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Background/Introduction CT coronary angiography (CTCA) Fractional Flow Reserve (FFRCT) is a key investigation in chronic coronary syndrome (CCS) guidelines. FFR calculated from CTCA may help improve CTCA specificity for flow limiting disease, preventing unnecessary invasive coronary angiography (ICA). Purpose To (1) assess the treatment planning potential of FFRCT by determining the concordance of FFRCT with an ICA +/− invasive physiological assessment for the detection of flow limiting CAD in a real world NHS setting and (2) concordance sub-analysis of concordance of invasive iFR and FFRCT. Methods A single-centre retrospective analysis of a prospectively maintained clinical CTCA database. We identified patients with CCS who had CTCA FFRCT and subsequent ICA from August 2018 to January 2021. Concordance was assessed on a per patient and per vessel basis (major epicardial vessels: left main stem [LMS], left anterior descending artery [LAD], circumflex [LCx], right coronary artery [RCA]). Two non-invasive ischaemia thresholds were examined an FFRCT ≤0.8 and 70% (or >50% in the LMS) and/or an end vessel iFR ≤0.89 / FFR ≤0.8. All vessels that underwent an iFR, at the interventionists discretion, were then assessed relative to their end-vessel FFRCT. Results 565 patients had a CTCA with FFRCT and 164 patients had a subsequent ICA and were suitable for analysis. On a per patient basis 69% of those referred to ICA with an FFRCT ≤0.8 of at least one major epicardial vessel had any flow limiting CAD at ICA. With an FFRCT A total of 120 vessels were included in the iFR subsection analysis. The mean FFRCT was 0.71 (±0.13) and mean iFR was 0.89 (±0.1). Accuracy was 54% (95% CI 45–63%) with a sensitivity of 89% (95% CI 76–96%), specificity 32% (95% CI 22–44%), positive predictive value 45% (95% CI 40–50%) and negative predictive value of 83% (95% CI 66–92%). A Pearson's correlation coefficient of 0.23 was found. Conclusion This study demonstrated that the negative predictive value of FFRCT was excellent, including importantly for LMS analysis. The specificity on a per vessel basis was good with the exception of the LAD assessment. This may have implications for interventional planning with this imaging modality. FFRCT correlated poorly with invasive iFR in this subsection analysis although selection bias may be contributing. There remains a significant proportion of patients referred for an ICA where no flow limiting CAD is found. Funding Acknowledgement Type of funding sources: None. Table 1. Per vessel concordance analysis of potential flow limiting FFRCT relative to clinical ICA findings. Analysed with an ischaemia threshold of FFRCT ≤0.80 and

Reptiles, like other vertebrates, rely on immunity to defend themselves from infection. The energetic cost of an immune response is liable to scale with infection severity, prompting constraints on other self-maintenance traits if immune prioritization exceeds energy budget. In this study, adult male side-blotched lizards (Uta stansburiana) were injected with saline (control) or high (20 µg g−1 body mass) or low (10 µg g−1 body mass) concentrations of lipopolysaccharide (LPS) to simulate bacterial infections of discrete severities. The costs and consequences of the immune response were assessed through comparisons of change in resting metabolic rate (RMR), energy metabolites (glucose, glycerol, triglycerides), innate immunity (bactericidal ability), sprint speed and oxidative status (antioxidant capacity, reactive oxygen metabolites). High-LPS lizards had the lowest glucose levels and greatest sprint reductions, while their RMR and bactericidal ability were similar to those of control lizards. Low-LPS lizards had elevated RMR and bactericidal ability, but glucose levels and sprint speed changes between those of high-LPS and control lizards. Levels of glycerol, triglycerides, reactive oxygen metabolites and antioxidant capacity did not differ by treatment. Taken together, energy expenditure for the immune response varies in a non-linear fashion with challenge severity, posing consequences for performance and self-maintenance processes in a reptile.

Following the Ridgecrest earthquake sequence, consisting of an M 6.4 foreshock and M 7.1 mainshock along with many other events, the Geotechnical Extreme Events Reconnaissance association deployed a team to gather perishable data. The team focused their efforts on documenting ground deformations including surface fault rupture south of the Naval Air Weapons Station China Lake, and liquefaction features in Trona and Argus. The team published a report within two weeks of the M 7.1 mainshock. This article presents data products gathered by the team, which are now published and publicly accessible. The data products presented herein include ground-based observations using Global Positioning System trackers, digital cameras, and hand-measuring devices, as well as unmanned aerial vehicle-based imaging products using Structure from Motion to create point clouds and digital surface models. The article describes the data products, as well as tools available for interacting with the products.

Ramelteon is a melatonin receptor agonist that is approved for the treatment of insomnia. It is widely used due to its relatively benign side effect profile and lack of dependence or withdrawal. Due to its tolerability, clinicians have attempted to utilize ramelteon to normalize the sleep/wake patterns in patients with delirium as a safer alternative to antipsychotics or other medications. We present the case of a 75-year-old man with long-standing dementia who was hospitalized due to mental status changes, agitation, and sleep disturbance. After addressing possible underlying causes with minimal improvement, the team initiated treatment with ramelteon (8mg nightly) which resulted in rapid improvement of symptoms. Uses and mechanisms of action of ramelteon will be reviewed, as well as current pharmacologic treatments of delirium. Prior research studies and case reports regarding the use of ramelteon in the treatment of delirium will be discussed and suggestions made regarding possible areas of future study.

