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The ^{244}Pu(^{50}Ti,xn)^{294-x}Lv reaction was investigated at Lawrence Berkeley National Laboratory's 88-Inch Cyclotron. The experiment was aimed at the production of a superheavy element with Z≥114 by irradiating an actinide target with a beam heavier than ^{48}Ca. Produced Lv ions were separated from the unwanted beam and nuclear reaction products using the Berkeley Gas-filled Separator and implanted into a newly commissioned focal-plane detector system. Two decay chains were observed and assigned to the decay of ^{290}Lv. The production cross section was measured to be σ_{prod}=0.44(_{-0.28}^{+0.58})  pb at a center-of-target center-of-mass energy of 220(3) MeV. This represents the first published measurement of the production of a superheavy element near the "island of stability," with a beam of ^{50}Ti and is an essential precursor in the pursuit of searching for new elements beyond Z=118.

Worldwide trends to delay childbearing have increased parental ages at birth. Older parental age may harm offspring health, but mechanisms remain unclear. Alterations in offspring DNA methylation (DNAm) patterns could play a role as aging has been associated with methylation changes in gametes of older individuals. We meta-analyzed epigenome-wide associations of parental age with offspring blood DNAm of over 9500 newborns and 2000 children (5-10 years old) from the Pregnancy and Childhood Epigenetics consortium. In newborns, we identified 33 CpG sites in 13 loci with DNAm associated with maternal age (PFDR

Poly(ethylene oxide) (PEO)-based composite electrolytes (PCEs) are considered as promising candidates for next-generation lithium-metal batteries (LMBs) due to their high safety, easy fabrication, and good electrochemical stability. Here, we utilize operando grazing-incidence small-angle and wide-angle X-ray scattering to probe the correlation of electrochemically induced changes and the buried morphology and crystalline structure of the PCE. Results show that the two irreversible reactions, PEO-Li+ reduction and TFSI- decomposition, cause changes in the crystalline structure, array orientation, and morphology of the PCE. In addition, the reversible Li plating/stripping process alters the inner morphology, especially the PEO-LiTFSI domain radius and distance between PEO-LiTFSI domains, rather than causing crystalline structure and orientation changes. This work provides a new path to monitor a working battery in real time and to a detailed understanding of the Li+ diffusion mechanism, which is essential for developing highly transferable and interface-stable PCE-based LMBs.

Colloidal self-assembly allows rational design of structures on the micrometer and submicrometer scale. One architecture that can generate complete three-dimensional photonic bandgaps is the diamond cubic lattice, which has remained difficult to realize at length scales comparable with the wavelength of visible or ultraviolet light. In this work, we demonstrate three-dimensional photonic crystals self-assembled from DNA origami that act as precisely programmable patchy colloids. Our DNA-based nanoscale tetrapods crystallize into a rod-connected diamond cubic lattice with a periodicity of 170 nanometers. This structure serves as a scaffold for atomic-layer deposition of high-refractive index materials such as titanium dioxide, yielding a tunable photonic bandgap in the near-ultraviolet.

Este año se cumplen 200 años de relaciones diplomáticas entre Estados Unidos y Argentina, que han implicado la cooperación en una amplia gama de campos, incluido el turismo. En procura de identificar nuevos enfoques para mejorar la capacidad de los parques nacionales para la planificación y gestión del uso público que sean de mutuo beneficio y desarrollar otras formas de ofrecer experiencias de mayor calidad a los visitantes, la Embajada de los Estados Unidos de América en Buenos Aires, la Sociedad George Wright, el Servicio de Parques Nacionales de los Estados Unidos y la Administración de Parques Nacionales de la Argentina propusieron el “Programa Binacional de Intercambio para Mejorar las Experiencias de los Visitantes en los Parques Nacionales” como un intercambio de aprendizaje conjunto entre los dos países. Este artículo presenta la sistematización de la experiencia de la aplicación y adaptación del Modelo Interinstitucional de Manejo de Visitantes de los Estados Unidos de América para la gestión del uso público en cinco parques nacionales de la Argentina. Ofrece una visión general del marco, resume el proyecto desarrollado con los parques y, lo que es más importante, discute las lecciones aprendidas y las recomendaciones para la futura implementación del modelo en Argentina, y posiblemente, en otros países de América Latina.

This year marks 200 years of diplomatic relations between the United States and Argentina, which has involved cooperation across a wide range of fields, including tourism. In the interest of finding new approaches to improve the capacity of nation­al parks for public use planning and management and develop mutually beneficial ways to deliver higher-quality visitor experiences, the United States of America Embassy in Buenos Aires, the George Wright Society, the US National Park Service, and the Administration of National Parks in Argentina proposed the “Binational Exchange Program to Enhance Visitor Experiences in National Parks” as a co-learning exchange between the two countries. Through a critical review, this article focuses on the application and adaptation of the US Interagency Visitor Use Management Framework for public use management in five national parks in Argentina. The article offers an overview of the framework, summarizes the project developed with the parks, and, more importantly, discusses lessons learned and recommendations for future implementation of the model in Argentina and, possibly, other countries in Latin America.

Transition metal oxynitrides are a promising class of functional materials for photoelectrochemical (PEC) applications. Although these compounds are most commonly synthesized via ammonolysis of oxide precursors, such synthetic routes often lead to poorly controlled oxygen-to-nitrogen anion ratios, and the harsh nitridation conditions are incompatible with many substrates, including transparent conductive oxides. Here, we report direct reactive sputter deposition of a family of zirconium oxynitride thin films and the comprehensive characterization of their tunable structural, optical, and functional PEC properties. Systematic increases of the oxygen content in the reactive sputter gas mixture enable access to different crystalline structures within the zirconium oxynitride family. Increasing oxygen contents lead to a transition from metallic to semiconducting to insulating phases. In particular, crystalline Zr2ON2-like films have band gaps in the UV-visible range and are n-type semiconductors. These properties, together with a valence band maximum position located favorably relative to the water oxidation potential, make them viable photoanode candidates. Using chopped linear sweep voltammetry, we indeed confirm that our Zr2ON2 films are PEC-active for the oxygen evolution reaction in alkaline electrolytes. We further show that high-vacuum annealing boosts their PEC performance characteristics. Although the observed photocurrents are low compared to state-of-the-art photoanodes, these dense and planar thin films can offer a valuable platform for studying oxynitride photoelectrodes, as well as for future nanostructuring, band gap engineering, and defect engineering efforts.

The seventh iteration of the reference genome assembly for Rattus norvegicus-mRatBN7.2-corrects numerous misplaced segments and reduces base-level errors by approximately 9-fold and increases contiguity by 290-fold compared with its predecessor. Gene annotations are now more complete, improving the mapping precision of genomic, transcriptomic, and proteomics datasets. We jointly analyzed 163 short-read whole-genome sequencing datasets representing 120 laboratory rat strains and substrains using mRatBN7.2. We defined ∼20.0 million sequence variations, of which 18,700 are predicted to potentially impact the function of 6,677 genes. We also generated a new rat genetic map from 1,893 heterogeneous stock rats and annotated transcription start sites and alternative polyadenylation sites. The mRatBN7.2 assembly, along with the extensive analysis of genomic variations among rat strains, enhances our understanding of the rat genome, providing researchers with an expanded resource for studies involving rats.

Mentalization, operationalized as reflective functioning (RF), is the ability to understand ones own and anothers mental world implicitly or explicitly. RF is a newly discovered research field in Iran and is largely under-studied in Eastern cultures in general, underscoring the high need for cross-cultural studies in this field of research. A qualitative method was used to examine the ability to understand, process, and respond to high-arousal attachment situations in typical and clinical populations of Iranian children recruited from a Tehran primary school. A well-known semi-structured interview commonly used to assess RF in children was used to collect data. Required information on internalizing and externalizing symptoms, demographic information, and all formal diagnoses of children were collected by parents. The results indicated the identification of four different profiles of RF in children, one of which was adaptive, while the other three were maladaptive. Also, the results showed that typically developing children and those having a high social and economic status (SES) were characterized as having a more adaptive profile of RF, while children from the clinical population and those with a low SES reported a more maladaptive profile (passive mentalizing, helpless mentalizing, narcissistic mentalizing) of RF. The present study is an important step in increasing our understanding of the development of mentalization in children and has significant educational and clinical implications.

