The transcription factor Runx3 guards cytotoxic CD8+ effector T cells against deviation towards follicular helper T cell lineage.

Activated CD8+ T cells differentiate into cytotoxic effector (TEFF) cells that eliminate target cells. How TEFF cell identity is established and maintained is not fully understood. We found that Runx3 deficiency limited clonal expansion and impaired upregulation of cytotoxic molecules in TEFF cells. Runx3-deficient CD8+ TEFF cells aberrantly upregulated genes characteristic of follicular helper T (TFH) cell lineage, including Bcl6, Tcf7 and Cxcr5. Mechanistically, the Runx3-CBFß transcription factor complex deployed H3K27me3 to Bcl6 and Tcf7 genes to suppress the TFH program. Ablating Tcf7 in Runx3-deficient CD8+ TEFF cells prevented the upregulation of TFH genes and ameliorated their defective induction of cytotoxic genes. As such, Runx3-mediated Tcf7 repression coordinately enforced acquisition of cytotoxic functions and protected the cytotoxic lineage integrity by preventing TFH-lineage deviation.

Sifting through CD8+ T Cell Memory.

In this issue of Immunity, Gerlach et al. (2016) describe three distinct memory CD8+ T cell subsets based upon expression of the fractalkine receptor CX3CR1. Their findings revise the paradigm of effector and central memory T cells by revealing a subset of CD8+ memory T cells defined by intermediate levels of expression of CX3CR1 that conducts tissue surveillance.

CD8+ T Cells Utilize Highly Dynamic Enhancer Repertoires and Regulatory Circuitry in Response to Infections.

Differentiation of effector and memory CD8+ T cells is accompanied by extensive changes in the transcriptome and histone modifications at gene promoters; however, the enhancer repertoire and associated gene regulatory networks are poorly defined. Using histone mark chromatin immunoprecipitation coupled with deep sequencing, we mapped the enhancer and super-enhancer landscapes in antigen-specific naive, differentiated effector, and central memory CD8+ T cells during LCMV infection. Epigenomics-based annotation revealed a highly dynamic repertoire of enhancers, which were inherited, de novo activated, decommissioned and re-activated during CD8+ T cell responses. We employed a computational algorithm to pair enhancers with target gene promoters. On average, each enhancer targeted three promoters and each promoter was regulated by two enhancers. By identifying enriched transcription factor motifs in enhancers, we defined transcriptional regulatory circuitry at each CD8+ T cell response stage. These multi-dimensional datasets provide a blueprint for delineating molecular mechanisms underlying functional differentiation of CD8+ T cells.

Risk factors for stroke in penetrating cerebrovascular injuries.

OBJECTIVE: Penetrating cerebrovascular injuries (PCVI) are associated with a high incidence of mortality and neurological events. The optimal treatment strategy of PCVI, especially when damage control measures are required, remains controversial. The aim of this study was to describe the management of PCVI and patient outcomes at a level 1 trauma center where vascular injuries are managed predominantly by trauma surgeons. METHODS: An institutional trauma registry was queried for patients with PCVI from 2011 to 2021. Patients with common carotid artery (CCA), internal carotid artery (ICA), or vertebral artery injuries were included for analysis. The primary outcome was in-hospital stroke. The secondary outcomes were in-hospital mortality and in-hospital stroke or death. A subgroup analysis was completed of arterial repair (primary repair or interposition graft) vs ligation or embolization vs temporary intravascular shunting at the index procedure. RESULTS: We analyzed 54 patients with PCVI. Overall, the in-hospital stroke rate was 17% and in-hospital mortality was 26%. Twenty-one patients (39%) underwent arterial interventions for PCVI. Ten patients underwent arterial repair, six patients underwent ligation or embolization, and five patients underwent intravascular shunting as a damage control strategy with a plan for delayed repair. The rate of in-hospital stroke was 30% after arterial repair, 0% after arterial ligation or embolization, and 80% after temporary intravascular shunting. There was a significant difference in the stroke rate between the three subgroups (P = .015). Of the 32 patients who did not have an intervention to the CCA, ICA, or vertebral artery, 1 patient with ICA occlusion and 1 patient with CCA intimal injury developed in-hospital stroke. The mortality rate was 0% after arterial repair, 50% after ligation or embolization, and 60% after intravascular shunting. The rate of stroke or death was 30% in the arterial repair group, 50% in the ligation or embolization group, and 100% in the temporary intravascular shunting group. CONCLUSIONS: High rates of stroke and mortality were seen in patients requiring damage control after PCVI. In particular, temporary intravascular shunting was associated with a high incidence of in-hospital stroke and a 100% rate of stroke or death. Further investigation is needed into the factors related to these finding and whether the use of temporary intravascular shunting in PCVI is an advisable strategy.

