Comparative analysis of dimethyl fumarate and teriflunomide in relapsing-remitting multiple sclerosis.

BACKGROUND AND PURPOSE: In relapsing-remitting multiple sclerosis (RRMS), analyses from observational studies comparing dimethyl fumarate (DMF) and teriflunomide showed conflicting results. We aimed to compare the effectiveness of DMF and teriflunomide in a real-world setting, where both drugs are licensed as first-line therapies for RRMS. METHODS: We included all patients who initiated DMF or teriflunomide between 2013 and 2022, listed in the Swiss National Treatment Registry. Coarsened exact matching was applied using age, gender, disease duration, baseline Expanded Disability Status Scale (EDSS) score, time since last relapse, and relapse rate in the previous year as matching variables. Time to relapse and time to 12-month confirmed EDSS worsening were compared using Cox proportional hazard models. RESULTS: In total, 2028 patients were included in this study, of whom 1498 were matched (DMF: n = 1090, 69.6% female, mean age 45.1 years, median EDSS score 2.0; teriflunomide: n = 408, 68.9% female, mean age 45.1 years, median EDSS score 2.0). Time to relapse and time to EDSS worsening was longer in the DMF than the teriflunomide group (hazard ratio 0.734, p = 0.026 and hazard ratio 0.576, p = 0.003, respectively). CONCLUSION: Analysis of real-world data showed that DMF treatment was associated with more favorable outcomes than teriflunomide treatment.

Longitudinal reliability of outcome measures in patients with Duchenne muscular dystrophy.

INTRODUCTION: The definition of reliable outcome measures is of increasing interest in patients with Duchenne muscular dystrophy (DMD). METHODS: In this retrospective study, we analyzed the longitudinal reliability of clinical and radiological endpoints in 29 ambulant patients with DMD. Clinical outcome measures included motor function measure (MFM) and timed function tests, while quantitative MRI data were mean fat fraction (MFF) and T2 relaxation time of thigh muscles. Statistical analysis was based on 3-, 6-, and 12-month follow-up data. RESULTS: Quantitative MRI using the MFF was the most sensitive and powerful marker of disease progression with a sample size of four at 1-year follow-up, followed by the D1 domain of MFM (standing and transfer function) with a sample size of 12. DISCUSSION: Our data support the longitudinal design of clinical trials over at least 12 months and the combinational use of clinical and radiological surrogate outcome measures.

Rivaroxaban plasma levels in acute ischemic stroke and intracerebral hemorrhage.

OBJECTIVE: Information about rivaroxaban plasma level (RivLev) may guide treatment decisions in patients with acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH) taking rivaroxaban. METHODS: In a multicenter registry-based study (Novel Oral Anticoagulants in Stroke Patients collaboration; ClinicalTrials.gov: NCT02353585) of patients with stroke while taking rivaroxaban, we compared RivLev in patients with AIS and ICH. We determined how many AIS patients had RivLev ≤ 100ng/ml, indicating possible eligibility for thrombolysis, and how many ICH patients had RivLev ≥ 75ng/ml, making them possibly eligible for the use of specific reversal agents. We explored factors associated with RivLev (Spearman correlation, regression models) and studied the sensitivity and specificity of international normalized ratio (INR) thresholds to substitute RivLev using cross tables and receiver operating characteristic curves. RESULTS: Among 241 patients (median age = 80 years, interquartile range [IQR] = 73-84; median time from onset to admission = 2 hours, IQR = 1-4.5 hours; median RivLev = 89ng/ml, IQR = 31-194), 190 had AIS and 51 had ICH. RivLev was similar in AIS patients (82ng/ml, IQR = 30-202) and ICH patients (102ng/ml, IQR = 51-165; p = 0.24). Trough RivLev(≤137ng/ml) occurred in 126/190 (66.3%) AIS and 34/51 (66.7%) ICH patients. Among AIS patients, 108/190 (56.8%) had RivLev ≤ 100ng/ml. In ICH patients, 33/51 (64.7%) had RivLev ≥ 75ng/ml. RivLev was associated with rivaroxaban dosage, and inversely with renal function and time since last intake (each p < 0.05). INR ≤ 1.0 had a specificity of 98.9% and a sensitivity of 25.7% to predict RivLev ≤ 100ng/ml. INR ≥ 1.4 had a sensitivity of 59.3% and specificity of 90.1% to predict RivLev ≥ 75ng/ml. INTERPRETATION: RivLev did not differ between patients with AIS and ICH. Half of the patients with AIS under rivaroxaban had a RivLev low enough to consider thrombolysis. In ICH patients, two-thirds had a RivLev high enough to meet the eligibility for the use of a specific reversal agent. INR thresholds perform poorly to inform treatment decisions in individual patients. Ann Neurol 2018;83:451-459.

