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Surveillance for hepatocellular carcinoma in chronic viral hepatitis:Is it time to personalize it?

World Journal of Gastroenterology 2021年第33期27卷 5536-5554页

作者： Coskun Ozer Demirtas maurizia Rossana brunetto Department of Gastroenterology and Hepatology Marmara UniversitySchool of MedicineIstanbul 34854Turkey Department of Clinical and Experimental Medicine University Hospital of PisaPisa 56125Italy Hepatology Unit University Hospital of PisaPisa 56125Italy Biostructure and Bio-imaging Institute National Research Council of ItalyNaples 56125Italy

Surveillance with abdominal ultrasound with or without alpha-fetoprotein is recommended by clinical practice guidelines for patients who are considered to be at risk of developing hepatocellular carcinoma(HCC),including those with cirrhosis,advanced fibrosis and special subgroups of chronic hepatitis B(CHB).Application of the standard surveillance strategy to all patients with chronic liver disease(CLD)with or without cirrhosis imposes major sustainability and economic burdens on healthcare ***,a number of HCC risk scores were constructed,mainly from Asian cohorts,to stratify the HCC prediction in patients with ***,even if less than for CHB,a few scoring systems were developed for chronic hepatitis C patients or cirrhotic patients with CLD of different ***,a few newsworthy HCC-risk algorithms were developed for patients with cirrhosis using the combination of serologic HCC markers and clinical ***,the HCC risk stratification appears at hand by several validated multiple score systems,but their optimal performance is obtained only in populations who show highly homogenous clinic-pathologic,epidemiologic,etiologic and therapeutic characteristics and this limitation poses a major drawback to their sustainable use in clinical practice.A better understanding of the dynamic process driving the progression from CLD to HCC derived from studies based on molecular approaches and genetics,epigenetics and liquid biopsy will enable the identification of new biomarkers to define the individual risk of HCC in the near future,with the possibility to achieve a real and cost/effective personalization of surveillance.

关键词： Hepatocellular carcinoma Surveillance Chronic viral hepatitis Risk score Risk-stratification Hepatitis B virus Hepatitis C virus

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Bio-mathematical models of viral dynamics to tailor antiviral therapy in chronic viral hepatitis

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World Journal of Gastroenterology 2009年第5期15卷 531-537页

作者： maurizia Rossana brunetto Piero Colombatto Ferruccio Bonino UO Epatologia Azienda Ospedaliero-Universitaria Pisana 56100 Pisa Italy Direzione Scientifica Fondazione IRCCS Ospedale Maggiore Policlinico Mangiagalli and Regina Elena di Milano 20122 Milano Italy

The simulation of the dynamics of viral infections by mathematical equations has been applied successfully to the study of viral infections during antiviral therapy. Standard models applied to viral hepatitis describe the viral load decline in the f irst 2-4 wk of antiviral therapy, but do not adequately simulate the dynamics of viral infection for the following period. The hypothesis of a constant clearance rate of the infected cells provides an unrealistic estimation of the time necessary to reach the control or the clearance of hepatitis B virus (HBV)/ hepatitis C virus (HCV) infection. To overcome the problem, we have developed a new multiphasic model in which the immune system activity is modulated by a negative feedback caused by the infected cells reduction, and alanine aminotransferase kinetics serve as a surrogate marker of infected-cell clearance. By this approach, we can compute the dynamics of infected cells during the whole treatment course, and find a good correlation between the number of infected cells at the end of therapy and the long-term virological response in patients with chronic hepatitis C. The new model successfully describes the HBV infection dynamics far beyond the third month of antiviral therapy under the assumption that the sum of infected and non-infected cells remains roughly constant during therapy, and both target and infected cells concur in the hepatocyte turnover. In clinical practice, these new models will allow the development of simulators of treatment response that will be used as an "automatic pilot" for tailoring antiviral therapy in chronic hepatitis B as well as chronic hepatitis C patients.

