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Visual illusions from astronauts in space have been reported to be associated with the passage of high energy charged particles through visual structures (retina, optic nerve, brain). Similar effects have also been reported by patients under proton and heavy ion therapies. This prompted us to investigate whether protons at the Loma Linda University Proton Therapy and Research Center (PTRC) may also affect other sensory systems beside evoking similar perceptions on the visual system. A retrospective review of proton radiotherapy patient records at PTRC identified 29 sensory reports from 19 patients who spontaneously reported visual, olfactory, auditory and gustatory illusions during treatment. Our results suggest that protons can evoke neuronal responses sufficient to elicit conscious sensory illusion experiences, in four senses (auditory, taste, smell, and visual) analogous to those from normal sensory inputs. The regions of the brain receiving the highest doses corresponded with the anatomical structures associated with each type of illusion. Our findings suggest that more detailed queries about sensory illusions during proton therapy are warranted, possibly integrated with quantitative effect descriptions (such as electroencephalography) and can provide additional physiological basis for understanding the effects of protons on central nervous system tissues, needed for radiation risk assessment in advance of deep space human exploration.

Description, Space radiation affects memory in male and not in female mice, and it is dependent on the innate immune system response., In the coming decade, astronauts will travel back to the moon in preparation for future Mars missions. Exposure to galactic cosmic radiation (GCR) is a major obstacle for deep space travel. Using multivariate principal components analysis, we found sex-dimorphic responses in mice exposed to accelerated charged particles to simulate GCR (GCRsim); males displayed impaired spatial learning, whereas females did not. Mechanistically, these GCRsim-induced learning impairments corresponded with chronic microglia activation and synaptic alterations in the hippocampus. Temporary microglia depletion shortly after GCRsim exposure mitigated GCRsim-induced deficits measured months after the radiation exposure. Furthermore, blood monocyte levels measured early after GCRsim exposure were predictive of the late learning deficits and microglia activation measured in the male mice. Our findings (i) advance our understanding of charged particle–induced cognitive challenges, (ii) provide evidence for early peripheral biomarkers for identifying late cognitive deficits, and (iii) offer potential therapeutic strategies for mitigating GCR-induced cognitive loss.

BACKGROUND: Sixty million rural residents have limited access to orthopedic care due to a small rural orthopedic surgery workforce. Increases in specialized training add to the challenge of attracting orthopedic surgeons to rural communities. Answering the call for research on models to meet the needs of rural orthopedic patients, we examine long-term trends in visiting consultant clinics (VCCs) in Iowa, a state with a large rural population. METHODS: The Office of Statewide Clinical Education Programs (Carver College of Medicine) compiles an annual report of outreach clinic locations, frequencies and participating physicians. Trends in the total number of VCCs, days and locations (1989-2018) were analysed using joinpoint analysis. RESULTS: Total clinic days grew rapidly from 1992-1997 (Average Percent Change: 19.7%) before a decline ending in 2009 (APC: -4.1%). A new growth period (2009-2013, APC: 7.5%) preceded another decline (APC: -3.6%) ending in 2018. The number of cities hosting a VCC grew from 56 (1989) to a peak of 90 (1999) and fell an average of 0.9% a year thereafter. More than 80% of all VCCs in the last ten years were offered 2 or more times per month. The average participation rate for Iowa-based orthopedic surgeons was 44%. The mean number of VCCs staffed by a single physician was 1.32 (std. dev. = 0.53) with a median of 1. The average number of VCC days per month for a participating physician was 3.22 (std. dev. = 2.41) with a median of 2.66. CONCLUSION: The VCC model of rural outreach is sustainable (30+ year history) and self-funded. Most clinics occur with sufficient frequency to allow timely follow-up care. This model of rural outreach is supported by the participation of a large segment (44%) of Iowa’s orthopedic surgeons. Visiting orthopedic surgeons provide access to care in 65 of the 76 Critical Access Hospitals in Iowa offering orthopedic services compared to 8 staffed by a local orthopedic surgeon. Level of Evidence: V

