ResearchPad - 120 https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Clinical and imaging features of children with autoimmune encephalitis and MOG antibodies]]> https://www.researchpad.co/article/elastic_article_15504 To describe the presentations, radiologic features, and outcomes of children with autoimmune encephalitis associated with myelin oligodendrocyte glycoprotein antibodies (MOG abs).MethodsIdentification of children fulfilling the diagnostic criteria for possible autoimmune encephalitis (AE) and testing positive for serum MOG abs. Chart review and comprehensive analysis of serum MOG abs using live cell assays and rat brain immunohistochemistry.ResultsTen children (4 girls, 6 boys) with AE and serum MOG abs were identified. The median age at onset was 8.0 years (range: 4–16 years). Children presented with a combination of encephalopathy (10/10), headache (7/10), focal neurologic signs (7/10), or seizures (6/10). CSF pleocytosis was common (9/10, median 80 white cell count/μL, range: 21–256). Imaging showed cortical and deep gray matter involvement in all in addition to juxtacortical signal alterations in 6/10 children. No involvement of other white matter structures or contrast enhancement was noted. MOG abs were detected in all children (median titer 1:640; range: 1:320–1:10,540). Nine children had a favorable outcome at discharge (modified Rankin scale of < 2). Five of 10 children had up to 3 additional demyelinating relapses associated with persisting MOG abs. One child had NMDA receptor (NMDAR) abs at initial presentation. A second child had a third demyelinating episode with MOG abs with overlapping NMDAR encephalitis.DiscussionAE associated with serum MOG abs represents a distinct form of autoantibody-mediated encephalitis in children. We therefore recommend including MOG abs testing in the workup of children with suspected AE. ]]> <![CDATA[Quasi-Herglotz functions and convex optimization]]> https://www.researchpad.co/article/Nf93cfa79-431d-45b1-bce6-01ec489aef85

We introduce the set of quasi-Herglotz functions and demonstrate that it has properties useful in the modelling of non-passive systems. The linear space of quasi-Herglotz functions constitutes a natural extension of the convex cone of Herglotz functions. It consists of differences of Herglotz functions and we show that several of the important properties and modelling perspectives are inherited by the new set of quasi-Herglotz functions. In particular, this applies to their integral representations, the associated integral identities or sum rules (with adequate additional assumptions), their boundary values on the real axis and the associated approximation theory. Numerical examples are included to demonstrate the modelling of a non-passive gain medium formulated as a convex optimization problem, where the generating measure is modelled by using a finite expansion of B-splines and point masses.

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<![CDATA[Onset of clinical and MRI efficacy of ocrelizumab in relapsing multiple sclerosis]]> https://www.researchpad.co/article/N797f3dfd-a0b5-447d-bb06-e2add961244f

Objective

To assess the onset of ocrelizumab efficacy on brain MRI measures of disease activity in the phase II study in relapsing-remitting multiple sclerosis (RRMS), and relapse rate in the pooled phase III studies in relapsing multiple sclerosis (RMS).

Methods

Brain MRI activity was determined in the phase II trial at monthly intervals in patients with RRMS receiving placebo, ocrelizumab (600 mg), or intramuscular interferon (IFN) β-1a (30 μg). Annualized relapse rate (ARR; over various epochs) and time to first relapse were analyzed in the pooled population of the phase III OPERA (A Study of Ocrelizumab in Comparison With Interferon Beta-1a [Rebif] in Participants With Relapsing Multiple Sclerosis) I and OPERA II trials in patients with RMS receiving ocrelizumab (600 mg) or subcutaneous IFN-β-1a (44 μg).

Results

In patients with RRMS, ocrelizumab reduced the number of new T1 gadolinium-enhancing lesions by week 4 vs placebo (p = 0.042) and by week 8 vs intramuscular IFN-β-1a (p < 0.001). Ocrelizumab also reduced the number of new or enlarging T2 lesions appearing between weeks 4 and 8 vs both placebo and IFN-β-1a (both p < 0.001). In patients with RMS, ocrelizumab significantly reduced ARR (p = 0.005) and the probability of time to first protocol-defined relapse (p = 0.014) vs subcutaneous IFN-β-1a within the first 8 weeks.

