Real-world persistence of multiple sclerosis disease-modifying therapies.

BACKGROUND AND PURPOSE: Treatment persistence is the continuation of therapy over time. It reflects a combination of treatment efficacy and tolerability. We aimed to describe real-world rates of persistence on disease-modifying therapies (DMTs) for people with multiple sclerosis (pwMS) and reasons for DMT discontinuation. METHODS: Treatment data on 4366 consecutive people with relapse-onset multiple sclerosis (MS) were pooled from 13 UK specialist centres during 2021. Inclusion criteria were exposure to at least one MS DMT and a complete history of DMT prescribing. PwMS in blinded clinical trials were excluded. Data collected included sex, age at MS onset, age at DMT initiation, DMT treatment dates, and reasons for stopping or switching DMT. For pwMS who had received immune reconstituting therapies (cladribine/alemtuzumab), discontinuation date was defined as starting an alternative DMT. Kaplan-Meier survival analyses were used to express DMT persistence. RESULTS: In 6997 treatment events (1.6 per person with MS), median time spent on any single maintenance DMT was 4.3 years (95% confidence interval = 4.1-4.5 years). The commonest overall reasons for DMT discontinuation were adverse events (35.0%) and lack of efficacy (30.3%). After 10 years, 20% of people treated with alemtuzumab had received another subsequent DMT, compared to 82% of people treated with interferon or glatiramer acetate. CONCLUSIONS: Immune reconstituting DMTs may have the highest potential to offer a single treatment for relapsing MS. Comparative data on DMT persistence and reasons for discontinuation are valuable to inform treatment decisions and in personalizing treatment in MS.

MG 53 Protein Protects Aortic Valve Interstitial Cells From Membrane Injury and Fibrocalcific Remodeling.

Background The aortic valve of the heart experiences constant mechanical stress under physiological conditions. Maladaptive valve injury responses contribute to the development of valvular heart disease. Here, we test the hypothesis that MG 53 (mitsugumin 53), an essential cell membrane repair protein, can protect valvular cells from injury and fibrocalcific remodeling processes associated with valvular heart disease. Methods and Results We found that MG 53 is expressed in pig and human patient aortic valves and observed aortic valve disease in aged Mg53-/- mice. Aortic valves of Mg53-/- mice showed compromised cell membrane integrity. In vitro studies demonstrated that recombinant human MG 53 protein protects primary valve interstitial cells from mechanical injury and that, in addition to mediating membrane repair, recombinant human MG 53 can enter valve interstitial cells and suppress transforming growth factor-ß-dependent activation of fibrocalcific signaling. Conclusions Together, our data characterize valve interstitial cell membrane repair as a novel mechanism of protection against valvular remodeling and assess potential in vivo roles of MG 53 in preventing valvular heart disease.

STRmix™ collaborative exercise on DNA mixture interpretation.

An intra and inter-laboratory study using the probabilistic genotyping (PG) software STRmix™ is reported. Two complex mixtures from the PROVEDIt set, analysed on an Applied Biosystems™ 3500 Series Genetic Analyzer, were selected. 174 participants responded. For Sample 1 (low template, in the order of 200 rfu for major contributors) five participants described the comparison as inconclusive with respect to the POI or excluded him. Where LRs were assigned, the point estimates ranging from 2 × 104 to 8 × 106. For Sample 2 (in the order of 2000 rfu for major contributors), LRs ranged from 2 × 1028 to 2 × 1029. Where LRs were calculated, the differences between participants can be attributed to (from largest to smallest impact): This study demonstrates a high level of repeatability and reproducibility among the participants. For those results that differed from the mode, the differences in LR were almost always minor or conservative.

When knowing can replace seeing in audiovisual integration of actions.

The ability to predict the effects of actions is necessary to behave properly in our physical and social world. Here, we describe how the ability to predict the consequence of complex gestures can change the way we integrate sight and sound when relevant visual information is missing. Six drummers and six novices were asked to judge audiovisual synchrony for drumming point-light displays where the visual information was manipulated to eliminate or include the drumstick-drumhead impact point. In the condition with only the arm information novices were unable to detect asynchrony whereas drummers were able to. Additionally, in the conditions that included the impact point drummers perceived the best alignment when the sight preceded the sound, while in the arm only condition they perceived the best alignment when the sound occurred together with or preceded the sight, as it would be expected if they were predicting the beat occurrence. Taken together these findings suggest that humans can acquire, through practice, internal models of action which can be used to replace missing information when integrating multisensory signals from the environment.

Evidence-based strategies to improve immunization compliance of postgraduate medical trainees at large academic-medical facilities.

The purpose of this evaluation is to assess the effectiveness of the modifications made by the University of Toronto Postgraduate Medical Education to improve medical trainee compliance with the immunization standards set forth in national guidelines, provincial regulations and protocols and university policy. Trainee compliance with immunization requirements were evaluated as of January 2003, 2004 and 2005. Statistically significant increases in compliance rates for all required immunizations--hepatitis B virus, measles, rubella and chicken pox--and tuberculosis skin tests were observed. University of Toronto postgraduate medical trainees are now highly compliant with the Hospital Management Regulation 965 of the Ontario Public Hospitals Act, Canadian Immunization Guide, Public Health Agency of Canada guidelines for prevention and control of occupational infections in healthcare and the University of Toronto Faculty of Medicine immunization policy.

Judgment of disfluency in people who stutter and people who do not stutter: results from magnitude estimation.

Two experiments used a magnitude estimation paradigm to test whether perception of disfluency is a function of whether the speaker and the listener stutter or do not stutter. Utterances produced by people who stutter were judged as "less fluent," and, critically, this held for apparently fluent utterances as well as for utterances identified as containing disfluency. Additionally, people who stutter tended to perceive utterances as less fluent, independent of who produced these utterances. We argue that these findings are consistent with a view that articulatory differences between the speech of people who stutter and people who do not stutter lead to perceptually relevant vocal differences. We suggest that these differences are detected by the speech self-monitoring system (which uses speech perception) resulting in covert repairs. Our account therefore shares characteristics with the Covert Repair (Postma & Kolk, 1993) and Vicious Circle (Vasic & Wijnen, 2005) hypotheses. It differs from the Covert Repair hypothesis in that it no longer assumes an additional deficit at the phonological planning level. It differs from the Vicious Circle hypothesis in that it no longer attributes hypervigilant monitoring to unknown, external factors. Rather, the self-monitor becomes hypervigilant because the speaker is aware that his/her speech is habitually deviant, even when it is not, strictly speaking, disfluent.