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5. Prognostic models and autoimmune liver diseases

Author

D'Amato, D, Carbone, M, D'Amato D., Carbone M., D'Amato, D, Carbone, M, D'Amato D., and Carbone M.

Abstract

Autoimmune liver diseases (AILDs) are complex diseases with unknown causes and immune-mediated pathophysiology. In primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) disease modifying drugs are available which improve patient quality and quantity of life. In primary sclerosing cholangitis (PSC) no medical therapy is available and the only accepted treatment is liver transplantation (LT). PBC, PSC and AIH possess features that describe the archetype of patients within each disorder. On the other hand, the classical disorders are not homogeneous, and patients within each diagnosis may present with a range of clinical, biochemical, serological, and histological findings. Singularly, they are considered rare diseases, but together, they account for approximately 20% of LTs in Europe and USA. Management of these patients is complex, as AILDs are relatively uncommon in clinical practice with challenges in developing expertise, disease presentation can be sneaky, clinical phenotypes and disease course are heterogeneous. Prognostic models are key tools for clinicians to assess patients’ risk and to provide personalized care to patients. Aim of this review is to discuss challenges of the management of AILDs and how the available prognostic models can help. We will discuss the prognostic models developed in AILDs, with a special focus on the prognostic models that can support the clinical management of patients with AILDs: in PBC models based on ursodeoxycholic acid (UDCA) response and markers of liver fibrosis; in PSC several markers including biochemistry, disease stage and radiological semiquantitative markers; and finally in AIH, markers of disease stage and disease activity.

Published
2023

8. Metric Learning in Histopathological Image Classification: Opening the Black Box

Author

Amato, D, Calderaro, S, Lo Bosco, G, Rizzo, R, Vella, Filippo, Amato, D, Calderaro, S, Lo Bosco, G, Rizzo, R, and Vella, Filippo

Subjects
WSI, triplet networks, embedding, Settore INF/01 - Informatica, patient level accuracy, metric learning, breast cancer imaging, BreakHis, classification interpretability, visualization
Abstract

The application of machine learning techniques to histopathology images enables advances in the field, providing valuable tools that can speed up and facilitate the diagnosis process. The classification of these images is a relevant aid for physicians who have to process a large number of images in long and repetitive tasks. This work proposes the adoption of metric learning that, beyond the task of classifying images, can provide additional information able to support the decision of the classification system. In particular, triplet networks have been employed to create a representation in the embedding space that gathers together images of the same class while tending to separate images with different labels. The obtained representation shows an evident separation of the classes with the possibility of evaluating the similarity and the dissimilarity among input images according to distance criteria. The model has been tested on the BreakHis dataset, a reference and largely used dataset that collects breast cancer images with eight pathology labels and four magnification levels. Our proposed classification model achieves relevant performance on the patient level, with the advantage of providing interpretable information for the obtained results, which represent a specific feature missed by the all the recent methodologies proposed for the same purpose.

Published
2023

10. Predictors of serious adverse events and non-response in cirrhotic patients with primary biliary cholangitis treated with obeticholic acid

Author

De Vincentis, A, D'Amato, D, Cristoferi, L, Gerussi, A, Malinverno, F, Lleo, A, Colapietro, F, Marra, F, Galli, A, Fiorini, C, Coco, B, Brunetto, M, Niro, G, Cotugno, R, Saitta, C, Cozzolongo, R, Losito, F, Giannini, E, Labanca, S, Marzioni, M, Marconi, G, Morgando, A, Pellicano, R, Vanni, E, Cazzagon, N, Floreani, A, Chessa, L, Morelli, O, Muratori, L, Pellicelli, A, Pompili, M, Ponziani, F, Tortora, A, Rosina, F, Russello, M, Cannavo, M, Simone, L, Storato, S, Vigano, M, Abenavoli, L, D'Anto, M, De Gasperi, E, Distefano, M, Scifo, G, Zolfino, T, Calvaruso, V, Cuccorese, G, Palitti, V, Sacco, R, Bertino, G, Frazzetto, E, Alvaro, D, Mulinacci, G, Palermo, A, Scaravaglio, M, Terracciani, F, Galati, G, Ronca, V, Zuin, M, Claar, E, Izzi, A, Picardi, A, Invernizzi, P, Vespasiani-Gentilucci, U, Carbone, M, Feletti, V, Mussetto, A, Venere, R, Bernaccioni, G, Graciella Pigozzi, M, Fagiuoli, S, Terreni, N, Pozzoni, P, Baiocchi, L, Grassi, G, Vinci, M, Bellia, V, Boldizzoni, R, Casella, S, Omazzi, B, Poggi, G, De Vincentis A., D'Amato D., Cristoferi L., Gerussi A., Malinverno F., Lleo A., Colapietro F., Marra F., Galli A., Fiorini C., Coco B., Brunetto M., Niro G. A., Cotugno R., Saitta C., Cozzolongo R., Losito F., Giannini E. G., Labanca S., Marzioni M., Marconi G., Morgando A., Pellicano R., Vanni E., Cazzagon N., Floreani A., Chessa L., Morelli O., Muratori L., Pellicelli A., Pompili M., Ponziani F., Tortora A., Rosina F., Russello M., Cannavo M., Simone L., Storato S., Vigano M., Abenavoli L., D'Anto M., De Gasperi E., Distefano M., Scifo G., Zolfino T., Calvaruso V., Cuccorese G., Palitti V. P., Sacco R., Bertino G., Frazzetto E., Alvaro D., Mulinacci G., Palermo A., Scaravaglio M., Terracciani F., Galati G., Ronca V., Zuin M., Claar E., Izzi A., Picardi A., Invernizzi P., Vespasiani-Gentilucci U., Carbone M., Feletti V., Mussetto A., Venere R., Bernaccioni G., Graciella Pigozzi M., Fagiuoli S., Terreni N., Pozzoni P., Baiocchi L., Grassi G., Vinci M., Bellia V., Boldizzoni R., Casella S., Omazzi B., Poggi G., De Vincentis, A, D'Amato, D, Cristoferi, L, Gerussi, A, Malinverno, F, Lleo, A, Colapietro, F, Marra, F, Galli, A, Fiorini, C, Coco, B, Brunetto, M, Niro, G, Cotugno, R, Saitta, C, Cozzolongo, R, Losito, F, Giannini, E, Labanca, S, Marzioni, M, Marconi, G, Morgando, A, Pellicano, R, Vanni, E, Cazzagon, N, Floreani, A, Chessa, L, Morelli, O, Muratori, L, Pellicelli, A, Pompili, M, Ponziani, F, Tortora, A, Rosina, F, Russello, M, Cannavo, M, Simone, L, Storato, S, Vigano, M, Abenavoli, L, D'Anto, M, De Gasperi, E, Distefano, M, Scifo, G, Zolfino, T, Calvaruso, V, Cuccorese, G, Palitti, V, Sacco, R, Bertino, G, Frazzetto, E, Alvaro, D, Mulinacci, G, Palermo, A, Scaravaglio, M, Terracciani, F, Galati, G, Ronca, V, Zuin, M, Claar, E, Izzi, A, Picardi, A, Invernizzi, P, Vespasiani-Gentilucci, U, Carbone, M, Feletti, V, Mussetto, A, Venere, R, Bernaccioni, G, Graciella Pigozzi, M, Fagiuoli, S, Terreni, N, Pozzoni, P, Baiocchi, L, Grassi, G, Vinci, M, Bellia, V, Boldizzoni, R, Casella, S, Omazzi, B, Poggi, G, De Vincentis A., D'Amato D., Cristoferi L., Gerussi A., Malinverno F., Lleo A., Colapietro F., Marra F., Galli A., Fiorini C., Coco B., Brunetto M., Niro G. A., Cotugno R., Saitta C., Cozzolongo R., Losito F., Giannini E. G., Labanca S., Marzioni M., Marconi G., Morgando A., Pellicano R., Vanni E., Cazzagon N., Floreani A., Chessa L., Morelli O., Muratori L., Pellicelli A., Pompili M., Ponziani F., Tortora A., Rosina F., Russello M., Cannavo M., Simone L., Storato S., Vigano M., Abenavoli L., D'Anto M., De Gasperi E., Distefano M., Scifo G., Zolfino T., Calvaruso V., Cuccorese G., Palitti V. P., Sacco R., Bertino G., Frazzetto E., Alvaro D., Mulinacci G., Palermo A., Scaravaglio M., Terracciani F., Galati G., Ronca V., Zuin M., Claar E., Izzi A., Picardi A., Invernizzi P., Vespasiani-Gentilucci U., Carbone M., Feletti V., Mussetto A., Venere R., Bernaccioni G., Graciella Pigozzi M., Fagiuoli S., Terreni N., Pozzoni P., Baiocchi L., Grassi G., Vinci M., Bellia V., Boldizzoni R., Casella S., Omazzi B., and Poggi G.

Abstract

Background & Aims: Obeticholic acid (OCA) has recently been restricted in patients with primary biliary cholangitis (PBC) with “advanced cirrhosis” because of its narrow therapeutic index. We aimed to better define the predicting factors of hepatic serious adverse events (SAEs) and non-response in cirrhotic patients undergoing OCA therapy. Methods: Safety and efficacy of treatment were evaluated in a cohort of consecutive PBC cirrhotic patients started with OCA. OCA response was evaluated according to the Poise criteria. Risk factors for hepatic SAEs and non-response were reported as risk ratios (RR) with 95% confidence intervals (CIs). Results: One hundred PBC cirrhotics were included, 97 Child-Pugh class A and 3 class B. Thirty-one had oesophageal varices and 5 had a history of ascites. Thirty-three per cent and 32% of patients achieved a biochemical response at 6 and 12 months respectively. Male sex (adjusted-RR 1.75, 95%CI 1.42–2.12), INR (1.37, 1.00–1.87), Child-Pugh score (1.79, 1.28–2.50), MELD (1.17, 1.04–1.30) and bilirubin (1.83, 1.11–3.01) were independently associated with non-response to OCA. Twenty-two patients discontinued OCA within 12 months: 10 for pruritus, 9 for hepatic SAEs (5 for jaundice and/or ascitic decompensation; 4 for upper digestive bleeding). INR (adjusted-RR 1.91, 95%CI 1.10–3.36), lower albumin levels (0.18, 0.06–0.51), Child-Pugh score (2.43, 1.50–4.04), history of ascites (3.5, 1.85–6.5) and bilirubin (1.30, 1.05–1.56), were associated with hepatic SAEs. A total bilirubin≥1.4 mg/dl at baseline was the most accurate biochemical predictor of hepatic SAEs under OCA. Conclusions: An accurate baseline assessment is crucial to select cirrhotic patients who can benefit from OCA. Although OCA is effective in one third of cirrhotics, bilirubin level ≥1.4 mg/dl should discourage from its use.

Published
2022

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

Author

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, Carbone, M, Cristoferi, L., Porta, M., Bernasconi, D. P., 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. G., Antolini, L., Corso, R., Sironi, S., Fagiuoli, S., Invernizzi, P., Carbone, M., 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, Carbone, M, Cristoferi, L., Porta, M., Bernasconi, D. P., 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. G., Antolini, L., Corso, R., Sironi, S., Fagiuoli, S., Invernizzi, P., and Carbone, M.

Published
2022

12. Role of ductular reaction and ductular–canalicular junctions in identifying severe primary biliary cholangitis

Author

Overi, D, Carpino, G, Cristoferi, L, Onori, P, Kennedy, L, Francis, H, Zucchini, N, Rigamonti, C, Vigano, M, Floreani, A, D'Amato, D, Gerussi, A, Venere, R, Alpini, G, Glaser, S, Alvaro, D, Invernizzi, P, Gaudio, E, Cardinale, V, Carbone, M, Overi D., Carpino G., Cristoferi L., Onori P., Kennedy L., Francis H., Zucchini N., Rigamonti C., Vigano M., Floreani A., D'Amato D., Gerussi A., Venere R., Alpini G., Glaser S., Alvaro D., Invernizzi P., Gaudio E., Cardinale V., Carbone M., Overi, D, Carpino, G, Cristoferi, L, Onori, P, Kennedy, L, Francis, H, Zucchini, N, Rigamonti, C, Vigano, M, Floreani, A, D'Amato, D, Gerussi, A, Venere, R, Alpini, G, Glaser, S, Alvaro, D, Invernizzi, P, Gaudio, E, Cardinale, V, Carbone, M, Overi D., Carpino G., Cristoferi L., Onori P., Kennedy L., Francis H., Zucchini N., Rigamonti C., Vigano M., Floreani A., D'Amato D., Gerussi A., Venere R., Alpini G., Glaser S., Alvaro D., Invernizzi P., Gaudio E., Cardinale V., and Carbone M.

Abstract

Background & Aims: Primary biliary cholangitis (PBC) is a chronic cholangiopathy characterised by immuno-mediated injury of interlobular bile ducts leading to intrahepatic cholestasis and progressive liver fibrosis. PBC histology is characterised by portal inflammation, progressive fibrosis, ductopenia, and the appearance of the so-called ductular reaction. The aim of the present study was to investigate the pathogenetic relevance of ductular reaction in PBC. Methods: Liver biopsies were collected from naïve people with PBC (N = 87). Clinical–serological parameters were obtained at diagnosis and after 1 year of ursodeoxycholic acid (UDCA) treatment. Histological staging was performed on all slides according to multiple scoring systems and criteria for PBC. Liver samples were obtained from Mdr2−/− mice treated with or without UDCA. Samples were processed for histology, immunohistochemistry, and immunofluorescence. Results: Ductular reaction in people with PBC correlated with the disease stage and liver fibrosis, but not with disease activity; an extensive ductular reaction correlated with serum alkaline phosphatase levels at diagnosis, response to UDCA, and individuals’ estimated survival, independently from other histological parameters, including disease stage. In people with PBC, reactive ductules were associated with the establishment of junctions with bile canaliculi and with fibrogenetic cell activation. Consistently, in a mouse model of intrahepatic cholestasis, UDCA treatment was effective in reducing ductular reaction and fibrosis and increasing ductular–canalicular junctions. Conclusions: Extensive ductular reaction outlines a severe histologic phenotype in PBC and is associated with an inadequate therapy response and a worse estimated prognosis. Lay summary: In people affected by primary biliary cholangitis (PBC), the histological appearance of extensive ductular reaction identifies individuals at risk of progressive fibrosis. Ductular reaction at dia

Published
2022

13. Corrigendum to ‘An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs’ [J Hepatol 2021;75(3):572–581] (Journal of Hepatology (2021) 75(3) (572–581), (S0168827821003342), (10.1016/j.jhep.2021.04.055))

