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Aim of the study: To analyze the hepatitis B virus (HBV) infection and mortality in Poland according to sociodemographic characteristics, trends over time, and the impact of the COVID-19 pandemic on hepatitis B epidemiology. Material and methods: We examined HBV infection cases and deaths reported by national registries and used Joinpoint analysis to estimate time trends in the years 2005-2021. To assess the impact of the COVID-19 pandemic on HBV infection, we used monthly information and compared 2020-2022 with 2019. Results: The Joinpoint analysis showed that in Poland between 2005 and 2021, there were pronounced decreasing trends of acute HBV infection, and during the pandemic period, acute HBV infection dramatically decreased (annual percent change, APC2019-2021 for men -57.65%, and women -42.10%, both ptrend < 0.05). There was a fluctuation in trends for chronic HBV infection, shifting from positive to negative in both genders in 2016, and over the pandemic, there were decreasing trends (APC2019-2021 for men -26.94% and women -28.96%, both ptrend < 0.05). From March to July 2022, the value of the diagnosis rate of HBV infection was lower compared to the respective months in 2019, but from September to December 2022, the rate changes were positive. Mortality due to HBV infection decreased in both genders, mainly within the 2005-2019 period. Conclusions: During the COVID-19 pandemic, a sharp decrease in HBV diagnosis rates in Poland, especially in acute cases, was observed. However, trends of hepatitis B infection require further monitoring. It is necessary to introduce a national screening program that also encompasses the population of migrants and improve the linkage to care. [ABSTRACT FROM AUTHOR]

Background: The cause of acute paediatric hepatitis of unknown aetiology (2022) has not been established despite extensive investigation., Objective: To summarise the evidence for and against a causal role for human adenovirus (HAdv), adeno-associated virus 2 (AAV-2) and SARS-CoV-2 in outbreaks of paediatric hepatitis in 2022., Methods: We appraised and summarised relevant evidence for each of the Bradford Hill criteria for causality using quantitative (statistical modelling) and qualitative (narrative coherence) approaches. Each team member scored the evidence base for each criterion separately for HAdv, AAV-2 and SARS-CoV-2; differences were resolved by discussion. We additionally examined criteria of strength and temporality by examining the lagged association between SARS-CoV-2 positivity, respiratory HAdv positivity, positive faecal HAdv specimens and excess A&E attendances in 1-4 years for liver conditions in England., Results: Assessing criteria using the published literature and our modelling: for HAdv three Bradford Hill criteria (strength, consistency and temporality) were partially met; and five criteria (consistency, coherence, experimental manipulation, analogy and temporality) were minimally met. For AAV-2, the strength of association criterion was fully met, five criteria (consistency, temporality, specificity, biological gradient and plausibility) were partially met and three (coherence, analogy and experimental manipulation) were minimally met. For SARS-CoV-2, five criteria (strength of association, plausibility, temporality, coherence and analogy) were fully met; one (consistency) was partially met and three (specificity, biological gradient and experimental manipulation) were minimally met., Conclusion: Based on the Bradford Hill criteria and modelling, HAdv alone is unlikely to be the cause of the recent increase in hepatitis in children. The causal link between SARS-CoV-2, and to a lesser degree AAV-2, appears substantially stronger but remains unproven. Hepatitis is a known complication of multisystem inflammatory syndrome in children following COVID-19, and SARS-CoV-2 has been linked to increased susceptibility to infection post-COVID-19, which may suggest complex causal pathways including a possible interaction with AAV-2 infection/reactivation in hosts that are genetically susceptible or sensitised to infection., Competing Interests: Competing interests: CRM and DG are members of OzSAGE, an independent body that advises on COVID-19 policy. CRM was on the WHO COVID-19 Vaccine Composition Technical Advisory Group from 2021-2024 and receives funding from Sanofi for influenza research. She has done speaker engagements for Moderna, Pfizer, Seqirus and Sanofi in 2024., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

The World Health Organization has issued a global alert on Acute Severe Hepatitis of Unknown Aetiology (AS-HEP-UA) since 23 April 2022,and there was still uncertainty regarding the association of AS-HEP-UA with SARS-CoV-2 as well as adenovirus. This study aimed to summarize the infection of SARS-CoV-2 and co-infections with adenovirus, as well as clinical features and outcomes in patients with AS-HEP-UA. PubMed, Embase, Web of Science, and the Cochrane Library were searched from 1 October 2021 to 8 December 2022 for studies about patients with AS-HEP-UA. This study was registered in the PROSPERO database (CRD42023385056). We has included 14 eligible articles. The main clinical features of AS-HEP-UA were jaundice (65%) and vomiting (59%), while other clinical features included diarrhea (45%), abdominal pain (37%), and fever (31%), roughly 10% of the children required liver transplantation. The overall positivity rate for SARS-CoV-2 was 21.6% (95% CI: 0.126-0.319), with 25.5% (95% CI: 0.161-0.358) for previous infections. The positivity rate for adenovirus infection was 58.6% (95% CI:0.429-0.736) while co-infection with SARS-CoV-2 was 17.5% (95% CI: 0.049-0.342). Moreover, we found that the positive rate of SARS-CoV-2 for this hepatitis outbreak was correlated with region by subgroup analysis. In conclusion, the positive rate of adenovirus was higher than SARS-CoV-2, and the relationship between AS-Hep-UA and COVID-19 is not significant. However, it cannot be excluded that the COVID-19 epidemic is an indirect causative agent of AS-Hep-UA, which requires a larger cohort of AS-Hep-UA patients to uncover additional findings., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Shan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: The impact of acute severe hepatitis of unknown origin in children (SHIC) subject to a medical alert in 2022 medical alert is poorly understood., Materials and Methods: Observational study of the incidence, aetiology and clinical presentation of acute hypertransaminasaemia (HTRA) with laboratory values in the severe range (ALT and/or AST ≥ 500 U/L) in paediatric patients (age 0 to 16 years) in one health care zone from 2012 to 2022, comparing the periods of the SHIC alert and the SARS-CoV2 pandemic with previous years., Results: The incidence of severe HTRA of any cause was 195.28 per 100 000 blood tests, with an incidence of 181.38 in the SHIC alert period and 166.09 during the SARS-CoV-2 pandemic, without statistically significant differences. Hepatitis of unknown origin accounted for 7.42% of total cases and transaminase levels normalised in 126 days (SD, 99.4). During the SHIC alert period there was a nonsignificant trend towards a higher incidence, as occurred in 2012 and 2018. In this group of cases, there was a significant increase in the presence of fever, vomiting and upper respiratory symptoms and lower levels of albumin and alkaline phosphatase. One patient required a liver transplant., Conclusions: In our setting, there was no significant increase in the incidence of severe HTRA of any aetiology or of unknown source during either the SHIC alert or the SARS-CoV2 pandemic. In the SHIC alert period, a clinical pattern emerged characterised by an increase in nonspecific infectious symptoms, so we cannot rule out a higher prevalence of an infectious agent different from the usual involved pathogens, but it did not cause a significant change in epidemiological trends., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.)

