Association of Disease-Modifying Treatment With Outcome in Patients With Relapsing Multiple Sclerosis and Isolated MRI Activity.

BACKGROUND AND OBJECTIVES: Isolated value of MRI metrics in relapsing multiple sclerosis (RMS) as a surrogate marker of response to disease-modifying treatment (DMT) and, thus, as decision criteria for DMT escalation in the absence of clinical signs of disease activity is still a matter of debate. The aim of this study was to investigate whether DMT escalation based on isolated MRI activity affects clinical outcome. METHODS: Combining data from 5 MS centers in Austria and Switzerland, we included patients with RMS aged at least 18 years who (1) had initiated first-line, low-to-moderate-efficacy DMT (interferon ß, glatiramer acetate, teriflunomide, or dimethyl fumarate) continued for ≥12 months, (2) were clinically stable (no relapses or disability progression) on DMT for 12 months, (3) had MRI at baseline and after 12 months on DMT, and (4) had available clinical follow-up for ≥2 years after the second MRI. The primary endpoint was occurrence of relapse during follow-up. The number of new T2 lesions (T2L) and DMT strategy (continuing low-/moderate-efficacy DMT vs escalating DMT) were used as covariates in regression analyses. RESULTS: A total of 131 patients with RMS, median age of 36 (25th-75th percentiles: 29-43) years, 73% women, were included and observed over a median period of 6 (5-9) years after second MRI. Sixty-two (47%) patients had relapse. Patients who continued first-line DMT had a 3-fold increased risk of relapse given 2 new T2L (hazard ratio [HR] 3.2, lower limit [LL] of 95% CI: 1.5) and a 4-fold increased risk given ≥3 new T2L (HR 4.0, LL-CI: 2.1). Escalation of DMT lowered the risk of relapse in patients with 2 new T2L by approximately 80% (HR 0.2, upper limit [UL] of 95% CI: 1.3) and with ≥3 new T2L by 70% (HR 0.3, UL-CI: 0.8). In case of only 1 new T2L, the increased risk of relapse and the treatment effect did not reach statistical significance of 5%. DISCUSSION: In our real-world cohort of patients clinically stable under low-to-moderate-efficacy DMT, escalation of DMT based on isolated MRI activity decreased risk of further relapse when at least 2 new T2L had occurred. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that clinically stable patients with MS on low-/moderate-efficacy DMT with ≥3 new T2L on MRI who escalate DMT have a reduced risk of relapse and Expanded Disability Status Scale progression.

Sex impacts treatment decisions in multiple sclerosis.

BACKGROUND: Individual disease-modifying treatment (DMT) decisions might differ between female and male people with MS (pwMS). OBJECTIVE: To identify sex-related differences in DMT strategies over the past decades in a real-world setting. METHODS: In this cohort study, data from the Austrian Multiple Sclerosis Treatment Registry (AMSTR), a nationwide prospectively collected registry mandatory for reimbursement, were retrospectively analyzed. Of 4840 pwMS, those with relapsing-remitting MS, aged at least 18 years, who started DMT and had at least two clinical visits, were identified. At baseline, demographics, Expanded Disability Status Scale (EDSS) score, annualized relapse rate (ARR) in the prior 12 months and MRI lesion load were assessed. At follow-up, ARR, EDSS scores, and DMT were determined. RESULTS: A total of 4224 pwMS were included into the study and had a median of 10 (IQR 5-18) clinical visits over an observation period of 3.5 (IQR 1.5-6.1) years. Multivariable Cox regression analysis revealed that the probability of DMT escalation due to relapse activity was lower in female than male pwMS (HR 4.1 vs. 8.3 per ARR). Probability of discontinuing moderate-effective DMT was higher in female pwMS when they were younger (HR 1.03 per year), and lower in male pwMS at higher age (HR 0.92). Similarly, female pwMS were more likely to stop highly effective DMT than male pwMS (HR 1.7). Among others, the most frequent reason for DMT discontinuation was family planning in female pwMS. All sex-related effects were independent of disease activity, such as MRI lesion load, baseline ARR or EDSS. CONCLUSIONS: Real-world treatment decisions are influenced by sex-related aspects. Awareness of these associations should prevent unwarranted differences in MS care.

