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This study examined the extent to which college algebra instructors employ pedagogical practices previously found to assist students master difficult STEM content material and address their own previous math deficits. Faculty classroom behaviors were assessed with a modified version of the Generalized Observation and Reflection Platform (GORP). While it was not surprising that math faculty frequently lectured and wrote on the board, results also revealed that recommended practices were infrequently employed by instructors teaching college algebra. More specifically, faculty teaching introductory college algebra rarely addressed students' misconceptions, made references to their students' prior knowledge, or employed metacognitive teaching strategies. Moreover, while being observed, faculty never applied a mathematical concept to real life. Moreover, mathematics instructors rarely praised their students. The implications of these findings for professional development and hiring requirements are discussed and emphasized for college math department chairs and administrators generally. Results also highlighted the usefulness of the GORP assessment tool for assessing faculty classroom behaviors.

Background: At the onset of the COVID-19 pandemic, schools closed across the United States. Given the impact of virtual learning and lost access to school resources, schools eventually reopened with COVID-19 mitigation protocols in place. This qualitative study sought to understand parental perceptions of school-based COVID-19 mitigation strategies. Methods: Using a phenomenology approach, nine focus groups were completed with 40 parents of children in grades K-8 representing eight Maryland counties. Based on acceptance of masking policies (as indicated on a survey), parents were sorted into 2 groups--lower and higher masking acceptance. A thematic analysis was conducted for each group and themes were compared between the 2 groups. Results: The main themes were related to parents' general sentiments regarding COVID-19, compliance, pandemic-related changes over time, changes in personal opinions, and in-person learning. Both groups described challenges related to inconsistent COVID-19 mitigation policies and practices, the challenges of rapid and frequent changes in guidelines during the pandemic, and the benefits of in-person learning. Conclusions: Parents of elementary and middle school children, regardless of general acceptance of masking policies, shared concerns about implementation and guidance regarding school-based mitigation strategies.

Background: The COVID-19 pandemic disrupted routine school operations, including school health programs. This study aims to describe the pandemic's impact on school health service delivery from the perspective of Maryland school health partners. Methods: We conducted semi-structured interviews with health service representatives from public schools (K-12) between July and December 2021. Interviews were recorded, transcribed, and coded through an iterative process to develop analytic themes. Results: Twenty school health partners from 15 Maryland school districts participated. Participants identified key impacts of COVID-19 on school health: (1) COVID-19 disrupted delivery of services such as dental, mental health, and preventative care, (2) COVID-19 necessitated changes in service delivery platforms, (3) COVID-19 affected school health staff through increased responsibilities and staffing shortages, and (4) COVID-19 prompted schools to become hubs for community outreach and health education. Implications for School Health Policy, Practice, and Equity: Consideration of school health service disruptions and the increased demands on service providers may inform future priorities for school administrators, health departments, and policymakers. Conclusions: COVID-19 impacted the timing and method of service delivery as well as the roles of school health staff and schools themselves in public health and education.

We assessed the biomass burning (BB) smoke aerosol optical depth (AOD) simulations of 11 global models that participated in the AeroCom phase III BB emission experiment. By comparing multi-model simulations and satellite observations in the vicinity of fires over 13 regions globally, we (1) assess model-simulated BB AOD performance as an indication of smoke source–strength, (2) identify regions where the common emission dataset used by the models might underestimate or overestimate smoke sources, and (3) assess model diversity and identify underlying causes as much as possible. Using satellite-derived AOD snapshots to constrain source strength works best where BB smoke from active sources dominates background non-BB aerosol, such as in boreal forest regions and over South America and southern hemispheric Africa. The comparison is inconclusive where the total AOD is low, as in many agricultural burning areas, and where the background is high, such as parts of India and China. Many inter-model BB AOD differences can be traced to differences in values for the mass ratio of organic aerosol to organic carbon, the BB aerosol mass extinction efficiency, and the aerosol loss rate from each model. The results point to a need for increased numbers of available BB cases for study in some regions and especially to a need for more extensive regional-to-global-scale measurements of aerosol loss rates and of detailed particle microphysical and optical properties; this would both better constrain models and help distinguish BB from other aerosol types in satellite retrievals. More generally, there is the need for additional efforts at constraining aerosol source strength and other model attributes with multi-platform observations.

Climate variability in the last millennium (past 1000 years) is dominated by the effects of large-magnitude volcanic eruptions; however, a long-standing mismatch exists between model-simulated and tree-ring-derived surface cooling. Accounting for the self-limiting effects of large sulfur dioxide (SO2) injections and the limitations in tree-ring records, such as lagged responses due to biological memory, reconciles some of the discrepancy, but uncertainties remain, particularly for the largest tropical eruptions. The representation of volcanic forcing in the latest generation of climate models has improved significantly, but most models prescribe the aerosol optical properties rather than using SO2 emissions directly and including interactions between the aerosol, chemistry, and dynamics. Here, we use the UK Earth System Model (UKESM) to simulate the climate of the last millennium (1250–1850 CE) using volcanic SO2 emissions. Averaged across all large-magnitude eruptions, we find similar Northern Hemisphere (NH) summer cooling compared with other last-millennium climate simulations from the Paleoclimate Modelling Intercomparison Project Phase 4 (PMIP4), run with both SO2 emissions and prescribed forcing, and a continued overestimation of surface cooling compared with tree-ring reconstructions. However, for the largest-magnitude tropical eruptions in 1257 (Mt. Samalas) and 1815 (Mt. Tambora), some models, including UKESM1, suggest a smaller NH summer cooling that is in better agreement with tree-ring records. In UKESM1, we find that the simulated volcanic forcing differs considerably from the PMIP4 dataset used in models without interactive aerosol schemes, with marked differences in the hemispheric spread of the aerosol, resulting in lower forcing in the NH when SO2 emissions are used. Our results suggest that, for the largest tropical eruptions, the spatial distribution of aerosol can account for some of the discrepancies between model-simulated and tree-ring-derived cooling. Further work should therefore focus on better resolving the spatial distribution of aerosol forcing for past eruptions.

Fuego, an active volcano in Guatemala, explodes regularly and generates powerful infrasound for which amplitude regularly exceeds 10 Pa at 10 km where rural communities are located. This study focuses on infrasound recorded at the Fuego Volcano Observatory, a ∼250 m3 building located ∼8 km from the vent. Records from infrasound sensors deployed on either side of a wall facing the volcano were used to measure differential dynamic pressures of more than 50 Pa imparted to the wall facing the volcano. We calculated the building’s infrasonic response as a function of frequency for situations where interior doors were both open and closed and found a remarkably well-defined ∼7.5 Hz tone induced by acoustic oscillations when the interior door was open. The transfer functions, from a week-long period of recording and 34 explosions, show that closing internal doors diminishes infrasonic resonance and could potentially reduce window damage.

