COVID-19 in Multiple Sclerosis: Clinically reported outcomes from the UK Multiple Sclerosis Register.

BACKGROUND: In March 2020, the United Kingdom Multiple Sclerosis Register (UKMSR) established an electronic case return form, designed collaboratively by MS neurologists, to record data about COVID-19 infections in people with MS (pwMS). OBJECTIVES: Examine how hospital admission and mortality are affected by disability, age and disease modifying treatments (DMTs) in people with Multiple Sclerosis with COVID-19. METHODS: Anonymised data were submitted by clinical teams. Regression models were tested for predictors of hospitalisation and mortality outcomes. Separate analyzes compared the first and second 'waves' of the pandemic. RESULTS: Univariable analysis found hospitalisation and mortality were associated with increasing age, male gender, comorbidities, severe disability, and progressive MS; severe disability showed the highest magnitude of association. Being on a DMT was associated with a small, lower risk. Multivariable analysis found only age and male gender were significant. Post hoc analysis demonstrated that factors were significant for hospitalisation but not mortality. In the second wave, hospitalisation and mortality were lower. Separate models of the first and second wave using age and gender found they had a more important role in the second wave. CONCLUSIONS: Features associated with poor outcome in COVID-19 are similar to other populations and being on a DMT was not found to be associated with adverse outcomes, consistent with smaller studies. Once in hospital, no factors were predictive of mortality. Reassuringly, mortality appears lower in the second wave.

A two-way molecular dialogue between embryo and endosperm is required for seed development.

The plant embryonic cuticle is a hydrophobic barrier deposited de novo by the embryo during seed development. At germination, it protects the seedling from water loss and is, thus, critical for survival. Embryonic cuticle formation is controlled by a signaling pathway involving the ABNORMAL LEAF SHAPE1 subtilase and the two GASSHO receptor-like kinases. We show that a sulfated peptide, TWISTED SEED1 (TWS1), acts as a GASSHO ligand. Cuticle surveillance depends on the action of the subtilase, which, unlike the TWS1 precursor and the GASSHO receptors, is not produced in the embryo but in the neighboring endosperm. Subtilase-mediated processing of the embryo-derived TWS1 precursor releases the active peptide, triggering GASSHO-dependent cuticle reinforcement in the embryo. Thus, a bidirectional molecular dialogue between embryo and endosperm safeguards cuticle integrity before germination.

Atlantic bluefin tuna Thunnus thynnus feeding ecology in the northern Gulf of Mexico: a preliminary description of diet from the western Atlantic spawning grounds.

A combination of stomach contents, nitrogen stable-isotope and tissue C:N values are presented to demonstrate feeding activity of Atlantic bluefin tuna Thunnus thynnus on the Gulf of Mexico (GOMEX) spawning grounds. Diets include teleosts, cephalopods, crustaceans and a pelagic tunicate (Pyrosoma atlanticum). Results reveal the need to classify the GOMEX as a T. thynnus feeding ground.

Systemic complement profiling in multiple sclerosis as a biomarker of disease state.

BACKGROUND: There is increasing evidence of significant and dynamic systemic activation and upregulation of complement in multiple sclerosis (MS), which may contribute to disease pathogenesis. OBJECTIVE: We aimed to investigate the pathological role of complement in MS and the potential role for complement profiling as a biomarker of MS disease state. METHODS: Key components of the classical, alternative and terminal pathways of complement were measured in plasma and cerebrospinal fluid (CSF) of patients with MS in different clinical phases of disease and in matched controls. RESULTS: Increased plasma levels of C3 (p<0.003), C4 (p<0.001), C4a (p<0.001), C1 inhibitor (p<0.001), and factor H (p<0.001), and reduced levels of C9 (p<0.001) were observed in MS patients compared with controls. Combined profiling of these analytes produced a statistical model with a predictive value of 97% for MS and 73% for clinical relapse when combined with selected demographic data. CSF-plasma correlations suggested that source of synthesis of these components was both systemic and central. CONCLUSION: These data provide further evidence of alterations in both local and systemic expression and activation of complement in MS and suggest that complement profiling may be informative as a biomarker of MS disease, although further work is needed to determine its use in distinguishing MS from its differential.

