Publications by authors named "Andreas Cerny"

74 Publications

A deep transfer learning approach for wearable sleep stage classification with photoplethysmography.

NPJ Digit Med 2021 Sep 15;4(1):135. Epub 2021 Sep 15.

Department of Electrical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands.

Unobtrusive home sleep monitoring using wrist-worn wearable photoplethysmography (PPG) could open the way for better sleep disorder screening and health monitoring. However, PPG is rarely included in large sleep studies with gold-standard sleep annotation from polysomnography. Therefore, training data-intensive state-of-the-art deep neural networks is challenging. In this work a deep recurrent neural network is first trained using a large sleep data set with electrocardiogram (ECG) data (292 participants, 584 recordings) to perform 4-class sleep stage classification (wake, rapid-eye-movement, N1/N2, and N3). A small part of its weights is adapted to a smaller, newer PPG data set (60 healthy participants, 101 recordings) through three variations of transfer learning. Best results (Cohen's kappa of 0.65 ± 0.11, accuracy of 76.36 ± 7.57%) were achieved with the domain and decision combined transfer learning strategy, significantly outperforming the PPG-trained and ECG-trained baselines. This performance for PPG-based 4-class sleep stage classification is unprecedented in literature, bringing home sleep stage monitoring closer to clinical use. The work demonstrates the merit of transfer learning in developing reliable methods for new sensor technologies by reusing similar, older non-wearable data sets. Further study should evaluate our approach in patients with sleep disorders such as insomnia and sleep apnoea.
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http://dx.doi.org/10.1038/s41746-021-00510-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443610PMC
September 2021

Acute autoimmune-like hepatitis with atypical anti-mitochondrial antibody after mRNA COVID-19 vaccination: A novel clinical entity?

J Autoimmun 2021 09 15;123:102706. Epub 2021 Jul 15.

Epatocentro Ticino, Via Soldino 5, 6900, Lugano, Switzerland; King's College London Faculty of Life Sciences & Medicine, Institute of Liver Studies, MowatLabs, London, UK; Faculty of Biomedical Sciences, Università Della Svizzera Italiana, 6900, Lugano, Switzerland. Electronic address:

Autoimmune phenomena and clinically apparent autoimmune diseases, including autoimmune hepatitis, are increasingly been reported not only after natural infection with the SARS-CoV-2 virus, but also after vaccination against it. We report the case of a 63-year old man without a history of autoimmunity or SARS-CoV-2 natural infection who experienced acute severe autoimmune-like hepatitis seven days after the first dose of the mRNA-1273 SARS-CoV-2 vaccine. Liver histology showed inflammatory portal infiltrate with interface hepatitis, lobular and centrilobular inflammation with centrilobular necrosis, in absence of fibrosis and steatosis. Serum immunoglobulin G was slightly elevated. Autoimmune liver serology showed an indirect immunofluorescence pattern on triple rodent tissue compatible with anti-mitochondrial antibody (AMA), but, unexpectedly, this pattern was not mirrored by positivity for primary biliary cholangitis (PBC)-specific molecular tests, indicating that this antibody is different from classical AMA. Anti-nuclear antibody (ANA) was also positive with a rim-like indirect immunofluorescence pattern on liver and HEp2 cell substrates, similar to PBC-specific ANA; however, anti-gp210 and a large panel of molecular-based assays for nuclear antigens were negative, suggesting a unique ANA in our patient. He carries the HLA DRB1*11:01 allele, which is protective against PBC. Response to prednisone treatment was satisfactory. The clinical significance of these novel specificities needs to be further evaluated in this emerging condition.
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http://dx.doi.org/10.1016/j.jaut.2021.102706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279947PMC
September 2021

Methylene Blue has a potent antiviral activity against SARS-CoV-2 and H1N1 influenza virus in the absence of UV-activation in vitro.

Sci Rep 2021 07 12;11(1):14295. Epub 2021 Jul 12.

Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland.

Methylene blue is an FDA (Food and Drug Administration) and EMA (European Medicines Agency) approved drug with an excellent safety profile. It displays broad-spectrum virucidal activity in the presence of UV light and has been shown to be effective in inactivating various viruses in blood products prior to transfusions. In addition, its use has been validated for methemoglobinemia and malaria treatment. In this study, we first evaluated the virucidal activity of methylene blue against influenza virus H1N1 upon different incubation times and in the presence or absence of light activation, and then against SARS-CoV-2. We further assessed the therapeutic activity of methylene blue by administering it to cells previously infected with SARS-CoV-2. Finally, we examined the effect of co-administration of the drug together with immune serum. Our findings reveal that methylene blue displays virucidal preventive or therapeutic activity against influenza virus H1N1 and SARS-CoV-2 at low micromolar concentrations and in the absence of UV-activation. We also confirm that MB antiviral activity is based on several mechanisms of action as the extent of genomic RNA degradation is higher in presence of light and after long exposure. Our work supports the interest of testing methylene blue in clinical studies to confirm a preventive and/or therapeutic efficacy against both influenza virus H1N1 and SARS-CoV-2 infections.
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http://dx.doi.org/10.1038/s41598-021-92481-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8275569PMC
July 2021

It is All in the Wrist: Wearable Sleep Staging in a Clinical Population versus Reference Polysomnography.

Nat Sci Sleep 2021 28;13:885-897. Epub 2021 Jun 28.

Department of Electrical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands.

