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This study investigates the potential of mobile global navigation satellite system (GNSS) transmissometry (GNSS-T) measurements for estimating vegetation optical depth (VOD) in temperate forests, focusing on the Soil Moisture Active Passive (SMAP) validation experiment in 2022 (SMAPVEX22). Our methodology employed a dual-GNSS receiver setup, with one receiver positioned in open terrain to serve as a reference for direct signals, and another deployed on a mobile unit (helmet-based or robotic system) to spatially sample vegetation across expansive forested regions during SMAPVEX22. We assessed the stability of direct signal measurements over multiple days, demonstrating the reliability of the GNSS-T measurements. We reported the VOD measurement results for various sites across different forest regions during intensive observation periods and evaluated their correlation with respect to in situ vegetation parameters such as basal area, biomass, canopy height, and diameter breast height, finding a strong correlation with the basal area ($R^{2}=0.73$). In addition, with a predictive regression model, we demonstrated a strong dependence of the measured VOD on combination of such forest parameters. An evaluation of the VOD values at different satellite elevation angles highlighted an increasing trend in VOD with the incidence angle. The results showed the potential utility of mobile GNSS-T for generating large-scale VOD observations. Although spatially averaged VOD maps might not be directly comparable to spaceborne observations, combining mobile GNSS-T data with other sensors such as LiDAR can provide a reliable reference for airborne or spaceborne VOD estimates.

Full-wave simulations at L-band using the fast hybrid multiple scattering theory method (FHMSTM) have been applied to the Harvard Forest in Massachusetts using the Soil Moisture Active Passive Validation Experiment 2022 (SMAPVEX22) dataset. Due to the limitations of commercial full-wave electromagnetic solvers, the FHMSTM is our choice considering its efficient and fast solutions. During SMAPVEX22, scientists collected a dataset of tree sizes, tree positions (derived from light detection and ranging measurement), and microwave signals utilizing the Global Navigation Satellite System Transmissometry approach. The 3-D geometric forest model provides 300 trees with heights up to 19 m by processing the dataset. We import the forest model into the FHMSTM and analyze microwave propagation at MA401. The FHMSTM analysis shows that the transmissivity ranges from 0.627 to 0.674 for the vertically polarized incident wave source and from 0.593 to 0.665 for the horizontally polarized incident wave source. To validate the FHMSTM, a comparison is made with the GNSS signals. The comparison results of microwaves are in good agreement, demonstrating the physical results such as shadowing effects under the trees and higher electric amplitudes at some points in forests compared to that of the open area. We also analyze the effects of tapered trees in this study.

Data were collected across multiple forested domains during the Soil Moisture Active Passive Validation Experiment 2019–2022 to improve understanding of soil moisture retrievals under dense vegetation. Soil surface roughness was one of many soil and vegetation parameters sampled during intensive operations periods during the spring and summer of 2022 because of its importance to retrieval accuracy (rougher soils have a higher emissivity and reduced sensitivity to soil moisture compared to smooth soils with otherwise identical characteristics). A total of 410 valid pinboard transects were collected across 24 sites between the two temperate forest domains located in the northeastern United States. Two experimental methods (handheld lidar and ultrasonic robot) were additionally tested at select sites. After removal of topographic slope, the forest floor was found to be relatively smooth with average rms heights of $9+-1 \,{\mathrm{mm}}$ in the central Massachusetts domain and $6+-1 \,{\mathrm{mm}}$ in the Millbrook, New York domain. These correspond to estimates of the model roughness parameter, $h$, of 0.31 and 0.16, respectively, which is within the range of accepted lookup table values but smoother than suggested by recent studies retrieving $h$ over forests.

Counterfeiting of microelectronic parts is an ever-growing threat to the reliability and security of electronic systems. A study was conducted to investigate techniques for the detection of counterfeit microelectronic parts. Authentic, remarked, and cloned parts were included in the study. The data presented in this paper is the first collection of quantitative data on counterfeit testing, including the performance of individual test methods. Testing was performed by a test laboratory based on SAE AS6171 methods, and the reported results included qualitative observations and observed counterfeit defects. The study demonstrated that standards-based methods effectively detect remarked and cloned microelectronic parts. Cloned parts are of particular concern as more sophisticated versions contain fewer defects and are at risk of not being detected. Two of the cloned part numbers included in the study were found to have few counterfeit defects, all of which could be corrected by a counterfeiter to avoid detection. Insights into the performance of individual test methods based on the type of counterfeit are presented. These results contribute to the ongoing efforts to mitigate the risks from counterfeit microelectronics by continually improving testing standards and practices, such as the possible need to perform additional testing to ensure cloned parts are detected.

Abstract We present a new national data set of historical sundown towns in the United States linked to contemporary spatial information – i.e., the Historical Sundown Towns Linked to US Census Geographies database. Sundown towns are places that once enacted legal or conventional practices meant to restrict the movement or residency of Black people and other people of color within their borders. Our data are based upon rich prior research by historians identifying where these racial restrictions on movement were practiced across the nation. We provide spatial information on these sundown towns, facilitating their linkage to contemporary and historical Census data from 1940 to 2020. These data present an important resource for scientists conducting quantitative studies of the durable legacies of historical racism, enabling granular analyses of the long-term consequences of an understudied form of historical racial control.

Abstract Background Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are debilitating diseases associated with divergent histopathological changes in the lungs. At present, due to cost and technical limitations, profiling cell types is not practical in large epidemiology cohorts (n > 1000). Here, we used computational deconvolution to identify cell types in COPD and IPF lungs whose abundances and cell type-specific gene expression are associated with disease diagnosis and severity. Results We analyzed lung tissue RNA-seq data from 1026 subjects (COPD, n = 465; IPF, n = 213; control, n = 348) from the Lung Tissue Research Consortium. We performed RNA-seq deconvolution, querying thirty-eight discrete cell-type varieties in the lungs. We tested whether deconvoluted cell-type abundance and cell type-specific gene expression were associated with disease severity. The abundance score of twenty cell types significantly differed between IPF and control lungs. In IPF subjects, eleven and nine cell types were significantly associated with forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO), respectively. Aberrant basaloid cells, a rare cells found in fibrotic lungs, were associated with worse FVC and DLCO in IPF subjects, indicating that this aberrant epithelial population increased with disease severity. Alveolar type 1 and vascular endothelial (VE) capillary A were decreased in COPD lungs compared to controls. An increase in macrophages and classical monocytes was associated with lower DLCO in IPF and COPD subjects. In both diseases, lower non-classical monocytes and VE capillary A cells were associated with increased disease severity. Alveolar type 2 cells and alveolar macrophages had the highest number of genes with cell type-specific differential expression by disease severity in COPD and IPF. In IPF, genes implicated in the pathogenesis of IPF, such as matrix metallopeptidase 7, growth differentiation factor 15, and eph receptor B2, were associated with disease severity in a cell type-specific manner. Conclusions Utilization of RNA-seq deconvolution enabled us to pinpoint cell types present in the lungs that are associated with the severity of COPD and IPF. This knowledge offers valuable insight into the alterations within tissues in more advanced illness, ultimately providing a better understanding of the underlying pathological processes that drive disease progression.