Duchenne muscular dystrophy (DMD) is a fatal, progressive muscle disease caused by the absence of functional dystrophin protein. Previous studies in mdx mice, a common DMD model, identified impaired autophagy with lysosomal insufficiency and impaired autophagosomal degradation as consequences of dystrophin deficiency. Thus, we hypothesized that lysosomal abundance would be decreased and degradation of autophagosomes would be impaired in muscles of D2-mdx mice. To test this hypothesis, diaphragm and gastrocnemius muscles from 11 month-old D2-mdx and DBA/2J (healthy) mice were collected. Whole muscle protein from diaphragm and gastrocnemius muscles, and protein from a cytosolic fraction (CF) and a lysosome-enriched fraction (LEF) from gastrocnemius muscles, were isolated and used for western blotting. Initiation of autophagy was not robustly activated in whole muscle protein from diaphragm and gastrocnemius, however, autophagosome formation markers were elevated in dystrophic muscles. Autophagosome degradation was impaired in D2-mdx diaphragms but appeared to be maintained in gastrocnemius muscles. To better understand this muscle-specific distinction, we investigated autophagic signaling in CFs and LEFs from gastrocnemius muscles. Within the LEF we discovered that the degradation of autophagosomes was similar between groups. Further, our data suggest an expanded, though impaired, lysosomal pool in dystrophic muscle. Notably, these data indicate a degree of muscle specificity as well as model specificity with regard to autophagic dysfunction in dystrophic muscles. Stimulation of autophagy in dystrophic muscles may hold promise for DMD patients as a potential therapeutic, however, it will be critical to choose the appropriate model and muscles that most closely recapitulate findings from human patients to further develop these therapeutics.

Since its inception in 1965, the Older Americans Act (OAA) has been marked by lofty goals, mixed mandates, and uneven accomplishments. The formal rationale behind the OAA holds that a comprehensive array of service interventions can effectively help elders remain in community settings. Not only is this an outcome that is unquestionably desired by older persons, but it is one which may, as well, be cost-effective from a public finance perspective. Older persons constituted a very legitimate political constituency, based both on the sympathetic attitudes Americans have held toward the old and on the massive data pointing to the economic, social, and physical problems that confronted older Americans. Targeting based on income inadequacy is theoretically the most straightforward approach to concentrating limited resources, but it is made extremely difficult administratively when there is no direct way to ascertain what are a potential client’s economic means.

Wounding events (predation attempts, competitive combat) result in injuries and/or infections that induce integrated immune responses for the recovery process. Despite the survival benefits of immunity in this context, the costs incurred may require investment to be diverted from traits contributing to immediate and/or future survival, such as locomotor performance and oxidative status. Yet, whether trait constraints manifest likely depends on wound severity and the implications for energy budget. For this study, food intake, body mass, sprint speed, and oxidative indices (reactive oxygen metabolites, antioxidant capacity) were monitored in male side-blotched lizards (Uta stansburiana) healing from cutaneous wounds of discrete sizes (control, small, large). Results indicate that larger wounds induced faster healing, reduced food consumption, and led to greater oxidative stress over time. Granted wounding did not differentially affect body mass or sprint speed overall, small-wounded lizards with greater wound area healed had faster sprint speeds while large-wounded lizards with greater wound area healed had slower sprint speeds. During recovery from either wound severity, however, healing and sprint performance did not correspond with food consumption, body mass loss, nor oxidative status. These findings provide support that energy budget, locomotor performance, and oxidative status of a reptile are linked to wound recovery to an extent, albeit dependent on wound severity.

Marek's disease (MD) is an alphaherpesvirus (Marek's disease virus, MDV)-induced pathology of chickens associated with paralysis, immunosuppression, neurological signs, and T-cell lymphomas. MD is controlled in poultry production via live attenuated vaccines. The purpose of the current study was to compare methods for precipitating exosomes from vaccinated and protected chicken sera (VEX) and tumor-bearing chicken sera (TEX) for biomarker analysis of vaccine-induced protection and MD lymphomas respectively. A standard polyethylene glycol (PEG, 8%) method was compared to a commercial reagent (total exosome isolation reagent, TEI) for exosome yield and RNA content. Although exosomes purified by PEG or TEI were comparable in size and morphology, TEI-reagent yielded 3-4-fold greater concentration. Relative expression of 8 out of 10 G. gallus- and MDV1-encoded miRNAs examined displayed significant difference depending upon the precipitation method used. Standard PEG yields comparable, albeit lower amounts of exosomes than the TEI-reagent and a distinctive miRNA composition., Immunology; Virology; Animal science; Transcriptomics; Veterinary medicine; Hematological system; miRNA; Marek's disease virus; Extracellular vesicle; Exosome precipitation.

