Brain injections of glial cytoplasmic inclusions induce a multiple system atrophy-like pathology.

Synucleinopathies encompass several neurodegenerative diseases, which include Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. These diseases are characterized by the deposit of α-synuclein aggregates in intracellular inclusions in neurons and glial cells. Unlike Parkinson's disease and dementia with Lewy bodies, where aggregates are predominantly neuronal, multiple system atrophy is associated with α-synuclein cytoplasmic inclusions in oligodendrocytes. Glial cytoplasmic inclusions are the pathological hallmark of multiple system atrophy and are associated with neuroinflammation, modest demyelination and, ultimately, neurodegeneration. To evaluate the possible pathogenic role of glial cytoplasmic inclusions, we inoculated glial cytoplasmic inclusion-containing brain fractions obtained from multiple system atrophy patients into the striatum of non-human primates. After a 2-year in vivo phase, extensive histochemical and biochemical analyses were performed on the whole brain. We found loss of both nigral dopamine neurons and striatal medium spiny neurons, as well as loss of oligodendrocytes in the same regions, which are characteristics of multiple system atrophy. Furthermore, demyelination, neuroinflammation and α-synuclein pathology were also observed. These results show that the α-synuclein species in multiple system atrophy-derived glial cytoplasmic inclusions can induce a pathological process in non-human primates, including nigrostriatal and striatofugal neurodegeneration, oligodendroglial cell loss, synucleinopathy and gliosis. The present data pave the way for using this experimental model for MSA research and therapeutic development.

Bidirectional gut-to-brain and brain-to-gut propagation of synucleinopathy in non-human primates.

In Parkinson's disease, synucleinopathy is hypothesized to spread from the enteric nervous system, via the vagus nerve, to the CNS. Here, we compare, in baboon monkeys, the pathological consequences of either intrastriatal or enteric injection of α-synuclein-containing Lewy body extracts from patients with Parkinson's disease. This study shows that patient-derived α-synuclein aggregates are able to induce nigrostriatal lesions and enteric nervous system pathology after either enteric or striatal injection in a non-human primate model. This finding suggests that the progression of α-synuclein pathology might be either caudo-rostral or rostro-caudal, varying between patients and disease subtypes. In addition, we report that α-synuclein pathological lesions were not found in the vagal nerve in our experimental setting. This study does not support the hypothesis of a transmission of α-synuclein pathology through the vagus nerve and the dorsal motor nucleus of the vagus. Instead, our results suggest a possible systemic mechanism in which the general circulation would act as a route for long-distance bidirectional transmission of endogenous α-synuclein between the enteric and the central nervous systems. Taken together, our study provides invaluable primate data exploring the role of the gut-brain axis in the initiation and propagation of Parkinson's disease pathology and should open the door to the development and testing of new therapeutic approaches aimed at interfering with the development of sporadic Parkinson's disease.

Identification of TRPV1 Ion Channels Agonists of Tropaeolum tuberosum in Human Skin Keratinocytes.

Tropaeolum tuberosum, commonly known as Mashua, is an herbal remedy used in traditional Andean medicine for the relief of kidney and bladder pain, as well as contusions. This study aimed to evaluate the fractions and isolated compounds from T. tuberosum with analgesic activity mediated by the transient receptor potential vanilloid-1 receptor. A bioguided phytochemical analysis based on NMR/MS was performed to identify the compounds of the n-heptane fractions from samples of purple tubers of T. tuberosum. The transient receptor potential vanilloid-1 agonist and antagonist activity were assessed through the measurement of intracellular Ca2+ in HEK001 cells. The chemical structure determination led to the identification of two alkamides: N-(2-hydroxyethyl)-7Z,10Z,13Z,16Z-docosatetraenamide (1: ) and N-oleoyldopamine (2: ). Both compounds induced increased intracellular calcium flow with IC50 values of 3.2 nM and 7.9 nM, respectively, thus activating the transient receptor potential vanilloid-1 receptor. Our research is the first report to show that these two compounds isolated from T. tuberosum can act as agonists of the transient receptor potential vanilloid-1 receptor, providing scientific evidence for the traditional use of this species in pain relief.

