julilili42/papers huggingface dataset:
Application of big-data for epidemiological studies of refractive error
2021-04-23

Purpose To examine whether data sourced from electronic medical records (EMR) and a large industrial spectacle lens manufacturing database can estimate refractive error distribution within large populations as an alternative to typical population surveys of refractive error. Subjects A total of 555,528 patient visits from 28 Irish primary care optometry practices between the years 1980 and 2019 and 141,547,436 spectacle lens sales records from an international European lens manufacturer between the years 1998 and 2016. Methods Anonymized EMR data included demographic, refractive and visual acuity values. Anonymized spectacle lens data included refractive data. Spectacle lens data was separated into lenses containing an addition (ADD) and those without an addition (SV). The proportions of refractive errors from the EMR data and ADD lenses were compared to published results from the European Eye Epidemiology (E3) Consortium and the Gutenberg Health Study (GHS). Results Age and gender matched proportions of refractive error were comparable in the E3 data and the EMR data, with no significant difference in the overall refractive error distribution (χ 2 = 527, p = 0.29, DoF = 510). EMR data provided a closer match to the E3 refractive error distribution by age than the ADD lens data. The ADD lens data, however, provided a closer approximation to the E3 data for total myopia prevalence than the GHS data, up to age 64. Conclusions The prevalence of refractive error within a population can be estimated using EMR data in the absence of population surveys. Industry derived sales data can also provide insights on the epidemiology of refractive errors in a population over certain age ranges. EMR and industrial data may therefore provide a fast and cost-effective surrogate measure of refractive error distribution that can be used for future health service planning purposes.
Nanoimaging of Orientational Defects in Semiconducting Organic Films
2021-04-23

The development of defect analysis for inorganic semiconductors in the past century paved the way for the success story of today's electronics. By analogy, defect analysis plays a critical role in developing and improving devices based on organic molecular semiconductors. However, because of weak molecular interactions, absent in inorganic semiconductors, device-relevant thin organic films are susceptible to the formation of defects in the molecular orientation, which in turn have a profound impact on the performance in the optoelectronic applications. To address this problem, we broaden the applicability of scattering-type scanning near-field optical microscopy (s-SNOM) and utilize the light-induced anisotropic response of vibrational modes to reveal the defects in molecular orientation. We show that in the case of molecular islands with steep crystal facets only the scattered s-SNOM optical amplitude can be exploited to describe the molecular arrangement reliably, while the phase-based analysis leads to artifacts. The presented s-SNOM analysis of molecular defects can be universally applied to diverse topographies, even at the nanoscale.
Influence of Chêneau-Brace Therapy on Lumbar and Thoracic Spine and Its Interdependency with Cervical Spine Alignment in Patients with Adolescent Idiopathic Scoliosis (AIS)
2021-04-23

Chêneau-brace is an effective therapy tool for treatment in adolescent idiopathic scoliosis (AIS). Data on potential interdependent changes of the sagittal profile including the cervical spine are still sparse. The purpose of this study was to evaluate in-brace changes of the thoracic and lumbar spine and their influence on the pelvis and the cervical spine and apical vertebral rotation was reported. Ninety-three patients with AIS undergoing Chêneau-bracing were included. Patients were stratified by lumbar, thoracic and global spine alignment into normolordotic vs. hyperlordotic or normokyphotic vs. hypokyphotic or anteriorly aligned vs. posteriorly aligned groups. The coronal Cobb angle was significantly decreased in all groups indicating good correction while in-brace therapy. Sagittally, in-brace treatment led to significant flattening of lumbar lordosis (LL) in all stratified groups. Thoracic kyphosis (TK) was significantly flattened in the normokyphotic group, but no TK changes were noticed in the hypokyphotic group. Pelvic tilt (PT) stayed unchanged during the in-brace therapy. Chêneau-brace showed marginal changes in the lower cervical spine but had no influence on the upper cervical spine. The apical vertebral axis in primary and secondary curves was unchanged during the first radiological follow-up. Results from this study contribute to better understanding of initial spine behavior in sagittal and axial plane in the context of bracing.
Anti-intellectualism, instructive representations, and the intentional action argument
2021-04-23