Serum Neurofilament light: A biomarker of neuronal damage in multiple sclerosis.

OBJECTIVE: Neurofilament light chains (NfL) are unique to neuronal cells, are shed to the cerebrospinal fluid (CSF), and are detectable at low concentrations in peripheral blood. Various diseases causing neuronal damage have resulted in elevated CSF concentrations. We explored the value of an ultrasensitive single-molecule array (Simoa) serum NfL (sNfL) assay in multiple sclerosis (MS). METHODS: sNfL levels were measured in healthy controls (HC, n = 254) and two independent MS cohorts: (1) cross-sectional with paired serum and CSF samples (n = 142), and (2) longitudinal with repeated serum sampling (n = 246, median follow-up = 3.1 years, interquartile range [IQR] = 2.0-4.0). We assessed their relation to concurrent clinical, imaging, and treatment parameters and to future clinical outcomes. RESULTS: sNfL levels were higher in both MS cohorts than in HC (p < 0.001). We found a strong association between CSF NfL and sNfL (ß = 0.589, p < 0.001). Patients with either brain or spinal (43.4pg/ml, IQR = 25.2-65.3) or both brain and spinal gadolinium-enhancing lesions (62.5pg/ml, IQR = 42.7-71.4) had higher sNfL than those without (29.6pg/ml, IQR = 20.9-41.8; ß = 1.461, p = 0.005 and ß = 1.902, p = 0.002, respectively). sNfL was independently associated with Expanded Disability Status Scale (EDSS) assessments (ß = 1.105, p < 0.001) and presence of relapses (ß = 1.430, p < 0.001). sNfL levels were lower under disease-modifying treatment (ß = 0.818, p = 0.003). Patients with sNfL levels above the 80th, 90th, 95th, 97.5th, and 99th HC-based percentiles had higher risk of relapses (97.5th percentile: incidence rate ratio = 1.94, 95% confidence interval [CI] = 1.21-3.10, p = 0.006) and EDSS worsening (97.5th percentile: OR = 2.41, 95% CI = 1.07-5.42, p = 0.034). INTERPRETATION: These results support the value of sNfL as a sensitive and clinically meaningful blood biomarker to monitor tissue damage and the effects of therapies in MS. Ann Neurol 2017;81:857-870.

Long-term results of revision total hip arthroplasty with a cemented femoral component.

INTRODUCTION: In revision total hip arthroplasty (THA), the cancellous bone is normally completely removed out of the femoral canal during stem extraction. This situation is comparable to primary THA following the shape-closed concept, with some authors advocating to remove the metaphyseal cancellous bone to enhance press-fit stability ("French paradox"). The aim of this study was to investigate the long-term outcome, regarding survival and radiological results, of a cemented straight stem when used for revision THA and to compare these results to the results of the same stem in primary THA. MATERIALS AND METHODS: 178 stem revisions performed between 01/1994 and 08/2008 using the Virtec straight stem were included. The cumulative incidence for re-revision was calculated using a competing risk model. Risk factors for re-revision of the stem were analyzed using an absolute risk regression model. Radiographs analyzed for osteolysis, debonding and subsidence had a minimum follow-up of 10 years. RESULTS: The cumulative incidence for re-revision due to aseptic loosening of the stem was 5.5% (95% CI, 2.9-10.2%) at 10 years. Aseptic loosening was associated with younger age, larger defect size and larger stem size. After a minimum 10-year follow-up, osteolysis was seen in 39 of 80 revision THA. Compared to the results in primary THA, the survival in revision THA with the same implant was inferior. CONCLUSIONS: Cemented straight stems used for revision THA showed excellent long-term results regarding survivorship and radiological outcome. This stem therefore offers a valuable and cost-effective option in revision THA.

