Hubble flow variance and the cosmic rest frame

We characterize the radial and angular variance of the Hubble flow in the COMPOSITE sample of 4534 galaxies, on scales in which much of the flow is in the nonlinear regime. With no cosmological assumptions other than the existence of a suitably averaged linear Hubble law, we find with decisive Bayesian evidence (ln B >> 5) that the Hubble constant averaged in independent spherical radial shells is closer to its asymptotic value when referred to the rest frame of the Local Group, rather than the standard rest frame of the Cosmic Microwave Background. An exception occurs for radial shells in the range 40/h-60/h Mpc. Angular averages reveal a dipole structure in the Hubble flow, whose amplitude changes markedly over the range 32/h-62/h Mpc. Whereas the LG frame dipole is initially constant and then decreases significantly, the CMB frame dipole initially decreases but then increases. The map of angular Hubble flow variation in the LG rest frame is found to coincide with that of the residual CMB temperature dipole, with correlation coefficient -0.92. These results are difficult to reconcile with the standard kinematic interpretation of the motion of the Local Group in response to the clustering dipole, but are consistent with a foreground non-kinematic anisotropy in the distance-redshift relation of 0.5% on scales up to 65/h Mpc. Effectively, the differential expansion of space produced by nearby nonlinear structures of local voids and denser walls and filaments cannot be reduced to a local boost. This hypothesis suggests a reinterpretation of bulk flows, which may potentially impact on calibration of supernovae distances, anomalies associated with large angles in the CMB anisotropy spectrum, and the dark flow inferred from the kinematic Sunyaev-Zel'dovich effect. It is consistent with recent studies that find evidence for a non-kinematic dipole in the distribution of distant radio sources.Comment: 37 pages, 9 tables, 13 figures; v2 adds extensive new analysis (including additional subsections, tables, figures); v3 adds a Monte Carlo analysis (with additional table, figure) which further tightens the statistical robustness of the dipole results; v4 adds further clarifications, small corrections, references and discussion of Planck satellite results; v5 typos fixed, matches published versio

Dark energy as a mirage

Motivated by the observed cosmic matter distribution, we present the following conjecture: due to the formation of voids and opaque structures, the average matter density on the path of the light from the well-observed objects changes from Omega_M ~ 1 in the homogeneous early universe to Omega_M ~ 0 in the clumpy late universe, so that the average expansion rate increases along our line of sight from EdS expansion Ht ~ 2/3 at high redshifts to free expansion Ht ~ 1 at low redshifts. To calculate the modified observable distance-redshift relations, we introduce a generalized Dyer-Roeder method that allows for two crucial physical properties of the universe: inhomogeneities in the expansion rate and the growth of the nonlinear structures. By treating the transition redshift to the void-dominated era as a free parameter, we find a phenomenological fit to the observations from the CMB anisotropy, the position of the baryon oscillation peak, the magnitude-redshift relations of type Ia supernovae, the local Hubble flow and the nucleosynthesis, resulting in a concordant model of the universe with 90% dark matter, 10% baryons, no dark energy, 15 Gyr as the age of the universe and a natural value for the transition redshift z_0=0.35. Unlike a large local void, the model respects the cosmological principle, further offering an explanation for the late onset of the perceived acceleration as a consequence of the forming nonlinear structures. Additional tests, such as quantitative predictions for angular deviations due to an anisotropic void distribution and a theoretical derivation of the model, can vindicate or falsify the interpretation that light propagation in voids is responsible for the perceived acceleration.Comment: 33 pages, 2 figs; v2: minor clarifications, results unchanged; v3: matches the version published in General Relativity and Gravitatio

Arthroscopic partial meniscectomy versus placebo surgery for a degenerative meniscus tear : a 2-year follow-up of the randomised controlled trial

