The future of European Nephrology 'Guidelines' - a declaration of intent by European Renal Best Practice (ERBP)

The disparities of medical practice, together with a growing number of possible interventions, have increased the demand for well-conceived guidance for practitioners [1]. However, this development is hampered by the number and quality of scientific studies that test medical hypotheses, which are often unsatisfactory. This is especially true in nephrology, where well-conducted controlled trials are rare [2]. Because patients with renal failure are generally excluded from controlled studies in the general population [3], the development of sufficiently well-founded guidance in nephrology has always been difficult. With the development of European Best Practice Guidelines (EBPG), the European Renal Association–European Dialysis and Transplantation Association (ERA–EDTA) has created its own guidance-generating process. Similar initiatives have also arisen in the USA (Kidney Disease Outcome Initiative—K/DOQI), Australia (Caring for Australasians with Renal Impairment—CARI), Canada (Canadian Society of Nephrology—CSN), the UK (United Kingdom Renal Association—UKRA), as well as at several other locations around the world. These institutions have generated a plethora of often parallel recommendations on similar topics but sometimes with different messages [4]. The question can be asked: ‘Is there still a place for an institution generating European nephrology guidance?’ If there is, how should such an initiative be managed to conform with current demands? To answer these questions, the Council of ERA–EDTA set up a commission that convened three times in the course of 2008–09. The present text is a distillation of the discussions, reflections and final conclusions of this commission. It is an ad hoc document, reflecting the current status. In the future, concepts and attitudes might change, as medical thinking is influenced by changes in practice, needs, general philosophy, ethics and political/financial conditions

Empirical bayes analysis of sequencing-based transcriptional profiling without replicates

Background: Recent technological advancements have made high throughput sequencing an increasingly popular approach for transcriptome analysis. Advantages of sequencing-based transcriptional profiling over microarrays have been reported, including lower technical variability. However, advances in technology do not remove biological variation between replicates and this variation is often neglected in many analyses. Results: We propose an empirical Bayes method, titled Analysis of Sequence Counts (ASC), to detect differential expression based on sequencing technology. ASC borrows information across sequences to establish prior distribution of sample variation, so that biological variation can be accounted for even when replicates are not available. Compared to current approaches that simply tests for equality of proportions in two samples, ASC is less biased towards highly expressed sequences and can identify more genes with a greater log fold change at lower overall abundance. Conclusions: ASC unifies the biological and statistical significance of differential expression by estimating the posterior mean of log fold change and estimating false discovery rates based on the posterior mean. The implementation in R is available at http://www.stat.brown.edu/Zwu/research.aspx

Contrasting patterns of population structure and gene flow facilitate exploration of connectivity in two widely distributed temperate octocorals

This is the final version of the article. Available from Springer Nature via the DOI in this record.Connectivity is an important component of metapopulation dynamics in marine systems and can influence population persistence, migration rates and conservation decisions associated with Marine Protected Areas (MPAs). In this study, we compared the genetic diversity, gene flow and population structure of two octocoral species, Eunicella verrucosa and Alcyonium digitatum, in the northeast Atlantic (ranging from the northwest of Ireland and the southern North Sea, to southern Portugal), using two panels of thirteen and eight microsatellite loci, respectively. Our results identified regional genetic structure in E. verrucosa partitioned between populations from southern Portugal, northwest Ireland, and Britain/France; subsequent hierarchical analysis of population structure also indicated reduced gene flow between southwest Britain and northwest France. However, over a similar geographical area, A. digitatum showed little evidence of population structure, suggesting high gene flow and/or a large effective population size; indeed, the only significant genetic differentiation detected in A. digitatum occurred between North Sea samples and those from the English Channel/northeast Atlantic. In both species the vast majority of gene flow originated from sample sites within regions, with populations in southwest Britain being the predominant source of contemporary exogenous genetic variants for the populations studied. Unsurprisingly, historical patterns of gene flow appeared more complex, though again southwest Britain appeared an important source of genetic variation for both species. Our findings have major conservation implications, particularly for E. verrucosa, a protected species in UK waters and listed by the IUCN as ‘Vulnerable’, and for the designation and management of European MPAs.We thank Natural England (project No. RP0286, contract No. SAE 03-02-146), the NERC (grant No. NE/L002434/1) and the University of Exeter for funding this research. Additional funding for sample collection, travel and microsatellite development was provided by the EU Framework 7 ASSEMBLE programme, agreement no. 227799, and NERC grant No. NBAF-362

