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1. A quantitative MRCP-derived score for medium-term outcome prediction in primary sclerosing cholangitis

Author

Laura Cristoferi, Marco Porta, Davide Paolo Bernasconi, Filippo Leonardi, Alessio Gerussi, Giacomo Mulinacci, Andrea Palermo, Camilla Gallo, Miki Scaravaglio, Eliana Stucchi, Cesare Maino, Davide Ippolito, Daphne D'Amato, Carlos Ferreira, Alessandra Nardi, Rajarshi Banerjee, Maria Grazia Valsecchi, Laura Antolini, Rocco Corso, Sandro Sironi, Stefano Fagiuoli, Pietro Invernizzi, Marco Carbone, Cristoferi, L, Porta, M, Bernasconi, D, Leonardi, F, Gerussi, A, Mulinacci, G, Palermo, A, Gallo, C, Scaravaglio, M, Stucchi, E, Maino, C, Ippolito, D, D'Amato, D, Ferreira, C, Nardi, A, Banerjee, R, Valsecchi, M, Antolini, L, Corso, R, Sironi, S, Fagiuoli, S, Invernizzi, P, and Carbone, M

Subjects
sclerosing cholangitis, Artificial intelligence, Hepatology, Prognostic score, Gastroenterology, Primary sclerosing cholangiti, MRCP
Abstract

Background: Magnetic resonance cholangiopancreatography (MRCP) is the gold standard for diagnosis of patients with primary sclerosing cholangitis (PSC). The semi-quantitative MRCP-derived Anali scores proposed for risk stratification, have poor-to-moderate inter-reader agreement. Aims: To evaluate the prognostic performance of quantitative MRCP metrics in PSC. Methods: This is a retrospective study of PSC patients undergoing MRCP. Images were processed using MRCP+ software (Perspectum Ltd, Oxford) that provides quantitative biliary features, semi-automatically extracted by artificial intelligence-driven analysis of MRCP-3D images. The prognostic value of biliary features has been assessed for all hepato-biliary complications. Results: 87 PSC patients have been included in the analysis. Median follow-up from MRCP to event/censoring of 30.9 months (Q1-Q3=13.6–46.6). An adverse outcome occurred in 27 (31.0%) patients. The number of biliary strictures (HR=1.05 per unit, 95%CI 1.02–1.08, p < 0.0001), spleen length (HR=1.16 per cm, 95%CI 1.01–1.34, p = 0.039), adjusted for height, age at MRCP, and time from diagnosis to MRCP predicted higher risk of hepatobiliary complications. These were incorporated into a the quantitative MRCP-derived PSC (qMRCP-PSC) score (C-statistic=0.80). After 3-fold cross-validation, qMRCP-PSC outperformed the Anali score in our cohort (C-statistic of 0.78 vs 0.64) and enabled the discrimination of survival of PSC patients (log-rank p < 0.0001). Conclusions: The qMRCP-PSC score identified patients at higher risk of hepatobiliary complications and outperformed the available radiological scores. It represents a novel quantitative biomarker for disease monitoring and a potential surrogate endpoint for clinical trials.

Published
2023

2. Risk stratification in primary sclerosing cholangitis

Author

Pietro Invernizzi, Giacomo Mulinacci, Andrea Palermo, Martina Lucà, Marco Carbone, Laura Cristoferi, Alessio Gerussi, Mulinacci, G, Cristoferi, L, Palermo, A, Lucà, M, Gerussi, A, Invernizzi, P, and Carbone, M

Subjects
medicine.medical_specialty, sclerosing, business.industry, Endocrinology, Diabetes and Metabolism, Cholangiti, MEDLINE, Gastroenterology, Biomarker, medicine.disease, Primary sclerosing cholangitis, Liver disorder, Disease course, Clinical Practice, Liver disease, Risk stratification, Internal Medicine, Medicine, Diagnostic imaging, Biomarker discovery, business, Intensive care medicine
Abstract

Primary Sclerosing Cholangitis (PSC) is a chronic liver disorder commonly affecting young patients and associated with uncertain prognosis and elevated risk of end-stage liver disease and hepatobiliary cancer. Rate of progression in PSC is heterogeneous and accurately predicting the disease course is of paramount importance to clinical practice and interventional trial design. So far, efforts have brought to the development of models looking at short-to-middle-term outcome using composite models including clinical, laboratory, radiological and histological parameters with limited performance. In the era of whole genome sequencing and digital innovation, the time is ripe for the development of stratified medicine in PSC. Efforts should be directed toward developing wellphenotyped cohorts of patients with longitudinal follow-up across sustained periods of time, application of novel image-processing technology, and biomarker discovery using multi-omics platforms.

Published
2023

4. Systematic review-pancreatic involvement in inflammatory bowel disease

Author

Sara Massironi, Ilaria Fanetti, Chiara Viganò, Lorena Pirola, Maria Fichera, Laura Cristoferi, Gabriele Capurso, Pietro Invernizzi, Silvio Danese, Massironi, S, Fanetti, I, Vigano, C, Pirola, L, Fichera, M, Cristoferi, L, Capurso, G, Invernizzi, P, and Danese, S

Subjects
Hepatology, Gastroenterology, Gallstones, Inflammatory Bowel Diseases, Inflammatory bowel disease, Autoimmune Diseases, Pancreatitis, Chronic, Acute Disease, Chronic Disease, Humans, Pharmacology (medical), Colitis, Ulcerative, Exocrine Pancreatic Insufficiency, pancreas
Abstract

Background: Inflammatory bowel disease (IBD) is a chronic inflammatory immune-mediated disorder of the gut with frequent extra-intestinal complications. Pancreatic involvement in IBD is not uncommon and comprises a heterogeneous group of conditions, including acute pancreatitis (AP), chronic pancreatitis (CP), autoimmune pancreatitis (AIP) and pancreatic exocrine insufficiency (PEI); however, data on such an association remain sparse and heterogeneous. Method: PubMed/MEDLINE and EMBASE databases were searched for studies investigating pancreatic involvement in patients with IBD. Results: Four thousand one hundred and twenty-one records were identified and 547 screened; finally, 124 studies were included in the review. AP is the most frequent pancreatic manifestation in IBD; the majority of AP cases in IBD are due to gallstones and drugs but cases of idiopathic AP are increasingly reported. AIP is a rare disease, but a strong association with IBD has been demonstrated, especially for type 2 and ulcerative colitis. The pathogenetic link between IBD and AIP remains unclear, but an immune-mediated pathway seems plausible. An association between CP and PEI with IBD has also been suggested, but data are to date scarce and conflicting. Conclusion: This is the first systematic review of the association between IBD and pancreatic diseases. Gallstones and drugs should be considered the most probable causes of AP in IBD, with type 2 AIP also being possible.

Published
2022

5. LLM-PBC: Logic Learning Machine-Based Explainable Rules Accurately Stratify the Genetic Risk of Primary Biliary Cholangitis

Author

Alessio, Gerussi, Damiano, Verda, Claudio, Cappadona, Laura, Cristoferi, Davide Paolo, Bernasconi, Sandro, Bottaro, Marco, Carbone, Marco, Muselli, Pietro, Invernizzi, Rosanna, Asselta, On Behalf Of The Italian Pbc Genetics Study Group, Gerussi, A, Verda, D, Cappadona, C, Cristoferi, L, Bernasconi, D, Bottaro, S, Carbone, M, Muselli, M, Invernizzi, P, and Asselta, R

Subjects
genomic, genome-wide association study, machine learning, Hepatology, explainable artificial intelligence, precision medicine, autoimmunity, Gastroenterology, Medicine (miscellaneous), risk stratification, primary biliary cholangitis, liver, genomics, primary biliary cholangiti
Abstract

Background: The application of Machine Learning (ML) to genetic individual-level data represents a foreseeable advancement for the field, which is still in its infancy. Here, we aimed to evaluate the feasibility and accuracy of an ML-based model for disease risk prediction applied to Primary Biliary Cholangitis (PBC). Methods: Genome-wide significant variants identified in subjects of European ancestry in the recently released second international meta-analysis of GWAS in PBC were used as input data. Quality-checked, individual genomic data from two Italian cohorts were used. The ML included the following steps: import of genotype and phenotype data, genetic variant selection, supervised classification of PBC by genotype, generation of “if-then” rules for disease prediction by logic learning machine (LLM), and model validation in a different cohort. Results: The training cohort included 1345 individuals: 444 were PBC cases and 901 were healthy controls. After pre-processing, 41,899 variants entered the analysis. Several configurations of parameters related to feature selection were simulated. The best LLM model reached an Accuracy of 71.7%, a Matthews correlation coefficient of 0.29, a Youden’s value of 0.21, a Sensitivity of 0.28, a Specificity of 0.93, a Positive Predictive Value of 0.66, and a Negative Predictive Value of 0.72. Thirty-eight rules were generated. The rule with the highest covering (19.14) included the following genes: RIN3, KANSL1, TIMMDC1, TNPO3. The validation cohort included 834 individuals: 255 cases and 579 controls. By applying the ruleset derived in the training cohort, the Area under the Curve of the model was 0.73. Conclusions: This study represents the first illustration of an ML model applied to common variants associated with PBC. Our approach is computationally feasible, leverages individual-level data to generate intelligible rules, and can be used for disease prediction in at-risk individuals.

Published
2022

6. Accuracy of Transient Elastography in Assessing Fibrosis at Diagnosis in Naïve Patients With Primary Biliary Cholangitis: A Dual Cut-Off Approach

Author

Cristina Rigamonti, Rosanna Venere, Carla De Benedittis, Guido Carpino, Pietro Invernizzi, Italian Pbc Registry, Elisabetta Degasperi, Giacomo Mulinacci, Marco Carbone, Sarah Elisabeth O’Donnell, Diletta Overi, Sara Labanca, Vito Di Marco, A. Ciaccio, Vincenzo Cardinale, Mauro Viganò, Andrea Palermo, Annarosa Floreani, Daphne D’Amato, Nora Cazzagon, Vincenzo Ronca, Donatella Barisani, Laura Cristoferi, Federica Malinverno, Marco Marzioni, Domenico Alvaro, Clara Mancuso, Vincenza Calvaruso, Anna Fichera, Martina Lucà, Federica Cerini, Alessandra Nardi, Eugenio Gaudio, Antonino Picciotto, Nicola Zucchini, Monica Leutner, Alessio Gerussi, Laura Cristoferi, Vincenza Calvaruso, Diletta Overi 5 , Mauro Viganò 6 , Cristina Rigamonti 7 , Elisabetta Degasperi 8 , Vincenzo Cardinale 9 , Sara Labanca 10 , Nicola Zucchini 11 , Anna Fichera, Vito Di Marco, Monica Leutner 12 , Rosanna Venere 13 , Antonino Picciotto 10 , Martina Lucà 1 2 , Giacomo Mulinacci 1 2 , Andrea Palermo 1 2 , Alessio Gerussi 1 2 , Daphne D'Amato 1 2 , Sarah Elisabeth O'Donnell 1 2 , Federica Cerini 6 , Carla De Benedittis 7 , Federica Malinverno 1 2 , Vincenzo Ronca 1 2 , Clara Mancuso 1 2 , Nora Cazzagon 14 , Antonio Ciaccio 1 2 , Donatella Barisani 1 , Marco Marzioni 15 , Annarosa Floreani 16 17 , Domenico Alvaro 9 , Eugenio Gaudio 5 , Pietro Invernizzi 1 2 , Guido Carpino # 18 , Alessandra Nardi # 19 , Marco Carbone, Cristoferi, L, Calvaruso, V, Overi, D, Viganò, M, Rigamonti, C, Degasperi, E, Cardinale, V, Labanca, S, Zucchini, N, Fichera, A, Di Marco, V, Leutner, M, Venere, R, Picciotto, A, Lucà, M, Mulinacci, G, Palermo, A, Gerussi, A, D'Amato, D, O'Donnell, S, Cerini, F, De Benedittis, C, Malinverno, F, Ronca, V, Mancuso, C, Cazzagon, N, Ciaccio, A, Barisani, D, Marzioni, M, Floreani, A, Alvaro, D, Gaudio, E, Invernizzi, P, Carpino, G, Nardi, A, and Carbone, M

Subjects
area under curve, 0301 basic medicine, medicine.medical_specialty, liver cirrhosis, Diagnostic accuracy, risk stratification, PBC, Gastroenterology, primary biliary cholangiti, elasticity imaging techniques, female, humans, biliary, male, middle aged, ROC curve, sensitivity and specificity, Therapy naive, 03 medical and health sciences, 0302 clinical medicine, Fibrosis, Internal medicine, medicine, Hepatology, Receiver operating characteristic, medicine.diagnostic_test, Liver Cirrhosis, Biliary, business.industry, Original Articles, medicine.disease, transient elastography, Autoimmune, Cholestatic and Biliary Disease, 030104 developmental biology, Liver biopsy, Cohort, Original Article, 030211 gastroenterology & hepatology, diagnostic accuracy, Cut-off, Transient elastography, business, fibrosi
Abstract

Background & aims Liver fibrosis holds a relevant prognostic meaning in primary biliary cholangitis (PBC). Non-invasive fibrosis evaluation using vibration-controlled transient elastography (VCTE) is routinely performed. However, there is limited evidence on its accuracy at diagnosis in PBC. We aimed to estimate the diagnostic accuracy of VCTE in assessing advanced fibrosis at disease presentation in PBC. Approach & results We collected data from 167 consecutive treatment-naive PBC patients who underwent liver biopsy(LB) at diagnosis at six Italian centers. VCTE examinations were completed within 12 weeks of LB. Biopsies were scored by two blinded expert pathologists, according to Ludwig system. Diagnostic accuracy was estimated using the area under the receiver operating characteristic curves(AUROCs) for advanced fibrosis (Ludwig stage≥III). The effects of biochemical and clinical parameters on liver stiffness measurement (LSM) were appraised. Derivation cohort consisted of 126 patients with valid LSM and LB, VCTE identified patients with advanced fibrosis with AUROC of 0.89. LSM cut-offs ≤6.5kPa and >11.0kPa enabled to exclude and confirm, respectively, advanced fibrosis (negative predictive value[NPV]=0.94, positive predictive value[PPV]=0.89, error rate=5.6%). These values were externally validated in an independent cohort of 91 PBC patients(NPV=0.93, PPV=0.89, error rate=8.6%). Multivariable analysis found the only parameter affecting LSM was fibrosis stage. No association was found with BMI and liver biochemistry. Conclusions In a multicenter study of treatment-naive PBC patients, we identified two cut-offs (LSM≤6.5kPa and>11.0kPa) able to discriminate at diagnosis the presence or the absence, respectively, of advanced fibrosis in PBC patients, with external validation. In patients with LSM between these two cut-offs, VCTE is not reliable and liver biopsy should be evaluated for accurate disease staging. BMI and liver biochemistry did not affect LSMs.

