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Collecting detailed, objective pre-crash information has been a challenge for the transportation community. While simulator studies, crash databases, and police accident reports/investigations help provide data that contribute to our overall understanding of crash risk, such studies are limited in that they cannot provide accurate information about the seconds and factors immediately preceding a crash or near-crash as such events occur in the real world. The naturalistic driving study method helps to fill this knowledge gap, with participants’ personal vehicles equipped with discreet instrumentation that includes cameras and sensors that continually collect kinematic, environmental, and behavioral data as drivers go about their normal driving routines. The naturalistic driving study of the Second Strategic Highway Research Program (SHRP 2) constitutes the largest such study with video to date. It captured more than 1900 light-vehicle crashes and 6900 near-crashes, making it a robust resource for researchers who wish to find solutions that help mitigate the occurrence of safety-critical events on national highways. The study database comprises more than 32 million miles of continuous data from over 3500 drivers across six data collection sites in the United States, allowing also for the study of traffic operations and management. The methods used to design this large-scale study, recruit participants, and highlights of the collected data are included; overall management of the study and its strengths and weakness are also discussed.

Allocation of scarce livers for transplantation seeks to balance competing ethical principles of autonomy, utility, and justice. Given the history and ongoing dependence of transplantation on public support for funding and organs, understanding and incorporating public attitudes into allocation decisions seems appropriate. In the context of the current controversy around liver allocation, we sought to determine public preferences about issues relevant to the debate. We performed multiple surveys of attitudes around donation and evaluated these using conjoint analysis and clarifying follow-up questions. We found little public support that allocation decisions should be based solely on risk of waiting-list mortality. Strong public sentiment supported maximizing outcomes after transplantation, prioritizing US citizens or residents, keeping organs local, and considering cost in allocation decisions. We then present a methodology for incorporating these preferences into the Model for End-Stage Liver Disease (or MELD) priority score. Taken together, these findings suggest that current allocation schemes do not accurately reflect public preferences and suggest a framework to better align allocation with the values of the public.

Background Sedentary lifestyle morbidities are common among children with congenital heart disease (CHD). Understanding the physical activity trajectory from early childhood could enhance intervention timing/effectiveness. Methods 154 children (56% male) were recruited at 12-47 months of age for this prospective, longitudinal, observational study. Physical activity and sedentary behaviour (7-day accelerometry) and motor skill (Peabody Developmental Motor Scales-2) were assessed every 8 months until 5 years of age and then annually. Mixed effect repeated measures regression models described outcome trajectories across study assessments. Results Children had an innocent heart murmur (n=28), CHD with insignificant hemodynamics not requiring treatment (n=47), CHD treated by catheterization or surgery without cardiopulmonary bypass (n=31), or CHD treated surgically with bypass (n=48). Motor skill was age appropriate (Peabody 49.0±8.4) but participants had lower physical activity (143±41 mins/day) and higher sedentary time (598±89 mins/day) than healthy peers, starting at 18 months of age. Movement behaviours were not related to treatment group (p>0.10), and physical activity was below the recommended 180 mins/day. Over time, physical activity, sedentary time and motor skill were primarily related to the baseline measure of each outcome (p Conclusions Children with simple or complex CHD or innocent heart murmurs have an increased risk for sedentary lifestyles. Their physical activity and sedentary behaviours are established prior to 2 years of age, persist until school age, and are unrelated to motor skill. These results emphasize the need for interventions targeting the youngest children seen in a cardiac clinic, regardless of CHD diagnosis or innocent murmur.

Cerebrovascular dysfunction is increasingly recognized as a major contributor to Alzheimer9s disease (AD). CD2-associated protein (CD2AP), an important predisposing factor for the disease, is enriched in the brain endothelium but the function of protein in the brain vasculature remains undefined. Here, we report that lower levels of CD2AP in brain vessels of human AD volunteers are associated with cognitive deficits. In awake mice, we show that brain endothelial CD2AP regulates cerebral blood flow during resting state and functional hyperemia. In the endothelium, CD2AP controls the levels and signaling of apolipoprotein E receptor 2 (ApoER2), a receptor activated by Reelin glycoprotein that is linked to memory function. Further, Reelin promotes brain vessel dilation and functional hyperemia and both effects are modulated by endothelial CD2AP. Finally, lower levels of ApoER2 in brain vessels are associated with vascular defects and cognitive dysfunction in AD individuals. Thus, deregulation of CD2AP impairs neurovascular coupling and harnessing the biology of the Reelin-ApoER2-CD2AP signaling axis in the brain endothelium may improve brain vascular dysfunction in AD patients.

