Slowly expanding/evolving lesions as a magnetic resonance imaging marker of chronic active multiple sclerosis lesions.

BACKGROUND:Chronic lesion activity driven by smoldering inflammation is a pathological hallmark of progressive forms of multiple sclerosis (MS). OBJECTIVE:To develop a method for automatic detection of slowly expanding/evolving lesions (SELs) on conventional brain magnetic resonance imaging (MRI) and characterize such SELs in primary progressive MS (PPMS) and relapsing MS (RMS) populations. METHODS:We defined SELs as contiguous regions of existing T2 lesions showing local expansion assessed by the Jacobian determinant of the deformation between reference and follow-up scans. SEL candidates were assigned a heuristic score based on concentricity and constancy of change in T2- and T1-weighted MRIs. SELs were examined in 1334 RMS patients and 555 PPMS patients. RESULTS:Compared with RMS patients, PPMS patients had higher numbers of SELs (p = 0.002) and higher T2 volumes of SELs (p < 0.001). SELs were devoid of gadolinium enhancement. Compared with areas of T2 lesions not classified as SEL, SELs had significantly lower T1 intensity at baseline and larger decrease in T1 intensity over time. CONCLUSION:We suggest that SELs reflect chronic tissue loss in the absence of ongoing acute inflammation. SELs may represent a conventional brain MRI correlate of chronic active MS lesions and a candidate biomarker for smoldering inflammation in MS

Evaluation of no evidence of progression or active disease (NEPAD) in patients with primary progressive multiple sclerosis in the ORATORIO trial.

ObjectiveNo evidence of progression or active disease (NEPAD) is a novel combined endpoint defined by the absence of both progression and inflammatory disease activity in primary progressive multiple sclerosis (PPMS). In the placebo-controlled phase III ORATORIO study (NCT01194570), we investigated the effect of ocrelizumab on this comprehensive outcome and its components in a post-hoc analysis.MethodsThe proportion of patients with NEPAD (no evidence of progression [NEP; no 12-week confirmed progression of ≥1/≥0.5 points on the Expanded Disability Status Scale if the baseline score was ≤5.5/>5.5 points, respectively; no 12-week confirmed progression of ≥20% on the Timed 25-Foot Walk test and 9-Hole Peg Test], no brain magnetic resonance imaging activity [no new/enlarging T2 lesions and no T1 gadolinium-enhancing lesions], and no protocol-defined relapse) from baseline to week 120 was determined in ocrelizumab- (600 mg; n = 465) and placebo-treated (n = 234) patients.ResultsThe majority of ORATORIO study patients with PPMS experienced clinical progression or evidence of disease activity. From baseline to week 120, 29.9% and 42.7% ocrelizumab-treated compared to 9.4% and 29.1% placebo-treated patients maintained NEPAD (relative risk [95% confidence interval {CI}], 3.15 [2.07-4.79]; p < 0.001) and NEP (relative risk [95% CI], 1.47 [1.17-1.84]; p < 0.001), respectively. Effects on the individual components of both measures were consistent with the compound outcomes.InterpretationCompared to placebo, ocrelizumab enhanced 3-fold the proportion of PPMS patients with no evidence of either progression or inflammatory disease activity. NEPAD may represent a sensitive and meaningful comprehensive measure of disease control in patients with PPMS. Ann Neurol 2018;84:527-536

Chronic white matter lesion activity predicts clinical progression in primary progressive multiple sclerosis.