Purpose: There is great interest in unobtrusive long-term sleep measurements using wearable devices based on reflective photoplethysmography (PPG). Unfortunately, consumer devices are not validated in patient populations and therefore not suitable for clinical use. Several sleep staging algorithms have been developed and validated based on ECG-signals. However, translation from these techniques to data derived by wearable PPG is not trivial, and requires the differences between sensing modalities to be integrated in the algorithm, or having the model trained directly with data obtained with the target sensor. Either way, validation of PPG-based sleep staging algorithms requires a large dataset containing both gold standard measurements and PPG-sensor in the applicable clinical population. Here, we take these important steps towards unobtrusive, long-term sleep monitoring.

Methods: We developed and trained an algorithm based on wrist-worn PPG and accelerometry. The method was validated against reference polysomnography in an independent clinical population comprising 244 adults and 48 children (age: 3 to 82 years) with a wide variety of sleep disorders.

Results: The classifier achieved substantial agreement on four-class sleep staging with an average Cohen's kappa of 0.62 and accuracy of 76.4%. For children/adolescents, it achieved even higher agreement with an average kappa of 0.66 and accuracy of 77.9%. Performance was significantly higher in non-REM parasomnias (kappa = 0.69, accuracy = 80.1%) and significantly lower in REM parasomnias (kappa = 0.55, accuracy = 72.3%). A weak correlation was found between age and kappa ( = -0.30, p<0.001) and age and accuracy ( = -0.22, p<0.001).

Conclusion: This study shows the feasibility of automatic wearable sleep staging in patients with a broad variety of sleep disorders and a wide age range. Results demonstrate the potential for ambulatory long-term monitoring of clinical populations, which may improve diagnosis, estimation of severity and follow up in both sleep medicine and research.
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http://dx.doi.org/10.2147/NSS.S306808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253894PMC
June 2021

Safety of mRNA-Based Vaccines for SARS CoV-2.

Chem Res Toxicol 2021 08 19;34(8):1823-1825. Epub 2021 May 19.

Fondazione Epatocentro Ticino, Lugano 6900, Switzerland.

SARS-CoV-2 has infected more than 100 million people, causing 2 million deaths globally. Studies on the development of a vaccine ended up with different formulations. We herein discuss the safety record of the two approved vaccines.
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http://dx.doi.org/10.1021/acs.chemrestox.1c00129DOI Listing
August 2021

Estimating sleep stages using cardiorespiratory signals: validation of a novel algorithm across a wide range of sleep-disordered breathing severity.

J Clin Sleep Med 2021 07;17(7):1343-1354

Philips Sleep and Respiratory Care, Vienna, Austria.

Study Objectives: We have developed the CardioRespiratory Sleep Staging (CReSS) algorithm for estimating sleep stages using heart rate variability and respiration, allowing for estimation of sleep staging during home sleep apnea tests. Our objective was to undertake an epoch-by-epoch validation of algorithm performance against the gold standard of manual polysomnography sleep staging.

Methods: Using 296 polysomnographs, we created a limited montage of airflow and heart rate and deployed CReSS to identify each 30-second epoch as wake, light sleep (N1 + N2), deep sleep (N3), or rapid eye movement (REM) sleep. We calculated Cohen's kappa and the percentage of accurately identified epochs. We repeated our analyses after stratification by sleep-disordered breathing (SDB) severity, and after adding thoracic respiratory effort as a backup signal for periods of invalid airflow.

Results: CReSS discriminated wake/light sleep/deep sleep/REM sleep with 78% accuracy; the kappa value was 0.643 (95% confidence interval, 0.641-0.645). Discrimination of wake/sleep demonstrated a kappa value of 0.711 and accuracy of 89%, non-REM sleep/REM sleep demonstrated a kappa of 0.790 and accuracy of 94%, and light sleep/deep sleep demonstrated a kappa of 0.469 and accuracy of 87%. Kappa values did not vary by more than 0.07 across subgroups of no SDB, mild SDB, moderate SDB, and severe SDB. Accuracy increased to 80%, with a kappa value of 0.680 (95% confidence interval, 0.678-0.682), when CReSS additionally utilized the thoracic respiratory effort signal.

Conclusions: We observed substantial agreement between CReSS and the gold-standard comparator of manual sleep staging of polysomnographic signals, which was consistent across the full range of SDB severity. Future research should focus on the extent to which CReSS reduces the discrepancy between the apnea-hypopnea index and the respiratory event index, and the ability of CReSS to identify REM sleep-related obstructive sleep apnea.
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http://dx.doi.org/10.5664/jcsm.9192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8314617PMC
July 2021

ABCB4 variants in adult patients with cholestatic disease are frequent and underdiagnosed.

Dig Liver Dis 2021 03 31;53(3):329-344. Epub 2020 Dec 31.

Epatocentro Ticino, Lugano, Switzerland; Institute of Liver Studies, MowatLabs, King's College Hospital, Denmark Hill, London, United Kingdom. Electronic address:

Background: Heterozygous ABCB4 variants are not routinely tested in adults with cholestasis because of their supposed rarity and high costs.

Methods: Nineteen adult patients presenting with unexplained cholestasis, and/or recurrent gallstones were included; genotyping was not done in five due to lack of health insurance approval.

Results: heterozygous ABCB4 variants were identified in seven patients, followed by cascade testing of 12 family members: one patient underwent liver transplantation at age 40 for end-stage liver disease; one had compensated cirrhosis; all symptomatic adults had gallstones, including four with low phospholipid-associated cholelithiasis; four had intrahepatic cholestasis of pregnancy; all children and one 54-year old female were asymptomatic. Genotype: Families A and C: c.2211G>A (p.Ala737=) combined with c.959C>T (p.Ser320Phe) in one subject; Family B: c.1130T>C (p.Ile377Thr); Family D: large deletion removing ABCB4 exons 1-4 plus ABCB1, RUNDC3B, SLC25A40, DBF4, ADAM22 exons 1-3; Family E: c.1565T>C (p.Phe522Ser) ; Family F: c.1356+2T>C combined with c.217C>G (p.Leu73Val). All patients responded to ursodeoxycholic acid.

