Paediatric multiple sclerosis and antibody-associated demyelination: clinical, imaging, and biological considerations for diagnosis and care

The field of acquired CNS neuroimmune demyelination in children is transforming. Progress in assay development, refinement of diagnostic criteria, increased biological insights provided by advanced neuroimaging techniques, and high-level evidence for the therapeutic efficacy of biological agents are redefining diagnosis and care. Three distinct neuroimmune conditions-multiple sclerosis, myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and aquaporin-4 antibody-associated neuromyelitis optica spectrum disorder (AQP4-NMOSD)-can now be distinguished, with evidence from humans and animal models supporting distinct pathobiological disease mechanisms. The development of highly effective therapies for adult-onset multiple sclerosis and AQP4-NMOSD that suppress relapse rate by more than 90% has motivated advocacy for trials in children. However, doing clinical trials is challenging because of the rarity of these conditions in the paediatric age group, necessitating new approaches to trial design, including age-based trajectory modelling based on phase 3 studies in adults. Despite these limitations, the future for children and adolescents living with multiple sclerosis, MOGAD, or AQP4-NMOSD is far brighter than in years past, and will be brighter still if successful therapies to promote remyelination, enhance neuroprotection, and remediate cognitive deficits can be further accelerated

Treatment Approaches for MOG-Ab-Associated Demyelination in Children

Purpose of review The purpose of this review is to summarize current understanding regarding the treatment of myelin oligodendrocyte glycoprotein antibody (MOG-Ab)-associated demyelination in children. Emphasis is placed on the unique obstacles we face when predicting the risk of relapse and the important implications of such challenges when planning treatment protocols. Recent findings MOG-Abs are consistently identified in a range of acquired demyelinating syndromes (ADS) in adults and children with a clinical phenotype distinct of MS and AQP4-Ab neuromyelitis optica spectrum disorder. Although initially thought to be associated with a benign disease, recent reports of children who are treatment-resistant and developed progressive disability over time raise important questions about how children with relapsing MOG-Ab disease should be managed. Summary MOG-Abs are common in children with ADS with both monophasic and relapsing disease courses. Treatment of patients with MOG-Ab-associated demyelination includes management of acute relapses and chronic immunotherapy for those with relapsing disease. Emerging consensus supports distinction of treatment strategies from those typically used for relapsing remitting MS, and several groups debate whether to follow treatment protocols akin to those for AQP4-Ab NMOSD. A key challenge remains predicting the severity of the disease at onset. Collaborative international consensus to derive shared clinical evaluative platforms standardized biological and neuroimaging protocols which can be used clinically, and partnered research programs are required to advance personalized treatment for children with MOG-Ab-associated demyelination

Formation of pedestalled, relict lakes on the McMurdo Ice Shelf, Antarctica

ABSTRACTSurface debris covers much of the western portion of the McMurdo Ice Shelf and has a strong influence on the local surface albedo and energy balance. Differential ablation between debris-covered and debris-free areas creates an unusual heterogeneous surface of topographically low, high-ablation, and topographically raised (‘pedestalled’), low-ablation areas. Analysis of Landsat and MODIS satellite imagery from 1999 to 2018, alongside field observations from the 2016/2017 austral summer, shows that pedestalled relict lakes (‘pedestals’) form when an active surface meltwater lake that develops in the summer, freezes-over in winter, resulting in the lake-bottom debris being masked by a high-albedo, superimposed, ice surface. If this ice surface fails to melt during a subsequent melt season, it experiences reduced surface ablation relative to the surrounding debris-covered areas of the ice shelf. We propose that this differential ablation, and resultant hydrostatic and flexural readjustments of the ice shelf, causes the former supraglacial lake surface to become increasingly pedestalled above the lower topography of the surrounding ice shelf. Consequently, meltwater streams cannot flow onto these pedestalled features, and instead divert around them. We suggest that the development of pedestals has a significant influence on the surface-energy balance, hydrology and flexure of the ice shelf.Ia

