The digital twin is a rather new industrial control and automation systems concept. While the approach so far has gained interest mainly due to capabilities to make advanced simulations and ...optimizations, recently the possibilities for enhanced security have got attention within the research community. In this article, we discuss how a digital twin replication model and corresponding security architecture can be used to allow data sharing and control of security-critical processes. We identify design-driving security requirements for digital twin based data sharing and control. We show that the proposed state synchronization design meets the expected digital twin synchronization requirements and give a high-level design and evaluation of other security components of the architecture. We also make performance evaluations of a proof of concept for protected software upgrade using the proposed digital twin design. Our new security framework provides a foundation for future research work in this promising new area.
To examine the effects of disease activity, disability, and disease-modifying therapies (DMTs) on serum neurofilament light (NFL) and the correlation between NFL concentrations in serum and CSF in ...multiple sclerosis (MS).
NFL concentrations were measured in paired serum and CSF samples (n = 521) from 373 participants: 286 had MS, 45 had other neurologic conditions, and 42 were healthy controls (HCs). In 138 patients with MS, the serum and CSF samples were obtained before and after DMT treatment with a median interval of 12 months. The CSF NFL concentration was measured with the UmanDiagnostics NF-light enzyme-linked immunosorbent assay. The serum NFL concentration was measured with an in-house ultrasensitive single-molecule array assay.
In MS, the correlation between serum and CSF NFL was
= 0.62 (
< 0.001). Serum concentrations were significantly higher in patients with relapsing-remitting MS (16.9 ng/L) and in patients with progressive MS (23 ng/L) than in HCs (10.5 ng/L,
< 0.001 and
< 0.001, respectively). Treatment with DMT reduced median serum NFL levels from 18.6 (interquartile range IQR 12.6-32.7) ng/L to 15.7 (IQR 9.6-22.7) ng/L (
< 0.001). Patients with relapse or with radiologic activity had significantly higher serum NFL levels than those in remission (
< 0.001) or those without new lesions on MRI (
< 0.001).
Serum and CSF NFL levels were highly correlated, indicating that blood sampling can replace CSF taps for this particular marker. Disease activity and DMT had similar effects on serum and CSF NFL concentrations. Repeated NFL determinations in peripheral blood for detecting axonal damage may represent new possibilities in MS monitoring.
Objectives
To compare the assessment of patients with multiple sclerosis (MS) using synthetic and conventional MRI.
Materials and methods
Synthetic and conventional axial images were prospectively ...acquired for 52 patients with diagnosed MS. Quantitative MRI (qMRI) was used for measuring proton density and relaxation times (T1, T2) and then, based on these parameters, synthetic T1W, T2W and FLAIR images were calculated. Image stacks were reviewed blindly, independently and in random order by two radiologists. The number and location for all lesions were documented and categorised. A combined report of lesion load and presence of contrast-enhancing lesions was compiled for each patient. Agreement was evaluated using kappa statistic.
Results
There was no significant difference in lesion detection using synthetic and conventional MRI in any anatomical region or for any of the three image types. Inter- and intra-observer agreements were mainly higher (
p
< 0.05) using conventional images but there was no significant difference in any specific region or for any image type. There was no significant difference in the outcome of the combined reports.
Conclusion
Synthetic MR images show potential to be used in the assessment of MS dissemination in space (DIS) despite a slightly lower inter- and intra-observer agreement compared to conventional MRI.
Key Points
• Synthetic MR images may potentially be useful in the assessment of MS.
• Examination times may be shortened.
• Inter- and intra-observer agreement is generally higher using conventional MRI.
