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Abstract Magnetic materials are composed of the simple building blocks of magnetic moments on a crystal lattice that interact via magnetic exchange. Yet from this simplicity emerges a remarkable diversity of magnetic states. Some reveal the deep quantum mechanical origins of magnetism, for example, quantum spin liquid (QSL) states in which magnetic moments remain disordered at low temperatures despite being strongly correlated through quantum entanglement. A promising theoretical model of a QSL is the Kitaev model, composed of unusual bond-dependent exchange interactions, but experimentally, this model is challenging to realise. Here we show that the material requirements for the Kitaev QSL survive an extended pseudo-edge-sharing superexchange pathway of Ru3+ octahedra within the honeycomb layers of the inorganic framework solid, RuP3SiO11. We confirm the requisite $${j}_{{\mathsf{eff}}}=\frac{1}{2}$$ j eff = 1 2 state of Ru3+ in RuP3SiO11 and resolve the hierarchy of exchange interactions that provide experimental access to an unexplored region of the Kitaev model.

Summary: Given expanding studies in epidemiology and disease-oriented human studies offering hundreds of associations between the human “ome” and disease, prioritizing molecules relevant to disease mechanisms among this growing breadth is important. Here, we link the circulating proteome to human heart failure (HF) propensity (via echocardiographic phenotyping and clinical outcomes) across the lifespan, demonstrating key pathways of fibrosis, inflammation, metabolism, and hypertrophy. We observe a broad array of genes encoding proteins linked to HF phenotypes and outcomes in clinical populations dynamically expressed at a transcriptional level in human myocardium during HF and cardiac recovery (several in a cell-specific fashion). Many identified targets do not have wide precedent in large-scale genomic discovery or human studies, highlighting the complementary roles for proteomic and tissue transcriptomic discovery to focus epidemiological targets to those relevant in human myocardium for further interrogation.

Abstract Background Utilization of electronic patient-reported outcome (ePRO) tools to monitor symptoms in patients undergoing cancer treatment has shown clinical benefits. Tennessee Oncology (TO) implemented an ePRO platform in 2019, allowing patients to report their health status online. We conducted a real-world, multicenter, observational, non-interventional cohort study to evaluate utilization of this platform in adults with solid tumors who initiated immuno-oncology (IO) therapy as monotherapy or in combination at TO clinics. Methods Patients initiating IO therapy prior to platform implementation were included in a historical control (HC) cohort; those initiating treatment after implementation were included in the ePRO cohort, which was further divided into ePRO users (platform enrollment ≤ 45 days from IO initiation) and non-users. Data were extracted from electronic medical records; patients were followed for up to 6 months (no minimum follow up). Outcomes included patient characteristics, treatment patterns, duration of therapy (DoT), and overall survival (OS). Results Data were collected for 538 patients in the HC and 1014 in the ePRO cohort; 319 in the ePRO cohort were ePRO users (uptake rate 31%). Baseline age was higher, more patients had stage IV disease at diagnosis, and more received monotherapy (82 vs 52%, respectively) in the HC vs the ePRO cohort. Median follow-up was 181.0 days (range 0.0–182.6) in the HC and 175.0 (0.0–184.0) in the ePRO cohort. Median DoT of index IO regimen was 5.1 months (95% confidence interval [CI], 4.4–NE) in the HC cohort vs not estimable (NE) in the ePRO cohort. Multivariable regression adjusting for baseline differences confirmed lower risk of treatment discontinuation in the ePRO vs HC cohort: hazard ratio (HR) 0.83 (95% CI, 0.71–0.97); p

Abstract The actualization of high strength and ductility in alloys, in addition to providing strong, formable materials, can lead to reduced weights in practical applications. However, increasing strength typically comes at the cost of lowering the ductility and vice-versa, referred to as the strength–ductility trade-off. In this work, we investigate the thermo-mechanical response of a 3-element multifunctional NiTi–Nb nanocomposite material that overcomes this trade-off, as it exhibits a high strength of 980 MPa and an ultrahigh ductility of 58% at fracture. The remarkable properties are attributed to the underlying microstructure of Nb nanofibers dispersed in an NiTi matrix. Deformation is accommodated via the shape memory transformation of the active NiTi matrix in concert with elastoplastic deformation of Nb nanofibers embedded within the matrix. Consequently, the material exhibits multifunctionality and recovers deformation during heating via the reversion of the stress-induced martensitic transformation in the NiTi matrix. The high strength and high ductility of this 3-element nanocomposite material puts it amongst the best performing high-entropy alloys (HEAs) that are typically made up of five or more elements.

Abstract Public and Patient Involvement in research is becoming a requirement on most research funding applications; this includes both healthcare and lab-based research. Whilst case studies and practical guides have been developed and are well documented for PPI in healthcare research, there is very little guidance available for PPI in lab-based research. In this piece we discuss our experience of how we have successfully involved patients in our translational cancer research, which is focused on developing personalised treatment for high-grade serous ovarian cancer. We discuss the benefits it has made to both our research and to us as researchers. The patients involved write about their experience, what they enjoyed, and the benefits they felt. Although PPI is quite topical and is being widely discussed, there is hesitancy among researchers, especially those in lab-based research about getting started because of a lack of practical guidance about how to implement it. Here, we have shared our experience, hopefully providing a practical example of how PPI can be incorporated into a lab-based research project.

