The varied functions of local vocational advisory councils

Citizen involvement in public education has been a tradition in our country

Tenure and Due Process

The legal significance of tenure is reviewed in this article as it relates to the new and developing laws of due process. The authors suggest that expectancy of re-employment may become a new form of property right

Ozanimod in relapsing multiple sclerosis : Pooled safety results from the clinical development program

Background: Ozanimod, an oral sphingosine 1-phosphate receptor 1 and 5 modulator, is approved in multiple countries for the treatment of relapsing multiple sclerosis (RMS). In phase 3 trials, ozanimod was well tolerated and superior to interferon beta-1a 30 µg once-weekly in reducing clinical and radiologic disease activity. The objective of this integrated safety analysis was to evaluate the safety of extended ozanimod exposure in participants with RMS from all clinical trials and compare it with phase 3 trial data. Methods: We report pooled incidence and study duration‒adjusted incidence rates (IR) of treatment-emergent adverse events (TEAEs) from an interim data cut (January 31, 2019) of RMS participants treated with ozanimod. Data were pooled from a phase 1 pharmacokinetic/pharmacodynamic trial, a placebo-controlled phase 2 trial with dose-blinded extension, 2 large active-controlled phase 3 trials, and an open-label extension (OLE). Results were compared with pooled phase 3 trial data. Results: At the data cutoff, 2631 RMS participants had exposure to ozanimod 0.92 mg (mean 32.0 months) and 2787 had exposure to either ozanimod 0.46 or 0.92 mg (mean 37.1 months). The IRs per 1000 person-years (PY) for any TEAE (772.2) and serious TEAEs (33.2) in the overall population were similar to those in the phase 3 population (896.1 and 31.2, respectively). There were no serious opportunistic infections. There were no second-degree or higher atrioventricular blocks on electrocardiogram. Hepatic enzyme elevations declined over time. Malignancy rates remained low with longer exposure. Pulmonary function tests showed minimal reductions in lung function. Seven ozanimod-treated participants with comorbid risk factors had confirmed macular edema, including 3 in the ongoing OLE. Conclusions: Safety results in this larger RMS population with greater ozanimod exposure demonstrated no new safety concerns and were consistent with phase 3 trial results

Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis : Up to 5 years of follow-up in the DAYBREAK open-label extension trial

Background: Ozanimod, an oral sphingosine 1-phosphate receptor 1 and 5 modulator, is approved in multiple countries for treatment of relapsing forms of MS. Objective: To characterize long-term safety and efficacy of ozanimod. Methods: Patients with relapsing MS who completed a phase 1‒3 ozanimod trial were eligible for an open-label extension study (DAYBREAK) of ozanimod 0.92 mg/d. DAYBREAK began 16 October 2015; cutoff for this interim analysis was 2 February 2021. Results: This analysis included 2494 participants with mean 46.8 (SD 11.9; range 0.033‒62.7) months of ozanimod exposure in DAYBREAK. During DAYBREAK, 2143 patients (85.9%) had treatment-emergent adverse events (TEAEs; similar in nature to those in the parent trials), 298 (11.9%) had a serious TEAE, and 75 (3.0%) discontinued treatment due to TEAEs. Serious infections (2.8%), herpes zoster infections (1.7%), confirmed macular edema cases (0.2%), and cardiac TEAEs (2.8%) were infrequent. Adjusted annualized relapse rate was 0.103 (95% confidence interval, 0.086‒0.123). Over 48 months, 71% of patients remained relapse free. Adjusted mean numbers of new/enlarging T2 lesions/scan and gadolinium-enhancing lesions were low and similar across parent trial treatment subgroups. Conclusions: This long-term extension of ozanimod trials confirmed a favorable safety/tolerability profile and sustained benefit on clinical and magnetic resonance imaging measures of disease activity

Phenotypic Similarity of Transmissible Mink Encephalopathy in Cattle and L-type Bovine Spongiform Encephalopathy in a Mouse Model

L-type BSE is a more likely candidate for the origin of TME than typical BSE

Switching Multiple Sclerosis Patients with Breakthrough Disease to Second-Line Therapy

