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3. Evidence-Based Consensus Guidelines Series for MicroPulse Transscleral Laser Therapy - Surgical Technique, Post-Operative Care, Expected Outcomes and Retreatment/Enhancements

Author

Grippo TM, Töteberg-Harms M, Giovingo M, Francis BA, de Crom RMPC, Jerkins B, Brubaker JW, An J, Radcliffe N, and Noecker R

Subjects
glaucoma, micropulse, transscleral laser treatment, Ophthalmology, RE1-994
Abstract

Tomas M Grippo,1 Marc Töteberg-Harms,2 Michael Giovingo,3 Brian A Francis,4 Ronald RMPC de Crom,5 Brian Jerkins,6 Jacob W Brubaker,7 Jella An,8 Nathan Radcliffe,9 Robert Noecker10 1Grippo Glaucoma and Cataract Center, Buenos Aires, Argentina; 2Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA, USA; 3Cook County Health, Chicago, IL, USA; 4Department of Ophthalmology, Doheny and Stein Eye Institutes, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA; 5University Eye Clinic, Maastricht University Medical Centre, Maastricht, the Netherlands; 6Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, TN, USA; 7Sacramento Eye Consultants, Sacramento, CA, USA; 8Department of Ophthalmology, Wilmer Eye Institute, John Hopkins School of Medicine, Bethesda, MD, USA; 9Glaucoma Department, New York Eye and Ear Infirmary, New York, NY, USA; 10Ophthalmic Consultants of Connecticut, Fairfield, CT, USACorrespondence: Tomas M Grippo, Grippo Glaucoma and Cataract Center, 250 Luis Maria Campos, 1st Floor, Suite O, Capital Federal, 1426, Argentina, Tel +54-11-4-774-2930, Email tomasgrippo@yahoo.comPurpose: To provide expert consensus and evidence-based current guidelines on treatment technique, postoperative care, expected outcomes and retreatment for MicroPulse Transscleral Laser Treatment (TLT).Methods: A comprehensive search of PubMed led to the identification and analysis of 61 studies on MicroPulse TLT. To provide guidance in areas where there was not enough available literature, a three-round Delphi method was conducted involving 10 international experts in MicroPulse TLT.Results: The response rate was 70% in the first round, 70% in the second round, and 80% in the third round of the Delphi method. Once all responses were aggregated, a live meeting was held with 90% attendance, and consensus was achieved on each of the findings detailed in this manuscript.Conclusion: Used within appropriate treatment parameters, with proper technique and patient selection, MicroPulse TLT is a safe and effective treatment for many types and severities of glaucoma. MicroPulse TLT represents a useful addition to the glaucoma armamentarium.Keywords: glaucoma, MicroPulse, transscleral laser treatment

Published
2023

4. Evidence-Based Consensus Guidelines Series for MicroPulse Transscleral Laser Therapy: Dosimetry and Patient Selection

Author

Grippo TM, de Crom RMPC, Giovingo M, Töteberg-Harms M, Francis BA, Jerkins B, Brubaker JW, Radcliffe N, An J, and Noecker R

Subjects
glaucoma, micropulse, transscleral laser treatment, Ophthalmology, RE1-994
Abstract

Tomas M Grippo,1 Ronald MPC de Crom,2 Michael Giovingo,3 Marc Töteberg-Harms,4 Brian A Francis,5 Brian Jerkins,6 Jacob W Brubaker,7 Nathan Radcliffe,8 Jella An,9 Robert Noecker10 1Department of Ophthalmology, Hospital Aleman, Buenos Aires, Argentina; 2University Eye Clinic, Maastricht University Medical Centre, Maastricht, the Netherlands; 3Department of Ophthalmology, Cook County Health, Chicago, Illinois, USA; 4Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA, USA; 5Department of Ophthalmology, Doheny and Stein Eye Institutes, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA; 6Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, TN, USA; 7Sacramento Eye Consultants, Sacramento, CA, USA; 8New York Eye and Ear Infirmary, New York, NY, USA; 9Department of Ophthalmology, Wilmer Eye Institute, John Hopkins School of Medicine, Bethesda, MD, USA; 10Department of Ophthalmology, School of Medicine, Yale University, New Haven, CT, USACorrespondence: Tomas M Grippo, 250 Luis Maria Campos, 1st Floor, Suite O, Capital Federal, Buenos Aires, 1426, Argentina, Tel +54-11-4-774-2930, Email tomasgrippo@yahoo.comPurpose: To provide consensus-based current guidelines on optimal dosimetry and patient selection for MicroPulse Transscleral Laser Therapy (TLT) based on a review of the literature and a Delphi method.Methods: A comprehensive search of Pub Med led to the identification and analysis of 61 studies on MicroPulse TLT that contained information on laser settings and patient selection. To determine consensus in areas where there was not enough available literature, a three-round Delphi method was conducted.Results: The response rate was 90% in the first round, 90% in the second round, and 80% in the third round of the Delphi technique. Once all responses were aggregated, a live meeting was held with 80% attendance, and consensus was achieved on each of the findings detailed in this manuscript.Conclusion: Micropulse TLT is a useful addition to the glaucoma armamentarium. When used with proper surgical technique at energy settings within the boundaries described in this manuscript, MicroPulse TLT is a safe and effective treatment for many types and stages of glaucoma. Based on current knowledge and experience, the consensus recommendation of this expert panel is that the standard MicroPulse TLT settings using the revised MicroPulse P3 Probe should be 2500 mW, 31.3% duty cycle, and 4 sweeps at a sweep velocity of 20 seconds each per hemisphere. Both hemispheres avoiding the 3 and 9 clock hours should be treated. The panel also reached consensus on patient selection for MicroPulse TLT providing guidance for the use of the procedure.Keywords: glaucoma, MicroPulse, transscleral laser therapy

Published
2022

5. Theme 1 Epidemiology and Informatics.

Author

Dugom, L., Chavira, J., Butler, L., Oranski, J., Gutierrez, G., Hoover, B., Griffen, S., Dailey, W., Oskarsson, B., Ly, C., Miller, T., Ravits, J., Harms, M., Shneider, N., Ladha, S., Harris, B., Streicher, N., Carpenter, C., Holmes, C., and Ajroud-Driss, S.

Subjects
MOTOR neuron diseases, LEAD exposure, AMYOTROPHIC lateral sclerosis, SPINAL muscular atrophy, COVID-19 pandemic, DYSLIPIDEMIA, APOLIPOPROTEIN E
Abstract

The article discusses the initiation of a natural history study of ALS by Target ALS to capture multi-omic, clinical, and demographic datasets linked to longitudinal biofluids. Efforts are made to include historically underrepresented ethnicities and races in the study. The study aims to enroll 800 symptomatic ALS participants and 200 healthy controls from diverse populations worldwide. The study has enrolled 125 participants to date, with 24% of ALS participants known to have genetic mutations. The study also explores the prevalence of ALS in Kazakhstan and the influence of environmental factors on the disease. [Extracted from the article]

Published
2024
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6. Surveillance van enterale, vector-overdraagbare en zoönotische infecties. Jaarrapportage 2023

Author

Friesema, I, Pijnacker, R, Tulen, L, van den Berg, O, Adriaansens, D, Obels, I, van den Wijngaard, K, Harms, M, Lanzl, M, Mughini Gras, L, van den Beld, M, Franz, E, Friesema, I, Pijnacker, R, Tulen, L, van den Berg, O, Adriaansens, D, Obels, I, van den Wijngaard, K, Harms, M, Lanzl, M, Mughini Gras, L, van den Beld, M, and Franz, E

