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Background & Aims: Patients with vascular liver diseases (VLD) are at higher risk of both severe courses of COVID-19 disease and thromboembolic events. The impact of SARS-CoV-2 vaccination in patients with VLD has not been described and represents the aim of our study. Methods: International, multicenter, prospective observational study in patients with VLD analyzing the incidence of COVID-19 infection after vaccination, severity of side effects, occurrence of thromboembolic events and hepatic decompensation. In a subgroup of patients, the humoral and cellular responses to vaccination were also analyzed. Results: A total of 898 patients from 14 European centers – part of the VALDIG network – were included, 872 (97.1%) patients received two vaccine doses (fully vaccinated), and 674 (75.1%) three doses. Of the total cohort, 151/898 had a COVID-19 infection prior to vaccination, of whom 9/151 (5.9%) were re-infected. Of the 747/898 patients who were not previously infected, 11.2% (84/747) were diagnosed with a COVID-19 infection during the study period. Two infected patients required intensive care unit admission and infection was fatal in two fully vaccinated patients. Adverse effects were reported in around 40% of patients, with local side effects being the most frequent. During the study period, 31 (3.5%) patients had thromboembolic events and 21 (2.3%) hepatic decompensations. No cases of vaccine-induced thrombocytopenia were reported. Vaccine immunogenicity was assessed in 36 patients; seroconversion reached 100% and IFNy T-cell responses significantly increased post two mRNA-1273 vaccine doses. Conclusion: Patients with VLD seem to have a preserved immune response to SARS-CoV-2 vaccination, which appears to be safe and effective in preventing severe COVID-19 infection. Our study cannot definitively establish a direct link between vaccination and thrombotic events, though the contribution of vaccination as a cofactor in VLD remains to be elucidated. Impact and implications:: Patients with vascular liver disease (VLD) are at increased risk of both SARS-CoV-2 infection and severe COVID-19 disease. The potential risks associated with vaccination against this infection need thorough investigation. Our research enhances the understanding of the effects of COVID-19 vaccination in patients with VLD, highlighting its good tolerability. Moreover, patients with VLD appear to have a preserved immune response to SARS-CoV-2 vaccination, providing protection against severe COVID-19 infection. Our study cannot definitively establish a direct link between vaccination and thrombotic events, and no cases of vaccine-induced thrombocytopenia were reported.

Abstract The rapid development of safe and effective vaccines helped to prevent severe disease courses after SARS-CoV-2 infection and to mitigate the progression of the COVID-19 pandemic. While there is evidence that vaccination may reduce the risk of developing post-COVID-19 conditions (PCC), this effect may depend on the viral variant. Therapeutic effects of post-infection vaccination have been discussed but the data for individuals with PCC remains inconclusive. In addition, extremely rare side effects after SARS-CoV-2 vaccination may resemble the heterogeneous PCC phenotype. Here, we analyze the plasma levels of 25 cytokines and SARS-CoV-2 directed antibodies in 540 individuals with or without PCC relative to one or two mRNA-based COVID-19 vaccinations as well as in 20 uninfected individuals one month after their initial mRNA-based COVID-19 vaccination. While none of the SARS-CoV-2 naïve individuals reported any persisting sequelae or exhibited PCC-like dysregulation of plasma cytokines, we detected lower levels of IL-1β and IL-18 in patients with ongoing PCC who received one or two vaccinations at a median of six months after infection as compared to unvaccinated PCC patients. This reduction correlated with less frequent reporting of persisting gastrointestinal symptoms. These data suggest that post-infection vaccination in patients with PCC might be beneficial in a subgroup of individuals displaying gastrointestinal symptoms.

GaAs-based photocathodes are the only viable source capable of providing spin-polarized electrons for accelerator applications. This type of photocathode requires a thin surface layer, in order to achieve negative electron affinity (NEA) for efficient photoemission. However, this layer is vulnerable to environmental and operational effects, leading to a decay of the quantum efficiency η characterized by a decay constant or lifetime τ. In order to increase τ, additional agents can be introduced during the activation procedure to improve the chemical robustness of the surface layer. This paper presents the results of recent research on Li as an enhancement agent for photocathode activation using Cs and O_{2}, forming Cs-O_{2}-Li as an enhanced NEA layer. Measurements yielded an increase in lifetime by a factor of up to 19±2 and an increase in extracted charge by a factor of up to 16.5±2.4, without significant reduction of η. This performance is equal to or better than that reported for other enhanced NEA layers so far.

Background/Objectives: The efficacy of monovalent BNT162b2 Omicron XBB.1.5 booster vaccination in liver transplant recipients (LTRs) has yet to be described, particularly regarding the immune response to emerging variants like JN.1. Methods: This study evaluated humoral and cellular immune responses in 34 liver transplant recipients (LTRs) with varying SARS-CoV-2 immune histories before and after receiving a BNT162b2 Omicron XBB.1.5 booster vaccination. The assessment involved variant-specific serology, pseudovirus neutralization tests, and Interferon-γ release assays. Results: Participants had a median of four prior vaccinations, with 91.2% having a history of infection. Post-vaccination, significant increases in both Wuhan anti-S and Omicron-specific IgG antibodies and improved neutralization of B.1, XBB.1.5, and JN.1 pseudovirus particles were observed. Also, T-cell responses significantly increased post-vaccination. However, 17.6% of LTRs had no neutralizing antibodies against XBB.1.5 and JN.1, while 100% of healthy controls did. Shortly after vaccination, 18% of patients developed mild COVID-19. These LTRs had particularly low immune responses at baseline. Conclusions: The monovalent XBB.1.5 booster improved overall SARS-CoV-2-specific immunity. However, some LTRs still showed low or undetectable immune responses, indicating that ongoing monitoring and further booster doses are necessary in this high-risk group.

