An anti-eCIRP strategy for necrotizing enterocolitis.

BACKGROUND: Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease characterized by intestinal inflammation and injury, with high mortality risk. Extracellular cold-inducible RNA-binding protein (eCIRP) is a recently discovered damage-associated molecular pattern that propagates inflammation and tissue injury; however, the role of eCIRP in NEC remains unknown. We hypothesize that eCIRP exacerbates NEC pathogenesis and the novel eCIRP-scavenging peptide, milk fat globule-epidermal growth factor-factor VIII (MFG-E8)-derived oligopeptide 3 (MOP3), attenuates NEC severity, serving as a new therapeutic strategy to treat NEC. METHODS: Stool samples from premature neonates were collected prospectively and eCIRP levels were measured. Wild-type (WT) and CIRP-/- mouse pups were subjected to NEC utilizing a combination of hypoxia and hypercaloric formula orogastric gavage with lipopolysaccharide supplementation. In parallel, WT pups were treated with MOP3 or vehicle. Endpoints including NEC severity, intestinal injury, barrier dysfunction, lung injury, and overall survival were determined. RESULTS: Stool samples from NEC neonates had elevated eCIRP levels compared to healthy age-matched controls (p < 0.05). CIRP-/- pups were significantly protected from NEC severity, intestinal injury, bowel inflammation, intestinal barrier dysfunction, lung injury, and systemic inflammation. NEC survival was 100% for CIRP-/- pups compared to 65% for WT (p < 0.05). MOP3 treatment recapitulated the benefits afforded by CIRP-knockdown, preventing NEC severity, improving inflammatory profiles, and attenuating organ injury. MOP3 treatment improved NEC survival to 80% compared to 50% for vehicle treatment (p < 0.05). CONCLUSIONS: eCIRP exacerbates NEC evidenced by protection with CIRP-deficiency and administration of MOP3, a CIRP-directed therapeutic, in a murine model. Thus, eCIRP is a novel target with human relevance, and MOP3 is a promising treatment for lethal NEC.

Management of Persistent Low-Suspicion Cervical Lymphadenopathy in Pediatric Patients.

INTRODUCTION: Cervical lymphadenopathy in children is typically self-limited; however, the management of persistent lymphadenopathy remains unclear. This study aimed to evaluate the management and outcomes of patients with persistent cervical lymphadenopathy. METHODS: Single-institution, retrospective review of children <18 years undergoing ultrasound (US) for cervical lymphadenopathy from 2013 to 2021 was performed. Patients were stratified into initial biopsy, delayed biopsy, or no biopsy groups. Clinical characteristics and workup were compared, and multivariate analyses were performed to assess predictors of delayed biopsy. RESULTS: 568 patients were identified, with 493 patients having no biopsy, 41 patients undergoing initial biopsy, and 34 patients undergoing delayed biopsy. Presenting symptoms differed: no biopsy patients were younger, were more likely to present to the emergency department, and had clinical findings often associated with acute illness. Patients with USs revealing abnormal vascularity or atypical architecture were more likely to be biopsied. History of malignancy, symptoms >1 week but <3 months, and atypical or change in architecture on US was associated with delayed biopsy. Patients with long-term follow-up (LTF) were followed for a median of 99.0 days. Malignancies were identified in 12 patients (2.1%). All malignancies were diagnosed within 14 days of presentation, and no malignancies were identified in LTF. CONCLUSIONS: Patients with persistent low suspicion lymphadenopathy are often followed for long durations; however, in this cohort, no malignancies were diagnosed during LTF. We propose an algorithm of forgoing a biopsy and employing primary care surveillance and education, which may be appropriate for these patients in the proper setting.

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.

Recovery of Skill Decay After COVID-19 Redeployments and Implications for Competency Attainment.

