julilili42/papers huggingface dataset:
Optimizing Patient Selection for Interhospital Transfer and Endovascular Therapy in Acute Ischemic Stroke: Real-World Data From a Supraregional, Hub-and-Spoke Neurovascular Network in Germany
2020-12-04

Background: Interhospital transfer for endovascular treatment (EVT) within neurovascular networks might result in transfer of patients who will not undergo EVT (futile transfer). Limited evidence exists on factors associated with the primary patient selection for interhospital transfer from primary stroke centers (PSCs) to comprehensive stroke centers (CSCs), or EVT-workflow parameters that may render a transfer futile. Methods: A prospective, registry-based study was performed between July 1, 2017 and June 30, 2018, at a hub-and-spoke neurovascular network in southwest Germany, comprising 12 referring PSCs and one designated CSC providing round-the-clock EVT at the University Hospital Tübingen. Patients with acute ischemic stroke due to suspected large artery occlusion (LAO) were included upon emergency interhospital transfer inquiry (ITI). Results: ITI was made for 154 patients, 91 (59%) of whom were transferred to the CSC. Non-transferred patients (41%) had significantly higher premorbid modified Rankin scale scores (mRS) compared to transferred patients [median (IQR): 2 (1–3) vs. 0 (0–1), p &amp;lt; 0.001]. Interhospital transfer was denied due to: distal vessel occlusion (44.4%), or non-verifiable LAO (33.3%) in computed tomography angiography (CTA) upon teleconsultation by CSC neuroradiologists; limited Stroke-Unit or ventilation capacity (9.5%), or limited neuroradiological capacity at the CSC (12.7%). The CT-to-ITI interval was significantly longer in patients denied interhospital transfer [median (IQR): 43 (29–56) min] compared to transferred patients [29 (15–55), p = 0.029]. No further differences in EVT-workflow, and no differences in the 3-month mRS outcomes were noted between non-transferred and transferred patients [median (IQR): 2 (0–5) vs. 3 (1–4), p = 0.189]. After transfer to the CSC, 44 (48%) patients underwent EVT. The Alberta stroke program early CT score [ORadj (95% CI): 1.786 (1.573–2.028), p &amp;lt; 0.001] and the CT-to-ITI interval [0.994 (0.991–0.998), p = 0.001] were significant predictors of the likelihood of EVT performance. Conclusion: Our findings show that hub-and-spoke neurovascular network infrastructures efficiently enable access to EVT to patients with AIS due to LAO, who are primarily admitted to PSCs without on-site EVT availability. As in real-world settings optimal allocation of EVT resources is warranted, teleconsultation by experienced endovascular interventionists and prompt interhospital-transfer-inquiries are crucial to reduce the futile transfer rates and optimize patient selection for EVT within neurovascular networks.
Analyzing the linguistic complexity of German learner language in a reading comprehension task
2020-12-04

Abstract While traditionally linguistic complexity analysis of learner language is mostly based on essays, there is increasing interest in other task types. This is crucial for obtaining a broader empirical basis for characterizing language proficiency and highlights the need to advance our understanding of how task and learner properties interact in shaping the linguistic complexity of learner productions. It also makes it important to determine which complexity measures generalize well across which tasks. In this paper, we investigate the linguistic complexity of answers to reading comprehension questions written by foreign language learners of German at the college level. Analyzing the corpus with computational linguistic methods identifying a wide range of complexity features, we explore which linguistic complexity analyses can successfully be performed for such short answers, how learner proficiency impacts the results, how generalizable they are across different contexts, and how the quality of the underlying analysis impacts the results.
The impact of a physician’s recommendation and gender on informed decision making: A randomized controlled study in a simulated decision situation
2020-12-04