Published
2021

7. Effects of immunosuppressive drugs on COVID-19 severity in patients with autoimmune hepatitis

Author

George N. Dalekos, Cristina Rigamonti, Godolfino Miranda Zazueta, Ali Rıza Calışkan, Annarosa Floreani, Berat Ebik, Kadri Atay, Aylin Demirezer Bolat, Nazım Ekin, Eric M. Yoshida, Graciela Castro Narro, Fatih Güzelbulut, Murat Biyik, Manuel Mendizabal, Renumathy Dhanasekaran, Stefano Fagiuoli, Thomas D. Schiano, Ellina Lytvyak, Shalom Frager, Nataly Chris Escajadillo Vargas, Yucel Ustundag, Ramazan Idilman, Andreea M. Catana, Alvaro Urzúa, Ahmet Yavuz, Staffan Wahlin, Mesut Aydin, Cumali Efe, Laura Cristoferi, Hatef Massoumi, Maria Vincent, Sandro Ruiz Garcia, Evrim Kahramanoğlu-Aksoy, Natalia Ratusnu, Craig Lammert, Sümeyra Yıldırım, Mário Reis Álvares-da-Silva, Murat Harputoğlu, Marina Silveira, Murat Kiyici, Fátima Higuera-de la Tijera, Nurhan Demir, Cynthia Levy, Einar Bjornsson, Javier Brahm, Rotonya M. Carr, Nidah S. Khakoo, Andres Jose Gomez Aldana, Murat Akyildiz, Leyla Nazal, Alessio Gerussi, Tuğçe Eşkazan, Zeynep Ellik, Pietro Invernizzi, Fulya Gunsar, Ezequiel Ridruejo, Eleonora De Martin, Tugrul Purnak, Fatih Eren, Hüseyin Kaçmaz, Margarita Anders, Nikolaos K. Gatselis, Romee Snijders, Sezgin Barutçu, Costica Aloman, Alexandra Heurgue-Berlot, Bianca Magro, Jonathan Aguirre, Kader Irak, Koray Tascilar, Aldo J. Montano-Loza, Marcelo Silva, David N. Assis, Joost P.H. Drenth, Eira Cerda Reyes, Ibrahim Hatemi, Mirta Peralta, Sanjaya K. Satapathy, James L. Boyer, Yasemin H. Balaban, Efe, C, Lammert, C, Tascilar, K, Dhanasekaran, R, Ebik, B, Higuera-de la Tijera, F, Caliskan, A, Peralta, M, Gerussi, A, Massoumi, H, Catana, A, Purnak, T, Rigamonti, C, Aldana, A, Khakoo, N, Nazal, L, Frager, S, Demir, N, Irak, K, Melekoglu-Ellik, Z, Kacmaz, H, Balaban, Y, Atay, K, Eren, F, Alvares-da-Silva, M, Cristoferi, L, Urzua, A, Eskazan, T, Magro, B, Snijders, R, Barutcu, S, Lytvyak, E, Zazueta, G, Demirezer-Bolat, A, Aydin, M, Heurgue-Berlot, A, De Martin, E, Ekin, N, Yildirim, S, Yavuz, A, Biyik, M, Narro, G, Kiyici, M, Akyildiz, M, Kahramanoglu-Aksoy, E, Vincent, M, Carr, R, Gunsar, F, Reyes, E, Harputluoglu, M, Aloman, C, Gatselis, N, Ustundag, Y, Brahm, J, Vargas, N, Guzelbulut, F, Garcia, S, Aguirre, J, Anders, M, Ratusnu, N, Hatemi, I, Mendizabal, M, Floreani, A, Fagiuoli, S, Silva, M, Idilman, R, Satapathy, S, Silveira, M, Drenth, J, Dalekos, G, Assis, D, Bjornsson, E, Boyer, J, Yoshida, E, Invernizzi, P, Levy, C, Montano-Loza, A, Schiano, T, Ridruejo, E, Wahlin, S, Akyıldız, Murat (ORCID 0000-0002-2080-7528 & YÖK ID 123080), Efe, Cumalı, Lammert, Craig, Taşçılar, Koray, Dhanasekaran, Renumathy, Ebik, Berat, Higuera-de la Tijera, Fatima, Çalışkan, Ali R., Peralta, Mirta, Gerussi, Alessio, Massoumi, Hatef, Catana, Andreea M., Purnak, Tuğrul, Rigamonti, Cristina, Aldana, Andres J. G., Khakoo, Nidah, Nazal, Leyla, Frager, Shalom, Demir, Nurhan, Irak, Kader, Melekoğlu-Ellik, Zeynep, Kaçmaz, Hüseyin, Balaban, Yasemin, Atay, Kadri, Eren, Fatih, Alvares-da-Silva, Mario R., Cristoferi, Laura, Urzua, Alvaro, Eskazan, Tugce, Magro, Bianca, Snijders, Romee, Barutçu, Sezgin, Lytvyak, Ellina, Zazueta, Godolfino M., Demirezer-Bolat, Aylin, Aydın, Mesut, Heurgue-Berlot, Alexandra, De Martin, Eleonora, Ekin, Nazım, Yıldırım, Sumeyra, Yavuz, Ahmet, Bıyık, Murat, Narro, Graciela C., Kıyıcı, Murat, Kahramanoğlu-Aksoy, Evrim, Vincent, Maria, Carr, Rotonya M., Günsar, Fulya, Reyes, Eira C., Harputluoğlu, Murat, Aloman, Costica, Gatselis, Nikolaos K., Üstündağ, Yücel, Brahm, Javier, Vargas, Nataly C. E., Güzelbulut, Fatih, Garcia, Sandro R., Aguirre, Jonathan, Anders, Margarita, Ratusnu, Natalia, Hatemi, İbrahim, Mendizabal, Manuel, Floreani, Annarosa, Fagiuoli, Stefano, Silva, Marcelo, İdilman, Ramazan, Satapathy, Sanjaya K., Silveira, Marina, Drenth, Joost P. H., Dalekos, George N., Assis, David N., Bjornsson, Einar, Boyer, James L., Yoshida, Eric M., Invernizzi, Pietro, Levy, Cynthia, Montano-Loza, Aldo J., Schiano, Thomas D., Ridruejo, Ezequiel, Wahlin, Staffan, and School of Medicine

Subjects
Adult, Male, medicine.medical_specialty, budesonide, Cirrhosis, Adolescent, Gastroenterology and hepatology, medicine.medical_treatment, Azathioprine, Autoimmune hepatitis, mercaptopurine, Liver transplantation, Gastroenterology, Young Adult, Sars-Cov-2 Infection, Internal medicine, medicine, Humans, Autoimmunity, Budesonide, Mercaptopurine, SARS-CoV-2, Aged, Retrospective Studies, Mechanical ventilation, Aged, 80 and over, azathioprine, liver transplantation, Hepatology, business.industry, autoimmunity, COVID-19, Immunosuppression, Odds ratio, Middle Aged, medicine.disease, Tacrolimus, Liver-Transplant Recipients, Hospitalization, Hepatitis, Autoimmune, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Pharmaceutical Preparations, Female, business, medicine.drug
Abstract

Background We investigated associations between baseline use of immunosuppressive drugs and severity of Coronavirus Disease 2019 (COVID-19) in autoimmune hepatitis (AIH). Patients and methods Data of AIH patients with laboratory confirmed COVID-19 were retrospectively collected from 15 countries. The outcomes of AIH patients who were on immunosuppression at the time of COVID-19 were compared to patients who were not on AIH medication. The clinical courses of COVID-19 were classified as (i)-no hospitalization, (ii)-hospitalization without oxygen supplementation, (iii)-hospitalization with oxygen supplementation by nasal cannula or mask, (iv)-intensive care unit (ICU) admission with non-invasive mechanical ventilation, (v)-ICU admission with invasive mechanical ventilation or (vi)-death and analysed using ordinal logistic regression. Results We included 254 AIH patients (79.5%, female) with a median age of 50 (range, 17-85) years. At the onset of COVID-19, 234 patients (92.1%) were on treatment with glucocorticoids (n = 156), thiopurines (n = 151), mycophenolate mofetil (n = 22) or tacrolimus (n = 16), alone or in combinations. Overall, 94 (37%) patients were hospitalized and 18 (7.1%) patients died. Use of systemic glucocorticoids (adjusted odds ratio [aOR] 4.73, 95% CI 1.12-25.89) and thiopurines (aOR 4.78, 95% CI 1.33-23.50) for AIH was associated with worse COVID-19 severity, after adjusting for age-sex, comorbidities and presence of cirrhosis. Baseline treatment with mycophenolate mofetil (aOR 3.56, 95% CI 0.76-20.56) and tacrolimus (aOR 4.09, 95% CI 0.69-27.00) were also associated with more severe COVID-19 courses in a smaller subset of treated patients. Conclusion Baseline treatment with systemic glucocorticoids or thiopurines prior to the onset of COVID-19 was significantly associated with COVID-19 severity in patients with AIH., Italian Ministry of University and Research (MIUR)-Department of Excellence project PREMIA (PREcision MedIcine Approach: bringing biomarker research to clinic), A. Gerussi, L. Cristoferi, and P. Invernizzi acknowledge that this research was partially supported by the Italian Ministry of University and Research (MIUR)-Department of Excellence project PREMIA (PREcision MedIcine Approach: bringing biomarker research to clinic).

Published
2021

8. Precision medicine in primary biliary cholangitis

Author

Marco Carbone, Laura Cristoferi, Alessio Gerussi, Vincenzo Ronca, Pietro Invernizzi, Ronca, V, Gerussi, A, Cristoferi, L, Carbone, M, and Invernizzi, P

Subjects
medicine.medical_specialty, precision medicine, omic, risk stratification, Chenodeoxycholic Acid, primary biliary cholangiti, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Gastrointestinal Agents, Health care, medicine, Humans, Intensive care medicine, Liver Cirrhosis, Biliary, business.industry, Gastroenterology, Obeticholic acid, Precision medicine, Omics, Clinical Practice, chemistry, 030220 oncology & carcinogenesis, Precision Medicine Initiative, Risk stratification, Disease Progression, 030211 gastroenterology & hepatology, business
Abstract

For many years the one-size-fits-all approach has been the only one available to manage patients affected by primary biliary cholangitis. The introduction of obeticholic acid in 2016 as a second-line treatment, together with the creation and validation of several biochemically based scores to stratify the risk of progressive disease, has opened up the need to redefine clinical practice by changing the actual paradigm. The precision medicine initiative is a model of patient-centered health care that aims to improve medicine based on genotypic and molecular characteristics that correlate to specific phenotypic, individual characteristics. In summary, the aim of the precision medicine is to define the right treatment for the right person at the right time. The availability of a second-line disease-modifying drug and new molecules in phase 2 or 3 trials makes this an exciting time for the precision medicine initiative in primary biliary cholangitis. In this review we describe the current risk stratification tools and we track a possible path towards the application of precision medicine in clinical daily life.

Published
2019

10. Elastography in Autoimmune Liver Diseases

Author

Marco Carbone, Laura Cristoferi, and Pietro Invernizzi

Subjects
medicine.medical_specialty, Cirrhosis, medicine.diagnostic_test, business.industry, Retrospective cohort study, Autoimmune hepatitis, medicine.disease, Gastroenterology, Primary sclerosing cholangitis, Cholestasis, Fibrosis, Internal medicine, Medicine, Elastography, business, Transient elastography
Abstract

Non-invasive assessment of fibrosis is a key step in prognostication and monitoring of patients with autoimmune liver diseases (AILDs). Vibration-controlled transient elastography (VCTE) has been the most widely used tool of fibrosis staging which showed high accuracy in identifying advanced fibrosis and cirrhosis in AILD. However, evidence about its accuracy are often based on retrospective cohort studies with small samples. Furthermore, the role of potential confounding factors (i.e. liver inflammation and cholestasis) has not been fully established yet. In this chapter, we review the evidence on the use of VCTE in AILDs focusing on strengths and limitations.

Published
2021

11. Takayasu arteritis and primary sclerosing cholangitis: A casual association or different phenotypes of the same disease?

Author

Laura Cristoferi, Andrea Palermo, Marco Carbone, Giacomo Mulinacci, Pietro Invernizzi, Mulinacci, G, Palermo, A, Cristoferi, L, Invernizzi, P, and Carbone, M

Subjects
Vasculitis, medicine.medical_specialty, Vasculiti, Short communication, Immunology, Takayasu arteritis, Disease, Gastroenterology, Inflammatory bowel disease, Disease course, Primary sclerosing cholangitis, Takayasu arteriti, Pathogenesis, Internal medicine, medicine, Immunology and Allergy, cardiovascular diseases, skin and connective tissue diseases, Bile duct, business.industry, Primary sclerosing cholangiti, RC581-607, medicine.disease, Phenotype, medicine.anatomical_structure, Etiology, Immunologic diseases. Allergy, business
Abstract

Takayasu arteritis and primary sclerosing cholangitis are two rare disorders. The pathogenesis of Takayasu arteritis involves immune-mediated mechanisms, and corticosteroids represent the mainstay for treatment. Conversely, the aetiology of primary sclerosing cholangitis remains elusive, even if dysimmunity seems to be one of the contributors to bile duct damage. Despite this, immunosuppressants do not alter disease course. In this paper we describe the association of these two rare disorders, with an unexpected normalization of cholestatic enzymes following steroid treatment. This might hint a novel subtype of sclerosing cholangitis with a prevalent immunebackground, or a local manifestation of Takayasu arteritis., Highlights • Unusual association of two rare entities: PSC (supported by the presence of IBD) and TA. • Onset of Takayasu after PSC diagnosis. • Lack of response to UDCA and fibrates. • Improvement of liver function tests after steroid treatment. • No changes on biliary tree reported on MRCP.

Published
2021

12. Outcome of COVID-19 in Patients With Autoimmune Hepatitis: An International Multicenter Study

Author

Fátima Higuera-de la Tijera, Renumathy Dhanasekaran, Mirta Peralta, C. Levy, Laura Cristoferi, Hüseyin Kaçmaz, Romee Snijders, David N. Assis, Cristina Rigamonti, Ali Rıza Calışkan, Nidah S. Khakoo, Alessio Gerussi, Alvaro Urzúa, Ezequiel Ridruejo, Yasemin H. Balaban, Craig Lammert, Ersin Batıbay, Kader Irak, Thomas D. Schiano, Marina Silveira, Fatih Eren, Berat Ebik, Kadri Atay, Andreea M. Catana, Cumali Efe, Staffan Wahlin, Murat Harputluoglu, Ibrahim Hatemi, Einar Bjornsson, Nurhan Demir, Murat Akyildiz, Manuel Mendizabal, Murat Kiyici, Costica Aloman, Rotonya M. Carr, Nazım Ekin, Ramazan Idilman, Marcelo Silva, Andres Jose Gomez Aldana, James L. Boyer, Murat Torgutalp, Tugrul Purnak, Zeynep Ellik, Leyla Nazal, Shalom Frager, Joost P.H. Drenth, Hatef Massoumi, Pietro Invernizzi, Efe, C, Dhanasekaran, R, Lammert, C, Ebik, B, Higuera-de la Tijera, F, Aloman, C, Riza Caliskan, A, Peralta, M, Gerussi, A, Massoumi, H, Catana, A, Torgutalp, M, Purnak, T, Rigamonti, C, Gomez Aldana, A, Khakoo, N, Kacmaz, H, Nazal, L, Frager, S, Demir, N, Irak, K, Ellik, Z, Balaban, Y, Atay, K, Eren, F, Cristoferi, L, Batibay, E, Urzua, A, Snijders, R, Kiyici, M, Akyildiz, M, Ekin, N, Carr, R, Harputluoglu, M, Hatemi, I, Mendizabal, M, Silva, M, Idilman, R, Silveira, M, Drenth, J, Assis, D, Bjornsson, E, Boyer, J, Invernizzi, P, Levy, C, Schiano, T, Ridruejo, E, Wahlin, S, Akyıldız, Murat, Efe, C., Dhanasekaran, R., Lammert, C., Ebi, B., Higuera-de la Tijera, F., Aloman, C., Çalışkan, A. R., Peralta, M., Gerussi, A., Massoumi, H., Catana, A. M., Torgutalp, M., Pürnak T., Rigamonti, C., Aldana, A. J. G., Khakoo, N., Kaçmaz, H., Nazal, L., Frager, S., Demir, N., Irak, K., Ellik, Z. M., Balaban, Y., Atay, K., Eren, F., Cristoferi, L., Batıbay, E., Urzua, Á., Snijders, R., Kıyıcı, M., Ekin, N., Carr, R. M., Harputoğlu, M., Hatemi, İ., Mendizabal, M., Silva, M., İdilman, R., Silveira, M., Drenth, J. P. H., Assis, D. N., Björnsson, E., Boyer, J. L., Invernizzi, P., Levy, C., Schiano, T. D., Ridruejo, E., Wahlin, S., and School of Medicine

Subjects
Adult, Male, medicine.medical_specialty, Cirrhosis, Adolescent, medicine.medical_treatment, America, Autoimmune hepatitis, Liver transplantation, liver, Gastroenterology, Young Adult, AIH, Retrospective Studie, Internal medicine, purl.org/becyt/ford/3.2 [https], medicine, Humans, Propensity Score, Determinants, Retrospective Studies, Aged, Hepatitis, Liver injury, Aged, 80 and over, Hepatology, business.industry, COVID-19, Immunosuppression, Retrospective cohort study, Middle Aged, medicine.disease, Autoimmunity, Liver failure, Mycophenolate mofetil, Steroids, Tacrolimus, Europe, Hepatitis, Autoimmune, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Cohort, Female, purl.org/becyt/ford/3 [https], Americas, Erratum, business, Rapid Communication, Human
Abstract

Background: data regarding outcome of Coronavirus disease 2019 (COVID-19) in patients with autoimmune hepatitis (AIH) are lacking. Patients and methods: we performed a retrospective study on AIH patients with COVID-19 from 34 centres in Europe and the Americas. We analyzed factors associated with severe COVID-19 outcomes defined as the need for mechanical ventilation, intensive care admission, and/or death. The outcomes of patients with AIH were compared to a propensity-score matched cohort of non-AIH patients with chronic liver diseases (CLD) and COVID-19. The frequency and clinical significance of new-onset liver injury (alanine aminotransferase>2xupper limit of normal) during COVID-19 was also evaluated. Results: we included 110 AIH patients (80%,female) with a median age of 49 (range:18-85) years at COVID-19 diagnosis. New-onset liver injury was observed in 37.1% (33/89) of the patients. Use of antivirals was associated with liver injury (p=0.041; odds ratio (OR) 3.36[1.05-10.78]) while continued immunosuppression during COVID-19 was associated with a lower rate of liver injury (p=0.009; OR 0.26[0.09-0.71]). The rates of severe COVID-19 (15.5% vs 20.2% p=0.231) and all-cause mortality (10% vs 11.5%; p=0.852) were not different between AIH and non-AIH CLD. Cirrhosis was an independent predictor of severe COVID-19 in patients with AIH (p, Italian Ministry of University; Research (MIUR)-Department of Excellence Project PREMIA; AMAF Monza ONLUS; AIRCS

Published
2021

13. Primary Sclerosing Cholangitis

Author

Pietro Invernizzi, Marco Carbone, Alessio Gerussi, Laura Cristoferi, Floreani, A, Cristoferi, L, Gerussi, A, Carbone, M, and Invernizzi, P

Subjects
medicine.medical_specialty, endocrine system diseases, Colorectal cancer, Inflammation, digestive system, Inflammatory bowel disease, Gastroenterology, Primary sclerosing cholangitis, Cholangiocarcinoma, Fibrosis, Internal medicine, Medicine, Risk stratification, business.industry, Gallbladder, digestive, oral, and skin physiology, Primary sclerosing cholangiti, medicine.disease, digestive system diseases, Gut-liver axi, medicine.anatomical_structure, Hepatocellular carcinoma, Cholestatic liver disease, medicine.symptom, business
Abstract

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive biliary inflammation and fibrosis. PSC has a strong association with inflammatory bowel disease (IBD), which is diagnosed in 60-80% of patients. The coexistence of the PSC and IBD increases the risk for colorectal cancer (CRC). Furthermore, PSC predisposes to the occurrence of other neoplastic conditions, such as cholangiocarcinoma (CCA), gallbladder, and hepatocellular carcinoma. The pathogenesis of PSC is still unclear. Current evidence supports a multifactorial etiology, where genetic predisposition, altered gut microbiota, and immune-mediated phenomena play a crucial role. The highly variable natural history of PSC, with possible intercurrent clinical events (e.g., cholangitis, biliary lithiasis) that could be dissociated from the severity of underlying liver disease with consequent fluctuant clinical symptoms and serum cholestasis marker, makes the prognostic assessment of these patients challenging. To date, no effective medical therapy has been registered, and liver transplantation is the only therapeutic option in patients developing end-stage liver disease. In this chapter, we describe epidemiological and clinical features of PSC, current understanding of its pathogenesis, and address challenges and opportunities associated with its management while focusing on risk stratification.