Purpose Studies are required to determine whether exposures to radiation encountered during manned missions in deep space may have adverse effects on the cardiovascular system. Most of the prior studies on effects of simulated space radiation on the heart and vasculature have been performed in mouse models. To provide data from a second animal species, two studies were performed to assess effects of high-energy charged particle radiation on the heart and abdominal aorta in a rat model. Materials and methods In study A, male Long Evans rats were exposed to whole-body protons (250 MeV, 0.5 Gy) or oxygen ions (16O, 600 MeV/n, 0.5 Gy), and ultrasonography was used to measure in vivo cardiac function and blood flow parameters at 3, 5, 9 and 12 months after radiation, followed by tissue collection at 12 months. In study B, male Long Evans rats were exposed to 16O (1 GeV/n, 0.01-0.25 Gy), and hearts collected at 6 to 7 and 12 months for histology and western-blots. Results Both protons (250 MeV) and 16O (600 MeV/n) caused a decrease in left ventricular posterior wall thickness at 3-5 months, but did not change echocardiographic measures of cardiac function. In Pulsed-wave Doppler assessment of the abdominal aorta, an increase was seen in mean velocity, peak velocity, and velocity time integral at 12 months after 16O (600 MeV/n), suggesting a change in vascular function. There were no significant changes in histopathology or histological quantification of total collagens in heart or aorta. On the other hand, an increase was seen in a 75 kDa peptide of collagen type III in the left ventricle of rats exposed to protons (250 MeV) and 16O (600 MeV/n and 1 GeV/n), suggesting that radiation caused remodeling of existing collagens in the heart. 16O (600 MeV/n and 1 GeV/n) caused increases in left ventricular protein levels of immune cell markers CD2, CD4, CD8, and CD68. Conclusion A single low dose of whole body protons or 16O in male Long Evans rats did not change cardiac function or induce gross pathological changes in the heart or aorta, but induced mild changes in vascular function and remodeling of existing collagens in the heart. Altogether, studies in prior mouse models and the current work in rats indicate minor changes in cardiac function and structure after a low dose of single-ion radiation.

Space travel presents a number of environmental challenges to the central nervous system, including changes in gravitational acceleration that alter the terrestrial synergies between perception and action, galactic cosmic radiation that can damage sensitive neurons and structures, and multiple factors (isolation, confinement, altered atmosphere, and mission parameters, including distance from Earth) that can affect cognition and behavior. Travelers to Mars will be exposed to these environmental challenges for up to 3 years, and space-faring nations continue to direct vigorous research investments to help elucidate and mitigate the consequences of these long-duration exposures. This article reviews the findings of more than 50 years of space-related neuroscience research on humans and animals exposed to spaceflight or analogs of spaceflight environments, and projects the implications and the forward work necessary to ensure successful Mars missions. It also reviews fundamental neurophysiology responses that will help us understand and maintain human health and performance on Earth.

This study has established the impact that 1-15 cGy 600 MeV/n

There is concern that degradation of vision as a result of space flight may compromise both mission goals and long-term quality of life after space travel. The visual disturbances may be due to a combination of intracerebral pressure changes and exposure to ionizing radiation. The retina and the retinal vasculature play important roles in vision, yet have not been studied extensively in relation to space travel and space radiation. The goal of the present study was to characterize oxidative damage and apoptosis in retinal endothelial cells after whole-body gamma-ray, proton and oxygen ((16)O) ion radiation exposure at 0.1 to 1 Gy. Six month old male C57Bl/6J mice were exposed whole-body to 600 MeV/n (16)O ions (0, 0.1, 0.25, 1 Gy), solar particle events (SPE)-like protons (0, 0.1, 0.25, 0.5 Gy) or (60)Co gamma-rays (0, 0.1, 0.25, 0.5 Gy). Eyes were isolated for examining endothelial nitric oxide synthase (eNOS) expression and characterization of apoptosis in retina and retinal endothelial cells at 2 weeks post irradiation. The expression of eNOS was significantly increased in the retina following proton and (16)O ions exposure. (16)O ions induced over 2-fold increase in eNOS expression compared to protons at the 2-week post irradiation time point (p

There are serious concerns about possible late radiation damage to ocular tissue from prolonged space radiation exposure, and occupational and medical procedures. This study aimed to investigate the effects of whole-body high-energy proton exposure at a single dose on apoptosis, oxidative stress, and blood-retina barrier (BRB) integrity in the retina and optic nerve head (ONH) region and to compare these radiation-induced effects with those produced by fractionated dose. Six-month-old C57BL/6 male mice were either sham irradiated or received whole-body high energy proton irradiation at an acute single dose of 0.5 Gy or 12 equal dose fractions for a total dose of 0.5 Gy over twenty-five days. At four months following irradiation, mice were euthanized and ocular tissues were collected for histochemical analysis. Significant increases in the number of apoptotic cells were documented in the mouse retinas and ONHs that received proton radiation with a single or fractionated dose (p < 0.05). Immunochemical analysis revealed enhanced immunoreactivity for oxidative biomarker, 4-hydroxynonenal (4-HNE) in the retina and ONH following single or fractionated protons with more pronounced changes observed with a single dose of 0.5 Gy. BRB integrity was also evaluated with biomarkers of aquaporin-4 (AQP-4), a water channel protein, a tight junction (TJ) protein, Zonula occludens-1 (ZO-1), and an adhesion molecule, the platelet endothelial cell adhesion molecule-1 (PECAM-1). A significantly increased expression of AQP-4 was observed in the retina following a single dose exposure compared to controls. There was also a significant increase in the expression of PECAM-1 and a decrease in the expression of ZO-1 in the retina. These changes give a strong indication of disturbance to BRB integrity in the retina. Interestingly, there was very limited immunoreactivity of AQP-4 and ZO-1 seen in the ONH region, pointing to possible lack of BRB properties as previously reported. Our data demonstrated that exposure to proton radiation of 0.5 Gy induced oxidative stress-associated apoptosis in the retina and ONH, and changes in BRB integrity in the retina. Our study also revealed the differences in BRB biomarker distribution between these two regions. In response to radiation insults, the cellular response in the retina and ONH may be differentially regulated in acute or hyperfractionated dose schedules.

