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Abstract Tumor-associated macrophages (TAMs) residing in the tumor microenvironment (TME) are characterized by their pivotal roles in tumor progression, antitumor immunity, and TME remodeling. However, a thorough comparative characterization of tumor-TAM crosstalk across IDH-defined categories of glioma remains elusive, likely contributing to mixed outcomes in clinical trials. We delineated the phenotypic heterogeneity of TAMs across IDH-stratified gliomas. Notably, two TAM subsets with a mesenchymal phenotype were enriched in IDH-WT glioblastoma (GBM) and correlated with poorer patient survival and reduced response to anti-PD-1 immune checkpoint inhibitor (ICI). We proposed SLAMF9 receptor as a potential therapeutic target. Inference of gene regulatory networks identified PPARG, ELK1, and MXI1 as master transcription factors of mesenchymal BMD-TAMs. Our analyses of reciprocal tumor-TAM interactions revealed distinct crosstalk in IDH-WT tumors, including ANXA1-FPR1/3, FN1-ITGAVB1, VEGFA-NRP1, and TNFSF12-TNFRSF12A with known contribution to immunosuppression, tumor proliferation, invasion and TAM recruitment. Spatially resolved transcriptomics further elucidated the architectural organization of highlighted communications. Furthermore, we demonstrated significant upregulation of ANXA1, FN1, NRP1, and TNFRSF12A genes in IDH-WT tumors using bulk RNA-seq and RT-qPCR. Longitudinal expression analysis of candidate genes revealed no difference between primary and recurrent tumors indicating that the interactive network of malignant states with TAMs does not drastically change upon recurrence. Collectively, our study offers insights into the unique cellular composition and communication of TAMs in glioma TME, revealing novel vulnerabilities for therapeutic interventions in IDH-WT GBM.

Abstract Background Severe COVID-19 carries a high morbidity and mortality. Previous studies have shown an association between COVID-19 severity and SARS-CoV-2 viral load (VL). We sought to measure VL in multiple compartments (urine, plasma, lower respiratory tract) in patients admitted to the intensive care unit (ICU) with severe COVID-19 pneumonia and correlate with clinical outcomes. Methods Plasma, urine, and endotracheal aspirate (ETA) samples were obtained on days 1, 3, 7, 14, and 21 from subjects admitted to the ICU with severe COVID-19. VL was measured via reverse transcriptase polymerase chain reaction. Clinical data was collected from the electronic health record. Grouped comparisons were performed using Student’s t-test or 1-way ANOVA. Linear regression was used to correlate VL from different compartments collected at the same time. Logistic regression was performed to model ventilator-freedom at 28 days as a function of peak plasma VL. Results We enrolled 57 subjects with severe COVID-19 and measured VL in plasma (n = 57), urine (n = 25), and ETA (n = 34). Ventilator-associated pneumonia developed in 63% of subjects. 49% of subjects were viremic on study day 1. VL in plasma and ETA both significantly decreased by day 14 (P

Research on the use of digital devices to conduct tasks across work and non-work domains (i.e., boundary-crossing ICT use) grows rapidly. To gain an overview of this expanding field, we conducted a systematic search in 14 databases (e.g., WoS, PsycINFO) for studies examining the outcomes of performing 1) work-related tasks during non-work time and 2) non-work tasks during work time. After screening 17,388 abstracts, 398 were read in full text, and 159 publications were included. Most studies used cross-sectional interviews or self-report survey data of employees in high-income countries. The work-family interface, individual work and health outcomes were commonly studied, while family and organizational outcomes received little attention. Moreover, research with a multilevel perspective and studies examining objective outcomes (e.g., divorce, sick leave) were scarce and the performance of non-work tasks during work time was often ignored. Despite the burgeoning literature, there is an urgent need to arrive at a common conceptualization and operationalization of boundary-crossing ICT use to be able to compare findings across studies and disciplines. We suggest a new definition and future agenda to contribute to a deeper understanding of the field.

