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Article: Metformin Increases Cell Viability and Regulates Pro-Inflammatory Response to Mtb.

Naicker, Nikita / Rodel, Hylton / Perumal, Rubeshan / Ganga, Yashica / Bernstein, Mallory / Benede, Ntombi / Abdool Karim, Salim / Padayacthi, Nesri / Sigal, Alex / Naidoo, Kogieleum

Infection and drug resistance

2023 Volume 16, Page(s) 3629–3638

Abstract: Introduction: Current TB treatment regimens are pathogen-directed and can be severely compromised by the development of drug resistance. Metformin has been proposed as an adjunctive therapy for TB, however relatively little is known about how metformin ... ...

Abstract	Introduction: Current TB treatment regimens are pathogen-directed and can be severely compromised by the development of drug resistance. Metformin has been proposed as an adjunctive therapy for TB, however relatively little is known about how metformin modulates the cellular interaction between Mtb and macrophages. We aimed to characterize how metformin modulates Mtb growth within macrophages. Methods: We utilized live cell tracking through time-lapse microscopy to better understand the biological effect of metformin in response to Mtb infection. Furthermore, the potent first-line anti-TB drug, isoniazid, was used as a comparator and as a companion drug. Results: Metformin caused a 14.2-fold decrease in Mtb growth compared to the untreated control. Metformin combined with isoniazid controlled Mtb growth is slightly better than isoniazid alone. Metformin demonstrated the ability to regulate the cytokine and chemokine response over a 72 hour period, better than isoniazid only. Conclusion: We provide novel evidence that metformin controls mycobacterial growth by increasing host cell viability, and a direct and independent pro-inflammatory response to Mtb. Understanding the impact of metformin on Mtb growth within macrophages will advance our current knowledge on metformin as an adjunctive therapy, providing a new host-directed approach to TB treatment.
Language	English
Publishing date	2023-06-07
Publishing country	New Zealand
Document type	Journal Article
ZDB-ID	2494856-1
ISSN	1178-6973
ISSN	1178-6973
DOI	10.2147/IDR.S401403
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Distinct T cell functional profiles in SARS-CoV-2 seropositive and seronegative children associated with endemic human coronavirus cross-reactivity.

medRxiv : the preprint server for health sciences

2023

Abstract: SARS-CoV-2 infection in children typically results in asymptomatic or mild disease. There is a paucity of studies on antiviral immunity in African children. We investigated SARS-CoV-2-specific T cell responses in 71 unvaccinated asymptomatic South ... ...

Abstract	SARS-CoV-2 infection in children typically results in asymptomatic or mild disease. There is a paucity of studies on antiviral immunity in African children. We investigated SARS-CoV-2-specific T cell responses in 71 unvaccinated asymptomatic South African children who were seropositive or seronegative for SARS-CoV-2. SARS-CoV-2-specific CD4+ T cell responses were detectable in 83% of seropositive and 60% of seronegative children. Although the magnitude of the CD4+ T cell response did not differ significantly between the two groups, their functional profiles were distinct, with SARS-CoV-2 seropositive children exhibiting a higher proportion of polyfunctional T cells compared to their seronegative counterparts. The frequency of SARS-CoV-2-specific CD4+ T cells in seronegative children was associated with the endemic human coronavirus (HCoV) HKU1 IgG response. Overall, the presence of SARS-CoV-2-responding T cells in seronegative children may result from cross-reactivity to endemic coronaviruses and could contribute to the relative protection from disease observed in SARS-CoV-2-infected children.
Language	English
Publishing date	2023-05-23
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.05.16.23290059
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Article ; Online: Impact of SARS-CoV-2 exposure history on the T cell and IgG response.

Keeton, Roanne / Tincho, Marius B / Suzuki, Akiko / Benede, Ntombi / Ngomti, Amkele / Baguma, Richard / Chauke, Masego V / Mennen, Mathilda / Skelem, Sango / Adriaanse, Marguerite / Grifoni, Alba / Weiskopf, Daniela / Sette, Alessandro / Bekker, Linda-Gail / Gray, Glenda / Ntusi, Ntobeko A B / Burgers, Wendy A / Riou, Catherine

Cell reports. Medicine

2022 Volume 4, Issue 1, Page(s) 100898

Abstract: Multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposures, from infection or vaccination, can potently boost spike antibody responses. Less is known about the impact of repeated exposures on T cell responses. Here, we compare the ... ...

