Author: "Marson A. G." / Database: OAIster - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Marson A. G."' showing total 96 results

Start Over Author "Marson A. G." Database OAIster

96 results on '"Marson A. G."'

1. Variation in seizure risk increases from antiseizure medication withdrawal among patients with well-controlled epilepsy: a pooled analysis

Author: Projectafdeling KIND, Neurologen, Brain, Terman, Samuel W, Slinger, Geertruida, Koek, Adriana, Skvarce, Jeremy, Springer, Mellanie V, Ziobro, Julie M, Burke, James F, Otte, Willem M, Thijs, Roland D, Lossius, Morten I, Marson, Anthony G, Bonnett, Laura J, Braun, Kees Pj, Projectafdeling KIND, Neurologen, Brain, Terman, Samuel W, Slinger, Geertruida, Koek, Adriana, Skvarce, Jeremy, Springer, Mellanie V, Ziobro, Julie M, Burke, James F, Otte, Willem M, Thijs, Roland D, Lossius, Morten I, Marson, Anthony G, Bonnett, Laura J, and Braun, Kees Pj
Published: 2024

2. The outcomes measured and reported in intracranial meningioma clinical trials: A systematic review

Author: Millward, Christopher P; https://orcid.org/0000-0001-7727-1157, Keshwara, Sumirat M, Armstrong, Terri S; https://orcid.org/0000-0002-2414-0492, Barrington, Heather; https://orcid.org/0000-0001-9103-2670, Bell, Sabrina, Brodbelt, Andrew R, Bulbeck, Helen, Dirven, Linda; https://orcid.org/0000-0001-9157-9895, Grundy, Paul L, Islim, Abdurrahman I, Javadpour, Mohsen, Koszdin, Shelli D, Marson, Anthony G, McDermott, Michael W, Meling, Torstein R, Oliver, Kathy, Plaha, Puneet, Preusser, Matthias; https://orcid.org/0000-0003-3541-2315, Santarius, Thomas, Srikandarajah, Nisaharan; https://orcid.org/0000-0001-9578-508X, Taphoorn, Martin J B; https://orcid.org/0000-0001-9949-4722, Turner, Carole, Watts, Colin; https://orcid.org/0000-0003-3531-8791, Weller, Michael; https://orcid.org/0000-0002-1748-174X, Williamson, Paula R, Zadeh, Gelareh; https://orcid.org/0000-0002-6637-4502, Zamanipoor Najafabadi, Amir H, Jenkinson, Michael D, Aldape, Kenneth; https://orcid.org/0000-0001-5119-7550, et al, Millward, Christopher P; https://orcid.org/0000-0001-7727-1157, Keshwara, Sumirat M, Armstrong, Terri S; https://orcid.org/0000-0002-2414-0492, Barrington, Heather; https://orcid.org/0000-0001-9103-2670, Bell, Sabrina, Brodbelt, Andrew R, Bulbeck, Helen, Dirven, Linda; https://orcid.org/0000-0001-9157-9895, Grundy, Paul L, Islim, Abdurrahman I, Javadpour, Mohsen, Koszdin, Shelli D, Marson, Anthony G, McDermott, Michael W, Meling, Torstein R, Oliver, Kathy, Plaha, Puneet, Preusser, Matthias; https://orcid.org/0000-0003-3541-2315, Santarius, Thomas, Srikandarajah, Nisaharan; https://orcid.org/0000-0001-9578-508X, Taphoorn, Martin J B; https://orcid.org/0000-0001-9949-4722, Turner, Carole, Watts, Colin; https://orcid.org/0000-0003-3531-8791, Weller, Michael; https://orcid.org/0000-0002-1748-174X, Williamson, Paula R, Zadeh, Gelareh; https://orcid.org/0000-0002-6637-4502, Zamanipoor Najafabadi, Amir H, Jenkinson, Michael D, Aldape, Kenneth; https://orcid.org/0000-0001-5119-7550, and et al
Abstract: Background Meningioma clinical trials have assessed interventions including surgery, radiotherapy, and pharmacotherapy. However, agreement does not exist on what, how, and when outcomes of interest should be measured. To do so would allow comparative analysis of similar trials. This systematic review aimed to summarize the outcomes measured and reported in meningioma clinical trials. Methods Systematic literature and trial registry searches were performed to identify published and ongoing intracranial meningioma clinical trials (PubMed, Embase, Medline, CINAHL via EBSCO, and Web of Science, completed January 22, 2022). Reported outcomes were extracted verbatim, along with an associated definition and method of measurement if provided. Verbatim outcomes were deduplicated and the resulting unique outcomes were grouped under standardized outcome terms. These were classified using the taxonomy proposed by the “Core Outcome Measures in Effectiveness Trials” (COMET) initiative. Results Thirty published articles and 18 ongoing studies were included, describing 47 unique clinical trials: Phase 2 n = 33, phase 3 n = 14. Common interventions included: Surgery n = 13, radiotherapy n = 8, and pharmacotherapy n = 20. In total, 659 verbatim outcomes were reported, of which 84 were defined. Following de-duplication, 415 unique verbatim outcomes remained and were grouped into 115 standardized outcome terms. These were classified using the COMET taxonomy into 29 outcome domains and 5 core areas. Conclusions Outcome measurement across meningioma clinical trials is heterogeneous. The standardized outcome terms identified will be prioritized through an eDelphi survey and consensus meeting of key stakeholders (including patients), in order to develop a core outcome set for use in future meningioma clinical trials.
Published: 2024

3. The outcomes measured and reported in observational studies of incidental and untreated intracranial meningioma: A systematic review

Author: Millward, Christopher P; https://orcid.org/0000-0001-7727-1157, Islim, Abdurrahman I, Armstrong, Terri S; https://orcid.org/0000-0002-2414-0492, Barrington, Heather; https://orcid.org/0000-0001-9103-2670, Bell, Sabrina, Brodbelt, Andrew R, Bulbeck, Helen, Dirven, Linda; https://orcid.org/0000-0001-9157-9895, Grundy, Paul L, Javadpour, Mohsen, Keshwara, Sumirat M, Koszdin, Shelli D, Marson, Anthony G, McDermott, Michael W, Meling, Torstein R, Oliver, Kathy, Plaha, Puneet, Preusser, Matthias; https://orcid.org/0000-0003-3541-2315, Santarius, Thomas, Srikandarajah, Nisaharan; https://orcid.org/0000-0001-9578-508X, Taphoorn, Martin J B; https://orcid.org/0000-0001-9949-4722, Turner, Carole, Watts, Colin; https://orcid.org/0000-0003-3531-8791, Weller, Michael; https://orcid.org/0000-0002-1748-174X, Williamson, Paula R, Zadeh, Gelareh; https://orcid.org/0000-0002-6637-4502, Zamanipoor Najafabadi, Amir H, Jenkinson, Michael D, Aldape, Kenneth; https://orcid.org/0000-0001-5119-7550, et al, Millward, Christopher P; https://orcid.org/0000-0001-7727-1157, Islim, Abdurrahman I, Armstrong, Terri S; https://orcid.org/0000-0002-2414-0492, Barrington, Heather; https://orcid.org/0000-0001-9103-2670, Bell, Sabrina, Brodbelt, Andrew R, Bulbeck, Helen, Dirven, Linda; https://orcid.org/0000-0001-9157-9895, Grundy, Paul L, Javadpour, Mohsen, Keshwara, Sumirat M, Koszdin, Shelli D, Marson, Anthony G, McDermott, Michael W, Meling, Torstein R, Oliver, Kathy, Plaha, Puneet, Preusser, Matthias; https://orcid.org/0000-0003-3541-2315, Santarius, Thomas, Srikandarajah, Nisaharan; https://orcid.org/0000-0001-9578-508X, Taphoorn, Martin J B; https://orcid.org/0000-0001-9949-4722, Turner, Carole, Watts, Colin; https://orcid.org/0000-0003-3531-8791, Weller, Michael; https://orcid.org/0000-0002-1748-174X, Williamson, Paula R, Zadeh, Gelareh; https://orcid.org/0000-0002-6637-4502, Zamanipoor Najafabadi, Amir H, Jenkinson, Michael D, Aldape, Kenneth; https://orcid.org/0000-0001-5119-7550, and et al
Abstract: Background The clinical management of patients with incidental intracranial meningioma varies markedly and is often based on clinician choice and observational data. Heterogeneous outcome measurement has likely hampered knowledge progress by preventing comparative analysis of similar cohorts of patients. This systematic review aimed to summarize the outcomes measured and reported in observational studies. Methods A systematic literature search was performed to identify published full texts describing active monitoring of adult cohorts with incidental and untreated intracranial meningioma (PubMed, EMBASE, MEDLINE, and CINAHL via EBSCO, completed January 24, 2022). Reported outcomes were extracted verbatim, along with an associated definition and method of measurement if provided. Verbatim outcomes were de-duplicated and the resulting unique outcomes were grouped under standardized outcome terms. These were classified using the taxonomy proposed by the “Core Outcome Measures in Effectiveness Trials” (COMET) initiative. Results Thirty-three published articles and 1 ongoing study were included describing 32 unique studies: study designs were retrospective n = 27 and prospective n = 5. In total, 268 verbatim outcomes were reported, of which 77 were defined. Following de-duplication, 178 unique verbatim outcomes remained and were grouped into 53 standardized outcome terms. These were classified using the COMET taxonomy into 9 outcome domains and 3 core areas. Conclusions Outcome measurement across observational studies of incidental and untreated intracranial meningioma is heterogeneous. The standardized outcome terms identified will be prioritized through an eDelphi survey and consensus meeting of key stakeholders (including patients), in order to develop a Core Outcome Set for use in future observational studies.
Published: 2024

4. Service delivery, behavioural, and self-management interventions for adults with epilepsy

Author: Huang, Yun, Fleeman, Nigel, Doherty, Alison, Wilson, Neil, Boland, Paul, Clegg, Andrew, Shaw, Elizabeth J, Nevitt, Sarah J, Tudur Smith, Catrin, Hill, Ruaraidh A, Marson, Anthony G, Huang, Yun, Fleeman, Nigel, Doherty, Alison, Wilson, Neil, Boland, Paul, Clegg, Andrew, Shaw, Elizabeth J, Nevitt, Sarah J, Tudur Smith, Catrin, Hill, Ruaraidh A, and Marson, Anthony G
Abstract: This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To evaluate the benefits and harms of different behavioural interventions, self‐management education and models of service delivery in promoting seizure control and improving quality of life‐related outcomes for adults with epilepsy compared to usual care or another behavioural intervention.
Published: 2023
Full Text: View/download PDF

5. Service delivery, behavioural, and self-management interventions for adults with epilepsy

Author: Huang, Yun, Fleeman, Nigel, Doherty, Alison, Wilson, Neil, Boland, Paul, Clegg, Andrew, Shaw, Elizabeth J, Nevitt, Sarah J, Tudur Smith, Catrin, Hill, Ruaraidh A, Marson, Anthony G, Huang, Yun, Fleeman, Nigel, Doherty, Alison, Wilson, Neil, Boland, Paul, Clegg, Andrew, Shaw, Elizabeth J, Nevitt, Sarah J, Tudur Smith, Catrin, Hill, Ruaraidh A, and Marson, Anthony G
Abstract: This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To evaluate the benefits and harms of different behavioural interventions, self‐management education and models of service delivery in promoting seizure control and improving quality of life‐related outcomes for adults with epilepsy compared to usual care or another behavioural intervention.
Published: 2023
Full Text: View/download PDF

6. Service delivery, behavioural, and self-management interventions for children with epilepsy

Author: Fleeman, Nigel, Panebianco, Mariangela, Hill, Ruaraidh A, Doherty, Alison, Nevitt, Sarah J, Boland, Paul, Clegg, Andrew, Wilson, Neil, Shaw, Elizabeth J, Marson, Anthony G, Fleeman, Nigel, Panebianco, Mariangela, Hill, Ruaraidh A, Doherty, Alison, Nevitt, Sarah J, Boland, Paul, Clegg, Andrew, Wilson, Neil, Shaw, Elizabeth J, and Marson, Anthony G
Abstract: Objectives This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To evaluate the benefits and harms of different behavioural interventions, self‐management education and models of service delivery in promoting seizure control and improving quality of life‐related outcomes for children with epilepsy compared to usual care or another behavioural intervention.
Published: 2023

7. Service delivery, behavioural, and self-management interventions for children with epilepsy

Author: Fleeman, Nigel, Panebianco, Mariangela, Hill, Ruaraidh A, Doherty, Alison, Nevitt, Sarah J, Boland, Paul, Clegg, Andrew, Wilson, Neil, Shaw, Elizabeth J, Marson, Anthony G, Fleeman, Nigel, Panebianco, Mariangela, Hill, Ruaraidh A, Doherty, Alison, Nevitt, Sarah J, Boland, Paul, Clegg, Andrew, Wilson, Neil, Shaw, Elizabeth J, and Marson, Anthony G
Abstract: Objectives This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To evaluate the benefits and harms of different behavioural interventions, self‐management education and models of service delivery in promoting seizure control and improving quality of life‐related outcomes for children with epilepsy compared to usual care or another behavioural intervention.
Published: 2023

8. Service delivery, behavioural, and self-management interventions for children with epilepsy

Author: Fleeman, Nigel, Panebianco, Mariangela, Hill, Ruaraidh A, Doherty, Alison, Nevitt, Sarah J, Boland, Paul, Clegg, Andrew, Wilson, Neil, Shaw, Elizabeth J, Marson, Anthony G, Fleeman, Nigel, Panebianco, Mariangela, Hill, Ruaraidh A, Doherty, Alison, Nevitt, Sarah J, Boland, Paul, Clegg, Andrew, Wilson, Neil, Shaw, Elizabeth J, and Marson, Anthony G
Abstract: Objectives This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To evaluate the benefits and harms of different behavioural interventions, self‐management education and models of service delivery in promoting seizure control and improving quality of life‐related outcomes for children with epilepsy compared to usual care or another behavioural intervention.
Published: 2023

9. The prevalence of comorbidities in epilepsy: a systematic review

Author: Doherty, Alison, Harrison, Joanna, Christian, Danielle, Boland, Paul, Harris, Cath, Hill, James Edward, Stephani, Anne-Marie, Reed, Janet, Duffield, Stephen, Marson, Tony G, Clegg, Andrew, Doherty, Alison, Harrison, Joanna, Christian, Danielle, Boland, Paul, Harris, Cath, Hill, James Edward, Stephani, Anne-Marie, Reed, Janet, Duffield, Stephen, Marson, Tony G, and Clegg, Andrew
Abstract: Comorbidities are associated with adverse patient outcomes. The authors conducted a systematic review according to a pre-determined protocol, established PRISMA guidelines and reporting standards to estimate the prevalence of common comorbidities in people with epilepsy, and to explore whether the burden is greater in more deprived populations. In total, 107 studies were included and reviewed. The results indicate that the most common comorbidities in people with epilepsy are anxiety (19.2%) and major depressive disorder (17.4%). Among adults with epilepsy, common comorbidities include hypertension (18.2%), stroke (14.5%), heart disease (11%), diabetes (10.2%) and arthritis (9.2%). There was no evidence that the income status of a country was a moderating factor for the prevalence of anxiety and depression in people with epilepsy. However, prevalence rates for hypertension and stroke were lower for lower-income countries where epilepsy is a more common symptom of brain infection or injury. The analyses were affected by the heterogeneity of the included studies and should therefore be interpreted cautiously.
Published: 2022

10. The prevalence of comorbidities in epilepsy: a systematic review

Author: Doherty, Alison, Harrison, Joanna, Christian, Danielle, Boland, Paul, Harris, Cath, Hill, James Edward, Stephani, Anne-Marie, Reed, Janet, Duffield, Stephen, Marson, Tony G, Clegg, Andrew, Doherty, Alison, Harrison, Joanna, Christian, Danielle, Boland, Paul, Harris, Cath, Hill, James Edward, Stephani, Anne-Marie, Reed, Janet, Duffield, Stephen, Marson, Tony G, and Clegg, Andrew
Abstract: Comorbidities are associated with adverse patient outcomes. The authors conducted a systematic review according to a pre-determined protocol, established PRISMA guidelines and reporting standards to estimate the prevalence of common comorbidities in people with epilepsy, and to explore whether the burden is greater in more deprived populations. In total, 107 studies were included and reviewed. The results indicate that the most common comorbidities in people with epilepsy are anxiety (19.2%) and major depressive disorder (17.4%). Among adults with epilepsy, common comorbidities include hypertension (18.2%), stroke (14.5%), heart disease (11%), diabetes (10.2%) and arthritis (9.2%). There was no evidence that the income status of a country was a moderating factor for the prevalence of anxiety and depression in people with epilepsy. However, prevalence rates for hypertension and stroke were lower for lower-income countries where epilepsy is a more common symptom of brain infection or injury. The analyses were affected by the heterogeneity of the included studies and should therefore be interpreted cautiously.
Published: 2022

11. Opportunities and challenges for the development of 'core outcome sets' in neuro-oncology.

Author: Millward, Christopher P, Millward, Christopher P, Armstrong, Terri S, Barrington, Heather, Brodbelt, Andrew R, Bulbeck, Helen, Byrne, Anthony, Dirven, Linda, Gamble, Carrol, Grundy, Paul L, Islim, Abdurrahman I, Javadpour, Mohsen, Keshwara, Sumirat M, Krishna, Sandhya T, Mallucci, Conor L, Marson, Anthony G, McDermott, Michael W, Meling, Torstein R, Oliver, Kathy, Pizer, Barry, Plaha, Puneet, Preusser, Matthias, Santarius, Thomas, Srikandarajah, Nisaharan, Taphoorn, Martin JB, Watts, Colin, Weller, Michael, Williamson, Paula R, Zadeh, Gelareh, Zamanipoor Najafabadi, Amir H, Jenkinson, Michael D, Millward, Christopher P, Millward, Christopher P, Armstrong, Terri S, Barrington, Heather, Brodbelt, Andrew R, Bulbeck, Helen, Byrne, Anthony, Dirven, Linda, Gamble, Carrol, Grundy, Paul L, Islim, Abdurrahman I, Javadpour, Mohsen, Keshwara, Sumirat M, Krishna, Sandhya T, Mallucci, Conor L, Marson, Anthony G, McDermott, Michael W, Meling, Torstein R, Oliver, Kathy, Pizer, Barry, Plaha, Puneet, Preusser, Matthias, Santarius, Thomas, Srikandarajah, Nisaharan, Taphoorn, Martin JB, Watts, Colin, Weller, Michael, Williamson, Paula R, Zadeh, Gelareh, Zamanipoor Najafabadi, Amir H, and Jenkinson, Michael D
Abstract: Core Outcome Sets (COS) define minimum outcomes to be measured and reported in clinical effectiveness trials for a particular health condition/health area. Despite recognition as critical to clinical research design for other health areas, none have been developed for neuro-oncology. COS development projects should carefully consider: scope (how the COS should be used), stakeholders involved in development (including patients as both research partners and participants), and consensus methodologies used (typically a Delphi survey and consensus meeting), as well as dissemination plans. Developing COS for neuro-oncology is potentially challenging due to extensive tumor subclassification (including molecular stratification), different symptoms related to anatomical tumor location, and variation in treatment options. Development of a COS specific to tumor subtype, in a specific location, for a particular intervention may be too narrow and would be unlikely to be used. Equally, a COS that is applicable across a wider area of neuro-oncology may be too broad and therefore lack specificity. This review describes why and how a COS may be developed, and discusses challenges for their development, specific to neuro-oncology. The COS under development are briefly described, including: adult glioma, incidental/untreated meningioma, meningioma requiring intervention, and adverse events from surgical intervention for pediatric brain tumors.
Published: 2022

12. Development of 'Core Outcome Sets' for Meningioma in Clinical Studies (The COSMIC Project): protocol for two systematic literature reviews, eDelphi surveys and online consensus meetings.

Author: Millward, Christopher P, Millward, Christopher P, Armstrong, Terri S, Barrington, Heather, Bell, Sabrina, Brodbelt, Andrew R, Bulbeck, Helen, Crofton, Anna, Dirven, Linda, Georgious, Theo, Grundy, Paul L, Islim, Abdurrahman I, Javadpour, Mohsen, Keshwara, Sumirat M, Koszdin, Shelli D, Marson, Anthony G, McDermott, Michael W, Meling, Torstein R, Oliver, Kathy, Plaha, Puneet, Preusser, Matthias, Santarius, Thomas, Srikandarajah, Nisaharan, Taphoorn, Martin JB, Turner, Carole, Watts, Colin, Weller, Michael, Williamson, Paula R, Zadeh, Gelareh, Zamanipoor Najafabadi, Amir H, Jenkinson, Michael D, EORTC BTG, ICOM, EANO, SNO, RANO-PRO, BNOS, SBNS, BIMS, TBTC, International Brain Tumour Alliance, Brainstrust, and Brain Tumour Foundation of Canada, Millward, Christopher P, Millward, Christopher P, Armstrong, Terri S, Barrington, Heather, Bell, Sabrina, Brodbelt, Andrew R, Bulbeck, Helen, Crofton, Anna, Dirven, Linda, Georgious, Theo, Grundy, Paul L, Islim, Abdurrahman I, Javadpour, Mohsen, Keshwara, Sumirat M, Koszdin, Shelli D, Marson, Anthony G, McDermott, Michael W, Meling, Torstein R, Oliver, Kathy, Plaha, Puneet, Preusser, Matthias, Santarius, Thomas, Srikandarajah, Nisaharan, Taphoorn, Martin JB, Turner, Carole, Watts, Colin, Weller, Michael, Williamson, Paula R, Zadeh, Gelareh, Zamanipoor Najafabadi, Amir H, Jenkinson, Michael D, and EORTC BTG, ICOM, EANO, SNO, RANO-PRO, BNOS, SBNS, BIMS, TBTC, International Brain Tumour Alliance, Brainstrust, and Brain Tumour Foundation of Canada
Abstract: IntroductionMeningioma is the most common primary intracranial tumour in adults. The majority are non-malignant, but a proportion behave more aggressively. Incidental/minimally symptomatic meningioma are often managed by serial imaging. Symptomatic meningioma, those that threaten neurovascular structures, or demonstrate radiological growth, are usually resected as first-line management strategy. For patients in poor clinical condition, or with inoperable, residual or recurrent disease, radiotherapy is often used as primary or adjuvant treatment. Effective pharmacotherapy treatments do not currently exist. There is heterogeneity in the outcomes measured and reported in meningioma clinical studies. Two 'Core Outcome Sets' (COS) will be developed: (COSMIC: Intervention) for use in meningioma clinical effectiveness trials and (COSMIC: Observation) for use in clinical studies of incidental/untreated meningioma.Methods and analysisTwo systematic literature reviews and trial registry searches will identify outcomes measured and reported in published and ongoing (1) meningioma clinical effectiveness trials, and (2) clinical studies of incidental/untreated meningioma. Outcomes include those that are clinician reported, patient reported, caregiver reported and based on objective tests (eg, neurocognitive tests), as well as measures of progression and survival. Outcomes will be deduplicated and categorised to generate two long lists. The two long lists will be prioritised through two, two-round, international, modified eDelphi surveys including patients with meningioma, healthcare professionals, researchers and those in caring/supporting roles. The two final COS will be ratified through two 1-day online consensus meetings, with representation from all stakeholder groups.Ethics and disseminationInstitutional review board (University of Liverpool) approval was obtained for the conduct of this study. Participant eConsent will be obtained prior to participation in the eDelphi surv
Published: 2022

13. Opportunities and challenges for the development of 'core outcome sets' in neuro-oncology.

Author: Millward, Christopher P, Millward, Christopher P, Armstrong, Terri S, Barrington, Heather, Brodbelt, Andrew R, Bulbeck, Helen, Byrne, Anthony, Dirven, Linda, Gamble, Carrol, Grundy, Paul L, Islim, Abdurrahman I, Javadpour, Mohsen, Keshwara, Sumirat M, Krishna, Sandhya T, Mallucci, Conor L, Marson, Anthony G, McDermott, Michael W, Meling, Torstein R, Oliver, Kathy, Pizer, Barry, Plaha, Puneet, Preusser, Matthias, Santarius, Thomas, Srikandarajah, Nisaharan, Taphoorn, Martin JB, Watts, Colin, Weller, Michael, Williamson, Paula R, Zadeh, Gelareh, Zamanipoor Najafabadi, Amir H, Jenkinson, Michael D, Millward, Christopher P, Millward, Christopher P, Armstrong, Terri S, Barrington, Heather, Brodbelt, Andrew R, Bulbeck, Helen, Byrne, Anthony, Dirven, Linda, Gamble, Carrol, Grundy, Paul L, Islim, Abdurrahman I, Javadpour, Mohsen, Keshwara, Sumirat M, Krishna, Sandhya T, Mallucci, Conor L, Marson, Anthony G, McDermott, Michael W, Meling, Torstein R, Oliver, Kathy, Pizer, Barry, Plaha, Puneet, Preusser, Matthias, Santarius, Thomas, Srikandarajah, Nisaharan, Taphoorn, Martin JB, Watts, Colin, Weller, Michael, Williamson, Paula R, Zadeh, Gelareh, Zamanipoor Najafabadi, Amir H, and Jenkinson, Michael D
Abstract: Core Outcome Sets (COS) define minimum outcomes to be measured and reported in clinical effectiveness trials for a particular health condition/health area. Despite recognition as critical to clinical research design for other health areas, none have been developed for neuro-oncology. COS development projects should carefully consider: scope (how the COS should be used), stakeholders involved in development (including patients as both research partners and participants), and consensus methodologies used (typically a Delphi survey and consensus meeting), as well as dissemination plans. Developing COS for neuro-oncology is potentially challenging due to extensive tumor subclassification (including molecular stratification), different symptoms related to anatomical tumor location, and variation in treatment options. Development of a COS specific to tumor subtype, in a specific location, for a particular intervention may be too narrow and would be unlikely to be used. Equally, a COS that is applicable across a wider area of neuro-oncology may be too broad and therefore lack specificity. This review describes why and how a COS may be developed, and discusses challenges for their development, specific to neuro-oncology. The COS under development are briefly described, including: adult glioma, incidental/untreated meningioma, meningioma requiring intervention, and adverse events from surgical intervention for pediatric brain tumors.
Published: 2022

14. Development of 'Core Outcome Sets' for Meningioma in Clinical Studies (The COSMIC Project): protocol for two systematic literature reviews, eDelphi surveys and online consensus meetings.

