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Rhabdoid tumours (RT) are an aggressive malignancy affecting <2-year-old infants, characterised by biallelic loss-of-function alterations in SWI/SNF-related BAF chromatin remodelling complex subunit B1 (SMARCB1) in nearly all cases. Germline SMARCB1 alterations are found in ~30% of patients and define the RT Predisposition Syndrome type 1 (RTPS1). Uveal melanoma (UVM), the most common primary intraocular cancer in adults, does not harbour SMARCB1 alterations. We report two cases of a previously undescribed intraocular malignancy that shared some features with UVM and RT, but was also distinct from these entities. Both female patients, aged 23 and 14 years, underwent enucleation, and the tumours were subjected to comprehensive genomic, DNA methylation, and transcriptomic profiling. Pathological examination showed large, amelanotic intraocular tumours with epithelioid features, expressing melanocytic markers [S100P, SOX10, Melan-A, PMEL (HMB45), TYR] as seen using immunohistochemistry (IHC), but with little or no melanin production. Both tumours harboured biallelic loss-of-function SMARCB1 alterations, associated with loss of SMARCB1 (BAF47/INI1) expression on IHC. Their genomic profiles were atypical both for UVM and for RT, and no pathogenic variants were found in other genes tested, including those recurrently altered in UVM. In both patients, a germline SMARCB1 variant was found. However, there was no relevant family history of cancer. Transcriptome and methylome profiling suggested that these tumours were distinct from RT, UVM, and skin melanomas. RNAseq confirmed expression of early and late genes related to melanocytic differentiation. The first patient died of metastatic disease 16 months after diagnosis, the second was disease-free 10 months after completion of treatment. In summary, we report two cases of a previously undescribed, aggressive SMARCB1-deficient intraocular malignancy with melanocytic differentiation, which occurs in young patients, is distinct from UVM and RT, and expands the RTPS1 spectrum. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Background and Purpose: Cognitive impairment in multiple sclerosis (MS) is common and is associated with problems in employment, driving ability, and quality of life. Since cognitive impairment at time of diagnosis is predictive of disability progression, early assessment and annual monitoring is recommended. The Brief International Cognitive Assessment in Multiple Sclerosis (BICAMS) was introduced as a time-efficient screening tool that can easily be applied in standard clinical care. However, besides application, tests need to be analysed and the raw values obtained must be interpreted accordingly. Since normative values have not been available for German-speaking countries, BICAMS has not been implemented in clinical routine. The aim of this study was to calculate German normative BICAMS data to improve the current diagnostic process for people with MS., Methods: Healthy control subjects in different age categories were recruited to enable regression-based norm analysis. Raw scores for each BICAMS test were converted into scaled scores before they were regressed for age, age squared, gender, and education. The obtained scores were then normalised to a z-score by dividing the difference between the scaled score and the predicted score by the root mean squared error of the model., Results: In all, 237 HCs were recruited (68.8% female, 31.2% male) and examined with BICAMS. Datasets entered the regression-based norms analysis and formed the basis for a final z-score calculation. To simplify handling in everyday clinical practice, nomograms and look-up tables were created which provide clinicians with age- and education-corrected norms., Conclusion: Our work fills the gaps between BICAMS application, evaluation and interpretation and will make a significant contribution to more regular cognitive assessment of MS patients., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Medulloblastoma (MB) is one of the most prevalent embryonal malignant brain tumors. Current classification organizes these tumors into four molecular subgroups (WNT, SHH, Group 3, and Group 4 MB). Recently, a comprehensive classification has been established, identifying numerous subtypes, some of which exhibit a poor prognosis. It is critical to establish effective subtyping methods for accurate diagnosis and patient's management that strikes a delicate balance between improving outcomes and minimizing the risk of comorbidities., Methods: We evaluated the ability of Nanopore sequencing to provide clinically relevant methylation and copy number profiles of MB. Nanopore sequencing was applied to an EPIC cohort of 44 frozen MB, benchmarked against the gold standard EPIC array, and further evaluated on an integrated diagnosis cohort of 116 MB., Results: Most MB of both cohorts (42/44; 95.5% and 106/116; 91.4% respectively) were accurately subgrouped by Nanopore sequencing. Employing Flongle flow cells for 18 MB allowed a more rapid and cost-effective analysis, with 94.4% (17/18) being correctly classified. Nanopore sequencing