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We conducted a research campaign in a neotropical rainforest in Costa Rica throughout the drought phase of an El-Nino Southern Oscillation event to determine microbial community dynamics and soil C fluxes. Our study included nests of the leafcutter ant Atta cephalotes, as soil disturbances made by these ecosystem engineers may influence microbial drought response. Drought decreased the diversity of microbes and the abundance of core microbiome taxa, including Verrucomicrobial bacteria and Sordariomycete fungi. Despite initial responses of decreasing diversity and altered composition, 6 months post-drought the microbiomes were similar to pre-drought conditions, demonstrating the resilience of soil microbial communities to drought events. A. cephalotes nests altered fungal composition in the surrounding soil, and reduced both fungal mortality and growth of Acidobacteria post-drought. Drought increased CH4 consumption in soils due to lower soil moisture, and A. cephalotes nests decrease the variability of CH4 emissions in some soil types. CH4 emissions were tracked by the abundance of methanotrophic bacteria and fungal composition. These results characterize the microbiome of tropical soils across both time and space during drought and provide evidence for the importance of leafcutter ant nests in shaping soil microbiomes and enhancing microbial resilience during climatic perturbations.

BackgroundRadiotherapy is an essential component of cancer treatment, yet many countries do not have adequate capacity to serve all patients who would benefit from it. Allocation systems are needed to guide patient prioritization for radiotherapy in resource-limited contexts. These systems should be informed by allocation principles deemed relevant to stakeholders. This study explores the ethical dilemmas and views of decision-makers engaged in real-world prioritization of scarce radiotherapy resources at a cancer center in Rwanda in order to identify relevant principles.MethodsSemi-structured interviews were conducted with a purposive sample of 22 oncology clinicians, program leaders, and clinical advisors. Interviews explored the factors considered by decision-makers when prioritizing patients for radiotherapy. The framework method of thematic analysis was used to characterize these factors. Bioethical analysis was then applied to determine their underlying normative principles.ResultsParticipants considered both clinical and non-clinical factors relevant to patient prioritization for radiotherapy. They widely agreed that disease curability should be the primary overarching driver of prioritization, with the goal of saving the most lives. However, they described tension between curability and competing factors including age, palliative benefit, and waiting time. They were divided about the role that non-clinical factors such as social value should play, and agreed that poverty should not be a barrier.ConclusionsMultiple competing principles create tension with the agreed upon overarching goal of maximizing lives saved, including another utilitarian approach of maximizing life-years saved as well as non-utilitarian principles, such as egalitarianism, prioritarianism, and deontology. Clinical guidelines for patient prioritization for radiotherapy can combine multiple principles into a single allocation system to a significant extent. However, conflicting views about the role that social factors should play, and the dynamic nature of resource availability, highlight the need for ongoing work to evaluate and refine priority setting systems based on stakeholder views.

Soils are the largest source of atmospheric nitrous oxide (N2O), a powerful greenhouse gas. Dry soils rarely harbor anoxic conditions to favor denitrification, the predominant N2O-producing process, yet, among the largest N2O emissions have been measured after wetting summer-dry desert soils, raising the question: Can denitrifiers endure extreme drought and produce N2O immediately after rainfall? Using isotopic and molecular approaches in a California desert, we found that denitrifiers produced N2O within 15 minutes of wetting dry soils (site preference = 12.8 ± 3.92 per mil, δ15Nbulk = 18.6 ± 11.1 per mil). Consistent with this finding, we detected nitrate-reducing transcripts in dry soils and found that inhibiting microbial activity decreased N2O emissions by 59%. Our results suggest that despite extreme environmental conditions-months without precipitation, soil temperatures of ≥40°C, and gravimetric soil water content of

Abstract Aneuploidy is a hallmark of human cancer, yet the molecular mechanisms to cope with aneuploidy-induced cellular stresses remain largely unknown. Here, we induce chromosome mis-segregation in non-transformed RPE1-hTERT cells and derive multiple stable clones with various degrees of aneuploidy. We perform a systematic genomic, transcriptomic and proteomic profiling of 6 isogenic clones, using whole-exome DNA, mRNA and miRNA sequencing, as well as proteomics. Concomitantly, we functionally interrogate their cellular vulnerabilities, using genome-wide CRISPR/Cas9 and large-scale drug screens. Aneuploid clones activate the DNA damage response and are more resistant to further DNA damage induction. Aneuploid cells also exhibit elevated RAF/MEK/ERK pathway activity and are more sensitive to clinically-relevant drugs targeting this pathway, and in particular to CRAF inhibition. Importantly, CRAF and MEK inhibition sensitize aneuploid cells to DNA damage-inducing chemotherapies and to PARP inhibitors. We validate these results in human cancer cell lines. Moreover, resistance of cancer patients to olaparib is associated with high levels of RAF/MEK/ERK signaling, specifically in highly-aneuploid tumors. Overall, our study provides a comprehensive resource for genetically-matched karyotypically-stable cells of various aneuploidy states, and reveals a therapeutically-relevant cellular dependency of aneuploid cells.