Conclusions: We found ABCB4 variants in half of the adults with unexplained cholestasis and/or recurrent gallstones presenting at our center, suggesting that this condition is underdiagnosed and undertreated, with serious consequences not only for the patients and their families, but also in terms of healthcare costs.
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http://dx.doi.org/10.1016/j.dld.2020.12.003DOI Listing
March 2021

Primary biliary cholangitis with normal alkaline phosphatase: A neglected clinical entity challenging current guidelines.

J Autoimmun 2021 01 20;116:102578. Epub 2020 Nov 20.

Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College London Faculty of Life Sciences & Medicine at King's College Hospital, Denmark Hill, London, SE5 9RS, United Kingdom.

Background & Aim: The diagnosis of primary biliary cholangitis (PBC), an uncommon immune-mediated cholestatic liver disease, is based on positive circulating anti-mitochondrial (AMA) and/or PBC-specific anti-nuclear autoantibodies (ANA), coupled with elevated serum alkaline phopsphatase (ALP) levels. Timely initiation of treatment with ursodeoxycholic acid prevents progression to cirrhosis and liver failure. We aimed at investigating liver histology in patients with normal ALP level and positive AMA and/or PBC-specific ANA.

Methods: We searched the Swiss PBC Cohort Study database, which includes subjects with positive PBC autoimmune serology and normal ALP levels, for patients who underwent a liver biopsy. Histological slides were centrally reviewed by an expert liver pathologist, and sera were centrally re-tested for AMA and ANA.

Results: 30 patients were included; 90% females, median age 53 (range 27-72) years. Twenty-four (80%) had liver histology typical for (n = 2), consistent with (n = 16) or suggestive of (n = 6) PBC, including three of four AMA-negative ANA-positive patients. Among 22 ursodeoxycholic acid treated patients, 14 had elevated GGT levels before treatment; a significant decrease of the median GGT level between pre- (1.46 x ULN) and post- (0.43 x ULN) treatment (p = 0.0018) was observed.

Conclusions: In our series, a high proportion of AMA positive patients with normal ALP levels have PBC. For the first time we show histological diagnosis of PBC in AMA-negative/PBC-specific ANA-positive subjects and the potential role of GGT as a biomarker in PBC patients with normal baseline ALP levels. Current guidelines for the diagnosis of PBC do not cover the whole extent of PBC presentation, with important clinical implications in terms of timely treatment initiation.
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http://dx.doi.org/10.1016/j.jaut.2020.102578DOI Listing
January 2021

All-Cause Mortality and Causes of Death in the Swiss Hepatitis C Cohort Study (SCCS).

Open Forum Infect Dis 2020 Aug 25;7(8):ofaa308. Epub 2020 Jul 25.

Institute of Global Health, University of Geneva, Geneva, Switzerland.

Background: With direct-acting antiviral agents (DAAs), mortality rates and causes of death among persons with hepatitis C virus (HCV) infection may change over time. However, the emergence of such trends may be delayed by the slow progression of chronic hepatitis C. To date, detailed analyses of cause-specific mortality among HCV-infected persons over time remain limited.

Methods: We evaluated changes in causes of death among Swiss Hepatitis C Cohort Study (SCCS) participants from 2008 to 2016. We analyzed risk factors for all-cause and cause-specific mortality, accounting for changes in treatment, fibrosis stage, and use of injectable drugs over time. Mortality ascertainment was completed by linking lost-to-follow-up participants to the Swiss Federal Statistical Office death registry.

Results: We included 4700 SCCS participants, of whom 478 died between 2008 and 2016. The proportion of unknown causes of death decreased substantially after linkage, from 42% to 10%. Leading causes of death were liver failure (crude death rate 4.4/1000 person-years), liver cancer (3.4/1000 person-years), and nonliver cancer (2.8/1000 person-years), with an increasing proportion of cancer-related deaths over time. Cause-specific analysis showed that persons with sustained virologic response were less at risk for liver-related mortality than those never treated or treated unsuccessfully.

Conclusions: Although the expected decrease in mortality is not yet observable, causes of death among HCV-infected persons have evolved over time. With the wider use of DAAs, liver-related mortality is expected to decline in the future. Continued monitoring of cause-specific mortality will remain important to assess the long-term effect of DAAs and design effective interventions.
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http://dx.doi.org/10.1093/ofid/ofaa308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443104PMC
August 2020

The complement system in liver diseases: Evidence-based approach and therapeutic options.

J Transl Autoimmun 2019 Dec 18;2:100017. Epub 2019 Sep 18.

Labormedizinisches Zentrum Dr. Risch, Waldeggstrasse 37, CH-3097, Liebefeld bei Bern, Switzerland.

Complement is usually seen to largely originate from the liver to accomplish its tasks systemically - its return to the production site has long been underestimated. Recent progress in genomics, therapeutic effects on complement, standardised possibilities in medical laboratory tests and involvement of complosome brings the complement system with its three major functions of opsonization, cytolysis and phagocytosis back to liver biology and pathology. The LOINC™ system features 20 entries for the C3 component of complement to anticipate the application of artificial intelligence data banks algorythms of which are fed with patient-specific data connected to standard lab assays for liver function. These advancements now lead to increased vigilance by clinicians. This reassessment article will further elucidate the distribution of synthesis sites to the three germ layer-derived cell systems and the role complement now known to play in embryogenesis, senescence, allotransplantation and autoimmune disease. This establishes the liver as part of the gastro-intestinal system in connection with nosological entities never thought of, such as the microbiota-liver-brain axis. In neurological disease etiology infectious and autoimmune hepatitis play an important role in the context of causative reactive complement activation. The mosaic of autoimmunity, i.e. multiple combinations of the many factors producing varying clinical pictures, leads to the manifold facets of liver autoimmunity.
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http://dx.doi.org/10.1016/j.jtauto.2019.100017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388403PMC
December 2019

Clinical characteristics and management of a liver transplanted patient admitted with SARS-CoV-2 infection.