Abstract Global Earth system models are often enlisted to assess the impacts of climate variability and change on marine ecosystems. In this study, we compare high frequency (daily) outputs of potential ecosystem stressors, such as sea surface temperature and surface pH, and associated variables from an Earth system model (GFDL ESM4.1) with high frequency time series from a global network of moorings to directly assess the capacity of the model to resolve local biogeochemical variability on time scales from daily to interannual. Our analysis indicates variability in surface temperature is most consistent between ESM4.1 and observations, with a Pearson correlation coefficient of 0.93 and bias of 0.40°C, followed by variability in surface salinity. Physical variability is reproduced with greater accuracy than biogeochemical variability, and variability on seasonal and longer time scales is more consistent between the model and observations than higher frequency variability. At the same time, the well‐resolved seasonal and longer timescale variability is a reasonably good predictor, in many cases, of the likelihood of extreme events. Despite limited model representation of high frequency variability, model and observation‐based assessments of the fraction of days experiencing surface T‐pH and T‐Ωarag multistressor conditions show reasonable agreement, depending on the stressor combination and threshold definition. We also identify circumstances in which some errors could be reduced by accounting for model biases.

Student development theory has been an important guide in practice; however, few theories focus on both the individual and the influence of the environment. Spencer's (1997) Phenomenological Variant of Ecological Systems Theory (PVEST) examines the individual, the environment, and the role of environmental feedback on self-perceptions, with a specific focus on how this feedback influences student experiences and outcomes. PVEST allows for assessing the processes by which an individual can develop strategies to resist negative feedback from oppressive environments, as well as how individuals use different coping mechanisms. In this chapter, we apply PVEST to individual student-level exemplars, as well as examples within counseling and classroom microcontexts to demonstrate the importance of environmental influence as well as phenomenological individual differences in interpretations and self-perception. Ultimately, we demonstrate how PVEST is a theoretical mechanism to focus on both the person and their phenomenological experiences (PEs), and offer larger implications for use in higher education contexts.

DNA repair in response to DSBs in the preimplantation embryo is hard to analyze. Here the authors show that over 25% of pre-existing heterozygous loci in control single blastomere samples appeared as homozygous after whole genome amplification, therefore, they validated gene editing seen in human embryos in ESCs.

The accurate forecast of persistent orographic cold-air pools in numerical weather prediction models is essential for the optimal integration of wind energy into the electrical grid during these events. Model development efforts during the second Wind Forecast Improvement Project (WFIP2) aimed to address the challenges related to this. We evaluated three versions of the National Oceanic and Atmospheric Administration (NOAA) High-Resolution Rapid Refresh model with two different horizontal grid spacings against in situ and remote sensing observations to investigate how developments in physical parameterizations and numerical methods targeted during WFIP2 impacted the simulation of a persistent cold-air pool in the Columbia River basin. Differences amongst model versions were most apparent in simulated temperature and low-level cloud fields during the persistent phase of the cold-air pool. The model developments led to an enhanced low-level cloud cover, resulting in better agreement with the observations. This removed a diurnal cycle in the near-surface temperature bias at stations throughout the basin by reducing a cold bias during the night and a warm bias during the day. However, low-level clouds did not clear sufficiently during daytime in the newest model version, which leaves room for further model developments. The model developments also led to a better representation of the decay of the cold-air pool by slowing down its erosion.

Abstract The distribution of turbulent kinetic energy (TKE) and its budget terms is estimated in simulated tropical cyclones (TCs) of various intensities. Each simulated TC is subject to storm motion, wind shear, and oceanic coupling. Different storm intensities are achieved through different ocean profiles in the model initialization. For each oceanic profile, the atmospheric simulations are performed with and without TKE advection. In all simulations, the TKE is maximized at low levels (i.e., below 1 km) and ∼0.5 km radially inward of the azimuthal‐mean radius of maximum wind speed at 1‐km height. As in a previous study, the axisymmetric TKE decreases with height in the eyewall, but more abruptly in simulations without TKE advection. The largest TKE budget terms are shear generation and dissipation, though variability in vertical turbulent transport and buoyancy production affect the change in the azimuthal‐mean TKE distribution. The general relationships between the TKE budget terms are consistent across different radii, regardless of storm intensity. In terms of the asymmetric distribution in the eyewall, TKE is maximized in the front‐left quadrant where the sea surface temperature (SST) is highest and is minimized in the rear‐right quadrant where the SST is the lowest. In the category‐5 simulation, the height of the TKE maximum varies significantly in the eyewall between quadrants and is between ∼400 m in the rear‐right quadrant and ∼1,000 m in the front‐left quadrant. When TKE advection is included in the simulations, the maximum eyewall TKE values are downwind compared to the simulations without TKE advection.

