Optimal Volume of Moderate-to-Vigorous Physical Activity Postconcussion in Children and Adolescents.

Importance: Determining the optimal volume of early moderate-to-vigorous-intensity physical activity (MVPA) after concussion and its association with subsequent symptom burden is important for early postinjury management recommendations. Objectives: To investigate the association between cumulative MVPA (cMVPA) over 2 weeks and subsequent symptom burden at 1 week, 2 weeks, and 4 weeks postinjury in children and examine the association between cMVPA and odds of persisting symptoms after concussion (PSAC) at 2 weeks and 4 weeks postinjury. Design, Setting, and Participants: This multicenter cohort study used data from a randomized clinical trial that was conducted from March 2017 to December 2019 at 3 Canadian pediatric emergency departments in participants aged 10.00 to 17.99 years with acute concussion of less than 48 hours. Data were analyzed from July 2022 to December 2023. Exposure: cMVPA postinjury was measured with accelerometers worn on the waist for 24 hours per day for 13 days postinjury, with measurements deemed valid if participants had 4 or more days of accelerometer data and 3 or fewer consecutive days of missing data. cMVPA at 1 week and 2 weeks postinjury was defined as cMVPA for 7 days and 13 days postinjury, respectively. Multiple imputations were carried out on missing MVPA days. Main Outcomes and measures: Self-reported postconcussion symptom burden at 1 week, 2 weeks, and 4 weeks postinjury using the Health and Behavior Inventory (HBI). PSAC was defined as reliable change on the HBI. A linear mixed-effect model was used for symptom burden at 1 week, 2 weeks, and 4 weeks postinjury with a time × cMVPA interaction. Logistic regressions assessed the association between cMVPA and PSAC. All models were adjusted for prognostically important variables. Results: In this study, 267 of 456 children (119 [44.6%] female; median [IQR] age, 12.9 [11.5 to 14.4] years) were included in the analysis. Participants with greater cMVPA had significantly lower HBI scores at 1 week (75th percentile [258.5 minutes] vs 25th percentile [90.0 minutes]; difference, -5.45 [95% CI, -7.67 to -3.24]) and 2 weeks postinjury (75th percentile [565.0 minutes] vs 25th percentile [237.0 minutes]; difference, -2.85 [95% CI, -4.74 to -0.97]) but not at 4 weeks postinjury (75th percentile [565.0 minutes] vs 25th percentile [237.0 minutes]; difference, -1.24 [95% CI, -3.13 to 0.64]) (P = .20). Symptom burden was not lower beyond the 75th percentile for cMVPA at 1 week or 2 weeks postinjury (1 week, 259 minutes; 2 weeks, 565 minutes) of cMVPA. The odds ratio for the association between 75th and 25th percentile of cMVPA and PSAC was 0.48 (95% CI, 0.24 to 0.94) at 2 weeks. Conclusions and Relevance: In children and adolescents with acute concussion, 259 minutes of cMVPA during the first week postinjury and 565 minutes of cMVPA during the second week postinjury were associated with lower symptom burden at 1 week and 2 weeks postinjury. At 2 weeks postinjury, higher cMVPA volume was associated with 48% reduced odds of PSAC compared with lower cMVPA volume.

Severe outcomes following pediatric cannabis intoxication: a prospective cohort study of an international toxicology surveillance registry.

INTRODUCTION: An increasing number of jurisdictions have legalized recreational cannabis for adult use. The subsequent availability and marketing of recreational cannabis has led to a parallel increase in rates and severity of pediatric cannabis intoxications. We explored predictors of severe outcomes in pediatric patients who presented to the emergency department with cannabis intoxication. METHODS: In this prospective cohort study, we collected data on all pediatric patients (<18 years) who presented with cannabis intoxication from August 2017 through June 2020 to participating sites in the Toxicology Investigators Consortium. In cases that involved polysubstance exposure, patients were included if cannabis was a significant contributing agent. The primary outcome was a composite severe outcome endpoint, defined as an intensive care unit admission or in-hospital death. Covariates included relevant sociodemographic and exposure characteristics. RESULTS: One hundred and thirty-eight pediatric patients (54% males, median age 14.0 years, interquartile range 3.7-16.0) presented to a participating emergency department with cannabis intoxication. Fifty-two patients (38%) were admitted to an intensive care unit, including one patient who died. In the multivariable logistic regression analysis, polysubstance ingestion (adjusted odds ratio = 16.3; 95% confidence interval: 4.6-58.3; P < 0.001)) and cannabis edibles ingestion (adjusted odds ratio = 5.5; 95% confidence interval: 1.9-15.9; P = 0.001) were strong independent predictors of severe outcome. In an age-stratified regression analysis, in children older than >10 years, only polysubstance abuse remained an independent predictor for the severe outcome (adjusted odds ratio 37.1; 95% confidence interval: 6.2-221.2; P < 0.001). As all children 10 years and younger ingested edibles, a dedicated multivariable analysis could not be performed (unadjusted odds ratio 3.3; 95% confidence interval: 1.6-6.7). CONCLUSIONS: Severe outcomes occurred for different reasons and were largely associated with the patient's age. Young children, all of whom were exposed to edibles, were at higher risk of severe outcomes. Teenagers with severe outcomes were frequently involved in polysubstance exposure, while psychosocial factors may have played a role.

