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Abstract Assessment of immune correlates of severe COVID-19 has been hampered by the low numbers of severe cases in COVID-19 vaccine efficacy (VE) trials. We assess neutralizing and binding antibody levels at 4 weeks post-Ad26.COV2.S vaccination as correlates of risk and of protection against severe-critical COVID-19 through 220 days post-vaccination in the ENSEMBLE trial (NCT04505722), constituting ~4.5 months longer follow-up than our previous correlates analysis and enabling inclusion of 42 severe-critical vaccine-breakthrough cases. Neutralizing antibody titer is a strong inverse correlate of severe-critical COVID-19, with estimated hazard ratio (HR) per 10-fold increase 0.35 (95% CI: 0.13, 0.90). In a multivariable model, HRs are 0.31 (0.11, 0.89) for neutralizing antibody titer and 1.22 (0.49, 3.02) for anti-Spike binding antibody concentration. VE against severe-critical COVID-19 rises with neutralizing antibody titer: 63.1% (95% CI: 40.0%, 77.3%) at unquantifiable [

Abstract Few studies have reported on the accuracy of self‐reported hypertension history among older postmenopausal women, which was this study's objective. Participants were postmenopausal women enrolled in the Osteoporosis and Periodontal Disease (OsteoPerio) study, an ancillary investigation of the Women's Health Initiative Observational Study (WHI‐OS) at the Buffalo, New York, clinical site. Participants self‐reported their history of physician diagnosed hypertension treated with medication at WHI‐OS enrollment (1993–1998; n = 1342, mean age 63 years), then 3 years later at OsteoPerio enrollment (1997–2001; n = 1342), and again at OsteoPerio Year 5 follow‐up (2002–2005; n = 1020). At each time point, medication inventories were recorded and served as the criterion with which self‐report was compared in the present study. Physician diagnosed‐treated hypertension was also self‐reported annually on mailed health update questionnaires in the WHI‐OS and were compared against medication inventory at the subsequent clinic exam. Of those participants who self‐reported a history of hypertension at WHI enrollment, OsteoPerio enrollment, and OsteoPerio Year 5 follow‐up, 41.2%, 90.3%, and 94.4%, respectively, had anti‐hypertensive pills in their medication inventory. Across the three time points, sensitivity and specificity ranged from 0.72 to 0.98 and from 0.85 to 0.95, and kappa coefficients ranged from 0.52 to 0.79 when comparing self‐report with medication inventory. For self‐reported newly physician‐diagnosed and treated hypertension on the annual health update questionnaire, 88.4% and 95.2% of those reporting hypertension had anti‐hypertensive pills in the subsequent medication inventory. In general, sensitivity and kappa were lower in women aged ≥70 versus

Abstract Background Obesity, and in particular abdominal obesity, is associated with an increased risk of developing a variety of chronic diseases. Obesity, aging, and menopause are each associated with differential shifts in the gut microbiome. Obesity causes chronic low-grade inflammation due to increased lipopolysaccharide (LPS) levels which is termed “metabolic endotoxemia.” We examined the association of visceral adiposity tissue (VAT) area, circulating endotoxemia markers, and the gut bacterial microbiome in a cohort of aged postmenopausal women. Methods Fifty postmenopausal women (mean age 78.8 ± 5.3 years) who had existing adipose measurements via dual x-ray absorptiometry (DXA) were selected from the extremes of VAT: n = 25 with low VAT area (45.6 ± 12.5 cm2) and n = 25 with high VAT area (177.5 ± 31.3 cm2). Dietary intake used to estimate the Healthy Eating Index (HEI) score was assessed with a food frequency questionnaire. Plasma LPS, LPS-binding protein (LBP), anti-LPS antibodies, anti-flagellin antibodies, and anti-lipoteichoic acid (LTA) antibodies were measured by ELISA. Metagenomic sequencing was performed on fecal DNA. Female C57BL/6 mice consuming a high-fat or low-fat diet were treated with 0.4 mg/kg diet-derived fecal isolated LPS modeling metabolic endotoxemia, and metabolic outcomes were measured after 6 weeks. Results Women in the high VAT group showed increased Proteobacteria abundance and a lower Firmicutes/Bacteroidetes ratio. Plasma LBP concentration was positively associated with VAT area. Plasma anti-LPS, anti-LTA, and anti-flagellin IgA antibodies were significantly correlated with adiposity measurements. Women with high VAT showed significantly elevated LPS-expressing bacteria compared to low VAT women. Gut bacterial species that showed significant associations with both adiposity and inflammation (anti-LPS IgA and LBP) were Proteobacteria (Escherichia coli, Shigella spp., and Klebsiella spp.) and Veillonella atypica. Healthy eating index (HEI) scores negatively correlated with % body fat and anti-LPS IgA antibodies levels. Preclinical murine model showed that high-fat diet-fed mice administered a low-fat diet fecal-derived LPS displayed reduced body weight, decreased % body fat, and improved glucose tolerance test parameters when compared with saline-injected or high-fat diet fecal-derived LPS-treated groups consuming a high-fat diet. Conclusions Increased VAT in postmenopausal women is associated with elevated gut Proteobacteria abundance and immunogenic metabolic endotoxemia markers. Low-fat diet-derived fecal-isolated LPS improved metabolic parameters in high-fat diet-fed mice giving mechanistic insights into potential pro-health signaling mediated by under-acylated LPS isoforms. Video Abstract

Extracellular vesicles (EVs) have emerged as potential biomarkers for diagnosing a range of diseases without invasive procedures. Extracellular vesicles also offer advantages compared to synthetic vesicles for delivery of various drugs; however, limitations in segregating EVs from other particles and soluble proteins have led to inconsistent EV retrieval rates with low levels of purity. Here, we report a new high-yield (88.47 %) and rapid (

Abstract Knowledge on the occurrence and behaviour of baleen whales around sub-Antarctic regions is limited, and usually based on short, seasonal sighting research from shore or research vessels and whaling records, neither of which provide accurate and comprehensive year-round perspectives of these animals’ ecology. We investigated the seasonal acoustic occurrence and diel vocalizing pattern of baleen whales around the sub-Antarctic Prince Edward Islands (PEIs) using passive acoustic monitoring data from mid-2021 to mid-2023, detecting six distinct baleen whale songs from Antarctic blue whales, Madagascan pygmy blue whales, fin whales, Antarctic minke whales, humpback whales, and sei whales. Antarctic blue and fin whales were detected year-round whereas the other species’ songs were detected seasonally, including a new Antarctic minke whale bio-duck song sub-type described here for the first time. Antarctic minke and sei whales were more vocally active at night-time whereas the other species had no clear diel vocalizing patterns. Random forest models identified month and/or sea surface temperature as the most important predictors of all baleen whale acoustic occurrence. These novel results highlight the PEIs as a useful habitat for baleen whales given the number of species that inhabit or transit through this region.

Abstract In the phase 3 Coronavirus Efficacy (COVE) trial (NCT04470427), post-dose two Ancestral Spike-specific binding (bAb) and neutralizing (nAb) antibodies were shown to be correlates of risk (CoR) and of protection against Ancestral-lineage COVID-19 in SARS-CoV-2 naive participants. In the SARS-CoV-2 Omicron era, Omicron subvariants with varying degrees of immune escape now dominate, seropositivity rates are high, and booster doses are administered, raising questions on whether and how these developments affect the bAb and nAb correlates. To address these questions, we assess post-boost BA.1 Spike-specific bAbs and nAbs as CoRs and as correlates of booster efficacy in COVE. For naive individuals, bAbs and nAbs inversely correlate with Omicron COVID-19: hazard ratios (HR) per 10-fold marker increase (95% confidence interval) are 0.16 (0.03, 0.79) and 0.31 (0.10, 0.96), respectively. In non-naive individuals the analogous results are similar: 0.15 (0.04, 0.63) and 0.28 (0.07, 1.08). For naive individuals, three vs two-dose booster efficacy correlates with predicted nAb titer at exposure, with estimates -8% (-126%, 48%), 50% (25%, 67%), and 74% (49%, 87%), at 56, 251, and 891 Arbitrary Units/ml. These results support the continued use of antibody as a surrogate endpoint.