Author: Millward, Christopher P, Millward, Christopher P, Armstrong, Terri S, Barrington, Heather, Bell, Sabrina, Brodbelt, Andrew R, Bulbeck, Helen, Crofton, Anna, Dirven, Linda, Georgious, Theo, Grundy, Paul L, Islim, Abdurrahman I, Javadpour, Mohsen, Keshwara, Sumirat M, Koszdin, Shelli D, Marson, Anthony G, McDermott, Michael W, Meling, Torstein R, Oliver, Kathy, Plaha, Puneet, Preusser, Matthias, Santarius, Thomas, Srikandarajah, Nisaharan, Taphoorn, Martin JB, Turner, Carole, Watts, Colin, Weller, Michael, Williamson, Paula R, Zadeh, Gelareh, Zamanipoor Najafabadi, Amir H, Jenkinson, Michael D, EORTC BTG, ICOM, EANO, SNO, RANO-PRO, BNOS, SBNS, BIMS, TBTC, International Brain Tumour Alliance, Brainstrust, and Brain Tumour Foundation of Canada, Millward, Christopher P, Millward, Christopher P, Armstrong, Terri S, Barrington, Heather, Bell, Sabrina, Brodbelt, Andrew R, Bulbeck, Helen, Crofton, Anna, Dirven, Linda, Georgious, Theo, Grundy, Paul L, Islim, Abdurrahman I, Javadpour, Mohsen, Keshwara, Sumirat M, Koszdin, Shelli D, Marson, Anthony G, McDermott, Michael W, Meling, Torstein R, Oliver, Kathy, Plaha, Puneet, Preusser, Matthias, Santarius, Thomas, Srikandarajah, Nisaharan, Taphoorn, Martin JB, Turner, Carole, Watts, Colin, Weller, Michael, Williamson, Paula R, Zadeh, Gelareh, Zamanipoor Najafabadi, Amir H, Jenkinson, Michael D, and EORTC BTG, ICOM, EANO, SNO, RANO-PRO, BNOS, SBNS, BIMS, TBTC, International Brain Tumour Alliance, Brainstrust, and Brain Tumour Foundation of Canada
Abstract: IntroductionMeningioma is the most common primary intracranial tumour in adults. The majority are non-malignant, but a proportion behave more aggressively. Incidental/minimally symptomatic meningioma are often managed by serial imaging. Symptomatic meningioma, those that threaten neurovascular structures, or demonstrate radiological growth, are usually resected as first-line management strategy. For patients in poor clinical condition, or with inoperable, residual or recurrent disease, radiotherapy is often used as primary or adjuvant treatment. Effective pharmacotherapy treatments do not currently exist. There is heterogeneity in the outcomes measured and reported in meningioma clinical studies. Two 'Core Outcome Sets' (COS) will be developed: (COSMIC: Intervention) for use in meningioma clinical effectiveness trials and (COSMIC: Observation) for use in clinical studies of incidental/untreated meningioma.Methods and analysisTwo systematic literature reviews and trial registry searches will identify outcomes measured and reported in published and ongoing (1) meningioma clinical effectiveness trials, and (2) clinical studies of incidental/untreated meningioma. Outcomes include those that are clinician reported, patient reported, caregiver reported and based on objective tests (eg, neurocognitive tests), as well as measures of progression and survival. Outcomes will be deduplicated and categorised to generate two long lists. The two long lists will be prioritised through two, two-round, international, modified eDelphi surveys including patients with meningioma, healthcare professionals, researchers and those in caring/supporting roles. The two final COS will be ratified through two 1-day online consensus meetings, with representation from all stakeholder groups.Ethics and disseminationInstitutional review board (University of Liverpool) approval was obtained for the conduct of this study. Participant eConsent will be obtained prior to participation in the eDelphi surv
Published: 2022

15. The prevalence of comorbidities in epilepsy: a systematic review

Author: Doherty, Alison, Harrison, Joanna, Christian, Danielle, Boland, Paul, Harris, Cath, Hill, James Edward, Stephani, Anne-Marie, Reed, Janet, Duffield, Stephen, Marson, Tony G, Clegg, Andrew, Doherty, Alison, Harrison, Joanna, Christian, Danielle, Boland, Paul, Harris, Cath, Hill, James Edward, Stephani, Anne-Marie, Reed, Janet, Duffield, Stephen, Marson, Tony G, and Clegg, Andrew
Abstract: Comorbidities are associated with adverse patient outcomes. The authors conducted a systematic review according to a pre-determined protocol, established PRISMA guidelines and reporting standards to estimate the prevalence of common comorbidities in people with epilepsy, and to explore whether the burden is greater in more deprived populations. In total, 107 studies were included and reviewed. The results indicate that the most common comorbidities in people with epilepsy are anxiety (19.2%) and major depressive disorder (17.4%). Among adults with epilepsy, common comorbidities include hypertension (18.2%), stroke (14.5%), heart disease (11%), diabetes (10.2%) and arthritis (9.2%). There was no evidence that the income status of a country was a moderating factor for the prevalence of anxiety and depression in people with epilepsy. However, prevalence rates for hypertension and stroke were lower for lower-income countries where epilepsy is a more common symptom of brain infection or injury. The analyses were affected by the heterogeneity of the included studies and should therefore be interpreted cautiously.
Published: 2022

16. The prevalence of comorbidities in epilepsy: a systematic review

Author: Doherty, Alison, Harrison, Joanna, Christian, Danielle, Boland, Paul, Harris, Cath, Hill, James Edward, Stephani, Anne-Marie, Reed, Janet, Duffield, Stephen, Marson, Tony G, Clegg, Andrew, Doherty, Alison, Harrison, Joanna, Christian, Danielle, Boland, Paul, Harris, Cath, Hill, James Edward, Stephani, Anne-Marie, Reed, Janet, Duffield, Stephen, Marson, Tony G, and Clegg, Andrew
Abstract: Comorbidities are associated with adverse patient outcomes. The authors conducted a systematic review according to a pre-determined protocol, established PRISMA guidelines and reporting standards to estimate the prevalence of common comorbidities in people with epilepsy, and to explore whether the burden is greater in more deprived populations. In total, 107 studies were included and reviewed. The results indicate that the most common comorbidities in people with epilepsy are anxiety (19.2%) and major depressive disorder (17.4%). Among adults with epilepsy, common comorbidities include hypertension (18.2%), stroke (14.5%), heart disease (11%), diabetes (10.2%) and arthritis (9.2%). There was no evidence that the income status of a country was a moderating factor for the prevalence of anxiety and depression in people with epilepsy. However, prevalence rates for hypertension and stroke were lower for lower-income countries where epilepsy is a more common symptom of brain infection or injury. The analyses were affected by the heterogeneity of the included studies and should therefore be interpreted cautiously.
Published: 2022

17. The prevalence of comorbidities in epilepsy: a systematic review

Author: Doherty, Alison, Harrison, Joanna, Christian, Danielle, Boland, Paul, Harris, Cath, Hill, James Edward, Stephani, Anne-Marie, Reed, Janet, Duffield, Stephen, Marson, Tony G, Clegg, Andrew, Doherty, Alison, Harrison, Joanna, Christian, Danielle, Boland, Paul, Harris, Cath, Hill, James Edward, Stephani, Anne-Marie, Reed, Janet, Duffield, Stephen, Marson, Tony G, and Clegg, Andrew
Abstract: Comorbidities are associated with adverse patient outcomes. The authors conducted a systematic review according to a pre-determined protocol, established PRISMA guidelines and reporting standards to estimate the prevalence of common comorbidities in people with epilepsy, and to explore whether the burden is greater in more deprived populations. In total, 107 studies were included and reviewed. The results indicate that the most common comorbidities in people with epilepsy are anxiety (19.2%) and major depressive disorder (17.4%). Among adults with epilepsy, common comorbidities include hypertension (18.2%), stroke (14.5%), heart disease (11%), diabetes (10.2%) and arthritis (9.2%). There was no evidence that the income status of a country was a moderating factor for the prevalence of anxiety and depression in people with epilepsy. However, prevalence rates for hypertension and stroke were lower for lower-income countries where epilepsy is a more common symptom of brain infection or injury. The analyses were affected by the heterogeneity of the included studies and should therefore be interpreted cautiously.
Published: 2022

18. Role of Common Genetic Variants for Drug-Resistance to Specific Anti-Seizure Medications

Author: Wolking, Stefan, Campbell, Ciarán, Stapleton, Caragh, McCormack, Mark, Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Krause, Roland, Kunz, Wolfram S., Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Sisodiya, Sanjay M., Cavalleri, Gianpiero L., Lerche, Holger, ???, Epipgx Consortium, Wolking, Stefan, Campbell, Ciarán, Stapleton, Caragh, McCormack, Mark, Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Krause, Roland, Kunz, Wolfram S., Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Sisodiya, Sanjay M., Cavalleri, Gianpiero L., Lerche, Holger, and ???, Epipgx Consortium
Abstract: Objective: Resistance to anti-seizure medications (ASMs) presents a significant hurdle in the treatment of people with epilepsy. Genetic markers for resistance to individual ASMs could support clinicians to make better-informed choices for their patients. In this study, we aimed to elucidate whether the response to individual ASMs was associated with common genetic variation.Methods: A cohort of 3,649 individuals of European descent with epilepsy was deeply phenotyped and underwent single nucleotide polymorphism (SNP)-genotyping. We conducted genome-wide association analyses (GWASs) on responders to specific ASMs or groups of functionally related ASMs, using non-responders as controls. We performed a polygenic risk score (PRS) analyses based on risk variants for epilepsy and neuropsychiatric disorders and ASM resistance itself to delineate the polygenic burden of ASM-specific drug resistance.Results: We identified several potential regions of interest but did not detect genome-wide significant loci for ASM-specific response. We did not find polygenic risk for epilepsy, neuropsychiatric disorders, and drug-resistance associated with drug response to specific ASMs or mechanistically related groups of ASMs.Significance: This study could not ascertain the predictive value of common genetic variants for ASM responder status. The identified suggestive loci will need replication in future studies of a larger scale.
Published: 2021

19. Role of Common Genetic Variants for Drug-Resistance to Specific Anti-Seizure Medications

Author: Wolking, Stefan, Campbell, Ciarán, Stapleton, Caragh, McCormack, Mark, Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Krause, Roland, Kunz, Wolfram S., Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Sisodiya, Sanjay M., Cavalleri, Gianpiero L., Lerche, Holger, ???, Epipgx Consortium, Wolking, Stefan, Campbell, Ciarán, Stapleton, Caragh, McCormack, Mark, Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Krause, Roland, Kunz, Wolfram S., Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Sisodiya, Sanjay M., Cavalleri, Gianpiero L., Lerche, Holger, and ???, Epipgx Consortium
Abstract: Objective: Resistance to anti-seizure medications (ASMs) presents a significant hurdle in the treatment of people with epilepsy. Genetic markers for resistance to individual ASMs could support clinicians to make better-informed choices for their patients. In this study, we aimed to elucidate whether the response to individual ASMs was associated with common genetic variation.Methods: A cohort of 3,649 individuals of European descent with epilepsy was deeply phenotyped and underwent single nucleotide polymorphism (SNP)-genotyping. We conducted genome-wide association analyses (GWASs) on responders to specific ASMs or groups of functionally related ASMs, using non-responders as controls. We performed a polygenic risk score (PRS) analyses based on risk variants for epilepsy and neuropsychiatric disorders and ASM resistance itself to delineate the polygenic burden of ASM-specific drug resistance.Results: We identified several potential regions of interest but did not detect genome-wide significant loci for ASM-specific response. We did not find polygenic risk for epilepsy, neuropsychiatric disorders, and drug-resistance associated with drug response to specific ASMs or mechanistically related groups of ASMs.Significance: This study could not ascertain the predictive value of common genetic variants for ASM responder status. The identified suggestive loci will need replication in future studies of a larger scale.
Published: 2021

20. Assessing the role of rare genetic variants in drug-resistant, non-lesional focal epilepsy

Author: Wolking, Stefan, Moreau, Claudia, McCormack, Mark, Krause, Roland, Krenn, Martin, Consortium, Epipgx, Berkovic, Samuel, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Lerche, Holger, Marson, Anthony G., O’Brien, Terence J., Petrovski, Slave, Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Zimprich, Fritz, Sisodiya, Sanjay M., Girard, Simon L., Cossette, Patrick, Wolking, Stefan, Moreau, Claudia, McCormack, Mark, Krause, Roland, Krenn, Martin, Consortium, Epipgx, Berkovic, Samuel, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Lerche, Holger, Marson, Anthony G., O’Brien, Terence J., Petrovski, Slave, Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Zimprich, Fritz, Sisodiya, Sanjay M., Girard, Simon L., and Cossette, Patrick
Abstract: Objective Resistance to antiseizure medications (ASMs) is one of the major concerns in the treatment of epilepsy. Despite the increasing number of ASMs available, the proportion of individuals with drug-resistant epilepsy remains unchanged. In this study, we aimed to investigate the role of rare genetic variants in ASM resistance. Methods We performed exome sequencing of 1,128 individuals with non-familial non-acquired focal epilepsy (NAFE) (762 non-responders, 366 responders) and were provided with 1,734 healthy controls. We undertook replication in a cohort of 350 individuals with NAFE (165 non-responders, 185 responders). We performed gene-based and gene-set-based kernel association tests to investigate potential enrichment of rare variants in relation to drug response status and to risk for NAFE. Results We found no gene or gene set that reached genome-wide significance. Yet, we identified several prospective candidate genes – among them DEPDC5, which showed a potential association with resistance to ASMs. We found some evidence for an enrichment of truncating variants in dominant familial NAFE genes in our cohort of non-familial NAFE and in association with drug-resistant NAFE. Interpretation Our study identifies potential candidate genes for ASM resistance. Our results corroborate the role of rare variants for non-familial NAFE and imply their involvement in drug-resistant epilepsy. Future large-scale genetic research studies are needed to substantiate these findings.
Published: 2021

21. Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Motelow, Joshua E., Povysil, Gundula, Dhindsa, Ryan S., Stanley, Kate E., Allen, Andrew S., Feng, Yen-Chen Anne, Howrigan, Daniel P., Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Cusick, Caroline, Singh, Tarjinder, Heyne, Henrike, Byrnes, Andrea E., Churchhouse, Claire, Watts, Nick, Solomonson, Matthew, Lal, Dennis, Gupta, Namrata, Neale, Benjamin M., Cavalleri, Gianpiero L., Cossette, Patrick, Cotsapas, Chris, Jonghe, Peter De, Dixon-Salazar, Tracy, Guerrini, Renzo, Hakonarson, Hakon, Heinzen, Erin L., Helbig, Ingo, Kwan, Patrick, Marson, Anthony G., Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Stewart, Randy, Weckhuysen, Sarah, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, Krause, Roland, May, Patrick, McKenna, Kevin, Regan, Brigid M., Bennett, Caitlin A., Leu, Costin, Leech, Stephanie L., O’Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Ali, Quratulain Zulfiqar, Sadoway, Tara R., Krestel, Heinz, Schaller, André, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Christou, Yiolanda, Štěrbová, Katalin, Vlčková, Markéta, Sedláčková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Neubauer, Bernd A., Zimprich, Friedrich, Feucht, Martha, Reinthaler, Eva M., Kunz, Wolfram S., Zsurka, Gábor, Surges, Rainer, Baumgartner, Tobias, Wrede, Randi Von, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, Baalen, Andreas Van, Spiczak, Sarah Von, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Kurlemann, Gerhard, Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, Lauxmann, Stephan, Boßelmann, Christian, Kegele, Josua, Hengsbach, Christian, Rau, Sarah, Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Borggräfe, Ingo, Schankin, Christoph J., Schubert-Bast, Susanne, Schreiber, Herbert, Mayer, Thomas, Korinthenberg, Rudolf, Brockmann, Knut, Wolff, Markus, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Saarela, Anni, Timonen, Oskari, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Rheims, Sylvain, Lesca, Gaetan, Ryvlin, Philippe, Maillard, Louis, Valton, Luc, Derambure, Philippe, Bartolomei, Fabrice, Hirsch, Edouard, Michel, Véronique, Chassoux, Francine, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Baker, Mark D., Fonferko-Shadrach, Beata, Lawthom, Charlotte, Anderson, Joseph, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Delanty, Norman, Doherty, Colin P., Shukralla, Arif, El-Naggar, Hany, Widdess-Walsh, Peter, Barišić, Nina, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Ragona, Francesca, Zara, Federico, Iacomino, Michele, Riva, Antonella, Madia, Francesca, Vari, Maria Stella, Salpietro, Vincenzo, Scala, Marcello, Mancardi, Maria Margherita, Nobili, Lino, Amadori, Elisabetta, Giacomini, Thea, Bisulli, Francesca, Pippucci, Tommaso, Licchetta, Laura, Minardi, Raffaella, Tinuper, Paolo, Muccioli, Lorenzo, Mostacci, Barbara, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Barba, Carmen, Hirose, Shinichi, Ishii, Atsushi, Suzuki, Toshimitsu, Inoue, Yushi, Yamakawa, Kazuhiro, Beydoun, Ahmad, Nasreddine, Wassim, Zgheib, Nathalie Khoueiry, Tumiene, Birute, Utkus, Algirdas, Sadleir, Lynette G., King, Chontelle, Caglayan, S. Hande, Arslan, Mutluay, Yapıcı, Zuhal, Topaloglu, Pınar, Kara, Bulent, Yis, Uluc, Turkdogan, Dilsad, Gundogdu-Eken, Aslı, Bebek, Nerses, Tsai, Meng-Han, Ho, Chen-Jui, Lin, Chih-Hsiang, Lin, Kuang-Lin, Chou, I.-Jun, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Noebels, Jeffrey L., Goldman, Alicia, Busch, Robyn M., Jehi, Lara, Najm, Imad M., Ferguson, Lisa, Khoury, Jean, Glauser, Tracy A., Clark, Peggy O., Buono, Russell J., Ferraro, Thomas N., Sperling, Michael R., Lo, Warren, Privitera, Michael, French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Greenberg, David A., Ellis, Colin A., Goldberg, Ethan, Helbig, Katherine L., Cosico, Mahgenn, Vaidiswaran, Priya, Fitch, Eryn, Berkovic, Samuel F., Lerche, Holger, Lowenstein, Daniel H., Goldstein, David B., Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Motelow, Joshua E., Povysil, Gundula, Dhindsa, Ryan S., Stanley, Kate E., Allen, Andrew S., Feng, Yen-Chen Anne, Howrigan, Daniel P., Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Cusick, Caroline, Singh, Tarjinder, Heyne, Henrike, Byrnes, Andrea E., Churchhouse, Claire, Watts, Nick, Solomonson, Matthew, Lal, Dennis, Gupta, Namrata, Neale, Benjamin M., Cavalleri, Gianpiero L., Cossette, Patrick, Cotsapas, Chris, Jonghe, Peter De, Dixon-Salazar, Tracy, Guerrini, Renzo, Hakonarson, Hakon, Heinzen, Erin L., Helbig, Ingo, Kwan, Patrick, Marson, Anthony G., Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Stewart, Randy, Weckhuysen, Sarah, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, Krause, Roland, May, Patrick, McKenna, Kevin, Regan, Brigid M., Bennett, Caitlin A., Leu, Costin, Leech, Stephanie L., O’Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Ali, Quratulain Zulfiqar, Sadoway, Tara R., Krestel, Heinz, Schaller, André, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Christou, Yiolanda, Štěrbová, Katalin, Vlčková, Markéta, Sedláčková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Neubauer, Bernd A., Zimprich, Friedrich, Feucht, Martha, Reinthaler, Eva M., Kunz, Wolfram S., Zsurka, Gábor, Surges, Rainer, Baumgartner, Tobias, Wrede, Randi Von, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, Baalen, Andreas Van, Spiczak, Sarah Von, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Kurlemann, Gerhard, Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, Lauxmann, Stephan, Boßelmann, Christian, Kegele, Josua, Hengsbach, Christian, Rau, Sarah, Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Borggräfe, Ingo, Schankin, Christoph J., Schubert-Bast, Susanne, Schreiber, Herbert, Mayer, Thomas, Korinthenberg, Rudolf, Brockmann, Knut, Wolff, Markus, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Saarela, Anni, Timonen, Oskari, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Rheims, Sylvain, Lesca, Gaetan, Ryvlin, Philippe, Maillard, Louis, Valton, Luc, Derambure, Philippe, Bartolomei, Fabrice, Hirsch, Edouard, Michel, Véronique, Chassoux, Francine, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Baker, Mark D., Fonferko-Shadrach, Beata, Lawthom, Charlotte, Anderson, Joseph, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Delanty, Norman, Doherty, Colin P., Shukralla, Arif, El-Naggar, Hany, Widdess-Walsh, Peter, Barišić, Nina, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Ragona, Francesca, Zara, Federico, Iacomino, Michele, Riva, Antonella, Madia, Francesca, Vari, Maria Stella, Salpietro, Vincenzo, Scala, Marcello, Mancardi, Maria Margherita, Nobili, Lino, Amadori, Elisabetta, Giacomini, Thea, Bisulli, Francesca, Pippucci, Tommaso, Licchetta, Laura, Minardi, Raffaella, Tinuper, Paolo, Muccioli, Lorenzo, Mostacci, Barbara, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Barba, Carmen, Hirose, Shinichi, Ishii, Atsushi, Suzuki, Toshimitsu, Inoue, Yushi, Yamakawa, Kazuhiro, Beydoun, Ahmad, Nasreddine, Wassim, Zgheib, Nathalie Khoueiry, Tumiene, Birute, Utkus, Algirdas, Sadleir, Lynette G., King, Chontelle, Caglayan, S. Hande, Arslan, Mutluay, Yapıcı, Zuhal, Topaloglu, Pınar, Kara, Bulent, Yis, Uluc, Turkdogan, Dilsad, Gundogdu-Eken, Aslı, Bebek, Nerses, Tsai, Meng-Han, Ho, Chen-Jui, Lin, Chih-Hsiang, Lin, Kuang-Lin, Chou, I.-Jun, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Noebels, Jeffrey L., Goldman, Alicia, Busch, Robyn M., Jehi, Lara, Najm, Imad M., Ferguson, Lisa, Khoury, Jean, Glauser, Tracy A., Clark, Peggy O., Buono, Russell J., Ferraro, Thomas N., Sperling, Michael R., Lo, Warren, Privitera, Michael, French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Greenberg, David A., Ellis, Colin A., Goldberg, Ethan, Helbig, Katherine L., Cosico, Mahgenn, Vaidiswaran, Priya, Fitch, Eryn, Berkovic, Samuel F., Lerche, Holger, Lowenstein, Daniel H., and Goldstein, David B.
Abstract: Summary Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.
Published: 2021

22. Assessing the role of rare genetic variants in drug-resistant, non-lesional focal epilepsy

Author: Wolking, Stefan, Moreau, Claudia, McCormack, Mark, Krause, Roland, Krenn, Martin, Consortium, Epipgx, Berkovic, Samuel, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Lerche, Holger, Marson, Anthony G., O’Brien, Terence J., Petrovski, Slave, Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Zimprich, Fritz, Sisodiya, Sanjay M., Girard, Simon L., Cossette, Patrick, Wolking, Stefan, Moreau, Claudia, McCormack, Mark, Krause, Roland, Krenn, Martin, Consortium, Epipgx, Berkovic, Samuel, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Lerche, Holger, Marson, Anthony G., O’Brien, Terence J., Petrovski, Slave, Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Zimprich, Fritz, Sisodiya, Sanjay M., Girard, Simon L., and Cossette, Patrick
Abstract: Objective Resistance to antiseizure medications (ASMs) is one of the major concerns in the treatment of epilepsy. Despite the increasing number of ASMs available, the proportion of individuals with drug-resistant epilepsy remains unchanged. In this study, we aimed to investigate the role of rare genetic variants in ASM resistance. Methods We performed exome sequencing of 1,128 individuals with non-familial non-acquired focal epilepsy (NAFE) (762 non-responders, 366 responders) and were provided with 1,734 healthy controls. We undertook replication in a cohort of 350 individuals with NAFE (165 non-responders, 185 responders). We performed gene-based and gene-set-based kernel association tests to investigate potential enrichment of rare variants in relation to drug response status and to risk for NAFE. Results We found no gene or gene set that reached genome-wide significance. Yet, we identified several prospective candidate genes – among them DEPDC5, which showed a potential association with resistance to ASMs. We found some evidence for an enrichment of truncating variants in dominant familial NAFE genes in our cohort of non-familial NAFE and in association with drug-resistant NAFE. Interpretation Our study identifies potential candidate genes for ASM resistance. Our results corroborate the role of rare variants for non-familial NAFE and imply their involvement in drug-resistant epilepsy. Future large-scale genetic research studies are needed to substantiate these findings.
Published: 2021

23. Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Motelow, Joshua E., Povysil, Gundula, Dhindsa, Ryan S., Stanley, Kate E., Allen, Andrew S., Feng, Yen-Chen Anne, Howrigan, Daniel P., Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Cusick, Caroline, Singh, Tarjinder, Heyne, Henrike, Byrnes, Andrea E., Churchhouse, Claire, Watts, Nick, Solomonson, Matthew, Lal, Dennis, Gupta, Namrata, Neale, Benjamin M., Cavalleri, Gianpiero L., Cossette, Patrick, Cotsapas, Chris, Jonghe, Peter De, Dixon-Salazar, Tracy, Guerrini, Renzo, Hakonarson, Hakon, Heinzen, Erin L., Helbig, Ingo, Kwan, Patrick, Marson, Anthony G., Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Stewart, Randy, Weckhuysen, Sarah, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, Krause, Roland, May, Patrick, McKenna, Kevin, Regan, Brigid M., Bennett, Caitlin A., Leu, Costin, Leech, Stephanie L., O’Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Ali, Quratulain Zulfiqar, Sadoway, Tara R., Krestel, Heinz, Schaller, André, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Christou, Yiolanda, Štěrbová, Katalin, Vlčková, Markéta, Sedláčková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Neubauer, Bernd A., Zimprich, Friedrich, Feucht, Martha, Reinthaler, Eva M., Kunz, Wolfram S., Zsurka, Gábor, Surges, Rainer, Baumgartner, Tobias, Wrede, Randi Von, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, Baalen, Andreas Van, Spiczak, Sarah Von, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Kurlemann, Gerhard, Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, Lauxmann, Stephan, Boßelmann, Christian, Kegele, Josua, Hengsbach, Christian, Rau, Sarah, Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Borggräfe, Ingo, Schankin, Christoph J., Schubert-Bast, Susanne, Schreiber, Herbert, Mayer, Thomas, Korinthenberg, Rudolf, Brockmann, Knut, Wolff, Markus, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Saarela, Anni, Timonen, Oskari, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Rheims, Sylvain, Lesca, Gaetan, Ryvlin, Philippe, Maillard, Louis, Valton, Luc, Derambure, Philippe, Bartolomei, Fabrice, Hirsch, Edouard, Michel, Véronique, Chassoux, Francine, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Baker, Mark D., Fonferko-Shadrach, Beata, Lawthom, Charlotte, Anderson, Joseph, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Delanty, Norman, Doherty, Colin P., Shukralla, Arif, El-Naggar, Hany, Widdess-Walsh, Peter, Barišić, Nina, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Ragona, Francesca, Zara, Federico, Iacomino, Michele, Riva, Antonella, Madia, Francesca, Vari, Maria Stella, Salpietro, Vincenzo, Scala, Marcello, Mancardi, Maria Margherita, Nobili, Lino, Amadori, Elisabetta, Giacomini, Thea, Bisulli, Francesca, Pippucci, Tommaso, Licchetta, Laura, Minardi, Raffaella, Tinuper, Paolo, Muccioli, Lorenzo, Mostacci, Barbara, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Barba, Carmen, Hirose, Shinichi, Ishii, Atsushi, Suzuki, Toshimitsu, Inoue, Yushi, Yamakawa, Kazuhiro, Beydoun, Ahmad, Nasreddine, Wassim, Zgheib, Nathalie Khoueiry, Tumiene, Birute, Utkus, Algirdas, Sadleir, Lynette G., King, Chontelle, Caglayan, S. Hande, Arslan, Mutluay, Yapıcı, Zuhal, Topaloglu, Pınar, Kara, Bulent, Yis, Uluc, Turkdogan, Dilsad, Gundogdu-Eken, Aslı, Bebek, Nerses, Tsai, Meng-Han, Ho, Chen-Jui, Lin, Chih-Hsiang, Lin, Kuang-Lin, Chou, I.-Jun, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Noebels, Jeffrey L., Goldman, Alicia, Busch, Robyn M., Jehi, Lara, Najm, Imad M., Ferguson, Lisa, Khoury, Jean, Glauser, Tracy A., Clark, Peggy O., Buono, Russell J., Ferraro, Thomas N., Sperling, Michael R., Lo, Warren, Privitera, Michael, French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Greenberg, David A., Ellis, Colin A., Goldberg, Ethan, Helbig, Katherine L., Cosico, Mahgenn, Vaidiswaran, Priya, Fitch, Eryn, Berkovic, Samuel F., Lerche, Holger, Lowenstein, Daniel H., Goldstein, David B., Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Motelow, Joshua E., Povysil, Gundula, Dhindsa, Ryan S., Stanley, Kate E., Allen, Andrew S., Feng, Yen-Chen Anne, Howrigan, Daniel P., Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Cusick, Caroline, Singh, Tarjinder, Heyne, Henrike, Byrnes, Andrea E., Churchhouse, Claire, Watts, Nick, Solomonson, Matthew, Lal, Dennis, Gupta, Namrata, Neale, Benjamin M., Cavalleri, Gianpiero L., Cossette, Patrick, Cotsapas, Chris, Jonghe, Peter De, Dixon-Salazar, Tracy, Guerrini, Renzo, Hakonarson, Hakon, Heinzen, Erin L., Helbig, Ingo, Kwan, Patrick, Marson, Anthony G., Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Stewart, Randy, Weckhuysen, Sarah, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, Krause, Roland, May, Patrick, McKenna, Kevin, Regan, Brigid M., Bennett, Caitlin A., Leu, Costin, Leech, Stephanie L., O’Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Ali, Quratulain Zulfiqar, Sadoway, Tara R., Krestel, Heinz, Schaller, André, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Christou, Yiolanda, Štěrbová, Katalin, Vlčková, Markéta, Sedláčková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Neubauer, Bernd A., Zimprich, Friedrich, Feucht, Martha, Reinthaler, Eva M., Kunz, Wolfram S., Zsurka, Gábor, Surges, Rainer, Baumgartner, Tobias, Wrede, Randi Von, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, Baalen, Andreas Van, Spiczak, Sarah Von, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Kurlemann, Gerhard, Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, Lauxmann, Stephan, Boßelmann, Christian, Kegele, Josua, Hengsbach, Christian, Rau, Sarah, Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Borggräfe, Ingo, Schankin, Christoph J., Schubert-Bast, Susanne, Schreiber, Herbert, Mayer, Thomas, Korinthenberg, Rudolf, Brockmann, Knut, Wolff, Markus, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Saarela, Anni, Timonen, Oskari, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Rheims, Sylvain, Lesca, Gaetan, Ryvlin, Philippe, Maillard, Louis, Valton, Luc, Derambure, Philippe, Bartolomei, Fabrice, Hirsch, Edouard, Michel, Véronique, Chassoux, Francine, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Baker, Mark D., Fonferko-Shadrach, Beata, Lawthom, Charlotte, Anderson, Joseph, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Delanty, Norman, Doherty, Colin P., Shukralla, Arif, El-Naggar, Hany, Widdess-Walsh, Peter, Barišić, Nina, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Ragona, Francesca, Zara, Federico, Iacomino, Michele, Riva, Antonella, Madia, Francesca, Vari, Maria Stella, Salpietro, Vincenzo, Scala, Marcello, Mancardi, Maria Margherita, Nobili, Lino, Amadori, Elisabetta, Giacomini, Thea, Bisulli, Francesca, Pippucci, Tommaso, Licchetta, Laura, Minardi, Raffaella, Tinuper, Paolo, Muccioli, Lorenzo, Mostacci, Barbara, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Barba, Carmen, Hirose, Shinichi, Ishii, Atsushi, Suzuki, Toshimitsu, Inoue, Yushi, Yamakawa, Kazuhiro, Beydoun, Ahmad, Nasreddine, Wassim, Zgheib, Nathalie Khoueiry, Tumiene, Birute, Utkus, Algirdas, Sadleir, Lynette G., King, Chontelle, Caglayan, S. Hande, Arslan, Mutluay, Yapıcı, Zuhal, Topaloglu, Pınar, Kara, Bulent, Yis, Uluc, Turkdogan, Dilsad, Gundogdu-Eken, Aslı, Bebek, Nerses, Tsai, Meng-Han, Ho, Chen-Jui, Lin, Chih-Hsiang, Lin, Kuang-Lin, Chou, I.-Jun, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Noebels, Jeffrey L., Goldman, Alicia, Busch, Robyn M., Jehi, Lara, Najm, Imad M., Ferguson, Lisa, Khoury, Jean, Glauser, Tracy A., Clark, Peggy O., Buono, Russell J., Ferraro, Thomas N., Sperling, Michael R., Lo, Warren, Privitera, Michael, French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Greenberg, David A., Ellis, Colin A., Goldberg, Ethan, Helbig, Katherine L., Cosico, Mahgenn, Vaidiswaran, Priya, Fitch, Eryn, Berkovic, Samuel F., Lerche, Holger, Lowenstein, Daniel H., and Goldstein, David B.
Abstract: Summary Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.
Published: 2021

24. A pilot randomized trial of incentive strategies to promote HIV retesting in rural Uganda.

Author: Chamie, Gabriel, Chamie, Gabriel, Ndyabakira, Alex, Marson, Kara G, Emperador, Devy M, Kamya, Moses R, Havlir, Diane V, Kwarisiima, Dalsone, Thirumurthy, Harsha, Chamie, Gabriel, Chamie, Gabriel, Ndyabakira, Alex, Marson, Kara G, Emperador, Devy M, Kamya, Moses R, Havlir, Diane V, Kwarisiima, Dalsone, and Thirumurthy, Harsha
Abstract: BACKGROUND:Retesting for HIV is critical to identifying newly-infected persons and reinforcing prevention efforts among at-risk adults. Incentives can increase one-time HIV testing, but their role in promoting retesting is unknown. We sought to test feasibility and acceptability of incentive strategies, including commitment contracts, to promote HIV retesting among at-risk adults in rural Uganda. METHODS:At-risk HIV-negative adults were enrolled in a pilot trial assessing feasibility and acceptability of incentive strategies to promote HIV retesting three months after enrollment. Participants were randomized (1:1:3) to: 1) no incentive; 2) standard cash incentive (~US$4); and 3) commitment contract: participants could voluntarily make a low- or high-value deposit that would be returned with added interest (totaling ~US$4 including the deposit) upon retesting or lost if participants failed to retest. Contracts sought to promote retesting by leveraging loss aversion and addressing present bias via pre-commitment. Outcomes included acceptability of trial enrollment, contract feasibility (proportion of participants making deposits), and HIV retesting uptake. RESULTS:Of 130 HIV-negative eligible adults, 123 (95%) enrolled and were randomized: 74 (60%) to commitment contracts, 25 (20%) to standard incentives, and 24 (20%) to no incentive. Of contract participants, 69 (93%) made deposits. Overall, 93 (76%) participants retested for HIV: uptake was highest in the standard incentive group (22/25 [88%]) and lowest in high-value contract (26/36 [72%]) and no incentive (17/24 [71%]) groups. CONCLUSION:In a randomized trial of strategies to promote HIV retesting among at-risk adults in Uganda, incentive strategies, including commitment contracts, were feasible and had high acceptability. Our findings suggest use of incentives for HIV retesting merits further comparison in a larger trial. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT:02890459.
Published: 2020

25. Pharmacoresponse in genetic generalized epilepsy: a genome-wide association study

Author: Wolking, Stefan, Schulz, Herbert, Nies, Anne T., McCormack, Mark, Schaeffeler, Elke, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Klein, Karl M., Krenn, Martin, Moller, Rikke S., Nikanorova, Marina, Weckhuysen, Sarah, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Zimprich, Fritz, Weber, Yvonne G., Krause, Roland, Sisodiya, Sanjay, Schwab, Matthias, Sander, Thomas, Lerche, Holger, Wolking, Stefan, Schulz, Herbert, Nies, Anne T., McCormack, Mark, Schaeffeler, Elke, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Klein, Karl M., Krenn, Martin, Moller, Rikke S., Nikanorova, Marina, Weckhuysen, Sarah, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Zimprich, Fritz, Weber, Yvonne G., Krause, Roland, Sisodiya, Sanjay, Schwab, Matthias, Sander, Thomas, and Lerche, Holger
Abstract: Aim: Pharmacoresistance is a major burden in epilepsy treatment. We aimed to identify genetic biomarkers in response to specific antiepileptic drugs (AEDs) in genetic generalized epilepsies (GGE). Materials & methods: We conducted a genome-wide association study (GWAS) of 3.3 million autosomal SNPs in 893 European subjects with GGE - responsive or nonresponsive to lamotrigine, levetiracetam and valproic acid. Results: Our GWAS of AED response revealed suggestive evidence for association at 29 genomic loci (p <10(-5)) but no significant association reflecting its limited power. The suggestive associations highlight candidate genes that are implicated in epileptogenesis and neurodevelopment. Conclusion: This first GWAS of AED response in GGE provides a comprehensive reference of SNP associations for hypothesis-driven candidate gene analyses in upcoming pharmacogenetic studies.
Published: 2020

26. Individual participant data meta-analysis of intervention studies with time-to-event outcomes : A review of the methodology and an applied example

Author: de Jong, Valentijn M T, Moons, Karel G M, Riley, Richard D, Smith, Catrin Tudur, Marson, Anthony G, Eijkemans, Marinus J C, Debray, Thomas P A, de Jong, Valentijn M T, Moons, Karel G M, Riley, Richard D, Smith, Catrin Tudur, Marson, Anthony G, Eijkemans, Marinus J C, and Debray, Thomas P A
Published: 2020

27. Individual participant data meta-analysis of intervention studies with time-to-event outcomes : A review of the methodology and an applied example

Author: de Jong, Valentijn M T, Moons, Karel G M, Riley, Richard D, Smith, Catrin Tudur, Marson, Anthony G, Eijkemans, Marinus J C, Debray, Thomas P A, de Jong, Valentijn M T, Moons, Karel G M, Riley, Richard D, Smith, Catrin Tudur, Marson, Anthony G, Eijkemans, Marinus J C, and Debray, Thomas P A
Published: 2020

28. Event Horizon Telescope imaging of the archetypal blazar 3C 279 at an extreme 20 microarcsecond resolution

Author: Kim, Jae-Young, Krichbaum, Thomas P., Broderick, Avery E., Wielgus, Maciek, Blackburn, Lindy, Gomez, Jose L., Johnson, Michael D., Bouman, Katherine L., Chael, Andrew, Akiyama, Kazunori, Jorstad, Svetlana, Marscher, Alan P., Issaoun, Sara, Janssen, Michael, Chan, Chi-kwan, Savolainen, Tuomas, Pesce, Dominic W., Ozel, Feryal, Alberdi, Antxon, Alef, Walter, Asada, Keiichi, Azulay, Rebecca, Baczko, Anne-Kathrin, Ball, David, Balokovic, Mislav, Barrett, John, Bintley, Dan, Boland, Wilfred, Bower, Geoffrey C., Bremer, Michael, Brinkerink, Christiaan D., Brissenden, Roger, Britzen, Silke, Broguiere, Dominique, Bronzwaer, Thomas, Byun, Do-Young, Carlstrom, John E., Chatterjee, Shami, Chatterjee, Koushik, Chen, Ming-Tang, Chen, Yongjun, Cho, Ilje, Christian, Pierre, Conway, John E., Cordes, James M., Crew, Geoffrey B., Cui, Yuzhu, Davelaar, Jordy, De Laurentis, Mariafelicia, Deane, Roger, Dempsey, Jessica, Desvignes, Gregory, Dexter, Jason, Doeleman, Sheperd S., Eatough, Ralph P., Falcke, Heino, Fish, Vincent L., Fomalont, Ed, Fraga-Encinas, Raquel, Friberg, Per, Fromm, Christian M., Galison, Peter, Gammie, Charles F., Garcia, Roberto, Gentaz, Olivier, Georgiev, Boris, Goddi, Ciriaco, Gold, Roman, Gu, Minfeng, Gurwell, Mark, Hada, Kazuhiro, Hecht, Michael H., Hesper, Ronald, Ho, Luis C., Ho, Paul, Honma, Mareki, Huang, Chih-Wei L., Huang, Lei, Hughes, David H., Ikeda, Shiro, Inoue, Makoto, James, David J., Jannuzi, Buell T., Jeter, Britton, Jiang, Wu, Jimenez-Rosales, Alejandra, Jung, Taehyun, Karami, Mansour, Karuppusamy, Ramesh, Kawashima, Tomohisa, Keating, Garrett K., Kettenis, Mark, Kim, Junhan, Kim, Jongsoo, Kino, Motoki, Koay, Jun Yi, Koch, Patrick M., Koyama, Shoko, Kramer, Michael, Kramer, Carsten, Kuo, Cheng-Yu, Lauer, Tod R., Lee, Sang-Sung, Li, Yan-Rong, Li, Zhiyuan, Lindqvist, Michael, Lico, Rocco, Liu, Kuo, Liuzzo, Elisabetta, Lo, Wen-Ping, Lobanov, Andrei P., Loinard, Laurent, Lonsdale, Colin, Lu, Ru-Sen, MacDonald, Nicholas R., Mao, Jirong, Markoff, Sera, Marrone, Daniel P., Marti-Vidal, Ivan, Matsushita, Satoki, Matthews, Lynn D., Medeiros, Lia, Menten, Karl M., Mizuno, Yosuke, Mizuno, Izumi, Moran, James M., Moriyama, Kotaro, Moscibrodzka, Monika, Mueller, Cornelia, Nagai, Hiroshi, Nagar, Neil M., Nakamura, Masanori, Narayan, Ramesh, Narayanan, Gopal, Natarajan, Iniyan, Neri, Roberto, Ni, Chunchong, Noutsos, Aristeidis, Okino, Hiroki, Olivares, Hector, Ortiz-Leon, Gisela N., Oyama, Tomoaki, Palumbo, Daniel C. M., Park, Jongho, Patel, Nimesh, Pen, Ue-Li, Pietu, Vincent, Plambeck, Richard, PopStefanija, Aleksandar, Porth, Oliver, Prather, Ben, Preciado-Lopez, Jorge A., Psaltis, Dimitrios, Pu, Hung-Yi, Ramakrishnan, Venkatessh, Rao, Ramprasad, Rawlings, Mark G., Raymond, Alexander W., Rezzolla, Luciano, Ripperda, Bart, Roelofs, Freek, Rogers, Alan, Ros, Eduardo, Rose, Mel, Roshanineshat, Arash, Rottmann, Helge, Roy, Alan L., Ruszczyk, Chet, Ryan, Benjamin R., Rygl, Kazi L. J., Sanchez, Salvador, Sanchez-Arguelles, David, Sasada, Mahito, Schloerb, F. Peter, Schuster, Karl-Friedrich, Shao, Lijing, Shen, Zhiqiang, Small, Des, Sohn, Bong Won, SooHoo, Jason, Tazaki, Fumie, Tiede, Paul, Tilanus, Remo P. J., Titus, Michael, Toma, Kenji, Torne, Pablo, Trent, Tyler, Traianou, Efthalia, Trippe, Sascha, Tsuda, Shuichiro, van Bemmel, Ilse, van Langevelde, Huib Jan, van Rossum, Daniel R., Wagner, Jan, Wardle, John, Ward-Thompson, Derek, Weintroub, Jonathan, Wex, Norbert, Wharton, Robert, Wong, George N., Wu, Qingwen, Yoon, Doosoo, Young, Andre, Young, Ken, Younsi, Ziri, Yuan, Feng, Yuan, Ye-Fei, Zensus, J. Anton, Zhao, Guangyao, Zhao, Shan-Shan, Zhu, Ziyan, Algaba, Juan-Carlos, Allardi, Alexander, Amestica, Rodrigo, Anczarski, Jadyn, Bach, Uwe, Baganoff, Frederick K., Beaudoin, Christopher, Benson, Bradford A., Berthold, Ryan, Blanchard, Jay M., Blundell, Ray, Bustamente, Sandra, Cappallo, Roger, Castillo-Dominguez, Edgar, Chang, Chih-Cheng, Chang, Shu-Hao, Chang, Song-Chu, Chen, Chung-Chen, Chilson, Ryan, Chuter, Tim C., Rosado, Rodrigo Cordova, Coulson, Iain M., Crowley, Joseph, Derome, Mark, Dexter, Matthew, Dornbusch, Sven, Dudevoir, Kevin A., Dzib, Sergio A., Eckart, Andreas, Eckert, Chris, Erickson, Neal R., Everett, Wendeline B., Faber, Aaron, Farah, Joseph R., Fath, Vernon, Folkers, Thomas W., Forbes, David C., Freund, Robert, Gomez-Ruiz, Arturo, I, Gale, David M., Gao, Feng, Geertsema, Gertie, Graham, David A., Greer, Christopher H., Grosslein, Ronald, Gueth, Frederic, Haggard, Daryl, Halverson, Nils W., Han, Chih-Chiang, Han, Kuo-Chang, Hao, Jinchi, Hasegawa, Yutaka, Henning, Jason W., Hernandez-Gomez, Antonio, Herrero-Illana, Ruben, Heyminck, Stefan, Hirota, Akihiko, Hoge, James, Huang, Yau-De, Impellizzeri, C. M. Violette, Jiang, Homin, John, David, Kamble, Atish, Keisler, Ryan, Kimura, Kimihiro, Kono, Yusuke, Kubo, Derek, Kuroda, John, Lacasse, Richard, Laing, Robert A., Leitch, Erik M., Li, Chao-Te, Lin, Lupin C-C, Liu, Ching-Tang, Liu, Kuan-Yu, Lu, Li-Ming, Marson, Ralph G., Martin-Cocher, Pierre L., Massingill, Kyle D., Matulonis, Callie, McColl, Martin P., McWhirter, Stephen R., Messias, Hugo, Meyer-Zhao, Zheng, Michalik, Daniel, Montana, Alfredo, Montgomerie, William, Mora-Klein, Matias, Muders, Dirk, Nadolski, Andrew, Navarro, Santiago, Neilsen, Joseph, Nguyen, Chi H., Nishioka, Hiroaki, Norton, Timothy, Nowak, Michael A., Nystrom, George, Ogawa, Hideo, Oshiro, Peter, Parsons, Harriet, Penalver, Juan, Phillips, Neil M., Poirier, Michael, Pradel, Nicolas, Primiani, Rurik A., Raffin, Philippe A., Rahlin, Alexandra S., Reiland, George, Risacher, Christopher, Ruiz, Ignacio, Saez-Madain, Alejandro F., Sassella, Remi, Schellart, Pim, Shaw, Paul, Silva, Kevin M., Shiokawa, Hotaka, Smith, David R., Snow, William, Souccar, Kamal, Sousa, Don, Sridharan, T. K., Srinivasan, Ranjani, Stahm, William, Stark, Antony A., Story, Kyle, Timmer, Sjoerd T., Vertatschitsch, Laura, Walther, Craig, Wei, Ta-Shun, Whitehorn, Nathan, Whitney, Alan R., Woody, David P., Wouterloot, Jan G. A., Wright, Melvin, Yamaguchi, Paul, Yu, Chen-Yu, Zeballos, Milagros, Zhang, Shuo, Ziurys, Lucy, Kim, Jae-Young, Krichbaum, Thomas P., Broderick, Avery E., Wielgus, Maciek, Blackburn, Lindy, Gomez, Jose L., Johnson, Michael D., Bouman, Katherine L., Chael, Andrew, Akiyama, Kazunori, Jorstad, Svetlana, Marscher, Alan P., Issaoun, Sara, Janssen, Michael, Chan, Chi-kwan, Savolainen, Tuomas, Pesce, Dominic W., Ozel, Feryal, Alberdi, Antxon, Alef, Walter, Asada, Keiichi, Azulay, Rebecca, Baczko, Anne-Kathrin, Ball, David, Balokovic, Mislav, Barrett, John, Bintley, Dan, Boland, Wilfred, Bower, Geoffrey C., Bremer, Michael, Brinkerink, Christiaan D., Brissenden, Roger, Britzen, Silke, Broguiere, Dominique, Bronzwaer, Thomas, Byun, Do-Young, Carlstrom, John E., Chatterjee, Shami, Chatterjee, Koushik, Chen, Ming-Tang, Chen, Yongjun, Cho, Ilje, Christian, Pierre, Conway, John E., Cordes, James M., Crew, Geoffrey B., Cui, Yuzhu, Davelaar, Jordy, De Laurentis, Mariafelicia, Deane, Roger, Dempsey, Jessica, Desvignes, Gregory, Dexter, Jason, Doeleman, Sheperd S., Eatough, Ralph P., Falcke, Heino, Fish, Vincent L., Fomalont, Ed, Fraga-Encinas, Raquel, Friberg, Per, Fromm, Christian M., Galison, Peter, Gammie, Charles F., Garcia, Roberto, Gentaz, Olivier, Georgiev, Boris, Goddi, Ciriaco, Gold, Roman, Gu, Minfeng, Gurwell, Mark, Hada, Kazuhiro, Hecht, Michael H., Hesper, Ronald, Ho, Luis C., Ho, Paul, Honma, Mareki, Huang, Chih-Wei L., Huang, Lei, Hughes, David H., Ikeda, Shiro, Inoue, Makoto, James, David J., Jannuzi, Buell T., Jeter, Britton, Jiang, Wu, Jimenez-Rosales, Alejandra, Jung, Taehyun, Karami, Mansour, Karuppusamy, Ramesh, Kawashima, Tomohisa, Keating, Garrett K., Kettenis, Mark, Kim, Junhan, Kim, Jongsoo, Kino, Motoki, Koay, Jun Yi, Koch, Patrick M., Koyama, Shoko, Kramer, Michael, Kramer, Carsten, Kuo, Cheng-Yu, Lauer, Tod R., Lee, Sang-Sung, Li, Yan-Rong, Li, Zhiyuan, Lindqvist, Michael, Lico, Rocco, Liu, Kuo, Liuzzo, Elisabetta, Lo, Wen-Ping, Lobanov, Andrei P., Loinard, Laurent, Lonsdale, Colin, Lu, Ru-Sen, MacDonald, Nicholas R., Mao, Jirong, Markoff, Sera, Marrone, Daniel P., Marti-Vidal, Ivan, Matsushita, Satoki, Matthews, Lynn D., Medeiros, Lia, Menten, Karl M., Mizuno, Yosuke, Mizuno, Izumi, Moran, James M., Moriyama, Kotaro, Moscibrodzka, Monika, Mueller, Cornelia, Nagai, Hiroshi, Nagar, Neil M., Nakamura, Masanori, Narayan, Ramesh, Narayanan, Gopal, Natarajan, Iniyan, Neri, Roberto, Ni, Chunchong, Noutsos, Aristeidis, Okino, Hiroki, Olivares, Hector, Ortiz-Leon, Gisela N., Oyama, Tomoaki, Palumbo, Daniel C. M., Park, Jongho, Patel, Nimesh, Pen, Ue-Li, Pietu, Vincent, Plambeck, Richard, PopStefanija, Aleksandar, Porth, Oliver, Prather, Ben, Preciado-Lopez, Jorge A., Psaltis, Dimitrios, Pu, Hung-Yi, Ramakrishnan, Venkatessh, Rao, Ramprasad, Rawlings, Mark G., Raymond, Alexander W., Rezzolla, Luciano, Ripperda, Bart, Roelofs, Freek, Rogers, Alan, Ros, Eduardo, Rose, Mel, Roshanineshat, Arash, Rottmann, Helge, Roy, Alan L., Ruszczyk, Chet, Ryan, Benjamin R., Rygl, Kazi L. J., Sanchez, Salvador, Sanchez-Arguelles, David, Sasada, Mahito, Schloerb, F. Peter, Schuster, Karl-Friedrich, Shao, Lijing, Shen, Zhiqiang, Small, Des, Sohn, Bong Won, SooHoo, Jason, Tazaki, Fumie, Tiede, Paul, Tilanus, Remo P. J., Titus, Michael, Toma, Kenji, Torne, Pablo, Trent, Tyler, Traianou, Efthalia, Trippe, Sascha, Tsuda, Shuichiro, van Bemmel, Ilse, van Langevelde, Huib Jan, van Rossum, Daniel R., Wagner, Jan, Wardle, John, Ward-Thompson, Derek, Weintroub, Jonathan, Wex, Norbert, Wharton, Robert, Wong, George N., Wu, Qingwen, Yoon, Doosoo, Young, Andre, Young, Ken, Younsi, Ziri, Yuan, Feng, Yuan, Ye-Fei, Zensus, J. Anton, Zhao, Guangyao, Zhao, Shan-Shan, Zhu, Ziyan, Algaba, Juan-Carlos, Allardi, Alexander, Amestica, Rodrigo, Anczarski, Jadyn, Bach, Uwe, Baganoff, Frederick K., Beaudoin, Christopher, Benson, Bradford A., Berthold, Ryan, Blanchard, Jay M., Blundell, Ray, Bustamente, Sandra, Cappallo, Roger, Castillo-Dominguez, Edgar, Chang, Chih-Cheng, Chang, Shu-Hao, Chang, Song-Chu, Chen, Chung-Chen, Chilson, Ryan, Chuter, Tim C., Rosado, Rodrigo Cordova, Coulson, Iain M., Crowley, Joseph, Derome, Mark, Dexter, Matthew, Dornbusch, Sven, Dudevoir, Kevin A., Dzib, Sergio A., Eckart, Andreas, Eckert, Chris, Erickson, Neal R., Everett, Wendeline B., Faber, Aaron, Farah, Joseph R., Fath, Vernon, Folkers, Thomas W., Forbes, David C., Freund, Robert, Gomez-Ruiz, Arturo, I, Gale, David M., Gao, Feng, Geertsema, Gertie, Graham, David A., Greer, Christopher H., Grosslein, Ronald, Gueth, Frederic, Haggard, Daryl, Halverson, Nils W., Han, Chih-Chiang, Han, Kuo-Chang, Hao, Jinchi, Hasegawa, Yutaka, Henning, Jason W., Hernandez-Gomez, Antonio, Herrero-Illana, Ruben, Heyminck, Stefan, Hirota, Akihiko, Hoge, James, Huang, Yau-De, Impellizzeri, C. M. Violette, Jiang, Homin, John, David, Kamble, Atish, Keisler, Ryan, Kimura, Kimihiro, Kono, Yusuke, Kubo, Derek, Kuroda, John, Lacasse, Richard, Laing, Robert A., Leitch, Erik M., Li, Chao-Te, Lin, Lupin C-C, Liu, Ching-Tang, Liu, Kuan-Yu, Lu, Li-Ming, Marson, Ralph G., Martin-Cocher, Pierre L., Massingill, Kyle D., Matulonis, Callie, McColl, Martin P., McWhirter, Stephen R., Messias, Hugo, Meyer-Zhao, Zheng, Michalik, Daniel, Montana, Alfredo, Montgomerie, William, Mora-Klein, Matias, Muders, Dirk, Nadolski, Andrew, Navarro, Santiago, Neilsen, Joseph, Nguyen, Chi H., Nishioka, Hiroaki, Norton, Timothy, Nowak, Michael A., Nystrom, George, Ogawa, Hideo, Oshiro, Peter, Parsons, Harriet, Penalver, Juan, Phillips, Neil M., Poirier, Michael, Pradel, Nicolas, Primiani, Rurik A., Raffin, Philippe A., Rahlin, Alexandra S., Reiland, George, Risacher, Christopher, Ruiz, Ignacio, Saez-Madain, Alejandro F., Sassella, Remi, Schellart, Pim, Shaw, Paul, Silva, Kevin M., Shiokawa, Hotaka, Smith, David R., Snow, William, Souccar, Kamal, Sousa, Don, Sridharan, T. K., Srinivasan, Ranjani, Stahm, William, Stark, Antony A., Story, Kyle, Timmer, Sjoerd T., Vertatschitsch, Laura, Walther, Craig, Wei, Ta-Shun, Whitehorn, Nathan, Whitney, Alan R., Woody, David P., Wouterloot, Jan G. A., Wright, Melvin, Yamaguchi, Paul, Yu, Chen-Yu, Zeballos, Milagros, Zhang, Shuo, and Ziurys, Lucy
Abstract: 3C 279 is an archetypal blazar with a prominent radio jet that show broadband flux density variability across the entire electromagnetic spectrum. We use an ultra-high angular resolution technique - global Very Long Baseline Interferometry (VLBI) at 1.3 mm (230 GHz) - to resolve the innermost jet of 3C 279 in order to study its fine-scale morphology close to the jet base where highly variable gamma -ray emission is thought to originate, according to various models. The source was observed during four days in April 2017 with the Event Horizon Telescope at 230 GHz, including the phased Atacama Large Millimeter/submillimeter Array (ALMA), at an angular resolution of similar to 20 mu as (at a redshift of z=0.536 this corresponds to similar to 0.13 pc similar to 1700 Schwarzschild radii with a black hole mass M-BH=8x10(8) M-circle dot). Imaging and model-fitting techniques were applied to the data to parameterize the fine-scale source structure and its variation. We find a multicomponent inner jet morphology with the northernmost component elongated perpendicular to the direction of the jet, as imaged at longer wavelengths. The elongated nuclear structure is consistent on all four observing days and across different imaging methods and model-fitting techniques, and therefore appears robust. Owing to its compactness and brightness, we associate the northern nuclear structure as the VLBI core. This morphology can be interpreted as either a broad resolved jet base or a spatially bent jet. We also find significant day-to-day variations in the closure phases, which appear most pronounced on the triangles with the longest baselines. Our analysis shows that this variation is related to a systematic change of the source structure. Two inner jet components move non-radially at apparent speeds of similar to 15 c and similar to 20 c (similar to 1.3 and similar to 1.7 mu as day(-1), respectively), which more strongly supports the scenario of traveling shocks or instabilities in a be
Published: 2020