Evaluation of activation criteria in paediatric multi-trauma.

Objective: To explore the optimal set of trauma activation criteria predicting paediatric patients' need for acute care following multi-trauma, with particular attention to Glasgow Coma Scale (GCS) cut-off value. Methods: A retrospective cohort study of paediatric multi-trauma patients aged 0 to 16 years, performed at a Level 1 paediatric trauma centre. Trauma activation criteria and GCS levels were examined with respect to patients' need for acute care, defined as: direct to operating room disposition, intensive care unit admission, need for acute interventions in the trauma room, or in-hospital death. Results: We enrolled 436 patients (median age 8.0 years). The following predicted need for acute care: GCS <14 (adjusted odds ratio [aOR] 23.0, 95% confidence interval [CI]: 11.5 to 45.9, P < 0.001), hemodynamic instability: (aOR 3.7, 95% CI: 1.2-8.1, P = 0.01), open pneumothorax/flail chest (aOR: 20.0, 95% CI: 4.0 to 98.7, P < 0.001), spinal cord injury (aOR 15.4, 95% CI; 2.4 to 97.1, P = 0.003), blood transfusion at the referring hospital (aOR: 7.7, 95% CI: 1.3 to 44.2, P = 0.02) and GSW to the chest, abdomen, neck, or proximal extremities (aOR 11.0, 95% CI; 1.7 to 70.8, P = 0.01). Using these activation criteria would have decreased over- triage by 10.7%, from 49.1% to 37.2% and under-triage by 1.3%, from 4.7% to 3.5%, in our cohort of patients. Conclusions: Using GCS<14, hemodynamic instability, open pneumothorax/flail chest, spinal cord injury, blood transfusion at the referring hospital, and GSW to the chest, abdomen, neck of proximal extremities, as T1 activation criteria could decrease over- and under-triage rates. Prospective studies are needed to validate the optimal set of activation criteria in paediatric patients.

Reliability and feasibility of optic nerve point-of-care ultrasound in pediatric patients with ventricular shunts.

PURPOSE: To determine the interrater reliability of optic nerve sheath diameter (ONSD) and optic disc elevation (ODE) via ocular ultrasound by emergency and neurosurgery providers in children with ventricular shunts, and to explore the feasibility of acquiring and measuring images. METHODS: Two novices who underwent focused training and one expert in ocular ultrasound independently acquired images and measured ONSD and ODE on the same children, 0-18 years with ventricular shunts, blinded to each other's images and measurements. Patient tolerance, image quality, and time-to-complete exams were recorded. Images meeting a priori defined quality metrics were included. Mixed models and bootstrap analysis were used to obtain inter-rater reliability and 95% confidence intervals. RESULTS: Eighty-one children were enrolled from August 2016 to July 2017, with mean age 9.6 years (SD 5.25, range 5 months-17.7 years). High-quality images (≥ 4 on 7-point quality Likert scale) were obtained in 83% of ONSD assessments and 95% of ODE assessments. The ICCONSD was 0.82 (95% CI 0.76-0.91) for right eyes and 0.73 (95% CI 0.69-0.85) for left, while ICCODE was 0.81 (95% CI 0.75-0.89) for right eyes and 0.85 (95% CI 0.79-0.91) for left. Mean study duration (both eyes) was 2:52 min (SD 54 s). CONCLUSION: Clinicians generated high-quality ocular ultrasound images with excellent interrater reliability when acquiring and measuring images of ONSD and ODE in children with ventricular shunts.

Caregiver-reported delay in presentation to pediatric emergency departments for fear of contracting COVID-19: a multi-national cross-sectional study.