Abstract Background Cancer patients are known to be associated with increased risk of cardiovascular disease. However, no studies have examined the differential impact of hematologic malignancies (HMs) and solid tumors (STs) on cardiac morphology at the tissue level. Objective We aimed to examine histopathological features alongside cardiovascular biomarkers in patients with HMs and STs who underwent post-mortem evaluation. Methods We analyzed cardiac changes in 198 patients with HMs and 164 patients with solid tumors STs. We compared demographics, echocardiogram data, exposure to various antineoplastic agents, and post-mortem findings. Additionally, cardiac histological validation was conducted on post-mortem cardiac specimens to examine cardiac tissue morphology, focusing on cardiomyocyte nuclear density, collagen content, and collagen fiber orientation. Results HM patients displayed significantly disordered collagen fiber alignment (0.71 vs 0.83, P = 0.027), and reduced cardiomyocyte nuclear density (56 vs 72, P = 0.002) compared to ST patients. Similarly, hemoglobin level was decreased (6.71 vs 8.06, P

Abstract The role of myeloid cells in the pathogenesis of SARS-CoV-2 is well established, in particular as drivers of cytokine production and systemic inflammation characteristic of severe COVID-19. However, the potential for myeloid cells to act as bona fide targets of productive SARS-CoV-2 infection, and the specifics of entry, remain unclear. Using a panel of anti-SARS-CoV-2 monoclonal antibodies (mAbs) we performed a detailed assessment of antibody-mediated infection of monocytes/macrophages. mAbs with the most consistent potential to mediate infection were those targeting a conserved region of the receptor binding domain (RBD; group 1/class 4). Infection was closely related to the neutralising concentration of the mAbs, with peak infection occurring below the IC50, while pre-treating cells with remdesivir or FcγRI-blocking antibodies inhibited infection. Studies performed in primary macrophages demonstrated high-level and productive infection, with infected macrophages appearing multinucleated and syncytial. Infection was not seen in the absence of antibody with the same quantity of virus. Addition of ruxolitinib significantly increased infection, indicating restraint of infection through innate immune mechanisms rather than entry. High-level production of pro-inflammatory cytokines directly correlated with macrophage infection levels. We hypothesise that infection via antibody-FcR interactions could contribute to pathogenesis in primary infection, systemic virus spread or persistent infection.

Data sharing increasingly underpins collaborative research to address complex regional and global public health problems. Advances in analytic tools, including machine learning, have expanded the potential benefits derived from large global repositories of open data. Participating in open data collaboratives offers opportunities for Caribbean researchers to advance the health of the region’s population through shared data-driven science and policy. However, ethical challenges complicate these efforts. Here we discuss fundamental challenges that threaten to impede progress if not strategically addressed, including power dynamics among funders and researchers in high-income countries and Caribbean stakeholders; research and health equity; threats to privacy; and risk of stigma. These challenges may be exacerbated by resource and infrastructure limitations often seen in small island developing states (SIDS) and low- and middle-income countries. We propose a framework for Safeguarding Health And Research data sharing by promoting Equity (SHARE) for Caribbean researchers and communities participating in shared data science. Using the SHARE framework can support regionally relevant and culturally responsive work already underway in the region and further develop capacity for intentional sharing and (re)use of Caribbean health data.

We report a patient in North Carolina, USA, with Heartland virus infection whose diagnosis was complicated by previous Ehrlichia chaffeensis infection. We identified E. ewingii–infected and Bourbon virus–infected tick pools at the patient’s residence. Healthcare providers should consider testing for tickborne viruses if ehrlichiosis is suspected.

Abstract Background Tracking the emergence, introduction and spread of SARS-CoV-2 variants of concern are essential for informing public health strategies. In 2021, Cambodia faced two major epidemic waves of SARS-CoV-2 triggered by the successive rise of the Alpha and Delta variants. Methods Phylodynamic analysis of 1,163 complete SARS-CoV-2 genomes from Cambodia, along with global sequences, were conducted between February and September 2021 to infer viral introductions, molecular epidemiology and population dynamics. The relationship between epidemic trends and control strategies were evaluated. Bayesian phylogeographic reconstruction was employed to estimate and contrast the spatiotemporal dynamics of the Alpha and Delta variants over time. Results Here we reveal that the Alpha variant displays rapid lineage diversification, accompanied by the acquisition of a spike E484K mutation that coincides with the national implementation of mass COVID-19 vaccination. Despite nationwide control strategies and increased vaccination coverage, the Alpha variant was quickly displaced by Delta variants that exhibits a higher effective reproductive number. Phylogeographic inference indicates that the Alpha variant was introduced through south-central region of Cambodia, with strong diffusion rates from the capital of Phnom Penh to other provinces, while the Delta variant likely entered the country via the northern border provinces. Conclusions Continual genomic surveillance and sequencing efforts, in combination with public health strategies, play a vital role in effectively tracking and responding to the emergence, evolution and dissemination of future emerging variants.

Abstract Background Some studies in humans show that the concurrent use of clopidogrel and omeprazole decreases plasma clopidogrel active metabolite (CAM) concentrations and clopidogrel antiplatelet effects. Whether this drug interaction occurs in cats is unknown. Hypothesis We hypothesized that administration of clopidogrel with omeprazole would decrease plasma CAM concentrations and decrease clopidogrel antiplatelet effects in healthy cats. Animals Ten domestic cats. Methods In this 2‐sequence, 2‐period, 2‐treatment randomized crossover study, healthy cats were randomly assigned to receive clopidogrel only (18.75 mg PO q24h) or clopidogrel with omeprazole (1 mg/kg PO q12h) for 10 days, followed by a 2‐week washout period, and then the opposite treatment for another 10 days. Blood was collected by jugular venipuncture on days 0, 5, and 10. Plasma CAM concentrations were measured using high‐performance liquid chromatography‐tandem mass spectrometry. Platelet function was evaluated using Plateletworks, Multiplate Analyzer, and Platelet Function Analyzer‐100 (PFA‐100). Results Multiplate Analyzer and PFA‐100 detected no difference in platelet function between days or treatment groups. Plateletworks detected a significant difference (P

Abstract We investigated tail-belting (TB), the newly-discovered freeze avoidance behavior among wild rodents. When temperatures dropped to -6 °C, wild mice (Apodemus agrarius and Apodemus flavicollis) were observed curling their tails inward and positioning it on the back. A literature search suggested TB had never been documented, presumably because rodents, especially in the laboratory, are seldomly assayed under cold stress. Due to the infrequent occurrence of the behavior, we used infrared and thermal cameras to confirm observations. We also collected tail-skin samples to investigate whether any physiological mechanisms might co-occur with TB. If such mechanisms were found, they could inform wider debate involving freeze protection among mammals, and could potentially lead to understanding mammal susceptibility or resilience to sudden temperature changes such as those associated with climate change. Lastly, we scored behaviors by bank voles (Myodes glareolus) which unexpectedly visited chambers. Across four winters, we observed TB in both Apodemus species during subzero conditions, but bank voles never performed the behavior. We also confirmed that TB occurs as an adaptive reflex which warms the tail. From tissue samples, we found that free amino acids, peptides, and glycoproteins were significantly higher during cold-stress. Thus, TB may have been accompanied by the expression of cold-protective proteins which ostensibly enable the peripheral body parts of mammals to survive temperatures well below 0 °C. These findings should inspire new dialogue regarding the role of lipids in tissues of peripheral organs in mammals. By extension, our findings may lead to the discovery of a putative cryoprotection mechanism among mammals.

