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Trauma-induced coagulopathy (TIC) is provoked by multiple mechanisms and is perceived to be one driver of massive transfusions (MT). Single laboratory values using prothrombin time (INR) or thrombelastography (TEG) are used to clinically define this complex process. We used a proteomics approach to test whether current definitions of TIC (INR, TEG, or clinical judgement) are sufficient to capture the majority of protein changes associated with MT.Eight level-I trauma centers contributed blood samples from patients available early after injury. TIC was defined as INR1.5 (INR-TIC), TEG maximum amplitude50mm (TEG-TIC), or clinical judgement (Clin-TIC) by the trauma surgeon. MT was defined as10 units of red blood cells in 24 hours or4 units RBC/hour during the first 4 hr. SomaLogic proteomic analysis of 1,305 proteins was performed. Pathways associated with proteins dysregulated in patients with each TIC definition and MT were identified.Patients (n=211) had a mean injury severity score of 24, with a MT and mortality rate of 22% and 12%, respectively. We identified 578 SOMAscan analytes dysregulated among MT patients, of which INR-TIC, TEG-TIC, and Clin-TIC patients showed dysregulation only in 25%, 3%, and 4% of these, respectively. TIC definitions jointly failed to show changes in 73% of the protein levels associated with MT, and failed to identify 26% of patients that received a massive transfusion. INR-TIC and TEG-TIC patients showed dysregulation of proteins significantly associated with complement activity. Proteins dysregulated in Clin-TIC or massive transfusion patients were not significantly associated with any pathway.These data indicate there are unexplored opportunities to identify patients at risk for massive bleeding. Only a small subset of proteins that are dysregulated in patients receiving MT are statistically significantly dysregulated among patients whose TIC is defined based solely on laboratory measurements or clinical assessment.

Highlights Abstract Background: Tunneled central lines are used to deliver medications, hydration, and total parenteral nutrition. The current modality for their securement is by a transparent sterile adhesive. Mechanical line traumas, including line fissures, breaks and dislodgements, occur frequently in children. A novel device, the Central Line Securement Vest, was created to protect central lines from mechanical trauma. Objective: We present here our experience with the device and report its use in patients with intestinal failure treated at our institution. Methods: All patients who have used the Central Line Securement Vest at our institution during the last decade were identified. We reviewed the patients’ electronic records and compared the rate of line mechanical trauma, line infections, line replacements, Emergency Department (ED) visits, and hospital admissions for a period of 12 months before and after the use of the device. Results: Ten patients were identified. Four patients had purchased the device at the time of line insertion. Six patients had a period of time of line use before beginning use of the device. The rate of line traumas and infections decreased after using the device: 0.19 ± 0.15 vs 0.05 ± 0.04 trauma/month, pre– vs post–device use, P < 0.05. Similarly, the rate of line infections decreased post–device use: 0.18 ± 0.13 vs 0.09 ± 0.06 infections/month, pre– vs post–device use, P < 0.05. The rate of line replacements, ED visits, and hospital admissions were similar pre– and post–device use. Conclusion: We report here our institution’s experience with a novel central line securement device designed to protect the line from mechanical trauma.

OBJECTIVES To assess the impact of antifibrinolytics in children with life-threatening hemorrhage. DESIGN Secondary analysis of the MAssive Transfusion epidemiology and outcomes In Children study dataset, a prospective observational study of children with life-threatening bleeding events. SETTING Twenty-four children's hospitals in the United States, Canada, and Italy. PATIENTS Children 0-17 years old who received greater than 40 mL/kg of total blood products over 6 hours or were transfused under activation of massive transfusion protocol. INTERVENTION/EXPOSURE Children were compared according to receipt of antifibrinolytic medication (tranexamic acid or aminocaproic acid) during the bleeding event. MEASURES AND MAIN RESULTS Patient characteristics, medications administered, and clinical outcomes were analyzed using Cox proportional hazard and Kaplan-Meier survival analysis. The primary outcome was 24-hour mortality. Of 449 patients analyzed, median age was 7 years (2-15 yr), and 55% were male. The etiology of bleeding was 46% traumatic, 34% operative, and 20% medical. Twelve percent received antifibrinolytic medication during the bleeding event (n = 54 unique subjects; n = 18 epsilon aminocaproic acid, n = 35 tranexamic acid, and n = 1 both). The antifibrinolytic group was comparable with the nonantifibrinolytic group on baseline demographic and physiologic parameters; the antifibrinolytic group had longer massive transfusion protocol duration, received greater volume blood products, and received factor VII more frequently. In the antifibrinolytic group, there was significantly less 6-hour mortality overall (6% vs 17%; p = 0.04) and less 6-hour mortality due to hemorrhage (4% vs 14%; p = 0.04). After adjusting for age, bleeding etiology, Pediatric Risk of Mortality score, and plasma deficit, the antifibrinolytic group had decreased mortality at 6- and 24-hour postbleed (adjusted odds ratio, 0.29 [95% CI, 0.09-0.93]; p = 0.04 and adjusted odds ratio, 0.45 [95% CI, 0.21-0.98]; p = 0.04, respectively). CONCLUSIONS Administration of antifibrinolytic medications during the life-threatening event was independently associated with improved 6- and 24-hour survivals in bleeding children. Consideration should be given to use of antifibrinolytics in pediatric patients with life-threatening hemorrhage.

In paediatric trauma patients, there are limited prospective data regarding blood components and mortality, with some literature suggesting decreased mortality with high ratios of plasma and platelets to red blood cells (RBCs) in massive transfusions; however, most paediatric massive transfusions occur for non-traumatic aetiologies and few studies assess blood product ratios in these children. This study's objective was to evaluate whether high blood product ratios or low deficits conferred a survival benefit in children with non-traumatic life-threatening bleeding.This is a secondary analysis of the five-year, multicentre, prospective, observational massive transfusion epidemiology and outcomes in children study of children with life-threatening bleeding from US, Canadian and Italian medical centres. Primary interventions were plasma:RBC and platelets:RBC (high ratio ≥1:2 ml/kg) and plasma and platelet deficits. The primary outcome was mortality at 6 h, 24 h and 28 days. Multivariate logistic regression models were used to determine independent associations with mortality.A total of 222 children were included from 24 medical centres: 145 children (median [interquartile range] age 2.1 years [0.3-11.8]) with operative bleeding and 77 (8.0 years [1.2-14.7]) with medical bleeding. In adjusted analyses, neither blood product ratios nor deficits were associated with mortality at 6 h, 24 h or 28 days.This paper addresses a lack of prospective data in children regarding optimal empiric massive transfusion strategies in non-traumatic massive haemorrhage and in finding no decrease in mortality with high plasma or platelet to RBC ratios or lower deficits supports an exploratory analysis for mortality.