OBJECTIVE: To determine if caregivers of children presenting to pediatric emergency departments (EDs) during the COVID-19 pandemic are delaying presenting to care for fear of contracting COVID-19. METHODS: This was a pre-planned secondary analysis of a cross-sectional survey study of caregivers accompanying their children aged 0-19 years to 16 pediatric EDs in 5 countries from May to June 2020. An anonymous online survey, completed by caregivers via RedCAP, included caregiver and child demographics, presenting complaints, if they delayed presentation and whether symptoms worsened during this interval, as well as caregiver concern about the child or caregiver having COVID-19 at the time of ED visit. RESULTS: Of 1543 caregivers completing the survey, 287 (18.6%) reported a delay in seeking ED care due to concerns of contracting COVID-19 in the hospital. Of those, 124 (43.2%) stated their child's symptoms worsened during the waiting interval. Caregiver relationship to child [mother] (OR 1.85, 95% CI 1.27-2.76), presence of chronic illness in child (OR 1.78. 95% CI 1.14-2.79), younger age of caregiver (OR 0.965, 95% CI 0.943-0.986), and caregiver concerns about lost work during the pandemic (OR 1.08, 95% CI 1.04-1.12) were independently associated with a COVID-19-related delayed presentation in multivariable regression analysis. CONCLUSIONS: Almost one in five caregivers reported delaying ED presentation for their ill or injured child specifically due to fear of contracting COVID-19 while in hospital, with mothers, younger caregivers, caregivers of children with chronic illness, and those concerned about lost work more likely to report delaying ED presentation.

RéSUMé: OBJECTIF: Déterminer si les aidants des enfants qui se présentent aux services d'urgence pédiatriques (SU) pendant la pandémie de COVID-19 retardent leur présentation pour prendre soin d'eux par crainte de contracter la COVID-19. MéTHODES: Il s'agissait d'une analyze secondaire planifiée à l'avance d'une étude d'enquête transversale auprès des soignants accompagnant leurs enfants âgés de 0 à 19 ans dans 16 urgences pédiatriques de 5 pays entre mai et juin 2020. Une enquête anonyme en ligne, remplie par les soignants via RedCAP, comprenait les données démographiques du soignant et de l'enfant, les plaintes présentées, s'ils ont retardé la présentation et si les symptômes se sont aggravés pendant cet intervalle, ainsi que l'inquiétude du soignant quant à la présence de COVID-19 chez l'enfant ou le soignant au moment de la visite aux urgences. RéSULTATS: Sur les 1 543 soignants ayant répondu à l'enquête, 287 (18.6 %) ont déclaré avoir retardé le recours aux urgences par crainte de contracter le COVID-19 à l'hôpital. Parmi eux, 124 (43.2%) ont déclaré que les symptômes de leur enfant s'étaient aggravés pendant l'intervalle d'attente. Dans l'analyse de régression multivariable, le lien entre la personne qui s'occupe de l'enfant et la mère (OR 1.85, IC95 % 1.27­2.76), la présence d'une maladie chronique chez l'enfant (OR 1.78, IC95 % 1.14-2.79), le jeune âge de la personne qui s'occupe de l'enfant (OR 0.965, IC95 % 0.943-0.986) et les préoccupations de la personne qui s'occupe de l'enfant concernant la perte de travail pendant la pandémie (OR 1.08, IC95 % 1.04­1.12) ont été associés de manière indépendante à une présentation tardive. CONCLUSIONS: Près d'un soignant sur cinq a déclaré avoir retardé la présentation aux urgences de son enfant malade ou blessé par crainte de contracter le COVID-19 pendant son séjour à l'hôpital, avec les mères, les jeunes aidants, les soignants d'enfants souffrant de maladies chroniques et les personnes préoccupées par la perte de travail sont plus susceptibles de retarder la présentation aux urgences.

Life-Threatening Bleeding in Children: A Prospective Observational Study.

