Author: "L. Hauser" / Language: english - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"L. Hauser"' showing total 445 results

Start Over Author "L. Hauser" Language english

445 results on '"L. Hauser"'

1. Effect of Plyometric Jump Training on Skeletal Muscle Hypertrophy in Healthy Individuals: A Systematic Review With Multilevel Meta-Analysis

Author: F. Arntz, B. Mkaouer, A. Markov, B. J. Schoenfeld, J. Moran, R. Ramirez-Campillo, M. Behrens, P. Baumert, R. M. Erskine, L. Hauser, and H. Chaabene
Subjects: muscle tissue, muscle strength, stretch shortening cycle exercise, muscle growth, human physical conditioning, youth sports, Physiology, QP1-981
Abstract: Objective: To examine the effect of plyometric jump training on skeletal muscle hypertrophy in healthy individuals.Methods: A systematic literature search was conducted in the databases PubMed, SPORTDiscus, Web of Science, and Cochrane Library up to September 2021.Results: Fifteen studies met the inclusion criteria. The main overall finding (44 effect sizes across 15 clusters median = 2, range = 1–15 effects per cluster) indicated that plyometric jump training had small to moderate effects [standardised mean difference (SMD) = 0.47 (95% CIs = 0.23–0.71); p < 0.001] on skeletal muscle hypertrophy. Subgroup analyses for training experience revealed trivial to large effects in non-athletes [SMD = 0.55 (95% CIs = 0.18–0.93); p = 0.007] and trivial to moderate effects in athletes [SMD = 0.33 (95% CIs = 0.16–0.51); p = 0.001]. Regarding muscle groups, results showed moderate effects for the knee extensors [SMD = 0.72 (95% CIs = 0.66–0.78), p < 0.001] and equivocal effects for the plantar flexors [SMD = 0.65 (95% CIs = −0.25–1.55); p = 0.143]. As to the assessment methods of skeletal muscle hypertrophy, findings indicated trivial to small effects for prediction equations [SMD = 0.29 (95% CIs = 0.16–0.42); p < 0.001] and moderate-to-large effects for ultrasound imaging [SMD = 0.74 (95% CIs = 0.59–0.89); p < 0.001]. Meta-regression analysis indicated that the weekly session frequency moderates the effect of plyometric jump training on skeletal muscle hypertrophy, with a higher weekly session frequency inducing larger hypertrophic gains [β = 0.3233 (95% CIs = 0.2041–0.4425); p < 0.001]. We found no clear evidence that age, sex, total training period, single session duration, or the number of jumps per week moderate the effect of plyometric jump training on skeletal muscle hypertrophy [β = −0.0133 to 0.0433 (95% CIs = −0.0387 to 0.1215); p = 0.101–0.751].Conclusion: Plyometric jump training can induce skeletal muscle hypertrophy, regardless of age and sex. There is evidence for relatively larger effects in non-athletes compared with athletes. Further, the weekly session frequency seems to moderate the effect of plyometric jump training on skeletal muscle hypertrophy, whereby more frequent weekly plyometric jump training sessions elicit larger hypertrophic adaptations.
Published: 2022
Full Text: View/download PDF

2. Long-term analysis of infections and associated risk factors in patients with multiple sclerosis treated with ocrelizumab: pooled analysis of 13 interventional clinical trials

Author: Tobias Derfuss, Robert Bermel, Chien-Ju Lin, Stephen L. Hauser, Ludwig Kappos, Timothy Vollmer, Giancarlo Comi, Gavin Giovannoni, Hans-Peter Hartung, Martin S. Weber, Jianmei Wang, Nikki Jessop, Cathy Chognot, Licinio Craveiro, and Amit Bar-Or
Subjects: Neurology. Diseases of the nervous system, RC346-429
Abstract: Background: Patients with multiple sclerosis (PwMS) have an increased risk of infections. Objectives: To characterize incidence, clinical characteristics, outcomes and risk factors of infections, and serious infections (SIs) in ocrelizumab (OCR)-treated PwMS. Design: Post-hoc analysis of pooled data from 6155 patients in 13 clinical trials. Methods: Descriptive analyses of clinical characteristics and outcomes were reported over ⩽14 years. A Poisson Generalized Estimating Equation model was constructed to examine risk factors in a subgroup of patients with longer exposure to OCR ( n = 2092). Results: Over a median (max) treatment period of 3.7 (13.9) years, 420/6155 patients (6.8%) experienced 583 SIs, excluding coronavirus disease 2019. Incidence rates in relapsing multiple sclerosis (RMS; 1.50 per 100 patient years [95% confidence interval (CI): 1.34–1.68]) and progressive multiple sclerosis (PMS; 3.70 [95% CI: 3.27–4.17]) remained stable over this period. Lower respiratory tract, urinary tract, abdominal and gastrointestinal, and skin infections were the most commonly reported SIs. Most SIs (~90%) resolved, and treatment with OCR was continued in >80% of cases. The presence of 1 or ⩾2 comorbidities (rate ratio = 1.66, 2.73, respectively), recent relapse activity (2.06), and Expanded Disability Status Scale (EDSS) score ⩾6.0 (2.02) were significant risk factors for SIs in patients with RMS treated over a median (max) period of 8.3 (11.2) years. In patients with primary PMS treated over a median (max) period of 7.1 (11.8) years, an EDSS score ⩾6.0 was associated with the greatest risk of SIs, a 4-fold increase (rate ratio, 4.31), followed by abnormal immunoglobulin (Ig)M levels (1.89), the presence of ⩾2 comorbidities (1.80), and having overweight/obesity (1.46). Time on OCR and abnormal IgG levels were not significantly associated with an increased SI risk. Conclusion: Continuous long-term treatment with OCR is associated with a manageable infection risk profile. Optimal disease control and addressing modifiable risk factors may reduce the risk of infections.
Published: 2024
Full Text: View/download PDF

3. Inflammatory and neurodegenerative serum protein biomarkers increase sensitivity to detect clinical and radiographic disease activity in multiple sclerosis

Author: Tanuja Chitnis, Ferhan Qureshi, Victor M. Gehman, Michael Becich, Riley Bove, Bruce A. C. Cree, Refujia Gomez, Stephen L. Hauser, Roland G. Henry, Amal Katrib, Hrishikesh Lokhande, Anu Paul, Stacy J. Caillier, Adam Santaniello, Neda Sattarnezhad, Shrishti Saxena, Howard Weiner, Hajime Yano, and Sergio E. Baranzini
Subjects: Science
Abstract: Abstract The multifaceted nature of multiple sclerosis requires quantitative biomarkers that can provide insights related to diverse physiological pathways. To this end, proteomic analysis of deeply-phenotyped serum samples, biological pathway modeling, and network analysis were performed to elucidate inflammatory and neurodegenerative processes, identifying sensitive biomarkers of multiple sclerosis disease activity. Here, we evaluated the concentrations of > 1400 serum proteins in 630 samples from three multiple sclerosis cohorts for association with clinical and radiographic new disease activity. Twenty proteins were associated with increased clinical and radiographic multiple sclerosis disease activity for inclusion in a custom assay panel. Serum neurofilament light chain showed the strongest univariate correlation with gadolinium lesion activity, clinical relapse status, and annualized relapse rate. Multivariate modeling outperformed univariate for all endpoints. A comprehensive biomarker panel including the twenty proteins identified in this study could serve to characterize disease activity for a patient with multiple sclerosis.
Published: 2024
Full Text: View/download PDF

4. 3003 Prognostic value of on-treatment serum neurofilament light chain for neT2 lesions relapsing MS patients: pooled analysis of ASCLEPIOS I/II

Author: Jeannette Lechner-Scott, Wenjia Wei, Heinz Wiendl, Xavier Montalban, Stephen L Hauser, Tjalf Ziemssen, Douglas L Arnold, Enrique Alvarez, Tobias Derfuss, Thomas P Leist, Alit Bhatt, and Ibolya Boer
Subjects: Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Published: 2024
Full Text: View/download PDF

5. The Women in the Principal's Office: A Mixed Methods Study of Principal Time Use and the Gendered Division of Household Labor

Author: Megan L. Hauser
Abstract: Over a century of research on K-12 public school principal time use (PTU) illustrates that principals spend time on professional tasks beyond the instructional hours of their school days. Similarly, a century of research on the division of household labor suggests that women spend more time on household labor than men daily. However, no prior PTU study has recognized this gendered imbalance of household labor. The purpose of this study was to collect PTU data and household labor time use data from female and male principals, assistant principals, and aspiring principals to explore how the additional time demands of household labor may be impacting the disproportionate number of female principals to female teachers. Twenty principal pipeline participants (PPPs), composed of ten women and men from two northeastern states, completed a 24-hour electronic time diary for seven consecutive days to record their professional and household tasks in phase one of the explanatory sequential mixed methods study. For phase two of the study, two women and two men from each PPP group participated in semi-structured interviews based on their quantitative time diary data. The final connected quantitative and qualitative results indicated that women in the present study spent more time on their professional tasks as they advanced along the principal pipeline, and this time was more likely to be marked by multitasking and blurring professional and household boundaries to manage their competing demands than their male counterparts. Female assistant principals were the only PPP group of women who recorded more time spent on household tasks than their male counterparts. Additionally, women and men in the present study valued convenience and proximity to home when considering their current professional roles and possible advancement along the principal pipeline. Recommendations for future research are offered and implications for practitioners and policymakers are discussed. [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page: http://www.proquest.com/en-US/products/dissertations/individuals.shtml.]
Published: 2023

6. Repeated passive visual experience modulates spontaneous and non-familiar stimuli-evoked neural activity

Author: Suraj Niraula, William L. Hauser, Adam G. Rouse, and Jaichandar Subramanian
Subjects: Medicine, Science
Abstract: Abstract Familiarity creates subjective memory of repeated innocuous experiences, reduces neural and behavioral responsiveness to those experiences, and enhances novelty detection. The neural correlates of the internal model of familiarity and the cellular mechanisms of enhanced novelty detection following multi-day repeated passive experience remain elusive. Using the mouse visual cortex as a model system, we test how the repeated passive experience of a 45° orientation-grating stimulus for multiple days alters spontaneous and non-familiar stimuli evoked neural activity in neurons tuned to familiar or non-familiar stimuli. We found that familiarity elicits stimulus competition such that stimulus selectivity reduces in neurons tuned to the familiar 45° stimulus; it increases in those tuned to the 90° stimulus but does not affect neurons tuned to the orthogonal 135° stimulus. Furthermore, neurons tuned to orientations 45° apart from the familiar stimulus dominate local functional connectivity. Interestingly, responsiveness to natural images, which consists of familiar and non-familiar orientations, increases subtly in neurons that exhibit stimulus competition. We also show the similarity between familiar grating stimulus-evoked and spontaneous activity increases, indicative of an internal model of altered experience.
Published: 2023
Full Text: View/download PDF

7. The Development of Ofatumumab, a Fully Human Anti-CD20 Monoclonal Antibody for Practical Use in Relapsing Multiple Sclerosis Treatment

Author: Stephen L. Hauser, Ludwig Kappos, Amit Bar-Or, Heinz Wiendl, David Paling, Mitzi Williams, Ralf Gold, Andrew Chan, Ron Milo, Ayan Das Gupta, Goeril Karlsson, Roseanne Sullivan, Gordon Graham, Martin Merschhemke, Dieter A. Häring, and Patrick Vermersch
Subjects: ALITHIOS, Anti-CD20 monoclonal antibody, ASCLEPIOS I/II, Benefit-risk, Ofatumumab, Relapsing multiple sclerosis, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract The importance of B cells in multiple sclerosis (MS) has been demonstrated through the advent of B-cell-depleting anti-CD20 antibody therapies. Ofatumumab is the first fully human anti-CD20 monoclonal antibody (mAb) developed and tested for subcutaneous (SC) self-administration at monthly doses of 20 mg, and has been approved in the US, UK, EU, and other regions and countries worldwide for the treatment of relapsing MS. The development goal of ofatumumab was to obtain a highly efficacious anti-CD20 therapy, with a safety and tolerability profile that allows for self-administration by MS patients at home and a positive benefit–risk balance for use in the broad relapsing MS population. This development goal was enabled by the unique binding site, higher affinity to B cells, and higher potency of ofatumumab compared to previous anti-CD20 mAbs; these properties of ofatumumab facilitate rapid B-cell depletion and maintenance with a low dose at a low injection volume (20 mg/0.4 ml). The high potency in turn enables the selective targeting of B cells that reside in the lymphatic system via subcutaneous (SC) administration. Through a comprehensive dose-finding program in two phase 2 studies (one intravenous and one SC) and model simulations, it was found that safety and tolerability can be further improved, and the risk of systemic injection-related reactions (IRRs) minimized, by avoiding doses ≥ 30 mg, and by reaching initial and rapid B-cell depletion via stepwise weekly administration of ofatumumab at Weeks 0, 1, and 2 (instead of a single high dose). Once near-complete B-cell depletion is reached, it can be maintained by monthly doses of 20 mg/0.4 ml. Indeed, in phase 3 trials (ASCLEPIOS I/II), rapid and sustained near-complete B-cell depletion (largely independent of body weight, race and other factors) was observed with this dosing regimen, which resulted in superior efficacy of ofatumumab versus teriflunomide on relapse rates, disability worsening, neuronal injury (serum neurofilament light chain), and imaging outcomes. Likely due to its fully human nature, ofatumumab has a low immunogenic risk profile—only 2 of 914 patients receiving ofatumumab in ASCLEPIOS I/II developed anti-drug antibodies—and this may also underlie the infrequent IRRs (20% with ofatumumab vs. 15% with the placebo injection in the teriflunomide arm) that were mostly (99.8%) mild to moderate in severity. The overall rates of infections and serious infections in patients treated with ofatumumab were similar to those in patients treated with teriflunomide (51.6% vs. 52.7% and 2.5% vs. 1.8%, respectively). The benefit–risk profile of ofatumumab was favorable compared to teriflunomide in the broad RMS population, and also in the predefined subgroups of both recently diagnosed and/or treatment-naïve patients, as well as previously disease-modifying therapy-treated patients. Interim data from the ongoing extension study (ALITHIOS) have shown that long-term treatment with ofatumumab up to 4 years is well-tolerated in RMS patients, with no new safety risks identified. In parallel to the phase 3 trials in which SC administration was carried out with a pre-filled syringe, an autoinjector pen for more convenient self-administration of the ofatumumab 20 mg dose was developed and is available for use in clinical practice. Graphical Abstract
Published: 2023
Full Text: View/download PDF

8. High-resolution DNA methylation screening of the major histocompatibility complex in multiple sclerosis

Author: Qin Ma, Danillo G. Augusto, Gonzalo Montero-Martin, Stacy J. Caillier, Kazutoyo Osoegawa, Bruce A. C. Cree, Stephen L. Hauser, Alessandro Didonna, Jill A. Hollenbach, Paul J. Norman, Marcelo Fernandez-Vina, and Jorge R. Oksenberg
Subjects: DNA methylation, major histocompatibility complex, multiple sclerosis, differentially methylated regions, DNA methylation quantitative trait loci, Neurology. Diseases of the nervous system, RC346-429
Abstract: BackgroundThe HLA-DRB1 gene in the major histocompatibility complex (MHC) region in chromosome 6p21 is the strongest genetic factor identified as influencing multiple sclerosis (MS) susceptibility. DNA methylation changes associated with MS have been consistently detected at the MHC region. However, understanding the full scope of epigenetic regulations of the MHC remains incomplete, due in part to the limited coverage of this region by standard whole genome bisulfite sequencing or array-based methods.MethodsWe developed and validated an MHC capture protocol coupled with bisulfite sequencing and conducted a comprehensive analysis of the MHC methylation landscape in blood samples from 147 treatment naïve MS study participants and 129 healthy controls.ResultsWe identified 132 differentially methylated region (DMRs) within MHC region associated with disease status. The DMRs overlapped with established MS risk loci. Integration of the MHC methylome with human leukocyte antigen (HLA) genetic data indicate that the methylation changes are significantly associated with HLA genotypes. Using DNA methylation quantitative trait loci (mQTL) mapping and the causal inference test (CIT), we identified 643 cis-mQTL-DMRs paired associations, including 71 DMRs possibly mediating causal relationships between 55 single nucleotide polymorphisms (SNPs) and MS risk.ResultsThe results describe MS-associated methylation changes in MHC region and highlight the association between HLA genotypes and methylation changes. Results from the mQTL and CIT analyses provide evidence linking MHC region variations, methylation changes, and disease risk for MS.
Published: 2023
Full Text: View/download PDF

9. Integration of epigenetic and genetic profiles identifies multiple sclerosis disease-critical cell types and genes

Author: Qin Ma, Hengameh Shams, Alessandro Didonna, Sergio E. Baranzini, Bruce A. C. Cree, Stephen L. Hauser, Roland G. Henry, and Jorge R. Oksenberg
Subjects: Biology (General), QH301-705.5
Abstract: The combined analysis of single cell and bulk epigenetic datasets and multiple sclerosis GWAS reveals the enrichment of genetic susceptibility signals in B cells and monocyte-microglia cell types.
Published: 2023
Full Text: View/download PDF

10. Blood neurofilament light levels predict non-relapsing progression following anti-CD20 therapy in relapsing and primary progressive multiple sclerosis: findings from the ocrelizumab randomised, double-blind phase 3 clinical trialsResearch in context

Author: Amit Bar-Or, Gian-Andrea Thanei, Christopher Harp, Corrado Bernasconi, Ulrike Bonati, Anne H. Cross, Saloumeh Fischer, Laura Gaetano, Stephen L. Hauser, Robert Hendricks, Ludwig Kappos, Jens Kuhle, David Leppert, Fabian Model, Annette Sauter, Harold Koendgen, Xiaoming Jia, and Ann E. Herman
Subjects: Multiple sclerosis, Ocrelizumab, NfL, Biomarker, Disease progression, Medicine, Medicine (General), R5-920
Abstract: Summary: Background: Neurofilament light chain (NfL), a neuronal cytoskeletal protein that is released upon neuroaxonal injury, is associated with multiple sclerosis (MS) relapsing activity and has demonstrated some prognostic ability for future relapse-related disease progression, yet its value in assessing non-relapsing disease progression remains unclear. Methods: We examined baseline and longitudinal blood NfL levels in 1421 persons with relapsing MS (RMS) and 596 persons with primary progressive MS (PPMS) from the pivotal ocrelizumab MS trials. NfL treatment-response and risk for disease worsening (including disability progression into the open-label extension period and slowly expanding lesions [SELs] on brain MRI) at baseline and following treatment with ocrelizumab were evaluated using time-to-event analysis and linear regression models. Findings: In persons from the RMS control arms without acute disease activity and in the entire PPMS control arm, higher baseline NfL was prognostic for greater whole brain and thalamic atrophy, greater volume expansion of SELs, and clinical progression. Ocrelizumab reduced NfL levels vs. controls in persons with RMS and those with PPMS, and abrogated the prognostic value of baseline NfL on disability progression. Following effective suppression of relapse activity by ocrelizumab, NfL levels at weeks 24 and 48 were significantly associated with long-term risk for disability progression, including up to 9 years of observation in RMS and PPMS. Interpretation: Highly elevated NfL from acute MS disease activity may mask a more subtle NfL abnormality that reflects underlying non-relapsing progressive biology. Ocrelizumab significantly reduced NfL levels, consistent with its effects on acute disease activity and disability progression. Persistently elevated NfL levels, observed in a subgroup of persons under ocrelizumab treatment, demonstrate potential clinical utility as a predictive biomarker of increased risk for clinical progression. Suppression of relapsing biology with high-efficacy immunotherapy provides a window into the relationship between NfL levels and future non-relapsing progression. Funding: F. Hoffmann-La Roche Ltd.
Published: 2023
Full Text: View/download PDF

11. Excitation-inhibition imbalance disrupts visual familiarity in amyloid and non-pathology conditions

Author: Suraj Niraula, Julia J. Doderer, Shreya Indulkar, Kalen P. Berry, William L. Hauser, Oliver J. L’Esperance, Jasmine Z. Deng, Griffin Keeter, Adam G. Rouse, and Jaichandar Subramanian
Subjects: CP: Neuroscience, Biology (General), QH301-705.5
Abstract: Summary: Neuronal hyperactivity induces memory deficits in Alzheimer’s disease. However, how hyperactivity disrupts memory is unclear. Using in vivo synaptic imaging in the mouse visual cortex, we show that structural excitatory-inhibitory synapse imbalance in the apical dendrites favors hyperactivity in early amyloidosis. Consistent with this, natural images elicit neuronal hyperactivity in these mice. Compensatory changes that maintain activity homeostasis disrupt functional connectivity and increase population sparseness such that a small fraction of neurons dominates population activity. These properties reduce the selectivity of neural response to natural images and render visual recognition memory vulnerable to interference. Deprivation of non-specific visual experiences improves the neural representation and behavioral expression of visual familiarity. In contrast, in non-pathological conditions, deprivation of non-specific visual experiences induces disinhibition, increases excitability, and disrupts visual familiarity. We show that disrupted familiarity occurs when the fraction of high-responsive neurons and the persistence of neural representation of a memory-associated stimulus are not constrained.
Published: 2023
Full Text: View/download PDF

12. Prognostic Value of Serum Neurofilament Light Chain for Disease Activity and Worsening in Patients With Relapsing Multiple Sclerosis: Results From the Phase 3 ASCLEPIOS I and II Trials

Author: Tjalf Ziemssen, Douglas L. Arnold, Enrique Alvarez, Anne H. Cross, Roman Willi, Bingbing Li, Petra Kukkaro, Harald Kropshofer, Krishnan Ramanathan, Martin Merschhemke, Bernd Kieseier, Wendy Su, Dieter A. Häring, Stephen L. Hauser, Ludwig Kappos, and Jens Kuhle
Subjects: serum neurofilament light chain, prognostic biomarker, MS disease activity, lesion formation, brain atrophy, Immunologic diseases. Allergy, RC581-607
Abstract: ObjectiveThis study aims to confirm the prognostic value of baseline serum neurofilament light chain (sNfL) for on-study disease activity and worsening in patients with relapsing MS (RMS).BackgroundPrevious post-hoc studies suggested that sNfL could be a prognostic biomarker in RMS. In the phase 3 ASCLEPIOS I/II trials in which ofatumumab demonstrated better efficacy outcomes than teriflunomide, treatment with ofatumumab also led to significantly reduced sNfL levels compared to teriflunomide treatment.Design/MethodsIn this study, we report protocol-planned analyses from the pooled ASCLEPIOS I/II trials (N=1882). Per protocol, patients were stratified by median baseline sNfL levels (9.3 pg/ml) into high (>median) and low (≤median) categories to prognosticate: annualized rate of new/enlarging T2 (neT2) lesions in year 1 and 2, annualized relapse rate, annual percentage change in whole brain (WB) and regional brain volume [thalamus, white matter (WM), cortical gray matter (cGM)], and disability outcomes. Similar analyses were performed for the recently diagnosed (within 3 years), treatment-naive patients (no prior disease-modifying therapy) subgroup.ResultsHigh versus low sNfL at baseline was prognostic of increased on-study T2 lesion formation at year 1 (relative increase: ofatumumab +158%; teriflunomide +69%, both p
Published: 2022
Full Text: View/download PDF

13. Building a Precision Medicine Delivery Platform for Clinics: The University of California, San Francisco, BRIDGE Experience

Author: Riley Bove, Erica Schleimer, Paul Sukhanov, Michael Gilson, Sindy M Law, Andrew Barnecut, Bruce L Miller, Stephen L Hauser, Stephan J Sanders, and Katherine P Rankin
Subjects: Computer applications to medicine. Medical informatics, R858-859.7, Public aspects of medicine, RA1-1270
Abstract: Despite an ever-expanding number of analytics with the potential to impact clinical care, the field currently lacks point-of-care technological tools that allow clinicians to efficiently select disease-relevant data about their patients, algorithmically derive clinical indices (eg, risk scores), and view these data in straightforward graphical formats to inform real-time clinical decisions. Thus far, solutions to this problem have relied on either bottom-up approaches that are limited to a single clinic or generic top-down approaches that do not address clinical users’ specific setting-relevant or disease-relevant needs. As a road map for developing similar platforms, we describe our experience with building a custom but institution-wide platform that enables economies of time, cost, and expertise. The BRIDGE platform was designed to be modular and scalable and was customized to data types relevant to given clinical contexts within a major university medical center. The development process occurred by using a series of human-centered design phases with extensive, consistent stakeholder input. This institution-wide approach yielded a unified, carefully regulated, cross-specialty clinical research platform that can be launched during a patient’s electronic health record encounter. The platform pulls clinical data from the electronic health record (Epic; Epic Systems) as well as other clinical and research sources in real time; analyzes the combined data to derive clinical indices; and displays them in simple, clinician-designed visual formats specific to each disorder and clinic. By integrating an application into the clinical workflow and allowing clinicians to access data sources that would otherwise be cumbersome to assemble, view, and manipulate, institution-wide platforms represent an alternative approach to achieving the vision of true personalized medicine.
Published: 2022
Full Text: View/download PDF

