From post-COVID-19-associated myocarditis to hemopericardium: a dangerous domino effect

The majority of patients infected with Severe Acute Respiratory Syndrome-COrona-Virus-2(SARS-CoV-2)either completely recover from symptoms in a few days or stay asymptomatic.[1−3]Nevertheless,a consistent proportion of subjects with a history of probable or confirmed SARS-CoV-2 infection refers persistency,new occurrence,relapse,or fluctuation of symptoms,and these manifestations are defined as post-COVID-19 condition.[4]Of note,the post-acute sequelae of COVID-19 include several cardiac manifestations,including direct myocardial and pericardial injury/inflammation,as well as cardiomyopathies and arrythmias,sustained by viral infiltration and/or dysregulation of adaptive immune response.[5]Even though rare,acute myocarditis may be an important post-COVID-19 condition and may be associated with the occurrence of new-onset atrial fibrillation.

Development and validation of a risk score for advanced colorectal adenoma recurrence after endoscopic resection

AIM: To develop and validate a risk score for advanced colorectal adenoma(ACA) recurrence after endoscopic polypectomy.METHODS: Out of 3360 patients who underwent colon polypectomy at University of Foggia between 2004 and 2008, data of 843 patients with 1155 ACAs was retrospectively reviewed. Surveillance intervals were scheduled by guidelines at 3 years and primary endpoint was considered 3-year ACA recurrence. Baseline clinical parameters and the main features of ACAs were entered into a Cox regression analysis and variables with P < 0.05 in the univariate analysis were then tested as candidate variables into a stepwise Cox regression model(conditional backward selection). The regression coefficients of the Cox regression model were multiplied by 2 and rounded in order to obtain easy to use point numbers facilitating the calculation of the score. To avoid overoptimistic results due to model fitting and evaluation in the same dataset, we performed an internal 10-fold cross-validation by means of bootstrap sampling. RESULTS: Median lesion size was 16 mm(12-23) while median number of adenomas was 2.5(1-3), whereof the number of ACAs was 1.5(1-2). At 3 years after polypectomy, recurrence was observed in 229 ACAs(19.8%), of which 157(13.5%) were metachronous neoplasms and 72(6.2%) local recurrences. Multivariate analysis, after exclusion of the variable "type of resection" due to its collinearity with other predictive factors, confirmed lesion size, number of ACAs and grade of dysplasia as significantly associated to the primary outcome. The score was then built by multiplying the regression coefficients times 2 and the cut-off point 5 was selected by means of a Receiver Operating Characteristic curve analysis. In particular, 248 patients with 365 ACAs fell in the higher-risk group(score ≥ 5) where 3-year recurrence was detected in 174 ACAs(47.6%) whereas the remaining 595 patients with 690 ACAs were included in the low-risk group(score < 5) where 3-year recurrence rate was 7.9%(55/690 ACAs). Area under the curve of the model was 0.81(0.72-0.86) with an overall classification error rate of 0.09. The model was finally validated by means of 10-fold cross validation.CONCLUSION: Our study provides support for the use of a novel risk score as a clinical predictor of ACA recurrence after colon polypectomy.

Lymphocyte-to-monocyte ratio predicts survival after radiofrequency ablation for colorectal liver metastases