29. A pilot randomized trial of incentive strategies to promote HIV retesting in rural Uganda.

Author: Chamie, Gabriel, De Socio, Giuseppe Vittorio1, Chamie, Gabriel, Ndyabakira, Alex, Marson, Kara G, Emperador, Devy M, Kamya, Moses R, Havlir, Diane V, Kwarisiima, Dalsone, Thirumurthy, Harsha, Chamie, Gabriel, De Socio, Giuseppe Vittorio1, Chamie, Gabriel, Ndyabakira, Alex, Marson, Kara G, Emperador, Devy M, Kamya, Moses R, Havlir, Diane V, Kwarisiima, Dalsone, and Thirumurthy, Harsha
Abstract: BackgroundRetesting for HIV is critical to identifying newly-infected persons and reinforcing prevention efforts among at-risk adults. Incentives can increase one-time HIV testing, but their role in promoting retesting is unknown. We sought to test feasibility and acceptability of incentive strategies, including commitment contracts, to promote HIV retesting among at-risk adults in rural Uganda.MethodsAt-risk HIV-negative adults were enrolled in a pilot trial assessing feasibility and acceptability of incentive strategies to promote HIV retesting three months after enrollment. Participants were randomized (1:1:3) to: 1) no incentive; 2) standard cash incentive (~US$4); and 3) commitment contract: participants could voluntarily make a low- or high-value deposit that would be returned with added interest (totaling ~US$4 including the deposit) upon retesting or lost if participants failed to retest. Contracts sought to promote retesting by leveraging loss aversion and addressing present bias via pre-commitment. Outcomes included acceptability of trial enrollment, contract feasibility (proportion of participants making deposits), and HIV retesting uptake.ResultsOf 130 HIV-negative eligible adults, 123 (95%) enrolled and were randomized: 74 (60%) to commitment contracts, 25 (20%) to standard incentives, and 24 (20%) to no incentive. Of contract participants, 69 (93%) made deposits. Overall, 93 (76%) participants retested for HIV: uptake was highest in the standard incentive group (22/25 [88%]) and lowest in high-value contract (26/36 [72%]) and no incentive (17/24 [71%]) groups.ConclusionIn a randomized trial of strategies to promote HIV retesting among at-risk adults in Uganda, incentive strategies, including commitment contracts, were feasible and had high acceptability. Our findings suggest use of incentives for HIV retesting merits further comparison in a larger trial.Trial registrationClinicalTrials.gov identifier: NCT:02890459.
Published: 2020

30. Individual participant data meta-analysis of intervention studies with time-to-event outcomes : A review of the methodology and an applied example

Author: de Jong, Valentijn M T, Moons, Karel G M, Riley, Richard D, Smith, Catrin Tudur, Marson, Anthony G, Eijkemans, Marinus J C, Debray, Thomas P A, de Jong, Valentijn M T, Moons, Karel G M, Riley, Richard D, Smith, Catrin Tudur, Marson, Anthony G, Eijkemans, Marinus J C, and Debray, Thomas P A
Published: 2020

31. Testing association of rare genetic variants with resistance to three common antiseizure medications

Author: European Commission - EC [sponsor], Wolking, Stefan, Moreau, Claudia, Nies, Anne T., Schaeffeler, Elke, McCormack, Mark, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Krenn, Martin, Møller, Rikke S., Nikanorova, Marina, Weber, Yvonne G., Weckhuysen, Sarah, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Zimprich, Fritz, Schwab, Matthias, Krause, Roland, Sisodiya, Sanjay M., Cossette, Patrick, Girard, Simon L., Lerche, Holger, EpiPGX Consortium, European Commission - EC [sponsor], Wolking, Stefan, Moreau, Claudia, Nies, Anne T., Schaeffeler, Elke, McCormack, Mark, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Krenn, Martin, Møller, Rikke S., Nikanorova, Marina, Weber, Yvonne G., Weckhuysen, Sarah, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Zimprich, Fritz, Schwab, Matthias, Krause, Roland, Sisodiya, Sanjay M., Cossette, Patrick, Girard, Simon L., Lerche, Holger, and EpiPGX Consortium
Abstract: Objective Drug resistance is a major concern in the treatment of individuals with epilepsy. No genetic markers for resistance to individual antiseizure medication (ASM) have yet been identified. We aimed to identify the role of rare genetic variants in drug resistance for three common ASMs: levetiracetam (LEV), lamotrigine (LTG), and valproic acid (VPA). Methods A cohort of 1622 individuals of European descent with epilepsy was deeply phenotyped and underwent whole exome sequencing (WES), comprising 575 taking LEV, 826 LTG, and 782 VPA. We performed gene- and gene set–based collapsing analyses comparing responders and nonresponders to the three drugs to determine the burden of different categories of rare genetic variants. Results We observed a marginally significant enrichment of rare missense, truncating, and splice region variants in individuals who were resistant to VPA compared to VPA responders for genes involved in VPA pharmacokinetics. We also found a borderline significant enrichment of truncating and splice region variants in the synaptic vesicle glycoprotein (SV2) gene family in nonresponders compared to responders to LEV. We did not see any significant enrichment using a gene-based approach. Significance In our pharmacogenetic study, we identified a slightly increased burden of damaging variants in gene groups related to drug kinetics or targeting in individuals presenting with drug resistance to VPA or LEV. Such variants could thus determine a genetic contribution to drug resistance.
Published: 2020

32. Testing association of rare genetic variants with resistance to three common antiseizure medications

Author: European Commission - EC [sponsor], Wolking, Stefan, Moreau, Claudia, Nies, Anne T., Schaeffeler, Elke, McCormack, Mark, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Krenn, Martin, Møller, Rikke S., Nikanorova, Marina, Weber, Yvonne G., Weckhuysen, Sarah, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Zimprich, Fritz, Schwab, Matthias, Krause, Roland, Sisodiya, Sanjay M., Cossette, Patrick, Girard, Simon L., Lerche, Holger, EpiPGX Consortium, European Commission - EC [sponsor], Wolking, Stefan, Moreau, Claudia, Nies, Anne T., Schaeffeler, Elke, McCormack, Mark, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Krenn, Martin, Møller, Rikke S., Nikanorova, Marina, Weber, Yvonne G., Weckhuysen, Sarah, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Zimprich, Fritz, Schwab, Matthias, Krause, Roland, Sisodiya, Sanjay M., Cossette, Patrick, Girard, Simon L., Lerche, Holger, and EpiPGX Consortium
Abstract: Objective Drug resistance is a major concern in the treatment of individuals with epilepsy. No genetic markers for resistance to individual antiseizure medication (ASM) have yet been identified. We aimed to identify the role of rare genetic variants in drug resistance for three common ASMs: levetiracetam (LEV), lamotrigine (LTG), and valproic acid (VPA). Methods A cohort of 1622 individuals of European descent with epilepsy was deeply phenotyped and underwent whole exome sequencing (WES), comprising 575 taking LEV, 826 LTG, and 782 VPA. We performed gene- and gene set–based collapsing analyses comparing responders and nonresponders to the three drugs to determine the burden of different categories of rare genetic variants. Results We observed a marginally significant enrichment of rare missense, truncating, and splice region variants in individuals who were resistant to VPA compared to VPA responders for genes involved in VPA pharmacokinetics. We also found a borderline significant enrichment of truncating and splice region variants in the synaptic vesicle glycoprotein (SV2) gene family in nonresponders compared to responders to LEV. We did not see any significant enrichment using a gene-based approach. Significance In our pharmacogenetic study, we identified a slightly increased burden of damaging variants in gene groups related to drug kinetics or targeting in individuals presenting with drug resistance to VPA or LEV. Such variants could thus determine a genetic contribution to drug resistance.
Published: 2020

33. Pharmacoresponse in genetic generalized epilepsy: a genome-wide association study

Author: Wolking, Stefan, Schulz, Herbert, Nies, Anne T., McCormack, Mark, Schaeffeler, Elke, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Klein, Karl M., Krenn, Martin, Møller, Rikke S., Nikanorova, Marina, Weckhuysen, Sarah, Consortium, Epipgx, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Zimprich, Fritz, Weber, Yvonne G., Krause, Roland, Sisodiya, Sanjay, Schwab, Matthias, Sander, Thomas, Lerche, Holger, Wolking, Stefan, Schulz, Herbert, Nies, Anne T., McCormack, Mark, Schaeffeler, Elke, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Klein, Karl M., Krenn, Martin, Møller, Rikke S., Nikanorova, Marina, Weckhuysen, Sarah, Consortium, Epipgx, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Zimprich, Fritz, Weber, Yvonne G., Krause, Roland, Sisodiya, Sanjay, Schwab, Matthias, Sander, Thomas, and Lerche, Holger
Abstract: Aim: Pharmacoresistance is a major burden in epilepsy treatment. We aimed to identify genetic biomarkers in response to specific antiepileptic drugs (AEDs) in genetic generalized epilepsies (GGE). Materials methods: We conducted a genome-wide association study (GWAS) of 3.3 million autosomal SNPs in 893 European subjects with GGE – responsive or nonresponsive to lamotrigine, levetiracetam and valproic acid. Results: Our GWAS of AED response revealed suggestive evidence for association at 29 genomic loci (p <10-5) but no significant association reflecting its limited power. The suggestive associations highlight candidate genes that are implicated in epileptogenesis and neurodevelopment. Conclusion: This first GWAS of AED response in GGE provides a comprehensive reference of SNP associations for hypothesis-driven candidate gene analyses in upcoming pharmacogenetic studies.
Published: 2020

34. Pharmacoresponse in genetic generalized epilepsy: a genome-wide association study

Author: Wolking, Stefan, Schulz, Herbert, Nies, Anne T., McCormack, Mark, Schaeffeler, Elke, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Klein, Karl M., Krenn, Martin, Møller, Rikke S., Nikanorova, Marina, Weckhuysen, Sarah, Consortium, Epipgx, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Zimprich, Fritz, Weber, Yvonne G., Krause, Roland, Sisodiya, Sanjay, Schwab, Matthias, Sander, Thomas, Lerche, Holger, Wolking, Stefan, Schulz, Herbert, Nies, Anne T., McCormack, Mark, Schaeffeler, Elke, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Klein, Karl M., Krenn, Martin, Møller, Rikke S., Nikanorova, Marina, Weckhuysen, Sarah, Consortium, Epipgx, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Zimprich, Fritz, Weber, Yvonne G., Krause, Roland, Sisodiya, Sanjay, Schwab, Matthias, Sander, Thomas, and Lerche, Holger
Abstract: Aim: Pharmacoresistance is a major burden in epilepsy treatment. We aimed to identify genetic biomarkers in response to specific antiepileptic drugs (AEDs) in genetic generalized epilepsies (GGE). Materials methods: We conducted a genome-wide association study (GWAS) of 3.3 million autosomal SNPs in 893 European subjects with GGE – responsive or nonresponsive to lamotrigine, levetiracetam and valproic acid. Results: Our GWAS of AED response revealed suggestive evidence for association at 29 genomic loci (p <10-5) but no significant association reflecting its limited power. The suggestive associations highlight candidate genes that are implicated in epileptogenesis and neurodevelopment. Conclusion: This first GWAS of AED response in GGE provides a comprehensive reference of SNP associations for hypothesis-driven candidate gene analyses in upcoming pharmacogenetic studies.
Published: 2020

35. Individual participant data meta-analysis of intervention studies with time-to-event outcomes: A review of the methodology and an applied example

Author: JC onderzoeksprogramma Methodologie, Epi Methoden Team 2, Epi Methoden, Circulatory Health, Cancer, Biostatistiek Onderzoek, Infection & Immunity, Child Health, JC onderzoeksprogramma Infectieziekten, de Jong, Valentijn M T, Moons, Karel G M, Riley, Richard D, Smith, Catrin Tudur, Marson, Anthony G, Eijkemans, Marinus J C, Debray, Thomas P A, JC onderzoeksprogramma Methodologie, Epi Methoden Team 2, Epi Methoden, Circulatory Health, Cancer, Biostatistiek Onderzoek, Infection & Immunity, Child Health, JC onderzoeksprogramma Infectieziekten, de Jong, Valentijn M T, Moons, Karel G M, Riley, Richard D, Smith, Catrin Tudur, Marson, Anthony G, Eijkemans, Marinus J C, and Debray, Thomas P A
Published: 2020

36. Pharmacoresponse in genetic generalized epilepsy: a genome-wide association study

Author: Wolking, Stefan, Schulz, Herbert, Nies, Anne T., McCormack, Mark, Schaeffeler, Elke, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Klein, Karl M., Krenn, Martin, Moller, Rikke S., Nikanorova, Marina, Weckhuysen, Sarah, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Zimprich, Fritz, Weber, Yvonne G., Krause, Roland, Sisodiya, Sanjay, Schwab, Matthias, Sander, Thomas, Lerche, Holger, Wolking, Stefan, Schulz, Herbert, Nies, Anne T., McCormack, Mark, Schaeffeler, Elke, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Klein, Karl M., Krenn, Martin, Moller, Rikke S., Nikanorova, Marina, Weckhuysen, Sarah, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Zimprich, Fritz, Weber, Yvonne G., Krause, Roland, Sisodiya, Sanjay, Schwab, Matthias, Sander, Thomas, and Lerche, Holger
Abstract: Aim: Pharmacoresistance is a major burden in epilepsy treatment. We aimed to identify genetic biomarkers in response to specific antiepileptic drugs (AEDs) in genetic generalized epilepsies (GGE). Materials & methods: We conducted a genome-wide association study (GWAS) of 3.3 million autosomal SNPs in 893 European subjects with GGE - responsive or nonresponsive to lamotrigine, levetiracetam and valproic acid. Results: Our GWAS of AED response revealed suggestive evidence for association at 29 genomic loci (p <10(-5)) but no significant association reflecting its limited power. The suggestive associations highlight candidate genes that are implicated in epileptogenesis and neurodevelopment. Conclusion: This first GWAS of AED response in GGE provides a comprehensive reference of SNP associations for hypothesis-driven candidate gene analyses in upcoming pharmacogenetic studies.
Published: 2020

