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Article: Extracellular Vesicles as Drug Delivery Systems in Organ Transplantation: The Next Frontier.

Spiers, Harry V M / Stadler, Lukas K J / Smith, Hugo / Kosmoliaptsis, Vasilis

2023 Volume 15, Issue 3

Abstract: Extracellular vesicles are lipid bilayer-delimited nanoparticles excreted into the extracellular space by all cells. They carry a cargo rich in proteins, lipids and DNA, as well as a full complement of RNA species, which they deliver to recipient cells ... ...

Abstract	Extracellular vesicles are lipid bilayer-delimited nanoparticles excreted into the extracellular space by all cells. They carry a cargo rich in proteins, lipids and DNA, as well as a full complement of RNA species, which they deliver to recipient cells to induce downstream signalling, and they play a key role in many physiological and pathological processes. There is evidence that native and hybrid EVs may be used as effective drug delivery systems, with their intrinsic ability to protect and deliver a functional cargo by utilising endogenous cellular mechanisms making them attractive as therapeutics. Organ transplantation is the gold standard for treatment for suitable patients with end-stage organ failure. However, significant challenges still remain in organ transplantation; prevention of graft rejection requires heavy immunosuppression and the lack of donor organs results in a failure to meet demand, as manifested by growing waiting lists. Pre-clinical studies have demonstrated the ability of EVs to prevent rejection in transplantation and mitigate ischemia reperfusion injury in several disease models. The findings of this work have made clinical translation of EVs possible, with several clinical trials actively recruiting patients. However, there is much to be uncovered, and it is essential to understand the mechanisms behind the therapeutic benefits of EVs. Machine perfusion of isolated organs provides an unparalleled platform for the investigation of EV biology and the testing of the pharmacokinetic and pharmacodynamic properties of EVs. This review classifies EVs and their biogenesis routes, and discusses the isolation and characterisation methods adopted by the international EV research community, before delving into what is known about EVs as drug delivery systems and why organ transplantation represents an ideal platform for their development as drug delivery systems.
Language	English
Publishing date	2023-03-09
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics15030891
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Article ; Online: Molecular Mismatch and the Risk for T Cell-Mediated Rejection.

Wiebe, Chris / Nickerson, Peter W / Kosmoliaptsis, Vasilis

American journal of kidney diseases : the official journal of the National Kidney Foundation

2022 Volume 80, Issue 6, Page(s) 704–706

MeSH term(s)	Humans ; T-Lymphocytes ; Graft Rejection ; Histocompatibility ; Graft Survival
Language	English
Publishing date	2022-09-01
Publishing country	United States
Document type	Editorial ; Comment
ZDB-ID	604539-x
ISSN	1523-6838 ; 0272-6386
ISSN (online)	1523-6838
ISSN	0272-6386
DOI	10.1053/j.ajkd.2022.06.005
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Article ; Online: Large adrenal mass heralding the diagnosis of occult extra-adrenal malignancy in two patients.

Anderton, James / Ghobrial, Marios / Kosmoliaptsis, Vasilis / Casey, Ruth

BMJ case reports

2021 Volume 14, Issue 2

Abstract: We report two cases highlighting the role of fluorine-18-fluorodeoxyglucose positron emission tomography/computerised tomography (18F FDG PET/CT) in the diagnostic and preoperative workup of indeterminate adrenal masses. Case 1: a 60-year-old man was ... ...

Abstract	We report two cases highlighting the role of fluorine-18-fluorodeoxyglucose positron emission tomography/computerised tomography (18F FDG PET/CT) in the diagnostic and preoperative workup of indeterminate adrenal masses. Case 1: a 60-year-old man was diagnosed with a large left-sided adrenal mass with indeterminate radiological characteristics on CT. Biochemical investigations ruled out tumour hypersecretion. 18F FDG PET/CT was performed to exclude metastases and identified a pulmonary nodule in the left upper lobe. Histology of the resected adrenal tumour demonstrated a secondary metastasis from an adenocarcinoma of the lung. Case 2: an 88-year-old male was found to have a heterogeneous and vascular left-sided suprarenal mass and a smaller right-sided adrenal nodule. Both adrenal nodules had indeterminate radiological characteristics. Biochemical investigations were negative. PET/CT demonstrated high avidity in the bilateral adrenal nodules but no extra-adrenal FDG avid disease. Histology demonstrated a metastatic carcinoma of pulmonary origin.
MeSH term(s)	Adrenal Gland Neoplasms/diagnostic imaging ; Adrenal Gland Neoplasms/surgery ; Aged, 80 and over ; Fluorodeoxyglucose F18 ; Humans ; Lung Neoplasms/diagnostic imaging ; Male ; Middle Aged ; Positron Emission Tomography Computed Tomography ; Positron-Emission Tomography ; Radiopharmaceuticals
Chemical Substances	Radiopharmaceuticals ; Fluorodeoxyglucose F18 (0Z5B2CJX4D)
Language	English
Publishing date	2021-02-22
Publishing country	England
Document type	Case Reports ; Journal Article
ISSN	1757-790X
ISSN (online)	1757-790X
DOI	10.1136/bcr-2020-239463
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Article ; Online: HLA molecular mismatches and induced donor-specific tolerance in combined living donor kidney and hematopoietic stem cell transplantation.