Drivers of spatio-temporal population dynamics of game species in a mountain landscape.

Since the end of the nineteenth century, socio-economic changes have greatly altered the Central European landscape and the structural and functional quality of habitats. Urban sprawl areas have appeared, a reduction of multiple forest uses has resulted in the densification of forests and agricultural land use has changed fundamentally through specialisation and intensification. Many of these changes affect biodiversity. To determine the important drivers of spatio-temporal dynamics of the population of 28 game species, we first considered a total of 130 potential explanatory variables. Second, we aggregated the main drivers of single-species models for habitat guilds. Third, we evaluated the results to aid in the development and implementation of mitigation measures for different ecoregions. We used harvest data as a surrogate for population density from 1875 to 2014 in South Tyrol, Italy. In generalised linear models, we used environmental characteristics such as climate, landscape diversity and structures, land cover, hunting, wildlife diseases, competition and predation, land-use type, and intensity (including pesticide use) as explanatory variables to predict the spatio-temporal dynamics of game species. The important drivers are land use and management changes (intensification in the agriculturally favourable areas, extensification or abandonment in the unfavourable areas) as well as associated changes in the landscape features, diversity and structure, and hunting management. Climatic variables, interspecific competition and diseases only play a subordinate role. The dynamics of the habitat guilds and their drivers provide concrete indications for measures to maintain or improve the habitat quality for the investigated species. Particularly important are transfer payments to ensure extensive agricultural use, increasingly through the takeover of personnel costs, but also for the installation of an independent body that monitors and evaluates the effectiveness of the measures.

Subarachnoid haemorrhage or traumatic lumbar puncture. Differentiation by cerebrospinal fluid parameters in a multivariable approach.

Lumbar puncture (LP) is recommended in patients with thunderclap headache and negative computed tomography to rule out spontaneous subarachnoid haemorrhage (SAH). Blood contamination of cerebrospinal fluid (CSF) due to traumatic LP poses a diagnostic dilemma. Therefore, routine CSF parameters were investigated to distinguish between SAH and a traumatic LP. CSF red blood cell (RBC), white blood cell (WBC) count, total protein, CSF colour and supernatant were used for group comparisons of patients with SAH and 'symptomatic controls'. Due to variable time intervals between bleeding onset and LP in SAH patients in contrast to patients with traumatic LP, where blood contamination of CSF occurs at the time of LP, CSF variables were adjusted for decay in time to allow comparability. Logistic regression analysis identified bloody CSF [odds ratio (OR) 32.6], xanthochromic supernatant [OR 15.5] and WBCadjusted [OR 4.5 (per increase of 100/µl)] as predictors of SAH, while age, sex and CSF total proteinadjusted were no predictors. Optimal cut-point of RBCadjusted (determined at day 1 after bleeding) was > 3667/µl to identify SAH patients with a 97% sensitivity and 94% specificity. Combination of low RBC and clear CSF supernatant was found in none of SAH patients. Combined CSF RBC count and CSF supernatant reliably distinguished traumatic LP from SAH.

Screening for osteoporosis in people with MS: A new risk score.

BACKGROUND: Due to the demographic development and improved treatment options, the role of comorbidities is of increasing importance in the medical care of people with MS (pwMS). A higher risk of osteoporosis is well known in chronic autoimmune diseases, and is also described in MS. While there are several screening guidelines in the elderly or in patients with rheumatoid arthritis, there are no generally accepted recommendations when to perform bone mineral testing in pwMS under the age of 65 years. We aimed to determine risk factors of osteoporosis in pwMS and to develop a risk score which can be applied in daily clinical routine. METHODS: Densitometry (hip and lumbar spine) was performed in 159 pwMS aged ≤65 years and in 81 age- and sex-matched healthy controls (HC). Osteoporosis was defined according to WHO criteria as a bone density 2.5 standard deviation or more below the mean of young adults. Risk factors were identified by logistic regression analysis. RESULTS: Osteoporosis occurred more frequently in postmenopausal pwMS and male pwMS as compared to HC. Besides age, sex, menopausal status in females, body-mass-index and smoking, a higher degree of disability - as assessed by the Expanded Disability Status Scale - was identified as MS specific risk factor for osteoporosis, whereas the cumulative glucocorticoid dose was not associated with osteoporosis risk. Based on these risk factors, we developed an MS-specific risk score which allows to estimate the individual probability of osteoporosis. CONCLUSION: This risk score enables individual screening recommendation for pwMS and, subsequently, early prevention of osteoporosis which probably should result in reduction of fractures and morbidity.