37. Event Horizon Telescope imaging of the archetypal blazar 3C 279 at an extreme 20 microarcsecond resolution

Author: Kim, Jae-Young, Krichbaum, Thomas P., Broderick, Avery E., Wielgus, Maciek, Blackburn, Lindy, Gomez, Jose L., Johnson, Michael D., Bouman, Katherine L., Chael, Andrew, Akiyama, Kazunori, Jorstad, Svetlana, Marscher, Alan P., Issaoun, Sara, Janssen, Michael, Chan, Chi-kwan, Savolainen, Tuomas, Pesce, Dominic W., Ozel, Feryal, Alberdi, Antxon, Alef, Walter, Asada, Keiichi, Azulay, Rebecca, Baczko, Anne-Kathrin, Ball, David, Balokovic, Mislav, Barrett, John, Bintley, Dan, Boland, Wilfred, Bower, Geoffrey C., Bremer, Michael, Brinkerink, Christiaan D., Brissenden, Roger, Britzen, Silke, Broguiere, Dominique, Bronzwaer, Thomas, Byun, Do-Young, Carlstrom, John E., Chatterjee, Shami, Chatterjee, Koushik, Chen, Ming-Tang, Chen, Yongjun, Cho, Ilje, Christian, Pierre, Conway, John E., Cordes, James M., Crew, Geoffrey B., Cui, Yuzhu, Davelaar, Jordy, De Laurentis, Mariafelicia, Deane, Roger, Dempsey, Jessica, Desvignes, Gregory, Dexter, Jason, Doeleman, Sheperd S., Eatough, Ralph P., Falcke, Heino, Fish, Vincent L., Fomalont, Ed, Fraga-Encinas, Raquel, Friberg, Per, Fromm, Christian M., Galison, Peter, Gammie, Charles F., Garcia, Roberto, Gentaz, Olivier, Georgiev, Boris, Goddi, Ciriaco, Gold, Roman, Gu, Minfeng, Gurwell, Mark, Hada, Kazuhiro, Hecht, Michael H., Hesper, Ronald, Ho, Luis C., Ho, Paul, Honma, Mareki, Huang, Chih-Wei L., Huang, Lei, Hughes, David H., Ikeda, Shiro, Inoue, Makoto, James, David J., Jannuzi, Buell T., Jeter, Britton, Jiang, Wu, Jimenez-Rosales, Alejandra, Jung, Taehyun, Karami, Mansour, Karuppusamy, Ramesh, Kawashima, Tomohisa, Keating, Garrett K., Kettenis, Mark, Kim, Junhan, Kim, Jongsoo, Kino, Motoki, Koay, Jun Yi, Koch, Patrick M., Koyama, Shoko, Kramer, Michael, Kramer, Carsten, Kuo, Cheng-Yu, Lauer, Tod R., Lee, Sang-Sung, Li, Yan-Rong, Li, Zhiyuan, Lindqvist, Michael, Lico, Rocco, Liu, Kuo, Liuzzo, Elisabetta, Lo, Wen-Ping, Lobanov, Andrei P., Loinard, Laurent, Lonsdale, Colin, Lu, Ru-Sen, MacDonald, Nicholas R., Mao, Jirong, Markoff, Sera, Marrone, Daniel P., Marti-Vidal, Ivan, Matsushita, Satoki, Matthews, Lynn D., Medeiros, Lia, Menten, Karl M., Mizuno, Yosuke, Mizuno, Izumi, Moran, James M., Moriyama, Kotaro, Moscibrodzka, Monika, Mueller, Cornelia, Nagai, Hiroshi, Nagar, Neil M., Nakamura, Masanori, Narayan, Ramesh, Narayanan, Gopal, Natarajan, Iniyan, Neri, Roberto, Ni, Chunchong, Noutsos, Aristeidis, Okino, Hiroki, Olivares, Hector, Ortiz-Leon, Gisela N., Oyama, Tomoaki, Palumbo, Daniel C. M., Park, Jongho, Patel, Nimesh, Pen, Ue-Li, Pietu, Vincent, Plambeck, Richard, PopStefanija, Aleksandar, Porth, Oliver, Prather, Ben, Preciado-Lopez, Jorge A., Psaltis, Dimitrios, Pu, Hung-Yi, Ramakrishnan, Venkatessh, Rao, Ramprasad, Rawlings, Mark G., Raymond, Alexander W., Rezzolla, Luciano, Ripperda, Bart, Roelofs, Freek, Rogers, Alan, Ros, Eduardo, Rose, Mel, Roshanineshat, Arash, Rottmann, Helge, Roy, Alan L., Ruszczyk, Chet, Ryan, Benjamin R., Rygl, Kazi L. J., Sanchez, Salvador, Sanchez-Arguelles, David, Sasada, Mahito, Schloerb, F. Peter, Schuster, Karl-Friedrich, Shao, Lijing, Shen, Zhiqiang, Small, Des, Sohn, Bong Won, SooHoo, Jason, Tazaki, Fumie, Tiede, Paul, Tilanus, Remo P. J., Titus, Michael, Toma, Kenji, Torne, Pablo, Trent, Tyler, Traianou, Efthalia, Trippe, Sascha, Tsuda, Shuichiro, van Bemmel, Ilse, van Langevelde, Huib Jan, van Rossum, Daniel R., Wagner, Jan, Wardle, John, Ward-Thompson, Derek, Weintroub, Jonathan, Wex, Norbert, Wharton, Robert, Wong, George N., Wu, Qingwen, Yoon, Doosoo, Young, Andre, Young, Ken, Younsi, Ziri, Yuan, Feng, Yuan, Ye-Fei, Zensus, J. Anton, Zhao, Guangyao, Zhao, Shan-Shan, Zhu, Ziyan, Algaba, Juan-Carlos, Allardi, Alexander, Amestica, Rodrigo, Anczarski, Jadyn, Bach, Uwe, Baganoff, Frederick K., Beaudoin, Christopher, Benson, Bradford A., Berthold, Ryan, Blanchard, Jay M., Blundell, Ray, Bustamente, Sandra, Cappallo, Roger, Castillo-Dominguez, Edgar, Chang, Chih-Cheng, Chang, Shu-Hao, Chang, Song-Chu, Chen, Chung-Chen, Chilson, Ryan, Chuter, Tim C., Rosado, Rodrigo Cordova, Coulson, Iain M., Crowley, Joseph, Derome, Mark, Dexter, Matthew, Dornbusch, Sven, Dudevoir, Kevin A., Dzib, Sergio A., Eckart, Andreas, Eckert, Chris, Erickson, Neal R., Everett, Wendeline B., Faber, Aaron, Farah, Joseph R., Fath, Vernon, Folkers, Thomas W., Forbes, David C., Freund, Robert, Gomez-Ruiz, Arturo, I, Gale, David M., Gao, Feng, Geertsema, Gertie, Graham, David A., Greer, Christopher H., Grosslein, Ronald, Gueth, Frederic, Haggard, Daryl, Halverson, Nils W., Han, Chih-Chiang, Han, Kuo-Chang, Hao, Jinchi, Hasegawa, Yutaka, Henning, Jason W., Hernandez-Gomez, Antonio, Herrero-Illana, Ruben, Heyminck, Stefan, Hirota, Akihiko, Hoge, James, Huang, Yau-De, Impellizzeri, C. M. Violette, Jiang, Homin, John, David, Kamble, Atish, Keisler, Ryan, Kimura, Kimihiro, Kono, Yusuke, Kubo, Derek, Kuroda, John, Lacasse, Richard, Laing, Robert A., Leitch, Erik M., Li, Chao-Te, Lin, Lupin C-C, Liu, Ching-Tang, Liu, Kuan-Yu, Lu, Li-Ming, Marson, Ralph G., Martin-Cocher, Pierre L., Massingill, Kyle D., Matulonis, Callie, McColl, Martin P., McWhirter, Stephen R., Messias, Hugo, Meyer-Zhao, Zheng, Michalik, Daniel, Montana, Alfredo, Montgomerie, William, Mora-Klein, Matias, Muders, Dirk, Nadolski, Andrew, Navarro, Santiago, Neilsen, Joseph, Nguyen, Chi H., Nishioka, Hiroaki, Norton, Timothy, Nowak, Michael A., Nystrom, George, Ogawa, Hideo, Oshiro, Peter, Parsons, Harriet, Penalver, Juan, Phillips, Neil M., Poirier, Michael, Pradel, Nicolas, Primiani, Rurik A., Raffin, Philippe A., Rahlin, Alexandra S., Reiland, George, Risacher, Christopher, Ruiz, Ignacio, Saez-Madain, Alejandro F., Sassella, Remi, Schellart, Pim, Shaw, Paul, Silva, Kevin M., Shiokawa, Hotaka, Smith, David R., Snow, William, Souccar, Kamal, Sousa, Don, Sridharan, T. K., Srinivasan, Ranjani, Stahm, William, Stark, Antony A., Story, Kyle, Timmer, Sjoerd T., Vertatschitsch, Laura, Walther, Craig, Wei, Ta-Shun, Whitehorn, Nathan, Whitney, Alan R., Woody, David P., Wouterloot, Jan G. A., Wright, Melvin, Yamaguchi, Paul, Yu, Chen-Yu, Zeballos, Milagros, Zhang, Shuo, Ziurys, Lucy, Kim, Jae-Young, Krichbaum, Thomas P., Broderick, Avery E., Wielgus, Maciek, Blackburn, Lindy, Gomez, Jose L., Johnson, Michael D., Bouman, Katherine L., Chael, Andrew, Akiyama, Kazunori, Jorstad, Svetlana, Marscher, Alan P., Issaoun, Sara, Janssen, Michael, Chan, Chi-kwan, Savolainen, Tuomas, Pesce, Dominic W., Ozel, Feryal, Alberdi, Antxon, Alef, Walter, Asada, Keiichi, Azulay, Rebecca, Baczko, Anne-Kathrin, Ball, David, Balokovic, Mislav, Barrett, John, Bintley, Dan, Boland, Wilfred, Bower, Geoffrey C., Bremer, Michael, Brinkerink, Christiaan D., Brissenden, Roger, Britzen, Silke, Broguiere, Dominique, Bronzwaer, Thomas, Byun, Do-Young, Carlstrom, John E., Chatterjee, Shami, Chatterjee, Koushik, Chen, Ming-Tang, Chen, Yongjun, Cho, Ilje, Christian, Pierre, Conway, John E., Cordes, James M., Crew, Geoffrey B., Cui, Yuzhu, Davelaar, Jordy, De Laurentis, Mariafelicia, Deane, Roger, Dempsey, Jessica, Desvignes, Gregory, Dexter, Jason, Doeleman, Sheperd S., Eatough, Ralph P., Falcke, Heino, Fish, Vincent L., Fomalont, Ed, Fraga-Encinas, Raquel, Friberg, Per, Fromm, Christian M., Galison, Peter, Gammie, Charles F., Garcia, Roberto, Gentaz, Olivier, Georgiev, Boris, Goddi, Ciriaco, Gold, Roman, Gu, Minfeng, Gurwell, Mark, Hada, Kazuhiro, Hecht, Michael H., Hesper, Ronald, Ho, Luis C., Ho, Paul, Honma, Mareki, Huang, Chih-Wei L., Huang, Lei, Hughes, David H., Ikeda, Shiro, Inoue, Makoto, James, David J., Jannuzi, Buell T., Jeter, Britton, Jiang, Wu, Jimenez-Rosales, Alejandra, Jung, Taehyun, Karami, Mansour, Karuppusamy, Ramesh, Kawashima, Tomohisa, Keating, Garrett K., Kettenis, Mark, Kim, Junhan, Kim, Jongsoo, Kino, Motoki, Koay, Jun Yi, Koch, Patrick M., Koyama, Shoko, Kramer, Michael, Kramer, Carsten, Kuo, Cheng-Yu, Lauer, Tod R., Lee, Sang-Sung, Li, Yan-Rong, Li, Zhiyuan, Lindqvist, Michael, Lico, Rocco, Liu, Kuo, Liuzzo, Elisabetta, Lo, Wen-Ping, Lobanov, Andrei P., Loinard, Laurent, Lonsdale, Colin, Lu, Ru-Sen, MacDonald, Nicholas R., Mao, Jirong, Markoff, Sera, Marrone, Daniel P., Marti-Vidal, Ivan, Matsushita, Satoki, Matthews, Lynn D., Medeiros, Lia, Menten, Karl M., Mizuno, Yosuke, Mizuno, Izumi, Moran, James M., Moriyama, Kotaro, Moscibrodzka, Monika, Mueller, Cornelia, Nagai, Hiroshi, Nagar, Neil M., Nakamura, Masanori, Narayan, Ramesh, Narayanan, Gopal, Natarajan, Iniyan, Neri, Roberto, Ni, Chunchong, Noutsos, Aristeidis, Okino, Hiroki, Olivares, Hector, Ortiz-Leon, Gisela N., Oyama, Tomoaki, Palumbo, Daniel C. M., Park, Jongho, Patel, Nimesh, Pen, Ue-Li, Pietu, Vincent, Plambeck, Richard, PopStefanija, Aleksandar, Porth, Oliver, Prather, Ben, Preciado-Lopez, Jorge A., Psaltis, Dimitrios, Pu, Hung-Yi, Ramakrishnan, Venkatessh, Rao, Ramprasad, Rawlings, Mark G., Raymond, Alexander W., Rezzolla, Luciano, Ripperda, Bart, Roelofs, Freek, Rogers, Alan, Ros, Eduardo, Rose, Mel, Roshanineshat, Arash, Rottmann, Helge, Roy, Alan L., Ruszczyk, Chet, Ryan, Benjamin R., Rygl, Kazi L. J., Sanchez, Salvador, Sanchez-Arguelles, David, Sasada, Mahito, Schloerb, F. Peter, Schuster, Karl-Friedrich, Shao, Lijing, Shen, Zhiqiang, Small, Des, Sohn, Bong Won, SooHoo, Jason, Tazaki, Fumie, Tiede, Paul, Tilanus, Remo P. J., Titus, Michael, Toma, Kenji, Torne, Pablo, Trent, Tyler, Traianou, Efthalia, Trippe, Sascha, Tsuda, Shuichiro, van Bemmel, Ilse, van Langevelde, Huib Jan, van Rossum, Daniel R., Wagner, Jan, Wardle, John, Ward-Thompson, Derek, Weintroub, Jonathan, Wex, Norbert, Wharton, Robert, Wong, George N., Wu, Qingwen, Yoon, Doosoo, Young, Andre, Young, Ken, Younsi, Ziri, Yuan, Feng, Yuan, Ye-Fei, Zensus, J. Anton, Zhao, Guangyao, Zhao, Shan-Shan, Zhu, Ziyan, Algaba, Juan-Carlos, Allardi, Alexander, Amestica, Rodrigo, Anczarski, Jadyn, Bach, Uwe, Baganoff, Frederick K., Beaudoin, Christopher, Benson, Bradford A., Berthold, Ryan, Blanchard, Jay M., Blundell, Ray, Bustamente, Sandra, Cappallo, Roger, Castillo-Dominguez, Edgar, Chang, Chih-Cheng, Chang, Shu-Hao, Chang, Song-Chu, Chen, Chung-Chen, Chilson, Ryan, Chuter, Tim C., Rosado, Rodrigo Cordova, Coulson, Iain M., Crowley, Joseph, Derome, Mark, Dexter, Matthew, Dornbusch, Sven, Dudevoir, Kevin A., Dzib, Sergio A., Eckart, Andreas, Eckert, Chris, Erickson, Neal R., Everett, Wendeline B., Faber, Aaron, Farah, Joseph R., Fath, Vernon, Folkers, Thomas W., Forbes, David C., Freund, Robert, Gomez-Ruiz, Arturo, I, Gale, David M., Gao, Feng, Geertsema, Gertie, Graham, David A., Greer, Christopher H., Grosslein, Ronald, Gueth, Frederic, Haggard, Daryl, Halverson, Nils W., Han, Chih-Chiang, Han, Kuo-Chang, Hao, Jinchi, Hasegawa, Yutaka, Henning, Jason W., Hernandez-Gomez, Antonio, Herrero-Illana, Ruben, Heyminck, Stefan, Hirota, Akihiko, Hoge, James, Huang, Yau-De, Impellizzeri, C. M. Violette, Jiang, Homin, John, David, Kamble, Atish, Keisler, Ryan, Kimura, Kimihiro, Kono, Yusuke, Kubo, Derek, Kuroda, John, Lacasse, Richard, Laing, Robert A., Leitch, Erik M., Li, Chao-Te, Lin, Lupin C-C, Liu, Ching-Tang, Liu, Kuan-Yu, Lu, Li-Ming, Marson, Ralph G., Martin-Cocher, Pierre L., Massingill, Kyle D., Matulonis, Callie, McColl, Martin P., McWhirter, Stephen R., Messias, Hugo, Meyer-Zhao, Zheng, Michalik, Daniel, Montana, Alfredo, Montgomerie, William, Mora-Klein, Matias, Muders, Dirk, Nadolski, Andrew, Navarro, Santiago, Neilsen, Joseph, Nguyen, Chi H., Nishioka, Hiroaki, Norton, Timothy, Nowak, Michael A., Nystrom, George, Ogawa, Hideo, Oshiro, Peter, Parsons, Harriet, Penalver, Juan, Phillips, Neil M., Poirier, Michael, Pradel, Nicolas, Primiani, Rurik A., Raffin, Philippe A., Rahlin, Alexandra S., Reiland, George, Risacher, Christopher, Ruiz, Ignacio, Saez-Madain, Alejandro F., Sassella, Remi, Schellart, Pim, Shaw, Paul, Silva, Kevin M., Shiokawa, Hotaka, Smith, David R., Snow, William, Souccar, Kamal, Sousa, Don, Sridharan, T. K., Srinivasan, Ranjani, Stahm, William, Stark, Antony A., Story, Kyle, Timmer, Sjoerd T., Vertatschitsch, Laura, Walther, Craig, Wei, Ta-Shun, Whitehorn, Nathan, Whitney, Alan R., Woody, David P., Wouterloot, Jan G. A., Wright, Melvin, Yamaguchi, Paul, Yu, Chen-Yu, Zeballos, Milagros, Zhang, Shuo, and Ziurys, Lucy
Abstract: 3C 279 is an archetypal blazar with a prominent radio jet that show broadband flux density variability across the entire electromagnetic spectrum. We use an ultra-high angular resolution technique - global Very Long Baseline Interferometry (VLBI) at 1.3 mm (230 GHz) - to resolve the innermost jet of 3C 279 in order to study its fine-scale morphology close to the jet base where highly variable gamma -ray emission is thought to originate, according to various models. The source was observed during four days in April 2017 with the Event Horizon Telescope at 230 GHz, including the phased Atacama Large Millimeter/submillimeter Array (ALMA), at an angular resolution of similar to 20 mu as (at a redshift of z=0.536 this corresponds to similar to 0.13 pc similar to 1700 Schwarzschild radii with a black hole mass M-BH=8x10(8) M-circle dot). Imaging and model-fitting techniques were applied to the data to parameterize the fine-scale source structure and its variation. We find a multicomponent inner jet morphology with the northernmost component elongated perpendicular to the direction of the jet, as imaged at longer wavelengths. The elongated nuclear structure is consistent on all four observing days and across different imaging methods and model-fitting techniques, and therefore appears robust. Owing to its compactness and brightness, we associate the northern nuclear structure as the VLBI core. This morphology can be interpreted as either a broad resolved jet base or a spatially bent jet. We also find significant day-to-day variations in the closure phases, which appear most pronounced on the triangles with the longest baselines. Our analysis shows that this variation is related to a systematic change of the source structure. Two inner jet components move non-radially at apparent speeds of similar to 15 c and similar to 20 c (similar to 1.3 and similar to 1.7 mu as day(-1), respectively), which more strongly supports the scenario of traveling shocks or instabilities in a be
Published: 2020

38. Pharmacoresponse in genetic generalized epilepsy: a genome-wide association study

Author: EpiPGx Consortium, Wolking, Stefan, Schulz, Herbert, Nies, Anne T, McCormack, Mark, Schäffeler, Elke, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Klein, Karl Martin, Krenn, Martin, Møller, Rikke S., Nikanorova, Marina, Weckhuysen, Sarah, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico J., Zimprich, Fritz, Weber, Yvonne G., Krause, Roland, Sisodiya, Sanjay M., Schwab, Matthias, Sander, Thomas, Lerche, Holger, EpiPGx Consortium, Wolking, Stefan, Schulz, Herbert, Nies, Anne T, McCormack, Mark, Schäffeler, Elke, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Klein, Karl Martin, Krenn, Martin, Møller, Rikke S., Nikanorova, Marina, Weckhuysen, Sarah, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico J., Zimprich, Fritz, Weber, Yvonne G., Krause, Roland, Sisodiya, Sanjay M., Schwab, Matthias, Sander, Thomas, and Lerche, Holger
Abstract: Aim: Pharmacoresistance is a major burden in epilepsy treatment. We aimed to identify genetic biomarkers in response to specific antiepileptic drugs (AEDs) in genetic generalized epilepsies (GGE). Materials & methods: We conducted a genome-wide association study (GWAS) of 3.3 million autosomal SNPs in 893 European subjects with GGE – responsive or nonresponsive to lamotrigine, levetiracetam and valproic acid. Results: Our GWAS of AED response revealed suggestive evidence for association at 29 genomic loci (p <10-5) but no significant association reflecting its limited power. The suggestive associations highlight candidate genes that are implicated in epileptogenesis and neurodevelopment. Conclusion: This first GWAS of AED response in GGE provides a comprehensive reference of SNP associations for hypothesis-driven candidate gene analyses in upcoming pharmacogenetic studies.
Published: 2020

39. Real-world performance of the new US HIV testing algorithm in medical settings.

Author: Marson, Kara G, Marson, Kara G, Marlin, Robert, Pham, Phong, Cohen, Stephanie E, Jones, Diane, Roemer, Marguerite, Peters, Philip J, Haller, Barbara, Pilcher, Christopher D, Marson, Kara G, Marson, Kara G, Marlin, Robert, Pham, Phong, Cohen, Stephanie E, Jones, Diane, Roemer, Marguerite, Peters, Philip J, Haller, Barbara, and Pilcher, Christopher D
Abstract: BackgroundOur medical center laboratory recently adapted its 24/7, two-hourly testing program to use an ARCHITECT-Multispot-viral load (AR-MS-VL) algorithm in place of a previous rapid test-immunofluorescence (RT-IF) algorithm.ObjectivesWe evaluated screening test performance, acute case detection, turnaround time and ability to resolve HIV status under the new algorithm.Study designWe considered consecutive HIV tests from January to November 2015. AR-MS-VL results at Zuckerberg San Francisco General Hospital and Trauma Center (ZSFG) were compared with RT-IF results at ZSFG and also with AR-MS-VL results in the recently completed CDC Screening Targeted Populations to Interrupt On-going Chains of HIV Transmission with Enhanced Partner Notification (STOP) Study for targeted testing of MSM at publicly funded testing sites in San Francisco.ResultsAmong 21,985 HIV tests performed at ZSFG, 16,467 were tested by RT-IF and 5518 by AR-MS-VL. There were 321 HIV infections detected, of which 274 (84%) were known HIV+ cases, and 47 were newly identified HIV infections. Considering only patients of HIV-negative or -unknown status, prevalence was 0.22%. Under the AR-MS-VL algorithm, turnaround times for screening results and full algorithm results were 3 and 21h; status-unresolved cases were reduced (from 47% to 22%) compared with the RT-IF algorithm. The positive predictive value (PPV) of a new-positive AR screening test was low (0.44) at ZSFG, where no acute infections were detected. At STOP Study sites where HIV prevalence was higher and acute infection was more common, the AR PPV was higher (0.93). All 24 false-positive AR screening tests at ZSFG had a signal/cutoff (S/CO) ratio of <15 and all 88 true-positive tests had S/CO ratio >15. Of 62 acute infections in the STOP Study, 23 (37%) had an S/CO<15.DiscussionAn AR-MS-VL algorithm is feasible and can return rapid results in a large medical center. In this setting, reactive 4th generation assay tests that are negativ
Published: 2017