Conclusion

Epoch analysis of MRI-measured lesion activity in the phase II study and relapse rate in the phase III studies consistently revealed a rapid suppression of acute MRI and clinical disease activity following treatment initiation with ocrelizumab in patients with RRMS and RMS, respectively.

Classification of evidence

This study provides Class II evidence that for patients with RRMS and RMS, ocrelizumab suppressed MRI activity within 4 weeks and clinical disease activity within 8 weeks.

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<![CDATA[An inflammatory milieu]]> https://www.researchpad.co/article/Na9fe5b6d-195f-49d5-8971-d49c80e5823f ]]> <![CDATA[Clinical spectrum of POLR3-related leukodystrophy caused by biallelic POLR1C pathogenic variants]]> https://www.researchpad.co/article/Nc2e3b675-cad7-4c30-aaf0-98b224d8f134

Objective

To determine the clinical, radiologic, and molecular characteristics of RNA polymerase III-related leukodystrophy (POLR3-HLD) caused by biallelic POLR1C pathogenic variants.

Methods

A cross-sectional observational study involving 25 centers worldwide was conducted. Clinical and molecular information was collected on 23 unreported and previously reported patients with POLR3-HLD and biallelic pathogenic variants in POLR1C. Brain MRI studies were reviewed.

Results

Fourteen female and 9 male patients aged 7 days to 23 years were included in the study. Most participants presented early in life (birth to 6 years), and motor deterioration was seen during childhood. A notable proportion of patients required a wheelchair before adolescence, suggesting a more severe phenotype than previously described in POLR3-HLD. Dental, ocular, and endocrine features were not invariably present (70%, 50%, and 50%, respectively). Five patients (22%) had a combination of hypomyelinating leukodystrophy and abnormal craniofacial development, including 1 individual with clear Treacher Collins syndrome (TCS) features. Brain MRI revealed hypomyelination in all cases, often with areas of pronounced T2 hyperintensity corresponding to T1 hypointensity of the white matter. Twenty-nine different pathogenic variants (including 12 new disease-causing variants) in POLR1C were identified.

Conclusions

This study provides a comprehensive description of POLR3-HLD caused by biallelic POLR1C pathogenic variants based on the largest cohort of patients to date. These results suggest distinct characteristics of POLR1C-related disorder, with a spectrum of clinical involvement characterized by hypomyelinating leukodystrophy with or without abnormal craniofacial development reminiscent of TCS.

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<![CDATA[Defining and expanding the phenotype of QARS-associated developmental epileptic encephalopathy]]> https://www.researchpad.co/article/N78398b08-34c8-4bbf-8bef-634630dcca64

Objective

The study is aimed at widening the clinical and genetic spectrum and at assessing genotype-phenotype associations in QARS encephalopathy.

Methods

Through diagnostic gene panel screening in an epilepsy cohort, and recruiting through GeneMatcher and our international network, we collected 10 patients with biallelic QARS variants. In addition, we collected data on 12 patients described in the literature to further delineate the associated phenotype in a total cohort of 22 patients. Computer modeling was used to assess changes on protein folding.

Results

Biallelic pathogenic variants in QARS cause a triad of progressive microcephaly, moderate to severe developmental delay, and early-onset epilepsy. Microcephaly was present at birth in 65%, and in all patients at follow-up. Moderate (14%) or severe (73%) developmental delay was characteristic, with no achievement of sitting (85%), walking (86%), or talking (90%). Additional features included irritability (91%), hypertonia/spasticity (75%), hypotonia (83%), stereotypic movements (75%), and short stature (56%). Seventy-nine percent had pharmacoresistant epilepsy with mainly neonatal onset. Characteristic cranial MRI findings include early-onset progressive atrophy of cerebral cortex (89%) and cerebellum (61%), enlargement of ventricles (95%), and age-dependent delayed myelination (88%). A small subset of patients displayed a less severe phenotype.

Conclusions

These data revealed first genotype-phenotype associations and may serve for improved interpretation of new QARS variants and well-founded genetic counseling.

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<![CDATA[Effect of Vergence/Accommodative Therapy on Reading in Children with Convergence Insufficiency: A Randomized Clinical Trial]]> https://www.researchpad.co/article/N3607d213-bf66-4446-8fbd-c620beef7470

SIGNIFICANCE

The results of this study suggest that clinicians providing vergence/accommodative therapy for the treatment of childhood convergence insufficiency should not suggest that such treatment, on average, will lead to improvements on standardized assessments of reading performance after 16 weeks of treatment.