Abstract The layered-ruthenate family of materials possess an intricate interplay of structural, electronic and magnetic degrees of freedom that yields a plethora of delicately balanced ground states. This is exemplified by Ca3Ru2O7, which hosts a coupled transition in which the lattice parameters jump, the Fermi surface partially gaps and the spins undergo a 90∘ in-plane reorientation. Here, we show how the transition is driven by a lattice strain that tunes the electronic bandwidth. We apply uniaxial stress to single crystals of Ca3Ru2O7, using neutron and resonant x-ray scattering to simultaneously probe the structural and magnetic responses. These measurements demonstrate that the transition can be driven by externally induced strain, stimulating the development of a theoretical model in which an internal strain is generated self-consistently to lower the electronic energy. We understand the strain to act by modifying tilts and rotations of the RuO6 octahedra, which directly influences the nearest-neighbour hopping. Our results offer a blueprint for uncovering the driving force behind coupled phase transitions, as well as a route to controlling them.

Abstract Aims Beta‐blockers are proven to improve survival among patients with heart failure with reduced ejection fraction. Their efficacy in patients with heart failure with reduced ejection fraction and pacemaker devices has not been demonstrated. Our aim was to test the hypothesis that beta‐blocker therapy is associated with improved survival in patients with chronic heart failure and a pacemaker rhythm on electrocardiogram (ECG). Methods and results This is a post hoc analysis from the GISSI‐HF randomized clinical trial. We evaluated efficacy of beta‐blockers by creating Cox proportional hazards models adjusting for pacemaker rhythm and heart rate, among other variables. Interactions between pacemaker rhythm, heart rate, and beta‐blocker were also examined. Of the 6975 patients enrolled in the GISSI‐HF trial, 813 (11.7%) had a pacemaker rhythm on baseline ECG. Of these 813 patients, 511 (62.9%) were receiving beta‐blocker therapy. The effect of beta‐blocker therapy on mortality was assessed using multivariable Cox proportional hazards adjusted for 27 co‐variates. In the whole cohort, beta‐blocker therapy was significantly associated with reduced mortality (hazard ratio 0.79 [0.72–0.87], P

In this study, the microbiota of multiple body sites from 101 marine fish species from Southern California were sampled and analysed. The authors compared diversity measures while also establishing a method to estimate microbial biomass. Body site is shown to be the strongest driver of microbial diversity and patterns of phylosymbiosis are observed across the gill, skin and hindgut.

Background Studies in mice and small patient subsets implicate metabolic dysfunction in cardiac remodeling in aortic stenosis, but no large comprehensive studies of human metabolism in aortic stenosis with long‐term follow‐up and characterization currently exist. Methods and Results Within a multicenter prospective cohort study, we used principal components analysis to summarize 12 echocardiographic measures of left ventricular structure and function pre–transcatheter aortic valve implantation in 519 subjects (derivation). We used least absolute shrinkage and selection operator regression across 221 metabolites to define metabolic signatures for each structural pattern and measured their relation to death and multimorbidity in the original cohort and up to 2 validation cohorts (N=543 for overall validation). In the derivation cohort (519 individuals; median age, 84 years, 45% women, 95% White individuals), we identified 3 axes of left ventricular remodeling, broadly specifying systolic function, diastolic function, and chamber volumes. Metabolite signatures of each axis specified both known and novel pathways in hypertrophy and cardiac dysfunction. Over a median of 3.1 years (205 deaths), a metabolite score for diastolic function was independently associated with post–transcatheter aortic valve implantation death (adjusted hazard ratio per 1 SD increase in score, 1.54 [95% CI, 1.25–1.90]; P

Abstract B-site ordered 4d 1 and 5d 1 double perovskites have a number of potential exotic ground states including multipolar order, quantum spin liquids and valence bond glass states. These arise from the complex interactions of spin-orbital entangled J eff = 3/2 pseudospins on the geometrically frustrated fcc lattice. The 4d 1 Mo5+ perovskite Ba2YMoO6 has been suggested to have a valence bond glass ground state. Here we report on the low temperature properties of powder samples of isostructural Ba2LuMoO6: the only other known cubic 4d 1 perovskite with one magnetic cation. Our muon spectroscopy experiments show that magnetism in this material remains dynamic down to 60 mK without any spin freezing or magnetic order. A singlet-triplet excitation with a gap of Δ = 28 meV is observed in inelastic neutron scattering. These results are interpreted as a disordered valence bond glass ground state similar to Ba2YMoO6. Our results highlight the differences of the 4d 1 double perovskites in comparison to cubic 5d 1 analogues, which have both magnetic and multipolar order.

