Search

Background: It is well established that SARS-CoV-2 is readily transmitted in indoor environments; however questions remain about the relative importance of different transmission mechanisms, the risks associated with non-clinical indoor environments and activities and the role of ventilation and plumbing systems in mitigating or amplifying transmission. This rapid evidence review identifies and integrates evidence from three distinct disciplines: epidemiology, microbiology and fluid dynamics. Objectives: This review addresses the following research questions: 1. What evidence is there for aerosolised transmission? 2. What evidence is there for faecal-oral transmission? 3. What evidence is there regarding the role of ventilation systems in indoor transmission? 4. What evidence is there regarding the role of plumbing systems in indoor transmission? 5. What evidence is there regarding transmission via different indoor surfaces (materials and specific objects)? 6. What evidence is there for the transmission in indoor residential settings? 7. What evidence is there for transmission in indoor workplace settings? 8. What evidence is there for transmission in other indoor settings (social, community, leisure, religious, public transport)? 9. Do particular activities convey greater risk (e.g. shouting, singing, eating together, sharing bedrooms)? 10. What evidence is there for the appropriate length of distancing between people? Data sources: Searches were conducted in PubMed, medRxiv, arXiv, Scopus, WHO COVID-19 database, Compendex & Inspec. Eligibility criteria: We included studies reporting data on any indoor setting except schools, any indoor activities and any potential means of transmission. Additional screening criteria were modified slightly for the three study disciplines. Title and abstract and full text screening was conducted by a single reviewer, with rejections assessed by a second reviewer. Data extraction, quality appraisal and data synthesis: We used Joanna Briggs Institute and Critical Appraisal Skills Programme tools for evaluating epidemiological studies and developed bespoke tools for the evaluation of study types not covered by these instruments. Data extraction was limited to a minimum set of items, given the rapid nature of this review. Data extraction and quality assessment were conducted by a single reviewer. We conducted a meta-analysis of secondary attack rates in household transmission. Otherwise, data were synthesised narratively. Results and conclusion: Literature searches yielded a total of 1573 unique articles. After screening and quality assessment, fifty-eight articles were retained for analysis. Experimental evidence from fluid mechanics and microbiological studies demonstrates that aerosolised transmission is theoretically possible; however, we found no conclusive epidemiological evidence of this occurring. The evidence suggests that ventilation systems have the potential to decrease virus transmission near the source through dilution but to increase transmission further away from the source through dispersal. There is compelling evidence that, if infectious virus is present in faeces, defective plumbing systems can amplify transmission within high-rise buildings. However, although viral RNA can be detected in stool samples, we found no evidence for the detection of live infectious virus in faeces, nor did we find any examples of faecal-oral transmission. Laboratory studies suggest that the virus survives for longer on smooth surfaces and at lower temperatures. Environmental sampling studies have recovered small amounts of viral RNA from a wide range of frequently touched objects and surfaces; however, we did not find any such studies which had successfully cultured live virus from collected samples and epidemiological studies are inconclusive on the extent of fomite transmission. We found many examples of transmission in settings characterised by close and prolonged indoor contact, such as households (pooled secondary attack rate 11%, 95 % confidence interval 9, 13), communal residential settings, workplaces and religious gatherings. There were insufficient data to evaluate the transmission risks associated with specific activities; however workplace challenges related to poverty, such as continuing to work whilst ill, especially when attendance is incentivised, warrant further attention. Finally, the physical properties of droplets generated by coughing, speaking and breathing are well characterised and reinforce the importance of maintaining 2 metres social distance to reduce droplet transmission.