Kappa free light chain and neurofilament light independently predict early multiple sclerosis disease activity-a cohort study.

BACKGROUND: Inter-individual courses of multiple sclerosis (MS) are extremely variable. The objective of this study was to investigate whether κ-free light chain (κ-FLC) index and serum neurofilament light (sNfL) have an additive predictive value for MS disease activity. METHODS: Patients with early MS who had cerebrospinal fluid (CSF) and serum sampling at disease onset were followed for four years. At baseline, age, sex, disease duration, number of T2-hyperintense (T2L), and contrast-enhancing T1 lesions (CEL) on MRI were determined. During follow-up, the occurrence of a second clinical attack and start of disease-modifying treatment (DMT) were registered. κ-FLC was measured by nephelometry, and κ-FLC index calculated as [CSF κ-FLC/serum κ-FLC]/albumin quotient. sNfL was determined by single-molecule array, and age- and body-mass-index adjusted Z scores were calculated. FINDINGS: A total of 86 patients at a mean age of 33 ± 10 years and with a female predominance of 67% were included; 36 (42%) patients experienced a second clinical attack during follow-up. Cox regression analysis adjusted for age, sex, T2L, CEL, disease and follow-up duration, and DMT use during follow-up revealed that both κ-FLC index as well as sNfL Z score independently predict time to second clinical attack. The chance for freedom of relapse within 12 months was 2% in patients with high levels of κ-FLC index (>100) and high sNfL Z score (>3), 30% in patients with high κ-FLC index (>100) and lower sNfL Z score (≤3), 70% in patients with lower κ-FLC index (≤100) but high sNfL Z score (>3), and 90% in patients with lower levels of κ-FLC index (≤100) and sNfL Z score (≤3). INTERPRETATION: κ-FLC index and sNfL Z score have an additive predictive value for early MS disease activity that is independent of known predictors. FUNDING: This study was funded by a grant of the charitable foundation of the Austrian Multiple Sclerosis Society.

Sexual dysfunction in female and male people with multiple sclerosis: disability, depression and hormonal status matter.

BACKGROUND AND PURPOSE: Sexual dysfunction (SD) in people with multiple sclerosis (pwMS) is common and an often underestimated issue in the care of pwMS. The objective of the study was to evaluate risk factors for SD in pwMS, correlate its prevalence with patient-reported measures (quality of life and physical activity) and analyse its association with hormonal status. METHODS: Sexual dysfunction was determined in 152 pwMS using the Multiple Sclerosis Intimacy and Sexuality Questionnaire 19. A logistical regression model was used to identify independent risk factors for SD. RESULTS: The prevalence of SD in pwMS was 47%. Independent risk factors for the development of SD were ever-smoking (odds ratio [OR] 3.4, p = 0.023), disability as measured by the Expanded Disability Status Scale (OR 2.0, p < 0.001), depression (OR 4.3, p = 0.047) and bladder and bowel dysfunction (OR 8.8, p < 0.001); the use of disease-modifying treatment was associated with a lower risk for SD (OR 0.32, p = 0.043). SD was associated with worse quality of life (Multiple Sclerosis Impact Scale 29: physical score 6.3 vs. 40.0; psychological score 8.3 vs. 33.3; both p < 0.001) and lower physical activity (Baecke questionnaire, p < 0.001). Laboratory analysis revealed significantly higher luteinizing hormone and follicle-stimulating hormone levels and lower 17-beta oestradiol, androstenedione, dehydroepiandrosterone sulfate, oestrone and anti-Mullerian hormone levels in female pwMS with SD. In male pwMS and SD, there was a significant decrease in inhibin B levels. CONCLUSIONS: Our findings highlight the requirement of a holistic approach to SD in MS including physical, neurourological and psychosocial factors. Active screening for SD, especially in patients with disability, depression or bladder and bowel dysfunction, is recommended.