Abstract	Multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposures, from infection or vaccination, can potently boost spike antibody responses. Less is known about the impact of repeated exposures on T cell responses. Here, we compare the prevalence and frequency of peripheral SARS-CoV-2-specific T cell and immunoglobulin G (IgG) responses in 190 individuals with complex SARS-CoV-2 exposure histories. As expected, an increasing number of SARS-CoV-2 spike exposures significantly enhances the magnitude of IgG responses, while repeated exposures improve the number of T cell responders but have less impact on SARS-CoV-2 spike-specific T cell frequencies in the circulation. Moreover, we find that the number and nature of exposures (rather than the order of infection and vaccination) shape the spike immune response, with spike-specific CD4 T cells displaying a greater polyfunctional potential following hybrid immunity compared with vaccination only. Characterizing adaptive immunity from an evolving viral and immunological landscape may inform vaccine strategies to elicit optimal immunity as the pandemic progress.
MeSH term(s)	Humans ; Antibody Formation ; CD4-Positive T-Lymphocytes ; COVID-19/epidemiology ; Immunoglobulin G ; SARS-CoV-2 ; T-Lymphocytes
Chemical Substances	Immunoglobulin G
Language	English
Publishing date	2022-12-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ISSN	2666-3791
ISSN (online)	2666-3791
DOI	10.1016/j.xcrm.2022.100898
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Infection pre-Ad26.COV2.S-vaccination primes greater class switching and reduced CXCR5 expression by SARS-CoV-2-specific memory B cells.

Krause, Robert G E / Moyo-Gwete, Thandeka / Richardson, Simone I / Makhado, Zanele / Manamela, Nelia P / Hermanus, Tandile / Mkhize, Nonhlanhla N / Keeton, Roanne / Benede, Ntombi / Mennen, Mathilda / Skelem, Sango / Karim, Farina / Khan, Khadija / Riou, Catherine / Ntusi, Ntobeko A B / Goga, Ameena / Gray, Glenda / Hanekom, Willem / Garrett, Nigel /

Bekker, Linda-Gail / Groll, Andreas / Sigal, Alex / Moore, Penny L / Burgers, Wendy A / Leslie, Alasdair

NPJ vaccines

2023 Volume 8, Issue 1, Page(s) 119

Abstract: Neutralizing antibodies strongly correlate with protection for COVID-19 vaccines, but the corresponding memory B cells that form to protect against future infection are relatively understudied. Here we examine the effect of prior SARS-CoV-2 infection on ... ...

Abstract	Neutralizing antibodies strongly correlate with protection for COVID-19 vaccines, but the corresponding memory B cells that form to protect against future infection are relatively understudied. Here we examine the effect of prior SARS-CoV-2 infection on the magnitude and phenotype of the memory B cell response to single dose Johnson and Johnson (Ad26.COV2.S) vaccination in South African health care workers. Participants were either naïve to SARS-CoV-2 or had been infected before vaccination. SARS-CoV-2-specific memory B-cells expand in response to Ad26.COV2.S and are maintained for the study duration (84 days) in all individuals. However, prior infection is associated with a greater frequency of these cells, a significant reduction in expression of the germinal center chemokine receptor CXCR5, and increased class switching. These B cell features correlated with neutralization and antibody-dependent cytotoxicity (ADCC) activity, and with the frequency of SARS-CoV-2 specific circulating T follicular helper cells (cTfh). Vaccination-induced effective neutralization of the D614G variant in both infected and naïve participants but boosted neutralizing antibodies against the Beta and Omicron variants only in participants with prior infection. In addition, the SARS-CoV-2 specific CD8+ T cell response correlated with increased memory B cell expression of the lung-homing receptor CXCR3, which was sustained in the previously infected group. Finally, although vaccination achieved equivalent B cell activation regardless of infection history, it was negatively impacted by age. These data show that phenotyping the response to vaccination can provide insight into the impact of prior infection on memory B cell homing, CSM, cTfh, and neutralization activity. These data can provide early signals to inform studies of vaccine boosting, durability, and co-morbidities.
Language	English
Publishing date	2023-08-12
Publishing country	England
Document type	Journal Article
ISSN	2059-0105
ISSN (online)	2059-0105
DOI	10.1038/s41541-023-00724-9
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Article: Homologous Ad26.COV2.S vaccination results in reduced boosting of humoral responses in hybrid immunity, but elicits antibodies of similar magnitude regardless of prior infection.