Ensuring healthy and sustainable food systems in increasing social, economic, and ecological change is a key global priority to protect human and environmental health. Seafood is an essential component of these food systems and a critical source of nutrients, especially in coastal communities. However, despite rapid transformations in aquatic food systems, and our urgent need to understand them, there is a dearth of data connecting harvested food production to actualized food consumption. Many analyses suggest institutional, legal, or technological innovations to improve food systems, but few have analyzed the pathways through which people already gain access to nutritious food. Here, using a random forest model and cluster analysis of a nationally representative data set from Kiribati, we operationalize access theory to trace the flows of consumptive benefit in a fisheries-based food system. We demonstrate that the market access mechanism is the key mechanism mediating seafood access in Kiribati, but importantly, the highest seafood consumption households showed lower market access, pointing to the importance of non-market acquisition (e.g., home production and gifting). We reveal six distinct household strategies that employ different sets of access mechanisms to ensure high levels of local seafood consumption in different contexts. We demonstrate the impacts of these strategies on the composition of household seafoods consumed, stressing the need to support these existing successful strategies. Finally, we point to key policy and management insights (e.g., improved infrastructure, shifts in species management) that may be more effective in reinforcing these existing pathways than commonly proposed food system interventions.

The instability of perovskite absorbers under various environmental stressors is the most significant obstacle to widespread commercialization of perovskite solar cells. Herein, we study the evolution of crystal structure and microstrain present in naked triple-cation mixed CsMAFA-based perovskite films under heat, UV, and visible light (1 Sun) conditions by grazing-incidence wide-angle X-ray scattering (GIWAXS). We find that the microstrain is gradient distributed along the surface normal of the films, decreasing from the upper surface to regions deeper within the film. Moreover, heat, UV, and visible light treatments do not interfere with the crystalline orientations within annealed polycrystalline films. However, when subjected to heat, the naked perovskite films exhibit a rapid component decomposition, induced by phase separation and ion migration. Conversely, under exposure to UV and 1 Sun light soaking, the naked perovskite films undergo a self-optimization structure evolution during degradation and develop into smoother films with reduced surface potential fluctuations.

Attenuated total reflection surface-enhanced infrared absorption spectroscopy (ATR-SEIRAS) is a powerful method for probing interfacial chemical processes. However, SEIRAS-active nanostructured metallic thin films for the in situ analysis of electrochemical phenomena are often unstable under biased aqueous conditions. In this work, we present a surface-enhancing structure based on etched black Si internal reflection elements with Au-coatings for in situ electrochemical ATR-SEIRAS. Using electrochemical potential-dependent adsorption and desorption of 4-methoxypyridine on Au, we demonstrate that black Si-based substrates offer advantages over commonly used structures, such as electroless-deposited Au on Si and electrodeposited Au on ITO-coated Si, due to the combination of high stability, sensitivity, and conductivity. These characteristics are especially valuable for time-resolved measurements where stable substrates are required over extended times. Furthermore, the low sheet resistance of Au layers on black Si reduces the RC time constant of the electrochemical cell, enabling a significantly higher time resolution compared to that of traditional substrates. Thus, we employ black Si-based substrates in conjunction with rapid- and step-scan Fourier transform infrared (FTIR) spectroscopy to investigate the adsorption and desorption kinetics of 4-methoxypyridine during in situ electrochemical potential steps. Adsorption is shown to be diffusion-limited, which allows for the determination of the mean molecular area in a fully established monolayer. Moreover, no significant changes in the peak ratios of vibrational modes with different orientations relative to the molecular axis are observed, suggesting a single adsorption mode and no alteration of the average molecular orientation during the adsorption process. Overall, this study highlights the enhanced performance of black Si-based substrates for both steady-state and time-resolved in situ electrochemical ATR-SEIRAS, providing a powerful platform for kinetic and mechanistic investigations of electrochemical interfaces.

Maternal educational attainment (MEA) shapes offspring health through multiple potential pathways. Differential DNA methylation may provide a mechanistic understanding of these long-term associations. We aimed to quantify the associations of MEA with offspring DNA methylation levels at birth, in childhood and in adolescence. Using 37 studies from high-income countries, we performed meta-analysis of epigenome-wide association studies (EWAS) to quantify the associations of completed years of MEA at the time of pregnancy with offspring DNA methylation levels at birth (n = 9 881), in childhood (n = 2 017), and adolescence (n = 2 740), adjusting for relevant covariates. MEA was found to be associated with DNA methylation at 473 cytosine-phosphate-guanine sites at birth, one in childhood, and four in adolescence. We observed enrichment for findings from previous EWAS on maternal folate, vitamin-B12 concentrations, maternal smoking, and pre-pregnancy BMI. The associations were directionally consistent with MEA being inversely associated with behaviours including smoking and BMI. Our findings form a bridge between socio-economic factors and biology and highlight potential pathways underlying effects of maternal education. The results broaden our understanding of bio-social associations linked to differential DNA methylation in multiple early stages of life. The data generated also offers an important resource to help a more precise understanding of the social determinants of health.

Higher birth order is associated with altered risk of many disease states. Changes in placentation and exposures to in utero growth factors with successive pregnancies may impact later life disease risk via persistent DNA methylation alterations. We investigated birth order with Illumina DNA methylation array data in each of 16 birth cohorts (8164 newborns) with European, African, and Latino ancestries from the Pregnancy and Childhood Epigenetics Consortium. Meta-analyzed data demonstrated systematic DNA methylation variation in 341 CpGs (FDR adjusted P

Circulating vitamin B12 concentrations during pregnancy are associated with offspring health. Foetal DNA methylation changes could underlie these associations. Within the Pregnancy And Childhood Epigenetics Consortium, we meta-analysed epigenome-wide associations of circulating vitamin B12 concentrations in mothers during pregnancy (n = 2,420) or cord blood (n = 1,029), with cord blood DNA methylation. Maternal and newborn vitamin B12 concentrations were associated with DNA methylation at 109 and 7 CpGs, respectively (False Discovery Rate P-value

PURPOSE: Anti-PD-1 therapy provides clinical benefit in 40-50% of patients with relapsed and/or metastatic head and neck squamous cell carcinoma (RM-HNSCC). Selection of anti- PD-1 therapy is typically based on patient PD-L1 immunohistochemistry (IHC) which has low specificity for predicting disease control. Therefore, there is a critical need for a clinical biomarker that will predict clinical benefit to anti-PD-1 treatment with high specificity. METHODS: Clinical treatment and outcomes data for 103 RM-HNSCC patients were paired with RNA-sequencing data from formalin-fixed patient samples. Using logistic regression methods, we developed a novel biomarker classifier based on expression patterns in the tumor immune microenvironment to predict disease control with monotherapy PD-1 inhibitors (pembrolizumab and nivolumab). The performance of the biomarker was internally validated using out-of-bag methods. RESULTS: The biomarker significantly predicted disease control (65% in predicted non-progressors vs. 17% in predicted progressors, p

Identification of regulators of Toxoplasma gondii bradyzoite development and cyst formation is the most direct way to address the importance of parasite development in long-term persistence and reactivation of this parasite. Here we show that a T. gondii gene (named Regulator of Cystogenesis 1; ROCY1) is sufficient for T. gondii bradyzoite formation in vitro and in vivo. ROCY1 encodes an RNA binding protein that has a preference for 3 regulatory regions of hundreds of T. gondii transcripts, and its RNA-binding domains are required to mediate bradyzoite development. Female mice infected with ΔROCY1 parasites have reduced (>90%) cyst burden. While viable parasites can be cultivated from brain tissue for up to 6 months post-infection, chronic brain-resident ΔROCY1 parasites have reduced oral infectivity compared to wild type. Despite clear defects in bradyzoite formation and oral infectivity, ΔROCY1 parasites were able to reactivate with similar timing and magnitude as wild type parasites for up to 5 months post-infection. Therefore while ROCY1 is a critical regulator of the bradyzoite developmental pathway, it is not required for parasite reactivation, raising new questions about the persisting life stage responsible for causing recrudescent disease.

