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HBsAg loss with anti-HBs acquisition is considered a functional cure and ideal treatment goal for patients with CHB. Our group have reported the efficacy of therapeutic vaccine with HBsAg and HBcAg (NASVAC) by intranasal and subcutaneous injection. In this study, we investigated the safety and efficacy of newly developed CVP-NASVAC, which contained NASVAC with mucoadhesive carboxyl vinyl polymer (CVP) in the dedicated device.A single dose, open-label, phase IIa clinical trial of CVP-NASVAC was conducted. Patients with CHB treated with nucleoside/nucleotide analogs (NAs) and HBV carriers not undergoing anti-HBV treatment were enrolled. CVP-NASVAC was injected through the nose for, in total, 10 times. Participants were followed-up for 18 months, and their HBsAg reduction and anti-HBs induction assessed as endpoints.Among the patients with CHB treated with NAs (n = 27) and HBV carriers without NAs (n = 36), 74.1% and 75.0% exhibited reductions in their baseline HBsAg, and the mean reductions were -0.1454 logAnti-HBs induction and HBsAg reduction was observed after CVP-NASVAC treatment in some patients with CHB. The CVP-NASVAC is a safe treatment, which might expect to achieve functional cure for patients with CHB.

Nonalcoholic fatty liver disease (NAFLD) has currently emerged as the most common liver disorder in both developed and developing countries. It has been observed that NAFLD exhibits sexual dimorphism, and there is limited understanding on the sex differences in adults with NAFLD. Nonalcoholic fatty liver disease shows marked differences in prevalence and severity with regards to gender. There are considerable biological disparities between males and females attributed to differences in the chromosomal makeup and sex hormone levels, distinct from the gender differences resulting from the sociocultural influences that lead to differences in lifestyle, which have a significant impact on the pathogenesis of this complex disorder. A multitude of factors contributes to the gender disparities seen and need to be researched in-depth to better understand the mechanisms behind them and the therapeutic measures that can be taken. In this article, we will review the gender disparities seen in NAFLD, as well as recent studies highlighting certain gender-specific factors contributing to its varying prevalence and severity.Nagral A, Bangar M, Menezes S

Therapeutic plasma exchange (PLEX) removes toxins and different mediators from plasma in patients with acute-on-chronic liver failure (ACLF).To observe the safety and outcome of PLEX in ACLF patients in Bangladesh.Twenty-eight patients with ACLF attending Bangabandhu Sheikh Mujib Medical University from September 2020 to May 2021 were enrolled in the study. The patients were given different treatment modalities and followed up for 3 months or up to death. The patients were divided into two groups, each containing 14 patients of ACLF. One group of 14 patients received standard medical therapy (SMT) for ACLF and the second group of 14 patients received SMT plus PLEX.At 90 days, a total of 13 patients (46.43%) survived, of them 8 (57.1%) belonged to PLEX group and 5 (35.7%) were from SMT group. Serum bilirubin and ALT declined significantly after 7 and 30 days but not after 90 days in PLEX group in comparison to SMT group (The study presented here has shown that PLEX is safe in Bangladeshi in ACLF patients, but its efficacy remains to be checked in large-scale randomized trial or in combination therapy with other procedures in ACLF patients.Al Mukit A, Al Mahtab M, Rahim MA

Coinfection of B virus (HBV) and hepatitis Delta virus (HDV) lead to severe forms of progressive liver diseases. However, commercially available antiviral drugs have shown considerable adverse effects and low efficacy in managing these patients. Thus, there is a pressing need to develop new, innovative, and evidence-based therapies for these pathological entities. In line with this, some investigators have attempted to develop anti-viral drugs targeting HBV/HDV coinfection. In another development, investigators have also attempted to establish immune therapy targeting for HBV infection as recovery or effective control of HBV infection also lead to efficient control of HDV infection. This review has discussed an account of the evolving antiviral and immune therapeutic drugs for HBV/HDV infection. Also, based on current scientific knowledge how we have described the pros and cons of these drugs as no suitable drug has been developed during the last forty years for treating HBV infection except the availability of two” repurposed drugs”; interferons and its derivatives and nucleoside analogs, for managing HBV or HBV/HDV coinfection. It seems that an evolving and innovative therapeutic regimen that combines both antiviral drugs and immune modulators may be the best and realistic option for management of HBV/HDV coinfection.

