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Background: Until now, limited clinical significance had been reported for disseminated tumor cells (DTCs) in gynecologic malignancies. DTCs were previously reported not to be associated with established risk factors, L1CAM immunoreactivity, and outcome in endometrial carcinoma (EC). This study's primary objective was to investigate potential correlations of DTCs in the bone marrow (BM) of EC patients with disease-related survival, and a secondary objective was to evaluate associations between molecular classification of EC and DTCs. Methods: Patients treated for primary EC at Tuebingen University women's hospital between 2003 and 2016 were identified. A total of 402 patients with a complete set of BM cytology, molecular, and clinical data were evaluable. Results: DTC occurrence was distributed equally among all four molecular groups (p = 0.651). DTC positivity was associated with a less favorable disease-free survival (HR: 1.86, 95% CI: 1.03–3.36, p = 0.036) and progression-free survival (HR: 1.86, 95% CI: 1.01–3.44, p = 0.045). Presence of DTCs was associated with a higher frequency of distant disease recurrence (p = 0.017). Conclusions: In line with our previous findings, tumor cell dissemination is not associated with molecular features in our large cohort of primary EC patients. Since DTCs seem to be associated with survival and location of disease recurrence, further studies are needed to decisively define their role in EC survival. [ABSTRACT FROM AUTHOR]

This work combines experimental observations from the ASDEX Upgrade tokamak with related gyrokinetic simulations of the turbulence moving from L-mode toward, and beyond, the L–H transition. Dedicated experiments have been performed with slow steps of increasing electron cyclotron heating power. Gyrokinetic simulations of the edge turbulence of these plasmas highlight the key roles of the non-linear electromagnetic effects and the external flow shear (E × B shear), both related to the evolution of the plasma pressure profile with increasing heating power. The increase in the plasma βe destabilizes turbulence at low toroidal mode numbers, that, in turn, is strongly suppressed by the external flow shear. This allows the plasma pressure profiles to evolve without a sharp rise in the turbulent fluxes. When all the experimentally measured plasma parameters are consistently included as inputs of the local gyrokinetic simulations, both the experimental electron and ion heat fluxes are quantitatively reproduced on the whole L-mode phase of the selected discharge. Simulations carried out with edge parameters of an ELM-free H-mode phase still show the importance of the mechanisms discussed earlier while also indicating possible limitations of the local approach. [ABSTRACT FROM AUTHOR]

This work characterizes the core transport physics of SPARC early-campaign plasmas using the PORTALS-CGYRO framework. Empirical modeling of SPARC plasmas with L-mode confinement indicates an ample window of breakeven (Q > 1) without the need of H-mode operation. Extensive modeling of multi-channel (electron energy, ion energy, and electron particle) flux-matched conditions with the nonlinear CGYRO code for turbulent transport coupled to the macroscopic plasma evolution using PORTALS reveals that the maximum fusion performance to be attained will be highly dependent on the near-edge pressure. Stiff core transport conditions are found, particularly when fusion gain approaches unity, and predicted density peaking is found to be in line with empirical databases of particle source-free H-modes. Impurity optimization is identified as a potential avenue to increase fusion performance while enabling core-edge integration. Extensive validation of the quasilinear TGLF model builds confidence in reduced-model predictions. The implications of projecting L-mode performance to high-performance and burning-plasma devices is discussed, together with the importance of predicting edge conditions. [ABSTRACT FROM AUTHOR]

Simple Summary: Malignant melanoma is the deadliest form of skin cancer. Since resistance and relapse to established therapy regimes for the treatment of malignant melanoma still occur frequently, the development of novel therapeutics is the key to improve patient prognosis. The study aimed to understand the function of the natural compound Garcinol on melanoma cells to contribute to its potential use in tumor therapy. We could show that Garcinol reduced proliferation and induced apoptosis in melanoma cells. Furthermore, we showed that melanoma cells expressing T-cadherin (CDH13) respond more sensitively to garcinol treatment. We postulate, that particularly T-cadherin-positive-patients could be receptive to garcinol therapy. Targeted therapies with chemotherapeutic agents and immunotherapy with checkpoint inhibitors are among the systemic therapies recommended in the guidelines for clinicians to treat melanoma. Although there have been constant improvements in the treatment of melanoma, resistance to the established therapies continues to occur. Therefore, the purpose of this study was to explore the function of garcinol with regards to specific cancer properties such as proliferation and apoptosis. Garcinol, a natural compound isolated from the plant also known as mangosteen (Garcinia mangostana), is a newly discovered option for cancer treatment. Numerous pharmaceutical substances are derived from plants. For example, the derivates of camptothecin, extracted from the bark of the Chinese tree of happiness (Camptotheca acuminate), or paclitaxel, extracted from the bark of the Western yew tree (Taxus brevifolia), are used as anti-cancer drugs. Here, we show that garcinol reduced proliferation and induced apoptosis in melanoma cell lines. In addition, we found that those cells that are positive for the expression of the cell–cell adhesion molecule T-cadherin (CDH13) respond more sensitively to treatment with garcinol. After knock-down experiments with an siRNA pool against T-cadherin, the sensitivity to garcinol decreased and proliferation and anti-apoptotic behavior of the cells was restored. We conclude that patients who are T-cadherin-positive could especially benefit from a therapy with garcinol. [ABSTRACT FROM AUTHOR]

Background: The German Rivermead Post-Concussion Symptoms Questionnaire (RPQ) can be used to assess post-concussion symptoms (PCS) after traumatic brain injury (TBI) in adults, adolescents, and children. Methods: In this study, we examined the psychometric properties of the German RPQ proxy version (N = 146) for children (8—12 years) after TBI at the item, total and scale score level. Construct validity was analyzed using rank correlations with the proxy-assessed Post-Concussion Symptoms Inventory (PCSI-P), the Patient Health Questionnaire 9 (PHQ-9), and the Generalized Anxiety Disorder Scale 7 (GAD-7). Furthermore, sensitivity testing was performed concerning subjects' sociodemographic and injury-related characteristics. Differential item functioning (DIF) was analyzed to assess the comparability of RPQ proxy ratings for children with those for adolescents. Results: Good internal consistency was demonstrated regarding Cronbach's α (0.81—0.90) and McDonald's ω (0.84—0.92). The factorial validity of a three-factor model was superior to the original one-factor model. Proxy ratings of the RPQ total and scale scores were strongly correlated with the PCSI-P (ϱ = 0.50—0.69), as well as moderately to strongly correlated with the PHQ-9 (ϱ = 0.49—0.65) and the GAD-7 (ϱ = 0.44—0.64). The DIF analysis revealed no relevant differences between the child and adolescent proxy versions. Conclusions: The German RPQ proxy is a psychometrically reliable and valid instrument for assessing PCS in children after TBI. Therefore, RPQ self- and proxy-ratings can be used to assess PCS in childhood as well as along the lifespan of an individual after TBI. [ABSTRACT FROM AUTHOR]