Published
2021

14. Real-world experience with obeticholic acid in patients with primary biliary cholangitis

Author

Anna Morgando, Mauro Viganò, Ana Lleo, Maurizio Pompili, Elisabetta De Gasperi, Daphne D’Amato, Alessandro Mussetto, Nora Cazzagon, Pietro Invernizzi, Francesca Colapietro, Vincenzo Ronca, Sara Labanca, Ester Vanni, M.R. Cannavò, Francesco Losito, Ernesto Claar, G. Scifo, Giovanni Galati, Umberto Vespasiani-Gentilucci, Silvia Storato, Alessio Gerussi, Grazia Anna Niro, Antonio Izzi, Barbara Omazzi, Antonio De Vincentis, Valentina Feletti, Giuseppe Grassi, Valeria Pace Palitti, Clara Mancuso, Vincenza Calvaruso, Evelise Frazzetto, Roberto Boldizzoni, Marco Marzioni, Floriano Rosina, Andrea Palermo, Antonino Picciotto, Valentina Bellia, Gaetano Bertino, Italian Pbc Registry, Guido Poggi, Rodolfo Sacco, Domenico Alvaro, Luigi Muratori, Maria Vinci, Marie Graciella Pigozzi, Raffaele Cozzolongo, Natalia Terreni, Annarosa Floreani, Maurizio Russello, Marco Distefano, Rinaldo Pellicano, Maria D'Antò, Marco Carbone, Rosanna Venere, R. Fontana, Antonio Picardi, Silvia Casella, S. E. O'Donnell, Federica Malinverno, Stefano Fagiuoli, Laura Cristoferi, Luchino Chessa, Giacomo Mulinacci, Pietro Pozzoni, Antonino Castellaneta, Giulia Marconi, Adriano M. Pellicelli, Francesca Romana Ponziani, Leonardo Baiocchi, D'Amato, D, De Vincentis, A, Malinverno, F, Vigano, M, Alvaro, D, Pompili, M, Picciotto, A, Palitti, V, Russello, M, Storato, S, Pigozzi, M, Calvaruso, V, De Gasperi, E, Lleo, A, Castellaneta, A, Pellicelli, A, Cazzagon, N, Floreani, A, Muratori, L, Fagiuoli, S, Niro, G, Feletti, V, Cozzolongo, R, Terreni, N, Marzioni, M, Pellicano, R, Pozzoni, P, Baiocchi, L, Chessa, L, Rosina, F, Bertino, G, Vinci, M, Morgando, A, Vanni, E, Scifo, G, Sacco, R, D'Anto, M, Bellia, V, Boldizzoni, R, Casella, S, Omazzi, B, Poggi, G, Cristoferi, L, Gerussi, A, Ronca, V, Venere, R, Ponziani, F, Cannavo, M, Mussetto, A, Fontana, R, Losito, F, Frazzetto, E, Distefano, M, Colapietro, F, Labanca, S, Marconi, G, Grassi, G, Galati, G, O'Donnell, S, Mancuso, C, Mulinacci, G, Palermo, A, Claar, E, Izzi, A, Picardi, A, Invernizzi, P, Carbone, M, Vespasiani-Gentilucci, U, D'Amato D, De Vincentis A, Malinverno F, Viganò M, Alvaro D, Pompili M, Picciotto A, Palitti VP, Russello M, Storato S, Pigozzi MG, Calvaruso V, De Gasperi E, Lleo A, Castellaneta A, Pellicelli A, Cazzagon N, Floreani A, Muratori L, Fagiuoli S, Niro GA, Feletti V, Cozzolongo R, Terreni N, Marzioni M, Pellicano R, Pozzoni P, Baiocchi L, Chessa L, Rosina F, Bertino G, Vinci M, Morgando A, Vanni E, Scifo G, Sacco R, D'Antò M, Bellia V, Boldizzoni R, Casella S, Omazzi B, Poggi G, Cristoferi L, Gerussi A, Ronca V, Venere R, Ponziani F, Cannavò M, Mussetto A, Fontana R, Losito F, Frazzetto E, Distefano M, Colapietro F, Labanca S, Marconi G, Grassi G, Galati G, O'Donnell SE, Mancuso C, Mulinacci G, Palermo A, Claar E, Izzi A, Picardi A, Invernizzi P, Carbone M, Vespasiani-Gentilucci U, and Italian PBC Registry and the Club Epatologi Ospedalieri (CLEO)/Associazione Italiana Gastroenterologi ed Endoscopisti Digestivi Ospedalieri (AIGO) PBC Study Group.

Subjects
upper limit of normal, Cirrhosis, ALT, AMA, Autoimmunity, antinuclear antibodies, ULN, PBC, Gastroenterology, UDCA, Settore MED/12, ULN, upper limit of normal, obeticholic acid, aRR, adjusted risk ratio, CRFs, case record form, AST, aspartate transferase, Clinical endpoint, GGT, gamma-glutamyl transferase, QC, primary biliary cholangitis, Ursodeoxycholic acid, ANA, TCC, Cholestasi, TIPS, Treatment Completer Cohort, ANA, antinuclear antibodie, medicine.medical_specialty, RR, UDCA, ursodeoxycholic acid, TIPS, transjugular intrahepatic portosystemic shunt, OCA, Cirrhosi, ALP, alkaline phosphatase, autoimmune hepatitis, medicine.disease, digestive system diseases, Discontinuation, Keywords: AIH, autoimmune hepatiti, QC, quality control, chemistry, gamma-glutamyl transferase, randomised controlled trial, electronic data capture, antimitochondrial antibodies, aspartate transferase, Autoimmune hepatitis, chemistry.chemical_compound, AIH, CRFs, Immunology and Allergy, adjusted risk ratio, ANA, antinuclear antibodies, RR, risk ratio, Overall cohort, ALT, alanine transferase, AMA, antimitochondrial antibodie, Cholestasis, CRFs, case record forms, Obeticholic acid, Overlap PBC-AIH, ursodeoxycholic acid, OCA, obeticholic acid, Tolerability, alkaline phosphatase, RCT, Research Article, medicine.drug, case record forms, Context (language use), AMA, antimitochondrial antibodies, Internal medicine, EDC, electronic data capture, transjugular intrahepatic portosystemic shunt, Internal Medicine, medicine, RCT, randomised controlled trial, OC, lcsh:RC799-869, quality control, alanine transferase, AST, aRR, Hepatology, business.industry, AIH, autoimmune hepatitis, TCC, Treatment Completer Cohort, PBC, primary biliary cholangiti, GGT, risk ratio, OC, Overall cohort, ALP, lcsh:Diseases of the digestive system. Gastroenterology, PBC, primary biliary cholangitis, business, EDC
Abstract

Background & aims Obeticholic acid (OCA) is the second-line treatment approved for patients with primary biliary cholangitis (PBC) and an inadequate response or intolerance to ursodeoxycholic acid. We aimed to evaluate the effectiveness and safety of OCA under real-world conditions. Methods Patients were recruited into the Italian PBC Registry, a multicentre, observational cohort study that monitors patients with PBC at national level. The primary endpoint was the biochemical response according to Poise criteria; the secondary endpoint was the biochemical response according to normal range criteria, defined as normal levels of bilirubin, alkaline phosphatase (ALP), and alanine aminotransferase (ALT) at 12 months. Safety and tolerability were also assessed. Results We analysed 191 patients until at least 12 months of follow-up. Median age was 57 years, 94% female, 61 (32%) had cirrhosis, 28 (15%) had histologically proven overlap with autoimmune hepatitis (PBC-AIH). At 12 months, significant median reductions of ALP (-32.3%), ALT (-31.4%), and bilirubin (-11.2%) were observed. Response rates were 42.9% according to Poise criteria, and 11% by normal range criteria. Patients with cirrhosis had lower response than patients without cirrhosis (29.5% vs. 49.2%, p = 0.01), owing to a higher rate of OCA discontinuation (30% vs. 12%, p = 0.004), although with similar ALP reduction (29.4% vs. 34%, p = 0.53). Overlap PBC-AIH had a similar response to pure PBC (46.4% vs. 42.3%, p = 0.68), with higher ALT reduction at 6 months (-38% vs. -29%, p = 0.04). Thirty-three patients (17%) prematurely discontinued OCA because of adverse events, of whom 11 experienced serious adverse events. Treatment-induced pruritus was the leading cause of OCA discontinuation (67%). Conclusions Effectiveness and safety of OCA under real-world conditions mirror those in the Poise trial. Patients with cirrhosis had lower tolerability. Overlap PBC-AIH showed higher ALT reduction at 6 months compared with patients with pure PBC. Lay summary Obeticholic acid (OCA) was shown to be effective in more than one-third of patients not responding to ursodeoxycholic acid in a real-world context in Italy. Patients with cirrhosis had more side effects with OCA, and this led to suspension of the drug in one-third of patients. OCA was also effective in patients who had overlap between autoimmune hepatitis and primary biliary cholangitis., Graphical abstract, Highlights • Under real-world conditions, OCA was effective in ~43% of patients who were non-responders to UDCA, according to Poise criteria. • Patients with cirrhosis showed lower efficacy (29.5%), mainly attributed to reduced tolerability and higher discontinuation rate. • Patients with overlap AIH-PBC showed a comparable efficacy to pure PBC, with a higher ALT reduction at 6 months. • Most patients with PBC are still in need of additional therapy if aiming to normalise liver biochemistry.

