Erlandsenboel8925

Interleukin 7 receptor α-chain is crucial for the development and maintenance of T cells and is genetically associated with autoimmune disorders including multiple sclerosis (MS), a demyelinating disease of the CNS. Seclidemstat ic50 Exon 6 of IL7R encodes for the transmembrane domain of the receptor and is regulated by alternative splicing inclusion or skipping of IL7R exon 6 results in membrane-bound or soluble IL7R isoforms, respectively. We previously identified a SNP (rs6897932) in IL7R exon 6, strongly associated with MS risk and showed that the risk allele (C) increases skipping of the exon, resulting in elevated levels of sIL7R. This has important pathological consequences as elevated levels of sIL7R has been shown to exacerbate the disease in the experimental autoimmune encephalomyelitis mouse model of MS. Understanding the regulation of exon 6 splicing provides important mechanistic insights into the pathogenesis of MS. Here we report two mechanisms by which IL7R exon 6 is controlled. First, a competition between PTBP1 and U2AF2 at the polypyrimidine tract (PPT) of intron 5, and second, an unexpected U2AF2-mediated assembly of spicing factors in the exon. We noted the presence of a branchpoint sequence (BPS) (TACTAAT or TACTAAC) within exon 6, which is stronger with the C allele. We also noted that the BPS is followed by a PPT and conjectured that silencing could be mediated by the binding of U2AF2 to that tract. In support of this model, we show that evolutionary conservation of the exonic PPT correlates well with the degree of alternative splicing of exon 6 in two non-human primate species and that U2AF2 binding to this PPT recruits U2 snRNP components to the exon. link2 These observations provide the first explanation for the stronger silencing of IL7R exon 6 with the disease associated C allele at rs6897932.

To assess the benefits and limitations of whole genome sequencing (WGS) compared to exome sequencing (ES) or multigene panel (MGP) in the molecular diagnosis of developmental and epileptic encephalopathies (DEE).

We performed WGS of 30 comprehensively phenotyped DEE patient trios that were undiagnosed after first-tier testing, including chromosomal microarray and either research ES (n = 15) or diagnostic MGP (n = 15).

Eight diagnoses were made in the 15 individuals who received prior ES (53%) 3 individuals had complex structural variants; 5 had ES-detectable variants, which now had additional evidence for pathogenicity. Eleven diagnoses were made in the 15 MGP-negative individuals (68%); the majority (n = 10) involved genes not included in the panel, particularly in individuals with postneonatal onset of seizures and those with more complex presentations including movement disorders, dysmorphic features, or multiorgan involvement. A total of 42% of diagnoses were autosomal recessive or X-chromosome linked.

WGS was able to improve diagnostic yield over ES primarily through the detection of complex structural variants (n = 3). The higher diagnostic yield was otherwise better attributed to the power of re-analysis rather than inherent advantages of the WGS platform. Additional research is required to assist in the assessment of pathogenicity of novel noncoding and complex structural variants and further improve diagnostic yield for patients with DEE and other neurogenetic disorders.

WGS was able to improve diagnostic yield over ES primarily through the detection of complex structural variants (n = 3). The higher diagnostic yield was otherwise better attributed to the power of re-analysis rather than inherent advantages of the WGS platform. Additional research is required to assist in the assessment of pathogenicity of novel noncoding and complex structural variants and further improve diagnostic yield for patients with DEE and other neurogenetic disorders.

To determine the publication rate of motor-rehabilitation trials poststroke and the consistency between registry records and their corresponding main publications in trial design, primary objectives and outcomes, eligibility criteria, and sample size.

We searched 18 clinical trial registries to identify randomized controlled trials of motor-based stroke rehabilitation registered after July 2005 and completed before April 2017. Eligible trials included adults with stroke, with at least one outcome measure related to motor function. Information in the registry records was compared with that of their main publications, if any.

Three hundred twenty-three trials met our eligibility criteria; we were unable to find a peer-reviewed publication reporting the main findings for 46% (150/323) of these. link3 Of the 169 trials with peer-reviewed articles published in English, 141 (83%) were consistent with the registry record in trial design, 100 (59%) were consistent in primary objectives, 71 (42%) were consistent in pr meta-analysis to help ensure that reviews are unbiased.

We developed and investigated the feasibility of a machine learning-based automated rating for the 2 cardinal symptoms of Parkinson disease (PD) resting tremor and bradykinesia.

Using OpenPose, a deep learning-based human pose estimation program, we analyzed video clips for resting tremor and finger tapping of the bilateral upper limbs of 55 patients with PD (110 arms). Key motion parameters, including resting tremor amplitude and finger tapping speed, amplitude, and fatigue, were extracted to develop a machine learning-based automatic Unified Parkinson's Disease Rating Scale (UPDRS) rating using support vector machine (SVM) method. To evaluate the performance of this model, we calculated weighted κ and intraclass correlation coefficients (ICCs) between the model and the gold standard rating by a movement disorder specialist who is trained and certified by the Movement Disorder Society for UPDRS rating. These values were compared to weighted κ and ICC between a nontrained human rater and the gold standard.

