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Article: Counties with Lower Insurance Coverage and Housing Problems Are Associated with Both Slower Vaccine Rollout and Higher COVID-19 Incidence.

Donadio, Gregory / Choudhary, Mayank / Lindemer, Emily / Pawlowski, Colin / Soundararajan, Venky

2021 Volume 9, Issue 9

Abstract: Equitable vaccination distribution is a priority for outcompeting the transmission of COVID-19. Here, the impact of demographic, socioeconomic, and environmental factors on county-level vaccination rates and COVID-19 incidence changes is assessed. In ... ...

Abstract	Equitable vaccination distribution is a priority for outcompeting the transmission of COVID-19. Here, the impact of demographic, socioeconomic, and environmental factors on county-level vaccination rates and COVID-19 incidence changes is assessed. In particular, using data from 3142 US counties with over 328 million individuals, correlations were computed between cumulative vaccination rate and change in COVID-19 incidence from 1 December 2020 to 6 June 2021, with 44 different demographic, environmental, and socioeconomic factors. This correlation analysis was also performed using multivariate linear regression to adjust for age as a potential confounding variable. These correlation analyses demonstrated that counties with high levels of uninsured individuals have significantly lower COVID-19 vaccination rates (Spearman correlation: -0.460,
Language	English
Publishing date	2021-08-31
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2703319-3
ISSN	2076-393X
ISSN	2076-393X
DOI	10.3390/vaccines9090973
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: On the Origins of Omicron's Unique Spike Gene Insertion.

Venkatakrishnan, A J / Anand, Praveen / Lenehan, Patrick J / Suratekar, Rohit / Raghunathan, Bharathwaj / Niesen, Michiel J M / Soundararajan, Venky

Vaccines

2022 Volume 10, Issue 9

Abstract: The emergence of a heavily mutated SARS-CoV-2 variant (Omicron; Pango lineage B.1.1.529 and BA sublineages) and its rapid spread to over 75 countries raised a global public health alarm. Characterizing the mutational profile of Omicron is necessary to ... ...

Abstract	The emergence of a heavily mutated SARS-CoV-2 variant (Omicron; Pango lineage B.1.1.529 and BA sublineages) and its rapid spread to over 75 countries raised a global public health alarm. Characterizing the mutational profile of Omicron is necessary to interpret its clinical phenotypes which are shared with or distinctive from those of other SARS-CoV-2 variants. We compared the mutations of the initially circulating Omicron variant (now known as BA.1) with prior variants of concern (Alpha, Beta, Gamma, and Delta), variants of interest (Lambda, Mu, Eta, Iota, and Kappa), and ~1500 SARS-CoV-2 lineages constituting ~5.8 million SARS-CoV-2 genomes. Omicron's Spike protein harbors 26 amino acid mutations (23 substitutions, 2 deletions, and 1 insertion) that are distinct compared to other variants of concern. While the substitution and deletion mutations appeared in previous SARS-CoV-2 lineages, the insertion mutation (ins214EPE) was not previously observed in any other SARS-CoV-2 lineage. Here, we consider and discuss various mechanisms through which the nucleotide sequence encoding for ins214EPE could have been acquired, including local duplication, polymerase slippage, and template switching. Although we are not able to definitively determine the mechanism, we highlight the plausibility of template switching. Analysis of the homology of the inserted nucleotide sequence and flanking regions suggests that this template-switching event could have involved the genomes of SARS-CoV-2 variants (e.g., the B.1.1 strain), other human coronaviruses that infect the same host cells as SARS-CoV-2 (e.g., HCoV-OC43 or HCoV-229E), or a human transcript expressed in a host cell that was infected by the Omicron precursor.
Language	English
Publishing date	2022-09-09
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2703319-3
ISSN	2076-393X
ISSN	2076-393X
DOI	10.3390/vaccines10091509
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Article: Genetic alteration of human MYH6 is mimicked by SARS-CoV-2 polyprotein: mapping viral variants of cardiac interest.