Physical activity is promoted for optimal health but may carry risks for children who require medically necessary activity restrictions. The sensitivity, specificity, and reliability of the Get Active Questionnaire (GAQ) for identifying children needing special considerations during physical activity was evaluated among parents of 207 children aged 3 to 14 years (97 (47%) female, mean age of 8.4 ± 3.7 years). GAQ responses were compared with reports obtained directly from the treating physician (n = 192/207) and information in the medical chart (clinic notes/physician letter, n = 111/207). Parent GAQ responses (either “No to all questions” or “Yes to 1 or more questions”) agreed with physician (κ = 0.16, p = 0.003) and medical record (κ = 0.15, p = 0.003) reports regarding the need for special consideration during physical activity (Yes/No). Sensitivity was 71% (20/28) and specificity was 59% (96/164), with few false-negative responses. The GAQ was most effective for rheumatology and cardiology patients. False positives were 29% to 46%, except among chronic pain (80%) and rehabilitation (75%) patients. Test–retest reliability was moderate (Cronbach’s α = 0.70) among 57 parents who repeated the GAQ 1 week later. The GAQ effectively identified children not requiring physical activity restrictions and those with medical conditions similar to those of concern among adults. Additional questions from a qualified exercise professional, as recommended for a “Yes” response on the GAQ, should reduce the false-positive burden. Indicating the timeframe of reference for each question and including an option to describe other special considerations (e.g., medication, supervision) are recommended.

Background Combined heart and liver transplant (CHLT) is a complex procedure that is being increasingly performed. Because of the relative rarity of this procedure, graft and patient outcomes are still being assessed and risk factors for graft and patient survival are unknown. Materials and Methods This is a retrospective study from 1989 to 2014 of CHLT in the United Network for Organ Sharing database. Endpoints were graft and patient survival at 1, 3, and 5 years, and risk factors were assessed using multivariable Cox proportional hazard models. Results The cohort included 186 patients. Both graft and patient survival at 1, 3, and 5 years were 85%, 77%, and 74%, respectively. Diabetes (hazard ratio [95% CI]: 2.28 [1.05, 4.92]; P = .036) was significantly associated with risk for graft failure and patient mortality in multivariable analysis. The post–2006 transplant era was associated with significantly improved graft survival and overall survival (hazard ratio [95% CI]: 0.45 [0.24, 0.87]; P = .017). Conclusions Acceptable outcomes are achievable in CHLT through careful candidate selection. As we continue to perform more CHLTs, outcomes and selection criteria need to be continually assessed.

Background: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory condition caused by dysregulation of the immune system. HLH can develop in children with a variety of underlying causes including genetic cause, infection, autoimmune diseases, malignancy, etc. The symptoms of HLH are often similar to other conditions such as bacterial sepsis or systemic inflammatory response syndrome. This is a problem as the similarities among those different diseases make it difficult for the doctors to diagnose HLH and this can possibly lead to a delay in treatment. 50-75% mortality is reported in patients with secondary HLH (non-inherited) who do not receive treatment. Elevated serum ferritin level, referred to as hyperferritinemia, is the most characteristic feature of HLH and may be helpful in diagnosing HLH apart from other illnesses. This research investigates the incidences of patients with elevated serum ferritin level at the pediatric intensive care unit (PICU) of Alberta Children’s Hospital from 2014-2018 to gain a better understanding of HLH and hyperferritinemia. Objectives: The objectives of the study are i. identify diseases associated with hyperferritinemia on the PICU; ii. predict which PICU patient with hyperferritinemia is at risk to develop HLH during PICU admission; and iii. determine mortality risk in patients with hyperferritinemia and HLH at the PICU. Methods: This project is a retrospective chart review. A literature review was performed on the topic of hyperferritinemia and HLH, and relevant variables were identified for creating a Redcap database. Patient charts and medical records were examined for data collection of different elements including diagnosis, laboratory values, treatments, and survival status. Data of 91 patients who presented with hyperferritinemia in PICU from 2014 to 2018 is being examined. Results: Although this study is currently in progress, it is anticipated to provide insight into the features associated with hyperferritinemia and determine patients with hyperferritinemia who are at risk of developing HLH. Conclusion: Overall, the findings from this study may contribute to better understanding of hyperferritinemia and HLH in pediatric patients and contribute to decreasing mortality and morbidity of patients with hyperferritinemia and HLH.

