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Purpose: People chronically infected with hepatitis C virus (HCV) have diminished patient-reported outcomes (PROs). This study aimed to compare the impact of elbasvir/grazoprevir (EBR/GZR) treatment versus sofosbuvir with pegylated interferon and ribavirin (SOF/PR) on changes in PROs: 1) during the treatment period and 2) at posttreatment follow-up. Patients and methods: PRO data collected during the Phase III C-EDGE Head-2-Head (H2H) open-label study was analyzed. In this trial, patients infected with HCV were randomized 1:1 to receive either EBR/GZR or SOF/PR for 12 weeks. Patients self-administered the Short Form-36 version 2 (SF-36v2®) Health Survey Acute (1-week recall) Form and the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Scale at baseline, during treatment, and posttreatment. Between-group differences in mean change of PRO scores from baseline were estimated during the treatment period and also at the posttreatment follow-up. Effect sizes were calculated to evaluate if the detected change in mean PRO scores is clinically meaningful between groups. Results: There were 255 patients (99.2% White, 54.1% female, 74.9% treatment naïve) included in the analysis. During the treatment period, significant declines in SF-36v2 scores were observed across all domains for the SOF/PR group. Compared to the SOF/PR group, the EBR/GZR group reported more improvement in scores across all SF-36v2 domain scores at the end of the treatment period. At treatment week 12, the between-group differences for 6 out of the 8 domain scores for these patients reflected at least moderate effects (effect sizes >0.5). No significant between-group differences in change in SF-36v2 scores from baseline were detected posttreatment. The decline in SF-36v2 scores observed during the treatment period for the SOF/PR group returned to near baseline scores or above posttreatment. Treatment with EBR/GZR did not impact fatigue scores, but treatment with SOF/PR led to increased fatigue scores during treatment which resolved by posttreatment follow-up week 12. Conclusion: This study demonstrated that HCV treatment with EBR/GZR resulted in a significantly better PRO profile as compared to SOF/PR. PROs are an important consideration as worsening PROs experienced during treatment may negatively influence adherence and ultimately contribute to an unfavorable clinical outcome. Clinical trials.gov Identifier: NCT02358044 [ABSTRACT FROM AUTHOR]

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Complementarity-determining region 3 (CDR3) of B-cell receptors (BCRs) and T-cell receptors are the major site of antigen recognition, which determines a unique clone type, and are considered to be the representative of the disease. In the present study, high-throughput sequencing was used to analyze the association of characteristics of the BCR immunoglobulin heavy chain (IGH) and the T-cell receptor β chain (TRB) CDR3 genes in PTC and corresponding pericarcinous tissues from patients. A difference of CDR3 length distributions of total IGH CDR3 sequences between the two groups was revealed. IGHV3-11/IGHJ6, TRBV2/TRBJ1-2 and TRBV2/TRBJ1-1 may be biomarkers for the development of PTC. Furthermore, it was revealed that the extent of the common clonotype expressions at the amino acid level was slightly higher compared with the nucleotide level. The Shannon entropy demonstrated a diversity reduction in PTC compared with the pericarcinous group, and the highly expended clone (HEC) expression of PTC was higher compared with that of the corresponding pericarcinous group. Additionally, the highest clone frequency percentage of IGH and TRB was at 0.1-1.0% degree of expansion, as HEC expression was higher in PTC compared with the matched group. There was no shared clone of HECs in the two groups either at the amino acid level or at the nucleotide expression level. The differential expression of CDR3 sequences of PTC have been identified in the present study. Further research is required for assessing the immune repertoire size, diversity, cloning tracking and finding public clones of T-cell and B-cell populations in the development of PTC. [ABSTRACT FROM AUTHOR]