Background: Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, the roll-out of vaccines and therapeutic agents, as well as the emergence of novel SARS-CoV-2 variants, have shown significant effects on disease severity. Methods: Patients hospitalized at our center between January 2020 and April 2022 were attributed to subgroups depending on which SARS-CoV-2 variant was predominantly circulating in Germany: (i) Wild-type: January 1, 2020, to March 7, 2021, (ii) Alpha variant: August 3, 2021, to June 27, 2021, (iii) Delta variant: June 28, 2021, to December 26, 2021, and (iv) Omicron variant: December 27, 2021, to April 30, 2022. Results: Between January 2020 and April 2022, 1500 patients with SARS-CoV-2 infections were admitted to the University Medical Center Hamburg-Eppendorf. The rate of patients who were admitted to the intensive care unit (ICU) decreased from 31.2% (n = 223) in the wild-type group, 28.5% (n = 72) in the Alpha variant group, 18.8% (n = 67) in the Delta variant group, and 13.4% (n = 135) in the Omicron variant group. Also, in-hospital mortality decreased from 20.6% (n = 111) in the wild-type group, 17.5% (n = 30) in the Alpha variant group, 16.8% (n = 33) in the Delta variant group, and 6.6% (n = 39) in the Omicron variant group. The median duration of hospitalization was similar in all subgroups and ranged between 11 and 15 days throughout the pandemic. Conclusions: In-hospital mortality and rate of ICU admission among hospitalized COVID-19 patients steadily decreased throughout the pandemic. However, the practically unchanged duration of hospitalization demonstrates the persistent burden of COVID-19 on the healthcare system.

Not available.

Abstract Background Unpredictable vegetative deteriorations made the treatment of patients with acute COVID-19 on intensive care unit particularly challenging during the first waves of the pandemic. Clinical correlates of dysautonomia and their impact on the disease course in critically ill COVID-19 patients are unknown. Methods We retrospectively analyzed data collected during a single-center observational study (March 2020–November 2021) which was performed at the University Medical Center Hamburg-Eppendorf, a large tertiary medical center in Germany. All patients admitted to ICU due to acute COVID-19 disease during the study period were included (n = 361). Heart rate variability (HRV) and blood pressure variability (BPV) per day were used as clinical surrogates of dysautonomia and compared between survivors and non-survivors at different time points after admission. Intraindividual correlation of vital signs with laboratory parameters were calculated and corrected for age, sex and disease severity. Results Patients who deceased in ICU had a longer stay (median days ± IQR, survivors 11.0 ± 27.3, non-survivors 14.1 ± 18.7, P = 0.85), in contrast time spent under invasive ventilation was not significantly different (median hours ± IQR, survivors 322 ± 782, non-survivors 286 ± 434, P = 0.29). Reduced HRV and BPV predicted lethal outcome in patients staying on ICU longer than 10 days after adjustment for age, sex, and disease severity. Accordingly, HRV was significantly less correlated with inflammatory markers (e.g. CRP and Procalcitonin) and blood carbon dioxide in non-survivors in comparison to survivors indicating uncoupling between autonomic function and inflammation in non-survivors. Conclusions Our study suggests autonomic dysfunction as a contributor to mortality in critically ill COVID-19 patients during the first waves of the pandemic. Serving as a surrogate for disease progression, these findings could contribute to the clinical management of COVID-19 patients admitted to the ICU. Furthermore, the suggested measure of dysautonomia and correlation with other laboratory parameters is non-invasive, simple, and cost-effective and should be evaluated as an additional outcome parameter in septic patients treated in the ICU in the future.

Background: While the sexual transmissibility of HAV in MSM has been extensively described, the potential for sexual transmission of HEV has not been definitively established. Although HEV has been detected in the ejaculate of chronically infected men, studies among MSM PrEP users in France did not observe an elevated anti-HEV seroprevalence as an indicator of increased exposure risk by sexual intercourse. Patients and methods: A total of 111 unselected PrEP users and 111 age- and sex-matched blood donors were tested for anti-HEV IgG, IgM and HEV (PCR). Of the participants 79/111 (71 %) responded to a questionnaire covering topics as sexual preferences, previous sexually transmitted diseases, profession, food consumption, and pet ownership. Results: The anti-HEV IgG seroprevalence in PrEP users (22 %) did not differ significantly from the rate in controls (17 %). While one PrEP user and three controls tested positive for anti-HEV IgM, all PrEP users and controls tested PCR negative. Conclusion: In immunocompetent individuals with frequent changes of sexual partners, the epidemiology of Hepatitis E Virus does not significantly involve the sexual transmission route.

IntroductionTumor-associated macrophages (TAMs) represent an important cell population within the tumor microenvironment, but little is known about the phenotype and function of these cells. The present study aims to characterize macrophages in high-grade serous ovarian cancer (HGSOC).MethodsPhenotype and expression of co-regulatory markers were assessed on TAMs derived from malignant ascites (MA) or peripheral blood (PB) by multiparametric flow cytometry. Samples were obtained from HGSOC patients (n=29) and healthy donors (HDs, n=16). Additional expression analysis was performed by RNAseq (n=192). Correlation with clinically relevant parameters was conducted and validated by a second patient cohort (n=517). Finally, the role of TIGIT in repolarization and phagocytosis was investigated in vitro.ResultsExpression of the M2-associated receptors CD163, CD204, and CD206, as well as of the co-regulatory receptors TIGIT, CD226, TIM-3, and LAG-3 was significantly more frequent on macrophages in HGSOC than in HDs. CD39 and CD73 were broadly expressed on (mainly M2) macrophages, but without a clear clustering in HGSOC. CD163 mRNA levels were higher in TAMs from patients with residual tumor mass after surgery and associated with a shorter overall survival. In addition, TIGIT expression was associated with a higher tumor grading, indicating a prognostic relevance of M2 infiltration in HGSOC. TIGIT blockade significantly reduced the frequency of M2 macrophages. Moreover, combined blockade of TIGIT and CD47 significantly increased phagocytosis of ovarian cancer cells by TAMs in comparison to a single blockade of CD47.ConclusionCombined blockade of TIGIT and CD47 represents a promising approach to enhance anti-CD47-facilitated phagocytosis.

