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BACKGROUND: A prophylactic vaccine for hepatitis C virus (HCV) requires generation of strong humoral as well as CD4(+) and CD8(+) T cell responses. METHODS: The immunomodulatory effects of the combination of 2 adjuvants, synthetic oligodeoxynucleotides containing immunostimulatory cytosine-guanine dinucleotide motifs emulsified with Montanide ISA720 (M-ISA720/CpG), were investigated using the murine model. RESULTS: Administration of recombinant HCV (rHCV) nonstructural (NS) 3 and NS5B proteins plus M-ISA720/CpG (hereafter, 'M-ISA720/CpG/rHCV protein') induced high anti-NS3 and anti-NS5B immunoglobulin (Ig) G titers, with the IgG2a isotype being predominant. NS3- and NS5B-specific interferon (IFN)- gamma - and interleukin-2-producing CD4(+) T cell responses, as assessed by enzyme-linked immunospot assay, were significantly more vigorous in mice immunized with M-ISA720/CpG/rHCV protein than in control mice immunized without adjuvant. NS3- and NS5B-specific IFN- gamma -producing CD8(+) T cell percentages, as measured by direct ex vivo intracellular cytokine staining assay, were, respectively, a mean+/-SD of 0.14% +/- 0.04% and 0.15% +/- 0.05% in mice immunized with M-ISA720/CpG/rHCV protein. Furthermore, boosting with recombinant NS3 expression plasmid DNA after priming with M-ISA720/CpG-adjuvanted rNS3 strikingly enhanced both CD4(+) and CD8(+) T cell responses. CONCLUSION: Immunization with M-ISA720/CpG/rHCV protein is capable of inducing potent humoral as well as HCV-specific T helper type 1-biased CD4(+) and CD8(+) T cell responses. A DNA boost after a protein prime--a reversal of the conventional approach--may provide an alternative path to the development of an effective HCV vaccine. Copyright © 2006 Infectious Diseases Society of America [ABSTRACT FROM AUTHOR]

Competing Interests: Competing interests: T.M.B. is co-founder and Chair of the Hepatitis B Foundation and is on the board of Hepion, Harlingene Life Sciences, Cirna Diagnostics and SAB: Excision. C.A.C. is President of the Hepatitis B Foundation, which has received grants from Gilead Sciences, GSK, Roche, Dynavax and Moderna, all outside of the submitted work. J.J.F. declares competing interests with Abbott, Abbvie, Bluejay, Gilead, GSK, Pfizer, Roche and Vir. R.G.G. is the Medical Director at the Hepatitis B Foundation, and has consulted for or received honoraria from Abacus, Aligos, Altimunne, Antios, Dynavax, Enyo, Gilead Sciences, GlaxoSmithKline, Janssen, Precision BioSciences, Tune Therapeutics, Venatorx and Virion. J.-T.G. is co-founder of RimmSting Life Sciences, is a member of the scientific advisory board for GeneLancet Biosciences, and is a scientific consultant for Brii BioSciences, Argo Pharmaceuticals and ARV Technologies. I.M.J. has acted as a consultant or advisor for Aligos Therapeutics, Altimmune, Arbutus Biopharma, Arrowhead Pharmaceuticals, Assembly Biosciences, Biomarin Pharmaceuticals, Bristol Myers Squibb, Gilead Sciences, GSK, Intercept Pharmaceuticals, Janssen Pharmaceuticals, Madrigal Pharmaceuticals, Merck, Moderna, NeuroBo Pharmaceuticals, Novo Nordisk, Precision Biosciences and RedHill Biopharma, and has received grants or research support from Astrazeneca, Assembly Biosciences, AusperBio, Bristol Myers Squibb, Cymabay Therapeutics, Eiger Biopharmaceuticals, Eli Lilly, Enanta Pharmaceuticals, Genfit, Genkyotex, Gilead, GSK, Inventiva, Intercept Pharmaceuticals, Ipsen, Janssen Pharmaceuticals, Madrigal, Merck, Mirum Pharmaceuticals, Novo Nordisk and the Rockefeller Institute (NIH supported). M.S. has received grants from Grifols, GSK, Vir and the National Institutes of Health, and has received personal fees from AbbVie, Aligos, Immunocore, Gilead Sciences, GSK, Pfizer, Virion and Vir. F.Z. consults for Aligos, Antios, Arbutus, Assembly, Enanta, Enochian, Gilead, GSK, Roche, Viravaxx and Zhimeng, and has received research grants from Assembly, Beam, Janssen and Viravaxx. H.J.A., P.D.B., C.M.R., W.M.S. and C.LT. declare no competing interests.