Cardiac Noradrenaline Turnover and Heat Shock Protein 27 Phosphorylation in Dyskinetic Monkeys.

BACKGROUND: Autonomic dysfunction is a well-known dominant symptom in the advanced stages of Parkinson's disease. However, the role of cardiac sympathetic nerves still needs to be elucidated. OBJECTIVES: To evaluate cardiac sympathetic response in Parkinsonian and dyskinetic monkeys. METHODS: Adult male monkeys were divided into 1 of the following 3 groups: controls, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine+levodopa-treated animals. Noradrenaline, its metabolite normetanephrine, and phospho-Heat shock proten 27 (p-Hsp27) at serine 82 levels were analyzed in the left and right ventricles of the heart. Tyrosine hydroxylase immunohistochemistry was performed in the ventral mesencephalon. RESULTS: The results were the following: (1) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intoxication significantly increased normetanephrine levels and decreased noradrenaline turnover in the right ventricle without changes in the left ventricle; however, (2) levodopa treatment decreased noradrenaline levels and enhanced the normetanephrine/noradrenaline ratio in parallel with a very significant increase of Hsp27 activity in both ventricles. CONCLUSIONS: Levodopa treatment could induce protective cardiac effects through the increased Hsp27 activity. © 2019 International Parkinson and Movement Disorder Society.

Effect of NAC treatment and physical activity on neuroinflammation in subchronic Parkinsonism; is physical activity essential?

BACKGROUND: Neuroprotective strategies are becoming relevant to slow down dopaminergic cell death and inflammatory processes related to the progressive neurodegeneration in Parkinson's disease (PD). Interestingly, among others, physical activity (PA) or anti-oxidant agents (such as N-acetyl-L-cysteine, NAC) are common therapeutic strategies. Therefore, this study aims to analyze if there is a synergistic effect of physical activity along with NAC treatment on dopaminergic degeneration and neuroinflammatory response in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism model after subchronic intoxication. METHODS: To ascertain this possibility, 48 8-week-old male mice (C57BL/6 strain) were used. Twenty four of them were placed individually in cages where voluntary physical activity was automatically monitored during 30 days and were divided into groups: (i) control; (ii) NAC; (iii) MPTP, and (iv) MPTP+NAC. The other 24 mice were divided into the same four groups but without physical activity. RESULTS: The data collected during the treatment period showed that there was an overall increase in the total running distance in all groups under physical activity, including Parkinsonian animals. However, the monitoring data per day showed that the activity routine by MPTP and MPTP+NAC groups was disrupted by alterations in the circardian rhythm because of MPTP intoxication. Results from post-mortem studies in the substantia nigra pars compacta (SNpc) showed significant decrease in the number of TH+ cells in all MPTP groups. Moreover, TH+ expression in the striatum was significantly decreased in all MPTP groups. Thus, PA + NAC treatment do not protect dopaminergic neurons against a subchronic intoxication of MPTP. Regarding glial response, the results obtained from microglial analysis do not show significant increase in the number of Iba-1+ cell in MPTP+NAC and MPTP+PA + NAC. In the striatum, a significant decrease is observed only in the MPTP+NAC group compared with that of the MPTP group. The microglial results are reinforced by those obtained from the analysis of astroglial response, in which a decrease in the expression of GFAP+ cells are observed in MPTP+NAC and MPTP+PA + NAC compared with MPTP groups both in the SNpc and in the striatum. Finally, from the study of the astroglial response by the co-localization of GFAP/S100b, we described some expression patterns observed based on the severity of the damage produced by the MPTP intoxication in the different treated groups. CONCLUSIONS: These results suggest that the combination of physical activity with an anti-oxidant agent does not have a synergistic neuroprotective effect in the nigrostriatal pathway. Our results show a potential positive effect, only due to NAC treatment, on the neuroinflammatory response after subchronic MPTP intoxication. Thus, physical activity is not essential, under these conditions. However, we believe that physical activity, used for therapeutic purposes, has a beneficial long-term effect. In this line, these results open the door to design longer studies to demonstrate its promising effect as neuroprotective strategy.