Many pediatric healthcare providers believe that capillary refill time is a measure of perfusion and cardiac output in children. Despite its widespread use, there are no studies examining the relationship of capillary refill time to cardiac output in noncritically ill children. This study examined the inter-rater reliability of capillary refill time and its relationship to hemoglobin and with cardiac output in pediatric patients undergoing cardiac catheterization.Prospective observational study.Tertiary care pediatric hospital.A total of 58 children, ages 0.3-17 yrs, with congenital heart disease undergoing cardiac catheterization.Two clinicians performed two measurements of capillary refill time in a standardized fashion on 58 children undergoing cardiac catheterization. Cardiac output was determined by the Fick method within 15 mins of the first assessment of capillary refill time (time 1).Capillary refill time and cardiac output measurements were obtained in 44 children, and 108 paired measurements of capillary refill time were obtained to assess inter-rater reliability. The mean capillary refill time was 1.2 secs (±0.5 secs), and the mean cardiac output was 3.6 L/min/m (2.2-5.7 L/min/m). The inter-rater intraclass correlation coefficient was 0.12 (time 1) (95% confidence interval -0.15 to +0.37) and was 0.32 (95% confidence interval 0.058-0.54) at the end of the catheterization (time 2). A significant association was noted between average capillary refill time at time 1 and hemoglobin, with higher hemoglobin correlating with longer capillary refill time (p = .015). There was no significant correlation between the average capillary refill time taken at the time of cardiac output measurement (time 1) and measured cardiac output (r = .331, 95% confidence interval for r, .066-.552).We found that the inter-rater reliability of capillary refill time was poor and variable under controlled conditions and capillary refill time was not correlated with cardiac output in anesthetized nonacutely ill pediatric patients undergoing cardiac catheterization. Caution should be used in inferring cardiac output from capillary refill time measurements alone.

Isolation of an artery is a rare congenital defect in which a vessel arises anomalously from the pulmonary arteries rather than the aorta. Isolated left subclavian artery and (less commonly) isolated left brachiocephalic artery have been described in association with various complex congenital heart defects. We present a very unusual case of isolated left brachiocephalic artery associated with transposition of the great arteries. The case suggests that this defect arises from pathological involution of embryologic aortic arches rather than from malseptation.

PurposePlasma osteopontin (OPN) levels in advanced non–small-cell lung cancer (NSCLC) correlate with therapeutic response and survival, but the utility of plasma OPN for diagnosis and monitoring of early-stage NSCLC has not been investigated. We hypothesize that plasma OPN levels are elevated in early-stage NSCLC and decrease with resection.Patients and MethodsPresurgery plasma OPN levels (in ng/mL) were measured by enzyme-linked immunosorbent assay (ELISA) in a discovery set of 60 patients with early-stage NSCLC and were compared with data from 56 cancer-free smokers. Presurgery OPN was validated in an independent cohort of 96 patients with resectable NSCLC. The presurgery levels in the latter cohort were compared with matched postsurgery levels. Perioperative OPN levels were correlated with demographics, tumor characteristics, and perioperative events. OPN was monitored during follow-up.ResultsDiscovery set presurgery NSCLC OPN (271 ± 31 ng/mL) was higher than smokers (40 ± 2 ng/mL; P = .001). Presurgery OPN was similar in the NSCLC validation cohort (324 ng/mL ± 20 ng/mL; P = .134). Postsurgery OPN (256 ng/mL ± 21 ng/mL) measured at mean of 9.8 weeks (range, 2 to 46 weeks) was lower than presurgery OPN (P = .005). Time from surgery significantly impacted postsurgery OPN: OPN ≤ 6 weeks postsurgery (303 n/mL ± 26 ng/mL) was higher than OPN greater than 6 weeks postsurgery (177 ng/mL ± 29 ng/mL; P = .003). Multivariate analysis noted correlations between albumin and creatinine to presurgery OPN and use of thoracotomy to postsurgery OPN. Recurrence rate was 5% at 29 weeks mean follow-up. OPN at recurrence was elevated from postsurgery nadir.ConclusionPlasma OPN levels are elevated in early-stage NSCLC. They are reduced after resection and appear to increase with recurrence. Plasma OPN may have utility as a biomarker in early-stage NSCLC.

The accurate evaluation of crash causal factors can provide fundamental information for effective transportation policy, vehicle design, and driver education. Naturalistic driving (ND) data collected with multiple onboard video cameras and sensors provide a unique opportunity to evaluate risk factors during the seconds leading up to a crash. This paper uses a National Academy of Sciences-sponsored ND dataset comprising 905 injurious and property damage crash events, the magnitude of which allows the first direct analysis (to our knowledge) of causal factors using crashes only. The results show that crash causation has shifted dramatically in recent years, with driver-related factors (i.e., error, impairment, fatigue, and distraction) present in almost 90% of crashes. The results also definitively show that distraction is detrimental to driver safety, with handheld electronic devices having high use rates and risk.

