julilili42/papers huggingface dataset:
Occurrence and Severity of Venous Air Embolism During Neurosurgical Procedures in Semi-Sitting Versus Supine Position
2021-06-02

<title>Abstract</title> <italic>Background:</italic> Patients undergoing neurosurgical procedures in the posterior cranial fossa can be placed in different positions: the semi-sitting position or the supine position. The major risk of the semi-sitting positioning is venous air embolism (VAE). However, VAEs may also occur in the supine position.<italic>Objective:</italic> In a prospective study, we investigated the incidence of VAE based on the positioning of the patients (trial registration 553/2013BO1).<italic>Methods:</italic> In a single-center study with 137 patients, we prospectively evaluated the occurrence of VAEs in patients in the supine and semi-sitting position over the period from January 2014 to April 2015. All patients were monitored for VAE by the use of a transesophageal echocardiography (TEE).<italic>Results:</italic> 50% of all participating patients experienced a VAE (with 56% of these patients undergoing surgery in the semi-sitting position and 11% in the prone position). 86% of the VAEs were just detected by the use of a TEE. We only observed VAEs with a decrease in EtCO<sub>2</sub> in the semi-sitting position. However, none of the patients had any hemodynamic changes due to the VAE. We found that surgeries in patients with a preexisting intracardial shunt such as a patent foramen ovale (PFO) less likely resulted in VAEs (42% vs. 58%).<italic>Conclusion:</italic> The semi-sitting position with TEE monitoring and a standardized protocol, including a deep central venous line is a safe and advantageous technique, taking also account of a significant rate of VAEs. VAEs also occur in the supine position, however, less frequently.
Including Explicit Priors on Phase Duration in Bayesian 14C Dating
2021-06-02

&#x0D; &#x0D; &#x0D; Bayesian modelling of radiocarbon dates directly integrates information obtained through archaeological analysis. Here, I explain how to add known information/reasonable assumptions about the length of a deposition phase, using the example of date sequences from two Early Neolithic communities in the Aegean whose dating has been hotly debated, i.e. basal Knossos (Crete) and Nea Nikomedeia (Northern Greece). The consequences of the re-evaluation of their dates are discussed for the broader picture of the Neolithisation in the Aegean and for the chronology of the regional use of stamps.&#x0D; &#x0D; &#x0D;
Revealing x-ray and gamma ray temporal and spectral similarities in the GRB 190829A afterglow
2021-06-03

An intrinsic gamma-ray burst afterglow Long gamma-ray bursts (GRBs) are emitted by relativistic jets generated during the collapse of a massive star in a distant galaxy. The GRB itself lasts only a few seconds but is followed by an afterglow that can persist for hours or days. The H.E.S.S. Collaboration observed the afterglow of GRB 190829A, a nearby long GRB. The proximity of this burst allowed it to be detected at tera–electron volt energies that would otherwise be absorbed in the intergalactic medium. By analyzing the spectrum and light curve at x-ray and gamma-ray wavelengths, the authors show that the afterglow cannot be explained by standard models. Science , abe8560, this issue p. 1081
Kinases as Potential Therapeutic Targets for Anti-coronaviral Therapy
2021-06-03

The global coronavirus disease-19 (COVID-19) has affected more than 140 million and killed more than 3 million people worldwide as of April 20, 2021. The novel human severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been identified as an etiological agent for COVID-19. Several kinases have been proposed as possible mediators of multiple viral infections, including life-threatening coronaviruses like SARS-CoV-1, Middle East syndrome coronavirus (MERS-CoV), and SARS-CoV-2. Viral infections hijack abundant cell signaling pathways, resulting in drastic phosphorylation rewiring in the host and viral proteins. Some kinases play a significant role throughout the viral infection cycle (entry, replication, assembly, and egress), and several of them are involved in the virus-induced hyperinflammatory response that leads to cytokine storm, acute respiratory distress syndrome (ARDS), organ injury, and death. Here, we highlight kinases that are associated with coronavirus infections and their inhibitors with antiviral and potentially anti-inflammatory, cytokine-suppressive, or antifibrotic activity.
Controlling the Covalent Reactivity of a Kinase Inhibitor with Light
2021-06-03

