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Acute-on-chronic liver failure (ACLF) is a life-threatening syndrome characterized by decompensation of cirrhosis, severe systemic inflammation and organ failures. ACLF is frequently triggered by intra- and/or extrahepatic insults, such as bacterial infections, alcohol-related hepatitis or flares of hepatic viruses. The imbalance between systemic inflammation and immune tolerance causes organ failures through the following mechanisms: (i) direct damage of immune cells/mediators; (ii) worsening of circulatory dysfunction resulting in organ hypoperfusion and (iii) metabolic alterations with prioritization of energetic substrates for inflammation and peripheral organ 'energetic crisis'. Currently, the management of ACLF includes the support of organ failures, the identification and treatment of precipitating factors and expedited assessment for liver transplantation (LT). Early LT should be considered in patients with ACLF grade 3, who are unlikely to recover with the available treatments and have a mortality rate > 70% at 28 days. However, the selection of transplant candidates and their prioritization on the LT waiting list need standardization. Future challenges in the ACLF field include a better understanding of pathophysiological mechanisms leading to inflammation and organ failures, the development of specific treatments for the disease and personalized treatment approaches. Herein, we reviewed the current knowledge and future perspectives on mechanisms and treatment of ACLF., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The Inflammatory Bowel Disease (IBD) patients have adopted lifestyle modifications to prevent infection via SARS COV-2., Aims: This study aims to examine rate of serious infections and opportunistic infections in the pre-pandemic and pandemic period, and to analyse if the risk associated with medications used to treat IBD were potentially modified by associated change in lifestyle., Methods: We conducted a retrospective cohort study of patients from the US national Veteran Affairs Healthcare System (VAHS). Patients were stratified into two groups: pre-pandemic (prior to SARS COV-2 pandemic) and pandemic (during SARS COV-2 pandemic) and outcomes were measured in these groups. Primary outcome was occurrence of any serious infection. Secondary outcome was occurrence of any opportunistic infection., Results: There were 17,202 IBD patients in the pre-pandemic era and 15,903 patients in the pandemic era. The pre-pandemic era had a significantly higher proportion of serious infections relative to the pandemic era (5.1% vs. 4.4%, p = 0.002). The proportion of opportunistic infections were similar between pre-pandemic and pandemic eras (0.3% vs. 0.3%, p = 0.82). Relative to 5-ASA, patients taking anti-TNF (HR = 1.50 (1.31-1.72)), anti-TNF+TP (HR = 1.56 (1.24-1.95)) or vedolizumab (HR = 1.81 (1.49-2.20)) had an increased hazard of serious infection (p > 0.001)., Conclusion: In a nationwide cohort of IBD patients, we found that risk of serious infections could possibly be affected by behavioural modifications due to SARS-COV-2 pandemic., (© 2023 John Wiley & Sons Ltd.)

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) may have favourable neurohumoral and metabolic effects in patients with chronic liver disease. However, studies examining SGLT2i in this population have been limited to patients with non-alcoholic fatty liver disease and have focused on surrogate biomarkers. Our aim was to evaluate whether SGLT2i can reduce the incidence of ascites and death over a period of 36 months in patients with cirrhosis and diabetes mellitus. Using electronic health data from Veterans Affairs hospitals in the United States, we conducted a propensity score matched intention-to-treat analysis among veterans on metformin who subsequently received either SGLT2i or dipeptidyl peptidase-4 inhibitors. Among 423 matched pairs (in total, 846 patients), we found no significant difference in the risk for ascites (hazard ratio 0.68 for SGLT2i, 95% confidence interval 0.37-1.25; p = .22) but did find that SGLT2i users had a reduced risk for death (adjusted hazard ratio 0.33, 95% confidence interval 0.11-0.99; p < .05). In comparison with dipeptidyl peptidase-4 inhibitors, SGLT2i may improve survival for patients with cirrhosis who require additional pharmacotherapy for diabetes mellitus beyond metformin, but confirmatory studies are necessary., (© 2021 John Wiley & Sons Ltd.)

