Search

Chinese have a higher stroke incidence and a different distribution of ischemic stroke (IS) subtypes as compared with Caucasians. Herein we aimed to investigate the prevalence and associations of major risk factors in IS and its subtypes in Chinese patients. From 2006 to 2011, we included 4953 acute IS patients consecutively recruited in National Taiwan University Hospital Stroke Registry (mean age 68 years; male 59%). For each risk factor, we accessed the proportion in all IS patients, and calculated odds ratios for each main IS subtype versus other subtypes. Multiple logistic regression models were used to adjust for confounders, and to examine the associations of risk factors with IS subtypes. Compared with other ischemic subtypes, large artery atherosclerotic and lacunar strokes were associated with hypertension, diabetes, and hyperlipidaemia, while cardioembolic strokes were associated with ischemic heart disease. Furthermore, the associations with hypertension and diabetes became stronger in lacunar strokes after adjusting for confounders, but not in other ischemic subtypes. Here we report the variable effects of risk factors on different IS subtypes in Chinese patients in Taiwan. Our findings could help shed light on different mechanisms of IS subtypes and provide targets to make more effective strategies for IS prevention.

Objective It is unclear whether how people with long-term conditions express distress, and how clinicians respond, influences perceptions of consultation outcomes. The pilot study examined emotional distress and reassurance in consultations with people whose long-term conditions (at the time of consultations) were treated using active surveillance or symptom management (as no curative treatment was suitable). Methods An observational pilot study was conducted involving consultations between people with long-term conditions and their respective clinician. Consultations between three clinicians (two Huntington’s Disease; one Prostate Cancer) and 22 people with long-term conditions (11 Huntington’s Disease; 11 Prostate Cancer) were audio-recorded. Participants also completed an expanded Consultation and Relational Empathy (CARE) Measure. Two researchers coded sessions using Verona Coding Definitions of Emotional Sequences (VR-CoDES/VR-CoDES-P). Code frequencies were calculated, t tests performed between conditions, and Pearson’s correlations performed for associations between CARE responses and clinician utterances. Results People with long-term conditions expressed emotional distress on average 4.45 times per session, averaging 1.09 Concern and 3.36 Cue utterances. Clinicians responded with more explicit (2.59) and space-providing (3.36), than non-explicit (1.86) and space-reducing (1.09), responses per session. Clinicians expressed spontaneous reassurance on average 5.18 times per session, averaging 3.77 Cognitive and 1.5 Affective reassurance utterances. Huntington’s Disease consultations featured significantly more 'Cues', 'Concerns' and 'Overall' 'Emotional Distress', and 'Cognitive' and 'Overall' ‘Reassurance'. Conclusion Emotional distress was expressed more using hints than explicit concern utterances. Clinicians predominantly explicitly explored distress rather than providing information/advice and provided advice using spontaneous cognitive reassurance. People with Huntington’s Disease expressed more concerns and received more reassurance, indicating different needs between conditions. Future research is required to explore emotional distress and reassurance in a larger sample of participants and long-term condition types, and how the practical implications of these findings may be used to enhance outcomes of consultations. Trial registration N/A.

Background: In response to an outbreak of severe meningococcal disease caused by serogroup W, the UK introduced the meningococcal ACWY (MenACWY) for adolescents and new university students as a control measure. Objective: To estimate MenACWY vaccine uptake and identify factors associated with uptake, barriers and motivations towards vaccination among university students. Design: Mixed methods including a cross-sectional survey, 7 interviews and 1 focus group. Setting: A Scottish university between April and May 2016. Methods: Inclusion criteria were Results: MenACWY uptake among the sample was 71.5% (549/768). Older students (22–24 years) were less likely than younger students (18 years) to have been vaccinated [adjusted odds ratio (aOR) = 0.21; 95% confidence interval (CI) = 0.06–0.77], and male students were less likely to be vaccinated than female students (aOR = 0.667; 95% CI = 0.45–0.96). In comparison to international students, domestic students had a significantly higher odds of vaccination (aOR = 3.89; 95% CI = 2.64–5.72). Communication barriers were most frequently identified as reasons for non-vaccination. Most vaccination occurred before starting university (76.7%, 421/549), highlighting access barriers. Meningococcal disease knowledge was low; a significant association ( p Conclusion: Students outside main UK-based, core age cohorts were under-immunised and focused efforts are needed to improve vaccination rates. Future student vaccination programmes could focus on raising awareness of the serious implications of meningococcal disease. Additional benefit may be gained from emphasising the benefits of vaccinations for society as a whole.

Introduction SUPREMO is a phase 3 randomised trial evaluating radiotherapy post-mastectomy for intermediate-risk breast cancer. 1688 patients were enrolled from 16 countries between 2006 and 2013. We report the results of central pathology review carried out for quality assurance. Patients and methods A single recut haematoxylin and eosin (H&E) tumour section was assessed by one of two reviewing pathologists, blinded to the originally reported pathology and patient data. Tumour type, grade and lymphovascular invasion were reviewed to assess if they met the inclusion criteria. Slides from potentially ineligible patients on central review were scanned and reviewed online together by the two pathologists and a consensus reached. A subset of 25 of these cases was double-reported independently by the pathologists prior to the online assessment. Results The major contributors to the trial were the UK (75%) and the Netherlands (10%). There is a striking difference in lymphovascular invasion (LVi) rates (41.6 vs. 15.1% (UK); p =

BACKGROUND: In 2018, there was a record incidence of measles and other vaccine-preventable diseases across developed countries. Declining childhood immunisation uptake in southeast Scotland-an area with a large, highly mobile, and socioeconomically diverse population-threatens regional herd immunity and warrants investigation of suboptimal coverage. As deprivation of social and material resources increases risk of non-vaccination, we examined here the relationship between deprivation, uptake, and timeliness for four routine childhood vaccines and identified trends over the past decade.METHODS: This retrospective cohort study analysed immunisation data from the Scottish Immunisation Recall System (SIRS) for four routine childhood vaccines in the UK: the third dose of the primary vaccine (TPV), both doses of measles, mumps, rubella (MMR 1 and MMR 2), and the preschool booster (PSB). Immunisations (N = 329,897) were administered between 2008 and 2018. Deprivation was measured via the Scottish Index of Multiple Deprivation (SIMD), ranking postcodes by deprivation decile. Chi-squared tests and cox proportional hazards models assessed the relationship between uptake, timeliness, and deprivation.RESULTS: There is strong evidence for an association between deprivation, uptake, and timeliness. Uptake for all childhood immunisations are very high, especially for TPV and MMR 1 (>98.0%), though certain deprivation deciles exhibit increased risks of non-vaccination for all vaccines. Delay was pronounced for the 40% most deprived population and for immunisations scheduled at later ages. Absolute PSB and MMR 2 uptake has improved since 2008; however, disparities in uptake have increased for all vaccines since the 2006 birth cohort.CONCLUSION: Both timeliness and uptake are strongly associated with deprivation. While absolute uptake was high for all vaccines, relative uptake and timeliness has been worsening for most groups; the reason for this decline is unclear. Here we identified subgroups that may require targeted interventions to facilitate uptake and timeliness for essential childhood vaccines.

