1,169 research outputs found
Interplanetary Ridesharing: Exploring Potential CubeSat Trajectories
Ever since the revolutionary CubeSat form factor took hold in the Aerospace industry, there has been a desire to send them further and further into space. This thesis introduces an optimization approach to deployment that explores new possibilities of interplanetary CubeSats. In this approach there are three categories of objective functions that are defined by the type of trajectory of a âprimaryâ spacecraft, which carries the CubeSat deployer. These categories are flyby, orbiter, and lander. For each category the objective function starts with four design variables. These are the ÎV of the deployer broken up into three component directions and the true anomaly at the time of deployment. The method then calculates the mission specific objective to be minimized and uses MatlabÂźâs built in gradient-based optimizer, fmincon. The results show that in the flyby category, the CubeSat has a significantly different turning angle than the primary. The CubeSat can even flyby on the opposite side of the planet. In the orbiter case it is shown that the method works by testing it with two objective functions, the difference in inclination and the difference in eccentricity between the primary and the CubeSat. It is shown that the inclination can be changed by 0.1314° and the eccentricity can be changed by 0.0033. These values, although low in magnitude, are an order of magnitude greater than non-optimal deployment scenarios. Still, another optimization method is introduced to find out how much extra ÎV the CubeSat would need to reach a desired change. This shows that with just an extra 75 m/s of ÎV, the CubeSat can change its orbit by 5°. This could come from either a propulsion system or a modified deployer. The final category, lander, used the flight path angle when entering the atmosphere as an objective. The method shows that flight path angle can be changed by 2.6°. Overall, these examples have proven that the method can find optimal solutions to CubeSat deployment scenarios at other planets
Standard versus short stem cemented Exeter<sup>Âź</sup> when used for primary total hip arthroplasty:a survivorship analysis
Aims: The aims were to compare the survival of the cemented standard (150 mm) with the short (DDH [35.5 mm offset or less], number 1 short stem [125 mm options of 37.5 mm, 44 mm, 50 mm offset] and revision [44/00/125]) Exeter Âź V40 femoral stems when used for primary total hip arthroplasty (THA). Methods: Patients were retrospectively identified from an arthroplasty database. A total of 664 short stem Exeter Âź variants were identified, of which 229 were DDH stems, 208 number 1 stems and 227 revision stems were implanted between 2011 and 2020. A control group of 698 standard Exeter Âź stems used for THA was set up, and were followed up for a minimum of 10 years follow-up (implanted 2011). All-cause survival was assessed for THA and for the stem only. Adjusted analysis was undertaken for age, sex and ASA grade. Results: The median survival time for the short stems varied according to design: DDH had a survival time of 6.7 years, number 1 stems 4.1 years, and revision stems 7.2 years. Subjects in the short stem group (n = 664) were significantly younger (mean difference 5.1, P < 0.001) and were more likely to be female (odds ratio 1.89, 95% CI 1.50 to 2.39, P < 0.001), compared to the standard group. There were no differences in THA (P = 0.26) or stem (P = 0.35) survival at 5 years (adjusted THA: 98.3% vs. 97.2%; stem 98.7% vs. 97.8%) or 10 years (adjusted THA 97.0% vs. 96.0 %; stem 96.7% vs. 96.2%) between standard and short stem groups, respectively. At 5 years no differences were found in THA (DDH: 96.7%, number 1 97.5%, revision 97.3%, standard 98.6%) or stem (DDH: 97.6%, number 1 99.0%, revision 97.3%, standard 98.2%) survival between/among the different short stems or when compared to the standard group. Conclusion: The Exeter Âź short stems offer equivocal survival when compared to the standard stem at 5- to 10-year follow-up, which does not seem to be influenced by the short stem design.</p
Evaluation of cholinergic deficiency in preclinical Alzheimer\u27s disease using pupillometry
Cortical cholinergic deficiency is prominent in Alzheimerâs disease (AD), and published findings of diminished pupil flash response in AD suggest that this deficiency may extend to the visual cortical areas and anterior eye. Pupillometry is a low-cost, noninvasive technique that may be useful for monitoring cholinergic deficits which generally lead to memory and cognitive disorders. The aim of the study was to evaluate pupillometry for early detection of AD by comparing the pupil flash response (PFR) in AD (N=14) and cognitively normal healthy control (HC, N=115) participants, with the HC group stratified according to high (N=38) and low (N=77) neocortical amyloid burden (NAB). Constriction phase PFR parameters were significantly reduced in AD compared to HC (maximum acceleration p \u3c 0.05, maximum velocity p \u3c 0.0005, average velocity p \u3c 0.005, and constriction amplitude p \u3c 0.00005). The high-NAB HC subgroup had reduced PFR response cross-sectionally, and also a greater decline longitudinally, compared to the low-NAB subgroup, suggesting changes to pupil response in preclinical AD. The results suggest that PFR changes may occur in the preclinical phase of AD. Hence, pupillometry has a potential as an adjunct for noninvasive, cost-effective screening for preclinical AD
Enhanced stability and local structure in biologically relevant amorphous materials containing pyrophosphate