INTRODUCTION: The mechanistic definition of chronic pancreatitis (CP) identifies acute pancreatitis (AP) as a precursor stage. We hypothesized that clinical AP frequently precedes the diagnosis of CP and is associated with patient- and disease-related factors. We describe the prevalence, temporal relationship and associations of AP in a well-defined North American cohort. METHODS: We evaluated data from 883 patients with CP prospectively enrolled in the North American Pancreatitis Studies across 27 US centers between 2000 and 2014. We determined how often patients had one or more episodes of AP and its occurrence in relationship to the diagnosis of CP. We used multivariable logistic regression to determine associations for prior AP. RESULTS: There were 624/883 (70.7%) patients with prior AP, among whom 161 (25.8%) had AP within 2 years, 115 (18.4%) within 3–5 years, and 348 (55.8%) >5 years prior to CP diagnosis. Among 504 AP patients with available information, 436 (86.5%) had >1 episode. On multivariable analyses, factors associated with increased odds of having prior AP were a younger age at CP diagnosis, white race, abdominal pain, pseudocyst(s) and pancreatic duct dilatation/stricture, while factors associated with a lower odds of having prior AP were exocrine insufficiency and pancreatic atrophy. When compared with patients with 1 episode, those with >1 AP episode were diagnosed with CP an average of 5 years earlier. CONCLUSIONS: Nearly three-quarters of patients were diagnosed with AP prior to CP diagnosis. Identifying which AP patients are at-risk for future progression to CP may provide opportunities for primary and secondary prevention.

BACKGROUND: Many persons with a history of smoking tobacco have clinically significant respiratory symptoms despite an absence of airflow obstruction as assessed by spirometry. They are often treated with medications for chronic obstructive pulmonary disease (COPD), but supporting evidence for this treatment is lacking. METHODS: We randomly assigned persons who had a tobacco-smoking history of at least 10 pack-years, respiratory symptoms as defined by a COPD Assessment Test score of at least 10 (scores range from 0 to 40, with higher scores indicating worse symptoms), and preserved lung function on spirometry (ratio of forced expiratory volume in 1 second [FEV(1)] to forced vital capacity [FVC] ≥0.70 and FVC ≥70% of the predicted value after bronchodilator use) to receive either indacaterol (27.5 μg) plus glycopyrrolate (15.6 μg) or placebo twice daily for 12 weeks. The primary outcome was at least a 4-point decrease (i.e., improvement) in the St. George’s Respiratory Questionnaire (SGRQ) score (scores range from 0 to 100, with higher scores indicating worse health status) after 12 weeks without treatment failure (defined as an increase in lower respiratory symptoms treated with a long-acting inhaled bronchodilator, glucocorticoid, or antibiotic agent). RESULTS: A total of 535 participants underwent randomization. In the modified intention-to-treat population (471 participants), 128 of 227 participants (56.4%) in the treatment group and 144 of 244 (59.0%) in the placebo group had at least a 4-point decrease in the SGRQ score (difference, −2.6 percentage points; 95% confidence interval [CI], −11.6 to 6.3; adjusted odds ratio, 0.91; 95% CI, 0.60 to 1.37; P=0.65). The mean change in the percent of predicted FEV(1) was 2.48 percentage points (95% CI, 1.49 to 3.47) in the treatment group and −0.09 percentage points (95% CI, −1.06 to 0.89) in the placebo group, and the mean change in the inspiratory capacity was 0.12 liters (95% CI, 0.07 to 0.18) in the treatment group and 0.02 liters (95% CI, −0.03 to 0.08) in the placebo group. Four serious adverse events occurred in the treatment group, and 11 occurred in the placebo group; none were deemed potentially related to the treatment or placebo. CONCLUSIONS: Inhaled dual bronchodilator therapy did not decrease respiratory symptoms in symptomatic, tobacco-exposed persons with preserved lung function as assessed by spirometry. (Funded by the National Heart, Lung, and Blood Institute and others; RETHINC ClinicalTrials.gov number, NCT02867761.)

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.

BackgroundAlpha-1 antitrypsin deficiency (AATD) is a genetic condition that causes early onset pulmonary emphysema and airways obstruction. The complete mechanisms via which AATD causes lung disease are not fully understood. To improve our understanding of the pathogenesis of AATD, we investigated gene expression profiles of bronchoalveolar lavage (BAL) and peripheral blood mononuclear cells (PBMCs) in AATD individuals.MethodsWe performed RNA-Seq on RNA extracted from matched BAL and PBMC samples isolated from 89 subjects enrolled in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study. Subjects were stratified by genotype and augmentation therapy. Supervised and unsupervised differential gene expression analyses were performed using Weighted Gene Co-expression Network Analysis (WGCNA) to identify gene profiles associated with subjects’ clinical variables. The genes in the most significant WGCNA module were used to cluster AATD individuals. Gene validation was performed by NanoString nCounter Gene Expression Assay.ResultWe observed modest effects of AATD genotype and augmentation therapy on gene expression. When WGCNA was applied to BAL transcriptome, one gene module, ME31 (2312 genes), correlated with the highest number of clinical variables and was functionally enriched with numerous immune T-lymphocyte related pathways. This gene module identified two distinct clusters of AATD individuals with different disease severity and distinct PBMC gene expression patterns.ConclusionsWe successfully identified novel clusters of AATD individuals where severity correlated with increased immune response independent of individuals’ genotype and augmentation therapy. These findings may suggest the presence of previously unrecognised disease endotypes in AATD that associate with T-lymphocyte immunity and disease severity.

New neuroprotective therapies for severe traumatic brain injury (TBI) have not translated from pre-clinical to clinical success. Numerous explanations have been suggested in both the pre-clinical and clinical arenas. Coverage of TBI in the lay press has reinvigorated interest, creating a golden age of TBI research with innovative strategies to circumvent roadblocks. We discuss the need for more robust therapies. We present concepts for traditional and novel approaches to defining therapeutic targets. We review lessons learned from the ongoing work of the pre-clinical drug and biomarker screening consortium Operation Brain Trauma Therapy and suggest ways to further enhance pre-clinical consortia. Biomarkers have emerged that empower choice and assessment of target engagement by candidate therapies. Drug combinations may be needed, and it may require moving beyond conventional drug therapies. Precision medicine may also link the right therapy to the right patient, including new approaches to TBI classification beyond the Glasgow Coma Scale or anatomical phenotyping-incorporating new genetic and physiologic approaches. Therapeutic breakthroughs may also come from alternative approaches in clinical investigation (comparative effectiveness, adaptive trial design, use of the electronic medical record, and big data). The full continuum of care must also be represented in translational studies, given the important clinical role of pre-hospital events, extracerebral insults in the intensive care unit, and rehabilitation. TBI research from concussion to coma can cross-pollinate and further advancement of new therapies. Misconceptions can stifle/misdirect TBI research and deserve special attention. Finally, we synthesize an approach to deliver therapeutic breakthroughs in this golden age of TBI research.

This study evaluates the impact of a 6-month care management intervention for 206 children diagnosed with comorbid attention deficit hyperactivity disorder (ADHD) from a sample of 321 five- to 12-year-old children recruited for treatment of behavior problems in 8 pediatric primary care offices. Practices were cluster-randomized to Doctor Office Collaboration Care (DOCC) or Enhanced Usual Care (EUC). Chart reviews documented higher rates of service delivery, prescription of medication for ADHD, and titration in DOCC (vs EUC). Based on complex conditional models, DOCC showed greater acute improvement in individualized ADHD treatment goals and follow-up improvements in quality of life and ADHD and oppositional defiant disorder goals. Medication use had a significant effect on acute and follow-up ADHD symptom reduction and quality of life. Medication continuity was associated with some long-term gains. A collaborative care intervention for behavior problems that incorporated treatment guidelines for ADHD in primary care was more effective than psychoeducation and facilitated referral to community treatment.

