Interfacial Tensions near Critical Endpoints: Experimental Checks of EdGF Theory

Predictions of the extended de Gennes-Fisher local-functional theory for the universal scaling functions of interfacial tensions near critical endpoints are compared with experimental data. Various observations of the binary mixture isobutyric acid $+$ water are correlated to facilitate an analysis of the experiments of Nagarajan, Webb and Widom who observed the vapor-liquid interfacial tension as a function of {\it both} temperature and density. Antonow's rule is confirmed and, with the aid of previously studied {\it universal amplitude ratios}, the crucial analytic ``background'' contribution to the surface tension near the endpoint is estimated. The residual singular behavior thus uncovered is consistent with the theoretical scaling predictions and confirms the expected lack of symmetry in $(T-T_c)$. A searching test of theory, however, demands more precise and extensive experiments; furthermore, the analysis highlights, a previously noted but surprising, three-fold discrepancy in the magnitude of the surface tension of isobutyric acid $+$ water relative to other systems.Comment: 6 figure

Fluctuation theorem for currents and Schnakenberg network theory

A fluctuation theorem is proved for the macroscopic currents of a system in a nonequilibrium steady state, by using Schnakenberg network theory. The theorem can be applied, in particular, in reaction systems where the affinities or thermodynamic forces are defined globally in terms of the cycles of the graph associated with the stochastic process describing the time evolution.Comment: new version : 16 pages, 1 figure, to be published in Journal of Statistical Physic

Microscopic View on Short-Range Wetting at the Free Surface of the Binary Metallic Liquid Gallium-Bismuth: An X-ray Reflectivity and Square Gradient Theory Study

We present an x-ray reflectivity study of wetting at the free surface of the binary liquid metal gallium-bismuth (Ga-Bi) in the region where the bulk phase separates into Bi-rich and Ga-rich liquid phases. The measurements reveal the evolution of the microscopic structure of wetting films of the Bi-rich, low-surface-tension phase along different paths in the bulk phase diagram. A balance between the surface potential preferring the Bi-rich phase and the gravitational potential which favors the Ga-rich phase at the surface pins the interface of the two demixed liquid metallic phases close to the free surface. This enables us to resolve it on an Angstrom level and to apply a mean-field, square gradient model extended by thermally activated capillary waves as dominant thermal fluctuations. The sole free parameter of the gradient model, i.e. the so-called influence parameter, $\kappa$, is determined from our measurements. Relying on a calculation of the liquid/liquid interfacial tension that makes it possible to distinguish between intrinsic and capillary wave contributions to the interfacial structure we estimate that fluctuations affect the observed short-range, complete wetting phenomena only marginally. A critical wetting transition that should be sensitive to thermal fluctuations seems to be absent in this binary metallic alloy.Comment: RevTex4, twocolumn, 15 pages, 10 figure

Circulating adrenomedullin estimates survival and reversibility of organ failure in sepsis: the prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock-1 (AdrenOSS-1) study

Background: Adrenomedullin (ADM) regulates vascular tone and endothelial permeability during sepsis. Levels of circulating biologically active ADM (bio-ADM) show an inverse relationship with blood pressure and a direct relationship with vasopressor requirement. In the present prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock 1 (, AdrenOSS-1) study, we assessed relationships between circulating bio-ADM during the initial intensive care unit (ICU) stay and short-term outcome in order to eventually design a biomarker-guided randomized controlled trial. Methods: AdrenOSS-1 was a prospective observational multinational study. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use, and need for renal replacement therapy. AdrenOSS-1 included 583 patients admitted to the ICU with sepsis or septic shock. Results: Circulating bio-ADM levels were measured upon admission and at day 2. Median bio-ADM concentration upon admission was 80.5 pg/ml [IQR 41.5-148.1 pg/ml]. Initial SOFA score was 7 [IQR 5-10], and 28-day mortality was 22%. We found marked associations between bio-ADM upon admission and 28-day mortality (unadjusted standardized HR 2.3 [CI 1.9-2.9]; adjusted HR 1.6 [CI 1.1-2.5]) and between bio-ADM levels and SOFA score (p < 0.0001). Need of vasopressor/inotrope, renal replacement therapy, and positive fluid balance were more prevalent in patients with a bio-ADM > 70 pg/ml upon admission than in those with bio-ADM ≤ 70 pg/ml. In patients with bio-ADM > 70 pg/ml upon admission, decrease in bio-ADM below 70 pg/ml at day 2 was associated with recovery of organ function at day 7 and better 28-day outcome (9.5% mortality). By contrast, persistently elevated bio-ADM at day 2 was associated with prolonged organ dysfunction and high 28-day mortality (38.1% mortality, HR 4.9, 95% CI 2.5-9.8). Conclusions: AdrenOSS-1 shows that early levels and rapid changes in bio-ADM estimate short-term outcome in sepsis and septic shock. These data are the backbone of the design of the biomarker-guided AdrenOSS-2 trial. Trial registration: ClinicalTrials.gov, NCT02393781. Registered on March 19, 2015