Immunoglobulin A nephropathy (IgAN) is a type of glomerular disorder associated with immune dysregulation, and understanding B‑/T‑cell receptors (BCRs/TCRs) may be valuable for the development of specific immunotherapeutic interventions. In the present study, B and T cells were isolated from IgAN patients and healthy controls, and the composition of the BCR/TCR complementarity‑determining region (CDR)3 was analyzed by multiplex polymerase chain reaction, high‑throughput sequencing and bioinformatics. The present results revealed that the BCR/TCR CDR3 clones were expressed at very low frequencies, and the composition of clone types in patients with IgAN was skewed; the majority of clones were unique, and only 12 BCR and 228 TCR CDR3 clones were public ones, of which 16 were expressed at a significantly higher frequency in patients with IgAN (P<0.001). There were also certain conserved amino acid residues between unique clones or groups, and the residues GMDV, EQY and EQF were recurring only in the IgAN group. In addition, some VDJ gene recombinations indicated great variation between groups, including 4 high‑frequency VDJ gene recombinations in the IgAN patients (P<0.001). Immune repertoires provide novel information, and conserved BCR/TCR CDR3 clones and VDJ gene recombinations with great variation may be potential therapeutic targets for IgAN patients. [ABSTRACT FROM AUTHOR]

The primary objective of a multiregional clinical trial (MRCT) is to assess the efficacy of all participating regions and evaluate the probability of applying the overall results to a specific region. The consistency assessment of the target region with the overall results is the most common way of evaluating the efficacy in a specific region. Recently, Huang et al. (2012) proposed an additional trial in the target region to an MRCT to evaluate the efficacy in the target ethnic (TE) population under the framework of simultaneous global drug development program (SGDDP). However, the operating characteristics of this statistical framework were not well considered. Therefore, a nested group sequential program for regional efficacy evaluation is proposed in this paper. It is an extension of Huang’s SGDDP framework and allows interim analysis after MRCT and in the course of local clinical trial (LCT) phase. It is able to well control the family-wise type I error in the program level and enhances the flexibility of the program. In LCT sample size estimation, we introduce virtual trial, which is transformed from the original program by using discounting factor, and an iteration method is employed to calculate the sample size and stopping boundaries of interim analyses. The proposed sample size estimation method is validated in the simulations and the effect of varied weight, effect size of TE population, and design setting is explored. Examples with normal end point, binary end point, and survival end point are shown to illustrate the application of the proposed nested group sequential program. [ABSTRACT FROM PUBLISHER]

Phellodendron amurenseRupr. produces berberine, a valuable ingredient in Chinese medicine. We examined how berberine content varied in different parts of the tree with age and geography in Northeast China. Berberine levels in root bark, trunk bark, and perennial branch bark, annual branches, and leaves were estimated by high-performance liquid chromatography. Root, trunk, and perennial branch barks had significantly higher berberine content than annual branches and leaves. Moreover, berberine content varied significantly with both longitude and latitude in samples of these three plant parts. The populations growing at low longitude and latitude contained significantly more berberine than those growing at high longitude and latitude. These results provide a scientific basis for the reasonable cultivation and efficient use ofP. amurense. [ABSTRACT FROM AUTHOR]

Background & Aims Direct-acting antiviral agents have improved treatment outcomes for patients with hepatitis C virus (HCV) infection; however, head-to-head comparisons are limited. The C-EDGE Head-2-Head Study compared the safety and efficacy of elbasvir/grazoprevir (EBR/GZR) with sofosbuvir plus pegylated interferon/ribavirin (SOF/PR) in patients with HCV infection. Methods This was a randomized, open-label, phase III trial. Two hundred fifty-seven patients with HCV genotype (GT)1 or 4 infection and baseline viral load >10,000 IU/ml were randomized to receive 12 weeks of EBR/GZR 50 mg/100 mg once daily (n = 129) or sofosbuvir (400 mg once daily) plus PR (n = 128). Primary efficacy objective was sustained virologic response 12 weeks after the end of therapy (SVR12, HCV RNA <15 IU/ml). The primary safety objective was the proportion of patients experiencing a tier 1 safety event. Results The majority of patients were non-cirrhotic (83.1%), treatment-naïve (74.9%) and had HCV GT1b infection (82.0%). SVR12 rates were 99.2% (128/129) and 90.5% (114/126) in the EBR/GZR and SOF/PR groups, respectively. The estimated adjusted difference in SVR12 was 8.8% (95% confidence interval [CI], 3.6–15.3%). Because the lower bound of the 1-sided 1-sample exact test was greater than −10% and greater than zero, both non-inferiority and superiority of EBR/GZR vs. SOF/PR were established. The frequency of tier 1 safety events was lower among patients receiving EBR/GZR than SOF/PR (0.8% vs. 27.8%, between group difference, 27.0% [95% CI, −35.5% to −19.6%; p <0.001]). Conclusions EBR/GZR has a superior efficacy and safety profile in patients with HCV GT1 or 4 infection compared with SOF/PR. Lay summary The combination of elbasvir/grazoprevir for 12 weeks was highly effective in treating patients with chronic hepatitis C, genotypes 1 or 4 infection. This regimen was more effective than sofosbuvir/pegylated interferon/ribavirin for 12 weeks, and was notably superior in patients regarded as difficult to treat, including those with previous treatment failure, cirrhosis, or a high baseline viral load. The combination of elbasvir/grazoprevir also demonstrated a superior safety and tolerability profile based on fewer serious adverse events, no serious drug-related adverse events, and no treatment discontinuations. Clinical trial registration Clinical trials.gov Identifier: NCT02358044. [ABSTRACT FROM AUTHOR]

