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  1. Article ; Online: Farnesyltransferase-inhibitors exert in vitro immunosuppressive capacity by inhibiting human B-cells

    Shilei Xu / Sebastian Dolff / Nils Mülling / Hagen S. Bachmann / Yang Dai / Monika Lindemann / Ming Sun / Oliver Witzke / Andreas Kribben / Benjamin Wilde

    Frontiers in Transplantation, Vol

    2023  Volume 2

    Abstract: ObjectivesFarnesyltransferase inhibitors (FTI), which inhibit the prenylation of Ras GTPases, were developed as anti-cancer drugs. As additional target proteins for prenylation were identified in the past, it is likely that FTI have potential value for ... ...

    Abstract ObjectivesFarnesyltransferase inhibitors (FTI), which inhibit the prenylation of Ras GTPases, were developed as anti-cancer drugs. As additional target proteins for prenylation were identified in the past, it is likely that FTI have potential value for therapeutic purposes beyond cancer. The effect of FTI on B-cells remains unclear. To address this issue, we investigated the effects of in vitro FTI treatment on effector and regulatory B-cells in healthy controls and renal transplant patients.MethodsFor this purpose, B-cells were isolated from the peripheral blood of healthy controls and renal transplant patients. Purified B-cells were stimulated via Toll-like-receptor 9 (TLR-9) in the presence or absence of FTI. Regulatory functions, such as IL-10 and Granzyme B (GrB) secretion, were assessed by flow cytometry. In addition, effector B-cell functions, such as plasma cell formation and IgG secretion, were studied.ResultsThe two FTI Lonafarnib and tipifarnib both suppressed TLR-9-induced B-cell proliferation. Maturation of IL-10 producing B-cells was suppressed by FTI at high concentrations as well as induction of GrB-secreting B-cells. Plasma blast formation and IgG secretion were potently suppressed by FTI. Moreover, purified B-cells from immunosuppressed renal transplant patients were also susceptible to FTI-induced suppression of effector functions, evidenced by diminished IgG secretion.ConclusionFTI suppress in vitro B-cell proliferation and plasma cell formation while partially preserving IL-10 as well as GrB production of B-cells. Thus, FTI may have immunosuppressive capacity encouraging further studies to investigate the potential immunomodulatory value of this agent.
    Keywords B-cells ; plasma cells ; farnesyltransferase inhibitors ; renal transplantation ; humoral rejection ; Specialties of internal medicine ; RC581-951
    Subject code 610
    Language English
    Publishing date 2023-11-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: CD107a+ (LAMP-1) Cytotoxic CD8+ T-Cells in Lupus Nephritis Patients

    Anika Wiechmann / Benjamin Wilde / Bartosz Tyczynski / Kerstin Amann / Wayel H. Abdulahad / Andreas Kribben / Karl Sebastian Lang / Oliver Witzke / Sebastian Dolff

    Frontiers in Medicine, Vol

    2021  Volume 8

    Abstract: Cytotoxic CD8+ T-cells play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). The aim of this study was to investigate the role of CD107a (LAMP-1) on cytotoxic CD8+ T-cells in SLE-patients in particular with lupus nephritis. ... ...

    Abstract Cytotoxic CD8+ T-cells play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). The aim of this study was to investigate the role of CD107a (LAMP-1) on cytotoxic CD8+ T-cells in SLE-patients in particular with lupus nephritis. Peripheral blood of SLE-patients (n = 31) and healthy controls (n = 21) was analyzed for the expression of CD314 and CD107a by flow cytometry. Kidney biopsies of lupus nephritis patients were investigated for the presence of CD8+ and C107a+ cells by immunohistochemistry and immunofluorescence staining. The percentages of CD107a+ on CD8+ T-cells were significantly decreased in SLE-patients as compared to healthy controls (40.2 ± 18.5% vs. 47.9 ± 15.0%, p = 0.02). This was even more significant in SLE-patients with inactive disease. There was a significant correlation between the percentages of CD107a+CD8+ T-cells and SLEDAI. The evaluation of lupus nephritis biopsies showed a significant number of CD107a+CD8+ T-cells mainly located in the peritubular infiltrates. The intrarenal expression of CD107a+ was significantly correlated with proteinuria. These results demonstrate that CD8+ T-cells of patients with systemic lupus erythematosus have an altered expression of CD107a which seems to be associated with disease activity. The proof of intrarenal CD107a+CD8+ suggests a role in the pathogenesis of lupus nephritis.
    Keywords cytotoxic T-cells ; CD107a ; LAMP-1 ; lupus nephritis ; SLE ; Medicine (General) ; R5-920
    Subject code 610
    Language English
    Publishing date 2021-03-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: BTLA Expression on Th1, Th2 and Th17 Effector T-Cells of Patients with Systemic Lupus Erythematosus Is Associated with Active Disease