Abstract Covalent kinase inhibitors account for some of the most successful drugs that have recently entered the clinic and many others are in preclinical development. A common strategy is to target cysteines in the vicinity of the ATP binding site using an acrylamide electrophile. To increase the tissue selectivity of kinase inhibitors, it could be advantageous to control the reactivity of these electrophiles with light. Here, we introduce covalent inhibitors of the kinase JNK3 that function as photoswitchable affinity labels (PALs). Our lead compounds contain a diazocine photoswitch, are poor non‐covalent inhibitors in the dark, and become effective covalent inhibitors after irradiation with visible light. Our proposed mode of action is supported by X‐ray structures that explain why these compounds are unreactive in the dark and undergo proximity‐based covalent attachment following exposure to light.
Dystonia Management: What to Expect From the Future? The Perspectives of Patients and Clinicians Within DystoniaNet Europe
2021-06-03

Improved care for people with dystonia presents a number of challenges. Major gaps in knowledge exist with regard to how to optimize the diagnostic process, how to leverage discoveries in pathophysiology into biomarkers, and how to develop an evidence base for current and novel treatments. These challenges are made greater by the realization of the wide spectrum of symptoms and difficulties faced by people with dystonia, which go well-beyond motor symptoms. A network of clinicians, scientists, and patients could provide resources to facilitate information exchange at different levels, share mutual experiences, and support each other's innovative projects. In the past, collaborative initiatives have been launched, including the American Dystonia Coalition , the European Cooperation in Science and Technology (COST— which however only existed for a limited time), and the Dutch DystonieNet project. The European Reference Network on Rare Neurological Diseases includes dystonia among other rare conditions affecting the central nervous system in a dedicated stream. Currently, we aim to broaden the scope of these initiatives to a comprehensive European level by further expanding the DystoniaNet network, in close collaboration with the ERN-RND. In line with the ERN-RND, the mission of DystoniaNet Europe is to improve care and quality of life for people with dystonia by, among other endeavors, facilitating access to specialized care, overcoming the disparity in education of medical professionals, and serving as a solid platform to foster international clinical and research collaborations. In this review, both professionals within the dystonia field and patients and caregivers representing Dystonia Europe highlight important unsolved issues and promising new strategies and the role that a European network can play in activating them.
New Method for Efficient siRNA Delivery in Retina Explants: Reverse Magnetofection
2021-06-03

The prevalence of retinal disorders associated with visual impairment and blindness is increasing worldwide, while most of them remain without effective treatment. Pharmacological and molecular therapy development is hampered by the lack of effective drug delivery into the posterior segment of the eye. Among molecular approaches, RNA-interference (RNAi) features strong advantages, yet delivering it to the inner layer of the retina appears extremely challenging. To address this, we developed an original magnetic nanoparticles (MNPs)-based transfection method that allows the efficient delivery of siRNA in all retinal layers of rat adult retinas through magnetic targeting. To establish delivery of RNAi throughout the retina, we have chosen organotypic retinal explants as an <i>ex vivo</i> model and for future high content screening of molecular drugs. Conversely to classic Magnetofection, and similar to conditions in the posterior chamber of the eye, our methods allows attraction of siRNA complexed to MNPs from the culture media into the explant. Our method termed "Reverse Magnetofection" provides a novel and nontoxic strategy for RNAi-based molecular as well as gene therapy in the retina that can be transferred to a wide variety of organ explants.
Patterns of recent natural selection on genetic loci associated with sexually differentiated human body size and shape phenotypes
2021-06-03