Management of stressors requires an understanding of how multiple stressors interact, how different species respond to those interactions and the underlying mechanisms driving observed patterns in species’ responses. Salinization and rising temperatures are two pertinent stressors predicted to intensify in freshwater ecosystems, posing concern for how susceptible organisms achieve and maintain homeostasis (i.e. allostasis). Here, glucocorticoid hormones (e.g. cortisol), responsible for mobilizing energy (e.g. glucose) to relevant physiological processes for the duration of stressors, are liable to vary in response to the duration and severity of salinization and temperature rises. With field and laboratory studies, we evaluated how both salinity and temperature influence basal and stress-reactive cortisol and glucose levels in age 1+ mottled sculpin (Cottus bairdii), mountain sucker (Catostomus platyrhynchus) and Colorado River cutthroat trout (Oncorhynchus clarki pleuriticus). We found that temperature generally had the greatest effect on cortisol and glucose concentrations and the effect of salinity was often temperature dependent. We also found that when individuals were chronically exposed to higher salinities, baseline concentrations of cortisol and glucose usually declined as salinity increased. Reductions in baseline concentrations facilitated stronger stress reactivity for cortisol and glucose when exposed to additional stressors, which weakened as temperatures increased. Controlled temperatures near the species’ thermal maxima became the overriding factor regulating fish physiology, resulting in inhibitory responses. With projected increases in freshwater salinization and temperatures, efforts to reduce the negative effects of increasing temperatures (i.e. increased refuge habitats and riparian cover) could moderate the inhibitory effects of temperature-dependent effects of salinization for freshwater fishes.

Additive Manufacturing (AM) has brought significant design and fabrication opportunities for complex components with internal features such as liquid rocket engine thrust chambers not previously possible. This technology allows for significant cost savings and schedule reductions in addition to new performance optimization through weight reduction and increased margins. Specific to regeneratively-cooled combustion chambers and nozzles for liquid rocket engines, additive manufacturing offers the ability to form the complex internal coolant channels and the closeout of the channels to contain the high pressure liquid propellants with a single operation. Much of additive manufacturing development has focused on monolithic alloys using Laser Powder Bed Fusion (L-PBF), which do not allow for complete optimization of the structure. The National Aeronautics and Space Administration (NASA) completed feasibility of an AM bimetallic L-PBF GRCop-84 copper-alloy combustion chamber with an AM electron beam freeform Inconel 625 structural jacket under the Low Cost Upper Stage Propulsion (LCUSP) Project. A follow-on project called Rapid Analysis and Manufacturing Propulsion Technology (RAMPT) is under development to further expand large-scale multi-alloy thrust chambers while maturing composite overwrap technology for significant weight savings opportunities. The RAMPT project has three primary objectives: 1) Advancing blown powder Directed Energy Deposition (DED) to fabricate integral-channel large scale nozzles, 2) Develop composite overwrap technology to reduce weight and provide structural capability for thrust chamber assemblies, and 3) Develop bimetallic and multi-metallic additively manufactured radial and axial joints to optimize material performance. In addition to these primary manufacturing developments, analytical modeling efforts compliment the process development to simulate the AM processes to reduce build failures and distortions. The RAMPT project is also maturing the supply chain for various manufacturing processes described above in addition to L-PBF of GRCop-42. This paper will present an overview of the RAMPT project, the process development and hardware progress to date, material and hot-fire testing results, along with future developments.

Author(s): Zimmaro, Paolo; Nweke, Chukwuebuka C; Hernandez, Janis L; Hudson, Kenneth S; Hudson, Martin B; Ahdi, Sean K; Boggs, Matthew L; Davis, Craig A; Goulet, Christine A; Brandenberg, Scott J; Hudnut, Kenneth W; Stewart, Jonathan P | Abstract: ABSTRACT The 2019 Ridgecrest earthquake sequence produced a 4 July Mn6.5 foreshock and a 5 July Mn7.1 mainshock, along with 23 events with magnitudes greater than 4.5 in the 24nhr period following the mainshock. The epicenters of the two principal events were located in the Indian Wells Valley, northwest of Searles Valley near the towns of Ridgecrest, Trona, and Argus. We describe observed liquefaction manifestations including sand boils, fissures, and lateral spreading features, as well as proximate non-ground failure zones that resulted from the sequence. Expanding upon results initially presented in a report of the Geotechnical Extreme Events Reconnaissance Association, we synthesize results of field mapping, aerial imagery, and inferences of ground deformations from Synthetic Aperture Radar-based damage proxy maps (DPMs). We document incidents of liquefaction, settlement, and lateral spreading in the Naval Air Weapons Station China Lake US military base and compare locations of these observations to pre- and postevent mapping of liquefaction hazards. We describe liquefaction and ground-failure features in Trona and Argus, which produced lateral deformations and impacts on several single-story masonry and wood frame buildings. Detailed maps showing zones with and without ground failure are provided for these towns, along with mapped ground deformations along transects. Finally, we describe incidents of massive liquefaction with related ground failures and proximate areas of similar geologic origin without ground failure in the Searles Lakebed. Observations in this region are consistent with surface change predicted by the DPM. In the same region, geospatial liquefaction hazard maps are effective at identifying broad percentages of land with liquefaction-related damage. We anticipate that data presented in this article will be useful for future liquefaction susceptibility, triggering, and consequence studies being undertaken as part of the Next Generation Liquefaction project.

Insecticides can exert strong selection on insect pest species, including those that vector diseases, and have led to rapid evolution of resistance. Despite such rapid evolution, relatively little is known about standing genetic variation for resistance in insecticide‐susceptible populations of many species. To help fill this knowledge gap, we generated genotyping‐by‐sequencing data from insecticide‐susceptible Phlebotomus papatasi and Lutzomyia longipalpis sand flies that survived or died from a sub‐diagnostic exposure to either permethrin or malathion using a modified version of the Centers for Disease Control and Prevention bottle bioassay. Multi‐locus genome‐wide association mapping methods were used to quantify standing genetic variation for insecticide resistance in these populations and to identify specific alleles associated with insecticide survival. For each insecticide treatment, we estimated the proportion of the variation in survival explained by the genetic data (i.e., “chip” heritability) and the number and contribution of individual loci with measurable effects. For all treatments, survival to an insecticide exposure was heritable with a polygenic architecture. Both P. papatasi and L. longipalpis had alleles for survival that resided within many genes throughout their genomes. The implications for resistance conferred by many alleles, as well as inferences made about the utility of laboratory insecticide resistance association studies compared to field observations, are discussed.