IntroductionThe Child Health and Nutrition Research Initiative (CHNRI) method for health research prioritisation relies on stakeholders weighting criteria used to assess research options. These weights in turn impact on the final scores and ranks assigned to research options. Three quarters of CHNRI studies published to date have not involved stakeholders in criteria weighting. Of those that have, few incorporated members of the public into stakeholder groups. Those that have compared different stakeholder groups, such as donors, researchers, or policy makers, showed that different groups place different values upon CHNRI criteria. When choosing the composition of a stakeholder group, it may be important to understand factors that may influence weighting. Drawing upon a group of international public stakeholders, this study explores some of the effects of individual and demographic characteristics has on the weights assigned to the most commonly used CHNRI criteria, with the aim of informing future researchers on avoiding future biases.MethodsIndividual and demographic information and 5-point Likert scale responses to questions about the importance of 15 CHNRI criteria were collected from 1031 “Turkers” (Amazon Mechanical Turk workers) via Amazon Mechanical Turk (AMT), which is an online crowdsourcing platform. Thirteen of the fifteen criteria were analysed using random-intercept models and the remaining two were analysed through logistic regression.ResultsSelf-reported health status explained most of the variability in participants’ responses across criteria (11/15 criteria), followed by being female (10/15), ethnicity (9/15), employment (8/15), and religion (7/15). Differences across criteria indicate that when choosing stakeholder groups, researchers need to consider these factors to minimise bias.ConclusionResearchers should collect and report more detailed information from stakeholders, including individual and demographic characteristics, and ensure participation from both genders, multiple ethnicities, religious beliefs,and people with differing health statuses to be transparent regarding possible biases in health research prioritisation. Our analyses indicate that these factors do influence the relative importance of these values, even when the data appears fairly homogeneous.

Background Chinese populations are reported to have a different distribution of ischemic stroke subtypes compared with Caucasians. Aims To understand this better, we aimed to evaluate the differences in prevalence of risk factors in ischemic stroke and their distributions among ischemic stroke subtypes in Chinese vs. Caucasians. Summary or review We systematically sought studies conducted since 1990 with data on frequency of risk factors among ischemic stroke subtypes in Chinese or Caucasians. For each risk factor, we calculated study-specific and random effects pooled estimates in Chinese and Caucasians separately for: prevalence among ischemic stroke; odds ratios, comparing prevalence for each ischemic stroke subtype vs. all others. We included seven studies among 16 199 Chinese, and eleven among 16 189 Caucasian ischemic stroke patients. Risk factors studied were hypertension, diabetes, atrial fibrillation, ischemic heart disease, hypercholesterolemia, smoking and alcohol. Chinese ischemic stroke patients had younger onset of stroke than Caucasians, similar prevalence of hypertension, diabetes, smoking and alcohol, and significantly lower prevalence of atrial fibrillation, ischemic heart disease and hypercholesterolemia. Risk factor associations with ischemic stroke subtypes were mostly similar among Chinese and Caucasian ischemic stroke patients. Compared with all other ischemic subtypes, diabetes was more common in large artery stroke, atrial fibrillation and ischemic heart disease in cardioembolic stroke, and hypertension and diabetes in lacunar stroke. Conclusion Our study showed a lower prevalence of atrial fibrillation, ischemic heart disease and hypercholesterolemia in Chinese, and mostly similar risk factor associations in Chinese and Caucasian ischemic stroke patients. Further analyses of individual patient data to allow adjustment for confounders are needed to confirm and extend these findings.

Objective Innate immune responses to pulmonary resection may be critical in the pathogenesis of important postoperative pulmonary complications and potentially longer-term survival. We sought to compare innate immunity of patients undergoing major pulmonary resection for bronchogenic carcinoma via video-assisted thoracoscopic surgery (VATS) and thoracotomy. Methods Bronchoalveolar lavage was conducted in the contralateral lung before staging bronchoscopy and mediastinoscopy and immediately after lung resection. Blood and exhaled nitric oxide were sampled preoperatively and at 6, 24, and 48 hours postoperatively. Results Forty patients were included (26 VATS and 14 thoracotomy). There was a lower systemic cytokine response from lung resection undertaken by VATS compared with thoracotomy [interleukin 6 (IL-6), analysis of variance (ANOVA) P = 0.026; IL-8, ANOVA P = 0.018; and IL-10, ANOVA P = 0.047]. The VATS patients had higher perioperative serum albumin levels (ANOVA P = 0.001). Lower levels of IL-10 were produced by lipopolysaccharide-stimulated blood monocytes from the VATS patients compared with the thoracotomy patients at 6 hours postoperatively (geometric mean ratio, 1.16; 95% confidence interval, 1.08–1.33; P = 0.011). No statistically significant differences in the neutrophil phagocytic capacity, overall leukocyte count, or differential leukocyte count were found between the surgical groups (ANOVA P > 0.05). No statistically significant differences in bronchoalveolar lavage fluid parameters were found. Exhaled nitric oxide levels fell postoperatively, which reached statistical significance at 48 hours (geometric mean ratio, 1.2; 95% confidence interval, 1.02–1.46; P = 0.029). There were no significant differences found between the surgical groups (ANOVA P = 0.331). Conclusions Overall, a trend toward greater proinflammatory and anti-inflammatory responses is seen with lung resection performed via thoracotomy compared with VATS.

There are concerns about the reporting quality of asthma trials. To describe the reporting of contemporary asthma trials and to identify factors associated with better reporting quality. Two reviewers independently searched MEDLINE for randomised controlled trials (RCTs) of asthma published between January 2010 and July 2012 in leading generalist and specialist journals. We calculated the proportion of trials that adequately reported each Consolidated Standards of Reporting Trials (CONSORT) checklist item and an overall quality score for each trial. Factors associated with better reporting quality were investigated. Thirty-five RCTs satisfied our eligibility criteria. Four trials adequately reported 60% of items. Seventeen of the 38 CONSORT items were consistently well reported in more than two-thirds of the articles. In contrast, nine items were poorly reported in more than half the trials — namely, identification as a randomised trial in the title (40.0%), an adequate structured summary/abstract (48.6%), details of eligibility criteria (34.3%), recruitment (48.6%), randomisation procedures (22.9%), intervention (38.5%), harms (34.3%), the funding source (45.7%), and access to the full trial protocol (17.1%). Studies led by teams in high-income country settings were associated with better quality of reporting (relative risk=1.33, 95% CI 1.09 to 1.64). The quality of reporting in contemporary asthma literature remains suboptimal. We have identified important areas in which reporting quality needs to be improved.

Rationale: Depletion of monocytes reduces LPS-induced lung inflammation in mice, suggesting monocytes as potential therapeutic targets in acute lung injury.Objectives: To investigate whether depletion of circulating blood monocytes has beneficial effects on markers of systemic and pulmonary inflammation in a human model of acute lung inflammation.Methods: A total of 30 healthy volunteers were enrolled in a randomized controlled trial. Volunteers inhaled LPS at baseline, and were randomized to receive active mononuclear cell depletion by leukapheresis, or sham leukapheresis, in a double-blind fashion (15 volunteers per group). Serial blood counts were measured, bronchoalveolar lavage (BAL) was performed at 9 hours, and [18F]fluorodeoxyglucose positron emission tomography at 24 hours. The primary endpoint was the increment in circulating neutrophils at 8 hours.Measurements and Main Results: As expected, inhalation of LPS induced neutrophilia and an up-regulation of inflammatory mediators in the blood and lu...

Background: Chinese populations have a higher stroke incidence, a higher proportion of intracerebral hemorrhage (ICH), and a lower proportion of ischemic stroke (IS) as compared with white populations. The reasons are not fully understood. Methods: To evaluate the differences of major risk factors between ICH and IS in Chinese stroke patients, we analysed acute ICH and IS patients consecutively recruited in National Taiwan University Hospital Stroke Registry from 2006 to 2011. We used multiple logistic regression models to examine the associations of risk factors with ICH vs. IS. Also, we conducted subgroup analyses when a strongly significant interaction was detected. Results: We included a total of 1,373 ICH and 4,953 IS patients. ICH patients were younger than IS patients (mean age 61 vs. 68 years, p < 0.001), but there was no significant difference in gender (males 62 vs. 59%, p = 0.064). A logistic regression model adjusted for age, gender, and other major risk factors showed that both hypertension (OR 2.23, 95% CI 1.74-2.87) and alcohol intake (OR 1.44, 95% CI 1.16-1.77) had significantly stronger associations with ICH than IS, whereas diabetes, atrial fibrillation, ischemic heart disease, hyperlipidemia, smoking, and transient ischemic attack were less associated with ICH than IS. In subgroup analyses, the association of hypertension with ICH vs. IS was more marked in younger patients. Conclusion: Hypertension and alcohol intake are more strongly associated with ICH than IS in Chinese stroke patients, especially in younger patients.

