Country, Sex, EDSS Change and Therapy Choice Independently Predict Treatment Discontinuation in Multiple Sclerosis and Clinically Isolated Syndrome

We conducted a prospective study, MSBASIS, to assess factors leading to first treatment discontinuation in patients with a clinically isolated syndrome (CIS) and early relapsing-remitting multiple sclerosis (RRMS). The MSBASIS Study, conducted by MSBase Study Group members, enrols patients seen from CIS onset, reporting baseline demographics, cerebral magnetic resonance imaging (MRI) features and Expanded Disability Status Scale (EDSS) scores. Follow-up visits report relapses, EDSS scores, and the start and end dates of MS-specific therapies. We performed a multivariable survival analysis to determine factors within this dataset that predict first treatment discontinuation. A total of 2314 CIS patients from 44 centres were followed for a median of 2.7 years, during which time 1247 commenced immunomodulatory drug (IMD) treatment. Ninety percent initiated IMD after a diagnosis of MS was confirmed, and 10% while still in CIS status. Over 40% of these patients stopped their first IMD during the observation period. Females were more likely to cease medication than males (HR 1.36, p = 0.003). Patients treated in Australia were twice as likely to cease their first IMD than patients treated in Spain (HR 1.98, p = 0.001). Increasing EDSS was associated with higher rate of IMD cessation (HR 1.21 per EDSS unit, p<0.001), and intramuscular interferon-β-1a (HR 1.38, p = 0.028) and subcutaneous interferon-β-1a (HR 1.45, p = 0.012) had higher rates of discontinuation than glatiramer acetate, although this varied widely in different countries. Onset cerebral MRI features, age, time to treatment initiation or relapse on treatment were not associated with IMD cessation. In this multivariable survival analysis, female sex, country of residence, EDSS change and IMD choice independently predicted time to first IMD cessation

Natalizumab treatment shows low cumulative probabilities of confirmed disability worsening to EDSS milestones in the long-term setting.

Abstract Background Though the Expanded Disability Status Scale (EDSS) is commonly used to assess disability level in relapsing-remitting multiple sclerosis (RRMS), the criteria defining disability progression are used for patients with a wide range of baseline levels of disability in relatively short-term trials. As a result, not all EDSS changes carry the same weight in terms of future disability, and treatment benefits such as decreased risk of reaching particular disability milestones may not be reliably captured. The objectives of this analysis are to assess the probability of confirmed disability worsening to specific EDSS milestones (i.e., EDSS scores ≥3.0, ≥4.0, or ≥6.0) at 288 weeks in the Tysabri Observational Program (TOP) and to examine the impact of relapses occurring during natalizumab therapy in TOP patients who had received natalizumab for ≥24 months. Methods TOP is an ongoing, open-label, observational, prospective study of patients with RRMS in clinical practice. Enrolled patients were naive to natalizumab at treatment initiation or had received ≤3 doses at the time of enrollment. Intravenous natalizumab (300 mg) infusions were given every 4 weeks, and the EDSS was assessed at baseline and every 24 weeks during treatment. Results Of the 4161 patients enrolled in TOP with follow-up of at least 24 months, 3253 patients with available baseline EDSS scores had continued natalizumab treatment and 908 had discontinued (5.4% due to a reported lack of efficacy and 16.4% for other reasons) at the 24-month time point. Those who discontinued due to lack of efficacy had higher baseline EDSS scores (median 4.5 vs. 3.5), higher on-treatment relapse rates (0.82 vs. 0.23), and higher cumulative probabilities of EDSS worsening (16% vs. 9%) at 24 months than those completing therapy. Among 24-month completers, after approximately 5.5 years of natalizumab treatment, the cumulative probabilities of confirmed EDSS worsening by 1.0 and 2.0 points were 18.5% and 7.9%, respectively (24-week confirmation), and 13.5% and 5.3%, respectively (48-week confirmation). The risks of 24- and 48-week confirmed EDSS worsening were significantly higher in patients with on-treatment relapses than in those without relapses. An analysis of time to specific EDSS milestones showed that the probabilities of 48-week confirmed transition from EDSS scores of 0.0–2.0 to ≥3.0, 2.0–3.0 to ≥4.0, and 4.0–5.0 to ≥6.0 at week 288 in TOP were 11.1%, 11.8%, and 9.5%, respectively, with lower probabilities observed among patients without on-treatment relapses (8.1%, 8.4%, and 5.7%, respectively). Conclusions In TOP patients with a median (range) baseline EDSS score of 3.5 (0.0–9.5) who completed 24 months of natalizumab treatment, the rate of 48-week confirmed disability worsening events was below 15%; after approximately 5.5 years of natalizumab treatment, 86.5% and 94.7% of patients did not have EDSS score increases of ≥1.0 or ≥2.0 points, respectively. The presence of relapses was associated with higher rates of overall disability worsening. These results were confirmed by assessing transition to EDSS milestones. Lower rates of overall 48-week confirmed EDSS worsening and of transitioning from EDSS score 4.0–5.0 to ≥6.0 in the absence of relapses suggest that relapses remain a significant driver of disability worsening and that on-treatment relapses in natalizumab-treated patients are of prognostic importance

