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1. Prevalence and risk factors of birth-related posttraumatic stress among parents: A comparative systematic review and meta-analysis

Author

Heyne, C.S., Kazmierczak, M., Souday, R., Horesh, D., Lambregtse-van den Berg, M., Weigl, T., Horsch, A., Oosterman, M., Dikmen-Yildiz, P., and Garthus-Niegel, S.

Subjects
Female, Humans, Mothers, Parents, Prevalence, Risk Factors, Stress Disorders, Post-Traumatic/diagnosis, Stress Disorders, Post-Traumatic/epidemiology, Stress Disorders, Post-Traumatic/etiology, Childbirth, Perinatal mental health, Posttraumatic stress, Posttraumatic stress disorder
Abstract

This systematic review and meta-analysis aimed to determine mean estimates of prevalence rates for fulfilling all diagnostic criteria of posttraumatic stress disorder (PTSD) or at least showing significant levels of posttraumatic stress (PTSS) in relation to the traumatic event of childbirth. For the first time, both mothers and fathers were included in the synthesis. Studies were identified through systematic database search and manual searches, irrespective of language. Meta-analyses of 154 studies (N = 54,711) applied a random-effects model to four data sets, resulting in pooled prevalence rates of 4.7% for PTSD and 12.3% for PTSS in mothers. Lower rates of 1.2% for PTSD and 1.3% for PTSS were found among fathers. Subgroup analyses showed elevated rates in targeted samples (those with a potential risk status) most distinctly for maternal PTSS. The significant amount of heterogeneity between studies could not be explained to a satisfactory degree through meta-regression. Given the substantial percentage of affected parents, the adoption of adequate prevention and intervention strategies is needed. As this field of research is evolving, attention should be broadened to the whole family system, which may directly and indirectly be affected by birth-related PTSD. Further studies on paternal PTSD/PTSS are particularly warranted.

Published
2022

2. Treatment Outcome Trends for Non-Ruptured Abdominal Aortic Aneurysms: A Nationwide Prospective Cohort Study

Author

Alberga, Anna J., Karthaus, Eleonora G., Wilschut, Janneke A., de Bruin, Jorg L., Akkersdijk, George P., Geelkerken, Robert H., Hamming, Jaap F., Wever, Jan J., Verhagen, Hence J. M., van den Akker, P. J., Akkersdijk, G. P., Akkersdijk, W. L., van Andringa de Kempenaer, M. G., Arts, C. H. P., Avontuur, A. M., Bakker, O. J., Balm, R., Barendregt, W. B., Bekken, J. A., Bender, M. H. M., Bendermacher, B. L. W., van den Berg, M., Beuk, R. J., Blankensteijn, J. D., Bode, A. S., Bodegom, M. E., van der Bogt, K. E. A., Boll, A. P. M., Booster, M. H., Borger van der Burg, B. L. S., de Borst, G. J., Bos-van Rossum, W. T. G. J., Bosma, J., Botman, J. M. J., Bouwman, L. H., Brehm, V., de Bruijn, M. T., de Bruin, J. L., Brummel, P., van Brussel, J. P., Buijk, S. E., Buimer, M. G., Buscher, H. C. J. L., Cancrinus, E., Castenmiller, P. H., Cazander, G., Cuypers, P. H. W. M., Daemen, J. H. C., Dawson, I., Dierikx, J. E., Dijkstra, M. L., Diks, J., Dinkelman, M. K., Dirven, M., Dolmans, D. E. J. G. J., van Dortmont, L. M. C., Drouven, J. W., van der Eb, M. M., Eefting, D., van Eijck, G. J. W. M., Elshof, J. W. M., Elsman, B. H. P., van der Elst, A., van Engeland, M. I. A., van Eps, G. S., Faber, M. J., de Fijter, W. M., Fioole, B., Fritschy, W. M., Jin, P. H. P. F. K., Geelkerken, R. H., van Gent, W. B., Glade, G. J., Govaert, B., Groenendijk, R. P. R., de Groot, H. G. W., van den Haak, R. F. F., de Haan, E. F. A., Hajer, G. F., Hamming, J. F., van Hattum, E. S., Hazenberg, C. E. V. B., Hedeman Joosten, P. P. H. A., Helleman, J. N., van der Hem, L. G., Hendriks, J. M., van Herwaarden, J. A., Heyligers, J. M. M., Hinnen, J. W., Hissink, R. J., Ho, G. H., den Hoed, P. T., Hoedt, M. T. C., van Hoek, F., Hoencamp, R., Hoffmann, W. H., Hoksbergen, A. W. J., Hollander, E. J. F., Huisman, L. C., Hulsebos, R. G., Huntjens, K. M. B., Idu, M. M., Jacobs, M. J. H. M., van der Jagt, M. F. P., Jansbeken, J. R. H., Janssen, R. J. L., Jiang, H. H. L., de Jong, S. C., Jongbloed-Winkel, T. A., Jongkind, V., Kapma, M. R., Keller, B. P. J. A., Jahrome, A. K., Kievit, J. K., Klemm, P. L., Klinkert, P., Koedam, N. A., Koelemaij, M. J. W., Kolkert, J. L. P., Koning, G. G., Koning, O. H. J., Konings, R., Krasznai, A. G., Kropman, R. H. J., Kruse, R. R., van der Laan, L., van der Laan, M. J., van Laanen, J. H. H., van Lammeren, G. W., Lamprou, D. A. A., Lardenoije, J. H. P., Lauret, G. J., Leenders, B. J. M., Legemate, D. A., Leijdekkers, V. J., Lemson, M. S., Lensvelt, M. M. A., Lijkwan, M. A., van der Linden, F. T. H. P. M., Lung, P. F. Liqui, Loos, M. J. A., Loubert, M. C., van de Luijtgaarden, K. M., Mahmoud, D. E. A. K., Manshanden, C. G., Mattens, E. C. J. L., Meerwaldt, R., Mees, B. M. E., Menting, T. P., Metz, R., de Mol van Otterloo, J. C. A., Molegraaf, M. J., Montauban van Swijndregt, Y. C. A., Morak, M. J. M., van de Mortel, R. H. W., Mulder, W., Nagesser, S. K., Naves, C. C. L. M., Nederhoed, J. H., Nevenzel, A. M., de Nie, A. J., Nieuwenhuis, D. H., van Nieuwenhuizen, R. C., Nieuwenhuizen, J., Nio, D., Oomen, A. P. A., Oranen, B. I., Oskam, J., Palamba, H. W., Peppelenbosch, A. G., van Petersen, A. S., Petri, B. J., Pierie, M. E. N., Ploeg, A. J., Pol, R. A., Ponfoort, E. D., Poyck, P. P. C., Prent, A., Raa, S. ten, Raymakers, J. T. F. J., Reichmann, B. L., Reijnen, M. M. P. J., de Ridder, J. A. M., Rijbroek, A., van Rijn, M. J. E., de Roo, R. A., Rouwet, E. V., Saleem, B. R., van Sambeek, M. R. H. M., Samyn, M. G., van ’t Sant, H. P., van Schaik, J., van Schaik, P. M., Scharn, D. M., Scheltinga, M. R. M., Schepers, A., Schlejen, P. M., Schlösser, F. J. V., Schol, F. P. G., Scholtes, V. P. W., Schouten, O., Schreve, M. A., Schurink, G. W. H., Sikkink, C. J. J. M., Slaa, A. te, Smeets, H. J., Smeets, L., Smeets, R. R., de Smet, A. A. E. A., Smit, P. C., Smits, T. M., Snoeijs, M. G. J., Sondakh, A. O., Speijers, M. J., van der Steenhoven, T. J., van Sterkenburg, S. M. M., Stigter, D. A. A., Stokmans, R. A., Strating, R. P., Stultiëns, G. N. M., Sybrandy, J. E. M., Teijink, J. A. W., Telgenkamp, B. J., Testroote, M. J. G., Tha-in, T., The, R. M., Thijsse, W. J., Thomassen, I., Tielliu, I. F. J., van Tongeren, R. B. M., Toorop, R. J., Tournoij, E., Truijers, M., Türkcan, K., Tutein Nolthenius, R. P., Ünlü, C., Vaes, R. H. D., Vahl, A. C., Veen, E. J., Veger, H. T. C., Veldman, M. G., Verhagen, H. J. M., Verhoeven, B. A. N., Vermeulen, C. F. W., Vermeulen, E. G. J., Vierhout, B. P., van der Vijver-Coppen, R. J., Visser, M. J. T., van der Vliet, J. A., van Vlijmen - van Keulen, C. J., van der Vorst, J. R., Vos, A. W. F., Vos, C. G., Vos, G. A., de Vos, B., Voûte, M. T., Vriens, B. H. R., Vriens, P. W. H. E., de Vries, D. K., de Vries, J. P. P. M., de Vries, M., de Vries, A. C., van der Waal, C., Waasdorp, E. J., Wallis de Vries, B. M., van Walraven, L. A., van Wanroi, J. L., Warlé, M. C., van Weel, V., van Well, A. M. E., Welten, G. M. J. M., Wever, J. J., Wiersema, A. M., Wikkeling, O. R. M., Willaert, W. I. M., Wille, J., Willems, M. C. M., Willigendael, E. M., Wilschut, E. D., Wisselink, W., Witte, M. E., Wittens, C. H. A., Wong, C. Y., Yazar, O., Yeung, K. K., Zeebregts, C. J. A. M., van Zeeland, M. L. P., ACS - Microcirculation, Anesthesiology, Physiology, ACS - Pulmonary hypertension & thrombosis, Surgery, ACS - Atherosclerosis & ischemic syndromes, VU University medical center, ACS - Diabetes & metabolism, TechMed Centre, Multi-Modality Medical Imaging, Medical Biochemistry, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism

Subjects
Male, Time Factors, Operative procedure, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Risk Assessment, Blood Vessel Prosthesis Implantation, Postoperative Complications, Risk Factors, Humans, Hospital Mortality, Prospective Studies, Registries, Treatment outcome, Aged, Netherlands, Retrospective Studies, Aged, 80 and over, Endovascular Procedures, Quality of care, Middle Aged, Endovascular procedure, Abdominal aortic aneurysm, Surgery, Female, Trends, Cardiology and Cardiovascular Medicine, Aortic Aneurysm, Abdominal
Abstract

Contains fulltext : 251573.pdf (Publisher’s version ) (Open Access) OBJECTIVE: The Dutch Surgical Aneurysm Audit (DSAA) initiative was established in 2013 to monitor and improve nationwide outcomes of aortic aneurysm surgery. The objective of this study was to examine whether outcomes of surgery for intact abdominal aortic aneurysms (iAAA) have improved over time. METHODS: Patients who underwent primary repair of an iAAA by standard endovascular (EVAR) or open surgical repair (OSR) between 2014 and 2019 were selected from the DSAA for inclusion. The primary outcome was peri-operative mortality trend per year, stratified by OSR and EVAR. Secondary outcomes were trends per year in major complications, textbook outcome (TbO), and characteristics of treated patients. The trends per year were evaluated and reported in odds ratios per year. RESULTS: In this study, 11 624 patients (74.8%) underwent EVAR and 3 908 patients (25.2%) underwent OSR. For EVAR, after adjustment for confounding factors, there was no improvement in peri-operative mortality (aOR [adjusted odds ratio] 1.06, 95% CI 0.94 - 1.20), while major complications decreased (2014: 10.1%, 2019: 7.0%; aOR 0.91, 95% CI 0.88 - 0.95) and the TbO rate increased (2014: 68.1%, 2019: 80.9%; aOR 1.13, 95% CI 1.10 - 1.16). For OSR, the peri-operative mortality decreased (2014: 6.1%, 2019: 4.6%; aOR 0.89, 95% CI 0.82 - 0.98), as well as major complications (2014: 28.6%, 2019: 23.3%; aOR 0.95, 95% CI 0.91 - 0.99). Furthermore, the proportion of TbO increased (2014: 49.1%, 2019: 58.3%; aOR 1.05, 95% CI 1.01 - 1.10). In both the EVAR and OSR group, the proportion of patients with cardiac comorbidity increased. CONCLUSION: Since the establishment of this nationwide quality improvement initiative (DSAA), all outcomes of iAAA repair following EVAR and OSR have improved, except for peri-operative mortality following EVAR which remained unchanged.

Published
2022

3. Tamoxifen for the treatment of polycystic liver disease

Author

Aapkes, Sophie E., Bernts, Lucas H.P., van den Berg, M., Gansevoort, Ron T., and Drenth, Joost P.H.

Subjects
tamoxifen, Antineoplastic Agents, Hormonal, Cysts, Liver Diseases, Middle Aged, polycystic liver disease, estrogen, Humans, Female, Clinical Case Report, case-report, Tomography, X-Ray Computed, Research Article, hepatic cyst, Follow-Up Studies
Abstract

Rationale: Polycystic liver disease is a rare disease characterized by the growth of numerous cysts in the liver. The liver function remains well preserved, but liver volumes can grow very large, and some patients ultimately need a liver transplantation. Other treatment options are limited and there is an unmet need for new therapeutic options. Patient concerns: We describe a 59-year-old patient with pain in the abdomen, especially when bending forward. Five years ago, she was diagnosed with breast cancer and as an incidental finding a couple of large liver cysts were diagnosed, explaining her abdominal pain. Diagnosis: Polycystic liver disease with several large liver cysts. Interventions: The patient was treated with tamoxifen, an estrogen receptor modulator, as treatment for her hormone receptor positive breast cancer. One of the liver cysts was aspirated. Outcomes: In the 4.6 years after the start of tamoxifen treatment, 20 mg once daily, the volume of her liver cysts decreased remarkably. There was a reduction of combined cyst volume from 311 mL to 22 mL without percutaneous drainage. Lessons: Epidemiological as well as experimental evidence supports a pivotal role for estrogens as a driver for growth of polycystic livers. Estrogen antagonism has often been proposed as a therapeutic target, but supporting evidence is lacking in the literature. We hypothesize that the decrease in cyst size in this patient was caused by tamoxifen therapy, suggesting an in vivo antagonistic effect on cystic cholangiocytes. This is an important finding because tamoxifen could be a promising new treatment option for polycystic liver disease.

Published
2021

4. Female reproductive function after treatment of childhood acute lymphoblastic leukemia

Author

van Dulmen-den Broeder E, van den Berg M, van Dijk M, W.J.E. (Wim) Tissing, Dorine Bresters, van den Heuvel-Eibrink M, Catharina C. M. Beerendonk, Cécile M. Ronckers, L. C. M. Kremer, van der Pal, H.J.H., Gertjan J.L. Kaspers, A. Overbeek, van der Heiden-van der Loo M, Roshandel R, Jacqueline J. Loonen, van Leeuwen F, Birgitta Versluys, C.B. Lambalk, Obstetrics and gynaecology, Pediatric surgery, CCA - Cancer Treatment and quality of life, Amsterdam Reproduction & Development (AR&D), and Guided Treatment in Optimal Selected Cancer Patients (GUTS)

Subjects
Adult, Anti-Mullerian Hormone, Pediatrics, medicine.medical_specialty, childhood cancer survivors, pregnancy outcomes, acute lymphoblastic leukemia, Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18], 03 medical and health sciences, Ovarian function, 0302 clinical medicine, Cancer Survivors, Pregnancy, Medicine, Humans, reproductive function, Child, Childhood Acute Lymphoblastic Leukemia, Retrospective Studies, Menarche, fertility, business.industry, Obstetrics, Hematology, Odds ratio, Total body irradiation, Precursor Cell Lymphoblastic Leukemia-Lymphoma, medicine.disease, Antral follicle, Pediatric cancer, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], pediatric cancer, Reproductive Health, Oncology, 030220 oncology & carcinogenesis, Pediatrics, Perinatology and Child Health, Cohort, Female, Follicle Stimulating Hormone, business, After treatment, 030215 immunology
Abstract

Contains fulltext : 244604.pdf (Publisher’s version ) (Closed access) BACKGROUND: The aim was to evaluate self-reported reproductive characteristics and markers of ovarian function in a nationwide cohort of female survivors of childhood acute lymphoblastic leukemia (ALL), because prior investigations have produced conflicting data. PROCEDURE: Self-reported reproductive characteristics were assessed by questionnaire among 357 adult 5-year survivors, treated between 1964 and 2002, and 836 controls. Ovarian function was assessed by serum levels of anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH), and inhibin B and by antral follicle count (AFC). Differences between controls and (subgroups of) survivors (total group, chemotherapy [CT]-only group, CT and radiotherapy [RT] group) were analyzed. RESULTS: Survivors treated with CT only do not differ from controls regarding timing of menarche, virginity status, desire for children, or pregnancy rates. Compared to controls, the CT+RT group was at significantly increased risk of a younger age at menarche (P

Published
2021

5. Assessing anti-estrogenic effects of AHR ligands in primary human and rat endometrial epithelial cells

Author

van den Brand, A. D., Rubinstein, E., de Jong, P. C., van den Berg, M., van Duursen, M. B.M., One Health Toxicologie, Environmental Sciences, E&H: Environmental Health and Toxicology, AIMMS, One Health Toxicologie, and Environmental Sciences

Subjects
Polychlorinated Dibenzodioxins, Uterus, Endogeny, 010501 environmental sciences, Toxicology, Endometrium, Ligands, 01 natural sciences, Rats, Sprague-Dawley, Gene expression, heterocyclic compounds, (Anti)-estrogenicity, Cells, Cultured, Progesterone, Aryl hydrocarbon receptor, 0303 health sciences, biology, Estradiol, Estrogen receptor binding, Chemistry, Estrogen Antagonists, Middle Aged, respiratory system, Neoplasm Proteins, medicine.anatomical_structure, Cytochrome P-450 CYP1B1, Female, Receptors, Progesterone, Adult, medicine.medical_specialty, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Cytochrome P-450 CYP1A1, Animals, Humans, 030304 developmental biology, 0105 earth and related environmental sciences, Epithelial Cells, Estrogens, GREB1, stomatognathic diseases, Endocrinology, Receptors, Aryl Hydrocarbon, biology.protein, Hormone
Abstract

Unopposed estrogenic action in the uterus can lead to the development of endometrial cancer in both humans and rats. Aryl hydrocarbon receptor (AHR) activation gives rise to anti-estrogenic actions and may consequently reduce the development of endometrial cancer. In this study, the anti-estrogenic potential of the AHR ligands 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and DELAQ, a metabolite of the pharmaceutical laquinimod, was assessed in in primary human and rat endometrial epithelial cells (EECs) with and without co-exposure to endogenous hormones. In human EECs, estradiol and progesterone did not affect AHR gene expression, but in rat EECs, progesterone decreased Ahre xpression (1.4-fold). In accordance, AHR-mediated induction of Cyp1a1/1b1 expression by DELAQ and TCDD decreased in hormone-treated rat EECs. DELAQ was 22-fold more potent than TCDD in human EECs in inducing CYP1A1/1B1 gene expression, while DELAQ was approximately 16−33-fold less potent than TCDD in rat EECs. In human EECs, 10 nM DELAQ decreased estradiol-induced expression of growth-regulated estrogen receptor binding 1 (GREB1) by 1.8-fold. In rat EECs, both DELAQ and TCDD did not affect the expression of estradiol-induced genes. This study shows that AHR ligand DELAQ, but not TCDD, causes anti-estrogenic effects in primary human EECs. Furthermore, although AHR-mediated CYP1A1/1B1/Cyp1a1/1b1 induction by DELAQ and TCDD was stronger in rat EECs than human EECs, this did not result in apparent anti-estrogenic effects in the rat cells. This study shows that primary human and rat endometrial cells respond differently towards hormones and AHR ligands. This should be considered in human risk assessment based on rodent studies.

Published
2020

6. Three patients with probable aerotoxic syndrome

Author

Hageman, G, Pal, T M, Nihom, J, MackenzieRoss, S J, van den Berg, M, Environmental Sciences, One Health Toxicologie, Environmental Sciences, and One Health Toxicologie

Subjects
Adult, Male, Aircraft, Central nervous system, Air Pollutants, Occupational, Toxicology, Bioinformatics, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Aerotoxic syndrome, organophosphates, Flight attendant, Occupational Exposure, medicine, Humans, cabin crew, 030212 general & internal medicine, contaminated cabin air, Butyrylcholinesterase, CNS/Psychological, biology, business.industry, Organophosphate, Paraoxonase, people.profession, 030208 emergency & critical care medicine, General Medicine, Middle Aged, Occupational Diseases, Pilots, medicine.anatomical_structure, chemistry, Air Pollution, Indoor, biology.protein, Aircrew, Female, Neurotoxicity Syndromes, medicine.symptom, people, business, aerotoxic syndrome, Balance problems
Abstract

INTRODUCTION: "Aerotoxic syndrome" is a debated entity. Regulatory authorities consider long-term health effects to be an unlikely consequence of exposure to contaminated air because several air quality monitoring studies report low concentrations of toxic chemicals in cabin air. We describe two pilots and one flight attendant, who developed ill health during their flying career which improved after cessation of flying. CASE DETAILS: The most frequently reported symptoms were headache, balance problems, fatigue, gastro-intestinal complaints and cognitive impairment. One of these patients had reduced levels of butyrylcholinesterase after a flight suggesting exposure to organophosphate compounds had occurred. All three were found to have elevated neuronal and glial auto-antibodies, biomarkers of central nervous system injury, and all three had genetic polymorphisms of paraoxonase (PON-1) and two of cytochrome P450, leading to a reduced ability to metabolize organophosphate compound (OPs). DISCUSSION: A similar constellation of symptoms has been described in other studies of aircrew, although objective evidence of exposure is lacking in most of these studies. Reduced levels of butyrylcholinesterases in one of our cases is suggestive of causation and elevated neuronal and glial autoantibodies provide objective evidence of damage to the central nervous system. We consider further research is warranted.