While there is huge promise in monitoring physiological parameters in free-living organisms, we also find high amounts of variability over time and space. This variation requires us to capitalize on long-term physiological monitoring to adequately address questions of population health, conservation status, or evolutionary trends as long-term sampling can examine ecoimmunological and endocrine interactions in wild populations while accounting for the variation that often makes ecophysiological field studies difficult to compare. In this study, we tested how immune efficacy and endocrinology interact while accounting for ecological context and environmental conditions in two snake species. Specifically, we measured bacterial killing ability, steroid hormones, and morphological characteristics in multiple populations of the Western Terrestrial Gartersnake (Thamnophis elegans) and Common Gartersnake (T. sirtalis) for multiple seasons over 6 years. Leveraging this long-term dataset, we tested how a broad immune measure and endocrine endpoints interact while accounting for individual traits, sampling date, and environmental conditions. Across both species, we found bacterial killing ability to be directly related to corticosterone (CORT) and temperature and greater overall in the spring compared to the fall. We found CORT and testosterone yielded relationships with individual sex, sampling temperature, and time of year. Wild populations can exhibit high amounts of variation in commonly collected physiological endpoints, highlighting the complexity and difficulty inherent in interpreting single endpoints without taking ecological and environmental conditions into account. Our study emphasizes the importance of reporting the environmental conditions under which the sampling occurred to allow for better contextualization and comparison between studies.

Reptiles rely on thermal heat exchange to achieve body temperatures (Tbody ) conducive to maintaining homeostasis. Diurnal changes in the thermal environment are therefore liable to influence allostatic mediation of survival processes (e.g., immunity) during environmental challenges or stressors. However, the extent to which Tbody prompts individual variation in physiology remains largely unexplored in reptiles. Our study tested how circulating energy-mobilizing hormone, energy metabolites, and immunity can vary across basal and stress-induced allostatic states for plateau side-blotched lizards (Uta stansburiana uniformis) residing in a heterogeneous thermal environment. We collected baseline and acute stress blood samples from male lizards to compare changes in plasma corticosterone (CORT), glucose, and bacterial killing ability (BKA) in relation to each other and Tbody . We hypothesized each physiological parameter differs between allostatic states, whereby stress-induced activity increases from baseline. At basal and stress-induced states, we also hypothesized circulating CORT, glucose, and BKA directly correspond with each other and Tbody . We found both CORT and BKA increased while glucose instead decreased from acute stress. At basal and stress-induced allostatic states, we found CORT to be directly related to Tbody while BKA was inversely related to CORT. We also found BKA and glucose were directly related at baseline, but inversely related following acute stress. Overall, these results demonstrate allostatic outcomes from acute stress in a free-living reptile and the role of temperature in mediating energetic state and immunity. Future research on reptilian allostasis should consider multiple environmental conditions and their implications for physiological performance and survival.

Satellite cells (SCs) are muscle-specific stem cells that have a central role in muscle remodeling. Despite their therapeutic potential, SC-based therapies have been met with numerous logistical challenges, limiting their ability to effectively treat systemic muscle diseases, such as Duchenne muscular dystrophy (DMD). Delivery of SC-derived extracellular vesicles (SC-EVs) may unlock the potential offered by SCs and overcome their numerous limitations.PurposeThe purpose of this investigation was to determine the extent to which SC-EVs could restore mitochondrial function in cultured myotubes following oxidative injury.MethodsSC-EVs were isolated from cultured SCs from C57 mice and quantified using nanoparticle tracking analysis (NTA). C2C12 myotubes were cultured and divided into four treatment groups: untreated control, treated for 24 h with SC-EV, 24 h exposure to 50 μM H2O2followed by a 24 h recovery period with no treatment, or 24 h exposure to 50 μM H2O2followed by a 24 h treatment with SC-EV. Inter-group differences in mitochondrial function were assessed via one-way ANOVA with Tukey post hoc analysis (pResultsGiven the seeding density used, we calculated that each SC releases approximately 2.35 × 105± 3.10 × 104EVs per 24 h. Further, using fluorescent microscopy, we verified SC-EVs deliver cargo into myotubes, some of which was localized to the mitochondria. H2O2exposure resulted in a 42% decline in peak mitochondrial respiration (p=0.0243) as well as a 46% reduction in spare respiratory capacity (p=0.0185) relative to the untreated control group. Subsequent treatment with SC-EVs (3.12×108SC-EV; 24 h) following H2O2exposure restored 76% of peak mitochondrial respiration (p=0.0187) and 84% of spare respiratory capacity in the damaged myotubes (p=0.0198). SC-EVs did not affect mitochondrial function in the undamaged myotubes.ConclusionCollectively, these data demonstrate SC-EVs may represent a novel therapeutic approach for treatment of myopathies associated with mitochondrial dysfunction.

