Direct observation of the oxygen isotope effect on the in-plane magnetic field penetration depth in optimally doped YBa2_2Cu3_3O7−δ_{7-\delta}

We report the first direct observation of the oxygen-isotope ($^{16}$O/$^{18}$O) effect on the in-plane penetration depth $\lambda_{ab}$ in a nearly optimally doped YBa$_2$Cu$_3$O$_{7-\delta}$ film using the novel low-energy muon-spin rotation technique. Spin polarized low energy muons are implanted in the film at a known depth $z$ beneath the surface and precess in the local magnetic field $B(z)$. This feature allows us to measure directly the profile $B(z)$ of the magnetic field inside the superconducting film in the Meissner state and to make a model independent determination of $\lambda_{ab}$. A substantial isotope shift $\Delta\lambda_{ab}/\lambda_{ab}=2.8(7)$% at 4 K is observed, implying that the in-plane effective supercarrier mass $m_{ab}^\ast$ is oxygen-isotope dependent with $\Delta m_{ab}^\ast/m_{ab}^\ast = 5.5(1.4)$.Comment: 4 pages, 2 figure

Prediction of Cardiovascular Events by Using Non-Vascular Findings on Routine Chest CT

Background: Routine computed tomography (CT) examinations contain an abundance of findings unrelated to the diagnostic question. Those with prognostic significance may contribute to early detection and treatment of disease, irrelevant findings can be ignored. We aimed to assess the association between unrequested chest CT findings in lungs, mediastinum and pleura and future cardiovascular events. Methods: Multi-center case-cohort study in 5 tertiary and 3 secondary care hospitals involving 10410 subjects who underwent routine chest CT for non-cardiovascular reasons. 493 cardiovascular hospitalizations or deaths were recorded during an average follow-up time of 17.8 months. 1191 patients were randomly sampled to serve as a control subcohort. Hazard ratios and annualized event rates were calculated. Results: Abnormalities in the lung (26–44%), pleura (14–15%) and mediastinum (20%) were common. Hazard ratios after adjustment for age and sex were for airway wall thickening 2.26 (1.59–3.22), ground glass opacities 2.50 (1.72–3.62), consolidations 1.97 (1.12–3.47), pleural effusions 2.77 (1.81–4.25) and lymph-nodes 2.04 (1.40–2.96). Corresponding annual event rates were 5.5%, 6.0%, 3.8%, 10.2 % and 4.4%. Conclusions: We have identified several common chest CT findings that are predictive for future risk of cardiovascular events and found that other findings have little utility for this. The added value of the non-vascular predictors to establishe

Diagnosis of diffuse idiopathic skeletal hyperostosis with chest computed tomography:inter-observer agreement

To evaluate and improve the interobserver agreement for the CT-based diagnosis of diffuse idiopathic skeletal hyperostosis (DISH). Six hundred participants of the CT arm of a lung cancer screening trial were randomly divided into two groups. The first 300 CTs were scored by five observers for the presence of DISH based on the original Resnick criteria for radiographs. After analysis of the data a consensus meeting was organised and the criteria were slightly modified regarding the definition of 'contiguous', the definition of 'flowing ossifications' and the viewing plane and window level. Subsequently, the second set of 300 CTs was scored by the same observers. kappa >= 0.61 was considered good agreement. The 600 male participants were on average 63.5 (SD 5.3) years old and had smoked on average 38.0 pack-years. In the first round kappa values ranged from 0.32 to 0.74 and 7 out of 10 values were below 0.61. After the consensus meeting the interobserver agreement ranged from 0.51 to 0.86 and 3 out of 10 values were below 0.61. The agreement improved significantly. This is the first study that reports interobserver agreement for the diagnosis of DISH on chest CT, showing mostly good agreement for modified Resnick criteria. . DISH is diagnosed on fluoroscopic and radiographic examinations using Resnick criteria . Evaluation of DISH on chest CT was modestly reproducible with the Resnick criteria . A consensus meeting and Resnick criteria modification improved inter-rater reliability for DISH . Reproducible CT criteria for DISH aids research into this poorly understood entity

Increased Elastin Degradation in Pseudoxanthoma Elasticum Is Associated with Peripheral Arterial Disease Independent of Calcification

Pseudoxanthoma elasticum (PXE) results in extensive fragmentation and calcification of elastin fibers in the peripheral arteries, which results in peripheral arterial disease (PAD). Current research focuses on the role of calcifications in the pathogenesis of PXE. Elastin degradation and calcification are shown to interact and may amplify each other. This study aims to compare plasma desmosines, a measure of elastin degradation, between PXE patients and controls and to investigate the association between desmosines and (1) arterial calcification, (2) PAD, and (3) PAD independent of arterial calcification in PXE. Plasma desmosines were quantified with liquid chromatography-tandem mass spectrometry in 93 PXE patients and 72 controls. In PXE patients, arterial calcification mass was quantified on CT scans. The ankle brachial index (ABI) after treadmill test was used to analyze PAD, defined as ABI < 0.9, and the Fontaine classification was used to distinguish symptomatic and asymptomatic PAD. Regression models were built to test the association between desmosines and arterial calcification and arterial functioning in PXE. PXE patients had higher desmosines than controls (350 (290-410) ng/L vs. 320 (280-360) ng/L, p = 0.02). After adjustment for age, sex, body mass index, smoking, type 2 diabetes mellitus, and pulmonary abnormalities, desmosines were associated with worse ABI (β (95%CI): -68 (-132; -3) ng/L), more PAD (β (95%CI): 40 (7; 73) ng/L), and higher Fontaine classification (β (95%CI): 30 (6; 53) ng/L), but not with arterial calcification mass. Lower ABI was associated with higher desmosines, independent from arterial calcification mass (β (95%CI): -0.71(-1.39; -0.01)). Elastin degradation is accelerated in PXE patients compared to controls. The association between desmosines and ABI emphasizes the role of elastin degradation in PAD in PXE. Our results suggest that both elastin degradation and arterial calcification independently contribute to PAD in PXE