Abstract Objective This study examined the influence of physicians’ recommendations and gender on the decision‐making process in a preference‐sensitive situation. Methods N = 201 participants were put in a hypothetical scenario in which they suffered from a rupture of the anterior cruciate ligament (ACL). They received general information on two equally successful treatment options for this injury (surgery vs physiotherapy) and answered questions regarding their treatment preference, certainty and satisfaction regarding their decision and attitude towards the treatment options. Then, participants watched a video that differed regarding physician's recommendation (surgery vs physiotherapy) and physician's gender (female vs male voice and picture). Afterwards, they indicated again their treatment preference, certainty, satisfaction and attitude, as well as the physician's professional and social competence. Results Participants changed their treatment preferences in the direction of the physician's recommendation ( P &lt; .001). Decision certainty ( P &lt; .001) and satisfaction ( P &lt; .001) increased more strongly if the physician's recommendation was congruent with the participant's prior attitude than if the recommendation was contrary to the participant's prior attitude. Finally, participants’ attitudes towards the recommended treatment became more positive (surgery recommendation: P &lt; .001; physiotherapy recommendation: P &lt; .001). We found no influence of the physician's gender on participants’ decisions, attitudes, or competence assessments. Conclusion This research indicates that physicians should be careful with recommendations when aiming for shared decisions, as they might influence patients even if the patients have been made aware that they should take their personal preferences into account. This could be particularly problematic if the recommendation is not in line with the patient's preferences.
Publisher Correction: A community-based transcriptomics classification and nomenclature of neocortical cell types
2020-12-04

In the version of this article initially published, author Thomas V. Wuttke’s affiliation was shown incorrectly. Dr. Wuttke is affiliated with University of Tübingen, Tübingen, Germany. The error has been corrected in the PDF and HTML versions of this article.
Faculty Opinions recommendation of Comprehensive profiling of an aging immune system reveals clonal GZMK+ CD8+ T cells as conserved hallmark of inflammaging.
2020-12-04

Systematic understanding of immune aging on a whole-body scale is currently lacking. We characterized age-associated alterations in immune cells across multiple mouse organs using single-cell RNA and antigen receptor sequencing and flow cytometry-based validation. We defined organ-specific and common immune alterations and identified a subpopulation of age-associated granzyme K (GZMK)-expressing CD8+ T (Taa) cells that are distinct from T effector memory (Tem) cells. Taa cells were highly clonal, had specific epigenetic and transcriptional signatures, developed in response to an aged host environment, and expressed markers of exhaustion and tissue homing. Activated Taa cells were the primary source of GZMK, which enhanced inflammatory functions of non-immune cells. In humans, proportions of the circulating GZMK+CD8+ T cell population that shares transcriptional and epigenetic signatures with mouse Taa cells increased during healthy aging. These results identify GZMK+ Taa cells as a potential target to address age-associated dysfunctions of the immune system.Copyright © 2020 Elsevier Inc. All rights reserved. PMID: 33271118
Clinical validation of kinematic assessments of post-stroke upper limb movements with a multi-joint arm exoskeleton
2020-12-04

Abstract BACKGROUND: The clinical evaluation of the upper limb of severely impaired stroke patient is challenging. Sensor-based assessments may allow for an objective evaluation of this patient population. This study investigated the validity of a device-assisted approach in comparison to the clinical outcome that it is supposed to reflect. METHODS: In nineteen severely impaired chronic stroke patients, we applied a gravity-compensating, multi-joint arm exoskeleton (Armeo Spring) and compared this sensor-based assessment with the clinical outcome measure Upper Extremity Fugl-Meyer Assessment (UE-FMA) scale. Specifically, we assessed separately and subsequently the range of motion in joint space for four single joints (i.e., angles of wrist, elbow, arm, and shoulder movement), and the closing and opening of the hand with a pressure sensor placed in the handle. The same position (neutral zero) with a distance of 90 degrees between forearm and upper arm was taken as the starting position for all assessments. RESULTS: Within the kinematic parameters, a strong correlation was observed between wrist and elbow movements (r &gt; 0.7, p&lt;0.003; Bonferroni corrected). The UE-FMA was significantly predicted by a multiple regression model (F (5, 13) = 12.22, p &lt; 0.0005, adj. R2 = 0.83). Both shoulder rotation and grip pressure added significantly (p &lt; 0.05) to the prediction with the standardized coefficients β of 0.55 and 0.38, respectively. CONCLUSIONS: By applying an exoskeleton-based self-contained evaluation of single-joint movements, a clinically valid assessment of the upper limb range of motion in severely impaired stroke patients is feasible. Shoulder rotation contributed most relevantly to the prediction of the clinical status. These findings need to be confirmed in a large, independent patient cohort.
CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia
2020-12-05

Transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD) are severe monogenic diseases with severe and potentially life-threatening manifestations. BCL11A is a transcription factor that represses γ-globin expression and fetal hemoglobin in erythroid cells. We performed electroporation of CD34+ hematopoietic stem and progenitor cells obtained from healthy donors, with CRISPR-Cas9 targeting the <i>BCL11A</i> erythroid-specific enhancer. Approximately 80% of the alleles at this locus were modified, with no evidence of off-target editing. After undergoing myeloablation, two patients - one with TDT and the other with SCD - received autologous CD34+ cells edited with CRISPR-Cas9 targeting the same <i>BCL11A</i> enhancer. More than a year later, both patients had high levels of allelic editing in bone marrow and blood, increases in fetal hemoglobin that were distributed pancellularly, transfusion independence, and (in the patient with SCD) elimination of vaso-occlusive episodes. (Funded by CRISPR Therapeutics and Vertex Pharmaceuticals; ClinicalTrials.gov numbers, NCT03655678 for CLIMB THAL-111 and NCT03745287 for CLIMB SCD-121.).
Oscillatory brain activity and maintenance of verbal and visual working memory: A systematic review
2020-12-05

Abstract Brain oscillations likely play a significant role in the storage of information in working memory (WM). Despite the wide popularity of the topic, current attempts to summarize the research in the field are narrative reviews. We address this gap by providing a descriptive systematic review, in which we investigated oscillatory correlates of maintenance of verbal and visual information in WM. The systematic approach enabled us to challenge some common views popularized by previous research. The identified literature (100 EEG/MEG studies) highlighted the importance of theta oscillations in verbal WM: frontal midline theta enhanced with load in most verbal studies, while more equivocal results have been obtained in visual studies. Increasing WM load affected alpha activity in most studies, but the direction of the effect was inconsistent: the ratio of studies that found alpha increase versus decrease with increasing load was 80/20% in the verbal WM domain and close to 60/40% in the visual domain. Alpha asymmetry (left &lt; right) was a common finding in both verbal and visual WM studies. Beta and gamma activity studies yielded the least convincing data: a diversity in the spatial and frequency distribution of beta activity prevented us from making a coherent conclusion; gamma rhythm was virtually neglected in verbal WM studies with no systematic support for sustained gamma changes during the delay in EEG studies in general.
Elevated Circulating Glutamate Is Associated With Subclinical Atherosclerosis Independently of Established Risk Markers: A Cross-Sectional Study
2020-12-05

Abstract Objective Elevated plasma glutamate levels are associated with an increased risk of cardiovascular disease (CVD). Because plasma glutamate levels are also strongly associated with visceral adiposity, nonalcoholic fatty liver disease, insulin resistance, and high circulating levels of branched-chain amino acids (BCAAs), it is unknown to what extent elevated circulating glutamate is an independent marker of an increased risk of atherosclerosis. Methods Plasma levels of glutamate and BCAAs were measured in 102 individuals who were precisely phenotyped for body fat mass and distribution (magnetic resonance [MR] tomography), liver fat content (1H-MR spectroscopy), insulin sensitivity (oral glucose tolerance test and hyperinsulinemic, euglycemic clamp [N = 57]), and carotid intima media thickness (cIMT). Results Plasma glutamate levels, adjusted for age, sex, body fat mass, and visceral fat mass, correlated positively with liver fat content and cIMT (all std β ≥ .22, all P ≤ .023) and negatively with insulin sensitivity (std β ≤ –.31, P ≤ .002). Glutamate levels also were associated with cIMT, independently of additional adjustment for liver fat content, insulin sensitivity and BCAAs levels (std β ≥ .24, P ≤ .02). Furthermore, an independent positive association of glutamate and interleukin-6 (IL-6) levels was observed (N = 50; std β = .39, P = .03). Although glutamate, adjusted for age, sex, body fat mass, and visceral fat mass, also correlated positively with cIMT in this subgroup (std β = .31, P = .02), after additional adjustment for the parameters liver fat content, insulin sensitivity, BCAAs, or IL-6 levels, adjustment for IL-6 most strongly attenuated this relationship (std β = .28, P = .05). Conclusions Elevated plasma glutamate levels are associated with increased cIMT, independently of established CVD risk factors, and this relationship may in part be explained by IL-6-associated subclinical inflammation.
Photon spectrum of asymmetric dark stars
2020-12-05