Overlap between Atlantic bluefin tuna spawning grounds and observed Deepwater Horizon surface oil in the northern Gulf of Mexico.

The 2010 Deepwater Horizon oil spill impacted the northern Gulf of Mexico (GOM) during the spring spawning season of Atlantic bluefin tuna (BFT). Overlap between BFT spawning habitat and surface oil in the northern GOM was examined using satellite-derived estimates of oil coverage, and spawning habitat models. Results suggested that although eggs and larvae were likely impacted by oil-contaminated waters in the eastern GOM, high abundances of larvae were located elsewhere, especially in the western GOM. Overall, less than 10% of BFT spawning habitat was predicted to have been covered by surface oil, and less than 12% of larval BFT were predicted to have been located within contaminated waters in the northern GOM, on a weekly basis. Our results provide preliminary but important initial estimates of the effects of the spill on larval BFT mortality, as concern continues over the appropriate management responses to impacts of the spill.

The prevalence of neuromyelitis optica in South East Wales.

BACKGROUND AND PURPOSE: Neuromyeltis optica (NMO) is a neuroinflammatory disorder considered rare in Caucasian populations. However, accurate population-based epidemiological data for NMO and NMO spectrum disorder (NMO-SD) from Western populations employing validated diagnostic criteria remain limited. We sought therefore to estimate the prevalence and clinical features of NMO in a north European Caucasian population in South East Wales. METHODS: Patients were identified by a comprehensive, multistage ascertainment strategy employing a regional neuroinflammatory disease register, hospital diagnostic databases personal physician referrals and regional requests for anti-aquaporin-4 antibodies (anti-AQP4). RESULTS: Fourteen Caucasian patients (11 patients with NMO and three with NMO-SD) were identified in a population of 712,572 (19.6/million; 95% CIs: 12.2-29.7). There was an excess of females (female:male 12:2), 11/14 were anti-AQP4 positive and 5/14 had disease onset under the age of 20 years. CONCLUSION: This study suggests that NMO and related spectrum disorders are at least as frequent in Northern European populations as in non-Caucasian populations and that the demographic profile of prevalent patients differs from clinic-based cohorts.

Age at onset as a determinant of presenting phenotype and initial relapse recovery in multiple sclerosis.

BACKGROUND: Age at onset modifies prognosis in multiple sclerosis (MS) and may also exert an effect on the characteristics of disease ignition. Understanding how age influences presentation informs disease management and may allow differentiation of distinct clinical sub-groups. OBJECTIVES: To determine the nature of age-specific presentations of relapsing-remitting MS (RRMS) with respect to onset symptoms, gender ratios and index event outcomes. METHODS: In a prospective, population-based sample of 1424 patients in South-East Wales we examined associations between age at onset, clinical features and outcome of the onset event, making specific comparisons between paediatric, adolescent and late-onset MS. RESULTS: Age at onset varied significantly between sexes (Male 31.2, Female 29.3, p = 0.002), 0.7% had paediatric onset, 2.7% adolescent onset and 2.8% late-onset MS (>50 years). Optic neuritis was common in younger patients and declined after age 30. Lower limb motor, facial sensory, sexual and sphincteric symptoms rose with age independent of sex and disease course. F:M ratios were highest <16 years of age and declined with increasing age, with a male excess in those over 50. Probability of complete recovery from index event declined with age from 87.4% in the youngest group to 68% in the eldest (p = 0.009). CONCLUSIONS: Age at disease onset in RRMS exerts a significant effect on gender ratios and presenting phenotype, and allows identification of specific clinical sub-groups. In addition, ability to recover from initial relapse declines with age, suggesting accumulation of disability in MS is an age-dependent response to relapse.

SU-E-T-417: Tomotherapy Isocentricity: Is it Good Enough for Stereotactic Radiosurgery?