Introduction There is considerable variation in the approach to infants presenting to the emergency department (ED) with fever. The authors primary aim was to develop a robust set of algorithms using community ED data to inform modifications of broader clinical guidance. Methods The authors report the development of California Febrile Infant Risk Stratification Tool (CA FIRST) using key components of the Roseville Protocol (ROS) and American Academy of Pediatrics (AAP) Clinical Practice Guideline (CPG). Expanded guidance was derived using a retrospective analysis of a cohort of 3527 febrile infants aged 7-90 days presenting to any Kaiser Permanente Northern California ED between 2010 and 2019 who underwent a core febrile infant evaluation. Results Melding ROS and AAP CPG algorithms in infants 7-60 days old, CA FIRST Algorithms had comparable performance characteristics to ROS and AAP CPG. CA FIRST enhancements included guidance on febrile infants 61-90 days old, high-risk infants, infants with bronchiolitis, and infants who received immunizations within the prior 48 hours. This retrospective analysis revealed that of 235 febrile infants 22-90 days old with respiratory syncytial virus and 221 who had fever in the 48 hours following vaccination, there were no cases of invasive bacterial infection. Discussion CA FIRST is a set of 13 algorithms providing a thoughtful and flexible approach to the febrile infant while minimizing unnecessary interventions. Conclusions CA FIRST Algorithms empower clinicians to manage most febrile infants. Algorithms are being modified as new data become available, imparting useful and ever-current educational information within a learning health care system.

BACKGROUND: Seasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear. METHODS: We carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1-11 years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points. RESULTS: We identified associations between birth season and DNAm (False Discovery Rate-adjusted p values

Hybrid perovskite semiconductor materials are predicted to lock chirality into place and encode asymmetry into their electronic states, while softness of their crystal lattice accommodates lattice strain to maintain high crystal quality with low defect densities, necessary for high luminescence yields. We report photoluminescence quantum efficiencies as high as 39% and degrees of circularly polarized photoluminescence of up to 52%, at room temperature, in the chiral layered hybrid lead-halide perovskites (R/S/Rac)-3BrMBA2PbI4 [3BrMBA = 1-(3-bromphenyl)-ethylamine]. Using transient chiroptical spectroscopy, we explain the excellent photoluminescence yields from suppression of nonradiative loss channels and high rates of radiative recombination. We further find that photoexcitations show polarization lifetimes that exceed the time scales of radiative decays, which rationalize the high degrees of polarized luminescence. Our findings pave the way toward high-performance solution-processed photonic systems for chiroptical applications and chiral-spintronic logic at room temperature.

Preventing the biogenesis of disease-relevant proteins is an attractive therapeutic strategy, but attempts to target essential protein biogenesis factors have been hampered by excessive toxicity. Here we describe KZR-8445, a cyclic depsipeptide that targets the Sec61 translocon and selectively disrupts secretory and membrane protein biogenesis in a signal peptide-dependent manner. KZR-8445 potently inhibits the secretion of pro-inflammatory cytokines in primary immune cells and is highly efficacious in a mouse model of rheumatoid arthritis. A cryogenic electron microscopy structure reveals that KZR-8445 occupies the fully opened Se61 lateral gate and blocks access to the lumenal plug domain. KZR-8445 binding stabilizes the lateral gate helices in a manner that traps select signal peptides in the Sec61 channel and prevents their movement into the lipid bilayer. Our results establish a framework for the structure-guided discovery of novel therapeutics that selectively modulate Sec61-mediated protein biogenesis.

BACKGROUND: The clinical burden of Long COVID, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and other post-infectious fatiguing illnesses (PIFI) is increasing. There is a critical need to advance understanding of the effectiveness and sustainability of innovative approaches to clinical care of patients having these conditions. METHODS: We aim to assess the effectiveness of a Long COVID and Fatiguing Illness Recovery Program (LC&FIRP) in a two-arm, single-blind, pragmatic, quality improvement, professional cluster, randomized controlled trial in which 20 consenting clinicians across primary care clinics in a Federally Qualified Health Center system in San Diego, CA, will be randomized at a ratio of 1:1 to either participate in (1) weekly multi-disciplinary team-based case consultation and peer-to-peer sharing of emerging best practices (i.e., teleECHO (Extension for Community Healthcare Outcomes)) with monthly interactive webinars and quarterly short courses or (2) monthly interactive webinars and quarterly short courses alone (a control group); 856 patients will be assigned to participating clinicians (42 patients per clinician). Patient outcomes will be evaluated according to the study arm of their respective clinicians. Quantitative and qualitative outcomes will be measured at 3- and 6-months post-baseline for clinicians and every 3-months post assignment to a participating clinician for patients. The primary patient outcome is change in physical function measured using the Patient-Reported Outcomes Measurement Information System (PROMIS)-29. Analyses of differences in outcomes at both the patient and clinician levels will include a linear mixed model to compare change in outcomes from baseline to each post-baseline assessment between the randomized study arms. A concurrent prospective cohort study will compare the LC&FIRP patient population to the population enrolled in a university health system. Longitudinal data analysis approaches will allow us to examine differences in outcomes between cohorts. DISCUSSION: We hypothesize that weekly teleECHO sessions with monthly interactive webinars and quarterly short courses will significantly improve clinician- and patient-level outcomes compared to the control group. This study will provide much needed evidence on the effectiveness of a technology-enabled multi-disciplinary team-based care model for the management of Long COVID, ME/CFS, and other PIFI within a federally qualified health center. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05167227 . Registered on December 22, 2021.

The mechanisms of cognitive decline after intraventricular hemorrhage (IVH) in some patients continue to be poorly understood. Multiple rodent models of intraventricular or subarachnoid hemorrhage have only shown mild or even no cognitive impairment on subsequent behavioral testing. In this study, we show that intraventricular hemorrhage only leads to a significant spatial memory deficit in the Morris water maze if it occurs in the setting of an elevated intracranial pressure (ICP). Histopathological analysis of these IVH + ICP animals did not show evidence of neuronal degeneration in the hippocampal formation after 2 weeks but instead showed significant microglial activation measured by lacunarity and fractal dimensions. RNA sequencing of the hippocampus showed distinct enrichment of genes in the IVH + ICP group but not in IVH alone having activated microglial signaling pathways. The most significantly activated signaling pathway was the classical complement pathway, which is used by microglia to remove synapses, followed by activation of the Fc receptor and DAP12 pathways. Thus, our study lays the groundwork for identifying signaling pathways that could be targeted to ameliorate behavioral deficits after IVH.

Astroviruses cause a spectrum of diseases spanning asymptomatic infections to severe diarrhea, but little is understood about their pathogenesis. We previously determined that small intestinal goblet cells were the main cell type infected by murine astrovirus-1. Here, we focused on the host immune response to infection and inadvertently discovered a role for indoleamine 2,3-dioxygenase 1 (Ido1), a host tryptophan catabolizing enzyme, in the cellular tropism of murine and human astroviruses. We identified that Ido1 expression was highly enriched among infected goblet cells, and spatially corresponded to the zonation of infection. Because Ido1 can act as a negative regulator of inflammation, we hypothesized it could dampen host antiviral responses. Despite robust interferon signaling in goblet cells, as well as tuft cell and enterocyte bystanders, we observed delayed cytokine induction and suppressed levels of fecal lipocalin-2. Although we found Ido-/- animals were more resistant to infection, this was not associated with fewer goblet cells nor could it be rescued by knocking out interferon responses, suggesting that IDO1 instead regulates cell permissivity. We characterized IDO1-/- Caco-2 cells and observed significantly reduced human astrovirus-1 infection. Together this study highlights a role for Ido1 in astrovirus infection and epithelial cell maturation.