Resuscitative Thoracotomy for Traumatic Cardiac Arrest: Potential Impact of Resource Constraint on Outcomes and Blood Product Utilization.

INTRODUCTION: Resuscitative thoracotomy (RT) in the setting of traumatic arrest serves as a vital but resource-intensive intervention. The COVID-19 pandemic has created critical shortages, sharpening the focus on efficient resource utilization. This study aims to compare RT performance and blood product utilization before and after the onset of the COVID-19 pandemic for patients in traumatic cardiac arrest. METHODS: All patients undergoing RT for traumatic cardiac arrest in the emergency department at our American College of Surgeons-verified Level 1 trauma center (August 01, 2017-July 31, 2022) were included in this retrospective observational study. Study groups were dichotomized into pre-COVID (before October 03, 2020) versus COVID (from October 03, 2020 on) based on patient arrival date demographics, clinical/injury data, and outcomes were collected. The primary outcome was blood product transfusion <4 h after presentation. RESULTS: 445 RTs (2% of 23,488 trauma encounters) were performed over the study period: Pre-COVID, n = 209 (2%) versus COVID, n = 236 (2%) (P = 0.697). Survival to discharge was equivalent Pre-COVID versus COVID (n = 22, 11% versus n = 21, 9%, P = 0.562). RT patients during COVID consumed a median of 1 unit less packed red blood cells at the 4 h measurement (3.0 [1.8-7.0] versus 3.9 [2.0-10.0] units, P = 0.012) and 1 unit less of platelets at the 4 h measurement (4.3 [2.6-10.0] versus 5.7 [2.9-14.4] units, P = 0.012) compared to Pre-COVID. These findings were persistent after performing multivariable negative binomial regression. CONCLUSIONS: Rates of RT and survival after RT remained consistent during the pandemic. Despite comparable RT frequency, packed red blood cells and platelet transfusions were reduced, likely reflecting resource expenditure minimization during the severe blood shortages that occurred during the pandemic. RT performance for patients in traumatic arrest may, therefore, be feasible during global pandemics at prepandemic frequencies as long as particular attention is paid to resource expenditure.

Reduced T Cell Priming in Microbially Experienced "Dirty" Mice Results from Limited IL-27 Production by XCR1+ Dendritic Cells.

Successful vaccination strategies offer the potential for lifelong immunity against infectious diseases and cancer. There has been increased attention regarding the limited translation of some preclinical findings generated using specific pathogen-free (SPF) laboratory mice to humans. One potential reason for the difference between preclinical and clinical findings lies in maturation status of the immune system at the time of challenge. In this study, we used a "dirty" mouse model, where SPF laboratory mice were cohoused (CoH) with pet store mice to permit microbe transfer and immune system maturation, to investigate the priming of a naive T cell response after vaccination with a peptide subunit mixed with polyinosinic-polycytidylic acid and agonistic anti-CD40 mAb. Although this vaccination platform induced robust antitumor immunity in SPF mice, it failed to do so in microbially experienced CoH mice. Subsequent investigation revealed that despite similar numbers of Ag-specific naive CD4 and CD8 T cell precursors, the expansion, differentiation, and recall responses of these CD4 and CD8 T cell populations in CoH mice were significantly reduced compared with SPF mice after vaccination. Evaluation of the dendritic cell compartment revealed reduced IL-27p28 expression by XCR1+ dendritic cells from CoH mice after vaccination, correlating with reduced T cell expansion. Importantly, administration of recombinant IL-27:EBI3 complex to CoH mice shortly after vaccination significantly boosted Ag-specific CD8 and CD4 T cell expansion, further implicating the defect to be T cell extrinsic. Collectively, our data show the potential limitation of exclusive use of SPF mice when testing vaccine efficacy.

