Nonfatal Emergency Department Visits Associated with Fall-Related Fractured Skulls of Infants Aged 0-4 Months.

BACKGROUND: Children aged 0-4 years have the highest rate of emergency department (ED) visits for traumatic brain injury (TBI); falls are the leading cause. Infants younger than 2 years are more likely to sustain a fractured skull after a fall. OBJECTIVE: This study examined caregiver actions and products associated with ED visits for fall-related fractured skulls in infants aged 0-4 months. METHODS: Data were analyzed from the 2001-2017 National Electronic Injury Surveillance System-All Injury Program. Case narratives of infants aged 0-4 months who visited an ED for a fall-related skull fracture were examined to code caregiver actions preceding the fall. Product codes determined fall location and product type involved (e.g., flooring, bed, or stairs). All national estimates were weighted. RESULTS: There were more than 27,000 ED visits (weighted estimate) of infants aged 0-4 months for a nonfatal fall-related fractured skull between 2001 and 2017. Most were younger than 2 months (46.7%) and male (54.4%). Falls occurred primarily in the home (69.9%) and required hospitalization (76.4%). Primary caregiver actions coded involved placing (58.6%), dropping (22.7%), and carrying an infant (16.6%). Floor surfaces were the most common product (mentioned in 24.0% of the cases). CONCLUSIONS: Fall-related fractured skulls are a health and developmental concern for infants, highlighting the importance of a comprehensive assessment at the time of the injury to better understand adult actions. Findings indicated the need to develop prevention messages that include safe carrying and placement of infants.

Quantifying head impact exposure, mechanisms and kinematics using instrumented mouthguards in female high school lacrosse.

Current debate exists regarding the need for protective headwear in female lacrosse. To inform this issue, the current study quantified head impact exposure, mechanisms and kinematics in female lacrosse using instrumented mouthguards. A female high school varsity lacrosse team of 17 players wore the Stanford Instrumented Mouthguard (MiG) during 14 competitive games. Video footage was reviewed to remove false-positive recordings and verify head impacts, which resulted in a rate of 0.32 head impacts per athlete-exposure. Of the 31 video-confirmed head impacts, 54.8% were identified as stick contacts, 38.7% were player contacts and 6.5% were falls. Stick contacts had the greatest peak head kinematics. The most common impact site was the side of the head (35.5%), followed by the face/jaw (25.8%), forehead (6.5%), and crown (6.5%). Impacts to the face/jaw region of the head had significantly (p < 0.05) greater peak kinematics compared to other regions of the head, which may have resulted from the interaction of the impacting surface, or the lower jaw, and the sensor. The current study provides initial data regarding the frequency, magnitude and site of impacts sustained in female high school lacrosse. A larger sample size of high quality head impact data in female lacrosse is required to confirm these findings.

Differentiating children with sepsis with and without acute respiratory distress syndrome using proteomics.

Both sepsis and acute respiratory distress syndrome (ARDS) rely on imprecise clinical definitions leading to heterogeneity, which has contributed to negative trials. Because circulating protein/DNA complexes have been implicated in sepsis and ARDS, we aimed to develop a proteomic signature of DNA-bound proteins to discriminate between children with sepsis with and without ARDS. We performed a prospective case-control study in 12 children with sepsis with ARDS matched to 12 children with sepsis without ARDS on age, severity of illness score, and source of infection. We performed co-immunoprecipitation and downstream proteomics in plasma collected ≤ 24 h of intensive care unit admission. Expression profiles were generated, and a random forest classifier was used on differentially expressed proteins to develop a signature which discriminated ARDS. The classifier was tested in six independent blinded samples. Neutrophil and nucleosome proteins were over-represented in ARDS, including two S100A proteins, superoxide dismutase (SOD), and three histones. Random forest produced a 10-protein signature that accurately discriminated between children with sepsis with and without ARDS. This classifier perfectly assigned six independent blinded samples as having ARDS or not. We validated higher expression of the most informative discriminating protein, galectin-3-binding protein, in children with ARDS. Our methodology has applicability to isolation of DNA-bound proteins from plasma. Our results support the premise of a molecular definition of ARDS, and give preliminary insight into why some children with sepsis, but not others, develop ARDS.