Nuclear factor of activated T cells 5 (NFAT5) and cyclooxygenase 2 (COX2; PTGS2) both participate in diverse pathologies including cancer progression. However, the biological role of the NFAT5-COX2 signaling pathway in human endometrial cancer has remained elusive. The present study explored whether NFAT5 is expressed in endometrial tumors and if NFAT5 participates in cancer progression. To gain insights into the underlying mechanisms, NFAT5 protein abundance in endometrial cancer tissue was visualized by immunohistochemistry and endometrial cancer cells (Ishikawa and HEC1a) were transfected with NFAT5 or with an empty plasmid. As a result, NFAT5 expression is more abundant in high-grade than in low-grade endometrial cancer tissue. RNA sequencing analysis of NFAT5 overexpression in Ishikawa cells upregulated 37 genes and downregulated 20 genes. Genes affected included cyclooxygenase 2 and hypoxia inducible factor 1α (HIF1A). NFAT5 transfection and/or treatment with HIF-1α stabilizer exerted a strong stimulating effect on HIF-1α promoter activity as well as COX2 expression level and prostaglandin E2 receptor (PGE2) levels. Our findings suggest that activation of NFAT5—HIF-1α—COX2 axis could promote endometrial cancer progression. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide OBJECTIVES Decellularized aortic homografts (DAH) were introduced in 2008 as a further option for paediatric aortic valve replacement (AVR). METHODS Prospective, multicentre follow-up of all paediatric patients receiving DAH for AVR in 8 European centres. RESULTS A total of 143 DAH were implanted between February 2008 and February 2023 in 137 children (106 male, 74%) with a median age of 10.8 years (interquartile range 6.6–14.6). Eighty-four (59%) had undergone previous cardiac operations and 24 (17%) had undergone previous AVR. The median implanted DAH diameter was 21 mm (interquartile range 19–23). The median operation duration was 348 min (227–439) with a median cardiopulmonary bypass time of 212 min (171–257) and a median cross-clamp time of 135 min (113–164). After a median follow-up of 5.3 years (3.3–7.2, max. 15.2 years), the primary efficacy end-points peak gradient (median 14 mmHg, 9–28) and regurgitation (median 0.5, interquartile range 0–1, grade 0–3) showed good results but an increase over time. Freedom from death/explantation/endocarditis/bleeding/thromboembolism at 5 years were 97.8 ± 1.2/88.7 ± 3.3/99.1 ± 0.9/100 and 99.2 ± 0.8%, respectively. Freedom from death/explantation/endocarditis/bleeding/thromboembolism at 10 years were 96.3 ± 1.9/67.1 ± 8.0/93.6 ± 3.9/98.6 ± 1.4 and 86.9 ± 11.6%, respectively. In total, 21 DAH were explanted. Seven were replaced by a mechanical AVR, 1 Ross operation was performed and a re-do DAH was implanted in 13 patients with no redo mortality. The calculated expected adverse events were lower for DAH compared to cryopreserved homograft patients (mean age 8.4 years), and in the same range as for Ross patients (9.2 years) and mechanical AVR (13.0 years). CONCLUSIONS This large-scale prospective analysis demonstrates excellent mid-term survival using DAH with adverse event rates comparable to paediatric Ross procedures. [ABSTRACT FROM AUTHOR]

Malignant melanoma remains the most lethal form of skin cancer, exhibiting poor prognosis after forming distant metastasis. Owing to their potential tumor-suppressive properties by regulating oncogenes and tumor suppressor genes, microRNAs are important player in melanoma development and progression. We defined the loss of miR-101-3p expression in melanoma cells compared with melanocytes and melanoblast-related cells as an early event in tumor development and aimed to understand the tumor suppressive role of miR-101-3p and its regulation of important cellular processes. Reexpression of miR-101-3p resulted in inhibition of proliferation, increase in DNA damage, and induction of apoptosis. We further determined the nuclear structure protein Lamin B1, which influences nuclear processes and heterochromatin structure, ATRX, CASP3, and PARP as an important direct target of miR-101-3p. RNA sequencing and differential gene expression analysis after miR-101-3p reexpression supported our findings and the importance of loss of mir-101-3p for melanoma progression. The validated functional effects are related to genomic instability, as recent studies suggest miRNAs plays a key role in mediating this cellular process. Therefore, we concluded that miR-101-3p reexpression increases the genomic instability, leading to irreversible DNA damage, which leads to apoptosis induction. Our findings suggest that the loss of miR-101-3p in melanoma serves as an early event in melanoma progression by influencing the genomic integrity to maintain the increased bioenergetic demand. [ABSTRACT FROM AUTHOR]

Ground-based remote sensing instruments have been widely used for atmospheric research but applications for air quality monitoring remain limited. Compared to an in situ instrument that provides air quality conditions at the ground level, most remote sensing instruments are sensitive to a broad range of altitudes, often providing only integrated column observations. These column data can be more difficult to interpret and to relate to surface values and hence to "nose-height-level" health factors. This research utilized ground-based remote sensing and in situ air quality observations in the Canadian Oil Sands Region to investigate some of their differences. Vertical column densities (VCDs) of SO2 and NO2 retrieved by Pandora spectrometers located at the Oski-Otin site at Fort McKay, (Alberta, Canada), from 2013–2019 were analyzed along with measurements of SO2 and NO2 surface concentrations and meteorological data. Aerosol optical depth (AOD) observations by CIMEL sunphotometer were compared with surface PM2.5 data. The Oski-Otin site is surrounded by several large bitumen mining operations within the Athabasca Oil Sands Region (AOSR) with significant NO2 emissions from the mining fleet. Two major bitumen upgraders that are 20 km south-east of the site have total SO2 and NO2 emissions of about 40 kt yr-1 and 20 kt yr-1 respectively. It was demonstrated that remote sensing data from Pandora and CIMEL combined with high vertical resolution wind profiles can provide information about pollution sources and plume characteristics. Elevated SO2 VCDs are clearly observed for times with south and south-eastern winds, particularly at 200–300 m altitude (above ground level). High NO2 VCD values were observed from other directions (e.g., north-west) with less prominent impacts from 200–300 m winds. In situ ground observations of SO2 and NO2 show a different sensitivity with wind profiles, indicating they are less sensitive to elevated plumes than remote sensing instruments. In addition to measured wind data and lidar observed boundary layer height (BLH), modelled wind profiles and BLH from ERA-5 have been used to further examine the correlation between column and surface observations. The results show that the ratio of measured column and surface concentration values could show positive or negative correlation with BLH, which depends on the height of emission sources (e.g., emissions from high stacks or near surface). This study explores differences between remote sensing and in situ instruments in terms of their vertical, horizontal, and temporal sampling differences. Understanding and resolving these differences are critical for future analyses linking satellite, ground-based remote sensing, and in situ observations in air quality monitoring and research. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is a metabolically heterogeneous disease, and although the concept of heterogeneous cancer metabolism is known, its precise role in human breast cancer is yet to be fully elucidated. Methods: We investigated in an explorative approach a cohort of 42 primary mamma carcinoma patients with positron emission tomography/magnetic resonance imaging (PET/MR) prior to surgery, followed by histopathology and molecular diagnosis. From a subset of patients, which showed high metabolic heterogeneity based on tracer uptake and pathology classification, tumour centre and periphery specimen tissue samples were further investigated by a targeted breast cancer gene expression panel and quantitative metabolomics by nuclear magnetic resonance (NMR) spectroscopy. All data were analysed in a combinatory approach. Results: [18F]FDG (2‐deoxy‐2‐[fluorine‐18]fluoro‐d‐glucose) tracer uptake confirmed dominance of glucose metabolism in the breast tumour centre, with lower levels in the periphery. Additionally, we observed differences in lipid and proliferation related genes between luminal A and B subtypes in the centre and periphery. Tumour periphery showed elevated acetate levels and enrichment in lipid metabolic pathways genes especially in luminal B. Furthermore, serine was increased in the periphery and higher expression of thymidylate synthase (TYMS) indicated one‐carbon metabolism increased in tumour periphery. The overall metabolic activity based on [18F]FDG uptake of luminal B subtype was higher than that of luminal A and the difference between the periphery and centre increased with tumour grade. Conclusion: Our analysis indicates variations in metabolism among different breast cancer subtypes and sampling locations which details the heterogeneity of the breast tumours. Correlation analysis of [18F]FDG tracer uptake, transcriptome and tumour metabolites like acetate and serine facilitate the search for new candidates for metabolic tracers and permit distinguishing luminal A and B. This knowledge may help to differentiate subtypes preclinically or to provide patients guide for neoadjuvant therapy and optimised surgical protocols based on individual tumour metabolism. [ABSTRACT FROM AUTHOR]