Levels of sex differences for human body size and shape phenotypes are hypothesized to have adaptively reduced following the agricultural transition as part of an evolutionary response to relatively more equal divisions of labor and new technology adoption. In this study, we tested this hypothesis by studying genetic variants associated with five sexually differentiated human phenotypes: height, body mass, hip circumference, body fat percentage, and waist circumference. We first analyzed genome-wide association (GWAS) results for UK Biobank individuals (~194,000 females and ~167,000 males) to identify a total of 114,199 single nucleotide polymorphisms (SNPs) significantly associated with at least one of the studied phenotypes in females, males, or both sexes (P&lt;5x10 -8 ). From these loci we then identified 3,016 SNPs (2.6%) with significant differences in the strength of association between the female- and male-specific GWAS results at a low false-discovery rate (FDR&lt;0.001). Genes with known roles in sexual differentiation are significantly enriched for co-localization with one or more of these SNPs versus SNPs associated with the phenotypes generally but not with sex differences (2.73-fold enrichment; permutation test; P = 0.0041). We also confirmed that the identified variants are disproportionately associated with greater phenotype effect sizes in the sex with the stronger association value. We then used the singleton density score statistic, which quantifies recent (within the last ~3,000 years; post-agriculture adoption in Britain) changes in the frequencies of alleles underlying polygenic traits, to identify a signature of recent positive selection on alleles associated with greater body fat percentage in females (permutation test; P = 0.0038; FDR = 0.0380), directionally opposite to that predicted by the sex differences reduction hypothesis. Otherwise, we found no evidence of positive selection for sex difference-associated alleles for any other trait. Overall, our results challenge the longstanding hypothesis that sex differences adaptively decreased following subsistence transitions from hunting and gathering to agriculture.
Complete response of merkel cell carcinoma with brain metastases to pembrolizumab and radiotherapy: A case report
2021-06-03

Our aim is to present the importance of mobile Handheld Lung Ultrasound (HLUS) in COVID-19 patients at the bedside, which is a pre-screening tool with high diagnostic value that can provide triage of symptomatic patients at home (pre-hospital), emergency services, Intensive Care Units (ICU). In this context, the current role and importance of HLUS at the bedside in COVID-19 pneumonia has been summarized.
The pre-clinical discovery and development of osimertinib used to treat non-small cell lung cancer
2021-06-04

<b>Introduction</b>: Osimertinib is currently the only FDA- and EMA-approved third-generation small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). It was initially indicated for second-line treatment of patients with metastatic <i>EGFR</i> T790M mutation-positive non-small cell lung cancer (NSCLC) and got approved for first-line treatment of <i>EGFR</i> activation mutation-positive metastatic NSCLC in 2018. Most recently, the FDA granted approval for the adjuvant treatment of patients with early-stage mutated <i>EGFR</i> NSCLC after tumor resection.<b>Areas covered</b>: This drug discovery case history focuses on the key studies that led to the preclinical discovery and development of osimertinib. The authors focus on published preclinical studies by scientists from AstraZeneca and highlight key events in the clinical development.<b>Expert opinion</b>: Although eventually compromised by the cellular plasticity of the tumor and the inevitable acquisition of drug resistance through the use of osimertinib, its key role in the treatment of NSCLC with specific <i>EGFR</i> mutations will be maintained in the near future. As the genome of EGFR is highly labile and since the rapid development of new mutants remains an issue, there is still room for improvement for the next generation of inhibitors.
Evaluating grazing response strategies in winter annuals: A multi‐trait approach
2021-06-04

Abstract Plants minimize fitness losses through grazing by three fundamental strategies: tolerance, avoidance and escape. Annual species have been traditionally assumed to escape grazing through their short life cycle and seed dormancy; however, their grazing response strategies remain almost unexplored. How traits and their coordination affect species' grazing responses, and whether the generalized grazing model, which posits convergent filtering by grazing and drought, is applicable to this ecologically and economically important species group thus remain unclear. We used a trait‐based approach to evaluate grazing response strategies of winter annuals from the Middle East. Across 23 species, we examined the coordination of 16 traits hypothesized to be relevant for grazing responses, and linked them to species' fecundity responses, as proxy for fitness responses, to simulated grazing in controlled conditions, to species' abundance responses to grazing in the field and to species' distribution along a large‐scale rainfall gradient. Winter annuals exhibited both grazing escape and to a lesser extent tolerance indicated by (a) independent coordination of escape and tolerance traits, and (b) maintenance of higher fecundity in species with more pronounced escape or tolerance traits under simulated grazing. In the natural habitat, species with a more pronounced escape but not tolerance strategy maintained higher abundance under grazing in dry habitats, indicating convergent favouring of escape by both grazing and drought. However, this finding at the local scale was not mirrored by a strategy shift along a large‐scale rainfall gradient. Synthesis . The convergent favouring of escape traits by grazing and drought in annuals is consistent with the generalized grazing model. This model, which has been developed for perennials based on the avoidance strategy, can thus be extended to annuals based on escape, a finding that should facilitate projecting consequences of global change in drylands dominated by annuals.
Impaired Myocardial Function Is Prognostic for Severe Respiratory Failure in the Course of COVID-19 Infection
2021-06-04