Cerebrospinal fluid kappa free light chains for the diagnosis of multiple sclerosis: A systematic review and meta-analysis.

BACKGROUND: Intrathecal immunoglobulin-G synthesis is a hallmark of multiple sclerosis (MS), which can be detected by oligoclonal IgG bands (OCB) or by κ-free light chains (κ-FLC) in cerebrospinal fluid. OBJECTIVE: To perform a systematic review and meta-analysis to evaluate whether κ-FLC index has similar diagnostic value to identify patients with clinically isolated syndrome (CIS) or MS compared to OCB, and to determine κ-FLC index cut-off. METHODS: PubMed was searched for studies that assessed diagnostic sensitivity and specificity of κ-FLC index and OCB to discriminate CIS/MS patients from control subjects. Two reviewers following preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines performed study eligibility assessment and data extraction. Findings from studies were analyzed with bivariate mixed models. RESULTS: A total of 32 studies were included in the meta-analysis to evaluate diagnostic value of κ-FLC index. Sensitivity and specificity ranged from 52% to 100% (weighted average: 88%) and 69% to 100% (89%) for κ-FLC index and from 37% to 100% (85%) and 74% to 100% (92%) for OCB. Mean difference of sensitivity and specificity between κ-FLC index and OCB was 2 and -4 percentage points. Diagnostic accuracy determined by mixed models revealed no significant difference between κ-FLC index and OCB. A discriminatory cut-off for κ-FLC index was determined at 6.1. CONCLUSION: The findings indicate that κ-FLC index has similar diagnostic accuracy in MS as OCB.

Chasing shadows: Cytologically detected shadow cells in the cerebrospinal fluid of patients with multiple sclerosis.

BACKGROUND: Pathophysiology of multiple sclerosis (MS) is dominated by both inflammation and neurodegeneration. A correlation between inflammation and regulated cell death has been suggested previously. Shadow cells in the cerebrospinal fluid (CSF) are considered apoptotic cells. OBJECTIVE: To assess the occurrence of shadow cells in MS patients in comparison to other neurological diseases (OND). METHODS: We conducted cytological examination of CSF in 114 MS patients and 125 patients with OND, who had diagnostic lumbar puncture at the Department of Neurology, Medical University of Innsbruck, with time to laboratory processing ≤0.5 h, showed a CSF white blood cell (WBC) count ≤50/µl and a red blood cell (RBC) count ≤500/µl. Shadow cells were counted by two blinded, independent, experienced investigators, using a standardized approach on microscopic slides. RESULTS: The number of shadow cells did not statistically significantly differ between patients with MS (median: 12, IQR: 0-85) and OND (median 6, IQR: 0-94; p = 0.106). Multivariable regression analysis including age, sex, time to laboratory processing, CSF WBC and RBC count, CSF/serum glucose ratio, CSF/serum albumin quotient and disease group as independent variables, identified WBC count as significant predictor of shadow cells (ß [ln WBC count]=0.73, p<10-9), whereas the disease group had no impact (p = 0.466). CONCLUSIONS: Occurrence of shadow cells in the CSF seems to depend on the extent of inflammatory cells rather than MS disease-specific mechanisms.

Freeze dehydration vs. supercooling of mesophyll cells: Impact of cell wall, cellular and tissue traits on the extent of water displacement.

