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114 results on '"Wiel L"'

1. Real-Time Outlier Detection in Time Series Data of Water Sensors

Author

van de Wiel, L., van Es, D. M., Feelders, A. J., Goos, Gerhard, Founding Editor, Hartmanis, Juris, Founding Editor, Bertino, Elisa, Editorial Board Member, Gao, Wen, Editorial Board Member, Steffen, Bernhard, Editorial Board Member, Woeginger, Gerhard, Editorial Board Member, Yung, Moti, Editorial Board Member, Lemaire, Vincent, editor, Malinowski, Simon, editor, Bagnall, Anthony, editor, Guyet, Thomas, editor, Tavenard, Romain, editor, and Ifrim, Georgiana, editor

Published
2020
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2. Addressing the consequences of the corporatization of reproductive medicine

Author

Attinger, SA, Jackson, E, Karpin, I, Kerridge, I, Newson, AJ, Stewart, C, van de Wiel, L, Lipworth, W, Attinger, SA, Jackson, E, Karpin, I, Kerridge, I, Newson, AJ, Stewart, C, van de Wiel, L, and Lipworth, W

Abstract

In Australia and the UK, commercialization and corporatization of assisted reproductive technologies have created a marketplace of clinics, products, and services. While this has arguably increased choice for patients, 'choice', shaped by commercial imperatives may not mean better-quality care. At present, regulation of clinics (including clinic-corporations) and clinicians focuses on the doctor-patient dyad and the clinic-consumer dyad. Scant attention has been paid to the conflicts between the clinic-corporation's duty to its shareholders and investors, the medical profession's duty to the corporations within which they practice, and the obligations of both clinicians and corporations to patients and to health systems. Frameworks of regulation based in corporate governance and business ethics, such as stakeholder models and 'corporate social responsibility', have well-recognized limits and may not translate well into healthcare settings. This means that existing governance frameworks may not meet the needs of patients or health systems. We argue for the development of novel regulatory approaches that more explicitly characterize the obligations that both corporations and clinicians in corporate environments have to patients and to society, and that promote fulfilment of these obligations. We consider mechanisms for application in the multi-jurisdictional setting of Australia, and the single jurisdictional settings of the UK.

Published
2024

5. Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction

Author

den Hoed, Joery, de Boer, Elke, Voisin, N, Dingemans, A, Guex, N, Wiel, L, Nellaker, C, Amudhavalli, S, Banka, S, Bena, F, Ben-Zeev, B, Bonagura, V, Bruel, A, Brunet, T, Brunner, H. G., Chew, H. B., Chrast, J., Cimbalistienė, Loreta, Coon, Hilary, study, The DDD, Délot, Emmanuèlle C, Démurger, Florence, Denommé-Pichon, Anne-Sophie, Depienne, C., Donnai, Dian, Dyment, David A, Elpeleg, Orly, Faivre, L, Gilissen, Christian, Granger, L., Haber, Benjamin, Hachiya, Yasuo, Abedi, Yasmin Hamzavi, Hanebeck, Jennifer, Hehir-Kwa, Jayne Y, Horist, Brooke, Itai, Toshiyuki, Jackson, Adam, Jewell, Rosalyn, Jones, Kelly L., Joss, Shelagh, Kashii, Hirofumi, Kato, Mitsuhiro, Kattentidt-Mouravieva, Anja A, Kok, Fernando, Kotzaeridou, Urania, Krishnamurthy, Vidya, Kučinskas, Vaidutis, Kuechler, Alma, Lavillaureix, Alinoë, Liu, Pengfei, Manwaring, Linda, Matsumoto, Naomichi, Mazel, Benoît, McWalter, Kirsty, Meiner, Vardiella, Mikati, Mohamad A., Miyatake, Satoko, Mizuguchi, Takeshi, Moey, Lip H., Mohammed, Shehla, Mor-Shaked, Hagar, Mountford, Hayley, Newbury-Ecob, Ruth, Odent, Sylvie, Orec, Laura, Osmond, Matthew, Palculict, Timothy Blake, Parker, Michael, Petersen, Andrea K., Pfundt, Rolph, Preikšaitienė, Eglė, Radtke, Kelly, Ranza, Emmanuelle, Rosenfeld, Jill A., Santiago-Sim, Teresa, Schwager, Caitlin, Sinnema, Margje, Blok, Lot Snijders, Spillmann, Rebecca C., Stegmann, Alexander P A, Thiffault, Isabelle, Tran, Linh, Vaknin-Dembinsky, Adi, Vedovato-dos-Santos, Juliana H., Schrier Vergano, Samantha A., Vilain, Eric, Vitobello, Antonio, Wagner, Matias, Waheeb, Androu, Willing, Marcia C., Zuccarelli, Britton D, Kini, Usha, Newbury, Dianne F., Kleefstra, Tjitske, Reymond, Alexandre, Fisher, Simon E., and Vissers, Lisenka E L M

Abstract

Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression and a severe phenotype. Contrastingly, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay and encode truncated proteins, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.

Published
2020

6. Evidence for 28 genetic disorders discovered by combining healthcare and research data

Author

Kaplanis, J., Samocha, K.E., Wiel, L., Zhang, Z., Arvai, K.J., Eberhardt, R.Y., Gallone, G., Lelieveld, S.H., Martin, H.C., McRae, J.F., Short, P.J., Torene, R.I., de Boer, E., Danecek, P., Gardner, E.J., Huang, N., Lord, J., Martincorena, I., Pfundt, R., Reijnders, M.R.F., Yeung, A., Yntema, H.G., Deciphering Developmental Disorders Study, Vissers, L.E.L.M., Juusola, J., Wright, C.F., Brunner, H.G., Firth, H.V., FitzPatrick, D.R., Barrett, J.C., Hurles, M.E., Gilissen, C., and Retterer, K.

Abstract

De novo mutations in protein-coding genes are a well-established cause of developmental disorders. However, genes known to be associated with developmental disorders account for only a minority of the observed excess of such de novo mutations. Here, to identify previously undescribed genes associated with developmental disorders, we integrate healthcare and research exome-sequence data from 31,058 parent–offspring trios of individuals with developmental disorders, and develop a simulation-based statistical test to identify gene-specific enrichment of de novo mutations. We identified 285 genes that were significantly associated with developmental disorders, including 28 that had not previously been robustly associated with developmental disorders. Although we detected more genes associated with developmental disorders, much of the excess of de novo mutations in protein-coding genes remains unaccounted for. Modelling suggests that more than 1,000 genes associated with developmental disorders have not yet been described, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of genes associated with developmental disorders.

Published
2020

7. Real-time Outlier Detection in Time Series Data of Water Sensors

Author

Wiel, L. van de, Feelders, A.J. (Thesis Advisor), Krempl, G.M., Wiel, L. van de, Feelders, A.J. (Thesis Advisor), and Krempl, G.M.

Abstract

We compare multiple methods for real time outlier detection in time series data of water sensors. We present an outlier detection pipeline for this purpose. Multivariate models as well as univariate models are compared empirically by adding simulated outliers to the data to assess model performance. Quantile regression performed by the multi layer perceptron model using the tilted loss function is apt to model time series in a multivariate approach, provided we have access to reliable, correlated time series. Univariate models like auto-regressive models can be useful for detecting specific kinds of outliers such as extreme values. We show that the models are able to detect realistic, real life outliers.