Infections with hepatotropic viruses are associated with various immune phenomena. Hepatitis D virus (HDV) causes the most severe form of viral hepatitis. However, few recent data are available on non-disease-specific and non-organ-specific antibody (NOSA) titers and immunoglobulin G (IgG) levels in chronic hepatitis D (CHD) patients. Here, we examined the NOSA titers and IgG levels of 40 patients with CHD and different disease courses and compared them to 70 patients with chronic hepatitis B (CHB) infection. 43% of CHD patients had previously undergone treatment with pegylated interferon-α (IFN-α). The antibody display of 46 untreated patients diagnosed with autoimmune hepatitis (AIH) was used as a reference. The frequency of elevated NOSA titers (CHD 69% vs. CHB 43%, p

IntroductionThe nonstructural protein 12 (NSP12) of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) has a high sequence identity with common cold coronaviruses (CCC).MethodsHere, we comprehensively assessed the breadth and specificity of the NSP12-specific T-cell response after in vitro T-cell expansion with 185 overlapping 15-mer peptides covering the entire SARS-CoV-2 NSP12 at single-peptide resolution in a cohort of 27 coronavirus disease 2019 (COVID-19) patients. Samples of nine uninfected seronegative individuals, as well as five pre-pandemic controls, were also examined to assess potential cross-reactivity with CCCs.ResultsSurprisingly, there was a comparable breadth of individual NSP12 peptide-specific CD4+ T-cell responses between COVID-19 patients (mean: 12.82 responses; range: 0–25) and seronegative controls including pre-pandemic samples (mean: 12.71 responses; range: 0–21). However, the NSP12-specific T-cell responses detected in acute COVID-19 patients were on average of a higher magnitude. The most frequently detected CD4+ T-cell peptide specificities in COVID-19 patients were aa236–250 (37%) and aa246–260 (44%), whereas the peptide specificities aa686–700 (50%) and aa741–755 (36%), were the most frequently detected in seronegative controls. In CCC-specific peptide-expanded T-cell cultures of seronegative individuals, the corresponding SARS-CoV-2 NSP12 peptide specificities also elicited responses in vitro. However, the NSP12 peptide-specific CD4+ T-cell response repertoire only partially overlapped in patients analyzed longitudinally before and after a SARS-CoV-2 infection.DiscussionThe results of the current study indicate the presence of pre-primed, cross-reactive CCC-specific T-cell responses targeting conserved regions of SARS-CoV-2, but they also underline the complexity of the analysis and the limited understanding of the role of the SARS-CoV-2 specific T-cell response and cross-reactivity with the CCCs.

Background & Aims: Bulevirtide is a first-in-class entry inhibitor of hepatitis B surface antigen. In July 2020, bulevirtide was conditionally approved for the treatment of hepatitis D, the most severe form of viral hepatitis, which frequently causes end-stage liver disease and hepatocellular carcinoma. Herein, we report the first data from a large multicenter real-world cohort of patients with hepatitis D treated with bulevirtide at a daily dose of 2 mg without additional interferon. Methods: In a joint effort with 16 hepatological centers, we collected anonymized retrospective data from patients treated with bulevirtide for chronic hepatitis D. Results: Our analysis is based on data from 114 patients, including 59 (52%) with cirrhosis, receiving a total of 4,289 weeks of bulevirtide treatment. A virologic response defined as an HDV RNA decline of at least 2 log or undetectable HDV RNA was observed in 87/114 (76%) cases with a mean time to virologic response of 23 weeks. In 11 cases, a virologic breakthrough (>1 log-increase in HDV RNA after virologic response) was observed. After 24 weeks of treatment, 19/33 patients (58%) had a virologic response, while three patients (9%) did not achieve a 1 log HDV RNA decline. No patient lost hepatitis B surface antigen. Alanine aminotransferase levels improved even in patients not achieving a virologic response, including five patients who had decompensated cirrhosis at the start of treatment. Treatment was well tolerated and there were no reports of drug-related serious adverse events. Conclusions: In conclusion, we confirm the safety and efficacy of bulevirtide monotherapy in a large real-world cohort of patients with hepatitis D treated in Germany. Future studies need to explore the long-term benefits and optimal duration of bulevirtide treatment. Impact and implications: Clinical trials proved the efficacy of bulevirtide for chronic hepatitis D and led to conditional approval by the European Medical Agency. Now it is of great interest to investigate the effects of bulevirtide treatment in a real-world setting. In this work, we included data from 114 patients with chronic hepatitis D who were treated with bulevirtide at 16 German centers. A virologic response was seen in 87/114 cases. After 24 weeks of treatment, only a small proportion of patients did not respond to treatment. At the same time, signs of liver inflammation improved. This observation was independent from changes in hepatitis D viral load. The treatment was generally well tolerated. In the future, it will be of interest to investigate the long-term effects of this new treatment.