Author

Cordell H. J., Cordell, H, Fryett, J, Ueno, K, Darlay, R, Aiba, Y, Hitomi, Y, Kawashima, M, Nishida, N, Khor, S, Gervais, O, Kawai, Y, Nagasaki, M, Tokunaga, K, Tang, R, Shi, Y, Li, Z, Juran, B, Atkinson, E, Gerussi, A, Carbone, M, Asselta, R, Cheung, A, de Andrade, M, Baras, A, Horowitz, J, Ferreira, M, Sun, D, Jones, D, Flack, S, Spicer, A, Mulcahy, V, Byun, J, Han, Y, Sandford, R, Lazaridis, K, Amos, C, Hirschfield, G, Seldin, M, Invernizzi, P, Siminovitch, K, Ma, X, Nakamura, M, Mells, G, Mason, A, Vincent, C, Xie, G, Zhang, J, Affronti, A, Almasio, P, Alvaro, D, Andreone, P, Andriulli, A, Azzaroli, F, Battezzati, P, Benedetti, A, Bragazzi, M, Brunetto, M, Bruno, S, Calvaruso, V, Cardinale, V, Casella, G, Cazzagon, N, Ciaccio, A, Coco, B, Colli, A, Colloredo, G, Colombo, M, Colombo, S, Cristoferi, L, Cursaro, C, Croce, L, Crosignani, A, D'Amato, D, Donato, F, Elia, G, Fabris, L, Fagiuoli, S, Ferrari, C, Floreani, A, Galli, A, Giannini, E, Grattagliano, I, Lampertico, P, Lleo, A, Malinverno, F, Mancuso, C, Marra, F, Marzioni, M, Massironi, S, Mattalia, A, Miele, L, Milani, C, Morini, L, Morisco, F, Muratori, L, Muratori, P, Niro, G, O'Donnell, S, Picciotto, A, Portincasa, P, Rigamonti, C, Ronca, V, Rosina, F, Spinzi, G, Strazzabosco, M, Tiribelli, C, Toniutto, P, Valenti, L, Vinci, M, Zuin, M, Nakamura, H, Abiru, S, Nagaoka, S, Komori, A, Yatsuhashi, H, Ishibashi, H, Ito, M, Migita, K, Ohira, H, 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, 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, Tanaka, A, Takikawa, 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, Kawata, K, 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, H, E, Tanaka, T, Yamashiki, N, Tamura, S, Sugawara, Y, Kokudo, N, Chalasani, N, Luketic, V, Odin, J, Chopra, K, Abecasis, G, Cantor, M, Coppola, G, Economides, A, Lotta, L, Overton, J, Reid, J, Shuldiner, A, Beechert, C, Forsythe, C, Fuller, E, Gu, Z, Lattari, M, Lopez, A, Schleicher, T, Padilla, M, Toledo, K, Widom, L, Wolf, S, Pradhan, M, Manoochehri, K, Ulloa, R, Bai, X, Balasubramanian, S, Barnard, L, Blumenfeld, A, Eom, G, Habegger, L, Hawes, A, Khalid, S, Maxwell, E, Salerno, W, Staples, J, Jones, M, Mitnaul, L, Sturgess, R, Healey, C, Yeoman, A, Gunasekera, A, Kooner, P, Kapur, K, Sathyanarayana, V, Kallis, Y, Subhani, J, Harvey, R, Mccorry, R, Rooney, P, Ramanaden, D, Evans, R, Mathialahan, T, Gasem, J, Shorrock, C, Bhalme, M, Southern, P, Tibble, J, Gorard, D, Jones, S, Srivastava, B, Foxton, M, Collins, C, Elphick, D, Karmo, M, Porras-Perez, F, Mendall, M, Yapp, T, Patel, M, Ede, R, Sayer, J, Jupp, J, Fisher, N, Carter, M, Koss, K, Shah, J, Piotrowicz, A, Scott, G, Grimley, C, Gooding, I, Williams, S, Tidbury, J, Lim, G, Cheent, K, Levi, S, Mansour, D, Beckley, M, Hollywood, C, Wong, T, Marley, R, Ramage, J, Gordon, H, Ridpath, J, Ngatchu, T, Bob Grover, V, Shidrawi, R, Abouda, G, Corless, L, Narain, M, Rees, I, Brown, A, Taylor-Robinson, S, Wilkins, J, Grellier, L, Banim, P, Das, D, Heneghan, M, Curtis, H, Matthews, H, Mohammed, F, Aldersley, M, Srirajaskanthan, R, Walker, G, Mcnair, A, Sharif, A, Sen, S, Bird, G, Prince, M, Prasad, G, Kitchen, P, Barnardo, A, Oza, C, Sivaramakrishnan, N, Gupta, P, Shah, A, Evans, C, Saha, S, Pollock, K, Bramley, P, Mukhopadhya, A, Barclay, S, Mcdonald, N, Bathgate, A, Palmer, K, Dillon, J, Rushbrook, S, Przemioslo, R, Mcdonald, C, Millar, A, Tai, C, Mitchell, S, Metcalf, J, Shaukat, S, Ninkovic, M, Shmueli, U, Davis, A, Naqvi, A, Lee, T, Ryder, S, Collier, J, Klass, H, Cramp, M, Sharer, N, Aspinall, R, Ghosh, D, Douds, A, Booth, J, Williams, E, Hussaini, H, Christie, J, Mann, S, Thorburn, D, Marshall, A, Patanwala, I, Ala, A, Maltby, J, Matthew, R, Corbett, C, Vyas, S, Singhal, S, Gleeson, D, Misra, S, Butterworth, J, George, K, Harding, T, Douglass, A, Mitchison, H, Panter, S, Shearman, J, Bray, G, Roberts, M, Butcher, G, Forton, D, Mahmood, Z, Cowan, M, Ch'Ng, C, Rahman, M, Whatley, G, Wesley, E, Mandal, A, Jain, S, Pereira, S, Wright, M, Trivedi, P, Gordon, F, Unitt, E, Palejwala, A, Austin, A, Vemala, V, Grant, A, Higham, A, Brind, A, Mathew, R, Cox, M, Ramakrishnan, S, King, A, Whalley, S, Fraser, J, Thomson, S, Bell, A, Wong, V, Kia, R, Gee, I, Keld, R, Ransford, R, Gotto, J, Millson, C, Tarocchi, M, Cordell H. J., Fryett J. J., Ueno K., Darlay R., Aiba Y., Hitomi Y., Kawashima M., Nishida N., Khor S. -S., Gervais O., Kawai Y., Nagasaki M., Tokunaga K., Tang R., Shi Y., Li Z., Juran B. D., Atkinson E. J., Gerussi A., Carbone M., Asselta R., Cheung A., de Andrade M., Baras A., Horowitz J., Ferreira M. A. R., Sun D., Jones D. E., Flack S., Spicer A., Mulcahy V. L., Byun J., Han Y., Sandford R. N., Lazaridis K. N., Amos C. I., Hirschfield G. M., Seldin M. F., Invernizzi P., Siminovitch K. A., Ma X., Nakamura M., Mells G. F., Mason A., Vincent C., Xie G., Zhang J., Affronti A., Almasio P. L., Alvaro D., Andreone P., Andriulli A., Azzaroli F., Battezzati P. M., Benedetti A., Bragazzi M. C., Brunetto M., Bruno S., Calvaruso V., Cardinale V., Casella G., Cazzagon N., Ciaccio A., Coco B., Colli A., Colloredo G., Colombo M., Colombo S., Cristoferi L., Cursaro C., Croce L. S., Crosignani A., D'Amato D., Donato F., Elia G., Fabris L., Fagiuoli S., Ferrari C., Floreani A., Galli A., Giannini E., Grattagliano I., Lampertico P., Lleo A., Malinverno F., Mancuso C., Marra F., Marzioni M., Massironi S., Mattalia A., Miele L., Milani C., Morini L., Morisco F., Muratori L., Muratori P., Niro G. A., O'Donnell S., Picciotto A., Portincasa P., Rigamonti C., Ronca V., Rosina F., Spinzi G., Strazzabosco M., Tiribelli C., Toniutto P., Valenti L., Vinci M., Zuin M., Nakamura H., Abiru S., Nagaoka S., Komori A., Yatsuhashi H., Ishibashi H., Ito M., Migita K., Ohira H., 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., 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., Tanaka A., Takikawa 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., Kawata K., 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., H E., Tanaka T., Yamashiki N., Tamura S., Sugawara Y., Kokudo N., Chalasani N., Luketic V., Odin J., Chopra K., Abecasis G., Cantor M., Coppola G., Economides A., Lotta L. A., Overton J. D., Reid J. G., Shuldiner A., Beechert C., Forsythe C., Fuller E. D., Gu Z., Lattari M., Lopez A., Schleicher T. D., Padilla M. S., Toledo K., Widom L., Wolf S. E., Pradhan M., Manoochehri K., Ulloa R. H., Bai X., Balasubramanian S., Barnard L., Blumenfeld A., Eom G., Habegger L., Hawes A., Khalid S., Maxwell E. K., Salerno W., Staples J. C., Jones M. B., Mitnaul L. J., Sturgess R., Healey C., Yeoman A., Gunasekera A. V. J., Kooner P., Kapur K., Sathyanarayana V., Kallis Y., Subhani J., Harvey R., McCorry R., Rooney P., Ramanaden D., Evans R., Mathialahan T., Gasem J., Shorrock C., Bhalme M., Southern P., Tibble J. A., Gorard D. A., Jones S., Mells G., Mulcahy V., Srivastava B., Foxton M. R., Collins C. E., Elphick D., Karmo M., Porras-Perez F., Mendall M., Yapp T., Patel M., Ede R., Sayer J., Jupp J., Fisher N., Carter M. J., Koss K., Shah J., Piotrowicz A., Scott G., Grimley C., Gooding I. R., Williams S., Tidbury J., Lim G., Cheent K., Levi S., Mansour D., Beckley M., Hollywood C., Wong T., Marley R., Ramage J., Gordon H. M., Ridpath J., Ngatchu T., Bob Grover V. P., Shidrawi R. G., Abouda G., Corless L., Narain M., Rees I., Brown A., Taylor-Robinson S., Wilkins J., Grellier L., Banim P., Das D., Heneghan M. A., Curtis H., Matthews H. C., Mohammed F., Aldersley M., Srirajaskanthan R., Walker G., McNair A., Sharif A., Sen S., Bird G., Prince M. I., Prasad G., Kitchen P., Barnardo A., Oza C., Sivaramakrishnan N. N., Gupta P., Shah A., Evans C. D. J., Saha S., Pollock K., Bramley P., Mukhopadhya A., Barclay S. T., McDonald N., Bathgate A. J., Palmer K., Dillon J. F., Rushbrook S. M., Przemioslo R., McDonald C., Millar A., Tai C., Mitchell S., Metcalf J., Shaukat S., Ninkovic M., Shmueli U., Davis A., Naqvi A., Lee T. J. W., Ryder S., Collier J., Klass H., Cramp M. E., Sharer N., Aspinall R., Ghosh D., Douds A. C., Booth J., Williams E., Hussaini H., Christie J., Mann S., Thorburn D., Marshall A., Patanwala I., Ala A., Maltby J., Matthew R., Corbett C., Vyas S., Singhal S., Gleeson D., Misra S., Butterworth J., George K., Harding T., Douglass A., Mitchison H., Panter S., Shearman J., Bray G., Roberts M., Butcher G., Forton D., Mahmood Z., Cowan M., Ch'ng C. L., Rahman M., Whatley G. C. A., Wesley E., Mandal A., Jain S., Pereira S. P., Wright M., Trivedi P., Gordon F. H., Unitt E., Palejwala A., Austin A., Vemala V., Grant A., Higham A. D., Brind A., Mathew R., Cox M., Ramakrishnan S., King A., Whalley S., Fraser J., Thomson S. J., Bell A., Wong V. S., Kia R., Gee I., Keld R., Ransford R., Gotto J., Millson C., Tarocchi M., Cordell H. J., Cordell, H, Fryett, J, Ueno, K, Darlay, R, Aiba, Y, Hitomi, Y, Kawashima, M, Nishida, N, Khor, S, Gervais, O, Kawai, Y, Nagasaki, M, Tokunaga, K, Tang, R, Shi, Y, Li, Z, Juran, B, Atkinson, E, Gerussi, A, Carbone, M, Asselta, R, Cheung, A, de Andrade, M, Baras, A, Horowitz, J, Ferreira, M, Sun, D, Jones, D, Flack, S, Spicer, A, Mulcahy, V, Byun, J, Han, Y, Sandford, R, Lazaridis, K, Amos, C, Hirschfield, G, Seldin, M, Invernizzi, P, Siminovitch, K, Ma, X, Nakamura, M, Mells, G, Mason, A, Vincent, C, Xie, G, Zhang, J, Affronti, A, Almasio, P, Alvaro, D, Andreone, P, Andriulli, A, Azzaroli, F, Battezzati, P, Benedetti, A, Bragazzi, M, Brunetto, M, Bruno, S, Calvaruso, V, Cardinale, V, Casella, G, Cazzagon, N, Ciaccio, A, Coco, B, Colli, A, Colloredo, G, Colombo, M, Colombo, S, Cristoferi, L, Cursaro, C, Croce, L, Crosignani, A, D'Amato, D, Donato, F, Elia, G, Fabris, L, Fagiuoli, S, Ferrari, C, Floreani, A, Galli, A, Giannini, E, Grattagliano, I, Lampertico, P, Lleo, A, Malinverno, F, Mancuso, C, Marra, F, Marzioni, M, Massironi, S, Mattalia, A, Miele, L, Milani, C, Morini, L, Morisco, F, Muratori, L, Muratori, P, Niro, G, O'Donnell, S, Picciotto, A, Portincasa, P, Rigamonti, C, Ronca, V, Rosina, F, Spinzi, G, Strazzabosco, M, Tiribelli, C, Toniutto, P, Valenti, L, Vinci, M, Zuin, M, Nakamura, H, Abiru, S, Nagaoka, S, Komori, A, Yatsuhashi, H, Ishibashi, H, Ito, M, Migita, K, Ohira, H, 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, 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, Tanaka, A, Takikawa, 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, Kawata, K, 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, H, E, Tanaka, T, Yamashiki, N, Tamura, S, Sugawara, Y, Kokudo, N, Chalasani, N, Luketic, V, Odin, J, Chopra, K, Abecasis, G, Cantor, M, Coppola, G, Economides, A, Lotta, L, Overton, J, Reid, J, Shuldiner, A, Beechert, C, Forsythe, C, Fuller, E, Gu, Z, Lattari, M, Lopez, A, Schleicher, T, Padilla, M, Toledo, K, Widom, L, Wolf, S, Pradhan, M, Manoochehri, K, Ulloa, R, Bai, X, Balasubramanian, S, Barnard, L, Blumenfeld, A, Eom, G, Habegger, L, Hawes, A, Khalid, S, Maxwell, E, Salerno, W, Staples, J, Jones, M, Mitnaul, L, Sturgess, R, Healey, C, Yeoman, A, Gunasekera, A, Kooner, P, Kapur, K, Sathyanarayana, V, Kallis, Y, Subhani, J, Harvey, R, Mccorry, R, Rooney, P, Ramanaden, D, Evans, R, Mathialahan, T, Gasem, J, Shorrock, C, Bhalme, M, Southern, P, Tibble, J, Gorard, D, Jones, S, Srivastava, B, Foxton, M, Collins, C, Elphick, D, Karmo, M, Porras-Perez, F, Mendall, M, Yapp, T, Patel, M, Ede, R, Sayer, J, Jupp, J, Fisher, N, Carter, M, Koss, K, Shah, J, Piotrowicz, A, Scott, G, Grimley, C, Gooding, I, Williams, S, Tidbury, J, Lim, G, Cheent, K, Levi, S, Mansour, D, Beckley, M, Hollywood, C, Wong, T, Marley, R, Ramage, J, Gordon, H, Ridpath, J, Ngatchu, T, Bob Grover, V, Shidrawi, R, Abouda, G, Corless, L, Narain, M, Rees, I, Brown, A, Taylor-Robinson, S, Wilkins, J, Grellier, L, Banim, P, Das, D, Heneghan, M, Curtis, H, Matthews, H, Mohammed, F, Aldersley, M, Srirajaskanthan, R, Walker, G, Mcnair, A, Sharif, A, Sen, S, Bird, G, Prince, M, Prasad, G, Kitchen, P, Barnardo, A, Oza, C, Sivaramakrishnan, N, Gupta, P, Shah, A, Evans, C, Saha, S, Pollock, K, Bramley, P, Mukhopadhya, A, Barclay, S, Mcdonald, N, Bathgate, A, Palmer, K, Dillon, J, Rushbrook, S, Przemioslo, R, Mcdonald, C, Millar, A, Tai, C, Mitchell, S, Metcalf, J, Shaukat, S, Ninkovic, M, Shmueli, U, Davis, A, Naqvi, A, Lee, T, Ryder, S, Collier, J, Klass, H, Cramp, M, Sharer, N, Aspinall, R, Ghosh, D, Douds, A, Booth, J, Williams, E, Hussaini, H, Christie, J, Mann, S, Thorburn, D, Marshall, A, Patanwala, I, Ala, A, Maltby, J, Matthew, R, Corbett, C, Vyas, S, Singhal, S, Gleeson, D, Misra, S, Butterworth, J, George, K, Harding, T, Douglass, A, Mitchison, H, Panter, S, Shearman, J, Bray, G, Roberts, M, Butcher, G, Forton, D, Mahmood, Z, Cowan, M, Ch'Ng, C, Rahman, M, Whatley, G, Wesley, E, Mandal, A, Jain, S, Pereira, S, Wright, M, Trivedi, P, Gordon, F, Unitt, E, Palejwala, A, Austin, A, Vemala, V, Grant, A, Higham, A, Brind, A, Mathew, R, Cox, M, Ramakrishnan, S, King, A, Whalley, S, Fraser, J, Thomson, S, Bell, A, Wong, V, Kia, R, Gee, I, Keld, R, Ransford, R, Gotto, J, Millson, C, Tarocchi, M, Cordell H. J., Fryett J. J., Ueno K., Darlay R., Aiba Y., Hitomi Y., Kawashima M., Nishida N., Khor S. -S., Gervais O., Kawai Y., Nagasaki M., Tokunaga K., Tang R., Shi Y., Li Z., Juran B. D., Atkinson E. J., Gerussi A., Carbone M., Asselta R., Cheung A., de Andrade M., Baras A., Horowitz J., Ferreira M. A. R., Sun D., Jones D. E., Flack S., Spicer A., Mulcahy V. L., Byun J., Han Y., Sandford R. N., Lazaridis K. N., Amos C. I., Hirschfield G. M., Seldin M. F., Invernizzi P., Siminovitch K. A., Ma X., Nakamura M., Mells G. F., Mason A., Vincent C., Xie G., Zhang J., Affronti A., Almasio P. L., Alvaro D., Andreone P., Andriulli A., Azzaroli F., Battezzati P. M., Benedetti A., Bragazzi M. C., Brunetto M., Bruno S., Calvaruso V., Cardinale V., Casella G., Cazzagon N., Ciaccio A., Coco B., Colli A., Colloredo G., Colombo M., Colombo S., Cristoferi L., Cursaro C., Croce L. S., Crosignani A., D'Amato D., Donato F., Elia G., Fabris L., Fagiuoli S., Ferrari C., Floreani A., Galli A., Giannini E., Grattagliano I., Lampertico P., Lleo A., Malinverno F., Mancuso C., Marra F., Marzioni M., Massironi S., Mattalia A., Miele L., Milani C., Morini L., Morisco F., Muratori L., Muratori P., Niro G. A., O'Donnell S., Picciotto A., Portincasa P., Rigamonti C., Ronca V., Rosina F., Spinzi G., Strazzabosco M., Tiribelli C., Toniutto P., Valenti L., Vinci M., Zuin M., Nakamura H., Abiru S., Nagaoka S., Komori A., Yatsuhashi H., Ishibashi H., Ito M., Migita K., Ohira H., 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., 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., Tanaka A., Takikawa 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., Kawata K., 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., H E., Tanaka T., Yamashiki N., Tamura S., Sugawara Y., Kokudo N., Chalasani N., Luketic V., Odin J., Chopra K., Abecasis G., Cantor M., Coppola G., Economides A., Lotta L. A., Overton J. D., Reid J. G., Shuldiner A., Beechert C., Forsythe C., Fuller E. D., Gu Z., Lattari M., Lopez A., Schleicher T. D., Padilla M. S., Toledo K., Widom L., Wolf S. E., Pradhan M., Manoochehri K., Ulloa R. H., Bai X., Balasubramanian S., Barnard L., Blumenfeld A., Eom G., Habegger L., Hawes A., Khalid S., Maxwell E. K., Salerno W., Staples J. C., Jones M. B., Mitnaul L. J., Sturgess R., Healey C., Yeoman A., Gunasekera A. V. J., Kooner P., Kapur K., Sathyanarayana V., Kallis Y., Subhani J., Harvey R., McCorry R., Rooney P., Ramanaden D., Evans R., Mathialahan T., Gasem J., Shorrock C., Bhalme M., Southern P., Tibble J. A., Gorard D. A., Jones S., Mells G., Mulcahy V., Srivastava B., Foxton M. R., Collins C. E., Elphick D., Karmo M., Porras-Perez F., Mendall M., Yapp T., Patel M., Ede R., Sayer J., Jupp J., Fisher N., Carter M. J., Koss K., Shah J., Piotrowicz A., Scott G., Grimley C., Gooding I. R., Williams S., Tidbury J., Lim G., Cheent K., Levi S., Mansour D., Beckley M., Hollywood C., Wong T., Marley R., Ramage J., Gordon H. M., Ridpath J., Ngatchu T., Bob Grover V. P., Shidrawi R. G., Abouda G., Corless L., Narain M., Rees I., Brown A., Taylor-Robinson S., Wilkins J., Grellier L., Banim P., Das D., Heneghan M. A., Curtis H., Matthews H. C., Mohammed F., Aldersley M., Srirajaskanthan R., Walker G., McNair A., Sharif A., Sen S., Bird G., Prince M. I., Prasad G., Kitchen P., Barnardo A., Oza C., Sivaramakrishnan N. N., Gupta P., Shah A., Evans C. D. J., Saha S., Pollock K., Bramley P., Mukhopadhya A., Barclay S. T., McDonald N., Bathgate A. J., Palmer K., Dillon J. F., Rushbrook S. M., Przemioslo R., McDonald C., Millar A., Tai C., Mitchell S., Metcalf J., Shaukat S., Ninkovic M., Shmueli U., Davis A., Naqvi A., Lee T. J. W., Ryder S., Collier J., Klass H., Cramp M. E., Sharer N., Aspinall R., Ghosh D., Douds A. C., Booth J., Williams E., Hussaini H., Christie J., Mann S., Thorburn D., Marshall A., Patanwala I., Ala A., Maltby J., Matthew R., Corbett C., Vyas S., Singhal S., Gleeson D., Misra S., Butterworth J., George K., Harding T., Douglass A., Mitchison H., Panter S., Shearman J., Bray G., Roberts M., Butcher G., Forton D., Mahmood Z., Cowan M., Ch'ng C. L., Rahman M., Whatley G. C. A., Wesley E., Mandal A., Jain S., Pereira S. P., Wright M., Trivedi P., Gordon F. H., Unitt E., Palejwala A., Austin A., Vemala V., Grant A., Higham A. D., Brind A., Mathew R., Cox M., Ramakrishnan S., King A., Whalley S., Fraser J., Thomson S. J., Bell A., Wong V. S., Kia R., Gee I., Keld R., Ransford R., Gotto J., Millson C., and Tarocchi M.

