Background
Season of birth influences allergy risk; however, the biological mechanisms underlying this observation are unclear. The environment affects DNA methylation, with potentially long‐lasting ...effects on gene expression and disease. This study examined whether DNA methylation could underlie the association between season of birth and allergy.
Methods
In a subset of 18‐year‐old participants from the Isle of Wight (IoW) birth cohort (n = 367), the risks of birth season on allergic outcomes were estimated. Whole blood epigenome‐wide DNA methylation was measured, and season‐associated CpGs detected using a training‐and‐testing‐based technique. Validation method examined the 8‐year‐old Prevention and Incidence of Asthma and Mite Allergy (PIAMA) cohort. The relationships between DNA methylation, season of birth and allergy were examined. CpGs were analysed in IoW third‐generation cohort newborns.
Results
Autumn birth increased risk of eczema, relative to spring birth. Methylation at 92 CpGs showed association with season of birth in the epigenome‐wide association study. In validation, significantly more CpGs had the same directionality than expected by chance, and four were statistically significant. Season‐associated methylation was enriched among networks relating to development, the cell cycle and apoptosis. Twenty CpGs were nominally associated with allergic outcomes. Two CpGs were marginally on the causal pathway to allergy. Season‐associated methylation was largely absent in newborns, suggesting it arises post‐natally.
Conclusions
This study demonstrates that DNA methylation in adulthood is associated with season of birth, supporting the hypothesis that DNA methylation could mechanistically underlie the effect of season of birth on allergy, although other mechanisms are also likely to be involved.
Hepatocellular carcinoma (HCC) represents an increasing fraction of liver transplant indications; the role of living donor liver transplant (LDLT) remains unclear. In the Adult‐to‐Adult Living Donor ...Liver Transplantation Cohort Study, patients with HCC and an LDLT or deceased donor liver transplant (DDLT) for which at least one potential living donor had been evaluated were compared for recurrence and posttransplant mortality rates. Mortality from date of evaluation of each recipient's first potential living donor was also analyzed. Unadjusted 5‐year HCC recurrence was significantly higher after LDLT (38%) than DDLT (11%), (p = 0.0004). After adjustment for tumor characteristics, HCC recurrence remained significantly different between LDLT and DDLT recipients (hazard ratio (HR) = 2.35; p = 0.04) for the overall cohort but not for recipients transplanted following the introduction of MELD prioritization. Five‐year posttransplant survival was similar in LDLT and DDLT recipients from time of transplant (HR = 1.32; p = 0.27) and from date of LDLT evaluation (HR = 0.73; p = 0.36). We conclude that the higher recurrence observed after LDLT is likely due to differences in tumor characteristics, pretransplant HCC management and waiting time.
The higher rate of recurrence of hepatocellular carcinoma after living donor liver transplantation observed in the Adult‐to‐Adult Living Donor Liver Transplantation Cohort Study is likely due to differences in tumor characteristics, pretransplant carcinoma management and waiting time. See editorial by Trotter on page 2873.
We reported here three simple, low cost and easy to accomplish strategies for the fabrication of microelectrodes and other conductive patterns using ordinary office laser‐printers. In this work, ...toner patterns were directly printed onto the flexible substrate, acting as a mask to create the intended conductive design. To highlight the versatility of such technology, toner‐printed patterns were employed in two diverse ways: one in which the patterned toner had the exact design of the electrode and other employing a reverse toner‐printed pattern. The first one was used for the adaptation of the well‐known printed circuit board (PCB) fabrication technique, but using direct toner printing (DTP) in an already conductive flexible substrate. The second was employed for the two remaining strategies: one based on the deposition of conductive film, followed by lift‐off process; and another based on drop‐casting of a conductive ink into the formed toner cavities, followed by thermal cure. As proof‐of‐concept, all three DTP strategies were used for the fabrication of miniaturized gold electrodes in polyimide substrate, and electrochemical performance of each obtained electrode was evaluated by cyclic voltammetry. Insights about DTP technology, alignment issues, advantages, limitations and resolution of each presented approach were provided. Finally, direct toner printing showed to be a simple, affordable and quite promising technology for the fabrication of low cost point‐of‐care electrochemical devices using flexible platforms.
Summary Background Several direct-acting antivirals for chronic hepatitis C virus (HCV) infection are available, but they are limited by tolerability and dosing schedules. Once-daily daclatasvir, a ...potent NS5A replication complex inhibitor, was generally well tolerated in phase 1 studies. We assessed daclatasvir in combination with pegylated interferon (peginterferon) and ribavirin for chronic HCV. Methods In this double-blind, parallel-group, dose-finding, phase 2a study, treatment-naive patients with HCV genotype-1 infection (without cirrhosis) from 14 centres in the USA and France were randomly assigned (1:1:1:1) to receive peginterferon alfa-2a (180 μg per week) and ribavirin (1000–1200 mg daily) plus placebo or 3 mg, 10 mg, or 60 mg of daclatasvir taken once daily, for 48 weeks. The primary efficacy endpoint was undetectable HCV RNA at 4 weeks and 12 weeks after start of treatment (extended rapid virological response, eRVR). Analysis was of all participants who received one dose of study drug. We used descriptive analyses to compare results. This study is registered with ClinicalTrials.gov , number NCT00874770. Findings 48 patients were randomly assigned (12 per group); all received at least one dose of study drug. 15 patients discontinued treatment before week 48. Five of 12 patients (42%, 80% CI 22–64%) who received 3 mg daclatasvir achieved eRVR, compared with ten of 12 (83%, 61–96%) who received 10 mg daclatasvir, nine of 12 (75%, 53–90%) who received 60 mg daclatasvir, and one of 12 (8%, 1–29%) who received placebo. Adverse events and discontinuations as a result of adverse events occurred with similar frequency across groups. Interpretation Daclatasvir seems to be a potent NS5A replication complex inhibitor that increases the antiviral potency of peginterferon and ribavirin. Our findings support the further development of regimens containing 60 mg daclatasvir for the treatment of chronic genotype-1 HCV infection. Funding Bristol-Myers Squibb.