Presented here is a novel method of reducing the computational cost of analyzing the vibrational properties of a single-walled carbon nanotube (CNT) containing multi-vacancy defects (MVDs), while maintaining a high degree of accuracy. This reduced-order model method is described as modal domain reduction (MDR). In the MDR method, a linearized model of a perturbed CNT is first transformed into modal coordinates derived from the pristine system, taking into account the differences in the numbers of degrees of freedom for the pristine CNT and the CNT with MVDs. Next, the system is divided into primary modes, on the basis of the frequency range of interest, and remaining or secondary modes. The impact of secondary modes on primary modes is captured by the dynamic condensation method. The accuracy of MDR is demonstrated on linearized models of nanotubes of differing diameter and chirality and with different sized MVDs. The natural frequencies and normal modes of these reduced-order models are calculated and compared to the results for the full-order systems.

A real-time, in-process cure monitoring system employing a guided wave-based concept for carbon fiber reinforced polymer composites was developed. The system included a single piezoelectric disc that was bonded to the surface of the composite for excitation, and an embedded phase-shifted fiber Bragg grating for sensing. The phase-shifted fiber Bragg grating almost simultaneously measured both quasi-static strain and the ultrasonic guided wave-based signals throughout the cure cycle. A traditional FBG was also used as a base for evaluating the high sensitivity of the phase-shifted fiber Bragg grating sensor. Composite physical properties (degree of cure and glass transition temperature) were correlated to the amplitude and time of arrival of the guided wave-based measurements during the cure cycle. In addition, key state transitions (gelation and vitrification) were identified from the experimental data. The physical properties and state transitions were validated using cure process modeling software (e.g. RAVEN®). This system demonstrated the capability of using an embedded phase-shifted fiber Bragg grating to sense a wide bandwidth of signals during cure. The distinct advantages of a fiber optic-based system include multiplexing of multiple gratings along a single optical fiber, small size compared to piezoelectric sensors, ability to embed or surface mount, utilization in harsh environments, electrically passive operation, and electromagnetic interference (EMI) immunity. The embedded phase-shifted fiber Bragg grating fiber optic sensor can monitor the entire life-cycle of the composite structure from curing, post-cure/assembly, and in-service creating “smart structures”.

Prolonged heat stress represents a continuing threat to human health and agricultural production. Despite the broad, negative impact of prolonged hyperthermia little is known about underlying pathological mechanisms leading to negative health outcomes, which has limited the development of etiological interventions and left clinicians and producers with only cooling and rehydration strategies. The purpose of this investigation was to determine the extent to which prolonged environment-induced hyperthermia altered autophagy in oxidative skeletal muscle in a large animal model, serving the dual purpose of accurately modeling human physiology as well as agricultural production. We hypothesized that prolonged hyperthermia would induce autophagy in skeletal muscle, independent of the accompanying caloric restriction. To test this hypothesis pigs were treated as follows: thermoneutral (20 °C), heat stress (35 °C), or were held under thermoneutral conditions but pair-fed to the heat stress group for seven days. Upon euthanasia the red portion of the semitendinosus was collected. We found that prolonged hyperthermic exposure increased oxidative stress without a corresponding change in antioxidant enzyme activities. Hyperthermia prevented initiation of autophagy despite increased markers of nucleation, elongation and autophagosome formation. However, p62 relative protein abundance, which is inversely correlated with autophagic degradation, was strongly increased suggesting suppressed degradation of autophagosomes. Markers of mitophagy and mitochondrial abundance were largely similar between groups. These data indicate that faulty autophagy plays a key role in hyperthermic muscle dysfunction.

In his surprise election as president, Donald Trump enjoyed disproportionate electoral support from older voters, many of whom saw in Trump a person who would work to reverse demographic, economic, and cultural forces that had transformed American life as they had long seen it. Yet, Trump's campaign and incumbency has also been very much about gutting the Washington policy establishment of officials, bureaucrats, and lobbyists (aka, "the swamp") which, for more than half a century, has been instrumental in enacting and expanding legislation that has benefitted older Americans far more than any other social policy constituency in the country. This article contrasts the value-oriented electoral support Trump enjoyed from older Americans with their interest concerns centered on policies such as the Affordable Care Act, Medicaid, and a host of smaller grant-in-aid programs. It then reviews the strong institutional base seniors and their advocates have in Washington, posing whether interest-oriented concerns may outweigh ideological ones as policy options emerge from a Republican-controlled government prior to the 2018 elections.

BACKGROUND: Liver disease mortality increased by 400% in the UK between 1970 and 2010, resulting in rising pressures on acute hospital services, and an increasing need for end-of-life care. We aimed to assess the effect of demographic, clinical, and health-care factors on costs, patterns of health-care use, and place of death in a national cohort of patients with cirrhosis and ascites in their last year of life.METHODS: We did a retrospective, nationwide analysis of all patients who died from cirrhosis in England between 2013 and 2015, who required large-volume paracentesis in their last year of life. The outcomes measured were health-care costs accrued in the last year of life, number of inpatient days in last year of life, 30-day readmission rate, and occurrence of unplanned hospital death (probability of dying in hospital after unplanned admission). Using generalised linear and logistic regression models, we examined the effect of 12 independent variables on each outcome: sex, ethnicity, age at death, index of multiple deprivation quintile, year of death, liver disease causing death, place of death, time from index presentation in last year of life to death, whether enrolled in a day-case paracentesis service (care group), paracentesis ratio (number of day-case large-volume paracentesis procedures as a proportion of the total number of procedures in the last year of life), number of hospital episodes in the last year of life (not involving large-volume paracentesis), and number of large-volume paracentesis procedures in the last year of life.FINDINGS: Between Jan 1, 2013, and Dec 31, 2015, 13 818 people in England died from liver disease and had large-volume paracentesis within their last year of life. For all patients, mean cost of the last year of life was £21 113 (SD 16 881), 17 888 (52·5%) of 34 068 readmissions occurred within 30 days of discharge, and 10 341 (74·8%) of 13 818 deaths occurred in hospital, of which 10 045 (97·1%) followed an emergency hospital admission. Patients who attended a day-case large-volume paracentesis service within their last year of life had significant reductions in cost (-£4240, 95% CI -4829 to -3651; pINTERPRETATION: The use of day-case large-volume paracentesis services in the last year of life was associated with lower costs, reduced pressure on acute hospital services, and a lower probability of dying in hospital, compared with patients who received exclusively unplanned care in their last year of life. Wider adoption of day-case models of care could reduce costs and improve outcomes in the last year of life.FUNDING: David Telling Charitable Trust.