PDF file - 492KB, Supplementary Figure S2. (A) Effect of 5-azaCdR at 1.0 microM concentration on non-transformed NorHep cell growth throughout 20 day-treatment. NorHep cells were seeded at a density of 3 x 105 per a 10-cm tissue culture dish. The medium was replaced with fresh medium containing 1.0 microM 5-azaCdR every 24 h for 3 days and every 48 h for the following 17 days (20 days in total). During the experiment the cells were split every 4-5 days after reaching 80 percent confluence and counted on day 3, 6, 9, 12, 14, and 20. (B-D) Expression and methylation levels of RASAL2 and NENF in NorHep after 1 microM 5-azaCdR treatment for 3 (3d) or 20 days (20d). Relative expression is expressed as a percentage of expression in control non-treated cells. Average methylation state of CpG sites was determined by pyrosequencing in control and treated cells for NENF after 3 days of exposure and for RASAL2 after 20 days (no changes were observed after 3 days as shown in Supplementary Figure S1). All results represent mean � S.D. of two or three independent experiments - ***P < 0.001, **P < 0.01, *P < 0.05.

PDF file - 701KB, Supplementary Figure S6. (A) 1) Expression of the depleted genes, RASAL2 and NENF, quantified by QPCR after first (I) and second (II) transfection of Hep3B HCC cell line with scrambled siRNA (siCtrl) and siRNA directed to RASAL2 (siRASAL2) or NENF (siNENF). 2) Effect on cell growth after first (day 3), second (day 6) and third (day 9) transfection with siRASAL2 or siNENF. 3) Effect on cell invasion as measured by Boyden chamber invasion assay after second transfection with siRASAL2 or siNENF. For Hep3B cells transfected with siRASAL2 or siNENF, evaluation of expression after third transfection was not possible due to the reduced cell number after three transfections. Therefore, invasive assay measurements were performed after second transfection. All results represent mean � S.D. of two or three determinations in either two or three independent experiments - ***P < 0.001, **P < 0.01, *P < 0.05. (B) HepG2 and SkHep1 cells were transfected twice with siCtrl, siRASAL2 or siNENF followed by subcutaneous injection of 2x106 HepG2 and 1x106 SkHep1 cells into the NOD/SCID mice as described in the Materials and Methods. Each group was composed of six male mice 4-6 weeks old. Differences in tumor volume were monitored starting from post-injection week 2 until the mice were sacrificed and are demonstrated in charts. Results represent the mean � SEM for each group of animals - ***P < 0.001, **P < 0.01, *P < 0.05.

PDF file - 71KB, Supplementary Table S2. A list of kinases whose phosphorylation was examined in SkHep1 liver cancer cells after RASAL2, NENF or combined RASAL2 and NENF depletion. The level of phosphorylation is expressed as a percentage of phosphorylation in the control - cells transfected with scrambled siRNA. Phosphorylation of a panel of 26 kinases was assessed using Proteome Profiler Array (R&D Systems Inc., MN, USA).

PDF file - 961KB, Supplementary Figure S1. (A,B) Extensive methylation analysis of RASAL2 (A) and NENF (B) promoters in cells treated with 5-azaCdR, different cell lines and patients. Average methylation state of CpG sites was determined by pyrosequencing in NorHep and HepG2 cells treated with 1.0 microM 5-azaCdR for 3 days, in control HepG2, SkHep1 and NorHep cells, as well as in HCC patients. All results represent mean � S.D. of two or three independent experiments - ***P < 0.001, **P < 0.01, *P < 0.05. Methylation level of 58 CpG sites was determined within RASAL2 in NorHep treated with 5-azaCdR (note that for convenience CpGs were numbered relative to CpGs shown in Figure 1). Five sets of primers encompassing 1446 bp fragment were used (Supplementary Table S1C). Since no relevant changes at CpGs upstream to CpGs 1-3 were observed, the number of tested regions was limited to 13 CpGs in patients and 14 CpGs in HepG2 cells treated with 5-azaCdR and in the comparison of methylation state in different cell lines. The most relevant changes were observed at CpGs 1-3 as shown in Figure 1. Only methylation at these sites distinguished normal hepatocytes from cancer cells. Within NENF promoter, methylation level of 27 CpGs was tested in NorHep treated with 5-azaCdR. Three sets of primers encompassing 846 bp fragment were used (Supplementary Table S1C). Since no relevant changes at CpGs upstream to CpG (-)2 were observed, the number of tested regions was limited to 13 CpGs in patients and 17 CpGs in HepG2 cells treated with 5-azaCdR and in the comparison of methylation state in different cell lines. The most relevant changes were observed at CpGs 1-5 as shown in Figure 1.