PURPOSE

The purpose of this study was to determine the effect of office-based vergence/accommodative therapy on reading performance in 9- to 14-year-old children with symptomatic convergence insufficiency.

METHODS

In a multicenter clinical trial, 310 children 9 to 14 years old with symptomatic convergence insufficiency were randomized in a 2:1 ratio to 16 weeks of office-based vergence/accommodative therapy or office-based placebo therapy, respectively. The primary outcome was change in reading comprehension as measured by the reading comprehension subtest of the Wechsler Individual Achievement Test, Third Edition (WIAT-III) at the 16-week outcome. Secondary reading outcomes of word identification, reading fluency, listening comprehension, comprehension of extended text, and reading comprehension were also evaluated.

RESULTS

The adjusted mean improvement in WIAT-III reading comprehension was 3.7 (95% confidence interval [CI], 2.6 to 4.7) standard score points in the vergence/accommodative therapy group and 3.8 (95% CI, 2.4 to 5.2) points in the placebo therapy group, with an adjusted mean group difference of −0.12 (95% CI, −1.89 to 1.66) points that was not statistically significant. No statistically significant treatment group differences were found for any of the secondary reading outcome measures.

CONCLUSIONS

For children aged 9 to 14 years with symptomatic convergence insufficiency, office-based vergence/accommodative therapy was no more effective than office-based placebo therapy for improving reading performance on standardized reading tests after 16 weeks of treatment.

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<![CDATA[Treatment of Symptomatic Convergence Insufficiency in Children Enrolled in the Convergence Insufficiency Treatment Trial–Attention & Reading Trial]]> https://www.researchpad.co/article/Ne830819d-c059-4b41-9a68-6b6f7662a99e

ABSTRACT

SIGNIFICANCE

These data confirm the effectiveness of office-based vergence/accommodative therapy for improving convergence in children with symptomatic convergence insufficiency. They also highlight the importance of using a primary outcome measure that is as objective as possible rather than relying solely on self-reported symptoms for studies of binocular vision in children.

PURPOSE

The purpose of this study was to report changes in clinical signs and symptoms of convergence insufficiency (secondary outcome measures) from a multicenter clinical trial (Convergence Insufficiency Treatment Trial–Attention & Reading Trial [CITT-ART]) evaluating the effectiveness of vergence/accommodative therapy for improving reading and attention in children with symptomatic convergence insufficiency.

METHODS

Three hundred eleven children aged 9 to 14 years with symptomatic convergence insufficiency were randomly assigned to 16 weeks of office-based vergence/accommodative therapy or to placebo therapy. Improvements in (1) near point of convergence (NPC), (2) positive fusional vergence (PFV), and (3) self-reported symptoms (Convergence Insufficiency Symptom Survey [CISS] score) were compared after 16 weeks of treatment.

RESULTS

Mean NPC improved 10.4 cm in the vergence/accommodative and 6.2 cm in the placebo therapy group (mean difference of −4.2 cm [95% confidence interval {CI}, −5.2 to −3.2 cm; P < .001]); mean PFV increased 23.2 and 8.8Δ in the vergence/accommodative and placebo therapy groups, respectively (mean difference of 14.4Δ [95% CI, 12.1 to 16.8Δ; P < .001]). The mean CISS score improved 11.8 and 10.4 points in the vergence/accommodative and placebo therapy groups, respectively (mean difference of 1.5 points [95% CI, −3.8 to +0.8 points; P = .21]).

CONCLUSIONS

Our results demonstrate that office-based vergence/accommodative therapy is effective for improving the NPC and PFV in children with symptomatic convergence insufficiency. However, given that both treatment groups had a similar reduction in self-reported symptoms, it may not be prudent to use the CISS alone as a measure of successful treatment.

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<![CDATA[Contribution of normal aging to brain atrophy in MS]]> https://www.researchpad.co/article/N6475fbba-0f1d-4623-9bc0-c35c7013e9f6

Objective

To identify the top brain regions affected by MS-specific atrophy (i.e., atrophy in excess of normal aging) and to test whether normal aging and MS-specific atrophy increase or decrease in these regions with age.