Hepatitis C virus (HCV) is predominantly transmitted through parenteral exposures to infectious blood or body fluids. In 2019, approximately 58 million people worldwide were infected with HCV, and 290,000 deaths occurred due to hepatitis C-related conditions, despite hepatitis C being curable. There are substantial barriers to elimination, including the lack of widespread point-of-care diagnostics, cost of treatment, stigma associated with hepatitis C, and challenges in reaching marginalized populations, such as people who inject drugs. The World Health Organization (WHO) has set goals to eliminate hepatitis C by 2030. Several countries, including Australia, Egypt, Georgia, and Rwanda, have made remarkable progress toward hepatitis C elimination. In the United States, the Biden-Harris administration recently issued a plan for the national elimination of hepatitis C. Global progress has been uneven, however, and will need to accelerate considerably to reach the WHO's 2030 goals. Nevertheless, the global elimination of hepatitis C is within reach and should remain a high public health priority.

Introduction: Patients in emergency departments (EDs) constitute a diverse population with multiple health-related risk factors, many of which are associated with intimate partner violence (IPV). This paper examines the interaction effect of depression, posttraumatic stress disorder (PTSD), impulsivity, drug use, adverse childhood experiences (ACEs), at-risk drinking, and having a hazardous drinker partner with gender on mutual physical IPV in an urban ED sample., Methods: Research assistants surveyed 1037 married, cohabiting, or partnered patients in face-to-face interviews (87% response rate) regarding IPV exposure, alcohol and drug use, psychological distress, ACEs, and other sociodemographic features. IPV was measured with the Revised Conflict Tactics Scale. Interaction effects were examined in multinomial and logistic models., Results: Results showed a significant interaction of gender and PTSD (odds ratio [OR] 3.06, 95% CI 1.21-7.23, p < 0.05) for mutual IPV. Regarding main effects, there were also statistically significant positive associations between mutual physical IPV and at-risk drinking (OR 1.73, 95% CI 1.07-2.77, p < 0.05), having a hazardous drinker partner (OR 2.19, 95% CI 1.35-3.55, p < 0.01), illicit drug use (OR 2.09, 95% CI 1.18-3.71, p < 0.01), ACEs (OR 1.23, 95% CI 1.06-1.42, p < 0.01), days of cannabis use past in the 12 months (OR 1.003, 95% CI 1.002-1.005, p < 0.001), and impulsivity (OR 2.04, 95% CI 1.29-3.22, p < 0.01)., Conclusions: IPV risk assessment in EDs will be more effective if implemented with attention to patients' gender and the presence of various and diverse other risk factors, especially PTSD., (© 2023 Society for Academic Emergency Medicine.)

Liver steatosis, inflammation, and variable degrees of fibrosis are the pathological manifestations of nonalcoholic steatohepatitis (NASH), an aggressive presentation of the most prevalent chronic liver disease in the Western world known as nonalcoholic fatty liver (NAFL). Mitochondrial hepatocyte dysfunction is a primary event that triggers inflammation, affecting Kupffer and hepatic stellate cell behaviour. Here, we consider the role of impaired mitochondrial function caused by lipotoxicity during oxidative stress in hepatocytes. Dysfunction in oxidative phosphorylation and mitochondrial ROS production cause the release of damage-associated molecular patterns from dying hepatocytes, leading to activation of innate immunity and trans-differentiation of hepatic stellate cells, thereby driving fibrosis in NASH., (© 2023. The Author(s).)