A New Interface for Conceptual Design Based on Object Reconstruction from a Single Freehand Sketch

are troublesome for curvature-based classification, and (b) it has a short execution time that is not dependent on the length of the stroke or the number of sample points acquired (assuming coordinates have been summed while drawing the stroke). The procedure can therefore be used to provide continuous feedback of the interpreted entity during drawing, in real time. However, in spite of this ability, it is evident that geometrical-based classification is inherently limited and a more general, context-sensitive approach must be pursued. A new endpoint clustering scheme has also been presented based on adaptive tolerances at different parts of the sketch. The proposed formulation provides a framework for implementing various criteria for determining local thresholds, such as detail sensitive criteria, dynamic criteria, or other application specific criteria. Again, clustering can be improved using a contextsensitive approach. Acknowledgments This research has been supported in part by the Fund for 4 Pavlidis, T., and Van Wyk, C. J., 1985, "An Automatic Beautifler for Drawings and Illustrations," SIGGRAPH 85, Vol. 19, No. 3, pp. 225-234. 5 Bengi, F., and Ozguc, B., 1990, "Architectural Sketch Recognition," Architectural Science Review, Vol. 33, pp. 3-16. 6 Eggli, L., BrUderlin, B. P., and Elber, G. Introduction Improperly designed engineering products may fail in fatigue causing losses in revenue and personal injury or death. Currently, these failures are avoided by either using expensive design techniques involving extensive modeling and testing or by over designing the part. The expense of testing and modification of the initial design is reduced if the design criterion gives a good initial approximation. Several design approaches have been developed to address the problem of fatigue damage of ductile metals loaded with positive mean and alternating stresses. The Bagci, Gerber, Nichihara, modified Goodman, Quadratic, and Soderberg lines are a few of the techniques that have been proposed to address the problem. This paper presents the modified Findley line for designing parts which experience positive mean stress fatigue loading. The modified Findley line is based on the assumption that the critical shear decreases with an increase in the normal stress acting on the same plane, and is simple and less conservative than the modified Goodman line. The Modified Findley Line Flavenot and Skalli (1984) stated "the mechanism corresponding to the initiation of fatigue cracks is most often the shearing of crystallographic planes. It appears logical then to have a criterion relating the normal stress to alternating shear stress which might be local shear stress in most favorable oriented plane." This assumption was used before by Stanfield (1935), who suggested that both the shear and normal stresses on the fatigue plane should be considered in a fatigue failure criterion and proposed the relation (1) where TN and ON are the shear and normal stresses components on the critical plane; /and k are materials constants. Stulen and Cummings (1954), and Findley et al. (195 6) used similar forms as fatigue criteria to address the problem of absolutely reversing fatigue. Findley (1959) used the linear relationship between shear stress and normal stress on a critical plane to include the effect of mean stress on the fatigue of metals under combined loading. Journal of Mechanical Design MARCH 1997, Vol. 119/135 Copyright © 1997 by ASME where a^^" and <7" are the maximum and alternating fatigue stresses; / and k are experimental constants. Since these constants may vary with the design parameters, including materials, the actual design must be tested to determine the values of / and k. To experimentally find the values of these constants, the life of the part is determined, and at this point the values of / and k are of only academic interest. Thus, if the fatigue criterion presented in Eq. It should be noted that the negative root of Eq. Upon the application of condition (b), Eq. (4) becomes /=A:5",. Equations Substituting Eqs. 5" -[-S" + 4SI + 4(5", -5")(S", -a") ], (10) 2(5",-5") which is called the modified Findley line. Comparison With Actual Experimental Data The modified Findley, Gerber, and modified Goodman lines were compared with the experimentally developed fatigue data found in the literature. Typical data showing the fatigue points of both ferrous and non-ferrous ductile materials are shown in As shown in these figures and comparison done by Wang (1995), the modified Findley line falls between the modified Goodman line and Gerber parabola, which is supported by Conclusion The modified Findley line is based on the assumption that the critical shear decreases with an increase in the normal stress acting on the same plane, then by using ultimate strength and endurance limit as parameters to obtain a good initial approximation. Limited fatigue data is available in the open literature, and more comparison should be made before the modified Findley line is universally adopted. However, form the references found, it appears that the modified Findley line is a strong candidate for .fatigue criterion for parts made of non-ferrous ductile materials, and is conservative for ferrous parts. For a design engineer, the modified Findley line is simple and easy to use, and represents a very promising approach for leading to reasonable starting designs involving positive mean stress fatigue. Reference

