sFlt-1 and NTproBNP independently predict mortality in a cohort of heart failure patients.

Objective: Soluble fms-like tyrosine kinase-1 (sFlt-1) is a circulating receptor for VEGF-A. Recent reports of elevated plasma levels of sFlt-1 in coronary heart disease and heart failure (HF) motivated our study aimed at investigating the utility of sFlt-1 as a prognostic biomarker in heart failure patients. Methods: ELISA assays for sFlt-1 and NTproBNP were performed in n=858 patients from a prospective multicentre, observational study (the PEOPLE study) of outcome among patients after appropriate treatment for an episode of acute decompensated HF in New Zealand. Plasma was sampled at a baseline visit and stored at -80°C. Statistical tests were adjusted for patient age at baseline visit, skewed data were log-adjusted and the endpoint for clinical outcome analysis was all-cause death. Patients were followed for a median of 3.63 (range 0.74-5.50) years. Results: Mean baseline plasma sFlt-1 was 125 +/- 2.01 pg/ml. sFlt-1 was higher in patients with HF with reduced ejection fraction (HFrEF) (130 +/- 2.62 pg/ml, n=553) compared to those with HF with preserved EF (HFpEF) (117 +/-3.59 pg/ml, n=305; p=0.005). sFlt-1 correlated with heart rate (r=0.148, p<0.001), systolic blood pressure (r=-0.139, p<0.001) and LVEF (r=-0.088, p=0.019). A Cox proportional hazards model showed sFlt-1 was a predictor of all-cause death (HR=6.30, p<0.001) in the PEOPLE cohort independent of age, NTproBNP, ischaemic aetiology, and NYHA class (n=842, 274 deaths), established predictors of mortality in the PEOPLE cohort. Conclusion: sFlt-1 levels at baseline should be investigated further as a predictor of death; complementary to established prognostic biomarkers in heart failure

The key role of nitric oxide in hypoxia: hypoxic vasodilation and energy supply-demand matching

Significance: a mismatch between energy supply and demand induces tissue hypoxia with the potential to cause cell death and organ failure. Whenever arterial oxygen concentration is reduced, increases in blood flow - 'hypoxic vasodilation' - occur in an attempt to restore oxygen supply. Nitric oxide is a major signalling and effector molecule mediating the body's response to hypoxia, given its unique characteristics of vasodilation (improving blood flow and oxygen supply) and modulation of energetic metabolism (reducing oxygen consumption and promoting utilization of alternative pathways). Recent advances: this review covers the role of oxygen in metabolism and responses to hypoxia, the hemodynamic and metabolic effects of nitric oxide, and mechanisms underlying the involvement of nitric oxide in hypoxic vasodilation. Recent insights into nitric oxide metabolism will be discussed, including the role for dietary intake of nitrate, endogenous nitrite reductases, and release of nitric oxide from storage pools. The processes through which nitric oxide levels are elevated during hypoxia are presented, namely (i) increased synthesis from nitric oxide synthases, increased reduction of nitrite to nitric oxide by heme- or pterin-based enzymes and increased release from nitric oxide stores, and (ii) reduced deactivation by mitochondrial cytochrome c oxidase. Critical issues: several reviews covered modulation of energetic metabolism by nitric oxide, while here we highlight the crucial role NO plays in achieving cardiocirculatory homeostasis during acute hypoxia through both vasodilation and metabolic suppression Future directions: we identify a key position for nitric oxide in the body's adaptation to an acute energy supply-demand mismatc

Standing genetic variation and compensatory evolution in transgenic organisms: a growth-enhanced salmon simulation

Genetically modified strains usually are generated within defined genetic backgrounds to minimize variation for the engineered characteristic in order to facilitate basic research investigations or for commercial application. However, interactions between transgenes and genetic background have been documented in both model and commercial agricultural species, indicating that allelic variation at transgene-modifying loci are not uncommon in genomes. Engineered organisms that have the potential to allow entry of transgenes into natural populations may cause changes to ecosystems via the interaction of their specific phenotypes with ecosystem components and services. A transgene introgressing through natural populations is likely to encounter a range of natural genetic variation (among individuals or sub-populations) that could result in changes in phenotype, concomitant with effects on fitness and ecosystem consequences that differ from that seen in the progenitor transgenic strain. In the present study, using a growth hormone transgenic salmon example, we have modeled selection of modifier loci (single and multiple) in the presence of a transgene and have found that accounting for genetic background can significantly affect the persistence of transgenes in populations, potentially reducing or reversing a “Trojan gene” effect. Influences from altered life history characteristics (e.g., developmental timing, age of maturation) and compensatory demographic/ecosystem controls (e.g., density dependence) also were found to have a strong influence on transgene effects. Further, with the presence of a transgene in a population, genetic backgrounds were found to shift in non-transgenic individuals as well, an effect expected to direct phenotypes away from naturally selected optima. The present model has revealed the importance of understanding effects of selection for background genetics on the evolution of phenotypes in populations harbouring transgenes

