Background: During the COVID-19 pandemic, public health measures to encourage social distancing have been implemented, including cancellation of school and organized sports. A resulting change in pediatric fracture epidemiology is expected. This study examines the impact of the COVID-19 pandemic on fracture incidence and characteristics. Methods: This is a retrospective cohort study comparing acute fractures presenting to a single level I pediatric trauma hospital during the COVID-19 pandemic with fractures during a prepandemic period at the same institution. The “pandemic” cohort was gathered from March 15 to April 15, 2020 and compared with a “prepandemic” cohort from the same time window in 2018 and 2019. Results: In total, 1745 patients presenting with acute fractures were included. There was a significant decrease in the incidence of fractures presenting to our practice during the pandemic (22.5±9.1/d vs. 9.6±5.1/d, P<0.001). The presenting age for all fractures decreased during the pandemic (7.5±4.3 vs. 9.4±4.4 y, P<0.001) because of decreased fracture burden among adolescents. There were also a decrease in the number of fractures requiring surgery (2.2±1.8/d vs. 0.8±0.8/d, P<0.001). During the pandemic, there was an increase in the proportion of injuries occurring at home (57.8% vs. 32.5%, P<0.001) or on bicycles (18.3% vs. 8.2%, P<0.001), but a decrease in those related to sports (7.2% vs. 26.0%, P<0.001) or playgrounds (5.2% vs. 9.0%, P<0.001). There was no increase in time-to-presentation. Patients with distal radius torus fractures were more likely to receive a velcro splint during the pandemic (44.2% vs. 25.9%, P=0.010). Conclusions: Pediatric fracture volume has decreased 2.5-fold during the COVID-19 pandemic, partially because of cessation of organized sports and decreased playground use. In endemic regions, lower trauma volume may allow redeployment of orthopaedic surgeons and staff to other clinical arenas. Given the rising proportion of bicycling injuries, an emphasis on basic safety precautions could improve public health. An observed increase in the prescription of velcro splints for distal radius fractures highlights an opportunity for simplified patient care during the pandemic. Level of Evidence: Level III.

Objective NMDA induced pial artery dilation (PAD) is reversed to vasoconstriction after fluid percussion brain injury (FPI). Tissue type plasminogen activator (tPA) is upregulated and the tPA antagonist, EEIIMD, prevents impaired NMDA PAD after FPI. Mitogen activated protein kinase (MAPK), a family of at least 3 kinases, ERK, p38 and JNK, is also upregulated after TBI. We hypothesize that tPA impairs NMDA induced cerebrovasodilation after FPI in a MAPK isoform dependent mechanism. Methods Lateral FPI was induced in newborn pigs. The closed cranial window technique was used to measure pial artery diameter and to collect CSF. ERK, p38, and JNK MAPK concentrations in CSF were quantified by ELISA. Results CSF JNK MAPK was increased by FPI, increased further by tPA, but blocked by JNK antagonists SP600125 and D-JNKI1. FPI modestly increased p38 and ERK isoforms of MAPK. NMDA induced PAD was reversed to vasoconstriction after FPI, whereas dilator responses to papaverine were unchanged. tPA, in post FPI CSF concentration, potentiated NMDA induced vasoconstriction while papaverine dilation was unchanged. SP 600125 and D-JNKI1, blocked NMDA induced vasoconstriction and fully restored PAD. The ERK antagonist U 0126 partially restored NMDA-induced PAD, while the p38 inhibitor SB203580 aggravated NMDA-induced vasoconstriction observed in the presence of tPA after FPI. Discussion These data indicate that tPA contributes to impairment of NMDA mediated cerebrovasodilation after FPI through JNK, while p38 may be protective. These data suggest that inhibition of the endogenous plasminogen activator system and JNK may improve cerebral hemodynamic outcome post TBI.