The role of Mre- proteins and teichoic acids during morphological differentiation of Streptomyces coelicolor A3(2)

Das mre- Gencluster ist bei vielen stäbchenförmigen Bakterien für das laterale Längenwachstum und die Ausbildung der Zellgestalt verantwortlich. Obwohl die filamentös wachsenden Streptomyceten ein von DivIVA abhängiges apikales Spitzenwachstum zeigen, besitzen sie auch ein mre- Gencluster bestehend aus mreB, mreC, mreD, PBP2 und sfr (rodA). Geninaktivierungsexperimente haben gezeigt, dass Streptomyces coelicolor A3(2) die mre- Gene während der morphologischen Differenzierung für die Ausbildung einer stressresistenten Sporenwand benötigt. Um mehr über die Funktion der Mre- Proteine bei der Sporenwandsynthese herauszufinden, wurden Bacterial Two Hybrid (BTH) Untersuchungen durchgeführt. Hierbei zeigte sich ein ähnliches Interaktionsmuster, wie es für den lateralen Zellwandsynthesekomplex stäbchenförmiger Bakterien beschrieben ist. Es wurde eine S. coelicolor- Genbank angelegt und gescreent; dabei konnten bisher unbekannte Interaktionspartner der Mre- Proteine identifiziert werden. Darunter befanden sich ein vom dcw- Gencluster kodiertes, für Actinomyceten spezifisches Membranprotein unbekannter Funktion (SCO2097), eine Serin / Threoninkinase vom Eukaryontentyp (SCO4778) sowie zwei möglicherweise an der Teichonsäurebiosynthese beteiligte Proteine (SCO2578, SCO2584). Geninaktivierungsexperimente führten zu den Mutanten delta2097 und EMK2584; diese waren den mre- Mutanten sehr ähnlich und produzierten morphologisch auffällige Sporen. Dies bestätigte die Beteiligung der mit der Genbank identifizierten Interaktionspartner an der Sporulation. Des Weiteren wurde die auf Grund der Proteininteraktionen vermutete Verknüpfung von Sporenwand- und Teichonsäuresynthese näher untersucht. Dafür wurde das S. coelicolor Genom nach möglichen Teichonsäurebiosynthesegenen durchsucht. Es wurden zwei Gencluster identifiziert, welche unter anderem für acht Glycosyl / Glycerophosphotransferasen kodieren. Eine Deletionsmutante der tagF homologen Glycerophosphotransferase SCO2997 wurde konstruiert. Die Mutante war in ihrem vegetativen Wachstum nicht beeinträchtigt. Ihre Sporen jedoch besaßen eine unregelmäßige Form mit einer signifikant vom Wildtyp M145 unterschiedlichen Längenverteilung. Außerdem waren die Sporen empfindlicher gegenüber Hitze, Lysozym und Vancomycin. Dies lässt auf eine defekte Sporenwand schließen. Die Ergebnisse der BTH- Experimente ergaben ein komplexes Netzwerk von Interaktionen zwischen den Mre- Proteinen, Penicillinbindeproteinen, morphogenen Proteinen sowie an der Teichonsäuresynthese beteiligten Proteinen. Funktionelle Beziehungen wurden durch die Phänotypen der Deletionsmutanten unterstützt und führten zum Modell des Streptomyces Spore wall Synthesizing Complex (SSSC). Der SSSC ist sowohl an der Peptidoglykan- als auch an der Teichonsäuresynthese der Sporenwand beteiligt.The mre- gene cluster is involved in the lateral elongation growth and cell shape of numerous rod shaped bacteria. Although the filamentous growing Streptomycetes grow by apical tip extension located by DivIVA they also own an mre gene cluster, consisting of mreB, mreC, mreD, PBP2 and sfr (rodA). Deletion mutants showed that Streptomyces coelicolor needs the mre genes for morphological differentiation and the synthesis of a thickened spore wall. Bacterial Two Hybrid studies showed a similiar interaction pattern of the Mre- Proteins as had been shown for rod shaped bacteria. By screening a genomic library futher interaction partners of this complex were identified. This led to the model of the Streptomyces Spore wall Synthesizing Complex (SSSC). Two of these proteins belong to a putative teichoic acid synthesizing gene cluster. In order to find out more about the connection between peptidoglykan and teichoic acid synthesis deletion mutants (SCO2584 and SCO2997) were constructed and characterized. They showed a similar phenotype resembling the mre mutants. This confirms a role of the SSSC in peptidoglykan and in teichoic acid synthesis