The extent of freeze dehydration of mesophyll cells in response to extracellular ice varies from supercooling to severe freezing cytorrhysis. The structural factors involved are poorly understood. In a comparison of mesophyll cells of 11 species, the factors "cell wall", "cellular" and "tissue" traits were investigated. The extent of freeze dehydration was quantified as reduction in the sectional area during controlled freezing in the presence of ice. The cell wall thickness, cell size, cell area and the relative area of intercellular spaces were determined. The modulus of elasticity was determined by psychrometry. To grasp the relationships between factors and with freeze dehydration, we applied a principal component analysis. The first two components explain 84% of the variance in the dataset. The first principal component correlated negatively with the extent of freeze dehydration and relative area of intercellular spaces, and positively with the squared cell wall thickness to cell size ratio, elasticity and cell wall thickness. The cell size parameters determined the second principal component. Supercooling appeared preferable in cells with a high squared cell wall thickness to cell size ratio and a low relative area of intercellular spaces. Such factors are hypothesised to affect the magnitude of negative turgor pressure being built up below the turgor loss point. Negative turgor pressure slows dehydration by reducing the water potential gradient to the extracellular ice. With high levels of freeze dehydration, sufficient intercellular spaces for extracellular ice accommodation are needed. The low relative area of intercellular spaces increases cell-to-cell contact area and could support tissue stability.

Longitudinal ventricular cerebrospinal fluid profile in patients with spontaneous subarachnoid hemorrhage.

Background: Spontaneous subarachnoid hemorrhage (SAH) is a severe neurological disease that frequently requires placement of external ventricular drainage (EVD). Cerebrospinal fluid (CSF) obtained via the drain is used to detect potential complications of SAH. Objective: This study aimed to describe the longitudinal profile of routine CSF parameters in patients with SAH and to identify associations with neurological complications. Methods: A total of thirty-three patients with spontaneous SAH who required an EVD and had at least three consecutive CSF samples collected over a period of more than 7 days were included in this study. Results: A median of 6 longitudinally collected CSF samples per patient were available within 1-22 days after SAH onset. Overall, red blood cells (RBC) steadily decreased over time, whereas white blood cells (WBC) and total protein (TP) increased until days 6 and 13, respectively, and decreased thereafter. The estimated decay rates of RBC, WBC, and TP were 28, 22, and 6% per day. Distinct CSF patterns over time were linked to known complications after SAH. Patients with rebleeding showed increased RBC, TP, and phagocytosing cells compared to patients without re-bleeding. For ventriculitis, an elevated cell index with a higher proportion of granulocytes was characteristic. CSF of patients with delayed cerebral ischemia showed increased RBC and WBC compared to patients without DCI. Early CSF WBC and cell index were predictive for the occurrence of DCI and ventriculitis later during the disease course. The amount of daily CSF drainage via EVD had no impact on routine CSF parameters. Conclusion: Longitudinal CSF characteristics are associated with SAH-related complications.

A first attempt at a holistic analysis of various influencing factors on the fish fauna in the Eastern European Alps.

Fish are some of the most threatened vertebrates in the world due to their often-sensitive response to environmental changes. Major land-use changes in the European Alps have direct and indirect impacts on fish communities, and these impacts are expected to increase in the future. Therefore, the identification of factors that are associated with the distribution of fish communities is of great importance to develop guidelines for management, precautions and sustainable use of running waters. In this study, the relationship of various factors - landscape structure and land use, topography, morphology, hydrology, physical and chemical water characteristics, hormonally active substances, pesticides, food availability, fisheries and piscivores birds - with fish assemblages are analysed. Field data from 81 stream sections from 2001 metres above sea level (m.a.s.l.) down to 219 m.a.s.l. are used in the study. The results reveal that the number of fish species has a strong association with topographic characteristics in the catchment area as well as with landscape configuration. Fish abundance and biomass are associated mostly with land-use type, hydrology, morphology as well as topography. In addition, there are indirect connections between fish abundance and biomass through land-use type, topography, water properties and hydromorphology. The results clearly indicate that not a single factor, but a multitude of factors are associated with the fish communities in the Eastern European Alps.

Small matching grants for women entrepreneurs: lessons from the past recession.

