Viral hepatitis C: from unravelling the nature of disease to cure and global elimination.

This review summarises the key achievements from the discovery of HCV to the development of effective treatment and global elimination strategies. Better understanding of HCV structure, enzymes and lifecycle led to the introduction of new drug targets and the discovery of DAA. Massive public health interventions are required, such as screening, access to care, treatment and post-care follow up, to make the most of DAA potential. Screening must be supported by fast, accessible, sensitive, specific HCV diagnostic tests and non-invasive methods to determine stage of liver disease. Linkage to care and treatment access are critical components of a comprehensive HCV elimination program and decentralization plays a key role in ensuring their effectiveness. Key messages.Effective and simple screening strategies, rapid diagnostic tools, linkage to healthcare and accessible treatment are key elements to achieve the WHO's goal. Incorporating treatment as prevention strategies into elimination programs together with preventive education and harm reduction interventions can have a profound and lasting impact on reducing both the incidence and prevalence of HCV. However, WHO goal can be challenging to implement because of need for high financial resources and strong political commitment.

Six-lead electrocardiography compared to single-lead electrocardiography and photoplethysmography of a wrist-worn device for atrial fibrillation detection controlled by premature atrial or ventricular contractions: six is smarter than one.

Background: Smartwatches are commonly capable to record a lead-I-like electrocardiogram (ECG) and perform a photoplethysmography (PPG)-based atrial fibrillation (AF) detection. Wearable technologies repeatedly face the challenge of frequent premature beats, particularly in target populations for screening of AF. Objective: To investigate the potential diagnostic benefit of six-lead ECG compared to single-lead ECG and PPG-based algorithm for AF detection of the wrist-worn device. Methods and results: From the database of DoubleCheck-AF 249 adults were enrolled in AF group (n = 121) or control group of SR with frequent premature ventricular (PVCs) or atrial (PACs) contractions (n = 128). Cardiac rhythm was monitored using a wrist-worn device capable of recording continuous PPG and simultaneous intermittent six-lead standard-limb-like ECG. To display a single-lead ECG, the six-lead ECGs were trimmed to lead-I-like ECGs. Two diagnosis-blinded cardiologists evaluated reference, six-lead and single-lead ECGs as "AF", "SR", or "Cannot be concluded". AF detection based on six-lead ECG, single-lead ECG, and PPG yielded a sensitivity of 99.2%, 95.7%, and 94.2%, respectively. The higher number of premature beats per minute was associated with false positive outcomes of single-lead ECG (18.80 vs. 5.40 beats/min, P < 0.01), six-lead ECG (64.3 vs. 5.8 beats/min, P = 0.018), and PPG-based detector (13.20 vs. 5.60 beats/min, P = 0.05). Single-lead ECG required 3.4 times fewer extrasystoles than six-lead ECG to result in a false positive outcome. In a control subgroup of PACs, the specificity of six-lead ECG, single-lead ECG, and PPG dropped to 95%, 83.8%, and 90%, respectively. The diagnostic value of single-lead ECG (AUC 0.898) was inferior to six-lead ECG (AUC 0.971) and PPG-based detector (AUC 0.921). In a control subgroup of PVCs, the specificity of six-lead ECG, single-lead ECG, and PPG was 100%, 96.4%, and 96.6%, respectively. The diagnostic value of single-lead ECG (AUC 0.961) was inferior to six-lead ECG (AUC 0.996) and non-inferior to PPG-based detector (AUC 0.954). Conclusions: A six-lead wearable-recorded ECG demonstrated the superior diagnostic value of AF detection compared to a single-lead ECG and PPG-based AF detection. The risk of type I error due to the widespread use of smartwatch-enabled single-lead ECGs in populations with frequent premature beats is significant.

High Specificity Wearable Device With Photoplethysmography and Six-Lead Electrocardiography for Atrial Fibrillation Detection Challenged by Frequent Premature Contractions: DoubleCheck-AF.

