Emerging probing perspective of two-dimensional materials physics: terahertz emission spectroscopy.

Terahertz (THz) emission spectroscopy (TES) has emerged as a highly effective and versatile technique for investigating the photoelectric properties of diverse materials and nonlinear physical processes in the past few decades. Concurrently, research on two-dimensional (2D) materials has experienced substantial growth due to their atomically thin structures, exceptional mechanical and optoelectronic properties, and the potential for applications in flexible electronics, sensing, and nanoelectronics. Specifically, these materials offer advantages such as tunable bandgap, high carrier mobility, wideband optical absorption, and relatively short carrier lifetime. By applying TES to investigate the 2D materials, their interfaces and heterostructures, rich information about the interplay among photons, charges, phonons and spins can be unfolded, which provides fundamental understanding for future applications. Thus it is timely to review the nonlinear processes underlying THz emission in 2D materials including optical rectification, photon-drag, high-order harmonic generation and spin-to-charge conversion, showcasing the rich diversity of the TES employed to unravel the complex nature of these materials. Typical applications based on THz emissions, such as THz lasers, ultrafast imaging and biosensors, are also discussed. Step further, we analyzed the unique advantages of spintronic terahertz emitters and the future technological advancements in the development of new THz generation mechanisms leading to advanced THz sources characterized by wide bandwidth, high power and integration, suitable for industrial and commercial applications. The continuous advancement and integration of TES with the study of 2D materials and heterostructures promise to revolutionize research in different areas, including basic materials physics, novel optoelectronic devices, and chips for post-Moore's era.

Continuous palliative sedation until death: a qualitative study of palliative care clinicians' experiences.

BACKGROUND: The practice of continuous palliative sedation until death is the subject of much medical and ethical debate, which is reflected in the inconsistency that persists in the literature regarding the definition and indications of palliative sedation. AIM: This study aims to gain a better understanding of palliative care clinicians' experiences with continuous palliative sedation. DESIGN: We conducted a qualitative study based on focus group discussions. SETTING/PARTICIPANTS: We conducted six focus groups with a total of 28 palliative care clinicians (i.e., 15 nurses, 12 physicians, and 1 end-of-life doula) from diverse care settings across Canada, where assisted dying has recently been legalized. RESULTS: An interpretative phenomenological analysis was used to consolidate the data into six key themes: responding to suffering; grappling with uncertainty; adapting care to ensure ongoing quality; grounding clinical practice in ethics; combining medical expertise, relational tact, and reflexivity; and offering an alternative to assisted death. CONCLUSIONS: Interaction with the patient's family, uncertainty about the patient's prognosis, the concurrent practice of assisted dying, and the treatment of existential suffering influence the quality of sedation and indicate a lack of clear palliative care guidelines. Nevertheless, clinicians exhibit a reflective and adaptive capacity that can facilitate good practice.

A Brief Tool to Screen Patients for Precarious Employment: A Validation Study.

PURPOSE: Precarious employment, defined by temporary contracts, unstable employment, or job insecurity, is increasingly common and is associated with inconsistent access to benefits, lower income, and greater exposure to physical and psycholosocial hazards. Clinicians can benefit from a simple approach to screen for precarious employment to improve their understanding of a patient's social context, help with diagnoses, and inform treatment plans and intersectional interventions. Our objective was to validate a screening tool for precarious employment. METHODS: We used a 3-item screening tool that covered key aspects of precarious employment: non-standard employment, variable income, and violations of occupational health and safety rights and protections. Answers were compared with classification using the Poverty and Employment Precarity in Southern Ontario Employment Index. Participants were aged 18 years and older, fluent in English, and employed. They were recruited in 7 primary care clinic waiting rooms in Toronto, Canada over 12 months. RESULTS: A total of 204 people aged 18-72 years (mean 38 [SD 11.3]) participated, of which 93 (45.6%) identified as men and 119 (58.3%) self-reported as White. Participants who reported 2 or more of the 3 items as positive were almost 4 times more likely to be precariously employed (positive likelihood ratio = 3.84 [95% CI, 2.15-6.80]). CONCLUSIONS: A 3-item screening tool can help identify precarious employment. Our tool is useful for starting a conversation about employment precarity and work conditions in clinical settings. Implementation of this screening tool in health settings could enable better targeting of resources for managing care and connecting patients to legal and employment support services.

