Selected exercise and skeletal muscle characteristics of African distance runners

African runners dominate distance running both in South Africa and internationally. Therefore, the aim of this thesis was to compare selected exercise and skeletal muscle characteristics in well-trained African and Caucasian 10 km runners to determine if evidence exists of differences between these groups with respect to these physiological and biochemical characteristics. Furthermore, the relationship between exercise and skeletal muscle characteristics was investigated. Sedentary individuals from each population group were also studied to determine if differences existed in untrained skeletal muscle between groups. Maximal oxygen consumption and peak treadmill speed were measured using an incremental treadmill protocol whilst submaximal exercise characteristics were measured during a specifically designed protocol consisting of four sequential submaximal workloads relative to the peak treadmill speed of the individual. The final workload was maintained until fatigue with resistance to fatigue defined as total test time. Running economy was measured at a treadmill speed of 16.1 km/hr. Race pace characteristics were measured directly at race pace. Characteristics measured during exercise tests were oxygen uptake, minute ventilation, respiratory exchange ratio and heart rate whilst plasma lactate concentration was determined immediately after exercise. Skeletal muscle characteristics were determined by needle biopsy of the vastus lateralis muscle. Skeletal muscle enzymes citrate synthase, phosphofructokinase, 3-hydroxyacyl CoA dehydrogenase, hexokinase and carnitine palmityl transferase were assayed spectrophotometrically. Skeletal muscle buffering capacity was measured using by titration and fibre type proportions were analysed histochemically. Comparisons between groups were made with the Student's t-test for unpaired data whilst the relationships between variables were analysed using the Pearson's correlation coefficient. The first major finding was that when exercising at the same relative percentage of individual maximal treadmill velocity, African distance runners were able to exercise for longer than the Caucasians (1376±227 vs 1137±126 sec, p<0.01) with lower plasma lactate accumulation (4.8±3.2 vs 7.7±2.8 mmol/l,p<0.05). Time to fatigue was significantly related to a lower plasma lactate concentration (r=-0.63) and a lower respiratory exchange ratio (r=-0.53). The second major finding indicated that African runners were able to race 10 km at a higher percentage of their maximal oxygen uptake (93.5 vs 86.0%, p<0.005), whilst eliciting only a comparable plasma lactate concentration and respiratory exchange ratio. The third main finding was that the African runners were more economical than the Caucasian runners (p<0.05). The fourth main finding is that the African runners had a 50% greater activity of citrate synthase (p<0.005) and 3-hydroxyacyl CoA dehydrogenase (p<0.01) in the vastus lateralis than the Caucasians and this could not be explained by fibre type proportions, because the proportion of type I fibres was lower in the African runners (p<0.05). Citrate synthase activity, was related to the runners' ability to resist fatigue at high intensity relative to their individual peak treadmill velocity (r=0.70, p<0.05). A higher CS activity was related to a lower plasma lactate concentration and a lower RER. The sixth main finding of this thesis was that skeletal muscle buffering capacity of the Caucasian runners was higher than that of the African runners (p<0.05). A methodological study of buffering capacity in rats showed the buffering capacity was largely dependent upon fibre type and protein concentration, however these parameters could not explain the difference observed between the African and Caucasian runners. Furthermore, despite the differences in skeletal muscle characteristics observed between African and Caucasian runners in the current thesis, there was no evidence of these differences being inherently present in sedentary African and Caucasian individuals. In conclusion, the current series of studies do provide evidence of differences in selected exercise and skeletal muscle characteristics between African and Caucasian distance runners, with the African runners possessing exercise and skeletal muscle profiles that are considered to be more advantageous for endurance performance

Transcriptional silencing of long noncoding RNA GNG12-AS1 uncouples its transcriptional and product-related functions.

