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2. Influence of early identification and therapy on long-term outcomes in early-onset MTHFR deficiency

Author

Yverneau, M., Leroux, S., Imbard, A., Gleich, F., Arion, A., Moreau, C., Nassogne, M.C., Szymanowski, M., Tardieu, M., Touati, G., Bueno, M., Chapman, K.A., Chien, Y.H., Huemer, M., Ješina, P., Janssen, M.C.H., Kölker, S., Kožich, V., Lavigne, C., Lund, A.M., Mochel, F., Morris, A., Pons, M.R., Porras-Hurtado, G.L., Benoist, J.F., Damaj, L., Schiff, M., Yverneau, M., Leroux, S., Imbard, A., Gleich, F., Arion, A., Moreau, C., Nassogne, M.C., Szymanowski, M., Tardieu, M., Touati, G., Bueno, M., Chapman, K.A., Chien, Y.H., Huemer, M., Ješina, P., Janssen, M.C.H., Kölker, S., Kožich, V., Lavigne, C., Lund, A.M., Mochel, F., Morris, A., Pons, M.R., Porras-Hurtado, G.L., Benoist, J.F., Damaj, L., and Schiff, M.

Abstract

Item does not contain fulltext, MTHFR deficiency is a severe inborn error of metabolism leading to impairment of the remethylation of homocysteine to methionine. Neonatal and early-onset patients mostly exhibit a life-threatening acute neurologic deterioration. Furthermore, data on early-onset patients' long-term outcomes are scarce. The aims of this study were (1) to study and describe the clinical and laboratory parameters of early-onset MTHFR-deficient patients (i.e., ≤3 months of age) and (2) to identify predictive factors for severe neurodevelopmental outcomes in a cohort with early and late onset MTHFR-deficient patients. To this end, we conducted a retrospective, multicentric, international cohort study on 72 patients with MTHFR deficiency from 32 international metabolic centres. Characteristics of the 32 patients with early-onset MTHFR deficiency were described at time of diagnosis and at the last follow-up visit. Logistic regression analysis was used to identify predictive factors of severe neurodevelopmental outcome in a broader set of patients with early and non-early-onset MTHFR deficiency. The majority of early-onset MTHFR-deficient patients (n = 32) exhibited neurologic symptoms (76%) and feeding difficulties (70%) at time of diagnosis. At the last follow-up visit (median follow-up time of 8.1 years), 76% of treated early-onset patients (n = 29) exhibited a severe neurodevelopmental outcome. Among the whole study population of 64 patients, pre-symptomatic diagnosis was independently associated with a significantly better neurodevelopmental outcome (adjusted OR 0.004, [0.002-0.232]; p = 0.003). This study provides evidence for benefits of pre-symptomatic diagnosis and appropriate therapeutic management, highlighting the need for systematic newborn screening for MTHFR deficiency and pre-symptomatic treatment that may improve outcome.

Published
2022

4. Long-term effects of medical management on growth and weight in individuals with urea cycle disorders

Author

Posset, R. (Roland), Garbade, S.F. (Sven), Gleich, F. (Florian), Gropman, A.L. (Andrea L.), Lonlay, P. (Pascale) de, Hoffmann, G.F. (Georg), Garcia-Cazorla, A. (Angeles), Nagamani, S.C.S. (Sandesh C. S.), Baumgartner, M.R. (Matthias), Schulze, A. (Andreas), Dobbelaere, D. (Dries), Yudkoff, M. (Marc), Kölker, S. (Stefan), Zielonka, M. (Matthias), Ah Mew, N. (Nicholas), Berry, S.A. (Susan A.), McCandless, S.E. (Shawn E.), Coughlin, C. (Curtis), Enns, G. (Gregory), Gallagher, R.C. (Renata C.), Burrage, L.C. (Lindsay C.), Seminara, J. (Jennifer), Harding, C.O. (Cary O.), Burgard, P. (Peter), Le Mons, C. (Cynthia), Merritt, J.L. (J. Lawrence), Stricker, T. (Tamar), Bedoyan, J. (Jirair), Berry, G.T. (Gerard T.), Diaz, G.A. (George A.), Wong, D. (Derek), Tuchman, M. (Mendel), Waisbren, S. (Susan), Weisfeld-Adams, J.D. (James D), Burlina, A.B. (Alberto), Leão Teles, E. (Elisa), Pedrón-Giner, C. (Consuelo), Lund, A.M. (Allan M.), Dionisi-Vici, C. (Carlo), Williams, M. (Monique), Mütze, U. (Ulrike), Karall, D. (Daniela), Blasco-Alonso, J. (Javier), Couce, M.L. (Maria L.), Sykut-Cegielska, J. (Jolanta), Augoustides-Savvopoulou, P. (Persa), Ruiz Gomez, A. (Angeles), Barić, I. (Ivo), Schiff, M. (Manuel), Chien, Y.-H. (Yin-Hsiu), Lindner, M. (Martin), Chabrol, B. (Brigitte), Skouma, A. (Anastasia), Zeman, J. (Jiri), Sokal, E. (Etienne), Santer, R. (Rene), Eyskens, F. (François), Freisinger, P. (Peter), Peña-Quintana, L. (Luis), Roland, D. (Dominique), Cortès-Saladelafont, E. (Elisenda), Djordjevic, M. (Maja), Posset, R. (Roland), Garbade, S.F. (Sven), Gleich, F. (Florian), Gropman, A.L. (Andrea L.), Lonlay, P. (Pascale) de, Hoffmann, G.F. (Georg), Garcia-Cazorla, A. (Angeles), Nagamani, S.C.S. (Sandesh C. S.), Baumgartner, M.R. (Matthias), Schulze, A. (Andreas), Dobbelaere, D. (Dries), Yudkoff, M. (Marc), Kölker, S. (Stefan), Zielonka, M. (Matthias), Ah Mew, N. (Nicholas), Berry, S.A. (Susan A.), McCandless, S.E. (Shawn E.), Coughlin, C. (Curtis), Enns, G. (Gregory), Gallagher, R.C. (Renata C.), Burrage, L.C. (Lindsay C.), Seminara, J. (Jennifer), Harding, C.O. (Cary O.), Burgard, P. (Peter), Le Mons, C. (Cynthia), Merritt, J.L. (J. Lawrence), Stricker, T. (Tamar), Bedoyan, J. (Jirair), Berry, G.T. (Gerard T.), Diaz, G.A. (George A.), Wong, D. (Derek), Tuchman, M. (Mendel), Waisbren, S. (Susan), Weisfeld-Adams, J.D. (James D), Burlina, A.B. (Alberto), Leão Teles, E. (Elisa), Pedrón-Giner, C. (Consuelo), Lund, A.M. (Allan M.), Dionisi-Vici, C. (Carlo), Williams, M. (Monique), Mütze, U. (Ulrike), Karall, D. (Daniela), Blasco-Alonso, J. (Javier), Couce, M.L. (Maria L.), Sykut-Cegielska, J. (Jolanta), Augoustides-Savvopoulou, P. (Persa), Ruiz Gomez, A. (Angeles), Barić, I. (Ivo), Schiff, M. (Manuel), Chien, Y.-H. (Yin-Hsiu), Lindner, M. (Martin), Chabrol, B. (Brigitte), Skouma, A. (Anastasia), Zeman, J. (Jiri), Sokal, E. (Etienne), Santer, R. (Rene), Eyskens, F. (François), Freisinger, P. (Peter), Peña-Quintana, L. (Luis), Roland, D. (Dominique), Cortès-Saladelafont, E. (Elisenda), and Djordjevic, M. (Maja)