Breast conserving resection with free margins is the gold standard treatment for early breast cancer recommended by guidelines worldwide. Therefore, reliable discrimination between normal and malignant tissue at the resection margins is essential. In this study, normal and abnormal tissue samples from breast cancer patients were characterized ex vivo by optical emission spectroscopy (OES) based on ionized atoms and molecules generated during electrosurgical treatment. The aim of the study was to determine spectroscopic features which are typical for healthy and neoplastic breast tissue allowing for future real-time tissue differentiation and margin assessment during breast cancer surgery. A total of 972 spectra generated by electrosurgical sparking on normal and abnormal tissue were used for support vector classifier (SVC) training. Specific spectroscopic features were selected for the classification of tissues in the included breast cancer patients. The average classification accuracy for all patients was 96.9%. Normal and abnormal breast tissue could be differentiated with a mean sensitivity of 94.8%, a specificity of 99.0%, a positive predictive value (PPV) of 99.1% and a negative predictive value (NPV) of 96.1%. For 66.6% patients all classifications reached 100%. Based on this convincing data, a future clinical application of OES-based tissue differentiation in breast cancer surgery seems to be feasible. [ABSTRACT FROM AUTHOR]

The Mayer–Rokitansky–Küster–Hauser syndrome is characterized by aplasia of the uterus and upper two-thirds of the vagina. While it can appear as an isolated genital malformation, it is often associated with extragenital abnormalities, with little still known about the pathogenetic background. To provide an overview of associated malformations and syndromes as well as to examine possible ties between the rudimentary tissue and patient characteristics, we analyzed a cohort of 469 patients with MRKHS as well as 298 uterine rudiments removed during surgery. A total of 165 of our patients (35.2%) had associated malformations (MRKHS type II). Renal defects were the most common associated malformation followed by skeletal abnormalities. Several patients had atypical associated malformations or combined syndromes. Uterine rudiments were rarer in patients with associated malformations than in patients without them. Rudiment size ranged from 0.3 cm3 to 184.3 cm3 with a mean value of 7.9 cm3. Importantly, MRKHS subtype or concomitant malformations were associated with a different frequency of uterine tissue as well as a different rudiment size and incidence of endometrial tissue, thereby indicating a clear heterogeneity of the phenotype. Further research into the associated molecular pathways and potential differences between MRKHS subtypes is needed. [ABSTRACT FROM AUTHOR]

Pediatric health-related quality of life (HRQoL) as a measure of subjective wellbeing and functioning has received increasing attention over the past decade. HRQoL in children and adolescents following pediatric traumatic brain injury (pTBI) has been poorly studied, and performing adequate measurements in this population is challenging. This study compares child/adolescent and parent reports of HRQoL following pTBI using the newly developed Quality of Life after Brain Injury in Children and Adolescents (QOLIBRI-KID/ADO) questionnaire. Three hundred dyads of 8–17-year-old children/adolescents and their parents were included in the study. The parent–child agreement, estimated using intraclass correlation coefficients and Cohen's κ, displayed poor to moderate concordance. Approximately two-fifths of parents (39.3%) tended to report lower HRQoL for their children/adolescents on the total QOLIBRI-KID/ADO score. At the same time, about one-fifth (21.3%) reported higher HRQoL Total scores for their children/adolescents. The best agreement for parents rating adolescents (aged 13–17 years) was found in terms of the Total score and the Cognition and Self scale scores. To date, parent-reported HRQoL has been the preferred choice in pediatric research after TBI. However, with a parent–child disagreement of approximately 60%, our results highlight the importance of considering self-reports for children/adolescents capable of answering or completing the HRQoL measures. [ABSTRACT FROM AUTHOR]

JET experiments using the fuel mixture envisaged for fusion power plants, deuterium and tritium (D–T), provide a unique opportunity to validate existing D–T fusion power prediction capabilities in support of future device design and operation preparation. The 2021 JET D–T experimental campaign has achieved D–T fusion powers sustained over 5 s in ITER-relevant conditions i.e. operation with the baseline or hybrid scenario in the full metallic wall. In preparation of the 2021 JET D–T experimental campaign, extensive D–T predictive modelling was carried out with several assumptions based on D discharges. To improve the validity of ITER D–T predictive modelling in the future, it is important to use the input data measured from 2021 JET D–T discharges in the present core predictive modelling, and to specify the accuracy of the D–T fusion power prediction in comparison with the experiments. This paper reports on the validation of the core integrated modelling with TRANSP, JINTRAC, and ETS coupled with a quasilinear turbulent transport model (Trapped Gyro Landau Fluid or QualLiKiz) against the measured data in 2021 JET D–T discharges. Detailed simulation settings and the heating and transport models used are described. The D–T fusion power calculated with the interpretive TRANSP runs for 38 D–T discharges (12 baseline and 26 hybrid discharges) reproduced the measured values within 20 %. This indicates the additional uncertainties, that could result from the measurement error bars in kinetic profiles, impurity contents and neutron rates, and also from the beam-thermal fusion reaction modelling, are less than 20 % in total. The good statistical agreement confirms that we have the capability to accurately calculate the D–T fusion power if correct kinetic profiles are predicted, and indicates that any larger deviation of the D–T fusion power prediction from the measured fusion power could be attributed to the deviation of the predicted kinetic profiles from the measured kinetic profiles in these plasma scenarios. Without any posterior adjustment of the simulation settings, the ratio of predicted D–T fusion power to the measured fusion power was found as 65%–96% for the D–T baseline and 81%–97% for D–T hybrid discharge. Possible reasons for the lower D–T prediction are discussed and future works to improve the fusion power prediction capability are suggested. The D–T predictive modelling results have also been compared to the predictive modelling of the counterpart D discharges, where the key engineering parameters are similar. Features in the predicted kinetic profiles of D–T discharges such as underprediction of ne are also found in the prediction results of the counterpart D discharges, and it leads to similar levels of the normalized neutron rate prediction between the modelling results of D–T and the counterpart D discharges. This implies that the credibility of D–T fusion power prediction could be a priori estimated by the prediction quality of the preparatory D discharges, which will be attempted before actual D–T experiments. [ABSTRACT FROM AUTHOR]

