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Cladribine tablets (CladT) is an established disease-modifying therapy for multiple sclerosis (MS), with an estimated cumulative exposure of 65,000 people/126,000 person-years since launch (to December 2022). The CLARION study aimed to enroll 8000 participants (4000 in the CladT and fingolimod cohorts) and relied on secondary use of data from pre-existing MS registries/data sources (except in Germany, where primary data collection is performed). Participant counts were obtained periodically and by August 2023 included 10 participating MS registries/data sources across 17 countries. Participant characteristics and representativeness were assessed from 8 MS registries/data sources (cut off September 2022 – August 2023). By August 2023, 9555 people with MS were included in CLARION from the 10 participating MS registries/data sources (n=5266 and n=4289, respectively, in the CladT and fingolimod cohorts). Participants were included mostly from the Italian MS Registry (34.2%), MSBase (multiple countries; 17.5%), Norwegian MS Registry and Biobank (11.4%), and the MS Documentation System 3D (MSDS3D, Germany; 10.1%). The majority of participants were female and the average age at MS onset and diagnosis was in the early thirties. Over 90% of people included in CLARION have a confirmed diagnosis of relapsing-remitting MS. Representativeness of the MS population is adequately addressed by the participation of several countries in the European region and countries with different prevalence of MS and incidence rate of malignancies and infections, in particular tuberculosis. The study size was successfully reached in both cohorts, allowing for the CLARION study to generate meaningful real-world evidence concerning the safety profile of CladT during follow-up over the coming decade, in a representative MS population. [ABSTRACT FROM AUTHOR]

• Decision of treatment initiation for MS is influenced by several factors. • Physicians' risk perception was not a leading factor for treatment switch. • Most cited reason for treatment switch is lack of efficacy. • Treatment initiation with high efficacy DMTs as a first line can be considered. The decision of initiating treatment for multiple sclerosis (MS) with a high-efficacy DMT (HE DMT) or non–high-efficacy DMT (non-HE DMT) is influenced by several factors, including risk perception of patients and physicians. Investigate the influence of physicians' risk perception on decision-making when switching treatments for MS and the reasons for switching. Data were drawn from the Adelphi Real-World MS Disease-Specific Program (a retrospective survey) and analysis included people with RMS identified between 2017– 2021. Of 4129 patients with reasons for switch available, 3538 switched from non-HE DMT and 591 from HE DMT. Overall, 4.7% of patients were switched treatment by their physicians due to the risk of malignancies and infections including PML risk. The proportion of switches that were made due to the risk of PML were 23.9% in the HE DMT and 0.5% in the non-HE DMT groups. The top reasons for switching were relapse frequency (non-HE DMT vs HE-DMT: 26.8% vs 15.2%), lack of efficacy (20.9 vs 11.7) and increased number of MRI lesions (20.3% vs 12.4%). Physicians' risk perception of malignancies and infection excluding PML was not a leading factor when switching treatment. The risk of PML was a key factor, especially for switching patients from HE DMTs. In both groups, lack of efficacy was the key contributing factor for switching. Initiating the treatment with HE DMTs may potentially reduce the number of switches due to sub-optimal efficacy. These findings might help physicians to engage more in discussions with patients about the benefit/risk profile of DMTs. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Since the Proterozoic, there has been a set of deformation cycles in central Australia culminating in the Alice Springs Orogeny around 400Ma. These events occurred away from plate boundaries and involved extension as well as compression, although their precise history remains difficult to unravel from the geologic record. Much evidence of deformation is left in the central Australian crust, which features significant Moho topography and an associated gravity signal. In the past, several mechanical models invoked crustal thickening and considerable compression to explain these geophysical characteristics. However, it is hard to envisage extensive deformation affecting the crust alone, but leaving no deformation record in the sub-crustal lithosphere. In recent seismic tomography studies, there is continuous seismically-fast lithosphere in central Australia below depths of about 100km. In this region, the uppermost lithospheric mantle is seismically slow, but exhibits no significant attenuation of seismic waves. These new constraints make simple crustal thickening unlikely to be the main mechanism to generate variations of the Moho depth in central Australia. Here we propose a mechanical model of deformation that involves the entire lithosphere. We make no strong assumptions about the history of deformation cycles. Our model does not require lithospheric thickening at any stage of the deformation cycle, and results in a present-day scenario compatible with shallow as well as deep constraints on the lithosphere structure. [Copyright &y& Elsevier]

Abstract: Background: Little is known about relationships between Cognitive Impairment (CI) and verbal fluency measures in patients with a Clinically Isolated Syndrome (CIS) suggestive of Multiple Sclerosis. The aim of this study was to assess the extent of verbal fluency deficits and their predictive value for the presence of a CI in a population of CIS patients. Methods: CI was detected by the Rao's Brief Repeatable Battery (BRB) and the Stroop Test (ST) in 100 CIS patients. The BRB includes the Word List Generation (WLG) test for semantic verbal fluency. The FAS test was used to investigate phonemic verbal fluency. CI was defined as the failure in at least 3 tests on BRB (without WLG to exclude criterion contamination bias) and ST. Results: Eleven patients failed in at least 3 of the BRB tests and were classified as cognitively impaired. The comparison of Receiver Operating Characteristic curves showed that the Area Under the Curve (AUC) of the WLG was not significantly different from the AUC of the FAS (0.787 vs 0.755; p =N.S.). A cut-off <17 words for the WLG achieved 64% of sensitivity and a 79% of specificity, and a cut-off <28 words achieved 82% of sensitivity and a 66% of specificity in discriminating patients with CI. Conclusions: Verbal fluency deficits occur early in the disease course and may predict the presence of CI in CIS patients. [Copyright &y& Elsevier]