14. Simultaneous assessment of regional distributions of atrophy across the neuraxis in MS patients

Author: Patrick Freund, Nico Papinutto, Antje Bischof, Michela Azzarito, Gina Kirkish, John Ashburner, Alan Thompson, Stephen L. Hauser, and Roland G. Henry
Subjects: Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract: Background: The ability to assess brain and cord atrophy simultaneously would improve the efficiency of MRI to track disease evolution. Objective: To test a promising tool to simultaneously map the regional distribution of atrophy in multiple sclerosis (MS) patients across the brain and cord. Methods: Voxel-based morphometry combined with a statistical parametric mapping probabilistic brain-spinal cord (SPM-BSC) template was applied to standard T1-weighted magnetic resonance imaging (MRI) scans covering the brain and cervical cord from 37 MS patients and 20 healthy controls (HC). We also measured the cord area at C2-C3 with a semi-automatic segmentation method using (i) the same T1-weighted acquisitions used for the new voxel-based analysis and (ii) dedicated spinal cord phase sensitive inversion recovery (PSIR) acquisitions. Cervical cord findings derived from the three approaches were compared to each other and the goodness to fit to clinical scores was assessed by regression analyses. Results: The SPM-BSC approach revealed a severity-dependent pattern of atrophy across the cervical cord and thalamus in MS patients when compared to HCs. The magnitude of cord atrophy was confirmed by the semi-automatic extraction approach at C2-C3 using both standard brain T1-weighted and advanced cord dedicated acquisitions. Associations between atrophy of cord and thalamus with disability and cognition were demonstrated. Conclusion: Atrophy in the brain and cervical cord of MS patients can be identified simultaneously and rapidly at the voxel-level. The SPM-BSC approach yields similar results as available standard processing tools with the added advantage of performing the analysis simultaneously and faster.
Published: 2022
Full Text: View/download PDF

15. Aberrant STAT phosphorylation signaling in peripheral blood mononuclear cells from multiple sclerosis patients

Author: Ester Canto, Noriko Isobe, Alessandro Didonna, MS-EPIC Study Group, Stephen L. Hauser, and Jorge R. Oksenberg
Subjects: STAT proteins, Multiple sclerosis, Phosphoflow cytometry, Interferon signaling, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Background Multiple sclerosis (MS) is characterized by increased activation of peripheral blood mononuclear cells (PBMCs), linked to perturbations in the phosphorylation of signaling proteins. Methods We developed a phosphoflow cytometry protocol to assess the levels of 11 phosphorylated nuclear proteins at baseline conditions and after cell activation in distinct PBMC populations from 41 treatment-naïve relapsing-remitting (RR) MS subjects and 37 healthy controls, and in a second cohort of 9 untreated RRMS patients and 10 secondary progressive (SP) MS patients. Levels of HLA-ABC, HLA-E, and HLA-DR were also assessed. Phosphorylation levels of selected proteins were also assessed in mouse splenocytes isolated from myelin oligodendrocyte glycoprotein (MOG)35–55-induced experimental autoimmune encephalomyelitis (EAE). Results Modest differences were observed at baseline between patients and controls, with general lower phosphorylation levels in cells from affected individuals. Conversely, a dramatic increase in phosphorylated p38MAPK and STAT proteins was observed across all cell types in MS patients compared to controls after in vitro activation. A similar phosphorylation profile was observed in mouse lymphocytes primed in vivo with MOG. Furthermore, levels of all p-STAT proteins were found directly correlated with HLA expression in monocytes. Levels of phosphorylated proteins did not differ between relapsing-remitting and secondary progressive MS patients either in baseline conditions or after stimulation. Lastly, phosphorylation levels appear to be independent of the genotype. Conclusion The response to IFN-α through STAT proteins signaling is strongly dysregulated in MS patients irrespective of disease stage. These findings suggest that the aberrant activation of this pathway could lead to changes in the expression of HLA molecules in antigen presenting cells, which are known to play important roles in the regulation of the immune response in health and disease.
Published: 2018
Full Text: View/download PDF

16. A Predictive Autoantibody Signature in Multiple Sclerosis

Author: Colin R. Zamecnik, Gavin M. Sowa, Ahmed Abdelhak, Ravi Dandekar, Rebecca D. Bair, Kristen J. Wade, Christopher M. Bartley, Asritha Tubati, Refujia Gomez, Camille Fouassier, Chloe Gerungan, Jessica Alexander, Anne E. Wapniarski, Rita P. Loudermilk, Erica L. Eggers, Kelsey C. Zorn, Kirtana Ananth, Nora Jabassini, Sabrina A. Mann, Nicholas R. Ragan, Adam Santaniello, Roland G. Henry, Sergio E. Baranzini, Scott S. Zamvil, Riley M. Bove, Chu-Yueh Guo, Jeffrey M. Gelfand, Richard Cuneo, H.-Christian von Büdingen, Jorge R. Oksenberg, Bruce AC Cree, Jill A. Hollenbach, Ari J. Green, Stephen L. Hauser, Mitchell T. Wallin, Joseph L. DeRisi, and Michael R. Wilson
Subjects: Article
Abstract: Although B cells are implicated in multiple sclerosis (MS) pathophysiology, a predictive or diagnostic autoantibody remains elusive. Here, the Department of Defense Serum Repository (DoDSR), a cohort of over 10 million individuals, was used to generate whole-proteome autoantibody profiles of hundreds of patients with MS (PwMS) years before and subsequently after MS onset. This analysis defines a unique cluster of PwMS that share an autoantibody signature against a common motif that has similarity with many human pathogens. These patients exhibit antibody reactivity years before developing MS symptoms and have higher levels of serum neurofilament light (sNfL) compared to other PwMS. Furthermore, this profile is preserved over time, providing molecular evidence for an immunologically active prodromal period years before clinical onset. This autoantibody reactivity was validated in samples from a separate incident MS cohort in both cerebrospinal fluid (CSF) and serum, where it is highly specific for patients eventually diagnosed with MS. This signature is a starting point for further immunological characterization of this MS patient subset and may be clinically useful as an antigen-specific biomarker for high-risk patients with clinically- or radiologically-isolated neuroinflammatory syndromes.
Published: 2023

17. Ofatumumab versus Teriflunomide in Multiple Sclerosis

Author: Hauser S. L., Bar-Or A., Cohen J. A., Comi G., Correale J., Coyle P. K., Cross A. H., de Seze J., Leppert D., Montalban X., Selmaj K., Wiendl H., Kerloeguen C., Willi R., Li B., Kakarieka A., Tomic D., Goodyear A., Pingili R., Haring D. A., Ramanathan K., Merschhemke M., Kappos L., Stephen L Hauser, Ludwig Kappos, Amit Bar-Or, Jeffrey A Cohen, Giancarlo Comi, Jorge Correale, Patricia K Coyle, Anne Cross, Jerome de Seze, Xavier Montalban, Krzysztof Selmaj, Heinz Wiendl, Stephen C Reingold, Garry R Cutter, Thomas Doerner, Hans-Peter Hartung, Per Soelberg Sørensen, Israel Steiner, Jerry S Wolinsky, Carlos Ballario, Christian Calvo Vildoso, Jorge Gustavo Jose, Norma Haydee Deri, Susana Liwacki, Jeannette Lechner-Scott, John Parratt, Suzanne Hodgkinson, Eva-Maria Maida, Fritz Leutmezer, Barbara Willekens, Bart Van Wijmeersch, Guy Laureys, Jo Caekebeke, Karine Geens, Ludo Vanopdenbosch, Olivier Deryck, Valerie Delvaux, Vincent Van Pesch, Ivan Milanov, Ivaylo Tarnev, Lyubomir Haralanov, Maria Manova Slavova, Penko Shotekov, Francois Emond, Francois Grandmaison, Francois Jacques, Liesly Lee, Marie Sarah Gagne Brosseau, Mark Freedman, Martin Cloutier, Robert Carruthers, Sarah Morrow, Yves Lapierre, Anton Vladic, Hana Bokun, Igor Antoncic, Marija Bosnjak Pasic, Mario Habek, Silva Butkovic Soldo, Vladimira Vuletic, Alena Martinkova, Eva Meluzinova, Ivana Stetkarova, Jan Mares, Jolana Markova, Marta Vachova, Martin Valis, Michaela Tyblova, Michal Dufek, Ondrej Skoda, Pavel Hradilek, Ana Voldsgaard Jensen, Helle Hvilsted Nielsen, Kristina Svendsen, Mads Ravnborg, Peter Vestergaard Rasmussen, Katrin Gross-Paju, Sulev Haldre, Juha Pekka Eralinna, Marja-Liisa Sumelahti, Bruno Brochet, Celine Louapre, Christine Lebrun-Frenay, David Axel Laplaud, Gilles Edan, Giovanni Castelnovo, Marc Debouverie, Patrick Vermersch, Pierre Clavelou, Pierre Labauge, Achim Berthele, Aiden Haghikia, Anselm Kornhuber, Arnfin Bergmann, Benedikt Frank, Birte Elias-Hamp, Bjoern Tackenberg, Brigitte Wildemann, Erik Strauss, Eugen Schlegel, Florian Then Bergh, Gereon Nelles, Hayrettin Tumani, Karl-Otto Sigel, Martin Stangel, Matthias Boehringer, Olaf Martin Hoffmann, Patrick Oschmann, Reinhard Hohlfeld, Silke Walter, Sylvia Menck, Till Sprenger, Tjalf Ziemssen, Veit Ulrich Becker, Vera Straeten, Konstantinos Kilidireas, Konstantinos Voumvourakis, Nikolaos Fakas, Nikolaos Grigoriadis, Agnes Koves, Csilla Rozsa, Krisztina Kovacs, Laszlo Vecsei, Satori Maria, Zita Biro, Anshu Rohatgi, Dheeraj Khurana, Jeyaraj Durai Pandian, Joy Dev Mukherji, Lekha Pandit, Meena Angamuthu Kanikannan, Pahari Ghosh, Rahul Chakor, Rahul Kulkarni, Roopkumar Gursahani, Sangeeta Ravat, Srinivasa Rangasetty, Suresh Kumar, Alla Shifrin, Arnon Karni, Radi Shahien, Ron Milo, Antonio Uccelli, Carlo Pozzilli, Francesco Sacca, Giacomo Lus, Girolama Alessandra Marfia, Laura Brambilla, Marco Salvetti, Massimo Filippi, Mauro Zaffaroni, Paolo Gallo, Silvia Rossi, Simona Bonavita, Valeria Studer, Andrejs Millers, Guntis Karelis, Jolanta Kalnina, Dalia Mickeviciene, Rasa Kizlaitiene, Angelica Carbajal Ramirez, Juan Jose Lopez Prieto, Beatrijs Wokke, Bob W Van Oosten, Peter Van Domburg, Raymond Hupperts, Rogier Q Hintzen, Astrid Edland, Cesar Castaneda, Julio Perez, Martin Gavidia, Andrzej Wiak, Bartosz Karaszewski, Elzbieta Jasinska, Halina Bartosik Psujek, Iwona Jastrzebska, Jaroslaw Slawek, Maciej Maciejowski, Miroslaw Dziki, Monika Adamczyk Sowa, Robert Bonek, Waldemar Fryze, Ana Martins Da Silva, Angela Timoteo, Antonio Vasco Salgado, Carlos Capela, Carlos Veira, Filipe Correia, Joao Cerqueira, Joao De Sa, Livia De Sousa, Raquel Gouveia, Alina Sergeevna Agafina, Anna Naumovna Belova, Denis Viktorovich Sazonov, Dmitry Pokhabov, Ekaterina Igorevna Kairbekova, Elena Gennadievna Arefieva, Farit Axatovich Khabirov, Igor Vyacheslavovich Litvinenko, Igor Stolyarov, Irina Aleksandrovna Sokolova, Larisa Ivanovna Volkova, Maria Vafaevna Davydovskaya, Maria Nikolaevna Zaharova, Nadezhda Alekseevna Malkova, Natalia Agafonovna Totolyan, Nikolay Vasilievich Dorogov, Stella Anatolievna Sivertseva, Egon Kurca, Georgi Krastev, Miroslav Brozman, Peter Koleda, Peter Turcani, Peter Valkovic, Viera Hancinova, Vladimir Donath, Chris Retief, Michael Isaacs, Albert Saiz Hinarejos, Alfredo Rodriguez Antigüedad, Bonaventura Casanova Estruch, Celia Oreja-Guevara, Gemma Reig Rosello, Jose Carlos Alvarez Cermeño, Jose Martinez Rodriguez, Jose Meca Lallana, Juan Antonio Garcia Merino, Lucia Forero Diaz, Lucienne Costa Frossard Franca, Luis Querol Gutierrez, Lluis Ramio Torrenta, Pedro Serrano Castro, Rafael Arroyo Gonzalez, Sara Eichau Madueño, Sergio Martinez Yelamos, Tamara Castillo Trivino, Virgina Meca Lallana, Xaviere Montalban Gairin, Fredrik Piehl, Jan Lycke, Chiara Zecca, Tobias Derfuss, Thy-Sheng Lin, Somsak Tiamkao, Ayse Nur Yuceyar, Aysun Soysal, Belgin Petek Balci, Cavit Boz, Husnu Efendi, Murat Terzi, Serhan Sevim, Serkan Ozakbas, Andrew Gale, Ben Turner, David Barnes, David Paling, Eli Silber, James Overell, Matthew Craner, Aaron Carlson, Adam Wolff, Adaeze Onuoha, Adnan Subei, Ahmad Ata, Aimee Borazanci, Akram Dastagir, Alberto Vasquez, Alison Brooke Allen, Andrew P Keegan, Angel Carrasco, Angel R Chinea Martinez, Ann Bass, Annette Okai, April Erwin, Ariel Antezana-Antezana, Barbara Green, Bharathy E Sundaram, Bhupendra Khatri, Bhupesh Dihenia, Bogdan Gheorghiu, Brian Costell, Brian Steingo, Bruce L Hughes, Carrie M Hersh, Christopher Laganke, Christopher Luzzio, Corey Ford, Craig Edward Herrman, Craig Senzon, Cynthia Huffman, Daniel R Wynn, David D O Bear, David Lesch, David H Mattson, David Weisman, Deborah A Burke, Dennis W Dietrich, Deren Huang, Derrick Robertson, Djamchid Lotfi, Don Joseph Alfonso, Dusan Stefoski, Edward J Fox, Emily Pharr, Enrique Alvarez, Evanthia Bernitsas, Faria Amjad, Gabriel Pardo, Geoffrey Eubank, Gerald Mcintosh, Giles F Crowell, Hemanth Rao, J Michael Hemphill, Jack H Florin, Jacqueline Nicholas, James Napier, James Scott, Jason M Silversteen, Javier Vasallo, Jean-Raphael Schneider, Jeanette Wendt, Jeffrey Cohen, Jeffrey Gross, Jeffrey Groves, Jeffrey Kaplan, Jessica Stulc, Joanna A Cooper, John Foley, John Scagnelli, Jonathan C Calkwood, Jose Pizarro Otero, Jose Rafecas, Joshua Katz, Juliette S Saad, Katherine Standley, Keith Edwards, Kenneth Sharlin, Khurram Bashir, Kimberly Wagner, Kore Liow, Larry Lee Blankenship Jr, Laszlo Mate, Liliana Montoya, Lon D Lynn, Mark Agius, Mark Cascione, Mark Allan Goldstein, Mark Janicki, Martin R Bialow, Mary Denise Hughes, Matthew J Baker, Michelle Apperson, Michelle B Kuczma, M Mateo Paz Soldan, Mirela Cerghet, Nathaniel Robb Whaley, Paul K Winner, Pavle Repovic, Praful Kelkar, Romero Rekha Pillai, Ricardo Ayala, Richard Sater, Randall Trudell, Robert Fairborn Armstrong, Robert Thomas Nahouraii, Robert Naismith, Ronald S Murray, Samuel Hunter, Sara Qureshi, Sharon Lynch, Sibyl Wray, Silvia R Delgado, Stacy Donlon, Stanley Cohan, Stanya Smith, Stuart James Shafer, Susan Azalone, Susan Hibbs, Tamara A Miller, Thomas Giancarlo, Troy Desai, Varun K Saxena, Virginia Simnad, William David Honeycutt, William Logan, William E McElveen, William Wagner, University of California [San Francisco] (UCSF), University of California, Perelman School of Medicine, University of Pennsylvania [Philadelphia], Cleveland Clinic, IRCCS Ospedale San Raffaele [Milan, Italy], Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia [Buenos Aires] (FLENI), FLENI, Stony Brook University [SUNY] (SBU), State University of New York (SUNY), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), CIC Strasbourg (Centre d’Investigation Clinique Plurithématique (CIC - P) ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)-Hôpital de Hautepierre [Strasbourg]-Nouvel Hôpital Civil de Strasbourg, University Hospital Basel [Basel], Vall d'Hebron University Hospital [Barcelona], University of Warmia and Mazury [Olsztyn], University of Münster, Novartis Pharma S.A.S., Novartis Pharmaceuticals, University of Basel (Unibas), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Willekens, Barbara, ASCLEPIOS I and ASCLEPIOS II Trial Groups, Hauser, S. L., Bar-Or, A., Cohen, J. A., Comi, G., Correale, J., Coyle, P. K., Cross, A. H., de Seze, J., Leppert, D., Montalban, X., Selmaj, K., Wiendl, H., Kerloeguen, C., Willi, R., Li, B., Kakarieka, A., Tomic, D., Goodyear, A., Pingili, R., Haring, D. A., Ramanathan, K., Merschhemke, M., Kappos, L., Asclepios, I and ASCLEPIOS II Trial Group, Filippi, M, L Hauser, Stephen, Kappos, Ludwig, Bar-Or, Amit, A Cohen, Jeffrey, Comi, Giancarlo, Correale, Jorge, K Coyle, Patricia, Cross, Anne, de Seze, Jerome, Montalban, Xavier, Selmaj, Krzysztof, Wiendl, Heinz, C Reingold, Stephen, R Cutter, Garry, Doerner, Thoma, Hartung, Hans-Peter, Soelberg Sørensen, Per, Steiner, Israel, S Wolinsky, Jerry, Ballario, Carlo, Calvo Vildoso, Christian, Gustavo Jose, Jorge, Haydee Deri, Norma, Liwacki, Susana, Lechner-Scott, Jeannette, Parratt, John, Hodgkinson, Suzanne, Maida, Eva-Maria, Leutmezer, Fritz, Van Wijmeersch, Bart, Laureys, Guy, Caekebeke, Jo, Geens, Karine, Vanopdenbosch, Ludo, Deryck, Olivier, Delvaux, Valerie, Van Pesch, Vincent, Milanov, Ivan, Tarnev, Ivaylo, Haralanov, Lyubomir, Manova Slavova, Maria, Shotekov, Penko, Emond, Francoi, Grandmaison, Francoi, Jacques, Francoi, Lee, Liesly, Sarah Gagne Brosseau, Marie, Freedman, Mark, Cloutier, Martin, Carruthers, Robert, Morrow, Sarah, Lapierre, Yve, Vladic, Anton, Bokun, Hana, Antoncic, Igor, Bosnjak Pasic, Marija, Habek, Mario, Butkovic Soldo, Silva, Vuletic, Vladimira, Martinkova, Alena, Meluzinova, Eva, Stetkarova, Ivana, Mares, Jan, Markova, Jolana, Vachova, Marta, Valis, Martin, Tyblova, Michaela, Dufek, Michal, Skoda, Ondrej, Hradilek, Pavel, Voldsgaard Jensen, Ana, Hvilsted Nielsen, Helle, Svendsen, Kristina, Ravnborg, Mad, Vestergaard Rasmussen, Peter, Gross-Paju, Katrin, Haldre, Sulev, Pekka Eralinna, Juha, Sumelahti, Marja-Liisa, Brochet, Bruno, Louapre, Celine, Lebrun-Frenay, Christine, Axel Laplaud, David, Edan, Gille, Castelnovo, Giovanni, Debouverie, Marc, Vermersch, Patrick, Clavelou, Pierre, Labauge, Pierre, Berthele, Achim, Haghikia, Aiden, Kornhuber, Anselm, Bergmann, Arnfin, Frank, Benedikt, Elias-Hamp, Birte, Tackenberg, Bjoern, Wildemann, Brigitte, Strauss, Erik, Schlegel, Eugen, Then Bergh, Florian, Nelles, Gereon, Tumani, Hayrettin, Sigel, Karl-Otto, Stangel, Martin, Boehringer, Matthia, Martin Hoffmann, Olaf, Oschmann, Patrick, Hohlfeld, Reinhard, Walter, Silke, Menck, Sylvia, Sprenger, Till, Ziemssen, Tjalf, Ulrich Becker, Veit, Straeten, Vera, Kilidireas, Konstantino, Voumvourakis, Konstantino, Fakas, Nikolao, Grigoriadis, Nikolao, Koves, Agne, Rozsa, Csilla, Kovacs, Krisztina, Vecsei, Laszlo, Maria, Satori, Biro, Zita, Rohatgi, Anshu, Khurana, Dheeraj, Durai Pandian, Jeyaraj, Dev Mukherji, Joy, Pandit, Lekha, Angamuthu Kanikannan, Meena, Ghosh, Pahari, Chakor, Rahul, Kulkarni, Rahul, Gursahani, Roopkumar, Ravat, Sangeeta, Rangasetty, Srinivasa, Kumar, Suresh, Shifrin, Alla, Karni, Arnon, Shahien, Radi, Milo, Ron, Uccelli, Antonio, Pozzilli, Carlo, Sacca, Francesco, Lus, Giacomo, Alessandra Marfia, Girolama, Brambilla, Laura, Salvetti, Marco, Filippi, Massimo, Zaffaroni, Mauro, Gallo, Paolo, Rossi, Silvia, Bonavita, Simona, Studer, Valeria, Millers, Andrej, Karelis, Gunti, Kalnina, Jolanta, Mickeviciene, Dalia, Kizlaitiene, Rasa, Carbajal Ramirez, Angelica, Jose Lopez Prieto, Juan, Wokke, Beatrij, W Van Oosten, Bob, Van Domburg, Peter, Hupperts, Raymond, Q Hintzen, Rogier, Edland, Astrid, Castaneda, Cesar, Perez, Julio, Gavidia, Martin, Wiak, Andrzej, Karaszewski, Bartosz, Jasinska, Elzbieta, Bartosik Psujek, Halina, Jastrzebska, Iwona, Slawek, Jaroslaw, Maciejowski, Maciej, Dziki, Miroslaw, Adamczyk Sowa, Monika, Bonek, Robert, Fryze, Waldemar, Martins Da Silva, Ana, Timoteo, Angela, Vasco Salgado, Antonio, Capela, Carlo, Veira, Carlo, Correia, Filipe, Cerqueira, Joao, De Sa, Joao, De Sousa, Livia, Gouveia, Raquel, Sergeevna Agafina, Alina, Naumovna Belova, Anna, Viktorovich Sazonov, Deni, Pokhabov, Dmitry, Igorevna Kairbekova, Ekaterina, Gennadievna Arefieva, Elena, Axatovich Khabirov, Farit, Vyacheslavovich Litvinenko, Igor, Stolyarov, Igor, Aleksandrovna Sokolova, Irina, Ivanovna Volkova, Larisa, Vafaevna Davydovskaya, Maria, Nikolaevna Zaharova, Maria, Alekseevna Malkova, Nadezhda, Agafonovna Totolyan, Natalia, Vasilievich Dorogov, Nikolay, Anatolievna Sivertseva, Stella, Kurca, Egon, Krastev, Georgi, Brozman, Miroslav, Koleda, Peter, Turcani, Peter, Valkovic, Peter, Hancinova, Viera, Donath, Vladimir, Retief, Chri, Isaacs, Michael, Saiz Hinarejos, Albert, Rodriguez Antigüedad, Alfredo, Casanova Estruch, Bonaventura, Oreja-Guevara, Celia, Reig Rosello, Gemma, Carlos Alvarez Cermeño, Jose, Martinez Rodriguez, Jose, Meca Lallana, Jose, Antonio Garcia Merino, Juan, Forero Diaz, Lucia, Costa Frossard Franca, Lucienne, Querol Gutierrez, Lui, Ramio Torrenta, Llui, Serrano Castro, Pedro, Arroyo Gonzalez, Rafael, Eichau Madueño, Sara, Martinez Yelamos, Sergio, Castillo Trivino, Tamara, Meca Lallana, Virgina, Montalban Gairin, Xaviere, Piehl, Fredrik, Lycke, Jan, Zecca, Chiara, Derfuss, Tobia, Lin, Thy-Sheng, Tiamkao, Somsak, Nur Yuceyar, Ayse, Soysal, Aysun, Petek Balci, Belgin, Boz, Cavit, Efendi, Husnu, Terzi, Murat, Sevim, Serhan, Ozakbas, Serkan, Gale, Andrew, Turner, Ben, Barnes, David, Paling, David, Silber, Eli, Overell, Jame, Craner, Matthew, Carlson, Aaron, Wolff, Adam, Onuoha, Adaeze, Subei, Adnan, Ata, Ahmad, Borazanci, Aimee, Dastagir, Akram, Vasquez, Alberto, Brooke Allen, Alison, P Keegan, Andrew, Carrasco, Angel, R Chinea Martinez, Angel, Bass, Ann, Okai, Annette, Erwin, April, Antezana-Antezana, Ariel, Green, Barbara, E Sundaram, Bharathy, Khatri, Bhupendra, Dihenia, Bhupesh, Gheorghiu, Bogdan, Costell, Brian, Steingo, Brian, L Hughes, Bruce, M Hersh, Carrie, Laganke, Christopher, Luzzio, Christopher, Ford, Corey, Edward Herrman, Craig, Senzon, Craig, Huffman, Cynthia, R Wynn, Daniel, O Bear, David D, Lesch, David, H Mattson, David, Weisman, David, A Burke, Deborah, W Dietrich, Denni, Huang, Deren, Robertson, Derrick, Lotfi, Djamchid, Joseph Alfonso, Don, Stefoski, Dusan, J Fox, Edward, Pharr, Emily, Alvarez, Enrique, Bernitsas, Evanthia, Amjad, Faria, Pardo, Gabriel, Eubank, Geoffrey, Mcintosh, Gerald, F Crowell, Gile, Rao, Hemanth, Michael Hemphill, J, H Florin, Jack, Nicholas, Jacqueline, Napier, Jame, Scott, Jame, M Silversteen, Jason, Vasallo, Javier, Schneider, Jean-Raphael, Wendt, Jeanette, Cohen, Jeffrey, Gross, Jeffrey, Groves, Jeffrey, Kaplan, Jeffrey, Stulc, Jessica, A Cooper, Joanna, Foley, John, Scagnelli, John, C Calkwood, Jonathan, Pizarro Otero, Jose, Rafecas, Jose, Katz, Joshua, S Saad, Juliette, Standley, Katherine, Edwards, Keith, Sharlin, Kenneth, Bashir, Khurram, Wagner, Kimberly, Liow, Kore, Lee Blankenship Jr, Larry, Mate, Laszlo, Montoya, Liliana, D Lynn, Lon, Agius, Mark, Cascione, Mark, Allan Goldstein, Mark, Janicki, Mark, R Bialow, Martin, Denise Hughes, Mary, J Baker, Matthew, Apperson, Michelle, B Kuczma, Michelle, Mateo Paz Soldan, M, Cerghet, Mirela, Robb Whaley, Nathaniel, K Winner, Paul, Repovic, Pavle, Kelkar, Praful, Rekha Pillai, Romero, Ayala, Ricardo, Sater, Richard, Trudell, Randall, Fairborn Armstrong, Robert, Thomas Nahouraii, Robert, Naismith, Robert, S Murray, Ronald, Hunter, Samuel, Qureshi, Sara, Lynch, Sharon, Wray, Sibyl, R Delgado, Silvia, Donlon, Stacy, Cohan, Stanley, Smith, Stanya, James Shafer, Stuart, Azalone, Susan, Hibbs, Susan, A Miller, Tamara, Giancarlo, Thoma, Desai, Troy, K Saxena, Varun, Simnad, Virginia, David Honeycutt, William, Logan, William, E McElveen, William, Wagner, William, Stephen, L Hauser, Ludwig, Kappo, Amit, Bar-Or, Jeffrey, A Cohen, Giancarlo, Comi, Jorge, Correale, Patricia, K Coyle, Anne, Cro, Jerome de Seze, Xavier, Montalban, Krzysztof, Selmaj, Heinz, Wiendl, Stephen, C Reingold, Garry, R Cutter, Thomas, Doerner, Hans-Peter, Hartung, Per Soelberg Sørensen, Israel, Steiner, Jerry, S Wolinsky, Carlos, Ballario, Christian Calvo Vildoso, Jorge Gustavo Jose, Norma Haydee Deri, Susana, Liwacki, Jeannette, Lechner-Scott, John, Parratt, Suzanne, Hodgkinson, Eva-Maria, Maida, Fritz, Leutmezer, Barbara, Willeken, Bart Van Wijmeersch, Guy, Laurey, Karine, Geen, Ludo, Vanopdenbosch, Olivier, Deryck, Valerie, Delvaux, Vincent Van Pesch, Ivan, Milanov, Ivaylo, Tarnev, Lyubomir, Haralanov, Maria Manova Slavova, Penko, Shotekov, Francois, Emond, Francois, Grandmaison, Francois, Jacque, Liesly, Lee, Marie Sarah Gagne Brosseau, Mark, Freedman, Martin, Cloutier, Robert, Carruther, Sarah, Morrow, Yves, Lapierre, Anton, Vladic, Hana, Bokun, Igor, Antoncic, Marija Bosnjak Pasic, Mario, Habek, Silva Butkovic Soldo, Vladimira, Vuletic, Alena, Martinkova, Eva, Meluzinova, Ivana, Stetkarova, Jan, Mare, Jolana, Markova, Marta, Vachova, Martin, Vali, Michaela, Tyblova, Michal, Dufek, Ondrej, Skoda, Pavel, Hradilek, Ana Voldsgaard Jensen, Helle Hvilsted Nielsen, Kristina, Svendsen, Mads, Ravnborg, Peter Vestergaard Rasmussen, Katrin, Gross-Paju, Sulev, Haldre, Juha Pekka Eralinna, Marja-Liisa, Sumelahti, Bruno, Brochet, Celine, Louapre, Christine, Lebrun-Frenay, David Axel Laplaud, Gilles, Edan, Giovanni, Castelnovo, Marc, Debouverie, Patrick, Vermersch, Pierre, Clavelou, Pierre, Labauge, Achim, Berthele, Aiden, Haghikia, Anselm, Kornhuber, Arnfin, Bergmann, Benedikt, Frank, Birte, Elias-Hamp, Bjoern, Tackenberg, Brigitte, Wildemann, Erik, Strau, Eugen, Schlegel, Florian Then Bergh, Gereon, Nelle, Hayrettin, Tumani, Karl-Otto, Sigel, Martin, Stangel, Matthias, Boehringer, Olaf Martin Hoffmann, Patrick, Oschmann, Reinhard, Hohlfeld, Silke, Walter, Sylvia, Menck, Till, Sprenger, Tjalf, Ziemssen, Veit Ulrich Becker, Vera, Straeten, Konstantinos, Kilidirea, Konstantinos, Voumvouraki, Nikolaos, Faka, Nikolaos, Grigoriadi, Agnes, Kove, Csilla, Rozsa, Krisztina, Kovac, Laszlo, Vecsei, Satori, Maria, Zita, Biro, Anshu, Rohatgi, Dheeraj, Khurana, Jeyaraj Durai Pandian, Joy Dev Mukherji, Lekha, Pandit, Meena Angamuthu Kanikannan, Pahari, Ghosh, Rahul, Chakor, Rahul, Kulkarni, Roopkumar, Gursahani, Sangeeta, Ravat, Srinivasa, Rangasetty, Suresh, Kumar, Alla, Shifrin, Arnon, Karni, Radi, Shahien, Ron, Milo, Antonio, Uccelli, Carlo, Pozzilli, Sacca', Francesco, Giacomo, Lu, Girolama Alessandra Marfia, Laura, Brambilla, Marco, Salvetti, Massimo, Filippi, Mauro, Zaffaroni, Paolo, Gallo, Silvia, Rossi, Simona, Bonavita, Valeria, Studer, Andrejs, Miller, Guntis, Kareli, Jolanta, Kalnina, Dalia, Mickeviciene, Rasa, Kizlaitiene, Angelica Carbajal Ramirez, Juan Jose Lopez Prieto, Beatrijs, Wokke, Bob, W Van Oosten, Peter Van Domburg, Raymond, Huppert, Rogier, Q Hintzen, Astrid, Edland, Cesar, Castaneda, Julio, Perez, Martin, Gavidia, Andrzej, Wiak, Bartosz, Karaszewski, Elzbieta, Jasinska, Halina Bartosik Psujek, Iwona, Jastrzebska, Jaroslaw, Slawek, Maciej, Maciejowski, Miroslaw, Dziki, Monika Adamczyk Sowa, Robert, Bonek, Waldemar, Fryze, Ana Martins Da Silva, Angela, Timoteo, Antonio Vasco Salgado, Carlos, Capela, Carlos, Veira, Filipe, Correia, Joao, Cerqueira, Joao De Sa, Livia De Sousa, Raquel, Gouveia, Alina Sergeevna Agafina, Anna Naumovna Belova, Denis Viktorovich Sazonov, Dmitry, Pokhabov, Ekaterina Igorevna Kairbekova, Elena Gennadievna Arefieva, Farit Axatovich Khabirov, Igor Vyacheslavovich Litvinenko, Igor, Stolyarov, Irina Aleksandrovna Sokolova, Larisa Ivanovna Volkova, Maria Vafaevna Davydovskaya, Maria Nikolaevna Zaharova, Nadezhda Alekseevna Malkova, Natalia Agafonovna Totolyan, Nikolay Vasilievich Dorogov, Stella Anatolievna Sivertseva, Egon, Kurca, Georgi, Krastev, Miroslav, Brozman, Peter, Koleda, Peter, Turcani, Peter, Valkovic, Viera, Hancinova, Vladimir, Donath, Chris, Retief, Michael, Isaac, Albert Saiz Hinarejos, Alfredo Rodriguez Antigüedad, Bonaventura Casanova Estruch, Celia, Oreja-Guevara, Gemma Reig Rosello, Jose Carlos Alvarez Cermeño, Jose Martinez Rodriguez, Jose Meca Lallana, Juan Antonio Garcia Merino, Lucia Forero Diaz, Lucienne Costa Frossard Franca, Luis Querol Gutierrez, Lluis Ramio Torrenta, Pedro Serrano Castro, Rafael Arroyo Gonzalez, Sara Eichau Madueño, Sergio Martinez Yelamos, Tamara Castillo Trivino, Virgina Meca Lallana, Xaviere Montalban Gairin, Fredrik, Piehl, Jan, Lycke, Chiara, Zecca, Tobias, Derfu, Thy-Sheng, Lin, Somsak, Tiamkao, Ayse Nur Yuceyar, Aysun, Soysal, Belgin Petek Balci, Cavit, Boz, Husnu, Efendi, Murat, Terzi, Serhan, Sevim, Serkan, Ozakba, Andrew, Gale, Ben, Turner, David, Barne, David, Paling, Eli, Silber, James, Overell, Matthew, Craner, Aaron, Carlson, Adam, Wolff, Adaeze, Onuoha, Adnan, Subei, Ahmad, Ata, Aimee, Borazanci, Akram, Dastagir, Alberto, Vasquez, Alison Brooke Allen, Andrew, P Keegan, Angel, Carrasco, Angel, R Chinea Martinez, Ann, Ba, Annette, Okai, April, Erwin, Ariel, Antezana-Antezana, Barbara, Green, Bharathy, E Sundaram, Bhupendra, Khatri, Bhupesh, Dihenia, Bogdan, Gheorghiu, Brian, Costell, Brian, Steingo, Bruce, L Hughe, Carrie, M Hersh, Christopher, Laganke, Christopher, Luzzio, Corey, Ford, Craig Edward Herrman, Craig, Senzon, Cynthia, Huffman, Daniel, R Wynn, David D, O Bear, David, Lesch, David, H Mattson, David, Weisman, Deborah, A Burke, Dennis, W Dietrich, Deren, Huang, Derrick, Robertson, Djamchid, Lotfi, Don Joseph Alfonso, Dusan, Stefoski, Edward, J Fox, Emily, Pharr, Enrique, Alvarez, Evanthia, Bernitsa, Faria, Amjad, Gabriel, Pardo, Geoffrey, Eubank, Gerald, Mcintosh, Giles, F Crowell, Hemanth, Rao, J Michael Hemphill, Jack, H Florin, Jacqueline, Nichola, James, Napier, James, Scott, Jason, M Silversteen, Javier, Vasallo, Jean-Raphael, Schneider, Jeanette, Wendt, Jeffrey, Cohen, Jeffrey, Gro, Jeffrey, Grove, Jeffrey, Kaplan, Jessica, Stulc, Joanna, A Cooper, John, Foley, John, Scagnelli, Jonathan, C Calkwood, Jose Pizarro Otero, Jose, Rafeca, Joshua, Katz, Juliette, S Saad, Katherine, Standley, Keith, Edward, Kenneth, Sharlin, Khurram, Bashir, Kimberly, Wagner, Kore, Liow, Larry Lee Blankenship Jr, Laszlo, Mate, Liliana, Montoya, Lon, D Lynn, Mark, Agiu, Mark, Cascione, Mark Allan Goldstein, Mark, Janicki, Martin, R Bialow, Mary Denise Hughes, Matthew, J Baker, Michelle, Apperson, Michelle, B Kuczma, M Mateo Paz Soldan, Mirela, Cerghet, Nathaniel Robb Whaley, Paul, K Winner, Pavle, Repovic, Praful, Kelkar, Romero Rekha Pillai, Ricardo, Ayala, Richard, Sater, Randall, Trudell, Robert Fairborn Armstrong, Robert Thomas Nahouraii, Robert, Naismith, Ronald, S Murray, Samuel, Hunter, Sara, Qureshi, Sharon, Lynch, Sibyl, Wray, Silvia, R Delgado, Stacy, Donlon, Stanley, Cohan, Stanya, Smith, Stuart James Shafer, Susan, Azalone, Susan, Hibb, Tamara, A Miller, Thomas, Giancarlo, Troy, Desai, Varun, K Saxena, Virginia, Simnad, William David Honeycutt, William, Logan, William, E McElveen, William, Wagner, University of California [San Francisco] (UC San Francisco), University of California (UC), University of Pennsylvania, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nouvel Hôpital Civil de Strasbourg-Hôpital de Hautepierre [Strasbourg], Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Herrada, Anthony, and UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire
Subjects: Male, MESH: Multiple Sclerosis, Relapsing-Remitting, T-Lymphocytes, Hydroxybutyrates, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, Pharmacology, Relapsing-Remitting, MESH: Magnetic Resonance Imaging, chemistry.chemical_compound, 0302 clinical medicine, Teriflunomide, Monoclonal, MESH: Double-Blind Method, 030212 general & internal medicine, Humanized, MESH: Toluidines, B-Lymphocytes, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, Subcutaneous, B-Lymphocyte, Brain, General Medicine, Magnetic Resonance Imaging, MESH: Crotonates, Crotonates, Pyrimidine metabolism, Disease Progression, Female, MESH: Disease Progression, Antibody, Human, Adult, Multiple Sclerosis, Toluidines, medicine.drug_class, Injections, Subcutaneous, Injections, Subcutaneou, Monoclonal antibody, Ofatumumab, Settore MED/26, Antibodies, Monoclonal, Humanized, Crotonate, Antibodies, Injections, 03 medical and health sciences, MESH: Brain, Multiple Sclerosis, Relapsing-Remitting, Double-Blind Method, MESH: B-Lymphocytes, Nitriles, medicine, Humans, MESH: Kaplan-Meier Estimate, MESH: Humans, business.industry, Multiple sclerosis, MESH: Injections, Subcutaneous, MESH: Adult, medicine.disease, MESH: Male, MESH: T-Lymphocytes, T-Lymphocyte, Multicenter study, chemistry, MESH: Antibodies, Monoclonal, Humanized, biology.protein, Human medicine, business, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Background: Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known.Methods: In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume.Results: Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, -0.11; 95% confidence interval [CI], -0.16 to -0.06; P
Published: 2020
Full Text: View/download PDF