enabled us to accurately subtype 28/30 (93.3%) MB., Conclusion: This study, conducted on the largest cohort of MB analyzed with Nanopore sequencing to date, establishes the proof of concept that this modern and innovative technology is well-suited for MB classification. Nanopore sequencing demonstrates a robust capacity for precise subtyping of MB, a critical advancement that holds significant potential for enhancing patient stratification in future clinical trials. Its ability to deliver quick and cost-effective results firmly establishes it as a game-changer in the field of MB classification., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: Infantile myofibromatosis is characterized by the development of myofibroblastic tumors in young children. In most cases, the disease is caused by somatic gain-of-function variants in platelet-derived growth factor (PDGF) receptor beta (PDGFRB). Here, we reported a novel germline intronic PDGFRB variant, c.2905-8G>A, in 6 unrelated infants with multifocal myofibromatosis and their relatives., Methods: We performed constitutional and tumor DNA and RNA sequencing to identify novel variants, which were subsequently characterized in cellular assays., Results: All patients had multiple skin nodules, 4 had bone lesions, and 2 had aggressive disease with bowel obstruction. The c.2905-8G>A substitution creates an alternative acceptor splice site in intron 21, inserting 2 codons in the PDGFRB transcript. Functional studies revealed that the splice change induced a partial loss of function, contrasting with previously described variants. In 4 tumor samples, we identified a second somatic hit at position Asp850 in PDGFRB exon 18, triggering constitutive receptor activation and resistance to imatinib. In addition to vinblastine and methotrexate, 2 patients received imatinib without objective response. One of them switched to dasatinib with concomitant improvement., Conclusion: This splice-site PDGFRB variant favors the development of myofibroma, featuring an acquired oncogenic variant in the same gene and resistance to targeted therapy., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Background: Rhabdoid tumors (RT) are aggressive, rare tumors predominantly affecting young children, characterized by biallelic SMARCB1 gene inactivation. While most SMARCB1 alterations are acquired de novo, a third of cases exhibit germline alterations, defining Rhabdoid Tumors Predisposition Syndrome. With the increased sensitivity of next-generation sequencing (NGS), mosaicisms in genes linked to genetic diseases are more detectable. This study focuses on exploring SMARCB1 germline alterations, notably mosaicism in blood samples of children with RT and in parents, using a custom NGS panel., Methods: A cohort of 280 children and 140 parents with germline analysis was studied. Germline DNA from 111 children with RT and 32 parents were reanalyzed with a custom NGS panel with 1500X average depth targeting the SMARCB1 gene to identify intragenic variants not detected with conventional low-sensitivity methods. Follow-up data was obtained for 77 patients., Results: Nine previously undetected mosaicism cases were identified, totaling 17/280 patients with a mosaic variant (6.1%) in the cohort, with variant allele frequencies between 0.9% and 33%, thus highlighting the prior underestimation of its prevalence. Follow-up data showed that 4 out of 7 survivors with mosaic variants developed distinct novel tumors, 2 sharing SMARCB1 alterations with the initial tumor, emphasizing the potential clinical impact of SMARCB1 mosaicism., Conclusions: The hitherto underestimated rate of SMARCB1 mosaicism in RT underscores the need for optimized genetic counseling and oncological monitoring. The findings have significant medical implications, considering the dire prognosis of RT., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: Transient Bartter syndrome related to pathogenic variants of MAGED2 is the most recently described antenatal Bartter syndrome. Despite its transient nature, it is the most severe form of Bartter syndrome in the perinatal period. Our aim was to describe 14 new cases and to try to explain the incomplete penetrance in women., Methods: We report on 14 new cases, including 3 females, and review the 40 cases described to date. We tested the hypothesis that MAGED2 is transcriptionally regulated by differential methylation of its CpG-rich promotor by pyrosequencing of DNA samples extracted from fetal and adult leukocytes and kidney samples., Results: Analysis of the data from 54 symptomatic patients showed spontaneous resolution of symptoms in 27% of cases, persistent complications in 41% of cases, and fatality in 32% of cases. Clinical anomalies were reported in 76% of patients, mostly renal anomalies (52%), cardiovascular anomalies (29%), and dysmorphic features (13%). A developmental delay was reported in 24% of patients. Variants were found in all regions of the gene. Methylation analysis of the MAGED2 CpG-rich promotor showed a correlation with gender, independent of age, tissue or presence of symptoms, excluding a role for this mechanism in the incomplete penetrance in