SCUBA divers as oceanographic samplers: The potential of dive computers to augment aquatic temperature monitoring

Monitoring temperature of aquatic waters is of great importance, with modelled, satellite and in-situ data providing invaluable insights into long-term environmental change. However, there is often a lack of depth-resolved temperature measurements. Recreational dive computers routinely record temperature and depth, so could provide an alternate and highly novel source of oceanographic information to fill this data gap. In this study, a citizen science approach was used to obtain over 7,000 scuba diver temperature profiles. The accuracy, offset and lag of temperature records was assessed by comparing dive computers with scientific conductivity-temperature-depth instruments and existing surface temperature data. Our results show that, with processing, dive computers can provide a useful and novel tool with which to augment existing monitoring systems all over the globe, but especially in under-sampled or highly changeable coastal environments

Laser Cooling of Optically Trapped Molecules

Calcium monofluoride (CaF) molecules are loaded into an optical dipole trap (ODT) and subsequently laser cooled within the trap. Starting with magneto-optical trapping, we sub-Doppler cool CaF and then load $150(30)$ CaF molecules into an ODT. Enhanced loading by a factor of five is obtained when sub-Doppler cooling light and trapping light are on simultaneously. For trapped molecules, we directly observe efficient sub-Doppler cooling to a temperature of $60(5)$ $\mu\text{K}$. The trapped molecular density of $8(2)\times10^7$ cm$^{-3}$ is an order of magnitude greater than in the initial sub-Doppler cooled sample. The trap lifetime of 750(40) ms is dominated by background gas collisions.Comment: 5 pages, 5 figure

Buffering of Segmental and Chromosomal Aneuploidies in Drosophila melanogaster

Chromosomal instability, which involves the deletion and duplication of chromosomes or chromosome parts, is a common feature of cancers, and deficiency screens are commonly used to detect genes involved in various biological pathways. However, despite their importance, the effects of deficiencies, duplications, and chromosome losses on the regulation of whole chromosomes and large chromosome domains are largely unknown. Therefore, to explore these effects, we examined expression patterns of genes in several Drosophila deficiency hemizygotes and a duplication hemizygote using microarrays. The results indicate that genes expressed in deficiency hemizygotes are significantly buffered, and that the buffering effect is general rather than being mainly mediated by feedback regulation of individual genes. In addition, differentially expressed genes in haploid condition appear to be generally more strongly buffered than ubiquitously expressed genes in haploid condition, but, among genes present in triploid condition, ubiquitously expressed genes are generally more strongly buffered than differentially expressed genes. Furthermore, we show that the 4th chromosome is compensated in response to dose differences. Our results suggest general mechanisms have evolved that stimulate or repress gene expression of aneuploid regions as appropriate, and on the 4th chromosome of Drosophila this compensation is mediated by Painting of Fourth (POF)

Cardiometabolic risk and the MTHFR C677T variant in children treated with second-generation antipsychotics

Second-generation antipsychotics (SGAs) are increasingly being used to treat children with a variety of psychiatric illnesses. Metabolic syndrome (MetS), a risk factor for cardiovascular disease, is a side-effect of SGA-treatment. We conducted a cross-sectional study and assessed the association of the methylenetetrahydrofolate reductase (MTHFR) C677T variant with features of MetS in SGA-treated (n=105) and SGA–naïve (n=112) children. We targeted the MTHFR C677T variant, because it is associated with risk for cardiovascular disease, and features of MetS in adults without psychiatric illness. MetS in children is based on the presence of any three of the following: waist circumference ⩾90th percentile for age and sex; plasma triglyceride ⩾1.24 mmol l−1; plasma high-density lipoprotein-cholesterol ⩽1.03 mmol l−1; systolic or diastolic blood pressure ⩾90th percentile for age, sex, and height; and fasting glucose ⩾5.6 mmol l−1. We found that 15% of SGA-treated children had MetS compared with 2% of SGA-naïve children (OR 8.113, P<0.05). No effect of the MTHFR C677T variant on psychiatric diagnosis was observed. The MTHFR 677T allele was associated (P<0.05) with MetS (OR 5.75, 95% CI= 1.18–28.12) in SGA-treated children. Models adjusted for duration of SGA treatment, ethnicity, sex, age and use of other medications revealed a positive relationship between the MTHFR 677T allele and diastolic blood pressure Z-scores (P=0.001) and fasting plasma glucose (P<0.05) in SGA-treated children. These findings illustrate the high prevalence of MetS in SGA-treated children and suggest metabolic alterations associated with the MTHFR C677T variant may have a role in the development of MetS features in SGA-treated children