Moyo-Gwete, Thandeka / Richardson, Simone I / Keeton, Roanne / Hermanus, Tandile / Spencer, Holly / Manamela, Nelia P / Ayres, Frances / Makhado, Zanele / Motlou, Thopisang / Tincho, Marius B / Benede, Ntombi / Ngomti, Amkele / Baguma, Richard / Chauke, Masego V / Mennen, Mathilda / Adriaanse, Marguerite / Skelem, Sango / Goga, Ameena / Garrett, Nigel /

Bekker, Linda-Gail / Gray, Glenda / Ntusi, Ntobeko A B / Riou, Catherine / Burgers, Wendy A / Moore, Penny L

medRxiv : the preprint server for health sciences

2023

Abstract: The impact of previous SARS-CoV-2 infection on the durability of Ad26.COV2.S vaccine-elicited responses, and the effect of homologous boosting has not been well explored. We followed a cohort of healthcare workers for 6 months after receiving the Ad26 ... ...

Abstract	The impact of previous SARS-CoV-2 infection on the durability of Ad26.COV2.S vaccine-elicited responses, and the effect of homologous boosting has not been well explored. We followed a cohort of healthcare workers for 6 months after receiving the Ad26.COV2.S vaccine and a further one month after they received an Ad26.COV2.S booster dose. We assessed longitudinal spike-specific antibody and T cell responses in individuals who had never had SARS-CoV-2 infection, compared to those who were infected with either the D614G or Beta variants prior to vaccination. Antibody and T cell responses elicited by the primary dose were durable against several variants of concern over the 6 month follow-up period, regardless of infection history. However, at 6 months after first vaccination, antibody binding, neutralization and ADCC were as much as 33-fold higher in individuals with hybrid immunity compared to those with no prior infection. Antibody cross-reactivity profiles of the previously infected groups were similar at 6 months, unlike at earlier time points suggesting that the effect of immune imprinting diminishes by 6 months. Importantly, an Ad26.COV2.S booster dose increased the magnitude of the antibody response in individuals with no prior infection to similar levels as those with previous infection. The magnitude of spike T cell responses and proportion of T cell responders remained stable after homologous boosting, concomitant with a significant increase in long-lived early differentiated CD4 memory T cells. Thus, these data highlight that multiple antigen exposures, whether through infection and vaccination or vaccination alone, result in similar boosts after Ad26.COV2.S vaccination.
Language	English
Publishing date	2023-03-15
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.03.15.23287288
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Article ; Online: Homologous Ad26.COV2.S vaccination results in reduced boosting of humoral responses in hybrid immunity, but elicits antibodies of similar magnitude regardless of prior infection.

Bekker, Linda-Gail / Gray, Glenda / Ntusi, Ntobeko A B / Riou, Catherine / Burgers, Wendy A / Moore, Penny L

PLoS pathogens

2023 Volume 19, Issue 11, Page(s) e1011772

Abstract	The impact of previous SARS-CoV-2 infection on the durability of Ad26.COV2.S vaccine-elicited responses, and the effect of homologous boosting has not been well explored. We followed a cohort of healthcare workers for 6 months after receiving the Ad26.COV2.S vaccine and a further one month after they received an Ad26.COV2.S booster dose. We assessed longitudinal spike-specific antibody and T cell responses in individuals who had never had SARS-CoV-2 infection, compared to those who were infected with either the D614G or Beta variants prior to vaccination. Antibody and T cell responses elicited by the primary dose were durable against several variants of concern over the 6 month follow-up period, regardless of infection history. However, at 6 months after first vaccination, antibody binding, neutralization and ADCC were as much as 59-fold higher in individuals with hybrid immunity compared to those with no prior infection. Antibody cross-reactivity profiles of the previously infected groups were similar at 6 months, unlike at earlier time points, suggesting that the effect of immune imprinting diminishes by 6 months. Importantly, an Ad26.COV2.S booster dose increased the magnitude of the antibody response in individuals with no prior infection to similar levels as those with previous infection. The magnitude of spike T cell responses and proportion of T cell responders remained stable after homologous boosting, concomitant with a significant increase in long-lived early differentiated CD4 memory T cells. Thus, these data highlight that multiple antigen exposures, whether through infection and vaccination or vaccination alone, result in similar boosts after Ad26.COV2.S vaccination.
MeSH term(s)	Humans ; Ad26COVS1 ; COVID-19/prevention & control ; SARS-CoV-2 ; Antibodies ; Vaccination ; Adaptive Immunity ; Antibodies, Viral ; Antibodies, Neutralizing ; Immunity, Humoral
Chemical Substances	Ad26COVS1 (JT2NS6183B) ; Antibodies ; Antibodies, Viral ; Antibodies, Neutralizing
Language	English
Publishing date	2023-11-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1011772
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Article ; Online: Comparing the immune abnormalities in MIS-C to healthy children and those with inflammatory disease reveals distinct inflammatory cytokine production and a monofunctional T cell response.

