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  1. Article ; Online: The mutational dynamics of short tandem repeats in large, multigenerational families.

    Steely, Cody J / Watkins, W Scott / Baird, Lisa / Jorde, Lynn B

    Genome biology

    2022  Volume 23, Issue 1, Page(s) 253

    Abstract: Background: Short tandem repeats (STRs) compose approximately 3% of the genome, and mutations at STR loci have been linked to dozens of human diseases including amyotrophic lateral sclerosis, Friedreich ataxia, Huntington disease, and fragile X syndrome. ...

    Abstract Background: Short tandem repeats (STRs) compose approximately 3% of the genome, and mutations at STR loci have been linked to dozens of human diseases including amyotrophic lateral sclerosis, Friedreich ataxia, Huntington disease, and fragile X syndrome. Improving our understanding of these mutations would increase our knowledge of the mutational dynamics of the genome and may uncover additional loci that contribute to disease. To estimate the genome-wide pattern of mutations at STR loci, we analyze blood-derived whole-genome sequencing data for 544 individuals from 29 three-generation CEPH pedigrees. These pedigrees contain both sets of grandparents, the parents, and an average of 9 grandchildren per family.
    Results: We use HipSTR to identify de novo STR mutations in the 2nd generation of these pedigrees and require transmission to the third generation for validation. Analyzing approximately 1.6 million STR loci, we estimate the empirical de novo STR mutation rate to be 5.24 × 10
    Conclusions: Approximately 30% of new STR mutations occur within Alu elements, which compose only 11% of the genome, but only 10% are found in LINE-1 insertions, which compose 17% of the genome. Phasing these mutations to the parent of origin shows that parental transmission biases vary among families. We estimate the average number of de novo genome-wide STR mutations per individual to be approximately 85, which is similar to the average number of observed de novo single nucleotide variants.
    MeSH term(s) Humans ; Extended Family ; Microsatellite Repeats ; Mutation ; Pedigree ; Genome
    Language English
    Publishing date 2022-12-12
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2040529-7
    ISSN 1474-760X ; 1474-760X
    ISSN (online) 1474-760X
    ISSN 1474-760X
    DOI 10.1186/s13059-022-02818-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Mobile element insertions and associated structural variants in longitudinal breast cancer samples.

    Steely, Cody J / Russell, Kristi L / Feusier, Julie E / Qiao, Yi / Tavtigian, Sean V / Marth, Gabor / Jorde, Lynn B

    Scientific reports

    2021  Volume 11, Issue 1, Page(s) 13020

    Abstract: While mobile elements are largely inactive in healthy somatic tissues, increased activity has been found in cancer tissues, with significant variation among different cancer types. In addition to insertion events, mobile elements have also been found to ... ...

    Abstract While mobile elements are largely inactive in healthy somatic tissues, increased activity has been found in cancer tissues, with significant variation among different cancer types. In addition to insertion events, mobile elements have also been found to mediate many structural variation events in the genome. Here, to better understand the timing and impact of mobile element insertions and associated structural variants in cancer, we examined their activity in longitudinal samples of four metastatic breast cancer patients. We identified 11 mobile element insertions or associated structural variants and found that the majority of these occurred early in tumor progression. Most of the variants impact intergenic regions; however, we identified a translocation interrupting MAP2K4 involving Alu elements and a deletion in YTHDF2 involving mobile elements that likely inactivate reported tumor suppressor genes. The high variant allele fraction of the translocation, the loss of the other copy of MAP2K4, the recurrent loss-of-function mutations found in this gene in other cancers, and the important function of MAP2K4 indicate that this translocation is potentially a driver mutation. Overall, using a unique longitudinal dataset, we find that most variants are likely passenger mutations in the four patients we examined, but some variants impact tumor progression.
    MeSH term(s) Alleles ; Breast Neoplasms/genetics ; Chromosomes, Human/genetics ; DNA Transposable Elements/genetics ; Female ; Gene Dosage ; Genomic Structural Variation ; Humans ; Longitudinal Studies ; MAP Kinase Kinase 4/genetics ; Mutagenesis, Insertional/genetics
    Chemical Substances DNA Transposable Elements ; MAP Kinase Kinase 4 (EC 2.7.12.2) ; MAP2K4 protein, human (EC 2.7.12.2)
    Language English
    Publishing date 2021-06-22
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-021-92444-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Pathogenic Effect of

