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Jillian Kallman Price,1 Lynn H Gerber,1,2 Maria Stepanova,1– 3 Leyla de Avila,1 Ali A Weinstein,4 Huong Pham,1 Fatema Nader,1 Mariam Afendy,1 Kathy Terra,3 Patrick Austin,1 Wisna’odom Keo,1 Andrei Racila,1 James Michael Estep,1 Suzannah Gerber,1 Manisha Verma,1 Pegah Golabi,1 Brian P Lam,1– 3 Zobair Younossi1– 3 1Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA; 2Inova Medicine, Inova Health System, Falls Church, VA, USA; 3Center for Liver Disease, Department of Medicine, Inova Fairfax Medical Campus, Falls Church, VA, USA; 4Department of Global and Community Health, George Mason University, Fairfax, VA, USACorrespondence: Jillian Kallman Price, Research Investigator, Outcomes Research, Beatty Liver and Obesity Research Program, Center for Integrated Research, Department of Medicine, Inova Health System, Claude Moore Health Education and Research Building, Inova Fairfax Medical Campus, 3300 Gallows Road, Falls Church, VA, 22042, USA, Tel +1-703-776-3032, Fax +1-703- 776-4386, Email Jillian.Price@inova.orgIntroduction: Many with post-acute SARS-CoV-2 (PASC) have persistent symptoms impacting physical and cognitive function, decreased health and health-related life quality. Monoclonal antibody (mAb) treatment was available to acutely infected patients which might improve these outcomes.Purpose: To compare patient perception of PASC symptoms for those receiving bamlanivimab or casirivimab and imdevimab (mAbs) to those not receiving this treatment (non-mAbs). To compare changes between these groups in symptoms, function and quality of life over a 6-month follow-up.Patients and Methods: Consented adults > 28 days post-infection with positive SARS-CoV-2 qPCR or antigen test and SARS-CoV-2 infection between March of 2020 and July of 2022 were enrolled. This prospective, repeated measure observational study reports baseline through 6-month follow-up. Extensive sociodemographic data, detailed medical history, COVID-19 symptom history, and standardized measures of well-being, depression, anxiety, stigma, cognition, symptom assessment, distress, and health status were collected.Results: 323 participants [101 mAb, 221 non-mAb, 52.7± 15.5 years, 47.7% male, body mass index (BMI) 31.4± 8.4] were analyzed. Fewer symptoms at baseline were reported in mAb versus non-mAb participants (1.06± 1.31 vs 1.78± 2.15, respectively p=0.0177) 6 months: (0.911± 1.276 mAb vs.1.75± 2.22 non-mAb, p=0.0427). Both groups showed significant within-group decreases in symptom number (52 to 21 mAb, 126 to 63 non-mAb) and symptom burden (p=0.0088 mAb, p< 0.00001 non-mAb). mAb patients had significantly shorter infection-to-baseline interval (days) (120.4± 55.3 mAb vs 194.0± 89.3 non-mAb, p< 0.00001); less frequent history of myocardial infarction (0.0 vs 3.9%, p=0.0464); headache (2.0% vs.11.8%, p=0.0046), rash (3.1% vs 9.9%, p=0.0377), and miscellaneous muscle complaints (2.0% vs 12.3%, p=0.0035), plus significantly better 6-month mood. (2.2% vs 13.2%, p=0.0390).Conclusion: mAb treated participants had reduced symptom burden and consistently reported fewer symptoms than non-mAb at all time points despite less time since acute illness. Both groups reported a statistically significant decrease in symptoms by 6-month visit with no statistically significant differences between them at follow-up.Keywords: monoclonal antibodies, patient-reported outcomes, symptom burden, recovery, COVID-19