Pharmacokinetics and pharmacodynamics of single doses of rivaroxaban in obese patients prior to and after bariatric surgery.

AIMS: Venous thromboembolism is an important cause of postoperative morbidity and mortality in bariatric surgery. Studies of direct oral anticoagulants (DOACs) are not available in this surgical field. The objective of this phase 1 clinical trial was to investigate pharmacokinetic and pharmacodynamic (PK/PD) parameters of rivaroxaban in bariatric patients. METHODS: In this single-centre study, obese patients received single oral doses of rivaroxaban (10 mg) 1 day prior to and 3 days after bariatric surgery. PK and PD parameters were assessed at baseline and during 24 h after drug ingestion. RESULTS: Six Roux-en-Y gastric bypass patients and six sleeve gastrectomy patients completed the study. Mean rivaroxaban area under plasma concentration-time curve, peak plasma concentration, time to peak plasma concentration and terminal half-life were 971.9 µg·h l-1 (coefficient of variation: 10.6), 135.3 µg l-1 (26.7), 1.5 h and 13.1 h (34.1) prior to and 1165.8 (21.9), 170.0 (15.9), 1.5 and 8.9 (44.6) postsurgery for SG patients and 933.7 µg·h l-1 (22.3), 136.5 µg l-1 (10.7), 1.5 h und 13.8 h (46.6) prior to and 1029.4 (7.4), 110.8 (31.8), 2.5 and 15 (60.0) postsurgery for Roux-en-Y gastric bypass patients, respectively. Prothrombin fragments (F1 + 2) decreased during the first 12 hours and increased thereafter in the pre- and the postbariatric setting. Thrombin-antithrombin complexes dropped within 1-3 h in the prebariatric setting and remained low after surgery until they increased at 24 h postdose. Rivaroxaban was well tolerated and no relevant safety issues were observed. CONCLUSIONS: Bariatric surgery does not appear to alter PK of rivaroxaban in a clinically relevant way. Effective prophylactic postbariatric anticoagulation is supported by changes in PD.

Generating evidence on a risk-based monitoring approach in the academic setting - lessons learned.

BACKGROUND: In spite of efforts to employ risk-based strategies to increase monitoring efficiency in the academic setting, empirical evidence on their effectiveness remains sparse. This mixed-methods study aimed to evaluate the risk-based on-site monitoring approach currently followed at our academic institution. METHODS: We selected all studies monitored by the Clinical Trial Unit (CTU) according to Risk ADApted MONitoring (ADAMON) at the University Hospital Basel, Switzerland, between 01.01.2012 and 31.12.2014. We extracted study characteristics and monitoring information from the CTU Enterprise Resource Management system and from monitoring reports of all selected studies. We summarized the data descriptively. Additionally, we conducted semi-structured interviews with the three current CTU monitors. RESULTS: During the observation period, a total of 214 monitoring visits were conducted in 43 studies resulting in 2961 documented monitoring findings. Our risk-based approach predominantly identified administrative (46.2%) and patient right findings (49.1%). We identified observational study design, high ADAMON risk category, industry sponsorship, the presence of an electronic database, experienced site staff, and inclusion of vulnerable study population to be factors associated with lower numbers of findings. The monitors understand the positive aspects of a risk-based approach but fear missing systematic errors due to the low frequency of visits. CONCLUSIONS: We show that the factors mostly increasing the risk for on-site monitoring findings are underrepresented in the current risk analysis scheme. Our risk-based on-site approach should further be complemented by centralized data checks, allowing monitors to transform their role towards partners for overall trial quality, and success.

Validity of mobile electronic data capture in clinical studies: a pilot study in a pediatric population.

