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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Laparoscopic Ventral Hernia Repair Postoperative Complications in End Stage Renal Disease Patients.

Background: The prevalence of patients with end stage renal disease (ESRD) requiring general surgical procedures is increasing. Our aim was to explore the effect of ESRD on patients undergoing elective laparoscopic ventral hernia repair. Methods: The American College of Surgeons National Surgical Quality Improvement Program (2010-2015) database was used to identify patients who underwent elective laparoscopic ventral hernia repair. Multivariable analysis was performed adjusting for risk variables including age, gender, race, comorbidity status, body mass index ≥ 35, and presence of ESRD. Results: A total of 8,789 patients undergoing elective laparoscopic ventral hernia repair were identified. Sixty-four patients (0.73%) had ESRD. ESRD was identified as an independent risk factor for postoperative pneumonia (odds ration [OR] 6.91, p = 0.00363), sepsis (OR 18.58, p = 0.000286), and length of stay (IRR 1.63, 95% confidence interval 1.19 - 2.27, p = 0.0036). Conclusions: ESRD patients undergoing elective laparoscopic ventral hernia repair had an increased risk of postoperative pneumonia, sepsis, and length of stay. Clinicians should be cognizant of these risks when performing elective operations on ESRD patients.

Rare, long-term complication after pancreatoduodenectomy-a case report of cecal volvulus.

Complications after pancreatoduodenectomy are common, and range widely in timing of presentation, relation to pancreatobiliary pathology, and necessity of operative intervention. We present a case of a 74-year-old male with history of pancreatoduodenectomy for pancreatic adenocarcinoma who presented 11 months after index operation with cecal volvulus and required emergent right hemicolectomy. Prior history of pancreatoduodenectomy with mobilization of the right colon likely predisposed him to development of this surgical emergency. Patients have altered gastrointestinal anatomy after pancreatoduodenectomy and special care is necessary to protect the afferent biliopancreatic limb during intraoperative exploration, and particularly if right colectomy is necessary.

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.