    Russell, Kristi L / Downie, Jonathan M / Gibson, Summer B / Tsetsou, Spyridoula / Keefe, Matthew D / Duran, Jerry A / Figueroa, Karla P / Bromberg, Mark B / Murtaugh, L Charles / Bonkowsky, Joshua L / Pulst, Stefan M / Jorde, Lynn B

    Neurology

    2021  Volume 97, Issue 3, Page(s) e225–e235

    Abstract: Objective: To identify novel disease associated loci for amyotrophic lateral sclerosis (ALS), we used sequencing data and performed in vitro and in vivo experiments to demonstrate pathogenicity of mutations identified in : Methods: We analyzed exome ... ...

    Abstract Objective: To identify novel disease associated loci for amyotrophic lateral sclerosis (ALS), we used sequencing data and performed in vitro and in vivo experiments to demonstrate pathogenicity of mutations identified in
    Methods: We analyzed exome sequences of 87 patients with sporadic ALS and 324 controls, with confirmatory sequencing in independent ALS cohorts of >2,800 patients. For the top hit,
    Results: Four heterozygous rare, nonsynonymous mutations in
    Conclusion: Together, these results strongly suggest that variants in
    Language English
    Publishing date 2021-07-19
    Publishing country United States
    Document type Journal Article ; Comment
    ZDB-ID 207147-2
    ISSN 1526-632X ; 0028-3878
    ISSN (online) 1526-632X
    ISSN 0028-3878
    DOI 10.1212/WNL.0000000000012285
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Mobile element insertions and associated structural variants in longitudinal breast cancer samples

    Cody J. Steely / Kristi L. Russell / Julie E. Feusier / Yi Qiao / Sean V. Tavtigian / Gabor Marth / Lynn B. Jorde

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

    2021  Volume 12

    Abstract: Abstract While mobile elements are largely inactive in healthy somatic tissues, increased activity has been found in cancer tissues, with significant variation among different cancer types. In addition to insertion events, mobile elements have also been ... ...

    Abstract Abstract While mobile elements are largely inactive in healthy somatic tissues, increased activity has been found in cancer tissues, with significant variation among different cancer types. In addition to insertion events, mobile elements have also been found to mediate many structural variation events in the genome. Here, to better understand the timing and impact of mobile element insertions and associated structural variants in cancer, we examined their activity in longitudinal samples of four metastatic breast cancer patients. We identified 11 mobile element insertions or associated structural variants and found that the majority of these occurred early in tumor progression. Most of the variants impact intergenic regions; however, we identified a translocation interrupting MAP2K4 involving Alu elements and a deletion in YTHDF2 involving mobile elements that likely inactivate reported tumor suppressor genes. The high variant allele fraction of the translocation, the loss of the other copy of MAP2K4, the recurrent loss-of-function mutations found in this gene in other cancers, and the important function of MAP2K4 indicate that this translocation is potentially a driver mutation. Overall, using a unique longitudinal dataset, we find that most variants are likely passenger mutations in the four patients we examined, but some variants impact tumor progression.
    Keywords Medicine ; R ; Science ; Q
    Subject code 616 ; 572
    Language English
    Publishing date 2021-06-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article: Vitamin D supplementation does not improve CVD risk factors in vitamin D-insufficient subjects.

    Kubiak, Julia / Thorsby, Per Medbøe / Kamycheva, Elena / Jorde, Rolf

    Endocrine connections

    2018  Volume 7, Issue 6, Page(s) 840–849

    Abstract: ... lipids (total-, LDL- and HDL-cholesterol, triglycerides, apolipoproteins A1 and B), and glucose ... 34 nmol/L were included, with 411 subjects completing the study. Serum 25(OH)D levels increased ... with 56 nmol/L and decreased with 4 nmol/L in the vitamin D and placebo group, respectively. We found no ...