Chronic HCV infection remains a global health concern due to its involvement in hepatic and extrahepatic diseases, including B cell non-Hodgkin lymphoma (BNHL). Clinical and epidemiological evidence support a causal role for HCV in BNHL development, although mechanistic insight is lacking. We performed RNA-sequencing on peripheral B cells from patients with HCV alone, BNHL alone, and HCV-associated BNHL to identify unique and shared transcriptional profiles associated with transformation. In patients with HCV-associated BNHL, we observed the enrichment of an anergic-like gene signature and evidence of clonal expansion that was correlated with the expression of epigenetic regulatory genes. Our data support a role for viral-mediated clonal expansion of anergic-like B cells in HCV-associated BNHL development and suggest epigenetic dysregulation as a potential mechanism driving expansion. We propose epigenetic mechanisms may be involved in both HCV-associated lymphoma and regulation of B cell anergy, representing an attractive target for clinical interventions., Competing Interests: RB is currently an employee and shareholder of 10X Genomics, and HZ is currently an employee of BioNTech. The views expressed are the authors’ own and do not represent the National Institutes of Health, the Department of Health and Human Services, or the U.S. Federal government.

Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis worldwide. An increased risk for HEV infection has been reported in organ-transplant recipients, mainly from Europe. Prospective data on HEV prevalence in the United States (U.S.) organ transplant population are limited. To determine the prevalence and factors associated with HEV infection among solid organ transplant-recipients, we conducted a prospective, cross-sectional, multicentre study among transplant-recipients and age- and organ-matched waitlist patients. Participants answered a risk-exposure questionnaire and were tested for HEV-RNA (in-house PCR), HEV-IgG, and IgM (ELISA, Wantai). Among 456 participants, 224 were transplant-recipients, and 232 were waitlist patients. The mean age was 58 years, 35% female, and 74% White. HEV seroprevalence of the entire cohort was 20.2% and associated with older age (p < 0.0001) and organ transplantation (p = 0.02). The HEV seropositivity was significantly higher among transplant-recipients compared with waitlist patients (24% vs. 16.4%, p = 0.042). Among transplant recipients, relative-risk of being HEV seropositive increased with older age (RR = 3.4 [1.07-10.74] in patients >70 years compared with ≤50 years, p = 0.037); history of graft hepatitis (2.2 [1.27-3.72], p = 0.005); calcineurin inhibitor use (RR = 1.9 [1.03-3.34], p = 0.02); and kidney transplantation (2.4 [1.15-5.16], p = 0.02). HEV-RNA, genotype 3 was detected in only two patients (0.4%), both transplant-recipients. HEV seroprevalence was higher among transplant-recipients than waitlist patients. HEV should be considered in transplant-recipients presenting with graft hepatitis. Detection of HEV-RNA was rare, suggesting that progression to chronic HEV infection is uncommon in transplant-recipients in the U.S., (© 2022 John Wiley & Sons Ltd. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

The emergence and global spread of the SARS-CoV-2 Omicron variants, which carry an unprecedented number of mutations, raise serious concerns due to the reduced efficacy of current vaccines and resistance to therapeutic antibodies. Here, we report the generation and characterization of two potent human monoclonal antibodies, NA8 and NE12, against the receptor-binding domain of the SARS-CoV-2 spike protein. NA8 interacts with a highly conserved region and has a breadth of neutralization with picomolar potency against the Beta variant and the Omicron BA.1 and BA.2 sublineages and nanomolar potency against BA.2.12.1 and BA.4. Combination of NA8 and NE12 retains potent neutralizing activity against the major SARS-CoV-2 variants of concern. Cryo-EM analysis provides the structural basis for the broad and complementary neutralizing activity of these two antibodies. We confirm the in vivo protective and therapeutic efficacies of NA8 and NE12 in the hamster model. These results show that broad and potent human antibodies can overcome the continuous immune escape of evolving SARS-CoV-2 variants., Competing Interests: Declaration of interests Z.C., P.F., K.W., P.Z., P.L., U.J.B., and Y.M. are named on an unpublished patent application filed by the National Institutes of Health related to the work described herein., (Copyright © 2022. Published by Elsevier Inc.)