Abstract A Type 1 Diabetes Genetic Risk Score (T1DGRS) aids diagnosis and prediction of Type 1 Diabetes (T1D). While traditionally derived from imputed array genotypes, Whole Genome Sequencing (WGS) provides a more direct approach and is now increasingly used in clinical and research studies. We investigated the concordance between WGS-based and array-based T1DGRS across genetic ancestries in 149,265 UK Biobank participants using WGS, TOPMed-imputed, and 1000 Genomes-imputed array genotypes. In the overall cohort, WGS-based T1DGRS demonstrated strong correlation with TOPMed-imputed array-based score (r = 0.996, average WGS-based score 0.0028 standard deviations (SD) lower, p

Childhood adversity can have detrimental impacts on life course mental and physical health. Timing, nature, severity, and chronicity of adversity are thought to explain much of the variability in health and developmental outcomes among exposed individuals. The current study seeks to characterize heterogeneity in adverse experiences over time at the individual, family, and neighborhood domains in a cohort of predominantly Black children (85% Black and 15% White, 46.2% girls, 67.2% free/reduced lunch in first grade), and to examine associations with mental health from sixth grade to age 26. Participants were part of a randomized universal preventive interventions trial in first grade with prospective follow-up through early adulthood. Separate models characterized heterogeneity in adversity in elementary, middle, and high schools. Changes in adversity over time and relationships with mental health (anxiety, depression, suicidal behaviors) were investigated using a random-intercept latent transition analysis (RI-LTA). We identified three-class solutions in early childhood, middle school, and high school. Generally, both a higher and a lower poly-adversity class were observed at each time point, with varying nature of adversity characterized by the third class. RI-LTA indicated prevalent within-individual changes in adverse exposure over time and differential associations with mental health and suicidal behaviors. Results suggest that treating adverse exposures as a static construct may limit the ability to characterize salientvariation over time. Identifying complexity in adverse experiences and their relation to health and well-being is key for developing and implementing effective prevention and early intervention efforts to mitigate negative effects through the life course.

Nigella sativa L., which is commonly referred to as black cumin, is a globally recognized plant for the nutraceutical and pharmaceutical values of its seed oil. While numerous studies have investigated Nigella oil, there is a scarcity of information regarding the variation of key phytoconstituents in Nigella oil from diverse seed sources. It is also unclear whether the variation in phytoconstituents across different seed sources translates to variations in their respective oils, which is important for understanding their health benefits. Additionally, there is a gap in information on how specific phytochemicals transfer from seed to oil during the oil pressing. Therefore, this study investigated Nigella sourced from different genotypes and agricultural practices (planting densities and sowing times) to determine total phenolic content (TPC), antioxidant capacity (FRAP and CUPRAC), thymoquinone (TQ), and fatty acid composition. The results showed significant variation of TPC (87.4–144.1 mg gallic acid equivalents (GAE)/100 g), FRAP (454.1–560.9 mg Trolox equivalents (TE)/100 g), CUPRAC (356.3–482.5 mg TE/100 g), TQ (1493.5–2268.4 mg TQ/100 g), saturated fatty acid (SFA) (65.9–83.7 mg/g), monounsaturated fatty acid (MUFA) (42.5–67.8 mg/g), and polyunsaturated fatty acid (PUFA) (266.1–383.4 mg/g) in the oil derived from the seeds of different genotypes and agricultural practices. The total transfer of TPC, FRAP, and CUPRAC into the screw-pressed oil was relatively low, contributing only 2.3–3.7%, 7.1–11.7%, and 1.5–2.3%, respectively, of their total value in the respective seed. However, the transfer of TQ, SFA, MUFA, and PUFA was observed to be comparatively higher, contributing 32.8–48.5%, 60.8–84.2%, 45.6–74.4%, and 43.1–69.4%, respectively, of their total value in the respective seed. There was no strong correlation observed among TPC, FRAP, CUPRAC, and TQ, and none of the fatty acids showed a strong correlation with these variables.

Abstract Background The purpose of this study is to assess the feasibility of mixed-reality (MixR) visualization for patient setup in breast and chest wall radiotherapy (RT) by performing a first-in-human clinical trial comparing MixR with a 3-point alignment. Methods IRB approval was granted for a study incorporating MixR during the setup process for patients undergoing proton (n = 10) or photon (n = 8) RT to the breast or chest wall. For each patient, MixR was utilized for five fractions and compared against another five fractions using 3-point alignment. During fractions with MixR, the patient was aligned by at least one therapist wearing a HoloLens 2 device who was able to guide the process by simultaneously and directly viewing the patient and a hologram of the patient’s surface derived from their simulation CT scan. Alignment accuracy was quantified with cone-beam CT (CBCT) for photon treatments and CBCT plus kV/kV imaging for proton treatments. Registration time was tracked throughout the setup process as well as the amount of image guidance (IGRT) utilized for final alignment. Results In the proton cohort, the mean 3D shift was 0.96 cm using 3-point alignment and 1.18 cm using MixR. An equivalence test indicated that the difference in registration accuracy between the two techniques was less than 0.5 cm. In the photon cohort, the mean 3D shift was 1.18 cm using 3-point alignment and 1.00 cm using MixR. An equivalence test indicated that the difference in registration accuracy was less than 0.3 cm. Minor differences were seen in registration time and the amount of IGRT utilization. Conclusions MixR for patient setup for breast cancer RT is possible at the level of accuracy and efficiency provided by a 3-point alignment. Further developments in marker tracking, feedback, and a better understanding of the perceptual challenges of MixR are needed to achieve a similar level of accuracy as provided by modern surface-guided radiotherapy (SGRT) systems. Trial registration ClinicalTrials.gov, UFHPTI 2015-BR05: Improving Breast Radiotherapy Setup and Delivery Using Mixed-Reality Visualization, NCT05178927.

Abstract We have identified endoplasmic reticulum oxidoreductase 1 alpha (ERO1A) as a poor prognostic indicator in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (EGFR MUT-NSCLC). In addition, comparison of high versus low ERO1A expression among cohorts of EGFR MUT-NSCLC primary samples revealed that ERO1A expression correlated with increased expression of proteins that regulate secretion. Using the CPTAC proteomic data set in lung adenocarcinoma we found that high ERO1A protein expression correlated with both extracellular matrix and matrix modifying enzymes. In this report, we found that ablating ERO1A expression was a determinant of clonogenicity, tumor sphere formation, spheroid growth and growth in vivo, as well as response to Osimertinib. We validated that ERO1A-knockout EGFR MUT-LUAD cell lines demonstrated a reduction in secretion of both laminin gamma 2 (LAMC2) and the collagen modifying enzyme lysyl oxidase-like 2 (LOXL2). Our work supports the role of ERO1A in modulating the tumor microenvironment that is likely to contribute to tumor progression.

Several additives have been shown to reduce enteric methane emissions from ruminants when supplied in feed. However, utilising this method to deliver such methane-reducing compounds (MRCs) in extensive grazing systems is challenging. Use of livestock drinking water presents a novel method to deliver MRCs to animals in those systems. This work evaluated 13 MRCs for suitability to be deployed in this manner. Compounds were analysed for solubility and stability in aqueous solution using Fourier transform infrared-attenuated total reflectance (FTIR-ATR) spectroscopy. Furthermore, aqueous solutions of MRCs were subjected to variations in temperature and starting pH of water used to assess solubility and stability of the MRCs in simulated water trough conditions, also using FTIR-ATR spectroscopy. In vitro batch culture fermentations were carried out using a medium-quality tropical grass feed substrate, to simulate pastures consumed by cattle in extensive grazing systems. Measurements were made of total gas and methane production, in vitro dry matter digestibility (IVDMD), and volatile fatty acid (VFA) concentration. Of the MRCs tested, 12 were found to be soluble and stable in water using the FTIR method employed, whilst the other could not be measured. Of the 12 soluble and stable MRCs, one containing synthetic tribromomethane (Rumin8 Investigational Veterinary Product) reduced methane production by 99% (p = 0.001) when delivered aqueously in vitro, without a reduction in IVDMD (p = 0.751), with a shift towards decreased acetate and increased propionate production and decreased total VFA production (p < 0.001). Other compounds investigated also appeared suitable, and the methods developed in this study could be used to guide future research in the area.

