Financial toxicity in early-onset colorectal cancer: A National Health Interview Survey study.

BACKGROUND: Financial toxicity is increasingly recognized as a devastating outcome of cancer treatment but is poorly characterized in patients with early-onset colorectal cancer. Young patients are particularly vulnerable to financial toxicity as they are frequently underinsured and may suffer significant disruptions to professional and financial growth. We hypothesized that financial toxicity associated with colorectal cancer treatment confers long-lasting effects on patients' well-being and disproportionately impacts patients diagnosed at <50 years of age. METHODS: A retrospective cross-sectional analysis of the National Health Interview Survey from years 2019 to 2021 was performed. Patients with a history of colorectal cancer were included and stratified by age at diagnosis. Randomly selected age-matched controls with no cancer history were used for comparison. The primary endpoint was financial toxicity, as assessed by a composite score formulated from 12 National Health Interview Survey items. The secondary endpoint was food security assessed by the United States Department of Agriculture's food security scale, embedded in the National Health Interview Survey. RESULTS: When compared to age-matched controls, patients with colorectal cancer experienced significant financial toxicity, as reflected by a composite financial toxicity score (P = .027). Within patients with colorectal cancer, female sex (adjusted odds ratio = 1.46, P = .046) and early-onset disease (adjusted odds ratio = 2.11, P = .002) were found to significantly increase the risk of financial toxicity. Patients with early-onset colorectal cancer more frequently experienced food insecurity (P = .011), delayed necessary medical care (P = .053), mental health counseling (P = .043), and filling prescriptions (P = .007) due to cost when compared to patients with average-onset colorectal cancer. CONCLUSION: Colorectal cancer is associated with significant long-term financial toxicity, which disproportionately impacts patients diagnosed at <50 years of age. Targeted interventions are warranted to reduce financial toxicity for patients with high-risk colorectal cancer.

A novel opsonic eCIRP inhibitor for lethal sepsis.

Sepsis is a life-threatening inflammatory condition partly orchestrated by the release of various damage-associated molecular patterns such as extracellular cold-inducible RNA-binding protein (eCIRP). Despite advances in understanding the pathogenic role of eCIRP in inflammatory diseases, novel therapeutic strategies to prevent its excessive inflammatory response are lacking. Milk fat globule-epidermal growth factor-VIII (MFG-E8) is critical for the opsonic clearance of apoptotic cells, but its potential involvement in the removal of eCIRP was previously unknown. Here, we report that MFG-E8 can strongly bind eCIRP to facilitate αvß3-integrin-dependent internalization and lysosome-dependent degradation of MFG-E8/eCIRP complexes, thereby attenuating excessive inflammation. Genetic disruption of MFG-E8 expression exaggerated sepsis-induced systemic accumulation of eCIRP and other cytokines, and consequently exacerbated sepsis-associated acute lung injury. In contrast, MFG-E8-derived oligopeptide recapitulated its eCIRP binding properties, and significantly attenuated eCIRP-induced inflammation to confer protection against sepsis. Our findings suggest a novel therapeutic approach to attenuate eCIRP-induced inflammation to improve outcomes of lethal sepsis.

Antigen-presenting aged neutrophils induce CD4+ T cells to exacerbate inflammation in sepsis.

Extracellular cold-inducible RNA-binding protein (eCIRP) is a key mediator of severity and mortality in sepsis. We found that stimulation of mouse bone marrow-derived neutrophils (BMDNs) with eCIRP generated a distinct neutrophil subpopulation, characterized by cell surface markers of both antigen-presenting cells and aged neutrophils as well as expression of IL-12, which we named antigen-presenting aged neutrophils (APANs). The frequency of APANs was significantly increased in the blood, spleen, and lungs of WT mice subjected to cecal ligation and puncture-induced sepsis but not in CIRP-/- mice. Patients with sepsis had a significant increase in circulating APAN counts compared with healthy individuals. Compared with non-APAN-transfered mice, APAN-transferred septic mice had increased serum levels of injury and inflammatory markers, exacerbated acute lung injury (ALI), and worsened survival. APANs and CD4+ T cells colocalized in the spleen, suggesting an immune interaction between these cells. APANs cocultured with CD4+ T cells significantly induced the release of IFN-γ via IL-12. BMDNs stimulated with eCIRP and IFN-γ underwent hyper-NETosis. Stimulating human peripheral blood neutrophils with eCIRP also induced APANs, and stimulating human neutrophils with eCIRP and IFN-γ caused hyper-NETosis. Thus, eCIRP released during sepsis induced APANs to aggravate ALI and worsen the survival of septic animals via CD4+ T cell activation, Th1 polarization, and IFN-γ-mediated hyper-NETosis.