INTRODUCTION: The COVID-19 pandemic immediately interrupted procedural training. The lasting impact of reduced caseloads and service redeployments on procedural-resident training has been underexplored. This longitudinal study investigated the long-term perspectives of skill decay after short breaks in training and implications for ensuring resident competency attainment. METHODS: Web-based cross-sectional surveys distributed immediately after (June 2020) compared to 1 y after (July 2021) COVID-19 redeployments at two tertiary academic medical centers of an integrated health system in New York. Participants included general surgery, surgical subspecialty, and anesthesiology residents and faculty. RESULTS: Fifty-five residents and 33 faculty completed the survey. Ninety-point nine percent of residents and 36.4% of faculty were redeployed to COVID-ICUs. Sixty-three-point seven percent of residents and 75.0% of faculty reported a reduction in resident technical skills in the short-term, with significantly less (45.5% of residents and 21.2% of faculty) reporting persistent reduction in technical skill after 1 y (P = 0.001, P < 0.001). Seventy-five percent of residents and 100% of faculty were confident residents would be able to practice independently at the conclusion of their training. Sixty-five-point five percent of residents and 63.6% of faculty felt that residents experienced a durable improvement in critical care skills. Residents also reported a positive long-term impact on professional core competencies at 1 y. CONCLUSIONS: Longitudinal surveillance of residents after COVID-19 redeployments suggests washout of temporary skill decay and return of resident confidence upon resumption of traditional training. This may provide insight into the impact of other short-term training interruptions on resident skill and promote greater resident support upon training resumption to ensure competency attainment.

Failing Hearts Are More Vulnerable to Sympathetic, but Not Vagal Stimulation-Induced, Atrial Fibrillation-Ameliorated with Dantrolene Treatment.

BACKGROUND: Both vagal (VS) and sympathetic (SS) stimulations can increase atrial fibrillation (AF) inducibility, with VS being known as more arrhythmogenic in normal hearts. Heart failure (HF) results in autonomic dysfunction (characterized by sympathetic activation and vagal withdrawal) and is associated with an increased AF incidence. This study investigated whether failing hearts, compared with normal control hearts, respond differently to autonomic stimulation-induced AF arrhythmogenesis and the effect of dantrolene on SS-enhanced AF in HF. METHODS AND RESULTS: A rat myocardial infarction (MI) HF model was used. In experiment 1, AF inducibility was compared in 9 MI-HF rats versus 10 sham-control animals at baseline, during VS, and during SS with isoproterenol infusion. In experiment 2, dantrolene treatment (n = 8) was compared with placebo-control (n = 9) on SS-induced AF inducibility in HF. Compared with the sham-control, baseline AF inducibility was higher in the MI-HF group. AF inducibility was augmented in both groups by autonomic stimulation. However, under VS the increased magnitude was less in the MI-HF group (49% ± 11% vs 80% ± 10%; P = .029), but under SS was significantly more (53% ± 8% vs 6% ± 7%; P < .001), compared with sham-control. Dantrolene significantly attenuated SS-enhanced AF in HF (69% ± 6% vs 29% ± 9%; P = .006). CONCLUSIONS: Failing hearts are less sensitive to VS, but more vulnerable to SS-induced AF compared with normal-control hearts. Dantrolene can significantly attenuate SS-enhanced AF in HF, indicating that cardiac ryanodine receptor dysfunction may play a critical role in SS-enhanced AF in HF, and stabilizing leaky ryanodine receptor with the use of dantrolene may be a new treatment option in this condition.

Electronic effects on a one-pot aromatization cascade involving alkynyl-Prins cyclization, Friedel-Crafts alkylation and dehydration to tricyclic benzo[f]isochromenes.

A three-step domino reaction between 1-aryl-3-hexyne-2,6-diol derivatives and aldehydes is used to construct tricyclic 1,4-dihydro-2H-benzo[f]isochromenes. The cascade is initiated by BF3·OEt2 and involves alkynyl-Prins cyclization, Friedel-Crafts alkenylation, and dehydration/aromatization to create a new, central aromatic ring and eliminate 2 equiv. of water. Electron-donating substituents on the aryl ring of the 1-aryl-3-hexyne-2,6-diols significantly increase overall yields as do electron-rich aldehyde reaction partners. For 2,4-disubstituted 2H-benzo[f]isochromene products, diastereoselectivities in the alkynyl-Prins reaction are ∼1.4 : 1 in favor of the cis-diastereomer. The stereochemistry of one cis-product was verified by X-ray crystallographic analysis and a second structure was also verified by X-ray analysis.