PDF file - 690KB, Supplementary Figure S7. Impact of RASAL2 and NENF depletion on on expression of genes of DNA methylation machinery, DNMT1, MBD2, DNMT3A, and DNMT3B. DNMT1 (A), MBD2 (B), DNMT3A (C), and DNMT3B (D) expression levels quantified by QPCR in HepG2 and SkHep1 liver cancer cells transfected with siRASAL2 or siNENF as compared to siCtrl. All results represent mean � S.D. of three determinations in either two or three independent experiments - ***P < 0.001, **P < 0.01, *P < 0.05.

PDF file - 774KB, Supplementary Figure S3. RASAL2 and NENF are overexpressed in different types of human cancers. RASAL2 or NENF depletion decreases cancer cell growth and invasive capacities in liver cancer. Changes defined using different siRNA sequences (siRASAL2-1 and siNENF-1) than in Figure 2-4. (A) Cancer gene expression microarray data for RASAL2 and NENF. The normal versus tumor gene expression data were obtained from Oncomine and are presented as log2-transformed median centered per array, and SD-normalized to 1 per array. All the presented changes are statistically significant (P < 0.05). (B,E) Expression of the depleted genes, RASAL2 and NENF, quantified by QPCR after first (I), second (II) and third (III) transfection of HepG2 (B) and SkHep1 (E) with scrambled siRNA (siCtrl) and siRNA directed to RASAL2 (siRASAL2-1) or NENF (siNENF-1). (C,F) Effect on cell growth after first (day 3), second (day 6) and third (day 9) transfection with siRASAL2-1 or siNENF-1 in HepG2 (C) and SkHep1 (F) cells. (D,G) Effect on cell invasion as measured by Boyden chamber invasion assay after second transfection with siRASAL2-1 or siNENF-1 in HepG2 (D) and SkHep1 (G) cells. All results represent mean � S.D. of three determinations in either two or three independent experiments - ***P < 0.001, **P < 0.01, *P < 0.05. (H) Expression of RASAL2 and NENF in HCC (n=3) and CHB (chronic hepatitis B infection - cirrhosis, n=3) samples from Bangladeshi cohort as measured by QPCR. Each point represents a value for one sample. All patients provided written informed consent, and the Ethics Committee from Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh approved the study. Bangladeshi cohort consisted of 4 HCC patients and 4 CHB patients in Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh (Table 2). The HCC samples were obtained at ultrasonogram guided fine needle aspiration, while the CHB samples were obtained at per-cutaneous liver biopsy using Tru-cut biopsy needle. In both cases local anaesthesia was used. International Centre for Diarrhoeal Diseases Research, Bangladesh (icddr,b) acknowledges with gratitude the commitment of donors to the Centre's research efforts.

PDF file - 685KB, Supplementary Figure S8. Expression of different RASAL2 transcript variants in liver cancer cells and normal hepatocytes. (A,B) Expression of RASAL2 as measured by QPCR using primers specific to transcript variant 1 and specific to variant 2 in HepG2 cells (A) and normal hepatocytes (NorHep, B) upon treatment with 1.0 microM 5-azaCdR. (C) Expression of different RASAL2 isoforms in liver cancer cells and NorHep. All results represent mean � S.D. of two or three independent experiments - ***P < 0.001, **P < 0.01, *P < 0.05.

