Association of Nonalcoholic Fatty Liver Disease With COVID-19 Severity and Pulmonary Thrombosis: CovidFAT, a Prospective, Observational Cohort Study.

Background: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease associated with systemic changes in immune response, which might be associated with coronavirus disease 2019 (COVID-19) severity. The aim of this study was to investigate the impact of NAFLD on COVID-19 severity and outcomes. Methods: A prospective observational study included consecutively hospitalized adult patients, hospitalized between March and June 2021, with severe COVID-19. Patients were screened for fatty liver by ultrasound and subsequently diagnosed with NAFLD. Patients were daily followed until discharge, and demographic, clinical, and laboratory data were collected and correlated to clinical outcomes. Results: Of the 216 patients included, 120 (55.5%) had NAFLD. The NAFLD group had higher C-reactive protein (interquartile range [IQR]) (84.7 [38.6-129.8] mg/L vs 66.9 [32.2-97.3] mg/L; P = .0340), interleukin-6 (49.19 [22.66-92.04] ng/L vs 13.22 [5.29-39.75] ng/L; P < .0001), aspartate aminotransferase (58 [40-81] IU/L vs 46 [29-82] IU/L; P = .0123), alanine aminotransferase (51 [32-73] IU/L vs 40 [23-69] IU/L; P = .0345), and lactate dehydrogenase (391 [285-483] IU/L vs 324 [247-411] IU/L; P = .0027). The patients with NAFLD had higher disease severity assessed by 7-category ordinal scale, more frequently required high-flow nasal cannula or noninvasive ventilation (26, 21.66%, vs 10, 10.42%; P = .0289), had longer duration of hospitalization (IQR) (10 [8-15] days vs 9 [6-12] days; P = .0018), and more frequently had pulmonary thromboembolism (26.66% vs 13.54%; P = .0191). On multivariable analyses, NAFLD was negatively associated with time to recovery (hazard ratio, 0.64; 95% CI, 0.48 to 0.86) and was identified as a risk factor for pulmonary thrombosis (odds ratio, 2.15; 95% CI, 1.04 to 4.46). Conclusions: NAFLD is associated with higher COVID-19 severity, more adverse outcomes, and more frequent pulmonary thrombosis.

Redox-active cysteines in TGACG-BINDING FACTOR 1 (TGA1) do not play a role in salicylic acid or pathogen-induced expression of TGA1-regulated target genes in Arabidopsis thaliana.

Salicylic acid (SA) is an important signaling molecule of the plant immune system. In Arabidopsis thaliana, SA biosynthesis is indirectly modulated by the closely related transcription factors TGACG-BINDING FACTOR 1 and 4 (TGA1 and TGA4, respectively). They activate expression of SYSTEMIC ACQUIRED RESISTANCE DEFICIENT1, the gene product of which regulates the key SA biosynthesis gene ISOCHORISMATE SYNTHASE 1. Since TGA1 interacts with the SA receptor NONEXPRESSOR OF PATHOGENESIS-RELATED GENES 1 (NPR1) in a redox-dependent manner and since the redox state of TGA1 is altered in SA-treated plants, TGA1 was assumed to play a role in the NPR1-dependent signaling cascade. Here, we identified 193 out of 2090 SA-induced genes that require TGA1/TGA4 for maximal expression after SA treatment. One robustly TGA1/TGA4-dependent gene encodes for the SA hydroxylase DOWNY MILDEW RESISTANT 6-LIKE OXYGENASE 1, suggesting an additional regulatory role of TGA1/TGA4 in SA catabolism. Expression of TGA1/TGA4-dependent genes in mock/SA-treated or Pseudomonas-infected plants was rescued in the tga1 tga4 double mutant after introduction of a mutant genomic TGA1 fragment encoding a TGA1 protein without any cysteines. Thus, the functional significance of the observed redox modification of TGA1 in SA-treated tissues remains enigmatic.

