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2. Age Moderates the Effect of Obesity on Mortality Risk in Critically Ill Patients With COVID-19: A Nationwide Observational Cohort Study*

Author

den Uil, Corstiaan A., Termorshuizen, Fabian, Rietdijk, Wim J. R., Sablerolles, Roos S. G., van der Kuy, Hugo P. M., Haas, Lenneke E. M., van der Voort, Peter H. J., de Lange, Dylan W., Pickkers, Peter, de Keizer, Nicolette F., Arbous, M. S., Barnas, M. G. W., Boer, D. P., Bosman, R. J., Brunnekreef, G. B., de Bruin, M. Th., de Graaff, M. J., de Jong, R. M., de Meijer, A. R., de Ruijter, W., de Waal, R., Dijkhuizen, A., Dongelmans, D. A., Dormans, T. P. J., Draisma, A., Drogt, I., Eikemans, B. J. W., Elbers, P. W. G., Epker, J. L., Erkamp, M. L., Festen-Spanjer, B., Frenzel, T., Georgieva, L., Gritters, N. C., Hené, I. Z., Hoeksema, M., Holtkamp, J. W. M., Hoogendoorn, M. E., Jacobs, C. J. G. M., Janssen, I. T. A., Kieft, H., Koetsier, M. P., Koning, T. J. J., Kreeftenberg, H., Kusadasi, N., Lens, J. A., Lutisan, J. G., Mehagnoul-Schipper, D. J., Moolenaar, D., Nooteboom, F., Postma, N., Pruijsten, R. V., Ramnarain, D., Reidinga, A. C., Rengers, E., Rijkeboer, A. A., Rijpstra, T., Rozendaal, F. W., Schnabel, R. M., Silderhuis, V. M., Spijkstra, J. J., Spronk, P. E., te Velde, L. F., Urlings-Strop, L. C., van den Berg, A. E., van den Berg, R., van der Horst, I. C. C., van Driel, E. M., van Gulik, L., van Iersel, F. M., van Lieshout, M., van Oers, J. A. H., van Slobbe-Bijlsma, E. R., van Tellingen, M., Vandeputte, J., Verbiest, D. P., Versluis, D. J., Verweij, E., Vrolijk-de Mos, M., and Wesselink, R. M. J.

Published
2023
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3. Development and evaluation of regression tree models for predicting in-hospital mortality of a national registry of COVID-19 patients over six pandemic surges.

Author

Schut, M. C., Dongelmans, D. A., de Lange, D. W., Brinkman, S., Verbiest, D. P., te Velde, L. F., van Driel, E. M., Rijpstra, T., Elbers, P. H. J., Houwink, A. P. I., Georgieva, L., Verweij, E., de Jong, R. M., van Iersel, F. M., Koning, T. J. J., Rengers, E., Kusadasi, N., Erkamp, M. L., van den Berg, R., and Jacobs, C. J. M. G.

Subjects
REGRESSION trees, COVID-19, HOSPITAL mortality, REGRESSION analysis, COVID-19 pandemic, MEDICAL registries
Abstract

Background: Objective prognostic information is essential for good clinical decision making. In case of unknown diseases, scarcity of evidence and limited tacit knowledge prevent obtaining this information. Prediction models can be useful, but need to be not only evaluated on how well they predict, but also how stable these models are under fast changing circumstances with respect to development of the disease and the corresponding clinical response. This study aims to provide interpretable and actionable insights, particularly for clinicians. We developed and evaluated two regression tree predictive models for in-hospital mortality of COVID-19 patient at admission and 24 hours (24 h) after admission, using a national registry. We performed a retrospective analysis of observational routinely collected data. Methods: Two regression tree models were developed for admission and 24 h after admission. The complexity of the trees was managed via cross validation to prevent overfitting. The predictive ability of the model was assessed via bootstrapping using the Area under the Receiver-Operating-Characteristic curve, Brier score and calibration curves. The tree models were assessed on the stability of their probabilities and predictive ability, on the selected variables, and compared to a full-fledged logistic regression model that uses variable selection and variable transformations using splines. Participants included COVID-19 patients from all ICUs participating in the Dutch National Intensive Care Evaluation (NICE) registry, who were admitted at the ICU between February 27, 2020, and November 23, 2021. From the NICE registry, we included concerned demographic data, minimum and maximum values of physiological data in the first 24 h of ICU admission and diagnoses (reason for admission as well as comorbidities) for model development. The main outcome measure was in-hospital mortality. We additionally analysed the Length-of-Stay (LoS) per patient subgroup per survival status. Results: A total of 13,369 confirmed COVID-19 patients from 70 ICUs were included (with mortality rate of 28%). The optimism-corrected AUROC of the admission tree (with seven paths) was 0.72 (95% CI: 0.71–0.74) and of the 24 h tree (with 11 paths) was 0.74 (0.74–0.77). Both regression trees yielded good calibration and variable selection for both trees was stable. Patient subgroups comprising the tree paths had comparable survival probabilities as the full-fledged logistic regression model, survival probabilities were stable over six COVID-19 surges, and subgroups were shown to have added predictive value over the individual patient variables. Conclusions: We developed and evaluated regression trees, which operate at par with a carefully crafted logistic regression model. The trees consist of homogenous subgroups of patients that are described by simple interpretable constraints on patient characteristics thereby facilitating shared decision-making. [ABSTRACT FROM AUTHOR]