Growth failure is well-recognized in pediatric inflammatory bowel disease (PIBD;18 years). We aimed to examine whether antitumor necrosis factor (TNF) therapy improves growth in a PIBD population-based cohort.A retrospective review of all Scottish children receiving anti-TNF (infliximab [IFX] and adalimumab [ADA]) from 2000 to 2012 was performed; height was collected at 12 months before anti-TNF (T-12), start (T0), and 12 (T+12) months after anti-TNF.Ninety-three of 201 treated with IFX and 28 of 49 with ADA had satisfactory growth data; 66 had full pubertal data. Univariate analysis demonstrated early pubertal stages (Tanner 1-3 n = 44 vs T4-5 n = 22), disease remission, disease duration ≥2 years, and duration of IFX ≥12 months were associated with improved linear growth for IFX; for ADA only improvement was seen in Tanner 1-3. For IFX, Tanner 1-3 median Δ standard deviation scores for height (Ht SDS) -0.3 (-0.7, 0.2) at T0 changed to 0.04 (-0.5, 0.7) at T+12 (P 0.001) versus -0.01 (-0.5, 0.9) at T0 in T4-5 changed to -0.01 (-0.4, 0.2) at T+12 (P 0.05). For IFX disease duration ≥2 year, median Δ Ht SDS was -0.13 (-0.6, 0.3) at T0 then 0.07 (-0.3, 0.6) at T+12 (P 0.001). Remission improved Δ Ht SDS (median Δ Ht SDS -0.14 [-0.6, 0.3] at T0 to 0.17 [-0.2, 0.7] at T+12 [P 0.001]). Multiple regression analysis demonstrated corticosteroid usage at T0 predicted improved Δ Ht SDS at T+12 for IFX and ADA.Anti-TNF therapy is more likely to be associated with growth improvement when used at earlier stages of puberty with remission a key growth-promoting strategy in pediatric Crohn disease.

Ventilator-acquired pneumonia (VAP) is a common reason for antimicrobial therapy in the intensive care unit (ICU). Biomarker-based diagnostics could improve antimicrobial stewardship through rapid exclusion of VAP. Bronchoalveloar lavage (BAL) fluid biomarkers have previously been shown to allow the exclusion of VAP with high confidence. This is a prospective, multi-centre, randomised, controlled trial to determine whether a rapid biomarker-based exclusion of VAP results in fewer antibiotics and improved antimicrobial management. Patients with clinically suspected VAP undergo BAL, and VAP is confirmed by growth of a potential pathogen at > 104 colony-forming units per millilitre (CFU/ml). Patients are randomised 1:1, to either a ‘biomarker-guided recommendation on antibiotics’ in which BAL fluid is tested for IL-1β and IL-8 in addition to routine microbiology testing, or to ‘routine use of antibiotics’ in which BAL undergoes routine microbiology testing only. Clinical teams are blinded to intervention until 6 hours after randomisation, when biomarker results are reported to the clinician. The primary outcome is a change in the frequency distribution of antibiotic-free days (AFD) in the 7 days following BAL. Secondary outcome measures include antibiotic use at 14 and 28 days; ventilator-free days; 28-day mortality and ICU mortality; sequential organ failure assessment (SOFA) at days 3, 7 and 14; duration of stay in critical care and the hospital; antibiotic-associated infections; and antibiotic-resistant pathogen cultures up to hospital discharge, death or 56 days. A healthcare-resource-utilisation analysis will be calculated from the duration of critical care and hospital stay. In addition, safety data will be collected with respect to performing BAL. A sample size of 210 will be required to detect a clinically significant shift in the distribution of AFD towards more patients having fewer antibiotics and therefore more AFD. This trial will test whether a rapid biomarker-based exclusion of VAP results in rapid discontinuation of antibiotics and therefore improves antibiotic management in patients with suspected VAP. ISRCTN65937227 . Registered on 22 August 2013. ClinicalTrials.gov, NCT01972425 . Registered on 24 October 2013.

Aims: Elevated expression of DNA repair and replicationgenes has been reported in thick, non-fixed primarymelanomas that subsequently went on to metastasize,when compared to non-recurrent primary tumours.This increased expression could contribute to theextreme resistance shown by melanoma to DNA-dam-aging chemotherapeutics. We have investigated thehypothesis that levels of key DNA repair and replicationproteins are prognostic biomarkers in melanoma.Methods and results: We used a tissue microarraycontaining samples from all stages of melanomagenesisto investigate the hypothesis that levels of key DNArepair and replication proteins are prognostic biomar-kers in a larger, more representative and readilyavailable set of fixed primary melanomas. High expres-sion of topoisomerase IIa (TOP2A), that relievestorsional stress during DNA replication, and XRCC5(Ku80), required for DNA double-strand break repair,were associated with significantly worse survival.Conclusions: Two (XRCC5 and TOP2A) of seven DNArepair and replication proteins studied were prognosticfor melanoma.Keywords: chemotherapy, ERCC1, melanomagenesis, topoisomerase IIa, XRCC5

BackgroundDepression is common in chronic illness and screening for depression has been widely recommended. There have been no large studies of screening for depression in routine care for patients with chronic illness.MethodWe performed a retrospective cohort study to examine the timing of new depression diagnosis or treatment in relation to annual screening for depression in patients with coronary heart disease (CHD) or diabetes. We examined a database derived from 1.3 million patients registered with general practices in Scotland for the year commencing 1 April 2007. Eligible patients had either CHD or diabetes, were screened for depression during the year and either received a new diagnosis of depression or commenced a new course of antidepressant (excluding those commonly used to treat diabetic neuropathy). Analysis was by the self-controlled case-series method with the outcome measure being the relative incidence (RI) in the period 1–28 days after screening compared to other times.ResultsA total of 67358 patients were screened for depression and 2269 received a new diagnosis or commenced treatment. For the period after screening, the RI was 3.03 [95% confidence interval (CI) 2.44–3.78] for diagnosis and 1.78 (95% CI 1.54–2.05) for treatment. The number needed to screen was 976 (95% CI 886–1104) for a new diagnosis and 687 (95% CI 586–853) for new antidepressant treatment.ConclusionsSystematic screening for depression in patients with chronic disease in primary care results in a significant but small increase in new diagnosis and treatment in the following 4 weeks.

Background and Objectives There is increasing evidence that monocytes play a key role in the pathogenesis of acute lung inflammation. Mononuclear cell (MNC) leukapheresis can be used to remove large numbers of monocytes from circulating blood; however, the detailed characteristics of monocyte subpopulations removed by MNC leukapheresis, and the biological effects on the lung, remain incompletely defined. Material and Methods Six healthy male volunteers underwent MNC leukapheresis of four total blood volumes. Blood was collected at 0, 2, 4, 6, 8 and 24 h; bronchoscopy with bronchoalveolar lavage (BAL) was performed at 8–9 h. Multiparameter flow cytometry was used to identify subpopulations of monocytes in blood and monocyte-like cells in BAL fluid. Results A median of 5·57 × 109 monocytes were retrieved. Blood monocyte counts indicated that the circulating blood monocyte pool was actively replenished during leukapheresis and subsequently contained a greater proportion of classical (CD14++ CD16−) monocytes. A particular subpopulation of monocyte-like cells, reminiscent of classical monocytes, was also prominent in BAL fluid after leukapheresis. Conclusion Mononuclear cell leukapheresis was safe. The greater proportion of classical monocytes present in blood after MNC leukapheresis may be clinically significant. MNC leukapheresis also appears to affect the proportion of monocyte-like cells in the lung; however, we found no evidence that leukapheresis has a clinically important pro-inflammatory effect in the human lung.