There is increasing interest in Australian finger lime (Citrus australasica) due to its nutritional and bioactive potential. In this study, polar extracts from five finger lime cultivars were investigated for their potential bioactivity using a range of assays: antioxidant capacity (total phenolic content (TPC), ferric reducing antioxidant power (FRAP), and cupric reducing antioxidant capacity (CUPRAC)), total monomeric anthocyanin content (TMAC), anti-diabetic activity (α-glucosidase and α-amylase inhibition), anti-Alzheimer activity (acetylcholinesterase inhibition), Skin-whitening activity skin-brightening activity (tyrosinase inhibition), and anti-inflammatory activity (COX-2 inhibition). Commercial Tahitian lime was used as a “control” (comparison). The TPC ranged from 328 to 779 mg GAE/100 g dry weight (DW) in the pulp (compared to 1043 mg GAE/100 g for Tahitian lime) and from 755 to 1048 mg GAE/100 g in the peel (1704 mg GAE/100 g for Tahitian lime). A similar range of variation was seen for FRAP, ranging from 114 to 436 mg TE/100 g DW in the pulp (422 mg TE/100 g for Tahitian lime) and 259 to 495 mg TE/100 g DW in the peel (491 mg TE/100 g for Tahitian lime). Similarly, the TFC was generally lower in finger lime pulp (100–392 mg QE/100 g DW) compared to Tahitian lime (312 mg QE/100 g). The polar extracts did not show any significant inhibition of α-glucosidase, α-amylase, tyrosinase, or COX-2. One finger lime variety showed moderate (>50%) inhibition of acetylcholinesterase (AChE) at the highest concentration screened (~1500 mg/L), as did Tahitian lime. Additionally, in silico docking against acetylcholinesterase suggested that some of the polyphenols present, including catechin, quercetin-3-glucoside, and cyanidin-3-glucoside, could potentially dock to AChE and inhibit it. This is the first time the species has been investigated for many of these bioactive properties, and also the first time in silico docking has been performed to explore which potential compounds from this species could provide its bioactivity. Although little bioactivity was generally found across the applied bioassays, these findings nevertheless provide important basic data for future research and any claims about the potential health benefits of Australian finger lime.

Abstract Post marketing safety surveillance depends in part on the ability to detect concerning clinical events at scale. Spontaneous reporting might be an effective component of safety surveillance, but it requires awareness and understanding among healthcare professionals to achieve its potential. Reliance on readily available structured data such as diagnostic codes risks under-coding and imprecision. Clinical textual data might bridge these gaps, and natural language processing (NLP) has been shown to aid in scalable phenotyping across healthcare records in multiple clinical domains. In this study, we developed and validated a novel incident phenotyping approach using unstructured clinical textual data agnostic to Electronic Health Record (EHR) and note type. It’s based on a published, validated approach (PheRe) used to ascertain social determinants of health and suicidality across entire healthcare records. To demonstrate generalizability, we validated this approach on two separate phenotypes that share common challenges with respect to accurate ascertainment: (1) suicide attempt; (2) sleep-related behaviors. With samples of 89,428 records and 35,863 records for suicide attempt and sleep-related behaviors, respectively, we conducted silver standard (diagnostic coding) and gold standard (manual chart review) validation. We showed Area Under the Precision-Recall Curve of ~ 0.77 (95% CI 0.75–0.78) for suicide attempt and AUPR ~ 0.31 (95% CI 0.28–0.34) for sleep-related behaviors. We also evaluated performance by coded race and demonstrated differences in performance by race differed across phenotypes. Scalable phenotyping models, like most healthcare AI, require algorithmovigilance and debiasing prior to implementation.

Coarse mineral dust particles have been observed much further from the Sahara than expected based on theory. They have impacts different to finer particles on Earth's radiative budget, as well as carbon and hydrological cycles, though they tend to be under-represented in climate models. We use measurements of the full dust size distribution from aircraft campaigns over the Sahara, Canaries, Cabo Verde and Caribbean. We assess the observed and modelled dust size distribution over long-range transport at high vertical resolution using the Met Office Unified Model, which represents dust up to 63.2 µm diameter, greater than most climate models. We show that the model generally replicates the vertical distribution of the total dust mass but transports larger dust particles too low in the atmosphere. Importantly, coarse particles in the model are deposited too quickly, resulting in an underestimation of dust mass that is exacerbated with westwards transport; the 20–63 µm dust mass contribution between 2 and 3.7 km altitude is underestimated by factors of up to 11 in the Sahara, 140 in the Canaries and 240 in Cabo Verde. In the Caribbean, there is negligible modelled contribution of d > 20 µm particles to total mass, compared to 10 % in the observations. This work adds to the growing body of research that demonstrates the need for a process-based evaluation of climate model dust simulations to identify where improvements could be implemented.

This study investigated the role of experiential learning and peer mentors in undergraduate biology at a community college. While the impact on all students was studied, special attention was paid to the effect interventions had on underrepresented minority students. Thirty-three sections of an introductory biology class were randomly assigned to either treatment or control. Sections assigned to treatment received content enhancements geared at active learning strategies and metacognition. A portion of treatment sections also had the presence of peer mentors as part of their laboratory course. Results showed grade distributions were not significantly different when comparing control and treatment sections, but there was a significant increase in final course grade when mentors were present in the laboratory, and when enrichments alone were provided. These methods were just as impactful for minority students, indicating that active learning and peer support may help to decrease student attrition in introductory biology classes.

Many practical disaster reports are published daily worldwide in various forms, including after-action reports, response plans, impact assessments, and resiliency plans. These reports serve as vital resources, allowing future generations to learn from past events and better mitigate and prepare for future disasters. However, this extensive practical literature often has limited impact on research and practice due to challenges in synthesizing and analyzing the reports. In this study, we 1) present a corpus of practical reports for text mining and 2) introduce an approach to extract insights from the corpus using select text mining tools. We validate the approach through a case study examining practical reports on the preparedness of the U.S. Pacific Northwest for a magnitude 9 Cascadia Subduction Zone earthquake, which has the potential to disrupt lifeline infrastructures for months. To explore opportunities and challenges associated with text mining of practical disaster reports, we conducted a brief survey of potential user groups. The case study illustrates the types of insights that our approach can extract from a corpus. Notably, it reveals potential differences in priorities between Washington and Oregon state-level emergency management, uncovers latent sentiments expressed within the reports, and identifies inconsistent vocabulary across the field. Survey results highlight that while simple tools may yield insights that are primarily interpretable by experienced professionals, more advanced tools utilizing large language models, such as Generative Pre-trained Transformer (GPT), offer more accessible insights, albeit with known risk associated with current artificial intelligence technologies. To ensure reproducibility, all supporting data and code are made publicly available (DOI: 10.17603/ds2-9s7w-9694).