Objective To assess if arthroscopic partial meniscectomy (APM) is superior to placebo surgery in the treatment of patients with degenerative tear of the medial meniscus. Methods In this multicentre, randomised, participant-blinded and outcome assessor-blinded, placebo-surgery controlled trial, 146 adults, aged 35-65 years, with knee symptoms consistent with degenerative medial meniscus tear and no knee osteoarthritis were randomised to APM or placebo surgery. The primary outcome was the between-group difference in the change from baseline in the Western Ontario Meniscal Evaluation Tool (WOMET) and Lysholm knee scores and knee pain after exercise at 24 months after surgery. Secondary outcomes included the frequency of unblinding of the treatment-group allocation, participants' satisfaction, impression of change, return to normal activities, the incidence of serious adverse events and the presence of meniscal symptoms in clinical examination. Two subgroup analyses, assessing the outcome on those with mechanical symptoms and those with unstable meniscus tears, were also carried out. Results In the intention-to-treat analysis, there were no significant between-group differences in the mean changes from baseline to 24 months in WOMET score: 27.3 in the APM group as compared with 31.6 in the placebo-surgery group (between-group difference, -4.3; 95% CI, -11.3 to 2.6); Lysholm knee score: 23.1 and 26.3, respectively (-3.2; -8.9 to 2.4) or knee pain after exercise, 3.5 and 3.9, respectively (-0.4; -1.3 to 0.5). There were no statistically significant differences between the two groups in any of the secondary outcomes or within the analysed subgroups. Conclusions In this 2-year follow-up of patients without knee osteoarthritis but with symptoms of a degenerative medial meniscus tear, the outcomes after APM were no better than those after placebo surgery. No evidence could be found to support the prevailing ideas that patients with presence of mechanical symptoms or certain meniscus tear characteristics or those who have failed initial conservative treatment are more likely to benefit from APM.Peer reviewe

Panama and the WTO : new constitutionalism of trade policy and global tax governance

"Corrigendum" in Review of International Political Economy, 24(4), p. 738 (DOI: 10.1080/09692290.2017.1332547).Tax havens and tax flight have lately received increasing attention, while interest toward multilateral trade policies has somewhat diminished. We argue that more attention needs to be paid exactly to the interrelations between trade and tax policies. Drawing from two case studies on Panama's trade disputes, we show how World Trade Organization (WTO) rules can be used both to resist attempts to sanction secrecy structures and to promote measures against tax flight. The theory of new constitutionalism can help to explain how trade treaties can 'lock in' tax policies. However, our case studies show that trade policy not only 'locks in' democratic policy-making, but also enables tax havens to use their commercialized sovereignty to resists anti-secrecy measures. What is being 'locked in' are the policy tools, not necessarily the policies. The changing relationship between trade and tax policies can also create new and unexpected tools for tackling tax evasion, underlining the importance of epistemic arbitrage in the context of new constitutionalism. In principle, political actors with sufficient technical and juridical knowledge can shape global tax governance to various directions regardless of their formal position in the world political hierarchies. This should be taken into account when trade treaties are being negotiated or revised.Peer reviewe

Exome-wide somatic mutation characterization of small bowel adenocarcinoma

Small bowel adenocarcinoma (SBA) is an aggressive disease with limited treatment options. Despite previous studies, its molecular genetic background has remained somewhat elusive. To comprehensively characterize the mutational landscape of this tumor type, and to identify possible targets of treatment, we conducted the first large exome sequencing study on a population-based set of SBA samples from all three small bowel segments. Archival tissue from 106 primary tumors with appropriate clinical information were available for exome sequencing from a patient series consisting of a majority of confirmed SBA cases diagnosed in Finland between the years 2003-2011. Paired-end exome sequencing was performed using Illumina HiSeq 4000, and OncodriveFML was used to identify driver genes from the exome data. We also defined frequently affected cancer signalling pathways and performed the first extensive allelic imbalance (Al) analysis in SBA. Exome data analysis revealed significantly mutated genes previously linked to SBA (TP53, KRAS, APC, SMAD4, and BRAF), recently reported potential driver genes (SOX9, ATM, and ARID2), as well as novel candidate driver genes, such as ACVR2A, ACVR1B, BRCA2, and SMARCA4. We also identified clear mutation hotspot patterns in ERBB2 and BRAF. No BRAF V600E mutations were observed. Additionally, we present a comprehensive mutation signature analysis of SBA, highlighting established signatures 1A, 6, and 17, as well as U2 which is a previously unvalidated signature. Finally, comparison of the three small bowel segments revealed differences in tumor characteristics. This comprehensive work unveils the mutational landscape and most frequently affected genes and pathways in SBA, providing potential therapeutic targets, and novel and more thorough insights into the genetic background of this tumor type.Peer reviewe

