Classical and semi-classical energy conditions

The standard energy conditions of classical general relativity are (mostly) linear in the stress-energy tensor, and have clear physical interpretations in terms of geodesic focussing, but suffer the significant drawback that they are often violated by semi-classical quantum effects. In contrast, it is possible to develop non-standard energy conditions that are intrinsically non-linear in the stress-energy tensor, and which exhibit much better well-controlled behaviour when semi-classical quantum effects are introduced, at the cost of a less direct applicability to geodesic focussing. In this article we will first review the standard energy conditions and their various limitations. (Including the connection to the Hawking--Ellis type I, II, III, and IV classification of stress-energy tensors). We shall then turn to the averaged, nonlinear, and semi-classical energy conditions, and see how much can be done once semi-classical quantum effects are included.Comment: V1: 25 pages. Draft chapter, on which the related chapter of the book "Wormholes, Warp Drives and Energy Conditions" (to be published by Springer), will be based. V2: typos fixed. V3: small typo fixe

Study of Peri-Articular Anaesthetic for Replacement of the Knee (SPAARK): study protocol for a patient-blinded, randomised controlled superiority trial of liposomal bupivacaine

Background: Optimising the management of peri-operative pain and recovery following knee replacement has been identified as a patient priority. Current pain relief strategies use opiate-based analgesia; however, up to 50% of patients experience significant side effects. Local anaesthetic incisional infiltration is one alternative. The length of the duration of action is a major limiting factor of current local anaesthetic techniques. Liposomal bupivacaine has been reported to be effective for up to 72 h. This randomised controlled trial will evaluate the clinical and cost effectiveness of liposomal bupivacaine. Methods: SPAARK is a patient-blinded, multi-centre, active comparator, superiority, two-arm, parallel-group randomised controlled trial. Five hundred patients undergoing knee replacement will be recruited and randomised to liposomal bupivacaine plus bupivacaine hydrochloride or bupivacaine hydrochloride alone. The co-primary outcomes are the Quality of Recovery 40 measured at 72 h post-surgery and also cumulative pain measured daily using a 0–10 visual analogue scale for the first 3 days following surgery. Secondary outcomes include cumulative opioid consumption, fitness for discharge, functional outcomes assessed using the Oxford Knee Score and American Knee Society Score, the EuroQol five dimensions instrument and complications. A cost utility analysis is also planned. Discussion: The clinical effectiveness and cost effectiveness of liposomal bupivacaine have yet to be evaluated in the National Health Service, making this trial appropriate and timely. Trial registration: ISRCTN registry, ISRCTN54191675. Registered on 14 November 2017

Single-neuron dynamics in human focal epilepsy

Epileptic seizures are traditionally characterized as the ultimate expression of monolithic, hypersynchronous neuronal activity arising from unbalanced runaway excitation. Here we report the first examination of spike train patterns in large ensembles of single neurons during seizures in persons with epilepsy. Contrary to the traditional view, neuronal spiking activity during seizure initiation and spread was highly heterogeneous, not hypersynchronous, suggesting complex interactions among different neuronal groups even at the spatial scale of small cortical patches. In contrast to earlier stages, seizure termination is a nearly homogenous phenomenon followed by an almost complete cessation of spiking across recorded neuronal ensembles. Notably, even neurons outside the region of seizure onset showed significant changes in activity minutes before the seizure. These findings suggest a revision of current thinking about seizure mechanisms and point to the possibility of seizure prevention based on spiking activity in neocortical neurons

Inflammatory Markers and Risk of Hip Fracture in Older White Women: The Study of Osteoporotic Fractures †