Altered postural control in the trunk/hip musculature is a characteristic of multiple neurological and musculoskeletal conditions. Previously it was not possible to determine if altered cortical and subcortical sensorimotor brain activation underlies impairments in postural control. This study used a novel fMRI-compatible paradigm to identify the brain activation associated with postural control in the trunk and hip musculature. BOLD fMRI imaging was conducted as participants performed two versions of a lower limb task involving lifting the left leg to touch the foot to a target. For the supported leg raise (SLR) the leg is raised from the knee while the thigh remains supported. For the unsupported leg raise (ULR) the leg is raised from the hip, requiring postural muscle activation in the abdominal/hip extensor musculature. Significant brain activation during the SLR task occurred predominantly in the right primary and secondary sensorimotor cortical regions. Brain activation during the ULR task occurred bilaterally in the primary and secondary sensorimotor cortical regions, as well as cerebellum and putamen. In comparison with the SLR, the ULR was associated with significantly greater activation in the right premotor/SMA, left primary motor and cingulate cortices, primary somatosensory cortex, supramarginal gyrus/parietal operculum, superior parietal lobule, cerebellar vermis, and cerebellar hemispheres. Cortical and subcortical regions activated during the ULR, but not during the SLR, were consistent with the planning, and execution of a task involving multisegmental, bilateral postural control. Future studies using this paradigm will determine mechanisms underlying impaired postural control in patients with neurological and musculoskeletal dysfunction.

Flavin adenine dinucleotide (FAD) interacts with flavoproteins to mediate oxidation-reduction reactions required for cellular energy demands. Not surprisingly, mutations that alter FAD binding to flavoproteins cause rare inborn errors of metabolism (IEMs) that disrupt liver function and render fasting intolerance, hepatic steatosis, and lipodystrophy. In our study, depleting FAD pools in mice with a vitamin B2-deficient diet (B2D) caused phenotypes associated with organic acidemias and other IEMs, including reduced body weight, hypoglycemia, and fatty liver disease. Integrated discovery approaches revealed B2D tempered fasting activation of target genes for the nuclear receptor PPARα, including those required for gluconeogenesis. We also found PPARα knockdown in the liver recapitulated B2D effects on glucose excursion and fatty liver disease in mice. Finally, treatment with the PPARα agonist fenofibrate activated the integrated stress response and refilled amino acid substrates to rescue fasting glucose availability and overcome B2D phenotypes. These findings identify metabolic responses to FAD availability and nominate strategies for the management of organic acidemias and other rare IEMs.

The correlation between the broad line region radius and continuum luminosity (R-L relation) of active galactic nuclei (AGNs) is critical for single-epoch mass estimates of supermassive black holes (SMBHs). At z ∼ 1-2, where AGN activity peaks, the R-L relation is constrained by the reverberation mapping (RM) lags of the Mg II line. We present 25 Mg II lags from the Australian Dark Energy Survey RM project based on 6 yr of monitoring. We define quantitative criteria to select good lag measurements and verify their reliability with simulations based on both the damped random walk stochastic model and the rescaled, resampled versions of the observed light curves of local, well-measured AGN. Our sample significantly increases the number of Mg II lags and extends the R-L relation to higher redshifts and luminosities. The relative iron line strength RFe has little impact on the R-L relation. The best-fitting Mg II R-L relation has a slope α = 0.39 ± 0.08 with an intrinsic scatter σrl = 0.15+−000203. The slope is consistent with previous measurements and shallower than the H β R-L relation. The intrinsic scatter of the new R-L relation is substantially smaller than previous studies and comparable to the intrinsic scatter of the H β R-L relation. Our new R-L relation will enable more precise single-epoch mass estimates and SMBH demographic studies at cosmic noon.

PurposeThe ongoing lack of data standardization severely undermines the potential for automated learning from the vast amount of information routinely archived in electronic health records (EHRs), Radiation Oncology Information Systems (ROIS), treatment planning systems (TPSs), and other cancer care and outcomes databases. The effort sought to create a standardized ontology for clinical data, social determinants of health (SDOH), and other radiation oncology concepts and interrelationships.Methods and materialsThe American Association of Physicists in Medicine's (AAPM's) Big Data Science Committee (BDSC) was initiated July of 2019 to explore common ground from the stakeholders' collective experience of issues that typically compromise the formation of large inter- and intra- institutional databases from EHRs. The BDSC adopted an iterative, cyclical approach to engaging stakeholders beyond its membership to optimize the integration of diverse perspectives from the community.ResultsWe developed the Operational Ontology for Oncology (O3) which identified 42 key elements, 359 attributes, 144 value sets, and 155 relationships ranked in relative importance of clinical significance, likelihood of availability in EHRs, or the ability to modify routine clinical processes to permit aggregation. Recommendations are provided for best use and development of the O3 to four constituencies: device manufacturers, centers of clinical care, researchers, and professional societies.ConclusionsO3 is designed to extend and interoperate with existing global infrastructure and data science standards. The implementation of these recommendations will lower the barriers for aggregation of information that could be used creating large, representative, findable, accessible, interoperable and reusable (FAIR) datasets supporting the scientific objectives of grant programs. The construction of comprehensive "real world" datasets and application of advanced analytic techniques, including artificial intelligence (AI), holds the potential to revolutionize patient management and improve outcomes by leveraging increased access to information derived from larger, more representative datasets.

Nafion ionomer, composed of hydrophobic perfluorocarbon backbones and hydrophilic sulfonic acid side chains, is the most widely used additive for preparing catalyst layers (CLs) for electrochemical CO2 reduction, but its impact on the performance of CO2 electrolysis remains poorly understood. Here, we systematically investigate the role of the catalyst ink formulation on CO2 electrolysis using commercial CuO nanoparticles as the model pre-catalyst. We find that the presence of Nafion is essential for achieving stable product distributions due to its ability to stabilize the catalyst morphology under reaction conditions. Moreover, the Nafion content and solvent composition (water/alcohol fraction) regulate the internal structure of Nafion coatings, as well as the catalyst morphology, thereby significantly impacting CO2 electrolysis performance, resulting in variations of C2+ product Faradaic efficiency (FE) by >3×, with C2+ FE ranging from 17 to 54% on carbon paper substrates. Using a combination of ellipsometry and in situ Raman spectroscopy during CO2 reduction, we find that such selectivity differences stem from changes to the local reaction microenvironment. In particular, the combination of high water/alcohol ratios and low Nafion fractions in the catalyst ink results in stable and favorable microenvironments, increasing the local CO2/H2O concentration ratio and promoting high CO surface coverage to facilitate C2+ production in long-term CO2 electrolysis. Therefore, this work provides insights into the critical role of Nafion binders and underlines the importance of optimizing Nafion/solvent formulations as a means of enhancing the performance of electrochemical CO2 reduction systems.

Reverberation mapping measurements have been used to constrain the relationship between the size of the broad-line region and luminosity of active galactic nuclei (AGN). This R-L relation is used to estimate single-epoch virial black hole masses, and has been proposed to use to standardize AGN to determine cosmological distances. We present reverberation measurements made with Hβ from the 6-yr Australian Dark Energy Survey (OzDES) Reverberation Mapping Program. We successfully recover reverberation lags for eight AGN at 0.12 < z < 0.71, probing higher redshifts than the bulk of Hβ measurements made to date. Our fit to the R-L relation has a slope of α = 0.41 ± 0.03 and an intrinsic scatter of σ = 0.23 ± 0.02 dex. The results from our multi-object spectroscopic survey are consistent with previous measurements made by dedicated source-by-source campaigns, and with the observed dependence on accretion rate. Future surveys, including LSST, TiDES, and SDSS-V, which will be revisiting some of our observed fields, will be able to build on the results of our first-generation multi-object reverberation mapping survey.

The coupling of CO-generating molecular catalysts with copper electrodes in tandem schemes is a promising strategy to boost the formation of multi-carbon products in the electrocatalytic reduction of CO2. While the spatial distribution of the two components is important, this aspect remains underexplored for molecular-based tandem systems. Herein, we address this knowledge gap by studying tandem catalysts comprising Co-phthalocyanine (CoPc) and Cu nanocubes (Cucub). In particular, we identify the importance of the relative spatial distribution of the two components on the performance of the tandem catalyst by preparing CoPc-Cucub/C, wherein the CoPc and Cucub share an interface, and CoPc-C/Cucub, wherein the CoPc is loaded first on carbon black (C) before mixing with the Cucub. The electrocatalytic measurements of these two catalysts show that the faradaic efficiency towards C2 products almost doubles for the CoPc-Cucub/C, whereas it decreases by half for the CoPc-C/Cucub, compared to the Cucub/C. Our results highlight the importance of a direct contact between the CO-generating molecular catalyst and the Cu to promote C-C coupling, which hints at a surface transport mechanism of the CO intermediate between the two components of the tandem catalyst instead of a transfer via CO diffusion in the electrolyte followed by re-adsorption.