Abstract

Low protein diet and sodium or glycerol phenylbutyrate, two pillars of recommended long-term therapy of individuals with urea cycle disorders (UCDs), involve the risk of iatrogenic growth failure. Limited evidence-based studies hamper our knowledge on the long-term effects of the proposed medical management in individuals with UCDs. We studied the impact of medical management on growth and weight development in 307 individuals longitudinally followed by the Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD). Intrauterine growth of all investigated UCDs and postnatal linear growth of asymptomatic individuals remained unaffected. Symptomatic individuals were at risk of progressive growth retardation independent from the underlying disease and the degree of natural protein restriction. Growth impairment was determined by disease severity and associated with reduced or borderline plasma branched-chain amino acid (BCAA) concentrations. Liver transplantation appeared to have a beneficial effect on growth. Weight development remained unaffected both in asymptomatic and symptomatic individuals. Progressive growth impairment depends on disease severity and plasma BCAA concentrations, but cannot be predicted by the amount of natural protein intake alone. Future clinical trials are necessary to evaluate whether supplementation with BCAAs might improve growth in UCDs.

Published
2020
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7. Phenotype, treatment practice and outcome in the cobalamin-dependent remethylation disorders and MTHFR deficiency: data from the E-HOD registry

Author

Huemer, M. Diodato, D. Martinelli, D. Olivieri, G. Blom, H. Gleich, F. Kölker, S. Kožich, V. Morris, A.A. Seifert, B. Froese, D.S. Baumgartner, M.R. Dionisi-Vici, C. Martin, C.A. Baethmann, M. Ballhausen, D. Blasco-Alonso, J. Boy, N. Bueno, M. Burgos Peláez, R. Cerone, R. Chabrol, B. Chapman, K.A. Couce, M.L. Crushell, E. Dalmau Serra, J. Diogo, L. Ficicioglu, C. García Jimenez, M.C. García Silva, M.T. Gaspar, A.M. Gautschi, M. González-Lamuño, D. Gouveia, S. Grünewald, S. Hendriksz, C. Janssen, M.C.H. Jesina, P. Koch, J. Konstantopoulou, V. Lavigne, C. Lund, A.M. Martins, E.G. Meavilla Olivas, S. Mention, K. Mochel, F. Mundy, H. Murphy, E. Paquay, S. Pedrón-Giner, C. Ruiz Gómez, M.A. Santra, S. Schiff, M. Schwartz, I.V. Scholl-Bürgi, S. Servais, A. Skouma, A. Tran, C. Vives Piñera, I. Walter, J. Weisfeld-Adams, J. the EHOD consortium

Abstract

Aim: To explore the clinical presentation, course, treatment and impact of early treatment in patients with remethylation disorders from the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD) international web-based registry. Results: This review comprises 238 patients (cobalamin C defect n = 161; methylenetetrahydrofolate reductase deficiency n = 50; cobalamin G defect n = 11; cobalamin E defect n = 10; cobalamin D defect n = 5; and cobalamin J defect n = 1) from 47 centres for whom the E-HOD registry includes, as a minimum, data on medical history and enrolment visit. The duration of observation was 127 patient years. In 181 clinically diagnosed patients, the median age at presentation was 30 days (range 1 day to 42 years) and the median age at diagnosis was 3.7 months (range 3 days to 56 years). Seventy-five percent of pre-clinically diagnosed patients with cobalamin C disease became symptomatic within the first 15 days of life. Total homocysteine (tHcy), amino acids and urinary methylmalonic acid (MMA) were the most frequently assessed disease markers; confirmatory diagnostics were mainly molecular genetic studies. Remethylation disorders are multisystem diseases dominated by neurological and eye disease and failure to thrive. In this cohort, mortality, thromboembolic, psychiatric and renal disease were rarer than reported elsewhere. Early treatment correlates with lower overall morbidity but is less effective in preventing eye disease and cognitive impairment. The wide variation in treatment hampers the evaluation of particular therapeutic modalities. Conclusion: Treatment improves the clinical course of remethylation disorders and reduces morbidity, especially if started early, but neurocognitive and eye symptoms are less responsive. Current treatment is highly variable. This study has the inevitable limitations of a retrospective, registry-based design. © 2018 SSIEM

Published
2018

10. Efficacy and safety of Velmanase alfa in the treatment of patients with alpha-mannosidosis: results from the core and extension phase analysis of a phase III multicentre, double-blind, randomised, placebo-controlled trial

Author

Borgwardt, L., Guffon, N. (Nathalie), Amraoui, Y., Dali, C.I., Meirleir, L. (Linda) de, Gil-Campos, M., Heron, B., Geraci, S, Ardigò, D., Cattaneo, F., Fogh, J., Hout, J.M.P. (Johanna) van den, Beck, M. (Markus), Jones, S.A. (Simon), Tylki-Szymanska, A., Haugsted, U., Lund, A.M. (Allan), Borgwardt, L., Guffon, N. (Nathalie), Amraoui, Y., Dali, C.I., Meirleir, L. (Linda) de, Gil-Campos, M., Heron, B., Geraci, S, Ardigò, D., Cattaneo, F., Fogh, J., Hout, J.M.P. (Johanna) van den, Beck, M. (Markus), Jones, S.A. (Simon), Tylki-Szymanska, A., Haugsted, U., and Lund, A.M. (Allan)