关键词： Viral hepatitis Bio-mathematical models Hepatitis B virus Hepatitis C virus Viral dynamics

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Brain-gut-liver interactions across the spectrum of insulin resistance in metabolic fatty liver disease

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World Journal of Gastroenterology 2021年第30期27卷 4999-5018页

作者： Eleni Rebelos Patricia Iozzo Maria Angela Guzzardi maurizia Rossana brunetto Ferruccio Bonino Turku PET Centre University of TurkuTurku 20500Finland Institute of Clinical Physiology National Research CouncilPisa 56124Italy Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Pisa University HospitalPisa 56121Italy Department of Clinical and Experimental Medicine University of PisaPisa 56121Italy Institute of Biostructure and Bioimaging National Research CouncilNapoli 80145Italy

Metabolic associated fatty liver disease(MAFLD),formerly named“nonalcoholic fatty liver disease”occurs in about one-third of the general population of developed countries worldwide and behaves as a major morbidity and mortality risk factor for major causes of death,such as cardio-vascular,digestive,metabolic,neoplastic and neuro-degenerative ***,progression of MAFLD and its associated systemic complications occur almost invariably in patients who experience the additional burden of intrahepatic and/or systemic inflammation,which acts as disease *** review is focused on the new knowledge about the brain-gut-liver axis in the context of metabolic dysregulations associated with fatty liver,where insulin resistance has been assumed to play an important *** emphasis has been given to digital imaging studies and in particular to positron emission tomography,as it represents a unique opportunity for the noninvasive in vivo study of tissue *** exhaustive revision of targeted animal models is also provided in order to clarify what the available preclinical evidence suggests for the causal interactions between fatty liver,dysregulated endogenous glucose production and insulin resistance.

关键词： Metabolic associated fatty liver disease Nonalcoholic fatty liver disease Endogenous glucose production Insulin resistance Steatohepatitis Inflammation

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Liver stiffness in the hepatitis B virus carrier:A non-invasive marker of liver disease influenced by the pattern of transaminases

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World Journal of Gastroenterology 2008年第40期14卷 6154-6162页

作者： Filippo Oliveri Barbara Coco Pietro Ciccorossi Piero Colombatto Veronica Romagnoli Beatrice Cherubini Ferruccio Bonino maurizia Rossana brunetto UO Epatologia Azienda Ospedaliero-Universitaria Pisana Università di Pisa Pisaand Direzione Scientifica della Fondazione IRCCS Ospedale Maggiore Policlinico

AIM： To investigate the usefulness of transient elastography by Fibroscan （FS）, a rapid non-invasive technique to evaluate liver fibrosis, in the management of chronic hepatitis B virus （HBV） carriers. METHODS： In 297 consecutive HBV carriers, we studied the correlation between liver stiffness （LS）, stage of liver disease and other factors potentially influencing FS measurements. In 87 chronic hepatitis B （CriB） patients, we monitored the FS variations according to the spontaneous or treatment-induced variations of biochemical activity during follow-up. RESULTS： FS values were 12.3 ± 3.3 kPa in acute hepatitis, 10.3 ± 8.8 kPa in chronic hepatitis, 4.3 ± 1.0 kPa in inactive carriers and 4.6 ± 1.2 kPa in blood donors. We identified the cut-offs of 7.5 and 11.8 kPa for the diagnosis of fibrosis ≥S3 and cirrhosis respectively, showing 93.9% and 86.5% sensitivity, 88.5% and 96.3% specificity, 76.7% and 86.7% positive predictive value （PPV）, 97.3% and 96.3% negative predictive value （NPV） and 90.1% and 94.2% diagnostic accuracy. At multivariate analysis in 171 untreated carriers, fibrosis stage （t = 13.187,P 〈 0.001）, active vs inactive HBV infection （t = 6.437, P 〈 0.001）, alanine aminotransferase （ALT）（t = 4.740, P 〈 0.001） and HBV-DNA levels （t = -2.046, P = 0.042） were independently associated with FS. Necroinflammation score （t = 2.158, 〉 10/18 vs ≤ 10/18, P = 0.035） and ALT levels （t = 3.566, P =0.001） were independently associated with LS in 83 untreated patients without cirrhosis and long-term biochemical remission （t = 4.662, P 〈 0.001） in 80 treated patients. During FS monitoring （mean followup 19.9 ± 7.1 mo） FS values paralleled those of ALT in patients with hepatitis exacerbation （with 1.2 to 4.4-fold increases in Crib patients） and showed a progressive decrease during antiviral therapy. CONCLUSION： FS is a non-invasive tool to monitor liver disease in chronic HBV carriers, provided that the pattern of biochemical activity is taken into account. In the inacti