Targeting sting to reduce sepsis-induced acute intestinal injury.

BACKGROUND: Sepsis is a dysregulated host response to infection syndrome leading to life-threatening organ dysfunction. Sepsis-induced intestinal dysfunction is a key element in the progression to multisystem organ failure. The stimulator of interferon genes is an intracellular protein implicated in intestinal injury in sepsis. H151, a small molecule inhibitor of stimulator of interferon genes, has not yet been studied as a potential therapeutic in sepsis. We hypothesize that H151 therapeutically reduces sepsis-induced acute intestinal injury. METHODS: Male mice underwent cecal ligation and puncture and were treated with intraperitoneal H151 (10 mg/kg body weight) or vehicle. Intestines and serum were collected for analysis 20 hours after cecal ligation and puncture. Oral gavage of mice with FITC-dextran was performed 15 hours after cecal ligation and puncture. Five hours after gavage, serum was collected, and intestinal permeability was assessed. Mice were monitored for 10 days after cecal ligation and puncture to assess survival. RESULTS: Zonula occludens 1 tight junctional protein expression was reduced after cecal ligation and puncture and recovered with H151 treatment. This was associated with a 62.3% reduction in intestinal permeability as assessed by fluorimetry. After cecal ligation and puncture, treatment with H151 was associated with a 58.7% reduction in intestinal histopathologic injury (P < .05) and a 56.6% reduction in intestinal apoptosis (P < .05). Intestinal myeloperoxidase activity was decreased by 70.8% after H151 treatment (P < .05). Finally, H151 improved 10-day survival from 33% to 80% after cecal ligation and puncture (P = .011). CONCLUSION: H151, a novel stimulator of interferon genes inhibitor, reduces intestinal injury, inflammation, and permeability when administered as a treatment for cecal ligation and puncture-induced sepsis. Thus, targeting stimulator of interferon genes shows promise as a therapeutic strategy to ameliorate sepsis-induced acute intestinal injury.

Social Media, Misinformation, and Online Patient Education in Emergency General Surgical Procedures.

INTRODUCTION: Patients use the internet to learn about diagnoses and treatment options. These sources vary in quality and accuracy of medical information. Thus, utilization of social media may lead to misinformation regarding treatment for patients in need of emergent general surgery procedures. METHODS: YouTube was searched with keywords "cholecystectomy," "cholecystitis," and "gallbladder surgery" and "appendectomy," "appendicitis," and "appendix surgery." For each procedure, the 100 videos with the greatest views were reviewed. Videos were assessed by four surgical trainees using validated instruments, DISCERN and the Patient Education Materials Assessment Tool (PEMAT), and Likert scales for patient education and misinformation. After appendectomy or cholecystectomy, patients completed a survey assessing use of social media preoperatively. RESULTS: The median DISCERN score was 28.0 of 75. The median PEMAT scores were 66.7% for understandability and 0% for actionability. Nearly half (49%) of videos provided no patient education and only 22% provided moderate or more. More than a third (35%) of videos contained misinformation. Doctors, medical education, and healthcare systems published videos with less misinformation, whereas patients, health/wellness groups published more misinformation (P < 0.001). Videos discoverable with colloquial terms "appendix surgery" and "gallbladder surgery" were more likely to contain misinformation (45.3%) compared to 20.5% of videos with misinformation discoverable using medical search terms only (P < 0.001). CONCLUSIONS: There is a range of video quality online with most videos of poor quality and provide little patient education. Understanding information available to patients online can tailor surgeon-patient discussions to combat misinformation and improve the informed consent process for patients.

A novel miRNA mimic attenuates organ injury after hepatic ischemia/reperfusion.