Clin Res Hepatol Gastroenterol 2020 11 10;44(6):e141-e144. Epub 2020 Jun 10.

Division of Infectious Diseases, Ente Ospedaliero Cantonale, Ospedale Civico and Ospedale Italiano, Lugano, Switzerland.

We present here the case of a 62-year-old man, who was referred to the emergency department with fever and cough for 3 days. He underwent liver transplantation 4 years earlier due to HCV and NASH-related cirrhosis with hepatocellular carcinoma. At admission he was in reduced general conditions. Nasopharyngeal smear specimen resulted positive for SARS-CoV-2 infection. Pulmonary low-dose CT-scan revealed bilateral subpleural ground-glass infiltrates. O2 saturation was 93%. A treatment with lopinavir/ritonavir and hydroxychloroquine twice daily was started. The patient received also cefepime and remained in isolation. Seven days later imaging showed a progression of the pulmonary infiltrates. Cefepime was replaced by meropenem. During the following 3 days the fever resolved, and the general conditions of the patient significantly improved. Consequently, treatment with lopinavir/ritonavir and hydroxychloroquine was stopped. The evolution of SARS-CoV-2 interstitial pneumonia in this immunosuppressed patient was moderate to severe and liver injury was not clinically significant. Despite its limitations, this case report confirm that the liver may be only mildly affected during SARS-CoV-2 infection, also in liver transplanted patients. Further studies are needed to assess whether the outcome of SARS-CoV-2 infection is worse in immunosuppressed patients than in the general population.
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http://dx.doi.org/10.1016/j.clinre.2020.05.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284277PMC
November 2020

Automatic sleep staging using heart rate variability, body movements, and recurrent neural networks in a sleep disordered population.

Sleep 2020 09;43(9)

Department of Electrical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.

Study Objectives: To validate a previously developed sleep staging algorithm using heart rate variability (HRV) and body movements in an independent broad cohort of unselected sleep disordered patients.

Methods: We applied a previously designed algorithm for automatic sleep staging using long short-term memory recurrent neural networks to model sleep architecture. The classifier uses 132 HRV features computed from electrocardiography and activity counts from accelerometry. We retrained our algorithm using two public datasets containing both healthy sleepers and sleep disordered patients. We then tested the performance of the algorithm on an independent hold-out validation set of sleep recordings from a wide range of sleep disorders collected in a tertiary sleep medicine center.

Results: The classifier achieved substantial agreement on four-class sleep staging (wake/N1-N2/N3/rapid eye movement [REM]), with an average κ of 0.60 and accuracy of 75.9%. The performance of the sleep staging algorithm was significantly higher in insomnia patients (κ = 0.62, accuracy = 77.3%). Only in REM parasomnias, the performance was significantly lower (κ = 0.47, accuracy = 70.5%). For two-class wake/sleep classification, the classifier achieved a κ of 0.65, with a sensitivity (to wake) of 72.9% and specificity of 94.0%.

Conclusions: This study shows that the combination of HRV, body movements, and a state-of-the-art deep neural network can reach substantial agreement in automatic sleep staging compared with polysomnography, even in patients suffering from a multitude of sleep disorders. The physiological signals required can be obtained in various ways, including non-obtrusive wrist-worn sensors, opening up new avenues for clinical diagnostics.
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http://dx.doi.org/10.1093/sleep/zsaa048DOI Listing
September 2020

Nonalcoholic fatty liver disease burden - Switzerland 2018-2030.

Swiss Med Wkly 2019 Dec 17;149:w20152. Epub 2019 Dec 17.

Center for Disease Analysis, Lafayette, Colorado, USA 0017208903817 | 0017204423453.

As a result of epidemic levels of obesity and diabetes mellitus, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) will contribute to increases in the liver-related disease burden in Switzerland. A Markov model was built to quantify fibrosis progression among the NAFLD and NASH populations, and predict disease burden up to 2030. Long-term trending of NAFLD prevalence was based on changes in the prevalence of adult obesity. Published estimates and surveillance data were applied to build and validate the model projections. The prevalence of NAFLD increased up to 2030 in tandem with projected increases in adult obesity. By 2030, there were an estimated 2,234,000 (1,918,000–2,553,000) NAFLD cases, or 24.3% (20.9–27.8%) of the total Swiss population (all ages). Increases in NASH cases were relatively greater than NAFLD cases. Incident cases of advanced liver disease are projected to increase by approximately 40% by 2030, and incident NAFLD liver deaths to increase from 580 deaths in 2018 to 820 deaths in 2030. Continued growth in obesity, in combination with an aging population, will result in increasing number of cases of advanced liver disease and mortality related to NAFLD and NASH. Slowing the growth in obesity and metabolic syndrome, along with future potential therapies, are required to reduce liver disease burden.  .
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http://dx.doi.org/10.4414/smw.2019.20152DOI Listing
December 2019

Neurologic complications of acute hepatitis E virus infection.

Neurol Neuroimmunol Neuroinflamm 2020 01 5;7(1). Epub 2019 Dec 5.

