Antithrombotics in the Fall Patient: Appropriateness and Risk-Benefit Analysis.

Falls are the leading cause of hospitalizations following trauma nationwide, resulting in over 3 million admissions in 2020. This population is typically aged, and many are prescribed antithrombotic (AT) therapy. In this prospective study, we aimed to analyze fall history while assessing appropriateness of AT regimen relative to fall risk. Patients presenting following ground level fall (GLF) and meeting inclusion criteria during the study period were enrolled. Primary outcome was the relationship between AT therapy necessity (CHA2DS2-VASc) and fall risk (Morse Fall Risk). The cohort of 30 patients had an average age of 77. CHA2DS2-VASc and Morse Fall Risk showed a moderate-positive correlation (r = 0.47; P = 0.012); however, 17% of patients categorized as high fall risk had a <5% 1-year risk of VTE. This study demonstrates that risks of hemorrhage may outweigh thromboembolism prophylaxis in a significant number of patients and sheds light on the astonishing fall volume in this population.

In vivo characterization of the maturation steps of a pigment dispersing factor neuropeptide precursor in the Drosophila circadian pacemaker neurons.

Pigment dispersing factor (PDF) is a key signaling molecule coordinating the neuronal network associated with the circadian rhythms in Drosophila. The precursor (proPDF) of the mature PDF (mPDF) consists of 2 motifs, a larger PDF-associated peptide (PAP) and PDF. Through cleavage and amidation, the proPDF is predicted to produce cleaved-PAP (cPAP) and mPDF. To delve into the in vivo mechanisms underlying proPDF maturation, we generated various mutations that eliminate putative processing sites and then analyzed the effect of each mutation on the production of cPAP and mPDF by 4 different antibodies in both ectopic and endogenous conditions. We also assessed the knockdown effects of processing enzymes on the proPDF maturation. At the functional level, circadian phenotypes were measured for all mutants and knockdown lines. As results, we confirm the roles of key enzymes and their target residues: Amontillado (Amon) for the cleavage at the consensus dibasic KR site, Silver (Svr) for the removal of C-terminal basic residues from the intermediates, PAP-KR and PDF-GK, derived from proPDF, and PHM (peptidylglycine-α-hydroxylating monooxygenase) for the amidation of PDF. Our results suggest that the C-terminal amidation occurs independently of proPDF cleavage. Moreover, the PAP domain is important for the proPDF trafficking into the secretory vesicles and a close association between cPAP and mPDF following cleavage seems required for their stability within the vesicles. These studies highlight the biological significance of individual processing steps and the roles of the PAP for the stability and function of mPDF which is essential for the circadian clockworks.

Symmetry reduction for deep reinforcement learning active control of chaotic spatiotemporal dynamics.

Deep reinforcement learning (RL) is a data-driven, model-free method capable of discovering complex control strategies for macroscopic objectives in high-dimensional systems, making its application toward flow control promising. Many systems of flow control interest possess symmetries that, when neglected, can significantly inhibit the learning and performance of a naive deep RL approach. Using a test-bed consisting of the Kuramoto-Sivashinsky equation (KSE), equally spaced actuators, and a goal of minimizing dissipation and power cost, we demonstrate that by moving the deep RL problem to a symmetry-reduced space, we can alleviate limitations inherent in the naive application of deep RL. We demonstrate that symmetry-reduced deep RL yields improved data efficiency as well as improved control policy efficacy compared to policies found by naive deep RL. Interestingly, the policy learned by the symmetry aware control agent drives the system toward an equilibrium state of the forced KSE that is connected by continuation to an equilibrium of the unforced KSE, despite having been given no explicit information regarding its existence. That is, to achieve its goal, the RL algorithm discovers and stabilizes an equilibrium state of the system. Finally, we demonstrate that the symmetry-reduced control policy is robust to observation and actuation signal noise, as well as to system parameters it has not observed before.

Role of JNK, MEK and adenylyl cyclase signalling in speed and directionality of enteric neural crest-derived cells.

BACKGROUND: Cells derived from the neural crest colonize the developing gut and give rise to the enteric nervous system. The rate at which the ENCC population advances along the bowel will be affected by both the speed and directionality of individual ENCCs. The aim of the study was to use time-lapse imaging and pharmacological activators and inhibitors to examine the role of several intracellular signalling pathways in both the speed and the directionality of individual enteric neural crest-derived cells in intact explants of E12.5 mouse gut. Drugs that activate or inhibit intracellular components proposed to be involved in GDNF-RET and EDN3-ETB signalling in ENCCs were used. FINDINGS: Pharmacological inhibition of JNK significantly reduced ENCC speed but did not affect ENCC directionality. MEK inhibition did not affect ENCC speed or directionality. Pharmacological activation of adenylyl cyclase or PKA (a downstream cAMP-dependent kinase) resulted in a significant decrease in ENCC speed and an increase in caudal directionality of ENCCs. In addition, adenylyl cyclase activation also resulted in reduced cell-cell contact between ENCCs, however this was not observed following PKA activation, suggesting that the effects of cAMP on adhesion are not mediated by PKA. CONCLUSIONS: JNK is required for normal ENCC migration speed, but not directionality, while cAMP signalling appears to regulate ENCC migration speed, directionality and adhesion. Collectively, our data demonstrate that intracellular signalling pathways can differentially affect the speed and directionality of migrating ENCCs.

