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Abstract Purpose Loddo et al. (Br J Cancer 100:959–70, 2009) established the prognostic significance of cell cycle markers and "Cell-Cycle Phenotypes" in breast carcinoma. This study aims to 1) identify prognostic cell-cycle markers in sarcoma, and 2) assess the prognostic potential of specific cell-cycle phenotypes in sarcoma. Methods Tissue samples from 128 soft tissue sarcomas were stained for four cell cycle-specific markers: Mcm2, Geminin, Plk1, and H3S10ph. Only primary soft tissue tumors (liposarcoma, leiomyosarcoma, synovial sarcoma, and undifferentiated pleomorphic sarcoma) were included in the analysis. Any tumor coming from a recurrent or metastatic lesion were excluded from the analysis. Three cell-cycle phenotypes (I, II, III) were derived from marker expression patterns. Prognostic significance was evaluated in a subset of primary soft tissue sarcomas using Cox regression for survival analysis. Results Compared to phenotype I, the phenotype III tumors had a decreased 5-year overall survival (HR 6.81 [2.36–19.61]; p =

Abstract Sarcopenia is the age-related loss of skeletal muscle mass and function. Computed tomography (CT) assessments of sarcopenia utilize measurements of skeletal muscle cross-sectional area (SMA), radiation attenuation (SMRA), and intramuscular adipose tissue (IMAT). Unadjusted SMA is strongly correlated with both height and body mass index (BMI); therefore, SMA must be adjusted for body size to assess sarcopenic low muscle mass fairly in individuals of different heights and BMI. SMA/height (rather than $$SMA/height^2$$ S M A / h e i g h t 2 ) provides optimal height adjustment, and vertebra-specific relative muscle index (RMI) equations optimally adjust for both height and BMI. Since L3 measurement is not available in all CT scans, sarcopenic low muscle mass may be assessed using other levels. Both a mid-vertebral slice and an inferior slice have been used to define ‘L3 SMA’, but the effect of vertebral slice location on SMA measurements is unexplored. Healthy reference values for skeletal muscle measures at mid- and inferior vertebra slices between T10 and L5, have not yet been reported. We extracted T10 through L5 SMA, SMRA, and IMAT at a mid-vertebral and inferior slice using non-contrast-enhanced CT scans from healthy, adult kidney donor candidates between age 18 and 73. We compared paired differences in SMA between the mid-vertebral slice versus the inferior slice. We calculated the skeletal muscle gauge as $$SMG_{HT}=SMRA*SMI_{HT}$$ S M G HT = S M R A ∗ S M I HT . We used allometric analysis to find the optimal height scaling power for SMA. To enable comparisons with other published reference cohorts, we computed two height-adjusted measures; $$SMI_{HT}=SMA/height$$ S M I HT = S M A / h e i g h t (optimal) and $$SMI_{HT2}=SMA/height^2$$ S M I H T 2 = S M A / h e i g h t 2 (traditional). Using the young, healthy reference cohort, we utilized multiple linear regression to calculate relative muscle index z-scores ( $$RMI_{HT}$$ R M I HT , $$RMI_{HT2}$$ R M I H T 2 ), which adjust for both height and BMI, at each vertebra level. We assessed Pearson correlations of each muscle area measure versus age, height, weight, and BMI separately by sex and vertebra number. We assessed the differences in means between age 18–40 versus 20–40 as the healthy, young adult reference group. We reported means, standard deviations, and sarcopenia cutpoints (mean-2SD and 5th percentile) by sex and age group for all measures. Sex-specific allometric analysis showed that height to the power of one was the optimal adjustment for SMA in both men and women at all vertebra levels. Differences between mid-vertebra and inferior slice SMA were statistically significant at each vertebra level, except for T10 in men. $$SMI_{HT}$$ S M I HT was uncorrelated with height, whereas $$SMI_{HT2}$$ S M I H T 2 was negatively correlated with height at all vertebra levels. Both $$SMI_{HT}$$ S M I HT and $$SMI_{HT2}$$ S M I H T 2 were positively correlated with BMI at all vertebra levels. $$RMI_{HT}$$ R M I HT was uncorrelated with BMI, weight, and height (minimal positive correlation in women at $$\hbox {L3}_{inf}$$ L3 inf , $$\hbox {L4}_{mid}$$ L4 mid , and $$\hbox {L5}_{inf}$$ L5 inf ) whereas $$RMI_{HT2}$$ R M I H T 2 was uncorrelated with BMI, but negatively correlated with height and weight at all levels. There were no significant differences in SMA between 18–40 versus 20–40 age groups. Healthy reference values and sarcopenic cutpoints are reported stratified by sex, vertebra level, and age group for each measure. Height to the power of one (SMA/height) is the optimal height adjustment factor for SMA at all levels between $$\hbox {T10}_{mid}$$ T10 mid through $$\hbox {L5}_{inf}$$ L5 inf . The use of $$SMA/height^2$$ S M A / h e i g h t 2 should be discontinued as it retains a significant negative correlation with height and is therefore biased towards identifying sarcopenia in taller individuals. Measurement of SMA at a mid-vertebral slice is significantly different from measurement of SMA at an inferior aspect slice. Reference values should be used for the appropriate slice. We report sarcopenic healthy reference values for skeletal muscle measures at the mid-vertebral and inferior aspect slice for T10 through L5 vertebra levels. Relative muscle index (RMI) equations developed here minimize correlation with both height and BMI, producing unbiased assessments of relative muscle mass across the full range of body sizes. We recommend the use of these RMI equations in other cohorts.

Abstract Background Orthopedic procedures often require removing bone or pathological tissue, with traditional methods involving instruments like curettes and rongeurs. However, these methods can be time-consuming and lead to increased blood loss. To mitigate these side effects, vacuum-assisted tools have been developed to aid in tissue removal. These devices enable surgeons to suction tissue without discarding it, potentially improving outcomes in conditions such as osteomyelitis or tumor removal while enabling collection of the material for downstream applications. Despite limited research, vacuum-assisted devices show promise beyond bone marrow harvesting. This study assesses infection and clearance rates, estimated blood loss, and total procedure time associated with the use of vacuum-assisted tissue removal, with a goal to understand if these devices can be used for tissue removal across a variety of pathologic conditions. Methods A retrospective cohort study was conducted on patients undergoing orthopedic procedures with the Avitus® Bone Harvester repurposed from its original design from December 1, 2021, to July 1, 2023. Procedures were categorized into oncology, and debridement for infection cases. Infection cases were further categorized into those secondary to trauma and those involving primary infections (osteomyelitis and periprosthetic joint infection). Clinical variables, including demographics, intraoperative details, complications, and follow-up, were reviewed. Statistical analysis included descriptive statistics computed with R Studio. Results The study included 44 patients, with debridement for infection cases being the most common (primary infection: 45.5%; infection secondary to trauma: 18.1%), followed by oncology cases (36.4%). In all oncology cases, a definitive diagnosis was established using the device, and no post-operative infections were reported. The infection clearance rate was 85.0% for primary infection cases and 50.0% for cases of infection following trauma. Across the entire cohort, the average blood loss was 314.52 mL (sd: 486.74), and the average total procedure time was 160.93 min (sd: 91.07). The overall reoperation rate was 47.7%, with an unplanned reoperation rate of 11.4%. Conclusion The vacuum-assisted bone harvester was effectively utilized in a wide range of debridement and curettage procedures across diverse orthopedic surgeries. In oncology cases, the device enabled effective tissue removal with comparable recurrence rates, demonstrating its potential to minimize contamination while preserving tissue for accurate diagnoses. Additionally, a high rate of osteomyelitis eradication was observed in debridement for primary infection cases (85%). Despite the relatively high reoperation rate of 47.7%, it is crucial to interpret this figure within the context of the varied reasons for reoperation. Many of these reoperations were planned as part of a staged approach to treatment or were unrelated to the device's performance. It is crucial to acknowledge that isolating the device's contribution to these results can be difficult. The utilization of the device should be guided by considerations of cost-effectiveness and patient-specific risk factors.