Published
2020

8. De novo CLTC variants are associated with a variable phenotype from mild to severe intellectual disability, microcephaly, hypoplasia of the corpus callosum, and epilepsy

Author

Sa, MJN, Venselaar, H, Wiel, L, Trimouille, A, Lasseaux, E, Naudion, S, Lacombe, D, Piton, A, Vincent-Delorme, C, Zweier, C, Reis, A, Trollmann, R, Ruiz, A, Gabau, E, Vetro, A, Guerrini, R, Bakhtiari, S, Kruer, MC, Amor, DJ, Cooper, MS, Bijlsma, EK, Barakat, TS, van Dooren, MF, van Slegtenhorst, M, Pfundt, R, Gilissen, C, Willemsen, MA, de Vries, BBA, de Brouwer, APM, Koolen, DA, Sa, MJN, Venselaar, H, Wiel, L, Trimouille, A, Lasseaux, E, Naudion, S, Lacombe, D, Piton, A, Vincent-Delorme, C, Zweier, C, Reis, A, Trollmann, R, Ruiz, A, Gabau, E, Vetro, A, Guerrini, R, Bakhtiari, S, Kruer, MC, Amor, DJ, Cooper, MS, Bijlsma, EK, Barakat, TS, van Dooren, MF, van Slegtenhorst, M, Pfundt, R, Gilissen, C, Willemsen, MA, de Vries, BBA, de Brouwer, APM, and Koolen, DA

Abstract

PURPOSE: To delineate the genotype-phenotype correlation in individuals with likely pathogenic variants in the CLTC gene. METHODS: We describe 13 individuals with de novo CLTC variants. Causality of variants was determined by using the tolerance landscape of CLTC and computer-assisted molecular modeling where applicable. Phenotypic abnormalities observed in the individuals identified with missense and in-frame variants were compared with those with nonsense or frameshift variants in CLTC. RESULTS: All de novo variants were judged to be causal. Combining our data with that of 14 previously reported affected individuals (n = 27), all had intellectual disability (ID), ranging from mild to moderate/severe, with or without additional neurologic, behavioral, craniofacial, ophthalmologic, and gastrointestinal features. Microcephaly, hypoplasia of the corpus callosum, and epilepsy were more frequently observed in individuals with missense and in-frame variants than in those with nonsense and frameshift variants. However, this difference was not significant. CONCLUSIONS: The wide phenotypic variability associated with likely pathogenic CLTC variants seems to be associated with allelic heterogeneity. The detailed clinical characterization of a larger cohort of individuals with pathogenic CLTC variants is warranted to support the hypothesis that missense and in-frame variants exert a dominant-negative effect, whereas the nonsense and frameshift variants would result in haploinsufficiency.

Published
2020

11. A Systematic Review of Neuropsychological Tests for the Assessment of Dementia in Non-Western, Low-Educated or Illiterate Populations

Author

Franzen, S., Berg, E. (Esther) van den, Goudsmit, M., Jurgens, C.K., Wiel, L., Kalkisim, Y., Uysal-Bozkir, O., Ayhan, Y., Nielsen, T.R., Papma, J.M. (Janne), Franzen, S., Berg, E. (Esther) van den, Goudsmit, M., Jurgens, C.K., Wiel, L., Kalkisim, Y., Uysal-Bozkir, O., Ayhan, Y., Nielsen, T.R., and Papma, J.M. (Janne)

Abstract

Objective: Neuropsychological tests are important instruments to determine a cognitive profile, giving insight into the etiology of dementia; however, these tests cannot readily be used in culturally diverse, low-educated populations, due to their dependence upon (Western) culture, education, and literacy. In this review we aim to give an overview of studies investigating domain-specific cognitive tests used to assess dementia in non-Western, low-educated populations. The second aim was to examine the quality of these studies and of the adaptations for culturally, linguistically, and educationally diverse populations. Method: A systematic review was performed using six databases, without restrictions on the year or language of publication. Results: Forty-four studies were included, stemming mainly from Brazil, Hong Kong, Korea, and considering Hispanics/Latinos residing in the USA. Most studies focused on Alzheimer’s disease (n = 17) or unspecified dementia (n = 16). Memory (n = 18) was studied most often, using 14 different tests. The traditional Western tests in the domains of attention (n = 8) and construction (n = 15), were unsuitable for low-educated patients. There was little variety in instruments measuring executive functioning (two tests, n = 13), and language (n

Published
2019
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14. The Geodetic Signature of the Earthquake Cycle at Subduction Zones: Model Constraints on the Deep Processes

Author

Govers, R., Furlong, K.P., van de Wiel, L., Herman, M.W., Broerse, T., Tectonophysics, and Dep Aardwetenschappen

Subjects
Geophysics, Megathrust earthquakes, Afterslip, Viscoelastic relaxation, Seismic coupling, Aseismic creep
Abstract

Recent megathrust events in Tohoku (Japan), Maule (Chile), and Sumatra (Indonesia) were well recorded. Much has been learned about the dominant physical processes in megathrust zones: (partial) locking of the plate interface, detailed coseismic slip, relocking, afterslip, viscoelastic mantle relaxation, and interseismic loading. These and older observations show complex spatial and temporal patterns in crustal deformation and displacement, and significant differences among different margins. A key question is whether these differences reflect variations in the underlying processes, like differences in locking, or the margin geometry, or whether they are a consequence of the stage in the earthquake cycle of the margin. Quantitative models can connect these plate boundary processes to surficial and far-field observations. We use relatively simple, cyclic geodynamic models to isolate the first-order geodetic signature of the megathrust cycle. Coseismic and subsequent slip on the subduction interface is dynamically (and consistently) driven. A review of global preseismic, coseismic, and postseismic geodetic observations, and of their fit to the model predictions, indicates that similar physical processes are active at different margins. Most of the observed variability between the individual margins appears to be controlled by their different stages in the earthquake cycle. The modeling results also provide a possible explanation for observations of tensile faulting aftershocks and tensile cracking of the overriding plate, which are puzzling in the context of convergence/compression. From the inversion of our synthetic GNSS velocities we find that geodetic observations may incorrectly suggest weak locking of some margins, for example, the west Aleutian margin.

Published
2018

15. Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction

Author

Wesdorp, M. (Mieke), de Koning Gans, P.A.M. (P. A M), Schraders, M. (Margit), Oostrik, J. (Jaap), Huynen, M. (Martijn), Venselaar, H. (Hanka), Beynon, A.J. (Andy J.), van Gaalen, J. (Judith), Piai, V. (Vitória), Voermans, N.C. (Nicol), Rossum, M.M. (Michelle) van, Hartel, B.P. (Bas P.), Lelieveld, S.H. (Stefan H.), Wiel, L. (Laurens), Verbist, B. (Berit), Rotteveel, L.J. (Liselotte J.), Dooren, M.F. (Marieke) van, Lichtner, P. (Peter), Kunst, H.P.M. (Henricus P. M.), Feenstra, I. (Ilse), Admiraal, R.J.C. (Ronald J. C.), van Dooren, M.F. (M. F.), de Gier, H.H.W. (H. H.W.), Hoefsloot, E.H. (Lies), Schroeff, M.P. (Marc) van der, Kant, S.G. (Sarina), Rotteveel, L.J.C. (L. J.C.), Frints, S.G.M. (Suzanna), Hof, J.R. (J. R.), Stokroos, R.J. (Robert Jan), Vanhoutte, E.K. (Els), Admiraal, R.J. (Ronald), Feenstra, I. (I.), Kremer, H. (H.), Kunst, H.P.M. (Henricus P.M.), Pennings, R.J.E. (Ronald J.E.), Yntema, H.G. (H. G.), Essen, J.A. (Anthonie) van, Free, R.H. (Rolien), Klein-Wassink, J.S. (J. S.), Yntema, H.G., Pennings, R.J.E. (Ronald J. E.), Kremer, H. (Hannie), Wesdorp, M. (Mieke), de Koning Gans, P.A.M. (P. A M), Schraders, M. (Margit), Oostrik, J. (Jaap), Huynen, M. (Martijn), Venselaar, H. (Hanka), Beynon, A.J. (Andy J.), van Gaalen, J. (Judith), Piai, V. (Vitória), Voermans, N.C. (Nicol), Rossum, M.M. (Michelle) van, Hartel, B.P. (Bas P.), Lelieveld, S.H. (Stefan H.), Wiel, L. (Laurens), Verbist, B. (Berit), Rotteveel, L.J. (Liselotte J.), Dooren, M.F. (Marieke) van, Lichtner, P. (Peter), Kunst, H.P.M. (Henricus P. M.), Feenstra, I. (Ilse), Admiraal, R.J.C. (Ronald J. C.), van Dooren, M.F. (M. F.), de Gier, H.H.W. (H. H.W.), Hoefsloot, E.H. (Lies), Schroeff, M.P. (Marc) van der, Kant, S.G. (Sarina), Rotteveel, L.J.C. (L. J.C.), Frints, S.G.M. (Suzanna), Hof, J.R. (J. R.), Stokroos, R.J. (Robert Jan), Vanhoutte, E.K. (Els), Admiraal, R.J. (Ronald), Feenstra, I. (I.), Kremer, H. (H.), Kunst, H.P.M. (Henricus P.M.), Pennings, R.J.E. (Ronald J.E.), Yntema, H.G. (H. G.), Essen, J.A. (Anthonie) van, Free, R.H. (Rolien), Klein-Wassink, J.S. (J. S.), Yntema, H.G., Pennings, R.J.E. (Ronald J. E.), and Kremer, H. (Hannie)