Asymmetric Dark Stars, i.e. compact objects formed from the collapse of asymmetric dark matter could potentially produce a detectable photon flux if dark matter particles self-interact via dark photons that kinetically mix with ordinary photons. The morphology of the emitted spectrum is significantly different and therefore distinguishable from a typical black-body one. Given the above and the fact that asymmetric dark stars can have masses outside the range of neutron stars, the detection of such a spectrum can be considered as a smoking gun signature for the existence of these exotic stars.
Macrophage retrieval from 3D biomaterials: A detailed comparison of common dissociation methods
2020-12-05

The immune system is widely recognized as a crucial determinant in implant biocompatibility and tissue integration. In order to assess macrophage response to biomaterials, commonly used analysis techniques require the removal of cells from the material. This process inherently has a negative impact on the cells, but few studies have comprehensively compared different dissociation methods in terms of impact on cell yield, viability, phenotype and function. Cell scraping, EDTA at 4 °C, EDTA at 37 °C, trypsin, Accutase and the PromoCell macrophage detachment solution were compared in terms of cell yield and viability. The effect of Accutase on cell surface antigen conservancy and cell functionality was investigated. Lastly, effect of Accutase detachment of macrophages from electrospun biomaterials was analyzed. The efficiency of common cell detachment protocols for human monocyte-derived macrophages (MDMs) varies significantly between enzymatic and non-enzymatic approaches. In terms of surface marker detection, we showed that enzymatic detachment not only selectively cleaves the M2 markers CD206 and CD163, but we also identified that this effect is variable across donors. Furthermore, we observed that the process of cell detachment impairs macrophage endocytic ability. Lastly, we tested the efficiency of enzymatic cell detachment on electrospun 3D matrices designed for tissue engineering. Our results provide a thorough understanding of the advantages and disadvantages of commonly used cell dissociation methods and have important implications for studies investigating the macrophage response to biomaterials.
Conference report: dementia research and care and its impact in Switzerland
2020-12-05

In October 2019, a Swiss panel of experts met for the Dementia Summit in Brunnen, Switzerland, to discuss the latest scientific findings on basic and clinical research, as well as practical and political approaches to the challenges of dementia disorders in Switzerland. Here, we present the conference summary. To study pathophysiological changes, as well as the underlying mechanism of fluid biomarker changes, excellent experimental approaches, including transgenic mouse models, are available. Current knowledge about presymptomatic disease progression is largely derived from the longitudinal study of individuals with autosomal dominant mutations (Dominantly Inherited Alzheimer Network). Importantly, more than one third of identified dementia risk factors can be modified. For example, sleep disturbances are not only associated with dementia and neurodegeneration in specific brain regions, but also precede cognitive decline and contribute to the development of brain pathology. Regarding the neuropsychological examination of dementia disorders, standardised tests of social cognition, one of the six cognitive domains that must be assessed according to the fifth edition of the Diagnostic and Statistical Manual for Mental Disorders, are missing, but now under development. The most important new therapeutic approach in the treatment of Alzheimer’s disease is the current attempt to prevent β-amyloid accumulation. While until now clinical studies have failed because of side effects or insufficient clinical effectiveness, Biogen recently announced positive results of high doses of aducanumab, a monoclonal antibody against β-amyloid. Other approaches also show promise. In China, sodium oligomannate has been approved to treat Alzheimer's disease. The substance suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression. Assistive technologies for dementia patients can help identify relevant information for care and nursing, as well as measurements for clinical interventions. Dementia patients have a high risk of developing delirium, even in the home environment. Therefore, it is necessary to use and further develop multi-disciplinary and systematic detection and prevention strategies. Homecare models for dementia patients with multidisciplinary teams have been established and evaluated and should be expanded. Dementia is the third-leading cause of death in Switzerland. In palliative care for severe dementia, the improvement of quality of life is of primary importance. The goals of the National Dementia Strategy, to increase the quality of life in those affected and to reduce taboos surrounding the disease, are still unrealised. The need for further national and regional engagement in order to implement the different findings of the strategy has largely been acknowledged, and these implementations have become the core tasks of a national dementia platform.
Physiologically Based Precision Dosing Approach for Drug‐Drug‐Gene Interactions: A Simvastatin Network Analysis
2020-12-06