PURPOSE: To evaluate the isocenter accuracy of radiation beam relative to the Tomotherapy linear accelerator's mechanical axis using a simplified Winston Lutz test, and to determine if Tomotherapy system is accurate for SRS applications. METHODS: BrainLab Winston Lutz pointer was setup on the Tomotherapy couch to the isocenter according to the green lasers. Four static plans were created to deliver radiation with 1cm jaw opening, all MLC closed except the central two leaves, and gantry at 0, 90, 180 and 270 degree, respectively. Gafchromic EBT films were taped on a solid water slab and placed on opposite side of gantry at a fixed distance for each plan. After the exposure, the films were scanned using Vidar scanner along with a 1 cm scale drawn (Figure 1-A, 2-A). The images were first processed by ImageJ, using Find Edges function to enhance the visibility of the boundaries of the circles, from a metal ball in the pointer, and the rectangles defined by two central leaves and the jaws (Figure 1-B, 2-B). Then two diagonal lines were drawn on each rectangle, and a cross on each circle, with the cross sections representing the centers of the rectangles and circles, respectively (Figure 1-C, 2-C). RESULTS: The displacements of the centers of the circles from the centers of the rectangles for the first setup (films were 11cm from the isocenter) were 0.50, 0.707, 1.0 and 0.707 millimeters for each gantry angle, respectively, with an average of 0.73mm. The displacements of second setup (films were 25cm from the isocenter) were 0.54, 1.07, 0.87 and 0.54 millimeters, with an average of 0.75mm. CONCLUSIONS: The preliminary data show that the radiation isocenter agrees with mechanical isocenter well within one millimeter tolerance required for SRS treatments, which indicated Tomotherapy system is suitable for such applications.

Autoimmune disease after alemtuzumab treatment for multiple sclerosis in a multicenter cohort.

OBJECTIVE: To define the rate, timing, and clinical risk factors for the development of autoimmune disease (AID) after alemtuzumab treatment for multiple sclerosis (MS). METHODS: We analyzed prospective clinical and serologic data from 248 patients with MS treated with alemtuzumab, with median follow-up of 34.3 months (range 6.7-107.3). RESULTS: Novel AID developed in 22.2%. Thyroid AID was most frequent (15.7%). A range of hematologic, renal, and dermatologic AID were also observed as was asymptomatic development of novel autoantibodies. AID was seen from 2 weeks after initial treatment and was most frequent 12-18 months after first treatment. No new cases of AID were identified 60 months or more after initial treatment and risk of AID was independent of total alemtuzumab dose or interval of dosage. While established risk factors for AID including sex and age had no impact on AID frequency, both family history (odds ratio = 7.31, 95% confidence interval 3.02-17.68) of AID and a personal smoking history (odds ratio = 3.05, 95% confidence interval 1.50-6.19) were predictive of AID expression. CONCLUSIONS: Cumulative risk for AID in MS following alemtuzumab is 22.2%, most frequent between 12 and 18 months following first dose and evident for up to 5 years. Individual risk is modified by smoking and family history, which should be incorporated within the counseling process prior to treatment. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that the risk of AID after alemtuzumab treatment for MS is time-limited and modified by external factors.

Anti-EBNA-1 IgG is not a reliable marker of multiple sclerosis clinical disease activity.

BACKGROUND: Sero-epidemiological studies have demonstrated the association between multiple sclerosis (MS) and prior Epstein-Barr virus (EBV) infection. It has been hypothesized that intermittent peripheral EBV reactivation may drive continuing central inflammation. Recent investigation has shown significant differences in median serum levels of anti-EBV nuclear antigen-1 (EBNA-1) IgG between disease subgroups and positive correlation with disease activity reflected by number of Gd-enhancing lesions and T2 lesion volume. These important data have led to hopes that anti-EBNA-1 IgG may be useful as an easily accessible and effective biomarker of disease activity. METHODS: We examined the applicability of these findings in routine clinical practice, assessing a well-characterized cohort of 100 subjects (25 primary progressive, 25 stable relapsing remitting, 25 active relapsing remitting seen in acute relapse and 25 controls) for serum anti-EBNA-1 IgG using both the Liaison quantitative chemiluminescent assay and Biotest ELISA. RESULTS: We were unable to show a difference in quantitative analysis of serum anti-EBNA-1 IgG levels between disease subgroups and no correlation with phenotypic characteristics including age at onset (r = -0.17, P = 0.16), disease duration (r = 0.03, P = 0.78), EDSS (r = 0.03, P = 0.78) or MSSS (r = 0.02, P = 0.9). In addition, there was only moderate correlation between the two test methods used (intraclass correlation coefficient 0.67; 0.56-0.78) suggesting potential problems with test interpretation. CONCLUSIONS: We have been unable to determine a clinical value for serum anti-EBNA-1 IgG levels in MS or to confirm reported association with disease course and clinical disease activity.