Abstract Background In pragmatic trials, on-site partners, rather than researchers, lead intervention delivery, which may result in implementation variation. There is a need to quantitatively measure this variation. Applying the Framework for Implementation Fidelity (FIF), we develop an approach for measuring variability in site-level implementation fidelity. This approach is then applied to measure site-level fidelity in a cluster-randomized pragmatic trial of Music & MemorySM (M&M), a personalized music intervention targeting agitated behaviors in residents living with dementia, in US nursing homes (NHs). Methods Intervention NHs (N = 27) implemented M&M using a standardized manual, utilizing provided staff trainings and iPods for participating residents. Quantitative implementation data, including iPod metadata (i.e., song title, duration, number of plays), were collected during baseline, 4-month, and 8-month site visits. Three researchers developed four FIF adherence dimension scores. For Details of Content, we independently reviewed the implementation manual and reached consensus on six core M&M components. Coverage was the total number of residents exposed to the music at each NH. Frequency was the percent of participating residents in each NH exposed to M&M at least weekly. Duration was the median minutes of music received per resident day exposed. Data elements were scaled and summed to generate dimension-level NH scores, which were then summed to create a Composite adherence score. NHs were grouped by tercile (low-, medium-, high-fidelity). Results The 27 NHs differed in size, resident composition, and publicly reported quality rating. The Composite score demonstrated significant variation across NHs, ranging from 4.0 to 12.0 [8.0, standard deviation (SD) 2.1]. Scaled dimension scores were significantly correlated with the Composite score. However, dimension scores were not highly correlated with each other; for example, the correlation of the Details of Content score with Coverage was τ b = 0.11 (p = 0.59) and with Duration was τ b = − 0.05 (p = 0.78). The Composite score correlated with CMS quality star rating and presence of an Alzheimer’s unit, suggesting face validity. Conclusions Guided by the FIF, we developed and used an approach to quantitatively measure overall site-level fidelity in a multi-site pragmatic trial. Future pragmatic trials, particularly in the long-term care environment, may benefit from this approach. Trial registration Clinicaltrials.gov NCT03821844. Registered on 30 January 2019, https://clinicaltrials.gov/ct2/show/NCT03821844 .

Summary: Nucleic acid-binding polymers can have anti-inflammatory properties and beneficial effects in animal models of infection, trauma, cancer, and autoimmunity. PAMAM G3, a polyamidoamine dendrimer, is fully cationic bearing 32 protonable surface amines. However, while PAMAM G3 treatment leads to improved outcomes for mice infected with influenza, at risk of cancer metastasis, or genetically prone to lupus, its administration can lead to serosal inflammation and elevation of biomarkers of liver and kidney damage. Variants with reduced density of cationic charge through the interspersal of hydroxyl groups were evaluated as potentially better-tolerated alternatives. Notably, the variant PAMAM G3 50:50, similar in size as PAMAM G3 but with half the charge, was not toxic in cell culture, less associated with weight loss or serosal inflammation after parenteral administration, and remained effective in reducing glomerulonephritis in lupus-prone mice. Identification of such modified scavengers should facilitate their development as safe and effective anti-inflammatory agents.

