Polygenic risk scores for coronary artery disease and subsequent event risk amongst established cases

BACKGROUND: There is growing evidence that polygenic risk scores (PRS) can identify individuals with elevated lifetime risk of coronary artery disease (CAD). Whether they can also be used to stratify risk of subsequent events among those surviving a first CAD event remains uncertain, with possible biological differences between CAD onset and progression, and the potential for index event bias. METHODS: Using two baseline subsamples of UK Biobank; prevalent CAD cases (N = 10 287) and individuals without CAD (N = 393 108), we evaluated associations between a CAD PRS and incident cardiovascular and fatal outcomes. RESULTS: A 1 S.D. higher PRS was associated with increased risk of incident MI in participants without CAD (OR 1.33; 95% C.I. 1.29, 1.38), but the effect estimate was markedly attenuated in those with prevalent CAD (OR 1.15; 95% C.I. 1.06, 1.25); heterogeneity P = 0.0012. Additionally, among prevalent CAD cases, we found evidence of an inverse association between the CAD PRS and risk of all-cause death (OR 0.91; 95% C.I. 0.85, 0.98) compared to those without CAD (OR 1.01; 95% C.I. 0.99, 1.03); heterogeneity P = 0.0041. A similar inverse association was found for ischaemic stroke (Prevalent CAD (OR 0.78; 95% C.I. 0.67, 0.90); without CAD (OR 1.09; 95% C.I. 1.04, 1.15), heterogeneity P < 0.001). CONCLUSIONS: Bias induced by case stratification and survival into UK Biobank may distort associations of polygenic risk scores derived from case-control studies or populations initially free of disease. Differentiating between effects of possible biases and genuine biological heterogeneity is a major challenge in disease progression research

Spin- and energy relaxation of hot electrons at GaAs surfaces

The mechanisms for spin relaxation in semiconductors are reviewed, and the mechanism prevalent in p-doped semiconductors, namely spin relaxation due to the electron-hole exchange interaction, is presented in some depth. It is shown that the solution of Boltzmann-type kinetic equations allows one to obtain quantitative results for spin relaxation in semiconductors that go beyond the original Bir-Aronov-Pikus relaxation-rate approximation. Experimental results using surface sensitive two-photon photoemission techniques show that the spin relaxation-time of electrons in p-doped GaAs at a semiconductor/metal surface is several times longer than the corresponding bulk spin relaxation-times. A theoretical explanation of these results in terms of the reduced density of holes in the band-bending region at the surface is presented.Comment: 33 pages, 12 figures; earlier submission replaced by corrected and expanded version; eps figures now included in the tex

Factorization Properties of Soft Graviton Amplitudes

We apply recently developed path integral resummation methods to perturbative quantum gravity. In particular, we provide supporting evidence that eikonal graviton amplitudes factorize into hard and soft parts, and confirm a recent hypothesis that soft gravitons are modelled by vacuum expectation values of products of certain Wilson line operators, which differ for massless and massive particles. We also investigate terms which break this factorization, and find that they are subleading with respect to the eikonal amplitude. The results may help in understanding the connections between gravity and gauge theories in more detail, as well as in studying gravitational radiation beyond the eikonal approximation.Comment: 35 pages, 5 figure

Characterisation and induction of tissue-resident gamma delta T-cells to target hepatocellular carcinoma

Immunotherapy is now the standard of care for advanced hepatocellular carcinoma (HCC), yet many patients fail to respond. A major unmet goal is the boosting of T-cells with both strong HCC reactivity and the protective advantages of tissue-resident memory T-cells (TRM). Here, we show that higher intratumoural frequencies of γδ T-cells, which have potential for HLA-unrestricted tumour reactivity, associate with enhanced HCC patient survival. We demonstrate that γδ T-cells exhibit bona fide tissue-residency in human liver and HCC, with γδTRM showing no egress from hepatic vasculature, persistence for >10 years and superior anti-tumour cytokine production. The Vγ9Vδ2 T-cell subset is selectively depleted in HCC but can efficiently target HCC cell lines sensitised to accumulate isopentenyl-pyrophosphate by the aminobisphosphonate Zoledronic acid. Aminobisphosphonate-based expansion of peripheral Vγ9Vδ2 T-cells recapitulates a TRM phenotype and boosts cytotoxic potential. Thus, our data suggest more universally effective HCC immunotherapy may be achieved by combining aminobisphosphonates to induce Vγ9Vδ2TRM capable of replenishing the depleted pool, with additional intratumoural delivery to sensitise HCC to Vγ9Vδ2TRM-based targeting

