搜索结果：Hepatology research : the official journal of the Japan Society of Hepatology

The Journal of Bone and Joint Surgery. British volumeVol. 88-B, No. 2 AnnotationFree AccessThe international rank order of publications in major clinical orthopaedic journals from 2000 to 2004B. H. Bosker, C. C. P. M. VerheyenB. H. BoskerResearch FellowDepartment of Orthopaedic Surgery and Traumatology, Isala Clinics, Weezenlanden Hospital, P. O. Box 10500, 8000 GM Zwolle, The Netherlands.Search for more papers by this author, C. C. P. M. VerheyenConsultant Orthopaedic SurgeonDepartment of Orthopaedic Surgery and Traumatology, Isala Clinics, Weezenlanden Hospital, P. O. Box 10500, 8000 GM Zwolle, The Netherlands.Search for more papers by this authorPublished Online:1 Feb 2006https://doi.org/10.1302/0301-620X.88B2.17018AboutSectionsPDF/EPUB ToolsDownload CitationsTrack CitationsPermissionsAdd to Favourites ShareShare onFacebookTwitterLinked InRedditEmail Publications in peer-reviewed journals are the most important determinant by which research is rated and funding awarded. In this study, the publication rate in orthopaedic surgery of individual countries was scored in selected clinical journals in order to identify those which are making the principal contributions to the development of the orthopaedic discipline.A total of 15 major clinical orthopaedic journals was selected. All articles with abstracts were scored for the country of the corresponding author through a bibliometric search in Medline/PubMed over a period of five years (2000 to 2004). The total number of publications, the number adjusted for size of population and the impact factor of the journal were assessed for each country.A total of 13 311 articles were scored, of which 92% were generated by 15 countries with 47.4% by the United States, followed by Japan (8.0%) and the United Kingdom (7.3%). Corrected for population size, eight smaller European countries led this ranking with Sweden, Switzerland and Finland at the top, with the United States in their midst in sixth place. Japan and Finland scored the highest mean impact factor.This observational study demonstrates that the United States is the most productive country in absolute number of publications in the selected clinical orthopaedic journals, and when normalised for population size, the smaller European countries with a high proficiency in English were most successful.Our objective was to identify the countries which generate knowledge and progress in orthopaedic surgery and consider the factors that enabled them to be major contributors.MethodsThe major clinical orthopaedic journals were selected and ranked by the senior author (CCPMV) from the ‘orthopedics’ category of journals established by the Institute for Scientific Information as searched in April 2005.1 He chose to add the American Journal of Sports Medicine to that list. The 15 journals with the highest impact factor were chosen. The Medline/PubMed Journals Database2 was searched for these journals, and all articles with an abstract, as indicated in the ‘limits’ function in PubMed, were selected. The country of the corresponding author was used as the source nation for the article. Countries with fewer than 50 publications during the period tested were excluded. The mean impact factor for the period of review was calculated, as were the totals for each journal and country. For the calculation of publications per million inhabitants, the 2005 national population data were derived from the UN Population Information Network.3 The domestic expenditure on research as a percentage of the gross domestic product was taken as an indicator for the amount of national research funding.ResultsThere was a total of 13 311 articles with abstracts in the 15 chosen journals during the period of the review. All the selected journals were in English, 11 from the United States and four from Europe. The figures for the top 15 journals and countries are shown in Table I, in which the ranking order is determined by impact factor for the journals and by the total number of publications for the countries. The 15 countries listed account for 92% of the total number of articles, the first five countries for 71.9% and the United States by itself for 47.4%. The contribution from the United States was the highest in Orthopedic Clinics of North America (89.5%) and the American volume of the Journal of Bone and Joint Surgery (69.1%). The United Kingdom was responsible for 7.3% of the total scored articles. Its share in the British volume of the Journal of Bone and Joint Surgery was 37.7% of the 974 publications. Of these 367 articles, England had the highest share with 324 (88.2%), followed by Scotland with 38 (10.4%), Northern Ireland with four and Wales with one. Sweden scored 23.6% of the papers in the Acta Orthopedica Scandinavica, now Acta Orthopaedica. Table II ranks the publications per million inhabitants and establishes the position of each country. The data for domestic expenditure on research are listed as a percentage of the gross domestic product and are from 2002 or the last available year.4–6DiscussionThe United States has traditionally led the rankings in the output of publications in each of the 20 fields of science defined by the Institute for Scientific Information, and consequently also in clinical medicine overall.1 It is therefore not surprising that the same country also tops the ranking for total publications in major clinical orthopaedic journals. In similar recent studies of high-ranked journals in other medical specialties, their mean percentage was 37 (24 to 48).7–14When corrected for the size of population, the smaller western European countries (ranks 1 to 5, 7, 8) outrank the others, with the United States in their midst. The sixth place of the United States with clinical orthopaedic papers is substantially higher than their rank of 13 in the comparable list of publications in clinical medicine (1992 to 2002).15Some major western European countries perform rather poorly. France, Italy, Spain and Germany are low in lists normalised for population size in both clinical medicine and orthopaedics, as is Japan. Germany has some fine orthopaedic journals published in the native language such as Zeitschrift für Orthopädie und ihre Grenzgebiete, Der Unfallchirurg and Der Orthopäde with impact factors of approximately 0.50, but not sufficient to qualify for selection in the present study.We chose 15 major clinical orthopaedic journals since a broader selection would include a larger number of articles which will never be cited and therefore lack scientific impact. Narrowing the selection enhances the scientific quality of the selected papers but this disqualifies mainstream contributions. Many important contributions to orthopaedics are in publications which are not specific to orthopaedics and may be ranked higher than any journal in our list.The number of citations in top journals might be a more sensitive marker of scientific impact than the impact factor and the number of publications. However, it is hard to assess, and there is also a potential selection bias. We, therefore, decided to use the mean impact factor as an autonomous indicator of the prestige of a journal. Its limitations are acknowledged when used to compare large series but it has become an influential tool within the scientific world to evaluate research and award funding.16We originally planned to relate the total of clinical orthopaedic publications to the number of orthopaedic surgeons practising in a country, but it was not possible to construct such a list. It could also be argued that the number of scientists working in musculoskeletal research should also be included.The editorial process differs in the selected journals. Peer-reviewed journals such as both the American and British volumes of the Journal of Bone and Joint Surgery and Acta Orthopaedica are treated identically to those such as Clinical Orthopaedics and Related Research and Orthopedic Clinics of North America which have a relatively large number of invited manuscripts.It may be suggested that our findings are merely a reflection of the preference of editorial boards to select manuscripts written in proper English. Apart from the evident factor of size of population, national funding capacity and proficiency in English may also be important factors in the ranking.17The gross domestic expenditure on research as a percentage of gross domestic product was used as a determinant for the national funding capacity. Norway, Denmark, The Netherlands and Austria do well in clinical orthopaedic publications corrected for population size with relatively modest research funding, particularly when contrasted with Israel, Japan, Germany, Taiwan, South Korea and France. This finding contradicts the study from Man et al,17 who stated that publication output in major medical journals is linked to research funding at a national level. Their paper also suggested that proficiency in English may be an important determinant for publication in English-language medical journals. It is remarkable that five European countries where English is not the native language outrank all five where it is. The poor proficiency in English of the Mediterranean countries, as well as Japan, may partly explain their lower scores in publications corrected for population size.We are aware of only one other article that focuses on the ranking of countries with respect to publications in orthopaedic literature (1991 to 2001) which, in particular analysed the share of Japan.18 The selection of journals and articles was different from ours in that the top seven orthopaedic journals from the Institute for Scientific Information list were picked and it was not limited to articles with an abstract on Medline/PubMed. It therefore included editorials, letters to the editor and case reports. It focused on total production only, not taking population size into account.The conclusions from our study cannot be strict or definitive. However, it is obvious that, as in all other fields of science, the United States is the most productive country in terms of absolute number of publications (47.4%) in the selected clinical orthopaedic journals. When corrected for population size, the smaller European countries with a high proficiency in the English language were most successful.Table I. Top 15 countries ranked according to total of publications in clinical orthopedic journals (2000 to 2004)15 countries*IF†meanPublications totalUSJPUKGECASENLCHTRKOAUFRITFIAT* US, United States; JP, Japan; UK, United Kingdom; GE, Germany; CA, Canada; SE, Sweden; NL, Netherlands; CH, Switzerland; TR, Turkey; KO, South Korea; AU, Australia; FR, France; IT, Italy; FI, Finland; AT, Austria† mean impact factor between 2000 and 2004Spine2.20240910493371249714458812357485852255515Am J Sports Med2.1871344342173614241320-42348223J Bone Joint Surg [Am]2.061040719423224551015213199189810Arthroscopy1.5110124721094064211314133164101640520J Bone Joint Surg [Br]1.479747311936755293130351030342913627Eur Spine J1.30537572146803247514223492613127Clin Orthop1.262188140816451818028314514391934271333Knee Surg Sp Tr Arthrosc1.114074221316543413176251283064Orthop Clin North Am1.01257230-1281----7----Acta Orthop Scand1.0048321382247411434111277682410J Arthroplasty0.971019523681272164302020215231114613J Shoulder Elbow Surg0.93435206432925147618212117564J Orthop Trauma0.93541306242331326921141113322J Pediatric Orthop0.756453811933634-4323231916773Foot Ankle Int0.6665138523313413411182810271175Total publications (Ranking)133116315 (1)1070 (2)974 (3)668 (4)548 (5)407 (6)332 (7)307 (8)281 (9)280 (10)279 (11)241 (12)213 (13)179 (14)156 (15)Publ/10E6 inhabitants (Ranking)21.2 (6)8.4 (16)16.2 (11)8.1 (17)17.0 (9)45.0 (1)20.4 (7)41.3 (2)3.8 (21)5.9 (19)13.8 (13)4.0 (20)3.7 (22)34.1 (3)19.0 (8)Table II. Country ranking according to publications, impact factor and research spendingCountryPublications/10E6 (Ranking)Total publications (Ranking)Mean impact factor (Ranking)Research spending (% GDP*) (Ranking)* GDP, gross domestic productSweden45.0 (1)407 (6)1.36 (17)4.27 (2)Switzerland41.3 (2)307 (8)1.35 (18)2.63 (7)Finland34.1 (3)179 (14)1.58 (1)3.40 (3)Norway23.6 (4)109 (20)1.54 (3)1.62 (16)Denmark21.7 (5)118 (18)1.33 (19)2.19 (11)United States21.2 (6)6315 (1)1.44 (9)2.82 (6)Netherlands20.4 (7)332 (7)1.49 (5)1.94 (13)Austria19.0 (8)156 (15)1.39 (13)1.34 (18)Canada17.0 (9)548 (5)1.50 (4)1.85 (15)Israel16.8 (10)113 (19)1.25 (22)4.90 (1)United Kingdom16.2 (11)974 (3)1.41 (11)1.90 (14)Ireland14.5 (12)60 (23)1.24 (23)1.17 (19)Australia13.8 (13)279 (11)1.42 (10)1.53 (17)Greece9.2 (14)102 (21)1.38 (14)0.67 (22)Belgium9.0 (15)94 (22)1.33 (20)1.96 (12)Japan8.4 (16)1070 (2)1.58 (1)3.09 (4)Germany8.1 (17)668 (4)1.40 (12)2.50 (8)Taiwan6.2 (18)142 (16)1.46 (7)2.45 (9)South Korea5.9 (19)280 (10)1.45 (8)2.96 (5)France4.0 (20)241 (12)1.48 (6)2.20 (10)Turkey3.8 (21)281 (9)1.31 (21)0.64 (23)Italy3.7 (22)213 (13)1.38 (15)1.07 (20)Spain2.9 (23)125 (17)1.36 (16)0.96 (21)References1 Institute for Scientific Information. http://www.isinet.com (accessed 17/03/05). 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Crossref, Medline, ISI, Google Scholar15 Coppen A, Bailey J. 20 most-cited countries in clinical medicine ranked by population size. Lancet 2004;363:250. Crossref, Medline, ISI, Google Scholar16 Kurmis A. Understanding the limitations of the journal impact factor. J Bone Joint Surg [Am] 2003;85-A:2449–54. Google Scholar17 Man JP, Weinkauf JG, Tsang M, Sin DD. Why do some countries publish more than others?: an international comparison of research funding, english proficiency and publication output in highly ranked general medical journals. Eur J Epidemiol 2004;19:811–17. Medline, ISI, Google Scholar18 Rahman M, Sakamoto J, Fukui T. Japan’s share of articles in orthopedics. J Orthop Sci 2002;7:607–9. 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18 major orthopaedic journals compared for Impact Factor and SCImago4 January 2010 | BMC Musculoskeletal Disorders, Vol. 11, No. 1The 100 classic papers of orthopaedic surgery A BIBLIOMETRIC ANALYSISJ. C. Kelly, R. W. Glynn, D. E. O’Briain, P. Felle, J. P. McCabe1 October 2010 | The Journal of Bone and Joint Surgery. British volume, Vol. 92-B, No. 10Chirurgische Forschung im internationalen Vergleich4 March 2010 | Der Chirurg, Vol. 81, No. 4Letters to the editorThe Bulletin of the Royal College of Surgeons of England, Vol. 89, No. 4Geographic origin of publications in surgical journals31 October 2006 | British Journal of Surgery, Vol. 94, No. 2Trends in modern shoulder surgery: personal observationsJournal of Orthopaedic Science, Vol. 12, No. 1 Vol. 88-B, No. 2 Metrics History Published online 1 February 2006 Published in print 1 February 2006 InformationCopyright © 2006, The British Editorial Society of Bone and Joint Surgery: All rights reservedPDF download

