Cost Effectiveness of Fibrosis Assessment Prior to Treatment for Chronic Hepatitis C Patients

Chronic hepatitis C (HCV) is a liver disease affecting over 3 million Americans. Liver biopsy is the gold standard for assessing liver fibrosis and is used as a benchmark for initiating treatment, though it is expensive and carries risks of complications. FibroTest is a non-invasive biomarker assay for fibrosis, proposed as a screening alternative to biopsy.We assessed the cost-effectiveness of FibroTest and liver biopsy used alone or sequentially for six strategies followed by treatment of eligible U.S. patients: FibroTest only; FibroTest with liver biopsy for ambiguous results; FibroTest followed by biopsy to rule in; or to rule out significant fibrosis; biopsy only (recommended practice); and treatment without screening. We developed a Markov model of chronic HCV that tracks fibrosis progression. Outcomes were expressed as expected lifetime costs (2009 USD), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICER).Treatment of chronic HCV without fibrosis screening is preferred for both men and women. For genotype 1 patients treated with pegylated interferon and ribavirin, the ICERs are $5,400/QALY (men) and$6,300/QALY (women) compared to FibroTest only; the ICERs increase to $27,200/QALY (men) and$30,000/QALY (women) with the addition of telaprevir. For genotypes 2 and 3, treatment is more effective and less costly than all alternatives. In clinical settings where testing is required prior to treatment, FibroTest only is more effective and less costly than liver biopsy. These results are robust to multi-way and probabilistic sensitivity analyses.Early treatment of chronic HCV is superior to the other fibrosis screening strategies. In clinical settings where testing is required, FibroTest screening is a cost-effective alternative to liver biopsy

A Secure Recommendation System for Providing Context-Aware Physical Activity Classification for Users

Advances in Wireless Body Area Networks, where embedded accelerometers, gyroscopes, and other sensors empower users to track real-time health data continuously, have made it easier for users to follow a healthier lifestyle. Various other apps have been intended to choose suitable physical exercise, depending on the current healthcare environment. A Mobile Application (Mobile App) based recommendation system is a technology that allows users to select an apt activity that might suit their preferences. However, most of the current applications require constant input from end-users and struggle to include those who have hectic schedules or are not dedicated and self-motivated. This research introduces a methodology that uses a �Selective Cluster Cube� recommender system to intelligently monitor and classify user behavior by collecting accelerometer data and synchronizing with its calendar. We suggest customized daily workouts based on historical user and related user habits, interests, physical status, and accessibility. Simultaneously, the exposure of customer requirements to the server is also a significant concern. Developing privacy-preserving protocols with basic cryptographic techniques (e.g., protected multi-party computing or HE) is a standard solution to address privacy issues, but in combination with state-of-the-art advising frameworks, it frequently provides far-reaching solutions. This paper proposes a novel framework, a Privacy Protected Recommendation System (PRIPRO), that employs HE for securing private user data. The PRIPRO model is compared for accuracy and robustness using standard evaluation parameters against three datasets

Innate Host Response in Primary Human Hepatocytes with Hepatitis C Virus Infection

The interaction between hepatitis C virus (HCV) and innate antiviral defense systems in primary human hepatocytes is not well understood. The objective of this study is to examine how primary human hepatocytes response to HCV infection.An infectious HCV isolate JFH1 was used to infect isolated primary human hepatocytes. HCV RNA or NS5A protein in the cells was detected by real-time PCR or immunofluorescence staining respectively. Apoptosis was examined with flow cytometry. Mechanisms of HCV-induced IFN-β expression and apoptosis were determined.Primary human hepatocytes were susceptible to JFH1 virus and released infectious virus. IFN-α inhibited viral RNA replication in the cells. IFN-β and interferon-stimulated genes were induced in the cells during acute infection. HCV infection induced apoptosis of primary human hepatocytes through the TRAIL-mediated pathway. Silencing RIG-I expression in primary human hepatocytes inhibited IFN-β and TRAIL expression and blocked apoptosis of the cells, which facilitated viral RNA replication in the cells. Moreover, HCV NS34A protein inhibited viral induced IFN-β expression in primary human hepatocytes.Innate host response is intact in HCV-infected primary human hepatocytes. RIG-I plays a key role in the induction of IFN and TRAIL by viruses and apoptosis of primary human hepatocytes via activation of the TRAIL-mediated pathway. HCV NS34A protein appears to be capable of disrupting the innate antiviral host responses in primary human hepatocytes. Our study provides a novel mechanism by which primary human hepatocytes respond to natural HCV infection