women., Conclusion: This work enriches the phenotypic and genetic description of this recently described disease and deepens our understanding of the pathophysiological role and regulation of MAGED2. Finally, by describing the wide range of outcomes in patients, this work opens the discussion on genetic counseling offered to families., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Background: ELP1 pathogenic variants (PV) have been recently identified as the most frequent variants predisposing to Sonic Hedgehog (SHH) medulloblastomas (MB); however, guidelines are still lacking for genetic counseling in this new syndrome., Methods: We retrospectively reviewed clinical and genetic data of a French series of 29 ELP1 -mutated MB., Results: All patients developed SHH-MB, with a biallelic inactivation of PTCH1 found in 24 tumors. Other recurrent alterations encompassed the TP53 pathway and activation of MYCN/MYCL signaling. The median age at diagnosis was 7.3 years (range: 3-14). ELP1 -mutated MB behave as sporadic cases, with similar distribution within clinical and molecular risk groups and similar outcomes (5 y - OS = 86%); no unusual side effect of treatments was noticed. Remarkably, a germline ELP1 PV was identified in all patients with available constitutional DNA ( n  = 26); moreover, all tested familial trio ( n  = 11) revealed that the PVs were inherited. Two of the 26 index cases from the French series had a family history of MB; pedigrees from these patients and from 1 additional Dutch family suggested a weak penetrance. Apart from MB, no cancer was associated with ELP1 PVs; second tumors reported in 4 patients occurred within the irradiation fields, in the usual time-lapse for expected radiotherapy-induced neoplasms., Conclusions: The low penetrance, the "at risk' age window limited to childhood and the narrow tumor spectrum, question the actual benefit of genetic screening in these patients and their family. Our results suggest restricting ELP1 germline sequencing to patients with SHH-MB, depending on the parents" request., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

BRCA1 and BRCA2 are tumour suppressor genes that have been characterised as predisposition genes for the development of hereditary breast and ovarian cancers among other malignancies. The molecular diagnosis of this predisposition syndrome is based on the detection of inactivating variants of any type in those genes. But in the case of structural variants, functional consequences can be difficult to assess using standard molecular methods, as the precise resolution of their sequence is often impossible with short-read next generation sequencing techniques. It has been recently demonstrated that Oxford Nanopore long-read sequencing technology can accurately and rapidly provide genetic diagnoses of Mendelian diseases, including those linked to pathogenic structural variants. Here, we report the accurate resolution of a germline duplication event of exons 18-20 of BRCA1 using Nanopore sequencing with adaptive sampling target enrichment. This allowed us to classify this variant as pathogenic within a short timeframe of 10 days. This study provides a proof-of-concept that nanopore adaptive sampling is a highly efficient technique for the investigation of structural variants of tumour suppressor genes in a clinical context., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The MSH3 gene is part of the DNA mismatch repair system, but has never been shown to be involved in Lynch syndrome. A first report of four patients from two families, bearing biallelic MSH3 germline variants, with a phenotype of attenuated colorectal adenomatous polyposis raised the question of its involvement in hereditary cancer predisposition. The patients' tumours exhibited elevated microsatellite alterations at selected tetranucleotide repeats (EMAST), a hallmark of MSH3 deficiency., Methods: We report five new unrelated patients with MSH3 -associated polyposis. We describe their personal and familial history and study the EMAST phenotype in various normal and tumour samples, which are relevant findings based on the rarity of this polyposis subtype so far., Results: All patients had attenuated colorectal adenomatous polyposis, with duodenal polyposis in two cases. Both women had breast carcinomas. EMAST phenotype was present at various levels in different samples of the five patients, confirming the MSH3 deficiency, with a gradient of instability in polyps depending on their degree of dysplasia. The negative EMAST phenotype ruled out the diagnosis of germline MSH3 deficiency for two patients: one homozygous for a benign variant and one with a monoallelic large deletion., Conclusion: This report lends further credence to biallelic MSH3 germline pathogenic variants being involved in colorectal and duodenal adenomatous polyposis. Large-scale studies may help clarify the tumour spectrum and associated risks. Ascertainment of EMAST may help with the interpretation of variants of unknown significance. We recommend adding MSH3 to dedicated diagnostic gene panels., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Despite typically more pronounced cognitive and