关键词： Liver elastography Liver fibrosis Cirrhosis Hepatitis B virus Chronic hepatitis B

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Digital liver biopsy:Bio-imaging of fatty liver for translational and clinical research

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World Journal of Hepatology 2018年第2期10卷 231-245页

作者： Marcello Mancini Paul Summers Francesco Faita maurizia R brunetto Francesco Callea Andrea De Nicola Nicole Di Lascio Fabio Farinati Amalia Gastaldelli Bruno Gridelli Peppino Mirabelli Emanuele Neri Piero A Salvadori Eleni Rebelos Claudio Tiribelli Luca Valenti Marco Salvatore Ferruccio Bonino Institute of Biostructure and Bioimaging National Research CouncilNaples 80145Italy European Institute of Oncology(IEO)IRCCS Milan 20141Italy Institute of Clinical Physiology(IFC) National Research Council(CNR)Pisa 56124Italy Hepatology Unit Department of Clinical and Experimental MedicineUniversity Hospital of PisaPisa 56125Italy Department of Pathology Children Hospital Bambino GesùIRCCSRome 00165Italy ASL 2 Abruzzo Policlinico SS AnnunziataChieti 66100Italy Department of Gastroenterology Oncology and Surgical SciencesUniversity of PaduaPadua 35121Italy Cardio-metabolic Risk Laboratory Institute of Clinical Physiology(IFC)National Research Council(CNR)Pisa 56124Italy Institute for Health University of Pittsburgh Medical Center(UPMC)Chianciano Terme 53042Italy IRCCS SDN SpA Naples 80143Italy Diagnostic Radiology 3 Department of Translational ResearchUniversity of Pisa and“Ospedale S.Chiara”AOUPPisa 56126Italy Fondazione Italiana Fegato(FIF) Area Science ParkCampus BasovizzaTrieste 34012Italy Department of Pathophysiology and Transplantation Universitàdegli Studi di Milano and Department of Internal Medicine and Metabolic DiseasesFondazione IRCCS Ca’Granda Ospedale PoliclinicoMilan 20122Italy

The rapidly growing field of functional, molecular and structural bio-imaging is providing an extraordinary new opportunity to overcome the limits of invasive liver biopsy and introduce a "digital biopsy" for in vivo study of liver pathophysiology. To foster the application of bio-imaging in clinical and translational research, there is a need to standardize the methods of both acquisition and the storage of the bio-images of the liver. It can be hoped that the combination of digital, liquid and histologic liver biopsies will provide an innovative synergistic tri-dimensional approach to identifying new aetiologies, diagnostic and prognostic biomarkers and therapeutic targets for the optimization of personalized therapy of liver diseases and liver cancer. A group of experts of different disciplines(Special Interest Group for Personalized Hepatology of the Italian Association for the Study of the Liver, Institute for Biostructures and Bio-imaging of the National Research Council and Bio-banking and Biomolecular Resources Research Infrastructure) discussed criteria, methods and guidelines for facilitating the requisite application of data collection. This manuscript provides a multi-Author review of the issue with special focus on fatty liver.

关键词： Biobank Bio-imaging Fatty liver Genomics Liver biopsy Liver cancer Non-alcoholic fatty liver disease Non-alcoholic steatohepatitis Magnetic resonance Radiomics Ultrasound

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病毒性肝炎:乙型肝炎和丁型肝炎-临床(治疗、新化合物、耐药性) 一项在HBeAg阴性、慢性乙型肝炎(CHB)患者中比较磷丙替诺福韦(TAF)与富马酸替诺福韦二吡呋酯(TDF)的3期研究:96周时疗效和安全性结果

病毒性肝炎:乙型肝炎和丁型肝炎-临床(治疗、新化合物、耐药性) ...