To the Editor Autoimmune pancreatitis (AIP), a distinctive type of pancreatitis, is classified to 2 subtypes by the International Consensus of Diagnostic Criteria (ICDC) for AIP1: type 1 related with IgG4 [lymphoplasmacytic sclerosing pancreatitis, (LPSP)], and type 2 with granulocytic epithelial lesion (idiopathic duct-centric pancreatitis). The former one is suspected to be the pancreatic lesions of IgG4-related diseases.2 The patients with both types of AIP should be differed from pancreatic or bile-duct cancer because they often have pancreatic enlargement, mass formation, and obstructive jaundice. However, clinicopathological features of each one are quite different. The patients with type 1 AIP, commonly seen in older men, have frequently elevated serum levels of gammaglobulin, IgG, IgG4, or the presence of positive autoantibodies.1 They are often associated with other organ involvements (OOIs) such as sclerosing cholangitis, sclerosing sialadenitis, retroperitoneal fibrosis, and so on.1,2 Histopathologic features of LPSP are characterized by prominent infiltration of lymphocytes and IgG4-positive plasmacytes, storiform fibrosis, and obliterative phlebitis. Although treated effectively by steroid therapy, its long-term prognosis of type 1 AIP is not clear, relapse often occurs, and some cases are reported to be associated with pancreatic stones. On the other hand, type 2 AIP lacks abnormal immunological findings, and is seen in both sexes without significant differences, also in relatively young patients, and sometimes associated with inflammatory bowel disease. Steroid therapy is effective, but relapse is rare. Type 2 AIP is more often observed in Europe and United States in 20% to 60% of total AIP cases, but extremely rare in Japan. Previously, the Japan Pancreas Society (JPS) and the Research Committee for Intractable Pancreatic Disease by the Ministry of Labor, Health and Welfare of Japan (RCIPD-MLHWJ) proposed 2 kinds of Japanese diagnostic criteria for AIP in 20023 and 2006.4 The concepts o Japanese ones were based on being simple as much as possible and easy use for general physicians as well as pancreatologists. The ICDC for AIP1 firstly enable us to diagnose and compare 2 distinctive subtypes, type 1 and type2 AIP, independently. However, the ICDC is somewhat complicated for a general use. Different from western countries, extremely few cases of type 2 AIP have been confirmed in Japan. On the basis of the Japanese conditions, the JPS and RCIPD-MLHWJ revised them as the clinical diagnostic criteria for AIP 2011 (JPS2011), which took the basic concept of the ICDC as much as possible. In 2012, the Japanese version of the amendment for Japanese physicians5 has been published in the official journal of JPS, "Suizo." To better understand the Japanese situation in the diagnosis of AIP, we, herein, introduce the English version of the JPS2011 (see Table 1, Supplemental Digital Content 1, https://links.lww.com/MPA/A202) in "Pancreas," the official journal of JPS and American Pancreas Association, with permissions by Professor Takeyama, the editor-in-chief of "Suizo" and Professor Go, that of "Pancreas." The concept of the JPS2011 took basic concepts of both the Japanese previous criteria and type 1 in the ICDC as much as possible5: (1) simple for general physicians' use; (2) diffuse/segmental/focal classification on pancreatic imaging; (3) IgG4 alone as a serological marker; (4) sclerosing cholangitis, sclerosing sialadenitis, and retroperitoneal fibrosis as OOIs; (5) no classifications of level 1/2 in serum IgG4 and OOI; and (6) optional steroid trial only after denying malignancy by endosonography-guided fine needle aspiration (EUS-FNA). Although affiliations available for EUS-FNA have been increasing in Japan, endoscopic retrograde cholangiopancreatography (ERCP) procedures are more commonly performed than EUS-FNA. Therefore, different from the previous Japanese guidelines, the pancreatic parenchyma on computed tomography/magnetic resonance imaging is separated from the ductal image on ERCP. Endoscopic retrograde cholangiopancreatography is basically required in the focal/segmental type, but not in the typical diffuse type of AIP. MRCP is not available in the JPS2011 because of low resonance. The JPS2011 contains only IgG4 in serological markers, but not gammaglobulinemia, nonspecific autoantibodies such as antinuclear autoantibody.5 We confirmed that the cutoff level of serum IgG4 (<135 mg/dL) using 717 cases of AIP and 577 cases of pancreas cancer was appropriate.5 Histopathologic findings are the same as LPSP, which contains the following 4 histopathologic criteria: (1) prominent infiltration of lymphocytes and plasmacytes and fibrosis, (2) prominent infiltration of IgG4-positive plasma cells and lymphocytes, (3) storiform fibrosis, and (4) obliterative phlebitis. In the histological criterion regarding IgG4-positive cells, the Japanese comprehensive diagnostic criteria (CDC) for IgG4-related disease require both more than 10 IgG4-positive cells /HPF and more than 40% of the ratio of IgG4/IgG-positive cells.2 Different from the Japanese CDC criteria, the JPS2011 requires 1 criterion, more than 10 IgG4-positive cells/HPF by biopsy specimen, which follows the ICDC1 and the Consensus Statement on the Pathology of IgG4-related disease.6 The previous JPS2002 and JPS2006 criteria used in Japan did not contain OOI in diagnosis of AIP.2,3 Among many OOIs previously reported, sclerosing cholangitis, sclerosing sialoadenitis, and retroperitoneal fibrosis are recommended as the typical OOI in JPS2011, which follows the ICDC. As the same as Asian criteria or ICDC, an optional steroid trial was included in diagnostic criterion only after denying malignancy using EUS-FNA by experts. Different from the previous Japanese criteria, the patients with AIP are diagnosed as having definitive, probable, or possible AIP by a combination with criteria described previously, similar to the concept of the ICDC.4 Although the JPS2011 is focused on type 1 AIP, some patients with type 2 AIP, extremely rare in Japan, may be diagnosed as possible AIP. As ERCP is more commonly performed to diagnose AIP or pancreas cancer compared with EUS-FNA in Japan, ERCP is essentially required in the diagnosis of focal/segmental type of AIP. However, to follow the concept of the ICDC as much as possible, the following exceptional case can be acceptable only by an expertise. When a patient with a focal/segmental image of AIP on computed tomography/magnetic resonance imaging without ERCP findings fulfill more than one of III (serum IgG4), IVb (2 of pathological findings), and V(a/b) (OOI), he/she can be diagnosed as possible AIP only after the negative workup for malignancy by EUS-FNA, and confirmed as probable one by an optional steroid response. The RCIPD-MLHWJ is now studying a nationwide survey of type 2 AIP in Japan as well as type 1 AIP. When the clinical features of the Japanese patients with type 2 AIP are clarified in the near future, the clinical diagnostic guidelines in Japan should be modified. Kazuichi Okazaki, MD, PhD Department of Gastroenterology and Hepatology Kansai Medical University Osaka [email protected] Tooru Shimosegawa, MD, PhD Division of Gastroenterology Tohoku University Graduate School of Medicine Sendai, Japan The working Group Members of the Japan Pancreas Society and the Research Committee for Intractable Pancreatic Disease by the Ministry of Labor, Health and Welfare of Japan ACKNOWLEDGMENT This study was supported by a grant of Health and Labor Sciences Research Grants for Intractable Diseases, from the Minister of Labor and Welfare of Japan. The authors declare no conflict of interest. Supplemental digital content is available in the text.