Does antibacterial treatment for urinary tract infection contribute to the risk of breast cancer?

Low lignan status has been reported to be related to an elevated risk of breast cancer. Since lignan status is reduced by antibacterial medications, it is plausible to hypothesize that repeated use of antibiotics may also be a risk factor for breast cancer. History of treatment for urinary tract infection was studied for its prediction of breast cancer among 9461 Finnish women 19–89 years of age and initially cancer-free. During a follow-up in 1973–1991, a total of 157 breast cancer cases were diagnosed. Women reporting previous or present medication for urinary tract infection at baseline showed an elevated breast cancer risk in comparison with other women. The age-adjusted relative risk was 1.34 (95% confidence interval (CI) = 0.98–1.83). The association was concentrated to women under 50 years of age. The relative risk for these women was 1.74 (95% CI 1.13–2.68), whereas it was 0.97 (95% CI 0.59–1.58) for older women. The relative risk in the younger age-group was 1.47 (95% CI 0.73–2.97) during the first 10 years of follow-up, and 1.93 (95% CI 1.11–3.37) for follow-up times longer than 10 years. These data suggest that premenopausal women using long-term medication for urinary tract infections show a possible elevated risk of future breast cancer. The results are, however, still inconclusive and the hypothesis needs to be tested by other studies. © 2000 Cancer ResearchCampaig

Skeletal muscle proteomes reveal downregulation of mitochondrial proteins in transition from prediabetes into type 2 diabetes

Skeletal muscle insulin resistance is a central defect in the pathogenesis of type 2 diabetes (T2D). Here, we analyzed skeletal muscle proteome in 148 vastus lateralis muscle biopsies obtained from men covering all glucose tolerance phenotypes: normal, impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and T2D. Skeletal muscle proteome was analyzed by a sequential window acquisition of all theoretical mass spectra (SWATH-MS) proteomics technique. Our data indicate a downregulation in several proteins involved inmitochondrial electron transport or respiratory chain complex assembly already in IFG and IGT-muscles, with most profound decreases observed in T2D. Additional phosphoproteomic analysis reveals altered phosphorylation in several signaling pathways in IFG, IGT, and T2D muscles, including those regulating glucose metabolic processes, and the structure of muscle cells. These data reveal several alterations present in skeletalmuscle already in prediabetes and highlight impairedmitochondrial energy metabolism in the trajectory from prediabetes into T2D.Peer reviewe

Azulene-based compounds for targeting orexin receptors

A library of 70 000 synthetically accessible azulene-based compounds was virtually screened at the OX2 receptor. Based on the results, a series of azulene derivatives was synthesized and the binding to and activation of both orexin receptor subtypes were assessed. Two most promising binders were determined to have inhibition constants in the 3-9 mu M range and two other compounds showed weak OX2 receptor agonism. Furthermore, three compounds exhibited a concentration-dependent potentiation of the response to orexin-A at the OX1 but not the OX2 receptors. Altogether this data opens new approaches for further development of antagonists, agonists, and potentiators of orexin response based on the azulene scaffold. (C) 2018 Elsevier Masson SAS. All rights reserved.Peer reviewe