OBJECTIVES: The purpose of our study was to describe children with life-threatening bleeding. DESIGN: We conducted a prospective observational study of children with life-threatening bleeding events. SETTING: Twenty-four childrens hospitals in the United States, Canada, and Italy participated. SUBJECTS: Children 0-17 years old who received greater than 40 mL/kg total blood products over 6 hours or were transfused under massive transfusion protocol were included. INTERVENTIONS: Children were compared according bleeding etiology: trauma, operative, or medical. MEASUREMENTS AND MAIN RESULTS: Patient characteristics, therapies administered, and clinical outcomes were analyzed. Among 449 enrolled children, 55.0% were male, and the median age was 7.3 years. Bleeding etiology was 46.1% trauma, 34.1% operative, and 19.8% medical. Prior to the life-threatening bleeding event, most had age-adjusted hypotension (61.2%), and 25% were hypothermic. Children with medical bleeding had higher median Pediatric Risk of Mortality scores (18) compared with children with trauma (11) and operative bleeding (12). Median Glasgow Coma Scale scores were lower for children with trauma (3) compared with operative (14) or medical bleeding (10.5). Median time from bleeding onset to first transfusion was 8 minutes for RBCs, 34 minutes for plasma, and 42 minutes for platelets. Postevent acute respiratory distress syndrome (20.3%) and acute kidney injury (18.5%) were common. Twenty-eight-day mortality was 37.5% and higher among children with medical bleeding (65.2%) compared with trauma (36.1%) and operative (23.8%). There were 82 hemorrhage deaths; 65.8% occurred by 6 hours and 86.5% by 24 hours. CONCLUSIONS: Patient characteristics and outcomes among children with life-threatening bleeding varied by cause of bleeding. Mortality was high, and death from hemorrhage in this population occurred rapidly.

Willingness to Vaccinate Children against Influenza after the Coronavirus Disease 2019 Pandemic.

OBJECTIVES: To determine factors associated with parents who plan to vaccinate their children against influenza next year, especially those who did not vaccinate against influenza last year using a global survey. STUDY DESIGN: A survey of caregivers accompanying their children aged 1-19 years old in 17 pediatric emergency departments in 6 countries at the peak of the coronavirus disease 2019 (COVID-19) pandemic. Anonymous online survey included caregiver and child demographic information, vaccination history and future intentions, and concern about the child and caregiver having COVID-19 at the time of emergency department visit. RESULTS: Of 2422 surveys, 1314 (54.2%) caregivers stated they plan to vaccinate their child against influenza next year, an increase of 15.8% from the previous year. Of 1459 caregivers who did not vaccinate their children last year, 418 (28.6%) plan to do so next year. Factors predicting willingness to change and vaccinate included child's up-to-date vaccination status (aOR 2.03, 95% CI 1.29-3.32, P = .003); caregivers' influenza vaccine history (aOR 3.26, 95% CI 2.41-4.40, P < .010), and level of concern their child had COVID-19 (aOR 1.09, 95% CI 1.01-1.17, P = .022). CONCLUSIONS: Changes in risk perception due to COVID-19, and previous vaccination, may serve to influence decision-making among caregivers regarding influenza vaccination in the coming season. To promote influenza vaccination among children, public health programs can leverage this information.

Prepubescent Female Genital Examination Images: Evidence-Informed Learning Opportunities.

OBJECTIVES: To determine diagnoses and image features that are associated with difficult prepubescent female genital image interpretations. DESIGN AND SETTING: This was a mixed-methods study conducted at a tertiary care pediatric center using images from a previously developed education platform. PARTICIPANTS: Participants comprised 107 medical students, residents, fellows, and attendings who interpreted 158 cases to derive case difficulty estimates. INTERVENTIONS: This was a planned secondary analysis of participant performance data obtained from a prospective multi-center cross-sectional study. An expert panel also performed a descriptive review of images with the highest frequency of diagnostic error. MAIN OUTCOME MEASURES: We derived the proportion of participants who interpreted an image correctly, and features that were common in images with the most frequent diagnostic errors. RESULTS: We obtained 16,906 image interpretations. The mean proportion correct scores for each diagnosis were as follows: normal/normal variants 0.84 (95% confidence interval [CI] 0.82, 0.87); infectious/dermatology pathology 0.59 (95% CI 0.45, 0.73); anatomic pathology 0.61 (95% CI 0.41, 0.81); and, traumatic pathology 0.64 (95% CI 0.49, 0.79). The mean proportion correct scores varied by diagnosis (P < .001). The descriptive review demonstrated that poor image quality, infant genitalia, normal variant anatomy, external material (eg, diaper cream) in the genital area, and nonspecific erythema were common features in images with lower accuracy scores. CONCLUSIONS: A quantitative and qualitative examination of prepubescent female genital examination image interpretations provided insight into diagnostic challenges for this complex examination. These data can be used to inform the design of teaching interventions to improve skill in this area.

Factors associated with parents' willingness to enroll their children in trials for COVID-19 vaccination.