Innovative Application of Cerebral rSO2 Monitoring During Shunt Tap in Pediatric Ventricular Malfunctioning Shunts.

OBJECTIVE: This study aimed to determine the reliability and potential application of cerebral regional tissue oxygenation (rSO2) monitoring in malfunctioning ventricular shunts during tap. METHODS: This is a prospective case series using convenience sample in subjects with confirmed malfunctioning shunt who had left and right cerebral rSO2 monitoring every 5 seconds before, during, and 1 hour after shunt tap. RESULTS: Ninety-four subjects had cerebral rSO2 monitoring. Sixty-three subjects had proximal malfunctions, and 31 subjects had distal shunt malfunctions. The intrasubject's cerebral rSO2 trend and variability at pretap, during, and posttap times were highly correlated. Overall, the average rSO2 is lower in pretap as compared with posttap. Left cerebral rSO2 had lower means and larger SD as compared with right cerebral rSO2. Left pretap and posttap cerebral rSO2 variability was significantly associated with the location of shunt malfunction regardless of pretap, during, or posttap periods (P < 0.001), whereas right rSO2 variability was not predictive for malfunction location. Left cerebral rSO2 variability showed utility for identifying the location of malfunction with area under the receiver operating characteristic curve equal to 0.8. CONCLUSIONS: Reliable cerebral rSO2 readings before, during, and after shunt tap were demonstrated. Left cerebral rSO2 changes from before to after shunt tap were more predictive for shunt malfunction location than right cerebral rSO2 changes. Observing cerebral rSO2 changes in relationship to shunt tap represents a potential surrogate in measuring cerebral pressures and blood flow changes after cerebral spinal fluid drainage. Significantly greater cerebral rSO2 changes occur for distal malfunction versus proximal malfunction after shunt tap, indicating its potential as an adjunct tool for detecting shunt malfunction type.

Rubus urticifolius Compounds with Antioxidant Activity, and Inhibition Potential against Tyrosinase, Melanin, Hyaluronidase, Elastase, and Collagenase.

In our study, using chromatographic techniques, we isolated three bioactive compounds, which were structurally elucidated as (E)-2-(3-(3,4-dimethoxyphenyl)acrylamido)-N-methylbenzamide (1), 4-Hydroxyquinoline-2-carboxylic acid (2), and (E)-2-Cyano-3-(4-hydroxyphenyl)acrylic acid (3), using spectroscopic methods. The anti-melanogenic, anti-inflammatory, antioxidant, and anti-aging properties were evaluated in vitro by measuring the activity of pharmacological targets including tyrosinase, melanin, NF-κB, hyaluronidase, elastase, collagenase, and Nrf2. Our results show that compound 1 is the most active with IC50 values of 14.19 µM (tyrosinase inhibition), 22.24 µM (melanin inhibition), 9.82-12.72 µM (NF-κB inhibition), 79.71 µM (hyaluronidase inhibition), 80.13 µM (elastase inhibition), 76.59 µM (collagenase inhibition), and 116-385 nM (Nrf2 activation) in the THP-1, HEK001, WS1, and HMCB cells. These findings underscore the promising profiles of the aqueous extract of R. urticifolius at safe cytotoxic concentrations. Additionally, we report, for the first time, the isolation and characterisation of these nitrogenous compounds in the R. urticifolius species. Finally, compound 1, isolated from R. urticifolius, is a promising candidate for the development of more effective and safer compounds for diseases related to skin pigmentation, protection against inflammation, and oxidative stress.