Validity of patient-derived disability and clinical data in multiple sclerosis.

Patient-derived historical data are widely employed to make fundamental management decisions in multiple sclerosis, although the validity of the information provided is unclear. The objectives of this study were to determine validity of patient-derived historical data and to describe the utility of a locally relevant, patient-administered questionnaire designed to ascertain current disability and other important disease milestones. A well-described cohort of 99 patients was identified for whom comparable, detailed, prospective longitudinal clinician-derived data were available. Patient-derived data were collected by completion of a standardized questionnaire or telephone interview for comparison. Reliability analysis for current Expanded Disability Status Scale (EDSS) demonstrated an intraclass correlation coefficient of 0.79 between questionnaire and clinician-derived data in 79 patients, with complete agreement in 75.9%. Intraclass correlation coefficient for year of disease onset, diagnosis and onset of secondary progression was 0.86, 0.91 and 0.78, respectively. Time to EDSS >4.0, 6.0 and 8.0 all had an intraclass correlation coefficient of >0.9. Less robust agreement was observed for current disease course (Kappa coefficient 0.71), initial relapse rate (intraclass correlation coefficient 0.37) and clinical features at disease onset (Kappa 0.25). We conclude that self-reported questionnaires can provide reliable current and retrospective data on time-to-disability milestones with high levels of correlation observed for some additional elements, supporting the use of selected components of patient-derived data in clinical practice and for epidemiological studies.

Increasing prevalence and incidence of multiple sclerosis in South East Wales.

BACKGROUND AND AIMS: Epidemiological studies of multiple sclerosis suggest a trend of increasing disease prevalence in susceptible populations. The reasons for this are unclear and may be the results of methodological differences between studies, incomplete ascertainment or advances in technologies that allow the increased identification of early or mild disease. In addition, direct comparison of cross sectional prevalence estimates performed in different epochs in ethnically and geographically distinct populations may be inappropriate. METHODS: Using detailed phenotypic information and standardised methodology, a geographically defined Welsh population was resurveyed after a significant interval, establishing contemporary prevalence rates and examining demographic and clinical data to determine causes of changing disease frequency. RESULTS: Disease prevalence increased 45% from 101 to 146 per 100,000 population over 20 years. The greatest increase was observed in women between the ages of 45 and 54 years. No significant increase in disease frequency was observed in the male population overall, or within specific age groups. There was no demographic evidence for a pattern of earlier age at onset or diagnosis to explain increased disease frequency or decrease in mean age of the prevalent population. In addition, we failed to identify a pattern of recognition of patients with less severe disability. Although there was a modest 13% increase of 2.2 years in mean disease duration, and eight new previously prevalent patients were identified, the main cause of rising disease frequency was related to a 2.8-fold increase in disease incidence for women over 23 years from 2.65 to 7.30/100,000/year increasing the sex ratio of incident patients from 1.8 to 4.3 (women:men). CONCLUSION: Recent change in disease incidence and prevalence in this population is likely to be the result of environmental factors that have been operative in the past few decades in women alone and infers avoidable risk factors. Modelling of current overall incidence suggests a further increase in prevalence to 260 per 100 000 population within the next 20-40 years. Further studies are needed in order to identify recent changes in sex specific environment and lifestyle that confer susceptibility.

Complement in multiple sclerosis: its role in disease and potential as a biomarker.