Background & Aims: EASL guidelines recommend 8 weeks of treatment with sofosbuvir plus velpatasvir (SOF/VEL) for the treatment of acute or recently acquired HCV infection, but only 6- and 12-week data are available. Therefore, the aim of this study was to evaluate the safety and efficacy of a shortened 8-week SOF/VEL treatment for acute HCV monoinfection. Methods: In this investigator-initiated, prospective, multicentre, single-arm study, we recruited 20 adult patients with acute HCV monoinfection from nine centers in Germany. Patients received SOF/VEL (400/100 mg) as a fixed-dose combination tablet once daily for 8 weeks. The primary efficacy endpoint was the proportion of patients with sustained virological response 12 weeks after the end of treatment (SVR12). Results: The median HCV RNA viral load at baseline was 104,307 IU/ml; the distribution of HCV genotypes was as follows: GT1a/1b/2/3/4: n = 12/1/1/3/3. Thirteen (65%) of the 20 patients were taking medication for HIV pre-exposure prophylaxis. SVR12 was achieved in all patients who complied with the study protocol (n = 18/18 [100%], per protocol analysis), but the primary endpoint was not met in the intention-to-treat analysis (n = 18/20 [90%]) because two patients were lost to follow-up. One serious adverse event (unrelated to study drug) occurred during 12 weeks of post-treatment follow-up. Conclusions: The 8-week treatment with SOF/VEL was well tolerated and highly effective in all adherent patients with acute HCV monoinfection. Early treatment of hepatitis C might effectively prevent the spread of HCV in high-risk groups. Clinical Trial Number: NCT03818308. Impact and implications: The HepNet acute HCV-V study (NCT03818308), an investigator-initiated, single-arm, multicenter pilot study, demonstrates the efficacy and safety of 8 weeks of daily treatment with the fixed-dose combination sofosbuvir/velpatasvir (400/100 mg) in patients with acute hepatitis C virus (HCV) infection. All patients who completed therapy and were followed-up achieved sustained virologic response. Thus, early treatment with SOF/VEL which might effectively prevent the spread of HCV in high-risk groups can be recommended for patients with acute HCV monoinfection.

Introduction and Objectives: Recent translational research indicated a bidirectional relationship between NASH (non-alcoholic steatohepatitis) and periodontitis; however, few clinical cohorts have studied this in detail. Thus we investigated this assumed association in a well-defined cohort. Materials and Methods: Data were generated prospectively for 132 patients (32 patients with NASH and 100 unselected, consecutively collected, anonymized controls from a local dental practice): detailed periodontal parameters, i.e., pocket-probing-depths (PPD), bleeding-on-probing (BOP), plaque-index, and utilization of dental care were assessed and correlated with relevant hepatic parameters (liver stiffness via fibroscan, AST, ALT, bilirubin, and MELD-score). Gingiva samples were tested for Porphyromonas gingvalis (P.g.) and Actinobacillus actinomyctemcomitans (A.a.) by PCR. Results: 87.5% of NASH patients and 47% of controls suffered from moderate to severe periodontitis (p=0.01). Liver stiffness was significantly correlated with elevated PPD (p=0.02) and BOP (p=0.03). 34 % of the NASH patients did not make use of regular dental health care. In these patients, AST (p=0.04), MELD score (p

ABSTRACT In vitro data suggest the monoclonal antibody sotrovimab may have lost inhibitory capability against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant. We aimed to provide real-life data on clinical outcomes in hospitalized patients. We retrospectively analyzed patients who were treated at the University Medical Center Hamburg-Eppendorf, Germany, between December 2021 and June 2022. Out of all 1,254 patients, 185 were treated with sotrovimab: 147 patients received sotrovimab monotherapy, and 38 received combination treatment with sotrovimab and remdesivir. We compared in-hospital mortality for the different treatment regimens for patients treated on regular wards and the intensive care unit separately and performed propensity score matching by age, sex, comorbidities, immunosuppression, and additional dexamethasone treatment to select patients who did not receive antiviral treatment for comparison. No difference in in-hospital mortality was observed between any of the treatment groups and the respective control groups. These findings underline that sotrovimab adds no clinical benefit for hospitalized patients with SARS-CoV-2 Omicron variant infections. IMPORTANCE This study shows that among hospitalized patients with SARS-CoV-2 Omicron variant infection at risk of disease progression, treatment with sotrovimab alone or in combination with remdesivir did not decrease in-hospital mortality. These real-world clinical findings in combination with previous in vitro data about lacking neutralizing activity of sotrovimab against SARS-CoV-2 Omicron variant do not support sotrovimab as a treatment option in these patients.

Background and aimsThere is growing interest in T cell-based immune therapies for a functional cure of chronic HBV infection including check-point inhibition, T cell-targeted vaccines or TCR-grafted effector cells. All these approaches depend on recognition of HLA class I-presented viral peptides. The HBV core region 18-27 is an immunodominant target of CD8+ T cells and represents the prime target for T cell-based therapies. Here, a high-resolution analysis of the core18-27 specific CD8+ T cell and the selected escape pathways was performed.MethodsHLA class I typing and viral sequence analyses were performed for 464 patients with chronic HBV infection. HBV-specific CD8+ T-cell responses against the prototype and epitope variants were characterized by flow cytometry.ResultsConsistent with promiscuous presentation of the core18-27 epitope, antigen-specific T cells were detected in patients carrying HLA-A*02:01, HLA-B*35:01, HLA-B*35:03 or HLA-B*51:01. Sequence analysis confirmed reproducible selection pressure on the core18-27 epitope in the context of these alleles. Interestingly, the selected immune escape pathways depend on the presenting HLA-class I-molecule. Although cross-reactive T cells were observed, some epitope variants achieved functional escape by impaired TCR-interaction or disturbed antigen processing. Of note, selection of epitope variants was exclusively observed in HBeAg negative HBV infection and here, detection of variants associated with significantly greater magnitude of the CD8 T cell response compared to absence of variants.ConclusionThe core18-27 epitope is highly variable and under heavy selection pressure in the context of different HLA class I-molecules. Some epitope variants showed evidence for impaired antigen processing and reduced presentation. Viruses carrying such escape substitutions will be less susceptible to CD8+ T cell responses and should be considered for T cell-based therapy strategies.