Eye Tracking Metrics Differences among Uninjured Adolescents and Those with Acute or Persistent Post-Concussion Symptoms.

SIGNIFICANCE: Eye tracking assessments that include pupil metrics can supplement current clinical assessments of vision and autonomic dysfunction in concussed adolescents. PURPOSE: This study aimed to explore the utility of a 220-second eye tracking assessment in distinguishing eye position, saccadic movement, and pupillary dynamics among uninjured adolescents, those with acute post-concussion symptoms (≤28 days since concussion), or those with persistent post-concussion symptoms (>28 days since concussion). METHODS: Two hundred fifty-six eye tracking metrics across a prospective observational cohort of 180 uninjured adolescents recruited from a private suburban high school and 224 concussed adolescents, with acute or persistent symptoms, recruited from a tertiary care subspecialty concussion care program, 13 to 17 years old, from August 2017 to June 2021 were compared. Kruskal-Wallis tests were used, and Bonferroni corrections were applied to account for multiple comparisons and constructed receiver operating characteristic curves. Principal components analysis and regression models were applied to determine whether eye tracking metrics can augment clinical and demographic information in differentiating uninjured controls from concussed adolescents. RESULTS: Two metrics of eye position were worse in those with concussion than uninjured adolescents, and only one metric was significantly different between acute cases and persistent cases. Concussed adolescents had larger left and right mean, median, minimum, and maximum pupil size than uninjured controls. Concussed adolescents had greater differences in mean, median, and variance of left and right pupil size. Twelve metrics distinguished female concussed participants from uninjured; only four were associated with concussion status in males. A logistic regression model including clinical and demographics data and transformed eye tracking metrics performed better in predicting concussion status than clinical and demographics data alone. CONCLUSIONS: Objective eye tracking technology is capable of quickly identifying vision and pupillary disturbances after concussion, augmenting traditional clinical concussion assessments. These metrics may add to existing clinical practice for monitoring recovery in a heterogeneous adolescent concussion population.

Integrating Human and Nonhuman Primate Data to Estimate Human Tolerances for Traumatic Brain Injury.

Traumatic brain injury (TBI) contributes to a significant portion of the injuries resulting from motor vehicle crashes, falls, and sports collisions. The development of advanced countermeasures to mitigate these injuries requires a complete understanding of the tolerance of the human brain to injury. In this study, we developed a new method to establish human injury tolerance levels using an integrated database of reconstructed football impacts, subinjurious human volunteer data, and nonhuman primate data. The human tolerance levels were analyzed using tissue-level metrics determined using harmonized species-specific finite element (FE) brain models. Kinematics-based metrics involving complete characterization of angular motion (e.g., diffuse axonal multi-axial general evaluation (DAMAGE)) showed better power of predicting tissue-level deformation in a variety of impact conditions and were subsequently used to characterize injury tolerance. The proposed human brain tolerances for mild and severe TBI were estimated and presented in the form of injury risk curves based on selected tissue-level and kinematics-based injury metrics. The application of the estimated injury tolerances was finally demonstrated using real-world automotive crash data.

Assessment of Saccades and Gaze Stability in the Diagnosis of Pediatric Concussion.