MgV_{2}O_{4} is a spinel based on magnetic V^{3+} ions, which host both spin (S=1) and orbital (l_{eff}=1) moments. Owing to the underlying pyrochlore coordination of the magnetic sites, the spins in MgV_{2}O_{4} only antiferromagnetically order once the frustrating interactions imposed by the Fd3[over ¯]m lattice are broken through an orbitally-driven structural distortion at T_{S}≃60 K. Consequently, a Néel transition occurs at T_{N}≃40 K. Low-temperature spatial ordering of the electronic orbitals is fundamental to both the structural and magnetic properties; however, considerable discussion on whether it can be described by complex or real orbital ordering is ambiguous. We apply neutron spectroscopy to resolve the nature of the orbital ground state and characterize hysteretic spin-orbital correlations using x-ray and neutron diffraction. Neutron spectroscopy finds multiple excitation bands and we parametrize these in terms of a multilevel (or excitonic) theory based on the orbitally degenerate ground state. Meaningful for the orbital ground state, we report an “optical-like” mode at high energies that we attribute to a crystal-field-like excitation from the spin-orbital j_{eff}=2 ground-state manifold to an excited j_{eff}=1 energy level. We parametrize the magnetic excitations in terms of a Hamiltonian with spin-orbit coupling and local crystalline electric field distortions resulting from deviations from perfect octahedra surrounding the V^{3+} ions. We suggest that this provides compelling evidence for complex orbital order in MgV_{2}O_{4}. We then apply the consequences of this model to understand hysteretic effects in the magnetic diffuse scattering where we propose that MgV_{2}O_{4} displays a high-temperature orbital memory of the low-temperature spin order.

Abstract Metallic iridium oxides (iridates) provide a fertile playground to explore new phenomena resulting from the interplay between topological protection, spin-orbit and electron-electron interactions. To date, however, few studies of the low energy electronic excitations exist due to the difficulty in synthesising crystals with sufficiently large carrier mean-free-paths. Here, we report the observation of Shubnikov-de Haas quantum oscillations in high-quality single crystals of monoclinic SrIrO3 in magnetic fields up to 35 T. Analysis of the oscillations reveals a Fermi surface comprising multiple small pockets with effective masses up to 4.5 times larger than the calculated band mass. Ab-initio calculations reveal robust linear band-crossings at the Brillouin zone boundary, due to its non-symmorphic symmetry, and overall we find good agreement between the angular dependence of the oscillations and the theoretical expectations. Further evidence of strong electron correlations is realized through the observation of signatures of non-Fermi liquid transport as well as a large Kadowaki-Woods ratio. These collective findings, coupled with knowledge of the evolution of the electronic state across the Ruddlesden-Popper iridate series, establishes monoclinic SrIrO3 as a topological semimetal on the boundary of the Mott metal-insulator transition.

Sr3Ru2O7 exhibits a quantum critical point tunable by magnetic field and has been widely used in the study of criticality. Here, by using inelastic neutron scattering, the authors measure collective magnetic excitations near the quantum critical point and relate them to thermodynamic properties and spin density wave order.

Background Global longitudinal strain (GLS) is a sensitive measure of left ventricular function and a risk marker in severe aortic stenosis. We sought to determine whether biomarkers of cardiac damage (cardiac troponin) and stress (NT‐proBNP [N‐terminal pro‐B‐type natriuretic peptide]) could complement GLS to identify patients with severe aortic stenosis at highest risk. Methods and Results From a multicenter prospective cohort of patients with symptomatic severe aortic stenosis who underwent transcatheter aortic valve implantation, we measured absolute GLS (aGLS), cardiac troponin, and NT‐proBNP at baseline in 499 patients. Left ventricular ejection fraction 2; P≤0.002 for each) when the other biomarker was elevated, but not when the other biomarker was normal (interaction P=0.015). Conclusions Among patients with symptomatic severe aortic stenosis undergoing transcatheter aortic valve implantation, elevations in circulating cardiac troponin and NT‐proBNP are more common as GLS worsens. Biomarkers of cardiac damage and stress are independently associated with mortality after transcatheter aortic valve implantation, whereas GLS is not. These findings may have implications for risk stratification of asymptomatic patients to determine optimal timing of valve replacement.

With an aging population, kidney health becomes an important medical and socioeconomic factor. Kidney aging mechanisms are not well understood. We previously showed that podocytes isolated from aged mice exhibit increased expression of programmed cell death protein 1 (PD-1) surface receptor and its 2 ligands (PD-L1 and PD-L2). PDCD1 transcript increased with age in microdissected human glomeruli, which correlated with lower estimated glomerular filtration rate and higher segmental glomerulosclerosis and vascular arterial intima-to-lumen ratio. In vitro studies in podocytes demonstrated a critical role for PD-1 signaling in cell survival and in the induction of a senescence-associated secretory phenotype. To prove PD-1 signaling was critical to podocyte aging, aged mice were injected with anti–PD-1 antibody. Treatment significantly improved the aging phenotype in both kidney and liver. In the glomerulus, it increased the life span of podocytes, but not that of parietal epithelial, mesangial, or endothelial cells. Transcriptomic and immunohistochemistry studies demonstrated that anti–PD-1 antibody treatment improved the health span of podocytes. Administering the same anti–PD-1 antibody to young mice with experimental focal segmental glomerulosclerosis (FSGS) lowered proteinuria and improved podocyte number. These results suggest a critical contribution of increased PD-1 signaling toward both kidney and liver aging and in FSGS.