Abstract The adhesion receptor vascular endothelial (VE)-cadherin transduces an array of signals that modulate crucial lymphatic cell behaviors including permeability and cytoskeletal remodeling. Consequently, VE-cadherin must interact with a multitude of intracellular proteins to exert these functions. Yet, the full protein interactome of VE-cadherin in endothelial cells remains a mystery. Here, we use proximity proteomics to illuminate how the VE-cadherin interactome changes during junctional reorganization from dis-continuous to continuous junctions, triggered by the lymphangiogenic factor adrenomedullin. These analyses identified interactors that reveal roles for ADP ribosylation factor 6 (ARF6) and the exocyst complex in VE-cadherin trafficking and recycling. We also identify a requisite role for VE-cadherin in the in vitro and in vivo control of secretion of reelin—a lymphangiocrine glycoprotein with recently appreciated roles in governing heart development and injury repair. This VE-cadherin protein interactome shines light on mechanisms that control adherens junction remodeling and secretion from lymphatic endothelial cells.

Abstract Background Motivation is the inherent belief to guide students learning goals and behaviors to make continuous efforts and strengthen learning outcomes. Previous research reported the positive impacts of learning motivation on student success, but there have been limited efforts in systematically and structurally studying different types of motivations and their impacts on students’ success in engineering education. The current study contributes to the literature by systematically examining two important types of motivations and their influences on undergraduate engineering students in a theoretically grounded manner while using an advanced analytical approach. Methods The current study conducted a cross-sectional survey with undergraduate engineering students (n = 514) from 18 different schools across nine U.S. states. The survey assessed students’ self-report scores on six types of motivations to study developed based on formative research and the current literature and then collected students’ self-reported learning outcomes, current GPA, university satisfaction, engineering program satisfaction, and individual demographic factors. The data were then analyzed using structural equation modeling. Results The results showed that motivations related to family, personality, and academic expectations were consistently positively associated with all measured students’ success outcomes; motivations related to educators were associated with all four outcomes but student GPA; motivations related to course contents were associated with learning outcomes and student GPA; and motivations related to peers did not predict any of the four measured students’ success outcomes. Discussion We explain some of the unexpected results with further literature that examines engineering culture and ecology. We also make recommendations related to cognitive training, tailored engineering education, peer culture interventions, and family orientation programs.

Abstract Placenta Accreta Spectrum (PAS) and pre-eclampsia are obstetric disorders associated with significant maternal morbidity and mortality. As pre-eclampsia is characterised by shallow placental invasion and PAS by abnormally deep invasion, we sought to compare the biological processes dysregulated in PAS to those reported in pre-eclampsia. We demonstrate that many of the processes contributing to unregulated placental invasion in PAS are the mirror findings of those previously reported in pre-eclampsia. These comparisons of PAS to a more common obstetric condition allow a greater understanding of the biological processes contributing to PAS, which remains a very rare obstetric complication.

Abstract Producers in the U.S., particularly small-scale farmers and specialty crop growers, are unable to maintain their livelihoods with farming alone. This issue is convoluted by low farm gate prices stemming from the unequal distribution of market share and political support within the U.S. food supply chain. As a result, many farm activists and scholars have recommended a revitalization of parity pricing within U.S. policy. Parity pricing once served to set price floors considered to represent “fair” farm gate prices determined by the farm gate price and purchasing power of commodities during the parity period of 1910–1914. In this paper, we evaluate whether parity did exist during the set period of 1910–1914, showing farm incomes and non-farm incomes were not significantly different from one another during the parity period. We then explore the extent to which parity prices correspond to farm-gate prices, transfer terminal prices, and retail prices for a select group of twelve specialty crops. We show that farm gate prices are significantly lower than parity prices, do not necessarily translate into low prices for consumers, and do not consistently correlate with production costs. Lastly, we display the temporal correspondence between the end of parity pricing and declines in farm income. Our analysis contributes important evidence of the inequalities within production, payment, and pricing structures of specialty crops in the U.S. As such, we provide a critique of parity pricing arguing that parity pricing alone will not be sufficient to solve the complex and deeply rooted issues underpinning low farm gate prices and injustices within the U.S. food system. We conclude with a discussion of the impacts of low farm gate prices and areas for policy interventions.

Abstract Background Ménière's disease (MD) is a disorder of the inner ear that causes episodic bouts of severe dizziness, roaring tinnitus, and fluctuating hearing loss. To date, no targeted therapy exists. As such, we have undertaken a large whole genome sequencing study on carefully phenotyped unilateral MD patients with the goal of gene/pathway discovery and a move towards targeted intervention. This study was a retrospective review of patients with a history of Ménière's disease. Genomic DNA, acquired from saliva samples, was purified and subjected to whole genome sequencing. Results Stringent variant calling, performed on 511 samples passing quality checks, followed by gene-based filtering by recurrence and proximity in molecular interaction networks, led to 481 high priority MD genes. These high priority genes, including MPHOSPH8, MYO18A, TRIOBP, OTOGL, TNC, and MYO6, were previously implicated in hearing loss, balance, and cochlear function, and were significantly enriched in common variant studies of hearing loss. Validation in an independent MD cohort confirmed 82 recurrent genes. Pathway analysis pointed to cell–cell adhesion, extracellular matrix, and cellular energy maintenance as key mediators of MD. Furthermore, the MD-prioritized genes were highly expressed in human inner ear hair cells and dark/vestibular cells, and were differentially expressed in a mouse model of hearing loss. Conclusion By enabling the development of model systems that may lead to targeted therapies and MD screening panels, the genes and variants identified in this study will inform diagnosis and treatment of MD.

Abstract The transforming growth factor-beta (TGF-β) signaling pathway is a vital regulator of cell proliferation, differentiation, apoptosis, and extracellular matrix production. It functions through canonical SMAD-mediated processes and noncanonical pathways involving MAPK cascades, PI3K/AKT, Rho-like GTPases, and NF-κB signaling. This intricate signaling system is finely tuned by interactions between canonical and noncanonical pathways and plays key roles in both physiologic and pathologic conditions including tissue homeostasis, fibrosis, and cancer progression. TGF-β signaling is known to have paradoxical actions. Under normal physiologic conditions, TGF-β signaling promotes cell quiescence and apoptosis, acting as a tumor suppressor. In contrast, in pathological states such as inflammation and cancer, it triggers processes that facilitate cancer progression and tissue remodeling, thus promoting tumor development and fibrosis. Here, we detail the role that TGF-β plays in cancer and fibrosis and highlight the potential for future theranostics targeting this pathway.

Abstract Background Pathogenic Leptospira species are globally important zoonotic pathogens capable of infecting a wide range of host species. In marine mammals, reports of Leptospira have predominantly been in pinnipeds, with isolated reports of infections in cetaceans. Case presentation On 28 June 2021, a 150.5 cm long female, short-beaked common dolphin (Delphinus delphis delphis) stranded alive on the coast of southern California and subsequently died. Gross necropsy revealed multifocal cortical pallor within the reniculi of the kidney, and lymphoplasmacytic tubulointerstitial nephritis was observed histologically. Immunohistochemistry confirmed Leptospira infection, and PCR followed by lfb1 gene amplicon sequencing suggested that the infecting organism was L. kirschneri. Leptospira DNA capture and enrichment allowed for whole-genome sequencing to be conducted. Phylogenetic analyses confirmed the causative agent was a previously undescribed, divergent lineage of L. kirschneri. Conclusions We report the first detection of pathogenic Leptospira in a short-beaked common dolphin, and the first detection in any cetacean in the northeastern Pacific Ocean. Renal lesions were consistent with leptospirosis in other host species, including marine mammals, and were the most significant lesions detected overall, suggesting leptospirosis as the likely cause of death. We identified the cause of the infection as L. kirschneri, a species detected only once before in a marine mammal – a northern elephant seal (Mirounga angustirostris) of the northeastern Pacific. These findings raise questions about the mechanism of transmission, given the obligate marine lifestyle of cetaceans (in contrast to pinnipeds, which spend time on land) and the commonly accepted view that Leptospira are quickly killed by salt water. They also raise important questions regarding the source of infection, and whether it arose from transmission among marine mammals or from terrestrial-to-marine spillover. Moving forward, surveillance and sampling must be expanded to better understand the extent to which Leptospira infections occur in the marine ecosystem and possible epidemiological linkages between and among marine and terrestrial host species. Generating Leptospira genomes from different host species will yield crucial information about possible transmission links, and our study highlights the power of new techniques such as DNA enrichment to illuminate the complex ecology of this important zoonotic pathogen.