There is increasing evidence that amorphous inorganic materials play a key role in biomineralisation in many organisms, however the inherent instability of synthetic analogues in the absence of the complex in vivo matrix limits their study and clinical exploitation. To address this, we report here an approach that enhances long-term stability to >1 year of biologically relevant amorphous metal phosphates, in the absence of any complex stabilisers, by utilising pyrophosphates (P2O7 4-); species themselves ubiquitous in vivo. Ambient temperature precipitation reactions were employed to synthesise amorphous Ca2P2O7.nH2O and Sr2P2O7.nH2O (3.8 < n < 4.2) and their stability and structure were investigated. Pair distribution functions (PDF) derived from synchrotron X-ray data indicated a lack of structural order beyond ~8 A° in both phases, with this local order found to resemble crystalline analogues. Further studies, including 1H and 31P solid state NMR, suggest the unusually high stability of these purely inorganic amorphous phases is partly due to disorder in the PâOâP bond angles within the P2O7 units, which impede crystallization, and to water molecules, which are involved in H-bonds of various strengths within the structures and hamper the formation of an ordered network. In situ high temperature powder X-ray diffraction data indicated that the amorphous nature of both phases surprisingly persisted to ~450° C. Further NMR and TGA studies found that above ambient temperature some water molecules reacted with P2O7 anions, leading to the hydrolysis of some PâOâP linkages and the formation of HPO4 2- anions within the amorphous matrix. The latter anions then recombined into P2O7 ions at higher temperatures prior to crystallization. Together, these findings provide important new materials with unexplored potential for enzyme-assisted resorption and establish factors crucial to isolate further stable amorphous inorganic materials
Runx1 deficiency protects against adverse cardiac remodeling following myocardial infarction
Background: Myocardial infarction (MI) is a leading cause of heart failure and death worldwide. Preservation of contractile function and protection against adverse changes in ventricular architecture (cardiac remodeling) are key factors to limiting progression of this condition to heart failure. Consequently, new therapeutic targets are urgently required to achieve this aim. Expression of the Runx1 transcription factor is increased in adult cardiomyocytes after MI; however, the functional role of Runx1 in the heart is unknown.
Methods: To address this question, we have generated a novel tamoxifen-inducible cardiomyocyte-specific Runx1-deficient mouse. Mice were subjected to MI by means of coronary artery ligation. Cardiac remodeling and contractile function were assessed extensively at the whole-heart, cardiomyocyte, and molecular levels.
Results: Runx1-deficient mice were protected against adverse cardiac remodeling after MI, maintaining ventricular wall thickness and contractile function. Furthermore, these mice lacked eccentric hypertrophy, and their cardiomyocytes exhibited markedly improved calcium handling. At the mechanistic level, these effects were achieved through increased phosphorylation of phospholamban by protein kinase A and relief of sarco/endoplasmic reticulum Ca2+-ATPase inhibition. Enhanced sarco/endoplasmic reticulum Ca2+-ATPase activity in Runx1-deficient mice increased sarcoplasmic reticulum calcium content and sarcoplasmic reticulumâmediated calcium release, preserving cardiomyocyte contraction after MI.
Conclusions: Our data identified Runx1 as a novel therapeutic target with translational potential to counteract the effects of adverse cardiac remodeling, thereby improving survival and quality of life among patients with MI
Clinical Practice Recommendations on Genetic Testing of CYP2C9 and VKORC1 Variants in Warfarin Therapy
Objective: To systematically review evidence on genetic variants influencing outcomes during warfarin therapy and provide practice recommendations addressing the key questions: (1) Should genetic testing be performed in patients with an indication for warfarin therapy to improve achievement of stable anticoagulation and reduce adverse effects? (2) Are there subgroups of patients who may benefit more from genetic testing compared with others? (3) How should patients with an indication for warfarin therapy be managed based on their genetic test results? Methods: A systematic literature search was performed for VKORC1 and CYP2C9 and their association with warfarin therapy. Evidence was critically appraised, and clinical practice recommendations were developed based on expert group consensus. Results: Testing of VKORC1 (-1639G\u3eA), CYP2C92, and CYP2C93 should be considered for all patients, including pediatric patients, within the first 2 weeks of therapy or after a bleeding event. Testing for CYP2C95, 6, 8, or 11 and CYP4F2 (V433M) is currently not recommended. Testing should also be considered for all patients who are at increased risk of bleeding complications, who consistently show out-of-range international normalized ratios, or suffer adverse events while receiving warfarin. Genotyping results should be interpreted using a pharmacogenetic dosing algorithm to estimate the required dose. Significance: This review provides the latest update on genetic markers for warfarin therapy, clinical practice recommendations as a basis for informed decision making regarding the use of genotype-guided dosing in patients with an indication for warfarin therapy, and identifies knowledge gaps to guide future research.