BACKGROUND: Clinical studies in children are necessary yet conducting multiple visits at study centers remains challenging. The success of "care-at-home" initiatives and remote clinical trials suggests their potential to facilitate conduct of pediatric studies. This pilot aimed to study the feasibility of remotely collecting valid (i.e. complete and correct) saliva samples and clinical data utilizing mobile technology. METHODS: Single-center, prospective pilot study in children undergoing elective tonsillectomy at the University of Basel Children's Hospital. Data on pain scores and concomitant medication and saliva samples were collected by caregivers on two to four inpatient study days and on three consecutive study days at home. A tailored mobile application developed for this study supported data collection. The primary endpoint was the proportion of complete and correct caregiver-collected data (pain scale) and saliva samples in the at-home setting. Secondary endpoints included the proportion of complete and correct saliva samples in the inpatient setting, subjective feasibility for caregivers, and study cost. RESULTS: A total number of 23 children were included in the study of which 17 children, median age 6.0 years (IQR 5.0, 7.4), completed the study. During the at-home phase, 71.9% [CI = 64.4, 78.6] of all caregiver-collected pain assessments and 53.9% [CI = 44.2, 63.4] of all saliva samples were complete and correct. Overall, 64.7% [CI = 58.7, 70.4] of all data collected by caregivers at home was complete and correct. The predominant reason for incorrectness of data was adherence to the timing of predefined patient actions. Participating caregivers reported high levels of satisfaction and willingness to participate in similar trials in the future. Study costs for a potential sample size of 100 patients were calculated to be 20% lower for the at-home than for a traditional in-patient study setting. CONCLUSIONS: Mobile device supported studies conducted at home may provide a cost-effective approach to facilitate conduct of clinical studies in children. Given findings in this pilot study, data collection at home may focus on electronic data capture rather than biological sampling.

A better surgical resectability of WHO grade II gliomas is independent of favorable molecular markers.

A higher extent of resection (EOR) in WHO grade II gliomas (GIIG) is correlated with longer survival. However, the molecular markers also feature prognostic relevance. Here, we examined whether maximal EOR was related to the genetic profile. We retrospectively investigated the predictive value of 1p19q, IDH1, 53 expression and Ki67 index for the EOR in 200 consecutive GIIGs (2007-2013). Data were modeled in a linear model. The analysis was performed with two statistical methods (arcsin-sqrt and Beta-regression model with logit link). There was no deletion 1p19q in 118 cases, codeletion 1p19q (57 cases), single deletion 1p (4 cases) or19q (16 cases). 155 patients had a mutation of IDH1. p53 was graded in 4 degrees (0:92 cases, 1:52 cases, 2:31 cases, 3:8 cases). Mean Ki67 index was 5.2 % (range 1-20 %). Mean preoperative tumor volume was 60.8 cm(3) (range 3.3-250 cm(3)) and mean EOR was 0.917 (range 0.574-1). The statistical analysis was significant for a lower EOR in patients with codeletion 1p19q (OR 0.738, p = 0.0463) and with a single deletion 19q (OR 0.641, p = 0.0168). There was no significant correlation between IDH1 or p53 and the EOR. Higher Ki67 was marginally associated with higher EOR (p = 0.0603). The study demonstrates in a large cohort of GIIG that a higher EOR is not attributable to favorable genetic markers. This original result supports maximal surgical resection as an important therapeutic factor per se to optimize prognosis, independently of the molecular pattern.

Patient perception of meander-like versus radial breast ultrasound.

Background Radial breast ultrasound scanning (r-US) and commonly used meander-like ultrasound scanning (m-US) have recently been shown to be equally sensitive and specific with regard to the detection of breast malignancies. As patient satisfaction has a strong influence on patient compliance and thus on the quality of health care, we compare here the two US scanning techniques with regard to patient comfort during breast ultrasound (BUS) and analyze whether the patient has a preference for either scanning technique. Materials and Methods Symptomatic and asymptomatic women underwent both m-US and r-US scanning by two different examiners. Patient comfort and preference were assessed using a visual analog scale-based (VAS) questionnaire and were compared using a Mann-Whitney U test. Results Analysis of 422 VAS-based questionnaires showed that perceived comfort with r-US (r-VAS 8 cm, IQR [5.3, 9.1]) was significantly higher compared to m-US (m-VAS 5.6 cm, IQR [5.2, 7.4]) (p < 0.001). 53.8% of patients had no preference, 44.3% of patients clearly preferred r-US, whereas only 1.9% of patients preferred m-US. Conclusion: Patients experience a higher level of comfort with r-US and favor r-US over m-US. As the diagnostic accuracy of r-US has been shown to be comparable to that of m-US and the time required for examination is shorter, a switch from m-US to r-US in routine clinical practice might be beneficial. R-US offers considerable potential to positively affect patient compliance but also to save examination time and thus costs.