The Development of FVIII Inhibitor in Hispanic American Patients with Hemophilia A Critically Impacts Coagulation Potential

Background: Hemophilia A (HA) is caused by deficiencies in plasma-FVIII and heterogeneous factor-VIII-gene mutations that impair intrinsic coagulation amplification. In severe hemophilia A patients (HAPs), FVIII infusions are begun at toddlerhood to prevent hemarthrosis induced crippling. However, approximately 30% of these patients develop FVIII inhibitors. Gain-of-function mutations in the common pathway of coagulation increases coagulation potential and decreases bleeding and FVIII-utilization in HAPs which should decrease FVIII-inhibitor-risk. We identified loss-of-function mutations in this pathway which decrease coagulation-potential as they increase FVIII-inhibitor risk in HAPs. Methods: We screened Mexican-American-pedigrees of the South-Texas-Family-Study (STFS) for protein-altering-variants. Subjects were genotyped using Illumina-exome-24-chip. Protein-altering-variants were analyzed for associations with FII:C, PT, and aPTT. Linear-mixed-model-analyses was performed to estimate trait-heritability and examine single-nucleotide-variations (SNVs) for gene association. Significant associations’ p-values fell below Bonferroni-adjusted significance level. Results: Heritability-estimates for FII:C, aPTT, and PT were highly-significant with p-values of 0.49, 0.49, and 0.54 (for all, pT in the FII-gene (F2)—which encodes 543R\u3eL and has a large effect-size on each trait (for all, pT have lower FII:C levels but correspondingly prolonged aPTT and PT times. Conclusion: We hypothesize that FII-543R\u3eL (Prothrombin-RGV) likely contributes to the high-incidence of FVIII-inhibitor-development in HA-patients of Mexican-ancestry, resulting in higher risk of developing anti-tFVIII-antibodies than patients without the variant. Patients with the RGV variant are likely to bleed more which can require surgery, further increasing the development of FVIII inhibitor development

Hepatitis C Virus (HCV) Vertical Transmission in 12-Month-Old Infants Born to HCV-Infected Women and Assessment of Maternal Risk Factors

Background. Hepatitis C virus (HCV) is an underappreciated cause of pediatric liver disease, most frequently acquired by vertical transmission (VT). Current guidelines that include the option of screening infants for HCV RNA at 1–2 months are based on data prior to current real-time polymerase chain reaction (PCR)-based testing. Previous studies have demonstrated VT rates of 4%–15% and an association with high maternal viral load. We evaluated HCV RNA in infants with HCV VT and assessed maternal risk factors in a prospective cohort in Cairo, Egypt

Sequence Analysis of the IL28A/IL28B Inverted Gene Duplication That Contains Polymorphisms Associated with Treatment Response in Hepatitis C Patients

Several SNPs located in or around the IL28B gene are associated with response of patients infected with Hepatitis C virus to treatment with pegylated interferon-α +/− ribavirin or with spontaneous clearance of the virus. The results of such studies are so compelling that future treatment approaches are likely to involve clinical decisions being made on the basis of a patient's genotype. Since IL28B is a paralogue of IL28A with greater than 95% sequence identity, it is possible that without genotyping assay specificity, sequences in IL28A may contribute to genotype identification, and potentially confound treatment decisions. This study aimed to 1) examine DNA sequences in IL28B surrounding each of the reported associated SNPs and the corresponding regions in IL28A; and 2) develop a robust assay for rs12979860, the most ‘cosmopolitan’ SNP most strongly associated with treatment response across all global populations studied to date. Bioinformatic analysis of genomic regions surrounding IL28A and IL28B demonstrated that 3 SNPs were unique to IL28B, whereas the remaining 6 SNP regions shared >93% identity between IL28A and IL28B. Using a panel of DNA samples, PCR amplification followed by Sanger sequencing was used to examine IL28B SNPs and the corresponding regions in IL28A. For the overlapping SNPs, all 6 in IL28B were confirmed to be polymorphic whereas the corresponding positions in IL28A were monomorphic. Based upon IL28A and IL28B sequence data, a specific TaqMan® assay was developed for SNP rs12979860 that was 100% concordant to the sequence-derived genotypes. Analysis using a commercial assay identified one discordant result which led to a change in their genotype-calling algorithm. Where future treatment decisions are made upon the results of genotyping assays, it is very important that results are concordant with data from a sequence-based format. This is especially so in situations where designing specific PCR primers is a challenge