Background: Association of genetic factors with non-invasive tests (NITs) for MASLD has not been well established., Methods: Clinical and laboratory data, liver biopsy and/or liver stiffness measurement (LSM) by transient elastography were collected from MASLD patients seen in tertiary care hepatology practices. Minor allele frequency for genomic loci rs641738 (MBOAT7), rs58542926 (TM6SF2), rs738409 (PNPLA3), rs62305723 (HSD1713B) were evaluated for association with high ELF (≥11.3), high FIB-4 (≥3.25), high LSM (≥10 kPa), histologic fibrosis (stage 3/4 vs. stages 0-2)., Results: Among 2289 MASLD patients with available polymorphism and liver fibrosis/NIT data [52 ± 13 years, 46 % male, BMI 36.6 ± 9.9, 35 % type 2 diabetes (T2D)], 53 % had high-risk allele (C > G) at rs738409 (PNPLA3), 70 % high-risk allele (C > T) at rs641738 (MBOAT7), 18 % high-risk minor allele (C > T) at rs58542926 (TM6SF2), 11 % low-risk minor allele (G > A) at rs62305723 (HSD17b13). Only PNPLA3-rs738409 (47 % CC, 40 % CG, 13 % GG) was significantly associated with higher NIT scores and histologic fibrosis: high ELF 2.8 % CC vs. 8.1 % CG/GG; high FIB-4 4.7 % CC vs. 11.6 % CG/GG; high LSM 10 % vs. 19 %; advanced histologic fibrosis 34 % CC vs. 60 % CG/GG (all p < 0.01). Similar associations of PNPLA3-rs738409 with NITs were observed in a subgroup of MASLD patients with T2D (n = 799; all p < 0.05). The PNPLA3-rs738409 CG/GG genotype, older age and T2D were independently associated with high ELF [OR (95 % CI) = 3.25 (2.03-5.20)], FIB-4 [OR = 2.75 (1.90-3.98)], LSM [OR = 2.71 (1.60-4.59)] scores and advanced histologic fibrosis [OR = 2.56 (1.81-3.62)]., Conclusions: The polymorphism rs738409 in the PNPLA3 gene, T2D, and older age were independent predictors of high-risk MASLD., 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 Elsevier B.V. All rights reserved.)

An important extrahepatic consequence of Hepatitis C is its adverse impact on the central nervous system and cognitive performance. We aimed to determine whether there is a significant relationship between selected neurotransmitters and cytokines and cognitive performance in patients with Chronic Hepatitis C before and after achieving sustained virologic response (SVR). Pre-SVR, elevated kynurenine was associated with increased immediate and delayed visual memory, whereas post-SVR the positive associations are between kynurenine and immediate and delayed verbal memory. TGF-B was consistently negatively associated with both immediate and delayed visual memory pre- and post-SVR. These concomitant changes may have important clinical relevance., (Copyright © 2019. Published by Elsevier B.V.)

Background & Aims: Chronic hepatitis C (CHC) has a negative impact on patient-reported outcomes (PROs). Although most CHC patients who achieve sustained virologic response (SVR) show an improvement in PRO scores, some continue to experience impairment in PROs. The aim was to investigate if serum biomarkers (selected neurotransmitters and cytokines) are associated with changes in PROs in CHC patients who achieve SVR., Methods: Data were utilized from a prospective clinical trial of ledipasvir/sofosbuvir fixed-dose combination. Chronic genotype 1 HCV subjects without cirrhosis (N = 40, age: 45.3 ± 11.5, 48% male, 90% white) were treated for 12 weeks open label with 97% achieving SVR24. PRO questionnaires included Short Form-36 (SF-36), Fatigue Severity Scale (FSS), Beck Depression Inventory-II (BDI-II), Chronic Liver Disease Questionnaire-HCV (CLDQ-HCV) and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). Sera were used for measurement of selected neurotransmitters and cytokines. Data were collected at baseline and follow-up week 24., Results: Changes in physical health correlated with changes in several biomarkers. BDNF negatively correlated with SF-36 physical health summary score (rho = -0.34, P < 0.05), SF-36 physical functioning (rho = -0.34, P < 0.05), SF-36 bodily pain (rho = -0.39, P < 0.05) and FACIT-F physical well-being (rho = -0.54, P < 0.001). Changes in emotional well-being (FACIT-F) were positively associated with changes in serotonin (rho = 0.34, P < 0.05), but negatively associated with changes in GABA and BDNF (rho = -0.4, P = 0.01, and rho = -0.35, P < 0.05 respectively)., Conclusions: These data indicate relationships between PROs and serum biomarkers pre- and post-SVR in CHC. These concomitant changes may have important clinical relevance., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Mental and emotional health (MEH) impairment is commonly encountered in hepatitis C patients. Although the exact mechanism remains unknown, alterations in neurotransmitter and cytokine levels maybe associated with hepatitis C virus (HCV)-related MEH issues.The aim of the study was to assess association of serum biomarkers with self-reports of MEH in HCV patients before treatment and after achieving sustained virologic response (SVR).The HCV genotype-1-infected patients who achieved SVR at 12 weeks after treatment with ledipasvir (LDV)/sofosbuvir (SOF) ± ribavirin (RBV) were selected. Frozen serum samples from baseline, end of treatment (EOT), and posttreatment week 4 (PTW4) were used to assay 16 cytokines and monoamine neurotransmitters. Validated self-reports were used to assess MEH.Hundred patients were evaluated. Mean age was 53 years (57% male, 86% white). Compared with baseline, emotional well-being and emotional health significantly increased by EOT, and role emotional, emotional well-being, and emotional health significantly increased at PTW4 in the RBV-containing arm (P < 0.05). In patients taking LDV/SOF + RBV, serotonin levels were significantly decreased at PTW4 compared with baseline (P = 0.046). Compared with baseline, there were significant decreases in interleukin (IL)-10 levels at EOT and PTW4 in both treatment groups. The changes in IL-8 also differed significantly between LDV/SOF + RBV and LDV/SOF groups (P < 0.05). Changes in dopamine and tryptophan levels at EOT correlated with increasing emotional health scores, whereas changes in monocyte chemoattractant protein-1 at EOT and IL-8 at PTW4 correlated with increasing mental health scores. The neurotransmitters and cytokines were found to be independent predictors of MEH scores in multiple regression analysis.Cytokine and neurotransmitter changes are associated with mental and emotional health. Patient-reported outcome scores change during and after treatment., Competing Interests: ZMY has received research grants or is a consultant to Abbvie, BMS, Gilead, GSK, and Intercept. There are no other conflicts of interest related to this manuscript for other authors.

