Prevalence and Outcomes of High versus Low Ratio Plasma to Red Blood Cell Resuscitation in a Multi-Institutional Cohort of Severely Injured Children.

BACKGROUND: The benefit of targeting high ratio fresh frozen plasma (FFP):red blood cell (RBC) transfusion in pediatric trauma resuscitation is unclear as existing studies are limited to patients who retrospectively met criteria for massive transfusion. The purpose of this study is to evaluate the use of high ratio FFP:RBC transfusion and the association with outcomes in children presenting in shock. METHODS: A post-hoc analysis of a 24-institution prospective observational study (4/2018-9/2019) of injured children <18 years with elevated age-adjusted shock index was performed. Patients transfused within 24 hours were stratified into cohorts of low (<1:2) or high (>1:2) ratio FFP:RBC. Nonparametric Kruskal-Wallis and chi-square were used to compare characteristics and mortality. Competing risks analysis was used to compare extended (≥75th percentile) ventilator, intensive care, and hospital days while accounting for early deaths. RESULTS: Of 135 children with median (IQR) age 10 (5,14) years and weight 40 (20,64) kg, 85 (63%) received low ratio transfusion and 50 (37%) high ratio despite similar activation of institutional massive transfusion protocols (MTP; low-38%, high-46%, p = .34). Most patients sustained blunt injuries (70%). Median injury severity score was greater in high ratio patients (low-25, high-33, p = .01); however, hospital mortality was similar (low-24%, high-20%, p = .65) as was the risk of extended ventilator, ICU, and hospital days (all p > .05). CONCLUSION: Despite increased injury severity, patients who received a high ratio of FFP:RBC had comparable rates of mortality. These data suggest high ratio FFP:RBC resuscitation is not associated with worst outcomes in children who present in shock. MTP activation was not associated with receipt of high ratio transfusion, suggesting variability in MTP between centers. LEVEL OF EVIDENCE: Prospective cohort study, Level II.

Crystalloid volume is associated with short-term morbidity in children with severe traumatic brain injury: An Eastern Association for the Surgery of Trauma multicenter trial post hoc analysis.

OBJECTIVE: This study examined differences in clinical and resuscitation characteristics between injured children with and without severe traumatic brain injury (sTBI) and aimed to identify resuscitation characteristics associated with improved outcomes following sTBI. METHODS: This is a post hoc analysis of a prospective observational study of injured children younger than 18 years (2018-2019) transported from the scene, with elevated shock index pediatric-adjusted on arrival and head Abbreviated Injury Scale score of ≥3. Timing and volume of resuscitation products were assessed using χ 2t test, Fisher's exact t test, Kruskal-Wallis, and multivariable logistic regression analyses. RESULTS: There were 142 patients with sTBI and 547 with non-sTBI injuries. Severe traumatic brain injury patients had lower initial hemoglobin (11.3 vs. 12.4, p < 0.001), greater initial international normalized ratio (1.4 vs. 1.1, p < 0.001), greater Injury Severity Score (25 vs. 5, p < 0.001), greater rates of ventilator (59% vs. 11%, p < 0.001) and intensive care unit (ICU) requirement (79% vs. 27%, p < 0.001), and more inpatient complications (18% vs. 3.3%, p < 0.001). Severe traumatic brain injury patients received more prehospital crystalloid (25% vs. 15%, p = 0.008), ≥1 crystalloid boluses (52% vs. 24%, p < 0.001), and blood transfusion (44% vs. 12%, p < 0.001) than non-sTBI patients. Among sTBI patients, receipt of ≥1 crystalloid bolus (n = 75) was associated with greater ICU need (92% vs. 64%, p < 0.001), longer median ICU (6 vs. 4 days, p = 0.027) and hospital stay (9 vs. 4 days, p < 0.001), and more in-hospital complications (31% vs. 7.5%, p = 0.003) than those who received <1 bolus (n = 67). These findings persisted after adjustment for Injury Severity Score (odds ratio, 3.4-4.4; all p < 0.010). CONCLUSION: Pediatric trauma patients with sTBI received more crystalloid than those without sTBI despite having a greater international normalized ratio at presentation and more frequently requiring blood products. Excessive crystalloid may be associated with worsened outcomes, including in-hospital mortality, seen among pediatric sTBI patients who received ≥1 crystalloid bolus. Further attention to a crystalloid sparing, early transfusion approach to resuscitation of children with sTBI is needed. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Inflammation of the retinal pigment epithelium drives early-onset photoreceptor degeneration in Mertk-associated retinitis pigmentosa.

