Efficacy and Safety of Sofosbuvir/Velpatasvir/Voxilaprevir for Hepatitis C Virus (HCV) NS5A-Inhibitor Experienced Patients With Difficult to Cure Characteristics.

BACKGROUND: In clinical trials, hepatitis C virus (HCV) salvage treatment with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) achieved an SVR12 rate of >95% in NS5A-experienced participants. Lower SVR12 rates have been reported in real-world studies, particularly for genotype (GT)3 infection and cirrhosis. We determined the efficacy and safety of SOF/VEL/VOX in a large real-world cohort. METHODS: We assessed the efficacy of salvage SOF/VEL/VOX for HCV infection in NS5A-inhibitor experienced participants with cirrhosis and portal hypertension, prior liver transplantation (LT) or severe extra-hepatic manifestations. SOF/VEL/VOX was available via an early access program. The primary outcome was SVR12. Secondary outcome was frequency of adverse events (AE). FINDINGS: Ninety-seven participants were included. Median age was 58, 82% were male, 78% had cirrhosis, most with portal hypertension (61%, n = 46/76), and 18% had prior-LT. Of the cirrhotic participants, 96% were Child-Turcotte-Pugh class A, and 4% were class B. Of the 72% with GT3, 76% were also cirrhotic. By intention-to-treat analysis, SVR12 rate was 85% (n = 82/97). Per protocol, the SVR12 rate was 90%, including 91% in GT1 (GT1a n = 18/18, GT1b n = 2/4), 89% in GT3 (n = 59/66) and 100% in GT6 (n = 3/3). SVR12 in participants with GT3 and cirrhosis was 90%. No predictors of non-SVR12 were identified. There were 4 serious AEs including 1 death and 3 hepatic decompensation events. NS5A resistance-associated substitutions detected at baseline did not affect SVR12. CONCLUSIONS: This real-world study confirms high efficacy of SOF/VEL/VOX for the treatment of difficult-to-cure NS5A-inhibitor experienced patients, including those with GT3 and cirrhosis. Treatment was well tolerated in most; however, serious AEs can occur in those with advanced liver disease.

Clinical relevance of apolipoprotein E genotyping based on a family history of Alzheimer's disease.

Having a family history of Alzheimer' s disease (AD) may potentiate cumulative risk associated with phenotypic expression of the ε-4 allele of the apolipoprotein E (APOE) gene. In this study, we compared the genotype distribution and allele frequencies of APOE ε-2 (rs7412) and ε -4 (rs429358) in 537 South African individuals participating in a chronic disease screening program, in order to establish whether AD family history modulates the expression of their dyslipidemic effects. Significant differences in the genotype distribution for APOE ε-2 (p=0.034) as well as APOE ε-4 (p=0.038) were found between study participants with (n=67) and without (n=470) a family history of AD. LDL cholesterol levels were inversely associated with physical activity in the study group with a positive family history of AD (p<0.001) but not in those with a negative family history of AD (p=0.257). Similar to its existing use in the diagnosis of monogenic dyslipidemias such as familial hypercholesterolemia, clinical inquiry regarding family history was identified as an important determinant of eligibility for APOE genotyping performed in the context of chronic disease risk management. To our knowledge, this is the first study to demonstrate the modulating influence of AD family history on expression of a dyslipidemic phenotype associated with the APOE ε-4 allele. Our findings provide the scientific rationale supporting a novel clinical application for APOE genotyping as a means of identifying a genetic subgroup of dyslipidemic patients set to derive the greatest benefit from early lifestyle-based interventions aimed at decreasing cumulative risk for cardiovascular disease and prevention of AD later in life.

Genomic medicine and risk prediction across the disease spectrum.