The coronavirus disease 2019 (COVID-19) pandemic has taken an unprecedented global toll and vaccination is needed to restore healthy living. Timely inclusion of children in vaccination trials is critical. We surveyed caregivers of children seeking care in 17 Emergency Departments (ED) across 6 countries during the peak of the pandemic to identify factors associated with intent to participate in COVID-19 vaccine trials. Questions about child and parent characteristics, COVID-19 expressed concerns and parental attitudes toward participation in a trial were asked.Of 2768 completed surveys, 18.4% parents stated they would enroll their child in a clinical trial for a COVID-19 vaccine and 14.4% would agree to a randomized placebo-controlled study. Factors associated with willingness to participate were parents agreeing to enroll in a COVID-19 vaccine trial themselves (Odds Ratio (OR) 32.9, 95% Confidence Interval (CI) (21.9-51.2)) having an older child (OR 1.0 (1.0-1.01)), having children who received all vaccinations based on their country schedule (OR 2.67 (1.35-5.71)) and parents with high school education or lower (OR 1.79 (1.18-2.74)). Mothers were less likely to enroll their child in a trial (OR 0.68 (0.47-0.97)). Only one fifth of families surveyed will consider enrolling their child in a vaccine trial. Parental interest in participation, history of vaccinating their child, and the child being older all are associated with parents allowing their child to participate in a COVID vaccine trial. This information may help decision-makers and researchers shape their strategies for trial design and participation engagement in upcoming COVID19 vaccination trials.

Caregiver willingness to vaccinate their children against COVID-19: Cross sectional survey.

BACKGROUND: More than 100 COVID-19 vaccine candidates are in development since the SARS-CoV-2 genetic sequence was published in January 2020. The uptake of a COVID-19 vaccine among children will be instrumental in limiting the spread of the disease as herd immunity may require vaccine coverage of up to 80% of the population. Prior history of pandemic vaccine coverage was as low as 40% among children in the United States during the 2009 H1N1 influenza pandemic. PURPOSE: To investigate predictors associated with global caregivers' intent to vaccinate their children against COVID-19, when the vaccine becomes available. METHOD: An international cross sectional survey of 1541 caregivers arriving with their children to 16 pediatric Emergency Departments (ED) across six countries from March 26 to May 31, 2020. RESULTS: 65% (n = 1005) of caregivers reported that they intend to vaccinate their child against COVID-19, once a vaccine is available. A univariate and subsequent multivariate analysis found that increased intended uptake was associated with children that were older, children with no chronic illness, when fathers completed the survey, children up-to-date on their vaccination schedule, recent history of vaccination against influenza, and caregivers concerned their child had COVID-19 at the time of survey completion in the ED. The most common reason reported by caregivers intending to vaccinate was to protect their child (62%), and the most common reason reported by caregivers refusing vaccination was the vaccine's novelty (52%). CONCLUSIONS: The majority of caregivers intend to vaccinate their children against COVID-19, though uptake will likely be associated with specific factors such as child and caregiver demographics and vaccination history. Public health strategies need to address barriers to uptake by providing evidence about an upcoming COVID-19 vaccine's safety and efficacy, highlighting the risks and consequences of infection in children, and educating caregivers on the role of vaccination.

Caregivers' Willingness to Accept Expedited Vaccine Research During the COVID-19 Pandemic: A Cross-sectional Survey.

PURPOSE: This study determined the predictors of caregivers' willingness to accept an accelerated regulatory process for the development of vaccines against coronavirus disease 2019 (COVID-19). METHODS: An international cross-sectional survey was administered to 2557 caregivers of children in 17 pediatric emergency departments (EDs) across 6 countries from March 26, 2020, to June 30, 2020. Caregivers were asked to select 1 of 4 choices with which they most agreed regarding a proposed COVID-19 vaccine-approval process, in addition to questions regarding demographic characteristics, the ED visit, and attitudes about COVID-19. Univariate analyses were conducted using the Mann-Whitney U test for comparing non-normally distributed continuous variables, an independent t test for comparing normally distributed continuous variables, and a χ2 or Fisher exact test for categorical variables. Multivariate logistic regression analysis was used for determining independent factors associated with caregivers' willingness to accept abridged development of a COVID-19 vaccine. A P value of <0.05 was considered significant. FINDINGS: Almost half (1101/2557; 43%) of caregivers reported that they were willing to accept less rigorous testing and postresearch approval of a new COVID-19 vaccine. Independent factors associated with caregivers' willingness to accept expedited COVID-19 vaccine research included having children who were up to date on the vaccination schedule (odds ratio [OR] = 1.72; 95% CI, 1.29-2.31), caregivers' concern about having had COVID-19 themselves at the time of survey completion in the ED (OR = 1.1; 95% CI, 1.05-1.16), and caregivers' intent to have their children vaccinated against COVID-19 if a vaccine were to become available (OR = 1.84; 95% CI, 1.54-2.21). Compared with fathers, mothers completing the survey were less likely to approve of changes in the vaccine-development process (OR = 0.641; 95% CI, 0.529-0.775). IMPLICATIONS: Less than half of caregivers in this worldwide sample were willing to accept abbreviated COVID-19 vaccine testing. As a part of an effort to increase acceptance and uptake of a new vaccine, especially in order to protect children, public health strategies and individual providers should understand caregivers' attitudes toward the approval of a vaccine and consult them appropriately.