Gyro-fluid equations are velocity space moments of the gyrokinetic equations. Special gyro-Landau-fluid closures have been developed that include the damping due to kinetic resonances by fitting to the collisionless local plasma response functions. This damping allows for accurate linear eigenmodes to be computed with a relatively low number of velocity space moments compared to the number of velocity quadrature points in gyrokinetic codes. However, none of the published gyro-Landau-fluid closure schemes considers the Onsager symmetries of the resulting quasi-linear fluxes as a constraint. Onsager symmetry guarantees that the matrix of diffusivities is positive definite, an important property for the numerical stability of a transport solver. A two parameter real closure for improving the accuracy of low resolution gyro-fluid equations, which preserves the Onsager symmetry and allows higher velocity space moments, is presented in this paper. The new linear gyro-fluid system (GFS) is used to extend the TGLF quasi-linear transport model so that it can compute the energy and momentum fluxes due to parallel magnetic fluctuations, completing the transport matrix. The GFS equations do not use a bounce average approximation. The GFS equations are fully electromagnetic with general flux surface magnetic geometry, pitch angle scattering for electron collisions, and subsonic equilibrium toroidal rotation. Using GFS eigenmodes in the quasi-linear TGLF model will be shown to yield a more accurate match to fluxes computed by CGYRO turbulence simulations. Prospects for future applications of a quasi-linear theory to new plasma transport regimes and magnetic confinement devices in addition to tokamaks are opened by the flexibility of the GFS eigensolver. [ABSTRACT FROM AUTHOR]

The article focuses on the role of the National Coalition for Infant Health (NCfIH) in promoting patient-centered care for infants and their families through collaborative efforts, education, and advocacy. Topics include the vulnerability of infants, the importance of supporting education and awareness, and the need for effective policymaking to ensure access to appropriate healthcare for all infants, whether born at term or prematurely.

The STEP (Stability, Transport, Equilibrium, and Pedestal) integrated-modeling tool has been developed in OMFIT to predict stable, tokamak equilibria self-consistently with core-transport and pedestal calculations. STEP couples theory-based codes to integrate a variety of physics, including magnetohydrodynamic stability, transport, equilibrium, pedestal formation, and current-drive, heating, and fueling. The input/output of each code is interfaced with a centralized ITER-Integrated Modelling & Analysis Suite data structure, allowing codes to be run in any order and enabling open-loop, feedback, and optimization workflows. This paradigm simplifies the integration of new codes, making STEP highly extensible. STEP has been verified against a published benchmark of six different integrated models. Core-pedestal calculations with STEP have been successfully validated against individual DIII-D H-mode discharges and across more than 500 discharges of the H 98 , y 2 database, with a mean error in confinement time from experiment less than 19%. STEP has also reproduced results in less conventional DIII-D scenarios, including negative-central-shear and negative-triangularity plasmas. Predictive STEP modeling has been used to assess performance in several tokamak reactors. Simulations of a high-field, large-aspect-ratio reactor show significantly lower fusion power than predicted by a zero-dimensional study, demonstrating the limitations of scaling-law extrapolations. STEP predictions have found promising scenarios for an EXhaust and Confinement Integration Tokamak Experiment, including a high-pressure, 80%-bootstrap-fraction plasma. ITER modeling with STEP has shown that pellet fueling enhances fusion gain in both the baseline and advanced-inductive scenarios. Finally, STEP predictions for the SPARC baseline scenario are in good agreement with published results from the physics basis. [ABSTRACT FROM AUTHOR]

Despite tremendous progress in deciphering breast cancer at the genomic level, the pronounced intra- and intertumoral heterogeneity remains a major obstacle to the advancement of novel and more effective treatment approaches. Frequent treatment failure and the development of treatment resistance highlight the need for patient-derived tumor models that reflect the individual tumors of breast cancer patients and allow a comprehensive analyses and parallel functional validation of individualized and therapeutically targetable vulnerabilities in protein signal transduction pathways. Here, we introduce the generation and application of breast cancer patient-derived 3D microtumors (BC-PDMs). Residual fresh tumor tissue specimens were collected from n = 102 patients diagnosed with breast cancer and subjected to BC-PDM isolation. BC-PDMs retained histopathological characteristics, and extracellular matrix (ECM) components together with key protein signaling pathway signatures of the corresponding primary tumor tissue. Accordingly, BC-PDMs reflect the inter- and intratumoral heterogeneity of breast cancer and its key signal transduction properties. DigiWest®-based protein expression profiling of identified treatment responder and non-responder BC-PDMs enabled the identification of potential resistance and sensitivity markers of individual drug treatments, including markers previously associated with treatment response and yet undescribed proteins. The combination of individualized drug testing with comprehensive protein profiling analyses of BC-PDMs may provide a valuable complement for personalized treatment stratification and response prediction for breast cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Squamous cell cancer (SCC) of the vulva is one of the rare gynecological malignancies, and surgery is the initial treatment of choice for early-stage vulvar cancer. International guidelines offer conflicting recommendations regarding surgical and pathological tumor-free resection margins for SCC of the vulva. The aim of this study was therefore to analyze the node-negative patients with SCC of the vulva treated with surgery alone at the Department of Women's Health, University Clinic, Tuebingen, Germany with regard to the achieved marginal distance and its impact on prognosis. The present study observed no significant impact of pathological tumor-free resection margin distance following surgery in patients with node-negative SCC of the vulva on disease-free and overall survival. Background: The aim of this study was to evaluate the impact of pathological tumor-free margin distance on survival in SCC patients treated with surgery alone. Methods: This retrospective study included 128 patients with node-negative disease that received no adjuvant treatment. Disease-free and overall survival were analyzed according to pathological tumor-free margin distance. Results: The patients were subclassified into three resection margin category groups: "1 to 3 mm" (n = 42), ">3 to 8 mm" (n = 47) or ">8 mm" (n = 39). Thirty-nine of the 128 patients (30.5%) developed recurrent disease. Median follow-up for disease-free survival (DFS) was 6.49 years (95% CI 5.16 years; 7.62 years), and median follow-up for overall survival (OS) was 6.29 years (95% CI 5.45 years; 7.33 years). The 5-year DFS rate was 0.70 (95% CI: 0.62–0.79), and the 5-year OS rate was 0.79 (95% CI: 0.71–0.87). Regarding the survival outcome, there were no independent significant differences in either disease-free survival (DFS) (p = 0.300) or overall survival (p = 1.000) among patients within the three tumor-free resection margin categories. Multivariate analyses did not show any statistically significant association between tumor-free resection margin distance and recurrent disease or death, either when analyzed as a categorical variable or when analyzed as a continuous variable. Conclusion: The present study did not show a significant impact of pathological tumor-free resection margin distance following surgery in patients with node-negative SCC of the vulva (that did not receive adjuvant treatment) on disease-free and overall survival. [ABSTRACT FROM AUTHOR]

The subjective impact of the consequences of pediatric traumatic brain injury (pTBI) on different life dimensions should be assessed multidimensionally and as sensitively as possible using a disease-specific health-related quality of life (HRQoL) instrument. The development and psychometrics of the first such self-report questionnaire for children and adolescents after TBI are reported here. Focus group interviews with children, adolescents, and their parents, cognitive debriefing, item pool generation and reduction using Delphi expert panels were performed. The resulting version was psychometrically tested on 300 individuals aged 8–17 years. After item reduction based on factor analyses, differential item functioning, reliability, and validity were investigated. The final 35 items were associated with six scales (Cognition, Self, Daily Life and Autonomy, Social Relationships, Emotions, Physical Problems). Internal consistency and construct validity were satisfactory. Health-related Quality of life (HRQoL) was significantly lower in older and in female participants, as well as those with cognitive disabilities, anxiety, depression and post-concussion symptoms, than in comparative groups. The new QOLIBRI-KID/ADO is a comprehensive, multidimensional, reliable, and valid instrument, comparable in content and items to the QOLIBRI adult version. Therefore, disease-specific HRQoL can now be measured across the lifespan and may support the amelioration of treatment, care, rehabilitation, and daily life of children and adolescents after TBI. [ABSTRACT FROM AUTHOR]