Severe, early-onset photoreceptor (PR) degeneration associated with MERTK mutations is thought to result from failed phagocytosis by retinal pigment epithelium (RPE). Notwithstanding, the severity and onset of PR degeneration in mouse models of Mertk ablation are determined by the hypomorphic expression or the loss of the Mertk paralog Tyro3. Here, we find that loss of Mertk and reduced expression/loss of Tyro3 led to RPE inflammation even before eye-opening. Incipient RPE inflammation cascaded to involve microglia activation and PR degeneration with monocyte infiltration. Inhibition of RPE inflammation with the JAK1/2 inhibitor ruxolitinib mitigated PR degeneration in Mertk-/- mice. Neither inflammation nor severe, early-onset PR degeneration was observed in mice with defective phagocytosis alone. Thus, inflammation drives severe, early-onset PR degeneration-associated with Mertk loss of function.

Regulation of bone homeostasis by MERTK and TYRO3.

The fine equilibrium of bone homeostasis is maintained by bone-forming osteoblasts and bone-resorbing osteoclasts. Here, we show that TAM receptors MERTK and TYRO3 exert reciprocal effects in osteoblast biology: Osteoblast-targeted deletion of MERTK promotes increased bone mass in healthy mice and mice with cancer-induced bone loss, whereas knockout of TYRO3 in osteoblasts shows the opposite phenotype. Functionally, the interaction of MERTK with its ligand PROS1 negatively regulates osteoblast differentiation via inducing the VAV2-RHOA-ROCK axis leading to increased cell contractility and motility while TYRO3 antagonizes this effect. Consequently, pharmacologic MERTK blockade by the small molecule inhibitor R992 increases osteoblast numbers and bone formation in mice. Furthermore, R992 counteracts cancer-induced bone loss, reduces bone metastasis and prolongs survival in preclinical models of multiple myeloma, breast- and lung cancer. In summary, MERTK and TYRO3 represent potent regulators of bone homeostasis with cell-type specific functions and MERTK blockade represents an osteoanabolic therapy with implications in cancer and beyond.

Tissue-specific modifier alleles determine Mertk loss-of-function traits.

Knockout (KO) mouse models play critical roles in elucidating biological processes behind disease-associated or disease-resistant traits. As a presumed consequence of gene KO, mice display certain phenotypes. Based on insight into the molecular role of said gene in a biological process, it is inferred that the particular biological process causally underlies the trait. This approach has been crucial towards understanding the basis of pathological and/or advantageous traits associated with Mertk KO mice. Mertk KO mice suffer from severe, early-onset retinal degeneration. MERTK, expressed in retinal pigment epithelia, is a receptor tyrosine kinase with a critical role in phagocytosis of apoptotic cells or cellular debris. Therefore, early-onset, severe retinal degeneration was described to be a direct consequence of failed MERTK-mediated phagocytosis of photoreceptor outer segments by retinal pigment epithelia. Here, we report that the loss of Mertk alone is not sufficient for retinal degeneration. The widely used Mertk KO mouse carries multiple coincidental changes in its genome that affect the expression of a number of genes, including the Mertk paralog Tyro3. Retinal degeneration manifests only when the function of Tyro3 is concomitantly lost. Furthermore, Mertk KO mice display improved anti-tumor immunity. MERTK is expressed in macrophages. Therefore, enhanced anti-tumor immunity was inferred to result from the failure of macrophages to dispose of cancer cell corpses, resulting in a pro-inflammatory tumor microenvironment. The resistance against two syngeneic mouse tumor models observed in Mertk KO mice is not, however, phenocopied by the loss of Mertk alone. Neither Tyro3 nor macrophage phagocytosis by alternate genetic redundancy accounts for the absence of anti-tumor immunity. Collectively, our results indicate that context-dependent epistasis of independent modifier alleles determines Mertk KO traits.