Abstract Purpose To address a gap in radiation oncology education in low- and middle-income countries (LMICs), we sought to evaluate the effectiveness and generalizability of a refined curriculum on intensity modulated radiotherapy (IMRT) offered to existing radiation therapy (RT) clinics across Africa and Latin America (LATAM) at no cost. Methods A curriculum was created based on prior needs assessments and adapted for participating medical physicists, radiation oncologists, radiation therapists, and trainees in LMICs. English-speaking and Spanish-speaking teams of volunteer educators delivered 27 hour-long sessions 1–2 times weekly for 4 months using video conferencing to African and LATAM cohorts, respectively. Pre- and post-course multiple-choice examinations were administered to LATAM participants, and pre- and post-course self-confidence (1–5 Likert-scale) and open-ended feedback were collected from all participants. Results Twenty-five centers across Africa (13) and LATAM (12) participated, yielding a total of 332 enrolled participants (128 African, 204 LATAM). Sessions were delivered with a mean of 44 (22.5) and 85 (25.4) participants in the African and LATAM programs, respectively. Paired pre and post-course data demonstrated significant (p

Abstract Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.

This experiment (N = 1,019) examined how a state of processing fluency, induced through either an easy or difficult task (reading a simple vs. complex message or recalling few vs. many examples) impacted participants’ ability to subsequently detect misinformation. The results revealed that, as intended, easier tasks led to higher reports of processing fluency. In turn, increased processing fluency was positively associated with internal efficacy. Finally, internal efficacy was positively related to misinformation detection using a signal detection task. This work suggests that feelings of ease while processing information can promote confidence and a more discerning style of information processing. Given the proliferation of misinformation online, an understanding of how metacognitions – like processing fluency – can disrupt the tacit acceptance of information carries important democratic and normative implications.

BackgroundThe transition from pediatric to adult care poses a significant health system–level challenge impeding the delivery of quality health services for youth with chronic health conditions. In Canada and globally, the transition to adult care is regarded as a top priority in adolescent health in need of readily applicable, adaptable, and relevant national metrics to evaluate and benchmark transition success across disease populations and clinical care settings. Unfortunately, existing literature fails to account for the lack of engagement from youth and caregivers in developing indicators, and its applicability across chronic conditions, primary care involvement, and health equity considerations. ObjectiveOur proposed study aims to establish a consensus-driven set of quality indicators for the transition to adult care that are universally applicable across physical, developmental, and mental health conditions, clinical care settings, and health jurisdictions. MethodsUsing an integrated knowledge translation (iKT) approach, a panel comprising youth, caregivers, interdisciplinary health care providers, and health system leaders will be established to collaborate with our research team to ensure that the study methodology, materials, and knowledge dissemination are suitable and reflect the perspectives of youth and their families. We will then conduct an iterative 3-round Online Modified Delphi (OMD) study (n=160) to (1) compare and contrast the perspectives of youth, caregivers, health care providers, and health system leaders on quality indicators for transition; and (2) prioritize a key set of quality indicators for transition applicable across disease populations that are the most important, useful, and feasible in the Canadian context. Using the RAND/UCLA Appropriateness Method (RAM) multistage analytic approach, data from each panel and stakeholder group will be examined separately and compared to establish a key set of indicators endorsed by both panels. ResultsThe study is funded by the Canadian Institutes of Health Research and Physicians Services Incorporated. ConclusionsThis study will produce quality indicators to evaluate and inform action equitably to improve transition from pediatric to adult care for youth and their families in Canada. International Registered Report Identifier (IRRID)PRR1-10.2196/60860