Tyrosine Kinase Inhibition Activates Intratumoral γδ T Cells in Gastrointestinal Stromal Tumor.

γδ T cells are a rare but potent subset of T cells with pleiotropic functions. They commonly reside within tumors but the response of γδ T cells to tyrosine kinase inhibition is unknown. To address this, we studied a genetically engineered mouse model of gastrointestinal stromal tumor (GIST) driven by oncogenic Kit signaling that responds to the Kit inhibitor imatinib. At baseline, γδ T cells were antitumoral, as blockade of either γδ T-cell receptor or IL17A increased tumor weight and decreased antitumor immunity. However, imatinib therapy further stimulated intratumoral γδ T cells, as determined by flow cytometry and single-cell RNA sequencing (scRNA-seq). Imatinib expanded a highly activated γδ T-cell subset with increased IL17A production and higher expression of immune checkpoints and cytolytic effector molecules. Consistent with the mouse model, γδ T cells produced IL17A in fresh human GIST specimens, and imatinib treatment increased γδ T-cell gene signatures, as measured by bulk tumor RNA-seq. Furthermore, tumor γδ T cells correlated with survival in patients with GIST. Our findings highlight the interplay between tumor cell oncogene signaling and antitumor immune responses and identify γδ T cells as targets for immunotherapy in GIST.

Hybrid Shear-thinning Hydrogel Integrating Hyaluronic Acid with ROS-Responsive Nanoparticles.

Nanoparticle (NP) supra-assembly offers unique opportunities to tune macroscopic hydrogels' mechanical strength, material degradation, and drug delivery properties. Here, synthetic, reactive oxygen species (ROS)-responsive NPs are physically crosslinked with hyaluronic acid (HA) through guest-host chemistry to create shear-thinning NP/HA hydrogels. A library of triblock copolymers composed of poly(propylene sulfide)-bl-poly(N,N-dimethylacrylamide)-bl-poly(N,N-dimethylacrylamide-co-N-(1-adamantyl)acrylamide) are synthesized with varied triblock architectures and adamantane grafting densities and then self-assembled into NPs displaying adamantane on their corona. Self-assembled NPs are mixed with ß-cyclodextrin grafted HA to yield eighteen NP/HA hydrogel formulations. The NP/HA hydrogel platform demonstrates superior mechanical strength to HA-only hydrogels, susceptibility to oxidative/enzymatic degradation, and inherent cell-protective, antioxidant function. The performance of NP/HA hydrogels is shown to be affected by triblock architecture, guest/host grafting densities, and HA composition. In particular, the length of the hydrophilic second block and adamantane grafting density of self-assembled NPs significantly impacts hydrogel mechanical properties and shear-thinning behavior, while ROS-reactivity of poly(propylene sulfide) protects cells from cytotoxic ROS and reduces oxidative degradation of HA compared to HA-only hydrogels. This work provides insight into polymer structure-function considerations for designing hybrid NP/HA hydrogels and identifies antioxidant, shear-thinning hydrogels as promising injectable delivery platforms for small molecule drugs and therapeutic cells.

Multiple intratumoral sources of kit ligand promote gastrointestinal stromal tumor.

Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and is typically driven by a single mutation in the Kit or PDGFRA receptor. While highly effective, tyrosine kinase inhibitors (TKIs) are not curative. The natural ligand for the Kit receptor is Kit ligand (KitL), which exists in both soluble and membrane-bound forms. While KitL is known to stimulate human GIST cell lines in vitro, we used a genetically engineered mouse model of GIST containing a common human KIT mutation to investigate the intratumoral sources of KitL, importance of KitL during GIST oncogenesis, and contribution of soluble KitL to tumor growth in vivo. We discovered that in addition to tumor cells, endothelia and smooth muscle cells produced KitL in KitV558Δ/+ tumors, even after imatinib therapy. Genetic reduction of total KitL in tumor cells of KitV558Δ/+ mice impaired tumor growth in vivo. Similarly, genetic reduction of tumor cell soluble KitL in KitV558Δ/+ mice decreased tumor size. By RNA sequencing, quantitative PCR, and immunohistochemistry, KitL expression was heterogeneous in human GIST specimens. In particular, PDGFRA-mutant tumors had much higher KitL expression than Kit-mutant tumors, suggesting the benefit of Kit activation in the absence of mutant KIT. Serum KitL was higher in GIST patients with tumors resistant to imatinib and in those with tumors expressing more KitL RNA. Overall, KitL supports the growth of GIST at baseline and after imatinib therapy and remains a potential biomarker and therapeutic target.

Foreign body granuloma development after calcium hydroxylapatite injection for stress urinary incontinence: A literature review and case report.

Objectives: To present a case of foreign body granuloma (FBG) development after injection of calcium hydroxylapatite as a urethral bulking agent and to review all documented cases of this phenomenon in the literature. Methods: We analyzed a new case of calcium hydroxylapatite-induced FBG. We also conducted a literature review of the PubMed, Embase, CINAHL, and Web of Science databases through March 2022. Reports were included if they contained stress urinary incontinence patients that developed an FBG after calcium hydroxylapatite injection. The cases were reviewed for presenting symptoms, patient demographics, granuloma details, and surgical treatment. Results: We screened 250 articles and included six articles between 2006 and 2015 in addition to the present case. The median age of the patients was 65.5 years (range 45-93), and all patients were female. The most common presenting symptoms and the proportion of patients affected were difficulty voiding (4/8), recurrent urinary incontinence (3/8), and dyspareunia (2/8). The median time between the first CaHA injection and discovery of the FBG was 5 months (range 1-50). The median longest dimension of the FBGs was 1.85 cm (range 1.0-3.0). The 8 masses observed were evenly distributed throughout the urethra, with 3 in the bladder neck, 2 in the midurethra, and 3 in the distal urethra. Surgical excision was the predominant management choice, with some variation in technique. Conclusions: Severe, persistent lower urinary tract symptoms after calcium hydroxylapatite injection may indicate an FBG, which has been successfully managed with surgical excision.

Impact of emergency department arrival time on door-to-needle time in patients with acute stroke.

Background: This study aimed to identify which emergency department (ED) factors impact door-to-needle (DTN) time in acute stroke patients eligible for intravenous thrombolysis. The purpose of analyzing emergency department factors is to determine whether any modifiable factors could shorten the time to thrombolytics, thereby increasing the odds of improved clinical outcomes. Methods: This was a prospective observational quality registry study that included all patients that received alteplase for stroke. These data are our hospital data from the national Get With The Guidelines Registry. The Get With The Guidelines® Stroke Registry is a hospital-based program focused on improving care for patients diagnosed with a stroke. The program has over five million patients, and hospitals can access their own program data. The registry promotes the use of and adherence to scientific treatment guidelines to improve patient outcomes. The time of patient arrival to the ED was captured via the timestamp in the electronic health record. Arriving between Friday 6 p.m. and Monday 6 a.m. was classified as "weekend," regardless of the time of arrival. Time to CT, time-to-lab, and presence of a dedicated stroke team were also recorded. Emergency medical services (EMS) run sheets were used to verify arrival via ambulance. Results: Forty-nine percent of the cohort presented during the day shift, 24% during the night shift, and 27% on the weekend. A total of 85% were brought by EMS, and 15% of patients were walk-ins. The median DTN time during the day shift was 37 min (IQR 26-51, range 10-117). The median DTN time during the night shift was 59 min (IQR 39-89, range 34-195). When a dedicated stroke team was present, the median DTN time was 36 min, compared to 51 min when they were not present. The median door-to-CT time was 24 min (IQR 18-31 min). On univariate analyses, arriving during the night shift (P < 0.0001), arriving as a walk-in (P = 0.0080), and longer time-to-CT (P < 0.0001) were all associated with longer DTN time. Conversely, the presence of a dedicated stroke team was associated with a significantly shorter DTN time (P < 0.0001). Conclusion: Factors that contribute most to a delay in DTN time include arrival during the night shift, lack of a dedicated stroke team, longer time-to-CT read, and arrival as a walk-in. All of these are addressable factors from an operational standpoint and should be considered when performing quality improvement of hospital protocols.

