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.

Delphi Process for Validation of Fluid Treatment Algorithm for Critically Ill Pediatric Trauma Patients.

INTRODUCTION: While intravenous fluid therapy is essential to re-establishing volume status in children who have experienced trauma, aggressive resuscitation can lead to various complications. There remains a lack of consensus on whether pediatric trauma patients will benefit from a liberal or restrictive crystalloid resuscitation approach and how to optimally identify and transition between fluid phases. METHODS: A panel was comprised of physicians with expertise in pediatric trauma, critical care, and emergency medicine. A three-round Delphi process was conducted via an online survey, with each round being followed by a live video conference. Experts agreed or disagreed with each aspect of the proposed fluid management algorithm on a five-level Likert scale. The group opinion level defined an algorithm parameter's acceptance or rejection with greater than 75% agreement resulting in acceptance and greater than 50% disagreement resulting in rejection. The remaining were discussed and re-presented in the next round. RESULTS: Fourteen experts from five Level 1 pediatric trauma centers representing three subspecialties were included. Responses were received from 13/14 participants (93%). In round 1, 64% of the parameters were accepted, while the remaining 36% were discussed and re-presented. In round 2, 90% of the parameters were accepted. Following round 3, there was 100% acceptance by all the experts on the revised and final version of the algorithm. CONCLUSIONS: We present a validated algorithm for intavenous fluid management in pediatric trauma patients that focuses on the de-escalation of fluids. Focusing on this time point of fluid therapy will help minimize iatrogenic complications of crystalloid fluids within this patient population.

Impact of the COVID-19 pandemic on trauma activations at a pediatric level 1 trauma center in New York.

BACKGROUND: The disruptive effects on society and medical systems due to the coronavirus disease 2019 (COVID-19) pandemic are substantial and far-reaching. The effect of the pandemic on the quantity and quality of pediatric traumas is unclear and has a direct bearing on how scarce hospital resources should be allocated in a pandemic situation. METHODS: A retrospective review of the trauma registry was performed for trauma activations in the years 2018 through 2020 during the months of March, April, and May. Demographic and injury specific datapoints were compared across calendar years. RESULTS: There were 111, 100, and 52 trauma activations during the study interval in 2018, 2019, and 2020, respectively. There were fewer highest severity level activations in 2020 compared to 2018 and 2019 (1 vs 5 and 9; p < 0.01). The median Injury Severity Score was 5 in 2020 compared to 4 in both 2018 and 2019 (p < 0.01). More patients went directly to the operating room in 2020 compared to prior years (21.2% vs 8% and 6.1%; p < 0.01). There were fewer discharges from the emergency department (ED) (12.1% vs 36.6% and 32.7%). No increase in the number of child abuse reports and investigations was noted. There was no difference in the proportion of blunt versus penetrating trauma between years (p = 0.57). No pedestrians were struck by automobiles in 2020 compared to 12 and 14 in 2018 and 2019. However, there were a greater proportion of injuries from falls during 2020 compared to prior years. CONCLUSIONS: There were fewer trauma activations during the peak of the COVID pandemic compared to prior years. Due to the decrease in trauma volume during the peak of the pandemic, hospital resources could potentially be reallocated toward areas of greater need. LEVEL OF EVIDENCE: IV; Retrospective cohort study using historical controls.

The Pediatric Trauma Society Annual Meeting: An Analysis of Scholarly Output From the First 5 Years.