Abstract This paper examines Russia’s propaganda discourse on Twitter during the 2022 invasion of Ukraine. The study employs network analysis, natural language processing (NLP) techniques, and qualitative analysis to identify key communities and narratives associated with the prevalent and damaging narrative of “fascism/Nazism” in discussions related to the invasion. The paper implements a methodological pipeline to identify the main topics, and influential actors, as well as to examine the most impactful messages in spreading this disinformation narrative. Overall, this research contributes to the understanding of propaganda dissemination on social media platforms and provides insights into the narratives and communities involved in spreading disinformation during the invasion.

Abstract Both cancer and fibrosis are diseases involving dysregulation of cell signaling pathways resulting in an altered cellular microenvironment which ultimately leads to progression of the condition. The two disease entities share common molecular pathophysiology and recent research has illuminated the how each promotes the other. Multiple imaging techniques have been developed to aid in the early and accurate diagnosis of each disease, and given the commonalities between the pathophysiology of the conditions, advances in imaging one disease have opened new avenues to study the other. Here, we detail the most up-to-date advances in imaging techniques for each disease and how they have crossed over to improve detection and monitoring of the other. We explore techniques in positron emission tomography (PET), magnetic resonance imaging (MRI), second generation harmonic Imaging (SGHI), ultrasound (US), radiomics, and artificial intelligence (AI). A new diagnostic imaging tool in PET/computed tomography (CT) is the use of radiolabeled fibroblast activation protein inhibitor (FAPI). SGHI uses high-frequency sound waves to penetrate deeper into the tissue, providing a more detailed view of the tumor microenvironment. Artificial intelligence with the aid of advanced deep learning (DL) algorithms has been highly effective in training computer systems to diagnose and classify neoplastic lesions in multiple organs. Ultimately, advancing imaging techniques in cancer and fibrosis can lead to significantly more timely and accurate diagnoses of both diseases resulting in better patient outcomes.

Abstract Background Sarcoptic mange is a skin disease caused by the contagious ectoparasite Sarcoptes scabiei, capable of suppressing and extirpating wild canid populations. Starting in 2015, we observed a multi-year epizootic of sarcoptic mange affecting a red fox (Vulpes vulpes) population on Fire Island, NY, USA. We explored the ecological factors that contributed to the spread of sarcoptic mange and characterized the epizootic in a landscape where red foxes are geographically constrained. Methods We tested for the presence of S. scabiei DNA in skin samples collected from deceased red foxes with lesions visibly consistent with sarcoptic mange disease. We deployed 96–100 remote trail camera stations each year to capture red fox occurrences and used generalized linear mixed-effects models to assess the affects of red fox ecology, human and other wildlife activity, and island geography on the frequency of detecting diseased red foxes. We rated the extent of visual lesions in diseased individuals and mapped the severity and variability of the sarcoptic mange disease. Results Skin samples that we analyzed demonstrated 99.8% similarity to S. scabiei sequences in GenBank. Our top-ranked model (weight = 0.94) showed that diseased red foxes were detected more frequently close to roadways, close to territories of other diseased red foxes, away from human shelters, and in areas with more mammal activity. There was no evidence that detection rates in humans and their dogs or distance to the nearest red fox den explained the detection rates of diseased red foxes. Although detected infrequently, we observed the most severe signs of sarcoptic mange at the periphery of residential villages. The spread of visual signs of the disease was approximately 7.3 ha/week in 2015 and 12.1 ha/week in 2017. Conclusions We quantified two separate outbreaks of sarcoptic mange disease that occurred > 40 km apart and were separated by a year. Sarcoptic mange revealed an unfettered spread across the red fox population. The transmission of S. scabiei mites in this system was likely driven by red fox behaviors and contact between individuals, in line with previous studies. Sarcoptic mange is likely an important contributor to red fox population dynamics within barrier island systems. Graphical Abstract

Abstract Background Identifying patient‐, facility‐, and environment‐level factors that influence the initiation and retention of comprehensive lifestyle management interventions (CLMI) for urban and rural Veterans could improve obesity treatment and reach at Veterans Affairs (VA) facilities. Aims This study identified factors at these various levels that predicted treatment engagement, retention, and weight management among urban and rural Veterans. Methods A retrospective cohort study of 631,325 Veterans was designed using VA databases to identify Veterans with class II and III obesity during 2015–2017. Primary outcomes were initiation of CLMI, bariatric surgery, or obesity pharmacotherapy within 1 year of index date. Secondary outcomes included treatment retention and successful weight loss. Generalized linear mixed models were used to evaluate the relationships between factors and obesity‐related outcomes, with rurality differences assessed through interaction terms. Results Patient characteristics associated with increased odds of initiating CLMI included female sex (p

ABSTRACT Background Weight stigma is the social devaluation and denigration of individuals because of their excess body weight, resulting in poorer physical and mental health and healthcare avoidance. Attribution Theory and Goffman's theory of spoiled identity provided a general overarching framework for understanding weight stigma experiences. Objective Our purpose was to explore weight stigma experiences from a broad range of perspectives emphasizing identities typically excluded in the weight stigma literature. Design We conducted a qualitative descriptive study with data drawn from 73 substantive narrative comments from participants who responded to a larger survey. Results Analysis developed five themes: Working on weight, Not being overweight, Lack of help and empathy, Exposure and embarrassment and Positive experiences. Individuals who would be clinically assessed as overweight, especially men, often did not identify with having a weight problem and found the framing of personal responsibility for weight empowering. Participants with larger body sizes more often attributed embarrassment and shame about weight to treatment in the clinical setting. Older participants were more likely to have positive experiences. Conclusions The findings suggest ongoing tension between the framing of weight as a personal responsibility as opposed to a multifactorial condition with many uncontrollable aspects. Gender, age and body size shaped respondent perspectives, with some young male respondents finding empowerment through perceived personal control of weight. The healthcare system perpetuates weight stigma through lack of adequate equipment and excessively weight‐centric medical counselling. Recommending a healthy lifestyle to patients without support or personalized medical assessment may perpetuate weight stigma and associated detrimental health outcomes. Patient or Public Contribution Patients with obesity and overweight were integral to this study, providing comments for our qualitative analyses.

Abstract Climate change is rapidly transforming the coastal margins of Greenland. At the same time, there is increasing recognition that marine‐terminating glaciers provide unique and critical habitats to ice‐associated top predators. We investigated the connection between a top predator occupying glacial fjord systems in Northwest Greenland and the properties of Atlantic‐origin water and marine‐terminating glaciers through a multiyear interdisciplinary project. Using passive acoustic monitoring, we quantified the summer presence and autumn departure of narwhals (Monodon monoceros) at glacier fronts in Melville Bay and modeled what glacier fjord physical attributes are associated with narwhal occurrence. We found that narwhals are present at glacier fronts after Greenland Ice Sheet peak summer runoff and they remain there during the period when the water column is becoming colder and fresher. Narwhals occupied glacier fronts when ocean temperatures ranged from −0.6 to 0.8°C and salinities between 33.2 and 34.0 psu at around 200 m depth and they departed on their southbound migration between October and November. Narwhals' departure was approximately 4 weeks later in 2019 than in 2018, after an extreme 2019 summer heatwave event that also delayed sea ice formation by 2 months. Our study provides further support for the niche conservative narwhal's preference for cold ocean temperatures. These results may inform projections about how future changes will impact narwhal subpopulations, especially those occupying Greenland glacial fjords.