    Abstract Objective: Low serum 25(OH)D levels are associated with cardiovascular disease (CVD) and some of its risk factors. However, in interventional studies, the effects of vitamin D supplementation have been uncertain, possibly due to inclusion of vitamin D-sufficient subjects. Our aim was therefore to examine effects of vitamin D supplementation on CVD risk factors in vitamin D-insufficient subjects.
    Design: Double-blinded randomized controlled trial.
    Methods: A 4-month interventional study with high-dose vitamin D (100,000 IU loading dose, followed by 20,000 IU/week) or placebo with measurements of blood pressure, lipids (total-, LDL- and HDL-cholesterol, triglycerides, apolipoproteins A1 and B), and glucose metabolism parameters (blood glucose, HbA
    Results: A total of 422 subjects with mean serum 25(OH)D level 34 nmol/L were included, with 411 subjects completing the study. Serum 25(OH)D levels increased with 56 nmol/L and decreased with 4 nmol/L in the vitamin D and placebo group, respectively. We found no statistically significant differences between the two groups in any of the measured CVD risk factors, except for a minor increase in sRAGE in the vitamin D group. Stratified analyses of subjects with low baseline serum 25(OH)D levels alone, or combined with blood pressure, lipid and HOMA-IR values above the median for the cohort, did not skew the results in favour of vitamin D supplementation.
    Conclusion: Supplementation with vitamin D in subjects with baseline vitamin D insufficiency does not improve CVD risk factor profile.
    Language English
    Publishing date 2018-05-15
    Publishing country England
    Document type Journal Article
    ZDB-ID 2668428-7
    ISSN 2049-3614
    ISSN 2049-3614
    DOI 10.1530/EC-18-0144
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Large-scale Identification of Clonal Hematopoiesis and Mutations Recurrent in Blood Cancers.

    Feusier, Julie E / Arunachalam, Sasi / Tashi, Tsewang / Baker, Monika J / VanSant-Webb, Chad / Ferdig, Amber / Welm, Bryan E / Rodriguez-Flores, Juan L / Ours, Christopher / Jorde, Lynn B / Prchal, Josef T / Mason, Clinton C

    Cancer discovery

    2021  Volume 2, Issue 3, Page(s) 226–237

    Abstract: Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by detectable hematopoietic-associated gene mutations in a person without evidence of hematologic malignancy. We sought to identify additional cancer-presenting mutations usable for ... ...

    Abstract Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by detectable hematopoietic-associated gene mutations in a person without evidence of hematologic malignancy. We sought to identify additional cancer-presenting mutations usable for CHIP detection by performing a data mining analysis of 48 somatic mutation landscape studies reporting mutations at diagnoses of 7,430 adult and pediatric patients with leukemia or other hematologic malignancy. Following extraction of 20,141 protein-altering mutations, we identified 434 significantly recurrent mutation hotspots, 364 of which occurred at loci confidently assessable for CHIP. We then performed an additional large-scale analysis of whole-exome sequencing data from 4,538 persons belonging to three noncancer cohorts for clonal mutations. We found the combined cohort prevalence of CHIP with mutations identical to those reported at blood cancer mutation hotspots to be 1.8%, and that some of these CHIP mutations occurred in children. Our findings may help to improve CHIP detection and precancer surveillance for both children and adults. SIGNIFICANCE: This study identifies frequently occurring mutations across several blood cancers that may drive hematologic malignancies and signal increased risk for cancer when detected in healthy persons. We find clonal mutations at these hotspots in a substantial number of individuals from noncancer cohorts, including children, showcasing potential for improved precancer surveillance.
    Language English
    Publishing date 2021-03-03
    Publishing country United States
    Document type Journal Article ; Comment
    ZDB-ID 2625242-9
    ISSN 2159-8290 ; 2159-8274
    ISSN (online) 2159-8290
    ISSN 2159-8274
    DOI 10.1158/2643-3230.BCD-20-0094
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Large-Scale Identification of Clonal Hematopoiesis and Mutations Recurrent in Blood Cancers.

