Cognitive performance in relapsing remitting multiple sclerosis: A longitudinal study in daily practice using a brief computerized cognitive battery

<p>Abstract</p> <p>Background</p> <p>There is need for a cognitive test battery that can be easily used in clinical practice to detect or monitor cognitive performance in patients with multiple sclerosis (MS). In order to conduct, in this patient group, a preliminary investigation of the validity and utility of a brief computerized battery, the Cognitive Drug Research (CDR) battery, we longitudinally assessed cognition in patients with relapsing remitting (RR) MS.</p> <p>Methods</p> <p>Forty-three mildly disabled, clinically active RRMS patients were repeatedly assessed with the Digit Symbol Substitution Test (DSST), Paced Auditory Serial Addition Test (PASAT) and five composite scores derived from the CDR computerized cognitive test system (CDR System): Power of Attention, Continuity of Attention, Quality of Working Memory, Quality of Episodic Memory and Speed of Memory. The Multiple Sclerosis Functional Composite (MSFC) and Expanded Disability Status Scale (EDSS) measured disability.</p> <p>Results</p> <p>The composite scores from the CDR battery generally showed excellent test-retest reliability over the repeated assessments, though was low on occasions for the Quality of Working Memory and Quality of Episodic Memory measures. The CDR measures tended to be highly correlated with other measures of cognition (DSST and PASAT) and were also strongly related to disability (EDSS and MSFC). Baseline scores indicated large impairments to visual information processing speed and attention (DSST, Cohen's d 1.1; Power of Attention d 1.4 [reaction time on tasks of focussed and sustained attention]), and a moderate impairment both to sustained attention (Continuity of Attention d 0.6) and complex information processing speed (Speed of memory d 0.7 [reaction time on tasks of working and episodic Memory]), when compared to normative data derived from healthy volunteers enrolled in a series of separate, prior clinical trials. Working memory (Quality of Working Memory) and episodic memory (Quality of Episodic Memory) were unimpaired.</p> <p>Conclusions</p> <p>Preliminary validation of the CDR System indicated that for most, but not all measures psychometric properties were adequate and the measures were related to disability (EDSS and MSFC) and other measures of cognition.</p

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease.

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Adverse events of interferon beta-1a: a prospective multi-centre international ICH-GCP-based CRO-supported external validation study in daily practice.

Contains fulltext : 95629.pdf (publisher's version ) (Open Access)BACKGROUND: Due to methodological shortcomings the available post-registration data on the adverse events (AEs) occurring in interferon beta-1a (INFb-1a)-treated patients fail to adequately validate phase III data and only partially inform on safety in daily practice. We assessed AEs in relapsing remitting multiple sclerosis (RRMS) patients treated with intramuscular (IM) INFb-1a in daily practice using data quality assurance measures similar to those in phase III trials. METHODS: A prospective, International Conference on Harmonization (ICH) - Good Clinical Practice (GCP)-based, clinical research organization (CRO)-supported study in 36 practices in the Netherlands, Belgium, the United Kingdom and Luxembourg. During 24 months after start of IM INFb-1a treatment 275 RRMS patients were assessed for AEs' severity (mild, moderate, severe) and relationship to treatment (not, unlikely, likely, definite). Data were compared with those reported in the pivotal phase III trial. FINDINGS: 75.3% of the patients experienced one or more AEs that were likely or definitely related to INFb-1a. Of all AEs 40.5% were likely or definitely treatment-related; 68.5% of these were mild, and 3% severe. 6.6% of the patients discontinued treatment because of an AE. Compared to the pivotal phase III trial, we found statistically significantly lower incidences for most of the common AEs: headache, muscle ache, fatigue, fever, chills, nausea. One patient died following two cerebral vascular events in study month 22, both AEs were assessed as not related to INFb-1a. CONCLUSION: Three out of four RRMS patients treated with IM INFb-1a in daily practice experience treatment-related AEs, most of these being mild. Our data externally validate the favorable phase III safety profile of IM INFb-1a and suggest that the real-life incidence of treatment-related AEs is less than reported in the pivotal phase III trial. Larger studies are needed to detect rare, potentially hazardous AEs of IM INFb-1a

Valuing Skill Differences: Perceived Skill Complementarity and Dyadic Helping Behavior in Teams

This article reports effects of perceived skill dissimilarity and perceived skill complementarity on dyadic helping behavior using a cross-lagged panel\ud study. Specifically, the authors hypothesize that perceived skill dissimilarity\ud is negatively related, whereas perceived skill complementarity is positively\ud related, to self-rated and peer-rated dyadic helping behavior in teams. The\ud authors compare the effects of both perceptions in a sample of 301 unilateral\ud work relationships within 20 student research teams. The study shows that\ud perceived skill dissimilarity is unrelated to self-rated and peer-rated dyadic\ud helping behavior whereas perceived skill complementarity is positively\ud related to both self-rated and peer-rated dyadic helping behavior

dherence to Monthly Online Self-Assessments for Short-Term Monitoring: A One-Year Study in Relapsing Remitting Multiple Sclerosis Patients after Start of Disease Modifying Treatment.