Nuptial plumage colouration is seemingly favoured by females of avian species with regards to sexual selection. This particular secondary sexual characteristic has been previously shown to be a condition-dependent signal of individual quality among passerines with pigment-based colouration (i.e. yellows and reds). In contrast, relationships between structural plumage colouration (i.e. blues) and aspects of both physical quality and physiological function have been understudied. Using free-living Indigo Buntings (Passerina cyanea) as a study species, we compared the percentage of blue feather coverage to body condition, innate immune responses, antioxidant capacity, stress physiology, reproductive physiology, and parasitism. We found the overall percentage of blue feathers on individual birds to be positively correlated with testosterone levels and body condition, while negatively correlated with heterophil to lymphocyte ratio. Birds with more blue coverage were also less likely to harbour blood parasites. Our results indicate male Indigo Buntings with greater moult investment have better overall body condition, lower stress, increased testosterone levels, and decreased parasitic susceptibility.

Mechanical ventilation (MV) results in the rapid development of ventilator-induced diaphragm dysfunction (VIDD). While the mechanisms responsible for VIDD are not fully understood, recent data reveal that prolonged MV activates autophagy in the diaphragm, which may occur as a result of increased cellular reactive oxygen species (ROS) production. Therefore, we tested the hypothesis that (1) accelerated autophagy is a key contributor to VIDD; and that (2) oxidative stress is required to increase the expression of autophagy genes in the diaphragm. Our findings reveal that targeted inhibition of autophagy in the rat diaphragm prevented MV-induced muscle atrophy and contractile dysfunction. Attenuation of VIDD in these animals occurred as a result of increased diaphragm concentration of the antioxidant catalase and reduced mitochondrial ROS emission, which corresponded to reductions in the activity of calpain and caspase-3. To determine if increased ROS production is required for the upregulation of autophagy biomarkers in the diaphragm, rats that were administered the mitochondrial-targeted peptide SS-31 during MV. Results from this study demonstrated that mitochondrial ROS production in the diaphragm during MV is required for the increased expression of key autophagy genes (i.e. LC3, Atg7, Atg12, Beclin1 and p62), as well as for increased activity of cathepsin L. Together, these data reveal that autophagy is required for VIDD, and that autophagy inhibition reduces MV-induced diaphragm ROS production and prevents a positive feedback loop whereby increased autophagy is stimulated by oxidative stress, resulting in further increases in ROS and autophagy.

This investigation aims to explain and quantify the deviations of the Australian policy rate (set by Reserve Bank of Australia) from the Taylor Rule. A three-step econometric procedure designed to reflect the data-rich environment in which central banks operate is proposed using information for 229 macroeconomic series. This procedure can be applied to data for any economy with inflation targeting monetary rule. Our application with Australian data shows that approximately 65% of Australia’s policy rate deviation from the Taylor Rule can be explained systematically, with international factors and a domestic factor accounting for 41.9% and 22.5%, respectively, of the total variation in deviation from the rule.

Chronic kidney disease (CKD) causes loss of lean body mass by multiple mechanisms. This study examines whether autophagy-mediated proteolysis contributes to CKD-induced muscle wasting. We tested autophagy in the muscle of CKD mice with plantaris muscle overloading to mimic resistance exercise or with acupuncture plus low-frequency electrical stimulation (Acu/LFES) treatment. In CKD muscle, Bnip3, Beclin-1, and LC3II mRNAs and proteins were increased compared with those in control muscle, indicating autophagosome-lysosome formation induction. Acu/LFES suppressed the CKD-induced upregulation of autophagy. However, overloading increased autophagy-related proteins in normal and CKD muscle. Serum from uremic mice induces autophagy formation but did not increase the myosin degradation or actin break down in cultured muscle satellite cells. We examined mitochondrial biogenesis, copy number, and ATP production in cultured myotubes, and found all three aspects to be decreased by uremic serum. Inhibition of autophagy partially reversed this decline in cultured myotubes. In CKD mice, the mitochondrial copy number, biogenesis marker peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), mitochondrial transcription factor A (TFAM), and mitochondrial fusion marker Mitofusin-2 (Mfn2) are decreased. Both muscle overloading and Acu/LFES increased mitochondrial copy number, and reversed the CKD-induced decreases in PGC-1α, TFAM, and Mfn2. We conclude that the autophagy is activated in the muscle of CKD mice. However, myofibrillar protein is not directly broken down through autophagy. Instead, CKD-induced upregulation of autophagy leads to dysfunction of mitochondria and decrease of ATP production.