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is strongly associated with visceral adiposity. The secretion of adipocytokines from white adipose tissue (WAT) promoting necroinflammation, and/or fibrosis may play important roles in the pathogenesis of non-alcoholic steatohepatits (NASH). In a previous study, reduced expression of a number of miRNA species in WAT concomitant with histological diagnosis of NASH was successfully demonstrated. In this study, we measure the expression of several predicted miRNA regulatory targets relevant to NAFLD and NASH including mTOR, FAS, IL20, SEMA4C, ADAMTS6 and IL13RA. We then examine hepatic receptor expression by immunohistochemical staining and qPCR., Methods: White adipose tissue was collected from 24 obese patients undergoing bariatric surgery with biopsy-proven NAFLD. Extracted total RNAs from the adipose tissue were reverse transcribed and profiled for gene expression by qPCR for specific individual mRNA targets defined after identification by any two of three of the major prediction services: miRanda, TarBase or PicTar. All liver biopsies were read by a singly hepatopathologist. The same liver tissue was used to stain for hepatic receptor expression for FASLG and IL20. Additionally, the same tissue was used for qPCR for FASLG and IL20., Results: Increases in the expression of IL13RA, mTOR, IL20, SEMA4C and FAS were detected and negatively correlated with putative regulatory miRNA. Hepatic receptor expression for FAS and IL20 was noted to correlate with markers of inflammation and severity of NAFLD., Conclusion: These data are consistent with the hypothesis that specific adipocytokines secreted by WAT will impact hepatic tissue and participate in the pathogenesis of NASH., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Hepatitis C virus (HCV) and the hepatic manifestation of metabolic syndrome, nonalcoholic fatty liver disease, are the two major causes of chronic liver disease worldwide. Liver histology of both diseases can be associated with steatosis, oxidative stress and fibrogenesis. Although better defined for HCV, approximately 20% of patients with these diseases can also develop cirrhosis or hepatocellular carcinoma. In recent years, it has become clear that the presence of metabolic syndrome and nonalcoholic fatty liver disease negatively impacts HCV-related outcomes, while simultaneously, the progression of HCV may have metabolic consequences in that it encourages or exacerbates insulin resistance. A growing body of evidence suggests that successful treatment of HCV may rely on understanding and addressing the complex and often mutually confounding relationship between HCV and the individual elements that comprise metabolic syndrome.