Abstract Background Track PCC includes five geographic surveillance sites to conduct standardized population-based surveillance to estimate and track Post-COVID Conditions (PCC) by age, sex, race/ethnicity, geographic area, severity of initial infection, and risk factors among persons with evidence of SARS-CoV-2 infection (based on the Council of State and Territorial Epidemiologist [CSTE] case definitions for confirmed cases or laboratory-confirmed evidence of infection). Methods The study will estimate the incidence, prevalence, including temporal trends, and duration and severity of PCC symptoms, among children, adolescents, and adults. PCCs include a broad range of symptoms and conditions that continue or develop after acute SARS-CoV-2 infection or COVID-19 illness. Surveillance includes both passive and active components for diverse populations in Arizona, Indiana, and Utah as well as the Bronx Borough, NY, and part of Philadelphia County, PA. Passive surveillance will utilize electronic health records and health information exchanges within each site catchment area to longitudinally follow persons with COVID-19 to estimate PCC occurring at least 30 days after acute COVID-19 illness. Active surveillance will utilize self-report of PCCs from detailed surveys of persons ages 7 years and older with evidence of SARS-CoV-2 infection in the past 3 months. Respondents will complete follow-up surveys at 6-, 12- and 18-months post-infection. Discussion These data can help identify which groups are most affected by PCC, and what health differences among demographic groups exist, as well as indicate potential barriers to care. These additional levels of granularity can inform public health action and help direct needed clinical care for patients.

Abstract Many neurotransmitter receptors activate G proteins through exchange of GDP for GTP. The intermediate nucleotide-free state has eluded characterization, due largely to its inherent instability. Here we characterize a G protein variant associated with a rare neurological disorder in humans. Gαo K46E has a charge reversal that clashes with the phosphate groups of GDP and GTP. As anticipated, the purified protein binds poorly to guanine nucleotides yet retains wild-type affinity for G protein βγ subunits. In cells with physiological concentrations of nucleotide, Gαo K46E forms a stable complex with receptors and Gβγ, impeding effector activation. Further, we demonstrate that the mutant can be easily purified in complex with dopamine-bound D2 receptors, and use cryo-electron microscopy to determine the structure, including both domains of Gαo, without nucleotide or stabilizing nanobodies. These findings reveal the molecular basis for the first committed step of G protein activation, establish a mechanistic basis for a neurological disorder, provide a simplified strategy to determine receptor-G protein structures, and a method to detect high affinity agonist binding in cells.

Abstract Background Symbioses between primary producers and bacteria are crucial for nutrient exchange that fosters host growth and niche adaptation. Yet, how viruses that infect bacteria (phages) influence these bacteria-eukaryote interactions is still largely unknown. Here, we investigate the role of viruses on the genomic diversity and functional adaptations of bacteria associated with pelagic sargassum. This brown alga has dramatically increased its distribution range in the Atlantic in the past decade and is predicted to continue expanding, imposing severe impacts on coastal ecosystems, economies, and human health. Results We reconstructed 73 bacterial and 3963 viral metagenome-assembled genomes (bMAGs and vMAGs, respectively) from coastal Sargassum natans VIII and surrounding seawater. S. natans VIII bMAGs were enriched in prophages compared to seawater (28% and 0.02%, respectively). Rhodobacterales and Synechococcus bMAGs, abundant members of the S. natans VIII microbiome, were shared between the algae and seawater but were associated with distinct phages in each environment. Genes related to biofilm formation and quorum sensing were enriched in S. natans VIII phages, indicating their potential to influence algal association in their bacterial hosts. In-vitro assays with a bacterial community harvested from sargassum surface biofilms and depleted of free viruses demonstrated that these bacteria are protected from lytic infection by seawater viruses but contain intact and inducible prophages. These bacteria form thicker biofilms when growing on sargassum-supplemented seawater compared to seawater controls, and phage induction using mitomycin C was associated with a significant decrease in biofilm formation. The induced metagenomes were enriched in genomic sequences classified as temperate viruses compared to uninduced controls. Conclusions Our data shows that prophages contribute to the flexible genomes of S. natans VIII-associated bacteria. These prophages encode genes with symbiotic functions, and their induction decreases biofilm formation, an essential capacity for flexible symbioses between bacteria and the alga. These results indicate that prophage acquisition and induction contribute to genomic and functional diversification during sargassum-bacteria symbioses, with potential implications for algae growth. Video Abstract

Abstract Background Radiolabeled antibody 131I-omburtamab was administered intraventricularly in patients with leptomeningeal disease under an institutionally approved study (#NCT03275402). Radiation safety precautions were tailored for individual patients, enabling outpatient treatment based on in-depth, evidence-based recommendations for such precautions. The imperative advancement of streamlined therapeutic administration procedures, eliminating the necessity for inpatient isolation and resource-intensive measures, holds pivotal significance. This development bears broader implications for analogous therapies within the pediatric patient demographic. Methods Intraventricular radioimmunotherapy (RIT) with 925–1850 MBq (25–50 mCi) of 131I-omburtamab was administered via the Ommaya reservoir, in designated rooms within the pediatric ambulatory care center. Dosimeters were provided to staff involved in patient care to evaluate exposure during injection and post-administration. Post-administration exposure rate readings from the patient on contact, at 0.3 m, and at 1 m were taken within the first 30 min, and the room was surveyed after patient discharge. Duration of radiation exposure was calculated using standard U.S. Nuclear Regulatory Commission (US NRC) regulatory guidance recommendations combined with mean exposure rates and whole-body clearance estimates. Exposure rate measurements and clearance data provided patient-specific precautions for four cohorts by age: < 3 y/o, 3–10 y/o, 10–18 y/o, and 18+. Results Post-administration exposure rates for patients ranged from 0.16 to 0.46 µSv/hr/MBq at 0.3 m and 0.03–0.08 µSv/hr/MBq at 1 m. Radiation exposure precautions ranged from 1 to 10 days after release for the four evaluated cohorts. Based on the highest measured exposure rates and slowest whole-body clearance, the longest precautions were approximately 78% lower than the regulatory guidance recommendations. Radiation exposure to staff associated with 131I-omburtamab per administration was substantially below the annual regulatory threshold for individual exposure monitoring. Conclusion 131I-omburtamab can be administered on an outpatient basis, using appropriate patient-based radiation safety precautions that employ patient-specific exposure rate and biological clearance parameters. This trial is registered with the National Library of Medicine’s ClinicalTrials.gov. The registration number is NCT03275402, and it was registered on 7 September 2017. The web link is included here. https://clinicaltrials.gov/study/NCT03275402 .

Abstract The classical amyloid cascade hypothesis postulates that the aggregation of amyloid plaques and the accumulation of intracellular hyperphosphorylated Tau tangles, together, lead to profound neuronal death. However, emerging research has demonstrated that soluble amyloid-β oligomers (SAβOs) accumulate early, prior to amyloid plaque formation. SAβOs induce memory impairment and disrupt cognitive function independent of amyloid-β plaques, and even in the absence of plaque formation. This work describes the development and characterization of a novel anti-SAβO (E3) nanobody generated from an alpaca immunized with SAβO. In-vitro assays and in-vivo studies using 5XFAD mice indicate that the fluorescein (FAM)-labeled E3 nanobody recognizes both SAβOs and amyloid-β plaques. The E3 nanobody traverses across the blood–brain barrier and binds to amyloid species in the brain of 5XFAD mice. Imaging of mouse brains reveals that SAβO and amyloid-β plaques are not only different in size, shape, and morphology, but also have a distinct spatial distribution in the brain. SAβOs are associated with neurons, while amyloid plaques reside in the extracellular matrix. The results of this study demonstrate that the SAβO nanobody can serve as a diagnostic agent with potential theragnostic applications in Alzheimer’s disease.

Abstract Mast cells are immune cells minimally present in normal tendon tissue. The increased abundance of mast cells in tendinopathy biopsies and at the sites of tendon injury suggests an unexplored role of this cell population in overuse tendon injuries. Mast cells are particularly present in tendon biopsies from patients with more chronic symptom duration and a history of intensive mechanical loading. This study, therefore, examined the cross talk between mast cells and human tendon cells in either static or mechanically active conditions in order to explore the potential mechanistic roles of mast cells in overuse tendon injuries. A coculture of isolated human tenocytes and mast cells (HMC-1) combined with Flexcell Tension System for cyclic stretching of tenocytes was used. Additionally, human tenocytes were exposed to agonists and antagonists of substance P (SP) receptors. Mast cell degranulation was assessed by measuring β-hexosaminidase activity. Transwell and cell adhesion assays were used to evaluate mast cell migration and binding to tendon extracellular matrix components (collagen and fibronectin), respectively. Gene expressions were analyzed using real time qRT-PCR. Our results indicate that mechanical stimulation of human tenocytes leads to release of SP which, in turn, activates mast cells through the Mas-related G-protein-coupled receptor X2 (MRGPRX2). The degranulation and migration of mast cells in response to MRGPRX2 activation subsequently cause human tenocytes to increase their expression of inflammatory factors, matrix proteins and matrix metalloproteinase enzymes. These observations may be important in understanding the mechanisms by which tendons become tendinopathic in response to repetitive mechanical stimulation.