Introduction: Urban ED patients have elevated rates of substance use and intimate partner violence. The purpose of this study is to describe the risk profiles for intimate partner violence among urban ED patients who report at-risk alcohol use only, cannabis use only, or both types of substance use., Methods: Cross-sectional survey data were collected from study participants (N = 1037; 53% female; ages 18-50) following informed consent. We measured participants' past-year at-risk drinking (women/men who had 4+/5+ drinks in a day), cannabis use, psychosocial and demographic characteristics, and past-year physical intimate partner violence (assessed with the Revised Conflict Tactics Scale). We used bivariate analysis to assess whether rates of intimate partner violence perpetration and victimization differed by type of substance use behavior. Multivariate logistic regression models were estimated for each intimate partner violence outcome. All analyses were stratified by gender., Results: Rates of intimate partner violence differed significantly by type of substance use behavior and were highest among those who reported both at-risk drinking and cannabis use. Multivariate analysis showed that women who reported at-risk drinking only, cannabis use only, or both types of substance use had increased odds for intimate partner violence perpetration and victimization compared with women who reported neither type of substance use. Men's at-risk drinking and cannabis use were not associated with elevated odds of intimate partner violence perpetration or victimization., Discussion: Brief screening of patients' at-risk drinking and cannabis use behaviors may help identify those at greater risk for intimate partner violence and those in need of referral to treatment., (Copyright © 2022 Emergency Nurses Association. Published by Elsevier Inc. All rights reserved.)

Hepatitis C virus (HCV) infection is the most common blood-borne chronic infection in the United States. Chronic lymphocytic sialadenitis and sicca syndrome have been reported in chronic HCV infection. Up to 55% of these patients may have xerostomia; the mechanisms of the xerostomia and salivary gland (SG) hypofunction remain controversial. The objectives of this project are to establish if xerostomia associates with SG and HCV infection and to characterize the structural changes in SG and saliva composition. Eighteen HCV-infected patients with xerostomia were evaluated for SG dysfunction; 6 of these patients (patients 1-6) were further evaluated for SG histopathological changes and changes in saliva composition. The techniques used include clinical and laboratory assessment, SG ultrasonography, histological evaluation, sialochemical and proteomics analysis, and RNA in situ hybridization. All the HCV patients had low saliva flow, chronic sialadenitis, and SG fibrosis and lacked Sjögren syndrome (SS) characteristic autoantibodies. Further evaluation of a subgroup of 6 HCV patients (patients 1-6) demonstrated diffuse lymphocytic infiltrates that are predominantly CD8 + T cells with a significant increase in the number of inflammatory cells. Alcian Blue/periodic acid-Schiff staining showed significant changes in the ratio and intensity of the acinar secretory units of the HCV patients' minor SG. The submandibular glands showed significant ultrasonographic abnormalities in the parenchyma relative to the parotid glands. Significant changes were also observed in the concentration of sodium and mucin 5b. Although no significant correlation was observed between the lymphocytic infiltrates and the years of HCV chronic infection, a positive correlation was observed between HCV RNA-positive epithelial cells and the years of HCV infection. Consistent with the low saliva flow and xerostomia, patients showed changes in several markers of SG acinar and ductal function. Changes in the composition of the saliva suggest that HCV infection can cause xerostomia by mechanisms distinct from SS.

The ongoing coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has triggered a devastating global health, social and economic crisis. The RNA nature and broad circulation of this virus facilitate the accumulation of mutations, leading to the continuous emergence of variants of concern with increased transmissibility or pathogenicity 1 . This poses a major challenge to the effectiveness of current vaccines and therapeutic antibodies 1, 2 . Thus, there is an urgent need for effective therapeutic and preventive measures with a broad spectrum of action, especially against variants with an unparalleled number of mutations such as the recently emerged Omicron variant, which is rapidly spreading across the globe 3 . Here, we used combinatorial antibody phage-display libraries from convalescent COVID-19 patients to generate monoclonal antibodies against the receptor-binding domain of the SARS-CoV-2 spike protein with ultrapotent neutralizing activity. One such antibody, NE12, neutralizes an early isolate, the WA-1 strain, as well as the Alpha and Delta variants with half-maximal inhibitory concentrations at picomolar level. A second antibody, NA8, has an unusual breadth of neutralization, with picomolar activity against both the Beta and Omicron variants. The prophylactic and therapeutic efficacy of NE12 and NA8 was confirmed in preclinical studies in the golden Syrian hamster model. Analysis by cryo-EM illustrated the structural basis for the neutralization properties of NE12 and NA8. Potent and broadly neutralizing antibodies against conserved regions of the SARS-CoV-2 spike protein may play a key role against future variants of concern that evade immune control.