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第九届全国疑难及重症肝病大会

作者： maurizia brunetto Young Suk Lim Ed Gane Wai Kay Seto Marina Osipenko Sang Hoon Ahn Harry L.Janssen Akash Shukla Wan Long Chuang Huy Trinh Mustafa K.Celen John F.Flaherty Audrey H.Lau Anuj Gaggar Vithika Suri Neeru Bhardwaj Kyungpil Kim G Mani Subramanian Calvin Pan Namiki Izumi Patrick Marcellin Henry Chan Maria Buti University Hospital of Pisa Asan Medical Centre Erasmus Medical Center

背景和目的:TAF是替诺福韦(TFV)的一种新型前体药,在血浆中比TDF更稳定,增强了TFV进入肝细胞的给药,且循环TFV水平降低。这项在HBeAg阴性患者中比较TAF与TDF的随机双盲研究显示,之前在48周时,在HBV DNA小于29IU/mL的患者比例方面,TAF的...

背景和目的:TAF是替诺福韦(TFV)的一种新型前体药,在血浆中比TDF更稳定,增强了TFV进入肝细胞的给药,且循环TFV水平降低。这项在HBeAg阴性患者中比较TAF与TDF的随机双盲研究显示,之前在48周时,在HBV DNA小于29IU/mL的患者比例方面,TAF的疗效并不劣于TDF,且骨骼和肾脏影响改善。本文摘展示了96周治疗后的结果。方法:425例患者被随机分配到接受TAF 25mg QD(n=285)或TDF 300mg QD(n=140),且治疗144

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丙酚替诺福韦(TAF)和富马酸替诺福韦二吡呋酯(TDF)治疗用于HBeAg阴性和HBeAg阳性的慢性乙型肝炎患者三年疗效和安全性对比

丙酚替诺福韦(TAF)和富马酸替诺福韦二吡呋酯(TDF)治疗用于HBeAg...

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第十届全国疑难及重症肝病大会

作者： Henry Lik Yuen Chan Young-Suk LIM Wai Kay Walter Seto Kosh Agarwal maurizia R.brunetto Harry L.A.Janssen Florin Caruntu Tatjana Stepanova Owen Tsang Hiroshi Yatsuhashi Won Young Tak Chi-Yi Chen Mustafa Celen Vithika Suri John F.Flaherty Lanjia Lin Andrea Cathcart Anuj Gaggar Cong Cheng Calvin Q.Pan Shalimar Maria Buti Institute of Digestive Disease Department of Medicine and Therapeuticsand State Key Laboratory of Digestive DiseaseThe Chinese University of Hong Kong Gastroenterology Asan Medical CenterUniversity of Ulsan College of Medicine Queen Mary Hospital Institute of Liver Studies King’s College Hospital NHS Trust Hepatology Unit University Hospital of Pisa Toronto Centre for Liver Disease University Health Network Infectious Diseases National Institute for Infectious Diseases Matei Bals Modern Medicine Clinic Princess Margaret Hospital National Hospital Organization Nagasaki Medical Center Kyungpook National University Hospital Chia-Yi Christian Hospital Gilead Sciences Inc NYU Langone Medical Center Gastroenterology All India Institute of Medical Sciences Hospital Universitari Vall d’Hebron Dicle University Hospital Infectious Diseases

背景在2项设计相同的双盲、随机(2:1)、3期研究中,第48周和第96周时,TAF的疗效不劣于TDF,而且具有良好的肾脏和骨骼安全性。方案修订后,50%的入组患者的双盲(DB)治疗期再延长1年,而其余受试者在第96周(第2年)时更换为开放标签(OL)TAF。...

背景在2项设计相同的双盲、随机(2:1)、3期研究中,第48周和第96周时,TAF的疗效不劣于TDF,而且具有良好的肾脏和骨骼安全性。方案修订后,50%的入组患者的双盲(DB)治疗期再延长1年,而其余受试者在第96周(第2年)时更换为开放标签(OL)TAF。本研究评估了3年TAF和TDF治疗在接受相应药物的患者中的安全性和疗效对比结果。

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Clinical epidemiology of chronic viral hepatitis B:A Tuscany real-world large-scale cohort study

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World Journal of Hepatology 2018年第5期10卷 409-416页