During the economic slowdown caused by the financial crisis in 2008, grants for entrepreneurs were made available to support economic development. Whether such a policy instrument is effective for business development is a highly relevant question in the aftermath of the COVID-19. We evaluate the causal effects of small business development matching grants using a quasi-experimental approach. The grants were exclusively targeted to women entrepreneurs and provided during the recession after the financial crisis. Our findings demonstrate an increase in bank loans and a positive impact on turnover, value-added, capital, employment, and overall factor productivity for more experienced women entrepreneurs. As the grants are too small to have direct economic effects or indirect effects via the certification effect, they alleviate time and information constraints of women entrepreneurs. The cost-benefit analysis shows an increase in value-added that outweighs the scheme-related costs. Plain English Summary This study evaluates the effect of small public grants for women entrepreneurs. Grants were used for childcare and business consultancy costs to alleviate time and information constraints of women entrepreneurs. Benefiting from these grants resulted in higher bank loans. The women entrepreneurs on average invested more money in capital and had better performance measures like turnover and value-added. The effect was particularly evident among more experienced women entrepreneurs. The cost-benefit analysis shows grant-induced increase in value-added outweighs the scheme-related costs. The study implies small public grants for women entrepreneurs increase small firms' growth, and these grants are in addition a cost-effective policy tool.

Evidence for the importance of land use, site characteristics and vegetation composition for rooting in European Alps.

Plant rooting strongly affects most hydrological, biogeochemical and ecological processes in terrestrial ecosystems, as it presents the main pathway for carbon, water and nutrient transfer from soil to the atmosphere and is a key factor in stabilizing the soil layer. Few studies have actually investigated the link between phytosociological and structural vegetation composition and diversity in soil rooting parameters. Our study provides a comprehensive evaluation of plant cover and diversity effects on rooting parameters dependent on different land-use types along a north-south transect in the Eastern Alps. We conducted field studies of root biomass, rooting density and rooting depth for the six main land-use types: intensively and lightly used hay meadows, pastures, arable land, agriculturally unused grasslands and forests. The variation in rooting parameters was explained by different aspects of species and functional richness, species and functional composition, functional traits, abundance of key species and site variables depending on the land-use types. Our results showed that different characteristics of biodiversity explained the variance in root parameters (mass, density and depth) to a high degree (determination coefficient R2 values varied between 0.621 and 0.891). All rooting parameters increased with increasing plant species richness, as well as with a higher diversity of plant functional traits. The inclusion of site parameters significantly increased the explained variance, while we could not find evidence for key species and their abundance to provide additional explanatory power. Allowing the effects to vary depending on land-use types turned out to be a necessity supporting the importance of considering land-use types for rooting. The findings indicate that vegetation composition has a clear relationship with rooting parameters across different habitats in the European Alps. As the effect of plant composition differs with respect to the land-use type, rooting can be monitored by land management to achieve the desired benefits. For example, intensified rooting through extensive management decreases erosion risk and increases carbon uptake.

Kappa-Free Light Chains in CSF Predict Early Multiple Sclerosis Disease Activity.

OBJECTIVE: To investigate whether κ-free light chain (κ-FLC) index predicts multiple sclerosis (MS) disease activity independent of demographics, clinical characteristics, and MRI findings. METHODS: Patients with early MS who had CSF and serum sampling at disease onset were followed for 4 years. At baseline, age, sex, type of symptoms, corticosteroid treatment, and number of T2 hyperintense (T2L) and contrast-enhancing T1 lesions (CELs) on MRI were determined. During follow-up, the occurrence of a second clinical attack and start of disease-modifying therapy (DMT) were registered. κ-FLCs were measured by nephelometry, and κ-FLC index calculated as [CSF κ-FLC/serum κ-FLC]/albumin quotient. RESULTS: A total of 88 patients at a mean age of 33 ± 10 years and female predominance of 68% were included; 38 (43%) patients experienced a second clinical attack during follow-up. In multivariate Cox regression analysis adjusting for age, sex, T2L, CEL, disease and follow-up duration, administration of corticosteroids at baseline and DMT during follow-up revealed that κ-FLC index predicts time to second clinical attack. Patients with κ-FLC index >100 (median value 147) at baseline had a twice as high probability for a second clinical attack within 12 months than patients with low κ-FLC index (median 28); within 24 months, the chance in patients with high κ-FLC index was 4 times as high as in patients with low κ-FLC index. The median time to second attack was 11 months in patients with high κ-FLC index whereas 36 months in those with low κ-FLC index. CONCLUSION: High κ-FLC index predicts early MS disease activity. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with early MS, high κ-FLC index is an independent risk factor for early second clinical attack.