    Christoph Oster / Benjamin Wilde / Christof Specker / Ming Sun / Andreas Kribben / Oliver Witzke / Sebastian Dolff

    International Journal of Molecular Sciences, Vol 20, Iss 18, p

    2019  Volume 4505

    Abstract: An imbalanced T-cell homeostasis plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). Co-stimulatory and co-inhibitory molecules regulate T-cell differentiation, survival, and cytokine production. B- and T-lymphocyte ... ...

    Abstract An imbalanced T-cell homeostasis plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). Co-stimulatory and co-inhibitory molecules regulate T-cell differentiation, survival, and cytokine production. B- and T-lymphocyte attenuator (BTLA) is a co-inhibitory molecule which negatively regulates T-cell activation. The aim of this study was to investigate BTLA expression on regulatory and effector CD4 + T-cells in SLE patients with and without lupus nephritis (LN) during active and inactive disease. Therefore, peripheral blood of forty-one SLE patients and twenty-one healthy controls (HC) was phenotypically analyzed. Next, ex vivo stimulated T-cells were analyzed for the expression of BTLA on Th1-, Th2-, and Th17-effector cells by flow cytometry. Renal involvement was defined as biopsy-proven LN. Disease activity was assessed by SLE disease activity index (SLEDAI). Percentages of peripheral unstimulated BTLA + CD4 + T-cells were significantly decreased in SLE patients with active disease. However, ex vivo stimulated Th1, Th2, and Th17 effector T-cells, expressed increased percentages of BTLA expression in active disease. In contrast, the BTLA expression on CD4 + CD25 ++ CD127 − regulatory T-cells was not significantly different. BTLA seems to be an important co-inhibitory molecule in the T-cell homeostasis of patients with systemic lupus erythematosus and crucial for disease activity.
    Keywords SLE ; BTLA ; Costimulation ; IFN-γ ; IL-10 ; IL-17A ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Language English
    Publishing date 2019-09-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: IL-22 production of effector CD4+ T-cells is altered in SLE patients

    Sebastian Dolff / Claudia Scharpenberg / Christof Specker / Andreas Kribben / Oliver Witzke / Benjamin Wilde

    European Journal of Medical Research, Vol 24, Iss 1, Pp 1-

    2019  Volume 10

    Abstract: Abstract Background Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by T-cell-dependent B-cell activation and altered T-cell response. Co-stimulatory and co-inhibitory molecules regulate and exert T-cell differentiation, ... ...

    Abstract Abstract Background Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by T-cell-dependent B-cell activation and altered T-cell response. Co-stimulatory and co-inhibitory molecules regulate and exert T-cell differentiation, survival and cytokine production. CD134+ and PD-1+ T-cells in SLE patients are increased in SLE. The aim of this study was to characterize CD134+ and PD-1+CD4+ T-cells according to their ability to produce IFN-γ, IL-21 and IL-22 in SLE patients. Methods Peripheral blood of 39 SLE patients and 19 healthy controls (HC) was stimulated with phorbol myristate acetate (PMA) calcium ionophore (Ca-Io). The expression of IFN-γ, IL-21 and IL-22 T-cells within the CD134+ and PD-1+ T-cells was analyzed by flow cytometry. Disease activity was assessed by SLE Disease Activity Index. Results Peripheral unstimulated CD134+ and PD-1+ CD4+ T-cells were significantly increased in patients with lupus nephritis. Upon stimulation both, CD134+ and PD-1+ CD4+ T-cells, produced significantly less IFN-γ in SLE patients as compared to HC. The percentages of IL-22 within the CD134+CD4+ T-cells were also significantly decreased in SLE as compared to HC. Conclusion CD134+ and PD-1+CD4+ T-cells have mainly a Th1 effector T-cell signature. A lower proportion produces also IL-21 and IL-22. The impaired capacity to produce IFN-γ and IL-22 in SLE patients may contribute to the pathogenesis of the disease.
    Keywords SLE ; CD134 ; PD-1 ; IFN-γ ; IL-22 ; Medicine ; R
    Subject code 610 ; 570
    Language English
    Publishing date 2019-07-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Decline of Humoral Responses 6 Months after Vaccination with BNT162b2 (Pfizer–BioNTech) in Patients on Hemodialysis

    Michael Jahn / Johannes Korth / Oliver Dorsch / Olympia Evdoxia Anastasiou / Adalbert Krawczyk / Leonie Brochhagen / Lukas van de Sand / Burkhard Sorge-Hädicke / Bartosz Tyczynski / Oliver Witzke / Ulf Dittmer / Sebastian Dolff / Benjamin Wilde / Andreas Kribben

    Vaccines, Vol 10, Iss 327, p

    2022  Volume 327

    Abstract: This study analyzed binding and neutralizing antibody titers up to 6 months after standard vaccination with BNT162b2 (two doses of 30 µg each) in SARS-CoV-2 naïve patients (n = 59) on hemodialysis. Humoral vaccine responses were measured before and 6, 12, ...

