Search

In the area of cardiac monitoring, the use of digitally driven technologies is on the rise. While the development of medical products is advancing rapidly, allowing for new use-cases in cardiac monitoring and other areas, regulatory and legal requirements that govern market access are often evolving slowly, sometimes creating market barriers. This article gives a brief overview of the existing clinical studies regarding the use of smart wearables in cardiac monitoring and provides insight into the main regulatory and legal aspects that need to be considered when such products are intended to be used in a health care setting. Based on this brief overview, the article elaborates on the specific requirements in the main areas of authorization/certification and reimbursement/compensation, as well as data protection and data security. Three case studies are presented as examples of specific market access procedures: the USA, Germany, and Belgium. This article concludes that, despite the differences in specific requirements, market access pathways in most countries are characterized by a number of similarities, which should be considered early on in product development. The article also elaborates on how regulatory and legal requirements are currently being adapted for digitally driven wearables and proposes an ongoing evolution of these requirements to facilitate market access for beneficial medical technology in the future.

The project OPTIMAP is at the current stage a joint initiative of BGIC, GSSAC and DGFI-TUM. The development of an operational tool for ionospheric mapping and prediction is the main goal of the project.The ionosphere is a dispersive medium. Therefore, GNSS signals are refracted while they pass through the ionosphere. The magnitude of the refraction rate depends on the frequencies of the transmitted GNSS signals. The ionospheric disturbance on the GNSS signals paves the way of extracting Vertical Total Electron Content (VTEC) information of the ionosphere.In OPTIMAP, the representation of the global and regional VTEC signal is based on localizing B-spline basis functions. For global VTEC modeling, polynomial B-splines are employed to represent the latitudinal variations, whereas trigonometric B-splines are used for the longitudinal variations. The regional modeling in OPTIMAP relies on a polynomial B-spline representation for both latitude and longitude.The VTEC modeling in this study relies on both a global and a regional sequential estimator (Kalman filter) running in a parallel mode. The global VTEC estimator produces VTEC maps based on data from GNSS receiver stations which are mainly part of the global real-time IGS network. The global estimator relies on additional VTEC information obtained from a forecast procedure using ultra-rapid VTEC products. The regional estimator makes use of the VTEC product of the real-time global estimator as background information and generates high-resolution VTEC maps using real-time data from the EUREF Permanent GNSS Network. EUREF provides a network of very dense GNSS receivers distributed alongside Europe.Carrier phase observations acquired from GPS and GLONASS, which are transmitted in accordance with RTCM standard, are used for real-time regional VTEC modeling. After the acquisition of GNSS data, cycle slips for each satellite-receiver pair are detected, and ionosphere observations are constructed via the linear combination of carrier-phase observations in the data pre-processing step. The unknown B-spline coefficients, as well as the biases for each phase-continuous arc belonging to each receiver-satellite pair, are simultaneously estimated in the Kalman filter.Within this study, we compare the performance of regional and global VTEC products generated in real-time using the well-known dSTEC analysis.

BackgroundSensitive outcome measures for clinical trials on cerebellar ataxias are lacking. Most cerebellar ataxias progress very slowly and quantitative measurements are required to evaluate cerebellar dysfunction.MethodsWe evaluated two scales for rating cerebellar ataxias: the Composite Cerebellar Functional Severity (CCFS) Scale and Scale for the Assessment and Rating of Ataxia (SARA), in patients with spinocerebellar ataxia (SCA) and controls. We evaluated these scales for different diseases and investigated the factors governing the scores obtained. All patients were recruited prospectively.ResultsThere were 383 patients with Friedreich’s ataxia (FRDA), 205 patients with SCA and 168 controls. In FRDA, 31% of the variance of cerebellar signs with the CCFS and 41% of that with SARA were explained by disease duration, age at onset and the shorter abnormal repeat in the FXN gene. Increases in CCFS and SARA scores per year were lower for FRDA than for SCA (CCFS index: 0.123±0.123 per year vs 0.163±0.179, PConclusionsCerebellar dysfunction, as measured with the CCFS and SARA scales, was more severe in FRDA than in patients with SCA, but with lower progression indexes, within the limits of these types of indexes. Ceiling effects may occur at late stages, for both scales. The CCFS scale is rater-independent and could be used in a multicentre context, as it is simple, rapid and fully automated.Trial registration numberClinicalTrials.gov: NCT02069509.