Purpose: We utilized whole-genome mapping of promoters that are activated by DNA hypomethylation in hepatocellular carcinoma (HCC) clinical samples to shortlist novel targets for anticancer therapeutics. We provide a proof of principle of this approach by testing six genes short-listed in our screen for their essential role in cancer growth and invasiveness.Experimental Design: We used siRNA- or shRNA-mediated depletion to determine whether inhibition of these genes would reduce human tumor xenograft growth in mice as well as cell viability, anchorage-independent growth, invasive capacities, and state of activity of nodal signaling pathways in liver, breast, and bladder cancer cell lines.Results: Depletion of EXOSC4, RNMT, SENP6, WBSCR22, RASAL2, and NENF effectively and specifically inhibits cancer cell growth and cell invasive capacities in different types of cancer, but, remarkably, there is no effect on normal cell growth, suggesting a ubiquitous causal role for these genes in driving cancer growth and metastasis. Depletion of RASAL2 and NENF in vitro reduces their growth as explants in vivo in mice. RASAL2 and NENF depletion interferes with AKT, WNT, and MAPK signaling pathways as well as regulation of epigenetic proteins that were previously demonstrated to drive cancer growth and metastasis.Conclusion: Our results prove that genes that are hypomethylated and induced in tumors are candidate targets for anticancer therapeutics in multiple cancer cell types. Because these genes are particularly activated in cancer, they constitute a group of targets for specific pharmacologic inhibitors of cancer and cancer metastasis. Clin Cancer Res; 20(12); 3118–32. ©2014 AACR.

PDF file - 1284KB, Supplementary Figure S5. Effects of stable RASAL2 (A-D) or NENF (E-H) depletion on cell viability (A,E) and anchorage independent growth (B,F, soft agar assay) in HepG2, SkHep1, and NorHep. Three different shRNA sequences targeting NENF and six different shRNA sequences targeting RASAL2 were used that were limited to two shRNA sequences for each gene (shRASAL2-7 and sh-RASAL2-9, shNENF-2 and shNENF-1) that produced the best knockdown by lentiviral transduction. Expression of RASAL2 (C,D) and NENF (G,H) on mRNA and protein levels was measured, respectively, by QPCR after 10 days and by western blot after 14 days post-lentiviral transduction. Expression on mRNA is expressed as a percentage of control relative to GAPDH. For cell viability assay, control cells (sh-Scr, transduced with lentivirus expressing non-targeting RNA) and cells with stable depletion of the target genes were seeded at a density of 3-6 x 105 per a 10-cm tissue culture dish, counted and split every three days up to day 9 (schedule of transient transfection). All results represent mean � S.D. of at least three determinations - ***P < 0.001, **P < 0.01, *P < 0.05.

PDF file - 651KB, Supplementary Figure S4. Expression of RASAL2 and NENF on the protein level as determined by western blot using anti-RASAL2 (Bethyl Laboratories Inc., A302-109A) or anti-NENF (Abcam, ab74474) antibody at 1:1000 and 1:500 dilution, respectively. Protein levels were verified 48 h after first (I), second (II) or third (III) transfection of HepG2, SkHep1, and NorHep with siRNA directed to RASAL2 or NENF. Antibody to beta-actin was used as a loading control. For SkHep1 cells transfected with siRASAL2 or siNENF and for HepG2 cells transfected with siNENF, evaluation after third transfection was not possible due to the reduced cell number after three transfections.

Millions of people of the world suffer from chronic hepatitis B (CHB), a pathological entity in which the patients are chronically infected with hepatitis B virus (HBV) and express hepatitis B surface antigen (HBsAg) and HBV DNA, as well as evidence of liver damages. Considerable numbers of CHB patients develop cirrhosis of the liver and hepatocellular carcinoma if untreated. Two groups of drugs (interferons and nucleoside analogs) are used to treat CHB patients, but both are endowed with considerable adverse effects, increased costs, extended duration of therapy, and limited efficacy. Thus, there is a pressing need to develop new and innovative therapeutics for CHB patients, and many such drugs have been developed during the last four decades. Some of these drugs have inspired considerable optimism to be a game-changer for the treatment of CHB. Here, we first discuss why ongoing therapeutics such as interferon and nucleoside analogs could not stand the test of time. Next, we dissect the scope and limitation of evolving therapies for CHB by dissecting the cellular and molecular mechanisms of some of these innovative therapeutics.