Biomaterial scaffolds for non-invasive focal hyperthermia as a potential tool to ablate metastatic cancer cells.

Currently, there are very few therapeutic options for treatment of metastatic disease, as it often remains undetected until the burden of disease is too high. Microporous poly(ε-caprolactone) biomaterials have been shown to attract metastasizing breast cancer cells in vivo early in tumor progression. In order to enhance the therapeutic potential of these scaffolds, they were modified such that infiltrating cells could be eliminated with non-invasive focal hyperthermia. Metal disks were incorporated into poly(ε-caprolactone) scaffolds to generate heat through electromagnetic induction by an oscillating magnetic field within a radiofrequency coil. Heat generation was modulated by varying the size of the metal disk, the strength of the magnetic field (at a fixed frequency), or the type of metal. When implanted subcutaneously in mice, the modified scaffolds were biocompatible and became properly integrated with the host tissue. Optimal parameters for in vivo heating were identified through a combination of computational modeling and ex vivo characterization to both predict and verify heat transfer dynamics and cell death kinetics during inductive heating. In vivo inductive heating of implanted, tissue-laden composite scaffolds led to tissue necrosis as seen by histological analysis. The ability to thermally ablate captured cells non-invasively using biomaterial scaffolds has the potential to extend the application of focal thermal therapies to disseminated cancers.

Study of Fluorescence Quenching Ability of Graphene Oxide with a Layer of Rigid and Tunable Silica Spacer.

The fluorescence quenching property of graphene oxide (GO) has been newly demonstrated and applied for fluorescence imaging and biosensing. In this work, a new nanostructure was designed for effectively studying the quenching ability of GO. The key element in this design is the fabrication of a layer of rigid and thickness adjustable silica spacer for manipulating the distance between the GO and fluorophores. First, a silica core modified with organic dye molecules was prepared, followed by the formation of a silica shell with a tunable thickness. Afterward, the GO was wrapped around silica nanoparticles based on the electrostatic interaction between the negatively charged GO and positively charged silica. The quenching efficiency of GO to different dye molecules was studied at various spacer thicknesses and varying concentrations of GO. Fluorescence lifetime of fluorophores was measured to determine the quenching mechanism. We found that the quenching efficiency of GO was still around 30% when the distance between dyes and GO was increased to more than 30 nm, which indicated the long-distance quenching ability of GO and confirmed the previous theoretical calculation. The quenching mechanisms were proposed schematically based on our experimental results. We expected that the proposed nanostructure could act as a feasible model for studying GO quenching property and shed light on designing GO-based fluorescence sensing systems.

Anchoring-and-Adjustment During Affect Inferences.

People can easily infer the thoughts and feelings of others from brief descriptions of scenarios. But how do they arrive at these inferences? Three studies tested how, through anchoring-and-adjustment, people used semantic and numerical anchors (irrelevant values provided by experimenters) in inferring feelings from scenario descriptions. We showed that in a between-subject design, people's inference was biased toward anchoring information (Studies 1 and 2). People made fewer adjustments (anchoring increased) under time pressure in the high-anchor condition but not in the low-anchor condition (Study 3). When inferring affect from scenario descriptions, not only did people integrate their inference with the context, they adjusted away from the initial anchors provided by the experimenters. However, time pressure discouraged people from making adequate adjustments.

The Relation Between Valence and Arousal in Subjective Experience Varies With Personality and Culture.

OBJECTIVE: While in general arousal increases with positive or negative valence (a so-called V-shaped relation), there are large differences among individuals in how these two fundamental dimensions of affect are related in people's experience. In two studies, we examined two possible sources of this variation: personality and culture. METHOD: In Study 1, participants (Belgian university students) recalled a recent event that was characterized by high or low valence or arousal and reported on their feelings and their personality in terms of the Five-Factor Model. In Study 2, participants from Canada, China/Hong Kong, Japan, Korea, and Spain reported on their feelings in a thin slice of time and on their personality. RESULTS: In Study 1, we replicated the V-shape as characterizing the relation between valence and arousal, and identified personality correlates of experiencing particular valence-arousal combinations. In Study 2, we documented how the V-shaped relation varied as a function of Western versus Eastern cultural background and personality. CONCLUSIONS: The results showed that the steepness of the V-shaped relation between valence and arousal increases with Extraversion within cultures, and with a West-East distinction between cultures. Implications for the personality-emotion link and research on cultural differences in affect are discussed.