Abstract Spaceflight induces an immune response in astronauts. To better characterize this effect, we generated single-cell, multi-ome, cell-free RNA (cfRNA), biochemical, and hematology data for the SpaceX Inspiration4 (I4) mission crew. We found that 18 cytokines/chemokines related to inflammation, aging, and muscle homeostasis changed after spaceflight. In I4 single-cell multi-omics data, we identified a “spaceflight signature” of gene expression characterized by enrichment in oxidative phosphorylation, UV response, immune function, and TCF21 pathways. We confirmed the presence of this signature in independent datasets, including the NASA Twins Study, the I4 skin spatial transcriptomics, and 817 NASA GeneLab mouse transcriptomes. Finally, we observed that (1) T cells showed an up-regulation of FOXP3, (2) MHC class I genes exhibited long-term suppression, and (3) infection-related immune pathways were associated with microbiome shifts. In summary, this study reveals conserved and distinct immune disruptions occurring and details a roadmap for potential countermeasures to preserve astronaut health.

Abstract Measures of fMRI resting-state functional connectivity (rs-FC) are an essential tool for basic and clinical investigations of fronto-limbic circuits. Understanding the relationship between rs-FC and the underlying patterns of neural activity in these circuits is therefore vital. Here we introduced inhibitory designer receptors exclusively activated by designer drugs (DREADDs) into the amygdala of two male macaques. We evaluated the causal effect of activating the DREADD receptors on rs-FC and neural activity within circuits connecting amygdala and frontal cortex. Activating the inhibitory DREADD increased rs-FC between amygdala and ventrolateral prefrontal cortex. Neurophysiological recordings revealed that the DREADD-induced increase in fMRI rs-FC was associated with increased local field potential coherency in the alpha band (6.5–14.5 Hz) between amygdala and ventrolateral prefrontal cortex. Thus, our multi-modal approach reveals the specific signature of neuronal activity that underlies rs-FC in fronto-limbic circuits.

Abstract Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation.

Locusts and other migratory grasshoppers are transboundary pests. Monitoring and control, therefore, involve a complex system made up of social, ecological, and technological factors. Researchers and those involved in active management are calling for more integration between these siloed but often interrelated sectors. In this paper, we bring together 38 coauthors from six continents and 34 unique organizations, representing much of the social-ecological-technological system (SETS) related to grasshopper and locust management and research around the globe, to introduce current topics of interest and review recent advancements. Together, the paper explores the relationships, strengths, and weaknesses of the organizations responsible for the management of major locust-affected regions. The authors cover topics spanning humanities, social science, and the history of locust biological research and offer insights and approaches for the future of collaborative sustainable locust management. These perspectives will help support sustainable locust management, which still faces immense challenges such as fluctuations in funding, focus, isolated agendas, trust, communication, transparency, pesticide use, and environmental and human health standards. Arizona State University launched the Global Locust Initiative (GLI) in 2018 as a response to some of these challenges. The GLI welcomes individuals with interests in locusts and grasshoppers, transboundary pests, integrated pest management, landscape-level processes, food security, and/or cross-sectoral initiatives.

Population-level efforts are needed to increase levels of physical activity and healthy eating to reduce and manage chronic diseases such as obesity, cardiovascular disease, and type 2 diabetes. Interventions to increase public transit use may be one promising strategy, particularly for low-income communities or populations of color who are disproportionately burdened by health disparities and transportation barriers. This study employs a natural experiment design to evaluate the impacts of a citywide zero-fare transit policy in Kansas City, Missouri, on ridership and health indicators. In Aim 1, comparison to 9 similar cities without zero-fare transit is used to examine differential changes in ridership from 3 years before to 4 years after the adoption of zero-fare. In Aim 2, Kansas City residents are being recruited from a large safety net health system to compare health indicators between zero-fare riders and non- riders. Longitudinal data on BMI, cardiometabolic markers, and economic barriers to health are collected from the electronic health record from 2017 to 2024. Cross-sectional data on healthy eating and device-measured physical activity are collected from a subsample of participants as part of the study procedures (N = 360). Numerous baseline characteristics are collected to account for differences between Kansas City and comparison city bus routes (Aim 1) and between zero-fare riders and non-riders within Kansas City (Aim 2). Evidence on how zero-fare transit shapes population health through mechanisms related to improved economic factors, transportation, physical activity, and healthy eating among low-income groups is expected.

The purpose of this Delphi study was to identify the competencies needed by first-year, tenure-track faculty in the profession of agricultural education and its related specializations (i.e., teacher education, Extension education, leadership development, and agricultural communication) as perceived by hiring authorities. The expert panel was composed of 31 individuals across 25 states who were hiring authorities of agricultural education faculty. At the completion of the third round, there were a total of 52 competencies that reached consensus with the panel. The competencies were situated into three thematic categories: (a) professional skills, (b) technical skills, and (c) personal attributes. A visual framework, including the competencies, categories, and subcategories is presented. We recommend that this framework be used by graduate programs of agricultural education and related specializations as a potential framework for evaluating their programming. The time is ripe for a profession-wide conversation around the development and preparation of future faculty, and how to establish a community of scholars. Future research should be conducted to examine the best practices, such as mentorship and collaboration, to sustain and support faculty over their career and how such practices may be effectively implemented across the agricultural education professorate.

BackgroundThe environment shapes health behaviors and outcomes. Studies exploring this influence have been limited to research groups with the geographic information systems expertise required to develop built and social environment measures (eg, groups that include a researcher with geographic information system expertise). ObjectiveThe goal of this study was to develop an open-source, user-friendly, and privacy-preserving tool for conveniently linking built, social, and natural environmental variables to study participant addresses. MethodsWe built the automatic context measurement tool (ACMT). The ACMT comprises two components: (1) a geocoder, which identifies a latitude and longitude given an address (currently limited to the United States), and (2) a context measure assembler, which computes measures from publicly available data sources linked to a latitude and longitude. ACMT users access both of these components using an RStudio/RShiny-based web interface that is hosted within a Docker container, which runs on a local computer and keeps user data stored in local to protect sensitive data. We illustrate ACMT with 2 use cases: one comparing population density patterns within several major US cities, and one identifying correlates of cannabis licensure status in Washington State. ResultsIn the population density analysis, we created a line plot showing the population density (x-axis) in relation to distance from the center of the city (y-axis, using city hall location as a proxy) for Seattle, Los Angeles, Chicago, New York City, Nashville, Houston, and Boston with the distances being 1000, 2000, 3000, 4000, and 5000 m. We found the population density tended to decrease as distance from city hall increased except for Nashville and Houston, 2 cities that are notably more sprawling than the others. New York City had a significantly higher population density than the others. We also observed that Los Angeles and Seattle had similarly low population densities within up to 2500 m of City Hall. In the cannabis licensure status analysis, we gathered neighborhood measures such as age, sex, commute time, and education. We found the strongest predictive characteristic of cannabis license approval to be the count of female children aged 5 to 9 years and the proportion of females aged 62 to 64 years who were not in the labor force. However, after accounting for Bonferroni error correction, none of the measures were significantly associated with cannabis retail license approval status. ConclusionsThe ACMT can be used to compile environmental measures to study the influence of environmental context on population health. The portable and flexible nature of ACMT makes it optimal for neighborhood study research seeking to attribute environmental data to specific locations within the United States.

Summary: Large-scale analysis of single-cell gene expression has revealed transcriptomically defined cell subclasses present throughout the primate neocortex with gene expression profiles that differ depending upon neocortical region. Here, we test whether the interareal differences in gene expression translate to regional specializations in the physiology and morphology of infragranular glutamatergic neurons by performing Patch-seq experiments in brain slices from the temporal cortex (TCx) and motor cortex (MCx) of the macaque. We confirm that transcriptomically defined extratelencephalically projecting neurons of layer 5 (L5 ET neurons) include retrogradely labeled corticospinal neurons in the MCx and find multiple physiological properties and ion channel genes that distinguish L5 ET from non-ET neurons in both areas. Additionally, while infragranular ET and non-ET neurons retain distinct neuronal properties across multiple regions, there are regional morpho-electric and gene expression specializations in the L5 ET subclass, providing mechanistic insights into the specialized functional architecture of the primate neocortex.