Background Space travel is associated with continuous low dose rate exposure to high linear energy transfer (LET) radiation. Pathophysiological manifestations after low dose radiation exposure are strongly influenced by non-cytocidal radiation effects, including changes in the microbiome and host gene expression. Although the importance of the gut microbiome in the maintenance of human health is well established, little is known about the role of radiation in altering the microbiome during deep-space travel. Results Using a mouse model for exposure to high LET radiation, we observed substantial changes in the composition and functional potential of the gut microbiome. These were accompanied by changes in the abundance of multiple metabolites, which were related to the enzymatic activity of the predicted metagenome by means of metabolic network modeling. There was a complex dynamic in microbial and metabolic composition at different radiation doses, suggestive of transient, dose-dependent interactions between microbial ecology and signals from the host’s cellular damage repair processes. The observed radiation-induced changes in microbiota diversity and composition were analyzed at the functional level. A constitutive change in activity was found for several pathways dominated by microbiome-specific enzymatic reactions like carbohydrate digestion and absorption and lipopolysaccharide biosynthesis, while the activity in other radiation-responsive pathways like phosphatidylinositol signaling could be linked to dose-dependent changes in the abundance of specific taxa. Conclusions The implication of microbiome-mediated pathophysiology after low dose ionizing radiation may be an unappreciated biologic hazard of space travel and deserves experimental validation. This study provides a conceptual and analytical basis of further investigations to increase our understanding of the chronic effects of space radiation on human health, and points to potential new targets for intervention in adverse radiation effects. Electronic supplementary material The online version of this article (doi:10.1186/s40168-017-0325-z) contains supplementary material, which is available to authorized users.

Aims Identification and management of the Standard Modifiable Cardiovascular Risk Factors (SMuRFs; hypercholesterolaemia, hypertension, diabetes and smoking) has substantially improved cardiovascular disease outcomes. However, cardiovascular disease remains the leading cause of death worldwide. Suspecting an evolving pattern of risk factor profiles in the ST elevation myocardial infarction (STEMI) population with the improvements in primary care, we hypothesized that the proportion of 'SMuRFless' STEMI patients may have increased. Methods/results We performed a single centre retrospective study of consecutive STEMI patients presenting from January 2006 to December 2014. Over the study period 132/695 (25%) STEMI patients had 0 SMuRFs, a proportion that did not significantly change with age, gender or family history. The proportion of STEMI patients who were SMuRFless in 2006 was 11%, which increased to 27% by 2014 (odds ratio 1.12 per year, 95% confidence interval: 1.04-1.22). The proportion of patients with hypercholesterolaemia decreased (odds ratio 0.92, 95% confidence interval 0.86-0.98), as did the proportion of current smokers (odds ratio 0.93, 95% confidence interval 0.86-0.99), with no significant change in the proportion of patients with diabetes and hypertension. SMuRF status was not associated with extent of coronary disease; in-hospital outcomes, or discharge prescribing patterns. Conclusion The proportion of STEMI patients with STEMI poorly explained by SMuRFs is high, and is significantly increasing. This highlights the need for bold approaches to discover new mechanisms and markers for early identification of these patients, as well as to understand the outcomes and develop new targeted therapies.