Diurnal seismicity cycle linked to subsurface melting on an ice shelf

ABSTRACTSeismograms acquired on the McMurdo Ice Shelf, Antarctica, during an Austral summer melt season (November 2016–January 2017) reveal a diurnal cycle of seismicity, consisting of hundreds of thousands of small ice quakes limited to a 6–12 hour period during the evening, in an area where there is substantial subsurface melting. This cycle is explained by thermally induced bending and fracture of a frozen surface superimposed on a subsurface slush/water layer that is supported by solar radiation penetration and absorption. A simple, one-dimensional model of heat transfer driven by observed surface air temperature and shortwave absorption reproduces the presence and absence (as daily weather dictated) of the observed diurnal seismicity cycle. Seismic event statistics comparing event occurrence with amplitude suggest that the events are generated in a fractured medium featuring relatively low stresses, as is consistent with a frozen surface superimposed on subsurface slush. Waveforms of the icequakes are consistent with hydroacoustic phases at frequency ${\bf \gt} \bf 75\,{\bf Hz}$ and flexural-gravity waves at frequency $\bf {\bf \lt}25\,{\bf Hz}$. Our results suggest that seismic observation may prove useful in monitoring subsurface melting in a manner that complements other ground-based methods as well as remote sensing.</jats:p

Rituximab monitoring and redosing in pediatric neuromyelitis optica spectrum disorder.

Abstract OBJECTIVE: To study rituximab in pediatric neuromyelitis optica (NMO)/NMO spectrum disorders (NMOSD) and the relationship between rituximab, B cell repopulation, and relapses in order to improve rituximab monitoring and redosing. METHODS: Multicenter retrospective study of 16 children with NMO/NMOSD receiving 652 rituximab courses. According to CD19 counts, events during rituximab were categorized as "repopulation," "depletion," or "depletion failure" relapses (repopulation threshold CD19 6510 7 10(6) cells/L). RESULTS: The 16 patients (14 girls; mean age 9.6 years, range 1.8-15.3) had a mean of 6.1 events (range 1-11) during a mean follow-up of 6.1 years (range 1.6-13.6) and received a total of 76 rituximab courses (mean 4.7, range 2-9) in 42.6-year cohort treatment. Before rituximab, 62.5% had received azathioprine, mycophenolate mofetil, or cyclophosphamide. Mean time from rituximab to last documented B cell depletion and first repopulation was 4.5 and 6.8 months, respectively, with large interpatient variability. Earliest repopulations occurred with the lowest doses. Significant reduction between pre- and post-rituximab annualized relapse rate (ARR) was observed (p = 0.003). During rituximab, 6 patients were relapse-free, although 21 relapses occurred in 10 patients, including 13 "repopulation," 3 "depletion," and 4 "depletion failure" relapses. Of the 13 "repopulation" relapses, 4 had CD19 10-50 7 10(6) cells/L, 10 had inadequate monitoring ( 641 CD19 in the 4 months before relapses), and 5 had delayed redosing after repopulation detection. CONCLUSION: Rituximab is effective in relapse prevention, but B cell repopulation creates a risk of relapse. Redosing before B cell repopulation could reduce the relapse risk further. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that rituximab significantly reduces ARR in pediatric NMO/NMOSD. This study also demonstrates a relationship between B cell repopulation and relapses

Podoconiosis and soil-transmitted helminths (STHs): double burden of neglected tropical diseases in Wolaita zone, rural southern Ethiopia

Background Both podoconiosis and soil-transmitted helminth (STH) infections occur among barefoot people in areas of extreme poverty; however, their co-morbidity has not previously been investigated. We explored the overlap of STH infection and podoconiosis in Southern Ethiopia and quantified their separate and combined effects on prevalent anemia and hemoglobin levels in podoconiosis patients and health controls from the same area. Methods and Principal Findings A two-part comparative cross-sectional study was conducted in Wolaita zone, southern Ethiopia. Data were collected from adult patients presenting with clinically confirmed podoconiosis, and unmatched adult neighborhood controls living in the same administrative area. Information on demographic and selected lifestyle factors was collected using interviewer-administered questionnaires. Stool samples were collected and examined qualitatively using the modified formalin-ether sedimentation method. Hemoglobin level was determined using two different methods: hemoglobinometer and automated hematology analyzer. A total of 913 study subjects (677 podoconiosis patients and 236 controls) participated. The prevalence of any STH infection was 47.6% among patients and 33.1% among controls (p<0.001). The prevalence of both hookworm and Trichuris trichiura infections was significantly higher in podoconiosis patients than in controls (AOR 1.74, 95% CI 1.25 to2.42, AOR 6.53, 95% CI 2.34 to 18.22, respectively). Not wearing shoes and being a farmer remained significant independent predictors of infection with any STH. There was a significant interaction between STH infection and podoconiosis on reduction of hemoglobin level (interaction p value = 0.002). Conclusions Prevalence of any STH and hookworm infection was higher among podoconiosis patients than among controls. A significant reduction in hemoglobin level was observed among podoconiosis patients co-infected with hookworm and ‘non-hookworm STH’. Promotion of consistent shoe-wearing practices may have double advantages in controlling both podoconiosis and hookworm infection in the study area