Anand, Praveen / Lenehan, Patrick J / Niesen, Michiel / Yoo, Unice / Patwardhan, Dhruti / Montorzi, Marcelo / Venkatakrishnan, A J / Soundararajan, Venky

Cell death discovery

2022 Volume 8, Issue 1, Page(s) 124

Abstract: Acute cardiac injury has been observed in a subset of COVID-19 patients, but the molecular basis for this clinical phenotype is unknown. It has been hypothesized that molecular mimicry may play a role in triggering an autoimmune inflammatory reaction in ... ...

Abstract	Acute cardiac injury has been observed in a subset of COVID-19 patients, but the molecular basis for this clinical phenotype is unknown. It has been hypothesized that molecular mimicry may play a role in triggering an autoimmune inflammatory reaction in some individuals after SARS-CoV-2 infection. Here we investigate if linear peptides contained in proteins that are primarily expressed in the heart also occur in the SARS-CoV-2 proteome. Specifically, we compared the library of 136,704 8-mer peptides from 144 human proteins (including splicing variants) to 9926 8-mers from all the viral proteins in the reference SARS-CoV-2 proteome. No 8-mers were exactly identical between the reference human proteome and the reference SARS-CoV-2 proteome. However, there were 45 8-mers that differed by only one amino acid when compared to the reference SARS-CoV-2 proteome. Interestingly, analysis of protein-coding mutations from 141,456 individuals showed that one of these 8-mers from the SARS-CoV-2 Replicase polyprotein 1a/1ab (KIALKGGK) is identical to an MYH6 peptide encoded by the c.5410 C > A (Q1804K) genetic variation, which has been observed at low prevalence in Africans/African Americans (0.08%), East Asians (0.3%), South Asians (0.06%), and Latino/Admixed Americans (0.003%). Furthermore, analysis of 4.85 million SARS-CoV-2 genomes from over 200 countries shows that viral evolution has already resulted in 20 additional 8-mer peptides that are identical to human heart-enriched proteins encoded by reference sequences or genetic variants. Whether such mimicry contributes to cardiac inflammation during or after COVID-19 illness warrants further experimental evaluation. We suggest that SARS-CoV-2 variants harboring peptides identical to human cardiac proteins should be investigated as "viral variants of cardiac interest".
Language	English
Publishing date	2022-03-21
Publishing country	United States
Document type	Journal Article
ISSN	2058-7716
ISSN	2058-7716
DOI	10.1038/s41420-022-00914-9
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Article ; Online: High diversity in Delta variant across countries revealed by genome-wide analysis of SARS-CoV-2 beyond the Spike protein.

Suratekar, Rohit / Ghosh, Pritha / Niesen, Michiel J M / Donadio, Gregory / Anand, Praveen / Soundararajan, Venky / Venkatakrishnan, A J

Molecular systems biology

2022 Volume 18, Issue 2, Page(s) e10673

Abstract: The highly contagious Delta variant of SARS-CoV-2 has become a prevalent strain globally and poses a public health challenge around the world. While there has been extensive focus on understanding the amino acid mutations in the Delta variant's Spike ... ...

