Development of a composite model derived from cardiopulmonary exercise tests to predict mortality risk in patients with mild-to-moderate heart failure

Objective: Cardiopulmonary exercise testing (CPET) is used to predict outcome in patients with mild-to-moderate heart failure (HF). Single CPET-derived variables are often used, but we wanted to see if a composite score achieved better predictive power. Methods: Retrospective analysis of patient records at the Department of Cardiology, Castle Hill Hospital, Kingston-upon-Hull. 387 patients [median (25th-75th percentile)] [age 65 (56-72) years; 79% males; LVEF 34 (31-37) %] were included. Patients underwent a symptomlimited, maximal CPET on a treadmill. During a median follow up of 8.6 ± 2.1 years in survivors, 107 patients died. Survival models were built and validated using a hybrid approach between the bootstrap and Cox regression. Nine CPET-derived variables were included. Z-score defined each variable's predictive strength. Model coefficients were converted to a risk score. Results: Four CPET-related variables were independent predictors of all-cause mortality in the survival model: the presence of exertional oscillatory ventilation (EOV), increasing slope of the relation between ventilation and carbon dioxide production (VE/VCO2 slope), decreasing oxygen uptake efficiency slope (OUES), and an increase in the lowest ventilatory equivalent for carbon dioxide (VEqCO2 nadir). Individual predictors of mortality ranged from 0.60 to 0.71 using Harrell’s C-statistic, but the optimal combination of EOV + VE/VCO2 slope + OUES + VEqCO2 nadir reached 0.75. The Hull CPET risk score had a significantly higher area under the curve (0.78) when compared to the Heart Failure Survival Score (AUC=0.70;

Health benefits of 'grow your own' food in urban areas: implications for contaminated land risk assessment and risk management?

Compelling evidence of major health benefits of fruit and vegetable consumption, physical activity, and outdoor interaction with 'greenspace' have emerged in the past decade - all of which combine to give major potential health benefits from 'grow-your-own' (GYO) in urban areas. However, neither current risk assessment models nor risk management strategies for GYO in allotments and gardens give any consideration to these health benefits, despite their potential often to more than fully compensate the risks. Although urban environments are more contaminated by heavy metals, arsenic, polyaromatic hydrocarbons and dioxins than most rural agricultural areas, evidence is lacking for adverse health outcomes of GYO in UK urban areas. Rarely do pollutants in GYO food exceed statutory limits set for commercial food, and few people obtain the majority of their food from GYO. In the UK, soil contamination thresholds triggering closure or remediation of allotment and garden sites are based on precautionary principles, generating 'scares' that may negatively impact public health disproportionately to the actual health risks of exposure to toxins through own-grown food. By contrast, the health benefits of GYO are a direct counterpoint to the escalating public health crisis of 'obesity and sloth' caused by eating an excess of saturated fats, inadequate consumption of fresh fruit and vegetables combined with a lack of exercise. These are now amongst the most important preventable causes of illness and death. The health and wider societal benefits of 'grow-your-own' thus reveal a major limitation in current risk assessment methodologies which, in only considering risks, are unable to predict whether GYO on particular sites will, overall, have positive, negative, or no net effects on human health. This highlights a more general need for a new generation of risk assessment tools that also predict overall consequences for health to more effectively guide risk management in our increasingly risk-averse culture

Elucidation of the anaerobic pathway for the corrin component of cobalamin (vitamin B12)

It has been known for the past 20 years that two pathways exist in nature for the de novo biosynthesis of the coenzyme form of vitamin B12, adenosylcobalamin, representing aerobic and anaerobic routes. In contrast to the aerobic pathway, the anaerobic route has remained enigmatic because many of its intermediates have proven technically challenging to isolate, because of their inherent instability. However, by studying the anaerobic cobalamin biosynthetic pathway in Bacillus megaterium and using homologously overproduced enzymes, it has been possible to isolate all of the intermediates between uroporphyrinogen III and cobyrinic acid. Consequently, it has been possible to detail the activities of purified cobinamide biosynthesis (Cbi) proteins CbiF, CbiG, CbiD, CbiJ, CbiET, and CbiC, as well as show the direct in vitro conversion of 5-aminolevulinic acid into cobyrinic acid using a mixture of 14 purified enzymes. This approach has resulted in the isolation of the long sought intermediates, cobalt-precorrin-6A and -6B and cobalt-precorrin-8. EPR, in particular, has proven an effective technique in following these transformations with the cobalt(II) paramagnetic electron in the dyz orbital, rather than the typical dz2. This result has allowed us to speculate that the metal ion plays an unexpected role in assisting the interconversion of pathway intermediates. By determining a function for all of the pathway enzymes, we complete the tool set for cobalamin biosynthesis and pave the way for not only enhancing cobalamin production, but also design of cobalamin derivatives through their combinatorial use and modification

Lamellar Structures of MUC2-Rich Mucin: A Potential Role in Governing the Barrier and Lubricating Functions of Intestinal Mucus

Mucus is a ubiquitous feature of mammalian wet epithelial surfaces, where it lubricates and forms a selective barrier that excludes a range of particulates, including pathogens, while hosting a diverse commensal microflora. The major polymeric component of mucus is mucin, a large glycoprotein formed by several MUC gene products, with MUC2 expression dominating intestinal mucus. A satisfactory answer to the question of how these molecules build a dynamic structure capable of playing such a complex role has yet to be found, as recent reports of distinct layers of chemically identical mucin in the colon and anomalously rapid transport of nanoparticles through mucus have emphasized. Here we use atomic force microscopy (AFM) to image a MUC2-rich mucus fraction isolated from pig jejunum. In the freshly isolated mucin fraction, we find direct evidence for trigonally linked structures, and their assembly into lamellar networks with a distribution of pore sizes from 20 to 200 nm. The networks are two-dimensional, with little interaction between lamellae. The existence of persistent cross-links between individual mucin polypeptides is consistent with a non-self-interacting lamellar model for intestinal mucus structure, rather than a physically entangled polymer network. We only observe collapsed entangled structures in purified mucin that has been stored in nonphysiological conditions