    Abstract This study analyzed binding and neutralizing antibody titers up to 6 months after standard vaccination with BNT162b2 (two doses of 30 µg each) in SARS-CoV-2 naïve patients (n = 59) on hemodialysis. Humoral vaccine responses were measured before and 6, 12, and 24 weeks after the first vaccination. A chemiluminescent immunoassay (CLIA) was used to quantify SARS-CoV-2 IgG against the spike glycoprotein. SARS-CoV-2 neutralizing activity was tested against the wild-type virus. A multivariable binary regression model was used to identify risk factors for the absence of humoral immune responses at 6 months. At week 6, vaccine-specific seroconversion was detected in 96.6% of all patients with median anti-SARS-CoV-2 IgGs of 918 BAU/mL. At weeks 12 and 24, seroconversion rates decreased to 91.5% and 79.7%, and corresponding median binding antibody titers declined to 298 BAU/mL and 89 BAU/mL, respectively. Neutralizing antibodies showed a decay from 79.6% at week 6 to 32.8% at week 24. The risk factor with the strongest association for vanishing immune responses was low serum albumin ( p = 0.018). Regarding vaccine-specific humoral responses 6 months after the standard BNT162b2 vaccination schedule, SARS-CoV-2 naïve patients receiving hemodialysis must be considered at risk of becoming infected with SARS-CoV-2 and being infectious.
    Keywords BNT162b2 ; mRNA vaccines ; anti-SARS-CoV-2 IgG ; COVID-19 ; hemodialysis ; neutralizing antibodies ; Medicine ; R
    Subject code 616
    Language English
    Publishing date 2022-02-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Separating the wheat from the chaff—COVID-19 in a German emergency department

    David Fistera / Dirk Pabst / Annalena Härtl / Benedikt Michael Schaarschmidt / Lale Umutlu / Sebastian Dolff / Carola Holzner / Clemens Kill / Joachim Risse

    International Journal of Emergency Medicine, Vol 13, Iss 1, Pp 1-

    a case-control study

    2020  Volume 9

    Abstract: Abstract Background COVID-19 pandemia is a major challenge to worldwide health care systems. Whereas the majority of disease presents with mild symptoms that can be treated as outpatients, severely ill COVID-19 patients and patients presenting with ... ...

    Abstract Abstract Background COVID-19 pandemia is a major challenge to worldwide health care systems. Whereas the majority of disease presents with mild symptoms that can be treated as outpatients, severely ill COVID-19 patients and patients presenting with similar symptoms cross their ways in the emergency department. Especially, the variety of symptoms is challenging with primary triage. Are there parameters to distinguish between proven COVID-19 and without before? How can a safe and efficient management of these inpatients be achieved? Methods We conducted a retrospective analysis of 314 consecutive inpatient patients who presented with possible symptoms of COVID-19 in a German emergency department between March and April 2020 and were tested with a SARS-Cov-2 nasopharyngeal swab. Clinical parameters, Manchester Triage System categories, and lab results were compared between patients with positive and negative test results for SARS-Cov-2. Furthermore, we present the existing COVID-19 workflow model of the university hospital in Essen which proved to be efficient during pandemia. Results Forty-three of the 314 patients (13.7%) were tested positive for COVID-19 by SARS-Cov-2 nasopharyngeal swab. We did not find any laboratory parameter to distinguish safely between patients with COVID-19 and those with similar symptoms. Dysgeusia was the only clinical symptom that was significantly more frequent among COVID-19 patients. Conclusion Dysgeusia seems to be a typical symptom for COVID-19, which occurred in 14% of our COVID-19 patients. However, no valid parameters could be found to distinguish clinically between COVID-19 and other diseases with similar symptoms. Therefore, early testing, a strict isolation policy, and proper personal protection are crucial to maintain workflow and safety of patients and ED staff for the months to come. Trial registration German Clinical Trials registry, DRKS00021675
    Keywords COVID-19 ; Triage ; Clinical symptoms ; Emergency department ; SARS-Cov-2 ; Medical emergencies. Critical care. Intensive care. First aid ; RC86-88.9 ; covid19
    Subject code 610
    Language English
    Publishing date 2020-08-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Humoral Response to SARS-CoV-2-Vaccination with BNT162b2 (Pfizer-BioNTech) in Patients on Hemodialysis