Adverse childhood experiences (ACEs) contribute to numerous negative health outcomes across the life course and across generations. Here, we extend prior work by examining the association of maternal ACEs, and their interaction with financial stress and discrimination, with methylation status within eight differentially methylated regions (DMRs) in imprinted domains in newborns. ACEs, financial stress during pregnancy, and experience of discrimination were self-reported among 232 pregnant women. DNA methylation was assessed at PEG10/SGCE, NNAT, IGF2, H19, PLAGL1, PEG3, MEG3-IG, and DLK1/MEG3 regulatory sequences using pyrosequencing. Using multivariable linear regression models, we found evidence to suggest that financial stress was associated with hypermethylation of MEG3-IG in non-Hispanic White newborns; discrimination was associated with hypermethylation of IGF2 and NNAT in Hispanic newborns, and with hypomethylation of PEG3 in non-Hispanic Black newborns. We also found evidence that maternal ACEs interacted with discrimination to predict offspring PLAGL1 altered DMR methylation, in addition to interactions between maternal ACEs score and discrimination predicting H19 and SGCE/PEG10 altered methylation in non-Hispanic White newborns. However, these interactions were not statistically significant after multiple testing corrections. Findings from this study suggest that maternal ACEs, discrimination, and financial stress are associated with newborn aberrant methylation in imprinted gene regions.

Objective: Cancer treatment misinformation (CTM) is pervasive and impacts patient health outcomes. Cancer clinicians play an essential role in addressing CTM. We previously identified four self-reported responses that characterize the communication process clinicians engage in to address CTM. Clinicians 1) work to understand the misinformation; 2) correct the misinformation through education; 3) advise about future online searches; and 4) preserve the clinician-patient relationship. We sought to confirm and expand on the model we developed by observing cancer clinicians' communication while addressing CTM with a standardized patient (SP). Methods: 17 cancer clinicians were audio recorded in a SP encounter, in which a breast cancer SP asked three questions based on CTM. We thematically analyzed transcriptions of the recordings. Results: Clinicians used four responses with associated strategies and skills to address CTM in a standardized clinical encounter, confirming the previously developed model. The four responses were: (1) work to understand the misinformation; (2) correct the misinformation through education; (3) advise about future online searches; and (4) preserve the clinician-patient relationship. This observational approach allowed us to refine strategies within each response and identify communication skills clinicians enact to address CTM. Conclusion: These findings provide a strong foundation for the Misinformation Response Model for cancer clinicians. Future research should examine which components of the model are most effective in improving patient outcomes. Innovation: This is the first study observing clinicians' communication through simulated practice with SPs about CTM.

Background and objective: Visceral metastatic disease in prostate cancer patients conveys a poor prognosis. Using advanced imaging techniques, studies have demonstrated increasing detection rates of visceral metastasis. Visceral metastases are now seen in up to 30–60% of prostate cancer patients. Survival patterns of site-specific visceral metastasis are described poorly in the literature. Here, we sought to investigate survival patterns in prostate cancer patients according to their first detected site of visceral metastasis. Methods: Retrospectively, we identified 203 prostate cancer patients with visceral metastases from the Mayo Clinic Advanced Prostate Cancer Registry. Patients were divided into three groups according to the first site of visceral metastases detected: lung, brain, or liver. Visceral metastases were detected primarily on either metabolic imaging (C-11 choline) or prostate-specific membrane antigen positron emission tomography computed tomography (CT) scan. Confirmation of visceral metastasis diagnosis was established with either biopsy when feasible or focused conventional imaging, including focused CT or magnetic resonance imaging. Overall survival and cancer-specific survival were estimated using the Kaplan-Meier method. Univariate and multivariate Cox regression model was conducted to assess different variables that affect overall and cancer-specific survival. Key findings and limitations: Over a median (interquartile range) follow-up duration of 16.2 (3.9–49.8) mo, the overall and cancer-specific survival of the entire cohort suggests better survival patterns in patients with first-site lung metastases than in patients with first-site brain or liver metastases (p

The addition of methane-reducing compounds (MRCs) to livestock drinking water presents an alternative method for enteric methane mitigation in extensive systems where these compounds cannot be fed through the diet. This work evaluated several such compounds with the potential to be deployed in this manner. Methane-reducing compounds were selected based on the existing literature and likelihood of dissolution when combined with a commercially available water-based nutrient supplement (uPRO) (uPRO ORANGE®, DIT AgTech, QLD, Australia). This, in turn, would demonstrate the capacity for MRCs to be administered through animal drinking water when such supplements are in use. This technique requires the analysis of MRC solubility and stability in solution, which was completed via Fourier transform infrared-attenuated total reflectance spectroscopy. The uPRO supplement is comprised of urea, urea phosphate, and ammonium sulfate, providing nitrogen, phosphorus, and sulfur—limiting nutrients for ruminants grazing extensive systems during drier periods of the year. Accordingly, medium-quality Rhodes grass hay was used in fermentation runs to simulate a basal diet during the dry season. Methane-reducing compounds were assessed in accordance with each variable measured (gas/methane production, dry matter digestibility, stability under different environmental conditions) along with existing research in the field to determine the most suitable compound for co-administration. Whilst most compounds examined in this study appeared to retain their structure in solution with uPRO, fermentation results varied in terms of successful methane mitigation. The additive Agolin Ruminant L emerged as the most promising compound for further in vivo investigation.

Abstract Metabolite extraction is the critical first-step in metabolomics experiments, where it is generally regarded to inactivate and remove proteins. Here, arising from efforts to improve extraction conditions for polar metabolomics, we discover a proteomic landscape of over 1000 proteins within metabolite extracts. This is a ubiquitous feature across several common extraction and sample types. By combining post-resuspension stable isotope addition and enzyme inhibitors, we demonstrate in-extract metabolite interconversions due to residual transaminase activity. We extend these findings with untargeted metabolomics where we observe extensive protein-mediated metabolite changes, including in-extract formation of glutamate dipeptide and depletion of total glutathione. Finally, we present a simple extraction workflow that integrates 3 kDa filtration for protein removal as a superior method for polar metabolomics. In this work, we uncover a previously unrecognized, protein-mediated source of observer effects in metabolomics experiments with broad-reaching implications across all research fields using metabolomics and molecular metabolism.

Nigella sativa, also known as black cumin, is esteemed for its rich reservoir of health-benefitting phytoconstituents nestled within its seeds. The composition of its seeds can be influenced by factors such as genotype diversity and agricultural practices. Understanding these dynamics is important for maximizing the nutritional and medicinal attributes of the seeds. This study investigated how different genotypes, growing densities, and sowing times affect oil yield and phytoconstituents of Nigella seeds in Northern Australia. The aim was to find the optimal combination of these factors to maximize desirable compounds. Our findings revealed variability in oil yield and phytoconstituents among different genotypes, growing densities, and sowing times. No single genotype stood out as having elevated levels of all desired compounds. For instance, genotype AVTKS#5 had high total phenolic content (TPC) and antioxidant capacity, while AVTKS#8 and AVTKS#7 excelled in thymoquinone (TQ) and polyunsaturated fatty acids (PUFAs) and monounsaturated fatty acids (MUFAs), respectively. Planting density had a nuanced impact, with no significant effect on oil yield and CUPRAC values, but higher densities decreased TPC, FRAP, and TQ. Interestingly, seeds cultivated at 20 and 30 plants/m2 had higher ratios of MUFAs/SFAs, PUFAs/SFAs, and (MUFAs + PUFAs)/SFAs, indicating the importance of planting density in shaping fatty acid profiles. Sowing times also had a noticeable effect, with late sowing leading to a decrease in oil yield from 19% to 14%. May-sown seeds had higher TPC, FRAP, CUPRAC, and fatty acid ratios, while TQ levels peaked in June-sown seeds. Our study highlighted positive correlations among TPC, FRAP, CUPRAC, and TQ, emphasizing their collective contribution to the nutritional and medicinal potency of Nigella seeds. Fatty acids, on the other hand, showed no significant correlation with these parameters, indicating independent regulation. In summary, our comprehensive analysis provides insights into the factors (genotype and agronomic practice) that shape the phytochemical profile of Nigella seeds, and suggests better genotype, planting density, and time of sowing for the cultivation and quality production.

