Does testosterone mediate the relationship between vitamin D and prostate cancer? A systematic review and meta-analysis protocol.

BACKGROUND: Evidence from studies on prostate cancer progression have identified vitamin D to be a potentially important nutrient. However, the World Cancer Research Fund and American Institute for Cancer Research have reported the quality of this evidence to be limited and warrant further investigation. We plan to use the recently developed WCRF International/University of Bristol mechanistic systematic review framework to determine whether the observed association between vitamin D and prostate cancer exists through a plausible biological pathway. METHODS: This protocol sets out how we will perform a systematic review of the literature in human and animal studies. We will search the electronic databases MEDLINE, EMBASE, PubMed, and BIOSIS Citation Index without restrictions on year of publication or language. We will extract data from observational and experimental studies examining two inter-linked pathways in the relationship between vitamin D and prostate cancer progression: (1) vitamin D and testosterone, and (2) testosterone and prostate cancer progression. We focus on testosterone as its actions form a potentially novel intermediate mechanism that was identified via our online literature mining tools. The outcomes of interest include incidence or prevalence of prostate cancer, measures of prostate cancer progression (including biochemical recurrence, local, or distal metastases), and prostate cancer-specific mortality. We will assess study quality and the level of certainty of the evidence. We will analyse data where possible, using meta-analysis with forest plots or albatross plots; otherwise, a narrative synthesis will be performed. DISCUSSION: To our knowledge, this will be the first systematic synthesis of the evidence underpinning the vitamin D-testosterone-prostate cancer mechanistic pathway. The results of the review may inform future research, intervention trials, and public health messages.

MELODI: Mining Enriched Literature Objects to Derive Intermediates.

BACKGROUND: The scientific literature contains a wealth of information from different fields on potential disease mechanisms. However, identifying and prioritizing mechanisms for further analytical evaluation presents enormous challenges in terms of the quantity and diversity of published research. The application of data mining approaches to the literature offers the potential to identify and prioritize mechanisms for more focused and detailed analysis. METHODS: Here we present MELODI, a literature mining platform that can identify mechanistic pathways between any two biomedical concepts. RESULTS: Two case studies demonstrate the potential uses of MELODI and how it can generate hypotheses for further investigation. First, an analysis of ETS-related gene ERG and prostate cancer derives the intermediate transcription factor SP1, recently confirmed to be physically interacting with ERG. Second, examining the relationship between a new potential risk factor for pancreatic cancer identifies possible mechanistic insights which can be studied in vitro. CONCLUSIONS: We have demonstrated the possible applications of MELODI, including two case studies. MELODI has been implemented as a Python/Django web application, and is freely available to use at [www.melodi.biocompute.org.uk].

Stress, Illness Perceptions, Behaviors, and Healing in Venous Leg Ulcers: Findings From a Prospective Observational Study.

OBJECTIVE: The aim of the study was to investigate the impact of stress, illness perceptions, and behaviors on healing of venous leg ulcers. METHODS: A prospective observational study of 63 individuals for 24 weeks investigated possible psychosocial predictors of healing. There were two indices of healing: rate of change in ulcer area and number of weeks to heal. Psychological variables were assessed at baseline using self-report measures (Perceived Stress Scale, Hospital Anxiety and Depression Scale, Revised Illness Perception Questionnaire, adapted Summary of Diabetes Self-Care Activities, Adherence Questionnaire, and Short-Form Health Survey). RESULTS: Controlling for sociodemographic and clinical variables, for the 24 weeks, a slower rate of change in ulcer area was predicted by greater stress (standardized ß = -0.61, p = .008), depression (standardized ß = -0.51, p = .039), and holding negative perceptions or beliefs about the ulcer (standardized ß = -1.4, p = .045). By 24 weeks, 69% of ulcers had closed. A more negative emotional response to the ulcer at baseline (i.e., emotional representation of the ulcer) was associated with a greater number of weeks to heal (hazard ratio [HR] = 0.63, 95% confidence interval [CI] = 0.41-0.95, p = .028). Higher educational attainment (HR = 3.22, 95% CI = 1.37-7.55, p = .007) and better adherence to compression bandaging (HR = 1.41, 95% CI = 1.06-1.88, p = .019) were associated with fewer weeks to heal. No other psychosocial variable (stress, perceptions about the ulcer, health behaviors) predicted weeks to heal. CONCLUSIONS: Alongside ulcer-related predictors, psychological and sociodemographic factors were associated with healing. Future research should explore mediating mechanisms underlying these associations and develop interventions to target these variables.

