Risk stratification by pre-operative cardiopulmonary exercise testing improves outcomes following elective abdominal aortic aneurysm surgery : a cohort study

Background: In 2009, the NHS evidence adoption center and National Institute for Health and Care Excellence (NICE) published a review of the use of endovascular aneurysm repair (EVAR) of abdominal aortic aneurysms (AAAs). They recommended the development of a risk-assessment tool to help identify AAA patients with greater or lesser risk of operative mortality and to contribute to mortality prediction. A low anaerobic threshold (AT), which is a reliable, objective measure of pre-operative cardiorespiratory fitness, as determined by pre-operative cardiopulmonary exercise testing (CPET) is associated with poor surgical outcomes for major abdominal surgery. We aimed to assess the impact of a CPET-based risk-stratification strategy upon perioperative mortality, length of stay and non-operative costs for elective (open and endovascular) infra-renal AAA patients. Methods: A retrospective cohort study was undertaken. Pre-operative CPET-based selection for elective surgical intervention was introduced in 2007. An anonymized cohort of 230 consecutive infra-renal AAA patients (2007 to 2011) was studied. A historical control group of 128 consecutive infra-renal AAA patients (2003 to 2007) was identified for comparison. Comparative analysis of demographic and outcome data for CPET-pass (AT ≥ 11 ml/kg/min), CPET-fail (AT < 11 ml/kg/min) and CPET-submaximal (no AT generated) subgroups with control subjects was performed. Primary outcomes included 30-day mortality, survival and length of stay (LOS); secondary outcomes were non-operative inpatient costs. Results: Of 230 subjects, 188 underwent CPET: CPET-pass n = 131, CPET-fail n = 35 and CPET-submaximal n = 22. When compared to the controls, CPET-pass patients exhibited reduced median total LOS (10 vs 13 days for open surgery, n = 74, P < 0.01 and 4 vs 6 days for EVAR, n = 29, P < 0.05), intensive therapy unit requirement (3 vs 4 days for open repair only, P < 0.001), non-operative costs (£5,387 vs £9,634 for open repair, P < 0.001) and perioperative mortality (2.7% vs 12.6% (odds ratio: 0.19) for open repair only, P < 0.05). CPET-stratified (open/endovascular) patients exhibited a mid-term survival benefit (P < 0.05). Conclusion: In this retrospective cohort study, a pre-operative AT > 11 ml/kg/min was associated with reduced perioperative mortality (open cases only), LOS, survival and inpatient costs (open and endovascular repair) for elective infra-renal AAA surgery

Reproducibility of onset and recovery oxygen uptake kinetics in moderately impaired patients with chronic heart failure

Oxygen (O2) kinetics reflect the ability to adapt to or recover from exercise that is indicative of daily life. In patients with chronic heart failure (CHF), parameters of O2 kinetics have shown to be useful for clinical purposes like grading of functional impairment and assessment of prognosis. This study compared the goodness of fit and reproducibility of previously described methods to assess O2 kinetics in these patients. Nineteen CHF patients, New York Heart Association class II–III, performed two constant-load tests on a cycle ergometer at 50% of the maximum workload. Time constants of O2 onset- and recovery kinetics (τ) were calculated by mono-exponential modeling with four different sampling intervals (5 and 10 s, 5 and 8 breaths). The goodness of fit was expressed as the coefficient of determination (R2). Onset kinetics were also evaluated by the mean response time (MRT). Considering O2 onset kinetics, τ showed a significant inverse correlation with peak- \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document} \ifmmode\expandafter\dot\else\expandafter\.\fi{V}{\text{O}}_{2} \end{document} (R = −0.88, using 10 s sampling intervals). The limits of agreement of both τ and MRT, however, were not clinically acceptable. O2 recovery kinetics yielded better reproducibility and goodness of fit. Using the most optimal sampling interval (5 breaths), a change of at least 13 s in τ is needed to exceed normal test-to-test variations. In conclusion, O2 recovery kinetics are more reproducible for clinical purposes than O2 onset kinetics in moderately impaired patients with CHF. It should be recognized that this observation cannot be assumed to be generalizable to more severely impaired CHF patients

The influence of body weight on the pulmonary oxygen uptake kinetics in pre-pubertal children during moderate- and heavy intensity treadmill exercise

