Genetic Variation in the IL-6 and HLA-DQB1 Genes Is Associated with Spontaneous Clearance of Hepatitis C Virus Infection.

Background. Millions of people are infected with hepatitis C virus (HCV) worldwide and 30% spontaneously clear the infection. Reasons for HCV clearance without antiviral treatment are not well understood. Methods. Blood was collected for DNA analysis from patients with chronic HCV infection or evidence of spontaneous clearance. To overcome anticipated limitations of small sample size, primary analyses consisted of a candidate gene analysis of 12 preselected genes based on known association with host immunologic response to HCV infection. To further reduce the impact of multiple testing on power, a single likelihood ratio test was conducted for each gene using all associated SNPs assayed on the Illumina Quad 610/660W chip. Step-down permutation methods were used to adjust for multiple testing in all analyses. Results. Ninety-five and 62 patients with HCV chronic infection or spontaneous clearance, respectively, were included for analysis. HLA-DQB1 (p = 1.76⁎10(-5)) and IL-6 (p = 0.0007) genes were significantly associated with spontaneous HCV clearance. IL-28B was not significantly associated with spontaneous clearance (p = 0.17). Conclusion. Our whole-gene analytic strategy identified a previously unreported association of IL-6 with spontaneous clearance of HCV infection. We also confirmed the finding that HLA-DQB1 is associated with spontaneous resolution of HCV infection

α1D-Adrenoceptors are responsible for the high sensitivity and the slow time-course of noradrenaline-mediated contraction in conductance arteries

The objective of this study was to determine whether the different time-course characteristics of α1-adrenoceptor-mediated contraction in arteries can be related to the subtypes involved. Contractile responses to noradrenaline (NA) were compared with inositol phosphate accumulation and extracellular signal-regulated kinase (ERK)1/2 phosphorylation after α1-agonist stimuli in the same vessels in the presence or absence of α1-antagonists in rat or in α1-subtype knockout (KO) mice. Aorta, where α1D-AR is the main functional subtype, had higher sensitivity to NA (in respect of inositol phosphate [IP], pERK1/2, and contractile response) than tail artery, where the α1A-adrenoceptor subtype is predominant. Furthermore, the contraction in aorta exhibited a slower decay after agonist removal and this was consistent in all strains harboring α1D-adrenoceptors (from rat, α1B-KO, and wild-type [WT] mice) but was not observed in the absence of the α1D-adrenoceptor signal (α1D-adrenoceptor blocked rat aorta or aorta from α1D-KO). IP formation paralleled α1-adrenoceptor-mediated contraction (agonist present or postagonist) in aorta and tail artery. High sensitivity to agonist and persistence of response after agonist removal is a property of α1D-adrenoceptors. Therefore, the preponderance of this subtype in noninnervated conductance arteries such as aorta allows responsiveness to circulating catecholamines and prevents abrupt changes in vessel caliber when the stimulus fluctuates. Conversely, in innervated distributing arteries, high local concentrations of NA are required to activate α1A-adrenoceptors for a response that is rapid but short lived allowing fine adjustment of the contractile tone by perivascular sympathetic nerves

Ghost interactions in MEG/EEG source space : A note of caution on inter-areal coupling measures

When combined with source modeling, magneto- (MEG) and electroencephalography (EEG) can be used to study long-range interactions among cortical processes non-invasively. Estimation of such inter-areal connectivity is nevertheless hindered by instantaneous field spread and volume conduction, which artificially introduce linear correlations and impair source separability in cortical current estimates. To overcome the inflating effects of linear source mixing inherent to standard interaction measures, alternative phase- and amplitude-correlation based connectivity measures, such as imaginary coherence and orthogonalized amplitude correlation have been proposed. Being by definition insensitive to zero-lag correlations, these techniques have become increasingly popular in the identification of correlations that cannot be attributed to field spread or volume conduction. We show here, however, that while these measures are immune to the direct effects of linear mixing, they may still reveal large numbers of spurious false positive connections through field spread in the vicinity of true interactions. This fundamental problem affects both region-of-interest-based analyses and all-to-all connectome mappings. Most importantly, beyond defining and illustrating the problem of spurious, or "ghost" interactions, we provide a rigorous quantification of this effect through extensive simulations. Additionally, we further show that signal mixing also significantly limits the separability of neuronal phase and amplitude correlations. We conclude that spurious correlations must be carefully considered in connectivity analyses in MEG/EEG source space even when using measures that are immune to zero-lag correlations.Peer reviewe