Senev, Aleksandar / Tambur, Anat R / Kosmoliaptsis, Vasilis / Copley, Hannah Charlotte / García-Sánchez, Cynthia / Usenko, Crystal / Ildstad, Suzanne T / Leventhal, Joseph R

Frontiers in immunology

2024 Volume 15, Page(s) 1377535

Abstract: Introduction: We investigated the potential role of HLA molecular mismatches (MM) in achieving stable chimerism, allowing for donor-specific tolerance in patients undergoing combined living donor kidney and hematopoietic stem cell transplantation (HSCT). ...

Abstract	Introduction: We investigated the potential role of HLA molecular mismatches (MM) in achieving stable chimerism, allowing for donor-specific tolerance in patients undergoing combined living donor kidney and hematopoietic stem cell transplantation (HSCT). Methods: All patients with available DNA samples (N=32) who participated in a phase 2 clinical trial (NCT00498160) where they received an HLA mismatched co-transplantation of living donor kidney and facilitating cell-enriched HSCT were included in this study. High-resolution HLA genotyping data were used to calculate HLA amino acid mismatches (AAMM), Eplet MM, three-dimensional electrostatic mismatch scores (EMS-3D), PIRCHE scores, HLA-DPB1 T-cell epitope group MM, HLA-B leader sequence MM, and KIR ligands MM between the donor and recipient in both directions. HLA MM were analyzed to test for correlation with the development of chimerism, graft vs. host disease (GvHD), Results: Follow-up time of this cohort was 6-13.5 years. Of the 32 patients, 26 developed high-level donor or mixed stable chimerism, followed by complete withdrawal of immunosuppression (IS) in 25 patients. The remaining six of the 32 patients had transient chimerism or no engraftment and were maintained on IS (On-IS). In host versus graft direction, a trend toward higher median number of HLA-DRB1 MM scores was seen in patients On-IS compared to patients with high-level donor/mixed chimerism, using any of the HLA MM modalities; however, initial statistical significance was observed only for the EMS-3D score (0.45 [IQR, 0.30-0.61] vs. 0.24 [IQR, 0.18-0.36], respectively; p=0.036), which was lost when applying the Bonferroni correction. No statistically significant differences between the two groups were observed for AAMM, EMS-3D, Eplet MM, and PIRCHE-II scores calculated in graft versus host direction. No associations were found between development of chimerism and GvHD and non-permissive HLA-DPB1 T-cell epitope group MM, HLA-B leader sequence, and KIR ligands MM. Conclusion: Our results suggest an association between HLA-DRB1 molecular mismatches and achieving stable chimerism, particularly when electrostatic quality of the mismatch is considered. The non-permissive HLA-DPB1 T-cell epitope group, HLA-B leader sequence, and KIR ligands MM do not predict chimerism and GvHD in this combined kidney/HSCT transplant patient cohort. Further work is needed to validate our findings. Clinical trial registration: https://clinicaltrials.gov/study/NCT00498160, identifier NCT00498160.
MeSH term(s)	Humans ; Living Donors ; Epitopes, T-Lymphocyte ; HLA-DRB1 Chains ; Histocompatibility Testing ; Hematopoietic Stem Cell Transplantation/adverse effects ; Hematopoietic Stem Cell Transplantation/methods ; Graft vs Host Disease/etiology ; Kidney ; HLA-B Antigens
Chemical Substances	Epitopes, T-Lymphocyte ; HLA-DRB1 Chains ; HLA-B Antigens
Language	English
Publishing date	2024-03-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2024.1377535
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Article ; Online: Editorial: Future challenges and directions in determining allo-immunity in kidney transplantation.