IntroductionLittle is known about risk factors for both Long COVID and somatic symptoms that develop in individuals without a history of COVID-19 in response to the pandemic. There is reason to assume an interplay between pathophysiological mechanisms and psychosocial factors in the etiology of symptom persistence.ObjectiveTherefore, this study investigates specific risk factors for somatic symptom deterioration in a cohort of German adults with and without prior SARS-CoV-2 infection.MethodsGerman healthcare professionals underwent SARS-CoV-2 IgG antibody testing and completed self-rating questionnaires at baseline and 21 months later between April 2020 and February 2022. Differences in variables between the time points were analyzed and a regression analysis was performed to predict somatic symptom deterioration at follow-up.ResultsSeven hundred fifty-one adults completed both assessments. Until follow-up, n = 58 had contracted SARS-CoV-2 confirmed by serology. Between baseline and follow-up, signs of mental and physical strain increased significantly in the sample. Symptom expectations associated with COVID-19 and a self-reported history of COVID-19, but not serologically confirmed SARS-CoV-2 infection, significantly predicted somatic symptom deterioration at follow-up. A further predictor was baseline psychological symptom burden.ConclusionsThis study supports a disease-overarching biopsychosocial model for the development of burdensome somatic symptoms during the COVID-19 pandemic and supports research findings that symptom burden may be more related to the psychosocial effects of the pandemic than to infection itself. Future studies on Long COVID should include SARS-CoV-2 negative control groups and consider symptom burden prior to infection in order to avoid an overestimation of prevalence rates.

SARS-CoV-2 is still a major burden for global health despite effective vaccines. With the reduction of social distancing measures, infection rates are increasing in children, while data on the pediatric immune response to SARS-CoV-2 infection is still lacking. Although the typical disease course in children has been mild, emerging variants may present new challenges in this age group. Peripheral blood mononuclear cells (PBMC) from 51 convalescent children, 24 seronegative siblings from early 2020, and 51 unexposed controls were stimulated with SARS-CoV-2-derived peptide MegaPools from the ancestral and beta variants. Flow cytometric determination of activation-induced markers and secreted cytokines were used to quantify the CD4+ T cell response. The average time after infection was over 80 days. CD4+ T cell responses were detected in 61% of convalescent children and were markedly reduced in preschool children. Cross-reactive T cells for the SARS-CoV-2 beta variant were identified in 45% of cases after infection with an ancestral SARS-CoV-2 variant. The CD4+ T cell response was accompanied most predominantly by IFN-γ and Granzyme B secretion. An antiviral CD4+ T cell response was present in children after ancestral SARS-CoV-2 infection, which was reduced in the youngest age group. We detected significant cross-reactivity of CD4+ T cell responses to the more recently evolved immune-escaping beta variant. Our findings have epidemiologic relevance for children regarding novel viral variants of concern and vaccination efforts.

Thymocyte selection-associated high mobility group box (TOX) has been described to be a key regulator in the formation of CD8+ T cell exhaustion. Hepatitis C virus (HCV) infection with different lengths of antigen exposure in acute, chronic, and after resolution of HCV infection is the ideal immunological model to study the expression of TOX in HCV-specific CD8+ T cells with different exposure to antigen. HCV-specific CD8+ T cells from 35 HLA-A*01:01, HLA-A*02:01, and HLA-A*24:02 positive patients were analyzed with a 16-color FACS-panel evaluating the surface expression of lineage markers (CD3, CD8), ectoenzymes (CD39, CD73), markers of differentiation (CD45RO, CCR7, CD127), and markers of exhaustion and activation (TIGIT, PD-1, KLRG1, CD226) and transcription factors (TOX, Eomesodermin, T-bet). Here, we defined on-target T cells as T cells against epitopes without escape mutations and off-target T cells as those against a “historical” antigen mutated in the autologous sequence. TOX+HCV-specific CD8+ T cells from patients with chronic HCV and on-target T cells displayed co-expression of Eomesodermin and were associated with the formation of terminally exhausted CD127-PD1hi, CD39hi, CD73low CD8+ T cells. In contrast, TOX+HCV-specific CD8+ T cells in patients with off-target T cells represented a progenitor memory Tex phenotype characterized by CD127hi expression and a CD39low and CD73hi phenotype. TOX+HCV-specified CD8+ T cells in patients with a sustained virologic response were characterized by a memory phenotype (CD127+, CD73hi) and co-expression of immune checkpoints and Eomesodermin, indicating a key structure in priming of HCV-specific CD8+ T cells in the chronic stage, which persisted as a residual after therapy. Overall, the occurrence of TOX+HCV-specific CD8+ T cells was revealed at each disease stage, which impacted the development of progenitor Tex, intermediate Tex, and terminally exhausted T cell through an individual molecular footprint. In sum, TOX is induced early during acute infection but is modulated by changes in viral sequence and antigen recognition. In the case of antigen persistence, the interaction with Eomesodermin leads to the formation of terminally exhausted virus-specific CD8+ T cells, and there was a direct correlation of the co-expression of TOX and Eomes and terminally exhausted phenotype of virus-specific CD8+ T cells.