Indiana faces significant challenges in maternal and infant health, ranking 45th worst in infant mortality with a rate of 6.5 deaths per 1,000 live-births, and 21st in stillbirths. Indiana further has the 3rd highest rate of maternal mortality with 44 deaths per 100,000 live-births. Despite these alarming statistics, comprehensive surveillance of maternal and infant health is absent, and data often remains fragmented across disparate information systems. In response, the Indiana University Fairbanks School of Public Health and Regenstrief Institute secured a cooperative agreement through the CDC's Pregnant People-Infant Linked Longitudinal Surveillance (PILLARS) program, collaborating with the Indiana Health Information Exchange, Indiana Department of Health, and Marion County Public Health Department. The initiative aims to enhance Indiana's infrastructure for surveillance of maternal and child health (MCH) using electronic health records (EHRs), public health, and administrative data. Key efforts have included development, validation, and application of linkage algorithms across records for mothers and children; integration of case data across data sources; design of routine surveillance reports; and design of longitudinal studies to examine determinants and outcomes in MCH populations. Using deterministic linkage algorithms, we have created over 800,000 mother-infant dyads; this number will expand with the implementation of probabilistic approaches. We also have developed a computational phenotype for identifying cases of pregnancy in the EHR even when not explicitly flagged in the EHR. Future efforts will build on this infrastructure to draw from additional public health data sources and/or expand surveillance efforts to include prioritized MCH outcomes.

Metabolic rewiring is essential for tumor growth and progression to metastatic disease, yet little is known regarding how cancer cells modify their acquired metabolic programs in response to different metastatic microenvironments. We have previously shown that liver-metastatic breast cancer cells adopt an intrinsic metabolic program characterized by increased HIF-1α activity and dependence on glycolysis. Here, we confirm by in vivo stable isotope tracing analysis (SITA) that liver-metastatic breast cancer cells retain a glycolytic profile when grown as mammary tumors or liver metastases. However, hepatic metastases exhibit unique metabolic adaptations including elevated expression of genes involved in glutathione (GSH) biosynthesis and reactive oxygen species (ROS) detoxification when compared to mammary tumors. Accordingly, breast-cancer-liver-metastases exhibited enhanced de novo GSH synthesis. Confirming their increased capacity to mitigate ROS-mediated damage, liver metastases display reduced levels of 8-Oxo-2′-deoxyguanosine. Depletion of the catalytic subunit of the rate-limiting enzyme in glutathione biosynthesis, glutamate-cysteine ligase (GCLC), strongly reduced the capacity of breast cancer cells to form liver metastases, supporting the importance of these distinct metabolic adaptations.Loss of GCLC also affected the early steps of the metastatic cascade, leading to decreased numbers of circulating tumor cells (CTCs) and impaired metastasis to the liver and the lungs. Altogether, our results indicate that GSH metabolism could be targeted to prevent the dissemination of breast cancer cells.

Objective: Stable isotope studies have shown that hepatic de novo lipogenesis (DNL) plays an important role in the pathogenesis of intrahepatic lipid (IHL) deposition. Furthermore, previous research has demonstrated that fructose 1-phosphate (F1P) not only serves as a substrate for DNL, but also acts as a signalling metabolite that stimulates DNL from glucose. The aim of this study was to elucidate the mediators of F1P-stimulated DNL, with special focus on two key regulators of intrahepatic glucose metabolism, i.e., glucokinase regulatory protein (GKRP) and carbohydrate response element binding protein (ChREBP). Methods: Aldolase B deficient mice (Aldob−/−), characterized by hepatocellular F1P accumulation, enhanced DNL, and hepatic steatosis, were either crossed with GKRP deficient mice (Gckr−/−) or treated with short hairpin RNAs directed against hepatic ChREBP. Results: Aldob−/− mice showed higher rates of de novo palmitate synthesis from glucose when compared to wildtype mice (p

Abstract Real-time lab analysis is needed to support clinical decision making and research on human missions to the Moon and Mars. Powerful laboratory instruments, such as flow cytometers, are generally too cumbersome for spaceflight. Here, we show that scant test samples can be measured in microgravity, by a trained astronaut, using a miniature cytometry-based analyzer, the rHEALTH ONE, modified specifically for spaceflight. The base device addresses critical spaceflight requirements including minimal resource utilization and alignment-free optics for surviving rocket launch. To fully enable reduced gravity operation onboard the space station, we incorporated bubble-free fluidics, electromagnetic shielding, and gravity-independent sample introduction. We show microvolume flow cytometry from 10 μL sample drops, with data from five simultaneous channels using 10 μs bin intervals during each sample run, yielding an average of 72 million raw data points in approximately 2 min. We demonstrate the device measures each test sample repeatably, including correct identification of a sample that degraded in transit to the International Space Station. This approach can be utilized to further our understanding of spaceflight biology and provide immediate, actionable diagnostic information for management of astronaut health without the need for Earth-dependent analysis.

Abstract Background Evidence suggests that women’s abdominal pain is more likely to be minimised or dismissed by healthcare professionals than men’s. This can have a detrimental impact on health-related outcomes as well as quality of life. The aim of this study was to explore women’s experiences of seeking healthcare for abdominal pain in Ireland. Method A qualitative design and opportunity sampling approach were employed in this study. Fourteen women living in Ireland with experience of seeking healthcare for abdominal pain took part in one-to-one semi-structured interviews via video-conferencing software. Data were analysed using reflexive thematic analysis. Results Four themes were constructed from the data: [1] “Just Get on with It” – Normalisation and Invalidation; [2] “Bad Enough”? Costs of (Not) Seeking Help; [3] “Fight Your Case,” Fight for Care; and [4] “Out of the Loop” – Systemic Barriers to Care. Perceived invalidation of pain by healthcare professionals was common, as was internalised normalisation of pain. This created challenges when negotiating pain management solutions. Despite functional interference, participants felt their pain needed to reach an extreme level of severity before seeking help. Costs of private healthcare were implicated in delayed help-seeking. Participants felt the onus was on them to fight for care. Social support and information-seeking facilitated participants in this fight while systemic issues were identified as barriers to adequate care. Despite their frustrations, participants expressed empathy for healthcare professionals operating in a flawed system. Conclusions Participants described mostly negative experiences of seeking healthcare for abdominal pain, characterised by dismissal of symptoms and internalisation of normative views of women’s pain as less worthy of care. These experiences reinforced participants’ views that self-advocacy is essential to access care for their pain. There are systemic issues at play within the Irish healthcare system that limit women’s ability to access abdominal pain management support. Education and training for healthcare professionals on the Gender Pain Gap and its implications for patient care, as well as clear referral pathways for women presenting with abdominal pain, may help to ensure more equitable healthcare delivery for individuals with abdominal pain in Ireland.

This work aims to evaluate the anti-corrosion potential of ethyl dimethyl propylammonium bis (trifluoromethyl sulfonyl) imide (EDMPA-TFSI)-ionic liquid on AA3003 alloy in 0.5 M HCl solution in the presence and absence of potassium iodide at ambient and elevated temperatures. The corrosion inhibition of AA3003 alloy by EDMPA-TFSI in the presence of potassium iodide was evaluated using hydrogen evolution measurements at 303 K and 333 K. The results show that in the absence of potassium iodide, EDMPA-TFSI decelerates AA3003 corrosion in an acidic medium with a maximum inhibition efficiency of 93.2 % and 90.5 % obtained at 303 K and 333 K respectively. In the presence of potassium iodide, 94.7 % and 89.8 % inhibition efficiencies were obtained at 303 K and 333 K, respectively. This adsorption behavior is concordant with the Langmuir adsorption isotherm and the corrosion process in the presence of EDMPA-TFSI shows consistency with first-order reaction kinetics. New information on the application of EDMPA-TFSI as a workable corrosion inhibitor is provided herein.

Corticostriatal connections are essential for motivation, cognition, and behavioral flexibility. There is broad interest in using resting-state functional magnetic resonance imaging (rs-fMRI) to link circuit dysfunction in these connections with neuropsychiatric disorders. In this paper, we used tract-tracing data from non-human primates (NHPs) to assess the likelihood of monosynaptic connections being represented in rs-fMRI data of NHPs and humans. We also demonstrated that existing hub locations in the anatomical data can be identified in the rs-fMRI data from both species. To characterize this in detail, we mapped the complete striatal projection zones from 27 tract-tracer injections located in the orbitofrontal cortex (OFC), dorsal anterior cingulate cortex (dACC), ventromedial prefrontal cortex (vmPFC), ventrolateral PFC (vlPFC), and dorsal PFC (dPFC) of macaque monkeys. Rs-fMRI seeds at the same regions of NHP and homologous regions of human brains showed connectivity maps in the striatum mostly consistent with those observed in the tracer data. We then examined the location of overlap in striatal projection zones. The medial rostral dorsal caudate connected with all five frontocortical regions evaluated in this study in both modalities (tract-tracing and rs-fMRI) and species (NHP and human). Other locations in the caudate also presented an overlap of four frontocortical regions, suggesting the existence of different locations with lower levels of input diversity. Small retrograde tracer injections and rs-fMRI seeds in the striatum confirmed these cortical input patterns. This study sets the ground for future studies evaluating rs-fMRI in clinical samples to measure anatomical corticostriatal circuit dysfunction and identify connectional hubs to provide more specific treatment targets for neurological and psychiatric disorders.