OBJECTIVES:. The COVID-19 pandemic has claimed over eight hundred thousand lives in the United States alone, with older individuals and those with comorbidities being at higher risk of severe disease and death. Although severe acute respiratory syndrome coronavirus 2–induced hyperinflammation is one of the mechanisms underlying the high mortality, the association between age and innate immune responses in COVID-19 mortality remains unclear. DESIGN:. Flow cytometry of fresh blood and multiplexed inflammatory chemokine measurements of sera were performed on samples collected longitudinally from our cohort. Aggregate impact of comorbid conditions was calculated with the Charlson Comorbidity Index, and association between patient factors and outcomes was calculated via Cox proportional hazard analysis and repeated measures analysis of variance. SETTING:. A cohort of severely ill COVID-19 patients requiring ICU admission was followed prospectively. PATIENTS:. In total, 67 patients (46 male, age 59 ± 14 yr) were included in the study. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. Mortality in our cohort was 41.8%. We identified older age (hazard ratio [HR] 1.09 [95% CI 1.07–1.11]; p = 0.001), higher comorbidity index (HR 1.24 [95% CI 1.14–1.35]; p = 0.039), and hyponatremia (HR 0.90 [95% CI 0.82–0.99]; p = 0.026) to each independently increase risk for death in COVID-19. We also found that neutrophilia (R = 0.2; p = 0.017), chemokine C-C motif ligand (CCL) 2 (R = 0.3; p = 0.043), and C-X-C motif chemokine ligand 9 (CXCL9) (R = 0.3; p = 0.050) were weakly but significantly correlated with mortality. Older age was associated with lower monocyte (R = –0.2; p = 0.006) and cluster of differentiation (CD) 16+ cell counts (R = –0.2; p = 0.002) and increased CCL11 concentration (R = 0.3; p = 0.050). Similarly, younger patients (< 65 yr) demonstrated a rise in CD4 (b-coefficient = 0.02; p = 0.036) and CD8 (0.01; p = 0.001) counts, as well as CCL20 (b-coefficient = 6.8; p = 0.036) during their ICU stay. This CD8 count rise was also associated with survival (b-coefficient = 0.01; p = 0.023). CONCLUSIONS:. Age, comorbidities, and hyponatremia independently predict mortality in severe COVID-19. Neutrophilia and higher CCL2 and CXCL9 levels are also associated with higher mortality, while independent of age.

Introduction Vaccine hesitancy can lead to incomplete vaccination, increased risk of vaccine-preventable diseases, and distrust or conflict between physicians and patients. Yet many physicians are uncomfortable navigating vaccine hesitancy and educating vaccine-hesitant patients and families. We developed a vaccine hesitancy curriculum to increase vaccine knowledge, comfort, and communication skills in pediatric residents. Methods The curriculum consisted of four interactive 40-minute sessions delivered to pediatric residents over 10 months. The first two sessions discussed recommended childhood vaccines, the third session examined common vaccine misconceptions, and the final session reviewed vaccine hesitancy–specific communication skills, incorporating practice through role-playing. Residents completed pre- and posttests assessing knowledge and comfort as well as receiving a standardized patient (SP) assessment of vaccine-specific communication skills after the curriculum. Results Thirty-five residents were in the educational intervention group and 35 in a control group. Pretest scores did not differ significantly between the groups. The mean knowledge score for the intervention group increased from 47% on the pretest to 66% on the posttest. The mean self-reported comfort score (1 = low comfort, 5 = high comfort) for the intervention group increased from 2.9 on the pretest to 3.8 on the posttest. The control group showed no difference between pre- and posttest scores for knowledge or comfort. The mean postintervention SP assessment score was significantly higher for the intervention group (78%) than the control group (52%). Discussion Implementation of a comprehensive vaccine hesitancy curriculum resulted in improved vaccine knowledge, self-reported comfort, and communication skills among pediatric residents.