Background: The combination regimen with immune checkpoint inhibitors (ICIs) and other therapies has been widely applied for patients with non-small-cell lung cancer (NSCLC). To date, no literature has systematically addressed the risk of hepatitis associated with the combination therapy. We conducted this pharmacovigilance analysis using the Food and Drug Administration Adverse Event Reporting System (FAERS)., Patients and Methods: A total of 587,016 NSCLC reports were extracted from FAERS database spanning from the first quarter of 2013 to the second quarter of 2023. After filtering duplicate reports, logistic regression model was used to detect safety signals, and multivariable logistic regression model was used to confirm the interaction between ICI and other drugs., Results: Of the 81,512 patients with NSCLC, 2785 cases developed hepatitis. Multivariable logistic regression analyses revealed that the adjusted ROR of ICI combined with targeted therapy (TT) was the highest 1.64 (95% CI, 1.32-2.02; P < 0.0001) among all therapies, while that of TT and ICI treatment were 1.07 (95% CI, 0.98-1.17; P = 0.1097) and 1.12 (95% CI, 1.03-1.22; P = 0.0111), respectively. The adjusted ROR for the interaction effect was 1.64 (95% CI, 1.32-2.02; P < 0.0001). Furthermore, the adjusted ROR of ICI combined with KRAS-targeted drugs was the highest 3.03 (95% CI, 1.49-5.93; P = 0.0016) among all targeted drugs, with an adjusted ROR of 3.03 (95% CI, 1.49-5.93; P = 0.0016), indicating a meaningful interaction of these two kinds of drugs., Conclusion: We confirmed that combination treatment of ICI and TT is associated with the amplified risk of hepatitis, which is partly due to the interaction between ICI and TT, and the KRAS-targeted drugs may harbor the highest potential for hepatitis induction among TT drugs when combined with ICI. Besides, the combination treatment of ICI- and KRAS-targeted drugs also increases the incidence of colitis, pulmonary embolism and dehydration., Competing Interests: Declarations Conflict of interest There are no conflicts of interest to declare. Ethics approval Since the FAERS database is accessible to the public and patient records are anonymized and de-identified, ethical clearance and informed consent are not required for this study., (© 2024. The Author(s).)

Human adenovirus (HAdV) type F41 has been identified as a possible cause of the non-A-to-E hepatitis outbreak. This study uses wastewater monitoring to track HAdV F40 and F41, supporting clinical investigations and providing insights into the pathogen's role in the outbreak. Given the limited clinical monitoring in Sweden of HAdV-F40/41, this approach also helps estimate the true infection burden of this pathogen during the outbreak. This study developed three qPCR assays for the hexon, penton, and fiber genes of HAdV F40 and F41. The hexon assay was F41-specific, while the fiber assay detected multiple HAdV-F strains. Comprehensive monitoring of HAdV-F40/41 levels in Stockholm's wastewater was conducted over 1.5 years, capturing the period before, during, and after the outbreak. A significant infection wave was observed in spring 2022, with strains beyond lineage 2 contributing to the outbreak. Moreover, simultaneous SARS-CoV-2 surveillance revealed that HAdV-F infections peaked at different times from COVID-19, but the HAdV-F wave aligned with the relaxation of pandemic restrictions. These findings offer valuable insights for future HAdV-F investigations and confirm its role in the non-A-to-E hepatitis outbreak., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The top 20 highest burdened countries (in disability-adjusted life years) account for more than 75% of the global burden of viral hepatitis. An effective response in these 20 countries is crucial if global elimination targets are to be achieved. In this update of the Lancet Gastroenterology & Hepatology Commission on accelerating the elimination of viral hepatitis, we convene national experts from each of the top 20 highest burdened countries to provide an update on progress. Although the global burden of diseases is falling, progress towards elimination varies greatly by country. By use of a hepatitis elimination policy index conceived as part of the 2019 Commission, we measure countries' progress towards elimination. Progress in elimination policy has been made in 14 of 20 countries with the highest burden since 2018, with the most substantial gains observed in Bangladesh, India, Indonesia, Japan, and Russia. Most improvements are attributable to the publication of formalised national action plans for the elimination of viral hepatitis, provision of publicly funded screening programmes, and government subsidisation of antiviral treatments. Key themes that emerged from discussion between national commissioners from the highest burdened countries build on the original recommendations to accelerate the global elimination of viral hepatitis. These themes include the need for simplified models of care, improved access to appropriate diagnostics, financing initiatives, and rapid implementation of lessons from the COVID-19 pandemic., Competing Interests: Declaration of interests GSC is supported in part by the Biomedical Research Centre of Imperial College NHS Trust. In the last 36 months, IW has received grant funding from AbbVie, Arena, AstraZeneca, Novartis, and Pharco. JG has received funding from AbbVie, bioLytical, Camurus, Cepheid, Gilead, Hologic, and Indivior. YT has received funding from Fujirebio, Sysmex, AbbVie, GlaxoSmithKline, and Gilead Sciences. JVL acknowledges grants and speaker fees from AbbVie, Gilead Sciences, Merck Sharp and Dohme, and Roche Diagnostics to his institution; speaker fees from Echosens, Janssen, Novo Nordisk, and ViiV; consulting fees from GSK and Novavax; and support to ISGlobal (grant CEX2018-000806-S) funded by MCIN/AEI/10.13039/501100011033, and the Generalitat de Catalunya through the CERCA programme, outside of the submitted work. DLT has provided expert testimony for Merck; has worked on diagnostics with Abbott. Through the Taskforce for Global Health, LH and JWW have received support for the Coalition for Global Hepatitis Elimination from governmental, philanthropic, individual, and industry partners (Abbott Laboratories, AbbVie, Cepheid, Gilead Sciences, Merck, Pharco, Roche Diagnostics, Siemens, VBI Vaccines, and Zydus-Cadila). DA-P has received payment from Viatris and Inogen Pharmaceutical for delivering presentations at conferences. ADM received AU$300 in 2021 to review a grant for the National Medical Research Council, Singapore. HC received lecture fees from Gilead Sciences. A portion of MAD's compensation comes from the Bill & Melinda Gates Foundation Global Public Goods Grant through its funding of work done for the Global Burden of Diseases, Injuries & Risk Factors study. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: The purpose of this study was to provide a systematic review and, where possible, meta-analysis on the prevalence of physical health conditions in sexual minority men (SMM, i.e., gay- and bisexual-identified men) compared with heterosexual-identified men. Methods: A systematic literature search in the databases MEDLINE, Embase, CENTRAL, CINAHL, and Web of Science was conducted on epidemiological studies on physical health conditions, classified in the Global Burden of Disease project and published between 2000 and 2021. Meta-analyses comparing odds ratios were calculated. Results: In total, 23,649 abstracts were screened, and 32 studies were included in the systematic review. Main findings were that (1) Largest differences in prevalence by sexual identity were found for chronic respiratory diseases, particularly asthma: overall, SMM were significantly almost 50% more likely to suffer from asthma than heterosexual men. (2) Evidence of higher prevalence was also found for chronic kidney diseases and headache disorders in gay men and for hepatitis B/C in both gay and bisexual men. (3) We found an overall trend that bisexual men were more affected by some of the physical health conditions compared with gay men (e.g., cardiovascular diseases, asthma). However, regarding cancer, headache disorders, and hepatitis, gay men were more affected. Conclusion: We found evidence of physical health disparities by sexual identity, suggesting more health issues in SMM. Since some of these findings rely on few comparisons or small samples of SMM only, this review is intended to be a vehement plea for routinely including sexual identity assessment in health research and clinical practice.