Published
2020

7. Saccular Abdominal Aortic Aneurysms Patient Characteristics, Clinical Presentation, Treatment, and Outcomes in the Netherlands

Author

Karthaus, E.G., Tong, T.M.L., Vahl, A., Hamming, J.F., Akker, L.H. van den, Akker, P.J. van den, Akkersdijk, G.J., Akkersdijk, G.P., Akkersdijk, W.L., Kempenaer, M.G.V. de, Arts, C.H., Avontuur, J.A., Baal, J.G., Bakker, O.J., Balm, R., Barendregt, W.B., Bender, M.H., Bendermacher, B.L., Berg, M. van den, Berger, P., Beuk, R.J., Blankensteijn, J.D., Bleker, R.J., Bockel, J.H., Bodegom, M.E., Bogt, K.E., Boll, A.P., Booster, M.H., Burg, B.L.B. van der, Borst, G.J. de, Bos-van Rossum, W.T., Bosma, J., Botman, J.M., Bouwman, L.H., Breek, J.C., Brehm, V., Brinckman, M.J., Broek, T.H. van den, Brom, H.L., Bruijn, M.T. de, Bruin, J.L. de, Brummel, P., Brussel, J.P. van, Buijk, S.E., Buimer, M.G., Burger, D.H., Buscher, H.C., Butter, G. den, Cancrinus, E., Castenmiller, P.H., Cazander, G., Coveliers, H.M., Cuypers, P.H., Daemen, J.H., Dawson, I., Derom, A.F., Dijkema, A.R., Diks, J., Dinkelman, M.K., Dirven, M., Dolmans, D.E., Doorn R, C. van, Dortmont, L.M. van, Eb, M.M. van der, Eefting, D., Eijck, G.J. van, Elshof, J.W., Elsman, B.H., Elst, A. van der, Engeland, M.I. van, Eps, R.G. van, Faber, M.J., Fijter, W.M. de, Fioole, B., Fritschy, W.M., Geelkerken, R.H., Gent, W.B. van, Glade, G.J., Govaert, B., Groenendijk, R.P., Groot, H.G. de, Haak, R.F. van den, Haan, E.F. de, Hajer, G.F., Hattum, E.S. van, Hazenberg, C.E., Joosten, P.P.H.M., Helleman, J.N., Hem, L.G. van der, Hendriks, J.M., Herwaarden, J.A. van, Heyligers, J.M., Hinnen, J.W., Hissink, R.J., Ho, G.H., Hoed, P.T. den, Hoedt, M.T., Hoek, F. van, Hoencamp, R., Hoffmann, W.H., Hoksbergen, A.W., Hollander, E.J., Huisman, L.C., Hulsebos, R.G., Hunt-Jens, K.M., Idu, M.M., Jacobs, M.J., Jagt, M.F. van der, Jansbeken, J.R., Janssen, R.J., Jiang, H.H., Jong, S.C. de, Jongkind, V., Kapma, M.R., Keller, B.P., Jahrome, A.K., Kievit, J.K., Klemm, P.L., Klinkert, P., Knippenberg, B., Koedam, N.A., Koelemaij, M.J., Kolkert, J.L., Koning, G.G., Koning, O.H., Krasznai, A.G., Krol, R.M., Kropman, R.H., Kruse, R.R., Laan, L. van der, Laan, M.J. van der, Laanen, J.H. van, Lardenoye, J.H., Lawson, J.A., Legemate, D.A., Leijdekkers, V.J., Lemson, M.S., Lensvelt, M.M., Lijkwan, M.A., Lind, R.C., Linden, F.T. van der, Lung, P.F.L., Loos, M.J., Loubert, M.C., Mahmoud, D.E., Manshanden, C.G., Mattens, E.C., Meerwaldt, R., Mees, B.M., Metz, R., Minnee, R.C., Mol van Otterloo , J.C. de, Moll, F.L., Swijndregt, Y.C.M. van, Morak, M.J., Mortel, R.H. van de, Mulder, W., Nagesser, S.K., Naves, C.C., Nederhoed, J.H., Nevenzel-Putters, A.M., Nie, A.J. de, Nieuwenhuis, D.H., Nieuwen-Huizen, J., Nieuwenhuizen, R.C. van, Nio, D., Oomen, A.P., Oranen, B.I., Oskam, J., Palamba, H.W., Peppelenbosch, A.G., Petersen, A.S. van, Peterson, T.F., Petri, B.J., Pierie, M.E., Ploeg, A.J., Pol, R.A., Ponfoort, E.D., Poyck, P.P., Prent, A., Raa, S. ten, Raymakers, J.T., Reichart, M., Reichmann, B.L., Reijnen, M.M., Rijbroek, A., Rijn, M.J. van, Roo, R.A. de, Rouwet, E.V., Rupert, C.G., Saleem, B.R., Sambeek, M.R. van, Samyn, M.G., Sant, H.P. van 't, Schaik, J. van, Schaik, P.M. van, Scharn, D.M., Scheltinga, M.R., Schepers, A., Schlejen, P.M., Schlosser, F.J., Schol, F.P., Schouten, O., Schreinemacher, M.H., Schreve, M.A., Schurink, G.W., Sikkink, C.J., Siroen, M.P., Slaa, A. te, Smeets, H.J., Smeets, L., Smet, A.A. de, Smit, P. de, Smit, P.C., Smits, T.M., Snoeijs, M.G., Sondakh, A.O., Steenhoven, T.J. van der, Sterkenburg, S.M. van, Stigter, D.A., Stigter, H., Strating, R.P., Stultiens, G.N., Sybrandy, J.E., Teijink, J.A., Telgenkamp, B.J., Testroote, M.J., The, R.M., Thijsse, W.J., Tielliu, I.F., Tongeren, R.B. van, Toorop, R.J., Tordoir, J.H., Tournoij, E., Truijers, M., Turkean, K., Nolthenius, R.P.T., Unlu, C., Vafi, A.A., Vahl, A.C., Veen, E.J., Veger, H.T., Veldman, M.G., Verhagen, H.J., Verhoeven, B.A., Vermeulen, C.F., Vermeulen, E.G., Vierhout, B.P., Visser, M.J., Vliet, J.A. van der, Vlijmen-van Kuelen, C.J., Voesten, H.G., Voorhoeve, R., and Vos

Subjects
Male, medicine.medical_specialty, Aortic Rupture, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Treatment outcome, Patient characteristics, Hospital mortality, 030204 cardiovascular system & hematology, Dutch Surgical Aneurysm Audit (DSAA), Risk Assessment, Blood Vessel Prosthesis Implantation, 03 medical and health sciences, Aortic aneurysm, 0302 clinical medicine, Intervention (counseling), medicine, Humans, Hospital Mortality, Registries, 030212 general & internal medicine, cardiovascular diseases, threshold for elective surgery, Aged, Netherlands, Retrospective Studies, business.industry, General surgery, Follow up studies, Retrospective cohort study, Middle Aged, Saccular abdominal aortic aneurysm, medicine.disease, Survival Analysis, Surgery, Treatment Outcome, Elective Surgical Procedures, 030220 oncology & carcinogenesis, cardiovascular system, Female, 030211 gastroenterology & hepatology, Emergencies, Presentation (obstetrics), Tomography, X-Ray Computed, Cardiology and Cardiovascular Medicine, business, Aortic Aneurysm, Abdominal, Follow-Up Studies, Abdominal surgery
Abstract

Objective: The aim of this was to analyze differences between saccularshaped abdominal aortic aneurysms (SaAAAs) and fusiform abdominal aortic aneurysms (FuAAAs) regarding patient characteristics, treatment, and outcome, to advise a threshold for intervention for SaAAAs.Background: Based on the assumption that SaAAAs are more prone to rupture, guidelines suggest early elective treatment. However, little is known about the natural history of SaAAAs and the threshold for intervention is not substantiated.Methods: Observational study including primary repairs of degenerative AAAs in the Netherlands between 2016 and 2018 in which the shape was registered, registered in the Dutch Surgical Aneurysm Audit (DSAA). Patients were stratified by urgency of surgery; elective versus acute (symptomatic/ruptured). Patient characteristics, treatment, and outcome were compared between SaAAAs and FuAAAs.Results: A total of 7659 primary AAA-patients were included, 6.1% (n = 471) SaAAAs and 93.9% (n = 7188) FuAAAs. There were 5945 elective patients (6.5% SaAAA) and 1714 acute (4.8% SaAAA). Acute SaAAApatients were more often female (28.9% vs 17.2%, P = 0.007) compared with acute FuAAA-patients. SaAAAs had smaller diameters than FuAAAs, in elective (53.0mm vs 61 mm, P = 0.000) and acute (68mm vs 75 mm, P = 0.002) patients, even after adjusting for sex. In addition, 25.2% of acute SaAAA-patients presented with diameters

Published
2019

8. Primary endometrial 3D co-cultures: A comparison between human and rat endometrium

Author

van den Brand, A D, Rubinstein, E, de Jong, P C, van den Berg, M, van Duursen, M B M, One Health Toxicologie, dIRAS RA-1, One Health Toxicologie, dIRAS RA-1, E&H: Environmental Health and Toxicology, and AIMMS

Subjects
0301 basic medicine, Polychlorinated Dibenzodioxins, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Estrogen receptor, Quinolones, Hormone receptors, Ligands, Endometrium, Biochemistry, Rats, Sprague-Dawley, 0302 clinical medicine, Endocrinology, Gene expression, endometrium, Cells, Cultured, Aryl hydrocarbon receptor, biology, Chemistry, aryl hydrocarbon receptor, medicine.anatomical_structure, Hormone receptor, 030220 oncology & carcinogenesis, Molecular Medicine, Female, cytochrome P450 1A1, medicine.medical_specialty, Cytochrome P450 1A1, 03 medical and health sciences, Aromatase, In vivo, Cell Line, Tumor, Internal medicine, Cytochrome P-450 CYP1A1, medicine, Animals, Humans, Molecular Biology, Estrogen Receptor alpha, hormone receptors, Cytochrome P450, Epithelial Cells, Cell Biology, Coculture Techniques, 030104 developmental biology, Receptors, Aryl Hydrocarbon, biology.protein, Stromal Cells, Hormone
Abstract

Human and rat reproductive systems differ significantly with respect to hormonal cyclicity and endometrial cell behavior. However, species-differences in endometrial cell responses upon hormonal stimulation and exposure to potentially toxic compounds are poorly characterized. In this study, human and rat endometrial hormonal responses were assessed in vitro using a 3D co-culture model of primary human and rat endometrial cells. The models were exposed to the aryl hydrocarbon receptor (AHR) ligands 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), laquinimod, and its AHR active metabolite DELAQ. In both the human and rat endometrial models, estrogen receptor and progesterone receptor gene expression was modulated by the hormonal treatments, comparable to the in vivo situation. AHR gene expression in the human endometrial model did not change when exposed to hormones. In contrast, AHR expression decreased 2-fold in the rat model when exposed to predominantly progesterone, which resulted in a 2.8-fold attenuation of gene expression induction of cytochrome P450 1A1 (CYP1A1) by TCDD. TCDD and DELAQ, but not laquinimod, concentration-dependently induced CYP1A1 gene expression in both human and rat endometrial models. Interestingly, the relative degree of DELAQ to induce CYP1A1 was higher than that of TCDD in the human model, while it was lower in the rat model. These data clearly show species-differences in response to hormones and AHR ligands between human and rat endometrial cells in vitro, which might greatly affect the applicability of the rat as translational model for human endometrial effects. This warrants further development of human relevant, endometrium-specific test methods for risk assessment purposes.

Published
2019

9. Model-based economic evaluations in smoking cessation and their transferability to new contexts: A systematic review

Author

Berg, M, Cheung, KL, Hiligsmann, M, Evers, S, de Kinderen, RJA, Kulchaitanaroaj, P, and Pokhrel, S

Subjects
modelling, Models, Economic, systematic review, Cost-Benefit Analysis, transferability, Reviews, Humans, Smoking Cessation, Review, tobacco, Economic evaluation, smoking
Abstract

Aims To identify different types of models used in economic evaluations of smoking cessation, analyse the quality of the included models examining their attributes and ascertain their transferability to a new context. Methods A systematic review of the literature on the economic evaluation of smoking cessation interventions published between 1996 and April 2015, identified via Medline, EMBASE, NHS EED, and HTA. Checklist-based quality of the included studies and transferability scores were based on European Network of Health Economic Evaluation Databases (EURONHEED) criteria. Studies that were not in smoking cessation, not an original research, not a model-based economic evaluation, that did not consider adult population and not from a high income country were excluded. Findings Among the 64 economic evaluations included in the review, state-transition Markov model was the most frequently used method (n = 30/64) with Quality Adjusted Life Years (QALYs) being the most frequently used outcome measure in a lifetime horizon. A small number of the included studies (13/64) were eligible for EURONHEED transferability checklist. The overall transferability scores ranged from 0.50 to 0.97 with an average score of 0.75. The average score per section was 0.69 (range 0.35-0.92). Relative transferability of the studies could not be established due to a limitation present in the EURONHEED method. . Conclusion All existing economic evaluations in smoking cessation lack in one or more key study attributes necessary to be fully transferable to a new context. SP and PK’s time in this research was partly funded by the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement No. 602270 (EQUIPT).

Published
2017

10. Severity of Virilization Is Associated with Cosmetic Appearance and Sexual Function in Women with Congenital Adrenal Hyperplasia: A Cross-Sectional Study

Author

Zwan, Y.G. van der, Janssen, E.H.C.C., Callens, N., Wolffenbuttel, K.P., Cohen-Kettenis, P.T., Berg, M. van den, Drop, S.L., Dessens, A.B., Beerendonk, C.C., Otten, B.J., Feitz, W.F., Kwak, K., Medical psychology, NCA - Neurobiology of mental health, Pediatrics, Urology, and Obstetrics & Gynecology

Subjects
SAMPLE, Endocrinology, Diabetes and Metabolism, Urinary incontinence, Severity of Illness Index, Endocrinology, Gynecologic Surgical Procedures, Female Genital Self-Image, Tissue engineering and pathology Renal disorder [NCMLS 3], Young adult, Outcome, Sexual Function, Obstetrics, CAH, Coitus, INTERSEX CONDITIONS, Genitalia, Female, Middle Aged, Psychiatry and Mental health, Distress, FUNCTION INDEX FSFI, Dyspareunia, Psychosexual development, DISTRESS SCALE FSDS, Female, medicine.symptom, Anatomy, Psychology, Adult, Reoperation, medicine.medical_specialty, Adolescent, Esthetics, Urology, FEMINIZING GENITOPLASTY, AMBIGUOUS GENITALIA, 21-HYDROXYLASE DEFICIENCY, VALIDATION, Young Adult, medicine, MANAGEMENT, Humans, Congenital adrenal hyperplasia, ANDROGEN EXCESS, Gynecology, Adrenal Hyperplasia, Congenital, Virilization, medicine.disease, Human Reproduction [NCEBP 12], Sexual intercourse, Cross-Sectional Studies, Urinary Incontinence, Reproductive Medicine, Linear Models, Surgery, Sexual function, Stress, Psychological
Abstract

Item does not contain fulltext Introduction. Women with the classical form of congenital adrenal hyperplasia (CAH) are born with different degrees of virilization of the external genitalia. Feminizing surgery is often performed in childhood to change the appearance of the genitalia and to enable penile-vaginal intercourse later in life. There are suggestions that this affects sexual functioning. Aims. The aim is to study the anatomical, surgical, cosmetic, and psychosexual outcomes in women with CAH. Methods. Forty women with CAH, aged over 15 years, from two referral centers for management of Disorders of Sex Development in the Netherlands were included. Physical and functional status were assessed by a gynecological interview and examination. Sexual functioning was assessed with the Female Sexual Function Index and Female Sexual Distress Scale-Revised scales and compared with a reference group. Mean Outcome Measures. Surgery performed, anatomy, cosmetic score, sexual function and distress. Results. Thirty-six of the 40 women had undergone feminizing surgery; 25 women (69%) underwent more than one operation. Resurgery was performed in seven of the 13 (54%) women who had had a single-stage procedure. Anatomical assessment showed reasonable outcomes. Multiple linear regression showed that only level of confluence had a significant effect on cosmetic outcome, the impact depending on the number of surgeries performed. Cosmetic evaluations did not differ between the women and the gynecologists. Only 20 women had experience of intercourse. Eight women reported dyspareunia; seven women reported urinary incontinence. The women's perceived sexual functioning was less satisfactory than in the reference group, and they reported more sexual distress. Conclusion. The level of confluence was the major determinant for cosmetic outcome; the impact depended on the number of surgeries performed. Fifty-four percent of the women required resurgery after a single-stage procedure in childhood. Anatomical assessment showed reasonable outcomes. The women evaluated their sexual functioning and functional outcome less favorable than the reference group, and they experienced less often sexual intercourse. van der Zwan YG, Janssen EHCC, Callens N, Wolffenbuttel KP, Cohen-Kettenis PT, van den Berg M, Drop SLS, Dessens AB, Beerendonk C. Severity of virilization is associated with cosmetic appearance and sexual function in women with congenital adrenal hyperplasia: A cross-sectional study. J Sex Med 2013;10:866-875.

Published
2013

11. Stop or go?

Author

Molenaar, Nina, Brouwer, M. E., Bockting, C. L. H., Bonsel, G. J., Van der Veere, C. N., Torij, H. W., Hoogendijk, W., Duvekot, J. J., Burger, H. N., Lambregtse-van den Berg, M. P., Trauma and Grief, Leerstoel Bockting, Psychiatry, Obstetrics & Gynecology, Medical Oncology, Child and Adolescent Psychiatry / Psychology, Trauma and Grief, Leerstoel Bockting, Adult Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Public and occupational health, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Reproductive Origins of Adult Health and Disease (ROAHD), and Life Course Epidemiology (LCE)

Subjects
Pediatrics, Cost effectiveness, SEROTONIN REUPTAKE INHIBITORS, medicine.medical_treatment, POPULATION-BASED COHORT, Social Sciences, Antidepressive Agents/therapeutic use, law.invention, COST-EFFECTIVENESS, Study Protocol, 0302 clinical medicine, Randomized controlled trial, Clinical Protocols, law, Recurrence, Pregnancy, Medicine and Health Sciences, SSRI, Depressive Disorder/drug therapy, RECURRENT DEPRESSION, 030212 general & internal medicine, Relapse, Netherlands, Psychomotor learning, MAJOR DEPRESSIVE DISORDER, Depression, digestive, oral, and skin physiology, GENERAL MOVEMENTS, Antidepressants, Antidepressive Agents, Psychiatry and Mental health, Prenatal Exposure Delayed Effects, antidepressants, Major depressive disorder, Anxiety, Female, medicine.symptom, Psychology, MENTAL-HEALTH, Adult, medicine.medical_specialty, Prenatal Exposure Delayed Effects/prevention & control, MATERNAL DEPRESSION, PRETERM BIRTH, Cognitive therapy, behavioral disciplines and activities, 03 medical and health sciences, Selective serotonin reuptake inhibitors, mental disorders, medicine, Humans, study, Psychiatry, PRENATAL EXPOSURE, Depressive Disorder, Cognitive Behavioral Therapy, Prevention, Cognitive Behavioral Therapy/methods, Perinatal outcome, medicine.disease, 030227 psychiatry, Discontinuation, cognitive therapy, Cost-effectiveness, Serotonin Uptake Inhibitors/therapeutic use
Abstract

BACKGROUND: Approximately 6.2 % of women in the USA and 3.7 % of women in the UK, use Selective Serotonin Reuptake Inhibitors (SSRIs) during their pregnancies because of depression and/or anxiety. In the Netherlands, this prevalence is around 2 %. Nonetheless, SSRI use during pregnancy is still controversial. On the one hand SSRIs may be toxic to the intrauterine developing child, while on the other hand relapse or recurrence of depression during pregnancy poses risks for both mother and child. Among patients and professionals there is an urgent need for evidence from randomized studies to make rational decisions regarding continuation or tapering of SSRIs during pregnancy. At present, no such studies exist. METHODS/DESIGN: 'Stop or Go' is a pragmatic multicentre randomized non-inferiority trial among 200 pregnant women with a gestational age of less than 16 weeks who use SSRIs without clinically relevant depressive symptoms. Women allocated to the intervention group will receive preventive cognitive therapy with gradual, guided discontinuation of SSRIs under medical management (STOP). Women in the control group will continue the use of SSRIs (GO). Primary outcome will be the (cumulative) incidence of relapse or recurrence of maternal depressive disorder (as assessed by the Structured Clinical Interview for DSM disorders) during pregnancy and up to three months postpartum. Secondary outcomes will be child outcome (neonatal outcomes and psychomotor and behavioural outcomes up to 24 months postpartum), and health-care costs. Total study duration for participants will be therefore be 30 months. We specified a non-inferiority margin of 15 % difference in relapse risk. DISCUSSION: This study is the first to investigate the effect of guided tapering of SSRIs with preventive cognitive therapy from early pregnancy onwards as compared to continuation of SSRIs during pregnancy. We will study the effects on both mother and child with a pragmatic approach. Additionally, the study examines cost effectiveness. If non-inferiority of preventive cognitive therapy with guided tapering of SSRIs compared to intended continuation of SSRIs is demonstrated for the primary outcome, this may be the preferential strategy during pregnancy. TRIAL REGISTRATION: Netherlands Trial Register (NTR): NTR4694 ; registration date: 16-jul-2014.

Published
2016

12. Potentiation of the Human GABAA Receptor As a Novel Mode of Action of Lower-Chlorinated Non-Dioxin-Like PCBs

Author

Antunes Fernandes, E.C., Hendriks, H.S., van Kleef, R.G.D.M., van den Berg, M., Westerink, R.H.S., Risk Assessment of Toxic and Immunomodulatory Agents, Dep IRAS, Risk Assessment of Toxic and Immunomodulatory Agents, and Dep IRAS

Subjects
medicine.medical_specialty, Patch-Clamp Techniques, brain, in-vitro, Binding, Competitive, thyroid-hormone, Xenopus laevis, Dopamine, Internal medicine, medicine, Animals, Humans, Environmental Chemistry, rat, GABA-A Receptor Agonists, Mode of action, Receptor, VLAG, GABAA receptor, Chemistry, Neurotoxicity, food and beverages, Long-term potentiation, polychlorinated biphenyl congeners, General Chemistry, ester binding, medicine.disease, Polychlorinated Biphenyls, Food Quality and Design, Endocrinology, Mechanism of action, cerebellar granule cells, exposure, Toxicity, Female, developmental neurotoxicity, Chlorine, dopamine, medicine.symptom, medicine.drug
Abstract

PCBs are still ubiquitous pollutants despite the ban on their industrial and commercial use. To date, risk characterization and assessment of non-dioxin-like PCBs (NDL-PCBs), especially with respect to neurotoxicity, is hampered by a lack of data. Therefore, the effects of six common NDL congeners (PCB28, 52, 101, 138, 153 and 180) on human GABA(A) receptors, expressed in Xenopus oocytes, were investigated using the two-electrode voltage-clamp technique. When coapplied with GABA (at EC(20)), PCB28 and PCB52 concentration-dependently potentiate the GABA(A) receptor-mediated ion current. Though the LOEC for both PCB28 and PCB52 is 0.3 microM, PCB28 is more potent than PCB52 (maximum potentiation at 10 muM amounting to 98.3 +/- 12.5% and 25.5 +/- 1.4%, respectively). Importantly, coapplication of PCB28 (0.3 microM) and PCB52 (10 microM) resulted in an apparently additive potentiation of the GABA(A) response, whereas coapplication of PCB28 (0.3 microM) and PCB153 (10 microM) attenuated the PCB28-induced potentiation. The present results suggest that the potentiation of human GABA(A) receptor function is specific for lower-chlorinated NDL-PCBs and that higher molecular weight PCBs may attenuate this potentiation as a result of competitive binding to human GABA(A) receptors. Nonetheless, this novel mode of action could (partly) underlie the previously recognized NDL-PCB-induced neurobehavioral alterations.

Published
2009

13. Identification of vascular patients at very high risk for recurrent cardiovascular events : Validation of the current ACC/AHA very high risk criteria

Author

Van Den Berg, M. Johanneke, Bhatt, Deepak L., Kappelle, L. J., De Borst, Gert J., Cramer, Maarten J., Van Der Graaf, Yolanda, Steg, Ph Gabriel, Visseren, Frank L.J., Algra, A., Grobbee, D. E., and Rutten, G. E.H.M.