Methods

Six hundred fifty subjects (2,790 MRI time points) were analyzed: 520 subjects with relapse-onset MS from a 5-year prospective cohort with annual standardized 1-mm 3D T1-weighted images (3DT1s; 2,483 MRIs) and 130 healthy controls with longitudinal 3DT1s (307 MRIs). Rates of change in all FreeSurfer regions (v5.3) and Structural Image Evaluation Using Normalization of Atrophy (SIENA) were estimated with mixed-effects models. All FreeSurfer regions were ranked by the MS-specific atrophy slope/standard error ratio (βMS × time/SEβMS × time). In the top regions, age was added as an effect modifier to test whether MS-specific atrophy varied by age.

Results

The top-ranked regions were all gray matter structures. For SIENA, normal aging increased from 0.01%/y at age 30 years to −0.31%/y at age 60 years (−0.11% ± 0.032%/decade, p < 0.01), whereas MS-specific atrophy decreased from −0.38%/y at age 30 years to −0.12%/y at age 60 years (0.09% ± 0.035%/decade, p = 0.01). Similarly, in the thalamus, normal aging increased from −0.15%/y at age 30 years to −0.62%/y at age 60 years (−0.16% ± 0.079%/decade, p < 0.05), and MS-specific atrophy decreased from −0.59%/y at age 30 years to −0.05%/y at age 60 years (0.18% ± 0.08%/decade, p < 0.05). In the putamen and caudate, normal aging and MS-specific atrophy did not vary by age.

Conclusions

For SIENA and thalamic atrophy, the contribution of normal aging increases with age, but does not change in the putamen and caudate. This may have substantial implications to understand the biology of brain atrophy in MS.

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<![CDATA[Lymphocyte pharmacodynamics are not associated with autoimmunity or efficacy after alemtuzumab]]> https://www.researchpad.co/article/N51ed4511-2943-462a-b897-b9f37a2aa73d

Objective

To examine the association between peripheral blood lymphocyte pharmacodynamics and autoimmune adverse events (AEs) or return of disease activity in alemtuzumab-treated patients with relapsing-remitting MS.

Methods

Patients received 2 alemtuzumab courses (12 mg/d IV; 5 days at baseline, 3 days 12 months later) in the 2-year Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis studies (NCT00530348 and NCT00548405) and could then receive as-needed alemtuzumab or other disease-modifying therapy in a 4-year extension (NCT00930553). Lymphocytes were phenotyped quarterly over 2 years using fluorescence-activated cell sorting. Pharmacodynamic assessments included counts of total lymphocytes, CD3+ T cells, CD4+/CD8+ T cells (total/naive/memory/regulatory [Treg]), and CD19+ B cells (total/immature/mature/memory) and ratios of CD19+ (total/immature/mature/memory) to Treg (CD4+/CD8+) counts. Assessed autoimmune AEs included immune thrombocytopenia, nephropathies, and thyroid events. Efficacy assessments included relapses, 6-month confirmed disability worsening (CDW), and MRI disease activity.

Results

Lymphocyte repopulation patterns, including ratios between distinct lymphocyte subsets (e.g., CD19+ to Treg cell count ratios), showed no significant differences over 2 years in patients developing/not developing autoimmune AEs, relapses, CDW, or MRI activity through 6 years following alemtuzumab. Lymphocyte kinetics were also unrelated to multiple autoimmune AEs or extreme clinical phenotypes.

Conclusions

Repopulation kinetics of the evaluated peripheral lymphocyte subsets did not predict autoimmune AE occurrence or disease activity, including return of disease activity after 2 alemtuzumab courses. Further study is needed to investigate potential antigen-level markers of treatment response.

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<![CDATA[Untangling normal aging from disease-related brain atrophy in MS]]> https://www.researchpad.co/article/Nf10589fe-173b-431e-8788-944f39e1938f ]]> <![CDATA[Quantitative 7T MRI does not detect occult brain damage in neuromyelitis optica]]> https://www.researchpad.co/article/5c973e41d5eed0c48496b30c

Objective

To investigate and compare occult damages in aquaporin-4 (AQP4)-rich periependymal regions in patients with neuromyelitis optica spectrum disorder (NMOSD) vs healthy controls (HCs) and patients with multiple sclerosis (MS) applying quantitative T1 mapping at 7 Tesla (T) in a cross-sectional study.