A high proportion of peripheral human B cells produce polyreactive or autoreactive antibodies, which indicates that they have escaped the elimination of self-reactive B cells in the bone marrow. CD22 and Siglec-G are two inhibitory receptors of the sialic-acid-binding immunoglobulin-like lectin (Siglec) family that inhibit the B-cell antigen receptor (BCR) signal. The ability of these two receptors to bind sialic acids is crucial for regulating inhibition and inducing tolerance to self-antigens. Sialylated glycans are usually absent on microbes (although several pathogenic microorganisms have evolved strategies to mimic self by decorating their surfaces with sialic acids) but abundant in higher vertebrates and might, therefore, provide an important tolerogenic signal. Combined Siglec-G deficiency and CD22 deficiency leads to spontaneous autoimmunity in mice, and mutations in an enzyme that modifies Siglec ligands are directly linked to several autoimmune diseases in humans. New data show that high-affinity ligands for CD22 and Siglec-G can be used to induce antigen-specific B-cell tolerance, which might be one strategy for the treatment of autoimmune diseases in the future.

Background Erythropoietin (EPO) derivatives have been found to increase frataxin levels in Friedreich's ataxia (FRDA) in vitro. This multicenter, double-blind, placebo-controlled, phase II clinical trial aimed to evaluate the safety and tolerability of Lu AA24493 (carbamylated EPO; CEPO). Methods Thirty-six ambulatory FRDA patients harboring >400 GAA repeats were 2:1 randomly assigned to either CEPO in a fixed dose (325 µg thrice-weekly) or placebo. Safety and tolerability were assessed up to 103 days after baseline. Secondary outcome measures of efficacy (exploration of biomarkers and ataxia ratings) were performed up to 43 days after baseline. Results All patients received six doses of study medication. Adverse events were equally distributed between CEPO and placebo. There was no evidence for immunogenicity of CEPO after multiple dosing. Biomarkers, such as frataxin, or measures for oxidative stress and ataxia ratings did not differ between CEPO and placebo. Conclusion CEPO was safe and well tolerated in a 2-week treatment phase. Secondary outcome measures remained without apparent difference between CEPO and placebo. © 2014 International Parkinson and Movement Disorder Society

With the frequent use of magnetic resonance imaging (MRI), patients with subtle and diffuse symptoms due to small syrinx cavities increasingly present to neurosurgical care. In this respect, a dilated central canal, hydromyelia, must be separated from patients with true syringomyelia with an underlying disorder, as they do not share clinical and radiological features. We hypothesize that a differentiation of these two entities with distinct diagnostic tools is possible. To describe the entity of hydromyelia, we excluded all patients from the syringomyelia database (n = 142) with any obvious cause of a syringomyelia, any objective neurological deficits on clinical examination, pathological results on electrophysiological monitoring (SSEP, MEP, silent periods) or a widening of the spinal cord cavity of more than 6 mm on MRI [routine acquisitions with FLAIR, T1/T2-weighted images, Cine and CISS (constructive interference in steady-state) studies]. Life quality was assessed through SF-36 questionnaires and an individualized questionnaire for the clinical history, pain and alternative therapies. Forty patients (15 males/25 females) matched the criteria of a hydromyelia. With a mean age of 36.7 years (range 11–62), they almost all presented with pain (79%) or dysaesthesia of the limbs, with some having been an incidental finding (10%). Over a follow-up time of 36.9 months (range 6–93) there was no neurological or radiological deterioration. Patients with a hydromyelia do not share clinical or radiological characteristics with patients harbouring a true syringomyelia. As hydromyelia does not represent a disease with an underlying pathology, no clinical or radiological progression has been seen. With sophisticated diagnostic tools to rule out any pathology this subset of patients can be identified.

