Autonomic and circulatory alterations persist despite adequate resuscitation in a 5-day sepsis swine experiment.

Autonomic and vascular failures are common phenotypes of sepsis, typically characterized by tachycardia despite corrected hypotension/hypovolemia, vasopressor resistance, increased arterial stiffness and decreased peripheral vascular resistance. In a 5-day swine experiment of polymicrobial sepsis we aimed at characterizing arterial properties and autonomic mechanisms responsible for cardiovascular homeostasis regulation, with the final goal to verify whether the resuscitation therapy in agreement with standard guidelines was successful in restoring a physiological condition of hemodynamic profile, cardiovascular interactions and autonomic control. Twenty pigs were randomized to polymicrobial sepsis and protocol-based resuscitation or to prolonged mechanical ventilation and sedation without sepsis. The animals were studied at baseline, after sepsis development, and every 24 h during the 3-days resuscitation period. Beat-to-beat carotid blood pressure (BP), carotid blood flow, and central venous pressure were continuously recorded. The two-element Windkessel model was adopted to study carotid arterial compliance, systemic vascular resistance and characteristic time constant τ. Effective arterial elastance was calculated as a simple estimate of total arterial load. Cardiac baroreflex sensitivity (BRS) and low frequency (LF) spectral power of diastolic BP were computed to assess autonomic activity. Sepsis induced significant vascular and autonomic alterations, manifested as increased arterial stiffness, decreased vascular resistance and τ constant, reduced BRS and LF power, higher arterial afterload and elevated heart rate in septic pigs compared to sham animals. This compromised condition was persistent until the end of the experiment, despite achievement of recommended resuscitation goals by administered vasopressors and fluids. Vascular and autonomic alterations persist 3 days after goal-directed resuscitation in a clinically relevant sepsis model. We hypothesize that the addition of these variables to standard clinical markers may better profile patients' response to treatment and this could drive a more tailored therapy which could have a potential impact on long-term outcomes

Dissecting the Immunological Profiles in NSD3-Amplified LUSC through Integrative Multi-Scale Analyses.

The histone H3 lysine 36 (H3K36) methyltransferase NSD3, a neighboring gene of FGFR1, has been identified as a critical genetic driver of lung squamous cell carcinoma (LUSC). However, the molecular characteristics, especially the immunological roles of NSD3 in driving carcinogenesis, are poorly understood. In this study, we systematically integrated multi-omics data (e.g., genome, transcriptome, proteome, and TMA array) to dissect the immunological profiles in NSD3-amplified LUSC. Next, pharmaco-transcriptomic correlation analysis was implemented to identify the molecular underpinnings and therapeutic vulnerabilities in LUSC. We revealed that NSD3-amplified LUSC presents a non-inflamed tumor immune microenvironment (TIME) state in multiple independent LUSC patient cohorts. Predictably, elevated NSD3 expression was correlated with a worse immunotherapy outcome. Further molecular characterizations revealed that the high activity of unfolded protein response (UPR) signaling might be a pivotal mediator for the non-immunogenic phenotype of NSD3-amplified LUSC. Concordantly, we showed that NSD3-amplified LUSCs exhibited a more sensitive phenotype to compounds targeting UPR branches than the wild-type group. In brief, our multi-level analyses point to a previously unappreciated immunological role for NSD3 and provide therapeutic rationales for NSD3-amplified squamous lung cancer

Visually-Aware Audio Captioning With Adaptive Audio-Visual Attention

Audio captioning aims to generate text descriptions of audio clips. In the real world, many objects produce similar sounds. How to accurately recognize ambiguous sounds is a major challenge for audio captioning. In this work, inspired by inherent human multimodal perception, we propose visually-aware audio captioning, which makes use of visual information to help the description of ambiguous sounding objects. Specifically, we introduce an off-the-shelf visual encoder to extract video features and incorporate the visual features into an audio captioning system. Furthermore, to better exploit complementary audio-visual contexts, we propose an audio-visual attention mechanism that adaptively integrates audio and visual context and removes the redundant information in the latent space. Experimental results on AudioCaps, the largest audio captioning dataset, show that our proposed method achieves state-of-the-art results on machine translation metrics.Comment: INTERSPEECH 202