Chronic active and slowly expanding lesions with smouldering inflammation are neuropathological correlates of progressive multiple sclerosis pathology. T1 hypointense volume and signal intensity on T1-weighted MRI reflect brain tissue damage that may develop within newly formed acute focal inflammatory lesions or in chronic pre-existing lesions without signs of acute inflammation. Using a recently developed method to identify slowly expanding/evolving lesions in vivo from longitudinal conventional T2- and T1-weighted brain MRI scans, we measured the relative amount of chronic lesion activity as measured by change in T1 volume and intensity within slowly expanding/evolving lesions and non-slowly expanding/evolving lesion areas of baseline pre-existing T2 lesions, and assessed the effect of ocrelizumab on this outcome in patients with primary progressive multiple sclerosis participating in the phase III, randomized, placebo-controlled, double-blind ORATORIO study (n = 732, NCT01194570). We also assessed the predictive value of T1-weighted measures of chronic lesion activity for clinical multiple sclerosis progression as reflected by a composite disability measure including the Expanded Disability Status Scale, Timed 25-Foot Walk and 9-Hole Peg Test. We observed in this clinical trial population that most of total brain non-enhancing T1 hypointense lesion volume accumulation was derived from chronic lesion activity within pre-existing T2 lesions rather than new T2 lesion formation. There was a larger decrease in mean normalized T1 signal intensity and greater relative accumulation of T1 hypointense volume in slowly expanding/evolving lesions compared with non-slowly expanding/evolving lesions. Chronic white matter lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in slowly expanding/evolving lesions and in non-slowly expanding/evolving lesion areas of pre-existing lesions predicted subsequent composite disability progression with consistent trends on all components of the composite. In contrast, whole brain volume loss and acute lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in new focal T2 lesions did not predict subsequent composite disability progression in this trial at the population level. Ocrelizumab reduced longitudinal measures of chronic lesion activity such as T1 hypointense lesion volume accumulation and mean normalized T1 signal intensity decrease both within regions of pre-existing T2 lesions identified as slowly expanding/evolving and in non-slowly expanding/evolving lesions. Using conventional brain MRI, T1-weighted intensity-based measures of chronic white matter lesion activity predict clinical progression in primary progressive multiple sclerosis and may qualify as a longitudinal in vivo neuroimaging correlate of smouldering demyelination and axonal loss in chronic active lesions due to CNS-resident inflammation and/or secondary neurodegeneration across the multiple sclerosis disease continuum

Rapid In-Vitro Inactivation of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Using Povidone-Iodine Oral Antiseptic Rinse

Purpose To investigate the optimal contact time and concentration for viricidal activity of oral preparation of povidone‐iodine (PVP‐I) against SARS‐CoV‐2 (‘corona virus’) to mitigate the risk and transmission of the virus in the dental practice. Materials and Methods The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) USA‐WA1/2020 strain, virus stock was tested against oral antiseptic solutions consisting of aqueous povidone‐iodine (PVP‐I) as the sole active ingredient. The PVP‐I was tested at diluted concentrations of 0.5%, 1%, and 1.5%. Test media without any virus was added to 2 tubes of the compounds to serve as toxicity and neutralization controls. Ethanol (70%) was tested in parallel as a positive control, and water only as a negative control. The test solutions and virus were incubated at room temperature (22 ± 2 °C) for time periods of 15 and 30 seconds. The solution was then neutralized by a 1/10 dilution in minimum essential medium (MEM) 2% fetal bovine serum (FBS), 50 µg/mL gentamicin. Surviving virus from each sample was quantified by standard end‐point dilution assay and the log reduction value (LRV) of each compound compared to the negative (water) control was calculated. Results PVP‐I oral antiseptics at all tested concentrations of 0.5%, 1%, and 1.5%, completely inactivated SARS‐CoV‐2 within 15 seconds of contact. The 70% ethanol control group was unable to completely inactivate SARS‐CoV‐2 after 15 seconds of contact, but was able to inactivate the virus at 30 seconds of contact. Conclusions PVP‐I oral antiseptic preparations rapidly inactivated SARS‐CoV‐2 virus in vitro. The viricidal activity was present at the lowest concentration of 0.5 % PVP‐I and at the lowest contact time of 15 seconds. This important finding can justify the use of preprocedural oral rinsing with PVP‐I (for patients and health care providers) may be useful as an adjunct to personal protective equipment, for dental and surgical specialties during the COVID‐19 pandemic

Comparison of In Vitro Inactivation of SARS CoV-2 with Hydrogen Peroxide and Povidone-Iodine Oral Antiseptic Rinses