Non-alcoholic fatty liver disease (NAFLD) is a clinico-pathologic spectrum of conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). Although simple or bland steatosis follows a relatively benign clinical course, NASH can potentially progress to cirrhosis (approximately 10 to 15 percent) and hepatocellular carcinoma. NAFLD occurs in an estimated 25 to 30 percent of the US general population, while NASH is reported in 2 to 3 percent of the population. Even though common explanation for the increased prevalence of NAFLD is the increased rate of obesity, the risk of developing NAFLD and NASH is not limited to overweight and obese individuals. Currently, the only way to diagnose NASH or to assess the stage of fibrosis is by obtaining a liver biopsy. Liver biopsy is invasive, expensive, and associated with potential risks, including post biopsy pain, bleeding, organ perforation, and even death; serious complications can occur in 0.3 percent of liver biopsies with 0.01 percent being fatal. This review examines the current strategies for development of the non-invasive techniques that will one day replace liver biopsy and serve as a non-invasive gold standard for the diagnosis and staging of NASH.

Background: Hepatic stellate cells (HSC) are involved in hepatic fibrogenesis. Cell signaling associated with an insult to the liver affects an HSC transdifferentiation to fibrogenic myofibroblast-like cells., Aims: To investigate the transcriptional expression distinguishing HSC and myofibroblast-like cells between livers with and without cirrhosis., Methods: Tissue from ten cirrhotic livers (undergoing transplant) and four non-cirrhotic livers from the National Disease Research Interchange underwent cell separation to extract HSC and myofibroblast-like cell populations. Separated cell types as well as LI-90 cells were subjected to microarray analysis. Selected microarray results were verified by quantitative real-time PCR., Results: Differential expression of some genes, such as IL-1beta, IL-1alpha, and IL-6, was associated with both transdifferentiation and disease. Other genes, such as fatty acid 2-hydroxylase only show differential expression in association with disease. Functional analysis supported these findings, indicating some signal transduction pathways (IL-6) are involved in disease and activation, whereas retinoid X receptor signaling in HSC from cirrhotic and non-cirrhotic livers varies in scope and quality., Conclusions: These findings indicate distinct phenotypes for HSC from cirrhotic and non-cirrhotic livers. Furthermore, coordinated differential expression between genes involved in the same signal transduction pathways provides some insight into the mechanisms that may control the balance between fibrogenesis and fibrolysis.

Background: White adipose tissue (WAT) from visceral adiposity plays an important role in the pathogenesis of non-alcoholic steatohepatitis (NASH). Development of NASH and its progression to fibrosis is partially due to cytokines and adipokines produced by WAT. The aim of this study was to assess the association of hepatic fibrosis and NASH by evaluating the intrinsic differences in the inflammatory cytokine signaling in the visceral adipose tissue obtained from morbidly obese patients., Methods: We used targeted microarrays representing human genes involved in the inflammatory and fibrogenic reactions to profile visceral adipose samples of 15 well-matched NASH patients with and without fibrosis. Additionally, visceral adipose samples were subjected to real-time polymerase chain reaction profiling of 84 inflammations related genes., Results: Eight genes (CCL2, CCL4, CCL18, CCR1, IL10RB, IL15RA, and LTB) were differentially expressed in NASH with fibrosis. Additionally, an overlapping but distinct list of the differentially expressed genes were found in NASH with type II diabetes (DM; IL8, BLR1, IL2RA, CD40LG, IL1RN, IL15RA, and CCL4) as compared to NASH without DM., Conclusions: Inflammatory cytokines are differentially expressed in the adipose tissue of NASH with fibrosis, as well in NASH with DM. These findings point at the interaction of adipose inflammatory cytokines, DM, hepatic fibrosis in NASH, and its progression to cirrhosis and end-stage liver disease.

According to the standards developed by the Joint Commission on the Accreditation of Hospitals, all adverse drug reactions should be reported following written procedures. An Adverse Drug Reaction Reporting Program is conducted by the Department of Pharmacy Services under the direction of the Pharmacy and Therapeutics Committee. However, many of the adverse drug reactions that occur go unreported. The purpose of the study was to determine whether patients can be screened for particular adverse drug reactions by reviewing the charts of patients having medication orders for diphenhydramine. While 48% of the patients included in the study had received diphenhydramine for treatment of an allergic reaction to a medication, none of the cases involving these reactions were reported according to the written procedures governing the Adverse Drug Reaction Reporting Program. The results of the study indicate that by auditing the prescribing of certain medications one can identify patients having complications due to their drug therapy. A more comprehensive study program could be developed which would screen for many types of adverse drug reactions and audit all of the drugs used to treat these drug-induced illnesses.