Subcutaneous interferon β-1a in pediatric patients with multiple sclerosis: Regional differences in clinical features, disease management, and treatment outcomes in an international retrospective study

AbstractBackgroundTo further understand management of pediatric patients with multiple sclerosis (MS), we examined disease features, clinical practice patterns, and response to treatment in the United States (US) and seven other countries ('rest of World'; ROW).MethodsAnonymized data, recorded as part of routine clinical practice, were obtained from medical records (1997–2009) of study participants (who received subcutaneous interferon β-1a before age 18years) from the US and ROW. Samples were stratified by age (preadolescents [<12years] and adolescents [12–17years]).ResultsUS adolescents had a higher mean body mass index versus ROW adolescents (BMI; 27.2 versus 22.5kg/m2), started disease-modifying therapy (DMT) earlier after the first relapse, were more likely to have received a DMT before initiating subcutaneous interferon β-1a, had a higher relapse rate, and were more likely to switch from subcutaneous interferon β-1a to another DMT before the end of the observation period.ConclusionsThis retrospective analysis of a multinational sample of pediatric MS patients who received subcutaneous interferon β-1a found that those from the US had higher BMI, relapsed more frequently, and were managed differently, compared with ROW patients. Future prospective studies are needed to confirm these observations and ascertain their clinical significance

The Antarctic Peninsula Under a 1.5 degrees C Global Warming Scenario

Warming of the Antarctic Peninsula in the latter half of the twentieth century was greater than any other terrestrial environment in the Southern Hemisphere, and clear cryospheric and biological consequences have been observed. Under a global 1.5°C scenario, warming in the Antarctic Peninsula is likely to increase the number of days above 0°C, with up to 130 of such days each year in the northern Peninsula. Ocean turbulence will increase, making the circumpolar deep water (CDW) both warmer and shallower, delivering heat to the sea surface and to coastal margins. Thinning and recession of marine margins of glaciers and ice caps is expected to accelerate to terrestrial limits, increasing iceberg production, after which glacier retreat may slow on land. Ice shelves will experience continued increase in meltwater production and consequent structural change, but not imminent regional collapses. Marine biota can respond in multiple ways to climatic changes, with effects complicated by past resource extraction activities. Southward distribution shifts have been observed in multiple taxa during the last century and these are likely to continue. Exposed (ice free) terrestrial areas will expand, providing new habitats for native and non-native organisms, but with a potential loss of genetic diversity. While native terrestrial biota are likely to benefit from modest warming, the greatest threat to native biodiversity is from non-native terrestrial species

Automatic Quantum Error Correction

Criteria are given by which dissipative evolution can transfer populations and coherences between quantum subspaces, without a loss of coherence. This results in a form of quantum error correction that is implemented by the joint evolution of a system and a cold bath. It requires no external intervention and, in principal, no ancilla. An example of a system that protects a qubit against spin-flip errors is proposed. It consists of three spin 1/2 magnetic particles and three modes of a resonator. The qubit is the triple quantum coherence of the spins, and the photons act as ancilla.Comment: 16 pages 12 fig LaTex uses multicol, graphicx expanded version of letter submitted to Phys Rev Let

Optoelectronics with electrically tunable PN diodes in a monolayer dichalcogenide

One of the most fundamental devices for electronics and optoelectronics is the PN junction, which provides the functional element of diodes, bipolar transistors, photodetectors, LEDs, and solar cells, among many other devices. In conventional PN junctions, the adjacent p- and n-type regions of a semiconductor are formed by chemical doping. Materials with ambipolar conductance, however, allow for PN junctions to be configured and modified by electrostatic gating. This electrical control enables a single device to have multiple functionalities. Here we report ambipolar monolayer WSe2 devices in which two local gates are used to define a PN junction exclusively within the sheet of WSe2. With these electrically tunable PN junctions, we demonstrate both PN and NP diodes with ideality factors better than 2. Under excitation with light, the diodes show photodetection responsivity of 210 mA/W and photovoltaic power generation with a peak external quantum efficiency of 0.2%, promising numbers for a nearly transparent monolayer sheet in a lateral device geometry. Finally, we demonstrate a light-emitting diode based on monolayer WSe2. These devices provide a fundamental building block for ubiquitous, ultra-thin, flexible, and nearly transparent optoelectronic and electronic applications based on ambipolar dichalcogenide materials.Comment: 14 pages, 4 figure