The association of job demands and resources with burnout among emergency medical services professionals.

OBJECTIVE: Although burnout has been linked to negative workplace-level effects, prior studies have primarily focused on individuals rather than job-related characteristics. This study sought to evaluate variation in burnout between agencies and to quantify the relationship between burnout and job-related demands/resources among emergency medical services (EMS) professionals. METHODS: An electronic questionnaire was sent to all licensed, practicing EMS professionals in South Carolina. Work-related burnout was measured using the Copenhagen Burnout Inventory. Multivariable generalized estimating equations were used to estimate odds ratios (ORs) for specific job demands and resources while adjusting for confounding variables. Composite scores were used to simultaneously assess the relationship between burnout and job-related demands and resources. RESULTS: Among 1271 EMS professionals working at 248 EMS agencies, the median agency-level burnout was 35% (interquartile range [IQR]: 13% to 50%). Job-related demands, including time pressure, were associated with increased burnout. Traditional job-related resources, including pay and benefits, were associated with reduced burnout. Less tangible job resources, including autonomy, clinical performance feedback, social support, and adequate training demonstrated strong associations with reduced burnout. EMS professionals facing high job demands and low job resources demonstrated nearly a 10-fold increase in odds of burnout compared with those exposed to low demands and high resources (adjusted OR [aOR]: 9.50, 95% confidence interval [CI]: 6.39-14.10). High job resources attenuated the impact of high job demands. CONCLUSION: The proportion of EMS professionals experiencing burnout varied substantially across EMS agencies. Job resources, including those reflective of organizational culture, were associated with reduced burnout. Collectively, these findings suggest an opportunity to address burnout at the EMS agency level.

Does Emergency Medical Services Transportation Mitigate Post-stroke Discharge Disability? A Prospective Observational Study.

BACKGROUND: Whether emergency medical services (EMS) transport improves disability outcomes compared with other transport among acute ischemic stroke (AIS) patients is unknown. OBJECTIVE: To study severity-adjusted associations of hospital arrival mode (EMS vs. other transport) with in-hospital and discharge disability outcomes. DESIGN: Prospective observational study. PARTICIPANTS: AIS patients discharged April 2016 to October 2017 from a safety-net hospital in South Carolina. MAIN MEASURES: National Institutes of Health Stroke Scale (NIHSS) change at discharge (admission NIHSS score minus discharge NIHSS, continuous variable), 24-h NIHSS change (attaining high improvement, admission NIHSS minus 24-h NIHSS being 75th percentile or higher), door to neuroimaging (DTI) time, and IV alteplase receipt. NIHSS change was assessed within stroke severity groups, mild, moderate, and severe (admission NIHSS 0-5, 6-14, and ≥ 15, respectively). KEY RESULTS: Of 1168 patients, 838 were study-eligible (52% male, 52.4% Black, 72.2% EMS arrivals, 56.6% mild strokes). Severe and moderate stroke patients were more likely than mild stroke patients to use EMS (adjusted odds ratios, AOR [95% CI] 11.7 [5.0, 27.4] and 4.0 [2.6, 6.3], respectively). EMS arrival was associated with shorter DTI time (adjusted difference - 88.4 min) and higher likelihood of alteplase administration (AOR 5.3 [2.5, 11.4]), both key mediating variables in disability outcomes. High 24-h NIHSS improvement was more likely for EMS arrivals vs. other arrivals among moderate strokes (AOR 3.4 [1.1, 10.9]) and severe strokes (AOR > 999). EMS arrivals had substantially higher NIHSS improvement at discharge within the severe stroke group (adjusted NIHSS change at discharge, 5.9 points higher, p = 0.01). Alteplase recipients showed higher discharge NIHSS improvement than non-recipients (by 2.8 and 1.9 points among severe and moderate strokes, respectively; p = 0.01, 0.02). CONCLUSIONS: The findings offer evidence for including stroke education as a standard of care in the primary care management of patients with stroke-risk comorbidities/lifestyle in order to minimize post-stroke disability.

Validation of behavioral phenotypes in the BACHD rat model.