INTRODUCTION: Extracellular cold-inducible RNA-binding protein (eCIRP) is a novel mediator of inflammation and tissue injury. It has been shown that miRNA 130b-3p acts as an endogenous inhibitor of eCIRP. Because RNA mimics are unstable after in vivo administration, we have chemically engineered miRNA 130b-3p mimic (named PS-OMe miR130) to improve its stability by protection from nuclease activity. We hypothesize that PS-OMe miR130 reduces eCIRP-mediated injury and inflammation in a murine model of hepatic ischemia/reperfusion (I/R), a model of sterile inflammation. METHODS: Adult male mice underwent 70% hepatic ischemia for 60 minutes and 24-hour reperfusion. At the start of reperfusion, mice were treated intravenously with vehicle (phosphate-buffered saline) or PS-OMe miR130. Blood and liver tissue were collected after 24 hours for biochemical analysis. Apoptosis in the liver tissue was determined by transferase dUTP nick-end labeling assay. RESULTS: After hepatic I/R, organ injury markers including aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase significantly decreased after PS-OMe miR130 treatment. Furthermore, histological analysis of liver sections demonstrated significantly less injury in PS-OMe miR130 treatment mice versus vehicle mice. In addition, tumor necrosis factor α mRNA, interleukin-1ß mRNA, and neutrophil infiltration (myeloperoxidase activity and granulocyte receptor 1 immunohistochemistry) were significantly attenuated after PS-OMe miR130 treatment. Finally, apoptosis significantly decreased in liver tissue after treatment. CONCLUSION: PS-OMe miR130 decreases eCIRP-mediated injury and inflammation in a murine model of hepatic I/R.

An engineered miRNA PS-OMe miR130 inhibits acute lung injury by targeting eCIRP in sepsis.

BACKGROUND: Sepsis is caused by the dysregulated immune response due to an initial infection and results in significant morbidity and mortality in humans. Extracellular cold inducible RNA binding protein (eCIRP) is a novel mediator identified in sepsis. We have previously discovered that microRNA 130b-3p inhibits eCIRP mediated inflammation. As RNA mimics are very unstable in vivo, we hypothesize that an engineered miRNA 130b-3p mimic named PS-OMe miR130, improves stability of the miRNA by protection from nuclease activity. We further hypothesize that PS-OMe miR130 reduces not only eCIRP-mediated inflammation and but also acute lung injury in a murine model of polymicrobial sepsis. METHODS: Single stranded PS-OMe miR130 was synthesized and the binding affinity to eCIRP was evaluated using surface plasmon resonance (SPR) and computational modeling. Macrophages were treated with PS-OMe miR130 with and without eCIRP and cell supernatant analyzed for cytokines. In vitro stability and the in vivo half-life of PS-OMe miR130 were also assessed. The effect of PS-Ome miR130 on eCIRP's binding to TLR4 was evaluated by SPR analysis and modeling. Finally, the effect of PS-OMe miR130 on inflammation and injury was assessed in a murine model of sepsis. RESULTS: We demonstrate via SPR and computational modeling that PS-OMe miR130 has a strong binding affinity to eCIRP. This engineered miRNA decreases eCIRP induced TNF-α and IL-6 proteins, and it is highly stable in vitro and has a long in vivo half-life. We further demonstrate that PS-OMe miR130 blocks eCIRP binding to its receptor TLR4. Finally, we show that PS-OMe miR130 inhibits inflammation and lung injury, and improves survival in murine sepsis. CONCLUSION: PS-OMe miR130 can be developed as a novel therapeutic by inhibiting eCIRP-mediated inflammation and acute lung injury in sepsis.

Implementation and Assessment of Mentoring and Professionalism in Training (MAP-IT): A Humanistic Curriculum as a Tool to Address Burnout in Surgical Residents.

OBJECTIVE: Mentoring and Professionalism in Training (MAP-IT), a humanistic mentorship program, has demonstrated positive impact in non-surgical fields. This study assesses the feasibility of implementing MAP-IT in surgical residency and adapts MAP-IT to include residents-as-teachers (RAT). We hypothesize that MAP-IT will benefit surgical residents by building humanistic teaching skills, increasing resilience, reducing burnout, and improving connectedness. DESIGN: MAP-IT was implemented monthly during protected educational time. Faculty surgeons who had previously completed MAP-IT served as facilitators. Small groups consisted of 12 trainees, two faculty facilitators, and one resident facilitator. Each session comprised 60 minutes of reflection, readings, and discussion surrounding humanistic mentoring skills. The Maslach Burnout Inventory-Human Services Survey (MBI-HSS), Connor Davidson Resilience Scale (CD-RISC), and Humanistic Teaching Practices Effectiveness Questionnaire (HTPE) were administered before and after participation in MAP-IT. Qualitative interviews and surveys assessed residents' perspectives of the MAP-IT program. SETTING: MAP-IT was implemented at Northwell-North Shore/LIJ in Manhasset, NY in a general surgery residency program hosted by two tertiary care hospitals within a large health system. PARTICIPANTS: 55 residents participated as learners, five residents served as resident-facilitators, and 10 surgical faculty served as paired-facilitators of the MAP-IT course. RESULTS: 31.6% of residents had participated in a reflective medicine curriculum prior to MAP-IT, and these residents reported greater resilience and less burnout. This disparity was eliminated after participation in MAP-IT. Frequency of burnout was reduced from 64.1% to 46.1% after MAP-IT participation. Post-program, residents reported greater effectiveness in humanistic teaching practices when compared to baseline assessments. Quantitative and qualitative feedback demonstrated that MAP-IT was well received by resident participants and addressed a gap in their surgical training. CONCLUSIONS: A humanistic mentorship program involving RAT can be effectively implemented in surgical residency, is well-received by residents, and addresses a need surgical training by building skills and improving resident well-being.

