| 1. |
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| 2. |
- Beecham, Ashley H, et al.
(författare)
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Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.
- 2013
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:11, s. 1353-60
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Willis, M., et al.
(författare)
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An observational study of alemtuzumab following fingolimod for multiple sclerosis
- 2017
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Ingår i: Neurology-Neuroimmunology & Neuroinflammation. - : Ovid Technologies (Wolters Kluwer Health). - 2332-7812. ; 4:2
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To describe a series of patients with relapsing multiple sclerosis (MS) who experienced significant and unexpected disease activity within the first 12 months after switching from fingolimod to alemtuzumab. Methods: Patients with relapsing MS treated sequentially with fingolimod then alemtuzumab who experienced significant subsequent disease activity were identified by personal communication with 6 different European neuroscience centers. Results: Nine patients were identified. Median disease duration to alemtuzumab treatment was 94 (39-215) months and follow-up from time of first alemtuzumab cycle 20 (14-21) months. Following first alemtuzumab infusion cycle, 8 patients were identified by at least 1 clinical relapse and radiologic disease activity and 1 by significant radiologic disease activity alone. Conclusions: We acknowledge the potential for ascertainment bias; however, these cases may illustrate an important cause of reduced efficacy of alemtuzumab in a vulnerable group of patients with MS most in need of disease control. We suggest that significant and unexpected subsequent disease activity after alemtuzumab induction results from prolonged sequestration of autoreactive lymphocytes following fingolimod withdrawal, allowing these cells to be concealed from the usual biological effect of alemtuzumab. Subsequent lymphocyte egress then provokes disease reactivation. Further animal studies and clinical trials are required to confirm these phenomena and in the meantime careful consideration should be given to mode of action of individual therapies and sequential treatment effects in MS when designing personalized treatment regimens.
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| 4. |
- Green, Paul F., et al.
(författare)
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Post-breakup burial and exhumation of passive continental margins : Seven propositions to inform geodynamic models
- 2018
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Ingår i: Gondwana Research. - : Elsevier BV. - 1342-937X .- 1878-0571. ; 53:January, s. 58-81
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Tidskriftsartikel (refereegranskat)abstract
- Despite many years of study, the processes involved in the post-breakup development of passive margins remain poorly understood. Integration of apatite fission track analysis (AFTA) and stratigraphic landscape analysis (SLA) at a number of margins has provided new insights into the development of elevated passive continental margins (EPCMs). In particular, by integrating evidence from the preserved rock record and landscape with information on the deposition and erosional removal of rock units which are no longer present (“missing section”) these studies have highlighted the importance of episodic positive and negative vertical km-scale crustal movements. Based on these studies we present seven propositions regarding the formation of EPCMs and the nature of the controlling processes, viz:1: EPCMs are not the inevitable consequence of rifting and breakup2: Elevated topography at present-day EPCMs developed long after breakup3: Similar EPCM landscapes at different margins suggest similar controlling processes4: EPCMs have undergone episodic km-scale burial and exhumation rather than slow monotonic denudation, both before rifting and after breakup5: Post-breakup km-scale exhumation at continental margins is not restricted to presently elevated onshore regions6: Post-breakup km-scale burial and exhumation have affected presently low lying margins as well as EPCMs7: Exhumation events show a broad level of synchroneity over continents and across oceans and correlate with plate boundary events and changes in plate motions.These propositions imply that positive and negative vertical motions at passive margins are controlled by plate-scale processes. Another key conclusion is that present-day elevation alone provides no clue to the earlier history of a margin.Many of the key aspects of these propositions are absent from current geodynamic models of passive margin development. Understanding the processes that control vertical movements at passive continental margins requires development of realistic geodynamic models that honour these propositions.
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| 5. |
- Green, Paul F., et al.