To understand the current situation of hepatitis-related aplastic anemia (HAAA) in children, we analyzed the patients with HAAA admitted to our hospital in the past 5 years to understand the disease characteristics and prognosis. The clinical data of patients with HAAA admitted to our hospital from February 2017 to May 2022 were retrospectively analyzed. A total of 81 patients with HAAA, 56 males and 25 females. The median onset age was 5.9 years. The median time from hepatitis to occurrence of hemocytopenia was 30 days, and the median follow-up time was 2.77 years. There were 23 cases (28.5%) of severe aplastic anemia (SAA), 50 cases of very severe aplastic anemia (VSAA), and 8 cases of non-severe aplastic anemia (NSAA). At the beginning of the disease, cytotoxic T lymphocyte (CTL) was higher than normal in 60% of patients, and the median CD4/CD8 ratio was 0.2. As of follow-up, 72 children survived, 4 were lost, and 5 died. Thirty-four cases were treated with immunosuppressive therapy (IST), with a median follow-up time of 0.97 years. The total reaction rate was 73.5% (25/34), the complete reaction rate was 67.6% (23/34), and the nonreaction rate was 26.5% (9/34). Multivariate analysis suggested that co-infection was an independent risk factor affecting the efficacy of IST at 6 months, with an OR value of 16.76, 95% CI (1.23, 227.95), P=0.034. No independent influencing factors were found at the end of follow-up. The proportion of CTL cells in peripheral blood of children with HAAA is relatively increased, and IST is effective in 73.5% of children. Co-infection may prolongs the time to response to IST., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized advanced cancer management. Nevertheless, the generalized use of these medications has led to an increase in the incidence of adverse immune-mediated events and the liver is one of the most frequently affected organs. Liver involvement associated with the administration of immunotherapy is known as immune-mediated hepatitis (IMH), whose incidence and clinical characteristics have been described by different authors. It often presents as mild elevations of amino transferase levels, seen in routine blood tests, that spontaneously return to normal, but it can also manifest as severe transaminitis, possibly leading to the permanent discontinuation of treatment. The aim of the following review was to describe the most up-to-date concepts regarding the epidemiology, diagnosis, risk factors, and progression of IMH, as well as its incidence in different types of common cancers, including hepatocellular carcinoma. Treatment recommendations according to the most current guidelines are also provided., (Copyright © 2024 Asociación Mexicana de Gastroenterología. Published by Masson Doyma México S.A. All rights reserved.)

Background: Adenovirus is a known cause of hepatitis in immunocompromised children, but not in immunocompetent children. In April, 2022, following multiple reports of hepatitis of unknown aetiology and adenovirus viraemia in immunocompetent children in the USA and UK, the US Centers for Disease Control and Prevention (CDC) and jurisdictional health departments initiated national surveillance of paediatric acute hepatitis of unknown aetiology. We aimed to describe the clinical and epidemiological characteristics of children identified with hepatitis of unknown aetiology between Oct 1, 2021, and Sept 30, 2022, in the USA and to compare characteristics of those who tested positive for adenovirus with those who tested negative., Methods: In this national surveillance investigation in the USA, children were identified for investigation if they were younger than 10 years with elevated liver transaminases (>500 U/L) who had an unknown cause for their hepatitis and onset on or after Oct 1, 2021. We reviewed medical chart abstractions, which included data on demographics, underlying health conditions, signs and symptoms of illness, laboratory results, vaccination history, radiological and liver pathology findings, diagnoses and treatment received, and outcomes. Caregiver interviews were done to obtain information on symptoms and health-care utilisation for the hepatitis illness, medical history, illness in close contacts or at school or daycare, diet, travel, and other potential exposures. Blood, stool, respiratory, and tissue specimens were evaluated according to clinician discretion and available specimens were submitted to CDC for additional laboratory testing or pathology evaluation., Findings: Surveillance identified 377 patients from 45 US jurisdictions with hepatitis of unknown aetiology with onset from Oct 1, 2021, to Sept 30, 2022. The median age of patients was 2·8 years (IQR 1·2-5·0) and 192 (51%) were male, 184 (49%) were female, and one patient had sex unknown. Only 22 (6%) patients had a notable predisposing underlying condition. 347 patients (92%) were admitted to hospital, 21 (6%) subsequently received a liver transplant, and nine (2%) died. Among the 318 patients without notable underlying conditions, 275 were tested for adenovirus. Of these 116 (42%) had at least one positive specimen, and species F type 41 was the most frequent type identified (19 [73%] of 26 typed specimens were HAdV-41). Proportions of patients who had acute liver failure, received a liver transplant, and died were similar between those who tested positive for adenovirus compared with those who tested negative. Adenovirus species F was detected by polymerase chain reaction in nine pathology liver evaluations, but not by immunohistochemistry in seven of the nine with adequate liver tissue available. Interviews with caregivers yielded no common exposures., Interpretation: Adenovirus, alone or in combination with other factors, might play a potential role in acute hepatitis among immunocompetent children identified in this investigation, but the pathophysiologic mechanism of liver injury is unclear. To inform both prevention and intervention measures, more research is warranted to determine if and how adenovirus might contribute to hepatitis risk and the potential roles of other pathogens and host factors., Funding: None., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Aims: Shock of any cause leads to end-organ damage due to ischaemia, especially in perfusion-sensitive organs such as the liver. In septic shock, hypoxic hepatitis (S-HH) is defined as the 20-fold increase of the upper normal limit of aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) and is associated with a mortality of up to 60%. However, as pathophysiology, dynamics, and treatment differ between septic and cardiogenic shock (CS), the S-HH definition may not be suitable for CS. Therefore, we aim to evaluate if the S-HH definition is applicable in CS patients., Methods and Results: This analysis was based on a registry of all-comer CS patients treated between 2009 and 2019 at a tertiary care centre with exclusion of minors and patients without all necessary ASAT and ALAT values. N = 698. During in-hospital follow-up, 386 (55.3%) patients died. The S-HH was not significantly associated with in-hospital mortality in CS patients. To define HH among patients with CS (C-HH), optimal cut-off values were found to be ≥1.34-fold increase for ASAT and ≥1.51-fold increase for ALAT in serial measurements. The incidence of C-HH was 254/698 patients (36%) and C-HH showed a strong association with in-hospital mortality (odds ratio 2.36, 95% confidence interval: 1.61, 3.49)., Conclusion: The C-HH is a frequent and relevant comorbidity in patients with CS, although its definition varies from the established definition of HH in patients with septic shock. As C-HH contributed to excess mortality risk, these findings emphasize the need for further investigation of therapies reducing the occurrence of C-HH and also improving the associated outcome., Competing Interests: Conflict of interest: C.S. received speaker honoraria from AstraZeneca, outside the submitted work. B.S. received speaker fees from Abbott, Abiomed, and AstraZeneca, outside of the current study. All other authors do not declare any potential competing interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Abstract: Background & Aims: Chronic hepatitis D (delta) is a major global health burden. Clinical and virological characteristics of patients with hepatitis D virus (HDV) infection and treatment approaches in different regions world‐wide are poorly defined. Methods: The Hepatitis Delta International Network (HDIN) registry was established in 2011 with centres in Europe, Asia, North‐ and South America. Here, we report on clinical/ virological characteristics of the first 1576 patients with ongoing or past HDV infection included in the database until October 2016 and performed a retrospective outcome analysis. The primary aim was to investigate if the region of origin was associated with HDV replication and clinical outcome. Results: The majority of patients was male (n = 979, 62%) and the mean age was 36.7 years (range 1‐79, with 9% of patients younger than 20 years). Most patients were HBeAg‐negative (77%) and HDV‐RNA positive (85%). Cirrhosis was reported in 48.7% of cases which included 13% of patients with previous or ongoing liver decompensation. Hepatocellular carcinoma (HCC) developed in 30 patients (2.5%) and 44 (3.6%) underwent liver transplantation. Regions of origin were independently associated with clinical endpoints and detectability of HDV RNA. Antiviral therapy was administered to 356 patients with different treatment uptakes in different regions. Of these, 264 patients were treated with interferon‐a and 92 were treated with HBV‐Nucs only. Conclusions: The HDIN registry confirms the severity of hepatitis delta but also highlights the heterogeneity of patient characteristics and clinical outcomes in different regions. There is an urgent need for novel treatment options for HDV infection. [ABSTRACT FROM AUTHOR]