BACKGROUND The participation of neurologists and patients in studies on the effectiveness and safety of newly authorized drugs in multiple sclerosis (MS) is insufficient. Monthly online self-assessments using patient-reported outcomes may help in short-term monitoring of neurological changes and side effects. OBJECTIVE Investigate in relapsing-remitting (RR) MS patients the adherence to monthly online self-assessments after the start of disease modifying treatment. METHODS Observational study in 39 neurological departments in The Netherlands. Patients starting glatiramer acetate treatment were instructed to complete online the Modified Fatigue Impact Scale 5-item version and the 8-item Leeds Multiple Sclerosis Quality of Life scale every month during 1 year (T0 toT12). RESULTS Sixty-three investigators included 163 analyzable patients. At T3, 148 (90.8%) patients had completed all questionnaires; at T6, 142 (87.1%); at T9, 133 (81.6%); and at T12, 123 (75.5%). Eight (4.9%) patients did not complete any questionnaire. Median values for inter-assessment intervals ranged from 32 to 34 days (first quartile [Q1] 30 days, third quartile [Q3] 41 days), and the final assessment was at 417 days (median: Q1 385 days, Q3 480 days). Forty-three (26.3%) patients completed the questionnaires at all time points (completion adherent) with their final assessment within 30 days after the scheduled T12 (interval adherent). Eighty (49.1%) patients were completion adherent, but not interval adherent. Forty (24.5%) patients were not completion adherent, as they discontinued assessments prematurely. Men were more interval adherent than women (47.5% vs 20.0%; P = 0.001). CONCLUSION The observation that three out of four (75.5%) RRMS patients completed two short questionnaires at all monthly time points during 1 year after the start of disease modifying treatment suggests that intensive online monitoring in this patient group is feasible. As only one in five (19.6%) patients adhered to the time intervals between self-assessments, measures are needed that improve the timely completion of questionnaires.+ ID der Publikation: unilu_29636 + Sprache: Englisch + Letzte Aktualisierung: 2021-03-01 12:07:5

What's the difference? Insider perspectives on the importance, content, and meaning of interpersonal differences

This study presents a new approach to examine how team members experience interpersonal differences. This approach offers a way to examine how team members experience their differences with specific other individuals, and how these differences are related to the amount of perceived conflict with these individuals in an organizational context. Data from a non-profit governmental institution in The Netherlands were analysed, including 80 participants from 15 diverse teams. Five types of differences were salient to the individuals in this sample: differences related to extraversion; work pose; approach to work; task-related expertise; and seniority. Furthermore, individuals tend to contrast positive and negative evaluations of differences related to extraversion and approaches to work, but to conceptualize positive and negative evaluations of task-related expertise, seniority, and work pose as more mutually independent phenomena. Moreover, we found that differences related to task-related expertise were negatively related to both task and relationship conflict. In contrast, differences related to extraversion were positively related to both task and relationship conflict. Finally, the approach-to-work cluster was positively related to only task conflict

Relationship between working hours and power of attention, memory, fatigue, depression and self-efficacy one year after diagnosis of clinically isolated syndrome and relapsing remitting multiple sclerosis

The role of cognitive domain dysfunction with respect to vocational changes in persons with Clinically Isolated Syndrome (CIS) and early Relapsing Remitting Multiple Sclerosis (eRRMS) is insufficiently known. We investigated thirty-three patients - 14 CIS, 19 eRRMS -, mean (standard deviation [SD]) time since diagnosis 13.5 (4.8) months and mean (SD) Expanded Disability Status Scale (EDSS) score 1.3 (1.1). Patients were assessed on the CDR System, a set of automated tests of cognitive function, which yielded scores for Power of Attention (ms), Continuity of Attention (#), Working Memory (SI), Episodic Memory (#) and Speed of Memory (ms). Work-related items and the confounding variables fatigue, depression, disease impact and self-efficacy, were assessed by self-report questionnaires. Patients had poorer Power of Attention compared to normative data (1187 [161.5] vs. 1070 [98.6]; P<0.0001) and slower Speed of Memory (4043 [830.6]) vs. 2937 [586.1]; P<0.0001). Power of Attention (Pearson r = -0.42; P<0.04), Working Memory (r = 0.42; P<0.04) and depression r = -0.41; P<0.05) correlated with number of days worked per week. Fatigue (r = -0.56; P<0.005), self-efficacy (r = 0.56; P<0.005) and disease impact (r = -0.46; P<0.05) correlated with number of hours worked per week. Persons who wished to work less had poorer Power of Attention (1247 vs. 1116 ms; P<0.02), those who wished to change job had poorer Episodic Memory (1.35 vs. 1.57; p<0.03). People who reduced working hours within 12 months after diagnosis had higher fatigue and disease impact, and lower self-efficacy. The findings of this pilot study indicate that one year after the diagnosis of CIS and RRMS Power of Attention and Speed of Memory are reduced, that Power of Attention and Memory are associated with a capability of working less hours, and that fatigue, depression and disease impact may negatively, and self-efficacy positively affect working hours