Aim: Reliably diagnosing or safely excluding serous tubal intraepithelial carcinoma (STIC), a precursor lesion of tubo‐ovarian high‐grade serous carcinoma (HGSC), is crucial for individual patient care, for better understanding the oncogenesis of HGSC, and for safely investigating novel strategies to prevent tubo‐ovarian carcinoma. To optimize STIC diagnosis and increase its reproducibility, we set up a three‐round Delphi study. Methods and results: In round 1, an international expert panel of 34 gynecologic pathologists, from 11 countries, was assembled to provide input regarding STIC diagnosis, which was used to develop a set of statements. In round 2, the panel rated their level of agreement with those statements on a 9‐point Likert scale. In round 3, statements without previous consensus were rated again by the panel while anonymously disclosing the responses of the other panel members. Finally, each expert was asked to approve or disapprove the complete set of consensus statements. The panel indicated their level of agreement with 64 statements. A total of 27 statements (42%) reached consensus after three rounds. These statements reflect the entire diagnostic work‐up for pathologists, regarding processing and macroscopy (three statements); microscopy (eight statements); immunohistochemistry (nine statements); interpretation and reporting (four statements); and miscellaneous (three statements). The final set of consensus statements was approved by 85%. Conclusion: This study provides an overview of current clinical practice regarding STIC diagnosis amongst expert gynecopathologists. The experts' consensus statements form the basis for a set of recommendations, which may help towards more consistent STIC diagnosis. [ABSTRACT FROM AUTHOR]

Purpose: Preoperative risk stratification of newly diagnosed endometrial carcinoma (EC) patients has been hindered by only moderate prediction performance for many years. Recently ENDORISK, a Bayesian network model, showed high predictive performance. It was the aim of this study to validate ENDORISK by applying the model to a population-based case series of EC patients. Methods: ENDORISK was applied to a retrospective cohort of women surgically treated for EC from 2003 to 2013. Prediction accuracy for LNM as well as 5-year DSS was investigated. The model's overall performance was quantified by the Brier score, discriminative performance by area under the curve (AUC). Results: A complete dataset was evaluable from 247 patients. 78.1% cases were endometrioid histotype. The majority of patients (n = 156;63.2%) had stage IA disease. Overall, positive lymph nodes were found in 20 (8.1%) patients. Using ENDORISK predicted probabilities, most (n = 156;63.2%) patients have been assigned to low or very low risk group with a false-negative rate of 0.6%. AUC for LNM prediction was 0.851 [95% confidence interval (CI) 0.761–0.941] with a Brier score of 0.06. For 5-year DSS the AUC was 0.698 (95% CI 0.595–0.800) as Brier score has been calculated 0.09. Conclusions: We were able to successfully validate ENDORISK for prediction of LNM and 5-year DSS. Next steps will now have to focus on ENDORISK performance in daily clinical practice. In addition, incorporating TCGA-derived molecular subtypes will be of key importance for future extended use. This study may support further promoting of data-based decision-making tools for personalized treatment of EC. [ABSTRACT FROM AUTHOR]

The emission of SO 2 from the Athabasca Oil Sands Region (AOSR) has been shown to impact the surrounding forest area. Recent studies using aircraft-based measurements have demonstrated that deposition of SO 2 to the forest is at a rate many times higher than model estimates. Here we use the flux–gradient method to estimate SO 2 deposition rates at two tower sites in the boreal forest downwind of AOSR SO 2 emissions. We use both continuous and passive sampler measurements and compare the two techniques. The measurements infer SO 2 deposition velocities ranging from 2.1–5.9 cm s -1 (when corrections are applied). There are uncertainties associated with the passive sampler flux–gradient analysis, primarily due to an assumed Schmidt number, a required assumption of independent variables, and potential wind effects. We estimate the total uncertainty as ± 2 cm s -1. Accounting for these uncertainties, the range of measurements is approximately double the previous aircraft-based measurements (1.2–3.4 cm s -1) and more than 10 times higher than model estimates for the same measurement periods (0.1–0.6 cm s -1), suggesting that SO 2 in the AOSR has a much shorter lifetime in the atmosphere than is currently predicted by models. [ABSTRACT FROM AUTHOR]

The article focuses on the importance of involving Neonatal Intensive Care Unit (NICU) and Pediatric Intensive Care Unit (PICU) clinicians in hospital procurement processes for medications, devices, and supplies to ensure the safety of vulnerable infants and young children. It highlights the challenges of inefficient procurement, the need for tailored care for infants, and calls for policies incentivizing the development of medications specifically for neonatal and pediatric populations.

Background: HPV-related cervical cancer (CC) is the fourth most frequent cancer in women worldwide. Cell-free tumour DNA is a potent biomarker to detect treatment response, residual disease, and relapse. We investigated the potential use of cell-free circulating HPV-DNA (cfHPV-DNA) in plasma of patients with CC. Methods: cfHPV-DNA levels were measured using a highly sensitive next-generation sequencing-based approach targeting a panel of 13 high-risk HPV types. Results: Sequencing was performed in 69 blood samples collected from 35 patients, of which 26 were treatment-naive when the first liquid biopsy sample was retrieved. cfHPV-DNA was successfully detected in 22/26 (85%) cases. A significant correlation between tumour burden and cfHPV-DNA levels was observed: cfHPV-DNA was detectable in all treatment-naive patients with advanced-stage disease (17/17, FIGO IB3–IVB) and in 5/9 patients with early-stage disease (FIGO IA–IB2). Sequential samples revealed a decrease of cfHPV-DNA levels in 7 patients corresponding treatment response and an increase in a patient with relapse. Conclusions: In this proof-of-concept study we demonstrated the potential of cfHPV-DNA as a biomarker for therapy monitoring in patients with primary and recurrent CC. Our findings facilitate the development of a sensitive and precise, non-invasive, inexpensive, and easily accessible tool in CC diagnosis, therapy monitoring and follow-up. [ABSTRACT FROM AUTHOR]

Introduction: The intention of this study was to evaluate the level of anxiety and depression of malignant ovarian germ cell (MOGCT) and sex cord stromal tumors (SCST) survivors and to identify possible alterable cofactors. Methods: CORSETT was an observational, multicenter, mixed retrospective/prospective cohort study of the AGO Studygroup. Women who had been diagnosed with MOGCTs and SCSTs between 2001 and 2011 were asked to complete the Hospital Anxiety and Depression Scale (HADS) to evaluate distress. Predictors of distress (type of surgery, chemotherapy, time since diagnosis, recurrence, second tumor, pain) were investigated using multivariate linear regression analysis. Results: 150 MOGCT and SCST patients with confirmed histological diagnosis completed the questionnaire median seven years after diagnosis. They had a HADS total score ≥ 13 indicating severe mental distress in 34% of cases. Patients after fertility-conserving surgery had lower probability of severe mental distress than those without fertility-conserving treatment (β = − 3.1, p = 0.04). Pain was associated with the level of distress in uni- and multivariate analysis (coef 0.1, p < 0.01, coef. Beta 0.5). Discussion: Severe mental distress was frequent in patients with MOGCT and SCST and the level of pain was associated with the level of distress. Fertility conserving therapy, however, was associated with less mental distress. Screening and treatment of pain and depression is required to improve mental well-being in survivors of MOGCT and SCST. [ABSTRACT FROM AUTHOR]

