Palliative care has been one of the most rapidly growing fields of health care in the United States in the past decade. The benefits of palliative care have now been shown in multiple clinical ...trials, with increased patient and provider satisfaction, equal or better symptom control, more discernment of and honoring choices about place of death, fewer and less intensive hospital admissions in the last month of life, less anxiety and depression, less caregiver distress, and cost savings. The cost savings come from cost avoidance, or movement of a patient from a high cost setting to a lower cost setting. Barriers to expanded use include physician resistance, unrealistic expectations of patients and families, and lack of workforce. The future of palliative care includes more penetration into other fields such as nephrology, neurology, and surgery; further discernment of the most effective and cost-effective models; and establishment of more outpatient services.
The control of seed germination in response to environmental conditions is important for plant success.We investigated the role of the karrikin receptor KARRIKIN INSENSITIVE2 (KAI2) in the response ...of Arabidopsis seeds to osmotic stress, salinity and high temperature.
Germination of the kai2 mutant was examined in response to NaCl, mannitol and elevated temperature. The effect of karrikin on germination of wild-type seeds, hypocotyl elongation and the expression of karrikin-responsive genes was also examined in response to such stresses.
The kai2 seeds germinated less readily than wild-type seeds and germination was more sensitive to inhibition by abiotic stress. Karrikin-induced KAI2 signalling stimulated germination of wild-type seeds under favourable conditions, but, surprisingly, inhibited germination in the presence of osmolytes or at elevated temperature. By contrast, GA stimulated germination of wild-type seeds and mutants under all conditions. Karrikin induced expression of DLK2 and KUF1 genes and inhibited hypocotyl elongation independently of osmotic stress. Under mild osmotic stress, karrikin enhanced expression of DREB2A, WRKY33 and ERF5 genes, but not ABA signalling genes.
Thus, the karrikin-KAI2 signalling system can protect against abiotic stress, first by providing stress tolerance, and second by inhibiting germination under conditions unfavourable to seedling establishment.
•The derivation of the Mars Exploration Rover opacity record is described.•Dust aerosol size variations are characterized across seasons and storm events.•Clouds contribute to northern summer optical ...depth at the Opportunity site.•The dust significantly affects the energy balance and frequency of dust devils.
Dust aerosol plays a fundamental role in the behavior and evolution of the martian atmosphere. The first five Mars years of Mars Exploration Rover data provide an unprecedented record of the dust load at two sites. This record is useful for characterization of the atmosphere at the sites and as ground truth for orbital observations. Atmospheric extinction optical depths have been derived from solar images after calibration and correction for time-varying dust that has accumulated on the camera windows. The record includes local, regional, and globally extensive dust storms. Comparison with contemporaneous thermal infrared data suggests significant variation in the size of the dust aerosols, with a 1μm effective radius during northern summer and a 2μm effective radius at the onset of a dust lifting event. The solar longitude (LS) 20–136° period is also characterized by the presence of cirriform clouds at the Opportunity site, especially near LS=50° and 115°. In addition to water ice clouds, a water ice haze may also be present, and carbon dioxide clouds may be present early in the season. Variations in dust opacity are important to the energy balance of each site, and work with seasonal variations in insolation to control dust devil frequency at the Spirit site.
Modeling studies show that increased expression of nerve growth factor is associated with increased pain. This study tested the safety and efficacy of the monoclonal antibody tanezumab — which ...targets nerve growth factor — for the treatment of knee pain in patients with osteoarthritis.
Nerve growth factor is a neurotrophin that regulates the structure and function of responsive sensory neurons, including small-diameter nociceptive afferents. There has been increasing recognition of the potential role of nerve growth factor in pain modulation through nociceptor sensitization.
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In animals and humans, exogenous nerve growth factor increases pain either locally or systemically, depending on the dose and the route of administration.
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Increased expression of nerve growth factor is found in inflamed tissues from patients with conditions such as arthritis, pancreatitis, and prostatitis.
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Levels of nerve growth factor are also elevated in animal models of inflammatory pain, . . .