Cost-effectiveness of sentinel lymph node biopsy vs inguinofemoral lymphadenectomy in women with vulval cancer

background: This study examines the cost-effectiveness of sentinel lymph node biopsy, a potentially less morbid procedure, compared with inguinofemoral lymphadenectomy (IFL) among women with stage I and stage II vulval squamous cell carcinoma. methods: A model-based economic evaluation was undertaken based on clinical evidence from a systematic review of published sources. A decision tree model was developed with the structure being informed by clinical input, taking the perspective of the health-care provider. results: For overall survival for 2 years, IFL was found to be the most cost-effective option and dominated all other strategies, being the least costly and most effective. For morbidity-free related outcomes for 2 years, sentinel lymph node (SLN) biopsy with 99mTc and blue dye and haematoxylin & eosin (H&E) histopathology, with ultrastaging and immunohistochemistry reserved for those that test negative following H&E is likely to be the most effective approach. conclusion: SLN biopsy using 99mTc and blue dye with ultrastaging may be considered the most cost-effective strategy based on the outcome of survival free of morbidity for 2 years. The findings here also indicate that using blue dye and H&E for the identification of the SLN and the identification of metastasis, respectively, are not sensitive enough to be used on their own

The implementation of medical revalidation: an assessment using normalisation process theory

Abstract Background Medical revalidation is the process by which all licensed doctors are legally required to demonstrate that they are up to date and fit to practise in order to maintain their licence. Revalidation was introduced in the United Kingdom (UK) in 2012, constituting significant change in the regulation of doctors. The governing body, the General Medical Council (GMC), envisages that revalidation will improve patient care and safety. This potential however is, in part, dependent upon how successfully revalidation is embedded into routine practice. The aim of this study was to use Normalisation Process Theory (NPT) to explore issues contributing to or impeding the implementation of revalidation in practice. Methods We conducted seventy-one interviews with sixty UK policymakers and senior leaders at different points during the development and implementation of revalidation: in 2011 (n = 31), 2013 (n = 26) and 2015 (n = 14). We selected interviewees using purposeful sampling. NPT was used as a framework to enable systematic analysis across the interview sets. Results Initial lack of consensus over revalidation’s purpose, and scepticism about its value, decreased over time as participants recognised the benefits it brought to their practice (coherence category of NPT). Though acceptance increased across time, revalidation was not seen as a legitimate part of their role by all doctors. Key individuals, notably the Responsible Officer (RO), were vital for the successful implementation of revalidation in organisations (cognitive participation category). The ease with which revalidation could be integrated into working practices varied greatly depending on the type of role a doctor held and the organisation they work for and the provision of resources was a significant variable in this (collective action category). Formal evaluation of revalidation in organisations was lacking but informal evaluation was taking place. Revalidation had not yet reached the stage where feedback was being used for improvement (reflexive monitoring category). Conclusions Requiring all organisations to use the same revalidation model made revalidation easy to integrate into existing work for some but problematic for others. In order for revalidation to be fully embedded and successful, impeding factors, such as a lack of resources, need to be addressed

Genome-Wide Association Study and Gene Expression Analysis Identifies CD84 as a Predictor of Response to Etanercept Therapy in Rheumatoid Arthritis

Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA patients from 13 different collections. Patients were treated with one of three anti-TNF medications: etanercept (n = 733), infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528) at the 1q23 locus that was associated with change in disease activity score (ΔDAS) in the etanercept subset of patients (P = 8×10-8), but not in the infliximab or adalimumab subsets (P>0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 3′ UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1×10-11 in 228 non-RA patients and P = 0.004 in 132 RA patients). Consistent with the genetic findings, higher CD84 gene expression correlated with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant trend for better ΔDAS in a subset of RA patients with gene expression data (n = 31, etanercept-treated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA patients of Portuguese ancestry (n = 139, P = 0.4), but no association among patients of Japanese ancestry (n = 151, P = 0.8). Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity. These findings support a model in which CD84 genotypes and/or expression may serve as a useful biomarker for response to etanercept treatment in RA patients of European ancestry. © 2013 Cui et al