Investigation of linear gyrokinetic ion-scale modes ( k θ ρ s = 0.3) finds that a transition from ion temperature gradient to microtearing mode (MTM) dominance occurs as the density is increased near the pedestal region of a parameterized DIII-D sized tokamak. H-modes profile densities, temperatures, and equilibria are parameterized utilizing the OMFIT PRO_create module. With these profiles, linear gyrokinetic ion-scale instabilities are predicted with CGYRO. This transition (nMTM) has a weak dependence on radial location in the region near the top of the pedestal (ρ = 0.7 − 0.9), which allows simulating single radii to examine the approximate scaling of nMTM with global parameters. The critical nMTM is found to scale with plasma current. Additionally, increasing the minor radius by decreasing the aspect ratio and increasing the major radius are found to reduce nMTM. However, any relationship between nMTM and density limit physics remains unclear as nMTM increases relative to the Greenwald density with larger minor radius and with larger magnetic field, suggesting that the transport due to MTM may be less important for a reactor. Additionally, nMTM is sensitive to the pedestal temperature, the local electron and ion gradients, the ratio of ion to electron temperature T i / T e , and the current profile. MTMs are predicted to be the dominant instability in the core at similar Greenwald fractions for DIII-D, NSTX, and NSTX-U H-mode experiments, supporting the results of the parameterized study. Additionally, MTMs continue to be the dominant linear instability in a DIII-D L-mode after an H–L transition as the plasma approaches a density limit disruption despite the large change in plasma profiles. [ABSTRACT FROM AUTHOR]

Measurements of size-resolved aerosol concentration and fluxes were made in a forest in the Athabasca Oil Sands Region (AOSR) of Alberta, Canada, in August 2021 with the aim of investigating (a) particle size distributions from different sources, (b) size-resolved particle deposition velocities, and (c) the rate of vertical mixing in the canopy. Particle size distributions were attributed to different sources determined by wind direction. Air mixed with smokestack plumes from oil sands processing facilities had higher number concentrations with peak number at diameters near 70 nm. Aerosols from the direction of open-pit mine faces showed number concentration peaks near 150 nm and volume distribution peaks near 250 nm (with secondary peaks near 600 nm). Size-resolved deposition fluxes were calculated which show good agreement with previous measurements and a recent parameterization. There is a minimum deposition velocity of vd=0.02 cm s -1 for particles of 80 nm diameter; however, there is a large amount of variation in the measurements, and this value is not significantly different from zero in the 68 % confidence interval. Finally, gradient measurements of aerosol particles (with diameters <1 µ m) demonstrated nighttime decoupling of air within and above the forest canopy, with median lag times at night of up to 40 min and lag times between 2 and 5 min during the day. Aerosol mass fluxes (diameters <1 µ m) determined using flux–gradient methods (with different diffusion parameterizations) underestimate the flux magnitude relative to eddy covariance flux measurements when averaged over the nearly 1-month measurement period. However, there is significant uncertainty in the averages determined using the flux–gradient method. [ABSTRACT FROM AUTHOR]

Simple Summary: The development of novel therapies for cancer treatment is the key to improve patient prognosis. Cold atmospheric plasma (CAP) is a promising technology to treat all kinds of cancers, but the exact mechanisms of its action have not yet been identified. This study aimed to understand the effects of CAP treatment on melanoma cells to contribute to its potential use in tumor therapy. We identified a strong activation of the unfolded protein response along with a reduction in intracellular ceramide levels, which were linked to each other and to CAP-induced cell death. Furthermore, we showed that pharmacological reduction in ceramides strengthens the effects of CAP treatment in melanoma cells. Cold atmospheric plasma (CAP) describes a partially ionized gas carrying large amounts of reactive oxygen (ROS) and nitrogen species (RNS). Numerous studies reported strong antitumor activity of CAP, thus rendering it a promising approach for tumor therapy. Although several cellular mechanisms of its cytotoxicity were identified in recent years, the exact molecular effects and contributing signaling pathways are yet to be discovered. We discovered a strong activation of unfolded protein response (UPR) after CAP treatment with increased C/EBP homologous protein (CHOP) expression, which was mainly caused by protein misfolding and calcium loss in the endoplasmic reticulum. In addition, both ceramide level and ceramide metabolism were reduced after CAP treatment, which was then linked to the UPR activation. Pharmacological inhibition of ceramide metabolism resulted in sensitization of melanoma cells for CAP both in vitro and ex vivo. This study identified a novel mechanism of CAP-induced apoptosis in melanoma cells and thereby contributes to its potential application in tumor therapy. [ABSTRACT FROM AUTHOR]

Melanoma inhibitory activity/cartilage-derived retinoicacid-sensitive protein (MIA/CD-RAP) is a protein expressed and secreted by chondrocytes and cartilaginous tissues. MIA/CD-RAP-deficient mice develop milder osteoarthritis than wildtype mice. In this study, we investigated MIA/CD-RAP downstream targets to explain this reduced disease development. As a possible mediator, we could detect matrix metalloproteinase 13 (MMP13), and the influence of MIA/CD-RAP on MMP13 regulation was analyzed in vitro using SW1353 chondrosarcoma cells and primary chondrocytes. The femoral head cartilage of WT and MIA/CD-RAP −/− mice were cultured ex vivo to further investigate MMP13 activity. Finally, osteoarthritis was surgically induced via DMM in C57BL/6 mice, and the animals were treated with an MIA/CD-RAP inhibitory peptide by subcutaneously implanted pellets. MMP13 was regulated by MIA/CD-RAP in SW1353 cells, and MIA/CD-RAP −/− murine chondrocytes showed less expression of MMP13. Further, IL-1β-treated MIA/CD-RAP −/− chondrocytes displayed less MMP13 expression and activity. Additionally, MIA/CD-RAP-deficient ex vivo cultured cartilage explants showed less MMP13 activity as well as reduced cartilage degradation. The mice treated with the MIA/CD-RAP inhibitory peptide showed less osteoarthritis development. Our findings revealed MIA/CD-RAP as a new regulator of MMP13 and highlighted its role as a potential new target for osteoarthritis therapy. [ABSTRACT FROM AUTHOR]

The Rivermead Post-Concussion Symptoms Questionnaire (RPQ) assesses post-concussion symptoms (PCS) after traumatic brain injury (TBI). The current study examines the applicability of self-report and proxy versions of the German RPQ in adolescents (13–17 years) after TBI. We investigated reliability and validity on the total and scale score level. Construct validity was investigated by correlations with the Post-Concussion Symptoms Inventory (PCSI-SR13), Generalized Anxiety Disorder Scale 7 (GAD-7), and Patient Health Questionnaire 9 (PHQ-9) and by hypothesis testing regarding individuals' characteristics. Intraclass correlation coefficients (ICC) assessed adolescent–proxy agreement. In total, 148 adolescents after TBI and 147 proxies completed the RPQ. Cronbach's α (0.81–0.91) and McDonald's ω (0.84–0.95) indicated good internal consistency. The three-factor structure outperformed the unidimensional model. The RPQ was strongly correlated with the PCSI-SR13 (self-report: r = 0.80; proxy: r = 0.75) and moderately–strongly with GAD-7 and PHQ-9 (self-report: r = 0.36, r = 0.35; proxy: r = 0.53, r = 0.62). Adolescent–proxy agreement was fair (ICC [2,1] = 0.44, CI95% [0.41, 0.47]). Overall, both self-report and proxy assessment forms of the German RPQ are suitable for application in adolescents after TBI. As proxy ratings tend to underestimate PCS, self-reports are preferable for evaluations. Only if a patient is unable to answer, a proxy should be used as a surrogate. [ABSTRACT FROM AUTHOR]