Introduction: Rates of human papillomavirus (HPV) vaccination remain low and missed opportunities for HPV vaccination are widespread. Researchers have identified factors related to HPV vaccination, but less is known about missed opportunities. Methods: We used medical claims data from a large Midwestern insurance provider to explore relationships between adolescent and provider characteristics and missed opportunities for HPV vaccination. We stratified models by initiation status with adolescents who had received one or more HPV vaccinations in one group (n = 6,123) and adolescents with no record of an HPV vaccination in the other (n = 8,107). Results: There were significant differences in comparisons of all variables between initiators and non-initiators. Notably, non-initiators had lower rates of vaccination for HPV and other adolescent vaccinations, and fewer well-child visits. For all adolescents, birth year, having other recommended vaccines, and number of well-child visits were significantly associated with missed opportunities. Additionally, among initiators, pediatrician as a primary care provider and being in a rural area were significantly associated. Discussion: Overall, adolescents with greater healthcare utilization had more missed opportunities, indicating that, despite increased numbers of visits, providers are not taking advantage of these opportunities to vaccinate. Future research should prioritize developing a deeper understanding of why these missed opportunities are occurring and implementing new and existing strategies to prevent them. Reducing missed opportunities will help to prevent future HPV-related cancers and the significant morbidity and mortality that they can cause.

Abstract A series of simple ditopic hydrogen-bonding-capable molecules functionalized with 2,4-diamino-1,3,5-triazine (DAT), barbiturate (B), and phthalhydrazide (PH) on both termini of a 2,2′-bithiophene linker were designed and synthesized. The intrinsic electronic structures of the ditopic DAT, PH, and B molecules were investigated with ground-state density functional theory calculations. Their solution absorbance was investigated with UV-vis, where it was found that increasing size of R group substituents on the bithiophene linker resulted in a general blue-shift in solution absorbance maximum. The solid-state optical properties of ditopic DAT and B thin films were evaluated by UV-vis, and it was found that the solid-state absorbance was red-shifted with respect to solution absorbance in all cases. The three DAT molecules were vacuum-thermal-deposited onto Au(111) substrates and the morphologies were examined using scanning tunneling microscopy. (DAT-T)2 was observed to organize into six-membered rosettes on the surface, whereas (DAT-TMe)2 formed linear assemblies before and after thermal annealing. For (DAT-Toct)2 , an irregular arrangement was observed, while (B-TMe)2 showed several co-existent assembly patterns. The work presented here provides fundamental molecular–supramolecular relationships useful for semiconductive materials design based on ditopic hydrogen-bonding-capable building blocks.

Three-dimensional (3D) kinematic analysis of gait holds potential as a digital biomarker to identify neuropathologies, monitor disease progression, and provide a high-resolution outcome measure to monitor neurorehabilitation efficacy by characterizing the mechanisms underlying gait impairments. There is a need for 3D motion capture technologies accessible to community, clinical, and rehabilitation settings. Image-based markerless motion capture (MLMC) using neural network-based deep learning algorithms shows promise as an accessible technology in these settings. In this study, we assessed the feasibility of implementing 3D MLMC technology outside the traditional laboratory environment to evaluate its potential as a tool for outcomes assessment in neurorehabilitation. A sample population of 166 individuals aged 9–87 years (mean 43.7, S.D. 20.4) of varied health history were evaluated at six different locations in the community over a 3-month period. Participants walked overground at self-selected (SS) and fastest comfortable (FC) speeds. Feasibility measures considered the expansion, implementation, and practicality of this MLMC system. A subset of the sample population (46 individuals) walked over a pressure-sensitive walkway (PSW) concurrently with MLMC to assess agreement of the spatiotemporal gait parameters measured between the two systems. Twelve spatiotemporal parameters were compared using mean differences, Bland-Altman analysis, and intraclass correlation coefficients for agreement (ICC2,1) and consistency (ICC3,1). All measures showed good to excellent agreement between MLMC and the PSW system with cadence, speed, step length, step time, stride length, and stride time showing strong similarity. Furthermore, this information can inform the development of rehabilitation strategies targeting gait dysfunction. These first experiments provide evidence for feasibility of using MLMC in community and clinical practice environments to acquire robust 3D kinematic data from a diverse population. This foundational work enables future investigation with MLMC especially its use as a digital biomarker of disease progression and rehabilitation outcome.

