Study protocol: a randomised controlled trial investigating the effect of exercise training on peripheral blood gene expression in patients with stable angina

Background: Exercise training has been shown to reduce angina and promote collateral vessel development in patients with coronary artery disease. However, the mechanism whereby exercise exerts these beneficial effects is unclear. There has been increasing interest in the use of whole genome peripheral blood gene expression in a wide range of conditions to attempt to identify both novel mechanisms of disease and transcriptional biomarkers. This protocol describes a study in which we will assess the effect of a structured exercise programme on peripheral blood gene expression in patients with stable angina, and correlate this with changes in angina level, anxiety, depression, and exercise capacity. Methods/Design: Sixty patients with stable angina will be recruited and randomised 1: 1 to exercise training or conventional care. Patients randomised to exercise training will attend an exercise physiology laboratory up to three times weekly for supervised aerobic interval training sessions of one hour in total duration. Patients will undergo assessments of angina, anxiety, depression, and peripheral blood gene expression at baseline, after six and twelve weeks of training, and twelve weeks after formal exercise training ceases. Discussion: This study will provide comprehensive data on the effect of exercise training on peripheral blood gene expression in patients with angina. By correlating this with improvement in angina status we will identify candidate peripheral blood transcriptional markers predictive of improvements in angina level in response to exercise training

The "Petechiae in children" (PiC) study: Evaluating potential clinical decision rules for the management of feverish children with non-blanching rashes, including the role of point of care testing for Procalcitonin & Neisseria meningitidis DNA - a stu

© 2018 The Author(s). Background: Children commonly present to Emergency Departments (ED) with a non-blanching rash in the context of a feverish illness. While most have a self-limiting viral illness, this combination of features potentially represents invasive serious bacterial infection, including meningococcal septicaemia. A paucity of definitive diagnostic testing creates diagnostic uncertainty for clinicians; a safe approach mandates children without invasive disease are often admitted and treated with broad-spectrum antibiotics. Conversely, a cohort of children still experience significant mortality and morbidity due to late diagnosis. Current management is based on evidence which predates (i) the introduction of meningococcal B and C vaccines and (ii) availability of point of care testing (POCT) for procalcitonin (PCT) and Neisseria meningitidis DNA. Methods: This PiC study is a prospective diagnostic accuracy study evaluating (i) rapid POCT for PCT and N. meningitidis DNA and (ii) performance of existing clinical practice guidelines (CPG) for feverish children with non-blanching rash. All children presenting to the ED with a history of fever and non-blanching rash are eligible. Children are managed as normal, with detailed prospective collection of data pertinent to CPGs, and a throat swab and blood used for rapid POCT. The study is running over 2years and aims to recruit 300 children. Primary objective: Report on the diagnostic accuracy of POCT for (i) N. meningitidis DNA and (ii) PCT in the diagnosis of early MD Discussion: The PiC study will provide important information for policy makers regarding the value of POCT and on the utility and cost of emerging diagnostic strategies. The study will also identify which elements of existing CPGs may merit inclusion in any future study to derive clinical decision rules for this population

Carbon stable isotope analysis of cereal remains as a way to reconstruct water availability: preliminary results

Reconstructing past water availability, both as rainfall and irrigation, is important to answer questions about the way society reacts to climate and its changes and the role of irrigation in the development of social complexity. Carbon stable isotope analysis of archaeobotanical remains is a potentially valuable method for reconstructing water availability. To further define the relationship between water availability and plant carbon isotope composition and to set up baseline values for the Southern Levant, grains of experimentally grown barley and sorghum were studied. The cereal crops were grown at three stations under five different irrigation regimes in Jordan. Results indicate that a positive but weak relationship exists between irrigation regime and total water input of barley grains, but no relationship was found for sorghum. The relationship for barley is site-specific and inter-annual variation was present at Deir ‘Alla, but not at Ramtha and Khirbet as-Samra

Day occupation is associated with psychopathology for adolescents and young adults with Down syndrome

Background: Young adults with Down syndrome experience increased rates of emotional and behavioural problems compared with the general population. Most adolescents with Down syndrome living in Western Australia participate in sheltered employment as their main day occupation. Relationship between day occupation and changes in behaviour has not been examined. Therefore, the aim of this research was to explore any relationship between post school day occupations and changes in the young person’s behaviour. Methods: The Down syndrome Needs Opinion Wishes database was used for case ascertainment of young adults aged 15 to 32 years with Down syndrome. Families of 118 young people in this population-based database completed questionnaires in 2004, 2009 and 2011. The questionnaires addressed both young person characteristics such as age, gender, presence of impairments, behaviour, functioning in activities of daily living, and family characteristics such as income and family functioning. Post-school day occupations in which the young people were participating included open and sheltered employment, training and day recreation programs. Change in behaviour of young adults who remained in the same post-school day occupation from 2009 to 2011 (n = 103) were examined in a linear regression model adjusting for confounding variables including age, gender, prior functioning and behaviour in 2004 and family income.Results: In comparison to those young adults attending open employment from 2009 to 2011, those attending day recreation programs were reported to experience worsening in behaviour both in the unadjusted (effect size -0.14, 95% CI -0.24, -0.05) and adjusted models (effect size -0.15, 95% CI -0.29, -0.01). Conclusions: We found that the behaviour of those participating in open employment improved compared to those attending other day occupations. Further examination of the direction of this association is required

Evolutionary connectionism: algorithmic principles underlying the evolution of biological organisation in evo-devo, evo-eco and evolutionary transitions