Myosin Light-Chain Kinase Inhibition Potentiates the Antitumor Effects of Avapritinib in PDGFRA D842V-Mutant Gastrointestinal Stromal Tumor.

PURPOSE: To create an in vivo model of PDGFRA D842V-mutant gastrointestinal stromal tumor (GIST) and identify the mechanism of tumor persistence following avapritinib therapy. EXPERIMENTAL DESIGN: We created a patient-derived xenograft (PDX) of PDGFRA D842V-mutant GIST and tested the effects of imatinib, avapritinib, and ML-7, an inhibitor of myosin light-chain kinase (MYLK). Bulk tumor RNA sequencing and oncogenic signaling were evaluated. Apoptosis, survival, and actin cytoskeleton were evaluated in GIST T1 cells and isolated PDX cells in vitro. Human GIST specimens were analyzed for MYLK expression. RESULTS: The PDX was minimally responsive to imatinib but sensitive to avapritinib. Avapritinib therapy increased tumor expression of genes related to the actin cytoskeleton, including MYLK. ML-7 induced apoptosis and disrupted actin filaments in short-term cultures of PDX cells and decreased survival in GIST T1 cells in combination with imatinib or avapritinib. Combined therapy with ML-7 improved the antitumor effects of low-dose avapritinib in vivo. Furthermore, MYLK was expressed in human GIST specimens. CONCLUSIONS: MYLK upregulation is a novel mechanism of tumor persistence after tyrosine kinase inhibition. Concomitant MYLK inhibition may enable the use of a lower dose of avapritinib, which is associated with dose-dependent cognitive side effects.

Carcinoembryonic Antigen-Related Cell Adhesion Molecule Type 5 Receptor-Targeted Fluorescent Intraoperative Molecular Imaging Tracer for Lung Cancer: A Nonrandomized Controlled Trial.