The Base Deficit, International Normalized Ratio, and Glasgow Coma Scale (BIG) Score, and Functional Outcome at Hospital Discharge in Children With Traumatic Brain Injury.

OBJECTIVES: To examine the association of the base deficit, international normalized ratio, and Glasgow Coma Scale (BIG) score on emergency department arrival with functional dependence at hospital discharge (Pediatric Cerebral Performance Category ≥ 4) in pediatric multiple trauma patients with traumatic brain injury. DESIGN: A retrospective cohort study of a pediatric trauma database from 2001 to 2018. SETTING: Level 1 trauma program at a university-affiliated pediatric institution. PATIENTS: Two to 17 years old children sustaining major blunt trauma including a traumatic brain injury and meeting trauma team activation criteria. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two investigators, blinded to the BIG score, determined discharge Pediatric Cerebral Performance Category scores. The BIG score was measured on emergency department arrival. The 609 study patients were 9.7 ± 4.4 years old with a median Injury Severity Score 22 (interquartile range, 12). One-hundred seventy-one of 609 (28%) had Pediatric Cerebral Performance Category greater than or equal to 4 (primary outcome). The BIG constituted a multivariable predictor of Pediatric Cerebral Performance Category greater than or equal to 4 (odds ratio, 2.39; 95% CI, 1.81-3.15) after adjustment for neurosurgery requirement (odds ratio, 2.83; 95% CI, 1.69-4.74), pupils fixed and dilated (odds ratio, 3.1; 95% CI, 1.49-6.38), and intubation at the scene or referral hospital (odds ratio, 2.82; 95% CI, 1.35-5.87) and other postulated predictors of poor outcome. The area under the BIG receiver operating characteristic curve was 0.87 (0.84-0.90). Using an optimal BIG cutoff less than or equal to 8, sensitivity and negative predictive value for functional dependence at discharge were 93% and 96%, respectively, compared with a sensitivity of 79% and negative predictive value of 91% with Glasgow Coma Scale less than or equal to 8. In children with Glasgow Coma Scale 3, the BIG score was associated with brain death (odds ratio, 2.13; 95% CI, 1.58-2.36). The BIG also predicted disposition to inpatient rehabilitation (odds ratio, 2.26; 95% CI, 2.17-2.35). CONCLUSIONS: The BIG score is a simple, rapidly obtainable severity of illness score that constitutes an independent predictor of functional dependence at hospital discharge in pediatric trauma patients with traumatic brain injury. The BIG score may benefit Trauma and Neurocritical care programs in identifying ideal candidates for traumatic brain injury trials within the therapeutic window of treatment.

Influence of Hydrogen-Bonding Interactions on Nuclearity and Structure of Palladium Tiara-like Complexes.

The role of intramolecular hydrogen-bonding interactions upon the nuclearity of palladium tiara-like complexes is reported herein. The synthesis of three palladium tiaras is described with three related thiolate ligands that vary in their hydrogen-bonding capability, amide vs ester for N-acetylcysteamine (tiara 1) vs 2-mercaptoethyl acetate (tiara 2) or ethyl thioglycolate (tiara 3), and in the relative position of the ester group, 2-mercaptoethyl acetate (2) or ethyl thioglycolate (3). Mass spectrometry indicates that, in the absence of protic solvents, N-acetylcysteamine reacts to form exclusively a six-membered tiara, [Pd(SCH2CH2NHCOCH3)2]6, 1, whereas the ester containing analogues form both six- and eight-membered tiaras. Single-crystal X-ray diffraction studies indicate the significance of intramolecular N-H···O hydrogen bonds in determining the nuclearity of the amide-containing tiara 1. NMR studies indicate that 1 is not in equilibrium with larger tiaras in solution, and that the smaller size of the aggregate inhibits the fluxional behavior of the pendant thiolate ligands, typically observed for larger tiaras. Electrochemical investigations of 1 reveal reductive processes that exhibit an increase in current upon addition of acid, along with the formation of palladium nanoparticles.