The mechanisms of variation, selection and inheritance, on which evolution by natural selection depends, are not fixed over evolutionary time. Current evolutionary biology is increasingly focussed on understanding how the evolution of developmental organisations modifies the distribution of phenotypic variation, the evolution of ecological relationships modifies the selective environment, and the evolution of reproductive relationships modifies the heritability of the evolutionary unit. The major transitions in evolution, in particular, involve radical changes in developmental, ecological and reproductive organisations that instantiate variation, selection and inheritance at a higher level of biological organisation. However, current evolutionary theory is poorly equipped to describe how these organisations change over evolutionary time and especially how that results in adaptive complexes at successive scales of organisation (the key problem is that evolution is self-referential, i.e. the products of evolution change the parameters of the evolutionary process). Here we first reinterpret the central open questions in these domains from a perspective that emphasises the common underlying themes. We then synthesise the findings from a developing body of work that is building a new theoretical approach to these questions by converting well-understood theory and results from models of cognitive learning. Specifically, connectionist models of memory and learning demonstrate how simple incremental mechanisms, adjusting the relationships between individually-simple components, can produce organisations that exhibit complex system-level behaviours and improve the adaptive capabilities of the system. We use the term “evolutionary connectionism” to recognise that, by functionally equivalent processes, natural selection acting on the relationships within and between evolutionary entities can result in organisations that produce complex system-level behaviours in evolutionary systems and modify the adaptive capabilities of natural selection over time. We review the evidence supporting the functional equivalences between the domains of learning and of evolution, and discuss the potential for this to resolve conceptual problems in our understanding of the evolution of developmental, ecological and reproductive organisations and, in particular, the major evolutionary transitions

Temporal variation in sex allocation in the mealybug <em>Planococcus citri</em>:Adaptation, constraint, or both?

Sex ratio theory has been very successful in predicting under which circumstances parents should bias their investment towards a particular offspring sex. However, most examples of adaptive sex ratio bias come from species with well-defined mating systems and sex determining mechanisms, while in many other groups there is still an on-going debate about the adaptive nature of sex allocation. Here we study the sex allocation in the mealybug Planococcus citri, a species in which it is currently unclear how females adjust their sex ratio, even though experiments have shown support for facultative sex ratio adjustment. Previous work has shown that the sex ratio females produce changes over the oviposition period, with males being overproduced early and late in the laying sequence. Here we investigate this complex pattern further, examining both the robustness of the pattern and possible explanations for it. We first show that this sex allocation behaviour is indeed consistent across lines from three geographical regions. Second, we test whether females produce sons first in order to synchronize reproductive maturation of her offspring, although our data provide little evidence for this adaptive explanation. Finally we test the age at which females are able to mate successfully and show that females are able to mate and store sperm before adult eclosion. Whilst early-male production may still function in promoting protandry in mealybugs, we discuss whether mechanistic constraints limit how female allocate sex across their lifetime

“Medically unexplained” symptoms and symptom disorders in primary care: prognosis-based recognition and classification

Background: Many patients consult their GP because they experience bodily symptoms. In a substantial proportion of cases, the clinical picture does not meet the existing diagnostic criteria for diseases or disorders. This may be because symptoms are recent and evolving or because symptoms are persistent but, either by their character or the negative results of clinical investigation cannot be attributed to disease: so-called “medically unexplained symptoms” (MUS). MUS are inconsistently recognised, diagnosed and managed in primary care. The specialist classification systems for MUS pose several problems in a primary care setting. The systems generally require great certainty about presence or absence of physical disease, they tend to be mind-body dualistic, and they view symptoms from a narrow specialty determined perspective. We need a new classification of MUS in primary care; a classification that better supports clinical decision-making, creates clearer communication and provides scientific underpinning of research to ensure effective interventions. Discussion: We propose a classification of symptoms that places greater emphasis on prognostic factors. Prognosis-based classification aims to categorise the patient’s risk of ongoing symptoms, complications, increased healthcare use or disability because of the symptoms. Current evidence suggests several factors which may be used: symptom characteristics such as: number, multi-system pattern, frequency, severity. Other factors are: concurrent mental disorders, psychological features and demographic data. We discuss how these characteristics may be used to classify symptoms into three groups: self-limiting symptoms, recurrent and persistent symptoms, and symptom disorders. The middle group is especially relevant in primary care; as these patients generally have reduced quality of life but often go unrecognised and are at risk of iatrogenic harm. The presented characteristics do not contain immediately obvious cut-points, and the assessment of prognosis depends on a combination of several factors. Conclusion: Three criteria (multiple symptoms, multiple systems, multiple times) may support the classification into good, intermediate and poor prognosis when dealing with symptoms in primary care. The proposed new classification specifically targets the patient population in primary care and may provide a rational framework for decision-making in clinical practice and for epidemiologic and clinical research of symptoms

Cj1411c Encodes for a Cytochrome P450 Involved in Campylobacter jejuni 81-176 Pathogenicity

Cytochrome P450s are b-heme-containing enzymes that are able to introduce oxygen atoms into a wide variety of organic substrates. They are extremely widespread in nature having diverse functions at both biochemical and physiological level. The genome of C. jejuni 81-176 encodes a single cytochrome P450 (Cj1411c) that has no close homologues. Cj1411c is unusual in its genomic location within a cluster involved in the biosynthesis of outer surface structures. Here we show that E. coli expressed and affinity-purified C. jejuni cytochrome P450 is lipophilic, containing one equivalent Cys-ligated heme. Immunoblotting confirmed the association of cytochrome P450 with membrane fractions. A Cj1411c deletion mutant had significantly reduced ability to infect human cells and was less able to survive following exposure to human serum when compared to the wild type strain. Phenotypically following staining with Alcian blue, we show that a Cj1411c deletion mutant produces significantly less capsular polysaccharide. This study describes the first known membrane-bound bacterial cytochrome P450 and its involvement in Campylobacter virulence