Galectin-3 plays an important role in adhesion, proliferation, differentiation, angiogenesis and metastasis in multiple tumours. To investigate the role of galectin-3 in melanoma pathogenesis we examined the expression of galectin-3 in melanocytic lesions and analysed the correlation between galectin-3 expression and clinicopathologic factors including patient survival and BRAF mutation status.We evaluated the expression of galectin-3 in 53 cases of benign naevi, 31 cases of dysplastic naevi, 59 in-situ melanomas, 314 cases of primary melanoma and 69 metastatic melanomas using tissue microarray and immunohistochemistry.Marked differences in expression of galectin-3 were seen between different categories of melanocytic lesions (ANOVA p0.0001). An increase in expression of galectin-3 between benign naevi and thin primary melanomas and a progressive decrease in expression between thin primary melanomas and thicker melanomas or metastatic melanomas was seen. Strong galectin-3 expression was associated with improved overall survival (p=0.002 and p=0.0002 for cytoplasmic and nuclear expression, respectively) and melanoma-specific survival (p=0.017 and p=0.003 for cytoplasmic and nuclear expression, respectively). A multifactorial Cox regression analysis suggested that galectin-3 expression was an independent prognostic marker for overall survival in melanoma (risk ratio 0.73, 95% CI 0.547-0.970, p=0.031 for cytoplasmic expression and risk ratio 0.76, 95% CI 0.587-0.985, p=0.036 for nuclear expression). No association between galectin-3 expression and BRAF mutation status was observed.This study suggests that galectin-3 is a marker of progression in melanocytic lesions and a novel prognostic marker in primary melanoma.

The co-ordinated recruitment of monocyte subpopulations, neutrophils and regulatory T-cells (Tregs) during the early stages of human acute lung inflammation remains poorly understood. We therefore performed a detailed characterisation of these lineages in the blood and lungs in a model of human acute lung inflammation. Healthy volunteers inhaled lipopolysaccharide (LPS) or saline (n=6 for each group). Blood was collected at 0, 2, 4, 6 and 8 h and bronchoscopy with bronchoalveolar lavage (BAL) performed at 8 h. Multiparameter flow cytometry was used to characterise monocyte subpopulations, neutrophils and Tregs in the blood and lung. Inhalation of LPS was associated with significant blood and BAL fluid neutrophilia. Blood populations of monocyte subpopulations and Tregs were unaltered by LPS. In contrast, LPS induced an accumulation of a pulmonary monocyte-like cell (PMLC) population, which was further subdivided into "inducible" CD14(++)CD16(-) and "resident" CD14(++)CD16(+) subsets. Inducible PMLCs were significantly increased following LPS inhalation (p=0.0046), whereas resident PMLCs were unchanged. In addition, we noted a significant decrease in Tregs in BAL fluid with LPS inhalation (p=0.027). The early stages of LPS-induced inflammation in humans is characterised by pulmonary accumulation of a novel inducible monocyte-like subpopulation, accompanied by significant changes in both neutrophil and Treg numbers.

The high incidence of Scottish Crohn's disease (CD) is not explained by the common three NOD2/CARD15 variants. We aimed to identify population-specific NOD2/CARD15 coding variants. A total of 1478 (320 inflammatory bowel disease patients

The rs2241880A/G variant of the ATG16L1 gene has been associated with susceptibility to ileal Crohn's disease (CD) in adults. Our aim was to assess whether germline variation of ATG16L1 acts as an independent determinant of susceptibility to childhood-onset CD in the high-incidence Scottish population.In all, 2195 subjects (361 children (inflammatory bowel disease [IBD] diagnosis17 years), their parents (n = 634), 855 adult IBD patients, and 345 controls were genotyped. Case-control analysis was powered to detect effect sizes with an odds ratio (OR)1.39 in pediatric CD. Case-control analysis, transmission disequilibrium testing (TDT), analysis of variance (ANOVA) of growth parameter z-scores, Kruskal-Wallis test (age at diagnosis), and multifactorial genotype-phenotype analysis (Montreal classification) were performed. 7.8% of pediatric CD patients and 37.2% of adult CD patients had pure ileal disease.We confirmed the association of the rs2241880G-allele with adult-onset CD (60.7% versus controls 53.9%, P = 0.01, OR 1.32, 95% confidence interval [CI] 1.07-1.63) in contrast to childhood-onset CD (54.1% versus controls, P = 0.95, OR 1.01, 95% CI 0.80-1.26). TDT analysis was negative. Genotype-phenotype analysis demonstrated an association of pure ileal disease with the rs2241880G-allele (P = 0.02, OR 1.34, 95% CI 1.03-1.74). Using binary logistic regression analysis we confirmed the effect of rs2241880 genotype (GG) on ileal disease versus colonic disease (P = 0.03, OR 2.43, 95% CI 1.05-5.65). ATG16L1 genotype did not influence age at CD diagnosis. ANOVA of z-scores of height, weight, and body mass index (BMI) at CD diagnosis in children showed no association with genotype.The ATG16L1 variant is associated with susceptibility to adult CD in Scotland, but not early-onset disease. These contrasting effects are primarily driven by differences in disease location between early-onset and adult-onset disease.

This chapter explores calculating two types of analyses that are often used for repeated measures designs: within-subjects Analysis of Variance (ANOVA) and Event History Analysis. Within-subjects ANOVA is used when members of a particular sample are exposed to several different conditions or experiments and the measurement of the dependent variable is repeated in each condition, thus inducing correlation between the set of dependent variable measurements for each individual. Event history analysis, by contrast, helps researchers to determine the probability that an event occurs at a particular time interval, making it useful for research questions that want to know how long it takes before the event of interest happens. Both of these analyses have particular relevance for the field of human-computer interaction and this chapter will explore how to use R for these two types of analyses using the Mango watch example.

The clinical subclassification of Crohn's disease by phenotype has recently been reevaluated. We have investigated the relationships between smoking habit, age at diagnosis, disease location, and progression to stricturing or penetrating complications using the Montreal classification.408 patients (157 male, median age 29.4 yr) were assessed. Data were collected on smoking habit, age at diagnosis, anatomical distribution, and disease behavior. Follow-up data were available on all patients (median 10 yr).At diagnosis, ex-smokers (N = 53) were older than nonsmokers (N = 177) or current smokers (N = 178, medians 43.2 vs 28.3 or 28.9 yr, respectively, P0.001). Disease location differed according to smoking habit at diagnosis (chi(2)= 24.1, P= 0.02) as current smokers had less colonic (L2) disease than nonsmokers or ex-smokers (30%vs 45%, 50%, respectively). In univariate Kaplan-Meier survival analysis, smoking habit at diagnosis was not associated with time to development of stricturing disease, internal penetrating disease, perianal penetrating disease, or time to first surgery. Patients with isolated colonic (L2) disease were slower to develop strictures (P0.001) or internal penetrating disease (P= 0.001) and to require surgery (P0.001). Cox models with smoking habit as time-dependent covariates showed that, relative to ileal (L1) location of disease, progression to stricturing disease was less rapid for patients with colonic (L2) disease (HR 0.140, P0.001), but not independently affected by smoking habit. Progression to surgery was also slower for colonic (L2) than ileal (L1) disease location (HR 0.273, P0.001), but was independent of smoking habit.Smoking habit was associated with age at diagnosis and disease location in Crohn's disease, while disease location was associated with the rate of development of stricturing complications and requirement for surgery. The pathogenic basis of these observations needs to be explained.