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: Ventilator-associated pneumonia is the most common intensive care unit (ICU)-acquired infection, yet accurate diagnosis remains difficult, leading to overuse of antibiotics. Low concentrations of IL-1β and IL-8 in bronchoalveolar lavage fluid have been validated as effective markers for exclusion of ventilator-associated pneumonia. The VAPrapid2 trial aimed to determine whether measurement of bronchoalveolar lavage fluid IL-1β and IL-8 could effectively and safely improve antibiotic stewardship in patients with clinically suspected ventilator-associated pneumonia.Methods: VAPrapid2 was a multicentre, randomised controlled trial in patients admitted to 24 ICUs from 17 National Health Service hospital trusts across England, Scotland, and Northern Ireland. Patients were screened for eligibility and included if they were 18 years or older, intubated and mechanically ventilated for at least 48 h, and had suspected ventilator-associated pneumonia. Patients were randomly assigned (1:1) to biomarker-guided recommendation on antibiotics (intervention group) or routine use of antibiotics (control group) using a web-based randomisation service hosted by Newcastle Clinical Trials Unit. Patients were randomised using randomly permuted blocks of size four and six and stratified by site, with allocation concealment. Clinicians were masked to patient assignment for an initial period until biomarker results were reported. Bronchoalveolar lavage was done in all patients, with concentrations of IL-1β and IL-8 rapidly determined in bronchoalveolar lavage fluid from patients randomised to the biomarker-based antibiotic recommendation group. If concentrations were below a previously validated cutoff, clinicians were advised that ventilator-associated pneumonia was unlikely and to consider discontinuing antibiotics. Patients in the routine use of antibiotics group received antibiotics according to usual practice at sites. Microbiology was done on bronchoalveolar lavage fluid from all patients and ventilator-associated pneumonia was confirmed by at least 104 colony forming units per mL of bronchoalveolar lavage fluid. The primary outcome was the distribution of antibiotic-free days in the 7 days following bronchoalveolar lavage. Data were analysed on an intention-to-treat basis, with an additional per-protocol analysis that excluded patients randomly assigned to the intervention group who defaulted to routine use of antibiotics because of failure to return an adequate biomarker result. An embedded process evaluation assessed factors influencing trial adoption, recruitment, and decision making. This study is registered with ISRCTN, ISRCTN65937227, and ClinicalTrials.gov, NCT01972425.Findings: Between Nov 6, 2013, and Sept 13, 2016, 360 patients were screened for inclusion in the study. 146 patients were ineligible, leaving 214 who were recruited to the study. Four patients were excluded before randomisation, meaning that 210 patients were randomly assigned to biomarker-guided recommendation on antibiotics (n=104) or routine use of antibiotics (n=106). One patient in the biomarker-guided recommendation group was withdrawn by the clinical team before bronchoscopy and so was excluded from the intention-to-treat analysis. We found no significant difference in the primary outcome of the distribution of antibiotic-free days in the 7 days following bronchoalveolar lavage in the intention-to-treat analysis (p=0·58). Bronchoalveolar lavage was associated with a small and transient increase in oxygen requirements. Established prescribing practices, reluctance for bronchoalveolar lavage, and dependence on a chain of trial-related procedures emerged as factors that impaired trial processes.Interpretation: Antibiotic use remains high in patients with suspected ventilator-associated pneumonia. Antibiotic stewardship was not improved by a rapid, highly sensitive rule-out test. Prescribing culture, rather than poor test performance, might explain this absence of effect.Funding: UK Department of Health and the Wellcome Trust.

Background: NOD1/CARD4 and NOD2/CARD15 are both intracellular pattern-recognition receptors. The NOD1/CARD4 gene lies within a previously described inflammatory bowel disease (IBD) locus (7p14). An association has been suggested between the NOD1/CARD4+32656 deletion*1 variant of a complex deletion*1/insertion*2 polymorphism and IBD in 1 recent study in Europe. Our aim was to assess the influence of NOD1/CARD4+32656 on disease susceptibility and phenotype in the Scottish and Swedish IBD populations. Methods: A total of 3,962 individuals (1,791 IBD patients, 522 parents, 1,649 healthy controls) from 2 independent populations (Scotland and Sweden) were genotyped for NOD1/CARD4+32656 A/C by TaqMan and direct sequencing. Case-control, Transmission Disequilibrium Testing (TDT) and detailed genotype–phenotype (Montreal) analyses were performed. The case-control analysis had 80% power to detect an effect size of odds ratio (OR) 1.21 for IBD. Results: In case-control analyses in Scottish and Swedish patients, none of the genotypes studied in IBD, Crohn's disease (CD) or ulcerative colitis (UC), differed significantly from controls (deletion*1 allelic frequency 73.9%, 73.6%, 73.9%, and 73.6%, respectively: all P > 0.8). No epistatic interaction with NOD2/CARD15 was seen for CD susceptibility. TDT analysis in our Scottish early onset cohort was negative. Conclusions: This variant allele of NOD1/CARD4+32656 is not associated with a strong effect on susceptibility to IBD in children and adults in Northern Europe. A gene-wide haplotype-based approach may be preferable to analysis of individual variants to assess the contribution of the NOD1/CARD4 gene to IBD.