Induction of oxidative stress and related transcriptional effects of perfluorononanoic acid using an in vivo assessment

Perfluorononanoic acid (PFNA) is an organic pollutant ubiquitous in the environment. However, the potential toxicity of PFNA remains largely unknown in teleost fish. This study defined the oxidative stress and related transcriptional effects of PFNA at various concentrations on zebrafish larvae. Activities of superoxide dismutase were induced in PFNA-treated groups but attenuated with exposure to higher concentration. Catalase activity and lipid peroxidation were significantly inhibited or increased at the highest concentration, respectively. To test the apoptotic pathway, several genes related to cell apoptosis were examined using real-time PCR. The expression of p53, apoptosis-inducing factor (AIF) and c-Jun NH (2)-terminal kinase (JNK) was partially increased, while Bcl-2, an anti-apoptotic gene, was reduced, with no significant effects on Bax and caspase-3 during the exposure period. The effect of PFNA on lipid beta-oxidation system was investigated by examining the activity of peroxisome fatty acyl-COA oxidase (ACOX) and the expression of peroxisome proliferating activating receptors (PPARs). ACOX activity was moderately elevated with marginal significance and was not a significant consequence of PPAR alpha and PPAR gamma expression. The overall results suggest that turbulence of oxidative stress and apoptotic pathway is involved in PFNA-induced toxicity in zebrafish larvae, and the gene expression patterns are able to reveal some potential mechanisms of developmental toxicity. Crown Copyright (C) 2013 Published by Elsevier Inc. All rights reserved.Perfluorononanoic acid (PFNA) is an organic pollutant ubiquitous in the environment. However, the potential toxicity of PFNA remains largely unknown in teleost fish. This study defined the oxidative stress and related transcriptional effects of PFNA at various concentrations on zebrafish larvae. Activities of superoxide dismutase were induced in PFNA-treated groups but attenuated with exposure to higher concentration. Catalase activity and lipid peroxidation were significantly inhibited or increased at the highest concentration, respectively. To test the apoptotic pathway, several genes related to cell apoptosis were examined using real-time PCR. The expression of p53, apoptosis-inducing factor (AIF) and c-Jun NH (2)-terminal kinase (JNK) was partially increased, while Bcl-2, an anti-apoptotic gene, was reduced, with no significant effects on Bax and caspase-3 during the exposure period. The effect of PFNA on lipid beta-oxidation system was investigated by examining the activity of peroxisome fatty acyl-COA oxidase (ACOX) and the expression of peroxisome proliferating activating receptors (PPARs). ACOX activity was moderately elevated with marginal significance and was not a significant consequence of PPAR alpha and PPAR gamma expression. The overall results suggest that turbulence of oxidative stress and apoptotic pathway is involved in PFNA-induced toxicity in zebrafish larvae, and the gene expression patterns are able to reveal some potential mechanisms of developmental toxicity. Crown Copyright (C) 2013 Published by Elsevier Inc. All rights reserved

The Effects of Vasoconstriction and Volume Expansion on Veno-Arterial ECMO Flow.