Published
2021

15. X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis

Author

S. Abiru, John F. Dillon, Yasuhiro Miyake, Piero Portincasa, Giancarlo Spinzi, R. Harvey, T. Ngatchu, Agostino Colli, M. Taniai, K. Flahive, Masanori Abe, B. Hoeroldt, S. Holder, Howard Curtis, María Isabel Colombo, C. MacNicol, Gang Xie, Andrew Chilton, H. Hussaini, Cristina Rigamonti, M. Kato, Shintaro Yagi, G. Abouda, D. Tyrer, Chris D. Evans, Christopher I. Amos, K. Koss, Kazuaki Chayama, P. Premchand, K. Migita, Simon Panter, Marco Marzioni, Silvia Colombo, Konstantinos N. Lazaridis, M. Yagura, Ashley Brown, D. Gocher, Domenico Alvaro, K. Murata, Mark Wright, Piero Luigi Almasio, C. Healey, A. Ciaccio, N. Wheatley, Vincenzo Cardinale, T. Delahooke, Chiara Milani, T. Shewan, W. Stableforth, S. Levi, Mark L. Green, James V. Jones, Y. Baird, Aftab Ala, Burroughs Ak, D. Williams, K. Ario, P. Sanghi, Hemant Gupta, P. Southern, L. Farrington, M. Hamilton, Andrew D. Higham, I. Yabuuchi, H. Yatsuhashi, Lorenzo Morini, T. Yamamoto, Douglas Thorburn, M. Carnahan, N. Nishida, Susan Slininger, M. Koga, K. Honda, Annarosa Floreani, Andrew Douglass, K. Netherton, M. Yasunami, Hirohito Tsubouchi, F. Donato, K. Walker, U. Shmueli, Paolo Muratori, Ray Mathew, J. Maiden, E. Dungca, Subramaniam Ramakrishnan, S. Vyas, Helen Sweeting, Subrata Saha, T. Komeda, T. Komatsu, H. J. Lee, Maria Consiglia Bragazzi, T. Komura, C. Thomas, C. Shallcross, C. Duggan, J. Kordula, F. Muscariu, Lourdes Cumlat, Imran Patanwala, Giulia Cardamone, L. Morgan, J. Brighton, Masao Honda, H. Nakamura, David Jones, Raj Srirajaskanthan, M. E. Gershwin, T. Muro, L. Stafford, N. Fukushima, Graham P. Butcher, Andrea Crosignani, George Lipscomb, K. Hirata, Y. Nagaoki, S. Mann, Paul G. Richardson, David A Elphick, M. Mupudzi, Y. Ohara, E. Grieve, Gayle Clifford, Claudio Tiribelli, M. Quinn, G. Van Duyvenvoorde, E. Archer, Tatsuki Ichikawa, J. Maltby, T. Arinaga-Hino, Simon Williams, A. King, Yasuni Nakanuma, H. Doyle, A. Brind, Nora Cazzagon, H. Ota, Daphne D’Amato, K. Hogben, H. Wooldridge, J. Wilkins, Shuichi Kaneko, L. Hankey, Gordon Wood, Andrew Fraser, K. Martin, A. Naqvi, M. Ninkovic, M. Patel, Yoshihiko Maehara, Kapil Kapur, I. Amey, Vincenza Calvaruso, Kenichi Harada, T. Yamashita, James Neuberger, N. Taylor, T. Lee, J. Featherstone, C. Lawlor, K. Seward, Satoshi Yamagiwa, Andrea Galli, L. Tan, Kentaro Kikuchi, K. Furuta, Mark A. Ainsworth, Hiromasa Ohira, Esther Unitt, Yosuke Kawai, N. Lancaster, D. Simpson, R. Shidrawi, I. Salam, A.J. Bell, Pietro Andreone, J. Ishida, Voi Shim Wong, N Fisher, Andrew C. Douds, R. Penn, Matthew Foxton, A. Watson, Andrew Mason, S. Walsh, Hiromi Ishibashi, Daniel M. Forton, Giovanni Casella, H. Takaki, K. Yamauchi, Pietro Lampertico, Osamu Yokosuka, M. Koda, M. Davies, H. Mitchison, P. Gyawali, G. Bird, M. Hughes, L. Jones, C. Hamilton, A. Hynes, R. Galaska, Fabio Marra, Debasish Das, C. Cowley, A. Fouracres, Yasuhiko Sugawara, E. Mita, T. Saoshiro, Akinobu Taketomi, Robert P. Myers, R. Przemioslo, F. Wright, L. Hobson, L. Currie, J. Allison, J. Hails, Noriyo Yamashiki, Massimo Zuin, C. Grimley, Alessio Gerussi, S. Besley, Stefano Duga, A. Piotrowicz, H. Kouno, L. Dali-kemmery, H. Sakai, M. Mizokami, Stefano Fagiuoli, Amy Davis, Pier Maria Battezzati, Masao Nagasaki, Luigi Muratori, A. Mori, S. Desmennu, S. Jones, R. Abrahams, Keith George, F. Makita, J. Brown, D. Gorard, Satoru Joshita, M. Mills, Pierluigi Toniutto, S. Campbell, J. Butterworth, S. Dyer, Filomena Morisco, Norihiro Kokudo, T. Yapp, C. Shorrock, Floriano Rosina, E. Walker, Shinji Uemoto, H. Takahashi, Simon M. Rushbrook, K. Amor, E. Marshall, J. Browning, S. Batham, Luca Fabris, Paul R. Banim, Meenakshi Narain, M. Harada, Dermot Gleeson, N. Hirashima, M. Kikuchi, T. Nikami, Gideon M. Hirschfield, Carlo Ferrari, G. Prasad, O. Chirag, Katsushi Tokunaga, M. Nasseri, Rosanna Asselta, Y. Lu, Ken Shirabe, D. Sirdefield, George F. Mells, K. Sugi, R. Ayres, G. Whatley, A. Singhal, M. Leoni, N. Sivaramakrishnan, T. Harding, Rupert Ransford, Anton V J Gunasekera, C. Mulvaney-Jones, D. Ramanaden, M. Mendall, Muhammad F. Dawwas, Dave Jones, Luca Valenti, Earl J. Williams, Markus Gess, Peter Bramley, A. McNair, E. Hashimoto, P. Townshend, C. Ford, Mario Strazzabosco, Luca Miele, Matthew J Brookes, J. Colley, Mark Wilkinson, H. Dewhurst, Charles Millson, E. Shpuza, Shinji Shimoda, T. Himoto, P. Kitchen, M. Nakamuta, Hiroaki Nishimura, Martin Lombard, Kevork M. Peltekian, M. Pitcher, G. Lim, L. Graves, C. Palmer, S. Lord, S. Katsushima, S. Tripoli, Andrew Austin, N. White, B. Grover, S. Congreave, M. Prince, Rebecca Jones, K. Hirano, A. Shepherd, Y. Mano, Michael A. Heneghan, Richard Sandford, L. O'Donohoe, Marco Carbone, S. A. Rolls, Patrick Goggin, M. L. Cowan, M. Crossey, A. Loftus, K. Young, Mesbah Rahman, Cameron N. Ghent, E. Nambela, M. Xiong, L. Grellier, Sunil Dolwani, Antonio Picciotto, Gill Watts, Alberto Mattalia, Elvezia Maria Paraboschi, J. Orpe, Takeji Umemura, Yuki Hitomi, Fiona H. Gordon, Shotaro Sakisaka, A. Dias, Chin Lye Ch'ng, M. Carter, A. Mandal, Yufang Shi, Takafumi Ichida, N. Masaki, M. Oblak, S. Nagaoka, Kevin Yoong, O. Gervais, Minoru Nakamura, Kazuhiko Nakao, S. Taylor-Robinson, L. Kent, Sushma Saksena, A. Affronti, K. Boulton, R. Ede, H. Pateman, K. Yoshizawa, G. Bray, H. Ebinuma, Yeng Ang, Akio Ido, John Ramage, Richard Sturgess, C. Gray, E. Durant, M. Hayes, A. Saeed, J. Keggans, J. Gitahi, T. Valliani, Edoardo G. Giannini, C. Foale, A. Palegwala, Lory Saveria Crocè, K. Matsushita, S. Shaukat, J. Mclindon, S. Pearson, A. Barnardo, A. Wright, Mirko Tarocchi, R Marley, M. Kent, C. Dickson, A. Gibbins, J. Whiteman, S. Singhal, Richard Aspinall, M. Ito, Laura Cristoferi, Maurizia Rossana Brunetto, J. Booth, A. Bathgate, Morikazu Onji, A. Grant, A. Paton, Y. Aiba, P. Chan, J. Sayer, S. Whalley, T. Mathialahan, J. Gotto, T. Kanda, B. Williams, K. Elliott, P. Raymode, Akinobu Takaki, V. Silvestre, I. Gee, C. Hovell, Graham R. Foster, D. Cotterill, G. Stansfield, Grazia Anna Niro, J. Conder, Yoshiyuki Ueno, A. Shah, Jane Metcalf, S. Hayashi, T. Sato, S. Jain, J. Subhani, Donatella Barisani, A. McKay, Kuniaki Arai, Jeremy Shearman, Torao Tanaka, S. Glenn, S. E. O'Donnell, Federica Malinverno, Denise O'Donnell, R. Casey, N. Sharer, J. Bowles, J. Kendall, Maria Cristina Vinci, Antonio Benedetti, George MacFaul, K. Houghton, Vincenzo Ronca, P. Desousa, B. Holbrook, F. Ali, B. Longhurst, Atsushi Tanaka, Marek Czajkowski, R. Tang, Kazuhide Yamamoto, Y. Watanabe, Graeme J.M. Alexander, R. Cloudsdale, F. Hines, M. Karmo, Brian D. Juran, I. Gooding, Y. Takeyama, J. Fraser, A. Mukhopadhya, Sumihito Tamura, Hajime Takikawa, R. Damant, E. Wilhelmsen, M. Kobayashi, J. Tregonning, V. Lambourne, D. Clement, D. Braim, M. Shimada, S. Sen, Shaun Greer, C. Innes, E. Gunter, C. Brown, H. Klass, A. Komori, Andy Li, H. Fairlamb, N. Ncube, Yoshinori Shimada, M. Harrison, S. Marriott, I. Grattagliano, Savino Bruno, A. Naganuma, Xiangjun Gu, Michael F. Seldin, S. Thornthwaite, Peter R. Mills, Katherine A. Siminovitch, X. Liu, Masataka Seike, J. Curtis, Carmela Cursaro, Z. Li, Mikio Zeniya, K. Warner, B. Bird, Jane Collier, Bridget Gunson, S. Tsuruta, E. Tanqueray, Richard Evans, H. Kamitsukasa, R. Sugimoto, Jeremy Tibble, D. Neal, S. Ducker, Francesco Azzaroli, K. Spurdle, K. Ocker, M. Senju, C. Collins, Y. Nakamura, Matthew E. Cramp, Yuji Soejima, I. Drake, K. Ueno, T. Mannami, Clara Mancuso, M. Kawashima, M. Cox, S. S. Kohn, H. Shibata, Stephen D. Ryder, Christopher Macdonald, J. Ridpath, Stephen P. Pereira, L. March, Barbara Coco, J. Morrison, A. Broad, J. Verheyden, Angelo Andriulli, N. Higuchi, J. Musselwhite, R. Bishop, Gwen Baxter, Richard A. Miller, Guido Colloredo, A. Eastick, I. Rees, Deb Ghosh, L. Winter, Sara Massironi, R. McCorry, Gianfranco Elia, T. Kobata, N. Naeshiro, K. Pollock, J. Gasem, S. Gallagher, K. Jing, S. Misra, B. Shinder, Harriet Gordon, E. Takesaki, J. Sadeghian, S. Tsunematsu, Ana Lleo, M. Aldersley, Elizabeth J. Atkinson, Pietro Invernizzi, Heather J. Cordell, Asselta, R., Paraboschi, E. M., Gerussi, A., Cordell, H. J., Mells, G. F., Sandford, R. N., Jones, D. E., Nakamura, M., Ueno, K., Hitomi, Y., Kawashima, M., Nishida, N., Tokunaga, K., Nagasaki, M., Tanaka, A., Tang, R., Li, Z., Shi, Y., Liu, X., Xiong, M., Hirschfield, G., Siminovitch, K. A., Walker, E., Xie, G., Mason, A., Myers, R., Peltekian, K., Ghent, C., Atkinson, E., Juran, B., Lazaridis, K., Lu, Y., Gu, X., Jing, K., Amos, C., Affronti, A., Brunetto, M., Coco, B., Spinzi, G., Elia, G., Ferrari, C., Lleo, A., Muratori, L., Muratori, P., Portincasa, P., Colli, A., Bruno, S., Colloredo, G., Azzaroli, F., Andreone, P., Bragazzi, M., Alvaro, D., Cardinale, V., Cazzagon, N., Rigamonti, C., Floreani, A., Rosina, F., Ciaccio, A., Cristoferi, L., D'Amato, D., Malinverno, F., Mancuso, C., Massironi, S., Milani, C., O'Donnell, S. E., Ronca, V., Barisani, D., Lampertico, P., Donato, F., Fagiuoli, S., Almasio, P. L., Giannini, E., Cursaro, C., Colombo, M., Valenti, L., Miele, L., Andriulli, A., Niro, G. A., Grattagliano, I., Morini, L., Casella, G., Vinci, M., Battezzati, P. M., Crosignani, A., Zuin, M., Mattalia, A., Calvaruso, V., Colombo, S., Benedetti, A., Marzioni, M., Galli, A., Marra, F., Tarocchi, M., Picciotto, A., Morisco, F., Fabris, L., Croce, L. S., Tiribelli, C., Toniutto, P., Strazzabosco, M., Ch'Ng, C. L., Rahman, M., Yapp, T., Sturgess, R., Healey, C., Czajkowski, M., Gunasekera, A., Gyawali, P., Premchand, P., Kapur, K., Marley, R., Foster, G., Watson, A., Dias, A., Subhani, J., Harvey, R., Mccorry, R., Ramanaden, D., Gasem, J., Evans, R., Mathialahan, T., Shorrock, C., Lipscomb, G., Southern, P., Tibble, J., Gorard, D., Palegwala, A., Jones, S., Dawwas, M., Alexander, G., Dolwani, S., Prince, M., Foxton, M., Elphick, D., Mitchison, H., Gooding, I., Karmo, M., Saksena, S., Mendall, M., Patel, M., Ede, R., Austin, A., Sayer, J., Hankey, L., Hovell, C., Fisher, N., Carter, M., Koss, K., Piotrowicz, A., Grimley, C., Neal, D., Lim, G., Levi, S., Ala, A., Broad, A., Saeed, A., Wood, G., Brown, J., Wilkinson, M., Gordon, H., Ramage, J., Ridpath, J., Ngatchu, T., Grover, B., Shaukat, S., Shidrawi, R., Abouda, G., Ali, F., Rees, I., Salam, I., Narain, M., Brown, A., Taylor-Robinson, S., Williams, S., Grellier, L., Banim, P., Das, D., Chilton, A., Heneghan, M., Curtis, H., Gess, M., Drake, I., Aldersley, M., Davies, M., Jones, R., Mcnair, A., Srirajaskanthan, R., Pitcher, M., Sen, S., Bird, G., Barnardo, A., Kitchen, P., Yoong, K., Chirag, O., Sivaramakrishnan, N., Macfaul, G., Jones, D., Shah, A., Evans, C., Saha, S., Pollock, K., Bramley, P., Mukhopadhya, A., Fraser, A., Mills, P., Shallcross, C., Campbell, S., Bathgate, A., Shepherd, A., Dillon, J., Rushbrook, S., Przemioslo, R., Macdonald, C., Metcalf, J., Shmueli, U., Davis, A., Naqvi, A., Lee, T., Ryder, S. D., Collier, J., Klass, H., Ninkovic, M., Cramp, M., Sharer, N., Aspinall, R., Goggin, P., Ghosh, D., Douds, A., Hoeroldt, B., Booth, J., Williams, E., Hussaini, H., Stableforth, W., Ayres, R., Thorburn, D., Marshall, E., Burroughs, A., Mann, S., Lombard, M., Richardson, P., Patanwala, I., Maltby, J., Brookes, M., Mathew, R., Vyas, S., Singhal, S., Gleeson, D., Misra, S., Butterworth, J., George, K., Harding, T., Douglass, A., Panter, S., Shearman, J., Bray, G., Butcher, G., Forton, D., Mclindon, J., Cowan, M., Whatley, G., Mandal, A., Gupta, H., Sanghi, P., Jain, S., Pereira, S., Prasad, G., Watts, G., Wright, M., Neuberger, J., Gordon, F., Unitt, E., Grant, A., Delahooke, T., Higham, A., Brind, A., Cox, M., Ramakrishnan, S., King, A., Collins, C., Whalley, S., Li, A., Fraser, J., Bell, A., Wong, V. S., Singhal, A., Gee, I., Ang, Y., Ransford, R., Gotto, J., Millson, C., Bowles, J., Thomas, C., Harrison, M., Galaska, R., Kendall, J., Whiteman, J., Lawlor, C., Gray, C., Elliott, K., Mulvaney-Jones, C., Hobson, L., Van Duyvenvoorde, G., Loftus, A., Seward, K., Penn, R., Maiden, J., Damant, R., Hails, J., Cloudsdale, R., Silvestre, V., Glenn, S., Dungca, E., Wheatley, N., Doyle, H., Kent, M., Hamilton, C., Braim, D., Wooldridge, H., Abrahams, R., Paton, A., Lancaster, N., Gibbins, A., Hogben, K., Desousa, P., Muscariu, F., Musselwhite, J., Mckay, A., Tan, L., Foale, C., Brighton, J., Flahive, K., Nambela, E., Townshend, P., Ford, C., Holder, S., Palmer, C., Featherstone, J., Nasseri, M., Sadeghian, J., Williams, B., Rolls, S. -A., Hynes, A., Duggan, C., Crossey, M., Stansfield, G., Macnicol, C., Wilkins, J., Wilhelmsen, E., Raymode, P., Lee, H. -J., Durant, E., Bishop, R., Ncube, N., Tripoli, S., Casey, R., Cowley, C., Miller, R., Houghton, K., Ducker, S., Wright, F., Bird, B., Baxter, G., Keggans, J., Hughes, M., Grieve, E., Young, K., Williams, D., Ocker, K., Hines, F., Martin, K., Innes, C., Valliani, T., Fairlamb, H., Thornthwaite, S., Eastick, A., Tanqueray, E., Morrison, J., Holbrook, B., Browning, J., Walker, K., Congreave, S., Verheyden, J., Slininger, S., Stafford, L., O'Donnell, D., Ainsworth, M., Lord, S., Kent, L., March, L., Dickson, C., Simpson, D., Longhurst, B., Hayes, M., Shpuza, E., White, N., Besley, S., Pearson, S., Wright, A., Jones, L., Gunter, E., Dewhurst, H., Fouracres, A., Farrington, L., Graves, L., Marriott, S., Leoni, M., Tyrer, D., Dali-kemmery, L., Lambourne, V., Green, M., Sirdefield, D., Amor, K., Colley, J., Shinder, B., Jones, J., Mills, M., Carnahan, M., Taylor, N., Boulton, K., Tregonning, J., Brown, C., Clifford, G., Archer, E., Hamilton, M., Curtis, J., Shewan, T., Walsh, S., Warner, K., Netherton, K., Mupudzi, M., Gunson, B., Gitahi, J., Gocher, D., Batham, S., Pateman, H., Desmennu, S., Conder, J., Clement, D., Gallagher, S., Orpe, J., Chan, P., Currie, L., O'Donohoe, L., Oblak, M., Morgan, L., Quinn, M., Amey, I., Baird, Y., Cotterill, D., Cumlat, L., Winter, L., Greer, S., Spurdle, K., Allison, J., Dyer, S., Sweeting, H., Kordula, J., Aiba, Y., Nakamura, H., Abiru, S., Nagaoka, S., Komori, A., Yatsuhashi, H., Ishibashi, H., Ito, M., Kawai, Y., Kohn, S. -S., Gervais, O., Migita, K., Katsushima, S., Naganuma, A., Sugi, K., Komatsu, T., Mannami, T., Matsushita, K., Yoshizawa, K., Makita, F., Nikami, T., Nishimura, H., Kouno, H., Ota, H., Komura, T., Nakamura, Y., Shimada, M., Hirashima, N., Komeda, T., Ario, K., Nakamuta, M., Yamashita, T., Furuta, K., Kikuchi, M., Naeshiro, N., Takahashi, H., Mano, Y., Tsunematsu, S., Yabuuchi, I., Shimada, Y., Yamauchi, K., Sugimoto, R., Sakai, H., Mita, E., Koda, M., Tsuruta, S., Kamitsukasa, H., Sato, T., Masaki, N., Kobata, T., Fukushima, N., Higuchi, N., Ohara, Y., Muro, T., Takesaki, E., Takaki, H., Yamamoto, T., Kato, M., Nagaoki, Y., Hayashi, S., Ishida, J., Watanabe, Y., Kobayashi, M., Koga, M., Saoshiro, T., Yagura, M., Hirata, K., Takikawa, H., Ohira, H., Zeniya, M., Abe, M., Onji, M., Kaneko, S., Honda, M., Arai, K., Arinaga-Hino, T., Hashimoto, E., Taniai, M., Umemura, T., Joshita, S., Nakao, K., Ichikawa, T., Shibata, H., Yamagiwa, S., Seike, M., Honda, K., Sakisaka, S., Takeyama, Y., Harada, M., Senju, M., Yokosuka, O., Kanda, T., Ueno, Y., Kikuchi, K., Ebinuma, H., Himoto, T., Yasunami, M., Murata, K., Mizokami, M., Shimoda, S., Miyake, Y., Takaki, A., Yamamoto, K., Hirano, K., Ichida, T., Ido, A., Tsubouchi, H., Chayama, K., Harada, K., Nakanuma, Y., Maehara, Y., Taketomi, A., Shirabe, K., Soejima, Y., Mori, A., Yagi, S., Uemoto, S., Tanaka, T., Yamashiki, N., Tamura, S., Sugawara, Y., Kokudo, N., Carbone, M., Cardamone, G., Duga, S., Gershwin, M. E., Seldin, M. F., Invernizzi, P., Asselta R., Paraboschi E.M., Gerussi A., Cordell H.J., Mells G.F., Sandford R.N., Jones D.E., Nakamura M., Ueno K., Hitomi Y., Kawashima M., Nishida N., Tokunaga K., Nagasaki M., Tanaka A., Tang R., Li Z., Shi Y., Liu X., Xiong M., Hirschfield G., Siminovitch K.A., Walker E., Xie G., Mason A., Myers R., Peltekian K., Ghent C., Atkinson E., Juran B., Lazaridis K., Lu Y., Gu X., Jing K., Amos C., Affronti A., Brunetto M., Coco B., Spinzi G., Elia G., Ferrari C., Lleo A., Muratori L., Muratori P., Portincasa P., Colli A., Bruno S., Colloredo G., Azzaroli F., Andreone P., Bragazzi M., Alvaro D., Cardinale V., Cazzagon N., Rigamonti C., Floreani A., Rosina F., Ciaccio A., Cristoferi L., D'Amato D., Malinverno F., Mancuso C., Massironi S., Milani C., O'Donnell S.E., Ronca V., Barisani D., Lampertico P., Donato F., Fagiuoli S., Almasio P.L., Giannini E., Cursaro C., Colombo M., Valenti L., Miele L., Andriulli A., Niro G.A., Grattagliano I., Morini L., Casella G., Vinci M., Battezzati P.M., Crosignani A., Zuin M., Mattalia A., Calvaruso V., Colombo S., Benedetti A., Marzioni M., Galli A., Marra F., Tarocchi M., Picciotto A., Morisco F., Fabris L., Croce L.S., Tiribelli C., Toniutto P., Strazzabosco M., Ch'ng C.L., Rahman M., Yapp T., Sturgess R., Healey C., Czajkowski M., Gunasekera A., Gyawali P., Premchand P., Kapur K., Marley R., Foster G., Watson A., Dias A., Subhani J., Harvey R., McCorry R., Ramanaden D., Gasem J., Evans R., Mathialahan T., Shorrock C., Lipscomb G., Southern P., Tibble J., Gorard D., Palegwala A., Jones S., Dawwas M., Alexander G., Dolwani S., Prince M., Foxton M., Elphick D., Mitchison H., Gooding I., Karmo M., Saksena S., Mendall M., Patel M., Ede R., Austin A., Sayer J., Hankey L., Hovell C., Fisher N., Carter M., Koss K., Piotrowicz A., Grimley C., Neal D., Lim G., Levi S., Ala A., Broad A., Saeed A., Wood G., Brown J., Wilkinson M., Gordon H., Ramage J., Ridpath J., Ngatchu T., Grover B., Shaukat S., Shidrawi R., Abouda G., Ali F., Rees I., Salam I., Narain M., Brown A., Taylor-Robinson S., Williams S., Grellier L., Banim P., Das D., Chilton A., Heneghan M., Curtis H., Gess M., Drake I., Aldersley M., Davies M., Jones R., McNair A., Srirajaskanthan R., Pitcher M., Sen S., Bird G., Barnardo A., Kitchen P., Yoong K., Chirag O., Sivaramakrishnan N., MacFaul G., Jones D., Shah A., Evans C., Saha S., Pollock K., Bramley P., Mukhopadhya A., Fraser A., Mills P., Shallcross C., Campbell S., Bathgate A., Shepherd A., Dillon J., Rushbrook S., Przemioslo R., Macdonald C., Metcalf J., Shmueli U., Davis A., Naqvi A., Lee T., Ryder S.D., Collier J., Klass H., Ninkovic M., Cramp M., Sharer N., Aspinall R., Goggin P., Ghosh D., Douds A., Hoeroldt B., Booth J., Williams E., Hussaini H., Stableforth W., Ayres R., Thorburn D., Marshall E., Burroughs A., Mann S., Lombard M., Richardson P., Patanwala I., Maltby J., Brookes M., Mathew R., Vyas S., Singhal S., Gleeson D., Misra S., Butterworth J., George K., Harding T., Douglass 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Sadeghian J., Williams B., Rolls S.-A., Hynes A., Duggan C., Crossey M., Stansfield G., MacNicol C., Wilkins J., Wilhelmsen E., Raymode P., Lee H.-J., Durant E., Bishop R., Ncube N., Tripoli S., Casey R., Cowley C., Miller R., Houghton K., Ducker S., Wright F., Bird B., Baxter G., Keggans J., Hughes M., Grieve E., Young K., Williams D., Ocker K., Hines F., Martin K., Innes C., Valliani T., Fairlamb H., Thornthwaite S., Eastick A., Tanqueray E., Morrison J., Holbrook B., Browning J., Walker K., Congreave S., Verheyden J., Slininger S., Stafford L., O'Donnell D., Ainsworth M., Lord S., Kent L., March L., Dickson C., Simpson D., Longhurst B., Hayes M., Shpuza E., White N., Besley S., Pearson S., Wright A., Jones L., Gunter E., Dewhurst H., Fouracres A., Farrington L., Graves L., Marriott S., Leoni M., Tyrer D., Dali-kemmery L., Lambourne V., Green M., Sirdefield D., Amor K., Colley J., Shinder B., Jones J., Mills M., Carnahan M., Taylor N., Boulton K., Tregonning J., Brown C., Clifford G., Archer E., Hamilton M., Curtis J., Shewan T., Walsh S., Warner K., Netherton K., Mupudzi M., Gunson B., Gitahi J., Gocher D., Batham S., Pateman H., Desmennu S., Conder J., Clement D., Gallagher S., Orpe J., Chan P., Currie L., O'Donohoe L., Oblak M., Morgan L., Quinn M., Amey I., Baird Y., Cotterill D., Cumlat L., Winter L., Greer S., Spurdle K., Allison J., Dyer S., Sweeting H., Kordula J., Aiba Y., Nakamura H., Abiru S., Nagaoka S., Komori A., Yatsuhashi H., Ishibashi H., Ito M., Kawai Y., Kohn S.-S., Gervais O., Migita K., Katsushima S., Naganuma A., Sugi K., Komatsu T., Mannami T., Matsushita K., Yoshizawa K., Makita F., Nikami T., Nishimura H., Kouno H., Ota H., Komura T., Nakamura Y., Shimada M., Hirashima N., Komeda T., Ario K., Nakamuta M., Yamashita T., Furuta K., Kikuchi M., Naeshiro N., Takahashi H., Mano Y., Tsunematsu S., Yabuuchi I., Shimada Y., Yamauchi K., Sugimoto R., Sakai H., Mita E., Koda M., Tsuruta S., Kamitsukasa H., Sato T., Masaki N., Kobata T., Fukushima N., Higuchi N., Ohara Y., Muro T., Takesaki E., Takaki H., Yamamoto T., Kato M., Nagaoki Y., Hayashi S., Ishida J., Watanabe Y., Kobayashi M., Koga M., Saoshiro T., Yagura M., Hirata K., Takikawa H., Ohira H., Zeniya M., Abe M., Onji M., Kaneko S., Honda M., Arai K., Arinaga-Hino T., Hashimoto E., Taniai M., Umemura T., Joshita S., Nakao K., Ichikawa T., Shibata H., Yamagiwa S., Seike M., Honda K., Sakisaka S., Takeyama Y., Harada M., Senju M., Yokosuka O., Kanda T., Ueno Y., Kikuchi K., Ebinuma H., Himoto T., Yasunami M., Murata K., Mizokami M., Shimoda S., Miyake Y., Takaki A., Yamamoto K., Hirano K., Ichida T., Ido A., Tsubouchi H., Chayama K., Harada K., Nakanuma Y., Maehara Y., Taketomi A., Shirabe K., Soejima Y., Mori A., Yagi S., Uemoto S., Tanaka T., Yamashiki N., Tamura S., Sugawara Y., Kokudo N., Carbone M., Cardamone G., Duga S., Gershwin M.E., Seldin M.F., Invernizzi P., Asselta, R, Paraboschi, E, Gerussi, A, Cordell, H, Mells, G, Sandford, R, Jones, D, Nakamura, M, Ueno, K, Hitomi, Y, Kawashima, M, Nishida, N, Tokunaga, K, Nagasaki, M, Tanaka, A, Tang, R, Li, Z, Shi, Y, Liu, X, Xiong, M, Hirschfield, G, Siminovitch, K, Walker, E, Xie, G, Mason, A, Myers, R, Peltekian, K, Ghent, C, Atkinson, E, Juran, B, Lazaridis, K, Lu, Y, Gu, X, Jing, K, Amos, C, Affronti, A, Brunetto, M, Coco, B, Spinzi, G, Elia, G, Ferrari, C, Lleo, A, Muratori, L, Muratori, P, Portincasa, P, Colli, A, Bruno, S, Colloredo, G, Azzaroli, F, Andreone, P, Bragazzi, M, Alvaro, D, Cardinale, V, Cazzagon, N, Rigamonti, C, Floreani, A, Rosina, F, Ciaccio, A, Cristoferi, L, D'Amato, D, Malinverno, F, Mancuso, C, Massironi, S, Milani, C, O'Donnell, S, Ronca, V, Barisani, D, Lampertico, P, Donato, F, Fagiuoli, S, Almasio, P, Giannini, E, Cursaro, C, Colombo, M, Valenti, L, Miele, L, Andriulli, A, Niro, G, Grattagliano, I, Morini, L, Casella, G, Vinci, M, Battezzati, P, Crosignani, A, Zuin, M, Mattalia, A, Calvaruso, V, Colombo, S, Benedetti, A, Marzioni, M, Galli, A, Marra, F, Tarocchi, M, Picciotto, A, Morisco, F, Fabris, L, Croce, L, Tiribelli, C, Toniutto, P, Strazzabosco, M, Ch'Ng, C, Rahman, M, Yapp, T, Sturgess, R, Healey, C, Czajkowski, M, Gunasekera, A, Gyawali, P, Premchand, P, Kapur, K, Marley, R, Foster, G, Watson, A, Dias, A, Subhani, J, Harvey, R, Mccorry, R, Ramanaden, D, Gasem, J, Evans, R, Mathialahan, T, Shorrock, C, Lipscomb, G, Southern, P, Tibble, J, Gorard, D, Palegwala, A, Jones, S, Dawwas, M, Alexander, G, Dolwani, S, Prince, M, Foxton, M, Elphick, D, Mitchison, H, Gooding, I, Karmo, M, Saksena, S, Mendall, M, Patel, M, Ede, R, Austin, A, Sayer, J, Hankey, L, Hovell, C, Fisher, N, Carter, M, Koss, K, Piotrowicz, A, Grimley, C, Neal, D, Lim, G, Levi, S, Ala, A, Broad, A, Saeed, A, Wood, G, Brown, J, Wilkinson, M, Gordon, H, Ramage, J, Ridpath, J, Ngatchu, T, Grover, B, Shaukat, S, Shidrawi, R, Abouda, G, Ali, F, Rees, I, Salam, I, Narain, M, Brown, A, Taylor-Robinson, S, Williams, S, Grellier, L, Banim, P, Das, D, Chilton, A, Heneghan, M, Curtis, H, Gess, M, Drake, I, Aldersley, M, Davies, M, Jones, R, Mcnair, A, Srirajaskanthan, R, Pitcher, M, Sen, S, Bird, G, Barnardo, A, Kitchen, P, Yoong, K, Chirag, O, Sivaramakrishnan, N, Macfaul, G, Shah, A, Evans, C, Saha, S, Pollock, K, Bramley, P, Mukhopadhya, A, Fraser, A, Mills, P, Shallcross, C, Campbell, S, Bathgate, A, Shepherd, A, Dillon, J, Rushbrook, S, Przemioslo, R, Macdonald, C, Metcalf, J, Shmueli, U, Davis, A, Naqvi, A, Lee, T, Ryder, S, Collier, J, Klass, H, Ninkovic, M, Cramp, M, Sharer, N, Aspinall, R, Goggin, P, Ghosh, D, Douds, A, Hoeroldt, B, Booth, J, Williams, E, Hussaini, H, Stableforth, W, Ayres, R, Thorburn, D, Marshall, E, Burroughs, A, Mann, S, Lombard, M, Richardson, P, Patanwala, I, Maltby, J, Brookes, M, Mathew, R, Vyas, S, Singhal, S, Gleeson, D, Misra, S, Butterworth, J, George, K, Harding, T, Douglass, A, Panter, S, Shearman, J, Bray, G, Butcher, G, Forton, D, Mclindon, J, Cowan, M, Whatley, G, Mandal, A, Gupta, H, Sanghi, P, Jain, S, Pereira, S, Prasad, G, Watts, G, Wright, M, Neuberger, J, Gordon, F, Unitt, E, Grant, A, Delahooke, T, Higham, A, Brind, A, Cox, M, Ramakrishnan, S, King, A, Collins, C, Whalley, S, Li, A, Fraser, J, Bell, A, Wong, V, Singhal, A, Gee, I, Ang, Y, Ransford, R, Gotto, J, Millson, C, Bowles, J, Thomas, C, Harrison, M, Galaska, R, Kendall, J, Whiteman, J, Lawlor, C, Gray, C, Elliott, K, Mulvaney-Jones, C, Hobson, L, Van Duyvenvoorde, G, Loftus, A, Seward, K, Penn, R, Maiden, J, Damant, R, Hails, J, Cloudsdale, R, Silvestre, V, Glenn, S, Dungca, E, Wheatley, N, Doyle, H, Kent, M, Hamilton, C, Braim, D, Wooldridge, H, Abrahams, R, Paton, A, Lancaster, N, Gibbins, A, Hogben, K, Desousa, P, Muscariu, F, Musselwhite, J, Mckay, A, Tan, L, Foale, C, Brighton, J, Flahive, K, Nambela, E, Townshend, P, Ford, C, Holder, S, Palmer, C, Featherstone, J, Nasseri, M, Sadeghian, J, Williams, B, Rolls, S, Hynes, A, Duggan, C, Crossey, M, Stansfield, G, Macnicol, C, Wilkins, J, Wilhelmsen, E, Raymode, P, Lee, H, Durant, E, Bishop, R, Ncube, N, Tripoli, S, Casey, R, Cowley, C, Miller, R, Houghton, K, Ducker, S, Wright, F, Bird, B, Baxter, G, Keggans, J, Hughes, M, Grieve, E, Young, K, Williams, D, Ocker, K, Hines, F, Martin, K, Innes, C, Valliani, T, Fairlamb, H, Thornthwaite, S, Eastick, A, Tanqueray, E, Morrison, J, Holbrook, B, Browning, J, Walker, K, Congreave, S, Verheyden, J, Slininger, S, Stafford, L, O'Donnell, D, Ainsworth, M, Lord, S, Kent, L, March, L, Dickson, C, Simpson, D, Longhurst, B, Hayes, M, Shpuza, E, White, N, Besley, S, Pearson, S, Wright, A, Jones, L, Gunter, E, Dewhurst, H, Fouracres, A, Farrington, L, Graves, L, Marriott, S, Leoni, M, Tyrer, D, Dali-kemmery, L, Lambourne, V, Green, M, Sirdefield, D, Amor, K, Colley, J, Shinder, B, Jones, J, Mills, M, Carnahan, M, Taylor, N, Boulton, K, Tregonning, J, Brown, C, Clifford, G, Archer, E, Hamilton, M, Curtis, J, Shewan, T, Walsh, S, Warner, K, Netherton, K, Mupudzi, M, Gunson, B, Gitahi, J, Gocher, D, Batham, S, Pateman, H, Desmennu, S, Conder, J, Clement, D, Gallagher, S, Orpe, J, Chan, P, Currie, L, O'Donohoe, L, Oblak, M, Morgan, L, Quinn, M, Amey, I, Baird, Y, Cotterill, D, Cumlat, L, Winter, L, Greer, S, Spurdle, K, Allison, J, Dyer, S, Sweeting, H, Kordula, J, Aiba, Y, Nakamura, H, Abiru, S, Nagaoka, S, Komori, A, Yatsuhashi, H, Ishibashi, H, Ito, M, Kawai, Y, Kohn, S, Gervais, O, Migita, K, Katsushima, S, Naganuma, A, Sugi, K, Komatsu, T, Mannami, T, Matsushita, K, Yoshizawa, K, Makita, F, Nikami, T, Nishimura, H, Kouno, H, Ota, H, Komura, T, Nakamura, Y, Shimada, M, Hirashima, N, Komeda, T, Ario, K, Nakamuta, M, Yamashita, T, Furuta, K, Kikuchi, M, Naeshiro, N, Takahashi, H, Mano, Y, Tsunematsu, S, Yabuuchi, I, Shimada, Y, Yamauchi, K, Sugimoto, R, Sakai, H, Mita, E, Koda, M, Tsuruta, S, Kamitsukasa, H, Sato, T, Masaki, N, Kobata, T, Fukushima, N, Higuchi, N, Ohara, Y, Muro, T, Takesaki, E, Takaki, H, Yamamoto, T, Kato, M, Nagaoki, Y, Hayashi, S, Ishida, J, Watanabe, Y, Kobayashi, M, Koga, M, Saoshiro, T, Yagura, M, Hirata, K, Takikawa, H, Ohira, H, Zeniya, M, Abe, M, Onji, M, Kaneko, S, Honda, M, Arai, K, Arinaga-Hino, T, Hashimoto, E, Taniai, M, Umemura, T, Joshita, S, Nakao, K, Ichikawa, T, Shibata, H, Yamagiwa, S, Seike, M, Honda, K, Sakisaka, S, Takeyama, Y, Harada, M, Senju, M, Yokosuka, O, Kanda, T, Ueno, Y, Kikuchi, K, Ebinuma, H, Himoto, T, Yasunami, M, Murata, K, Mizokami, M, Shimoda, S, Miyake, Y, Takaki, A, Yamamoto, K, Hirano, K, Ichida, T, Ido, A, Tsubouchi, H, Chayama, K, Harada, K, Nakanuma, Y, Maehara, Y, Taketomi, A, Shirabe, K, Soejima, Y, Mori, A, Yagi, S, Uemoto, S, Tanaka, T, Yamashiki, N, Tamura, S, Sugawara, Y, Kokudo, N, Carbone, M, Cardamone, G, Duga, S, Gershwin, M, Seldin, M, Invernizzi, P, Asselta R, Paraboschi EM, Gerussi A, Cordell HJ, Mells GF, Sandford RN, Jones DE, Nakamura M, Ueno K, Hitomi Y, Kawashima M, Nishida N, Tokunaga K, Nagasaki M, Tanaka A, Tang R, Li Z, Shi Y, Liu X, Xiong M, Hirschfield G, Siminovitch KA, Canadian-US PBC Consortium, Italian PBC Genetics Study Group, UK-PBC Consortium, Japan PBC-GWAS Consortium, Carbone M, Cardamone G, Duga S, Gershwin ME, Seldin MF, Invernizzi P, and LiveR North