Escalating to medium- versus high-efficacy disease modifying therapy after low-efficacy treatment in relapsing remitting multiple sclerosis.

BACKGROUND: In patients with relapsing remitting multiple sclerosis (RRMS) on low-efficacy disease modifying therapies (DMT), the optimal strategy on how to escalate treatment once needed, remains unknown. METHODS: We studied RRMS patients on low-efficacy DMTs listed in the Swiss National Treatment Registry, who underwent escalation to either medium- or high-efficacy DMTs. Propensity score-based matching was applied using 12 clinically relevant variables. Both groups were also separately matched with control subjects who did not escalate therapy. Time to relapse and to disability worsening were evaluated using Cox proportional hazard models. RESULTS: Of 1037 eligible patients, we 1:1 matched 450 MS patients who switched from low-efficacy to medium-efficacy (n = 225; 76.0% females, aged 42.4 ± 9.9 years [mean ± SD], median EDSS 3.0 [IQR 2-4]) or high-efficacy DMTs (n = 225; 72.4% females, aged 42.2 ± 10.6 years, median EDSS 3.0 [IQR 2-4]). Escalation to high-efficacy DMTs was associated with lower hazards of relapses than medium-efficacy DMTs (HR = 0.67, 95% CI 0.47-0.95, p = .027) or control subjects (HR = 0.61, 95% CI 0.44-0.84, p = .003). By contrast, escalation from low to medium-efficacy DMTs did not alter the hazard for relapses when compared to controls (i.e. patients on low-efficacy DMT who did not escalate DMT during follow-up) CONCLUSION: Our nationwide registry analysis suggests that, once escalation from a low-efficacy DMT is indicated, switching directly to a high-efficacy treatment is superior to a stepwise escalation starting with a moderate-efficacy treatment.

Prospective Validation of Tubomanometry in Children With Normal Eustachian Tube Function.

OBJECTIVES: Tubomanometry (TMM), described initially by Estève, is a relatively new manometric method for testing the eustachian tube function (ETF). This study presents the analysis of the measurement of ETF of healthy children by TMM, which has, to date, not been properly evaluated. The objectives of the study were to establish normative data for TMM and to demonstrate TMM as a reliable and valid method for measuring ETF in children. DESIGN: The evaluation, after initial power analysis, comprised 35 children from 6 to 15 years of age with an intact tympanic membrane, no severe ET dysfunction, and less than three inflammations of the middle ear in their medical history. TMM was performed twice at three pressure levels for both ears. Statistical assessment of the various parameters of TMM was performed with emphasis on the R value and possible age dependency. RESULTS: The 90th percentile for the R value was calculated to be 1.12. No clinically relevant age effect regarding the use of TMM as a screening method for children was found. Healthy children showed an opening within normal limits for the so-called R value in 88%; a delayed opening was measured in 6%, and rarely no opening was measured in 2%. CONCLUSIONS: TMM is a reliable tool for measuring ETF in children. The normal limit for the R value should be set at 1.12. The proposed measuring algorithm and results can be used to calculate sensitivity and specificity in a future study.

How far MS lesion detection and segmentation are integrated into the clinical workflow? A systematic review.

INTRODUCTION: Over the past few years, the deep learning community has developed and validated a plethora of tools for lesion detection and segmentation in Multiple Sclerosis (MS). However, there is an important gap between validating models technically and clinically. To this end, a six-step framework necessary for the development, validation, and integration of quantitative tools in the clinic was recently proposed under the name of the Quantitative Neuroradiology Initiative (QNI). AIMS: Investigate to what extent automatic tools in MS fulfill the QNI framework necessary to integrate automated detection and segmentation into the clinical neuroradiology workflow. METHODS: Adopting the systematic Cochrane literature review methodology, we screened and summarised published scientific articles that perform automatic MS lesions detection and segmentation. We categorised the retrieved studies based on their degree of fulfillment of QNI's six-steps, which include a tool's technical assessment, clinical validation, and integration. RESULTS: We found 156 studies; 146/156 (94%) fullfilled the first QNI step, 155/156 (99%) the second, 8/156 (5%) the third, 3/156 (2%) the fourth, 5/156 (3%) the fifth and only one the sixth. CONCLUSIONS: To date, little has been done to evaluate the clinical performance and the integration in the clinical workflow of available methods for MS lesion detection/segmentation. In addition, the socio-economic effects and the impact on patients' management of such tools remain almost unexplored.