BackgroundPeople with structural vulnerabilities (including immigrants, people who use drugs, and those who are unhoused or uninsured) are more likely to experience COVID-19 testing disparities relative to other groups. We documented barriers and facilitators to COVID-19 testing and explored how structural vulnerabilities created and/or exacerbated COVID-19 testing barriers.MethodsBetween 2021 and 2022, we conducted semi-structured interviews with 34 members of structurally vulnerable populations and 27 key informants who provide health and social services to them. Our abductive analysis was iterative, utilizing both inductive and deductive coding processes. Recognizing that adequate and appropriate testing for COVID-19 is a complex health behavior that involves both decision-making and issues related to access, we developed a hybrid model of COVID-19 testing behavior to organize reported barriers. We then used that model for more in-depth analysis of structural vulnerabilities in the context of testing.ResultsOur model of testing behaviors provides a framework for understanding the many barriers and facilitators relevant to COVID-19 testing. After identifying locally-reported barriers, we found that specific conditions—economic precarity, legal precarity, the confusing U.S. healthcare landscape, English-exclusive environments, and stigmatizing medical encounters—make adequate and appropriate testing less likely by making COVID-19 testing feel riskier (entailing legal, financial, and psycho-social risks) and making healthcare, and thus vicariously testing, more difficult to access.ConclusionThe COVID-19 pandemic exposed disparities in health care delivery. To avoid under-testing and its associated health consequences during the next pandemic, public health efforts should address structural conditions to ameliorate risks and bolster testing infrastructure to improve access.

Summary: Haploinsufficiency of JAG1 is the primary cause of Alagille syndrome (ALGS), a rare, multisystem disorder. The identification of JAG1 intronic variants outside of the canonical splice region as well as missense variants, both of which lead to uncertain associations with disease, confuses diagnostics. Strategies to determine whether these variants affect splicing include the study of patient RNA or minigene constructs, which are not always available or can be laborious to design, as well as the utilization of computational splice prediction tools. These tools, including SpliceAI and Pangolin, use algorithms to calculate the probability that a variant results in a splice alteration, expressed as a Δ score, with higher Δ scores (>0.2 on a 0–1 scale) positively correlated with aberrant splicing. We studied the consequence of 10 putative splice variants in ALGS patient samples through RNA analysis and compared this to SpliceAI and Pangolin predictions. We identified eight variants with aberrant splicing, seven of which had not been previously validated. Combining these data with non-canonical and missense splice variants reported in the literature, we identified a predictive threshold for SpliceAI and Pangolin with high sensitivity (Δ score >0.6). Moreover, we showed reduced specificity for variants with low Δ scores (

Abstract Root metaxylems are phenotypically diverse structures whose function is particularly important under drought stress. Significant research has dissected the genetic machinery underlying metaxylem phenotypes in dicots, but that of monocots are relatively underexplored. In maize (Zea mays), a robust pipeline integrated a genome‐wide association study (GWAS) of root metaxylem phenes under well‐watered and water‐stress conditions with a gene co‐expression network to prioritize the strongest gene candidates. We identified 244 candidate genes by GWAS, of which 103 reside in gene co‐expression modules most relevant to xylem development. Several candidate genes may be involved in biosynthetic processes related to the cell wall, hormone signaling, oxidative stress responses, and drought responses. Of those, six gene candidates were detected in multiple root metaxylem phenes in both well‐watered and water‐stress conditions. We posit that candidate genes that are more essential to network function based on gene co‐expression (i.e., hubs or bottlenecks) should be prioritized and classify 33 essential genes for further investigation. Our study demonstrates a new strategy for identifying promising gene candidates and presents several gene candidates that may enhance our understanding of vascular development and responses to drought in cereals.

OverviewThis study provides empirical data on the knowledge and practices of biosafety and biosecurity professionals and researchers involved in research on enhanced Potential Pandemic Pathogens (ePPPs) and Dual Use Research of Concern (DURC) within various U.S. sectors. The goal is to improve public health interventions and oversight for DURC and ePPP, contributing valuable insights for policy development. A notable finding was the association between larger biosafety/biosecurity teams and a higher likelihood of conducting high-risk biological research.MethodsA survey of 541 biosafety and biosecurity professionals was conducted between March 8 and 10 April 2024, with results analyzed using SAS at a significance level of 0.05. The study received approval from the Institutional Review Boards (IRBs) at Arizona State University and the University of Nevada, Reno.ResultsGovernment organizations were more likely to conduct DURC compared to other sectors (e.g., Academic, Commercial, Consulting). Public institutions reviewed more experiments outside the scope of the U.S. DURC Policy than private for-profit institutions. Institutions with larger biosafety/biosecurity teams reported greater research activity and more effective non-compliance reporting mechanisms (e.g., anonymous hotlines, reporting forms). Additionally, financial support and the challenges of policy implementation varied significantly across sectors.DiscussionThe findings emphasize the need for appropriate staffing and resource allocation for high-risk biosafety and biosecurity research. A differentiated regulatory approach and equitable distribution of resources are essential for effective oversight. Moreover, robust non-compliance reporting systems are critical to mitigating the risks associated with DURC and ePPP research.

IntroductionIn the setting of pediatric and adolescent young adult cancer, increased access to genomic profiling has enhanced the detection of genetic variation associated with cancer predisposition, including germline syndromic conditions. Noonan syndrome (NS) is associated with the germline RAS pathway activating alterations and increased risk of cancer. Herein, we describe our comprehensive molecular profiling approach, the association of NS with glioma and glioneuronal tumors, and the clinical and histopathologic characteristics associated with the disease.MethodsWithin an institutional pediatric cancer cohort (n = 314), molecular profiling comprised of paired somatic disease–germline comparator exome analysis, RNA sequencing, and tumor classification by DNA methylation analysis was performed.ResultsThrough the implementation of paired analysis, this study identified 4 of 314 (1.3%) individuals who harbored a germline PTPN11 variant associated with NS, of which 3 individuals were diagnosed with a glioma or glioneuronal tumor. Furthermore, we extend this study through collaboration with a peer institution to identify two additional individuals with NS and a glioma or glioneuronal tumor. Notably, in three of five (60%) individuals, paired genomic profiling led to a previously unrecognized diagnosis of Noonan syndrome despite an average age of cancer diagnosis of 16.8 years. The study of the disease-involved tissue identified signaling pathway dysregulation through somatic alteration of genes involved in cellular proliferation, survival, and differentiation.DiscussionComparative pathologic findings are presented to enable an in-depth examination of disease characteristics. This comprehensive analysis highlights the association of gliomas and glioneuronal tumors with RASopathies and the potential therapeutic challenges and importantly demonstrates the utility of genomic profiling for the identification of germline cancer predisposition.

Abstract We report a case of a 41‐year‐old woman who developed pregnancy‐associated pyoderma gangrenosum (PG) at 4 weeks gestation. She was initially treated with prednisone, however, due to lack of improvement and risk of systemic corticosteroids in pregnancy, underwent a prednisone taper and was initiated on certolizumab pegol (CZP). The patient experienced complete wound re‐epithelialization 1 month after CZP initiation. She had no pregnancy complications except for prednisone‐associated gestational diabetes and gave birth to a healthy baby. CZP is a tumour necrosis factor‐inhibitor with negligible placental transfer and no known adverse effects in pregnancy. Its efficacy and safety for autoinflammatory dermatoses in pregnancy are very promising. This is the first case to report CZP treatment for PG in a pregnant patient.