Published
2024
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5. Comparison of patient characteristics and long-term mortality between transferred and non-transferred COVID-19 patients in Dutch intensive care units: A national cohort study

Author

Wortel, Safira A., Bakhshi-Raiez, Ferishta, Termorshuizen, Fabian, de Lange, Dylan W., Dongelmans, Dave A., de Keizer, Nicolette F., Arbous, M. S., Barnas, M. G. W., Bindels, A. J. G. H., Boer, D. P., Bosman, R. J., Brunnekreef, G. B., de Bruin, M. Th., de Graaff, M., de Jong, R. M., de Meijer, A. R., de Ruijter, W., de Waal, R., Dijkhuizen, A., Dormans, T. P. J., Draisma, A., Drogt, I., Eikemans, B. J. W., Elbers, P. W. G., Epker, J. L., Erkamp, M. L., Festen-Spanjer, B., Frenzel, T., Gommers, D., Gritters, N. C., Hené, I. Z., Hoeksema, M., Holtkamp, J. W. M., Hoogendoorn, M. E., Houwink, A. P. I., Jacobs, C. J. M. G., Janssen, I. T. A., Kieft, H., Koetsier, M. P., Koning, T. J. J., Kusadasi, N., Lens, J. A., Lutisan, J. G., Mehagnoul-Schipper, D. J., Moolenaar, D., Nooteboom, F., Pruijsten, R. V., Ramnarain, D., Reidinga, A. C., Rengers, E., Rijkeboer, A. A., Rozendaal, F. W., Schnabel, R. M., Silderhuis, V. M., Spijkstra, J. J., Spronk, P., te Velde, L. F., Urlings-Strop, L. C., van Bussel, B. C. T., van den Berg, A. E., van den Berg, R., van der Voort, P. H. J., van Driel, E. M., van Gulik, L., van Iersel, F. M., van Lieshout, M., van Slobbe-Bijlsma, E. R., van Tellingen, M., Vandeputte, J., Verbiest, D. P., Versluis, D. J., Verweij, E., Mos, M. Vrolijk-de, Wesselink, R. M. J., Graduate School, Medical Informatics, APH - Methodology, APH - Quality of Care, Intensive Care Medicine, APH - Digital Health, Radiology and Nuclear Medicine, ACS - Microcirculation, and ANS - Neurovascular Disorders

Subjects
COVID-19, intrahospital transfer, severity of illness, intensive care unit, mortality
Abstract

Background: COVID-19 patients were often transferred to other intensive care units (ICUs) to prevent that ICUs would reach their maximum capacity. However, transferring ICU patients is not free of risk. We aim to compare the characteristics and outcomes of transferred versus non-transferred COVID-19 ICU patients in the Netherlands. Methods: We included adult COVID-19 patients admitted to Dutch ICUs between March 1, 2020 and July 1, 2021. We compared the patient characteristics and outcomes of non-transferred and transferred patients and used a Directed Acyclic Graph to identify potential confounders in the relationship between transfer and mortality. We used these confounders in a Cox regression model with left truncation at the day of transfer to analyze the effect of transfers on mortality during the 180 days after ICU admission. Results: We included 10,209 patients: 7395 non-transferred and 2814 (27.6%) transferred patients. In both groups, the median age was 64 years. Transferred patients were mostly ventilated at ICU admission (83.7% vs. 56.2%) and included a larger proportion of low-risk patients (70.3% vs. 66.5% with mortality risk