Illness Beliefs Predict Mortality in Patients with Diabetic Foot Ulcers.

BACKGROUND: Patients' illness beliefs have been associated with glycaemic control in diabetes and survival in other conditions. OBJECTIVE: We examined whether illness beliefs independently predicted survival in patients with diabetes and foot ulceration. METHODS: Patients (n=169) were recruited between 2002 and 2007. Data on illness beliefs were collected at baseline. Data on survival were extracted on 1st November 2011. Number of days survived reflected the number of days from date of recruitment to 1st November 2011. RESULTS: Cox regressions examined the predictors of time to death and identified ischemia and identity beliefs (beliefs regarding symptoms associated with foot ulceration) as significant predictors of time to death. CONCLUSIONS: Our data indicate that illness beliefs have a significant independent effect on survival in patients with diabetes and foot ulceration. These findings suggest that illness beliefs could improve our understanding of mortality risk in this patient group and could also be the basis for future therapeutic interventions to improve survival.

The effects of perceived stress on biological parameters in healthcare professionals: A systematic review.

We synthesised evidence on biological correlates of psychological stress in hospital-based healthcare professionals, and examined whether there was evidence of consistent biological changes. Electronic databases were searched for empirical studies; 16 articles (0.6%) met the inclusion criteria. Evidence of a relationship between indices of psychological stress and biological parameters was limited and inconsistent. There was some evidence of a consistent relationship between natural killer cells and lymphocyte subpopulations. Considerable heterogeneity in the methods used was seen. Future prospective studies examining the relationship between indices of psychological stress and natural killer cells, including lymphocyte subsets, is required.

Illness beliefs predict self-care behaviours in patients with diabetic foot ulcers: a prospective study.

AIMS: Patients' illness beliefs are known to be influential determinants of self-care behaviours in many chronic conditions. In a prospective observational study we examined their role in predicting foot self-care behaviours in patients with diabetic foot ulcers. METHODS: Patients (n=169) were recruited from outpatient podiatry clinics. Clinical and demographic factors, illness beliefs and foot self-care behaviours were assessed as baseline (week 0). Foot self-care behaviours were assessed again 6, 12 and 24 weeks later. Linear regressions examined the contribution of beliefs at baseline to subsequent foot self-care behaviours, controlling for past behaviour (i.e., foot self-care at baseline) and clinical and demographic factors that may affect foot self-care (i.e., age and ulcer size). RESULTS: Our models accounted for between 42 and 58% of the variance in foot self-care behaviours. Even after controlling for past foot-care behaviours, age and ulcer size; patients' beliefs regarding the symptoms associated with ulceration, their understanding of ulceration and their perceived personal control over ulceration emerged as independent determinants of foot self-care. CONCLUSIONS: Patients' beliefs are important determinants of foot-care practices. They may, therefore, also be influential in determining ulcer outcomes. Interventions aimed at modifying illness beliefs may offer a means for promoting self-care and improving ulcer outcomes.

The association of maternal prenatal psychosocial stress with vascular function in the child at age 10-11 years: findings from the Avon longitudinal study of parents and children.