Abstract Hip fractures are the most devastating consequence of osteoporosis and impact 1 in 6 white women leading to a 2-3 fold increased mortality risk in the first year. Despite evidence of inflammatory markers in the pathogenesis of osteoporosis, few studies have examined their effect on hip fracture. To determine if high levels of inflammation increase hip fracture risk and explore mediation pathways, a case-cohort design nested in a cohort of 4709 white women from the Study of Osteoporotic Fractures was used. A random sample of 1171 women was selected as the subcohort (mean age 80.1 ± 4.2 years) plus the first 300 women with incident hip fracture. Inflammatory markers interleukin-6 (IL-6) and soluble receptors (SR) for IL-6 (IL-6 SR) and tumor necrosis factor (TNF SR1 and TNF SR2) were measured and participants were followed for a median (interquartile range) of 6.3 (3.7, 6.9) years. In multivariable models, the hazard ratio (HR) of hip fracture for women in the highest inflammatory marker level (quartile 4) was 1.64 (95% confidence interval [CI], 1.09-2.48, p trend=0.03) for IL-6 and 2.05 (95% CI, 1.35-3.12, p trend <0.01) for TNF SR1 when compared with women in the lowest level (quartile 1). Among women with 2 and 3-4 inflammatory markers in the highest quartile, the HR of hip fracture was 1.51 (95% CI, 1.07-2.14) and 1.42 (95% CI, 0.87-2.31) compared with women with 0-1 marker(s) in the highest quartile (p trend = 0.03). After individually adjusting for 7 potential mediators, cystatin-C (a biomarker of renal function) and bone mineral density (BMD) attenuated HRs among women with the highest inflammatory burden by 20% and 15%, respectively, suggesting a potential mediating role. Older white women with high inflammatory burden are at increased risk of hip fracture in part due to poor renal function and low BMD

Increased blood product use among coronary artery bypass patients prescribed preoperative aspirin and clopidogrel

BACKGROUND: The administration of antiplatelet drugs before coronary artery bypass graft surgery (CABG) is associated with an increased risk of major hemorrhage and related surgical reexploration. Little is known about the relative effect of combined clopidogrel and aspirin on blood product use around the time of CABG. We evaluated the associated risk between the combined use of aspirin and clopidogrel and the transfusion of blood products perioperatively. METHODS: We retrospectively studied a cohort of 659 individuals who underwent a first CABG, without concomitant valvular or aortic surgery, at a single large Canadian cardiac surgical centre between January 2000 and April 2002. The four study exposure groups were those prescribed aspirin (n = 105), clopidogrel (n = 11), the combination of both (n = 46), or neither drug (n = 497), within 7 days prior to CABG. The primary study outcome was the excessive transfusion of blood products during CABG and up to the second post-operative day, defined as ≥ 2 units of packed red blood cells (PRBC), ≥ 2 units of fresh frozen plasma, ≥ 5 units of cryoprecipitate or ≥ 5 units of platelets. Secondary outcomes included the mean number of transfused units of each type of blood product. RESULTS: A greater mean number of units of PRBC were transfused among those who received clopidogrel alone (2.9) or in combination with aspirin (2.4), compared to those on aspirin alone (1.9) or neither antiplatelet drug (1.4) (P = 0.001). A similar trend was seen for the respective mean number of transfused units of platelets (3.6, 3.7, 1.3 and 1.0; P < 0.001) and fresh frozen plasma (2.5, 3.1, 2.3, 1.6; P = 0.01). Compared to non-users, the associated risk of excessive blood product transfusion was highest among recipients of aspirin and clopidogrel together (adjusted OR 2.2, 95% CI 1.1–4.3). No significant association was seen among lone users of aspirin (adjusted OR 1.0, 95% CI 0.6–1.6) or clopidogrel (adjusted OR 0.7, 95% CI 0.2–2.5), compared to non-users. CONCLUSIONS: While combined use of aspirin and clopidogrel shortly before CABG surgery may increase the associated risk of excess transfusion of blood products perioperatively, several study limitations prevent any confident conclusions from being drawn. Beyond challenging these findings, future research might focus on the value of both intraoperative monitoring of platelet function, and the effectiveness of antifibrinolytic agents, at reducing the risk of postoperative bleeding

Transcriptomic Profiling of Virus-Host Cell Interactions following Chicken Anaemia Virus (CAV) Infection in an In Vivo Model.