Lim, Wai H / Ho, Julie / Kosmoliaptsis, Vasilis / Sapir-Pichhadze, Ruth

Frontiers in immunology

2022 Volume 13, Page(s) 1013711

MeSH term(s)	Forecasting ; Kidney Transplantation/adverse effects ; Transplantation, Homologous
Language	English
Publishing date	2022-08-31
Publishing country	Switzerland
Document type	Editorial
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.1013711
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Article ; Online: Influence of HLA Class II Polymorphism on Predicted Cellular Immunity Against SARS-CoV-2 at the Population and Individual Level.

Copley, Hannah C / Gragert, Loren / Leach, Andrew R / Kosmoliaptsis, Vasilis

Frontiers in immunology

2021 Volume 12, Page(s) 669357

Abstract: Development of adaptive immunity after COVID-19 and after vaccination against SARS-CoV-2 is predicated on recognition of viral peptides, presented on HLA class II molecules, by CD4+ T-cells. We capitalised on extensive high-resolution HLA data on twenty ... ...

Abstract	Development of adaptive immunity after COVID-19 and after vaccination against SARS-CoV-2 is predicated on recognition of viral peptides, presented on HLA class II molecules, by CD4+ T-cells. We capitalised on extensive high-resolution HLA data on twenty five human race/ethnic populations to investigate the role of HLA polymorphism on SARS-CoV-2 immunogenicity at the population and individual level. Within populations, we identify wide inter-individual variability in predicted peptide presentation from structural, non-structural and accessory SARS-CoV-2 proteins, according to individual HLA genotype. However, we find similar potential for anti-SARS-CoV-2 cellular immunity at the population level suggesting that HLA polymorphism is unlikely to account for observed disparities in clinical outcomes after COVID-19 among different race/ethnic groups. Our findings provide important insight on the potential role of HLA polymorphism on development of protective immunity after SARS-CoV-2 infection and after vaccination and a firm basis for further experimental studies in this field.
MeSH term(s)	Antigen Presentation ; CD4-Positive T-Lymphocytes/immunology ; COVID-19/genetics ; COVID-19/immunology ; Genotype ; Histocompatibility Antigens Class II/genetics ; Histocompatibility Antigens Class II/immunology ; Humans ; Immunity, Cellular ; Peptides/immunology ; Polymorphism, Genetic ; Proteome/immunology ; SARS-CoV-2/immunology ; Viral Proteins/immunology
Chemical Substances	Histocompatibility Antigens Class II ; Peptides ; Proteome ; Viral Proteins
Language	English
Publishing date	2021-07-19
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.669357
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Article ; Online: HLA-DQ Mismatches Lead to More Unacceptable Antigens, Greater Sensitization, and Increased Disparities in Repeat Transplant Candidates.

Isaacson, Dylan / Schold, Jesse D / Gmeiner, Michael W / Copley, Hannah C / Kosmoliaptsis, Vasilis / Tambur, Anat R

Journal of the American Society of Nephrology : JASN

2022 Volume 33, Issue 12, Page(s) 2293–2305

Abstract: Background: In single-center studies, HLA-DQ mismatches stimulate the most pathogenic donor-specific antibodies. However, because of limitations of transplant registries, this cannot be directly confirmed with registry-based analyses.: Methods: We ... ...

Abstract	Background: In single-center studies, HLA-DQ mismatches stimulate the most pathogenic donor-specific antibodies. However, because of limitations of transplant registries, this cannot be directly confirmed with registry-based analyses. Methods: We evaluated patients in the Scientific Registry of Transplant Recipients who were relisted after renal graft failure with new, unacceptable antigens corresponding to the HLA typing of their previous donor (UA-PD) as a proxy for donor-specific antibodies. Linear regression was applied to estimate the effects of HLA mismatches on UA-PD and the effects of UA-PD on calculated panel reactive antibody (cPRA) values for 4867 kidney recipients from 2010 to 2021. Results: Each additional HLA-DQ mismatch increased the probability of UA-PD by 25.2% among deceased donor transplant recipients and by 28.9% among living donor transplant recipients, significantly more than all other HLA loci ( Conclusions: HLA-DQ mismatches had the strongest associations with UA-PD, an effect that was greatest in African American and Hispanic recipients. cPRA increases with HLA-DQ UA-PD were equivalent or larger than any other HLA locus. This suggests a need to consider the effects of HLA-DQ in kidney allocation.
MeSH term(s)	Humans ; Transplants ; Transplant Recipients ; Antibodies ; Living Donors ; HLA-DQ Antigens/genetics
Chemical Substances	Antibodies ; HLA-DQ Antigens
Language	English
Publishing date	2022-08-31
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1085942-1
ISSN	1533-3450 ; 1046-6673
ISSN (online)	1533-3450
ISSN	1046-6673
DOI	10.1681/ASN.2022030296
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Zs.A 3344: Show issues