Derivation and validation of an improved pediatric shock index for predicting need for early intervention and outcomes in pediatric trauma.

BACKGROUND: Shock index, pediatric age adjusted (SIPA), has been widely applied in pediatric trauma but has limited precision because of the reference ranges used in its derivation. We hypothesized that a pediatric shock index (PSI) equation based on age-based vital signs would outperform SIPA. METHODS: A retrospective cohort of trauma patients aged 1 to 18 years from Trauma Quality Programs - Participant Use File 2010 to 2018 was performed. A random 70% training subset was used to derive Youden index-optimizing shock index (SI) cutoffs by age for blood transfusion within 4 hours. We used linear regression to derive equations representing the PSI cutoff for children 12 years or younger and 13 years or older. For children 13 years or older, the well-established SI of 0.9 remained optimal, consistent with SIPA and other indices. For children 12 years or younger in the 30% validation subset, we compared our age-based PSI to SIPA as predictors of early transfusion, mortality, pediatric intensive care unit admission, and injury severity score of ≥25. For bedside use, a simplified "rapid" pediatric shock index (rPSI) equation was also derived and compared with SIPA. RESULTS: A total of 439,699 patients aged 1 to 12 years met the inclusion criteria with 2,718 (1.3% of those with available outcome data) requiring transfusion within 4 hours of presentation. In the validation set, positive predictive values for early transfusion were higher for PSI (8.3%; 95% confidence interval [CI], 7.5-9.1%) and rPSI (6.3%; 95% CI, 5.7-6.9%) than SIPA (4.3%; 95% CI, 3.9-4.7%). For early transfusion, negative predictive values for both PSI (99.3%; 95% CI, 99.2-99.3%) and rPSI (99.3%; 95% CI, 99.2-99.4%) were similar to SIPA (99.4%; 95% CI, 99.3-99.4%). CONCLUSION: We derived the PSI and rPSI for use in pediatric trauma using empiric, age-based SI cutoffs. The PSI and rPSI achieved higher positive predictive values and similar negative predictive values to SIPA in predicting the need for early blood transfusion and mortality. LEVEL OF EVIDENCE: Prognostic/Epidemiological; level III.

The impact of parental bariatric surgery and patient age on laparoscopic sleeve gastrectomy outcomes in adolescents.

BACKGROUND: Adolescent obesity is multifactorial, but parental history is the most significant risk factor. Laparoscopic sleeve gastrectomy (LSG) is part of the multidisciplinary approach to adolescent weight loss. OBJECTIVE: We aimed to evaluate the effects of parental history of bariatric surgery, as well as age at time of operation, on adolescents who underwent LSG at our institution. METHODS: We performed a retrospective review of patients, aged 10 to 19 years, who underwent LSG from January 2010 to December 2019. The adolescent bariatric surgical dataset maintained by our group was used to obtain patient demographics, weight, body mass index (BMI), and parental history of bariatric surgery. RESULTS: Among 328 patients, 76 (23.2%) had parents who had previously undergone bariatric surgery. These patients were significantly heavier by weight (p = 0.012) at the time of operation but had no difference in postoperative weight loss. When all patients were compared by age at operation (< 16 years, n = 102, ≥ 16 years, n = 226), there were few differences in outcomes. CONCLUSIONS: LSG is an effective approach to surgical weight loss in adolescents. Patient age should not be a barrier to weight loss surgery, especially among patients with a parental history of obesity. By intervening at a younger age, the metabolic sequelae of obesity may be reduced.

Patterns of paediatric massive blood transfusion protocol use in trauma and non-trauma patients.