Purpose To evaluate the in vitro inactivation of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) with hydrogen peroxide (H2O2) and povidone‐iodine (PVP‐I) oral antiseptic rinses at clinically recommended concentrations and contact times. Materials and Methods SARS‐CoV‐2, USA‐WA1/2020 strain virus stock was prepared prior to testing by growing in Vero 76 cells. The culture media for prepared virus stock was minimum essential medium (MEM) with 2% fetal bovine serum (FBS) and 50 µg/mL gentamicin. Test compounds consisting of PVP‐I oral rinse solutions and H2O2 aqueous solutions were mixed directly with the virus solution so that the final concentration was 50% of the test compound and 50% of the virus solution. Thus PVP‐I was tested at concentrations of 0.5%, 1.25%, and 1.5%, and H2O2 was tested at 3% and 1.5% concentrations to represent clinically recommended concentrations. Ethanol and water were evaluated in parallel as standard positive and negative controls. All samples were tested at contact periods of 15 seconds and 30 seconds. Surviving virus from each sample was then quantified by standard end‐point dilution assay and the log reduction value of each compound compared to the negative control was calculated. Results After the 15‐second and 30‐second contact times, PVP‐I oral antiseptic rinse at all 3 concentrations of 0.5%, 1.25%, and 1.5% completely inactivated SARS‐CoV‐2. The H2O2 solutions at concentrations of 1.5% and 3.0% showed minimal viricidal activity after 15 seconds and 30 seconds of contact time. Conclusions SARS‐CoV‐2 virus was completely inactivated by PVP‐I oral antiseptic rinse in vitro, at the lowest concentration of 0.5 % and at the lowest contact time of 15 seconds. Hydrogen peroxide at the recommended oral rinse concentrations of 1.5% and 3.0% was minimally effective as a viricidal agent after contact times as long as 30 seconds. Therefore, preprocedural rinsing with diluted PVP‐I in the range of 0.5% to 1.5% may be preferred over hydrogen peroxide during the COVID‐19 pandemic

Seismicity of the central Afar rift and implications for Tendaho dam hazards

Temporary broadband seismic networks deployed from 2007 to 2011 around the Afar triple junction of the East African Rift System provide insights into seismicity patterns of the actively deforming crust around the 1.86 km3 impounded lake system behind the Tendaho dam. The observed seismicity correlates well with the active magmatic centres around central Afar. The area around the dam site is characterized by a network of intersecting NNE- and NW-trending faults. Seismicity clusters observed in the specified time interval indicate that both fault sets are active and are potential sources of seismogenic hazards. The dam neighbourhood is naturally active and it is a challenge to associate the observed seismic activity to either a change in magmato-tectonic conditions or attribute it to the influence of reservoir load. It is evident that the dam region experi- ences high levels of seismic and volcano-tectonic unrest, regardless of the origin of the activity. The spatial overlap of narrow zones of crustal seismicity and upper mantle low velocity zones observed in S-wave tomography models suggests that melt production zones guide the distribution of strain during continental rupture. Given its volcanically and seismically active setting, the Tendaho dam site and the surrounding region require continuous monitoring for the safety of downstream popu- lations and development infrastructures in the Afar National Regional State of Ethiopia

Chronic white matter lesion activity predicts clinical progression in primary progressive multiple sclerosis

