25 research outputs found
First principles calculation of inhomogeneous broadening in solid-state cw-EPR spectroscopy
We present a scheme for the first-principles calculation of EPR lineshapes for
continuous-wave-EPR spectroscopy (cw-EPR) of spin centers in complex chemical
environments. We specifically focus on poorly characterized systems, e.g.
powders and frozen glasses with variable microsolvation structures. Our
approach is based on ab initio molecular dynamics simulations and ab initio
calculations of the ensemble of g- and A-tensors along the trajectory. The
method incorporates temperature effects as well as the full anharmonicity of
the intra- and intermolecular degrees of freedom of the system. We apply this
scheme to compute the lineshape of a prototypical spin probe, the
nitrosodisulfonate dianionic radical (Fremy's salt), dissolved in a 50 : 50
mixture of water and methanol. We are able to determine the specific effect of
variations of local solvent composition and microsolvation structure on the
cw-EPR lineshape. Our molecular dynamics reveal a highly anisotropic solvation
structure with distinct spatial preferences for water and methanol around
Fremy's salt that can be traced back to a combination of steric and polar
influences. The overall solvation structure and conformational preferences of
Fremy's salt as found in our MD simulations agree very well with the results
obtained from EPR and orientation-selective ENDOR spectroscopy performed on
the frozen glass. The simulated EPR lineshapes show good agreement with the
experimental spectra. When combined with our MD results, they characterize the
lineshape dependence on local morphological fluctuations
Monogenic variants in dystonia: an exome-wide sequencing study
Background Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia. Methods For this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow. Findings We sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45%] of 222;excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19%] of 98) or isolated (16 [4%] of 388) dystonia. Across all categories of dystonia, 104 (65%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism. Interpretation In this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations
Tuebingen CD-25 Is a Sensitive Tool to Investigate Health-Related Quality of Life in Cushing's Disease Patients in the Course of the Disease
What's in a name? The impact of reputation and rankings on the teaching income of English universities
What's in a name? The impact of reputation and rankings on the teaching income of English universities
Quality of Life Changes Before and After Transsphenoidal Surgery for Sellar and Parasellar Lesions
Pediatric ICU Admissions After Adolescent Suicide Attempts During the Pandemic
BACKGROUND AND OBJECTIVES: The worldwide severe acute respiratory syndrome coronavirus 2 pandemic challenges adolescents' mental health. In this study, we aim to compare the number of pediatric ICU (PICU) admissions after suicide attempts during the first German lockdown and one year later during a second, prolonged lockdown with prepandemic years. METHODS: A retrospective multicenter study was conducted among 27 German PICUs. Cases < 18 years admitted to the PICU because of accidents or injuries between March 16 and May 31 of 2017 to 2021 were identified based on International Classification of Diseases, 10th Revision codes (German modification) and patient data entered into a database. This study is a subset analysis on suicide attempts in adolescents aged 12 to 17.9 years. The Federal Statistics Office was queried for data on fatal suicides, which were available only for 2020 in adolescents aged 10 to 17.9 years. RESULTS: Total admissions and suicide attempts declined during the first lockdown in 2020 (standardized morbidity ratio 0.74 (95% confidence interval; 0.58-0.92) and 0.69 (0.43-1.04), respectively) and increased in 2021 (standardized morbidity ratio 2.14 [1.86-2.45] and 2.84 [2.29-3.49], respectively). Fatal suicide rates remained stable between 2017 to 2019 and 2020 (1.57 vs 1.48 per 100 000 adolescent years) with monthly numbers showing no clear trend during the course of 2020. CONCLUSIONS: This study shows a strong increase in serious suicide attempts among adolescents during the course of the pandemic in Germany. More research is needed to understand the relation between pandemic prevention measures and suicidal ideation to help implement mental health support for adolescents