We analyzed the interrelationships of economic stressors, mental health problems, substance use, and intimate partner violence (IPV) among a sample of Hispanic emergency department patients and probed if Spanish language preference, which may represent low acculturation and/or immigrant status, had a protective effect, in accordance with the Hispanic health paradox. Study participants ( n = 520; 50% female; 71% Spanish speakers) provided cross-sectional survey data. Gender-stratified logistic regression models were estimated for mental health problems (PTSD, anxiety, depression), substance use (risky drinking, cannabis, illicit drug use), and IPV. Results showed that economic stressors were linked with mental health problems among men and women. Among men, PTSD was associated with greater odds of cannabis and illicit drug use. Men who used cannabis and illicit drugs were more likely to report IPV. Male Spanish speakers had lower odds of anxiety and cannabis use than English speakers. Female Spanish speakers had lower odds of substance use and IPV than English speakers. The protective effect of Spanish language preference on some mental health, substance use, and IPV outcomes was more pronounced among women. Future research should identify the mechanisms that underlie the protective effect of Spanish language preference and explore factors that contribute to the observed gender differences.

Background: Characterizing the kinetics of the antibody response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is of critical importance to developing strategies that may mitigate the public health burden of coronavirus disease 2019 (COVID-19). We conducted a prospective, longitudinal analysis of COVID-19 convalescent plasma donors at multiple time points over an 11-month period to determine how circulating antibody levels change over time following natural infection., Methods: From April 2020 to February 2021, we enrolled 228 donors. At each study visit, subjects either donated plasma or had study samples drawn only. Anti-SARS-CoV-2 donor testing was performed using the VITROS Anti-SARS-CoV-2 Total and IgG assays and an in-house fluorescence reduction neutralization assay., Results: Anti-SARS-CoV-2 antibodies were identified in 97% of COVID-19 convalescent donors at initial presentation. In follow-up analyses, of 116 donors presenting at repeat time points, 91.4% had detectable IgG levels up to 11 months after symptom recovery, while 63% had detectable neutralizing titers; however, 25% of donors had neutralizing levels that dropped to an undetectable titer over time., Conclusions: Our data suggest that immunological memory is acquired in most individuals infected with SARS-CoV-2 and is sustained in a majority of patients for up to 11 months after recovery. Clinical Trials Registration. NCT04360278., (Published by Oxford University Press for the Infectious Diseases Society of America 2021.)

Epitope III, a highly conserved amino acid motif of 524 APTYSW 529 on the hepatitis C virus (HCV) E2 glycoprotein, resides in the critical loop that binds to the host receptor CD81, thus making it one of the most important antibody targets for blocking HCV infections. Here, we have determined the X-ray crystal structure of epitope III at a 2.0-Å resolution when it was captured by a site-specific neutralizing antibody, monoclonal antibody 1H8 (mAb1H8). The snapshot of this complex revealed that epitope III has a relatively rigid structure when confined in the binding grooves of mAb1H8, which confers the residue specificity at both ends of the epitope. Such a high shape complementarity is reminiscent of the "lock and key" mode of action, which is reinforced by the incompatibility of an antibody binding with an epitope bearing specific mutations. By subtly positioning the side chains on the three residues of Tyr 527 , Ser 528 , and Trp 529 while preserving the spatial rigidity of the rest, epitope III in this cocrystal complex adopts a unique conformation that is different from previously described E2 structures. With further analyses of molecular docking and phage display-based peptide interactions, we recognized that it is the arrangements of two separate sets of residues within epitope III that create these discrete conformations for the epitope to interact selectively with either mAb1H8 or CD81. These observations thus raise the possibility that local epitope III conformational dynamics, in conjunction with sequence variations, may act as a regulatory mechanism to coordinate "mAb1H8-like" antibody-mediated immune defenses with CD81-initiated HCV infections., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)