Brain-computer interfaces (BCIs) are often based on the control of sensor motor processes, yet sensor motor processes are impaired in patients suffering from amyotrophic lateral sclerosis (ALS). We devised a new paradigm that targets higher level cognitive processes to transmit information from the user to the BCI. We instructed five ALS patients and eleven healthy subjects to either activate self-referential memories or to focus on processes without mnemonic content, while recording a high density electroencephalogram (EEG). Both tasks are likely to modulate activity in the default mode network (DMN) without involving sensor motor pathways. We find that the two tasks can be distinguished from band power modulations in the theta (3 -- 7 Hz) and alpha-range (8 -- 13 Hz) in fronto-parietal areas, consistent with modulation of neural activity in primary nodes of the DMN. Training a support vector machine (SVM) to discriminate the two tasks on theta- and alpha-power in the precuneus, as estimated by a beam forming procedure, resulted in above chance-level decoding accuracy after only one experimental session. Therefore, the presented work could serve as a basis for a novel tool which allows for simple, reliable communication with patients in late stages of ALS.

Summary Background The European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) is a prospective international registry investigating the natural history of Friedreich's ataxia. We used data from EFACTS to assess disease progression and the predictive value of disease-related factors on progression, and estimated sample sizes for interventional randomised clinical trials. Methods We enrolled patients with genetically confirmed Friedreich's ataxia from 11 European study sites in Austria, Belgium, France, Germany, Italy, Spain, and the UK. Patients were seen at three visits—baseline, 1 year, and 2 years. Our primary endpoint was the Scale for the Assessment and Rating of Ataxia (SARA). Secondary outcomes were the Inventory of Non-Ataxia Signs (INAS), the Spinocerebellar Ataxia Functional Index (SCAFI), phonemic verbal fluency (PVF), and the quality of life measures activities of daily living (ADL) and EQ-5D-3L index. We estimated the yearly progression for each outcome with linear mixed-effect modelling. This study is registered with ClinicalTrials.gov, number NCT02069509, and follow-up assessments and recruitment of new patients are ongoing. Findings Between Sept 15, 2010, and Nov 21, 2013, we enrolled 605 patients with Friedreich's ataxia. 546 patients (90%) contributed data with at least one follow-up visit. The progression rate on SARA was 0·77 points per year (SE 0·06) in the overall cohort. Deterioration in SARA was associated with younger age of onset (–0·02 points per year [0·01] per year of age) and lower SARA baseline scores (–0·07 points per year [0·01] per baseline point). Patients with more than 353 GAA repeats on the shorter allele of the FXN locus had a higher SARA progression rate (0·09 points per year [0·02] per additional 100 repeats) than did patients with fewer than 353 repeats. Annual worsening was 0·10 points per year (0·03) for INAS, −0·04 points per year (0·01) for SCAFI, 0·93 points per year (0·06) for ADL, and −0·02 points per year (0·004) for EQ-5D-3L. PVF performance improved by 0·99 words per year (0·14). To detect a 50% reduction in SARA progression at 80% power, 548 patients would be needed in a 1 year clinical trial and 184 would be needed for a 2 year trial. Interpretation Our results show that SARA is a suitable clinical rating scale to detect deterioration of ataxia symptoms over time; ADL is an appropriate measure to monitor changes in daily self-care activities; and younger age at disease onset is a major predictor for faster disease progression. The results of the EFACTS longitudinal analysis provide suitable outcome measures and sample size calculations for the design of upcoming clinical trials of Friedreich's ataxia. Funding European Commission.