Throughout history, Black women have taken their unique lived experiences to make changes through civic behaviors. At the same time, they hold a complex position in society, located at the intersection of multiple marginalizing identities that put them at risk of experiencing distinct forms of discrimination. To date, little research has examined the patterns of Black women’s civic behaviors and associations with discrimination experiences and well-being. This may be particularly salient during emerging adulthood, a key period of sociopolitical development and increasing mental health problems. The current study seeks to address this gap, drawing from theories of intersectionality and sociopolitical development. Participants included 103 emerging adult Black women (Mage = 24.27, SD = 2.76) with a range of civic experiences. Overall, anti-racist action was the most prevalent domain of civic behavior. Participants were about twice as likely to engage in traditional political behaviors (e.g., signing petitions, giving money) than political protest. Latent class analysis was used to identify three unique subgroups of civic behaviors: Stably Committed, Traditionally Engaged, or Low Engagement. Findings also showed that emerging adult Black women classified as Stably Committed experienced more discrimination and higher depressive symptoms. The current findings inform the creation of safe spaces for emerging adult Black women to be civically engaged as they navigate racism and sexism and take action to seek racial justice.

Background: Anti-Program-Death-1 (PD-1) is a standard adjuvant therapy for patients with resected melanoma. We hypothesized that there are discrepancies in survival, recurrence pattern and toxicity to adjuvant PD-1 between different ethnicities and melanoma subtypes. Objective: We performed a multicenter cohort study incorporating 6 independent institutions in Australia, China, Japan, and the United States. The primary outcomes were recurrence free survival (RFS) and overall survival (OS). Secondary outcomes were disease recurrence patterns and toxicities. Results: In total 534 patients were included. East-Asian/Hispanic/African reported significantly poorer RFS/OS. Nonacral cutaneous or melanoma of unknown primary reported the best RFS/OS, followed by acral, and mucosal was the poorest. Within the nonacral cutaneous or melanoma of unknown primary subtypes, East-Asian/Hispanic/African reported significantly poorer RFS/OS than Caucasian. In the multivariate analysis incorporating ethnicity/melanoma-subtype/age/sex/stage/lactate dehydrogenase/BRAF (v-Raf murine sarcoma viral oncogene homolog B)-mutation/adjuvant radiotherapy, East-Asian/Hispanic/African had independently significantly poorer outcomes (RFS: HR, 1.71; 95% CI, 1.19-2.44 and OS: HR, 2.34; 95% CI, 1.39-3.95), as was mucosal subtype (RFS: HR, 3.25; 95% CI, 2.04-5.17 and OS: HR, 3.20; 95% CI, 1.68-6.08). Mucosal melanoma was an independent risk factor for distant metastasis, especially liver metastasis. East-Asian/Hispanic/African had significantly lower incidence of gastrointestinal/musculoskeletal/respiratory/other-rare-type-toxicities; but higher incidences of liver toxicities. Limitations: A retrospective study. Conclusions: Ethnicity and melanoma subtype are associated with survival and recurrence pattern in melanoma patients treated with adjuvant anti-PD-1. Toxicity profile differs by ethnicity and may require a precision toxicity surveillance strategy.

OBJECTIVE: To identify individual-level early warning indicators of virologic failure in HIV patients receiving antiretroviral therapy (ART) in South Africa. DESIGN: A matched case–control study of individuals with and without virologic failure (VF) (>5 months on ART and HIV-1 plasma viral load >1,000 copies/mL) was conducted between June 2014 and June 2018. Of the 1,000 participants enrolled in the parent cohort, 96 experienced VF, and 199 additional controls were identified from the parent cohort and matched 1:2 (some matched 1:3) for sex, age, ART duration, and site. Participants were interviewed while clinical, pharmacy refill, laboratory, and objective pharmacological data were obtained. Multivariate conditional logistic regression models were constructed using model selection to identify factors associated with VF. Significant determinants of VF were identified using an alpha level of 0.05. RESULTS: In a full conditional model, higher cumulative ART adherence, quantified using tenofovir-diphosphate concentrations in dried blood spots (OR 0.26) and medication possession ratio (OR 0.98) were protective against VF, whereas an increase in total depression score (OR 1.20) was predictive of VF. CONCLUSION: This analysis demonstrates the importance of depression as a key individual-level early warning indicator of VF. Efforts to address mental health concerns among patients with people living with HIV could improve virologic suppression.

The foodborne pathogen Listeria monocytogenes can persist in produce processing environments, which increases the risk for food contamination. Increased resistance to antimicrobials commonly used in cleaning and sanitizing procedures may contribute to L. monocytogenes’ persistence in these environments. This study aimed to evaluate sanitizer resistance in L. monocytogenes isolates collected from three tree fruit packing facilities (F1, F2, and F3) during packing seasons 2020–2021 (Y1) and 2021–2022 (Y2), and to assess evidence of persistence based on the genomic similarity of isolates to historical isolates collected in previous years. L. monocytogenes isolates collected in 2020–2022 (n = 44) were tested for resistance to peroxyacetic acid (PAA) and a proprietary biofilm−removing agent using a broth microdilution assay. Further, L. monocytogenes isolates were whole genome sequenced and screened for the presence of antimicrobial resistance and virulence genes, as well as to assess the genomic similarity of isolates using the CFSAN SNP bioinformatic pipeline. Over half (57%) of the tested isolates had a PAA minimum inhibitory concentration (MIC) of 250 ppm, which was similar to the applied concentration of the PAA sanitizer in the three facilities (230 ppm). In contrast, 80% of tested isolates had a biofilm remover MIC of 0.13 ppm, which was substantially below the concentration applied in the facilities (137 ppm). Genomes of all tested isolates carried antimicrobial resistance (fosX, lin, mdrL, mprF, and norB) and virulence (inlA, inlB, plcA, plcB, prfA, hly, mpl, and iap) genes. L. monocytogenes isolates collected between 2020 and 2022 belonged to three distinct lineages, with 22 multilocus sequence types (MLSTs) belonging to 22 different clonal complexes. Genomic similarity analysis with historical isolates collected from the same facilities in 2016–2017 demonstrated a 5-year persistence of the genotypes ST 1003 and ST 554 in F2, which were no longer detected in 2022. Overall, our results highlight the need to re-evaluate sanitizer concentrations to effectively control persistent L. monocytogenes strains in tree fruit packing facilities.

Rice cultivation in Madurai district, Tamil Nadu, spans distinct cropping seasons: Kar (May – Jun), Semi-dry (Jul – Aug), Samba/ Late Samba (Aug – Sep), and Navarai (Dec – Jan), each with unique weather conditions and rice varieties. This study explores the correlation between weather parameters temperature, rainfall, humidity, sunshine hours, and wind speed and rice blast disease severity from 2021 to 2023. Using multiple linear regression with ordinary least squares (OLS), the analysis achieves high predictive accuracy (R² = 0.98). Results show that the maximum temperatures correlated negatively with disease severity (r = -0.869 to -0.892), while rainfall (r = 0.768 to 0.804) and wind speed (r = 0.766 to 0.938) correlated positively during the semi-dry season. Relative humidity exhibits varying impacts across seasons. These findings underscore the importance of tailored disease management strategies, such as targeted fungicidal applications during warmer seasons and optimized water management in others. By elucidating these dynamics, the study enhances understanding of weather-disease interactions, providing actionable insights to optimize disease management and enhance crop resilience in Madurai district.