COVID-19 may lead to severe acute respiratory distress syndrome (ARDS) resulting in increased morbidity and mortality. Heart failure and/or pre-existing cardiovascular disease may correlate with poor outcomes and thus require special attention from treating physicians. The present study sought to investigate a possible impact of impaired myocardial function as well as myocardial distress markers on mortality or ARDS with need for mechanical ventilation in 157 consecutive patients with confirmed SARS-CoV-2 infection. All patients were admitted and treated at the University Hospital of Tübingen, Germany, during the first wave of the pandemic. Electrocardiography, echocardiography, and routine blood sampling were performed at hospital admission. Impaired left-ventricular and right-ventricular function, tricuspid regurgitation &amp;gt; grade 1, and elevated RV-pressure as well as thrombotic and myocardial distress markers (D-dimers, NT-pro-BNP, and troponin-I) were associated with mechanical ventilation and/or all-cause mortality. Impaired cardiac function is more frequent amidst ARDS, leading to subsequent need for mechanical ventilation, and thus denotes a poor outcome in COVID-19. Since a causal treatment for SARS-CoV-2 infection is still lacking, guideline-compliant cardiovascular evaluation and treatment remains the best approach to improve outcomes in COVID-19 patients with cardiovascular comorbidities.
Body size perception in stroke patients with paresis
2021-06-04

Recent studies have suggested that people’s intent and ability to act also can influence their perception of their bodies’ peripersonal space. Vice versa one could assume that the inability to reach toward and grasp an object might have an impact on the subject’s perception of reaching distance. Here we tested this prediction by investigating body size and action capability perception of neurological patients suffering from arm paresis after stroke, comparing 32 right-brain-damaged patients (13 with left-sided arm paresis without additional spatial neglect, 10 with left-sided arm paresis and additional spatial neglect, 9 patients had neither arm paresis nor neglect) and 27 healthy controls. Nineteen of the group of right hemisphere stroke patients could be re-examined about five months after initial injury. Arm length was estimated in three different methodological approaches: explicit visual, explicit tactile/proprioceptive, and implicit reaching. Results fulfilled the working hypothesis. Patients with an arm paresis indeed perceived their bodies differently. We found a transient overestimation of the length of the contralesional, paretic arm after stroke. Body size and action capability perception for the extremities thus indeed seem to be tightly linked in humans.
Combining Optical Strong Mode Coupling with Polaritonic Coupling in a λ/2 Fabry–Pérot Microresonator
2021-06-04

Strong coupling has attracted much research interest motivated by the possibility to tune the energy levels of molecules enabling to control and modify chemical reactions. Strong coupling leads to the formation of new hybrid modes and is caused by coherent energy exchange between the individual constituents. Such a coherent energy exchange occurs when the coupling rate exceeds the damping rate of the individual components and has been observed for highly diverse systems. Here, we present a strongly coupled hybrid system consisting of a thin TDBC J-aggregate film inside an optical subwavelength microresonator coupled to a second microresonator. This hybrid structure combines strong coupling of purely optical modes with strong light–matter interaction. The coupling strength and damping sensitively depend on the position and concentration of the coupled molecules in the microresonator structure. Such a coupled system can be modeled by coupled damped oscillators, which allows to determine the coupling and damping constants. We show that the individual components making up the coupled hybrid system cannot be treated individually, but the coupled system needs to be considered as a whole. As a consequence, altering one parameter does influence the whole coupled system, and the individual components need to be carefully adapted to each other to achieve efficient coupling. These results can have important consequences for the field of optoelectronics or polaritonic chemistry.
Human genetic factors associated with pneumonia susceptibility, a cue for COVID-19 mortality
2021-06-04