Abstract

It has come to our attention that the name of one of the authors in our manuscript was incorrectly spelled ‘Jinyoung Byan’; the correct spelling is ‘Jinyoung Byun’ as in the author list above. In addition, the excel files of the supplementary tables were not included during the online publication of our article. These have now been made available online. We apologize for any inconvenience caused.

Published
2022

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

Author

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

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

16. Corrigendum to ‘An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs’ [J Hepatol 2021;75(3):572–581] (Journal of Hepatology (2021) 75(3) (572–581), (S0168827821003342), (10.1016/j.jhep.2021.04.055))

Author

Cordell, H. J., Fryett, J. J., Ueno, K., Darlay, R., Aiba, Y., Hitomi, Y., Kawashima, M., Nishida, N., Khor, S. -S., Gervais, O., Kawai, Y., Nagasaki, M., Tokunaga, K., Tang, R., Shi, Y., Li, Z., Juran, B. D., Atkinson, E. J., Gerussi, A., Carbone, M., Asselta, R., Cheung, A., de Andrade, M., Baras, A., Horowitz, J., Ferreira, M. A. R., Sun, D., Jones, D. E., Flack, S., Spicer, A., Mulcahy, V. L., Byun, J., Han, Y., Sandford, R. N., Lazaridis, K. N., Amos, C. I., Hirschfield, G. M., Seldin, M. F., Invernizzi, P., Siminovitch, K. A., Ma, X., Nakamura, M., Mells, G. F., Mason, A., Vincent, C., Xie, G., Zhang, J., Affronti, A., Almasio, P. L., Alvaro, D., Andreone, P., Andriulli, A., Azzaroli, F., Battezzati, P. M., Benedetti, A., Bragazzi, M., Brunetto, M., Bruno, S., Calvaruso, V., Cardinale, V., Casella, G., Cazzagon, N., Ciaccio, A., Coco, B., Colli, A., Colloredo, G., Colombo, M., Colombo, S., Cristoferi, L., Cursaro, C., Croce, L. S., Crosignani, A., D'Amato, D., Donato, F., Elia, G., Fabris, L., Fagiuoli, S., Ferrari, C., Floreani, A., Galli, A., Giannini, E., Grattagliano, I., Lampertico, P., Lleo, A., Malinverno, F., Mancuso, C., Marra, F., Marzioni, M., Massironi, S., Mattalia, A., Miele, L., Milani, C., Morini, L., Morisco, F., Muratori, L., Muratori, P., Niro, G. A., O'Donnell, S., Picciotto, A., Portincasa, P., Rigamonti, C., Ronca, V., Rosina, F., Spinzi, G., Strazzabosco, M., Tarocchi, M., Tiribelli, C., Toniutto, P., Valenti, L., Vinci, M., Zuin, M., Nakamura, H., Abiru, S., Nagaoka, S., Komori, A., Yatsuhashi, H., Ishibashi, H., Ito, M., Migita, K., Ohira, H., 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., 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., Tanaka, A., Takikawa, 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., Kawata, K., 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., H, E., Tanaka, T., Yamashiki, N., Tamura, S., Sugawara, Y., Kokudo, N., Chalasani, N., Luketic, V., Odin, J., Chopra, K., Abecasis, G., Cantor, M., Coppola, G., Economides, A., Lotta, L. A., Overton, J. D., Reid, J. G., Shuldiner, A., Beechert, C., Forsythe, C., Fuller, E. D., Gu, Z., Lattari, M., Lopez, A., Schleicher, T. D., Padilla, M. S., Toledo, K., Widom, L., Wolf, S. E., Pradhan, M., Manoochehri, K., Ulloa, R. H., Bai, X., Balasubramanian, S., Barnard, L., Blumenfeld, A., Eom, G., Habegger, L., Hawes, A., Khalid, S., Maxwell, E. K., Salerno, W., Staples, J. C., Jones, M. B., Mitnaul, L. J., Sturgess, R., Healey, C., Yeoman, A., Gunasekera, A. V., Kooner, P., Kapur, K., Sathyanarayana, V., Kallis, Y., Subhani, J., Harvey, R., Mccorry, R., Rooney, P., Ramanaden, D., Evans, R., Mathialahan, T., Gasem, J., Shorrock, C., Bhalme, M., Southern, P., Tibble, J. A., Gorard, D. A., Jones, S., Mells, G., Mulcahy, V., Srivastava, B., Foxton, M. R., Collins, C. E., Elphick, D., Karmo, M., Porras-Perez, F., Mendall, M., Yapp, T., Patel, M., Ede, R., Sayer, J., Jupp, J., Fisher, N., Carter, M. J., Koss, K., Shah, J., Piotrowicz, A., Scott, G., Grimley, C., Gooding, I. R., Williams, S., Tidbury, J., Lim, G., Cheent, K., Levi, S., Mansour, D., Beckley, M., Hollywood, C., Wong, T., Marley, R., Ramage, J., Gordon, H. M., Ridpath, J., Ngatchu, T., Bob Grover, V. P., Shidrawi, R. G., Abouda, G., Corless, L., Narain, M., Rees, I., Brown, A., Taylor-Robinson, S., Wilkins, J., Grellier, L., Banim, P., Das, D., Heneghan, M. A., Curtis, H., Matthews, H. C., Mohammed, F., Aldersley, M., Srirajaskanthan, R., Walker, G., Mcnair, A., Sharif, A., Sen, S., Bird, G., Prince, M. I., Prasad, G., Kitchen, P., Barnardo, A., Oza, C., Sivaramakrishnan, N. N., Gupta, P., Shah, A., Evans, C. D., Saha, S., Pollock, K., Bramley, P., Mukhopadhya, A., Barclay, S. T., Mcdonald, N., Bathgate, A. J., Palmer, K., Dillon, J. F., Rushbrook, S. M., Przemioslo, R., Mcdonald, C., Millar, A., Tai, C., Mitchell, S., Metcalf, J., Shaukat, S., Ninkovic, M., Shmueli, U., Davis, A., Naqvi, A., Lee, T. J., Ryder, S., Collier, J., Klass, H., Cramp, M. E., Sharer, N., Aspinall, R., Ghosh, D., Douds, A. C., Booth, J., Williams, E., Hussaini, H., Christie, J., Mann, S., Thorburn, D., Marshall, A., Patanwala, I., Ala, A., Maltby, J., Matthew, R., Corbett, C., Vyas, S., Singhal, S., Gleeson, D., Misra, S., Butterworth, J., George, K., Harding, T., Douglass, A., Mitchison, H., Panter, S., Shearman, J., Bray, G., Roberts, M., Butcher, G., Forton, D., Mahmood, Z., Cowan, M., Ch'Ng, C. L., Rahman, M., Whatley, G. C. A., Wesley, E., Mandal, A., Jain, S., Pereira, S. P., Wright, M., Trivedi, P., Gordon, F. H., Unitt, E., Palejwala, A., Austin, A., Vemala, V., Grant, A., Higham, A. D., Brind, A., Mathew, R., Cox, M., Ramakrishnan, S., King, A., Whalley, S., Fraser, J., Thomson, S. J., Bell, A., Wong, V. S., Kia, R., Gee, I., Keld, R., Ransford, R., Gotto, J., Millson, C., Cordell H.J., Fryett J.J., Ueno K., Darlay R., Aiba Y., Hitomi Y., Kawashima M., Nishida N., Khor S.-S., Gervais O., Kawai Y., Nagasaki M., Tokunaga K., Tang R., Shi Y., Li Z., Juran B.D., Atkinson E.J., Gerussi A., Carbone M., Asselta R., Cheung A., de Andrade M., Baras A., Horowitz J., Ferreira M.A.R., Sun D., Jones D.E., Flack S., Spicer A., Mulcahy V.L., Byun J., Han Y., Sandford R.N., Lazaridis K.N., Amos C.I., Hirschfield G.M., Seldin M.F., Invernizzi P., Siminovitch K.A., Ma X., Nakamura M., Mells G.F., Mason A., Vincent C., Xie G., Zhang J., Affronti A., Almasio P.L., Alvaro D., Andreone P., Andriulli A., Azzaroli F., Battezzati P.M., Benedetti A., Bragazzi M.C., Brunetto M., Bruno S., Calvaruso V., Cardinale V., Casella G., Cazzagon N., Ciaccio A., Coco B., Colli A., Colloredo G., Colombo M., Colombo S., Cristoferi L., Cursaro C., Croce L.S., Crosignani A., D'Amato D., Donato F., Elia G., Fabris L., Fagiuoli S., Ferrari C., Floreani A., Galli A., Giannini E., Grattagliano I., Lampertico P., Lleo A., Malinverno F., Mancuso C., Marra F., Marzioni M., Massironi S., Mattalia A., Miele L., Milani C., Morini L., Morisco F., Muratori L., Muratori P., Niro G.A., O'Donnell S., Picciotto A., Portincasa P., Rigamonti C., Ronca V., Rosina F., Spinzi G., Strazzabosco M., Tarocchi M., Tiribelli C., Toniutto P., Valenti L., Vinci M., Zuin M., Nakamura H., Abiru S., Nagaoka S., Komori A., Yatsuhashi H., Ishibashi H., Ito M., Migita K., Ohira H., 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., 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., Tanaka A., Takikawa 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., Kawata K., 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., H E., Tanaka T., Yamashiki N., Tamura S., Sugawara Y., Kokudo N., Chalasani N., Luketic V., Odin J., Chopra K., Abecasis G., Cantor M., Coppola G., Economides A., Lotta L.A., Overton J.D., Reid J.G., Shuldiner A., Beechert C., Forsythe C., Fuller E.D., Gu Z., Lattari M., Lopez A., Schleicher T.D., Padilla M.S., Toledo K., Widom L., Wolf S.E., Pradhan M., Manoochehri K., Ulloa R.H., Bai X., Balasubramanian S., Barnard L., Blumenfeld A., Eom G., Habegger L., Hawes A., Khalid S., Maxwell E.K., Salerno W., Staples J.C., Jones M.B., Mitnaul L.J., Sturgess R., Healey C., Yeoman A., Gunasekera A.V.J., Kooner P., Kapur K., Sathyanarayana V., Kallis Y., Subhani J., Harvey R., McCorry R., Rooney P., Ramanaden D., Evans R., Mathialahan T., Gasem J., Shorrock C., Bhalme M., Southern P., Tibble J.A., Gorard D.A., Jones S., Mells G., Mulcahy V., Srivastava B., Foxton M.R., Collins C.E., Elphick D., Karmo M., Porras-Perez F., Mendall M., Yapp T., Patel M., Ede R., Sayer J., Jupp J., Fisher N., Carter M.J., Koss K., Shah J., Piotrowicz A., Scott G., Grimley C., Gooding I.R., Williams S., Tidbury J., Lim G., Cheent K., Levi S., Mansour D., Beckley M., Hollywood C., Wong T., Marley R., Ramage J., Gordon H.M., Ridpath J., Ngatchu T., Bob Grover V.P., Shidrawi R.G., Abouda G., Corless L., Narain M., Rees I., Brown A., Taylor-Robinson S., Wilkins J., Grellier L., Banim P., Das D., Heneghan M.A., Curtis H., Matthews H.C., Mohammed F., Aldersley M., Srirajaskanthan R., Walker G., McNair A., Sharif A., Sen S., Bird G., Prince M.I., Prasad G., Kitchen P., Barnardo A., Oza C., Sivaramakrishnan N.N., Gupta P., Shah A., Evans C.D.J., Saha S., Pollock K., Bramley P., Mukhopadhya A., Barclay S.T., McDonald N., Bathgate A.J., Palmer K., Dillon J.F., Rushbrook S.M., Przemioslo R., McDonald C., Millar A., Tai C., Mitchell S., Metcalf J., Shaukat S., Ninkovic M., Shmueli U., Davis A., Naqvi A., Lee T.J.W., Ryder S., Collier J., Klass H., Cramp M.E., Sharer N., Aspinall R., Ghosh D., Douds A.C., Booth J., Williams E., Hussaini H., Christie J., Mann S., Thorburn D., Marshall A., Patanwala I., Ala A., Maltby J., Matthew R., Corbett C., Vyas S., Singhal S., Gleeson D., Misra S., Butterworth J., George K., Harding T., Douglass A., Mitchison H., Panter S., Shearman J., Bray G., Roberts M., Butcher G., Forton D., Mahmood Z., Cowan M., Ch'ng C.L., Rahman M., Whatley G.C.A., Wesley E., Mandal A., Jain S., Pereira S.P., Wright M., Trivedi P., Gordon F.H., Unitt E., Palejwala A., Austin A., Vemala V., Grant A., Higham A.D., Brind A., Mathew R., Cox M., Ramakrishnan S., King A., Whalley S., Fraser J., Thomson S.J., Bell A., Wong V.S., Kia R., Gee I., Keld R., Ransford R., Gotto J., and Millson C.

