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BackgroundChronic hepatitis C virus (HCV) infection with genotypes (GT) 1 and 2 accounts for over 50% of HCV infections globally, including over 97% of all HCV infections in Japan. Here, we report an integrated analysis of efficacy and safety of 8-week treatment with the all-oral, fixed-dose combination of the direct acting antivirals (DAA), glecaprevir and pibrentasvir (G/P), in DAA-naïve Japanese and overseas patients without cirrhosis and with HCV GT1 or GT2 infection.MethodsData from 899 DAA-naïve patients without cirrhosis and with HCV GT1 or GT2 infection treated with G/P (300/120 mg) for 8 weeks in the six Phase 2 or 3 overseas or Japan-only clinical trials were included. All patients who received ≥ 1 dose of G/P were included in an intent-to-treat (ITT) analysis. The objectives were to evaluate rate of sustained virologic response 12 weeks post-treatment (SVR12) and safety of the 8-week regimen in the ITT population.ResultsOverall, SVR12 was achieved by 98.9% (889/899) of DAA-naïve patients without cirrhosis, including 99.2% (597/602) of GT1-infected and 98.3% (292/297) of GT2-infected patients. Less than 1% (2/899) of patients overall and no Japanese patients experienced virologic failure. SVR12 rate was > 97% for patients regardless of baseline characteristics, and common comorbidities or co-medications. Overall, < 1% (2/899) discontinued G/P due to an adverse event (AE) and 1.6% (14/899) of patients experienced a serious AE.Conclusions8-week G/P treatment is safe and efficacious in DAA-naive patients without cirrhosis and with HCV GT1 or GT2 infection, demonstrating high SVR12 rates regardless of baseline patient and disease characteristics.ClinicalTrials.gov identifiersThe trials discussed in this paper were registered with ClinicalTrials.gov as follows: NCT02707952 (CERTAIN-1), NCT02723084 (CERTAIN-2), NCT02243280 (SURVEYOR-I), NCT02243293 (SURVEYOR-II), NCT02604017 (ENDURANCE-1), NCT02738138 (EXPEDITION-2).

INTRODUCTION:Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis and advanced liver disease, and viral clearance is associated with reduced risk of developing cirrhosis, hepatic decompensation, and death. Glecaprevir (NS3/4A protease inhibitor) and pibrentasvir (NS5A inhibitor) are direct-acting antivirals (DAAs) co-formulated as a once-daily, fixed-dose combination regimen (G/P) to treat genotype (GT) 1‒6 HCV infection. G/P has been licensed in the United States and Europe, supported by a phase 2/3 global clinical trial program demonstrating high efficacy with a favorable safety profile. The objective of this study was to describe the clinical characteristics and virologic response to G/P in Puerto Rican (PR) patients included in the G/P clinical program.METHODS:Data were pooled from 14 phase 2, 3, and 3b clinical trials conducted in 32 countries and representing 3,233 treatment-naive and treatment-experienced patients with chronic HCV GT1–6 infection who received G/P once-daily for 8, 12, or 16 weeks. The primary endpoints were percentage of patients with sustained virologic response 12 weeks after treatment (SVR12) and percentage with treatment-emergent adverse events (AEs).RESULTS:From the 3,233 patients included in the G/P clinical program, this sub-analysis included 79 (2%) patients from sites in Puerto Rico. Overall, 52 (66%) were male, 64 (81%) were white race and the median age was 56 years (range: 29–78). Most patients were infected with HCV GT1 (n = 69; 87%), of whom 71% (49/69) had GT1a infection, and overall, 63 (80%) were treatment-naïve. Additionally, 39 (53%) patients had baseline fibrosis stage F0–F1, while 25 (34%) had stage F4. The overall SVR12 rate was 97.5% (77/79), with two patients not achieving SVR12 due to non-virologic reasons (both missing SVR12 data). AEs occurred in 38 (48%) patients, with none leading to discontinuation. Serious AEs occurred in 4 (5%) patients but none were deemed by investigators to be related to DAAs. There were 4 (5%) grade ≥3 laboratory abnormalities, and none were deemed clinically meaningful.CONCLUSION:G/P achieved high SVR12 rates and was well-tolerated in Puerto Rican patients enrolled in the G/P clinical trial program. The efficacy and safety profile of G/P in Puerto Rican patients was comparable to the overall patient population in the G/P registrational trial program, and SVR12 rates were comparable to real-world studies of G/P.