To investigate the extent to which the incidence and mortality of a first-time stroke among younger and older adults changed from 2005 to 2018 in Denmark using nationwide registries.

We used the Danish Stroke Registry and the Danish National Patient Registry to identify patients 18 to 49 years of age (younger adults) and those ≥50 years of age (older adults) with a first-time ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage. We computed age-standardized incidence rates and 30-day and 1-year mortality risks separately for younger and older adults and according to smaller age groups, stroke subtype, sex, and severity (Scandinavian Stroke Scale score). Average annual percentage changes (AAPCs) were computed to assess temporal trends.

We identified 8,680 younger adults and 105,240 older adults with an ischemic stroke or intracerebral hemorrhage. The incidence rate per 100,000 person-years of ischemic stroke (20.8 in 2005 and 21.9 in 2018, AAPC -0.6 [95% confidence interval (CI) -1.5 to 0.3]) and intracerebral hemorrhage (2.2 in 2005 and 2.5 in 2018, AAPC 0.6 [95% CI -1.0 to 2.3]) remained steady in younger adults. In older adults, rates of ischemic stroke and intracerebral hemorrhage declined, particularly in those ≥70 years of age. Rates of subarachnoid hemorrhage declined, but more so in younger than older adults. Stroke mortality declined over time in both age groups, attributable largely to declines in the mortality after severe strokes. Most trends were similar for men and women.

The incidence of ischemic stroke and intracerebral hemorrhage was steady in younger adults from 2005 to 2018, while it dropped in adults >70 years of age. Stroke mortality declined during this time.

70 years of age. Stroke mortality declined during this time.

To test the hypothesis that de novo genetic variants are responsible for moyamoya disease (MMD) in children with unaffected relatives, we performed exome sequencing of 28 affected children and their unaffected parents.

Exome sequencing was performed on 28 trios of affected patients with MMD and unaffected parents.

We identified 3 novel rare de novo

variants, 1 in the RING domain and 2 in a highly conserved region distal to the RING domain (4,114-4,120). These de novo cases of MMD present at a young age with aggressive MMD and uniquely have additional occlusive vascular lesions, including renal artery stenosis. Two previously reported cases had de novo variants in the same limited region and presented young with aggressive MMD, and 1 case had narrowing of the inferior abdominal aorta.

These results indicate a novel syndrome associated with

rare variants defined by de novo mutations disrupting highly conserved amino acids in the RING domain and a discrete region distal to the RING domain delimited by amino acids 4,114 to 4,120 leading to onset of severe MMD before 3 years of age and occlusion of other arteries, including the abdominal aorta, renal, iliac, and femoral arteries.

These results indicate a novel syndrome associated with RNF213 rare variants defined by de novo mutations disrupting highly conserved amino acids in the RING domain and a discrete region distal to the RING domain delimited by amino acids 4,114 to 4,120 leading to onset of severe MMD before 3 years of age and occlusion of other arteries, including the abdominal aorta, renal, iliac, and femoral arteries.

To determine how young stroke survivors want their unmet needs to be addressed, we undertook an international online survey of people living with stroke.

Participants self-selected to complete an online survey that included a questionnaire on demographics and stroke-related characteristics, the Young Stroke Needs Screening Tool, and a questionnaire on how they wanted their needs to be met.

One hundred seventy-one responses were received (68% female respondents, mean age 45 years, interquartile range 36-51 years). Preferences for methods of meeting needs varied depending on the domain of need and participants' demographic and stroke-related characteristics. Face-to-face contact with a health care professional was a popular means of meeting needs, but methods outside of a traditional health care setting such as a succinct list of tips or peer support were widely acceptable and sometimes preferred.

This work provides the impetus for developing alternative methods of meeting young stroke survivors' needs, many of which are not resource intensive or do not require an appointment with a health care professional.

This work provides the impetus for developing alternative methods of meeting young stroke survivors' needs, many of which are not resource intensive or do not require an appointment with a health care professional.

To determine whether stable polymorphisms that define mitochondrial haplogroups in mitochondrial DNA (mtDNA) are associated with Pick disease risk, we genotyped 52 pathologically confirmed cases of Pick disease and 910 neurologically healthy controls and performed case-control association analysis.

Fifty-two pathologically confirmed cases of Pick disease from Mayo Clinic Florida (n = 38) and the University of Pennsylvania (n = 14) and 910 neurologically healthy controls collected from Mayo Clinic Florida were genotyped for unique mtDNA haplogroup-defining variants. Mitochondrial haplogroups were determined, and in a case-control analysis, associations of mtDNA haplogroups with risk of Pick disease were evaluated with logistic regression models that were adjusted for age and sex.

No individual mtDNA haplogroups or superhaplogroups were significantly associated with risk of Pick disease after adjustment for multiple testing (

< 0.0021, considered significant). However, nominally significant (

< 0.