Objective To assess the contribution of the 113 G→A missense mutation within the discs, large homolog 5 (DLG5) gene in childhood-onset inflammatory bowel disease (IBD) in Scotland. Study design Two-hundred and ninety-six children with IBD were studied. Parental DNA was also collected for transmission disequilibrium testing (TDT) analysis. Genotyping was performed by TaqMan®. Genotype-phenotype analysis was also undertaken. Socioeconomic status was assigned using a deprivation category (DepCat) score 1 through 7 (1 = most affluent). Results TDT analysis demonstrated a significant association with IBD ( P = .045). On unifactorial analysis, 113A carriage was associated with: (1) higher social class (DepCat 1 compared with 2-7, and 1-2 compared with 3-7) (66.7% vs 22.6%, P = .0005, OR 6.84 [1.99-23.55] and 37.2% vs 22.2%, P = .03, OR 2.08 [1.04-4.17], respectively); (2) higher height centile (>75 th centile vs th centile) (42.9% vs 23.1%, P = .01, OR 2.50 [1.18-5.28]); and (3) male sex in Crohn's disease (CD) (29.3% vs 16.9%, P = .04, OR 2.04 [1.01-4.11]). Multifactorial analysis demonstrated that higher social class (DepCat 1) was independently associated with carriage of variants of 113A ( P = .001, OR=6.92 [2.24-21.33]). Conclusions DLG5 113A is associated with increased susceptibility to IBD in Scottish children. The effect may be most marked for those children living in relative affluence.

We report the psychometric structure of a Croatian translation of the Eysenck Personality Questionnaire-Revised (short-form), its correlations with psychological distress (General Health Questionnaire-30), its heritability, and personality–psychological distress genetic correlations. The setting is a large (≈1000), family-based sample of men and women from an isolated Croatian island. The neuroticism and extraversion traits and the lie scale showed good psychometric characteristics. The translated psychoticism scale was unsatisfactory in this sample. It had a very low internal consistency, probably due in part to heavily biased item responses. There were significant additive genetic contributions to variation in neuroticism, extraversion, and psychological distress. Psychological distress had a very high genetic correlation with neuroticism, and a moderate genetic correlation with extraversion.

The incidence of Crohn's disease in Scottish children has increased steadily over 30 years. Many studies have investigated genetic influence or possible links with childhood events. We aimed to study sociodemographic and/or geographic distribution of juvenile=onset Crohn's disease in Scotland.Using a previously established and validated database covering the entire Scottish population, 580 Scottish children (16 years of age at symptom onset) with inflammatory bowel disease incident between 1981 and 1995 were identified. Postcodes of incident cases were classed for geographic location and material deprivation. Incidence rates (/100,000/year) were sex standardized to the 1991 census population. The effects of sex, geographic location, time, and deprivation category were estimated from a multifactorial Poisson regression model.The incidence of juvenile-onset Crohn's disease was 2.3 (95% CI: 2.0-2.5) for the time period 1981 to 1995 and was significantly higher in northern (3.1, 95% CI: 2.6-3.8) than in southern Scotland (2.1, 95% CI: 1.9-2.4, P0.001). The incidence of juvenile-onset ulcerative colitis did not show north/south variation ( P = 0.677). The relative risks of developing CD were significantly lower in postcode areas with deprivation categories 2-7 as compared with deprivation score 1 (most affluent, P = 0.033). This pattern was not seen for UC.There was an increased incidence of juvenile-onset Crohn's disease in northern compared with southern Scotland. Children from more affluent areas had a higher relative risk of developing Crohn's disease. Juvenile onset ulcerative colitis did not show north/south variation in incidence or association with affluence.

Background Practices vary in the duration of newly initiated antidepressant treatment, even after adjusting for patient characteristics. It was hypothesised that this may be because of differences between practices in demographic (practice deprivation and antidepressant prescribing rates), organisational (practice size and proportion of female GPs), and clinical factors (proportion of new episodes of depression coded). Aim To examine the effect of practice characteristics on the duration of new selective serotonin reuptake inhibitor antidepressant treatment in primary care. Design and setting Database cohort study of 28 027 patients from 237 GP practices in Scotland. Method Prescription data were used to estimate duration of treatment for individual patients beyond three time points: 30, 90, and 180 days. Data at patient and practice level were analysed by multilevel logistic regression to quantify the variation between practices. Results The mean rate of diagnostic coding for depression in patients beginning a course of treatment was 29% (range 0–80%). Practice-level deprivation and rate of new antidepressant prescribing were not associated with duration of treatment. The practice level factor most strongly associated with duration of treatment at practice level was the proportion of patients coded as having depression: odds ratio for continuing beyond 30 days was 1.54 (95% confidence interval [CI] = 1.22 to 1.94); beyond 90 days, 1.37 (95% CI = 1.09 to 1.71); and beyond 180 days 1.41 (95% CI = 1.10 to 1.82). Conclusion Encouraging coding and structured follow-up at the onset of treatment of depression is likely to reduce early discontinuation of antidepressant treatment and improve outcomes.

Background: Excessive use of empirical antibiotics is common in critically ill patients. Rapid biomarker-based exclusion of infection may improve antibiotic stewardship in ventilator-acquired pneumonia (VAP). However, successful validation of the usefulness of potential markers in this setting is exceptionally rare.Objectives: We sought to validate the capacity for specific host inflammatory mediators to exclude pneumonia in patients with suspected VAP. Methods: A prospective, multicentre, validation study of patients with suspected VAP was conducted in 12 intensive care units. VAP was confirmed following bronchoscopy by culture of a potential pathogen in bronchoalveolar lavage fluid (BALF) at >104 colony forming units per millilitre (cfu/mL). Interleukin-1 beta (IL-1β), IL-8, matrix metalloproteinase-8 (MMP-8), MMP-9 and human neutrophil elastase (HNE) were quantified in BALF. Diagnostic utility was determined for biomarkers individually and in combination. Results: Paired BALF culture and biomarker results were available for 150 patients. 53 patients (35%) had VAP and 97 (65%) patients formed the non-VAP group. All biomarkers were significantly higher in the VAP group (pConclusions: Low BALF IL-1β in combination with IL-8 confidently excludes VAP and could form a rapid biomarker-based rule-out test, with the potential to improve antibiotic stewardship.

Background High uptake of meningococcal ACWY (MenACWY) vaccine is considered fundamental for generating herd immunity across all age groups. We aimed to estimate MenACWY uptake, and identify any barriers and motivations towards vaccinations, among university students. Methods Our study used a mixed-methods approach. An online cross-sectional survey assessed vaccination uptake and qualitative data were obtained via one focus group [all vaccinated], and seven interviews [six vaccinated, one unvaccinated]) between April 21 and May 27, 2016. The inclusion criteria were age less than 25 years and attendance at university for the first time (MenACWY eligible). All first year undergraduates at the University of Edinburgh (n=5808) were invited to take part in the survey via email, and participants for the qualitative study were recruited through a question at the end of the survey. The primary outcome was MenACWY uptake, and secondary outcomes were barriers and motivations towards vaccination. Quantitative data were analysed with χ 2 tests and non-parametric tests, and a logistic regression model was used to assess confounding. Bias was assessed by comparing the demographics of the sample with the target population. Qualitative data were analysed with the principles of grounded theory. Findings 768 students (13%) took part in the survey. MenACWY uptake was 71·5% (549/768), but was significantly lower (p Interpretation Students outside main UK-based, core age cohorts were underimmunised, and targeted efforts are needed for these groups. To encourage vaccination, future student vaccination programmes could focus on raising awareness of the serious implications of disease (eg, limb loss). Additional value would be gained from emphasising the benefits of vaccinations for society as a whole. Funding University of Edinburgh.

Objectives The primary aim of this prospective study was to perform a comprehensive serial characterisation of monocyte and neutrophil function, circulating monocyte subsets, and bronchoalveolar lavage (BAL) fluid after lung resection. A secondary aim was to perform a pilot, hypothesis-generating evaluation of whether innate immune parameters were associated with postoperative pneumonia. Methods Forty patients undergoing lung resection were studied in detail. Blood monocytes and neutrophils were isolated preoperatively and at 6, 24 and 48 h postoperatively. BAL was performed preoperatively and immediately postoperatively. Monocyte subsets, monocyte responsiveness to lipopolysaccharide (LPS) and neutrophil phagocytic capacity were quantified at all time points. Differential cell count, protein and cytokine concentrations were measured in BAL. Pneumonia evaluation at 72 h was assessed using predefined criteria. Results After surgery, circulating subsets of classical and intermediate monocytes increased significantly. LPS-induced release of proinflammatory cytokines from monocytes increased significantly and by 48 h a more proinflammatory profile was found. Neutrophil phagocytosis demonstrated a small but significant fall. Factors associated with postoperative pneumonia were: increased release of specific proinflammatory and anti-inflammatory cytokines from monocytes; preoperative neutrophilia; and preoperative BAL cell count. Conclusions We conclude that postoperative lung inflammation is associated with specific changes in the cellular innate immune response, a better understanding of which may improve patient selection and prediction of complications in the future.