Genomic medicine is based on the knowledge that virtually every medical condition, disease susceptibility or response to treatment is caused, regulated or influenced by genes. Genetic testing may therefore add value across the disease spectrum, ranging from single-gene disorders with a Mendelian inheritance pattern to complex multi-factorial diseases. The critical factors for genomic risk prediction are to determine: (1) where the genomic footprint of a particular susceptibility or dysfunction resides within this continuum, and (2) to what extent the genetic determinants are modified by environmental exposures. Regarding the small subset of highly penetrant monogenic disorders, a positive family history and early disease onset are mostly sufficient to determine the appropriateness of genetic testing in the index case and to inform pre-symptomatic diagnosis in at-risk family members. In more prevalent polygenic non-communicable diseases (NCDs), the use of appropriate eligibility criteria is required to ensure a balance between benefit and risk. An additional screening step may therefore be necessary to identify individuals most likely to benefit from genetic testing. This need provided the stimulus for the development of a pathology-supported genetic testing (PSGT) service as a new model for the translational implementation of genomic medicine in clinical practice. PSGT is linked to the establishment of a research database proven to be an invaluable resource for the validation of novel and previously described gene-disease associations replicated in the South African population for a broad range of NCDs associated with increased cardio-metabolic risk. The clinical importance of inquiry concerning family history in determining eligibility for personalized genotyping was supported beyond its current limited role in diagnosing or screening for monogenic subtypes of NCDs. With the recent introduction of advanced microarray-based breast cancer subtyping, genetic testing has extended beyond the genome of the host to also include tumor gene expression profiling for chemotherapy selection. The decreasing cost of next generation sequencing over recent years, together with improvement of both laboratory and computational protocols, enables the mapping of rare genetic disorders and discovery of shared genetic risk factors as novel therapeutic targets across diagnostic boundaries. This article reviews the challenges, successes, increasing inter-disciplinary integration and evolving strategies for extending PSGT towards exome and whole genome sequencing (WGS) within a dynamic framework. Specific points of overlap are highlighted between the application of PSGT and exome or WGS, as the next logical step in genetically uncharacterized patients for whom a particular disease pattern and/or therapeutic failure are not adequately accounted for during the PSGT pre-screen. Discrepancies between different next generation sequencing platforms and low concordance among variant-calling pipelines caution against offering exome or WGS as a stand-alone diagnostic approach. The public reference human genome sequence (hg19) contains minor alleles at more than 1 million loci and variant calling using an advanced major allele reference genome sequence is crucial to ensure data integrity. Understanding that genomic risk prediction is not deterministic but rather probabilistic provides the opportunity for disease prevention and targeted treatment in a way that is unique to each individual patient.

Advanced level nursing in England: organisational challenges and opportunities.

AIM: To explore the background, activities and future development needs of advanced practice nurses within a large NHS Trust in England, allowing for a wider review of the current situation within the UK. BACKGROUND: There are currently no national requirements for advanced practice nursing within the UK, which has led to considerable variability in these roles. Recently, focus has been placed on local governance rather than regulation of advanced practice nursing. However, governance and coordinated workforce planning within the UK is in its infancy. METHODS: An electronic survey was sent to all nurses within one Trust identified as practising at an advanced level; a total of 136 responses were received. RESULTS: The survey identified considerable variation in titles, educational preparation and current activities even within similar roles. Some participants identified the need for more support in undertaking professional development activities. CONCLUSIONS: The findings echo the wider picture within the UK, and point to the need to actively work on developing strategies for governance, education, and succession planning for advanced practice nursing. IMPLICATIONS FOR NURSING MANAGEMENT: In the absence of national regulation, UK NHS Trusts should develop their own registers of advanced practice nurses in order to facilitate improved management, governance and workforce planning systems.

Significance of dietary folate intake, homocysteine levels and MTHFR 677 C>T genotyping in South African patients diagnosed with depression: test development for clinical application.