Abstract Upgrades to advanced scientific user facilities such as next-generation x-ray light sources, nanoscience centers, and neutron facilities are revolutionizing our understanding of materials across the spectrum of the physical sciences, from life sciences to microelectronics. However, these facility and instrument upgrades come with a significant increase in complexity. Driven by more exacting scientific needs, instruments and experiments become more intricate each year. This increased operational complexity makes it ever more challenging for domain scientists to design experiments that effectively leverage the capabilities of and operate on these advanced instruments. Large language models (LLMs) can perform complex information retrieval, assist in knowledge-intensive tasks across applications, and provide guidance on tool usage. Using x-ray light sources, leadership computing, and nanoscience centers as representative examples, we describe preliminary experiments with a Context-Aware Language Model for Science (CALMS) to assist scientists with instrument operations and complex experimentation. With the ability to retrieve relevant information from facility documentation, CALMS can answer simple questions on scientific capabilities and other operational procedures. With the ability to interface with software tools and experimental hardware, CALMS can conversationally operate scientific instruments. By making information more accessible and acting on user needs, LLMs could expand and diversify scientific facilities’ users and accelerate scientific output.

Abstract Acinar cell carcinoma (ACC) and pancreatoblastoma (PBL) are rare pancreatic malignancies with acinar differentiation. Proteogenomic profiling of ACC and PBL revealed distinct protein expression patterns compared to pancreatic ductal adenocarcinoma (PDAC) and benign pancreas. ACC and PBL exhibited similarities, with enrichment in proteins related to RNA processing, chromosome organization, and the mitoribosome, while PDACs overexpressed proteins associated with actin-based processes, extracellular matrix, and immune-active stroma. Pathway activity differences in metabolic adaptation, epithelial-to-mesenchymal transition, and DNA repair were characterized between these diseases. PBL showed upregulation of Wnt-CTNNB1 and IGF2 pathways. Seventeen ACC-specific proteins suggested connections to metabolic diseases with mitochondrial dysfunction, while 34 PBL-specific proteins marked this pediatric cancer with an embryonic stem cell phenotype and alterations in chromosomal proteins and the cell cycle. This study provides novel insights into the proteomic landscapes of ACC and PBL, offering potential targets for diagnostic and therapeutic development.

Abstract Background Ankylosing Spondylitis (AS) is a systemic chronic rheumatic disease characterized by involvement of the axial skeletal and sacroiliac joints. Although this disease is not rare amongst women of reproductive age, data regarding pregnancy outcomes have demonstrated conflicting results. We therefore aimed to compare pregnancy and perinatal outcomes between women who suffered from AS to those who did not. Methods A retrospective cohort study using the Healthcare Cost and Utilization Project, Nationwide Inpatient Sample (HCUP-NIS). Included in the study were all pregnant women who delivered or had a maternal death in the US between 2004 and 2014. Women with an ICD-9 diagnosis of AS before or during pregnancy were compared to those without. Pregnancy, delivery, and neonatal outcomes were compared between the two groups using multivariate logistic regression models adjusting for potential confounders. Results A total of 9,096,788 women were inclusion in the analysis. Amongst them, 383 women (3.8/100,000) had a diagnosis of AS and the rest were controls. Women with AS, compared to those without, were more likely to be older; Caucasian; from higher income quartiles; suffer from thyroid disorders, and have multiple pregnancies (p

Abstract Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.

Abstract Background Currently, there is no consensus on the optimal management of women with low prognosis in ART. In this Delphi consensus, a panel of international experts provided real-world clinical perspectives on a series of literature-supported consensus statements regarding the overall relevance of the POSEIDON criteria for women with low prognosis in ART. Methods Using a Delphi-consensus framework, twelve experts plus two Scientific Coordinators discussed and amended statements and supporting references proposed by the Scientific Coordinators (Round 1). Statements were distributed via an online survey to an extended panel of 53 experts, of whom 36 who voted anonymously on their level of agreement or disagreement with each statement using a six-point Likert-type scale (1 = Absolutely agree; 2 = More than agree; 3 = Agree; 4 = Disagree; 5 = More than disagree; 6 = Absolutely disagree) (Round 2). Consensus was reached if > 66% of participants agreed or disagreed. Results The extended panel voted on seventeen statements and subcategorized them according to relevance. All but one statement reached consensus during the first round; the remaining statement reached consensus after rewording. Statements were categorized according to impact, low-prognosis validation, outcomes and patient management. The POSEIDON criteria are timely and clinically sound. The preferred success measure is cumulative live birth and key management strategies include the use of recombinant FSH preparations, supplementation with r-hLH, dose increases and oocyte/embryo accumulation through vitrification. Tools such as the ART Calculator and Follicle-to-Oocyte Index may be considered. Validation data from large, prospective studies in each POSEIDON group are now needed to corroborate existing retrospective data. Conclusions This Delphi consensus provides an overview of expert opinion on the clinical implications of the POSEIDON criteria for women with low prognosis to ovarian stimulation.

Abstract Background Elevated concentrations of low-density lipoprotein cholesterol (LDL-C) are linked to dementia risk, and conversely, increased plasma concentrations of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein-A1 (Apo-A1) associate with decreased dementia risk. Inhibition of cholesteryl ester transfer protein (CETP) meaningfully affects the concentrations of these blood lipids and may therefore provide an opportunity to treat dementia. Methods Drug target Mendelian randomization (MR) was employed to anticipate the on-target effects of lower CETP concentration (μg/mL) on plasma lipids, cardiovascular disease outcomes, autopsy confirmed Lewy body dementia (LBD), as well as Parkinson’s dementia. Results MR analysis of lower CETP concentration recapitulated the blood lipid effects observed in clinical trials of CETP-inhibitors, as well as protective effects on coronary heart disease (odds ratio (OR) 0.92, 95% confidence interval (CI) 0.89; 0.96), heart failure, abdominal aortic aneurysm, any stroke, ischemic stroke, and small vessel stroke (0.90, 95%CI 0.85; 0.96). Consideration of dementia related traits indicated that lower CETP concentrations were associated higher total brain volume (0.04 per standard deviation, 95%CI 0.02; 0.06), lower risk of LBD (OR 0.81, 95%CI 0.74; 0.89) and Parkinson’s dementia risk (OR 0.26, 95%CI 0.14; 0.48). APOE4 stratified analyses suggested the LBD effect was most pronounced in APOE-ε4 + participants (OR 0.61 95%CI 0.51; 0.73), compared to APOE-ε4- (OR 0.89 95%CI 0.79; 1.01); interaction p-value 5.81 × 10− 4. Conclusions These results suggest that inhibition of CETP may be a viable strategy to treat dementia, with a more pronounced effect expected in APOE-ε4 carriers.