Subjects
PBC
Abstract

It has come to our attention that the name of one of the authors in our manuscript was incorrectly spelled ‘Jinyoung Byan’; the correct spelling is ‘Jinyoung Byun’ as in the author list above. In addition, the excel files of the supplementary tables were not included during the online publication of our article. These have now been made available online. We apologize for any inconvenience caused.

Published
2022

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

Author

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., Vigano M., Alvaro D., Pompili M., Picciotto A., Palitti V. P., Russello M., Storato S., Pigozzi M. G., Calvaruso V., De Gasperi E., Lleo A., Castellaneta A., Pellicelli A., Cazzagon N., Floreani A., Muratori L., Fagiuoli S., Niro G. A., 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. E., 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, 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., Vigano M., Alvaro D., Pompili M., Picciotto A., Palitti V. P., Russello M., Storato S., Pigozzi M. G., Calvaruso V., De Gasperi E., Lleo A., Castellaneta A., Pellicelli A., Cazzagon N., Floreani A., Muratori L., Fagiuoli S., Niro G. A., 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. E., Mancuso C., Mulinacci G., Palermo A., Claar E., Izzi A., Picardi A., Invernizzi P., Carbone M., and Vespasiani-Gentilucci U.

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 compare

Published
2021

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

Author

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 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, 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, 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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. 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E., Seldin M. F., and Invernizzi P.