Both NOD1/CARD4 and NOD2/CARD15 are intracellular pattern-recognition receptors involved in the innate immune response. Germline NOD2/CARD15 variation has a definite effect on susceptibility to Crohn's disease (CD) and phenotype, although this contribution is weak in Scotland and Scandinavia. The NOD1/CARD4 gene lies within the putative inflammatory bowel disease (IBD) locus at 7p14.3. We have assessed, in detail, the influence of germline NOD1/CARD4 variation on IBD susceptibility and phenotype in the Scottish population. Two thousand two hundred and ninety-six subjects, including 356 children with IBD, were involved in parallel case–control and family-based association studies. Nine tagging single-nucleotide polymorphisms (SNPs) were selected based on HapMap data spanning the whole of the NOD1/CARD4 gene. Our case–control SNP analysis was powered to detect an effect size with OR 1.5 for IBD and OR 1.6 for CD. No significant associations were observed between any of nine the NOD1/CARD4 SNPs studied and IBD, CD or ulcerative colitis (UC) (P > 0.05 for all). Haplotype case–control analysis was also negative (P > 0.05 in IBD, CD and UC). Multimarker transmission disequilibrium testing analysis was negative (P > 0.05 in IBD, CD and UC). NOD2/CARD15 variant carriage had no influence on NOD1/CARD4 effect on IBD susceptibility. This study represents the first application of a gene -wide haplotype-tagging approach to assess, in detail, the contribution of NOD1/CARD4 in IBD.

Introduction: Stakeholder involvement has been described as an indispensable part of health research priority setting. Yet, more than 75% of the exercises using the Child Health and Nutrition Research Initiative (CHNRI) methodology have omitted the step involving stakeholders in priority setting. Those that have used stakeholders have not used the public, possibly due to the difficulty of assembling and/or accessing a public stakeholder group. In order to strengthen future exercises using the CHNRI methodology, we have used a public stakeholder group to weight 15 CHNRI criteria, and to explore regional differences and whether being a health stakeholder is influential, and whether the criteria are collapsible.Methods: Using Amazon Mechanical Turk (AMT), an online crowdsourcing platform, we collected demographic information and conducted a Likert-scale format survey about the importance of the CHNRI criteria from 1,051 stakeholders. The Kruskal-Wallis test, with Dunn’s test for posthoc comparisons, was used to examine regional differences and Wilcoxon rank-sum test was used to analyse differences between stakeholders with health training/background and stakeholders without a health background and by region. A Factor Analysis (FA) was conducted on the criteria to identify the main domains connecting them. Criteria means were converted to weights.Results: There were regional differences in thirteen of fifteen criteria according to the Kruskal-Wallis test and differences in responses from health stakeholders versus those who were not in eleven of fifteen criteria using the Wilcoxon rank-sum test. Three components were identified: improve and impact results; implementation and affordability; and, study design and dissemination. A formula is provided to convert means to weights for future studies.Conclusion: In future CHNRI studies, researchers will need to ensure adequate representation from stakeholders to undue bias of CHNRI results. These results should be used in combination with other stakeholder groups, including government, donors, policy makers, and bilateral agencies. Global and regional stakeholder groups scored CHNRI criteria differently; due to this, researchers should consider which group to use in their CHNRI exercises.

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.

Background: Ventilator-associated pneumonia (VAP) is the most commonly fatal nosocomial infection. Clinical diagnosis of VAP remains notoriously inaccurate. The hypothesis was tested that significantly augmented inflammatory markers distinguish VAP from conditions closely mimicking VAP. Methods: A prospective, observational cohort study was carried out in two university hospital intensive care units recruiting 73 patients with clinically suspected VAP, and a semi-urban primary care practice recruiting a reference group of 21 age-and sex-matched volunteers. Growth of pathogens at >10(4) colony-forming units (cfu)/ml of bronchoalveolar lavage fluid (BALF) distinguished VAP from "non-VAP". Inflammatory mediators were quantified in BALF and serum. Mediators showing significant differences between patients with and without VAP were analysed for diagnostic utility by receiver operator characteristic (ROC) curves. Results: Seventy-two patients had recoverable lavaged-24% had VAP. BALF interleukin-1 beta (IL-1 beta), IL-8, granulocyte colony-stimulating factor and macrophage inflammatory protein-1 alpha were significantly higher in the VAP group (all p Conclusions: BALF IL-1 beta and IL-8 are amongst the strongest markers yet identified for accurately demarcating VAP within the larger population of patients with suspected VAP. These findings have potential implications for reduction in unnecessary antibiotic use but require further validation in larger populations.

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.