Alpha-band rhythms in visual task performance: phase-locking by rhythmic sensory stimulation

Oscillations are an important aspect of neuronal activity. Interestingly, oscillatory patterns are also observed in behaviour, such as in visual performance measures after the presentation of a brief sensory event in the visual or another modality. These oscillations in visual performance cycle at the typical frequencies of brain rhythms, suggesting that perception may be closely linked to brain oscillations. We here investigated this link for a prominent rhythm of the visual system (the alpha-rhythm, 8-12 Hz) by applying rhythmic visual stimulation at alpha-frequency (10.6 Hz), known to lead to a resonance response in visual areas, and testing its effects on subsequent visual target discrimination. Our data show that rhythmic visual stimulation at 10.6 Hz: 1) has specific behavioral consequences, relative to stimulation at control frequencies (3.9 Hz, 7.1 Hz, 14.2 Hz), and 2) leads to alpha-band oscillations in visual performance measures, that 3) correlate in precise frequency across individuals with resting alpha-rhythms recorded over parieto-occipital areas. The most parsimonious explanation for these three findings is entrainment (phase-locking) of ongoing perceptually relevant alpha-band brain oscillations by rhythmic sensory events. These findings are in line with occipital alpha-oscillations underlying periodicity in visual performance, and suggest that rhythmic stimulation at frequencies of intrinsic brain-rhythms can be used to reveal influences of these rhythms on task performance to study their functional roles

Progression of Biopsy-Measured Liver Fibrosis in Untreated Patients with Hepatitis C Infection: Non-Markov Multistate Model Analysis

BACKGROUND: Fibrosis stages from liver biopsies reflect liver damage from hepatitis C infection, but analysis is challenging due to their ordered but non-numeric nature, infrequent measurement, misclassification, and unknown infection times. METHODS: We used a non-Markov multistate model, accounting for misclassification, with multiple imputation of unknown infection times, applied to 1062 participants of whom 159 had multiple biopsies. Odds ratios (OR) quantified the estimated effects of covariates on progression risk at any given time. RESULTS: Models estimated that progression risk decreased the more time participants had already spent in the current stage, African American race was protective (OR 0.75, 95% confidence interval 0.60 to 0.95, p = 0.018), and older current age increased risk (OR 1.33 per decade, 95% confidence interval 1.15 to 1.54, p = 0.0002). When controlled for current age, older age at infection did not appear to increase risk (OR 0.92 per decade, 95% confidence interval 0.47 to 1.79, p = 0.80). There was a suggestion that co-infection with human immunodeficiency virus increased risk of progression in the era of highly active antiretroviral treatment beginning in 1996 (OR 2.1, 95% confidence interval 0.97 to 4.4, p = 0.059). Other examined risk factors may influence progression risk, but evidence for or against this was weak due to wide confidence intervals. The main results were essentially unchanged using different assumed misclassification rates or imputation of age of infection. DISCUSSION: The analysis avoided problems inherent in simpler methods, supported the previously suspected protective effect of African American race, and suggested that current age rather than age of infection increases risk. Decreasing risk of progression with longer time already spent in a stage was also previously found for post-transplant progression. This could reflect varying disease activity, with recent progression indicating active disease and high risk, while longer time already spent in a stage indicates quiescent disease and low risk

Social Contact Patterns in Vietnam and Implications for the Control of Infectious Diseases