Abstract

Unraveling the causes and pathomechanisms of progressive disorders is essential for the development of therapeutic strategies. Here, we identified heterozygous pathogenic missense variants of LMX1A in two families of Dutch origin with progressive nonsyndromic hearing impairment (HI), using whole exome sequencing. One variant, c.721G > C (p.Val241Leu), occurred de novo and is predicted to affect the homeodomain of LMX1A, which is essential for DNA binding. The second variant, c.290G > C (p.Cys97Ser), predicted to affect a zinc-binding residue of the second LIM domain that is involved in protein–protein interactions. Bi-allelic deleterious variants of Lmx1a are associated with a complex phenotype in mice, including deafness and vestibular defects, due to arrest of inner ear development. Although Lmx1a mouse mutants demonstrate neurological, skeletal, pigmentation and reproductive system abnormalities, no syndromic features were present in the participating subjects of either family. LMX1A has previously been suggested as a candidate gene for intellectual disability, but our data do not support this, as affected subjects displayed normal cognition. Large variability was observed in the age of onset (a)symmetry, severity and progression rate of HI. About half of the affected individuals displayed vestibular dysfunction and experienced symptoms thereof. The late-onset progressive phenotype and the absence of cochleovestibular malformations on computed tomography scans indicate that heterozygous defects of LMX1A do not result in severe developmental abnormalities in humans. We propose that a single LMX1A wild-type copy is sufficient for normal development but insufficient for maintenance of cochleovestibular function. Alternatively, minor cochleovestibular developmental abnormalities could eventually lead to the progressive phenotype seen in the families.

Published
2018
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16. Performance optimization of solving methods in ELEFANT and development of simPyFEM: An efficient educational tool for geodynamic simulations using Python

Author

Mos, J., Thieulot, C. (Thesis Advisor), Wiel, L. van de, Mos, J., Thieulot, C. (Thesis Advisor), and Wiel, L. van de

Abstract

Numerical models are used to develop a better physical understanding of small and large scale geodynamic processes over geological time scales. Through continuous development of computational techniques and methods, the accuracy and resolution of the models increases each year. Simulating geodynamic processes such as mantle convection or subduction requires the solve of a linear system in which efficient solvers and preconditioners can be used to yield low computation times and thus optimal performance. Many state of the art codes are fully parallel but even then can require multiple days or weeks to run large simulations. Implementing an efficient solver and preconditioner into ELEFANT is the first step into optimizing its performance. A free and open source package for scientific computing (PETSc) is used to facilitate this process. The second part of this thesis consists of the development of an educational tool for geodynamics called simPyFEM. By translating and optimizing a pre-exisiting code (simpleFEM) from Fortran to Python, its usability and versatility are improved. This modernization is inviting to students who are new to geodynamic modelling and want to experience the effect, on an educational level, of changing parameter such as viscosity, density and gravity.

Published
2018

18. Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction

Author

Wesdorp, M, Gans, P, Schraders, M, Oostrik, J, Huynen, MA, Venselaar, H, Beynon, AJ, van Gaalen, J, Piai, V, Voermans, N, van Rossum, MM, Hartel, B P, Lelieveld, SH, Wiel, L, Verbist, B, Rotteveel, LJ, van Dooren, Marieke, Lichtner, P, Kunst, HPM, Feenstra, I, Admiraal, RJC, Yntema, HG, Hoefsloot, EH, Pennings, RJE, Kremer, H, Wesdorp, M, Gans, P, Schraders, M, Oostrik, J, Huynen, MA, Venselaar, H, Beynon, AJ, van Gaalen, J, Piai, V, Voermans, N, van Rossum, MM, Hartel, B P, Lelieveld, SH, Wiel, L, Verbist, B, Rotteveel, LJ, van Dooren, Marieke, Lichtner, P, Kunst, HPM, Feenstra, I, Admiraal, RJC, Yntema, HG, Hoefsloot, EH, Pennings, RJE, and Kremer, H

Published
2018

20. Cortical phase changes measured using 7-T MRI in subjects with subjective cognitive impairment, and their association with cognitive function

Author

Rooden, S. van, Buijs, M., Vliet, M.E. van, Versluis, M.J., Webb, A.G., Oleksik, A.M., Wiel, L. van de, Middelkoop, H.A.M., Blauw, G.J., Weverling-Rynsburger, A.W.E., Goos, J.D.C., Flier, W.M. van der, Koene, T., Scheltens, P., Barkhof, F., Rest, O. van de, Slagboom, P.E., Buchem, M.A. van, and Grond, J. van der

Subjects
cognition, brain imaging, Alzheimer's disease, phase, AD pathology, human 7-T MRI, subjective cognitive impairment
Published
2016

22. KeCo: Kernel-Based Online Co-agreement Algorithm

Author

Wiel, L., Heskes, T., Levin, E., Japkowicz, N., Matwin, S., Japkowicz, N., and Matwin, S.

Subjects
Computer science, Non-linear, Biomedical Innovation, Large-scale, computer.software_genre, Machine learning, Kernel (linear algebra), Life, Online, Online algorithm, Biology, Co-agreement, Semi-supervised, business.industry, Data Science, Online machine learning, Multi-view, Classification, Kernel, MSB - Microbiology and Systems Biology, Kernel (statistics), Lecture Notes in Computer Science, ELSS - Earth, Life and Social Sciences, Artificial intelligence, Data mining, business, Healthy Living, Algorithm, computer
Abstract

We propose a kernel-based online semi-supervised algorithm that is applicable for large scale learning tasks. In particular, we use a multi-view learning framework and a co-agreement strategy to take into account unlabelled data and to improve classification performance of the algorithm. Unlike the standard online methods our algorithm is naturally applicable to many real-world situations where data is available in multiple representations. In addition our online algorithm allows learning non-linear relations in the data via kernel functions, that are efficiently embedded into the formulation of the algorithm. We test performance of the algorithm on several large-scale LIBSVM and UCI benchmark datasets and demonstrate improved performance in comparison to standard online learning methods. Last but not least, we make a Python implementation of our algorithm available for download (Available at https://github.com/laurensvdwiel/KeCo).

Published
2015

24. KeCo: Kernel-Based Online Co-agreement Algorithm

Author

Japkowicz, N., Matwin, S., Wiel, L., Heskes, T., Levin, E., Japkowicz, N., Matwin, S., Wiel, L., Heskes, T., and Levin, E.

Abstract

Contains fulltext : 147276.pdf (preprint version ) (Closed access)

Published
2015

25. Basal ganglia volume is strongly related to P3 event-related potential in premanifest Huntington's disease

Author

Jurgens, C.K., Hiele, K. van der, Reijntjes, R.H.A.M., Wiel, L. van de, Witjes-Ane, M.N.W., Grond, J. van der, Roos, R.A.C., Middelkoop, H.A.M., and Dijk, J.G. van

Subjects
Huntington's disease premanifest basal ganglia P3 erp motor
Abstract

Background: The P3 event-related potential (ERP) is presumably partly generated by the basal ganglia. Because degeneration of these brain structures starts many years before clinical disease onset in Huntington's disease (HD), studying the interplay between P3 characteristics and basal ganglia volumes in 'premanifest' carriers might lead to new insights into the disease process. Methods: Fourteen premanifest HD mutation carriers and twelve non-mutation carriers underwent clinical, MRI and P3-ERP investigations. The P3 was measured during the Sustained Attention to Response Task. Results: P3 amplitude and latency did not differ between groups. In carriers, longer P3 latency during Go-trials was strongly associated with smaller caudate, putamen and globus pallidus volumes (r values up to -0.827, P

Published
2011

26. Delineation of the clinical phenotype caused by de novo CLTC variants

Author

Sa, M. J. Nabais, Venselaar, H., Wiel, L., Trimouille, A., Lasseaux, E., Naudion, S., Lacombe, D., Piton, A., Vincent-Delorme, C., Zweier, C., André Reis, Trollmann, R., Ruiz, A., Gabau, E., Vetro, A., Guerrini, R., Bakhtiari, S., Kruer, M., Crompton, K., Amor, D. J., Bijlsma, E. K., Barakat, T. S., Dooren, M. F., Pfundt, R., Gilissen, C., Vries, B. B., Brouwer, A. P., and Koolen, D. A.

27. Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction

Author

den Hoed, J., de Boer, E., Voisin, N., Dingemans, A.J.M., Guex, N., Wiel, L., Nellaker, C., Amudhavalli, S.M., Banka, S., Bena, F.S., Ben-Zeev, B., Bonagura, V.R., Bruel, A.-L., Brunet, T., Brunner, H.G., Chew, H.B., Chrast, J., Cimbalistienė, L., Coon, H., Délot, E.C., Démurger, F., Denommé-Pichon, A.-S., Depienne, C., Donnai, D., Dyment, D.A., Elpeleg, O., Faivre, L., Gilissen, C., Granger, L., Haber, B., Hachiya, Y., Abedi, Y.H., Hanebeck, J., Hehir-Kwa, J.Y., Horist, B., Itai, T., Jackson, A., Jewell, R., Jones, K.L., Joss, S., Kashii, H., Kato, M., Kattentidt-Mouravieva, A.A., Kok, F., Kotzaeridou, U., Krishnamurthy, V., Kučinskas, V., Kuechler, A., Lavillaureix, A., Liu, P., Manwaring, L., Matsumoto, N., Mazel, B., McWalter, K., Meiner, V., Mikati, M.A., Miyatake, S., Mizuguchi, T., Moey, L.H., Mohammed, S., Mor-Shaked, H., Mountford, H., Newbury-Ecob, R., Odent, S., Orec, L., Osmond, M., Palculict, T.B., Parker, M., Petersen, A., Pfundt, R., Preikšaitienė, E., Radtke, K., Ranza, E., Rosenfeld, J.A., Santiago-Sim, T., Schwager, C., Sinnema, M., Blok, L.S., Spillmann, R.C., Stegmann, A.P.A., Thiffault, I., Tran, L., Vaknin-Dembinsky, A., Vedovato-dos-Santos, J.H., Vergano, S.A., Vilain, E., Vitobello, A., Wagner, M., Waheeb, A., Willing, M., Zuccarelli, B., Kini, U., Newbury, D.F., Kleefstra, T., Reymond, A., Fisher, S.E., Vissers, L.E.L.M., den Hoed, J., de Boer, E., Voisin, N., Dingemans, A.J.M., Guex, N., Wiel, L., Nellaker, C., Amudhavalli, S.M., Banka, S., Bena, F.S., Ben-Zeev, B., Bonagura, V.R., Bruel, A.-L., Brunet, T., Brunner, H.G., Chew, H.B., Chrast, J., Cimbalistienė, L., Coon, H., Délot, E.C., Démurger, F., Denommé-Pichon, A.-S., Depienne, C., Donnai, D., Dyment, D.A., Elpeleg, O., Faivre, L., Gilissen, C., Granger, L., Haber, B., Hachiya, Y., Abedi, Y.H., Hanebeck, J., Hehir-Kwa, J.Y., Horist, B., Itai, T., Jackson, A., Jewell, R., Jones, K.L., Joss, S., Kashii, H., Kato, M., Kattentidt-Mouravieva, A.A., Kok, F., Kotzaeridou, U., Krishnamurthy, V., Kučinskas, V., Kuechler, A., Lavillaureix, A., Liu, P., Manwaring, L., Matsumoto, N., Mazel, B., McWalter, K., Meiner, V., Mikati, M.A., Miyatake, S., Mizuguchi, T., Moey, L.H., Mohammed, S., Mor-Shaked, H., Mountford, H., Newbury-Ecob, R., Odent, S., Orec, L., Osmond, M., Palculict, T.B., Parker, M., Petersen, A., Pfundt, R., Preikšaitienė, E., Radtke, K., Ranza, E., Rosenfeld, J.A., Santiago-Sim, T., Schwager, C., Sinnema, M., Blok, L.S., Spillmann, R.C., Stegmann, A.P.A., Thiffault, I., Tran, L., Vaknin-Dembinsky, A., Vedovato-dos-Santos, J.H., Vergano, S.A., Vilain, E., Vitobello, A., Wagner, M., Waheeb, A., Willing, M., Zuccarelli, B., Kini, U., Newbury, D.F., Kleefstra, T., Reymond, A., Fisher, S.E., and Vissers, L.E.L.M.

Abstract

Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.

29. Authors

Author

Spalaris, C. N., primary, Ring, P. J., additional, Wright, E. A., additional, Vrijen, J., additional, van Westenbrugge, J. K., additional, Wiel, L. van der, additional, Rademakers, P. L. F., additional, Scheepens, C. P., additional, Schinkel, J. W., additional, Roy, Prodyot, additional, Spalaris, C. N., additional, Sessions, C. E., additional, Reynolds, S. D., additional, Hebbar, M. A., additional, Lewis, J. F., additional, Kiefer, J. H., additional, Uber, C. F., additional, Kirkland, G. R., additional, Davies, E. R., additional, Lambert, M. E., additional, Kennett, E. J., additional, Tavassoli, A. A., additional, Touron, H., additional, Weisz, M., additional, Connors, H. J., additional, Wood, D. S., additional, Simpson, J. L., additional, Robles, M. N., additional, Moss, S. A., additional, Balakrishnan, P. V., additional, McSweeney, P., additional, Frost, C. R., additional, Walmsley, P., additional, Van Drunen, G., additional, Cecco, V. S., additional, Renshaw, R. H., additional, Roy, S., additional, Bulischeck, T. S., additional, van Rooyen, D., additional, Kowaka, M., additional, Nagano, H., additional, Kudo, T., additional, Okada, Y., additional, Yagi, M., additional, Takaba, O., additional, Yonezawa, T., additional, Arioka, K., additional, Wolfe, C. R., additional, Esposito, J. N., additional, Whyte, D. D., additional, Gilkison, J. M., additional, Balavage, J. R., additional, Wootten, M. J., additional, Wozniak, S. M., additional, Emanuelson, R. H., additional, Levstek, D. F., additional, Moore, K. E., additional, Theus, G. J., additional, Airey, G. P., additional, Vaia, A. R., additional, Aspden, R. G., additional, Hurst, P., additional, Cowen, H. C., additional, Lewis, Michael W. J., additional, Campbell, Charles S., additional, Satoh, Kunihiko, additional, Toyoda, Masao, additional, Matsui, Shigetomo, additional, Mori, Eisuke, additional, Shimizu, Shigeki, additional, Satoh, Keisuke, additional, Druce, S. G., additional, Edwards, B. C., additional, Martin, J. W., additional, Talbot, D. E. J., additional, Mukherjee, B., additional, Haddad, M. H. El, additional, Vanderglas, M. L., additional, Leemans, D. V., additional, Brown, James, additional, Gonzalez, Francisco, additional, Iley, David, additional, McKay, Alexandra, additional, Vyas, Brijesh, additional, Czajkowski, Carl J., additional, and Weeks, John R., additional

Published
1981
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30. The risks of physicians’ conformism: reflections from the opioid overflow

Author

Luisa Cortellazzo Wiel, Egidio Barbi, Giorgio Cozzi, Cortellazzo Wiel, L., Cozzi, G., and Barbi, E.

Subjects
medicine.medical_specialty, Adolescent, Attitude of Health Personnel, Debate, media_common.quotation_subject, Pain, Addiction, Chronic pain, Practice Patterns, Opioid, Opioid-Related Disorder, 03 medical and health sciences, 0302 clinical medicine, Rating scale, 030225 pediatrics, medicine, Severe pain, Humans, 030212 general & internal medicine, Medical prescription, Practice Patterns, Physicians', Intensive care medicine, Child, Physician's Role, media_common, Acute pain, Opioids, Pain measurement, Analgesics, Opioid, Opioid-Related Disorders, Pain Measurement, Analgesics, Physicians', business.industry, lcsh:RJ1-570, lcsh:Pediatrics, General Medicine, medicine.disease, Good clinical practice, business, medicine.drug, Human
Abstract

Opioid-related mortality in adolescents is spreading in the US, with prescription opioids playing a crucial role in the development of addiction. We traced back to the process leading to the so called “opioid overflow”, trying to identify any modifiable attitude.Since the late 1990s, pain was labelled as the “fifth vital sign” and its proper management was prompted, encouraging the use of opioids for any pain scored at a Numerical Rating Scale (NRS) of 7 or higher. This assumption has some remarkable limitations. NRS is a proxy of pain severity in children, and pain measurement should be strengthened by a more comprehensive pain evaluation. Moreover, while remaining a fundamental therapeutic right of patients suffering postoperative or chronic severe pain, opioids show no evidence of superiority respect to non-opioid regimens in the management of pain from several acute conditions.Italy, as other European countries, is often reluctant to the use of opioids, even when highly recommendable, missing the opportunity of properly treating those selected patients with severe pain. Both attitudes can be viewed as the result of an extreme simplification of the complex process of pain evaluation and treatment, by means of a ‘one-size-fits-all’ approach.This highlights the need for a systematic and patient-tailored attitude to children in pain, avoiding applying guidelines without question. Good clinical practice must rely on guidelines, which, however, as often based on partial and insufficient data, can be questioned by emerging new evidence, and should not substitute our rational thinking, and capability to understand each patient, avoiding excessive conformism.