Background: Late-relapsing hepatitis after yellow fever (LHep-YF) during the convalescent phase of the disease has been described during recent yellow fever (YF) outbreaks in Brazil. LHep-YF is marked by a rebound in liver enzymes and nonspecific clinical manifestations around 46-60 days after YF symptom onset., Methods: Here we have characterized the clinical course and risk factors for LHep-YF using data from a representative cohort of patients who survived YF in Brazil, 2017-2018. A total of 221 YF-positive patients were discharged from the infectious disease reference hospital in Minas Gerais and were followed up at 30, 45, and 60 days post-symptom onset., Results: From 46 to 60 days post-symptom onset, 16% of YF patients (n = 36/221) exhibited a rebound of aminotransferases (aspartate aminotransferase or alanine aminotransferase >500 IU/L), alkaline phosphatase, and total bilirubin levels. Other etiologies of liver inflammation such as infectious hepatitis, autoimmune hepatitis, and metabolic liver disease were ruled out. Jaundice, fatigue, headache, and low platelet levels were associated with LHep-YF. Demographic factors, clinical manifestations, laboratory tests, ultrasound findings, and viral load during the acute phase of YF were not associated with the occurrence of LHep-YF., Conclusions: These findings provide new data on the clinical course of Late-relapsing hepatitis during the convalescent phase of YF and highlight the need for extended patient follow-up after acute YF., Competing Interests: Potential conflicts of interest. A. R. C. C. reports consulting fees from the International Horizon Scanning Initiative’s Horizon Scanning System tracked by ECRI, a global, independent authority on healthcare technology and safety. B. P. D. reports unpaid roles as financial council and vice-president of the Brazilian Society for Virology and as virology chair for the Brazilian Society for Microbiology. All other authors report no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Introduction: India is looking to achieve hepatitis elimination status by 2030 through vaccination, diagnostic tests, medicines, and education campaigns. Awareness generation is essential to orient people regarding hepatitis B and C. The present study was done to assess the knowledge regarding hepatitis among students and staff of academic institutions and raise awareness through a series of webinars., Materials and Methods: A cross-sectional study was conducted in 12 academic institutes from across the country between February and March 2022. The study included the dissemination of knowledge in the form of a webinar and the administration of a pre and postwebinar survey to assess the difference in the knowledge levels., Results: A total of 914 individuals participated in the sessions. The mean baseline score for general epidemiology (max = 13 points), treatment and complications (max = 7 points), and prevention (max = 5 points) were 10.9 ± 2.1, 4.6 ± 1.3, and 3.2 ± 1.3, respectively. Overall, the mean score increased from 18.5 ± 3.6 to 20.4 ± 3.4 postwebinar, with an increase of +7.3%., Conclusion: The study observed significant improvement in knowledge among the participants following a low-cost 1-day training in webinar mode. Such training programs can be upscaled and help in educating the general public on hepatitis., (© Journal of the Association of Physicians of India 2011.)

Pediatric acute hepatitis of unknown etiology has been reported globally since April 2022. In Japan, 139 possible cases with onset dates after October 2021 were reported as of December 2022. Three patients required liver transplants, but none died. Rates of adenovirus positivity (11/125, 9%) were lower than those for other countries.

An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland 1 in April 2022 and has now been identified in 35 countries 2 . Several recent studies have suggested an association with human adenovirus with this outbreak, a virus not commonly associated with hepatitis. Here we report a detailed case-control investigation and find an association between adeno-associated virus 2 (AAV2) infection and host genetics in disease susceptibility. Using next-generation sequencing, PCR with reverse transcription, serology and in situ hybridization, we detected recent infection with AAV2 in plasma and liver samples in 26 out of 32 (81%) cases of hepatitis compared with 5 out of 74 (7%) of samples from unaffected individuals. Furthermore, AAV2 was detected within ballooned hepatocytes alongside a prominent T cell infiltrate in liver biopsy samples. In keeping with a CD4 + T-cell-mediated immune pathology, the human leukocyte antigen (HLA) class II HLA-DRB1*04:01 allele was identified in 25 out of 27 cases (93%) compared with a background frequency of 10 out of 64 (16%; P = 5.49 × 10 -12 ). In summary, we report an outbreak of acute paediatric hepatitis associated with AAV2 infection (most likely acquired as a co-infection with human adenovirus that is usually required as a 'helper virus' to support AAV2 replication) and disease susceptibility related to HLA class II status., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