The quality of reporting of randomised controlled trials in asthma: systematic review protocol

Fecal calprotectin (FC) is increasingly used during the diagnosis of inflammatory bowel disease (IBD), outperforming blood markers during investigation in children. Tests that reduce endoscopy rates in children with suspected gut inflammation would be beneficial. We aimed to determine the usefulness of FC in children undergoing their primary investigation for suspected IBD by systematic review and meta-analysis.An electronic search was performed with keywords relating to IBD and calprotectin in multiple electronic resources from 1946 to May 2012; a hand search was also performed. Inclusion criteria were studies that reported FC levels before the endoscopic investigation of IBD in patients less than 18 years old. Studies were evaluated using the Quality Assessment of Diagnostic Accuracy Studies tool, and a meta-analysis was performed using a hierarchical summary receiver operating curve model.Eight papers met the inclusion criteria (six prospective and two retrospective case-control studies); methodological quality was determined in detail for each study. The 8 studies presented FC levels at presentation in 715 patients, 394 pediatric IBD patients, and 321 non-IBD controls. Pooled sensitivity and specificity for the diagnostic utility of FC during the investigation of suspected pediatric IBD were 0.978 (95% confidence interval (CI), 0.947-0.996) and 0.682 (95% CI, 0.502-0.863), respectively; the positive and negative likelihood ratios were 3.07 and 0.03, respectively.FC has a high sensitivity and a modest specificity during the diagnosis of suspected pediatric IBD. Further work is required to determine the effect of FC levels on endoscopy rates and its role during the re-evaluation of those with confirmed disease.

Elevated expression of DNA repair and replication genes has been reported in thick, non-fixed primary melanomas that subsequently went on to metastasize, when compared to non-recurrent primary tumours. This increased expression could contribute to the extreme resistance shown by melanoma to DNA-damaging chemotherapeutics. We have investigated the hypothesis that levels of key DNA repair and replication proteins are prognostic biomarkers in melanoma. We used a tissue microarray containing samples from all stages of melanomagenesis to investigate the hypothesis that levels of key DNA repair and replication proteins are prognostic biomarkers in a larger, more representative and readily available set of fixed primary melanomas. High expression of topoisomerase IIα (TOP2A), that relieves torsional stress during DNA replication, and XRCC5 (Ku80), required for DNA double-strand break repair, were associated with significantly worse survival. Two (XRCC5 and TOP2A) of seven DNA repair and replication proteins studied were prognostic for melanoma.

Background It is not known how much the duration of newly prescribed antidepressant treatment is influenced by patient characteristics or practice variation. Aim To describe the relationship between patient characteristics and the duration of new antidepressant treatment by general practices. Design and setting Large primary care database cohort study of all patients with a newly initiated course of eligible antidepressant treatment during 1 year, from a database of 237 Scottish practices. Method Detailed prescription data were used to estimate the duration of new antidepressant treatment for each patient. Cox proportional hazards regression was used to estimate the influence of patient characteristics on continuation of treatment and, by multilevel modelling, the variation between practices. Results A total of 28 027 (2.2%) patients commenced antidepressant treatment during the year; 75% continued beyond 30 days, 56% beyond 90 days, and 40% beyond 180 days. Treatment was less likely to be continued in patients from areas of high socioeconomic deprivation: hazard ratio 1.22 (95% confidence interval [CI] = 1.16 to 1.29); in patients under 35 years, 1.33 (95% CI = 1.28 to 1.37); and in those for whom the GP recorded no relevant diagnostic code, 1.16 (95% CI = 1.13 to 1.18). Models accounted for between 2.2% and 3.9% of the variation in treatment duration. Conclusion Patient demographic characteristics account for relatively little variation in the duration of new antidepressant treatment, though treatment was shorter in younger patients and those with greater socioeconomic deprivation. There is variation in treatment duration between practices and according to whether patients have a depression diagnosis coded in their records.

Critically ill patients are at heightened risk for nosocomial infections. The anaphylatoxin C5a impairs phagocytosis by neutrophils. However, the mechanisms by which this occurs and the relevance for acquisition of nosocomial infection remain undetermined. We aimed to characterize mechanisms by which C5a inhibits phagocytosis in vitro and in critically ill patients, and to define the relationship between C5a-mediated dysfunction and acquisition of nosocomial infection. In healthy human neutrophils, C5a significantly inhibited RhoA activation, preventing actin polymerization and phagocytosis. RhoA inhibition was mediated by PI3Kδ. The effects on RhoA, actin, and phagocytosis were fully reversed by GM-CSF. Parallel observations were made in neutrophils from critically ill patients, that is, impaired phagocytosis was associated with inhibition of RhoA and actin polymerization, and reversed by GM-CSF. Among a cohort of 60 critically ill patients, C5a-mediated neutrophil dysfunction (as determined by reduced CD88 expression) was a strong predictor for subsequent acquisition of nosocomial infection (relative risk, 5.8; 95% confidence interval, 1.5-22; P = .0007), and remained independent of time effects as assessed by survival analysis (hazard ratio, 5.0; 95% confidence interval, 1.3-8.3; P = .01). In conclusion, this study provides new insight into the mechanisms underlying immunocompromise in critical illness and suggests novel avenues for therapy and prevention of nosocomial infection.

BACKGROUND: For over two decades, the Nottingham Prognostic Index (NPI) has been used in the United Kingdom to calculate risk scores and inform management about breast cancer patients. It is derived using just three clinical variables - nodal involvement, tumour size and grade. New scientific methods now make cost-effective measurement of many biological characteristics of tumour tissue from breast cancer biopsy samples possible. However, the number of potential explanatory variables to be considered presents a statistical challenge. The aim of this study was to investigate whether in ER+ tamoxifen-treated breast cancer patients, biological variables can add value to NPI predictors, to provide improved prognostic stratification in terms of overall recurrence-free survival (RFS) and also in terms of remaining recurrence free while on tamoxifen treatment (RFoT). A particular goal was to enable the discrimination of patients with a very low risk of recurrence.METHODS: Tissue samples of 401 cases were analysed by microarray technology, providing biomarker data for 72 variables in total, from AKT, BAD, HER, MTOR, PgR, MAPK and RAS families. Only biomarkers screened as potentially informative (i.e., exhibiting univariate association with recurrence) were offered to the multivariate model. The multiple imputation method was used to deal with missing values, and bootstrap sampling was used to assess internal validity and refine the model.RESULTS: Neither the RFS nor RFoT models derived included Grade, but both had better predictive and discrimination ability than NPI. A slight difference was observed between models in terms of biomarkers included, and, in particular, the RFoT model alone included HER2. The estimated 7-year RFS rates in the lowest-risk groups by RFS and RFoT models were 95 and 97%, respectively, whereas the corresponding rate for the lowest-risk group of NPI was 89%.CONCLUSION: The findings demonstrate considerable potential for improved prognostic modelling by incorporation of biological variables into risk prediction. In particular, the ability to identify a low-risk group with minimal risk of recurrence is likely to have clinical appeal. With larger data sets and longer follow-up, this modelling approach has the potential to enhance an understanding of the interplay of biological characteristics, treatment and cancer recurrence. British Journal of Cancer (2010) 102, 1503 - 1510. doi:10.1038/sj.bjc.6605627 www.bjcancer.com (C) 2010 Cancer Research UK

The aim of this study was to explore the influence of testing for hepatitis C virus (HCV) and perceived HCV status on injecting risk behavior. A cross-sectional, community-wide survey was undertaken at multiple sites throughout Greater Glasgow during 2001-2002. Four hundred ninety-seven injecting drug users (IDUs) consented to participate and were interviewed using a structured questionnaire to ascertain HCV test history and injecting risk behavior. The average age of participants was 27 years and the majority of the sample were male (70.4%). Participants had been injecting for an average duration of 2.5 years. Logistic regression analysis revealed no significant associations between having been tested and injecting risk behavior. After adjustment for potential confounding variables, HCV-negatives were significantly less likely to borrow needles/syringes and spoons or filters as compared with unawares and were significantly less likely to borrow spoons or filters as compared with HCV-positives. Due to the cross-sectional design of the study, it is uncertain whether this reduction in risk behavior could be attributed to perception of HCV status. Further research is recommended to consolidate the evidence for this relationship.

