Chronic Hepatitis C Treatment in Patients with Drug Injection History: Findings of the INTEGRATE Prospective, Observational Study.

INTRODUCTION: People who inject drugs represent an under-treated chronic hepatitis C virus (HCV)-infected patient population. METHODS: INTEGRATE was a prospective, observational study investigating the effectiveness, safety, and adherence in routine clinical practice to telaprevir in combination with peg-interferon and ribavirin (Peg-IFN/RBV) in patients with history of injecting drug use chronically infected with genotype 1 HCV. RESULTS: A total of 46 patients were enrolled and included in the intent-to-treat (ITT) population. Among heroin and/or cocaine users (n = 37; 80%), 22% reported use in the past month; 74% (34/46) of patients were on opioid substitution therapy in the pre-treatment phase, and 43% (20/46) discontinued HCV treatment prematurely. Sustained virologic response rate was 54% (25/46) in the ITT population and 74% (25/34) in the per protocol (evaluable-for-effectiveness) population. The main reason for failure in the ITT analysis was loss to follow-up (n = 8; 17%). Adverse events occurred in 91% (42/46) of patients. Mean patient-reported adherence to study drugs was >89% at Week 4, Week 12 and end of treatment. CONCLUSION: Despite a high rate of treatment discontinuation (including loss to follow-up), self-reported adherence to treatment was good and virologic cure rates were similar to those reported in large real-world cohorts. Our findings suggest that people with a history of injecting drug use should be considered for treatment of chronic HCV infection, and highlight the need for improvements in patient support to boost retention in care and, in turn, help to prevent reinfection and transmission. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier, NCT01980290. FUNDING: Janssen Pharmaceuticals

Safety and on-treatment efficacy of telaprevir: the early access programme for patients with advanced hepatitis C

Background and aim Severe adverse events (AEs) compromise the outcome of direct antiviral agent-based treatment in patients with advanced liver fibrosis due to HCV infection. HEP3002 is an ongoing multinational programme to evaluate safety and efficacy of telaprevir (TVR) plus pegylated-interferon-alpha (PEG-IFN alpha) and ribavirin (RBV) in patients with advanced liver fibrosis caused by HCV genotype 1 (HCV-1).Methods 1782 patients with HCV-1 and bridging fibrosis or compensated cirrhosis were prospectively recruited from 16 countries worldwide, and treated with 12 weeks of TVR plus PEG-IFN/RBV, followed by 12 or 36 weeks of PEG-IFN and RBV (PR) alone dependent on virological response to treatment and previous response type.Results 1587 patients completed 12 weeks of triple therapy and 4 weeks of PR tail (53% cirrhosis, 22% HCV-1a). By week 12, HCV RNA was undetectable in 85% of naives, 88% of relapsers, 80% of partial responders and 72% of null responders. Overall, 931 patients (59%) developed grade 1-4 anaemia (grade 3/4 in 31%), 630 (40%) dose reduced RBV, 332 (21%) received erythropoietin and 157 (10%) were transfused. Age and female gender were the strongest predictors of anaemia. 64 patients (4%) developed a grade 3/4 rash. Discontinuation of TVR due to AEs was necessary in 193 patients (12%). Seven patients died (0.4%, six had cirrhosis).Conclusions in compensated patients with advanced fibrosis due to HCV-1, triple therapy with TVR led to satisfactory rates of safety, tolerability and on-treatment virological response with adequate managements of AEs.Janssen PharmaceuticsUniv Milan, Div Gastroenterol, Dept Med, Fdn IRCCS Ca Granda Osped Maggiore Policlin, Milan, ItalyHosp Univ 12 Octubre, Secc Aparato Digest, Madrid, SpainIM Sechenov First Moscow State Med Univ, EM Tareev Clin Nephrol Internal & Occupat Med, Moscow, RussiaUniversidade Federal de São Paulo, Viral Hepatitis Div Infect Dis, Outpatient Clin HIV, São Paulo, BrazilUniv Sydney, Royal Prince Alfred Hosp, AW Morrow Gastroenterol & Liver Ctr, Sydney, NSW 2006, AustraliaCharles Univ Prague, Fac Med 1, Dept Internal Med, Prague, Czech RepublicCent Mil Hosp Prague, Prague, Czech RepublicUniv Libre Brussels, Dept Gastroenterol Hepatopancreatol & Digest Onco, Erasme Univ Hosp, Liver Unit, Brussels, BelgiumCarol Davila Univ Med & Pharm, Natl Inst Infect Dis, Bucharest, RomaniaJanssen Pharmaceut, B-2340 Beerse, BelgiumJanssen Pharmaceut, Paris, FranceJanssen Res & Dev, Titusville, NJ USAJanssen Res & Dev, High Wycombe, Bucks, EnglandJanssen Cilag AG, Zug, SwitzerlandHannover Med Sch, D-30623 Hannover, GermanyUniversidade Federal de São Paulo, Viral Hepatitis Div Infect Dis, Outpatient Clin HIV, São Paulo, BrazilWeb of Scienc

