Association Between Ex Vivo Human Ulcerative Colitis Explant Protein Secretion Profiles and Disease Behaviour.

BACKGROUND: The clinical course of ulcerative colitis (UC) is variable. There is an unmet clinical need for biomarkers of UC disease behaviour. We aimed to evaluate the association between ex vivo human UC explant conditioned media (explant-CM) secreted protein profiles and UC disease behaviour. METHODS: UC patients undergoing endoscopy were prospectively recruited. Endoscopic biopsies were collected and explant-CM generated. Association between explant-CM protein secretion profiles and disease progression was evaluated. Disease progression was defined as the requirement for corticosteroid therapy, UC-related hospitalisation, UC-related surgery or the introduction of a new immunomodulatory agent. Association between explant-CM secreted protein profiles and anti-TNF failure status was also evaluated. p values < 0.05 were considered significant in analyses. RESULTS: Twenty-four UC patients were included (age [median, range]) 55 [21-72] years; 50% female. Disease progression during follow-up occurred in twelve (50%) patients. Multivariate analysis, including endoscopic remission status, demonstrated reduced IL-2 secretion to be independently associated with UC disease progression, p = 0.01. In univariate analysis, anti-TNF failure status was associated with significantly increased IL-17A/F (p = 0.015) and IL-12 / IL-23p40 (p = 0.044) concentrations. In multivariate analysis, there was a trend towards an association between IL-17A/F and anti-TNF failure status (p = 0.069); FLT-1 was demonstrated to be independently associated with anti-TNF failure status (p = 0.016). CONCLUSION: Reduced explant-CM secreted IL-2 is associated with UC disease progression. Increased secretion of IL-23 pathway-associated cytokines was observed in anti-TNF failure status consistent with previous reports. Ex vivo human UC explants, generated from endoscopic biopsies, have potential as precision medicine tools in inflammatory bowel disease.

Oral hygiene behaviour automaticity: Are toothbrushing and interdental cleaning habitual behaviours?

OBJECTIVES: Toothbrushing and interdental cleaning are critical to maintaining good oral health. Literature is beginning to suggest that these behaviours may be conducted automatically, although the instigation ('deciding to do') and execution ('doing') of these behaviours has never been examined separately. The objective of this study was to test a theoretically informed supposition that oral hygiene behaviours in adults are automatic behaviours. METHODS: One hundred and fifty participants attending three types of dental providers covering emergency and routine dental services, completed a questionnaire. The self-reported behavioural automaticity index scale (SRBAI) was used to measure behavioural automaticity. RESULTS: Morning toothbrushing SRBAI scores were higher than evening scores (Z=-3.315, p = 0.001). Automaticity scores for instigating both toothbrushing and interdental cleaning were also higher compared to execution (toothbrushing: Z=-2.601, p = 0.009 and interdental cleaning: Z=-2.256. p = 0.024). Toothbrushing automaticity scores were associated with age, gender and self-efficacy, whereas interdental cleaning automaticity scores were associated with intention. Individuals in lower socio-economic status (SES) occupations had significantly higher automaticity scores for interdental cleaning compared to those with higher SES roles. CONCLUSIONS: A high proportion of people undertake toothbrushing and interdental cleaning automatically, especially in relation to embarking on these behaviours. This is most pronounced in morning toothbrushing. CLINICAL SIGNIFICANCE: Promoting improvements in oral hygiene behaviour toothbrushing and interdental cleaning are key strategies in preventing caries and periodontal disease. A greater understanding of what prompts and sustains these behaviours helps inform how behaviour change efforts should be approached.

How liquid biopsies can change clinical practice in oncology.

Cell-free DNA fragments are shed into the bloodstream by tumor cells. The analysis of circulating tumor DNA (ctDNA), commonly known as liquid biopsy, can be exploited for a variety of clinical applications. ctDNA is being used to genotype solid cancers non-invasively, to track tumor dynamics and to detect the emergence of drug resistance. In a few settings, liquid biopsies have already entered clinical practice. For example, ctDNA is used to guide treatment in a subset of lung cancers. In this review, we discuss how recent improvements in the sensitivity and accuracy of ctDNA analyses have led to unprecedented advances in this research field. We further consider what is required for the routine deployment of liquid biopsies in the clinical diagnostic space. We pinpoint technical hurdles that liquid biopsies have yet to overcome, including preanalytical and analytical challenges. We foresee how liquid biopsies will transform clinical practice: by complementing (or replacing) imaging to monitor treatment response and by detecting minimal residual disease after surgery with curative intent.