Successful and beneficial collaboration relies on the dedication individuals to cooperate, the established culture of collaboration and cooperation and a desire and willingness to collaborate. Agricultural educators and Extension agents often find themselves in competition for members rather than cooperation to develop members. Working in conjunction with one another in a concerted effort allows the two groups to develop youth into more efficient and effective leaders and citizens. This study utilized the Theory of Planned Behavior (Ajzen, 1985). As applied to this study, this theory would hold that the variables of interest, personal and professional demographics within the two groups, to influence collaboration levels between agricultural educators and extension agents because these factors can shape and include attitudes, subjective norms, and perceived behavioral controls. This study found perceptions between school-based agricultural educators and Extension agents do hold positive views of cooperation. However, this cooperation does not happen very often outside of well-established instances. Upon examination of this study, we recommend further research be done to maintain an accurate reading of cooperation between these two entities and delve further into what motivates them.

IntroductionConventional culture conditions, such as in T-flasks, require that oxygen diffuse through the medium to reach the islets; in turn, islet surface area density is limited by oxygen availability. To culture a typical clinical islet preparation may require more than 20 T-175 flasks at the standard surface area density of 200 IE/cm2. To circumvent this logistical constraint, we tested islets cultured on top of silicon gas-permeable (GP) membranes which place islets in close proximity to ambient oxygen.MethodsOxygenation of individual islets under three culture conditions, standard low-density, non-GP high density, and GP high density, were first modeled with finite element simulations. Porcine islets from 30 preparations were cultured for 2 days in devices with GP membrane bottoms or in paired cultures under conventional conditions. Islets were seeded at high density (HD, ∼4000 IE/cm2, as measured by DNA) in both GP and non-GP devices.ResultsIn simulations, individual islets under standard culture conditions and high density cultures on GP membranes were both well oxygenated whereas non-GP high density cultured islets were anoxic. Similarly, compared to the non-GP paired controls, islet viability and recovery were significantly increased in HD GP cultures. The diabetes reversal rate in nude diabetic mice was similar for HD GP devices and standard cultures but was minimal with non-GP HD cultures.DiscussionCulturing islets in GP devices allows for a 20-fold increase of islet surface area density, greatly simplifying the culture process while maintaining islet viability and metabolism.

Virtual reality (VR) is an emerging technology that can enhance experiences and outcomes in mental healthcare. However, mental health therapists have been slow to adopt VR into practice. Implementation of telehealth-based VR therapy (tele-VR) could catalyze adoption and innovation in mental healthcare. To explore therapists’ perspectives on tele-VR, we conducted a cross-sectional survey of practicing mental health providers in the United States in June-July 2023. We analyzed 176 completed surveys from therapists, of whom 51.14% had no prior experience with VR, only 6.25% had used VR clinically, and 56.82% had neutral impressions of VR for therapy. Despite therapists’ general inexperience with VR, therapists indicated a wide variety of tele-VR simulations (e.g., social situations, flying, heights) and features (e.g., personalized spaces, homework, interactivity) would be moderately to extremely useful for their practices. Therapists also requested additional VR simulations and features for their telehealth clients such as behavioral skills training, exposure therapy, gender identity therapy, and psychological assessments in VR. Therapists rated Health Insurance Portability and Accountability Act compliance, the ability to try VR before buying, affordability for therapists, accessibility for clients, and insurance coverage as the five most influential implementation factors for tele-VR. Overall, therapists were generally inexperienced and neutral about VR for telehealth therapy, but were interested in tele-VR for specific applications. These findings provide actionable directions for future research and collaborative development of therapeutic VR content and features.

Background Digital Mental Health Interventions (DMHIs) that meet the definition of a medical device are regulated by the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK. The MHRA uses procedures that were originally developed for pharmaceuticals to assess the safety of DMHIs. There is recognition that this may not be ideal, as is evident by an ongoing consultation for reform led by the MHRA and the National Institute for Health and Care Excellence. Aims The aim of this study was to generate an experts’ consensus on how the medical regulatory method used for assessing safety could best be adapted for DMHIs. Method An online Delphi study containing three rounds was conducted with an international panel of 20 experts with experience/knowledge in the field of UK digital mental health. Results Sixty-four items were generated, of which 41 achieved consensus (64%). Consensus emerged around ten recommendations, falling into five main themes: Enhancing the quality of adverse events data in DMHIs; Re-defining serious adverse events for DMHIs; Reassessing short-term symptom deterioration in psychological interventions as a therapeutic risk; Maximising the benefit of the Yellow Card Scheme; and Developing a harmonised approach for assessing the safety of psychological interventions in general. Conclusion The implementation of the recommendations provided by this consensus could improve the assessment of safety of DMHIs, making them more effective in detecting and mitigating risk.

BackgroundDigital health and telemedicine are potentially important strategies to decrease health care’s environmental impact and contribution to climate change by reducing transportation-related air pollution and greenhouse gas emissions. However, we currently lack robust national estimates of emissions savings attributable to telemedicine. ObjectiveThis study aimed to (1) determine the travel distance between participants in US telemedicine sessions and (2) estimate the net reduction in carbon dioxide (CO2) emissions attributable to telemedicine in the United States, based on national observational data describing the geographical characteristics of telemedicine session participants. MethodsWe conducted a retrospective observational study of telemedicine sessions in the United States between January 1, 2022, and February 21, 2023, on the doxy.me platform. Using Google Distance Matrix, we determined the median travel distance between participating providers and patients for a proportional sample of sessions. Further, based on the best available public data, we estimated the total annual emissions costs and savings attributable to telemedicine in the United States. ResultsThe median round trip travel distance between patients and providers was 49 (IQR 21-145) miles. The median CO2 emissions savings per telemedicine session was 20 (IQR 8-59) kg CO2). Accounting for the energy costs of telemedicine and US transportation patterns, among other factors, we estimate that the use of telemedicine in the United States during the years 2021-2022 resulted in approximate annual CO2 emissions savings of 1,443,800 metric tons. ConclusionsThese estimates of travel distance and telemedicine-associated CO2 emissions costs and savings, based on national data, indicate that telemedicine may be an important strategy in reducing the health care sector’s carbon footprint.

A case report detailing, for the first time, a case of laboratory-confirmed zoster in an astronaut on board the International Space Station is presented. The findings of reduced T-cell function, cytokine imbalance, and increased stress hormones which preceded the event are detailed. Relevance for deep space countermeasures is discussed.

The menisci increase the contact area of load bearing in the knee and thus disperse the mechanical stress via their circumferential tensile fibers. Traumatic meniscus injuries cause mechanical symptoms in the knee, and are more prevalent amongst younger, more active patients, compared to degenerative tears amongst the elderly population. Traumatic meniscus tears typically result from the load-and-shear mechanism in the knee joint. The treatment depends on the size, location, and pattern of the tear. For non-repairable tears, partial or total meniscal resection decreases its tensile stress and increases joint contact stress, thus potentiating the risk of arthritis. A longitudinal vertical tear pattern at the peripheral third red-red zone leads to higher healing potential after repair. The postoperative rehabilitation protocols after repair range from immediate weight-bearing with no range of motion restrictions to non-weight bearing and delayed mobilization for weeks. Pediatric and adolescent patients may require special considerations due to their activity levels, or distinct pathologies such as a discoid meniscus. Further biomechanical and biologic evidence is needed to guide surgical management, postoperative rehabilitation protocols, and future technology applications for traumatic meniscus injuries.

Introduction: Neurological consultation for patients infected with SARS-CoV-2 is common; it is currently unknown whether the neurologist’s approach to inpatient consultation of patients with SARS-CoV-2 should differ from the paradigm used to evaluate hospitalized patients with similar respiratory viruses. The goal of the present study is to determine if the preponderance of new neurologic diagnoses differs between inpatients with SARS-CoV-2 and similar non-SARS-CoV-2 respiratory viruses for whom neurology is consulted. Methods: We performed a retrospective chart analysis of inpatient neurologic consultations at three major Philadelphia-based hospitals. We compared the final neurologic diagnosis of 152 patients infected with SARS-CoV-2 to 54 patients with a similar ubiquitous non-SARS-CoV-2 respiratory virus (influenza A, influenza B, respiratory syncytial virus, rhinovirus, or adenovirus, the most commonly tested respiratory viruses at our institution). Secondary metrics included age, sex, level of care, prior neurologic diagnoses, and mortality. A multinomial logistic regression model was utilized to evaluate the relative difference between diagnostic category groups on all metrics. Results: The proportion of patients with seizure who were infected with SARS-CoV-2 admitted to an intensive care unit (ICU) was significantly higher than those who were admitted to a medical–surgical floor. SARS-CoV-2 was also associated with increased risk for ICU admission compared to other common respiratory viruses. SARS-CoV-2 inpatients requiring neurologic consultation were also more likely to be older and female as compared to the non-SARS-CoV-2 cohort. In other domains, the proportion of neurologic diagnoses between SAR-CoV-2 and non-SARS-CoV-2 respiratory viruses showed no significant difference. Conclusion: Patients requiring inpatient neurologic consultation with a diagnosis of SARS-CoV-2 infection or another respiratory virus were found to be remarkably similar in terms of their ultimate neurologic diagnosis, with the exception of a larger preponderance of seizure in critical-care-level patients with SARS-CoV-2 infection. Our study suggests that the neurological approach to patients hospitalized with SARS-CoV-2 should be similar to that for patients with similar common respiratory infections, noting that seizure was seen more frequently in critically ill patients infected with SARS-CoV-2.