40. First M87 Event Horizon Telescope Results. I. The Shadow of the Supermassive Black Hole

Author: Akiyama, Kazunori, Alberdi, Antxon, Alef, Walter, Asada, Keiichi, Azulay, Rebecca, Baczko, Anne-Kathrin, Ball, David, Balokovic, Mislav, Barrett, John, Bintley, Dan, Blackburn, Lindy, Boland, Wilfred, Bouman, Katherine L., Bower, Geoffrey C., Bremer, Michael, Brinkerink, Christiaan D., Brissenden, Roger, Britzen, Silke, Broderick, Avery E., Broguiere, Dominique, Bronzwaer, Thomas, Byun, Do-Young, Carlstrom, John E., Chael, Andrew, Chan, Chi-kwan, Chatterjee, Shami, Chatterjee, Koushik, Chen, Ming-Tang, Chen, Yongjun, Cho, Ilje, Christian, Pierre, Conway, John E., Cordes, James M., Crew, Geoffrey B., Cui, Yuzhu, Davelaar, Jordy, De Laurentis, Mariafelicia, Deane, Roger, Dempsey, Jessica, Desvignes, Gregory, Dexter, Jason, Doeleman, Sheperd S., Eatough, Ralph P., Falcke, Heino, Fish, Vincent L., Fomalont, Ed, Fraga-Encinas, Raquel, Freeman, William T., Friberg, Per, Fromm, Christian M., Gomez, Jose L., Galison, Peter, Gammie, Charles F., Garcia, Roberto, Gentaz, Olivier, Georgiev, Boris, Goddi, Ciriaco, Gold, Roman, Gu, Minfeng, Gurwell, Mark, Hada, Kazuhiro, Hecht, Michael H., Hesper, Ronald, Ho, Luis C., Ho, Paul, Honma, Mareki, Huang, Chih-Wei L., Huang, Lei, Hughes, David H., Ikeda, Shiro, Inoue, Makoto, Issaoun, Sara, James, David J., Jannuzi, Buell T., Janssen, Michael, Jeter, Britton, Jiang, Wu, Johnson, Michael D., Jorstad, Svetlana, Jung, Taehyun, Karami, Mansour, Karuppusamy, Ramesh, Kawashima, Tomohisa, Keating, Garrett K., Kettenis, Mark, Kim, Jae-Young, Kim, Junhan, Kim, Jongsoo, Kino, Motoki, Koay, Jun Yi, Koch, Patrick M., Koyama, Shoko, Kramer, Michael, Kramer, Carsten, Krichbaum, Thomas P., Kuo, Cheng-Yu, Lauer, Tod R., Lee, Sang-Sung, Li, Yan-Rong, Li, Zhiyuan, Lindqvist, Michael, Liu, Kuo, Liuzzo, Elisabetta, Lo, Wen-Ping, Lobanov, Andrei P., Loinard, Laurent, Lonsdale, Colin, Lu, Ru-Sen, MacDonald, Nicholas R., Mao, Jirong, Markoff, Sera, Marrone, Daniel P., Marscher, Alan P., Marti-Vidal, Ivan, Matsushita, Satoki, Matthews, Lynn D., Medeiros, Lia, Menten, Karl M., Mizuno, Yosuke, Mizuno, Izumi, Moran, James M., Moriyama, Kotaro, Moscibrodzka, Monika, Mueller, Cornelia, Nagai, Hiroshi, Nagar, Neil M., Nakamura, Masanori, Narayan, Ramesh, Narayanan, Gopal, Natarajan, Iniyan, Neri, Roberto, Ni, Chunchong, Noutsos, Aristeidis, Okino, Hiroki, Olivares, Hector, Ortiz-Leon, Gisela N., Oyama, Tomoaki, Ozel, Feryal, Palumbo, Daniel C. M., Patel, Nimesh, Pen, Ue-Li, Pesce, Dominic W., Pietu, Vincent, Plambeck, Richard, PopStefanija, Aleksandar, Porth, Oliver, Prather, Ben, Preciado-Lopez, Jorge A., Psaltis, Dimitrios, Pu, Hung-Yi, Ramakrishnan, Venkatessh, Rao, Ramprasad, Rawlings, Mark G., Raymond, Alexander W., Rezzolla, Luciano, Ripperda, Bart, Roelofs, Freek, Rogers, Alan, Ros, Eduardo, Rose, Mel, Roshanineshat, Arash, Rottmann, Helge, Roy, Alan L., Ruszczyk, Chet, Ryan, Benjamin R., Rygl, Kazi L. J., Sanchez, Salvador, Sanchez-Arguelles, David, Sasada, Mahito, Savolainen, Tuomas, Schloerb, F. Peter, Schuster, Karl-Friedrich, Shao, Lijing, Shen, Zhiqiang, Small, Des, Sohn, Bong Won, SooHoo, Jason, Tazaki, Fumie, Tiede, Paul, Tilanus, Remo P. J., Titus, Michael, Toma, Kenji, Torne, Pablo, Trent, Tyler, Trippe, Sascha, Tsuda, Shuichiro, van Bemmel, Ilse, van Langevelde, Huib Jan, van Rossum, Daniel R., Wagner, Jan, Wardle, John, Weintroub, Jonathan, Wex, Norbert, Wharton, Robert, Wielgus, Maciek, Wong, George N., Wu, Qingwen, Young, Ken, Young, Andre, Younsi, Ziri, Yuan, Feng, Yuan, Ye-Fei, Zensus, J. Anton, Zhao, Guangyao, Zhao, Shan-Shan, Zhu, Ziyan, Algaba, Juan-Carlos, Allardi, Alexander, Amestica, Rodrigo, Anczarski, Jadyn, Bach, Uwe, Baganoff, Frederick K., Beaudoin, Christopher, Benson, Bradford A., Berthold, Ryan, Blanchard, Jay M., Blundell, Ray, Bustamente, Sandra, Cappallo, Roger, Castillo-Dominguez, Edgar, Chang, Chih-Cheng, Chang, Shu-Hao, Chang, Song-Chu, Chen, Chung-Chen, Chilson, Ryan, Chuter, Tim C., Rosado, Rodrigo Cordova, Coulson, Iain M., Crawford, Thomas M., Crowley, Joseph, David, John, Derome, Mark, Dexter, Matthew, Dornbusch, Sven, Dudevoir, Kevin A., Dzib, Sergio A., Eckart, Andreas, Eckert, Chris, Erickson, Neal R., Everett, Wendeline B., Faber, Aaron, Farah, Joseph R., Fath, Vernon, Folkers, Thomas W., Forbes, David C., Freund, Robert, Gomez-Ruiz, Arturo I., Gale, David M., Gao, Feng, Geertsema, Gertie, Graham, David A., Greer, Christopher H., Grosslein, Ronald, Gueth, Frederic, Haggard, Daryl, Halverson, Nils W., Han, Chih-Chiang, Han, Kuo-Chang, Hao, Jinchi, Hasegawa, Yutaka, Henning, Jason W., Hernandez-Gomez, Antonio, Herrero-Illana, Ruben, Heyminck, Stefan, Hirota, Akihiko, Hoge, James, Huang, Yau-De, Impellizzeri, C. M. Violette, Jiang, Homin, Kamble, Atish, Keisler, Ryan, Kimura, Kimihiro, Kono, Yusuke, Kubo, Derek, Kuroda, John, Lacasse, Richard, Laing, Robert A., Leitch, Erik M., Li, Chao-Te, Lin, Lupin C. -C., Liu, Ching-Tang, Liu, Kuan-Yu, Lu, Li-Ming, Marson, Ralph G., Martin-Cocher, Pierre L., Massingill, Kyle D., Matulonis, Callie, McColl, Martin P., McWhirter, Stephen R., Messias, Hugo, Meyer-Zhao, Zheng, Michalik, Daniel, Montana, Alfredo, Montgomerie, William, Mora-Klein, Matias, Muders, Dirk, Nadolski, Andrew, Navarro, Santiago, Neilsen, Joseph, Nguyen, Chi H., Nishioka, Hiroaki, Norton, Timothy, Nowak, Michael A., Nystrom, George, Ogawa, Hideo, Oshiro, Peter, Parsons, Harriet, Paine, Scott N., Penalver, Juan, Phillips, Neil M., Poirier, Michael, Pradel, Nicolas, Primiani, Rurik A., Raffin, Philippe A., Rahlin, Alexandra S., Reiland, George, Risacher, Christopher, Ruiz, Ignacio, Saez-Madain, Alejandro F., Sassella, Remi, Schellart, Pim, Shaw, Paul, Silva, Kevin M., Shiokawa, Hotaka, Smith, David R., Snow, William, Souccar, Kamal, Sousa, Don, Sridharan, T. K., Srinivasan, Ranjani, Stahm, William, Stark, Anthony A., Story, Kyle, Timmer, Sjoerd T., Vertatschitsch, Laura, Walther, Craig, Wei, Ta-Shun, Whitehorn, Nathan, Whitney, Alan R., Woody, David P., Wouterloot, Jan G. A., Wright, Melvin, Yamaguchi, Paul, Yu, Chen-Yu, Zeballos, Milagros, Zhang, Shuo, Ziurys, Lucy, Akiyama, Kazunori, Alberdi, Antxon, Alef, Walter, Asada, Keiichi, Azulay, Rebecca, Baczko, Anne-Kathrin, Ball, David, Balokovic, Mislav, Barrett, John, Bintley, Dan, Blackburn, Lindy, Boland, Wilfred, Bouman, Katherine L., Bower, Geoffrey C., Bremer, Michael, Brinkerink, Christiaan D., Brissenden, Roger, Britzen, Silke, Broderick, Avery E., Broguiere, Dominique, Bronzwaer, Thomas, Byun, Do-Young, Carlstrom, John E., Chael, Andrew, Chan, Chi-kwan, Chatterjee, Shami, Chatterjee, Koushik, Chen, Ming-Tang, Chen, Yongjun, Cho, Ilje, Christian, Pierre, Conway, John E., Cordes, James M., Crew, Geoffrey B., Cui, Yuzhu, Davelaar, Jordy, De Laurentis, Mariafelicia, Deane, Roger, Dempsey, Jessica, Desvignes, Gregory, Dexter, Jason, Doeleman, Sheperd S., Eatough, Ralph P., Falcke, Heino, Fish, Vincent L., Fomalont, Ed, Fraga-Encinas, Raquel, Freeman, William T., Friberg, Per, Fromm, Christian M., Gomez, Jose L., Galison, Peter, Gammie, Charles F., Garcia, Roberto, Gentaz, Olivier, Georgiev, Boris, Goddi, Ciriaco, Gold, Roman, Gu, Minfeng, Gurwell, Mark, Hada, Kazuhiro, Hecht, Michael H., Hesper, Ronald, Ho, Luis C., Ho, Paul, Honma, Mareki, Huang, Chih-Wei L., Huang, Lei, Hughes, David H., Ikeda, Shiro, Inoue, Makoto, Issaoun, Sara, James, David J., Jannuzi, Buell T., Janssen, Michael, Jeter, Britton, Jiang, Wu, Johnson, Michael D., Jorstad, Svetlana, Jung, Taehyun, Karami, Mansour, Karuppusamy, Ramesh, Kawashima, Tomohisa, Keating, Garrett K., Kettenis, Mark, Kim, Jae-Young, Kim, Junhan, Kim, Jongsoo, Kino, Motoki, Koay, Jun Yi, Koch, Patrick M., Koyama, Shoko, Kramer, Michael, Kramer, Carsten, Krichbaum, Thomas P., Kuo, Cheng-Yu, Lauer, Tod R., Lee, Sang-Sung, Li, Yan-Rong, Li, Zhiyuan, Lindqvist, Michael, Liu, Kuo, Liuzzo, Elisabetta, Lo, Wen-Ping, Lobanov, Andrei P., Loinard, Laurent, Lonsdale, Colin, Lu, Ru-Sen, MacDonald, Nicholas R., Mao, Jirong, Markoff, Sera, Marrone, Daniel P., Marscher, Alan P., Marti-Vidal, Ivan, Matsushita, Satoki, Matthews, Lynn D., Medeiros, Lia, Menten, Karl M., Mizuno, Yosuke, Mizuno, Izumi, Moran, James M., Moriyama, Kotaro, Moscibrodzka, Monika, Mueller, Cornelia, Nagai, Hiroshi, Nagar, Neil M., Nakamura, Masanori, Narayan, Ramesh, Narayanan, Gopal, Natarajan, Iniyan, Neri, Roberto, Ni, Chunchong, Noutsos, Aristeidis, Okino, Hiroki, Olivares, Hector, Ortiz-Leon, Gisela N., Oyama, Tomoaki, Ozel, Feryal, Palumbo, Daniel C. M., Patel, Nimesh, Pen, Ue-Li, Pesce, Dominic W., Pietu, Vincent, Plambeck, Richard, PopStefanija, Aleksandar, Porth, Oliver, Prather, Ben, Preciado-Lopez, Jorge A., Psaltis, Dimitrios, Pu, Hung-Yi, Ramakrishnan, Venkatessh, Rao, Ramprasad, Rawlings, Mark G., Raymond, Alexander W., Rezzolla, Luciano, Ripperda, Bart, Roelofs, Freek, Rogers, Alan, Ros, Eduardo, Rose, Mel, Roshanineshat, Arash, Rottmann, Helge, Roy, Alan L., Ruszczyk, Chet, Ryan, Benjamin R., Rygl, Kazi L. J., Sanchez, Salvador, Sanchez-Arguelles, David, Sasada, Mahito, Savolainen, Tuomas, Schloerb, F. Peter, Schuster, Karl-Friedrich, Shao, Lijing, Shen, Zhiqiang, Small, Des, Sohn, Bong Won, SooHoo, Jason, Tazaki, Fumie, Tiede, Paul, Tilanus, Remo P. J., Titus, Michael, Toma, Kenji, Torne, Pablo, Trent, Tyler, Trippe, Sascha, Tsuda, Shuichiro, van Bemmel, Ilse, van Langevelde, Huib Jan, van Rossum, Daniel R., Wagner, Jan, Wardle, John, Weintroub, Jonathan, Wex, Norbert, Wharton, Robert, Wielgus, Maciek, Wong, George N., Wu, Qingwen, Young, Ken, Young, Andre, Younsi, Ziri, Yuan, Feng, Yuan, Ye-Fei, Zensus, J. Anton, Zhao, Guangyao, Zhao, Shan-Shan, Zhu, Ziyan, Algaba, Juan-Carlos, Allardi, Alexander, Amestica, Rodrigo, Anczarski, Jadyn, Bach, Uwe, Baganoff, Frederick K., Beaudoin, Christopher, Benson, Bradford A., Berthold, Ryan, Blanchard, Jay M., Blundell, Ray, Bustamente, Sandra, Cappallo, Roger, Castillo-Dominguez, Edgar, Chang, Chih-Cheng, Chang, Shu-Hao, Chang, Song-Chu, Chen, Chung-Chen, Chilson, Ryan, Chuter, Tim C., Rosado, Rodrigo Cordova, Coulson, Iain M., Crawford, Thomas M., Crowley, Joseph, David, John, Derome, Mark, Dexter, Matthew, Dornbusch, Sven, Dudevoir, Kevin A., Dzib, Sergio A., Eckart, Andreas, Eckert, Chris, Erickson, Neal R., Everett, Wendeline B., Faber, Aaron, Farah, Joseph R., Fath, Vernon, Folkers, Thomas W., Forbes, David C., Freund, Robert, Gomez-Ruiz, Arturo I., Gale, David M., Gao, Feng, Geertsema, Gertie, Graham, David A., Greer, Christopher H., Grosslein, Ronald, Gueth, Frederic, Haggard, Daryl, Halverson, Nils W., Han, Chih-Chiang, Han, Kuo-Chang, Hao, Jinchi, Hasegawa, Yutaka, Henning, Jason W., Hernandez-Gomez, Antonio, Herrero-Illana, Ruben, Heyminck, Stefan, Hirota, Akihiko, Hoge, James, Huang, Yau-De, Impellizzeri, C. M. Violette, Jiang, Homin, Kamble, Atish, Keisler, Ryan, Kimura, Kimihiro, Kono, Yusuke, Kubo, Derek, Kuroda, John, Lacasse, Richard, Laing, Robert A., Leitch, Erik M., Li, Chao-Te, Lin, Lupin C. -C., Liu, Ching-Tang, Liu, Kuan-Yu, Lu, Li-Ming, Marson, Ralph G., Martin-Cocher, Pierre L., Massingill, Kyle D., Matulonis, Callie, McColl, Martin P., McWhirter, Stephen R., Messias, Hugo, Meyer-Zhao, Zheng, Michalik, Daniel, Montana, Alfredo, Montgomerie, William, Mora-Klein, Matias, Muders, Dirk, Nadolski, Andrew, Navarro, Santiago, Neilsen, Joseph, Nguyen, Chi H., Nishioka, Hiroaki, Norton, Timothy, Nowak, Michael A., Nystrom, George, Ogawa, Hideo, Oshiro, Peter, Parsons, Harriet, Paine, Scott N., Penalver, Juan, Phillips, Neil M., Poirier, Michael, Pradel, Nicolas, Primiani, Rurik A., Raffin, Philippe A., Rahlin, Alexandra S., Reiland, George, Risacher, Christopher, Ruiz, Ignacio, Saez-Madain, Alejandro F., Sassella, Remi, Schellart, Pim, Shaw, Paul, Silva, Kevin M., Shiokawa, Hotaka, Smith, David R., Snow, William, Souccar, Kamal, Sousa, Don, Sridharan, T. K., Srinivasan, Ranjani, Stahm, William, Stark, Anthony A., Story, Kyle, Timmer, Sjoerd T., Vertatschitsch, Laura, Walther, Craig, Wei, Ta-Shun, Whitehorn, Nathan, Whitney, Alan R., Woody, David P., Wouterloot, Jan G. A., Wright, Melvin, Yamaguchi, Paul, Yu, Chen-Yu, Zeballos, Milagros, Zhang, Shuo, and Ziurys, Lucy
Abstract: When surrounded by a transparent emission region, black holes are expected to reveal a dark shadow caused by gravitational light bending and photon capture at the event horizon. To image and study this phenomenon, we have assembled the Event Horizon Telescope, a global very long baseline interferometry array observing at a wavelength of 1.3 mm. This allows us to reconstruct event-horizon-scale images of the supermassive black hole candidate in the center of the giant elliptical galaxy M87. We have resolved the central compact radio source as an asymmetric bright emission ring with a diameter of 42 +/- 3 mu as, which is circular and encompasses a central depression in brightness with a flux ratio greater than or similar to 10: 1. The emission ring is recovered using different calibration and imaging schemes, with its diameter and width remaining stable over four different observations carried out in different days. Overall, the observed image is consistent with expectations for the shadow of a Kerr black hole as predicted by general relativity. The asymmetry in brightness in the ring can be explained in terms of relativistic beaming of the emission from a plasma rotating close to the speed of light around a black hole. We compare our images to an extensive library of ray-traced general-relativistic magnetohydrodynamic simulations of black holes and derive a central mass of M = (6.5 +/- 0.7) x 10(9) M-circle dot. Our radio-wave observations thus provide powerful evidence for the presence of supermassive black holes in centers of galaxies and as the central engines of active galactic nuclei. They also present a new tool to explore gravity in its most extreme limit and on a mass scale that was so far not accessible.
Published: 2019

41. Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Feng, Yen-Chen Anne, Howrigan, Daniel P., Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Singh, Tarjinder, Heyne, Henrike, Byrnes, Andrea, Churchhouse, Claire, Watts, Nick, Solomonson, Matthew, Lal, Dennis, Heinzen, Erin L., Dhindsa, Ryan S., Stanley, Kate E., Cavalleri, Gianpiero L., Hakonarson, Hakon, Helbig, Ingo, Krause, Roland, May, Patrick, Weckhuysen, Sarah, Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Cossette, Patrick, Cotsapas, Chris, Jonghe, Peter De, Dixon-Salazar, Tracy, Guerrini, Renzo, Kwan, Patrick, Marson, Anthony G., Stewart, Randy, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, McKenna, Kevin, Regan, Brigid M., Bellows, Susannah T., Leu, Costin, Bennett, Caitlin A., Johns, Esther M. C., Macdonald, Alexandra, Shilling, Hannah, Burgess, Rosemary, Weckhuysen, Dorien, Bahlo, Melanie, O’Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Sadoway, Tara R., Mo, Kelly, Krestel, Heinz, Gallati, Sabina, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Štěrbová, Katalin, Vlčková, Markéta, Sedláčková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Kunz, Wolfram S., Zsurka, Gábor, Elger, Christian E., Bauer, Jürgen, Rademacher, Michael, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, Baalen, Andreas Van, Spiczak, Sarah Von, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Kurlemann, Gerhard, Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, Hengsbach, Christian, Rau, Sarah, Maisch, Ana F., Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Schubert-Bast, Susanne, Schreiber, Herbert, Borggräfe, Ingo, Schankin, Christoph J., Mayer, Thomas, Korinthenberg, Rudolf, Brockmann, Knut, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Auvinen, Pia, Saarela, Anni, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Barišić, Nina, Delanty, Norman, Doherty, Colin P., Shukralla, Arif, McCormack, Mark, El-Naggar, Hany, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Zara, Federico, Iacomino, Michele, Madia, Francesca, Vari, Maria Stella, Mancardi, Maria Margherita, Salpietro, Vincenzo, Bisulli, Francesca, Tinuper, Paolo, Licchetta, Laura, Pippucci, Tommaso, Stipa, Carlotta, Minardi, Raffaella, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Marini, Carla, Suzuki, Toshimitsu, Inoue, Yushi, Yamakawa, Kazuhiro, Tumiene, Birute, Sadleir, Lynette G., King, Chontelle, Mountier, Emily, Caglayan, S. Hande, Arslan, Mutluay, Yapıcı, Zuhal, Yis, Uluc, Topaloglu, Pınar, Kara, Bulent, Turkdogan, Dilsad, Gundogdu-Eken, Aslı, Bebek, Nerses, Uğur-İşeri, Sibel, Baykan, Betül, Salman, Barış, Haryanyan, Garen, Yücesan, Emrah, Kesim, Yeşim, Özkara, Çiğdem, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Buono, Russell J., Ferraro, Thomas N., Sperling, Michael R., Lo, Warren, Privitera, Michael, French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Khankhanian, Pouya, Helbig, Katherine L., Ellis, Colin A., Spalletta, Gianfranco, Piras, Fabrizio, Piras, Federica, Gili, Tommaso, Ciullo, Valentina, Reif, Andreas, McQuillin, Andrew, Bass, Nick, McIntosh, Andrew, Blackwood, Douglas, Johnstone, Mandy, Palotie, Aarno, Pato, Michele T., Pato, Carlos N., Bromet, Evelyn J., Carvalho, Celia Barreto, Achtyes, Eric D., Azevedo, Maria Helena, Kotov, Roman, Lehrer, Douglas S., Malaspina, Dolores, Marder, Stephen R., Medeiros, Helena, Morley, Christopher P., Perkins, Diana O., Sobell, Janet L., Buckley, Peter F., Macciardi, Fabio, Rapaport, Mark H., Knowles, James A., Fanous, Ayman H., McCarroll, Steven A., Gupta, Namrata, Gabriel, Stacey B., Daly, Mark J., Lander, Eric S., Lowenstein, Daniel H., Goldstein, David B., Lerche, Holger, Berkovic, Samuel F., Neale, Benjamin M., Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Feng, Yen-Chen Anne, Howrigan, Daniel P., Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Singh, Tarjinder, Heyne, Henrike, Byrnes, Andrea, Churchhouse, Claire, Watts, Nick, Solomonson, Matthew, Lal, Dennis, Heinzen, Erin L., Dhindsa, Ryan S., Stanley, Kate E., Cavalleri, Gianpiero L., Hakonarson, Hakon, Helbig, Ingo, Krause, Roland, May, Patrick, Weckhuysen, Sarah, Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Cossette, Patrick, Cotsapas, Chris, Jonghe, Peter De, Dixon-Salazar, Tracy, Guerrini, Renzo, Kwan, Patrick, Marson, Anthony G., Stewart, Randy, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, McKenna, Kevin, Regan, Brigid M., Bellows, Susannah T., Leu, Costin, Bennett, Caitlin A., Johns, Esther M. C., Macdonald, Alexandra, Shilling, Hannah, Burgess, Rosemary, Weckhuysen, Dorien, Bahlo, Melanie, O’Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Sadoway, Tara R., Mo, Kelly, Krestel, Heinz, Gallati, Sabina, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Štěrbová, Katalin, Vlčková, Markéta, Sedláčková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Kunz, Wolfram S., Zsurka, Gábor, Elger, Christian E., Bauer, Jürgen, Rademacher, Michael, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, Baalen, Andreas Van, Spiczak, Sarah Von, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Kurlemann, Gerhard, Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, Hengsbach, Christian, Rau, Sarah, Maisch, Ana F., Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Schubert-Bast, Susanne, Schreiber, Herbert, Borggräfe, Ingo, Schankin, Christoph J., Mayer, Thomas, Korinthenberg, Rudolf, Brockmann, Knut, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Auvinen, Pia, Saarela, Anni, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Barišić, Nina, Delanty, Norman, Doherty, Colin P., Shukralla, Arif, McCormack, Mark, El-Naggar, Hany, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Zara, Federico, Iacomino, Michele, Madia, Francesca, Vari, Maria Stella, Mancardi, Maria Margherita, Salpietro, Vincenzo, Bisulli, Francesca, Tinuper, Paolo, Licchetta, Laura, Pippucci, Tommaso, Stipa, Carlotta, Minardi, Raffaella, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Marini, Carla, Suzuki, Toshimitsu, Inoue, Yushi, Yamakawa, Kazuhiro, Tumiene, Birute, Sadleir, Lynette G., King, Chontelle, Mountier, Emily, Caglayan, S. Hande, Arslan, Mutluay, Yapıcı, Zuhal, Yis, Uluc, Topaloglu, Pınar, Kara, Bulent, Turkdogan, Dilsad, Gundogdu-Eken, Aslı, Bebek, Nerses, Uğur-İşeri, Sibel, Baykan, Betül, Salman, Barış, Haryanyan, Garen, Yücesan, Emrah, Kesim, Yeşim, Özkara, Çiğdem, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Buono, Russell J., Ferraro, Thomas N., Sperling, Michael R., Lo, Warren, Privitera, Michael, French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Khankhanian, Pouya, Helbig, Katherine L., Ellis, Colin A., Spalletta, Gianfranco, Piras, Fabrizio, Piras, Federica, Gili, Tommaso, Ciullo, Valentina, Reif, Andreas, McQuillin, Andrew, Bass, Nick, McIntosh, Andrew, Blackwood, Douglas, Johnstone, Mandy, Palotie, Aarno, Pato, Michele T., Pato, Carlos N., Bromet, Evelyn J., Carvalho, Celia Barreto, Achtyes, Eric D., Azevedo, Maria Helena, Kotov, Roman, Lehrer, Douglas S., Malaspina, Dolores, Marder, Stephen R., Medeiros, Helena, Morley, Christopher P., Perkins, Diana O., Sobell, Janet L., Buckley, Peter F., Macciardi, Fabio, Rapaport, Mark H., Knowles, James A., Fanous, Ayman H., McCarroll, Steven A., Gupta, Namrata, Gabriel, Stacey B., Daly, Mark J., Lander, Eric S., Lowenstein, Daniel H., Goldstein, David B., Lerche, Holger, Berkovic, Samuel F., and Neale, Benjamin M.
Abstract: Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology.
Published: 2019

42. Comparative effectiveness of antiepileptic drugs in juvenile myoclonic epilepsy

Author: Silvennoinen, Katri, de Lange, Nikola Maria, Zagaglia, Sara, Balestrini, Simona, Androsova, Ganna, Wassenaar, Merel, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Berghuis, Bianca, Campbell, Ellen, Coppola, Antonietta, Francis, Ben, Wolking, Stefan, Cavalleri, Gianpiero L., Craig, John, Delanty, Norman, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Lerche, Holger, Marson, Anthony G., O’Brien, Terence J., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, van der Palen, Job, Krause, Roland, Depondt, Chantal, Sisodiya, Sanjay M., Consortium, The Epipgx, Silvennoinen, Katri, de Lange, Nikola Maria, Zagaglia, Sara, Balestrini, Simona, Androsova, Ganna, Wassenaar, Merel, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Berghuis, Bianca, Campbell, Ellen, Coppola, Antonietta, Francis, Ben, Wolking, Stefan, Cavalleri, Gianpiero L., Craig, John, Delanty, Norman, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Lerche, Holger, Marson, Anthony G., O’Brien, Terence J., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, van der Palen, Job, Krause, Roland, Depondt, Chantal, Sisodiya, Sanjay M., and Consortium, The Epipgx
Abstract: Objective To study the effectiveness and tolerability of antiepileptic drugs (AEDs) commonly used in juvenile myoclonic epilepsy (JME). Methods People with JME were identified from a large database of individuals with epilepsy, which includes detailed retrospective information on AED use. We assessed secular changes in AED use and calculated rates of response (12-month seizure freedom) and adverse drug reactions (ADRs) for the five most common AEDs. Retention was modeled with a Cox proportional hazards model. We compared valproate use between males and females. Results We included 305 people with 688 AED trials of valproate, lamotrigine, levetiracetam, carbamazepine, and topiramate. Valproate and carbamazepine were most often prescribed as the first AED. The response rate to valproate was highest among the five AEDs (42.7\%), and significantly higher than response rates for lamotrigine, carbamazepine, and topiramate; the difference to the response rate to levetiracetam (37.1\%) was not significant. The rates of ADRs were highest for topiramate (45.5\%) and valproate (37.5\%). Commonest ADRs included weight change, lethargy, and tremor. In the Cox proportional hazards model, later start year (1.10 [1.08-1.13], P < 0.001) and female sex (1.41 [1.07-1.85], P = 0.02) were associated with shorter trial duration. Valproate was associated with the longest treatment duration; trials with carbamazepine and topiramate were significantly shorter (HR [CI]: 3.29 [2.15-5.02], P < 0.001 and 1.93 [1.31-2.86], P < 0.001). The relative frequency of valproate trials shows a decreasing trend since 2003 while there is an increasing trend for levetiracetam. Fewer females than males received valproate (76.2 vs 92.6\%, P = 0.001). Significance In people with JME, valproate is an effective AED; levetiracetam emerged as an alternative. Valproate is now contraindicated in women of childbearing potential without special precautions. With appropriate selection and safeguards in place
Published: 2019

43. Genomic and clinical predictors of lacosamide response in refractory epilepsies

Author: Heavin, Sinéad B., McCormack, Mark, Wolking, Stefan, Slattery, Lisa, Walley, Nicole, Avbersek, Andreja, Novy, Jan, Sinha, Saurabh R., Radtke, Rod, Doherty, Colin, Auce, Pauls, Craig, John, Johnson, Michael R., Koeleman, Bobby P. C., Krause, Roland, Kunz, Wolfram S., Marson, Anthony G., O'Brien, Terence J., Sander, Josemir W., Sills, Graeme J., Stefansson, Hreinn, Striano, Pasquale, Zara, Federico, EPIGEN Consortium, EpiPGX Consortium, Depondt, Chantal, Sisodiya, Sanjay, Goldstein, David, Lerche, Holger, Cavalleri, Gianpiero L., Delanty, Norman, Heavin, Sinéad B., McCormack, Mark, Wolking, Stefan, Slattery, Lisa, Walley, Nicole, Avbersek, Andreja, Novy, Jan, Sinha, Saurabh R., Radtke, Rod, Doherty, Colin, Auce, Pauls, Craig, John, Johnson, Michael R., Koeleman, Bobby P. C., Krause, Roland, Kunz, Wolfram S., Marson, Anthony G., O'Brien, Terence J., Sander, Josemir W., Sills, Graeme J., Stefansson, Hreinn, Striano, Pasquale, Zara, Federico, EPIGEN Consortium, EpiPGX Consortium, Depondt, Chantal, Sisodiya, Sanjay, Goldstein, David, Lerche, Holger, Cavalleri, Gianpiero L., and Delanty, Norman
Abstract: Objective Clinical and genetic predictors of response to antiepileptic drugs (AEDs) are largely unknown. We examined predictors of lacosamide response in a real-world clinical setting. Methods We tested the association of clinical predictors with treatment response using regression modeling in a cohort of people with refractory epilepsy. Genetic assessment for lacosamide response was conducted via genome-wide association studies and exome studies, comprising 281 candidate genes. Results Most patients (479/483) were treated with LCM in addition to other AEDs. Our results corroborate previous findings that patients with refractory genetic generalized epilepsy (GGE) may respond to treatment with LCM. No clear clinical predictors were identified. We then compared 73 lacosamide responders, defined as those experiencing greater than 75% seizure reduction or seizure freedom, to 495 nonresponders (<25% seizure reduction). No variants reached the genome-wide significance threshold in our case-control analysis. Significance No genetic predictor of lacosamide response was identified. Patients with refractory GGE might benefit from treatment with lacosamide.
Published: 2019