Abstract SLC22A10 is an orphan transporter with unknown substrates and function. The goal of this study is to elucidate its substrate specificity and functional characteristics. In contrast to orthologs from great apes, human SLC22A10, tagged with green fluorescent protein, is not expressed on the plasma membrane. Cells expressing great ape SLC22A10 orthologs exhibit significant accumulation of estradiol-17β-glucuronide, unlike those expressing human SLC22A10. Sequence alignments reveal a proline at position 220 in humans, which is a leucine in great apes. Replacing proline with leucine in SLC22A10-P220L restores plasma membrane localization and uptake function. Neanderthal and Denisovan genomes show proline at position 220, akin to modern humans, indicating functional loss during hominin evolution. Human SLC22A10 is a unitary pseudogene due to a fixed missense mutation, P220, while in great apes, its orthologs transport sex steroid conjugates. Characterizing SLC22A10 across species sheds light on its biological role, influencing organism development and steroid homeostasis.

Abstract Inflammation induced by lung infection is a double-edged sword, moderating both anti-viral and immune pathogenesis effects; the mechanism of the latter is not fully understood. Previous studies suggest the vasculature is involved in tissue injury. Here, we report that expression of Sparcl1, a secreted matricellular protein, is upregulated in pulmonary capillary endothelial cells (EC) during influenza-induced lung injury. Endothelial overexpression of SPARCL1 promotes detrimental lung inflammation, with SPARCL1 inducing ‘M1-like’ macrophages and related pro-inflammatory cytokines, while SPARCL1 deletion alleviates these effects. Mechanistically, SPARCL1 functions through TLR4 on macrophages in vitro, while TLR4 inhibition in vivo ameliorates excessive inflammation caused by endothelial Sparcl1 overexpression. Finally, SPARCL1 expression is increased in lung ECs from COVID-19 patients when compared with healthy donors, while fatal COVID-19 correlates with higher circulating SPARCL1 protein levels in the plasma. Our results thus implicate SPARCL1 as a potential prognosis biomarker for deadly COVID-19 pneumonia and as a therapeutic target for taming hyperinflammation in pneumonia.

Abstract Harnessing electronic excitations involving coherent coupling to bosonic modes is essential for the design and control of emergent phenomena in quantum materials. In situations where charge carriers induce a lattice distortion due to the electron-phonon interaction, the conducting states get “dressed", which leads to the formation of polaronic quasiparticles. The exploration of polaronic effects on low-energy excitations is in its infancy in two-dimensional materials. Here, we present the discovery of an interlayer plasmon polaron in heterostructures composed of graphene on top of single-layer WS2. By using micro-focused angle-resolved photoemission spectroscopy during in situ doping of the top graphene layer, we observe a strong quasiparticle peak accompanied by several carrier density-dependent shake-off replicas around the single-layer WS2 conduction band minimum. Our results are explained by an effective many-body model in terms of a coupling between single-layer WS2 conduction electrons and an interlayer plasmon mode. It is important to take into account the presence of such interlayer collective modes, as they have profound consequences for the electronic and optical properties of heterostructures that are routinely explored in many device architectures involving 2D transition metal dichalcogenides.

Abstract Background Gut dysbiosis has been linked with both HIV infection and diabetes, but its interplay with metabolic and inflammatory responses in diabetes, particularly in the context of HIV infection, remains unclear. Methods We first conducted a cross-sectional association analysis to characterize the gut microbial, circulating metabolite, and immune/inflammatory protein features associated with diabetes in up to 493 women (~ 146 with prevalent diabetes with 69.9% HIV +) of the Women’s Interagency HIV Study. Prospective analyses were then conducted to determine associations of identified metabolites with incident diabetes over 12 years of follow-up in 694 participants (391 women from WIHS and 303 men from the Multicenter AIDS Cohort Study; 166 incident cases were recorded) with and without HIV infection. Mediation analyses were conducted to explore whether gut bacteria–diabetes associations are explained by altered metabolites and proteins. Results Seven gut bacterial genera were identified to be associated with diabetes (FDR-q

Abstract Optimal treatment of infants with many renally cleared drugs must account for maturational differences in renal transporter (RT) activity. Pediatric physiologically‐based pharmacokinetic (PBPK) models may incorporate RT activity, but this requires ontogeny profiles for RT activity in children, especially neonates, to predict drug disposition. Therefore, RT expression measurements from human kidney postmortem cortical tissue samples were normalized to represent a fraction of mature RT activity. Using these data, maximum likelihood estimated the distributions of RT activity across the pediatric age spectrum, including preterm and term neonates. PBPK models of four RT substrates (acyclovir, ciprofloxacin, furosemide, and meropenem) were evaluated with and without ontogeny profiles using average fold error (AFE), absolute average fold error (AAFE), and proportion of observations within the 5–95% prediction interval. Novel maximum likelihood profiles estimated ontogeny distributions for the following RT: OAT1, OAT3, OCT2, P‐gp, URAT1, BCRP, MATE1, MRP2, MRP4, and MATE‐2 K. Profiles for OAT3, P‐gp, and MATE1 improved infant furosemide and neonate meropenem PBPK model AFE from 0.08 to 0.70 and 0.53 to 1.34 and model AAFE from 12.08 to 1.44 and 2.09 to 1.36, respectively, and improved the percent of data within the 5–95% prediction interval from 48% to 98% for neonatal ciprofloxacin simulations, respectively. Even after accounting for other critical population‐specific maturational differences, novel RT ontogeny profiles substantially improved neonatal PBPK model performance, providing validated estimates of maturational differences in RT activity for optimal dosing in children.

Abstract Endocrine therapy (ET) for breast cancer treatment is associated with cognitive complaints, but their etiology is poorly understood. To address this, we developed and implemented an ambulatory assessment protocol consisting of wearable activity monitors, brief surveys of affect, context, and perceived impairments, and ultra-brief performance-based measures of cognition. Newly diagnosed, ER/PR+, stage 0-III, female breast cancer patients, were recruited. Ambulatory assessments were conducted on smart phones and wearable activity monitors were used to monitor sleep and physical activity. Participants were asked to complete five 7-day measurement bursts (one before starting ET and one each month for 4 consecutive months while on ET). We observed a consent rate of 36%, 27 women completed the study. Of the women that withdrew, 91% dropped prior to the midpoint of follow up. There were no significant differences in demographics, clinical breast cancer characteristics, sleep or physical activity patterns, or measures of cognition between women who completed versus withdrew. Women who did not complete the study provided fewer valid days of baseline data. In conclusion, while some women may be overwhelmed with their cancer diagnosis, we did not identify any predictive characteristics of women whom did not complete the study. This novel method enables the prospective study of psychological changes associated with cancer treatment, capturing a wide array of information about behavior, experience, and cognition, thus providing a picture of the lived experiences of cancer patients before and during exposure to ET.

Abstract Free-text analysis using machine learning (ML)-based natural language processing (NLP) shows promise for diagnosing psychiatric conditions. Chat Generative Pre-trained Transformer (ChatGPT) has demonstrated preliminary initial feasibility for this purpose; however, whether it can accurately assess mental illness remains to be determined. This study evaluates the effectiveness of ChatGPT and the text-embedding-ada-002 (ADA) model in detecting post-traumatic stress disorder following childbirth (CB-PTSD), a maternal postpartum mental illness affecting millions of women annually, with no standard screening protocol. Using a sample of 1295 women who gave birth in the last six months and were 18+ years old, recruited through hospital announcements, social media, and professional organizations, we explore ChatGPT’s and ADA’s potential to screen for CB-PTSD by analyzing maternal childbirth narratives. The PTSD Checklist for DSM-5 (PCL-5; cutoff 31) was used to assess CB-PTSD. By developing an ML model that utilizes numerical vector representation of the ADA model, we identify CB-PTSD via narrative classification. Our model outperformed (F1 score: 0.81) ChatGPT and six previously published large text-embedding models trained on mental health or clinical domains data, suggesting that the ADA model can be harnessed to identify CB-PTSD. Our modeling approach could be generalized to assess other mental health disorders.