Large Pore Mesoporous Silica and Organosilica Nanoparticles for Pepstatin A Delivery in Breast Cancer Cells.

(1) Background: Nanomedicine has recently emerged as a new area of research, particularly to fight cancer. In this field, we were interested in the vectorization of pepstatin A, a peptide which does not cross cell membranes, but which is a potent inhibitor of cathepsin D, an aspartic protease particularly overexpressed in breast cancer. (2) Methods: We studied two kinds of nanoparticles. For pepstatin A delivery, mesoporous silica nanoparticles with large pores (LPMSNs) and hollow organosilica nanoparticles (HOSNPs) obtained through the sol⁻gel procedure were used. The nanoparticles were loaded with pepstatin A, and then the nanoparticles were incubated with cancer cells. (3) Results: LPMSNs were monodisperse with 100 nm diameter. HOSNPs were more polydisperse with diameters below 100 nm. Good loading capacities were obtained for both types of nanoparticles. The nanoparticles were endocytosed in cancer cells, and HOSNPs led to the best results for cancer cell killing. (4) Conclusions: Mesoporous silica-based nanoparticles with large pores or cavities are promising for nanomedicine applications with peptides.

Treatment of Elderly Patients with Chronic Hepatitis C: A Retrospective Cohort Study.

The prevalence of chronic hepatitis C increases in elderly patients. The aims of this study were to identify the factors associated with hepatocellular carcinoma (HCC) and end-stage liver disease development and to evaluate the efficacy and safety of pegylated interferon (PEG-IFNα) plus ribavirin (RBV) therapy in elderly patients. A retrospective cohort study included all consecutive pa-tients with hepatitis C virus (HCV) infection treated with PEG-IFNα+RBV between 2003 and 2013. Elderly patients had a higher frequency of poor prognostic factors including genotype 1 infec-tion, high fibrosis, and high fibrosis index based on four factors (FIB-4) score. The sustained virologic response (SVR) rate for genotype 1 was significantly lower (35.8% vs. 57.1%), while the frequency of PEG-IFNα (27.2% vs. 7.8%), RBV dose reduction (19.6% vs. 9.7%) and treatment discontinuation (13.0% vs. 4.1%) was significantly higher in elderly patients. However, age was not associated with SVR in multivariate analysis, and comparable SVR rates were achieved when adjusted for fibrosis score (Ishak ≤3: 66.7% vs. 69.8%). During the follow-up, HCC was diagnosed in 18 elderly patients (3 SVR+, 4 SVR- and 9 untreated patients). In conclusion, selected elderly patients can achieve comparable SVR rates as younger patients, but with a higher rate of side effects. Since complications of HCV infection occur more frequently in elderly patients, they should be given priority for antiviral therapy.

Treatment of chronic hepatitis C in Croatian war veterans: experiences from Croatian reference center for viral hepatitis.

AIM: To examine the risk factors, comorbidity, severity of liver disease, treatment course, and outcome in Croatian war veterans with chronic hepatitis C, especially those suffering from posttraumatic stress disorder (PTSD). METHODS: We collected medical records of 170 adult men diagnosed with chronic hepatitis C who started treatment with a combination of pegylated interferon-alpha and ribavirin between January 2003 and June 2009 at the Croatian Reference Centre for Viral Hepatitis. RESULTS: Participants' mean age was 43 ± 9 years. Among 170 participants, there were 37 war veterans (22%). The main risk factor in veteran patients were operative procedures with transfusions (46% vs 5% in non-veterans; P < 0.001) and in non-veteran patients intravenous drug use (42.1% vs 13%; P < 0.001). The average duration of infection was longer in war veterans (14.5 ± 3.4 vs 12.2 ± 7.2 years; P = 0.020). The percentage of PTSD comorbidity in the whole group was 11% (18/170) and in the war veterans group 49% (18/37). The prevalence of sustained virological response in patients with PTSD was 50% and in patients without PTSD 56%. Treatment reduction in patients with PTSD (33%) was higher than in patients without PTSD (12%; P = 0.030). CONCLUSION: Croatian war veterans are a group with high risk of chronic hepatitis C infection because many of them were wounded during the Croatian War 1991-1995. Considerations about PTSD as a contraindication for interferon treatment are unjustified. If treated, patients with PTSD have an equal chance of achieving sustained virological response as patients without PTSD.