Methods

Eleven patients with NMOSD (median Expanded Disability Status Scale [EDSS] score 3.5, disease duration 9.3 years, age 43.7 years, and 11 female) seropositive for anti-AQP4 antibodies, 7 patients with MS (median EDSS score 1.5, disease duration 3.6, age 30.2 years, and 4 female), and 10 HCs underwent 7T MRI. The imaging protocol included T2*-weighted (w) imaging and an MP2RAGE sequence yielding 3D T1w images and quantitative T1 maps. We semiautomatically marked the lesion-free periependymal area around the cerebral aqueduct and the lateral, third, and fourth ventricles to finally measure and compare the T1 relaxation time within these areas.

Results

We did not observe any differences in the T1 relaxation time between patients with NMOSD and HCs (all p > 0.05). Contrarily, the T1 relaxation time was longer in patients with MS vs patients with NMOSD (lateral ventricle p = 0.056, third ventricle p = 0.173, fourth ventricle p = 0.016, and cerebral aqueduct p = 0.048) and vs HCs (third ventricle p = 0.027, fourth ventricle p = 0.013, lateral ventricle p = 0.043, and cerebral aqueduct p = 0.005).

Conclusion

Unlike in MS, we did not observe subtle T1 changes in lesion-free periependymal regions in NMOSD, which supports the hypothesis of a rather focal than diffuse brain pathology in NMOSD.

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<![CDATA[Real-world validation of the 2017 McDonald criteria for pediatric MS]]> https://www.researchpad.co/article/5c5f19ddd5eed0c484699dd0

Objective

To compare the diagnostic accuracy of the McDonald 2017 vs the McDonald 2010 criteria to predict a second attack of MS (clinically definite MS [CDMS]) at the first attack of acquired demyelinating syndromes (ADS).

Methods

One hundred sixty-four children (aged <18 years) with an incident attack of ADS were included in a prospective multicenter study between June 2006 and December 2016. Brain (and spinal if available) MRI was performed ≤3 months after symptom onset. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were compared at baseline between the 2010 and 2017 criteria.

Results

Among the 164 patients, 110 patients (67%) presented without encephalopathy (ADS–, female 63%; median age 14.8 years, IQR 11.3–16.1years) and 54 (33%) with encephalopathy (acute disseminated encephalomyelitis [ADEM], female 52%; median age 4.0 years, IQR 2.6–6.1 years). Of the 110 ADS– patients, 52 (47%) were diagnosed with CDMS within a median follow-up of 4.5 years (IQR 2.6–6.7 years). The sensitivity was higher for the 2017 criteria than for the 2010 criteria (83%; 95% CI 67–92, vs 49%; 95% CI 33–65; p < 0.001), but the specificity was lower (73%; 95% CI 59–84 vs 87%; 95% CI 74–94, p = 0.02). At baseline, 48 patients fulfilled the 2017 criteria compared with 27 patients when using the 2010 criteria. The results for children aged <12 years without encephalopathy were similar. In patients with ADEM, 8% fulfilled the 2010 criteria and 10% the 2017 criteria at baseline but no patient fulfilled the criteria for CDMS.

Conclusions

The McDonald 2017 criteria are more sensitive than the McDonald 2010 criteria for predicting CDMS at baseline. These criteria can also be applied in children aged <12 years without encephalopathy but not in children with ADEM.

Classification of evidence

This study provides Class II evidence that in children with ADS, the 2017 McDonald criteria are more sensitive but less specific than the 2010 McDonald criteria for predicting CDMS.

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<![CDATA[Anti-HMGCR myopathy may resemble limb-girdle muscular dystrophy]]> https://www.researchpad.co/article/5c2d42add5eed0c484e060b4

Objective

To determine the prevalence and clinical features of anti-HMGCR myopathy among patients with presumed limb-girdle muscular dystrophy (LGMD) in whom genetic testing has failed to elucidate causative mutations.

Methods

Patients with presumed LGMD and unrevealing genetic testing were selected based on a few clinico-pathologic features and tested for anti-HMGCR autoantibodies (n = 11). These clinico-pathologic features are peak creatine kinase (CK) greater than 1,000 IU/L and at least 3 of the following features: (1) limb-girdle pattern of weakness, (2) selective involvement of posterior thigh on clinical examination or muscle imaging, (3) dystrophic changes on muscle biopsy, and (4) no family history of muscular dystrophy.