作者： Cristina Stasi Caterina Silvestri Roberto Berni maurizia Rossana brunetto Anna Linda Zignego Cristina Orsini Stefano Milani Liana Ricciardi Andrea De Luca Pierluigi Blanc Cesira Nencioni Donatella Aquilini Alessandro Bartoloni Giampaolo Bresci Santino Marchi Franco Filipponi Piero Colombatto Paolo Forte Andrea Galli Sauro Luchi Silvia Chigiotti Alessandro Nerli Giampaolo Corti Rodolfo Sacco Paola Carrai Angelo Ricchiuti Massimo Giusti Paolo Almi Andrea Cozzi Silvia Carloppi Giacomo Laffi Fabio Voller Francesco Cipriani Observatory of Epidemiology Regional Health Agency of TuscanyFlorence 50141Italy Center for Systemic Manifestations of Hepatitis Viruses(MaSVE) Internal Medicine and Liver UnitDepartment of Experimental and Clinical MedicineCareggi University HospitalFlorence 50134Italy Web Solutions Data Visualization and Scientific DocumentationRegional Health Agency of TuscanyFlorence 50141Italy Hepatology Unit Department of Clinical and Experimental MedicineUniversity Hospital of PisaPisa 56100Italy Gastroenterology Research Unit Department of Experimental and Clinical Biomedical Sciences“Mario Serio”Careggi University HospitalFlorence 50134Italy Infectious Disease Unit Hospital of LuccaLucca 55100Italy Infectious Diseases Unit Department of Medical BiotechnologiesSiena University HospitalSiena 53100Italy Infectious Disease Unit “S.Maria Annunziata”HospitalPonte a Niccheri 50012Italy Infectious Disease Unit Hospital of GrossetoGrosseto 58100Italy Infectious Disease Unit Hospital of PratoPrato 59100Italy Infectious and Tropical Diseases Unit Department of Experimental and Clinical MedicineCareggi University HospitalFlorence 50134Italy Gastroenterology and Metabolic Disorders Department of SurgeryCisanello University HospitalPisa 56100Italy Gastroenterology Unit Department of Translational Research and New Technologies in Medicine and SurgeryCisanello University Hospital of PisaPisa 56100Italy Liver Surgery and Transplantation Unit Department of Surgical PathologyMedicineMolecular and Critical AreaCisanello University HospitalPisa 56100Italy Internal Medicine Unit “San Jacopo”HospitalPistoia 51100Italy Infectious Diseases and Hepatology Unit Department of Internal and Specialized MedicineUniversity Hospital of SienaSiena 53100Italy Gastroenterology Unit San Giuseppe HospitalEmpoli 50053Italy Internal Medicine and Liver Unit Department of Experimental and Clinical MedicineCareggi University HospitalFlorence 50135Italy Department of Prevention Central Tuscany Local UnitFlorence 5

AIM To build a regional database of chronic patients to define the clinical epidemiology of hepatitis B virus(HBV)-infected patients in the Tuscan public health care *** This study used a cross-sectional cohort design. We evaluated chronic viral hepatitis patients with HBV referred to the outpatient services of 16 hospital units. Information in the case report forms included main demographic data, blood chemistry data, viral hepatitis markers, instrumental evaluations, and eligibility for treatment or ongoing therapy and liver transplantation. RESULTS Of 4015 chronic viral hepatitis patients, 1096(27.3%) were HBV infected. The case report form was correctly completed for only 833 patients(64% males, 36% females; mean age 50.1 ± 15.4). Of these HBV-infected patients, 73% were Caucasian, 21% Asian, 4% Central African, 1% North African and 1% American. Stratifying patients by age and nationality, we found that 21.7% of HBV-infected patients were aged < 34 years(only 2.8% were Italian). The most represented routes of transmission were nosocomial/dental procedures(23%), mother-to-child(17%) and sexual transmission(12%). The most represented HBV genotypes were D(72%) and A(14%). Of the patients, 24.7% of patients were HBe Ag positive, and 75.3% were HBe Ag negative. Of the HBV patients 7% were anti-HDV positive. In the whole cohort, 26.9% were cirrhotic(35.8% aged < 45 years), and 47% were eligible for or currently undergoing treatment, of whom 41.9 % were cirrhotic. CONCLUSION Only 27.3% of chronic viral hepatitis patients were HBV infected. Our results provide evidence of HBV infection in people aged < 34 years, especially in the foreign population not protected by vaccination. In our cohort of patients, liver cirrhosis was also found in young adults.