mental health issues in progressive disease courses of multiple sclerosis (PMS), rehabilitation research in this subgroup is rare. The efficacy of two non-pharmacological interventions with positive results from prior investigations was therefore examined in PMS specifically., Methods: Persons with PMS (pwPMS) received either computerized cognitive training (BrainStim), standardized cognitive-behavioral group sessions (Metacognitive Training [MaTiMS]), or a combination of both in an ambulatory setting. Neuropsychological assessment was conducted before and after the four-week intervention., Results: 37 participants (13 with primary/24 with secondary PMS, mean age = 52.87, SD age = 7.11, mean EDSS = 4.02, SD EDSS = 1.35) entered analyses. The BrainStim group improved in immediate and delayed verbal memory, recognition, verbal working memory, and perceived cognitive deficits while experiencing increased anxiety post-intervention. MaTiMS participants reported high program satisfaction and less cognitive difficulties at retest. The Combination group performed better in immediate and delayed verbal memory, and in information processing speed after training. Descriptive data further indicated positive effects on anxiety and depression in the MaTiMS and Combination group., Conclusions: While objective cognitive performance improved when explicitly trained, psychoeducative sessions contributed to subjective mental health. The combination of both approaches is thus suggested, considering the specific needs of pwPMS treated in an ambulatory setting.

Aims: The mutY DNA glycosylase encoded by the MUTYH gene prevents G:C → T:A transversions through the base excision repair DNA repair system. Germline biallelic pathogenic variants in MUTYH cause an adenomatous polyposis called MUTYH-associated polyposis (MAP), an autosomal recessive disease (OMIM: 608456), with an increased risk of colorectal cancer. Digestive lesions in this context show an excess of G:C → T:A transversions, individualising a specific mutational signature associated with MUTYH deficiency called signature SBS36. Predisposition to other tumours in patients with germline biallelic pathogenic variants in MUTYH is suspected but remains unclear. We report the first case of medulloblastoma in a patient with MAP, carrying the homozygous pathogenic variant c.1227&#95;1228dup, p.(Glu410Glyfs*43) in MUTYH., Methods: Whole exome sequencing was performed on the medulloblastoma to enlighten single nucleotide variants of interest, microsatellite status and mutational signature. The objective was to determine the involvement of MUTYH deficiency in the oncogenesis of this medulloblastoma., Results: The medulloblastoma has the mutational signature SBS36 and driver pathogenic variants in CTNNB1, PTCH1 and KDM6A corresponding to G:C → T:A transversions, suggesting a role of MUTYH deficiency in oncogenesis., Conclusions: Therefore, medulloblastoma could be a rare manifestation associated with germline biallelic pathogenic variants in MUTYH., (© 2023 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)

Objective: We aimed at examining the effects of a known metacognitive training in MS (MaTiMS) and its modification with an additional neuroeducational module and mindfulness-based exercises (MaTiMS-modified) on neuropsychiatric and cognitive outcomes in people with progressive multiple sclerosis (pwpMS). Exploratively, we investigated whether the modification may show an additional benefit., Methods: Both interventions were administered in small groups of ambulatory patients. Neuropsychological testing before and after the 3- to 4-week intervention phase comprised patient reported outcomes and cognitive tests. After 3, 6 and 12 months, participants completed online surveys. Analysis of change scores (between baseline and retest) with t-tests (Mann-Whitney U and Wilcoxon tests, respectively) and mixed ANCOVAs with repeated measures for comparison of both interventions were conducted., Results: A total of 65 pwpMS turned to a final sample of 50 (n = 15 excluded due to drop-outs, occurrence of relapse or steroid treatment). Change scores within MaTiMS revealed no significant effect on the PDQ-20 total score and only a significant effect on the subscale retrospective memory lasting 3 months with a moderate effect size. In contrast, MaTiMS-modified revealed a highly significant change in PDQ-20 total compared to baseline and significant improvements with small to moderate effect sizes on all PDQ-20 subscales (lasting until 3 months), in self-efficacy, stress, visuo-spatial working memory (moderate effect sizes), and fatigue (small effect size). While no interaction effect between time and group could be revealed, a significant main effect for time was found in PDQ-20 total., Conclusion: Both MaTiMS and MaTiMS-modified positively affected perceived cognitive deficits. However, our data speak in favor of additional benefits by adding neuroeducational and mindfulness-based exercises thus being valuable methods to support brain health including self-efficacy, perceived stress, and fatigue, even in patients with a chronic and progressive brain disease., (© 2023. The Author(s).)

