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Beta-Amyloid 1–42 peptide (βA42) is a cerebro-spinal fluid (CSF) biomarker, key element of the NIA Alzheimer's disease diagnostic criteria. The enzyme-linked immunosorbent assay (ELISA) has been the mainstay method for βA42 measurement on cerebrospinal fluid (CSF). Recently, a new βA42 measurement method in chemiluminescence enzyme immunoassay (CLEIA) is available on Lumipulse G 600 II automatic platform. The aim of the work was to evaluate the concordance of the ELISA and the new method (CLEIA) in the CSF βA42 levels measurement. CSF βA42 levels were assayed in 49 samples using the ELISA method (Innotest β- amyloid 1–42, Fujirebio Europe N.V., Gent, Belgium) and CLEIA method on Lumipulse G600II fully automatic platform (Lumipulse G β- amyloid 1–42, Fujirebio Europe N.V., Gent, Belgium). We compared values of the two methods using acceptability interval based on Inherent Combined Imprecision (ICI), the Passing-Bablok regression analysis, the Pearson correlation coefficient (r) and the Bland-Altman plot. The analysis of the ICI showed that the two methods differ substantially. The regression equation (y = −103.04 + 1.52×) highlighted the presence of proportional systematic difference, without significant deviation from linearity (p =.42). The Pearson correlation coefficient was 0.826. The Bland-Altman plot analysis showed a significant systematic difference in the two methods: ELISA measurements were in average –27.06% (95% CI –31.89 to −22.23%) lower compared to CLEIA ones. Our study highlighted a difference between the two methods. Therefore, the cut-off for the normal levels of βA42 should be reviewed in the laboratory report. • The concordance between the CLEIA, a new method for βA42, and ELISA, the mainstay method, was evaluated. • Several statistical approaches and graphical tools (Bland-Altman and Mountain plots) were considered. • A systematic difference between the two methods was found. • The normal limit in the laboratory should be revised based on the new CLEIA method. [ABSTRACT FROM AUTHOR]

• Almost one third (29.4%) of the survey persons with MS reported volunteering. • Study participants most often volunteered in cultural and charitable organizations. • Having a university degree was positively associated with volunteering. • Being male and being a homemaker increased chances of volunteering. • Having a lower ability to perform everyday tasks decreased chances of volunteering. Informal and formal volunteering engagement is a proxy for social integration and may have beneficial effects for physical and mental well-being in persons with multiple sclerosis (pwMS). As literature on the topic among the pwMS is lacking, this study aimed to determine frequency and type of volunteering performed by pwMS and to identify factors associated with volunteering. Cross-sectional, self-reported data of 615 pwMS participating in the Swiss Multiple Sclerosis Registry were analyzed using descriptive statistics to determine frequency and type of volunteering engagement. Univariable and multivariable generalized linear models with binomial distribution and log link function were used to identify factors associated with volunteering. Age, sex, employment status and gait disability were added to the multivariable model as fixed confounders. Sociodemographic, health-, work- and daily activity-related factors were included in the analysis. About one third (29.4%) of participants reported engagement in volunteering activities, most often through charities (16.02%) and cultural organizations (14.36%). In the multivariable model, participants who had a university degree were more likely to volunteer than those with lower level of education (RR = 1.48 95% CI [1.14; 1.91]). The ability to pursue daily activities (as measured by the EQ-5D subscale) was strongly associated with participation in volunteering among pwMS. Compared with pwMS who had no or only slight limitations in daily activities, those with severe problems were markedly less likely to engage in volunteering (RR = 0.41, 95% CI [0.21; 0.80]). Finally, pwMS who reported caring for and supporting their family (i.e., being a homemaker) were more likely to engage in volunteering activities than those who did not (RR = 1.52, 95% CI [1.15; 2.01]). Nearly one in three pwMS engaged in diverse volunteering activities. Having a university degree, being less limited in daily activities and being a homemaker increased the probability of pursuing volunteering activities. Contingent on individual-level motivations, resources or physical abilities, pwMS who experience challenges in performing daily activities or social barriers should be made aware of barrier-free offers of socially inclusive and volunteering activities, often provided by the national MS societies and health leagues. [ABSTRACT FROM AUTHOR]

