years who underwent haemodialysis (HD) or peritoneal dialysis (PD) for at least 3 months at Thong Nhat Hospital, Ho Chi Minh City, Vietnam from May 2020 to July 2021. QoL was measured using the validated Vietnamese version of the EuroQol-5 Dimensional-5 Level (EQ-5D-5L). The factors associated with the QoL of patients with ESRD undergoing dialysis were identified using multiple linear regression analysis. RESULTS: In total, 131 (73.6%) and 47 (26.4%) patients underwent HD and PD, respectively. Overall, 178 (55.6%) patients were men (median age, 66 [56-79] years). The mean EQ-5D-5L score was significantly higher in patients undergoing PD than in those undergoing HD (0.848 ± 0.183 vs. 0.766 ± 0.231; p = 0.030). Older age (ß = -0.006; p < 0.001) and peptic ulcer disease (ß = -0.083; p = 0.029) were associated with lower QoL scores. PD treatment was associated with higher QoL scores (ß = 0.065; p = 0.046). CONCLUSIONS: It is necessary to improve the QoL of patients undergoing dialysis, especially of elderly patients and patients with peptic ulcer disease. PD may be a better method for maintenance dialysis, if applicable, in terms of QoL.

iANP-EC: Identifying Anticancer Natural Products Using Ensemble Learning Incorporated with Evolutionary Computation.

Cancer is one of the most deadly diseases that annually kills millions of people worldwide. The investigation on anticancer medicines has never ceased to seek better and more adaptive agents with fewer side effects. Besides chemically synthetic anticancer compounds, natural products are scientifically proved as a highly potential alternative source for anticancer drug discovery. Along with experimental approaches being used to find anticancer drug candidates, computational approaches have been developed to virtually screen for potential anticancer compounds. In this study, we construct an ensemble computational framework, called iANP-EC, using machine learning approaches incorporated with evolutionary computation. Four learning algorithms (k-NN, SVM, RF, and XGB) and four molecular representation schemes are used to build a set of classifiers, among which the top-four best-performing classifiers are selected to form an ensemble classifier. Particle swarm optimization (PSO) is used to optimise the weights used to combined the four top classifiers. The models are developed by a set of curated 997 compounds which are collected from the NPACT and CancerHSP databases. The results show that iANP-EC is a stable, robust, and effective framework that achieves an AUC-ROC value of 0.9193 and an AUC-PR value of 0.8366. The comparative analysis of molecular substructures between natural anticarcinogens and nonanticarcinogens partially unveils several key substructures that drive anticancerous activities. We also deploy the proposed ensemble model as an online web server with a user-friendly interface to support the research community in identifying natural products with anticancer activities.

Origin of Free Energy Barriers of Decarboxylation and the Reverse Process of CO2 Capture in Dimethylformamide and in Water.

In aqueous solution, biological decarboxylation reactions proceed irreversibly to completion, whereas the reverse carboxylation processes are typically powered by the hydrolysis of ATP. The exchange of the carboxylate of ring-substituted arylacetates with isotope-labeled CO2 in polar aprotic solvents reported recently suggests a dramatic change in the partition of reaction pathways. Yet, there is little experimental data pertinent to the kinetic barriers for protonation and thermodynamic data on CO2 capture by the carbanions of decarboxylation reactions. Employing a combined quantum mechanical and molecular mechanical simulation approach, we investigated the decarboxylation reactions of a series of organic carboxylate compounds in aqueous and in dimethylformamide solutions, revealing that the reverse carboxylation barriers in solution are fully induced by solvent effects. A linear Bell-Evans-Polanyi relationship was found between the rates of decarboxylation and the Gibbs energies of reaction, indicating diminishing recombination barriers in DMF. In contrast, protonation of the carbanions by the DMF solvent has large free energy barriers, rendering the competing exchange of isotope-labeled CO2 reversible in DMF. The finding of an intricate interplay of carbanion stability and solute-solvent interaction in decarboxylation and carboxylation could be useful to designing novel materials for CO2 capture.