Abstract

RIVM rapport:Infecties aan maag en darmen, zogeheten enterale infecties, worden veroorzaakt door verschillende bacteriën, parasieten of virussen. Meestal krijgen mensen daarvan maag-darmklachten, zoals overgeven, buikpijn en/of (bloederige) diarree. In sommige gevallen kunnen de klachten ernstig zijn, zoals hepatitis, bloedvergiftiging of hersenvliesontsteking. Mensen raken meestal besmet via voedsel of water dat in contact is gekomen met ontlasting van mensen of dieren. Als de ziekteverwekker via dieren wordt overgedragen, spreken we van zoönosen. Goede hygiëne in toiletten en keukens en bij de bereiding van vlees is heel belangrijk om een besmetting te voorkomen. In 2022 was het aantal mensen met maag-darminfecties veel lager door de coronapandemie, in 2023 was dat effect bijna niet meer te zien. Het aantal infecties was vergelijkbaar met de jaren voor de pandemie. Wel viel in 2023 het hoge aantal infecties op met Shigella, Shiga toxine-producerende E. coli (STEC), norovirus en Cryptosporidium. De stijging van shigellose is vooral te zien onder mannen die seks hebben met mannen (MSM). Voor de andere ziekteverwekkers is geen duidelijke oorzaak bekend. In 2023 is bij verschillende uitbraken onderzocht welke bron de oorzaak was: een uitbraak door de Campylobacter-bacterie, vier uitbraken door de Salmonella-bacterie en één door de STEC-bacterie. Alleen van twee salmonellose-uitbraken is de bron gevonden. Dat waren eieren van leghenbedrijven die besmet waren via besmet voer; en droge worst die niet genoeg was gerijpt. Ook geleedpotigen, zoals muggen en teken, kunnen bacteriën, parasieten en virussen bij zich dragen waar mensen ziek van worden. Hersen(vlies)infecties door het tekenencefalitisvirus zijn in 2023 in drie nieuwe gebieden in Nederland vastgesteld. Tot slot liepen dat jaar een recordaantal reizigers een dengue (knokkelkoorts) infectie op. Deze toename is in de hele wereld te zien. Het RIVM houdt bij hoe vaak dit soort infecties in Nederland voorkomen en brengt uitbraken i, Gastrointestinal, or enteric, infections are caused by various bacterial, parasitic and viral pathogens. Infected people usually experience gastrointestinal complaints, such as vomiting, abdominal pain and/or diarrhoea (which may be bloody). In some cases, serious complaints may develop, such as hepatitis, blood poisoning or meningitis. People usually become infected through food or water that has come into contact with human or animal faeces. When transmitted via animals, we speak of zoonoses. Good hygiene in toilets and kitchens and when preparing meat is very important to prevent infection. In 2022, the number of people with gastrointestinal infections was much lower due to the coronavirus pandemic, in 2023, this effect was almost no longer visible. The number of infections was comparable to the years before the pandemic. However, a notable factor in 2023 was the high number of infections with Shigella, Shiga toxin-producing E. coli (STEC), the norovirus, Cryptosporidium and leptospirosis. The increase in shigellosis was mainly seen among men who have sex with men (MSM). No clear cause is known for the other pathogens. In 2023, an active outbreak investigation was conducted into an outbreak of campylobacteriosis, four salmonellosis outbreaks and a STEC outbreak. The source of only two salmonellosis outbreaks was found. These were eggs from laying hen farms that had been contaminated via contaminated feed; and dry sausage that had insufficiently matured. Arthropods, such as mosquitoes and ticks, can also carry bacteria, parasites and viruses that make people ill. Tickborne encephalitis infections were diagnosed in three new areas in the Netherlands in 2023. Finally, there were a record number of travellers with a dengue infection in 2023. This increase was seen all over the world. RIVM keeps track of how often these types of infections occur in the Netherlands and maps outbreaks. An outbreak is when two or more people are infected by the same source. RIVM then tri

Published
2024

7. Surveillance van enterale, vector-overdraagbare en zoönotische infecties : Jaarrapportage 2023

Author

Friesema, I., Pijnacker, R., Tulen, L., Berg, O. van den, Adriaansens, D., Obels, I., Wijngaard, K. van den, Harms, M., Lanzl, M., Mughini Gras, L., Beld, M. van den, Franz, E., Friesema, I., Pijnacker, R., Tulen, L., Berg, O. van den, Adriaansens, D., Obels, I., Wijngaard, K. van den, Harms, M., Lanzl, M., Mughini Gras, L., Beld, M. van den, and Franz, E.

Abstract

Infecties aan maag en darmen, zogeheten enterale infecties, worden veroorzaakt door verschillende bacteriën, parasieten of virussen. Meestal krijgen mensen daarvan maag-darmklachten, zoals overgeven, buikpijn en/of (bloederige) diarree. In sommige gevallen kunnen de klachten ernstig zijn, zoals hepatitis, bloedvergiftiging of hersenvliesontsteking. In 2023 is bij verschillende uitbraken onderzocht welke bron de oorzaak was: een uitbraak door de Campylobacter-bacterie, vier uitbraken door de Salmonella-bacterie en één door de STEC-bacterie. Alleen van twee salmonellose-uitbraken is de bron gevonden. Dat waren eieren van leghenbedrijven die besmet waren via besmet voer; en droge worst die niet genoeg was gerijpt.

Published
2024

9. Refractive Outcomes After Trabecular Micro-Bypass Stents (iStent Inject) with Cataract Extraction in Open-Angle Glaucoma

Author

Ioannidis AS, Töteberg-Harms M, Hamann T, and Hodge C

Subjects
glaucoma, cataract surgery, trabecular micro-bypass stents, astigmatism, intraocular lenses, Ophthalmology, RE1-994
Abstract

Alexandros S Ioannidis, 1, 2 Marc Töteberg-Harms, 3 Timothy Hamann, 3 Christopher Hodge 1, 4, 5 1Vision Eye Institute Blackburn South, Melbourne, VIC, Australia; 2Royal Melbourne Hospital, Melbourne, VIC, Australia; 3Department of Ophthalmology, University Hospital Zurich, Zurich, Switzerland; 4Sydney Medical School, The University of Sydney, Sydney, NSW, Australia; 5Graduate School of Health, University of Technology Sydney, Sydney, NSW, AustraliaCorrespondence: Alexandros S IoannidisVision Eye Institute Blackburn South, 156 Canterbury Road, Blackburn South, VIC 3130, AustraliaTel +61 3 9877 6288Fax +61 3 9894 2691Email alexioannidis.ai@gmail.comPurpose: Simultaneous cataract and glaucoma surgery has traditionally been challenging for the anterior segment surgeon. The introduction of minimally invasive glaucoma surgery (MIGS) in conjunction with cataract surgery appears safe and effective in lowering intraocular pressure. Although a significant visual impact leading from the combined procedure is unexpected, we aim to describe the refractive outcomes in a cohort of patients undergoing simultaneous cataract removal and iStent inject and discuss the potential implications of combined surgery in patients with co-existent glaucoma.Patients and Methods: This is a retrospective consecutive case series inclusive of patients undergoing combined femtosecond laser-assisted cataract surgery and the insertion of two trabecular micro-bypass stents (iStent inject). Visual acuity, refraction and astigmatic vector analysis were collated and analysed from the preoperative and 4 weeks postoperative visits.Results: One hundred and six eyes of 89 patients from 2 surgeons were included in the original cohort. The mean absolute difference from target refraction was 0.36 ± 0.25D. 73.9% of eyes were within ± 0.5D of the refractive target and 98.9% of eyes were within ± 1.00D. 73.8% of eyes had 0.5D or less residual refractive astigmatism following the procedure.Conclusion: We present a novel cohort of glaucoma patients undergoing combined trabecular micro-bypass stents (iStent inject) and cataract surgery achieving excellent refractive outcomes. The results of this study indicate that this second-generation device is refractively neutral.Keywords: glaucoma, cataract surgery, trabecular micro-bypass stents, astigmatism, intraocular lenses

Published
2020

11. P281 Quality of life in adults with dysferlinopathy: international clinical outcome study of dysferlinopathy

Author

Hilsden, H., primary, James, M., additional, Dressman, H Gordish, additional, Day, J., additional, Mendell, J., additional, Torron, R Fernandez, additional, Harms, M., additional, Pestronk, A., additional, Vissing, J., additional, Desai, U., additional, Yoshimura, M., additional, Shin, J., additional, Mozaffar, T., additional, Stojkovic, T., additional, Pegoraro, E., additional, Raivas, J Bevilacqu, additional, Olive, M., additional, Paradas, C., additional, Straub, V., additional, and Mayhew, A., additional

Published
2023
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15. Research from low-income and middle-income countries will benefit global health and the physiotherapy profession, but it requires support.

Author

Sharma, S, Verhagen, AP, Elkins, M, Brismée, J-M, Fulk, GD, Taradaj, J, Steen, L, Jette, A, Moore, A, Stewart, A, Hoogenboom, BJ, Söderlund, A, Harms, M, Pinto, RZ, Sharma, S, Verhagen, AP, Elkins, M, Brismée, J-M, Fulk, GD, Taradaj, J, Steen, L, Jette, A, Moore, A, Stewart, A, Hoogenboom, BJ, Söderlund, A, Harms, M, and Pinto, RZ

Published
2023

16. C9orf72 is required for proper macrophage and microglial function in mice

Author

O'Rourke, J. G., Bogdanik, L., Yáñez, A., Lall, D., Wolf, A. J., Muhammad, A. K. M. G., Ho, R., Carmona, S., Vit, J.P., Zarrow, J., Kim, K. J., Bell, S., Harms, M. B., Miller, T. M., Dangler, C. A., Underhill, D. M., Goodridge, H. S., Lutz, C. M., and Baloh, R. H.