Abstract Intellectualists hold that knowledge-how is a species of knowledge-that, and consequently that the knowledge involved in skill is propositional. In support of this view, the intentional action argument holds that since skills manifest in intentional action and since intentional action necessarily depends on propositional knowledge, skills necessarily depend on propositional knowledge. We challenge this argument, and suggest that instructive representations, as opposed to propositional attitudes, can better account for an agent’s reasons for action. While a propositional-causal theory of action, according to which intentional action must be causally produced “in the right way” by an agent’s proposition-involving reasons, has long held sway, we draw on Elizabeth Anscombe’s insights offer a path toward an alternative theory of action. In so doing, we reject the implicitly Cartesian conception of knowledge at the core of the intentional action argument, while hanging on to the idea that mental states are representations of a certain kind. Our argument provides theoretical support for anti-intellectualism by equipping philosophers with an account of non-propositional, practical content.
Oxytocin receptor expression patterns in the human brain across development
2021-04-23

Background: Oxytocin plays a vital role in social behavior and homeostatic processes, with animal models indicating that oxytocin receptor (OXTR) expression patterns in the brain influence behavior and physiology. However, the developmental trajectory of OXTR gene expression is unclear, which is considerable knowledge gap as many psychiatric illnesses emerge early in life and genes tend to be differentially regulated across development. Methods: We calculated spatiotemporal expression patterns for 16660 genes in the human brain using transcriptome data from 57 donors across the lifespan. Next, we explored the evolutionary origin of these patterns using a comparative gene expression dataset from 38 macaque donors. Finally, we determined the functional significance of OXTR spatiotemporal co-expression patterns via the annotation of genetic associations with psychiatric and body composition phenotypes.Results: OXTR expression in the brain accelerated before birth with a peak in early childhood and OXTR expression was highly correlated with dopamine receptor D2 expression across development. These gene expression patterns were not observed in a comparative macaque sample, suggesting they might be evolutionarily new features. In addition, a network of genes strongly spatiotemporally coupled with OXTR was enriched in schizophrenia, cognitive, and body composition phenotypes, with elements of this gene network having undergone positive selection in humans but not macaques.Conclusions: These results demonstrate that oxytocin signaling plays an important role in a diverse set of psychological and physiological processes across the lifespan. Identifying a critical window of OXTR expression in the brain, together with associated genes, may help illuminate our understanding of disease etiology.
Inter-choice dependent super-network weights.
2021-04-23

The automatic design of architectures for neural networks, Neural Architecture Search, has gained a lot of attention over the recent years, as the thereby created networks repeatedly broke state-of-the-art results for several disciplines. The network search spaces are often finite and designed by hand, in a way that a fixed and small number of decisions constitute a specific architecture. Given these circumstances, inter-choice dependencies are likely to exist and affect the network search, but are unaccounted for in the popular one-shot methods. We extend the Single-Path One-Shot search-networks with additional weights that depend on combinations of choices and analyze their effect. Experiments in NAS-Bench 201 and SubImageNet based search spaces show an improved super-network performance in only-convolutions settings and that the overhead is nearly negligible for sequential network designs.
Dravet variantSCN1AA1783Vimpairs interneuron firing predominantly by altered channel activation
2021-04-23

Abstract Dravet syndrome (DS) is a developmental epileptic encephalopathy mainly caused by functional Na V 1.1 haploinsufficiency in interneurons (IN). Recently, a new conditional mouse model expressing the recurrent human p.A1783V missense variant has become available. Here we provide an electrophysiological characterization of this variant in tsA201 cells, revealing both altered voltage-dependence of activation and slow inactivation without reduced sodium peak current density. Simulating IN excitability in a Hodgkin-Huxley one-compartment model suggested surprisingly similar firing deficits for Scn1a A1783V and full haploinsufficiency as caused by heterozygous truncation variants. Impaired Na V A1783V channel activation was predicted to have a significantly larger impact on channel function than altered slow inactivation and is therefore proposed as the main mechanism underlying IN dysfunction. The computational model was validated in cortical organotypic slice cultures derived from conditional Scn1a A1783V mice. Pan-neuronal activation of the p.A1783V variant in vitro confirmed the predicted IN firing deficit while demonstrating normal excitability of pyramidal neurons. Taken together these data demonstrate that despite maintained physiological peak currents density LOF gating properties may match effects of full haploinsufficiency on neuronal level, thereby causing DS. Highlights Na V 1.1 A1783V alters voltage-dependence of activation and slow inactivation while not affecting fast inactivation. Depolarizing and hyperpolarizing shifts of activation and slow inactivation curves result in combined channel loss of function (LOF). Simulations of Na V 1.1 A1783V interneuronal properties indicate reduced action potential firing rates comparable to full SCN1A haploinsufficiency, which is often found in Dravet syndrome. In silico modelling identifies impaired channel activation as the predominant mechanism of channel LOF. Panneuronal induction of Scn1a +/A1783V in a cortical slice culture model confirms restriction of loss of function and its restriction to interneurons.
Recurrent fusions inPLAGL1define a distinct subset of pediatric-type supratentorial ependymoma
2021-04-23