Hyperosmolar agents are cornerstone therapies for pediatric severe traumatic brain injury. Guideline recommendations for 3% hypertonic saline (HTS) are based on limited numbers of patients, and no study to date has supported a recommendation for mannitol.To characterize current use of hyperosmolar agents in pediatric severe traumatic brain injury and assess whether HTS or mannitol is associated with greater decreases in intracranial pressure (ICP) and/or increases in cerebral perfusion pressure (CPP).In this comparative effectiveness research study, 1018 children were screened and 18 were excluded; 787 children received some form of hyperosmolar therapy during the ICP-directed phase of care, with 521 receiving a bolus. Three of these children were excluded because they had received only bolus administration of both HTS and mannitol in the same hour, leaving 518 children (at 44 clinical sites in 8 countries) for analysis. The study was conducted from February 1, 2014, to September 31, 2017, with follow-up for 1 week after injury. Final analysis was performed July 20, 2021.Boluses of HTS and mannitol were administered.Data on ICP and CPP were collected before and after medication administration. Statistical methods included linear mixed models and corrections for potential confounding variables to compare the 2 treatments.A total of 518 children (mean [SD] age, 7.6 [5.4] years; 336 [64.9%] male; 274 [52.9%] White) were included. Participants' mean (SD) Glasgow Coma Scale score was 5.2 (1.8). Bolus HTS was observed to decrease ICP and increase CPP (mean [SD] ICP, 1.03 [6.77] mm Hg; P .001; mean [SD] CPP, 1.25 [12.47] mm Hg; P .001), whereas mannitol was observed to increase CPP (mean [SD] CPP, 1.20 [11.43] mm Hg; P = .009). In the primary outcome, HTS was associated with a greater reduction in ICP compared with mannitol (unadjusted β, -0.85; 95% CI, -1.53 to -0.19), but no association was seen after adjustments (adjusted β, -0.53; 95% CI, -1.32 to 0.25; P = .18). No differences in CPP were observed. When ICP was greater than 20 mm Hg, greater than 25 mm Hg, or greater than 30 mm Hg, HTS outperformed mannitol for each threshold in observed ICP reduction (20 mm Hg: unadjusted β, -2.51; 95% CI, -3.86 to -1.15, P .001;25 mm Hg: unadjusted β, -3.88; 95% CI, -5.69 to -2.06, P .001;30 mm Hg: unadjusted β, -4.07; 95% CI, -6.35 to -1.79, P .001), with results remaining significant for ICP greater than 25 mm Hg in adjusted analysis.In this comparative effectiveness research study, bolus HTS was associated with lower ICP and higher CPP, whereas mannitol was associated only with higher CPP. After adjustment for confounders, both therapies showed no association with ICP and CPP. During ICP crises, HTS was associated with better performance than mannitol.

To assess the impact of plasma and platelet ratios and deficits in injured children with life-threatening bleeding.Secondary analysis of the MAssive Transfusion epidemiology and outcomes In Children study dataset, a prospective observational study of children with life-threatening bleeding events.Twenty-four childrens hospitals in the United States, Canada, and Italy.Injured children 0-17 years old who received greater than 40 mL/kg total blood products over 6 hours or were transfused under activation of massive transfusion protocol.Weight-adjusted blood product volumes received during the bleeding event were recorded. Plasma:RBC ratio (plasma/RBC weight-adjusted volume in mL/kg) and platelet:RBC ratio (platelet/RBC weight-adjusted volume in mL/kg) were analyzed. Plasma deficit was calculated as RBC mL/kg - plasma mL/kg; platelet deficit was calculated as RBC mL/kg - platelet mL/kg.Of 191 patients analyzed, median (interquartile range) age was 10 years (5-15 yr), 61% were male, 61% blunt mechanism, and median (interquartile range) Injury Severity Score was 29 (24-38). After adjusting for Pediatric Risk of Mortality score, cardiac arrest, use of vasoactive medications, and blunt mechanism, a high plasma:RBC ratio (1:2) was associated with improved 6-hour survival compared with a low plasma:RBC ratio (odds ratio [95% CI] = 0.12 [0.03-0.52]; p = 0.004). Platelet:RBC ratio was not associated with survival. After adjusting for age, Pediatric Risk of Mortality score, cardiac arrest, and mechanism of injury, 6-hour and 24-hour mortality were increased in children with greater plasma deficits (10% and 20% increased odds of mortality for every 10 mL/kg plasma deficit at 6 hr [p = 0.04] and 24 hr [p = 0.01], respectively); 24-hour mortality was increased in children with greater platelet deficits (10% increased odds of 24-hr mortality for every 10 mL/kg platelet deficit [p = 0.02)]).In injured children, balanced resuscitation may improve early survival according to this hypothesis generating study. Multicenter clinical trials are needed to assess whether clinicians should target ratios and deficits as optimal pediatric hemostatic resuscitation practice.

Traumatic brain injury (TBI) has the highest incidence of all common neurological disorders, and poses a substantial public health burden. TBI is increasingly documented not only as an acute condition but also as a chronic disease with long-term consequences, including an increased risk of late-onset neurodegeneration. The first Lancet Neurology Commission on TBI, published in 2017, called for a concerted effort to tackle the global health problem posed by TBI. Since then, funding agencies have supported research both in high-income countries (HICs) and in low-income and middle-income countries (LMICs). In November 2020, the World Health Assembly, the decision-making body of WHO, passed resolution WHA73.10 for global actions on epilepsy and other neurological disorders, and WHO launched the Decade for Action on Road Safety plan in 2021. New knowledge has been generated by large observational studies, including those conducted under the umbrella of the International Traumatic Brain Injury Research (InTBIR) initiative, established as a collaboration of funding agencies in 2011. InTBIR has also provided a huge stimulus to collaborative research in TBI and has facilitated participation of global partners. The return on investment has been high, but many needs of patients with TBI remain unaddressed. This update to the 2017 Commission presents advances and discusses persisting and new challenges in prevention, clinical care, and research.

Importance Severe asthma exacerbations cause significant morbidity and costs. Whether vitamin D3supplementation reduces severe childhood asthma exacerbations is unclear. Objective To determine whether vitamin D3supplementation improves the time to a severe exacerbation in children with asthma and low vitamin D levels. Design, Setting, and Participants The Vitamin D to Prevent Severe Asthma Exacerbations (VDKA) Study was a randomized, double-blind, placebo-controlled clinical trial of vitamin D3supplementation to improve the time to severe exacerbations in high-risk children with asthma aged 6 to 16 years taking low-dose inhaled corticosteroids and with serum 25-hydroxyvitamin D levels less than 30 ng/mL. Participants were recruited from 7 US centers. Enrollment started in February 2016, with a goal of 400 participants; the trial was terminated early (March 2019) due to futility, and follow-up ended in September 2019. Interventions Participants were randomized to vitamin D3, 4000 IU/d (n = 96), or placebo (n = 96) for 48 weeks and maintained with fluticasone propionate, 176 μg/d (6-11 years old), or 220 μg/d (12-16 years old). Main Outcomes and Measures The primary outcome was the time to a severe asthma exacerbation. Secondary outcomes included the time to a viral-induced severe exacerbation, the proportion of participants in whom the dose of inhaled corticosteroid was reduced halfway through the trial, and the cumulative fluticasone dose during the trial. Results Among 192 randomized participants (mean age, 9.8 years; 77 girls [40%]), 180 (93.8%) completed the trial. A total of 36 participants (37.5%) in the vitamin D3group and 33 (34.4%) in the placebo group had 1 or more severe exacerbations. Compared with placebo, vitamin D3supplementation did not significantly improve the time to a severe exacerbation: the mean time to exacerbation was 240 days in the vitamin D3group vs 253 days in the placebo group (mean group difference, −13.1 days [95% CI, −42.6 to 16.4]; adjusted hazard ratio, 1.13 [95% CI, 0.69 to 1.85];P = .63). Vitamin D3supplementation, compared with placebo, likewise did not significantly improve the time to a viral-induced severe exacerbation, the proportion of participants whose dose of inhaled corticosteroid was reduced, or the cumulative fluticasone dose during the trial. Serious adverse events were similar in both groups (vitamin D3group, n = 11; placebo group, n = 9). Conclusions and Relevance Among children with persistent asthma and low vitamin D levels, vitamin D3supplementation, compared with placebo, did not significantly improve the time to a severe asthma exacerbation. The findings do not support the use of vitamin D3supplementation to prevent severe asthma exacerbations in this group of patients. Trial Registration ClinicalTrials.gov Identifier:NCT02687815