Deriving acceptable limits for non-mutagenic impurities in medicinal products - Durational adjustments.

ICH Q3A/B guidelines are not intended for application during the clinical research phase of development and durationally adjusted qualification thresholds are not included. A central tenet of ICH Q3A is that lifetime exposure to 1 mg/day of an unqualified non-mutagenic impurity (NMI) is not a safety concern. An analysis of in vivo toxicology data from 4878 unique chemicals with established NO(A)ELs was conducted to determine whether durationally adjusted qualification limits can be supported. Although not recommended in ICH Q3A/B, a conservative approach was taken by using allometric scaling in the analysis. Following allometric scaling of the 5th percentile of the distribution of NO(A)ELs from available chronic toxicology studies, it was reconfirmed that there is a safety basis for the 1 mg/day qualification threshold in ICH Q3A. Additionally, allometric scaling of the 5th percentile of the distribution of NO(A)ELs from sub-acute and sub-chronic toxicology studies could support acceptable limits of 20 and 5 mg/day for an unqualified NMI for dosing durations of less than or greater than one month, respectively. This analysis supports durationally adjusted NMI qualification thresholds for pharmaceuticals that protect patient safety and contribute to 3Rs efforts for qualifying impurities using new approach methods.

BID expression determines the apoptotic fate of cancer cells after abrogation of the spindle assembly checkpoint by AURKB or TTK inhibitors.

BACKGROUND: Drugs targeting the spindle assembly checkpoint (SAC), such as inhibitors of Aurora kinase B (AURKB) and dual specific protein kinase TTK, are in different stages of clinical development. However, cell response to SAC abrogation is poorly understood and there are no markers for patient selection. METHODS: A panel of 53 tumor cell lines of different origins was used. The effects of drugs were analyzed by MTT and flow cytometry. Copy number status was determined by FISH and Q-PCR; mRNA expression by nCounter and RT-Q-PCR and protein expression by Western blotting. CRISPR-Cas9 technology was used for gene knock-out (KO) and a doxycycline-inducible pTRIPZ vector for ectopic expression. Finally, in vivo experiments were performed by implanting cultured cells or fragments of tumors into immunodeficient mice. RESULTS: Tumor cells and patient-derived xenografts (PDXs) sensitive to AURKB and TTK inhibitors consistently showed high expression levels of BH3-interacting domain death agonist (BID), while cell lines and PDXs with low BID were uniformly resistant. Gene silencing rendered BID-overexpressing cells insensitive to SAC abrogation while ectopic BID expression in BID-low cells significantly increased sensitivity. SAC abrogation induced activation of CASP-2, leading to cleavage of CASP-3 and extensive cell death only in presence of high levels of BID. Finally, a prevalence study revealed high BID mRNA in 6% of human solid tumors. CONCLUSIONS: The fate of tumor cells after SAC abrogation is driven by an AURKB/ CASP-2 signaling mechanism, regulated by BID levels. Our results pave the way to clinically explore SAC-targeting drugs in tumors with high BID expression.

And Miles to Go Before We Sleep: EAST Diversity and Inclusivity Progress and Remaining Challenges.