Abstract

Introduction This phase III, double-blind, randomised, placebo-controlled trial (and extension phase) was designed to assess the efficacy and safety of velmanase alfa (VA) in alpha-mannosidosis (AM) patients. Methods Twenty-five patients were randomised to weekly 1 mg/kg VA or placebo for 52 weeks. At study conclusion, placebo patients switched to VA; 23 patients continued receiving VA in compassionate-use/follow-on studies and were evaluated in the extension phase [last observation (LO)]. Co-primary endpoints were changes in serum oligosaccharide (S-oligo) and in the 3-min stair-climb test (3MSCT). Results Mean relative change in S-oligo in the VA arm was −77.6% [95% confidence interval (CI) −81.6 to −72.8] at week 52 and −62.9% (95% CI −85.8 to −40.0) at LO; mean relative change in the placebo arm was −24.1% (95% CI −40.3 to −3.6) at week 52 and −55.7% (95% CI −76.4 to −34.9) at LO after switch to active treatment. Mean relative change in 3MSCT at week 52 was −1.1% (95% CI −9.0 to 7.6) and − % (95% CI −13.4 to 6.5) for VA and placebo, respectively. At LO, the mean relative change was 3.9% (95% CI −5.5 to 13.2) in the VA arm and 9.0% (95% CI −10.3 to 28.3) in placebo patients after switch to active treatment. Similar improvement pattern was observed in secondary parameters. A post hoc analysis investigated whether some factors at baseline could account for treatment outcome; none of those factors were predictive of the response to VA, besides age. Conclusions These findings support the utility of VA for the treatment of AM, with more evident benefit over time and when treatment is started in the paediatric age.

Published
2018
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11. Comprehensive long-term efficacy and safety of recombinant human alpha-mannosidase (velmanase alfa) treatment in patients with alpha-mannosidosis

Author

Lund, A.M. (Allan), Borgwardt, L., Cattaneo, F., Ardigò, D., Geraci, S, Gil-Campos, M., Meirleir, L. (Linda) de, Laroche, C., Dolhem, P., Cole, D, Tylki-Szymanska, A., Lopez-Rodriguez, M., Guillén-Navarro, E., Dali, C.I., Héron, B., Fogh, J., Muschol, N., Phillips, D.E. (David E), Hout, J.M.P. (Johanna) van den, Jones, S.A. (Simon), Amraoui, Y., Harmatz, P., Guffon, N. (Nathalie), Lund, A.M. (Allan), Borgwardt, L., Cattaneo, F., Ardigò, D., Geraci, S, Gil-Campos, M., Meirleir, L. (Linda) de, Laroche, C., Dolhem, P., Cole, D, Tylki-Szymanska, A., Lopez-Rodriguez, M., Guillén-Navarro, E., Dali, C.I., Héron, B., Fogh, J., Muschol, N., Phillips, D.E. (David E), Hout, J.M.P. (Johanna) van den, Jones, S.A. (Simon), Amraoui, Y., Harmatz, P., and Guffon, N. (Nathalie)

Abstract

Introduction Long-term outcome data provide important insights into the clinical utility of enzyme replacement therapies. Such data are presented for velmanase alfa in the treatment of alpha-mannosidosis (AM). Methods Patient data (n = 33; 14 adults, 19 paediatric) from the clinical development programme for velmanase alfa were integrated in this prospectively-designed analysis of long-term efficacy and safety. Patients who participated in the phase I/II or phase III trials and were continuing to receive treatment after completion of the trials were invited to participate in a comprehensive evaluation visit to assess long-term outcomes. Primary endpoints were changes in serum oligosaccharide and the 3-minute stair climb test (3MSCT). Results Mean (SD) treatment exposure was 29.3 (15.2) months. Serum oligosaccharide levels were significantly reduced in the overall population at 12 months (mean change: –72.7%, P < 0.001) and remained statistically significant at last observation (−62.8%, P < 0.001). A mean improvement of +9.3% in 3MSCT was observed at 12 months (P = 0.013), which also remained statistically significant at last observation (+13.8%, P = 0.004), with a more pronounced improvement detected in the paediatric subgroup. No treatment-emergent adverse events were reported leading to permanent treatment discontinuation. Conclusions Patients treated with velmanase alfa experienced improvements in biochemical and functional measures that were maintained for up to 4 years. Long term follow-up is important and further supports the use of velmanase alfa as an effective and well-tolerated treatment for AM. Based on the currently available data set, no baseline characteristic can be predictive of treatment outcome. Early treatment during paediatric age showed better outcome in functional endpoints.

Published
2018
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12. Correction to: Impact of age at onset and newborn screening on outcome in organic acidurias

Author

Heringer, J. (Jana), Valayannopoulos, V. (Vassili), Lund, A.M. (Allan), Wijburg, F.A. (Frits), Freisinger, P. (Peter), Barić, I. (Ivo), Baumgartner, M.R. (Matthias), Burgard, P. (Peter), Burlina, A.B. (Alberto), Chapman, K. (Kimberly), Cortès i Saladelafont, E. (Elisenda), Karall, D. (Daniela), Mühlhausen, C. (Chris), Riches, V. (Victoria), Schiff, M. (Manuel), Sykut-Cegielska, J. (Jolanta), Walter, J.H. (John), Zeman, J. (Jiri), Chabrol, B. (Brigitte), Kölker, S. (Stefan), Heringer, J. (Jana), Valayannopoulos, V. (Vassili), Lund, A.M. (Allan), Wijburg, F.A. (Frits), Freisinger, P. (Peter), Barić, I. (Ivo), Baumgartner, M.R. (Matthias), Burgard, P. (Peter), Burlina, A.B. (Alberto), Chapman, K. (Kimberly), Cortès i Saladelafont, E. (Elisenda), Karall, D. (Daniela), Mühlhausen, C. (Chris), Riches, V. (Victoria), Schiff, M. (Manuel), Sykut-Cegielska, J. (Jolanta), Walter, J.H. (John), Zeman, J. (Jiri), Chabrol, B. (Brigitte), and Kölker, S. (Stefan)

Abstract

Due to an unfortunate error during the typesetting process, the collaborators were presented incorrectly.