Background Low-titer group O whole-blood (LTOWB) is being used for children with life-threatening traumatic bleeding. A survey was conducted to determine current LTOWB utilization and interest in participation in a randomized control trial (RCT) of LTOWB versus standard blood component transfusion in this population. Study design and methods Transfusion medicine (TM) directors and pediatric trauma directors at 36 US children's hospitals were surveyed by e-mail in June 2020. Hospitals were selected by participation in the Massive Transfusion Epidemiology and Outcomes in Children Study or being among the largest 30 children's hospitals by bed capacity per the Becker Hospital Review. Results The response rate was 83.3% (30/36) from TM directors and 88.9% (32/36) from trauma directors. The median of massive transfusion protocol activations for traumatic bleeding was reported as 12 (IQR 5.8-20) per year by TM directors. LTOWB was used by 18.8% (6/32) of trauma directors. Survey responses indicate that 86.7% (26/30) of TM directors and 90.6% (29/32) of trauma directors either moderately or strongly agree that a LTOWB RCT is important to perform. About 83.3% (25/30) of TM directors and 93.8% (30/32) of trauma directors were willing to participate in the proposed trial. About 80% (24/30) of TM directors and 71.9% (23/32) of trauma directors would transfuse RhD+ LTOWB to male children, but fewer would transfuse Rh + LTOWB to females [20% (6/30) TM directors and 37.5% (12/32) of trauma directors]. Conclusions A majority of respondents supported an RCT comparing LTOWB to component therapy in children with severe traumatic bleeding.

Diversion of cerebrospinal fluid (CSF) has been used for decades as a treatment for children with severe traumatic brain injury (TBI) and is recommended by evidenced-based guidelines. However, these recommendations are based on limited studies.To determine whether CSF diversion is associated with improved Glasgow Outcome Score-Extended for Pediatrics (GOS-EP) and decreased intracranial pressure (ICP) in children with severe TBI.This observational comparative effectiveness study was performed at 51 clinical centers that routinely care for children with severe TBI in 8 countries (US, United Kingdom, Spain, the Netherlands, Australia, New Zealand, South Africa, and India) from February 2014 to September 2017, with follow-up at 6 months after injury (final follow-up, October 22, 2021). Children with severe TBI were included if they had Glasgow Coma Scale (GCS) scores of 8 or lower, had intracranial pressure (ICP) monitor placed on-site, and were aged younger than 18 years. Children were excluded if they were pregnant or an ICP monitor was not placed at the study site. Consecutive children were screened and enrolled, data regarding treatments were collected, and at discharge, consent was obtained for outcomes testing. Propensity matching for pretreatment characteristics was performed to develop matched pairs for primary analysis. Data analyses were completed on April 18, 2022.Clinical care followed local standards, including the use of CSF diversion (or not), with patients stratified at the time of ICP monitor placement (CSF group vs no CSF group).The primary outcome was GOS-EP at 6 months, while ICP was considered as a secondary outcome. CSF vs no CSF was treated as an intention-to-treat analysis, and a sensitivity analysis was performed for children who received delayed CSF diversion.A total of 1000 children with TBI were enrolled, including 314 who received CSF diversion (mean [SD] age, 7.18 [5.45] years; 208 [66.2%] boys) and 686 who did not (mean [SD] age, 7.79 [5.33] years; 437 [63.7%] boys). The propensity-matched analysis included 98 pairs. In propensity score-matched analyses, there was no difference between groups in GOS-EP (median [IQR] difference, 0 [-3 to 1]; P = .08), but there was a decrease in overall ICP in the CSF group (mean [SD] difference, 3.97 [0.12] mm Hg; P .001).In this comparative effectiveness study, CSF diversion was not associated with improved outcome at 6 months after TBI, but a decrease in ICP was observed. Given the higher quality of evidence generated by this study, current evidence-based guidelines related to CSF diversion should be reconsidered.

BACKGROUND: Observational studies have yielded inconsistent findings for the relation between vitamin D level and total IgE or allergic sensitization. OBJECTIVE: To determine whether vitamin D supplementation reduces levels of total IgE and IgE to each of two common indoor allergens in children with asthma and low vitamin D levels. METHODS: Total IgE, IgE to Dermatophagoides pteronyssinus (Der p), and IgE to Blattella germanica (Bla g) were measured at the randomization and exit visits for 174 participants in the Vitamin D Kids Asthma study (VDKA), a multicenter, double-blind, randomized placebo-controlled trial of vitamin D(3) supplementation (4,000 IU/day) to prevent severe exacerbations in children with persistent asthma and vitamin D levels

Sulfonylurea receptor-1 (SUR1) is recognized increasingly as a key contributor to cerebral edema, hemorrhage progression, and possibly neuronal death in multiple forms of acute brain injury. SUR1 inhibition may be protective and is actively undergoing evaluation in Phase-2/3 trials of traumatic brain injury (TBI) and stroke. In adult TBI, SUR1 expression is associated with intracranial hypertension and contusion expansion; its role in pediatric TBI remains unexplored. We tested 61 cerebrospinal fluid (CSF) samples from 16 pediatric patients with severe TBI enrolled in the multicenter Phase-3 randomized controlled “Cool Kids” trial and seven non-brain injured pediatric controls for SUR1 expression by enzyme-linked immunosorbent assay. Linear mixed models evaluated associations between mean SUR1 and intracranial pressure (ICP) over the first seven days and pediatric Glasgow Outcome Scale-Extended (GOS-E Peds) over the initial year after injury. SUR1 was undetectable in control CSF and increased versus control in nine of 16 patients with TBI. Mean SUR1 was not associated with age, sex, or therapeutic hypothermia. Each 1-point increase in initial Glasgow Coma Score was associated with a 1.68 ng/mL decrease in CSF SUR1. The CSF SUR1 was associated with increased ICP over seven days (b = 0.73, p = 0.004) and worse (higher) GOS-E Peds score (b = 0.24, p = 0.004). In this exploratory pediatric study, CSF SUR1 was undetectable in controls and variably elevated in severe TBI. Mean CSF SUR1 concentration was associated with ICP and outcome. These findings are distinct from our previous report in adults with severe TBI, where SUR1 was detected universally. SUR1 may be a viable therapeutic target in a subset of pediatric TBI, and further study is warranted.