Objectives: Ketone bodies are endogenous metabolites produced during fasting or a ketogenic diet that have pleiotropic effects on aging pathways. Ketone esters (KEs) are compounds that induce ketosis without dietary changes, but KEs have not been studied in an older adult population. The primary objective of this trial was to assess the tolerability and safety of KE ingestion in a cohort of older adults. Design: Randomized, placebo-controlled, double-blinded, parallel-arm trial (NCT05585762). Setting: General community, Northern California, USA. Participants: Community-dwelling older adults, independent in activities of daily living, with no unstable acute medical conditions (n = 30; M = 15, F = 15; age = 76 y, range 65–90 y) were randomized and n = 23 (M = 14, F = 9) completed the protocol. Intervention: Participants were randomly allocated to consume either KE (25 g bis-octanoyl (R)-1,3-butanediol) or a taste, appearance, and calorie-matched placebo (PLA) containing canola oil daily for 12 weeks. Measurements: Tolerability was assessed using a composite score from a daily log for 2-weeks, and then via a bi-weekly phone interview. Safety was assessed by vital signs and lab tests at screening and weeks 0, 4 and 12, along with tabulation of adverse events. Results: There was no difference in the prespecified primary outcome of proportion of participants reporting moderate or severe nausea, headache, or dizziness on more than one day in a two-week reporting period (KE n = 2 (14.3% [90% CI = 2.6–38.5]); PLA n = 1 (7.1% [90% CI = 0.4–29.7]). Dropouts numbered four in the PLA group and two in the KE group. A greater number of symptoms were reported in both groups during the first two weeks; symptoms were reported less frequently between 2 and 12 weeks. There were no clinically relevant changes in safety labs or vital signs in either group. Conclusions: This KE was safe and well-tolerated in this study of healthy older adults. These results provide an initial foundation for use of KEs in clinical research with older adults.

Abstract CSMD1 (Cub and Sushi Multiple Domains 1) is a well-recognized regulator of the complement cascade, an important component of the innate immune response. CSMD1 is highly expressed in the central nervous system (CNS) where emergent functions of the complement pathway modulate neural development and synaptic activity. While a genetic risk factor for neuropsychiatric disorders, the role of CSMD1 in neurodevelopmental disorders is unclear. Through international variant sharing, we identified inherited biallelic CSMD1 variants in eight individuals from six families of diverse ancestry who present with global developmental delay, intellectual disability, microcephaly, and polymicrogyria. We modeled CSMD1 loss-of-function (LOF) pathogenesis in early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells (hESCs). We show that CSMD1 is necessary for neuroepithelial cytoarchitecture and synchronous differentiation. In summary, we identified a critical role for CSMD1 in brain development and biallelic CSMD1 variants as the molecular basis of a previously undefined neurodevelopmental disorder.

Abstract Immune checkpoint inhibitor-mediated colitis (IMC) is a common adverse event of treatment with immune checkpoint inhibitors (ICI). We hypothesize that genetic susceptibility to Crohn’s disease (CD) and ulcerative colitis (UC) predisposes to IMC. In this study, we first develop a polygenic risk scores for CD (PRSCD) and UC (PRSUC) in cancer-free individuals and then test these PRSs on IMC in a cohort of 1316 patients with ICI-treated non-small cell lung cancer and perform a replication in 873 ICI-treated pan-cancer patients. In a meta-analysis, the PRSUC predicts all-grade IMC (ORmeta=1.35 per standard deviation [SD], 95% CI = 1.12–1.64, P = 2×10−03) and severe IMC (ORmeta=1.49 per SD, 95% CI = 1.18–1.88, P = 9×10−04). PRSCD is not associated with IMC. Furthermore, PRSUC predicts severe IMC among patients treated with combination ICIs (ORmeta=2.20 per SD, 95% CI = 1.07–4.53, P = 0.03). Overall, PRSUC can identify patients receiving ICI at risk of developing IMC and may be useful to monitor patients and improve patient outcomes.

Nigella sativa L. (generally known as black cumin) is a medicinal plant prized for its therapeutic and nutritional benefits. Its seed oil is used extensively in pharmaceuticals, nutraceuticals, cosmetics, and cooking. However, extracting oil to satisfy the world’s needs leaves behind plenty of solid residues. The seeds of Nigella are loaded with health-benefiting phytoconstituents, but so might their extraction residues. While much research on seeds and oil has been carried out, there is relatively little information about solid residue, particularly regarding health-benefiting phytoconstituents. Additionally, there is a knowledge gap relating to how phytoconstituents transfer from seeds to solid residue during oil extraction and any loss of key phytoconstituents that may occur during this transfer. Understanding the health-benefiting phytoconstituents in Nigella solid residue is crucial for unlocking its full potential for value-added applications in health and nutrition. Moreover, understanding the dynamics of these phytoconstituent transfers is essential for optimizing extraction processes and preserving the nutritional and therapeutic value of the derived products. Therefore, this study investigated the composition of the screw-press solid residues of different Nigella genotypes grown under similar environmental conditions. The results showed moderate variation in the levels of potential health-benefitting phytoconstituents in Nigella solid residues regarding total phenolic content (TPC) (720.5–934.8 mg GAE/100 g), ferric reducing antioxidant capacity (FRAP) (853.1–1010.5 mg TE/100 g), cupric reducing antioxidant capacity (CUPRAC) (3863.1–4801.5 mg TE/100 g), thymoquinone (TQ) (156.0–260.1 mg/100 g), saturated fatty acid (SFA) (2.0–2.2 mg/g), monounsaturated fatty acid (MUFA) (2.0–3.6 mg/g), and polyunsaturated fatty acid (PUFA) (8.2–12.1 mg/g). Notably, TPC, FRAP, and CUPRAC had high transfer rates into the solid residue (78.1–85.9%, 65.4–75.7%, and 84.5–90.4%, respectively), whereas TQ, SFA, MUFA, and PUFA showed lower transfer rates (15.9–19.3%, 7.5–8.9%, 12.0–18.3%, and 6.5–7.5%, respectively). When summing the values of individual phytoconstituents transferred into oil and solid residue from their respective seeds during processing, it was found that only 80.6–88.3% of TPC, 74.2–84.4% of FRAP, 86.3–92.3% of CUPRAC, 54.4–64.9% of TQ, 68.5–92.4% of SFA, 76.2–90.6% of MUFA, and 51.6–76.6% of PUFA were transferred from the total value present in their respective seeds.

To quantify the ecological impacts of organic sediments and environmental dredging, benthic mollusks were chosen as bioindicators of environmental change, measured as sediment organic content and associated parameters. Data on species richness, ecological diversity (which was measured as biodiversity), and abundances were collected alongside sediment and near-bottom water quality data before, during, and after environmental dredging. Organic sediment content was found to have an inverse logarithmic relationship with benthic mollusk biodiversity, species richness, and abundance. Post hoc analyses found that percent dissolved oxygen, which correlates with sediment organic content, was responsible for 29.31–34.12% of the benthic mollusk community variation. Sediments with lower organic content had higher biodiversity (organism densities up to 1 organism m−2), abundance (over 2.0 × 105 organisms m−2), and species richness (organism densities up to 4 organisms m−2). In comparison, sediments with higher organic content had low biodiversity (organism densities 0–1 organisms m−2), abundance (as low as 0 organisms m−2), and species richness (organism densities as low as 0 organisms m−2).