Purpose: To examine the between-day absolute reliability of gait parameters acquired with Theia3D markerless motion capture for use in biomechanical and clinical settings.Methods: Twenty-one (7 M,14 F) participants aged between 18 and 73 years were recruited in community locations to perform two walking tasks: self-selected and fastest-comfortable walking speed. Participants walked along a designated walkway on two separate days.Joint angle kinematics for the hip, knee, and ankle, for all planes of motion, and spatiotemporal parameters were extracted to determine absolute reliability between-days. For kinematics, absolute reliability was examined using: full curve analysis [root mean square difference (RMSD)] and discrete point analysis at defined gait events using standard error of measurement (SEM). The absolute reliability of spatiotemporal parameters was also examined using SEM and SEM%.Results: Markerless motion capture produced low measurement error for kinematic full curve analysis with RMSDs ranging between 0.96° and 3.71° across all joints and planes for both walking tasks. Similarly, discrete point analysis within the gait cycle produced SEM values ranging between 0.91° and 3.25° for both sagittal and frontal plane angles of the hip, knee, and ankle. The highest measurement errors were observed in the transverse plane, with SEM >5° for ankle and knee range of motion. For the majority of spatiotemporal parameters, markerless motion capture produced low SEM values and SEM% below 10%.Conclusion: Markerless motion capture using Theia3D offers reliable gait analysis suitable for biomechanical and clinical use.

Current research on Coastal and Marine Tourism (CTM) in South Africa focuses on two main coastal tourism provinces (KwaZulu-Natal and Western Cape) as well as specific CMT activities such as whale watching and shark cage diving. This study, therefore, contributes to the body of knowledge on CMT by focusing on the Eastern Cape and undertaking a provincial level analysis. Coastal and Marine Tourism location visitor profiles in terms of socio-economic profile, types of CMT visitors, types of CMT activities participated and future interest in the Eastern Cape, South Africa. CMT encompasses activities and resources in and near coastal and marine areas that attract visitors who participate in a range of active and passive business, adventure, leisure and recreational activities that generate socio-economic and environmental benefits. A quantitative approach is adopted, drawing on 700 visitor surveys that were conducted at purposively selected CMT locations in the Eastern Cape. Visitors were from a range of socio-economic backgrounds. There were high levels of participation in CMT activities, especially coastal leisure and recreational activities. Results indicate increased CMT location visitation demand. From a sustainability and responsible tourism perspective, understanding who visits CMT sites assists in ensuring effective planning to manage demand and protect/ conserve coastal and marine resources.

Abstract Discrepancies in the low-energy quasiparticle dispersion extracted from angle-resolved photoemission, scanning tunneling spectroscopy, and quantum oscillation data are common and have long haunted the field of quantum matter physics. Here, we directly test the consistency of results from these three techniques by comparing data from the correlated metal Sr2RhO4. Using established schemes for the interpretation of the experimental data, we find good agreement for the Fermi surface topography and carrier effective masses. Hence, the apparent absence of such an agreement in other quantum materials, including the cuprates, suggests that the electronic states in these materials are of different, non-Fermi liquid-like nature. Finally, we discuss the potential and challenges in extracting carrier lifetimes from photoemission and quasiparticle interference data.

Background: Liquid biopsies offer significant potential for informing on cancer progression and therapeutic resistance via minimally invasive serial monitoring of genetic alterations. Although the cancer epigenome is a central driving force in most neoplasia, the accuracy of monitoring the tumor methylome using liquid biopsies remains relatively unknown. Objectives: to investigate how well two types of liquid biopsy (urine and blood) capture the prostate cancer methylome, and may thus serve as a non-invasive surrogate for studying the tumor epigenome. Methods: A cohort of four metastatic treatment naïve prostate cancer (PCa) patients was selected. Matched biopsy cores (tumor and histologically matched-normal), post-DRE, pre-biopsy urine, and peripheral blood plasma were available for each subject. DNA methylation was profiled utilizing the Infinium® MethylationEPIC BeadChip (Illumina) and analysed using the RnBeads software. Significantly (FDR adjusted P < 0.05) differentially methylated probes (DMPs) between tumor and MN were identified and examined in the liquids (done at a grouped and individual subject level). Results: DNA methylation analysis of urine and blood in men with metastatic PCa showed highly correlated patterns between the different liquid types (ρ = 0.93, P < 0.0001), with large contributions from non-tumor sources. DNA methylation profiles of liquids were more similar between subjects, than intra-individual liquid-tumor correlations. Overall, both urine and plasma are viable surrogates for tumor tissue biopsies, capturing up to 39.40% and 64.14% of tumor-specific methylation alterations, respectively. Conclusion: We conclude that both urine and blood plasma are easily accessible and sensitive biofluids for the study of PCa epigenomic alterations.