OBJECTIVE: To evaluate the discriminatory ability of different repetition increments of saccades and gaze stability testing for diagnosing concussion in adolescents. DESIGN: Cross-sectional. SETTING: Suburban high school and academic pediatric tertiary care center. PARTICIPANTS: Sixty-nine adolescent athletes within 28 days of a sports- or recreation-related concussion and 69 adolescent athletes without recent concussion. ASSESSMENT OF INDEPENDENT VARIABLES: Symptom provocation with horizontal and vertical saccades and gaze stability testing performed up to 30 repetitions. MAIN OUTCOME MEASURES: Sensitivity and specificity at 10-repetition increments (≤10, ≤20, ≤30) and area under the receiver operating characteristic curves (AUC) of a visio-vestibular examination (VVE) subscore, scored 0 to 4 based on the number of assessments with symptom provocation, at each repetition increment. RESULTS: Sensitivity improved when increasing from ≤10 to ≤20 to ≤30 repetitions for horizontal (25% to 50% to 69%) and vertical (32% to 52% to 74%) saccades and horizontal (19% to 45% to 71%) and vertical (23% to 45% to 72%) gaze stability. Specificity was comparable at ≤10 and ≤20 repetitions, but decreased at ≤30 repetitions across assessments. For a VVE subscore (0-4) based on the number of symptomatic assessments, the discriminatory ability of the test was highest at ≤20 repetitions (AUC of 0.79) with an optimal subscore of one (sensitivity 59%, specificity 96%). CONCLUSIONS: A VVE including a higher threshold level of repetitions for saccades and gaze stability has improved discriminatory ability for concussion, with an optimized AUC of 0.79 at ≤20 repetitions. CLINICAL RELEVANCE: The findings in this study suggest that a higher threshold level of repetitions of 2 commonly used visio-vestibular assessments enables clinicians to more accurately diagnose youth concussion.

Laboratory Assessment of a Headband-Mounted Sensor for Measurement of Head Impact Rotational Kinematics.

Head impact sensors measure head kinematics in sports, and sensor accuracy is crucial for investigating the potential link between repetitive head loading and clinical outcomes. Many validation studies mount sensors to human head surrogates and compare kinematic measures during loading from a linear impactor. These studies are often unable to distinguish intrinsic instrumentation limitations from variability caused by sensor coupling. The aim of the current study was to evaluate intrinsic sensor error in angular velocity in the absence of coupling error for a common head impact sensor. Two Triax SIM-G sensors were rigidly attached to a preclinical rotational injury device and subjected to rotational events to assess sensor reproducibility and accuracy. Peak angular velocities between the SIM-G sensors paired for each test were correlated (R2 > 0.99, y = 1.00x, p < 0.001). SIM-G peak angular velocity correlated with the reference (R2 = 0.96, y = 0.82x, p < 0.001); however, SIM-G underestimated the magnitude by 15.0% ± 1.7% (p < 0.001). SIM-G angular velocity rise time (5% to 100% of peak) correlated with the reference (R2 = 0.97, y = 1.06x, p < 0.001) but exhibited a slower fall time (100% to 5% of peak) by 9.0 ± 3.7 ms (p < 0.001). Assessing sensor performance when rigidly coupled is a crucial first step to interpret on-field SIM-G rotational kinematic data. Further testing in increasing biofidelic conditions is needed to fully characterize error from other sources, such as coupling.

Proceedings From the Ice Hockey Summit III: Action on Concussion.

OBJECTIVES: The Ice Hockey Summit III provided updated scientific evidence on concussions in hockey to inform these 5 objectives: (1) describe sport related concussion (SRC) epidemiology; (2) classify prevention strategies; (3) define objective, diagnostic tests; (4) identify treatment; and (5) integrate science and clinical care into prioritized action plans and policy. METHODS: Our action plan evolved from 40 scientific presentations. The 155 attendees (physicians, athletic trainers, physical therapists, nurses, neuropsychologists, scientists, engineers, coaches, and officials) voted to prioritize these action items in the final Summit session. RESULTS: To (1) establish a national and international hockey database for SRCs at all levels; (2) eliminate body checking in Bantam youth hockey games; (3) expand a behavior modification program (Fair Play) to all youth hockey levels; (4) enforce game ejection penalties for fighting in Junior A and professional hockey leagues; (5) establish objective tests to diagnose concussion at point of care; and (6) mandate baseline testing to improve concussion diagnosis for all age groups. CONCLUSIONS: Expedient implementation of the Summit III prioritized action items is necessary to reduce the risk, severity, and consequences of concussion in the sport of ice hockey.