Grafted Human Embryonic Progenitors Expressing Neurogenin-2 Stimulate Axonal Sprouting and Improve Motor Recovery after Severe Spinal Cord Injury

7 p.Background: Spinal cord injury (SCI) is a widely spread pathology with currently no effective treatment for any symptom. Regenerative medicine through cell transplantation is a very attractive strategy and may be used in different non-exclusive ways to promote functional recovery. We investigated functional and structural outcomes after grafting human embryonic neural progenitors (hENPs) in spinal cord-lesioned rats.Methods and Principal Findings: With the objective of translation to clinics we have chosen a paradigm of delayed grafting, i.e., one week after lesion, in a severe model of spinal cord compression in adult rats. hENPs were either naive or engineered to express Neurogenin 2 (Ngn2). Moreover, we have compared integrating and non-integrating lentiviral vectors, since the latter present reduced risks of insertional mutagenesis. We show that transplantation of hENPs transduced to express Ngn2 fully restore weight support and improve functional motor recovery after severe spinal cord compression at thoracic level. This was correlated with partial restoration of serotonin innervations at lumbar level, and translocation of 5HT1A receptors to the plasma membrane of motoneurons. Since hENPs were not detectable 4 weeks after grafting, transitory expression of Ngn2 appears sufficient to achieve motor recovery and to permit axonal regeneration. Importantly, we also demonstrate that transplantation of naive hENPs is detrimental to functional recovery.Conclusions and Significance: Transplantation and short-term survival of Ngn2-expressing hENPs restore weight support after SCI and partially restore serotonin fibers density and 5HT1A receptor pattern caudal to the lesion. Moreover, grafting of naive-hENPs was found to worsen the outcome versus injured only animals, thus pointing to the possible detrimental effect of stem cell-based therapy per se in SCI. This is of major importance given the increasing number of clinical trials involving cell grafting developed for SCI patients.This study was supported by the European Union FP6 "RESCUE" STREP; the "Institut pour la Recherche sur la Moelle Epiniere"; the "Academie de Medecine"; the "Societe Francaise de Neurochirurgie"; "Verticale" and the "Association Demain Debout Aquitaine". The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Final results of the telaprevir access program: Fibroscan values predict safety and efficacy in hepatitis c patients with advanced fibrosis or cirrhosis

Background: Liver stiffness determined by transient elastography is correlated with hepatic fibrosis stage and has high accuracy for detecting severe fibrosis and cirrhosis in chronic hepatitis C patients. We evaluated the clinical value of baseline FibroScan values for the prediction of safety and efficacy of telaprevir-based therapy in patients with advanced fibrosis and cirrhosis in the telaprevir Early Access Program HEP3002. Methods: 1,772 patients with HCV-1 and bridging fibrosis or cirrhosis were treated with telaprevir plus pegylated interferon-α and ribavirin (PR) for 12 weeks followed by PR alone, the total treatment duration depending on virological response and previous response type. Liver fibrosis stage was determined either by liver biopsy or by non-invasive markers. 1,282 patients (72%) had disease stage assessed by FibroScan; among those 46% were classified as Metavir F3 at baseline and 54% as F4. Results: Overall, 1,139 patients (64%) achieved a sustained virological response (SVR) by intentionto- treat analysis. Baseline FibroScan values were tested for association with SVR and the occurrence of adverse events. By univariate analysis, higher baseline FibroScan values were predictive of lower sustained virological response rates and treatment-related anemia. By multivariate analysis, FibroScan was no longer statistically significant as an independent predictor, but higher FibroScan values were correlated with the occurrence of infections and serious adverse events. Conclusions: FibroScan has a limited utility as a predictor of safety and efficacy in patients treated with telaprevir-based triple therapy. Nevertheless it can be used in association with other clinical and biological parameters to help determine patients who will benefit from the triple regiments. © 2015 Lepida et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Spatio-Temporal Progression of Grey and White Matter Damage Following Contusion Injury in Rat Spinal Cord