BackgroundMonoclonal antibody (mAb) treatment for COVID-19 is associated with improved clinical outcomes. However, there is limited information regarding the impact of treatment on symptoms and the prevalence of post-COVID Conditions (PCC). Understanding of the association between time to mAb infusion and the development of PCC is also limited.MethodsThis longitudinal study was conducted among patients with COVID-19 who received mAb infusions at a Federally Qualified Health Center in San Diego, CA. A series of telephone interviews were conducted at baseline and follow-up (14 days and 28+ days). A comprehensive symptom inventory was completed and physical and mental health status were measured using PROMIS-29 and PHQ-2. Pearson's Chi-squared tests and independent two-sample t-tests were performed to test for association between time to mAb infusion and outcomes at follow-up. A Poisson regression model was used to analyze whether time to mAb infusion predicts risk of developing PCC.ResultsParticipants (N = 411) were 53% female, ranged in age from 16 to 92 years (mean 50), and a majority (56%) were Latino/Hispanic. Cross-sectional findings revealed a high symptom burden at baseline (70% of patients had cough, 50% had fever, and 44% had headache). The prevalence of many symptoms decreased substantially by the final follow-up survey (29% of patients had cough, 3% had fever, and 28% had headache). Longitudinal findings indicated that 10 symptoms decreased in prevalence from baseline to final follow-up, 2 remained the same, and 14 increased. The severity of symptoms and most patient-reported physical and mental health measure scores decreased over time. The prevalence of PCC was 69% when PCC was defined as ≥ 1 symptom at final follow-up. Time to mAb infusion was not significantly associated with any outcome at follow-up. Time to infusion was not associated with PCC status at final follow-up in the crude or adjusted Poisson regression models.ConclusionsThe prevalence of PCC was high among this patient population following COVID-19 mAb treatment. Time to mAb infusion did not predict the development of PCC. Further research in these areas is essential to answer urgent clinical questions about effective treatments of COVID-19.

Mentalization refers to the ability to understand the mental states of oneself and those of others that motivate action and behavior. Mentalization has generally been linked to adaptive development and healthy functioning whereas diminished mentalization has been associated with maladaptive development and psychopathology. The vast majority of research on mentalization and developmental trajectories, however, is based on Western countries. The overall aim of this study was therefore to examine mentalizing abilities in a novel sample of 153 typically developing and atypically developing Iranian children (Mage = 9.41, SDage = 1.10, Range = 8-11, 54.2% females) recruited from a primary school and health clinic in Tehran. The children completed semi-structured interviews that were later transcribed and coded for mentalization. The parents provided reports on internalizing and externalizing symptoms, demographic information, and all formal diagnoses of the children. The results pointed at general age and sex differences across the two groups. Older children showed more adaptive mentalization compared to the younger children; boys and girls used different mentalizing strategies when facing difficult situations. The typically developing children were better at mentalizing than the atypically developing children. Finally, more adaptive mentalization was associated with lower externalizing and internalizing symptoms among all children. The findings of this study contributes with expanding mentalization research to also encompass non-Western populations and the results hold crucial educational and therapeutic implications.

BackgroundThis study identified early immune gene responses in peripheral blood associated with 90-day ischemic stroke (IS) outcomes.MethodsPeripheral blood samples from the CLEAR trial IS patients at ≤ 3 h, 5 h, and 24 h after stroke were compared to vascular risk factor matched controls. Whole-transcriptome analyses identified genes and networks associated with 90-day IS outcome assessed using the modified Rankin Scale (mRS) and the NIH Stroke Scale (NIHSS).ResultsThe expression of 467, 526, and 571 genes measured at ≤ 3, 5 and 24 h after IS, respectively, were associated with poor 90-day mRS outcome (mRS ≥ 3), while 49, 100 and 35 genes at ≤ 3, 5 and 24 h after IS were associated with good mRS 90-day outcome (mRS ≤ 2). Poor outcomes were associated with up-regulated genes or pathways such as IL-6, IL-7, IL-1, STAT3, S100A12, acute phase response, P38/MAPK, FGF, TGFA, MMP9, NF-kB, Toll-like receptor, iNOS, and PI3K/AKT. There were 94 probe sets shared for poor outcomes vs. controls at all three time-points that correlated with 90-day mRS; 13 probe sets were shared for good outcomes vs. controls at all three time-points; and 46 probe sets were shared for poor vs. good outcomes at all three time-points that correlated with 90-day mRS. Weighted Gene Co-Expression Network Analysis (WGCNA) revealed modules significantly associated with 90-day outcome for mRS and NIHSS. Poor outcome modules were enriched with up-regulated neutrophil genes and with down-regulated T cell, B cell and monocyte-specific genes; and good outcome modules were associated with erythroblasts and megakaryocytes. Finally, genes identified by genome-wide association studies (GWAS) to contain significant stroke risk loci or loci associated with stroke outcome including ATP2B, GRK5, SH3PXD2A, CENPQ, HOXC4, HDAC9, BNC2, PTPN11, PIK3CG, CDK6, and PDE4DIP were significantly differentially expressed as a function of stroke outcome in the current study.ConclusionsThis study suggests the immune response after stroke may impact functional outcomes and that some of the early post-stroke gene expression markers associated with outcome could be useful for predicting outcomes and could be targets for improving outcomes.

BackgroundAfter ischemic stroke (IS), peripheral leukocytes infiltrate the damaged region and modulate the response to injury. Peripheral blood cells display distinctive gene expression signatures post-IS and these transcriptional programs reflect changes in immune responses to IS. Dissecting the temporal dynamics of gene expression after IS improves our understanding of immune and clotting responses at the molecular and cellular level that are involved in acute brain injury and may assist with time-targeted, cell-specific therapy.MethodsThe transcriptomic profiles from peripheral monocytes, neutrophils, and whole blood from 38 ischemic stroke patients and 18 controls were analyzed with RNA-seq as a function of time and etiology after stroke. Differential expression analyses were performed at 0-24 h, 24-48 h, and >48 h following stroke.ResultsUnique patterns of temporal gene expression and pathways were distinguished for monocytes, neutrophils, and whole blood with enrichment of interleukin signaling pathways for different time points and stroke etiologies. Compared to control subjects, gene expression was generally upregulated in neutrophils and generally downregulated in monocytes over all times for cardioembolic, large vessel, and small vessel strokes. Self-organizing maps identified gene clusters with similar trajectories of gene expression over time for different stroke causes and sample types. Weighted Gene Co-expression Network Analyses identified modules of co-expressed genes that significantly varied with time after stroke and included hub genes of immunoglobulin genes in whole blood.ConclusionsAltogether, the identified genes and pathways are critical for understanding how the immune and clotting systems change over time after stroke. This study identifies potential time- and cell-specific biomarkers and treatment targets.