Subjects
Canadian-US PBC Consortium, 0301 basic medicine, Male, Linkage disequilibrium, Genome-wide association study, Disease, PBC, Settore MED/03 - GENETICA MEDICA, Linkage Disequilibrium, 0302 clinical medicine, UK-PBC Consortium, Genotype, Mitochondrial Precursor Protein Import Complex Proteins, Italian PBC Genetics Study Group, Odds Ratio, X-Wide Association Study, Japan PBC-GWAS Consortium, X chromosome, Genetics, Liver Cirrhosis, Biliary, Gastroenterology, Forkhead Transcription Factors, DNA-Binding Proteins, Shal Potassium Channels, 030211 gastroenterology & hepatology, Female, Adult, Monosaccharide Transport Proteins, Superenhancer, Locus (genetics), Single-nucleotide polymorphism, Biology, Protein Serine-Threonine Kinases, Polymorphism, Single Nucleotide, Article, White People, 03 medical and health sciences, Asian People, Proto-Oncogene Proteins, Endopeptidases, Humans, Cell Lineage, Genetic Predisposition to Disease, Meta-analysi, Genetic association, Chromosomes, Human, X, Gastroenterology & Hepatology, Hepatology, 1103 Clinical Sciences, Meta-analysis, 030104 developmental biology, Genetic Loci, 1114 Paediatrics and Reproductive Medicine, 1109 Neurosciences, Carrier Proteins, Genome-Wide Association Study
Abstract