44. Comparative effectiveness of antiepileptic drugs in juvenile myoclonic epilepsy

Author: Silvennoinen, Katri, de Lange, Nikola Maria, Zagaglia, Sara, Balestrini, Simona, Androsova, Ganna, Wassenaar, Merel, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Berghuis, Bianca, Campbell, Ellen, Coppola, Antonietta, Francis, Ben, Wolking, Stefan, Cavalleri, Gianpiero L., Craig, John, Delanty, Norman, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Lerche, Holger, Marson, Anthony G., O’Brien, Terence J., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, van der Palen, Job, Krause, Roland, Depondt, Chantal, Sisodiya, Sanjay M., Consortium, The Epipgx, Silvennoinen, Katri, de Lange, Nikola Maria, Zagaglia, Sara, Balestrini, Simona, Androsova, Ganna, Wassenaar, Merel, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Berghuis, Bianca, Campbell, Ellen, Coppola, Antonietta, Francis, Ben, Wolking, Stefan, Cavalleri, Gianpiero L., Craig, John, Delanty, Norman, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Lerche, Holger, Marson, Anthony G., O’Brien, Terence J., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, van der Palen, Job, Krause, Roland, Depondt, Chantal, Sisodiya, Sanjay M., and Consortium, The Epipgx
Abstract: Objective To study the effectiveness and tolerability of antiepileptic drugs (AEDs) commonly used in juvenile myoclonic epilepsy (JME). Methods People with JME were identified from a large database of individuals with epilepsy, which includes detailed retrospective information on AED use. We assessed secular changes in AED use and calculated rates of response (12-month seizure freedom) and adverse drug reactions (ADRs) for the five most common AEDs. Retention was modeled with a Cox proportional hazards model. We compared valproate use between males and females. Results We included 305 people with 688 AED trials of valproate, lamotrigine, levetiracetam, carbamazepine, and topiramate. Valproate and carbamazepine were most often prescribed as the first AED. The response rate to valproate was highest among the five AEDs (42.7\%), and significantly higher than response rates for lamotrigine, carbamazepine, and topiramate; the difference to the response rate to levetiracetam (37.1\%) was not significant. The rates of ADRs were highest for topiramate (45.5\%) and valproate (37.5\%). Commonest ADRs included weight change, lethargy, and tremor. In the Cox proportional hazards model, later start year (1.10 [1.08-1.13], P < 0.001) and female sex (1.41 [1.07-1.85], P = 0.02) were associated with shorter trial duration. Valproate was associated with the longest treatment duration; trials with carbamazepine and topiramate were significantly shorter (HR [CI]: 3.29 [2.15-5.02], P < 0.001 and 1.93 [1.31-2.86], P < 0.001). The relative frequency of valproate trials shows a decreasing trend since 2003 while there is an increasing trend for levetiracetam. Fewer females than males received valproate (76.2 vs 92.6\%, P = 0.001). Significance In people with JME, valproate is an effective AED; levetiracetam emerged as an alternative. Valproate is now contraindicated in women of childbearing potential without special precautions. With appropriate selection and safeguards in place
Published: 2019

45. Genomic and clinical predictors of lacosamide response in refractory epilepsies

Author: Heavin, Sinéad B., McCormack, Mark, Wolking, Stefan, Slattery, Lisa, Walley, Nicole, Avbersek, Andreja, Novy, Jan, Sinha, Saurabh R., Radtke, Rod, Doherty, Colin, Auce, Pauls, Craig, John, Johnson, Michael R., Koeleman, Bobby P. C., Krause, Roland, Kunz, Wolfram S., Marson, Anthony G., O'Brien, Terence J., Sander, Josemir W., Sills, Graeme J., Stefansson, Hreinn, Striano, Pasquale, Zara, Federico, EPIGEN Consortium, EpiPGX Consortium, Depondt, Chantal, Sisodiya, Sanjay, Goldstein, David, Lerche, Holger, Cavalleri, Gianpiero L., Delanty, Norman, Heavin, Sinéad B., McCormack, Mark, Wolking, Stefan, Slattery, Lisa, Walley, Nicole, Avbersek, Andreja, Novy, Jan, Sinha, Saurabh R., Radtke, Rod, Doherty, Colin, Auce, Pauls, Craig, John, Johnson, Michael R., Koeleman, Bobby P. C., Krause, Roland, Kunz, Wolfram S., Marson, Anthony G., O'Brien, Terence J., Sander, Josemir W., Sills, Graeme J., Stefansson, Hreinn, Striano, Pasquale, Zara, Federico, EPIGEN Consortium, EpiPGX Consortium, Depondt, Chantal, Sisodiya, Sanjay, Goldstein, David, Lerche, Holger, Cavalleri, Gianpiero L., and Delanty, Norman
Abstract: Objective Clinical and genetic predictors of response to antiepileptic drugs (AEDs) are largely unknown. We examined predictors of lacosamide response in a real-world clinical setting. Methods We tested the association of clinical predictors with treatment response using regression modeling in a cohort of people with refractory epilepsy. Genetic assessment for lacosamide response was conducted via genome-wide association studies and exome studies, comprising 281 candidate genes. Results Most patients (479/483) were treated with LCM in addition to other AEDs. Our results corroborate previous findings that patients with refractory genetic generalized epilepsy (GGE) may respond to treatment with LCM. No clear clinical predictors were identified. We then compared 73 lacosamide responders, defined as those experiencing greater than 75% seizure reduction or seizure freedom, to 495 nonresponders (<25% seizure reduction). No variants reached the genome-wide significance threshold in our case-control analysis. Significance No genetic predictor of lacosamide response was identified. Patients with refractory GGE might benefit from treatment with lacosamide.
Published: 2019

46. Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Feng, Yen-Chen Anne, Howrigan, Daniel P., Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Singh, Tarjinder, Heyne, Henrike, Byrnes, Andrea, Churchhouse, Claire, Watts, Nick, Solomonson, Matthew, Lal, Dennis, Heinzen, Erin L., Dhindsa, Ryan S., Stanley, Kate E., Cavalleri, Gianpiero L., Hakonarson, Hakon, Helbig, Ingo, Krause, Roland, May, Patrick, Weckhuysen, Sarah, Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Cossette, Patrick, Cotsapas, Chris, Jonghe, Peter De, Dixon-Salazar, Tracy, Guerrini, Renzo, Kwan, Patrick, Marson, Anthony G., Stewart, Randy, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, McKenna, Kevin, Regan, Brigid M., Bellows, Susannah T., Leu, Costin, Bennett, Caitlin A., Johns, Esther M. C., Macdonald, Alexandra, Shilling, Hannah, Burgess, Rosemary, Weckhuysen, Dorien, Bahlo, Melanie, O’Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Sadoway, Tara R., Mo, Kelly, Krestel, Heinz, Gallati, Sabina, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Štěrbová, Katalin, Vlčková, Markéta, Sedláčková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Kunz, Wolfram S., Zsurka, Gábor, Elger, Christian E., Bauer, Jürgen, Rademacher, Michael, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, Baalen, Andreas Van, Spiczak, Sarah Von, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Kurlemann, Gerhard, Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, Hengsbach, Christian, Rau, Sarah, Maisch, Ana F., Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Schubert-Bast, Susanne, Schreiber, Herbert, Borggräfe, Ingo, Schankin, Christoph J., Mayer, Thomas, Korinthenberg, Rudolf, Brockmann, Knut, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Auvinen, Pia, Saarela, Anni, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Barišić, Nina, Delanty, Norman, Doherty, Colin P., Shukralla, Arif, McCormack, Mark, El-Naggar, Hany, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Zara, Federico, Iacomino, Michele, Madia, Francesca, Vari, Maria Stella, Mancardi, Maria Margherita, Salpietro, Vincenzo, Bisulli, Francesca, Tinuper, Paolo, Licchetta, Laura, Pippucci, Tommaso, Stipa, Carlotta, Minardi, Raffaella, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Marini, Carla, Suzuki, Toshimitsu, Inoue, Yushi, Yamakawa, Kazuhiro, Tumiene, Birute, Sadleir, Lynette G., King, Chontelle, Mountier, Emily, Caglayan, S. Hande, Arslan, Mutluay, Yapıcı, Zuhal, Yis, Uluc, Topaloglu, Pınar, Kara, Bulent, Turkdogan, Dilsad, Gundogdu-Eken, Aslı, Bebek, Nerses, Uğur-İşeri, Sibel, Baykan, Betül, Salman, Barış, Haryanyan, Garen, Yücesan, Emrah, Kesim, Yeşim, Özkara, Çiğdem, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Buono, Russell J., Ferraro, Thomas N., Sperling, Michael R., Lo, Warren, Privitera, Michael, French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Khankhanian, Pouya, Helbig, Katherine L., Ellis, Colin A., Spalletta, Gianfranco, Piras, Fabrizio, Piras, Federica, Gili, Tommaso, Ciullo, Valentina, Reif, Andreas, McQuillin, Andrew, Bass, Nick, McIntosh, Andrew, Blackwood, Douglas, Johnstone, Mandy, Palotie, Aarno, Pato, Michele T., Pato, Carlos N., Bromet, Evelyn J., Carvalho, Celia Barreto, Achtyes, Eric D., Azevedo, Maria Helena, Kotov, Roman, Lehrer, Douglas S., Malaspina, Dolores, Marder, Stephen R., Medeiros, Helena, Morley, Christopher P., Perkins, Diana O., Sobell, Janet L., Buckley, Peter F., Macciardi, Fabio, Rapaport, Mark H., Knowles, James A., Fanous, Ayman H., McCarroll, Steven A., Gupta, Namrata, Gabriel, Stacey B., Daly, Mark J., Lander, Eric S., Lowenstein, Daniel H., Goldstein, David B., Lerche, Holger, Berkovic, Samuel F., Neale, Benjamin M., Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Feng, Yen-Chen Anne, Howrigan, Daniel P., Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Singh, Tarjinder, Heyne, Henrike, Byrnes, Andrea, Churchhouse, Claire, Watts, Nick, Solomonson, Matthew, Lal, Dennis, Heinzen, Erin L., Dhindsa, Ryan S., Stanley, Kate E., Cavalleri, Gianpiero L., Hakonarson, Hakon, Helbig, Ingo, Krause, Roland, May, Patrick, Weckhuysen, Sarah, Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Cossette, Patrick, Cotsapas, Chris, Jonghe, Peter De, Dixon-Salazar, Tracy, Guerrini, Renzo, Kwan, Patrick, Marson, Anthony G., Stewart, Randy, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, McKenna, Kevin, Regan, Brigid M., Bellows, Susannah T., Leu, Costin, Bennett, Caitlin A., Johns, Esther M. C., Macdonald, Alexandra, Shilling, Hannah, Burgess, Rosemary, Weckhuysen, Dorien, Bahlo, Melanie, O’Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Sadoway, Tara R., Mo, Kelly, Krestel, Heinz, Gallati, Sabina, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Štěrbová, Katalin, Vlčková, Markéta, Sedláčková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Kunz, Wolfram S., Zsurka, Gábor, Elger, Christian E., Bauer, Jürgen, Rademacher, Michael, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, Baalen, Andreas Van, Spiczak, Sarah Von, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Kurlemann, Gerhard, Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, Hengsbach, Christian, Rau, Sarah, Maisch, Ana F., Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Schubert-Bast, Susanne, Schreiber, Herbert, Borggräfe, Ingo, Schankin, Christoph J., Mayer, Thomas, Korinthenberg, Rudolf, Brockmann, Knut, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Auvinen, Pia, Saarela, Anni, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Barišić, Nina, Delanty, Norman, Doherty, Colin P., Shukralla, Arif, McCormack, Mark, El-Naggar, Hany, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Zara, Federico, Iacomino, Michele, Madia, Francesca, Vari, Maria Stella, Mancardi, Maria Margherita, Salpietro, Vincenzo, Bisulli, Francesca, Tinuper, Paolo, Licchetta, Laura, Pippucci, Tommaso, Stipa, Carlotta, Minardi, Raffaella, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Marini, Carla, Suzuki, Toshimitsu, Inoue, Yushi, Yamakawa, Kazuhiro, Tumiene, Birute, Sadleir, Lynette G., King, Chontelle, Mountier, Emily, Caglayan, S. Hande, Arslan, Mutluay, Yapıcı, Zuhal, Yis, Uluc, Topaloglu, Pınar, Kara, Bulent, Turkdogan, Dilsad, Gundogdu-Eken, Aslı, Bebek, Nerses, Uğur-İşeri, Sibel, Baykan, Betül, Salman, Barış, Haryanyan, Garen, Yücesan, Emrah, Kesim, Yeşim, Özkara, Çiğdem, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Buono, Russell J., Ferraro, Thomas N., Sperling, Michael R., Lo, Warren, Privitera, Michael, French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Khankhanian, Pouya, Helbig, Katherine L., Ellis, Colin A., Spalletta, Gianfranco, Piras, Fabrizio, Piras, Federica, Gili, Tommaso, Ciullo, Valentina, Reif, Andreas, McQuillin, Andrew, Bass, Nick, McIntosh, Andrew, Blackwood, Douglas, Johnstone, Mandy, Palotie, Aarno, Pato, Michele T., Pato, Carlos N., Bromet, Evelyn J., Carvalho, Celia Barreto, Achtyes, Eric D., Azevedo, Maria Helena, Kotov, Roman, Lehrer, Douglas S., Malaspina, Dolores, Marder, Stephen R., Medeiros, Helena, Morley, Christopher P., Perkins, Diana O., Sobell, Janet L., Buckley, Peter F., Macciardi, Fabio, Rapaport, Mark H., Knowles, James A., Fanous, Ayman H., McCarroll, Steven A., Gupta, Namrata, Gabriel, Stacey B., Daly, Mark J., Lander, Eric S., Lowenstein, Daniel H., Goldstein, David B., Lerche, Holger, Berkovic, Samuel F., and Neale, Benjamin M.
Abstract: Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology.
Published: 2019

47. First M87 Event Horizon Telescope Results. I. The Shadow of the Supermassive Black Hole

Author: Akiyama, Kazunori, Alberdi, Antxon, Alef, Walter, Asada, Keiichi, Azulay, Rebecca, Baczko, Anne-Kathrin, Ball, David, Balokovic, Mislav, Barrett, John, Bintley, Dan, Blackburn, Lindy, Boland, Wilfred, Bouman, Katherine L., Bower, Geoffrey C., Bremer, Michael, Brinkerink, Christiaan D., Brissenden, Roger, Britzen, Silke, Broderick, Avery E., Broguiere, Dominique, Bronzwaer, Thomas, Byun, Do-Young, Carlstrom, John E., Chael, Andrew, Chan, Chi-kwan, Chatterjee, Shami, Chatterjee, Koushik, Chen, Ming-Tang, Chen, Yongjun, Cho, Ilje, Christian, Pierre, Conway, John E., Cordes, James M., Crew, Geoffrey B., Cui, Yuzhu, Davelaar, Jordy, De Laurentis, Mariafelicia, Deane, Roger, Dempsey, Jessica, Desvignes, Gregory, Dexter, Jason, Doeleman, Sheperd S., Eatough, Ralph P., Falcke, Heino, Fish, Vincent L., Fomalont, Ed, Fraga-Encinas, Raquel, Freeman, William T., Friberg, Per, Fromm, Christian M., Gomez, Jose L., Galison, Peter, Gammie, Charles F., Garcia, Roberto, Gentaz, Olivier, Georgiev, Boris, Goddi, Ciriaco, Gold, Roman, Gu, Minfeng, Gurwell, Mark, Hada, Kazuhiro, Hecht, Michael H., Hesper, Ronald, Ho, Luis C., Ho, Paul, Honma, Mareki, Huang, Chih-Wei L., Huang, Lei, Hughes, David H., Ikeda, Shiro, Inoue, Makoto, Issaoun, Sara, James, David J., Jannuzi, Buell T., Janssen, Michael, Jeter, Britton, Jiang, Wu, Johnson, Michael D., Jorstad, Svetlana, Jung, Taehyun, Karami, Mansour, Karuppusamy, Ramesh, Kawashima, Tomohisa, Keating, Garrett K., Kettenis, Mark, Kim, Jae-Young, Kim, Junhan, Kim, Jongsoo, Kino, Motoki, Koay, Jun Yi, Koch, Patrick M., Koyama, Shoko, Kramer, Michael, Kramer, Carsten, Krichbaum, Thomas P., Kuo, Cheng-Yu, Lauer, Tod R., Lee, Sang-Sung, Li, Yan-Rong, Li, Zhiyuan, Lindqvist, Michael, Liu, Kuo, Liuzzo, Elisabetta, Lo, Wen-Ping, Lobanov, Andrei P., Loinard, Laurent, Lonsdale, Colin, Lu, Ru-Sen, MacDonald, Nicholas R., Mao, Jirong, Markoff, Sera, Marrone, Daniel P., Marscher, Alan P., Marti-Vidal, Ivan, Matsushita, Satoki, Matthews, Lynn D., Medeiros, Lia, Menten, Karl M., Mizuno, Yosuke, Mizuno, Izumi, Moran, James M., Moriyama, Kotaro, Moscibrodzka, Monika, Mueller, Cornelia, Nagai, Hiroshi, Nagar, Neil M., Nakamura, Masanori, Narayan, Ramesh, Narayanan, Gopal, Natarajan, Iniyan, Neri, Roberto, Ni, Chunchong, Noutsos, Aristeidis, Okino, Hiroki, Olivares, Hector, Ortiz-Leon, Gisela N., Oyama, Tomoaki, Ozel, Feryal, Palumbo, Daniel C. M., Patel, Nimesh, Pen, Ue-Li, Pesce, Dominic W., Pietu, Vincent, Plambeck, Richard, PopStefanija, Aleksandar, Porth, Oliver, Prather, Ben, Preciado-Lopez, Jorge A., Psaltis, Dimitrios, Pu, Hung-Yi, Ramakrishnan, Venkatessh, Rao, Ramprasad, Rawlings, Mark G., Raymond, Alexander W., Rezzolla, Luciano, Ripperda, Bart, Roelofs, Freek, Rogers, Alan, Ros, Eduardo, Rose, Mel, Roshanineshat, Arash, Rottmann, Helge, Roy, Alan L., Ruszczyk, Chet, Ryan, Benjamin R., Rygl, Kazi L. J., Sanchez, Salvador, Sanchez-Arguelles, David, Sasada, Mahito, Savolainen, Tuomas, Schloerb, F. Peter, Schuster, Karl-Friedrich, Shao, Lijing, Shen, Zhiqiang, Small, Des, Sohn, Bong Won, SooHoo, Jason, Tazaki, Fumie, Tiede, Paul, Tilanus, Remo P. J., Titus, Michael, Toma, Kenji, Torne, Pablo, Trent, Tyler, Trippe, Sascha, Tsuda, Shuichiro, van Bemmel, Ilse, van Langevelde, Huib Jan, van Rossum, Daniel R., Wagner, Jan, Wardle, John, Weintroub, Jonathan, Wex, Norbert, Wharton, Robert, Wielgus, Maciek, Wong, George N., Wu, Qingwen, Young, Ken, Young, Andre, Younsi, Ziri, Yuan, Feng, Yuan, Ye-Fei, Zensus, J. Anton, Zhao, Guangyao, Zhao, Shan-Shan, Zhu, Ziyan, Algaba, Juan-Carlos, Allardi, Alexander, Amestica, Rodrigo, Anczarski, Jadyn, Bach, Uwe, Baganoff, Frederick K., Beaudoin, Christopher, Benson, Bradford A., Berthold, Ryan, Blanchard, Jay M., Blundell, Ray, Bustamente, Sandra, Cappallo, Roger, Castillo-Dominguez, Edgar, Chang, Chih-Cheng, Chang, Shu-Hao, Chang, Song-Chu, Chen, Chung-Chen, Chilson, Ryan, Chuter, Tim C., Rosado, Rodrigo Cordova, Coulson, Iain M., Crawford, Thomas M., Crowley, Joseph, David, John, Derome, Mark, Dexter, Matthew, Dornbusch, Sven, Dudevoir, Kevin A., Dzib, Sergio A., Eckart, Andreas, Eckert, Chris, Erickson, Neal R., Everett, Wendeline B., Faber, Aaron, Farah, Joseph R., Fath, Vernon, Folkers, Thomas W., Forbes, David C., Freund, Robert, Gomez-Ruiz, Arturo I., Gale, David M., Gao, Feng, Geertsema, Gertie, Graham, David A., Greer, Christopher H., Grosslein, Ronald, Gueth, Frederic, Haggard, Daryl, Halverson, Nils W., Han, Chih-Chiang, Han, Kuo-Chang, Hao, Jinchi, Hasegawa, Yutaka, Henning, Jason W., Hernandez-Gomez, Antonio, Herrero-Illana, Ruben, Heyminck, Stefan, Hirota, Akihiko, Hoge, James, Huang, Yau-De, Impellizzeri, C. M. Violette, Jiang, Homin, Kamble, Atish, Keisler, Ryan, Kimura, Kimihiro, Kono, Yusuke, Kubo, Derek, Kuroda, John, Lacasse, Richard, Laing, Robert A., Leitch, Erik M., Li, Chao-Te, Lin, Lupin C. -C., Liu, Ching-Tang, Liu, Kuan-Yu, Lu, Li-Ming, Marson, Ralph G., Martin-Cocher, Pierre L., Massingill, Kyle D., Matulonis, Callie, McColl, Martin P., McWhirter, Stephen R., Messias, Hugo, Meyer-Zhao, Zheng, Michalik, Daniel, Montana, Alfredo, Montgomerie, William, Mora-Klein, Matias, Muders, Dirk, Nadolski, Andrew, Navarro, Santiago, Neilsen, Joseph, Nguyen, Chi H., Nishioka, Hiroaki, Norton, Timothy, Nowak, Michael A., Nystrom, George, Ogawa, Hideo, Oshiro, Peter, Parsons, Harriet, Paine, Scott N., Penalver, Juan, Phillips, Neil M., Poirier, Michael, Pradel, Nicolas, Primiani, Rurik A., Raffin, Philippe A., Rahlin, Alexandra S., Reiland, George, Risacher, Christopher, Ruiz, Ignacio, Saez-Madain, Alejandro F., Sassella, Remi, Schellart, Pim, Shaw, Paul, Silva, Kevin M., Shiokawa, Hotaka, Smith, David R., Snow, William, Souccar, Kamal, Sousa, Don, Sridharan, T. K., Srinivasan, Ranjani, Stahm, William, Stark, Anthony A., Story, Kyle, Timmer, Sjoerd T., Vertatschitsch, Laura, Walther, Craig, Wei, Ta-Shun, Whitehorn, Nathan, Whitney, Alan R., Woody, David P., Wouterloot, Jan G. A., Wright, Melvin, Yamaguchi, Paul, Yu, Chen-Yu, Zeballos, Milagros, Zhang, Shuo, Ziurys, Lucy, Akiyama, Kazunori, Alberdi, Antxon, Alef, Walter, Asada, Keiichi, Azulay, Rebecca, Baczko, Anne-Kathrin, Ball, David, Balokovic, Mislav, Barrett, John, Bintley, Dan, Blackburn, Lindy, Boland, Wilfred, Bouman, Katherine L., Bower, Geoffrey C., Bremer, Michael, Brinkerink, Christiaan D., Brissenden, Roger, Britzen, Silke, Broderick, Avery E., Broguiere, Dominique, Bronzwaer, Thomas, Byun, Do-Young, Carlstrom, John E., Chael, Andrew, Chan, Chi-kwan, Chatterjee, Shami, Chatterjee, Koushik, Chen, Ming-Tang, Chen, Yongjun, Cho, Ilje, Christian, Pierre, Conway, John E., Cordes, James M., Crew, Geoffrey B., Cui, Yuzhu, Davelaar, Jordy, De Laurentis, Mariafelicia, Deane, Roger, Dempsey, Jessica, Desvignes, Gregory, Dexter, Jason, Doeleman, Sheperd S., Eatough, Ralph P., Falcke, Heino, Fish, Vincent L., Fomalont, Ed, Fraga-Encinas, Raquel, Freeman, William T., Friberg, Per, Fromm, Christian M., Gomez, Jose L., Galison, Peter, Gammie, Charles F., Garcia, Roberto, Gentaz, Olivier, Georgiev, Boris, Goddi, Ciriaco, Gold, Roman, Gu, Minfeng, Gurwell, Mark, Hada, Kazuhiro, Hecht, Michael H., Hesper, Ronald, Ho, Luis C., Ho, Paul, Honma, Mareki, Huang, Chih-Wei L., Huang, Lei, Hughes, David H., Ikeda, Shiro, Inoue, Makoto, Issaoun, Sara, James, David J., Jannuzi, Buell T., Janssen, Michael, Jeter, Britton, Jiang, Wu, Johnson, Michael D., Jorstad, Svetlana, Jung, Taehyun, Karami, Mansour, Karuppusamy, Ramesh, Kawashima, Tomohisa, Keating, Garrett K., Kettenis, Mark, Kim, Jae-Young, Kim, Junhan, Kim, Jongsoo, Kino, Motoki, Koay, Jun Yi, Koch, Patrick M., Koyama, Shoko, Kramer, Michael, Kramer, Carsten, Krichbaum, Thomas P., Kuo, Cheng-Yu, Lauer, Tod R., Lee, Sang-Sung, Li, Yan-Rong, Li, Zhiyuan, Lindqvist, Michael, Liu, Kuo, Liuzzo, Elisabetta, Lo, Wen-Ping, Lobanov, Andrei P., Loinard, Laurent, Lonsdale, Colin, Lu, Ru-Sen, MacDonald, Nicholas R., Mao, Jirong, Markoff, Sera, Marrone, Daniel P., Marscher, Alan P., Marti-Vidal, Ivan, Matsushita, Satoki, Matthews, Lynn D., Medeiros, Lia, Menten, Karl M., Mizuno, Yosuke, Mizuno, Izumi, Moran, James M., Moriyama, Kotaro, Moscibrodzka, Monika, Mueller, Cornelia, Nagai, Hiroshi, Nagar, Neil M., Nakamura, Masanori, Narayan, Ramesh, Narayanan, Gopal, Natarajan, Iniyan, Neri, Roberto, Ni, Chunchong, Noutsos, Aristeidis, Okino, Hiroki, Olivares, Hector, Ortiz-Leon, Gisela N., Oyama, Tomoaki, Ozel, Feryal, Palumbo, Daniel C. M., Patel, Nimesh, Pen, Ue-Li, Pesce, Dominic W., Pietu, Vincent, Plambeck, Richard, PopStefanija, Aleksandar, Porth, Oliver, Prather, Ben, Preciado-Lopez, Jorge A., Psaltis, Dimitrios, Pu, Hung-Yi, Ramakrishnan, Venkatessh, Rao, Ramprasad, Rawlings, Mark G., Raymond, Alexander W., Rezzolla, Luciano, Ripperda, Bart, Roelofs, Freek, Rogers, Alan, Ros, Eduardo, Rose, Mel, Roshanineshat, Arash, Rottmann, Helge, Roy, Alan L., Ruszczyk, Chet, Ryan, Benjamin R., Rygl, Kazi L. J., Sanchez, Salvador, Sanchez-Arguelles, David, Sasada, Mahito, Savolainen, Tuomas, Schloerb, F. Peter, Schuster, Karl-Friedrich, Shao, Lijing, Shen, Zhiqiang, Small, Des, Sohn, Bong Won, SooHoo, Jason, Tazaki, Fumie, Tiede, Paul, Tilanus, Remo P. J., Titus, Michael, Toma, Kenji, Torne, Pablo, Trent, Tyler, Trippe, Sascha, Tsuda, Shuichiro, van Bemmel, Ilse, van Langevelde, Huib Jan, van Rossum, Daniel R., Wagner, Jan, Wardle, John, Weintroub, Jonathan, Wex, Norbert, Wharton, Robert, Wielgus, Maciek, Wong, George N., Wu, Qingwen, Young, Ken, Young, Andre, Younsi, Ziri, Yuan, Feng, Yuan, Ye-Fei, Zensus, J. Anton, Zhao, Guangyao, Zhao, Shan-Shan, Zhu, Ziyan, Algaba, Juan-Carlos, Allardi, Alexander, Amestica, Rodrigo, Anczarski, Jadyn, Bach, Uwe, Baganoff, Frederick K., Beaudoin, Christopher, Benson, Bradford A., Berthold, Ryan, Blanchard, Jay M., Blundell, Ray, Bustamente, Sandra, Cappallo, Roger, Castillo-Dominguez, Edgar, Chang, Chih-Cheng, Chang, Shu-Hao, Chang, Song-Chu, Chen, Chung-Chen, Chilson, Ryan, Chuter, Tim C., Rosado, Rodrigo Cordova, Coulson, Iain M., Crawford, Thomas M., Crowley, Joseph, David, John, Derome, Mark, Dexter, Matthew, Dornbusch, Sven, Dudevoir, Kevin A., Dzib, Sergio A., Eckart, Andreas, Eckert, Chris, Erickson, Neal R., Everett, Wendeline B., Faber, Aaron, Farah, Joseph R., Fath, Vernon, Folkers, Thomas W., Forbes, David C., Freund, Robert, Gomez-Ruiz, Arturo I., Gale, David M., Gao, Feng, Geertsema, Gertie, Graham, David A., Greer, Christopher H., Grosslein, Ronald, Gueth, Frederic, Haggard, Daryl, Halverson, Nils W., Han, Chih-Chiang, Han, Kuo-Chang, Hao, Jinchi, Hasegawa, Yutaka, Henning, Jason W., Hernandez-Gomez, Antonio, Herrero-Illana, Ruben, Heyminck, Stefan, Hirota, Akihiko, Hoge, James, Huang, Yau-De, Impellizzeri, C. M. Violette, Jiang, Homin, Kamble, Atish, Keisler, Ryan, Kimura, Kimihiro, Kono, Yusuke, Kubo, Derek, Kuroda, John, Lacasse, Richard, Laing, Robert A., Leitch, Erik M., Li, Chao-Te, Lin, Lupin C. -C., Liu, Ching-Tang, Liu, Kuan-Yu, Lu, Li-Ming, Marson, Ralph G., Martin-Cocher, Pierre L., Massingill, Kyle D., Matulonis, Callie, McColl, Martin P., McWhirter, Stephen R., Messias, Hugo, Meyer-Zhao, Zheng, Michalik, Daniel, Montana, Alfredo, Montgomerie, William, Mora-Klein, Matias, Muders, Dirk, Nadolski, Andrew, Navarro, Santiago, Neilsen, Joseph, Nguyen, Chi H., Nishioka, Hiroaki, Norton, Timothy, Nowak, Michael A., Nystrom, George, Ogawa, Hideo, Oshiro, Peter, Parsons, Harriet, Paine, Scott N., Penalver, Juan, Phillips, Neil M., Poirier, Michael, Pradel, Nicolas, Primiani, Rurik A., Raffin, Philippe A., Rahlin, Alexandra S., Reiland, George, Risacher, Christopher, Ruiz, Ignacio, Saez-Madain, Alejandro F., Sassella, Remi, Schellart, Pim, Shaw, Paul, Silva, Kevin M., Shiokawa, Hotaka, Smith, David R., Snow, William, Souccar, Kamal, Sousa, Don, Sridharan, T. K., Srinivasan, Ranjani, Stahm, William, Stark, Anthony A., Story, Kyle, Timmer, Sjoerd T., Vertatschitsch, Laura, Walther, Craig, Wei, Ta-Shun, Whitehorn, Nathan, Whitney, Alan R., Woody, David P., Wouterloot, Jan G. A., Wright, Melvin, Yamaguchi, Paul, Yu, Chen-Yu, Zeballos, Milagros, Zhang, Shuo, and Ziurys, Lucy
Abstract: When surrounded by a transparent emission region, black holes are expected to reveal a dark shadow caused by gravitational light bending and photon capture at the event horizon. To image and study this phenomenon, we have assembled the Event Horizon Telescope, a global very long baseline interferometry array observing at a wavelength of 1.3 mm. This allows us to reconstruct event-horizon-scale images of the supermassive black hole candidate in the center of the giant elliptical galaxy M87. We have resolved the central compact radio source as an asymmetric bright emission ring with a diameter of 42 +/- 3 mu as, which is circular and encompasses a central depression in brightness with a flux ratio greater than or similar to 10: 1. The emission ring is recovered using different calibration and imaging schemes, with its diameter and width remaining stable over four different observations carried out in different days. Overall, the observed image is consistent with expectations for the shadow of a Kerr black hole as predicted by general relativity. The asymmetry in brightness in the ring can be explained in terms of relativistic beaming of the emission from a plasma rotating close to the speed of light around a black hole. We compare our images to an extensive library of ray-traced general-relativistic magnetohydrodynamic simulations of black holes and derive a central mass of M = (6.5 +/- 0.7) x 10(9) M-circle dot. Our radio-wave observations thus provide powerful evidence for the presence of supermassive black holes in centers of galaxies and as the central engines of active galactic nuclei. They also present a new tool to explore gravity in its most extreme limit and on a mass scale that was so far not accessible.
Published: 2019