We postulate that myelin injury contributes to cholesterol release from myelin and cholesterol dysmetabolism which contributes to Abeta dysmetabolism, and combined with genetic and AD risk factors, leads to increased Abeta and amyloid plaques. Increased Abeta damages myelin to form a vicious injury cycle. Thus, white matter injury, cholesterol dysmetabolism and Abeta dysmetabolism interact to produce or worsen AD neuropathology. The amyloid cascade is the leading hypothesis for the cause of Alzheimer's disease (AD). The failure of clinical trials based on this hypothesis has raised other possibilities. Even with a possible new success (Lecanemab), it is not clear whether this is a cause or a result of the disease. With the discovery in 1993 that the apolipoprotein E type 4 allele (APOE4) was the major risk factor for sporadic, late-onset AD (LOAD), there has been increasing interest in cholesterol in AD since APOE is a major cholesterol transporter. Recent studies show that cholesterol metabolism is intricately involved with Abeta (Aβ)/amyloid transport and metabolism, with cholesterol down-regulating the Aβ LRP1 transporter and upregulating the Aβ RAGE receptor, both of which would increase brain Aβ. Moreover, manipulating cholesterol transport and metabolism in rodent AD models can ameliorate pathology and cognitive deficits, or worsen them depending upon the manipulation. Though white matter (WM) injury has been noted in AD brain since Alzheimer's initial observations, recent studies have shown abnormal white matter in every AD brain. Moreover, there is age-related WM injury in normal individuals that occurs earlier and is worse with the APOE4 genotype. Moreover, WM injury precedes formation of plaques and tangles in human Familial Alzheimer's disease (FAD) and precedes plaque formation in rodent AD models. Restoring WM in rodent AD models improves cognition without affecting AD pathology. Thus, we postulate that the amyloid cascade, cholesterol dysmetabolism and white matter injury interact to produce and/or worsen AD pathology. We further postulate that the primary initiating event could be related to any of the three, with age a major factor for WM injury, diet and APOE4 and other genes a factor for cholesterol dysmetabolism, and FAD and other genes for Abeta dysmetabolism.

Despite a growing evidence base documenting associations between neighborhood characteristics and the risk of developing high blood pressure, little work has established the role played by neighborhood social organization exposures in racial/ethnic disparities in hypertension risk. There is also ambiguity around prior estimates of neighborhood effects on hypertension prevalence, given the lack of attention paid to individuals' exposures to both residential and nonresidential spaces. This study contributes to the neighborhoods and hypertension literature by using novel longitudinal data from the Los Angeles Family and Neighborhood Survey to construct exposure-weighted measures of neighborhood social organization characteristics-organizational participation and collective efficacy-and examine their associations with hypertension risk, as well as their relative contributions to racial/ethnic differences in hypertension. We also assess whether the hypertension effects of neighborhood social organization vary across our sample of Black, Latino, and White adults. Results from random effects logistic regression models indicate that adults living in neighborhoods where people are highly active in informal and formal organizations have a lower probability of being hypertensive. This protective effect of exposure to neighborhood organizational participation is also significantly stronger for Black adults than Latino and White adults, such that, at high levels of neighborhood organizational participation, the observed Black-White and Black-Latino hypertension differences are substantially reduced to nonsignificance. Nonlinear decomposition results also indicate that almost one-fifth of the Black-White hypertension gap can be explained by differential exposures to neighborhood social organization.

Quiescence, or dormancy, is a response to stressful conditions in which an organism slows or halts physiological functioning. Although most species that undergo dormancy maintain complex microbiomes, there is little known about how dormancy influences and is influenced by the host's microbiome, including in the temperate coral Astrangia poculata. Northern populations of A. poculata undergo winter quiescence. Here, we characterized wild A. poculata microbiomes in a high-resolution sampling time series before, during, and after quiescence using 16S rRNA gene sequencing on active (RNA) and present (DNA) microbiomes. We observed a restructuring of the coral microbiome during quiescence that persisted after reemergence. Upon entering quiescence, corals shed copiotrophic microbes, including putative pathogens, suggesting a removal of these taxa as corals cease normal functioning. During and after quiescence, bacteria and archaea associated with nitrification were enriched, suggesting that the quiescent microbiome may replace essential functions through supplying nitrate to corals and/or microbes. Overall, this study demonstrates that key microbial groups related to quiescence in A. poculata may play a role in the onset or emergence from dormancy and long-term regulation of the microbiome composition. The predictability of dormancy in A. poculata provides an ideal natural manipulation system to further identify factors that regulate host-microbial associations. IMPORTANCE Using a high-resolution sampling time series, this study is the first to demonstrate a persistent microbial community shift with quiescence (dormancy) in a marine organism, the temperate coral Astrangia poculata. Furthermore, during this period of community turnover, there is a shedding of putative pathogens and copiotrophs and an enhancement of the ammonia-oxidizing bacteria (Nitrosococcales) and archaea ("Candidatus Nitrosopumilus"). Our results suggest that quiescence represents an important period during which the coral microbiome can reset, shedding opportunistic microbes and enriching for the reestablishment of beneficial associates, including those that may contribute nitrate while the coral animal is not actively feeding. We suggest that this work provides foundational understanding of the interplay of microbes and the host's dormancy response in marine organisms.

Low-grade, sustained inflammation in white adipose tissue (WAT) characterizes obesity and coincides with type 2 diabetes mellitus (T2DM). However, pharmacological targeting of inflammation lacks durable therapeutic effects in insulin-resistant conditions. Through a computational screen, we discovered that the FDA-approved rheumatoid arthritis drug auranofin improved insulin sensitivity and normalized obesity-associated abnormalities, including hepatic steatosis and hyperinsulinemia in mouse models of T2DM. We also discovered that auranofin accumulation in WAT depleted inflammatory responses to a high-fat diet without altering body composition in obese wild-type mice. Surprisingly, elevated leptin levels and blunted beta-adrenergic receptor activity achieved by leptin receptor deletion abolished the antidiabetic effects of auranofin. These experiments also revealed that the metabolic benefits of leptin reduction were superior to immune impacts of auranofin in WAT. Our studies uncover important metabolic properties of anti-inflammatory treatments and contribute to the notion that leptin reduction in the periphery can be accomplished to treat obesity and T2DM.

The peripheral immune system response to Intracerebral Hemorrhage (ICH) may differ with ICH in different brain locations. Thus, we investigated peripheral blood mRNA expression of Deep ICH, Lobar ICH, and vascular risk factor-matched control subjects (n = 59). Deep ICH subjects usually had hypertension. Some Lobar ICH subjects had cerebral amyloid angiopathy (CAA). Genes and gene networks in Deep ICH and Lobar ICH were compared to controls. We found 774 differentially expressed genes (DEGs) and 2 co-expressed gene modules associated with Deep ICH, and 441 DEGs and 5 modules associated with Lobar ICH. Pathway enrichment showed some common immune/inflammatory responses between locations including Autophagy, T Cell Receptor, Inflammasome, and Neuroinflammation Signaling. Th2, Interferon, GP6, and BEX2 Signaling were unique to Deep ICH. Necroptosis Signaling, Protein Ubiquitination, Amyloid Processing, and various RNA Processing terms were unique to Lobar ICH. Finding amyloid processing pathways in blood of Lobar ICH patients suggests peripheral immune cells may participate in processes leading to perivascular/vascular amyloid in CAA vessels and/or are involved in its removal. This study identifies distinct peripheral blood transcriptome architectures in Deep and Lobar ICH, emphasizes the need for considering location in ICH studies/clinical trials, and presents potential location-specific treatment targets.

ImportanceIt is unknown whether and to what degree trials submitted to the US FDA to support drug approval adhere to NCCN guideline-recommended care in their baseline and surveillance CNS imaging protocols.ObjectiveWe sought to characterize the frequency with which the trials cited in US FDA drug approvals for first line advanced NSCLC between 2015 and 2020 deviated from NCCN guideline-recommended care for baseline and surveillance CNS imaging.Design, setting, and participantsRetrospective observational analysis using publicly available data of (1) list of trials cited by the FDA in drug approvals for first line advanced NSCLC from 2015 to 2020 (2) individual trial protocols (3) published trial data and supplementary appendices (4) archived versions of the NCCN guidelines for NSCLC from 2009 to 2018 (the years during which the trials were enrolling).Main outcomes and measuresEstimated percentage of trials for first line advanced NSCLC leading to FDA approval which deviated from NCCN guideline-recommended care with regards to CNS baseline and surveillance imaging.ResultsA total of 14 studies that had been cited in FDA drug approvals for first line advanced NSCLC met our inclusion criteria between January 1, 2015 and September 30, 2020. Of these trials, 8 (57.1%) deviated from NCCN guidelines in their baseline CNS imaging requirement. The frequency of re-assessment of CNS disease was variable amongst trials as well, with 9 (64.3%) deviating from NCCN recommendations.Conclusions and relevanceThe trials supporting US FDA drug approvals in first line advanced NSCLC often have CNS imaging requirements that do not adhere to NCCN guidelines. Many trials permit alternative, substandard methods and the proportion of patients undergoing each modality is uniformly not reported. Nonstandard CNS surveillance protocols are common. To best serve patients with advanced NSCLC in the US, drug approvals by the FDA must be based on trials that mirror clinical practice and have imaging requirements consistent with current US standard of care.