Correlation between lymph node size on pathology and metastatic disease in right-sided colon cancer: A retrospective review.

BACKGROUND: Identification of positive lymph nodes in colon cancer can significantly impact treatment. Few studies have examined the role of lymph node size in staging and prognosis. This study evaluated the relationship between lymph node size and lymph node metastases in right-sided colon cancer. METHODS: Retrospective chart review was performed for patients undergoing colectomy for right-sided colon cancer from 2015 to 2020 across a single multi-hospital health system. Patients under age 18 or who did not have invasive adenocarcinoma upon pathological examination were excluded. Primary endpoints assessed lymph node size and lymph node metastases. 572 patients were stratified by lymph node size; lymph nodes ≥5 mm (n = 308) were characterized as enlarged. RESULTS: All surgical specimens examined had adequate number of lymph nodes for staging. 33.9% of all specimens examined contained lymph node metastases. Patients with enlarged lymph nodes were significantly more likely to have lymph node metastases than those with normal-sized lymph nodes (p < 0.001). Enlarged lymph nodes were associated with advanced nodal staging. CONCLUSIONS: Patients with enlarged nodes were significantly more likely to have lymph node metastases than those with normal-sized lymph nodes. Further research to analyze these enlarged lymph nodes on radiologic imaging is warranted to determine the role of radiographic assessment of lymph node size during pre-operative staging.

Practice-Based Learning and Improvement: Improving Morbidity and Mortality Review Using Natural Language Processing.

INTRODUCTION: Practice-Based Learning and Improvement, a core competency identified by the Accreditation Council for Graduate Medical Education, carries importance throughout a physician's career. Practice-Based Learning and Improvement is cultivated by a critical review of complications, yet methods to accurately identify complications are inadequate. Machine-learning algorithms show promise in improving identification of complications. We compare a manual-supplemented natural language processing (ms-NLP) methodology against a validated electronic morbidity and mortality (MM) database, the Morbidity and Mortality Adverse Event Reporting System (MARS) to understand the utility of NLP in MM review. METHODS: The number and severity of complications were compared between MARS and ms-NLP of surgical hospitalization discharge summaries among three academic medical centers. Clavien-Dindo (CD) scores were assigned to cases with identified complications and classified into minor (CD I-II) or major (CD III-IV) harm. RESULTS: Of 7774 admissions, 987 cases were identified to have 1659 complications by MARS and 1296 by ms-NLP. MARS identified 611 (62%) cases, whereas ms-NLP identified 670 (68%) cases. Less than one-third of cases (299, 30.3%) were detected by both methods. MARS identified a greater number of complications with major harm (457, 46.30%) than did ms-NLP (P < 0.0001). CONCLUSIONS: Both a prospectively maintained MM database and ms-NLP review of discharge summaries fail to identify a significant proportion of postoperative complications and overlap 1/3 of the time. ms-NLP more frequently identifies cases with minor complications, whereas prospective voluntary reporting more frequently identifies major complications. The educational benefit of reporting and analysis of complication data may be supplemented by ms-NLP but not replaced by it at this time.

H151, A SMALL MOLECULE INHIBITOR OF STING AS A NOVEL THERAPEUTIC IN INTESTINAL ISCHEMIA-REPERFUSION INJURY.