Abstract Purpose To evaluate the accuracy and reproducibility of a quantitative magnetic resonance (qMR) imaging method (QRAPMASTER) for simultaneous measurements of T1 and T2 relaxation times, and ...proton density (PD). Materials and Methods Measurements of T1, T2, and PD with qMR were performed using phantoms with different relaxation times and concentrations of heavy water. Healthy volunteers were examined with different head coils. Regional measurements were performed in normal-appearing white and gray matter from the healthy control subjects, and in multiple sclerosis (MS) patients. Results In phantom measurements, QRAPMASTER slightly underestimated T1, and T2 variations between repeated measurements were modest. PD was generally overestimated. The overall relative difference was − 1.2 ± 5.3% (T1), − 6.6 ± 1.9% (T2), and 0.7 ± 5.1% (PD). In healthy volunteers, there were no statistically significant differences of T1, T2 or PD using different head coils. Values of T1, T2, and PD obtained in healthy controls and MS patients were within reference ranges. However, significant differences were found in normal-appearing gray and white matter. Conclusion QRAPMASTER can be considered a sufficiently accurate and reproducible method for use in clinical practice. Neuropathology in normal-appearing brain tissue may be revealed using this MR method, with putative implications for quantification of tissue damage in neurological diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Objective:
The impact of present disease‐modifying treatments (DMTs) in multiple sclerosis (MS) on nerve injury and reactive astrogliosis is still unclear. Therefore, we studied the effect of ...natalizumab treatment on the release of 2 brain‐specific tissue damage markers into cerebrospinal fluid (CSF) in MS patients.
Methods:
CSF samples from 92 patients with relapsing forms of MS were collected in a prospective manner prior to natalizumab treatment and after 6 or 12 months. In 86 cases, natalizumab was used as second‐line DMT due to breakthrough of disease activity. The levels of neurofilament light (NFL) and glial fibrillary acidic protein (GFAP) were determined using highly sensitive in‐house developed enzyme‐linked immunosorbent assays.
Results:
Natalizumab treatment led to a 3‐fold reduction of NFL levels, from a mean value of 1,300 (standard deviation SD, 2,200) to 400 (SD, 270) ng/l (p < 0.001). The later value was not significantly different from that found in healthy control subjects (350ng/l; SD, 170; n = 28). Subgroup analysis revealed a consistent effect on NFL release, regardless of previous DMT or whether patients had relapses or were in remission within 3 months prior to natalizumab treatment. No differences between pre‐ and post‐treatment levels of GFAP were detected.
Interpretation:
Our data demonstrate that natalizumab treatment reduces the accumulation of nerve injury in relapsing forms of MS. It is anticipated that highly effective anti‐inflammatory treatment can reduce axonal loss, thereby preventing development of permanent neurological disability. Ann Neurol 2010
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
To investigate changes in the cerebrospinal fluid (CSF) immunological profile after treatment switch from first-line injectables to rituximab in patients with relapsing-remitting MS (RRMS), and to ...compare the profile in MS patients with healthy controls (HC).
Cerebrospinal fluid from 70 patients with clinically stable RRMS and 55 HC was analysed by a multiplex electrochemiluminescence method for a broad panel of cytokines and immunoactive substances before, and over a two-year period after, treatment switch to rituximab. After quality assessment of data, using a predefined algorithm, 14 analytes were included in the final analysis.
Ten of the 14 analytes differed significantly in MS patients compared with HC at baseline. Levels of IP-10 (CXCL10), IL-12/23p40, IL-6, sVCAM1, IL-15, sICAM1 and IL-8 (CXCL8) decreased significantly after treatment switch to rituximab. The cytokines IP-10 and IL-12/IL-23p40 displayed the largest difference versus HC at baseline and also the largest relative reduction after therapy switch to rituximab.
We found significant changes in the immunological profile after therapy switch to rituximab in RRMS in the direction towards the values of HC. IP-10 and IL12/IL-23p40 deserve further studies as part of the immunopathogenesis of MS as well as for the mode of action of rituximab in MS.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background. In patients with multiple sclerosis (MS), there is a decline in muscle strength and physical capacity due to demyelination and axonal loss in the central nervous system. In patients with ...advanced MS or in a later stage of the disease, also respiratory impairment may occur. The degree of pulmonary dysfunction in the earlier stages of MS has not been thoroughly described. Therefore, the primary aims of this study are to describe pulmonary function and respiratory muscle strength in patients with a moderate disease course and to identify associations between respiratory muscle strength and functional capacity. Methods. A sample of 48 patients with a diagnosis of MS and mean age 56±11 years was studied using a descriptive cross-sectional design. The patients had a disease duration of 24±11 years and a median Expanded Disability Status Scale (EDSS) score of 4.5 (interquartile range 4.0-6.5). Pulmonary function assessed