Low folate intake in the presence of the functional MTHFR 677 C > T (rs1801133) polymorphism is an important cause of elevated homocysteine levels previously implicated in major depressive disorder (MDD) and many other chronic diseases. In this study the clinical relevance and inter-relationship of these aspects were evaluated in 86 South African patients diagnosed with MDD and 97 population-matched controls participating in a chronic diseases screening program. A questionnaire-based clinical and nutrition assessment was performed, homocysteine levels determined, and all study participants genotyped for MTHFR 677 C > T (rs1801133) using allele-specific TaqMan technology. The folate score was found to be significantly lower in the patient group compared to controls (p = 0.003) and correlated with increased body mass index (BMI), particularly in females with MDD (p = 0.009). BMI was significantly higher in the MDD patients compared with controls after adjustment for age and sex (p = 0.015), but this association was no longer significant after further adjustment for the level of folate intake in the diet. In MDD patients but not controls, the minor T-allele of MTHFR 677 C > T was associated with increased BMI (p = 0.032), which in turn correlated significantly with increased homocysteine levels. The significant association between BMI and homocysteine levels was observed in both the MDD patient (p = 0.049) and control (p = 0.018) study groups. The significantly higher homocysteine levels observed in MDD patients compared to controls after adjustment for age and sex (p = 0.030), therefore appears to be mediated by the effects of MTHFR 677 C > T and low folate intake on BMI. Detection of the low-penetrance MTHFR 677 C > T mutation reinforces the importance of folate intake above the recommended daily dose to prevent or restore dysfunction of the methylation pathway.

The fat mass and obesity-associated FTO rs9939609 polymorphism is associated with elevated homocysteine levels in patients with multiple sclerosis screened for vascular risk factors.

UNLABELLED: The previously reported link between homocysteine and obesity, both identified as established risk factors for multiple sclerosis (MS), has not previously been studied in relation to the fat mass and obesity-associated (FTO) gene. AIM: To investigate the mechanism underlying homocysteine accumulation in MS patients. A total of 114 patients and 195 population-matched controls were analysed for the FTO rs9939609 polymorphism. Homocysteine levels were measured in a subgroup of 60 patients and 87 controls screened for multiple vascular risk factors. After adjustment for potential confounders, the risk-associated FTO rs9939609 A-allele was associated with raised homocysteine levels (p = 0.003) in patients diagnosed with MS, but not in controls. Homocysteine levels correlated positively with body mass index (BMI) (p = 0.045) and total cholesterol levels (p = 0.048). Both homocysteine (p = 0.011) and BMI (p = 0.017) were significantly reduced with higher intake of folate in the diet. Higher BMI also correlated with increased intake of saturated/trans fat (p < 0.01) and low physical activity (p < 0.006). Daily intake of at least five fruits and vegetables had a favourable lowering effect on the Expanded Disability Status Scale (EDSS) (p = 0.035), while smoking increased MS disability (p < 0.001). This study has shown for the first time that having a diagnosis of MS moderates the effect of the FTO rs9939609 polymorphism on homocysteine levels. This is consistent with the role of FTO in demethylation and epigenetic changes. Identification of FTO rs9939609 reinforces the importance of adequate fruit, vegetable and folate and restriction of saturated/trans fat intake in the diet.

College major, gender and heterosexism reconsidered under more controlled conditions.

To test the hypothesis that under controlled conditions respondent's gender and college major are related to heterosexism, four groups (n = 40 each)-male psychology majors, female psychology majors, male non-psychology majors, and female non-psychology majors-were formed from an initial sample of convenience (N = 1,947) of urban university students. Respondents were matched for age, race, college level, closeness of relationships to lesbian and gay men, religious affiliation, and religious attendance. Each student was requested to complete the Herek Attitude Scale towards Lesbians and Gay Men and these scores were subjected to a three factor (2x2x2) mixed analysis of variance. The three factors were respondent's gender, respondent's college major, and target's gender with repeated measures on target's gender. A significant respondent's gender by target's gender F(1/156) = 50.59, p < .001 interaction was observed. Male respondent's attitude toward gay males was significantly more negative than that of the other groups which did not differ significantly from one another. Significant main effects due to respondent's gender F(1/156) = 11.9, p < .001 and target's gender F(1/156) = 43.1, p < .001 were also observed. No significant college major effect F(1/156) = 1.60, p >.05 or interaction was found.