To the Editor: In 2010, the International Consensus Diagnostic Criteria (ICDC) for autoimmune pancreatitis (AIP) were proposed to address the pathogenesis, clinical features, and treatment of AIP on a global level.1 The ICDC were the first to enable the diagnosis and comparison of the 2 distinctive subtypes of AIP: type 1 and type 2. Because the diagnosis of AIP in Western countries was based mainly on pathological findings using endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) in contrast to the Japanese diagnostic procedures giving priority to image findings using endoscopic retrograde pancreatography (ERP) especially for differentiation from pancreatic cancer, the ICDC were exempt from the ERP procedure, whereas previous Japanese diagnostic criteria and Asian criteria required it.2–4 The ICDC also adopted the diagnostic item of steroid therapy effectiveness as a treatment option. However, the ICDC were somewhat complicated for general use, and extremely few cases of type 2 AIP have been confirmed in Japan. Accordingly, the Japan Pancreas Society (JPS) and the Research Program on Intractable Disease from the Ministry of Labor, Health, and Welfare of Japan (RPID-MLHWJ) amended the ICDC into the Japanese clinical diagnostic criteria for AIP 2011 (JPS2011), which adhered closely to the basic concepts of the ICDC.5,6 The JPS2011 incorporated elements of both the previous Japanese criteria and type 1 AIP in the ICDC as much as possible and was designed to be simple for general physician use. The JPS2011 included: (1) diffuse/segmental/focal classification on pancreatic imaging; (2) IgG4 alone as a serological marker; (3) sclerosing cholangitis, sclerosing sialadenitis, and retroperitoneal fibrosis as other organ involvement (OOI); (4) no classifications of level 1/2 in serum IgG4 or OOI; and (5) optional steroid trial only after excluding malignancy by EUS-FNA. Endoscopic retrograde pancreatography was basically required for focal/segmental type AIP, but not for the typical diffuse type. Magnetic resonance cholangiopancreatography (MRCP) was not an item in the JPS2011 due to inadequate resolution at the time. Because the diagnostic use of ERP is limited in Japan and the quality of MRCP images has improved recently, JPS and RPID-MLHWJ have proposed revision of the JPS2011 mainly to establish a procedure that includes MRCP and negative findings of malignancy by EUS-FNA to complement the diagnostic ability of ERP. In 2018, a report entitled “Japanese Clinical Diagnostic Criteria for Autoimmune Pancreatitis, 2018: Revision of Japanese Clinical Diagnostic Criteria for Autoimmune Pancreatitis 2011” was published in Suizo, the official journal of the JPS.7 To better understand the Japanese clinical picture in AIP diagnosis, we herein introduce the English version of the JPS2018: Revision of the JPS2011 (Supplemental Table 1, https://links.lww.com/MPA/A751) in Pancreas, the official journal of JPS and American Pancreas Association, with the permission of the respective Editors-in-Chief of Suizo and Pancreas, Professors Sata and Go. Because advancements in MRI, such as 3T units, have rendered the image quality of MRCP nearly equivalent to that of ERP, MRCP is now considered to complement ERP to some extent and has been included in diagnostic procedures. The diagnostic criteria of “II. Image findings showing irregular narrowing of the main pancreatic duct” have been divided into ERP and MRCP, and a statement on MRCP findings was added to the Explanations section as “Narrowing or invisibleness of the main pancreatic duct is seen on MRCP and is extended to a certain degree, sometimes appearing as a multiple skip lesion. No significant dilation is observed above the narrowed area upstream of the main duct. It is usually difficult to evaluate side branches arising from narrowed portions of the main pancreatic duct. Although image quality of MRCP depends on the MR unit and scan parameters, it is necessary to acquire sufficient good quality images for the detailed evaluation of the pancreatic duct.” In addition, the item of “No neoplastic cells detected by EUS-FNA” was added to the section of “IV. Pathological finding” to indicate negative findings of malignancy by EUS-FNA as IVc. Regarding diagnostic ability, ERP was adjusted to be equivalent to the combination of MRCP and IVc (negative findings of malignancy by EUS-FNA) in the diagnostic procedure. Many RPID-MLHWJ and JPS members have expressed difficulty in excluding malignancy by EUS-FNA. Even so, at the time of EUS-FNA, negative findings of malignancy combined with other results, such as elevated serum IgG4 and OOIs, are able to identify the possibility of AIP. To clarify this, we have added the following statement to the section “IV. Pathological findings of the pancreas”: “Although EUS-FNA is a useful tool to exclude cancer, the absence of neoplastic cells alone is insufficient; it is also important to exclude cancer using the image findings shown in I-2). Moreover, the diagnostic process should be done carefully, with comprehensive evaluation of serological findings and other organ involvement.” Additionally, useful image findings to differentiate between AIP and pancreatic cancer were proposed by a radiological committee and incorporated into the section of “I. Enlarged pancreas” as “Abdominal CT▪MRI: It is recommended to perform dynamic contrast-enhanced CT▪MRI with bolus injection of contrast medium wherever possible. Useful findings for differentiation from pancreatic cancer are speckled/dotted enhancement and capsule-like rim at the parenchymal phase as well as delayed homogeneous enhancement. Capsule-like rim is seen as a band-like low-intensity area on T2-weighed images. Duct-penetrating sign is another characteristic finding of focal AIP and is rarely seen,” as well as “Even when characteristic findings for AIP can be found, careful diagnostic procedures should be conducted to exclude the possibility of pancreatic cancer if concurrent findings suggestive of cancer are present, such as upstream dilation of the main pancreatic duct, heterogeneous delayed enhancement, or severe stenosis of involved arteries.” As kidney lesion was already included as an OOI in the ICDC, it seemed logical to add it to the OOI list of the JPS2011, which also contained sclerosing cholangitis, sclerosing dacryoadenitis/sialadenitis, and retroperitoneal fibrosis. The JPS2018 revisions are expected to improve diagnostic accuracy for AIP and enable earlier disease identification and treatment. Shigeyuki Kawa, MD, PhD Department of Internal Medicine Matsumoto Dental University Shiojiri, Japan [email protected]Terumi Kamisawa, MD, PhD Department of Internal Medicine Tokyo Metropolitan Komagome Hospital Tokyo, JapanKenji Notohara, MD, PhD Department of Anatomic Pathology Kurashiki Central Hospital Kurashiki, JapanYasunari Fujinaga, MD, PhD Department of Radiology Shinshu University School of Medicine Matsumoto, JapanDai Inoue, MD, PhD Department of Radiology Kanazawa University Graduate School of Medical Science Kanazawa, JapanTakashi Koyama, MD, PhD Department of Diagnostic Radiology Kurashiki Central Hospital Kurashiki, JapanKazuichi Okazaki, MD, PhD Department of Gastroenterology and Hepatology Kansai Medical University Osaka Osaka, Japan On behalf of the Working Group Members of the Japan Pancreas Society and The Research Program on Intractable Diseases from the Ministry of Labor and Welfare of Japan