Vertical open-bore MRI scanners generate significantly less radiofrequency heating around implanted leads: A study of deep brain stimulation implants in 1.2T OASIS scanners versus 1.5T horizontal systems.

PURPOSE: Patients with active implants such as deep brain stimulation (DBS) devices are often denied access to MRI due to safety concerns associated with the radiofrequency (RF) heating of their electrodes. The majority of studies on RF heating of conductive implants have been performed in horizontal close-bore MRI scanners. Vertical MRI scanners which have a 90° rotated transmit coil generate fundamentally different electric and magnetic field distributions, yet very little is known about RF heating of implants in this class of scanners. We performed numerical simulations as well as phantom experiments to compare RF heating of DBS implants in a 1.2T vertical scanner (OASIS, Hitachi) compared to a 1.5T horizontal scanner (Aera, Siemens). METHODS: Simulations were performed on 90 lead models created from post-operative CT images of patients with DBS implants. Experiments were performed with wires and commercial DBS devices implanted in an anthropomorphic phantom. RESULTS: We found significant reduction of 0.1 g-averaged specific absorption rate (30-fold, P < 1 × 10-5 ) and RF heating (9-fold, P < .026) in the 1.2T vertical scanner compared to the 1.5T conventional scanner. CONCLUSION: Vertical MRI scanners appear to generate lower RF heating around DBS leads, providing potentially heightened safety or the flexibility to use sequences with higher power levels than on conventional systems.

3,3'-Diindolylmethane Exhibits Significant Metabolism after Oral Dosing in Humans.

3,3'-Diindolylmethane (DIM), a major phytochemical derived from ingestion of cruciferous vegetables, is also a dietary supplement. In preclinical models, DIM is an effective cancer chemopreventive agent and has been studied in a number of clinical trials. Previous pharmacokinetic studies in preclinical and clinical models have not reported DIM metabolites in plasma or urine after oral dosing, and the pharmacological actions of DIM on target tissues is assumed to be solely via the parent compound. Seven subjects (6 males and 1 female) ranging from 26-65 years of age, on a cruciferous vegetable-restricted diet prior to and during the study, took 2 BioResponse DIM 150-mg capsules (45.3 mg DIM/capsule) every evening for one week with a final dose the morning of the first blood draw. A complete time course was performed with plasma and urine collected over 48 hours and analyzed by UPLC-MS/MS. In addition to parent DIM, two monohydroxylated metabolites and 1 dihydroxylated metabolite, along with their sulfate and glucuronide conjugates, were present in both plasma and urine. Results reported here are indicative of significant phase 1 and phase 2 metabolism and differ from previous pharmacokinetic studies in rodents and humans, which reported only parent DIM present after oral administration. 3-((1H-indole-3-yl)methyl)indolin-2-one, identified as one of the monohydroxylated products, exhibited greater potency and efficacy as an aryl hydrocarbon receptor agonist when tested in a xenobiotic response element-luciferase reporter assay using Hepa1 cells. In addition to competitive phytochemical-drug adverse reactions, additional metabolites may exhibit pharmacological activity highlighting the importance of further characterization of DIM metabolism in humans. SIGNIFICANCE STATEMENT: 3,3'-Diindolylmethane (DIM), derived from indole-3-carbinol in cruciferous vegetables, is an effective cancer chemopreventive agent in preclinical models and a popular dietary supplement currently in clinical trials. Pharmacokinetic studies to date have found little or no metabolites of DIM in plasma or urine. In marked contrast, we demonstrate rapid appearance of mono- and dihydroxylated metabolites in human plasma and urine as well as their sulfate and glucuronide conjugates. The 3-((1H-indole-3-yl)methyl)indolin-2-one metabolite exhibited significant aryl hydrocarbon receptor agonist activity, emphasizing the need for further characterization of the pharmacological properties of DIM metabolites.

Effect of Device Configuration and Patient's Body Composition on the RF Heating and Nonsusceptibility Artifact of Deep Brain Stimulation Implants During MRI at 1.5T and 3T.