Published
2017
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13. Report on the sixth blind test of organic crystal structure prediction methods

Author

Reilly, A.M., Cooper, R.I., Adjiman, C.S., Bhattacharya, S., Boese, A.D., Brandenburg, J.G., Bygrave, P.J., Bylsma, R., Campbell, J.E., Car, R., Case, D.H., Chadha, R., Cole, J.C., Cosburn, K., Cuppen, H.M., Curtis, F., Day, G.M., DiStasio, R.A., Dzyabchenko, A., van Eijck, B.P., Elking, D.M., Ende, J.A. van den, Facelli, J.C., Ferraro, M.B., Fusti-Molnar, L., Gatsiou, C.A., Gee, T.S., Gelder, R. de, Ghiringhelli, L.M., Goto, H., Grimme, S., Guo, R., Hofmann, D.W.M., Hoja, J., Hylton, R.K., Iuzzolino, L., Jankiewicz, W., de Jong, D.T., Kendrick, J., de Klerk, N.J.J., Ko, H.Y., Kuleshova, L.N., Li, X.Y., Lohani, S., Leusen, F.J.J., Lund, A.M., Lv, J., Ma, Y.T., Marom, N., Masunov, A.E., McCabe, P., McMahon, D.P., Meekes, H.L.M., Metz, M.P., Misquitta, A.J., Mohamed, S., Monserrat, B., Needs, R.J., Neumann, M.A., Nyman, J., Obata, S., Oberhofer, H., Oganov, A.R., Orendt, A.M., Pagola, G.I., Pantelides, C.C., Pickard, C.J., Podeszwa, R., Price, L.S., Price, S.L., Pulido, A., Read, M.G., Reuter, K., Schneider, E., Schober, C., Shields, G.P., Singh, P., Sugden, I.J., Szalewicz, K., Taylor, C.R., Tkatchenko, A., Tuckerman, M.E., Vacarro, F., Vasileiadis, M., Vazquez-Mayagoitia, A., Vogt, L., Wang, Y.C., Watson, R.E., de Wijs, G.A., Yang, J., Zhu, Q., Groom, C.R., Reilly, A.M., Cooper, R.I., Adjiman, C.S., Bhattacharya, S., Boese, A.D., Brandenburg, J.G., Bygrave, P.J., Bylsma, R., Campbell, J.E., Car, R., Case, D.H., Chadha, R., Cole, J.C., Cosburn, K., Cuppen, H.M., Curtis, F., Day, G.M., DiStasio, R.A., Dzyabchenko, A., van Eijck, B.P., Elking, D.M., Ende, J.A. van den, Facelli, J.C., Ferraro, M.B., Fusti-Molnar, L., Gatsiou, C.A., Gee, T.S., Gelder, R. de, Ghiringhelli, L.M., Goto, H., Grimme, S., Guo, R., Hofmann, D.W.M., Hoja, J., Hylton, R.K., Iuzzolino, L., Jankiewicz, W., de Jong, D.T., Kendrick, J., de Klerk, N.J.J., Ko, H.Y., Kuleshova, L.N., Li, X.Y., Lohani, S., Leusen, F.J.J., Lund, A.M., Lv, J., Ma, Y.T., Marom, N., Masunov, A.E., McCabe, P., McMahon, D.P., Meekes, H.L.M., Metz, M.P., Misquitta, A.J., Mohamed, S., Monserrat, B., Needs, R.J., Neumann, M.A., Nyman, J., Obata, S., Oberhofer, H., Oganov, A.R., Orendt, A.M., Pagola, G.I., Pantelides, C.C., Pickard, C.J., Podeszwa, R., Price, L.S., Price, S.L., Pulido, A., Read, M.G., Reuter, K., Schneider, E., Schober, C., Shields, G.P., Singh, P., Sugden, I.J., Szalewicz, K., Taylor, C.R., Tkatchenko, A., Tuckerman, M.E., Vacarro, F., Vasileiadis, M., Vazquez-Mayagoitia, A., Vogt, L., Wang, Y.C., Watson, R.E., de Wijs, G.A., Yang, J., Zhu, Q., and Groom, C.R.

Abstract

Contains fulltext : 162023.pdf (publisher's version ) (Open Access)

Published
2016

14. A study of the clinical and radiological features in a cohort of 93 patients with a COL2A1 mutation causing spondyloepiphyseal dysplasia congenita or a related phenotype

Author

Terhal, P.A., Nievelstein, R.J., Verver, E.J., Topsakal, V., Dommelen, P. van, Hoornaert, K., Merrer, M. Le, Zankl, A., Simon, M.E., Smithson, S.F., Marcelis, C.L.M., Kerr, B., Clayton-Smith, J., Kinning, E., Mansour, S., Elmslie, F., Goodwin, L., Hout, A.H. van der, Veenstra-Knol, H.E., Herkert, J.C., Lund, A.M., Hennekam, R.C., Mégarbané, A., Lees, M.M., Wilson, L.C., Male, A., Hurst, J., Alanay, Y., Annerén, G., Betz, R.C., Bongers, E.M.H.F., Cormier-Daire, V., Dieux, A., David, A., Elting, M.W., Ende, J. van den, Green, A., Hagen, J.M. van, Hertel, N.T., Holder-Espinasse, M., Hollander, N. den, Homfray, T., Hove, H.D., Price, S., Raas-Rothschild, A., Rohrbach, M., Schroeter, B., Suri, M., Thompson, E.M., Tobias, E.S., Toutain, A., Vreeburg, M., Wakeling, E., Knoers, N.V.A.M., Coucke, P., Mortier, G.R., Terhal, P.A., Nievelstein, R.J., Verver, E.J., Topsakal, V., Dommelen, P. van, Hoornaert, K., Merrer, M. Le, Zankl, A., Simon, M.E., Smithson, S.F., Marcelis, C.L.M., Kerr, B., Clayton-Smith, J., Kinning, E., Mansour, S., Elmslie, F., Goodwin, L., Hout, A.H. van der, Veenstra-Knol, H.E., Herkert, J.C., Lund, A.M., Hennekam, R.C., Mégarbané, A., Lees, M.M., Wilson, L.C., Male, A., Hurst, J., Alanay, Y., Annerén, G., Betz, R.C., Bongers, E.M.H.F., Cormier-Daire, V., Dieux, A., David, A., Elting, M.W., Ende, J. van den, Green, A., Hagen, J.M. van, Hertel, N.T., Holder-Espinasse, M., Hollander, N. den, Homfray, T., Hove, H.D., Price, S., Raas-Rothschild, A., Rohrbach, M., Schroeter, B., Suri, M., Thompson, E.M., Tobias, E.S., Toutain, A., Vreeburg, M., Wakeling, E., Knoers, N.V.A.M., Coucke, P., and Mortier, G.R.