Chromatin as alarmins in necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease primarily affecting premature neonates, marked by poorly understood pro-inflammatory signaling cascades. Recent advancements have shed light on a subset of endogenous molecular patterns, termed chromatin-associated molecular patterns (CAMPs), which belong to the broader category of damage-associated molecular patterns (DAMPs). CAMPs play a crucial role in recognizing pattern recognition receptors and orchestrating inflammatory responses. This review focuses into the realm of CAMPs, highlighting key players such as extracellular cold-inducible RNA-binding protein (eCIRP), high mobility group box 1 (HMGB1), cell-free DNA, neutrophil extracellular traps (NETs), histones, and extracellular RNA. These intrinsic molecules, often perceived as foreign, have the potential to trigger immune signaling pathways, thus contributing to NEC pathogenesis. In this review, we unravel the current understanding of the involvement of CAMPs in both preclinical and clinical NEC scenarios. We also focus on elucidating the downstream signaling pathways activated by these molecular patterns, providing insights into the mechanisms that drive inflammation in NEC. Moreover, we scrutinize the landscape of targeted therapeutic approaches, aiming to mitigate the impact of tissue damage in NEC. This in-depth exploration offers a comprehensive overview of the role of CAMPs in NEC, bridging the gap between preclinical and clinical insights.

The Novel MFG-E8-derived Oligopeptide, MOP3, Improves Outcomes in a Preclinical Murine Model of Neonatal Sepsis.

INTRODUCTION: Neonatal sepsis is a devastating inflammatory condition that remains a leading cause of morbidity and mortality. Milk fat globule-EGF-factor VIII (MFG-E8) is a glycoprotein that reduces inflammation, whereas extracellular cold-inducible RNA binding protein (eCIRP) worsens inflammation. This study aimed to determine the therapeutic potential of a novel MFG-E8-derived oligopeptide 3 (MOP3) designed to clear eCIRP and protect against inflammation, organ injury, and mortality in neonatal sepsis. METHODS: C57BL6 mouse pups were injected intraperitoneally with cecal slurry (CS) and treated with MOP3 (20 µg/g) or vehicle. 10 h after injection, blood, lungs, and intestines were collected for analyses, and in a 7-day experiment, pups were monitored for differences in mortality. RESULTS: MOP3 treatment protected septic pups from inflammation by reducing eCIRP, IL-6, TNFα, and LDH. MOP3 reduced lung and intestinal inflammation and injury as assessed by reductions in tissue mRNA levels of inflammatory markers, histopathologic injury, and apoptosis in lung and intestines. MOP3 also significantly improved 7-day overall survival for CS-septic mouse pups compared to vehicle (75% vs. 46%, respectively). CONCLUSION: Deriving from MFG-E8 and designed to clear eCIRP, MOP3 protects against sepsis-induced inflammation, organ injury, and mortality in a preclinical model of neonatal sepsis, implicating it as an exciting potential new therapeutic. LEVEL OF EVIDENCE: Level 1.

Pediatric, Adolescent and Young Adult (AYA) Peritoneal and Pleural Mesothelioma: A National Cancer Database Review.

PURPOSE: Malignant peritoneal and pleural mesothelioma are rare in young patients, with a paucity of data regarding clinical characteristics and outcomes. We aimed to describe the clinical characteristics, treatment strategies, and outcomes for pediatric and adolescent/young adult (AYA) patients. METHODS: The National Cancer Database (NCDB) was queried for malignant peritoneal and pleural mesothelioma in pediatric and AYA patients (ages 0-39) from 2004 to 2019. Stratification was performed for pediatric (age 0-21) and young adult (age 22-39) patients. Chi-squared, multivariable cox regression, and Kaplan-Meier analyses were performed. RESULTS: We identified 570 total patients, 46 pediatric and 524 young adult, with mesothelioma (363 peritoneal and 207 pleural). There were significant differences in sex distribution as patients with peritoneal mesothelioma were more frequently female (63.1%). Patients with peritoneal mesothelioma were more likely to have radical surgery compared to pleural mesothelioma (56.7% v. 24.6%, respectively). A majority of patients with peritoneal and pleural mesothelioma received chemotherapy (66.4% and 61.4%, respectively). For peritoneal mesothelioma, surgical resection was associated with improved overall survival, whereas male sex, neoadjuvant chemotherapy, and radiation were associated with worse overall survival. For pleural mesothelioma, intraoperative chemotherapy was associated with improved overall survival, whereas Black race was associated with worse overall survival. Mean overall survival was greater for patients with peritoneal mesothelioma (125 months) compared to those with pleural mesothelioma (69 months), which remained significant after stratification of pediatric and young adult patients. CONCLUSION: By analyzing a large cohort of pediatric and AYA mesothelioma, this study highlights clinical, prognostic, and survival differences between peritoneal and pleural disease. LEVEL OF EVIDENCE: Level III. TYPE OF STUDY: Retrospective.