Hepatitis E virus is increasingly being reported to cause chronic infection in immunocompromised patients. However, less is known about patients with an underlying hematologic disease. In particular, the impact of hepatitis E infection on oncological therapy has been poorly described. In this retrospective single-center study, we analyzed 35 hematologic patients with hepatitis E, including 20 patients under active oncological treatment and 15 patients who were in the posttreatment follow-up or under active surveillance. The primary aim was to describe the clinical courses with particular focus on any hepatitis E-related therapy modifications of cancer-directed therapy. In the majority (60%) of patients who were under active oncological treatment, hepatitis E-related therapy modifications were made, and 25% of deaths were due to progression of the hematologic disease. In patients receiving concomitant oncological treatment, no hepatitis Erelated deaths occurred. In contrast, two patients in the follow-up group died from hepatitis E-associated acute-onchronic liver failure. Chronic hepatitis E was observed in 34% of all cases and 43% received ribavirin therapy; of those, 27% achieved a sustained virological response. CD20-directed therapy was the only independent risk factor for developing chronic hepatitis E. We conclude that CD20-directed treatment at any time point is a risk factor for developing chronic hepatitis E. Nevertheless, since mortality from the progression of hematologic disease was higher than hepatitis E-related mortality, we suggest careful case-by-case decisions on modifications of cancer treatment. Patients in the posttreatment follow-up phase may also suffer from severe courses and hepatitis E chronicity occurs as frequently as in patients undergoing active therapy.

Background & Aims: Direct-acting antiviral (DAA) regimens provide a cure in >95% of patients with chronic HCV infection. However, in some patients in whom therapy fails, resistance-associated substitutions (RASs) can develop, limiting retreatment options and risking onward resistant virus transmission. In this study, we evaluated RAS prevalence and distribution, including novel NS5A RASs and clinical factors associated with RAS selection, among patients who experienced DAA treatment failure. Methods: SHARED is an international consortium of clinicians and scientists studying HCV drug resistance. HCV sequence linked metadata from 3,355 patients were collected from 22 countries. NS3, NS5A, and NS5B RASs in virologic failures, including novel NS5A substitutions, were examined. Associations of clinical and demographic characteristics with RAS selection were investigated. Results: The frequency of RASs increased from its natural prevalence following DAA exposure: 37% to 60% in NS3, 29% to 80% in NS5A, 15% to 22% in NS5B for sofosbuvir, and 24% to 37% in NS5B for dasabuvir. Among 730 virologic failures, most were treated with first-generation DAAs, 94% had drug resistance in ≥1 DAA class: 31% single-class resistance, 42% dual-class resistance (predominantly against protease and NS5A inhibitors), and 21% triple-class resistance. Distinct patterns containing ≥2 highly resistant RASs were common. New potential NS5A RASs and adaptive changes were identified in genotypes 1a, 3, and 4. Following DAA failure, RAS selection was more frequent in older people with cirrhosis and those infected with genotypes 1b and 4. Conclusions: Drug resistance in HCV is frequent after DAA treatment failure. Previously unrecognized substitutions continue to emerge and remain uncharacterized. Lay summary: Although direct-acting antiviral medications effectively cure hepatitis C in most patients, sometimes treatment selects for resistant viruses, causing antiviral drugs to be either ineffective or only partially effective. Multidrug resistance is common in patients for whom DAA treatment fails. Older patients and patients with advanced liver diseases are more likely to select drug-resistant viruses. Collective efforts from international communities and governments are needed to develop an optimal approach to managing drug resistance and preventing the transmission of resistant viruses.

Backgroundγδ T cells are unconventional T cells that have been demonstrated to be crucial for the pathogenesis and potentially for the cure of HIV-1 infection. The ectonucleotidase CD39 is part of the purinergic pathway that regulates immune responses by degradation of pro-inflammatory ATP in concert with CD73. Few studies on the expression of the ectoenzymes CD73 and CD39 on human γδ T cells in HIV have been performed to date.MethodsPBMC of n=86 HIV-1-infected patients were compared to PBMC of n=26 healthy individuals using 16-color flow cytometry determining the surface expression of CD39 and CD73 on Vδ1 and Vδ2 T cells in association with differentiation (CD45RA, CD28, CD27), activation and exhaustion (TIGIT, PD-1, CD38, and HLA-DR), and assessing the intracellular production of pro- and anti-inflammatory cytokines (IL-2, TGF-ß, TNF-α, Granzyme B, IL-10, IFN-γ) after in vitro stimulation with PMA/ionomycin.ResultsCD39 and CD73 expression on γδ T cells were inversed in HIV infection which correlated with HIV disease progression and immune activation. CD39, but not CD73 expression on γδ T cells of ART-treated patients returned to levels comparable with those of healthy individuals. Only a small subset (

Packed bed plasma reactors (PBPRs) inherently have complex geometries where the volume between the electrodes is filled with dielectric/catalytic pellets to form a large array of voids. While the dimension of the plasma region can be several centimeters, the size of a single void at the edges and pores of dielectrics/pellets can reach micrometer dimensions. The understanding of plasma propagation on these diverse length scales is essential for optimizing and controlling plasma processes performed in such discharges. It is known that plasmas are generated in PBPRs as multiple pulses due to cathode-directed positive streamers in the volume, surface ionization waves, or surface streamers over the dielectric surface and stationary microdischarges at the contact points of adjacent dielectrics. In this work, we have investigated the discharge formation and propagation as a function of applied voltage in simplified PBPRs with a single layer of hexagonally arranged hemispherical pellets, operated in helium, using phase and space resolved optical emission spectroscopy. Despite similar discharge conditions at multiple positions, the emission intensity during each pulse spreads like a wave from the center to the edges in the whole discharge cell. The emission due to surface ionization waves is significantly reduced compared to earlier works. These observations could be explained by possible interactions between adjacent microdischarges, already known in other arrays of microdischarges or adjacent streamers. Higher resolution images of the contact points show that the discharge has fine structures with stronger emission at the edges of the contact points; this effect is enhanced as a function of the driving voltage amplitude. This is possibly the consequence of non-uniform electric field distribution at the contact points due to the polarization of dielectrics.