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system with a poorly defined and complex immunopathogenesis. Although initiated by reactive T cells, persistent inflammation is evident throughout the disease course. A contribution from complement has long been suspected, based on the results of pathological and functional studies which have demonstrated complement activation products in MS brain and biological fluids. However, the extent and nature of complement activation and its contribution to disease phenotype and long-term outcome remain unclear. Furthermore, functional polymorphisms in components and regulators of the complement system which cause dysregulation, and are known to contribute to other autoimmune inflammatory disorders, have not been investigated to date in MS in any detail. In this paper we review evidence from pathological, animal model and human functional and genetic studies, implicating activation of complement in MS. We also evaluate the potential of complement components and regulators and their polymorphic variants as biomarkers of disease, and suggest appropriate directions for future research.

Size and age estimates at sexual maturity for the little skate Leucoraja erinacea from the western Gulf of Maine, U.S.A.

Size and age estimates at sexual maturity were determined for 162 male and 273 female little skates Leucoraja erinacea collected from the western Gulf of Maine. Maturity ogives suggest that 50% maturity in females occurs at age 9.5 years and 480 mm total length (LT), whereas 50% maturity in males occurs at a slightly younger age of 7.7 years and smaller size of 460 mm LT. Age estimates were made from 389 L. erinacea ranging in size from 93 to 570 mm LT. The index of average per cent error and age-bias plots indicated that the ageing methods were precise and non-biased. Additionally, annual periodicity of band formation was validated with oxytetracycline in eight individuals (three males and five females) ranging in age from 3 to 12 years. In conclusion, results from this study indicate that L. erinacea exhibits characteristics that make other elasmobranch populations highly susceptible to overexploitation.

Change in disability in patients with multiple sclerosis: a 20-year prospective population-based analysis.

BACKGROUND: In patients with multiple sclerosis (MS), the natural history of the disease is of considerable importance to predict and understand long-term outcome and inform choices made by patients and clinicians. This information should ideally be derived from data that reflects the entire disease course. METHODS: In this study, morbidity data from a prevalent cohort established in 1985 have been re-examined after an interval of 20 years to assess factors that may be important in determining outcome. RESULTS: Of 379 patients who fulfilled criteria for definite or probable MS in the original population-based cohort, 221 (58.3%) had died, 149 (39.3%) were alive and 9 (2.4%) were untraceable. Mean Expanded Disability Status Scale (EDSS) score in 1985 was 5.15 (SD 2.7, range 0-9.5) and 8.01 (SD 2.6, range 0-10) in those alive in 2005. Mean worsening of EDSS scores in surviving patients was +3.02 EDSS points, but 14.0% had worsened by <1 EDSS point over 20 years. 61.4% of patients with EDSS 3.5-5.5 and 82.2% of those with an EDSS of or=6 after 20 years. Lower baseline EDSS scores (p<0.0001), higher pyramidal functional system score (p = 0.02) and a greater number of functional systems involved (p = 0.001) were significantly more likely to be associated with greater worsening of disability. Of those with benign disease in 1985, only 19% remained benign after 20 years of follow-up; however, 12.6% of patients had minimal disability after at least 20 years after their disease onset and 14% of patients failed to worsen by >or=1 EDSS point. CONCLUSIONS: This study emphasises the importance of long-term epidemiological studies and the development of clinically relevant measures that effectively predict outcome and can guide decisions on therapeutic management.

Signalling during epidermal development.

The process of L1 specification early in plant embryogenesis, and subsequent maintenance and elaboration of epidermal organization, are fundamental to plant growth and fitness. To occur in a co-ordinated fashion, these processes require considerable cell-cell cross-talk. It is perhaps then unsurprising that several classes of plant RLKs (receptor-like kinases), as well as other membrane-localized signalling components, have been implicated both in epidermal specification and in patterning events governing the distribution of epidermal cell types. However, despite our growing knowledge of the roles of these signalling molecules, remarkably little is understood regarding their function at the cellular level. In particular the potential role of regulated proteolytic cleavage in controlling the activity of signalling molecules at the plant plasma membrane has remained largely unaddressed despite its massive importance in signalling in animal systems. Because of the relative physical accessibility of their expression domains, molecules involved in epidermal development present opportunities for investigating mechanisms of cell-cell signalling in planta. Advances in understanding the potential regulatory processing of membrane-localized signalling molecules during epidermal development will be examined using parallels with animal systems to highlight potential future directions for this field of research.