Viral infections may predispose the airways to secondary bacterial infections that can lead to unfavorable progression of principally self-limiting illnesses. Such complicated respiratory infections include pneumonia, bronchitis, sinusitis, acute otitis media, and sepsis, which cause high morbidity and lethality. Some of the pathogenic consequences of viral infections, like the expression of bacterial adhesion receptors and the disturbance of physical barrier integrity due to inflammation, may create permissive conditions for co-infections. Influenza virus A (H3N2) is a major pathogen that causes secondary bacterial infections and inflammation that lead to pneumonia. The herbal medicine Echinacea purpurea, on the other hand, has been widely used to prevent and treat viral respiratory infections, and recent clinical data suggest that it may prevent secondary infection complications as well. We investigated the role of standardized E. purpurea (Echinaforce® extract or EF) on H3N2-induced adhesion of live nontypeable Haemophilus influenzae (NTHi) and Staphylococcus aureus, along with the expression of bacterial receptors, intracellular adhesion molecule-1 (ICAM-1), fibronectin, and platelet activating factor receptor (PAFr), by BEAS-2B cells. Inflammatory processes were investigated by determining the cellular expression of IL-6 and IL-8 and the involvement of Toll-like receptor (TLR-4) and NFκB p65. We found that influenza virus A infection increased the adhesion of H. influenzae and S. aureus to bronchial epithelial cells via upregulated expression of the ICAM-1 receptor and, to some extent, of fibronectin and PAFr. Echinaforce (EF) significantly reduced the expression of ICAM-1, fibronectin, and PAFr and consequently the adhesion of both bacterial strains. EF also effectively prevented the super-expression of inflammatory cytokines by suppressing the expression of NFκB and possibly TLR-4. These results indicate that E. purpurea has the potential to reduce the risk of respiratory complications by preventing virus-induced bacterial adhesion and through the inhibition of inflammation super-stimulation (cytokine storms).

Duchenne muscular dystrophy (DMD) is caused by the absence of functional dystrophin protein and results in progressive muscle wasting. Dystrophin deficiency leads to a host of dysfunctional cellular processes including impaired autophagy. Autophagic dysfunction appears to be due, at least in part, to decreased lysosomal abundance mediated by decreased nuclear localization of transcription factor EB (TFEB), a transcription factor responsible for lysosomal biogenesis. PGC‐1α overexpression decreased disease severity in dystrophin‐deficient skeletal muscle and increased PGC‐1α has been linked to TFEB activation in healthy muscle. The purpose of this study was to determine the extent to which PGC‐1α overexpression increased nuclear TFEB localization, increased lysosome abundance, and increased autophagosome degradation. We hypothesized that overexpression of PGC‐1α would drive TFEB nuclear translocation, increase lysosome biogenesis, and improve autophagosome degradation. To address this hypothesis, we delivered PGC‐1α via adeno‐associated virus (AAV) vector injected into the right limb of 3‐week‐old mdx mice and the contralateral limbs received a sham injection. At 6 weeks of age, this approach increased PGC‐1α transcript by 60‐fold and increased TFEB nuclear localization in gastrocnemii from PGC‐1α treated limbs by twofold compared to contralateral controls. Furthermore, lamp2, a marker of lysosome abundance, was significantly elevated in muscles from limbs overexpressing PGC‐1α. Lastly, increased LC3II and similar p62 in PGC‐1α overexpressing‐limbs compared to contralateral limbs are supportive of increased degradation of autophagosomes. These data provide mechanistic insight into PGC‐1α‐mediated benefits to dystrophin‐deficient muscle, such that increased TFEB nuclear localization in dystrophin‐deficient muscle leads to increased lysosome biogenesis and autophagy., Degradation of autophagosomes appears to be impaired in dystrophic skeletal muscle in part due to reduced lysosome abundance. We found that PGC‐1alpha mediated TFEB nuclear translocation, increased lysosome abundance, and degradation of autophagosomes.

The glucocorticoid hormone corticosterone (CORT) has classically been used in ecophysiological studies as a proxy for stress and energy mobilization, but rarely are CORT and the energy metabolites themselves concurrently measured. To examine CORT's role in mobilizing glucose in a wild reptile, we conducted two studies. The first study measured natural baseline and stress-induced blood-borne CORT and glucose levels in snakes during spring emergence and again when snakes return to the denning sites in fall. Our second study manipulated the hypothalamic pituitary adrenal axis in male snakes in the fall by taking a baseline blood sample, then subjecting individuals to one of five treatments (no injection, saline, CORT, adrenocorticotropin hormone, and metyrapone). Subsequent samples were taken at 30 minutes and 60 minutes. In both studies, we found that glucose levels do increase with the acute stress, but that the relationship was not directly related to CORT elevation. In the second study, we found that none of the HPA axis manipulations directly affected blood glucose levels, further indicating that CORT may play a complex, but not direct role in glucose mobilization in snakes. This study highlights the need for testing mechanisms in wild organisms by combining in situ observations with manipulative studies.

