Development of inter-particle friction in a railway ballast

A detailed experimental programme investigated how the coefficient of friction at particle contacts for a typical UK railway ballast varied during cyclic loading. Despite a decrease of roughness, the friction coefficient increased steadily, stabilising in the region of tens of cycles. In contrast to previous work on the contact behaviour of sands, water inundation caused a significant but reversible decrease of the coefficient, while the generation of a significant amount of abraded fines did not affect it, nor did the load level

Crack propagation in brittle solid containing 3D surface fracture under uniaxial compression

2003-2004 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe

Radium-223 chloride: a potential new treatment for castration-resistant prostate cancer patients with metastatic bone disease

Michael R Harrison, Terence Z Wong, Andrew J Armstrong, Daniel J GeorgeDuke Cancer Institute, Durham, NC, USABackground: Radium-223 chloride (223Ra; Alpharadin) is an alpha-emitting radioisotope that targets areas of osteoblastic metastasis and is excreted by the small intestine. When compared with beta-emitters (eg, strontium-89, samarium-153), 223Ra delivers a high quantity of energy per track length with short tissue penetration.Objective: This review describes the mechanism, radiobiology, and preclinical development of 223Ra and discusses the clinical data currently available regarding its safety and efficacy profile.Methods: Data from clinical trials including abstracts were collected and reviewed using the PubMed Database, as well as the American Society of Clinical Oncology abstract database.Conclusion: Current bone-targeted therapies fall into two main categories: antiresorptive agents (eg, zoledronic acid, denosumab), which have been shown to delay skeletal-related events, and radiopharmaceuticals (eg, samarium-153), which may have a role in pain palliation. Historically, neither antiresorptive agents nor radiopharmaceuticals have shown definitive evidence of improved overall survival or other antitumor effects in metastatic castrate-resistant prostate cancer (mCRPC). Radiopharmaceuticals are limited by myelosuppresion, thrombocytopenia, and renal excretion. In a recently reported randomized Phase III trial in men with symptomatic bone-metastatic CRPC who had received or were ineligible for docetaxel chemotherapy, 223Ra treatment resulted in improved overall survival and delayed skeletal-related events. Toxicity consisted of minor gastrointestinal side effects and mild neutropenia and thrombocytopenia that were rarely severe. Pending regulatory approval, 223Ra may represent a unique and distinct option for an important subgroup of patients with mCRPC; future trials should address its use in combination or in sequence with existing and novel agents.Keywords: Alpharadin, 223Ra, radium-223, radionuclide therapy, metastatic castrate-resistant prostate cancer, bone metastase

Telemonitoring after discharge from hospital with heart failure: cost-effectiveness modelling of alternative service designs.

Objectives To estimate the cost-effectiveness of remote monitoring strategies versus usual care for adults recently discharged after a heart failure (HF) exacerbation. Design Decision analysis modelling of cost-effectiveness using secondary data sources. Setting Acute hospitals in the UK. Patients Patients recently discharged (within 28 days) after a HF exacerbation. Interventions Structured telephone support (STS) via human to machine (STS HM) interface, (2) STS via human to human (STS HH) contact and (3) home telemonitoring (TM), compared with (4) usual care. Main outcome measures The incremental cost per quality-adjusted life year (QALY) gained by each strategy compared to the next most effective alternative and the probability of each strategy being cost-effective at varying willingness to pay per QALY gained. Results TM was the most cost-effective strategy in the scenario using these base case costs. Compared with usual care, TM had an estimated incremental cost effectiveness ratio (ICER) of £11 873/QALY, whereas STS HH had an ICER of £228 035/QALY against TM. STS HM was dominated by usual care. Threshold analysis suggested that the monthly cost of TM has to be higher than £390 to have an ICER greater than £20 000/QALY against STS HH. Scenario analyses performed using higher costs of usual care, higher costs of STS HH and lower costs of TM do not substantially change the conclusions. Conclusions Cost-effectiveness analyses suggest that TM was an optimal strategy in most scenarios, but there is considerable uncertainty in relation to clear descriptions of the interventions and robust estimation of costs

Preclinical discovery of apixaban, a direct and orally bioavailable factor Xa inhibitor

Apixaban (BMS-562247; 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide), a direct inhibitor of activated factor X (FXa), is in development for the prevention and treatment of various thromboembolic diseases. With an inhibitory constant of 0.08 nM for human FXa, apixaban has greater than 30,000-fold selectivity for FXa over other human coagulation proteases. It produces a rapid onset of inhibition of FXa with association rate constant of 20 μM−1/s approximately and inhibits free as well as prothrombinase- and clot-bound FXa activity in vitro. Apixaban also inhibits FXa from rabbits, rats and dogs, an activity which parallels its antithrombotic potency in these species. Although apixaban has no direct effects on platelet aggregation, it indirectly inhibits this process by reducing thrombin generation. Pre-clinical studies of apixaban in animal models have demonstrated dose-dependent antithrombotic efficacy at doses that preserved hemostasis. Apixaban improves pre-clinical antithrombotic activity, without excessive increases in bleeding times, when added on top of aspirin or aspirin plus clopidogrel at their clinically relevant doses. Apixaban has good bioavailability, low clearance and a small volume of distribution in animals and humans, and a low potential for drug–drug interactions. Elimination pathways for apixaban include renal excretion, metabolism and biliary/intestinal excretion. Although a sulfate conjugate of Ο-demethyl apixaban (O-demethyl apixaban sulfate) has been identified as the major circulating metabolite of apixaban in humans, it is inactive against human FXa. Together, these non-clinical findings have established the favorable pharmacological profile of apixaban, and support the potential use of apixaban in the clinic for the prevention and treatment of various thromboembolic diseases