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Article ; Online: The UK kidney donor risk index poorly predicts long-term transplant survival in paediatric kidney transplant recipients.

Kim, Jon Jin / Curtis, Rebecca M K / Reynolds, Ben / Marks, Stephen D / Drage, Martin / Kosmoliaptsis, Vasilis / Dudley, Jan / Williams, Alun

Frontiers in immunology

2023 Volume 14, Page(s) 1207145

Abstract: Background: The UK kidney offering scheme introduced a kidney donor risk index (UK-KDRI) to improve the utility of deceased-donor kidney allocations. The UK-KDRI was derived using adult donor and recipient data. We assessed this in a paediatric cohort ... ...

Abstract	Background: The UK kidney offering scheme introduced a kidney donor risk index (UK-KDRI) to improve the utility of deceased-donor kidney allocations. The UK-KDRI was derived using adult donor and recipient data. We assessed this in a paediatric cohort from the UK transplant registry. Methods: We performed Cox survival analysis on first kidney-only deceased brain-dead transplants in paediatric (<18 years) recipients from 2000-2014. The primary outcome was death-censored allograft survival >30 days post-transplant. The main study variable was UK-KDRI derived from seven donor risk-factors, categorised into four groups (D1-low risk, D2, D3 and D4-highest risk). Follow-up ended on 31-December-2021. Results: 319/908 patients experienced transplant loss with rejection as the main cause (55%). The majority of paediatric patients received donors from D1 donors (64%). There was an increase in D2-4 donors during the study period, whilst the level of HLA mismatching improved. The KDRI was not associated with allograft failure. In multi-variate analysis, increasing recipient age [adjusted HR and 95%CI: 1.05(1.03-1.08) per-year, p<0.001], recipient minority ethnic group [1.28(1.01-1.63), p<0.05), dialysis before transplant [1.38(1.04-1.81), p<0.005], donor height [0.99 (0.98-1.00) per centimetre, p<0.05] and level of HLA mismatch [Level 3: 1.92(1.19-3.11); Level 4: 2.40(1.26-4.58) versus Level 1, p<0.01] were associated with worse outcomes. Patients with Level 1 and 2 HLA mismatches (0 DR +0/1 B mismatch) had median graft survival >17 years regardless of UK-KDRI groups. Increasing donor age was marginally associated with worse allograft survival [1.01 (1.00-1.01) per year, p=0.05]. Summary: Adult donor risk scores were not associated with long-term allograft survival in paediatric patients. The level of HLA mismatch had the most profound effect on survival. Risk models based on adult data alone may not have the same validity for paediatric patients and therefore all age-groups should be included in future risk prediction models.
MeSH term(s)	Adult ; Humans ; Child ; Kidney Transplantation/adverse effects ; Tissue Donors ; Transplantation, Homologous ; Transplants ; Graft Survival ; United Kingdom/epidemiology
Language	English
Publishing date	2023-06-02
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1207145
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Article ; Online: Qualitative, rather than quantitative, differences between HLA-DQ alleles affect HLA-DQ immunogenicity in organ transplantation.

Maguire, Chelsea / Crivello, Pietro / Fleischhauer, Katharina / Isaacson, Dylan / Casillas, Aurora / Kramer, Cynthia S M / Copley, Hannah C / Heidt, Sebastiaan / Kosmoliaptsis, Vasilis / Meneghini, Maria / Gmeiner, Michael / Schold, Jesse / Louzoun, Yoram / Tambur, Anat R

HLA

2024 Volume 103, Issue 4, Page(s) e15455

Abstract: Prolonging the lifespan of transplanted organs is critical to combat the shortage of this life-saving resource. Chronic rejection, with irreversible demise of the allograft, is often caused by the development of donor-specific HLA antibodies. Currently, ... ...