Background & aims: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. Methods: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). Results: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10-4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10-6; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028-1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09-1.26; P = 9.93 × 10-8), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10-9; OR, 1.33; 95% CI, 1.21-1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively). Conclusions: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.

Published
2021

16. EP1211: RADIOMICS-BASED MODEL FOR OUTCOME PREDICTION IN PRIMARY SCLEROSING CHOLANGITIS

Author

Laura Cristoferi, Marco Porta, Davide Paolo Bernasconi, Filippo Leonardi, Giacomo Mulinacci, Andrea Palermo, Alessio Gerussi, Camilla Gallo, Miki Scaravaglio, Eliana Stucchi, Cesare Maino, Davide Ippolito, Daphne D'Amato, Carlos Ferreira, Marija Mavar, Rajarshi Banerjee, Laura Antolini, Maria Grazia Valsecchi, Stefano Fagiuoli, Pietro Invernizzi, and Marco Carbone

Subjects
Hepatology, Gastroenterology
Published
2022

17. Additive beneficial effects of Fibrates combined with Obeticholic acid in the treatment of patients with Primary Biliary Cholangitis and inadequate response to second-line therapy: data from the Italian PBC Study Group

Author

G. Marconi, Clara Mancuso, Chiara Milani, Nora Cazzagon, A. Floreani, Laura Cristoferi, Alessio Gerussi, Marco Marzioni, S. E. O'Donnell, Federica Malinverno, Marco Carbone, Pietro Invernizzi, Daphne D’Amato, D'Amato, D, O'Donnell, S, Cazzagon, N, Marconi, G, Gerussi, A, Cristoferi, L, Malinverno, F, Mancuso, C, Milani, C, Marzioni, M, Floreani, A, Invernizzi, P, and Carbone, M

Subjects
medicine.medical_specialty, Second-line therapy, Hepatology, business.industry, Obeticholic Acid, Gastroenterology, Obeticholic acid, chemistry.chemical_compound, chemistry, Internal medicine, Medicine, Primary Biliary Cholangiti, Fibrate, New Therapy, business, Beneficial effects
Published
2020

18. Primary biliary cholangitis: a multifaceted pathogenesis with potential therapeutic targets

Author

Chiara Milani, Vincenzo Ronca, Marco Carbone, Laura Cristoferi, Pietro Invernizzi, Alessio Gerussi, Carbone, M, Milani, C, Gerussi, A, Ronca, V, Cristoferi, L, and Invernizzi, P

Subjects
medicine.medical_specialty, Primary (chemistry), Hepatology, Biliary cirrhosi, business.industry, Biliary cirrhosis, Biliary fibrosis, Autoimmunity, PBC, medicine.disease, medicine.disease_cause, Gastroenterology, Pathogenesis, Cholestasis, Cholestasi, Internal medicine, Biliary fibrosi, medicine, business
Published
2020

19. COVID-19 in Patients With Inflammatory Bowel Disease: A Single-center Observational Study in Northern Italy

Author

Maria Fichera, Laura Cristoferi, Alessandro Redaelli, Pietro Invernizzi, Chiara Viganò, Lorena Pirola, Sara Massironi, Marco Dinelli, Martina Mauri, Marianna Bravo, Vigano, C, Massironi, S, Pirola, L, Cristoferi, L, Fichera, M, Bravo, M, Mauri, M, Redaelli, A, Dinelli, M, and Invernizzi, P

Subjects
Male, Crohn’s disease, Clinical Laboratory Technique, Single Center, Inflammatory bowel disease, ulcerative coliti, Immunosuppressive Agent, COVID-19 Testing, Risk Factors, Prevalence, Immunology and Allergy, Medicine, Letter to the Editor, Crohn's disease, Gastroenterology, Middle Aged, Ulcerative colitis, Italy, Female, Risk Adjustment, Symptom Assessment, Coronavirus Infections, Immunosuppressive Agents, Human, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Pneumonia, Viral, Betacoronavirus, inflammatory bowel disease, Internal medicine, Humans, In patient, Pandemics, AcademicSubjects/MED00260, Ibdjnl/1, ulcerative colitis, Betacoronaviru, Pandemic, Coronavirus Infection, Clinical Laboratory Techniques, SARS-CoV-2, business.industry, Risk Factor, COVID-19, Inflammatory Bowel Diseases, medicine.disease, Northern italy, Observational study, Contact Tracing, business
Published
2020

20. FRI-011-Ductular reaction, intermediate hepatocites and fibrosis extension correlate with prediction of treatment failure to ursodeoxycholic acid in primary biliary cholangitis

Author

George F. Mells, Eugenio Gaudio, Massimiliano Cadamuro, Nicola Zucchini, Diletta Overi, Giulia Bonato, Domenico Alvaro, Vincenzo Cardinale, Alessandra Nardi, Mauro Viganò, Alessio Gerussi, Marco Carbone, Monica Leutner, Laura Cristoferi, David Jones, Guido Carpino, Pietro Invernizzi, Vincenzo Ronca, Cristina Rigamonti, Cristoferi, L, Carpino, G, Cardinale, V, Rigamonti, C, Overi, D, Zucchini, N, Leutner, M, Viganò, M, Nardi, A, Gerussi, A, Ronca, V, Cadamuro, M, Bonato, G, Alvaro, D, Gaudio, E, Jones, D, Invernizzi, P, Mells, G, and Carbone, M

Subjects
ductular reaction, medicine.medical_specialty, Primary (chemistry), Hepatology, business.industry, primary biliary cholangitis, Reaction intermediate, medicine.disease, Gastroenterology, Treatment failure, Ursodeoxycholic acid, Fibrosis, Internal medicine, medicine, business, medicine.drug
Published
2019

21. Prevalence of upper gastrointestinal endoscopic findings in the community: A systematic review of studies in unselected samples of subjects

Author

Franco Bazzoli, Stefano Rabitti, Leonardo Henry Eusebi, Nico Pagano, Laura Cristoferi, Rocco Maurizio Zagari, and Amanda Vestito

Subjects
medicine.medical_specialty, Prevalence, Gastroenterology, Asymptomatic, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Epidemiology, medicine, Esophagus, Stomach cancer, Hepatology, biology, business.industry, Stomach, Helicobacter pylori, medicine.disease, biology.organism_classification, digestive system diseases, medicine.anatomical_structure, 030220 oncology & carcinogenesis, 030211 gastroenterology & hepatology, medicine.symptom, business, Esophagitis
Abstract

Background and Aim Upper gastrointestinal endoscopic findings, such as esophagitis, Barrett's esophagus, peptic ulcer, and malignancy, represent a public health problem. This systematic review aimed to evaluate the prevalence of upper gastrointestinal endoscopic findings in the community. Methods A systematic search was conducted in PUBMED and EMBASE to May 2015. Studies were eligible if they reported the prevalence of upper gastrointestinal endoscopic findings in unselected samples of the community. Results Twelve articles were eligible, nine reported data from three endoscopic surveys (n = 3063 subjects), and three from national screening programs (n = 84 153). The overall prevalence of upper gastrointestinal endoscopic findings in the community was 30% in the Kalixanda study (Sweden), 24.9% in the Loiano–Monghidoro study (Italy), and 68.9% in the Systematic Investigation of Gastrointestinal Diseases study (China). The pooled prevalence of esophagitis, endoscopically suspected esophageal metaplasia (ESEM), peptic ulcer, and gastric cancer in all studies was 11.2, 5.1, 6.8, and 0.33%, respectively. The most frequent finding was esophagitis in Europe, with a prevalence of 15.5% in Sweden and 11.8% in Italy, and peptic ulcer in China (17.1%), both in asymptomatic and symptomatic individuals. The prevalence of Helicobacter pylori was positively associated with the prevalence of peptic ulcer (r = 0.91) but negatively associated with the prevalence of both esophagitis (r = −0.99) and ESEM (r = −0.95). Conclusions Upper gastrointestinal endoscopic findings are present in at least a quarter of subjects in the community with different patterns in Western and Eastern countries, both in asymptomatic and symptomatic subjects. H. pylori prevalence negatively impacts on the prevalence of reflux-related esophageal findings.

Published
2016

23. A Smooth Esophageal Stricture Causing Dysphagia

Author

Alberto Tringali, Valentina Caputo, Francesco Pugliese, Valentina Motta, Giulia Bonato, Marcello Cintolo, Laura Cristoferi, Lorenzo Dioscoridi, Massimiliano Mutignani, Massimo Torre, Serena Conforti, Edoardo Forti, Forti, E, Bonato, G, Dioscoridi, L, Cintolo, M, Pugliese, F, Cristoferi, L, Tringali, A, Caputo, V, Motta, V, Torre, M, Conforti, S, and Mutignani, M

Subjects
medicine.medical_specialty, Esophageal Neoplasms, Biopsy, Fine-Needle, Esophageal Stenosi, Metastasi, Metastasis, Endosonography, 03 medical and health sciences, Speech and Hearing, 0302 clinical medicine, Internal medicine, medicine, Humans, Deglutition Disorder, Lung cancer, Esophageal Neoplasm, Esophageal stricture, Fine-needle aspiration, Lung, medicine.diagnostic_test, business.industry, Gastroenterology, Hepatology, Middle Aged, medicine.disease, Dysphagia, Endoultrasonography, medicine.anatomical_structure, Otorhinolaryngology, 030220 oncology & carcinogenesis, Esophageal Stenosis, 030211 gastroenterology & hepatology, Female, Radiology, medicine.symptom, business, Deglutition Disorders, Human
Abstract

Dysphagia in patients with lung cancer is usually due to direct invasion from bronchogenic carcinomas or nodal localizations, while metastases from distant lung neoplasms are considered rare. We report a case of a smooth esophageal narrowing secondary to intramural metastasis from pulmonary adenocarcinoma in a patient with no previous history of neoplasia. Since standard linear echoendoscope could not overpass the malignant stricture, we obtained a histological diagnosis by fine-needle aspiration biopsy using an echobronchoscope (EBUS), due to its lower diameter. The EBUS scope represents a valuable tool to obtain cytological specimens in patients with esophageal strictures.

