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Article: SARS-CoV-2 Mutations and Variants May Muddle the Sensitivity of COVID-19 Diagnostic Assays

Alkhatib, Mohammad / Carioti, Luca / D’Anna, Stefano / Ceccherini-Silberstein, Francesca / Svicher, Valentina / Salpini, Romina

Microorganisms. 2022 Aug. 02, v. 10, no. 8

2022

Abstract: The performance of diagnostic polymerase chain reaction (PCR) assays can be impacted by SARS-CoV-2 variability as this is dependent on the full complementarity between PCR primers/probes and viral target templates. Here, we investigate the genetic ... ...

Abstract	The performance of diagnostic polymerase chain reaction (PCR) assays can be impacted by SARS-CoV-2 variability as this is dependent on the full complementarity between PCR primers/probes and viral target templates. Here, we investigate the genetic variability of SARS-CoV-2 regions recognized by primers/probes utilized by PCR diagnostic assays based on nucleotide mismatching analysis. We evaluated the genetic variation in the binding regions of 73 primers/probes targeting the Nucleocapsid (N, N = 36), Spike (S, N = 22), and RNA-dependent RNA-polymerase/Helicase (RdRp/Hel, N = 15) of the publicly available PCR-based assays. Over 4.9 million high-quality SARS-CoV-2 genome sequences were retrieved from GISAID and were divided into group-A (all except Omicron, >4.2 million) and group-B (only Omicron, >558 thousand). In group-A sequences, a large range of variability in primers/probes binding regions in most PCR assays was observed. Particularly, 87.7% (64/73) of primers/probes displayed ≥1 mismatch with their viral targets, while 8.2% (6/73) contained ≥2 mismatches and 2.7% (2/73) contained ≥3 mismatches. In group-B sequences, 32.9% (24/73) of primers/probes were characterized by ≥1 mismatch, 13.7% (10/73) by ≥2 mismatches, and 5.5% (4/73) by ≥3 mismatches. The high rate of single and multiple mismatches- found in the target regions of molecular assays used worldwide for SARS-CoV-2 diagnosis reinforces the need to optimize and constantly update these assays according to SARS-CoV-2 genetic evolution and the future emergence of novel variants.
Keywords	COVID-19 infection ; Severe acute respiratory syndrome coronavirus 2 ; evolution ; genetic variation ; genome ; nucleocapsid ; polymerase chain reaction
Language	English
Dates of publication	2022-0802
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2720891-6
ISSN	2076-2607
ISSN	2076-2607
DOI	10.3390/microorganisms10081559
Database	NAL-Catalogue (AGRICOLA)

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Article: SARS-CoV-2 Mutations and Variants May Muddle the Sensitivity of COVID-19 Diagnostic Assays.

Alkhatib, Mohammad / Carioti, Luca / D'Anna, Stefano / Ceccherini-Silberstein, Francesca / Svicher, Valentina / Salpini, Romina

Microorganisms

2022 Volume 10, Issue 8

Abstract	The performance of diagnostic polymerase chain reaction (PCR) assays can be impacted by SARS-CoV-2 variability as this is dependent on the full complementarity between PCR primers/probes and viral target templates. Here, we investigate the genetic variability of SARS-CoV-2 regions recognized by primers/probes utilized by PCR diagnostic assays based on nucleotide mismatching analysis. We evaluated the genetic variation in the binding regions of 73 primers/probes targeting the Nucleocapsid (N, N = 36), Spike (S, N = 22), and RNA-dependent RNA-polymerase/Helicase (RdRp/Hel, N = 15) of the publicly available PCR-based assays. Over 4.9 million high-quality SARS-CoV-2 genome sequences were retrieved from GISAID and were divided into group-A (all except Omicron, >4.2 million) and group-B (only Omicron, >558 thousand). In group-A sequences, a large range of variability in primers/probes binding regions in most PCR assays was observed. Particularly, 87.7% (64/73) of primers/probes displayed ≥1 mismatch with their viral targets, while 8.2% (6/73) contained ≥2 mismatches and 2.7% (2/73) contained ≥3 mismatches. In group-B sequences, 32.9% (24/73) of primers/probes were characterized by ≥1 mismatch, 13.7% (10/73) by ≥2 mismatches, and 5.5% (4/73) by ≥3 mismatches. The high rate of single and multiple mismatches- found in the target regions of molecular assays used worldwide for SARS-CoV-2 diagnosis reinforces the need to optimize and constantly update these assays according to SARS-CoV-2 genetic evolution and the future emergence of novel variants.
Language	English
Publishing date	2022-08-02
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720891-6
ISSN	2076-2607
ISSN	2076-2607
DOI	10.3390/microorganisms10081559
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: First National Prevalence in Italian Horse Population and Phylogenesis Highlight a Fourth Sub-Type Candidate of Equine Hepacivirus.