Effect of increased inspired oxygen on exercise performance in patients with heart failure and normal ejection fraction

Introduction: We investigated whether increased concentrations of inspired oxygen (FiO2) affects exercise tolerance in patients with heart failure and normal ejection fraction (HeFNEF). Methods: 46 patients (mean age 75 years (63% male) and median NTproBNP 1432 (interquartile range: 543–2378 ng/l)) with HeFNEF (defined as signs or symptoms of heart failure requiring treatment with diuretics, with a left ventricular ejection fraction of >45% by echocardiography and amino terminal pro brain natriuretic peptide (NTproBNP) >220 ng/l) completed three maximal incremental exercise tests with different FiO2 (21%, 28% and 40%) in random order. FiO2 was controlled by investigator but blinded to patients. The primary outcome was exercise time (ET). Results: Increasing FiO2 significantly increased exercise time (522 ± 180 seconds for 21% to 543 ± 176 seconds, and 542 ± 177 seconds, for 28% and 40%, respectively, P = 0.04) with no difference in peak workload (57 ± 25 W, 58 ± 25 W and 57 ± 25 W, for 21%, 28% and 40%, respectively, P = 0.50). There was an increase in oxygen saturation but no change in peak heart rate with increasing FiO2. Compared to patients with LVEF ≥50%, patients with LVEF between 45 and 49% had a significantly greater exercise time and peak workload. There was a correlation between the difference in exercise time between FiO2 21% and 40% and age; but not with BMI, haemoglobin, creatinine or NTproBNP. Conclusion: Increasing FiO2 during exertion leads to a small increase in exercise time in patients with HeFNEF

Chandra Reveals Heavy Obscuration and Circumnuclear Star Formation in Seyfert 2 Galaxy NGC 4968

We present the Chandra imaging and spectral analysis of NGC 4968, a nearby (z = 0.00986) Seyfert 2 galaxy. We discover extended ($\sim$1 kpc) X-ray emission in the soft band (0.5 - 2 keV) that is neither coincident with the narrow line region nor the extended radio emission. Based on spectral modeling, it is linked to on-going star formation ($\sim$2.6-4 M_{\sun} yr$^{-1}$). The soft emission at circumnuclear scales (inner $\sim$400 pc) originates from hot gas, with kT $\sim$ 0.7 keV, while the most extended thermal emission is cooler (kT $\sim$ 0.3 keV). We refine previous measurements of the extreme Fe K$\alpha$ equivalent width in this source (EW = 2.5$^{+2.6}_{-1.0}$ keV), which suggests the central engine is completely embedded within Compton-thick levels of obscuration. Using physically motivated models fit to the Chandra spectrum, we derive a Compton-thick column density ($N_{\rm H} > 1.25\times10^{24}$ cm$^{-2}$) and an intrinsic hard (2-10 keV) X-ray luminosity of $\sim$3-8$\times 10^{42}$ erg s$^{-1}$ (depending on the presumed geometry of the obscurer), which is over two orders of magnitude larger than that observed. The large Fe K$\alpha$ EW suggests a spherical covering geometry, which could be confirmed with X-ray measurements above 10 keV. NGC 4968 is similar to other active galaxies that exhibit extreme Fe K$\alpha$ EWs (i.e., $>$2 keV) in that they also contain ongoing star formation. This work supports the idea that gas associated with nuclear star formation may increase the covering factor of the enshrouding gas and play a role in obscuring AGN.Comment: 11 pages, 8 figures, 4 tables. Accepted for publication in Ap

Solenoidal turbulent modes and star formation efficiency in Galactic-plane molecular clouds

It is speculated that the high star-formation efficiency observed in spiral-arm molecular clouds is linked to the prevalence of compressive (curl-free) turbulent modes, while the shear-driven solenoidal (divergence-free) modes appear to be the main cause of the low star-formation efficiency that characterises clouds in the Central Molecular Zone. Similarly, analysis of the Orion B molecular cloud has confirmed that, although turbulent modes vary locally and at different scales within the cloud, the dominant solenoidal turbulence is compatible with its low star formation rate. This evidence points to inter-and intra-cloud fluctuations of the solenoidal modes being an agent for the variability of star formation efficiency. We present a quantitative estimation of the relative fractions of momentum density in the solenoidal modes of turbulence in a large sample of plane molecular clouds in the \ce{^{13}CO}/\ce{C^{18}O} ($J=3\rightarrow 2$) Heterodyne Inner Milky Way Plane Survey (CHIMPS). We find a negative correlation between the solenoidal fraction and star-formation efficiency. This feature is consistent with the hypothesis that solenoidal modes prevent or slow down the collapse of dense cores. In addition, the relative power in the solenoidal modes of turbulence (solenoidal fraction) appears to be higher in the Inner Galaxy declining with a shallow gradient with increasing Galactocentric distance. Outside the Inner Galaxy, the slowly, monotonically declining values suggest that the solenoidal fraction is unaffected by the spiral arms.Comment: 16 pages, 14 figure