Subjects
Adult, Male, medicine.medical_specialty, Arterial disease, Disease, 030204 cardiovascular system & hematology, Risk Assessment, Cardiovascular events, 03 medical and health sciences, 0302 clinical medicine, Recurrence, Risk Factors, Internal medicine, Diabetes mellitus, Prevalence, Journal Article, Medicine, Humans, In patient, 030212 general & internal medicine, Prospective Studies, Registries, health care economics and organizations, Aged, Dyslipidemias, Netherlands, Secondary prevention, business.industry, Incidence (epidemiology), Incidence, Smoking, Middle Aged, medicine.disease, Atherosclerosis, Risk prediction, Very high risk, Early Diagnosis, Cardiovascular Diseases, Female, business, Cardiology and Cardiovascular Medicine, Mace, Diabetic Angiopathies, Glomerular Filtration Rate
Abstract

Aims: To validate and assess performance of the current ACC/AHA very high risk criteria in patients with clinically manifest arterial disease. Methods and results: Data were used from the SMART study (n = 7216) and REACH Registry (n = 48 322), two prospective cohorts of patients with manifest atherosclerotic arterial disease. Prevalence and incidence rates of recurrent major adverse cardiovascular events (MACE) were calculated, according to the ACC/AHA VHR criteria (cardiovascular disease combined with diabetes, smoking, dyslipidaemia, and/or recent recurrent coronary events). Performance of the ACC/AHA criteria was compared with single very high risk factors in terms of C-statistics and Net Reclassification Index. All patients were at VHR according to the ESC guidelines (incidence of recurrent MACE in SMART was 2.4/100PY, with 95% CI 2.3-2.5/100PY and in REACH 5.1/100PY with 95% CI 5.0-5.3/100PY). In SMART 57% of the patients were at VHR according to the ACC/AHA criteria (incidence of recurrent MACE 2.7/100PY, 95% CI 2.5-2.9/100PY) and in REACH this was 64% (5.9/100PY, 95% CI 5.7-6.1/100PY). The C-statistic for the ACC/AHA VHR criteria was 0.53 in REACH and 0.54 in SMART. Very high risk factors with comparable or slightly better performance were eGFR < 45, polyvascular disease and age >70 years. Around two third of the patients meeting the ACC/AHA VHR criteria had a predicted 10-year risk of recurrent MACE 70 years performs as well as the ACC/AHA VHR criteria.

Published
2017

14. Mode of action and dose-response framework analysis for receptor-mediated toxicity: The aryl hydrocarbon receptor as a case study

Author

Budinsky, R. A., Schrenk, D., Simon, T., Van Den Berg, M., Reichard, J. F., Silkworth, J. B., Aylward, L. L., Brix, A., Gasiewicz, T., Kaminski, N., Perdew, G., Starr, T. B., Walker, N. J., Rowlands, J. C., LS IRAS Tox Algemeen, Risk Assessment of Toxic and Immunomodulatory Agents, IRAS RATIA1, LS IRAS Tox Algemeen, Risk Assessment of Toxic and Immunomodulatory Agents, and IRAS RATIA1

Subjects
medicine.medical_specialty, TCDD, Polychlorinated Dibenzodioxins, Apoptosis, Toxicology, Modulating factors, Internal medicine, medicine, Animals, Humans, Mode of action, Receptor, Dose-response assessment, Cell Proliferation, Key events, Dioxin, Dose-Response Relationship, Drug, biology, Cell growth, Liver Neoplasms, Human relevance framework, medicine.disease, Aryl hydrocarbon receptor, Mitochondria, Oxidative Stress, Cell Transformation, Neoplastic, Endocrinology, Liver, Receptors, Aryl Hydrocarbon, Toxicity, Carcinogens, biology.protein, Cancer research, Tumor promotion, Liver cancer
Abstract

Dioxins and dioxin-like compounds are tumor promoters that cause liver cancer in rats and mice. The aryl hydrocarbon receptor (AHR) has been implicated as a key component in this tumor promotion response. Despite extensive knowledge of the toxicology of dioxins, no mode of action (MOA) hypothesis for their tumorigenicity has been formally documented using the Human Relevance MOA framework developed by the International Programme on Chemical Safety (IPCS). To address this information gap, an expert panel was convened as part of a workshop on receptor-mediated liver tumorigenicity. Liver tumors induced by ligands of the AHR were assessed using data for dioxins and related chemicals as a case study. The panel proposed a MOA beginning with sustained AHR activation, eventually leading to liver tumors via a number of other processes, including increased cell proliferation of previously initiated altered hepatic foci, inhibition of intrafocal apoptosis and proliferation of oval cells. These processes have been identified and grouped as three key events within the hepatocarcinogenic MOA: (1) sustained AHR activation, (2) alterations in cellular growth and homeostasis and (3) pre-neoplastic tissue changes. These key events were identified through application of the Bradford-Hill considerations in terms of both their necessity for the apical event/adverse outcome and their human relevance. The panel identified data supporting the identification and dose-response behavior of key events, alteration of the dose-response by numerous modulating factors and data gaps that potentially impact the MOA. The current effort of applying the systematic frameworks for identifying key events and assessing human relevance to the AHR activation in the tumorigenicity of dioxins and related chemicals is novel at this time. The results should help direct future regulatory efforts and research activities aimed at better understanding the potential human cancer risks associated with dioxin exposure.

Published
2014

15. Impact of remuneration on guideline adherence: Empirical evidence in general practice

Author

van Dijk, C.E., Verheij, R.A., Spreeuwenberg, P., van den Berg, M., Groenewegen, P.P., Braspenning, J.C., et al, [No Value], SGPL Stadsgeografie, Afd sociologie, Social Urban Transitions, Social Networks, Solidarity and Inequality, Tranzo, Scientific center for care and wellbeing, SGPL Stadsgeografie, Afd sociologie, Social Urban Transitions, and Social Networks, Solidarity and Inequality

Subjects
medicine.medical_specialty, Longitudinal study, Implementation Science [NCEBP 3], Empirical Research, Remuneration, Empirical research, quality of care, medicine, Humans, Longitudinal Studies, Medical prescription, Empirical evidence, guideline adherence, Netherlands, Quality of Health Care, general practice, Capitation, Guideline adherence, business.industry, Medical record, Public Health, Environmental and Occupational Health, The Netherlands, Family medicine, Original Article, Family Practice, business, remuneration system
Abstract

Background and objective. Changes in the Dutch GP remuneration system provided the opportunity to study the effects of changes in financial incentives on the quality of care. Separate remuneration systems for publicly insured patients (capitation) and privately insured patients (fee-for-service) were replaced by a combined system of capitation and fee-for-service for all in 2006. The effects of these changes on the quality of care in terms of guideline adherence were investigated. Design and setting. A longitudinal study from 2002 to 2009 using data from patient electronic medical records in general practice. A multilevel (patient and practice) approach was applied to study the effect of changes in the remuneration system on guideline adherence. Subjects. 21 421 to 39 828 patients from 32 to 52 general practices (dynamic panel of GPs). Main outcome measures. Sixteen guideline adherence indicators on prescriptions and referrals for acute and chronic conditions. Results. Guideline adherence increased between 2002 and 2008 by 7% for (formerly) publicly insured patients and 10% for (formerly) privately insured patients. In general, no significant differences in the trends for guideline adherence were found between privately and publicly insured patients, indicating the absence of an effect of the remuneration system on guideline adherence. Adherence to guidelines involving more time investment in terms of follow-up contacts was affected by changes in the remuneration system. For publicly insured patients, GPs showed a higher trend for guideline adherence for guidelines involving more time investment in terms of follow-up contacts compared with privately insured patients. Conclusion. The change in the remuneration system had a limited impact on guideline adherence.Keywords: General practice, guideline adherence, quality of care, remuneration system, The Netherlands

Published
2013

16. A mechanistic insight into 3,4-methylenedioxymethamphetamine ('ecstasy')-mediated hepatotoxicity

Author

Antolino-Lobo, I., Meulenbelt, J., van den Berg, M., van Duursen, M.B.M., Risk Assessment of Toxic and Immunomodulatory Agents, Dep IRAS, Risk Assessment of Toxic and Immunomodulatory Agents, and Dep IRAS

Subjects
Hallucinogen, Drug, medicine.medical_treatment, media_common.quotation_subject, Ecstasy, Poison control, Pharmacology, mental disorders, Animals, Humans, Medicine, Adverse effect, 3,4-Methylenedioxyamphetamine, media_common, Immunosuppression Therapy, Polymorphism, Genetic, General Veterinary, Illicit Drugs, business.industry, MDMA, Stimulant, Liver, Chemical and Drug Induced Liver Injury, business, Drug metabolism, psychological phenomena and processes, medicine.drug
Abstract

3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is a popular drug of abuse among young people with stimulant and hallucinogenic properties. The drug is generally thought to be safe among consumers due to its low-mortality rates. However, MDMA-adverse effects can occur and the risks are not clearly associated to a specific pattern since the consumption quantity seems not to be correlated with the initiation and severity of the injury. MDMA-mediated adverse health effects have been widely studied and can be evoked by multiple factors such as hyperthermia, polydrug abuse (drug-drug interactions), the altered release of neurotransmitters, impairment of mitochondrial function and apoptosis, metabolism and immune responses. Another adverse effect often associated with MDMA is liver toxicity, yet the mechanism of MDMA-induced liver toxicity is not completely understood. A critical starting point appears to be the hepatic metabolism of MDMA by phase I and II enzymes, leading to reactive metabolites. Elucidating the mechanism of hepatic injury mediated by MDMA is of high toxicological and clinical relevance. In this review, an overview of the literature and the latest findings with respect to the mechanism of MDMA-mediated liver toxicity is described.

Published
2012

17. Differential roles of phase I and phase II enzymes in 3,4-methylendioxymethamphetamine-induced cytotoxicity

Author

Antolino Lobo, I., Meulenbelt, J., Nijmeijer, S.M., Scherpenisse, P., van den Berg, M., van Duursen, M.B.M., Risk Assessment of Toxic and Immunomodulatory Agents, Dep IRAS, Risk Assessment of Toxic and Immunomodulatory Agents, and Dep IRAS

Subjects
Male, Cell Survival, N-Methyl-3,4-methylenedioxyamphetamine, Pharmaceutical Science, Pharmacology, Models, Biological, chemistry.chemical_compound, mental disorders, medicine, Animals, Humans, Buthionine sulfoximine, Troleandomycin, Enzyme Inhibitors, Cytotoxicity, Cell Line, Transformed, biology, CYP3A4, CYP1A2, Cytochrome P450, MDMA, Glutathione, Metabolic Detoxication, Phase II, Rats, chemistry, Biochemistry, biology.protein, Microsomes, Liver, Metabolic Detoxication, Phase I, psychological phenomena and processes, medicine.drug
Abstract

Metabolism plays an important role in the toxic effects caused by 3,4-methylenedioxymethamphetamine (MDMA). Most research has focused on the involvement of CYP2D6 enzyme in MDMA bioactivation, and less is known about the contribution of other cytochrome P450 (P450) and phase II metabolism. In this study, we researched the differential roles of phase I P450 enzymes CYP1A2, CYP3A4, and CYP2D6 and phase II enzymes glutathione S-transferase (GST) and catechol-O-methyltransferase (COMT) on the toxic potential of MDMA. MDMA acts as inhibitor of its own metabolism with a relative potency of inhibition of CYP2D>CYP3A>> CYP1A in rat liver microsomes and in human liver [immortalized human liver epithelial cells (THLE)] cells transfected with individual CYP1A2, CYP3A4, or CYP2D6. Cytotoxicity measurements [by 3,(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] in THLE cells showed that the inhibition of phase I enzymes CYP1A2 by alpha-naphthoflavone and CYP3A4 by troleandomycin does not affect MDMA-induced cytotoxicity. MDMA metabolism by CYP2D6 significantly increased cytotoxicity, which was counteracted by CYP2D6 inhibition by quinidine. Inhibition of COMT by 2'-fluoro-3,4-dihydroxy-5-nitrobenzophenone (Ro-41-0960) and GST by buthionine sulfoximine showed that COMT is mainly involved in detoxification of CYP2D6-formed MDMA metabolites, whereas glutathione (GSH) is mainly involved in detoxification of CYP3A4-formed MDMA metabolites. Liquid chromatography/tandem mass spectrometry analyses of MDMA-metabolites in the THLE cell culture media confirmed formation of the specific MDMA metabolites and corroborated the observed cytotoxicity. Our data suggest that CYP2D6 as well as CYP3A4 play an important role in MDMA bioactivation. In addition, further studies are needed to address the differential roles of CYP3A4 and GSH/GST in MDMA bioactivation and detoxification.

Published
2010

18. Chemopreventive actions by enterolactone and 13 VIOXX-related lactone derivatives in H295R human adrenocortical carcinoma cells

Author

van Duursen, M.B.M., Nijmeijer, S.M., Ruchirawat, S., van den Berg, M., Risk Assessment of Toxic and Immunomodulatory Agents, and Dep IRAS

Subjects
medicine.medical_specialty, endocrine system, Cell cycle checkpoint, Neoplasms, Hormone-Dependent, Gene Expression, Phytoestrogens, Biology, Toxicology, Lignans, chemistry.chemical_compound, Lactones, Structure-Activity Relationship, Enterolactone, 4-Butyrolactone, Internal medicine, Cell Line, Tumor, medicine, Adrenocortical Carcinoma, Humans, Sulfones, Cytotoxicity, chemistry.chemical_classification, Flavonoids, Mitogen-Activated Protein Kinase Kinases, Cell Cycle, Cancer, Steroid 17-alpha-Hydroxylase, General Medicine, Cell cycle, medicine.disease, In vitro, Adrenal Cortex Neoplasms, Endocrinology, Enzyme, chemistry, Cell culture, Enzyme Induction, Cancer research, Protein Processing, Post-Translational
Abstract

Cytochrome P450c17 (CYP17) has been linked to various hormone-related diseases, including breast cancer, thus being a potential target for cancer chemoprevention. We studied the naturally occurring phytochemical enterolactone (ENL) and 13 VIOXX-related lactone derivatives (CRI-1 to CRI-13) for their effects on CYP17 activity and expression and on cell cycle status in the human H295R adrenocorticocarcinoma cell line. Of the tested compounds, only CRI-3, -7, -10 and -12 showed to be inhibitors of CYP17 activity in H295R cells. This inhibition was not due to decreased mRNA expression, but was apparently caused by post-translational modification of the CYP17 enzyme. The MAPK kinase (MEK) inhibitor PD98059 induced CYP17 activity by 24%, while co-incubation of the CRI-s with PD98059, reduced CYP17 activity even further than the reduction caused by the CRI-s alone. In addition, CRI-3, -7, -10 and -12 arrested the cell cycle in the G(2)/M phase. The structure-activity similarities of the CRI-s with known micro-tubule binding agents strongly suggest that cell cycle arrest is a result of interaction with tubulin. We conclude that the proposed cancer chemopreventive actions of ENL are not mediated through interaction with CYP17 or cell cycle status. Of the VIOXX-related lactone derivatives, CRI-7 could prove useful in the prevention of hormone-dependent cancers, such as breast cancer, since in vitro it shows low cytotoxicity, it is a potent inhibitor of CYP17 activity and strong inducer of cell cycle arrest.

Published
2010

19. Activation and potentiation of human GABAA receptors by non-dioxin-like-PCBs depends on chlorination pattern

Author

Antunes Fernandes, E.C., Hendriks, H.S., van Kleef, R.G.D.M., Reniers, A., Andersson, P.L., van den Berg, M., Westerink, R.H.S., Risk Assessment of Toxic and Immunomodulatory Agents, and Dep IRAS

Subjects
Agonist, medicine.medical_specialty, Patch-Clamp Techniques, medicine.drug_class, recombinant gaba(a), Toxicology, Partial agonist, brominated flame retardants, Structure-Activity Relationship, Xenopus laevis, children, Postsynaptic potential, Internal medicine, neurotoxicity, medicine, Animals, Humans, GABA-A Receptor Agonists, Patch clamp, Receptor, gamma-Aminobutyric Acid, VLAG, GABAA receptor, Chemistry, Long-term potentiation, Receptors, GABA-A, Polychlorinated Biphenyls, inhibition, congeners, Endocrinology, Food Quality and Design, polychlorinated-biphenyls pcbs, working, exposure, Oocytes, Biophysics, Environmental Pollutants, Female, Chlorine, Neurotransmitter transport, dopamine
Abstract

The neurotoxic potential of non-dioxin-like polychlorinated biphenyls (NDL-PCBs) is characterized by disruption of presynaptic processes, including calcium homeostasis and neurotransmitter transport. Recently, using a limited set of congeners, we demonstrated that PCB28 and PCB52 can potentiate postsynaptic GABA(A) receptors. In the present study, effects of 20 NDL-PCBs and 2 dioxin-like PCBs, selected based on their chemical variation and abundance in the environment, on human GABA(A) receptors were investigated. GABA(A) receptors were expressed in Xenopus oocytes, and NDL-PCB effects were determined using the two-electrode voltage-clamp technique. Results demonstrate that lower chlorinated PCB19, PCB28, PCB47, PCB51, PCB52, PCB95, and PCB100 act as a partial agonists (at low receptor occupancy), i.e., potentiating the receptor response during coapplication with GABA (at EC(20)). Importantly, PCB19, PCB47, PCB51, and PCB100 can also act as full agonist, i.e., activate the GABA(A) receptor in the absence of GABA. Potentiation and activation of the GABA(A) receptor is concentration dependent and limited to NDL-PCBs that have 3-5 chlorine atoms, 1-3 ortho-substitutions, an equal number (0-1) of meta-substitutions on both phenyl rings, and do not have an adjacent para- and meta-substitution on the same phenyl ring. Activation and potentiation of the GABA(A) receptor by PCB47, the most potent congener (lowest observed effect concentration of 10nM), is attenuated when coapplied with PCB19, PCB28, PCB153, or PCB180, indicative for competitive binding. Considering the importance of GABA-ergic signaling for brain development, motor coordination, learning, and memory, this mode of action can contribute to the previously observed NDL-PCB-induced neurobehavioral and neurodevelopmental effects and should be included in human risk assessment.

Published
2010

20. Biology of Vascular Malformations of the Brain

Author

Leblanc, Gg, Golanov, E, Awad, Ia, Young, Wl, Biology of Vascular Malformations of the Brain NINDS Workshop Collaborators:Awad, I, Berg, M, Chopp, M, Gale, Nw, Gunel, M, Lo, Eh, Marchuk, D, Rigamonti, D, Tournier Lasserve, E, Blasig, Ie, Boudreau, N, Ginsberg, M, Jin, K, Johnson, Gl, Kim, H, Lawton, Mt, Letarte, M, Li, Dy, Mohr, Jp, Nishimura, S, Noonan, Douglas, Pawlikowska, L, Plate, Kh, Shenkar, R, Al Shahi Salman, R, Ball, Kl, Clancy, Ms, Connolly SE Jr, Derry, B, Faurobert, E, Gault, J, Hannegan, L, Hashimoto, T, Keep, Rf, Lee, C, Mccarty, J, Morrison, L, Ning, M, Nunn, Mf, Oh, Sp, Plahn, Bk, Pratt, Ca, Pratt, Wb, Spatz, M, Stapf, C, Yang, Gy, and Zhang, J.

Subjects
Intracranial Arteriovenous Malformations, Hemangioma, Cavernous, Central Nervous System, Pathology, medicine.medical_specialty, Angiogenesis, Cerebral arteries, Gene mutation, medicine.disease_cause, Article, medicine, Animals, Humans, Genetic Predisposition to Disease, Telangiectasia, Advanced and Specialized Nursing, Mutation, Neovascularization, Pathologic, business.industry, Gene Expression Regulation, Developmental, Arteriovenous malformation, Cerebral Arteries, medicine.disease, Disease Models, Animal, Etiology, Telangiectasia, Hereditary Hemorrhagic, Neurology (clinical), medicine.symptom, Cardiology and Cardiovascular Medicine, business
Abstract

Background and Purpose—This review discusses recent research on the genetic, molecular, cellular, and developmental mechanisms underlying the etiology of vascular malformations of the brain (VMBs), including cerebral cavernous malformation, sporadic brain arteriovenous malformation, and the arteriovenous malformations of hereditary hemorrhagic telangiectasia.Summary of Review—The identification of gene mutations and genetic risk factors associated with cerebral cavernous malformation, hereditary hemorrhagic telangiectasia, and sporadic arteriovenous malformation has enabled the development of animal models for these diseases and provided new insights into their etiology. All of the genes associated with VMBs to date have known or plausible roles in angiogenesis and vascular remodeling. Recent work suggests that the angiogenic process most severely disrupted by VMB gene mutation is that of vascular stabilization, the process whereby vascular endothelial cells form capillary tubes, strengthen their intercellular junctions, and recruit smooth muscle cells to the vessel wall. In addition, there is now good evidence that in some cases, cerebral cavernous malformation lesion formation involves a genetic 2-hit mechanism in which a germline mutation in one copy of a cerebral cavernous malformation gene is followed by a somatic mutation in the other copy. There is also increasing evidence that environmental second hits can produce lesions when there is a mutation to a single allele of a VMB gene.Conclusions—Recent findings begin to explain how mutations in VMB genes render vessels vulnerable to rupture when challenged with other inauspicious genetic or environmental factors and have suggested candidate therapeutics. Understanding of the cellular mechanisms of VMB formation and progression in humans has lagged behind that in animal models. New knowledge of lesion biology will spur new translational work. Several well-established clinical and genetic database efforts are already in place, and further progress will be facilitated by collaborative expansion and standardization of these.

Published
2009

21. Determination of matrilysin activity in gastrointestinal neoplasia

Author

Hawinkels, L.J.A.C., Verspaget, H.W., Berg, M. van den, Hanemaaijer, R., Sier, C.F.M., and TNO Kwaliteit van Leven

Subjects
Biomedical Research, Digestive system cancer, Tumor Markers, Biological, Matrix Metalloproteinase 7, Humans, Enzyme activity, Colorectal Neoplasms, Biology, Controlled study, Immunohistochemistry, Western blotting
Published
2007

22. Rheological and immunological findings in dockers with vibration-induced white fingers

Author

Gudmundsson M, Berg M, Tarkowski A, and Torén K

Subjects
Adult, Male, medicine.medical_specialty, Anti-nuclear antibody, Immunoglobulins, Fibrinogen, Vibration, Fingers, Internal medicine, Blood plasma, medicine, Humans, Rheumatoid factor, Ships, medicine.diagnostic_test, biology, Chemistry, Smoking, Public Health, Environmental and Occupational Health, Autoantibody, Raynaud Disease, Middle Aged, Blood Viscosity, Blood proteins, Occupational Diseases, Endocrinology, Case-Control Studies, Erythrocyte sedimentation rate, Immunology, biology.protein, Antibody, Rheology, medicine.drug
Abstract

The aim of the present study was to characterize rheological and immunological features involved in the pathogenesis of vibration-induced white fingers (VWF). Plasma viscosity, at two shear rates (580 s-1 and 1164 s-1), levels of immunoglobulins (IgG, IgM, IgA), circulating immune complexes, rheumatoid factor, antinuclear antibodies, fibronectin, fibrinogen, hemoglobin and erythrocyte sedimentation rate were analysed in 30 male dockers with VWF and in 30 healthy male referents unexposed for hand-arm vibrations. Decreased plasma viscosity was observed among the men with VWF, although formal significance (P less than 0.05) was only obtained at shear rate 580 s-1. The decrease was mainly seen among smokers. In the study there were no significant differences between the VWF group and the referents with regard to immunoglobulin levels, autoantibodies and other plasma proteins. From the study it is concluded that workers with VWF may have a decreased plasma viscosity. The biological relevance of this observation is uncertain and deserves further study.