Bidirectional lipid droplet velocities are controlled by differential binding strengths of HCV Core DII protein

Host cell lipid droplets (LD) are essential in the hepatitis C virus (HCV) life cycle and are targeted by the viral capsid core protein. Core-coated LDs accumulate in the perinuclear region and facilitate viral particle assembly, but it is unclear how mobility of these LDs is directed by core. Herein we used two-photon fluorescence, differential interference contrast imaging, and coherent anti-Stokes Raman scattering microscopies, to reveal novel core-mediated changes to LD dynamics. Expression of core protein’s lipid binding domain II (DII-core) induced slower LD speeds, but did not affect directionality of movement on microtubules. Modulating the LD binding strength of DII-core further impacted LD mobility, revealing the temporal effects of LD-bound DII-core. These results for DII-core coated LDs support a model for core-mediated LD localization that involves core slowing down the rate of movement of LDs until localization at the perinuclear region is accomplished where LD movement ceases. The guided localization of LDs by HCV core protein not only is essential to the viral life cycle but also poses an interesting target for the development of antiviral strategies against HCV

Infant Safety during and after Maternal Valacyclovir Therapy in Conjunction with Antiretroviral HIV-1 Prophylaxis in a Randomized Clinical Trial

<div><h3>Background</h3><p>Maternal administration of the acyclovir prodrug valacyclovir is compatible with pregnancy and breastfeeding. However, the safety profile of prolonged infant and maternal exposure to acyclovir in the context of antiretrovirals (ARVs) for prevention of mother-to-child HIV-1 transmission (PMTCT) has not been described.</p> <h3>Methods</h3><p>Pregnant Kenyan women co-infected with HIV-1/HSV-2 with CD4 counts > 250 cells/mm³ were enrolled at 34 weeks gestation and randomized to twice daily 500 mg valacyclovir or placebo until 12 months postpartum. Women received zidovudine from 28 weeks gestation and single dose nevirapine was given to women and infants at the time of delivery for PMTCT. Infant blood was collected at 6 weeks for creatinine and ALT. Breast milk specimens were collected at 2 weeks postpartum from 71 women in the valacyclovir arm; acyclovir levels were determined for a random sample of 44 (62%) specimens. Fisher’s Exact and Wilcoxon rank-sum tests were used for analysis.</p> <h3>Results</h3><p>One hundred forty-eight women were randomized and 146 mother-infant pairs were followed postpartum. PMTCT ARVs were administered to 98% of infants and all mothers. Valacyclovir was not associated with infant or maternal toxicities or adverse events, and no congenital malformations were observed. Infant creatinine levels were all normal (< 0.83 mg/dl) and median creatinine (median 0.50 mg/dl) and infant growth did not differ between study arms. Acyclovir was detected in 35 (80%) of 44 breast milk samples collected at 2 weeks postpartum. Median and maximum acyclovir levels were 2.62 and 10.15 mg/ml, respectively (interquartile range 0.6–4.19).</p> <h3>Conclusions</h3><p>Exposure to PMTCT ARVs and acyclovir after maternal administration of valacyclovir during pregnancy and postpartum to women co-infected with HIV-1/HSV-2 was not associated with an increase in infant or maternal toxicities or adverse events.</p> <h3>Trial Registration</h3><p>ClinicalTrials.gov <a href="http://clinicaltrials.gov/ct2/show/NCT00530777">NCT00530777</a></p> </div