Pathway-Based Analysis of a Melanoma Genome-Wide Association Study: Analysis of Genes Related to Tumour-Immunosuppression

Systemic immunosuppression is a risk factor for melanoma, and sunburn-induced immunosuppression is thought to be causal. Genes in immunosuppression pathways are therefore candidate melanoma-susceptibility genes. If variants within these genes individually have a small effect on disease risk, the association may be undetected in genome-wide association (GWA) studies due to low power to reach a high significance level. Pathway-based approaches have been suggested as a method of incorporating a priori knowledge into the analysis of GWA studies. In this study, the association of 1113 single nucleotide polymorphisms (SNPs) in 43 genes (39 genomic regions) related to immunosuppression have been analysed using a gene-set approach in 1539 melanoma cases and 3917 controls from the GenoMEL consortium GWA study. The association between melanoma susceptibility and the whole set of tumour-immunosuppression genes, and also predefined functional subgroups of genes, was considered. The analysis was based on a measure formed by summing the evidence from the most significant SNP in each gene, and significance was evaluated empirically by case-control label permutation. An association was found between melanoma and the complete set of genes (pemp = 0.002), as well as the subgroups related to the generation of tolerogenic dendritic cells (pemp = 0.006) and secretion of suppressive factors (pemp = 0.0004), thus providing preliminary evidence of involvement of tumour-immunosuppression gene polymorphisms in melanoma susceptibility. The analysis was repeated on a second phase of the GenoMEL study, which showed no evidence of an association. As one of the first attempts to replicate a pathway-level association, our results suggest that low power and heterogeneity may present challenges

Search for Cosmic-ray Boosted Sub-GeV Dark Matter using Recoil Protons at Super-Kamiokande

We report a search for cosmic-ray boosted dark matter with protons using the 0.37 megaton$\times$years data collected at Super-Kamiokande experiment during the 1996-2018 period (SKI-IV phase). We searched for an excess of proton recoils above the atmospheric neutrino background from the vicinity of the Galactic Center. No such excess is observed, and limits are calculated for two reference models of dark matter with either a constant interaction cross-section or through a scalar mediator. This is the first experimental search for boosted dark matter with hadrons using directional information. The results present the most stringent limits on cosmic-ray boosted dark matter and exclude the dark matter-nucleon elastic scattering cross-section between $10^{-33}\text{ cm}^{-2}$ and $10^{-27}\text{ cm}^{-2}$ for dark matter mass from 10 MeV/$c^2$ to 1 GeV/$c^2$.Comment: With 1-page appendi

Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148

Genome wide association studies (GWAS) have mapped multiple independent cancer susceptibility loci to chr5p15.33. Here, we show that fine-mapping of pancreatic and testicular cancer GWAS within one of these loci (Region 2 in CLPTM1L) focuses the signal to nine highly correlated SNPs. Of these, rs36115365-C associated with increased pancreatic and testicular but decreased lung cancer and melanoma risk, and exhibited preferred protein-binding and enhanced regulatory activity. Transcriptional gene silencing of this regulatory element repressed TERT expression in an allele-specific manner. Proteomic analysis identifies allele-preferred binding of Zinc finger protein 148 (ZNF148) to rs36115365-C, further supported by binding of purified recombinant ZNF148. Knockdown of ZNF148 results in reduced TERT expression, telomerase activity and telomere length. Our results indicate that the association with chr5p15.33-Region 2 may be explained by rs36115365, a variant influencing TERT expression via ZNF148 in a manner consistent with elevated TERT in carriers of the C allele

Search for astrophysical electron antineutrinos in Super-Kamiokande with 0.01wt% gadolinium-loaded water

We report the first search result for the flux of astrophysical electron antineutrinos for energies O(10) MeV in the gadolinium-loaded Super-Kamiokande (SK) detector. In June 2020, gadolinium was introduced to the ultra-pure water of the SK detector in order to detect neutrons more efficiently. In this new experimental phase, SK-Gd, we can search for electron antineutrinos via inverse beta decay with efficient background rejection and higher signal efficiency thanks to the high efficiency of the neutron tagging technique. In this paper, we report the result for the initial stage of SK-Gd with a $22.5\times552$ $\rm kton\cdot day$ exposure at 0.01% Gd mass concentration. No significant excess over the expected background in the observed events is found for the neutrino energies below 31.3 MeV. Thus, the flux upper limits are placed at the 90% confidence level. The limits and sensitivities are already comparable with the previous SK result with pure-water ($22.5 \times 2970 \rm kton\cdot day$) owing to the enhanced neutron tagging