Spinal cord fMRI is a useful tool for studying spinal mechanisms of pain, hence for analgesic drug development. Its technical feasibility in both humans and rats has been demonstrated. This study investigates the reproducibility, robustness, and spatial accuracy of fMRI of lumbar spinal cord activation due to transcutaneous noxious and non-noxious electrical stimulation of the hindpaw in α-chloralose-anesthetized rats. Blood oxygenation level-dependent (BOLD) and blood volume-weighted fMRI data were acquired without and with intravenous injection of ultra small superparamagnetic iron oxide particles (USPIO), respectively, using a gradient echo (GE) echo planar imaging (EPI) technique at 4.7 T. Neuronal activation in the spinal cord induced by noxious stimulation to the hindpaw (2 ms wide, 5 mA amplitude, known to activate C-fibers) can be robustly detected by both fMRI techniques with excellent reproducibility and peaked at the stimulus frequency of 40 Hz. However, both fMRI techniques were not sensitive to neuronal activation in spinal cord induced by non-noxious stimulation (0.3 ms, 1.5 mA, known only to activate A-fibers). Spatially, the fMRI signal extended ∼ 5 mm in the longitudinal direction, covering L 3–L 5 segments. In the cross-sectional direction, the highest signal change of blood volume-weighted fMRI was in the middle of the ipsilateral dorsal horn, which roughly corresponds to laminae V and VI, while the highest signal change of BOLD fMRI was in the ipsilateral dorsal surface. This study demonstrates that spinal cord fMRI can be performed in anesthetized rats reliably and reproducibly offering it as a potential tool for analgesic drug discovery.

Prior studies have shown that neurons within the spinal cord are sensitive to response-outcome relations, a form of instrumental learning. Spinally transected rats that receive shock to one hind leg learn to maintain the leg in a flexed position that minimizes net shock exposure (controllable shock). Prior exposure to uncontrollable stimulation (intermittent shock) inhibits this spinally mediated learning. Here it is shown that uncontrollable stimulation undermines the recovery of function after a spinal contusion injury. Rats received a moderate injury (12.5 mm drop) and recovery was monitored for 6 weeks. In Experiment 1, rats received varying amounts of intermittent tailshock 1–2 days after injury. Just 6 min of intermittent shock impaired locomotor recovery. In Experiment 2, rats were shocked 1, 4, or 14 days after injury. Delaying the application of shock exposure reduced its negative effect on recovery. In Experiment 3, rats received controllable or uncontrollable shock 24 and 48 h after injury. Only uncontrollable shock disrupted recovery of locomotor function. Uncontrollably shocked rats also exhibited higher vocalization thresholds to aversive stimuli (heat and shock) applied below the injury. Across the three experiments, exposure to uncontrollable shock, (1) delayed the recovery of bladder function;(2) led to greater mortality and spasticity; and (3) increased tissue loss (white and gray matter) in the region of the injury. The results indicate that uncontrollable stimulation impairs recovery after spinal cord injury and suggest that reducing sources of uncontrolled afferent input (e.g., from peripheral tissue injury) could benefit patient recovery.

Pangenotypic, all-oral direct-acting antivirals, such as glecaprevir/pibrentasvir (G/P), are recommended for treatment of hepatitis C virus (HCV) infection. Concerns exist about the impact on efficacy in patients with suboptimal adherence, particularly with shorter treatment durations. These post hoc analyses evaluated adherence (based on pill count) in patients prescribed 8- or 12-week G/P, the impact of nonadherence on sustained virologic response at post-treatment week 12 (SVR12), factors associated with nonadherence, and efficacy in patients interrupting G/P treatment. Data were pooled from 10 phase 3 clinical trials of treatment-naive patients with HCV genotype 1-6 without cirrhosis/with compensated cirrhosis (treatment adherence analysis) and 13 phase 3 clinical trials of all patients with HCV (interruption analysis). Among 2,149 patients included, overall mean adherence was 99.4%. Over the treatment duration, adherence decreased (weeks 0-4: 100%; weeks 5-8: 98.3%; and weeks 9-12: 97.1%) and the percentage of patients with ≥80% or ≥90% adherence declined. SVR12 rate in the intention-to-treat (ITT) population was 97.7% (modified ITT SVR12 99.3%) and remained high in nonadherent patients in the modified ITT population (<90%: 94.4%-100%; <80%: 83.3%-100%). Psychiatric disorders were associated with <80% adherence, and shorter treatment duration was associated with ≥80% adherence. Among 2,902 patients in the interruption analysis, 33 (1.1%) had a G/P treatment interruption of ≥1 day, with an SVR12 rate of 93.9% (31/33). No virologic failures occurred. These findings support the impact of treatment duration on adherence rates and further reinforce the concept of \"treatment forgiveness\" with direct-acting antivirals.