Cerebral regional oxygen saturation monitoring in pediatric malfunctioning shunt patients.

BACKGROUND: Shunt malfunction produces increased intracranial pressure causing decreased cerebral regional perfusion and tissue O(2)sat. Cerebral regional oxygen saturation (rSO(2)) by near-infrared spectroscopy represents tissue perfusion and oxygen saturation. Cerebral rSO(2) is used to detect cerebral ischemia in pediatric clinical settings. OBJECTIVE: The objective of the study was to determine the reliability of cerebral rSO(2) in pediatric malfunctioning shunt. METHODS: A prospective observational study of pediatric patients presented to the pediatric emergency department was conducted. Confirmed malfunctioning shunt subjects had cerebral rSO(2) monitoring. RESULTS: A total of 131 malfunctioning shunt subjects had cerebral rSO(2) monitoring. Patient's central trend and intrasubject variability of cerebral rSO(2) readings for left and right probe and malfunction sites (n = 131) are as follows: Intrasubject left and right rSO(2) Pearson correlation was -0.46 to 0.98 (mean ± SD, 0.35 ± 0.34; median, 0.34; interquartile range, 0.06-0.61). The correlation coefficients of 99 subjects between left and right rSO(2) was significantly different (P < .001), suggesting that intrasubjects' left and right rSO(2) are highly correlated. Sample mean difference between left and right rSO(2) were -1.7% (95% confidence interval [CI], -1.8 to -1.6; P < .001) supporting overall left lower than right. Intraclass correlation for left rSO(2) was 87.4% (95% CI, 87.2%-87.6%), and that for right rSO(2) was 83.8% (95% CI, 83.8%-84%), showing intersubject differences accounting for the variation, and relative to intersubject variation, intrasubjects readings are consistent. Intrasubjects, left and right rSO(2) highly correlate and are asymmetrical. Left and right rSO(2) are consistent in intrasubject with large rSO(2) variations in trend and variability across subjects. CONCLUSION: This study demonstrates reliable cerebral rSO(2) readings in subjects with malfunctioning shunts, with asymmetrical cerebral rSO(2) hemispheric dynamics within subjects.

Intravenous hypertonic saline use in the pediatric emergency department.

OBJECTIVES: The objective of this study was to describe the use, dosing, and administration of intravenous hypertonic saline (IHS) use in a pediatric emergency department. METHODS: This was a retrospective chart review of patients 0 to 18 years receiving IHS as part of their management in a pediatric ED with an annual volume of more than 50,000 visits. RESULTS: Over 4 years, 56 patients received IHS as part of their management in the emergency department. Clinical scenarios for IHS administration included traumatic brain injury with concern for increased intracranial pressure in 19 patients (34%), diabetic ketoacidosis with altered mental status in 18 (32%), hyponatremia without seizure activity in 6 (10.7%), hyponatremic seizure in 3 (5.4%), and altered mental status secondary to a nontraumatic, non-diabetic ketoacidosis cause in 10 (17.9%). The median age of the patients was 11.3 years (interquartile range, 6-13.9 years) receiving a median dose of 4.1 mL/kg (interquartile range, 3.08-5 mL/kg) of IHS. The median time for administration of the IHS was 17 minutes, with 87% of doses given via peripheral intravenous catheters. Approximately one fourth (26.8%) of patients received their dose in 10 minutes or less, with 7.2% of patients receiving a bolus of IHS in 3 minutes or less. We found no evidence of adverse effects. CONCLUSIONS: Intravenous hypertonic saline use is increasing within the pediatric emergency department. Within this institution, it is most frequently used at a dosing range of 3 to 5 mL/kg and does not require central venous access for rapid infusion.

Cortical Lewy body injections induce long-distance pathogenic alterations in the non-human primate brain.