Published
2016

17. Selinunt, Sizilien. Forschungen in Selinunt, Teil 1. Ein neues Modell für die Stadt Selinunt. Die Feldarbeiten des Jahres 2021

Author

Jonasch, M, Adorno, L, Burgio, A, Di Maggio, A, Harms, M., Schlöffel, M, Schneider, S, Wilken, D, Jonasch, M, Adorno, L, Burgio, A, Di Maggio, A, Harms, M, Schlöffel, M, Schneider, S, Wilken, D, and Harms, M.

Subjects
Selinunte, Excavation, Archaeological survey, Metodological approach, Settore L-ANT/09 - Topografia Antica
Abstract

Since 2021, the German Research Foundation has been funding a new interdisciplinary field project to investigate the urban fabric of the Greek colony of Selinous in a spatially comprehensive and diachronic perspective. The project aims at extending the existing model of the ideal Greek city by considering also the historically conditioned fractures in the urban development and the multiple transformations of the living space between the 7th and 3rd century BCE. This is to be pursued by large scale archaeological, geophysical and geoarchaeological prospections, small excavations in selected areas and the thorough study of the finds and archaeobiological remains. This is a report about the first field campaigns of the various specialist disciplines and a presentation of some preliminary results.

Published
2022

18. Science on ecosystems and people to support the Kunming-Montreal Global Biodiversity Framework

Author

Schröter, M., Berbés-Blázquez, M., Albert, C., Hill, R., Krause, T., Loos J., Mannetti, L., Martín-López, B., Neelakantan, A., Parrotta, J., Quintas-Soriano, C., Abson, D., Alkemade, R., Amelung, B., Baptiste, B., Barrios, E., Djoudi, H., Drakou, E., Durance, I., García Llorente, M., Geneletti, D., Harmáčková, Z., Jacobs, S., Kaiser, N., Kingsley, J., Klain, S., Martínez-Harms, M., Murali, R., O’Farrell, P., Pandit, R., Pereira, L., Rana, S., Riechers, M., Rusch, G., Sala, J., Schulp, C., Sitas, N., Subramanian, S., Villasante, S., and Oudenhoven, A.P.E. van

Subjects
Ecosystems Research, Biology
Published
2023

22. P.178 Clinical classification of variants in the valosin containing protein gene associated with multisystem proteinopathy

Author

Manera, J. Díaz, primary, Schiava, M., additional, Ikenaga, C., additional, Stojkovic, T., additional, Nishino, I., additional, Nair, S., additional, Manousakis, G., additional, Quinn, C., additional, Sahenk, Z., additional, Monforte, M., additional, Oldfors, A., additional, Pal, E., additional, Gomez, B. Velez, additional, de Bleecker, J., additional, Farrugia, M., additional, Harms, M., additional, Ralston, S., additional, Fernandez, J. Sotoca, additional, and Bevilacqua, J., additional

Published
2022
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25. A Comparison of Prognostic Scores (Mayo, UK-PBC, and GLOBE) in Primary Biliary Cholangitis

Author

Goet, J, Murillo Perez, C, Harms, M, Floreani, A, Cazzagon, N, Bruns, T, Prechter, F, Dalekos, G, Verhelst, X, Gatselis, N, Lindor, K, Lammers, W, Gulamhusein, A, Reig, A, Carbone, M, Nevens, F, Hirschfield, G, van der Meer, A, van Buuren, H, Hansen, B, Pares, A, Goet J. C., Murillo Perez C. F., Harms M. H., Floreani A., Cazzagon N., Bruns T., Prechter F., Dalekos G. N., Verhelst X., Gatselis N. K., Lindor K. D., Lammers W. J., Gulamhusein A., Reig A., Carbone M., Nevens F., Hirschfield G. M., van der Meer A. J., van Buuren H. R., Hansen B. E., Pares A., Goet, J, Murillo Perez, C, Harms, M, Floreani, A, Cazzagon, N, Bruns, T, Prechter, F, Dalekos, G, Verhelst, X, Gatselis, N, Lindor, K, Lammers, W, Gulamhusein, A, Reig, A, Carbone, M, Nevens, F, Hirschfield, G, van der Meer, A, van Buuren, H, Hansen, B, Pares, A, Goet J. C., Murillo Perez C. F., Harms M. H., Floreani A., Cazzagon N., Bruns T., Prechter F., Dalekos G. N., Verhelst X., Gatselis N. K., Lindor K. D., Lammers W. J., Gulamhusein A., Reig A., Carbone M., Nevens F., Hirschfield G. M., van der Meer A. J., van Buuren H. R., Hansen B. E., and Pares A.

Abstract

INTRODUCTION: Comparative data on scores that predict outcome in primary biliary cholangitis (PBC) are scarce. We aimed to assess and compare the prognostic value of the Mayo Risk Score (MRS, 1989 and 1994), UK-PBC score, and GLOBE score in a large international cohort of patients with PBC. METHODS: Ursodeoxycholic acid-treated patients from 7 centers participating in the GLOBAL PBC Study Group were included. The discriminatory performance of the scores was assessed with concordance statistics at yearly intervals up to 5 years. Model for End-stage Liver Disease was included for comparison. Prediction accuracy was assessed by comparing predicted survival and actual survival in Kaplan-Meier analyses. RESULTS: A total of 1,100 ursodeoxycholic acid-treated patients with PBC were included, with a mean (SD) age of 53.6 (12.0) years, of whom 1,003 (91%) were female. During a median follow-up of 7.6 (interquartile range 4.1-11.7) years, 42 patients underwent liver transplantation, and 127 patients died. At 1 year, the concordance statistic for Model for End-stage Liver Disease was 0.68 (95% confidence interval [CI] 0.64-0.72), 0.74 (95% CI 0.67-0.80) for the UK-PBC score, 0.76 (95% CI 0.72-0.81) for the MRS (1989 and 1994), and 0.80 (95% CI 0.76-0.84) for the GLOBE score. The GLOBE score showed superior discriminatory performance, but differences were not statistically different. For all scores, discriminatory performance increased in those with bilirubin >0.6 × ULN and advanced fibrosis estimated with Fibrosis-4. The predicted (median) minus observed 5-year transplant-free survival was +0.4% and +2.5% for the MRS (1989) and GLOBE score, respectively. DISCUSSION: All prognostic scores developed for PBC (GLOBE, UK-PBC, and MRS) demonstrated comparable discriminating performance for liver transplantation or death as well as good prediction accuracy.

Published
2021

26. Number needed to treat with ursodeoxycholic acid therapy to prevent liver transplantation or death in primary biliary cholangitis

Author

Harms, M, De Veer, R, Lammers, W, Corpechot, C, Thorburn, D, Janssen, H, Lindor, K, Trivedi, P, Hirschfield, G, Pares, A, Floreani, A, Mayo, M, Invernizzi, P, Battezzati, P, Nevens, F, Ponsioen, C, Mason, A, Kowdley, K, Hansen, B, Buuren, H, Van Der Meer, A, Harms M. H., De Veer R. C., Lammers W. J., Corpechot C., Thorburn D., Janssen H. L. A., Lindor K. D., Trivedi P. J., Hirschfield G. M., Pares A., Floreani A., Mayo M. J., Invernizzi P., Battezzati P. M., Nevens F., Ponsioen C. Y., Mason A. L., Kowdley K. V., Hansen B. E., Buuren H. R. V., Van Der Meer A. J., Harms, M, De Veer, R, Lammers, W, Corpechot, C, Thorburn, D, Janssen, H, Lindor, K, Trivedi, P, Hirschfield, G, Pares, A, Floreani, A, Mayo, M, Invernizzi, P, Battezzati, P, Nevens, F, Ponsioen, C, Mason, A, Kowdley, K, Hansen, B, Buuren, H, Van Der Meer, A, Harms M. H., De Veer R. C., Lammers W. J., Corpechot C., Thorburn D., Janssen H. L. A., Lindor K. D., Trivedi P. J., Hirschfield G. M., Pares A., Floreani A., Mayo M. J., Invernizzi P., Battezzati P. M., Nevens F., Ponsioen C. Y., Mason A. L., Kowdley K. V., Hansen B. E., Buuren H. R. V., and Van Der Meer A. J.