48. Rare coding variants in genes encoding GABA(A) receptors in genetic generalised epilepsies: an exome-based case-control study

Author: May, Patrick, Girard, Simon, Harrer, Merle, Bobbili, Dheeraj R., Schubert, Julian, Wolking, Stefan, Becker, Felicitas, Lachance-Touchette, Pamela, Meloche, Caroline, Gravel, Micheline, Niturad, Cristina E., Knaus, Julia, De Kovel, Carolien, Toliat, Mohamad, Polvi, Anne, Iacomino, Michele, Guerrero-Lopez, Rosa, Baulac, Stephanie, Marini, Carla, Thiele, Holger, Altmueller, Janine, Jabbari, Kamel, Ruppert, Ann-Kathrin, Jurkowski, Wiktor, Lal, Dennis, Rusconi, Raffaella, Cestele, Sandrine, Terragni, Benedetta, Coombs, Ian D., Reid, Christopher A., Striano, Pasquale, Caglayan, Hande, Siren, Auli, Everett, Kate, Moller, Rikke S., Hjalgrim, Helle, Muhle, Hiltrud, Helbig, Ingo, Kunz, Wolfram S., Weber, Yvonne G., Weckhuysen, Sarah, De Jonghe, Peter, Sisodiya, Sanjay M., Nabbout, Rima, Franceschetti, Silvana, Coppola, Antonietta, Vari, Maria S., Trenite, Dorothee Kasteleijn-Nolst, Baykan, Betul, Ozbek, Ugur, Bebek, Nerses, Klein, Karl M., Rosenow, Felix, Nguyen, Dang K., Dubeau, Francois, Carmant, Lionel, Lortie, Anne, Desbiens, Richard, Clement, Jean-Francois, Cieuta-Walti, Cecile, Sills, Graeme J., Auce, Pauls, Francis, Ben, Johnson, Michael R., Marson, Anthony G., Berghuis, Bianca, Sander, Josemir W., Avbersek, Andreja, McCormack, Mark, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Krenn, Martin, Zimprich, Fritz, Peter, Sarah, Nikanorova, Marina, Kraaij, Robert, van Rooij, Jeroen, Balling, Rudi, Ikram, M. Arfan, Uitterlinden, Andre G., Avanzini, Giuliano, Schorge, Stephanie, Petrou, Steven, Mantegazza, Massimo, Sander, Thomas, LeGuern, Eric, Serratosa, Jose M., Koeleman, Bobby P. C., Palotie, Aarno, Lehesjoki, Anna-Elina, Nothnagel, Michael, Nuernberg, Peter, Maljevic, Snezana, Zara, Federico, Cossette, Patrick, Krause, Roland, Lerche, Holger, May, Patrick, Girard, Simon, Harrer, Merle, Bobbili, Dheeraj R., Schubert, Julian, Wolking, Stefan, Becker, Felicitas, Lachance-Touchette, Pamela, Meloche, Caroline, Gravel, Micheline, Niturad, Cristina E., Knaus, Julia, De Kovel, Carolien, Toliat, Mohamad, Polvi, Anne, Iacomino, Michele, Guerrero-Lopez, Rosa, Baulac, Stephanie, Marini, Carla, Thiele, Holger, Altmueller, Janine, Jabbari, Kamel, Ruppert, Ann-Kathrin, Jurkowski, Wiktor, Lal, Dennis, Rusconi, Raffaella, Cestele, Sandrine, Terragni, Benedetta, Coombs, Ian D., Reid, Christopher A., Striano, Pasquale, Caglayan, Hande, Siren, Auli, Everett, Kate, Moller, Rikke S., Hjalgrim, Helle, Muhle, Hiltrud, Helbig, Ingo, Kunz, Wolfram S., Weber, Yvonne G., Weckhuysen, Sarah, De Jonghe, Peter, Sisodiya, Sanjay M., Nabbout, Rima, Franceschetti, Silvana, Coppola, Antonietta, Vari, Maria S., Trenite, Dorothee Kasteleijn-Nolst, Baykan, Betul, Ozbek, Ugur, Bebek, Nerses, Klein, Karl M., Rosenow, Felix, Nguyen, Dang K., Dubeau, Francois, Carmant, Lionel, Lortie, Anne, Desbiens, Richard, Clement, Jean-Francois, Cieuta-Walti, Cecile, Sills, Graeme J., Auce, Pauls, Francis, Ben, Johnson, Michael R., Marson, Anthony G., Berghuis, Bianca, Sander, Josemir W., Avbersek, Andreja, McCormack, Mark, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Krenn, Martin, Zimprich, Fritz, Peter, Sarah, Nikanorova, Marina, Kraaij, Robert, van Rooij, Jeroen, Balling, Rudi, Ikram, M. Arfan, Uitterlinden, Andre G., Avanzini, Giuliano, Schorge, Stephanie, Petrou, Steven, Mantegazza, Massimo, Sander, Thomas, LeGuern, Eric, Serratosa, Jose M., Koeleman, Bobby P. C., Palotie, Aarno, Lehesjoki, Anna-Elina, Nothnagel, Michael, Nuernberg, Peter, Maljevic, Snezana, Zara, Federico, Cossette, Patrick, Krause, Roland, and Lerche, Holger
Abstract: Background Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy. Methods For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABA(A) receptors and was compared to the respective GABA(A) receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes. Findings Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABA(A) receptors in cases (odds ratio [OR] 2.40 [95% CI 1.41-4.10]; p(Nonsyn)=0.0014, adjusted p(Nonsyn)=0.019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1.46 [95% CI 1.05-2.03]; p(Nonsyn)=0.0081, adjusted p(Nonsyn)=0.016). Comparison of genes encoding GABA(A) receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare missense variants for 15 GABA(A) receptor genes in cases compare
Published: 2018

49. Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies

Author: Abou-Khalil, Bassel, Auce, Pauls, Avbersek, Andreja, Bahlo, Melanie, Balding, David J., Bast, Thomas, Baum, Larry, Becker, Albert J., Becker, Felicitas, Berghuis, Bianca, Berkovic, Samuel F., Boysen, Katja E., Bradfield, Jonathan P., Brody, Lawrence C., Buono, Russell J., Campbell, Ellen, Cascino, Gregory D., Catarino, Claudia B., Cavalleri, Gianpiero L., Cherny, Stacey S., Chinthapalli, Krishna, Coffey, Alison J., Compston, Alastair, Coppola, Antonietta, Cossette, Patrick, Craig, John J., de Haan, Gerrit-Jan, De Jonghe, Peter, de Kovel, Carolien G. F., Delanty, Norman, Depondt, Chantal, Devinsky, Orrin, Dlugos, Dennis J., Doherty, Colin P., Elger, Christian E., Eriksson, Johan G., Ferraro, Thomas N., Feucht, Martha, Francis, Ben, Franke, Andre, French, Jacqueline A., Freytag, Saskia, Gaus, Verena, Geller, Eric B., Gieger, Christian, Glauser, Tracy, Glynn, Simon, Goldstein, David B., Gui, Hongsheng, Guo, Youling, Haas, Kevin F., Hakonarson, Hakon, Hallmann, Kerstin, Haut, Sheryl, Heinzen, Erin L., Helbig, Ingo, Hengsbach, Christian, Hjalgrim, Helle, Iacomino, Michele, Ingason, Andres, Jamnadas-Khoda, Jennifer, Johnson, Michael R., Kalviainen, Reetta, Kantanen, Anne-Mari, Kasperaviciute, Dalia, Trenite, Dorothee Kasteleijn-Nolst, Kirsch, Heidi E., Knowlton, Robert C., Koeleman, Bobby P. C., Krause, Roland, Krenn, Martin, Kunz, Wolfram S., Kuzniecky, Ruben, Kwan, Patrick, Lal, Dennis, Lau, Yu-Lung, Lehesjoki, Anna-Elina, Lerche, Holger, Leu, Costin, Lieb, Wolfgang, Lindhout, Dick, Lo, Warren D., Lopes-Cendes, Iscia, Lowenstein, Daniel H., Malovini, Alberto, Marson, Anthony G., Mayer, Thomas, McCormack, Mark, Mills, James L., Mirza, Nasir, Moerzinger, Martina, Moller, Rikke S., Molloy, Anne M., Muhle, Hiltrud, Newton, Mark, Ng, Ping-Wing, Noethen, Markus M., Nuernberg, Peter, O'Brien, Terence J., Oliver, Karen L., Palotie, Aarno, Pangilinan, Faith, Peter, Sarah, Petrovski, Slave, Poduri, Annapurna, Privitera, Michael, Radtke, Rodney, Rau, Sarah, Reif, Philipp S., Reinthaler, Eva M., Rosenow, Felix, Sander, Josemir W., Sander, Thomas, Scattergood, Theresa, Schachter, Steven C., Schankin, Christoph J., Scheffer, Ingrid E., Schmitz, Bettina, Schoch, Susanne, Sham, Pak C., Shih, Jerry J., Sills, Graeme J., Sisodiya, Sanjay M., Slattery, Lisa, Smith, Alexander, Smith, David F., Smith, Michael C., Smith, Philip E., Sonsma, Anja C. M., Speed, Doug, Sperling, Michael R., Steinhoff, Bernhard J., Stephani, Ulrich, Stevelink, Remi, Strauch, Konstantin, Striano, Pasquale, Stroink, Hans, Surges, Rainer, Tan, K. Meng, Thio, Liu Lin, Thomas, G. Neil, Todaro, Marian, Tozzi, Rossana, Vari, Maria S., Vining, Eileen P. G., Visscher, Frank, von Spiczak, Sarah, Walley, Nicole M., Weber, Yvonne G., Wei, Zhi, Weisenberg, Judith, Whelan, Christopher D., Widdess-Walsh, Peter, Wolff, Markus, Wolking, Stefan, Yang, Wanling, Zara, Federico, Zimprich, Fritz, Abou-Khalil, Bassel, Auce, Pauls, Avbersek, Andreja, Bahlo, Melanie, Balding, David J., Bast, Thomas, Baum, Larry, Becker, Albert J., Becker, Felicitas, Berghuis, Bianca, Berkovic, Samuel F., Boysen, Katja E., Bradfield, Jonathan P., Brody, Lawrence C., Buono, Russell J., Campbell, Ellen, Cascino, Gregory D., Catarino, Claudia B., Cavalleri, Gianpiero L., Cherny, Stacey S., Chinthapalli, Krishna, Coffey, Alison J., Compston, Alastair, Coppola, Antonietta, Cossette, Patrick, Craig, John J., de Haan, Gerrit-Jan, De Jonghe, Peter, de Kovel, Carolien G. F., Delanty, Norman, Depondt, Chantal, Devinsky, Orrin, Dlugos, Dennis J., Doherty, Colin P., Elger, Christian E., Eriksson, Johan G., Ferraro, Thomas N., Feucht, Martha, Francis, Ben, Franke, Andre, French, Jacqueline A., Freytag, Saskia, Gaus, Verena, Geller, Eric B., Gieger, Christian, Glauser, Tracy, Glynn, Simon, Goldstein, David B., Gui, Hongsheng, Guo, Youling, Haas, Kevin F., Hakonarson, Hakon, Hallmann, Kerstin, Haut, Sheryl, Heinzen, Erin L., Helbig, Ingo, Hengsbach, Christian, Hjalgrim, Helle, Iacomino, Michele, Ingason, Andres, Jamnadas-Khoda, Jennifer, Johnson, Michael R., Kalviainen, Reetta, Kantanen, Anne-Mari, Kasperaviciute, Dalia, Trenite, Dorothee Kasteleijn-Nolst, Kirsch, Heidi E., Knowlton, Robert C., Koeleman, Bobby P. C., Krause, Roland, Krenn, Martin, Kunz, Wolfram S., Kuzniecky, Ruben, Kwan, Patrick, Lal, Dennis, Lau, Yu-Lung, Lehesjoki, Anna-Elina, Lerche, Holger, Leu, Costin, Lieb, Wolfgang, Lindhout, Dick, Lo, Warren D., Lopes-Cendes, Iscia, Lowenstein, Daniel H., Malovini, Alberto, Marson, Anthony G., Mayer, Thomas, McCormack, Mark, Mills, James L., Mirza, Nasir, Moerzinger, Martina, Moller, Rikke S., Molloy, Anne M., Muhle, Hiltrud, Newton, Mark, Ng, Ping-Wing, Noethen, Markus M., Nuernberg, Peter, O'Brien, Terence J., Oliver, Karen L., Palotie, Aarno, Pangilinan, Faith, Peter, Sarah, Petrovski, Slave, Poduri, Annapurna, Privitera, Michael, Radtke, Rodney, Rau, Sarah, Reif, Philipp S., Reinthaler, Eva M., Rosenow, Felix, Sander, Josemir W., Sander, Thomas, Scattergood, Theresa, Schachter, Steven C., Schankin, Christoph J., Scheffer, Ingrid E., Schmitz, Bettina, Schoch, Susanne, Sham, Pak C., Shih, Jerry J., Sills, Graeme J., Sisodiya, Sanjay M., Slattery, Lisa, Smith, Alexander, Smith, David F., Smith, Michael C., Smith, Philip E., Sonsma, Anja C. M., Speed, Doug, Sperling, Michael R., Steinhoff, Bernhard J., Stephani, Ulrich, Stevelink, Remi, Strauch, Konstantin, Striano, Pasquale, Stroink, Hans, Surges, Rainer, Tan, K. Meng, Thio, Liu Lin, Thomas, G. Neil, Todaro, Marian, Tozzi, Rossana, Vari, Maria S., Vining, Eileen P. G., Visscher, Frank, von Spiczak, Sarah, Walley, Nicole M., Weber, Yvonne G., Wei, Zhi, Weisenberg, Judith, Whelan, Christopher D., Widdess-Walsh, Peter, Wolff, Markus, Wolking, Stefan, Yang, Wanling, Zara, Federico, and Zimprich, Fritz
Abstract: The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology.
Published: 2018

50. Rare coding variants in genes encoding GABA(A) receptors in genetic generalised epilepsies: an exome-based case-control study

Author: May, Patrick, Girard, Simon, Harrer, Merle, Bobbili, Dheeraj R., Schubert, Julian, Wolking, Stefan, Becker, Felicitas, Lachance-Touchette, Pamela, Meloche, Caroline, Gravel, Micheline, Niturad, Cristina E., Knaus, Julia, De Kovel, Carolien, Toliat, Mohamad, Polvi, Anne, Iacomino, Michele, Guerrero-Lopez, Rosa, Baulac, Stephanie, Marini, Carla, Thiele, Holger, Altmueller, Janine, Jabbari, Kamel, Ruppert, Ann-Kathrin, Jurkowski, Wiktor, Lal, Dennis, Rusconi, Raffaella, Cestele, Sandrine, Terragni, Benedetta, Coombs, Ian D., Reid, Christopher A., Striano, Pasquale, Caglayan, Hande, Siren, Auli, Everett, Kate, Moller, Rikke S., Hjalgrim, Helle, Muhle, Hiltrud, Helbig, Ingo, Kunz, Wolfram S., Weber, Yvonne G., Weckhuysen, Sarah, De Jonghe, Peter, Sisodiya, Sanjay M., Nabbout, Rima, Franceschetti, Silvana, Coppola, Antonietta, Vari, Maria S., Trenite, Dorothee Kasteleijn-Nolst, Baykan, Betul, Ozbek, Ugur, Bebek, Nerses, Klein, Karl M., Rosenow, Felix, Nguyen, Dang K., Dubeau, Francois, Carmant, Lionel, Lortie, Anne, Desbiens, Richard, Clement, Jean-Francois, Cieuta-Walti, Cecile, Sills, Graeme J., Auce, Pauls, Francis, Ben, Johnson, Michael R., Marson, Anthony G., Berghuis, Bianca, Sander, Josemir W., Avbersek, Andreja, McCormack, Mark, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Krenn, Martin, Zimprich, Fritz, Peter, Sarah, Nikanorova, Marina, Kraaij, Robert, van Rooij, Jeroen, Balling, Rudi, Ikram, M. Arfan, Uitterlinden, Andre G., Avanzini, Giuliano, Schorge, Stephanie, Petrou, Steven, Mantegazza, Massimo, Sander, Thomas, LeGuern, Eric, Serratosa, Jose M., Koeleman, Bobby P. C., Palotie, Aarno, Lehesjoki, Anna-Elina, Nothnagel, Michael, Nuernberg, Peter, Maljevic, Snezana, Zara, Federico, Cossette, Patrick, Krause, Roland, Lerche, Holger, May, Patrick, Girard, Simon, Harrer, Merle, Bobbili, Dheeraj R., Schubert, Julian, Wolking, Stefan, Becker, Felicitas, Lachance-Touchette, Pamela, Meloche, Caroline, Gravel, Micheline, Niturad, Cristina E., Knaus, Julia, De Kovel, Carolien, Toliat, Mohamad, Polvi, Anne, Iacomino, Michele, Guerrero-Lopez, Rosa, Baulac, Stephanie, Marini, Carla, Thiele, Holger, Altmueller, Janine, Jabbari, Kamel, Ruppert, Ann-Kathrin, Jurkowski, Wiktor, Lal, Dennis, Rusconi, Raffaella, Cestele, Sandrine, Terragni, Benedetta, Coombs, Ian D., Reid, Christopher A., Striano, Pasquale, Caglayan, Hande, Siren, Auli, Everett, Kate, Moller, Rikke S., Hjalgrim, Helle, Muhle, Hiltrud, Helbig, Ingo, Kunz, Wolfram S., Weber, Yvonne G., Weckhuysen, Sarah, De Jonghe, Peter, Sisodiya, Sanjay M., Nabbout, Rima, Franceschetti, Silvana, Coppola, Antonietta, Vari, Maria S., Trenite, Dorothee Kasteleijn-Nolst, Baykan, Betul, Ozbek, Ugur, Bebek, Nerses, Klein, Karl M., Rosenow, Felix, Nguyen, Dang K., Dubeau, Francois, Carmant, Lionel, Lortie, Anne, Desbiens, Richard, Clement, Jean-Francois, Cieuta-Walti, Cecile, Sills, Graeme J., Auce, Pauls, Francis, Ben, Johnson, Michael R., Marson, Anthony G., Berghuis, Bianca, Sander, Josemir W., Avbersek, Andreja, McCormack, Mark, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Krenn, Martin, Zimprich, Fritz, Peter, Sarah, Nikanorova, Marina, Kraaij, Robert, van Rooij, Jeroen, Balling, Rudi, Ikram, M. Arfan, Uitterlinden, Andre G., Avanzini, Giuliano, Schorge, Stephanie, Petrou, Steven, Mantegazza, Massimo, Sander, Thomas, LeGuern, Eric, Serratosa, Jose M., Koeleman, Bobby P. C., Palotie, Aarno, Lehesjoki, Anna-Elina, Nothnagel, Michael, Nuernberg, Peter, Maljevic, Snezana, Zara, Federico, Cossette, Patrick, Krause, Roland, and Lerche, Holger
Abstract: Background Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy. Methods For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABA(A) receptors and was compared to the respective GABA(A) receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes. Findings Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABA(A) receptors in cases (odds ratio [OR] 2.40 [95% CI 1.41-4.10]; p(Nonsyn)=0.0014, adjusted p(Nonsyn)=0.019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1.46 [95% CI 1.05-2.03]; p(Nonsyn)=0.0081, adjusted p(Nonsyn)=0.016). Comparison of genes encoding GABA(A) receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare missense variants for 15 GABA(A) receptor genes in cases compare
Published: 2018

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Publication Year Range

Publication Type

Database

Publisher

96 results on '"Marson A. G."'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources