Development of a method for determining binaural sensitivity to temporal fine structure.

OBJECTIVE: To develop and evaluate a test of the ability to process binaural temporal-fine-structure (TFS) information. The test was intended to provide a graded measure of TFS sensitivity for all listeners. DESIGN: Sensitivity to TFS was assessed at a sensation level of 30 dB using the established TFS-LF test at centre frequencies of 250, 500 and 750 Hz, and using the new TFS-AF test, in which the interaural phase difference (IPD) was fixed and the frequency was adaptively varied. IPDs varied from 30 to 180°. STUDY SAMPLE: Nine young (19-25 years) and 23 older (47-84 years) listeners with normal hearing over the tested frequency range. RESULTS: For the young listeners, thresholds on the TFS-AF test did not improve significantly with repeated testing. The rank-ordering of performance across listeners was independent of the size of the IPD, and moderate-to-strong correlations were observed between scores for the TFS-LF and TFS-AF tests. Older listeners who were unable to complete the TFS-LF test were all able to complete the TFS-AF test. CONCLUSIONS: No practice effects and strong correlations with an established test of binaural TFS sensitivity make the TFS-AF test a good candidate for the assessment of supra-threshold binaural processing

Association between operator volume and mortality in primary percutaneous coronary intervention

Background There is a paucity of real-world data assessing the association of operator volumes and mortality specific to primary percutaneous coronary intervention (PPCI). Methods Demographic, clinical and outcome data for all patients undergoing PPCI in Leeds General Infirmary, UK, between 1 January 2009 and 31 December 2011, and 1 January 2013 and 31 December 2013, were obtained prospectively. Operator volumes were analysed according to annual operator PPCI volume (low volume: 1–54 PPCI per year; intermediate volume: 55–109 PPCI per year; high volume: ≥110 PPCI per year). Cox proportional hazards regression analyses were undertaken to investigate 30-day and 12-month all-cause mortality, adjusting for confounding factors. Results During this period, 4056 patients underwent PPCI, 3703 (91.3%) of whom were followed up for a minimum of 12 months. PPCI by low-volume operators was associated with significantly higher adjusted 30-day mortality (HR 1.48 (95% CI 1.05 to 2.08); p=0.02) compared with PPCI performed by high-volume operators, with no significant difference in adjusted 12-month mortality (HR 1.26 (95% CI 0.96 to 1.65); p=0.09). Comparisons between low-volume and intermediate-volume operators, and between intermediate and high-volume operators, showed no significant differences in 30-day and 12-month mortality. Conclusions Low operator volume is independently associated with higher probability of 30-day mortality compared with high operator volume, suggesting a volume–outcome relationship in PPCI at a threshold higher than current recommendations

Baryonic Popcorn

In the large N limit cold dense nuclear matter must be in a lattice phase. This applies also to holographic models of hadron physics. In a class of such models, like the generalized Sakai-Sugimoto model, baryons take the form of instantons of the effective flavor gauge theory that resides on probe flavor branes. In this paper we study the phase structure of baryonic crystals by analyzing discrete periodic configurations of such instantons. We find that instanton configurations exhibit a series of "popcorn" transitions upon increasing the density. Through these transitions normal (3D) lattices expand into the transverse dimension, eventually becoming a higher dimensional (4D) multi-layer lattice at large densities. We consider 3D lattices of zero size instantons as well as 1D periodic chains of finite size instantons, which serve as toy models of the full holographic systems. In particular, for the finite-size case we determine solutions of the corresponding ADHM equations for both a straight chain and for a 2D zigzag configuration where instantons pop up into the holographic dimension. At low density the system takes the form of an "abelian anti-ferromagnetic" straight periodic chain. Above a critical density there is a second order phase transition into a zigzag structure. An even higher density yields a rich phase space characterized by the formation of multi-layer zigzag structures. The finite size of the lattices in the transverse dimension is a signal of an emerging Fermi sea of quarks. We thus propose that the popcorn transitions indicate the onset of the "quarkyonic" phase of the cold dense nuclear matter.Comment: v3, 80 pages, 18 figures, footnotes 5 and 7 added, version to appear in the JHE

Association of MC1R Variants and host phenotypes with melanoma risk in CDKN2A mutation carriers: a GenoMEL study

<p><b>Background</b> Carrying the cyclin-dependent kinase inhibitor 2A (CDKN2A) germline mutations is associated with a high risk for melanoma. Penetrance of CDKN2A mutations is modified by pigmentation characteristics, nevus phenotypes, and some variants of the melanocortin-1 receptor gene (MC1R), which is known to have a role in the pigmentation process. However, investigation of the associations of both MC1R variants and host phenotypes with melanoma risk has been limited.</p> <p><b>Methods</b> We included 815 CDKN2A mutation carriers (473 affected, and 342 unaffected, with melanoma) from 186 families from 15 centers in Europe, North America, and Australia who participated in the Melanoma Genetics Consortium. In this family-based study, we assessed the associations of the four most frequent MC1R variants (V60L, V92M, R151C, and R160W) and the number of variants (1, ≥2 variants), alone or jointly with the host phenotypes (hair color, propensity to sunburn, and number of nevi), with melanoma risk in CDKN2A mutation carriers. These associations were estimated and tested using generalized estimating equations. All statistical tests were two-sided.</p> <p><b>Results</b> Carrying any one of the four most frequent MC1R variants (V60L, V92M, R151C, R160W) in CDKN2A mutation carriers was associated with a statistically significantly increased risk for melanoma across all continents (1.24 × 10−6 ≤ P ≤ .0007). A consistent pattern of increase in melanoma risk was also associated with increase in number of MC1R variants. The risk of melanoma associated with at least two MC1R variants was 2.6-fold higher than the risk associated with only one variant (odds ratio = 5.83 [95% confidence interval = 3.60 to 9.46] vs 2.25 [95% confidence interval = 1.44 to 3.52]; Ptrend = 1.86 × 10−8). The joint analysis of MC1R variants and host phenotypes showed statistically significant associations of melanoma risk, together with MC1R variants (.0001 ≤ P ≤ .04), hair color (.006 ≤ P ≤ .06), and number of nevi (6.9 × 10−6 ≤ P ≤ .02).</p> <p><b>Conclusion</b> Results show that MC1R variants, hair color, and number of nevi were jointly associated with melanoma risk in CDKN2A mutation carriers. This joint association may have important consequences for risk assessments in familial settings.</p&gt