Abstract

Objective The clinical benefit of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC) has never been reported in absolute measures. The aim of this study was to assess the number needed to treat (NNT) with UDCA to prevent liver transplantation (LT) or death among patients with PBC. Methods The NNT was calculated based on the untreated LT-free survival and HR of UDCA with respect to LT or death as derived from inverse probability of treatment weighting-adjusted Cox proportional hazard analyses within the Global PBC Study Group database. Results We included 3902 patients with a median follow-up of 7.8 (4.1-12.1) years. The overall HR of UDCA was 0.46 (95% CI 0.40 to 0.52) and the 5-year LT-free survival without UDCA was 81% (95% CI 79 to 82). The NNT to prevent one LT or death within 5 years (NNT 5y) was 11 (95% CI 9 to 13). Although the HR of UDCA was similar for patients with and without cirrhosis (0.33 vs 0.31), the NNT 5y was 4 (95% CI 3 to 5) and 20 (95% CI 14 to 34), respectively. Among patients with low alkaline phosphatase (ALP) (≤2× the upper limit of normal (ULN)), intermediate ALP (2-4× ULN) and high ALP (>4× ULN), the NNT 5y to prevent one LT or death was 26 (95% CI 15 to 70), 11 (95% CI 8 to 17) and 5 (95% CI 4 to 8), respectively. Conclusion The absolute clinical efficacy of UDCA with respect to LT or death varied with baseline prognostic characteristics, but was high throughout. These findings strongly emphasise the incentive to promptly initiate UDCA treatment in all patients with PBC and may improve patient compliance.

Published
2020

27. Long-term impact of preventive UDCA therapy after transplantation for primary biliary cholangitis

Author

Corpechot, C, Chazouilleres, O, Belnou, P, Montano-Loza, A, Mason, A, Ebadi, M, Eurich, D, Chopra, S, Jacob, D, Schramm, C, Sterneck, M, Bruns, T, Reuken, P, Rauchfuss, F, Roccarina, D, Thorburn, D, Gerussi, A, Trivedi, P, Hirschfield, G, Mcdowell, P, Nevens, F, Boillot, O, Bosch, A, Giostra, E, Conti, F, Poupon, R, Pares, A, Reig, A, Donato, M, Malinverno, F, Floreani, A, Russo, F, Cazzagon, N, Verhelst, X, Goet, J, Harms, M, van Buuren, H, Hansen, B, Carrat, F, Dumortier, J, Corpechot C., Chazouilleres O., Belnou P., Montano-Loza A. J., Mason A., Ebadi M., Eurich D., Chopra S., Jacob D., Schramm C., Sterneck M., Bruns T., Reuken P., Rauchfuss F., Roccarina D., Thorburn D., Gerussi A., Trivedi P., Hirschfield G., McDowell P., Nevens F., Boillot O., Bosch A., Giostra E., Conti F., Poupon R., Pares A., Reig A., Donato M. F., Malinverno F., Floreani A., Russo F. P., Cazzagon N., Verhelst X., Goet J., Harms M., van Buuren H., Hansen B., Carrat F., Dumortier J., Corpechot, C, Chazouilleres, O, Belnou, P, Montano-Loza, A, Mason, A, Ebadi, M, Eurich, D, Chopra, S, Jacob, D, Schramm, C, Sterneck, M, Bruns, T, Reuken, P, Rauchfuss, F, Roccarina, D, Thorburn, D, Gerussi, A, Trivedi, P, Hirschfield, G, Mcdowell, P, Nevens, F, Boillot, O, Bosch, A, Giostra, E, Conti, F, Poupon, R, Pares, A, Reig, A, Donato, M, Malinverno, F, Floreani, A, Russo, F, Cazzagon, N, Verhelst, X, Goet, J, Harms, M, van Buuren, H, Hansen, B, Carrat, F, Dumortier, J, Corpechot C., Chazouilleres O., Belnou P., Montano-Loza A. J., Mason A., Ebadi M., Eurich D., Chopra S., Jacob D., Schramm C., Sterneck M., Bruns T., Reuken P., Rauchfuss F., Roccarina D., Thorburn D., Gerussi A., Trivedi P., Hirschfield G., McDowell P., Nevens F., Boillot O., Bosch A., Giostra E., Conti F., Poupon R., Pares A., Reig A., Donato M. F., Malinverno F., Floreani A., Russo F. P., Cazzagon N., Verhelst X., Goet J., Harms M., van Buuren H., Hansen B., Carrat F., and Dumortier J.

Abstract

Background & Aims: Recurrence of primary biliary cholangitis (PBC) after liver transplantation (LT) is frequent and can impair graft and patient survival. Ursodeoxycholic acid (UDCA) is the current standard therapy for PBC. We investigated the effect of preventive exposure to UDCA on the incidence and long-term consequences of PBC recurrence after LT. Methods: We performed a retrospective cohort study in 780 patients transplanted for PBC, between 1983–2017 in 16 centers (9 countries), and followed-up for a median of 11 years. Among them, 190 received preventive UDCA (10–15 mg/kg/day). The primary outcome was histological evidence of PBC recurrence. The secondary outcomes were graft loss, liver-related death, and all-cause death. The association between preventive UDCA and outcomes was quantified using multivariable-adjusted Cox and restricted mean survival time (RMST) models. Results: While recurrence of PBC significantly shortened graft and patient survival, preventive exposure to UDCA was associated with reduced risk of PBC recurrence (adjusted hazard ratio [aHR] 0.41; 95% CI 0.28–0.61; p <0.0001), graft loss (aHR 0.33; 95% CI 0.13–0.82; p <0.05), liver-related death (aHR 0.46; 95% CI 0.22–0.98; p <0.05), and all-cause death (aHR 0.69; 95% CI 0.49–0.96; p <0.05). On RMST analysis, preventive UDCA led to a survival gain of 2.26 years (95% CI 1.28–3.25) over a period of 20 years. Exposure to cyclosporine rather than tacrolimus had a complementary protective effect alongside preventive UDCA, reducing the cumulative incidence of PBC recurrence and all-cause death. Conclusions: Preventive UDCA after LT for PBC is associated with a reduced risk of disease recurrence, graft loss, and death. A regimen combining cyclosporine and preventive UDCA is associated with the lowest risk of PBC recurrence and mortality. Lay summary: Recurrence of primary biliary cholangitis after liver transplantation is frequent and can impair graft and patient survival. We perform

Published
2020

29. Statistical inference through estimation: recommendations from the International Society of Physiotherapy Journal Editors.

Author

Elkins, MR, Pinto, RZ, Verhagen, A, Grygorowicz, M, Söderlund, A, Guemann, M, Gómez-Conesa, A, Blanton, S, Brismée, J-M, Agarwal, S, Jette, A, Karstens, S, Harms, M, Verheyden, G, Sheikh, U, Elkins, MR, Pinto, RZ, Verhagen, A, Grygorowicz, M, Söderlund, A, Guemann, M, Gómez-Conesa, A, Blanton, S, Brismée, J-M, Agarwal, S, Jette, A, Karstens, S, Harms, M, Verheyden, G, and Sheikh, U

Published
2022

32. Cell environment shapes TDP-43 function with implications in neuronal and muscle disease

Author

Šušnjar, U. Škrabar, N. Brown, A.-L. Abbassi, Y. Phatnani, H. Phatnani, H. Fratta, P. Kwan, J. Sareen, D. Broach, J.R. Simmons, Z. Arcila-Londono, X. Lee, E.B. Van Deerlin, V.M. Shneider, N.A. Fraenkel, E. Ostrow, L.W. Baas, F. Berry, J.D. Butovsky, O. Baloh, R.H. Shalem, O. Heiman-Patterson, T. Stefanis, L. Chandran, S. Pal, S. Smith, C. Malaspina, A. Hammell, M.G. Patsopoulos, N.A. Dubnau, J. Poss, M. Zhang, B. Zaitlen, N. Hornstein, E. Miller, T.M. Dardiotis, E. Bowser, R. Menon, V. Harms, M. Atassi, N. Lange, D.J. MacGowan, D.J. McMillan, C. Aronica, E. Harris, B. Ravits, J. Crary, J. Thompson, L.M. Raj, T. Paganoni, S. Adams, D.J. Babu, S. Drory, V. Gotkine, M. Broce, I. Phillips-Cremins, J. Nath, A. Finkbeiner, S. Cox, G.A. Cortese, A. Cereda, C. Bugiardini, E. Cardani, R. Meola, G. Ripolone, M. Moggio, M. Romano, M. Secrier, M. Fratta, P. Buratti, E. NYGC ALS Consortium

Subjects
mental disorders, nutritional and metabolic diseases, nervous system diseases
Abstract

TDP-43 (TAR DNA-binding protein 43) aggregation and redistribution are recognised as a hallmark of amyotrophic lateral sclerosis and frontotemporal dementia. As TDP-43 inclusions have recently been described in the muscle of inclusion body myositis patients, this highlights the need to understand the role of TDP-43 beyond the central nervous system. Using RNA-seq, we directly compare TDP-43-mediated RNA processing in muscle (C2C12) and neuronal (NSC34) mouse cells. TDP-43 displays a cell-type-characteristic behaviour targeting unique transcripts in each cell-type, which is due to characteristic expression of RNA-binding proteins, that influence TDP-43’s performance and define cell-type specific splicing. Among splicing events commonly dysregulated in both cell lines, we identify some that are TDP-43-dependent also in human cells. Inclusion levels of these alternative exons are altered in tissues of patients suffering from FTLD and IBM. We therefore propose that TDP-43 dysfunction contributes to disease development either in a common or a tissue-specific manner. © 2022, The Author(s).