To assess the influence of obesity on the oxygen uptake (V˙O2) kinetics of pre-pubertal children during moderate- and heavy intensity treadmill exercise. We hypothesised that obese (OB) children would demonstrate significantly slower V˙O2 kinetics than their normal weight (NW) counterparts during moderate- and heavy intensity exercise. 18 OB (9.8 ± 0.5 years; 24.1 ± 2.0 kg m2) and 19 NW (9.7 ± 0.5 years; 17.6 ± 1.0 kg m2) children completed a graded-exercise test to volitional exhaustion and two submaximal constant work rate treadmill tests at moderate (90 % gas exchange threshold) and heavy (∆40 %) exercise intensities. Bodyweight significantly influenced the V˙O2 kinetics during both moderate- and heavy exercise intensities (P < 0.05). During moderate intensity exercise, the phase II τ (OB: 30 ± 13 cf. NW: 22 ± 7 s), mean response time (MRT; OB: 35 ± 16 cf. NW: 25 ± 10 s), phase II gain (OB: 156 ± 21 cf. NW: 111 ± 18 mLO2 kg−1 km−1) and oxygen deficit (OB: 0.36 ± 0.11 cf. NW: 0.20 ± 0.06 L) were significantly higher in the OB children (all P < 0.05). During heavy intensity exercise, the τ (OB: 33 ± 9 cf. NW: 27 ± 6 s; P < 0.05) and phase II gain (OB: 212 ± 61 cf. NW: 163 ± 23 mLO2 kg−1 km−1; P < 0.05) were similarly higher in the OB children. A slow component was observed in all participants during heavy intensity exercise, but was not influenced by weight status. In conclusion, this study demonstrates that weight status significantly influences the dynamic V˙O2 response at the onset of treadmill exercise in children and highlights that the deleterious effects of being obese are already manifest pre-puberty

Dorsal Striatum and Its Limbic Connectivity Mediate Abnormal Anticipatory Reward Processing in Obesity

Obesity is characterized by an imbalance in the brain circuits promoting reward seeking and those governing cognitive control. Here we show that the dorsal caudate nucleus and its connections with amygdala, insula and prefrontal cortex contribute to abnormal reward processing in obesity. We measured regional brain glucose uptake in morbidly obese (n = 19) and normal weighted (n = 16) subjects with 2-[18F]fluoro-2-deoxyglucose ([18F]FDG) positron emission tomography (PET) during euglycemic hyperinsulinemia and with functional magnetic resonance imaging (fMRI) while anticipatory food reward was induced by repeated presentations of appetizing and bland food pictures. First, we found that glucose uptake rate in the dorsal caudate nucleus was higher in obese than in normal-weight subjects. Second, obese subjects showed increased hemodynamic responses in the caudate nucleus while viewing appetizing versus bland foods in fMRI. The caudate also showed elevated task-related functional connectivity with amygdala and insula in the obese versus normal-weight subjects. Finally, obese subjects had smaller responses to appetizing versus bland foods in the dorsolateral and orbitofrontal cortices than did normal-weight subjects, and failure to activate the dorsolateral prefrontal cortex was correlated with high glucose metabolism in the dorsal caudate nucleus. These findings suggest that enhanced sensitivity to external food cues in obesity may involve abnormal stimulus-response learning and incentive motivation subserved by the dorsal caudate nucleus, which in turn may be due to abnormally high input from the amygdala and insula and dysfunctional inhibitory control by the frontal cortical regions. These functional changes in the responsiveness and interconnectivity of the reward circuit could be a critical mechanism to explain overeating in obesity

Dorsal Striatum and Its Limbic Connectivity Mediate Abnormal Anticipatory Reward Processing in Obesity