Nanoscale phase-engineering of thermal transport with a Josephson heat modulator

Macroscopic quantum phase coherence has one of its pivotal expressions in the Josephson effect [1], which manifests itself both in charge [2] and energy transport [3-5]. The ability to master the amount of heat transferred through two tunnel-coupled superconductors by tuning their phase difference is the core of coherent caloritronics [4-6], and is expected to be a key tool in a number of nanoscience fields, including solid state cooling [7], thermal isolation [8, 9], radiation detection [7], quantum information [10, 11] and thermal logic [12]. Here we show the realization of the first balanced Josephson heat modulator [13] designed to offer full control at the nanoscale over the phase-coherent component of thermal currents. Our device provides magnetic-flux-dependent temperature modulations up to 40 mK in amplitude with a maximum of the flux-to-temperature transfer coefficient reaching 200 mK per flux quantum at a bath temperature of 25 mK. Foremost, it demonstrates the exact correspondence in the phase-engineering of charge and heat currents, breaking ground for advanced caloritronic nanodevices such as thermal splitters [14], heat pumps [15] and time-dependent electronic engines [16-19].Comment: 6+ pages, 4 color figure

Rectification of electronic heat current by a hybrid thermal diode

We report the realization of an ultra-efficient low-temperature hybrid heat current rectifier, thermal counterpart of the well-known electric diode. Our design is based on a tunnel junction between two different elements: a normal metal and a superconducting island. Electronic heat current asymmetry in the structure arises from large mismatch between the thermal properties of these two. We demonstrate experimentally temperature differences exceeding $60$ mK between the forward and reverse thermal bias configurations. Our device offers a remarkably large heat rectification ratio up to $\sim 140$ and allows its prompt implementation in true solid-state thermal nanocircuits and general-purpose electronic applications requiring energy harvesting or thermal management and isolation at the nanoscale.Comment: 8 pages, 6 color figure

Development of an invasively monitored porcine model of acetaminophen-induced acute liver failure

Background: The development of effective therapies for acute liver failure (ALF) is limited by our knowledge of the pathophysiology of this condition, and the lack of suitable large animal models of acetaminophen toxicity. Our aim was to develop a reproducible invasively-monitored porcine model of acetaminophen-induced ALF. Method: 35kg pigs were maintained under general anaesthesia and invasively monitored. Control pigs received a saline infusion, whereas ALF pigs received acetaminophen intravenously for 12 hours to maintain blood concentrations between 200-300 mg/l. Animals surviving 28 hours were euthanased. Results: Cytochrome p450 levels in phenobarbital pre-treated animals were significantly higher than non pre-treated animals (300 vs 100 pmol/mg protein). Control pigs (n=4) survived 28-hour anaesthesia without incident. Of nine pigs that received acetaminophen, four survived 20 hours and two survived 28 hours. Injured animals developed hypotension (mean arterial pressure; 40.8+/-5.9 vs 59+/-2.0 mmHg), increased cardiac output (7.26+/-1.86 vs 3.30+/-0.40 l/min) and decreased systemic vascular resistance (8.48+/-2.75 vs 16.2+/-1.76 mPa/s/m3). Dyspnoea developed as liver injury progressed and the increased pulmonary vascular resistance (636+/-95 vs 301+/-26.9 mPa/s/m3) observed may reflect the development of respiratory distress syndrome. Liver damage was confirmed by deterioration in pH (7.23+/-0.05 vs 7.45+/-0.02) and prothrombin time (36+/-2 vs 8.9+/-0.3 seconds) compared with controls. Factor V and VII levels were reduced to 9.3 and 15.5% of starting values in injured animals. A marked increase in serum AST (471.5+/-210 vs 42+/-8.14) coincided with a marked reduction in serum albumin (11.5+/-1.71 vs 25+/-1 g/dL) in injured animals. Animals displayed evidence of renal impairment; mean creatinine levels 280.2+/-36.5 vs 131.6+/-9.33 mumol/l. Liver histology revealed evidence of severe centrilobular necrosis with coagulative necrosis. Marked renal tubular necrosis was also seen. Methaemoglobin levels did not rise >5%. Intracranial hypertension was not seen (ICP monitoring), but there was biochemical evidence of encephalopathy by the reduction of Fischer's ratio from 5.6 +/- 1.1 to 0.45 +/- 0.06. Conclusion: We have developed a reproducible large animal model of acetaminophen-induced liver failure, which allows in-depth investigation of the pathophysiological basis of this condition. Furthermore, this represents an important large animal model for testing artificial liver support systems

Analytic two-loop form factors in N=4 SYM

The original publication is available at www.springerlink.co