Background: Consumer smartwatches have gained attention as mobile health (mHealth) tools able to detect atrial fibrillation (AF) using photoplethysmography (PPG) or a short strip of electrocardiogram (ECG). PPG has limited accuracy due to the movement artifacts, whereas ECG cannot be used continuously, is usually displayed as a single-lead signal and is limited in asymptomatic cases. Objective: DoubleCheck-AF is a validation study of a wrist-worn device dedicated to providing both continuous PPG-based rhythm monitoring and instant 6-lead ECG with no wires. We evaluated its ability to differentiate between AF and sinus rhythm (SR) with particular emphasis on the challenge of frequent premature beats. Methods and Results: We performed a prospective, non-randomized study of 344 participants including 121 patients in AF. To challenge the specificity of the device two control groups were selected: 95 patients in stable SR and 128 patients in SR with frequent premature ventricular or atrial contractions (PVCs/PACs). All ECG tracings were labeled by two independent diagnosis-blinded cardiologists as "AF," "SR" or "Cannot be concluded." In case of disagreement, a third cardiologist was consulted. A simultaneously recorded ECG of Holter monitor served as a reference. It revealed a high burden of ectopy in the corresponding control group: 6.2 PVCs/PACs per minute, bigeminy/trigeminy episodes in 24.2% (31/128) and runs of ≥3 beats in 9.4% (12/128) of patients. AF detection with PPG-based algorithm, ECG of the wearable and combination of both yielded sensitivity and specificity of 94.2 and 96.9%; 99.2 and 99.1%; 94.2 and 99.6%, respectively. All seven false-positive PPG-based cases were from the frequent PVCs/PACs group compared to none from the stable SR group (P < 0.001). In the majority of these cases (6/7) cardiologists were able to correct the diagnosis to SR with the help of the ECG of the device (P = 0.012). Conclusions: This is the first wearable combining PPG-based AF detection algorithm for screening of AF together with an instant 6-lead ECG with no wires for manual rhythm confirmation. The system maintained high specificity despite a remarkable amount of frequent single or multiple premature contractions.

Evolution and Revolution of Hepatitis C Management: From Non-A, Non-B Hepatitis Toward Global Elimination.

Discovery of hepatitis C in 1989 allowed basic research to identify critical components of hepatitis C virus (HCV) structure and life cycle. Interferon (IFN)-α was introduced as first treatment for chronic hepatitis C and later was enhanced by pegylation, addition of ribavirin, and resulted in improved sustained virologic response. Better understanding of HCV structure, enzymes, and lifecycle led to the discovery of direct-acting antivirals and IFN-free era. Successful HCV therapy created a rare possibility of global disease eradication, which is now a major goal internationally. However, hepatitis C remains a major public health challenge, and more resources are needed to reach global elimination.

SERPINA1 and HSD17B13 Gene Variants in Patients with Liver Fibrosis and Cirrhosis.

BACKGROUND AND AIMS: Two single nucleotide polymorphisms (SNPs) in SERPINA1 (Pi*Z rs28929474 and Pi*S rs17580) are risk factors for developing liver cirrhosis. A recent study identified a common SNP in HSD17B13 (rs72613567) that conferred protection from chronic liver disease. The aim of the present study was to test these associations in a cohort of Lithuanian patients with liver fibrosis or cirrhosis. METHODS: The study included 302 patients with cirrhosis, 127 patients with liver fibrosis (METAVIR stages I-III) and 548 controls, all from Lithuania. SNPs were genotyped by quantitative PCR, using TaqMan allelic discrimination assays. Adjusted p value of ≤ 0.016 was considered significant. RESULTS: Genotype distributions of SERPINA1 and HSD17B13 SNPs were in Hardy-Weinberg equilibrium. SERPINA1 Pi*Z was not associated with liver fibrosis or cirrhosis. HSD17B13 rs10433937 (in high linkage disequilibrium with rs72613567; r 2 =0.96) also showed no overall association with liver disease, but the GG- genotype was associated with reduced risk of liver fibrosis (aOR 0.37, p=0.03). SERPINA1 Pi*S was associated with higher risk of developing hepatic fibrosis (aOR 3.42, p=0.001) and cirrhosis (aOR 2.59, p=0.02). CONCLUSIONS: We found that SERPINA1 Pi*S variant conferred an increased risk of developing liver fibrosis, while SERPINA1 Pi*Z and HSD17B13 rs10433937 were not associated with liver fibrosis or cirrhosis of different aetiology.

TM6SF2 and MBOAT7 Gene Variants in Liver Fibrosis and Cirrhosis.

Previous large-scale genetic studies identified single nucleotide polymorphisms (SNPs) of the TM6SF2 and MBOAT7 genes as risk factors for alcoholic liver cirrhosis and non-alcoholic fatty liver disease. In this study, we tried to evaluate the association between TM6SF2 variant rs58542926 and MBOAT7 variant rs641738 and the risk of hepatic fibrosis or liver cirrhosis of different etiology. In parallel, we also aimed to evaluate whether these two SNPs modify the effects of the PNPLA3 rs738409 risk variant for the development of hepatic fibrosis and liver cirrhosis. The study was conducted at the Department of Gastroenterology, Lithuanian University of Health Sciences Hospital, and included 334 patients with liver cirrhosis, 128 patients with liver fibrosis, and 550 controls. SNPs were genotyped by quantitative PCR, using TaqMan allelic discrimination assays. Overall, TM6SF2 rs58542926 as well as MBOAT7 rs641738 were not linked to hepatic fibrosis, alcohol or hepatitis C virus induced liver cirrhosis in an Eastern European population. These genetic variations also did not mediate the effect of PNPLA3 rs738409 SNP for liver developing liver fibrosis or liver cirrhosis.