BACKGROUND: Patients with deep brain stimulation (DBS) implants have limited access to MRI due to safety concerns associated with RF-induced heating. Currently, MRI in these patients is allowed in 1.5T horizontal bore scanners utilizing pulse sequences with reduced power. However, the use of 3T MRI in such patients is increasingly reported based on limited safety assessments. Here we present the results of comprehensive RF heating measurements for two commercially available DBS systems during MRI at 1.5T and 3T. PURPOSE: To assess the effect of imaging landmark, DBS lead configuration, and patient's body composition on RF heating of DBS leads during MRI at 1.5T and 3T. STUDY TYPE: Phantom and ex vivo study. POPULATION/SUBJECTS/PHANTOM/SPECIMEN/ANIMAL MODEL: Gel phantoms and cadaver brain. FIELD STRENGTH/SEQUENCE: 1.5T and 3T, T1 -weighted turbo spin echo. ASSESSMENT: RF heating was measured at the tips of DBS leads implanted in brain-mimicking gel. Image artifact was assessed in a cadaver brain implanted with an isolated DBS lead. STATISTICAL TESTS: Descriptive. RESULTS: We observed substantial fluctuation in RF heating, mainly affected by phantom composition and DBS lead configuration, ranging from 0.14°C to 23.73°C at 1.5T, and from 0.10°C to 7.39°C at 3T. The presence of subcutaneous fat substantially altered RF heating at the electrode tips (3.06°C < ∆T < 19.05° C). Introducing concentric loops in the extracranial portion of the lead at the surgical burr hole reduced RF heating by up to 89% at 1.5T and up to 98% at 3T compared to worst-case heating scenarios. DATA CONCLUSION: Device configuration and patient's body composition substantially altered the RF heating of DBS leads during MRI. Interestingly, certain lead trajectories consistently reduced RF heating and image artifact. Level of Evidence 1 Technical Efficacy Stage 1 J. MAGN. RESON. IMAGING 2021;53:599-610.

Machine learning-based prediction of MRI-induced power absorption in the tissue in patients with simplified deep brain stimulation lead models.

Interaction of an active electronic implant such as a deep brain stimulation (DBS) system and MRI RF fields can induce excessive tissue heating, limiting MRI accessibility. Efforts to quantify RF heating mostly rely on electromagnetic (EM) simulations to assess individualized specific absorption rate (SAR), but such simulations require extensive computational resources. Here, we investigate if a predictive model using machine learning (ML) can predict the local SAR in the tissue around tips of implanted leads from the distribution of the tangential component of the MRI incident electric field, Etan. A dataset of 260 unique patient-derived and artificial DBS lead trajectories was constructed, and the 1 g-averaged SAR, 1gSARmax, at the lead-tip during 1.5 T MRI was determined by EM simulations. Etan values along each lead's trajectory and the simulated SAR values were used to train and test the ML algorithm. The resulting predictions of the ML algorithm indicated that the distribution of Etan could effectively predict 1gSARmax at the DBS lead-tip (R = 0.82). Our results indicate that ML has the potential to provide a fast method for predicting MR-induced power absorption in the tissue around tips of implanted leads such as those in active electronic medical devices.

Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate is Non-inferior to Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate in Treatment-naive Adults With Human Immunodeficiency Virus-1 Infection: Week 48 Results of the DRIVE-AHEAD Trial.