The association between the admission to wards with open- vs. closed-door policy and the use of coercive measures.

Introduction: Psychiatric treatment on a ward with open-door policy is associated with reduced numbers of coercive measures. The effect of the door policy of previous stays, however, has not been investigated. Methods: The data set consisted of 22,172 stays by adult inpatients in a psychiatric university hospital between 2010 and 2019. Pairs of consecutive stays were built. The outcome variable was the occurrence of coercive measures during the second stay. Results: Compared to treatments on wards with a closed-door policy at both stays, treatments on wards with an open-door policy at the second stay had smaller odds for coercive measures (OR ranging between 0.09 and 0.33, p < 0.01). In addition, coercive measures were more frequent in treatment histories where patients previously treated on a closed ward were admitted to a ward with an open-door policy and subsequently transferred to a ward with a closed-door policy at the second stay (OR=2.97, p = 0.046). Discussion: Treatment under open-door policy is associated with fewer coercive measures, even in patients with previous experience of closed-door settings. The group of patients who were admitted to a ward with an open-door, then transmitted to a ward with a closed-door policy seem to be prone to experience coercive measures. Clinical strategies to keep these patients in treatment in an open-door setting could further reduce coercive measures.

Personalized maps of T1 relaxometry abnormalities provide correlates of disability in multiple sclerosis patients.

OBJECTIVES AND AIMS: Quantitative MRI (qMRI) has greatly improved the sensitivity and specificity of microstructural brain pathology in multiple sclerosis (MS) when compared to conventional MRI (cMRI). More than cMRI, qMRI also provides means to assess pathology within the normal-appearing and lesion tissue. In this work, we further developed a method providing personalized quantitative T1 (qT1) abnormality maps in individual MS patients by modeling the age dependence of qT1 alterations. In addition, we assessed the relationship between qT1 abnormality maps and patients' disability, in order to evaluate the potential value of this measurement in clinical practice. METHODS: We included 119 MS patients (64 relapsing-remitting MS (RRMS), 34 secondary progressive MS (SPMS), 21 primary progressive MS (PPMS)), and 98 Healthy Controls (HC). All individuals underwent 3T MRI examinations, including Magnetization Prepared 2 Rapid Acquisition Gradient Echoes (MP2RAGE) for qT1 maps and High-Resolution 3D Fluid Attenuated Inversion Recovery (FLAIR) imaging. To calculate personalized qT1 abnormality maps, we compared qT1 in each brain voxel in MS patients to the average qT1 obtained in the same tissue (grey/white matter) and region of interest (ROI) in healthy controls, hereby providing individual voxel-based Z-score maps. The age dependence of qT1 in HC was modeled using linear polynomial regression. We computed the average qT1 Z-scores in white matter lesions (WMLs), normal-appearing white matter (NAWM), cortical grey matter lesions (GMcLs) and normal-appearing cortical grey matter (NAcGM). Lastly, a multiple linear regression (MLR) model with the backward selection including age, sex, disease duration, phenotype, lesion number, lesion volume and average Z-score (NAWM/NAcGM/WMLs/GMcLs) was used to assess the relationship between qT1 measures and clinical disability (evaluated with EDSS). RESULTS: The average qT1 Z-score was higher in WMLs than in NAWM. (WMLs: 1.366 ± 0.409, NAWM: -0.133 ± 0.288, [mean ± SD], p < 0.001). The average Z-score in NAWM in RRMS patients was significantly lower than in PPMS patients (p = 0.010). The MLR model showed a strong association between average qT1 Z-scores in white matter lesions (WMLs) and EDSS (R2 = 0.549, ß = 0.178, 97.5 % CI = 0.030 to 0.326, p = 0.019). Specifically, we measured a 26.9 % increase in EDSS per unit of qT1 Z-score in WMLs in RRMS patients (R2 = 0.099, ß = 0.269, 97.5 % CI = 0.078 to 0.461, p = 0.007). CONCLUSIONS: We showed that personalized qT1 abnormality maps in MS patients provide measures related to clinical disability, supporting the use of those maps in clinical practice.