From the Department of Neurology (P.R., G.M., C.S., C.Z., G.D., A.K.-L., C.G.), Neurocenter of Southern Switzerland, Lugano, CH; Laboratory of Microbiology EOLAB (E.P., G.M.), Bellinzona, CH; Faculty of Biomedical Sciences, USI (G.M., C.Z., A.K.-L., C.G.), Lugano, CH; Division of Gastroenterology and Hepatology, Lausanne University Hospital (M.F., D.M.), Lausanne, CH; Institute of Microbiology, Lausanne University Hospital (R.S.), Lausanne, CH; Laboratory of Immunology, Lausanne University Hospital (V.A.), CH; Department of Hepatology, Hospital of Bellinzona (F.B.), CH; Division of Infectious Diseases (E.B.), Hospital of Lugano, CH; Epatocentro Ticino (B.T.B.-P., A.C.), Lugano, CH; Queens Park (H.R.D.), London, UK; Synlab Ticino (C.Z.), Bioggio, CH; and Unilabs Ticino (B.M.), Lugano, CH.

Objective: To assess the prevalence and clinical features of neurologic involvement in patients with acute hepatitis E virus (HEV) infection in Southern Switzerland.

Methods: Among 1,940 consecutive patients investigated for acute hepatitis E, we identified 141 cases of acute of HEV infection (anti-HEV immunoglobulin M and immunoglobulin G both reactive and/or HEV RNA positive) between June 2014 and September 2017. Neurologic cases were followed up for 6 months. We compared patients with and without neurologic symptoms.

Results: Neurologic symptoms occurred in 43 acute HEV cases (30.4%) and consisted of neuralgic amyotrophy (NA, n = 15, 10.6%) and myalgia (n = 28, 19.8%). All NA cases were immunocompetent. Men had higher odds (OR = 5.2, CI 1.12-24.0, = 0.03) of developing NA after infection with HEV, and in 3 couples simultaneously infected with HEV, only men developed NA. Bilateral involvement of NA was predominant (2:1) and occurred only in men. Seven NA cases were viremic (all genotype 3), but HEV was undetectable in their CSF. In the acute phase of NA, 9 patients were treated with intravenous immunoglobulin and 4 with prednisone, reporting no side effects and improvement in pain and strength. Myalgia occurred both without (n = 16) or with (n = 12) concomitant elevated serum creatinine kinase. Seven cases with myalgia in the shoulder girdle did not have muscle weakness ("forme fruste" of NA).

Conclusions: Neurologic symptoms occurred in one-third of acute HEV infections and consisted of NA and myalgia. NA seems to occur more frequently in men infected by HEV and has a predominant (but not exclusive) bilateral involvement.
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http://dx.doi.org/10.1212/NXI.0000000000000643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935854PMC
January 2020

Sleep stage classification from heart-rate variability using long short-term memory neural networks.

Sci Rep 2019 Oct 2;9(1):14149. Epub 2019 Oct 2.

Royal Philips, Research, High Tech Campus 34, 5656 AE, Eindhoven, The Netherlands.

Automated sleep stage classification using heart rate variability (HRV) may provide an ergonomic and low-cost alternative to gold standard polysomnography, creating possibilities for unobtrusive home-based sleep monitoring. Current methods however are limited in their ability to take into account long-term sleep architectural patterns. A long short-term memory (LSTM) network is proposed as a solution to model long-term cardiac sleep architecture information and validated on a comprehensive data set (292 participants, 584 nights, 541.214 annotated 30 s sleep segments) comprising a wide range of ages and pathological profiles, annotated according to the Rechtschaffen and Kales (R&K) annotation standard. It is shown that the model outperforms state-of-the-art approaches which were often limited to non-temporal or short-term recurrent classifiers. The model achieves a Cohen's k of 0.61 ± 0.15 and accuracy of 77.00 ± 8.90% across the entire database. Further analysis revealed that the performance for individuals aged 50 years and older may decline. These results demonstrate the merit of deep temporal modelling using a diverse data set and advance the state-of-the-art for HRV-based sleep stage classification. Further research is warranted into individuals over the age of 50 as performance tends to worsen in this sub-population.
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http://dx.doi.org/10.1038/s41598-019-49703-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775145PMC
October 2019

Autoimmune liver serology before and after successful treatment of chronic hepatitis C by direct acting antiviral agents.

J Autoimmun 2019 08 30;102:89-95. Epub 2019 Apr 30.

DIMEC, University of Bologna, Bologna, Italy.

Background And Aims: Chronic hepatitis C virus (HCV) infection is associated with a wide range of immunopathological manifestations, which are significantly improved by successful interferon-based treatment. There is paucity of data on the impact of interferon-free HCV clearance on immunopathological manifestations, which might be expected to disappear more frequently as compared to what reported in interferon-induced HCV-clearance. We have investigated liver autoimmune serology before and after interferon-free clearance of HCV by treatment with direct acting antiviral agents (DAA).

Method: Patients within the Swiss Hepatitis C Cohort Study who underwent successful (SVR 12) HCV treatment with DAA were tested for autoimmune liver serology according to dedicated guidelines before and at least 6 months after end of treatment.

Results: A total of 235 patients were included; 62% males; median age 56 years; 27% with cirrhosis. Median time between end of DAA treatment and post-treatment serum sampling was 17 months. At least one autoantibody before treatment was found in 175 (74%) patients ; 32 (14%) were positive for 2 autoantibodies; no patient was positive for anti-SLA, anti-LC1 or typical AMA before or after DAA. ANA disappeared in 34%, SMA in 52% and anti-LKM1 in one of two patients after successful treatment, but, unexpectedly, one or more autoantibodies appeared in 27% of pre-treatment negative subjects.

Conclusion: HCV clearance by DAA is associated with autoantibody disappearance in more than one third of the patients who were positive before treatment. However, the majority of the patients remain autoantibody-positive and 27% of those who were negative before treatment developed autoantibodies after DAA-induced HCV clearance. These data confirm that HCV infection is associated with autoimmunity and show that the autoimmune imprint persists after viral clearance by DAA, suggesting that long-term follow-up may be warranted.
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http://dx.doi.org/10.1016/j.jaut.2019.04.019DOI Listing
August 2019

Controlling HCV in Switzerland: running against the clock.