Background Raised intracellular Na+ impairs cardiac contractility in severe heart failure (HF). β3 adrenoceptor (β3 AR) agonists activate cardiomyocyte Na+-K+ pump-mediated Na+ export. Treatment with a selective β3 AR agonist in patients with severely reduced left ventricular ejection fraction (LVEF) and stable HF improves LVEF. We examined effects of β3 AR agonists on Na+-K+ pump function in experimental severe HF characterized by organ congestion and, in parallel, the clinical response in human treatment-refractory worsening chronic HF (WCHF). Methods The circumflex coronary artery was ligated in rabbits to induce HF. Treatment with β3 AR agonists was started 2 weeks later and effects on congestive signs were assessed, including ascites and the primary outcome, lung: body weight ratio. Na+-K+ pump current was measured in voltage-clamped myocytes from non-infarcted myocardium. The β3 AR agonist mirabegron was prescribed off-label to patients hospitalized with advanced HF (stage D) that was refractory to maximally tolerated guideline-directed treatment and intravenous furosemide, with or without inotropes, as assessed by ≥2 cardiologists. Results Rabbits developed severe HF with markedly increased lung:body weight ratio and ascites. Na+-K+ pump current was decreased in myocytes from rabbits with HF. β3 AR agonists eliminated pump inhibition, significantly reduced lung:body weight ratio and prevalence of ascites. Mirabegron was given to 9 patients aged 74 ± 7 years (mean ± SD) with advanced HF. LVEF was 26 ± 5%. Signs and symptoms improved within 1-2 days of treatment. Mirabegron was well-tolerated and improvement of ≥1 NYHA Class maintained by all early after discharge. One patient died from HF at 16 months, 4 died from other causes at 2 – 30 months and 4 remain alive at 30 ± 5 months with NYHA Class II symptoms. Conclusion Treatment with β3 AR agonist in a pre-clinical model of severe HF can reverse Na+-K+ pump inhibition and improve organ congestion implicating pump inhibition as a reversible myocardial dysfunction that is a useful treatment target. The changed in-hospital clinical trajectory and a more favourable post-discharge course than expected in advanced HF, suggests efficacy of β3 AR agonist shown in the animal model might translate into efficacy in advanced human HF.

Long Interspersed Nucleotide Element 1 (LINE-1) retrotransposons are heavily methylated and are the most abundant transposable elements in mammalian genomes. Here, we investigated the differential DNA methylation within the LINE-1 under normal conditions and in response to environmentally relevant doses of sparsely and densely ionizing radiation. We demonstrate that DNA methylation of LINE-1 elements in the lungs of C57BL6 mice is dependent on their evolutionary age, where the elder age of the element is associated with the lower extent of DNA methylation. Exposure to 5-aza-2′-deoxycytidine and methionine-deficient diet affected DNA methylation of selective LINE-1 elements in an age- and promoter type-dependent manner. Exposure to densely IR, but not sparsely IR, resulted in DNA hypermethylation of older LINE-1 elements, while the DNA methylation of evolutionary younger elements remained mostly unchanged. We also demonstrate that exposure to densely IR increased mRNA and protein levels of LINE-1 via the loss of the histone H3K9 dimethylation and an increase in the H3K4 trimethylation at the LINE-1 5′-untranslated region, independently of DNA methylation. Our findings suggest that DNA methylation is important for regulation of LINE-1 expression under normal conditions, but histone modifications may dictate the transcriptional activity of LINE-1 in response to exposure to densely IR.

Background Although many case series have been published on the treatment of shoulder periprosthetic joint infection (PJI), few provide direct comparison of outcomes. This systematic review synthesizes the available English literature on shoulder PJI to quantify treatment effectiveness. Methods The PubMed and Embase databases were searched in April 2014. Keywords included "shoulder replacement infection" and "shoulder arthroplasty infection." Of 663 titles, 55 manuscripts underwent full-text review after application of exclusion criteria. Thirty articles were finally included. Results Propionibacterium acnes was most commonly reported, representing 38.9% of infections, followed by Staphylococcus species. Risk factors for shoulder PJI include previous surgery, increased age, male gender, increased body mass index, and diabetes mellitus. The average white blood cell count in 13 studies was 7472 cells/µL. Ten studies reported a mean erythrocyte sedimentation rate of 27.6 mm/h, whereas 14 studies reported a mean C-reactive protein level of 2.6 mg/dL. P. acnes in intraoperative culture specimens was an independent risk factor for failed treatment for shoulder PJI. When outcomes were pooled, no statistical difference was found in the success rates of 1-stage, 2-stage, or resection arthroplasty revision; each displayed a success rate >90%. However, single-stage revision produced the highest mean Constant score; implant retention resulted in the best range of motion. Conclusions Our data suggest that single-stage revision can be as effective as 2-stage or resection treatments; however, the retrospective nature of these data precluded our ability to control for confounding variables. Future studies on shoulder PJI should involve direct comparisons of 1-stage vs. 2-stage treatment while comparing cost, morbidity, and functional outcomes.