BackgroundThe COVID-19 pandemic disrupted medical care in the US, leading to a significant drop in utilization of some types of health services. We sought to quantify how the pandemic influenced obstetrics and gynecology care at two large health care organizations.Materials and methodsComparing 2020 to 2019, we quantified changes to obstetrics and gynecology care at two large health care organizations in the United States, Allegheny Health Network (in western Pennsylvania) and Johns Hopkins University (in Maryland). The analysis considered the numbers of surgical encounters, in-person visits, and telemedicine visits. For each system, we quantified temporal changes in surgical volume, in-person and telemedicine visits, and financial impact related to professional fee revenues. We used segmented regression to evaluate longitudinal effects.ResultsAt both institutions, the volume of care was similar in the first few months of 2020 compared to 2019 but dropped precipitously in March 2020. From April to June 2020, surgical volumes were 67% of the same period in 2019 at Allegheny Health and 48% of the same period in 2019 at Johns Hopkins. During that same interval, televisits accounted for approximately 21% of all ambulatory care at both institutions. Although surgical and ambulatory volumes recovered in the second half of 2020, annual surgical volumes in 2020 were significantly lower than 2019 at both institutions (pConclusionsObstetrical and gynecologic ambulatory visits and gynecologic surgeries were sharply reduced during the COVID-19 pandemic. Although care volumes returned to 2019 levels in late 2020, we observed an overall reduction in the volume of care provided and a 9% reduction in professional revenue for both institutions.

During the second Wind Forecast Improvement Project (WFIP2; October 2015–March 2017, held in the Columbia River Gorge and Basin area of eastern Washington and Oregon states), several improvements to the parameterizations used in the High Resolution Rapid Refresh (HRRR – 3 km horizontal grid spacing) and the High Resolution Rapid Refresh Nest (HRRRNEST – 750 m horizontal grid spacing) numerical weather prediction (NWP) models were tested during four 6-week reforecast periods (one for each season). For these tests the models were run in control (CNT) and experimental (EXP) configurations, with the EXP configuration including all the improved parameterizations. The impacts of the experimental parameterizations on the forecast of 80 m wind speeds (wind turbine hub height) from the HRRR and HRRRNEST models are assessed, using observations collected by 19 sodars and three profiling lidars for comparison. Improvements due to the experimental physics (EXP vs. CNT runs) and those due to finer horizontal grid spacing (HRRRNEST vs. HRRR) and the combination of the two are compared, using standard bulk statistics such as mean absolute error (MAE) and mean bias error (bias). On average, the HRRR 80 m wind speed MAE is reduced by 3 %–4 % due to the experimental physics. The impact of the finer horizontal grid spacing in the CNT runs also shows a positive improvement of 5 % on MAE, which is particularly large at nighttime and during the morning transition. Lastly, the combined impact of the experimental physics and finer horizontal grid spacing produces larger improvements in the 80 m wind speed MAE, up to 7 %–8 %. The improvements are evaluated as a function of the model's initialization time, forecast horizon, time of the day, season of the year, site elevation, and meteorological phenomena. Causes of model weaknesses are identified. Finally, bias correction methods are applied to the 80 m wind speed model outputs to measure their impact on the improvements due to the removal of the systematic component of the errors.

Overuse of nitrogen (N), an essential nutrient in food production systems, can lead to health issues and environmental degradation. Two parameters related to N efficiency, N Conversion Efficiency (NCE) and N Internal Efficiency (NIE), measure the amount of total biomass or grain produced, respectively, per unit of N in the plant. Utilizing remote sensing to improve these efficiency measures may positively impact the stewardship of agricultural N use in maize (Zea mays L.) production. We investigated in-season hyperspectral imaging for prediction of end-season whole-plant N concentration (pN), NCE, and NIE, using partial least squares regression (PLSR) models. Image data were collected at two mid-season growth stages (V16/V18 and R1/R2) from manned aircraft and unmanned aerial vehicles for three site years of 5 to 9 maize hybrids grown under 3 N treatments and 2 planting densities. PLSR models resulted in accurate predictions for pN at R6 (R2 = 0.73; R2 = 0.68) and NCE at R6 (R2 = 0.71; R2 = 0.73) from both imaging times. Additionally, the PLSR models based on the R1 images, the second imaging, accurately distinguished the highest and lowest ranked hybrids for pN and NCE across N rates. Neither timepoint resulted in accurate predictions for NIE. Genotype selection efficiency for end-season pN and NCE was increased through the use of the in-season PLSR imaging models, potentially benefiting early breeding screening methods.