[Post-transplant lymphoproliferative disease in liver transplant recipients--Merkur University Hospital single center experience]. / Post-transplantacijska limfoproliferativna bolest u bolesnika s transplantacijom jetre - iskustvo KB Merkur.

Post-transplant lymphoproliferative disorder (PTLD) is an increasingly recognized condition as the number of solid organ and bone marrow transplant recipients increases. It can be a life threatening fulminant disorder and affects approximately 8% of solid organ transplant recipients. Epstein-Barr virus (EBV) is closely involved in the pathogenesis of PTLD and the majority of PTLD cases arise in response to primary infection with EBV or to re-activation of previously acquired EBV. The principal risk factors underlying the development of PTLD are the degree of overall immunosuppression and EBV serostatus of the recipient. The most commonly used pathologic classification of PTLD is the World Health Organization classification, which divides PTLD into three categories: early lesions, polymorphic PTLD, and monomorphic PTLD. Early lesions are characterized by reactive plasmacytic hyperplasia. Polymorphic PTLD may be either polyclonal or monoclonal and is characterized by destruction of the underlying lymphoid architecture, necrosis, and nuclear atypia. In monomorphic PTLD, the majority of cases (>80%) arise from B cells, similar to non-Hodgkin's lymphoma in immunocompetent hosts. The most common subtype is diffuse large B-cell lymphoma, but Burkitt's/Burkitt's-like lymphoma and plasma cell myeloma are also seen. Rarely T-cell variants occur, which include peripheral T-cell lymphomas and, rarely, other uncommon types, including gamma/delta T-cell lymphoma and T-natural killer (NK) cell varieties. Hodgkin's disease-like lymphoma is very unusual. An accurate diagnosis of PTLD requires a high index of suspicion, since the disorder may present subtly and/or extranodally. Radiologic evidence of a mass or the presence of elevated serum markers (such as increased LDH levels) are suggestive of PTLD, with positive finding on ultrasonography, computed tomography, magnetic resonance and/or positron emission tomography scanning (possibly indicating metabolically active areas) also favoring the diagnosis. The management of PTLD poses a major therapeutic challenge and although there is reasonable agreement about the overall principles of treatment, there is still considerable controversy about the optimal treatment of individual patients. EBV-related PTLDs are a significant cause of mortality in patients undergoing orthotopic liver transplantation with the observed mortality rate of up to 50%. This paper presents the experience acquired at Merkur University Hospital in the diagnosis and treatment of patients with liver transplantation and PTLD.

[Molecular diagnosis of hepatitis C and hepatitis B infection]. / Molekularna dijagnostika infekcije virusom hepatitisa C i hepatitisa B.

Molecular methods are a well-established part of routine diagnostic work-up in patients infected with hepatitis B virus (HBV) and hepatitis C virus (HCV). Confirmation of active viral replication in infected patients is based on detection and/or quantification of viral genome in serum by molecular assays. Diagnostic algorithm for hepatitis C includes detection and/or quantification of HCV RNA in serum of infected patients and HCV genotyping. Diagnostic work-up in patients with hepatitis B includes quantification of HBV DNA in serum, HBV genotyping, and determination of resistance to nucleoside and nucleotide analogues. Real-time polymerase chain reaction (PCR) is the standard recommended molecular method for quantification of HCV RNA and HBV DNA in clinical samples. Due to superior sensitivity, real-time PCR assays can provide both qualitative detection of viral genome and quantification. Molecular diagnosis of HCV and HBV infections in clinical laboratories should be limited to certified standardized assays.