SpliceAI is an open-source deep learning splicing prediction algorithm that has demonstrated in the past few years its high ability to predict splicing defects caused by DNA variations. However, its outputs present several drawbacks: (1) although the numerical values are very convenient for batch filtering, their precise interpretation can be difficult, (2) the outputs are delta scores which can sometimes mask a severe consequence, and (3) complex delins are most often not handled. We present here SpliceAI-visual, a free online tool based on the SpliceAI algorithm, and show how it complements the traditional SpliceAI analysis. First, SpliceAI-visual manipulates raw scores and not delta scores, as the latter can be misleading in certain circumstances. Second, the outcome of SpliceAI-visual is user-friendly thanks to the graphical presentation. Third, SpliceAI-visual is currently one of the only SpliceAI-derived implementations able to annotate complex variants (e.g., complex delins). We report here the benefits of using SpliceAI-visual and demonstrate its relevance in the assessment/modulation of the PVS1 classification criteria. We also show how SpliceAI-visual can elucidate several complex splicing defects taken from the literature but also from unpublished cases. SpliceAI-visual is available as a Google Colab notebook and has also been fully integrated in a free online variant interpretation tool, MobiDetails ( https://mobidetails.iurc.montp.inserm.fr/MD )., (© 2023. The Author(s).)

Introduction: In addition to physical and cognitive symptoms, patients with multiple sclerosis (MS) have an increased risk of experiencing mental health problems., Methods: This narrative review provides an overview of the appearance and epidemiology of affective symptoms in MS such as depression, anxiety, bipolar disorder, euphoria, and pseudobulbar affect. Furthermore, the association between affective symptoms and quality of life and the currently used diagnostic instruments for assessing these symptoms are considered whereby relevant studies published between 2009 and 2021 were included in the review., Results: Patients with mild and moderate disability more frequently reported severe problems with depression and anxiety than severe mobility problems. Apart from the occurrence of depression, little is known about the association of other affective symptoms such as anxiety, bipolar disorder, euphoria, and pseudobulbar affect and subsyndromal symptoms, which fail to meet the diagnostic criteria but are nevertheless a significant source of distress. Although there are a few recommendations in the research to perform routine screenings for diagnosable affective disorders, a standardized diagnostic procedure to assess subsyndromal symptoms is still lacking. As the applied measurements are diverse and show low accuracy to detect these symptoms, patients who experience affective symptoms are less likely to be identified., Discussion: In addition to the consideration of definite psychiatric diagnoses, there is an unmet need for a common definition and assessment of disease-related affective symptoms in MS. Future studies should focus on the improvement and standardization of a common diagnostic procedure for subsyndromal affective symptoms in MS to enable integrated and optimal care for patients., (© 2022. The Author(s).)

High oxygen affinity hemoglobin (HOAH) is the main cause of constitutional erythrocytosis. Mutations in the genes coding the alpha and beta globin chains ( HBA1 , HBA2 and HBB ) strengthen the binding of oxygen to hemoglobin (Hb), bringing about tissue hypoxia and a secondary erythrocytosis. The diagnosis of HOAH is based upon the identification of a mutation in HBA1 , HBA2 or HBB in specialized laboratories. Phenotypic studies of Hb are also useful, but electrophoretic analysis can be normal in 1/3 of cases. The establishment of the dissociation curve of Hb can be used as another screening test, a shift to the left indicating an increased affinity for Hb. The direct measurement of venous P50 using a Hemox Analyzer is of great importance, but due to specific analytic conditions, it is only available in a few specialized laboratories. Alternatively, an estimated measurement of the P50 can be obtained in most of the blood gas analyzers on venous blood. The aim of our study was therefore to determine whether a normal venous P50 value could rule out HOAH. We sequenced the HBB , HBA1 and HBA2 genes of 75 patients with idiopathic erythrocytosis. Patients had previously undergone an exhaustive medical check-up after which the venous P50 value was defined as normal. Surprisingly, sequencing detected HOAH in three patients (Hb Olympia in two patients, and Hb St Nazaire in another). A careful retrospective examination of their medical files revealed that (i) one of the P50 samples was arterial; (ii) there was some air in another sample; and (iii) the P50 measurement was not actually done in one of the patients. Our study shows that in real life conditions, due to pre-analytical contingencies, a venous P50 value that is classified as being normal may not be sufficient to rule out a diagnosis of HOAH. Therefore, we recommend the systematic sequencing of the HBB , HBA1 and HBA2 genes in the exploration of idiopathic erythrocytosis.