Objective Traumatic brain injury (TBI) contributes to morbidity in children and boys are disproportionately represented. Cerebral autoregulation is impaired after TBI, contributing to poor outcome. Cerebral Perfusion Pressure (CPP) is often normalized by use of vasopressors to increase MAP. In prior studies, we observed that phenylephrine prevented in female but exacerbated impairment of autoregulation in male piglets after fluid percussion injury (FPI). In contrast, dopamine prevented impairment of autoregulation in both sexes after FPI, suggesting that pressor choice impacts outcome. The ERK isoform of mitogen activated protein kinase (MAPK) produces hemodynamic impairment after FPI, but the role of the cytokine IL-6 is unknown. We investigated whether norepinephrine (NE) sex dependently protects autoregulation and limits histopathology after FPI and the role of ERK and IL-6 in that outcome. Design Prospective, randomized animal study. Setting University laboratory. Subjects Newborn (1–5 day old) pigs. Interventions CPP, CBF, and pial artery diameter were determined before and after FPI in piglets equipped with a closed cranial window and post treated with NE. CSF ERK MAPK was determined by ELISA. Measurements and Main Results NE does not protect autoregulation or prevent reduction in CBF in male but fully protects autoregulation in female piglets after FPI. Papaverine induced dilation was unchanged by FPI and NE. NE increased ERK MAPK upregulation in male but blocked such upregulation in female piglets after FPI. NE aggravated IL-6 upregulation in males in an ERK MAPK dependent mechanism but blocked IL-6 upregulation in females after FPI. NE augments loss of neurons in CA1 and CA3 hippocampus of male piglets after FPI in an ERK MAPK and IL-6 dependent manner, but prevents loss of neurons in females after FPI. Conclusions NE protects autoregulation and limits hippocampal neuronal cell necrosis via modulation of ERK MAPK and IL-6 after FPI in a sex dependent manner.

Objective TBI contributes to morbidity in children and boys are disproportionately represented. Autoregulation is impaired more in male compared to female piglets after TBI through sex dependent upregulation of the spasmogen ET-1 and ERK mitogen activated protein kinase (MAPK, a family of 3 kinases, ERK, p38 and JNK). Elevation of mean arterial pressure (MAP) leading to increased cerebral perfusion pressure (CPP) via phenylephrine (Phe) improves impairment of autoregulation after TBI in female but not male piglets through modulation of ET-1 and ERK MAPK upregulation, blocked in females, but aggravated in males. We hypothesized that pressor choice to elevate CPP is important in improving cerebral hemodynamics after TBI and that dopamine (DA) will prevent impairment of autoregulation in both male and female piglets through blockade of ET-1 and ERK MAPK. Design Prospective, randomized animal study. Setting University laboratory. Subjects Newborn (1–5 day old) pigs. Interventions CPP and pial artery diameter were determined before and after lateral fluid percussion brain injury was produced in piglets equipped with a closed cranial window. DA (15 μg/Kg/min iv) was administered 30 min post FPI. CSF ERK MAPK was determined by ELISA. Measurements and Main Results DA increased CPP equivalently in both sexes and prevented sex dependent reductions in pial artery diameter after FPI. Loss of pial artery dilation during hypotension was greater in male compared to female piglets after FPI, but DA prevented such impairment equivalently in both sexes post injury. ET-1 and ERK MAPK release was greater in male compared to female piglets after FPI, but DA also blocked their upregulation equivalently in male and female piglets after FPI. Conclusions These data indicate that DA is protective of autoregulation after FPI in both sexes. These observations advocate for the consideration of development of sex based therapies for treatment of hemodynamic sequalae of pediatric TBI.

Traumatic brain injury (TBI) contributes to morbidity in children, and boys are disproportionately represented. Cerebral autoregulation is impaired after TBI, contributing to poor outcome. Cerebral perfusion pressure (CPP) is often normalized by use of vasoactive agents to increase mean arterial pressure (MAP). In prior studies of 1-to 5-day-old newborn piglets, we observed that norepinephrine (NE) preferentially protected cerebral autoregulation and prevented hippocampal necrosis in females but not males after fluid percussion injury (FPI). The ERK isoform of mitogen activated protein kinase (MAPK) produces hemodynamic impairment after FPI, but less is known about the role of the cytokine interleukin-6 (IL-6). We investigated whether NE protects autoregulation and limits histopathology after FPI in older juvenile (4-week-old) pigs and the role of ERK and IL-6 in that outcome by sex. Results show that NE significantly protects autoregulation and prevents reduction in cerebral blood flow (CBF) in both male and female juvenile pigs after FPI; co-administration of the ERK antagonist U 0126 with NE fully protects both indices of outcome. Papaverine induced dilation was unchanged by FPI and NE. NE blunted ERK MAPK and IL-6 upregulation in both males and females after FPI. NE attenuated loss of neurons in CA1 and CA3 hippocampus of males and females after FPI. These data indicate that NE protects autoregulation and limits hippocampal neuronal cell necrosis via blockade of ERK and IL-6 after FPI in both male and female juvenile pigs. These data suggest that use of NE to improve outcome after TBI is both sex and age dependent.