Importance: Localization of subcentimeter ground glass opacities during minimally invasive thoracoscopic lung cancer resections is a significant challenge in thoracic oncology. Intraoperative molecular imaging has emerged as a potential solution, but the availability of suitable fluorescence agents is a limiting factor. Objective: To evaluate the suitability of SGM-101, a carcinoembryonic antigen-related cell adhesion molecule type 5 (CEACAM5) receptor-targeted near-infrared fluorochrome, for molecular imaging-guided lung cancer resections, because glycoprotein is expressed in more than 80% of adenocarcinomas. Design, Setting, and Participants: For this nonrandomized, proof-of-principal, phase 1 controlled trial, patients were divided into 2 groups between August 1, 2020, and January 31, 2022. Patients with known CEACAM5-positive gastrointestinal tumors suggestive of lung metastasis were selected as proof-of-principle positive controls. The investigative group included patients with lung nodules suggestive of primary lung malignant neoplasms. Patients 18 years or older without significant comorbidities that precluded surgical exploration with suspicious pulmonary nodules requiring surgical biopsy were included in the study. Interventions: SGM-101 (10 mg) was infused up to 5 days before index operation, and pulmonary nodules were imaged using a near-infrared camera system with a dedicated thoracoscope. Main Outcomes and Measures: SGM-101 localization to pulmonary nodules and its correlation with CEACAM5 glycoprotein expression by the tumor as quantified by tumor and normal pulmonary parenchymal fluorescence. Results: Ten patients (5 per group; 5 male and 5 female; median [IQR] age, 66 [58-69] years) with 14 total lesions (median [range] lesion size, 0.91 [0.90-2.00] cm) were enrolled in the study. In the control group of 4 patients (1 patient did not undergo surgical resection because of abnormal preoperative cardiac clearance findings that were not deemed related to SGM-101 infusion), the mean (SD) lesion size was 1.33 (0.48) cm, 2 patients had elevated serum CEA markers, and 2 patients had normal serum CEA levels. Of the 4 patients who underwent surgical intervention, those with 2+ and 3+ tissue CEACAM5 expression had excellent tumor fluorescence, with a mean (SD) tumor to background ratio of 3.11 (0.45). In the patient cohort, the mean (SD) lesion size was 0.68 (0.22) cm, and no elevations in serum CEA levels were found. Lack of SGM-101 fluorescence was associated with benign lesions and with lack of CEACAM5 staining. Conclusions and Relevance: This in-human proof-of-principle nonrandomized controlled trial demonstrated SGM-101 localization to CEACAM5-positive tumors with the detection of real-time near-infrared fluorescence in situ, ex vivo, and by immunofluorescence microscopy. These findings suggest that SGM-101 is a safe, receptor-specific, and feasible intraoperative molecular imaging fluorochrome that should be further evaluated in randomized clinical trials. Trial Registration: ClinicalTrials.gov identifier: NCT04315467.

Pediatric Bradycardia Is Undertreated in the Prehospital Setting: A Retrospective Multi-Agency Analysis.

BACKGROUND: Bradycardia is the most common terminal cardiac electrical activity in children, and early recognition and treatment is necessary to avoid cardiac arrest. Interventions such as oxygen, chest compressions, epinephrine, and atropine recommended by American Heart Association (AHA) Pediatric Advanced Life support (PALS) guidelines have been shown to improve outcomes (including higher survival rates) for inpatient pediatric patients with bradycardia. However, little is known about the epidemiology of pediatric prehospital bradycardia. We sought to investigate the incidence and management of pediatric bradycardia in the prehospital setting by emergency medical services (EMS). METHODS: This was a retrospective study of 911 scene response prehospital encounters for patients ages 0-18 years in 2019 from the United States ESO Research Data Collaborative. We defined age-based bradycardia per the 2015 AHA PALS guidelines. We performed general descriptive statistics and a univariate analysis examining any PALS-recommended interventions in the presence of altered mental status, hypotension for age, and a first heart rate less than 60. RESULTS: Of 7,422,710 encounters in the 2019 ESO Data Collaborative, 1,209 patients met inclusion criteria. Most (58.5%) were male, and the median age was 2 years (interquartile range 0-13 years). One-quarter (24.7%) of patients received fluids, and bag-valve mask ventilation was the most common airway intervention (12.1% of patients). Receipt of any PALS-recommended interventions was associated with age-adjusted hypotension (odds ratio (OR) 4.0, 95% confidence interval (CI) 3.9-5.4) and altered mental status (OR 15.5, 95% CI 10.7-22.3), but not a first heart rate less than 60 bpm (OR 0.9, 95% CI 0.6-1.1). CONCLUSIONS: To our knowledge, this study is the first to examine the incidence and management of prehospital pediatric bradycardia. Incidence was rare, but adherence to PALS guidelines was variable. Further research and education are needed to ensure proper prehospital treatment of pediatric bradycardia.

Immunotherapy for GI Malignancies, Ready for Prime Time?