BACKGROUND Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is gaining widespread use in the treatment of severe cardiorespiratory failure. Blood volume expansion is commonly used to increase ECMO flow (QECMO), with risk of positive fluid balance and worsening prognosis. We studied the effects of vasoconstriction on recruitment of blood volume as an alternative for increasing QECMO, based on the concepts of venous return. METHODS In a closed chest, centrally cannulated porcine preparation (n = 9) in ventricular fibrillation and VA-ECMO with vented left atrium, mean systemic filling pressure (MSFP) and venous return driving pressure (VRdP) were determined in Euvolemia, during Vasoconstriction (norepinephrine 0.05, 0.125 and 0.2 μg/kg/min) and following Volume Expansion (3 boluses of 10 mL/kg Ringer's lactate). Maximum achievable QECMO was examined. RESULTS Vasoconstriction and Volume Expansion both increased maximum achievable QECMO, delivery of oxygen (DO2) and MSFP, but right atrial pressure increased in parallel. VRdP did not change. The vascular elastance curve was shifted to the left by Vasoconstriction, with recruitment of stressed volume. It was shifted to the right by Volume Expansion with direct expansion of stressed volume. Volume Expansion decreased resistance to venous return and pump afterload. CONCLUSIONS In a circulation completely dependent on ECMO support, maximum achievable flow directly depended on the vascular factors governing venous return - i.e. closing conditions, stressed vascular volume and the elastance and resistive properties of the vasculature. Both treatments increased maximum achievable ECMO flow at stable DO2, via increases in stressed volume by different mechanisms. Vascular resistance and pump afterload decreased with Volume Expansion

Microstructure and Mechanical Properties of TiC/TiB Composite Ceramic Coatings In-Situ Synthesized by Ultrasonic Vibration-Assisted Laser Cladding

Laser cladding coating has many advantages in surface modification, such as a small heat-affected zone, and good metallurgical bonding. However, some serious problems such as pores, and poor forming quality still exist in the coating. To suppress these problems, a novel process of ultrasonic vibration-assisted laser cladding process was adopted to in-situ synthesize TiC/TiB composite ceramic coating on the surface of titanium alloy. Results showed that the introduction of ultrasonic vibration effectively improved the surface topography of the coating, reduced the number of pores in the coating, refined the crystal grains of the coating, decreased the residual tensile stress in the coating, and increased the micro-hardness of the coating. The tribological properties of the coating were significantly improved by the ultrasonic vibration, the wear resistance of the coating fabricated with ultrasonic vibration at power of 400 W increased about 1.2 times compared with the coating fabricated without ultrasonic vibration, and the friction coefficient decreased by 50%

Wave separation analysis to assess cardiovascular alterations induced by sepsis

Objective: Sepsis induces a severe decompensation of arterial and cardiac functional properties, leading to important modifications of arterial blood pressure (ABP) waveform, not resolved by recommended therapy, as shown by previous works. The aim of this study is to quantify the changes in ABP waveform morphology and wave reflections during a long-term swine experiment of polymicrobial sepsis and resuscitation, to deepen the understanding of the cardiovascular response to standard resuscitation therapy. Methods: We analyzed 14 pigs: polymicrobial sepsis was induced in 9 pigs followed by standard resuscitation and 5 pigs were treated as sham controls. Septic animals were studied at baseline (T1), after sepsis development (T2), and after 24h (T3) and 48h (T4) of therapy administration, and sham controls at the same time points. ABP and arterial blood flow were measured in the left and right carotid artery, respectively. Pulse wave analysis and wave separation techniques were used to estimate arterial input impedance, carotid characteristic impedance, forward and backward waves, indices of wave reflections such as reflection magnitude and reflection index, and augmentation index. Results: Sepsis led to an acute alteration of ABP waveform passing from type A to type B or C; consistently, the reflection phenomena were significantly reduced. The resuscitation was successful in reaching targeted hemodynamic stability, but it failed in restoring a physiological blood propagation and reflection. Conclusion: Septic pigs persistently showed altered reflected waves even after 48 hours of successful therapy according to guidelines, suggesting a persistent hidden cardiovascular disorder. Significance: The proposed indices may be useful to unravel the complex cardiovascular response to therapy administration in septic patients and could potentially be used for risk stratification of patient deterioration. Whether alterations of blood propagation and reflection contribute to persisting organ dysfunction after hemodynamic stabilization should be further investigated