Butters, Claire / Benede, Ntombi / Moyo-Gwete, Thandeka / Richardson, Simone I / Rohlwink, Ursula / Shey, Muki / Ayres, Frances / Manamela, Nelia P / Makhado, Zanele / Balla, Sashkia R / Madzivhandila, Mashudu / Ngomti, Amkele / Baguma, Richard / Facey-Thomas, Heidi / Spracklen, Timothy F / Day, Jonathan / van der Ross, Hamza / Riou, Catherine / Burgers, Wendy A /

Scott, Christiaan / Zühlke, Liesl / Moore, Penny L / Keeton, Roanne S / Webb, Kate

Clinical immunology (Orlando, Fla.)

2023 Volume 259, Page(s) 109877

Abstract: Multisystem inflammatory syndrome in children (MIS-C) is a severe, hyperinflammatory disease that occurs after exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The underlying immune pathology of MIS-C is incompletely understood, ... ...

Abstract	Multisystem inflammatory syndrome in children (MIS-C) is a severe, hyperinflammatory disease that occurs after exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The underlying immune pathology of MIS-C is incompletely understood, with limited data comparing MIS-C to clinically similar paediatric febrile diseases at presentation. SARS-CoV-2-specific T cell responses have not been compared in these groups to assess whether there is a T cell profile unique to MIS-C. In this study, we measured inflammatory cytokine concentration and SARS-CoV-2-specific humoral immunity and T cell responses in children with fever and suspected MIS-C at presentation (n = 83) where MIS-C was ultimately confirmed (n = 58) or another diagnosis was made (n = 25) and healthy children (n = 91). Children with confirmed MIS-C exhibited distinctly elevated serum IL-10, IL-6, and CRP at presentation. No differences were detected in SARS-CoV-2 spike IgG serum concentration, neutralisation capacity, antibody dependant cellular phagocytosis, antibody dependant cellular cytotoxicity or SARS-CoV-2-specific T cell frequency between the groups. Healthy SARS-CoV-2 seropositive children had a higher proportion of polyfunctional SARS-CoV-2-specific CD4+ T cells compared to children with MIS-C and those with other inflammatory or infectious diagnoses, who both presented a largely monofunctional SARS-CoV-2-specific CD4+ T cell profile. Treatment with steroids and/or intravenous immunoglobulins resulted in rapid reduction of inflammatory cytokines but did not affect the SARS-CoV-2-specific IgG or CD4+ T cell responses in MIS-C. In these data, MIS-C had a unique cytokine profile but not a unique SARS-CoV-2 specific humoral or T cell cytokine response.
MeSH term(s)	Humans ; Child ; COVID-19 ; SARS-CoV-2 ; Cytokines ; Immunoglobulin G ; Fever ; Antibodies, Viral ; Connective Tissue Diseases ; Systemic Inflammatory Response Syndrome
Chemical Substances	Cytokines ; Immunoglobulin G ; Antibodies, Viral
Language	English
Publishing date	2023-12-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1459903-x
ISSN	1521-7035 ; 1521-6616
ISSN (online)	1521-7035
ISSN	1521-6616
DOI	10.1016/j.clim.2023.109877
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Article ; Online: Distinct T cell polyfunctional profile in SARS-CoV-2 seronegative children associated with endemic human coronavirus cross-reactivity.

Benede, Ntombi / Tincho, Marius B / Walters, Avril / Subbiah, Vennesa / Ngomti, Amkele / Baguma, Richard / Butters, Claire / Hahnle, Lina / Mennen, Mathilda / Skelem, Sango / Adriaanse, Marguerite / Facey-Thomas, Heidi / Scott, Christiaan / Day, Jonathan / Spracklen, Timothy F / van Graan, Strauss / Balla, Sashkia R / Moyo-Gwete, Thandeka / Moore, Penny L /

MacGinty, Rae / Botha, Maresa / Workman, Lesley / Johnson, Marina / Goldblatt, David / Zar, Heather J / Ntusi, Ntobeko A B / Zühlke, Liesl / Webb, Kate / Riou, Catherine / Burgers, Wendy A / Keeton, Roanne S

iScience

2023 Volume 27, Issue 1, Page(s) 108728

Abstract: SARS-CoV-2 infection in children typically results in asymptomatic or mild disease. There is a paucity of studies on SARS-CoV-2 antiviral immunity in African children. We investigated SARS-CoV-2-specific T cell responses in 71 unvaccinated asymptomatic ... ...