Abstract A new release of the Monte Carlo event generator Herwig (version 7.3) has been launched. This iteration encompasses several enhancements over its predecessor, version 7.2. Noteworthy upgrades include: the implementation of a process-independent electroweak angular-ordered parton shower integrated with QCD and QED radiation; a new recoil scheme for initial-state radiation improving the behaviour of the angular-ordered parton shower; the incorporation of the heavy quark effective theory to refine the hadronization and decay of excited heavy mesons and heavy baryons; a dynamic strategy to regulate the kinematic threshold of cluster splittings within the cluster hadronization model; several improvements to the structure of the cluster hadronization model allowing for refined models; the possibility to extract event-by-event hadronization corrections in a well-defined way; the possibility of using the string model, with a dedicated tune. Additionally, a new tuning of the parton shower and hadronization parameters has been executed. This article discusses the novel features introduced in version 7.3.0.

Abstract Established invasive species represent one of the most harmful and challenging threats to native biodiversity, necessitating methods for Early Detection and Rapid Response. Cryptic invasions are particularly challenging and often require expensive and time-consuming molecular surveys which limits their usefulness for management. We present a novel application of the Fluidigm SNP-Type Assay to identify rare non-native alleles that significantly reduces the cost and time to generate diagnostic results. We demonstrate the efficacy of this method using experimental Fluidigm pools (99% accuracy) and sequence data (96% accuracy). We apply our novel methodology to an endangered population of California tiger salamanders in Sonoma County where two individual non-native tiger salamander hybrids have previously been detected since 2008. We screened 5805 larvae in 387 sample-pools containing 15 larvae each. We did not detect any non-native hybrids in the population, a result that was verified with sequence data, though we strongly recommend additional years of sampling to confirm hybrid absence. Our success with a challenging, large-genome amphibian suggests this method may be applied to any system, and would be particularly useful when it is necessary for conservation practitioners to rapidly identify rare taxa or genes of interest.

Fermentation by lactic acid bacteria has been used for millennia to preserve food and make it more palatable. These microorganisms may also generate bioactive compounds with the potential to serve as components in active edible food packaging or as alternative therapeutics. Dairy waste products, especially whey, provide a substrate for growth of these bacteria, and can be incorporated into the formulations of edible food packaging. This minireview deals with the use of dairy waste to grow lactic acid bacteria to produce bioactive compounds, specifically antimicrobial peptides and immunoregulatory molecules, and their potential use in food and therapeutic applications.

Summary: Background: Chronic Obstructive Pulmonary Disease (COPD) has a broad spectrum of clinical characteristics. The aetiology of these differences is not well understood. The objective of this study is to assess whether respiratory genetic variants cluster by phenotype and associate with COPD heterogeneity. Methods: We clustered genome-wide association studies of COPD, lung function, and asthma and phenotypes from the UK Biobank using non-negative matrix factorization. We constructed cluster-specific genetic risk scores and tested these scores for association with phenotypes in non-Hispanic white subjects in the COPDGene study. Findings: We identified three clusters from 482 variants and 44 traits from genetic associations in 379,337 UK Biobank participants. Variants from asthma, COPD, and lung function were found in all three clusters. Clusters displayed varying effects on white blood cell counts, height, and body mass index (BMI)-related phenotypes in the UK Biobank. In the COPDGene cohort, cluster-specific genetic risk scores were associated with differences in steroid use, BMI, lymphocyte counts, and chronic bronchitis, as well as variations in gene and protein expression. Interpretation: Our results suggest that multi-phenotype analysis of obstructive lung disease-related risk variants may identify genetically driven phenotypic patterns in COPD. Funding: MHC was supported by R01HL149861, R01HL135142, R01HL137927, R01HL147148, and R01HL089856. HA and HJ were supported by ANR-20-CE36-0009-02 and ANR-16-CONV-0005. The COPDGene study (NCT00608764) is supported by grants from the NHLBI (U01HL089897 and U01HL089856), by NIH contract 75N92023D00011, and by the COPD Foundation through contributions made to an Industry Advisory Committee that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer and Sunovion.

Introduction: Cloaca with a common channel greater than 3 cm typically requires urogenital separation rather than total urogenital mobilization. The purpose of this report was to describe our experience managing a female infant with an usual form of cloaca where all structures inserted onto the bladder neck. Case presentation: A female infant with a single perineal opening underwent loop sigmoid colostomy shortly after birth. She voided spontaneously and had no hydrocolpos. She underwent exam under anesthesia, cystoscopy, and cloacogram under a single anesthetic at 5 months of age. This revealed five structures that inserted directly into the bladder: a central rectal fistula, two hemivaginas and hemiuteri bilaterally, and two ureters without hydronephrosis. The outflow tract was a long common channel measuring 5.2 cm. This patient was reviewed in a multidisciplinary setting and underwent repair at 10 months of age. We performed a midline laparotomy and opened the anterior wall of the bladder to visualize the structures that inserted posteriorly. Foley catheter and ureteric stents were placed. The rectal fistula and hemivaginas were mobilized off the bladder internally. Vaginal replacement was performed using a transverse portion of rectum. Additional colonic length was achieved by converting the loop colostomy to an end-loop. The abdomen was closed and posterior sagittal anorectoplasty was performed in a prone position. Conclusion: This infant underwent repair of a “bladder neck” cloaca using a transvesicular approach. She is now 35 months of age and thriving. She developed neurogenic bladder requiring clean intermittent catheterization and is working on fecal continence.

Purpose: The aim is to assess GPT-4V's (OpenAI) diagnostic accuracy and its capability to identify glaucoma-related features compared to expert evaluations. Design: Evaluation of multimodal large language models for reviewing fundus images in glaucoma. Subjects: A total of 300 fundus images from 3 public datasets (ACRIMA, ORIGA, and RIM-One v3) that included 139 glaucomatous and 161 nonglaucomatous cases were analyzed. Methods: Preprocessing ensured each image was centered on the optic disc. GPT-4's vision-preview model (GPT-4V) assessed each image for various glaucoma-related criteria: image quality, image gradability, cup-to-disc ratio, peripapillary atrophy, disc hemorrhages, rim thinning (by quadrant and clock hour), glaucoma status, and estimated probability of glaucoma. Each image was analyzed twice by GPT-4V to evaluate consistency in its predictions. Two expert graders independently evaluated the same images using identical criteria. Comparisons between GPT-4V's assessments, expert evaluations, and dataset labels were made to determine accuracy, sensitivity, specificity, and Cohen kappa. Main Outcome Measures: The main parameters measured were the accuracy, sensitivity, specificity, and Cohen kappa of GPT-4V in detecting glaucoma compared with expert evaluations. Results: GPT-4V successfully provided glaucoma assessments for all 300 fundus images across the datasets, although approximately 35% required multiple prompt submissions. GPT-4V's overall accuracy in glaucoma detection was slightly lower (0.68, 0.70, and 0.81, respectively) than that of expert graders (0.78, 0.80, and 0.88, for expert grader 1 and 0.72, 0.78, and 0.87, for expert grader 2, respectively), across the ACRIMA, ORIGA, and RIM-ONE datasets. In Glaucoma detection, GPT-4V showed variable agreement by dataset and expert graders, with Cohen kappa values ranging from 0.08 to 0.72. In terms of feature detection, GPT-4V demonstrated high consistency (repeatability) in image gradability, with an agreement accuracy of ≥89% and substantial agreement in rim thinning and cup-to-disc ratio assessments, although kappas were generally lower than expert-to-expert agreement. Conclusions: GPT-4V shows promise as a tool in glaucoma screening and detection through fundus image analysis, demonstrating generally high agreement with expert evaluations of key diagnostic features, although agreement did vary substantially across datasets. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Objective: To facilitate discussion surrounding the use of AI in medicine so that it may lead to improved surgeon and patient outcomes in the future. Background: Artificial intelligence (AI) refers to algorithms that utilize data to mimic human cognition. Machine learning (ML) is a subset of AI that enables the algorithm to improve without explicit human direction. Methods: Narrative overview of the literature synthesized from searches of computerized databases and authoritative texts. Discussion: There are forms of ML in use both in research and clinical settings today, which can personalize medical care in the future. In spine surgery, AI can affect care in the following domains: pre-operative workup, surgical planning, and outcome prediction. The use of AI in adult spinal deformity (ASD) poses unique opportunities for growth, as outcomes after ASD are often difficult to predict due to disease complexity. Recently, the use of AI modeling has gained traction with large multi-institutional organizations, leading to robust publications aided by an abundance of prospectively collected data. However, current AI usage still has concerns that should not be taken lightly. Conclusion: In the following review, we outline the basis of AI, its current clinical uses and potential benefits, and its various challenges.