Abstract	The highly contagious Delta variant of SARS-CoV-2 has become a prevalent strain globally and poses a public health challenge around the world. While there has been extensive focus on understanding the amino acid mutations in the Delta variant's Spike protein, the mutational landscape of the rest of the SARS-CoV-2 proteome (25 proteins) remains poorly understood. To this end, we performed a systematic analysis of mutations in all the SARS-CoV-2 proteins from nearly 2 million SARS-CoV-2 genomes from 176 countries/territories. Six highly prevalent missense mutations in the viral life cycle-associated Membrane (I82T), Nucleocapsid (R203M, D377Y), NS3 (S26L), and NS7a (V82A, T120I) proteins are almost exclusive to the Delta variant compared to other variants of concern (mean prevalence across genomes: Delta = 99.74%, Alpha = 0.06%, Beta = 0.09%, and Gamma = 0.22%). Furthermore, we find that the Delta variant harbors a more diverse repertoire of mutations across countries compared to the previously dominant Alpha variant. Overall, our study underscores the high diversity of the Delta variant between countries and identifies a list of amino acid mutations in the Delta variant's proteome for probing the mechanistic basis of pathogenic features such as high viral loads, high transmissibility, and reduced susceptibility against neutralization by vaccines.
MeSH term(s)	COVID-19 ; Humans ; Mutation ; Mutation, Missense ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus/genetics
Chemical Substances	Spike Glycoprotein, Coronavirus
Language	English
Publishing date	2022-01-18
Publishing country	England
Document type	Journal Article
ZDB-ID	2193510-5
ISSN	1744-4292 ; 1744-4292
ISSN (online)	1744-4292
ISSN	1744-4292
DOI	10.15252/msb.202110673
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Article ; Online: Counties with lower insurance coverage are associated with both slower vaccine rollout and higher COVID-19 incidence across the United States

Lindemer, Emily / Choudhary, Mayank / Donadio, Gregory / Pawlowski, Colin / Soundararajan, Venky

medRxiv

Abstract: Efficient and equitable vaccination distribution is a priority for effectively outcompeting the transmission of COVID-19 globally. A recent study from the Centers for Disease Control and Prevention (CDC) identified that US counties with high social ... ...

Abstract	Efficient and equitable vaccination distribution is a priority for effectively outcompeting the transmission of COVID-19 globally. A recent study from the Centers for Disease Control and Prevention (CDC) identified that US counties with high social vulnerability according to metrics such as poverty, unemployment, low income, and no high school diploma, have significantly lower rates of vaccination compared to the national average1. Here, we build upon this analysis to consider associations between county-level vaccination rates and 68 different demographic, socioeconomic, and environmental factors for 1,510 American counties with over 228 million individuals for which vaccination data was also available. Our analysis reveals that counties with high levels of uninsured individuals have significantly lower COVID-19 vaccination rates (Spearman correlation: -0.264), despite the fact that the CDC has mandated that all COVID-19 vaccines are free and cannot be denied to anyone based upon health insurance coverage or immigration status. Furthermore, we find that the counties with high levels of uninsured individuals tend to have the highest COVID-19 incidence rates in March 2021 relative to December 2020 (Spearman correlation: 0.388). Among the 68 factors analyzed, insurance coverage is the only factor which is highly correlated with both vaccination rate and change in COVID-19 incidence during the vaccination period (\|Spearman correlation\| > 0.25). We also find that counties with higher percentages of Black and Hispanic individuals have significantly lower vaccination rates (Spearman correlations: -0.128, -0.136) and lesser declines of COVID-incidence rates (Spearman correlations: 0.334, 0.330) during the vaccination period. Surprisingly however, after controlling for race, we find that the association between lack of insurance coverage and vaccination rate as well as COVID-19 incidence rates is largely driven by counties with a majority white population. Among the counties with high proportions of white residents (top 10% decile), the association between insurance coverage and vaccination rate is significant (Spearman correlation: -0.210, p-value: 0.002), but among counties with low proportions of white residents (bottom 10% decile) this association is not significant (Spearman correlation: 0.072, p-value: 0.088). Taken together, this study highlights the fact that intricate socioeconomic factors are correlated not just to COVID-19 vaccination rates, but also to COVID-19 incidence fluctuations, underscoring the need to improve COVID-19 vaccination campaigns in marginalized communities. The strong positive correlation between low levels of health insurance coverage and low vaccination rates is particularly concerning, and calls for improved public health messaging to emphasize the fact that health insurance is not required to be eligible for any of the FDA-authorized COVID-19 vaccines in the United States.
Keywords	covid19
Language	English
Publishing date	2021-03-26
Publisher	Cold Spring Harbor Laboratory Press
Document type	Article ; Online
DOI	10.1101/2021.03.24.21254270
Database	COVID19

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Article ; Online: Global connectivity of hub residues in Oncoprotein structures encodes genetic factors dictating personalized drug response to targeted Cancer therapy.