• PwMS are 1.5 times more frequently affected by material deprivation than the general Swiss population. • High symptom burden at the transition from work force to receiving disability benefits appeared to be vulnerable for material deprivation. • Higher education, older age, having a Swiss citizenship, living with a spouse or a partner or being currently employed were independently associated with a lower risk of material deprivation. Multiple sclerosis (MS) impacts education, future career pathways and working capability and therefore may negatively impact the financial situation of persons with MS (pwMS) in Switzerland. We therefore investigated the financial situation and its influencing sociodemographic and disease-specific factors of pwMS compared to the general Swiss population with focus on material deprivation (MD). Data on the financial situation of pwMS were collected via a specific questionnaire added to the regular, semi-annual follow-up assessments of the Swiss Multiple Sclerosis Registry. Questions were taken in an unmodified format from the standardized "Statistics on Income and Living Conditions" (SILC) questionnaire 2019 of the Federal Statistical Office of Switzerland which evaluates the financial situation of the general Swiss population, enabling a direct comparison of pwMS with the general Swiss population. PwMS were 1.5 times more frequently affected by MD than the general Swiss population (6.3% of pwMS versus 4.2% of the general Swiss population) which was confirmed in a multivariable logistic regression analysis of pooled SILC and Swiss Multiple Sclerosis Registry (SMSR) data. High symptom burden, having only mandatory schooling, well as having a pending disability insurance application (as opposed to no application or receiving benefits) were associated with a higher odds of MD whereas higher education, older age, having a Swiss citizenship, living with a spouse or a partner or being currently employed were independently associated with a lower odds of MD. MS has a negative impact on the financial situation and is associated with MD. PwMS with a high symptom burden at the transition from work force to receiving disability benefits appeared to be vulnerable for MD. Higher education, older age, having a Swiss citizenship, living with a spouse or a partner or being currently employed were independently associated with a lower odds of MD. [ABSTRACT FROM AUTHOR]

• Associations of age and MS duration with comorbidities and disability were explored using registry data. • Hypertension, diabetes, and cancer were associated with age, and cardiac disease was associated with both age and MS duration. • While having at least moderate gait disability was associated with both age and MS duration, severe was associated with MS duration only. • The spline analysis suggested a non-linear increase of having at least moderate gait disability with age. While comorbidities increase with age, duration of multiple sclerosis (MS) leads to disability accumulation in persons with MS. The influence of ageing vis-a-vis MS duration remains largely unexplored. We studied the independent associations of ageing and MS duration with disability and comorbidities in the Swiss MS Registry participants. Self-reported data was cross-sectionally analyzed using confounder-adjusted logistic regression models for 6 outcomes: cancer, type 2 diabetes (T2D), hypertension, cardiac diseases, depression, and having at least moderate or severe gait disability. Using cubic splines, we explored non-linear changes in risk shapes. Among 1615 participants age was associated with cardiac diseases (OR 1.05, 95% CI [1.02, 2.08]), hypertension (OR 1.08, 95% CI [1.06, 2.10]), T2D (OR 1.10, 95%CI [1.05, 1.16]) and cancer (OR 1.04, 95% CI [1.01, 1.07]). MS duration was not associated with comorbidities, except for cardiac diseases (OR 1.03, 95% CI [1.00, 1.06]). MS duration and age were independently associated with having at least moderate gait disability (OR 1.06, 95% CI [1.04, 1.07]; OR 1.04, 95% CI [1.02, 1.05], respectively), and MS duration was associated with severe gait disability (OR 1.05, 95% CI [1.03, 1.08]). The spline analysis suggested a non-linear increase of having at least moderate gait disability with age. Presence of comorbidities was largely associated with age only. Having at least moderate gait disability was associated with both age and MS duration, while having severe gait disabity was associated with MS duration only. [ABSTRACT FROM AUTHOR]