We report a comprehensive experimental investigation of the magnetic structure of the cycloidal phase in Ca_{3}Ru_{2}O_{7}, which mediates the spin reorientation transition and establishes its magnetic phase diagram. In zero applied field, single-crystal neutron diffraction data confirm the scenario deduced from an earlier resonant x-ray scattering study: For 46.7K

Standard clinical assessments of mild traumatic brain injury are inadequate to detect subtle abnormalities that can be revealed by sophisticated diagnostic technology. An association has been observed between sport-related concussion (SRC) and subsequent musculoskeletal injury, but the underlying neurophysiological mechanism is not currently understood. A cohort of 16 elite athletes (10 male, 6 female), which included nine individuals who reported a history of SRC (5 male, 4 female) that occurred between 4 months and 8 years earlier, volunteered to participate in a 12-session program for assessment and training of perceptual-motor efficiency. Performance metrics derived from single- and dual-task whole-body lateral and diagonal reactive movements to virtual reality targets in left and right directions were analyzed separately and combined in various ways to create composite representations of global function. Intra-individual variability across performance domains demonstrated very good SRC history classification accuracy for the earliest 3-session phase of the program (Reaction Time Dispersion AUC = 0.841; Deceleration Dispersion AUC = 0.810; Reaction Time Discrepancy AUC = 0.825, Deceleration Discrepancy AUC = 0.794). Good earliest phase discrimination was also found for Composite Asymmetry between left and right movement directions (AUC = 0.778) and Excursion Average distance beyond the minimal body displacement necessary for virtual target deactivation (AUC = 0.730). Sensitivity derived from Youden's Index for the 6 global factors ranged from 67 to 89% and an identical specificity value of 86% for all of them. Median values demonstrated substantial improvement from the first 3-session phase to the last 3-session phase for Composite Asymmetry and Excursion Average. The results suggest that a Composite Asymmetry value ≥ 0.15 and an Excursion Average value ≥ 7 m, provide reasonable qualitative approximations for clinical identification of suboptimal perceptual-motor performance. Despite acknowledged study limitations, the findings support a hypothesized relationship between whole-body reactive agility performance and functional connectivity among brain networks subserving sensory perception, cognitive decision-making, and motor execution. A complex systems approach appears to perform better than traditional data analysis methods for detection of subtle perceptual-motor impairment, which has the potential to advance both clinical management of SRC and training for performance enhancement.

Recently, many approaches have been developed to improve the performance of nanomaterials. Combining more than one nanomaterial is one such approach that achieves superior results. However, during the fabrication of nanomaterials or formulation of end products, materials can be released into the ambient air and be inhaled by workers. The adverse health outcomes of inhaling such compounds are unknown. In this study, we examined such effects in combining two of the most utilized nanomaterials in several industrial sectors: zinc oxide (ZnO) and cerium oxide (CeO2). These materials can be found together in sunscreens, polyvinyl alcohol (PVA) films, and construction products. The aim of this study was to assess the adverse biological outcomes of CeO2–ZnO nano-mixtures in human lung epithelial cells. A549 human lung epithelial cells were treated with increasing concentrations of ZnO or CeO2 NPs alone, or as a mixture of both, under submerged conditions for 24 h. After treatment, cell viability, reactive oxygen species (ROS) formation, cell membrane integrity, and cytokine production were examined. ZnO NPs showed a dose-dependent trend for all endpoints. CeO2 NPs did not exhibit any toxic effect in any individual concentrations. When higher doses of ZnO were combined with increasing doses of CeO2, loss of cell viability and an elevation in cell membrane leakage were observed. Interleukin 8 (IL-8) and ROS generation were higher when ZnO NPs were combined with CeO2 NPs, compared to cells that were treated with ZnO alone. The release of monocyte chemoattractant protein-1 (MCP-1) was reduced in the cells that were treated with higher doses of ZnO and CeO2. Thus, the presence of CeO2 enhanced the toxicity of ZnO in A549 cells at non-toxic levels of CeO2. This suggests an additive toxicity of these two nanomaterials.

Background The optimal threshold of left ventricular ejection fraction (LVEF) that should prompt aortic valve replacement (AVR) in asymptomatic patients with high‐gradient severe aortic stenosis (AS) is controversial. The aim of this study was to assess the relationship between LVEF and mortality benefit in comparing early AVR versus watchful waiting in asymptomatic patients with severe AS. Methods and Results MEDLINE, Embase, Web of Science, and Google Scholar were searched for observational studies and randomized controlled trials on adults with asymptomatic severe AS. Severe AS was defined by a peak aortic velocity ≥4 m/s and/or mean aortic valve gradient ≥40 mm Hg and/or calculated aortic valve area