Treatment of arterial calcification in patients with chronic limb threatening ischemia with etidronate: protocol of an investigator-initiated multicenter, double blind, placebo-controlled, randomized clinical trial

BACKGROUND: Pathologic studies have shown that in patients with critical limb threatening ischaemia (CLTI) medial arterial calcifications are frequently found and may be responsible for aggravating the disease. These extensive calcifitcations are found not only in arteries of the leg but also in the coronary arteries and the aorta. The progression of these calcifications is fast and they stiffen the vessel wall and may thus increase the cardiovascular risk. Reduction of progression of calcification may not only reduce the burden of CLTI but may also reduce the high residual cardiovascular risk. Medial calcifications have been halted by etidronate in other trials. Its potential to reduce the burden from peripheral vascular disease in CLTI and residual cardiovascular risk remains to be established. METHODS: This is an investigator-initiated multicenter, double blind, placebo-controlled, randomized trial comparing the effects of etidronate versus placebo in patients with CLTI. Subjects will be randomized to either treatment with etidronate for 12 months (cyclical 20 mg/kg for 2 weeks on and 10 weeks off) orally or placebo for 12 months (in a similar routine). The primary endpoint is the change in arterial calcification as quantified by CT-scan. Secondary endpoints are the number of amputations above and below the ankle, mortality, number of vascular interventions and quality of life. DISCUSSION: Up to now, the inert end stage of vascular disease in patients with CLTI, has been considered calcification of vessel walls. We believe there is reason to reverse causation and hypothesize that calcification causes vascular disease. This reversal can be proven in a clinical trial if halting the calcification process improves the outcome of the patient. Therefore we use etidronate, a bisphosphate that has proven to stop the calcification in several rare monogenetic calcifying diseases. We aim to perform this mechanistic proof-of-concept study hopefully leading to a clinical outcome study later on

Histopathological characterization of intimal lesions and arterial wall calcification in the arteries of the leg of elderly cadavers

Introduction: Although arteries of the leg have been studied in extensively diseased amputation specimens, little is known about the composition of vascular lesions present in the general population. The aim of this study was to describe the natural development of adaptive intimal thickening, atherosclerotic lesion development and vascular calcification in the leg of a general elderly population. Materials and Methods: Two hundred and seventy postmortem samples from the popliteal and posterior tibial arteries of 14 elderly cadavers were studied histologically. Results: Atherosclerotic lesions were more frequently observed in the popliteal (60%) than in the posterior tibial artery (34%; p <.0005). These atherosclerotic plaques were most often nonatheromatous (80% and 83% for popliteal and posterior tibial plaques, respectively). The atheroma's that were present were small (most <25% of plaque area). Atherosclerotic plaque calcification was observed more often in the popliteal (39%) than in the posterior tibial samples (17%; p <.0005). Medial arterial calcification was observed more often in the posterior tibial (62%) than in the popliteal samples (46%; p =.008). Plaque calcification and medial arterial calcification were not associated with lumen stenosis. Conclusions: In the leg of elderly cadavers, the presence of atherosclerotic plaque and intimal calcification decreases from the proximal popliteal artery to the more distal posterior tibial artery and most atherosclerotic lesions are of the fibrous nonatheromatous type. In contrast, the presence and severity of medial calcification increases from proximal to distal

A magnetization and 11^{11}B NMR study of Mg1−x_{1-x}Alx_xB2_2 superconductors

We demonstrate for the first time the magnetic field distribution of the pure vortex state in lightly doped Mg$_{1-x}$Al$_x$B$_2$ ($x\leq 0.025$) powder samples, by using $^{11}$B NMR in magnetic fields of 23.5 and 47 kOe. The magnetic field distribution at T=5 K is Al-doping dependent, revealing a considerable decrease of anisotropy in respect to pure MgB$_2$. This result correlates nicely with magnetization measurements and is consistent with $\sigma$-band hole driven superconductivity for MgB$_2$

Genome-wide binding of the CRISPR endonuclease Cas9 in mammalian cells

Bacterial type II CRISPR-Cas9 systems have been widely adapted for RNA-guided genome editing and transcription regulation in eukaryotic cells, yet their in vivo target specificity is poorly understood. Here we mapped genome-wide binding sites of a catalytically inactive Cas9 (dCas9) from Streptococcus pyogenes loaded with single guide RNAs (sgRNAs) in mouse embryonic stem cells (mESCs). Each of the four sgRNAs we tested targets dCas9 to between tens and thousands of genomic sites, frequently characterized by a 5-nucleotide seed region in the sgRNA and an NGG protospacer adjacent motif (PAM). Chromatin inaccessibility decreases dCas9 binding to other sites with matching seed sequences; thus 70% of off-target sites are associated with genes. Targeted sequencing of 295 dCas9 binding sites in mESCs transfected with catalytically active Cas9 identified only one site mutated above background levels. We propose a two-state model for Cas9 binding and cleavage, in which a seed match triggers binding but extensive pairing with target DNA is required for cleavage.National Institutes of Health (U.S.) (Grant RO1-GM34277)National Institutes of Health (U.S.) (Grant R01-CA133404)National Cancer Institute (U.S.) (Grant PO1-CA42063)National Cancer Institute (U.S.) (Cancer Center Support (Core) Grant P30-CA14051)National Institutes of Health (U.S.) (Director's Pioneer Award 1DP1-MH100706)Damon Runyon Cancer Research FoundationKinship Foundation. Searle Scholars ProgramSimons Foundatio