OBJECTIVE: The aim of this study was to examine the diversity, equity, and inclusion landscape in academic trauma surgery and the EAST organization. SUMMARY BACKGROUND DATA: In 2019, the Eastern Association for the Surgery of Trauma (EAST) surveyed its members on equity and inclusion in the #EAST4ALL survey and assessed leadership representation. We hypothesized that women and surgeons of color (SOC) are underrepresented as EAST members and leaders. METHODS: Survey responses were analyzed post-hoc for representation of females and SOC in academic appointments and leadership, EAST committees, and the EAST board, and compared to the overall respondent cohort. EAST membership and board demographics were compared to demographic data from the Association of American Medical Colleges. RESULTS: Of 306 respondents, 37.4% identified as female and 23.5% as SOC. There were no significant differences in female and SOC representation in academic appointments and EAST committees compared to their male and white counterparts. In academic leadership, females were underrepresented ( P < 0.0001), whereas SOC were not ( P = 0.08). Both females and SOC were underrepresented in EAST board membership ( P = 0.002 and P = 0.043, respectively). Of EAST's 33 presidents, 3 have been white women (9%), 2 have been Black, non-African American men (6%), and 28 (85%) have been white men. When compared to 2017 AAMC data, women are well-represented in EAST's 2020 membership ( P < 0.0001) and proportionally represented on EAST's 2019-2020 board ( P > 0.05). CONCLUSIONS: The #EAST4ALL survey suggests that women and SOC may be underrepresented as leaders in academic trauma surgery. However, lack of high-quality demographic data makes evaluating representation of structurally marginalized groups challenging. National trauma organizations should elicit data from their members to re-assess and promote the diversity landscape in trauma surgery.

A Cluster Randomized Trial of Primary Care Practice Redesign to Integrate Behavioral Health for Those Who Need It Most: Patients With Multiple Chronic Conditions.

PURPOSE: Patient outcomes can improve when primary care and behavioral health providers use a collaborative system of care, but integrating these services is difficult. We tested the effectiveness of a practice intervention for improving patient outcomes by enhancing integrated behavioral health (IBH) activities. METHODS: We conducted a pragmatic, cluster randomized controlled trial. The intervention combined practice redesign, quality improvement coaching, provider and staff education, and collaborative learning. At baseline and 2 years, staff at 42 primary care practices completed the Practice Integration Profile (PIP) as a measure of IBH. Adult patients with multiple chronic medical and behavioral conditions completed the Patient-Reported Outcomes Measurement Information System (PROMIS-29) survey. Primary outcomes were the change in 8 PROMIS-29 domain scores. Secondary outcomes included change in level of integration. RESULTS: Intervention assignment had no effect on change in outcomes reported by 2,426 patients who completed both baseline and 2-year surveys. Practices assigned to the intervention improved PIP workflow scores but not PIP total scores. Baseline PIP total score was significantly associated with patient-reported function, independent of intervention. Active practices that completed intervention workbooks (n = 13) improved patient-reported outcomes and practice integration (P ≤ .05) compared with other active practices (n = 7). CONCLUSION: Intervention assignment had no effect on change in patient outcomes; however, we did observe improved patient outcomes among practices that entered the study with greater IBH. We also observed more improvement of integration and patient outcomes among active practices that completed the intervention compared to active practices that did not. Additional research is needed to understand how implementation efforts to enhance IBH can best reach patients.

Risk factors and outcomes in pediatric blunt cardiac injuries.

PURPOSE: Unlike adults, less is known of the etiology and risk factors for blunt cardiac injury (BCI) in children. Identifying risk factors for BCI in pediatric patients will allow for more specific screening practices following blunt trauma. METHODS: A retrospective review was performed using the Trauma Quality Improvement Program (TQIP) database from 2017 to 2019. All patients ≤ 16 years injured following blunt trauma were included. Demographics, mechanism, associated injuries, injury severity, and outcomes were collected. Univariate and multivariate regression was used to determine specific risk factors for BCI. RESULTS: Of 266,045 pediatric patients included in the analysis, the incidence of BCI was less than 0.2%. The all-cause mortality seen in patients with BCI was 26%. Motor-vehicle collisions (MVCs) were the most common mechanism, although no association with seatbelt use was seen in adolescents (p = 0.158). The strongest independent risk factors for BCI were pulmonary contusions (OR 15.4, p < 0.001) and hemothorax (OR 8.9, p < 0.001). CONCLUSIONS: Following trauma, the presence of pulmonary contusions or hemothorax should trigger additional screening investigations specific for BCI in pediatric patients.