AIM: To test the correlation between lymphocyte-tomonocyte ratio(LMR) and survival after radiofrequency ablation(RFA) for colorectal liver metastasis(CLMs). METHODS: From July 2003 to Feb 2012, 127 consecutive patients with 193 histologically-proven unresectable CLMs were treated with percutaneous RFA at the University of Foggia. All patients had undergone primary colorectal tumor resection before RFA and received systemic chemotherapy. LMR was calculated by dividing lymphocyte count by monocyte count assessed at baseline. Treatment-related toxicity was defined as any adverse events occurred within 4 wk after the procedure. Overall survival(OS) and time to recurrence(TTR) were estimated from the date of RFA by Kaplan-Meier with plots and median(95%CI). The inferential analysis for time to event data was conducted using the Cox univariate and multivariate regression model to estimate hazard ratios(HR) and 95%CI. Statistically significant variables from the univariate Cox analysis were considered for the multivariate models.RESULTS: Median age was 66 years(range 38-88) and patients were prevalently male(69.2%). Median LMR was 4.38%(0.79-88) whereas median number of nodules was 2(1-3) with a median maximum diameter of 27 mm(10-45). Median OS was 38 mo(34-53) and survival rate(SR) was 89.4%, 40.4% and 33.3% at 1, 4 and 5 years respectively in the whole cohort. Running log-rank test analysis found 3.96% as the most significant prognostic cut-off point for LMR and stratifying the study population by this LMR value median OS resulted 55 mo(37-69) in patients with LMR > 3.96% and 34(26-39) mo in patients with LMR ≤ 3.96%(HR = 0.53, 0.34-0.85, P = 0.007). Nodule size and LMR were the only significant predictors for OS in multivariate analysis. Median TTR was 29 mo(22-35) with a recurrence-free survival(RFS) rate of 72.6%, 32.1% and 21.8% at 1, 4 and 5 years, respectively in the whole study group. Nodule size and LMR were confirmed as significant prognostic factors for TTR in multivariate Cox regression. TTR, when stratified by LMR, was 35 mo(28-57) in the group > 3.96% and 25 mo(18-30) in the group ≤ 3.96%(P = 0.02).CONCLUSION: Our study provides support for the use of LMR as a novel predictor of outcome for CLM patients.

Impact of sodium glucose cotransporter-2 inhibitors on liver steatosis/fibrosis/inflammation and redox balance in non-alcoholic fatty liver disease

BACKGROUND Sodium glucose cotransporter-2 inhibitors(SGLT2-I)are the most recently approved drugs for type 2 diabetes(T2D).Recent clinical trials of these compounds reported beneficial cardiovascular(CV)and renal outcomes.A major cause of vascular dysfunction and CV disease in diabetes is hyperglycemia associated with inflammation and oxidative stress.Pre-clinical studies demonstrated that SGLT2-I reduce glucotoxicity and promote anti-inflammatory effects by lowering oxidative stress.AIM To investigate the effects of SGLT2-I on markers of oxidative stress,inflammation,liver steatosis,and fibrosis in patients of T2D with non-alcoholic fatty liver disease(NAFLD).METHODS We referred fifty-two consecutive outpatients treated with metformin monotherapy and exhibiting poor glycemic control to our centre.We introduced the outpatients to an SGLT2-I(dapagliflozin,empagliflozin,or canagliflozin;n=26)or a different hypoglycemic drug[other glucose-lowering drugs(OTHER),n=26].We evaluated circulating interleukins and serum hydroxynonenal(HNE)-or malondialdehyde(MDA)-protein adducts,fatty liver index(FLI),NAFLD fibrosis score,aspartate aminotransferase(AST)/alanine aminotransferase(ALT)ratio,AST-to-platelet-ratio index(APRI),and fibrosis-4 on the day before(T0)and following treatment for six months(T1).We also performed transient elastography at T0 and T1.RESULTS Add-on therapy resulted in improved glycemic control and reduced fasting blood glucose in both groups.Of note,following treatment for six months,a reduction of FLI and APRI,as well as of the FibroScan result,was reported in patients treated with SGLT2-I,but not in the OTHER group;furthermore,in the SGLT2-I group,we reported lower circulating levels of interleukin(IL)-1β,IL-6,tumor necrosis factor,vascular endothelial growth factor,and monocyte chemoattractant protein-1,and higher levels of IL-4 and IL-10.We did not observe any modification in circulating interleukins in the OTHER group.Finally,serum HNE-and MDA-protein adducts decreased significantly in SGLT2-I rather than OTHER patients and correlated with liver steatosis and fibrosis scores.CONCLUSION The present data indicate that treatment with SGLT2-I in patients with T2D and NAFLD is associated with improvement of liver steatosis and fibrosis markers and circulating pro-inflammatory and redox status,more than optimizing glycemic control.