Harmful alcohol use is a leading risk factor for injury-related death and disability in low- and middle-income countries (LMICs). Brief negotiational interventions (BNIs) in emergency departments (EDs) effectively reduce alcohol intake and re-injury rates. However, most BNIs are developed in high-income countries, with limited evidence of their effectiveness in LMICs. To address this gap, we culturally adapted a BNI for alcohol-related injury patients at Kilimanjaro Christian Medical Centre (KCMC), a tertiary hospital in Tanzania. Our study followed the ADAPT guidance to culturally adapt an existing high-income country BNI for use in the KCMC, a tertiary hospital in Tanzania. The adaptation included: 1) a systematic review of effective alcohol harm reduction interventions in similar settings; 2) consultations with local and international healthcare professionals experienced in counseling and substance abuse treatment; 3) group discussions to refine goals and finalize adaptations. The adapted BNI protocol and assessment scales ensured intervention fidelity. At KCMC, 30% of injury patients screened positive for alcohol use disorder (AUD), with a five-fold increased risk of injury, primarily from road traffic accidents and violence. A systematic review highlighted limited data on patient-level interventions in low-resource settings. Our adapted BNI, 'Punguza Pombe Kwa Afya Yako (PPKAY)', based on the FRAMES model, showed high feasibility and acceptability, with 84% of interventions achieving ≥80% adherence and 98% patient satisfaction. PPKAY is the first culturally adapted alcohol BNI for injury patients in an African ED. Our study demonstrates our approach to adapting substance use interventions for use in low resource settings and shows that cultural adaptation of alcohol use interventions is feasible, beneficial and empowering for our team. Our study lays a framework and method for other low resourced settings to integrate cultural adaptation into the implementation of a BNI in low resource EDs.

Synthetic compounds are widely used in cancer drug discovery. Chemotherapies aim to inhibit proliferation and induce apoptosis however, they have limitations. This study aims to explore in vitro anti-proliferative, pro-apoptotic, and anti-metastatic effects of 2-imino-7-methoxy-4-(4-fluorophenyl)-2h-1,3-thiazine [3,2-a] benzimidazole against pancreatic and melanoma cancer cell lines. Cell viability assays were conducted using Alamar blue assay. Caspase 3/7 activation was evaluated using caspase-Glo® 3/7 substrate reagent. Gene expression was analyzed using conventional polymerase chain reaction (PCR). Cell migration was assessed using wound healing. Alamar blue assay showed that the molecule studied exhibited antiproliferative activity on both the PaCa-2 and A375 cell lines, however, with higher cytotoxicity on PaCa-2 which suggests that it is cell-line dependent. Caspase 3/7 activity was upregulated in PaCa-2 and downregulated in A375, suggesting caspase-dependent and caspase-independent cell death, respectively. p53 and Bax were upregulated on both cell lines which suggests that the compound might have induced apoptosis and autophagy. Wound healing showed a decreased cell migration on both cell lines an important stage of metastasis. The study suggests that the study molecule can be a promising chemotherapeutic agent in the development of new anticancer drugs.

First-order stochastic dominance is a core principle in rational decision-making. If lottery A has a higher or equal chance of winning an amount $x $ or more compared to lottery B for all x, and a strictly higher chance for at least one $x $ , then A should be preferred over B. Previous research suggests that violations of this principle may result from failures in recognizing coalescing equivalence. In Expected Utility Theory (EUT) and Cumulative Prospect Theory (CPT), gambles are represented as probability distributions, where probabilities of equivalent events can be combined, ensuring stochastic dominance. In contrast, the Transfer of Attention Exchange (TAX) model represents gambles as trees with branches for each probability and outcome, making it possible for coalescing and stochastic dominance violations to occur. We conducted two experiments designed to train participants in identifying dominance by splitting coalesced gambles. By toggling between displays of coalesced and split forms of the same choice problem, participants were instructed to recognize stochastic dominance. Despite this training, violations of stochastic dominance were only minimally reduced, as if people find it difficult—or even resist—shifting from a trees-with-branches representation (as in the TAX model) to a cognitive recognition of the equivalence among different representations of the same choice problem.

Abstract Background Studies have identified individual blood biomarkers associated with chronic obstructive pulmonary disease (COPD) and related phenotypes. However, complex diseases such as COPD typically involve changes in multiple molecules with interconnections that may not be captured when considering single molecular features. Methods Leveraging proteomic data from 3,173 COPDGene Non-Hispanic White (NHW) and African American (AA) participants, we applied sparse multiple canonical correlation network analysis (SmCCNet) to 4,776 proteins assayed on the SomaScan v4.0 platform to derive sparse networks of proteins associated with current vs. former smoking status, airflow obstruction, and emphysema quantitated from high-resolution computed tomography scans. We then used NetSHy, a dimension reduction technique leveraging network topology, to produce summary scores of each proteomic network, referred to as NetSHy scores. We next performed a genome-wide association study (GWAS) to identify variants associated with the NetSHy scores, or network quantitative trait loci (nQTLs). Finally, we evaluated the replicability of the networks in an independent cohort, SPIROMICS. Results We identified networks of 13 to 104 proteins for each phenotype and exposure in NHW and AA, and the derived NetSHy scores significantly associated with the variable of interests. Networks included known (sRAGE, ALPP, MIP1) and novel molecules (CA10, CPB1, HIS3, PXDN) and interactions involved in COPD pathogenesis. We observed 7 nQTL loci associated with NetSHy scores, 4 of which remained after conditional analysis. Networks for smoking status and emphysema, but not airflow obstruction, demonstrated a high degree of replicability across race groups and cohorts. Conclusions In this work, we apply state-of-the-art molecular network generation and summarization approaches to proteomic data from COPDGene participants to uncover protein networks associated with COPD phenotypes. We further identify genetic associations with networks. This work discovers protein networks containing known and novel proteins and protein interactions associated with clinically relevant COPD phenotypes across race groups and cohorts.