Drug‐drug interactions (DDIs) and drug‐gene interactions (DGIs) are well known mediators for adverse drug reactions (ADRs), which are among the leading causes of death in many countries. Because physiologically based pharmacokinetic (PBPK) modeling has demonstrated to be a valuable tool to improve pharmacotherapy affected by DDIs or DGIs, it might also be useful for precision dosing in extensive interaction network scenarios. The presented work proposes a novel approach to extend the prediction capabilities of PBPK modeling to complex drug‐drug‐gene interaction (DDGI) scenarios. Here, a whole‐body PBPK network of simvastatin was established, including three polymorphisms ( SLCO1B1 (rs4149056), ABCG2 (rs2231142), and CYP3A5 (rs776746)) and four perpetrator drugs (clarithromycin, gemfibrozil, itraconazole, and rifampicin). Exhaustive network simulations were performed and ranked to optimize 10,368 DDGI scenarios based on an exposure marker cost function. The derived dose recommendations were translated in a digital decision support system, which is available at simvastatin.precisiondosing.de . Although the network covers only a fraction of possible simvastatin DDGIs, it provides guidance on how PBPK modeling could be used to individualize pharmacotherapy in the future. Furthermore, the network model is easily extendable to cover additional DDGIs. Overall, the presented work is a first step toward a vision on comprehensive precision dosing based on PBPK models in daily clinical practice, where it could drastically reduce the risk of ADRs.
Immune Checkpoint Blockade in Advanced Cutaneous Squamous Cell Carcinoma: What Do We Currently Know in 2020?
2020-12-06

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer that predominantly arises in chronically sun-damaged skin. Immunosuppression, genetic disorders such as xeroderma pigmentosum (XP), exposure to certain drugs and environmental noxae have been identified as major risk factors. Surgical removal of cSCC is the therapy of choice and mostly curative in early stages. However, a minority of patients develop locally advanced tumors or distant metastases that are still challenging to treat. Immune checkpoint blockade (ICB) targeting CTLA-4, PD-L1 and PD-1 has tremendously changed the field of oncological therapy and especially the treatment of skin cancers as tumors with a high mutational burden. In this review, we focus on the differences between cSCC and cutaneous melanoma (CM) and their implications on therapy, summarize the current evidence on ICB for the treatment of advanced cSCC and discuss the chances and pitfalls of this therapy option for this cancer entity. Furthermore, we focus on special subgroups of interest such as organ transplant recipients, patients with hematologic malignancies, XP and field cancerization.
Redefining the role of Ca2+-permeable channels in photoreceptor degeneration using diltiazem
2020-12-06

ABSTRACT Hereditary degeneration of photoreceptors has been linked to over-activation of Ca 2+ -permeable channels, excessive Ca 2+ -influx, and downstream activation of Ca 2+ -dependent calpain-type proteases. Unfortunately, after more than 20 years of pertinent research, unequivocal evidence proving significant and reproducible photoreceptor protection with Ca 2+ -channel blockers is still lacking. Here, we show that both D- and L-cis enantiomers of the anti-hypertensive drug diltiazem were very effective at blocking photoreceptor Ca 2+ -influx, most probably by blocking the pore of Ca 2+ -permeable channels. Yet, unexpectedly, this block neither reduced the activity of calpain-type proteases, nor did it result in photoreceptor protection. Remarkably, application of the L-cis enantiomer of diltiazem even led to a strong increase in photoreceptor cell death. These findings shed doubt on the previously proposed links between Ca 2+ and retinal degeneration and are highly relevant for future therapy development as they may serve to refocus research efforts towards alternative, Ca 2+ -independent degenerative mechanisms.