Abstract Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 ( PLAGL1 ) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2 , which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of largely ependymoma-like tumors. Immunohistochemically, tumors were GFAP-positive and OLIG2- and SOX10-negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. Consistent with other fusion-positive ependymal groups, all tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Analysis of time to progression or recurrence revealed survival times comparable to those of patients with ZFTA:RELA -fused ependymoma. In summary, our findings suggest the existence of a novel group of supratentorial ependymomas that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.
Integration of Complementary and Integrative Medicine Competencies in General Practice Postgraduate Education – Development of a Novel Competency Catalogue in Germany
2021-04-23

Abstract Background Complementary and Integrative medical procedures (CIM) play an important role in general practice (GP). Consequently, in some countries (e.g. USA, Australia) specific curricula for the integration of CIM competencies in GP postgraduate education exist. Although Germany is one of the countries where CIM is strongly integrated in general practice, no such catalogue exists up to date. The aim of this study was to define a set of CIM competencies that are seen as relevant and feasible for postgraduate education in the German general practice setting. Methods Firstly, a survey among GP trainees (n= 138) was performed in order to assess needs and attitudes towards CIM. Then, existing competency-based CIM curricula were identified in international literature, translated into German and compared with the needs assessment from the survey. Finally, in a multi-stage Delphi procedure, GP trainers, GP trainees and members of professional CIM associations (n= 131) evaluated a list of CIM competencies according to relevance and feasibility for general practice. Results Within this multistage process a final catalogue of 16 competencies was defined, covering the following areas: Medical knowledge, patient care and communication, practice-based learning, professionalism and competencies based on the German health care system. Conclusion The final catalogue of CIM competencies is intended to serve for GP training complementing the German competency-based curriculum for general practice. These competencies cover basic skills and are not intended to replace existing additional qualifications awarded by the medical associations in specific CIM methods, such as acupuncture or manual medicine. Therefore, a list of relevant competencies on CIM is available in order to serve as add-on for postgraduate education in general practice in Germany.
Designing a SARS-CoV-2 T-Cell-Inducing Vaccine for High-Risk Patient Groups
2021-04-24

We describe the results of two vaccinations of a self-experimenting healthy volunteer with SARS-CoV-2-derived peptides performed in March and April 2020, respectively. The first set of peptides contained eight peptides predicted to bind to the individual’s HLA molecules. The second set consisted of ten peptides predicted to bind promiscuously to several HLA-DR allotypes. The vaccine formulation contained the new TLR 1/2 agonist XS15 and was administered as an emulsion in Montanide as a single subcutaneous injection. Peripheral blood mononuclear cells isolated from blood drawn before and after vaccinations were assessed using Interferon-γ ELISpot assays and intracellular cytokine staining. We detected vaccine-induced CD4 T cell responses against six out of 11 peptides predicted to bind to HLA-DR after 19 days, following vaccination, for one peptide already at day 12. We used these results to support the design of a T-cell-inducing vaccine for application in high-risk patients, with weakened lymphocyte performance. Meanwhile, an according vaccine, incorporating T cell epitopes predominant in convalescents, is undergoing clinical trial testing.
A Special View of What Was Almost Forgotten: p38δ MAPK
2021-04-25

The p38δ mitogen-activated protein kinase is an important signal transduction enzyme. p38δ has recently emerged as a drug target due to its tissue-specific expression patterns and its critical roles in regulation of cellular processes related to cancer and inflammatory diseases, such as cell proliferation, cell migration, apoptosis, and inflammatory responses. However, potent and specific p38δ inhibitors have not been defined so far. Moreover, in cancer disease, p38δ appears to act as a tumor suppressor or tumor promoter according to cancer and cell type studied. In this review, we outline the current understanding of p38δ roles in each cancer type, to define whether it is possible to delineate new cancer therapies based on small-molecule p38δ inhibitors. We also highlight recent advances made in the design of molecules with potential to inhibit p38 isoforms and discuss structural approaches to guide the search for p38δ inhibitors.
Specific changes in sleep oscillations after blocking human metabotropic glutamate receptor 5 in the absence of altered memory function
2021-04-25