Published
1992

23. Expression of homeobox genes in the gastrointestinal tract

Author

van den Berg M, Rings E, and Pieter C. F. Stokkers

Subjects
Gastrointestinal tract, business.industry, Gastroenterology, Homeobox A1, Genes, Homeobox, Gene Expression, Pediatrics, Perinatology and Child Health, Cancer research, Medicine, Homeobox, Humans, business, CDX2, Digestive System
Published
1998

24. Endothelial marker proteins in hyperhomocysteinemia

Author

Jong, S.C. de, Stehouwer, C.D.A., Berg, M. van den, Vischer, U.M., Rauwerda, J.A., Emeis, J.J., and Gaubius Instituut TNO

Subjects
Adult, Male, congenital, hereditary, and neonatal diseases and abnormalities, Thrombomodulin, Arterial Occlusive Diseases, Middle Aged, Blood Coagulation Factors, Fibronectins, Risk Factors, Tissue Plasminogen Activator, Plasminogen Activator Inhibitor 1, von Willebrand Factor, cardiovascular system, Humans, Biological Markers, Female, Endothelium, Vascular, Antigens, Homocysteine
Abstract

Hyperhomocysteinemia is associated with severe, premature atherosclerosis and thromboembolism. The mechanisms involved in the atherogenic and thrombotic complications of hyperhomocysteinemia are not understood. It has been suggested that hyperhomocysteinemia predisposes to atherosclerosis by injuring the vascular endothelium. Whether hyperhomocysteinema is independently associated with changed endothelial function, either in the absence or the presence of clinically manifest atherosclerotic disease, is, however, not known. Therefore we investigated, both in patients with peripheral arterial occlusive disease and in healthy individuals, whether plasma protein markers of endothelial function differed between subjects with, and subjects without hyperhomocysteinemia. We studied 80 individuals under the age of 56 years: healthy individuals with (n = 20) and without (n = 20) hyperhomocysteinemia and patients with peripheral arterial occlusive disease with (n = 20) and without (n = 20) hyperhomocysteinemia. The following endothelium-derived proteins were measured as markers of endothelial cell function: von Willebrand factor (vWf) and von Willebrand factor propeptide (vWf: AgII), tissue-type plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), cellular fibronectin (cFN) and thrombomodulin (TM). In addition we assessed C-reactive protein (CRP). vWf, vWf: AgII, tPA and CRP were significantly higher in the patients with peripheral arterial occlusive disease than in the healthy individuals. No differences in marker protein plasma levels were found between individuals with, and those without hyperhomocysteinemia, apart from vWf, which was significantly raised in hyperhomocysteinemic as compared to normohomocysteinemic patients. We did not find any evidence for an independent association between hyperhomocysteinemia and protein markers of endothelial cell function in healthy subjects. Copyright © 1997 Schattauer Verlag

Published
1997

25. Working with protocols: a sociological view

Author

Berg M

Subjects
Male, Pragmatic reasoning, business.industry, media_common.quotation_subject, Decision Making, Constructive, Patient Care Planning, Epistemology, Mental Processes, Work (electrical), Clinical Protocols, Physicians, Diagnosis, Internal Medicine, Medicine, Humans, Female, Sociology, Function (engineering), business, media_common
Abstract

This sociological study discusses three assumptions on the nature of medical work, which can be found in protocols. First, protocols assume that medical data exist as clear-cut, elementary bits of information. Second, they assume that medical criteria are well-defined and pre-set, fixed rules, which merely have to be applied. Finally, protocols depict medical work as a sequence of individual steps which each need to be terminated before the following can be made. Sociological studies of physicians at work, however, show that medical work is characterised by interactive, pragmatic reasoning, by fluid criteria, and by the (re)constructive nature of medical data. By discussing the three assumptions, this article demonstrates how medical personnel have to actively intervene to prevent the protocols' misalignment with the nature of medical work from creating problems. This does not mean that protocols are 'bad tools': the fact that it takes work to get a technology to function does not disqualify it. But this observation does imply that protocols cannot be regarded as tools which simply 'support' the work of physicians. Also, these observations shed an interesting light on the prevalent claim that protocols 'rationalise' medical work.

Published
1996

26. PCB-47, PBDE-47, and 6-OH-PBDE-47 differentially modulate human GABA A and alpha4beta2 nicotinic acetylcholine receptors

Author

Hendriks, H.S., Antunes Fernandes, E.C., Bergman, A., van den Berg, M., Westerink, R.H.S., Risk Assessment of Toxic and Immunomodulatory Agents, and Dep IRAS

Subjects
Agonist, brominated flame-retardant, polybrominated diphenyl ethers, endocrine system, Patch-Clamp Techniques, medicine.drug_class, hippocampus, Quantitative Structure-Activity Relationship, 010501 environmental sciences, Pharmacology, Receptors, Nicotinic, perinatal exposure, Toxicology, 01 natural sciences, Partial agonist, gamma-Aminobutyric acid, GABAA-rho receptor, adult mice, neonatal brain-development, 03 medical and health sciences, Xenopus laevis, 0302 clinical medicine, Neurotransmitter receptor, medicine, spontaneous behavior, Animals, Humans, GABA-A Receptor Agonists, Receptor, long-term potentiation, metabolites, reproductive and urinary physiology, 0105 earth and related environmental sciences, VLAG, GABAA receptor, Chemistry, Receptors, GABA-A, polychlorinated-biphenyls, Polychlorinated Biphenyls, Nicotinic agonist, Food Quality and Design, 13. Climate action, Oocytes, Drug Therapy, Combination, Environmental Pollutants, Female, 030217 neurology & neurosurgery, medicine.drug, Signal Transduction
Abstract

Polychlorinated biphenyls (PCBs) and the structurally related polybrominated diphenyl ethers (PBDEs) are abundant persistent organic pollutants that exert several comparable neurotoxic effects. Importantly, hydroxylated metabolites of PCBs and PBDEs have an increased neurotoxic potency. Recently, we demonstrated that PCBs can act as (partial) agonist on GABA(A) neurotransmitter receptors, with PCB-47 being the most potent congener. It is, however, unknown whether PBDE-47 and its metabolite 6-OH-PBDE-47 exert similar effects and if these effects are limited to GABA(A) receptors only. We therefore investigated effects of PCB-47, PBDE-47, and 6-OH-PBDE-47 on the inhibitory GABA(A) and excitatory α(4)β(2) nicotinic acetylcholine (nACh) receptor expressed in Xenopus oocytes using the two-electrode voltage-clamp technique. Since human exposure is generally not limited to individual compounds, experiments with binary mixtures were also performed. The results demonstrate that PCB-47 and 6-OH-PBDE-47 act as full and partial agonist on the GABA(A) receptor. However, both congeners act as antagonist on the nACh receptor. PBDE-47 does not affect either type of receptor. Binary mixtures of PCB-47 and 6-OH-PBDE-47 induced an additive activation as well as potentiation of GABA(A) receptors, whereas this mixture resulted in an additive inhibition of nACh receptors. Binary mixtures of PBDE-47 and 6-OH-PBDE-47 yielded similar effects as 6-OH-PBDE-47 alone. These findings demonstrate that GABA(A) and nACh receptors are affected differently by PCB-47 and 6-OH-PBDE-47, with inhibitory GABA(A)-mediated signaling being potentiated and excitatory α(4)β(2) nACh-mediated signaling being inhibited. Considering these opposite actions and the additive interaction of the congeners, these effects are likely to be augmented in vivo.

Published
2010

27. Genetic Basis of Alagille Syndrome Deciphered

Author

van den Berg M, Rings E, and Pieter C. F. Stokkers

Subjects
business.industry, Calcium-Binding Proteins, DNA Mutational Analysis, Gastroenterology, Membrane Proteins, Proteins, Bioinformatics, medicine.disease, Alagille Syndrome, Mutation, Pediatrics, Perinatology and Child Health, Alagille syndrome, Humans, Intercellular Signaling Peptides and Proteins, Medicine, Serrate-Jagged Proteins, business
Published
1998

28. Measles Vaccination and Inflammatory Bowel Disease

Author

Rings E, Pieter C. F. Stokkers, and van den Berg M

Subjects
business.industry, Measles Vaccine, Gastroenterology, Inflammatory Bowel Diseases, medicine.disease, Inflammatory bowel disease, Measles, Vaccination, Crohn Disease, Risk Factors, Pediatrics, Perinatology and Child Health, Immunology, medicine, Humans, Colitis, Ulcerative, business
Published
1998

29. Epidemiological studies of the influence of sunlight on the skin

Author

Berg M

Subjects
Adult, Male, Sweden, Sunlight, Humans, Female, Photosensitivity Disorders, Telangiectasis, Middle Aged, Skin Diseases, Facial Dermatoses, Aged, Heliotherapy
Abstract

We examined and interviewed 809 randomly selected individuals (56% women and 44% men, mean age 44 years) from 4 Swedish cities; 1.7% had the sun-reactive skin type I, 26.2% type II, 61.3% type III and 10.7% type IV. Some variations in the distribution of skin types were found between the cities. One hundred subjects (12.4%), mostly women (p less than 0.001), had a history of polymorphous light eruption. People with skin type IV had significantly fewer facial skin problems than the rest of the subjects (p less than 0.05). The majority of subjects with atopic eczema, acne vulgaris or seborrheic dermatitis experienced improvement after exposure to sunlight. Individuals with rosacea also experienced improvement more often than impairment from exposure to sunlight. Facial telangiectases occurred in 57% of the subjects, unilaterally in 8.5% of the cases. The occurrence of telangiectases increased with increasing age (p less than 0.001), increasing sunbathing (p less than 0.01) and poor pigmentation ability (p less than 0.05).

Published
1989

30. The soluble leukocyte-associated Ig-like receptor (LAIR)-2 antagonizes the collagen/LAIR-1 inhibitory immune interaction

Author

Lebbink, R. J., Den Berg, M. C. W., Ruiter, T., Raynal, N., Roon, J. A. G., Peter Lenting, Jin, B. Q., and Meyaard, L.

Subjects
Adult, Aged, 80 and over, Male, Research Support, Non-U.S. Gov't, Immunity, Middle Aged, Ligands, Binding, Competitive, Cell Line, Arthritis, Rheumatoid, Pregnancy, Synovial Fluid, Leukocytes, Mononuclear, Journal Article, Humans, Female, Collagen, Receptors, Immunologic, Aged
Abstract

Leukocyte-associated Ig-like receptor (LAIR)-1 is a collagen-receptor that inhibits immune cell function upon collagen binding. Next to LAIR-1, the human genome encodes LAIR-2, a putative soluble homolog. In this study we show, for the first time, that the LAIR-2 gene is broadly transcribed in human PBMC, mirroring the expression profile of LAIR-1. LAIR-2 protein is expressed as a soluble receptor exhibiting high affinity for various collagen molecules to which it binds in a hydroxyproline-dependent manner. In vitro stimulation of PBMC induces secretion of LAIR-2. We detect high amounts of LAIR-2 in urine of pregnant women, indicating that the soluble receptor is indeed produced in vivo and can be cleared from the body via urine. Furthermore, LAIR-2 levels are increased in synovial fluid of patients with rheumatoid arthritis as compared with osteoarthritis patients. We hypothesize that soluble LAIR-2 may function as a natural competitor for LAIR-1, thereby regulating its inhibitory potential. Indeed, LAIR-2 prevents binding of human LAIR-1 to collagens and LAIR-1 cross-linking in vitro, suggesting that the protein has an immunoregulatory function in vivo. Hence, we reveal a novel mechanism of immune regulation by a soluble LAIR receptor regulating the inhibitory potential of the membrane-bound LAIR-1 via competition for ligands.

31. Mitochondria in cultured human muscle cells depleted of mitochondrial DNA

Author

Nh, Herzberg, Esther Middelkoop, Adorf M, Hl, Dekker, Mj, Galen, Van den Berg M, Pa, Bolhuis, and Van den Bogert C

Subjects
Cell Nucleus, L-Lactate Dehydrogenase, Muscle Proteins, Citrate (si)-Synthase, DNA, Mitochondrial, beta-N-Acetylhexosaminidases, Mitochondria, Muscle, Electron Transport, Electron Transport Complex IV, Proton-Translocating ATPases, Oxygen Consumption, Gene Expression Regulation, Glutamate Dehydrogenase, Ethidium, Humans, DNA Damage
Abstract

Cultured human muscle cells were depleted of mitochondrial DNA (mtDNA) by prolonged treatment with ethidium bromide (EB). In these respiration-deficient muscle cells neither cytochrome c oxidase activity nor mtDNA were detectable. However, mitochondrial matrix enzymes remained present and were localized in mitochondria-like organelles, as shown by subcellular fractionation. Metabolic labeling showed synthesis of cytochrome c oxidase subunits coded by nuclear DNA (nDNA). These results indicate that depletion of mtDNA in cultured human myoblasts does not inhibit expression of nDNA-coded mitochondrial proteins. The characteristic thread-like pattern of mitochondria was lost in mtDNA-depleted myoblasts, as shown by immunofluorescence with antibodies against cytochrome c oxidase and the F1 part of the mitochondrial ATP synthase (F1-ATPase) and by fluorescence of the carbocyanine dye, 3,3'-dipentyloxacarbocyanine iodide (DiOC5(3)). The organelles visualized by these methods were round and swollen and had a localization different from lysosomes as shown by double-labeling with mitochondrial and lysosomal antibodies. These results indicate that not only synthesis, but also import of mitochondrial proteins into mitochondria-like organelles remains possible in respiration-deficient cells.

33. The in vivo effects of oral anticoagulants in man: Comparison between liver and non-hepatic tissues

Author

de Boer-van den Berg M, Henk H.W. Thijssen, and Cees Vermeer

Subjects
Vitamin, medicine.medical_specialty, Vitamin K, Osteocalcin, Administration, Oral, Reductase, 4-Hydroxycoumarins, chemistry.chemical_compound, In vivo, Internal medicine, Microsomes, medicine, Humans, chemistry.chemical_classification, biology, Vitamin K2, Calcium-Binding Proteins, Anticoagulants, Hematology, Endocrinology, Enzyme, chemistry, Organ Specificity, biology.protein, Microsome, Microsomes, Liver
Abstract

SummaryThe in vivo effects of oral anticoagulant therapy with 4–hydroxycoumarins on various vitamin K–dependent enzyme systems in man were compared. In hepatic microsomes obtained from donors who has been treated with 4–hydroxycoumarins for more than 6 months, the vitamin K 2,3 epoxide reductase activity and the DTT–dependent vitamin K quinone reductase activity were diminished to 35% and 20% of the corresponding normal values. In the non–hepatic tissues, only a small decrease in vitamin K 2,3 epoxide reductase activity could be demonstrated, while no differences were found in the vitamin K quinone reductase activities. In none of the tissues a significant increase of non–carboxylated precursor proteins was observed, whereas also vitamin K hydroquinone–dependent carboxylase activities seemed to be unaffected by the anticoagulant treatment.

34. [Favorable results of conservative treatment with isosorbide dinitrate in 25 patients with fourth-degree hemorrhoids: a pilot study]

Author

van den Berg M, Hj, Stroeken, and Anton G.M. Hoofwijk

Subjects
Adult, Male, Ointments, Administration, Topical, Vasodilator Agents, Humans, Female, Pilot Projects, Prospective Studies, Isosorbide Dinitrate, Middle Aged, Hemorrhoids, Aged
Abstract

To evaluate application of isosorbide dinitrate 1% ointment in the treatment of fourth-degree haemorrhoids.Prospective pilot study.Twenty-five consecutive patients, 12 men and 13 women, with a median age of 48 years (range: 30-78), presenting in the period October 1999-December 2001 with fourth-degree haemorrhoids, were treated with isosorbide dinitrate 1% ointment.In 24 out of 25 patients (96%) the objective, reduction of the stangulated haemorrhoids and relief of pain, was achieved. In one patient the haemorrhoids were not reduced. This patient was cured after classic haemorrhoidectomy. Two patients interrupted the treatment because of severe headache, but after renewed instructions they continued the therapy and were cured.Isosorbide dinitrate 1% ointment gave good results in the treatment of fourth-degree haemorrhoids, with only few side effects.