DNA methylation is a key epigenetic mechanism, needed for proper control over the expression of genetic information and silencing of repetitive elements. Exposure to ionizing radiation, aside from its strong genotoxic potential, may also affect the methylation of DNA, within the repetitive elements, in particular. In this study, we exposed C57BL/6J male mice to low absorbed mean doses of two types of space radiation-proton (0.1 Gy, 150 MeV, dose rate 0.53 ± 0.08 Gy/min), and heavy iron ions ((56)Fe) (0.5 Gy, 600 MeV/n, dose rate 0.38 ± 0.06 Gy/min). Radiation-induced changes in cardiac DNA methylation associated with repetitive elements were detected. Specifically, modest hypomethylation of retrotransposon LINE-1 was observed at day 7 after irradiation with either protons or (56)Fe. This was followed by LINE-1, and other retrotransposons, ERV2 and SINE B1, as well as major satellite DNA hypermethylation at day 90 after irradiation with (56)Fe. These changes in DNA methylation were accompanied by alterations in the expression of DNA methylation machinery and affected the one-carbon metabolism pathway. Furthermore, loss of transposable elements expression was detected in the cardiac tissue at the 90-day time-point, paralleled by substantial accumulation of mRNA transcripts, associated with major satellites. Given that the one-carbon metabolism pathway can be modulated by dietary modifications, these findings suggest a potential strategy for the mitigation and, possibly, prevention of the negative effects exerted by ionizing radiation on the cardiovascular system. Additionally, we show that the methylation status and expression of repetitive elements may serve as early biomarkers of exposure to space radiation.

Electric fields produced by advanced pulsed microwave transmitter technology now readily exceed the Institute of Electrical and Electronic Engineers (IEEE) C.95.1 peak E-field limit of 100 kV/m, highlighting a need for scientific validation of such a specific limit. Toward this goal, we exposed Jurkat Clone E-6 human lymphocyte preparations to 20 high peak power microwave (HPPM) pulses (120 ns duration) with a mean peak amplitude of 2.3 MV/m and standard deviation of 0.1 with the electric field at cells predicted to range from 0.46 to 2.7 MV/m, well in excess of current standard limit. We observed that membrane integrity and cell morphology remained unchanged 4 h after exposure and cell survival 24 h after exposure was not statistically different from sham exposure or control samples. Using flow cytometry to analyze membrane disruption and morphological changes per exposed cell, no changes were observed in HPPM-exposed samples. Current IEEE C95.1-2005 standards for pulsed radiofrequency exposure limits peak electric field to 100 kV/m for pulses shorter than 100 ms [IEEE (1995) PC95.1-Standard for Safety Levels with Respect to Human Exposure to Electric, Magnetic and Electromagnetic Fields, 0 Hz to 300 GHz, Institute of Electrical and Electronic Engineers: Piscataway, NJ, USA]. This may impose large exclusion zones that limit HPPM technology use. In this study, we offer evidence that maximum permissible exposure of 100 kV/m for peak electric field may be unnecessarily restrictive for HPPM devices. Bioelectromagnetics. 37:141-151, 2016. © 2016 Wiley Periodicals, Inc.

Summary What is known and objective While research has examined the likelihood that drugs progress across phases of clinical trials, no research to date has examined the types of product development strategies that are the most likely to be successful in clinical trials. This research seeks to identify the strategies that are most likely to reach the market—those generated using a novel product development strategy or strategies that combine a company's expertise with both drugs and indications, which we call combined experience strategies. Methods We evaluate the success of product development strategies in the drug development process for a sample of 2562 clinical trials completed by 406 US pharmaceutical companies. To identify product development strategies, we coded each clinical trial according to whether it consisted of an indication or a drug that was new to the firm. Accordingly, a clinical trial that consists of both an indication and a drug that were both new to the firm represents a novel product development strategy; indication experience is a product development strategy that consists of an indication that a firm had tested previously in a clinical trial, but with a drug that was new to the firm; drug experience is a product development strategy that consists of a drug that the firm had prior experience testing in clinical trials, but with an indication that was new to the firm; combined experience consists of both a drug and an indication that the firm had experience testing in clinical trials. Success rates for product development strategies across clinical phases were calculated for the clinical trials in our sample. Results and discussion Combined experience strategies had the highest success rate. More than three and a half percent (0·036) of the trials that combined experience with drugs and indications eventually reached the market. The next most successful strategy is drug experience (0·025) with novel strategies trailing closely (0·024). Indication experience strategies are the least successful (0·008). These differences are statistically significant. What is new and conclusion The primary contribution of this study is that product development strategies combining experience with drugs and indications strategies are the most likely to reach the market, even though they are least common strategy. Therefore, combined experience strategies remain underutilized. The findings also suggest a promising path for pursuing combined experience strategies: gaining expertise with drugs is likely to be a more effective path to gaining the expertise necessary for developing subsequent recombination strategies.

Academic, public or special librarians interact with a variety of patrons–students, faculty members, community patrons, or other employees–and often need tools to manage their time and responsibilities in the library. Scheduling appointments and events often takes an inordinate amount of time away from their most important work. This paper reviews LibCal, an online calendaring platform, and three of its components: the appointment scheduler, event scheduler, and room booking service. The functionality of each LibCal component will be thoroughly discussed along with its pros and cons based on the author’s experience. After considering these factors, recommendations are made in regards to adoption and use.