Background Asplenia or functional hyposplenism are risk factors for severe infections, and vaccinations against encapsulated bacteria are advised. There are only limited data regarding the spleen function of cirrhotic patients. Methods We evaluated spleen function in patients with liver cirrhosis, who were prospectively enrolled in this study. Spleen function was evaluated by the measurement of pitted erythrocytes. Functional hyposplenism was defined as a percentage of PE of >15%. Results 117 patients, mean age 58.4 years and 61.5% (n = 72) male with liver cirrhosis were included. Functional hyposplenism was diagnosed in 28/117 patients (23.9%). Pitted erythrocytes correlated with albumin (p = 0.024), bilirubin (pConclusion A quarter of patients with liver cirrhosis and almost 50% of patients with Child C cirrhosis have functional hyposplenism. Functional hyposplenism is associated with poor liver function and the degree of portal hypertension, which is characterized by higher liver stiffness measurements in transient elastography.

Abstract Objectives Potential differences in the breadth, distribution and magnitude of CD4+ T‐cell responses directed against the SARS‐CoV‐2 spike glycoprotein between vaccinees, COVID‐19 patients and subjects who experienced both ways of immunisation have not been comprehensively compared on a peptide level. Methods Following virus‐specific in vitro cultivation, we determined the T‐cell responses directed against 253 individual overlapping 15‐mer peptides covering the entire SARS‐CoV‐2 spike glycoprotein using IFN‐γ ELISpot and intracellular cytokine staining. In vitro HLA binding was determined for selected peptides. Results We mapped 955 single peptide‐specific CD4+ T‐cell responses in a cohort of COVID‐19 patients (n = 8), uninfected vaccinees (n = 16) and individuals who experienced both infection and vaccination (n = 11). Patients and vaccinees (two‐time and three‐time vaccinees alike) had a comparable number of CD4+ T‐cell responses (median 26 vs. 29, P = 0.7289). Most of these specificities were conserved in B.1.1.529 and the BA.4 and BA.5 sublineages. The highest magnitude of these in vitro IFN‐γ CD4+ T‐cell responses was observed in COVID‐19 patients (median 0.35%), and three‐time vaccinees showed a higher magnitude than two‐time vaccinees (median 0.091% vs. 0.175%, P

A large body of research has examined the link between personality and face-to-face (FtF) communication knowledge, skills, abilities, and other characteristics (KSAOs). With the rise of digital media, text-based computer-mediated (CM) communication KSAOs have gained increasing attention. We conducted two studies to investigate how personality relates to KSAOs in the different contexts of FtF and CM communication. Contrasting perspectives hypothesize that the results in the FtF and CM contexts would be very similar or distinctly different. In Study 1 (n = 454), an online panel study, the Big Five personality dimensions were assessed and their relationships to FtF and CM communication KSAOs were investigated. Structural equation models and relative weight regression analyses showed that these personality dimensions, mostly extraversion and neuroticism, explained more variance in FtF as compared to CM communication KSAOs. Study 2 (n = 173), conducted in a laboratory context, showed similar results compared to Study 1. In addition, when the Big Five personality dimensions were assessed with a CM frame of reference, more variance was explained in CM than in FtF communication KSAOs. These results point to the importance of considering context effects in communication and in personality research: FtF and CM communication KSAOs need to be differentiated. If not properly contextualized, the relevance of personality and communication competencies in predicting criteria may be underestimated due to contextual mismatches.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver pathology worldwide. In mice and humans, NAFLD progression is characterized by the appearance of TREM2-expressing macrophages in the liver. However, their mechanistic contributions to disease progression have not been completely elucidated. Here, we show that TREM2+ macrophages prevent the generation of a pro-inflammatory response elicited by LPS-laden lipoproteins in vitro. Further, Trem2 expression regulates bone-marrow-derived macrophages (BMDMs) and Kupffer cell capacity to phagocyte apoptotic cells in vitro, which is dependent on CD14 activation. In line with this, loss of Trem2 resulted in an increased pro-inflammatory response, which ultimately aggravated liver fibrosis in murine models of NAFLD. Similarly, in a human NAFLD cohort, plasma levels of TREM2 were increased and hepatic TREM2 expression was correlated with higher levels of liver triglycerides and the acquisition of a fibrotic gene signature. Altogether, our results suggest that TREM2+ macrophages have a protective function during the progression of NAFLD, as they are involved in the processing of pro-inflammatory lipoproteins and phagocytosis of apoptotic cells and, thereby, are critical contributors for the re-establishment of liver homeostasis.

At the start of the pandemic, liver transplant recipients (LTR) were at high risk of developing severe COVID-19. Here, the outcomes of breakthrough infections in fully vaccinated LTR (n = 98) during the Omicron wave were assessed. In most patients, a mild disease course was observed, but 11 LTR (11.2%) required hospitalization for COVID-19-related complications. All patients survived. The LTR requiring hospitalization were older (67 years vs. 54 years; p < 0.001), had a higher Charlson comorbidity index (9 vs. 5; p < 0.001), and a lower anti-S RBD titer (Roche Elecsys) prior to infection (508.3 AU/mL vs. 2044 AU/mL; p = 0.03). Long-lasting symptoms for ≥4 weeks were reported by 37.5% of LTR (30/80). Risk factors in LTR included female sex (p = 0.01; Odds Ratio (OR) = 4.92 (95% confidence interval (CI) (1.5–16.5)) and dyspnea (p = 0.009; OR = 7.2 (95% CI (1.6–31.6)) during infection. Post-infection high anti-S RBD antibody levels were observed in LTR, and healthy controls (HC), while the cellular immune response, assessed by interferon-gamma release assay (EUROIMMUN), was significantly lower in LTR compared with HC (p < 0.001). In summary, in fully vaccinated LTR, SARS-CoV-2 breakthrough infections during the Omicron wave led to mild disease courses in the majority of patients and further boosted the humoral and cellular hybrid anti-SARS-CoV-2-directed immune response. While all patients survived, older and multimorbid LTR with low baseline antibody titers after vaccination still had a substantial risk for a disease course requiring hospitalization due to COVID-19-related complications.