Gastrointestinal (GI) cancers include esophageal, gastric, pancreatic, hepatobiliary, and colorectal malignancies. Immunotherapy has proved to be an important treatment method for cancer, and its use for a wide range of GI malignancies has been evaluated recently. This article discusses the type and mechanism of various immunotherapies under investigation in GI cancer. The study also reviews recent clinical trials, with a particular focus on overall survival, and discusses their achievements and limitations. Immunotherapy has shown efficacy for microsatellite instability high colorectal cancer and some promise in some gastroesophageal junction and gastric cancers. Meanwhile, it has not been effective for pancreatic or neuroendocrine tumors. The identification of novel biomarkers likely will guide selection of therapy for individual patients. Nevertheless, immunotherapy for GI cancers is in its infancy, and many other classes of immune therapies are being developed besides anti-PD1 and anti-PDL1. Thus, although immunotherapy has not seen a dramatic advance to date, it still has great potential.

NLRC5 overexpression in ovarian tumors remodels the tumor microenvironment and increases T-cell reactivity toward autologous tumor-associated antigens.

Introduction: Epithelial ovarian cancer (OC) stands as one of the deadliest gynecologic malignancies, urgently necessitating novel therapeutic strategies. Approximately 60% of ovarian tumors exhibit reduced expression of major histocompatibility complex class I (MHC I), intensifying immune evasion mechanisms and rendering immunotherapies ineffective. NOD-like receptor CARD domain containing 5 (NLRC5) transcriptionally regulates MHC I genes and many antigen presentation machinery components. We therefore explored the therapeutic potential of NLRC5 in OC. Methods: We generated OC cells overexpressing NLRC5 to rescue MHC I expression and antigen presentation and then assessed their capability to respond to PD-L1 blockade and an infected cell vaccine. Results: Analysis of microarray datasets revealed a correlation between elevated NLRC5 expression and extended survival in OC patients; however, NLRC5 was scarcely detected in the OC tumor microenvironment. OC cells overexpressing NLRC5 exhibited slower tumor growth and resulted in higher recruitment of leukocytes in the TME with lower CD4/CD8 T-cell ratios and increased activation of T cells. Immune cells from peripheral blood, spleen, and ascites from these mice displayed heightened activation and interferon-gamma production when exposed to autologous tumor-associated antigens. Finally, as a proof of concept, NLRC5 overexpression within an infected cell vaccine platform enhanced responses and prolonged survival in comparison with control groups when challenged with parental tumors. Discussion: These findings provide a compelling rationale for utilizing NLRC5 overexpression in "cold" tumor models to enhance tumor susceptibility to T-cell recognition and elimination by boosting the presentation of endogenous tumor antigens. This approach holds promise for improving antitumoral immune responses in OC.

Tyrosine Kinase Inhibition Alters Intratumoral CD8+ T-cell Subtype Composition and Activity.

Targeted therapy with a tyrosine kinase inhibitor (TKI) such as imatinib is effective in treating gastrointestinal stromal tumor (GIST), but it is rarely curative. Despite the presence of a robust immune CD8+ T-cell infiltrate, combining a TKI with immune-checkpoint blockade (ICB) in advanced GIST has achieved only modest effects. To identify limitations imposed by imatinib on the antitumor immune response, we performed bulk RNA sequencing (RNA-seq), single-cell RNA-seq, and flow cytometry to phenotype CD8+ T-cell subsets in a genetically engineered mouse model of GIST. Imatinib reduced the frequency of effector CD8+ T cells and increased the frequency of naïve CD8+ T cells within mouse GIST, which coincided with altered tumor chemokine production, CD8+ T-cell recruitment, and reduced CD8+ T-cell intracellular PI3K signaling. Imatinib also failed to induce intratumoral T-cell receptor (TCR) clonal expansion. Consistent with these findings, human GISTs sensitive to imatinib harbored fewer effector CD8+ T cells but more naïve CD8+ T cells. Combining an IL15 superagonist (IL15SA) with imatinib restored intratumoral effector CD8+ T-cell function and CD8+ T-cell intracellular PI3K signaling, resulting in greater tumor destruction. Combination therapy with IL15SA and ICB resulted in the greatest tumor killing and maintained an effector CD8+ T-cell population in the presence of imatinib. Our findings highlight the impact of oncogene inhibition on intratumoral CD8+ T cells and support the use of agonistic T-cell therapy during TKI and/or ICB administration.