18. Ocrelizumab in relapsing and primary progressive multiple sclerosis: Pharmacokinetic and pharmacodynamic analyses of OPERA I, OPERA II and ORATORIO

Author: Fabian Model, Ludwig Kappos, Stephen L. Hauser, Heidemarie Kletzl, Ekaterina Gibiansky, Andreas Günther, Claire Petry, Ann Herman, Francois Mercier, Yumi Yamamoto, and Qing Wang
Subjects: Phases of clinical research, Relapsing-Remitting, Neurodegenerative, 030226 pharmacology & pharmacy, Gastroenterology, 0302 clinical medicine, population analysis, Monoclonal, Medicine, Pharmacology (medical), 030212 general & internal medicine, Pharmacology & Pharmacy, Humanized, education.field_of_study, Pharmacology and Pharmaceutical Sciences, Multiple Sclerosis, Chronic Progressive, Chronic Progressive, Original Article, medicine.drug, medicine.medical_specialty, Multiple Sclerosis, pharmacokinetic-pharmacodynamic, Population, Primary Progressive Multiple Sclerosis, Antibodies, Monoclonal, Humanized, Autoimmune Disease, Antibodies, 03 medical and health sciences, Multiple Sclerosis, Relapsing-Remitting, Pharmacokinetics, Internal medicine, pharmacokinetic–pharmacodynamic, pharmacodynamics, Humans, Immunologic Factors, In patient, education, Pharmacology, business.industry, Multiple sclerosis, neurology, pharmacokinetic&#8211, Neurosciences, Original Articles, medicine.disease, Brain Disorders, pharmacodynamic, Pharmacodynamics, Ocrelizumab, business
Abstract: AimsOcrelizumab is a humanized monoclonal antibody that selectively targets CD20-positive B cells and is indicated for treatment of patients with relapsing forms of multiple sclerosis (RMS) or primary progressive multiple sclerosis (PPMS). The pharmacokinetics and pharmacodynamics of ocrelizumab in patients with RMS or PPMS were assessed.MethodsA population pharmacokinetic model was developed based on data from the Phase II study and the Phase III studies OPERA I and OPERA II in patients with RMS. Data from the ORATORIO Phase III study in patients with PPMS became available after model finalization and was used for external model evaluation.ResultsThe ocrelizumab serum concentration vs time course was accurately described by a 2-compartment model with time-dependent clearance. Body weight was found to be the main covariate. The area under the concentration-time curve over the dosing interval was estimated to be 26% higher for patients with RMS weighing 90kg when compared with the 60-90kg group. The terminal half-life of ocrelizumab was estimated as 26days. The extent of B-cell depletion in blood, as the pharmacodynamic marker, was greater with increasing ocrelizumab exposure.ConclusionThe pharmacokinetics of ocrelizumab was described with pharmacokinetic parameters typical for an immunoglobulin G1 monoclonal antibody, with body weight as the main covariate. The pharmacokinetics and B-cell depletion in blood were comparable across the RMS and PPMS trials, and the extent of blood B-cell depletion was greater with higher exposure.
Published: 2020

19. Multiple sclerosis: two decades of progress

Author: Bruce A C Cree, Jorge R Oksenberg, and Stephen L Hauser
Subjects: Multiple Sclerosis, Humans, Neurology (clinical), Article
Published: 2022

20. Age, gender and normalization covariates for spinal cord gray matter and total cross-sectional areas at cervical and thoracic levels: A 2D phase sensitive inversion recovery imaging study.

Author: Nico Papinutto, Regina Schlaeger, Valentina Panara, Alyssa H Zhu, Eduardo Caverzasi, William A Stern, Stephen L Hauser, and Roland G Henry
Subjects: Medicine, Science
Abstract: The source of inter-subject variability and the influence of age and gender on morphometric characteristics of the spinal cord, such as the total cross-sectional area (TCA), the gray matter (GM) and white matter (WM) areas, currently remain under investigation. Understanding the effect of covariates such as age, gender, brain volumes, and skull- and vertebra-derived metrics on cervical and thoracic spinal cord TCA and GM areas in healthy subjects would be fundamental for exploring compartment specific changes in neurological diseases affecting the spinal cord. Using Magnetic Resonance Imaging at 3T we investigated 32 healthy subjects using a 2D phase sensitive inversion recovery sequence and we measured TCA, GM and WM areas at 4 cervical and thoracic levels of the spinal cord. We assessed age and gender relationships of cord measures and explored associations between cord measures and a) brain volumes and b) skull- and vertebra-derived metrics. Age and gender had a significant effect on TCA, WM and GM areas (with women and elderly having smaller values than men and younger people respectively), but not on the GM area/TCA ratio. The total intracranial volume and C3 vertebra dimensions showed the highest correlations with cord measures. When used in multi-regression models, they reduced cord areas group variability by approximately a third. Age and gender influences on cord measures and normalization strategies here presented might be of use in the study of compartment specific changes in various neurological diseases affecting the spinal cord.
Published: 2015
Full Text: View/download PDF