Cellular mechanisms of secondary damage progression following spinal cord injury remain unclear. We have studied the extent of tissue damage from 15 min to 10 weeks after injury using morphological and biochemical estimates of lesion volume and surviving grey and white matter. This has been achieved by semi-quantitative immunocytochemical methods for a range of cellular markers, quantitative counts of white matter axonal profiles in semi-thin sections and semi-quantitative Western blot analysis, together with behavioural tests (BBB scores, ledged beam, random rung horizontal ladder and DigiGait™ analysis). We have developed a new computer-controlled electronic impactor based on a linear motor that allows specification of the precise nature, extent and timing of the impact. Initial (15 min) lesion volumes showed very low variance (1.92±0.23 mm3, mean±SD, n = 5). Although substantial tissue clearance continued for weeks after injury, loss of grey matter was rapid and complete by 24 hours, whereas loss of white matter extended up to one week. No change was found between one and 10 weeks after injury for almost all morphological and biochemical estimates of lesion size or behavioural methods. These results suggest that previously reported apparent ongoing injury progression is likely to be due, to a large extent, to clearance of tissue damaged by the primary impact rather than continuing cell death. The low variance of the impactor and the comprehensive assessment methods described in this paper provide an improved basis on which the effects of potential treatment regimes for spinal cord injury can be assessed

The Forward Physics Facility at the High-Luminosity LHC

High energy collisions at the High-Luminosity Large Hadron Collider (LHC) produce a large number of particles along the beam collision axis, outside of the acceptance of existing LHC experiments. The proposed Forward Physics Facility (FPF), to be located several hundred meters from the ATLAS interaction point and shielded by concrete and rock, will host a suite of experiments to probe standard model (SM) processes and search for physics beyond the standard model (BSM). In this report, we review the status of the civil engineering plans and the experiments to explore the diverse physics signals that can be uniquely probed in the forward region. FPF experiments will be sensitive to a broad range of BSM physics through searches for new particle scattering or decay signatures and deviations from SM expectations in high statistics analyses with TeV neutrinos in this low-background environment. High statistics neutrino detection will also provide valuable data for fundamental topics in perturbative and non-perturbative QCD and in weak interactions. Experiments at the FPF will enable synergies between forward particle production at the LHC and astroparticle physics to be exploited. We report here on these physics topics, on infrastructure, detector, and simulation studies, and on future directions to realize the FPF's physics potential

Endocrinologic, neurologic, and visual morbidity after treatment for craniopharyngioma

Craniopharyngiomas are locally aggressive tumors which typically are focused in the sellar and suprasellar region near a number of critical neural and vascular structures mediating endocrinologic, behavioral, and visual functions. The present study aims to summarize and compare the published literature regarding morbidity resulting from treatment of craniopharyngioma. We performed a comprehensive search of the published English language literature to identify studies publishing outcome data of patients undergoing surgery for craniopharyngioma. Comparisons of the rates of endocrine, vascular, neurological, and visual complications were performed using Pearson’s chi-squared test, and covariates of interest were fitted into a multivariate logistic regression model. In our data set, 540 patients underwent surgical resection of their tumor. 138 patients received biopsy alone followed by some form of radiotherapy. Mean overall follow-up for all patients in these studies was 54 ± 1.8 months. The overall rate of new endocrinopathy for all patients undergoing surgical resection of their mass was 37% (95% CI = 33–41). Patients receiving GTR had over 2.5 times the rate of developing at least one endocrinopathy compared to patients receiving STR alone or STR + XRT (52 vs. 19 vs. 20%, χ2P < 0.00001). On multivariate analysis, GTR conferred a significant increase in the risk of endocrinopathy compared to STR + XRT (OR = 3.45, 95% CI = 2.05–5.81, P < 0.00001), after controlling for study size and the presence of significant hypothalamic involvement. There was a statistical trend towards worse visual outcomes in patients receiving XRT after STR compared to GTR or STR alone (GTR = 3.5% vs. STR 2.1% vs. STR + XRT 6.4%, P = 0.11). Given the difficulty in obtaining class 1 data regarding the treatment of this tumor, this study can serve as an estimate of expected outcomes for these patients, and guide decision making until these data are available

Syndromics: A Bioinformatics Approach for Neurotrauma Research

Substantial scientific progress has been made in the past 50 years in delineating many of the biological mechanisms involved in the primary and secondary injuries following trauma to the spinal cord and brain. These advances have highlighted numerous potential therapeutic approaches that may help restore function after injury. Despite these advances, bench-to-bedside translation has remained elusive. Translational testing of novel therapies requires standardized measures of function for comparison across different laboratories, paradigms, and species. Although numerous functional assessments have been developed in animal models, it remains unclear how to best integrate this information to describe the complete translational “syndrome” produced by neurotrauma. The present paper describes a multivariate statistical framework for integrating diverse neurotrauma data and reviews the few papers to date that have taken an information-intensive approach for basic neurotrauma research. We argue that these papers can be described as the seminal works of a new field that we call “syndromics”, which aim to apply informatics tools to disease models to characterize the full set of mechanistic inter-relationships from multi-scale data. In the future, centralized databases of raw neurotrauma data will enable better syndromic approaches and aid future translational research, leading to more efficient testing regimens and more clinically relevant findings