Abstract

Item does not contain fulltext

Published
2015

15. Alu-Alu Recombination Underlying the First Large Genomic Deletion in GlcNAc-Phosphotransferase Alpha/Beta (GNPTAB) Gene in a MLII Alpha/Beta Patient

Author

Coutinho, Maria Francisca, da Silva Santos, Liliana, Lacerda, Lúcia, Quental, Sofia, Wibrand, F., Lund, A.M., Johansen, K.B., Prata, Maria João, and Alves, Sandra

Subjects
Mucolipidosis II, Doenças Genéticas
Abstract

Mucolipidosis type II α/β is a severe, autosomal recessive lysosomal storage disorder, caused by a defect in the GNPTAB gene that codes for the α/β subunits of the GlcNAc-phosphotransferase. To date, over 100 different mutations have been identified in MLII α/β patients, but no large deletions have been reported. Here we present the first case of a large homozygous intragenic GNPTAB gene deletion (c.3435-386_3602 + 343del897) encompassing exon 19, identified in a ML II α/β patient. Long-range PCR and sequencing methodologies were used to refine the characterization of this rearrangement, leading to the identification of a 21 bp repetitive motif in introns 18 and 19. Further analysis revealed that both the 5' and 3' breakpoints were located within highly homologous Alu elements (Alu-Sz in intron 18 and Alu-Sq2, in intron 19), suggesting that this deletion has probably resulted from Alu-Alu unequal homologous recombination. RT-PCR methods were used to further evaluate the consequences of the alteration for the processing of the mutant pre mRNA GNPTAB, revealing the production of three abnormal transcripts: one without exon 19 (p.Lys1146_Trp1201del); another with an additional loss of exon 20 (p.Arg1145Serfs*2), and a third in which exon 19 was substituted by a pseudoexon inclusion consisting of a 62 bp fragment from intron 18 (p.Arg1145Serfs*16). Interestingly, this 62 bp fragment corresponds to the Alu-Sz element integrated in intron 18.This represents the first description of a large deletion identified in the GNPTAB gene and contributes to enrich the knowledge on the molecular mechanisms underlying causative mutations in ML II. This work was supported by FCT - project PIC/IC/83252/2007 (http://alfa.fct.mctes.pt/). Coutinho MF and Quental S received grants from the FCT (SFRH/BD/48103/2008; SFRH/BPD/64025/2009).

Published
2012

17. X-linked congenital ptosis and associated intellectual disability, short stature, microcephaly, cleft palate, digital and genital abnormalities define novel Xq25q26 duplication syndrome

Author

Moller, R.S., Jensen, L.R., Maas, S.M., Filmus, J., Capurro, M., Hansen, C., Marcelis, C.L.M., Ravn, K., Andrieux, J., Mathieu, M., Kirchhoff, M., Rodningen, O.K., Leeuw, N. de, Yntema, H.G., Froyen, G., Vandewalle, J., Ballon, K., Klopocki, E., Joss, S., Tolmie, J., Knegt, A.C., Lund, A.M., Hjalgrim, H., Kuss, A.W., Tommerup, N., Ullmann, R., Brouwer, A.P.M. de, Stromme, P., Kjaergaard, S., Tumer, Z., Kleefstra, T., Moller, R.S., Jensen, L.R., Maas, S.M., Filmus, J., Capurro, M., Hansen, C., Marcelis, C.L.M., Ravn, K., Andrieux, J., Mathieu, M., Kirchhoff, M., Rodningen, O.K., Leeuw, N. de, Yntema, H.G., Froyen, G., Vandewalle, J., Ballon, K., Klopocki, E., Joss, S., Tolmie, J., Knegt, A.C., Lund, A.M., Hjalgrim, H., Kuss, A.W., Tommerup, N., Ullmann, R., Brouwer, A.P.M. de, Stromme, P., Kjaergaard, S., Tumer, Z., and Kleefstra, T.

Abstract

Item does not contain fulltext, Submicroscopic duplications along the long arm of the X-chromosome with known phenotypic consequences are relatively rare events. The clinical features resulting from such duplications are various, though they often include intellectual disability, microcephaly, short stature, hypotonia, hypogonadism and feeding difficulties. Female carriers are often phenotypically normal or show a similar but milder phenotype, as in most cases the X-chromosome harbouring the duplication is subject to inactivation. Xq28, which includes MECP2 is the major locus for submicroscopic X-chromosome duplications, whereas duplications in Xq25 and Xq26 have been reported in only a few cases. Using genome-wide array platforms we identified overlapping interstitial Xq25q26 duplications ranging from 0.2 to 4.76 Mb in eight unrelated families with in total five affected males and seven affected females. All affected males shared a common phenotype with intrauterine- and postnatal growth retardation and feeding difficulties in childhood. Three had microcephaly and two out of five suffered from epilepsy. In addition, three males had a distinct facial appearance with congenital bilateral ptosis and large protruding ears and two of them showed a cleft palate. The affected females had various clinical symptoms similar to that of the males with congenital bilateral ptosis in three families as most remarkable feature. Comparison of the gene content of the individual duplications with the respective phenotypes suggested three critical regions with candidate genes (AIFM1, RAB33A, GPC3 and IGSF1) for the common phenotypes, including candidate loci for congenital bilateral ptosis, small head circumference, short stature, genital and digital defects.

Published
2014

18. A Patient with Complex I Deficiency Caused by a Novel ACAD9 Mutation Not Responding to Riboflavin Treatment

Author

Nouws, J., Wibrand, F., Brand, M.A. van den, Venselaar, H., Duno, M., Lund, A.M., Trautner, S., Nijtmans, L.G.J., Ostergard, E., Nouws, J., Wibrand, F., Brand, M.A. van den, Venselaar, H., Duno, M., Lund, A.M., Trautner, S., Nijtmans, L.G.J., and Ostergard, E.