As of August 2022, clusters of acute severe hepatitis of unknown aetiology in children have been reported from 35 countries, including the USA 1,2 . Previous studies have found human adenoviruses (HAdVs) in the blood from patients in Europe and the USA 3-7 , although it is unclear whether this virus is causative. Here we used PCR testing, viral enrichment-based sequencing and agnostic metagenomic sequencing to analyse samples from 16 HAdV-positive cases from 1 October 2021 to 22 May 2022, in parallel with 113 controls. In blood from 14 cases, adeno-associated virus type 2 (AAV2) sequences were detected in 93% (13 of 14), compared to 4 (3.5%) of 113 controls (P < 0.001) and to 0 of 30 patients with hepatitis of defined aetiology (P < 0.001). In controls, HAdV type 41 was detected in blood from 9 (39.1%) of the 23 patients with acute gastroenteritis (without hepatitis), including 8 of 9 patients with positive stool HAdV testing, but co-infection with AAV2 was observed in only 3 (13.0%) of these 23 patients versus 93% of cases (P < 0.001). Co-infections by Epstein-Barr virus, human herpesvirus 6 and/or enterovirus A71 were also detected in 12 (85.7%) of 14 cases, with higher herpesvirus detection in cases versus controls (P < 0.001). Our findings suggest that the severity of the disease is related to co-infections involving AAV2 and one or more helper viruses., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background & Aims: The etiology of the current acute severe non-A-E hepatitis epidemic in children remains unclear. We aimed to describe the occurrence and outcomes of acute severe hepatitis in pediatric patients in North-West Germany over a period of more than 30 years and in the context of the current epidemic., Methods: We analyzed all cases of acute severe hepatitis in childhood, as defined by the World Health Organization, at Hannover Medical School from 1990 and at the University Hospital of Essen from 2009 to 16 May 2022. We separated cases into a historic cohort (1990-2018) and a COVID-19 era cohort (2019-2022)., Results: After application of exclusion criteria, 107 patients with acute severe hepatitis were identified (2.32 cases/center/year). Annual incidence per center rose significantly from 2.2 (historic cohort until 2018) to 4.25/center/year (from 2019, p = 0.002). Of all cases, 75.7% presented with jaundice, while 53.3% had clinical signs of infection. Two cases of adenovirus were proven (2004/2016), other pathogens detected were HHV-6 (4), CMV, HSV, EBV(3). Sixty-nine patients (64.5%) met the criteria of pediatric acute liver failure, with 44 requiring liver transplantation. In the current cohort, patients with infection, gastrointestinal symptoms and higher alanine aminotransferase had a better chance of transplant-free survival, whereas hepatic encephalopathy, higher international normalized ratio and bilirubin predicted a poor outcome. Twenty-five patients developed hepatitis-associated aplastic anemia and 19 patients (17.8%) died., Conclusions: Acute non-A-E-hepatitis in children is a rare but severe entity, often leading to acute liver failure. Clinical presentation in our current cohort resembles 2022 NAEH cases, with improved outcomes compared to historic controls. The rising incidence of NAEH in our centers since 2019, in the absence of adenoviral infection, indicates other potential triggers of similar NAEH cases., Impact and Implications: As the current epidemic of severe acute non-A-E-hepatitis cases in children highlights our limited understanding in the field, we aim to describe current cases, characterizing the presentation over time, and defining similarities and discrepancies before and during the COVID-19 pandemic. Our data show a rising incidence of non-A-E-hepatitis cases since the beginning of the COVID-19 pandemic. These cases were not associated with adenoviral infections, suggesting that the recently described accumulation of adenovirus infections in relationship to hepatitis is a new trigger for a known phenomenon, rather than a new disease entity. Therefore, the role of protective isolation and subsequent lack of contact with trivial infections in children during the pandemic should be the subject of further examinations. We expect our data to contribute to a better understanding of severe acute hepatitis in childhood, increased vigilance for this potentially lethal disease beyond the current epidemic, and ultimately improved clinical diagnosis and care., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK 1 . Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children., (© 2023. The Author(s).)

During April-July 2022, outbreaks of severe acute hepatitis of unknown etiology (SAHUE) were reported in 35 countries. Five percent of cases required liver transplantation, and 22 patients died. Viral metagenomic studies of clinical samples from SAHUE cases showed a correlation with human adenovirus F type 41 (HAdV-F41) and adeno-associated virus type 2 (AAV2). To explore the association between those DNA viruses and SAHUE in children in Ireland, we quantified HAdV-F41 and AAV2 in samples collected from a wastewater treatment plant serving 40% of Ireland's population. We noted a high correlation between HAdV-F41 and AAV2 circulation in the community and SAHUE clinical cases. Next-generation sequencing of the adenovirus hexon in wastewater demonstrated HAdV-F41 was the predominant HAdV type circulating. Our environmental analysis showed increased HAdV-F41 and AAV2 prevalence in the community during the SAHUE outbreak. Our findings highlight how wastewater sampling could aid in surveillance for respiratory adenovirus species.

Fowl adenovirus (FAdV) serotypes are involved in a variety of clinical manifestations in poultry and has resulted in substantial economic loss to the poultry farmers. Despite the endemicity of Inclusion body hepatitis (IBH) in South Asian countries, including India, its etiology is not well studied. In western India, the rural poultry flocks obtained from the vaccinated parents were experiencing disease outbreaks with substantial economic losses due to heavy outbreaks and mortality. Therefore, the study was conducted to decipher the molecular epidemiology of the FAdV from field outbreaks in western India. A total of 37 commercial broiler poultry flocks and 29 village poultry flocks of western India were visited during 2019 to 2021. Out of these, 19.14% flocks showed incidence of IBH during the age of 15 to 35 days. The mortality ranged from 3.3 percent to 55.28 percent. The samples were subjected for amplification of partial hexon gene covering loop 1 and loop 2. The results revealed 48.28% positivity by PCR. The sequence analysis identified 14 isolates as species D serotype 11 with 0.97 to 0.99% divergence and two as species E serotype 8b with 0.99% divergence. The FAdV-11 isolates showed amino acid substitutions D195N, T399A, N417S, and N496H. The amino acids I188 and N195 were conserved in FAdV-11. The molecular clock in Bayesian methods was used to determine most common ancestor. The isolates MH379249 and MH379248 were determined the most recent common ancestor for FAdV-11 and FAdV-8b isolates. The analysis suggested evolution of 10 FAdV-11 strains in 2012, and four FAdV-11 strains and two FAdV-8b strains in 2018., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Hepatotoxicity is a major immune-related adverse event that may become life-threatening. The impact of adding immune checkpoint blockade (ICB) to systemic therapy on the incidence of hepatotoxicity remains unknown. We performed a systematic review and meta-analysis to compare the incidence of hepatotoxicity among patients with cancer who received therapy with and without addition of ICB. PubMed, Embase, Web of Science, and Cochrane Library were searched to select phase 3 randomized controlled trials (RCTs) evaluating the effect of adding ICB to systemic therapy, placebo, or supportive care. The odds ratio (OR) of any grade and grade 3-5 hepatitis, elevations in aspartate aminotransferase (AST), and alanine aminotransferase (ALT) was pooled for meta-analysis. 43 RCTs with 28,905 participants were analyzed. Addition of ICB increased the incidence of hepatitis (any grade: OR, 2.13, 95% confidence interval [CI] 1.52-2.97, grade 3-5: OR, 2.66, 95% CI 1.72-4.11), elevated AST (any grade: OR, 2.16, 95% CI 1.73-2.70, grade 3-5: OR, 2.72, 95% CI 1.86-3.99), and elevated ALT (any grade: OR, 2.01, 95% CI 1.59-2.54, grade 3-5: OR, 2.40, 95% CI 1.62-3.55). Subgroup analysis based on the ICB mechanism revealed no significant heterogeneity among each mechanism for hepatitis (any Grade: I 2  = 11.1%, p for heterogeneity = 0.32, grade 3-5: I 2  = 0%, p = 0.48). Adding ICB to systemic therapy increases the incidence of hepatotoxicity regardless of the mechanism of ICB. Hepatotoxicity is common and vigilant monitoring of liver function is required during ICB therapy for patients with cancer., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Since April 2022, severe acute hepatitis of unknown origin in children has spread to 35 countries and regions around the world, and more than 1 010 cases have been reported. Since the severe acute hepatitis of unknown origin involves a wide range of areas and has a high rate, it is critical to identify the etiology and establish effective preventive, diagnostic and therapeutic measures as soon as possible. This study discusses the possible mechanisms and countermeasures of the severe acute hepatitis of unknown origin in children. It speculates that the occurrence of the recent severe acute hepatitis might be related to adenovirus, adeno-associated virus infection, and the COVID-19 epidemic, while the difference in HLA polymorphism among different races might be related to the fact that reported cases were more common in Europe and the United States. Based on the currently available evidence, it can be preliminarily judged that the risk of large-scale outbreak of severe acute hepatitis of unknown origin in children would be low in China, but the persistent awareness and vigilance of the etiology is still needed.