Real-time video analysis allows the identification of large vessel occlusion in patients with suspected stroke: feasibility trial of a "telestroke" pathway in Northwestern Switzerland.

Background and aim: Loss of time is a major obstacle to efficient stroke treatment. Our telestroke path intends to optimize prehospital triage using a video link connecting ambulance personnel and a stroke physician. The objectives were as follows: (1) To identify patients suffering a stroke and (2) in particular large vessel occlusion (LVO) strokes as candidates for endovascular treatment. We have chosen the Rapid Arterial Occlusion Evaluation (RACE) scale for this purpose. Methods: This analysis aimed to verify the feasibility of prehospital stroke identification by video assessment. In this prospective telestroke cohort study, we included 97 subjects, in which the RACE score (items: facial palsy, arm and leg motor function, head and gaze deviation, and aphasia or agnosia) was applied, and the assessment videotaped by a trained member of the Emergency Medical Services (EMS) in the field using a mobile device. Each recorded patient video was independently assessed by three experienced stroke physicians from a certified stroke center and compared to the neuroimaging gold standard. Within this feasibility study, the stroke code was not altered by the outcome of the RACE assessment, and all patients underwent the standard procedures within the emergency unit. Results: We analyzed 97 patients (median age 78 years, 53% women), of whom 51 (52.6%) suffered an acute stroke, 12 (23.5%) of which were due to an LVO and 46 patients had symptoms mimicking a stroke. The sensitivity of stroke identification was 77.8%, and specificity was 53.6%. In regard to the identification of an LVO, sensitivity was 69.4% and specificity was 84.3%. The inter-rater agreement in the RACE-score assessment was ICC = 0.82 (intraclass-correlation coefficient). Conclusion: These results confirm our hypothesis that the local telestroke concept is feasible. It allows correct (i) stroke and (ii) LVO identification in the majority of the cases and thus has the potential to assist in efficient prehospital triage.

Metabolic markers of short and long-term exogenous DL-beta-hydroxybutyrate supplementation in episodic migraine patients: an exploratory analysis of a randomized-controlled-trial.

Background: Emerging findings propose that the pathophysiology of migraine may be associated with dysfunctional metabolic mechanisms. Recent findings suggest that migraine attacks are a response to the cerebral energy deficit, and ingestion of ketone bodies stabilizes the generation of a migraine attack. Based on these findings, ketone body supplementation is postulated as a prophylactic treatment approach to restore cerebral metabolism deficiency. Metabolic markers are unexplored after exogenous ketone body supplementation in episodic migraineurs. Therefore, the present single-arm uncontrolled explorative analysis evaluated blood ketone body and glucose concentration after short and long-term 6 g exogenous DL-Mg-Ca-beta-hydroxybutyrate (DL-ßHB) supplementation. Methods: The presented data are part of the MigraKet randomized-control cross-over clinical trial of 41 episodic migraineurs (Number NCT03132233). Patients were given a single dose of 6 g DL-ßHB. Ketone body and glucose blood concentration were assessed before intake, 20, and 40 min after DL-ßHB intake. Ketone body, glucose concentration and glycated hemoglobin values were evaluated after 12 weeks of 18 g DL-ßHB ingestion (total dose), taken three times daily (6g/dose; 3x/day). Linear models explored the association between the ketone body and glucose levels. Results: Ketone body concentration increased within-group to a mean of 0.46 (0.30) mmol/L after 40 min post- DL-ßHB supplementation [estimate = 0.24 mmol/L, CI = (0.20.0.27), p < 0.01]. This within-group increase of ketone body concentration did not change after repeated daily intake of DL-ßHB supplementation over 12 weeks [estimate = 0.00 mmol/L, CI = (-0.03.0.04), p = 0.794]. DL-ßHB intake significantly reduced blood glucose concentration within-group from a mean baseline of 4.91 (0.42) mmol/L to 4.75 (0.47) mmol/L 40 min post-DL-ßHB supplementation [estimate = -0.16 mmol/L, CI = (-0.15, 0.03), p < 0.01]. Repeated DL-ßHB supplementation for 12 weeks showed no change within-group in acute ketone bodies concentration [estimate = 0.00 mmol/L, CI = (-0.03.0.04), p = 0.794] and in the HbA1c value [estimate = 0.02, CI = (-0.07.0.11), p = 0.69]. Conclusion: A single dose of 6 g DL-ßHB significantly elevated blood ketone bodies and decreased blood glucose concentration within-group in episodic migraineurs. Long-term DL-ßHB supplementation for 12 weeks showed no effect within-group on acute ketone body concentration and had not impact on HbA1c. The elevation of the ketone body concentration was moderate, indicating that nutritional ketosis was not reached. Therefore, a dose higher than 6 g of DL-ßHB is required to reach the nutritional level of ketosis. ClinicalTrials.gov Identifier: NCT03132233.