Huntington disease (HD) is a neurodegenerative disorder caused by a polyglutamine expansion in the HTT gene. Various HD animal models have been generated to mimic the motor, cognitive and neuropsychiatric disturbances that affect HD patients. Reproducing disease phenotypes within these models is essential to identify reliable readouts for therapy studies. We validated behavioral phenotypes shown earlier by other research groups in the BACHD rat model, using both previously applied and novel tests for motor, cognitive and anxiety-like behaviors. We first confirmed known BACHD rats' phenotypes in rotarod, open field (OF) and elevated plus maze (EPM) tests. We then assessed the reproducibility of key phenotypes in the model using new tests: cliff hanging, passive avoidance (PA), Morris water maze (MWM), light dark box and light spot tests. We confirmed impaired motor coordination in the rotarod test and reduced activity in the OF. In line with earlier results in BACHD rats using different tests, we showed impaired reversal learning in MWM and decreased anxiety-like behavior with the light spot test supporting the validity of BACHD rats as a model of HD. Results in the EPM, light dark box, cliff hanging and PA tests did not confirm earlier findings. This may depend on phenotype inconsistencies or rather be related to differences in environmental variables, test typology, experimental settings, animal age and chosen behavioral parameters.

Why acute ischemic stroke patients in the United States use or do not use emergency medical services transport? Findings of an inpatient survey.

BACKGROUND: Patients with acute ischemic stroke (AIS) who use emergency medical services (EMS) receive quicker reperfusion treatment which, in turn, mitigates post-stroke disability. However, nationally only 59% use EMS. We examined why AIS patients use or do not use EMS. METHODS: During 2016-2018, a convenience sample of AIS patients admitted to a primary stroke center in South Carolina were surveyed during hospitalization if they were medically fit, available for survey when contacted, and consented to participate. The survey was programed into EpiInfo with skip patterns to minimize survey burden and self-administered on a touchscreen computer. Survey questions covered symptom characteristics, knowledge of stroke and EMS importance, subjective reactions, role of bystanders and financial factors. Descriptive and multiple regression analyses were performed. RESULTS: Of 108 inpatients surveyed (out of 1179 AIS admissions), 49% were male, 44% African American, mean age 63.5 years, 59% mild strokes, 75 (69%) arrived by EMS, 33% were unaware of any stroke symptom prior to stroke, and 75% were unaware of the importance of EMS use for good outcome. Significant factors that influenced EMS use decisions (identified by regression analysis adjusting for stroke severity) were: prior familiarity with stroke (self or family/friend with stroke) adjusted odds ratio, 5.0 (95% confidence interval, 1.6, 15.1), perceiving symptoms as relevant for self and indicating possible stroke, 26.3 (7.6, 91.1), and bystander discouragement to call 911, 0.1 (0.01,0.7). Further, all 27 patients who knew the importance of EMS had used EMS. All patients whose physician office advised actions other than calling EMS at symptom onset, did not use EMS. CONCLUSION: Systematic stroke education of patients with stroke-relevant comorbidities and life-style risk factors, and public health educational programs may increase EMS use and mitigate post-stroke disability.

Correction: Further investigation of phenotypes and confounding factors of progressive ratio performance and feeding behavior in the BACHD rat model of Huntington disease.

[This corrects the article DOI: 10.1371/journal.pone.0173232.].

Further investigation of phenotypes and confounding factors of progressive ratio performance and feeding behavior in the BACHD rat model of Huntington disease.

Huntington disease is an inherited neurodegenerative disorder characterized by motor, cognitive, psychiatric and metabolic symptoms. We recently published a study describing that the BACHD rat model of HD shows an obesity phenotype, which might affect their motivation to perform food-based behavioral tests. Further, we argued that using a food restriction protocol based on matching BACHD and wild type rats' food consumption rates might resolve these motivational differences. In the current study, we followed up on these ideas in a longitudinal study of the rats' performance in a progressive ratio test. We also investigated the phenotype of reduced food consumption rate, which is typically seen in food-restricted BACHD rats, in greater detail. In line with our previous study, the BACHD rats were less motivated to perform the progressive ratio test compared to their wild type littermates, although the phenotype was no longer present when the rats' food consumption rates had been matched. However, video analysis of food consumption tests suggested that the reduced consumption rate found in the BACHD rats was not entirely based on differences in hunger, but likely involved motoric impairments. Thus, restriction protocols based on food consumption rates are not appropriate when working with BACHD rats. As an alternative, we suggest that studies where BACHD rats are used should investigate how the readouts of interest are affected by motivational differences, and use appropriate control tests to avoid misleading results. In addition, we show that BACHD rats display distinct behavioral changes in their progressive ratio performance, which might be indicative of striatal dysfunction.

Tracking of magnetite labeled nanoparticles in the rat brain using MRI.