Evaluating collections and ultimately removing content poses a variety of difficult issues, including choosing appropriate deselection criteria, communicating with stakeholders, providing accountability, and managing the overall timetable to finish projects on time. The Science and Engineering librarians at Brigham Young University evaluated their entire print collection of over 350,000 items within one year, significantly reducing the number of items kept on the open shelves and the physical collection footprint. Keys to accomplishing this project were extensive preparation, tracking progress and accountability facilitated by Google Sheets and an interactive GIS stacks map, and stakeholder feedback facilitated by a novel web-based tool. This case study discusses guidelines to follow and pitfalls to avoid for any organization that is considering a large- or small-scale collection evaluation project.

This study has established the impact that 1-15 cGy 600 MeV/n 28Si radiation had on cognitive flexibility performance, glutamatergic synaptic transmission and plasticity in the prelimbic area (PrL) of the medial prefrontal cortex (mPFC) of ∼10-month-old (at the time of irradiation) male Wistar rats. Exposure to 1 cGy 600 MeV/n 28Si ions resulted in significantly impaired performance in the simple (SD) and compound discrimination (CD) stages of the attentional set shifting (ATSET) task. However, there was a pronounced non-linear dose response for cognitive impairment. Should similar effects occur in astronauts, the impairment of SD performance would result in a decreased ability to identify and learn the "rules" required to respond to new tasks/situations, while the impaired CD performance would result in a decreased ability to identify and maintain focus on relevant aspects of the task being conducted. The irradiated rats were also screened for performance in a task for unconstrained cognitive flexibility (UCFlex), often referred to as creative problem solving. Exposure to 1, 5 and 10 cGy resulted in a significant reduction in UCFlex performance, in an apparent all-or-none responsive manner. Importantly, performance in the ATSET test was not indicative of UCFlex performance. From a risk assessment perspective, these findings suggest that a value based on a single behavioral end point may not fully represent the cognitive deficits induced by space radiation, even within the cognitive flexibility domain. After completion of the cognitive flexibility testing, in vitro electrophysiological assessments of glutamatergic synaptic transmission and plasticity were performed in slices of the PrL cortex of 10 cGy irradiated rats. Extracellular recordings of field excitatory postsynaptic potentials revealed that radiation significantly decreased long-term depression in layer L5. Patch-clamp whole cell recordings in pyramidal neurons of the L2-3 revealed reduced frequency of spontaneous excitatory postsynaptic currents indicating alterations in presynaptic glutamate release and impaired neuronal spiking (e.g., decreased action potential amplitudes) in irradiated neurons. However, there was no obvious correlation between magnitudes of these electrophysiological decrements and the cognitive performance status of the irradiated rats. These data suggest that while radiation-induced changes in synaptic plasticity in the PrL cortex may be associated with cognitive impairment, they are most likely not the sole determinant of the incidence and severity of such impairments.

Exposure to galactic cosmic rays (GCR) poses an obstacle to successful deep space missions, including missions to the Moon or Mars. Previously, we and others have identified chronic cognitive impairments associated with GCR in rodent model systems. The persistent cognitive loss previously reported is indicative of global changes in different regions of the brain, including the prefrontal cortex and the hippocampus. It has been shown that both of these brain regions are involved in social functions. Here we demonstrate that four months after a single exposure to oxygen ionizing radiation, which is a component of GCR, adult male mice have social memory deficits. Importantly, we identified circulating levels of CD8 T cells as predictors of social behavioral changes. Thus, CD8 T cells could be used as a potential peripheral biomarker. To the best of our knowledge we demonstrate for the first time that GCR-induced impairments in social behavior are directly linked to peripheral immune changes. These results further advance our understanding of the challenges encountered during space exploration.

Interplanetary exploration will be humankind's most ambitious expedition and the journey required to do so, is as intimidating as it is intrepid. One major obstacle for successful deep space travel is the possible negative effects of galactic cosmic radiation (GCR) exposure. Here, we investigate for the first time how combined GCR impacts long-term behavioral and cellular responses in male and female mice. We find that a single exposure to simulated GCR induces long-term cognitive and behavioral deficits only in the male cohorts. GCR exposed male animals have diminished social interaction, increased anxiety-like phenotype and impaired recognition memory. Remarkably, we find that the female cohorts did not display any cognitive or behavioral deficits after GCR exposure. Mechanistically, the maladaptive behavioral responses observed only in the male cohorts correspond with microglia activation and synaptic loss in the hippocampus, a brain region involved in the cognitive domains reported here. Furthermore, we measured reductions in AMPA expressing synaptic terminals in the hippocampus. No changes in any of the molecular markers measured here are observed in the females. Taken together these findings suggest that GCR exposure can regulate microglia activity and alter synaptic architecture, which in turn leads to a range of cognitive alterations in a sex dependent manner. These results identify sex-dependent differences in behavioral and cognitive domains revealing promising cellular and molecular intervention targets to reduce GCR-induced chronic cognitive deficits thereby boosting chances of success for humans in deep space missions such as the upcoming Mars voyage.