    Michael Jahn / Johannes Korth / Oliver Dorsch / Olympia Evdoxia Anastasiou / Burkhard Sorge-Hädicke / Bartosz Tyczynski / Anja Gäckler / Oliver Witzke / Ulf Dittmer / Sebastian Dolff / Benjamin Wilde / Andreas Kribben

    Vaccines, Vol 9, Iss 360, p

    2021  Volume 360

    Abstract: mRNA-based SARS-CoV-2 vaccines offer a preventive strategy against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections that is of interest in the care of patients on hemodialysis (HDP). We measured humoral immune responses in 72 HDP ... ...

    Abstract mRNA-based SARS-CoV-2 vaccines offer a preventive strategy against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections that is of interest in the care of patients on hemodialysis (HDP). We measured humoral immune responses in 72 HDP after standard vaccination with two doses of the mRNA-based SARS-CoV-2 vaccine BNT162b2 (Pfizer-BioNTech). Antibody responses were evaluated with an anti-SARS-CoV-2 IgG ChemiLuminescent ImmunoAssay (CLIA) two weeks after the second dose. In addition, SARS-CoV-2 IgG was determined in a control of 16 healthy healthcare workers (HCW). The control group of HCW has shown a strong antibody response with a median (MD (Q1; Q3)) antibody titer of 800.0 AU/mL (520.5; 800.0). In comparison to HCW, HDP under 60 years of age responded equally (597.0 AU/mL (410.5; 800.0), p = 0.051). However, the antibody responses of the HDP negatively correlated with age (r 2 = 0.2954 p < 0.0001), leading to significantly lower antibody titers in HDP over 60 years (280.0 AU/mL (45.7; 477.0), p < 0.0001). To thoroughly understand the immunogenicity of the new mRNA-based vaccines in HDP, longitudinal data on the effectiveness and durability of antibody responses are needed. Modifications of immunization schedules should be considered in HDP with low or without antibody responsiveness after standard vaccination to boost immune reactivity and prolong protective effects in these vulnerable patients.
    Keywords SARS-CoV-2 ; mRNA-vaccines ; hemodialysis ; chronic kidney disease ; COVID-19 ; antibody titers ; Medicine ; R
    Subject code 616
    Language English
    Publishing date 2021-04-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Abnormal Expression Pattern of the IL-2 Receptor β-Chain on CD4+ T Cells in ANCA-Associated Vasculitis

    Benjamin Wilde / André Hoerning / Andreas Kribben / Oliver Witzke / Sebastian Dolff

    Disease Markers, Vol

    2014  Volume 2014

    Abstract: Background/Aim. ANCA-associated vasculitis (AAV) is a small-vessel vasculitis of autoimmune origin. In addition to autoantibodies, T cells have a pivotal pathophysiological role in this disease. T-cell homeostasis and immune tolerance critically depend ... ...

    Abstract Background/Aim. ANCA-associated vasculitis (AAV) is a small-vessel vasculitis of autoimmune origin. In addition to autoantibodies, T cells have a pivotal pathophysiological role in this disease. T-cell homeostasis and immune tolerance critically depend on IL-2 and its receptor expressed by T cells. In this study, we investigated the IL-2 receptor (IL-2r) expression on CD4+ T cells in AAV. Methods. Thirty patients with AAV and 15 age-matched healthy controls (HC) were enrolled. T cells from peripheral blood were analysed by flow cytometry for expression of the IL-2r α- and β-chain. Results. The IL-2r α-chain was overexpressed in AAV as compared to HC (36±16% versus 20±9%, P<0.005). The IL-2r-β-chain expression was significantly reduced on CD25+ CD4+ T-cells and CD4+CD25+FoxP3pos regulatory T-cells (Tregs; AAV versus HC: 48±14% versus 62±9%, P=0.002 and 38±18% versus 68±5%, P=0.002). Low β-chain expression in AAV was associated with relapsing disease and systemic vasculitis with renal involvement. Conclusion. The IL-2r expression pattern is abnormal in AAV. To our knowledge, we are the first to show that the β-chain expression is drastically diminished on T cells in AAV and related to a less favorable disease course. Given the indispensable function of the β-chain in IL-2 signaling of T cells, diminished expression may contribute to disturbed immune homeostasis in AAV.
    Keywords Medicine (General) ; R5-920
    Subject code 570
    Language English
    Publishing date 2014-01-01T00:00:00Z
    Publisher Hindawi Limited
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: CXCR4 blockade reduces the severity of murine heart allograft rejection by plasmacytoid dendritic cell-mediated immune regulation