21. A Convolutional Neural Network based Cascade Reconstruction for the IceCube Neutrino Observatory

Author: J. Werthebach, A. Franckowiak, Chujie Chen, Ioana Codrina Maris, K. Hoshina, A. Steuer, A. Weindl, Maryon Ahrens, P. Schlunder, Saskia Philippen, Glenn Spiczak, G. Momenté, Segev BenZvi, Spencer Klein, M. Rameez, Sam De Ridder, Frederik Tenholt, R. Nagai, D. F. Cowen, Martin Unland Elorrieta, Stephen L. Hauser, Christoph Raab, Nadège Iovine, Barbara Skrzypek, Kara Hoffman, Sarah Mancina, N. van Eijndhoven, U. Naumann, Raamis Hussain, D. Berley, G. C. Hill, Tobias Hoinka, Vedant Basu, Steve Sclafani, J. Kiryluk, B. J. P. Jones, Andres Medina, D. Mockler, Bunheng Ty, Ralph Engel, Moritz Kellermann, U. Katz, Emily Dvorak, Timo Karg, K. Andeen, D. R. Nygren, Marek Kowalski, D. Kang, Giovanni Renzi, K. D. de Vries, M. Stamatikos, Hershal Pandya, Wolfgang Rhode, Robert Stein, A.A. Alves, Pablo Correa, D. Seckel, S. Fahey, Javier Gonzalez, Roxanne Turcotte, Maximilian Karl Scharf, Alexander Trettin, P. B. Price, I. Taboada, Gisela Anton, Michael O. Wolf, Lenka Tomankova, Max Renschler, Y. Makino, Matthias Vraeghe, Tyce DeYoung, K. Tollefson, D. J. Koskinen, K. Rawlins, Nathan Whitehorn, C. Weaver, T. Anderson, B. A. Clark, Francesco Lucarelli, Brandom Pries, L. Schumacher, Devyn Rysewyk Cantu, P. Peiffer, J. Kim, Daria Pankova, E. Friedman, M. Kauer, Alan Coleman, John Hardin, Shefali Shefali, Nora Valtonen-Mattila, M. E. Huber, D. B. Fox, Alexander Fritz, D. Z. Besson, T. O. B. Schmidt, E. Bourbeau, Suyong Choi, M. Silva, Najia Moureen Binte Amin, J. P. Lazar, Sebastian Böser, R. Morse, Spencer Griswold, Jakob Bottcher, T. Montaruli, David A. Williams, A. Goldschmidt, K. Mase, Abdul Rehman, David Kappesser, Kurt Woschnagg, Paul Evenson, Clara E. Hill, Le Viet Nguyen, Sebastian Sanchez Herrera, Marcos Santander, Carsten Rott, L. Gerhardt, Y. Popovych, J. Evans, Maria Tselengidou, D. Soldin, J. B. Tjus, Chiara Bellenghi, Alexander A. Harnisch, Benjamin Bastian, Anastasia Maria Barbano, Markus Ackermann, S. W. Barwick, Matti Jansson, Immacolata Carmen Rea, P. Eller, Simone Garrappa, H. Schieler, Dmitry Chirkin, Kael Hanson, A. Kyriacou, A. Olivas, Hermann Kolanoski, Simeon Reusch, A. O. Pollmann, Elisa Bernardini, K. Meagher, S. Hickford, J. C. Gallagher, Kirill Filimonov, Mehmet Gunduz, Agnieszka Leszczyńska, R. C. Bay, Alexander Kappes, Pranav Dave, Jan Soedingrekso, K. Krings, Xianwu Xu, J. Sandroos, James Madsen, Lu Lu, M. J. Weiss, Stef Verpoest, H. Dujmovic, Austin Schneider, Juan Carlos Diaz-Velez, Jenni Adams, K.-H. Becker, Yiqian Xu, M. Plum, A. Wallace, Katharina Morik, J. Stettner, Daniel Bindig, Ramesh Koirala, Gerrit Wrede, C.P. de los Heros, Thomas Huber, Ek Narayan Paudel, Allan Hallgren, Matt Dunkman, R. Joppe, T. Stezelberger, Colin Turley, S. Kopper, Christian Glaser, Paolo Desiati, S. Sarker, C. Alispach, Damian Pieloth, R. G. Stokstad, Ali Kheirandish, Sreetama Goswami, Minjin Jeong, Martin Ha Minh, T. Glüsenkamp, Janet Conrad, G. Krückl, Jannis Necker, Sebastian Baur, R. Cross, Sebastian Fiedlschuster, Surujhdeo Seunarine, Ken'ichi Kin, Jannes Brostean-Kaiser, Chunfai Tung, Alejandro Diaz, M. J. Larson, M. U. Nisa, Tim Ruhe, E. O'Sullivan, René Reimann, Chad Finley, Federica Bradascio, A. V. Balagopal, Alexander Burgman, M. Meier, Michael Campana, F. Huang, Christoph Tönnis, Benjamin Hokanson-Fasig, E. Blaufuss, Leander Fischer, Gerrit Roellinghoff, Mirco Hunnefeld, Marie Oehler, Thomas Stuttard, William Luszczak, G. H. Collin, Sarah Pieper, Dirk Ryckbosch, S. Robertson, R. Snihur, A. Ludwig, Wing Yan Ma, Yang Lyu, Grant Parker, L. Köpke, Karl J. Clark, Juanan Aguilar, I. Safa, Merlin Schaufel, James DeLaunay, Marjon Moulai, Olga Botner, Cristian Jesus Lozano Mariscal, Kendall Mahn, L. Classen, Johan Wulff, K. Wiebe, Timothyblake Watson, J. J. Beatty, Tianlu Yuan, Stephan Meighen-Berger, S. Yoshida, Kayla Leonard, A. Ishihara, V. Baum, H. Niederhausen, Won Nam Kang, Joshua Hignight, A. Sharma, Sukeerthi Dharani, Francis Halzen, J. Merz, Paras Koundal, Mike Richman, X. Bai, Konstancja Satalecka, F. McNally, Emma C. Hettinger, I. Ansseau, Michael Kovacevich, Theo Glauch, Juliana Stachurska, H. Dembinski, Reina H. Maruyama, Frank G. Schröder, Summer Blot, Thomas Ehrhardt, D. Tosi, D. van Eijk, Mark Weyrauch, Spencer Axani, Elisa Lohfink, Aaron Fienberg, Amirreza Raissi, S. Tilav, Michael DuVernois, Carlos Arguelles, Jessie Micallef, Stephanie Bron, R. S. Busse, Y. L. Li, J. P. Yanez, Gerald Przybylski, Christian Haack, Christopher Wiebusch, R. Halliday, Kunal Deoskar, K. Helbing, Alexander Sandrock, N. Kurahashi, Todor Stanev, Benedikt Riedel, Cristina Lagunas Gualda, C. Wendt, G. W. Sullivan, A. Karle, James E. Braun, Philipp Furst, D. Hebecker, G. de Wasseige, George Japaridze, Roger Moore, Paul Coppin, Andrea Turcati, T. Gregoire, J. van Santen, R. Hoffmann, Alex Pizzuto, Gary Binder, J. Bourbeau, Richard Naab, Zhedong Zhang, C. Walck, Thomas K. Gaisser, Ava Ghadimi, Franziska Tischbein, Seongjin In, Elisa Resconi, Alessio Porcelli, P. Mallik, Catherine De Clercq, M. Rongen, Qinrui Liu, Martina Karl, Jochen M. Schneider, Christian Spiering, Justin Vandenbroucke, Maria Prado Rodriguez, Abhishek Desai, Xinyue Kang, Claudio Kopper, S. C. Nowicki, Subir Sarkar, T. Kintscher, Frederik Hermann Lauber, Justin Lanfranchi, David Vannerom, Ben Smithers, Jean Pierre Twagirayezu, A. Haungs, Rui An, Nahee Park, K. Hultqvist, Darren Grant, T. Stürwald, Z. Griffith, Felix Henningsen, A. R. Fazely, Simona Toscano, J. L. Kelley, Markus Ahlers, Erik Ganster, Samvel Ter-Antonyan, Rasha Abbasi, B. J. Whelan, Jan Weldert, L. Halve, Physics, Faculty of Sciences and Bioengineering Sciences, Vriendenkring VUB, Elementary Particle Physics, and collaboration, The IceCube
Subjects: FOS: Computer and information sciences, Computer Science - Machine Learning, Astrophysics::High Energy Astrophysical Phenomena, cs.LG, Data analysis, FOS: Physical sciences, Fitting methods, 01 natural sciences, Convolutional neural network, Calibration, Cluster finding, Neutrino detectors, Pattern recognition, High Energy Physics - Experiment, IceCube Neutrino Observatory, Machine Learning (cs.LG), High Energy Physics - Experiment (hep-ex), 0103 physical sciences, 010303 astronomy & astrophysics, Instrumentation, Mathematical Physics, 010308 nuclear & particles physics, business.industry, hep-ex, Deep learning, Detector, Neutrino detector, Computer engineering, Orders of magnitude (time), 13. Climate action, Cascade, Pattern recognition (psychology), Artificial intelligence, business
Abstract: Continued improvements on existing reconstruction methods are vital to the success of high-energy physics experiments, such as the IceCube Neutrino Observatory. In IceCube, further challenges arise as the detector is situated at the geographic South Pole where computational resources are limited. However, to perform real-time analyses and to issue alerts to telescopes around the world, powerful and fast reconstruction methods are desired. Deep neural networks can be extremely powerful, and their usage is computationally inexpensive once the networks are trained. These characteristics make a deep learning-based approach an excellent candidate for the application in IceCube. A reconstruction method based on convolutional architectures and hexagonally shaped kernels is presented. The presented method is robust towards systematic uncertainties in the simulation and has been tested on experimental data. In comparison to standard reconstruction methods in IceCube, it can improve upon the reconstruction accuracy, while reducing the time necessary to run the reconstruction by two to three orders of magnitude., Comment: 39 pages, 15 figures, submitted to Journal of Instrumentation; added references
Published: 2021

22. A specific amino acid motif of HLA-DRB1 mediates risk and interacts with smoking history in Parkinson’s disease

Author: Marcelo Fernandez-Vina, Stephen L. Hauser, Maneesh K. Misra, Wesley M. Marin, Jorge R. Oksenberg, Jill A. Hollenbach, Neda Nemat-Gorgani, Adam Renschen, Adam Santaniello, Lisa E. Creary, Kirsten M. Anderson, Gonzalo Montero-Martín, Vincent Damotte, Caroline M. Tanner, Kazutoyo Osoegawa, Paul Norman, Peter Parham, Ravi Dandekar, and Stacy J. Caillier
Subjects: Male, Models, Molecular, Aging, Genotype, Genotyping Techniques, Parkinson's disease, Amino Acid Motifs, Peptide binding, Human leukocyte antigen, Neurodegenerative, Epitope, smoking, Pathogenesis, Models, Risk Factors, Tobacco, Genetics, Medicine, Humans, Risk factor, Allele, HLA-DRB1, Multidisciplinary, Tobacco Smoke and Health, business.industry, Prevention, Arthritis, Human Genome, Smoking, Neurosciences, Molecular, Parkinson Disease, Odds ratio, Biological Sciences, Brain Disorders, HLA, Immunology, Parkinson’s disease, Female, business, shared epitope, HLA-DRB1 Chains
Abstract: Significance Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disease with both familial and sporadic forms and a clear genetic component. In addition, underlying immunoregulatory dysfunction and inflammatory processes have been implicated in PD pathogenesis. In this study, deep sequencing of HLA genes, which encode highly variable cell surface immune receptors, reveals specific variants conferring either risk or protection in PD. Because a history of cigarette smoking is known to be protective in PD, we analyzed the interaction of these genetic variants with smoking history in PD patients and healthy controls and found that the genetic effects are modified by history of cigarette smoking. These results provide a molecular model that explains the unique epidemiology of smoking in PD., Parkinson’s disease (PD) is a neurodegenerative disease in which genetic risk has been mapped to HLA, but precise allelic associations have been difficult to infer due to limitations in genotyping methodology. Mapping PD risk at highest possible resolution, we performed sequencing of 11 HLA genes in 1,597 PD cases and 1,606 controls. We found that susceptibility to PD can be explained by a specific combination of amino acids at positions 70–74 on the HLA-DRB1 molecule. Previously identified as the primary risk factor in rheumatoid arthritis and referred to as the “shared epitope” (SE), the residues Q/R-K/R-R-A-A at positions 70–74 in combination with valine at position 11 (11-V) is highly protective in PD, while risk is attributable to the identical epitope in the absence of 11-V. Notably, these effects are modified by history of cigarette smoking, with a strong protective effect mediated by a positive history of smoking in combination with the SE and 11-V (P = 10−4; odds ratio, 0.51; 95% confidence interval, 0.36–0.72) and risk attributable to never smoking in combination with the SE without 11-V (P = 0.01; odds ratio, 1.51; 95% confidence interval, 1.08–2.12). The association of specific combinations of amino acids that participate in critical peptide-binding pockets of the HLA class II molecule implicates antigen presentation in PD pathogenesis and provides further support for genetic control of neuroinflammation in disease. The interaction of HLA-DRB1 with smoking history in disease predisposition, along with predicted patterns of peptide binding to HLA, provide a molecular model that explains the unique epidemiology of smoking in PD.
Published: 2019

23. Risk for Hepatitis E Virus Transmission by Solvent/Detergent-Treated Plasma

Author: Xavier Tinard, Rachid Djoudi, Azzedine Assal, Florence Abravanel, Carole Mantovani, Pierre Tiberghien, Sébastien Lhomme, L. Hauser, Sylvie Gross, Pierre Gallian, Pascal Morel, Jacques Izopet, Elodie Pouchol, Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), and Etablissement Français du Sang [La Plaine Saint-Denis] (EFS)
Subjects: Microbiology (medical), infectious dose, Epidemiology, viruses, retrospective study, [SDV]Life Sciences [q-bio], Detergents, 030231 tropical medicine, lcsh:Medicine, hepatitis E virus, medicine.disease_cause, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, 0302 clinical medicine, Hepatitis E virus, Humans, Medicine, lcsh:RC109-216, Solvent detergent plasma, 030212 general & internal medicine, plasma, Retrospective Studies, Risk for Hepatitis E Virus Transmission by Solvent/Detergent–Treated Plasma, business.industry, Transmission (medicine), Research, Infectious dose, lcsh:R, transmission, virus diseases, Hepatitis E, medicine.disease, Virology, 3. Good health, zoonoses, Infectious Diseases, HEV, Solvents, RNA, Viral, blood donors, Infectious risk, solvent/detergent–treated plasma, France, business, Viral load
Abstract: International audience; Hepatitis E has emerged as a major transfusion-transmitted infectious risk. Two recipients of plasma from 2 lots (A and B) of pooled solvent/detergent-treated plasma were found to be infected by hepatitis E virus (HEV) that was determined to have been transmitted by the solvent/detergent-treated plasma. HEV RNA viral loads were 433 IU in lot A and 55 IU in lot B. Retrospective studies found that 100% (13/13) of evaluable lot A recipients versus 18% (3/17) of evaluable lot B recipients had been infected by HEV (p50,000 IU were infected, most likely by the HEV-containing solvent/detergent-treated plasma, versus only 7% with a transfused HEV RNA load
Published: 2020
Full Text: View/download PDF

24. EV-Scale Sterile Neutrino Search Using Eight Years of Atmospheric Muon Neutrino Data from the IceCube Neutrino Observatory

Author: K. Tollefson, Albrecht Karle, U. Katz, R. S. Busse, G. H. Collin, Christopher Wiebusch, Kunal Deoskar, Thomas Ehrhardt, P. Schlunder, R. Hellauer, Spencer Axani, D. B. Fox, Kayla Leonard, R. Maunu, Alan Coleman, Sukeerthi Dharani, Francis Halzen, J. Merz, S. Hickford, R. Joppe, A. Wallace, Delia Tosi, Sebastian Baur, M. G. Aartsen, Carlos Arguelles, David Vannerom, I. Ansseau, Hermann Kolanoski, Juliana Stachurska, H. Dembinski, Stef Verpoest, Jessie Micallef, Matthias Vraeghe, George Japaridze, Roger Moore, Tim Ruhe, N. Kurahashi, Todor Stanev, C. Wendt, Ioana Codrina Maris, H. Bagherpour, Johan Wulff, Sebastian Böser, Olga Botner, J. Kim, Elisa Bernardini, A. Ludwig, Christoph Raab, Nadège Iovine, Timothyblake Watson, D. Heereman, Gisela Anton, M. Stamatikos, J. Bourbeau, K. Rawlins, G. de Wasseige, Won Nam Kang, V. Baum, Jenni Adams, D. Berley, G. C. Hill, H. Niederhausen, A. Steuer, C. Alispach, Bunheng Ty, Stephen L. Hauser, Raamis Hussain, Janet Conrad, B. Relethford, Jan Soedingrekso, Ralph Engel, Moritz Kellermann, Z. Griffith, Y. Makino, Seongjin In, R. Hoffmann, James Madsen, Konstancja Satalecka, Benjamin Bastian, Theo Glauch, Anastasia Maria Barbano, Saskia Philippen, F. Jonske, R. Cross, M. J. Larson, Lu Lu, T. Kittler, X. Bai, G. Neer, Alexander Fritz, A. Goldschmidt, D. van Eijk, Lenka Tomankova, Giovanni Renzi, D. Seckel, S. Fahey, Elisa Resconi, Alessio Porcelli, Claudio Kopper, Daniel Bindig, G. Krückl, Alejandro Diaz, C. Pérez de los Heros, E. O’Sullivan, Le Viet Nguyen, Wing Yan Ma, James DeLaunay, Marjon Moulai, R. G. Stokstad, K. Krings, M. Plum, P. B. Price, William Luszczak, M. Kauer, Suyong Choi, David Kappesser, S. E. Sanchez Herrera, Francesco Lucarelli, T. O. B. Schmidt, Tyce DeYoung, Chad Finley, Nathan Whitehorn, Immacolata Carmen Rea, Matti Jansson, D. Z. Besson, C. Walck, Thomas K. Gaisser, G. B. Yodh, A. Kyriacou, M. Silva, Najia Moureen Binte Amin, K.-H. Becker, Yiqian Xu, Qinrui Liu, J. Becker Tjus, T. Glüsenkamp, Subir Sarkar, Martina Karl, Matt Dunkman, Kendall Mahn, Christoph Tönnis, F. Huang, K. Meagher, Jochen M. Schneider, J. Stettner, T. R. Wood, Kurt Woschnagg, Paul Evenson, T. Palczewski, S. De Ridder, Y. L. Li, G. W. Sullivan, J. J. Beatty, Tianlu Yuan, Jeffrey Lazar, Chunfai Tung, James E. Braun, Alexander Trettin, E. Cheung, J. Werthebach, Thomas Stuttard, Mirco Hunnefeld, Marie Oehler, Alexander Sandrock, Elisa Lohfink, Thomas Meures, N. L. Strotjohann, M. A. Unland Elorrieta, M. Wallraff, Michael DuVernois, Benjamin Hokanson-Fasig, Felix Henningsen, Karl J. Clark, Simone Garrappa, Dmitry Chirkin, Sarah Pieper, D. Hebecker, Anatoli Fedynitch, K. Helbing, Chujie Chen, Dirk Ryckbosch, Joshua Hignight, M. Zöcklein, T. Grégoire, Timo Sturwald, J. C. Gallagher, Timo Karg, Gerald Przybylski, Federica Bradascio, Yang Lyu, Alexander Kappes, Alexander Burgman, M. Song, T. L. Carver, Paras Koundal, Mike Richman, Sarah Mancina, Paul Coppin, Anna Franckowiak, Tobias Hoinka, Vedant Basu, Steve Sclafani, F. McNally, A. R. Fazely, M. Usner, Grant Parker, R. Halliday, Stephan Meighen-Berger, K. D. de Vries, Gerrit Wrede, Andrea Turcati, J. van Santen, K. Hoshina, Glenn Spiczak, Thomas Huber, G. Momenté, Merlin Schaufel, A. Stößl, J. Kiryluk, K. Andeen, D. R. Nygren, Marek Kowalski, A. Weindl, Maryon Ahrens, Frederik Tenholt, R. Nagai, M. Medici, M. Rameez, Javier Gonzalez, Roxanne Turcotte, Alex Pizzuto, D. F. Cowen, Reina H. Maruyama, E. Pinat, N. Kulacz, U. Naumann, Martin Rongen, Ek Narayan Paudel, Allan Hallgren, Giorgio Maggi, K. Wiebe, A. Balagopal, Gary Binder, Zhedong Zhang, E. Unger, Simona Toscano, J. Auffenberg, Pablo Correa, Summer Blot, Brian Clark, C. De Clercq, P. Heix, K. Mase, P. Mallik, M. E. Huber, A. O'Murchadha, Marcos Santander, Ramesh Koirala, David A. Williams, L. Schumacher, Benedikt Riedel, S. Tilav, Max Renschler, D. Kang, D. J. Koskinen, Markus Ackermann, S. W. Barwick, L. Gerhardt, M. J. Weiss, E. Bourbeau, J. P. Yanez, Ben Smithers, Colin Turley, A. Olivas, S. Kopper, Spencer Griswold, I. Taboada, Michael O. Wolf, René Reimann, A. Haungs, M. Prado Rodriguez, Maria Tselengidou, D. Soldin, Nahee Park, Pranav Dave, K. Hultqvist, Darren Grant, E. Blaufuss, Mehmet Gunduz, Agnieszka Leszczyńska, R. C. Bay, M. Günder, Austin Schneider, Steven Robertson, Juan Carlos Diaz-Velez, Shefali Shefali, L. Classen, T. Stezelberger, Abdul Rehman, Carsten Rott, Y. Popovych, T. Kintscher, Frederik Hermann Lauber, Xianwu Xu, A. Terliuk, J. Sandroos, C. Bohm, Justin Lanfranchi, Christian Spiering, Justin Vandenbroucke, Abhishek Desai, S. C. Nowicki, Rasha Abbasi, B. J. Whelan, Jan Weldert, L. Halve, Philipp Eller, J. Felde, J. Buscher, D. Rysewyk Cantu, A. Obertacke Pollmann, J. L. Kelley, Markus Ahlers, Erik Ganster, Samvel Ter-Antonyan, Frank G. Schröder, J. Lünemann, N. van Eijndhoven, C. Haack, Emily Dvorak, Aaron Fienberg, Amirreza Raissi, Minjin Jeong, Chris Weaver, Stephanie Bron, C. J. Lozano Mariscal, H. Dujmovic, L. Rauch, S. Yoshida, Surujhdeo Seunarine, R. Snihur, Juanan Aguilar, Kael Hanson, A. Ishihara, Maximilian Meier, Paolo Desiati, Segev BenZvi, Spencer Klein, B. J. P. Jones, Andres Medina, Kara Hoffman, D. Mockler, Hershal Pandya, Daria Pankova, E. Friedman, Wolfgang Rhode, Robert Stein, L. Wills, P. Muth, R. Morse, Jakob Bottcher, T. Montaruli, Maximilian Karl Scharf, P. Peiffer, Ibrahim Safa, Damian Pieloth, Ali Kheirandish, W. Van Driessche, Jannes Brostean-Kaiser, M. U. Nisa, L. Köpke, T. Anderson, John Hardin, H. Schieler, Kirill Filimonov, Physics, Faculty of Sciences and Bioengineering Sciences, Vriendenkring VUB, and Elementary Particle Physics
Subjects: Sterile neutrino, Physics::Instrumentation and Detectors, General Physics and Astronomy, sterile [neutrino], 01 natural sciences, Cosmology, IceCube, High Energy Physics - Experiment, Subatomär fysik, High Energy Physics - Experiment (hep-ex), High Energy Physics - Phenomenology (hep-ph), Astronomi, astrofysik och kosmologi, Subatomic Physics, TOOL, Astronomy, Astrophysics and Cosmology, atmosphere [muon], Muon neutrino, Physics, oscillation [neutrino], Astrophysics::Instrumentation and Methods for Astrophysics, hep-ph, neutrino: sterile, mass difference [neutrino], ddc, muon: atmosphere, observatory, High Energy Physics - Phenomenology, Physique des particules élémentaires, signature, Particle physics, data analysis method, Scale (ratio), Astrophysics::High Energy Astrophysical Phenomena, neutrino: mass difference, FOS: Physical sciences, IceCube Neutrino Observatory, statistical analysis, 0103 physical sciences, OSCILLATIONS, ddc:530, 010306 general physics, hep-ex, ICE, High Energy Physics::Phenomenology, neutrino: mixing angle, CONVERSION, Physics and Astronomy, COSMOLOGY, High Energy Physics::Experiment, neutrino: oscillation, BAYESIAN-INFERENCE, mixing angle [neutrino], experimental results
Abstract: Physical review letters 125(14), 141801 (1-11) (2020). doi:10.1103/PhysRevLett.125.141801, The results of a 3+1 sterile neutrino search using eight years of data from the IceCube Neutrino Observatory are presented. A total of 305 735 muon neutrino events are analyzed in reconstructed energy-zenith space to test for signatures of a matter-enhanced oscillation that would occur given a sterile neutrino state with a mass-squared differences between 0.01 and 100 eV$^2$. The best-fit point is found to be at sin$^2$($2θ_{24}$)=0.10 and $Δm_{41}^2$=4.5 eV$^2$, which is consistent with the no sterile neutrino hypothesis with a $p$ value of 8.0%., Published by APS, College Park, Md.
Published: 2020
Full Text: View/download PDF