Objectives: To explore a potential country-based ecological link between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant (B.1.1.529) infection and an apparent current global outbreak of severe hepatitis of unknown etiology among children., Methods: We examined country-level statistical associations between reported detection of one or more unexplained severe hepatitis cases in children and the cumulative number of Omicron (B.1.1.529) cases in 38 Organisation for Economic Co-operation and Development (OECD) member countries plus Romania., Results: At least one focal hepatitis case was detected in 12 of the 39 countries included in our analysis. Numbers of confirmed Omicron cases reported in these 12 countries ranged from 4.4 to 11.9 million. Among the remaining 27 countries, this measure ranged from 0.5 to 5.5 million cases. Countries which reported focal hepatitis cases experienced higher precedent population burdens of Omicron cases relative to those which did not report any such hepatitis cases (p=0.013)., Conclusion: Prior exposure to Omicron variant (B.1.1.529) may be associated with an increased risk for severe hepatitis among children, indicating a critical need to conduct cofactor studies., Competing Interests: Conflict of interest We declare that we have no conflict of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

On April 21, 2022, CDC issued a health advisory † encouraging U.S. clinicians to report all patients aged <10 years with hepatitis of unknown etiology to public health authorities, after identification of similar cases in both the United States (1) and Europe. § A high proportion of initially reported patients had adenovirus detected in whole blood specimens, thus the health advisory encouraged clinicians to consider requesting adenovirus testing, preferentially on whole blood specimens. For patients meeting the criteria in the health advisory (patients under investigation [PUIs]), jurisdictional public health authorities abstracted medical charts and interviewed patient caregivers. As of June 15, 2022, a total of 296 PUIs with hepatitis onset on or after October 1, 2021, were reported from 42 U.S. jurisdictions. The median age of PUIs was 2 years, 2 months. Most PUIs were hospitalized (89.9%); 18 (6.1%) required a liver transplant, and 11 (3.7%) died. Adenovirus was detected in a respiratory, blood, or stool specimen of 100 (44.6%) of 224 patients. ¶ Current or past infection with SARS-CoV-2 (the virus that causes COVID-19) was reported in 10 of 98 (10.2%) and 32 of 123 (26.0%) patients, respectively. No common exposures (e.g., travel, food, or toxicants) were identified. This nationwide investigation is ongoing. Further clinical data are needed to understand the cause of hepatitis in these patients and to assess the potential association with adenovirus., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Since January 2022, acute severe hepatitis cases with unknown etiology in children have occurred in many countries in Europe and the United States, and 43.8% of the cases were positive for human adenovirus (HAdV), and some cases were identified as HAdV-41. However, more evidences including etiology, genomics, liver pathology, and immunohistochemistry are needed to determine the main cause of this outbreak. At present, due to the lack of systematic surveillance and research on hepatitis caused by HAdV infection, it is impossible to determine whether there are similar hepatitis cases occurred in China. It is urgent to carry out HAdV virolgocial surveillance based on clinical symptom, and potential risk of acute severe hepatitis should be studied as soon as possible according to the available relevant clinical, epidemiological and virological data, as well as risk factor information, which will provide scientific and technical support for the prevention and control of HAdV-related diseases.

In April 2022, the United Kingdom was the first to report 74 cases of severe acute hepatitis in children monitored across different parts of the country. Hepatitis A to E viruses were not the common infectious etiological agents. As a result, the World Health Organization is closely monitoring reports of its unknown etiology and high severity incidence, and has warned that more cases are likely to come. As of May 1, 2022, 20 countries in the world have reported 228 cases. This paper briefly introduces the general situation of this outbreak.

Purpose: Immune checkpoint inhibitor (ICI)-induced hepatitis belongs to the frequently occurring immune-related adverse events (irAEs), particularly with the combination therapy involving ipilimumab and nivolumab. However, predisposing factors predicting the occurrence of ICI-induced hepatitis are barely known. We investigated the association of preexisting autoantibodies in the development of ICI-induced hepatitis in a prospective cohort of cancer patients., Methods: Data from a prospective biomarker cohort comprising melanoma and non-small cell lung cancer (NSCLC) patients were used to analyze the incidence of ICI-induced hepatitis, putatively associated factors, and outcome., Results: 40 patients with melanoma and 91 patients with NSCLC received ICI between July 2016 and May 2019. 11 patients developed ICI-induced hepatitis (8.4%). Prior to treatment, 45.5% of patients in the hepatitis cohort and 43.8% of the control cohort showed elevated titers of autoantibodies commonly associated with autoimmune liver diseases (p = 0.82). We found two nominally significant associations between the occurrence of ICI-induced hepatitis and HLA alleles associated with autoimmune liver diseases among NSCLC patients. Of note, significantly more patients with ICI-induced hepatitis developed additional irAEs in other organs (p = 0.0001). Neither overall nor progression-free survival was affected in the hepatitis group., Conclusion: We found nominally significant associations of ICI-induced hepatitis with two HLA alleles. ICI-induced hepatitis showed no correlation with liver-specific autoantibodies, but frequently co-occurred with irAEs affecting other organs. Unlike other irAEs, ICI-induced hepatitis is not associated with a better prognosis., (© 2021. The Author(s).)