Chicken Anaemia Virus (CAV) is an economically important virus that targets lymphoid and erythroblastoid progenitor cells leading to immunosuppression. This study aimed to investigate the interplay between viral infection and the host's immune response to better understand the pathways that lead to CAV-induced immunosuppression. To mimic vertical transmission of CAV in the absence of maternally-derived antibody, day-old chicks were infected and their responses measured at various time-points post-infection by qRT-PCR and gene expression microarrays. The kinetics of mRNA expression levels of signature cytokines of innate and adaptive immune responses were determined by qRT-PCR. The global gene expression profiles of mock-infected (control) and CAV-infected chickens at 14 dpi were also compared using a chicken immune-related 5K microarray. Although in the thymus there was evidence of induction of an innate immune response following CAV infection, this was limited in magnitude. There was little evidence of a Th1 adaptive immune response in any lymphoid tissue, as would normally be expected in response to viral infection. Most cytokines associated with Th1, Th2 or Treg subsets were down-regulated, except IL-2, IL-13, IL-10 and IFNγ, which were all up-regulated in thymus and bone marrow. From the microarray studies, genes that exhibited significant (greater than 1.5-fold, false discovery rate <0.05) changes in expression in thymus and bone marrow on CAV infection were mainly associated with T-cell receptor signalling, immune response, transcriptional regulation, intracellular signalling and regulation of apoptosis. Expression levels of a number of adaptor proteins, such as src-like adaptor protein (SLA), a negative regulator of T-cell receptor signalling and the transcription factor Special AT-rich Binding Protein 1 (SATB1), were significantly down-regulated by CAV infection, suggesting potential roles for these genes as regulators of viral infection or cell defence. These results extend our understanding of CAV-induced immunosuppression and suggest a global immune dysregulation following CAV infection

Polyomic profiling reveals significant hepatic metabolic alterations in glucagon-receptor (GCGR) knockout mice: implications on anti-glucagon therapies for diabetes

<p>Abstract</p> <p>Background</p> <p>Glucagon is an important hormone in the regulation of glucose homeostasis, particularly in the maintenance of euglycemia and prevention of hypoglycemia. In type 2 Diabetes Mellitus (T2DM), glucagon levels are elevated in both the fasted and postprandial states, which contributes to inappropriate hyperglycemia through excessive hepatic glucose production. Efforts to discover and evaluate glucagon receptor antagonists for the treatment of T2DM have been ongoing for approximately two decades, with the challenge being to identify an agent with appropriate pharmaceutical properties and efficacy relative to potential side effects. We sought to determine the hepatic & systemic consequence of full glucagon receptor antagonism through the study of the glucagon receptor knock-out mouse (Gcgr^-/-) compared to wild-type littermates.</p> <p>Results</p> <p>Liver transcriptomics was performed using Affymetric expression array profiling, and liver proteomics was performed by iTRAQ global protein analysis. To complement the transcriptomic and proteomic analyses, we also conducted metabolite profiling (~200 analytes) using mass spectrometry in plasma. Overall, there was excellent concordance (R = 0.88) for changes associated with receptor knock-out between the transcript and protein analysis. Pathway analysis tools were used to map the metabolic processes in liver altered by glucagon receptor ablation, the most notable being significant down-regulation of gluconeogenesis, amino acid catabolism, and fatty acid oxidation processes, with significant up-regulation of glycolysis, fatty acid synthesis, and cholesterol biosynthetic processes. These changes at the level of the liver were manifested through an altered plasma metabolite profile in the receptor knock-out mice, e.g. decreased glucose and glucose-derived metabolites, and increased amino acids, cholesterol, and bile acid levels.</p> <p>Conclusions</p> <p>In sum, the results of this study suggest that the complete ablation of hepatic glucagon receptor function results in major metabolic alterations in the liver, which, while promoting improved glycemic control, may be associated with adverse lipid changes.</p

The Illusion of Owning a Third Arm

Could it be possible that, in the not-so-distant future, we will be able to reshape the human body so as to have extra limbs? A third arm helping us out with the weekly shopping in the local grocery store, or an extra artificial limb assisting a paralysed person? Here we report a perceptual illusion in which a rubber right hand, placed beside the real hand in full view of the participant, is perceived as a supernumerary limb belonging to the participant's own body. This effect was supported by questionnaire data in conjunction with physiological evidence obtained from skin conductance responses when physically threatening either the rubber hand or the real one. In four well-controlled experiments, we demonstrate the minimal required conditions for the elicitation of this “supernumerary hand illusion”. In the fifth, and final experiment, we show that the illusion reported here is qualitatively different from the traditional rubber hand illusion as it is characterised by less disownership of the real hand and a stronger feeling of having two right hands. These results suggest that the artificial hand ‘borrows’ some of the multisensory processes that represent the real hand, leading to duplication of touch and ownership of two right arms. This work represents a major advance because it challenges the traditional view of the gross morphology of the human body as a fundamental constraint on what we can come to experience as our physical self, by showing that the body representation can easily be updated to incorporate an additional limb