Application of carbohydrate arrays coupled with mass spectrometry to detect activity of plant-polysaccharide degradative enzymes from the fungus Aspergillus niger.

Renewables-based biotechnology depends on enzymes to degrade plant lignocellulose to simple sugars that are converted to fuels or high-value products. Identification and characterization of such lignocellulose degradative enzymes could be fast-tracked by availability of an enzyme activity measurement method that is fast, label-free, uses minimal resources and allows direct identification of generated products. We developed such a method by applying carbohydrate arrays coupled with MALDI-ToF mass spectrometry to identify reaction products of carbohydrate active enzymes (CAZymes) of the filamentous fungus Aspergillus niger. We describe the production and characterization of plant polysaccharide-derived oligosaccharides and their attachment to hydrophobic self-assembling monolayers on a gold target. We verify effectiveness of this array for detecting exo- and endo-acting glycoside hydrolase activity using commercial enzymes, and demonstrate how this platform is suitable for detection of enzyme activity in relevant biological samples, the culture filtrate of A. niger grown on wheat straw. In conclusion, this versatile method is broadly applicable in screening and characterisation of activity of CAZymes, such as fungal enzymes for plant lignocellulose degradation with relevance to biotechnological applications as biofuel production, the food and animal feed industry.

The BIG Score and Prediction of Mortality in Pediatric Blunt Trauma.

OBJECTIVES: To examine the association between in-hospital mortality and the BIG (composed of the base deficit [B], International normalized ratio [I], Glasgow Coma Scale [G]) score measured on arrival to the emergency department in pediatric blunt trauma patients, adjusted for pre-hospital intubation, volume administration, and presence of hypotension and head injury. We also examined the association between the BIG score and mortality in patients requiring admission to the intensive care unit (ICU). STUDY DESIGN: A retrospective 2001-2012 trauma database review of patients with blunt trauma ≤ 17 years old with an Injury Severity score ≥ 12. Charts were reviewed for in-hospital mortality, components of the BIG score upon arrival to the emergency department, prehospital intubation, crystalloids ≥ 20 mL/kg, presence of hypotension, head injury, and disposition. RESULTS: 50/621 (8%) of the study patients died. Independent mortality predictors were the BIG score (OR 11, 95% CI 6-25), prior fluid bolus (OR 3, 95% CI 1.3-9), and prior intubation (OR 8, 95% CI 2-40). The area under the receiver operating characteristic curve was 0.95 (CI 0.93-0.98), with the optimal BIG cutoff of 16. With BIG <16, death rate was 3/496 (0.006, 95% CI 0.001-0.007) vs 47/125 (0.38, 95% CI 0.15-0.7) with BIG ≥ 16, (P < .0001). In patients requiring admission to the ICU, the BIG score remained predictive of mortality (OR 14.3, 95% CI 7.3-32, P < .0001). CONCLUSIONS: The BIG score accurately predicts mortality in a population of North American pediatric patients with blunt trauma independent of pre-hospital interventions, presence of head injury, and hypotension, and identifies children with a high probability of survival (BIG <16). The BIG score is also associated with mortality in pediatric patients with trauma requiring admission to the ICU.

Synthesis of 19-substituted geldanamycins with altered conformations and their binding to heat shock protein Hsp90.

The benzoquinone ansamycin geldanamycin and its derivatives are inhibitors of heat shock protein Hsp90, an emerging target for novel therapeutic agents both in cancer and in neurodegeneration. However, the toxicity of these compounds to normal cells has been ascribed to reaction with thiol nucleophiles at the quinone 19-position. We reasoned that blocking this position would ameliorate toxicity, and that it might also enforce a favourable conformational switch of the trans-amide group into the cis-form required for protein binding. Here, we report an efficient synthesis of such 19-substituted compounds and realization of our hypotheses. Protein crystallography established that the new compounds bind to Hsp90 with, as expected, a cis-amide conformation. Studies on Hsp90 inhibition in cells demonstrated the molecular signature of Hsp90 inhibitors: decreases in client proteins with compensatory increases in other heat shock proteins in both human breast cancer and dopaminergic neural cells, demonstrating their potential for use in the therapy of cancer or neurodegenerative diseases.