Published
2018

24. Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score

Author

Marco Carbone, Alessandra Nardi, Steve Flack, Guido Carpino, Nikoletta Varvaropoulou, Caius Gavrila, Ann Spicer, Jonathan Badrock, Francesca Bernuzzi, Vincenzo Cardinale, Holly F Ainsworth, Michael A Heneghan, Douglas Thorburn, Andrew Bathgate, Rebecca Jones, James M Neuberger, Pier Maria Battezzati, Massimo Zuin, Simon Taylor-Robinson, Maria F Donato, John Kirby, Robert Mitchell-Thain, Annarosa Floreani, Fotios Sampaziotis, Luigi Muratori, Domenico Alvaro, Marco Marzioni, Luca Miele, Fabio Marra, Edoardo Giannini, Eugenio Gaudio, Vincenzo Ronca, Giulia Bonato, Laura Cristoferi, Federica Malinverno, Alessio Gerussi, Deborah D Stocken, Heather J Cordell, Gideon M Hirschfield, Graeme J Alexander, Richard N Sandford, David E Jones, Pietro Invernizzi, George F Mells, Caradog Thomas, Meshbah Rahman, Tom Yapp, Chin Lye Ch'ng, Melanie Harrison, Richard Sturgess, Roman Galaska, Chris Healey, Jessica Whiteman, Marek Czaijkowski, Catherine Gray, Anton Gunasekera, Pranab Gyawli, Purushothaman Premchand, Steven Mann, Keith Elliott, Kapil Kapur, Alan Watson, Graham Foster, Paul Trembling, Javaid Subhani, Rory Harvey, Roger McCorry, Carolyn Adgey, Lucie Hobson, Caroline Mulvaney-Jones, Richard Evans, Thiriloganathan Mathialahan, David Ramanaden, Jaber Gasem, Greta Van Duyvenvoorde, Christopher Shorrock, Katie Seward, Paul Southern, Jeremy Tibble, Ruth Penn, David Gorard, Jane Maiden, Rose Damant, Altaf Palegwala, Susan Jones, Graeme Alexander, George Mells, Richard Sandford, Sunil Dolwani, Martin Prince, Valeria Silvestre, Matthew Foxton, Eleanor Dungca, Harriet Mitchison, Natalie Wheatley, Ian Gooding, Helen Doyle, Mazn Karmo, Melanie Kent, Sushma Saksena, Delyth Braim, Minesh Patel, Susan Lord, Roland Ede, Alison Paton, Andrew Austin, Nicola Lancaster, Joanna Sayer, Andrew Gibbins, Karen Hogben, Chris Hovell, Neil Fisher, Martyn Carter, Konrad Koss, Janine Musselwhite, Florin Muscariu, Andrzej Piotreowicz, Alexandra McKay, Charles Grimley, David Neal, Lai Ting Tan, Guan Lim, Jacqueline Brighton, Carole Foale, Aftab Ala, Athar Saeed, Kerry Flahive, Gordon Wood, Paula Townshend, Chris Ford, Jonathan Brown, Jean Kordula, Jane Bowles, Mark Wilkinson, Caroline Palmer, John Ramage, Harriet Gordon, James Featherstone, Jo Ridpath, Theodore Ngatchu, Sass Levi, Syed Shaukat, Joy Sadeghian, Ray Shidrawi, Bronwen Williams, George Abouda, Sarah Jones, Claire Duggan, Abigail Hynes, Mark Narain, Ian Rees, Imroz Salam, Mary Crossey, Ashley Brown, Carolyn MacNicol, Simon Williams, Elva Wilhelmsen, Paul Banim, Parizade Raymode, Andrew Chilton, Debasish Das, Hye-Jeong Lee, Howard Curtis, Michael Heneghan, Markus Gess, Emma Durant, IM Drake, Rebecca Bishop, Mervyn Davies, Mark Aldersley, Noma Ncube, Alistair McNair, Raj Srirajaskanthan, Sambit Sen, Rebecca Casey, George Bird, Mike Mendall, Caroline Cowley, Adrian Barnardo, Paul Kitchen, Kevin Yoong, Kelly Amore, Dawn Sirdefield, Jacky Orpe, Ray Mathew, George MacFaul, Aruna Wrigth, Amir Shah, Chris Evans, Janie Keggans, Bridget Bird, Gwen Baxter, Subrata Saha, Katharine Pollock, Maggie Hughes, Peter Bramley, Emma Grieve, Karin Young, Andrew Fraser, Ashis Mukhopadhya, Kate Ocker, Peter Mills, Francis Hines, Chris Shallcross, Joy Wilkins, Leonie Grellier, Stewart Campbell, Kirsty Martin, Caron Innes, Alan Shepherd, Simon Rushbrook, Talal Valliani, Robert Przemioslo, Helen Fairlamb, Chris Macdonald, Anne Eastick, Jane Metcalf, Elizabeth Tanqueray, Udi Shmueli, Becky Holbrook, Andrew Davis, Julie Browning, Asifabbas Naqvi, Kirsten Walker, Tom Lee, Juliette Verheyden, Susan Slininger, Stephen D Ryder, Roger Chapman, Jane Collier, Denise O'Donnell, Lizzie Stafford, Kate Williamson, Linda Kent, Howard Klass, Mary Ninkovic, Linda March, Matthew Cramp, Diane Simpson, Christine Dickson, Nicholas Sharer, Maria Hayes, Patrick Goggin, Mary Quinne, Sallyanne Pearson, Barbara Hoeroldt, Linda Jones, Alice Wright, Jonathan Booth, Alison Loftus, George Lipscomb, Hannah Dewhurst, Emma Gunter, Earl Williams, Anna Fouracres, Liz Farrington, Lyn Graves, Hyder Hussaini, Bill Stableforth, Suzie Marriott, Reuben Ayres, Marina Leoni, Andrew Burroughs, Eileen Marshall, David Tyrer, Kate Martin, Martin Lombard, Imran Patanwala, Lola Dali-Kemmery, Victoria Lambourne, Julia Maltby, Samir Vyas, Julie Colley, Bal Shinder, Saket Singhal, Jayne Jones, Marisa Mills, Dermot Gleeson, Mandy Carnahan, Jeff Butterworth, Kerenza Boulton, Natalie Taylor, Keith George, Tim Harding, Julie Tregonning, Andrew Douglass, Carly Brown, Gayle Clifford, Simon Panter, Denise Gocher, Jeremy Shearman, Gary Bray, Maria Hamilton, Graham Butcher, Daniel Forton, John Mclindon, Janette Curtis, Debashis Das, Tracey Shewan, Matthew Cowan, Gregory Whatley, Mariam Nasseri, Bob Grover, Nurani Sivaramakrishnan, Samantha Ducker, Kathryn Houghton, David Jones, Laura Griffiths, Sherill Tripoli, Maxton Pitcher, Ervin Shpuza, Nikki White, Deb Ghosh, Andrew Douds, Marie Green, Matthew Brookes, Lourdes Cumlat, Voi Shim Wong, Karen Warner, Kimberley Netherton, Adtya Mandal, Snjiv Jain, Hemant Gupta, Pradeep Sanghi, Steve Pereira, James Neuberger, Bridget Gunson, Gideon Hirschfield, Reina Teegan Lim, Susan Gallagher, Darren Clement, Alison Brind, Gill Watts, Mcdonald Mupudzi, Mark Wright, Jane Gitahi, Fiona Gordon, Denis Gocher, Esther Unitt, Hilary Pateman, Sally Batham, Toby Delahooke, Allister Grant, Jill Conder, Andrew Higham, Mark Cox, Lynn O'Donohoe, Lynn Currie, Alistair King, Metod Oblak, Carole Collins, Simon Whalley, Marie Quinn, Yolanda Baird, Isobel Amey, Jocelyn Fraser, Andy Li, Donna Cotterill, Andrew Bell, Amit Singhal, Ian Gee, Sandra Greer, Yeng Ang, Rupert Ransford, Joanna Allison, James Gotto, Simon Dyer, Helen Sweeting, Charles Millson, Giancarlo Labbadia, Maria Consiglia Bragazzi, Pietro Andreone, Francesco Azzaroli, Andrea Galli, Mirko Tarocchi, Antonio Gasbarrini, Antonio Grieco, Giuseppe Marrone, Maria Francesca Donato, Luca Valenti, Luca Maroni, Cristina Rigamonti, Antonino Picciotto, Carbone, M, Nardi, A, Flack, S, Carpino, G, Varvaropoulou, N, Gavrila, C, Spicer, A, Badrock, J, Bernuzzi, F, Cardinale, V, Ainsworth, H, Heneghan, M, Thorburn, D, Bathgate, A, Jones, R, Neuberger, J, Battezzati, P, Zuin, M, Taylor-Robinson, S, Donato, M, Kirby, J, Mitchell-Thain, R, Floreani, A, Sampaziotis, F, Muratori, L, Alvaro, D, Marzioni, M, Miele, L, Marra, F, Giannini, E, Gaudio, E, Ronca, V, Bonato, G, Cristoferi, L, Malinverno, F, Gerussi, A, Stocken, D, Cordell, H, Hirschfield, G, Alexander, G, Sandford, R, Jones, D, Invernizzi, P, Mells, G, Thomas, C, Rahman, M, Yapp, T, Lye Ch'ng, C, Harrison, M, Sturgess, R, Galaska, R, Healey, C, Whiteman, J, Czaijkowski, M, Gray, C, Gunasekera, A, Gyawli, P, Premchand, P, Mann, S, Elliott, K, Kapur, K, Watson, A, Foster, G, Trembling, P, Subhani, J, Harvey, R, Mccorry, R, Adgey, C, Hobson, L, Mulvaney-Jones, C, Evans, R, Mathialahan, T, Ramanaden, D, Gasem, J, Van Duyvenvoorde, G, Shorrock, C, Seward, K, Southern, P, Tibble, J, Penn, R, Gorard, D, Maiden, J, Damant, R, Palegwala, A, Jones, S, Dolwani, S, Prince, M, Silvestre, V, Foxton, M, Dungca, E, Mitchison, H, Wheatley, N, Gooding, I, Doyle, H, Karmo, M, Kent, M, Saksena, S, Braim, D, Patel, M, Lord, S, Ede, R, Paton, A, Austin, A, Lancaster, N, Sayer, J, Gibbins, A, Hogben, K, Hovell, C, Fisher, N, Carter, M, Koss, K, Musselwhite, J, Muscariu, F, Piotreowicz, A, Mckay, A, Grimley, C, Neal, D, Ting Tan, L, Lim, G, Brighton, J, Foale, C, Ala, A, Saeed, A, Flahive, K, Wood, G, Townshend, P, Ford, C, Brown, J, Kordula, J, Bowles, J, Wilkinson, M, Palmer, C, Ramage, J, Gordon, H, Featherstone, J, Ridpath, J, Ngatchu, T, Levi, S, Shaukat, S, Sadeghian, J, Shidrawi, R, Williams, B, Abouda, G, Duggan, C, Hynes, A, Narain, M, Rees, I, Salam, I, Crossey, M, Brown, A, Macnicol, C, Williams, S, Wilhelmsen, E, Banim, P, Raymode, P, Chilton, A, Das, D, Lee, H, Curtis, H, Gess, M, Durant, E, Drake, I, Bishop, R, Davies, M, Aldersley, M, Ncube, N, Mcnair, A, Srirajaskanthan, R, Sen, S, Casey, R, Bird, G, Mendall, M, Cowley, C, Barnardo, A, Kitchen, P, Yoong, K, Amore, K, Sirdefield, D, Orpe, J, Mathew, R, Macfaul, G, Wrigth, A, Shah, A, Evans, C, Keggans, J, Bird, B, Baxter, G, Saha, S, Pollock, K, Hughes, M, Bramley, P, Grieve, E, Young, K, Fraser, A, Mukhopadhya, A, Ocker, K, Mills, P, Hines, F, Shallcross, C, Wilkins, J, Grellier, L, Campbell, S, Martin, K, Innes, C, Shepherd, A, Rushbrook, S, Valliani, T, Przemioslo, R, Fairlamb, H, Macdonald, C, Eastick, A, Metcalf, J, Tanqueray, E, Shmueli, U, Holbrook, B, Davis, A, Browning, J, Naqvi, A, Walker, K, Lee, T, Verheyden, J, Slininger, S, Ryder, S, Chapman, R, Collier, J, O'Donnell, D, Stafford, L, Williamson, K, Kent, L, Klass, H, Ninkovic, M, March, L, Cramp, M, Simpson, D, Dickson, C, Sharer, N, Hayes, M, Goggin, P, Quinne, M, Pearson, S, Hoeroldt, B, Jones, L, Wright, A, Booth, J, Loftus, A, Lipscomb, G, Dewhurst, H, Gunter, E, Williams, E, Fouracres, A, Farrington, L, Graves, L, Hussaini, H, Stableforth, B, Marriott, S, Ayres, R, Leoni, M, Burroughs, A, Marshall, E, Tyrer, D, Lombard, M, Patanwala, I, Dali-Kemmery, L, Lambourne, V, Maltby, J, Vyas, S, Colley, J, Shinder, B, Singhal, S, Jones, J, Mills, M, Gleeson, D, Carnahan, M, Butterworth, J, Boulton, K, Taylor, N, George, K, Harding, T, Tregonning, J, Douglass, A, Brown, C, Clifford, G, Panter, S, Gocher, D, Shearman, J, Bray, G, Hamilton, M, Butcher, G, Forton, D, Mclindon, J, Curtis, J, Shewan, T, Cowan, M, Whatley, G, Nasseri, M, Grover, B, Sivaramakrishnan, N, Ducker, S, Houghton, K, Griffiths, L, Tripoli, S, Pitcher, M, Shpuza, E, White, N, Ghosh, D, Douds, A, Green, M, Brookes, M, Cumlat, L, Wong, V, Warner, K, Netherton, K, Mandal, A, Jain, S, Gupta, H, Sanghi, P, Pereira, S, Gunson, B, Lim, R, Gallagher, S, Clement, D, Brind, A, Watts, G, Mupudzi, M, Wright, M, Gitahi, J, Gordon, F, Unitt, E, Pateman, H, Batham, S, Delahooke, T, Grant, A, Conder, J, Higham, A, Cox, M, O'Donohoe, L, Currie, L, King, A, Oblak, M, Collins, C, Whalley, S, Quinn, M, Baird, Y, Amey, I, Fraser, J, Li, A, Cotterill, D, Bell, A, Singhal, A, Gee, I, Greer, S, Ang, Y, Ransford, R, Allison, J, Gotto, J, Dyer, S, Sweeting, H, Millson, C, Labbadia, G, Bragazzi, M, Andreone, P, Azzaroli, F, Galli, A, Tarocchi, M, Gasbarrini, A, Grieco, A, Marrone, G, Valenti, L, Maroni, L, Rigamonti, C, Picciotto, A, Sampaziotis, Fotios [0000-0003-0812-7586], Sandford, Richard [0000-0002-7437-0560], Apollo - University of Cambridge Repository, Carbone, Marco, Nardi, Alessandra, Flack, Steve, Carpino, Guido, Varvaropoulou, Nikoletta, Gavrila, Caiu, Spicer, Ann, Badrock, Jonathan, Bernuzzi, Francesca, Cardinale, Vincenzo, Ainsworth, Holly F, Heneghan, Michael A, Thorburn, Dougla, Bathgate, Andrew, Jones, Rebecca, Neuberger, James M, Battezzati, Pier Maria, Zuin, Massimo, Taylor-Robinson, Simon, Donato, Maria F, Kirby, John, Mitchell-Thain, Robert, Floreani, Annarosa, Sampaziotis, Fotio, Muratori, Luigi, Alvaro, Domenico, Marzioni, Marco, Miele, Luca, Marra, Fabio, Giannini, Edoardo, Gaudio, Eugenio, Ronca, Vincenzo, Bonato, Giulia, Cristoferi, Laura, Malinverno, Federica, Gerussi, Alessio, Stocken, Deborah D, Cordell, Heather J, Hirschfield, Gideon M, Alexander, Graeme J, Sandford, Richard N, Jones, David E, Invernizzi, Pietro, Mells, George F, Thomas, Caradog, Rahman, Meshbah, Yapp, Tom, Lye Ch'ng, Chin, Harrison, Melanie, Sturgess, Richard, Galaska, Roman, Healey, Chri, Whiteman, Jessica, Czaijkowski, Marek, Gray, Catherine, Gunasekera, Anton, Gyawli, Pranab, Premchand, Purushothaman, Mann, Steven, Elliott, Keith, Kapur, Kapil, Watson, Alan, Foster, Graham, Trembling, Paul, Subhani, Javaid, Harvey, Rory, McCorry, Roger, Adgey, Carolyn, Hobson, Lucie, Mulvaney-Jones, Caroline, Evans, Richard, Mathialahan, Thiriloganathan, Ramanaden, David, Gasem, Jaber, Van Duyvenvoorde, Greta, Shorrock, Christopher, Seward, Katie, Southern, Paul, Tibble, Jeremy, Penn, Ruth, Gorard, David, Maiden, Jane, Damant, Rose, Palegwala, Altaf, Jones, Susan, Alexander, Graeme, Mells, George, Sandford, Richard, Dolwani, Sunil, Prince, Martin, Silvestre, Valeria, Foxton, Matthew, Dungca, Eleanor, Mitchison, Harriet, Wheatley, Natalie, Gooding, Ian, Doyle, Helen, Karmo, Mazn, Kent, Melanie, Saksena, Sushma, Braim, Delyth, Patel, Minesh, Lord, Susan, Ede, Roland, Paton, Alison, Austin, Andrew, Lancaster, Nicola, Sayer, Joanna, Gibbins, Andrew, Hogben, Karen, Hovell, Chri, Fisher, Neil, Carter, Martyn, Koss, Konrad, Musselwhite, Janine, Muscariu, Florin, Piotreowicz, Andrzej, McKay, Alexandra, Grimley, Charle, Neal, David, Ting Tan, Lai, Lim, Guan, Brighton, Jacqueline, Foale, Carole, Ala, Aftab, Saeed, Athar, Flahive, Kerry, Wood, Gordon, Townshend, Paula, Ford, Chri, Brown, Jonathan, Kordula, Jean, Bowles, Jane, Wilkinson, Mark, Palmer, Caroline, Ramage, John, Gordon, Harriet, Featherstone, Jame, Ridpath, Jo, Ngatchu, Theodore, Levi, Sa, Shaukat, Syed, Sadeghian, Joy, Shidrawi, Ray, Williams, Bronwen, Abouda, George, Jones, Sarah, Duggan, Claire, Hynes, Abigail, Narain, Mark, Rees, Ian, Salam, Imroz, Crossey, Mary, Brown, Ashley, MacNicol, Carolyn, Williams, Simon, Wilhelmsen, Elva, Banim, Paul, Raymode, Parizade, Chilton, Andrew, Das, Debasish, Lee, Hye-Jeong, Curtis, Howard, Heneghan, Michael, Gess, Marku, Durant, Emma, Drake, I.M., Bishop, Rebecca, Davies, Mervyn, Aldersley, Mark, Ncube, Noma, McNair, Alistair, Srirajaskanthan, Raj, Sen, Sambit, Casey, Rebecca, Bird, George, Mendall, Mike, Cowley, Caroline, Barnardo, Adrian, Kitchen, Paul, Yoong, Kevin, Amore, Kelly, Sirdefield, Dawn, Orpe, Jacky, Mathew, Ray, MacFaul, George, Wrigth, Aruna, Shah, Amir, Evans, Chri, Keggans, Janie, Bird, Bridget, Baxter, Gwen, Saha, Subrata, Pollock, Katharine, Hughes, Maggie, Bramley, Peter, Grieve, Emma, Young, Karin, Fraser, Andrew, Mukhopadhya, Ashi, Ocker, Kate, Mills, Peter, Hines, Franci, Shallcross, Chri, Wilkins, Joy, Grellier, Leonie, Campbell, Stewart, Martin, Kirsty, Innes, Caron, Shepherd, Alan, Rushbrook, Simon, Valliani, Talal, Przemioslo, Robert, Fairlamb, Helen, Macdonald, Chri, Eastick, Anne, Metcalf, Jane, Tanqueray, Elizabeth, Shmueli, Udi, Holbrook, Becky, Davis, Andrew, Browning, Julie, Naqvi, Asifabba, Walker, Kirsten, Lee, Tom, Verheyden, Juliette, Slininger, Susan, Ryder, Stephen D, Chapman, Roger, Collier, Jane, O'Donnell, Denise, Stafford, Lizzie, Williamson, Kate, Kent, Linda, Klass, Howard, Ninkovic, Mary, March, Linda, Cramp, Matthew, Simpson, Diane, Dickson, Christine, Sharer, Nichola, Hayes, Maria, Goggin, Patrick, Quinne, Mary, Pearson, Sallyanne, Hoeroldt, Barbara, Jones, Linda, Wright, Alice, Booth, Jonathan, Loftus, Alison, Lipscomb, George, Dewhurst, Hannah, Gunter, Emma, Williams, Earl, Fouracres, Anna, Farrington, Liz, Graves, Lyn, Hussaini, Hyder, Stableforth, Bill, Marriott, Suzie, Ayres, Reuben, Leoni, Marina, Burroughs, Andrew, Marshall, Eileen, Tyrer, David, Martin, Kate, Lombard, Martin, Patanwala, Imran, Dali-Kemmery, Lola, Lambourne, Victoria, Maltby, Julia, Vyas, Samir, Colley, Julie, Shinder, Bal, Singhal, Saket, Jones, Jayne, Mills, Marisa, Gleeson, Dermot, Carnahan, Mandy, Butterworth, Jeff, Boulton, Kerenza, Taylor, Natalie, George, Keith, Harding, Tim, Tregonning, Julie, Douglass, Andrew, Brown, Carly, Clifford, Gayle, Panter, Simon, Gocher, Denise, Shearman, Jeremy, Bray, Gary, Hamilton, Maria, Butcher, Graham, Forton, Daniel, Mclindon, John, Curtis, Janette, Das, Debashi, Shewan, Tracey, Cowan, Matthew, Whatley, Gregory, Nasseri, Mariam, Grover, Bob, Sivaramakrishnan, Nurani, Ducker, Samantha, Houghton, Kathryn, Jones, David, Griffiths, Laura, Tripoli, Sherill, Pitcher, Maxton, Shpuza, Ervin, White, Nikki, Ghosh, Deb, Douds, Andrew, Green, Marie, Brookes, Matthew, Cumlat, Lourde, Wong, Voi Shim, Warner, Karen, Netherton, Kimberley, Mandal, Adtya, Jain, Snjiv, Gupta, Hemant, Sanghi, Pradeep, Pereira, Steve, Neuberger, Jame, Gunson, Bridget, Hirschfield, Gideon, Lim, Reina Teegan, Gallagher, Susan, Clement, Darren, Brind, Alison, Watts, Gill, Mupudzi, Mcdonald, Wright, Mark, Gitahi, Jane, Gordon, Fiona, Gocher, Deni, Unitt, Esther, Pateman, Hilary, Batham, Sally, Delahooke, Toby, Grant, Allister, Conder, Jill, Higham, Andrew, Cox, Mark, O'Donohoe, Lynn, Currie, Lynn, King, Alistair, Oblak, Metod, Collins, Carole, Whalley, Simon, Quinn, Marie, Baird, Yolanda, Amey, Isobel, Fraser, Jocelyn, Li, Andy, Cotterill, Donna, Bell, Andrew, Singhal, Amit, Gee, Ian, Greer, Sandra, Ang, Yeng, Ransford, Rupert, Allison, Joanna, Gotto, Jame, Dyer, Simon, Sweeting, Helen, Millson, Charle, Labbadia, Giancarlo, Bragazzi, Maria Consiglia, Andreone, Pietro, Azzaroli, Francesco, Galli, Andrea, Tarocchi, Mirko, Gasbarrini, Antonio, Grieco, Antonio, Marrone, Giuseppe, Donato, Maria Francesca, Valenti, Luca, Maroni, Luca, Rigamonti, Cristina, Picciotto, Antonino, and Medical Research Council (MRC)