This study was performed to explore the feasibility of tracing nanoparticles for drug transport in the healthy rat brain with a clinical MRI scanner. Phantom studies were performed to assess the R1 ( =  1/T1) relaxivity of different magnetically labeled nanoparticle (MLNP) formulations that were based on biodegradable human serum albumin and that were labeled with magnetite of different size. In vivo MRI measurements in 26 rats were done at 3T to study the effect and dynamics of MLNP uptake in the rat brain and body. In the brain, MLNPs induced T1 changes were quantitatively assessed by T1 relaxation time mapping in vivo and compared to post-mortem results from fluorescence imaging. Following intravenous injection of MLNPs, a visible MLNP uptake was seen in the liver and spleen while no visual effect was seen in the brain. However a histogram analysis of T1 changes in the brain demonstrated global and diffuse presence of MLNPs. The magnitude of these T1 changes scaled with post-mortem fluorescence intensity. This study demonstrates the feasibility of tracking even small amounts of magnetite labeled NPs with a sensitive histogram technique in the brain of a living rodent.

Comparison of pharmacological modulation of APP metabolism in primary chicken telencephalic neurons and in a human neuroglioma cell line.

Sequential cleavage of amyloid precursor protein (APP) by ß- and γ-secretases and the formation of Aß peptides are pivotal for Alzheimer's disease. Therefore, a large number of drugs has been developed targeting APP metabolism. However, many pharmacological compounds have been identified in vitro in immortalized APP overexpressing cell lines rather than in primary neurons. Here, we compared the effect of already characterized secretase inhibitors and modulators on Aß formation in primary chicken telencephalic neurons and in a human neuroglioma cell line (H4) ectopically expressing human APP with the Swedish double mutation. Primary chicken neurons replicated the effects of a ß-secretase inhibitor (ß-secretase inhibitor IV), two γ-secretase inhibitors (DAPM, DAPT), two non-steroidal-anti-inflammatory drugs (sulindac sulfide, CW), and of the calpain inhibitor calpeptin. With the exception of the two γ-secretase inhibitors, all tested compounds were more efficacious in primary chicken telencephalic neurons than in the immortalized H4 cell line. Moreover, H4 cells failed to reproduce the effect of calpeptin. Hence, primary chicken telencephalic neurons represent a suitable cell culture model for testing drugs interfering with APP processing and are overall more sensitive to pharmacological interference than immortalized H4 cells ectopically expressing mutant human APP.

Cognition-enhancing properties of Dimebon in a rat novel object recognition task are unlikely to be associated with acetylcholinesterase inhibition or N-methyl-D-aspartate receptor antagonism.

Dimebon (dimebolin) treatment enhances cognition in patients with Alzheimer's disease (AD) or Huntington's disease. Although Dimebon was originally thought to improve cognition and memory through inhibition of acetylcholinesterase (AChE) and the N-methyl-d-aspartate (NMDA) receptor, the low in vitro affinity for these targets suggests that these mechanisms may not contribute to its clinical effects. To test this hypothesis, we assessed whether Dimebon enhances cognition in rats and if such an action is related to either mechanism or additional candidate mechanisms. Acute oral administration of Dimebon to rats (0.05, 0.5, and 5 mg/kg) enhanced cognition in a novel object recognition task and produced Dimebon brain concentrations of 1.7 +/- 0.43, 14 +/- 5.1, and 172 +/- 94 nM, respectively. At these concentrations, Dimebon did not alter the activity of recombinant human or rat brain AChE. Unlike the AChE inhibitors donepezil and galantamine, Dimebon did not change acetylcholine levels in the hippocampus or prefrontal cortex of freely moving rats. Dimebon displays affinity for the NMDA receptor (K(i) = 105 +/- 18 microM) that is considerably higher than brain concentrations associated with cognition enhancement in the novel object recognition task and 200-fold weaker than that of memantine (K(i) = 0.54 +/- 0.05 microM). Dimebon did not block NMDA-induced calcium influx in primary neuronal cells (IC(50) > 50 microM), consistent with a lack of significant effect on this pathway. The cognition-enhancing effects of Dimebon are unlikely to be mediated by AChE inhibition or NMDA receptor antagonism, and its mechanism of action appears to be distinct from currently approved medications for AD.

Apolipoprotein A-I coating of protamine-oligonucleotide nanoparticles increases particle uptake and transcytosis in an in vitro model of the blood-brain barrier.