Fertility, gonadal and sexual function in survivors of testicular cancer

Modern treatments cure most testicular cancer patients, so an important goal is to minimise toxicity. Fertility and sexual functioning are key issues for patients. We have evaluated these outcomes in a cross-sectional study of long-term survivors of testicular cancer. In total, 680 patients treated between 1982 and 1992 completed the EORTC Qly-C-30(qc30) questionnaire, the associated testicular cancer specific module and a general health and fertility questionnaire. Patients have been subdivided according to treatment received: orchidectomy either alone (surveillance, S n=169), with chemotherapy (C, n=272), radiotherapy (R, n=158), or both chemotherapy and radiotherapy (C/RT n=81). In the surveillance group, 6% of patients had an elevated LH, 41% an elevated FSH and 11% a low (<10 nmol l−1) testosterone. Hormonal function deteriorated with additional treatment, but the effect in general was small. Low testosterone was more common in the C/RT group (37% P=0.006), FSH abnormalities were more common after chemotherapy (C 49%, C/RT 71% both P<0.005) and LH abnormalities after radiotherapy (11% P<0.01) and chemotherapy (10%, P<0.001). Baseline hormone data were available for 367 patients. After treatment, compared to baseline, patients receiving chemotherapy had significantly greater elevations of FSH (median rise of 6 (IQR 3–9.25) iu l−1 compared to 3 (IQR 1–5) iu l−1 for S; P<0.001) and a fall (compared to a rise in the surveillance group) in median testosterone levels (−2 (IQR −8.0 to −1.5) vs 1.0. (IQR −4.0–4.0) P<0.001). Patients with low testosterone (but not elevated FSH) had lower quality of life scores related to sexual functioning on the testicular cancer specific module and lower physical, social and role functioning on the EORTC Qly C-30. Patients with a low testosterone also had higher body mass index and blood pressure. Treatment was associated with reduction in sexual activity and patients receiving chemotherapy had more concerns about fathering children. In total, 207 (30%) patients reported attempting conception of whom 159 (77%) were successful and a further 10 patients were successful after infertility treatment with an overall success rate of 82%. There was a lower overall success rate after chemotherapy (C 71%; CRT 67% compared to S 85% (P=0.028)). Elevated FSH levels were associated with reduced fertility (normal FSH 91% vs elevated 68% P<0.001). In summary, gonadal dysfunction is common in patients with a history of testicular cancer even when managed by orchidectomy alone. Treatment with chemotherapy in particular can result in additional impairment. Gonadal dysfunction reduces quality of life and has an adverse effect on patient health. Most patients retain their fertility, but the risk of infertility is likely to be increased by chemotherapy. Screening for gonadal dysfunction should be considered in the follow-up of testicular cancer survivors

Evidence for PTGER4, PSCA, and MBOAT7 as risk genes for gastric cancer on the genome and transcriptome level

Genetic associations between variants on chromosome 5p13 and 8q24 and gastric cancer (GC) have been previously reported in the Asian population. We aimed to replicate these findings and to characterize the associations at the genome and transcriptome level. We performed a fine-mapping association study in 1926 GC patients and 2012 controls of European descent using high dense SNP marker sets on both chromosomal regions. Next, we performed expression quantitative trait locus (eQTL) analyses using gastric transcriptome data from 143 individuals focusing on the GC associated variants. On chromosome 5p13 the strongest association was observed at rs6872282 (P = 2.53 × 10-04) and on chromosome 8q24 at rs2585176 (P = 1.09 × 10-09). On chromosome 5p13 we found cis-eQTL effects with an upregulation of PTGER4 expression in GC risk allele carrier (P = 9.27 × 10-11). On chromosome 8q24 we observed cis-eQTL effects with an upregulation of PSCA expression in GC risk allele carrier (P = 2.17 × 10-47). In addition, we found trans-eQTL effects for the same variants on 8q24 with a downregulation of MBOAT7 expression in GC risk allele carrier (P = 3.11 × 10-09). In summary, we confirmed and refined the previously reported GC associations at both chromosomal regions. Our data point to shared etiological factors between Asians and Europeans. Furthermore, our data imply an upregulated expression of PTGER4 and PSCA as well as a downregulated expression of MBOAT7 in gastric tissue as risk-conferring GC pathomechanisms

Germline variation in the insulin-like growth factor pathway and risk of Barrett's esophagus and esophageal adenocarcinoma

Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett’s esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q < 0.1 when assessed using data from the largest available BE/EAC GWAS meta-analysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE

No Association Between Vitamin D Status and Risk of Barrett's Esophagus or Esophageal Adenocarcinoma: A Mendelian Randomization Study.

BACKGROUND & AIMS: Epidemiology studies of circulating concentrations of 25 hydroxy vitamin D (25(OH)D) and risk of esophageal adenocarcinoma (EAC) have produced conflicting results. We conducted a Mendelian randomization study to determine the associations between circulating concentrations of 25(OH)D and risks of EAC and its precursor, Barrett's esophagus (BE). METHODS: We conducted a Mendelian randomization study using a 2-sample (summary data) approach. Six single-nucleotide polymorphisms (SNPs; rs3755967, rs10741657, rs12785878, rs10745742, rs8018720, and rs17216707) associated with circulating concentrations of 25(OH)D were used as instrumental variables. We collected data from 6167 patients with BE, 4112 patients with EAC, and 17,159 individuals without BE or EAC (controls) participating in the Barrett's and Esophageal Adenocarcinoma Consortium, as well as studies from Bonn, Germany, and Cambridge and Oxford, United Kingdom. Analyses were performed separately for BE and EAC. RESULTS: Overall, we found no evidence for an association between genetically estimated 25(OH)D concentration and risk of BE or EAC. The odds ratio per 20 nmol/L increase in genetically estimated 25(OH)D concentration for BE risk estimated by combining the individual SNP association using inverse variance weighting was 1.21 (95% CI, 0.77-1.92; P = .41). The odds ratio for EAC risk, estimated by combining the individual SNP association using inverse variance weighting, was 0.68 (95% CI, 0.39-1.19; P = .18). CONCLUSIONS: In a Mendelian randomization study, we found that low genetically estimated 25(OH)D concentrations were not associated with risk of BE or EAC