25. IceCube-Gen2: The Window to the Extreme Universe

Author: J. Kim, A. Gartner, A. Obertacke Pollmann, B. Hoffmann, J. L. Kelley, Markus Ahlers, Jenni Adams, Akimichi Taketa, D. van Eijk, Daniel Bindig, G. H. Collin, T. C. Arlen, Robert Lahmann, J. J. Beatty, Tianlu Yuan, U. Nauman, Azadeh Keivani, Y. L. Li, Karl J. Clark, T. Kintscher, M. Song, T. L. Carver, Paras Koundal, Michael Kovacevich, Christian Glaser, Frederik Hermann Lauber, T. Huege, Erik Ganster, Benedikt Riedel, D. Seckel, Anna Nelles, R. G. Stokstad, F. McNally, R. Maunu, M. Prado Rodriguez, Kayla Leonard, N. Kurahashi, James E. Braun, Amy Connolly, Samvel Ter-Antonyan, A. Terliuk, Justin Lanfranchi, Pranav Dave, Jannis Necker, C. Wendt, S. Wren, A. Sharma, Sukeerthi Dharani, David Vannerom, M. H. Shaevitz, Alexander Trettin, Reina H. Maruyama, Francis Halzen, J. Merz, K. Krings, Rasha Abbasi, Ben Smithers, Qinrui Liu, M. J. Larson, T. Anderson, Summer Blot, G. de Wasseige, I. Ansseau, D. Hebecker, Jorge Torres, Killian Holzapfel, Martina Karl, C. J. Lozano Mariscal, John Hardin, Jean Pierre Twagirayezu, Daniel García-Fernández, T. Stezelberger, S. Mandalia, E. O'Sullivan, R. Hoffmann, M. Plum, Juliana Stachurska, H. Dembinski, C. Pérez de los Heros, S. Márka, G. WSullivan, A. Haungs, Paul Coppin, Z. Griffith, J. C. Gallagher, Saskia Philippen, Federica Bradascio, Jochen M. Schneider, Srubabati Goswami, Andrea Turcati, Wing Yan Ma, Nahee Park, Y. Makino, Sarah Mancina, C. Walck, M. Kauer, Suyong Choi, Anna Franckowiak, Tobias Hoinka, Chad Finley, David Kappesser, T. Gregoire, Ella Roberts, J. van Santen, S. De Ridder, Jan Weldert, Chunfai Tung, F. Jonske, Ken'ichi Kin, L. Halve, Philipp Eller, K. Hultqvist, N. L. Strotjohann, H. Dujmovic, Vedant Basu, M. A. Unland Elorrieta, Alex Pizzuto, K. D. de Vries, I. CMariş, Gerrit Wrede, R. Gernhaeuser, Thomas Huber, Matti Jansson, Thomas K. Gaisser, M. Richman, Christoph Tönnis, James DeLaunay, Gary Binder, K.-H. Becker, Ek Narayan Paudel, Allan Hallgren, U. Latif, Hiroyuki Tanaka, I. Safa, Steve Sclafani, J. Kiryluk, K. Andeen, P. B. Price, H. Schieler, Kirill Filimonov, Segev BenZvi, Alexander Fritz, D. Z. Besson, Darren Grant, Marjon Moulai, Yiqian Xu, Felix Henningsen, S. Robertson, Aswathi Balagopal, Francesco Lucarelli, Pisin Chen, Matt Dunkman, Merlin Schaufel, Patrick Allison, Spencer Klein, Cosmin Deaconu, Tim Ruhe, A. Ludwig, George Japaridze, Javier Gonzalez, C. B. Krauss, Roxanne Turcotte, T. O. B. Schmidt, Simona Toscano, Roger Moore, P. Heix, R. S. Busse, Chujie Chen, Pablo Correa, L. Gerhard, S. De Kockere, J. Felde, Surujhdeo Seunarine, R. Snihur, J. Buscher, D. Rysewyk Cantu, A. Weindl, R. Hellauer, Giorgio Maggi, H. Niederhausen, Mauricio Bustamante, D. Southall, Julia Böttcher, J. Bourbeau, Lenka Tomankova, Maryon Ahrens, A. Burgman, Christopher Wiebusch, Darko Veberič, Juanan Aguilar, T. R. Wood, Christian Spiering, Frederik Tenholt, R. Nagai, L. Schumacher, C. De Clercq, Benjamin Hokanson-Fasig, L. V. Nguyen, C. Lagunas Gualda, K. Hughes, Kara Hoffman, C. Alispach, J. M. LoSecco, Joshua Hignight, K. Helbing, Timo Sturwald, Xinyue Kang, Richard Naab, Kunal Deoskar, Janet Conrad, Zackary Meyers, K. Meagher, Mehmet Gunduz, Agnieszka Leszczyńska, R. C. Bay, David A. Williams, Kurt Woschnagg, M. Zöcklein, M. Silva, Claudio Kopper, Eric Oberla, Ramesh Koirala, E. Cheung, Thomas Stuttard, Martin Rongen, Najia Moureen Binte Amin, R. Cross, Paul Evenson, A. Karle, Sebastian Böser, Seongjin In, Johannes Werthebach, J. P. Lazar, Markus Ackermann, Austin Schneider, Yang Lyu, Justin Vandenbroucke, Juan Carlos Diaz-Velez, Beverley A. Clark, Timo Karg, Sarah Pieper, Hershal Pandya, Wolfgang Rhode, Zhedong Zhang, P. Schlunder, A. Ishihara, Elisa Resconi, Subir Sarkar, William Luszczak, Clara E. Hill, Ava Ghadimi, Alessio Porcelli, Alan Coleman, J. Auffenberg, Grant Parker, Robert Stein, Dirk Ryckbosch, Benjamin Bastian, Anastasia Maria Barbano, Abhishek Desai, T. Kittler, J. Nam, P. Mallik, E. Blaufuss, S. Zierke, T. Stanev, M. Bohmer, Stephan Meighen-Berger, Simone Garrappa, P. Muth, Dmitry Chirkin, M. E. Huber, Marcos Santander, Christoph Raab, Nadège Iovine, J. Becker Tjus, L. Classen, Colin Turley, S. C. Nowicki, K. Farrag, M. Kleifges, O. Kalekin, A. Olivas, Alexander Kappes, D. Berley, G. C. Hill, Abigail G. Vieregg, Frank G. Schröder, D. Heinen, Erin Carnie-Bronca, N. Kulacz, D. Tosi, J. C. Hanson, Bunheng Ty, Ralph Engel, Moritz Kellermann, Gisela Anton, Elisa Lohfink, Elisa Bernardini, Damian Pieloth, Ali Kheirandish, Jan Soedingrekso, Giovanni Renzi, Michael DuVernois, Jannes Brostean-Kaiser, K. Wiebe, S. Fahey, A. R. Fazely, Tyce DeYoung, J. Lünemann, Thomas Ehrhardt, Nathan Whitehorn, Immacolata Carmen Rea, M. U. Nisa, Aaron Fienberg, Gerald Przybylski, G. Krückl, L. Papp, Amirreza Raissi, L. Köpke, Chris Weaver, R. Halliday, Alejandro Diaz, Stephanie Bron, S. Söldner-Rembold, James Pinfold, Ryan Burley, M. Riegel, H. Bagherpour, Stephanie Wissel, Olga Botner, Y. Pan, A. Steuer, S. Tilav, D. Kang, M. deWith, V. Baum, J. P. Yanez, I. Taboada, Stephen L. Hauser, Raamis Hussain, Michael O. Wolf, M. Stamatikos, John Evans, Shefali Shefali, Christoph Welling, Abdul Rehman, Carsten Rott, K. Tollefson, A. Goldschmidt, Y. Popovych, Troels Petersen, S. E. Sanchez Herrera, Simeon Reusch, S. Hickford, Xianwu Xu, J. Sandroos, C. Bohm, R. Joppe, Spencer Axani, Sebastian Baur, Carlos Arguelles, Jessie Micallef, Teppei Katori, K. Rawlins, James Madsen, Lu Lu, M. G. Aartsen, T. Glüsenkamp, M. Meier, Michael Campana, P. Sandstrom, Kendall Mahn, B. J. P. Jones, K. Hoshina, Glenn Spiczak, Andres Medina, G. Momenté, D. Mockler, M. Rameez, D. F. Cowen, Daria Pankova, E. Friedman, R. Morse, T. Montaruli, E. Unger, Maximilian Karl Scharf, P. Peiffer, J. Stettner, Gerrit Roellinghoff, Mirco Hunnefeld, Marie Oehler, Max Renschler, D. J. Koskinen, E. Bourbeau, Spencer Griswold, Maria Tselengidou, D. Soldin, Z. Márka, Minjin Jeong, L. Rauch, S. Yoshida, N. van Eijndhoven, C. Haack, Emily Dvorak, D. R. Nygren, Marek Kowalski, Kael Hanson, Paolo Desiati, J. Haugen, Lars Steffen Weinstock, Johan Wulff, Won Nam Kang, Timothyblake Watson, X. Bai, G. Neer, Konstancja Satalecka, Theo Glauch, U. Katz, Alexander Sandrock, Ilse Plaisier, K. Mase, D. B. Fox, Hermann Kolanoski, M. J. Weiss, Stef Verpoest, Imre Bartos, David J. Smith, S. Kopper, René Reimann, Leander Fischer, F. Huang, Matthias Vraeghe, Physics, Faculty of Sciences and Bioengineering Sciences, Vriendenkring VUB, and Elementary Particle Physics
Subjects: Physics, High Energy Astrophysical Phenomena (astro-ph.HE), astro-ph.HE, Nuclear and High Energy Physics, Active galactic nucleus, 010308 nuclear & particles physics, High-energy astronomy, Gravitational wave, media_common.quotation_subject, Astrophysics::High Energy Astrophysical Phenomena, Astrophysics::Instrumentation and Methods for Astrophysics, Astronomy, FOS: Physical sciences, Cosmic ray, 01 natural sciences, Universe, Neutron star, 0103 physical sciences, Neutrino, Neutrino astronomy, Astrophysics - High Energy Astrophysical Phenomena, 010303 astronomy & astrophysics, media_common
Abstract: The observation of electromagnetic radiation from radio to $\gamma$-ray wavelengths has provided a wealth of information about the universe. However, at PeV (10$^{15}$ eV) energies and above, most of the universe is impenetrable to photons. New messengers, namely cosmic neutrinos, are needed to explore the most extreme environments of the universe where black holes, neutron stars, and stellar explosions transform gravitational energy into non-thermal cosmic rays. The discovery of cosmic neutrinos with IceCube has opened this new window on the universe. In this white paper, we present an overview of a next-generation instrument, IceCube-Gen2, which will sharpen our understanding of the processes and environments that govern the universe at the highest energies. IceCube-Gen2 is designed to: 1) Resolve the high-energy neutrino sky from TeV to EeV energies; 2) Investigate cosmic particle acceleration through multi-messenger observations; 3) Reveal the sources and propagation of the highest energy particles in the universe; 4) Probe fundamental physics with high-energy neutrinos. IceCube-Gen2 will increase the annual rate of observed cosmic neutrinos by a factor of ten compared to IceCube, and will be able to detect sources five times fainter than its predecessor. Furthermore, through the addition of a radio array, IceCube-Gen2 will extend the energy range by several orders of magnitude compared to IceCube. Construction will take 8 years and cost about \$350M. The goal is to have IceCube-Gen2 fully operational by 2033. IceCube-Gen2 will play an essential role in shaping the new era of multi-messenger astronomy, fundamentally advancing our knowledge of the high-energy universe. This challenging mission can be fully addressed only in concert with the new survey instruments across the electromagnetic spectrum and gravitational wave detectors which will be available in the coming years., Comment: 56 pages, 29 figures
Published: 2020
Full Text: View/download PDF

26. A major histocompatibility Class I locus contributes to multiple sclerosis susceptibility independently from HLA-DRB1*15:01.

Author: Bruce A C Cree, John D Rioux, Jacob L McCauley, Pierre-Antoine F D Gourraud, Philippe Goyette, Joseph McElroy, Philip De Jager, Adam Santaniello, Timothy J Vyse, Peter K Gregersen, Daniel Mirel, David A Hafler, Jonathan L Haines, Margaret A Pericak-Vance, Alastair Compston, Stephen J Sawcer, Jorge R Oksenberg, Stephen L Hauser, IMAGEN, and IMSGC
Subjects: Medicine, Science
Abstract: In Northern European descended populations, genetic susceptibility for multiple sclerosis (MS) is associated with alleles of the human leukocyte antigen (HLA) Class II gene DRB1. Whether other major histocompatibility complex (MHC) genes contribute to MS susceptibility is controversial.A case control analysis was performed using 958 single nucleotide polymorphisms (SNPs) spanning the MHC assayed in two independent datasets. The discovery dataset consisted of 1,018 cases and 1,795 controls and the replication dataset was composed of 1,343 cases and 1,379 controls. The most significantly MS-associated SNP in the discovery dataset was rs3135391, a Class II SNP known to tag the HLA-DRB1*15:01 allele, the primary MS susceptibility allele in the MHC (O.R. = 3.04, p < 1 x 10(-78)). To control for the effects of the HLA-DRB1*15:01 haplotype, case control analysis was performed adjusting for this HLA-DRB1*15:01 tagging SNP. After correction for multiple comparisons (false discovery rate = .05) 52 SNPs in the Class I, II and III regions were significantly associated with MS susceptibility in both datasets using the Cochran Armitage trend test. The discovery and replication datasets were merged and subjects carrying the HLA-DRB1*15:01 tagging SNP were excluded. Association tests showed that 48 of the 52 replicated SNPs retained significant associations with MS susceptibility independently of the HLA-DRB1*15:01 as defined by the tagging SNP. 20 Class I SNPs were associated with MS susceptibility with p-values < or = 1 x 10(-8). The most significantly associated SNP was rs4959039, a SNP in the downstream un-translated region of the non-classical HLA-G gene (Odds ratio 1.59, 95% CI 1.40, 1.81, p = 8.45 x 10(-13)) and is in linkage disequilibrium with several nearby SNPs. Logistic regression modeling showed that this SNP's contribution to MS susceptibility was independent of the Class II and Class III SNPs identified in this screen.A MHC Class I locus contributes to MS susceptibility independently of the HLA-DRB1*15:01 haplotype.
Published: 2010
Full Text: View/download PDF

27. IL2RA genetic heterogeneity in multiple sclerosis and type 1 diabetes susceptibility and soluble interleukin-2 receptor production.

Author: Lisa M Maier, Christopher E Lowe, Jason Cooper, Kate Downes, David E Anderson, Christopher Severson, Pamela M Clark, Brian Healy, Neil Walker, Cristin Aubin, Jorge R Oksenberg, Stephen L Hauser, Alistair Compston, Stephen Sawcer, International Multiple Sclerosis Genetics Consortium, Philip L De Jager, Linda S Wicker, John A Todd, and David A Hafler
Subjects: Genetics, QH426-470
Abstract: Multiple sclerosis (MS) and type 1 diabetes (T1D) are organ-specific autoimmune disorders with significant heritability, part of which is conferred by shared alleles. For decades, the Human Leukocyte Antigen (HLA) complex was the only known susceptibility locus for both T1D and MS, but loci outside the HLA complex harboring risk alleles have been discovered and fully replicated. A genome-wide association scan for MS risk genes and candidate gene association studies have previously described the IL2RA gene region as a shared autoimmune locus. In order to investigate whether autoimmunity risk at IL2RA was due to distinct or shared alleles, we performed a genetic association study of three IL2RA variants in a DNA collection of up to 9,407 healthy controls, 2,420 MS, and 6,425 T1D subjects as well as 1,303 MS parent/child trios. Here, we report "allelic heterogeneity" at the IL2RA region between MS and T1D. We observe an allele associated with susceptibility to one disease and risk to the other, an allele that confers susceptibility to both diseases, and an allele that may only confer susceptibility to T1D. In addition, we tested the levels of soluble interleukin-2 receptor (sIL-2RA) in the serum from up to 69 healthy control subjects, 285 MS, and 1,317 T1D subjects. We demonstrate that multiple variants independently correlate with sIL-2RA levels.
Published: 2009
Full Text: View/download PDF

28. Onset of clinical and MRI efficacy of ocrelizumab in relapsing multiple sclerosis

Author: Laura Julian, Jian Han, Frederik Barkhof, Shibeshih Belachew, Hans-Peter Hartung, Annette Sauter, Amit Bar-Or, Jerry S. Wolinsky, Ludwig Kappos, David K.B. Li, Stephen L. Hauser, Harold Koendgen, Julie Napieralski, Radiology and nuclear medicine, and Amsterdam Neuroscience - Neuroinfection & -inflammation
Subjects: Male, Time Factors, Phases of clinical research, Neurodegenerative, Relapsing-Remitting, Gastroenterology, law.invention, 0302 clinical medicine, Randomized controlled trial, Immunologic, law, Recurrence, Monoclonal, Humanized, Cancer, education.field_of_study, medicine.diagnostic_test, Brain, Middle Aged, Magnetic Resonance Imaging, 3. Good health, Treatment Outcome, 6.1 Pharmaceuticals, 030220 oncology & carcinogenesis, Cognitive Sciences, Female, Interferon beta-1a, medicine.drug, Adult, medicine.medical_specialty, Multiple Sclerosis, Clinical Trials and Supportive Activities, Clinical Sciences, Population, Placebo, Antibodies, Monoclonal, Humanized, Antibodies, Article, 03 medical and health sciences, Rare Diseases, Multiple Sclerosis, Relapsing-Remitting, Adjuvants, Immunologic, Clinical Research, Internal medicine, medicine, Humans, Immunologic Factors, Adjuvants, education, Neurology & Neurosurgery, business.industry, Multiple sclerosis, Neurosciences, Evaluation of treatments and therapeutic interventions, Magnetic resonance imaging, medicine.disease, Brain Disorders, Clinical trial, Ocrelizumab, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: ObjectiveTo assess the onset of ocrelizumab efficacy on brain MRI measures of disease activity in the phase II study in relapsing-remitting multiple sclerosis (RRMS), and relapse rate in the pooled phase III studies in relapsing multiple sclerosis (RMS).MethodsBrain MRI activity was determined in the phase II trial at monthly intervals in patients with RRMS receiving placebo, ocrelizumab (600 mg), or intramuscular interferon (IFN) β-1a (30 μg). Annualized relapse rate (ARR; over various epochs) and time to first relapse were analyzed in the pooled population of the phase III OPERA (A Study of Ocrelizumab in Comparison With Interferon Beta-1a [Rebif] in Participants With Relapsing Multiple Sclerosis) I and OPERA II trials in patients with RMS receiving ocrelizumab (600 mg) or subcutaneous IFN-β-1a (44 μg).ResultsIn patients with RRMS, ocrelizumab reduced the number of new T1 gadolinium-enhancing lesions by week 4 vs placebo (p = 0.042) and by week 8 vs intramuscular IFN-β-1a (p < 0.001). Ocrelizumab also reduced the number of new or enlarging T2 lesions appearing between weeks 4 and 8 vs both placebo and IFN-β-1a (both p < 0.001). In patients with RMS, ocrelizumab significantly reduced ARR (p = 0.005) and the probability of time to first protocol-defined relapse (p = 0.014) vs subcutaneous IFN-β-1a within the first 8 weeks.ConclusionEpoch analysis of MRI-measured lesion activity in the phase II study and relapse rate in the phase III studies consistently revealed a rapid suppression of acute MRI and clinical disease activity following treatment initiation with ocrelizumab in patients with RRMS and RMS, respectively.Classification of evidenceThis study provides Class II evidence that for patients with RRMS and RMS, ocrelizumab suppressed MRI activity within 4 weeks and clinical disease activity within 8 weeks.
Published: 2019
Full Text: View/download PDF

29. Serological and metagenomic interrogation of cerebrospinal fluid implicates enteroviruses in pediatric acute flaccid myelitis

Author: Leslie Benson, Cristina M. Tato, Gavin A. Sowa, Michelle Tan, Debarko Banerji, Carly K. Cheung, Mark P. Gorman, Joseph L. DeRisi, Debra A. Wadford, Charles Y. Chiu, Isobel A. Hawes, Amy A. Gelfand, Hannah A. Sample, Cynthia Yen, M. Steven Oberste, Brian D. O’Donovan, Emily D. Crawford, Kalpathy S. Krishnamoorthy, Rachel L. Marine, Benjamin Briggs, W. Allan Nix, Tanuja Chitnis, Carol A. Glaser, Terry Fei Fan Ng, Kendall B. Nash, Kelsey C. Zorn, John E. Pak, Victoria Chu, Michael R. Wilson, Adriana S. Lopez, Wesley Wu, Samuel R. Dominguez, Joy Z. Ding, Jennifer L. Konopka-Anstadt, Bethany L. Johnson-Kerner, Rene Sit, Ryan D. Schubert, Ariane Soldatos, Akshaya Ramesh, Stephen L. Hauser, Lillian M. Khan, Amy Lyden, Kevin Messacar, Riley Bove, Hugh J. McMillan, and Prashanth S. Ramachandran
Subjects: 0303 health sciences, Phage display, biology, RNA, medicine.disease_cause, Virology, Acute flaccid myelitis, Virus, 3. Good health, Serology, 03 medical and health sciences, 0302 clinical medicine, Cerebrospinal fluid, medicine, biology.protein, Enterovirus, 030212 general & internal medicine, Antibody, 030304 developmental biology
Abstract: BackgroundSince 2014, the United States has experienced a biennial spike in pediatric acute flaccid myelitis (AFM). Epidemiologic evidence suggests non-polio enteroviruses (EVs) are a potential etiology, yet EV RNA is rarely detected in cerebrospinal fluid (CSF) and only inconsistently identified from the respiratory tract, serum, or stool.MethodsWe interrogated CSF from children with AFM (n=42) and pediatric controls with other neurologic diseases (OND) (n=58). Samples were incubated with T7 bacteriophage expressing 481,966 sixty-two amino acid peptides with a fourteen amino acid overlap tiled across all known vertebrate virus and arbovirus genomes, an adaption of the VirScan method. Antibody-bound phage were deep sequenced to quantify enriched peptides with normalized counts expressed as reads per hundred thousand (rpK). EV antibody findings were confirmed with ELISA using whole viral protein 1 (VP1) from contemporary enterovirus (EV) A71 and D68 strains. Separately, metagenomic next-generation sequencing (mNGS) of CSF RNA, both unbiased and with targeted enrichment for EVs, was performed.ResultsThe most significantly enriched viral family by VirScan of CSF in AFM versus OND controls wasPicornaviridae(mean rpK 11,266 versus mean rpK 950, p-adjusted < 0.001, Wilcoxon signed-rank test with Bonferroni adjustment). EnrichedPicornaviridaepeptides belonged almost entirely to the genusEnterovirus.The mean EV VP1 ELISA signal in AFM (mean OD 0.51) was significantly higher than OND controls (mean OD 0.08, p-value < 0.001, Mann-Whitney test). mNGS did not detect additional enterovirus RNA in CSF.ConclusionDespite the rare detection of EV RNA in the CNS of patients with AFM, a pan-viral serologic assay identified high levels of CSF EV antibodies in AFM CSF compared to CSF from OND controls. These results provide further evidence for a causal role of non-polio enteroviruses in AFM.
Published: 2019
Full Text: View/download PDF

30. A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis

Author: Seema Kalra, Graeme J. Stewart, Katrina Dedham, Tfm Andlauer, Frauke Zipp, X Jia, Adam Santaniello, Bertrand Fontaine, Stacy J Caillier, Giancarlo Comi, Hanne F. Harbo, Ashley Beecham, Lisa F. Barcellos, Jacob L. McCauley, Aarno Palotie, P. L. De Jager, Ji Kira, Noriko Isobe, B. Hemmer, Lincoln, Farren B.S. Briggs, Christina M. Lill, Sergio E. Baranzini, Booth, F. Martinelli-Boneschi, A. Oturai, Pierre Duquette, Janna Saarela, A Compston, Roland G. Henry, D Efthimios, Chris Cotsapas, Jonathan L. Haines, Clive Hawkins, Federica Esposito, David A. Hafler, Giorgos M. Hadjigeorgiou, Elisabeth Gulowsen Celius, Stephen Sawcer, Lohith Madireddy, Oksenberg, Christiane Gasperi, Bac Cree, Luisa Bernardinelli, Felix Luessi, A Ivinson, Nikolaos A. Patsopoulos, Steffan D. Bos, Tomas Olsson, Bénédicte Dubois, Ingrid Kockum, Dana Horakova, Margaret A. Pericak-Vance, R Q Hintzen, An Goris, Sandra D'Alfonso, Tone Berge, Michael Khalil, Stephen L. Hauser, Bruce V. Taylor, Kicheol Kim, Roland Martin, Pierre-Antoine Gourraud, Manuel Comabella, Apollo - University of Cambridge Repository, Immunology, Neurology, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Janna Saarela / Principal Investigator, and Genomics of Neurological and Neuropsychiatric Disorders
Subjects: 0301 basic medicine, General Physics and Astronomy, Genome-wide association study, 02 engineering and technology, Neurodegenerative, Genome informatics, Genome-wide association studies, PATHWAY, Genes, Regulator, 2.1 Biological and endogenous factors, GWAS, Aetiology, lcsh:Science, CYTOSCAPE, Multidisciplinary, Systems Biology, 1184 Genetics, developmental biology, physiology, Single Nucleotide, RC346, 021001 nanoscience & nanotechnology, ddc, Multidisciplinary Sciences, Trait, Science & Technology - Other Topics, 0210 nano-technology, Biotechnology, EXPRESSION, Cell type, Cellular signalling networks, Multiple Sclerosis, Genotype, POLYGENIC RISK SCORE, Science, Systems biology, Computational biology, Biology, Autoimmune Disease, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, Multiple sclerosis, 03 medical and health sciences, Immune system, Clinical Research, MD Multidisciplinary, Genetics, medicine, Humans, Genetic Predisposition to Disease, Polymorphism, GENOME-WIDE ASSOCIATION, Author Correction, Gene, Genetic association, Science & Technology, Inflammatory and immune system, Regulator, Human Genome, Neurosciences, General Chemistry, medicine.disease, Brain Disorders, International Multiple Sclerosis Genetics Consortium, 030104 developmental biology, Genes, Gene Expression Regulation, lcsh:Q, 3111 Biomedicine, Genome-Wide Association Study
Abstract: Genome-wide association studies (GWAS) have identified more than 50,000 unique associations with common human traits. While this represents a substantial step forward, establishing the biology underlying these associations has proven extremely difficult. Even determining which cell types and which particular gene(s) are relevant continues to be a challenge. Here, we conduct a cell-specific pathway analysis of the latest GWAS in multiple sclerosis (MS), which had analyzed a total of 47,351 cases and 68,284 healthy controls and found more than 200 non-MHC genome-wide associations. Our analysis identifies pan immune cell as well as cell-specific susceptibility genes in T cells, B cells and monocytes. Finally, genotype-level data from 2,370 patients and 412 controls is used to compute intra-individual and cell-specific susceptibility pathways that offer a biological interpretation of the individual genetic risk to MS. This approach could be adopted in any other complex trait for which genome-wide data is available., Genome-wide association studies (GWAS) have so far uncovered more than 200 loci for multiple sclerosis (MS). Here, the authors integrate data from various sources for a cell type-specific pathway analysis of MS GWAS results that specifically highlights the involvement of the immune system in disease pathogenesis.
Published: 2019
Full Text: View/download PDF