• In MS patients, total sleep time, wake after sleep onset and REM-sleep correlated with cognitive abnormalities. • Worse global cognitive functioning, memory and attention performances were associated with reduced sleep efficacy, and longer periods of nocturnal wake. • Reduced REM-sleep was correlated with poorer attention performances. • Trait anxiety moderated the relationship between nocturnal wake and memory. • Treatment of sleep and psychiatric disturbances may contribute to mitigate cognitive disorders in MS. Multiple sclerosis (MS) patients with cognitive impairment (CI) frequently suffer from sleep disturbances and emotional symptoms. The aim of this study was to investigate the relationship between CI and sleep disturbances and the role of anxiety and depression on this relationship in MS patients. Prospective cross-sectional study including 80 MS patients that underwent neurologic, cognitive, psychiatric assessment, and polysomnographic registration. Partial correlations analysis adjusted by demographic and clinical variables were used to investigate associations between cognitive and sleep measures. Moderator role effect of psychiatric symptoms was also explored with linear models. Thirty-six MS patients had CI. In all patients, worse performances at global, memory and attention cognitive domains were correlated with reduced sleep efficacy and longer periods of nocturnal wake (NW), while poor attention performances were associated with reduced REM-sleep (r = 0.26, p = 0.022). Memory performances were also negatively correlated with anxiety (r = −0.27, p = 0.015). The relationship between NW and memory performances was moderated by trait anxiety (p < 0.001). Our findings suggest that low sleep efficiency, NW, and reduced REM-sleep might affect cognitive abilities in MS. Higher trait anxiety appeared to impact on the relationship between increased NW and poor memory performances. Treatment of sleep and psychiatric disturbances may contribute to mitigating cognitive disorders in MS. [ABSTRACT FROM AUTHOR]

Objective To investigate the efficacy of a proactive feeding regimen (PFR) in reducing hospital length of stay in a population of moderately preterm small for gestational age (SGA) infants. Study design SGA infants (z-score <-1.28) of gestational age (GA) 32-36 weeks and birth weight (BW) >1499 g were allocated at random to receive either a PFR, starting with 100 mL/kg/day and gradually increasing to 200 mL/kg/day by day 4, or a standard feeding regimen, starting with 60 mL/kg/day and gradually increasing to 170 mL/kg/day by day 9. All infants received human milk. Results A total of 72 infants were randomized to the 2 groups, 36 to the PFR group (mean GA, 35.1 ± 0.7 weeks; mean BW, 1761 ± 177 g) and 36 to the standard feeding regimen group (mean GA, 35.5 ± 1.2 weeks; mean BW, 1754 ± 212 g). Infants in the PFR group were discharged significantly earlier (mean, 9.8 ± 3.1 days vs 11.9 ± 4.7 days; P = .029). The need for intravenous fluids (2.8% vs 33.3%; P = .0013) and the incidence of hypoglycemia (0 vs 33.3%; P = .00016) were significantly lower in the PFR group. Feeding intolerance and fecal calprotectin levels did not differ between the 2 groups. Conclusion A PFR in moderately preterm SGA infants is well tolerated and significantly reduces both the length of stay and the risk of neonatal hypoglycemia. [ABSTRACT FROM AUTHOR]

• Based on 668 relapsing-remitting MS (RRMS) cases, associations of the disease-modifying therapy (DMT) status were explored. • 21% of persons were not on a DMT, 67% received a DMT for more, and 13% for less than 6 months. • Disease-modifying therapies (DMTs) reduce relapse rates and disease progression, but not all persons with RRMS receive DMT. • Self-reported side-effects were common and varied substantially across the five most frequently used DMTs. • The majority of persons with RRMS were on long-term DMT, this however does not necessarily imply a burden-free life. Several disease-modifying therapies (DMTs), covering a broad spectrum of mechanisms of action, have been approved by regulatory agencies for the treatment of relapsing-remitting multiple sclerosis (RRMS). However, only little is known about the current real-world treatment situation in Switzerland. Based on data from a diverse population of 668 persons with RRMS from the Swiss Multiple Sclerosis Registry (SMSR), the present study aims to fill this gap with a descriptive, cross-sectional approach. Data originated from the SMSR baseline questionnaire and follow-up surveys. Data on current health status and life situation in the last 6 months were extracted from the survey distributed throughout 2020 and 2021, while data on disease-modifying therapy (DMT) histories were included from preceding surveys. Initially, data was stratified into three DMT groups according to the current DMT status (NO (No DMT), CONTINUED (DMT started more than 6 months ago), and NEW (DMT started less than 6 months ago)). In a subsequent analysis, the sample was stratified into groups corresponding to the five most frequently prescribed DMTs. Self-reported outcomes including therapy discontinuation or interruption, relapses and side-effects in the last 6 months were analyzed per group. Life and health situation parameters were also determined and analyzed. The study population consisted of 445 (66.6%) individuals belonging to the CONTINUED , 84 (12.6%) to the NEW , and 139 (20.8%) to the NO group. Within the NO group, 24 (17.3%) reported relapses. Furthermore, self-reported relapses (28 (33.3%)), side-effects (39 (46.4%)), and treatment discontinuations or interruptions (30 (35.7%)) occurred more frequently in the NEW compared to the CONTINUED group (37 (8.3%), 125 (28.1%), 8 (1.8%), respectively). The three groups also differed with respect to age, time since diagnosis, number of symptoms, DMT history, and health-related quality of life. The five most frequently prescribed DMTs included fingolimod (33.4%), dimethyl fumarate (25.0%), ocrelizumab (23.6%), natalizumab (10.6%) and teriflunomide (7.5%). The frequency of self-reported relapses ranged from 9.7% to 13.6%. Notable differences were found in the number of self-reported side-effects, ranging from 9.1% with natalizumab to 56.7% with dimethyl fumarate. This cross-sectional analysis suggested that the majority of individuals with RRMS in Switzerland continuously receive tolerable DMT. However, groups not receiving DMT or struggling with side-effects or continued disease worsening while on DMT still persist. It is conceivable that the number of self-reported symptoms indicates the need for more detailed clarification of the DMT characteristics and expectations of treatment outcomes. Injectable DMTs no longer play a major role in the treatment of RRMS in Switzerland and a trend toward an early use of potent drugs is emerging. [ABSTRACT FROM AUTHOR]