IntroductionThere is a pressing need to develop novel drugs for treating patients with chronic hepatitis B (CHB), as commercially available antiviral drugs are endowed with safety and efficacy concerns.MethodsA phase III clinical trial was conducted with a therapeutic vaccine containing two antigens of the hepatitis B virus (HBV; named NASVAC) in 78 patients with CHB expressing both HBV DNA and elevated levels of alanine aminotransferase (ALT) in the blood. Five years after the end of treatment (EOT), 60 NASVAC-recipient patients were enrolled in this long-term follow-up study to evaluate the safety, antiviral potential, and liver-protective capacity of NASVAC.ResultsNASVAC exhibited an excellent safety profile 5 years after EOT. The levels of HBV DNA in the sera were reduced in 55 of the 60 patients, and 45 of them were negative for HBV DNA in the sera. ALT levels were also normalized in 40 of the 60 patients 5 years after EOT. None of the patients receiving NASVAC developed liver cirrhosis or cancer.DiscussionThe present study is the first to exhibit long-term follow-up data of a finite immune therapy for CHB that is safe and endowed with potent antiviral and liver-protecting capacities.

Background: With the rising global prevalence of fatty liver disease related to metabolic dysfunction, the association of this common liver condition with chronic kidney disease (CKD) has become increasingly evident. In 2020, the more inclusive term metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed to replace the term non-alcoholic fatty liver disease (NAFLD). The observed association between MAFLD and CKD and our understanding that CKD can be a consequence of underlying metabolic dysfunction support the notion that individuals with MAFLD are at higher risk of having and developing CKD compared with those without MAFLD. However, to date, there is no appropriate guidance on CKD in individuals with MAFLD. Furthermore, there has been little attention paid to the link between MAFLD and CKD in the Nephrology community. Methods and Results: Using a Delphi-based approach, a multidisciplinary panel of 50 international experts from 26 countries reached a consensus on some of the open research questions regarding the link between MAFLD and CKD. Conclusions: This Delphi-based consensus statement provided guidance on the epidemiology, mechanisms, management and treatment of MAFLD and CKD, as well as the relationship between the severity of MAFLD and risk of CKD, which establish a framework for the early prevention and management of these two common and interconnected diseases.

BackgroundThe biosimilarity for erythropoietin (EPO) functionality of GBPD002 (test candidate) and Eprex®(comparator) has been evaluated by comparing the pharmacokinetic (PK) and pharmacodynamic (PD) properties following subcutaneous injection.MethodsThis was a randomized, double-blinded, two-sequence, crossover clinical trial. Subjects were randomly assigned and received a dose (4,000 IU) of either the test or comparator EPO, and received the alternative formulations after 4-weeks of washout period.ResultsThe PK parameters,viz., maximum observed concentration (Cmax) and area under the curve extrapolated to infinity (AUC0-inf), were calculated with the serum EPO concentrations from blood samples and were found comparable for both formulations. The geometric mean ratios (at 90% CI) of the Cmaxand AUCinfwere 0.89 and 1.16, respectively, which were within the regulatory range of 0.80 – 1.25. The time-matched serum EPO concentrations and PD markers (reticulocyte, hematocrit, hemoglobin, and red blood cell) denoted a counterclockwise hysteresis, suggesting a time delay between the observed concentration and the response. ANOVA-derivedP-values (>0.05) for the effectors clearly revealed the similarity between effects on PD markers for the test and comparator drugs. Both formulations were found tolerated well, and anti-drug antibodies were not observed.ConclusionsThus, the two formulations are projected to be used interchangeably in clinical settings.

© Asian Pacific Association for the Study of the Liver 2023, Background: Fatty liver disease in the absence of excessive alcohol consumption is an increasingly common condition with a global prevalence of ~ 25-30% and is also associated with cardiovascular disease (CVD). Since systemic metabolic dysfunction underlies its pathogenesis, the term metabolic (dysfunction)-associated fatty liver disease (MAFLD) has been proposed for this condition. MAFLD is closely intertwined with obesity, type 2 diabetes mellitus and atherogenic dyslipidemia, which are established cardiovascular risk factors. Unlike CVD, which has received attention in the literature on fatty liver disease, the CVD risk associated with MAFLD is often underestimated, especially among Cardiologists. Methods and results: A multidisciplinary panel of fifty-two international experts comprising Hepatologists, Endocrinologists, Diabetologists, Cardiologists and Family Physicians from six continents (Asia, Europe, North America, South America, Africa and Oceania) participated in a formal Delphi survey and developed consensus statements on the association between MAFLD and the risk of CVD. Statements were developed on different aspects of CVD risk, ranging from epidemiology to mechanisms, screening, and management. Conculsions: The expert panel identified important clinical associations between MAFLD and the risk of CVD that could serve to increase awareness of the adverse metabolic and cardiovascular outcomes of MAFLD. Finally, the expert panel also suggests potential areas for future research.