BACKGROUND: The Pediatric Trauma Society (PTS) is a multidisciplinary organization, with scientific presentations at its annual meeting addressing trauma care from prehospital through rehabilitation. OBJECTIVE: The purpose of this study was to identify and describe the scholarly areas of focus of presentations at the annual meeting over the society's first 5 years and evaluate research dissemination. METHODS: Data were collected on abstracts presented between 2014 and 2018, including titles, authors, and abstract classification. PubMed and Google Scholar searches identified abstracts that resulted in publications. Journal impact factors were identified. RESULTS: Over 5 years, 491 of 635 (77.3%) abstracts were accepted. The number of submitted and accepted abstracts increased, but the acceptance rate was stable (range = 72.1%-81.2%, p = NS [nonsignificant]). The most frequently accepted categories included "Epidemiology," "Abdominal or Thoracic Trauma," and "Neurosurgery or Traumatic Brain Injury (TBI)," whereas "Trauma Nursing" and "Quality Improvement" were less common. Among the 2014-2016 abstracts, 55.4% of podium and 24.3% of poster presentations were published. Abstracts categorized as "Epidemiology," "Education & Injury Prevention," and "Neurosurgery or TBI" were commonly presented but uncommonly published. The median journal impact factor of publications was 2.1 and 2.0 for podium and poster presentations, respectively (ranging from 0.11 to 10.25). CONCLUSION: Most of the scholarly effort presented at the PTS remains unpublished. Published work is mainly in low-impact factor journals. Mentorship in the publication process and encouragement of multidisciplinary collaboration within the society are needed to address limitations in the number and potential impact of the scientific content of the annual meeting. This type of analysis is relevant not only to the PTS but also to any professional society seeking to improve its impact.

Targeting the eCIRP/TREM-1 interaction with a small molecule inhibitor improves cardiac dysfunction in neonatal sepsis.

BACKGROUND: Neonatal sepsis and the associated myocardial dysfunction remain a leading cause of infant mortality. Extracellular cold-inducible RNA-binding protein (eCIRP) acts as a ligand of triggering receptor expressed on myeloid cells-1 (TREM-1). M3 is a small CIRP-derived peptide that inhibits the eCIRP/TREM-1 interaction. We hypothesize that the eCIRP/TREM-1 interaction in cardiomyocytes contributes to sepsis-induced cardiac dysfunction in neonatal sepsis, while M3 is cardioprotective. METHODS: Serum was collected from neonates in the Neonatal Intensive Care Unit (NICU). 5-7-day old C57BL/6 mouse pups were used in this study. Primary murine neonatal cardiomyocytes were stimulated with recombinant murine (rm) CIRP with M3. TREM-1 mRNA and supernatant cytokine levels were assayed. Mitochondrial oxidative stress, ROS, and membrane potential were assayed. Neonatal mice were injected with rmCIRP and speckle-tracking echocardiography was conducted to measure cardiac strain. Sepsis was induced by i.p. cecal slurry. Mouse pups were treated with M3 or vehicle. After 16 h, echocardiography was performed followed by euthanasia for tissue analysis. A 7-day survival study was conducted. RESULTS: Serum eCIRP levels were elevated in septic human neonates. rmCIRP stimulation of cardiomyocytes increased TREM-1 gene expression. Stimulation of cardiomyocytes with rmCIRP upregulated TNF-α and IL-6 in the supernatants, while this upregulation was inhibited by M3. Stimulation of cardiomyocytes with rmCIRP resulted in a reduction in mitochondrial membrane potential (MMP) while M3 treatment returned MMP to near baseline. rmCIRP caused mitochondrial calcium overload; this was inhibited by M3. rmCIRP injection impaired longitudinal and radial cardiac strain. Sepsis resulted in cardiac dysfunction with a reduction in cardiac output and left ventricular end diastolic diameter. Both were improved by M3 treatment. Treatment with M3 attenuated serum, cardiac, and pulmonary levels of pro-inflammatory cytokines compared to vehicle-treated septic neonates. M3 dramatically increased sepsis survival. CONCLUSIONS: Inhibition of eCIRP/TREM-1 interaction with M3 is cardioprotective, decreases inflammation, and improves survival in neonatal sepsis. Trial registration Retrospectively registered.

Management and outcomes of peripancreatic fluid collections and pseudocysts following non-operative management of pancreatic injuries in children.