Aggregation of α-synuclein (α-syn) is the cornerstone of neurodegenerative diseases termed synucleinopathies, which include Parkinson's Disease (PD), Dementia with Lewy Bodies (DLB), and Multiple System Atrophy (MSA). These synucleinopathies are characterized by the deposit of aggregated α-syn in intracellular inclusions observable in neurons and glial cells. In PD and DLB, these aggregates, predominantly located in neurons, are called Lewy Bodies (LBs). These LBs are one of the pathological hallmarks of PD and DLB, alongside dopaminergic neuron loss in the substantia nigra. Previous studies have demonstrated the ability of PD patient-derived LB fractions to induce nigrostriatal neurodegeneration and α-syn pathology when injected into the striatum or the enteric nervous system of non-human primates. Here, we report the pathological consequences of injecting these LB fractions into the cortex of non-human primates. To this end, we inoculated mesencephalic PD patient-derived LB fractions into the prefrontal cortex of baboon monkeys terminated one year later. Extensive analyses were performed to evaluate pathological markers known to be affected in LB pathologies. We first assessed the hypothesized presence of phosphorylated α-syn at S129 (pSyn) in the prefrontal cortices. Second, we quantified the neuronal, microglial, and astrocytic cell survival in the same cortices. Third, we characterized these cortical LB injections' putative impact on the integrity of the nigrostriatal system. Overall, we observed pSyn accumulation around the injection site in the dorsal prefrontal cortex, in connected cortical regions, and further towards the striatum, suggesting α-syn pathological propagation. The pathology was also accompanied by neuronal loss in these prefrontal cortical regions and the caudate nucleus, without, however, loss of nigral dopamine neurons. In conclusion, this pilot study provides novel data demonstrating the toxicity of patient-derived extracts, their potential to propagate from the cortex to the striatum in non-human primates, and a possible primate model of DLB.

Age variability in pediatric injuries from falls.

OBJECTIVE: The objective of this study is to examine the nature and circumstances surrounding pediatric fall-related injuries for specific age groups and their implications for age-appropriate injury prevention efforts. METHODS: This is a retrospective analysis of data (October 2006 to April 2009) from the trauma registry of a level 1 pediatric trauma center. Inclusion criteria are patients admitted because of fall-related injury younger than 15 years (n = 675). Injury mechanism specifics were obtained from medical records. RESULTS: Falls were the leading cause of admissions and accounted for 37% of all cases during this period. Most pediatric fall-related injuries (73%) occurred between 1 and 9 years of age. Although infants accounted for only 8% of fall injuries, a greater proportion of these children were more severely injured. The mean Injury Severity Score for infants was significantly greater than the overall average (P < .001). Causes of fall injuries vary by age and have been discussed. CONCLUSIONS: The high incidence of pediatric fall injuries warrants dedicated injury prevention education. Injury prevention efforts need to be age appropriate in terms of focus, target audience, and setting. Recommendations for injury prevention are discussed.

Ketamine sedation is not associated with clinically meaningful elevation of intraocular pressure.

BACKGROUND: Ketamine is widely used for procedural sedation, but there is limited knowledge on whether ketamine use is associated with elevated intraocular pressure (IOP). OBJECTIVE: The aim of this study was to examine whether there are clinically important elevations of IOP associated with ketamine use during pediatric procedural sedation. METHODS: We prospectively enrolled children without ocular abnormalities undergoing procedural sedation that included ketamine for nonperiorbital injuries. We measured IOP for each eye before and at 1, 3, 5, 15, and 30 minutes after initial intravenous ketamine administration. We performed Bland-Altman plots to determine if IOP measurements in both eyes were in agreement. Linear regression was used to model the mean IOP of both eyes as a function of time, dose, and age, with a robust sandwich estimator to account for repeated measures. RESULTS: Among 25 participants, median (interquartile range) age was 11 (9-12) years, and 18 (72%) were male. Median ketamine dose was 1.88 mg/kg (interquartile range, 1.43-2.03 mg/kg; range 0.96-4 mg/kg). Bland-Altman plots demonstrated a mean difference of IOP between eyes near zero at all time points. The largest predicted difference from baseline IOP occurred at 15 minutes, with an estimated change of 1.09 mm Hg (95% confidence interval, -0.37 to 2.55). The association between ketamine dose and mean IOP was not statistically significant or clinically meaningful (P = .90; estimated slope, 0.119 [95% confidence interval, -1.71 to 1.95]). There were no clinically meaningful levels of increased measured average IOP reached at any time point. CONCLUSIONS: At dosages of 4 mg/kg or less, there are not clinically meaningful associations of ketamine with elevation of IOP.