Functional support-the availability of material aid, emotional support, or companionship-promotes general well-being. For men who have sex with men (MSM) living with HIV, having a person who supports you associates with viral suppression. This study examines the association between supportive partnerships and HIV viral suppression among middle-aged and aging MSM living with HIV. A total of 423 middle-aged and aging MSM (mean age, 58.2 years) from the Multicenter AIDS Cohort Study provided self-reported data about their partnerships. Separate Poisson regression models assessed how partnership type, support, strain, and duration from April 2017 were associated with repeated viral load measurements up to April 2019. Of the follow-up visits (N = 1289), 90.0% of participants were virally suppressed. Most participants reported being non-Hispanic White (61.0%) and college-educated (83.4%). Participants were asked about their primary partnerships (i.e., "someone they are committed to above anyone else") and secondary partnerships (i.e., those who can also be intimate or supportive but not necessarily romantic or sexual). The participants reported: no partnerships (45.2%), only primary partnerships (31.0%), only secondary partnerships (11.1%), or both primary and secondary partnerships (12.8%). Primary and secondary partnerships had mean (SD) durations of 15.9 (11.3) and 25.2 (16.5) years, respectively. Participants reporting both primary and secondary partnerships (compared with no partnership) showed significantly higher odds of being virally suppressed (adjusted prevalence ratio [aPR], 1.04; 95% CI, 1.00-1.08; p = 0.043). Albeit not statistically significant, primary-only (aPR, 1.01; 95% CI, 0.97-1.06; p = 0.547) or secondary-only (aPR, 1.03; 95% CI, 0.98-1.08; p = 0.224) partnership types were positively associated with viral suppression. Partner support and strain were not associated with viral suppression in any partnership group. Being older and non-Hispanic Black were positively and negatively associated with viral suppression, respectively. Encouraging partnerships should be considered one of clinicians' many tools to help middle-aged and aging MSM achieve long-term viral suppression.

Qsp1 is a secreted quorum sensing peptide required for virulence of the fungal meningitis pathogen Cryptococcus neoformans. Qsp1 functions to control cell wall integrity in vegetatively growing cells and also functions in mating. Rather than acting on a cell surface receptor, Qsp1 is imported to act intracellularly via the predicted oligopeptide transporter Opt1. Here, we identify a transcription factor network as a target of Qsp1. Using whole-genome chromatin immunoprecipitation, we find Qsp1 controls the genomic associations of three transcription factors to genes whose outputs are regulated by Qsp1. One of these transcription factors, Cqs2, is also required for the action of Qsp1 during mating, indicating that it might be a shared proximal target of Qsp1. Consistent with this hypothesis, deletion of CQS2 impacts the binding of other network transcription factors specifically to Qsp1-regulated genes. These genetic and genomic studies illuminate mechanisms by which an imported peptide acts to modulate eukaryotic gene expression.

Abstract Background Prevention of unnecessary biopsies and overtreatment of indolent disease remains a challenge in the management of prostate cancer. Novel non-invasive tests that can identify clinically significant (intermediate-risk and high-risk) diseases are needed to improve risk stratification and monitoring of prostate cancer patients. Here, we investigated a panel of six DNA methylation biomarkers in urine samples collected post-digital rectal exam from patients undergoing prostate biopsy, for their utility to guide decision making for diagnostic biopsy and early detection of aggressive prostate cancer. Results We recruited 408 patients in risk categories ranging from benign to low-, intermediate-, and high-risk prostate cancer from three international cohorts. Patients were separated into 2/3 training and 1/3 validation cohorts. Methylation biomarkers were analyzed in post-digital rectal exam urinary sediment DNA by quantitative MethyLight assay and investigated for their association with any or aggressive prostate cancers. We developed a Prostate Cancer Urinary Epigenetic (ProCUrE) assay based on an optimal two-gene (HOXD3 and GSTP1) LASSO model, derived from methylation values in the training cohort, and assessed ProCUrE’s diagnostic and prognostic ability for prostate cancer in both the training and validation cohorts. ProCUrE demonstrated improved prostate cancer diagnosis and identification of patients with clinically significant disease in both the training and validation cohorts. Using three different risk stratification criteria (Gleason score, D’Amico criteria, and CAPRA score), we found that the positive predictive value for ProCUrE was higher (59.4–78%) than prostate specific antigen (PSA) (38.2–72.1%) for all risk category comparisons. ProCUrE also demonstrated additive value to PSA in identifying GS ≥ 7 PCa compared to PSA alone (DeLong’s test p = 0.039), as well as additive value to the PCPT risk calculator for identifying any PCa and GS ≥ 7 PCa (DeLong’s test p = 0.011 and 0.022, respectively). Conclusions ProCUrE is a promising non-invasive urinary methylation assay for the early detection and prognostication of prostate cancer. ProCUrE has the potential to supplement PSA testing to identify patients with clinically significant prostate cancer.

Abstract For almost fifty years, geochemists have been interpreting the clues from Pb isotopic ratios concerning mantle composition and evolution separately. The Pb isotopes of ocean island basalts (OIB) indicate that their mantle source is heterogeneous, most likely due to the presence of end-components derived from recycled crust and sediment. Some OIB have unusually high 206Pb/204Pb coming from one of the end-components with a long time-integrated high 238U/204Pb or μ (HIMU). Most OIB and many mid-ocean ridge basalts (MORB) also have high 206Pb/204Pb, indicating a HIMU-like source. Moreover, measured 232Th/238U (κ) for most MORB are lower than those deduced from their 208Pb/204Pb and 206Pb/204Pb. Such high μ and low κ features of oceanic basalts are inconsistent with the known geochemical behavior of U, Pb and Th and temporal evolution of the mantle; these have been respectively termed the 1st and 2nd Pb paradox. Here we show that subducted marine carbonates can be a source for HIMU and a solution to the Pb paradoxes. The results are consistent with the predictions of the marine carbonate recycling hypothesis that posits the Pb isotopes of oceanic basalts indicate a common origin and/or magma generation process.