Background: Sleep consolidates declarative memory by repeated replay linked to the cardinal oscillations of non-rapid eye movement (NonREM) sleep. However, there is so far little evidence of classical glutamatergic plasticity induced by this replay. Rather, we have previously reported that blocking N-methyl-D-aspartate (NMDA) or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors does not affect sleep-dependent consolidation of declarative memory. Aims: The aim of this study was to investigate the role of metabotropic glutamate receptor 5 (mGluR5) in memory processing during sleep. Methods: In two placebo-controlled within-subject crossover experiments with 20 healthy humans each, we used fenobam to block mGluR5 during sleep. In Experiment I, participants learned word-pairs (declarative task) and a finger sequence (procedural task) in the evening, then received the drug and recall was tested the next morning. To cover possible effects on synaptic renormalization processes during sleep, in Experiment II participants learned new word-pairs in the morning after sleep. Results/outcomes: Surprisingly, fenobam neither reduced retention of memory across sleep nor new learning after sleep, although it severely altered sleep architecture and memory-relevant EEG oscillations. In NonREM sleep, fenobam suppressed 12–15 Hz spindles but augmented 2–4 Hz delta waves, whereas in rapid eye movement (REM) sleep it suppressed 4–8 Hz theta and 16–22 Hz beta waves. Notably, under fenobam NonREM spindles became more consistently phase-coupled to the slow oscillation. Conclusions/interpretations: Our findings indicate that mGluR5-related plasticity is not essential for memory processing during sleep, even though mGlurR5 are strongly implicated in the regulation of the cardinal sleep oscillations.
Real-life survey of pitfalls and successes of precision medicine in genetic epilepsies
2021-04-26

Objective The term ‘precision medicine’ describes a rational treatment strategy tailored to one person that reverses or modifies the disease pathophysiology. In epilepsy, single case and small cohort reports document nascent precision medicine strategies in specific genetic epilepsies. The aim of this multicentre observational study was to investigate the deeper complexity of precision medicine in epilepsy. Methods A systematic survey of patients with epilepsy with a molecular genetic diagnosis was conducted in six tertiary epilepsy centres including children and adults. A standardised questionnaire was used for data collection, including genetic findings and impact on clinical and therapeutic management. Results We included 293 patients with genetic epilepsies, 137 children and 156 adults, 162 females and 131 males. Treatment changes were undertaken because of the genetic findings in 94 patients (32%), including rational precision medicine treatment and/or a treatment change prompted by the genetic diagnosis, but not directly related to known pathophysiological mechanisms. There was a rational precision medicine treatment for 56 patients (19%), and this was tried in 33/56 (59%) and was successful (ie, &gt;50% seizure reduction) in 10/33 (30%) patients. In 73/293 (25%) patients there was a treatment change prompted by the genetic diagnosis, but not directly related to known pathophysiological mechanisms, and this was successful in 24/73 (33%). Significance Our survey of clinical practice in specialised epilepsy centres shows high variability of clinical outcomes following the identification of a genetic cause for an epilepsy. Meaningful change in the treatment paradigm after genetic testing is not yet possible for many people with epilepsy. This systematic survey provides an overview of the current application of precision medicine in the epilepsies, and suggests the adoption of a more considered approach.
Investigation of Autosomal Genetic Sex Differences in Parkinson's Disease
2021-04-26

Objective Parkinson's disease (PD) is a complex neurodegenerative disorder. Men are on average ~ 1.5 times more likely to develop PD compared to women with European ancestry. Over the years, genomewide association studies (GWAS) have identified numerous genetic risk factors for PD, however, it is unclear whether genetics contribute to disease etiology in a sex‐specific manner. Methods In an effort to study sex‐specific genetic factors associated with PD, we explored 2 large genetic datasets from the International Parkinson's Disease Genomics Consortium and the UK Biobank consisting of 13,020 male PD cases, 7,936 paternal proxy cases, 89,660 male controls, 7,947 female PD cases, 5,473 maternal proxy cases, and 90,662 female controls. We performed GWAS meta‐analyses to identify distinct patterns of genetic risk contributing to disease in male versus female PD cases. Results In total, 19 genomewide significant regions were identified and no sex‐specific effects were observed. A high genetic correlation between the male and female PD GWAS were identified (rg = 0.877) and heritability estimates were identical between male and female PD cases (~ 20%). Interpretation We did not detect any significant genetic differences between male or female PD cases. Our study does not support the notion that common genetic variation on the autosomes could explain the difference in prevalence of PD between males and females cases at least when considering the current sample size under study. Further studies are warranted to investigate the genetic architecture of PD explained by X and Y chromosomes and further evaluate environmental effects that could potentially contribute to PD etiology in male versus female patients. ANN NEUROL 2021;90:41–48