Abstract The risk for community acquired pneumonia (CAP) is partially driven by genetics. To identify the CAP-associated genetic risk loci, we performed a meta-analysis of clinically diagnosed CAP (3,310 individuals) with 2,655 healthy controls. The findings revealed CYP1A1 variants (rs2606345, rs4646903, rs1048943) associated with pneumonia. We observed rs2606345 [G vs T; OR=1.49(1.29-1.69); p=0.0001; I 2 = 15.5%], and rs1048943 [T vs G; OR= 1.31(0.90-1.71); p=0.002; I 2 =19.3%] as risk markers and rs4646903 [T vs C; OR= 0.79(0.62-0.96); p=0.03; I 2 =0%] as a protective marker for susceptibility to CAP, when compared with healthy controls. Our meta-analysis showed the presence of CYP1A1 SNP alleles contributing significant risk toward pneumonia susceptibility. Interestingly, we observed a striking difference of allele frequency for rs2606345 ( CYP1A1 ) among Europeans, Africans and Asians which may provide a possible link for observed variations in death due to coronavirus disease 2019 (COVID-19), a viral pneumonia. We report, for the first time, a significant positive correlation for the risk allele (T or A) of rs2606345, with a higher COVID-19 mortality rate worldwide and within a genetically heterogeneous nation like India. Mechanistically, the risk allele ‘A’ (rs2606345) is associated with lower expression of CYP1A1 and presumably leads to reduced capacity for xenobiotic detoxification. We note that ambient air pollution, a powerful inducer of CYP1A1 gene expression, is globally associated with lower, not higher mortality, as would normally be predicted. In conclusion, we find that CYP1A1 alleles are associated with CAP mortality, presumably via altered xenobiotic metabolism. We speculate that gene-environment interactions governing CYP1A1 expression may influence COVID-19 mortality.
Extraskeletal Ewing sarcoma in children, adolescents, and young adults. An analysis of three prospective studies of the Cooperative Weichteilsarkomstudiengruppe (CWS)
2021-06-05

Abstract Background We have analyzed the outcome of patients with localized extraskeletal Ewing sarcoma (EES) treated in three consecutive Cooperative Weichteilsarkomstudiengruppe (CWS) soft tissue sarcoma (STS) studies: CWS‐91, CWS‐96, and CWS‐2002P. Methods Patients were treated in CWS‐91 with four‐ (vincristine, dactinomycin, doxorubicin, and ifosfamide [VAIA] or cyclophosphamide [VACA II]) or five‐drug (+etoposide [EVAIA]) cycles, in CWS‐96 they were randomly assigned to receive VAIA or CEVAIE (+carboplatin and etoposide), and in CWS‐2002P with VAIA III plus optional maintenance therapy (MT) with cyclophosphamide and vinblastine. Local therapy consisted of resection and/or radiotherapy (RT). Results Two hundred forty‐three patients fulfilled the eligibility criteria. The 5‐year event‐free survival (EFS) and overall survival (OS) were 63% (95% confidence interval [CI] 57–69) and 73% (95% CI 67–79), respectively. The 5‐year EFS by study was 64% (95% CI 54–74) in CWS‐91, 57% (95% CI 48–66) in CWS‐96, and 79% (95% CI 67–91) in CWS‐2002P (n.s.). The 5‐year OS was 72% (95% CI 62–82) in CWS‐91, 70% (95% CI 61–79) in CWS‐96, and 86% (95% CI 76–96) in CWS‐2002P (n.s.). In CWS‐96, 5‐year EFS and OS in the VAIA arm versus the CEVAIE were 65% (95% CI 52–81) versus 55% (95% CI 39–76) log‐rank p = .13, and 85% (95% CI 75–96) versus 61% (95% CI 45–82), log‐rank p = .09. Conclusion Our analysis provides interesting information on the treatment and specificities of EES, which can be useful for a better understanding of this rare entity and should be considered in the development of future clinical trials for Ewing sarcoma defined as FET–ETS fusion positive tumors.