A Multi-Component Model of the Developing Retinocollicular Pathway Incorporating Axonal and Synaptic Growth

During development, neurons extend axons to different brain areas and produce stereotypical patterns of connections. The mechanisms underlying this process have been intensively studied in the visual system, where retinal neurons form retinotopic maps in the thalamus and superior colliculus. The mechanisms active in map formation include molecular guidance cues, trophic factor release, spontaneous neural activity, spike-timing dependent plasticity (STDP), synapse creation and retraction, and axon growth, branching and retraction. To investigate how these mechanisms interact, a multi-component model of the developing retinocollicular pathway was produced based on phenomenological approximations of each of these mechanisms. Core assumptions of the model were that the probabilities of axonal branching and synaptic growth are highest where the combined influences of chemoaffinity and trophic factor cues are highest, and that activity-dependent release of trophic factors acts to stabilize synapses. Based on these behaviors, model axons produced morphologically realistic growth patterns and projected to retinotopically correct locations in the colliculus. Findings of the model include that STDP, gradient detection by axonal growth cones and lateral connectivity among collicular neurons were not necessary for refinement, and that the instructive cues for axonal growth appear to be mediated first by molecular guidance and then by neural activity. Although complex, the model appears to be insensitive to variations in how the component developmental mechanisms are implemented. Activity, molecular guidance and the growth and retraction of axons and synapses are common features of neural development, and the findings of this study may have relevance beyond organization in the retinocollicular pathway

Maternal high-fat diet prevents developmental programming by early-life stress

Anxiety disorders and depression are well-documented in subjects exposed to adverse childhood events. Recently, maternal obesity and/or maternal consumption of high-fat diets (HFD) have been also proposed as risk factors for offspring mental health. Here using an animal model in rats, we explored the combinatorial effects of a maternal HFD (40% of energy from fat without impact on maternal weight; during gestation and lactation) and maternal separation (MS) in offspring. In the prefrontal cortex (PFC) of pups, MS led to changes in the expression of several genes such as Bdnf (brain derived neurotrophic factor), 5HT-r1a (serotonin receptor 1a) and Rest4 (neuron-restrictive silencer element, repressor element 1, silencing transcription factor (Rest), splicing variant 4). Surprisingly, perinatal HFD strongly attenuated the developmental alterations induced by MS. Furthermore, maternal HFD totally prevented the endophenotypes (anxiety, spatial memory, social behavior, hypothalamic–pituitary–adrenal (HPA) axis response to stress, hippocampal neurogenesis and visceral pain) associated with MS at adulthood. Finally, we also demonstrated that HFD intake reduced anxiety and enhanced maternal care in stressed dams. Overall, our data suggest that a HFD restricted to gestation and lactation, which did not lead to overweight in dams, had limited effects in unstressed offspring, highlighting the role of maternal obesity, rather than fat exposure per se, on brain vulnerability during development.Environnement psychosocial précoce, empreintes biologiques et épigénétiques et état de santé à l'âge adult

Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the contributions of risk factor exposures to specific health outcomes, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 aims to provide comprehensive estimates of exposure levels, relative health risks, and attributable burden of disease for 88 risk factors in 204 countries and territories and 811 subnational locations, from 1990 to 2021. Methods: The GBD 2021 risk factor analysis used data from 54 561 total distinct sources to produce epidemiological estimates for 88 risk factors and their associated health outcomes for a total of 631 risk–outcome pairs. Pairs were included on the basis of data-driven determination of a risk–outcome association. Age-sex-location-year-specific estimates were generated at global, regional, and national levels. Our approach followed the comparative risk assessment framework predicated on a causal web of hierarchically organised, potentially combinative, modifiable risks. Relative risks (RRs) of a given outcome occurring as a function of risk factor exposure were estimated separately for each risk–outcome pair, and summary exposure values (SEVs), representing risk-weighted exposure prevalence, and theoretical minimum risk exposure levels (TMRELs) were estimated for each risk factor. These estimates were used to calculate the population attributable fraction (PAF; ie, the proportional change in health risk that would occur if exposure to a risk factor were reduced to the TMREL). The product of PAFs and disease burden associated with a given outcome, measured in disability-adjusted life-years (DALYs), yielded measures of attributable burden (ie, the proportion of total disease burden attributable to a particular risk factor or combination of risk factors). Adjustments for mediation were applied to account for relationships involving risk factors that act indirectly on outcomes via intermediate risks. Attributable burden estimates were stratified by Socio-demographic Index (SDI) quintile and presented as counts, age-standardised rates, and rankings. To complement estimates of RR and attributable burden, newly developed burden of proof risk function (BPRF) methods were applied to yield supplementary, conservative interpretations of risk–outcome associations based on the consistency of underlying evidence, accounting for unexplained heterogeneity between input data from different studies. Estimates reported represent the mean value across 500 draws from the estimate's distribution, with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values across the draws. Findings: Among the specific risk factors analysed for this study, particulate matter air pollution was the leading contributor to the global disease burden in 2021, contributing 8·0% (95% UI 6·7–9·4) of total DALYs, followed by high systolic blood pressure (SBP; 7·8% [6·4–9·2]), smoking (5·7% [4·7–6·8]), low birthweight and short gestation (5·6% [4·8–6·3]), and high fasting plasma glucose (FPG; 5·4% [4·8–6·0]). For younger demographics (ie, those aged 0–4 years and 5–14 years), risks such as low birthweight and short gestation and unsafe water, sanitation, and handwashing (WaSH) were among the leading risk factors, while for older age groups, metabolic risks such as high SBP, high body-mass index (BMI), high FPG, and high LDL cholesterol had a greater impact. From 2000 to 2021, there was an observable shift in global health challenges, marked by a decline in the number of all-age DALYs broadly attributable to behavioural risks (decrease of 20·7% [13·9–27·7]) and environmental and occupational risks (decrease of 22·0% [15·5–28·8]), coupled with a 49·4% (42·3–56·9) increase in DALYs attributable to metabolic risks, all reflecting ageing populations and changing lifestyles on a global scale. Age-standardised global DALY rates attributable to high BMI and high FPG rose considerably (15·7% [9·9–21·7] for high BMI and 7·9% [3·3–12·9] for high FPG) over this period, with exposure to these risks increasing annually at rates of 1·8% (1·6–1·9) for high BMI and 1·3% (1·1–1·5) for high FPG. By contrast, the global risk-attributable burden and exposure to many other risk factors declined, notably for risks such as child growth failure and unsafe water source, with age-standardised attributable DALYs decreasing by 71·5% (64·4–78·8) for child growth failure and 66·3% (60·2–72·0) for unsafe water source. We separated risk factors into three groups according to trajectory over time: those with a decreasing attributable burden, due largely to declining risk exposure (eg, diet high in trans-fat and household air pollution) but also to proportionally smaller child and youth populations (eg, child and maternal malnutrition); those for which the burden increased moderately in spite of declining risk exposure, due largely to population ageing (eg, smoking); and those for which the burden increased considerably due to both increasing risk exposure and population ageing (eg, ambient particulate matter air pollution, high BMI, high FPG, and high SBP). Interpretation: Substantial progress has been made in reducing the global disease burden attributable to a range of risk factors, particularly those related to maternal and child health, WaSH, and household air pollution. Maintaining efforts to minimise the impact of these risk factors, especially in low SDI locations, is necessary to sustain progress. Successes in moderating the smoking-related burden by reducing risk exposure highlight the need to advance policies that reduce exposure to other leading risk factors such as ambient particulate matter air pollution and high SBP. Troubling increases in high FPG, high BMI, and other risk factors related to obesity and metabolic syndrome indicate an urgent need to identify and implement interventions

Interactive Education is Associated With Lower Incidence of Pedestrian-Related Injury in Children

BackgroundPedestrian-related injuries are a significant contributor to preventable mortality and disability in children. We hypothesized that interactive pedestrian safety education is associated with increased knowledge, safe crosswalk behaviors, and lower incidence of pedestrian-related injuries in elementary school-aged children.MethodsAn interactive street-crossing simulation was implemented at target elementary schools in Los Angeles County beginning in 2009. Mixed-methods were used to evaluate the impact of this intervention. Multiple-choice examinations were used to test pedestrian safety knowledge, anonymous observations were used to assess street-crossing behaviors, and statewide traffic records were used to report pedestrian injuries in elementary school-aged (4-11 y) children in participating school districts. Pedestrian injury incidence was compared 1 y before and after the intervention, standardized to the incidence in the entire City of Los Angeles.ResultsA total of 1424 and 1522 children completed the pretest and post-test, respectively. Correct answers increased for nine of ten questions (all P < 0.01). Children more frequently looked both ways before crossing the street after the intervention (10% versus 41%, P < 0.001). There were 6 reported pedestrian-related injuries in intervention school districts in the year before the intervention and 2 injuries in the year after the intervention, resulting in a significantly lower injury incidence (standardized rate ratio 0.28; 95% CI, 0.11-0.73).ConclusionPedestrian safety education at Los Angeles elementary schools was associated with increased knowledge, safe street-crossing behavior, and lower incidence of pediatric pedestrian-related injury. Formal pedestrian safety education should be considered with injury prevention efforts in similar urban communities

Symptomatic catheter-associated thrombosis in pediatric trauma patients: Choose your access wisely