Abstract Staging amyloid-beta (Aβ) pathophysiology according to the intensity of neurodegeneration could identify individuals at risk for cognitive decline in Alzheimer’s disease (AD). In blood, phosphorylated tau (p-tau) associates with Aβ pathophysiology but an AD-type neurodegeneration biomarker has been lacking. In this multicenter study (n = 1076), we show that brain-derived tau (BD-tau) in blood increases according to concomitant Aβ (“A”) and neurodegeneration (“N”) abnormalities (determined using cerebrospinal fluid biomarkers); We used blood-based A/N biomarkers to profile the participants in this study; individuals with blood-based p-tau+/BD-tau+ profiles had the fastest cognitive decline and atrophy rates, irrespective of the baseline cognitive status. Furthermore, BD-tau showed no or much weaker correlations with age, renal function, other comorbidities/risk factors and self-identified race/ethnicity, compared with other blood biomarkers. Here we show that blood-based BD-tau is a biomarker for identifying Aβ-positive individuals at risk of short-term cognitive decline and atrophy, with implications for clinical trials and implementation of anti-Aβ therapies.

Abstract Plant biomass is a fundamental ecosystem attribute that is sensitive to rapid climatic changes occurring in the Arctic. Nevertheless, measuring plant biomass in the Arctic is logistically challenging and resource intensive. Lack of accessible field data hinders efforts to understand the amount, composition, distribution, and changes in plant biomass in these northern ecosystems. Here, we present The Arctic plant aboveground biomass synthesis dataset, which includes field measurements of lichen, bryophyte, herb, shrub, and/or tree aboveground biomass (g m−2) on 2,327 sample plots from 636 field sites in seven countries. We created the synthesis dataset by assembling and harmonizing 32 individual datasets. Aboveground biomass was primarily quantified by harvesting sample plots during mid- to late-summer, though tree and often tall shrub biomass were quantified using surveys and allometric models. Each biomass measurement is associated with metadata including sample date, location, method, data source, and other information. This unique dataset can be leveraged to monitor, map, and model plant biomass across the rapidly warming Arctic.

Abstract Collective attention and memory involving significant events can be quantitatively studied via social media data. Previous studies analyzed user attention to discrete events that do not change post-event, and assume universal public attention patterns. However, dynamic events with ongoing updates are common, yielding varied individual attention patterns. We explore memory of U.S. companies filing Chapter 11 bankruptcy and being mentioned on X (formerly Twitter). Unlike discrete events, Chapter 11 entails ongoing financial changes as the company typically remains operational, influencing post-event attention dynamics. We collected 248,936 X mentions for 74 companies before and after each bankruptcy. Attention surged after bankruptcy, with distinct Low and High persistence levels compared with pre-bankruptcy attention. The two tweeting patterns were modeled using biexponential models, successfully predicting (F1-score: 0.81) post-bankruptcy attention persistence. Studying bankruptcy events on social media reveals diverse attention patterns, demonstrates how pre-bankruptcy attention affects post-bankruptcy recollection, and provides insights into memory of dynamic events.

Abstract We performed a deep proteogenomic analysis of bulk tumor and laser microdissection enriched tumor cell populations from high-grade serous ovarian cancer (HGSOC) tissue specimens spanning a broad spectrum of purity. We identified patients with longer progression-free survival had increased immune-related signatures and validated proteins correlating with tumor-infiltrating lymphocytes in 65 tumors from an independent cohort of HGSOC patients, as well as with overall survival in an additional 126 HGSOC patient cohort. We identified that homologous recombination deficient (HRD) tumors are enriched in pathways associated with metabolism and oxidative phosphorylation that we validated in independent patient cohorts. We further identified that polycomb complex protein BMI-1 is elevated in HR proficient (HRP) tumors, that elevated BMI-1 correlates with poor overall survival in HRP but not HRD HGSOC patients, and that HRP HGSOC cells are uniquely sensitive to BMI-1 inhibition.

Abstract Background Recruiting large cohorts efficiently can speed the translation of findings into care across a range of scientific disciplines and medical specialties. Recruitment can be hampered by factors such as financial barriers, logistical concerns, and lack of resources for patients and clinicians. These and other challenges can lead to underrepresentation in groups such as rural residents and racial and ethnic minorities. Here we discuss the implementation of various recruitment strategies for enrolling participants into a large, prospective cohort study, assessing the need for adaptations and making them in real-time, while maintaining high adherence to the protocol and high participant satisfaction. Methods While conducting a large, prospective trial of a multi-cancer early detection blood test at Geisinger, an integrated health system in central Pennsylvania, we monitored recruitment progress, adherence to the protocol, and participants’ satisfaction. Tracking mechanisms such as paper records, electronic health records, research databases, dashboards, and electronic files were utilized to measure each outcome. We then reviewed study procedures and timelines to list the implementation strategies that were used to address barriers to recruitment, protocol adherence and participant satisfaction. Results Adaptations to methods that contributed to achieving the enrollment goal included offering multiple recruitment options, adopting group consenting, improving visit convenience, increasing the use of electronic capture and the tracking of data and source documents, staffing optimization via leveraging resources external to the study team when appropriate, and integrating the disclosure of study results into routine clinical care without adding unfunded work for clinicians. We maintained high protocol adherence and positive participant experience as exhibited by a very low rate of protocol deviations and participant complaints. Conclusion Recruiting rapidly for large studies – and thereby facilitating clinical translation – requires a nimble, creative approach that marshals available resources and changes course according to data. Planning a rigorous assessment of a study’s implementation outcomes prior to study recruitment can further ground study adaptations and facilitate translation into practice. This can be accomplished by proactively and continuously assessing and revising implementation strategies.

Abstract Porphyromonas gingivalis, a Gram-negative anaerobic bacterium commonly found in human subgingival plaque, is a major etiologic agent for periodontitis and has been associated with multiple systemic pathologies. Many P. gingivalis strains have been identified and different strains possess different virulence factors. Current oral microbiome approaches (16S or shotgun) have been unable to differentiate P. gingivalis strains. This study presents a new approach that aims to improve the accuracy of strain identification, using a detection method based on sequencing of the intergenic spacer region (ISR) which is variable between P. gingivalis strains. Our approach uses two-step PCR to amplify only the P. gingivalis ISR region. Samples are then sequenced with an Illumina sequencer and mapped to specific strains. Our approach was validated by examining subgingival plaque from 153 participants with and without periodontal disease. We identified the avirulent strain ATCC33277/381 as the most abundant strain across all sample types. The W83/W50 strain was significantly enriched in periodontitis, with 13% of participants harboring that strain. Overall, this approach can have significant implications not only for the diagnosis and treatment of periodontal disease but also for other diseases where P. gingivalis or its toxins have been implicated, such as Alzheimer's disease.

Abstract In the ENSEMBLE randomized, placebo-controlled phase 3 trial (NCT04505722), estimated single-dose Ad26.COV2.S vaccine efficacy (VE) was 56% against moderate to severe–critical COVID-19. SARS-CoV-2 Spike sequences were determined from 484 vaccine and 1,067 placebo recipients who acquired COVID-19. In this set of prespecified analyses, we show that in Latin America, VE was significantly lower against Lambda vs. Reference and against Lambda vs. non-Lambda [family-wise error rate (FWER) p

Abstract Background Peer review is essential to the advancement of knowledge. However, training on how to conduct peer review is limited, unorganized, and not well studied. Thus, we sought to determine if a structured mentored peer-review program improved peer review training as measured by multiple quantitative and qualitative assessments. Methods This pre-post intervention study enrolled 55 mentees across 5 cohorts from 2020 to 2023. Each cohort completed pre-program evaluations, participated in 2 mentored reviews, and completed post-program evaluations over 6 months. Mentors and mentees completed pre-program demographic and review experience questionnaires. Outcome measures included (1) total and sub-scores on the modified Review Quality Index (mRQI) applied to the same pre-selected research manuscript reviewed by mentees both pre and post intervention, (2) mentee self-perceived comfort with and understanding of the review process using a custom questionnaire, and (3) mentor satisfaction surveys. Pre- and post-program measures were compared using the Wilcoxon signed-rank test. Results Post-program total modified RQI score (median (IQR) = 31 (26.3–35.8)) was higher than pre-program total score (26.6 (19.7–29.7)) for the 42 mentees who completed both pre- and post-program reviews. Mentees reported improved perception of review (median (IQR) pre = 4 (3–4), post = 5 (4–5)) and editorial processes (pre = 3 (2–4), post = 4 (4–5)) as well as self-perceived confidence in completing an independent review of both scientific (median (IQR) pre = 2 (2–3), post = 4 (4–4)) and non-scientific (pre = 3 (2–4), post = 4 (4–5)) manuscripts following program participation. p