Background: Doravirine (DOR), a novel non-nucleoside reverse-transcriptase inhibitor (NNRTI), is active against wild-type Human Immunodeficiency Virus (HIV)-1 and the most common NNRTI-resistant variants, and has a favorable and unique in vitro resistance profile. Methods: DRIVE-AHEAD is a phase 3, double-blind, non-inferiority trial. Antiretroviral treatment-naive adults with ≥1000 HIV-1 RNA copies/mL were randomized (1:1) to once-daily, fixed-dose DOR at 100 mg, lamivudine at 300 mg, and tenofovir disoproxil fumarate (TDF) at 300 mg (DOR/3TC/TDF) or to efavirenz at 600 mg, emtricitabine at 200 mg, and TDF at 300 mg (EFV/FTC/TDF) for 96 weeks. The primary efficacy endpoint was the proportion of participants with <50 HIV-1 RNA copies/mL at week 48 (Food and Drug Administration snapshot approach; non-inferiority margin 10%). Results: Of the 734 participants randomized, 728 were treated (364 per group) and included in the analyses. At week 48, 84.3% (307/364) of DOR/3TC/TDF recipients and 80.8% (294/364) of EFV/FTC/TDF recipients achieved <50 HIV-1 RNA copies/mL (difference 3.5%, 95% CI, -2.0, 9.0). DOR/3TC/TDF recipients had significantly lower rates of dizziness (8.8% vs 37.1%), sleep disorders/disturbances (12.1% vs 25.2%), and altered sensorium (4.4% vs 8.2%) than EFV/FTC/TDF recipients. Mean changes in fasting low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) were significantly different between DOR/3TC/TDF and EFV/FTC/TDF (-1.6 vs +8.7 mg/dL and -3.8 vs +13.3 mg/dL, respectively). Conclusions: In HIV-1 treatment-naive adults, DOR/3TC/TDF demonstrated non-inferior efficacy to EFV/FTC/TDF at week 48 and was well tolerated, with significantly fewer neuropsychiatric events and minimal changes in LDL-C and non-HDL-C compared with EFV/FTC/TDF. Clinical Trials Registration: NCT02403674.

Elbasvir/grazoprevir in black adults with hepatitis C virus infection: a pooled analysis of phase 2/3 clinical trials.

OBJECTIVES: Although direct-acting antiviral regimens have dramatically improved the treatment of hepatitis C virus (HCV) infection, there is some evidence that black race may be an independent predictor of treatment failure. We report a retrospective analysis of black participants receiving elbasvir/grazoprevir (EBR/GZR) in nine phase 2/3 clinical trials. METHODS: Black participants with chronic HCV genotype 1 or 4 (GT1 or GT4) infection who received EBR 50 mg/GZR 100 mg once daily for 12 weeks, or in combination with ribavirin for 16 weeks, were included. The primary end point was sustained virologic response 12 weeks after completion of therapy (SVR12, HCV RNA < 15 IU/mL). RESULTS: Compared with nonblack participants (n = 1310), black participants (n = 332) were more likely to have chronic kidney disease stage 4/5 (9.2% vs. 31.0%, respectively), while other comorbidities were similar between the groups. In black and nonblack participants receiving EBR/GZR for 12 weeks, SVR12 rates were 93.7% (282/301) and 94.2% (1072/1138) in those with GT1 infection, and 93.8% (15/16) and 94.6% (88/93) in those with GT4 infection. SVR12 was 100.0% (15/15) in black participants and 97.5% (77/79) in nonblack participants with GT1 infection receiving EBR/GZR plus ribavirin for 16 weeks. Rates of drug-related adverse events (AEs) were 30% vs. 36.6%, and serious AEs were 7.6% vs. 3.4% in black and nonblack participants, respectively. CONCLUSION: EBR/GZR showed high efficacy in black participants with HCV GT1 or GT4 infection and was generally well tolerated, with a safety profile similar to that reported overall in phase 2/3 clinical trials.

Elbasvir/Grazoprevir for Patients With Hepatitis C Virus Infection and Inherited Blood Disorders: A Phase III Study.