Purpose: Preclinical studies show that adavosertib, a WEE1 kinase inhibitor, sensitizes TP53 -mutant cells to chemotherapy. We hypothesized that adavosertib, plus chemotherapy, would enhance efficacy versus placebo in TP53 -mutated ovarian cancer., Patients and Methods: Following safety run-in, this double-blind phase II trial (NCT01357161) randomized women with TP53 -mutated, platinum-sensitive ovarian cancer to oral adavosertib (225 mg twice daily for 2.5 days/21-day cycle) or placebo, plus carboplatin (AUC5) and paclitaxel (175 mg/m 2 ), until disease progression or for six cycles. The primary endpoints were progression-free survival (PFS) by enhanced RECIST v1.1 [ePFS (volumetric)] and safety. Secondary/exploratory objectives included PFS by RECIST v1.1 (single dimension), objective response rate, overall survival, and analysis of tumor gene profile versus sensitivity to adavosertib., Results: A total of 121 patients were randomized to adavosertib (A+C; n = 59) and placebo (P+C; n = 62) plus chemotherapy. Adding adavosertib to chemotherapy improved ePFS [median, 7.9 (95% confidence interval (CI), 6.9-9.9) vs. 7.3 months (5.6-8.2); HR 0.63 (95% CI, 0.38-1.06); two-sided P = 0.080], meeting the predefined significance threshold ( P < 0.2). Clinical benefit was observed following A+C for patients with different TP53 mutation subtypes, identifying possible response biomarkers. An increase in adverse events was seen with A+C versus P+C: greatest for diarrhea (adavosertib 75%; placebo 37%), vomiting (63%; 27%), anemia (53%; 32%), and all grade ≥3 adverse events (78%; 65%)., Conclusions: Establishing an optimal strategy for managing tolerability and identifying specific patient populations most likely to benefit from treatment may increase clinical benefit. Future studies should consider additional adavosertib doses within the chemotherapy treatment cycle and the potential for maintenance therapy., (©2020 American Association for Cancer Research.)

The arbovirus life cycle involves viral transfer between a vertebrate host and an arthropod vector, and acquisition of virus from an infected mammalian host by a vector is an essential step in this process. Here, we report that flavivirus nonstructural protein-1 (NS1), which is abundantly secreted into the serum of an infected host, plays a critical role in flavivirus acquisition by mosquitoes. The presence of dengue virus (DENV) and Japanese encephalitis virus NS1s in the blood of infected interferon-α and γ receptor-deficient mice (AG6) facilitated virus acquisition by their native mosquito vectors because the protein enabled the virus to overcome the immune barrier of the mosquito midgut. Active immunization of AG6 mice with a modified DENV NS1 reduced DENV acquisition by mosquitoes and protected mice against a lethal DENV challenge, suggesting that immunization with NS1 could reduce the number of virus-carrying mosquitoes as well as the incidence of flaviviral diseases. Our study demonstrates that flaviviruses utilize NS1 proteins produced during their vertebrate phases to enhance their acquisition by vectors, which might be a result of flavivirus evolution to adapt to multiple host environments.