• Effectiveness of cladribine appears similar in aged (≥50 years) and young (<50 years) people with MS. • Cladribine-induced lymphopenia is comparable between aged and young people with MS. • Adverse events and infections during cladribine treatment are numerically more frequent among aged and disabled people with MS. Clinical trial data regarding efficacy and safety of cladribine in MS are limited to young individuals, and the overall risk-benefit profile does not necessarily applies to elderly patients. We investigated effectiveness and safety outcomes in MS patients initiating cladribine at ≥50 years (n=35) and <50 years (n=62), over a median follow-up of 12.4 months. There were no differences in time to evidence of disease activity (HR=0.73, 95%CI=0.18-2.91, p=0.657), post-treatment lymphocyte counts (β=0.24, p=0.825) or occurrence of adverse events (OR=0.84, 95%CI=0.24-2.93, p=0.791) between age groups. Female sex and greater disability were associated with higher risk of adverse events (especially infections). These limited data do not suggest safety concerns regarding use of cladribine in elderly MS. [ABSTRACT FROM AUTHOR]

We performed a pilot trial investigating the effect of a steroid taper on adrenal function and safety measures after acute MS relapses. Twenty-five patients were randomized to either prednisone taper (n=12) or placebo (n=13) after 3 days of intravenous methylprednisolone. No patient showed signs of adrenal insufficiency at any time by cortisol response to ACTH. This significantly increased between baseline and 6 months in both groups. Patients remained clinically and radiologically stable, but those under prednisone taper experienced more frequently mood disorders, hyperglycaemia and weight increase. If confirmed by sufficiently powered studies, these results would question the need of a steroid taper following short-term intravenous methylprednisolone. [ABSTRACT FROM AUTHOR]