Subjects
Male, Cholagogues and Choleretics, Cirrhosis, medicine.medical_treatment, PROGRESSION, Liver transplantation, PHENOTYPE, Gastroenterology, UDCA, 0302 clinical medicine, Primary biliary cirrhosis, Risk Factors, Medicine, Age of Onset, CIRRHOSIS, TREE, OUTCOMES, Settore MED/12 - Gastroenterologia, medicine.diagnostic_test, Liver Cirrhosis, Biliary, Ursodeoxycholic Acid, Area under the curve, URSODIOL, Middle Aged, Ursodeoxycholic acid, Treatment Outcome, Primary biliary cholangitis, ursodeoxycholic acid, 030220 oncology & carcinogenesis, Liver biopsy, Area Under Curve, 030211 gastroenterology & hepatology, Female, Life Sciences & Biomedicine, medicine.drug, medicine.medical_specialty, CONTROLLED-TRIAL, Hepatology, Decision Support Techniques, Time-to-Treatment, Biliary injury, 03 medical and health sciences, Internal medicine, Humans, Transaminases, Science & Technology, Gastroenterology & Hepatology, Italian PBC Study Group and the UK–PBC Consortium, business.industry, Bilirubin, medicine.disease, Alkaline Phosphatase, ROC Curve, CELLS, Linear Models, business
Abstract

Background: Treatment guidelines recommend a stepwise approach to primary biliary cholangitis: all patients begin treatment with ursodeoxycholic acid (UDCA) monotherapy and those with an inadequate biochemical response after 12 months are subsequently considered for second-line therapies. However, as a result, patients at the highest risk can wait the longest for effective treatment. We determined whether UDCA response can be accurately predicted using pretreatment clinical parameters. Methods: We did logistic regression analysis of pretreatment variables in a discovery cohort of patients in the UK with primary biliary cholangitis to derive the best-fitting model of UDCA response, defined as alkaline phosphatase less than 1·67 times the upper limit of normal (ULN), measured after 12 months of treatment with UDCA. We validated the model in an external cohort of patients with primary biliary cholangitis and treated with UDCA in Italy. Additionally, we assessed correlations between model predictions and key histological features, such as biliary injury and fibrosis, on liver biopsy samples. Findings: 2703 participants diagnosed with primary biliary cholangitis between Jan 1, 1998, and May 31, 2015, were included in the UK-PBC cohort for derivation of the model. The following pretreatment parameters were associated with lower probability of UDCA response: higher alkaline phosphatase concentration (p

Published
2018

25. Malignancies in Primary Sclerosing Cholangitis - A Continuing Threat

Author

Giulia Bonato, Mario Strazzabosco, Luca Fabris, Laura Cristoferi, Bonato, G, Cristoferi, L, Strazzabosco, M, and Fabris, L

Subjects
Oncology, medicine.medical_specialty, endocrine system diseases, Colorectal cancer, Cholangitis, Sclerosing, Colorectal Neoplasm, liver, digestive system, Inflammatory bowel disease, Gastroenterology, Article, Primary sclerosing cholangitis, Cholangiocarcinoma, Liver disease, Neoplasms, Internal medicine, medicine, Humans, Neoplastic transformation, Bile Duct Neoplasm, Gallbladder Neoplasm, Primary Sclerosing Cholangiti, Primary Sclerosing Cholangiti, liver, cholangiocarcinoma, hepatocarcinoma, Cancer prevention, business.industry, Inflammatory Bowel Disease, digestive, oral, and skin physiology, Cancer, General Medicine, Inflammatory Bowel Diseases, medicine.disease, Ulcerative colitis, digestive system diseases, Bile Duct Neoplasms, hepatocarcinoma, Gallbladder Neoplasms, Colorectal Neoplasms, business, Human
Abstract

Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease of unknown etiology, primarily targeting cholangiocytes at any portion of the biliary tree. No effective medical treatments are currently available. A unique feature of PSC is its close association (about 80%) with inflammatory bowel disease (IBD), mainly ulcerative colitis (UC). As in many chronic inflammatory conditions, cancer development can complicate PSC, accounting for >40% of deaths. Cholangiocarcinoma (CCA), gallbladder carcinoma (GBC) and colorectal carcinoma (CRC) have been variably associated to PSC, with a prevalence up to 13-14%. The risk of cancer is one of the most challenging issues in the management of PSC; it raises several questions about cancer surveillance, early diagnosis, prevention and treatment. Key Messages: Among the different cancers complicating PSC, CCA is the most relevant, because it is more frequent (incidence of 0.5-1.5%) and because the prognosis is poor (5-year survival Conclusions: PSC may be regarded as paradigmatic of the sequence leading from chronic inflammatory epithelial damage to neoplastic transformation. Understanding the molecular mechanisms regulating this pathogenetic sequence, may improve strategies of disease surveillance and cancer prevention and treatment. PSC is a chronic inflammatory cholangiopathy of unknown etiology but likely immune-mediated, characterized by peribiliary inflammation and fibrosis leading to strictures in any portion (intra- and/or extrahepatic) of the bile duct system. No effective medical treatments are currently available. A unique feature of PSC is the close association (about 80%) with IBD, mainly UC, often diagnosed before PSC (PSC/UC). As in other chronic inflammatory diseases, development of malignancies is a feared complication of PSC.

Published
2015

26. P.08.3 MULTIPLE PLASTIC STENT (MPS) VERSUS FCSEMS FOR MANAGING POST LIVER TRANSPLANTATION BILIARY STRICTURE: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CONTROLLED TRIAL

Author

M. Mutignani, Marcello Cintolo, A. Tringali, Giulia Bonato, Laura Cristoferi, Edoardo Forti, Lorenzo Dioscoridi, and Francesco Pugliese

Subjects
medicine.medical_specialty, Hepatology, business.industry, medicine.medical_treatment, Gastroenterology, Liver transplantation, law.invention, Surgery, Randomized controlled trial, law, Meta-analysis, medicine, Plastic stent, business
Published
2018

27. Pre-treatment risk stratification in primary biliary cholangitis: A predictive model to guide first-line combination therapy

Author

Simon D. Taylor-Robinson, Luigi Muratori, Gideon M. Hirschfield, E.G. Giannini, Michael A. Heneghan, Marco Carbone, Richard Sandford, Giulia Bonato, Heather J. Cordell, James Neuberger, J. Kirby, Fabio Marra, Marco Marzioni, Holly F. Ainsworth, Laura Cristoferi, Guido Carpino, Luca Miele, Eugenio Gaudio, Roger Jones, George F. Mells, R. Mitchell-Thain, A. Floreani, Vincenzo Ronca, D. Thorburn, Pietro Invernizzi, Alessandra Nardi, Federica Malinverno, Graeme J.M. Alexander, P.M. Battezzati, Andrew Bathgate, Massimo Zuin, D.E.J. Jones, Fotios Sampaziotis, Vincenzo Cardinale, Domenico Alvaro, Deborah D. Stocken, Maria Francesca Donato, and Alessio Gerussi

Subjects
Pre treatment, medicine.medical_specialty, Hepatology, business.industry, Internal medicine, Risk stratification, Gastroenterology, medicine, business
Published
2018

30. P.04.21 PSEUDOCYSTS' METAL STENT DRAINAGE: STENT REMOVAL IS NOT MANDATORY

Author

Laura Cristoferi, Edoardo Forti, Francesco Pugliese, A. Tringali, Marcello Cintolo, Giulia Bonato, Lorenzo Dioscoridi, and M. Mutignani

Subjects
medicine.medical_specialty, Hepatology, business.industry, Stent removal, medicine.medical_treatment, Gastroenterology, medicine, Stent, Drainage, business, Surgery
Published
2018

34. V.01.7 A CHALLENGING ESOPHAGEAL FOREIGN BODY

Author

A. Tringali, Marcello Cintolo, D. Falchetti, M. Heinen, Laura Cristoferi, M. Mutignani, Edoardo Forti, Lorenzo Dioscoridi, and Francesco Pugliese

Subjects
medicine.medical_specialty, Hepatology, business.industry, General surgery, Gastroenterology, medicine, Esophageal foreign body, business
Published
2018

35. Subject Index Vol. 33, Suppl. 2, 2015

Author

Alessia Libra, Bettina E. Hansen, Haiyan Zhang, Niek de Vries, Luigi Muratori, Yvonne Bury, Carin M. van Nieuwkerk, Lucas Maillette de Buy Wenniger, Ulrich Beuers, Mario Strazzabosco, Ansgar W. Lohse, Laura Cristoferi, Alessandra Tovoli, Hendrik Vilstrup, Fabio Cassani, Brian K. Chung, Henk R. van Buuren, Olivier Chazouillères, Barbara Namer, Dina Tiniakos, Margaret Corrigan, Rodrigo Liberal, Raoul Poupon, Andreas E. Kremer, Lowiek M. Hubers, G Paumgartner, Emina Halilbasic, Gaia Deleonardi, Luca Fabris, Gideon M. Hirschfield, Christoph Schramm, Willem J Lammers, Peter Uhd Jepsen, Ruth Bolier, Maren H. Harms, Michael Trauner, Dermot Gleeson, Pere Ginès, Pietro Invernizzi, Marco Carbone, Albert Parés, Diego Vergani, Druckerei Stückle, Erica Barbato, Marieke E. Doorenspleet, Lisbet Grønbæk, Guan Wee Wong, Laura Jopson, Giulia Bonato, John G. Brain, Marco Lenzi, Paolo Muratori, Erik A.J. Rauws, Michael Fischer, Helena Cortez-Pinto, Lohse Angsar, Gerd Bouma, Claudia D. Fuchs, Ronald P.J. Oude Elferink, Giorgina Mieli-Vergani, Michael A. Heneghan, Cyriel Y. Ponsioen, Ana Lleo, Kirsten Boonstra, David Jones, Johannes Herkel, Harald Hofer, Tom H. Karlsen, Claudine Lalanne, Paul L. Klarenbeek, and Marcial Sebode

Subjects
medicine.medical_specialty, Index (economics), business.industry, Gastroenterology, Physical therapy, medicine, Subject (documents), General Medicine, business
Published
2015

37. Geoepidemiology and (epi-)genetics in primary biliary cholangitis

Author

Laura Cristoferi, Atsushi Tanaka, Roberto Rosa, Pietro Invernizzi, Rosa, R, Cristoferi, L, Tanaka, A, and Invernizzi, P

Subjects
Epigenomics, 0301 basic medicine, Epigenomic, Concordance, Genome-wide association study, Human leukocyte antigen, Disease, Global Health, 03 medical and health sciences, 0302 clinical medicine, Ductopenia, Genetic, MED/12 - GASTROENTEROLOGIA, Humans, Medicine, Genetic Predisposition to Disease, Epigenetics, Allele, Genetic association, X-chromosome monosomy, DNA methylation, Geoepidemiology, Geography, Liver Cirrhosis, Biliary, business.industry, Gastroenterology, Epigenetic, 030104 developmental biology, Primary biliary cholangiti, Immunology, 030211 gastroenterology & hepatology, business, Genome-Wide Association Study, Human
Abstract

Primary biliary cholangitis (PBC) is a rare female preponderant chronic autoimmune cholestatic liver disease, characterized by intrahepatic ductopenia and progressive fibrosis. During last decades incidence and prevalence showed an increasing rate which vary widely worldwide demonstrating an important interaction between environmental and genetic factors. Heritability suggested by familial occurrence and monozygotic twins concordance have been confirmed in more studies. Epigenetics mechanisms such as histone modification and DNA methylation can partially explain predisposition and inheritance of this disease. Nevertheless, an association with specific class II human leukocyte antigen (HLA) variants have been reported, showing an increase risk in susceptibility. More recently, data regarding a strong protective association between PBC and HLA alleles confirmed this association. After recent genome-wide association studies (GWAS), a more intricate interaction between PBC and the HLA region has been shown. Furthermore, GWAS also identified several immune-related-genes implicated. More genome-wide association studies on this disease are needed to reach a complete and systematic knowledge of this disease. In this review we discuss more recent issued data on geoepidemiology of PBC and the role of (epi-)genetic mechanisms in its pathogenesis.

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38. Radiomics-based model for outcome prediction in primary sclerosing cholangitis

Author

Laura Cristoferi, Marco Porta, Davide Bernasconi, Leonardi Filippo, Giacomo Mulinacci, Andrea Palermo, Alessio Gerussi, Miki Scaravaglio, Camilla Gallo, Eliana Stucchi, Cesare Maino, Davide Ippolito, Daphne D’Amato, Carlos Ferreira, Marija Mavar-Haramija, Rajarshi Banerjee, Laura Antolini, Maria Grazie Valsecchi, Stefano Fagiuoli, Pietro Invernizzi, and Marco Carbone

Subjects
Hepatology, Gastroenterology

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