Serum neurofilament light chain reference database for individual application in paediatric care: a retrospective modelling and validation study.

BACKGROUND: 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. METHODS: 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). FINDINGS: 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). INTERPRETATION: 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. FUNDING: Swiss National Science Foundation, US National Institutes of Health, and the National Multiple Sclerosis Society.

Implementation of Motor Function Measure score percentile curves - Predicting motor function loss in Duchenne muscular dystrophy.

The Motor Function Measure is a standardized scoring system to evaluate motor function and monitor disease progression in neuromuscular diseases such as Duchenne muscular dystrophy. There are no available reference percentile curves for this measure. The aim of this analysis was to generate Motor Function Measure percentile curves for ambulant and non-ambulant patients affected by Duchenne Muscular Dystrophy, providing the opportunity to better evaluate the status and progression of an individual patient compared to other patients in the same age group. Data of patients aged between 6 and 15 years (819 measurements) was obtained from the international Motor Function Measure database. Age-dependent percentile curves were estimated using a "Generalized additive model for location, scale and shape" as suggested by the World Health Organisation Multicentre Growth Reference Study Group. Percentile curves for the Motor Function Measure total score and its sub-scores for patients with and without treatment with glucocorticoids are presented. Mean scores decline with age. Patients treated with glucocorticoids have higher mean values compared to glucocorticoid-naïve patients at the same age. The percentile curves with the online tool extend the clinical utility of the Motor Function Measure by facilitating the interpretation of individual standing and disease progression.

Brain atrophy measurement over a MRI scanner change in multiple sclerosis.

BACKGROUND: A change in MRI hardware impacts brain volume measurements. The aim of this study was to use MRI data from multiple sclerosis (MS) patients and healthy control subjects (HCs) to statistically model how to adjust brain atrophy measures in MS patients after a major scanner upgrade. METHODS: We scanned 20 MS patients and 26 HCs before and three months after a major scanner upgrade (1.5 T Siemens Healthineers Magnetom Avanto to 3 T Siemens Healthineers Skyra Fit). The patient group also underwent standardized serial MRIs before and after the scanner change. Percentage whole brain volume changes (PBVC) measured by Structural Image Evaluation using Normalization of Atrophy (SIENA) in the HCs was used to estimate a corrective term based on a linear model. The factor was internally validated in HCs, and then applied to the MS group. RESULTS: Mean PBVC during the scanner change was higher in MS than HCs (-4.1 ± 0.8 % versus -3.4 ± 0.6 %). A fixed corrective term of 3.4 (95% confidence interval: 3.13-3.67)% was estimated based on the observed average changes in HCs. Age and gender did not have a significant influence on this corrective term. After adjustment, a linear mixed effects model showed that the brain atrophy measures in MS during the scanner upgrade were not anymore associated with the scanner type (old vs new scanner; p = 0.29). CONCLUSION: A scanner change affects brain atrophy measures in longitudinal cohorts. The inclusion of a corrective term based on changes observed in HCs helps to adjust for the known and unknown factors associated with a scanner upgrade on a group level.