Multiple sclerosis and drug discovery:A work of translation

Multiple sclerosis (MS) is after trauma the most important neurological disease in young adults, affecting 1 per 1000 individuals. With currently available medications, most of these targeting the immune system, satisfactory results have been obtained in patients with relapsing MS, but these can have serious adverse effects. Moreover, despite some promising developments, such as with B cell targeting therapies or sphingosine-1-phosphate modulating drugs, there still is a high unmet need of safe drugs with broad efficacy in patients with progressive MS. Despite substantial investments and intensive preclinical research, the proportion of promising lead compounds that reaches the approved drug status remains disappointingly low. One cause lies in the poor predictive validity of MS animal models used in the translation of pathogenic mechanisms into safe and effective treatments for the patient. This disturbing situation has raised criticism against the relevance of animal models used in preclinical research and calls for improvement of these models. This publication presents a potentially useful strategy to enhance the predictive validity of MS animal models, namely, to analyze the causes of failure in forward translation (lab to clinic) via reverse translation (clinic to lab). Through this strategy new insights can be gained that can help generate more valid MS models

Cerebrospinal fluid anti-myelin antibodies are related to magnetic resonance measures of disease activity in multiple sclerosis

0.001), together constituting 85% of all positive CSF samples. In contrast, elevated anti-myelin IgG antibody reactivity was present in a minority of IND patients (21%), marginally present in controls (5%) and absent in OND patients (0%). Most strikingly, anti-myelin IgG antibody reactivity was related to the number of T2 lesions (r = 0.31, p = 0.041) and gadolinium enhancing T1 lesions (r = 0.37, p = 0.016) on brain MRI in CIS and relapse onset MS patients. Conclusion: CSF anti-myelin IgG antibodies are promising specific biomarkers in CIS and relapse onset MS and correlate with MR measures of disease activit

Concomitant granule cell neuronopathy in patients with natalizumab-associated PML

Granule cell neuronopathy (GCN) is a rare JC virus infection of the cerebellar granule cell neurons in immunocompromised patients. On brain imaging, GCN is characterized by cerebellar atrophy which can be accompanied by infratentorial white matter lesions. The objective of this study is to investigate the prevalence of MRI findings suggestive of GCN in a large natalizumab-associated progressive multifocal leukoencephalopathy (PML) cohort. MRI scans from before, at the time of, and during follow-up after diagnosis of PML in 44 natalizumab-treated MS patients, and a control group of 25 natalizumab-treated non-PML MS patients were retrospectively reviewed for imaging findings suggestive of GCN. To assess and quantify the degree of cerebellar atrophy, we used a 4 grade rating scale. Three patients in the PML group showed imaging findings suggestive of GCN and none in the control group. In two of these PML patients, cerebellar atrophy progressed from grade 0 at the time of diagnosis of isolated supratentorial PML to grade 1 and 2 after 2.5 and 3 months, respectively, in the absence of infratentorial white mater lesions. The third patient had grade 1 cerebellar atrophy before diagnosis of infra- and supratentorial PML, and showed progression of cerebellar atrophy to grade 2 in the 3 months following PML diagnosis. None of the other eight patients with infratentorial PML lesions developed cerebellar atrophy suggestive of GCN. Three cases with imaging findings suggestive of GCN were detected among 44 natalizumab-associated PML patients. GCN may, therefore, be more common than previously considered in natalizumab-associated PML patients

Precision ephemerides for gravitational-wave searches – IV : corrected and refined ephemeris for Scorpius X-1

Low-mass X-ray binaries have long been theorised as potential sources of continuous gravitational-wave radiation, yet there is no observational evidence from recent LIGO/Virgo observing runs. Even for the theoretically ‘loudest’ source, Sco X-1, the upper limit on gravitational-wave strain has been pushed ever lower. Such searches require precise measurements of the source properties for sufficient sensitivity and computational feasibility. Collating over 20 years of high-quality spectroscopic observations of the system, we present a precise and comprehensive ephemeris for Sco X-1 through radial velocity measurements, performing a full homogeneous reanalysis of all relevant datasets and correcting previous analyses. Our Bayesian approach accounts for observational systematics and maximises not only precision, but also the fidelity of uncertainty estimates — crucial for informing principled continuous-wave searches. Our extensive dataset and analysis also enables us to construct the highest signal-to-noise, highest resolution phase-averaged spectrum of a low-mass X-ray binary to date. Doppler tomography reveals intriguing transient structures present in the accretion disk and flow driven by modulation of the accretion rate, necessitating further characterisation of the system at high temporal and spectral resolution. Our ephemeris corrects and supersedes previous ephemerides, and provides a factor three reduction in the number of templates in the search space, facilitating precision searches for continuous gravitational-wave emission from Sco X-1 throughout the upcoming LIGO/Virgo/KAGRA O4 observing run and beyond

Randomized trial of daily high-dose vitamin D3 in patients with RRMS receiving subcutaneous interferon β-1a