Background: Hypoxic hepatitis (HH) is an important clinical entity in patients in the intensive care unit (ICU). The aims of the study were to assess the etiology, clinical characteristics and outcomes of HH in the ICU of a tertiary hospital. Secondary aim was to analyze the effects of concomitant ischemia in other organs than the liver., Methods: All patients with HH, 2011-2018, in a university hospital ICU were included. Data were collected on etiology, relevant clinical data and outcome. HH was defined by an increase in aminotransferases ≥10 times the upper limit of normal within 48 h from a clinical event of cardiac, circulatory or respiratory failure. Other causes of liver cell necrosis were excluded., Results: Of 9,931 patients hospitalized in the ICU, 159 (1.6%) fulfilled criteria for HH. In-hospital mortality occurred in 85 (53%) and 60 (38%) survived one year. Median ICU stay was five days (interquartile range (IQR) 3-10) and median hospital stay 16 days (IQR 7-32). Shock (48%), cardiac arrest (25%) and hypoxia (13%) were the most common causes of HH. Acute kidney injury (81%), rhabdomyolysis (50%), intestinal ischemia (6%) and ischemic pancreatitis (3%) occurred concomitantly. Age (odds ratio (OR) 1.05 (95% CI 1.02-1.09)), serum lactate (OR 2.61 (95% CI 1.23-5.50)) and lactate dehydrogenase (OR 1.14 (95% CI 1.02-1.27)) were predictors of mortality., Conclusions: Hypoxic hepatitis was related to shock in approximately 50% of cases and associated with high in-hospital mortality. HH was commonly associated with ischemia in other organs. In-hospital mortality was associated with age, lactate and LD.

Background: Most immune-related adverse event (irAE) patterns and treatment guidelines are based on western clinical data. We evaluated the incidence and patterns of irAEs in patients treated with immune-checkpoint inhibitors (ICI) in Thailand., Methods: All solid tumor patients treated with ICIs were retrospectively reviewed in a multicenter analysis. The study aims to evaluate the incidence of irAEs and their characteristics, treatments, outcomes, and impact on survival. All irAEs were graded using the CTCAE version 4.0. Characteristics of irAEs including time to onset, duration of irAEs, specific treatments, and outcomes of irAEs were reviewed. The Chi-square or Fisher's exact test was used to compare variables. Overall survival (OS) was estimated by the Kaplan-Meier method, and compared by the log-rank test. A p-value < 0.05 was considered statistically significant., Results: irAEs of any grade were observed in 98 of 414 patients (24%), whereas grades 3-4 irAEs were observed in 5.6%. The majority of patients (78%) were treated with monotherapy ICI (anti-PD1/PD-L1 92%). The most common all-grade irAEs were hypothyroidism (7.5%), hepatitis (6.5%), and rash (4.8%). Median onset of overall irAEs was 63 days. Pancreatitis and pneumonitis had the earliest onset at 30 and 34 days, respectively. ICIs were rechallenged in 68 of 98 patients with irAE. Eleven of sixty-eight patients (11.2%) with initial irAE had reoccurrence after ICI rechallenge. Based on a multivariate analysis, pre-existing hypothyroidism, ICI used in a clinical trial setting, and combinations of ICI/ICI were independent factors predicting irAE occurrence. Patients with irAE had a statistically significant longer overall survival (OS) when compared to patients without irAE (p = 0.019). A multivariate analysis revealed that occurrence of irAE was an independent prognostic factor for OS (HR 0.70, 95% CI 0.51-0.96; p = 0.028)., Conclusion: irAE was commonly observed in Thai cancer patients treated with ICIs. Most irAEs were low-grade and manageable. Re-occurrence of irAE after re-challenging ICI was not uncommonly observed. Patients who experienced irAEs might have significantly longer OS compared to patients without irAEs. However, OS in this study should be interpreted with caution since it might be affected by various tumor types, treatment settings, dosing schedule, and ICI combinations., (© 2021. The Author(s).)

Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Stephen L. Guthery reports institutional grant funding from the National Institute for Digestive Diseases and Kidney Diseases (NIDDK) and institutional funding from NIDDK to the Childhood Liver Disease Research Network. No other potential conflicts of interest were disclosed.

Abstract: The pathogenesis of hepatocellular carcinoma (HCC) can be divided into viral infection (VIR) and nonviral (NVIR) infection. Two types of HCC performed different tumor immune microenvironment (TIME) which directly affected prognosis of HCC. This study aimed to identify an effective 2 types of HCC prognostic gene signature that related to immune TIME.The differential expression genes (DEGs) were analyzed by Limma R package from the Cancer Genome Atlas. Immune related genes getting from IMMport database were matched to DEGs for testing prognosis. Prognostic index (PI) consisted of prognostic immune related genes was calculated in different types of HCC by COX regression and the correlation with the abundance of immune infiltrates, including 6 type cells, via gene modules. Tumor immune estimation resource database was applied to analyze TIME. Finally, the correlations between PI of DEGs and TIICs were analyzed by the Spearman method.Results showed that PI consisted of 11 messenger RNAs in VIR and 12 messenger RNAs in NVIR groups. The PI related to HCC prognosis has different correlations with immune infiltrating cells in VIR and NVIR groups. The PI value of DEGs has significant correlations with neutrophils (R = 0.22, P-value = .029) and dendritic (R = 0.21, P-value = .036) infiltration levels in VIR group. However, in NVIR group, the result showed there were no significant correlations between PI and other 5 type cell infiltration levels (P-value > .05).The 11-gene signature in VIR and 12-gene signature in NVIR group selected based on data from the Cancer Genome Atlas database had a different correlation with immune infiltrating cells of HCC patients., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Hepatitis E virus (HEV) is the leading cause of acute hepatitis throughout the world. Increasing blood component transfusion-associated HEV infections highlight the need for reliable virus inactivation procedures for plasma derivatives from pooled plasma donations., Study Design and Methods: An animal infection study was conducted to evaluate the efficiency of HEV inactivation by pasteurization during the manufacturing process of the von Willebrand Factor/Factor VIII (VWF/FVIII) concentrate Haemate P/Humate-P (CSL Behring, Marburg, Germany). For this purpose, groups of pigs were inoculated with stabilized VWF/FVIII intermediate spiked with HEV-positive liver homogenate and exposed to increasing incubation times of 0, 3, 6, and 10 h at 60°C. Animals were evaluated for virus replication over 27 days and in a subsequent trial over 92 days., Results: Virus replication was detected in animals up to the 6-h pasteurization group. In contrast, pasteurization for 10 h did not reveal virus detection when the observation period was 27 days. In an additional experiment using the 10-h pasteurized material, two individuals started virus excretion and seroconverted when the observation period was extended to 92 days. Based on the total infection rate (2 of 12) of the animals inoculated with the sample pasteurized for 10 h, a virus reduction factor of at least 4.7 log 10 is calculated., Conclusion: This study demonstrates that pasteurization at 60°C for 10 h of an HEV-positive plasma derivative leads to the effective reduction of infectivity, resulting in a VWF/FVIII product with an appropriate margin of safety for HEV., (© 2021 The Authors. Transfusion published by Wiley Periodicals LLC. on behalf of AABB.)