Caries and fluoride processes.

OBJECTIVES: The purpose of the work was to establish the level and source of salivary fluoride, whether it could interact with tooth mineral and whether it was able to effect calcium re-acquisition and remineralisation. METHODS: Fluoride in saliva and in solution was measured by electrode, calcium by complexometric titration and phosphate colourimetrically-to measure salivary fluoride, its uptake by mineral and the effects of such low levels on calcium and phosphate levels in solution in contact with suspensions of mineral hydroxyapatite. RESULTS: Fluoride levels in saliva were low but could interact with hydroxyapatite. Such levels caused apatite crystallite growth and preferential acquisition of calcium by calcium-deficient apatite. CONCLUSIONS: Salivary fluoride contents rose with increasing water fluoride levels. It was acquired by hydroxyapatite mineral. Topical fluoride was stored on oral tissues. Even these low fluoride contents could cause mineral crystallite growth with preferential calcium uptake. On a mineral area basis these effects were caused by quite low fluoride uptakes. These findings do not support reliance upon large fluoride uptakes by tooth enamel as evidence for commensurate caries reductions.

The use of fluorescein-enhanced quantitative light-induced fluorescence to monitor de- and re-mineralization of in vitro root caries.

The use of fluorescein-enhanced quantitative light-induced fluorescence (QLF) in the detection of in vitro root caries demineralization and reminerlization was investigated. Fourteen previously extracted human premolar roots were selected and determined to be caries-free. Cementum was removed and nail varnish applied leaving an exposed window. Positive and negative controls were selected. During a demineralizing regimen, roots were removed at regular intervals (12, 48, 72 and 120 h) and immersed in sodium fluorescein (0.2 mg L(-1)). Following gentle rinsing, each root was examined using QLF before being returned to the demineralizing solution. Following 120 h, each tooth was sectioned through the lesion and one-half retained for transverse micro radiography (TMR) analysis. The remaining half were subjected to a remineralizing regimen undergoing the same fluorescein and QLF examinations at 7, 28 and 36 days. Results showed that QLF effectively monitored demineralization/remineralization of root dentine as represented by fluorescein penetration. TMR analysis showed good correlations with QLF (DeltaZ/DeltaQ) after demineralization (r = 0.89) and remineralization (r = 0.84). The technique could represent an in vivo method for root caries detection and classification.

Mast cells, histamine and the pathogenesis of intestinal damage in experimental Trypanosoma brucei brucei infections.

Intestinal damage with increased permeability is a prominent feature of experimental African trypanosomiasis. The possible involvement of mast cells and histamine in the altered gut integrity was investigated, at the level of the jejunum, in BALB/c mice infected with Trypanosoma brucei brucei. Mast cells were studied by selective staining of granule content with Alcian Blue/Safranin and quantitative histology, and histamine concentrations were determined by a fluorimetric method. Mast-cell activation, shown by a marked reduction in the numbers of positive-staining cells seen per villous section, was prominent on days 7 and 14 post-infection (there was, for example, a reduction to 36% of the control value by day 14; P=0.0001). By day 21, however, there were 131% more staining cells per villous section in the infected mice than in the uninfected controls (P=0.003). Histamine levels in homogenates of the jejunal mucosae of the infected mice were found to be significantly elevated at each time-point. The maximum increase was observed on day 14, when the numbers of granulated mast cells were at their lowest, with mean (S.E.) concentrations of 6.744 (0.890) ng/mg tissue for the infected mice and 2.813 (0.321) ng/mg for the uninfected controls (P=0.0008). The jejunal mucosa suffered progressive morphological damage during the infection, with oedema of the lamina propria and villi and disruption of the endothelium. These results indicate that mast cells are involved with the intestinal pathology that develops during experimental African trypanosomiasis.