Background: Primary hyperoxaluria type 1 (PH1) is a rare monogenic disorder characterized by excessive hepatic production of oxalate leading to recurrent nephrolithiasis, nephrocalcinosis, and progressive kidney damage, often requiring renal replacement therapy (RRT). Though systemic oxalate deposition is well-known, the natural history of PH1 during RRT has not been systematically described. In this study, we describe the clinical, laboratory, and echocardiographic features of a cohort of PH1 patients on RRT.Methods: Patients with PH1 enrolled in the Rare Kidney Stone Consortium PH Registry who progressed to require RRT, had ≥2 plasma oxalate (pOx) measurements 3–36 months after start of RRT, and at least one pair of pOx measurements between 6 and 18 months apart were retrospectively analyzed. Clinical, echocardiographic, and laboratory results were obtained from the Registry.Results: The 17 PH1 patients in our cohort had a mean total HD hours/week of 17.4 (SD 7.9; range 7.5–36) and a range of age of RRT start of 0.2–75.9 years. The average change in plasma oxalate (pOx) over time on RRT was −0.74 [−2.9, 1.4] μmol/L/month with the mean pOx never declining below 50 μmol/L. Over time on RRT, oxalosis progressively developed in multiple organ systems. Echocardiography performed on 13 subjects showed worsening of left ventricular global longitudinal strain correlated with pOx (p < 0.05).Conclusions: Even when a cohort of PH1 patients were treated with intensified RRT, their predialysis pOx remained above target and they developed increasing evidence of oxalosis. Echocardiographic data suggest that cardiac dysfunction could be related to elevated pOx and may worsen over time.

Turner syndrome is a rare disorder resulting from complete or partial loss of the second sex chromosome. Common manifestations include delayed growth, premature ovarian failure, congenital heart defects, endocrine disorders, lymphedema, and webbed neck. People with Turner syndrome have significantly increased mortality risk primarily due to cardiovascular abnormalities. The mechanisms that lead to these defects are not completely understood and are obscured by the significant variability of both karyotype and phenotype without consistent correlation between the two. This paper presents a review of the recent literature surrounding the symptoms, mechanisms, diagnosis, and treatment of Turner syndrome with a focus on cardiovascular manifestations. With technological advancements in genetics, the molecular processes of Turner syndrome have begun to be dissected. Certain genes on the X chromosome that typically escape inactivation have been implicated in both specific manifestations and broader risk categories. Recently identified genome-wide epigenetic changes may help explain the variability in presentation. It remains unclear as to how the combination of these factors results in the overall clinical picture, but advances in genomic, genetic, epigenetic, and -omics technology hold promise for providing insights that will improve the medical management of individuals with Turner syndrome.

As research into the biotic effects of ocean acidification has increased, the methods for simulating these environmental changes in the laboratory have multiplied. Here we describe the atmospheric carbon control simulator (ACCS) for the maintenance of plankton under controlled pCO2 conditions, designed for species sensitive to the physical disturbance introduced by the bubbling of cultures and for studies involving trophic interaction. The system consists of gas mixing and equilibration components coupled with large-volume atmospheric simulation chambers. These chambers allow gas exchange to counteract the changes in carbonate chemistry induced by the metabolic activity of the organisms. The system is relatively low cost, very flexible, and when used in conjunction with semi-continuous culture methods, it increases the density of organisms kept under realistic conditions, increases the allowable time interval between dilutions, and/or decreases the metabolically driven change in carbonate chemistry during these intervals. It accommodates a large number of culture vessels, which facilitate multi-trophic level studies and allow the tracking of variable responses within and across plankton populations to ocean acidification. It also includes components that increase the reliability of gas mixing systems using mass flow controllers.

Sponges are early-diverging marine organisms that establish complex symbioses with microorganisms. Here, Thomas et al.analyse the microbial communities associated with 81 species of sponges from around the world, shedding light on the ecological and evolutionary drivers of these host-microbe associations.