Neonatal stroke is a leading cause of long-term disability and currently available rehabilitation treatments are insufficient to promote recovery. Activating neural precursor cells (NPCs) in adult rodents, in combination with rehabilitation, can accelerate functional recovery following stroke. Here, we describe a novel method of constraint-induced movement therapy (CIMT) in a rodent model of neonatal stroke that leads to improved functional outcomes, and we asked whether the recovery was correlated with expansion of NPCs. A hypoxia/ischemia (H/I) injury was induced on postnatal day 8 (PND8) via unilateral carotid artery ligation followed by systemic hypoxia. One week and two weeks post-H/I, CIMT was administered in the form of 3 botulinum toxin (Botox) injections, which induced temporary paralysis in the unaffected limb. Functional recovery was assessed using the foot fault task. NPC proliferation was assessed using the neurosphere assay and EdU immunohistochemistry. We found that neonatal H/I injury alone expands the NPC pool by >2.5-fold relative to controls. We determined that using Botox injections as a method to provide CIMT results in significant functional motor recovery after H/I. However, CIMT does not lead to enhanced NPC activation or migration into the injured parenchyma in vivo. At the time of functional recovery, increased numbers of proliferating inflammatory cells were found within the injured motor cortex. Together, these findings suggest that NPC activation following CIMT does not account for the observed functional improvement and suggests that CIMT-mediated modification of the CNS inflammatory response may play a role in the motor recovery., (© 2020 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Background The purpose of this study was to examine gender differences in authorship of manuscripts in select high-impact cardiology journals during the early coronavirus disease 2019 (COVID-19) pandemic. Methods and Results All manuscripts published between March 1, 2019 to June 1, 2019 and March 1, 2020 to June 1, 2020 in 4 high-impact cardiology journals ( Journal of the American College of Cardiology , Circulation , JAMA Cardiology , and European Heart Journal ) were identified using bibliometric data. Authors' genders were determined by matching first name with predicted gender using a validated multinational database (Genderize.io) and manual adjudication. Proportions of women and men first, co-first, senior, and co-senior authors, manuscript types, and whether the manuscript was COVID-19 related were recorded. In 2019, women were first authors of 176 (22.3%) manuscripts and senior authors of 99 (15.0%) manuscripts. In 2020, women first authored 230 (27.4%) manuscripts and senior authored 138 (19.3%) manuscripts. Proportions of woman first and senior authors were significantly higher in 2020 compared with 2019. Women were more likely to be first authors if the manuscript's senior author was a woman (33.8% for woman first/woman senior versus 23.4% for woman first/man senior; P <0.001). Women were less likely to be first authors of COVID-19-related original research manuscripts ( P =0.04). Conclusions Representation of women as key authors of manuscripts published in major cardiovascular journals increased during the early COVID-19 pandemic compared with similar months in 2019. However, women were significantly less likely to be first authors of COVID-19-related original research manuscripts. Future investigation into the gender-disparate impacts of COVID-19 on academic careers is critical.

Aims: High dose melphalan (HDM) and autologous stem cell transplant (ASCT) is standard of care for multiple myeloma (MM), but there is significant variability in melphalan exposure (area under the plasma drug concentration-time curve, AUC) when using body surface area-based dosing. Our aim was to establish a method of pharmacokinetic (PK) testing for real-time melphalan dose adjustments., Methods: We performed a prospective PK study of melphalan 140 or 200 mg/m 2 in MM patients undergoing ASCT. Twenty MM patients were administered HDM on days -2 and - 1, with PK sampling at 8-10 time points. PK testing was performed on day -2 in all patients, and on day -1 in 5 patients., Results: Less than 20% interpatient variation in the day -2 and - 1 AUC was observed. The day -2 range in AUC (4.95-11.28 mg h/L) confirmed significant interpatient variability. The hypothetical total dose ranged from 133-302 mg/m 2 to achieve the total median AUC. A 4-time point AUC (0, 30, 150 and 240 min) highly correlated with the AUC from the 8-time point schedule. A higher AUC correlated with increased risk of febrile neutropenia (P = .05)., Conclusion: Here we outline the methods to establish novel melphalan dosing using PK testing in MM patients undergoing ASCT to target a desired melphalan AUC., (© 2020 The British Pharmacological Society.)

Background: Mortality for patients with acute-on-chronic liver failure (ACLF) may be underestimated by the model for end-stage liver disease-sodium (MELD-Na) score., Aim: To assess waitlist outcomes across varying grades of ACLF among a cohort of patients listed with a MELD-Na score ≥35, and therefore having similar priority for liver transplantation., Methods: We analysed the United Network for Organ Sharing (UNOS) database, years 2010-2017. Waitlist outcomes were evaluated using Fine and Gray's competing risks regression., Results: We identified 6342 candidates at listing with a MELD-Na score ≥35, of whom 3122 had ACLF-3. Extra-hepatic organ failures were present primarily in patients with four to six organ failures. Competing risks regression revealed that candidates listed with ACLF-3 had a significantly higher risk for 90-day waitlist mortality (Sub-hazard ratio (SHR) = 1.41; 95% confidence interval [CI] 1.12-1.78) relative to patients with lower ACLF grades. Subgroup analysis of ACLF-3 revealed that both the presence of three organ failures (SHR = 1.40, 95% CI 1.20-1.63) or four to six organ failures at listing (SHR = 3.01; 95% CI 2.54-3.58) was associated with increased waitlist mortality. Candidates with four to six organ failures also had the lowest likelihood of receiving liver transplantation (SHR = 0.61, 95% CI 0.54-0.68). The Share 35 rule was associated with reduced 90-day waitlist mortality among the full cohort of patients listed with ACLF-3 and MELD-Na score ≥35 (SHR = 0.59; 95% CI 0.49-0.70). However, Share 35 rule implementation was not associated with reduced waitlist mortality among patients with four to six organ failures (SHR = 0.76; 95% CI 0.58-1.02)., Conclusions: The MELD-Na score disadvantages patients with ACLF-3, both with and without extra-hepatic organ failures. Incorporation of organ failures into allocation policy warrants further exploration., (© 2020 John Wiley & Sons Ltd.)

Background & Aims: Acute on chronic liver failure (ACLF) causes high short-term mortality in patients with previously stable chronic liver disease. To date there are no models to predict which patients are likely to develop ACLF, and existing models to predict ACLF mortality are based on limited cohorts. We sought to create novel risk prediction scores using a large cohort of patients with cirrhosis., Methods: We performed a retrospective cohort study of 74 790 patients with incident cirrhosis in the Veterans Health Administration database using randomized 70% derivation/30% validation sets. ACLF events were identified per the European ACLF criteria. Multivariable logistic regression was used to derive prediction models for developing ACLF at 3, 6 and 12 months, and ACLF mortality at 28 and 90 days. Mortality models were compared to model for end-stage liver disease (MELD), MELD-sodium and the Chronic Liver Failure Consortium (CLIF-C) ACLF score., Results: Models for the developing ACLF had very good discrimination (concordance [C] statistics 0.83-0.87) at all timepoints. Models for ACLF mortality also had good discrimination at 28 and 90 days (C-statistics 0.79-0.82), and were superior to MELD, MELD-sodium and the CLIF-C ACLF score. The calibration of the novel models was excellent at all timepoints., Conclusion: We have obtained highly-predictive models for developing ACLF, as well as for ACLF short-term mortality in a diverse United States cohort. These may be used to identify outpatients at significant risk of ACLF, which may prompt closer follow-up or early transplant referral, and facilitate decision making for patients with diagnosed ACLF, including escalation of care, expedited transplant evaluation or palliation., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Patients with cirrhosis have increased peri-operative mortality risk relative to non-cirrhotic patients, however, the impact of surgical procedure category on this risk is poorly understood., Methods: We performed a retrospective cohort study of cirrhosis surgery admissions using the National Inpatient Sample between 2012 and 2014 to estimate the adjusted odds of in-hospital mortality by surgical procedure category., Results: In-hospital mortality differed by surgical procedure category. Relative to major orthopedic surgeries, major abdominal surgeries had the highest odds of in-hospital mortality (odds ratio [OR] 8.27, 95% confidence interval [CI] 5.96-11.49), followed by major cardiovascular surgeries (OR 3.45, 95% CI 2.33-5.09). There was also a significant interaction term, whereby elective/non-elective admission status impacted in-hospital mortality risk differently for each surgical procedure category (P < 0.001)., Conclusion: In-hospital mortality varies substantially by surgical procedure type. Accounting for procedure type in models may improve risk prediction for peri-operative mortality in patients with cirrhosis., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: Epidemiological studies of deoxyribonucleic acid (DNA) methylation in airway disease have largely been conducted using blood or buccal samples. However, given tissue specificity of DNA methylation, these surrogate tissues may not allow reliable inferences about methylation in the lung. We sought to compare the pattern of DNA methylation in blood, buccal and nasal epithelial cells to that in airway epithelial cells from children., Methods: Samples of blood, and buccal, nasal and airway epithelium were obtained from six children undergoing elective anaesthesia for adenotonsillectomy. DNA methylation was assessed at 450 000 5'-C-phosphate-G-3' (CpG) sites using the Illumina HumanMethylation450 array., Results: Eighteen samples from all sites were suitable for analysis. Hierarchical clustering demonstrated that the methylation profile in nasal epithelium was most representative of that in airway epithelium; the profile in buccal cells was moderately similar and that in blood was least similar., Conclusion: DNA methylation in blood poorly reflects methylation in airway epithelium. Future epidemiological studies of DNA methylation and airway diseases should consider measurement of methylation either in buccal cells or, preferably, in nasal epithelial cells., (©2017 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