Abusive alcohol use and chronic hepatitis C virus (HCV) commonly co-exist and both need to be addressed in liver disease. With high rates of HCV cure with new therapies, attention needs to turn ...toward ongoing abusive alcohol patterns that may determinately impact liver health both before and after liver transplant.
Abstract
Aims
To provide an overview of published literature on the interaction of alcohol and hepatitis C virus (HCV) in the accelerated progression of liver disease to cirrhosis as relates to decision-making for the management of the liver transplant candidate and recipient.
Methods
General PubMed search was employed along with expert input to identify the relevant articles on the topic. The authors also utilized both backward and forward citation review of the relevant articles and reviews to identify articles on identified topic.
Results
In HCV cases, heavy alcohol use has been associated with more severe fibrosis, but even low rates of use may have deleterious effects. Patients with chronic hepatitis C and alcoholic liver disease can be cured of the HCV—theoretically positively impacting outcome and reducing the need for liver transplantation. Current antiviral therapy achieves virologic cure or sustained viral response (SVR) in over 90% of cases. Antiviral therapy is so effective that most liver transplant candidates or recipients can be cured of HCV either prior to or after transplantation. However, despite successful antiviral therapy, liver disease may progress after SVR due to the effects of ongoing alcohol use.
Conclusion
Antiviral therapy in patients with HCV plus alcohol should improve pre- and post-transplant outcomes, but providers must remain firm in limiting use of alcohol to avoid progression of liver disease post HCV cure.
Short Summary
Abusive alcohol use and chronic hepatitis C virus (HCV) commonly co-exist and both need to be addressed in liver disease. With high rates of HCV cure with new therapies, attention needs to turn toward ongoing abusive alcohol patterns that may determinately impact liver health both before and after liver transplant.
Patients with advanced hepatitis C virus (HCV) are at risk of death and are candidates for liver transplantation. After transplantation, HCV recurs and may rapidly progress to cirrhosis and graft ...loss. Treatment is needed to prevent progression of disease and minimize recurrence after liver transplantation. We evaluated the effectiveness, tolerability, and outcome of a low accelerating dose regimen (LADR) of antiviral therapy in the treatment of patients with advanced HCV. One hundred twenty-four patients (male/female ratio 81:43; age range 37-71 years; 70% genotype 1) were treated with LADR. Sixty-three percent had clinical complications of cirrhosis (ascites, spontaneous bacterial peritonitis, varices, variceal hemorrhage, encephalopathy). The mean Child-Turcotte-Pugh (CTP) score was 7.4 +/- 2.3, and the mean MELD score was 11.0 +/- 3.7. Fifty-six patients were CTP class A, 45 were class B, and 23 were class C. Forty-six percent were HCV RNA-negative at end of treatment, and 24% were HCV RNA-negative at last follow-up. Sustained virological response (SVR) was 13% in patients infected with genotype 1 HCV and 50% in patients infected with non-1 genotypes (P < .0001). Non-1 genotype, CTP class A (genotype 1 only), and ability to tolerate full dose and duration of treatment (P < .0001) were predictors of SVR. Twelve of 15 patients who were HCV RNA-negative before transplantation remained HCV RNA-negative 6 months or more after transplantation. In conclusion, in a sizeable proportion of patients with advanced HCV, LADR may render blood free of HCV RNA, stabilize clinical course, and prevent posttransplantation recurrence.
In this paper, we introduce a novel approach for the detection of electroactive analytes by using oxidant species accumulated in pseudocapacitors surface. We demonstrated that pseudocapacitors can be ...quickly discharged when in contact with electroactive species. Thus, the variation of potential can be monitored during the discharging process and correlated with the analyte concentration. Based on this, two electroanalytical methods were proposed: continuous discharging detection and pulsed discharging detection. As a proof of concept, these methods were employed for glucose, fructose and sucrose detection using an ion chromatograph containing an electrochemical detector. Copper|cupric oxide in alkaline medium was used as the pseudocapacitive system. The obtained results proved to be very promising and the analytical curves showed good linearity in both methods. In addition, this novel approach for the detection of saccharides based on potential variation as a result of the discharging of the pseudocapacitor in contact with the analyte is very attractive because it does not require current reading. Therefore, our approach can be applied to other pseudocapacitive systems, opening new possibilities for several electroanalytical applications.
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•Electroanalytical application of pseudocapacitors.•Different strategies for pseudocapacitor discharge by electroactive species.•Novel approach for the determination of glucose and other saccharides.
More than one-third of listed potential liver recipients in the US are infected with the hepatitis C virus (HCV). Recurrence of infection with HCV after liver transplantation is associated with ...accelerated graft loss and diminished patient survival. Current HCV treatments using peginterferon and ribavirin either alone or with first generation protease inhibitors (telaprevir, boceprevir) are limited by suboptimal viral response, drug-drug interaction, and side effects, some of which may be graft- or life-threatening. Rapid advances in new drug therapy for HCV promise to improve outcomes, reduce side effects and drug-drug interaction, shorten treatment duration, and simplify treatment regimens.
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