Swiss Med Wkly 2019 03 24;149:w20005. Epub 2019 Mar 24.

Epatocentro Ticino, Lugano, Switzerland.

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http://dx.doi.org/10.4414/smw.2019.20005DOI Listing
March 2019

Autoimmune liver disease serology in acute hepatitis E virus infection.

J Autoimmun 2018 11 7;94:1-6. Epub 2018 Jul 7.

DIMEC, University of Bologna, Bologna, Italy.

The etiology of autoimmune hepatitis (AIH) is unknown, though hepatotropic viruses may be potential triggers. Hepatitis E virus (HEV) infection, an increasingly recognized cause of acute hepatitis, has been misdiagnosed as AIH due to the occurrence of autoantibodies during its acute phase. It has also been suggested that HEV infection may lead to or unmask AIH. The HEV seroprevalence has been ascertained in patients with AIH, but the prevalence of AIH-related autoantibodies in patients with HEV infection has not been systematically tested. We aimed to investigate whether acute HEV infection is associated with the presence of AIH-relevant autoantibodies, following the liver autoimmune serology guidelines of the International AIH Group. We tested 48 patients with acute HEV infection. Half of them had at least one autoantibody, 17% two autoantibodies. Anti-nuclear antibody (ANA) were detected in 16 (33%), anti-smooth muscle antibody (SMA) in 10 (21%), and anti-neutrophil cytoplasmic antibody (ANCA) in 7 (14.6%). Of note, two patients showed SMA with VG or VGT patterns and five had ANA with homogeneous appearance, both being typical of AIH type 1. Other AIH-specific autoantibodies were negative. Atypical anti-mitochondrial antibody, without evidence of primary biliary cholangitis, was positive in one patient, disappearing at follow-up. Follow-up (median 12 months) serum was available from seven autoantibody positive patients: two became negative, while five remained positive, although no patient developed AIH to date. In conclusion, autoantibodies are frequently present during acute HEV infection, indicating that HEV should always be excluded before diagnosing AIH. Importantly, a minority of patients with acute hepatitis E develops AIH-specific autoantibodies, and, though they did not progress to autoimmune liver disease in the short-term, they warrant long-term monitoring.
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http://dx.doi.org/10.1016/j.jaut.2018.07.006DOI Listing
November 2018

Geoepidemiology of Primary Biliary Cholangitis: Lessons from Switzerland.

Clin Rev Allergy Immunol 2018 Apr;54(2):295-306

Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.

No data on primary biliary cholangitis (PBC) are available in Switzerland. We established a national patient cohort to obtain information on PBC phenotypes and disease course in Switzerland. Local databases in all university hospitals and in two large secondary centers were searched for case finding. In addition, all primary care physicians, gastroenterologists, rheumatologists, and dermatologists were invited to contribute patients from their own medical records. PBC diagnosis was centrally reviewed. Five hundred one PBC patients were identified, 474 were included in data analysis, and 449 of them were enrolled by tertiary centers. The catchment area accounts for approximately one third of the Swiss population or approximately 2.8 million inhabitants. The median age at diagnosis was 53 years, 84% were women, and 86% were anti-mitochondrial antibody positive. The median follow-up was 5.4 years, 12.6% experienced a liver-related endpoint. Splenomegaly was present at diagnosis in one quarter of patients and in half of male patients. Approximately one third were non-responders to ursodeoxycholic acid (UDCA). The median transplant-free survival at 10 years was 85%. The following variables were independently associated with poor outcome: low platelet count at baseline (HR = 0.99, p < 0.0001), elevated alkaline phosphatase at baseline (HR = 1.36, p < 0.0001), elevated bilirubin at baseline (HR = 1.11, p = 0.001), and elevated alanine aminotransaminase (HR = 1.35, p = 0.04) after 12 months of UDCA therapy. The AUROC for the UK-PBC risk score at 5, 10, and 15 years was 0.82. The AUROC for the Globe score at 5, 10, and 15 years was 0.77. Patients included in this study are currently being enrolled in a prospective nationwide registry with biobank, taking advantage of the collaboration network generated by this study. Our study provides the first snapshot of PBC in Switzerland, describing a diagnostic delay with one quarter of patients diagnosed when already in the cirrhotic stage. We were also able to externally validate the UK-PBC risk score and the Globe score. The ongoing nationwide prospective registry will be fundamental to improve disease awareness and interdisciplinary collaborations and will serve as a platform for clinical and translational research.

Trial Registration Number: clinicaltrials.gov : NCT02846896; SNCTP000001870.
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http://dx.doi.org/10.1007/s12016-017-8656-xDOI Listing
April 2018

Hepatitis.

Authors:
Andreas Cerny

Ther Umsch 2017 Jul;74(3):77

1 Epatocentro Ticino, Lugano.

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http://dx.doi.org/10.1024/0040-5930/a000888DOI Listing
July 2017

Detection of Nocturnal Scratching Movements in Patients with Atopic Dermatitis Using Accelerometers and Recurrent Neural Networks.

IEEE J Biomed Health Inform 2018 07 8;22(4):1011-1018. Epub 2017 Jun 8.