by spirometry, respiratory muscle strength, peak cough flow and peripheral oxygen saturation, subjective breathing and coughing ability, and physical capacity measured using the 6MWT were evaluated. Results. The patients had normal pulmonary function with no significant abnormalities in dynamic spirometry (vital capacity 103±16% predicted, forced expiratory volume in 1 second 95±15% predicted). Peak expiratory flow rate 89±17% predicted was in the lower limit of normal. Respiratory muscle strength, determined by maximal inspiratory (MIP) and expiratory (MEP) static pressures, was normal but with large differences between individuals. MIP ranged from 26 to 143 cmH2O (98±31% predicted); the MEP values ranged from 43 to 166 cmH2O (104±29% predicted), with two patients having values below the lower limit of normal. Significant positive associations between MIP as well as MEP were found in several pulmonary function variables. A significant negative association was found between EDSS score and MEP (r=−0.312, p=0.031). Mean peak cough flow was 389±70 L/min, which is comparable with the values reported for healthy adults. The patients did not experience a severely decreased ability to take deep breaths or cough. There was a moderate correlation between MEP and physical capacity, as assessed by the 6MWT (r=0.399, p=0.010) and between peak expiratory flow (PEF) and the 6MWT (r=0.311, p=0.048). Conclusion. Respiratory muscle strength, pulmonary function assessed by spirometry, and peak cough flow were normal in patients with mild to moderate MS; however, there were large individual differences demonstrating low respiratory muscle strength in some patients. Significant associations between MEP and functional capacity and between MEP and disease severity were found, indicating that patients with impaired respiratory muscle strength have lower functional capacity and more severe disease.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Objective
To estimate risks for all‐cause mortality and for severe COVID‐19 in multiple sclerosis patients and across relapsing–remitting multiple sclerosis patients exposed to disease‐modifying ...therapies.
Methods
We conducted a Swedish nationwide population‐based multi‐register linkage cohort study and followed all multiple sclerosis patients (n = 17,692 in March 2020), individually age‐, sex‐, and region‐matched to five population‐based controls (n = 86,176 in March 2020) during March 2020–June 2021. We compared annual all‐cause mortality within and across cohorts, and assessed incidence rates and relative risks for hospitalization, intensive care admission, and death due to COVID‐19 in relation to disease‐modifying therapy use, using Cox regression.
Results
Absolute all‐cause mortality among multiple sclerosis patients was higher from March to December 2020 than in previous years, but relative risks versus the population‐based controls were similar to preceding years. Incidence rates of hospitalization, intensive care admission, and death due to COVID‐19 remained in line with those for all‐cause hospitalization, intensive care admission, and mortality. Among relapsing–remitting patients on rituximab, trends for differences in risk of hospitalization due to COVID‐19 remained in the demographics‐, socioeconomic status‐, comorbidity‐, and multiple sclerosis severity‐adjusted model.
Interpretation
Risks of severe COVID‐19‐related outcomes were increased among multiple sclerosis patients as a whole compared to population controls, but risk increases were also seen for non‐COVID‐19 hospitalization, intensive care admission, and mortality, and did not significantly differ during the pandemic compared to pre‐pandemic years. The risk conveyed by disease‐modifying therapies was smaller than previously assumed, likely as a consequence of the possibility to better control for confounders.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Axonal loss is the main cause of irreversible disability in multiple sclerosis (MS). Serum neurofilament light (sNfL) is a biomarker of axonal disintegration. In this nested case–control study, blood ...samples from 519 presymptomatic persons (age range 4–39 years) who later received an MS diagnosis showed higher sNfL concentrations than 519 matched controls (p < 0.0001), noticeable at least 10 years before clinical MS onset. Mean values for pre‐MS and control groups were 9.6 pg/mL versus 7.4 pg/mL 0–5 years before onset, and 6.4 pg/mL versus 5.8 pg/mL 5–10 years before onset. These results support that axonal injury occurs early in MS pathogenesis.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background
High 25-hydroxyvitamin D concentrations have been associated with a reduced risk of multiple sclerosis, with indications of a stronger effect among young individuals.
Objective
Investigate ...the 25-hydroxyvitamin D association with multiple sclerosis and test if this association is age dependent.
Methods
Prospectively drawn blood samples from individuals later developing relapsing–remitting multiple sclerosis and controls matched for biobank, sex, age and date of sampling, were analysed with liquid chromatography tandem mass spectrometry.
Results
High levels of 25-hydroxyvitamin D (top quintile) were associated with a reduced multiple sclerosis risk (odds ratio 0.68, 95% confidence interval 0.50–0.93).
Conclusion
These findings further support a role for vitamin D in MS aetiology.
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