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease that frequently develops in middle-aged women.1 In patients with PBC, small bile ducts in the liver are believed to be damaged by autoimmune reactions.2 Patients were diagnosed as having PBC when two or more of the following three features are observed: (i) elevated cholestatic enzymes; (ii) presence of antimitochondrial autoantibodies; and (iii) in particular, histological findings as chronic non-suppurative destructive cholangitis.3 When the disease entity of PBC was established more than 50 years ago,4 advanced liver diseases showing histological findings of cirrhosis were found in most patients with PBC. Consequently, a nomenclature for primary biliary “cirrhosis” was reasonably accepted by all hepatologists and gastroenterologists worldwide. Introduction of antimitochondrial autoantibodies as a tool for screening examination, however, enabled physicians to diagnose patients with chronic cholestatic diseases as having PBC during the earlier stages before developing cirrhosis.5 Moreover, spread of the use of ursodeoxycholic acid as a first-line therapeutic agent contributed to the inhibition of liver disease progression from the non-cirrhotic stage to the cirrhotic stage in a large number of patients with PBC.6 In Japan, approximately 70–80% of patients with PBC were shown to be diagnosed as having “asymptomatic PBC” in recent years.3 Thus, the nomenclature of primary biliary “cirrhosis” is regarded as a misnomer, both from clinical and histological aspects. As a result, patients inevitably misunderstand the stage of their disease and at the same time have to bear the substantial burden in their social activities. During 2014 and 2015, the governing boards of both the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD) approved the change of nomenclature for PBC from “primary biliary cirrhosis” to “primary biliary cholangitis”. Each published statements in their official journals,7, 8 followed by the publication of identical articles in several major journals in the fields of gastroenterology and hepatology.9-11 In contrast, in Japan, the Intractable Hepato-Biliary Diseases Study Group, supported by Health Labor Science Research Grants from Research on Measures for Intractable Diseases, administered a questionnaire survey regarding the nomenclature for PBC to 18 experts in clinical research of PBC in 2014. Although all agreed to revise the nomenclature for PBC, unanimous consent was not obtained. Of the 18 Japanese experts, 11 supported the nomenclature of “cholangitis”, whereas 5 and 2 experts proposed “cholangiopathy” and other nomenclatures, respectively. “Biliary” and “cholangitis” may appear to be redundant repetition, and “cholangitis” does not exactly reflect the pathological features observed in the liver of patients with PBC. Considering consistency with the nomenclature approved by EASL and AASLD, the Study Group decided to adopt the nomenclature of “primary biliary cholangitis”, to keep a well-known abbreviation “PBC”. However, an alternative nomenclature for PBC, which more accurately represents the disease entity, should be established in the future. In December 2015, the Intractable Hepato-Biliary Diseases Study Group of Japan addressed the proposal regarding revision of the nomenclature for PBC to the governing boards of the Japanese Society of Gastroenterology (JSGE) and the Japan Society of Hepatology (JSH), and the nomenclature “primary biliary cholangitis (PBC)” was approved in January 2015 and March 2015 by JSH and JSGE, respectively. The societies jointly proposed the novel nomenclature to the Japanese Association of Medical Sciences in April 2014, and the nomenclature “primary biliary cholangitis” will be officially used by the Ministry of Health, Labor and Welfare of Japan following discussion by the committee for regulation of medical terms, organized in the Japanese Association of Medical Sciences. We sincerely call on all members of JSGE and JSH to use from this moment on the name “primary biliary cholangitis”, instead of primary biliary “cirrhosis”, for the disease known by its abbreviation PBC.