Published
2022

34. Combination of bevacizumab and 2-weekly pegylated liposomal doxorubicin as first-line therapy for locally recurrent or metastatic breast cancer. A multicenter, single-arm phase II trial (SAKK 24/06)

Author

Rochlitz, C., Ruhstaller, T., Lerch, S., Spirig, C., Huober, J., Suter, T., Bühlmann, M., Fehr, M., Schönenberger, A., von Moos, R., Winterhalder, R., Rauch, D., Müller, A., Mannhart-Harms, M., Herrmann, R., Cliffe, B., Mayer, M., and Zaman, K.

Published
2011
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40. Ursodeoxycholic acid therapy and liver transplant-free survival in patients with primary biliary cholangitis

Author

Harms, M, van Buuren, H, Corpechot, C, Thorburn, D, Janssen, H, Lindor, K, Hirschfield, G, Pares, A, Floreani, A, Mayo, M, Invernizzi, P, Battezzati, P, Nevens, F, Ponsioen, C, Mason, A, Kowdley, K, Lammers, W, Hansen, B, van der Meer, A, Harms M. H., van Buuren H. R., Corpechot C., Thorburn D., Janssen H. L. A., Lindor K. D., Hirschfield G. M., Pares A., Floreani A., Mayo M. J., Invernizzi P., Battezzati P. M., Nevens F., Ponsioen C. Y., Mason A. L., Kowdley K. V., Lammers W. J., Hansen B. E., van der Meer A. J., Harms, M, van Buuren, H, Corpechot, C, Thorburn, D, Janssen, H, Lindor, K, Hirschfield, G, Pares, A, Floreani, A, Mayo, M, Invernizzi, P, Battezzati, P, Nevens, F, Ponsioen, C, Mason, A, Kowdley, K, Lammers, W, Hansen, B, van der Meer, A, Harms M. H., van Buuren H. R., Corpechot C., Thorburn D., Janssen H. L. A., Lindor K. D., Hirschfield G. M., Pares A., Floreani A., Mayo M. J., Invernizzi P., Battezzati P. M., Nevens F., Ponsioen C. Y., Mason A. L., Kowdley K. V., Lammers W. J., Hansen B. E., and van der Meer A. J.

Abstract

Background & Aims: The clinical efficacy of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC) remains subject to debate as definitive randomized controlled trials are lacking. We aimed to determine whether UDCA prolongs liver transplant (LT)-free survival in patients with PBC. Methods: This international cohort study included patients from the Global PBC Study Group database, originating from 8 countries in Europe and North America. Both UDCA-treated and untreated patients were included. LT and death were assessed as a combined endpoint through Cox regression analyses, with inverse probability treatment weighting (IPTW). Results: In the 3,902 patients included, the mean (SD) age was 54.3 (11.9) years, 3,552 patients (94.0%) were female, 3,529 patients (90.4%) were treated with UDCA and 373 patients (9.6%) were not treated. The median (interquartile range) follow-up was 7.8 (4.1–12.1) years. In total, 721 UDCA-treated patients and 145 untreated patients died or underwent LT. After IPTW, the 10-year cumulative LT-free survival was 79.7% (95% CI 78.1–81.2) among UDCA-treated patients and 60.7% (95% CI 58.2–63.4) among untreated patients (p <0.001). UDCA was associated with a statistically significant reduced risk of LT or death (hazard ratio 0.46, 95% CI 0.40–0.52; p <0.001). The hazard ratio remained statistically significant in all stages of disease. Patients classified as inadequate biochemical responders after 1 year of UDCA had a lower risk of LT or death than patients who were not treated (adjusted hazard ratio 0.56; 95% CI 0.45–0.69; p <0.001). Conclusion: The use of UDCA improves LT-free survival among patients with PBC, regardless of the disease stage and the observed biochemical response. These findings support UDCA as the current universal standard of care in PBC. Lay summary: In this international multicenter study of 3,902 patients with primary biliary cholangitis, we found that treatment with ursodeoxycholic acid is associated

Published
2019

45. An agenda for research and action toward diverse and just futures for life on Earth

Author

Wyborn, C., Montana, J., Kalas, N., Clement, S., Davila, F., Knowles, N., Louder, E., Balan, M., Chambers, J., Christel, L., Forsyth, T., Henderson, G., Izquierdo Tort, S., Lim, M., Martinez-Harms, M. J., Merçon, J., Nuesiri, E., Pereira, L., Pilbeam, V., Turnhout, E., Wood, S., Ryan, M., Wyborn, C., Montana, J., Kalas, N., Clement, S., Davila, F., Knowles, N., Louder, E., Balan, M., Chambers, J., Christel, L., Forsyth, T., Henderson, G., Izquierdo Tort, S., Lim, M., Martinez-Harms, M. J., Merçon, J., Nuesiri, E., Pereira, L., Pilbeam, V., Turnhout, E., Wood, S., and Ryan, M.

Abstract

Decades of research and policy interventions on biodiversity have insufficiently addressed the dual issues of biodiversity degradation and social justice. New approaches are therefore needed. We devised a research and action agenda that calls for a collective task of revisiting biodiversity toward the goal of sustaining diverse and just futures for life on Earth. Revisiting biodiversity involves critically reflecting on past and present research, policy, and practice concerning biodiversity to inspire creative thinking about the future. The agenda was developed through a 2-year dialogue process that involved close to 300 experts from diverse disciplines and locations. This process was informed by social science insights that show biodiversity research and action is underpinned by choices about how problems are conceptualized. Recognizing knowledge, action, and ethics as inseparable, we synthesized a set of principles that help navigate the task of revisiting biodiversity. The agenda articulates 4 thematic areas for future research. First, researchers need to revisit biodiversity narratives by challenging conceptualizations that exclude diversity and entrench the separation of humans, cultures, economies, and societies from nature. Second, researchers should focus on the relationships between the Anthropocene, biodiversity, and culture by considering humanity and biodiversity as tied together in specific contexts. Third, researchers should focus on nature and economies by better accounting for the interacting structures of economic and financial systems as core drivers of biodiversity loss. Finally, researchers should enable transformative biodiversity research and action by reconfiguring relationships between human and nonhuman communities in and through science, policy, and practice. Revisiting biodiversity necessitates a renewed focus on dialogue among biodiversity communities and beyond that critically reflects on the past to channel research and action toward

Published
2021

46. An agenda for research and action toward diverse and just futures for life on Earth

Author

Environmental Governance, Wyborn, C., Montana, J., Kalas, N., Clement, S., Davila, F., Knowles, N., Louder, E., Balan, M., Chambers, J., Christel, L., Forsyth, T., Henderson, G., Izquierdo Tort, S., Lim, M., Martinez-Harms, M. J., Merçon, J., Nuesiri, E., Pereira, L., Pilbeam, V., Turnhout, E., Wood, S., Ryan, M., Environmental Governance, Wyborn, C., Montana, J., Kalas, N., Clement, S., Davila, F., Knowles, N., Louder, E., Balan, M., Chambers, J., Christel, L., Forsyth, T., Henderson, G., Izquierdo Tort, S., Lim, M., Martinez-Harms, M. J., Merçon, J., Nuesiri, E., Pereira, L., Pilbeam, V., Turnhout, E., Wood, S., and Ryan, M.