OBJECTIVE: To retrospectively determine the frequency of N-Methyl-D-Aspartate (NMDA) receptor (NMDAR) autoantibodies in patients with different forms of dementia.METHODS: Clinical characterization of 660 patients with dementia, neurodegenerative disease without dementia, other neurological disorders and age-matched healthy controls combined with retrospective analysis of serum or cerebrospinal fluid (CSF) for the presence of NMDAR antibodies. Antibody binding to receptor mutants and the effect of immunotherapy were determined in a subgroup of patients.RESULTS: Serum NMDAR antibodies of IgM, IgA, or IgG subtypes were detected in 16.1% of 286 dementia patients (9.5% IgM, 4.9% IgA, and 1.7% IgG) and in 2.8% of 217 cognitively healthy controls (1.9% IgM and 0.9% IgA). Antibodies were rarely found in CSF. The highest prevalence of serum antibodies was detected in patients with "unclassified dementia" followed by progressive supranuclear palsy, corticobasal syndrome, Parkinson's disease-related dementia, and primary progressive aphasia. Among the unclassified dementia group, 60% of 20 patients had NMDAR antibodies, accompanied by higher frequency of CSF abnormalities, and subacute or fluctuating disease progression. Immunotherapy in selected prospective cases resulted in clinical stabilization, loss of antibodies, and improvement of functional imaging parameters. Epitope mapping showed varied determinants in patients with NMDAR IgA-associated cognitive decline.INTERPRETATION: Serum IgA/IgM NMDAR antibodies occur in a significant number of patients with dementia. Whether these antibodies result from or contribute to the neurodegenerative disorder remains unknown, but our findings reveal a subgroup of patients with high antibody levels who can potentially benefit from immunotherapy.

Here, we systemati-cally screened a representative cohort of patients with adult-onset ataxia for underlying leukodystrophies and analyzedits phenotypic presentation.One hundred five ataxia patients from independent fami-lies were recruited as a continuous series from the ataxiaclinic in T€ubingen according to the following inclusion crite-ria: (1) age of onset of ataxia 16 years, (2) family historyconsistent with autosomal-recessive inheritance, and (3)prior exclusion of Friedreich ataxia in patients with age ofonset 25 years and prior exclusion of common subtypesof spinocerebellar ataxia (SCA1, -2, -3, -6, -7, -17) inpatients with onset 25 years. All patients underwent abasic screening that included serum levels of very-long-chainfatty acids for X-linked adrenoleukodystrophy/adrenomyelo-neuropathy (ALD/AMN) and enzyme activities for meta-chromatic leukodystrophy (MLD), GM1 gangliosidosis,GM2 gangliosidosis variants (Tay-Sachs disease [TS] andSandhoff disease [SD]), and Krabbe disease (KD) in culturedleukocytes. If phenotypic evidence or MR imaging was sug-gestive of other types of neurometabolic disorders, we alsoperformed the respective genetic or biochemical testing, forexample, screening for Niemann-Pick disease type C (NPC)in patients with vertical-gaze palsy, for cerebrotendinousxanthomatosis (CTX) in cases of cognitive dysfunction, andfor leukencephalopathy with brainstem and spinal cordinvolvement and lactate elevation (LBSL) or vanishing whitematter disease (VWMD).Standardized clinical characterization included signs ofcorticospinal tract affection, dystonia, peripheral polyneu-ropathy (muscular atrophy or absent reflexes in combinationwith pallhypesthesia), or psychiatric comorbidities (exceptfor depression, as it is a common and unspecific feature ofchronic progressive disease

In this case study the development of cloud properties (cloud optical depth, effective radius and cloud top height) during the life-cycle of a convective cloud system over Europe was analyzed. To retrieve the properties we developed a retrieval scheme based on the radiative transfer code MOMO and an optimal estimation procedure. Input data are the visible to short-wavelength infrared channels from SEVIRI. In contrast to many other retrieval schemes we used 4 channels simultaneously. Especially the 3,9μm channel provides additional information due to the fact that it measures solar reflectance and thermal emission and allows the inclusion of cloud top height into the retrieval. By using a time series of SEVIRI measurements we want to provide and examine the microphysical development of the cloud over life-time. We monitored the growth of the system and found the most active parts of the convection with the highest water content and optical depth in those regions where the cloud top height is largest, too. The effective radius of the cloud particles is largest in older regions of the cloud system, where the cloud is already decaying.