35. ECMO for COVID-19 patients in Europe and Israel

Author

Lorusso, Roberto, Combes, Alain, Coco, Valeria Lo, De Piero, Maria Elena, Belohlavek, Jan, Delnoij, Thijs, van der Horst, Iwan, Miranda, Dinis Reis, van der Linden, Marcel, van der Heijden, JJ, Scholten, Erik, van Belle-van Haren, Nicole, Lagrand, Wim, de Jong, Sytse, Candura, Dario, Maas, Jacinta, van den Berg, MJ van Gijlswijk, Malfertheiner, Maximilian, Dreier, Esther, Mueller, Thomas, Boeken, Udo, Akhyari, Payam, Lichtenberg, Artur, Saeed, Diyar, Thiele, Holger, Baumgaertel, Matthias, Schmitto, Jan D, Mariani, Silvia, Thielmann, Matthias, Brenner, Thorsten, Benk, Cristoph, Czerny, Martin, Kalbhenn, Johannes, Maier, Sven, Schibilsky, David, Staudacher, Dawid L, Henn, Philipp, Iuliu, Torje, Muellenbach, Ralf, Reyher, Christian, Rolfes, Caroline, Zacharowski, Kai, Lotz, Gosta, Sonntagbauer, Michael, Kersten, Alexander, Karagiannidis, Christian, Schafer, Simone, Fichte, Julia, Hopf, Hans-Bernd, Samalavicius, Robertas, Lorini, Luca, Ghitti, Davide, Grazioli, Lorenzo, Loforte, Antonio, Baiocchi, Massimo, Checco, Erika Dal, Pacini, Davide, Meani, Paolo, Cappai, Antioco, Russo, Claudio Francesco, Bottiroli, Maurizio, Mondino, Michele, Ranucci, Marco, Fina, Dario, Ballotta, Andrea, Scandroglio, Anna Mara, Zangrillo, Alberto, Pieri, Marina, Nardelli, Pasquale, Fominskiy, Evgeny, Landoni, Giovanni, Fanelli, Vito, Brazzi, Luca, Montrucchio, Giorgia, Sales, Gabriele, Simonetti, Umberto, Urbino, Rosario, Livigni, Sergio, Degani, Antonella, Raffa, Giuseppe, Pilato, Michele, Martucci, Gennaro, Arcadipane, Antonio, Chiarini, Giovanni, Latronico, Nicola, Cattaneo, Sergio, Puglia, Carmine, Reina, Gianfranco, Sponga, Sandro, Livi, Ugolino, Foti, Giuseppe, Giani, Marco, Rona, Roberto, Avalli, Leonello, Bombino, Michela, Costa, Maria Cristina, Carozza, Roberto, Donati, Abele, Piciche, Marco, Favaro, Alessandro, Salvador, Loris, Danzi, Vinicio, Zanin, Anita, Condello, Ignazio, Fiore, Flavio, Moscarelli, Marco, Nasso, Giuseppe, Speziale, Giuseppe, Sandrelli, Luca, Montalto, Andrea, Musumeci, Francesco, Circelli, Alessandro, Gamberini, Emiliano, Russo, Emanuele, Benni, Marco, Agnoletti, Vanni, Rociola, Ruggero, Milano, Aldo D, Grasso, Salvatore, Civita, Antonio, Murgolo, Francesco, Pilato, Emanuele, Comentale, Giuseppe, Montisci, Andrea, Alessandri, Francesco, Tosi, Antonella, Pugliese, Francesco, Carelli, Simone, Grieco, Domenico Luca, Antonelli, Massimo, Ramoni, Enrico, Di Nardo, Matteo, Maisano, Francesco, Bettex, Dominique, Weber, Alberto, Grunenfelder, Jurg, Consiglio, Jolanda, Hansjoerg, Jenni, Haenggi, Matthias, Agus, Gianluca, Doeble, Thomas, Zenklusen, Urs, Bechtold, Xavier, Stockman, Bernard, De Backer, Daniel, Giglioli, Simone, Meyns, Bart, Vercaemst, Leen, Herman, Greet, Meersseman, Philippe, Vandenbriele, Christophe, Dauwe, Dieter, Vlasselaers, Dirk, Raes, Matthias, Debeuckelaere, Gerdy, Rodrigus, Inez, Biston, Patrick, Piagnerelli, Michael, Peperstraete, Harlinde, Germay, Olivier, Vandewiele, Korneel, Vandeweghe, Dimitri, Witters, Ine, Havrin, Sven, Bourgeois, Marc, Taccone, Fabio Silvio, Nobile, Leda, Lheureux, Olivier, Brasseur, Alexandre, Creteur, Jacques, Defraigne, Jean-Olivier, Misset, Benoit, Courcelle, Romain, Timmermans, Philippe, Lehaen, Jeroen, Frederik, Bonte, Riera, Jordi, Castro, Miguel angel, Gallart, Elisabet, Martinez-Martinez, Maria, Argudo, Eduard, Garcia-de-Acilu, Marina, de Pablo Sanchez, Raul, Ortiz, Aaron Blandino, Cabanes, Mari-Paz Fuset, Higa, Karina Osorio, Cassina, Albert Miralles, Berbel, Daniel Ortiz, Sanchez-Salado, Jose Carlos, Arnau, Blasco-Lucas, de Gopegui, Pablo Ruiz, Ricart, Pilar, Sandoval, Elena, Veganzones, Javier, Millan, Pablo, de la Sota, Perez, Santa Teresa, Patricia, Alcantara, Sara, Alvarez, Jorge Duerto, Gonzalez, Anxela Vidal, Lopez, Marta, Gordillo, Antonio, Naranjo-Izurieta, Jose, Costa, Ricardo Gimeno, Albacete Moreno, Carlos L, de Ayala, Jose angel, Blanco-Schweizer, Pablo, Andres, Nicolas Hidalgo, Boado, Victoria, Martinez, Jose Maria Nunez, Casal, Vanesa Gomez, Garcia, Esperanza Fernandez, Martin-Villen, Luis, Climent, Joaquin Colomina, Pinto, Luis F, Leprince, Pascal, Lebreton, Guillaume, Juvin, Charles, Schmidt, Matthieu, Pineton, Marc, Folliguet, Thierry, Saiydoun, Gabriel, Gaudard, Philippe, Colson, Pascal, Obadia, Jean-Francois, Pozzi, Matteo, Fellahi, Jean Luc, Yonis, Hodane, Richard, Jean Christophe, Parasido, Alessandro, Verhoye, Jean-Philippe, Flecher, Erwan, Ajrhourh, Lucrezia, Nesseler, Nicolas, Mansour, Alexandre, Guinot, Pierre-Gregoire, Zarka, Jonathan, Besserve, Patricia, Makhoul, Maged, Bolotin, Gil, Kassif, Yigal, Soufleris, Dimitros, Schellongowski, Peter, Bonaros, Nikolaos, Krapf, Christoph, Ebert, Kathrin, Mair, Peter, Kothleutner, Florian, Kowalewsky, Mariusz, Christensen, Steffen, Pedersen, Finn Moller, Balik, Martin, Blaha, Jan, Lips, Michal, Otahal, Michal, Camporota, Luigi, Daly, Kathleen, Agnew, Nicola, Barker, Julian, Head, Laura, Garcia, Miguel, Ledot, Stephane, Aquino, Verna, Lewis, Rebecca, Worthy, Jennifer, Noor, Hamza, Scott, Ian, O'Brien, Serena, Conrick-Martin, Ian, Carton, Edmund, Gillon, Stuart, Flemming, Lucy, Broman, Lars Mikael, Grins, Edgars, Ketskalo, Michail, Tsarenko, Sergey, Popugaev, Konstantin, Minin, Sergei, Kornilov, Igor, Skopets, Alexander, Kornelyuk, Roman, Turchaninov, Alexandr, Gorjup, Vojka, Shelukhin, Daniil, Dsouki, Youssef El, Sargin, Murat, Kaygin, Mehmet Ali, Liana, Shestakova, Puss, Severin, Soerensen, Gro, Magnus, Rosen, Kanetoft, Mikael, Watson, Pia, Redfors, Bengt, Krenner, Niklas, Velia Antonini, M, Barrett, Nicholas A, Belliato, Mirko, Davidson, Mark, Finney, Simon, Fowles, Jo-Anne, Halbe, Maximilian, Hennig, Felix, Jones, Tim, Pinto, Luis, Smith, Jonathan, Roeleveld, Peter, Swol, Justyna, Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Cardiovascular Research Institute Maastricht (CARIM), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), First Faculty of Medicine Charles University [Prague], Intensive Care Medicine, AII - Inflammatory diseases, ANS - Neuroinfection & -inflammation, EuroECMO COVID-19 Working Group, Euro-ELSO Steering Committee, Lorusso, Roberto, Combes, Alain, Coco, Valeria Lo, De Piero, Maria Elena, Belohlavek, Jan (EuroECMO COVID-19, Workinggroup, Euro-ELSO Steering, Committee), Zangrillo, A, Landoni, G, CTC, MUMC+: MA Med Staf Spec CTC (9), RS: Carim - V04 Surgical intervention, MUMC+: MA Alg Ond Onderz CTC (9), Lorusso, R, Combes, A, Coco, V, De Piero, M, Belohlavek, J, Delnoij, T, van der Horst, I, Miranda, D, van der Linden, M, van der Heijden, J, Scholten, E, van Belle-van Haren, N, Lagrand, W, de Jong, S, Candura, D, Maas, J, van den Berg, M, Malfertheiner, M, Dreier, E, Mueller, T, Boeken, U, Akhyari, P, Lichtenberg, A, Saeed, D, Thiele, H, Baumgaertel, M, Schmitto, J, Mariani, S, Thielmann, M, Brenner, T, Benk, C, Czerny, M, Kalbhenn, J, Maier, S, Schibilsky, D, Staudacher, D, Henn, P, Iuliu, T, Muellenbach, R, Reyher, C, Rolfes, C, Zacharowski, K, Lotz, G, Sonntagbauer, M, Kersten, A, Karagiannidis, C, Schafer, S, Fichte, J, Hopf, H, Samalavicius, R, Lorini, L, Ghitti, D, Grazioli, L, Loforte, A, Baiocchi, M, Checco, E, Pacini, D, Meani, P, Cappai, A, Russo, C, Bottiroli, M, Mondino, M, Ranucci, M, Fina, D, Ballotta, A, Scandroglio, A, Pieri, M, Nardelli, P, Fominskiy, E, Fanelli, V, Brazzi, L, Montrucchio, G, Sales, G, Simonetti, U, Urbino, R, Livigni, S, Degani, A, Raffa, G, Pilato, M, Martucci, G, Arcadipane, A, Chiarini, G, Latronico, N, Cattaneo, S, Puglia, C, Reina, G, Sponga, S, Livi, U, Foti, G, Giani, M, Rona, R, Avalli, L, Bombino, M, Costa, M, Carozza, R, Donati, A, Piciche, M, Favaro, A, Salvador, L, Danzi, V, Zanin, A, Condello, I, Fiore, F, Moscarelli, M, Nasso, G, Speziale, G, Sandrelli, L, Montalto, A, Musumeci, F, Circelli, A, Gamberini, E, Russo, E, Benni, M, Agnoletti, V, Rociola, R, Milano, A, Grasso, S, Civita, A, Murgolo, F, Pilato, E, Comentale, G, Montisci, A, Alessandri, F, Tosi, A, Pugliese, F, Carelli, S, Grieco, D, Antonelli, M, Ramoni, E, Di Nardo, M, Maisano, F, Bettex, D, Weber, A, Grunenfelder, J, Consiglio, J, Hansjoerg, J, Haenggi, M, Agus, G, Doeble, T, Zenklusen, U, Bechtold, X, Stockman, B, De Backer, D, Giglioli, S, Meyns, B, Vercaemst, L, Herman, G, Meersseman, P, Vandenbriele, C, Dauwe, D, Vlasselaers, D, Raes, M, Debeuckelaere, G, Rodrigus, I, Biston, P, Piagnerelli, M, Peperstraete, H, Germay, O, Vandewiele, K, Vandeweghe, D, Witters, I, Havrin, S, Bourgeois, M, Taccone, F, Nobile, L, Lheureux, O, Brasseur, A, Creteur, J, Defraigne, J, Misset, B, Courcelle, R, Timmermans, P, Lehaen, J, Frederik, B, Riera, J, Castro, M, Gallart, E, Martinez-Martinez, M, Argudo, E, Garcia-de-Acilu, M, de Pablo Sanchez, R, Ortiz, A, Cabanes, M, Higa, K, Cassina, A, Berbel, D, Sanchez-Salado, J, Arnau, B, de Gopegui, P, Ricart, P, Sandoval, E, Veganzones, J, Millan, P, de la Sota, P, Santa Teresa, P, Alcantara, S, Alvarez, J, Gonzalez, A, Lopez, M, Gordillo, A, Naranjo-Izurieta, J, Costa, R, Albacete Moreno, C, de Ayala, J, Blanco-Schweizer, P, Andres, N, Boado, V, Martinez, J, Casal, V, Garcia, E, Martin-Villen, L, Climent, J, Pinto, L, Leprince, P, Lebreton, G, Juvin, C, Schmidt, M, Pineton, M, Folliguet, T, Saiydoun, G, Gaudard, P, Colson, P, Obadia, J, Pozzi, M, Fellahi, J, Yonis, H, Richard, J, Parasido, A, Verhoye, J, Flecher, E, Ajrhourh, L, Nesseler, N, Mansour, A, Guinot, P, Zarka, J, Besserve, P, Makhoul, M, Bolotin, G, Kassif, Y, Soufleris, D, Schellongowski, P, Bonaros, N, Krapf, C, Ebert, K, Mair, P, Kothleutner, F, Kowalewsky, M, Christensen, S, Pedersen, F, Balik, M, Blaha, J, Lips, M, Otahal, M, Camporota, L, Daly, K, Agnew, N, Barker, J, Head, L, Garcia, M, Ledot, S, Aquino, V, Lewis, R, Worthy, J, Noor, H, Scott, I, O'Brien, S, Conrick-Martin, I, Carton, E, Gillon, S, Flemming, L, Broman, L, Grins, E, Ketskalo, M, Tsarenko, S, Popugaev, K, Minin, S, Kornilov, I, Skopets, A, Kornelyuk, R, Turchaninov, A, Gorjup, V, Shelukhin, D, Dsouki, Y, Sargin, M, Kaygin, M, Liana, S, Puss, S, Soerensen, G, Magnus, R, Kanetoft, M, Watson, P, Redfors, B, Krenner, N, Velia Antonini, M, Barrett, N, Belliato, M, Davidson, M, Finney, S, Fowles, J, Halbe, M, Hennig, F, Jones, T, Smith, J, Roeleveld, P, Swol, J, Lorusso R., Combes A., Coco V.L., De Piero M.E., and Belohlavek J, EuroECMO COVID-19 WorkingGroup, and Euro-ELSO Steering Committee, Pacini D

Subjects
2019-20 coronavirus outbreak, medicine.medical_specialty, Letter, Coronavirus disease 2019 (COVID-19), Pain medicine, medicine.medical_treatment, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), [SDV]Life Sciences [q-bio], MEDLINE, 610 Medicine & health, 030204 cardiovascular system & hematology, Critical Care and Intensive Care Medicine, 03 medical and health sciences, Extracorporeal Membrane Oxygenation, covid, ecmo, respiratory failure, 0302 clinical medicine, Critical Care Medicine, General & Internal Medicine, Anesthesiology, medicine, Extracorporeal membrane oxygenation, Humans, Israel, ComputingMilieux_MISCELLANEOUS, Science & Technology, business.industry, COVID-19, 030208 emergency & critical care medicine, 3. Good health, Europe, Emergency medicine, Human medicine, ECMO, business, Life Sciences & Biomedicine, Human
Abstract

ispartof: INTENSIVE CARE MEDICINE vol:47 issue:3 pages:344-348 ispartof: location:United States status: published

Published
2021

36. Genome-wide association analyses identify novel Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility

Author

Barc, Julien, Tadros, Rafik, Glinge, Charlotte, Chiang, David Y., Jouni, Mariam, Simonet, Floriane, Jurgens, Sean J., Baudic, Manon, Nicastro, Michele, Potet, Franck, Offerhaus, Joost A., Walsh, Roddy, Choi, Seung Hoan, Verkerk, Arie O., Mizusawa, Yuka, Anys, Soraya, Minois, Damien, Arnaud, Marine, Duchateau, Josselin, Wijeyeratne, Yanushi D., Muir, Alison, Papadakis, Michael, Castelletti, Silvia, Torchio, Margherita, Ortuño, Cristina Gil, Lacunza, Javier, Giachino, Daniela F., Cerrato, Natascia, Martins, Raphaël P., Campuzano, Oscar, Van Dooren, Sonia, Thollet, Aurélie, Kyndt, Florence, Mazzanti, Andrea, Clémenty, Nicolas, Bisson, Arnaud, Corveleyn, Anniek, Stallmeyer, Birgit, Dittmann, Sven, Saenen, Johan, Noël, Antoine, Honarbakhsh, Shohreh, Rudic, Boris, Marzak, Halim, Rowe, Matthew K., Federspiel, Claire, Le Page, Sophie, Placide, Leslie, Milhem, Antoine, Barajas-Martinez, Hector, Beckmann, Britt-Maria, Krapels, Ingrid P., Steinfurt, Johannes, Winkel, Bo Gregers, Jabbari, Reza, Shoemaker, Moore B., Boukens, Bas J., Škorić-Milosavljević, Doris, Bikker, Hennie, Manevy, Federico, Lichtner, Peter, Ribasés, Marta, Meitinger, Thomas, Müller-Nurasyid, Martina, Strauch, Konstantin, Peters, Annette, Schulz, Holger, Schwettmann, Lars, Leidl, Reiner, Heier, Margit, Veldink, Jan H., van den Berg, Leonard H., Van Damme, Philip, Cusi, Daniele, Lanzani, Chiara, Rigade, Sidwell, Charpentier, Eric, Baron, Estelle, Bonnaud, Stéphanie, Lecointe, Simon, Donnart, Audrey, Le Marec, Hervé, Chatel, Stéphanie, Karakachoff, Matilde, Bézieau, Stéphane, London, Barry, Tfelt-Hansen, Jacob, Roden, Dan, Odening, Katja E., Cerrone, Marina, Chinitz, Larry A., Volders, Paul G., van de Berg, Maarten P., Laurent, Gabriel, Faivre, Laurence, Antzelevitch, Charles, Kääb, Stefan, Arnaout, Alain Al, Dupuis, Jean-Marc, Pasquie, Jean-Luc, Billon, Olivier, Roberts, Jason D., Jesel, Laurence, Borggrefe, Martin, Lambiase, Pier D., Mansourati, Jacques, Loeys, Bart, Leenhardt, Antoine, Guicheney, Pascale, Maury, Philippe, Schulze-Bahr, Eric, Robyns, Tomas, Breckpot, Jeroen, Babuty, Dominique, Priori, Silvia G., Napolitano, Carlo, Defaye, Pascal, Anselme, Frédéric, Darmon, Jean Philippe, Wiart, François, de Asmundis, Carlo, Brugada, Pedro, Brugada, Ramon, Arbelo, Elena, Brugada, Josep, Mabo, Philippe, Behar, Nathalie, Giustetto, Carla, Molina, Maria Sabater, Gimeno, Juan R., Hasdemir, Can, Schwartz, Peter J., Crotti, Lia, McKeown, Pascal P., Sharma, Sanjay, Behr, Elijah R., Haissaguerre, Michel, Sacher, Frédéric, Rooryck, Caroline, Tan, Hanno L., Remme, Carol A., Postema, Pieter G., Delmar, Mario, Ellinor, Patrick T., Lubitz, Steven A., Gourraud, Jean-Baptiste, Tanck, Michael W., George, Alfred L., MacRae, Calum A., Burridge, Paul W., Dina, Christian, Probst, Vincent, Wilde, Arthur A., Schott, Jean-Jacques, Redon, Richard, Bezzina, Connie R., KORA-Study Group, Nantes Referral Ctr Inherited Card, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Santé - François Bonamy, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Amsterdam UMC - Amsterdam University Medical Center, The MINE study (J.H.V.) has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 772376—EScORIAL). The collaboration project is cofunded by the PPP Allowance made available by Health~Holland, Top Sector Life Sciences & Health, to stimulate public–private partnerships. This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113, 085475 and 090355. The KORA research platform (KORA, Cooperative Research in the Region of Augsburg) was initiated and financed by the Helmholtz Zentrum München—German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. J. Barc is supported by the research program Etoiles montantes des Pays de la Loire REGIOCARD RPH081-U1087-REG-PDL, ANR JCJC LEARN (R21006NN, RPV21014NNA) and by the H2020-MSCA-IF-2014 Program of the European Commission (RISTRAD-661617). R.T. is supported by the Canadian Heart Rhythm Society’s George Mines Award, the European Society of Cardiology research award, and the Philippa and Marvin Carsley Cardiology Chair. D.Y.C. is supported by Fondation Leducq and National Institutes of Health (NIH) NHGRI T32 (no. 1T32HG010464-01). M. Baudic was supported by IRP—VERACITIES—New Mechanisms for VEntricular ARrhythmia And CardIomeTabolic DIseasES, an I-SITE NExT health and engineering initiative (Ecole Centrale and Nantes University) and by the IRP—GAINES—Genetic Architecture IN cardiovascular disEaSes funded by INSERM and CNRS. R.W. is supported by an Amsterdam Cardiovascular Sciences fellowship. S.C. is supported by the NHLBI BioData Catalyst Fellows Program. C.A.R. is supported by Fondation Leducq, the Dutch Heart Foundation (CVON PREDICT2) and the Innovational Research Incentives Scheme Vidi grant from the Netherlands Organisation for Health Research and Development (ZonMw, 91714371). Y.D.W. is supported by the Robert Lancaster Memorial Fund. M.P. is supported by Cardiac Risk in the Young. S.V.D. is supported by Wetenschappelijk Fonds Willy Gepts VUB-UZ Brussel, project ‘Unravelling the molecular genetic pathways of Brugada Syndrome by cardiomics research’, VUB IRP project ‘IMAGica: an Integrative personalized Medical Approach for Genetic diseases, Inherited Cardia Arrhythmias as a model’ and Innoviris BRIDGE 2017, project ‘IGenCare: Integrated Personalised Medical Genomics Care Solution for Patients with Rare Genetic Diseases’. S.H. is supported by the Barts BRC. B.R. is supported by the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research). B.G.W. is supported by the Danish Heart Foundation. M.B.S. is supported by K23HL127704. Project MinE Belgium was supported by a grant from IWT (no. 140935), the ALS Liga België, the National Lottery of Belgium and the KU Leuven Opening the Future Fund. D.C. and C.L. are supported by HYPERGENES (HEALTH-F4-2007). D.R. is supported by R01 HL149826, P50 GM115305. P.J.S. acknowledges the support of Leducq Foundation for Cardiovascular Research grant 18CVD05. P.V.D. is supported by the Netherlands CardioVascular Research Initiative (CVON PREDICT2). C.A. is supported by NIH HL47678 and HL138103, W.W. Smith Charitable Trust and Wistar Morris Fund. M.B. is Supported by the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research). P.D.L. is supported by UCL/UCLH Biomedicine NIHR and Barts BRC. B.L. is supported by GOA—Antigone 33933. J.B. is supported by a Senior Clinical Fellowship of the Flemish Science Foundation (FWO). E.B. is supported by the British Heart Foundation including BHF Clinical Research Training Fellowship (FS/11/71/28918: Future diagnostic role and new genetic loci in SADS), Cardiac Risk in the Young and Robert Lancaster Memorial fund sponsored by McColl’s Ltd. Retail Group. H.L.T. is supported by the European Union’s Horizon 2020 research and innovation program under acronym ESCAPE-NET, registered under grant agreement no. 733381, and the Dutch Heart Foundation (CVON RESCUED and PREDICT2 projects). M.D. is supported by NIH-RO1 HL134328. P.T.E. was supported by the Fondation Leducq (14CVD01), the NIH (1RO1HL092577, R01HL128914, K24HL105780), the American Heart Association (18SFRN34110082) and by a research grant from Bayer AG to the Broad Institute. S.A.L. is supported by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007. J.-B.G. received a grant from the Fédération Française de Cardiologie (PREVENT project). A.L.G. is supported by the Fondation Leducq. C.A.M.R. is supported by the Leducq Foundation and Burroughs Wellecome Fund. A.A.W. is supported by the Dutch Heart Foundation (CVON PREDICT2 project). J.-J.S. is supported by the Fondation pour la Recherche Médicale (DEQ20140329545). R.R. and P.G. are supported by the National Agency for Research (ANR-GENSUD-14-CE10-0001). C.R.B. is supported by the Dutch Heart Foundation (CVON PREDICT2 project), the Netherlands Organization for Scientific Research (VICI fellowship, 016.150.610) and Fondation Leducq (17CVD02)., Barc, J, Tadros, R, Glinge, C, Chiang, D, Jouni, M, Simonet, F, Jurgens, S, Baudic, M, Nicastro, M, Potet, F, Offerhaus, J, Walsh, R, Hoan Choi, S, Verkerk, A, Mizusawa, Y, Anys, S, Minois, D, Arnaud, M, Duchateau, J, Wijeyeratne, Y, Muir, A, Papadakis, M, Castelletti, S, Torchio, M, Gil Ortuño, C, Lacunza, J, Giachino, D, Cerrato, N, Martins, R, Campuzano, O, Van Dooren, S, Thollet, A, Kyndt, F, Mazzanti, A, Clémenty, N, Bisson, A, Corveleyn, A, Stallmeyer, B, Dittmann, S, Saenen, J, Noël, A, Honarbakhsh, S, Rudic, B, Marzak, H, Rowe, M, Federspiel, C, Le Page, S, Placide, L, Milhem, A, Barajas-Martinez, H, Beckmann, B, Krapels, I, Steinfurt, J, Gregers Winkel, B, Jabbari, R, Shoemaker, M, Boukens, B, Škorić-Milosavljević, D, Bikker, H, Manevy, F, Lichtner, P, Ribasés, M, Meitinger, T, Müller-Nurasyid, M, Group, K, Veldink, J, van den Berg, L, Van Damme, P, Cusi, D, Lanzani, C, Rigade, S, Charpentier, E, Baron, E, Bonnaud, S, Lecointe, S, Donnart, A, Le Marec, H, Chatel, S, Karakachoff, M, Bézieau, S, London, B, Tfelt-Hansen, J, Roden, D, Odening, K, Cerrone, M, Chinitz, L, Volders, P, van de Berg, M, Laurent, G, Faivre, L, Antzelevitch, C, Kääb, S, Al Arnaout, A, Dupuis, J, Pasquie, J, Billon, O, Roberts, J, Jesel, L, Borggrefe, M, Lambiase, P, Mansourati, J, Loeys, B, Leenhardt, A, Guicheney, P, Maury, P, Schulze-Bahr, E, Robyns, T, Breckpot, J, Babuty, D, Priori, S, Napolitano, C, Referral Center for inherited cardiac arrhythmia, N, de Asmundis, C, Brugada, P, Brugada, R, Arbelo, E, Brugada, J, Mabo, P, Behar, N, Giustetto, C, Sabater Molina, M, Gimeno, J, Hasdemir, C, Schwartz, P, Crotti, L, Mckeown, P, Sharma, S, Behr, E, Haissaguerre, M, Sacher, F, Rooryck, C, Tan, H, Remme, C, Postema, P, Delmar, M, Ellinor, P, Lubitz, S, Gourraud, J, Tanck, M, L. George Jr., A, Macrae, C, Burridge, P, Dina, C, Probst, V, Wilde, A, Schott, J, Redon &amp, R, Bezzina, C, Cardiology, Graduate School, Medical Biology, ACS - Amsterdam Cardiovascular Sciences, ACS - Heart failure & arrhythmias, Human Genetics, ACS - Pulmonary hypertension & thrombosis, ARD - Amsterdam Reproduction and Development, APH - Methodology, Epidemiology and Data Science, MUMC+: DA KG Polikliniek (9), RS: Carim - H02 Cardiomyopathy, Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), RS: Carim - H04 Arrhythmogenesis and cardiogenetics, and Cardiovascular Centre (CVC)

Subjects
EXPRESSION, [SDV]Life Sciences [q-bio], DIAGNOSIS, GUIDELINES, ANNOTATION, Article, NAV1.5 Voltage-Gated Sodium Channel, Young Adult, MANAGEMENT, Genetics, GWAS, Humans, Genetic Predisposition to Disease, 610 Medicine & health, SCN5A, Alleles, Brugada Syndrome, Allele, [SDV.GEN]Life Sciences [q-bio]/Genetics, HERITABILITY, Microtubule-Associated Protein, Brugada Syndrome, GWAS, SNPs, COMMON VARIANTS, Mutation, Disease Susceptibility, Human medicine, ENRICHMENT, Microtubule-Associated Proteins, SNPs, Human, GENERATION, Genome-Wide Association Study
Abstract