Abstract

Contains fulltext : 127628.pdf (publisher's version ) (Open Access), Here we report a patient with a new pathogenic mutation in ACAD9. Shortly after birth she presented with respiratory insufficiency and a high lactate level. At age 7 weeks, she was diagnosed with severe hypertrophic cardiomyopathy and she suffered from muscle weakness and hypotonia. Her condition deteriorated during intercurrent illnesses and she died at 6 months of age in cardiogenic shock. Analysis of respiratory chain activities in muscle and fibroblasts revealed an isolated complex I deficiency. A genome-wide screen for homozygosity revealed several homozygous regions. Four candidate genes were found and sequencing revealed a homozygous missense mutation in ACAD9. The mutation results in an Ala220Val amino acid substitution located near the catalytic core of ACAD9. SDS and BN-PAGE analysis showed severely decreased ACAD9 and complex I protein levels, and lentiviral complementation of patient fibroblasts partially rescued the complex I deficiency. Riboflavin supplementation did not ameliorate the complex I deficiency in patient fibroblasts. More than a dozen ACAD9 patients with complex I deficiency have been identified in the last 3 years, indicating that ACAD9 is important for complex I assembly, and that ACAD9 mutations are a relatively frequent cause of complex I deficiency.

Published
2014

19. Mortality and cause of death in mucopolysaccharidosis type II-a historical review based on data from the Hunter Outcome Survey (HOS)

Author

Jones, S.A., Almássy, Z., Beck, Miroslav, Burt, K., Clarke, J.T., Giugliani, R., Hendriksz, C., Kroepfl, T., Lavery, L., Lin, S.P., Malm, G., Ramaswami, U., Tincheva, R., Wraith, J.E., Bodamer, O., De Meirleir, L., Melgar, D., Boy, R., Horovitz, D., Clarke, J., Clarke, L., Mabe, P., Barišić, Ingeborg, Barić, Ivo, Zeman, J., Lund, A.M., Guffon, N., Valayannopoulos, V., Héron, B., Beck, M., Frenking, G.S., Muschol, N., Zafeiriou, D., Gabrielli, O., Cicognani, A., DiRocco, M., Parini, R., and Scarpa, M.

Subjects
Adult, Male, medicine.medical_specialty, Pediatrics, Adolescent, Idursulfase, Iduronate Sulfatase, Cohort Studies, Young Adult, Cause of Death, Epidemiology, Genetics, medicine, Humans, Mucopolysaccharidosis type II, Young adult, Child, Genetics (clinical), Cause of death, Mucopolysaccharidosis II, Retrospective Studies, MPS type II, business.industry, Data Collection, Age Factors, Infant, Hunter syndrome, Enzyme replacement therapy, medicine.disease, Surgery, Treatment Outcome, Child, Preschool, Female, Settore MED/35 - MALATTIE CUTANEE E VENEREE, business, medicine.drug, Cohort study
Abstract

Mucopolysaccharidosis type II (MPS II or Hunter syndrome) is a progressive, multisystemic disease caused by a deficiency of iduronate-2-sulfatase. Patients with the severe form of the disease have cognitive impairment and typically die in the second decade of life. Patients with the less severe form do not experience significant cognitive involvement and may survive until the fifth or sixth decade of life. We studied the relationship of both severity of MPS II and the time period in which patients died with age at death in 129 patients for whom data were entered retrospectively into HOS (Hunter Outcome Survey), the only large-scale, multinational observational study of patients with MPS II. Median age at death was significantly lower in patients with cognitive involvement compared with those without cognitive involvement (11.7 versus 14.1 years ; p = 0.024). These data indicate that cognitive involvement is indicative of more severe disease and lower life expectancy in patients with MPS II. Median age at death was significantly lower in patients who died in or before 1985 compared with those who died after 1985 (11.3 versus 14.1 years ; p alpha 0.001). The difference in age at death between patients dying in or before, relative to after, the selected cut-off date of 1985 may reflect improvements in patient identification, care and management over the past two decades. Data from patients who died after 1985 could serve as a control in analyses of the effects of enzyme replacement therapy with idursulfase on mortality in patients with MPS II.

Published
2008

20. Avator: how to look for patterns in deception mechanisms at work

Author

Matysiak, A.J., Markopoulos, P., Czerwinski, M., Lund, A.M., and Tan, D.S.

Abstract

In this paper we introduce AVATOR – a research tool for investigating use patterns for different deception mechanisms in awareness systems. We also present a setup for the study on representing availability status in awareness systems we intend to conduct with this tool.

Published
2008

21. Supporting the analytical reasoning process in information visualization

Author

Shrinivasan, Y.B., Wijk, van, J.J., Czerwinski, M., Lund, A.M., Tan, D.S., Algorithms, Geometry and Applications, and Visualization

Subjects
Visual analytics, Information visualization, Process (engineering), Computer science, Human–computer interaction, business.industry, State (computer science), Artifact (software development), Reuse, business, Visualization, Analytic reasoning
Abstract

This paper presents a new information visualization framework that supports the analytical reasoning process. It consists of three views - a data view, a knowledge view and a navigation view. The data view offers interactive information visualization tools. The knowledge view enables the analyst to record analysis artifacts such as findings, hypotheses and so on. The navigation view provides an overview of the exploration process by capturing the visualization states automatically. An analysis artifact recorded in the knowledge view can be linked to a visualization state in the navigation view. The analyst can revisit a visualization state from both the navigation and knowledge views to review the analysis and reuse it to look for alternate views. The whole analysis process can be saved along with the synthesized information. We present a user study and discuss the perceived usefulness of a prototype based on this framework that we have developed.