31. Ni Foam-Supported Fe-Doped β-Ni(OH)2 Nanosheets Show Ultralow Overpotential for Oxygen Evolution Reaction

Author: Yat Li, Yifan Ye, Mingpeng Chen, Shanwen Wang, Scott R. J. Oliver, Jinghua Guo, Tianyi Kou, and Jesse L. Hauser
Subjects: Materials science, Activation barrier, Renewable Energy, Sustainability and the Environment, Oxygen evolution, Energy Engineering and Power Technology, 02 engineering and technology, Overpotential, 010402 general chemistry, 021001 nanoscience & nanotechnology, Electrochemistry, 01 natural sciences, 0104 chemical sciences, Catalysis, chemistry.chemical_compound, Fuel Technology, Affordable and Clean Energy, Chemical engineering, chemistry, Chemistry (miscellaneous), Fe doped, Materials Chemistry, Hydroxide, 0210 nano-technology, Current density
Abstract: © 2019 American Chemical Society. Oxygen evolution reaction (OER) involves multiple electron-transfer processes, resulting in a high activation barrier. Developing catalysts with low overpotential and high intrinsic activity toward OER is critical but challenging. Here we report a major advancement in decreasing the overpotential for oxygen evolution reaction. Ni foam-supported Fe-doped β-Ni(OH) 2 nanosheets achieve an overpotential of 219 mV at the geometric current density of 10 mA cm -2 . To our knowledge, this is the best value reported for Ni- or Fe hydroxide-based OER catalysts. In addition, the catalyst yields a current density of 6.25 mA cm -2 at the overpotential of 300 mV when it is normalized to the electrochemical surface area of the catalyst. This intrinsic catalytic activity is also better than the values reported for most state-of-the-art OER catalysts at the same overpotential.
Published: 2019
Full Text: View/download PDF

32. Harrisons Manual of Medicine, 20th Edition

Author: Dennis L. Kasper, Anthony S. Fauci, Stephen L. Hauser, Dan L. Longo, J. Larry Jameson, Joseph Loscalzo, Dennis L. Kasper, Anthony S. Fauci, Stephen L. Hauser, Dan L. Longo, J. Larry Jameson, and Joseph Loscalzo
Abstract: All the authority of the most trusted brand in medical content in a convenient, portable guide The Harrison's Manual, derived from most clinically salient content featured in Harrison's Principles of Internal Medicine, 20th Edition, delivers numerous clinical algorithms in one practical, portable resource. The Manual also includes abundant quick reference tables, plus concise text—providing rapid access to bedside information when decisions need to be made quickly. This full color summary guide covers all diseases and conditions commonly seen in inpatient general medicine, so you can be sure to find invaluable content directly to your workflow and practice. The 20th edition has been updated to reflect the latest clinical developments in medicine. The Manual truly makes it easy to find what you need at the point of care. The easy-to-navigate chapters cover symptoms/signs, medical emergencies, specific diseases, and care of the hospitalized patient, with a particular focus on: Etiology and Epidemiology Clinically Relevant Pathophysiology Signs and Symptoms Differential Diagnosis Physical and Laboratory Findings Therapeutics Practice Guidelines, and more
Published: 2019

33. Exploration of Anti-Yo and Anti-Hu paraneoplastic neurological disorders by PhIP-Seq reveals a highly restricted pattern of antibody epitopes

Author: Travis Kassimatis, Anastasia Zekeridou, Sean J. Pittock, Michael R. Wilson, Audrey Parent, Brian D. O’Donovan, Mark S. Anderson, Sara E. Vazquez, Caleigh Mandel-Brehm, Stephen L. Hauser, Joseph L. DeRisi, Jamin Liu, and Eric D. Chow
Subjects: Autoimmune disease, Immune system, Phage display, Antigen, biology, Immunology, Autoantibody, biology.protein, Human proteome project, medicine, Antibody, medicine.disease, Epitope
Abstract: Paraneoplastic neurological disorders (PNDs) are immune-mediated diseases of the nervous system understood to manifest as part of a misdirected anti-tumor immune response. Identifying PND-associated autoantibodies and their cognate antigens can assist with proper diagnosis and treatment while also enhancing our understanding of tumor-associated immune processes, triggers for autoimmune disease, and the functional significance of onconeuronal proteins. Here, we employed an enhanced version of phage display immunoprecipitation and sequencing (PhIP-Seq) leveraging a library of over 731,000 unique phage clones tiling across the entire human proteome to detect autoantibodies and create high-resolution epitope profiles in serum and CSF samples from patients suffering from two common PNDs, the anti-Yo (n = 36 patients) and anti-Hu syndromes (n = 44 patients). All patient samples positive for anti-Yo antibody by a validated clinical assay yielded polyspecific enrichment of phage presenting peptides from the canonical anti-Yo (CDR2 and CDR2L) antigens, while 38% of anti-Hu patients (17/44) had a serum and/or CSF sample that significantly enriched peptides deriving from the ELAVL family of proteins, the anti-Hu autoantigenic target. The anti-Hu antibodies showed a remarkably convergent antigenic signature across 15/17 patients corresponding to residues surrounding and including the degenerate motif, RLDxLL, shared by ELAVL2, 3 and 4. Lastly, PhIP-Seq identified several known and novel autoantigens in these same patient samples, representing potential biomarkers that could aid in the diagnosis and prognosis of PND and cancer.
Published: 2018
Full Text: View/download PDF

34. Longitudinally persistent cerebrospinal fluid B-cells resist treatment in multiple sclerosis

Author: Martin S. Weber, William Harkin, Natalie S. Pierson, Hao Wu, Ariele L. Greenfield, Ravi Dandekar, Michael R. Wilson, Stephen L. Hauser, H.-Christian von Büdingen, Sarah Laurent, Bruce A.C. Cree, Antje Bischof, Erica L. Eggers, Akshaya Ramesh, and Roland G. Henry
Subjects: 0303 health sciences, Oligoclonal band, biology, business.industry, Multiple sclerosis, Central nervous system, Meninges, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Cerebrospinal fluid, medicine.anatomical_structure, Immune system, Parenchyma, Immunology, medicine, biology.protein, Antibody, business, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: B-cells are key contributors to chronic autoimmune pathology in multiple sclerosis (MS). Clonally related B-cells exist in the cerebrospinal fluid (CSF), meninges, and central nervous system (CNS) parenchyma of MS patients. Longitudinally stable CSF oligoclonal band (OCB) antibody patterns suggest some local CNS B-cell persistence; however, the longitudinal B-cell dynamics within and between the CSF and blood remain unknown. We sought to address this by performing immunoglobulin heavy chain variable region repertoire sequencing on B-cells from longitudinally collected blood and CSF samples of MS patients (n=10). All patients were untreated at the time of the initial sampling; the majority (n=7) were treated with immune modulating therapies 1.2 (+/−0.3 SD) years later during the second sampling. We found clonal persistence of B-cells in the CSF of five patients; these B-cells were frequently immunoglobulin (Ig) class-switched and CD27+. We identified specific blood B-cell subsets that appear to provide input into CNS repertoires over time. We demonstrate complex patterns of clonal B-cell persistence in CSF and blood, even in patients on high-efficacy immune modulating therapy. Our findings support the concept that peripheral B-cell activation and CNS-compartmentalized immune mechanisms are in part therapy-resistant.
Published: 2018
Full Text: View/download PDF

35. Identification of MS-specific serum miRNAs in an international multicenter study

Author: Roopali Gandhi, Tanuja Chitnis, Mohsen Khademi, Bonnie I. Glanz, Maja Jagodic, Maria Antonietta Mazzola, Anu Paul, Pia Kivisäkk, Camilo Diaz-Cruz, Samia J. Khoury, Brian C. Healy, Keren Regev, Radhika Raheja, Howard L. Weiner, Tomas Olsson, Stephen L. Hauser, Fredrik Piehl, and Jorge R. Oksenberg
Subjects: 0301 basic medicine, False discovery rate, Oncology, medicine.medical_specialty, Multiple Sclerosis, Wilcoxon signed-rank test, Disease, Neurodegenerative, Autoimmune Disease, Spearman's rank correlation coefficient, Article, 03 medical and health sciences, 0302 clinical medicine, Clinical Research, Internal medicine, Genetics, medicine, screening and diagnosis, Expanded Disability Status Scale, business.industry, Multiple sclerosis, Neurosciences, medicine.disease, Brain Disorders, 4.1 Discovery and preclinical testing of markers and technologies, body regions, Detection, 030104 developmental biology, Neurology, Multiple comparisons problem, Cohort, embryonic structures, Neurology (clinical), business, 030217 neurology & neurosurgery, Biotechnology
Abstract: ObjectiveTo identify circulating microRNAs (miRNAs) linked to disease, disease stage, and disability in MS across cohorts.MethodsSamples were obtained from the Comprehensive Longitudinal Investigation of Multiple Sclerosis (CLIMB, Boston, MA), EPIC (San Francisco, CA), AMIR (Beirut, Lebanon) as part of the SUMMIT consortium, and Stockholm Prospective Assessment of Multiple Sclerosis (Stockholm, Sweden) cohorts. Serum miRNA expression was measured using locked nucleic acid–based quantitative PCR. Four groups were compared: (1) MS vs healthy control (HC), (2) relapsing-remitting (RR) vs HC, (3) secondary progressive (SP) vs HC, and (4) RR vs SP. A Wilcoxon rank-sum test was used for the comparisons. The association between each miRNA and the Expanded Disability Status Scale (EDSS) score was assessed using the Spearman correlation coefficient. For each comparison, the p values were corrected for multiple comparisons using the approach of Benjamini and Hochberg to control the false discovery rate.ResultsIn the CLIMB cohort, 5 miRNAs (hsa-miR-484, hsa-miR-140-5p, hsa-miR-320a, hsa-miR-486-5p, and hsa-miR-320c) showed a significant difference between patients with MS and healthy individuals; among these, miR-484 remained significant after accounting for multiple comparisons (p = 0.01). When comparing RRMS with HCs, hsa-miR-484 showed a significant difference (p = 0.004) between the groups after accounting for multiple group comparisons. When SP and HC were compared, 6 miRNAs (hsa-miR-484, hsa-miR-140-5p, hsa-miR-142-5p, hsa-miR-320a, hsa-miR-320b, and hsa-miR-320c) remained significantly different after accounting for multiple comparisons. Disability correlation analysis with miRNA provided 4 miRNAs (hsa-miR-320a, hsa-miR-337-3p, hsa-miR-199a-5p, and hsa-miR-142-5p) that correlated with the EDSS during the internal reproducibility phase. Among these, hsa-miR-337-3p was the most statistically significant miRNA that negatively correlated with the EDSS in three of the MS cohorts tested.ConclusionsThese findings further confirm the use of circulating serum miRNAs as biomarkers to diagnose and monitor disease status in MS.Classification of evidenceThis study provides Class III evidence that levels of circulating miRNAs identify patients with MS.
Published: 2018

36. Low frequency and rare coding variation contributes to multiple sclerosis risk

Author: Fredrik Karpe, Graeme Stewart, Jan Hillert, Elisabetta Mascia, Matt J. Neville, Verena Grummel, Jonathan L. Haines, Kate Fitzgerald, Bernhard Hemmer, Julia Y Mescheriakova, Benedicte A. Lie, Efthimios Luessi, Federica Esposito, Andreas Ziegler, Ioanna Konidari, Cristin McCabe, Keith R. Edwards, Roland Martin, Daniele Cusi, Elisabeth Gulowsen Celius, Cristina Agliardi, Anne Spurkland, Georgios M. Hadjigeorgiou, Lena Guillot-Noel, Antonios Bayas, Uwe K. Zettl, Kjell-Morten Myhr, Maria Ban, Rogier Q. Hintzen, Frauke Zipp, Mireia Sospedra, Till F. M. Andlauer, Adrian J. Ivinson, Mary F. Davis, Mark Lathrop, Daniela Galimberti, Pierre-Antoine Gourraud, Genevieve Lachance, Bruce A.C. Cree, Robin Lemmens, Ashley Beecham, Steffan D. Bos, Bruce V. Taylor, Maurizio Leone, Manuel Comabella, Maja Jagodic, Helle Bach Søndergaard, David A. Hafler, Ingrid Kockum, Nadia Barizzone, Ralf Gold, Tania Kümpfel, Per Soelberg Sørensen, Seema Kalra, An Goris, Philip Van Damme, Marie B. D'hooghe, Cathy Schaefer, Efthimios Dardiotis, Alastair Compston, Lotti Tajoori, Sandra D'Alfonso, Ilijas Jelcic, Stephen Sawcer, Brigitte Wildemann, Friedemann Paul, Lise Wegner Thoerner, Silvia Delgado, Tomas Olsson, Mitja Mitrovic, Hayrettin Tumani, Henrik Ullum, Lisa F. Barcellos, Xavier Montalban, Ellen Lathi, Finn Sellebjerg, Thomas Werge, Christina M. Lill, Pernilla Stridh, Paul I.W. de Bakker, Cornelia M. van Duijn, Jyoti Khadake, Jac Charlesworth, Melissa Sorosina, Christiane Gasperi, Stephen L. Hauser, Anne H. Cross, Isabelle Cournu-Rebeix, Nikolaos A. Patsopoulos, Fredrik Piehl, Lars Alfredsson, Bertrand Fontaine, Marieme Dembele, Margaret A. Pericak-Vance, Janna Saarela, Ulf Ziemann, Annette Bang Oturai, Stacy J. Caillier, Jorge R. Oksenberg, Bénédicte Dubois, Björn Tackenberg, Christoph Heesen, Jacob L. McCauley, Florian Then Bergh, Clemens Warnke, Sergio E. Baranzini, Peter A. Calabresi, Chris Cotsapas, Clive Hawkins, Martin Stangel, Hakon Hakonarson, Sandra Vukusik, Christiane Graetz, Heinz Wiendl, Howard L. Weiner, Laura Piccio, Giancarlo Comi, Ralf A. Linker, Luisa Bernardinelli, Cristoforo Comi, Filippo Martinelli-Boneschi, Hanne F. Harbo, Dorothea Buck, Clara P. Manrique, David R. Booth, Benjamin Knier, Philip L. De Jager, Viola Pongratz, Laura Ferrè, Vincent Damotte, Adam Santaniello, Theresa Dankowski, and Pirro G. Hysi
Subjects: Genetics, 0303 health sciences, Linkage disequilibrium, Multiple sclerosis, Disease, Biology, Heritability, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, medicine, Epistasis, Coding region, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract: Multiple sclerosis is a common, complex neurological disease, where almost 20% of risk heritability can be attributed to common genetic variants, including >230 identified by genome-wide association studies (Patsopoulos et al., 2017). Multiple strands of evidence suggest that the majority of the remaining heritability is also due to the additive effects of individual variants, rather than epistatic interactions between these variants, or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that as much as 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independently of common variant signals, which highlight a key role for regulatory T cell homeostasis and regulation, IFNγ biology and NFκB signaling in MS pathogenesis. As low-frequency variants do not show substantial linkage disequilibrium with other variants, and as coding variants are more interpretable and experimentally tractable than non-coding variation, our discoveries constitute a rich resource for dissecting the pathobiology of MS.
Published: 2018
Full Text: View/download PDF

37. No evidence of disease activity (NEDA) analysis by epochs in patients with relapsing multiple sclerosis treated with ocrelizumab vs interferon beta-1a

Author: Eva Havrdova, Jian Han, Iain Bennett, Shibeshih Belachew, Giancarlo Comi, Douglas L. Arnold, Gavin Giovannoni, Ludwig Kappos, Anthony Traboulsee, Fred D. Lublin, Stephen L. Hauser, Regine Buffels, Laura Julian, Krzysztof Selmaj, Julie Napieralski, Hans-Peter Hartung, Amit Bar-Or, and Hideki Garren
Subjects: medicine.medical_specialty, Multiple Sclerosis, Clinical Trials and Supportive Activities, Neurodegenerative, NEDA, Autoimmune Disease, Gastroenterology, Disease activity, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Clinical Research, Internal medicine, medicine, In patient, Disability progression, 030212 general & internal medicine, relapse, business.industry, Multiple sclerosis, Neurosciences, Interferon beta-1a, medicine.disease, Brain Disorders, Original Research Paper, disability progression, T2 lesions, Ocrelizumab, MRI activity, Neurology (clinical), business, disease activity, 030217 neurology & neurosurgery, medicine.drug
Abstract: Background No evidence of disease activity (NEDA; defined as no 12-week confirmed disability progression, no protocol-defined relapses, no new/enlarging T2 lesions and no T1 gadolinium-enhancing lesions) using a fixed-study entry baseline is commonly used as a treatment outcome in multiple sclerosis (MS). Objective The objective of this paper is to assess the effect of ocrelizumab on NEDA using re-baselining analysis, and the predictive value of NEDA status. Methods NEDA was assessed in a modified intent-to-treat population ( n = 1520) from the pooled OPERA I and OPERA II studies over various epochs in patients with relapsing MS receiving ocrelizumab (600 mg) or interferon beta-1a (IFN β‐1a; 44 μg). Results NEDA was increased with ocrelizumab vs IFN β-1a over 96 weeks by 75% ( p Conclusion Superior efficacy with ocrelizumab compared with IFN β-1a was consistently seen in maintaining NEDA status in all epochs evaluated. By contrast with IFN β-1a, the majority of patients with disease activity early in the study subsequently attained NEDA status with ocrelizumab.
Published: 2018

38. Ovarian aging is associated with gray matter volume and disability in women with MS

Author: Jennifer Graves, Stephen L. Hauser, Jorge R. Oksenberg, Alyssa H. Zhu, Roland G. Henry, Ruth M. Greenblatt, Geralyn Lambert-Messerlian, Marcelle I. Cedars, Peter Bacchetti, Emmanuelle Waubant, and Bruce A.C. Cree
Subjects: Adult, Anti-Mullerian Hormone, medicine.medical_specialty, Aging, Multiple Sclerosis, Cross-sectional study, Standard score, Gastroenterology, Article, 03 medical and health sciences, Disability Evaluation, Young Adult, 0302 clinical medicine, Internal medicine, medicine, Humans, Longitudinal Studies, Young adult, Gray Matter, Aged, 030219 obstetrics & reproductive medicine, Expanded Disability Status Scale, business.industry, Ovary, Case-control study, Middle Aged, Magnetic Resonance Imaging, Confidence interval, Cross-Sectional Studies, Case-Control Studies, Cohort, Female, Neurology (clinical), business, Body mass index, 030217 neurology & neurosurgery, Biomarkers, Follow-Up Studies
Abstract: ObjectiveTo determine if ovarian aging as measured by levels of anti-Müllerian hormone (AMH) is associated with pattern of multiple sclerosis (MS) progression in women.MethodsWomen with MS and healthy controls were included from a longitudinal research cohort with up to 10 years follow-up. Plasma AMH levels were measured by ELISA for baseline and years 3, 5, and 8–10. Mixed effects logistic and linear regression models were employed, with adjustments for age, disease duration, and other covariables as appropriate.ResultsAMH levels were similar (0.98-fold difference, 95% confidence interval [CI] 0.69–1.37, p = 0.87) in women with MS (n = 412, mean age 42.6 years) and healthy controls (n = 180, mean age 44 years). In a multivariable model of women with MS, including adjustments for age, body mass index, and disease duration, 10-fold lower AMH level was associated with 0.43-higher Expanded Disability Status Scale (EDSS) score (95% CI 0.15–0.70, p = 0.003), 0.25-unit worse MS Functional Composite z score (95% CI −0.40 to −0.10, p = 0.0015), and 7.44 mm3 lower cortical gray matter volume (95% CI −14.6 to −0.30; p = 0.041) at baseline. In a multivariable random-intercept–random-slope model using all observations over time, 10-fold decrease in AMH was associated with a 0.27 increase in EDSS (95% CI 0.11–0.43, p = 0.006) and 5.48 mm3 (95% CI 11.3–0.33, p = 0.065) and 4.55 mm3 (95% CI 9.33–0.23, p = 0.062) decreases in total gray and cortical gray matter, respectively.ConclusionAs a marker of ovarian aging, lower AMH levels were associated with greater disability and gray matter loss in women with MS independent of chronological age and disease duration.
Published: 2018

39. Harrison's Principles of Internal Medicine 20/E (Vol.1 & Vol.2) (ebook)

Author: Dennis L. Kasper, Anthony S. Fauci, Stephen L. Hauser, Dan L. Longo, J. Larry Jameson, Joseph Loscalzo, Dennis L. Kasper, Anthony S. Fauci, Stephen L. Hauser, Dan L. Longo, J. Larry Jameson, and Joseph Loscalzo
Abstract: MASTER MODERN MEDICINE! Introducing the Landmark Twentieth Edition of the Global Icon of Internal Medicine The definitive guide to internal medicine is more essential than ever with the latest in disease mechanisms, updated clinical trial results and recommended guidelines, state-of-the art radiographic images, therapeutic approaches and specific treatments, hundreds of demonstrative full-color drawings, and practical clinical decision trees and algorithms Recognized by healthcare professionals worldwide as the leading authority on applied pathophysiology and clinical medicine, Harrison's Principles of Internal Medicine gives you the informational foundation you need to provide the best patient care possible. Essential for practice and education, the landmark 20th Edition features: Thoroughly revised content—covering the many new breakthroughs and advances in clinical medicine that have occurred since the last edition of Harrison's. Chapters on acute and chronic hepatitis, management of diabetes, immune-based therapies in cancer, multiple sclerosis, cardiovascular disease, HIV, and many more, deliver the very latest information on disease mechanisms, diagnostic options, and the specific treatment guidance you need to provide optimal patient care. State-of-the-art coverage of disease mechanisms: Harrison's focuses on pathophysiology with rigor, and with the goal of linking disease mechanisms to treatments. Improved understanding of how diseases develop and progress not only promotes better decision-making and higher value care, but also makes for fascinating reading and improved retention. Harrison's summarizes important new basic science developments, such as the role of mitochondria in programmed and necrotic cell death, the immune system's role in cancer development and treatment, the impact of telomere shortening in the aging and disease processes, and the role of the microbiome in health and disease. Understanding the role of inflammation in cardiovascular disease, the precise mechanisms of immune deficiency in HIV/AIDS, prions and misfolded proteins in neurodegenerative diseases, and obesity as a predisposition to diabetes are just a few examples of how this edition provides essential pathophysiology information for health professionals. All-new sections covering a wide range of new and emerging areas of vital interest to all healthcare professionals. New sections include: Sex and Gender-based Issues in Medicine; Obesity, Diabetes Mellitus, and Metabolic Syndrome; and Consultative Medicine—Plus, a new Part covering cutting-edge topics in research and clinical medicine includes great new chapters on the role of Epigenetics in Health and Disease, Behavioral Strategies to Improve Health, Genomics and Infectious Diseases, Emerging Neuro-Therapeutic Technologies, and Telomere Function in Health and Disease, and Network System Medicine. Important and timely new chapters—such as Promoting Good Health, LGBT Health, Systems of Healthcare, Approach to Medical Consultation, Pharmacogenomics, Antimicrobial Resistance, Worldwide Changes in Patterns of Infectious Diseases, Neuromyelitis Optica, and more—offer the very latest, definitive perspectives on must-know topics in medical education and practice. Updated clinical guidelines, expert opinions, and treatment approaches from world-renowned editors and authors contribute to the accuracy and immediacy of the text material and present a clear blueprint for optimizing patient outcomes. End-of-chapter suggested readings reinforce the text material and provide a robust platform for further study and research.
Published: 2018