Impact of senescence on the transdifferentiation process of human hepatic progenitor-like cells

BACKGROUND Senescence is characterized by a decline in hepatocyte function,with impairment of metabolism and regenerative capacity.Several models that duplicate liver functions in vitro are essential tools for studying drug metabolism,liver diseases,and organ regeneration.The human HepaRG cell line represents an effective model for the study of liver metabolism and hepatic progenitors.However,the impact of senescence on HepaRG cells is not yet known.AIM To characterize the effects of senescence on the transdifferentiation capacity and mitochondrial metabolism of human HepaRG cells.METHODS We compared the transdifferentiation capacity of cells over 10(passage 10[P10])vs P20.Aging was evaluated by senescence-associated(SA)beta-galactosidase activity and the comet assay.HepaRG transdifferentiation was analyzed by confocal microscopy and flow cytometry(expression of cluster of differentiation 49a[CD49a],CD49f,CD184,epithelial cell adhesion molecule[EpCAM],and cytokeratin 19[CK19]),quantitative PCR analysis(expression of albumin,cytochrome P4503A4[CYP3A4],γ-glutamyl transpeptidase[γ-GT],and carcinoembryonic antigen[CEA]),and functional analyses(albumin secretion,CYP3A4,andγ-GT).Mitochondrial respiration and the ATP and nicotinamide adenine dinucleotide(NAD^(+))/NAD with hydrogen(NADH)content were also measured.RESULTS SAβ-galactosidase staining was higher in P20 than P10 HepaRG cells;in parallel,the comet assay showed consistent DNA damage in P20 HepaRG cells.With respect to P10,P20 HepaRG cells exhibited a reduction of CD49a,CD49f,CD184,EpCAM,and CK19 after the induction of transdifferentiation.Furthermore,lower gene expression of albumin,CYP3A4,andγ-GT,as well as reduced albumin secretion capacity,CYP3A4,andγ-GT activity were reported in transdifferentiated P20 compared to P10 cells.By contrast,the gene expression level of CEA was not reduced by transdifferentiation in P20 cells.Of note,both cellular and mitochondrial oxygen consumption was lower in P20 than in P10 transdifferentiated cells.Finally,both ATP and NAD^(+)/NADH were depleted in P20 cells with respect to P10 cells.CONCLUSION SA mitochondrial dysfunction may limit the transdifferentiation potential of HepaRG cells,with consequent impairment of metabolic and regenerative properties,which may alter applications in basic studies.

Nuclear factor erythroid 2-related factor 2-mediated signaling and metabolic associated fatty liver disease

Oxidative stress is a key driver in the development and progression of several diseases,including metabolic associated fatty liver disease(MAFLD).This condition includes a wide spectrum of pathological injuries,extending from simple steatosis to inflammation,fibrosis,cirrhosis,and hepatocellular carcinoma.Excessive buildup of lipids in the liver is strictly related to oxidative stress in MAFLD,progressing to liver fibrosis and cirrhosis.The nuclear factor erythroid 2-related factor 2(NRF2)is a master regulator of redox homeostasis.NRF2 plays an important role for cellular protection by inducing the expression of genes related to antioxidant,anti-inflammatory,and cytoprotective response.Consistent evidence demonstrates that NRF2 is involved in every step of MAFLD development,from simple steatosis to inflammation,advanced fibrosis,and initiation/progression of hepatocellular carcinoma.NRF2 activators regulate lipid metabolism and oxidative stress alleviating the fatty liver disease by inducing the expression of cytoprotective genes.Thus,modulating NRF2 activation is crucial not only in understanding specific mechanisms underlying MAFLD progression but also to characterize effective therapeutic strategies.This review outlined the current knowledge on the effects of NRF2 pathway,modulators,and mechanisms involved in the therapeutic implications of liver steatosis,inflammation,and fibrosis in MAFLD.

Coronavirus disease 2019 and non-alcoholic fatty liver disease

The coronavirus disease 2019(COVID-19)pandemic may present with a broad range of clinical manifestations,from no or mild symptoms to severe disease.Patients with specific pre-existing comorbidities,such as obesity and type 2 diabetes,are at high risk of coming out with a critical form of COVID-19.Nonalcoholic fatty liver disease(NAFLD)is the most common chronic liver disease,and,because of its frequent association with metabolic alterations including obesity and type 2 diabetes,it has recently been re-named as metabolic-associated fatty liver disease(MAFLD).Several studies and systematic reviews pointed out the increased risk of severe COVID-19 in NAFLD/MAFLD patients.Even though dedicated mechanistic studies are missing,this higher probability may be justified by systemic low-grade chronic inflammation associated with immune dysregulation in NAFLD/MAFLD,which could trigger cytokine storm and hypercoagulable state after severe acute respiratory syndrome coronavirus 2 infection.This review focuses on the predisposing role of NAFLD/MAFLD in favoring severe COVID-19,discussing the available information on specific risk factors,clinical features,outcomes,and pathogenetic mechanisms.