Light and nitrogen availability are basic requirements for photosynthesis. Changing in light intensity and nitrogen concentration may require adaptive physiological and life process changes in phytoplankton cells. Our previous study demonstrated that two Thalassiosira species exhibited, respectively, distinctive physiological responses to light and nitrogen stresses. Transcriptomic analyses were employed to investigate the mechanisms behind the different physiological responses observed in two diatom species of the genus Thalassiosira. The results indicate that the congeneric species are different in their cellular responses to the same shifting light and nitrogen conditions. When conditions changed to high light with low nitrate (HLLN), the large-celled T. punctigera was photodamaged. Thus, the photosynthesis pathway and carbon fixation related genes were significantly down-regulated. In contrast, the small-celled T. pseudonana sacrificed cellular processes, especially amino acid metabolisms, to overcome the photodamage. When changing to high light with high nitrate (HLHN) conditions, the additional nitrogen appeared to compensate for the photodamage in the large-celled T. punctigera, with the tricarboxylic acid cycle (TCA cycle) and carbon fixation significantly boosted. Consequently, the growth rate of T. punctigera increased, which suggest that the larger-celled species is adapted for forming post-storm algal blooms. The impact of high light stress on the small-celled T. pseudonana was not mitigated by elevated nitrate levels, and photodamage persisted.

Aim: Nusinersen, administered by intrathecal injection at a dose of 12 mg, is indicated across all ages for the treatment of spinal muscular atrophy (SMA). Evidence on real-world healthcare resource use (HRU) and costs among patients taking nusinersen remains limited. This study aimed to evaluate real-world HRU and costs associated with nusinersen use through US claims databases. Patients & methods: Using the Merative™ MarketScan Research Databases, patients with SMA receiving nusinersen were identified from commercial (January 2017 to June 2020) and Medicaid claims (January 2017 to December 2019). Those likely to have complete information on the date of nusinersen initiation and continuous enrollment 12 months pre- and post-index (first record of nusinersen treatment) were retained. Number and costs (US$ 2020) of inpatient admissions and emergency department (ED) visits, unrelated to nusinersen administration, were evaluated for 12 months pre- and post-nusinersen initiation and stratified by age: pediatric (

BackgroundMany patients use artificial intelligence (AI) chatbots as a rapid source of health information. This raises important questions about the reliability and effectiveness of AI chatbots in delivering accurate and understandable information.PurposeTo evaluate and compare the accuracy, conciseness, and readability of responses from OpenAI ChatGPT-4 and Google Bard to patient inquiries concerning the novel 177Lu-PSMA-617 therapy for prostate cancer.Materials and methodsTwo experts listed the 12 most commonly asked questions by patients on 177Lu-PSMA-617 therapy. These twelve questions were prompted to OpenAI ChatGPT-4 and Google Bard. AI-generated responses were distributed using an online survey platform (Qualtrics) and blindly rated by eight experts. The performances of the AI chatbots were evaluated and compared across three domains: accuracy, conciseness, and readability. Additionally, potential safety concerns associated with AI-generated answers were also examined. The Mann-Whitney U and chi-square tests were utilized to compare the performances of AI chatbots.ResultsEight experts participated in the survey, evaluating 12 AI-generated responses across the three domains of accuracy, conciseness, and readability, resulting in 96 assessments (12 responses x 8 experts) for each domain per chatbot. ChatGPT-4 provided more accurate answers than Bard (2.95 ± 0.671 vs 2.73 ± 0.732, p=0.027). Bard’s responses had better readability than ChatGPT-4 (2.79 ± 0.408 vs 2.94 ± 0.243, p=0.003). Both ChatGPT-4 and Bard achieved comparable conciseness scores (3.14 ± 0.659 vs 3.11 ± 0.679, p=0.798). Experts categorized the AI-generated responses as incorrect or partially correct at a rate of 16.6% for ChatGPT-4 and 29.1% for Bard. Bard’s answers contained significantly more misleading information than those of ChatGPT-4 (p = 0.039).ConclusionAI chatbots have gained significant attention, and their performance is continuously improving. Nonetheless, these technologies still need further improvements to be considered reliable and credible sources for patients seeking medical information on 177Lu-PSMA-617 therapy.

Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, improving outcomes for many patients. However, toxicities termed immune-related adverse events (irAEs) are limitations of these revolutionary treatments. These irAEs may resolve with treatment or ICI cessation (acute) or persist many months beyond therapy cessation (chronic). Acute irAEs were the first to be recognized and are thus more well studied. However, chronic irAEs have been highlighted in recent years and are becoming a topic of more intensive investigation. These chronic irAEs have been noted to affect many different organ systems, including endocrine, rheumatologic, gastrointestinal, dermatologic, neurologic, and cardiovascular systems. In this review, we discuss current knowledge surrounding the frequency, time course, and risk factors associated with chronic irAEs affecting various organ systems, treatment approaches, and future directions.

BackgroundImmune checkpoint inhibitor (ICI)-induced myocarditis is a rare immune-related adverse event (irAE) with a fatality rate of 40%–46%. However, irMyocarditis can be asymptomatic. Thus, improved monitoring, detection and therapy are needed. This study aims to generate knowledge on pathogenesis and assess outcomes in cancer centers with intensified patient management.MethodsPatients with cardiac irAEs from the SERIO registry (www.serio-registry.org) were analyzed for demographics, ICI-related information (type of ICI, therapy line, combination with other drugs, onset of irAE, and tumor response), examination results, irAE treatment and outcome, as well as oncological endpoints. Cardiac biopsies of irMyocarditis cases (n = 12) were analyzed by Nanostring and compared to healthy heart muscle (n = 5) and longitudinal blood sampling was performed for immunophenotyping of irMyocarditis-patients (n = 4 baseline and n = 8 during irAE) in comparison to patients without toxicity under ICI-therapy (n = 4 baseline and n = 7 during ICI-therapy) using flow cytometry.ResultsA total of 51 patients with 53 cardiac irAEs induced by 4 different ICIs (anti-PD1, anti-PD-L1, anti-CTLA4) were included from 12 centers in 3 countries. Altogether, 83.0% of cardiac irAEs were graded as severe or life-threatening, and 11.3% were fatal (6/53). Thus, in centers with established consequent troponin monitoring, work-up upon the rise in troponin and consequent treatment of irMyocarditis with corticosteroids and –if required–second-line therapy mortality rate is much lower than previously reported. The median time to irMyocarditis was 36 days (range 4–1,074 days) after ICI initiation, whereas other cardiotoxicities, e.g. asystolia or myocardiopathy, occurred much later. The cytokine-mediated signaling pathway was differentially regulated in myocardial biopsies as compared to healthy heart based on enrichment Gene Ontology analysis. Additionally, longitudinal peripheral blood mononuclear cell (PBMC) samples from irMyocarditis-patients indicated ICI-driven enhanced CD4+ Treg cells and reduced CD4+ T cells. Immunophenotypes, particularly effector memory T cells of irMyocarditis-patients differed from those of ICI-treated patients without side effects. LAG3 expression on T cells and PD-L1 expression on dendritic cells could serve as predictive indicators for the development of irMyocarditis.ConclusionInterestingly, our cohort shows a very low mortality rate of irMyocarditis-patients. Our data indicate so far unknown local and systemic immunological patterns in cardiotoxicity.