Preparing residents to practice integrated behavioral health care: Multi-site feasibility study of a competency-based curriculum.

OBJECTIVE: Workforce development is essential for the dissemination of team-based integrated behavioral healthcare. There is limited literature on training family medicine residents to function within an integrated behavioral health (IBH) system. The purpose of this pilot study was to assess the feasibility and value of an IBH competency-based curriculum for family medicine residents across multiple programs. METHODS: Residency programs were recruited using professional listservs and networks to test a competency-based, multi-modal curriculum for preparing residents to practice IBH in primary care. Faculty instructors who led the workshop were invited to complete semi-structured interviews to examine the feasibility and appropriateness of the curriculum. Interview data were analyzed using thematic analysis to identify, analyze, and report patterns. Residents completed a survey of perceived IBH skill and knowledge before and after training. A paired-sample t-test was used to determine significant differences pre- and post-training. RESULTS: All five instructors completed interviews. Results suggest IBH training is valuable. Instructors gave specific feedback on online modules, implementation flexibility, and adjusting faculty development to differing levels of experience. Nineteen of forty residents (48%) completed anonymous pre-, post-, and retrospective-training surveys. Residents reported an increase in competence after training. CONCLUSION: The results of this pilot suggest that IBH training implementation is feasible, desirable, timely, and may improve resident ability to work on an IBH team. Training should accommodate variations in program structure and faculty expertise.

Use of Cold-Stored Whole Blood is Associated With Improved Mortality in Hemostatic Resuscitation of Major Bleeding: A Multicenter Study.

OBJECTIVE: The aim of this study was to identify a mortality benefit with the use of whole blood (WB) as part of the resuscitation of bleeding trauma patients. BACKGROUND: Blood component therapy (BCT) is the current standard for resuscitating trauma patients, with WB emerging as the blood product of choice. We hypothesized that the use of WB versus BCT alone would result in decreased mortality. METHODS: We performed a 14-center, prospective observational study of trauma patients who received WB versus BCT during their resuscitation. We applied a generalized linear mixed-effects model with a random effect and controlled for age, sex, mechanism of injury (MOI), and injury severity score. All patients who received blood as part of their initial resuscitation were included. Primary outcome was mortality and secondary outcomes included acute kidney injury, deep vein thrombosis/pulmonary embolism, pulmonary complications, and bleeding complications. RESULTS: A total of 1623 [WB: 1180 (74%), BCT: 443(27%)] patients who sustained penetrating (53%) or blunt (47%) injury were included. Patients who received WB had a higher shock index (0.98 vs 0.83), more comorbidities, and more blunt MOI (all P <0.05). After controlling for center, age, sex, MOI, and injury severity score, we found no differences in the rates of acute kidney injury, deep vein thrombosis/pulmonary embolism or pulmonary complications. WB patients were 9% less likely to experience bleeding complications and were 48% less likely to die than BCT patients ( P <0.0001). CONCLUSIONS: Compared with BCT, the use of WB was associated with a 48% reduction in mortality in trauma patients. Our study supports the use of WB use in the resuscitation of trauma patients.

HDAC11 deficiency disrupts oncogene-induced hematopoiesis in myeloproliferative neoplasms.