Soundararajan, Venky / Aravamudan, Murali

Scientific reports

2014 Volume 4, Page(s) 7294

Abstract: The efficacy and mechanisms of therapeutic action are largely described by atomic bonds and interactions local to drug binding sites. Here we introduce global connectivity analysis as a high-throughput computational assay of therapeutic action--inspired ... ...

Abstract	The efficacy and mechanisms of therapeutic action are largely described by atomic bonds and interactions local to drug binding sites. Here we introduce global connectivity analysis as a high-throughput computational assay of therapeutic action--inspired by the Google page rank algorithm that unearths most "globally connected" websites from the information-dense world wide web (WWW). We execute short timescale (30 ps) molecular dynamics simulations with high sampling frequency (0.01 ps), to identify amino acid residue hubs whose global connectivity dynamics are characteristic of the ligand or mutation associated with the target protein. We find that unexpected allosteric hubs--up to 20 Å from the ATP binding site, but within 5 Å of the phosphorylation site--encode the Gibbs free energy of inhibition (ΔG(inhibition)) for select protein kinase-targeted cancer therapeutics. We further find that clinically relevant somatic cancer mutations implicated in both drug resistance and personalized drug sensitivity can be predicted in a high-throughput fashion. Our results establish global connectivity analysis as a potent assay of protein functional modulation. This sets the stage for unearthing disease-causal exome mutations and motivates forecast of clinical drug response on a patient-by-patient basis. We suggest incorporation of structure-guided genetic inference assays into pharmaceutical and healthcare Oncology workflows.
MeSH term(s)	Binding Sites/genetics ; Drug Resistance, Neoplasm/genetics ; Humans ; Molecular Dynamics Simulation ; Molecular Targeted Therapy/methods ; Mutation/genetics ; Neoplasms/drug therapy ; Neoplasms/genetics ; Oncogene Proteins/genetics ; Precision Medicine/methods ; Protein Binding/genetics ; Protein Kinases/genetics
Chemical Substances	Oncogene Proteins ; Protein Kinases (EC 2.7.-)
Language	English
Publishing date	2014-12-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/srep07294
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Benchmarking evolutionary tinkering underlying human-viral molecular mimicry shows multiple host pulmonary-arterial peptides mimicked by SARS-CoV-2.

Venkatakrishnan, A J / Kayal, Nikhil / Anand, Praveen / Badley, Andrew D / Church, George M / Soundararajan, Venky

Cell death discovery

2020 Volume 6, Issue 1, Page(s) 96

Abstract: The hand of molecular mimicry in shaping SARS-CoV-2 evolution and immune evasion remains to be deciphered. Here, we report 33 distinct 8-mer/9-mer peptides that are identical between SARS-CoV-2 and the human reference proteome. We benchmark this ... ...

Abstract	The hand of molecular mimicry in shaping SARS-CoV-2 evolution and immune evasion remains to be deciphered. Here, we report 33 distinct 8-mer/9-mer peptides that are identical between SARS-CoV-2 and the human reference proteome. We benchmark this observation against other viral-human 8-mer/9-mer peptide identity, which suggests generally similar extents of molecular mimicry for SARS-CoV-2 and many other human viruses. Interestingly, 20 novel human peptides mimicked by SARS-CoV-2 have not been observed in any previous coronavirus strains (HCoV, SARS-CoV, and MERS). Furthermore, four of the human 8-mer/9-mer peptides mimicked by SARS-CoV-2 map onto HLA-B40:01, HLA-B40:02, and HLA-B35:01 binding peptides from human PAM, ANXA7, PGD, and ALOX5AP proteins. This mimicry of multiple human proteins by SARS-CoV-2 is made salient by single-cell RNA-seq (scRNA-seq) analysis that shows the targeted genes significantly expressed in human lungs and arteries; tissues implicated in COVID-19 pathogenesis. Finally, HLA-A03 restricted 8-mer peptides are found to be shared broadly by human and coronaviridae helicases in functional hotspots, with potential implications for nucleic acid unwinding upon initial infection. This study presents the first scan of human peptide mimicry by SARS-CoV-2, and via its benchmarking against human-viral mimicry more broadly, presents a computational framework for follow-up studies to assay how evolutionary tinkering may relate to zoonosis and herd immunity.
Keywords	covid19
Language	English
Publishing date	2020-10-02
Publishing country	United States
Document type	Journal Article
ISSN	2058-7716
ISSN	2058-7716
DOI	10.1038/s41420-020-00321-y
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Article ; Online: Paediatric safety assessment of BNT162b2 vaccination in a multistate hospital-based electronic health record system in the USA: a retrospective analysis.