Primary Care Workforce And Continuous Medical Education In China: Lessons To Learn From A Nationwide Cross-sectional Survey

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Class III obesity is a risk factor for the development of acute on chronic liver failure in patients with decompensated cirrhosis

BACKGROUND AND AIMS: Acute on chronic liver failure (ACLF) is a syndrome of systemic inflammation and organ failures. Obesity, also characterized by chronic inflammation, is a risk factor among patients with cirrhosis for decompensation, infection, and mortality. Our aim was to test the hypothesis that obesity predisposes to ACLF development in patients with decompensated cirrhosis. METHODS: We examined the United Network for Organ Sharing (UNOS) database, from 2005-2016, characterizing patients at wait-listing as non-obese (BMI < 30), obese class I-II (BMI 30-39.9) and obese class III (BMI≥40). ACLF was determined based on the CANONIC study definition. We used Cox proportional hazards regression to assess the association between obesity and ACLF development at liver transplantation (LT). We confirmed our findings using the Nationwide Inpatient Sample (NIS), years 2009-2013, using validated diagnostic coding algorithms to identify obesity, hepatic decompensation and ACLF. Logistic regression evaluated the association between obesity and ACLF occurrence. RESULTS: Among 387,884 with decompensated cirrhosis, 116,704 patients (30.1%) were identified as having ACLF in both databases. Multivariable modeling from the UNOS database revealed class III obesity to be an independent risk factor for ACLF at LT (HR=1.24, 95% CI 1.09-1.41, p<0.001). This finding was confirmed using the NIS (OR=1.30, 95% CI 1.25-1.35, p<0.001). Regarding specific organ failures, analysis of both registries demonstrated patients with class I-II and class III obesity had greater prevalence of renal failure. CONCLUSION: Class III obesity is a newly identified risk factor for ACLF development in patients with decompensated cirrhosis. Obese patients have a particularly higher prevalence of renal failure as a component of ACLF. These findings have important implications regarding stratifying risk and preventing the occurrence of ACLF. LAY SUMMARY: In this study, we identify that among patients with decompensated cirrhosis, class III obesity is a modifiable risk factor for the development of acute on chronic liver failure (ACLF). We further demonstrate that regarding the specific organ failures associated with ACLF, renal failure is significantly more prevalent among obese patients, particularly class III obesity. These findings underscore the importance of weight management in cirrhosis, to reduce the risk of ACLF. Patients with class III obesity should be monitored closely for the development of renal failure

The effects of immediate vision on implicit hand maps

Perceiving the external spatial location of the limbs using position sense requires that immediate proprioceptive afferent signals be combined with a stored body model specifying the size and shape of the body. Longo and Haggard (Proc Natl Acad Sci USA 107:11727–11732, 2010) developed a method to isolate and measure this body model in the case of the hand in which participants judge the perceived location in external space of several landmarks on their occluded hand. The spatial layout of judgments of different landmarks is used to construct implicit hand maps, which can then be compared with actual hand shape. Studies using this paradigm have revealed that the body model of the hand is massively distorted, in a highly stereotyped way across individuals, with large underestimation of finger length and overestimation of hand width. Previous studies using this paradigm have allowed participants to see the locations of their judgments on the occluding board. Several previous studies have demonstrated that immediate vision, even when wholly non-informative, can alter processing of somatosensory signals and alter the reference frame in which they are localised. The present study therefore investigated whether immediate vision contributes to the distortions of implicit hand maps described previously. Participants judged the external spatial location of the tips and knuckles of their occluded left hand either while being able to see where they were pointing (as in previous studies) or while blindfolded. The characteristic distortions of implicit hand maps reported previously were clearly apparent in both conditions, demonstrating that the distortions are not an artefact of immediate vision. However, there were significant differences in the magnitude of distortions in the two conditions, suggesting that vision may modulate representations of body size and shape, even when entirely non-informative

Rats distinguish between absence of events and lack of evidence in contingency learning.

The goal of three experiments was to study whether rats are aware of the difference between absence of events and lack of evidence. We used a Pavlovian extinction paradigm in which lights consistently signaling sucrose were suddenly paired with the absence of sucrose. The crucial manipulation involved the absent outcomes in the extinction phase. Whereas in the Cover conditions, access to the drinking receptacle was blocked by a metal plate, in the No Cover conditions, the drinking receptacle was accessible. The Test phase showed that in the Cover conditions, the measured expectancies of sucrose were clearly at a higher level than in the No Cover conditions. We compare two competing theories potentially explaining the findings. A cognitive theory interprets the observed effect as evidence that the rats were able to understand that the cover blocked informational access to the outcome information, and therefore the changed learning input did not necessarily signify a change of the underlying contingency in the world. An alternative associationist account, renewal theory, might instead explain the relative sparing of extinction in the Cover condition as a consequence of context change. We discuss the merits of both theories as accounts of our data and conclude that the cognitive explanation is in this case preferred