Introduction: Only 53% of American adults receive influenza vaccination, and disparities in vaccination exist among particular racial and ethnic groups. This study determines how race, ethnicity, sex, and rurality are associated with influenza vaccination adherence in a national Veteran Health Affairs Administration cohort. Methods: The authors examined differences in documented influenza vaccinations for the 2019–2020 influenza season among Veteran Health Affairs Administration patients in a retrospective cohort study using Veteran Health Affairs Administration administrative electronic health record data. The author used logistic regression to model receipt of influenza vaccination in association with race, ethnicity, sex, and rurality while controlling for clinical diagnoses, demographics, and ambulatory care utilization. The authors also stratified the models by sex and rurality. Results: Among 5,943,918 veterans, 48.6% received influenza vaccination. Unadjusted comparisons showed that those who were vaccinated were more likely to be White, to be of male sex, and to be older. Similar proportions of unvaccinated and unvaccinated veterans were from rural settings. In adjusted models, Black race was most strongly associated with decreased vaccination (AOR=0.69; 95% CI=0.69, 0.70), and American Indian/Alaskan Native race also had reduced odds of vaccination (AOR=0.94; 95% CI=0.92, 0.95) compared with White race. Female veterans had increased odds of vaccination (AOR=1.20; 95% CI=1.19, 1.20) compared with men. Rurality (AOR=0.97; 95% CI=0.96, 0.97) was associated with a small decreased odds of vaccination compared with urban. In stratified models, Black veterans were less likely to receive influenza vaccination regardless of sex and rurality than White veterans. American Indian/Alaska Native female veterans had equal odds of vaccination as White female veterans, whereas American Indian/Alaska Native male veterans had reduced odds of vaccination compared with White male veterans. Conclusions: During the 2019–2020 influenza season, Black and American Indian/Alaskan Native veterans had lower odds of vaccination. Despite the Veteran Health Affairs Administration's universal approach to healthcare, racial disparities still exist in preventive care.

Vaccine safety and immunogenicity data in human immunodeficiency virus (HIV)-exposed uninfected (HEU) children are important for decision-making in HIV and typhoid co-endemic countries. In an open-label study, we recruited Malawian HEU and HIV unexposed uninfected (HUU) infants aged 9 – 11 months. HEU participants were randomized to receive Vi-tetanus toxoid conjugate vaccine (Vi-TT) at 9 months, Vi-TT at 15 months, or Vi-TT at 9 and 15 months. HUU participants received Vi-TT at 9 and 15 months. Safety outcomes included solicited and unsolicited adverse events (AE) and serious AEs (SAEs) within 7 days, 28 days, and 6 months of vaccination, respectively. Serum was collected before and at day 28 after each vaccination to measure anti-Vi IgG antibodies by enzyme-linked immunosorbent assay (ELISA). Cohort 1 (66 participants) enrollment began 02 December 2019, and follow-up was terminated before completion due to the COVID-19 pandemic. Cohort 2 (100 participants) enrollment began 25 March 2020. Solicited AEs were mostly mild, with no significant differences between HEU and HUU participants or one- and two-dose groups. All six SAEs were unrelated to vaccination. Anti-Vi geometric mean titers (GMT) increased significantly from 4.1 to 4.6 ELISA units (EU)/mL at baseline to 2572.0 – 4117.6 EU/mL on day 28 post-vaccination, and similarly between HEU and HUU participants for both one- and two-dose schedules. All participants seroconverted (>4-fold increase in GMT) by the final study visit. Our findings of comparable safety and immunogenicity of Vi-TT in HUU and HEU children support country introductions with single-dose Vi-TT in HIV-endemic countries.

As society grapples with the emerging significance and implications of Large Language Models (LLMs), such as OpenAI’s ChatGPT, or Google’s Gemini, as well as other advancements in modern generative Artificial Intelligence (AI), it is crucial to recognize the existing role that data, algorithms, and online social networks have already played in shaping our contemporary society. This review article provides the first comprehensive examination of the current state of knowledge, across disciplinary divides, on how online influences impact offline behaviors, laying the necessary groundwork for investigating and researching the potential impact that these new technologies will have on our “offline” lives. Through a deep-dive collection of articles (n=149), we review and analyze research with measurable Online-to-Offline impacts (n=88). Within this Online-to-Offline criteria, we identify five emergent cross-cutting themes, namely: Social Diffusion, Social Reinforcement, Social Boundary & Identity Maintenance, Cognitive and Attitudinal Research, and Research on Vulnerable & Marginalized Impacts. Through a second wave snowball collection process, we construct a citation network from the broader Online and Offline research literature, allowing us to locate the Online-to-Offline subset as part of a larger intellectual discussion. Finally, we conduct a Term Frequency-Inverse Document Frequency (TF-IDF) analysis of terms used in the titles of these online/offline research papers, from 1990 to 2023, to identify the evolution of researchers’ conceptualization and framing of Online and Offline research across the past 30 years. The meta-review, presentation of high-level cross-cutting interdisciplinary themes, co-citation network analysis, and TF-IDF analysis collectively provide a cohesive and deeper understanding of the research space of online/offline influences. By taking stock of the ways in which online factors have already shaped individual, group, or organizational behaviors and social dynamics broadly in “offline” contexts, this work aims to provide a cohesive theoretical and empirical foundation for future researchers to better anticipate, address, and frame the future consequences of the rapidly evolving digitally influenced landscape we find ourselves in today.

A maternal vaccine and long-acting monoclonal antibody (mAb) were recently approved to protect infants against respiratory syncytial virus (RSV). We identified subgroups of pregnant people with different preferences for RSV preventives and respondent characteristics associated with subgroup membership. An online survey, including a discrete choice experiment (DCE), was conducted among US pregnant people. RSV preventive attributes included effectiveness, duration of protection during RSV season, injection recipient/timing, preventive type (vaccine or mAb), and type of visit required to receive injection. In DCE choice tasks, pregnant people selected between two hypothetical preventive profiles with varying attribute-levels and a no-preventive option. Logistic regression, including latent class analysis (LCA), was used to analyze the data. Of 992 pregnant people (mean age: 30.0 years), 60.3% were expecting their second/later birth. LCA identified three preference subgroups: ‘Effectiveness’ (preventive choice mostly driven by increases in effectiveness; 51.4% class membership probability), ‘Season’ (preventive choice mostly driven by improvement in duration of protection during the RSV season; 39.2% class membership probability), and ‘No Preventive’ (frequently chose no-preventive option; 9.4% class membership probability). ‘Effectiveness’ and ‘Season’ preferred maternal vaccine over mAb; mAb was preferred by ‘No Preventive.’ Perceiving RSV as serious for infants, higher health literacy, and lower household income were associated with ‘Effectiveness.’ Perceiving RSV as serious for pregnant people was associated with ‘Season.’ Perceiving RSV to not be serious for pregnant people and not being employed were associated with ‘No Preventive.’ Subgroups of pregnant people vary in preferences for RSV preventives. Most pregnant people preferred a maternal vaccine, although some may be more willing to accept alternative preventive options.