Importance: Alteration in lung microbes is associated with disease progression in idiopathic pulmonary fibrosis. Objective: To assess the effect of antimicrobial therapy on clinical outcomes. Design, Setting, and Participants: Pragmatic, randomized, unblinded clinical trial conducted across 35 US sites. A total of 513 patients older than 40 years were randomized from August 2017 to June 2019 (final follow-up was January 2020). Interventions: Patients were randomized in a 1:1 allocation ratio to receive antimicrobials (n = 254) or usual care alone (n = 259). Antimicrobials included co-trimoxazole (trimethoprim 160 mg/sulfamethoxazole 800 mg twice daily plus folic acid 5 mg daily, n = 128) or doxycycline (100 mg once daily if body weight

To characterize inpatient rehabilitation services for children with severe traumatic brain injury (TBI), we included 254 children, whose parents/guardians reported receipt of rehabilitation within a 12-month follow-up period, from a multinational observational study. Children discharged to an inpatient rehabilitation or skilled nursing facility after acute care were classified into the "inpatient rehabilitation" group, and children discharged home after acute care were classified into the "non-inpatient rehabilitation" group. Multivariable regression analyses determined the associations of sociodemographic and clinical characteristics with rehabilitation groups. Children receiving inpatient rehabilitation had a shorter length of acute hospitalization. Children from the UK were less likely to receive inpatient rehabilitation compared to children from the US. Future studies are warranted to extend current findings by identifying the reasons behind differential access to inpatient rehabilitation among children with severe TBI.

Vitamin D supplementation, compared with placebo, had no significant effect on percent predicted lung function measures (FEV1, FVC, or FEV1/FVC), asthma control, or asthma-related quality of life in children with asthma and low vitamin D levels. Observational studies have shown that low vitamin D levels are linked to worse lung function and poor asthma control in children with asthma. We hypothesized that vitamin D supplementation would improve function, disease control, and quality of life in children with asthma (ages 6–16 years) and vitamin D levels below 30 ng·mL−1. We tested this hypothesis in a secondary analysis of data from the Vitamin D Kids Asthma Study (VDKA), a randomized, double-blind, parallel, placebo-controlled clinical trial. Each participant in the VDKA was randomly assigned to either daily placebo capsules or daily vitamin D3 (4000 IU) plus low-dose inhaled fluticasone propionate. Of the 192 randomized participants, 176 were included in the analysis of change in percent predicted lung function measures (FEV1, FVC, and FEV1/FVC) and asthma control scores. Of these 176 participants, 94 were also included in the analysis of change in asthma-related quality of life scores, as they were 10 years and older. Linear regression was used for the multivariable analysis of vitamin D supplementation and each outcome, which was adjusted for study site, race, sex, and time in the study. In this analysis, vitamin D supplementation was not significantly associated with change in any outcome (lung function measures, asthma control, or asthma-related quality of life) between the randomization and exit visits. Our results do not support recommending vitamin D supplementation to improve lung function, asthma control, or asthma-related quality of life in children with asthma and vitamin D levels below 30 ng·mL−1. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Han has nothing to disclose. Conflict of interest: Dr. Forno has nothing to disclose. Conflict of interest: Dr. Bacharier has nothing to disclose. Conflict of interest: Dr. Phipatanakul reports personal fees from GSK, Genentech, Novartis, Regeneron, Sanofi, and Teva, grants from Genentech, Novartis, Regeneron, Sanofia, Circassia, Monaghen, Thermo Fisher, Alk Abello, Lincoln Diagnostics, GSK, Kaleo, and Merck, grants from Genentech, Regeneron, Novartis, and the US NIH, outside the submitted work; . Conflict of interest: Dr. Guilbert reports personal fees from American Board of Pediatrics (Pediatric Pulmonary Sub-board), GSK, TEVA, and Sanofi/Regeneron, grants from Astra-Zeneca, Novartis, and Sanofi/Regeneron, non-financial support from Up To Date, outside the submitted work; . Conflict of interest: Dr. Cabana reports other from United States Preventive Services Task Force (USPSTF), outside the submitted work; . Conflict of interest: Dr. Ross has nothing to disclose. Conflict of interest: Dr. Blatter has nothing to disclose. Conflict of interest: Dr. Rosser has nothing to disclose. Conflict of interest: Dr. Durrani has nothing to disclose. Conflict of interest: Dr. Luther has nothing to disclose. Conflict of interest: Dr. Wisniewski has nothing to disclose. Conflict of interest: Dr. Celedon reports non-financial support from Pharmavite and GSK, during the conduct of the study; non-financial support from Merck, outside the submitted work.Dr. Celedon reports non-financial support from Pharmavite and GSK, during the conduct of the study; non-financial support from Merck, outside the submitted work; .

Importance Severe asthma exacerbations cause significant morbidity and costs. Whether vitamin D3supplementation reduces severe childhood asthma exacerbations is unclear. Objective To determine whether vitamin D3supplementation improves the time to a severe exacerbation in children with asthma and low vitamin D levels. Design, Setting, and Participants The Vitamin D to Prevent Severe Asthma Exacerbations (VDKA) Study was a randomized, double-blind, placebo-controlled clinical trial of vitamin D3supplementation to improve the time to severe exacerbations in high-risk children with asthma aged 6 to 16 years taking low-dose inhaled corticosteroids and with serum 25-hydroxyvitamin D levels less than 30 ng/mL. Participants were recruited from 7 US centers. Enrollment started in February 2016, with a goal of 400 participants; the trial was terminated early (March 2019) due to futility, and follow-up ended in September 2019. Interventions Participants were randomized to vitamin D3, 4000 IU/d (n = 96), or placebo (n = 96) for 48 weeks and maintained with fluticasone propionate, 176 μg/d (6-11 years old), or 220 μg/d (12-16 years old). Main Outcomes and Measures The primary outcome was the time to a severe asthma exacerbation. Secondary outcomes included the time to a viral-induced severe exacerbation, the proportion of participants in whom the dose of inhaled corticosteroid was reduced halfway through the trial, and the cumulative fluticasone dose during the trial. Results Among 192 randomized participants (mean age, 9.8 years; 77 girls [40%]), 180 (93.8%) completed the trial. A total of 36 participants (37.5%) in the vitamin D3group and 33 (34.4%) in the placebo group had 1 or more severe exacerbations. Compared with placebo, vitamin D3supplementation did not significantly improve the time to a severe exacerbation: the mean time to exacerbation was 240 days in the vitamin D3group vs 253 days in the placebo group (mean group difference, −13.1 days [95% CI, −42.6 to 16.4]; adjusted hazard ratio, 1.13 [95% CI, 0.69 to 1.85];P = .63). Vitamin D3supplementation, compared with placebo, likewise did not significantly improve the time to a viral-induced severe exacerbation, the proportion of participants whose dose of inhaled corticosteroid was reduced, or the cumulative fluticasone dose during the trial. Serious adverse events were similar in both groups (vitamin D3group, n = 11; placebo group, n = 9). Conclusions and Relevance Among children with persistent asthma and low vitamin D levels, vitamin D3supplementation, compared with placebo, did not significantly improve the time to a severe asthma exacerbation. The findings do not support the use of vitamin D3supplementation to prevent severe asthma exacerbations in this group of patients. Trial Registration ClinicalTrials.gov Identifier:NCT02687815

Introduction: There is growing evidence that computer-delivered or computer-assisted forms of cognitive behavior therapy (CCBT) are helpful, but cost-effectiveness versus standard therapies is not well established. Objective: To evaluate the cost-effectiveness of a therapist-supported method for CCBT in comparison to standard cognitive behavior therapy (CBT). Methods: A total of 154 drug-free major depressive disorder outpatients were randomly assigned to either 16 weeks of standard CBT (up to twenty 50-min sessions) or CCBT using the Good Days Ahead program (including up to 5.5 h of therapist contact). Outcomes were assessed at baseline, weeks 8 and 16, and at 3 and 6 months post-treatment. Economic analyses took into account the costs of services received and work/social role impairment. Results: In the context of almost identical efficacy, a form of CCBT that used only about one third the amount of therapist contact as conventional CBT was highly cost-effective compared to conventional therapy and reduced the adjusted cost of treatment by USD 945 per patient. Conclusions: A method of CCBT that blended internet-delivered modules and abbreviated therapeutic contact reduced the cost of treatment substantially without adversely affecting outcomes. Results suggest that use of this approach can more than double the access to CBT. Because clinician support in CCBT can be provided by telephone, videoconference, and/or email, this highly efficient form of treatment could be a major advance in remote treatment delivery.