Published
2021

47. Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis

Author

Johnson, J, Chia, R, Miller, D, Li, R, Kumaran, R, Abramzon, Y, Alahmady, N, Renton, A, Topp, S, Gibbs, J, Cookson, M, Sabir, M, Dalgard, C, Troakes, C, Jones, A, Shatunov, A, Iacoangeli, A, Al Khleifat, A, Ticozzi, N, Silani, V, Gellera, C, Blair, I, Dobson-Stone, C, Kwok, J, Bonkowski, E, Palvadeau, R, Tienari, P, Morrison, K, Shaw, P, Al-Chalabi, A, Brown, R, Calvo, A, Mora, G, Al-Saif, H, Gotkine, M, Leigh, F, Chang, I, Perlman, S, Glass, I, Scott, A, Shaw, C, Basak, A, Landers, J, Chiò, A, Crawford, T, Smith, B, Traynor, B, Fallini, C, Gkazi, A, Scotter, E, Kenna, K, Keagle, P, Tiloca, C, Vance, C, Colombrita, C, King, A, Pensato, V, Castellotti, B, Baas, F, Ten Asbroek, A, McKenna-Yasek, D, Mclaughlin, R, Polak, M, Asress, S, Esteban-Pérez, J, Stevic, Z, D'Alfonso, S, Mazzini, L, Comi, G, Del Bo, R, Ceroni, M, Gagliardi, S, Querin, G, Bertolin, C, van Rheenen, W, Rademakers, R, van Blitterswijk, M, Lauria, G, Duga, S, Corti, S, Cereda, C, Corrado, L, Sorarù, G, Williams, K, Nicholson, G, Leblond-Manry, C, Rouleau, G, Hardiman, O, Veldink, J, van den Berg, L, Pall, H, Turner, M, Talbot, K, Taroni, F, García-Redondo, A, Wu, Z, Glass, J, Ratti, A, Adeleye, A, Soltis, A, Alba, C, Viollet, C, Bacikova, D, Hupalo, D, Sukumar, G, Pollard, H, Wilkerson, M, Martinez, E, Ahmed, S, Arepalli, S, Baloh, R, Bowser, R, Brady, C, Brice, A, Broach, J, Campbell, R, Camu, W, Cooper-Knock, J, Ding, J, Drepper, C, Drory, V, Dunckley, T, Eicher, J, England, B, Faghri, F, Feldman, E, Floeter, M, Fratta, P, Geiger, J, Gerhard, G, Gibson, S, Hardy, J, Harms, M, Heiman-Patterson, T, Hernandez, D, Jansson, L, Kirby, J, Kowall, N, Laaksovirta, H, Landeck, N, Landi, F, Le Ber, I, Lumbroso, S, Macgowan, D, Maragakis, N, Mouzat, K, Murphy, N, Myllykangas, L, Nalls, M, Orrell, R, Ostrow, L, Pamphlett, R, Pickering-Brown, S, Pioro, E, Pletnikova, O, Pliner, H, Pulst, S, Ravits, J, Rivera, A, Robberecht, W, Rogaeva, E, Rollinson, S, Rothstein, J, Scholz, S, Sendtner, M, Sidle, K, Simmons, Z, Singleton, A, Smith, N, Stone, D, Troncoso, J, Valori, M, Van Damme, P, Van Deerlin, V, Van Den Bosch, L, Zinman, L, Angelocola, S, Ausiello, F, Barberis, M, Bartolomei, I, Battistini, S, Bersano, E, Bisogni, G, Borghero, G, Brunetti, M, Cabona, C, Canale, F, Canosa, A, Cantisani, T, Capasso, M, Caponnetto, C, Cardinali, P, Carrera, P, Casale, F, Colletti, T, Conforti, F, Conte, A, Conti, E, Corbo, M, Cuccu, S, Dalla Bella, E, D'Errico, E, Demarco, G, Dubbioso, R, Ferrarese, C, Ferraro, P, Filippi, M, Fini, N, Floris, G, Fuda, G, Gallone, S, Gianferrari, G, Giannini, F, Grassano, M, Greco, L, Iazzolino, B, Introna, A, La Bella, V, Lattante, S, Liguori, R, Logroscino, G, Logullo, F, Lunetta, C, Mandich, P, Mandrioli, J, Manera, U, Manganelli, F, Marangi, G, Marinou, K, Marrosu, M, Martinelli, I, Messina, S, Moglia, C, Mosca, L, Murru, M, Origone, P, Passaniti, C, Petrelli, C, Petrucci, A, Pozzi, S, Pugliatti, M, Quattrini, A, Ricci, C, Riolo, G, Riva, N, Russo, M, Sabatelli, M, Salamone, P, Salivetto, M, Salvi, F, Santarelli, M, Sbaiz, L, Sideri, R, Simone, I, Simonini, C, Spataro, R, Tanel, R, Tedeschi, G, Ticca, A, Torriello, A, Tranquilli, S, Tremolizzo, L, Trojsi, F, Vasta, R, Vacchiano, V, Vita, G, Volanti, P, Zollino, M, Zucchi, E, Johnson, Janel O, Chia, Ruth, Miller, Danny E, Li, Rachel, Kumaran, Ravindran, Abramzon, Yevgeniya, Alahmady, Nada, Renton, Alan E, Topp, Simon D, Gibbs, J Raphael, Cookson, Mark R, Sabir, Marya S, Dalgard, Clifton L, Troakes, Claire, Jones, Ashley R, Shatunov, Aleksey, Iacoangeli, Alfredo, Al Khleifat, Ahmad, Ticozzi, Nicola, Silani, Vincenzo, Gellera, Cinzia, Blair, Ian P, Dobson-Stone, Carol, Kwok, John B, Bonkowski, Emily S, Palvadeau, Robin, Tienari, Pentti J, Morrison, Karen E, Shaw, Pamela J, Al-Chalabi, Ammar, Brown, Robert H, Calvo, Andrea, Mora, Gabriele, Al-Saif, Hind, Gotkine, Marc, Leigh, Fawn, Chang, Irene J, Perlman, Seth J, Glass, Ian, Scott, Anna I, Shaw, Christopher E, Basak, A Nazli, Landers, John E, Chiò, Adriano, Crawford, Thomas O, Smith, Bradley N, Traynor, Bryan J, Fallini, Claudia, Gkazi, Athina Soragia, Scotter, Emma L, Kenna, Kevin P, Keagle, Pamela, Tiloca, Cinzia, Vance, Caroline, Colombrita, Claudia, King, Andrew, Pensato, Viviana, Castellotti, Barbara, Baas, Frank, Ten Asbroek, Anneloor L M A, McKenna-Yasek, Diane, McLaughlin, Russell L, Polak, Meraida, Asress, Seneshaw, Esteban-Pérez, Jesús, Stevic, Zorica, D'Alfonso, Sandra, Mazzini, Letizia, Comi, Giacomo P, Del Bo, Roberto, Ceroni, Mauro, Gagliardi, Stella, Querin, Giorgia, Bertolin, Cinzia, van Rheenen, Wouter, Rademakers, Rosa, van Blitterswijk, Marka, Lauria, Giuseppe, Duga, Stefano, Corti, Stefania, Cereda, Cristina, Corrado, Lucia, Sorarù, Gianni, Williams, Kelly L, Nicholson, Garth A, Leblond-Manry, Claire, Rouleau, Guy A, Hardiman, Orla, Veldink, Jan H, van den Berg, Leonard H, Pall, Hardev, Turner, Martin R, Talbot, Kevin, Taroni, Franco, García-Redondo, Alberto, Wu, Zheyang, Glass, Jonathan D, Ratti, Antonia, Adeleye, Adelani, Soltis, Anthony R, Alba, Camille, Viollet, Coralie, Bacikova, Dagmar, Hupalo, Daniel N, Sukumar, Gauthaman, Pollard, Harvey B, Wilkerson, Matthew D, Martinez, Elisa McGrath, Ahmed, Sarah, Arepalli, Sampath, Baloh, Robert H, Bowser, Robert, Brady, Christopher B, Brice, Alexis, Broach, James, Campbell, Roy H, Camu, William, Cooper-Knock, John, Ding, Jinhui, Drepper, Carsten, Drory, Vivian E, Dunckley, Travis L, Eicher, John D, England, Bryce K, Faghri, Faraz, Feldman, Eva, Floeter, Mary Kay, Fratta, Pietro, Geiger, Joshua T, Gerhard, Glenn, Gibson, Summer B, Hardy, John, Harms, Matthew B, Heiman-Patterson, Terry D, Hernandez, Dena G, Jansson, Lilja, Kirby, Janine, Kowall, Neil W, Laaksovirta, Hannu, Landeck, Natalie, Landi, Francesco, Le Ber, Isabelle, Lumbroso, Serge, MacGowan, Daniel J L, Maragakis, Nicholas J, Mouzat, Kevin, Murphy, Natalie A, Myllykangas, Liisa, Nalls, Mike A, Orrell, Richard W, Ostrow, Lyle W, Pamphlett, Roger, Pickering-Brown, Stuart, Pioro, Erik P, Pletnikova, Olga, Pliner, Hannah A, Pulst, Stefan M, Ravits, John M, Rivera, Alberto, Robberecht, Wim, Rogaeva, Ekaterina, Rollinson, Sara, Rothstein, Jeffrey D, Scholz, Sonja W, Sendtner, Michael, Sidle, Katie C, Simmons, Zachary, Singleton, Andrew B, Smith, Nathan, Stone, David J, Troncoso, Juan C, Valori, Miko, Van Damme, Philip, Van Deerlin, Vivianna M, Van Den Bosch, Ludo, Zinman, Lorne, Angelocola, Stefania M, Ausiello, Francesco P, Barberis, Marco, Bartolomei, Ilaria, Battistini, Stefania, Bersano, Enrica, Bisogni, Giulia, Borghero, Giuseppe, Brunetti, Maura, Cabona, Corrado, Canale, Fabrizio, Canosa, Antonio, Cantisani, Teresa A, Capasso, Margherita, Caponnetto, Claudia, Cardinali, Patrizio, Carrera, Paola, Casale, Federico, Colletti, Tiziana, Conforti, Francesca L, Conte, Amelia, Conti, Elisa, Corbo, Massimo, Cuccu, Stefania, Dalla Bella, Eleonora, D'Errico, Eustachio, DeMarco, Giovanni, Dubbioso, Raffaele, Ferrarese, Carlo, Ferraro, Pilar M, Filippi, Massimo, Fini, Nicola, Floris, Gianluca, Fuda, Giuseppe, Gallone, Salvatore, Gianferrari, Giulia, Giannini, Fabio, Grassano, Maurizio, Greco, Lucia, Iazzolino, Barbara, Introna, Alessandro, La Bella, Vincenzo, Lattante, Serena, Liguori, Rocco, Logroscino, Giancarlo, Logullo, Francesco O, Lunetta, Christian, Mandich, Paola, Mandrioli, Jessica, Manera, Umberto, Manganelli, Fiore, Marangi, Giuseppe, Marinou, Kalliopi, Marrosu, Maria Giovanna, Martinelli, Ilaria, Messina, Sonia, Moglia, Cristina, Mosca, Lorena, Murru, Maria R, Origone, Paola, Passaniti, Carla, Petrelli, Cristina, Petrucci, Antonio, Pozzi, Susanna, Pugliatti, Maura, Quattrini, Angelo, Ricci, Claudia, Riolo, Giulia, Riva, Nilo, Russo, Massimo, Sabatelli, Mario, Salamone, Paolina, Salivetto, Marco, Salvi, Fabrizio, Santarelli, Marialuisa, Sbaiz, Luca, Sideri, Riccardo, Simone, Isabella, Simonini, Cecilia, Spataro, Rossella, Tanel, Raffaella, Tedeschi, Gioacchino, Ticca, Anna, Torriello, Antonella, Tranquilli, Stefania, Tremolizzo, Lucio, Trojsi, Francesca, Vasta, Rosario, Vacchiano, Veria, Vita, Giuseppe, Volanti, Paolo, Zollino, Marcella, Zucchi, Elisabetta, Johnson, J, Chia, R, Miller, D, Li, R, Kumaran, R, Abramzon, Y, Alahmady, N, Renton, A, Topp, S, Gibbs, J, Cookson, M, Sabir, M, Dalgard, C, Troakes, C, Jones, A, Shatunov, A, Iacoangeli, A, Al