Atopic dermatitis is a chronic inflammatory skin condition affecting both children and adults and is associated with pruritus. A method for objectively quantifying nocturnal scratching events could aid in the development of therapies for atopic dermatitis and other pruritic disorders. High-resolution wrist actigraphy (three-dimensional accelerometer sensors sampled at 20 Hz) is a noninvasive method to record movement. This paper presents an algorithm to detect nocturnal scratching events based on actigraphy data. The twofold process consists of segmenting the data into "no motion," "single handed motion," and "both handed motion" followed by discriminating motion segments into scratching and other motion using a bidirectional recurrent neural network classifier. The performance was compared against manually scored infrared video data collected from 24 subjects (6 healthy controls and 18 atopic dermatitis patients) demonstrating an score of 0.68 and a rank correlation of 0.945. The algorithm clearly outperformed a published reference method based on wrist actigraphy ( score of 0.09 and a rank correlation of 0.466). The results suggest that scratching movements can be discriminated from other nocturnal movements accurately.
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http://dx.doi.org/10.1109/JBHI.2017.2710798DOI Listing
July 2018

A systematic review and meta-analysis of HCV clearance.

Liver Int 2017 10 30;37(10):1431-1445. Epub 2017 Mar 30.

Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland.

While hepatitis C exemplifies the role of host genetics in infectious diseases outcomes, there is no comprehensive overview of polymorphisms influencing spontaneous and/or treatment-induced hepatitis C virus clearance. We performed a systematic review and meta-analysis of host polymorphisms associated with these phenotypes. Literature search was conducted using combinations of keywords in three databases. Studies were reviewed and relevant data systematically extracted for subsequent meta-analyses. Polymorphisms from candidate gene studies were tested in two cohorts of HCV-infected patients with available genomic data. The literature search yielded 8'294 citations, among which 262 studies were selected. In the meta-analysis of 27 HLA studies, the most significant associations with spontaneous hepatitis C virus clearance included DQB1*02, DQB1*03, DRB1*04 and DRB1*11. In the meta-analysis of 16 studies of KIR genes and their HLA-ligands, KIR2DS3 was associated with both spontaneous and treatment-induced clearance, and the HLA-C2 ligand with failure to spontaneously clear the virus. In a pooled analysis of 105 candidate genes and two genome-wide association studies, we observed associations of single nucleotide polymorphisms from nine genes (EIF2AK2, IFNAR2, ITPA, MBL2, MX1, OASL, SPP1, TGFB1, TNK2) with response to interferon-based therapy. Meta-analysis of 141 studies confirmed the association of IFNL3/4 polymorphisms with spontaneous and treatment-induced hepatitis C virus clearance, even in previously underpowered groups, such as hepatitis C virus genotypes 2/3-infected patients. This study may contribute to a better understanding of hepatitis C virus immunopathogenesis and highlights the complex role of host genetics in hepatitis C virus clearance.
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http://dx.doi.org/10.1111/liv.13401DOI Listing
October 2017

A new 3p25 locus is associated with liver fibrosis progression in human immunodeficiency virus/hepatitis C virus-coinfected patients.

Hepatology 2016 11 29;64(5):1462-1472. Epub 2016 Jul 29.

Équipe Génomique, Bioinformatique et Applications (EA4627), Chaire de Bioinformatique, Conservatoire National des Arts et Métiers, Paris, France.

There is growing evidence that human genetic variants contribute to liver fibrosis in subjects with hepatitis C virus (HCV) monoinfection, but this aspect has been little investigated in patients coinfected with HCV and human immunodeficiency virus (HIV). We performed the first genome-wide association study of liver fibrosis progression in patients coinfected with HCV and HIV, using the well-characterized French National Agency for Research on AIDS and Viral Hepatitis CO13 HEPAVIH cohort. Liver fibrosis was assessed by elastography (FibroScan), providing a quantitative fibrosis score. After quality control, a genome-wide association study was conducted on 289 Caucasian patients, for a total of 8,426,597 genotyped (Illumina Omni2.5 BeadChip) or reliably imputed single-nucleotide polymorphisms. Single-nucleotide polymorphisms with P values <10 were investigated in two independent replication cohorts of European patients infected with HCV alone. Two signals of genome-wide significance (P < 5 × 10 ) were obtained. The first, on chromosome 3p25 and corresponding to rs61183828 (P = 3.8 × 10 ), was replicated in the two independent cohorts of patients with HCV monoinfection. The cluster of single-nucleotide polymorphisms in linkage disequilibrium with rs61183828 was located close to two genes involved in mechanisms affecting both cell signaling and cell structure (CAV3) or HCV replication (RAD18). The second signal, obtained with rs11790131 (P = 9.3 × 10 ) on chromosome region 9p22, was not replicated.

Conclusion: This genome-wide association study identified a new locus associated with liver fibrosis severity in patients with HIV/HCV coinfection, on chromosome 3p25, a finding that was replicated in patients with HCV monoinfection; these results provide new relevant hypotheses for the pathogenesis of liver fibrosis in patients with HIV/HCV coinfection that may help define new targets for drug development or new prognostic tests, to improve patient care. (Hepatology 2016;64:1462-1472).
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http://dx.doi.org/10.1002/hep.28695DOI Listing
November 2016

Screening for liver cancer in high risk patients in Switzerland: Yes, it works, but No, we do not do it systematically!

Authors:
Andreas Cerny

Swiss Med Wkly 2015 23;145:w14231. Epub 2015 Dec 23.

Epatocentro Ticino, Lugano, Switzerland.

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http://dx.doi.org/10.4414/smw.2015.14231DOI Listing
September 2016

[Update Chronic Viral Hepatitis B and C].