Hyperglycemic hyperosmolar syndrome in the pediatric patient: a case report and review of the literature.

Hyperglycemic hyperosmolar syndrome (HHS) is a potentially deadly complication of diabetes mellitus that can often be the presenting symptom of the condition in the pediatric population. There is a danger that HHS may not be included in the differential of critical patients because it is still a somewhat rare entity in the pediatric population. However, recent data regarding population trends indicate that HHS will continue to appear more and more commonly in the pediatric population with diabetes. The following case describes an adolescent with many of the typical features of the pediatric patient with HHS as the presenting symptom of diabetes mellitus. The literature regarding HHS in children is still sparse, and much must be extrapolated from adult studies given its relatively recent increased incidence. Included is a brief review of the most recent data regarding epidemiology, treatment, and complications that would be pertinent to the pediatric emergency physician.

Hypothermia is associated with poor outcome in pediatric trauma patients.

OBJECTIVE: The objective of the study was to determine if hypothermia in pediatric trauma patients is associated with increased mortality. METHODS: We reviewed the charts of level 1 trauma patients aged 3 months to 17 years who presented between September 2006 and March 2008. We analyzed data for patients with temperatures recorded within 30 minutes of arrival to the pediatric emergency department. Logistic regression models were used to test for associations of hypothermia with death while adjusting for mode of transport, season of year, and presence of intracranial pathology as documented by an abnormal head computed tomographic scan. RESULTS: Of the 226 level 1 trauma patients presenting during the study period, 190 met inclusion criteria. Twenty-one patients (11%) died. The odds ratio (OR) of a hypothermic patient dying was 9.2 times that of a normothermic patient when adjusting for seasonal variation (95% confidence interval [CI], 3.2-26.2; P < 0.0001). The OR of a hypothermic patient dying was 8.7 times that of a normothermic patient when adjusting for mode of transport (ground vs air) (95% CI, 3.1-24.6; P < 0.0001). Although it did not reach statistical significance, there was a trend toward an association between hypothermia and the presence of traumatic brain injury as evidenced by an abnormal head computed tomographic scan (OR = 2.4; 95% CI, 0.9-6.0; P = .07). CONCLUSIONS: Hypothermia is a risk factor for increased mortality in pediatric trauma patients. This pilot study warrants a more detailed, multicenter analysis to assess the impact of hypothermia in the pediatric trauma patient.

Near-infrared spectroscopy in the critical setting.

Near-infrared spectroscopy is a noninvasive means of determining real-time changes in regional oxygen saturation of cerebral and somatic tissues. Hypoxic neurologic injuries not only involve devastating effects on patients and their families but also increase health care costs to the society. At present, monitors of cerebral function such as electroencephalograms, transcranial Doppler, jugular bulb mixed venous oximetry, and brain tissue oxygenation monitoring involve an invasive procedure, are operator-dependent, and/or lack the sensitivity required to identify patients at risk for cerebral hypoxia. Although 20th century advances in the understanding and management of resuscitation of critically ill and injured children have focused on global parameters (ie, pulse oximetry, capnography, base deficit, lactate, etc), a growing body of evidence now points to regional disturbances in microcirculation that will lead us in a new direction of adjunctive tissue monitoring and response to resuscitation. In the coming years, near-infrared spectroscopy will be accepted as a way for clinicians to more quickly and noninvasively identify patients with altered levels of cerebral and/or somatic tissue oxygenation and, in conjunction with global physiologic parameters, guide efficient and effective resuscitation to improve outcomes for critically ill and injured pediatric patients.