The role of the lattice in the correlated metal-insulator transition of Ca2RuO4 has led to significant interest but experiments that are at the same time sensitive to crystal and electronic structure are difficult. Riccò et al. successfully combine ARPES measurements with in situ strain tuning across the Mott transition.

Classifying indolent prostate cancer represents a significant clinical challenge. We investigated whether integrating data from different omic platforms could identify a biomarker panel with improved performance compared to individual platforms alone. DNA methylation, transcripts, protein and glycosylation biomarkers were assessed in a single cohort of patients treated by radical prostatectomy. Novel multiblock statistical data integration approaches were used to deal with missing data and modelled via stepwise multinomial logistic regression, or LASSO. After applying leave‐one‐out cross‐validation to each model, the probabilistic predictions of disease type for each individual panel were aggregated to improve prediction accuracy using all available information for a given patient. Through assessment of three performance parameters of area under the curve (AUC) values, calibration and decision curve analysis, the study identified an integrated biomarker panel which predicts disease type with a high level of accuracy, with Multi AUC value of 0.91 (0.89, 0.94) and Ordinal C‐Index (ORC) value of 0.94 (0.91, 0.96), which was significantly improved compared to the values for the clinical panel alone of 0.67 (0.62, 0.72) Multi AUC and 0.72 (0.67, 0.78) ORC. Biomarker integration across different omic platforms significantly improves prediction accuracy. We provide a novel multiplatform approach for the analysis, determination and performance assessment of novel panels which can be applied to other diseases. With further refinement and validation, this panel could form a tool to help inform appropriate treatment strategies impacting on patient outcome in early stage prostate cancer.

Abstract Background Epidemiological studies have linked exposures to ambient fine particulate matter (PM2.5) and traffic with autonomic nervous system imbalance (ANS) and cardiac pathophysiology, especially in individuals with preexisting disease. It is unclear whether metabolic syndrome (MetS) increases susceptibility to the effects of PM2.5. We hypothesized that exposure to traffic-derived primary and secondary organic aerosols (P + SOA) at ambient levels would cause autonomic and cardiovascular dysfunction in rats exhibiting features of MetS. Male Sprague Dawley (SD) rats were fed a high-fructose diet (HFrD) to induce MetS, and exposed to P + SOA (20.4 ± 0.9 μg/m3) for 12 days with time-matched comparison to filtered-air (FA) exposed MetS rats; normal diet (ND) SD rats were separately exposed to FA or P + SOA (56.3 ± 1.2 μg/m3). Results In MetS rats, P + SOA exposure decreased HRV, QTc, PR, and expiratory time overall (mean effect across the entirety of exposure), increased breathing rate overall, decreased baroreflex sensitivity (BRS) on three exposure days, and increased spontaneous atrioventricular (AV) block Mobitz Type II arrhythmia on exposure day 4 relative to FA-exposed animals receiving the same diet. Among ND rats, P + SOA decreased HRV only on day 1 and did not significantly alter BRS despite overall hypertensive responses relative to FA. Correlations between HRV, ECG, BRS, and breathing parameters suggested a role for autonomic imbalance in the pathophysiologic effects of P + SOA among MetS rats. Autonomic cardiovascular responses to P + SOA at ambient PM2.5 levels were pronounced among MetS rats and indicated blunted vagal influence over cardiovascular physiology. Conclusions Results support epidemiologic findings that MetS increases susceptibility to the adverse cardiac effects of ambient-level PM2.5, potentially through ANS imbalance.

Although there has been a renewed interest in the field of cancer metabolism in the last decade, the link between metabolism and DNA damage/DNA repair in cancer has yet to be appreciably explored. In this review, we examine the evidence connecting DNA damage and repair mechanisms with cell metabolism through three principal links. (1) Regulation of methyl- and acetyl-group donors through different metabolic pathways can impact DNA folding and remodeling, an essential part of accurate double strand break repair. (2) Glutamine, aspartate, and other nutrients are essential for de novo nucleotide synthesis, which dictates the availability of the nucleotide pool, and thereby influences DNA repair and replication. (3) Reactive oxygen species, which can increase oxidative DNA damage and hence the load of the DNA-repair machinery, are regulated through different metabolic pathways. Interestingly, while metabolism affects DNA repair, DNA damage can also induce metabolic rewiring. Activation of the DNA damage response (DDR) triggers an increase in nucleotide synthesis and anabolic glucose metabolism, while also reducing glutamine anaplerosis. Furthermore, mutations in genes involved in the DDR and DNA repair also lead to metabolic rewiring. Links between cancer metabolism and DNA damage/DNA repair are increasingly apparent, yielding opportunities to investigate the mechanistic basis behind potential metabolic vulnerabilities of a substantial fraction of tumors.