Most organs have tissue-resident immune cells. Human organoids lack these immune cells, which limits their utility in modeling many normal and disease processes. Here, we describe that pluripotent ...stem cell-derived human colonic organoids (HCOs) co-develop a diverse population of immune cells, including hemogenic endothelium (HE)-like cells and erythromyeloid progenitors that undergo stereotypical steps in differentiation, resulting in the generation of functional macrophages. HCO macrophages acquired a transcriptional signature resembling human fetal small and large intestine tissue-resident macrophages. HCO macrophages modulate cytokine secretion in response to pro- and anti-inflammatory signals and were able to phagocytose and mount a robust response to pathogenic bacteria. When transplanted into mice, HCO macrophages were maintained within the colonic organoid tissue, established a close association with the colonic epithelium, and were not displaced by the host bone-marrow-derived macrophages. These studies suggest that HE in HCOs gives rise to multipotent hematopoietic progenitors and functional tissue-resident macrophages.
Initiation and progression of cerebral aneurysms is known to be driven by complex interactions between biological and hemodynamic factors, but the hemodynamic mechanism which drives aneurysm growth ...is unclear. We employed robust modeling and computational methods, including temporal and spatial convergence studies, to study hemodynamic characteristics of cerebral aneurysms and identify differences in these characteristics between growing and stable aneurysms.
Eleven pairs of growing and non-growing cerebral aneurysms, matched in both size and location, were modeled from MRA and CTA images, then simulated using computational fluid dynamics (CFD). Key hemodynamic characteristics, including wall shear stress (WSS), oscillatory shear index (OSI), and portion of the aneurysm under low shear, were evaluated. Statistical analysis was then performed using paired Wilcoxon rank sum tests.
The portion of the aneurysm dome under 70% of the parent artery mean wall shear stress was higher in growing aneurysms than in stable aneurysms and had the highest significance among the tested metrics (
= 0.08). Other metrics of area under low shear had similar levels of significance.
These results align with previously observed hemodynamic trends in cerebral aneurysms, indicating a promising direction for future study of low shear area and aneurysm growth. We also found that mesh resolution significantly affected simulated WSS in cerebral aneurysms. This establishes that robust computational modeling methods are necessary for high fidelity results. Together, this work demonstrates that complex hemodynamics are at play within cerebral aneurysms, and robust modeling and simulation methods are needed to further study this topic.
Background
Screening high-risk individuals (HRI) can detect potentially curable pancreatic ductal adenocarcinoma (PDAC) and its precursors. We describe the outcomes of high-risk individuals (HRI) ...after pancreatic resection of screen-detected neoplasms.
Methods
Asymptomatic HRI enrolled in the prospective Cancer of the Pancreas Screening (CAPS) studies from 1998 to 2014 based on family history or germline mutations undergoing surveillance for at least 6 months were included. Pathologic diagnoses, hospital length of stay, incidence of diabetes mellitus, operative morbidity, need for repeat operation, and disease-specific mortality were determined.
Results
Among 354 HRI, 48 (13.6%) had 57 operations (distal pancreatectomy (31), Whipple (20), and total pancreatectomy (6)) for suspected pancreatic neoplasms presenting as a solid mass (22), cystic lesion(s) (25), or duct stricture (1). The median length of stay was 7 days (IQR 5–11). Nine of the 42 HRI underwent completion pancreatectomy for a new lesion after a median of 3.8 years (IQR 2.5–7.6). Postoperative complications developed in 17 HRI (35%); there were no perioperative deaths. New-onset diabetes mellitus after partial resection developed in 20% of HRI. Fourteen PDACs were diagnosed, 11 were screen-detected, 10 were resectable, and 9 had an R0 resection. Metachronous PDAC developed in remnant pancreata of 2 HRI. PDAC-related mortality was 4/10 (40%), with 90% 1-year survival and 60% 5-year survival, respectively.
Conclusions
Screening HRI can detect PDAC with a high resectability rate. Surgical treatment is associated with a relatively short length of stay and low readmission rate, acceptable morbidity, zero 90-day mortality, and significant long-term survival.