Drug delivery to the brain is severely restricted by formation of tight junctions between adjacent brain capillary endothelial cells (BCEC). In the present study we have evaluated the effects of protamine-oligonucleotide nanoparticles (proticles) on the functional properties of primary porcine BCEC and characterized uptake and transcytosis of proticles by these cells. Proticles had no adverse effects on BCEC properties relevant to blood-brain barrier (BBB) function. Transcytosis of (125)I-labeled proticles across polarized BCEC cultures occurred in a time- and concentration-dependent manner. As apolipoproteins were suggested to enhance cellular proticle uptake, proticle coating was performed with apoA-I, the major apolipoprotein component of high density lipoproteins. Adsorption of apoA-I on the surface of proticles resulted in significantly improved uptake and transcytosis properties as compared to uncoated proticles. ApoA-I coating enhanced proticle delivery to astrocytes in an in vitro model of the BBB almost twofold. Blocking of scavenger receptor class B, type I (the prime receptor for high density lipoprotein/apoA-I that is expressed on BCEC) reduced transcytosis of apoA-I-coated proticles to levels observed for uncoated proticles. Our data indicate that apoA-I-coating of proticles could be a feasible targeting technology to improve delivery across the BBB.

Is alpha-synuclein pathology a target for treatment of neurodegenerative disorders?

Since the discovery that mutations of alpha-synuclein (AS) gene are responsible for rare forms of familiar Parkinson's disease this synaptic protein attracted increased interest. AS is the main constituent of Lewy bodies. In spite the physiological function is still unclear there is an ongoing discussion if over-expression is already dangerous, or if toxicity is subjected to oligomers, protofibrilles or mature aggregates. The fact that the central hydrophobic part of AS is a constituent of amyloid plaques in Alzheimer patients and the finding that a majority of AD patients have Lewy bodies and Lewy neurites in specific brain areas, raised our interest in the possible contribution of AS to pathogenesis of AD. Beta-synuclein (betaS) a protein of the same gene family seems to be a naturally occurring anti aggregatory factor preventing AS aggregation in vitro and in vivo. The N-terminal amino acid sequence 1 to 15 is responsible for this effect. Based on this finding we synthesized a peptide library with different sequence variations. Several of these peptides displayed distinct neuroprotective activity in tissue culture models of neurodegeneration induced by oxidative stress or Abeta1-42. In spite these peptides have a short half-life, in vivo significant reduction in brain plaque load and improvement of behavioral deficits was demonstrated in an APP-tg mouse model after intranasal treatment for 2 months. KEGV, the shortest sequence was also active after intraperitoneal application. Neuroprotective data in tissue cultures and results from transgenic mice are some how in conflict because in vitro effects can not be explained by the antiaggregatory potential, but most likely by interaction of betaS derivates with anti-apoptotic PI3/Akt cell signaling or interference with anti-oxidative pathways (JNK/JIB). The possibility that such betaS derived peptidomimetics might act as neuroprotectants and at the same time prevent protein missfolding suggests possible therapeutic usefulness in different neurodegenerative disorders.

Beta-Synuclein-derived peptides with neuroprotective activity: an alternative treatment of neurodegenerative disorders?

The 140-amino-acid protein alpha-synuclein (alpha-syn) is the major constituent of Lewy bodies. The protein interacts with several intracellular signal transduction pathways. Reasons for onset of abnormal aggregation of alpha-syn are unclear. Metal ions, oxidative stress, and beta-amyloid 1-42 (Abeta1-42) are important induction factors for alpha-syn aggregation. beta-Synuclein (beta-syn) can counteract alpha-syn aggregation. Cross-breeding of beta-syn transgenic mice with animals overexpressing alpha-syn significantly decreased alpha-syn-positive neuronal inclusion bodies and improved motor function. This was an important proof of concept for the role of beta-syn in regulating alpha-syn aggregation. A drug discovery program based on peptide derivatives (N-terminal amino acids 1-15) of beta-syn was initiated. For screening, tissue culture models simulating disease-specific conditions were utilized. They protected against growth factor withdrawal, Abeta toxicity, and oxidative stress. Three peptides were selected (KEGV, SMAKEGV, MDFMKGLSMAKE) for in vivo studies because they also decreased expression of Abeta1-40 and Abeta1-42. First, in vivo experiments were made in human amyloid precursor protein (APP [Swedish and London mutation]) transgenic mice, as well as alpha-syn transgenic mice. Treatment was performed with the peptides as an intraperitoneal injection or as intranasal droplets for 2 mo. Behavioral studies in APP transgenic mice were performed after 1 and 2 mo of treatment and showed clear effects of these peptides.