Published
2022

14. Novel Orally Formulated Mixed Micelles Optimize Vitamin K Absorption Under Bile-Deficient Conditions

Author

Apotheek Onderzoek 2, Metabole ziekten patientenzorg, Child Health, Infection & Immunity, Genetica Sectie Metabole Diagnostiek, DBG Metabole en Endocriene Ziekten, MDL patientenzorg, Rooimans, Thijs, Minderhoud, Tanca, Leal, Nerea, Vromans, Herman, van Nostrum, Cornelus, van Hasselt, Peter, Rodriguez, M., Sun, F., Oussoren, C., Slot, T. K., van der Ham, M., Janssens, G. E.P.J., de Sain-van der Velden, M. G.M., Houwen, R. H.J., de Koning, T. J., Hennink, W. E., Lipophilic Drug Delivery Despite Cholestasis Study Group, Apotheek Onderzoek 2, Metabole ziekten patientenzorg, Child Health, Infection & Immunity, Genetica Sectie Metabole Diagnostiek, DBG Metabole en Endocriene Ziekten, MDL patientenzorg, Rooimans, Thijs, Minderhoud, Tanca, Leal, Nerea, Vromans, Herman, van Nostrum, Cornelus, van Hasselt, Peter, Rodriguez, M., Sun, F., Oussoren, C., Slot, T. K., van der Ham, M., Janssens, G. E.P.J., de Sain-van der Velden, M. G.M., Houwen, R. H.J., de Koning, T. J., Hennink, W. E., and Lipophilic Drug Delivery Despite Cholestasis Study Group

Published
2021

21. De novo variants in CAMTA1 cause a syndrome variably associated with spasticity, ataxia, and intellectual disability

Author

Wijnen, I.G.M., Veenstra-Knol, Hermine E., Vansenne, F., Gerkes, E.H., Koning, T. de, Vos, Y.J., Tijssen, Marina A. J., Sival, D., Darin, N., Vanhoutte, E.K., Oosterloo, M., Pennings, M., Warrenburg, B.P.C. van de, Kamsteeg, E.J., Wijnen, I.G.M., Veenstra-Knol, Hermine E., Vansenne, F., Gerkes, E.H., Koning, T. de, Vos, Y.J., Tijssen, Marina A. J., Sival, D., Darin, N., Vanhoutte, E.K., Oosterloo, M., Pennings, M., Warrenburg, B.P.C. van de, and Kamsteeg, E.J.

Abstract

Contains fulltext : 220425.pdf (Publisher’s version ) (Closed access), Previously, intragenic CAMTA1 copy number variants (CNVs) have been shown to cause non-progressive, congenital ataxia with or without intellectual disability (OMIM#614756). However, ataxia, intellectual disability, and dysmorphic features were all incompletely penetrant, even within families. Here, we describe four patients with de novo nonsense, frameshift or missense CAMTA1 variants. All four patients predominantly manifested features of ataxia and/or spasticity. Borderline intellectual disability and dysmorphic features were both present in one patient only, and other neurological and behavioural symptoms were variably present. Neurodevelopmental delay was found to be mild. Our findings indicate that also nonsense, frameshift and missense variants in CAMTA1 can cause a spastic ataxia syndrome as the main phenotype.

Published
2020

42. Carbohydrate-deficient glycoprotein syndromes become congenital disorders of glycosylation: An updated nomenclature for CDG

Author

Aebi, M., Helenius, A., Schenk, B., Barone, R., Fiumara, A., Berger, E.G., Hennet, T., Imbach, T., Stutz, A., Bjursell, C., Uller, A., Wahlström, J.G., Briones, P., Cardo, E., Clayton, P., Winchester, B., Cormier-Dalre, V., de Lonlay, P., Cuer, M., Dupré, T., Seta, N., de Koning, T., Dorland, L., de Loos, F., Kupers, L., Fabritz, L., Hasilik, M., Marquardt, T., Niehues, R., Freeze, H., Grünewald, S., Heykants, L., Jaeken, J., Matthijs, G., Schollen, E., xKeir, G. Keir, Kjaergaard, S., Schwartz, M., Skovby, F., Klein, A., Roussel, P., Körner, C., Lübke, T., Thiel, C., von Figura, K., Koscielak, J., Krasnewich, D., Lehle, L., Peters, V., Raab, M., Saether, O., Schachter, H., Van Schaftingen, E., Verbert, A., Vilaseca, A., Wevers, R., and Yamashita, K.

