Comparative effectiveness of autologous hematopoietic stem cell transplant vs fingolimod, natalizumab, and ocrelizumab in highly active relapsing-remitting multiple sclerosis

Importance: Autologous hematopoietic stem cell transplant (AHSCT) is available for treatment of highly active multiple sclerosis (MS). Objective: To compare the effectiveness of AHSCT vs fingolimod, natalizumab, and ocrelizumab in relapsing-remitting MS by emulating pairwise trials. Design, Setting, and Participants: This comparative treatment effectiveness study included 6 specialist MS centers with AHSCT programs and international MSBase registry between 2006 and 2021. The study included patients with relapsing-remitting MS treated with AHSCT, fingolimod, natalizumab, or ocrelizumab with 2 or more years study follow-up including 2 or more disability assessments. Patients were matched on a propensity score derived from clinical and demographic characteristics. Exposure: AHSCT vs fingolimod, natalizumab, or ocrelizumab. Main outcomes: Pairwise-censored groups were compared on annualized relapse rates (ARR) and freedom from relapses and 6-month confirmed Expanded Disability Status Scale (EDSS) score worsening and improvement. Results: Of 4915 individuals, 167 were treated with AHSCT; 2558, fingolimod; 1490, natalizumab; and 700, ocrelizumab. The prematch AHSCT cohort was younger and with greater disability than the fingolimod, natalizumab, and ocrelizumab cohorts; the matched groups were closely aligned. The proportion of women ranged from 65% to 70%, and the mean (SD) age ranged from 35.3 (9.4) to 37.1 (10.6) years. The mean (SD) disease duration ranged from 7.9 (5.6) to 8.7 (5.4) years, EDSS score ranged from 3.5 (1.6) to 3.9 (1.9), and frequency of relapses ranged from 0.77 (0.94) to 0.86 (0.89) in the preceding year. Compared with the fingolimod group (769 [30.0%]), AHSCT (144 [86.2%]) was associated with fewer relapses (ARR: mean [SD], 0.09 [0.30] vs 0.20 [0.44]), similar risk of disability worsening (hazard ratio [HR], 1.70; 95% CI, 0.91-3.17), and higher chance of disability improvement (HR, 2.70; 95% CI, 1.71-4.26) over 5 years. Compared with natalizumab (730 [49.0%]), AHSCT (146 [87.4%]) was associated with marginally lower ARR (mean [SD], 0.08 [0.31] vs 0.10 [0.34]), similar risk of disability worsening (HR, 1.06; 95% CI, 0.54-2.09), and higher chance of disability improvement (HR, 2.68; 95% CI, 1.72-4.18) over 5 years. AHSCT (110 [65.9%]) and ocrelizumab (343 [49.0%]) were associated with similar ARR (mean [SD], 0.09 [0.34] vs 0.06 [0.32]), disability worsening (HR, 1.77; 95% CI, 0.61-5.08), and disability improvement (HR, 1.37; 95% CI, 0.66-2.82) over 3 years. AHSCT-related mortality occurred in 1 of 159 patients (0.6%). Conclusion: In this study, the association of AHSCT with preventing relapses and facilitating recovery from disability was considerably superior to fingolimod and marginally superior to natalizumab. This study did not find evidence for difference in the effectiveness of AHSCT and ocrelizumab over a shorter available follow-up time

Timing of syenite-charnockite magmatism and ruby- and sapphire metamorphism in the Mogok valley region, Myanmar

We thank the Oxford–Burma Aung San Suu Kyi trust for funding research and fieldwork visits to Myanmarfor MS,NG and LR. Geochronology was funded by UCSB and NSF grants EAR-1348003and EAR-1551054.The Mogok metamorphic belt (MMB) extends for over 1,000 km along central Burma from the Andaman Sea to the East Himalayan syntaxis and represents exhumed lower and middle crustal metamorphic rocks of the Sibumasu plate. In the Mogok valley region, the MMB consists of regional high‐grade marbles containing calcite + phlogopite + spinel + apatite ± diopside ± olivine and hosts world class ruby and sapphire gemstones. The coarse‐grained marbles have been intruded by orthopyroxene‐ and clinopyroxene‐bearing charnockite‐syenite sheet‐like intrusions that have skarns around the margins. Syenites range from hornblende‐ to quartz‐bearing and frequently show layering that could be a primary igneous texture or a later metamorphic overprint. Calc‐silicate skarns contain both rubies and blue sapphires with large biotites. Rubies occur in marbles with scapolite, phlogopite, graphite, occasional diopside, and blue apatite. Both marbles and syenites have been intruded by the Miocene Kabaing garnet‐muscovite‐biotite peraluminous leucogranite. New mapping and structural observations combined with U‐Th‐Pb zircon, monazite, and titanite geochronology from syenites, charnockites, leucogranites, meta‐rhyolite‐tuffs, and skarns have revealed a complex multiphase igneous and metamorphic history for the MMB. U‐Pb zircon ages of the charnockite‐syenites fall into three categories, Jurassic (170–168 Ma), latest Cretaceous to early Paleocene (~68‐63 Ma), and late Eocene–Oligocene (44–21 Ma). New ages from five samples suggest that metamorphism in the presence of garnet and melt occurred between ~45 and 24 Ma. U‐Pb titanite ages from the ruby marbles and meta‐skarns at Le Oo mine in the Mogok valley are 21 Ma, similar to titanite ages from an adjacent syenite (22 Ma). U‐Th‐Pb dating shows that all the metamorphic ages are Late Cretaceous–early Miocene and related to the India‐Sibumasu collision.Publisher PDFPeer reviewe

Simultaneous Relevant Feature Identification and Classification in High-Dimensional Spaces

Molecular profiling technologies monitor thousands of transcripts, proteins, metabolites or other species concurrently in biological samples of interest. Given two-class, high-dimensional profiling data, nominal Liknon [4] is a specific implementation of a methodology for performing simultaneous relevant feature identification and classification. It exploits the well-known property that minimising an l_1 norm (via linear programming) yields a sparse hyperplane [15, 26, 2, 8, 17]. This work (i) examines computational, software and practical issues required to realise nominal Liknon, (ii) summarises results from its application to five real world data sets, (iii) outlines heuristic solutions to problems posed by domain experts when interpreting the results and (iv) defines some future directions of the research