Objective:Patients with bipolar disorder have recurrent major depression, residual mood symptoms, and limited treatment options. Building on promising pilot data, the authors conducted a 6-week randomized double-blind placebo-controlled trial to investigate the efficacy of adjunctive bright light therapy at midday for bipolar depression. The aims were to determine remission rate, depression symptom level, and rate of mood polarity switch, as well as to explore sleep quality.Method:The study enrolled depressed adults with bipolar I or II disorder who were receiving stable dosages of antimanic medication (excluding patients with hypomania or mania, mixed symptoms, or rapid cycling). Patients were randomly assigned to treatment with either 7,000-lux bright white light or 50-lux dim red placebo light (N=23 for each group). Symptoms were assessed weekly with the Structured Interview Guide for the Hamilton Depression Scale With Atypical Depression Supplement (SIGH-ADS), the Mania Rating Scale, and the Pittsburg...

Summary Trauma is a leading cause of death and morbidity worldwide. Here, we present the analysis of a longitudinal multi-omic dataset comprising clinical, cytokine, endotheliopathy biomarker, lipidome, metabolome, and proteome data from severely injured humans. A “systemic storm” pattern with release of 1,061 markers, together with a pattern suggestive of the “massive consumption” of 892 constitutive circulating markers, is identified in the acute phase post-trauma. Data integration reveals two human injury response endotypes, which align with clinical trajectory. Prehospital thawed plasma rescues only endotype 2 patients with traumatic brain injury (30-day mortality: 30.3 versus 75.0%; p = 0.0015). Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) was identified as the most predictive circulating biomarker to identify endotype 2-traumatic brain injury (TBI) patients. These response patterns refine the paradigm for human injury, while the datasets provide a resource for the study of critical illness, trauma, and human stress responses., Graphical abstract, Highlights An integrated longitudinal multi-omic analysis of the human response to trauma Systemic storm and massive consumption patterns are related to early mortality Unique resolution and non-resolution signatures across multiple “omics” platforms Only endotype 2-TBI patients with high UCHL1 levels benefit from early plasma, Wu et al. report a longitudinal multi-omic analysis of the circulation in trauma patients. Cross-platform data integration reveals a massive systemic release of cellular contents (“systemic storm”) and simultaneous consumption of blood constituents. Also defined are patient endotypes that differ in outcomes and responses to early plasma administration.

BackgroundExposure to violence has been associated with lower lung function in cross-sectional studies.MethodsWe examined whether increasing violence-related distress over time is associated with worse lung function and worse asthma control or quality of life in a secondary analysis of a 48-week randomised clinical trial in 98 youth with asthma (aged 9–16 years) treated with low-dose inhaled corticosteroids (Vitamin D Kids Asthma Study (VDKA)). We then replicated our findings for lung function in a prospective study of 232 Puerto Rican youth followed for an average of 5.4 years. Violence-related distress was assessed using the Checklist of Children's Distress Symptoms (CCDS) scale. Our outcomes of interest were percent predicted lung function measures and (in VDKA only) asthma control (assessed using the Asthma Control Test) and asthma-related quality of life (assessed using the Pediatric Asthma Quality of Life Questionnaire (PAQLQ)).ResultsIn a multivariable analysis in VDKA, each 1-point increment in CCDS score was associated with decrements of 3.27% in forced expiratory volume in 1 s (FEV1) % pred (95% CI −6.44– −0.22%; p=0.04), 2.65% in forced vital capacity (FVC) % pred (95% CI −4.86– −0.45%; p=0.02) and 0.30 points in the overall PAQLQ score (95% CI −0.50– −0.10 points; p1 and FVC were obtained in the prospective study of Puerto Rican youth.ConclusionsOur findings suggest that violence-related distress may worsen lung function and quality of life in youth with asthma (even those treated with low-dose inhaled corticosteroids), and further support policies to reduce exposure to violence among children in the USA and Puerto Rico.

Objective Few data about the development of infants born to women with bipolar disorder have been published. We hypothesized that infants of women with bipolar disorder (by DSM-IV criteria) treated with psychotropics (BD+) or untreated with psychotropics (BD-) would demonstrate poorer cognitive and behavioral development than infants of controls. On the basis of previous studies, we expected that psychotropic-exposed infants of women in the BD+ group would have poorer neuromotor performance during infancy. Methods This longitudinal study included 197 mother-infant dyads recruited to participate between July 2006 and March 2011: 81 with prenatal maternal bipolar disorder without psychotropic treatment (BD-, n = 27) or bipolar disorder with psychotropic exposure (BD+, n = 54) and 116 in which infants were exposed to neither bipolar disorder nor psychotropics. Maternal psychopathology and pharmacotherapy exposure assessments were completed at 20, 30, and 36 prenatal weeks and 12, 26, and 52 weeks postpartum. Infants were evaluated with the Bayley Scales of Infant Development, Second Edition, which included the psychomotor (Psychomotor Development Index [PDI]), cognitive (Mental Development Index [MDI]), and behavioral (Behavioral Rating Scale [BRS]) components. Results Neither prenatal exposure to BD- or BD+ significantly impacted overall PDI (P = .2449), MDI (P = .7886), or BRS (P = .6072) scores. However, we observed a significant effect of BD+ exposure-by-time interaction for the BRS Motor Quality index (F₂₄₅ = 3.16, P = .0441), with BD+ exposed infants less likely to be above the 75th percentile at the 52-week assessment (mean = 11.5%) compared with BD- (mean = 40.0%) and nonexposed infants (mean = 48.4%). Conclusions We found no significant impact of prenatal BD- or BD+ exposure on infant PDI, MDI, or overall BRS scores at 12, 26, or 52 weeks of age, with most scores remaining within normal limits. Consistent with previous studies, we found a specific effect of prenatal BD+ exposure on quality of motor functioning at 1 year. However, the majority of infants were within normal limits on this developmental outcome. Trial registration ClinicalTrials.gov identifier: NCT00585702.