BACKGROUND: The spread of infectious diseases from person to person is determined by the frequency and nature of contacts between infected and susceptible members of the population. Although there is a long history of using mathematical models to understand these transmission dynamics, there are still remarkably little empirical data on contact behaviors with which to parameterize these models. Even starker is the almost complete absence of data from developing countries. We sought to address this knowledge gap by conducting a household based social contact diary in rural Vietnam. METHODS AND FINDINGS: A diary based survey of social contact patterns was conducted in a household-structured community cohort in North Vietnam in 2007. We used generalized estimating equations to model the number of contacts while taking into account the household sampling design, and used weighting to balance the household size and age distribution towards the Vietnamese population. We recorded 6675 contacts from 865 participants in 264 different households and found that mixing patterns were assortative by age but were more homogenous than observed in a recent European study. We also observed that physical contacts were more concentrated in the home setting in Vietnam than in Europe but the overall level of physical contact was lower. A model of individual versus household vaccination strategies revealed no difference between strategies in the impact on R(0). CONCLUSIONS AND SIGNIFICANCE: This work is the first to estimate contact patterns relevant to the spread of infections transmitted from person to person by non-sexual routes in a developing country setting. The results show interesting similarities and differences from European data and demonstrate the importance of context specific data

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

New Therapies, Evidence, and Guidance in Hepatitis C Management: Expert Practices and Insights from an Educational Symposium at the AMCP 27th Annual Meeting Expo.

BACKGROUND: The 2013-2014 approvals of new direct-acting antiviral (DAA) therapies for hepatitis C virus (HCV) infection have engendered a paradigm shift in HCV treatment and management, offering the potential for a cure at a population level. The availability of the highly effective and relatively safe DAAs prompted revisions to guidance recommendations based on new clinical trial evidence. In the context of this paradigm shift and considerations of the costs associated with the new DAAs, managed care professionals face new questions and challenges regarding HCV treatment and management approaches. To address the continuing education needs of this group, PRIME Education, Inc. (PRIME) conducted a symposium on HCV at the 27th Annual Meeting Expo of the Academy of Managed Care Pharmacy. Moderated by Michael R. Stinchon, Jr., RPh, the program panel featured 2 internationally recognized leaders in hepatitis C treatment and research: Norah Terrault, MD, MPH, and Alex Monto, MD.  OBJECTIVE: To summarize the educational symposium presentations and discussions. METHODS: This article is organized by key questions that the panelists and attendees raised for discussion during the 2-hour symposium. The questions addressed methods for assessing liver fibrosis; comprehensive patient assessment to inform treatment decisions; the influence of viral load on decisions about treatment duration; the role of ribavirin in optimizing treatment efficacy; unmet treatment needs for patients with HCV genotype 3 or advanced liver disease; and managed care strategies for patient education, adherence promotion, and care coordination. In answering attendee questions on these issues, the expert panelists presented established evidence, and recognizing limitations to current evidence and guidance recommendations, they discussed applications of clinical judgment and offered their views and practices regarding individualized care for patients with HCV.  SUMMARY: In response to questions about the utility of noninvasive methods for assessing liver fibrosis, the expert panel presented a comparative overview of the methodology, accuracy, risks, limitations, and costs of noninvasive tests and liver biopsy. Discussion highlighted the strengths of noninvasive methods for diagnosing advanced disease and cirrhosis and the methods limitations that pose barriers to ensuring that patients receive necessary antiviral therapy. Based on guidance recommendations, treatment should be prioritized in patients with advanced fibrosis or cirrhosis (Metavir score F3 to F4). While acknowledging the importance of this recommendation, the symposium panelists also argued that making effective decisions about whom, and when, to treat requires a more comprehensive clinical approach to patient assessment and adjusting recommended priorities according to individual patient considerations. This approach involves evaluating outcomes such as extrahepatic complications, including those affecting quality of life, functional status, and work productivity. In response to questions regarding decisions about DAA therapy duration based on viral load, the panel engaged the audience in thinking critically about evidence-based cutoff values and natural fluctuations of HCV RNA concentrations. Discussions centered on the importance of clinical judgment to ensure that the treatment duration promotes the highest efficacy and avoids risks of relapse. The panel responded to several audience questions about the role of ribavirin in new DAA regimens. Evidence-based presentations and discussions focused on patient-specific factors that must be considered to inform effective decisions about adding ribavirin. The panel took a similar approach to answering questions about emerging challenges and the difficult-to-treat populations of patients with HCV genotype 3 or advanced liver disease. The symposium concluded with presentation of, and discussion on, managed care strategies for educating patients about appropriate HCV medication use, improving adherence, and coordinating care provided by the interprofessional team.  CONCLUSIONS: The availability of new DAAs for HCV raises new questions and challenges for managed care professionals, especially regarding prioritizing patients for immediate therapy as well as treatment and management approaches that account for the needs of individual patients and subpopulations. The educational symposium summarized in this article directly addressed key questions and challenges through presentations of evidence, guidance recommendations, and interactive discussions on the views and practices of international leaders in HCV treatment and research