• Physiotherapy (PT) may alleviate multiple sclerosis symptoms, yet little is known about usage and barriers. • PT usage was studied based on self-reports of 1493 Swiss Multiple Sclerosis Registry participants. • PT usage was higher in persons with primary-progressive MS, higher symptom burden, or recent stays at a rehabilitation clinic. • No association between PT supply and percent PT users per Swiss canton was detected. • PT uptake differences were observed by language region, which warrant further investigations. Physiotherapy may alleviate many multiple sclerosis (MS) symptoms, yet very little is known about physiotherapy accessibility and possible barriers in persons with MS (pwMS). We therefore aimed to elucidate physiotherapy use and possible access-barriers using data from 1493 pwMS from the Swiss Multiple Sclerosis Registry (SMSR), a patient-centered, longitudinal, observational MS study. We used data of the SMSR to investigate the question at hand in a multivariable logistic regression model with regularly receiving physiotherapy (yes/no) as the outcome. Potential explanatory variables were investigated following an AIC-driven model selection approach and consisted of a priori specified socio-demographic variables, health status, and personal or social mobility variables. As a last step, the impact of physiotherapist supply on regular use was assessed in the final model. Missing data were handled by multiple imputation (main analysis), and complete case sensitivity analyses were performed. The main analysis included 1493 participants. In the multivariable logistic regression, positive associations were found between the use of physiotherapy and the following variables: having a primary-progressive MS (Odds Ratio (OR) [95% Confidence Intervals] 1.97 [1.18; 3.29]), being more severely impaired (EDSS 4-6.5 OR 1.84 [1.16; 2.91]), higher number of current symptoms (1 OR 3.31 [1.63; 6.74], 2-3 OR 3.43 [1.8; 6.53], 4-5 OR 4.44 [2.28; 8.66], 6-7 OR 4.06 [1.90; 8.70], 8-9 OR 3.87 [1.71; 8.75], being on disability pension (OR 1.75 [1.24; 2.46], or having applied for it OR 2.25 [1.31; 3.85]), having gait problems (OR 1.58 [1.11; 2.23]), having been in a rehabilitation clinic in the past 12 months (OR 4.43 [2.17; 9.03]), and currently being on disease-modifying treatment (OR 1.61 [1.12; 2.31]). Negative associations were found for a higher quality of life (OR 0.92 [0.85; 0.98]), working more than 80% (OR 0.47 [0.30; 0.75]) and being from the French language region (OR 0.66 [0.47; 0.94]). No association between physiotherapist supply and regular physiotherapy use was detected. In a large, Swiss-based MS population, little evidence for socio-demographic barriers to physical therapy was found. Physiotherapy uptake was higher among pwMS with more impairments, lower health-related quality of life, or who have been discharged recently from inpatient rehabilitation. The uptake differences by language region warrant further investigations. [ABSTRACT FROM AUTHOR]

Clinician-assessed Expanded Disease Status Scale (EDSS) is gold standard in clinical investigations but normally unavailable in population-based, patient-centred MS-studies. Our objective was to develop a self-reported gait measure reflecting EDSS-categories. We developed the self-reported disability status scale (SRDSS) with three categories (≤3.5, 4–6.5, ≥7) based on three mobility-related questions. The SRDSS was determined for 173 persons with MS and validated against clinical EDSS to calculate sensitivity and specificity. Accuracy was 88.4% (153 correctly classified) and weighted kappa 0.73 (0.62–0.84). Sensitivity/specificity-pairs were 94.5%/77.8%, 69.0%/94.7% and 100%/98.2% for SRDSS ≤3.5, 4–6.5 and ≥7, respectively. Self-reported SRDSS approximates EDSS-categories well and fosters comparability between clinical and population-based studies. [ABSTRACT FROM AUTHOR]

• Treatment of a patient with MS rebound after fingolimod withdrawal. • Immune gene profiling showed rapid effects of rituximab on the T cell transcriptome. • Rituximab leads to the normalization of T cell responses even after severe rebound. Discontinuation of disease-modifying therapy with fingolimod can lead to severe Multiple Sclerosis (MS) rebound activity; however, this phenomenon remains mechanistically incompletely understood, and the short-term impact of a therapy switch on inflammatory gene expression in T lymphocytes is unknown. We present the clinico-radiological and immunological description of a case of rebound activity after fingolimod discontinuation and switching to rituximab treatment in a relapsing-remitting MS patient. After severe rebound, a reduction in the expression of inflammatory cytokines and transcription factors was rapidly observed after administration of methylprednisolone and rituximab. Rituximab led to an effective suppression of inflammatory activity, and at least in this specific case it represented a valid switching approach after fingolimod discontinuation. [ABSTRACT FROM AUTHOR]