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel Na(V)1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on Na(V)1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings. Genome-wide association analyses identify new susceptibility loci for Brugada syndrome. Functional studies implicate microtubule-related trafficking effects on sodium channel expression as an underlying molecular mechanism., European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program [772376-EScORIAL]; Health~Holland; Top Sector Life Sciences Health; Wellcome Trust [076113, 085475, 090355]; Helmholtz Zentrum Munchen-German Research Center for Environmental Health - German Federal Ministry of Education and Research; State of Bavaria; Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universitat, as part of LMUinnovativ; research program Etoiles montantes des Pays de la Loire [REGIOCARD RPH081-U1087-REG-PDL]; ANR JCJC LEARN [R21006NN, RPV21014NNA]; H2020-MSCA-IF-2014 Program of the European Commission [RISTRAD-661617]; Canadian Heart Rhythm Society's George Mines Award; European Society of Cardiology research award; Philippa and Marvin Carsley Cardiology Chair; Fondation Leducq; National Institutes of Health (NIH) NHGRI T32 [1T32HG010464-01]; IRP-VERACITIES-New Mechanisms for VEntricular ARrhythmia And CardIomeTabolic DIseasES an I-SITE NExT health and engineering initiative (Ecole Centrale); IRP-VERACITIES-New Mechanisms for VEntricular ARrhythmia And CardIomeTabolic DIseasES an I-SITE NExT health and engineering initiative (Nantes University); IRP-GAINES-Genetic Architecture IN cardiovascular disEaSes - INSERM; CNRS; Amsterdam Cardiovascular Sciences fellowship; NHLBI BioData Catalyst Fellows Program; Dutch Heart Foundation [CVON PREDICT2]; Innovational Research Incentives Scheme Vidi grant from the Netherlands Organisation for Health Research and Development (ZonMw) [91714371]; Robert Lancaster Memorial Fund; Cardiac Risk in the Young; Wetenschappelijk Fonds Willy Gepts VUB-UZ Brussel; VUB IRP project `IMAGica: an Integrative personalized Medical Approach for Genetic diseases, Inherited Cardia Arrhythmias as a model' and Innoviris BRIDGE 2017; project `IGenCare: Integrated Personalised Medical Genomics Care Solution for Patients with Rare Genetic Diseases'; Barts BRC; DZHK (German Centre for Cardiovascular Research); BMBF (German Ministry of Education and Research); Danish Heart Foundation; IWT [140935]; ALS Liga Belgie; National Lottery of Belgium; KU Leuven Opening the Future Fund; HYPERGENES [HEALTH-F4-2007]; Leducq Foundation for Cardiovascular Research grant [18CVD05]; Netherlands CardioVascular Research Initiative [CVON PREDICT2]; NIH [HL47678, HL138103, 1RO1HL092577, R01HL128914, K24HL105780]; W.W. Smith Charitable Trust; Wistar Morris Fund; GOA-Antigone [33933]; Senior Clinical Fellowship of the Flemish Science Foundation (FWO); British Heart Foundation; BHF Clinical Research Training Fellowship [FS/11/71/28918]; Cardiac Risk in the Young and Robert Lancaster Memorial fund - McColl's Ltd. Retail Group; European Union's Horizon 2020 research and innovation program under acronym ESCAPE-NET [733381]; Dutch Heart Foundation; Fondation Leducq [14CVD01, 17CVD02]; American Heart Association [18SFRN34110082, 18SFRN34250007]; Bayer AG; NIH grant [1R01HL139731]; Federation Francaise de Cardiologie (PREVENT project); Leducq Foundation; Burroughs Wellecome Fund; Fondation pour la Recherche Medicale [DEQ20140329545]; National Agency for Research [ANR-GENSUD-14-CE10-0001]; Netherlands Organization for Scientific Research (VICI fellowship) [016.150.610]; [K23HL127704]; [R01 HL149826]; [P50 GM115305]; [NIH-RO1 HL134328], We are greatly indebted to the patients included in the study. We thank V. Cotard, C. Goutsmedt, M.-F. Le Cunff and N. Bourgeais for assistance in patient recruitment and L. Beekman for his technical support. We thank the biological resource centre for biobanking (CHU Nantes, Nantes Universite, Centre de ressources biologiques (BB0033-00040), F-44000 Nantes, France) for applying the following guidelines68. We are most grateful to the Genomics and Bioinformatics Core Facility of Nantes (GenoBiRD, Biogenouest, IFB) for its technical support. This research has been conducted using the UK Biobank resource; we are grateful to UK Biobank participants. The MINE study (J.H.V.) has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement no. 772376-EScORIAL). The collaboration project is cofunded by the PPP Allowance made available by Health~Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships. This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk.Funding for the project was provided by the Wellcome Trust under award 076113, 085475 and 090355. The KORA research platform (KORA, Cooperative Research in the Region of Augsburg) was initiated and financed by the Helmholtz Zentrum Munchen-German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universitat, as part of LMUinnovativ. J. Barc is supported by the research program Etoiles montantes des Pays de la Loire REGIOCARD RPH081-U1087-REG-PDL, ANR JCJC LEARN (R21006NN, RPV21014NNA) and by the H2020-MSCA-IF-2014 Program of the European Commission (RISTRAD-661617). R.T. is supported by the Canadian Heart Rhythm Society's George Mines Award, the European Society of Cardiology research award, and the Philippa and Marvin Carsley Cardiology Chair. D.Y.C. is supported by Fondation Leducq and National Institutes of Health (NIH) NHGRI T32 (no. 1T32HG010464-01). M. Baudic was supported by IRP-VERACITIES-New Mechanisms for VEntricular ARrhythmia And CardIomeTabolic DIseasES, an I-SITE NExT health and engineering initiative (Ecole Centrale and Nantes University) and by the IRP-GAINES-Genetic Architecture IN cardiovascular disEaSes funded by INSERM and CNRS. R.W. is supported by an Amsterdam Cardiovascular Sciences fellowship. S.C. is supported by the NHLBI BioData Catalyst Fellows Program. C.A.R. is supported by Fondation Leducq, the Dutch Heart Foundation (CVON PREDICT2) and the Innovational Research Incentives Scheme Vidi grant from the Netherlands Organisation for Health Research and Development (ZonMw; 91714371). Y.D.W. is supported by the Robert Lancaster Memorial Fund. M.P. is supported by Cardiac Risk in the Young. S.V.D. is supported by Wetenschappelijk Fonds Willy Gepts VUB-UZ Brussel, project `Unravelling the molecular genetic pathways of Brugada Syndrome by cardiomics research', VUB IRP project `IMAGica: an Integrative personalized Medical Approach for Genetic diseases, Inherited Cardia Arrhythmias as a model' and Innoviris BRIDGE 2017, project `IGenCare: Integrated Personalised Medical Genomics Care Solution for Patients with Rare Genetic Diseases'. S.H. is supported by the Barts BRC. B.R.; is supported by the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research). B.G.W. is supported by the Danish Heart Foundation. M.B.S. is supported by K23HL127704. Project MinE Belgium was supported by a grant from IWT (no. 140935), the ALS Liga Belgie, the National Lottery of Belgium and the KU Leuven Opening the Future Fund. D.C. and C.L. are supported by HYPERGENES (HEALTH-F4-2007). D.R. is supported by R01 HL149826, P50 GM115305. P.J.S. acknowledges the support of Leducq Foundation for Cardiovascular Research grant 18CVD05. P.V.D. is supported by the Netherlands CardioVascular Research Initiative (CVON PREDICT2). C.A. is supported by NIH HL47678 and HL138103, W.W. Smith Charitable Trust and Wistar Morris Fund. M.B. is Supported by the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research). P.D.L. is supported by UCL/UCLH Biomedicine NIHR and Barts BRC. B.L. is supported by GOA-Antigone 33933. J.B. is supported by a Senior Clinical Fellowship of the Flemish Science Foundation (FWO). E.B. is supported by the British Heart Foundation including BHF Clinical Research Training Fellowship (FS/11/71/28918: Future diagnostic role and new genetic loci in SADS), Cardiac Risk in the Young and Robert Lancaster Memorial fund sponsored by McColl's Ltd. Retail Group. H.L.T. is supported by the European Union's Horizon 2020 research and innovation program under acronym ESCAPE-NET, registered under grant agreement no. 733381, and the Dutch Heart Foundation (CVON RESCUED and PREDICT2 projects). M.D. is supported by NIH-RO1 HL134328. P.T.E. was supported by the Fondation Leducq (14CVD01), the NIH (1RO1HL092577, R01HL128914, K24HL105780), the American Heart Association (18SFRN34110082) and by a research grant from Bayer AG to the Broad Institute. S.A.L. is supported by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007. J.-B.G. received a grant from the Federation Francaise de Cardiologie (PREVENT project). A.L.G. is supported by the Fondation Leducq. C.A.M.R. is supported by the Leducq Foundation and Burroughs Wellecome Fund. A.A.W. is supported by the Dutch Heart Foundation (CVON PREDICT2 project). J.-J.S. is supported by the Fondation pour la Recherche Medicale (DEQ20140329545). R.R. and P.G. are supported by the National Agency for Research (ANR-GENSUD-14-CE10-0001). C.R.B. is supported by the Dutch Heart Foundation (CVON PREDICT2 project), the Netherlands Organization for Scientific Research (VICI fellowship, 016.150.610) and Fondation Leducq (17CVD02).

Published
2022

37. Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy

Author

Paul M.L. Janssen, Jeff S. Healey, Nara Sobriera, Hugh Calkins, Samantha L. Simmons, Sharon L. Graw, Peter J. Mohler, Mona El-Refaey, Robert W. Davies, Brittney Murray, Danna A. Spears, Kirti Mittal, Duy T. Nguyen, Jason D. Roberts, Crystal Tichnell, Maarten P. van den Berg, J. Peter van Tintelen, Nathaniel P. Murphy, Sara N. Koenig, Daniel P. Judge, Philip C. Ursell, Meriam Åström Aneq, Mei Han, Crystal F. Kline, Robert A. Hegele, Anna Gréen, Luisa Mestroni, Andrew D. Krahn, Robert M. Hamilton, Amy C. Sturm, Arthur A.M. Wilde, Babak Nazer, Frank I. Marcus, Gianfranco Sinagra, Michael H. Gollob, Alberto Codima, David A. Chiasson, Chantal J. M. van Opbergen, Matthew R.G. Taylor, Shabana Aafaqi, Cynthia A. James, Edgar T. Hoorntje, Martin J. Gardner, Tamara T. Koopmann, Ellen R. Lubbers, Meena Fatah, Anthony Tang, Hassan Musa, Muhammad Rafiq, Loren E. Wold, Allan C. Skanes, Thomas J. Hund, John F. Robinson, Melvin M. Scheinman, Elisabeth M. Lodder, Toon A.B. van Veen, Roberts, J. D., Murphy, N. P., Hamilton, R. M., Lubbers, E. R., James, C. A., Kline, C. F., Gollob, M. H., Krahn, A. D., Sturm, A. C., Musa, H., El-Refaey, M., Koenig, S., Aneq, M. A., Hoorntje, E. T., Graw, S. L., Davies, R. W., Rafiq, M. A., Koopmann, T. T., Aafaqi, S., Fatah, M., Chiasson, D. A., Taylor, M. R. G., Simmons, S. L., Han, M., Van Opbergen, C. J. M., Wold, L. E., Sinagra, G., Mittal, K., Tichnell, C., Murray, B., Codima, A., Nazer, B., Nguyen, D. T., Marcus, F. I., Sobriera, N., Lodder, E. M., Van Den Berg, M. P., Spears, D. A., Robinson, J. F., Ursell, P. C., Green, A. K., Skanes, A. C., Tang, A. S., Gardner, M. J., Hegele, R. A., Van Veen, T. A. B., Wilde, A. A. M., Healey, J. S., Janssen, P. M. L., Mestroni, L., Van Tintelen, J. P., Calkins, H., Judge, D. P., Hund, T. J., Scheinman, M. M., Mohler, P. J., Cardiovascular Centre (CVC), Cardiology, Human Genetics, and ACS - Heart failure & arrhythmias

Subjects
Male, 0301 basic medicine, Indoles, Cardiac fibrosis, Cell- och molekylärbiologi, Cardiomyopathy, Arrhythmias, Cardiovascular, Medical and Health Sciences, Sudden cardiac death, Maleimides, Mice, 0302 clinical medicine, 2.1 Biological and endogenous factors, Aetiology, Wnt Signaling Pathway, Arrhythmogenic Right Ventricular Dysplasia, beta Catenin, Mice, Knockout, Ejection fraction, Cardiology, Cardiovascular disease, Cell Biology, Genetic diseases, Wnt signaling pathway, General Medicine, Phenotype, 3. Good health, Heart Disease, 030220 oncology & carcinogenesis, Female, Arrhythmia, Research Article, Ankyrins, Knockout, Immunology, 03 medical and health sciences, Rare Diseases, Clinical Research, ANK2, Journal Article, medicine, Animals, Humans, Loss function, Animal, business.industry, Myocardium, medicine.disease, Disease Models, Animal, 030104 developmental biology, Disease Models, Cancer research, business, Cell and Molecular Biology
Abstract

Arrhythmogenic cardiomyopathy (ACM) is an inherited arrhythmia syndrome characterized by severe structural and electrical cardiac phenotypes, including myocardial fibrofatty replacement and sudden cardiac death. Clinical management of ACM is largely palliative, owing to an absence of therapies that target its underlying pathophysiology, which stems partially from our limited insight into the condition. Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced ejection fraction, cardiac fibrosis, and premature death. Desmosomal structure and function appeared preserved in diseased human and murine specimens in the presence of markedly abnormal beta-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and beta-catenin. A pharmacological activator of the WNT/beta-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes. Our findings introduce what we believe to be a new pathway for ACM, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and beta-catenin, and evidence for targeted activation of the WNT/beta-catenin pathway as a potential treatment for this disease. Funding Agencies|Marianne Barrie Philanthropic Fund; Canadian Institutes of Health Research [RN332805]; Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation; Dutch Federation of University Medical Centers; Netherlands Organisation for Health Research and Development; Royal Netherlands Academy of Sciences [CVON-PREDICT 2012-10]; Netherlands Cardiovascular Research Initiative - Dutch Heart Foundation [CVON2012-10 PREDICT CVON2018-30 PREDICT2, CVON2015-12 eDETECT]; Netherlands Organization for Scientific Research (NWO) [040.11.586]; Fondation Leducq [16 CVD 02]; Dr. Francis P. Chiramonte Private Foundation; Leyla Erkan Family Fund for ARVD Research; Robin Shah ARVD Fund at Johns Hopkins; Bogle Foundation; Healing Hearts Foundation; Campanella Family; Patrick J. Harrison Family; Peter French Memorial Foundation; Wilmerding Endowments; NIH [HL135754, HL134824, HL139348, HL135096, HL114383, HL114893, HL137331, HL137325, 2UM1HG006542, UL1 TR 001079]; Ohio State Frick Center; JB Project

Published
2019

38. Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls

Author

Charles Antzelevitch, Ahmad S. Amin, Bo Gregers Winkel, Dan M. Roden, Stefan Kääb, Jonathan R. Skinner, Seiko Ohno, Julien Barc, Birgit Stallmeyer, Carla Giustetto, Connie R. Bezzina, Francesco Mazzarotto, Tomas Robyns, Carlo Napolitano, Stellan Mörner, Doris Škorić-Milosavljević, Sven Dittmann, Kenichiro Yamagata, Sonia Van Dooren, Anniek Corveleyn, Carlo de Asmundis, Ramon Brugada, K Usuda, Yuji Tanaka, Sven Zumhagen, Tadashi Nakajima, Johan Saenen, Elijah R. Behr, Hector Barajas-Martinez, Stéphane Bézieau, Masao Yoshinaga, Georgia Sarquella-Brugada, Paul G.A. Volders, Juan R. Gimeno, Lia Crotti, Charlotte Glinge, Andrea Mazzanti, Ingrid P.C. Krapels, Nicola Whiffin, Sebastian Clauss, Yoshiaki Kaneko, James S. Ware, Minoru Horie, Keiko Shimamoto, Isabelle Denjoy, Pieter G. Postema, Christian Krijger, Takeshi Aiba, Masahiko Kurabayashi, Pyotr G. Platonov, Regina Sebastiano, Cristina Gil Ortuño, Annika Rydberg, Roddy Walsh, Michael J. Ackerman, Hideki Itoh, M. Benjamin Shoemaker, Can Hasdemir, Pascale Guicheney, J. Martijn Bos, Frederic Sacher, Takeru Makiyama, Julieta Lazarte, Maarten P. van den Berg, Dominique Babuty, David J. Tester, Silvia Castelletti, Jacques Mansourati, Antoine Leenhardt, Paul A. van der Zwaag, Sanjay Sharma, Elena Arbelo, Candan Celen, Pier D. Lambiase, Maria Christina Kotta, Johannes Steinfurt, Jean-Baptiste Gourraud, Pedro Brugada, Wataru Shimizu, Josep Brugada, Jørgen K. Kanters, Eline A. Nannenberg, Silvia G. Priori, Mary N. Sheppard, Richard Redon, Morten S. Olesen, Jeroen Breckpot, Britt M. Beckmann, Naomasa Makita, Martin Borggrefe, Rafik Tadros, Jean-Jacques Schott, Jacob Tfelt-Hansen, Steven A. Lubitz, Hatice Şahin, Najim Lahrouchi, Michael Papadakis, Daisuke Hazeki, Kenshi Hayashi, Oscar Campuzano, Katja E. Odening, Federica Dagradi, Eric Schulze-Bahr, Boris Rudic, Hiroki Kimoto, Vincent Probst, Jason D. Roberts, Raphaël P. Martins, Bart Loeys, Daniela F. Giachino, F. Kyndt, Kimie Ohkubo, Taisuke Ishikawa, Catarina Lundin, Lut Van Laer, Patrick T. Ellinor, Maria Sabater Molina, Peter J. Schwartz, Annika Winbo, Wellcome Trust, Rosetrees Trust, British Heart Foundation, Walsh, R, Lahrouchi, N, Tadros, R, Kyndt, F, Glinge, C, Postema, P, Amin, A, Nannenberg, E, Ware, J, Whiffin, N, Mazzarotto, F, Skoric-Milosavljevic, D, Krijger, C, Arbelo, E, Babuty, D, Barajas-Martinez, H, Beckmann, B, Bezieau, S, Bos, J, Breckpot, J, Campuzano, O, Castelletti, S, Celen, C, Clauss, S, Corveleyn, A, Crotti, L, Dagradi, F, de Asmundis, C, Denjoy, I, Dittmann, S, Ellinor, P, Ortuno, C, Giustetto, C, Gourraud, J, Hazeki, D, Horie, M, Ishikawa, T, Itoh, H, Kaneko, Y, Kanters, J, Kimoto, H, Kotta, M, Krapels, I, Kurabayashi, M, Lazarte, J, Leenhardt, A, Loeys, B, Lundin, C, Makiyama, T, Mansourati, J, Martins, R, Mazzanti, A, Morner, S, Napolitano, C, Ohkubo, K, Papadakis, M, Rudic, B, Molina, M, Sacher, F, Sahin, H, Sarquella-Brugada, G, Sebastiano, R, Sharma, S, Sheppard, M, Shimamoto, K, Shoemaker, M, Stallmeyer, B, Steinfurt, J, Tanaka, Y, Tester, D, Usuda, K, van der Zwaag, P, Van Dooren, S, Van Laer, L, Winbo, A, Winkel, B, Yamagata, K, Zumhagen, S, Volders, P, Lubitz, S, Antzelevitch, C, Platonov, P, Odening, K, Roden, D, Roberts, J, Skinner, J, Tfelt-Hansen, J, van den Berg, M, Olesen, M, Lambiase, P, Borggrefe, M, Hayashi, K, Rydberg, A, Nakajima, T, Yoshinaga, M, Saenen, J, Kaab, S, Brugada, P, Robyns, T, Giachino, D, Ackerman, M, Brugada, R, Brugada, J, Gimeno, J, Hasdemir, C, Guicheney, P, Priori, S, Schulze-Bahr, E, Makita, N, Schwartz, P, Shimizu, W, Aiba, T, Schott, J, Redon, R, Ohno, S, Probst, V, Arnaout, A, Amelot, M, Anselme, F, Billon, O, Defaye, P, Dupuis, J, Jesel, L, Laurent, G, Maury, P, Pasquie, J, Wiart, F, Behr, E, Barc, J, Bezzina, C, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), CIC - CHU Bichat, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHU Pontchaillou [Rennes], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Ege Üniversitesi, Cardiovascular Centre (CVC), Nantes Referral Ctr Inherited Car, Cardiology, Graduate School, ACS - Heart failure & arrhythmias, Human Genetics, ACS - Amsterdam Cardiovascular Sciences, ACS - Atherosclerosis & ischemic syndromes, MUMC+: DA KG Polikliniek (9), RS: Carim - H02 Cardiomyopathy, Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), RS: Carim - H04 Arrhythmogenesis and cardiogenetics, Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Clinical sciences, Heartrhythmmanagement, Medical Genetics, Reproduction and Genetics, and Cardio-vascular diseases

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Nantes Referral Center for inherited cardiac arrhythmia, Disease, Arrhythmias, 030105 genetics & heredity, ACMG/AMP guidelines, Brugada, LQTS, variant interpretation, Medicine, Genetics (clinical), Brugada Syndrome, Brugada syndrome, Genetics, Genetics & Heredity, education.field_of_study, medicine.diagnostic_test, Molecular pathology, 3. Good health, Long QT Syndrome, Medical genetics, Population Control, Cardiology and Cardiovascular Medicine, Cardiac, Medical Genetics, Life Sciences & Biomedicine, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Long QT syndrome, Population, 610 Medicine & health, BIO/18 - GENETICA, Article, 03 medical and health sciences, Humans, Genetic Testing, cardiovascular diseases, education, Medicinsk genetik, Genetic testing, 0604 Genetics, Science & Technology, business.industry, Genetic heterogeneity, MUTATIONS, ACMG/AMP guideline, Arrhythmias, Cardiac, 1103 Clinical Sciences, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, medicine.disease, Mutation, 030104 developmental biology, Human medicine, business
Abstract

Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate. Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants. Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 x 10(-18)) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 x 10(-13)). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency. Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing., Amsterdam Cardiovascular Sciences fellowship; Dutch Heart Foundation (CVON Predict-2/Concor-genes); Netherlands Organization for Scientific ResearchNetherlands Organization for Scientific Research (NWO) [VICI 016.150.610]; Fondation LeducqLeducq Foundation, R.W. is supported by an Amsterdam Cardiovascular Sciences fellowship. C.R.B. is supported by the Dutch Heart Foundation (CVON Predict-2/Concor-genes), Netherlands Organization for Scientific Research (VICI 016.150.610), and Fondation Leducq. See Supplement for all Acknowledgements.