Comparison of Video-Identified Head Contacts and Sensor-Recorded Events in High School Soccer.

Field studies have evaluated the accuracy of sensors to measure head impact exposure using video analysis, but few have studied false negatives. Therefore, the aim of the current study was to investigate the proportion of potential false negatives in high school soccer head impact data. High school athletes (23 females and 31 males) wore headband-mounted Smart Impact Monitor-G impact sensors during competitive soccer games. Video footage from 41 varsity games was analyzed by 2 independent reviewers to identify head contact events, which were defined as visually observed contact to the head. Of the 1991 video-identified head contact events for which sensors were functioning and worn by the players, 1094 (55%) were recorded by the sensors. For female players, 45% of video-identified head contact events were recorded by the sensor compared with 59% for male players. For both females and males, sensitivity varied by impact mechanism. By quantifying the proportion of potential false negatives, the sensitivity of a sensor can be characterized, which can inform the interpretation of previous studies and the design of future studies using head impact sensors. Owing to the difficulty in obtaining ground truth labels of head impacts, video review should be considered a complementary tool to head impact sensors.

Target detection in healthy 4-week old piglets from a passive two-tone auditory oddball paradigm.

BACKGROUND: Passive auditory oddball tests are effort independent assessments that evaluate auditory processing and are suitable for paediatric patient groups. Our goal was to develop a two-tone auditory oddball test protocol and use this clinical assessment in an immature large animal model. Event-related potentials captured middle latency P1, N1, and P2 responses in 4-week old (N = 16, female) piglets using a custom piglet 32- electrode array on 3 non-consecutive days. The effect of target tone frequency (250 Hz and 4000 Hz) on middle latency responses were tested in a subset of animals. RESULTS: Results show that infrequent target tone pulses elicit greater N1 amplitudes than frequent standard tone pulses. There was no effect of day. Electrodes covering the front of the head tend to elicit greater waveform responses. P2 amplitudes increased for higher frequency target tones (4000 Hz) than the regular 1000 Hz target tones (p < 0.05). CONCLUSIONS: Two-tone auditory oddball tests produced consistent responses day-to-day. This clinical assessment was successful in the immature large animal model.

Head Rotational Kinematics, Tissue Deformations, and Their Relationships to the Acute Traumatic Axonal Injury.

Head rotational kinematics and tissue deformation metrics obtained from finite element models (FEM) have the potential to be used as traumatic axonal injury (TAI) assessment criteria and headgear evaluation standards. These metrics have been used to predict the likelihood of TAI occurrence; however, their ability in the assessment of the extent of TAI has not been explored. In this study, a pig model of TAI was used to examine a wide range of head loading conditions in two directions. The extent of TAI was quantified through histopathology and correlated to the FEM-derived tissue deformations and the head rotational kinematics. Peak angular acceleration and maximum strain rate of axonal fiber and brain tissue showed relatively good correlation to the volume of axonal injury, with similar correlation trends for both directions separately or combined. These rotational kinematics and tissue deformations can estimate the extent of acute TAI. The relationships between the head kinematics and the tissue strain, strain rate, and strain times strain rate were determined over the experimental range examined herein, and beyond that through parametric simulations. These relationships demonstrate that peak angular velocity and acceleration affect the underlying tissue deformations and the knowledge of both help to predict TAI risk. These relationships were combined with the injury thresholds, extracted from the TAI risk curves, and the kinematic-based risk curves representing overall axonal and brain tissue strain and strain rate were determined for predicting TAI. After scaling to humans, these curves can be used for real-time TAI assessment.

Using Serum Amino Acids to Predict Traumatic Brain Injury: A Systematic Approach to Utilize Multiple Biomarkers.