BACKGROUND: Multiple sclerosis (MS) patients with breakthrough disease on immunomodulatory drugs are frequently offered to switch to natalizumab or immunosuppressants. The effect of natalizumab monotherapy in patients with breakthrough disease is unknown. METHODS: This is an open-label retrospective cohort study of 993 patients seen at least four times at the University of California San Francisco MS Center, 95 had breakthrough disease on first-line therapy (60 patients switched to natalizumab, 22 to immunosuppressants and 13 declined the switch [non-switchers]). We used Poisson regression adjusted for potential confounders to compare the relapse rate within and across groups before and after the switch. RESULTS: In the within-group analyses, the relapse rate decreased by 70% (95% CI 50,82%; p<0.001) in switchers to natalizumab and by 77% (95% CI 59,87%; p<0.001) in switchers to immunosuppressants; relapse rate in non-switchers did not decrease (6%, p =  0.87). Relative to the reduction among non-switchers, the relapse rate was reduced by 68% among natalizumab switchers (95% CI 19,87%; p = 0.017) and by 76% among the immunosuppressant switchers (95% CI 36,91%; p = 0.004). CONCLUSIONS: Switching to natalizumab or immunosuppressants in patients with breakthrough disease is effective in reducing clinical activity of relapsing MS. The magnitude of the effect and the risk-benefit ratio should be evaluated in randomized clinical trials and prospective cohort studies

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Association between B-cell depletion and attack risk in neuromyelitis optica spectrum disorder: An exploratory analysis from N-MOmentum, a double-blind, randomised, placebo-controlled, multicentre phase 2/3 trial

BACKGROUND: Inebilizumab is an anti-CD19 antibody approved for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults with aquaporin-4 autoantibodies. The relationship between B-cell, plasma-cell (PC), and immunoglobulin depletion with longitudinal reductions in NMOSD activity after inebilizumab treatment was characterised post hoc in an exploratory analysis from the N-MOmentum study (NCT02200770). METHODS: Peripheral blood CD20+ B cells, PC gene signature, and immunoglobulin levels were assessed throughout N-MOmentum (follow-up =2.5 years); correlations with clinical metrics and magnetic resonance imaging (MRI) lesion activity were assessed. FINDINGS: Inebilizumab induced durable B-cell and PC depletion within 1 week versus placebo. Although no association was observed between B-cell counts at time of attack and NMOSD activity, depth of B-cell depletion after the first dosing period correlated with clinical outcomes. All participants receiving inebilizumab demonstrated a robust long-term therapeutic response, and participants with =4 cells/µL after the first 6-month dosing interval had persistently deeper B-cell depletion, lower annualised attack rates (estimated rate [95% CI]: 0.034 [0.024–0.04] vs 0.086 [0.056–0.12]; p = 0.045), fewer new/enlarging T2 MRI lesions (0.49 [0.43–0.56] vs 1.36 [1.12–1.61]; p < 0.0001), and a trend towards decreased Expanded Disability Status Scale worsening (0.076 [0.06–0.10] vs 0.14 [0.10–0.18]; p = 0.093). Antibodies to inebilizumab, although present in a proportion of treated participants, did not alter outcomes. INTERPRETATION: This analysis suggests that compared with placebo, inebilizumab can provide specific, rapid, and durable depletion of B cells in participants with NMOSD. Although deep and persistent CD20+ B-cell depletion correlates with long-term clinical stability, early, deep B-cell depletion correlates with improved disease activity metrics in the first 2 years

GPI Spectra of HR8799 C, D, and E in H-K Bands with KLIP Forward Modeling

We demonstrate KLIP forward modeling spectral extraction on Gemini Planet Imager coronagraphic data of HR8799, using PyKLIP. We report new and re-reduced spectrophotometry of HR8799 c, d, and e from H-K bands. We discuss a strategy for choosing optimal KLIP PSF subtraction parameters by injecting fake sources and recovering them over a range of parameters. The K1/K2 spectra for planets c and d are similar to previously published results from the same dataset. We also present a K band spectrum of HR8799e for the first time and show that our H-band spectra agree well with previously published spectra from the VLT/SPHERE instrument. We compare planets c, d, and e with M, L, and T-type field objects. All objects are consistent with low gravity mid-to-late L dwarfs, however, a lack of standard spectra for low gravity late L-type objects lead to poor fit for gravity. We place our results in context of atmospheric models presented in previous publications and discuss differences in the spectra of the three planets