Abstract Protein biomarkers are associated with mortality in cardiovascular disease, but their effect on predicting respiratory and all-cause mortality is not clear. We tested whether a protein risk score (protRS) can improve prediction of all-cause mortality over clinical risk factors in smokers. We utilized smoking-enriched (COPDGene, LSC, SPIROMICS) and general population-based (MESA) cohorts with SomaScan proteomic and mortality data. We split COPDGene into training and testing sets (50:50) and developed a protRS based on respiratory mortality effect size and parsimony. We tested multivariable associations of the protRS with all-cause, respiratory, and cardiovascular mortality, and performed meta-analysis, area-under-the-curve (AUC), and network analyses. We included 2232 participants. In COPDGene, a penalized regression-based protRS was most highly associated with respiratory mortality (OR 9.2) and parsimonious (15 proteins). This protRS was associated with all-cause mortality (random effects HR 1.79 [95% CI 1.31–2.43]). Adding the protRS to clinical covariates improved all-cause mortality prediction in COPDGene (AUC 0.87 vs 0.82) and SPIROMICS (0.74 vs 0.6), but not in LSC and MESA. Protein–protein interaction network analyses implicate cytokine signaling, innate immune responses, and extracellular matrix turnover. A blood-based protein risk score predicts all-cause and respiratory mortality, identifies potential drivers of mortality, and demonstrates heterogeneity in effects amongst cohorts.

Abstract We report bio-structural, bio-chemical and bio-physical evidence demonstrating how small molecules can bind to both wild-type and mutant IDH1, but only inhibit the enzymatic activity of the mutant isoform. Enabled through x-ray crystallography, we characterized a series of small molecule inhibitors that bound to mutant IDH1 differently than the marketed inhibitor Ivosidenib, for which we have determined the x-ray crystal structure. Across the industry several mutant IDH1 inhibitor chemotypes bind to this allosteric IDH1 pocket and selectively inhibit the mutant enzyme. Detailed characterization by a variety of biophysical techniques and NMR studies led us to propose how compounds binding in the allosteric IDH1 R132H pocket inhibit the production of 2-Hydroxy glutarate.

Abstract Background Multiple sclerosis (MS) is a chronic neurological condition and the leading cause of non-traumatic disability in young adults. MS pathogenesis leads to the death of oligodendrocytes, demyelination, and progressive central nervous system neurodegeneration. Endogenous remyelination occurs in people with MS (PwMS) but is insufficient to repair the damage. Our preclinical studies in mice indicate that endogenous remyelination can be supported by the delivery of repetitive transcranial magnetic stimulation (rTMS). Our phase I trial concluded that 20 sessions of rTMS, delivered over 5 weeks, are safe and feasible for PwMS. This phase II trial aims to investigate the safety and preliminary efficacy of rTMS for PwMS. Methods Participants must be aged 18–65 years, diagnosed with MS by a neurologist, stable and relapse free for 6 months, have an Extended Disability Status Scale (EDSS) between 1.5 and 6 (inclusive), willing to travel to a study site every weekday for 4 consecutive weeks, and able to provide informed consent and access the internet. Participants from multiple centres will be randomised 2:1 (rTMS to sham) stratified by sex. The intervention will be delivered with a Magstim Rapid2 stimulator device and circular 90-mm coil or MagVenture MagPro stimulator device with C100 circular coil, positioned to stimulate a broad area including frontal and parietal cortices. For the rTMS group, pulse intensity will be set at 18% (MagVenture) or 25% (Magstim) of maximum stimulator output (MSO), and rTMS applied as intermittent theta burst stimulation (iTBS) (~ 3 min per side; 600 pulses). For the sham group, the procedure will be the same, but the intensity is set at 0%. Each participant will attend 20 intervention sessions over a maximum of 5 weeks. Outcome measures include MS Functional Composite Score (primary), Fatigue Severity Scale, Hospital Anxiety and Depression Scale, Quality of Life, and Pittsburgh Sleep Quality Index/Numeric Rating Scale and adverse events (secondary) and advanced MRI metrics (tertiary). Outcomes will be measured at baseline and after completing the intervention. Discussion This study will determine if rTMS can improve functional outcomes or other MS symptoms and determine whether rTMS has the potential to promote remyelination in PwMS. Trial registration Registered with Australian New Zealand Clinical Trials Registry, 20 January 2022; ACTRN12622000064707.

Abstract Severe febrile illnesses in children encompass life-threatening organ dysfunction caused by diverse pathogens and other severe inflammatory syndromes. A comparative approach to these illnesses may identify shared and distinct features of host immune dysfunction amenable to immunomodulation. Here, using immunophenotyping with mass cytometry and cell stimulation experiments, we illustrate trajectories of immune dysfunction in 74 children with multi-system inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2, 30 with bacterial infection, 16 with viral infection, 8 with Kawasaki disease, and 42 controls. We explore these findings in a secondary cohort of 500 children with these illnesses and 134 controls. We show that neutrophil activation and apoptosis are prominent in multi-system inflammatory syndrome, and that this is partially shared with bacterial infection. We show that memory T cells from patients with multi-system inflammatory syndrome and bacterial infection are exhausted. In contrast, we show viral infection to be characterized by a distinct signature of decreased interferon signaling and lower interferon receptor gene expression. Improved understanding of immune dysfunction may improve approaches to immunomodulator therapy in severe febrile illnesses in children.

Objective To assess the effect of endometrial thickness (EMT) on live birth rates (LBR) in women with endometrial lining between 7.0–9.9 mm. Methods This retrospective cohort study included women who underwent fresh and frozen embryo transfers between 2008 and 2018, grouped according to their maximum EMT; group 1, 7.0–7.9 mm; group 2, 8.0–8.9 mm; and group 3, 9.0–9.9 mm and underwent blastocyst transfer. Results The study included 7,091 in-vitro fertilization cycles: 1,385 in group 1, 3,000 in group 2, and 2,706 in group 3. The combined LBR was 22.2%. The mean age of women at oocyte retrieval day was 36.7±4.5 years. There was no difference in female age at oocyte retrieval or in the quality of embryos transferred between the three groups. Group 1 had more diagnoses of diminished ovarian reserve (25.8% vs. 19.5% and 19.1%; P

Abstract The sustainable management of Earth’s complex ecosystems requires an abundance of field data to support long term stewardship. Remotely sensed satellite data provide crucial supplements to field measurements and are essential for deriving key operational products for monitoring Earth systems. However, to accurately calibrate and validate the models used to develop monitoring datasets, coincident field measurements are required. In 2018 and 2019, data related to cotton (Gossypium hirsutum L.) crops were collected from five fields in two farms located in Georgia, USA. Collections were timed to coincide with satellite overpasses to support the development of remote sensing-based crop and soil data products. Data collected include soil moisture, plant water content, above ground biomass, crop height, plant phenology, and field management practices (row direction, row spacing, and plant density). The datasets include 512 records collected in 2018 and 303 records collected in 2019. The data are archived in the National Agricultural Library Ag Data Commons repository and are available for use by researchers seeking crop and soil validation data.