Chitin nanofibrils (CN) can be obtained from crustaceans and fungal sources and can be used for preparing coatings for bioplastic films, that are fundamental for developing a safe and sustainable biodegradable food packaging. Coatings with different concentrations of CN from shrimps were applied on different bioplastic substrates, like Poly (butylene succinate-co-adipate)/Poly(3-hydroxybutyrate-co-3-hydroxyvalerate (PBSA/PHBV) blend, Polybutylene succinate (PBS), and Polybutylene adipate terephthalate/Poly(lactic acid) (PBAT/PLA) blend, but the adhesion to the substrates was scarce. On the contrary, the fungal-based CN showed a better adhesion. Additionally, it was found that the use of an additive based on oligomeric lactic acid was useful to prepare a coating with an improved adhesion to bioplastics. The gas barrier properties to oxygen and water vapour of coated and un-coated films were measured, revealing an improvement of these properties thanks to applied coatings, especially towards the oxygen. Antimicrobial properties and biodegradation capacity were also evaluated revealing an antibacterial effect of the coatings that did not significantly interfere with their biodegradability. The results are discussed and interpreted considering the correlation between composition and macromolecular structures with the observed functional properties. [ABSTRACT FROM AUTHOR]

Simple Summary: Hormone receptor-positive (HR+), HER2-negative (HER2−) is the most common breast cancer subtype (approximately 75% of all breast cancer cases). Adjuvant chemotherapy can be administered to patients that undergo operative tumor removal with only few metastatic axillary lymph nodes (0–3). However, using classical risk biomarkers to guide adjuvant chemotherapy recommendation leads to overtreatment of patients including unnecessary possible chemotherapy-related toxicities. This prospective study assessed whether the multigene-expression assay Oncotype DX® that has been validated in two large clinical phase III trials, effectively reduces adjuvant chemotherapy recommendation in a real-world setting. This study could demonstrate that absolute adjuvant chemotherapy recommendation can be reduced by nearly 15% using Oncotype DX®. Furthermore, this study could show that the Oncotype DX® recurrence score correlates to classic biomarkers that are commonly used to classify the aggressiveness of breast cancer. Background: Patients with hormone receptor-positive (HR+), HER2-negative (HER2−) early breast cancer (eBC) with a high risk of relapse often undergo adjuvant chemotherapy. However, only a few patients will gain benefit from chemotherapy. Since classical tumor characteristics (grade, tumor size, lymph node involvement, and Ki67) are of limited value to predict chemotherapy efficacy, multigene expression assays such as the Oncotype DX® test were developed to reduce over- and undertreatment. The IRMA trial analyzed the impact of Recurrence Score® (RS) assessment on adjuvant treatment recommendations. Materials and methods: The RS result was assessed in patients with HR+/HER2− unilateral eBC with 0–3 pathologic lymph nodes who underwent primary surgical treatment at the Department for Women's Health of Tuebingen University, Germany. Therapy recommendations without knowledge of the RS result were compared to therapy recommendations with awareness of the RS result. Results: In total, 245 patients underwent RS assessment. Without knowledge of the RS result, 92/245 patients (37.6%) would have been advised to receive chemotherapy. After RS assessment, 56/245 patients (22.9%) were advised to undergo chemotherapy. Chemotherapy was waived in 47/92 patients (51.1%) that were initially recommended to receive it. Chemotherapy was added in 11/153 patients (7.2%) that were recommended to not receive it initially. Summary: Using the RS result to guide adjuvant treatment decisions in HR+/HER2− breast cancer led to a substantial reduction of chemotherapy. In view of the results achieved in prospective studies, the RS result is among other risk-factors suitable for the individualization of adjuvant systemic therapy. [ABSTRACT FROM AUTHOR]

The emission of SO2 from the Athabasca oil sands region (AOSR) has been shown to impact the surrounding forest area and human exposure. Recent studies using aircraft-based measurements have demonstrated that deposition of SO2 to the forest is at a rate many times higher than model estimates. Here we use the flux/gradient method to estimate SO2 deposition rates at two tower sites in the boreal forest downwind of AOSR SO2 emissions. We use both continuous and 15 passive sampler measurements and compare both techniques. The measurements predict SO2 deposition velocities ranging from 2.1-5.9 cm s-1. There are uncertainties associated with the passive sampler flux/gradient analysis, primarily due to an assumed Schmidt number, a required assumption of independent variables, and potential wind effects. We estimate the total uncertainty as ±2 cm s-1. Accounting for these uncertainties, the measurements are near (or slightly higher than) the previous aircraft-based measurements (1.2-3.2 cm s-1) and significantly higher than model estimates for the same measurement 20 periods (0.1-0.6 cm s-1), suggesting that SO2 has a much shorter lifetime in the atmosphere than is currently predicted by models. [ABSTRACT FROM AUTHOR]

Measurements of size-resolved aerosol concentration and fluxes were made in a forest in the Athabasca Oil Sands Region (AOSR) of Alberta, Canada in August 2021 with the aim of investigating a) particle size distributions from different sources, b) size-resolved particle deposition velocities, and c) the rate of vertical mixing in the canopy. Particle size distributions were attributed to different sources determined by wind direction. Background air from undeveloped forested areas air showed a peak number concentration for diameters near 70 nm while air mixed with upgrader smokestack plumes had higher number concentrations with peak number between diameters of 70 and 80 nm. Aerosols from the direction of open-pit mine faces showed number concentration peaks near 150 nm and volume distribution peaks near 250 nm (with secondary peaks near 600 nm). Size-resolved deposition fluxes were calculated which show good agreement with previous measurements and a recent parameterization. There is a minimum deposition velocity of vd = 0.02 cm s-1 for particles of 80 nm diameter; however, there is a large amount of variation in the measurements and this value is not significantly different from zero in the 68% confidence interval. Finally, gradient measurements of PM1 demonstrated nighttime decoupling of air within and above the forest canopy, with median lag times at night of up to 40 min, and lag times between 2 and 5 min during the day. PM1 fluxes determined using flux/gradient methods (with different diffusion parameterizations) underestimate the flux magnitude relative to eddy covariance flux measurements when averaged over the nearly 1-month measurement period. However, there is significant uncertainty in the averages determined using the flux/gradient method. [ABSTRACT FROM AUTHOR]

Wildfire impacts on air quality and climate are expected to be exacerbated by climate change with the most pronounced impacts in the boreal biome. Despite the large geographic coverage, there is limited information on boreal forest wildfire emissions, particularly for organic compounds, which are critical inputs for air quality model predictions of downwind impacts. In this study, airborne measurements of 193 compounds from 15 instruments, including 173 non-methane organics compounds (NMOG), were used to provide the most detailed characterization, to date, of boreal forest wildfire emissions. Highly speciated measurements showed a large diversity of chemical classes highlighting the complexity of emissions. Using measurements of the total NMOG carbon (NMOG T), the Σ NMOG was found to be 50 % ± 3 % to 53 % ± 3 % of NMOG T , of which, the intermediate- and semi-volatile organic compounds (I/SVOCs) were estimated to account for 7 % to 10 %. These estimates of I/SVOC emission factors expand the volatility range of NMOG typically reported. Despite extensive speciation, a substantial portion of NMOG T remained unidentified (47 % ± 15 % to 50 % ± 15 %), with expected contributions from more highly-functionalized VOCs and I/SVOCs. The emission factors derived in this study improve wildfire chemical speciation profiles and are especially relevant for air quality modelling of boreal forest wildfires. These aircraft-derived emission estimates were further linked with those derived from satellite observations demonstrating their combined value in assessing variability in modelled emissions. These results contribute to the verification and improvement of models that are essential for reliable predictions of near-source and downwind pollution resulting from boreal forest wildfires. [ABSTRACT FROM AUTHOR]