IMPORTANCE: Chronic lung diseases are a leading cause of morbidity and mortality. Unlike chronic obstructive pulmonary disease, clinical outcomes associated with proportional reductions in expiratory ...lung volumes without obstruction, otherwise known as preserved ratio impaired spirometry (PRISm), are poorly understood. OBJECTIVE: To examine the prevalence, correlates, and clinical outcomes associated with PRISm in US adults. DESIGN, SETTING, AND PARTICIPANTS: The National Heart, Lung, and Blood Institute (NHLBI) Pooled Cohorts Study was a retrospective study with harmonized pooled data from 9 US general population-based cohorts (enrollment, 65 251 participants aged 18 to 102 years of whom 53 701 participants had valid baseline lung function) conducted from 1971-2011 (final follow-up, December 2018). EXPOSURES: Participants were categorized into mutually exclusive groups by baseline lung function. PRISm was defined as the ratio of forced expiratory volume in the first second to forced vital capacity (FEV1:FVC) greater than or equal to 0.70 and FEV1 less than 80% predicted; obstructive spirometry FEV1:FVC ratio of less than 0.70; and normal spirometry FEV1:FVC ratio greater than or equal to 0.7 and FEV1 greater than or equal to 80% predicted. MAIN OUTCOMES AND MEASURES: Main outcomes were all-cause mortality, respiratory-related mortality, coronary heart disease (CHD)–related mortality, respiratory-related events (hospitalizations and mortality), and CHD-related events (hospitalizations and mortality) classified by adjudication or validated administrative criteria. Absolute risks were adjusted for age and smoking status. Poisson and Cox proportional hazards models comparing PRISm vs normal spirometry were adjusted for age, sex, race and ethnicity, education, body mass index, smoking status, cohort, and comorbidities. RESULTS: Among all participants (mean SD age, 53.2 15.8 years, 56.4% women, 48.5% never-smokers), 4582 (8.5%) had PRISm. The presence of PRISm relative to normal spirometry was significantly associated with obesity (prevalence, 48.3% vs 31.4%; prevalence ratio PR, 1.68 95% CI, 1.55-1.82), underweight (prevalence, 1.4% vs 1.0%; PR, 2.20 95% CI, 1.72-2.82), female sex (prevalence, 60.3% vs 59.0%; PR, 1.07 95% CI, 1.01-1.13), and current smoking (prevalence, 25.2% vs 17.5%; PR, 1.33 95% CI, 1.22-1.45). PRISm, compared with normal spirometry, was significantly associated with greater all-cause mortality (29.6/1000 person-years vs 18.0/1000 person-years; difference, 11.6/1000 person-years 95% CI, 10.0-13.1; adjusted hazard ratio HR, 1.50 95% CI, 1.42-1.59), respiratory-related mortality (2.1/1000 person-years vs 1.0/1000 person-years; difference, 1.1/1000 person-years 95% CI, 0.7-1.6; adjusted HR, 1.95 95% CI, 1.54-2.48), CHD-related mortality (5.4/1000 person-years vs 2.6/1000 person-years; difference, 2.7/1000 person-years 95% CI, 2.1-3.4; adjusted HR, 1.55 95% CI, 1.36-1.77), respiratory-related events (12.2/1000 person-years vs 6.0/1000 person-years; difference, 6.2/1000 person-years 95% CI, 4.9-7.5; adjusted HR, 1.90 95% CI, 1.69-2.14), and CHD-related events (11.7/1000 person-years vs 7.0/1000 person-years; difference, 4.7/1000 person-years 95% CI, 3.7-5.8; adjusted HR, 1.30 95% CI, 1.18-1.42). CONCLUSIONS AND RELEVANCE: In a large, population-based sample of US adults, baseline PRISm, compared with normal spirometry, was associated with a small but statistically significant increased risk for mortality and adverse cardiovascular and respiratory outcomes. Further research is needed to explore whether this association is causal.
A new night-time lane detection system and its accompanying framework are presented in this paper. The accompanying framework consists of an automated ground truth process and systematic storage of ...captured videos that will be used for training and testing. The proposed Advanced Lane Detector 2.0 (ALD 2.0) is an improvement over the ALD 1.0 or Layered Approach with integration of pixel remapping, outlier removal, and prediction with tracking. Additionally, a novel procedure to generate the ground truth data for lane marker locations is also proposed. The procedure consists of an original process called time slicing, which provides the user with unique visualization of the captured video and enables quick generation of ground truth information. Finally, the setup and implementation of a database hosting lane detection videos and standardized data sets for testing are also described. The ALD 2.0 is evaluated by means of the user-created annotations accompanying the videos. Finally, the planned improvements and remaining work are addressed.
•Thermal inertia and albedo are derived from ground temperature measurements along the Curiosity rover's traverse.•Diffuse water ice clouds or hazes can significantly influence ground temperatures in ...the southern fall and winter.•The shape of the diurnal ground temperature curve is used to isolate the bedrock thermal inertia from other materials within the sensor footprint.•Thermal inertias of sedimentary rock may be significantly higher than apparent in data sets with sparse local time coverage.
The REMS instrument onboard the Mars Science Laboratory rover, Curiosity, has measured ground temperature nearly continuously at hourly intervals for two Mars years. Coverage of the entire diurnal cycle at 1Hz is available every few martian days. We compare these measurements with predictions of surface-atmosphere thermal models to derive the apparent thermal inertia and thermally derived albedo along the rover's traverse after accounting for the radiative effects of atmospheric water ice during fall and winter, as is necessary to match the measured seasonal trend. The REMS measurements can distinguish between active sand, other loose materials, mudstone, and sandstone based on their thermophysical properties. However, the apparent thermal inertias of bedrock-dominated surfaces (∼350–550Jm−2K−1s−½) are lower than expected. We use rover imagery and the detailed shape of the diurnal ground temperature curve to explore whether lateral or vertical heterogeneity in the surface materials within the sensor footprint might explain the low inertias. We find that the bedrock component of the surface can have a thermal inertia as high as 650–1700Jm−2K−1s−½ for mudstone sites and ∼700Jm−2K−1s−½ for sandstone sites in models runs that include lateral and vertical mixing. Although the results of our forward modeling approach may be non-unique, they demonstrate the potential to extract information about lateral and vertical variations in thermophysical properties from temporally resolved measurements of ground temperature.