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.

NCCN Guideline Concordance Improves Survival in Pediatric and Young Adult Rectal Cancer.

BACKGROUND: Although management guidelines in adult rectal cancer are widely studied, no consensus guidelines exist for the management of pediatric and young adult rectal cancer. METHODS: The National Cancer Database (2004-2018) was queried for pediatric (age 0-21) and young adult (age 22-40) patients with rectal cancer. Patients were analyzed for receipt of National Comprehensive Cancer Network (NCCN) guideline-concordant therapy. Impact on survival was evaluated using Cox regression and Kaplan-Meier analysis. RESULTS: 6655 patients (108 pediatric and 6547 young adult patients) with rectal cancer were included. Similar to previously published NCCN quality measures with overall guideline concordance approaching 90 % in adults, 89.6 % of pediatric and 84.6 % of young adult patients were classified as receiving pre-operative guideline-concordant therapy. However, pediatric patients were significantly less likely to receive post-operative guideline-concordant therapy than young adult patients (65.3 % verse 76.7 %, respectively, p = 0.008). Risk of death was significantly lower for pediatric patients who received post-operative guideline-concordant therapy (HR, 0.313; CI, 0.168-0.581; p < 0.001). In young adult patients, risk of death was significantly lower for those who received pre-operative guideline-concordant therapy (HR, 0.376, CI 0.338-0.417, p < 0.001), and post-operative guideline-concordant therapy (HR, 0.456; CI 0.413-0.505; p < 0.001). DISCUSSION: NCCN-based guidelines may reasonably guide peri-operative management decisions and improve survival in pediatric and young adult rectal cancer. Given the rarity of this cancer in young patients, employment of an experienced surgical and oncologic multidisciplinary team, along with discussion and involvement of the patient and family, are keys for balancing risks and benefits to offering the best therapeutic strategy. TYPE OF STUDY: Retrospective. LEVEL OF EVIDENCE: Level III.

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.

A NOVEL OPSONIC EXTRACELLULAR CIRP INHIBITOR MOP3 ALLEVIATES GUT ISCHEMIA/REPERFUSION INJURY.

INTRODUCTION: Gut ischemia and reperfusion (I/R) injury promotes the release of damage-associated molecular patterns (DAMPs) such as extracellular cold-inducible RNA-binding protein (eCIRP). Gut I/R often leads to acute lung injury (ALI), a major contributor to mortality. Milk fat globule-epidermal growth factor-factor VIII-derived oligopeptide-3 (MOP3) is a novel peptide that attenuates sepsis by opsonizing eCIRP and facilitating its phagocytic clearance. We hypothesized that MOP3 reduces inflammation, mitigates gut and lung injury, and improves survival in gut I/R injury. METHODS: Phagocytosis of FITC-labeled eCIRP by intestinal epithelial cells was determined by confocal microscopy, and the cell supernatant was evaluated for cytokine expression by ELISA. Adult C57BL/6 mice underwent 60 min of gut ischemia via superior mesenteric artery occlusion followed by reperfusion. Mice were treated with MOP3 or vehicle via retro-orbital injection at the time of reperfusion. At 4 h post-I/R, blood, gut, and lungs were harvested for further assay. In additional mice, 36 h survival was assessed. Plasma levels of injury and inflammatory markers were measured with colorimetry and ELISA, respectively. Tissue mRNA expression was measured with qPCR. Myeloperoxidase (MPO), TUNEL, histologic injury, and ZO-1 immunohistochemistry assessments were performed. RESULTS: MOP3 significantly increased eCIRP phagocytosis by intestinal epithelial cells (p < 0.01) and decreased IL-6 release (p < 0.001). Gut I/R caused elevated plasma eCIRP levels. MOP3 treatment significantly reduced plasma levels of IL-1ß (p < 0.01), IL-6 (p < 0.05), and lactate dehydrogenase (p < 0.05) along with a significant decrease in gut (p < 0.05) and lung (p < 0.001) injury scores as well as gut cell death (p < 0.05). Moreover, MOP3 reduced pulmonary levels of chemokines and the granulocyte activation marker MPO after gut I/R. Mechanistically, ZO-1 expression in the gut was decreased following gut I/R injury, while MOP3 significantly reversed the decrease in ZO-1 mRNA expression (p < 0.001). Finally, mice treated with MOP3 exhibited a significant decrease in mortality (p < 0.05). CONCLUSIONS: Treatment with MOP3 effectively mitigates organ injury induced by gut I/R. This beneficial effect is attributed to the facilitation of eCIRP clearance, directing the potential of MOP3 as an innovative therapeutic approach for this critical and often fatal condition.