BACKGROUND: Detailed, comprehensive, and timely reporting on population health by underlying causes of disability and premature death is crucial to understanding and responding to complex patterns of disease and injury burden over time and across age groups, sexes, and locations. The availability of disease burden estimates can promote evidence-based interventions that enable public health researchers, policy makers, and other professionals to implement strategies that can mitigate diseases. It can also facilitate more rigorous monitoring of progress towards national and international health targets, such as the Sustainable Development Goals. For three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has filled that need. A global network of collaborators contributed to the production of GBD 2021 by providing, reviewing, and analysing all available data. GBD estimates are updated routinely with additional data and refined analytical methods. GBD 2021 presents, for the first time, estimates of health loss due to the COVID-19 pandemic. METHODS: The GBD 2021 disease and injury burden analysis estimated years lived with disability (YLDs), years of life lost (YLLs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries using 100 983 data sources. Data were extracted from vital registration systems, verbal autopsies, censuses, household surveys, disease-specific registries, health service contact data, and other sources. YLDs were calculated by multiplying cause-age-sex-location-year-specific prevalence of sequelae by their respective disability weights, for each disease and injury. YLLs were calculated by multiplying cause-age-sex-location-year-specific deaths by the standard life expectancy at the age that death occurred. DALYs were calculated by summing YLDs and YLLs. HALE estimates were produced using YLDs per capita and age-specific mortality rates by location, age, sex, year, and cause. 95% uncertainty intervals (UIs) were generated for all final estimates as the 2·5th and 97·5th percentiles values of 500 draws. Uncertainty was propagated at each step of the estimation process. Counts and age-standardised rates were calculated globally, for seven super-regions, 21 regions, 204 countries and territories (including 21 countries with subnational locations), and 811 subnational locations, from 1990 to 2021. Here we report data for 2010 to 2021 to highlight trends in disease burden over the past decade and through the first 2 years of the COVID-19 pandemic. FINDINGS: Global DALYs increased from 2·63 billion (95% UI 2·44-2·85) in 2010 to 2·88 billion (2·64-3·15) in 2021 for all causes combined. Much of this increase in the number of DALYs was due to population growth and ageing, as indicated by a decrease in global age-standardised all-cause DALY rates of 14·2% (95% UI 10·7-17·3) between 2010 and 2019. Notably, however, this decrease in rates reversed during the first 2 years of the COVID-19 pandemic, with increases in global age-standardised all-cause DALY rates since 2019 of 4·1% (1·8-6·3) in 2020 and 7·2% (4·7-10·0) in 2021. In 2021, COVID-19 was the leading cause of DALYs globally (212·0 million [198·0-234·5] DALYs), followed by ischaemic heart disease (188·3 million [176·7-198·3]), neonatal disorders (186·3 million [162·3-214·9]), and stroke (160·4 million [148·0-171·7]). However, notable health gains were seen among other leading communicable, maternal, neonatal, and nutritional (CMNN) diseases. Globally between 2010 and 2021, the age-standardised DALY rates for HIV/AIDS decreased by 47·8% (43·3-51·7) and for diarrhoeal diseases decreased by 47·0% (39·9-52·9). Non-communicable diseases contributed 1·73 billion (95% UI 1·54-1·94) DALYs in 2021, with a decrease in age-standardised DALY rates since 2010 of 6·4% (95% UI 3·5-9·5). Between 2010 and 2021, among the 25 leading Level 3 causes, age-standardised DALY rates increased most substantially for anxiety disorders (16·7% [14·0-19·8]), depressive disorders (16·4% [11·9-21·3]), and diabetes (14·0% [10·0-17·4]). Age-standardised DALY rates due to injuries decreased globally by 24·0% (20·7-27·2) between 2010 and 2021, although improvements were not uniform across locations, ages, and sexes. Globally, HALE at birth improved slightly, from 61·3 years (58·6-63·6) in 2010 to 62·2 years (59·4-64·7) in 2021. However, despite this overall increase, HALE decreased by 2·2% (1·6-2·9) between 2019 and 2021. INTERPRETATION: Putting the COVID-19 pandemic in the context of a mutually exclusive and collectively exhaustive list of causes of health loss is crucial to understanding its impact and ensuring that health funding and policy address needs at both local and global levels through cost-effective and evidence-based interventions. A global epidemiological transition remains underway. Our findings suggest that prioritising non-communicable disease prevention and treatment policies, as well as strengthening health systems, continues to be crucially important. The progress on reducing the burden of CMNN diseases must not stall; although global trends are improving, the burden of CMNN diseases remains unacceptably high. Evidence-based interventions will help save the lives of young children and mothers and improve the overall health and economic conditions of societies across the world. Governments and multilateral organisations should prioritise pandemic preparedness planning alongside efforts to reduce the burden of diseases and injuries that will strain resources in the coming decades. FUNDING: Bill & Melinda Gates Foundation.