Published
2020

39. Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome

Author

Yvonne M. Hoedemaekers, M. Ben Shoemaker, Pascale Guicheney, Antoine Leenhardt, Andrea Mazzanti, Minoru Horie, Jan H. Veldink, Isabelle Denjoy, Yu Kucho, Chiea Chuen Khor, Tomas Robyns, Carlo Napolitano, Peter Weeke, J. Martijn Bos, David J. Tester, Hanno L. Tan, Annika Rydberg, Patrick T. Ellinor, Pilar Galan, Taisuke Ishikawa, Seiko Ohno, Peter J. Schwartz, Masao Yoshinaga, Thomas Werge, Marta Ribasés, Bart Loeys, Jean-Jacques Schott, Jacob Tfelt-Hansen, Ulla-Britt Diamant, Marko Ernsting, Georgia Sarquella-Brugada, Yuka Mizusawa, Michael Christiansen, Pyotr G. Platonov, Annika Winbo, Thomas Meitinger, Keiko Shimamoto, Cristina Barlassina, Pieter G. Postema, Takeru Makiyama, Maarten P. van den Berg, Yanushi D. Wijeyeratne, Wataru Shimizu, Charles Antzelevitch, Christopher Newton-Cheh, Martina Müller-Nurasyid, Dan M. Roden, Vincent Probst, Takeshi Aiba, Lia Crotti, Daniele Cusi, Britt M. Beckmann, Johan Saenen, Peter Lichtner, Oscar Campuzano, Tin Aung, Nynke Hofman, Morten S. Olesen, Matteo Pedrazzini, Elijah R. Behr, Karen E. Morrison, Najim Lahrouchi, Katja E. Odening, Andrew D. Krahn, Kari L. Turkowski, J. Peter van Tintelen, Steven A. Lubitz, Federica Dagradi, Josep Brugada, Julien Barc, Birgit Stallmeyer, Stefan Kääb, Sven Zumhagen, Jonathan R. Skinner, Michael W.T. Tanck, Christopher Shaw, Brianna Davies, Eric Schulze-Bahr, Mineo Ozaki, Roddy Walsh, Antoine Andorin, Leonard H. van den Berg, Silvia G. Priori, Johannes Steinfurt, Jean-Baptiste Gourraud, Eline A. Nannenberg, Mark Lathrop, Rafik Tadros, Ramon Brugada, Leander Beekman, Peter M. Andersen, Ryan Pfeiffer, Boris Rudic, Reza Jabbari, Kanae Hasegawa, Jeroen Breckpot, Naomasa Makita, Michael J. Ackerman, Arthur A.M. Wilde, Hideki Itoh, Martin Borggrefe, Elena Arbelo, Connie R. Bezzina, Pamela J. Shaw, Ammar Al-Chalabi, Markus Munter, Cardiology, Graduate School, ACS - Heart failure & arrhythmias, ACS - Amsterdam Cardiovascular Sciences, Human Genetics, Epidemiology and Data Science, APH - Methodology, ACS - Atherosclerosis & ischemic syndromes, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences. Amsterdam University Medical Center, University of Amsterdam, European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart (ERN GUARD-Heart), Institut de Cardiologie de Montreal, Université de Montréal (UdeM), Istituto Auxologico Italiano, Shiga University of Medical Science, University of Fukui [Bunkyo], Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle (CRESS - U1153), Université Sorbonne Paris Nord-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CIC - CHU Bichat, Institut National de la Santé et de la Recherche Médicale (INSERM), Lahrouchi, N, Tadros, R, Crotti, L, Mizusawa, Y, Postema, P, Beekman, L, Walsh, R, Hasegawa, K, Barc, J, Ernsting, M, Turkowski, K, Mazzanti, A, Beckmann, B, Shimamoto, K, Diamant, U, Wijeyeratne, Y, Kucho, Y, Robyns, T, Ishikawa, T, Arbelo, E, Christiansen, M, Winbo, A, Jabbari, R, Lubitz, S, Steinfurt, J, Rudic, B, Loeys, B, Shoemaker, M, Weeke, P, Pfeiffer, R, Davies, B, Andorin, A, Hofman, N, Dagradi, F, Pedrazzini, M, Tester, D, Bos, J, Sarquella-Brugada, G, Campuzano, Ó, Platonov, P, Stallmeyer, B, Zumhagen, S, Nannenberg, E, Veldink, J, van den Berg, L, Al-Chalabi, A, Shaw, C, Shaw, P, Morrison, K, Andersen, P, Müller-Nurasyid, M, Cusi, D, Barlassina, C, Galan, P, Lathrop, M, Munter, M, Werge, T, Ribasés, M, Aung, T, Khor, C, Ozaki, M, Lichtner, P, Meitinger, T, van Tintelen, J, Hoedemaekers, Y, Denjoy, I, Leenhardt, A, Napolitano, C, Shimizu, W, Schott, J, Gourraud, J, Makiyama, T, Ohno, S, Itoh, H, Krahn, A, Antzelevitch, C, Roden, D, Saenen, J, Borggrefe, M, Odening, K, Ellinor, P, Tfelt-Hansen, J, Skinner, J, van den Berg, M, Olesen, M, Brugada, J, Brugada, R, Makita, N, Breckpot, J, Yoshinaga, M, Behr, E, Rydberg, A, Aiba, T, Kääb, S, Priori, S, Guicheney, P, Tan, H, Newton-Cheh, C, Ackerman, M, Schwartz, P, Schulze-Bahr, E, Probst, V, Horie, M, Wilde, A, Tanck, M, Bezzina, C, and Cardiovascular Centre (CVC)

Subjects
Multifactorial Inheritance, [SDV]Life Sciences [q-bio], Genome-wide association study, 030204 cardiovascular system & hematology, Severity of Illness Index, Sudden cardiac death, Electrocardiography, 0302 clinical medicine, inheritance pattern, Medicine, Cardiac and Cardiovascular Systems, Age of Onset, Genetics, 0303 health sciences, Kardiologi, Genetic disorder, genome-wide association study, Prognosis, 3. Good health, Phenotype, Medical genetics, Cardiology and Cardiovascular Medicine, Adult, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Genotype, Long QT syndrome, 610 Medicine & health, BIO/18 - GENETICA, QT interval, Polymorphism, Single Nucleotide, 03 medical and health sciences, Young Adult, Physiology (medical), long QT syndrome, Humans, Genetic Predisposition to Disease, cardiovascular diseases, Alleles, Genetic Association Studies, MED/01 - STATISTICA MEDICA, 030304 developmental biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, inheritance patterns, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, Heritability, medicine.disease, Genetic architecture, Genome-wide Association Study, Inheritance Patterns, Long Qt Syndrome, Case-Control Studies, Human medicine, business
Abstract

Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance ( P −8 ) near NOS1AP , KCNQ1 , and KLF12 , and 1 missense variant in KCNE1 (p.Asp85Asn) at the suggestive threshold ( P −6 ). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation ( h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r g =0.40; P =3.2×10 −3 ). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls ( P P Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.

Published
2020

40. Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

Author

Dennis O. Mook-Kanamori, Yalda Jamshidi, Peter K. Joshi, Seung Hoan Choi, Henry J. Lin, Rebecca D. Jackson, Alison D. Murray, May E. Montasser, Veikko Salomaa, Charles Kooperberg, Moritz F. Sinner, Gianfranco Sinagra, Luisa Foco, James G. Wilson, Johan Sundström, Kathleen A. Ryan, Eric A. Whitsel, Bruno H. Stricker, Sandosh Padmanabhan, Christopher Newton-Cheh, Ozren Polasek, Unnur Thorsteinsdottir, Niek Verweij, Pier D. Lambiase, Nathan R. Tucker, Stefan Kääb, Jun Ding, Stefan Weiss, Daniel F. Gudbjartsson, David Conen, Lars Lind, Ivana Kolcic, Lu-Chen Weng, J. Wouter Jukema, Kirill V. Tarasov, Xiuqing Guo, Stella Trompet, Patricia B. Munroe, Albert V. Smith, Elsayed Z. Soliman, Andrew Tinker, Antti Jula, J. Gustav Smith, Alexander P. Reiner, Sébastien Thériault, Kathryn L. Lunetta, Vilmundur Gudnason, Mika Kähönen, Massimo Mangino, Raymond Noordam, Joshua C. Bis, Alan R. Shuldiner, Tim D. Spector, Borbala Mifsud, Stefan van Duijvenboden, Jeffrey R. O'Connell, Emelia J. Benjamin, M. Benjamin Shoemaker, Stephan B. Felix, Peter W. Macfarlane, Lorenz Risch, Uwe Völker, Stephanie M. Gogarten, Maria Fernanda Lima-Costa, Julia Ramirez, Morten S. Olesen, Konstantin Strauch, Annette Peters, Aaron Isaacs, Steven A. Lubitz, Eric Boerwinkle, Carolina Roselli, James H. Cartwright, Nathalia M. Araujo, Ruth J. F. Loos, Diane Fatkin, Harry Campbell, Blair H. Smith, Thomas Meitinger, André G. Uitterlinden, Paul L. Huang, Tamara B. Harris, Kathleen F. Kerr, David J. Porteous, Martina Müller-Nurasyid, Francesco Cucca, Michiel Rienstra, Davíð O. Arnar, Amanda A. Seyerle, Caroline Hayward, M. Abdullah Said, Catriona L. K. Barnes, Kent D. Taylor, Nona Sotoodehnia, Nina Mononen, Dan M. Roden, Jonathan Marten, Terho Lehtimäki, Dan E. Arking, Anna F. Dominiczak, Jan A. Kors, Olli T. Raitakari, Igor Rudan, Yordi J. van de Vegte, Christopher P. Nelson, Erik Ingelsson, Ulrike Peters, Girish N. Nadkarni, Eduardo Tarazona-Santos, Edward G. Lakatta, Nina Hutri-Kähönen, Bruce M. Psaty, Patrick T. Ellinor, Christian Fuchsberger, Katharina Schramm, Amelia W. Hall, M. Yldau van der Ende, Alvaro Alonso, James F. Wilson, Sheila Ulivi, Rosa B. Thorolfsdottir, Stefanie Aeschbacher, Mary L. Biggs, Marten E. van den Berg, Nilesh J. Samani, Thibaud Boutin, Vilmantas Giedraitis, Honghuang Lin, Kjell Nikus, Helen R. Warren, Arie C. Maan, James J. Cranley, Adolfo Correa, Martin Gögele, Ian Ford, Katri Sääksjärvi, Georg Ehret, Michele Orini, Susan R. Heckbert, Cecilia M. Lindgren, Jie Yao, Maria Pina Concas, Pim van der Harst, Ioanna Ntalla, Jeffrey Haessler, Jerome I. Rotter, Pashupati P. Mishra, Michael J. Cutler, Erwin P. Bottinger, Cornelia M. van Duijn, Jennifer A. Brody, Paolo Gasparini, Lenore J. Launer, Andrew P. Morris, Renée de Mutsert, Aki S. Havulinna, James P. Cook, Hilma Holm, Patrick Sulem, Alessandro De Grandi, Cristian Pattaro, Gardar Sveinbjornsson, Antonio Luiz Pinho Ribeiro, Mark J. Caulfield, Gudmar Thorleifsson, Marcus Dörr, Muhammad B. Riaz, Peter P. Pramstaller, Yong Qian, Anubha Mahajan, Cathy C. Laurie, Kenneth Rice, Mark Chaffin, Kari Stefansson, Andrew A. Hicks, Solmaz Assa, Hao Mei, Leo-Pekka Lyytikäinen, Fabiola Del Greco M, Renan P. Souza, Michael Preuss, Adrienne M. Stilp, Barry London, Melanie Waldenberger, Christy L. Avery, Daniel Levy, Michael R. Barnes, Medical Informatics, Epidemiology, Internal Medicine, Weng, Lu-Chen [0000-0003-1475-4930], Hall, Amelia Weber [0000-0002-7915-0313], Tucker, Nathan R [0000-0002-5071-4218], Chaffin, Mark D [0000-0002-1234-5562], Roselli, Carolina [0000-0001-5267-6756], Barnes, Michael R [0000-0001-9097-7381], Mifsud, Borbala [0000-0003-3429-3094], Hayward, Caroline [0000-0002-9405-9550], Concas, Maria Pina [0000-0003-3598-2537], Boutin, Thibaud [0000-0003-4754-1675], Kolcic, Ivana [0000-0001-7918-6052], Rudan, Igor [0000-0001-6993-6884], Souza, Renan P [0000-0002-9479-4432], Giedraitis, Vilmantas [0000-0003-3423-2021], Ingelsson, Erik [0000-0003-2256-6972], Mahajan, Anubha [0000-0001-5585-3420], Morris, Andrew P [0000-0002-6805-6014], Hicks, Andrew A [0000-0001-6320-0411], Sundström, Johan [0000-0003-2247-8454], Nelson, Christopher P [0000-0001-8025-2897], Riaz, Muhammad B [0000-0002-5512-1745], Sinagra, Gianfranco [0000-0003-2700-8478], Mishra, Pashupati P [0000-0001-5177-3431], Caulfield, Mark J [0000-0001-9295-3594], Dominiczak, Anna [0000-0003-4913-3608], Risch, Lorenz [0000-0003-2692-6699], Joshi, Peter K [0000-0002-6361-5059], Wilson, James F [0000-0001-5751-9178], Isaacs, Aaron [0000-0001-5037-4834], van Duijn, Cornelia M [0000-0002-2374-9204], Gudnason, Vilmundur [0000-0001-5696-0084], Smith, Albert V [0000-0003-1942-5845], Loos, Ruth JF [0000-0002-8532-5087], Preuss, Michael H [0000-0001-5266-8465], Correa, Adolfo [0000-0002-9501-600X], Müller-Nurasyid, Martina [0000-0003-3793-5910], Waldenberger, Melanie [0000-0003-0583-5093], Mangino, Massimo [0000-0002-2167-7470], Rienstra, Michiel [0000-0002-2581-070X], van der Harst, Pim [0000-0002-2713-686X], Verweij, Niek [0000-0002-4303-7685], Fatkin, Diane [0000-0002-9010-9856], Brody, Jennifer A [0000-0001-8509-148X], Rice, Kenneth [0000-0002-3071-7278], Pattaro, Cristian [0000-0002-4119-0109], Wouter Jukema, J [0000-0002-3246-8359], Weiss, Stefan [0000-0002-3553-4315], Havulinna, Aki S [0000-0002-4787-8959], Sääksjärvi, Katri [0000-0002-5061-4911], Salomaa, Veikko [0000-0001-7563-5324], Rotter, Jerome I [0000-0001-7191-1723], Taylor, Kent D [0000-0002-2756-4370], Lakatta, Edward G [0000-0002-4772-0035], Lin, Honghuang [0000-0003-3043-3942], Lunetta, Kathryn L [0000-0002-9268-810X], Murray, Alison D [0000-0003-4915-4847], Porteous, David J [0000-0003-1249-6106], Smith, Blair H [0000-0002-5362-9430], Uitterlinden, André [0000-0002-7276-3387], Peters, Ulrike [0000-0001-5666-9318], Alonso, Alvaro [0000-0002-2225-8323], Ehret, Georg B [0000-0002-5730-0675], Soliman, Elsayed Z [0000-0001-5632-8150], Gogarten, Stephanie M [0000-0002-7231-9745], Kerr, Kathleen F [0000-0002-6438-9583], Abdullah Said, M [0000-0003-2920-7745], Orini, Michele [0000-0001-5773-0344], Ramirez, Julia [0000-0003-4130-5866], Van Duijvenboden, Stefan [0000-0001-8897-558X], Gudbjartsson, Daniel F [0000-0002-5222-9857], Sulem, Patrick [0000-0001-7123-6123], Thorolfsdottir, Rosa B [0000-0001-7475-0398], Benjamin, Emelia J [0000-0003-4076-2336], Stefansson, Kari [0000-0003-1676-864X], Ellinor, Patrick T [0000-0002-2067-0533], Jamshidi, Yalda [0000-0003-0151-6482], Lubitz, Steven A [0000-0002-9599-4866], Munroe, Patricia B [0000-0002-4176-2947], Apollo - University of Cambridge Repository, Medicum, Institute for Molecular Medicine Finland, Complex Disease Genetics, Helsinki Institute of Life Science HiLIFE, University of Helsinki, Cardiovascular Centre (CVC), Ntalla, I., Weng, L. -C., Cartwright, J. H., Hall, A. W., Sveinbjornsson, G., Tucker, N. R., Choi, S. H., Chaffin, M. D., Roselli, C., Barnes, M. R., Mifsud, B., Warren, H. R., Hayward, C., Marten, J., Cranley, J. J., Concas, M. P., Gasparini, P., Boutin, T., Kolcic, I., Polasek, O., Rudan, I., Araujo, N. M., Lima-Costa, M. F., Ribeiro, A. L. P., Souza, R. P., Tarazona-Santos, E., Giedraitis, V., Ingelsson, E., Mahajan, A., Morris, A. P., Del Greco M, F., Foco, L., Gogele, M., Hicks, A. A., Cook, J. P., Lind, L., Lindgren, C. M., Sundstrom, J., Nelson, C. P., Riaz, M. B., Samani, N. J., Sinagra, G., Ulivi, S., Kahonen, M., Mishra, P. P., Mononen, N., Nikus, K., Caulfield, M. J., Dominiczak, A., Padmanabhan, S., Montasser, M. E., O'Connell, J. R., Ryan, K., Shuldiner, A. R., Aeschbacher, S., Conen, D., Risch, L., Theriault, S., Hutri-Kahonen, N., Lehtimaki, T., Lyytikainen, L. -P., Raitakari, O. T., Barnes, C. L. K., Campbell, H., Joshi, P. K., Wilson, J. F., Isaacs, A., Kors, J. A., van Duijn, C. M., Huang, P. L., Gudnason, V., Harris, T. B., Launer, L. J., Smith, A. V., Bottinger, E. P., Loos, R. J. F., Nadkarni, G. N., Preuss, M. H., Correa, A., Mei, H., Wilson, J., Meitinger, T., Muller-Nurasyid, M., Peters, A., Waldenberger, M., Mangino, M., Spector, T. D., Rienstra, M., van de Vegte, Y. J., van der Harst, P., Verweij, N., Kaab, S., Schramm, K., Sinner, M. F., Strauch, K., Cutler, M. J., Fatkin, D., London, B., Olesen, M., Roden, D. M., Benjamin Shoemaker, M., Gustav Smith, J., Biggs, M. L., Bis, J. C., Brody, J. A., Psaty, B. M., Rice, K., Sotoodehnia, N., De Grandi, A., Fuchsberger, C., Pattaro, C., Pramstaller, P. P., Ford, I., Wouter Jukema, J., Macfarlane, P. W., Trompet, S., Dorr, M., Felix, S. B., Volker, U., Weiss, S., Havulinna, A. S., Jula, A., Saaksjarvi, K., Salomaa, V., Guo, X., Heckbert, S. R., Lin, H. J., Rotter, J. I., Taylor, K. D., Yao, J., de Mutsert, R., Maan, A. C., Mook-Kanamori, D. O., Noordam, R., Cucca, F., Ding, J., Lakatta, E. G., Qian, Y., Tarasov, K. V., Levy, D., Lin, H., Newton-Cheh, C. H., Lunetta, K. L., Murray, A. D., Porteous, D. J., Smith, B. H., Stricker, B. H., Uitterlinden, A., van den Berg, M. E., Haessler, J., Jackson, R. D., Kooperberg, C., Peters, U., Reiner, A. P., Whitsel, E. A., Alonso, A., Arking, D. E., Boerwinkle, E., Ehret, G. B., Soliman, E. Z., Avery, C. L., Gogarten, S. M., Kerr, K. F., Laurie, C. C., Seyerle, A. A., Stilp, A., Assa, S., Abdullah Said, M., Yldau van der Ende, M., Lambiase, P. D., Orini, M., Ramirez, J., Van Duijvenboden, S., Arnar, D. O., Gudbjartsson, D. F., Holm, H., Sulem, P., Thorleifsson, G., Thorolfsdottir, R. B., Thorsteinsdottir, U., Benjamin, E. J., Tinker, A., Stefansson, K., Ellinor, P. T., Jamshidi, Y., Lubitz, S. A., Munroe, P. B., Fysiologie, RS: FHML MaCSBio, RS: Carim - B01 Blood proteins & engineering, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Háskóli Íslands, and University of Iceland

Subjects
0301 basic medicine, Male, Multifactorial Inheritance, General Physics and Astronomy, Gene Expression, Genome-wide association study, 030204 cardiovascular system & hematology, Arrhythmias, Genome-wide association studies, CALCINEURIN, Electrocardiography, 0302 clinical medicine, Cardiovascular Disease, Multi-ancestry GWAS, ELEMENTS, Medicine, Cardiac and Cardiovascular Systems, Blóðrásarsjúkdómar, lcsh:Science, RISK, DECREASE, education.field_of_study, Multidisciplinary, Kardiologi, medicine.diagnostic_test, 1184 Genetics, developmental biology, physiology, Atrial fibrillation, 3142 Public health care science, environmental and occupational health, 3. Good health, Endophenotype, Arrhythmias, Cardiac, Cardiovascular Diseases, Endophenotypes, Female, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Quantitative Trait Loci, cardiovascular system, Cardiology, medicine.symptom, Erfðarannsóknir, Cardiac, Medical Genetics, Human, Bradycardia, medicine.medical_specialty, Science, GENOME-WIDE ASSOCIATION, ATRIAL-FIBRILLATION, MUTATIONS, DURATION, CARDIOMYOPATHY, BRADYCARDIA, Population, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Internal medicine, Cardiac conduction, PR interval, education, Medicinsk genetik, business.industry, Cardiovascular genetics, General Chemistry, Arfgengi, medicine.disease, 030104 developmental biology, lcsh:Q, business
Abstract

Publisher's version (útgefin grein), The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease., We provide all investigator and study-specific acknowledgements in Supplementary Note 1, and funding sources in Supplementary Note 2.