Background: Checkpoint inhibitor-induced hepatitis is an immune-related adverse event of programmed cell death protein 1 (PD-1) inhibition, cytotoxic T-lymphocyte associated 4 (CTLA-4) inhibition or the combination of both. Aim of this study was to assess whether checkpoint inhibitor-induced hepatitis is related to liver metastasis and outcome in a real-world nationwide cohort., Methods: Data from the prospective nationwide Dutch Melanoma Treatment Registry (DMTR) was used to analyze incidence, risk factors of checkpoint inhibitor-induced grade 3-4 hepatitis and outcome., Results: 2561 advanced cutaneous melanoma patients received 3111 treatments with checkpoint inhibitors between May 2012 and January 2019. Severe hepatitis occurred in 30/1620 (1.8%) patients treated with PD-1 inhibitors, in 29/1105 (2.6%) patients treated with ipilimumab and in 80/386 (20.7%) patients treated with combination therapy. Patients with hepatitis had a similar prevalence of liver metastasis compared to patients without hepatitis (32% vs. 27%; p = 0.58 for PD-1 inhibitors; 42% vs. 29%; p = 0.16 for ipilimumab; 38% vs. 43%; p = 0.50 for combination therapy). There was no difference in median progression free and overall survival between patients with and without hepatitis (6.0 months vs. 5.4 months progression-free survival; p = 0.61; 17.0 vs. 16.2 months overall survival; p = 0.44)., Conclusion: Incidence of hepatitis in a real-world cohort is 1.8% for PD-1 inhibitor, 2.6% for ipilimumab and 20.7% for combination therapy. Checkpoint inhibitor-induced hepatitis had no relation with liver metastasis and had no negative effect on the outcome.

Background: Immune checkpoint inhibitors (ICI) have become standard treatment in different tumor entities. However, safe treatment with ICI targeting the PD-1/PD-L1 axis requires early detection of immune-related adverse events (irAE). There exist different questionnaires of drug manufacturers for the detection of irAE that have not been validated so far., Methods: The prospective non-interventional ST-ICI trial studied treatment with PD-1/PD-L1 ICI alone or combined with radiotherapy. In the current analysis, the detection rate of self-reported irAE with a patient questionnaire containing 41 different questions was compared to clinician-reported irAE., Results: Between April 2017 and August 2019, a total of 104 patients were prospectively enrolled. NSCLC (44%) and HNSCC (42%) were the most frequent tumor entities. A total of 784 questionnaires were collected. A total of 29 irAE were reported by clinicians. The most frequent irAE was hypothyroidism (9%), followed by skin reactions (5%), hepatitis (4%), diarrhea (3%), and pneumonitis (3%). Questions that became significantly more often positive at time points of clinician-reported irAE were "weight change", "difficulty to grip things", "bloody or mucous stool" and "insomnia". Self-reported organ-specific questions detected at least 50% of clinician-reported irAE of gastrointestinal, lung, endocrine, and skin irAE. It was not possible to detect hepatic irAE with the questionnaire., Conclusion: Questionnaires can help to detect gastrointestinal, lung, endocrine, or skin irAE, but not hepatic irAE. Questions on "weight change" and "insomnia" may help to increase the detection rate of irAE, besides organ-specific questions. These results are a valuable contribution to the future development of a specific and practicable questionnaire for early self-reported detection of irAE during ICI therapy in cancer patients., Trial Registration: ClinicalTrials.gov, NCT03453892 . Registered on 05 March 2018.

There is a paucity of population health data on the experiences of transgender, non-binary, and other gender minority gay, bisexual, and queer men, and Two-Spirit people in Canada. To address this gap, this article presents a socio-demographic and health profile of trans and non-binary participants from the community-based bilingual 2018 Sex Now Survey. Participants were recruited in-person from Pride festivals in 15 communities to self-complete an anonymous paper-and-pen questionnaire. To be eligible, participants needed to be at least 15 years old, live in Canada, either report a non-heterosexual sexual identity or report sex with a man in the past 5 years, and not report gender identity as a woman. Through community consultations the survey was inclusive of trans men, non-binary people, and Two-Spirit people. Three gender groups (cisgender, transgender, and non-binary) were created, and trans and non-binary participants were compared with their cisgender peers across a variety of demographic, mental health, sexual health, and general health indicators. Odds ratios were calculated to determine initial significance for categorical variables, and adjusted odds ratios were calculated to control for five possible confounders (age, ethnoracial identity, country of birth, sexual identity, and financial strain). Significant differences emerged across all sets of indicators, with many of these findings remaining significant after adjusting for confounding variables, including significantly higher reported rates of mental health challenges and sexual health service barriers for trans and non-binary participants compared to the cisgender group. Trans and non-binary participants were also more likely to be in polyamorous relationships. Collectively, our findings demonstrate that trans and non-binary people experience significant disadvantages compared with cisgender sexual minority men. Improved educational supports and employment protections, access to queer and gender affirming healthcare, and trauma-informed mental health services are needed to improve the health wellbeing of trans and non-binary people in Canada., Competing Interests: The authors have declared that no competing interests exist.

Immune checkpoint inhibitors (ICI) predispose patients to immune-related adverse events (irAEs). Although hepatitis is a potentially lethal toxicity, the timing and outcomes have not been well described. In this retrospective study, patients from six international institutions were included if they were treated with ICIs and developed immune-related hepatitis. Patient and tumor characteristics, and hepatitis management and outcomes were evaluated. Of the 164 patients included, most were male (53.7%) with a median age of 63.0 years. Most patients had melanoma (83.5%) and stage IV disease (86.0%). Median follow-up was 585 days; median OS and PFS were not reached. The initial grade of hepatitis was most often grade 2 (30.5%) or 3 (45.7%) with a median time to onset of 61 days. Patients were most commonly asymptomatic (46.2%), but flu-like symptoms, including fatigue/anorexia (17.1%), nausea/emesis (14.0%), abdominal/back pain (11.6%), and arthralgias/myalgias (8.5%) occurred. Most patients received glucocorticoids (92.1%); the median time to improvement by one grade was 13.0 days, and the median time to complete resolution was 52.0 days. Second-line immunosuppression was required in 37 patients (22.6%), and steroid-dose re-escalation in 45 patients (27.4%). Five patients (3%) died of ICI-hepatitis or complications of hepatitis treatment. Ninety-one patients (58.6%) did not resume ICI; of 66 patients (40 grade 1/2, 26 grade 3/4) that were rechallenged, only 25.8% (n = 17) had recurrence. In this multi-institutional cohort, immune-related hepatitis was associated with excellent outcomes but frequently required therapy discontinuation, high-dose steroids, and second-line immunosuppression. Rechallenge was associated with a modest rate of hepatitis recurrence., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Background: Unproven stem cell treatments may involve serious health, personal, and financial considerations. Due to worldwide spread, illegal stem cell therapies have become a major public health problem. We have already witnessed numerous reports in the mass media of severe and occasionally even fatal outcomes after such therapies. However, there are only few scientifically documented cases in which the causality between stem cell therapy and side effects cannot be refuted., Case Presentation: Here we present a case report of a 48-year-old patient with serious side effects, including disseminated skin ulcers, hepatitis, and cardiomyopathy, with eventual fatal outcome following unproven stem cell treatment., Conclusions: The case of the patient presented here draws attention to the worst possible outcome of stem cell tourism. To effectively combat this issue, professionals and patients should be empowered with the right knowledge on possible side effects.

Competing Interests: The authors have declared that no competing interests exist.