BACKGROUND: Alcohol use is a leading risk factor for death and disability, but its overall association with health remains complex given the possible protective effects of moderate alcohol consumption on some conditions. With our comprehensive approach to health accounting within the Global Burden of Diseases, Injuries, and Risk Factors Study 2016, we generated improved estimates of alcohol use and alcohol-attributable deaths and disability-adjusted life-years (DALYs) for 195 locations from 1990 to 2016, for both sexes and for 5-year age groups between the ages of 15 years and 95 years and older. METHODS: Using 694 data sources of individual and population-level alcohol consumption, along with 592 prospective and retrospective studies on the risk of alcohol use, we produced estimates of the prevalence of current drinking, abstention, the distribution of alcohol consumption among current drinkers in standard drinks daily (defined as 10 g of pure ethyl alcohol), and alcohol-attributable deaths and DALYs. We made several methodological improvements compared with previous estimates: first, we adjusted alcohol sales estimates to take into account tourist and unrecorded consumption; second, we did a new meta-analysis of relative risks for 23 health outcomes associated with alcohol use; and third, we developed a new method to quantify the level of alcohol consumption that minimises the overall risk to individual health. FINDINGS: Globally, alcohol use was the seventh leading risk factor for both deaths and DALYs in 2016, accounting for 2·2% (95% uncertainty interval [UI] 1·5-3·0) of age-standardised female deaths and 6·8% (5·8-8·0) of age-standardised male deaths. Among the population aged 15-49 years, alcohol use was the leading risk factor globally in 2016, with 3·8% (95% UI 3·2-4·3) of female deaths and 12·2% (10·8-13·6) of male deaths attributable to alcohol use. For the population aged 15-49 years, female attributable DALYs were 2·3% (95% UI 2·0-2·6) and male attributable DALYs were 8·9% (7·8-9·9). The three leading causes of attributable deaths in this age group were tuberculosis (1·4% [95% UI 1·0-1·7] of total deaths), road injuries (1·2% [0·7-1·9]), and self-harm (1·1% [0·6-1·5]). For populations aged 50 years and older, cancers accounted for a large proportion of total alcohol-attributable deaths in 2016, constituting 27·1% (95% UI 21·2-33·3) of total alcohol-attributable female deaths and 18·9% (15·3-22·6) of male deaths. The level of alcohol consumption that minimised harm across health outcomes was zero (95% UI 0·0-0·8) standard drinks per week. INTERPRETATION: Alcohol use is a leading risk factor for global disease burden and causes substantial health loss. We found that the risk of all-cause mortality, and of cancers specifically, rises with increasing levels of consumption, and the level of consumption that minimises health loss is zero. These results suggest that alcohol control policies might need to be revised worldwide, refocusing on efforts to lower overall population-level consumption. FUNDING: Bill & Melinda Gates Foundation.

The global burden of cancer continues to increase largely because of the aging and growth of the world population alongside an increasing adoption of cancer-causing behaviors, particularly smoking, in economically developing countries. Based on the GLOBOCAN 2008 estimates, about 12.7 million cancer cases and 7.6 million cancer deaths are estimated to have occurred in 2008; of these, 56% of the cases and 64% of the deaths occurred in the economically developing world. Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among females, accounting for 23% of the total cancer cases and 14% of the cancer deaths. Lung cancer is the leading cancer site in males, comprising 17% of the total new cancer cases and 23% of the total cancer deaths. Breast cancer is now also the leading cause of cancer death among females in economically developing countries, a shift from the previous decade during which the most common cause of cancer death was cervical cancer. Further, the mortality burden for lung cancer among females in developing countries is as high as the burden for cervical cancer, with each accounting for 11% of the total female cancer deaths. Although overall cancer incidence rates in the developing world are half those seen in the developed world in both sexes, the overall cancer mortality rates are generally similar. Cancer survival tends to be poorer in developing countries, most likely because of a combination of a late stage at diagnosis and limited access to timely and standard treatment. A substantial proportion of the worldwide burden of cancer could be prevented through the application of existing cancer control knowledge and by implementing programs for tobacco control, vaccination (for liver and cervical cancers), and early detection and treatment, as well as public health campaigns promoting physical activity and a healthier dietary intake. Clinicians, public health professionals, and policy makers can play an active role in accelerating the application of such interventions globally.

The first edition of the clinical practice guidelines for liver cirrhosis was published in 2010, and the second edition was published in 2015 by the Japanese Society of Gastroenterology (JSGE). The revised third edition was recently published in 2020. This version has become a joint guideline by the JSGE and the Japan Society of Hepatology (JSH). In addition to the clinical questions (CQs), background questions (BQs) are new items for basic clinical knowledge, and future research questions (FRQs) are newly added clinically important items. Concerning the clinical treatment of liver cirrhosis, new findings have been reported over the past 5 years since the second edition. In this revision, we decided to match the international standards as much as possible by referring to the latest international guidelines. Newly developed agents for various complications have also made great progress. In comparison with the latest global guidelines, such as the European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD), we are introducing data based on the evidence for clinical practice in Japan. The flowchart for nutrition therapy was reviewed to be useful for daily medical care by referring to overseas guidelines. We also explain several clinically important items that have recently received focus and were not mentioned in the last editions. This digest version describes the issues related to the management of liver cirrhosis and several complications in clinical practice. The content begins with a diagnostic algorithm, the revised flowchart for nutritional therapy, and refracted ascites, which are of great importance to patients with cirrhosis. In addition to the updated antiviral therapy for hepatitis B and C liver cirrhosis, the latest treatments for non-viral cirrhosis, such as alcoholic steatohepatitis/non-alcoholic steatohepatitis (ASH/NASH) and autoimmune-related cirrhosis, are also described. It also covers the latest evidence regarding the diagnosis and treatment of liver cirrhosis complications, namely gastrointestinal bleeding, ascites, hepatorenal syndrome and acute kidney injury, hepatic encephalopathy, portal thrombus, sarcopenia, muscle cramp, thrombocytopenia, pruritus, hepatopulmonary syndrome, portopulmonary hypertension, and vitamin D deficiency, including BQ, CQ and FRQ. Finally, this guideline covers prognosis prediction and liver transplantation, especially focusing on several new findings since the last version. Since this revision is a joint guideline by both societies, the same content is published simultaneously in the official English journal of JSGE and JSH.

Histone methyltransferases are epigenetic regulators that modify key lysine and arginine residues on histones and are believed to play an important role in cancer development and maintenance. These epigenetic modifications are potentially reversible and as a result this class of enzymes has drawn great interest as potential therapeutic targets of small molecule inhibitors. Previous studies have suggested that the histone lysine methyltransferase G9a (EHMT2) is required to perpetuate malignant phenotypes through multiple mechanisms in a variety of cancer types. To further elucidate the enzymatic role of G9a in cancer, we describe herein the biological activities of a novel peptide-competitive histone methyltransferase inhibitor, A-366, that selectively inhibits G9a and the closely related GLP (EHMT1), but not other histone methyltransferases. A-366 has significantly less cytotoxic effects on the growth of tumor cell lines compared to other known G9a/GLP small molecule inhibitors despite equivalent cellular activity on methylation of H3K9me2. Additionally, the selectivity profile of A-366 has aided in the discovery of a potentially important role for G9a/GLP in maintenance of leukemia. Treatment of various leukemia cell lines in vitro resulted in marked differentiation and morphological changes of these tumor cell lines. Furthermore, treatment of a flank xenograft leukemia model with A-366 resulted in growth inhibition in vivo consistent with the profile of H3K9me2 reduction observed. In summary, A-366 is a novel and highly selective inhibitor of G9a/GLP that has enabled the discovery of a role for G9a/GLP enzymatic activity in the growth and differentiation status of leukemia cells.