    Feusier, Julie E / Arunachalam, Sasi / Tashi, Tsewang / Baker, Monika J / VanSant-Webb, Chad / Ferdig, Amber / Welm, Bryan E / Rodriguez-Flores, Juan L / Ours, Christopher / Jorde, Lynn B / Prchal, Josef T / Mason, Clinton C

    Blood cancer discovery

    2021  Volume 2, Issue 3, Page(s) 226–237

    Abstract: Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by detectable hematopoietic-associated gene mutations in a person without evidence of hematologic malignancy. We sought to identify additional cancer-presenting mutations useable for ...

    Abstract Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by detectable hematopoietic-associated gene mutations in a person without evidence of hematologic malignancy. We sought to identify additional cancer-presenting mutations useable for CHIP detection by performing a data mining analysis of 48 somatic mutation studies reporting mutations at diagnoses of 7,430 adult and pediatric patients with hematologic malignancies. Following extraction of 20,141 protein-altering mutations, we identified 434 significantly recurrent mutation hotspots, 364 of which occurred at loci confidently assessable for CHIP. We then performed an additional large-scale analysis of whole exome sequencing data from 4,538 persons belonging to three non-cancer cohorts for clonal mutations. We found the combined cohort prevalence of CHIP with mutations identical to those reported at blood cancer mutation hotspots to be 1.8%, and that some of these CHIP mutations occurred in children. Our findings may help to improve CHIP detection and pre-cancer surveillance for both children and adults.
    MeSH term(s) Adult ; Child ; Clonal Hematopoiesis ; Hematologic Neoplasms/diagnosis ; Hematopoiesis/genetics ; Humans ; Mutation ; Neoplasms/diagnosis
    Language English
    Publishing date 2021-03-03
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 3028898-8
    ISSN 2643-3249 ; 2643-3230
    ISSN (online) 2643-3249
    ISSN 2643-3230
    DOI 10.1158/2643-3230.BCD-20-0094
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  8. Article: Consanguinity and prereproductive mortality in the Utah Mormon population.

    Jorde, L B

    Human heredity

    2001  Volume 52, Issue 2, Page(s) 61–65

    Abstract: To test the effects of parental consanguinity on mortality among offspring, inbreeding coefficients were estimated for 303,675 members of the Utah Mormon population who were born between 1847 and 1945. Although consanguinity has been relatively rare in ... ...

    Abstract To test the effects of parental consanguinity on mortality among offspring, inbreeding coefficients were estimated for 303,675 members of the Utah Mormon population who were born between 1847 and 1945. Although consanguinity has been relatively rare in this population, the large sample size permitted the identification of more than 3,500 inbred offspring. Among the offspring of unrelated parents, 13.2% died before the age of 16. Significant elevations in prereproductive mortality were seen among the offspring of first-cousin marriages (22%) and among the offspring of closer unions (32%). The cor- responding relative risks are 1.70 (95% confidence limits = 1.52, 1.91) and 2.41 (95% confidence limits = 1.59, 3.41), respectively. Other categories of relationship did not produce significant elevations in offspring mortality. Similar results were obtained when a case-control approach was used to remove the effects of socioeconomic variation. Consistent with many other studies of populations with low consanguinity rates, this population experienced a relatively high absolute increase in mortality among the offspring of first-cousin marriages (9%). Preliminary evidence is offered for the hypothesis that mortality differentials are larger in populations with low inbreeding and low mortality because nongenetic causes of death do not obscure the effects of consanguinity.
    MeSH term(s) Christianity ; Cohort Studies ; Consanguinity ; Female ; Humans ; Male ; Mortality ; Utah
    Language English
    Publishing date 2001
    Publishing country Switzerland
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 2424-7
    ISSN 1423-0062 ; 0001-5652
    ISSN (online) 1423-0062
    ISSN 0001-5652
    DOI 10.1159/000053356
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  9. Article: Linkage disequilibrium and the search for complex disease genes.