The purpose of this study was to explore the use of water quality parameters as proxy variables for establishing a timeline for the postmortem submersion interval (PMSI). This research was conducted using mice in water samples collected from the Schuylkill river in Philadelphia, US, as well as deionized water for control. Parameters were monitored from initial placement of the specimens in water to the completion of the experiment three months later. These parameters included pH, dissolved oxygen (DO), turbidity, conductivity, total organic carbon (TOC), nitrite, nitrate, and heterotrophic bacteria. In addition, qualitative observations of the specimens were made using Total Aquatic Decomposition Score (TADS). Peak changes in conductivity, turbidity, and TOC parameters coincided with a TADS of 7–9, indicating a partially decomposed carcass. These results preliminarily suggest that standard, easy to measure water quality parameters could serve as potential indictors in estimating PMSI in surface water bodies, however more experimental and field studies are needed to replicate results and validate findings.

Lay Summary The chemical signatures of the bodies of lizards contain information about what they eat. We compared lizard chemical signatures between urban and rural areas in southern Utah and found that they have much broader diets in urban areas and that some chemical signatures were related to reproduction., Spatial and temporal variation in stoichiometric and stable isotope ratios of animals contains ecological information that we are just beginning to understand. In both field and lab studies, stoichiometric or isotopic ratios are related to physiological mechanisms underlying nutrition or stress. Conservation and ecosystem ecology may be informed by isotopic data that can be rapidly and non-lethally collected from wild animals, especially where human activity leaves an isotopic signature (e.g. via introduction of chemical fertilizers, ornamental or other non-native plants or organic detritus). We examined spatial and temporal variation in stoichiometric and stable isotope ratios of the toes of Uta stansburiana (side-blotched lizards) living in urban and rural areas in and around St. George, Utah. We found substantial spatial and temporal variation as well as context-dependent co-variation with reproductive physiological parameters, although certain key predictions such as the relationship between δ15N and body condition were not supported. We suggest that landscape change through urbanization can have profound effects on wild animal physiology and that stoichiometric and stable isotope ratios can provide unique insights into the mechanisms underlying these processes.

Background Duchenne muscular dystrophy is a muscle wasting disease caused by dystrophin gene mutations resulting in dysfunctional dystrophin protein. Autophagy, a proteolytic process, is impaired in dystrophic skeletal muscle though little is known about the effect of dystrophin deficiency on autophagy in cardiac muscle. We hypothesized that with disease progression autophagy would become increasingly dysfunctional based upon indirect autophagic markers. Methods Markers of autophagy were measured by western blot in 7-week-old and 17-month-old control (C57) and dystrophic (mdx) hearts. Results Counter to our hypothesis, markers of autophagy were similar between groups. Given these surprising results, two independent experiments were conducted using 14-month-old mdx mice or 10-month-old mdx/Utrn± mice, a more severe model of Duchenne muscular dystrophy. Data from these animals suggest increased autophagosome degradation. Conclusion Together these data suggest that autophagy is not impaired in the dystrophic myocardium as it is in dystrophic skeletal muscle and that disease progression and related injury is independent of autophagic dysfunction.

The preliminary design and development of an automated ultrasonic scanning system for in-situ composite cure monitoring and defect detection in the high temperature environment of an oven was completed. This preliminary design is a stepping stone to deployment in the high temperature and high pressure environment of an autoclave, the primary cure method of aerospace grade thermoset composites. Cure monitoring with real-time defect detection during the process could determine when defects form and how they move. In addition, real-time defect detection during cure could assist validating physics-based process models for predicting defects at all stages of the cure cycle. A physics-based process model for predicting porosity and fiber waviness originating during cure is currently under development by the NASA Advanced Composites Project (ACP). For the design, an ultrasonic contact scanner is enclosed in an insulating box that is placed inside an oven during cure. Throughout the cure cycle, the box is nitrogen-cooled to approximately room temperature to maintain a standard operating environment for the scanner. The composite part is mounted on the outside of the box in a vacuum bag on the build/tool plate. The build plate is attached to the bottom surface of the box. The scanner inspects the composite panel through the build plate, tracking the movement of defects introduced during layup and searching for new defects that may form during cure. The focus of this paper is the evaluation and selection of the build plate material and thickness. The selection was based on the required operating temperature of the scanner, the cure temperature of the composite material, thermal conductivity models of the candidate build plates, and a series of ultrasonic attenuation tests. This analysis led to the determination that a 63.5 mm thick build plate of borosilicate glass would be utilized for the system. The borosilicate glass plate was selected as the build plate material due to the low ultrasonic attenuation it demonstrated, its ability to efficiently insulate the scanner while supporting an elevated temperature on the part side of the plate, and the availability of a 63.5 mm thick plate without the need for lamination.

Epoxy matrix composites assembled with adhesives maximize the performance of aerospace structures, but the possibility of forming weak bonds requires the installation of redundant fasteners, which add weight and manufacturing cost. Co-cured joints (e.g. unitized composite structures) are immune to weak bonds because the uncured resin undergoes diffusion and mixing through the joint. A means of co-curing complex structures may reduce the need for redundant fasteners in bondlines. To this end, NASA started the AERoBOND project to develop novel joining materials to enable a “secondary-co-cure” assembly process. Aerospace epoxy resin systems reformulated with offset stoichiometry prevented the resin from advancing beyond the gel point during a conventional autoclave cure cycle up to 180 °C. The offset resins were applied to the joining surfaces of laminate preforms as prepreg. Two surfaces with complimentary offset resins were joined using conventional secondary bonding techniques. Preliminary efforts have indicated that the resulting joint has no discernable interface and appears as a conventional co-cured laminate under optical magnification. This report will discuss the initial work performed regarding formulation of the epoxy resin system using calorimetry, rheology, and mechanical testing.