BackgroundTraumatic injury and the presence of a central venous catheter are 2 of the strongest risk factors for venous thromboembolism in children. The purpose of this study was to determine the incidence of symptomatic, catheter-associated thrombosis in critically injured children. We hypothesized that femoral venous catheters are associated with a greater rate of thrombotic complications when compared with all other central venous access points.MethodsWe reviewed a retrospective cohort (2006-2016) of injured children (≤18 years) admitted to a pediatric intensive care unit with central access placed ≤7 days from admission. Symptomatic, catheter-associated thrombosis was determined by radiographic evidence. Poisson regression was used to compare the incidence of catheter-associated thrombosis per 1,000 catheter days between femoral and nonfemoral catheters. All comparisons were 2-tailed with α = 0.05.ResultsWe examined 209 pediatric trauma patients with central access (65% femoral, 19% subclavian, 11% arm vein, and 5% internal jugular). Femoral catheters were removed earlier (median [interquartile range] 4 [2-7] vs 8 [3-12] days, P < .001) and were larger in diameter (5 Fr [4-7] vs 4 Fr [4-4], P < .001) when compared with all other catheters. Catheter-associated thrombosis was more frequent in femoral versus nonfemoral catheters (18.4 vs 3.5 per 1,000 catheter days, P = .01).ConclusionFemoral venous catheters are associated with a greater incidence of symptomatic, catheter-associated thrombosis in pediatric trauma patients. When central venous access is indicated for injured children, the femoral site should be avoided. If a femoral venous catheter is necessary, use of a smaller catheter should be considered

Impact of simulation-based training on perceived provider confidence in acute multidisciplinary pediatric trauma resuscitation

© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. Purpose: Simulation-based training has the potential to improve team-based care. We hypothesized that implementation of an in situ multidisciplinary simulation-based training program would improve provider confidence in team-based management of severely injured pediatric trauma patients. Methods: An in situ multidisciplinary pediatric trauma simulation-based training program with structured debriefing was implemented at a free-standing children’s hospital. Trauma providers were anonymously surveyed 1 month before (pre-), 1 month after (post-), and 2 years after implementation. Results: Survey response rate was 49% (n = 93/190) pre-simulation, 22% (n = 42/190) post-simulation, and 79% (n = 150/190) at 2-year follow-up. These providers reported more anxiety (p = 0.01) and less confidence (p = 0.02) 1-month post-simulation. At 2-year follow-up, trained providers reported less anxiety (p = 0.02) and greater confidence (p = 0.01), compared to untrained providers. Conclusions: Implementation of an in situ multidisciplinary pediatric trauma simulation-based training program may initially lead to increased anxiety, but long-term exposure may lead to greater confidence. Level of evidence: II, Prospective cohort

Impact of simulation-based training on perceived provider confidence in acute multidisciplinary pediatric trauma resuscitation

© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. Purpose: Simulation-based training has the potential to improve team-based care. We hypothesized that implementation of an in situ multidisciplinary simulation-based training program would improve provider confidence in team-based management of severely injured pediatric trauma patients. Methods: An in situ multidisciplinary pediatric trauma simulation-based training program with structured debriefing was implemented at a free-standing children’s hospital. Trauma providers were anonymously surveyed 1 month before (pre-), 1 month after (post-), and 2 years after implementation. Results: Survey response rate was 49% (n = 93/190) pre-simulation, 22% (n = 42/190) post-simulation, and 79% (n = 150/190) at 2-year follow-up. These providers reported more anxiety (p = 0.01) and less confidence (p = 0.02) 1-month post-simulation. At 2-year follow-up, trained providers reported less anxiety (p = 0.02) and greater confidence (p = 0.01), compared to untrained providers. Conclusions: Implementation of an in situ multidisciplinary pediatric trauma simulation-based training program may initially lead to increased anxiety, but long-term exposure may lead to greater confidence. Level of evidence: II, Prospective cohort

Self-assessment of team performance using T-NOTECHS in simulated pediatric trauma resuscitation is not consistent with expert assessment

© 2018 Elsevier Inc. Background: The Trauma NOn-TECHnical Skills (T-NOTECHS) tool has been used to assess teamwork in trauma resuscitation, but its reliability and validity for self-assessment is unknown. Our purpose was to determine the reliability and validity of self-administered T-NOTECHS in pediatric trauma resuscitation. Methods: Simulated in situ resuscitations were evaluated using T-NOTECHS in real time by experts and immediately afterwards by team members. Reliability was analyzed with linear-weighted kappa and intra-class correlation. T-NOTECHS scores were compared between expert (gold-standard) and self-assessment. Results: Fifteen simulations were examined. T-NOTECHS scores were similar between self- and expert assessment for leadership. Self-assessment scores were higher than expert for the other domains and total composite score. Inter-rater reliability for total score was similar between the two groups, but differences were observed in the domains. Conclusions: Self-assessment is not interchangeable with expert rating when using T-NOTECHS. Future studies need to determine how self-assessment can be best utilized. Level of evidence: Studies of diagnostic accuracy – Level 2