Published
2020

41. The Second Team Haemophilia Education Meeting, 2016, Frankfurt, Germany

Author

Marijke van den Berg, Yesim Dargaud, Roseline d'Oiron, Edward Laane, Sayma Raza, Pål Andre Holme, Susan Halimeh, Lorenzo G. Mantovani, Sébastien Lobet, Andrea S. Doria, Raquel Ciuvalschi Maia, Erik Berntorp, Thomas Sannié, Pia Petrini, Athina Dettoraki, Paul McLaughlin, Maria Elisa Mancuso, Radoslaw Kaczmarek, Anna Farrell, Jan Blatný, Debra Pollard, David Perry, Hervé Chambost, Daniel P. Hart, Lochana Nanayakkara, Stephanie Taylor, Berntorp, E, Dargaud, Y, Hart, D, Lobet, S, Mancuso, M, D'Oiron, R, Perry, D, Pollard, D, van den Berg, M, Blatny, J, Chambost, H, Doria, A, Holme, P, Kaczmarek, R, Mantovani, L, Mclaughlin, P, Nanayakkara, L, Petrini, P, Sannie, T, Laane, E, Maia, R, Dettoraki, A, Farrell, A, Halimeh, S, Raza, S, and Taylor, S

Subjects
medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, 030204 cardiovascular system & hematology, Haemophilia, Hemophilia A, Hemophilia B, Patient care, 03 medical and health sciences, 0302 clinical medicine, HDE HEM PED, Multidisciplinary approach, hemic and lymphatic diseases, Germany, Medicine, Humans, Disease management (health), Congresses, Clotting factor, Patient Care Team, Health professionals, business.industry, Disease Management, Hematology, General Medicine, Treatment team, medicine.disease, 3. Good health, clotting factor concentrates, genetics, haemophilia, laboratory assays, multidisciplinary, real-life data, Europe, Family medicine, Physical therapy, Patient representatives, Health Facilities, business, Delivery of Health Care, 030215 immunology
Abstract

The first Team Haemophilia Education (THE) Meeting was held on 7-8 May 2015 in Amsterdam, The Netherlands. It aimed to promote the optimal care of patients with haemophilia through education of the multidisciplinary treatment team. This was achieved by reviewing the latest developments in haemophilia management, considering how these can be implemented in the clinic to improve patient care and providing a platform for networking and debate for all haemophilia treatment team members. The second THE Meeting was held on 19-20 May in Frankfurt, Germany, and participants included doctors, nurses, physiotherapists, patient representatives and data management staff from 20 different countries. Topics covered the role of the multidisciplinary team in delivering the best haemophilia care, challenges in the management of haemophilia across Europe, available clotting factor treatments, future treatments and the use of genetics in advising carriers of haemophilia. This report is a summary of the key developments in haemophilia care presented by various investigators and healthcare professionals at THE Meeting 2016. info:eu-repo/semantics/publishedVersion

Published
2017

42. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

Author

Yuki Bradford, Toshiko Tanaka, Jeffrey R. O'Connell, Florence Kyndt, Unnur Thorsteinsdottir, Ivana Kolcic, Xiaoyan Yin, Vincent Probst, Manolis Kellis, Christopher Newton-Cheh, Stefan Kääb, Argelia Medeiros-Domingo, Markus M. Nöthen, Paolo Gasparini, Jean-Jacques Schott, Ruth J. F. Loos, Thomas W. Mühleisen, Annukka Marjamaa, Morris Brown, Igor Rudan, Runjun D. Kumar, Peter J. Schwartz, Lars Lind, Martina Müller-Nurasyid, Xinchen Wang, Joshua C. Denny, Roberto Insolia, Soumya Raychaudhuri, Stephen W. Scherer, Bruno H. Stricker, Alexander Kluttig, Adamo Pio D'Adamo, Laurie A. Boyer, Moritz F. Sinner, Norbert Frey, Nour Eddine El Mokhtari, Thomas Meitinger, Jesper V. Olsen, Gerjan Navis, Steven R. Cummings, Richard W Morris, Nynke Hofman, Marcel den Hoed, Rudolf A. de Boer, Gonçalo R. Abecasis, Mark J. Daly, Dan M. Roden, Christian Gieger, Lyudmyla Kedenko, Marcus Dörr, Thomas P. Cappola, Afshin Parsa, Kari Stefansson, Markus Perola, Mark Eijgelsheim, Fredrik Nyberg, Robert M. Hamilton, Yalda Jamshidi, W. H. Linda Kao, Terho Lehtimäki, Annette Peters, David Schlessinger, Peter P. Pramstaller, James F. Wilson, Vilmundur Gudnason, Florian Kronenberg, Aroon D. Hingorani, Connie R. Bezzina, Abdennasser Bardai, Marylyn D. Ritchie, Andrew S. Plump, Johan Sundström, Daryl Waggott, Chrysoula Dalageorgou, Paul I.W. de Bakker, Uwe Völker, Aaron Isaacs, Oscar H. Franco, Yongmei Liu, Andrew N. Nicolaides, Lia Crotti, Cornelia M. van Duijn, Ben A. Oostra, Arne Pfeufer, Karl Werdan, Michael Morley, Jan A. Kors, Julien Barc, Lewin Eisele, Siegfried Perz, Stéphanie Chatel, Pieter A. van der Vleuten, Sara L. Pulit, Anna F. Dominiczak, Harry Campbell, Alice Ghidoni, Irene Mateo Leach, Nona Sotoodehnia, Nina Mononen, Henriette E. Meyer zu Schwabedissen, Alvaro Alonso, Fabiola Del Greco M, Dan E. Arking, Vera Adamkova, Mike A. Nalls, Valur Emilsson, Edward G. Lakatta, Kirill Tarasov, Alan F. Wright, Lenore J. Launer, Erik Ingelsson, Karin Halina Greiser, Ozren Polasek, Massimo Carella, Daniel F. Gudbjartsson, Bouwe P. Krijthe, Hanna Prucha, Per Hoffmann, Maura Griffin, Stefan Kiechl, Angel Carracedo, Ilja M. Nolte, Christine E. Moravec, Johann Willeit, Joshua C. Bis, Patricia B. Munroe, Marcello Ricardo Paulista Markus, Hailiang Huang, Mika Kähönen, Albert Hofman, Peter H. Whincup, Dirk J. van Veldhuisen, Michael Knoflach, Alicia Lundby, Serena Sanna, Hagen Kälsch, Bernhard Paulweber, Kamil Slowikowski, Luigi Ferrucci, Melanie Waldenberger, Marco Bobbo, Annukka M. Lahtinen, Ann-Christine Syvänen, J. Gustav Smith, Åsa Torinsson Naluai, Jaroslav A. Hubacek, Jeffrey Brandimarto, Wendy S. Post, Lude Franke, Mark J. Caulfield, Folkert W. Asselbergs, André G. Uitterlinden, Stefan Gustafsson, Pim van der Harst, David J. Tester, David S. Siscovick, David O. Arnar, Sarah H Wild, Elizabeth J. Rossin, Albert V. Smith, Bruce M. Psaty, Georg Ehret, Alan R. Shuldiner, Stephen Newhouse, Kimmo Kontula, Maria Brion, Andre Franke, Peter W. Macfarlane, Mika Kivimäki, Tamara B. Harris, Lasse Oikarinen, Tamara T. Koopmann, Kenneth B. Margulies, Aravinda Chakravarti, Gianfranco Sinagra, Maarten P. van den Berg, Veikko Salomaa, Karl-Heinz Jöckel, Daniel S. Evans, Caroline Hayward, Kimmo Porthan, Michael J. Ackerman, Jacqueline C.M. Witteman, Arthur A.M. Wilde, Martin G. Larson, Kasper Lage, Manuela Uda, Susan R. Heckbert, Joel S. Bader, Graham Watt, María Dolores Torres, Stephan B. Felix, Jerome I. Rotter, Pau Navarro, Meena Kumari, Johan Ärnlöv, Andrew D. Paterson, Antti Jula, Olli T. Raitakari, Raimund Erbel, Christopher J. O'Donnell, Britt M. Beckmann, Peter A. Noseworthy, Tim D. Spector, Wai K. Lee, Leopoldo Zelante, Nilesh J. Samani, John R. Giudicessi, Harold Snieder, Dag S. Thelle, David Ellinghaus, Eimo Martens, James B. Strait, Jorma S. A. Viikari, Andrew D. Johnson, Antonella Mulas, Hilma Holm, Johannes Haerting, Annamaria Iorio, Rebecca L. Zuvich, Sheila Ulivi, Andrew A. Hicks, Elijah R. Behr, Leo-Pekka Lyytikäinen, Bernhard Strohmer, Marco Orru, Claudia Lamina, Sandosh Padmanabhan, Christian Fuchsberger, Andrie G. Panayiotou, Ehret, Georg Benedikt, Internal Medicine, Public Health, Epidemiology, Rehabilitation Medicine, Medical Informatics, Clinical Genetics, Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Ethical, Legal, Social Issues in Genetics (ELSI), Stem Cell Aging Leukemia and Lymphoma (SALL), Arking, D, Pulit, S, Crotti, L, van der Harst, P, Munroe, P, Koopmann, T, Sotoodehnia, N, Rossin, E, Morley, M, Wang, X, Johnson, A, Lundby, A, Gudbjartsson, D, Noseworthy, P, Eijgelsheim, M, Bradford, Y, Tarasov, K, Dörr, M, Müller-Nurasyid, M, Lahtinen, A, Nolte, I, Smith, A, Bis, J, Isaacs, A, Newhouse, S, Evans, D, Post, W, Waggott, D, Lyytikäinen, L, Hicks, A, Eisele, L, Ellinghaus, D, Hayward, C, Navarro, P, Ulivi, S, Tanaka, T, Tester, D, Chatel, S, Gustafsson, S, Kumari, M, Morris, R, Naluai, A, Padmanabhan, S, Kluttig, A, Strohmer, B, Panayiotou, A, Torres, M, Knoflach, M, Hubacek, J, Slowikowski, K, Raychaudhuri, S, Kumar, R, Harris, T, Launer, L, Shuldiner, A, Alonso, A, Bader, J, Ehret, G, Huang, H, Kao, W, Strait, J, Macfarlane, P, Brown, M, Caulfield, M, Samani, N, Kronenberg, F, Willeit, J, Smith, J, Greiser, K, Meyer Zu Schwabedissen, H, Werdan, K, Carella, M, Zelante, L, Heckbert, S, Psaty, B, Rotter, J, Kolcic, I, Polašek, O, Wright, A, Griffin, M, Daly, M, Arnar, D, Hólm, H, Thorsteinsdottir, U, Denny, J, Roden, D, Zuvich, R, Emilsson, V, Plump, A, Larson, M, O'Donnell, C, Yin, X, Bobbo, M, D'Adamo, A, Iorio, A, Sinagra, G, Carracedo, A, Cummings, S, Nalls, M, Jula, A, Kontula, K, Marjamaa, A, Oikarinen, L, Perola, M, Porthan, K, Erbel, R, Hoffmann, P, Jöckel, K, Kälsch, H, Nöthen, M, den Hoed, M, Loos, R, Thelle, D, Gieger, C, Meitinger, T, Perz, S, Peters, A, Prucha, H, Sinner, M, Waldenberger, M, de Boer, R, Franke, L, van der Vleuten, P, Beckmann, B, Martens, E, Bardai, A, Hofman, N, Wilde, A, Behr, E, Dalageorgou, C, Giudicessi, J, Medeiros-Domingo, A, Kyndt, F, Probst, V, Ghidoni, A, Insolia, R, Hamilton, R, Scherer, S, Brandimarto, J, Margulies, K, Moravec, C, Greco, M, Fuchsberger, C, O'Connell, J, Lee, W, Watt, G, Campbell, H, Wild, S, El Mokhtari, N, Frey, N, Asselbergs, F, Mateo Leach, I, Navis, G, van den Berg, M, van Veldhuisen, D, Kellis, M, Krijthe, B, Franco, O, Hofman, A, Kors, J, Uitterlinden, A, Witteman, J, Kedenko, L, Lamina, C, Oostra, B, Abecasis, G, Lakatta, E, Mulas, A, Orrú, M, Schlessinger, D, Uda, M, Markus, M, Völker, U, Snieder, H, Spector, T, Arnlöv, J, Lind, L, Sundström, J, Syvänen, A, Kivimaki, M, Kähönen, M, Mononen, N, Raitakari, O, Viikari, J, Adamkova, V, Kiechl, S, Brion, M, Nicolaides, A, Paulweber, B, Haerting, J, Dominiczak, A, Nyberg, F, Whincup, P, Hingorani, A, Schott, J, Bezzina, C, Ingelsson, E, Ferrucci, L, Gasparini, P, Wilson, J, Rudan, I, Franke, A, Mühleisen, T, Pramstaller, P, Lehtimäki, T, Paterson, A, Parsa, A, Liu, Y, van Duijn, C, Siscovick, D, Gudnason, V, Jamshidi, Y, Salomaa, V, Felix, S, Sanna, S, Ritchie, M, Stricker, B, Stefansson, K, Boyer, L, Cappola, T, Olsen, J, Lage, K, Schwartz, P, Kääb, S, Chakravarti, A, Ackerman, M, Pfeufer, A, de Bakker, P, Newton-Cheh, C, Arking, Dan E., Pulit, Sara L., Crotti, Lia, Van Der Harst, Pim, Munroe, Patricia B., Koopmann, Tamara T., Sotoodehnia, Nona, Rossin, Elizabeth J., Morley, Michael, Wang, Xinchen, Johnson, Andrew D., Lundby, Alicia, Gudbjartsson, Daníel F., Noseworthy, Peter A., Eijgelsheim, Mark, Bradford, Yuki, Tarasov, Kirill V., Dörr, Marcu, Müller Nurasyid, Martina, Lahtinen, Annukka M., Nolte, Ilja M., Smith, Albert Vernon, Bis, Joshua C., Isaacs, Aaron, Newhouse, Stephen J., Evans, Daniel S., Post, Wendy S., Waggott, Daryl, Lyytikäinen, Leo Pekka, Hicks, Andrew A., Eisele, Lewin, Ellinghaus, David, Hayward, Caroline, Navarro, Pau, Ulivi, Sheila, Tanaka, Toshiko, Tester, David J., Chatel, Stéphanie, Gustafsson, Stefan, Kumari, Meena, Morris, Richard W., Naluai, Asa T., Padmanabhan, Sandosh, Kluttig, Alexander, Strohmer, Bernhard, Panayiotou, Andrie G., Torres, Maria, Knoflach, Michael, Hubacek, Jaroslav A., Slowikowski, Kamil, Raychaudhuri, Soumya, Kumar, Runjun D., Harris, Tamara B., Launer, Lenore J., Shuldiner, Alan R., Alonso, Alvaro, Bader, Joel S., Ehret, Georg, Huang, Hailiang, Kao, W. H. Linda, Strait, James B., Macfarlane, Peter W., Brown, Morri, Caulfield, Mark J., Samani, Nilesh J., Kronenberg, Florian, Willeit, Johann, Smith, J. Gustav, Greiser, Karin H., Zu Schwabedissen, Henriette Meyer, Werdan, Karl, Carella, Massimo, Zelante, Leopoldo, Heckbert, Susan R., Psaty, Bruce M., Rotter, Jerome I., Kolcic, Ivana, Polašek, Ozren, Wright, Alan F., Griffin, Maura, Daly, Mark J., Arnar, David O., Hólm, Hilma, Thorsteinsdottir, Unnur, Denny, Joshua C., Roden, Dan M., Zuvich, Rebecca L., Emilsson, Valur, Plump, Andrew S., Larson, Martin G., O'Donnell, Christopher J., Yin, Xiaoyan, Bobbo, Marco, D'Adamo, ADAMO PIO, Iorio, Annamaria, Sinagra, Gianfranco, Carracedo, Angel, Cummings, Steven R., Nalls, Michael A., Jula, Antti, Kontula, Kimmo K., Marjamaa, Annukka, Oikarinen, Lasse, Perola, Marku, Porthan, Kimmo, Erbel, Raimund, Hoffmann, Per, Jöckel, Karl Heinz, Kälsch, Hagen, Nöthen, Markus M., Den Hoed, Marcel, Loos, Ruth J. F., Thelle, Dag S., Gieger, Christian, Meitinger, Thoma, Perz, Siegfried, Peters, Annette, Prucha, Hanna, Sinner, Moritz F., Waldenberger, Melanie, De Boer, Rudolf A., Franke, Lude, Van Der Vleuten, Pieter A., Beckmann, Britt Maria, Martens, Eimo, Bardai, Abdennasser, Hofman, Nynke, Wilde, Arthur A. M., Behr, Elijah R., Dalageorgou, Chrysoula, Giudicessi, John R., Medeiros Domingo, Argelia, Barc, Julien, Kyndt, Florence, Probst, Vincent, Ghidoni, Alice, Insolia, Roberto, Hamilton, Robert M., Scherer, Stephen W., Brandimarto, Jeffrey, Margulies, Kenneth, Moravec, Christine E., Del Greco M, Fabiola, Fuchsberger, Christian, O'Connell, Jeffrey R., Lee, Wai K., Watt, Graham C. M., Campbell, Harry, Wild, Sarah H., El Mokhtari, Nour E., Frey, Norbert, Asselbergs, Folkert W., Leach, Irene Mateo, Navis, Gerjan, Van Den Berg, Maarten P., Van Veldhuisen, Dirk J., Kellis, Manoli, Krijthe, Bouwe P., Franco, Oscar H., Hofman, Albert, Kors, Jan A., Uitterlinden, André G., Witteman, Jacqueline C. M., Kedenko, Lyudmyla, Lamina, Claudia, Oostra, Ben A., Abecasis, Gonçalo R., Lakatta, Edward G., Mulas, Antonella, Orrú, Marco, Schlessinger, David, Uda, Manuela, Markus, Marcello R. P., Völker, Uwe, Snieder, Harold, Spector, Timothy D., Ärnlöv, Johan, Lind, Lar, Sundström, Johan, Syvänen, Ann Christine, Kivimaki, Mika, Kähönen, Mika, Mononen, Nina, Raitakari, Olli T., Viikari, Jorma S., Adamkova, Vera, Kiechl, Stefan, Brion, Maria, Nicolaides, Andrew N., Paulweber, Bernhard, Haerting, Johanne, Dominiczak, Anna F., Nyberg, Fredrik, Whincup, Peter H., Hingorani, Aroon D., Schott, Jean Jacque, Bezzina, Connie R., Ingelsson, Erik, Ferrucci, Luigi, Gasparini, Paolo, Wilson, James F., Rudan, Igor, Franke, Andre, Mühleisen, Thomas W., Pramstaller, Peter P., Lehtimäki, Terho J., Paterson, Andrew D., Parsa, Afshin, Liu, Yongmei, Van Duijn, Cornelia M., Siscovick, David S., Gudnason, Vilmundur, Jamshidi, Yalda, Salomaa, Veikko, Felix, Stephan B., Sanna, Serena, Ritchie, Marylyn D., Stricker, Bruno H., Stefansson, Kari, Boyer, Laurie A., Cappola, Thomas P., Olsen, Jesper V., Lage, Kasper, Schwartz, Peter J., Kääb, Stefan, Chakravarti, Aravinda, Ackerman, Michael J., Pfeufer, Arne, De Bakker, Paul I. W., Newton Cheh, Christopher, Cardiology, ACS - Amsterdam Cardiovascular Sciences, and Human Genetics

Subjects
Male, Candidate gene, Myocardium/metabolism, LOCI, Medizin, Heart electrophysiology, Genome-wide association study, Arrhythmias, Bioinformatics, Medical and Health Sciences, Heart Ventricle, Sudden cardiac death, Electrocardiography, PR INTERVAL, Arrhythmias, Cardiac/genetics, Death, Sudden, Cardiac/etiology, Genetics, ddc:616, Cardiac electrophysiology, Adult, Aged, Arrhythmias, Cardiac, Calcium Signaling, Death, Sudden, Cardiac, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Heart Ventricles, Humans, Long QT Syndrome, Middle Aged, Myocardium, Polymorphism, Single Nucleotide, COMMON VARIANTS, Heart Ventricles/metabolism, Single Nucleotide, Long QT Syndrome/genetics, CHRONIC HEART-FAILURE, Death, Heart ventricle arrhythmia, genetic association study, gene, SNP, heart, Genome-Wide Association Study/methods, Long QT syndrome, QRS DURATION, Cardiac, Cardiac/etiology, Human, QT interval, congenital, hereditary, and neonatal diseases and abnormalities, Electrocardiography/methods, TRPM7, BIO/18 - GENETICA, Cardiac/genetics, Biology, Article, sudden cardiac death, QRS complex, CARDIAC REPOLARIZATION, medicine, Repolarization, cardiovascular diseases, GENOME-WIDE ASSOCIATION, Polymorphism, MED/01 - STATISTICA MEDICA, calcium, ta1184, Calcium signaling, Calcium Signaling/genetics, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, ta3121, Cardiovascular risk, medicine.disease, SARCOPLASMIC-RETICULUM, Sudden, MODEL, Genetic association, myocardial repolarization, Genetic variability, Gene expression, Clinical Medicine, genetic, Controlled study
Abstract

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain similar to 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

Published
2014

43. Towards actionable international comparisons of health system performance: expert revision of the OECD framework and quality indicators

Author

F, Carinci, K, Van Gool, J, Mainz, J, Veillard, E C, Pichora, J M, Januel, I, Arispe, S M, Kim, N S, Klazinga, V, Raleigh, OECD Health Care Quality Indicators Expert Group, Haelterman, M., Meeus, P., Lacroix, J., Cenek, J., Barsøe, CR., Grau, K., Rooväli, L., Hämaläinen, P., Garcia, V., Grenier, C., Le Cossec, B., Marbach, M., Scheidt-Nave, C., Mulholland, D., Ekka-Zohar, A., Kumakawa, T., Okamoto, E., Byeon, EH., Kim, KH., Park, CS., Lepiksone, J., Berthet, F., Margue, C., Van Den Berg, M., Lindahl, AK., Narbuvold, H., Dudzik-Urbaniak, E., Boto, P., Lim, EK., Mok, WY., Pribakovic, R., Gogorcena, MA., Aggestam, M., Köster, M., Lawrence, M., Langenegger, M., Fehst, K., Yilmaz, S., Everard, K., Raleigh, V., APH - Aging & Later Life, APH - Quality of Care, Graduate School, APH - Amsterdam Public Health, and Public and occupational health

Subjects
Consensus, Quality management, Process management, Delphi Technique, Management science, International Cooperation, Health Policy, International comparisons, Comparability, Public Health, Environmental and Occupational Health, Delphi method, Organisation for Economic Co-Operation and Development/organization & administration, General Medicine, Quality Indicators, Health Care/standards, Quality of Health Care/standards, Humans, Organisation for Economic Co-Operation and Development/standards, Conceptual framework, Performance measurement, Business, Organisation for Economic Co-Operation and Development, Health policy, Quality Indicators, Health Care, Quality of Health Care, Health care quality
Abstract

Objective: To review and update the conceptual framework, indicator content and research priorities of the Organisation for Economic Cooperation and Development's (OECD) Health Care Quality Indicators (HCQI) project, after a decade of collaborative work. Design: A structured assessment was carried out using a modified Delphi approach, followed by a consensus meeting, to assess the suite of HCQI for international comparisons, agree on revisions to the original framework and set priorities for research and development. Setting: International group of countries participating to OECD projects. Participants: Members of the OECD HCQI expert group. Results: A reference matrix, based on a revised performance framework, was used to map and assess all seventy HCQI routinely calculated by the OECD expert group. A total of 21 indicators were agreed to be excluded, due to the following concerns: (i) relevance, (ii) international comparability, particularly where heterogeneous coding practices might induce bias, (iii) feasibility, when the number of countries able to report was limited and the added value did not justify sustained effort and (iv) actionability, for indicators that were unlikely to improve on the basis of targeted policy interventions. Conclusions: The revised OECD framework for HCQI represents a new milestone of a long-standing international collaboration among a group of countries committed to building common ground for performance measurement. The expert group believes that the continuation of this work is paramount to provide decision makers with a validated toolbox to directly act on quality improvement strategies.

Published
2015

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