Patients with CKD who are on hemodialysis are hyporesponsive to erythropoiesis-stimulating agents (ESAs) because of anemia of inflammation. Interleukin-6 (IL-6) induced hepcidin expression is a key ...mediator of such inflammation.
This phase 1/2, placebo-controlled trial assessed effects of ziltivekimab, a novel anti-IL-6 ligand antibody, in patients on hemodialysis with rs855791, a single nucleotide polymorphism of the
gene that is hypothesized to heighten susceptibility to IL-6-mediated inflammatory effects. After a screening period documenting stable ESA and iron dosing, we randomized 61 patients with elevated IL-6 (≥4 pg/ml) to receive placebo or ziltivekimab (doses of 2, 6, or 20 mg), administered intravenously every 2 weeks for 12 weeks during hemodialysis. ESA dose adjustments were allowed after 4 weeks. We analyzed safety and effects on inflammation, iron metabolism, serum albumin, and anti-drug antibodies.
No patient experienced dose-limiting toxicity. Four patients (two each in the 6- and 20-mg cohorts) died of a treatment-emergent adverse event. Compared with patients receiving placebo, those receiving ziltivekimab experienced significantly greater reductions of high-sensitivity C-reactive protein, serum amyloid A, and fibrinogen from baseline to end of treatment. Median ESA usage decreased by 15,000, 15,000, or 33,000 IU/wk per patient in the 2-, 6-, and 20-mg ziltivekimab cohorts, respectively, compared with no change in the placebo group. We also noted significant dose responses for decreased ESA resistance index and increased serum iron, total iron binding capacity, transferrin saturation, and serum albumin.
Ziltivekimab significantly improved markers of inflammation, reduced ESA requirements, and increased serum albumin in patients on hemodialysis with inflammation and hyporesponsiveness to ESA therapy.
Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of COR-001, NCT02868229.
karrikin response system of Arabidopsis Waters, Mark T; Scaffidi, Adrian; Sun, Yueming K ...
The Plant journal : for cell and molecular biology,
August 2014, Letnik:
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Journal Article
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Arabidopsis thaliana provides a powerful means to investigate the mode of action of karrikins, compounds produced during wildfires that stimulate germination of seeds of fire‐following taxa. These ...studies have revealed close parallels between karrikin signalling and strigolactone signalling. The two perception systems employ similar mechanisms involving closely related α/β‐fold hydrolases (KAI2 and AtD14) and a common F–box protein (MAX2). However, karrikins and strigolactones may be distinguished from each other and elicit different responses. The karrikin response requires a newly discovered protein (SMAX1), a homologue of rice protein D53 that is required for the strigolactone response. Mutants defective in the response to karrikins have seeds with increased dormancy, altered seedling photomorphogenesis and modified leaf shape. As the karrikin and strigolactone response mechanisms are so similar, it is speculated that the endogenous signalling compound for the KAI2 system may be a specific strigolactone. However, new results show that the proposed endogenous signalling compound is not produced by the known strigolactone biosynthesis pathway via carlactone. Structural studies of KAI2 protein and its interaction with karrikins and strigolactone analogues provide some insight into possible protein–ligand interactions, but are hampered by lack of knowledge of the endogenous ligand. The KAI2 system appears to be present throughout angiosperms, implying a fundamentally important function in plant biology.
Strigolactones (SLs) typically comprise a tricyclic ABC ring system linked through an enol-ether bridge to a butenolide D-ring. The stereochemistry of the butenolide ring is conserved but two ...alternative configurations of the B–C ring junction leads to two families of SLs, exemplified by strigol and orobanchol. Further modifications lead to production of many different strigolactones within each family. The D-ring structure is established by a carotenoid cleavage dioxygenase producing a single stereoisomer of carlactone, the likely precursor of all SLs. Subsequent oxidation involves cytochrome P₄₅₀ enzymes of the MAX1 family. In rice, MAX1 enzymes act stereospecifically to produce 4-deoxyorobanchol and orobanchol. Strigol- and orobanchol-type SLs have different activities in the control of seed germination and shoot branching, depending on plant species. This can partly be explained by different stereospecificity of SL receptors which includes the KAI2/HTL protein family in parasitic plants and the D14 protein functioning in shoot development. Many studies use chemically synthesised SL analogues such as GR24 which is prepared as a racemic mixture of two stereoisomers, one with the same stereo-configuration as strigol, and the other its enantiomer, which does not correspond to any known SL. In Arabidopsis, these two stereoisomers are preferentially perceived by AtD14 and KAI2, respectively, which activate different developmental pathways. Thus caution should be exercised in the use of SL racemic mixtures, while conversely the use of specific stereoisomers can provide powerful tools and yield critical information about receptors and signalling pathways in operation.
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