Results

Six patients tested positive for anti-HMGCR autoantibodies. In 4, there was a presymptomatic phase, lasting as long as 10 years, characterized by elevated CK levels without weakness. Muscle biopsies revealed variable degrees of a dystrophic pathology without prominent inflammation. In an independent cohort of patients with anti-HMGCR myopathy, 17 of 51 (∼33%) patients were initially presumed to have a form of LGMD based on clinico-pathologic features but were ultimately found to have anti-HMGCR myopathy. Most of these patients responded favorably to immunomodulatory therapies, evidenced by reduction of CK levels and improved strength.

Conclusions

Anti-HMGCR myopathy can resemble LGMD. Diagnosis of patients with a LGMD-like presentation of anti-HMGCR myopathy is critical because these patients may respond favorably to immunotherapy, especially those with shorter disease duration.

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<![CDATA[Delineating FOXG1 syndrome]]> https://www.researchpad.co/article/5c16ccd9d5eed0c484523874

Objective

To provide new insights into the FOXG1-related clinical and imaging phenotypes and refine the phenotype-genotype correlation in FOXG1 syndrome.

Methods

We analyzed the clinical and imaging phenotypes of a cohort of 45 patients with a pathogenic or likely pathogenic FOXG1 variant and performed phenotype-genotype correlations.

Results

A total of 37 FOXG1 different heterozygous mutations were identified, of which 18 are novel. We described a broad spectrum of neurodevelopmental phenotypes, characterized by severe postnatal microcephaly and developmental delay accompanied by a hyperkinetic movement disorder, stereotypes and sleep disorders, and epileptic seizures. Our data highlighted 3 patterns of gyration, including frontal pachygyria in younger patients (26.7%), moderate simplified gyration (24.4%) and mildly simplified or normal gyration (48.9%), corpus callosum hypogenesis mostly in its frontal part, combined with moderate-to-severe myelination delay that improved and normalized with age. Frameshift and nonsense mutations in the N-terminus of FOXG1, which are the most common mutation types, show the most severe clinical features and MRI anomalies. However, patients with recurrent frameshift mutations c.460dupG and c.256dupC had variable clinical and imaging presentations.

Conclusions

These findings have implications for genetic counseling, providing evidence that N-terminal mutations and large deletions lead to more severe FOXG1 syndrome, although genotype-phenotype correlations are not necessarily straightforward in recurrent mutations. Together, these analyses support the view that FOXG1 syndrome is a specific disorder characterized by frontal pachygyria and delayed myelination in its most severe form and hypogenetic corpus callosum in its milder form.

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<![CDATA[Improving the signal subtle feature extraction performance based on dual improved fractal box dimension eigenvectors]]> https://www.researchpad.co/article/5b5aa3a1463d7e0c4334c365

Because of the limitations of the traditional fractal box-counting dimension algorithm in subtle feature extraction of radiation source signals, a dual improved generalized fractal box-counting dimension eigenvector algorithm is proposed. First, the radiation source signal was preprocessed, and a Hilbert transform was performed to obtain the instantaneous amplitude of the signal. Then, the improved fractal box-counting dimension of the signal instantaneous amplitude was extracted as the first eigenvector. At the same time, the improved fractal box-counting dimension of the signal without the Hilbert transform was extracted as the second eigenvector. Finally, the dual improved fractal box-counting dimension eigenvectors formed the multi-dimensional eigenvectors as signal subtle features, which were used for radiation source signal recognition by the grey relation algorithm. The experimental results show that, compared with the traditional fractal box-counting dimension algorithm and the single improved fractal box-counting dimension algorithm, the proposed dual improved fractal box-counting dimension algorithm can better extract the signal subtle distribution characteristics under different reconstruction phase space, and has a better recognition effect with good real-time performance.