BACKGROUND: Peripancreatic fluid collection and pseudocyst development is a common sequela following non-operative management (NOM) of pancreatic injuries in children. Our purpose was to review management strategies and assess outcomes. METHODS: A multicenter, retrospective review was conducted of children treated with NOM following blunt pancreatic injury at 22 pediatric trauma centers between the years 2010 and 2015. Organized fluid collections were called "acute peripancreatic fluid collection" (APFC) if identified < 4 weeks and "pseudocyst" if > 4 weeks following injury. Data analysis included descriptive statistics Wilcoxon rank-sum, Kruskal-Wallis and t tests. RESULTS: One hundred patients with blunt pancreatic injury were identified. Median age was 8.5 years (range 1-16). Forty-two percent of patients (42/100) developed organized fluid collections: APFC 64% (27/42) and pseudocysts 36% (15/42). Median time to identification was 12 days (range 7-42). Most collections (64%, 27/42) were observed and 36% (15/42) underwent drainage: 67% (10/15) percutaneous drain, 7% (1/15) needle aspiration, and 27% (4/15) endoscopic transpapillary stent. A definitive procedure (cystogastrostomy/pancreatectomy) was required in 26% (11/42). Patients with larger collections (≥ 7.1 cm) had longer time to resolution. Comparison of outcomes in patients with observation vs drainage revealed no significant differences in TPN use (79% vs 75%, p = 1.00), hospital length of stay (15 vs 25 median days, p = 0.11), time to tolerate regular diet (12 vs 11 median days, p = 0.47), or need for definitive procedure (failure rate 30% vs 20%, p = 0.75). CONCLUSIONS: Following NOM of blunt pancreatic injuries in children, organized fluid collections commonly develop. If discovered early, most can be observed successfully, and drainage does not appear to improve clinical outcomes. Larger size predicts prolonged recovery. LEVEL OF EVIDENCE: III STUDY TYPE: Case series.

Decreased Pediatric Trauma Length of Stay and Improved Disposition With Implementation of Lewin's Change Model.

Although often cared for nonoperatively, trauma is a surgical disease managed by surgical services in a multidisciplinary manner. The American College of Surgeons Committee on Trauma (ACS COT) emphasizes this as part of the ACS COT verification process and expects nonsurgical service admission rate of less than 10%. In this project, we developed a collaborative care model captained by surgical services with medical service consultation to achieve this goal for optimal care of injured patients. The project was conducted at a freestanding pediatric trauma center undergoing verification as a Level 1 ACS COT pediatric trauma center. The trauma registry was utilized to obtain nonsurgical service admission rate from January 2011 to June 2015. Lewin's 3-Step Model was utilized to guide change. Adherence to the new ACS standards was continually tracked and fallouts were addressed on an individual basis. Overall compliance was reported routinely through trauma and hospital quality programs. Individual successes and accomplishments were recognized and reinforced. At the inception of the project, nonsurgical admission rate was 30%. Implementation of Lewin's 3-Step Model nonsurgical admission rate decreased to 3%, representing a reduction of 27%. In addition, a 21% reduction in hospital length of stay, 3.78-3 days, was demonstrated with no change in 30-day readmission rate. Lewin's change model facilitated culture change to achieve ACS COT standards and reduced nonsurgical admissions to less than 10%. Reduction in hospital length of stay supports an improvement in the efficiency of care when directed by the pediatric trauma surgery team.

Neonatal intestinal dysbiosis in necrotizing enterocolitis.

Necrotizing Enterocolitis (NEC) is one of the most devastating gastrointestinal diseases in neonates, particularly among preterm infants in whom surgical NEC is the leading cause of morbidity. NEC pathophysiology occurs in the hyper-reactive milieu of the premature gut after bacterial colonization. The resultant activation of the TLR4 pathway appears to be a strongly contributing factor. Advancements in metagenomics may yield new clarity to the relationship between the neonatal intestinal microbiome and the development of NEC. After a century without effective directed treatments, microbiome manipulation offers a promising therapeutic target for the prevention and treatment of this devastating disease.

Outpatient curettage and electrocautery as an alternative to primary surgical closure for pediatric gastrocutaneous fistulae.