This research compares Australian and Pakistani females on body image attitudes. The sample consisted of Caucasian-Australian and Pakistani first year university students, ranging in age from 17 to 22. The Pakistani sample was subdivided into two groups: Urdu-medium and English-medium, representing the middle and upper social classes, respectively. The results revealed that, although all the groups identified a similar body shape as the 'ideal', the Australian females expressed significantly higher levels of body dissatisfaction on all measures of body image than did the Pakistani females. Within the Pakistani sample, females from the English-medium institutions expressed greater weight concern than did the Urdu-medium females. The findings are discussed in terms of the possible role of cultural values in shaping the body image attitudes of young females.

Background: A number of cases of nephrotoxicity have been reported in patients with inflammatory bowel disease taking oral 5-aminosalicylic acid (5-ASA)., Aim: To evaluate the effects of 9 months of therapy with mesalazine or olsalazine on renal function in patients with ulcerative colitis in remission., Methods: Forty patients with ulcerative colitis in complete remission for 6 months were randomized to either olsalazine (n=20) or mesalazine (n=20 for nine months). Thirty-six of the 40 patients were on prior salicylate therapy. Disease activity was the measure ofclinical efficacy and was assessed by the Harvey-Bradshaw Index (HBI). Laboratory efficacy measurements included glomerular filtration rate (GFR), microalbuminuria, urinary gluthathione S-transferase (GST) and serum C-reactive protein (CRP). Safety analysis consisted of documentation of adverse events and laboratory values., Results: There was no significant reduction in the GFR overall on therapy. The levels of GFR adjusted for baseline were similar in the two treatment groups after 3, 6 and 9 months. A significantly higher percentage of mesalazine-treated patients experienced drug related adverse events, all of a minor nature. The incidence of adverse events causing early withdrawal was similar in the two treatment groups., Conclusion: Treatment with mesalazine or olsalazine for 9 months had no significant impact on GFR.

Background: Dyspepsia is a common symptom for which an organic cause is found in only 40% of patients. When no cause is apparent and the dyspepsia is considered to be idiopathic, a diagnosis of non-ulcer dyspepsia is made. The pathophysiology of non-ulcer dyspepsia is poorly understood and numerous theories have been put forward, including a theory of enhanced central serotoninergic receptor sensitivity., Aim: To determine the sensitivity of serotonin receptors in non-ulcer dyspepsia., Methods: Using a randomized, double-blind, placebo-controlled design, we compared buspirone (a serotonin type 1a partial agonist)-stimulated prolactin release in 50 patients and 59 healthy comparison subjects. Buspirone, 30 mg, or matching placebo was administered on two separate occasions and prolactin release over 180 min was monitored. Patients and healthy subjects received both treatments in random order, 1 week apart., Results: Overall, patients with non-ulcer dyspepsia had greater prolactin release in response to the buspirone challenge than the healthy comparison subjects, with differences most significant at 90 min following the challenge. Enhancement occurred in patients both with and without Helicobacter pylori infection. Female subjects, both patients and healthy volunteers, showed a greater response to buspirone than male subjects, and the augmentation of response observed in male and female patients was greater in females., Conclusions: Patients with non-ulcer dyspepsia have enhanced central serotoninergic responses and such responses are independent of H. pylori infection. Blockade of such receptors might be an appropriate therapeutic strategy.