Abstract Background Awareness with paralysis (AWP) is memory recall during neuromuscular blockade (NMB) and can cause significant psychological harm. Decades of effort and rigorous trials have been conducted to prevent AWP in the operating room, where prevalence is 0.1–0.2%. By contrast, AWP in mechanically ventilated emergency department (ED) patients is common, with estimated prevalence of 3.3–7.4% among survivors given NMB. Longer-acting NMB use is a critical risk for AWP, and we have shown an association between ED rocuronium use and increased AWP prevalence. As NMB are given to more than 90% of ED patients during tracheal intubation, this trial provides a platform to test an intervention aimed at reducing AWP. The overall objective is to test the hypothesis that limiting ED rocuronium exposure will significantly reduce the proportion of patients experiencing AWP. Methods This is a pragmatic, stepped wedge cluster randomized trial conducted in five academic EDs, and will enroll 3090 patients. Per the design, all sites begin in a control phase, under observational conditions. At 6-month intervals, sites sequentially enter a 2-month transition phase, during which we will implement the multifaceted intervention, which will rely on use of nudges and defaults to change clinician decisions regarding ED NMB use. During the intervention phase, succinylcholine will be the default NMB over rocuronium. The primary outcome is AWP, assessed with the modified Brice questionnaire, adjudicated by three independent, blinded experts. The secondary outcome is the proportion of patients developing clinically significant symptoms of post-traumatic stress disorder at 30 and 180 days after hospital discharge. We will also assess for symptoms of depression and anxiety, and health-related quality of life. A generalized linear model, adjusted for time and cluster interactions, will be used to compare AWP in control versus intervention phases, analyzed by intention-to-treat. Discussion The ED-AWARENESS-2 Trial will be the first ED-based trial aimed at preventing AWP, a critical threat to patient safety. Results could shape clinical use of NMB in the ED and prevent more than 10,000 annual cases of AWP related to ED care. Trial registration ClinicalTrials.gov identifier NCT05534243 . Registered 06, September 2022.

Human exploration of the solar system will expose crew members to galactic cosmic radiation (GCR), with a potential for adverse health effects. GCR particles (protons and ions) move at nearly the speed of light and easily penetrate space station walls, as well as the human body. Previously, we have shown reactivation of latent herpesviruses, including herpes simplex virus, Varicella zoster virus, Epstein–Barr virus, and cytomegalovirus (CMV), during stays at the International Space Station. Given the prevalence of latent CMV and the known propensity of space radiation to cause alterations in many cellular processes, we undertook this study to understand the role of GCR in reactivating latent CMV. Latently infected Kasumi cells with CMV were irradiated with 137Cs gamma rays, 150 MeV protons, 600 MeV/n carbon ions, 600 MeV/n iron ions, proton ions, and simulated GCR. The CMV copy number increased significantly in the cells exposed to radiation as compared with the non-irradiated controls. Viral genome sequencing did not reveal significant nucleotide differences among the compared groups. However, transcriptome analysis showed the upregulation of transcription of the UL49 ORF, implicating it in the switch from latent to lytic replication. These findings support our hypothesis that GCR may be a strong contributor to the reactivation of CMV infection seen in ISS crew members.

Background/Objectives: Glucagon-like peptide-1 agonists (GLP1As) are increasingly prescribed to treat obesity. While studies document how these medications impact dietary habits, their relationship to consumer food waste is unexplored. Approximately one-third of all food is wasted, which creates substantial economic and environmental damage. The purpose of this study is to assess how consumers alter food waste after beginning GLP1As and to identify factors associated with this relationship. Methods: Retrospectively reported changes in the amount of food wasted since beginning a GLP1A are gathered from a sample of 505 U.S. consumers via a self-administered online survey. Regression analysis yields associations between changes in post-GLP1A-uptake food waste and the length and type of medication use, medication side effects, post-uptake changes in dietary habits, and respondent characteristics. Results: A total of 25% of respondents agree they waste more food since beginning the medication, while 61% disagree. Respondents are significantly less likely to agree with this statement if they have been on the medication a longer time and are significantly more likely to agree if they reported experiencing nausea since beginning the medication. Dietary changes consistent with more vegetable intake are also significantly associated with less waste. Conclusions: Uptake of a novel class of anti-obesity medications may significantly affect food waste patterns. With the potential for widespread adoption of such medications, and given the societal import of reducing food waste, understanding the interaction of these two consumer trends is critical for projecting their joint impact on the food system and for equipping new GLP1A users to limit food waste.

The relationship of Amyotrophic Lateral Sclerosis, Parkinson’s disease, and other age-related neurodegenerative diseases with mitochondrial dysfunction has led to our study of the mitochondrial fission gene Drp1 in Drosophila melanogaster and aspects of aging. Previously, the Drp1 protein has been demonstrated to interact with the Drosophila Bcl-2 mitochondrial proteins, and Drp1 mutations can lead to mitochondrial dysfunction and neuronal loss. In this study, the Dopa decarboxylase-Gal4 (Ddc-Gal4) transgene was exploited to direct the expression of Drp1 and Drp1-RNAi transgenes in select neurons. Here, the knockdown of Drp1 seems to compromise locomotor function throughout life but does not alter longevity. The co-expression of Buffy suppresses the poor climbing induced by the knockdown of the Drp1 function. The consequences of Drp1 overexpression, which specifically reduced median lifespan and diminished climbing abilities over time, can be suppressed through the directed co-overexpression of pro-survival Bcl-2 gene Buffy or by the co-knockdown of the pro-cell death Bcl-2 homologue Debcl. Alteration of the expression of Drp1 acts to phenocopy neurodegenerative disease phenotypes in Drosophila, while overexpression of Buffy can counteract or rescue these phenotypes to improve overall health. The diminished healthy aging due to either the overexpression of Drp1 or the RNA interference of Drp1 has produced novel Drosophila models for investigating mechanisms underlying neurodegenerative disease.

Summary: Hippocampal pyramidal neuron activity underlies episodic memory and spatial navigation. Although extensively studied in rodents, extremely little is known about human hippocampal pyramidal neurons, even though the human hippocampus underwent strong evolutionary reorganization and shows lower theta rhythm frequencies. To test whether biophysical properties of human Cornu Amonis subfield 1 (CA1) pyramidal neurons can explain observed rhythms, we map the morpho-electric properties of individual CA1 pyramidal neurons in human, non-pathological hippocampal slices from neurosurgery. Human CA1 pyramidal neurons have much larger dendritic trees than mouse CA1 pyramidal neurons, have a large number of oblique dendrites, and resonate at 2.9 Hz, optimally tuned to human theta frequencies. Morphological and biophysical properties suggest cellular diversity along a multidimensional gradient rather than discrete clustering. Across the population, dendritic architecture and a large number of oblique dendrites consistently boost memory capacity in human CA1 pyramidal neurons by an order of magnitude compared to mouse CA1 pyramidal neurons.