BACKGROUND: The development of a gastrocutaneous fistula (GCF) after gastrostomy tube removal is a frequent complication that occurs 5%-45% of the time. Conservative therapy with chemical cauterization is frequently unsuccessful, and surgical GCF repair with open primary layered closure of the gastrotomy is often required. We describe an alternative approach of GCF closure that is an outpatient, less invasive procedure that allows patients to avoid the comorbidities of general endotracheal anesthesia and intraabdominal surgery. METHODS: This is an Institutional Review Board approved retrospective review of all patients who underwent GCF closure from January 2010 to July 2016 at a tertiary care children's hospital. Demographics including age, weight, body mass index, comorbidities, and initial indication for gastrostomy tube were recorded. Operative details such as ASA score, operative duration, type of anesthesia, and airway were noted. Based on surgeon preference, two types of operative closure were used during that time frame: primary layered closure or curettage and cautery (C&C). The latter is a procedure in which the fistula tract is first scraped with a fine curette, and then the fistula opening and tract are cauterized circumferentially. Finally, the presence of a persistent fistula and the need for formal reoperation were determined. RESULTS: Sixty-five unique patients requiring GCF closure were identified. Of those, 44 patients (67.6%) underwent primary closure and 21 patients (32.3%) underwent C&C. The success rate of primary closure was 97% with one patient experiencing wound breakdown with persistent fistula. The overall success rate of C&C was 66.7% (14/21). Among those 14 patients, 11 (52.4%) GCF patients were closed by 1 mo. An additional two patients' gastrocutaneous fistulae were closed by 4 mo (61.9%). One GCF was successfully closed with a second C&C procedure. Seven of the 21 patients (33.3%) required subsequent formal layered surgical closure. C&C had significantly shorter operative times (13.5 ± 14.7 min versus 93.4 ± 61.8, P <0.0001) and significantly shorter times in the postanesthesia care unit (101.8 ± 42.4 min versus 147 ± 86, P <0.0001). Patients were intubated with an endotracheal tube 88.6% of the time for primary closure and 23.8% of the time for C&C.Among patients admitted for an elective procedure, the average length of stay for primary closure was 1.9 d as compared to 0 d for the C&C group. Among patients who underwent C&C with a persistent fistula, there were no significant differences in time since initial creation of gastrostomy, age, body mass index, or ASA score. CONCLUSIONS: Our study verifies that primary closure remains the gold standard for persistent GCF. However, C&C is a safe, outpatient procedure that effectively treats a GCF the majority of the time in children. We suggest that in select patients, it may be an appropriate initial and definitive procedure for GCF closure.

Simple diverticulectomy is adequate for management of bleeding Meckel diverticulum.

PURPOSE: It is unclear whether simple diverticulectomy, rather than segmental bowel resection (SBR), is adequate treatment for gastrointestinal bleeding (GIB) secondary to Meckel diverticulum (MD). There is concern that ulcers in the adjacent bowel may continue to bleed if only the diverticulum is removed. This study seeks to determine if diverticulectomy is satisfactory treatment for bleeding MD. METHODS: A multi-institution, retrospective review was performed for patients with a diagnosis of MD and GIB who underwent simple diverticulectomy or small bowel resection. Exclusion criteria were comorbid surgical conditions and other causes of GIB. The primary outcome was post-operative bleeding during the initial hospitalization. Secondary outcomes were bleeding after discharge, transfusion or additional procedure requirement, re-admission, and overall complications. RESULTS: There were 59 patients who met study criteria (42 diverticulectomy, 17 SBR). One patient in the SBR group had early post-operative bleeding (p = 0.288). There was one re-admission (p = 0.288) and three total complications in the SBR group (p = 0.021). There were no cases of bleeding or other complications in the diverticulectomy group. CONCLUSION: This study suggests that simple diverticulectomy is adequate for treatment of GIB caused by MD. Furthermore, diverticulectomy appears to have a lower overall complication rate.

SRT1720, a sirtuin 1 activator, attenuates organ injury and inflammation in sepsis.