Nonalcoholic fatty liver disease (NAFLD) is one of the major and prevalent liver diseases from the national and global perspectives. It appears that considerable numbers of the general population have been suffering from NAFLD. When a patient with NAFLD also exhibits inflammation of the liver, the condition is regarded as nonalcoholic steatohepatitis (NASH). Nonalcoholic steatohepatitis is a pathological entity that may progress to cirrhosis of the liver (LC) and hepatocellular carcinoma (HCC). It is acceptable by all that the health burden of NAFLD and NASH is tremendous. Due to the increased prevalence of these pathologies, extensive research has been conducted regarding pathogenesis, diagnostic tools, and staging of the diseases. However, adequate and approved pharmacotherapy for these pathologies is lacking. The farnesoid receptor (FXR) is a bile acid-activated receptor. It regulates lipid, glucose, bile acid metabolism. Farnesoid receptor is also endowed with anti-inflammatory and anti-fibrotic properties on the liver. Obeticholic acid (OCA), a potent and selective FXR ligand, may become a promising molecule to combat NASH and advanced fibrosis. The present review briefly discusses the current recommendation of NASH management with available pharmacological treatments. The scope of OCA with a focus on recent data of major randomized controlled trials (RCTs) is discussed. On the basis of current data and recent interim analysis, OCA seems to improve insulin resistance, steatohepatitis, levels of alanine transaminase (ALT) and fibrosis in NASH. Dose-related adverse effects like pruritus and dyslipidemia may limit its usage. Also, its usage may be restricted in patients with NASH cirrhosis. More adequately powered RCTs that would contain NASH patients with different and heterogeneous properties would be required to develop consensus about these issues. The safety profile of different doses of OCA needs to be established in these patients as well as there remain considerable queries about these.Roy PP, Mahtab MA, Rahim MA

Acute-on-chronic liver failure (ACLF) is a rapidly progressive illness with high short-term mortality. Timely liver transplant (LT) may improve survival. We evaluated various indices for assessment of the severity of liver failure and their application for eligibility and timing of living donor LT (LDLT). Altogether 1021 patients were analyzed for the severity and organ failure at admission to determine transplant eligibility and 28 day survival with or without transplant. The ACLF cohort [mean age 44 ± 12.2 years, males 81%) was of sick patients; 55% willing for LT at admission, though 63% of them were ineligible due to sepsis or organ failure. On day 4, recovery in sepsis and/or organ failure led to an improvement in transplant eligibility from 37% at baseline to 63.7%. Delay in LT up to 7 days led to a higher incidence of multiorgan failure (p

Background: Hepatocellular carcinoma (HCC) is one of the fatal cancer types worldwide, and a variety of genetic factors are considered to be associated with this incidence. MDM2 gene plays a pivotal role in various pathways, which are essential to combat tumor formation. The study aimed to find out the associations of MDM2 (T309G, rs2279744) gene polymorphism with the development of HCC in the Bangladeshi population. Methods: A case-control study on 100 HCC patients and 110 control subjects was conducted. The genotyping of the MDM2 (T309G) gene was done using PCR-RFLP methods. Results: The percentage of TT and GG genotypes were significantly different (p0.05). In addition, patients having either GG or TG genotypes showed higher risk for HCC compared to control group (OR = 2.20; 95% CI = 1.21–4.14; P < 0.05). Conclusion: Our study suggested that the MDM2 gene may have a strong association with the development of HCC, and the GG allele could serve as an essential determinant to identify the higher risk of HCC in the Bangladeshi population.