    Jorde, L B

    Genome research

    2000  Volume 10, Issue 10, Page(s) 1435–1444

    MeSH term(s) Chromosome Mapping/methods ; Genetic Diseases, Inborn/genetics ; Genetic Markers/genetics ; Genetic Predisposition to Disease/genetics ; Humans ; Linkage Disequilibrium/genetics
    Chemical Substances Genetic Markers
    Language English
    Publishing date 2000-10-13
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S. ; Review
    ZDB-ID 1284872-4
    ISSN 1549-5469 ; 1088-9051 ; 1054-9803
    ISSN (online) 1549-5469
    ISSN 1088-9051 ; 1054-9803
    DOI 10.1101/gr.144500
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    In stock of ZB MED Cologne/Königswinter

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  10. Article ; Online: Left atrial to coronary sinus shunting for treatment of heart failure with mildly reduced or preserved ejection fraction: The ALT FLOW Early Feasibility Study 1-year results.

    Urey, Marcus A / Hibbert, Benjamin / Jorde, Ulrich / Eckman, Peter / Simard, Trevor / Labinaz, Marino / Nazer, Babak / Wiley, Mark / Gupta, Bhanu / Sauer, Andrew / Shah, Hirak / Sorajja, Paul / Pineda, Andres M / Missov, Emil / Mahmud, Ehtisham / Kahwash, Rami / Lilly, Scott / Latib, Azeem / Murthy, Sandhya /
    Fam, Neil / Garcia, Santiago / Chung, Eugene S / Klein, Liviu / Cheng, Richard / Houston, Brian A / Amoroso, Nicholas S / Chang, Lee / Gafoor, Sameer / Chaudhry, Sunit-Preet / Hermiller, James / Schwartz, Jonathan G / Aldaia, Lillian / Koulogiannis, Konstantinos / Gray, William A / Zahr, Firas

    European journal of heart failure

    2024  

    Abstract: Aims: Patients with heart failure and mildly reduced or preserved ejection fraction have limited therapeutic options. The ALT-FLOW Early Feasibility Study evaluated safety, haemodynamics and outcomes for the APTURE transcatheter shunt system, a novel ... ...

    Abstract Aims: Patients with heart failure and mildly reduced or preserved ejection fraction have limited therapeutic options. The ALT-FLOW Early Feasibility Study evaluated safety, haemodynamics and outcomes for the APTURE transcatheter shunt system, a novel left atrium to coronary sinus shunt in these patients.
    Methods and results: Safety and shunt implantation success was evaluated for all 116 enrolled patients. An analysis population of implanted patients with a left ventricular ejection fraction (LVEF) >40% (n = 95) was chosen to assess efficacy via paired comparison between baseline and follow-up haemodynamic (3 and 6 months), and echocardiographic, clinical and functional outcomes (6 months and 1 year). Health status and quality of life outcomes were assessed using the Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ-OSS). The primary safety endpoint, major adverse cardiac, cerebral, and renal events, and reintervention through 30 days, occurred in 3/116 patients (2.6%). All implanted shunts were patent at 1 year. In patients with LVEF >40%, the mean (95% confidence interval) reduction in exercise pulmonary capillary wedge pressure (PCWP) at 20 W was -5.7 (-8.6, -2.9) mmHg at 6 months (p < 0.001). At baseline, 8% had New York Heart Association class I-II status and improved to 68% at 1 year (p < 0.001). KCCQ-OSS at baseline was 39 (35, 43) and improved at 6 months and 1 year by 25 (20-30) and 27 (22-32) points, respectively (both p < 0.0001). No adverse changes in haemodynamic and echocardiographic indices of right heart function were observed at 1 year. Overall, the reduction in PCWP at 20 W and improvement in KCCQ-OSS in multiple subgroups were consistent with those observed for the entire population.
    Conclusions: In patients with heart failure and LVEF >40%, the APTURE shunt demonstrated an acceptable safety profile with significant sustained improvements in haemodynamic and patient-centred outcomes, underscoring the need for further evaluation of the APTURE shunt in a randomized trial.
    Language English
    Publishing date 2024-04-12
    Publishing country England
    Document type Journal Article
    ZDB-ID 1483672-5
    ISSN 1879-0844 ; 1388-9842
    ISSN (online) 1879-0844
    ISSN 1388-9842
    DOI 10.1002/ejhf.3241
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