Matson, Robert P / Niesen, Michiel J M / Levy, Emily R / Opp, Derek N / Lenehan, Patrick J / Donadio, Greg / O'Horo, John C / Venkatakrishnan, A J / Badley, Andrew D / Soundararajan, Venky

The Lancet. Digital health

2023 Volume 5, Issue 4, Page(s) e206–e216

Abstract: Background: The emergency use authorisation of BNT162b2 (tozinameran; Comirnaty, Pfizer-BioNTech) for children aged 5-17 years has resulted in rapid vaccination in the paediatric population. However, there are few studies of adverse events associated ... ...

Abstract	Background: The emergency use authorisation of BNT162b2 (tozinameran; Comirnaty, Pfizer-BioNTech) for children aged 5-17 years has resulted in rapid vaccination in the paediatric population. However, there are few studies of adverse events associated with vaccination in children. The aim of this study was to systematically assess the adverse events of two-dose BNT162b2 vaccination in the paediatric population. Methods: We conducted a retrospective analysis of patient electronic health records (EHRs) of children aged 5-17 years who received the primary two-dose series of the BNT162b2 vaccine between Jan 5, 2021, and Aug 5, 2022, at the Mayo Clinic Health System (MN, FL, AZ, IA, and WI), USA. Using natural language processing, we automatically curated adverse events reported by physicians in EHR clinical notes before and after vaccination. To determine significant adverse events after BNT162b2 vaccination, we calculated risk differences, which was defined as the percentage difference between the rate of children with an adverse event after a vaccine dose and the baseline rate of children with an adverse event before vaccination. 95% CIs and p values were calculated using the Miettinen and Nurminen score method. Findings: 56 436 individuals aged 5-17 years (20 227 aged 5-11 years and 36 209 aged 12-17 years) with EHRs in the Mayo Clinic Health Systems were included in the study. Overall, the reporting of adverse events remained low in passive surveillance. Serious adverse events were rare after the first and second doses of BNT162b2, with rates of anaphylaxis (six [0·01%] of 56 436), myocarditis (five [0·01%]), and pericarditis (three [0·01%]) consistent with previous studies. Among the 20 227 5-11-year-olds, there were increased risks of fatigue (58 after second dose vs 41 before first dose; risk difference [RD] Interpretation: Overall, this data suggests that vaccination with BNT162b2 in the paediatric population is generally safe and well-tolerated. Further research is warranted to investigate the basis for the increased risk of myocarditis in adolescent males. Additionally, further studies are needed to confirm whether the findings in our study population apply to the whole vaccinated paediatric population. Funding: nference.
MeSH term(s)	Adolescent ; Child ; Humans ; Male ; BNT162 Vaccine/adverse effects ; Electronic Health Records ; Hospitals ; Myocarditis ; Retrospective Studies ; United States/epidemiology ; Vaccination ; COVID-19/prevention & control
Chemical Substances	BNT162 Vaccine
Language	English
Publishing date	2023-03-24
Publishing country	England
Document type	Journal Article
ISSN	2589-7500
ISSN (online)	2589-7500
DOI	10.1016/S2589-7500(22)00253-9
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Article ; Online: SARS-CoV-2 strategically mimics proteolytic activation of human ENaC.