Abstract Introduction Migraine is under-diagnosed and under-treated. Many people with migraine do not seek medical care, and those who do may initially receive a different diagnosis and/or be dissatisfied with provided care on their journey before treatment with a CGRP-mAb (calcitonin-gene-related-peptide monoclonal antibody). Methods This is a cross-sectional, self-reported, online survey of subjects in Lilly’s Emgality® Patient Support Program in 2022. Questionnaires collected insights into subjects’ prior experiences with migraine and interactions with healthcare professionals before receiving CGRP-mAbs. Results Of the 250 participants with episodic and 250 with chronic migraine, 90% were female and white with a mean age of 26.2 years (± 11.9) at diagnosis and 40.6 (± 12.0) years at survey enrollment. Many participants (71%) suspected they had migraine before diagnosis, with 31% reluctant to seek help. Of these, approximately one-third were unaware of treatment, did not think that a physician could do anything more for migraine, would not take them seriously, or were reluctant due to a previous unhelpful experience. Participants mainly received information from friends/family (47%) or the internet (28%). Participants initially sought treatment due to an increase in migraine frequency (77%), attacks interfering with work or school (75%), or increased pain intensity (74%). Subjects saw a mean of 4.1 (± 4.3) healthcare providers before migraine diagnosis, and 20% of participants previously received a different diagnosis. Participants reported migraine causes included stress/anxiety/depression (42%), hormonal changes (30%), nutrition (20%), and weather (16%). Acute treatment of migraine included prescription (82%) and over-the-counter (50%) medications, changes in nutrition (62%), adjusting fluid intake (56%), and relaxation techniques (55%). Preventive medications included anticonvulsants (61%), antidepressants (44%), blood pressure-lowering medications (43%), and botulinum toxin A injections (17%). Most discontinuations were due to lack of efficacy or side effects. Conclusion People with migraine describe reluctance in seeking health care, and misunderstandings seem common especially in the beginning of their migraine journey. Graphical abstract available for this article. Graphical Abstract

Abstract The COVID-19 pandemic has led to the deaths of millions of people and severe global economic impacts. Small molecule therapeutics have played an important role in the fight against SARS-CoV-2, the virus responsible for COVID-19, but their efficacy has been limited in scope and availability, with many people unable to access their benefits, and better options are needed. EDP-235 is specifically designed to inhibit the SARS-CoV-2 3CLpro, with potent nanomolar activity against all SARS-CoV-2 variants to date, as well as clinically relevant human and zoonotic coronaviruses. EDP-235 maintains potency against variants bearing mutations associated with nirmatrelvir resistance. Additionally, EDP-235 demonstrates a ≥ 500-fold selectivity index against multiple host proteases. In a male Syrian hamster model of COVID-19, EDP-235 suppresses SARS-CoV-2 replication and viral-induced hamster lung pathology. In a female ferret model, EDP-235 inhibits production of SARS-CoV-2 infectious virus and RNA at multiple anatomical sites. Furthermore, SARS-CoV-2 contact transmission does not occur when naïve ferrets are co-housed with infected, EDP-235-treated ferrets. Collectively, these results demonstrate that EDP-235 is a broad-spectrum coronavirus inhibitor with efficacy in animal models of primary infection and transmission.

Abstract This paper presents the inaugural investigation of beyond the Standard Model (BSM) radiation processes, framed as a generalized, process- and model-independent parton shower algorithm within Herwig 7, based on direct translations of Universal FeynRules Output (UFO) constructed via Herwig’s ufo2herwig module. Leveraging the fact that shower kinematics are dictated by the spins of involved particles, we calculate comprehensive helicity-dependent branching kernels for all feasible splittings of scalars, fermions, and vector bosons, tailored to Herwig 7’s angular-ordering (AO) parton shower algorithm. Utilizing these kernels, we derive BSM splitting functions in the quasi-collinear limit, ensuring compatibility with the Standard Model (SM) and supersymmetry (SUSY) splitting functions when analogous parameter conditions are applied. These newly derived functions have been integrated into the Herwig 7 event generator framework. Comparative analyses with fixed-order matrix element calculations show good agreement for single radiation events. Moreover, the results showcase the influence of BSM radiation at the Large Hadron Collider (LHC) and envisage its implications for future collider endeavours. This research augments our comprehension of BSM radiation effects, with significant bearings on present and prospective collider-based inquiries.

Abstract P2X receptors are trimeric ATP-gated ion channels that activate diverse signaling cascades. Due to its role in apoptotic pathways, selective activation of P2X7 is a potential experimental tool and therapeutic approach in cancer biology. However, mechanisms of high-affinity P2X7 activation have not been defined. We report high-resolution cryo-EM structures of wild-type rat P2X7 bound to the high-affinity agonist BzATP as well as significantly improved apo receptor structures in the presence and absence of sodium. Apo structures define molecular details of pore architecture and reveal how a partially hydrated Na+ ion interacts with the conductance pathway in the closed state. Structural, electrophysiological, and direct binding data of BzATP reveal that three residues just outside the orthosteric ATP-binding site are responsible for its high-affinity agonism. This work provides insights into high-affinity agonism for any P2X receptor and lays the groundwork for development of subtype-specific agonists applicable to cancer therapeutics.

Abstract Reliable automatic diagnosis of Diabetic Retinopathy (DR) and Macular Edema (ME) is an invaluable asset in improving the rate of monitored patients among at-risk populations and in enabling earlier treatments before the pathology progresses and threatens vision. However, the explainability of screening models is still an open question, and specifically designed datasets are required to support the research. We present MAPLES-DR (MESSIDOR Anatomical and Pathological Labels for Explainable Screening of Diabetic Retinopathy), which contains, for 198 images of the MESSIDOR public fundus dataset, new diagnoses for DR and ME as well as new pixel-wise segmentation maps for 10 anatomical and pathological biomarkers related to DR. This paper documents the design choices and the annotation procedure that produced MAPLES-DR, discusses the interobserver variability and the overall quality of the annotations, and provides guidelines on using the dataset in a machine learning context.

Abstract Introduction Patients with chronic refractory gout face a considerable burden of disease due to unexpected flares characterized by severe and debilitating pain, which can lead to chronic pain and joint damage. This study aimed to understand the symptoms and impacts of chronic refractory gout on health-related quality of life (HRQoL). Methods A targeted literature review was conducted to identify and review key articles describing the symptoms and impacts of gout, and articles examining the psychometric performance of the Medical Outcomes Survey Short Form-36 (SF-36) and Health Assessment Questionnaire-Disability Index (HAQ-DI) in gout. Qualitative interviews were conducted with 20 participants with chronic refractory gout. The results were used to develop the conceptual model and determine the appropriateness of the SF-36 and HAQ-DI in evaluating HRQoL in this population. Results Most frequently reported symptoms included bodily pain (n = 18, 90.0%), joint swelling (n = 18, 90.0%), joint tenderness (n = 18, 90.0%), and joint pain (n = 16, 80.0%). Most frequently reported impacts were difficulties climbing a flight (n = 20, 100.0%) or several flights of stairs (n = 20, 100.0%), climbing five steps (n = 19, 95.0%), completing chores (n = 19, 95.0%), and running errands and shopping (n = 19, 95.0%). All assessed items from SF-36 and HAQ-DI were reported by ≥ 25% (n = 5) of participants and mapped sufficiently to concepts elicited by participants. Conclusions Patients with chronic refractory gout report symptoms and impacts that are highly bothersome and burdensome to everyday life. Items included in the HAQ-DI and SF-36 mapped directly to these symptoms and impacts and are relevant to understand the burden of disease of chronic refractory gout.