New Therapies, Evidence, and Guidance in Hepatitis C Management: Expert Practices and Insights from an Educational Symposium at the AMCP 27th Annual Meeting Expo

BACKGROUND: The 2013-2014 approvals of new direct-acting antiviral (DAA) therapies for hepatitis C virus (HCV) infection have engendered a paradigm shift in HCV treatment and management, offering the potential for a cure at a population level. The availability of the highly effective and relatively safe DAAs prompted revisions to guidance recommendations based on new clinical trial evidence. In the context of this paradigm shift and considerations of the costs associated with the new DAAs, managed care professionals face new questions and challenges regarding HCV treatment and management approaches. To address the continuing education needs of this group, PRIME Education, Inc. (PRIME) conducted a symposium on HCV at the 27th Annual Meeting Expo of the Academy of Managed Care Pharmacy. Moderated by Michael R. Stinchon, Jr., RPh, the program panel featured 2 internationally recognized leaders in hepatitis C treatment and research: Norah Terrault, MD, MPH, and Alex Monto, MD.  OBJECTIVE: To summarize the educational symposium presentations and discussions. METHODS: This article is organized by key questions that the panelists and attendees raised for discussion during the 2-hour symposium. The questions addressed methods for assessing liver fibrosis; comprehensive patient assessment to inform treatment decisions; the influence of viral load on decisions about treatment duration; the role of ribavirin in optimizing treatment efficacy; unmet treatment needs for patients with HCV genotype 3 or advanced liver disease; and managed care strategies for patient education, adherence promotion, and care coordination. In answering attendee questions on these issues, the expert panelists presented established evidence, and recognizing limitations to current evidence and guidance recommendations, they discussed applications of clinical judgment and offered their views and practices regarding individualized care for patients with HCV.  SUMMARY: In response to questions about the utility of noninvasive methods for assessing liver fibrosis, the expert panel presented a comparative overview of the methodology, accuracy, risks, limitations, and costs of noninvasive tests and liver biopsy. Discussion highlighted the strengths of noninvasive methods for diagnosing advanced disease and cirrhosis and the methods limitations that pose barriers to ensuring that patients receive necessary antiviral therapy. Based on guidance recommendations, treatment should be prioritized in patients with advanced fibrosis or cirrhosis (Metavir score F3 to F4). While acknowledging the importance of this recommendation, the symposium panelists also argued that making effective decisions about whom, and when, to treat requires a more comprehensive clinical approach to patient assessment and adjusting recommended priorities according to individual patient considerations. This approach involves evaluating outcomes such as extrahepatic complications, including those affecting quality of life, functional status, and work productivity. In response to questions regarding decisions about DAA therapy duration based on viral load, the panel engaged the audience in thinking critically about evidence-based cutoff values and natural fluctuations of HCV RNA concentrations. Discussions centered on the importance of clinical judgment to ensure that the treatment duration promotes the highest efficacy and avoids risks of relapse. The panel responded to several audience questions about the role of ribavirin in new DAA regimens. Evidence-based presentations and discussions focused on patient-specific factors that must be considered to inform effective decisions about adding ribavirin. The panel took a similar approach to answering questions about emerging challenges and the difficult-to-treat populations of patients with HCV genotype 3 or advanced liver disease. The symposium concluded with presentation of, and discussion on, managed care strategies for educating patients about appropriate HCV medication use, improving adherence, and coordinating care provided by the interprofessional team.  CONCLUSIONS: The availability of new DAAs for HCV raises new questions and challenges for managed care professionals, especially regarding prioritizing patients for immediate therapy as well as treatment and management approaches that account for the needs of individual patients and subpopulations. The educational symposium summarized in this article directly addressed key questions and challenges through presentations of evidence, guidance recommendations, and interactive discussions on the views and practices of international leaders in HCV treatment and research