BACKGROUND: Sepsis affects 800,000 patients in the United States annually with a mortality rate of up to 30%. Recent studies suggest that sepsis-associated metabolic derangements due to hypoxic tissue injury, impaired oxygen utilization, and mitochondrial dysfunction contribute to mortality. Sirtuin 1 (Sirt1) is a crucial modulator of energy metabolism during starvation states and has anti-inflammatory effects. Here, we hypothesized that SRT1720, a Sirt1 activator, could attenuate the severity of sepsis. MATERIALS AND METHODS: Male C57BL/6 mice (20-25 g) were subjected to cecal ligation and puncture (CLP) to induce sepsis. SRT1720 (5 or 20 mg/kg BW) or 10% dimethyl sulfoxide (vehicle) in 0.2-mL saline was injected intravenously at 5 h after CLP. Control animals were not subjected to any surgery. Blood and liver samples were harvested at 20 h after CLP for analysis. RESULTS: Administration of SRT1720 markedly reduced the serum levels of tissue injury markers (aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase) and renal injury markers (blood urea nitrogen and creatinine) in a dose-dependent manner after CLP. Furthermore, the levels of proinflammatory cytokines interleukin (IL)-1ß and IL-6 in the serum and liver were significantly inhibited by SRT1720 treatment after CLP. SRT1720 treatment resulted in a significantly decreased mRNA expression of inflammasome components (nucleotide oligomerization domain-like receptor protein 3, adapter apoptosis-associated speck-like protein containing caspase-recruitment domain, IL-1ß, and IL-18) in the liver, compared with the vehicle group. CONCLUSIONS: SRT1720 treatment attenuates multiorgan injury in septic mice. SRT1720 treatment also decreases the production of proinflammatory cytokines and reduces inflammasome activation. Thus, pharmacologic stimulation of Sirt1 may present a promising therapeutic strategy for sepsis.

Sirtuin 1 Stimulation Attenuates Ischemic Liver Injury and Enhances Mitochondrial Recovery and Autophagy.

OBJECTIVES: Hepatic ischemia-reperfusion is a major clinical problem with limited treatment options. The pathophysiology of hepatic ischemia-reperfusion is characterized by mitochondrial dysfunction and cellular energy deficits. Sirtuin 1 is an energy-sensing enzyme known to modulate mitochondrial biogenesis. We hypothesized that pharmacologic activation of sirtuin 1 is protective after hepatic ischemia-reperfusion injury. DESIGN: Animal study. SETTING: University-based experimental laboratory. SUBJECTS: Wild-type C57BL/6 mice. INTERVENTIONS: C57BL/6 mice were subjected to 60-minute partial hepatic ischemia-reperfusion and posttreated with sirtuin 1 activator, SRT1720 (20 mg/kg), or vehicle. Blood and liver were collected at 24 hours after ischemia-reperfusion for analyses of hepatic injury, adenosine triphosphate levels, mitochondrial mass, autophagy, inflammation, and oxidative stress. H4IIE hepatoma cells and rat primary hepatocytes were incubated with oxyrase to induce hypoxia followed by reoxygenation in the presence or absence of SRT1720 for assessment of mitochondrial mass, mitochondrial membrane potential, and autophagy. MEASUREMENTS AND MAIN RESULTS: SRT1720 restored the reduction in mitochondrial mass, enhanced autophagy, and preserved adenosine triphosphate levels in the liver after ischemia-reperfusion, which was associated with a decrease in ischemia-reperfusion-induced hepatic injury, apoptosis, and necrosis. Ischemia-reperfusion-induced inflammation was also significantly reduced by SRT1720 as measured by systemic and hepatic cytokine and chemokine levels, as well as a decrease in neutrophil infiltration to the liver. Furthermore, oxidative stress was markedly attenuated in the SRT1720-treated mice compared with the vehicle. SRT1720 treatment increased adenosine triphosphate levels and survival of cultured hepatocytes after hypoxia-reoxygenation. SRT1720 not only increased the mitochondrial mass but also increased mitochondrial membrane potential per cell in cultured hepatocytes after hypoxia-reoxygenation. Moreover, SRT1720 prevented the hypoxia-reoxygenation-induced mitochondrial depolarization and resulted in an enhancement of autophagy in cultured hepatocytes after hypoxia-reoxygenation. CONCLUSIONS: Pharmacologic stimulation of sirtuin 1 attenuates liver injury after hepatic ischemia-reperfusion by restoring mitochondrial mass and membrane potential, which is associated with the enhancement of autophagy.