(författare)
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Post-breakup burial and exhumation of the southern margin of Africa
- 2017
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Ingår i: Basin Research. - : Wiley-Blackwell. - 0950-091X .- 1365-2117. ; 29:1, s. 96-127
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Tidskriftsartikel (refereegranskat)abstract
- Despite many years of study, the processes involved in the development of the continental margin of southern Africa and the distinctive topography of the hinterland remain poorly understood. Previous thermochronological studies carried out within a monotonic cooling framework have failed to take into account constraints provided by Mesozoic sedimentary basins along the southern margin. We report apatite fission track analysis and vitrinite reflectance data in outcrop samples from the Late Jurassic to Early Cretaceous sedimentary fill of the Oudtshoorn, Gamtoos and Algoa Basins (Uitenhage Group), as well as isolated sedimentary remnants further west, plus underlying Paleozoic rocks (Cape Supergroup) and Permian-Triassic sandstones from the Karoo Supergroup around the Great Escarpment. Results define a series of major regional cooling episodes. Latest Triassic to Early Jurassic cooling which began between 205 and 180 Ma is seen dominantly in basement flanks to the Algoa and Gamtoos Basins. This episode may have affected a wider region but in most places any effects have been overprinted by later events. The effects of Early Cretaceous (beginning between 145 and 130 Ma) and Early to mid-Cretaceous (120-100 Ma) cooling are both delimited by major structures, while Late Cretaceous (85-75 Ma) cooling appears to have affected the whole region. These cooling events are all interpreted as dominantly reflecting exhumation. Higher Late Cretaceous paleotemperatures in samples from the core of the Swartberg Range, coupled with evidence for localised Cenozoic cooling, are interpreted as representing Cenozoic differential exhumation of the mountain range. Late Cretaceous paleotemperatures between 60 degrees C and 90 degrees C in outcropping Uitenhage Group sediments from the Oudtshoorn, Gamtoos and Algoa Basins require burial by between 1.2 and 2.2 km prior to Late Cretaceous exhumation. Because these sediments lie in depositional contact with underlying Paleozoic rocks in many places, relatively uniform Late Cretaceous paleotemperatures across most of the region, in samples of both basin fill and underlying basement, suggest the whole region may have been buried prior to Late Cretaceous exhumation. Cenozoic cooling (beginning between 30 and 20 Ma) is focussed mainly in mountainous regions and is interpreted as representing denudation which produced the modern-day relief. Features such as the Great Escarpment are not related to continental break up, as is often supposed, but are much younger (post-30 Ma). This history of post-breakup burial and subsequent episodic exhumation is very different from conventional ideas of passive margin evolution, and requires a radical re-think of models for development of continental margins.
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| 6. |
- Green, Paul F., et al.
(författare)
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The post-Caledonian thermo-tectonic evolution of Fennoscandia
- 2022
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Ingår i: Gondwana Research. - : Elsevier. - 1342-937X .- 1878-0571. ; 107, s. 201-234
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Tidskriftsartikel (refereegranskat)abstract
- The evolution of Fennoscandia following the early Devonian collapse of the Caledonian mountains is a matter of debate, due largely to the scarcity of post-Caledonian cover rocks. The preserved geological record therefore provides only partial documentation of the geological evolution. A more complete understanding is obtained by also considering evidence of rocks that were formerly present but have since been removed. We report apatite fission track data and associated thermal history constraints in 331 samples of Precambrian basement, younger sedimentary cover, Paleozoic and Mesozoic igneous rocks from outcrops and boreholes (up to 6 km depth) across Fennoscandia, which define thirteen phases of cooling (each representing kilometre-scale exhumation) over the last 1100 Myr. Key post-Caledonian episodes began in the intervals 311–307 Ma (late Carboniferous), 245–244 Ma (Middle Triassic), 170–167 Ma (Middle Jurassic), 102–92 Ma (mid-Cretaceous) and 23–21 Ma (early Miocene). These episodes, varying in magnitude, are recognised across Fennoscandia, and their effects are documented in the stratigraphic record and as prominent regional peneplains. The results define a history involving repeated episodes of regional burial and exhumation. Major offsets in Mesozoic paleotemperatures over short distances define kilometre-scale differential vertical displacements, emphasising the tectonic nature of the history. Results from Finland record the same events recognised in Norway and Sweden (though less pronounced), and are not consistent with long-term cratonic stability. The lack of preserved Phanerozoic sedimentary cover in Finland is interpreted to be due to complete removal during multiple episodes of denudation. In southern Norway and Sweden, early Miocene exhumation led to creation of a peneplain, which in Pliocene times was uplifted and dissected, producing the modern landscape. Post-Caledonian exhumation episodes defined here are broadly synchronous with similar events in Greenland, the British Isles and North America. Far-field transmission of plate-tectonic stress and/or mantle processes may explain the vertical movements described here.
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| 7. |
- Green, Paul F., et al.
(författare)
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Thermal history solutions from thermochronology must be governed by geological relationships : A comment on Jess et al. (2019)
- 2020
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Ingår i: Geomorphology. - : Elsevier BV. - 0169-555X .- 1872-695X. ; 360
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The recent study of the basement margin to the Nuussuaq Basin, West Greenland, by Jess et al. (2019) illustrates the problems introduced by extracting thermal histories from thermochronology data without taking into account the constraints provided by geological evidence. Their interpretations are incompatible with numerous aspects of the geology of the region, and as a result their conclusions are not valid.