Published
2021

31. Isolated Forehead Swelling

Author

Valentina Kiren, Alessia Saccari, Egidio Barbi, Luisa Cortellazzo Wiel, Irene Berti, Lorenzo Calligaris, Marco Rabusin, Daniela Nisticò, Nistico, D., Cortellazzo Wiel, L., Berti, I., Calligaris, L., Rabusin, M., Saccari, A., Barbi, E., and Kiren, V.

Subjects
medicine.medical_specialty, business.industry, acute lymphocytic leukemia, acute myeloid leukemia, extramedullary acute myeloid leukemia tumor, granulocytic sarcoma, leukemia cutis, myeloid sarcoma, Leukemia cutis, medicine.disease, Dermatology, medicine.anatomical_structure, Acute lymphocytic leukemia, Pediatrics, Perinatology and Child Health, leukemia cuti, medicine, Forehead, Myeloid sarcoma, medicine.symptom, Swelling, business
Abstract

N/A

Published
2021

32. The risks of adding orthostatic intolerance to the list of the differential diagnoses of somatic symptom disorder

Author

Luisa Cortellazzo Wiel, Giorgio Cozzi, Egidio Barbi, Cortellazzo Wiel, L., Cozzi, G., and Barbi, E.

Subjects
Pediatrics, medicine.medical_specialty, Nausea, Orthostatic intolerance, Somatic symptom disorder, Diagnosis, Differential, Diagnosis, medicine, Humans, Medical diagnosis, Medically Unexplained Symptom, Child, Gastrointestinal tract, business.industry, medicine.disease, Gastrointestinal Tract, Medically Unexplained Symptoms, Orthostatic Intolerance, Pediatrics, Perinatology and Child Health, Differential, Differential diagnosis, medicine.symptom, business, Human
Abstract

not available

Published
2021

33. Selumetinib in the Treatment of Symptomatic Intractable Plexiform Neurofibromas in Neurofibromatosis Type 1: A Prospective Case Series with Emphasis on Side Effects

Author

Flora Maria Murru, Francesco Baldo, Luca Basso, Andrea Magnolato, Antonio Giacomo Grasso, Marta Paulina Trojniak, Egidio Barbi, Irene Bruno, Luisa Cortellazzo Wiel, Alessandra Maestro, Baldo, F., Grasso, A. G., Cortellazzo Wiel, L., Maestro, A., Trojniak, M. P., Murru, F. M., Basso, L., Magnolato, A., Bruno, I., and Barbi, E.

Subjects
Male, medicine.medical_specialty, Neurofibromatosis 1, Side effect, Adolescent, Benzimidazoles, Child, Child, Preschool, Female, Humans, MAP Kinase Kinase 1, Magnetic Resonance Imaging, Neurofibroma, Plexiform, Prospective Studies, Irritability, Benzimidazole, 03 medical and health sciences, 0302 clinical medicine, Pharmacotherapy, Internal medicine, medicine, Neurofibroma, Pharmacology (medical), Neurofibromatosis, Preschool, Adverse effect, Prospective cohort study, 030203 arthritis & rheumatology, business.industry, medicine.disease, Plexiform, Pediatrics, Perinatology and Child Health, Selumetinib, medicine.symptom, business, 030217 neurology & neurosurgery, Human
Abstract

Background: Plexiform neurofibromas (PN) are congenital tumors that affect up to 50% of individuals with neurofibromatosis type 1. Despite their benign nature, they can grow rapidly and cause severe morbidities. Selumetinib, an inhibitor of mitogen-activated protein kinase (MEK) 1 and 2, was reported to induce a clinical response in pediatric subjects with inoperable PN. Objective: The aim of this paper is to describe a prospective case series of patients treated with selumetinib with emphasis on drug adverse events. Patients and methods: All the subjects who received selumetinib at the Pediatric Department of Scientific Research Institute and Hospital “Burlo Garofolo”, from November 2017 to January 2020, were progressively included. We monitored the patients with a follow-up visit every 3 months. MRI or CT scans to monitor the growth of the tumor were performed after 3 months of treatment, and then every 6–9 months. Results: Selumetinib was prescribed to nine children, with a total of 17 inoperable PN. The mean follow-up period was 12 months. During the follow-up, one patient experienced an ischemic stroke, unrelated to the treatment. Only minor adverse events were observed: six individuals developed gastrointestinal side effects, seven patients presented a mild form of acne, six had paronychia, four developed irritability, and two showed a mild increase in creatine kinase. None of the patients stopped the treatment. Tumor reduction > 20% was recorded in 16 out of 17 PN (94%). One PN remained stable. No tumor growth was recorded during the treatment. Conclusions: In this case series, selumetinib appears to be effective and safe for the pediatric population.

Published
2020

34. Beneficial effect of gabapentin in two children with Noonan syndrome and early-onset neuropathic pain

Author

Fabio Sirchia, Luisa Cortellazzo Wiel, Egidio Barbi, Laura De Nardi, Irene Bruno, Andrea Magnolato, Cortellazzo Wiel, L., De Nardi, L., Magnolato, A., Sirchia, F., Bruno, I., and Barbi, E.

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, Gabapentin, Adolescent, Young Adult, Genetics, medicine, Humans, Young adult, Age of Onset, Child, Genetics (clinical), Early onset, Aged, Pain Measurement, business.industry, Noonan Syndrome, Middle Aged, Temporomandibular Joint Dysfunction Syndrome, medicine.disease, Neuropathic pain, Noonan syndrome, Neuralgia, Female, Age of onset, business, medicine.drug
Abstract

not available

Published
2020

35. Unilateral leg swelling in a newborn

Author

Flora Maria Murru, Luisa Cortellazzo Wiel, Francesco Maria Risso, Egidio Barbi, Irene Berti, Meta Starc, Cortellazzo Wiel, L., Berti, I., Starc, M., Murru, F. M., Barbi, E., and Risso, F. M.

Subjects
Klippel-Trenaunay-Weber Syndrome, Capillary malformation, Vascular Malformations, growth, neonatology, Muscle hypertrophy, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, 030225 pediatrics, Biopsy, medicine, Humans, genetics, Right Thigh, Leg, medicine.diagnostic_test, dermatology, syndrome, business.industry, Ultrasound, Infant, Newborn, Magnetic resonance imaging, Anatomy, Hypertrophy, Capillaries, medicine.anatomical_structure, Pediatrics, Perinatology and Child Health, Female, genetic, business, Varices, Subcutaneous tissue
Abstract

A female neonate was born with asymmetric lower limbs, the right leg appearing enlarged, with thickened, reddish-purple skin and ectasic superficial reticulum (figure 1A,B). Limb pulses were present and symmetrical. The girl’s family history and prenatal scans were unremarkable. Laboratory findings were within the normal range, except for a mild thrombocytopenia (90 000/μL), which spontaneously resolved during the next few days. A leg X-ray and the Doppler analysis ruled out the presence of calcifications and venous varices, respectively. Ultrasound showed significant skin thickening, with marked dermal hypertrophy and hyperechogenicity. Magnetic resonance showed circumferential thickening of the derma, with mild hypertrophy of some perforating vessels (figure 2). A biopsy of the right thigh showed capillary malformations on histology.Figure 1(A, B) Hypertrophy of the right lower limb, with large capillary malformation extending to the gluteus and the external genitalia.Figure 2Axial THRIVE magnetic resonance scan of the thighs’ proximal third, showing circumferential dermal thickening and inhomogeneity of the right leg’s subcutaneous tissue.QuestionsBased on the clinical picture and investigations results, which is the most likely diagnosis?Beckwith-WiedemannCLOVES syndromeKlippel-Trenaunay syndromeKaposiform hemangioendotheliomaHow can the diagnosis be confirmed?CT with PETLymphoscintigraphyGenetic testingNone of the above, the diagnosis is clinicalWhat is the mainstay of management?Conservative with follow-upPharmacotherapySclerotherapySurgeryWhich of the following complications can occur?ScoliosisGlaucomaUrinary and gastrointestinal bleedingAll of the aboveAnswers can be found on page 02.

Published
2020

36. A Case of Uveitis in a Patient With Juvenile Myelomonocytic Leukemia Successfully Treated With Adalimumab

Author

Andrea Taddio, Serena Pastore, Luisa Cortellazzo Wiel, Alberto Tommasini, Cortellazzo Wiel, L., Pastore, S., Taddio, A., and Tommasini, A.

Subjects
CBL, Male, Anti-Inflammatory Agents, RALD, Context (language use), Germline, Uveitis, 03 medical and health sciences, 0302 clinical medicine, adalimumab, medicine, Adalimumab, Humans, autoimmune, JMML, RAS, uveitis, Child, Juvenile myelomonocytic leukemia, business.industry, Standard treatment, Hematology, medicine.disease, Prognosis, Leukemia, Oncology, Leukemia, Myelomonocytic, Juvenile, 030220 oncology & carcinogenesis, Sirolimus, Pediatrics, Perinatology and Child Health, Immunology, business, 030215 immunology, medicine.drug
Abstract

Patients with juvenile myelomonocytic leukemia due to germline CBL mutation (10% to 15%) may have a subacute course occasionally associated with autoimmune disorders, which may resemble RAS-associated autoimmune lymphoproliferative disorder. In both conditions, prognosis and standard treatment for autoimmune phenomena remain poorly understood. We report the case of a 7-year-old boy with juvenile myelomonocytic leukemia with severe steroid-dependent uveitis, who did not respond to several therapeutic attempts with immunosuppressant agents, including sirolimus, and was finally successfully treated with adalimumab. This case offers further insight into the management of autoimmune disorders in the context of predisposing genetic conditions.

Published
2019

37. Persisting Isolated Metacarpal Swelling and Pain in Adolescence: Consider Osteochondrosis

Author

Daniela Sanabor, Egidio Barbi, Serena Pastore, Luisa Cortellazzo Wiel, Giulia Gortani, Cortellazzo Wiel, L., Gortani, G., Pastore, S., Sanabor, D., and Barbi, E.

Subjects
metacarpal head, Adolescent, epiphyseal flattening, osteochondrosis, Pain, dietrich disease, metacarpophalangeal joint, medicine, Edema, Humans, Osteochondrosis, Orthodontics, business.industry, Metacarpophalangeal joint, Metacarpal Bones, medicine.disease, medicine.anatomical_structure, Pediatrics, Perinatology and Child Health, Female, Epiphyseal flattening, Swelling, medicine.symptom, business
Abstract

N/A

Published
2019

38. Unarousable child with a short bowel

Author

Luisa Cortellazzo Wiel, Grazia Di Leo, Giorgia Carlone, Ester Conversano, Giulia Gortani, Egidio Barbi, Chiara Zanchi, Cortellazzo Wiel, L., Conversano, E., Carlone, G., Di Leo, G., Gortani, G., Zanchi, C., and Barbi, E.

Subjects
Male, Chest Pain, Therapeutics, Paediatric Practice, 03 medical and health sciences, Lethargy, 0302 clinical medicine, Bloating, 030225 pediatrics, Intussusception (medical disorder), medicine, Humans, Family, Lactic Acid, Child, business.industry, Infant, Newborn, Metabolic acidosis, Short bowel syndrome, medicine.disease, Volvulus, Parenteral nutrition, medicine.anatomical_structure, Child, Preschool, Anesthesia, Pediatrics, Perinatology and Child Health, Abdomen, Acidosis, business
Abstract

Unarousable child with short bowelA 4-year-old boy was admitted with progressive lethargy of a few hours’ duration and no other symptoms. His medical history was relevant for short bowel syndrome (SBS), following neonatal volvulus, with residual bowel length of 23 cm and intact ileocecal valve. He had similar self-limiting episodes in the past, after weaning parenteral nutrition, especially after eating large meals. The day before, he had consumed a large amount of apples.Arterial blood gas (ABG) analysis showed metabolic acidosis with normal lactacidaemia (pH 7.09, pCO2 19 mm Hg, pO2 101 mm Hg, HCO3 5.8 mmol/L, BE −24, anion gap 29.4, chloride 116 mmol/L, L-lactate level 4 mmol/L).On admission, the child could be awakened, but he was confused with slurred speech (Glasgow Coma Scale 14), with a body temperature of 37 C°, a heart rate of 125 beats/min and a respiratory rate of 38 breaths/min. The abdomen was distended, without guarding and with normal bowel sounds. Blood glucose levels were normal, as well as white blood cell count, liver and kidney function test and C reactive protein. An abdominal ultrasound ruled out an intussusception. An abdominal X-ray was performed too (see figure 1).Figure 1Abdominal distension with gas and bloating.QuestionsWhich is the most likely diagnosis?EncephalitisD-lactic acidosisDehydration with third space fluid collection and acidosisHereditary fructose intolerance.How is this diagnosis confirmed?D lactic dosageBreath test for bacterial overgrowthUrine organic acid dosageSearch for reductive substances in the stools.How should this patient be managed?Intravenous fluids to facilitate D-lactic excretionRestrict carbohydrates in the dietIntravenous bicarbonatesAntibiotic treatment to reduce bowel bacterial overgrowth.Answers can be found on page 2.

Published
2020

39. Addressing the consequences of the corporatization of reproductive medicine.

Author

Attinger SA, Jackson E, Karpin I, Kerridge I, Newson AJ, Stewart C, van de Wiel L, and Lipworth W

Abstract

In Australia and the UK, commercialization and corporatization of assisted reproductive technologies have created a marketplace of clinics, products, and services. While this has arguably increased choice for patients, 'choice', shaped by commercial imperatives may not mean better-quality care. At present, regulation of clinics (including clinic-corporations) and clinicians focuses on the doctor-patient dyad and the clinic-consumer dyad. Scant attention has been paid to the conflicts between the clinic-corporation's duty to its shareholders and investors, the medical profession's duty to the corporations within which they practice, and the obligations of both clinicians and corporations to patients and to health systems. Frameworks of regulation based in corporate governance and business ethics, such as stakeholder models and 'corporate social responsibility', have well-recognized limits and may not translate well into healthcare settings. This means that existing governance frameworks may not meet the needs of patients or health systems. We argue for the development of novel regulatory approaches that more explicitly characterize the obligations that both corporations and clinicians in corporate environments have to patients and to society, and that promote fulfilment of these obligations. We consider mechanisms for application in the multi-jurisdictional setting of Australia, and the single jurisdictional settings of the UK., (© The Author(s) 2024. Published by Oxford University Press.)

Published
2024
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40. Molecular adaptations in response to exercise training are associated with tissue-specific transcriptomic and epigenomic signatures.

Author

Nair VD, Pincas H, Smith GR, Zaslavsky E, Ge Y, Amper MAS, Vasoya M, Chikina M, Sun Y, Raja AN, Mao W, Gay NR, Esser KA, Smith KS, Zhao B, Wiel L, Singh A, Lindholm ME, Amar D, Montgomery S, Snyder MP, Walsh MJ, and Sealfon SC

Subjects
Animals, Male, Rats, Female, DNA Methylation, Epigenesis, Genetic, Epigenomics, Adaptation, Physiological genetics, Organ Specificity, Rats, Sprague-Dawley, Physical Conditioning, Animal physiology, Transcriptome
Abstract

Regular exercise has many physical and brain health benefits, yet the molecular mechanisms mediating exercise effects across tissues remain poorly understood. Here we analyzed 400 high-quality DNA methylation, ATAC-seq, and RNA-seq datasets from eight tissues from control and endurance exercise-trained (EET) rats. Integration of baseline datasets mapped the gene location dependence of epigenetic control features and identified differing regulatory landscapes in each tissue. The transcriptional responses to 8 weeks of EET showed little overlap across tissues and predominantly comprised tissue-type enriched genes. We identified sex differences in the transcriptomic and epigenomic changes induced by EET. However, the sex-biased gene responses were linked to shared signaling pathways. We found that many G protein-coupled receptor-encoding genes are regulated by EET, suggesting a role for these receptors in mediating the molecular adaptations to training across tissues. Our findings provide new insights into the mechanisms underlying EET-induced health benefits across organs., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2024
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41. The functional impact of rare variation across the regulatory cascade.