Background: The implementation of pharmacogenetic (PGx) testing may contribute to health disparities if access to testing is inequitable, as medically underserved patients are prescribed higher rates of drugs with PGx guidelines and often experience the benefits of emerging health technologies last. Limited research has evaluated potential implementation of PGx testing in populations who are medically underserved and none have evaluated their preferences regarding PGx test characteristics and cost. Our study endeavored to assess the willingness to pay for PGx testing and key PGx test preferences in a nationwide cohort of medically underserved respondents.Methods: A survey was developed to assess willingness to pay and preferences for PGx testing through a discrete choice experiment (DCE). Five attributes of PGx tests were included in the DCE: doctor recommendation, wait time, number of actionable results, benefit of the test (avoid a side effect or address a health problem), and out-of-pocket cost. A convenience sample of U.S. adults with an average yearly household income of $42,000 or less was collected utilizing an online survey fielded by Qualtrics Research Services (Provo, UT). For the DCE analysis, conditional logit and mixed-logit regression models were utilized to determine relative utility of attributes and levels, conditional relative importance for each attribute, and marginal willingness to pay.Results: Respondents completed the survey with an 83.1% response completion rate. Following quality control procedures, 1,060 respondents were included in the final nationwide cohort. Approximately, 82% of respondents were willing to pay less than $100 for PGx testing, and a strong price ceiling was identified at $200. Out-of-pocket cost was the attribute identified as having the greatest relative importance on choice, while wait time had the lowest importance. Greater utility was observed if the PGx test was doctor recommended, had a higher number of actionable results, and resolved major or minor health problems compared with avoiding side effects.Conclusion: This first-of-its-kind study provides important insights into the willingness to pay for PGx testing and PGx test preferences of a large medically underserved population. Applying these findings can potentially lead to improvements in the successful implementation of PGx testing in this population.

BackgroundHypertension is the most prevalent risk factor for mortality globally. Uncontrolled hypertension is associated with excess morbidity and mortality, and nearly one-half of individuals with hypertension do not have the condition under control. Data from electronic health record (EHR) systems may be useful for community hypertension surveillance, filling a gap in local public health departments’ community health assessments and supporting the public health data modernization initiatives currently underway. To identify patients with hypertension, computable phenotypes are required. These phenotypes leverage available data elements—such as vitals measurements and medications—to identify patients diagnosed with hypertension. However, there are multiple methodologies for creating a phenotype, and the identification of which method most accurately reflects real-world prevalence rates is needed to support data modernization initiatives. ObjectiveThis study sought to assess the comparability of 6 different EHR-based hypertension prevalence estimates with estimates from a national survey. Each of the prevalence estimates was created using a different computable phenotype. The overarching goal is to identify which phenotypes most closely align with nationally accepted estimations. MethodsUsing the 6 different EHR-based computable phenotypes, we calculated hypertension prevalence estimates for Marion County, Indiana, for the period from 2014 to 2015. We extracted hypertension rates from the Behavioral Risk Factor Surveillance System (BRFSS) for the same period. We used the two 1-sided t test (TOST) to test equivalence between BRFSS- and EHR-based prevalence estimates. The TOST was performed at the overall level as well as stratified by age, gender, and race. ResultsUsing both 80% and 90% CIs, the TOST analysis resulted in 2 computable phenotypes demonstrating rough equivalence to BRFSS estimates. Variation in performance was noted across phenotypes as well as demographics. TOST with 80% CIs demonstrated that the phenotypes had less variance compared to BRFSS estimates within subpopulations, particularly those related to racial categories. Overall, less variance occurred on phenotypes that included vitals measurements. ConclusionsThis study demonstrates that certain EHR-derived prevalence estimates may serve as rough substitutes for population-based survey estimates. These outcomes demonstrate the importance of critically assessing which data elements to include in EHR-based computer phenotypes. Using comprehensive data sources, containing complete clinical data as well as data representative of the population, are crucial to producing robust estimates of chronic disease. As public health departments look toward data modernization activities, the EHR may serve to assist in more timely, locally representative estimates for chronic disease prevalence.

Adolescents living with HIV (ALHIV) face unique challenges resulting in persistent treatment gaps, particularly viral non-suppression. Country programs adopt policies, guidelines, and innovations, based on WHO recommendations and best practices from elsewhere. However, it is unclear to what extent these tools address the management of adolescents with viral non-suppression. We report on a review of guidelines for the provision of HIV services to ALHIV in Namibia. We conducted a systematic document review using Content Analysis and Thematic Analysis methodology, and the READ approach. We identified seven relevant policy documents, four of which somewhat addressed viral non-suppression (treatment gap) in ALHIV and outlined interventions to improve treatment outcomes in adolescents considering their lived experience and unique challenges. The persistent treatment gap may reflect policy implementation gaps in specifically addressing viral non-suppression. It may be worthwhile to leverage existing documents to develop specific operational guidance for ALHIV with unsuppressed viral loads.

Background: Constipation is characterized by symptoms of straining, hard stool, difficult evacuation, and infrequent bowel movements. Online surveys provide valuable information about patients’ perspectives, symptoms, management, treatment satisfaction, and risk factors. Methods: This survey explored subject experiences involving 20 gastrointestinal (GI) conditions. In total, 20,099 respondents in seven countries with varied cultural and socioeconomic backgrounds participated. Post hoc analysis of ‘self-reported constipation’ and related symptoms experienced within the past 6 months and the last episode of constipation provided data on prevalence, demographics, frequency and duration of episodes and related symptoms, impact on quality of life (QoL), management with or without laxatives, and resulting treatment satisfaction. Results: In total, 10,425 subjects reported constipation within 6 months and 2637 at the last episode. Prevalence was highest in females and younger adults. Most subjects reported various coexisting GI symptoms. Almost 80% of 6865 episodes reported by 5337 subjects occurred every 2–3 months to every 2–3 weeks. A higher frequency of constipation correlated with a greater impact on QoL. On a 10-point scale, the mean impact was 6.4. More than 90% of respondents had episodes ranging from 1 day to 1 week. More than 90% took action; 16% used laxatives, of whom 80.3% were satisfied. Conclusion: Constipation, a highly prevalent disorder, spans cultures and socioeconomic classes. Its chronic recurrence has a significant impact on QoL, resulting in symptom self-management in >90% of subjects. Significantly higher satisfaction rates in subjects treated with than without laxatives reflect subjects’ reports that self-reported constipation can be treated effectively with laxatives.

Camelina (Camelina sativa L. Crantz) is a low-input oilseed crop with great potential in bioenergy and industrial oils. Improving tolerance to high temperatures is essential for camelina agronomic sustainability. Two genotypes, Suneson and Pryzeth, were exposed to a transient 14-day heat stress at 37 °C during the reproductive stages. Four cohorts of pods along the main stem, which were at different stages from fully developed pods (C1), young pods (C2), open flowers (C3) and flowering buds (C4) at the time of heat treatment, were examined for morphological and seed quality traits at maturity. The main stem length was shortened in both genotypes. Pods and seeds in all cohorts were negatively affected by heat, resulting in lower seed yield and reduced oil content. Seed size and seed weight had the greatest reduction in C1, pod size reduction was found the most in C3, and the number of fertile pods that contain at least one seed was reduced in C3 and C4. These results suggest that heat stress effects are developmental stage specific. Heat stress significantly reduced fertility during flowering and inhibited storage product biosynthesis and accumulation during seed filling which resulted in smaller and lighter seeds. Analyzing seed composition indicated that oil content decreased while protein content increased in seeds from heat treated plants. In addition, fatty acid composition was altered with the reduction of omega-3 α-linolenic acid and concomitantly increased omega-6 linoleic acid being the most significantly affected. Our results also revealed the different responses in the two genotypes examined, suggesting genetic variation in camelina germplasm which can be explored to improve heat tolerance. This study provides resources and guidance for future studies to understand genetic and physiological mechanisms of heat stress and to assist in improving the sustainability of camelina production facing climate change.

Introduction This study will test the effectiveness of FIT Families (FIT), a multicomponent family-based behavioural intervention, against a credible attention control condition, Home-Based Family Support (HBFS). This protocol paper describes the design of a randomised clinical trial testing the efficacy of the FIT intervention. The protocol will assess the efficacy of FIT to improve health status in African American adolescents with obesity (AAAO) and their primary caregivers on primary (percent body fat) and secondary (physical activity, metabolic control, weight loss) outcomes and its cost-effectiveness.Methods 180 youth/caregiver dyads are randomised into FIT or HBFS, stratified by age, gender and baseline per cent overweight. The proposed study follows a two condition (FIT, HBFS) by four assessment time points. Tests will be conducted to identify potential relationship of baseline demographic and clinical variables to our dependent variables and see whether they are balanced between groups. It is hypothesised that youth/caregiver dyads randomised to FIT will show significantly greater reductions in percent body fat over a 12-month follow-up period compared with AAAO receiving HBFS. Preliminary findings are expected by November 2023.Ethics This protocol received IRB approval from the Medical University of South Carolina (Pro00106021; see ‘MUSC IRB 106021 Main Approval.doxc’ in online supplemental materials).Dissemination Dissemination activities will include summary documents designed for distribution to the broader medical community/family audience and submission of manuscripts, based on study results, to relevant peer-reviewed scientific high-impact journals.Trial registration number NCT04974554.