Clinical Practice Recommendations for the Management and Prevention of Cisplatin-Induced Hearing Loss Using Pharmacogenetic Markers
Currently no pharmacogenomics-based criteria exist to guide clinicians in identifying individuals who are at risk of hearing loss from cisplatin-based chemotherapy. This review summarizes findings from pharmacogenomic studies that report genetic polymorphisms associated with cisplatin-induced hearing loss and aims to (1) provide up-to-date information on new developments in the field, (2) provide recommendations for the use of pharmacogenetic testing in the prevention, assessment, and management of cisplatin-induced hearing loss in children and adults, and (3) identify knowledge gaps to direct and prioritize future research. These practice recommendations for pharmacogenetic testing in the context of cisplatin-induced hearing loss reflect a review and evaluation of recent literature, and are designed to assist clinicians in providing optimal clinical care for patients receiving cisplatin-based chemotherapy
Genes as Tags: The Tax Implications of Widely Available Genetic Information
This paper examines how progress in genetics\u27 specifically, the proliferation of knowledge about the human genome\u27 may influence the feasibility and desirability of a tax that is based on individual human endowments or ability. The paper explores various forms that such a genetic endowment tax-and-transfer regime might take and identifies some of the benefits and costs of such a regime. The authors take no position on whether a genetic endowment tax would be desirable or not. However, one contribution of the paper is to observe that current law in the U.S., which restricts the use of genetic information by insurers and employers, is equivalent to a form of genetic endowment tax. The paper also notes that, in the absence of a government-mandated transfer policy with respect to genetic endowments, private insurance markets may arise to fill the gap, allowing individuals to purchase insurance against the possibility of a bad genetic draw
Interpretation of the evidence for the efficacy and safety of statin therapy
This Review is intended to help clinicians, patients, and the public make informed decisions about statin therapy for
the prevention of heart attacks and strokes. It explains how the evidence that is available from randomised controlled
trials yields reliable information about both the effi cacy and safety of statin therapy. In addition, it discusses how
claims that statins commonly cause adverse eff ects refl ect a failure to recognise the limitations of other sources of
evidence about the eff ects of treatment. Large-scale evidence from randomised trials shows that statin therapy reduces
the risk of major vascular events (ie, coronary deaths or myocardial infarctions, strokes, and coronary revascularisation
procedures) by about one-quarter for each mmol/L reduction in LDL cholesterol during each year (after the fi rst) that
it continues to be taken. The absolute benefi ts of statin therapy depend on an individualâs absolute risk of occlusive
vascular events and the absolute reduction in LDL cholesterol that is achieved. For example, lowering LDL cholesterol
by 2 mmol/L (77 mg/dL) with an eff ective low-cost statin regimen (eg, atorvastatin 40 mg daily, costing about ÂŁ2 per
month) for 5 years in 10 000 patients would typically prevent major vascular events from occurring in about
1000 patients (ie, 10% absolute benefi t) with pre-existing occlusive vascular disease (secondary prevention) and in
500 patients (ie, 5% absolute benefi t) who are at increased risk but have not yet had a vascular event (primary
prevention). Statin therapy has been shown to reduce vascular disease risk during each year it continues to be taken,
so larger absolute benefi ts would accrue with more prolonged therapy, and these benefi ts persist long term. The only
serious adverse events that have been shown to be caused by long-term statin therapyâie, adverse eff ects of the
statinâare myopathy (defi ned as muscle pain or weakness combined with large increases in blood concentrations
of creatine kinase), new-onset diabetes mellitus, and, probably, haemorrhagic stroke. Typically, treatment
of 10 000 patients for 5 years with an eff ective regimen (eg, atorvastatin 40 mg daily) would cause about 5 cases of
myopathy (one of which might progress, if the statin therapy is not stopped, to the more severe condition of
rhabdomyolysis), 50â100 new cases of diabetes, and 5â10 haemorrhagic strokes. However, any adverse impact
of these side-eff ects on major vascular events has already been taken into account in the estimates of the absolute
benefi ts. Statin therapy may cause symptomatic adverse events (eg, muscle pain or weakness) in up to about
50â100 patients (ie, 0·5â1·0% absolute harm) per 10 000 treated for 5 years. However, placebo-controlled randomised
trials have shown defi nitively that almost all of the symptomatic adverse events that are attributed to statin therapy in
routine practice are not actually caused by it (ie, they represent misattribution). The large-scale evidence available
from randomised trials also indicates that it is unlikely that large absolute excesses in other serious adverse events
still await discovery. Consequently, any further fi ndings that emerge about the eff ects of statin therapy would not be
expected to alter materially the balance of benefi ts and harms. It is, therefore, of concern that exaggerated claims
about side-eff ect rates with statin therapy may be responsible for its under-use among individuals at increased risk of
cardiovascular events. For, whereas the rare cases of myopathy and any muscle-related symptoms that are attributed
to statin therapy generally resolve rapidly when treatment is stopped, the heart attacks or strokes that may occur if
statin therapy is stopped unnecessarily can be devastating
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