Introduction: HIV-infected prisoners lose viral suppression within the 12 weeks after release to the community. This prospective study evaluates the use of buprenorphine/naloxone (BPN/NLX) as a method to reduce relapse to opioid use and sustain viral suppression among released HIV-infected prisoners meeting criteria for opioid dependence (OD)., Methods: From 2005-2010, 94 subjects meeting DSM-IV criteria for OD were recruited from a 24-week prospective trial of directly administered antiretroviral therapy (DAART) for released HIV-infected prisoners; 50 (53%) selected BPN/NLX and were eligible to receive it for 6 months; the remaining 44 (47%) selected no BPN/NLX therapy. Maximum viral suppression (MVS), defined as HIV-1 RNA<50 copies/mL, was compared for the BPN/NLX and non-BPN/NLX (N = 44) groups., Results: The two groups were similar, except the BPN/NLX group was significantly more likely to be Hispanic (56.0% v 20.4%), from Hartford (74.4% v 47.7%) and have higher mean global health quality of life indicator scores (54.18 v 51.40). MVS after 24 weeks of being released was statistically correlated with 24-week retention on BPN/NLX [AOR = 5.37 (1.15, 25.1)], having MVS at the time of prison-release [AOR = 10.5 (3.21, 34.1)] and negatively with being Black [AOR = 0.13 (0.03, 0.68)]. Receiving DAART or methadone did not correlate with MVS., Conclusions: In recognition that OD is a chronic relapsing disease, strategies that initiate and retain HIV-infected prisoners with OD on BPN/NLX is an important strategy for improving HIV treatment outcomes as a community transition strategy.

Background: Many people living with HIV access healthcare systems through the emergency department (ED), and increased ED use may be indicative of disenfranchisement with primary HIV care, under-managed comorbid disease, or coincide with use of other healthcare resources. The goal of this study was to investigate ED use by HIV-infected prisoners transitioning to communities., Methods: We evaluated ED use by 151 HIV-infected released prisoners who were enrolled in a randomized controlled trial of directly administered versus self-administered antiretroviral therapy in Connecticut. Primary outcomes were quantity and type of ED visits and correlates of ED use were evaluated with multivariate models by Poisson regression., Results: In the 12 months post-release, there were 227 unique ED contacts made by 85/151 (56%) subjects. ED visits were primarily for acute febrile syndromes (32.6%) or pain (20.3%), followed by substance use issues (19.4%), trauma (18%), mental illness (11%), and social access issues (4.4%). Compared to those not utilizing the ED, users were more likely to be white, older, and unmarried, with less trust in their physician and poorer perceived physical health but greater social support. In multivariate models, ED use was correlated with moderate to severe depression (IRR = 1.80), being temporarily housed (IRR = 0.54), and alcohol addiction severity (IRR = 0.21) but not any surrogates of HIV severity., Conclusions: EDs are frequent sources of care after prison-release with visits often reflective of social and psychiatric instability. Future interventions should attempt to fill resource gaps, engage released prisoners in continuous HIV care, and address these substantial needs.

Background: As the age of a population increases, so too does the rate of disability. In addition, disability is likely to be more common in rural compared with urban areas. The present study aimed to examine the influence of rapid population changes in terms of age and rural/urban residence on the prevalence of disability., Methods: Data from the 1987 and 2006 China Sampling Surveys on Disability were used to estimate the impacts of rapid ageing and the widening urban-rural gap on the prevalence of disability. Stratum specific rates of disability were estimated by 5-year age-group and type of residence. The decomposition of rates method was used to calculate the rate difference for each stratum between the two surveys., Results: The crude disability rate increased from 4.89% in 1987 to 6.39% in 2006, a 1.5% increase over the 19 year period. However, after the compositional effects from the overall rates of changing age-structure in 1987 and 2006 were eliminated by standardization, the disability rate in 1987 was 6.13%, which is higher than that in 2006 (5.91%). While in 1987 the excess due to rural residence compared with urban was <1.0%, this difference increased to >1.5% by 2006, suggesting a widening disparity by type of residence. When rates were decomposed, the bulk of the disability could be attributed to ageing, and very little to rural residence. However, a wider gap in prevalence between rural and urban areas could be observed in some age groups by 2006., Conclusion: The increasing number of elderly disabled persons in China and the widening discrepancy of disability prevalence between urban and rural areas may indicate that the most important priorities for disability prevention in China are to reinforce health promotion in older adults and improve health services in rural communities.