The incidence of cutaneous melanoma is rising rapidly in a number of countries. The key environmental risk factor is exposure to the ultraviolet (UV) component in sunlight. The nucleotide excision repair (NER) pathway deals with the main forms of UV-induced DNA damage. We have investigated the hypothesis that polymorphisms in NER genes constitute genetic susceptibility factors for melanoma. However, not all melanomas arise on sun-exposed sites and so we investigated the hypothesis that genes involved in other pathways for the repair of oxidative DNA damage may also be involved in susceptibility to melanoma. Scotland, with its high incidence of melanoma and stable homogeneous population, was ideal for this case-control study, involving 596 Scottish melanoma patients and 441 population-based controls. Significant associations were found for the NER genes ERCC1 and XPF, with the strongest associations for melanoma cases aged 50 and under [ERCC1 odds ratio (OR) 1.59, P = 0.008; XPF OR 1.69, P = 0.003]. Although an XPD haplotype was associated with melanoma, it did not contain the variant 751 Gln allele, which has been associated with melanoma in some previous studies. No associations were found for the base excision repair and DNA damage response genes investigated. An association was also found for a polymorphism in the promoter of the vitamin D receptor gene, VDR (OR 1.88, P = 0.005). The products of the two NER genes, ERCC1 and XPF, where associations with melanoma were found, act together in a rate-limiting step in the repair pathway.

As the general population ages and life expectancy increases, health-care use by elderly people increases, including intensive care. Rationing and variation of access are ethically and politically challenging. We aimed to characterise the population-based incidence of intensive care unit (ICU) admissions of elderly people in Scotland; compare ICU admission and mortality between elderly and younger populations; and compare treatment intensity between these groups.We extracted complete, national 6-year cohort Scottish ICU admissions (Jan 1, 2005, to Dec 31, 2010) from the Scottish Intensive Care Society Audit Group database, which we linked to hospital Scottish Morbidity Record (SMR01) and death records. Annual incidence of ICU admissions of people aged 80 years or older was standardised for sex and socioeconomic status to the standard Scottish population (≥80 years) 2005-10. We compared mortality of elderly and younger people (65 years) using the log-rank test.During 2005-10, 47 779 people were admitted to ICU (4561 patients ≥80 years [9·5%, 35·0/10 000 population], 26 784 patients65 years [56·1%, 13·2/10 000]). Incidence of ICU admissions of elderly people fell from 36·6/10 000 population (95%CI 34·0-39·2) in 2005 to 30·3/10 000 (28·0-32·5) in 2010. ICU mortality was higher in elderly than in younger people (26·4% vs 16·1%, p0·0001) as was 6-year mortality (68·0% vs 34·5%, p0·0001). 2110 (80%) of 2627 elderly survivors were discharged home (younger 92%, 19 221/20 902), with a further 373 (14·2%) given rehabilitation (younger 1063, 5·1%) (χ(2)=525, p0·0001). Age was an independent predictor of mortality (odds ratio 1·46, 95% CI 1·23-1·73, p0·0001) after adjustment for confounders. In the pneumonia subgroup (elderly 294, younger 2167), mean acute physiology scores were similar (17·0 [SD 6·4] vs 17·6 [6·6]), organ support was higher in the elderly patients (77·0% vs 68·1%, p0·0001), and median ICU length of stay was lower (6 days [IQR 3-13] vs 8 [3-16], p0·0001).This study has shown that, by contrast with previously published research, admission rates of elderly people in Scotland fell between 2005 and 2010. Only the fittest elderly individuals were admitted to ICU, where initially they received a higher intensity of treatment than did younger patients; however, duration of ICU stay was shorter. Mortality rates were high, and age was an independent predictor of mortality.Funding assistance for AD's MPH from Scottish Intensive Care Society, Scottish Society of Anaesthetists, Edinburgh Anaesthetics Research and Education Fund.

Introduction: The incidence of early-onset CD in Scotland is among the highest worldwide. Three single nucleotide polymorphisms (SNPs) R702W, G908R and Leu1007finsC in the NOD2/CARD15 gene predispose to adult CD. We investigated the contribution of these variants to disease susceptibility and phenotype in the Scottish early-onset IBD population. Patients and Methods: 906 individuals including 247 Scottish IBD patients aged

Abstract —The physiological effects of angiotensin-converting enzyme (ACE) inhibition may be in part mediated by bradykinin. We investigated the effect of coadministration of the specific bradykinin B 2 receptor antagonist icatibant on hemodynamic and neurohormonal responses to acute intravenous ACE inhibition in normal men on a normal sodium diet. We performed a 4-phase, double-blind, double-dummy, placebo-controlled study in 12 male volunteers. The bradykinin antagonist icatibant (10 mg IV) was coadministered over the first 15 minutes of a 2-hour infusion of the ACE inhibitor perindoprilat (1.5 mg IV). Perindoprilat inhibited ACE activity and elicited the expected changes in active renin concentration and angiotensin peptides. Over the 3 hours after the start of drug infusion, perindoprilat lowered and icatibant increased mean arterial blood pressure (each P P 2 receptor antagonist icatibant attenuates the short-term blood pressure–lowering effect of acute ACE inhibition in normal men on a normal sodium diet. Bradykinin B 2 receptor antagonism alone increases resting blood pressure. Bradykinin may be involved in the control of blood pressure in the resting state in humans.

Objective We examined whether a panel of SNPs, systematically selected from genome-wide association studies (GWAS), could improve risk prediction of coronary heart disease (CHD), over-and-above conventional risk factors. These SNPs have already demonstrated reproducible associations with CHD; here we examined their use in long-term risk prediction. Study Design and Setting SNPs identified from meta-analyses of GWAS of CHD were tested in 840 men and women aged 55–75 from the Edinburgh Artery Study, a prospective, population-based study with 15 years of follow-up. Cox proportional hazards models were used to evaluate the addition of SNPs to conventional risk factors in prediction of CHD risk. CHD was classified as myocardial infarction (MI), coronary intervention (angioplasty, or coronary artery bypass surgery), angina and/or unspecified ischaemic heart disease as a cause of death; additional analyses were limited to MI or coronary intervention. Model performance was assessed by changes in discrimination and net reclassification improvement (NRI). Results There were significant improvements with addition of 27 SNPs to conventional risk factors for prediction of CHD (NRI of 54%, P

Objective Bronchoalveolar lavage (BAL) may be used to investigate acute inflammation following thoracic surgery. However, BAL has previously been found to induce an acute phase response in healthy and critically-ill patients complicating research analysis (1,2). We sought to examine the impact of BAL in thoracic surgery patients hypothesising that BAL would not lead to a significant additional acute inflammatory response. Methods Seventeen patients undergoing lung cancer staging bronchoscopy and mediastinoscopy were randomly assigned to have 220mls 0.9% NaCl BAL before surgery (n=10) or no BAL (n=7). Blood samples were taken pre-operatively followed by 6 and 24 hours post-operatively. Exhaled nitric oxide (eNO) was also measured at a flow rate of 50mls/sec at these times. All patients had a CXR at 24hrs and were evaluated for evidence of SIRS using pre-defined criteria. Results IL-6 and CRP increased post-operatively peaking at 6hrs and 24hrs respectively however there was no statistically significant difference between the increase for BAL and non-BAL patients (p>0.05). There was no significant increase or variation between the groups for IL-2, IL-4, IL-10, TNF-α or IFN-γ (p>0.05). eNO tended to decrease in the BAL group and increase in the non-BAL group at 6hrs although there was no significant difference between the groups (p=0.167). Post-operative CXR atelectasis developed in 3 patients (2 BAL). One patient in each group developed SIRS. Conclusion BAL has minimal impact on acute inflammation following bronchoscopy and mediastinoscopy. It may therefore be used to safely and reliably obtain samples for research or microbiology purposes in thoracic surgery patients. Huang Y-C T, Bassett MA, Levin D, Montilla, Ghio AJ. Acute Phase Reaction in Healthy Volunteers After Bronchoscopy with Lavage. Chest 2006; 129 (6): 1565–9. Terashima T, Amakawa K, Matsumaru A et al. BAL Induces an Increase in Peripheral Blood Neutrophils and Cytokine Levels in Healthy Volunteers and Patients with Pneumonia. Chest 2001; 119 (6): 1724–1729.