Protein acetylation is an important contributor to cancer initiation. Histone deacetylase 6 (HDAC6) controls JAK2 translation and protein stability and has been implicated in JAK2-driven diseases best exemplified by myeloproliferative neoplasms (MPNs). By using novel classes of highly selective HDAC inhibitors and genetically deficient mouse models, we discovered that HDAC11 rather than HDAC6 is necessary for the proliferation and survival of oncogenic JAK2-driven MPN cells and patient samples. Notably, HDAC11 is variably expressed in primitive stem cells and is expressed largely upon lineage commitment. Although Hdac11is dispensable for normal homeostatic hematopoietic stem and progenitor cell differentiation based on chimeric bone marrow reconstitution, Hdac11 deficiency significantly reduced the abnormal megakaryocyte population, improved splenic architecture, reduced fibrosis, and increased survival in the MPLW515L-MPN mouse model during primary and secondary transplantation. Therefore, inhibitors of HDAC11 are an attractive therapy for treating patients with MPN. Although JAK2 inhibitor therapy provides substantial clinical benefit in MPN patients, the identification of alternative therapeutic targets is needed to reverse MPN pathogenesis and control malignant hematopoiesis. This study establishes HDAC11 as a unique type of target molecule that has therapeutic potential in MPN.

Practical and Science-Based Strategy for Establishing Acceptable Intakes for Drug Product N-Nitrosamine Impurities.

The potential for N-nitrosamine impurities in pharmaceutical products presents a challenge for the quality management of medicinal products. N-Nitrosamines are considered cohort-of-concern compounds due to the potent carcinogenicity of many of the structurally simple chemicals within this structural class. In the past 2 years, a number of drug products containing certain active pharmaceutical ingredients have been withdrawn or recalled from the market due to the presence of carcinogenic low-molecular-weight N,N-dialkylnitrosamine impurities. Regulatory authorities have issued guidance to market authorization holders to review all commercial drug substances/products for the potential risk of N-nitrosamine impurities, and in cases where a significant risk of N-nitrosamine impurity is identified, analytical confirmatory testing is required. A key factor to consider prior to analytical testing is the estimation of the daily acceptable intake (AI) of the N-nitrosamine impurity. A significant proportion of N-nitrosamine drug product impurities are unique/complex structures for which the development of low-level analytical methods is challenging. Moreover, these unique/complex impurities may be less potent carcinogens compared to simple nitrosamines. In the present work, our objective was to derive AIs for a large number of complex N-nitrosamines without carcinogenicity data that were identified as potential low-level impurities. The impurities were first cataloged and grouped according to common structural features, with a total of 13 groups defined with distinct structural features. Subsequently, carcinogenicity data were reviewed for structurally related N-nitrosamines relevant to each of the 13 structural groups and group AIs were derived conservatively based on the most potent N-nitrosamine within each group. The 13 structural group AIs were used as the basis for assigning AIs to each of the structurally related complex N-nitrosamine impurities. The AIs of several N-nitrosamine groups were found to be considerably higher than those for the simple N,N-dialkylnitrosamines, which translates to commensurately higher analytical method detection limits.

Machine Learning for Military Trauma: Novel Massive Transfusion Predictive Models in Combat Zones.

BACKGROUND: Damage control resuscitation has become the standard of care in military and civilian trauma. Early identification of blood product requirements may aid in optimizing the clinical decision-making process while improving trauma related outcomes. This study aimed to assess and compare multiple machine learning models for predicting patients at highest risk for massive transfusion on the battlefield. METHODS: Supervised machine learning approaches using logistic regression, support vector machine, neural network, and random forest techniques were used to create predictive models for massive transfusion using standard prehospital and arrival data points from the Department of Defense Trauma Registry, 2008-2016. Seventy percent of the population was used for model development and performance was validated using the remaining 30%. Models were tested for accuracy and compared by standard performance statistics. RESULTS: A total of 22,158 patients (97% male, 58% penetrating injury, median age 25-29 y/o, average Injury Severity Score 9, with an overall mortality of 3%) were included in the analysis. Massive transfusion was required by 7.4% of patients. Overall accuracy was found to be above 90% in all models tested. Following cross validation and model training, the random forest model outperformed the alternatively tested models for precision, recall, and area under the curve. CONCLUSION: Machine learning techniques may allow for more optimal and rapid identification of combat trauma patients at highest risk for massive transfusion. These powerful approaches may uncover novel correlations and help improve triage, activation of massive transfusion resources, and trauma-related outcomes. Further research seeking to optimize and apply these algorithms to trauma-centered research should be pursued.