Khleifat, A, Ticozzi, N, Silani, V, Gellera, C, Blair, I, Dobson-Stone, C, Kwok, J, Bonkowski, E, Palvadeau, R, Tienari, P, Morrison, K, Shaw, P, Al-Chalabi, A, Brown, R, Calvo, A, Mora, G, Al-Saif, H, Gotkine, M, Leigh, F, Chang, I, Perlman, S, Glass, I, Scott, A, Shaw, C, Basak, A, Landers, J, Chiò, A, Crawford, T, Smith, B, Traynor, B, Fallini, C, Gkazi, A, Scotter, E, Kenna, K, Keagle, P, Tiloca, C, Vance, C, Colombrita, C, King, A, Pensato, V, Castellotti, B, Baas, F, Ten Asbroek, A, McKenna-Yasek, D, Mclaughlin, R, Polak, M, Asress, S, Esteban-Pérez, J, Stevic, Z, D'Alfonso, S, Mazzini, L, Comi, G, Del Bo, R, Ceroni, M, Gagliardi, S, Querin, G, Bertolin, C, van Rheenen, W, Rademakers, R, van Blitterswijk, M, Lauria, G, Duga, S, Corti, S, Cereda, C, Corrado, L, Sorarù, G, Williams, K, Nicholson, G, Leblond-Manry, C, Rouleau, G, Hardiman, O, Veldink, J, van den Berg, L, Pall, H, Turner, M, Talbot, K, Taroni, F, García-Redondo, A, Wu, Z, Glass, J, Ratti, A, Adeleye, A, Soltis, A, Alba, C, Viollet, C, Bacikova, D, Hupalo, D, Sukumar, G, Pollard, H, Wilkerson, M, Martinez, E, Ahmed, S, Arepalli, S, Baloh, R, Bowser, R, Brady, C, Brice, A, Broach, J, Campbell, R, Camu, W, Cooper-Knock, J, Ding, J, Drepper, C, Drory, V, Dunckley, T, Eicher, J, England, B, Faghri, F, Feldman, E, Floeter, M, Fratta, P, Geiger, J, Gerhard, G, Gibson, S, Hardy, J, Harms, M, Heiman-Patterson, T, Hernandez, D, Jansson, L, Kirby, J, Kowall, N, Laaksovirta, H, Landeck, N, Landi, F, Le Ber, I, Lumbroso, S, Macgowan, D, Maragakis, N, Mouzat, K, Murphy, N, Myllykangas, L, Nalls, M, Orrell, R, Ostrow, L, Pamphlett, R, Pickering-Brown, S, Pioro, E, Pletnikova, O, Pliner, H, Pulst, S, Ravits, J, Rivera, A, Robberecht, W, Rogaeva, E, Rollinson, S, Rothstein, J, Scholz, S, Sendtner, M, Sidle, K, Simmons, Z, Singleton, A, Smith, N, Stone, D, Troncoso, J, Valori, M, Van Damme, P, Van Deerlin, V, Van Den Bosch, L, Zinman, L, Angelocola, S, Ausiello, F, Barberis, M, Bartolomei, I, Battistini, S, Bersano, E, Bisogni, G, Borghero, G, Brunetti, M, Cabona, C, Canale, F, Canosa, A, Cantisani, T, Capasso, M, Caponnetto, C, Cardinali, P, Carrera, P, Casale, F, Colletti, T, Conforti, F, Conte, A, Conti, E, Corbo, M, Cuccu, S, Dalla Bella, E, D'Errico, E, Demarco, G, Dubbioso, R, Ferrarese, C, Ferraro, P, Filippi, M, Fini, N, Floris, G, Fuda, G, Gallone, S, Gianferrari, G, Giannini, F, Grassano, M, Greco, L, Iazzolino, B, Introna, A, La Bella, V, Lattante, S, Liguori, R, Logroscino, G, Logullo, F, Lunetta, C, Mandich, P, Mandrioli, J, Manera, U, Manganelli, F, Marangi, G, Marinou, K, Marrosu, M, Martinelli, I, Messina, S, Moglia, C, Mosca, L, Murru, M, Origone, P, Passaniti, C, Petrelli, C, Petrucci, A, Pozzi, S, Pugliatti, M, Quattrini, A, Ricci, C, Riolo, G, Riva, N, Russo, M, Sabatelli, M, Salamone, P, Salivetto, M, Salvi, F, Santarelli, M, Sbaiz, L, Sideri, R, Simone, I, Simonini, C, Spataro, R, Tanel, R, Tedeschi, G, Ticca, A, Torriello, A, Tranquilli, S, Tremolizzo, L, Trojsi, F, Vasta, R, Vacchiano, V, Vita, G, Volanti, P, Zollino, M, Zucchi, E, Johnson, Janel O, Chia, Ruth, Miller, Danny E, Li, Rachel, Kumaran, Ravindran, Abramzon, Yevgeniya, Alahmady, Nada, Renton, Alan E, Topp, Simon D, Gibbs, J Raphael, Cookson, Mark R, Sabir, Marya S, Dalgard, Clifton L, Troakes, Claire, Jones, Ashley R, Shatunov, Aleksey, Iacoangeli, Alfredo, Al Khleifat, Ahmad, Ticozzi, Nicola, Silani, Vincenzo, Gellera, Cinzia, Blair, Ian P, Dobson-Stone, Carol, Kwok, John B, Bonkowski, Emily S, Palvadeau, Robin, Tienari, Pentti J, Morrison, Karen E, Shaw, Pamela J, Al-Chalabi, Ammar, Brown, Robert H, Calvo, Andrea, Mora, Gabriele, Al-Saif, Hind, Gotkine, Marc, Leigh, Fawn, Chang, Irene J, Perlman, Seth J, Glass, Ian, Scott, Anna I, Shaw, Christopher E, Basak, A Nazli, Landers, John E, Chiò, Adriano, Crawford, Thomas O, Smith, Bradley N, Traynor, Bryan J, Fallini, Claudia, Gkazi, Athina Soragia, Scotter, Emma L, Kenna, Kevin P, Keagle, Pamela, Tiloca, Cinzia, Vance, Caroline, Colombrita, Claudia, King, Andrew, Pensato, Viviana, Castellotti, Barbara, Baas, Frank, Ten Asbroek, Anneloor L M A, McKenna-Yasek, Diane, McLaughlin, Russell L, Polak, Meraida, Asress, Seneshaw, Esteban-Pérez, Jesús, Stevic, Zorica, D'Alfonso, Sandra, Mazzini, Letizia, Comi, Giacomo P, Del Bo, Roberto, Ceroni, Mauro, Gagliardi, Stella, Querin, Giorgia, Bertolin, Cinzia, van Rheenen, Wouter, Rademakers, Rosa, van Blitterswijk, Marka, Lauria, Giuseppe, Duga, Stefano, Corti, Stefania, Cereda, Cristina, Corrado, Lucia, Sorarù, Gianni, Williams, Kelly L, Nicholson, Garth A, Leblond-Manry, Claire, Rouleau, Guy A, Hardiman, Orla, Veldink, Jan H, van den Berg, Leonard H, Pall, Hardev, Turner, Martin R, Talbot, Kevin, Taroni, Franco, García-Redondo, Alberto, Wu, Zheyang, Glass, Jonathan D, Ratti, Antonia, Adeleye, Adelani, Soltis, Anthony R, Alba, Camille, Viollet, Coralie, Bacikova, Dagmar, Hupalo, Daniel N, Sukumar, Gauthaman, Pollard, Harvey B, Wilkerson, Matthew D, Martinez, Elisa McGrath, Ahmed, Sarah, Arepalli, Sampath, Baloh, Robert H, Bowser, Robert, Brady, Christopher B, Brice, Alexis, Broach, James, Campbell, Roy H, Camu, William, Cooper-Knock, John, Ding, Jinhui, Drepper, Carsten, Drory, Vivian E, Dunckley, Travis L, Eicher, John D, England, Bryce K, Faghri, Faraz, Feldman, Eva, Floeter, Mary Kay, Fratta, Pietro, Geiger, Joshua T, Gerhard, Glenn, Gibson, Summer B, Hardy, John, Harms, Matthew B, Heiman-Patterson, Terry D, Hernandez, Dena G, Jansson, Lilja, Kirby, Janine, Kowall, Neil W, Laaksovirta, Hannu, Landeck, Natalie, Landi, Francesco, Le Ber, Isabelle, Lumbroso, Serge, MacGowan, Daniel J L, Maragakis, Nicholas J, Mouzat, Kevin, Murphy, Natalie A, Myllykangas, Liisa, Nalls, Mike A, Orrell, Richard W, Ostrow, Lyle W, Pamphlett, Roger, Pickering-Brown, Stuart, Pioro, Erik P, Pletnikova, Olga, Pliner, Hannah A, Pulst, Stefan M, Ravits, John M, Rivera, Alberto, Robberecht, Wim, Rogaeva, Ekaterina, Rollinson, Sara, Rothstein, Jeffrey D, Scholz, Sonja W, Sendtner, Michael, Sidle, Katie C, Simmons, Zachary, Singleton, Andrew B, Smith, Nathan, Stone, David J, Troncoso, Juan C, Valori, Miko, Van Damme, Philip, Van Deerlin, Vivianna M, Van Den Bosch, Ludo, Zinman, Lorne, Angelocola, Stefania M, Ausiello, Francesco P, Barberis, Marco, Bartolomei, Ilaria, Battistini, Stefania, Bersano, Enrica, Bisogni, Giulia, Borghero, Giuseppe, Brunetti, Maura, Cabona, Corrado, Canale, Fabrizio, Canosa, Antonio, Cantisani, Teresa A, Capasso, Margherita, Caponnetto, Claudia, Cardinali, Patrizio, Carrera, Paola, Casale, Federico, Colletti, Tiziana, Conforti, Francesca L, Conte, Amelia, Conti, Elisa, Corbo, Massimo, Cuccu, Stefania, Dalla Bella, Eleonora, D'Errico, Eustachio, DeMarco, Giovanni, Dubbioso, Raffaele, Ferrarese, Carlo, Ferraro, Pilar M, Filippi, Massimo, Fini, Nicola, Floris, Gianluca, Fuda, Giuseppe, Gallone, Salvatore, Gianferrari, Giulia, Giannini, Fabio, Grassano, Maurizio, Greco, Lucia, Iazzolino, Barbara, Introna, Alessandro, La Bella, Vincenzo, Lattante, Serena, Liguori, Rocco, Logroscino, Giancarlo, Logullo, Francesco O, Lunetta, Christian, Mandich, Paola, Mandrioli, Jessica, Manera, Umberto, Manganelli, Fiore, Marangi, Giuseppe, Marinou, Kalliopi, Marrosu, Maria Giovanna, Martinelli, Ilaria, Messina, Sonia, Moglia, Cristina, Mosca, Lorena, Murru, Maria R, Origone, Paola, Passaniti, Carla, Petrelli, Cristina, Petrucci, Antonio, Pozzi, Susanna, Pugliatti, Maura, Quattrini, Angelo, Ricci, Claudia, Riolo, Giulia, Riva, Nilo, Russo, Massimo, Sabatelli, Mario, Salamone, Paolina, Salivetto, Marco, Salvi, Fabrizio, Santarelli, Marialuisa, Sbaiz, Luca, Sideri, Riccardo, Simone, Isabella, Simonini, Cecilia, Spataro, Rossella, Tanel, Raffaella, Tedeschi, Gioacchino, Ticca, Anna, Torriello, Antonella, Tranquilli, Stefania, Tremolizzo, Lucio, Trojsi, Francesca, Vasta, Rosario, Vacchiano, Veria, Vita, Giuseppe, Volanti, Paolo, Zollino, Marcella, and Zucchi, Elisabetta