Anand, Praveen / Puranik, Arjun / Aravamudan, Murali / Venkatakrishnan, A J / Soundararajan, Venky

eLife

2020 Volume 9

Abstract: Molecular mimicry is an evolutionary strategy adopted by viruses to exploit the host cellular machinery. We report that SARS-CoV-2 has evolved a unique S1/S2 cleavage site, absent in any previous coronavirus sequenced, resulting in the striking mimicry ... ...

Abstract	Molecular mimicry is an evolutionary strategy adopted by viruses to exploit the host cellular machinery. We report that SARS-CoV-2 has evolved a unique S1/S2 cleavage site, absent in any previous coronavirus sequenced, resulting in the striking mimicry of an identical FURIN-cleavable peptide on the human epithelial sodium channel α-subunit (ENaC-α). Genetic alteration of ENaC-α causes aldosterone dysregulation in patients, highlighting that the FURIN site is critical for activation of ENaC. Single cell RNA-seq from 66 studies shows significant overlap between expression of ENaC-α and the viral receptor ACE2 in cell types linked to the cardiovascular-renal-pulmonary pathophysiology of COVID-19. Triangulating this cellular characterization with cleavage signatures of 178 proteases highlights proteolytic degeneracy wired into the SARS-CoV-2 lifecycle. Evolution of SARS-CoV-2 into a global pandemic may be driven in part by its targeted mimicry of ENaC-α, a protein critical for the homeostasis of airway surface liquid, whose misregulation is associated with respiratory conditions.
MeSH term(s)	Angiotensin-Converting Enzyme 2 ; Betacoronavirus/genetics ; Betacoronavirus/metabolism ; Betacoronavirus/pathogenicity ; COVID-19 ; Coronavirus Infections/virology ; Epithelial Sodium Channels/genetics ; Epithelial Sodium Channels/metabolism ; Host-Pathogen Interactions ; Humans ; Molecular Mimicry ; Pandemics ; Peptide Hydrolases/metabolism ; Peptidyl-Dipeptidase A/genetics ; Peptidyl-Dipeptidase A/metabolism ; Pneumonia, Viral/virology ; Proteolysis ; SARS-CoV-2 ; Substrate Specificity ; Viral Envelope Proteins/genetics ; Viral Envelope Proteins/metabolism ; Viral Proteins/genetics ; Viral Proteins/metabolism
Chemical Substances	Epithelial Sodium Channels ; S envelope protein, hepatitis B virus ; SCNN1A protein, human ; Viral Envelope Proteins ; Viral Proteins ; Peptide Hydrolases (EC 3.4.-) ; Peptidyl-Dipeptidase A (EC 3.4.15.1) ; ACE2 protein, human (EC 3.4.17.23) ; Ace2 protein, mouse (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
Keywords	covid19
Language	English
Publishing date	2020-05-26
Publishing country	England
Document type	Journal Article
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.58603
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Article ; Online: Identifying signs and symptoms of AL amyloidosis in electronic health records using natural language processing, diagnosis codes, and manually abstracted registry data.

Silvert, Eli / Hester, Laura / Ramudu, Eshwan / Pawlowski, Colin / Kranenburg, Britte / Buadi, Francis / Muchtar, Eli / Khaled, Samer / Tran, Namphuong / Soundararajan, Venky / Khan, Najat / Gertz, Morie / Dispenzieri, Angela

American journal of hematology

2023 Volume 98, Issue 9, Page(s) E255–E258

MeSH term(s)	Humans ; Electronic Health Records ; Natural Language Processing ; Immunoglobulin Light-chain Amyloidosis/diagnosis ; Routinely Collected Health Data ; Algorithms
Language	English
Publishing date	2023-07-04
Publishing country	United States
Document type	Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	196767-8
ISSN	1096-8652 ; 0361-8609
ISSN (online)	1096-8652
ISSN	0361-8609
DOI	10.1002/ajh.27019
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