Inhibition of melanin production and tyrosinase activity by flavonoids isolated from Loranthus acutifolius.

Activity-guided fractionations of leaves and stems from Loranthus acutifolius led to the isolation of 2',4',6-trimethoxyflavone (1), 3',4',5-trihydroxy-6,7,8-trimethoxyflavone (2), 2'4'-dihydroxy-6'-methoxy-chalcone (3) and 4',5-dihydroxy-6,7,8-trimethoxyflavone (4). The potential for inhibition against melanin production and tyrosinase activity of these 4 compounds was tested in B16-F10 cells. 2',4',6-trimethoxyflavone, 3',4',5-trihydroxy-6,7,8-trimethoxyflavone, 2'4'-dihydroxy-6'-methoxy-chalcone and 4',5-dihydroxy-6,7,8-trimethoxyflavone showed an inhibitory activity of melanin production with IC50 of 3.6 ± 0.05 µM, 8.1 ± 0.05 µM, 1.6 ± 0.03 µM and 6.5 ± 0.05 µM, respectively. In addition, 2',4',6-trimethoxyflavone, 3',4',5-trihydroxy-6,7,8-trimethoxyflavone, 2'4'-dihydroxy-6'-methoxy-chalcone and 4',5-dihydroxy-6,7,8-trimethoxyflavone were able to inhibit tyrosinase activity with IC50 of 4.0 ± 0.03 µM, 11.3 ± 0.05 µM, 5.7 ± 0.02 µM and 8.6 ± 0.04 µM, respectively. This is the first time that these compounds are reported in the L. acutifolius species showing anti-melanogenic activities.

Procalcitonin as a marker of severe bacterial infection in children in the emergency department.

Procalcitonin, the prohormone of calcitonin, is a relatively new and innovative marker of bacterial infection that has multiple potential applications in the pediatric emergency department. In healthy individuals, circulating levels of procalcitonin are generally very low (<0.05 ng/mL), but in the setting of severe bacterial infection and sepsis, levels can increase by hundreds to thousands of fold within 4 to 6 hours. Although the exact physiologic function of procalcitonin has not been determined, the consistent response and rapid rise of this protein in the setting of severe bacterial infection make procalcitonin a very useful biomarker for invasive bacterial disease. In Europe, serum procalcitonin measurements are frequently used in the diagnosis and the management of patients in a variety of clinical settings. To date, the use of procalcitonin has been limited in the United States, but this valuable biomarker has many potential applications in both the pediatric emergency department and the intensive care unit. The intent of this article is to review the history of procalcitonin, describe the kinetics of the molecule in response to bacterial infection, describe the laboratory methods available for measuring procalcitonin, examine the main causes of procalcitonin elevation, and evaluate the potential applications of procalcitonin measurements in pediatric patients.

Factors Associated With Physician Empowerment and Well-being at an Academic Medical Center.

OBJECTIVE: This study reports an institutional approach to rapidly measure burnout and gather physicians' opinions on workplace factors that empower well-being. METHODS: In July 2017, physicians at Vanderbilt University Medical Center were invited to participate in a two-question survey measuring self-reported burnout and providing an opportunity to describe structures that empower well-being. Free-text responses were analyzed and a linear regression model assessed factors associated with well-being. RESULTS: A total of 1135 physicians responded (43.3% response rate) with a mean well-being score of 56 (scale 0 to 100). Higher scores were associated with clinical fellow status (P = 0.002), male sex (P = 0.008), less allocation of time to clinical care (P < 0.001), and not commenting on "leadership" and "autonomy" in the free-text response. CONCLUSIONS: Brief surveys collecting perspectives on well-being can help employers identify high-risk groups and provide a roadmap for institutional change.