Cerebrospinal fluid protein in Guillain-Barré syndrome: Need for age-dependent interpretation.

BACKGROUND AND PURPOSE: Elevated cerebrospinal fluid (CSF) total protein in patients with acute ascending paresis is indicative of Guillain-Barré syndrome (GBS). Recent studies showed that the outdated, but still widely used upper reference limit (URL) for CSF total protein of 0.45 g/L leads to false-positive results, mainly as a result of lack of age-adjustment. The objective of this study was to assess the frequency of increased CSF total protein in adult GBS patients according to a new age-dependent URL. METHODS: Patients with GBS treated at the Medical University of Innsbruck between 2000 and 2018 were included in this study. Demographic, clinical, electrophysiological and CSF data were obtained from patients' medical charts. Frequency of increased CSF total protein depending on disease duration was compared using the conventional URL of 0.45 g/L and the age-dependent URL. RESULTS: Ninety-seven patients with GBS aged 57 ± 18 years, comprising 38% women, underwent CSF sampling within a median of 6 days after symptom onset. The median CSF total protein concentration was 0.65 g/L and correlated with disease duration. Overall, 74% of patients had elevated CSF total protein levels using the conventional URL, as opposed to 52% applying the age-dependent URL. At 0-3, 4-7, 8-14 and >14 days after disease onset, elevated CSF total protein was found in 46%, 84%, 78% and 100% of patients using the conventional URL, and in 32%, 53%, 65% and 64% of patients using the age-dependent URL. In multivariate analysis, significant predictors of elevated CSF total protein were disease duration and the demyelinating GBS variant. Similar results were obtained for CSF/serum albumin quotient (Qalb ). CONCLUSION: Fewer true-positives for CSF total protein and Qalb must be considered in suspected GBS, especially in the early disease course.

Free light chains in the cerebrospinal fluid. Comparison of different methods to determine intrathecal synthesis.

Background Free light chains (FLC) have been proposed as diagnostic biomarkers in the cerebrospinal fluid (CSF) of patients with inflammatory central nervous system (CNS) diseases. However, which method to use for determining an intrathecal FLC synthesis has not yet been clarified. The objective of this study was to compare the diagnostic performance of CSF FLC concentration, FLC quotient (QFLC), FLC index and FLC intrathecal fraction (FLCIF). Methods κ- and λ-FLC were measured by nephelometry under blinded conditions in CSF and serum sample pairs of patients with clinically isolated syndrome (CIS; n = 60), multiple sclerosis (MS; n = 60) and other neurological diseases (n = 60) from four different MS centers. QFLC was calculated as the ratio of CSF/serum FLC concentration, the FLC index as QFLC/albumin quotient and the percentage FLCIF by comparing QFLC to a previously empirically determined, albumin quotient-dependent reference limit. Results CSF FLC concentration, QFLC, FLC index and FLCIF of both the κ- and λ-isotype were significantly higher in patients with CIS and MS than in the control group, as well as in oligoclonal bands (OCB) positive than in OCB negative patients. Each parameter was able to identify MS/CIS patients and OCB positivity, however, diagnostic performance determined by receiver operating characteristic (ROC) analyses differed and revealed superiority of FLC index and FLCIF. Conclusions These findings support the diagnostic value of FLC measures that correct for serum FLC levels and albumin quotient, i.e. blood-CSF barrier function.

How Bispectral Index Compares to Spectral Entropy of the EEG and A-line ARX Index in the Same Patient.