Chronic active and slowly expanding lesions with smouldering inflammation are neuropathological correlates of progressive multiple sclerosis pathology. T1 hypointense volume and signal intensity on T1-weighted MRI reflect brain tissue damage that may develop within newly formed acute focal inflammatory lesions or in chronic pre-existing lesions without signs of acute inflammation. Using a recently developed method to identify slowly expanding/evolving lesions in vivo from longitudinal conventional T2- and T1-weighted brain MRI scans, we measured the relative amount of chronic lesion activity as measured by change in T1 volume and intensity within slowly expanding/evolving lesions and non-slowly expanding/evolving lesion areas of baseline pre-existing T2 lesions, and assessed the effect of ocrelizumab on this outcome in patients with primary progressive multiple sclerosis participating in the phase III, randomized, placebo-controlled, double-blind ORATORIO study (n = 732, NCT01194570). We also assessed the predictive value of T1-weighted measures of chronic lesion activity for clinical multiple sclerosis progression as reflected by a composite disability measure including the Expanded Disability Status Scale, Timed 25-Foot Walk and 9-Hole Peg Test. We observed in this clinical trial population that most of total brain non-enhancing T1 hypointense lesion volume accumulation was derived from chronic lesion activity within pre-existing T2 lesions rather than new T2 lesion formation. There was a larger decrease in mean normalized T1 signal intensity and greater relative accumulation of T1 hypointense volume in slowly expanding/evolving lesions compared with non-slowly expanding/evolving lesions. Chronic white matter lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in slowly expanding/evolving lesions and in non-slowly expanding/evolving lesion areas of pre-existing lesions predicted subsequent composite disability progression with consistent trends on all components of the composite. In contrast, whole brain volume loss and acute lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in new focal T2 lesions did not predict subsequent composite disability progression in this trial at the population level. Ocrelizumab reduced longitudinal measures of chronic lesion activity such as T1 hypointense lesion volume accumulation and mean normalized T1 signal intensity decrease both within regions of pre-existing T2 lesions identified as slowly expanding/evolving and in non-slowly expanding/evolving lesions. Using conventional brain MRI, T1-weighted intensity-based measures of chronic white matter lesion activity predict clinical progression in primary progressive multiple sclerosis and may qualify as a longitudinal in vivo neuroimaging correlate of smouldering demyelination and axonal loss in chronic active lesions due to CNS-resident inflammation and/or secondary neurodegeneration across the multiple sclerosis disease continuum

A multidisciplinary study of the final episode of the Manda Hararo dyke sequence, Ethiopia, and implications for trends in volcanism during the rifting cycle

The sequence of dyke intrusions between 2005 and 2010 in the Manda Hararo rift segment, Ethiopia, provided an opportunity to test conceptual models of continental rifting. Based on trends up to dyke 13 in the sequence, it was anticipated that, should magma supply continue, dykes would shorten in length and eruptions would increase in size and decrease in distance from the segment centre as extensional stress was progressively released. In this paper we revisit these predictions by presenting a comprehensive overview of the May 2010 dyke and fissure eruption, the 14th and last in the sequence, from InSAR, seismicity, satellite thermal data, ultra violet SO2 retrievals, and multiple LiDAR surveys. We find the dyke is longer than other eruptive dykes in the sequence, propagating in two directions from the segment centre, but otherwise fairly typical in terms of opening, propagation speed and geodetic and seismic moment. However, though the eruption is located closer to the segment centre, it is much smaller than previous events. We interpret this as indicating that either the Manda Hararo rifting event was magma limited, or that extensional stress varies north and south of the segment centre

Surface wave tomography across Afar, Ethiopia: crustal structure at a rift triple-junction zone

The Afar Depression in northeast Africa contains the rift triple-junction between the Nubia, Arabia and Somalia plates. We analyze Rayleigh wave group velocity from 250 regional earthquakes recorded by 40 broadband stations to study the crustal structure across Afar and adjacent plateau regions in northern Ethiopia. The dispersion velocities are inverted to obtain surface wave tomographic maps for periods between 5 and 25 seconds, sensitive to approximately the top 30 km of the lithosphere. The tomographic maps show a significant low dispersion velocity anomaly (>20%) within the upper crust, below the site of recent dyke intrusions (2005–present) in the Dabbahu and Manda-Hararo magmatic segments. Similar low velocity regions are imaged where magma intrusion in the Afar crust has been inferred over the last decade from seismicity or volcanic eruptions. We invert two group velocity curves to compare the S-wave velocity structure of the crust within an active magmatic segment with that of adjacent areas; the active region has a low velocity zone (Vs ∼ 3.2 km/s), between about 6–12 km, which we infer to be due to the presence of partial melt within the lower crust