关键词： Hepatitis B virus infection Liver fibrosis Cirrhosis Public health Epidemiology

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耐拉米夫定慢性乙型肝炎的个体化抗病毒治疗（下）

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传染病网络动态 2007年第7期 20-21页

作者： maurizia Rossana brunetto 董培玲（编译）杨露绮（审校）

由于ADV的主要安全问题，在使用这个存在高度肾损害危险药物时，寻找敏感、特异的早期肾损害指标判断病情，对服用高剂量ADV患者监测肾功能是很有必要的。间接的与肾小管毒性相关的代谢和功能改变是低血钾、代谢性酸中毒、低磷血症、高... 详细信息

由于ADV的主要安全问题，在使用这个存在高度肾损害危险药物时，寻找敏感、特异的早期肾损害指标判断病情，对服用高剂量ADV患者监测肾功能是很有必要的。间接的与肾小管毒性相关的代谢和功能改变是低血钾、代谢性酸中毒、低磷血症、高尿酸血症、尿糖阳性、

关键词：慢性乙型肝炎抗病毒治疗耐拉米夫定代谢性酸中毒个体高尿酸血症安全问题损害指标

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Clinical high-risk criteria of psychosis in 8–17-year-old community subjects and inpatients not suspected of developing psychosis

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World Journal of Psychiatry 2022年第3期12卷 425-449页

作者： Frauke Schultze-Lutter Petra Walger maurizia Franscini Nina Traber-Walker Naweed Osman Helene Walger Benno G Schimmelmann Rahel Flückiger Chantal Michel Department of Psychiatry and Psychotherapy Medical FacultyHeinrich-Heine UniversityDüsseldorf 40629North-Rhine WestphaliaGermany Department of Psychology Faculty of PsychologyAirlangga UniversitySurabaya 60286Indonesia University Hospital of Child and Adolescent Psychiatry and Psychotherapy University of BernBern 3000Switzerland Department of Child and Adolescent Psychiatry and Psychotherapy University of ZürichZürich 8032Germany Department of Psychiatry and Psychotherapy Ludwig-Maximilian-UniversityMunich 80336BavariaGermany University Hospital of Child and Adolescent Psychiatry University Hospital Hamburg-EppendorfHamburg 20246Germany

BACKGROUND In children and adolescents compared to adults,clinical high-risk of psychosis(CHR)criteria and symptoms are more prevalent but less psychosis-predictive and less clinically *** on high rates of non-converters to psychosis,especially in children and adolescents,it was suggested that CHR criteria were:(1)Pluripotential;(2)A transdiagnostic risk factor;and(3)Simply a severity marker of mental disorders rather than specifically *** any of these three alternative explanatory models were true,their prevalence should differ between persons with and without mental disorders,and their severity should be associated with functional impairment as a measure of *** To compare the prevalence and severity of CHR criteria/symptoms in children and adolescents of the community and *** In the mainly cross-sectional examinations,8–17-year-old community subjects(n=233)randomly chosen from the population register of the Swiss Canton Bern,and inpatients(n=306)with primary diagnosis of attention-deficit/hyperactivity disorder(n=86),eating disorder(n=97),anxiety including obsessive–compulsive disorder(n=94),or autism spectrum disorder(n=29),not clinically suspected to develop psychosis,were examined for CHR symptoms/*** items of the Structured Interview for Psychosis-Risk Syndromes(SIPS)were used to assess the symptomatic ultra-high-risk criteria,and the Schizophrenia Proneness Instrument,Child and Youth version(SPI-CY)was used to assess the 14 basic symptoms relevant to basic symptom *** examined group differences in frequency and severity of CHR symptoms/criteria usingχ^(2) tests and nonparametric tests with Cramer’s V and Rosenthal’s r as effect sizes,and their association with functioning using correlation *** The 7.3%prevalence rate of CHR criteria in community subjects did not differ significantly from the 9.5%rate in *** and severity of CHR criteria never differed bet

关键词： Psychotic disorders Risk assessment Minors Community Inpatients Psychosocial functioning

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