Bike Helmet Usage in the Most Disadvantaged Neighborhoods: A Focused Area for Trauma Prevention.

INTRODUCTION: There is a paucity of data to describe how neighborhood socioeconomic disadvantage (NSD) correlates with childhood injuries and outcomes. This study assesses the relationship of NSD to bicycle safety and trauma outcomes among pediatric bicycle versus automobile injuries. METHODS: Between 2008 and 2018, patients ≤18 y old with bicycle versus automobile injuries from a Level I pediatric trauma center were evaluated. Area Deprivation Index (ADI) was used to measure NSD. Patient demographics, injury, clinical data characteristics, and bike safety were analyzed. Traffic scene data from the Statewide Integrated Traffic Records System were matched to clinical records. Multivariate logistic regression was used to assess demographic characteristics related to helmet usage. RESULTS: Among 321 patients, 84% were male with a median age of 12 y [interquartile range 9-13], and 44% were of Hispanic ethnicity. Hispanic ethnicity was greater in the most disadvantaged ADI groups (P < 0.001). Mortality occurred in two patients, and most (96%) were discharged home. Of Statewide Integrated Traffic Records System matched traffic records, 81% were at locations without a bike lane. No differences were found in GCS, intensive care unit admission, or length of stay by ADI. Hispanic ethnicity and the highest deprivation group were independently associated with lower odds of wearing a helmet (AOR 0.35, 95% confidence interval 0.1-0.9, P = 0.03; AOR 0.33 95% confidence interval 0.17-0.62; P = 0.001), while patient age and sex were unrelated to helmet usage. CONCLUSIONS: Outcomes for bike versus auto trauma remains similar across ADI groups. However, bike helmet usage is significantly lower among Hispanic children and those from neighborhoods with greater socioeconomic disadvantage.

Urinary 11-dehydrothromboxane B2 aspirin efficacy testing is sensitive to perioperative inflammation in pediatric solid-organ transplant patients.

BACKGROUND: Evidence for aspirin efficacy testing in pediatrics is limited, especially outside of cardiology, yet thrombotic events have high morbidity in other areas such as pediatric transplant surgery. Debates about whether thromboembolic events while on aspirin represent "aspirin resistance" or "high on-treatment platelet reactivity" persist, given the poor intertest agreement between testing platforms. PROCEDURE: This prospective observational study involved measuring aspirin efficacy using ex vivo testing of platelet aggregation (VerifyNow-Aspirin, VN) and urine 11-dehydrothromboxane B2 (AsprinWorks, UTxB2) contemporaneously at up to three time points after major noncardiac organ transplant surgery. The collection days (CD) were the second and seventh days after stable aspirin dosing and then a convalescent time point 2-9 months later. RESULTS: Fifty-five participants (age range, 0-21 years) were enrolled, having undergone total pancreatectomy with islet autotransplantation (N = 36), orthotopic liver transplantation (N = 18), and combined liver-kidney transplantation (N = 1). Platelet reactivity measured by VN remained unchanged, whereas UTxB2, which was elevated postoperatively, decreased significantly from CD1 to CD2 and CD3. Discordance in therapeutic efficacy was noted per manufacturer cutoffs, with therapeutic VN results in 86% of tests, whereas 12% of UTxB2 were therapeutic. Age-based stratification of UTxB2 results using previously published pediatric median levels increased overall UTxB2 therapeutic rates (80%) and intertest concordance (67% vs 27% if using adult range). No thrombotic events were observed. CONCLUSIONS: Our data suggest that urine thromboxane production may be an underappreciated reflection of postoperative inflammation. Validation of pediatric normal ranges for UTxB2 is a critical next step.