A new quasilinear saturation model SAT3 has been developed for the purpose of calculating radial turbulent fluxes in the core of tokamak plasmas. The new model is shown to be able to better recreate the isotope mass dependence of nonlinear gyrokinetic fluxes compared to contemporary quasilinear models, including SAT2 (Staebler et al 2021 Nucl. Fusion 61 116007), while performing at least as well in other key equilibrium parameters. By first quantifying the isotope scaling of gyrokinetic flux spectra, it is shown that the deviation from the gyroBohm scaling of fluxes originates primarily in the magnitude of the saturated potentials. Using this result SAT3 was formulated using observations made from gyrokinetic data, including a novel and robust relation between the 1D potential spectrum and the radial spectral widths. This serves to define the underlying functional forms of SAT3 before then connecting to the linear dynamics, including a difference in saturation level between ITG- and TEM-dominated turbulence, with the resulting free parameters having been fit to a database of high-resolution nonlinear CGYRO simulations. Additional features outside of the database are included, including E × B shear and multi-ion plasma capability. The methodology used in the development of SAT3 represents an algorithm which can be used in the improvement and generation of future saturation models. [ABSTRACT FROM AUTHOR]

The article focuses on the National Coalition for Infant Health's call for industry-wide collaboration in addressing concerns raised by a Citizen Petition regarding harmful excipients in neonatal seizure treatment. Topics include the risks associated with inadequately scrutinized excipients; the U.S. Food & Drug Administration (FDA)'s approval of a safer alternative; and the FDA involvement to disseminate information and elevate neonatal care standards for a healthier and safer future.

Simple Summary: For personalized oncology, it is crucial to develop appropriate patient-derived tumor models that allow individualized validation of the most effective cancer therapy. The objective of this study was to develop and characterize a new patient-derived ovarian cancer tumor model composed of patient-derived microtumors (PDM) and autologous tumor-infiltrating lymphocytes (TIL). In contrast to other preclinical tumor models, such as patient-derived organoids, PDM are generated within 24 h from fresh ovarian tumor samples. From immunohistochemical comparison with the original primary tumor, we conclude that the histopathological features of the original tumor are essentially preserved. Importantly, we successfully identified treatment-sensitive and treatment-resistant tumor models for standard platinum-based therapy by reverse-phase protein array (RPPA) analysis of PDM. Furthermore, we were able to evaluate the efficacy of cancer immunotherapy by co-culturing PDM and autologous TILs. PDM and TILs may therefore serve as a preclinical platform to identify individualized, tailored cancer treatments in the future. In light of the frequent development of therapeutic resistance in cancer treatment, there is a strong need for personalized model systems representing patient tumor heterogeneity, while enabling parallel drug testing and identification of appropriate treatment responses in individual patients. Using ovarian cancer as a prime example of a heterogeneous tumor disease, we developed a 3D preclinical tumor model comprised of patient-derived microtumors (PDM) and autologous tumor-infiltrating lymphocytes (TILs) to identify individual treatment vulnerabilities and validate chemo-, immuno- and targeted therapy efficacies. Enzymatic digestion of primary ovarian cancer tissue and cultivation in defined serum-free media allowed rapid and efficient recovery of PDM, while preserving histopathological features of corresponding patient tumor tissue. Reverse-phase protein array (RPPA)-analyses of >110 total and phospho-proteins enabled the identification of patient-specific sensitivities to standard, platinum-based therapy and thereby the prediction of potential treatment-responders. Co-cultures of PDM and autologous TILs for individual efficacy testing of immune checkpoint inhibitor treatment demonstrated patient-specific enhancement of cytotoxic TIL activity by this therapeutic approach. Combining protein pathway analysis and drug efficacy testing of PDM enables drug mode-of-action analyses and therapeutic sensitivity prediction within a clinically relevant time frame after surgery. Follow-up studies in larger cohorts are currently under way to further evaluate the applicability of this platform to support clinical decision making. [ABSTRACT FROM AUTHOR]

New workflows have been developed for predictive modeling of magnetohydrodynamic (MHD) equilibrium in tokamak plasmas. The goal of this work is to predict the MHD equilibrium in tokamak discharges without having measurements of the kinetic profiles. The workflows include a cold start tool, which constructs all the profiles and power flows needed by transport codes; a Grad–Shafranov equilibrium solver; and various codes for the sources and sinks. For validation purposes, a database of DIII-D tokamak discharges has been constructed that is comprised of scans in the plasma current, toroidal magnetic field, and triangularity. Initial efforts focused on developing a workflow utilizing an empirically derived pressure model tuned to DIII-D discharges with monotonic safety factor profiles. This workflow shows good agreement with experimental kinetic equilibrium calculations, but is limited in that it is a single fluid (equal ion and electron temperatures) model and lacks H-mode pedestal predictions. The best agreement with the H-mode database is obtained using a theory-based workflow utilizing pressure profile predictions from a coupled TGLF turbulent transport and EPED pedestal models together with external magnetics and Motional Stark Effect (MSE) data to construct the equilibrium. Here, we obtain an average root mean square error of 5.1% in the safety factor profile when comparing the predicted and experimental kinetic equilibrium. We also find good agreement with the plasma stored energy, internal inductance, and pressure profiles. Including MSE data in the theory-based workflow results in noticeably improved agreement with the q-profiles in high triangularity discharges in comparison with the results obtained with magnetic data only. The predictive equilibrium workflow is expected to have wide applications in experimental planning, between-shot analysis, and reactor studies. [ABSTRACT FROM AUTHOR]

The properties of L-mode confinement have been investigated with a set of dedicated experiments in ASDEX Upgrade and with a related modelling activity with the transport code ASTRA and the quasi-linear turbulent transport model TGLFâ€"SAT2, with boundary conditions at the separatrix. The values at the boundary have been set by the two-point model for the electron temperature, with the ion temperature proportional to the electron temperature by a constant factor, and the electron density set by a constant fraction of the volume averaged density. The influx of neutrals has been set through a feedback procedure which ensures that in the simulation the same particle content as in the experiment is obtained. The sensitivity of the results under considerable variations in the choice of the boundary conditions has been investigated and found to be limited. The predictions of this full-radius modelling set-up have been compared to experimental results covering a scan in electron cyclotron resonance heating (ECRH) power in both hydrogen and deuterium plasmas, a plasma current scan with fixed magnetic field, under both ECRH and neutral beam injection heating, an increase in plasma density with constant ECRH power in hydrogen plasmas, as well as variations of the fraction of electron and ion heating at approximately constant total heating power, as well as a change of main ion from deuterium to hydrogen. The ASTRA-TGLF predictions have been found to reproduce all of the experimentally explored dependences with relatively good accuracy, providing evidence, for the first time to our knowledge, that the main properties of L-mode confinement can be reproduced by conventional full-radius transport modelling with a quasi-linear turbulent transport model. Evidences of largest disagreement, although usually not exceeding the 20%, have been found at high electron heating power, where TGLF underpredicts the electron and particularly the ion thermal stored energies, and in the current dependence of confinement, which, in electron heated conditions, is predicted to be weaker than in the experiment. [ABSTRACT FROM AUTHOR]