Nardini, Roberto / Pacchiarotti, Giulia / Svicher, Valentina / Salpini, Romina / Bellocchi, Maria Concetta / Conti, Raffaella / Sala, Marcello Giovanni / La Rocca, Davide / Carioti, Luca / Cersini, Antonella / Manna, Giuseppe / The Equine Hepatic Viruses Consortium / Scicluna, Maria Teresa

Viruses

2024 Volume 16, Issue 4

Abstract: Equine hepacivirus (EqHV, ...

Abstract	Equine hepacivirus (EqHV,
MeSH term(s)	Animals ; Italy/epidemiology ; Horses/virology ; Horse Diseases/virology ; Horse Diseases/epidemiology ; Phylogeny ; Prevalence ; Hepacivirus/genetics ; Hepacivirus/classification ; Hepacivirus/isolation & purification ; Hepatitis C/epidemiology ; Hepatitis C/virology ; Hepatitis C/veterinary ; Viral Nonstructural Proteins/genetics ; Genotype ; RNA, Viral/genetics
Chemical Substances	Viral Nonstructural Proteins ; RNA, Viral
Language	English
Publishing date	2024-04-16
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v16040616
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: First Case of a COVID-19 Patient Infected by Delta AY.4 with a Rare Deletion Leading to a N Gene Target Failure by a Specific Real Time PCR Assay: Novel Omicron VOC Might Be Doing Similar Scenario?

Alkhatib, Mohammad / Bellocchi, Maria Concetta / Marchegiani, Greta / Grelli, Sandro / Micheli, Valeria / Stella, Daniele / Zerillo, Bartolomeo / Carioti, Luca / Svicher, Valentina / Rogliani, Paola / Ceccherini-Silberstein, Francesca

Microorganisms. 2022 Jan. 25, v. 10, no. 2

2022

Abstract: Herein, we report a case of an Italian male infected by Delta sublineage AY.4 harboring an atypical deletion, leading to a N gene target failure (NGTF) by a commercial molecular assay for SARS-CoV-2 diagnosis (Allplexᵀᴹ SARS-CoV-2 Assay, Seegene). A 59- ... ...

Abstract	Herein, we report a case of an Italian male infected by Delta sublineage AY.4 harboring an atypical deletion, leading to a N gene target failure (NGTF) by a commercial molecular assay for SARS-CoV-2 diagnosis (Allplexᵀᴹ SARS-CoV-2 Assay, Seegene). A 59-year-old unvaccinated patient was hospitalized for pulmonary embolism, with first negative results obtained by both molecular and antigen tests. After several days of viral negativity, he presented positive results for E and RdRP/S genes, but negative in N gene. Negativity in N gene was repeatedly confirmed in the following days. Suspecting an infection by the Omicron variant, SARS-CoV-2 genome sequencing was rapidly performed from nasopharyngeal swab by MiSeq and revealed the presence of the Delta sublineage AY.4 variant with an atypical deletion of six nucleotides, leading to G214-G215 deletion in the Nucleocapsid, thus responsible for NGTF. The analysis of GISAID sequences (N = 2,618,373 12 January 2022) showed that G214-G215 deletion is rarely occurring in most circulating Delta lineages and sublineages in the globe and Europe, with an overall prevalence never exceeding 0.2%. Hence, this study highlights the importance to perform SARS-CoV-2 sequencing and to characterize novel mutations/deletions that could jeopardize the proper interpretation of molecular diagnostic tests. Based on these assumptions, the role of deletions in the recently identified Omicron variant deserves further investigation.
Keywords	COVID-19 infection ; Severe acute respiratory syndrome coronavirus 2 ; antigens ; embolism ; genes ; males ; nucleocapsid ; nucleotides ; patients ; quantitative polymerase chain reaction ; Europe
Language	English
Dates of publication	2022-0125
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2720891-6
ISSN	2076-2607
ISSN	2076-2607
DOI	10.3390/microorganisms10020268
Database	NAL-Catalogue (AGRICOLA)

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Article: Evaluation of HIV-1 integrase variability by combining computational and probabilistic approaches

Vergni, Davide / Santoni, Daniele / Bouba, Yagai / Lemme, Saverio / Fabeni, Lavinia / Carioti, Luca / Bertoli, Ada / Gennari, William / Forbici, Federica / Perno, Carlo Federico / Gagliardini, Roberta / Ceccherini-Silberstein, Francesca / Santoro, Maria Mercedes

Infection, genetics, and evolution. 2022 July, v. 101

2022

Abstract: This study aimed at updating previous data on HIV-1 integrase variability, by using effective bioinformatics methods combining different statistical instruments from simple entropy and mutation rate to more specific approaches such as Hellinger distance. ...