BACKGROUND: Bispectral index (BIS) monitoring of depth of anesthesia has pioneered the field for more recent monitoring devices like the A-line ARX Index (AAI) or the state (SE) and response entropy (RE) monitoring devices. Following an observational design the present study aimed to simultaneously compare in the same patient recorded BIS, AAI and entropy values. METHODS: Data from patients (n = 32) undergoing minor gynecological operations were analyzed. For all patients, standardized anesthesia was used. Before induction of anesthesia AEP electrodes, BIS and entropy sensors were simultaneously placed on the forehead and recordings were started at 3 minutes before induction and continued until patient transfer to the postanesthesia care unit. Markers were set at defined landmarks. RESULTS: Anesthesia reduced mean BIS, AAI and entropy values. During uneventful, and even more pronounced, during eventful anesthesia BIS/ entropy and BIS/ AAI values showed better correlation than did AAI and entropy values. The prediction probability (Pk) of AAI (0.824 ± 0.036) and RE (0.786 ± 0.040) or SE (0.781 ± 0.040) for preanesthesia awake, postanesthesia awake or anesthesia was comparable and significantly greater than that of BIS (0.705 ± 0.047). However, only 20% of BIS, AAI and entropy values simultaneously categorized the state of the patient as awake, inadequate anesthesia, optimal anesthesia or deep anesthesia. CONCLUSION: The prediction probability (Pk) of entropy and AAI was comparable and better than that of BIS. However, agreement between BIS, AAI and entropy measurements on patient state was poor.

Impact of Disease-Modifying Treatments on the Longitudinal Evolution of Anti-JCV Antibody Index in Multiple Sclerosis.

Background: Risk of natalizumab-related progressive multifocal leukoencephalopathy is associated with the presence of anti-JC-virus (JCV) antibodies. Objective: To investigate the impact of disease-modifying treatments (DMT) on the longitudinal evolution of anti-JCV antibody index. Methods: Patients with multiple sclerosis who had serum sampling at intervals of 6 ± 3 months over up to 6 years and who either started DMT (interferon-ß, glatiramer acetate or natalizumab) during the observation period with at least one serum sample available before and after treatment initiation or received no DMT during the observation period were included. Anti-JCV antibody serological status and index were determined by 2-step second-generation anti-JCV antibody assay. Results: A total of 89 patients were followed for a median time of 55.2 months. Of those, 62 (69.7%) started DMT and 27 (30.3%) were without therapy during the observation period. Variation of longitudinal anti-JCV antibody index ranged from 9 to 15% and was similar in patients with and without DMT. Applying a mixed model considering the combined effects of treatment and time as well as individual heterogeneity did not show a significant change of anti-JCV antibody index by the start of treatment with interferon-ß, glatiramer acetate, or natalizumab. Conclusion: Evaluated DMTs do not impact longitudinal anti-JCV antibody index evolution.

Do the Youth Olympic Games promote Olympism? Analysing a mission (im)possible from a local youth perspective.

On the basis of the Youth Olympic Games (YOG), we assess if and how the youth in the communities of the YOG host cities have been influenced concerning their perception of the Olympic values (OV) and the Olympic movement (OM). Special attention of the study is paid to the analysis of intervention mechanisms which the local youth underwent (e.g. attending the YOG on-site, participating in school programmes). Our study was conducted among 1004 adolescents living in the host region three years after the Innsbruck 2012 YOG had been staged. Our analyses extend the corresponding literature by (1) showing that the YOG and the involvement of the local youth in such an event have the power of creating an interest in the OM and its events, but do not have the power to influence the young citizens' perception of the OV significantly; (2) illustrating that the perception adolescents have of the OV depend mainly on their socio-demographic background, their a priori interest in sports events, social capital (norms, institutional trust) and the extent to which the youngsters follow the event in the different media; and (3) corroborating the hypothesis that intervention programmes (e.g. school programmes) for promoting (Olympic) values and ideals should not be single, obligatory and isolated activities. We conclude that it is not surprising that the International Olympic Committee has reformulated the goals for the YOG in the Olympic Agenda 2020, as some goals relating to the promotion of the OV might have been a mission impossible.