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<![CDATA[Reversible frontotemporal brain sagging syndrome]]> https://www.researchpad.co/article/5bc1e4a440307c75cdb9a1a7 ]]> <![CDATA[Noether's symmetry and conserved quantity for a time-delayed Hamiltonian system of Herglotz type]]> https://www.researchpad.co/article/5c1522efd5eed0c4840bd764

The variational problem of Herglotz type and Noether's theorem for a time-delayed Hamiltonian system are studied. Firstly, the variational problem of Herglotz type with time delay in phase space is proposed, and the Hamilton canonical equations with time delay based on the Herglotz variational problem are derived. Secondly, by using the relationship between the non-isochronal variation and the isochronal variation, two basic formulae of variation of the Hamilton–Herglotz action with time delay in phase space are derived. Thirdly, the definition and criterion of the Noether symmetry for the time-delayed Hamiltonian system are established and the corresponding Noether's theorem is presented and proved. The theorem we obtained contains Noether's theorem of a time-delayed Hamiltonian system based on the classical variational problem and Noether's theorem of a Hamiltonian system based on the variational problem of Herglotz type as its special cases. At the end of the paper, an example is given to illustrate the application of the results.

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<![CDATA[Predicting long-term disability outcomes in patients with MS treated with teriflunomide in TEMSO]]> https://www.researchpad.co/article/5b406bed463d7e567d2eef4e

Objective:

To predict long-term disability outcomes in TEMSO core (NCT00134563) and extension (NCT00803049) studies in patients with relapsing forms of MS treated with teriflunomide.

Methods:

A post hoc analysis was conducted in a subgroup of patients who received teriflunomide in the core study, had MRI and clinical relapse assessments at months 12 (n = 552) and 18, and entered the extension. Patients were allocated risk scores for disability worsening (DW) after 1 year of teriflunomide treatment: 0 = low risk; 1 = intermediate risk; and 2–3 = high risk, based on the occurrence of relapses (0 to ≥2) and/or active (new and enlarging) T2-weighted (T2w) lesions (≤3 or >3) after the 1-year MRI. Patients in the intermediate-risk group were reclassified as responders or nonresponders (low or high risk) according to relapses and T2w lesions on the 18-month MRI. Long-term risk (7 years) of DW was assessed by Kaplan-Meier survival curves.

Results:

In patients with a score of 2–3, the risk of 12-week–confirmed DW over 7 years was significantly higher vs those with a score of 0 (hazard ratio [HR] = 1.96, p = 0.0044). Patients reclassified as high risk at month 18 (18.6%) had a significantly higher risk of DW vs those in the low-risk group (81.4%; HR = 1.92; p = 0.0004).

Conclusions:

Over 80% of patients receiving teriflunomide were classified as low risk (responders) and had a significantly lower risk of DW than those at increased risk (nonresponders) over 7 years of follow-up in TEMSO. Close monitoring of relapses and active T2w lesions after short-term teriflunomide treatment predicts a differential rate of subsequent DW long term.

ClinicalTrials.gov identifier:

TEMSO, NCT00134563; TEMSO extension, NCT00803049.

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<![CDATA[Germline and somatic mutations in STXBP1 with diverse neurodevelopmental phenotypes]]> https://www.researchpad.co/article/5b46c1f5463d7e636e826abd

Objective:

To expand the clinical phenotype associated with STXBP1 gene mutations and to understand the effect of STXBP1 mutations in the pathogenesis of focal cortical dysplasia (FCD).

Methods:

Patients with STXBP1 mutations were identified in various ways: as part of a retrospective cohort study of epileptic encephalopathy; through clinical referrals of individuals (10,619) with developmental delay (DD) for chromosomal microarray; and from a collection of 5,205 individuals with autism spectrum disorder (ASD) examined by whole-genome sequencing.

Results:

Seven patients with heterozygous de novo mutations affecting the coding region of STXBP1 were newly identified. Three cases had radiologic evidence suggestive of FCD. One male patient with early infantile epileptic encephalopathy, DD, and ASD achieved complete seizure remission following resection of dysplastic brain tissue. Examination of excised brain tissue identified mosaicism for STXBP1, providing evidence for a somatic mechanism. Cell-type expression analysis suggested neuron-specific expression. A comprehensive analysis of the published data revealed that 3.1% of severe epilepsy cases carry a pathogenic de novo mutation within STXBP1. By contrast, ASD was rarely associated with mutations in this gene in our large cohorts.

Conclusions:

STXBP1 mutations are an important cause of epilepsy and are also rarely associated with ASD. In a case with histologically proven FCD, an STXBP1 somatic mutation was identified, suggesting a role in its etiology. Removing such tissue may be curative for STXBP1-related epilepsy.

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