The Glasgow Coma Scale (GCS) score has not been validated in children younger than 5 years and the clinical circumstances at the time of assignment can limit its applicability. This study describes the distribution of GCS scores in the population, the relationship between injury characteristics with the GCS score, and the association between the tripartite stratification of the GCS on mortality in children with severe traumatic brain injury (TBI). The first 200 children from a multi-center comparative effectiveness study in severe TBI (inclusion criteria: age 0–18 years, GCS ≤8 at the time of intracranial pressure [ICP] monitoring) were analyzed. After tripartite stratification of GCS scores (Group A, GCS 3; Group B, GCS 4 - 5; and Group C, GCS 6 - 8), analyses of variance and chi-square testing were performed. Mean age was 7.61 years ±5.33 and mortality was 19.1%. There was no difference in etiology or type/mechanism of injury between groups. However, groups demonstrated differences in neuromuscular blockade, endotracheal intubation, pre-hospital events (cardiac arrest and apnea), coagulopathy, and pupil response. Mortality between groups was different (42.2% Group A, 22.6% Group B, and 3.8% Group C; p

Objectives Chronic obstructive pulmonary disease (COPD) is more prevalent in HIV-infected individuals and is associated with persistent inflammation. Therapies unique to HIV are lacking. We performed a pilot study of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor rosuvastatin to determine effects on lung function. Design Randomized, placebo-controlled, triple-blinded trial. Methods HIV-infected individuals with abnormal lung function were recruited from an ongoing lung function study. Participants were randomized to 24 weeks of placebo (n = 11) or rosuvastatin (n = 11) using an adaptive randomization based on change in peripheral C-reactive protein levels at 30 days of treatment. Forced expiratory volume in 1 s (FEV1) and diffusing capacity for carbon monoxide (DLco)%-predicted were compared to baseline at 24 weeks in the two groups using a Wilcoxon rank-sum test. The %-predicted change at 24 weeks in pulmonary function variables was compared between groups using simulated randomization tests. Results The placebo group experienced a significant decline in FEV1%-predicted (P = 0.027), and no change in DLco%-predicted over 24 weeks. In contrast, FEV1%-predicted remained stable in the rosuvastatin group, and DLco%-predicted increased significantly (P = 0.027). There was no significant difference in absolute change in either measure between placebo and rosuvastatin groups. Conclusion In a pilot study, the use of rosuvastatin for 24 weeks appeared to slow worsening of airflow obstruction and to improve DLco in HIV-infected individuals with abnormal lung function, although comparison of absolute changes between the groups did not reach significance. This study is the first to test a therapy for COPD in an HIV-infected population, and large-scale clinical trials are needed.

Study objectivesTo determine if patients with childhood onsets (CO) of both major depression and insomnia disorder show blunted depression and insomnia treatment responses to concurrent interventions for both disorders compared to those with adult onsets (AO) of both conditions.MethodsThis study was a secondary analysis of data obtained from a multisite randomized clinical trial designed to test the efficacy of combining a psychological/behavior insomnia therapy with antidepressant medication to enhance depression treatment outcomes in patients with comorbid major depression and insomnia. This study included 27 adults with CO of depression and insomnia and 77 adults with AO of both conditions. They underwent a 16-week treatment including: (1) a standardized two-step pharmacotherapy for depression algorithm, consisting of escitalopram, sertraline, and desvenlafaxine in a prescribed sequence; and (2) either cognitive behavioral insomnia therapy (CBT-I) or a quasi-desensitization control (CTRL) therapy. Main outcome measures were the 17-item Hamilton Rating Scale for Depression (HRSD-17) and the Insomnia Severity Index (ISI) completed pre-treatment and every 2 weeks thereafter.ResultsThe AO and CO groups did not differ significantly in regard to their pre-treatment HRSD-17 and ISI scores. Mixed model analyses that adjusted for the number of insomnia treatment sessions attended showed that the AO group achieved significantly lower, subclinical scores on the HRSD-17 and ISI than did the CO group by the time of study exit. Moreover, a significant group by treatment arm interaction suggested that HRSD-17 scores at study exit remained significantly higher in the CO group receiving the CTRL therapy than was the case for the participants in the CO group receiving CBT-I. Greater proportions of the AO group achieved a priori criteria for remission of insomnia (49.3% vs. 29.2%, p = 0.04) and depression (45.5% vs. 29.6%, p = 0.07) than did those in the CO group.ConclusionsPatients with comorbid depression and insomnia who experienced the first onset of both disorders in childhood are less responsive to the treatments offered herein than are those with adult onsets of these comorbid disorders. Further research is needed to identify therapies that enhance the depression and insomnia treatment responses of those with childhood onsets of these two conditions.

Objective. To evaluate the performance of a type III home sleep testing (HST) monitor including its autoscoring algorithm, in a population of obese pregnant women. Methods. This was an ancillary study of an ongoing prospective study of obese (BMI of ≥30) pregnant women. For the primary study, women undergo serial in-lab polysomnograms (PSG) during pregnancy. Sleep apnea was defined as an apnea hypopnea index (AHI) of ≥ 5 events/hour. A subgroup of women were asked to wear an ApneaLink HST device for 1 night, within 2 weeks of a late pregnancy PSG (≥ 28 weeks’ gestation). The AHI obtained from PSG was compared to the AHI from the HST via autoscoring (HST-auto) as well as the AHI via technician scoring (HST-tech). We calculated Shrout Fleiss Fixed correlation coefficients (ICC) and looked at positive-positive and negative-negative agreement. Results. 43 women were recruited and we obtained 30 valid HST. The mean PSH AHI was 3.3 (±3.2, range 0.5-16.6). Six (20%) women had a positive PSG study. ICCs were 0.78 for HST-auto versus HST-tech, 0.76 for HST-auto versus PSG, and 0.70 for HST-tech versus PSG. Categorical agreement was also strong, with 24/30 (80.0%) for HST-auto versus HST-tech, 25/30 (83.3%) for HST-auto versus PSG, and 23/30 (76.7%) for HST-tech versus PSG. Conclusion. In obese women evaluated in late pregnancy, we found relatively high intraclass correlation and categorical agreement among HST-auto scores, HST-tech scores, and in-lab PSG results obtained within a two-week window. These results suggest that HST may be used to screen pregnant women for OSA.

Importance Mild traumatic brain injury (TBI) is experienced by 55.9 million people globally each year. The symptoms of mild TBI are diverse and sometimes long-lasting, requiring frequent use of pharmacological interventions to mitigate them. A thorough understanding of the data supporting pharmacological interventions is important for decision-making among clinicians treating this common injury. Objective To systematically review studies of pharmacological interventions and their associations with symptom burden reduction among patients with mild TBI and to use an evidence-based model to identify potential directions for future research that may aid in clinical decision-making. Evidence Review A systematic review was performed in PubMed, Scopus, and Web of Science. Search strings modified for the advanced search interfaces of each search engine were developed in consultation with a librarian and included combinations of search terms, such asbrain concussion,post-concussion syndrome,mild traumatic brain injury, andpharmacological treatment. Articles published between January 1, 2000, and July 1, 2020, were analyzed. Studies were included if (1) they were clinical studies with discrete analyses of participants with mild TBI or complicated mild TBI, (2) they were assessments of a pharmacological intervention, (3) they included human participants, and (4) they were published in a peer-reviewed journal in the English language. Studies were excluded if the severity of TBI among participants could not be ascertained (ie, inadequate definition of mild TBI) and the inclusion criteria for the study required intracranial hemorrhage. A total of 23 studies examining 20 pharmacological interventions met the inclusion criteria. Risk of bias was assessed using the Cochrane Risk of Bias for Randomized Trials (for randomized clinical trials) and the Cochrane Risk of Bias in Non-Randomized Studies of Interventions (for all other studies). Data were analyzed from June to September 2020. Findings A total of 1495 articles were identified; of those, 131 articles were excluded as duplicates. Titles and abstracts were screened for inclusion and exclusion criteria among the remaining 1364 articles, and 134 of those articles received a full-text review. After exclusions, 23 studies (11 randomized clinical trials, 7 prospective observational studies, 3 retrospective observational studies, and 2 case studies) examining 20 pharmacological interventions were identified for inclusion in the systematic review. Studies included 22 distinct participant populations comprising 8277 participants with mild TBI and 45 participants without TBI. Among 23 total studies, 8 studies specifically addressed the pediatric population, 9 studies had a low risk of bias, and 16 studies reported symptom burden reduction. Of the 20 pharmacological interventions examined in the studies, methylphenidate, sertraline hydrochloride, ondansetron, amitriptyline, and melatonin were the only medications included in multiple studies. Conclusions and Relevance This systematic review found a limited number of high-quality, clinically meaningful studies, particularly among children and individuals in the acute stage of injury; therefore, performing an evidence-based analysis that would inform clinical decision-making was not possible. Future studies are needed to focus on standardizing measures and increasing sample sizes (including large multicenter clinical trials) to generate a body of research that may provide additional options for the treatment of patients with mild TBI.