Background: Patients with multiple sclerosis (MS) suffer from cognitive impairment in 40-70% of the cases. There is evidence that the cognitive status is predictive for working ability and early retirement. Regular assessment of cognitive functionality is therefore urgently needed., Purpose: The German validation of the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) battery was evaluated in a multicentric way with respect to its feasibility in private neurological centers across Germany., Methods: Physician assistants were trained with respect to application and scoring of BICAMS. All scored test materials were evaluated by independent neuropsychological experts., Results: A total of 1606 BICAMS datasets were collected from 65 neurological centers. Of these 1573 datasets were analyzed of which 49.7% were correctly applied and scored while mistakes in application, scoring and transformation were found in 50.3%. Interrater reliability for each subtest was found to be ICC [Formula: see text] 0.953 when datasets containing mistakes were excluded., Discussion: In general, BICAMS is highly recommended to be applied in standard clinical care; however, it should be emphasized that although the interrater reliability in the final sample was high, serious mistakes were found in 50.3% of cases. From these findings we conclude that nonpsychological staff have to be even more intensively trained and supervised by experts in the application and scoring of BICAMS., (© 2021. The Author(s).)

Objective: Retinal layer thickness (RLT) measured by optical coherence tomography (OCT) is considered a noninvasive, cost-efficient marker of neurodegeneration in multiple sclerosis (MS). We aimed to investigate associations of RLT with cognitive performance and its potential as indicator of cognitive status in patients with MS by performing generalized estimating equation (GEE) analyses., Methods: In this cross-sectional study, patients with at least mild signs of cognitive impairment were examined by OCT as well as by the Brief International Cognitive Assessment for MS and tests assessing attention and executive functions (Trail Making Test [TMT] A and B). Associations of these factors were investigated using GEE models controlling for demographic and disease-related factors and correcting for multiple testing., Results: A total of 64 patients entered the study. In the final sample (n = 50 [n = 14 excluded due to missing data or drop-outs]; n = 44 relapsing-remitting MS and n = 6 secondary progressive MS, mean Expanded Disability Status Scale score = 2.59 [SD = 1.17], disease duration [median] = 7.34 [interquartile range = 12.1]), 36.0% were cognitively impaired. RLT of the macular retinal nerve fiber layer was associated with performance in TMT-B (β = -0.259). Analyses focusing on the upper and lower tertile of RLT additionally revealed associations between macular ganglion cell-inner plexiform layer and TMT-B and verbal short-term memory and learning, respectively., Conclusion: In patients with MS, at less advanced disease stages, RLT was especially associated with cognitive flexibility promoting OCT as a potential marker advocating further extensive neuropsychological examination., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Patients with Multiple Sclerosis (MS) have an increased risk of suffering from mental and neuropsychiatric symptoms. So far, a fundamental problem in the clinical care of MS patients is that these symptoms are underdiagnosed and, as a consequence, often remain untreated. Present assessment tools have not been developed to be applied in patients with MS. This study aims to develop and validate a new questionnaire to identify disease-related mental symptoms in MS patients., Methods: A questionnaire has been developed by including the following subscales: social and emotional health problems, anxiety, and depression. To evaluate test quality and internal consistency, an item analysis has been conducted. After matching MS patients and control subjects on age and gender, we conducted group comparisons, a Receiver Operating Characteristic (ROC) Curve analysis and a binary logistic regression model., Results: In total, 314 MS patients and 100 matched control subjects were analysed. After performed item analysis, the questionnaire revealed an excellent internal consistency (α=0.94). Compared to control subjects, MS patients showed significant mental health problems in all three dimensions. In comparison to the subscales, the dimension of social and emotional health problems revealed the highest accuracy (AUC = 0.75; d = 0.948) and turned out to be the only scale that reliably differentiated between the groups., Conclusions: MeSyMS constitutes a valid screening instrument to detect mental symptoms in MS. Social and emotional health problems turned out to be the most important aspect when identifying disease-related mental health symptoms in MS., (Copyright © 2021. Published by Elsevier B.V.)