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| 8. |
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| 9. |
- Kappos, Ludwig, et al.
(författare)
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Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study
- 2018
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 391, s. 1263-1273
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Tidskriftsartikel (refereegranskat)abstract
- © 2018 Elsevier Ltd Background: No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor 1,5 modulator, on disability progression in patients with SPMS. Methods: This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries. Using interactive response technology to assign numbers linked to treatme nt arms, patients (age 18–60 years) with SPMS and an Expanded Disability Status Scale score of 3·0–6·5 were randomly assigned (2:1) to once daily oral siponimod 2 mg or placebo for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events. The primary endpoint was time to 3-month CDP. Efficacy was assessed for the full analysis set (ie, all randomly assigned and treated patients); safety was assessed for the safety set. This trial is registered with ClinicalTrials.gov, number NCT01665144. Findings: 1651 patients were randomly assigned between Feb 5, 2013, and June 2, 2015 (1105 to the siponimod group, and 546 to the placebo group). One patient did not sign the consent form, and five patients did not receive study drug, all of whom were in the siponimod group. 1645 patients were included in the analyses (1099 in the siponimod group and 546 in the placebo). At baseline, the mean time since first multiple sclerosis symptoms was 16·8 years (SD 8·3), and the mean time since conversion to SPMS was 3·8 years (SD 3·5); 1055 (64%) patients had not relapsed in the previous 2 years, and 918 (56%) of 1651 needed walking assistance. 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study. 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month CDP (hazard ratio 0·79, 95% CI 0·65–0·95; relative risk reduction 21%; p=0·013). Adverse events occurred in 975 (89%) of 1099 patients receiving siponimod versus 445 (82%) of 546 patients receiving placebo; serious adverse events were reported for 197 (18%) patients in the siponimod group versus 83 (15%) patients in the placebo group. Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo. Initial dose titration mitigated cardiac first-dose effects. Frequencies of infections, malignancies, and fatalities did not differ between groups. Interpretation: Siponimod reduced the risk of disability progression with a safety profile similar to that of other S1P modulators and is likely to be a useful treatment for SPMS. Funding: Novartis Pharma AG.
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| 10. |
- Vallabh, S. M., et al.
(författare)
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Cerebrospinal fluid and plasma biomarkers in individuals at risk for genetic prion disease
- 2020
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Ingår i: Bmc Medicine. - : Springer Science and Business Media LLC. - 1741-7015. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Prion disease is neurodegenerative disease that is typically fatal within months of first symptoms. Clinical trials in this rapidly declining symptomatic patient population have proven challenging. Individuals at high lifetime risk for genetic prion disease can be identified decades before symptom onset and provide an opportunity for early therapeutic intervention. However, randomizing pre-symptomatic carriers to a clinical endpoint is not numerically feasible. We therefore launched a cohort study in pre-symptomatic genetic prion disease mutation carriers and controls with the goal of evaluating biomarker endpoints that may enable informative trials in this population. Methods We collected cerebrospinal fluid (CSF) and blood from pre-symptomatic individuals with prion protein gene (PRNP) mutations (N = 27) and matched controls (N = 16), in a cohort study at Massachusetts General Hospital. We quantified total prion protein (PrP) and real-time quaking-induced conversion (RT-QuIC) prion seeding activity in CSF and neuronal damage markers total tau (T-tau) and neurofilament light chain (NfL) in CSF and plasma. We compared these markers cross-sectionally, evaluated short-term test-retest reliability over 2-4 months, and conducted a pilot longitudinal study over 10-20 months. Results CSF PrP levels were stable on test-retest with a mean coefficient of variation of 7% for both over 2-4 months inN = 29 participants and over 10-20 months inN = 10 participants. RT-QuIC was negative in 22/23 mutation carriers. The sole individual with positive RT-QuIC seeding activity at two study visits had steady CSF PrP levels and slightly increased tau and NfL concentrations compared with the others, though still within the normal range, and remained asymptomatic 1 year later. T-tau and NfL showed no significant differences between mutation carriers and controls in either CSF or plasma. Conclusions CSF PrP will be interpretable as a pharmacodynamic readout for PrP-lowering therapeutics in pre-symptomatic individuals and may serve as an informative surrogate biomarker in this population. In contrast, markers of prion seeding activity and neuronal damage do not reliably cross-sectionally distinguish mutation carriers from controls. Thus, as PrP-lowering therapeutics for prion disease advance, "secondary prevention" based on prodromal pathology may prove challenging; instead, "primary prevention" trials appear to offer a tractable paradigm for trials in pre-symptomatic individuals.
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