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

19. An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs

Author

Cordell, H, Fryett, J, Ueno, K, Darlay, R, Aiba, Y, Hitomi, Y, Kawashima, M, Nishida, N, Khor, S, Gervais, O, Kawai, Y, Nagasaki, M, Tokunaga, K, Tang, R, Shi, Y, Li, Z, Juran, B, Atkinson, E, Gerussi, A, Carbone, M, Asselta, R, Cheung, A, de Andrade, M, Baras, A, Horowitz, J, Ferreira, M, Sun, D, Jones, D, Flack, S, Spicer, A, Mulcahy, V, Byan, J, Han, Y, Sandford, R, Lazaridis, K, Amos, C, Hirschfield, G, Seldin, M, Invernizzi, P, Siminovitch, K, Ma, X, Nakamura, M, Mells, G, Mason, A, Vincent, C, Xie, G, Zhang, J, Affronti, A, Almasio, P, Alvaro, D, Andreone, P, Andriulli, A, Azzaroli, F, Battezzati, P, Benedetti, A, Bragazzi, M, Brunetto, M, Bruno, S, Calvaruso, V, Cardinale, V, Casella, G, Cazzagon, N, Ciaccio, A, Coco, B, Colli, A, Colloredo, G, Colombo, M, Colombo, S, Cristoferi, L, Cursaro, C, Croce, L, Crosignani, A, D'Amato, D, Donato, F, Elia, G, Fabris, L, Fagiuoli, S, Ferrari, C, Floreani, A, Galli, A, Giannini, E, Grattagliano, I, Lampertico, P, Lleo, A, Malinverno, F, Mancuso, C, Marra, F, Marzioni, M, Massironi, S, Mattalia, A, Miele, L, Milani, C, Morini, L, Morisco, F, Muratori, L, Muratori, P, Niro, G, O'Donnell, S, Picciotto, A, Portincasa, P, Rigamonti, C, Ronca, V, Rosina, F, Spinzi, G, Strazzabosco, M, Tarocchi, M, Tiribelli, C, Toniutto, P, Valenti, L, Vinci, M, Zuin, M, Nakamura, H, Abiru, S, Nagaoka, S, Komori, A, Yatsuhashi, H, Ishibashi, H, Ito, M, Migita, K, Ohira, H, 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, 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, Tanaka, A, Takikawa, 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, Kawata, K, 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, H, E, Tanaka, T, Yamashiki, N, Tamura, S, Sugawara, Y, Kokudo, N, Chalasani, N, Luketic, V, Odin, J, Chopra, K, Abecasis, G, Cantor, M, Coppola, G, Economides, A, Lotta, L, Overton, J, Reid, J, Shuldiner, A, Beechert, C, Forsythe, C, Fuller, E, Gu, Z, Lattari, M, Lopez, A, Schleicher, T, Padilla, M, Toledo, K, Widom, L, Wolf, S, Pradhan, M, Manoochehri, K, Ulloa, R, Bai, X, Balasubramanian, S, Barnard, L, Blumenfeld, A, Eom, G, Habegger, L, Hawes, A, Khalid, S, Maxwell, E, Salerno, W, Staples, J, Jones, M, Mitnaul, L, Sturgess, R, Healey, C, Yeoman, A, Gunasekera, A, Kooner, P, Kapur, K, Sathyanarayana, V, Kallis, Y, Subhani, J, Harvey, R, Mccorry, R, Rooney, P, Ramanaden, D, Evans, R, Mathialahan, T, Gasem, J, Shorrock, C, Bhalme, M, Southern, P, Tibble, J, Gorard, D, Jones, S, Srivastava, B, Foxton, M, Collins, C, Elphick, D, Karmo, M, Porras-Perez, F, Mendall, M, Yapp, T, Patel, M, Ede, R, Sayer, J, Jupp, J, Fisher, N, Carter, M, Koss, K, Shah, J, Piotrowicz, A, Scott, G, Grimley, C, Gooding, I, Williams, S, Tidbury, J, Lim, G, Cheent, K, Levi, S, Mansour, D, Beckley, M, Hollywood, C, Wong, T, Marley, R, Ramage, J, Gordon, H, Ridpath, J, Ngatchu, T, Bob Grover, V, Shidrawi, R, Abouda, G, Corless, L, Narain, M, Rees, I, Brown, A, Taylor-Robinson, S, Wilkins, J, Grellier, L, Banim, P, Das, D, Heneghan, M, Curtis, H, Matthews, H, 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J., Fryett J. J., Ueno K., Darlay R., Aiba Y., Hitomi Y., Kawashima M., Nishida N., Khor S. -S., Gervais O., Kawai Y., Nagasaki M., Tokunaga K., Tang R., Shi Y., Li Z., Juran B. D., Atkinson E. J., Gerussi A., Carbone M., Asselta R., Cheung A., de Andrade M., Baras A., Horowitz J., Ferreira M. A. R., Sun D., Jones D. E., Flack S., Spicer A., Mulcahy V. L., Byan J., Han Y., Sandford R. N., Lazaridis K. N., Amos C. I., Hirschfield G. M., Seldin M. F., Invernizzi P., Siminovitch K. A., Ma X., Nakamura M., Mells G. F., Mason A., Vincent C., Xie G., Zhang J., Affronti A., Almasio P. L., Alvaro D., Andreone P., Andriulli A., Azzaroli F., Battezzati P. M., Benedetti A., Bragazzi M., Brunetto M., Bruno S., Calvaruso V., Cardinale V., Casella G., Cazzagon N., Ciaccio A., Coco B., Colli A., Colloredo G., Colombo M., Colombo S., Cristoferi L., Cursaro C., Croce L. S., Crosignani A., D'Amato D., Donato F., Elia G., Fabris L., Fagiuoli S., Ferrari C., Floreani A., Galli A., Giannini E., Grattagliano I., Lampertico P., Lleo A., Malinverno F., Mancuso C., Marra F., Marzioni M., Massironi S., Mattalia A., Miele L., Milani C., Morini L., Morisco F., Muratori L., Muratori P., Niro G. A., O'Donnell S., Picciotto A., Portincasa P., Rigamonti C., Ronca V., Rosina F., Spinzi G., Strazzabosco M., Tarocchi M., Tiribelli C., Toniutto P., Valenti L., Vinci M., Zuin M., Nakamura H., Abiru S., Nagaoka S., Komori A., Yatsuhashi H., Ishibashi H., Ito M., Migita K., Ohira H., 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., 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., Tanaka A., Takikawa 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., Kawata K., 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., H E., Tanaka T., Yamashiki N., Tamura S., Sugawara Y., Kokudo N., Chalasani N., Luketic V., Odin J., Chopra K., Abecasis G., Cantor M., Coppola G., Economides A., Lotta L. A., Overton J. D., Reid J. G., Shuldiner A., Beechert C., Forsythe C., Fuller E. D., Gu Z., Lattari M., Lopez A., Schleicher T. D., Padilla M. S., Toledo K., Widom L., Wolf S. E., Pradhan M., Manoochehri K., Ulloa R. H., Bai X., Balasubramanian S., Barnard L., Blumenfeld A., Eom G., Habegger L., Hawes A., Khalid S., Maxwell E. K., Salerno W., Staples J. C., Jones M. B., Mitnaul L. J., Sturgess R., Healey C., Yeoman A., Gunasekera A. V., Kooner P., Kapur K., Sathyanarayana V., Kallis Y., Subhani J., Harvey R., McCorry R., Rooney P., Ramanaden D., Evans R., Mathialahan T., Gasem J., Shorrock C., Bhalme M., Southern P., Tibble J. A., Gorard D. A., Jones S., Mells G., Mulcahy V., Srivastava B., Foxton M. R., Collins C. E., Elphick D., Karmo M., Porras-Perez F., Mendall M., Yapp T., Patel M., Ede R., Sayer J., Jupp J., Fisher N., Carter M. J., Koss K., Shah J., Piotrowicz A., Scott G., Grimley C., Gooding I. R., Williams S., Tidbury J., Lim G., Cheent K., Levi S., Mansour D., Beckley M., Hollywood C., Wong T., Marley R., Ramage J., Gordon H. M., Ridpath J., Ngatchu T., Bob Grover V. P., Shidrawi R. G., Abouda G., Corless L., Narain M., Rees I., Brown A., Taylor-Robinson S., Wilkins J., Grellier L., Banim P., Das D., Heneghan M. A., Curtis H., Matthews H. C., Mohammed F., Aldersley M., Srirajaskanthan R., Walker G., McNair A., Sharif A., Sen S., Bird G., Prince M. I., Prasad G., Kitchen P., Barnardo A., Oza C., Sivaramakrishnan N. N., Gupta P., Shah A., Evans C. D., Saha S., Pollock K., Bramley P., Mukhopadhya A., Barclay S. T., McDonald N., Bathgate A. J., Palmer K., Dillon J. F., Rushbrook S. M., Przemioslo R., McDonald C., Millar A., Tai C., Mitchell S., Metcalf J., Shaukat S., Ninkovic M., Shmueli U., Davis A., Naqvi A., Lee T. J., Ryder S., Collier J., Klass H., Cramp M. E., Sharer N., Aspinall R., Ghosh D., Douds A. C., Booth J., Williams E., Hussaini H., Christie J., Mann S., Thorburn D., Marshall A., Patanwala I., Ala A., Maltby J., Matthew R., Corbett C., Vyas S., Singhal S., Gleeson D., Misra S., Butterworth J., George K., Harding T., Douglass A., Mitchison H., Panter S., Shearman J., Bray G., Roberts M., Butcher G., Forton D., Mahmood Z., Cowan M., Ch'ng C. L., Rahman M., Whatley G. C. A., Wesley E., Mandal A., Jain S., Pereira S. P., Wright M., Trivedi P., Gordon F. H., Unitt E., Palejwala A., Austin A., Vemala V., Grant A., Higham A. D., Brind A., Mathew R., Cox M., Ramakrishnan S., King A., Whalley S., Fraser J., Thomson S. J., Bell A., Wong V. S., Kia R., Gee I., Keld R., Ransford R., Gotto J., Millson C., Cordell, H, Fryett, J, Ueno, K, Darlay, R, Aiba, Y, Hitomi, Y, Kawashima, M, Nishida, N, Khor, S, Gervais, O, Kawai, Y, Nagasaki, M, Tokunaga, K, Tang, R, Shi, Y, Li, Z, Juran, B, Atkinson, E, Gerussi, A, Carbone, M, Asselta, R, Cheung, A, de Andrade, M, Baras, A, Horowitz, J, Ferreira, M, Sun, D, Jones, D, Flack, S, Spicer, A, Mulcahy, V, Byan, J, Han, Y, Sandford, R, Lazaridis, K, Amos, C, Hirschfield, G, Seldin, M, Invernizzi, P, Siminovitch, K, Ma, X, Nakamura, M, Mells, G, Mason, A, Vincent, C, Xie, G, Zhang, J, Affronti, A, Almasio, P, Alvaro, D, Andreone, P, Andriulli, A, Azzaroli, F, Battezzati, P, Benedetti, A, Bragazzi, M, Brunetto, M, Bruno, S, Calvaruso, V, Cardinale, V, Casella, G, Cazzagon, N, Ciaccio, A, Coco, B, Colli, A, Colloredo, G, Colombo, M, Colombo, S, Cristoferi, L, Cursaro, C, Croce, L, Crosignani, A, D'Amato, D, Donato, F, Elia, G, Fabris, L, Fagiuoli, S, Ferrari, C, Floreani, A, Galli, A, Giannini, E, Grattagliano, I, Lampertico, P, Lleo, A, Malinverno, F, Mancuso, C, Marra, F, Marzioni, M, Massironi, S, Mattalia, A, Miele, L, Milani, C, Morini, L, Morisco, F, Muratori, L, Muratori, P, Niro, G, O'Donnell, S, Picciotto, A, Portincasa, P, Rigamonti, C, Ronca, V, Rosina, F, Spinzi, G, Strazzabosco, M, Tarocchi, M, Tiribelli, C, Toniutto, P, Valenti, L, Vinci, M, Zuin, M, Nakamura, H, Abiru, S, Nagaoka, S, Komori, A, Yatsuhashi, H, Ishibashi, H, Ito, M, Migita, K, Ohira, H, 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, 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, Tanaka, A, Takikawa, 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, Kawata, K, 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, H, E, Tanaka, T, Yamashiki, N, Tamura, S, Sugawara, Y, Kokudo, N, Chalasani, N, Luketic, V, Odin, J, Chopra, K, Abecasis, G, Cantor, M, Coppola, G, Economides, A, Lotta, L, Overton, J, Reid, J, Shuldiner, A, Beechert, C, Forsythe, C, Fuller, E, Gu, Z, Lattari, M, Lopez, A, Schleicher, T, Padilla, M, Toledo, K, Widom, L, Wolf, S, Pradhan, M, Manoochehri, K, Ulloa, R, Bai, X, Balasubramanian, S, Barnard, L, Blumenfeld, A, Eom, G, Habegger, L, Hawes, A, Khalid, S, Maxwell, E, Salerno, W, Staples, J, Jones, M, Mitnaul, L, Sturgess, R, Healey, C, Yeoman, A, Gunasekera, A, Kooner, P, Kapur, K, Sathyanarayana, V, Kallis, Y, Subhani, J, Harvey, R, Mccorry, R, Rooney, P, Ramanaden, D, Evans, R, Mathialahan, T, Gasem, J, Shorrock, C, Bhalme, M, Southern, P, Tibble, J, Gorard, D, Jones, S, Srivastava, B, Foxton, M, Collins, C, Elphick, D, Karmo, M, Porras-Perez, F, Mendall, M, Yapp, T, Patel, M, Ede, R, Sayer, J, Jupp, J, Fisher, N, Carter, M, Koss, K, Shah, J, Piotrowicz, A, Scott, G, Grimley, C, Gooding, I, Williams, S, Tidbury, J, Lim, G, Cheent, K, Levi, S, Mansour, D, Beckley, M, Hollywood, C, Wong, T, Marley, R, Ramage, J, Gordon, H, Ridpath, J, Ngatchu, T, Bob Grover, V, Shidrawi, R, Abouda, G, Corless, L, Narain, M, Rees, I, Brown, A, Taylor-Robinson, S, Wilkins, J, Grellier, L, Banim, P, Das, D, Heneghan, M, Curtis, H, Matthews, H, Mohammed, F, Aldersley, M, Srirajaskanthan, R, Walker, G, Mcnair, A, Sharif, A, Sen, S, Bird, G, Prince, M, Prasad, G, Kitchen, P, Barnardo, A, Oza, C, Sivaramakrishnan, N, Gupta, P, Shah, A, Evans, C, Saha, S, Pollock, K, Bramley, P, Mukhopadhya, A, Barclay, S, Mcdonald, N, Bathgate, A, Palmer, K, Dillon, J, Rushbrook, S, Przemioslo, R, Mcdonald, C, Millar, A, Tai, C, Mitchell, S, Metcalf, J, Shaukat, S, Ninkovic, M, Shmueli, U, Davis, A, Naqvi, A, Lee, T, Ryder, S, Collier, J, Klass, H, Cramp, M, Sharer, N, Aspinall, R, Ghosh, D, Douds, A, Booth, J, Williams, E, Hussaini, H, Christie, J, Mann, S, Thorburn, D, Marshall, A, Patanwala, I, Ala, A, Maltby, J, Matthew, R, Corbett, C, Vyas, S, Singhal, S, Gleeson, D, Misra, S, Butterworth, J, George, K, Harding, T, Douglass, A, Mitchison, H, Panter, S, Shearman, J, Bray, G, Roberts, M, Butcher, G, Forton, D, Mahmood, Z, Cowan, M, Ch'Ng, C, Rahman, M, Whatley, G, Wesley, E, Mandal, A, Jain, S, Pereira, S, Wright, M, Trivedi, P, Gordon, F, Unitt, E, Palejwala, A, Austin, A, Vemala, V, Grant, A, Higham, A, Brind, A, Mathew, R, Cox, M, Ramakrishnan, S, King, A, Whalley, S, Fraser, J, Thomson, S, Bell, A, Wong, V, Kia, R, Gee, I, Keld, R, Ransford, R, Gotto, J, Millson, C, Cordell H. J., Fryett J. J., Ueno K., Darlay R., Aiba Y., Hitomi Y., Kawashima M., Nishida N., Khor S. -S., Gervais O., Kawai Y., Nagasaki M., Tokunaga K., Tang R., Shi Y., Li Z., Juran B. D., Atkinson E. J., Gerussi A., Carbone M., Asselta R., Cheung A., de Andrade M., Baras A., Horowitz J., Ferreira M. A. R., Sun D., Jones D. E., Flack S., Spicer A., Mulcahy V. L., Byan J., Han Y., Sandford R. N., Lazaridis K. N., Amos C. I., Hirschfield G. M., Seldin M. F., Invernizzi P., Siminovitch K. A., Ma X., Nakamura M., Mells G. F., Mason A., Vincent C., Xie G., Zhang J., Affronti A., Almasio P. L., Alvaro D., Andreone P., Andriulli A., Azzaroli F., Battezzati P. M., Benedetti A., Bragazzi M., Brunetto M., Bruno S., Calvaruso V., Cardinale V., Casella G., Cazzagon N., Ciaccio A., Coco B., Colli A., Colloredo G., Colombo M., Colombo S., Cristoferi L., Cursaro C., Croce L. S., Crosignani A., D'Amato D., Donato F., Elia G., Fabris L., Fagiuoli S., Ferrari C., Floreani A., Galli A., Giannini E., Grattagliano I., Lampertico P., Lleo A., Malinverno F., Mancuso C., Marra F., Marzioni M., Massironi S., Mattalia A., Miele L., Milani C., Morini L., Morisco F., Muratori L., Muratori P., Niro G. A., O'Donnell S., Picciotto A., Portincasa P., Rigamonti C., Ronca V., Rosina F., Spinzi G., Strazzabosco M., Tarocchi M., Tiribelli C., Toniutto P., Valenti L., Vinci M., Zuin M., Nakamura H., Abiru S., Nagaoka S., Komori A., Yatsuhashi H., Ishibashi H., Ito M., Migita K., Ohira H., 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., 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., Tanaka A., Takikawa 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., Kawata K., 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., H E., Tanaka T., Yamashiki N., Tamura S., Sugawara Y., Kokudo N., Chalasani N., Luketic V., Odin J., Chopra K., Abecasis G., Cantor M., Coppola G., Economides A., Lotta L. A., Overton J. D., Reid J. G., Shuldiner A., Beechert C., Forsythe C., Fuller E. D., Gu Z., Lattari M., Lopez A., Schleicher T. D., Padilla M. S., Toledo K., Widom L., Wolf S. E., Pradhan M., Manoochehri K., Ulloa R. H., Bai X., Balasubramanian S., Barnard L., Blumenfeld A., Eom G., Habegger L., Hawes A., Khalid S., Maxwell E. K., Salerno W., Staples J. C., Jones M. B., Mitnaul L. J., Sturgess R., Healey C., Yeoman A., Gunasekera A. V., Kooner P., Kapur K., Sathyanarayana V., Kallis Y., Subhani J., Harvey R., McCorry R., Rooney P., Ramanaden D., Evans R., Mathialahan T., Gasem J., Shorrock C., Bhalme M., Southern P., Tibble J. A., Gorard D. A., Jones S., Mells G., Mulcahy V., Srivastava B., Foxton M. R., Collins C. E., Elphick D., Karmo M., Porras-Perez F., Mendall M., Yapp T., Patel M., Ede R., Sayer J., Jupp J., Fisher N., Carter M. J., Koss K., Shah J., Piotrowicz A., Scott G., Grimley C., Gooding I. R., Williams S., Tidbury J., Lim G., Cheent K., Levi S., Mansour D., Beckley M., Hollywood C., Wong T., Marley R., Ramage J., Gordon H. M., Ridpath J., Ngatchu T., Bob Grover V. P., Shidrawi R. G., Abouda G., Corless L., Narain M., Rees I., Brown A., Taylor-Robinson S., Wilkins J., Grellier L., Banim P., Das D., Heneghan M. A., Curtis H., Matthews H. C., Mohammed F., Aldersley M., Srirajaskanthan R., Walker G., McNair A., Sharif A., Sen S., Bird G., Prince M. I., Prasad G., Kitchen P., Barnardo A., Oza C., Sivaramakrishnan N. N., Gupta P., Shah A., Evans C. D., Saha S., Pollock K., Bramley P., Mukhopadhya A., Barclay S. T., McDonald N., Bathgate A. J., Palmer K., Dillon J. F., Rushbrook S. M., Przemioslo R., McDonald C., Millar A., Tai C., Mitchell S., Metcalf J., Shaukat S., Ninkovic M., Shmueli U., Davis A., Naqvi A., Lee T. J., Ryder S., Collier J., Klass H., Cramp M. E., Sharer N., Aspinall R., Ghosh D., Douds A. C., Booth J., Williams E., Hussaini H., Christie J., Mann S., Thorburn D., Marshall A., Patanwala I., Ala A., Maltby J., Matthew R., Corbett C., Vyas S., Singhal S., Gleeson D., Misra S., Butterworth J., George K., Harding T., Douglass A., Mitchison H., Panter S., Shearman J., Bray G., Roberts M., Butcher G., Forton D., Mahmood Z., Cowan M., Ch'ng C. L., Rahman M., Whatley G. C. A., Wesley E., Mandal A., Jain S., Pereira S. P., Wright M., Trivedi P., Gordon F. H., Unitt E., Palejwala A., Austin A., Vemala V., Grant A., Higham A. D., Brind A., Mathew R., Cox M., Ramakrishnan S., King A., Whalley S., Fraser J., Thomson S. J., Bell A., Wong V. S., Kia R., Gee I., Keld R., Ransford R., Gotto J., and Millson C.

Abstract

Backgrounds & Aims: Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intrahepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening. Methods: We combined new and existing genotype data for 10,516 cases and 20,772 controls from 5 European and 2 East Asian cohorts. Results: We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57th genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, which each play key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, JAK-STAT signalling, and differentiation of T helper (TH)1 and TH17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some of which are well-established in the treatment of other autoimmune disorders. Conclusions: This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders. Lay summary: Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10,516 people with PBC and 20,772 healthy individuals recruited in Canada, China

Published
2021

20. Multiple therapeutic targets in rare cholestatic liver diseases: Time to redefine treatment strategies

Author

Gerussi, A, D'Amato, D, Cristoferi, L, O'Donnell, S, Carbone, M, Invernizzi, P, Gerussi A., D'Amato D., Cristoferi L., O'Donnell S. E., Carbone M., Invernizzi P., Gerussi, A, D'Amato, D, Cristoferi, L, O'Donnell, S, Carbone, M, Invernizzi, P, Gerussi A., D'Amato D., Cristoferi L., O'Donnell S. E., Carbone M., and Invernizzi P.

Abstract

Primary biliary cholangitis and primary sclerosing cholangitis are rare diseases affecting the bile ducts and the liver. The limited knowledge of their pathogenesis leads to limited therapeutic options. Nevertheless, the landscape of novel therapies for these cholangiopathies is now rapidly changing, providing new treatment opportunities for patients and clinicians involved in their care. The aim of this review is to summarize the evidence of novel molecules under investigation for primary biliary cholangitis and primary sclerosing cholangitis and to discuss how they can potentially change current treatment paradigms.

Published
2020

22. New Therapeutic Targets in Autoimmune Cholangiopathies

Author

Gerussi, A, Luca, M, Cristoferi, L, Ronca, V, Mancuso, C, Milani, C, D'Amato, D, O'Donnell, S, Carbone, M, Invernizzi, P, Gerussi A., Luca M., Cristoferi L., Ronca V., Mancuso C., Milani C., D'Amato D., O'Donnell S. E., Carbone M., Invernizzi P., Gerussi, A, Luca, M, Cristoferi, L, Ronca, V, Mancuso, C, Milani, C, D'Amato, D, O'Donnell, S, Carbone, M, Invernizzi, P, Gerussi A., Luca M., Cristoferi L., Ronca V., Mancuso C., Milani C., D'Amato D., O'Donnell S. E., Carbone M., and Invernizzi P.

Abstract

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are autoimmune cholangiopathies characterized by limited treatment options. A more accurate understanding of the several pathways involved in these diseases has fostered the development of novel and promising targeted drugs. For PBC, the characterization of the role of farnesoid X receptor (FXR) and perixosome-proliferator activated receptor (PPAR) has paved the way to several clinical trials including different molecules with choleretic and antinflammatory action. Conversely, different pathogenetic models have been proposed in PSC such as the “leaky gut” hypothesis, a dysbiotic microbiota or a defect in mechanisms protecting against bile acid toxicity. Along these theories, new treatment approaches have been developed, ranging from drugs interfering with trafficking of lymphocytes from the gut to the liver, fecal microbiota transplantation or new biliary acids with possible immunomodulatory potential. Finally, for both diseases, antifibrotic agents are under investigation. In this review, we will illustrate current understanding of molecular mechanisms in PBC and PSC, focusing on actionable biological pathways for which novel treatments are being developed.

Published
2020

23. Accuracy of Liver Stiffness Measurement in assessing liver fibrosis in naïve patients with Primary Biliary Cholangitis

Author

Cristoferi, L, Nardi, A, Viganò, M, Rigamonti, C, Degasperi, E, Cardinale, V, Labanca, S, Zucchini, N, Leutner, M, Venere, R, Picciotto, A, Cazzagon, N, Lucà, M, Overi, D, Gerussi, A, D’Amato, D, O’Donnell, S, Cerini, F, De Benedittis, C, Cadamuro, M, Malinverno, F, Floreani, A, Alvaro, D, Gaudio, E, Invernizzi, P, Carpino, G, Carbone, M, Cristoferi L, Nardi A, Viganò M, Rigamonti C, Degasperi E, Cardinale V, Labanca S, Zucchini N, Leutner M, Venere R, Picciotto A, Cazzagon N, Lucà M, Overi D, Gerussi A, D’Amato D, O’Donnell S, Cerini F, De Benedittis C, Cadamuro M, Malinverno F, Floreani A, Alvaro D, Gaudio E, Invernizzi P, Carpino G, Carbone M, Cristoferi, L, Nardi, A, Viganò, M, Rigamonti, C, Degasperi, E, Cardinale, V, Labanca, S, Zucchini, N, Leutner, M, Venere, R, Picciotto, A, Cazzagon, N, Lucà, M, Overi, D, Gerussi, A, D’Amato, D, O’Donnell, S, Cerini, F, De Benedittis, C, Cadamuro, M, Malinverno, F, Floreani, A, Alvaro, D, Gaudio, E, Invernizzi, P, Carpino, G, Carbone, M, Cristoferi L, Nardi A, Viganò M, Rigamonti C, Degasperi E, Cardinale V, Labanca S, Zucchini N, Leutner M, Venere R, Picciotto A, Cazzagon N, Lucà M, Overi D, Gerussi A, D’Amato D, O’Donnell S, Cerini F, De Benedittis C, Cadamuro M, Malinverno F, Floreani A, Alvaro D, Gaudio E, Invernizzi P, Carpino G, and Carbone M

Abstract

Background and Aims: Non-invasive evaluation of liver fibrosis in primary biliary cholangitis (PBC) with Liver Stiffness Measurements (LSM) by Transient Elastography (TE) is routinely undertaken at diagnosis for disease staging and risk stratification. However, evidence on correlation between LSM and liver fibrosis is based on cross-sectional studies in PBC-treated patients. Moreover, the impact of potential confounders, e.g. cholestasis and steatosis, is unclear. Aim of our study was to investigate the accuracy of LSM to predict moderate to severe fibrosis in newly diagnosed PBC patients naïve to therapy. Method: We collected data from 182 adult patients who underwent liver biopsy (LB) for PBC at diagnosis in five Italian liver centers from Jan 2006 through Aug 2019. TE examinations within 3 months from LB were included. LB were scored centrally by two expert pathologists, blinded to clinical data and disease stage, according to Ludwig staging system. In all patients Fibrosis-4 (FIB-4) and aspartate aminotransferase [AST]/platelet ratio (APRI) score have been calculated. Diagnostic accuracy of LSM, FIB-4 and APRI score was estimated using the area under the receiver operating characteristic curves (AUROCs) for fibrosis. The effects of liver biochemistry and histological parameters were appraised using multivariable logistic model. Results: 123 PBC patients had adequate LB (≥9 portal tracts) and valid LSM values. According to histological assessment, Ludwig stage distribution was as follows: stage I = 38 (30.9%), stage II = 46(37.4%), stage III = 27 (21.9%), stage IV = 12 (9.8%). TE identified patients with Ludwig stage III/IV with an AUROC of 0.83 (95% confidence interval [CI] (0.74, 0.90)) (Fig.1). The optimal threshold was identified at 6.75kPa (CI (6.55, 7.50)), with 85% of sensitivity, 75% of specificity, 78% of accuracy and 6 false negative. TE was superior to APRI and FIB-4 having AUROC of 0.638 (CI = (0.535, 0.740)) and 0.641 (CI = (0.516, 0.766)), respecti

Published
2020

24. On the prediction of keyholes by propagation of the MOID

Author

Fuentes Muñoz, O, Pedrós Faura, A, Amato, D, Scheeres, DJ, and McMahon, JW

Subjects
Physics::Space Physics, Astrophysics::Earth and Planetary Astrophysics
Abstract

In this work we study the variation of the MOID between encounters so that we can determine the keyholes that exist in the B-plane. We compare the different methods to propagate the orbits of asteroids between planetary close encounters.

Published
2022

25. Enforcing state constraints in dynamical systems modelled with neural networks

Author

Cho, N and Amato, D

Abstract

Deep neural networks (NNs) are usually trained with unconstrained optimisation algorithms. With a reasoning similar to the constrained Kalman filter, incorporating known information in the form of equality constraints at certain checkpoints can potentially improve prediction accuracy. For continuous-time dynamical systems, the state constraints should be enforced in an ordinary differential equation (ODE) model which embeds NNs to represent a learned part of dynamics or a control policy. To this end, incremental correction methods are developed for post-processing of the dynamical systems modelled with NNs for which the parameters are determined by previous optimisation process. The proposed approach is to find a small amount of local correction needed to satisfy given state constraints with the updated solution. Algorithms for updating the neural network parameters and the control function are considered.

Published
2022

26. Effects of dopamine on leptin release and leptin gene (OB) expression in adipocytes from obese and hypertensive patients

Author

Alvarez-Aguilar C, Alvarez-Paredes AR, Lindholm B, Stenvinkel P, García-López E, Mejía-Rodríguez O, López-Meza JE, Amato D, and Paniagua R

Subjects
Diseases of the genitourinary system. Urology, RC870-923
Abstract

Cleto Alvarez-Aguilar,1–3 Alfonso Rafael Alvarez-Paredes,2 Bengt Lindholm,4 Peter Stenvinkel,4 Elvia García-López,4 Oliva Mejía-Rodríguez,5 Joel Edmundo López-Meza,6 Dante Amato,7 Ramon Paniagua8 1Hospital General Regional N°1, Instituto Mexicano del Seguro Social (IMSS), Morelia, 2Facultad de Ciencias Médicas y Biológicas "Dr. Ignacio Chávez" Universidad Michoacana de San Nicolás de Hidalgo (UMSNH), Morelia, Michoacán, 3División de Estudios Superiores, Universidad Nacional Autónoma de México (UNAM), México DF, México; 4Department of Clinical Science Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; 5Coordinación Delegacional de Investigación en Salud, IMSS, Morelia, 6Centro Multidisciplinario de Estudios en Biotecnología (CMEB), UMSNH, Morelia, Michoacán, 7Facultad de Estudios Superiores Iztacala, UNAM, Tlalnepantla, 8Unidad de Investigación en Enfermedades Nefrológicas, Hospital de Especialidades, CMN Siglo XXI, IMSS, México DF, México Background: A reduction of dopaminergic (DAergic) activity with increased prolactin levels has been found in obese and hypertensive patients, suggesting its involvement as a pathophysiological mechanism promoting hypertension. Similarly, leptin action increasing sympathetic activity has been proposed to be involved in mechanisms of hypertension. The aim of this study was to analyze the effects of DA, norepinephrine (NE), and prolactin on leptin release and leptin gene (OB) expression in adipocytes from obese and hypertensive patients. Methods: Leptin release and OB gene expression were analyzed in cultured adipocytes from 16 obese and hypertensive patients treated with DA (0.001, 0.01, 0.1, and 1.0 µmol/L), NE (1.0 µmol/L), insulin (0.1 µmol/L), and prolactin (1.0 µmol/L), and from five nonobese and normotensive controls treated with DA (1 µmol/L), NE (1 µmol/L), insulin (0.1 µmol/L), and prolactin (1.0 µmol/L). Results: A dose-related reduction of leptin release and OB gene messenger ribonucleic acid expression under different doses of DA was observed in adipocytes from obese hypertensive patients. Whereas prolactin treatment elicited a significant increase of both leptin release and OB gene expression, NE reduced these parameters. Although similar effects of DA and NE were observed in adipocytes from controls, baseline values in controls were reduced to 20% of the value in adipocytes from obese hypertensive patients. Conclusion: These results suggest that DAergic deficiency contributes to metabolic disorders linked to hyperleptinemia in obese and hypertensive patients. Keywords: dopamine, leptin, cultured adipocytes, obesity, hypertension

Published
2013

27. Spectral analysis of US Space Catalog ephemerides for LAGEOS-1

Author

Araya, IA and Amato, D

Subjects
Physics::Space Physics
Abstract

The US Space Catalog is the primary source of public ephemeris data on Resident Space Objects. Catalog ephemerides are published as Two-Line Elements (TLEs) which were originally defined as singly-averaged elements according to the Simplified General Perturbations 4 (SGP4) theory. Recently, TLEs have been derived through numerical fits to underlying special perturbations solutions. We conjecture that the numerical fit results in short-periodic terms being embedded in TLEs, and analyse the amplitude spectrum of piecewise continuous osculating solutions derived from TLE sequences for the LAGEOS-1 satellite. The orbital elements spectra contain short-periodic terms at frequencies larger than those reconstructed by the SGP4 theory, which supports the conjecture. For LAGEOS-1, short-periodic terms in addition to those already considered by SGP4 should not be added to TLEs in an effort to improve their accuracy, as they are likely to have been already partially embedded in the TLEs.

Published
2022

29. Frequency domain analysis of the mean and osculating trajectories of LAGEOS-1

Author

Amato, D and Araya, IA

Subjects
Physics::Space Physics
Abstract

Several crucial developments in orbital mechanics are obtained through the method of averaging, which is equivalent to integrating only the dominant harmonics of the Fourier series of the dynamics. Frequency analysis of the trajectory expressed in orbital elements facilitates an in-depth understanding of Earth satellite dynamics, and facilitates the interpretation of numerical results from special perturbations within the theoretical framework of celestial mechanics. In this work, we examine recent Two-Line Element series for LAGEOS-1 in the frequency domain, highlighting the presence of short-periodic terms that are likely introduced in the generation of TLEs from observations. We also propose employing well-established methods from signal processing, such as spectrograms, to examine the evolution of dissipative systems such as satellites in LEO.

Published
2021

30. Quality of life in patients with primary biliary cholangitis: a cross-geographical comparison

Author

Montali, L, Gragnano, A, Miglioretti, M, Frigerio, A, Vecchio, L, Gerussi, A, Cristoferi, L, Ronca, V, D’Amato, D, O’Donnell, S, Mancuso, C, Lucà, M, Yagi, M, Reig, A, Jopson, L, Pilar, S, Jones, D, Pares, A, Mells, G, Tanaka, A, Carbone, M, Invernizzi, P, Montali, Lorenzo, Gragnano, Andrea, Miglioretti, Massimo, Frigerio, Alessandra, Vecchio, Luca, Gerussi, Alessio, Cristoferi, Laura, Ronca, Vincenzo, D’Amato, Daphne, O’Donnell, Sarah Elizabeth, Mancuso, Clara, Lucà, Martina, Yagi, Minami, Reig, Anna, Jopson, Laura, Pilar, Sesé, Jones, Dave, Pares, Albert, Mells, George, Tanaka, Atsushi, Carbone, Marco, Invernizzi, Pietro, Montali, L, Gragnano, A, Miglioretti, M, Frigerio, A, Vecchio, L, Gerussi, A, Cristoferi, L, Ronca, V, D’Amato, D, O’Donnell, S, Mancuso, C, Lucà, M, Yagi, M, Reig, A, Jopson, L, Pilar, S, Jones, D, Pares, A, Mells, G, Tanaka, A, Carbone, M, Invernizzi, P, Montali, Lorenzo, Gragnano, Andrea, Miglioretti, Massimo, Frigerio, Alessandra, Vecchio, Luca, Gerussi, Alessio, Cristoferi, Laura, Ronca, Vincenzo, D’Amato, Daphne, O’Donnell, Sarah Elizabeth, Mancuso, Clara, Lucà, Martina, Yagi, Minami, Reig, Anna, Jopson, Laura, Pilar, Sesé, Jones, Dave, Pares, Albert, Mells, George, Tanaka, Atsushi, Carbone, Marco, and Invernizzi, Pietro

Abstract

Background & aims: Several symptoms impair the quality of life (QoL) of patients with primary biliary cholangitis (PBC). They are reported to vary significantly in different countries. Aim of our study was to explore whether there is a geographical clustering that accounts for symptoms in PBC. Methods: Data was analysed from four cohorts of PBC patients from the UK, Spain, Japan and Italy using the PBC-27 scale. Results: Overall, 569 patients from four cohorts were identified, including 515 females (90.5%) with a mean age of 61 years. The analysis provided evidence for strict factorial invariance of the scale, a robust indicator of its validity for cross-cultural research. The mean of the fatigue domain of British patients was significantly greater than that of the Japanese (p ​< ​0.05), Italian (p ​< ​0.05), and Spanish patients (p ​< ​0.001). The mean of the cognitive domain after 54 years of age, was significantly greater in the British patients than in the Japanese (p ​< ​0.05) and Spanish patients (p ​< ​0.01). However, after 69 years of age, there were not significant differences between countries. The mean of the emotion domain after 54 years of age, was greater in the British that in the Spanish (p ​< ​0.01) and Italian patients (p ​< ​0.01). Conclusions: Differences in the four countries concerning fatigue, cognitive and emotional dysfunction were found. The association of latitude and symptoms might provide new insights into the role of sun exposure, genetics and/or cultural component into disease phenotype in PBC.

Published
2021

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

Author

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, Federica, Fagiuoli, Stefano, Almasio, P. L., Giannini, E., Cursaro, C., Colombo, M., Valenti, L., Miele, Luca, Andriulli, A., Niro, G. A., Grattagliano, I., Morini, L., Casella, G., Vinci, Maria Rosaria, 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., Donato F., Fagiuoli S., Miele L. (ORCID:0000-0003-3464-0068), Vinci M., 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, Federica, Fagiuoli, Stefano, Almasio, P. L., Giannini, E., Cursaro, C., Colombo, M., Valenti, L., Miele, Luca, Andriulli, A., Niro, G. A., Grattagliano, I., Morini, L., Casella, G., Vinci, Maria Rosaria, 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., Donato F., Fagiuoli S., Miele L. (ORCID:0000-0003-3464-0068), and Vinci M.

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

32. Accuracy of Transient Elastography in assessing fibrosis at diagnosis in naïve patients with Primary Biliary Cholangitis: a dual cut-off approach

Author

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, Carbone, M, Cristoferi, Laura, Calvaruso, Vincenza, Overi, Diletta, Viganò, Mauro, Rigamonti, Cristina, Degasperi, Elisabetta, Cardinale, Vincenzo, Labanca, Sara, Zucchini, Nicola, Fichera, Anna, Di Marco, Vito, Leutner, Monica, Venere, Rosanna, Picciotto, Antonino, Lucà, Martina, Mulinacci, Giacomo, Palermo, Andrea, Gerussi, Alessio, D'Amato, Daphne, O'Donnell, Sarah Elisabeth, Cerini, Federica, De Benedittis, Carla, Malinverno, Federica, Ronca, Vincenzo, Mancuso, Clara, Cazzagon, Nora, Ciaccio, Antonio, Barisani, Donatella, Marzioni, Marco, Floreani, Annarosa, Alvaro, Domenico, Gaudio, Eugenio, Invernizzi, Pietro, Carpino, Guido, Nardi, Alessandra, Carbone, Marco, 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, Carbone, M, Cristoferi, Laura, Calvaruso, Vincenza, Overi, Diletta, Viganò, Mauro, Rigamonti, Cristina, Degasperi, Elisabetta, Cardinale, Vincenzo, Labanca, Sara, Zucchini, Nicola, Fichera, Anna, Di Marco, Vito, Leutner, Monica, Venere, Rosanna, Picciotto, Antonino, Lucà, Martina, Mulinacci, Giacomo, Palermo, Andrea, Gerussi, Alessio, D'Amato, Daphne, O'Donnell, Sarah Elisabeth, Cerini, Federica, De Benedittis, Carla, Malinverno, Federica, Ronca, Vincenzo, Mancuso, Clara, Cazzagon, Nora, Ciaccio, Antonio, Barisani, Donatella, Marzioni, Marco, Floreani, Annarosa, Alvaro, Domenico, Gaudio, Eugenio, Invernizzi, Pietro, Carpino, Guido, Nardi, Alessandra, and Carbone, Marco

Abstract

Background and Aims: Liver fibrosis holds a relevant prognostic meaning in primary biliary cholangitis (PBC). Noninvasive 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 (AF) at disease presentation in PBC. Approach and Results: We collected data from 167 consecutive treatment-naïve 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 the Ludwig system. Diagnostic accuracy was estimated using the area under the receiver operating characteristic curves (AUROCs) for AF (Ludwig stage ≥III). Effects of biochemical and clinical parameters on liver stiffness measurement (LSM) were appraised. The derivation cohort consisted of 126 patients with valid LSM and LB; VCTE identified patients with AF with an AUROC of 0.89. LSM cutoffs ≤6.5 and >11.0 kPa enabled to exclude and confirm, respectively, AF (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 that the only parameter affecting LSM was fibrosis stage. No association was found with BMI and liver biochemistry. Conclusions: In a multicenter study of treatment-naïve PBC patients, we identified two cutoffs (LSM ≤6.5 and >11.0 kPa) able to discriminate at diagnosis the absence or presence, respectively, of AF in PBC patients, with external validation. In patients with LSM between these two cutoffs, VCTE is not reliable and liver biopsy should be evaluated for accurate disease staging. BMI and liver biochemistry did not affect LSMs.

Published
2021

35. 1st Conference Clinical Trials on Alzheimer’s Disease September 17-18-19, 2008 School of Medecine Montpellier, France

Author

Gabelle, A., Roche, S., Gény, C., Portet, F., Touchon, J., Lehmann, S., De Meyer, G., Shapiro, F., Vanderstichele, H., Vanmechelen, E., Engelborghs, S., De Deyn, P. P., Shaw, L., Trojanowski, J., Nestor, S. M., Rupsingh, R., Borrie, M., Smith, M., Wells, J. L., Bartha, R., Blennow, K., De Meyer, G., Hansson, O., Minthon, L., Wallin, A., Zetterberg, H., Lewezuk, P., Vandertischele, H., Kornhuber, J., Wiltfang, J., Iqbal, K., Chalbot, S., Grundke-Iqbal, I., Gertz, H. J., Berwig, M., Leicht, H., Zhu, C. W., Leibman, C., Townsend, R., Mclaughlin, T., Scarmeas, N., Albert, M., Brandt, J., Blacker, D., Sano, M., Stern, Y., Bravo, G., Dubois, M. F., Hansel, S., Duguet, A. M., Robert, P. H., Deudon, A., Ake, N., Gervais, X., Leone, E., Lavallart, B., Amato, D., Zavitz, K., Green, R. C., Schneider, L. S., Swabb, E., Van Kan, G. Abellan, Carrie, I., Gillette, S., Soto, M. E., Gardette, J., Przybylski, C., Andrieu, S., Vellas, B., Dangour, A. D., Allen, E., Elbourne, D., Fletcher, A., Richards, M., Uauy, R., Green, R. C., Schneider, L. S., Zavitz, K. H., Wurtman, R. J., Peters, O., Lorenz, D., Möller, H. J., Frölich, L., Heuser, I., Vandenberghe, R., Thurfjell, L., Owenius, R., Brooks, D. J., Nelissen, N., Koole, M., Bormans, G., Van Laere, K., Boada, M., Muñoz, J., Tárraga, L., Ortiz, P., Hernández, I., Becker, J., López, O., Buendia, M., Pla, R., Grifols, J. R., Paez, A., Núñez, L., Ferrer, I., Lachno, D. R., De Groote, G., Kostanjevecki, V., Siemers, E. R., Willey, M. B., Ruiz, A., Ramírez-Lorca, R., Sáez, M. E., Mauleón, A., Rosende-Roca, M., Martínez-Lage, P., Gutiérrez, M., Real, L. Miguel, López-arrieta, J., Gayán, J., Antúnez, C., González-Pérez, A., Hugonot-Diener, L., Bchiri, J. El, Fraisse, M. L., Von Raison, F., Bone, M., Duron, E., Husson, J. M., Meeuwsen, E. J., Melis, R. J. F., Adang, E. M., Krabbe, P. F., Schölzel-Dorenbos, C. J. M., Ruckert, M. G. M. Olde, Truemner, J., Best, S., Lozanski, M., Nsiah, C., Wells, J., Tractenberg, R. E., Tractenberg, R. E., Chu, L. W., Yik, P. Y., Mok, W., Chung, C. P., Gauthier, S., Douillet, P., Doody, R., Fox, N. C., Orgogozo, J. M., Ingenbleek, Y., Bienvenu, J., Molloy, D. W., Standish, T., Cowan, D., Almeida, E., Diloreto, P., Woolmore-Goodwin, S., Clarke, J., Berardi, P., Smith, M., Purcell, T., Woolmore-Goodwin, S., Gutmanis, I., Borrie, M., Robert, P. H., Reynish, E., Cantet, C., Erder, M. H., Fillit, H., Hofbauer, R. K., Setyawan, J., Tourkodimitris, S., Fridman, M., Lyketsos, C., Unzeta, M., Valente, T., Hidalgo, J., Ramirez, B., Anglés, N., Morelló, J. R., Reguant, J., Boada, M., Claassen, J. A., Van Beek, A. H., Olde Rikkert, M. G., Roca, I., Cuberas, G., Castell, J., Buendia, M., Pla, R., Núñez, L., Ferrer, I., Latger, C., Tramoni, E., Elkhoury, C., Aubert-Khalfa, S., Ceccaldi, M., Schneeberger, A., Mandler, M., Otava, O., Mattner, F., Schmidt, W., Gatignol, P., David, C., Guitton, C., Plaza, M., Szaniszlo, P., German, P., Hajas, G., Kruzel, M., Boldogh, I., Wesnes, K., Satek, S., Turk, P., Satek, S., Vinay, M., Wetten, S., Li, H., Galwey, N., Gibson, R. A., Irizarry, M. C., Nourhashémi, F., Gillette-Guyonnet, S., Andrieu, S., Rolland, Y., Ousset, P. J., Verwey, N. A., Blennow, K., Clark, C., Cole, G. M., De Deyn, P. P., Galasko, D., Hampel, H., Hartmann, T., Kapaki, E., Lannfelt, L., Mehta, P. D., Parnetti, L., Petzold, A., Pirttila, T., Saleh, L., Skinningsrud, A., Swieten, J. C. V., Verbeek, M. M., Wiltfang, J., Younkin, S., Blankenstein, M. A., Ishihara-Paul, L., Viswanathan, A., Allen, J. K., Hyman, B. T., Betensky, R., Weil, J., The Alzheimer’s Disease Neuroimaging Initiative, The MAPT Study Investigators, The Xaliproden Ad Study Team, and the PLASA Group

Published
2008
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36. Reviewing the interface of bioeconomy and ecosystem service research

Author

D’Amato, D., Bartkowski, Bartosz, Droste, N., D’Amato, D., Bartkowski, Bartosz, and Droste, N.

Abstract

The bioeconomy is currently being globally promoted as a sustainability avenue involving several societal actors. While the bioeconomy is broadly about the substitution of fossil resources with bio-based ones, three main (competing or complementary) bioeconomy visions are emerging in scientific literature: resource, biotechnology, and agroecology. The implementation of one or more of these visions into strategies implies changes to land use and thus ecosystem services delivery, with notable trade-offs. This review aims to explore the interdisciplinary space at the interface of these two concepts. We reviewed scientific publications explicitly referring to bioeconomy and ecosystem services in their title, abstract, or keywords, with 45 documents identified as relevant. The literature appeared to be emerging and fragmented but eight themes were discernible (in order of decreasing occurrence frequency in the literature): a. technical and economic feasibility of biomass extraction and use; b. potential and challenges of the bioeconomy; c. frameworks and tools; d. sustainability of bio-based processes, products, and services; e. environmental sustainability of the bioeconomy; f. governance of the bioeconomy; g. biosecurity; h. bioremediation. Approximately half of the documents aligned to a resource vision of the bioeconomy, with emphasis on biomass production. Agroecology and biotechnology visions were less frequently found, but multiple visions generally tended to occur in each document. The discussion highlights gaps in the current research on the topic and argues for communication between the ecosystem services and bioeconomy communities to forward both research areas in the context of sustainability science.

Published
2020

37. Consensus statement of the Italian society of pediatric allergy and immunology for the pragmatic management of children and adolescents with allergic or immunological diseases during the COVID-19 pandemic

Author

Cardinale, F, Ciprandi, G, Barberi, S, Bernardini, R, Caffarelli, C, Calvani, M, Cavagni, G, Galli, E, Minasi, D, Del Giudice, M, Moschese, V, Novembre, E, Paravati, F, Peroni, D, Tosca, M, Traina, G, Tripodi, S, Marseglia, G, Amato, D, Anania, C, Anastasio, E, Antignani, R, Arasi, S, Baldassarre, M, Baldo, E, Barbalace, A, Barni, S, Betti, F, Bianchi, A, Bolzacchini, E, Bonini, M, Bottau, P, Bozzetto, S, Brighetti, M, Caimmi, D, Caimmi, S, Calzone, L, Cancrini, C, Caminiti, L, Capata, G, Capra, L, Capristo, C, Carboni, E, Carella, F, Castagnoli, R, Chiappini, E, Chiera, F, Chinellato, I, Chini, L, Cipriani, F, Civitelli, F, Comberiati, P, Contini, D, Corrente, S, Cravidi, C, Crisafulli, G, Cuomo, B, D'Auria, E, D'Elios, S, Decimo, F, Giustina, A, Piane, R, De Filippo, M, De Vittori, V, Diaferio, L, Di Mauro, M, Duse, M, Federici, S, Felice, G, Fenu, G, Ferrante, G, Foti, T, Franceschini, F, Ghiglioni, D, Giardino, G, Giovannini, M, Indirli, G, Indolfi, C, Landi, M, La Torre, F, Leone, L, Licari, A, Liotti, L, Lougaris, V, Maiello, N, Mantecca, P, Manti, S, Mariani, M, Martelli, A, Mastrorilli, C, Mastrorilli, V, Montin, D, Mori, F, Olcese, R, Ottaviano, G, Paglialunga, C, Pajno, G, Parisi, G, Pattini, S, Pecoraro, L, Pelosi, U, Pignata, C, Ricci, G, Ricci, S, Rizzi, S, Rizzo, C, Rosati, S, Rosso, P, Sangerardi, M, Santoro, A, Saretta, F, Sarti, L, Sartorio, M, Sgruletti, M, Soresina, A, Sfika, I, Sgrulletti, M, Tesse, N, Tranchino, V, Travaglini, A, Velia, M, Verduci, E, Vernich, M, Veronelli, E, Volpi, S, Votto, M, Zicari, A, Cardinale, F, Ciprandi, G, Barberi, S, Bernardini, R, Caffarelli, C, Calvani, M, Cavagni, G, Galli, E, Minasi, D, Del Giudice, M, Moschese, V, Novembre, E, Paravati, F, Peroni, D, Tosca, M, Traina, G, Tripodi, S, Marseglia, G, Amato, D, Anania, C, Anastasio, E, Antignani, R, Arasi, S, Baldassarre, M, Baldo, E, Barbalace, A, Barni, S, Betti, F, Bianchi, A, Bolzacchini, E, Bonini, M, Bottau, P, Bozzetto, S, Brighetti, M, Caimmi, D, Caimmi, S, Calzone, L, Cancrini, C, Caminiti, L, Capata, G, Capra, L, Capristo, C, Carboni, E, Carella, F, Castagnoli, R, Chiappini, E, Chiera, F, Chinellato, I, Chini, L, Cipriani, F, Civitelli, F, Comberiati, P, Contini, D, Corrente, S, Cravidi, C, Crisafulli, G, Cuomo, B, D'Auria, E, D'Elios, S, Decimo, F, Giustina, A, Piane, R, De Filippo, M, De Vittori, V, Diaferio, L, Di Mauro, M, Duse, M, Federici, S, Felice, G, Fenu, G, Ferrante, G, Foti, T, Franceschini, F, Ghiglioni, D, Giardino, G, Giovannini, M, Indirli, G, Indolfi, C, Landi, M, La Torre, F, Leone, L, Licari, A, Liotti, L, Lougaris, V, Maiello, N, Mantecca, P, Manti, S, Mariani, M, Martelli, A, Mastrorilli, C, Mastrorilli, V, Montin, D, Mori, F, Olcese, R, Ottaviano, G, Paglialunga, C, Pajno, G, Parisi, G, Pattini, S, Pecoraro, L, Pelosi, U, Pignata, C, Ricci, G, Ricci, S, Rizzi, S, Rizzo, C, Rosati, S, Rosso, P, Sangerardi, M, Santoro, A, Saretta, F, Sarti, L, Sartorio, M, Sgruletti, M, Soresina, A, Sfika, I, Sgrulletti, M, Tesse, N, Tranchino, V, Travaglini, A, Velia, M, Verduci, E, Vernich, M, Veronelli, E, Volpi, S, Votto, M, and Zicari, A

Abstract

The COVID-19 pandemic has surprised the entire population. The world has had to face an unprecedented pandemic. Only, Spanish flu had similar disastrous consequences. As a result, drastic measures (lockdown) have been adopted worldwide. Healthcare service has been overwhelmed by the extraordinary influx of patients, often requiring high intensity of care. Mortality has been associated with severe comorbidities, including chronic diseases. Patients with frailty were, therefore, the victim of the SARS-COV-2 infection. Allergy and asthma are the most prevalent chronic disorders in children and adolescents, so they need careful attention and, if necessary, an adaptation of their regular treatment plans. Fortunately, at present, young people are less suffering from COVID-19, both as incidence and severity. However, any age, including infancy, could be affected by the pandemic. Based on this background, the Italian Society of Pediatric Allergy and Immunology has felt it necessary to provide a Consensus Statement. This expert panel consensus document offers a rationale to help guide decision-making in the management of children and adolescents with allergic or immunologic diseases.

Published
2020

38. 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

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, Carbone, M, O'Donnell, SE, 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, Carbone, M, and O'Donnell, SE

Published
2020

40. Phase 3 Trials of Ixekizumab in Moderate-to-Severe Plaque Psoriasis

Author

Gordon, K. B, Blauvelt, A., Papp, K. A., Langley, R. G., Luger, T., Ohtsuki, M., Reich, K., Amato, D., Ball, S. G., Braun, D. K., Cameron, G. S., Erickson, J., Konrad, R. J., Muram, T. M., Nickoloff, B. J., Osuntokun, O. O., Secrest, R. J., Zhao, F., Mallbris, L., Leonardi, C. L., Uncover, 1 Study Group: Holly Hake Harris, Matheson, Robert T., Michael, Bukhalo, John H., Tu, Crowley, Jeffrey J., Grande, Kimberly K., Adnan, Nasir, Boni Elizabeth Elewski, James Alan Solomon, Liebhild, Stratmann, Claudia, Buettner, Thomas Peter Dirschka, Margrit Ruth Simon, Jens, Ulrich, Christine, Grigat, Mathias, Augustin, Andrei, Khariouzov, Gerhard, Sattler, Hans Michael Ockenfels, Fredrick Richard Behringer, Hector, Wiltz, Francisco, Flores, Kuettel, Kevin D., Ira Hughes Thorla, Jeffrey Keith Moore, Waterman, Gary L., George Joji Murakawa, Scott Alfred Fretzin, Frankel, Ellen H., Sunil Sharan Dhawan, Lucyna, Leszniewska, Maria, Poznanska, Anna Sobieszek Kundro, Chodorowska, Grazyna M., Katarzyna Turek Urasinska, Romuald, Maleszka, Andrzej, Kaszuba, Lidia, Rajzer, Elizbieta Barbara Szymanska, Lidia, Rudnicka, Neil James Korman, Jamie Debra Weisman, Truett, Artis P., Jeffry, Jacqmein, Steven Robert Cohen, Heller, Gary L., Jenkin, Peter J., Abe, Marcadis, George Sorin Tiplica, Anca Aghinitei Zbranca Toporas, Simona Laura Ianosi, Ion, Florea, Claus, Zachariae, Lars, Iversen, Annalisa, Patrizi, Romanelli, Marco, Christopher, Griffiths, John Berth Jones, John, Foerster, Savin, Ronald C., Nelson, Christopher G., Lyn Carol Chamberlain Guenther, Albrecht, Lorne E., Hong, Chih ho H., Arnon, Katz, Mani, Raman, Adam, David N., Aamir, Butt, Stephen Peter Shumack, Kurt Aaron Josef Gebauer, Lynda Jane Spelman, Shireen Kaur Sidhu, Michael George Freeman, Peter Anthony Foley, Lajos, Kemeny, Eva, Remenyik, Zsuzsanna, Karolyi, Marc, Bourcier, Wayne Douglas Carey, Victoria, Taraska, Derek, Haaland, Aditya Kumar Gupta, Catherine, Maari, Darryl Paul Toth, Michael, Sebastian, Sandra, Philipp, Roland, Kaufmann, Diamant, Thaci, Thomas Andreas Werfel, Leila, Parise, Ingo, Haase, Petra Staubach Renz, Shinichi, Imafuku, Juichiro, Nakayama, Tadashi, Terui, Hideki, Nakajima, Shigetoshi, Sano, Uncover, 2 Study Group, and Uncover, 3 Study Group

Subjects
Adult, Male, medicine.medical_specialty, Neutropenia, Tildrakizumab, Antibodies, Monoclonal, Humanized, Placebo, Severity of Illness Index, Antibodies, law.invention, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Candidiasis, Female, Humans, Inflammatory Bowel Diseases, Intention to Treat Analysis, Middle Aged, Psoriasis, Medicine (all), Internal medicine, Monoclonal, Medicine, Humanized, Risankizumab, Intention-to-treat analysis, business.industry, General Medicine, Clinical trial, Ixekizumab, Guselkumab, 030220 oncology & carcinogenesis, Physical therapy, business
Abstract

BACKGROUND Two phase 3 trials (UNCOVER-2 and UNCOVER-3) showed that at 12 weeks of treatment, ixekizumab, a monoclonal antibody against interleukin-17A, was superior to placebo and etanercept in the treatment of moderate-to-severe psoriasis. We report the 60-week data from the UNCOVER-2 and UNCOVER-3 trials, as well as 12-week and 60-week data from a third phase 3 trial, UNCOVER-1. METHODS We randomly assigned 1296 patients in the UNCOVER-1 trial, 1224 patients in the UNCOVER-2 trial, and 1346 patients in the UNCOVER-3 trial to receive subcutaneous injections of placebo (placebo group), 80 mg of ixekizumab every 2 weeks after a starting dose of 160 mg (2-wk dosing group), or 80 mg of ixekizumab every 4 weeks after a starting dose of 160 mg (4-wk dosing group). Additional cohorts in the UNCOVER-2 and UNCOVER-3 trials were randomly assigned to receive 50 mg of etanercept twice weekly. At week 12 in the UNCOVER-3 trial, the patients entered a long-term extension period during which they received 80 mg of ixekizumab every 4 weeks through week 60; at week 12 in the UNCOVER-1 and UNCOVER-2 trials, the patients who had a response to ixekizumab (defined as a static Physicians Global Assessment [sPGA] score of 0 [clear] or 1 [minimal psoriasis]) were randomly reassigned to receive placebo, 80 mg of ixekizumab every 4 weeks, or 80 mg of ixekizumab every 12 weeks through week 60. Coprimary end points were the percentage of patients who had a score on the sPGA of 0 or 1 and a 75% or greater reduction from baseline in Psoriasis Area and Severity Index (PASI 75) at week 12. RESULTS In the UNCOVER-1 trial, at week 12, the patients had better responses to ixekizumab than to placebo; in the 2-wk dosing group, 81.8% had an sPGA score of 0 or 1 and 89.1% had a PASI 75 response; in the 4-wk dosing group, the respective rates were 76.4% and 82.6%; and in the placebo group, the rates were 3.2% and 3.9% (P

Published
2016

41. TheGBAp.Trp378Gly mutation is a probable French-Canadian founder mutation causing Gaucher disease and synucleinopathies

Author

Ruskey, J.A., Zhou, S., Santiago, R., Franche, L.-A., Alam, A., Roncière, L., Spiegelman, D., Fon, E.A., Trempe, J.-F., Kalia, L.V., Postuma, R.B., Dupre, N., Rivard, G.-E., Assouline, S., Amato, D., and Gan-Or, Z.

Subjects
Genetics, Genetics(clinical)
Abstract

This is the peer reviewed version of the following article: [Ruskey, J.A., Zhou, S., Santiago, R., Franche, L.-A., Alam, A., Roncière, L., Spiegelman, D., Fon, E.A., Trempe, J.-F., Kalia, L.V., et al. (2018). TheGBAp.Trp378Gly mutation is a probable French-Canadian founder mutation causing Gaucher disease and synucleinopathies. Clinical Genetics 94, 339–345.], which has been published in final form at https://doi.org/10.1111/cge.13405. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. Deposited by shareyourpaper.org and openaccessbutton.org. We've taken reasonable steps to ensure this content doesn't violate copyright. However, if you think it does you can request a takedown by emailing help@openaccessbutton.org.

Published
2018

45. Where communities intermingle, diversity grows – The evolution of topics in ecosystem service research

Author

Droste, Nils, D’Amato, D., Goddard, J.J., Droste, Nils, D’Amato, D., and Goddard, J.J.

Abstract

We analyze how the content of ecosystem service research has evolved since the early 1990s. Conducting a computational bibliometric content analysis we process a corpus of 14,118 peer-reviewed scientific article abstracts on ecosystem services (ES) from Web of Science records. To provide a comprehensive content analysis of ES research literature, we employ a latent Dirichlet allocation algorithm. For three different time periods (1990–2000, 2001–2010, 2011–2016), we derive nine main ES topics arising from content analysis and elaborate on how they are related over time. The results show that natural science-based ES research analyzes oceanic, freshwater, agricultural, forest, and soil ecosystems. Pollination and land cover emerge as traceable standalone topics around 2001. Social science ES literature demonstrates a reflexive and critical lens on the role of ES research and includes critiques of market-oriented perspectives. The area where social and natural science converge most is about land use systems such as agriculture. Overall, we provide evidence of the strong natural science foundation, the highly interdisciplinary nature of ES research, and a shift in social ES research towards integrated assessments and governance approaches. Furthermore, we discuss potential reasons for observable topic developments.

Published
2018

46. Middle to Late Pleistocene activity of the northern Matese fault system (southern Apennines, Italy)

Author

Paolo Galli (a, Biagio Giaccio (b), Paolo Messina (b), Edoardo Peronace (b, Vincenzo Amato (d), Giuseppe Naso (a), Sebastian Nomade (e), Alison Pereira (e, Sabatino Piscitelli (g), Jessica Bellanova (g), Andrea Billi (b), Dominique Blamart (e), Antonio Galderisi (h), Alessandro Giocoli (i), Tony Stabile (g), Francoise Thil (e), Giocoli, A., Consiglio Nazionale delle Ricerche [Roma] (CNR), Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Università degli Studi del Molise (Unimol), Laboratoire des Sciences du Climat et de l'Environnement [Gif-sur-Yvette] (LSCE), Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Paléocéanographie (PALEOCEAN), Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Istituto di Metodologie per l'Analisi Ambientale (IMAA), Consiglio Nazionale delle Ricerche [Potenza] (CNR), Università degli studi di Napoli Federico II, ENEA - Casaccia, Roma, Géochrononologie Traceurs Archéométrie (GEOTRAC), National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), École normale supérieure - Paris (ENS-PSL), Università degli Studi del Molise = University of Molise (UNIMOL), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), and University of Naples Federico II = Università degli studi di Napoli Federico II

Subjects
earth-surface processes, Apennine, 40Ar/39Ar dating, active tectonics, Apennines, earthquakes, Late Pleistocene, Middle Pleistocene, paleoseismology, geophysics, Earthquake, 010504 meteorology & atmospheric sciences, Pleistocene, Outcrop, Paleoseismology, Slip (materials science), Structural basin, 010502 geochemistry & geophysics, 01 natural sciences, Active tectonic, Paleoseismologys, Apenninesesocene, [SDU.ENVI]Sciences of the Universe [physics]/Continental interfaces, environment, Tephra, ComputingMilieux_MISCELLANEOUS, Holocene, 0105 earth and related environmental sciences, [SDU.OCEAN]Sciences of the Universe [physics]/Ocean, Atmosphere, Earthquakes, Active tectonics, Earthquakesocene, Tectonics, 13. Climate action, Seismology, Geology
Abstract

An integrated investigation including geological, geomorphological, geophysical and structural survey, tephra analyses, 14C and 40Ar/39Ar dating, as well as paleoseismic trenching along the N-Matese fault system is presented. The study allowed the characterization of the tectonic mobility of this structure as well as the associated Bojano basin sedimentary-tectonic evolution since the early Middle Pleistocene, providing also new clues concerning the fault historical activity and the associated Mw > 6.5 earthquakes. We have found lines of evidence for > 1 mm/yr slip rate along the presently buried Bojano fault during the mid Middle Pleistocene, and similar rates for the main fault segments paralleling the Matese flanks. The buried Bojano fault significantly slowed down during the last 300 kyr, ceasing its activity before the Holocene. In turn, the segments outcropping along the Matese flanks reactivated at the onset of Late Pleistocene, after a long period of quiescence (480–110 ka), with robust slip rates that would seem even accelerating in post LGM times. Paleoseismic data suggest the occurrence of four Mw > 6.6 earthquakes in the past 3 ka, three of which match the little known 280 BC event, and the devastating 1456 and 1805 earthquakes. © 2017 Elsevier B.V.

Published
2017

47. TheGBAp.Trp378Gly mutation is a probable French-Canadian founder mutation causing Gaucher disease and synucleinopathies

Author

Ruskey, J.A., primary, Zhou, S., additional, Santiago, R., additional, Franche, L.-A., additional, Alam, A., additional, Roncière, L., additional, Spiegelman, D., additional, Fon, E.A., additional, Trempe, J.-F., additional, Kalia, L.V., additional, Postuma, R.B., additional, Dupre, N., additional, Rivard, G.-E., additional, Assouline, S., additional, Amato, D., additional, and Gan-Or, Z., additional

Published
2018
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50. Effects of industrial plantations on ecosystem services and livelihoods

Author

University of Helsinki, Department of Forest Sciences, D'Amato, D., Rekola, M., Wan, M., Cai, D., Toppinen, A., University of Helsinki, Department of Forest Sciences, D'Amato, D., Rekola, M., Wan, M., Cai, D., and Toppinen, A.

Abstract

This paper addresses the current research void on local community views of changes in ecosystem services associated with rapid land use transformation in the context of plantation-based forestry. This interview-based study, conducted in southern China, aims at assessing the perspectives of local communities of: 1) the effects of Eucalyptus industrial plantations on selected ecosystem services and on local development; and 2) opportunities for future community livelihood development, based on the relations with the government and with forest industry operating locally. We analysed data from semi-structured interviews with 70 villagers for their views on changes in ecosystem services after the establishment of plantations, and their future expectations on the local livelihood development. Most interviewees mentioned some negative development on environmental quality after the establishment of the industrial plantations, especially on soil and water. Furthermore, the reduced productivity of cropland surrounding industrial plantations, coupled with other financial drivers, induced several villagers to switch from agricultural crops to household plantations. In the absence of destructive typhoons, household plantations can provide owners more free time, higher income, while industrial plantations provided some employment opportunities. Interviewees' expectations for the future included receiving financial support and capacity building for household plantations and crops, support to local roads and schools, and higher employment opportunities. Some interviewees suggested that solutions should be implemented for improving degraded water quality, while others suggested reducing forestry operations. Even though being highly context-specific, our findings open up the discussion about the further community development opportunities in the context of plantation forestry. In particular, the potential of value sharing mechanisms between the private sector and the local communitie

Published
2017

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