BACKGROUND: Massive blood transfusion is infrequently required by children but can be a lifesaving intervention for haemorrhage or coagulopathy. Product volumes and ratios administered during the initiation of paediatric massive blood transfusion protocol (MBTP) are highly variable and the optimal component ratio is unknown. METHODS/MATERIALS: We performed a single-centre retrospective chart review of patients (<20 years) who received MBTP activation from August 2012 through January 2018. Logistic regression was used to determine the association between MBTP use characteristics (including blood product type and volume transfused, extracorporeal membrane oxygenation [ECMO] support, and cardiac arrest occurrence) and 24-h mortality. "Low" product ratio was defined as a ratio of plasma or platelets to red blood cells (RBCs) of <1:2 and "high" as ≥1:2. RESULTS: Ninety-eight MBTPs were activated for 89 patients (range 1-4 per patient). The most common underlying diagnoses were congenital heart disease (CHD, n = 28, 31.5%), followed by cardiopulmonary disease, and trauma. CHD patients required the greatest volume of RBCs (226.3 ml/kg, 95%CI [160.0, 292.7], p = 0.002) and platelets (46.7 ml/kg, 95%CI [33.2, 60.2], p < 0.001). A "low" product ratio was more common for the MBTP, with its incidence similar among the underlying diagnoses. CONCLUSION: An MBTP developed for trauma patients can be applied to non-trauma patients but standard MBTP components may not be optimal for all children. These findings show that underlying patient diagnoses may be a factor when designing an MBTP for a heterogeneous paediatric population.

AXL Inhibition in Macrophages Stimulates Host-versus-Leukemia Immunity and Eradicates Naïve and Treatment-Resistant Leukemia.

Acute leukemias are systemic malignancies associated with a dire outcome. Because of low immunogenicity, leukemias display a remarkable ability to evade immune control and are often resistant to checkpoint blockade. Here, we discover that leukemia cells actively establish a suppressive environment to prevent immune attacks by co-opting a signaling axis that skews macrophages toward a tumor-promoting tissue repair phenotype, namely the GAS6/AXL axis. Using aggressive leukemia models, we demonstrate that ablation of the AXL receptor specifically in macrophages, or its ligand GAS6 in the environment, stimulates antileukemic immunity and elicits effective and lasting natural killer cell- and T cell-dependent immune response against naïve and treatment-resistant leukemia. Remarkably, AXL deficiency in macrophages also enables PD-1 checkpoint blockade in PD-1-refractory leukemias. Finally, we provide proof-of-concept that a clinical-grade AXL inhibitor can be used in combination with standard-of-care therapy to cure established leukemia, regardless of AXL expression in malignant cells. SIGNIFICANCE: Alternatively primed myeloid cells predict negative outcome in leukemia. By demonstrating that leukemia cells actively evade immune control by engaging AXL receptor tyrosine kinase in macrophages and promoting their alternative priming, we identified a target which blockade, using a clinical-grade inhibitor, is vital to unleashing the therapeutic potential of myeloid-centered immunotherapy.This article is highlighted in the In This Issue feature, p. 2659.

Variations in the management of adolescent adnexal torsion at a single institution and the creation of a unified care pathway.

PURPOSE: Adnexal torsion is a gynecologic emergency, requiring intervention for tissue preservation. At our institution, torsion is managed by pediatric surgeons or gynecologists. We evaluated differences between specialties to streamline evaluation for children with gynecological emergencies, develop a clinical pathway, and prevent care delays. METHODS: A retrospective review of adolescents undergoing intervention for adnexal torsion from 2004-2018 was performed. Differences in time to intervention, operation duration, the procedure performed, and length of stay (LOS) between the specialties were analyzed. RESULTS: Eighty-six patients underwent 94 operations for presumed adnexal torsion with 87 positive cases. Pediatric surgeons performed 60 operations and 34 cases were performed by gynecologists. Preservation of fertility was the goal in both cohorts and the rate of oophoropexy, cystectomy, and oophorectomy were similar between the cohorts (p = 0.14, p = 1.0, p = 0.39, respectively). There was no difference in intra-operative time (p = 0.69). LOS was shorter in the gynecology cohort (median 1 day [1-2] vs. 2 days [2-3], p > 0.001). CONCLUSIONS: Adnexal torsion is a time-sensitive diagnosis requiring prompt intervention for ovarian or fallopian tube preservation. A multidisciplinary institutional care pathway should be developed and implemented.