Abstract In this work, we present a dataset that combines functional magnetic imaging (fMRI) and electroencephalography (EEG) to use as a resource for understanding human brain function in these two imaging modalities. The dataset can also be used for optimizing preprocessing methods for simultaneously collected imaging data. The dataset includes simultaneously collected recordings from 22 individuals (ages: 23–51) across various visual and naturalistic stimuli. In addition, physiological, eye tracking, electrocardiography, and cognitive and behavioral data were collected along with this neuroimaging data. Visual tasks include a flickering checkerboard collected outside and inside the MRI scanner (EEG-only) and simultaneous EEG-fMRI recordings. Simultaneous recordings include rest, the visual paradigm Inscapes, and several short video movies representing naturalistic stimuli. Raw and preprocessed data are openly available to download. We present this dataset as part of an effort to provide open-access data to increase the opportunity for discoveries and understanding of the human brain and evaluate the correlation between electrical brain activity and blood oxygen level-dependent (BOLD) signals.

Abstract Quantitative assessment of emphysema in CT scans has mostly focused on calculating the percentage of lung tissue that is deemed abnormal based on a density thresholding strategy. However, this overall measure of disease burden discards virtually all the spatial information encoded in the scan that is implicitly utilized in a visual assessment. This simplification is likely grouping heterogenous disease patterns and is potentially obscuring clinical phenotypes and variable disease outcomes. To overcome this, several methods that attempt to quantify heterogeneity in emphysema distribution have been proposed. Here, we compare three of those: one based on estimating a power law for the size distribution of contiguous emphysema clusters, a second that looks at the number of emphysema-to-emphysema voxel adjacencies, and a third that applies a parametric spatial point process model to the emphysema voxel locations. This was done using data from 587 individuals from Phase 1 of COPDGene that had an inspiratory CT scan and plasma protein abundance measurements. The associations between these imaging metrics and visual assessment with clinical measures (FEV $$_1$$ 1 , FEV $$_1$$ 1 -FVC ratio, etc.) and plasma protein biomarker levels were evaluated using a variety of regression models. Our results showed that a selection of spatial measures had the ability to discern heterogeneous patterns among CTs that had similar emphysema burdens. The most informative quantitative measure, average cluster size from the point process model, showed much stronger associations with nearly every clinical outcome examined than existing CT-derived emphysema metrics and visual assessment. Moreover, approximately 75% more plasma biomarkers were found to be associated with an emphysema heterogeneity phenotype when accounting for spatial clustering measures than when they were excluded.

Background: Whether laparoscopic approach to gastrectomy for gastric cancer (GC) reduces the risk of pneumonia remains unknown. In this study, we compared pneumonia outcomes for patients with GC who underwent either laparoscopic gastrectomy (LG) or open gastrectomy (OG). Methods: The ACS NSQIP database was queried to identify patients with GC who underwent LG or OG between Jan 2012 - Dec 2018. Outcomes were compared using regression models. A post-hoc analysis was performed for elderly patients. Results: The study cohort included 2661 patients, 23.4 % undergoing LG. Laparoscopic approach lowered pneumonia risk (OR 0.47, p = .028) and reduced hospital length of stay, (5.3 vs 7.1 days, p < .001). Elderly patients undergoing LG demonstrated similar benefits. Risk factors for pneumonia included advanced age, dyspnea and weight-loss, whereas laparoscopic approach reduced this risk. Conclusions: LG in patients with GC has both statistically and clinically significant advantages over OG with respect to pneumonia. Further studies are needed to validate the relationship between postoperative pneumonia and surgical approach for gastrectomy.

We report on a highly significant, positive association between anthrax vaccination and occurrence of Gulf War Illness (GWI) in 111 Gulf War veterans (42 with GWI and 69 controls). GWI was diagnosed in 47.1% of vaccinated veterans but only in 17.2% of non-vaccinated veterans (Pearson χ2 = 7.08, p = 0.008; odds ratio = 3.947; relative risk = 2.617), with 1.6x higher GWI symptom severity in vaccinated veterans (p = 0.007, F-test in analysis of covariance). Next, we tested the hypothesis that the susceptibility to GWI following anthrax vaccination could be due to inability to make antibodies against the anthrax protective antigen (PA), the key protein contained in the vaccine. Since the first step in initiating antibody production would be the binding of PA peptide fragments (typically 15-amino acid long [15-mer]) to peptide-binding motifs of human leukocyte antigen (HLA) Class II molecules, we assessed the binding-motif affinities of such HLA specific molecules to all linear 15-mer peptide fragments of the anthrax PA. We identified a total of 58 HLA Class II alleles carried by the veterans in our sample and found that, of those, 18 (31%) were present in the vaccinated group that did not develop GWI but were absent from the vaccinated group who developed GWI. Remarkably, in silico analyses revealed very high binding affinities of peptide-binding motifs of those 18 HLA alleles with fragments of anthrax vaccine PA, leading to the successful production of anti-PA antibodies. Conversely, the absence of these protective HLA alleles points to a reduced ability to develop antibodies against PA, thus resulting in harmful PA persistence and development of GWI.

Abstract Background Muscadine grape (Vitis rotundifolia) is resistant to many of the pathogens that negatively impact the production of common grape (V. vinifera), including the bacterial pathogen Xylella fastidiosa subsp. fastidiosa (Xfsf), which causes Pierce’s Disease (PD). Previous studies in common grape have indicated Xfsf delays host immune response with a complex O-chain antigen produced by the wzy gene. Muscadine cultivars range from tolerant to completely resistant to Xfsf, but the mechanism is unknown. Results We assembled and annotated a new, long-read genome assembly for ‘Carlos’, a cultivar of muscadine that exhibits tolerance, to build upon the existing genetic resources available for muscadine. We used these resources to construct an initial pan-genome for three cultivars of muscadine and one cultivar of common grape. This pan-genome contains a total of 34,970 synteny-constrained entries containing genes of similar structure. Comparison of resistance gene content between the ‘Carlos’ and common grape genomes indicates an expansion of resistance (R) genes in ‘Carlos.’ We further identified genes involved in Xfsf response by transcriptome sequencing ‘Carlos’ plants inoculated with Xfsf. We observed 234 differentially expressed genes with functions related to lipid catabolism, oxidation-reduction signaling, and abscisic acid (ABA) signaling as well as seven R genes. Leveraging public data from previous experiments of common grape inoculated with Xfsf, we determined that most differentially expressed genes in the muscadine response were not found in common grape, and three of the R genes identified as differentially expressed in muscadine do not have an ortholog in the common grape genome. Conclusions Our results support the utility of a pan-genome approach to identify candidate genes for traits of interest, particularly disease resistance to Xfsf, within and between muscadine and common grape.

Abstract Background Cartilaginous neoplasms can be challenging to grade; there is a need to create an evidence-based rubric for grading. The goal of this study was to identify histopathologic features of chondrosarcoma that were associated with 5-year survival and to compare these to traditional patient, tumor and treatment variables. Methods This was a retrospective review of all patients undergoing surgical resection of a primary chondrosarcoma with at least 2 years of follow up. All specimens were independently reviewed by two pathologists and histopathologic features scored. Univariate and multivariate analyses were performed utilizing Kaplan Meier and proportional hazards methods to identify variables associated with 5-year disease specific survival (DSS) and disease free survival (DFS). Results We identified 51 patients with an average follow up of 49 months eligible for inclusion. 30% of tumors were low grade, 45% were intermediate grade, and 25% were high grade. In a univariate analysis considering histopathologic factors, higher tumor mitotic rate (HR 8.9, p

Abstract Objective To perform a review evaluating management of and complications stemming from dog bite trauma sustained to the head and neck over the past decade. Data Sources PubMed and Cochrane Library. Methods The authors searched the PubMed and Cochrane Library databases for relevant published literature. A total of 12 peer‐reviewed canine‐exclusive series inclusive of 1384 patient cases describing facial dog bite trauma met inclusion criteria. Wounds including fractures, lacerations, contusions, and other soft‐tissue injuries were evaluated. Demographics related to clinical course and management, operating room requirements, and antibiotic usage were compiled and analyzed. Initial trauma and surgical management complications were also assessed. Results 75.5% of patients sustaining dog bites required surgical intervention. Of these patients, 7.8% suffered from postsurgical complications, including hypertrophic scarring (4.3%), postoperative infection (0.8%), or nerve deficits and persistent paresthesias (0.8%). Prophylactic antibiotics were administered to 44.3% of patients treated for facial dog bites and the overall infection rate was 5.6%. Concomitant fracture was present in 1.0% of patients. Conclusion Primary closure, often in the OR may be necessary, with few cases requiring grafts or flaps. Surgeons should be aware that the most common complication is hypertrophic scarring. Further research is needed to elucidate the role of prophylactic antibiotics.