Microglia are the main immune component in the brain that can regulate neuronal health and synapse function. Exposure to cosmic radiation can cause long-term cognitive impairments in rodent models thereby presenting potential obstacles for astronauts engaged in deep space travel. The mechanism/s for how cosmic radiation induces cognitive deficits are currently unknown. We find that temporary microglia depletion, one week after cosmic radiation, prevents the development of long-term memory deficits. Gene array profiling reveals that acute microglia depletion alters the late neuroinflammatory response to cosmic radiation. The repopulated microglia present a modified functional phenotype with reduced expression of scavenger receptors, lysosome membrane protein and complement receptor, all shown to be involved in microglia-synapses interaction. The lower phagocytic activity observed in the repopulated microglia is paralleled by improved synaptic protein expression. Our data provide mechanistic evidence for the role of microglia in the development of cognitive deficits after cosmic radiation exposure.

Background Physician assistants are expected to have an important role in providing both primary and specialty care. Iowa has a large rural (and aging) population and faces challenges to provide equitable access to care. This study examined changes in the Iowa physician assistant workforce (1995–2015) focusing on practice setting (primary v. subspecialty care) and geographic location (rural/urban, Health Professional Shortage Area). Documenting their current locations and service in HPSAs for primary care will help health planners track future changes. Methods Data from 1995–2015 from the Iowa Health Professions Inventory (Office of Statewide Clinical Education Programs, Carver College of Medicine, University of Iowa) were combined with US census data on rural location and HPSA status. SPSS was used to compare Iowa and national data. Growth trends were analyzed using joinpoint regression. Results The overall Iowa physician assistant workforce increased 161% between 1995 and 2015. In 2015, more than two-thirds (71%) were female and more than 30% practiced in rural counties. The average annual growth rate of primary care PAs (per 100,000 population) was significantly higher in the periods from 1995–1997 and 1997–2001 (22.4% and 7.4% respectively) than in period from 2001–2015 (3.8%). By 2015, 56% of Iowa’s physician assistants practiced in primary care (versus 29.6% nationally). Of these, 44% of primary care physician assistants in Iowa practiced in counties, geographic locations or worksites designated as Health Professional Shortage Areas for primary care. Conclusions A high proportion of Iowa’s physician assistant workforce practiced in primary care and many served patients in Health Professional Shortage Areas. The number of physician assistants in Iowa will continue to grow and serve an important role in providing access to health care, particularly to rural Iowans.

Interest in deep space exploration underlines the needs to investigate the effects of exposure to combined sources of space radiation. The lung is a target organ for radiation, and exposure to protons and heavy ions as radiation sources may lead to the development of degenerative disease and cancer. In this study, we evaluated the pro-fibrotic and epigenetic effects of exposure to protons (150 MeV/nucleon, 0.1 Gy) and heavy iron ions ((56)Fe, 600 MeV/nucleon, 0.5 Gy) alone or in combination (protons on Day 1 and (56)Fe on Day 2) in C57BL/6 male mice 4 weeks after irradiation. Exposure to (56)Fe, proton or in combination, did not result in histopathological changes in the murine lung. At the same time, combined exposure to protons and (56)Fe resulted in pronounced molecular alterations in comparison with either source of radiation alone. Specifically, we observed a substantial increase in the expression of cytokine Il13, loss of expression of DNA methyltransferase Dnmt1, and reactivation of LINE-1, SINE B1 retrotransposons, and major and minor satellites. Given the deleterious potential of the observed effects that may lead to development of chronic lung injury, pulmonary fibrosis, and cancer, future studies devoted to the investigation of the long-term effects of combined exposures to proton and heavy ions are clearly needed.

Objectives Assess the effect of aspiration thrombectomy on diagnosis and management of embolic acute myocardial infarction. Background Discrimination of embolic acute myocardial infarction from atherosclerotic plaque rupture/erosion prompts oral anticoagulation treatment of source of embolus, as well as avoiding unnecessary stenting and dual antiplatelet therapy. However, detection is difficult without aspiration. Methods We compared rates of diagnosis of embolic infarction for 2.5 years prior to (pre-RAT) and 2.5 years post routine aspiration thrombectomy (post-RAT). Baseline demographics, outcomes, and treatment strategies were also compared between the embolic infarction and atherosclerotic infarction. Results Diagnosed embolic infarction rose from 1.2% in the pre-RAT era to 2.8% in the post-RAT period (P