Identification of Risk Factors for Cervical Spine Injury from Pediatric Trauma Registry.

BACKGROUND: Cervical spine injuries are rare in children. Our goal is to establish guidelines for cervical spine clearance that are practical for our pediatric population, and, in the process, to reduce the risk of radiation exposure from unnecessary advanced imaging. METHODS: We retrospectively reviewed the records from the registries of two pediatric trauma centers from the past 11 years (January 2002 to June 2013). Patients aged 1 month to 17 years, who had a CT scan of the cervical spine due to trauma indication for possible cervical spine injury, were evaluated. RESULTS: Three risk factors were identified as being significant for the presence of a cervical spine injury. Patients who sustained a cervical spine injury were more likely to be male (p = 0.0261), were more severely injured with a higher injury severity score (ISS 16.39 ± 15.79 injured vs. 8.7 ± 9.4 uninjured), and presented with neck tenderness (p = 0.0001). CONCLUSION: In our study, significant cervical spine injury is related to male gender, higher ISS and neck tenderness.

Novel resveratrol analogues attenuate renal ischemic injury in rats.

BACKGROUND: Renal ischemia-reperfusion (I/R) is a severe clinical complication with no specific treatment. Resveratrol has been shown as a promising experimental agent in renal I/R due to its effect on cellular energy metabolism, oxidative stress, and inflammation. Recently, we identified two biologically active resveratrol analogues (RSVAs), RSVA405 and RSVA314. We hypothesized that both RSAVs would attenuate I/R-induced renal injury. METHODS: Adult male rats were subjected to renal I/R through bilateral renal pedicle clamping for 60 min, followed by reperfusion. RSVA405 (3 mg/kg Body Weight), RSVA314 (3 mg/kg Body Weight), or vehicle (10% dimethyl sulfoxide and 33% Solutol in phosphate buffered saline) were administered by intraperitoneal injection 1 h before ischemia. Blood and renal tissues were collected 24 h after I/R for evaluation. RESULTS: Administration of RSVA405 and RSVA314 significantly reduced the serum levels of renal dysfunction and injury markers, including creatinine, blood urea nitrogen, aspartate aminotransferase, and lactate dehydrogenase, compared with vehicle. The protective effect of RSVA405 and RSVA314 was also reflected on histologic evaluation. Both RSVAs reduced the number of apoptotic cells by more than 60% as determined by transferase dUTP nick end labeling assay, compared with vehicle. The renal adenosine triphosphate levels of the vehicle group was decreased to 52.4% of control, whereas those of the RSVA405 and RSVA314 groups were restored to 72.3% and 79.6% of control, respectively. Both RSVAs significantly reduced the protein expression of inducible nitric oxide synthase and nitrotyrosine and the messenger RNA levels of tumor necrosis factor-α, interleukin-6, and interleukin-1ß. CONCLUSIONS: RSVA405 and RSVA314 attenuate I/R-induced renal injury through the modulation of energy metabolism, oxidative stress, and inflammation.

Dystonia and tremor secondary to thalamic infarction successfully treated with thalamotomy of the ventralis intermedius nucleus.

BACKGROUND: Focal thalamic lesions have been associated with a variety of involuntary movements such as tremor, dystonia, and chorea-ballism. METHODS: We describe a patient with severe hyperkinesias of the right arm secondary to a thalamic infarction in the left postero-ventral region of the thalamus. RESULTS: The dystonia and tremor of the right upper limb were subsequently controlled with another surgical lesion of the ventralis intermedius nucleus of the thalamus. CONCLUSION: This observation suggests that ablative surgery might be applied to treat a movement disorder induced by the lesion of the same nucleus, which in addition lead to interesting pathophysiological conjectures.

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.

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.

Wounding patterns in pediatric firearm fatalities.