Institution	on behalf of the HIV drug-resistance group
Abstract	This study aimed at updating previous data on HIV-1 integrase variability, by using effective bioinformatics methods combining different statistical instruments from simple entropy and mutation rate to more specific approaches such as Hellinger distance. A total of 2133 HIV-1 integrase sequences were analyzed in: i) 1460 samples from drug-naïve [DN] individuals; ii) 386 samples from drug-experienced but INI-naïve [IN] individuals; iii) 287 samples from INI-experienced [IE] individuals. Within the three groups, 76 amino acid positions were highly conserved (≤0.2% variation, Hellinger distance: <0.25%), with 35 fully invariant positions; while, 80 positions were conserved (>0.2% to <1% variation, Hellinger distance: <1%). The H12-H16-C40-C43 and D64-D116-E152 motifs were all well conserved. Some residues were affected by dramatic changes in their mutation distributions, especially between DN and IE samples (Hellinger distance ≥1%). In particular, 15 positions (D6, S24, V31, S39, L74, A91, S119, T122, T124, T125, V126, K160, N222, S230, C280) showed a significant decrease of mutation rate in IN and/or IE samples compared to DN samples. Conversely, 8 positions showed significantly higher mutation rate in samples from treated individuals (IN and/or IE) compared to DN. Some of these positions, such as E92, T97, G140, Y143, Q148 and N155, were already known to be associated with resistance to integrase inhibitors; other positions including S24, M154, V165 and D270 are not yet documented to be associated with resistance. Our study confirms the high conservation of HIV-1 integrase and identified highly invariant positions using robust and innovative methods. The role of novel mutations located in the critical region of HIV-1 integrase deserves further investigation.
Keywords	amino acids ; bioinformatics ; entropy ; infection ; integrases ; mutation ; mutation rate
Language	English
Dates of publication	2022-07
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	2037068-4
ISSN	1567-1348
ISSN	1567-1348
DOI	10.1016/j.meegid.2022.105294
Database	NAL-Catalogue (AGRICOLA)

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Article: Viral resistance burden and APOBEC editing correlate with virological response in heavily treatment-experienced people living with multi-drug resistant HIV

Armenia, Daniele / Santoro, Maria Mercedes / Bellocchi, Maria Concetta / Carioti, Luca / Galli, Laura / Galli, Andrea / Scutari, Rossana / Salsi, Eleonora / Mussini, Cristina / Sterrantino, Gaetana / Calza, Leonardo / Rossetti, Barbara / Zazzi, Maurizio / Castagna, Antonella

International journal of antimicrobial agents. 2022 Jan., v. 59, no. 1

2022

Abstract: The impact of drug resistance mutational load and APOBEC editing in heavily treatment-experienced (HTE) people living with multidrug-resistant HIV has not been investigated.This study explored the HIV-DNA and HIV-RNA mutational load of drug resistance ... ...

Institution	PRESTIGIO Registry Study Group
Abstract	The impact of drug resistance mutational load and APOBEC editing in heavily treatment-experienced (HTE) people living with multidrug-resistant HIV has not been investigated.This study explored the HIV-DNA and HIV-RNA mutational load of drug resistance and APOBEC-related mutations through next-generation sequencing (NGS, Illumina MiSeq) in 20 failing HTE participants enrolled in the PRESTIGIO registry.The patients showed high levels of both HIV-DNA (4.5 [4.0–5.2] log₁₀ copies/10⁶ T-CD4+ cell) and HIV-RNA (4.5 [4.1–5.0] log₁₀ copies/mL) with complex resistance patterns in both compartments. Among the 255 drug-resistant mutations found, 66.3% were concordantly detected in both HIV-DNA and HIV-RNA; 71.3% of mutations were already present in historical Sanger genotypes. At an intra-patient frequency > 5%, a considerable proportion of mutations detected through DNA-NGS were found in historical genotypes but not through RNA-NGS, and few patients had APOBEC-related mutations. Of 14 patients who switched therapy, the five who failed treatment had DNA resistance with higher intra-patient frequency and higher DNA/RNA mutational load in a context of tendentially less pronounced APOBEC editing compared with those who responded.Using NGS in HIV-DNA and HIV-RNA together with APOBEC editing evaluation might help to identify HTE individuals with MDR who are more prone to experience virological failure.
Keywords	DNA ; RNA ; multiple drug resistance ; people ; therapeutics
Language	English
Dates of publication	2022-01
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	1093977-5
ISSN	1872-7913 ; 0924-8579
ISSN (online)	1872-7913
ISSN	0924-8579
DOI	10.1016/j.ijantimicag.2021.106492
Database	NAL-Catalogue (AGRICOLA)