Analysis of Readmission and Complications After Repair of Orbital Fractures Using California's Office of Statewide Health Planning and Development Database.

BACKGROUND: Orbital fractures represent one of the most common trauma-related facial fractures and may present with a variety of concomitant injuries. Many factors including age, associated diagnoses, and fracture complications are important in determining surgical candidacy. We used a statewide database to determine the prevalence of orbital fractures, rates of surgical repair during initial admission, and early patient outcomes. METHODS: A longitudinal analysis of patients with orbital fracture was performed using California's Office of Statewide Health Planning and Development patient discharge database for admissions occurring between January 2015 and December 2018.Patients were identified using International Classification of Diseases, Tenth Revision codes. The primary risk factor was surgical management of orbital fractures. The primary outcomes of interest were readmission requiring surgical management and complications of the fracture. Survival models were developed to evaluate the risk of a repair at readmission adjusting for relevant covariates. RESULTS: Of the 67,408 facial fractures included in our study, 8.7% (n = 5872) were diagnosed with orbital fractures. Among this population, 18.4% (n = 1082) underwent surgical repair during their initial admission. Patients were primarily male (71.1%; n = 4,173) and presented in a nonurgent fashion (93.7%; n = 5501). Less than half (42.8%) of patients with an urgent presentation and 16.8% of patients with a nonurgent presentation underwent repair. Centers of Medicaid & Medicare Services guidelines dictated presentation classification. Repair was associated with a significantly higher survival outcome. Orbital fractures were more frequently repaired in the setting of concomitant zygomatic, nasal, and LeFort I-III fractures. Increased risk in complications was observed in all concomitant fracture groups, and there existed a decreased risk of postsurgical complications in these same cohorts. CONCLUSIONS: Although most orbital fractures were managed nonoperatively, our analysis found that rates of repair for orbital floor, maxillary, and zygomatic fractures were greater than for other facial fractures. Concomitant fractures were associated with an increased hazard ratio for complications. Although low in prevalence overall, the most often observed postoperative complications in this population were diplopia, glaucoma, and blindness/low vision.

Using the Disruptive Score to Identify Publications That Changed Plastic Surgery Practice.

PURPOSE: The impact of academic publications is often characterized by the total number of future citations. However, this metric does not adequately characterize the true impact in terms of changing practices or paradigms. A new metric called the "disruption score" (DS) has been developed and validated in nonsurgical publications. This study aims to use the DS to identify the most disruptive publications in plastic surgery.The DS, a ratio of 2 numbers, varies between -1 and +1. Scores closer to -1 are developing papers that summarize the known literature while papers closer to +1 are disruptive-they result in a paradigm shift in the field of study. METHODS: A search was performed for all articles from 1954 to 2014 in the following journals: Plastic and Reconstructive Surgery; Aesthetic Surgery Journal; Journal of Plastic, Reconstructive, and Aesthetic Surgery; Annals of Plastic Surgery; Aesthetic Plastic Surgery; Clinics in Plastic Surgery; and Plastic Surgery. The disruptive score was calculated for each article.The top 100 papers ranked by DS were examined and any editorials/viewpoints, publications with less than 26 citations, or less than 3 references were excluded because of their subjective nature and smaller academic contribution. The remaining 64 publications were analyzed for topic, study type, and citation count. RESULTS: A total of 32,622 articles were found with a DS range from 0.385 to 0.923. The mean score of the top 64 articles was 0.539 with an average citation count of 195 and 9 references. Plastic and Reconstructive Surgery had the most disruptive papers with 50. There were no randomized controlled trials with a majority of the studies being technical descriptions or case series. CONCLUSIONS: There are many ways to measure academic success, but there are fewer ways to measure the impact of academic contributions. The DS is a novel measurement that can demonstrate when an article results in a paradigm shift as opposed to just total citation count. When applied to the plastic surgery literature, the DS demonstrates that technical innovation and creativity are the most academically impactful. Future evaluations of academic success should include the DS to measure the quality of academic contributions.