Anti-EGFR-resistant clones decay exponentially after progression: implications for anti-EGFR re-challenge.

BACKGROUND: Colorectal cancer (CRC) has been shown to acquire RAS and EGFR ectodomain mutations as mechanisms of resistance to epidermal growth factor receptor (EGFR) inhibition (anti-EGFR). After anti-EGFR withdrawal, RAS and EGFR mutant clones lack a growth advantage relative to other clones and decay; however, the kinetics of decay remain unclear. We sought to determine the kinetics of acquired RAS/EGFR mutations after discontinuation of anti-EGFR therapy. PATIENTS AND METHODS: We present the post-progression circulating tumor DNA (ctDNA) profiles of 135 patients with RAS/BRAF wild-type metastatic CRC treated with anti-EGFR who acquired RAS and/or EGFR mutations during therapy. Our validation cohort consisted of an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling. A separate retrospective cohort of 80 patients was used to evaluate overall response rate and progression free survival during re-challenge therapies. RESULTS: Our analysis showed that RAS and EGFR relative mutant allele frequency decays exponentially (r2=0.93 for RAS; r2=0.94 for EGFR) with a cumulative half-life of 4.4 months. We validated our findings using an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling, confirming exponential decay with an estimated half-life of 4.3 months. A separate retrospective cohort of 80 patients showed that patients had a higher overall response rate during re-challenge therapies after increasing time intervals, as predicted by our model. CONCLUSION: These results provide scientific support for anti-EGFR re-challenge and guide the optimal timing of re-challenge initiation.

A systematic review of interventions using cue-automaticity to improve the uptake of preventive healthcare in adults: applications to dental visiting.

OBJECTIVE: Since behaviour is underpinned by both cognitive and automatic processes, psychological interventions aiming to instigate or modify habitual behaviour (cue-automaticity interventions) offer an alternative to the more commonly used (mainly educational) strategies to increase preventive healthcare use. Theory suggests that low socio-economic (SES) groups are especially likely to benefit. Cue-automaticity describes how repetition of behaviour, initiated by a particular 'cue', in a constant context, leads to the automatic instigation and/or execution of behaviour. Our primary objective was to assess the effectiveness of cue-automaticity interventions to improve the uptake of adult preventive healthcare, and to consider how this might be applied to the design of interventions to promote preventive dental visiting. BASIC RESEARCH DESIGN: An electronic search, with citation snowballing, of cue-automaticity interventions to influence adult preventive healthcare use was undertaken. RESULTS: Searching identified 11,888 titles and abstracts. Paper screening left 26 papers, of which 6 RCTs met the inclusion criteria. All 6 incorporated an Implementation Intention (I-I) component. Four studies involved cancer screening and 2 involved vaccination programmes. Five studies showed a significantly positive increase in preventive healthcare use, while one did not. CONCLUSIONS: Whilst few studies using cue-automaticity to underpin the promotion of preventive care use have been undertaken, studies that do exist have promising results. As cue-automaticity interventions may be of particular benefit to low SES groups, research is needed to investigate whether cue-automaticity interventions can translate into reducing inequalities in attendance for dental check-ups.

Opportunistic screening for atrial fibrillation in a rural area.

INTRODUCTION: Opportunistic screening is an effective means of identifying subjects with Atrial Fibrillation (AF). Previous studies of opportunistic screening have been performed areas with high population density and before the development of novel oral anticoagulant drugs. We performed a study to determine feasibility of AF screening in a predominantly rural, low population density area. METHODS: Over 6 months, subjects 65 years and older were screened by local General Practitioners using radial pulse palpation confirmed by 12 lead Electrocardiogram. Data were recorded electronically and those with newly identified AF were followed up to examine management post diagnosis. RESULTS: In total, 7262 subjects were screened and an irregular pulse was found in 916 (12.6%) of whom 735 (10.1%) had known AF and 55 (0.76%) had newly detected AF. Of these 55 patients with newly documented AF, 28 (50.9%) were women, 38 (69.1%) had hypertension and eight (14.5%) had a smoking history. Mean body mass index in subjects with newly documented AF was 28.9 kg/m(2)(SD 5.6) There was no significant difference in gender mix (P = 0.4), smoking history (P = 0.8) or alcohol history (P = 0.8) with the overall population. Fifty-one (92.7%) subjects had a CHA2DS2VaSC score ≥ 2 of whom 33 (64.7%) were eventually anticoagulated and nine (17.6%) commenced on Aspirin. The rate of newly identified patients in AF was lower than in previous reported key studies because of a higher rate of subjects with known AF. CONCLUSION: Opportunistic AF screening in a rural environment identified a substantial number of new cases, although less than in previous screening studies.