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Article: Molecular and Structural Aspects of Clinically Relevant Mutations of SARS-CoV-2 RNA-Dependent RNA Polymerase in Remdesivir-Treated Patients.

Gratteri, Carmen / Ambrosio, Francesca Alessandra / Lupia, Antonio / Moraca, Federica / Catalanotti, Bruno / Costa, Giosuè / Bellocchi, Maria / Carioti, Luca / Salpini, Romina / Ceccherini-Silberstein, Francesca / Frazia, Simone La / Malagnino, Vincenzo / Sarmati, Loredana / Svicher, Valentina / Bryant, Sharon / Artese, Anna / Alcaro, Stefano

Pharmaceuticals (Basel, Switzerland)

2023 Volume 16, Issue 8

Abstract: 1) Background: SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) is a promising therapeutic target to fight COVID-19, and many RdRp inhibitors nucleotide/nucleoside analogs, such as remdesivir, have been identified or are in clinical studies. However, the ... ...

Abstract	(1) Background: SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) is a promising therapeutic target to fight COVID-19, and many RdRp inhibitors nucleotide/nucleoside analogs, such as remdesivir, have been identified or are in clinical studies. However, the appearance of resistant mutations could reduce their efficacy. In the present work, we structurally evaluated the impact of RdRp mutations found at baseline in 39 patients treated with remdesivir and associated with a different degree of antiviral response in vivo. (2) Methods: A refined bioinformatics approach was applied to assign SARS-CoV-2 clade and lineage, and to define RdRp mutational profiles. In line with such a method, the same mutations were built and analyzed by combining docking and thermodynamics evaluations with both molecular dynamics and representative pharmacophore models. (3) Results: Clinical studies revealed that patients bearing the most prevalent triple mutant P323L+671S+M899I, which was present in 41% of patients, or the more complex mutational profile P323L+G671S+L838I+D738Y+K91E, which was found with a prevalence of 2.6%, showed a delayed reduced response to remdesivir, as confirmed by the increase in SARS-CoV-2 viral load and by a reduced theoretical binding affinity versus RdRp (ΔGbind
Language	English
Publishing date	2023-08-12
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph16081143
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: First Case of a COVID-19 Patient Infected by Delta AY.4 with a Rare Deletion Leading to a N Gene Target Failure by a Specific Real Time PCR Assay: Novel Omicron VOC Might Be Doing Similar Scenario?

Microorganisms

2022 Volume 10, Issue 2

Abstract	Herein, we report a case of an Italian male infected by Delta sublineage AY.4 harboring an atypical deletion, leading to a N gene target failure (NGTF) by a commercial molecular assay for SARS-CoV-2 diagnosis (Allplex
Language	English
Publishing date	2022-01-25
Publishing country	Switzerland
Document type	Case Reports
ZDB-ID	2720891-6
ISSN	2076-2607
ISSN	2076-2607
DOI	10.3390/microorganisms10020268
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Evaluation of HIV-1 integrase variability by combining computational and probabilistic approaches.

Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases

2022 Volume 101, Page(s) 105294

Abstract	This study aimed at updating previous data on HIV-1 integrase variability, by using effective bioinformatics methods combining different statistical instruments from simple entropy and mutation rate to more specific approaches such as Hellinger distance. A total of 2133 HIV-1 integrase sequences were analyzed in: i) 1460 samples from drug-naïve [DN] individuals; ii) 386 samples from drug-experienced but INI-naïve [IN] individuals; iii) 287 samples from INI-experienced [IE] individuals. Within the three groups, 76 amino acid positions were highly conserved (≤0.2% variation, Hellinger distance: <0.25%), with 35 fully invariant positions; while, 80 positions were conserved (>0.2% to <1% variation, Hellinger distance: <1%). The H12-H16-C40-C43 and D64-D116-E152 motifs were all well conserved. Some residues were affected by dramatic changes in their mutation distributions, especially between DN and IE samples (Hellinger distance ≥1%). In particular, 15 positions (D6, S24, V31, S39, L74, A91, S119, T122, T124, T125, V126, K160, N222, S230, C280) showed a significant decrease of mutation rate in IN and/or IE samples compared to DN samples. Conversely, 8 positions showed significantly higher mutation rate in samples from treated individuals (IN and/or IE) compared to DN. Some of these positions, such as E92, T97, G140, Y143, Q148 and N155, were already known to be associated with resistance to integrase inhibitors; other positions including S24, M154, V165 and D270 are not yet documented to be associated with resistance. Our study confirms the high conservation of HIV-1 integrase and identified highly invariant positions using robust and innovative methods. The role of novel mutations located in the critical region of HIV-1 integrase deserves further investigation.
MeSH term(s)	Drug Resistance, Viral/genetics ; HIV Infections/drug therapy ; HIV Integrase/chemistry ; HIV Integrase Inhibitors/pharmacology ; HIV-1/genetics ; Humans ; Mutation
Chemical Substances	HIV Integrase Inhibitors ; HIV Integrase (EC 2.7.7.-) ; p31 integrase protein, Human immunodeficiency virus 1 (YY6481J2FF)
Language	English
Publishing date	2022-05-02
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2037068-4
ISSN	1567-7257 ; 1567-1348
ISSN (online)	1567-7257
ISSN	1567-1348
DOI	10.1016/j.meegid.2022.105294
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Update on SARS-CoV-2 Omicron Variant of Concern and Its Peculiar Mutational Profile.

Alkhatib, Mohammad / Salpini, Romina / Carioti, Luca / Ambrosio, Francesca Alessandra / D'Anna, Stefano / Duca, Leonardo / Costa, Giosuè / Bellocchi, Maria Concetta / Piermatteo, Lorenzo / Artese, Anna / Santoro, Maria Mercedes / Alcaro, Stefano / Svicher, Valentina / Ceccherini-Silberstein, Francesca

Microbiology spectrum

2022 Volume 10, Issue 2, Page(s) e0273221

Abstract: The process of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genetic diversification is still ongoing and has very recently led to the emergence of a new variant of concern (VOC), defined as Omicron or B.1.1.529. Omicron VOC is the most ... ...

Abstract	The process of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genetic diversification is still ongoing and has very recently led to the emergence of a new variant of concern (VOC), defined as Omicron or B.1.1.529. Omicron VOC is the most divergent variant identified so far and has generated immediate concern for its potential capability to increase SARS-CoV-2 transmissibility and, more worryingly, to escape therapeutic and vaccine-induced antibodies. Nevertheless, a clear definition of the Omicron VOC mutational spectrum is still missing. Herein, we provide a comprehensive definition and functional characterization (in terms of infectivity and/or antigenicity) of mutations characterizing the Omicron VOC. In particular, 887,475 SARS-CoV-2 Omicron VOC whole-genome sequences were retrieved from the GISAID database and used to precisely define its specific patterns of mutations across the different viral proteins. In addition, the functional characterization of Omicron VOC spike mutations was finely discussed according to published manuscripts. Lastly, residues characterizing the Omicron VOC and the previous four VOCs (Alpha, Beta, Gamma, and Delta) were mapped on the three-dimensional structure of the SARS-CoV-2 spike protein to assess their localization in the different spike domains. Overall, our study will assist with deciphering the Omicron VOC mutational profile and will shed more light on its clinical implications. This is critical considering that Omicron VOC is currently the predominant variant worldwide.
MeSH term(s)	COVID-19 ; Humans ; Mutation ; SARS-CoV-2/genetics ; Spike Glycoprotein, Coronavirus ; Vaccines
Chemical Substances	Spike Glycoprotein, Coronavirus ; Vaccines ; spike protein, SARS-CoV-2
Language	English
Publishing date	2022-03-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2807133-5
ISSN	2165-0497 ; 2165-0497
ISSN (online)	2165-0497
ISSN	2165-0497
DOI	10.1128/spectrum.02732-21
Database	MEDical Literature Analysis and Retrieval System OnLINE

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