Summary Regenerative medicine has great potential. The pace of scientific advance is exciting and the medical opportunities for regeneration and repair may be transformative. However, concerns continue to grow, relating to problems caused both by unscrupulous private clinics offering unregulated therapies based on little or no evidence and by premature regulatory approval on the basis of insufficient scientific rationale and clinical evidence. An initiative by the InterAcademy Partnership convened experts worldwide to identify opportunities and challenges, with a focus on stem cells. This was designed to be inclusive and consensus outputs reflected the diversity of the global research population. Among issues addressed for supporting research and innovation while protecting patients were ethical assessment; pre-clinical and clinical research; regulatory authorization and medicines access; and engagement with patients, policy makers, and the public. The InterAcademy Partnership (IAP) identified options for action for sharing good practice and building collaboration within the scientific community and with other stakeholders worldwide., Highlights • An inclusive IAP study examined global stem cell opportunities and challenges • Great potential leads to concerns for evidence base in unregulated clinics • Also concerns for premature regulatory approval without sufficient evidence • Recommendations for responsible research and innovation and collaborations, In this article, Fears and colleagues describe an inclusive global initiative by the InterAcademy Partnership examining stem cell opportunities and challenges. Great therapeutic potential brings concerns about the inadequate evidence base used by unregulated clinics. Concerns are also expressed about premature regulatory approval without sufficient evidence. Recommendations cover ethical assessment; pre-clinical and clinical research; regulatory authorization and medicines access; and engagement with patients, policy makers, and the public.

We evaluated the dynamics of hepatic encephalopathy (HE) and ammonia estimation in acute-on-chronic liver failure (ACLF) patients due to a paucity of evidence. ACLF patients recruited from the APASL-ACLF Research Consortium (AARC) were followed up till 30 days, death or transplantation, whichever earlier. Clinical details, including dynamic grades of HE and laboratory data, including ammonia levels, were serially noted. Of the 3009 ACLF patients, 1315 (43.7%) had HE at presentation; grades I–II in 981 (74.6%) and grades III–IV in 334 (25.4%) patients. The independent predictors of HE at baseline were higher age, systemic inflammatory response, elevated ammonia levels, serum protein, sepsis and MELD score (p

Multiple predictive models of mortality exist for acute-on-chronic liver failure (ACLF) patients that often create confusion during decision-making. We studied the natural history and evaluated the performance of prognostic models in ACLF patients.Prospectively collected data of ACLF patients from APASL-ACLF Research Consortium (AARC) was analyzed for 30-day outcomes. The models evaluated at days 0, 4, and 7 of presentation for 30-day mortality were: AARC (model and score), CLIF-C (ACLF score, and OF score), NACSELD-ACLF (model and binary), SOFA, APACHE-II, MELD, MELD-Lactate, and CTP. Evaluation parameters were discrimination (c-indices), calibration [accuracy, sensitivity, specificity, and positive/negative predictive values (PPV/NPV)], Akaike/Bayesian Information Criteria (AIC/BIC), Nagelkerke-RThirty-day survival of the cohort (n = 2864) was 64.9% and was lowest for final-AARC-grade-III (32.8%) ACLF. Performance parameters of all models were best at day 7 than at day 4 or day 0 (p 0.05 for C-indices of all models except NACSELD-ACLF). On comparison, day-7 AARC model had the numerically highest c-index 0.872, best accuracy 84.0%, PPV 87.8%, RAPASL-ACLF is often a progressive disease, and models assessed up to day 7 of presentation reliably predict 30-day mortality. Day-7 AARC model is a statistically robust tool for classifying risk of death and accurately predicting 30-day outcomes with relatively lower prediction errors. Day-7 AARC score 12 may be used as a futility criterion in APASL-ACLF patients.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has devastated the world with coronavirus disease 2019 (COVID-19), which has imparted a toll of at least 631 million reported cases with 6.57 million reported deaths. In order to handle this pandemic, vaccines against SARS-CoV-2 have been developed and billions of doses of various vaccines have been administered. In the meantime, several antiviral drugs and other treatment modalities have been developed to treat COVID-19 patients. At the end of the day, it seems that anti-SARS-CoV-2 vaccines and newly developed antiviral drugs may be improved based on various new developments. COVID-19 represents a virus-induced, immune-mediated pathological process. The severity of the disease is related to the nature and properties of the host immune responses. In addition, host immunity plays a dominant role in regulating the extent of COVID-19. The present reality regarding the role of anti-SARS-CoV-2 vaccines, persistence of SARS-CoV-2 infection even three years after the initiation of the pandemic, and divergent faces of COVID-19 have initiated several queries among huge populations, policy makers, general physicians, and scientific communities. The present review aims to provide some information regarding the molecular and cellular mechanisms underlying SARS-CoV-2 infection.