Published
2008
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23. Mucopolysaccharidosis type II: European recommendations for the diagnosis and multidisciplinary management of a rare disease

Author

Scarpa, M. (Maurizio), Almássy, Z. (Zsuzsanna), Beck, M. (Michael), Bodamer, O.A. (Olaf), Bruce, I.A. (Iain), Meirleir, L. (Linda) de, Guffon, N. (Nathalie), Guillen-Navarro, E. (Encarna), Hensman, P. (Pauline), Jones, S. (Simon), Kamin, W. (Wolfgang), Kampmann, C. (Christoph), Lampe, C. (Christina), Lavery, C.A. (Christine), Leão Teles, E. (Elisa), Link, B. (Bianca), Lund, A.M. (Allan), Malm, G. (Gunilla), Pitz, S. (Susanne), Rothera, M. (Michael), Stewart, C. (Catherine), Tylki-Szymaska, A. (Anna), Ploeg, A.T. (Ans) van der, Walker, R. (Robert), Zeman, J. (Jiri), Wraith, J.E. (James), Scarpa, M. (Maurizio), Almássy, Z. (Zsuzsanna), Beck, M. (Michael), Bodamer, O.A. (Olaf), Bruce, I.A. (Iain), Meirleir, L. (Linda) de, Guffon, N. (Nathalie), Guillen-Navarro, E. (Encarna), Hensman, P. (Pauline), Jones, S. (Simon), Kamin, W. (Wolfgang), Kampmann, C. (Christoph), Lampe, C. (Christina), Lavery, C.A. (Christine), Leão Teles, E. (Elisa), Link, B. (Bianca), Lund, A.M. (Allan), Malm, G. (Gunilla), Pitz, S. (Susanne), Rothera, M. (Michael), Stewart, C. (Catherine), Tylki-Szymaska, A. (Anna), Ploeg, A.T. (Ans) van der, Walker, R. (Robert), Zeman, J. (Jiri), and Wraith, J.E. (James)

Abstract

Mucopolysaccharidosis type II (MPS II) is a rare, life-limiting, X-linked recessive disease characterised by deficiency of the lysosomal enzyme iduronate-2-sulfatase. Consequent accumulation of glycosaminoglycans leads to pathological changes in multiple body systems. Age at onset, signs and symptoms, and disease progression are heterogeneous, and patients may present with many different manifestations to a wide range of specialists. Expertise in diagnosing and managing MPS II varies widely between countries, and substantial delays between disease onset and diagnosis can occur. In recent years, disease-specific treatments such as enzyme replacement therapy and stem cell transplantation have helped to address the underlying enzyme deficiency in patients with MPS II. However, the multisystem nature of this disorder and the irreversibility of some manifestations mean that most patients require substantial medical support from many different specialists, even if they are receiving treatment. This article presents an overview of how to recognise, diagnose, and care for patients with MPS II. Particular focus is given to the multidisciplinary nature of patient management, which requires input from paediatricians, specialist nurses, otorhinolaryngologists, orthopaedic surgeons, ophthalmologists, cardiologists, pneumologists, anaesthesiologists, neurologists, physiotherapists, occupational therapists, speech therapists, psychologists, social workers, homecare companies and patient societies. Take-home message. Expertise in recognising and treating patients with MPS II varies widely between countries. This article presents pan-European recommendations for the diagnosis and management of this life-limiting disease.

Published
2011
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24. Mucopolysaccharidosis type II (Hunter syndrome): A clinical review and recommendations for treatment in the era of enzyme replacement therapy

Author

Wraith, J.E. (James), Scarpa, M. (Maurizio), Beck, M. (Markus), Bodamer, O.A. (Olaf), Meirleir, L. (Linda) de, Guffon, N. (Nathalie), Lund, A.M. (Allan), Malm, G. (Gunilla), Ploeg, A.T. (Ans) van der, Zeman, J. (Jiri), Wraith, J.E. (James), Scarpa, M. (Maurizio), Beck, M. (Markus), Bodamer, O.A. (Olaf), Meirleir, L. (Linda) de, Guffon, N. (Nathalie), Lund, A.M. (Allan), Malm, G. (Gunilla), Ploeg, A.T. (Ans) van der, and Zeman, J. (Jiri)

Abstract

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is a rare X-linked recessive disease caused by deficiency of the lysosomal enzyme iduronate-2-sulphatase, leading to progressive accumulation of glycosaminoglycans in nearly all cell types, tissues and organs. Clinical manifestations include severe airway obstruction, skeletal deformities, cardiomyopathy and, in most patients, neurological decline. Death usually occurs in the second decade of life, although some patients with less severe disease have survived into their fifth or sixth decade. Until recently, there has been no effective therapy for MPS II, and care has been palliative. Enzyme replacement therapy (ERT) with recombinant human iduronate-2-sulphatase (idursulfase), however, has now been introduced. Weekly intravenous infusions of idursulfase have been shown to improve many of the signs and symptoms and overall wellbeing in patients with MPS II. This paper provides an overview of the clinical manifestations, diagnosis and symptomatic management of patients with MPS II and provides recommendations for the use of ERT. The issue of treating very young patients and those with CNS involvement is also discussed. ERT with idursulfase has the potential to benefit many patients with MPS II, especially if started early in the course of the disease.

Published
2008
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25. [Congenital methaemoglobinaemia: an infrequent cause of neonatal cyanosis]

Author

Smith, B., Christensen, E., Lund, A.M., Pryds, Ole, Smith, B., Christensen, E., Lund, A.M., and Pryds, Ole

Abstract

We present a case study of a newborn girl with a reduced erythrocytic nicotinamide adenine dinucleotide (NADH)-dependent methaemoglobin reductase level. Within the first days of life she developed cyanosis due to a methaemoglobin level of 21%. The hyperoxia test was characteristic, with normal increases in blood oxygen tension, whereas the oxygen saturation remained constant at 92%. Over the next months the methaemoglobin level decreased to 10%, and the girl did well without treatment Udgivelsesdato: 2008/8/11

Published
2008

26. Alpha-mannosidosis: characterization of CNS pathology and correlation between CNS pathology and cognitive function.

Author

Borgwardt, L., Danielsen, E.R., Thomsen, C., Månsson, J.E., Taouatas, N., Thuesen, A.M., Olsen, K.J., Fogh, J., Dali, C.I., and Lund, A.M.