INTRODUCTION:Pangenotypic, all-oral direct-acting antivirals, such as glecaprevir/pibrentasvir (G/P), are recommended for treatment of hepatitis C virus (HCV) infection. Concerns exist about the impact on efficacy in patients with suboptimal adherence, particularly with shorter treatment durations. These post hoc analyses evaluated adherence (based on pill count) in patients prescribed 8- or 12-week G/P, the impact of nonadherence on sustained virologic response at post-treatment week 12 (SVR12), factors associated with nonadherence, and efficacy in patients interrupting G/P treatment.METHODS:Data were pooled from 10 phase 3 clinical trials of treatment-naive patients with HCV genotype 1-6 without cirrhosis/with compensated cirrhosis (treatment adherence analysis) and 13 phase 3 clinical trials of all patients with HCV (interruption analysis).RESULTS:Among 2,149 patients included, overall mean adherence was 99.4%. Over the treatment duration, adherence decreased (weeks 0-4: 100%; weeks 5-8: 98.3%; and weeks 9-12: 97.1%) and the percentage of patients with ≥80% or ≥90% adherence declined. SVR12 rate in the intention-to-treat (ITT) population was 97.7% (modified ITT SVR12 99.3%) and remained high in nonadherent patients in the modified ITT population (<90%: 94.4%-100%; <80%: 83.3%-100%). Psychiatric disorders were associated with <80% adherence, and shorter treatment duration was associated with ≥80% adherence. Among 2,902 patients in the interruption analysis, 33 (1.1%) had a G/P treatment interruption of ≥1 day, with an SVR12 rate of 93.9% (31/33). No virologic failures occurred.DISCUSSION:These findings support the impact of treatment duration on adherence rates and further reinforce the concept of \"treatment forgiveness\" with direct-acting antivirals.

Research in our laboratory has demonstrated that spinal cord neurons can support instrumental learning. In these experiments, spinalized rats exposed to a contingency between foot position and shock onset learn to maintain their foot in a position that minimizes shock exposure. Shock presented independent of foot position (noncontingent shock) induces a behavioral deficit similar to learned helplessness. Other work has determined that the behavioral deficit can be induced by 6 min of shock and subverts plasticity for at least 48 hours. This effect was not observed in rats spinalized after shock. The goal of my dissertation was to characterize this effect by determining both the critical neurophysiological and neurochemical systems responsible for protecting spinal plasticity. Experiment 1 found that the protective effect was due to projections of the dorsolateral funiculus. Experiments 2–5 determined that serotonergic systems were responsible for the protective effect. Experiment 6 attempted unsuccessfully to use a serotonergic drug to foster locomotor recovery following shock exposure in a spinal injury paradigm.

A new example is unfolding in Tucson, Ariz. A company called World View Enterprises wants to offer tourists $75,000 rides in luxury high-altitude weather balloons. I think it's an interesting concept, and I might even buy a ticket. But even if I don't, as an Arizona taxpayer I'm already paying anyway, with more paying to come. World View's foray into tourism is a new venture and it still doesn't have Federal Aviation Administration permission to put passengers in weather balloons and launch them 32 kilometers into \"near space\" -- which is higher than airplanes fly but below the 100 kilometer boundary of outer space. That's a big gamble to take with taxpayer money. We've seen this movie before. Taxpayers pick up the tab for a brilliant idea on paper and it turns into a bust in practice. New Mexico taxpayers have sunk more than $200 million in a \"spaceport\" that Popular Mechanics recently called a \"ghost town.\" SunEdison, once the fastest-growing renewable energy company in the U.S., filed for bankruptcy last month despite receiving $650 million in federal subsidies. Rhode Island taxpayers lost $75 million when former Red Sox pitcher Curt Schilling's 38 Studios videogame company collapsed.

World View's foray into tourism is a new venture and it still doesn't have Federal Aviation Administration permission to put passengers in weather balloons and launch them 32 kilometers into \"near space\" -- which is higher than airplanes fly but below the 100 kilometer boundary of outer space.

World View's foray into tourism is a new venture and it still doesn't have Federal Aviation Administration permission to put passengers in weather balloons and launch them 32 kilometers into \"near space\"--which is higher than airplanes fly but below the 100 kilometer boundary of outer space.