A review of bed utilisation in the west of Ireland.

To ensure efficient use of Irish acute hospitals, the study aimed to assess the appropriateness of admission and days of care. The Appropriateness Evaluation Protocol (AEP) was applied to a stratified random sample of 286 medical and surgical, elective and non-elective patients from four acute hospitals in the west of Ireland. A total of 23 patients (8%) were inappropriately admitted. Of these 15 (65%) could have been avoided. Of the 34 elective/booked admissions, seven (21%) were inappropriate in terms of location of surgery criteria. Over three quarters of elective patients (77%) were admitted one or more days prior to surgery which was not justified for 13 (57%) of these patients. Over a quarter of days of care (n = 73, 26%) were inappropriate. Evidence of discharge planning was found for 48% of patients. The study provides a benchmark to monitor progress. Existing policies and programmes should be implemented and monitored.

Review of acute cancer beds.

A review of admissions to cancer services at University Hospital Galway (UHG) was undertaken to assess the appropriateness of hospital usage. All cancer specialty patients admitted from 26-28 May 2009 were reviewed (n = 82). Chi square tests, Exact tests, and One-way ANOVA were utilised to analyse key issues emerging from the data. Fifty (61%) were classified as emergencies. Twenty three (67%) occupied a designated cancer bed with 24 (30%) in outlying non-oncology wards. The mean length of stay was 29.3 days. Possible alternatives to admission were identified for 15 (19%) patients. There was no evidence of discharge planning for 50 (60%) admissions. There is considerable potential to make more appropriate utilisation of UHG for cancer patients, particularly in terms of reducing bed days and length of stay and the proportion of emergency cancer admissions, and further developing integrated systems of discharge planning.

Experience Sampling Methodology studies of depression: the state of the art.

BACKGROUND: Experience Sampling Methodology (ESM) is ideally suited to test the predictions, and inform the development of contemporary cognitive models of depression. Yet there has been no systematic examination of ESM in depression research. METHOD: A search of databases (PsychARTICLES, PsycINFO, AMED, Ovid Medline and CINAHL) was conducted to identify studies published within the last 25 years investigating major depressive disorder (MDD) using ESM. RESULTS: Altogether, 19 studies using ESM, or comparable methodologies, with clinically depressed individuals were identified and critically reviewed. The identified studies examined six aspects of MDD: methodological issues; positive and negative affect; cortisol secretion; antidepressant treatment; work performance; genetic risk factors. CONCLUSIONS: Despite some methodological limitations of existing studies, ESM has made a significant contribution to our current understanding of depression by consolidating existing theories, uncovering new and clinically relevant findings and identifying questions for future research. This review concludes by introducing the possibility of using ESM as an intervention tool in clinical practice and proposing that ESM could be useful for furthering knowledge of the causes of MDD.

The allusive cognitive deficit in paranoia: the case for mental time travel or cognitive self-projection.

Delusional beliefs are characteristic of psychosis and, of the delusions, the paranoid delusion is the single most common type associated with psychosis. The many years of research focused on neurocognition in schizophrenia, using standardized neurocognitive tests, have failed to find conclusive cognitive deficits in relation to positive symptoms. However, UK-based psychological research has identified sociocognitive anomalies in relation to paranoid thinking in the form of theory of mind (ToM), causal reasoning and threat-related processing anomalies. Drawing from recent neuroscientific research on the default mode network, this paper asserts that the common theme running through the psychological tests that are sensitive to the cognitive impairment of paranoia is the need to cognitively project the self through time, referred to as mental time travel. Such an understanding of the cognitive roots of paranoid ideation provides a synthesis between psychological and biological accounts of psychosis while also retaining the powerful argument that understanding abnormal thinking must start with models of normal cognition. This is the core theme running through the cognitive psychological literature of psychiatric disorders that enables research from this area to inform psychological therapy.

A transdiagnostic investigation of 'theory of mind' and 'jumping to conclusions' in patients with persecutory delusions.