Human infants are born helpless and entirely dependent on their adult caregivers for survival. It is this very helplessness, however, that serves as a powerful signal to nearby adults and reorganizes attention towards potential dangers. As members of an altricial and alloparental species, adults are perceptually sensitive to infantile cues. Infants change how adults attend to the world around them as well as how adults perceive affordances that can shape adaptive caregiving behaviors. By being sensitive to the presence of an infant, and their potential for getting into danger, adults can make decisions and respond to potential threats in ways that keep children safe from harm. Thus, we argue that parenthood represents a developmental transition that builds on existing perceptual biases, such as greater attention towards infantile cues, and serves as a useful model for studying threat perception. Here we review evidence that the task of providing care to children shapes how adults process information about threat, such as attention towards potential threat cues, perception of the social and physical world, and judgment of risk under uncertainty. We propose a theoretical framework of threat perception that focuses on how the demands of being a social altricial species, namely the demands of providing care to young, influence perceptual systems and plays a strong role in organizing how adults view the world around them. The motivated perceptual experiences of caregivers represent an untapped area of research that can increase our understanding of perceptual function and plasticity across the lifespan.

Abstract Models of the future of coral reefs are potentially sensitive to theoretical assumptions, variable selectivity, interactions, and scales. A number of these aspects were evaluated using boosted regression tree models of numbers of coral taxa trained on ~1000 field surveys and 35 spatially complete influential environmental proxies at moderate scales (~6.25 km2). Models explored influences of climate change, water quality, direct human‐resource extraction, and variable selection processes. We examined the predictions for numbers of coral taxa using all variables and compared them to models based on variables commonly used to predict climate change and human influences (eight and nine variables). Results indicated individual temperature variables alone had lower predictive ability (R2

Bacillus cereus biovar anthracis (Bcbva) causes anthrax-like disease in animals, particularly in the non-human primates and great apes of West and Central Africa. Genomic analyses revealed Bcbva as a member of the B. cereus species that carries two plasmids, pBCXO1 and pBCXO2, which have high sequence homology to the B. anthracis toxin and polyglutamate capsule encoding plasmids pXO1 and pXO2, respectively. To date, only a few studies have investigated the effect of variations in Bcbva sporulation, toxin, and capsule synthesis on animal and macrophage pathogenicity compared to B. anthracis, therefore more research is needed to gain a better understanding of the pathogenesis of this emerging infection. Here, we report that Bcbva can multiply and vegetatively survive on nutrient-rich media for a minimum of six days while generating spores. Sporulation of Bcbva occurred faster and more extensively than B. anthracis Ames. Bcbva tended to secrete less protective antigen (PA) than B. anthracis Ames when cultured in growth medium. We found Bcbva produced a substantially higher amount of attached poly-ƴ-D-glutamic acid (PDGA) capsule than B. anthracis Ames when grown in medium supplemented with human serum and CO2. In a phagocytosis assay, Bcbva spores showed reduced internalization by mouse macrophages compared to B. anthracis Ames. Our research demonstrated that Bcbva is more virulent than B. anthracis Ames using two in vivo models, Galleria mellonella larvae and guinea pigs. Following that, the efficacy of the veterinary vaccine Sterne strain 34F2 against anthrax-like disease was assessed in guinea pigs. Sterne vaccinated guinea pigs had significantly increased anti-PA titers compared to the unvaccinated control group. Toxin neutralizing antibody titers in vaccinated guinea pigs correlated with anti-PA titers. This indicates the Sterne vaccine provides adequate protection against Bcbva infection in laboratory animals.

2-Benzylbenzimidazole derivatives or ‘nitazenes’ are increasingly present on the recreational drug market. Here, we report the synthesis and pharmacological characterization of 15 structurally diverse nitazenes that might be predicted to emerge or grow in popularity. This work expands the existing knowledge about 2-benzylbenzimidazole structure-activity relationships (SARs), while also helping stakeholders (e.g., forensic toxicologists, clinicians, policymakers) in their risk assessment and preparedness for the potential next generation of nitazenes. In vitro µ-opioid receptor (MOR) affinity was determined via competition radioligand (3[H]DAMGO) binding assays in rat brain tissue. MOR activation (potency and efficacy) was studied by means of a cell-based β-arrestin 2 recruitment assay. For seven nitazenes, including etonitazene, opioid-like pharmacodynamic effects (antinociception, locomotor activity, body temperature changes) were evaluated after subcutaneous administration in male C57BL/6 J mice. The results showed that all nitazenes bound to MOR with nanomolar affinities, and the functional potency of several of them was comparable to or exceeded that of fentanyl. In vivo, dose-dependent effects were observed for antinociception, locomotor activity, and body temperature changes in mice. SAR insights included the high opioid-like activity of methionitazene, iso-butonitazene, sec-butonitazene, and the etonitazene analogues 1-ethyl-pyrrolidinylmethyl N-desalkyl etonitazene and ethylene etonitazene. The most potent analogue of the panel across all functional assays was α’-methyl etonitazene. Taken together, through critical pharmacological evaluation, this work provides a framework for strengthened preparedness and risk assessments of current and future nitazenes that have the potential to cause harm to users.

The giant striated muscle protein titin integrates into the developing sarcomere to form a stable myofilament system that is extended as myocytes fuse. The logistics underlying myofilament assembly and disassembly have started to emerge with the possibility to follow labeled sarcomere components. Here, we generated the mCherry knock-in at titin’s Z-disk to study skeletal muscle development and remodeling. We find titin’s integration into the sarcomere tightly regulated and its unexpected mobility facilitating a homogeneous distribution of titin after cell fusion – an integral part of syncytium formation and maturation of skeletal muscle. In adult mCherry-titin mice, treatment of muscle injury by implantation of titin-eGFP myoblasts reveals how myocytes integrate, fuse, and contribute to the continuous myofilament system across cell boundaries. Unlike in immature primary cells, titin proteins are retained at the proximal nucleus and do not diffuse across the whole syncytium with implications for future cell-based therapies of skeletal muscle disease.

Abstract Anacetrapib, a cholesteryl ester transfer protein (CETP) inhibitor previously under development, exhibited an usually extended terminal half‐life and large food effect and accumulated in adipose tissue. Other CETP inhibitors have not shown such effects. Obicetrapib, a potent selective CETP inhibitor, is undergoing Phase III clinical development. Dedicated assessments were conducted in pre‐clinical and Phase I and II clinical studies of obicetrapib to examine the pharmacokinetic issues observed with anacetrapib. After 9 months of dosing up to 50 mg/kg/day in cynomolgus monkeys, obicetrapib was completely eliminated from systemic circulation and not detected in adipose tissue after a 13‐week recovery period. In healthy humans receiving 1–25 mg of obicetrapib, the mean terminal half‐life of obicetrapib was 148, 131, and 121 h at 5, 10, and 25 mg, respectively, and food increased plasma levels by ~1.6‐fold with a 10 mg dose. At the end of treatment in Phase II trials, mean plasma levels of obicetrapib ranged from 194.5 ng/mL with 2.5 mg to 506.3 ng/mL with 10 mg. Plasma levels of obicetrapib decreased by 92.2% and 98.5% at four and 15 weeks post‐treatment, respectively. Obicetrapib shows no clinically relevant accumulation, is minimally affected by food, and has a mean terminal half‐life of 131 h for the 10 mg dose. These data support once daily, chronic dosing of obicetrapib in Phase III trials for dyslipidemia management.