PurposeObstructive sleep apnea (OSA) is a highly prevalent disorder associated with increased risk for cardiovascular disease, diabetes, and other chronic conditions. Unfortunately, up to 90% of individuals with OSA remain without a diagnosis or therapy. We assess the relationship between OSA and blood biomarkers, and test the hypothesis that combinations of markers provide a characteristic OSA signature with diagnostic screening value. This validation study was conducted in an independent cohort in order to replicate findings from a prior feasibility study.Patients and methodsThis multicenter prospective study consecutively enrolled adult male subjects with clinically suspected OSA. All subjects underwent overnight sleep studies. An asymptomatic control group was also obtained. Five biomarkers were tested: glycated hemoglobin (HbA1c), C-reactive protein (CRP), uric acid, erythropoietin (EPO), and interleukin-6 (IL-6).ResultsThe study enrolled 264 subjects. The combination of HbA1c+CRP+EPO (area under the curve 0.78) was superior to the Epworth Sleepiness Scale (ESS; 0.53) and STOP-Bang (0.70) questionnaires. In non-obese subjects, the combination of biomarkers (0.75) was superior to body mass index (BMI; 0.61). Sensitivity and specificity results, respectively, were: HbA1c+CRP+EPO (81% and 60%), ESS (78% and 19%), STOP-Bang (75% and 52%), BMI (81% and 56%), and BMI in non-obese patients (81% and 38%).ConclusionWe verify our hypothesis and replicate our prior feasibility findings that OSA is associated with a characteristic signature cluster of biomarker changes in men. Concurrent elevations of HbA1c, CRP, and EPO levels should generate a high suspicion of OSA and may have utility as an OSA screening tool. Biomarker combinations correlate with OSA severity and, therefore, may assist sleep centers in identifying and triaging higher risk patients for sleep study diagnosis and treatment.

Traumatic brain injury (TBI) contributes to morbidity in children, and boys are disproportionately represented. Endothelin-1 (ET-1) contributes to impaired autoregulation via oxygen (O 2 -) after TBI in piglets, but its relative role in males compared with females has not been previously investigated. Increased cerebral perfusion pressure (CPP) via phenylephrine (Phe) sex dependently improves impairment of autoregulation after TBI through modulation of extracellular signal-related kinase (ERK) mitogen-activated protein kinase (MAPK) upregulation, aggravated in males, but blocked in females. Activation of adenosine-5'-triphosphate (ATP) and Ca sensitive K channels produce vasodilation, contributing to autoregulation. We hypothesized that ET-1 upregulation is greater in males after TBI and that disturbed autoregulation will be prevented by Phe in a sex-dependent manner through modulation of ET-1, O 2 -, and ERK. Results show that ET-1 release was greater in males after fluid percussion injury (FPI), blunted by Phe in females, but aggravated in males. K channel vasodilation was impaired more in males than in females after TBI. Phe prevented reductions in K channel vasodilation in females, but further reduced dilation in males after TBI. Co-administration of BQ-123, U0126, or PEG-SOD (ET-1, ERK antagonist, and O 2 -scavenger) with Phe restored dilation to K agonists and hypotension in males after TBI. ERK upregulation was blocked by BQ-123 and PEG-SOD. These data indicate that TBI upregulates ET-1 more in males than in females. Elevation of CPP with Phe sex dependently prevents impairment of cerebral autoregulation after TBI through modulation of ET-1, O 2 -, and ERK mediated impairment of K channel vasodilation. These observations advocate for the consideration of development of sex-based therapies for the treatment of hemodynamic sequelae of pediatric TBI.

The sole FDA-approved treatment for acute stroke is recombinant tissue-type plasminogen activator (rtPA). However, rtPA aggravates the impairment of cerebrovasodilation induced by global hypoxia/ischemia; this impairment is attenuated by the preinjury treatment with the plasminogen activator inhibitor derivative EEIIMD. MAPK (a family of kinases, p38, and JNK) is upregulated after cerebral ischemia. In this study, we determined whether the novel plasminogen activator inhibitor-derived peptide, Ac-RMAPEEIIMDRPFLYVVR-amide, (PAI-1-DP) given 30 min before or 2 h after, focal central nervous system injury induced by photothrombosis would preserve responses to cerebrovasodilators and the role of p38 and JNK MAPK in such effects. Cerebrospinal fluid JNK and p38 levels were elevated by photothrombotic injury, an effect potentiated by rtPA. Cerebrovasodilation was blunted by photothrombosis and reversed to vasoconstriction by rtPA but restored to dilation by PAI-1-DP pre- and posttreatment. PAI-1-DP blocked JNK, but preserved p38 MAPK upregulation after photothrombosis. The JNK MAPK antagonist SP600125 prevented, and the p38 antagonist SB203580 potentiated, impaired cerebrovasodilation after photothrombosis. These data indicate that rtPA impairs cerebrovasodilation after injury by activating JNK, while p38 MAPK is protective, and that the novel peptide PAI-1-DP protects by inhibiting activation of JNK by rtPA. JNK MAPK inhibitors, including PAI-1-DP, may offer a novel approach to increase the benefit-to-risk ratio of thrombolytic therapy and enable its use in central nervous system ischemic disorders.