Published
1999
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46. Diagnostic approach to paediatric movement disorders: a clinical practice guide.

Author

Brandsma, Rick, Egmond, Martje E, Tijssen, Marina A J, Eggink, H, Gelauff, J M, Koens, L H, de Koning, T J, Sival, D A, van der Stouwe, A M M, van der Veen, S, and Zutt, R

Subjects
MOVEMENT disorders, MEDICAL personnel, NUCLEOTIDE sequencing, GENETIC testing, ETIOLOGY of diseases
Abstract

Paediatric movement disorders (PMDs) comprise a large group of disorders (tics, myoclonus, tremor, dystonia, chorea, Parkinsonism, ataxia), often with mixed phenotypes. Determination of the underlying aetiology can be difficult given the broad differential diagnosis and the complexity of the genotype–phenotype relationships. This can make the diagnostic process time‐consuming and difficult. In this overview, we present a diagnostic approach for PMDs, with emphasis on genetic causes. This approach can serve as a framework to lead the clinician through the diagnostic process in eight consecutive steps, including recognition of the different movement disorders, identification of a clinical syndrome, consideration of acquired causes, genetic testing including next‐generation sequencing, post‐sequencing phenotyping, and interpretation of test results. The aim of this approach is to increase the recognition and diagnostic yield in PMDs. What this paper adds: An up‐to‐date description and diagnostic framework for testing of paediatric movement disorders is presented.The framework helps to determine which patients will benefit from next‐generation sequencing. What this paper adds: An up‐to‐date description and diagnostic framework for testing of paediatric movement disorders is presented.The framework helps to determine which patients will benefit from next‐generation sequencing. [ABSTRACT FROM AUTHOR]

Published
2021
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47. Detecting intratumoral heterogeneity of EGFR activity by liposome-based in vivo transfection of a fluorescent biosensor

Author

Weitsman, G, Mitchell, NJ, Evans, R, Cheung, A, Kalber, TL, Bofinger, R, Fruhwirth, GO, Keppler, M, Wright, ZVF, Barber, PR, Gordon, P, de Koning, T, Wulaningsih, W, Sander, K, Vojnovic, B, Ameer-Beg, S, Lythgoe, M, Arnold, JN, Årstad, E, Festy, F, Hailes, HC, Tabor, AB, and Ng, T

Subjects
Mammary Neoplasms, Experimental, Nitric Oxide Synthase Type II, Breast Neoplasms, Biosensing Techniques, Transfection, Fluorescence, Neoplasm Proteins, ErbB Receptors, Mice, Cell Line, Tumor, Liposomes, Tumor Microenvironment, Animals, Humans, Female, Original Article
Abstract

Despite decades of research in the epidermal growth factor receptor (EGFR) signalling field, and many targeted anti-cancer drugs that have been tested clinically, the success rate for these agents in the clinic is low, particularly in terms of the improvement of overall survival. Intratumoral heterogeneity is proposed as a major mechanism underlying treatment failure of these molecule-targeted agents. Here we highlight the application of fluorescence lifetime microscopy (FLIM)-based biosensing to demonstrate intratumoral heterogeneity of EGFR activity. For sensing EGFR activity in cells, we used a genetically encoded CrkII-based biosensor which undergoes conformational changes upon tyrosine-221 phosphorylation by EGFR. We transfected this biosensor into EGFR-positive tumour cells using targeted lipopolyplexes bearing EGFR-binding peptides at their surfaces. In a murine model of basal-like breast cancer, we demonstrated a significant degree of intratumoral heterogeneity in EGFR activity, as well as the pharmacodynamic effect of a radionuclide-labeled EGFR inhibitor in situ. Furthermore, a significant correlation between high EGFR activity in tumour cells and macrophage-tumour cell proximity was found to in part account for the intratumoral heterogeneity in EGFR activity observed. The same effect of macrophage infiltrate on EGFR activation was also seen in a colorectal cancer xenograft. In contrast, a non-small cell lung cancer xenograft expressing a constitutively active EGFR conformational mutant exhibited macrophage proximity-independent EGFR activity. Our study validates the use of this methodology to monitor therapeutic response in terms of EGFR activity. In addition, we found iNOS gene induction in macrophages that are cultured in tumour cell-conditioned media as well as an iNOS activity-dependent increase in EGFR activity in tumour cells. These findings point towards an immune microenvironment-mediated regulation that gives rise to the observed intratumoral heterogeneity of EGFR signalling activity in tumour cells in vivo.

Published
2017
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48. Injuries due to foreign body aspirations in Georgia: A prevention perspective

Author

Gvetadze, P. Chkhaidze, I. Baldas, S. Comoretto, R. Gregori, D. Berchialla, P. Rodriguez, H. Zaupa, P. Spitzer, P. Demetriades, C. Slapák, I. Sokolova, L. Petridou, E. Antonio Caldeira Pais Clemente, M. Jakubíková, J. Van As, S. De Koning, T. Passali, D. Cuestas, G. Bouchikhi, N. Chinsky, A. Ro, H. Tortosa, S. Alassia, O. Abete, F. Sica, G. Di Blasio, A. Rodríguez, V. Taire, D. Paoli, B. Rene Marquez, C. Razetti, J. Adolfo Mariotti, C. Héctor Ariel, A. Zanetta, A. Dario, F. Milena Pabón, S. Quijano, A. Elena Nieto, M. Villca, N. Brkic, F. Reis, M. Manrique, D. Nkodo, Y. Ludemann, J. Cheng peng, J. Barón Puentes, O.U. Mladina, R. Gomez De La Rosa, E. Kalakouta, O. eas Melis, A. Zeitouni, F. Máchalová, M. Slapak, J. Pecková, P. Caye-Thomasen, P. Silva Chacon, F. Parker, J. Elsheikh, E. Ragab, A. Pitkäranta, A. Contencin Necker, P. Derelle, J. Duwelz, M. Francois, M. Pezzettigotta, S. Righini, C. Buzarov, J. Bernhard, R. Jahnke, V. Onder, G. Zieriacks, P. Siegfried, K. Koitschev, A. Kalampoki, V. Simasko, N. Skoulakis, C. Gulati, A. Camaioni, A. Cutrone, C. Gaudini, E. Grasso, D. Mansi, N. Messi, G. Orlando, C. Preziosi, S. Sorrentini, I. Trozzi, M. o Vigo, A. Villari, G. Cesare Passali, G. Maria Passali, F. Piantanida, R. Giordano, C. Mercuri, L. Cecconi, A. Giovari, M. Nishida, Y. Ussatayeva, G. Antonio De Hoyos Parra, R. Gonzalez, J.L. Eleuterio Gonzá lez, J. Emmanuel Ologe, F. Nasrullah, M. Melendez, A. Milanes, R. Chmielik, M. Belchior, T. Dan Cobzeanu, M. Cristian Gheorghe, D. Iorgulescu, A. Caius-Codrut Toader, M. Barkociová, J. Havelkova, B. Janka Koman, A. Zargi, M. Pumarola, F. Rubio, L. Perniás Peco, K. Stierna, P. Hsu, W. Arj-Ong, S. Chomchai, C. Chotigavanich, C. Hoep, L. Rinkel, R. Berraies, A. Aydin Baskent, E. Sarper Erikci, V. Onerci, M. Graham, J. Khwaja, S. Raine, C. Haloob, N. Doassans Goḿez Haedo, I. Mehta, D. Casselbrant, M. Susy Safe Working Group

Abstract

Background: Suffocation due to foreign bodies (FB) is a leading cause of death in children aged 0-3. No data from the former U.S.S.R. are available in the international scientific literature. Methods: Consecutive patients admitted at the Iashvili Central Children Hospital in Tbilisi, Georgia from 1989 to 2011 were analyzed. Injuries in the upper airways due to foreign bodies' inhalation were collected and compared with the Susy Safe Registry and the pooled estimates of the meta-analysis. Results: 2896 cases were collected. Distribution of injuries in children younger than 3 years was significantly higher than in the Susy Safe Registry and in the "High-Income" countries in the meta-analysis. Percentage of injuries due to organic objects (86%) was significantly higher than in published data. Conclusions: Since Georgia is not showing any substantial difference, both in epidemiology and treatment of foreign bodies injuries, as compared to the other case series, translation of public health initiatives from other most advanced prevention experiences is possible and it is likely to be effective. Level of evidence: Level V, Epidemiological case series. © 2015 Elsevier Ireland Ltd.

Published
2016

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