Direct-acting antiviral agents have not been studied exclusively in patients with inherited blood disorders and hepatitis C virus (HCV) infection. The objective of the randomized, placebo-controlled, phase III C-EDGE IBLD study was to assess the safety and efficacy of elbasvir/grazoprevir (EBR/GZR) in patients with inherited bleeding disorders and HCV infection. One hundred fifty-nine adults with HCV infection and sickle cell anemia, thalassemia, or hemophilia A/B or von Willebrand disease were enrolled at 31 study sites in the United States, Europe, Australia, Canada, Israel, and Thailand. Patients were given an oral, once-daily, fixed-dose combination of EBR/GZR 50 mg/100 mg for 12 weeks and randomized to the immediate-treatment group (ITG) or deferred-treatment group (DTG; placebo followed by active treatment). The primary endpoints were the proportion of patients in the ITG with unquantifiable HCV RNA 12 weeks posttreatment (sustained virological response 12 weeks after completion of study treatment; SVR12) and the comparison of safety in the ITG and DTG. In the ITG, 100 of 107 patients (93.5%) achieved SVR12, 6 relapsed, and 1 was lost to follow-up. SVR12 was achieved in 94.7% (18 of 19), 97.6% (40 of 41), and 89.4% (42 of 47) of patients with sickle cell disease, ß-thalassemia, and hemophilia A/B or von Willebrand disease, respectively. Serious adverse events were reported by 2.8% (n = 3) and 11.5% (n = 6) of patients in the ITG and DTG, respectively. Hemoglobin levels and international normalized ratio values were similar in patients receiving EBR/GZR and placebo; among patients with hemoglobinopathies, change in mean hemoglobin levels was similar in those receiving EBR/GZR compared to those receiving placebo. CONCLUSION: These results add to the expanding pool of data available for EBR/GZR, indicating a high level of efficacy and favorable tolerability in patients with HCV infection. (Hepatology 2017;66:736-745).

Efficacy of elbasvir and grazoprevir in participants with hepatitis C virus genotype 4 infection: A pooled analysis.

BACKGROUND & AIMS: The aim of this integrated analysis was to assess the efficacy of the once-daily combination of elbasvir 50 mg and grazoprevir 100 mg, with and without ribavirin in HCV genotype 4 (GT4)-infected participants enrolled in the Phase 2/3 clinical programme with elbasvir/grazoprevir. METHODS: Treatment-naïve and treatment-experienced participants 18 years of age or older with chronic HCV GT4 infection and baseline HCV RNA ≥10 000 IU/mL were included in the analysis. The analysis population was the full analysis set (FAS; all participants who received at least 1 dose of study medication) and a total of 155 HCV GT4 participants were evaluated. The primary endpoint was sustained virologic response at week 12 (SVR12; HCV RNA less than the lower limit of quantitation at 12 weeks after the completion of study therapy). RESULTS: Overall, among GT4-infected participants treated with 12 or 16 weeks of elbasvir/grazoprevir ± ribavirin, the SVR12 efficacy rates were 96.4% (107/111) in treatment-naïve participants and 88.6% (39/44) in treatment-experienced participants. The SVR12 rates were 96.0% (97/101) in treatment-naïve participants treated with 12 weeks of elbasvir/grazoprevir and 100% (8/8) in treatment-experienced participants treated with 16 weeks of elbasvir/grazoprevir plus ribavirin. Efficacy was not impacted by GT4 subtype. CONCLUSIONS: The regimens of 12 weeks of elbasvir/grazoprevir without ribavirin, and 16 weeks of elbasvir/grazoprevir plus ribavirin, were efficacious in HCV GT4-infected treatment-naïve and treatment-experienced participants respectively. Baseline NS5A resistance-associated substitutions did not impact the efficacy of elbasvir/grazoprevir in GT4-infected participants.

Control of hair follicle cell fate by underlying mesenchyme through a CSL-Wnt5a-FoxN1 regulatory axis.

Epithelial-mesenchymal interactions are key to skin morphogenesis and homeostasis. We report that maintenance of the hair follicle keratinocyte cell fate is defective in mice with mesenchymal deletion of the CSL/RBP-Jkappa gene, the effector of "canonical" Notch signaling. Hair follicle reconstitution assays demonstrate that this can be attributed to an intrinsic defect of dermal papilla cells. Similar consequences on hair follicle differentiation result from deletion of Wnt5a, a specific dermal papilla signature gene that we found to be under direct Notch/CSL control in these cells. Functional rescue experiments establish Wnt5a as an essential downstream mediator of Notch-CSL signaling, impinging on expression in the keratinocyte compartment of FoxN1, a gene with a key hair follicle regulatory function. Thus, Notch/CSL signaling plays a unique function in control of hair follicle differentiation by the underlying mesenchyme, with Wnt5a signaling and FoxN1 as mediators.