Allo-HSCT with CCR5Δ32/Δ32 donor cells is the only curative HIV-1 intervention. We investigated the impact of allo-HSCT on the viral reservoir in PBMCs and post-mortem tissue in two patients. IciS-05 and IciS-11 both received a CCR5Δ32/Δ32 allo-HSCT. Before allo-HSCT, ultrasensitive HIV-1 RNA quantification; HIV-1-DNA quantification; co-receptor tropism analysis; deep-sequencing and viral characterization in PBMCs and bone marrow; and post-allo-HSCT, ultrasensitive RNA and HIV-1-DNA quantification were performed. Proviral quantification, deep sequencing, and viral characterization were done in post-mortem tissue samples. Both patients harbored subtype B CCR5-tropic HIV-1 as determined genotypically and functionally by virus culture. Pre-allo-HSCT, HIV-1-DNA could be detected in both patients in bone marrow, PBMCs, and T-cell subsets. Chimerism correlated with detectable HIV-1-DNA LTR copies in cells and tissues. Post-mortem analysis of IciS-05 revealed proviral DNA in all tissue biopsies, but not in PBMCs. In patient IciS-11, who was transplanted twice, no HIV-1-DNA could be detected in PBMCs at the time of death, whereas HIV-1-DNA was detectable in the lymph node. In conclusion, shortly after CCR5Δ32/Δ32, allo-HSCT HIV-1-DNA became undetectable in PBMCs. However, HIV-1-DNA variants identical to those present before transplantation persisted in post-mortem-obtained tissues, indicating that these tissues play an important role as viral reservoirs.

Background: The immunogenicity of different COVID-19 vaccine regimens and combinations in naïve and convalescent individuals has not been formally tested in controlled studies, and real-life observational studies are scarce. Methods: We assessed the SARS-CoV-2 infection and COVID-19 vaccination-induced immunity of 697 hospital workers at the University Medical Center Hamburg-Eppendorf between 17 and 31 January 2022. Results: The overall prevalence of anti-NC-SARS-CoV-2 antibodies indicating prior infection was 9.8% (n = 68) and thus lower than the seroprevalence in the general population. All vaccinated individuals had detectable anti-S1-RBD-SARS-CoV-2 antibodies (median AU/mL [IQR]: 13,891 [8505–23,543]), indicating strong protection against severe COVID-19. Individuals who received three COVID-19 vaccine doses (median AU/mL [IQR]: 13,856 [8635–22,705]) and those who resolved a prior SARS-CoV-2 infection and had received two COVID-19 vaccine doses (median AU/mL [IQR] 13,409 [6934–25,000]) exhibited the strongest humoral immune responses. Conclusions: The current study indicates that three exposures to the viral spike protein by either SARS-CoV-2 infection or COVID-19 vaccination are necessary to elicit particularly strong humoral immune responses, which supports current vaccination recommendations.

Here, we longitudinally assessed the ex vivo frequency and phenotype of SARS-CoV-2 membrane protein (aa145–164) epitope-specific CD4+ T-cells of an anti-CD20-treated patient with prolonged viral positivity in direct comparison to an immunocompetent patient through an MHC class II DRB1*11:01 Tetramer analysis. We detected a high and stable SARS-CoV-2 membrane-specific CD4+ T-cell response in both patients, with higher frequencies of virus-specific CD4+ T-cells in the B-cell-depleted patient. However, we found an altered virus-specific CD4+ T-cell memory phenotype in the B-cell-depleted patient that was skewed towards late differentiated memory T-cells, as well as reduced frequencies of SARS-CoV-2-specific CD4+ T-cells with CD45RA− CXCR5+ PD-1+ circulating T follicular helper cell (cTFH) phenotype. Furthermore, we observed a delayed contraction of CD127− virus-specific effector cells. The expression of the co-inhibitory receptors TIGIT and LAG-3 fluctuated on the virus-specific CD4+ T-cells of the patient, but were associated with the inflammation markers IL-6 and CRP. Our findings indicate that, despite B-cell depletion and a lack of B-cell—T-cell interaction, a robust virus-specific CD4+ T-cell response can be primed that helps to control the viral replication, but which is not sufficient to fully abrogate the infection.

Severe infectious complications remain the main cause of mortality in leukemia patients due to a long period of profound neutropenia. Standardized regimens for antimicrobial, antifungal, and antiviral prophylaxis and therapy in neutropenic patients have improved infection-associated mortality. Nevertheless, many patients are refractory to these multidrug approaches. Tigecycline is a last-resort antibiotic with a broad-spectrum activity; unfortunately, clinical experience in multidrug-resistant febrile neutropenia is limited. The aim was to evaluate the efficacy of tigecycline treatment in comparison to standard treatment in this patient cohort. In this single center analysis, we analyzed the clinical courses of 73 patients with acute leukemia and diagnosis of febrile neutropenia resistant to hospital-based multidrug escalation levels who continued on a standard approach without antibiotics as the last resort (n = 30) or were switched to tigecycline in addition to carbapenem treatment (n = 43). We observed comparable overall response rates (decrease in C-reactive protein or resolution of fever) in both patient cohorts. Switching the antibiotic approach to tigecycline showed lower absolute sepsis (33% vs. 47%, p = 0.235) and infection-associated mortality rates (5% vs. 13%, p = 0.221). Prospective larger randomized studies are necessary to underline these results and to be able to generate reliable statistics.