Author

Li T, Ferraro N, Strober BJ, Aguet F, Kasela S, Arvanitis M, Ni B, Wiel L, Hershberg E, Ardlie K, Arking DE, Beer RL, Brody J, Blackwell TW, Clish C, Gabriel S, Gerszten R, Guo X, Gupta N, Johnson WC, Lappalainen T, Lin HJ, Liu Y, Nickerson DA, Papanicolaou G, Pritchard JK, Qasba P, Shojaie A, Smith J, Sotoodehnia N, Taylor KD, Tracy RP, Van Den Berg D, Wheeler MT, Rich SS, Rotter JI, Battle A, and Montgomery SB

Abstract

Each human genome has tens of thousands of rare genetic variants; however, identifying impactful rare variants remains a major challenge. We demonstrate how use of personal multi-omics can enable identification of impactful rare variants by using the Multi-Ethnic Study of Atherosclerosis, which included several hundred individuals, with whole-genome sequencing, transcriptomes, methylomes, and proteomes collected across two time points, 10 years apart. We evaluated each multi-omics phenotype's ability to separately and jointly inform functional rare variation. By combining expression and protein data, we observed rare stop variants 62 times and rare frameshift variants 216 times as frequently as controls, compared to 13-27 times as frequently for expression or protein effects alone. We extended a Bayesian hierarchical model, "Watershed," to prioritize specific rare variants underlying multi-omics signals across the regulatory cascade. With this approach, we identified rare variants that exhibited large effect sizes on multiple complex traits including height, schizophrenia, and Alzheimer's disease., Competing Interests: S.B.M. is an advisor to BioMarin, MyOme, and Tenaya Therapeutics. A.B. is a stockholder in Alphabet, Inc. and a consultant for Third Rock Ventures., (© 2023 The Author(s).)

Published
2023
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42. SARS-CoV-2-related bronchiolitis: a multicentre international study.

Author

Cozzi G, Sovtic A, Garelli D, Krivec U, Silvagni D, Corsini I, Colombo M, Giangreco M, Giannattasio A, Milani GP, Minute M, Marchetti F, Gatto A, Debbia C, Gortan AJ, Massaro M, Hatziagorou E, Ravidà D, Diamand R, Jones E, Visekruna J, Zago A, Barbi E, Amaddeo A, and Cortellazzo Wiel L

Subjects
Infant, Child, Humans, SARS-CoV-2, Retrospective Studies, Hospitalization, COVID-19 complications, COVID-19 epidemiology, Bronchiolitis diagnosis, Bronchiolitis epidemiology, Bronchiolitis therapy
Abstract

Background: Bronchiolitis is the main acute lower respiratory tract infection in infants. Data regarding SARS-CoV-2-related bronchiolitis are limited., Objective: To describe the main clinical characteristics of infants with SARS-CoV-2-related bronchiolitis in comparison with infants with bronchiolitis associated with other viruses., Setting, Patients, Interventions: A multicentre retrospective study was conducted in 22 paediatric emergency departments (PED) in Europe and Israel. Infants diagnosed with bronchiolitis, who had a test for SARS-CoV-2 and were kept in clinical observation in the PED or admitted to hospital from 1 May 2021 to 28 February 2022 were considered eligible for participation. Demographic and clinical data, diagnostic tests, treatments and outcomes were collected., Main Outcome Measures: The main outcome was the need for respiratory support in infants testing positive for SARS-CoV-2 compared with infants testing negative., Results: 2004 infants with bronchiolitis were enrolled. Of these, 95 (4.7%) tested positive for SARS-CoV-2. Median age, gender, weight, history of prematurity and presence of comorbidities did not differ between the SARS-CoV-2-positive and SARS-CoV-2-negative infants. Human metapneumovirus and respiratory syncytial virus were the viruses most frequently detected in the group of infants negative for SARS-CoV-2.Infants testing positive for SARS-CoV-2 received oxygen supplementation less frequently compared with SARS-CoV-2-negative patients, 37 (39%) vs 1076 (56.4%), p=0.001, OR 0.49 (95% CI 0.32 to 0.75). They received less ventilatory support: 12 (12.6%) high flow nasal cannulae vs 468 (24.5%), p=0.01; 1 (1.0%) continuous positive airway pressure vs 125 (6.6%), p=0.03, OR 0.48 (95% CI 0.27 to 0.85)., Conclusions: SARS-CoV-2 rarely causes bronchiolitis in infants. SARS-CoV-2-related bronchiolitis mostly has a mild clinical course., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2023
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43. De novo mutation hotspots in homologous protein domains identify function-altering mutations in neurodevelopmental disorders.

Author

Wiel L, Hampstead JE, Venselaar H, Vissers LELM, Brunner HG, Pfundt R, Vriend G, Veltman JA, and Gilissen C

Subjects
Humans, Protein Domains genetics, Mutation genetics, Neurodevelopmental Disorders genetics
Abstract

Variant interpretation remains a major challenge in medical genetics. We developed Meta-Domain HotSpot (MDHS) to identify mutational hotspots across homologous protein domains. We applied MDHS to a dataset of 45,221 de novo mutations (DNMs) from 31,058 individuals with neurodevelopmental disorders (NDDs) and identified three significantly enriched missense DNM hotspots in the ion transport protein domain family (PF00520). The 37 unique missense DNMs that drive enrichment affect 25 genes, 19 of which were previously associated with NDDs. 3D protein structure modeling supports the hypothesis of function-altering effects of these mutations. Hotspot genes have a unique expression pattern in tissue, and we used this pattern alongside in silico predictors and population constraint information to identify candidate NDD-associated genes. We also propose a lenient version of our method, which identifies 32 hotspot positions across 16 different protein domains. These positions are enriched for likely pathogenic variation in clinical databases and DNMs in other genetic disorders., Competing Interests: Declaration of interests The authors have no competing interests., (Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Published
2023
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45. Neuropsychological assessment in the multicultural memory clinic: Development and feasibility of the TULIPA battery.

Author

Franzen S, van den Berg E, Bossenbroek W, Kranenburg J, Scheffers EA, van Hout M, van de Wiel L, Goudsmit M, van Bruchem-Visser RL, van Hemmen J, Jiskoot LC, and Papma JM

Subjects
Humans, Neuropsychological Tests, Feasibility Studies, Language, Dementia diagnosis, Tulipa
Abstract

Neuropsychological assessment of culturally diverse populations is hindered by barriers in language, culture, education, and a lack of suitable tests. Furthermore, individuals from diverse backgrounds are often unfamiliar with being cognitively tested. The aim of this study was to develop a new neuropsychological test battery and study its feasibility in multicultural memory clinics., Composition of the TULIPA battery (Towards a Universal Language: Intervention and Psychodiagnostic Assessment) entailed a literature review and consultation with experts and individuals from diverse backgrounds. Feasibility was investigated by examining administration and completion rates and the frequency of factors complicating neuropsychological assessment in 345 patients from 37 countries visiting four multicultural memory clinics in the Netherlands., The test battery included existing tests such as the Cross-Cultural Dementia screening (CCD), Rowland Universal Dementia Assessment Scale (RUDAS), tests from the European Cross-Cultural Neuropsychological Test Battery, and newly developed tests. Completion rates for the test battery were generally high (82%-100%), except for CCD Dots subtest B (58%). Although tests of the "core" TULIPA battery were administered often (median: 6 of 7, IQR: 5-7), supplementary tests were administered less frequently (median: 1 of 9; IQR: 0-3). The number of administered tests correlated with disease severity (RUDAS, ρ=.33, adjusted p < .001), but not with other patient characteristics. Complicating factors were observed frequently, e.g. suboptimal effort (29%-50%), fatigue (29%), depression (37%-57%)., The TULIPA test battery is a promising new battery to assess culturally diverse populations in a feasible way, provided that complicating factors are taken into account., Supplemental data for this article is available online at https://doi.org/10.1080/13854046.2022.2043447 .

Published
2023
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46. Prevalence of SARS-CoV-2 positivity in infants with bronchiolitis: a multicentre international study.