Traumatic brain injury (TBI) can cause biochemical and metabolomic alterations in the brain tissue and serum. These alterations can be used for diagnosis and prognosis of TBI. Here, the serum concentrations of seventeen amino acids (AA) were studied for their potential utility as biomarkers of TBI. Twenty-five female, 4-week-old piglets received diffuse (n = 13) or focal (n = 12) TBI. Blood samples were obtained both pre-injury and at either 24-h or 4-days post-TBI. To find a robust panel of biomarkers, the results of focal and diffuse TBIs were combined and multivariate logistic regression analysis, coupled with the best subset selection technique and repeated k-fold cross-validation method, was used to perform a thorough search of all possible subsets of AAs. The combination of serum glycine, taurine, and ornithine was optimal for TBI diagnosis, with 80% sensitivity and 86% overall prediction rate, and showed excellent TBI diagnostic performance, with 100% sensitivity and 78% overall prediction rate, on a separate validation dataset including four uninjured and five injured animals. We found that combinations of biomarkers outperformed any single biomarker. We propose this 3-AA serum biomarker panel to diagnose mild-to-moderate focal/diffuse TBI. The systematic approaches implemented herein can be used for combining parameters from various TBI assessments to develop/evaluate optimal multi-factorial diagnostic/prognostic TBI metrics.

Infant skull fracture risk for low height falls.

Skull fractures are common injuries in young children, typically caused by accidental falls and child abuse. The paucity of detailed biomechanical data from real-world trauma in children has hampered development of biomechanical thresholds for skull fracture in infants. The objectives of this study were to identify biomechanical metrics to predict skull fracture, determine threshold values associated with fracture, and develop skull fracture risk curves for low-height falls in infants. To achieve these objectives, we utilized an integrated approach consisting of case evaluation, anthropomorphic reconstruction, and finite element simulation. Four biomechanical candidates for predicting skull fracture were identified (first principal stress, first principal strain, shear stress, and von Mises stress) and evaluated against well-witnessed falls in infants (0-6 months). Among the predictor candidates, first principal stress and strain correlated best with the occurrence of parietal skull fracture. The principal stress and strain thresholds associated with 50 and 95% probability of parietal skull fracture were 25.229 and 36.015 MPa and 0.0464 and 0.0699, respectively. Risk curves using these predictors determined that infant falls from 0.3 m had a low probability (0-54%) to result in parietal skull fracture, particularly with carpet impact (0-1%). Head-first falls from 0.9 m had a high probability of fracture (86-100%) for concrete impact and a moderate probability (34-81%) for carpet impact. Probabilities of fracture in 0.6 m falls were dependent on impact surface. Occipital impacts from 0.9 m onto the concrete also had the potential (27-90% probability) to generate parietal skull fracture. These data represent a multi-faceted biomechanical assessment of infant skull fracture risk and can assist in the differential diagnosis for head trauma in children.

HER2 Signaling Implicated in Regulating Alveolar Epithelial Permeability with Cyclic Stretch.

Mechanical ventilation can be damaging, and can cause or exacerbate ventilator-induced lung injury (VILI). The human epidermal growth factor receptor (HER) ligand neuregulin-1 (NRG1) activates HER2 heterodimerization with HER3, and has been implicated in inflammatory injuries. We hypothesized that HER2 activation contributes to VILI. We analyzed a database of differentially expressed genes between cyclically stretched and unstretched rat alveolar epithelial cells (RAEC) for HER ligands and validated the differential expression. The effect of the ligand and HER2 inhibition on RAEC permeability was tested, and in vivo relevance was assessed in a rat model of VILI. Analysis of our expression array revealed the upregulation of NRG1 and amphiregulin (AREG) with stretch. NRG1 protein, but not AREG, increased after stretch in culture media. Treatment with an NRG1-cleavage inhibitor (TAPI2) or an inhibitor of NRG1-binding (anti-HER3 antibody) reduced HER2 phosphorylation and partially mitigated stretch-induced permeability, with the upregulation of claudin-7. The results were reproduced by treatment with a direct inhibitor of HER2 phosphorylation (AG825). The transfection of microRNA miR-15b, predicted to negatively regulate NRG1, also attenuated stretch-induced permeability, and was associated with lower NRG1 mRNA levels. In rats ventilated at damaging tidal volumes, AG825 partly attenuated VILI. We concluded that cyclic stretch activates HER2 via the HER3 ligand NRG1, leading to increased permeability. Outcomes were mitigated by the downregulation of NRG1, prevention of NRG1 binding, and most strongly by the direct inhibition of HER2. In vivo HER2 inhibition also attenuated VILI. Ligand-dependent HER2 activation is a potential target for reducing VILI.

