Assessment of muscle wasting

Cachexia occurs commonly and is a significant cause of morbidity and up to 20% mortality in patients with cancer. Loss of muscle mass occurs as part of the cachexia wasting process and low muscle mass is a key element of the most recent consensus cachexia definition. Measuring muscle mass and changes in skeletal muscle is important to phenotype cachectic individuals and to monitor response to anti-cachectic treatments. This thesis investigates minimally invasive or burdensome methods of measuring muscle mass and muscle protein kinetics for use in a clinical or research setting. Quantification of muscle area on routine diagnostic cross-sectional imaging offers a novel and relatively non-invasive method of assessing both regional (and by extrapolation) whole body muscle mass. The need for such a direct measurement of muscle mass was demonstrated by showing that simple anthropometric formulae are unable to predict muscularity accurately (within 25%) when compared with estimates derived from patients diagnostic CT scans. It may be that qualitative changes in muscle may be more sensitive indices of the wasting process rather than qualitative change. Myosteatosis (infiltration of muscle by fat) is known to occur in both cachexia and age related sarcopenia and can be quantified using the Hounsfield spectrum observed on routine diagnostic CT scans. However, not all patients undergo routine CT scanning and there is a need for a biomarker derived from urine or blood. Consequently, cross sectional imaging was used to phenotype patients in a proteomic analysis of urine with the aim of identifying protein or peptide biomarkers associated with myosteatosis in cancer cachexia. A biomarker model for myosteatosis was developed with good sensitivity (97%) but poor specificity (71%). Many of the potential protein / peptide markers identified had poor associations with known mechanisms of muscle wasting and further study of the identified peptides in an extended cohort would help determine the validity of the present findings. However, two proteins with potential roles in muscle repair or neuromuscular function (Agarin and Cathepsin C) were identified and these may warrant targeted investigation with evaluation against sequential measures of muscle mass to determine their value in defining muscle loss over time. As different regional measures of muscularity are available, trunk (L3 CT) and limb muscle (quadriceps MRI) cross sectional measurements were compared with functional assessments to determine the optimal site for measurement. Neither measure proved superior to the other but appeared to reflect different aspects of function. Quadriceps muscle area correlated with quadriceps strength and power whilst truncal muscle area correlated more with complex movements such as the timed-up-and-go test. Changes in regional muscle area in patients with upper gastrointestinal cancer were assessed by upper and lower limb MRI before and after surgery and by L3 CT cross sectional area before and after neo-adjuvant chemotherapy. No change in limb muscularity was seen at 220 days post operatively compared with pre-op measurements. During neo-adjuvant chemotherapy a significant loss of truncal muscle occurred in the absence of significant weight loss suggesting that sequential cross sectional imaging is capable of detecting changes in body composition that may not be apparent clinically. Whilst sequential scans may document changes in muscularity, they do not describe the underlying levels of muscle synthesis or degradation that may regulate muscle volume. The final section of this thesis describes the development of a novel tracer method to measure skeletal muscle synthesis and its application in a study of patients with cancer and healthy volunteers. This novel method was able to measure skeletal muscle fractional synthetic rate (FSR) over a longer time-period than previous methods (weeks rather than hours) and reduced the burden on the patient by the use of a single oral tracer dose and single muscle biopsy. Comparison of synthesis rates in quadriceps and rectus abdominis showed higher rates in quadriceps, 0.067% per hour vs 0.058% per hour respectively. Despite a net loss of muscle as measured by serial CT scans, skeletal muscle FSR appeared to be marginally increased in weight losing patients with cancer compared with weight stable patients and healthy controls. When FSR was combined with measures of muscle mass it was demonstrated that only small differences between synthesis and degradation are required to see the levels of muscle wasting seen in patients with cancer. In summary, routine cross sectional imaging provides a useful and unique measure of muscularity that is associated with function in patients with cancer Sequential scans can provide additional information about changes in body composition even in the absence of weight loss. There are significant regional variations in both muscle wasting and skeletal muscle fractional synthetic rate. The combination of sequential estimates of muscle mass from diagnostic CT scans along with estimates of FSR allow assessment of the contribution of altered synthesis and degradation to muscle loss. In patients with upper GI cancer it would appear that increased degradation may be more important that altered synthesis. The relative change in either process to account for absolute loss of muscle mass is small. Such findings have implications for the targeted therapy of muscle wasting in cancer patients

The re-birth of the "beat": A hyperlocal online newsgathering model

This is an Author's Accepted Manuscript of an article published in Journalism Practice, 6(5-6), 754 - 765, 2012, copyright Taylor & Francis, available online at: http://www.tandfonline.com/10.1080/17512786.2012.667279.Scholars have long lamented the death of the 'beat' in news journalism. Today's journalists generate more copy than they used to, a deluge of PR releases often keeping them in the office, and away from their communities. Consolidation in industry has dislodged some journalists from their local sources. Yet hyperlocal online activity is thriving if journalists have the time and inclination to engage with it. This paper proposes an exploratory, normative schema intended to help local journalists systematically map and monitor their own hyperlocal online communities and contacts, with the aim of re-establishing local news beats online as networks. This model is, in part, technologically-independent. It encompasses proactive and reactive news-gathering and forward planning approaches. A schema is proposed, developed upon suggested news-gathering frameworks from the literature. These experiences were distilled into an iterative, replicable schema for local journalism. This model was then used to map out two real-world 'beats' for local news-gathering. Journalists working within these local beats were invited to trial the models created. It is hoped that this research will empower journalists by improving their information auditing, and could help re-define journalists' relationship with their online audiences

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

The abundance of large, piscivorous Ferox Trout (Salmo trutta) in Loch Rannoch, Scotland

Background Ferox Trout are large, long-lived piscivorous Brown Trout (Salmo trutta). Due to their exceptionally large size, Ferox Trout are highly sought after by anglers while their life-history strategy, which includes delayed maturation, multiphasic growth and extended longevity, is of interest to ecological and evolutionary modelers. However, despite their recreational and theoretical importance, little is known about the typical abundance of Ferox Trout. Methods To rectify this situation a 16 year angling-based mark-recapture study was conducted on Loch Rannoch, which at 19 km2 is one of the largest lakes in the United Kingdom. Results A hierarchical Bayesian Jolly-Seber analysis of the data suggest that if individual differences in catchability are negligible the population of Ferox Trout in Loch Rannoch in 2009 was approximately 71 fish. The results also suggest that a single, often unaccompanied, highly-experienced angler was able to catch roughly 8% of the available fish on an annual basis. Discussion It is recommended that anglers adopt a precautionary approach and release all trout with a fork length ≥400 mm caught by trolling in Loch Rannoch. There is an urgent need to assess the status of Ferox Trout in other lakes

The Movements of Ferox Trout, Salmo trutta, in a Scottish Highland Freshwater Loch

<p>Ferox trout (<em>Salmo trutta</em>) are the top fish predators in many Scottish lochs feeding on smaller trout and Arctic charr (<em>Salvelinus alpinus</em>) – their main prey species. Although once considered a separate species, ferox trout are brown trout which have switched to a mainly piscivorous diet. The diet switch not only boosts growth (the current UK rod caught record weight is 14.4kg), but also adds to longevity (the oldest confirmed UK ferox was 23 years old). The main aim of the study described was to investigate the movements of ferox trout in their natural habitat using acoustic, radio and data storage tags. </p