Timing and volume of crystalloid and blood products in pediatric trauma: An Eastern Association for the Surgery of Trauma multicenter prospective observational study.

BACKGROUND: The purpose of this study was to determine the relationship between timing and volume of crystalloid before blood products and mortality, hypothesizing that earlier transfusion and decreased crystalloid before transfusion would be associated with improved outcomes. METHODS: A multi-institutional prospective observational study of pediatric trauma patients younger than 18 years, transported from the scene of injury with elevated age-adjusted shock index on arrival, was performed from April 2018 to September 2019. Volume and timing of prehospital, emergency department, and initial admission resuscitation were assessed including calculation of 20 ± 10 mL/kg crystalloid boluses overall and before transfusion. Multivariable Cox proportional hazards and logistic regression models identified factors associated with mortality and extended intensive care, ventilator, and hospital days. RESULTS: In 712 children at 24 trauma centers, mean age was 7.6 years, median (interquartile range) Injury Severity Score was 9 (2-20), and in-hospital mortality was 5.3% (n = 38). There were 311 patients(43.7%) who received at least one crystalloid bolus and 149 (20.9%) who received blood including 65 (9.6%) with massive transfusion activation. Half (53.3%) of patients who received greater than one crystalloid bolus required transfusion. Patients who received blood first (n = 41) had shorter median time to transfusion (19.8 vs. 78.0 minutes, p = 0.005) and less total fluid volume (50.4 vs. 86.6 mL/kg, p = 0.033) than those who received crystalloid first despite similar Injury Severity Score (median, 22 vs. 27, p = 0.40). On multivariable analysis, there was no association with mortality (p = 0.51); however, each crystalloid bolus after the first was incrementally associated with increased odds of extended ventilator, intensive care unit, and hospital days (all p < 0.05). Longer time to transfusion was associated with extended ventilator duration (odds ratio, 1.11; p = 0.04). CONCLUSION: Resuscitation with greater than one crystalloid bolus was associated with increased need for transfusion and worse outcomes including extended duration of mechanical ventilation and hospitalization in this prospective study. These data support a crystalloid-sparing, early transfusion approach for resuscitation of injured children. LEVEL OF EVIDENCE: Therapeutic, level IV.

Health-Care Workers' Perception of Reimbursement for Complex Surgical Oncology Procedures.

Perception of physician reimbursement for surgical procedures is not well studied. The few existing studies illustrate that patients believe compensation to be higher than in reality. These studies focus on patient perceptions and have not assessed health-care workers' views. Our study examined health-care workers' perception of reimbursement for complex surgical oncology procedures. An anonymous online survey was distributed to employees at our cancer center with descriptions and illustrations of three oncology procedures-hepatectomy, gastrectomy, and pancreaticoduodenectomy. Participants estimated the Medicare fee and gave their perceived value of each procedure. Participants recorded their perception of surgeon compensation overall, both before and after revealing the Medicare fee schedule. Most of the 113 participants were physicians (33.6%) and nurses (28.3%). When blinded to the Medicare fee schedules, most felt that reimbursements were too low for all procedures (60-64%) and that surgeons were overall undercompensated (57%). Value predictions for each procedure were discordant from actual Medicare fee schedules, with overestimates up to 374 per cent. After revealing the Medicare fee schedules, 55 per cent of respondents felt that surgeons were undercompensated. Even among health-care workers, a large discrepancy exists between perceived and actual reimbursement. Revealing actual reimbursements did not alter perception on overall surgeon compensation.