This study examined the effects of prostaglandin F2α (PGF2α) and human chorionic gonadotropin (hCG) on the levels of PGF2α-receptor (PGF2α-R) mRNA and steroidogenesis, in the human granulosa luteal cell (hGLC). Human GLCs collected from patients undergoing in vitro fertilization, were cultured for 24 h, after which cells were exposed to culture media containing either vehicle, hCG (1 IU/mL), or hCG plus PGF2α (10−11–10−6 M), for a further 24 h. Following the treatment period, media were collected and stored (−20°C) until assayed for progesterone and 17β-estradiol (estradiol). Immediately following the treatment period, cells were extracted for total RNA. Transcripts for PGF2α-R were detected by PCR with two different sets of oligonucleotide primers based on the published human and rat PGF2α-R sequences. PCR products were confirmed to be those of PGF2α-R by size and by Southern blot hybridization with an internal oligo nucleotide probe. All experiments were performed a minimum of three times, on cells from a minimum of three separate patients. Prostaglandin F2α-R mRNA was significantly downregulated, whereas progesterone and estradiol production were significantly stimulated by hCG. Conversely, both low (10−11 M) and high concentrations (10−6 M) of PGF2α restored PGF2α-R mRNA levels to those of the controls, whereas steroidogenesis was significantly inhibited by these conditions. At a concentration of 10−9 M PGF2α-R mRNA was barely detectable. Progesterone and estradiol production were inversely related to PGF2α-R levels, since hCG-stimulated progesterone and estradiol production were completely restored in the presence of 10−9 M PGF2α. Messenger RNA levels for the housekeeping gene β-actin were unaltered by the above treatments. In conclusion, in the human granulosa luteal cell, PGF2α-R mRNA levels are inversely related to hCG-stimulated steroidogenesis (which was biphasic in nature). Moreover, in the presence of hCG, PGF2α downregulates its receptor mRNA, thus providing a potential form of negative feedback on its own actions, which may be important in rescuing the corpus luteum from PGF2α-mediated luteolysis should pregnancy occur.

Through selective activation of the gonadotropic signal transduction pathway, we have determined the probable site of the antigonadotropic effects of prostaglandin F2α (PGF2α) in the human granulosa-luteal cell (hGLC). The gonadotropic signal transduction pathway was activated at the level of the receptor (luteinizing hormone and β-adrenergic), stimulatory G protein (Gs), adenylate cyclase (AC), and protein kinase A (PKA) by human chorionic gonadotropin (hCG) and isoproterenol (Iso), cholera toxin (CTX), forskolin, and dibutryl cAMP (Db cAMP), respectively. Concomitantly, the ability of PGF2α to inhibit progesterone production in response to the activation of this cascade at these different levels was examined. hGLCs were obtained from in vitro fertilization patients and were precultured for 8 d in Medium 199 supplemented with fetal bovine serum (M199; 10% FBS). Following the preculture period, cells were treated with either vehicle or one of the above activators of the gonadotropic pathway, either in the absence or presence of PGF2α (in M199; No FBS). Following the treatment period, media were collected and assayed for progesterone by RIA. Prostaglandin F2α (10−6 M) significantly inhibited hCG (1 IU/mL), Iso (10−5 M), CTX (1 µg/mL), and forskolin- (10−5 M) stimulated progesterone production. Conversely, PGF2α did not inhibit progesterone production stimulated by a saturating concentration of Db cAMP (10−6 M). The ability of PGF2α to inhibit hCG- or CTX-stimulated progesterone production was attenuated by pertussis toxin (PTX; 50 ng/mL). In conclusion, through a pertussis toxinsensitive G protein, PGF2α inhibits progesterone production at a level below AC, and above the activation of PKA by cAMP.

Background Glycyl-tRNA synthetase (GARS) is an aminoacyl-tRNA synthetase (ARS) that links the amino acid glycine to its corresponding tRNA prior to protein translation and is one of three bifunctional ARS that are active within both the cytoplasm and mitochondria. Dominant mutations in GARS cause rare forms of Charcot-Marie-Tooth disease and distal spinal muscular atrophy. Case presentation We report a 12-year old girl who presented with clinical and biochemical features of a systemic mitochondrial disease including exercise-induced myalgia, non-compaction cardiomyopathy, persistent elevation of blood lactate and alanine and MRI evidence of mild periventricular leukomalacia. Using exome sequencing she was found to harbor compound heterozygous mutations within the glycyl-tRNA synthetase (GARS) gene; c.1904C > T; p.Ser635Leu and c.1787G > A; p.Arg596Gln. Each mutation occurred at a highly conserved site within the anticodon binding domain. Conclusion Our findings suggest that recessive mutations in GARS may cause systemic mitochondrial disease. This phenotype is distinct from patients with previously reported dominant mutations in this gene, thereby expanding the spectrum of disease associated with GARS dysregulation.

This report describes the study design for the Strategic Highway Research Program 2 (SHRP 2) Naturalistic Driving Study (NDS). Using a sophisticated recording package installed in vehicles, it will collect information on the day-to-day driving of about 3,100 volunteer drivers for up to 2 years. Participants will be recruited in six sites throughout the United States. In this report, potential users of the SHRP 2 NDS data or its findings will find information about the participant recruitment plan, informed consent and data protection procedures, driver assessment tests, the capabilities of the data acquisition system (DAS), quality control, and project management.