Clinical Trial Registration Number
NCT2000089
Purpose: The purposes of the present study were to (a) compare context-specific conceptions of friendship quality in youth sport and music, and (b) determine how friendship quality is related to ...motivational beliefs in sport and music. Method: Adolescents (N = 366; M
age
= 12.9, SD = 1.0) who were involved in both organized sport and music completed measures of domain-specific friendship quality, perceived competence, enjoyment, anxiety, and motivational orientation. Results: For purpose one, a repeated-measures MANOVA revealed that (a) boys and girls rated their best sport friends higher in self-esteem enhancement and supportiveness than their best music friends, (b) boys rated their best sport friends higher in loyalty and intimacy, things in common, companionship and pleasant play, and conflict resolution than their best music friends, (c) girls rated positive friendship quality dimensions higher than boys, and (d) there were no domain or gender differences in friendship conflict. For purpose two, structural equation modeling revealed that (a) for sport, positive friendship quality dimensions were directly associated with perceived competence and indirectly associated with enjoyment, anxiety, and motivational orientation, and (b) for music, positive friendship quality and friendship conflict were related to competence motivation variables. Conclusion: Collectively, findings indicate domain differences in friendship quality and the relationship between friendship quality and motivational outcomes in sport and music. Despite some domain differences, findings demonstrate the significance of friendship quality for adolescents involved in sport and music.
Prescribed fire has been increasingly promoted to reduce wildfire risk and restore fire‐adapted ecosystems. Yet, the complexities of forest ecosystem dynamics in response to disturbances, climate ...change, and drought stress, combined with myriad social and policy barriers, have inhibited widespread implementation. Using the forest succession model LANDIS‐II, we investigated the likely impacts of increasing prescribed fire frequency and extent on wildfire severity and forest carbon storage at local and landscape scales. Specifically, we ask how much prescribed fire is required to maintain carbon storage and reduce the severity and extent of wildfires under divergent climate change scenarios? We simulated four prescribed fire scenarios (no prescribed fire, business‐as‐usual, moderate increase, and large increase) in the Siskiyou Mountains of northwest California and southwest Oregon. At the local site scale, prescribed fires lowered the severity of projected wildfires and maintained approximately the same level of ecosystem carbon storage when reapplied at a ~15‐year return interval for 50‐year simulations. Increased frequency and extent of prescribed fire decreased the likelihood of aboveground carbon combustion during wildfire events. However, at the landscape scale, prescribed fire did not decrease the projected severity and extent of wildfire, even when large increases (up to 10× the current levels) of prescribed fire were simulated. Prescribed fire was most effective at reducing wildfire severity under a climate change scenario with increased temperature and precipitation and on sites with north‐facing aspects and slopes greater than 30°. Our findings suggest that placement matters more than frequency and extent to estimate the effects of prescribed fire, and that prescribed fire alone would not be sufficient to reduce the risk of wildfire and promote carbon sequestration at regional scales in the Siskiyou Mountains. To improve feasibility, we propose targeting areas of high concern or value to decrease the risk of high‐severity fire and contribute to meeting climate mitigation and adaptation goals. Our results support strategic and targeted landscape prioritization of fire treatments to reduce wildfire severity and increase the pace and scale of forest restoration in areas of social and ecological importance, highlighting the challenges of using prescribed fire to lower wildfire risk.
In glioblastoma (GBM), heterogeneous expression of amplified and mutated epidermal growth factor receptor (EGFR) presents a substantial challenge for the effective use of EGFR-directed therapeutics. ...Here we demonstrate that heterogeneous expression of the wild-type receptor and its constitutively active mutant form, EGFRvIII, limits sensitivity to these therapies through an interclonal communication mechanism mediated by interleukin-6 (IL-6) cytokine secreted from EGFRvIII-positive tumor cells. IL-6 activates a NF-κB signaling axis in a paracrine and autocrine manner, leading to bromodomain protein 4 (BRD4)-dependent expression of the prosurvival protein survivin (BIRC5) and attenuation of sensitivity to EGFR tyrosine kinase inhibitors (TKIs). NF-κB and survivin are coordinately up-regulated in GBM patient tumors, and functional inhibition of either protein or BRD4 in in vitro and in vivo models restores sensitivity to EGFR TKIs. These results provide a rationale for improving anti-EGFR therapeutic efficacy through pharmacological uncoupling of a convergence point of NF-κB-mediated survival that is leveraged by an interclonal circuitry mechanism established by intratumoral mutational heterogeneity.