BACKGROUND: Intestinal ischemia-reperfusion (I/R) injury is a severe disease associated with high mortality. Stimulator of interferon genes (STING) is an intracellular protein that is activated by cytosolic DNA and is implicated in I/R injury, resulting in transcription of type I interferons (IFN-α and IFN-ß) and other proinflammatory molecules. Extracellular cold-inducible RNA-binding protein (eCIRP), a damage-associated molecular pattern, induces STING activation. H151 is a small molecule inhibitor of STING that has not yet been studied as a potential therapeutic. We hypothesize that H151 reduces inflammation, tissue injury, and mortality after intestinal I/R. Methods: In vitro, RAW264.7 cells were pretreated with H151 then stimulated with recombinant murine (rm) CIRP, and IFN-ß levels in the culture supernatant were measured at 24 hours after stimulation. In vivo, male C57BL/6 mice were subjected to 60-minute intestinal ischemia via superior mesenteric artery occlusion. At the time of reperfusion, mice were intraperitoneally instilled with H151 (10 mg/kg BW) or 10% Tween-80 in PBS (vehicle). Four hours after reperfusion, the small intestines, lungs, and serum were collected for analysis. Mice were monitored for 24 hours after intestinal I/R to assess survival. Results: In vitro, H151 reduced rmCIRP-induced IFN-ß levels in a dose-dependent manner. In vivo, intestinal levels of pIRF3 were increased after intestinal I/R and decreased after H151 treatment. There was an increase in serum levels of tissue injury markers (lactate dehydrogenase, aspartate aminotransferase) and cytokine levels (interleukin 1ß, interleukin 6) after intestinal I/R, and these levels were decreased after H151 treatment. Ischemia-reperfusion-induced intestinal and lung injury and inflammation were significantly reduced after H151 treatment, as evaluated by histopathologic assessment, measurement of cell death, chemokine expression, neutrophil infiltration, and myeloperoxidase activity. Finally, H151 improved the survival rate from 41% to 81% after intestinal I/R. Conclusions: H151, a novel STING inhibitor, attenuates the inflammatory response and reduces tissue injury and mortality in a murine model of intestinal I/R. H151 shows promise as a potential therapeutic in the treatment of this disease.

"Residents as Teachers" Workshops Designed by Surgery Residents for Surgery Residents.

BACKGROUND: A core tenet of medical education is the expectation that senior residents will teach junior residents and medical students. However, many general surgery residency programs lack a formalized curriculum to equip trainees with necessary teaching skills. We evaluated the impact of resident-led residents-as-teachers (RAT) workshops (RATW) and assessed adaptability from in-person to virtual delivery. We hypothesized these courses would improve trainees' confidence in their roles as resident-teachers. METHODS: Pre-COVID-19, an in-person workshop for residents (PGY1-5) was conducted over two days. During the COVID-19 pandemic, a virtual RATW for incoming interns (PGY1) was conducted during intern boot camp. Topic fidelity was preserved between the two RATWs. Resident-educators were responsible for content and delivery; the program director and associate program directors served as facilitators only. Surveys were used to evaluate residents' confidence in four core topics. A Wilcoxon test was used to compare quantitative data. RESULTS: There was significant improvement in confidence in all areas following RATW attendance, except for "Teaching in the OR". In sub-analysis, there was a significant improvement in this category among incoming interns post-RATW (P < 0.001). The majority of interns agreed that the RATW helped them transition into their new teaching role and agreed that the resident-led RATW was effective. CONCLUSIONS: A resident-designed and resident-led RAT curriculum in general surgery effectively improves residents' confidence in teaching and is well received by residents. We recommend the implementation of a RAT curriculum in general surgery residency and intern boot camp. The RATW was well adapted to distance-learning format.

Parent reports of children's working memory, coping, and emotional/behavioral adjustment in pediatric brain tumor patients: A pilot study.

Neurocognitive problems in childhood survivors of brain tumors are well documented. Further, research has shown that problems in cognitive functioning may be associated with impairment in the use of complex strategies needed to cope with stress, including secondary control coping strategies (e.g., acceptance and cognitive reappraisal) which have been associated with fewer adjustment problems. The present study measured cognitive function, coping strategies, and adjustment in children ages 6-16 years at the time of brain tumor diagnosis and at two follow-up time-points up to 1 year post-diagnosis. In a prospective design, working memory was assessed in a total of 29 pediatric brain tumor patients prior to undergoing surgery, child self-reported coping was assessed at 6 months post-diagnosis, and parent-reported child adjustment was assessed at 12 months post-diagnosis. Significant correlations were found between working memory difficulties and secondary control coping. Secondary control coping was also negatively correlated with child attention and total problems. Regression analyses did not support secondary control coping mediating the association between working memory difficulties and child attention or total problems. These findings represent the first longitudinal assessment of the association between working memory, coping, and adjustment across the first year of a child's brain tumor diagnosis and suggest a possible role for early interventions addressing both working memory difficulties and coping in children with brain tumors.