Mutations in UBQLN2 have recently been shown to cause dominant X-linked amyotrophic lateral sclerosis (ALS) and ALS plus frontotemporal dementia (FTD). Information on their frequency in different populations is still rare, and a pure FTD phenotype has not yet been reported. Moreover, the mutational spectrum of known UBQLN2 mutations is still limited to its PXX repeat region. Based on a screening of 206 ALS and FTD patients, we here report 3 novel UBQLN2 mutations, accounting for 1.2% (2/161) ALS and 2.2% (1/45) FTD patients, including a patient with pure FTD. All mutations were located in highly conserved domains outside the PXX repeat region and not observed in 1450 ethnically matched control X-chromosomes. All affected patients presented with apparently sporadic disease. UBQLN2 mutations are rare in Central European ALS and FTD patients, but contribute significantly to patients with seemingly sporadic disease. UBQLN2 is able to cause any disease on the ALS-FTD continuum, including pure FTD. Because the pathogenic mechanism of UBQLN2 mutations is not limited to its PXX region, UBQLN2 screening in neurodegenerative patients should not be limited to this region.

Several studies have suggested a pathogenetic association between monoclonal gammopathy of undetermined significance (MGUS) and motor neuron diseases, including not only lower motor neuron syndrome...

Niemann-Pick type C (NPC) disease is a rare, usually fatal neurodegenerative lysosomal storage disorder. It is inherited in an autosomal-recessive fashion and caused by mutation of either NPC1 (95%) or NPC2 gene.1 Age at onset is broadly variable, ranging from neonatal fatal neurovisceral manifestations to a primarily neurodegenerative disease in adulthood that may be recognized as late as 70 years of age.1 Due to its diverse clinical manifestation, correct diagnosis is challenging, frequencies might be underestimated, and diagnosis may be delayed, in particular in patients with adult-onset disease. This is particularly momentous because a potential therapy for deceleration of disease progression is now available.2

Objective: We aimed to determine the frequency of leukodystrophies and its phenotypic spectrum in patients with ataxia of unknown cause. Background A broad spectrum of heterogeneous neurological disorders including lysosomal storage disorders present with chronic progressive cerebellar ataxia. Identifying the underlying etiology is important as it sometimes allows for initiation of pharmacological treatment. Design/Methods: We prospectively studied 107 index patients who presented with adult-onset cerebellar ataxia consistent with autosomal recessive inheritance. Patients were screened for lysosomal enzyme deficiencies including metachromatic leukodystrophy, GM1-Gangliosidosis, Tay-Sachs and Sandhoff9 disease, and Krabbe disease. If clinical evidence was suggestive of other types of leukodystrophies, additional genetic or metabolic testing was performed. Clinical characterization included neurological and psychiatric features and MR-imaging. Results: Screening for lysosomal disorders detected one patient with late-onset Tay Sachs disease and one with metachromatic leukodystrophy. Both patients presented with cognitive deficits and psychiatric comorbidity beside ataxia. Additonal tests revealed two patients with Nieman Pick disease type C, one with cerebrotendinous xanthomatosis, and one with leukencephalopathy with brain stem and spinal cord involvement and lactate elevation. All of them presented with additional signs like cognitive dysfunction, pyramidal affection and/or peripheral neuropathy. Conclusions: Leukodystrophies were responsible for 6% of cryptic ataxia in our series. The concomitant occurrence of cerebellar ataxia with cognitive dysfunction, psychiatric comorbidities, spasticity and/or neuropathy should prompt screening for lysosomal storage disorders. Hyperintensity of cerebral white matter on MR FLAIR images is not an obligate marker in adult-onset leukodystrophies. Supported by: German Ministry of Research and Education (BMBF) grant 01GM0838. Disclosure: Dr. Muller vom Hagen has nothing to disclose. Dr. Synofzik has received personal compensation for activities with Volkswagen Foundation, the Movement Disorder Society, and Fresenius Kabi. Dr. Schicks has nothing to disclose. Dr. Krageloh-Mann has nothing to disclose. Dr. Schoels has received research support from Deutsche Forschungsgemeinschaft, German Research Council, Leukonet, mitoNET, EUROSPA, RISCA, and the HSP-Selbsthilfegruppe Deutschland eV.