Abstract	Prolonging the lifespan of transplanted organs is critical to combat the shortage of this life-saving resource. Chronic rejection, with irreversible demise of the allograft, is often caused by the development of donor-specific HLA antibodies. Currently, enumerating molecular (amino acid) mismatches between recipient and donor is promoted to identify patients at higher risk of developing HLA antibodies, for use in organ allocation, and immunosuppression-minimization strategies. We have counseled against the incorporation of such approaches into clinical use and hypothesized that not all molecular mismatches equally contribute to generation of donor-specific immune responses. Herein, we document statistical shortcomings in previous study design: for example, use of individuals who lack the ability to generate donor-specific-antibodies (HLA identical) as part of the negative cohort. We provide experimental evidence, using CRISPR-Cas9-edited cells, to rebut the claim that the HLAMatchmaker eplets represent "functional epitopes." We further used unique sub-cohorts of patients, those receiving an allograft with two HLA-DQ mismatches yet developing antibodies only to one mismatch (2MM1DSA), to interrogate differential immunogenicity. Our results demonstrate that mismatches of DQα05-heterodimers exhibit the highest immunogenicity. Additionally, we demonstrate that the DQα chain critically contributes to the overall qualities of DQ molecules. Lastly, our data proposes that an augmented risk to develop donor-specific HLA-DQ antibodies is dependent on qualitative (evolutionary and functional) divergence between recipient and donor, rather than the mere number of molecular mismatches. Overall, we propose an immunological mechanistic rationale to explain differential HLA-DQ immunogenicity, with potential ramifications for other pathological processes such as autoimmunity and infections.
MeSH term(s)	Humans ; Alleles ; Isoantibodies ; Histocompatibility Testing ; Organ Transplantation ; HLA-DQ Antigens/genetics ; Graft Rejection/genetics
Chemical Substances	Isoantibodies ; HLA-DQ Antigens
Language	English
Publishing date	2024-04-04
Publishing country	England
Document type	Journal Article
ZDB-ID	2845111-9
ISSN	2059-2310 ; 2059-2302
ISSN (online)	2059-2310
ISSN	2059-2302
DOI	10.1111/tan.15455
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Zs.A 661: Show issues

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Article ; Online: Significance of HLA-DQ in kidney transplantation: time to reevaluate human leukocyte antigen-matching priorities to improve transplant outcomes? An expert review and recommendations.

Tambur, Anat R / Kosmoliaptsis, Vasilis / Claas, Frans H J / Mannon, Roslyn B / Nickerson, Peter / Naesens, Maarten

Kidney international

2021 Volume 100, Issue 5, Page(s) 1012–1022

Abstract: The weight of human leukocyte antigen (HLA) matching in kidney allocation algorithms, especially in the United States, has been devalued in a stepwise manner, supported by the introduction of modern immunosuppression. The intent was further to reduce the ...

Abstract	The weight of human leukocyte antigen (HLA) matching in kidney allocation algorithms, especially in the United States, has been devalued in a stepwise manner, supported by the introduction of modern immunosuppression. The intent was further to reduce the observed ethnic/racial disparity, as data emerged associating HLA matching with decreased access to transplantation for African American patients. In recent years, it has been increasingly recognized that a leading cause of graft loss is chronic antibody-mediated rejection, attributed to the development of de novo antibodies against mismatched donor HLA expressed on the graft. These antibodies are most frequently against donor HLA-DQ molecules. Beyond their impact on graft survival, generation of de novo donor-specific HLA antibodies also leads to increased sensitization, as measured by panel-reactive antibody metrics. Consequently, access to transplantation for patients returning to the waitlist in need of a second transplant is compromised. Herein, we address the implications of reduced HLA matching policies in kidney allocation. We highlight the observed diminished outcome data, the significant financial burden, the long-term health consequences, and, more important, the unintended consequences. We further provide recommendations to examine the impact of donor-recipient HLA class II and specifically HLA-DQα
MeSH term(s)	Graft Rejection/prevention & control ; Graft Survival ; HLA Antigens ; HLA-DQ Antigens ; Histocompatibility Testing ; Humans ; Isoantibodies ; Kidney Transplantation ; Tissue Donors
Chemical Substances	HLA Antigens ; HLA-DQ Antigens ; Isoantibodies
Language	English
Publishing date	2021-07-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	120573-0
ISSN	1523-1755 ; 0085-2538
ISSN (online)	1523-1755
ISSN	0085-2538
DOI	10.1016/j.kint.2021.06.026
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