Abstract	SARS-CoV-2 infection in children typically results in asymptomatic or mild disease. There is a paucity of studies on SARS-CoV-2 antiviral immunity in African children. We investigated SARS-CoV-2-specific T cell responses in 71 unvaccinated asymptomatic South African children who were seropositive or seronegative for SARS-CoV-2. SARS-CoV-2-specific CD4
Language	English
Publishing date	2023-12-14
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2023.108728
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Article ; Online: Homologous Ad26.COV2.S vaccination results in reduced boosting of humoral responses in hybrid immunity, but elicits antibodies of similar magnitude regardless of prior infection

Bekker, Linda-Gail / Gray, Glenda / Ntusi, Ntobeko A.B / Riou, Catherine / Burgers, Wendy A / Moore, Penny L

medRxiv

Abstract	The impact of previous SARS-CoV-2 infection on the durability of Ad26.COV2.S vaccine-elicited responses, and the effect of homologous boosting has not been well explored. We followed a cohort of healthcare workers for 6 months after receiving the Ad26.COV2.S vaccine and a further one month after they received an Ad26.COV2.S booster dose. We assessed longitudinal spike-specific antibody and T cell responses in individuals who had never had SARS-CoV-2 infection, compared to those who were infected with either the D614G or Beta variants prior to vaccination. Antibody and T cell responses elicited by the primary dose were durable against several variants of concern over the 6 month follow-up period, regardless of infection history. However, at 6 months after first vaccination, antibody binding, neutralization and ADCC were as much as 33-fold higher in individuals with hybrid immunity compared to those with no prior infection. Antibody cross-reactivity profiles of the previously infected groups were similar at 6 months, unlike at earlier time points suggesting that the effect of immune imprinting diminishes by 6 months. Importantly, an Ad26.COV2.S booster dose increased the magnitude of the antibody response in individuals with no prior infection to similar levels as those with previous infection. The magnitude of spike T cell responses and proportion of T cell responders remained stable after homologous boosting, concomitant with a significant increase in long-lived early differentiated CD4 memory T cells. Thus, these data highlight that multiple antigen exposures, whether through infection and vaccination or vaccination alone, result in similar boosts after Ad26.COV2.S vaccination.
Keywords	covid19
Language	English
Publishing date	2023-03-15
Publisher	Cold Spring Harbor Laboratory Press
Document type	Article ; Online
DOI	10.1101/2023.03.15.23287288
Database	COVID19

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Article ; Online: Distinct T cell functional profiles in SARS-CoV-2 seropositive and seronegative children associated with endemic human coronavirus cross-reactivity

medRxiv

Abstract: SUMMARY SARS-CoV-2 infection in children typically results in asymptomatic or mild disease. There is a paucity of studies on antiviral immunity in African children. We investigated SARS-CoV-2-specific T cell responses in 71 unvaccinated asymptomatic ... ...

Abstract	SUMMARY SARS-CoV-2 infection in children typically results in asymptomatic or mild disease. There is a paucity of studies on antiviral immunity in African children. We investigated SARS-CoV-2-specific T cell responses in 71 unvaccinated asymptomatic South African children who were seropositive or seronegative for SARS-CoV-2. SARS-CoV-2-specific CD4+ T cell responses were detectable in 83% of seropositive and 60% of seronegative children. Although the magnitude of the CD4+ T cell response did not differ significantly between the two groups, their functional profiles were distinct, with SARS-CoV-2 seropositive children exhibiting a higher proportion of polyfunctional T cells compared to their seronegative counterparts. The frequency of SARS-CoV-2-specific CD4+ T cells in seronegative children was associated with the endemic human coronavirus (HCoV) HKU1 IgG response. Overall, the presence of SARS-CoV-2-responding T cells in seronegative children may result from cross-reactivity to endemic coronaviruses and could contribute to the relative protection from disease observed in SARS-CoV-2-infected children. Key words: SARS-CoV-2, Children, IgG responses, T cell response, Polyfunctional profile, endemic HCoV
Keywords	covid19
Language	English
Publishing date	2023-05-23
Publisher	Cold Spring Harbor Laboratory Press
Document type	Article ; Online
DOI	10.1101/2023.05.16.23290059
Database	COVID19

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