OBJECTIVE: To investigate whether (1) maternal psychosocial stress (depression/anxiety) during pregnancy is associated with offspring vascular function and (2) whether any association differs depending on the gestational timing of exposure to stress. We also investigated whether any association is likely to be due to intrauterine mechanisms by (3) comparing with the association of paternal stress with offspring vascular function and (4) examining whether any prenatal association is explained by maternal postnatal stress. METHODS AND RESULTS: Associations were examined in a UK birth cohort, with offspring outcomes (systolic and diastolic blood pressure, SBP and DBP, endothelial function assessed by brachial artery flow-mediated dilatation (FMD); arterial stiffness assessed by carotid to radial pulse wave velocity (PWV), brachial artery distensibility (DC), and brachial artery diameter (BD) assessed at age 10-11 years (n = 4,318). Maternal depressive symptoms and anxiety were assessed at 18 and 32 weeks gestation and 8 months postnatally. Paternal symptoms were assessed at week 19. With the exception of DBP and BD, there were no associations of maternal depressive symptoms with any of the vascular outcomes. Maternal depressive and anxiety symptoms were associated with lower offspring DBP and wider BD, though the latter attenuated to the null with adjustment for confounding factors. Paternal symptoms were not associated with offspring outcomes. Maternal postnatal depressive symptoms were associated with lower offspring SBP. CONCLUSIONS: We found no evidence to support the hypothesis that maternal stress during pregnancy adversely affects offspring vascular function at age 10-12 years via intrauterine mechanisms.

Opportunities to say 'yes': rare speech automatisms in a case of progressive nonfluent aphasia and apraxia.

We describe the investigation of speech automatisms in a man with progressive nonfluent aphasia and apraxias. Occurrence of the automatisms yes and right, were analysed across a range of speech tasks varying in length, propositionality, lexical and articulatory complexity, whether tasks engaged internal generation or external triggering and articulatory distortions, and while completing pantomimes/gestures. No differences were found in occurrence across most tasks but there was a significant interaction between automatism production and apraxic speech errors and during limb praxic tasks, suggesting that production of the automatism was unrelated to linguistic or lexical variables, but was related to the presence of speech apraxia coupled with disinhibition.

Reducing the burden of chronic wounds: prevention and management of the diabetic foot in the context of clinical guidelines.

OBJECTIVES: Chronic wounds such as diabetic foot and venous leg ulcers are a major burden for health services. Our programme was developed to explore the psychological and behavioural factors that may influence both the incidence of chronic wounds and their progression. The present article focuses on two particular aspects of the programme: patient knowledge of diabetic foot ulceration and factors influencing foot-related behaviour in patients with and without foot ulcers; and patient and podiatrist perspectives of consultations for diabetic foot ulcers. METHODS: Two independent qualitative studies were undertaken: one with diabetic patients without a history of ulceration; and the other with diabetic patients with active ulceration and podiatrists treating these patients. RESULTS: We found that patients may find it difficult understanding the rationale underlying prevention and treatment of foot ulcers; ulcerated patients may find it difficult to engage in the management of their foot ulcer outside consultations; and some podiatrists feel frustrated and unsupported in their attempts at empowering and building partnerships with patients. CONCLUSION: Patient and practitioner factors may contribute to the effective implementation of clinical guidelines regarding education, partnership building and shared decision-making. These findings are discussed in relation to patient education, partnership building and shared decision-making as recommended in NICE guidelines.

The detection of multisensory stimuli in an orthogonal sensory space.

The detection of a stimulus can be considerably facilitated if the stimulus engages two or more sensory modalities simultaneously. This phenomenon, commonly referred to as multisensory (or cross-modal) facilitation, has been demonstrated behaviorally in cats and humans. A number of rules are thought to govern this phenomenon. These rules state that strong facilitation is to be expected only if the two sensory modalities are stimulated simultaneously and at the same place, and if the stimuli themselves are weak. However, these rules are not sufficient to allow accurate predictions of multimodal stimulus detection probabilities directly from physical stimulus parameters. Here we show that such predictions are possible on the basis of a simple and biologically plausible psychophysical model, which relates the detection of audio-visual, audio-tactile or visual-tactile stimuli to the Euclidean distance that these stimuli span in an orthogonal sensory space.

Phonetic and phonological analysis of progressive speech degeneration: a case study.

In this paper we report on an adult male participant with a rare form of progressive speech degeneration. We present acoustic phonetic data on his vowel and consonant production, and describe his prosody and syllable structure. We suggest possible phonological analyses of his speech, concluding that a gestural approach to phonology best characterizes his speech production and its degeneration.