Systematic evaluation of immune regulation and modulation

Cancer immunotherapies are showing promising clinical results in a variety of malignancies. Monitoring the immune as well as the tumor response following these therapies has led to significant advancements in the field. Moreover, the identification and assessment of both predictive and prognostic biomarkers has become a key component to advancing these therapies. Thus, it is critical to develop systematic approaches to monitor the immune response and to interpret the data obtained from these assays. In order to address these issues and make recommendations to the field, the Society for Immunotherapy of Cancer reconvened the Immune Biomarkers Task Force. As a part of this Task Force, Working Group 3 (WG3) consisting of multidisciplinary experts from industry, academia, and government focused on the systematic assessment of immune regulation and modulation. In this review, the tumor microenvironment, microbiome, bone marrow, and adoptively transferred T cells will be used as examples to discuss the type and timing of sample collection. In addition, potential types of measurements, assays, and analyses will be discussed for each sample. Specifically, these recommendations will focus on the unique collection and assay requirements for the analysis of various samples as well as the high-throughput assays to evaluate potential biomarkers

Mood and the Market: Can Press Reports of Investors’ Mood Predict Stock Prices?

We examined whether press reports on the collective mood of investors can predict changes in stock prices. We collected data on the use of emotion words in newspaper reports on traders’ affect, coded these emotion words according to their location on an affective circumplex in terms of pleasantness and activation level, and created indices of collective mood for each trading day. Then, by using time series analyses, we examined whether these mood indices, depicting investors’ emotion on a given trading day, could predict the next day’s opening price of the stock market. The strongest findings showed that activated pleasant mood predicted increases in NASDAQ prices, while activated unpleasant mood predicted decreases in NASDAQ prices. We conclude that both valence and activation levels of collective mood are important in predicting trend continuation in stock prices

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Simulation of anisotropic crack tip deformation processes and particle interactions in toughened polymers

This study develops a finite element-based simulation of submicrometer crack tip deformation processes in polymers to investigate local toughening effects. An initial study of how these processes interact with stiff inclusions is presented to enable further investigation of particulate toughening. Crack tip and process zone mechanisms, including polymer chain disentanglement, directional chain realignment with consequent anisotropy, and crack propagation, are considered in a dedicated user-defined material law. Such processes are generally homogenized on higher scale continuum levels analyses, but direct simulation can provide insight into toughening mechanisms that have been widely observed but not fully explained. The user material law herein was employed in a parametric study to investigate the relative importance of (1) the extent of local inelastic polymer chain realignment and (2) consequent anisotropic hardening of the realigned polymer chains. In order to explore the interaction of fracture processes with nanometer-scale inclusions, silica particles with varied spacing were also included in the simulations. The interaction between local stress concentration and energy dissipation mechanisms has been quantified. It is shown that in neat polymers, local yielding is the dominant toughening effect accounting for over 90% of the local energy absorption, whereas local stiffening alone would decrease toughness. Stiff inclusions were shown to generally decrease toughness, except in cases where local yielding greatly outweighs local stiffening effects. Roughly 45% increase in toughness was shown for a 250-nm particle spacing that balances the acceleration of elastic failure with the formation of a larger local yield zone size. This demonstrates the utility of employing dedicated material laws to microstructural scale analyses in providing design targets in material design

Microstructural effects on failure modes in highly aligned short carbon fiber composites

Aligned short carbon fiber (3‐5 mm) thermoplastic composites have potential for versatile manufacturability with little loss of mechanical properties in comparison to continuous reinforcement. Property prediction, failure behavior, and the effects of microstructural variation for these materials are not yet well explored. The finite element method was used to evaluate large domains encompassing characteristic discontinuous microstructures of thermoplastic matrix (PMMA) composites reinforced with short 3 to 5 mm carbon fibers with a high degree of alignment and conventional volume fractions. Virtual tests were performed on highly detailed microstructural simulations which included fiber‐matrix interface representation along with uniform or misaligned fiber morphologies. Stiffness, strength, and failure mechanisms were analyzed. It was shown that for ideal uniformly aligned short fiber reinforcements, the material maintains a high modulus within 95% of an equivalent continuous fiber‐reinforced polymer, along with relatively high strength at 80% of a carbon fiber reinforced polymer (CFRP). Failure modes depended on the toughness of the fiber‐matrix interface, transitioning from fiber rupture to a weaker fiber pullout failure for low interface properties. Simulations indicated that significant fiber misalignments on the order of 15% of fibers at ±15° off‐axis could sharply reduce local strength in the misaligned region to roughly 20% of the continuous fiber strength. Although partially affected by property dropoff owing to fiber off‐axis misalignment, this weakening was largely due to local matrix pockets in regions of high misalignment, which acted as failure initiation points. This work explores failure modes in highly aligned short fiber composites using detailed finite element based microstructural simulations. The results have helped identify key features in a morphology that demonstrate properties approaching those of continuous fiber reinforcement

Failure investigation of pure titanium bleed air ducts in jet fighters

•The bleed air ducts in jet fighters failed due to brittle fracture initiated from corrosion pits.•The ductility of titanium ducts was degraded by the ingress of hydrogen.•Computational fracture analysis was conducted to estimate critical crack size and failure conditions.•An advanced NDI method using electro-magnetic field has been developed to prevent similar failures. This paper describes the failure investigation of in-flight failures of bleed air ducts in jet fighters. Severe rupture had occurred at the bleed air duct during the flight that had caused the emergency landing situation. The tubular duct was manufactured using commercially pure titanium. An inspection revealed that all cracks occurred in the central portion of the bleed air duct. Examination of the fractured surfaces by using electron microscopy revealed that cracks initiated at multiple corrosion pits in the inner surface of the duct and these propagated by brittle cleavage cracking with occasional areas of fatigue striations induced by in-service cyclic pressure. Fractography, chemical analysis, and metallographic analysis confirmed that brittle fracture involved the ingress of hydrogen into a duct surface. The hydrogen effectively decreased the ductility of the duct which contributed to brittle fracture. The final destructive rupture of the duct can be explained by fracture mechanics. The critical crack size and stress induced by conditions at or near the operating load were estimated based on computational fracture analysis to explore the fracture mechanism. Asa consequence, a novel nondestructive inspection method has been developed to prevent such failures in future

A multiscale approach for virtual testing of highly aligned short carbon fiber composites

This paper presents an efficient multiscale approach for high fidelity virtual testing of highly aligned short fiber reinforced composites (SFRCs), based solely on constituent material and interface properties with no need of calibration data. The method is based on a hierarchical, bottom-up characterization of SFRCs and the link of mechanical behaviors of materials and microstructures from a lower scale to a higher scale. It starts with a microscopic unit cell model to estimate the transverse and shear properties of the aligned short fiber composites. Next, two types of mesoscale models with explicit consideration of fiber discontinuity and possible local fiber misalignments are employed to obtain effective properties of material domains with such morphologies. Such obtained meso-scale mechanical properties and damage behaviors are then integrated into the macroscale virtual laminar via the stochastically integrating of possible material defects. Results indicate that for perfectly aligned SFRCs the strength reduction is about 25% as compared to that of the continuously reinforced composites. However, misalignment of short fibers can cause a further strength reduction of 20–35% with the volume fraction of the misalign regions varying from 1% to 10%