INTRODUCTION: Pediatric firearm injury became the leading cause of death among U.S. children in 2020. Studies evaluating wounding patterns in military and mass casualty shootings have provided insights into treatment and potential salvageability in adults, however, similar studies in the pediatric population do not exist. Hence, our study aimed to analyze wounding patterns of pediatric firearm fatalities and associated demographics and characteristics, such as place of death, to better understand pediatric firearm injuries, potential salvageability, and opportunities to reduce firearm deaths among vulnerable pediatric populations. METHODS: A retrospective review of the National Violent Death Reporting System from 2005-2017 was performed on patients 18 and younger. Mortalities were stratified by patient age: <12 years and 13-18 years and by intent- homicide, suicide, and unintentional. Comparative and exploratory analyses of demographics, location of death and anatomic location of wounds were performed. RESULTS: Of 8,527 pediatric firearm mortalities identified, 4,728 were homicides, 3,180 were suicides and 619 were unintentional injuries. Suicide victims were most likely to be dead on scene and >90% of suicide victims suffered head/neck injuries. For victims of homicide, younger children were more likely to die on scene (61% vs 44% p < 0.001). The pattern of injury in homicides differed for younger children compared to adolescents, with younger children with more head/neck injuries and older children more thoracic, thoracoabdominal, abdominal, and junctional injuries. In both age groups, children with extremity, abdominal and thoracoabdominal injuries were more likely to die later in the emergency department or inpatient setting. CONCLUSIONS: Wounding patterns across pediatric firearm mortalities in the U.S. vary by age and intent. The majority of pediatric firearm deaths were due to head/neck injuries. Children with homicide and unintentional deaths had more wounding pattern variation, including more injuries to the thorax and abdomen, and a much lower rate of dead-on scene than suicide victims. Our study of wounding patterns among U.S. children killed by firearms highlights the complexity of these injuries and offers opportunities for tailored public health strategies across varying vulnerable pediatric populations.

A multicenter evaluation of pediatric emergency department injury visits during the COVID-19 pandemic.

BACKGROUND: Injuries, the leading cause of death in children 1-17 years old, are often preventable. Injury patterns are impacted by changes in the child's environment, shifts in supervision, and caregiver stressors. The objective of this study was to evaluate the incidence and proportion of injuries, mechanisms, and severity seen in Pediatric Emergency Departments (PEDs) during the COVID-19 pandemic. METHODS: This multicenter, cross-sectional study from January 2019 through December 2020 examined visits to 40 PEDs for children < 18 years old. Injury was defined by at least one International Classification of Disease-10th revision (ICD-10) code for bodily injury (S00-T78). The main study outcomes were total and proportion of PED injury-related visits compared to all visits in March through December 2020 and to the same months in 2019. Weekly injury visits as a percentage of total PED visits were calculated for all weeks between January 2019 and December 2020. RESULTS: The study included 741,418 PED visits for injuries pre-COVID-19 pandemic (2019) and during the COVID-19 pandemic (2020). Overall PED visits from all causes decreased 27.4% in March to December 2020 compared to the same time frame in 2019; however, the proportion of injury-related PED visits in 2020 increased by 37.7%. In 2020, injured children were younger (median age 6.31 years vs 7.31 in 2019), more commonly White (54% vs 50%, p < 0.001), non-Hispanic (72% vs 69%, p < 0.001) and had private insurance (35% vs 32%, p < 0.001). Injury hospitalizations increased 2.2% (p < 0.001) and deaths increased 0.03% (p < 0.001) in 2020 compared to 2019. Mean injury severity score increased (2.2 to 2.4, p < 0.001) between 2019 and 2020. Injuries declined for struck by/against (- 4.9%) and overexertion (- 1.2%) mechanisms. Injuries proportionally increased for pedal cycles (2.8%), cut/pierce (1.5%), motor vehicle occupant (0.9%), other transportation (0.6%), fire/burn (0.5%) and firearms (0.3%) compared to all injuries in 2020 versus 2019. CONCLUSIONS: The proportion of PED injury-related visits in March through December 2020 increased compared to the same months in 2019. Racial and payor differences were noted. Mechanisms of injury seen in the PED during 2020 changed compared to 2019, and this can inform injury prevention initiatives.