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.

Surgical Rehabilitation for Research Residents: A Pilot Program to Offset Surgical Skill Decay.

OBJECTIVE: Select general surgery residents in the surgeon-scientist pipeline dedicate time away from clinical residency to conduct research. However, these research residents (RR) are vulnerable to operative skill decay. The aim of this study is to assess the feasibility of implementation and impact of an organized intervention designed to combat skill decay experienced by RR. DESIGN: RR were enrolled in a pilot Surgical Rehabilitation Program (SRP). The SRP is comprised of 12 cadaver-based simulation sessions and supplemented with Fundamentals of Laparoscopic Surgery-based simulation workouts. The RR were integrated with the clinical residents (CR) during the cadaver sessions and were subsequently performance tested, surveyed, and interviewed. SETTING: One academic general surgery residency program graduating 8 chief residents yearly in New York. PARTICIPANTS: General surgery CR and residents on dedicated research years. RESULTS: Data were collected for all local RR (n = 8) and 77% (n = 37) of CR. Local RR conducted research within the same health system that sponsors the residency. RR experienced gaps in training ranging from 2 to 4 years. All RR were permitted to moonlight on surgical services, however performed 0 operations and only 0.88 procedures on average per shift. Although RR performed similarly to level-matched CR on basic laparoscopic tasks, they required significantly more time on laparoscopic suturing-based skills than CR (p < 0.001). RR had significantly lower confidence levels precadaver sessions but gained confidence postcadaver sessions (p < 0.05), whereas CR confidence was unchanged. Regarding the SRP, qualitative interviews revealed major themes emphasizing the integration of RR, exposure to CR and faculty, technical skill development, maintenance of surgical know-how, and improved confidence for RR. CONCLUSIONS: The implementation of such structured interventions, like our SRP, aimed at supporting RR over gap years is essential to help residents maintain skills and confidence needed to achieve their goals of becoming surgeon scientists.

Trends and Disparities in Firearm Deaths Among Children.

BACKGROUND AND OBJECTIVES: In 2020, firearm injuries became the leading cause of death among US children and adolescents. This study aimed to evaluate new 2021 data on US pediatric firearm deaths and disparities to understand trends compared with previous years. METHODS: Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research was queried for firearm mortalities in children/adolescents from 2018 to 2021. Absolute mortality, death rates, and characteristics were reported. Death rates were defined per 100 000 persons in that population per year. Death rates across states were illustrated via geographic heat maps, and correlations with state poverty levels were calculated. RESULTS: In 2021, firearms continued to be the leading cause of death among US children. From 2018 to 2021, there was a 41.6% increase in the firearm death rate. In 2021, among children who died by firearms, 84.8% were male, 49.9% were Black, 82.6% were aged 15 to 19 years, and 64.3% died by homicide. Black children accounted for 67.3% of firearm homicides, with a death rate increase of 1.8 from 2020 to 2021. White children accounted for 78.4% of firearm suicides. From 2020 to 2021, the suicide rate increased among Black and white children, yet decreased among American Indian or Alaskan Native children. Geographically, there were worsening clusters of firearm death rates in Southern states and increasing rates in Midwestern states from 2018 to 2021. Across the United States, higher poverty levels correlated with higher firearm death rates (R = 0.76, P < .001). CONCLUSIONS: US pediatric firearm deaths increased in 2021, above the spike in 2020, with worsening disparities. Implementation of prevention strategies and policies among communities at highest risk is critical.

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.

Hospital-Based Violence Intervention Programs to Reduce Firearm Injuries in Children: A Scoping Review.