A time series analysis of 871 543 pediatric emergency visits revealed that the coronavirus disease 2019 (COVID-19) lockdown and school closures were associated with a significant decrease in infectious diseases disseminated through airborne or fecal-oral transmission: common cold, gastroenteritis, bronchiolitis, and acute otitis. No change was found for urinary tract infections., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The international standard to screen for cognitive impairment in multiple sclerosis (MS) is BICAMS (Brief International Cognitive Assessment for MS). However, with an application time of approximately 20 minutes, the battery might be too time consuming from a pragmatic perspective of a routine examination., Objectives: To examine the relative sensitivity and specificity of a BICAMS short version and its validity compared to the total battery., Methods: The German BICAMS version was applied comprising the Symbol Digit Modalities Test (SDMT), the Brief Visuospatial Memory Test-Revised (BVMT-R) and the Rey Auditory Verbal Learning Test (RAVLT; German VLMT). Single tests and two-test combinations were compared regarding conformity with the total battery., Results: Examining 1320 MS patients, the two-test combination of SDMT-BVMT-R was the most sensitive (92.7%) to impairment and showed the strongest agreement with the total battery (κ = 0.95). Performing binary logistic regression analyses, this combination was also validated by its association with employment status., Conclusion: Application of the total BICAMS battery should be the goal to strive for. However, in time-restricted clinical settings, the combined application of SDMT and BVMT-R is a recommendable alternative with an application time of 10 minutes, while single tests alone are not sufficiently sensitive.

Background: Experiencing a decrease in working ability or even becoming unemployed is common in patients with multiple sclerosis (MS) and has a detrimental impact on the individual's quality of life, self-esteem, and on society's economic burden. Physical disability is still considered the most important predictor for patients' inability to work. This study aims to confirm and extend findings from prior studies indicating the additional importance of other demographical and clinical information accessible within a routine patient evaluation, placing particular emphasis on the inclusion of cognitive and neuropsychiatric measures, as well as on potential disease course differences., Methods: 159 MS patients (84 with a relapsing disease course (RMS); 75 with a progressive disease course (PMS)) were examined with the Brief International Cognitive Assessment for MS (BICAMS) battery, mood and fatigue questionnaires, and screened for subjectively experienced cognitive problems as well as for various person- and disease-related information (age, sex, education, age at diagnosis, disease duration, immunotherapy, number and nature of comorbidities, smoking and alcohol intake, sleep disturbances). These measures, along with Expanded Disability Status Scale (EDSS) scores were compared between unemployed, part- and full-time working patients. Significant variables were further entered into hierarchical regression models predicting employment status (employed vs. unemployed) as well as weekly hours at work in each disease subtype, respectively., Results: In patients with RMS, unemployed patients had higher EDSS scores, reported a higher number of comorbidities, more frequent past depressive episodes, a higher level of fatigue, and performed worse on the Symbol-Digit Modalities Test (SDMT) and the Brief Visuospatial Memory Test revised (BVMT-R). Besides EDSS, unemployment was predicted by SDMT, while weekly hours at work were further determined by the number of comorbidities, BVMT-R, and disease duration. In patients with PMS, unemployed patients also had higher EDSS scores, were younger at diagnosis, and showed a decreased performance in SDMT and the Rey Verbal Learning and Memory Test German version (Verbaler Lern- und Merkfaehigkeitstest; VLMT). Employment status as well as weekly working hours were both predicted by VLMT, educational level, and disease duration beyond EDSS in patients with PMS, while depressive episodes additionally impacted on employment status., Conclusions: Objectively assessed cognitive functions, neuropsychiatric symptoms (i.e. a history of depressive episodes, fatigue) as well as some specific clinical data (disease duration, comorbidities) add substantial value in the evaluation of working ability beyond physical disability. Since unemployment is associated with different major factors among disease courses, more comprehensive and customized assessments are needed to refine characterization of individual work ability and to adjust interventional strategies targeting employment maintenance., (Copyright © 2020. Published by Elsevier B.V.)