The objective of this study was to determine the etiology of febrile illnesses among patients from October 1, 1993 through September 30, 1999, in the urban community of Iquitos in the Amazon River Basin of Peru. Epidemiological and clinical data as well as blood samples were obtained from consenting patients at hospitals, health clinics and private residences. Samples were tested for arboviruses in cell cultures and for IgM and IgG antibodies by ELISA. Blood smears were examined for malaria, and sera were tested for antibodies to Leptospira spp. by ELISA and microscopic agglutination. Among 6,607 febrile patients studied, dengue viruses caused 14.6% of the cases, and Venezuelan equine encephalitis virus caused 2.5%, Oropouche virus 1.0%, Mayaro virus 0.4%, and other arboviruses caused 0.2% of the cases. Also, 22.9% of 4,844 patients tested were positive for malaria, and of 400 samples tested, 9% had evidence of acute leptospirosis. Although the study was not designed to assess the importance of these pathogens as a cause of human morbidity in the total population, these results indicate that arboviruses, leptospirosis, and malaria were the cause of approximately 50% of the febrile cases. Although the arboviruses that were diagnosed can produce asymptomatic infections, our findings increased the overall understanding of the relative health burden of these infections, as well as baseline knowledge needed for designing and implementing further studies to better assess the health impact and threat of these pathogens in the Amazon Basin of Peru.

Copper-based tandem schemes have emerged as promising strategies to promote the formation of multi-carbon products in the electrocatalytic CO2 reduction reaction. In such approaches, the CO-generating component of the tandem catalyst increases the local concentration of CO and thereby enhances the intrinsic carbon-carbon (C-C) coupling on copper. However, the optimal characteristics of the CO-generating catalyst for maximizing the C2 production are currently unknown. In this work, we developed tunable tandem catalysts comprising iron porphyrin (Fe-Por), as the CO-generating component, and Cu nanocubes (Cucub) to understand how the turnover frequency for CO (TOFCO) of the molecular catalysts impacts the C-C coupling on the Cu surface. First, we tuned the TOFCO of the Fe-Por by varying the number of orbitals involved in the π-system. Then, we coupled these molecular catalysts with the Cucub and assessed the current densities and faradaic efficiencies. We discovered that all of the designed Fe-Por boost ethylene production. The most efficient Cucub/Fe-Por tandem catalyst was the one including the Fe-Por with the highest TOFCO and exhibited a nearly 22-fold increase in the ethylene selectivity and 100 mV positive shift of the onset potential with respect to the pristine Cucub. These results reveal that coupling the TOFCO tunability of molecular catalysts with copper nanocatalysts opens up new possibilities towards the development of Cu-based catalysts with enhanced selectivity for multi-carbon product generation at low overpotential.

Traumatic brain injury (TBI) has the highest incidence of all common neurological disorders, and poses a substantial public health burden. TBI is increasingly documented not only as an acute condition but also as a chronic disease with long-term consequences, including an increased risk of late-onset neurodegeneration. The first Lancet Neurology Commission on TBI, published in 2017, called for a concerted effort to tackle the global health problem posed by TBI. Since then, funding agencies have supported research both in high-income countries (HICs) and in low-income and middle-income countries (LMICs). In November 2020, the World Health Assembly, the decision-making body of WHO, passed resolution WHA73.10 for global actions on epilepsy and other neurological disorders, and WHO launched the Decade for Action on Road Safety plan in 2021. New knowledge has been generated by large observational studies, including those conducted under the umbrella of the International Traumatic Brain Injury Research (InTBIR) initiative, established as a collaboration of funding agencies in 2011. InTBIR has also provided a huge stimulus to collaborative research in TBI and has facilitated participation of global partners. The return on investment has been high, but many needs of patients with TBI remain unaddressed. This update to the 2017 Commission presents advances and discusses persisting and new challenges in prevention, clinical care, and research. In LMICs, the occurrence of TBI is driven by road traffic incidents, often involving vulnerable road users such as motorcyclists and pedestrians. In HICs, most TBI is caused by falls, particularly in older people (aged ≥65 years), who often have comorbidities. Risk factors such as frailty and alcohol misuse provide opportunities for targeted prevention actions. Little evidence exists to inform treatment of older patients, who have been commonly excluded from past clinical trials—consequently, appropriate evidence is urgently required. Although increasing age is associated with worse outcomes from TBI, age should not dictate limitations in therapy. However, patients injured by low-energy falls (who are mostly older people) are about 50% less likely to receive critical care or emergency interventions, compared with those injured by high-energy mechanisms, such as road traffic incidents. Mild TBI, defined as a Glasgow Coma sum score of 13–15, comprises most of the TBI cases (over 90%) presenting to hospital. Around 50% of adult patients with mild TBI presenting to hospital do not recover to pre-TBI levels of health by 6 months after their injury. Fewer than 10% of patients discharged after presenting to an emergency department for TBI in Europe currently receive follow-up. Structured follow-up after mild TBI should be considered good practice, and urgent research is needed to identify which patients with mild TBI are at risk for incomplete recovery. The selection of patients for CT is an important triage decision in mild TBI since it allows early identification of lesions that can trigger hospital admission or life-saving surgery. Current decision making for deciding on CT is inefficient, with 90–95% of scanned patients showing no intracranial injury but being subjected to radiation risks. InTBIR studies have shown that measurement of blood-based biomarkers adds value to previously proposed clinical decision rules, holding the potential to improve efficiency while reducing radiation exposure. Increased concentrations of biomarkers in the blood of patients with a normal presentation CT scan suggest structural brain damage, which is seen on MR scanning in up to 30% of patients with mild TBI. Advanced MRI, including diffusion tensor imaging and volumetric analyses, can identify additional injuries not detectable by visual inspection of standard clinical MR images. Thus, the absence of CT abnormalities does not exclude structural damage—an observation relevant to litigation procedures, to management of mild TBI, and when CT scans are insufficient to explain the severity of the clinical condition. Although blood-based protein biomarkers have been shown to have important roles in the evaluation of TBI, most available assays are for research use only. To date, there is only one vendor of such assays with regulatory clearance in Europe and the USA with an indication to rule out the need for CT imaging for patients with suspected TBI. Regulatory clearance is provided for a combination of biomarkers, although evidence is accumulating that a single biomarker can perform as well as a combination. Additional biomarkers and more clinical-use platforms are on the horizon, but cross-platform harmonisation of results is needed. Health-care efficiency would benefit from diversity in providers. In the intensive care setting, automated analysis of blood pressure and intracranial pressure with calculation of derived parameters can help individualise management of TBI. Interest in the identification of subgroups of patients who might benefit more from some specific therapeutic approaches than others represents a welcome shift towards precision medicine. Comparative-effectiveness research to identify best practice has delivered on expectations for providing evidence in support of best practices, both in adult and paediatric patients with TBI. Progress has also been made in improving outcome assessment after TBI. Key instruments have been translated into up to 20 languages and linguistically validated, and are now internationally available for clinical and research use. TBI affects multiple domains of functioning, and outcomes are affected by personal characteristics and life-course events, consistent with a multifactorial bio-psycho-socio-ecological model of TBI, as presented in the US National Academies of Sciences, Engineering, and Medicine (NASEM) 2022 report. Multidimensional assessment is desirable and might be best based on measurement of global functional impairment. More work is required to develop and implement recommendations for multidimensional assessment. Prediction of outcome is relevant to patients and their families, and can facilitate the benchmarking of quality of care. InTBIR studies have identified new building blocks (eg, blood biomarkers and quantitative CT analysis) to refine existing prognostic models. Further improvement in prognostication could come from MRI, genetics, and the integration of dynamic changes in patient status after presentation. Neurotrauma researchers traditionally seek translation of their research findings through publications, clinical guidelines, and industry collaborations. However, to effectively impact clinical care and outcome, interactions are also needed with research funders, regulators, and policy makers, and partnership with patient organisations. Such interactions are increasingly taking place, with exemplars including interactions with the All Party Parliamentary Group on Acquired Brain Injury in the UK, the production of the NASEM report in the USA, and interactions with the US Food and Drug Administration. More interactions should be encouraged, and future discussions with regulators should include debates around consent from patients with acute mental incapacity and data sharing. Data sharing is strongly advocated by funding agencies. From January 2023, the US National Institutes of Health will require upload of research data into public repositories, but the EU requires data controllers to safeguard data security and privacy regulation. The tension between open data-sharing and adherence to privacy regulation could be resolved by cross-dataset analyses on federated platforms, with the data remaining at their original safe location. Tools already exist for conventional statistical analyses on federated platforms, however federated machine learning requires further development. Support for further development of federated platforms, and neuroinformatics more generally, should be a priority. This update to the 2017 Commission presents new insights and challenges across a range of topics around TBI: epidemiology and prevention (section 1); system of care (section 2); clinical management (section 3); characterisation of TBI (section 4); outcome assessment (section 5); prognosis (Section 6); and new directions for acquiring and implementing evidence (section 7). Table 1 summarises key messages from this Commission and proposes recommendations for the way forward to advance research and clinical management of TBI.