BACKGROUND: To compare the overall survival of patients with hepatocellular carcinoma (HCC) who were treated with lipiodol-based conventional transarterial chemoembolization (cTACE) with that of patients treated with drug-eluting bead transarterial chemoembolization (DEB-TACE). METHODS: By an electronic search of our radiology information system, we identified 674 patients that received TACE between November 2002 and July 2013. A total of 520 patients received cTACE, and 154 received DEB-TACE. In total, 424 patients were excluded for the following reasons: tumor type other than HCC (n=91), liver transplantation after TACE (n=119), lack of histological grading (n=58), incomplete laboratory values (n=15), other reasons (e.g., previous systemic chemotherapy) (n=114), or were lost to follow-up (n=27). Therefore, 250 patients were finally included for comparative analysis (n=174 cTACE; n=76 DEB-TACE). RESULTS: There were no significant differences between the two groups regarding sex, overall status (Barcelona Clinic Liver Cancer classification), liver function (Child-Pugh), portal invasion, tumor load, or tumor grading (all p>0.05). The mean number of treatment sessions was 4±3.1 in the cTACE group versus 2.9±1.8 in the DEB-TACE group (p=0.01). Median survival was 409 days (95% CI: 321-488 days) in the cTACE group, compared with 369 days (95% CI: 310-589 days) in the DEB-TACE group (p=0.76). In the subgroup of Child A patients, the survival was 602 days (484-792 days) for cTACE versus 627 days (364-788 days) for DEB-TACE (p=0.39). In Child B/C patients, the survival was considerably lower: 223 days (165-315 days) for cTACE versus 226 days (114-335 days) for DEB-TACE (p=0.53). CONCLUSION: The present study showed no significant difference in overall survival between cTACE and DEB-TACE in patients with HCC. However, the significantly lower number of treatments needed in the DEB-TACE group makes it a more appealing treatment option than cTACE for appropriately selected patients with unresectable HCC.

Initially, a set of guidelines for the use of ultrasound contrast agents was published in 2004 dealing only with liver applications. A second edition of the guidelines in 2008 reflected changes in the available contrast agents and updated the guidelines for the liver, as well as implementing some non-liver applications. Time has moved on, and the need for international guidelines on the use of CEUS in the liver has become apparent. The present document describes the third iteration of recommendations for the hepatic use of contrast enhanced ultrasound (CEUS) using contrast specific imaging techniques. This joint WFUMB-EFSUMB initiative has implicated experts from major leading ultrasound societies worldwide. These liver CEUS guidelines are simultaneously published in the official journals of both organizing federations (i.e., Ultrasound in Medicine and Biology for WFUMB and Ultraschall in der Medizin/European Journal of Ultrasound for EFSUMB). These guidelines and recommendations provide general advice on the use of all currently clinically available ultrasound contrast agents (UCA). They are intended to create standard protocols for the use and administration of UCA in liver applications on an international basis and improve the management of patients worldwide.

Given the increasing prevalence of diabetes and obesity worldwide, the deleterious effects of non-alcoholic fatty liver disease (NAFLD) are becoming a growing challenge for public health. NAFLD is the most common chronic liver disease in the Western world. NAFLD is closely associated with metabolic disorders, including central obesity, dyslipidaemia, hypertension, hyperglycaemia and persistent abnormalities of liver function tests.In general NAFLD is a common denominer for a broad spectrum of damage to the liver, which can be due to hepatocyte injury, inflammatory processes and fibrosis. This is normally seen on liver biopsy and can range from milder forms (steatosis) to the more severe forms (non-alcoholic steatohepatitis (NASH), advanced fibrosis, cirrhosis and liver failure). In these patients, advanced fibrosis is the major predictor of morbidity and liver-related mortality, and an accurate diagnosis of NASH and NAFLD is mandatory. Histologic evaluation with liver biopsy remains the gold standard to diagnose NAFLD. Diagnosis of NAFLD is defined as presence of hepatic steatosis, ballooning and lobular inflammation with or without fibrosis. Weight loss, dietary modification, and the treatment of underlying metabolic syndrome remain the mainstays of therapy once the diagnosis is established. Dietary recommendations and lifestyle interventions, weight loss, and the treatment of underlying metabolic syndrome remain the mainstays of therapy once the diagnosis is established with promising results but are difficult to maintain. Pioglitazone and vitamin E are recommended by guidelines in selected patients. This review gives an overview of NAFLD and its treatment options.

BACKGROUND/AIM: Hypercaloric diet ingestion and sedentary lifestyle result in obesity. Metabolic syndrome is a cluster of clinical features secondary to obesity, considered as a pre-diabetic condition and recognized as an independent risk factor for cardiovascular diseases. To better understand the relationship between obesity, metabolic syndrome and cardiovascular disease as well as for the development of novel therapeutic strategies, animal models that reproduce the etiology, course and outcomes of these pathologies are required. The aim of this work was to characterize the long-term effects of high-fat diet-induced obesity on the mice cardiovascular system, in order to make available a new animal model for diabetic cardiomyopathy. METHODS/RESULTS: Male C57BL/6 mice were fed with a standardized high-fat diet (obese) or regular diet (normal) for 16 months. Metabolic syndrome was evaluated testing plasma glucose, triglycerides, cholesterol, insulin, and glucose tolerance. Arterial pressure was measured using a sphygmomanometer (non invasive method) and by hemodynamic parameters (invasive method). Cardiac anatomy was described based on echocardiography and histological studies. Cardiac function was assessed by cardiac catheterization under a stress test. Cardiac remodelling and metabolic biomarkers were assessed by RT-qPCR and immunoblotting. As of month eight, the obese mice were overweight, hyperglycaemic, insulin resistant, hyperinsulinemic and hypercholesterolemic. At month 16, they also presented normal arterial pressure but altered vascular reactivity (vasoconstriction), and cardiac contractility reserve reduction, heart mass increase, cardiomyocyte hypertrophy, cardiac fibrosis, and heart metabolic compensations. By contrast, the normal mice remained healthy throughout the study. CONCLUSIONS: Mice fed with a high-fat diet for prolonged time recapitulates the etiology, course and outcomes of the early phases of human diabetic cardiomyopathy.

Hepatitis B (HBV) infection is endemic in Viet Nam, with up to 8.4 million individuals estimated to be chronically infected. We describe results of a large, multicentre seroepidemiological and molecular study of the prevalence of HBV infection and blood-borne viral coinfections in Viet Nam. Individuals with varying risk factors for infection (n = 8654) were recruited from five centres; Ha Noi, Hai Phong, Da Nang, Khanh Hoa and Can Tho. A mean prevalence rate of 10.7% was observed and levels of HBsAg were significantly higher in injecting drug users (IDUs) (17.4%, n = 174/1000) and dialysis patients (14.3%, n = 82/575) than in lower-risk groups (9.4%; p<0.001). Coinfection with HIV was seen in 28% of HBV-infected IDUs (n = 49/174) and 15.2% of commercial sex workers (CSWs; n = 15/99). HCV infection was present in 89.8% of the HBV-HIV coinfected IDUs (n = 44/49) and 40% of HBV-HIV coinfected CSWs (n = 16/40). Anti-HDV was detected in 10.7% (n = 34/318) of HBsAg positive individuals. Phylogenetic analysis of HBV S gene (n = 187) showed a predominance of genotype B4 (82.6%); genotypes C1 (14.6%), B2 (2.7%) and C5 (0.5%) were also identified. The precore mutation G1896A was identified in 35% of all specimens, and was more frequently observed in genotype B (41%) than genotype C (3%; p<0.0001). In the immunodominant 'a' region of the surface gene, point mutations were identified in 31% (n = 58/187) of sequences, and 2.2% (n = 4/187) and 5.3% (n = 10/187) specimens contained the major vaccine escape mutations G145A/R and P120L/Q/S/T, respectively. 368 HBsAg positive individuals were genotyped for the IL28B SNP rs12979860 and no significant association between the IL28B SNP and clearance of HBsAg, HBV viral load or HBeAg was observed. This study confirms the high prevalence of HBV infection in Viet Nam and also highlights the significant levels of blood-borne virus coinfections, which have important implications for hepatitis-related morbidity and development of effective management strategies.