Long noncoding RNAs (lncRNAs) regulate gene expression via their RNA product or through transcriptional interference, yet a strategy to differentiate these two processes is lacking. To address this, we used multiple small interfering RNAs (siRNAs) to silence GNG12-AS1, a nuclear lncRNA transcribed in an antisense orientation to the tumour-suppressor DIRAS3. Here we show that while most siRNAs silence GNG12-AS1 post-transcriptionally, siRNA complementary to exon 1 of GNG12-AS1 suppresses its transcription by recruiting Argonaute 2 and inhibiting RNA polymerase II binding. Transcriptional, but not post-transcriptional, silencing of GNG12-AS1 causes concomitant upregulation of DIRAS3, indicating a function in transcriptional interference. This change in DIRAS3 expression is sufficient to impair cell cycle progression. In addition, the reduction in GNG12-AS1 transcripts alters MET signalling and cell migration, but these are independent of DIRAS3. Thus, differential siRNA targeting of a lncRNA allows dissection of the functions related to the process and products of its transcription.The authors acknowledge all the members of Murrell, Rinn, Odom and Gergely laboratory as well as Massimiliano di Pietro, Klaas Mulder, Anna Git, Jason Carroll in Cambridge and Laurence Hurst (University of Bath) for reading and providing helpful comments on the manuscript. We also thank the Genomics, Microscopy and Bioinformatics core facilities at the Cambridge Institute for support, Christina Ernst for thumbnail image design, Ezgi Hacisuleyman for the design of the negative control vector, Cole Trapnell and David Hendrickson for providing us with lincExpress vector, Arjun Raj with the RNA FISH and Alaisdair Russell with the lentiviral work. This research was supported by The University of Cambridge, Cancer Research UK and Hutchison Whampoa Limited. The authors have no conflicting financial interests.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms1040

FORM: An Australian method for formulating and grading recommendations in evidence-based clinical guidelines

Extent: 8p.BACKGROUND: Clinical practice guidelines are an important element of evidence-based practice. Considering an often complicated body of evidence can be problematic for guideline developers, who in the past may have resorted to using levels of evidence of individual studies as a quasi-indicator for the strength of a recommendation. This paper reports on the production and trial of a methodology and associated processes to assist Australian guideline developers in considering a body of evidence and grading the resulting guideline recommendations. METHODS: In recognition of the complexities of clinical guidelines and the multiple factors that influence choice in health care, a working group of experienced guideline consultants was formed under the auspices of the Australian National Health and Medical Research Council (NHMRC) to produce and pilot a framework to formulate and grade guideline recommendations. Consultation with national and international experts and extensive piloting informed the process. RESULTS: The FORM framework consists of five components (evidence base, consistency, clinical impact, generalisability and applicability) which are used by guideline developers to structure their decisions on how to convey the strength of a recommendation through wording and grading via a considered judgement form. In parallel (but separate from the grading process) guideline developers are asked to consider implementation implications for each recommendation. CONCLUSIONS: The framework has now been widely adopted by Australian guideline developers who find it to be a logical and intuitive way to formulate and grade recommendations in clinical practice guidelines.Susan Hillier, Karen Grimmer-Somers, Tracy Merlin, Philippa Middleton, Janet Salisbury, Rebecca Tooher and Adele Westo

Decision-making of English Netball Superleague umpires: Contextual and dispositional influences

Objectives. The decisions made by officials have a direct bearing on the outcomes of competitive sport contests. In an exploratory study, we examine the interrelationships between the decisions made by elite netball umpires, the potential contextual and environmental influences (e.g., crowd size), and the umpires’ dispositional tendencies – specifically, their propensity to deliberate and ruminate on their decisions. Design/Method. Filmed footage from 60 England Netball Superleague matches was coded using performance analysis software. We measured the number of decisions made overall, and for home and away teams; league position; competition round; match quarter; and crowd size. Additionally, 10 umpires who officiated in the matches completed the Decision-Specific Reinvestment Scale (DSRS). Results. Regression analyses predicted that as home teams’ league position improved the number of decisions against away teams increased. A model comprising competition round and average league position of both teams predicted the number of decisions made in matches, but neither variable emerged as a significant predictor. The umpire analyses revealed that greater crowd size was associated with an increase in decisions against away teams. The Decision Rumination factor was strongly negatively related to the number of decisions in Quarters 1 and 3, this relationship was driven by fewer decisions against home teams by umpires who exhibited higher Rumination subscale scores. Conclusions. These findings strengthen our understanding of contextual, environmental, and dispositional influences on umpires’ decision-making behaviour. The tendency to ruminate upon decisions may explain the changes in decision behaviour in relation to the home team advantage effect

Extending an evidence hierarchy to include topics other than treatment: revising the Australian 'levels of evidence'