The relationship between perceived neighborhood contentedness and physical activity was evaluated in the Add Health study population. Wave I includes 20,745 respondents (collected between 1994 and 1995) and wave II includes 14,738 (71 %) of these same students (collected in 1996). Multinomial logistic regression was used to evaluate this relationship in both wave I and wave II of the sample. Higher levels of Perceived Neighborhood Contentedness were associated with higher reports of physical activity in both males and females and in both waves. For every one-point increment in PNS, males were 1.3 times as likely to report being highly physically active than low (95 % CI 1.23–1.37) in wave 1 and 1.25 times as likely in wave 2 (95 % CI 1.17–1.33). Females were 1.17 (95 % CI 1.12–1.22) times as likely to report being highly active than low and 1.22 times as likely in wave 2 (95 % CI 1.17–1.27) with every one-point increment. PNC appears to be significantly associated with physical activity in adolescents. Involving the community in the development of intervention programs could help to raise the contentedness of adolescents in these communities.

Background Unipolar and bipolar depression identified in the postpartum period have a heterogeneous etiology. The objectives of this study are to examine the risk factors that distinguish the timing of onset for unipolar and bipolar depression and the associations between depression onset by diagnosis, and general and atypical depressive symptoms. Methods Symptoms of depression were assessed at 4- to 6-weeks postpartum by the Structured Interview Guide for the Hamilton Depression Rating Scale-Atypical Depression Symptoms in an obstetrical sample of 727 women. Data were analyzed using ANOVA, Chi-square, and linear regression. Results Mothers with postpartum onset of depression were more likely to be older, Caucasian, educated, married/cohabitating, have one or no previous child, and have private insurance in contrast to mothers with pre-pregnancy and prenatal onset of depression. Mothers with bipolar depression were more likely to have a pre-pregnancy onset. Three general and two atypical depressive symptoms distinguished pre-pregnancy, during pregnancy, and postpartum depression onset, and the presence of agitation distinguished between unipolar and bipolar depression. Limitations The sample was urban, which may not be generalizable to other populations. The study was cross-sectional, which excludes potential late onset of depression (after 4–6 weeks) in the first postpartum year. Conclusions A collective set of factors predicted the onset of depression identified in the postpartum for mothers distinguished by episodes of unipolar versus bipolar depression, which can inform clinical interventions. Future research on the onset of major depressive episodes could inform prophylactic and early psychiatric interventions.

Context.—Jejunoileal neuroendocrine tumors (JINETs) are slow-growing, malignant tumors that are often associated with protracted survival, despite their frequent presentation at an advanced stage. A subset of JINETs is complicated by intestinal ischemic necrosis (IIN), which leads to their initial clinical presentation. Objective.—To assess the effect of IIN on overall survival in patients with JINETs. Design.—Ten JINETs with IIN during a 14-year period and a control group of 52 JINETs without IIN were identified retrospectively. The hematoxylin-eosin slides and gross descriptions were reviewed, and pathologic features were assessed. Overall survival was compared between the 2 groups using the Kaplan Meier method and Cox proportional hazards model. Results.—At 1 year postresection, only 40% (4 of 10) of the patients with IIN were alive, whereas 94% (49 of 52) of those without IIN were alive (P < .001). Patients with IIN were significantly older than those without IIN (median, 83 years versus 65.5 years, P = .001). By univariate Cox proportional hazards regression, IIN was associated with a 4.30-fold increased risk of death (95% confidence interval 1.75–10.56; P = .001). When controlling for age, advanced stage (stage III or IV), tumor grade, and synchronous carcinoma in a multivariate analysis, IIN showed a trend toward prognostic significance (2.31-fold increased risk of death; 95% confidence interval, 0.85–6.27; P = .10). Conclusions.—The pathologic identification of tumor-associated IIN portends a worse overall survival among patients with JINETs.

OBJECTIVES: The evidence to guide therapy in pediatric traumatic brain injury is lacking, including insight into the intracranial pressure/cerebral perfusion pressure thresholds in abusive head trauma. We examined intracranial pressure/cerebral perfusion pressure thresholds and indices of intracranial pressure and cerebral perfusion pressure burden in relationship with outcome in severe traumatic brain injury and in accidental and abusive head trauma cohorts. DESIGN: A prospective observational study. SETTING: PICU in a tertiary children's hospital. PATIENTS: Children less than18 years old admitted to a PICU with severe traumatic brain injury and who had intracranial pressure monitoring. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A pediatric traumatic brain injury database was interrogated with 85 patients (18 abusive head trauma) enrolled. Hourly intracranial pressure and cerebral perfusion pressure (in mm Hg) were collated and compared with various thresholds. C-statistics for intracranial pressure and cerebral perfusion pressure data in the entire population were determined. Intracranial hypertension and cerebral hypoperfusion indices were formulated based on the number of hours with intracranial pressure more than 20 mm Hg and cerebral perfusion pressure less than 50 mm Hg, respectively. A secondary analysis was performed on accidental and abusive head trauma cohorts. All of these were compared with dichotomized 6-month Glasgow Outcome Scale scores. The models with the number of hours with intracranial pressure more than 20 mm Hg (C = 0.641; 95% CI, 0.523-0.762) and cerebral perfusion pressure less than 45 mm Hg (C = 0.702; 95% CI, 0.586-0.805) had the best fits to discriminate outcome. Two factors were independently associated with a poor outcome, the number of hours with intracranial pressure more than 20 mm Hg and abusive head trauma (odds ratio = 5.101; 95% CI, 1.571-16.563). As the number of hours with intracranial pressure more than 20 mm Hg increases by 1, the odds of a poor outcome increased by 4.6% (odds ratio = 1.046; 95% CI, 1.012-1.082). Thresholds did not differ between accidental versus abusive head trauma. The intracranial hypertension and cerebral hypoperfusion indices were both associated with outcomes. CONCLUSIONS: The duration of hours of intracranial pressure more than 20 mm Hg and cerebral perfusion pressure less than 45 mm Hg best discriminated poor outcome. As the number of hours with intracranial pressure more than 20 mm Hg increases by 1, the odds of a poor outcome increased by 4.6%. Although abusive head trauma was strongly associated with unfavorable outcome, intracranial pressure/cerebral perfusion pressure thresholds did not differ between accidental and abusive head trauma. Language: en