Aim Faecal calprotectin (FC) is increasingly used as a marker of intestinal inflammation, especially in diagnosis of inflammatory bowel disease (IBD). A meta-analysis (Rheenen et al . BMJ 2010) evaluated adult and paediatric studies to October 2009 and concluded that FC has good discriminative power to safely exclude IBD. However, the seven paediatric studies only included a total of 226 paediatric IBD (PIBD) patients, therefore small study effect may have existed. We aimed to determine the usefulness of FC at presentation in children with suspected IBD by evaluating all the available literature. Methods A search was performed with keywords relating to IBD and calprotectin in several electronic resources from 1966 to November 2011. A hand search of articles was also performed, drawn from reference lists and meeting abstracts. Inclusion criteria were studies that reported FC levels prior to the endoscopic investigation of IBD in children less than 18 years old. There was no English language restriction. Each study was evaluated using the QUADAS tool and a meta-analysis of all included studies was performed using RevMan (v 5.1) and HSROC (R package). Pooled sensitivity and specificity was generated using a random effects model. Results A total of 73 papers were identified during the initial search. All were reviewed but only 8 met the inclusion criteria (6 prospective and 2 retrospective case-control studies). Two studies in the original BMJ meta-analysis (Bunn 2001, Kolho 2006) were excluded as both the IBD and control groups did not represent children undergoing primary investigation for suspected IBD. In total the studies presented FC levels at presentation in 394 IBD patients and 353 non-IBD controls. Pooled specificity and sensitivity for the diagnostic utility of FC during the investigation of suspected PIBD were 0.998 (95% CI 0.960-1.000) and 0.665 (95% CI 0.537-0.820) respectively. Conclusions FC has a high specificity but a modest specificity for the diagnosis of IBD in the paediatric population. The inclusion of two new larger studies and removal of two studies from the original meta-analysis led to an increase in the pooled sensitivity and reduction in pooled specificity. Furthermore, it is evident from other studies that use of a higher normal range (i.e. >200 ug/g) would significantly increase this specificity and therefore further work is required that report multiple cut off levels to truly appreciate the value of this test.

Introduction C reactive protein (CRP) is an acute phase reactant which may possibly link innate and adaptive immunity by binding proteins such as complement factor H. IBD patients with an elevated serum CRP have demonstrated a superior response to biological therapies suggesting that CRP may also play a role in IBD pathogenesis. In addition, a proportion of IBD patients do not have a raised CRP even in the presence of severe inflammatory disease. We aimed to assess the gene-wide association signal of the CRP gene to IBD and Crohn9s disease (CD) susceptibility by means of a detailed haplotype-tagging investigation. Methods 1215 subjects consisting of 465 robustly phenotyped patients diagnosed with inflammatory bowel disease (IBD) 0.1): rs1417938, rs1205, rs1130864, rs1935193 and rs11265263. Two additional SNPs, previously shown to influence serum CRP levels (rs3091244 and rs1800947) were also genotyped. Detailed phenotypic characteristics of this cohort were previously described. Detailed single marker and haplotype analysis by transmission disequilibrium testing (ParenTDT) was carried out using Haploview (with permutation analysis, n=100 000). Results After stringent permutation analysis the rs1417938 A allele, located in the first 59 intron of the CRP gene, showed significant over transmission to affected IBD patients (p=0.0446). The 7-marker haplotype ACACATC also showed significant distortion of transmission (p=0.0068) This same 7-marker haplotype was also significantly associated with Crohn9s disease (p=0.0165). Using a sliding-haplotype analysis to assess the extent of the IBD and CD-associated signal from the 59 end to the 39UTR of the CRP coding sequence demonstrated that the strongest signal (p=0.0013 for IBD, p=0.0050 for CD) was achieved with a haplotype spanning the entire CRP gene. Conclusion We have demonstrated that in a well defined population, using analysis that eliminates the need for population stratification, that inherited variation of the haplotype containing CRP is associated with IBD and CD susceptibility. Our analysis indicates that it is now warranted to submit the CRP gene to further deep sequencing and to re-evaluate the contribution of CRP to IBD pathogenesis beyond its usefulness as an inflammatory marker.

Introduction Inducible T cell costimulator ligand (ICOSLG) is intimately involved in the proliferation and differentiation of T lymphocytes. A locus on Chr. 21q22 harbouring the ICOSLG gene has been shown to influence susceptibility to adult and paediatric Crohn9s disease (CD) and ulcerative colitis (UC). Our aim was to perform a detailed analysis of ICOSLG using a genewide haplotype-tagging approach and to delineate the region of strongest association. Methods 416 patients diagnosed with inflammatory bowel disease (IBD) ICOSLG as well as the region extending to rs762421 which achieved recent genomewide significance. Detailed phenotypic characteristics of this cohort were previously described. SNPs were selected using HapMap data (based on solid spine of LD, MAF > 0.1). Detailed single marker and haplotype analysis by transmission disequilibrium testing (ParenTDT) was carried out using Haploview (permutation analysis, n=100 000). Results The two-marker haplotypes rs762421A/G – rs8126734A/G and rs283529G/C – rs4818890C/A (both located within the 39 UTR of ICOSLG ) showed weak associations with overall IBD susceptibility (p 2 with rs762421 was 0.78 and 0.21, respectively). The two-marker haplotype consisting of rs762421A and rs8126734G also showed significant distortion of transmission (p=0.03). Using a sliding-2 marker haplotype analysis to assess the extent of the CD-association signal from the 39UTR to the 59 end of the ICOSLG coding sequence we found that association signals did not extend upstream from rs8126734, thus implicating the 39 interval between rs762421 and rs8126734 as a target region for deep sequencing. Conclusion We have applied the first family-based association analysis of ICOSLG in childhood onset CD (thus minimising the effect of population stratification) to demonstrate that the signal at the 21q22 locus is due to germline variation at the 39 end of ICOSLG . Our analysis makes it less likely for non-synonymous ICOSLG SNPs or for other genes in the region to contribute significantly to inherited CD susceptibility. Deep sequencing of the 39 UTR of the ICOSLG gene is now warranted to identify causative variants, potentially affecting mRNA stability.

Recent genome-wide association studies have identified more than 70 loci which confer susceptibility to Crohn's disease (CD).1 However, the critical coding regions within most of these loci are largely unidentified and it is therefore important that further work is carried out to robustly identify the candidate genes to guide future deep sequencing studies. A locus on chromosome 21q22 harbouring several genes including inducible T cell costimulator ( ICOSLG ), autoimmune regulator ( AIRE ) and periodic tryptophan protein 2 homologue ( PWP2 ) has been shown to influence susceptibility to both adult and paediatric CD and ulcerative colitis (UC).1 2 The protein encoded by ICOSLG is intimately involved in the proliferation and differentiation of T lymphocytes (through binding with inducible T-cell costimulator (ICOS)), especially with regard to the balance between regulatory and Th17 subsets. We read with interest the …