OBJECTIVE: In the phase II, randomized, double-blind, placebo-controlled Supplementation of Vigantol Oil versus Placebo Add-on in Patients with Relapsing-Remitting Multiple Sclerosis (RRMS) Receiving Rebif Treatment (SOLAR) study (NCT01285401), we assessed the efficacy and safety of add-on vitamin D3 in patients with RRMS. METHODS: Eligible patients with RRMS treated with SC interferon-β-1a (IFN-β-1a) 44 μg 3 times weekly and serum 25(OH)D levels <150 nmol/L were included. From February 15, 2011, to May 11, 2015, 229 patients were included and randomized 1:1 to receive SC IFN-β-1a plus placebo (n = 116) or SC IFN-β-1a plus oral high-dose vitamin D3 14,007 IU/d (n = 113). The revised primary outcome was the proportion of patients with no evidence of disease activity (NEDA-3) at week 48. RESULTS: At 48 weeks, 36.3% of patients who received high-dose vitamin D3 had NEDA-3, without a statistically significant difference in NEDA-3 status between groups (placebo 35.3%; odds ratio 0.93; 95% confidence interval [CI] 0.53-1.63; p = 0.80). Compared with placebo, the high-dose vitamin D3 group had better MRI outcomes for combined unique active lesions (incidence rate ratio 0.68; 95% CI 0.52-0.89; p = 0.0045) and change from baseline in total volume of T2 lesions (difference in mean ranks: -0.074; p = 0.035). CONCLUSIONS: SOLAR did not establish a benefit for high-dose vitamin D3 as add-on to IFN-β-1a, based on the primary outcome of NEDA-3, but findings from exploratory outcomes suggest protective effects on development of new MRI lesions in patients with RRMS. CLINICALTRIALSGOV IDENTIFIER: NCT01285401. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with RRMS treated with SC IFN-β-1a, 48 weeks of cholecalciferol supplementation did not promote NEDA-3 status

Search for Gravitational Waves from Scorpius X-1 in LIGO O3 Data With Corrected Orbital Ephemeris

Improved observational constraints on the orbital parameters of the low-mass X-ray binary Scorpius~X-1 were recently published in Killestein et al (2023). In the process, errors were corrected in previous orbital ephemerides, which have been used in searches for continuous gravitational waves from Sco~X-1 using data from the Advanced LIGO detectors. We present the results of a re-analysis of LIGO detector data from the third observing run of Advanced LIGO and Advanced Virgo using a model-based cross-correlation search. The corrected region of parameter space, which was not covered by previous searches, was about 1/3 as large as the region searched in the original O3 analysis, reducing the required computing time. We have confirmed that no detectable signal is present over a range of gravitational-wave frequencies from $25\textrm{Hz}$ to $1600\textrm{Hz}$, analogous to the null result of Abbott et al (2022). Our search sensitivity is comparable to that of Abbott et al (2022), who set upper limits corresponding, between $100\textrm{Hz}$ and $200\textrm{Hz}$, to an amplitude $h_0$ of about $10^{-25}$ when marginalized isotropically over the unknown inclination angle of the neutron star's rotation axis, or less than $4\times 10^{-26}$ assuming the optimal orientation.Comment: 8 pages, 3 figures, 2 tables. Typeset with AASTeX 6.3.1. Accepted for publication in The Astrophysical Journal. arXiv admin note: text overlap with arXiv:2209.0286

Photometric study of the late-time near-infrared plateau in Type Ia supernovae

We present an in-depth study of the late-time near-infrared plateau in Type Ia supernovae (SNe Ia), which occurs between 70-500 d. We double the existing sample of SNe Ia observed during the late-time near-infrared plateau with new observations taken with the Hubble Space Telescope, Gemini, New Technology Telescope, the 3.5m Calar Alto Telescope, and the Nordic Optical Telescope. Our sample consists of 24 nearby SNe Ia at redshift < 0.025. We are able to confirm that no plateau exists in the Ks band for most normal SNe Ia. SNe Ia with broader optical light curves at peak tend to have a higher average brightness on the plateau in J and H, most likely due to a shallower decline in the preceding 100 d. SNe Ia that are more luminous at peak also show a steeper decline during the plateau phase in H. We compare our data to state-of-the-art radiative transfer models of nebular SNe Ia in the near-infrared. We find good agreement with the sub-Mch model that has reduced non-thermal ionisation rates, but no physical justification for reducing these rates has yet been proposed. An analysis of the spectral evolution during the plateau demonstrates that the ratio of [Fe II] to [Fe III] contribution in a near-infrared filter determines the light curve evolution in said filter. We find that overluminous SNe decline slower during the plateau than expected from the trend seen for normal SNe IaComment: 17 pages, 8 figures, Accepted for publication in MNRA

Whole plant cannabis extracts in the treatment of spasticity in multiple sclerosis: a systematic review

<p>Abstract</p> <p>Background</p> <p>Cannabis therapy has been considered an effective treatment for spasticity, although clinical reports of symptom reduction in multiple sclerosis (MS) describe mixed outcomes. Recently introduced therapies of combined Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD) extracts have potential for symptom relief with the possibility of reducing intoxication and other side effects. Although several past reviews have suggested that cannabinoid therapy provides a therapeutic benefit for symptoms of MS, none have presented a methodical investigation of newer cannabinoid treatments in MS-related spasticity. The purpose of the present review was to systematically evaluate the effectiveness of combined THC and CBD extracts on MS-related spasticity in order to increase understanding of the treatment's potential effectiveness, safety and limitations.</p> <p>Methods</p> <p>We reviewed MEDLINE/PubMed, Ovid, and CENTRAL electronic databases for relevant studies using randomized controlled trials. Studies were included only if a combination of THC and CBD extracts was used, and if pre- and post-treatment assessments of spasticity were reported.</p> <p>Results</p> <p>Six studies were systematically reviewed for treatment dosage and duration, objective and subjective measures of spasticity, and reports of adverse events. Although there was variation in the outcome measures reported in these studies, a trend of reduced spasticity in treated patients was noted. Adverse events were reported in each study, however combined TCH and CBD extracts were generally considered to be well-tolerated.</p> <p>Conclusion</p> <p>We found evidence that combined THC and CBD extracts may provide therapeutic benefit for MS spasticity symptoms. Although some objective measures of spasticity noted improvement trends, there were no changes found to be significant in post-treatment assessments. However, subjective assessment of symptom relief did often show significant improvement post-treatment. Differences in assessment measures, reports of adverse events, and dosage levels are discussed.</p