Obesity is characterized by an imbalance in the brain circuits promoting reward seeking and those governing cognitive control. Here we show that the dorsal caudate nucleus and its connections with amygdala, insula and prefrontal cortex contribute to abnormal reward processing in obesity. We measured regional brain glucose uptake in morbidly obese (n = 19) and normal weighted (n = 16) subjects with 2-[18F]fluoro-2-deoxyglucose ([18F]FDG) positron emission tomography (PET) during euglycemic hyperinsulinemia and with functional magnetic resonance imaging (fMRI) while anticipatory food reward was induced by repeated presentations of appetizing and bland food pictures. First, we found that glucose uptake rate in the dorsal caudate nucleus was higher in obese than in normal-weight subjects. Second, obese subjects showed increased hemodynamic responses in the caudate nucleus while viewing appetizing versus bland foods in fMRI. The caudate also showed elevated task-related functional connectivity with amygdala and insula in the obese versus normal-weight subjects. Finally, obese subjects had smaller responses to appetizing versus bland foods in the dorsolateral and orbitofrontal cortices than did normal-weight subjects, and failure to activate the dorsolateral prefrontal cortex was correlated with high glucose metabolism in the dorsal caudate nucleus. These findings suggest that enhanced sensitivity to external food cues in obesity may involve abnormal stimulus-response learning and incentive motivation subserved by the dorsal caudate nucleus, which in turn may be due to abnormally high input from the amygdala and insula and dysfunctional inhibitory control by the frontal cortical regions. These functional changes in the responsiveness and interconnectivity of the reward circuit could be a critical mechanism to explain overeating in obesity

Pharmacological differentiation of opioid receptor antagonists by molecular and functional imaging of target occupancy and food reward-related brain activation in humans

Opioid neurotransmission has a key role in mediating reward-related behaviours. Opioid receptor (OR) antagonists, such as naltrexone (NTX), can attenuate the behaviour-reinforcing effects of primary (food) and secondary rewards. GSK1521498 is a novel OR ligand, which behaves as an inverse agonist at the μ-OR sub-type. In a sample of healthy volunteers, we used [11C]-carfentanil positron emission tomography to measure the OR occupancy and functional magnetic resonance imaging (fMRI) to measure activation of brain reward centres by palatable food stimuli before and after single oral doses of GSK1521498 (range, 0.4–100 mg) or NTX (range, 2–50 mg). GSK1521498 had high affinity for human brain ORs (GSK1521498 effective concentration 50=7.10 ng ml−1) and there was a direct relationship between receptor occupancy (RO) and plasma concentrations of GSK1521498. However, for both NTX and its principal active metabolite in humans, 6-β-NTX, this relationship was indirect. GSK1521498, but not NTX, significantly attenuated the fMRI activation of the amygdala by a palatable food stimulus. We thus have shown how the pharmacological properties of OR antagonists can be characterised directly in humans by a novel integration of molecular and functional neuroimaging techniques. GSK1521498 was differentiated from NTX in terms of its pharmacokinetics, target affinity, plasma concentration–RO relationships and pharmacodynamic effects on food reward processing in the brain. Pharmacological differentiation of these molecules suggests that they may have different therapeutic profiles for treatment of overeating and other disorders of compulsive consumption

Disease and the Extended Phenotype: Parasites Control Host Performance and Survival through Induced Changes in Body Plan

BACKGROUND: By definition, parasites harm their hosts. However, some forms of parasite-induced alterations increase parasite transmission between hosts, such that manipulated hosts can be considered extensions of the parasite's phenotype. While well accepted in principle, surprisingly few studies have quantified how parasite manipulations alter host performance and survival under field and laboratory conditions. METHODOLOGY/PRINCIPAL FINDINGS: By interfering with limb development, the trematode Ribeiroia ondatrae causes particularly severe morphological alterations within amphibian hosts that provide an ideal system to evaluate parasite-induced changes in phenotype. Here, we coupled laboratory performance trials with a capture-mark-recapture study of 1388 Pacific chorus frogs (Pseudacris regilla) to quantify the effects of parasite-induced malformations on host locomotion, foraging, and survival. Malformations, which affected ~50% of metamorphosing frogs in nature, caused dramatic reductions in all measures of organismal function. Malformed frogs exhibited significantly shorter jumping distances (41% reduction), slower swimming speeds (37% reduction), reduced endurance (66% reduction), and lower foraging success relative to infected hosts without malformations. Furthermore, while normal and malformed individuals had comparable survival within predator-free exclosures, deformed frogs in natural populations had 22% lower biweekly survival than normal frogs and rarely recruited to the adult population over a two-year period. CONCLUSIONS/SIGNIFICANCE: Our results highlight the ability of parasites to deeply alter multiple dimensions of host phenotype with important consequences for performance and survival. These patterns were best explained by malformation status, rather than infection per se, helping to decouple the direct and indirect effects of parasitism on host fitness.Brett A. Goodman and Pieter T. J. Johnso