INTRODUCTION: Hospital-based violence intervention programs (HVIPs) have shown promise in preventing reinjury and enhancing recovery from violent injuries, including those related to firearms. Historically, HVIPs have primarily focused on at-risk adolescents and young adults. The aim of this study is to perform a scoping review of HVIPs targeting children under the age of 18, describe the evidence supporting these programs, and deduce the potential impact of expanding HVIPs to younger children. METHODS: A scoping review was performed utilizing PubMed database with search terms "violence intervention program" and pediatric, or children, or youth. Articles were screened for youth-inclusive violence programs, and the literature was analyzed for program descriptions, evidence supporting interventions, and barriers to evaluation. RESULTS: 36 studies (covering 23 programs) were identified that met criteria (including patients ≤18 years old), with only 4 programs including children under 10. Many HVIPs utilize brief hospital interventions with longitudinal wraparound outpatient services. Despite heterogeneity in programs and studied outcomes, many HVIPs demonstrated positive outcomes, such as reduction of risk factors, decreased reinjury, decreased violent behaviors, decreased criminal justice involvement, and positive attitude or behavioral changes. Only a few studies reported increased odds of enrollment and positive impact in younger patients specifically. CONCLUSIONS: Children are an impressionable population in which HVIPs may have significant impact; however, there remains a gap in targeted programs. Given that firearm injuries are the leading cause of death in children and adolescents, priority should be given to piloting, implementing, and evaluating HVIPs among younger age groups. LEVEL OF EVIDENCE: Level IV.

Chromatin-Associated Molecular Patterns (CAMPs) in sepsis.

Several molecular patterns have been identified that recognize pattern recognition receptors. Pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) are commonly used terminologies to classify molecules originating from pathogen and endogenous molecules, respectively, to heighten the immune response in sepsis. Herein, we focus on a subgroup of endogenous molecules that may be detected as foreign and similarly trigger immune signaling pathways. These chromatin-associated molecules, i.e., chromatin containing nuclear DNA and histones, extracellular RNA, mitochondrial DNA, telomeric repeat-containing RNA, DNA- or RNA-binding proteins, and extracellular traps, may be newly classified as chromatin-associated molecular patterns (CAMPs). Herein, we review the release of CAMPs from cells, their mechanism of action and downstream immune signaling pathways, and targeted therapeutic approaches to mitigate inflammation and tissue injury in inflammation and sepsis.

Extracellular CIRP Promotes GPX4-Mediated Ferroptosis in Sepsis.

Sepsis is characterized by life-threatening organ dysfunction caused by a dysregulated host response to infection. Extracellular cold-inducible RNA-binding protein (eCIRP) is a damage-associated molecular pattern (DAMP) that promotes inflammation and induces cell death via apoptosis, NETosis, and/or pyroptosis. Ferroptosis is a form of regulated cell death characterized by the accumulation of lipid peroxide on cellular membranes. We hypothesize that eCIRP induces ferroptosis in macrophages and lung tissue during sepsis. RAW 264.7 cells stimulated with recombinant murine (rm) CIRP significantly decreased the expression of glutathione peroxidase 4 (GPX4), a negative regulator of ferroptosis, and increased lipid reactive oxygen species (ROS) in a TLR4 dependent manner. In TLR4-/- peritoneal macrophages, depression of GPX4 expression and increase in lipid ROS levels were attenuated after rmCIRP-treatment compared to WT macrophages. rmCIRP also induced cell death in RAW 264.7 cells which was corrected by the ferroptosis inhibitor, ferrostatin-1 (Fer-1). Intraperitoneal injection of rmCIRP decreased GPX4 expression and increased lipid ROS in lung tissue, whereas the increase of lipid ROS was reduced by Fer-1 treatment. GPX4 expression was significantly decreased, while malondialdehyde (MDA), iron levels, and injury scores were significantly increased in lungs of WT mice after cecal ligation and puncture (CLP)-induced sepsis compared to CIRP-/- mice. Treatment with C23, a specific eCIRP inhibitor, in CLP mice alleviated the decrease in GPX4 and increase in MDA levels of lung tissue. These findings suggest that eCIRP induces ferroptosis in septic lungs by decreasing GPX4 and increasing lipid ROS. Therefore, regulation of ferroptosis by targeting eCIRP may provide a new therapeutic approach in sepsis and other inflammatory diseases.