Proceedings from the Ice Hockey Summit III: Action on Concussion.

The Ice Hockey Summit III provided updated scientific evidence on concussions in hockey to inform these five objectives: 1) describe sport-related concussion (SRC) epidemiology, 2) classify prevention strategies, 3) define objective, diagnostic tests, 4) identify treatment, and 5) integrate science and clinical care into prioritized action plans and policy. Our action plan evolved from 40 scientific presentations. The 155 attendees (physicians, athletic trainers, physical therapists, nurses, neuropsychologists, scientists, engineers, coaches, and officials) voted to prioritize these action items in the final Summit session. 1) Establish a national and international hockey data base for SRC at all levels, 2) eliminate body checking in Bantam youth hockey games, 3) expand a behavior modification program (Fair Play) to all youth hockey levels, 4) enforce game ejection penalties for fighting in Junior A and professional hockey leagues, 5) establish objective tests to diagnose concussion at point of care (POC), and 6) mandate baseline testing to improve concussion diagnosis for all age groups. Expedient implementation of the Summit III prioritized action items is necessary to reduce the risk, severity, and consequences of concussion in the sport of ice hockey.

Improved prediction of direction-dependent, acute axonal injury in piglets.

To guide development of safety equipment that reduces sports-related head injuries, we sought to enhance predictive relationships between head movement and acute axonal injury severity. The severity of traumatic brain injury (TBI) is influenced by the magnitude and direction of head kinematics. Previous studies have demonstrated correlation between rotational head kinematics and symptom severity in the adult. More recent studies have demonstrated brain injury age- and direction-dependence, relating head kinematics to white matter tract-oriented strains. We have recently developed and assessed novel rotational head kinematic parameters as predictors of white matter damage in the female immature piglet. We show that many previously published rotational kinematic injury predictor metrics poorly predict acute axonal pathology induced by rapid, non-impact head rotations and that inclusion of cerebral moments of inertia (MOI) in rotational head injury metrics refines prediction of diffuse axonal injury following rapid head rotations for two immature age groups. Rotational Work (RotWork) was the best significant predictor of traumatic axonal injury in both newborn and pre-adolescent piglets following head rotations in the axial, coronal, and sagittal planes. An improvement over current metrics, we find that RotWork, which incorporates head rotation rate, direction, and brain shape, significantly enhanced acute traumatic axonal injury prediction. For similar injury extent, the RotWork threshold is lower for the newborn piglet than the pre-adolescent.

Protein kinase R-like endoplasmatic reticulum kinase is a mediator of stretch in ventilator-induced lung injury.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a severe form of lung injury characterized by damage to the epithelial barrier with subsequent pulmonary edema and hypoxic respiratory failure. ARDS is a significant medical problem in intensive care units with associated high care costs. There are many potential causes of ARDS; however, alveolar injury associated with mechanical ventilation, termed ventilator-induced lung injury (VILI), remains a well-recognized contributor. It is thus critical to understand the mechanism of VILI. Based on our published preliminary data, we hypothesized that the endoplasmic reticulum (ER) stress response molecule Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK) plays a role in transmitting mechanosensory signals the alveolar epithelium. METHODS: ER stress signal responses to mechanical stretch were studied in ex-vivo ventilated pig lungs. To explore the effect of PERK inhibition on VILI, we ventilated live rats and compared lung injury parameters to non-ventilated controls. The effect of stretch-induced epithelial ER Ca2+ signaling on PERK was studied in stretched alveolar epithelial monolayers. To confirm the activation of PERK in human disease, ER stress signaling was compared between ARDS and non-ARDS lungs. RESULTS: Our studies revealed increased PERK-specific ER stress signaling in response to overstretch. PERK inhibition resulted in dose-dependent improvement of alveolar inflammation and permeability. Our data indicate that stretch-induced epithelial ER Ca2+ release is an activator of PERK. Experiments with human lung tissue confirmed PERK activation by ARDS. CONCLUSION: Our study provides evidences that PERK is a mediator stretch signals in the alveolar epithelium.