Praxis (Bern 1994) 2015 Dec;104(25):1393-7

1 Epatocentro Ticino, Lugano.

Chronic hepatitis B has a complex natural history. The age at infection, comorbidities, coinfections, and other, yet to be identified factors, determine the probability of developing a chronic infection. The HBV virus can never be completely eliminated and remains in the hepatocytes for life. However, to reach an inactive carrier status is a realistic goal of the therapy. For HBV treatment, pegylated interferon and direct antivirals are available. To screen persons at risk and to vaccinate all of the population are important prophylactic measures. Chronic hepatitis C infection leads, in 30% of cases, to liver cirrhosis. Treatment is recommended from fibrosis stage Metavir 2. New DAA allows short treatment, with a high response rate and very few adverse effects.
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http://dx.doi.org/10.1024/1661-8157/a002207DOI Listing
December 2015

Reduced IFNλ4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes.

Nat Commun 2014 Dec 23;5:5699. Epub 2014 Dec 23.

Department of Molecular Biology and Genetics, Aarhus University, Aarhus DK-8000, Denmark.

Hepatitis C virus (HCV) infections are the major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma worldwide. Both spontaneous and treatment-induced clearance of HCV depend on genetic variation within the interferon-lambda locus, but until now no clear causal relationship has been established. Here we demonstrate that an amino-acid substitution in the IFNλ4 protein changing a proline at position 70 to a serine (P70S) substantially alters its antiviral activity. Patients harbouring the impaired IFNλ4-S70 variant display lower interferon-stimulated gene (ISG) expression levels, better treatment response rates and better spontaneous clearance rates, compared with patients coding for the fully active IFNλ4-P70 variant. Altogether, these data provide evidence supporting a role for the active IFNλ4 protein as the driver of high hepatic ISG expression as well as the cause of poor HCV clearance.
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http://dx.doi.org/10.1038/ncomms6699DOI Listing
December 2014

Survival of hepatocellular carcinoma patients is significantly improving: a population-based study from southern Switzerland.

Cancer Epidemiol 2014 Dec 17;38(6):679-85. Epub 2014 Oct 17.

Ticino Cancer Registry, Institute of Pathology, 6600 Locarno, Switzerland. Electronic address:

Background: During the last 20 years, relevant diagnostic procedures and advanced treatments have been progressively introduced in the management of hepatocellular carcinoma (HCC). The aim of the present study was to assess up-to-date survival trends for HCC in southern Switzerland, a region with one of the highest incidence rates in the country.

Methods: HCCs diagnosed in 1996-2009 were selected by the Ticino Cancer Registry. Cancer-specific survival (CSS) analysis was performed using the Kaplan-Meier method by calendar period: 1996-2000, 2001-2005 and 2006-2009. The log-rank test was used to detect differences in survival curves. Simultaneous assessment of prognostic factors was performed by a multivariate analysis using the Cox proportional-hazards regression model.

Results: 619 HCCs were analysed. There was a significant increase of patients undergoing transarterial chemoembolisation (TACE), whereas patients undergoing curative or palliative supportive treatments remained unchanged (p < 0.0001). No shift to earlier stages was detected. Significant differences in CCS were observed by age-group (p < 0.0001), diagnosis period (p < 0.0001), diagnosis technique (p = 0.0035), Barcelona-Clinic liver cancer stage (p < 0.0001), treatment (p < 0.0001). Multivariate analysis confirmed the independent impact on CSS of factors above mentioned, not including the diagnosis technique. Death risk was higher for patients diagnosed in 1996-2000 (HR: 1.32; 95% CI: 1.03; 1.68) and 2001-2005 (HR: 1.33; 95% CI: 1.05; 1.67) in comparison with 2006-2009 (reference group).

Conclusions: The current population-based report describes a major increase in HCC survival. Simultaneously an increased use of TACE has been detected, probable cofactor of the observed survival increase. Possibly additional efforts could be made to decrease the HCC stage at diagnosis through active surveillance of cirrhotic patients to allow an increase in curative treatments. For sure efforts should be made to comply with a standardised staging system for HCC, particularly for comparative population-based issues.
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http://dx.doi.org/10.1016/j.canep.2014.09.008DOI Listing
December 2014

Elderly age is not a negative predictive factor for virological response to therapy with pegylated interferon-α and ribavirin in chronic hepatitis C virus patients.

Liver Int 2014 Apr 29;34(4):551-7. Epub 2013 Aug 29.

Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.

Background & Aims: Age is frequently discussed as negative host factor to achieve a sustained virological response (SVR) to antiviral therapy of chronic hepatitis C. However, elderly patients often show advanced fibrosis/cirrhosis as known negative predictive factor. The aim of this study was to assess age as an independent predictive factor during antiviral therapy.

Methods: Overall, 516 hepatitis C patients were treated with pegylated interferon-α and ribavirin, thereof 66 patients ≥60 years. We analysed the impact of host factors (age, gender, fibrosis, haemoglobin, previous hepatitis C treatment) and viral factors (genotype, viral load) on SVR per therapy course by performing a generalized estimating equations (GEE) regression modelling, a matched pair analysis and a classification tree analysis.

Results: Overall, SVR per therapy course was 42.9 and 26.1%, respectively, in young and elderly patients with hepatitis C virus (HCV) genotypes 1/4/6. The corresponding figures for HCV genotypes 2/3 were 74.4 and 84%. In the GEE model, age had no significant influence on achieving SVR. In matched pair analysis, SVR was not different in young and elderly patients (54.2 and 55.9% respectively; P = 0.795 in binominal test). In classification tree analysis, age was not a relevant splitting variable.

Conclusions: Age is not a significant predictive factor for achieving SVR, when relevant confounders are taken into account. As life expectancy in Western Europe at age 60 is more than 20 years, it is reasonable to treat chronic hepatitis C in selected elderly patients with relevant fibrosis or cirrhosis but without major concomitant diseases, as SVR improves survival and reduces carcinogenesis.
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http://dx.doi.org/10.1111/liv.12279DOI Listing
April 2014
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