Neurological conditions represent an important driver of paediatric disability burden worldwide. Measurement of serum neurofilament light chain (sNfL) concentrations, a specific marker of neuroaxonal injury, has the potential to contribute to the management of children with such conditions. In this context, the European Medicines Agency recently declared age-adjusted reference values for sNfL a top research priority. We aimed to establish an age-adjusted sNfL reference range database in a population of healthy children and adolescents, and to validate this database in paediatric patients with neurological conditions to affirm its clinical applicability. To generate a paediatric sNfL reference dataset, sNfL values were measured in a population of healthy children and adolescents (aged 0–22 years) from two large cohorts in Europe (the Coronavirus Antibodies in Kids from Bavaria study, Germany) and North America (a US Network of Paediatric Multiple Sclerosis Centers paediatric case-control cohort). Children with active or previous COVID-19 infection or SARS-CoV-2 antibody positivity at the time of sampling, or a history of primary systemic or neurological conditions were excluded. Linear models were used to restrospectively study the effect of age and weight on sNfL concentrations. We modelled the distribution of sNfL concentrations as a function of age-related physiological changes to derive reference percentile and Z score values via a generalised additive model for location, scale, and shape. The clinical utility of the new reference dataset was assessed in children and adolescents (aged 1–19 years) with neurological diseases (epilepsy, traumatic brain injury, bacterial CNS infections, paediatric-onset multiple sclerosis, and myelin oligodendrocyte glycoprotein antibody-associated disease) from the paediatric neuroimmunology clinic at the University of California San Francisco (San Francisco, CA, USA) and the Children's Hospital of the University of Regensburg (Regensburg, Germany). Samples from 2667 healthy children and adolescents (1336 [50·1%] girls and 1331 [49·9%] boys; median age 8·0 years [IQR 4·0–12·0]) were used to generate the reference database covering neonatal age to adolescence (target age range 0–20 years). In the healthy population, sNfL concentrations decreased with age by an estimated 6·8% per year until age 10·3 years (estimated multiplicative effect per 1 year increase 0·93 [95% CI 0·93–0·94], p<0·0001) and was mostly stable thereafter up to age 22 years (1·00 [0·52–1·94], p>0·99). Independent of age, the magnitude of the effect of weight on sNfL concentrations was marginal. Samples from 220 children with neurological conditions (134 [60·9%] girls and 86 [39·1%] boys; median age 14·7 years [IQR 10·8–16·5]) were used to validate the clinical utility of the reference Z scores. In this population, age-adjusted sNfL Z scores were higher than in the reference population of healthy children and adolescents (p<0·0001) with higher effect size metrics (Cohen's d =1·56) compared with the application of raw sNfL concentrations (d =1·28). The established normative sNfL values in children and adolescents provide a foundation for the clinical application of sNfL in the paediatric population. Compared with absolute sNfL values, the use of sNfL Z score was associated with higher effect size metrics and allowed for more accurate estimation of the extent of ongoing neuroaxonal damage in individual patients. Swiss National Science Foundation, US National Institutes of Health, and the National Multiple Sclerosis Society. [ABSTRACT FROM AUTHOR]

Objective: To compare and characterize major depressive disorder (MDD) subtypes (i.e., pure atypical, pure melancholic and mixed atypical-melancholic) and depression symptoms in persons with multiple sclerosis (PwMS) with persons without MS (Pw/oMS) fulfilling the DSM-5 criteria for a past 12-month MDD.Methods: MDD in PwMS (n = 92) from the Swiss Multiple Sclerosis Registry was compared with Pw/oMS (n = 277) from a Swiss community-based study. Epidemiological MDD diagnoses were based on the Mini-SPIKE (shortened form of the Structured Psychopathological Interview and Rating of the Social Consequences for Epidemiology). Logistic and multinomial regression analyses (adjusted for sex, age, civil status, depression and severity) were computed for comparisons and characterization. Latent class analysis (LCA) was conducted to empirically identify depression subtypes in PwMS.Results: PwMS had a higher risk for the mixed atypical-melancholic MDD subtype (OR = 2.22, 95% CI = 1.03-4.80) compared to Pw/oMS. MDD in PwMS was specifically characterized by a higher risk of the two somatic atypical depression symptoms 'weight gain' (OR = 6.91, 95% CI = 2.20-21.70) and 'leaden paralysis' (OR = 3.03, 95% CI = 1.35-6.82) and the symptom 'irritable/angry' (OR = 3.18, 95% CI = 1.08-9.39).Conclusions: MDD in PwMS was characterized by a higher risk for specific somatic atypical depression symptoms and the mixed atypical-melancholic MDD subtype. The pure atypical MDD subtype, however, did not differentiate between PwMS and Pw/oMS. Given the high phenomenological overlap with MS symptoms, the mixed atypical-melancholic MDD subtype represents a particular diagnostic challenge. [ABSTRACT FROM AUTHOR]