OBJECTIVE To compare elderly (≥ 80 yr), older (65-79 yr), and younger (< 65 yr) ICU admissions in Scotland in relation to trends in admission rates, regional variation in admissions, ICU treatment intensity, and ICU and 1-year mortality. DESIGN National 5-year cohort study of ICU first admissions (January 1, 2005, to December 31, 2009). SETTING All admissions to ICUs and combined units (level 2/3 care) in Scotland captured by the Scottish Intensive Care Society Audit Group database, linked with hospital discharge data and death records. PATIENTS A total of 40,142 patients: 3,865 were 80 years old or older (9.6%), 13,904 (34.6%) were 65-79 years old; and 22,373 were younger than 65 years (55.7%). INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Between 2005 and 2009, elderly admission rates decreased from 36.6/10,000 (95% CI, 34.0-39.2) in 2005 to 28.7/10,000 (95% CI, 26.5-30.9) in 2009 (p < 0.001; relative decrease, 22.0%); older admission rates also decreased, but less steeply (31.1 [95% CI, 29.9-32.2] to 26.1 [95% CI, 25.1-27.1] per 10,000 population; p < 0.001; relative decrease, 16.1%). Rates were static for younger patients. Restricted to mechanically ventilated elderly patients, rates ranged from 13.9 to 30.1/10,000 between healthboard administrative regions (p < 0.001). Emergency surgical diagnoses were more prevalent for elderly patients (elderly, 39.8%; older, 25.1%; younger, 20.3%; p < 0.001). Subgroup analyses limited to pneumonia admissions (elderly, n = 242; older, n = 1,226; younger, n = 1,836) indicated similar acute physiology scores, but fewer preexisting comorbidities among elderly patients (p = 0.007), who received a shorter duration of organ support and ICU stay. Mortality rates were higher in elderly patients at ICU discharge (elderly, 26.5%; older, 25.0%; younger, 17.0%; p < 0.001; confounder adjusted odds ratio elderly vs younger, 2.33 [95% CI, 2.11-2.58]; p < 0.001). Differences persisted at 1 year (elderly, 52.2%; older, 43.8%; younger, 27.6%; adjusted odds ratio elderly vs younger, 3.72 [95% CI, 3.42-4.06]; p < 0.001). CONCLUSIONS In Scotland, elderly and older ICU admission rates are decreasing, with regional geographic variation. Although limited by an absence of a measure of frailty, patient characteristics and treatment intensity suggest selection of less comorbid elderly patients, indicating possible rationing based on chronologic age.

BackgroundChinese populations have a higher proportion of intracerebral hemorrhage (ICH) in total strokes. However, the reasons are not fully understood.MethodsTo assess the differences in frequency of major risk factors between ICH and ischemic stroke (IS) in Chinese versus white populations of European descent, we systematically sought studies conducted since 1990 that compared frequency of risk factors between ICH and IS in Chinese or white populations. For each risk factor, in Chinese and Whites separately, we calculated study-specific and random effects pooled prevalence and odds ratios (ORs) for ICH versus IS.ResultsSix studies among 36,190 Chinese, and seven among 52,100 white stroke patients studied hypertension, diabetes, atrial fibrillation (AF), ischemic heart disease (IHD), hypercholesterolemia, smoking and alcohol. Pooled prevalence of AF was significantly lower in Chinese. Pooled ORs for ICH versus IS were mostly similar in Chinese and Whites. However, in Chinese--but not Whites--mean age was lower (62 versus 69 years), while hypertension and alcohol were significantly more frequent in ICH than IS (ORs 1.38, 95% CI 1.18-1.62, and 1.46, 1.12-1.91). Hypercholesterolemia and smoking were significantly less frequent in ICH in Whites, but not Chinese, while IHD, AF and diabetes were less frequent in ICH in both.ConclusionsDifferent risk factor distributions in ICH and IS raise interesting possibilities about variation in mechanisms underlying the different distributions of pathological types of stroke between Chinese and Whites. Further analyses in large, prospective studies, including adjustment for potential confounders, are needed to consolidate and extend these findings.

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.

Background and Aim Post-stroke fatigue is a common and distressing problem but little is known about its biological mechanisms. This cohort study was to investigate associations between C-reactive protein (CRP) and fatigue after stroke. Methods Patients were assessed at one, six and 12 months after their stroke onset, with the Fatigue Assessment Scale, a case definition of post-stroke fatigue, Hospital Anxiety and Depression Scale, and daily step counts. Blood samples were collected at each assessment and the CRP level was determined by a standard CRP immunoassay. Cross-sectional associations between CRP and fatigue at each time point were determined by Pearson correlation coefficient and independent-samples t-test. Whether CRP levels at one month predict fatigue scores at six and 12 months was explored by multiple linear regression, with anxiety, depression, and daily step counts as covariates. Results Sixty-five patients (mean age 67 years, 65% men) were included: 61 at one month, 49 at six months, and 41 at 12 months. CRP levels and fatigue scores were not associated at one month (p = 0.88) or 12 months (p = 0.56), but weakly associated at six months (r = 0.27, p = 0.04); however, this association was no longer significant (p = 0.14) after controlling for the effects of covariates. The CRP level was not associated with the fulfilment of case definition of post-stroke fatigue at any time points (all p > 0.05). The CRP level at one month was not a significant predictor for fatigue levels at either six months (p = 0.93) or 12 months (p = 0.78). Conclusions There is insufficient evidence for the association between CRP and PSF in stroke patients. Future studies with larger sample sizes and controlling for potential confounders are needed to investigate whether this association exists.

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.