Acceptance, drivers, and barriers to use eHealth interventions in patients with post-COVID-19 syndrome for management of post-COVID-19 symptoms: a cross-sectional study

Background: Post-COVID-19 syndrome is a new and debilitating disease without adequate treatment options. eHealth could be a reasonable approach for symptom management. Objectives: This study aims to evaluate the acceptance for eHealth interventions for symptom management in individuals with post-COVID-19 syndrome, as well as drivers and barriers influencing acceptance. Design: Cross-sectional study. Methods: This study was conducted from January 19 until 24 May 2022. Recruitment took place with a web-based survey. Acceptance and predictors of eHealth interventions were measured by the extended UTAUT model. Included in the model were the core predictor performance expectancy, social influence, and effort expectancy. Previously diagnosed mental illness was estimated and mental health by using the well-established Generalized Anxiety Disorder Scale-7 and the Patient Health Questionnaire Depression Scale. The effect of sociodemographic and medical data was assessed. Multiple hierarchical regression analyses as well as group comparisons were performed. Results: 342 individuals with post-COVID-19 syndrome were examined. The acceptance of eHealth interventions for symptom management was moderate to high (M = 3.60, SD = 0.89). Acceptance was significantly higher in individuals with lower/other education, patients with moderate to severe symptoms during initial COVID-19 infection, still significantly impaired patients, and individuals with a mental illness. Identified predictors of acceptance were age (β = .24, p  < .001), current condition including moderate (β = .49, p  = .002) and still significantly impaired (β = .67, p  < .001), digital confidence (β = .19, p  < .001), effort expectancy (β = .26, p  < .001), performance expectancy (β = .33, p  < .001), and social influence (β = .26, p  < .001). Conclusion: Patients with post-COVID-19 syndrome reported a satisfying level of acceptance and drivers and barriers could be identified. These factors need to be considered for the implementation and future use of eHealth interventions

The MreB-Like Protein Mbl of Streptomyces coelicolor A3(2) Depends on MreB for Proper Localization and Contributes to Spore Wall Synthesis▿ †

Most bacteria with a rod-shaped morphology contain an actin-like cytoskeleton consisting of MreB polymers, which form helical spirals underneath the cytoplasmic membrane to direct peptidoglycan synthesis for the elongation of the cell wall. In contrast, MreB of Streptomyces coelicolor is not required for vegetative growth but has a role in sporulation. Besides MreB, S. coelicolor encodes two further MreB-like proteins, Mbl and SCO6166, whose function is unknown. Whereas MreB and Mbl are highly similar, SCO6166 is shorter, lacking the subdomains IB and IIB of actin-like proteins. Here, we showed that MreB and Mbl are not functionally redundant but cooperate in spore wall synthesis. Expression analysis by semiquantitative reverse transcription-PCR revealed distinct expression patterns. mreB and mbl are induced predominantly during morphological differentiation. In contrast, sco6166 is strongly expressed during vegetative growth but switched off during sporulation. All genes could be deleted without affecting viability. Even a ΔmreB Δmbl double mutant was viable. Δsco6166 had a wild-type phenotype. ΔmreB, Δmbl, and ΔmreB Δmbl produced swollen, prematurely germinating spores that were sensitive to various kinds of stress, suggesting a defect in spore wall integrity. During aerial mycelium formation, an Mbl-mCherry fusion protein colocalized with an MreB-enhanced green fluorescent protein (MreB-eGFP) fusion protein at the sporulation septa. Whereas MreB-eGFP localized properly in the Δmbl mutant, Mbl-mCherry localization depended on the presence of a functional MreB protein. Our results revealed that MreB and Mbl cooperate in the synthesis of the thickened spore wall, while SCO6166 has a nonessential function during vegetative growth