Low-coordinate cobalt(II) terphenyl complexes: precursors to sterically encumbered ketones.

Cobalt(II) diaryl complexes react with CO to afford Co(2)(CO)(8) and sterically encumbered ketones whose structure varies depending on the nature of the aryl ligands.

Homologation and functionalization of carbon monoxide by a recyclable uranium complex.

Carbon monoxide (CO) is in principle an excellent resource from which to produce industrial hydrocarbon feedstocks as alternatives to crude oil; however, CO has proven remarkably resistant to selective homologation, and the few complexes that can effect this transformation cannot be recycled because liberation of the homologated product destroys the complexes or they are substitutionally inert. Here, we show that under mild conditions a simple triamidoamine uranium(III) complex can reductively homologate CO and be recycled for reuse. Following treatment with organosilyl halides, bis(organosiloxy)acetylenes, which readily convert to furanones, are produced, and this was confirmed by the use of isotopically (13)C-labeled CO. The precursor to the triamido uranium(III) complex is formed concomitantly. These findings establish that, under appropriate conditions, uranium(III) can mediate a complete synthetic cycle for the homologation of CO to higher derivatives. This work may prove useful in spurring wider efforts in CO homologation, and the simplicity of this system suggests that catalytic CO functionalization may soon be within reach.

PtII diimine chromophores with perfluorinated thiolate ligands: nature and dynamics of the charge-transfer-to-diimine lowest excited state.

The synthesis of new Pt(II) diimine complexes bearing perfluorinated thiolate ligands, Pt(II)(NN)(4-X-C(6)F(4)-S)(2), where NN = 2,2'-bipyridine or 1,10-phenanthroline and X = F or CN, is reported, together with an investigation of the nature and dynamics of their lowest excited states. A combined UV-vis, (spectro)electrochemical, resonance Raman, and time-resolved infrared (TRIR) study has suggested that the HOMO is mainly composed of thiolate(pi)/S(p)/Pt(d) orbitals and that the LUMO is largely localized on the pi*(diimine) orbital, thus revealing the [charge-transfer-to-diimine] nature of the lowest excited state. An enhancement of the thiolate ring vibrations, C-F vibrations, and the vibration of the CN-substituent on the thiolate moiety was observed in the resonance Raman spectra, whereas no such enhancement was seen for the nonfluorinated analogues. Thus, the introduction of fluorine substituents on the thiolate moiety probably leads to a more pronounced contribution of the intrathiolate modes to the HOMO compared to the analogous complexes with nonfluorinated thiolates. Furthermore, the introduction of the p-CN group into the thiolate moiety has allowed the dynamics of the lowest excited state of Pt(bpy)(4-CN-C(6)F(4)-S)(2) to be monitored by picosecond TRIR spectroscopy. The dynamics of the lowest [charge-transfer-to-diimine] excited state are governed by ca. 2-ps vibrational cooling and 35-ps back electron transfer.

NMR-based metabonomic studies on the biochemical effects of epicatechin in the rat.

Flavonoid consumption via tea drinking has been attributed a number of potential health benefits including cancer prevention, anti-inflammatory action, and cardioprotectant activity. Although the predominant flavonoids in fresh leaf and green tea are known to be flavan-3-ols and flavan-3-O-gallates ("the catechins"), the biochemical effects of tea polyphenol consumption on living systems are generally poorly understood. Metabonomic methods utilizing (1)H NMR spectroscopy of biofluids and principal component analysis (PCA) have been applied to investigate the bioavailability and metabolic responses of rats to a single dose of 22 mg of epicatechin (EC) dissolved in water. Urine samples were collected twice daily (0-8 and 8-24 h) from male Sprague-Dawley rats (n = 10) prior to dosing and for 2 days after dosing. A series of subtle urinary biochemical effects were evident from the (1)H NMR spectra showing that EC was both bioavailable and biochemically active. The identifiable biochemical effects associated with EC dosing included decreased urinary concentrations of taurine, citrate, dimethylamine, and 2-oxoglutarate. These effects were predominately seen within the first 8 h after dosing. EC metabolites were also observed in the urine during this time period. PCA of later time points after dosing (24-32 and 32-48 h) showed that the effects of EC were reversible. This is the first in vivo study demonstrating the overall endogenous metabolic effects of EC consumption and shows the bioavailability of EC via metabolic effects and excretion of EC metabolites.