Collecting occupation and hazards information in primary care using O*NET.

OBJECTIVE: The objective of this study was to determine the feasibility of collecting occupation and occupational hazard data in a primary care setting, using the Occupational Information Network (O*NET) database to assist with classification. METHODS: We collected data from 204 employed adult primary care patients in Toronto, Canada, on their occupation and exposure to occupational hazards, and mapped their job titles to the O*NET database. We compared their self-reported occupational hazard exposures with the likelihood of exposure on O*NET. RESULTS: Exposure to repetitive arm movement was reported by 78%, to vapors/gas/dust/fumes by 30%, to noise by 30%, and to heavy loads by 31%. Significant differences in exposure to vapors/gas/dust/fumes were associated with work precarity. We matched the majority of job titles (89%) to O*NET categories. CONCLUSIONS: Collecting employment information in primary care setting was feasible, with the majority of job titles mapping onto O*NET classifications.

Pulling Back from the Brink: A Multi-Pronged Approach to Address General Surgery Resident Clinical Work Hour Adherence.

PURPOSE: The conflict between prioritizing education for surgical trainees, promoting trainee wellness, and maintaining optimal patient care has remained challenging since the introduction of the Accreditation Council for Graduate Medical Education (ACGME) work hour restrictions in 2003. There is still a dearth of research examining which interventions successfully enable duty hour adherence. This study assessed the impact of a combination of strategic interventions on improving clinical work hour adherence. METHODS: Monthly clinical work hour submission rates were assessed for all general surgery residents at a single university-based residency program over a 3-year period (2018-2021). Interventions targeted 3 domains and were implemented between academic years 2018 to 2019 (control) and 2020 to 2021 (intervention): 1) improving the accuracy and transparency of work hour reporting, 2) facilitating more timely interventions, and 3) structural scheduling changes. All 80-hour work week and continuous work hour violations were assessed. Findings were also compared to the corresponding ACGME Resident Survey results. RESULTS: There was no significant difference in the rate of monthly work hour submissions pre- and postintervention (78% vs 75%, p = 0.057). However, the number of total reported monthly violations decreased significantly (mean 13.8 vs 2.4, p < 0.01), including decreases in both 80-hour work week and continuous work hour violations (mean 4.7 vs 1.6, p < 0.001 and 9.1 vs 0.8, p < 0.001, respectively). Reported compliance also increased on the annual ACGME resident surveys, where 61% vs 95% of residents felt they were compliant with the 80-hour work week and 71% vs 95% felt they were compliant with the continuous work hours (2018-19 vs 2020-21). CONCLUSION: Innovative strategies addressing schedule changes, the culture of work hour reporting, and early intervention significantly decreased the number of duty hour violations at our institution. Reported resident compliance also improved based on ACGME Resident Survey data. These data may inform similar multifaceted approaches at other institutions to improve overall work hour adherence.

Molecular and Immunologic Techniques in a Genetically Engineered Mouse Model of Gastrointestinal Stromal Tumor.

Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and is typically driven by a single mutation in the KIT receptor. Across tumor types, numerous mouse models have been developed in order to investigate the next generation of cancer therapies. However, in GIST, most in vivo studies use xenograft mouse models which have inherent limitations. Here, we describe an immunocompetent, genetically engineered mouse model of gastrointestinal stromal tumor harboring a KitV558Δ/+ mutation. In this model, mutant KIT, the oncogene responsible for most GISTs, is driven by its endogenous promoter leading to a GIST which mimics the histological appearance and immune infiltrate seen in human GISTs. Furthermore, this model has been used successfully to investigate both targeted molecular and immune therapies. Here, we describe the breeding and maintenance of a KitV558Δ/+ mouse colony. Additionally, this paper details the treatment and procurement of GIST, draining mesenteric lymph node, and adjacent cecum in KitV558Δ/+ mice, as well as sample preparation for molecular and immunologic analyses.