BACKGROUND: There are few studies to date of interventions to increase viral hepatitis screening among Asian Americans, who have high rates of chronic hepatitis B (HBV) infection. OBJECTIVE: To develop, implement, and test the efficacy of a mobile application (Hepatitis App) delivered in four languages to increase HBV screening among Asian Americans. DESIGN: Cluster-randomized clinical trial. PARTICIPANTS: Four hundred fifty-two Asian American patients ≥ 18 years of age, who had no prior HBV testing, and received primary care within two healthcare systems in San Francisco, CA. INTERVENTIONS: The intervention group received the Hepatitis App, delivering interactive video education on viral hepatitis in English, Cantonese, Mandarin, or Vietnamese and a provider printout (Provider Alert) and Provider Panel Notification. The comparison group received a mobile application delivering nutrition and physical activity education and Provider Panel Notification. MAIN MEASURES: Primary outcomes were patient-provider discussion about HBV and documentation of a HBV screening test within 3 months post-intervention. Secondary outcome was documentation of an order for a HBV screening test. KEY RESULTS: Participants had a mean age of 57 years and were 64% female, 80% foreign-born, and 44% with limited English fluency. At post-visit, over 80% of intervention participants reported they liked using the Hepatitis App. At 3-month follow-up, the intervention group was more likely than the comparison group (all P

Cerebral white matter hyperintensities are an important contributor to ageing brain pathology. Progression in white matter hyperintensity volume is associated with cognitive decline and gait impairment. Understanding the factors associated with white matter hyperintensity progression provides insight into pathogenesis and may identify novel treatment targets to improve cognitive health. We postulated that the immune system interaction with cerebral vessels and tissue may be associated with disease progression, and thus evaluated the relationship of blood leucocyte gene expression to progression of cerebral white matter hyperintensities. A brain MRI was obtained at baseline in 166 patients assessed for a cognitive complaint, and then repeated at regular intervals over a median of 5.9 years (interquartile range 3.5-8.2 years). White matter hyperintensity volumes were measured by semi-automated segmentation and percentage change in white matter hyperintensity per year calculated. A venous blood sample obtained at baseline was used to measure whole-genome expression by RNA sequencing. The relationship between change in white matter hyperintensity volumes over time and baseline leucocyte gene expression was analysed. The mean age was 77.8 (SD 7.5) years and 60.2% of participants were female. The median white matter hyperintensity volume was 13.4 ml (SD 17.4 ml). The mean change in white matter hyperintensity volume was 12% per year. Patients were divided in quartiles by percentage change in white matter hyperintensity volume, which was: -3.5% per year in quartile 1, 7.4% per year in quartile 2, 11.7% in quartile 3 and 33.6% per year in quartile 4. There were 148 genes associated with changing white matter hyperintensity volumes over time (P  |0.2|). Genes and pathways identified have roles in endothelial dysfunction, extracellular matrix remodelling, altered remyelination, inflammation and response to ischaemia. ADAM8, CFD, EPHB4, FPR2, Wnt-B-catenin, focal adhesion kinase and SIGLEC1 were among the identified genes. The progression of white matter hyperintensity volumes over time is associated with genes involved in endothelial dysfunction, extracellular matrix remodelling, altered remyelination, inflammation and response to ischaemia. Further studies are needed to evaluate the role of peripheral inflammation in relation to rate of white matter hyperintensity progression and the contribution to cognitive decline.

Photocatalytic platforms based on ultrathin reactive materials facilitate carrier transport and extraction but are typically restricted to a narrow set of materials and spectral operating ranges due to limited absorption and poor energy-tuning possibilities. Metasurfaces, a class of 2D artificial materials based on the electromagnetic design of nanophotonic resonators, allow optical absorption engineering for a wide range of materials. Moreover, tailored resonances in nanostructured materials enable strong absorption enhancement and thus carrier multiplication. Here, we develop an ultrathin catalytic metasurface platform that leverages the combination of loss-engineered substoichiometric titanium oxide (TiO2-x) and the emerging physical concept of optical bound states in the continuum (BICs) to boost photocatalytic activity and provide broad spectral tunability. We demonstrate that our platform reaches the condition of critical light coupling in a TiO2-x BIC metasurface, thus providing a general framework for maximizing light-matter interactions in diverse photocatalytic materials. This approach can avoid the long-standing drawbacks of many naturally occurring semiconductor-based ultrathin films applied in photocatalysis, such as poor spectral tunability and limited absorption manipulation. Our results are broadly applicable to fields beyond photocatalysis, including photovoltaics and photodetectors.

Renewable fuel generation is essential for a low carbon footprint economy. Thus, over the last five decades, a significant effort has been dedicated towards increasing the performance of solar fuels generating devices. Specifically, the solar to hydrogen efficiency of photoelectrochemical cells has progressed steadily towards its fundamental limit, and the faradaic efficiency towards valuable products in CO2 reduction systems has increased dramatically. However, there are still numerous scientific and engineering challenges that must be overcame in order to turn solar fuels into a viable technology. At the electrode and device level, the conversion efficiency, stability and products selectivity must be increased significantly. Meanwhile, these performance metrics must be maintained when scaling up devices and systems while maintaining an acceptable cost and carbon footprint. This roadmap surveys different aspects of this endeavor: system benchmarking, device scaling, various approaches for photoelectrodes design, materials discovery, and catalysis. Each of the sections in the roadmap focuses on a single topic, discussing the state of the art, the key challenges and advancements required to meet them. The roadmap can be used as a guide for researchers and funding agencies highlighting the most pressing needs of the field.

During the first hours after stroke onset, neurological deficits can be highly unstable: some patients rapidly improve, while others deteriorate. This early neurological instability has a major impact on long-term outcome. Here, we aimed to determine the genetic architecture of early neurological instability measured by the difference between the National Institutes of Health Stroke Scale (NIHSS) within 6 h of stroke onset and NIHSS at 24 h. A total of 5876 individuals from seven countries (Spain, Finland, Poland, USA, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found that 8.7% of NIHSS at 24 h of variance was explained by common genetic variations, and also that early neurological instability has a different genetic architecture from that of stroke risk. Eight loci (1p21.1, 1q42.2, 2p25.1, 2q31.2, 2q33.3, 5q33.2, 7p21.2 and 13q31.1) were genome-wide significant and explained 1.8% of the variability suggesting that additional variants influence early change in neurological deficits. We used functional genomics and bioinformatic annotation to identify the genes driving the association from each locus. Expression quantitative trait loci mapping and summary data-based Mendelian randomization indicate that ADAM23 (log Bayes factor = 5.41) was driving the association for 2q33.3. Gene-based analyses suggested that GRIA1 (log Bayes factor = 5.19), which is predominantly expressed in the brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated GNPAT (log Bayes factor = 7.64) ABCB5 (log Bayes factor = 5.97) for the 1p21.1 and 7p21.1 loci. Human brain single-nuclei RNA-sequencing indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23, a presynaptic protein and GRIA1, a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provide the first genetic evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischaemic stroke.