Author

Cozzi G, Cortellazzo Wiel L, Amaddeo A, Gatto A, Giangreco M, Klein-Kremer A, Bosis S, Silvagni D, Debbia C, Nanni L, Chiappa S, Minute M, Corsini I, Morabito G, Gortan AJ, Colombo M, Marchetti F, Garelli D, Piffer A, Cardinale F, Levy N, Curatola A, Gojsina B, Basu S, Barbi E, and Sovtic A

Abstract

Background: Bronchiolitis is the leading acute respiratory tract infection in infants during the winter season. Since the beginning of the SARS-CoV-2 pandemic, a reduction in the number of bronchiolitis diagnoses has been registered., Objective: The present study aimed to describe the incidence and clinical features of bronchiolitis during the 2020-2021 winter season in a large cohort of children in Europe and Israel, and to clarify the role of SARS-CoV-2., Setting, Patients, Interventions: We conducted a multicentre observational cross-sectional study in 23 paediatric emergency departments in Europe and Israel. Clinical and demographic data about all the cases of infants diagnosed with bronchiolitis from 1 October 2020 to 30 April 2021 were collected. For each enrolled patient, diagnostic tests, treatments and outcomes were reported., Main Outcome Measures: The main outcome was the prevalence of SARS-CoV-2-positive bronchiolitis., Results: Three hundred and fourteen infants received a diagnosis of bronchiolitis during the study period. Among 535 infants who tested positive for SARS-CoV-2, 16 (3%) had bronchiolitis. Median age, male sex predominance, weight, history of prematurity and presence of comorbidities did not differ between the SARS-CoV-2-positive and SARS-CoV-2-negative groups. Rhinovirus was the most common involved pathogen, while respiratory syncytial virus (RSV) was detected in one case. SARS-CoV-2 bronchiolitis had a mild clinical course, with one patient receiving oxygen supplementation and none requiring paediatric or neonatal intensive care unit admission., Conclusions: During the SARS-CoV-2 pandemic, a marked decrease in the number of bronchiolitis diagnoses and the disappearance of the RSV winter epidemic were observed. SARS-CoV-2-related bronchiolitis was rare and mostly displayed a mild clinical course., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2022
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47. Need for pharmacological analgesia after cast immobilisation in children with bone fractures: an observational cross-sectional study.

Author

Cozzi G, Cortellazzo Wiel L, Bassi A, Giangreco M, Dibello D, Rozzo M, Di Carlo V, Genovese MRL, and Barbi E

Subjects
Adolescent, Analgesics therapeutic use, Child, Cross-Sectional Studies, Humans, Pain etiology, Analgesia adverse effects, Fractures, Bone complications, Fractures, Bone therapy
Abstract

Background: Bone fractures are a common reason for children and adolescents to seek evaluation in the ED. Little is known about the pain experienced after cast immobilisation and discharge from the ED and its optimal management. We aimed to investigate the administration of pharmacological analgesia in the first days after cast immobilisation and to identify possible influencing variables., Methods: A prospective observational cross-sectional study was conducted at the ED of the children's hospital, Institute for Maternal and Child Health of Trieste, Italy, from October 2019 to June 2020. Patients aged 0-17 years with bone fractures were included. The primary outcome was the administration of analgesia during the 10 days following discharge, while secondary outcomes were the associated variables, including age, gender, fracture type and location, the mean limitation in usual activities and the frequency of re-evaluation at the ED for pain. Data were recorded through a questionnaire, completed by caregivers and collected by the researchers mainly through a telephone interview. The primary endpoint was evaluated as the ratio between the number of children who took at least one analgesic dose and the total enrolled children, while Χ 2 or Fisher's exact tests were used to assess secondary outcomes., Results: During the study period, 213 patients, mean age 10 years (IQR: 8-13), were enrolled. Among them, 137 (64.3%) did not take any analgesic during follow-up. Among children who were administered analgesia, 22 (28.9%) received it only on the first day, and 47 (61.8%) for less than 5 days. One hundred and sixty one patients (75.6%) did not report any limitation in usual activities because of pain. The administration of analgesia was not related to the child's age, gender or fracture site. Displaced fractures were associated with significantly more frequent analgesia being taken (OR 5.5, 95% CI 1.4 to 21.0)., Conclusion: Although some studies recommend scheduled analgesic treatment after discharge for bone fractures, this study would suggest analgesia on demand in children with non-displaced fractures, limiting scheduled analgesia to children with displaced fractures., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2022
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48. Unilateral leg swelling in a newborn.

Author

Cortellazzo Wiel L, Berti I, Starc M, Murru FM, Barbi E, and Risso FM

Subjects
Capillaries abnormalities, Female, Humans, Hypertrophy etiology, Infant, Newborn, Leg pathology, Pregnancy, Klippel-Trenaunay-Weber Syndrome complications, Klippel-Trenaunay-Weber Syndrome diagnosis, Klippel-Trenaunay-Weber Syndrome pathology, Vascular Malformations pathology
Abstract

A female neonate was born with asymmetric lower limbs, the right leg appearing enlarged, with thickened, reddish-purple skin and ectasic superficial reticulum (figure 1A,B). Limb pulses were present and symmetrical. The girl's family history and prenatal scans were unremarkable. Laboratory findings were within the normal range, except for a mild thrombocytopenia (90 000/μL), which spontaneously resolved during the next few days. A leg X-ray and the Doppler analysis ruled out the presence of calcifications and venous varices, respectively. Ultrasound showed significant skin thickening, with marked dermal hypertrophy and hyperechogenicity. Magnetic resonance showed circumferential thickening of the derma, with mild hypertrophy of some perforating vessels (figure 2). A biopsy of the right thigh showed capillary malformations on histology., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2022
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49. Nurses' Perceptions of the Quality of Procedural Sedation in Children Comparing Different Pharmacological Regimens.

Author

Curatola A, D'Agostin M, Favaretto E, Vittori G, Vidonis V, Strajn T, De Vita N, Saccari A, Barbi E, and Cortellazzo Wiel L

Abstract

Nurses play a pivotal role during pediatric procedural sedation and their perspective is an important indicator for the quality of care. The aim of this study is to examine nurses' satisfaction comparing four different pharmacological regimens used for pediatric sedation outside of the operating room. A prospective observational study was conducted in a third-level pediatric teaching hospital, involving all the nurses with experience in the field of pediatric procedural sedation. A 13-item survey was used to assess the level of nurses' satisfaction for the quality of sedation with four different analgesic-sedative drugs. Fifty-one questionnaires were completed by pediatric nurses, with a median length of experience of 10 years. Regarding the overall quality of the sedation, the highest median satisfaction scores were observed for propofol (8, IQR 7-9), dexmedetomidine (8, IQR 6-8) and midazolam (8, IQR 7-9). Ketamine (5, IQR 3-7) displayed the lowest score. When asked to rate their level of perceived safety, nurses gave high scores to all the four drugs studied, with no statistically significant difference between them. Non-pharmacological techniques during procedural sedation were judged as important by 38 (74.5%) nurses. According to this sample of pediatric nurses, the best quality of procedural sedation in children outside of the operating room is obtained with propofol, dexmedetomidine and midazolam. During procedural sedation, nurses feel safe overall, regardless of the pharmacological regimen used. Moreover, they highlighted the relevance on non-pharmacological approaches in the preparation of the child for the procedure.

Published
2022
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50. Passion, pressure and pragmatism: how fertility clinic medical directors view IVF add-ons.

Author

Iacoponi O, van de Wiel L, Wilkinson J, and Harper JC

Subjects
Emotions, Female, Fertility Clinics, Humans, Male, Fertilization in Vitro, Physician Executives
Abstract

Research Question: What are the views of the medical directors of fertility clinics on IVF add-ons?, Design: A total of 93 UK clinics were emailed with an invitation for their medical director to participate. Ten IVF clinic medical directors were interviewed to discuss their views on the use of IVF add-ons. Some of the interviewees were medical directors of an IVF clinic with multiple branches across the UK, meaning the total number of clinics accounted for in this study was 35 out of the 93 contacted. Thematic analysis was used to analyse the data., Results: The participants consisted of seven males and three females, with six from solely private clinics and four with NHS and private patients. Four themes were identified: clinical decision-making and the patient-doctor relationship; regulations and the add-on traffic light system; research and evidence; and commercialization and financialization of the IVF sector., Conclusions: UK IVF medical directors had a wide variety of views and experienced different pressures to offer IVF add-ons. The add-on discussion touches on core aspects of professional identity and the meaning of medical practice. The add-on debate points to broader changes in the organization of the IVF sector, which affect key aspects of practising (reproductive) medicine, including the patient-doctor relationship and responsibility for clinical decision-making, and the relationship between regulator and IVF clinic and between scientific evidence and clinical practice., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Published
2022
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