Patient-reported outcomes in metastatic castration-resistant prostate cancer

Many novel therapies are available for use in patients with metastatic castration-resistant prostate cancer (mCRPC), some of which convey substantial progression-free survival and overall survival benefits. Delaying disease progression and providing palliation of symptoms are primary therapeutic aims of treating patients with mCRPC; therefore, ensuring that the benefit-to-harm ratios are acceptable to patients, through systematic measurement of patient-reported outcomes (PROs) using validated tools, is vital. In this Perspectives, we appraised the published reports from clinical trials testing treatments of mCRPC over the past 5 years and found that PROs were either not being measured routinely, or if used, were often not reported adequately, thus hampering evaluation of the true effects of many of these treatments on patients' quality of life. Improvements are needed because data collected directly from patients, not just physician-collected safety data and adverse events, are crucial to inform clinical decision-making on treatment options

Symbiodinium Genotypic and Environmental Controls on Lipids in Reef Building Corals

BACKGROUND: Lipids in reef building corals can be divided into two classes; non-polar storage lipids, e.g. wax esters and triglycerides, and polar structural lipids, e.g. phospholipids and cholesterol. Differences among algal endosymbiont types are known to have important influences on processes including growth and the photobiology of scleractinian corals yet very little is known about the role of symbiont types on lipid energy reserves. METHODOLOGY/PRINCIPAL FINDINGS: The ratio of storage lipid and structural lipid fractions of Scott Reef corals were determined by thin layer chromatography. The lipid fraction ratio varied with depth and depended on symbiont type harboured by two corals (Seriatopora hystrix and Pachyseris speciosa). S. hystrix colonies associated with Symbiodinium C1 or C1/C# at deep depths (>23 m) had lower lipid fraction ratios (i.e. approximately equal parts of storage and structural lipids) than those with Symbiodinium D1 in shallow depths (<23 m), which had higher lipid fraction ratios (i.e. approximately double amounts of storage relative to structural lipid). Further, there was a non-linear relationship between the lipid fraction ratio and depth for S. hystrix with a modal peak at ∼23 m coinciding with the same depth as the shift from clade D to C types. In contrast, the proportional relationship between the lipid fraction ratio and depth for P. speciosa, which exhibited high specificity for Symbiodinium C3 like across the depth gradient, was indicative of greater amounts of storage lipids contained in the deep colonies. CONCLUSIONS/SIGNIFICANCE: This study has demonstrated that Symbiodinium exert significant controls over the quality of coral energy reserves over a large-scale depth gradient. We conclude that the competitive advantages and metabolic costs that arise from flexible associations with divergent symbiont types are offset by energetic trade-offs for the coral host

An orphan gene is necessary for preaxial digit formation during salamander limb development

Limb development in salamanders differs from other tetrapods in that the first digits to form are the two most anterior (preaxial dominance). This has been proposed as a salamander novelty and its mechanistic basis is unknown. Salamanders are the only adult tetrapods able to regenerate the limb, and the contribution of preaxial dominance to limb regeneration is unclear. Here we show that during early outgrowth of the limb bud, a small cohort of cells express the orphan gene Prod1 together with Bmp2, a critical player in digit condensation in amniotes. Disruption of Prod1 with a gene-editing nuclease abrogates these cells, and blocks formation of the radius and ulna, and outgrowth of the anterior digits. Preaxial dominance is a notable feature of limb regeneration in the larval newt, but this changes abruptly after metamorphosis so that the formation of anterior and posterior digits occurs together within the autopodium resembling an amniote-like pattern

The contribution of large genomic deletions at the CDKN2A locus to the burden of familial melanoma

Mutations in two genes encoding cell cycle regulatory proteins have been shown to cause familial cutaneous malignant melanoma (CMM). About 20% of melanoma-prone families bear a point mutation in the CDKN2A locus at 9p21, which encodes two unrelated proteins, p16INK4a and p14ARF. Rare mutations in CDK4 have also been linked to the disease. Although the CDKN2A gene has been shown to be the major melanoma predisposing gene, there remains a significant proportion of melanoma kindreds linked to 9p21 in which germline mutations of CDKN2A have not been identified through direct exon sequencing. The purpose of this study was to assess the contribution of large rearrangements in CDKN2A to the disease in melanoma-prone families using multiplex ligation-dependent probe amplification. We examined 214 patients from independent pedigrees with at least two CMM cases. All had been tested for CDKN2A and CDK4 point mutation, and 47 were found positive. Among the remaining 167 negative patients, one carried a novel genomic deletion of CDKN2A exon 2. Overall, genomic deletions represented 2.1% of total mutations in this series (1 of 48), confirming that they explain a very small proportion of CMM susceptibility. In addition, we excluded a new gene on 9p21, KLHL9, as being a major CMM gene