Abstract

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation. Objective: To identify the genetic variants associated with juvenile ALS. Design, setting, and participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism. Main outcomes and measures: De novo variants present only in the index case and not in unaffected family members. Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis

Published
2021

48. Rare and de novo coding variants in chromodomain genes in Chiari I malformation

Author

Sadler, B., Wilborn, J., Antunes, L., Kuensting, T., Hale, A. T., Gannon, S. R., Mccall, K., Cruchaga, C., Harms, M., Voisin, N., Reymond, A., Cappuccio, G., Burnetti-Pierri, N., Tartaglia, M., Niceta, M., Leoni, Chiara, Zampino, Giuseppe, Ashley-Koch, A., Urbizu, A., Garrett, M. E., Soldano, K., Macaya, A., Conrad, D., Strahle, J., Dobbs, M. B., Turner, T. N., Shannon, C. N., Brockmeyer, D., Limbrick, D. D., Gurnett, C. A., Haller, G., Leoni C., Zampino G. (ORCID:0000-0003-3865-3253), Sadler, B., Wilborn, J., Antunes, L., Kuensting, T., Hale, A. T., Gannon, S. R., Mccall, K., Cruchaga, C., Harms, M., Voisin, N., Reymond, A., Cappuccio, G., Burnetti-Pierri, N., Tartaglia, M., Niceta, M., Leoni, Chiara, Zampino, Giuseppe, Ashley-Koch, A., Urbizu, A., Garrett, M. E., Soldano, K., Macaya, A., Conrad, D., Strahle, J., Dobbs, M. B., Turner, T. N., Shannon, C. N., Brockmeyer, D., Limbrick, D. D., Gurnett, C. A., Haller, G., Leoni C., and Zampino G. (ORCID:0000-0003-3865-3253)

Abstract

Chiari I malformation (CM1), the displacement of the cerebellum through the foramen magnum into the spinal canal, is one of the most common pediatric neurological conditions. Individuals with CM1 can present with neurological symptoms, including severe headaches and sensory or motor deficits, often as a consequence of brainstem compression or syringomyelia (SM). We conducted whole-exome sequencing (WES) on 668 CM1 probands and 232 family members and performed gene-burden and de novo enrichment analyses. A significant enrichment of rare and de novo non-synonymous variants in chromodomain (CHD) genes was observed among individuals with CM1 (combined p = 2.4 × 10−10), including 3 de novo loss-of-function variants in CHD8 (LOF enrichment p = 1.9 × 10−10) and a significant burden of rare transmitted variants in CHD3 (p = 1.8 × 10−6). Overall, individuals with CM1 were found to have significantly increased head circumference (p = 2.6 × 10−9), with many harboring CHD rare variants having macrocephaly. Finally, haploinsufficiency for chd8 in zebrafish led to macrocephaly and posterior hindbrain displacement reminiscent of CM1. These results implicate chromodomain genes and excessive brain growth in CM1 pathogenesis.

Published
2021

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