Impact of clinical guidance and rapid molecular pathogen detection on evaluation and outcomes of febrile or hypothermic infants.

OBJECTIVE: To quantify the impact of clinical guidance and rapid respiratory and meningitis/encephalitis multiplex polymerase chain reaction (mPCR) testing on the management of infants. DESIGN: Before-and-after intervention study. SETTING: Tertiary-care children's hospital. PATIENTS: Infants ≤90 days old presenting with fever or hypothermia to the emergency department (ED). METHODS: The study spanned 3 periods: period 1, January 1, 2011, through December 31, 2014; period 2, January 1, 2015, through April 30, 2018; and period 3, May 1, 2018, through June 15, 2019. During period 1, no standardized clinical guideline had been established and no rapid pathogen testing was available. During period 2, a clinical guideline was implemented, but no rapid testing was available. During period 3, a guideline was in effect, plus mPCR testing using the BioFire FilmArray respiratory panel 2 (RP 2) and the meningitis encephalitis panel (MEP). Outcomes included antimicrobial and ancillary test utilization, length of stay (LOS), admission rate, 30-day mortality. Outcomes were compared across periods using Kruskal-Wallis and Pearson tests and interrupted time series analysis. RESULTS: Overall 5,317 patients were included: 2,514 in period 1, 2,082 in period 2, and 721 in period 3. Over the entire study period, we detected reductions in the use of chest radiographs, lumbar punctures, LOS, and median antibiotic duration. After adjusting for temporal trends, we observed that the introduction of the guideline was associated with reductions in ancillary tests and lumbar punctures. Use of mPCR testing with the febrile infant clinical guideline was associated with additional reductions in ancillary testing for all patients and a higher proportion of infants 29-60 days old being managed without antibiotics. CONCLUSIONS: Use of mPCR testing plus a guideline for young infant evaluation in the emergency department was associated with less antimicrobial and ancillary test utilization compared to the use of a guideline alone.

Management of occult fractures in the skeletally immature patient: cost analysis of implementing a limited trauma magnetic resonance imaging protocol.

STUDY OBJECTIVE: Fractures in children may not be visible in the result of initial radiography, and undertreatment and overtreatment of such fractures routinely occur. The purpose of this study was to evaluate the potential cost of implementing limited magnetic resonance imaging (MRI) at initial encounter, when radiographs are unrevealing. METHODS: This was a retrospective review of 204 emergency department pediatric patients presenting between January 1, 2005 and February 28, 2006 with appendicular trauma, with initially negative radiographic result and follow-up. Emergency department treatment categorization of (1) no treatment, (2) ACE wrap, (3) brace, (4) splint, or (5) casting was evaluated. Final determination of presence or absence of fracture was based on follow-up. Patients with fractures were considered undertreated when they received categories 1 to 3 care; patients without fractures were considered overtreated when they received categories 4 and 5 care. The percentage of patients undertreated or overtreated and direct and total costs were determined and analyzed in conjunction with the cost of a limited MRI at initial encounter. Total costs include direct and indirect costs (lost wages for each day off work for the parent). Cost estimates assume patients determined to be without fractures at follow-up will not return for follow-up clinical care or obtain additional imaging after MRI at initial encounter. RESULTS: Twenty-eight (13.7%) of the 204 patients had fractures at follow-up. Fifty one percent of patients without fractures were overtreated; 29% with fractures were undertreated. Mean direct cost for all patients and cost estimation with limited MRI protocol were $843.81 and $891.79, respectively (P = 0.365). However, mean total cost for all patients and cost estimation with limited MRI protocol was $1059.49 and $929.10, respectively (P = 0.02). CONCLUSIONS: Based on clinical grounds and initially negative radiographic results, slightly more than half of patients without fractures can be overtreated, and nearly one third of patients with fractures can be undertreated. Instituting a protocol that includes limited trauma MRI lowers the total cost of care without increasing direct cost, and appropriate care may be instituted at the outset.