To determine if high-activity older adults are adversely affected by distal radius malunion.Cross-sectional study.Hand clinics at a tertiary institution.Ninety-six patients 60 years or older at the time of fracture were evaluated at least 1 year after distal radius fracture.Physical Activity Scale of the Elderly scores stratified participants into high- and low-activity groups. Malunions were defined radiographically by change of ≥20 degrees of lateral tilt, ≥15 degrees radial inclination, ≥4 mm of ulnar variance, or ≥4 mm intra-articular gap or step-off, compared with the uninjured wrist.Patient-rated disability of the upper extremity was measured by the QuickDASH and visual analog scales (VAS) for pain/function. Strength and motion measurements objectively quantified wrist function.High-activity participants with a distal radius malunion were compared with high-activity participants with well-aligned fractures. There was no significant difference in QuickDASH scores, VAS function, strength, and wrist motion despite statistically, but not clinically, relevant increases in VAS pain scores (difference 0.5, P = 0.04) between the groups. Neither physical Activity Scale of the Elderly score (β = 0.001, 95% confidence interval: -0.002 to 0.004) nor malunion (β = 0.133, 95% confidence interval: -0.26 to 0.52) predicted QuickDASH scores in regression modeling after accounting for age, sex, and treatment. Operative management failed to improve outcomes and resulted in decreased grip strength (P = 0.05) and more frequent complications (26% vs. 7%, P = 0.01) when compared with nonoperative management.Even among highly active older adults, distal radius malunion does not affect functional outcomes. Judicious use of operative management is warranted provided heightened complication rates.Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Widening surgical indications for total elbow arthroplasty have resulted in increasing rates of implantation over the past several years. The need for advanced surgical techniques in the event of revision surgical treatment has become more apparent with time. Extraction of the ulnar component can be

Background Pre-hospital ECG and emergency department (ED) bypass direct to the catheter laboratory may optimize reperfusion times for patients with ST-segment elevation myocardial infarction. Questions remain over feasibility and safety during off hours. Aims To determine if presenting time of day is associated with differences in in-hospital and 30-day mortality and key reperfusion times. Methods/Results Seven hundred and twenty consecutive patients with STEMI triaged directly from the field to the catheter laboratory between June 2004–May 2013. Vital status was reported as of August 2013. The mean age was 65 ± 14 years, and 75.1% were male. Overall mortality (in-hospital/30 days) did not significantly differ for patients (3.4% in hours and 3.1% off hours; P = N/S). Symptom onset-to-arrival to the heart attack was non-significantly lower (100 minutes off hours (IQR 78–174) versus 110 minutes in hours (IQR 75–199), P = N/S). Call-to-balloon time was not significantly affected by the time of presentation: 150 min in hours (IQR 111–239) versus 154 minutes during off hours (IQR 115–225) P = N/S. Overall door-to-balloon time was 36 minutes (IQR 25–51), 34 minutes in hours (IQR 24–49) versus 40 minutes off hours (IQR 29–55) P = N/S. The overall false positive activation rate was only 13.1%, (in hours 12.2% vs. off hours 14.6%, respectively, P = N/S). Conclusions In a unit with an established field triage system facilitating ED bypass, reperfusion times and mortality are not significantly influenced by whether the patient presents during standard working hours or outside of these hours. (J Interven Cardiol 2015;28:24–31)

Aims: Radiation-induced disruption of mitochondrial function can elevate oxidative stress and contribute to the metabolic perturbations believed to compromise the functionality of the central nervous system. To clarify the role of mitochondrial oxidative stress in mediating the adverse effects of radiation in the brain, we analyzed transgenic (mitochondrial catalase [MCAT]) mice that overexpress human catalase localized to the mitochondria. Results: Compared with wild-type (WT) controls, overexpression of the MCAT transgene significantly decreased cognitive dysfunction after proton irradiation. Significant improvements in behavioral performance found on novel object recognition and object recognition in place tasks were associated with a preservation of neuronal morphology. While the architecture of hippocampal CA1 neurons was significantly compromised in irradiated WT mice, the same neurons in MCAT mice did not exhibit extensive and significant radiation-induced reductions in dendritic complexity. Irradiated neurons from MCAT mice maintained dendritic branching and length compared with WT mice. Protected neuronal morphology in irradiated MCAT mice was also associated with a stabilization of radiation-induced variations in long-term potentiation. Stabilized synaptic activity in MCAT mice coincided with an altered composition of the synaptic AMPA receptor subunits GluR1/2. Innovation: Our findings provide the first evidence that neurocognitive sequelae associated with radiation exposure can be reduced by overexpression of MCAT, operating through a mechanism involving the preservation of neuronal morphology. Conclusion: Our article documents the neuroprotective properties of reducing mitochondrial reactive oxygen species through the targeted overexpression of catalase and how this ameliorates the adverse effects of proton irradiation in the brain. Antioxid. Redox Signal. 22, 78–91.