Objective: To explore the hypothesis that serum neurofilament light chain (sNfL) indicative of neuroaxonal damage may improve precise disease profiling with regard to cognition and neuropsychiatric symptoms, we analyzed potential associations of sNfL levels with cognitive test scores, fatigue, depression, and anxiety., Methods: Patients with relapsing-remitting and secondary progressive MS (SPMS) underwent an elaborated assessment including MRI, various cognitive tests, and patient-reported outcomes. We determined sNfL levels by single molecule array (Simoa) assay. Relationships between sNfL, cognition, neuropsychiatric symptoms, and demographical data were analyzed using correlations, group comparisons, and regressions., Results: In 45 clinically stable patients with MS (Expanded Disability Status Scale = 2.73 ± 1.12, disease duration = 10.03 ± 7.49 years), 40.0% were cognitively impaired. Mean sNfL levels were 16.02 ± 10.39 pg/mL, with higher levels in the SPMS subgroup ( p = 0.038). sNfL levels did reliably link neither with the investigated cognitive and affective parameters nor with fatigue levels. The only relationship found in a small subgroup of patients with SPMS (n = 7) with visuospatial learning ( r = -0.950, p = 0.001) and memory ( r = -0.813; p = 0.026) disappeared when further controlling for age, educational level, and sex., Conclusions: In patients with stable MS at less advanced disease stages, sNfL did not convincingly relate to cognitive performance, fatigue, depression, or anxiety and thus may not serve as a surrogate biomarker for neuropsychological status in such populations., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

With the proposal of the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) battery, the need to screen for cognitive deficits within standard clinical care of patients with multiple sclerosis (MS) has been acknowledged. Data regarding how patient characteristics might predict low cognitive performance and therefore require particularly close monitoring is, however, limited so far. We investigated a large, nationwide patient cohort from ambulatory settings, representing the typical distribution of different subtypes, levels of physical disability, and disease durations. Besides cognitive testing with BICAMS, additional sampling of multiple demographics and clinical variables allowed us to characterize general and domain-specific prevalence patterns of cognitive impairment (CI) as well as to delineate which factors are associated with cognitive performance. In a total of 1,094 patients, CI was present in 28% (using a conservative cut-off of the 5th percentile below normative values), with information-processing speed being most frequently affected. Impairment was overall higher in patients with primary progressive (PPMS) and secondary progressive MS than in patients with relapsing-remitting (RR)MS. Regression modelling revealed that disease subtype (i.e., PPMS), long disease duration, high physical disability, unemployment, low educational level, high age, male sex, and the absence of current disease-modifying treatment were important predictors for worse BICAMS' test performance. These results emphasize the importance of continuous cognitive assessment during regular neurological follow-up visits, with a particular focus on patients being identified as high-risk subjects for CI according to the reported factors., (© 2020 The British Psychological Society.)

African trypanosomes encode three monothiol glutaredoxins (1-C-Grx1 to 3). 1-C-Grx1 has a putative CAYS active site and Cys181 as single additional cysteine. The recombinant protein forms non-covalent homodimers. As observed for other monothiol glutaredoxins, Trypanosoma brucei 1-C-Grx1 was not active in the glutaredoxin assay with hydroxyethyl disulfide and glutathione nor catalyzed the reduction of insulin disulfide. In addition, it lacked peroxidase activity and did not catalyze protein (de)glutathionylation. Upon oxidation, 1-C-Grx1 forms an intramolecular disulfide bridge and, to a minor degree, covalent dimers. Both disulfide forms are reduced by the parasite trypanothione/tryparedoxin system. 1-C-Grx1 shows mitochondrial localization. The total cellular concentration is at least 5 microm. Thus, 1-C-Grx1 is an abundant protein especially in the rudimentary organelle of the mammalian form of the parasite. Expression of 1-C-Grx1 in Grx5-deficient yeast cells with its authentic presequence targeted the protein to the mitochondria and partially restored the growth phenotype and aconitase activity of the mutant, and conferred resistance against hydroperoxides and diamide. The parasite Grx2 and 3 failed to substitute for Grx5. This is surprising because even bacterial and plant 1-Cys-glutaredoxins efficiently revert the defects, and may be due to the lack of two basic residues conserved in all but the trypanosomatid proteins.