Abstract Background United States drug overdose deaths are being driven by the increasing prevalence of fentanyl, but whether patients are knowingly using fentanyl is unclear. We examined the analytical confirmation of fentanyl in emergency department (ED) patients with documented heroin overdose. Hypothesis We hypothesized that the proportion of fentanyl and fentanyl analogs would be higher than that of confirmed heroin. Methods This is a subgroup analysis from a prospective multicenter consecutive cohort of ED patients age 18+ with opioid overdose presenting to 10 US sites within the Toxicology Investigators Consortium from 2020 to 2021. Toxicology analysis was performed using liquid chromatography quadrupole time‐of‐flight mass spectrometry. De‐identified toxicology results were paired with the clinical database. The primary outcome was the proportion of patients with fentanyl analytes detected in their serum. Results Of 1006 patients screened, 406 were eligible, and of 168 patients who reported that they had taken heroin or had a documented heroin overdose, 88% (n = 147) were in fact found to have fentanyl and/or a fentanyl analog present on serum analysis (p

ObjectiveExternalizing behavior problems (EBPs) are common in children, with significant long-term impact on the child and family members. Parents, particularly mothers, of children with EBPs often experience heightened emotional distress. One crucial factor affecting parents’ ability to manage this distress is their level of differentiation-of-self (DOS). Differentiated parents are more likely to engage in practices that meet their child’s psychological needs, thus supporting the self-determination theory principles vital for a child’s well-being. This study examined the impact of parental DOS on parenting practices and subsequently on the child’s EBPs, exploring possible differences between mothers and fathers.MethodsThirty-two mother–father dyads with children aged 6–14, diagnosed with EBPs participated. Parents completed the Differentiation of Self Inventory–Short Form, the Revised Parents as a Social Context Questionnaire, and the Strengths and Difficulties Questionnaire to assess parental DOS, practices, and child’s EBPs, respectively. Adjusted parallel mediation models examined the mediating role of parental practices in the relationship between parental DOS and a child’s EBPs.ResultsWhile no direct link between parental DOS and child’s symptoms was found, a complete mediation model indicated need-frustrating practices mediating between parental DOS and a child’s EBPs, for both mothers and fathers. Additionally, fathers’ need-supportive practices, but not mothers’, were negatively associated with the child’s symptoms.DiscussionThese findings highlight the interaction between parental traits, need-frustrating practices, and a child’s psychopathology. Notably, fathers’ supportive behaviors emerged as potential protective factors against child’s EBPs, suggesting promising directions for future research and interventions targeting fathers.

Introduction: Endothelial cells have a crucial function in transporting and exchanging various nutrients. O-GlcNAcylation, mediated by O-GlcNAc transferase (OGT), involves the addition of N-acetylglucosamine to proteins and serves as an intracellular nutrient sensing mechanism. However, the role of O-GlcNAcylation in endothelial cells remains poorly understood. Objective: This study investigated the role of O-GlcNAcylation in endothelial cells. Methods: Endothelial-cell-specific Ogt -knockout mice (Ogt-ECKO) were generated by crossing Ogt-floxed mice (Ogt-flox) with VE-Cadherin Cre ERT2 mice. Ogt-ECKO mice and Ogt-flox control mice were subjected to a normal or high-fat diet, and their body weight, glucose metabolism, and lipid metabolism were examined. Results: Ogt-ECKO mice exhibited reduced body weight compared with Ogt-flox control mice under a high-fat diet. Lipid absorption was significantly impaired in Ogt-ECKO mice. Changes in the intercellular junctions of small intestinal lacteal endothelial cells from a button-like to a zipper-like configuration were observed. Furthermore, Ogt-ECKO mice showed decreased expression of VEGFR3. The administration of a nitric oxide donor restored lipid absorption and reversed the morphological alterations in Ogt-ECKO mice. Conclusions: These findings demonstrate the critical role of O-GlcNAcylation in endothelial cells in lipid absorption in the intestine through the modulation of lacteal junction morphology. These results provide novel insight into the metabolic regulatory mechanisms under physiological conditions and have implications for the development of new therapeutic strategies for obesity.

There is a strong, positive relationship between childhood literacy and physical and mental health outcomes in adulthood. Through primary care-based literacy interventions, pediatricians reach children and their families long before they enter traditional education venues. In so doing, pediatricians play a key role in children's school readiness and in turn health outcomes. The current state of childhood literacy in United States defines an increasingly urgent platform for the healthcare profession generally, and pediatricians specifically, to embrace. Through reviewing the existing literature on the impact of childhood literacy on physical, mental, and social-emotional health outcomes, we hope to highlight the need for increased collaboration between the education and medical fields to further promote the literacy interventions in pediatric healthcare settings.