Iron has a fundamental role in many metabolic processes, including electron transport, deoxyribonucleotide synthesis, oxygen transport and many essential redox reactions involving haemoproteins and ...Fe–S cluster proteins. Defective iron homeostasis results in either iron deficiency or iron overload. Precise regulation of iron transport in mitochondria is essential for haem biosynthesis, haemoglobin production and Fe–S cluster protein assembly during red cell development. Here we describe a zebrafish mutant, frascati (frs), that shows profound hypochromic anaemia and erythroid maturation arrest owing to defects in mitochondrial iron uptake. Through positional cloning, we show that the gene mutated in the frs mutant is a member of the vertebrate mitochondrial solute carrier family (SLC25) that we call mitoferrin (mfrn). mfrn is highly expressed in fetal and adult haematopoietic tissues of zebrafish and mouse. Erythroblasts generated from murine embryonic stem cells null for Mfrn (also known as Slc25a37) show maturation arrest with severely impaired incorporation of 55Fe into haem. Disruption of the yeast mfrn orthologues, MRS3 and MRS4, causes defects in iron metabolism and mitochondrial Fe–S cluster biogenesis. Murine Mfrn rescues the defects in frs zebrafish, and zebrafish mfrn complements the yeast mutant, indicating that the function of the gene may be highly conserved. Our data show that mfrn functions as the principal mitochondrial iron importer essential for haem biosynthesis in vertebrate erythroblasts.
In critical care, the specific, structured approach to patient care known as a "time-limited trial" has been promoted in the literature to help patients, surrogate decision makers, and clinicians ...navigate consequential decisions about life-sustaining therapy in the face of uncertainty. Despite promotion of the time-limited trial approach, a lack of consensus about its definition and essential elements prevents optimal clinical use and rigorous evaluation of its impact. The objectives of this American Thoracic Society Workshop Committee were to establish a consensus definition of a time-limited trial in critical care, identify the essential elements for conducting a time-limited trial, and prioritize directions for future work. We achieved these objectives through a structured search of the literature, a modified Delphi process with 100 interdisciplinary and interprofessional stakeholders, and iterative committee discussions. We conclude that a time-limited trial for patients with critical illness is a collaborative plan among clinicians and a patient and/or their surrogate decision makers to use life-sustaining therapy for a defined duration, after which the patient's response to therapy informs the decision to continue care directed toward recovery, transition to care focused exclusively on comfort, or extend the trial's duration. The plan's 16 essential elements follow four sequential phases: consider, plan, support, and reassess. We acknowledge considerable gaps in evidence about the impact of time-limited trials and highlight a concern that if inadequately implemented, time-limited trials may perpetuate unintended harm. Future work is needed to better implement this defined, specific approach to care in practice through a person-centered equity lens and to evaluate its impact on patients, surrogates, and clinicians.
Girls on the Run is an after-school physical activity-based positive youth development program designed to enhance girls' social, psychological, and physical development. We evaluated the ...effectiveness of the program by employing a longitudinal design and mixed methods.
Girls (N = 203; aged 8-11 y) completed survey measures of positive youth development constructs (competence, confidence, connection, character, and caring), physical activity, and sedentary behavior prior to, at the end of, and 3 months after the season. Subsamples of girls, coaches, caregivers, and school personnel participated in focus groups. Coaches completed information about their team's community impact project and number of girls who completed the season-ending 5k.
The full sample improved in confidence and connection, whereas girls who started below the preseason average showed the greatest gains from preseason to postseason on all measures, and scores were maintained or continued to improve at follow-up. All stakeholders in focus groups corroborated evidence of season-long improvement in social and emotional behaviors and health outcomes. Involvement in the community impact project contributed to girls' growth in character and empathy skills.
Findings provide empirical evidence that Girls on the Run is effective in promoting positive youth development, including season-long and lasting change in competence, confidence, connection, character, caring, and physical activity, especially among girls who exhibited lower preseason scores than their peers.
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