BACKGROUND: A tendency to make hasty decisions on probabilistic reasoning tasks and a difficulty attributing mental states to others are key cognitive features of persecutory delusions (PDs) in the context of schizophrenia. This study examines whether these same psychological anomalies characterize PDs when they present in the context of psychotic depression. METHOD: Performance on measures of probabilistic reasoning and theory of mind (ToM) was examined in five subgroups differing in diagnostic category and current illness status. RESULTS: The tendency to draw hasty decisions in probabilistic settings and poor ToM tested using story format feature in PDs irrespective of diagnosis. Furthermore, performance on the ToM story task correlated with the degree of distress caused by and preoccupation with the current PDs in the currently deluded groups. By contrast, performance on the non-verbal ToM task appears to be more sensitive to diagnosis, as patients with schizophrenia spectrum disorders perform worse on this task than those with depression irrespective of the presence of PDs. CONCLUSIONS: The psychological anomalies associated with PDs examined here are transdiagnostic but different measures of ToM may be more or less sensitive to indices of severity of the PDs, diagnosis and trait- or state-related cognitive effects.

Outpatient experiences in acute hospitals.

BACKGROUND: Patient satisfaction surveys are useful in gaining an understanding of users' needs and their perceptions of the service received. AIM; To assess the views of outpatient department (OPD) attendees on the quality of service received. METHODS: OPD attendees were randomly selected from four acute hospitals in one health board region and sent a confidential postal questionnaire to assess their views on their visit. RESULTS: Of 3,037 attendees surveyed, there was a response rate of 75.7%. Levels of satisfaction were high at 94%. Doctors and nurses were perceived as friendly by 61% and 72%, professional by 44% and 30%, rushed by 8% and 7%, and rude by 1% and 1% of patients, respectively. Using logistic regression, age (being older), sex (being male), pain level (no pain), decisions about care (wanting more involvement) and being satisfied with their waiting time from arrival to being seen were significantly associated with a greater likelihood of being satisfied overall. CONCLUSION; Whilst there was a high level of satisfaction with the quality of care received, areas for improvement were highlighted from the patient's perspective.

Persecutory delusions: a review and theoretical integration.

Persecutory (paranoid) delusions are a frequently observed clinical phenomenon. In recent years, an increasing volume of research has attempted to explain these types of beliefs in terms of psychological mechanisms. Theories have emphasized early experience, perceptual abnormalities, motivational factors, and information-processing deficits. In this article we review relevant findings, including our own studies of the role of causal attributions and theory of mind deficits. We propose a new integrative model that builds on this work. The core of the model is an account of the way that causal attributions influence self-representations, which in turn influence future attributions: the attribution--self-representation cycle. We argue that biases in this cycle cause negative events to be attributed to external agents and hence contribute to the building of a paranoid world view. These abnormalities are amenable to investigation by functional neuroimaging, and recent studies have implicated specific areas of neuroactivation. However, these findings do not necessarily suggest that paranoid delusions are entirely biological in origin, and there is evidence that adverse early experience may play a role in determining the development of a cognitive vulnerability to paranoid thinking.

A mouse model for medulloblastoma and basal cell nevus syndrome.

Medulloblastoma (MB), a tumor of the cerebellum, is the most frequent type of malignant childhood brain tumor. Multiple genes are causally involved in medulloblastoma including PATCHED1 (PTCH). The Patchedl (Ptc1) protein is a receptor for Sonic hedgehog (Shh), a secreted protein ligand. Shh is involved in many signaling processes that control cell fate and growth, among which is its emission from Purkinje cells in the developing cerebellum. Purkinje cell-derived Shh stimulates mitosis of the granule cell precursors that may be the cell type of origin in medulloblastoma. Ptc1 limits the effects of the Shh signal, so mutations in PTCH may lead to persistent granule cell precursors susceptible to further genetic or environmental events that cause medulloblastoma. Mice heterozygous for patched (ptc1) mutations, like heterozygous PTCH humans, have a high rate of medulloblastoma as well as other tumors. We discuss features of the mouse model and how it is contributing to understanding the process of brain tumorigenesis.

Quality of life following total hip replacement.

Orthopaedic surgeons have traditionally used disease-specific scoring systems that focus on relief of pain and improvement in function. However, these allow little scope for patient assessed outcomes such as quality of life. This study assessed quality of life before and after Total Hip Replacement (THR) using the Short Form 36 (SF-36) questionnaire. 100 patients were interviewed pre-operatively and 9 months to one year post-operatively. Data on waiting times/length of stay/complication rates were collected by reviewing clinical notes. The mean length of stay was 22.0 +/- 10.6 days, with a pre-operative length of stay of 5.0 days. 12 patients in all had a post-operative complication, including one post-operative death. There was a statistically significant improvement in overall SF-36 score (+19%) and in 7 out of the 8 parameters that make up the SF-36 score (p < 0.001). Patients undergoing THR in Navan showed a statistically significant improvement in their quality of life post-operatively. Complication rates were in keeping with international norms. It is apparent that patients receive a high quality of care.