Background: In 1999 a four-level hierarchy of evidence was promoted by the National Health and Medical Research Council in Australia. The primary purpose of this hierarchy was to assist with clinical practice guideline development, although it was co-opted for use in systematic literature reviews and health technology assessments. In this hierarchy interventional study designs were ranked according to the likelihood that bias had been eliminated and thus it was not ideal to assess studies that addressed other types of clinical questions. This paper reports on the revision and extension of this evidence hierarchy to enable broader use within existing evidence assessment systems. Methods: A working party identified and assessed empirical evidence, and used a commissioned review of existing evidence assessment schema, to support decision-making regarding revision of the hierarchy. The aim was to retain the existing evidence levels I-IV but increase their relevance for assessing the quality of individual diagnostic accuracy, prognostic, aetiologic and screening studies. Comprehensive public consultation was undertaken and the revised hierarchy was piloted by individual health technology assessment agencies and clinical practice guideline developers. After two and a half years, the hierarchy was again revised and commenced a further 18 month pilot period. Results: A suitable framework was identified upon which to model the revision. Consistency was maintained in the hierarchy of "levels of evidence" across all types of clinical questions; empirical evidence was used to support the relationship between study design and ranking in the hierarchy wherever possible; and systematic reviews of lower level studies were themselves ascribed a ranking. The impact of ethics on the hierarchy of study designs was acknowledged in the framework, along with a consideration of how harms should be assessed. Conclusion: The revised evidence hierarchy is now widely used and provides a common standard against which to initially judge the likelihood of bias in individual studies evaluating interventional, diagnostic accuracy, prognostic, aetiologic or screening topics. Detailed quality appraisal of these individual studies, as well as grading of the body of evidence to answer each clinical, research or policy question, can then be undertaken as required.Tracy Merlin, Adele Weston and Rebecca Toohe

Decision-making of English Netball Superleague umpires: contextual and dispositional influences

Objectives: The decisions made by officials have a direct bearing on the outcomes of competitive sport contests. In an exploratory study, we examine the interrelationships between the decisions made by elite netball umpires, the potential contextual and environmental influences (e.g., crowd size), and the umpires' dispositional tendencies – specifically, their propensity to deliberate and ruminate on their decisions. Design/Method: Filmed footage from 60 England Netball Superleague matches was coded using performance analysis software. We measured the number of decisions made overall, and for home and away teams; league position; competition round; match quarter; and crowd size. Additionally, 10 umpires who officiated in the matches completed the Decision-Specific Reinvestment Scale (DSRS). Results: Regression analyses predicted that as home teams' league position improved the number of decisions against away teams increased. A model comprising competition round and average league position of both teams predicted the number of decisions made in matches, but neither variable emerged as a significant predictor. The umpire analyses revealed that greater crowd size was associated with an increase in decisions against away teams. The Decision Rumination factor was strongly negatively related to the number of decisions in Quarters 1 and 3, this relationship was driven by fewer decisions against home teams by umpires who exhibited higher Rumination subscale scores. Conclusions: These findings strengthen our understanding of contextual, environmental, and dispositional influences on umpires' decision-making behaviour. The tendency to ruminate upon decisions may explain the changes in decision behaviour in relation to the home team advantage effect

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Approaches to the investigation of periosteal new bone formation in palaeopathology

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Discrete Choice Experiment to Derive Willingness To Pay for Methyl Aminolevulinate Photodynamic Therapy Versus Simple Excision Surgery in Basal Cell Carcinoma

Objectives: This study aimed to determine willingness to pay (WTP) and preference for methyl aminolevulinate (MAL) photodynamic therapy compared with simple surgical excision for basal cell carcinoma (BCC). The relative preferences for individual features of the therapy were also determined. Design: A discrete-choice experiment was conducted to ascertain WTP and relative preferences for treatment of BCC among the general population. Subjects and methods: Sixty members of the general public (34 men, 26 women; mean age 50 +- 13 years) completed a written questionnaire. Participants indicated their preference between 12 pairs of scenarios representing BCC treatment. The paired scenarios comprised a fixed scenario representing current standard treatment (simple surgical excision) and an alternative scenario. Scenarios comprised five attributes: lesion response rate, risk of scarring, treatment description, possibility of infection and cost. Clinical attributes and levels were derived from clinical trial data. WTP values were in Australian dollars ($A, year 2001 values) and the study was conducted from the societal perspective. Results: The probability that MAL photodynamic therapy with topical anaesthesia would be accepted in preference to current treatment was 0.879, if there was no cost differential. Total incremental WTP was$A940 for MAL photodynamic therapy. The primary driver of total WTP was reduced risk of scarring, which contributed $A554, but treatment description and infection rate also made significant positive contributions. By contrast, the marginally higher lesion response rate with simple surgical excision (93%) compared with MAL photodynamic therapy (84%) did not significantly reduce WTP. Demographic factors had negligible influence upon the results. Sensitivity analyses indicated that incremental WTP for MAL photodynamic therapy was strongly influenced by the presence of anaesthetic. Conclusion: There appears to be a sizeable incremental WTP for MAL photodynamic therapy with anaesthetic for the treatment of BCC relative to simple surgical excision, and this is largely driven by better cosmetic outcomes.Basal-cell-cancer, Methyl-aminolevulinate, Photosensitisers, Phototherapy, Willingness-to-pay