BACKGROUND AND AIMS: Interferon (IFN)- free direct antiviral agents (DAAs) with rapid HCV eradication might evoke immunological reconstitutions, and some early recurrences of HCC after IFN-free DAAs have been reported. This study aimed to investigate whether natural killer group 2, member D (NKG2D) predicts early emergence of HCC after IFN-free DAAs. METHODS: We conducted a clinical practice-based observational study of 101 patients infected with genotype 1 HCV who received IFN-free (DAAs), and stratified them into those who did or did not develop early (i.e., during the 6-month surveillance period following treatment.) recurrence or occurrence of clinically evident HCC. We also analyzed the peripheral blood mononuclear cells, both before treatment and at end of treatment (EOT), of 24 of the patients who received IFN-free DAAs, and 16 who received IFN-combined protease inhibitor. RESULTS: We found early emergence of clinically evident HCC after IFN-free DAAs in 12 (12%) patients. Higher pre-treatment NKG2D expression, higher FIB-4 score, previous HCC history and failure to achieve sustained viral response were significant factors correlating to early HCC emergence. After IFN-free DAAs, a rapid decrease of NKG2D at EOT correlated with early HCC emergence in the IFN-free DAA-treated patients, but not in patients treated with the IFN-combined regimen. The decrease of NKG2D until EOT was predictive of early HCC emergence at a cut-off of -52% (AUC = 0.92). CONCLUSIONS: On-treatment decrease of NKG2D may be a useful predictor of early emerging HCC in patients treated with IFN-free DAAs.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western industrialised countries. The prevalence of NAFLD is increasing in parallel with the global rise in obesity and type 2 diabetes mellitus. NAFLD represents a spectrum of liver disease severity. NAFLD begins with accumulation of triacylglycerols in the liver (steatosis), and is defined by hepatic fatty infiltration amounting to greater than 5% by liver weight or the presence of over 5% of hepatocytes loaded with large fat vacuoles. In almost a quarter of affected individuals, steatosis progresses with the development of liver inflammation to non-alcoholic steatohepatitis (NASH). NASH is a potentially progressive liver condition and with ongoing liver injury and cell death can result in fibrosis. Progressive liver fibrosis may lead to the development of cirrhosis in a small proportion of patients. With the growing prevalence of NAFLD, there is an increasing need for a robust, accurate and non-invasive approach to diagnosing the different stages of this condition. This review will focus on (1) the biochemical tests and imaging techniques used to diagnose the different stages of NAFLD; and (2) a selection of the current management approaches focusing on lifestyle interventions and pharmacological therapies for NAFLD.

Despite advances in stem cell research, cell transplantation therapy for liver failure is impeded by a shortage of human primary hepatocytes (HPH), along with current differentiation protocol limitations. Several studies have examined the concept of co-culture of human induced pluripotent cells (hiPSCs) with various types of supporting non-parenchymal cells to attain a higher differentiation yield and to improve hepatocyte-like cell functions both in vitro and in vivo. Co-culturing hiPSCs with human endothelial cells (hECs) is a relatively new technique that requires more detailed studies. Using our 3D human embryoid bodies (hEBs) formation technology, we interlaced Human Adipose Microvascular Endothelial Cells (HAMEC) with hiPSCs, leading to a higher differentiation yield and notable improvements across a wide range of hepatic functions. We conducted a comprehensive gene and protein secretion analysis of our HLCs coagulation factors profile, showing promising results in comparison with HPH. Furthermore, a stage-specific glycomic analysis revealed that the differentiated hepatocyte-like clusters (HLCs) resemble the glycan features of a mature tissue rather than cells in culture. We tested our HLCs in animal models, where the presence of HAMEC in the clusters showed a consistently better performance compared to the hiPSCs only group in regard to persistent albumin secretion post-transplantation.

UNLABELLED: Chronic hepatitis B viral (HBV) infection remains a significant global health problem. Evidence-based guidelines are needed to help providers determine when treatment should be initiated, which medication is most appropriate, and when treatment can safely be stopped. The American Association for the Study of Liver Diseases HBV guideline methodology and writing committees developed a protocol a priori for this systematic review. We searched multiple databases for randomized controlled trials and controlled observational studies that enrolled adults ≥18 years old diagnosed with chronic HBV infection who received antiviral therapy. Data extraction was done by pairs of independent reviewers. We included 73 studies, of which 59 (15 randomized controlled trials and 44 observational studies) reported clinical outcomes. Moderate-quality evidence supported the effectiveness of antiviral therapy in patients with immune active chronic HBV infection in reducing the risk of cirrhosis, decompensated liver disease, and hepatocellular carcinoma. In immune tolerant patients, moderate-quality evidence supports improved intermediate outcomes with antiviral therapy. Only very low-quality evidence informed the questions about discontinuing versus continuing antiviral therapy in hepatitis B e antigen-positive patients who seroconverted from hepatitis B e antigen to hepatitis B e antibody and about the safety of entecavir versus tenofovir. Noncomparative and indirect evidence was available for questions about stopping versus continuing antiviral therapy in hepatitis B e antigen-negative patients, monotherapy versus adding a second agent in patients with persistent viremia during treatment, and the effectiveness of antivirals in compensated cirrhosis with low-level viremia. CONCLUSION: Most of the current literature focuses on the immune active phases of chronic HBV infection; decision-making in other commonly encountered and challenging clinical settings depends on indirect evidence.

Hepatitis C virus (HCV) is a genetically diverse pathogen infecting approximately 2-3% of the world's population. Herein, we describe results of a large, multicentre serological and molecular epidemiological study cataloguing the prevalence and genetic diversity of HCV in five regions of Vietnam; Ha Noi, Hai Phong, Da Nang, Khanh Hoa and Can Tho. Individuals (n=8654) with varying risk factors for infection were analysed for the presence of HCV Ab/Ag and, in a subset of positive specimens, for HCV RNA levels (n=475) and genotype (n=282). In lower risk individuals, including voluntary blood donors, military recruits and pregnant women, the prevalence of infection was 0.5% (n=26/5250). Prevalence rates were significantly higher (p<0.001) in intravenous drug users (IDUs; 55.6%, n=556/1000), dialysis patients (26.6%, n=153/575) commercial sex workers (CSWs; 8.7%, n=87/1000), and recipients of multiple blood transfusions (6.0%, n=32/529). The prevalence of HCV in dialysis patients varied but remained high in all regions (11-43%) and was associated with the receipt of blood transfusions [OR: 2.08 (1.85-2.34), p=0.001], time from first transfusion [OR: 1.07 (1.01-1.13), p=0.023], duration of dialysis [OR: 1.31 (1.19-1.43), p<0.001] and male gender [OR: 1.60 (1.06-2.41), p=0.026]. Phylogenetic analysis revealed high genetic diversity, particularly amongst dialysis and multi-transfused patients, identifying subtypes 1a (33%), 1b (27%), 2a (0.4%), 3a (0.7%), 3b (1.1%), 6a (18.8%), 6e (6.0%), 6h (4.6%), 6l (6.4%) and 2 clusters of novel genotype 6 variants (2.1%). HCV genotype 1 predominated in Vietnam (60%, n=169/282) but the proportion of infections attributable to genotype 1 varied between regions and risk groups and, in the Southern part of Vietnam, genotype 6 viruses dominated in dialysis and multi-transfused patients (73.9%). This study confirms a high prevalence of HCV infection in Vietnamese IDUs and, notably, reveals high levels of HCV infection associated with dialysis and blood transfusion.