Background: Heparin therapy may be effective in steroid resistant inflammatory bowel disease., Aim: A randomized pilot study, to compare unfractionated heparin as a first-line therapy with corticosteroids in colonic inflammatory bowel disease., Methods: Twenty patients with severe inflammatory bowel disease (ulcerative colitis, n=17; Crohn's colitis, n=3) were randomized to either intravenous heparin for 5 days, followed by subcutaneous heparin for 5 weeks (n=8), or high-dose intravenous hydrocortisone for 5 days followed by oral prednisolone 40 mg daily, reducing by 5 mg per day each week (n=12). After 5 days, non-responders in each treatment group were commenced on combination therapy. Response to therapy was monitored by: clinical disease activity (ulcerative colitis: Truelove and Witt Index; Crohn's colitis: Harvey and Bradshaw Index), stool frequency, serum C-reactive protein and alpha1 acid glycoprotein, endoscopic and histopathological grading., Results: The response rates were similar in both treatment groups: clinical activity index (heparin vs. steroid; 75% vs. 67%; P=0.23), stool frequency (75% vs. 67%; P=0.61), endoscopic (75% vs. 67%; P=0.4) and histopathological grading (63% vs. 50%; P=0.67). Both treatments were well-tolerated with no serious adverse events., Conclusion: Heparin as a first line therapy is as effective as corticosteroids in the treatment of colonic inflammatory bowel disease. Large multicentre randomized comparative studies are required to determine the role of heparin in the management of inflammatory bowel disease.

Transforming growth factor-beta1 (TGF-beta1) acts directly on haemopoietic progenitor cells to regulate their growth. To investigate a possible link between the action of TGF-beta1 and cell death regulators such as bcl-2, we utilized Ba/F3 cells, the interleukin-3 (IL-3)-dependent growth of which could be modulated by TGF-beta1, as well as haemopoietic progenitor cells. We demonstrate here that up-regulation of bcl-2 protein (Bcl-2) as well as that of an inhibitor of cyclin/cyclin-dependent kinase complex, p27, was associated with TGF-beta1-induced deceleration of the cell-cycling of haemopoietic progenitor cells and Ba/F3 cells. The data from cell-cycle analysis of Ba/F3 cells showed that TGF-beta1 retarded the G1 to S phase transition. Analysis of cells with the potential to express Bcl-2 in an inducible manner indicated that up-regulation of Bcl-2 was sufficient for not only an increase in the level of p27 but also to inhibit the cell growth. Using c-kit-overexpressing cells, we observed that the potential of TGF-beta1 to up-regulate the expression of Bcl-2 and p27 could be counteracted by the c-kit ligand, stem cell factor. These results demonstrate that Bcl-2 exerts an essential function in the regulation of G1 to S phase transition of haemopoietic cells by TGF-beta1.

We separated haemopoietic progenitors derived from marrow cells of 5-fluorouracil (5-FU)-treated mice into three groups, based on the stages of stem cell development and studied doubling time, using a serum-free clonal culture system. Stage I progenitors were those present in primary marrow cells from 5-FU-treated mice. Stages II and III progenitors were early and late progenies in culture of stage I progenitors respectively. The morphological analysis of colonies derived from stage I, II and III progenitors demonstrated an association of progression of stages with loss of multipotentiality. The doubling time of haemopoietic progenitors was estimated by sequential analysis of colony formation and studies of growth fraction. The time required for haemopoietic progenitors to double shortened as their stage of development progressed. Alteration in one doubling time of haemopoietic progenitors at progressive stages of stem cell development was seen in cultures supported by various combinations of growth factors, including interleukin-3 (IL-3), IL-11. and steel factor (SF), Cell-cycle analysis suggested that reduction of the doubling time of haemopoietic progenitors is probably due to a decrease in the time spent in the G1 phase of the cell cycle. Our results suggest that in early haemopoiesis the doubling time of haemopoietic progenitors may change with stem cell development.

We examined the role of the ligand for c-mpl. thrombopoietin (TPO). in murine early haemopoiesis. using a serum-free culture system. TPO in combination with the ligand for c-kit (SF) or interleukin-3 (IL-3) supported colony formation by marrow cells of 5-fluorouracil (5-FU)-treated mice whereas TPO alone yielded no colony. When blast cell colonies grown in the presence of TPO plus SF or TPO plus IL-3 were individually replated in suspension cultures containing serum and several growth factors, various combinations of myeloid lineages were seen, indicating that the progenitors supported by TPO plus SF or TPO plus IL-3 are multipotential. Delayed addition experiments demonstrated that TPO has the potential to effectively support the survival of haemopoietic progenitors. We then studied the effects of TPO on proliferative kinetics of cycling progenitors. TPO hastened IL-3-dependent growth of progenitors by shortening the time required for cell cycling. These results suggest that TPO as a single factor, can support the survival of haemopoietic progenitors and TPO synergizes with SF or IL-3 to act on early multipotential haemopoietic progenitors.