Abstract Cognitive or motor impairment is common among individuals with neurofibromatosis type 1 (NF1), an autosomal dominant tumor‐predisposition disorder. As many as 70% of children with NF1 report difficulties with spatial/working memory, attention, executive function, and fine motor movements. In contrast to the utilization of various Nf1 mouse models, here we employ an NF1+/ex42del miniswine model to evaluate the mechanisms and characteristics of these presentations, taking advantage of a large animal species more like human anatomy and physiology. The prefrontal lobe, anterior cingulate, and hippocampus from NF1+/ex42del and wild‐type miniswine were examined longitudinally, revealing abnormalities in mature oligodendrocytes and astrocytes, and microglial activation over time. Imbalances in GABA: Glutamate ratios and GAD67 expression were observed in the hippocampus and motor cortex, supporting the role of disruption in inhibitory neurotransmission in NF1 cognitive impairment and motor dysfunction. Moreover, NF1+/ex42del miniswine demonstrated slower and shorter steps, indicative of a balance‐preserving response commonly observed in NF1 patients, and progressive memory and learning impairments. Collectively, our findings affirm the effectiveness of NF1+/ex42del miniswine as a valuable resource for assessing cognitive and motor impairments associated with NF1, investigating the involvement of specific neural circuits and glia in these processes, and evaluating potential therapeutic interventions.

Background Tebentafusp, a bispecific (gp100×CD3) ImmTAC, significantly improved overall survival (OS) outcomes for HLA-A*02:01+ adult patients with untreated metastatic uveal melanoma (mUM) and showed promising survival in previously treated mUM with 1-year OS of 62% in the primary analysis of study IMCgp100-102. Here we report long-term outcomes from this phase 1/2 study in pretreated mUM.Patients and methods Patients with previously treated mUM received tebentafusp weekly intravenous at 20 µg dose 1, 30 µg dose 2 and either 54, 64, 68, or 73 µg (phase 1) or 68 µg (phase 2) dose 3+. The primary objective was overall response rate. Secondary objectives included OS and safety. OS was estimated by Kaplan-Meier methods. Association between OS and baseline covariates, on-treatment Response Evaluation Criteria in Solid Tumors (RECIST) response, baseline tumor biopsy and circulating-tumor DNA (ctDNA) changes were assessed.Results 146 patients were treated with tebentafusp: 19 in phase 1 and 127 in phase 2. With a median follow-up duration of 48.5 months, the median OS was 17.4 months (95% CI, 13.1 to 22.8), and the 1-year, 2-year, 3-year and 4-year OS rates were 62%, 40%, 23% and 14%, respectively. Improved survival was associated with lower ctDNA baseline levels and greater ctDNA reductions by week 9 on-treatment, with 100% 1-year, 73% 2-year and 45% 3-year OS rates for patients with ctDNA clearance. Baseline gp100 expression was not associated with survival, despite more RECIST responses among patients with higher expression. No new safety signals were reported with long-term dosing.Conclusions This study represents the longest follow-up of a Tcell receptor bispecific to date and confirms the durable survival benefits achieved with tebentafusp in previously treated mUM with good tolerability long-term. A role for ctDNA reduction as an early indicator of clinical benefit was again suggested for patients treated with tebentafusp.

Abstract Background For men with prostate cancer, radiographic progression may occur without a concordant rise in prostate‐specific antigen (PSA). Our study aimed to assess the prevalence of radiographic progression using C‐11 choline positron emission tomography (PET) imaging in patients achieving ultra‐low PSA values and to evaluate clinical outcomes in this patient population. Methods In a single institution study, we reviewed the prospectively maintained Mayo Clinic C‐11 Choline PET metastatic prostate cancer registry to identify patients experiencing radiographic disease progression (rDP) on C‐11 choline PET scan while the PSA value was less than 0.5 ng/mL. Disease progression was confirmed by tissue biopsy or response to subsequent therapy. Clinicopathologic variables were abstracted by trained research personnel. Overall survival was estimated using the Kaplan–Meier method. Intergroup differences were assessed using the log‐rank test. A univariate and multivariate Cox regression model was performed to investigate variables associated with poor survival after rDP. Results A total of 1323 patients within the registry experienced rDP between 2011 and 2021, including 220 (16.6%) men with rDP occurring at low PSA level. A median (interquartile range [IQR]) of 54.7 (19.7–106.9) months elapsed between the time of prostate cancer diagnosis and low PSA rDP, during which 173 patients (78%) developed castration‐resistant prostate cancer (CRPC). Sites of low PSA rDP included local recurrence (n = 17, 8%), lymph node (n = 90, 41%), bone (n = 94, 43%) and visceral metastases (n = 19, 9%). Biopsy at the time of rDP demonstrated small‐cell or neuroendocrine features in 21% of patients with available tissue. Over a median (IQR) follow‐up of 49.4 (21.3–95.1) months from the time of low PSA rDP, 46% (n = 102) of patients died. Factors associated with poorer survival outcomes include advanced age at rDP, CRPC status, bone and visceral metastasis (p value

The plant hormone indole-3-acetic acid (IAA), also known as auxin, plays important roles in plant growth and development, as well as in several plant–microbe interactions. IAA also acts as a microbial signal and in many bacteria regulates metabolism, stress responses, and virulence. In the bacterial plant pathogen Pseudomonas syringae pv. tomato strain DC3000 (PtoDC3000), exposure to IAA results in large-scale transcriptional reprogramming, including the differential expression of several known virulence genes. However, how PtoDC3000 senses and responds to IAA and what aspects of its biology are regulated by IAA is not understood. To investigate the mechanisms involved in perceiving and responding to IAA, we carried out a genetic screen for mutants with altered responses to IAA. One group of mutants of particular interest carried disruptions in the aefR gene encoding a TetR family transcriptional regulator. Gene expression analysis confirmed that the aefR mutants have altered responses to IAA. Thus, AefR is the first demonstrated auxin response regulator in PtoDC3000. We also investigated several aspects of PtoDC3000 biology that are regulated by both AefR and IAA, including antibiotic resistance, motility, and virulence. The observation that the aefR mutant has altered virulence on Arabidopsis, suggests that the sector of the IAA response regulated by aefR is important during pathogenesis. Our findings also provide evidence that AefR plays a role in coordinating changes in gene expression during the transition from early to late stages of infection. [Graphic: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Abstract Background Drowning is the leading cause of death for toddlers. When caregivers are knowledgeable about water safety, they can provide the best protection against drowning. The aim of this study is to survey caregivers of toddlers to better understand factors associated with water safety knowledge, attitudes about pool supervision, and toddler water competency skills. Methods An online survey of 650 parents/caregivers of 1–4-year-old toddlers asked about the caregiver’s water safety and swimming background and views on pool supervision. Surveys included a true/false section of ten basic water safety knowledge questions. Caregivers also reported on toddler swim lesson history and whether their toddler could perform six standard water competency skills. Linear regression identified factors predictive of water safety knowledge. Results On average, caregivers selected the correct answer on six out of ten water safety knowledge questions. Water safety knowledge was predicted by the relationship of the caregiver to the toddler, gender, race, education, prior CPR training, caregiver swim capability, and reported pool supervision style. On average, caregivers reported that their toddler could perform half of the water competency skills. The majority of the toddlers had taken swimming lessons. One third of caregivers believed that after a toddler has had swimming lessons, they don’t need to be watched as closely when they are in a pool. Conclusions Findings suggest that water safety knowledge is poor and that there are misconceptions about toddler supervision needs. Efforts are needed to improve water safety knowledge and to change perceptions about supervision among caregivers of toddlers.