Background: Symptom accommodation by family members (FMs) of individuals with posttraumatic stress disorder (PTSD) includes FMs’ participation in patients’ avoidance/safety behaviours and constraining self-expression to minimise conflict, potentially maintaining patients’ symptoms. The Significant Others’ Responses to Trauma Scale (SORTS) is the only existing measure of accommodation in PTSD but has not been rigorously psychometrically tested.Objective: We aimed to conduct further psychometric analyses to determine the factor structure and overall performance of the SORTS. Method: We conducted exploratory and confirmatory factor analyses using a sample of N = 715 FMs (85.7% female, 62.1% White, 86.7% romantic partners of individuals with elevated PTSD symptoms).Results: After dropping cross-loading items, results indicated good fit for a higher-order model of accommodation with two factors: an anger-related accommodation factor encompassed items related largely to minimising conflict, and an anxiety-related accommodation factor encompassed items related primarily to changes to the FM’s activities. Accommodation was positively related to PTSD severity and negatively related to relationship satisfaction, although the factors showed somewhat distinct associations. Item Response Theory analyses indicated that the scale provided good information and robust coverage of different accommodation levels.Conclusions: SORTS data should be analysed as both a single score as well as two factors to explore the factors’ potential differential performance across treatment and relationship outcomes.

AbstractBackground/Objectives There is a great unmet need for accessible adjunctive interventions to promote long-term recovery from substance use disorder (SUD). This study aimed to iteratively develop and test the initial feasibility and acceptability of Mindful Journey, a novel digital mindfulness-based intervention for promoting recovery among individuals with SUD.Patients/Materials Ten adults receiving outpatient treatment for SUD.Methods Phase 1 (n = 5) involved developing and testing a single introductory digital lesson. Phase 2 included a separate sample (n = 5) and involved testing all 15 digital lessons (each 30- to 45-minutes) over a 6-week period, while also receiving weekly brief phone coaching for motivational/technical support.Results Across both phases, quantitative ratings (rated on a 5-point scale) were all at or above a 4 (corresponding with ‘agree’) for key acceptability dimensions, such as usability, understandability, appeal of visual content, how engaging the content was, and helpfulness for recovery. Additionally, in both phases, qualitative feedback indicated that participants particularly appreciated the BOAT (Breath, Observe, Accept, Take a Moment) tool for breaking down mindfulness into steps. Qualitative feedback was used to iteratively refine the intervention. For example, based on feedback, we added a second core mindfulness tool, the SOAK (Stop, Observe, Appreciate, Keep Curious), and we added more example clients and group therapy videos. In Phase 2, 4 out of 5 participants completed all 15 lessons, providing initial evidence of feasibility. Participants reported that the phone coaching motivated them to use the app. The final version of Mindful Journey was a smartphone app with additional features, including brief on-the-go audio exercises and a library of mindfulness practices. Although, participants used these additional features infrequently.Conclusions Based on promising initial findings, future acceptability and feasibility testing in a larger sample is warranted. Future versions might include push notifications to facilitate engagement in the additional app features.

Abstract Understanding the mechanisms underlying viable seed production of perennial bunchgrasses is critical to improving restoration and conservation success in Great Basin sagebrush steppe rangelands. We studied the effects of pre‐ and post‐anthesis flag‐leaf removal and post‐anthesis seed‐head shading on reproductive effort in two important rangeland restoration species, the exotic crested wheatgrass (Agropyron cristatum) and native squirreltail (Elymus elymoides). Flag‐leaf removal had distinct, species‐specific effects on seed filling. Pre‐anthesis flag‐leaf removal in crested wheatgrass reduced the proportion of filled seeds, while post‐anthesis removal did not. In contrast, squirreltail increased filled seed proportions regardless of flag‐leaf removal timing. Neither flag‐leaf removal treatment affected seed quality, as quantified by seed‐specific mass (in grams per square meter), which significantly reduced with seed‐head shading in both species. Seed‐head shading reduced total propagule production (unfilled + filled seeds) in crested wheatgrass but increased it in squirreltail, possibly due to our shading method protecting from seed‐head herbivory or high‐light stress. Flag‐leaf removal in the squirreltail also induced a negative shading effect on filled seed area, mass, and specific mass. These findings suggest flag leaves can modulate reproductive effort outside of seed provisioning, either by maintaining pre‐fertilized seed viability, as in crested wheatgrass, or acting as a competitive sink to the fully emerged seed‐head, as in squirreltail. Moreover, this study demonstrates photosynthetic activity by the seed‐head itself is critical to the expression of seed quality traits important to seedling establishment success of semiarid perennial bunchgrasses.

Environmental enrichment combined with the glycine transporter-1 inhibitor Org24598 (EE+ORG) during cocaine-cue extinction (EXT) inhibited reacquisition of 1.0 mg/kg cocaine self-administration in male but not female rats in a previous investigation. In this investigation, we determined if this treatment benefit in males required EXT training and ascertained the molecular basis for the observed sex difference in treatment efficacy. Nine groups of male rats trained to self-administer 1.0 mg/kg cocaine or receiving yoked-saline underwent EXT or NoEXT with or without EE and/or ORG. Next, they underwent reacquisition of cocaine self-administration or were sacrificed for molecular analysis of 9 protein targets indicative of neuroplasticity in four brain regions. Two groups of female rats trained to self-administer 1.0 mg/kg cocaine also underwent EXT with or without EE + ORG and were sacrificed for molecular analysis, as above. EE + ORG facilitated the rate of EXT learning in both sexes, and importantly, the therapeutic benefit of EE + ORG for inhibiting cocaine relapse required EXT training. Males were more sensitive than females to neuroplasticity-inducing effects of EE + ORG, which prevented reductions in total GluA1 and PSD95 proteins selectively in basolateral amygdala of male rats trained to self-administer cocaine and receiving EXT. Females were deficient in expression of multiple protein targets, especially after EE + ORG. These included total GluA1 and PSD95 proteins in basolateral amygdala, and total TrkB protein in basolateral amygdala, dorsal hippocampus, and ventromedial prefrontal cortex. Together, these results support the clinical view that sex-specific pharmacological and behavioral treatment approaches may be needed during cue exposure therapy to inhibit cocaine relapse.

The van der Waals material hexagonal boron nitride (hBN) has emerged as a promising candidate for hosting room temperature single-photon emitters (SPEs) for next-generation quantum technologies. However, the requirement of a high temperature anneal (850 °C or higher) to activate the SPEs in hBN makes it difficult to integrate into hybrid structures that cannot tolerate such temperatures, including all silicon-based circuits. In this work, we present a method to deterministically activate quantum emitters in multilayered hBN on a process substrate, followed by a zero thermal budget transfer to a target substrate. This technique does not lead to any degradation or loss of photon purity in the hBN emitters and provides a procedure for combining high-purity emitters with other exciting photonic, magnetic, or electrical properties to explore new physical phenomena. The ability to transfer hBN emitters onto arbitrary substrates creates new technological possibilities to incorporate these quantum photonic properties into photonic integrated circuits and plasmonic devices.

Abstract Trade‐offs are crucial for species divergence and reproductive isolation. Trade‐offs between investment in growth versus defense against herbivores are implicated in tropical forest diversity. Empirically exploring the role of growth–defense trade‐offs in closely related species' reproductive isolation can clarify the eco‐evolutionary dynamics through which growth–defense trade‐offs contribute to diversity. Costus villosissimus and C. allenii are recently diverged, interfertile, and partially sympatric neotropical understory plant species primarily isolated by divergent habitat adaptation. This divergent adaptation involves differences in growth rate, which may constrain investment in defense. Here, we investigate growth–defense trade‐offs and how they relate to the divergent habitat adaptation that isolates these species. We characterize leaf toughness and chemistry, evaluate the feeding preferences of primary beetle herbivores in controlled trials and field‐based experiments, and investigate natural herbivory patterns. We find clear trade‐offs between growth and defense: slower‐growing C. allenii has tougher leaves and higher defensive chemical concentrations than faster‐growing C. villosissimus. Costus villosissimus has rapid growth‐based drought avoidance, enabling growth in drier habitats with few specialist herbivores. Therefore, growth–defense trade‐offs mediate synergistic biotic and abiotic selection, causing the divergent habitat adaptation that prevents most interspecific mating between C. villosissimus and C. allenii. Our findings advance understanding of ecological speciation by highlighting the interplay of biotic and abiotic selection that dictates the outcome of trade‐offs.