Subjects
COGNITIVE ability, CENTRAL nervous system, NUCLEAR magnetic resonance spectroscopy, MYELINATION, BIOMARKERS, OLIGOSACCHARIDES
Abstract

Alpha-mannosidosis (AM) (OMIM 248500) is a rare lysosomal storage disease. The understanding of the central nervous system ( CNS) pathology is limited. This study is the first describing the CNS pathology and the correlation between the CNS pathology and intellectual disabilities in human AM. Thirty-four patients, aged 6-35 years, with AM were included. Data from 13 healthy controls were included in the analysis of the magnetic resonance spectroscopy ( MRS). Measurements of CNS neurodegeneration biomarkers in cerebrospinal fluid ( CSF), CSF-oligosaccharides, and performance of cerebral magnetic resonance imaging ( MRI) and MRS were carried out. On MRI, 5 of 10 patients had occipital white matter ( WM) signal abnormalities, and 6 of 10 patients had age-inappropriate myelination. MRS demonstrated significantly elevated mannose complex in gray matter and WM. We found elevated concentrations of tau-protein, glial fibrillary acidic protein and neurofilament light protein in 97 patients, 74% and 41% of CSF samples, respectively. A negative correlation between CSF-biomarkers and cognitive function and CSF-oligosaccharides and cognitive function was found. The combination of MRS/ MRI changes, elevated concentrations of CSF-biomarkers and CSF-oligosaccharides suggests gliosis and reduced myelination, as part of the CNS pathology in AM. Our data demonstrate early neuropathological changes, which may be taken into consideration when planning initiation of treatment. [ABSTRACT FROM AUTHOR]

Published
2016
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40. Identification of two new mutations in the TAT gene in a Danish family with tyrosinaemia type II.

Author

Pasternack, S.M., Betz, R.C., Brandrup, F., Gade, E.F., Clemmensen, O., Lund, A.M., Christensen, E., and Bygum, A.

Subjects
CASE studies, DYSTROPHY, URINALYSIS, TYROSINE, AMINO acids, PHENYLALANINE
Abstract

The article presents a case study of 28-year old woman who has incapacitating palmoplantar keratoderma. She also has a severe nail dystrophy relative to onychophagia. Urine analysis showed an increased excretion of tyrosine and tyrosine metabolites without succinylacetone. To reduce the patient's plasma tyrosine level, she underwent a protein-restricted diet supplemented with essential and nonessential amino acids free from tyrosine and phenylalanine.

Published
2009
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41. Anthropometry of patients with osteogenesis imperfecta

Author

Lund, A.M., Skovby, F., and Müller, J.

Abstract

Standing height, sitting height, armspan, subischial leg length, head circumference, and growth hormone-insulin-like growth factor I (IGF-I) axis were determined in 86 patients with osteogenesis imperfecta. The aim of this study was to determine standing height and body proportions and their variability among osteogenesis imperfecta types and collagen defects. Mean standing height was reduced in all groups of patients, to the greatest extent and variability in osteogenesis imperfecta type III/IV and in those with qualitative collagen defects. The mean standing height of patients with osteogenesis imperfecta was lower than that of their unaffected first degree family members. Truncal height of patients with osteogenesis imperfecta was reduced; head size was increased, and this was more pronounced in patients with osteogenesis imperfecta type III/IV and qualitative collagen defects than in patients with osteogenesis imperfecta type I and quantitative collagen defects. Mean concentrations of IGF-I and IGF binding protein 3 (IGFBP-3) were low, but most values were within age specific reference values. The reduction of standing height appears to correlate with osteogenesis imperfecta type and the type of collagen defect. A relatively short trunk is typical and head circumference and body length are disproportionate.

Published
1999

42. Application of High-Sensitivity Troponin in Suspected Myocardial Infarction.

Author

Neumann JT, Twerenbold R, Ojeda F, Sörensen NA, Chapman AR, Shah ASV, Anand A, Boeddinghaus J, Nestelberger T, Badertscher P, Mokhtari A, Pickering JW, Troughton RW, Greenslade J, Parsonage W, Mueller-Hennessen M, Gori T, Jernberg T, Morris N, Liebetrau C, Hamm C, Katus HA, Münzel T, Landmesser U, Salomaa V, Iacoviello L, Ferrario MM, Giampaoli S, Kee F, Thorand B, Peters A, Borchini R, Jørgensen T, Söderberg S, Sans S, Tunstall-Pedoe H, Kuulasmaa K, Renné T, Lackner KJ, Worster A, Body R, Ekelund U, Kavsak PA, Keller T, Lindahl B, Wild P, Giannitsis E, Than M, Cullen LA, Mills NL, Mueller C, Zeller T, Westermann D, and Blankenberg S

Subjects
Adult, Aged, Biomarkers blood, Cohort Studies, Emergency Service, Hospital, Female, Humans, Male, Middle Aged, Prognosis, Sensitivity and Specificity, Troponin I blood, Myocardial Infarction blood, Myocardial Infarction diagnosis, Risk Assessment methods, Troponin blood
Abstract

Background: Data regarding high-sensitivity troponin concentrations in patients presenting to the emergency department with symptoms suggestive of myocardial infarction may be useful in determining the probability of myocardial infarction and subsequent 30-day outcomes., Methods: In 15 international cohorts of patients presenting to the emergency department with symptoms suggestive of myocardial infarction, we determined the concentrations of high-sensitivity troponin I or high-sensitivity troponin T at presentation and after early or late serial sampling. The diagnostic and prognostic performance of multiple high-sensitivity troponin cutoff combinations was assessed with the use of a derivation-validation design. A risk-assessment tool that was based on these data was developed to estimate the risk of index myocardial infarction and of subsequent myocardial infarction or death at 30 days., Results: Among 22,651 patients (9604 in the derivation data set and 13,047 in the validation data set), the prevalence of myocardial infarction was 15.3%. Lower high-sensitivity troponin concentrations at presentation and smaller absolute changes during serial sampling were associated with a lower likelihood of myocardial infarction and a lower short-term risk of cardiovascular events. For example, high-sensitivity troponin I concentrations of less than 6 ng per liter and an absolute change of less than 4 ng per liter after 45 to 120 minutes (early serial sampling) resulted in a negative predictive value of 99.5% for myocardial infarction, with an associated 30-day risk of subsequent myocardial infarction or death of 0.2%; a total of 56.5% of the patients would be classified as being at low risk. These findings were confirmed in an external validation data set., Conclusions: A risk-assessment tool, which we developed to integrate the high-sensitivity troponin I or troponin T concentration at emergency department presentation, its dynamic change during serial sampling, and the time between the obtaining of samples, was used to estimate the probability of myocardial infarction on emergency department presentation and 30-day outcomes. (Funded by the German Center for Cardiovascular Research [DZHK]; ClinicalTrials.gov numbers, NCT00470587, NCT02355457, NCT01852123, NCT01994577, and NCT03227159; and Australian New Zealand Clinical Trials Registry numbers, ACTRN12611001069943, ACTRN12610000766011, ACTRN12613000745741, and ACTRN12611000206921.)., (Copyright © 2019 Massachusetts Medical Society.)

Published
2019
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