Integrated Stress Response Mediates Epithelial Injury in Mechanical Ventilation.

Ventilator-induced lung injury (VILI) is a severe complication of mechanical ventilation that can lead to acute respiratory distress syndrome. VILI is characterized by damage to the epithelial barrier with subsequent pulmonary edema and profound hypoxia. Available lung-protective ventilator strategies offer only a modest benefit in preventing VILI because they cannot impede alveolar overdistension and concomitant epithelial barrier dysfunction in the inflamed lung regions. There are currently no effective biochemical therapies to mitigate injury to the alveolar epithelium. We hypothesize that alveolar stretch activates the integrated stress response (ISR) pathway and that the chemical inhibition of this pathway mitigates alveolar barrier disruption during stretch and mechanical ventilation. Using our established rat primary type I-like alveolar epithelial cell monolayer stretch model and in vivo rat mechanical ventilation that mimics the alveolar overdistension seen in acute respiratory distress syndrome, we studied epithelial responses to mechanical stress. Our studies revealed that the ISR signaling pathway is a key modulator of epithelial permeability. We show that prolonged epithelial stretch and injurious mechanical ventilation activate the ISR, leading to increased alveolar permeability, cell death, and proinflammatory signaling. Chemical inhibition of protein kinase RNA-like endoplasmic reticulum kinase, an upstream regulator of the pathway, resulted in decreased injury signaling and improved barrier function after prolonged cyclic stretch and injurious mechanical ventilation. Our results provide new evidence that therapeutic targeting of the ISR can mitigate VILI.

Circulating nucleosomes are associated with mortality in pediatric acute respiratory distress syndrome.

Mechanisms underlying pediatric acute respiratory distress syndrome (PARDS) are poorly understood. The recent implication of circulating nucleosomes as pathogenic in sepsis and trauma-associated ARDS in adults led us to investigate the significance of nucleosomes in PARDS. We conducted a prospective, observational study on children with PARDS at the Children's Hospital of Philadelphia between July 2014 and September 2015. Plasma was collected within 48 h of PARDS onset and nucleosomes quantified by enzyme-linked immunosorbent assay. Samples from 76 children with PARDS (11 deaths, 14%) were collected early [median 15 (IQR 7, 21) h] after PARDS onset. Nucleosome levels were higher in nonsurvivors [0.59 AU (IQR 0.46, 0.84)] relative to survivors [0.21 AU (IQR 0.08, 0.33), rank sum P < 0.001]. Nucleosome levels were not associated with either Berlin (P = 0.845) or PALICC (P = 0.886) oxygenation categories, nor with etiology of PARDS (P = 0.527). Nucleosomes were correlated with increasing numbers of nonpulmonary organ failures (P = 0.009 for trend), and were higher in patients whose PaO2 /FiO2 worsened (P = 0.012) over the first 72 h of PARDS. In regression analysis, nucleosome levels were independently associated with mortality after adjusting for either age, severity of illness score, number of nonpulmonary organ failures, vasopressor score, or PaO2 /FiO2 (all P < 0.05). In conclusion, plasma nucleosome levels in early PARDS were associated with increased mortality, correlated with number of nonpulmonary organ failures, and preceded worsening oxygenation. The potential utility of this biomarker for prognostication, risk stratification, and mechanistic insight should be investigated further.