    Jian Fu / Christian H. K. Lehmann / Xinning Wang / Mandy Wahlbuhl / Ida Allabauer / Benjamin Wilde / Lukas Amon / Sebastian Dolff / Robert Cesnjevar / Andreas Kribben / Joachim Woelfle / Wolfgang Rascher / Peter F. Hoyer / Diana Dudziak / Oliver Witzke / André Hoerning

    Scientific Reports, Vol 11, Iss 1, Pp 1-

    2021  Volume 14

    Abstract: Abstract Allograft-specific regulatory T cells (Treg cells) are crucial for long-term graft acceptance after transplantation. Although adoptive Treg cell transfer has been proposed, major challenges include graft-specificity and stability. Thus, there is ...

    Abstract Abstract Allograft-specific regulatory T cells (Treg cells) are crucial for long-term graft acceptance after transplantation. Although adoptive Treg cell transfer has been proposed, major challenges include graft-specificity and stability. Thus, there is an unmet need for the direct induction of graft-specific Treg cells. We hypothesized a synergism of the immunotolerogenic effects of rapamycin (mTOR inhibition) and plerixafor (CXCR4 antagonist) for Treg cell induction. Thus, we performed fully-mismatched heart transplantations and found combination treatment to result in prolonged allograft survival. Moreover, fibrosis and myocyte lesions were reduced. Although less CD3+ T cell infiltrated, higher Treg cell numbers were observed. Noteworthy, this was accompanied by a plerixafor-dependent plasmacytoid dendritic cells-(pDCs)-mobilization. Furthermore, in vivo pDC-depletion abrogated the plerixafor-mediated Treg cell number increase and reduced allograft survival. Our pharmacological approach allowed to increase Treg cell numbers due to pDC-mediated immune regulation. Therefore pDCs can be an attractive immunotherapeutic target in addition to plerixafor treatment.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2021-12-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: SARS-CoV-2 Seroprevalence in Healthcare Workers in Germany

    Johannes Korth / Benjamin Wilde / Sebastian Dolff / Jasmin Frisch / Michael Jahn / Adalbert Krawczyk / Mirko Trilling / Leonie Schipper / Sebastian Cordes / Birgit Ross / Monika Lindemann / Andreas Kribben / Ulf Dittmer / Oliver Witzke / Anke Herrmann / Olympia Evdoxia Anastasiou

    International Journal of Environmental Research and Public Health, Vol 18, Iss 4540, p

    A Follow-Up Study

    2021  Volume 4540

    Abstract: SARS-CoV-2 is a worldwide challenge for the medical sector. Healthcare workers (HCW) are a cohort vulnerable to SARS-CoV-2 infection due to frequent and close contact with COVID-19 patients. However, they are also well trained and equipped with ... ...

    Abstract SARS-CoV-2 is a worldwide challenge for the medical sector. Healthcare workers (HCW) are a cohort vulnerable to SARS-CoV-2 infection due to frequent and close contact with COVID-19 patients. However, they are also well trained and equipped with protective gear. The SARS-CoV-2 IgG antibody status was assessed at three different time points in 450 HCW of the University Hospital Essen in Germany. HCW were stratified according to contact frequencies with COVID-19 patients in (I) a high-risk group with daily contacts with known COVID-19 patients (n = 338), (II) an intermediate-risk group with daily contacts with non-COVID-19 patients (n = 78), and (III) a low-risk group without patient contacts (n = 34). The overall seroprevalence increased from 2.2% in March–May to 4.0% in June–July to 5.1% in October–December. The SARS-CoV-2 IgG detection rate was not significantly different between the high-risk group (1.8%; 3.8%; 5.5%), the intermediate-risk group (5.1%; 6.3%; 6.1%), and the low-risk group (0%, 0%, 0%). The overall SARS-CoV-2 seroprevalence remained low in HCW in western Germany one year after the outbreak of COVID-19 in Germany, and hygiene standards seemed to be effective in preventing patient-to-staff virus transmission.
    Keywords SARS-CoV-2 ; healthcare workers ; COVID-19 ; seroprevalence ; hygiene standards ; Medicine ; R
    Subject code 610
    Language English
    Publishing date 2021-04-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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