40. Harrison's Principles of Internal Medicine Self-Assessment and Board Review, 19th Edition and Harrison's Manual of Medicine 19th Edition (EBook) VAL PAK

Author: Charles Weiner, J. Larry Jameson, Anthony S. Fauci, Dennis L. Kasper, Stephen L. Hauser, Dan L. Longo, Joseph Loscalzo, Charles Weiner, J. Larry Jameson, Anthony S. Fauci, Dennis L. Kasper, Stephen L. Hauser, Dan L. Longo, and Joseph Loscalzo
Abstract: SPECIAL OFFER! SAVE WHEN YOU PURCHASE HARRISON'S PRINCIPLES OF INTERNAL MEDICINE SELF-ASSESSMENT AND BOARD REVIEW ALONG WITH THE COMPANION HARRISON'S MANUAL This dollar-saving Harrison's bundle includes two great resources: Harrison's Principles of Internal Medicine Self-Assessment and Board ReviewBased on the content of Harrison's Principles of Internal Medicine, Nineteenth Edition, this full-color study aid is essential for Internal Medicine Board certification or recertification/maintenance of certification, or as a refresher for any internal medicine examination. Reflecting the accuracy, currency, and wide scope of Harrison's, this complete review of internal medicine delivers more than 1,000 extremely challenging review questions, many of which utilize realistic patient scenarios, including radiographic and pathologic images. Each question is accompanied by explanations for correct and incorrect answers. These explanations -- which are derived from and cross-referenced to Harrison's Principles of Internal Medicine, Nineteenth Edition – are one of the most effective ways to learn and teach internal medicine. They are designed to bolster your understanding of pathophysiology, epidemiology, differential diagnosis, clinical decision making, and therapeutics. You will also find a beautiful full-color atlas. The package also includes….. Harrison's Manual of Medicine, Nineteenth Edition Harrison's Manual of Medicine is a concise, bedside resource derived from content found in Harrison's Principles of Internal Medicine, Nineteenth Edition. Perfect for use at the point of care, the Manual presents clinical information covering key aspects of the diagnosis, clinical manifestations, and treatment of the major diseases that are likely to be encountered in medical practice.Presented in full color and incorporating an efficient blend of succinct text, bullet points, algorithms, and tables Harrison's Manual of Medicine, Nineteenth Edition covers every area of clinical medicine, including:• Etiology and Epidemiology• Clinically Relevant Pathophysiology• Signs and Symptoms• Differential Diagnosis• Physical and Laboratory Findings• Therapeutics• Practice Guidelines
Published: 2017

41. Harrison's Principles and Practice of Internal Medicine 19th Edition and Harrison's Principles of Internal Medicine Self-Assessment and Board Review, 19th Edition (EBook)Val-Pak

Author: J. Larry Jameson, Anthony S. Fauci, Dennis L. Kasper, Stephen L. Hauser, Dan L. Longo, Joseph Loscalzo, Charles Weiner, J. Larry Jameson, Anthony S. Fauci, Dennis L. Kasper, Stephen L. Hauser, Dan L. Longo, Joseph Loscalzo, and Charles Weiner
Abstract: SPECIAL OFFER! SAVE WHEN YOU PURCHASE HARRISON'S PRINCIPLES OF INTERNAL MEDICINE, 19e ALONG WITH THE COMPANION BOARD REVIEW BOOK! This dollar-saving Harrison's bundle includes two great resources: Harrison's Principles of Internal Medicine, Nineteenth Edition Through six decades, no resource has matched the authority, esteemed scholarship, and scientific rigor of Harrison's Principles of Internal Medicine. Capturing the countless advances and developments across the full span of medicine, the 19th edition of Harrison's provides a complete update of essential content related to disease pathogenesis, clinical trials, current diagnostic methods and imaging approaches, evidence-based practice guidelines, and established and newly approved treatment methods. Here are just a few of the outstanding features of the Nineteenth Edition:•Presented in two volumes: Volume 1 is devoted to foundational principles, cardinal manifestations of disease and approach to differential diagnosis; Volume 2 covers disease pathogenesis and treatment•NEW chapters on important topics such as Men's Health, The Impact of Global Warming on Infectious Diseases, Fatigue, and many more•Critical updates in management and therapeutics in Hepatitis, Coronary Artery Disease, Ebola Virus Disease, Multiple Sclerosis, Diabetes, Hypertension, Deep Vein Thrombosis and Pulmonary Embolism, Acute and Chronic Kidney Disease, Inflammatory Bowel Disease, Lipoprotein Disorders, HIV and AIDS, and more.•Increased number of the popular Harrison's clinical algorithms; clinically relevant radiographic examples spanning hundreds of diseases; clinical-pathological images in full color; crystal clear, full color drawings and illustrations and helpful tables and summary lists that make clinical application of the content faster than ever•Access to outstanding multi-media resources including practical videos demonstrating essential bedside procedures, physical examination techniques, endoscopic findings, cardiovascular findings, and more The package also includes….. Harrison's Principles of Internal Medicine Self-Assessment and Board Review Based on the content of Harrison's Principles of Internal Medicine, Nineteenth Edition, this full-color study aid is essential for Internal Medicine Board certification or recertification/maintenance of certification, or as a refresher for any internal medicine examination. Reflecting the accuracy, currency, and wide scope of Harrison's, this complete review of internal medicine delivers more than 1,000 extremely challenging review questions, many of which utilize realistic patient scenarios, including radiographic and pathologic images. Each question is accompanied by explanations for correct and incorrect answers. These explanations -- which are derived from and cross-referenced to Harrison's Principles of Internal Medicine, Nineteenth Edition – are one of the most effective ways to learn and teach internal medicine. They are designed to bolster your understanding of pathophysiology, epidemiology, differential diagnosis, clinical decision making, and therapeutics. You will also find a beautiful full-color atlas.
Published: 2017

42. Harrison's Principles of Internal Medicine 19th Edition and Harrison's Manual of Medicine 19th Edition (EBook)VAL PAK

Author: J. Larry Jameson, Anthony S. Fauci, Dennis L. Kasper, Stephen L. Hauser, Dan L. Longo, Joseph Loscalzo, J. Larry Jameson, Anthony S. Fauci, Dennis L. Kasper, Stephen L. Hauser, Dan L. Longo, and Joseph Loscalzo
Abstract: SPECIAL OFFER! SAVE WHEN YOU PURCHASE HARRISON'S PRINCIPLES OF INTERNAL MEDICINE, 19e ALONG WITH THE COMPANION HARRISON'S MANUAL! This dollar-saving Harrison's bundle includes these two great resources: Harrison's Principles of Internal Medicine, Nineteenth Edition Through six decades, no resource has matched the authority, esteemed scholarship, and scientific rigor of Harrison's Principles of Internal Medicine. Capturing the countless advances and developments across the full span of medicine, the 19th edition of Harrison's provides a complete update of essential content related to disease pathogenesis, clinical trials, current diagnostic methods and imaging approaches, evidence-based practice guidelines, and established and newly approved treatment methods. Here are just a few of the outstanding features of the Nineteenth Edition:•Presented in two volumes: Volume 1 is devoted to foundational principles, cardinal manifestations of disease and approach to differential diagnosis; Volume 2 covers disease pathogenesis and treatment•NEW chapters on important topics such as Men's Health, The Impact of Global Warming on Infectious Diseases, Fatigue, and many more•Critical updates in management and therapeutics in Hepatitis, Coronary Artery Disease, Ebola Virus Disease, Multiple Sclerosis, Diabetes, Hypertension, Deep Vein Thrombosis and Pulmonary Embolism, Acute and Chronic Kidney Disease, Inflammatory Bowel Disease, Lipoprotein Disorders, HIV and AIDS, and more.•Increased number of the popular Harrison's clinical algorithms; clinically relevant radiographic examples spanning hundreds of diseases; clinical-pathological images in full color; crystal clear, full color drawings and illustrations and helpful tables and summary lists that make clinical application of the content faster than ever•Access to outstanding multi-media resources including practical videos demonstrating essential bedside procedures, physical examination techniques, endoscopic findings, cardiovascular findings, and more The package also includes….. Harrison's Manual of Medicine, Nineteenth Edition Harrison's Manual of Medicine is a concise, bedside resource derived from content found in Harrison's Principles of Internal Medicine, Nineteenth Edition. Perfect for use at the point of care, the Manual presents clinical information covering key aspects of the diagnosis, clinical manifestations, and treatment of the major diseases that are likely to be encountered in medical practice. Presented in full color and incorporating an efficient blend of succinct text, bullet points, algorithms, and tables Harrison's Manual of Medicine, Nineteenth Edition covers every area of clinical medicine, including:• Etiology and Epidemiology• Clinically Relevant Pathophysiology• Signs and Symptoms• Differential Diagnosis• Physical and Laboratory Findings• Therapeutics• Practice Guidelines
Published: 2017

43. The Multiple Sclerosis Genomic Map: Role of peripheral immune cells and resident microglia in susceptibility

Author: Ashley Beecham, David A. Hafler, Colombe J, Ublick K, Stephen Sawcer, Marcus C. S. Lee, Adam Santaniello, An Goris, Frank Seibold, Xavier Montalban, G. Comi, Christiane Gasperi, Sandra D'Alfonso, Federica Esposito, Laurent Peyrin-Biroulet, Frauke Zipp, Ioanna Konidari, Elisabeth Gulowsen Celius, Achim Berthele, Amoroso A, Rogier Q. Hintzen, Johan Van Limbergen, Marieme Dembele, Fredrik Karpe, Zhang W, Robbins A, Moiola L, Annette Bang Oturai, Cristin McCabe, Filippo Martinelli-Boneschi, M Lindén, Keith R Edwards, Hanne F. Harbo, Zuccalà M, Marc Lémann, Felix Luessi, Noriko Isobe, Nadia Barizzone, Renata D'Incà, Croft A, Ioannis S. Vlachos, Frohlich I, Martinelli, Daniela Galimberti, Efthimios Dardiotis, Lisa F. Barcellos, Brendan T. Keenan, Maja Jagodic, Ferdinando Clarelli, Bénédicte Dubois, Nicholas A. Kennedy, Lohith Madireddy, Grant W. Montgomery, Tommy Olsson, Phil De Jager, Lo A, Peter A. Calabresi, Brandes A, Chris Cotsapas, Bakker Pd, Steffan D. Bos, Christina M. Lill, Karban A, Thoerner Lw, Tojo James, Wong G, Harald Peeters, M.-M. Hoshi, Roberts R, Fredrik Piehl, Lars Alfredsson, Giorgos M. Hadjigeorgiou, Bertrand Fontaine, Melissa Sorosina, Benedetti M, Maria Ban, Jorge R. Oksenberg, Howard L. Weiner, Ingrid Kockum, Mireia Sospedra, Taylor Km, Henrik Ullum, Izaura Lima Bomfim, Stronati L, Molyneux P, Replogle J, Stacy J. Caillier, Zhang H, Till F. M. Andlauer, Margaret A. Pericak-Vance, Jan Hillert, Luisa Bernardinelli, Taibo Li, Helle Bach Søndergaard, Ilijas Jelcic, Nikolaos A. Patsopoulos, Silvia Delgado, Cathy Schaefer, Thomas Korn, Laura Piccio, Mark Mühlau, Deborah D. Proctor, B. Hemmer, Elizabeth M. Bradshaw, Hysi P, Megan C Neville, Mary F. Davis, Dorlan J. Kimbrough, Jyoti Khadake, Jean-Pierre Hugot, David Gomez-Cabrero, Murray L. Barclay, Anne H. Cross, Kasper Lage, Stephen L. Hauser, A Compston, Zimmer A, Ivinson A, Anne Spurkland, Jonas Halfvarson, Charles C. White, Biberacher, Zarzycki O, Kathryn C. Fitzgerald, Finn Sellebjerg, Ellis Patrick, Andrea Zauli, Bruce V. Taylor, Maurizio Leone, Genevieve Lachance, Marta Olah, B. Cree, Manuel Comabella, Arie Levine, Domizia Vecchio, Mathias Chamaillard, Mark Lathrop, Clara Guaschino, Roland Martin, Hanigan K, Pierre-Antoine F. D. Gourraud, Maria Cimpean, Jonathan L. Haines, Dorothea Buck, Marco Salvetti, Per Soelberg Sørensen, Noel Lg, Mitja Mitrovic, Graeme J. Stewart, Benjamin Knier, Ellen Lathi, Cottone M, Laura Ferrè, Winn P, Duijn Cv, Monica Milla, Tune H. Pers, I. Oikonomou, An D, David R. Booth, Rebeix Ic, Clara P. Manrique, Massey D, Evelyn Ng Sm, Törkvist L, Daniele Cusi, Shoostari P, Vatn Mh, Paola Cavalla, Silvia Santoro, Gossum Av, Seema Kalra, Paul Rutgeerts, Clive Hawkins, Sandra Vukusik, Khan Ma, Hakon Hakonarson, Paul Henderson, Christiane Graetz, Julia Y Mescheriakova, Jean-François Rahier, Panteliadis I, Cristina Agliardi, Grummel, Jacob L. McCauley, Amie Baker, Janna Saarela, Sergio E. Baranzini, J W Thorpe, and Damotte
Subjects: 0303 health sciences, Microglia, Multiple sclerosis, Central nervous system, Biology, medicine.disease, Major histocompatibility complex, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine.anatomical_structure, Autoimmune Process, Immunology, medicine, biology.protein, Gene, 030217 neurology & neurosurgery, X chromosome, 030304 developmental biology
Abstract: We assembled and analyzed genetic data of 47,351 multiple sclerosis (MS) subjects and 68,284 control subjects and establish a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 independent associations within the extended MHC. We used an ensemble of methods to prioritize up to 551 potentially associated MS susceptibility genes, that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we do find enrichment for MS genes in these brain - resident immune cells. Thus, while MS is most likely initially triggered by perturbation of peripheral immune responses the functional responses of microglia and other brain cells are also altered and may have a role in targeting an autoimmune process to the central nervous system.One Sentence Summary:We report a detailed genetic and genomic map of multiple sclerosis, and describe the role of putatively affected genes in the peripheral immune system and brain resident microglia.
Published: 2017

44. Harrisons Manual of Medicine, 19th Edition

Author: Dennis L. Kasper, Anthony S. Fauci, Stephen L. Hauser, Dan L. Longo, J. Larry Jameson, Joseph Loscalzo, Dennis L. Kasper, Anthony S. Fauci, Stephen L. Hauser, Dan L. Longo, J. Larry Jameson, and Joseph Loscalzo
Abstract: Essential Clinical Information Drawn From Harrison's Harrison's Manual of Medicine is a concise, bedside resource derived from content found in Harrison's Principles of Internal Medicine, Nineteenth Edition. Perfect for use at the point of care, the Manual presents clinical information covering key aspects of the diagnosis, clinical manifestations, and treatment of the major diseases that are likely to be encountered in medical practice. Presented in full color and incorporating an efficient blend of succinct text, bullet points, algorithms, and tables Harrison's Manual of Medicine, Nineteenth Edition covers every area of clinical medicine, including: · Etiology and Epidemiology · Clinically Relevant Pathophysiology · Signs and Symptoms · Differential Diagnosis · Physical and Laboratory Findings · Therapeutics · Practice Guidelines
Published: 2016

45. Harrison's Neurology in Clinical Medicine, 4th Edition

Author: Stephen L. Hauser, S. Andrew Josephson, Stephen L. Hauser, and S. Andrew Josephson
Abstract: Neurology – as only Harrison's can cover it A Doody's Core Title for 2017! Featuring a superb compilation of chapters related to neurology derived from Harrison's Principles of Internal Medicine, Nineteenth Edition (including content from the acclaimed Harrison's DVD), this concise, full-color clinical companion delivers the latest knowledge in the field backed by the scientific rigor and authority that have defined Harrison's. You will find 66 chapters from more than 90 renowned editors and contributors in a carry-anywhere presentation that is ideal for the classroom, clinic, ward, or exam/certification preparation. Features: • High-yield board review questions make this text ideal for keeping current and preparing for the boards • Current, complete coverage of clinically important topics in neurology, including Clinical Manifestations of Neurologic Diseases, Diseases of the Nervous System, Chronic Fatigue Syndrome, Psychiatric Disorders, and Alcoholism and Drug Dependency • Extensively updated to highlight recent advances in the understanding, diagnosis, treatment, and prevention of neurologic and psychiatric disorders; expanded coverage of neurodegenerative diseases; extensively revised chapter on cerebrovascular diseases; the latest breakthroughs in sleep disorders and migraine • Integration of pathophysiology with clinical management • Enhanced by numerous neuroimaging figures throughout the text and an expanded atlas of neuroimaging findings • Handy appendix of Laboratory Values of Clinical Importance
Published: 2016

46. Harrisons Principles of Internal Medicine Self-Assessment and Board Review

Author: Charles Wiener, Anthony S. Fauci, Eugene Braunwald, Dennis L. Kasper, Stephen L. Hauser, Dan L. Longo, J. Larry Jameson, Joseph Loscalzo, Cynthia Brown, Charles Wiener, Anthony S. Fauci, Eugene Braunwald, Dennis L. Kasper, Stephen L. Hauser, Dan L. Longo, J. Larry Jameson, Joseph Loscalzo, and Cynthia Brown
Abstract: Prepare for certification, MOC/recertification, and in-service exams with the most trusted name in medicine: Harrison's Harrison's Principles of Internal Medicine Self-Assessment and Board Review, 19th edition, is a completely revised and updated guide to help you prepare for your primary board certification, maintenance of certification/re-certification, and for in-service exams. An important component of the Harrison's set, this review reflects all of the most up-to-date material featured in the 19th edition of Harrison's Principles of Internal Medicine. This ultimate study partner contains more than 1000 revised and updated questions (and answers), simulating those on the primary certification exam. Integral to interactive self-assessment and in line with the core Harrison's text, the high-yield content reflects the weighting of subject matter included on the internal medicine board exam blueprint and spans the field of internal medicine.
Published: 2016

47. Harrison's Principles of Internal Medicine 19/E (Vol.1 & Vol.2) (ebook)

Author: Dennis L. Kasper, Anthony S. Fauci, Stephen L. Hauser, Dan L. Longo, J. Larry Jameson, Joseph Loscalzo, Dennis L. Kasper, Anthony S. Fauci, Stephen L. Hauser, Dan L. Longo, J. Larry Jameson, and Joseph Loscalzo
Abstract: The landmark guide to internal medicine— updated and streamlined for today's students and clinicians The only place you can get ALL the great content found in the two print volumes AND the acclaimed DVD in one convenient resource! Through six decades, no resource has matched the authority, esteemed scholarship, and scientific rigor of Harrison's Principles of Internal Medicine. Capturing the countless advances and developments across the full span of medicine, the new 19th edition of Harrison's provides a complete update of essential content related to disease pathogenesis, clinical trials, current diagnostic methods and imaging approaches, evidence-based practice guidelines, and established and newly approved treatment methods. Here are just a few of the outstanding features of the new Nineteenth Edition: Content is practically organized around two basic themes: education and clinical practice The teaching and learning sections cover foundational principles, cardinal manifestations of disease and approach to differential diagnosis; the content devoted to clinical practice focuses on disease pathogenesis and treatment NEW chapters on important topics such as Men's Health, The Impact of Global Warming on Infectious Diseases, Fatigue, and many more Critical updates in management and therapeutics in Hepatitis, Coronary Artery Disease, Ebola Virus Disease, Multiple Sclerosis, Diabetes, Hypertension, Deep Vein Thrombosis and Pulmonary Embolism, Acute and Chronic Kidney Disease, Inflammatory Bowel Disease, Lipoprotein Disorders, HIV and AIDS, and more. Increased number of the popular Harrison's clinical algorithms; clinically relevant radiographic examples spanning hundreds of diseases; clinical-pathological images in full color; crystal clear, full color drawings and illustrations and helpful tables and summary lists that make clinical application of the content faster than ever Outstanding multi-media resources including practical videos demonstrating essential bedside procedures, physical examination techniques, endoscopic findings, cardiovascular findings, are available for easy download Supporting the renowned coverage are supplemental resources that reflect and assist modern medical practice: more than 1,000 full-color photographs to aid visual recognition skills, hundreds of state-of-the-art radiographs, from plain film to 3D CT to PET Scans; beautiful illustrations that bring applied anatomy and processes to life; the renowned Harrison's patient-care algorithms, essential summary tables, and practical demonstrative videos. In addition, several digital atlases highlight noninvasive imaging, percutaneous revascularization, gastrointestinal endoscopy, diagnosis and management of vasculitis, and numerous other issues commonly encountered in clinical practice. Acclaim for Harrison's: “Covering nearly every possible topic in the field of medicine, the book begins with a phenomenal overview of clinical medicine, discussing important topics such as global medicine, decision-making in clinical practice, the concepts of disease screening and prevention, as well as the importance of medical disorders in specific groups (e.g. women, surgical patients, end of life). The extensive chapters that follow focus on a symptom-based presentation of disease and then illness organized by organ system. Numerous tables, graphs, and figures add further clarity to the text.'…Written by experts in the field, this book is updated with the latest advances in pathophysiology and treatment. It is organized in a way that makes reading from beginning to end a logical journey, yet each chapter can stand alone as a quick reference on a particular topic. “ Doody's Review Service reviewing the previous edition of
Published: 2015

48. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

Author: Bénédicte Dubois, Lucia Corrado, Deborah F. Mason, Allan G. Kermode, Pentti J. Tienari, Annette Bang Oturai, Charles Hillier, Adrian J. Ivinson, Stephen L. Hauser, Ashley Beecham, Jeannette Lechner-Scott, Vincent Thijs, Jonathan L. Haines, Sarah Edkins, Alexander T. Dilthey, Daniele Cusi, Guy Nagels, David A. Hafler, Mark Slee, Petra Nilsson, James S. Wiley, Lou Brundin, Amy Strange, Elizabeth Visser, Mireia Sospedra, Athena Hadjixenofontos, Sergio E. Baranzini, Jenny Link, Robert Andrews, Viola Biberacher, Helle Bach Søndergaard, Vittorio Martinelli, Tomas Olsson, Gillian L Hall, Stephen Sawcer, Stacy J. Caillier, Per Soelberg Sørensen, Céline Bellenguez, Cornelia M. van Duijn, Frauke Zipp, Nikolaos A. Patsopoulos, Cristin McCabe, Colin Freeman, Simon Broadley, Luisa Bernardinelli, Margaret A. Pericak-Vance, Jan Hillert, Wassila Carpentier, Sandip Shaunak, Anne Spurkland, Barnaby Fiddes, Judith Field, Jan Lycke, Christina M. Lill, Federica Esposito, Ioanna Konidari, Elisabeth Gulowsen Celius, Christian Gieger, Helmut Butzkueven, Ling Shen, James F. Wilson, Magdalena Lindén, Tejas S. Shah, Amie Baker, Dionysia K. Xifara, Hong Quach, Laura Bergamaschi, Rogier Q. Hintzen, Jacob L. McCauley, Janna Saarela, J W Thorpe, Christine Lebrun-Frenay, Felix Luessi, Sandra D'Alfonso, B. E. Kendall, Helga Westerlind, Giancarlo Comi, Nathalie Schnetz-Boutaud, Paola Brambilla, Chris Cotsapas, Anders Hamsten, William Camu, Achim Berthele, Kjell-Morten Myhr, Clive Hawkins, Richard Nicholas, James Harley, Carl A. Anderson, Keijo Koivisto, Irene Coman, Neil Robertson, Hakon Hakonarson, Finn Sellebjerg, Fredrik Piehl, Alessia Di Sapio, Loukas Moutsianas, Mehdi Alizadeh, Lars Alfredsson, Catherine Schaefer, David Rog, Virpi Leppa, C. Martin, Bruce A.C. Cree, Christopher Halfpenny, Irina Elovaara, Filippo Martinelli-Boneschi, Cordelia Langford, Hanne F. Harbo, Wim Robberecht, Isabelle Cournu-Rebeix, Steve Vucic, Izaura Lima Bomfim, Irene Y. Frohlich, Michelle Lee, Bertrand Fontaine, Bernhard Hemmer, Eva Zindler, Chris C. A. Spencer, Malin Larsson, Simon Shields, Ilijas Jelcic, Juliane Winkelmann, Jorge R. Oksenberg, Alastair Wilkins, Silvia Delgado, Volker Siffrin, Helena C. Kronsbein, Bruno Brochet, Panos Deloukas, Daniela Galimberti, Nikos Evangelou, Rebecca C. Selter, Maja Jagodic, Martin Duddy, Timothy Harrower, Per Hall, Nadia Barizzone, Siân Price, Matti Pirinen, Pierre-Antoine Gourraud, Thomas M.C. Binder, Giuseppe Liberatore, Mark Lathrop, M.-M. Hoshi, Garrett Hellenthal, Melissa Sorosina, Thomas Korn, Clara Guaschino, Roland Martin, Jeremy Hobart, Marco Salvetti, Peter Donnelly, Ingrid Kockum, An Goris, Alastair Compston, Mariaemma Rodegher, Dorothea Buck, Clara P. Manrique, Christiane Graetz, Benedicte A. Lie, Trevor J. Kilpatrick, Andrew Graham, Anu Kemppinen, Maria Ban, Gil McVean, John Zajicek, Hannah Blackburn, Mary F. Davis, Emilie Sundqvist, Bruce V. Taylor, Maurizio Leone, Lisa F. Barcellos, Fabio Macciardi, Gilles Defer, Vincent Damotte, Satu Männistö, Graeme J. Stewart, Gordon Mazibrada, Inger Lise Mero, Andre Franke, Philip L. De Jager, Verena Grummel, Mauri Reunanen, David R. Booth, Anna Ticca, Angela Jochim, Leentje Cosemans, Julia Y Mescheriakova, Cristina Agliardi, Paola Cavalla, Jeffrey C. Barrett, Sarah E. Hunt, Gavin Band, School of Life Sciences, University of Technology Sydney (UTS), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Profium Oy [Helsinki], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institute of Clinical Medicine [Oslo], Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Michigan Technological University (MTU), The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], The Wellcome Trust Sanger Institute [Cambridge], Génétique épidémiologique et structures des populations humaines (Inserm U535), Epidémiologie, sciences sociales, santé publique (IFR 69), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Service de neurologie [Bordeaux], CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Karolinska Institutet [Stockholm], Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Department of Statistics [Oxford], Centro Dino Ferrari [Milano], Università degli Studi di Milano [Milano] (UNIMI)-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Epidémiologie et Analyses en Santé Publique : risques, maladies chroniques et handicap (LEASP), Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medical Epidemiology and Biostatistics (MEB), University College of London [London] (UCL), Fondation Jean Dausset CEPH, Centre Hospitalier Universitaire de Nice (CHU Nice), Dublin Institute of Technology (DIT), University of California [Irvine] (UCI), University of California, Géosciences Environnement Toulouse (GET), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS), Kaiser Permanente, Universität Zürich [Zürich] = University of Zurich (UZH), University Hospitals Leuven [Leuven], Department Biostatistics University of North Carolina, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Institute of Bioinformatics and Systems Biology [München], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Yale University School of Medicine, Big Data Institute, Department of Clinical Neurosciences [Cambridge], University of Cambridge [UK] (CAM), Faculty of Engineering, Neuroprotection & Neuromodulation, Internal Medicine Specializations, Neurology, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier (INM), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS), Yale School of Medicine [New Haven, Connecticut] (YSM), University of Oxford, Università degli Studi di Milano = University of Milan (UNIMI)-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, University of California [Irvine] (UC Irvine), University of California (UC), Cardiology, Epidemiology, Oral and Maxillofacial Surgery, International Multiple Sclerosis Genetics, Consortium, Beecham, Ah, Patsopoulos, Na, Xifara, Dk, Davis, Mf, Kemppinen, A, Cotsapas, C, Shah, T, Spencer, C, Booth, D, Goris, A, Oturai, A, Saarela, J, Fontaine, B, Hemmer, B, Martin, C, Zipp, F, D'Alfonso, S, Martinelli Boneschi, F, Taylor, B, Harbo, Hf, Kockum, I, Hillert, J, Olsson, T, Ban, M, Oksenberg, Jr, Hintzen, R, Barcellos, Lf, Wellcome Trust Case Control Consortium, 2, International IBD Genetics, Consortium, Agliardi, C, Alfredsson, L, Alizadeh, M, Anderson, C, Andrews, R, Søndergaard, Hb, Baker, A, Band, G, Baranzini, Se, Barizzone, N, Barrett, J, Bellenguez, C, Bergamaschi, L, Bernardinelli, L, Berthele, A, Biberacher, V, Binder, Tm, Blackburn, H, Bomfim, Il, Brambilla, P, Broadley, S, Brochet, B, Brundin, L, Buck, D, Butzkueven, H, Caillier, Sj, Camu, W, Carpentier, W, Cavalla, P, Celius, Eg, Coman, I, Comi, Giancarlo, Corrado, L, Cosemans, L, Cournu Rebeix, I, Cree, Ba, Cusi, D, Damotte, V, Defer, G, Delgado, Sr, Deloukas, P, di Sapio, A, Dilthey, At, Donnelly, P, Dubois, B, Duddy, M, Edkins, S, Elovaara, I, Esposito, F, Evangelou, N, Fiddes, B, Field, J, Franke, A, Freeman, C, Frohlich, Iy, Galimberti, D, Gieger, C, Gourraud, Pa, Graetz, C, Graham, A, Grummel, V, Guaschino, C, Hadjixenofontos, A, Hakonarson, H, Halfpenny, C, Hall, G, Hall, P, Hamsten, A, Harley, J, Harrower, T, Hawkins, C, Hellenthal, G, Hillier, C, Hobart, J, Hoshi, M, Hunt, Se, Jagodic, M, Jelčić, I, Jochim, A, Kendall, B, Kermode, A, Kilpatrick, T, Koivisto, K, Konidari, I, Korn, T, Kronsbein, H, Langford, C, Larsson, M, Lathrop, M, Lebrun Frenay, C, Lechner Scott, J, Lee, Mh, Leone, Ma, Leppä, V, Liberatore, G, Lie, Ba, Lill, Cm, Lindén, M, Link, J, Luessi, F, Lycke, J, Macciardi, F, Männistö, S, Manrique, Cp, Martin, R, Martinelli, V, Mason, D, Mazibrada, G, Mccabe, C, Mero, Il, Mescheriakova, J, Moutsianas, L, Myhr, Km, Nagels, G, Nicholas, R, Nilsson, P, Piehl, F, Pirinen, M, Price, Se, Quach, H, Reunanen, M, Robberecht, W, Robertson, Np, Rodegher, M, Rog, D, Salvetti, M, Schnetz Boutaud, Nc, Sellebjerg, F, Selter, Rc, Schaefer, C, Shaunak, S, Shen, L, Shields, S, Siffrin, V, Slee, M, Sorensen, P, Sorosina, M, Sospedra, M, Spurkland, A, Strange, A, Sundqvist, E, Thijs, V, Thorpe, J, Ticca, A, Tienari, P, van Duijn, C, Visser, Em, Vucic, S, Westerlind, H, Wiley, J, Wilkins, A, Wilson, Jf, Winkelmann, J, Zajicek, J, Zindler, E, Haines, Jl, Pericak Vance, Ma, Ivinson, Aj, Stewart, G, Hafler, D, Hauser, Sl, Compston, A, Mcvean, G, De Jager, P, Sawcer, Sj, and Mccauley, J. L.
Subjects: Multiple Sclerosis, Genotype, [SDV]Life Sciences [q-bio], European Continental Ancestry Group, Genome-wide association study, CLEC16A, Biology, multiple sclerosis, Major histocompatibility complex, Polymorphism, Single Nucleotide, Article, White People, 03 medical and health sciences, 0302 clinical medicine, Research Support, N.I.H., Extramural, Gene Frequency, Polymorphism (computer science), Journal Article, Genetics, medicine, Humans, Genetic Predisposition to Disease, Allele, Genotyping, Allele frequency, 030304 developmental biology, 0303 health sciences, Research Support, Non-U.S. Gov't, Multiple sclerosis, Chromosome Mapping, Genetic Variation, medicine.disease, 3. Good health, Genetic Loci, biology.protein, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Genome-Wide Association Study
Abstract: International audience; Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
Published: 2016
Full Text: View/download PDF

49. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Author: Per Hall, Simon C. Potter, Richard Reynolds, Robert Heard, Gil McVean, An Goris, Joseph T. Glessner, Pamela Whittaker, Niall Tubridy, Olivier Gout, Ann-Christine Syvaenen, Leena Peltonen, Bénédicte Dubois, Anders Hamsten, Alastair Compston, Hugh S. Markus, Mariaemma Rodegher, Lisa F. Barcellos, Wendy Cozen, Rosetta M. Chiavacci, Jenefer M. Blackwell, William M. Carroll, Patricia P. Ramsay, Amie Baker, Krzysztof Selmaj, Serge Dronov, Zhan Su, C. Smestad, Stanley Hawkins, Janna Saarela, Matti Pirinen, Sabine Cepok, Gavin Band, Norman Klopp, Simon Heath, Sandra D'Alfonso, Peter Donnelly, Ina-Maria Rueckert, Deborah F. Mason, Alagurevathi Jayakumar, Hakon Hakonarson, Cecilia Kim, Colin Freeman, Jeannette Lechner-Scott, Marc Debouverie, Neil Robertson, Inger-Lise Mero, Paola Cavalla, Sabine Roesner, H-Erich Wichmann, Daniele Cusi, Wendy Ingram, Sarah Edkins, Tania Mihalova, Mark J. Daly, Mark Marriott, Roland Martin, Adrian J. Ivinson, Hong L. Quach, Jeremy Hobart, Filippo Martinelli Boneschi, Carmen Infante-Duarte, Catherine Schaefer, Irina Elovaara, Jonathan L. Haines, John Zajicek, Michelle Ricketts, Ananth C. Viswanathan, Colin A. Graham, Allan G. Kermode, Helmut Butzkueven, Kai Wang, John Mottershead, Francesca Taddeo, Stefan Schreiber, Aarno Palotie, Trevor Pickersgill, Naomi Hammond, David A. Hafler, Robert Plomin, Robin R. Lincoln, David Sexton, Jianjun Liu, Finn Sellebjerg, Françoise Clerget-Darpoux, David Brassat, Sarah E. Hunt, Per Soelberg Sørensen, Vittorio Martinelli, Eleni Giannoulatou, Paul I.W. de Bakker, Alexander T. Dilthey, Stephen Leslie, Ulrika Liljedahl, Hanne F. Harbo, Alison Page, Keijo Koivisto, Ingrid Kockum, Stephen L. Hauser, Ewa Tronczynska, Ayman Tourbah, K Baker, Panos Deloukas, Hannah Blackburn, Janusz Jankowski, Mauri Reunanen, Trevor J. Kilpatrick, Sheila Skidmore, Sergio E. Baranzini, Nicholas W. Wood, Fredrik Piehl, Lars Alfredsson, Daniela Galimberti, Federica Esposito, Marco Salvetti, Jennifer Liddle, Jenny Link, Helle Bach Søndergaard, Suzannah Bumpstead, Jonathan P. Bradfield, Richard C. Strange, Céline Bellenguez, David R. Booth, Refujia Gomez, Michael Wittig, Matthew A. Brown, Laura Bergamaschi, Elisabeth Gulowsen Celius, William E R Ollier, Juan P. Casas, Ling Shen, Loukas Moutsianas, Fabio Macciardi, Anne H. Cross, Maja Jagodic, Marie B. D'hooghe, Tomas Olsson, Mark D. Cossburn, O. T. McCann, Justin P. Rubio, Isabelle Cournu-Rebeix, Struan F.A. Grant, Colin N. A. Palmer, Matthew W. Gillman, John D. Rioux, Christopher G. Mathew, Maria Ban, Anna-Maija Sulonen, Garrett Hellenthal, Dorothea Buck, Jorge R. Oksenberg, Frauke Zipp, James Wason, Stephen Sawcer, Franca Rosa Guerini, Clive Hawkins, Cristin Aubin, Elvira Bramon, Paul A. Weston, Andre Franke, Laura Piccio, Jane Vickery, Nikolaos A. Patsopoulos, Jacob L. McCauley, Kristin G. Ardlie, A. Strange, Marcin P. Mycko, Richard C. Trembath, Giancarlo Comi, Gillian Ingram, Graeme J. Stewart, Allan L. Bernstein, Emilie Sundqvist, Xavier Montalban, Juliane Winkelmann, Rhian Gwilliam, Ruggero Capra, Bruce V. Taylor, Maurizio Leone, Brigid Simms-Acuna, Emma J. Davis, Bertrand Fontaine, Chris C. A. Spencer, Malin Larsson, Hans-Peter Hartung, Emma Gray, Virpi M. Leppä, Pablo Villoslada, Audrey Duncanson, Åslaug R. Lorentzen, Rathi Ravindrarajah, Izaura Lima Bomfim, Christian Schulze, Talat Islam, Manuel Comabella, Rita Dobosi, Simon Broadley, Bernhard Hemmer, Margaret A. Pericak-Vance, Jan Hillert, Michael Kabesch, J. Yaouanq, Mark Lathrop, Angelo Ghezzi, Rodney J. Scott, K Dixon, Jean Pelletier, Annette Bang Oturai, Mike Boggild, Philip L. De Jager, Anne Spurkland, M. Perez, Roby Abraham, Pentti J. Tienari, Matthew Waller, Katleen Clysters, Adam Santaniello, David Ellinghaus, Cordelia Langford, Anna Rautanen, Frank D. Mentch, Achim Berthele, Kjell-Morten Myhr, Simon J. Foote, Thomas M. Mack, Bruce A.C. Cree, Susan Pobywajlo, Ernest Willoughby, Haitao Zhang, M. B. Cox, Anu Kemppinen, Muna Hoshi, Sara Widaa, Claire Fontenille, Erika Salvi, Sara Lupoli, Aiden Corvin, Roberto Bergamaschi, Jim Stankovich, Rebecca L. Zuvich, Paola Naldi, Patrick M. A. Sleiman, Clinical sciences, Neuroprotection & Neuromodulation, Neurology, and Faculty of Psychology and Educational Sciences
Subjects: Immunity, Cellular/genetics, Cellular immunity, Multiple Sclerosis, Genome-wide association study, CLEC16A, Biology, Polymorphism, Single Nucleotide, Cell Differentiation/immunology, Europe/ethnology, Major Histocompatibility Complex/genetics, Major Histocompatibility Complex, 03 medical and health sciences, 0302 clinical medicine, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, HLA-A Antigens/genetics, Alleles, 030304 developmental biology, Genetic association, Genetics, 0303 health sciences, Immunity, Cellular, Multidisciplinary, HLA-A Antigens, Genome, Human, Multiple sclerosis, Genetic Predisposition to Disease/genetics, HLA-DR Antigens/genetics, Lymphocyte differentiation, Cell Differentiation, HLA-DR Antigens, T-Lymphocytes, Helper-Inducer, RC346, medicine.disease, Polymorphism, Single Nucleotide/genetics, Genetic architecture, 3. Good health, Europe, Sample Size, Immunology, Genome, Human/genetics, Multiple Sclerosis/genetics, 030217 neurology & neurosurgery, T-Lymphocytes, Helper-Inducer/cytology, Genome-Wide Association Study, HLA-DRB1 Chains
Abstract: Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
Published: 2016
Full Text: View/download PDF

50. Power estimation for non-standardized multisite studies

Author: Till Sprenger, Massimo Filippi, David A. Hafler, Sara Llufriu, Gina Kirkish, Mona K. Beyer, Pablo Villoslada, Xavier Montalban, Sandra D'Alfonso, Anisha Keshavan, Philippe Demaerel, Claus Zimmer, Pradip M. Pattany, Mike P. Wattjes, Christiane Graetz, Ludwig Kappos, Alessandro Carriero, Jorge R. Oksenberg, Jacob L. McCauley, Roland G. Henry, Alyssa H. Zhu, Adriane Gröger, Michael Amann, An Goris, Laura Gaetano, Antje Bischof, Filippo Martinelli-Boneschi, Hanne F. Harbo, Sergiu Groppa, Alessandro Stecco, Stefano Magon, Margaret A. Pericak-Vance, Daniel Pelletier, Frauke Zipp, Regina Schlaeger, Alex Rovira, Nico Papinutto, Friedemann Paul, Albert Saiz, Maria A. Rocca, Isabelle Cournu-Rebeix, William A. Stern, Howard L. Weiner, Bernhard Hemmer, Russell T. Shinohara, Manuel Comabella, Bénédicte Dubois, Rohit Bakshi, Jason C. Crane, Vinzenz Fleischer, Bernard M. J. Uitdehaag, Jens Wuerfel, Stephen L. Hauser, Mark Mühlau, Kesshi M. Jordan, Bertrand Fontaine, Keshavan, A, Paul, F, Beyer, Mk, Zhu, Ah, Papinutto, N, Shinohara, Rt, Stern, W, Amann, M, Bakshi, R, Bischof, A, Carriero, A, Comabella, M, Crane, Jc, D'Alfonso, S, Demaerel, P, Dubois, B, Filippi, M, Fleischer, V, Fontaine, B, Gaetano, L, Goris, A, Graetz, C, Gröger, A, Groppa, S, Hafler, Da, Harbo, Hf, Hemmer, B, Jordan, K, Kappos, L, Kirkish, G, Llufriu, S, Magon, S, Martinelli-Boneschi, F, Mccauley, J, Montalban, X, Muhlau, M, Pelletier, D, Pattany, Pm, Pericak-Vance, M, Rebeix, I, Rocca, M, Rovira, A, Schlaeger, R, Saiz, A, Sprenger, T, Stecco, A, Uitdehaag, Bm, Villoslada, P, Wattjes, Mp, Weiner, H, Wuerfel, J, Zimmer, C, Zipp, F, International Multiple Sclerosis Genetics, Consortium, Hauser, S, Oksenberg, Jr, Henry, Rg, Bioengineering Graduate Program (joint degree with UCSF), Department of Bioengineering [Berkeley], University of California [Berkeley], University of California-University of California-University of California [Berkeley], University of California-University of California-University of California [San Francisco] (UCSF), University of California, Department of Neurology [San Francisco], University of California [San Francisco] (UCSF), University of California-University of California, Max Delbrueck Centre for Molecular Medicine, NeuroCure Clinical Research Center and Clinical and Experimental Multiple Sclerosis Research Center, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Department of Radiology and Nuclear Medicine, Oslo University Hospital [Oslo], Department of Biostatistics and Epidemiology [Philadelphia], Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], Department of Neurology [Suisse], University Hospital Basel [Basel], Medical Image Analysis Center (MIAC AG), Brigham and Women's Hospital [Boston], Clinical Immunology, Department of Translational Medicine, UPO University, Vall d'Hebron University Hospital [Barcelona], Department of Radiology and Biomedical Imaging [San Francisco], Department of Health Sciences, UPO University, Department of Radiology[Leuven], University Hospitals Leuven [Leuven], Department of Neurosciences Leuven, University of Leuven K.U.Leuven, Institute of Experimental Neurology, Milan, University Medical Centre of the Johannes Gutenberg University Mainz, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), University Medical Centre of the Johannes Gutenberg-University Mainz, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Departments of Neurology and Immunobiology [Yale], Yale University School of Medicine, Department of Neurology [Oslo], Akershus University Hospital [Lørenskog], Department Neurology of the Klinikum rechts der Isar, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Munich Cluster of Systems Neurology (SyNery), Center for Neuroimmunology, Service of Neurology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Neuroimaging Research Unit, Scientific Institute and University Hospital San Raffaele, Milan, John P. Hussman Institute for Human Genomics, University of Miami Leonard M. Miller School of Medicine (UMMSM), TUM–Neuroimaging Center, Department of Radiology [Miami], DKD Helios Klinik Wiesbaden, Section of Neuroradiology [Novara], Maggiore Hospital, VU University Medical Center [Amsterdam], Dept Neuroradiology [Munich], Klinikums rechts der Isar, University of California [Berkeley] (UC Berkeley), University of California (UC)-University of California (UC)-University of California [Berkeley] (UC Berkeley), University of California (UC)-University of California (UC)-University of California [San Francisco] (UC San Francisco), University of California (UC), University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), University of Pennsylvania-University of Pennsylvania, Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Yale School of Medicine [New Haven, Connecticut] (YSM), Neurology, Amsterdam Neuroscience - Neuroinfection & -inflammation, and Radiology and nuclear medicine
Subjects: Computer science, Cognitive Neuroscience, computer.software_genre, Sensitivity and Specificity, 050105 experimental psychology, Imaging phantom, Article, Set (abstract data type), 03 medical and health sciences, 0302 clinical medicine, Distortion, Image Interpretation, Computer-Assisted, Calibration, medicine, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Humans, 0501 psychology and cognitive sciences, Segmentation, Computer Simulation, 10. No inequality, Scaling, Models, Statistical, medicine.diagnostic_test, 05 social sciences, Contrast (statistics), Brain, Reproducibility of Results, Magnetic resonance imaging, Equipment Design, Scale factor, Image Enhancement, Magnetic Resonance Imaging, United States, Equipment Failure Analysis, Europe, Neurology, Ordinary least squares, Data mining, Function and Dysfunction of the Nervous System, Artifacts, computer, 030217 neurology & neurosurgery, Algorithms
Abstract: A concern for researchers planning multisite studies is that scanner and T1-weighted sequence-related biases on regional volumes could overshadow true effects, especially for studies with a heterogeneous set of scanners and sequences. Current approaches attempt to harmonize data by standardizing hardware, pulse sequences, and protocols, or by calibrating across sites using phantom-based corrections to ensure the same raw image intensities. We propose to avoid harmonization and phantom-based correction entirely. We hypothesized that the bias of estimated regional volumes is scaled between sites due to the contrast and gradient distortion differences between scanners and sequences. Given this assumption, we provide a new statistical framework and derive a power equation to define inclusion criteria for a set of sites based on the variability of their scaling factors. We estimated the scaling factors of 20 scanners with heterogeneous hardware and sequence parameters by scanning a single set of 12 subjects at sites across the United States and Europe. Regional volumes and their scaling factors were estimated for each site using Freesurfer's segmentation algorithm and ordinary least squares, respectively. The scaling factors were validated by comparing the theoretical and simulated power curves, performing a leave-one-out calibration of regional volumes, and evaluating the absolute agreement of all regional volumes between sites before and after calibration. Using our derived power equation, we were able to define the conditions under which harmonization is not necessary to achieve 80% power. This approach can inform choice of processing pipelines and outcome metrics for multisite studies based on scaling factor variability across sites, enabling collaboration between clinical and research institutions. publisher: Elsevier articletitle: Power estimation for non-standardized multisite studies journaltitle: NeuroImage articlelink: http://dx.doi.org/10.1016/j.neuroimage.2016.03.051 content_type: article copyright: © 2016 The Authors. Published by Elsevier Inc. ispartof: NeuroImage vol:134 pages:281-294 ispartof: location:United States status: published
Published: 2016
Full Text: View/download PDF

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

Topic

Publication Year Range

Language

Category

Publication Type

Journal

Region

Database

Publisher

445 results on '"L. Hauser"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources