Type 1 diabetes incidence in Scotland between 2006 and 2019.

AIMS: To describe type 1 diabetes incidence in Scotland between 2006 and 2019. METHODS: Repeated annual cross-sectional studies of type 1 diabetes incidence were conducted. Incident cases were identified from the Scottish Care Information-Diabetes Collaboration (SCI-DC), a population-based register of people with diagnosed diabetes derived from primary and secondary care data. Mid-year population estimates for Scotland were used as the denominator to calculate annual incidence with stratification by age and sex. Joinpoint regression was used to investigate whether incidence changed during the study period. Age and sex-specific type 1 diabetes incidence over the whole time period was estimated by quintile of the Scottish Index of Multiple Deprivation (SIMD), an area-based measure, in which Q1 and Q5 denote the most and least deprived fifths of the population, respectively, with quasi-Poisson regression used to compare incidence for Q5 compared to Q1. RESULTS: The median (IQR) age of the study population of 14,564 individuals with incident type 1 diabetes was 24.1 (12.3-42.4) years, 56% were men, 23% were in Q1 and 16% were in Q5. Incidence of T1DM was higher in men than women overall (at around 22 and 17 per 100,000, respectively) and in under 15 year olds (approximately 40 per 100,000 in both sexes) than other age groups and was similar across the study period in all strata. There was an inverse association between socio-economic status and type 1 diabetes incidence for 15-29, 30-49 and 50+ year olds [incidence rate ratio (IRR) for Q5 compared to Q1; IRR (95% CI) 0.52 (0.47-0.58), 0.68 (0.61-0.76) and 0.53(0.46-0.61), respectively] but not for under 15 year olds [1.02 (0.92-1.12)]. CONCLUSION: Incidence of type 1 diabetes varies by age, sex and socio-economic status and has remained approximately stable from 2006 to 2019 in Scotland.

Acceptability and facilitators of and barriers to point-of-care HIV testing in a homeless-focused service in Gloucestershire: a qualitative evaluation.

OBJECTIVES: Late HIV diagnosis increases the risks of onward transmission, morbidity and mortality. Rapid point-of-care testing (POCT) reaches people who have never been tested and people living with HIV who are undiagnosed. This study explored the acceptability and feasibility of HIV POCT from the perspectives of service providers and users. METHODS: A pilot study introduced HIV POCT to one service in Gloucestershire, England. Eleven semi-structured interviews with service users and a focus group with three service providers were conducted. The Theoretical Framework of Acceptability and the Theoretical Domains Framework were used to design the topic guide and analysis. RESULTS: Acceptability of HIV POCT was high. Seven facilitators were identified (e.g. understanding the test purpose and process), alongside two potential barriers, one relevant to service providers and users (anxiety) and the other to service users (stigma). CONCLUSIONS: To maximize the benefits of implementation of HIV POCT, health care providers require appropriate training and supervision to offer and administer POCT.

Total Synthesis of (±)-Aspidospermidine, (±)-Aspidofractinine, (±)-Limaspermidine, and (±)-Vincadifformine via a Cascade and Common Intermediate Strategy.

A concise strategy for the total synthesis of several Aspidosperma alkaloids is reported. A Suzuki-Miyaura cross-coupling provides access to a 2-vinyl indole that undergoes a Diels-Alder cascade reaction with butyn-2-one to deliver a pyrroloindoline intermediate. This undergoes cascade amidation, reduction, skeletal rearrangement, and intramolecular Michael addition to provide a common intermediate containing the full framework of the Aspidosperma alkaloids. The utility of this intermediate is shown in the synthesis of four different natural products.

Selective CDK6 degradation mediated by cereblon, VHL, and novel IAP-recruiting PROTACs.

Inhibitors of CDK4 and CDK6 have emerged as important FDA-approved treatment options for breast cancer patients. The properties and pharmacology of CDK4/6 inhibitor medicines have been extensively profiled, and investigations into the degradation of these targets via a PROTAC strategy have also been reported. PROTACs are a novel class of small-molecules that offer the potential for differentiated pharmacology compared to traditional inhibitors by redirecting the cellular ubiquitin-proteasome system to degrade target proteins of interest. We report here the preparation of palbociclib-based PROTACs that incorporate binders for three different E3 ligases, including a novel IAP-binder, which effectively degrade CDK4 and CDK6 in cells. In addition, we show that the palbociclib-based PROTACs in this study that recruit different E3 ligases all exhibit preferential CDK6 vs. CDK4 degradation selectivity despite employing a selection of linkers between the target binder and the E3 ligase binder.

Interventions to improve appropriate antibiotic prescribing in long-term care facilities: a systematic review.

BACKGROUND: Overuse of antibiotics has contributed to antimicrobial resistance; a growing public health threat. In long-term care facilities, levels of inappropriate prescribing are as high as 75%. Numerous interventions targeting long-term care facilities' antimicrobial stewardship have been reported with varying, and largely unexplained, effects. Therefore, this review aimed to apply behavioural science frameworks to specify the component behaviour change techniques of stewardship interventions in long-term care facilities and identify those components associated with improved outcomes. METHOD: A systematic review (CRD42018103803) was conducted through electronic database searches. Two behavioural science frameworks, the Behaviour Change Wheel and Behaviour Change Technique Taxonomy were used to classify intervention descriptions into intervention types and component behaviour change techniques used. Study design and outcome heterogeneity prevented meta-analysis and meta-regression. Interventions were categorised as 'very promising' (all outcomes statistically significant), 'quite promising' (some outcomes statistically significant), or 'not promising' (no outcomes statistically significant). 'Promise ratios' (PR) were calculated for identified intervention types and behaviour change techniques by dividing the number of (very or quite) promising interventions featuring the intervention type or behaviour change technique by the number of interventions featuring the intervention type or behaviour change technique that were not promising. Promising intervention types and behaviour change techniques were defined as those with a PR ≥ 2. RESULTS: Twenty studies (of19 interventions) were included. Seven interventions (37%) were 'very promising', eight 'quite promising' (42%) and four 'not promising' (21%). Most promising intervention types were 'persuasion' (n = 12; promise ratio (PR) = 5.0), 'enablement' (n = 16; PR = 4.33) and 'education' (n = 19; PR = 3.75). Most promising behaviour change techniques were 'feedback on behaviour' (n = 9; PR = 8.0) and 'restructuring the social environment' (e.g. staff role changes; n = 8; PR = 7.0). CONCLUSION: Systematic identification of the active ingredients of antimicrobial stewardship in long-term care facilities was facilitated through the application of behavioural science frameworks. Incorporating environmental restructuring and performance feedback may be promising intervention strategies for antimicrobial stewardship interventions within long-term care facilities.

Comparisons of Risk Factors for Intracerebral Hemorrhage versus Ischemic Stroke in Chinese Patients.

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.

Disease Status and Pubertal Stage Predict Improved Growth in Antitumor Necrosis Factor Therapy for Pediatric Inflammatory Bowel Disease.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Epidemiology and outcomes of older patients admitted to Scottish intensive care units: a national database linkage study.

BACKGROUND: 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. METHODS: 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. FINDINGS: During 2005-10, 47 779 people were admitted to ICU (4561 patients ≥80 years [9·5%, 35·0/10 000 population], 26 784 patients <65 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%, p<0·0001) as was 6-year mortality (68·0% vs 34·5%, p<0·0001). 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, p<0·0001). Age was an independent predictor of mortality (odds ratio 1·46, 95% CI 1·23-1·73, p<0·0001) 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%, p<0·0001), and median ICU length of stay was lower (6 days [IQR 3-13] vs 8 [3-16], p<0·0001). INTERPRETATION: 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: Funding assistance for AD's MPH from Scottish Intensive Care Society, Scottish Society of Anaesthetists, Edinburgh Anaesthetics Research and Education Fund.

Equity of Access to Critical Care Among Elderly Patients in Scotland: A National Cohort Study.

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.

Synthesis and determination of absolute configuration of a non-peptidic αvß6 integrin antagonist for the treatment of idiopathic pulmonary fibrosis.

A diastereoselective synthesis of (S)-3-(3-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid (1), a potential therapeutic agent for the treatment of Idiopathic Pulmonary Fibrosis, which is currently undergoing Phase I clinical trials is reported. The key steps in the synthesis involved alkylation of 2-methylnaphthyridine with (R)-N-Boc-3-(iodomethyl)-pyrrolidine, and an asymmetric Rh-catalysed addition of an arylboronic acid to a 4-(N-pyrrolidinyl)crotonate ester. The overall yield of the seven linear step synthesis was 8% and the product was obtained in >99.5% ee proceeding with 80% de. The absolute configuration of 1 was established by an alternative asymmetric synthesis involving alkylation of an arylacetic acid using Evans oxazolidinone chemistry, acylation using the resulting 2-arylsuccinic acid, and reduction. The absolute configuration of the benzylic asymmetric centre was established as (S).

Diagnostic accuracy of pulmonary host inflammatory mediators in the exclusion of ventilator-acquired pneumonia.

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 >10(4) colony forming units per millilitre (cfu/mL). Interleukin-1 beta (IL-1ß), 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 (p<0.001). The area under the receiver operator characteristic curve for IL-1ß was 0.81; IL-8, 0.74; MMP-8, 0.76; MMP-9, 0.79 and HNE, 0.78. A combination of IL-1ß and IL-8, at the optimal cut-point, excluded VAP with a sensitivity of 100%, a specificity of 44.3% and a post-test probability of 0% (95% CI 0% to 9.2%). CONCLUSIONS: Low BALF IL-1ß 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.

Speciation control during Suzuki-Miyaura cross-coupling of haloaryl and haloalkenyl MIDA boronic esters.

Boronic acid solution speciation can be controlled during the Suzuki-Miyaura cross-coupling of haloaryl N-methyliminodiacetic acid (MIDA) boronic esters to enable the formal homologation of boronic acid derivatives. The reaction is contingent upon control of the basic biphase and is thermodynamically driven: temperature control provides highly chemoselective access to either BMIDA adducts at room temperature or boronic acid pinacol ester (BPin) products at elevated temperature. Control experiments and solubility analyses have provided some insight into the mechanistic operation of the formal homologation process.

The diagnostic accuracy of fecal calprotectin during the investigation of suspected pediatric inflammatory bowel disease: a systematic review and meta-analysis.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

A randomized controlled trial of peripheral blood mononuclear cell depletion in experimental human lung inflammation.

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 [(18)F]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 lungs of all volunteers. There was no significant difference between the depletion and sham groups in the mean increment in blood neutrophil count at 8 hours (6.16 × 10(9)/L and 6.15 × 10(9)/L, respectively; P = 1.00). Furthermore, there were no significant differences in BAL neutrophils or protein, positron emission tomography-derived measures of global lung inflammation, or cytokine levels in plasma or BAL supernatant between the study groups. No serious adverse events occurred, and no symptoms were significantly different between the groups. CONCLUSIONS: These findings do not support a role for circulating human monocytes in the early recruitment of neutrophils during LPS-mediated acute lung inflammation in humans.

"Knowing that I had HPV, I literally just shut down": A qualitative exploration of the psychosocial impact of human papillomavirus (HPV) in women living with mental health conditions.

OBJECTIVE: Psychological distress after testing positive for human papillomavirus (HPV) at cervical cancer screening is well documented in the general population. However, little is known about the impact of an HPV-positive result on those with pre-existing mental health conditions, who may be at higher risk of experiencing clinically significant distress. This study explored the psychosocial impact of HPV in women with co-morbid mental health conditions, as well as their experience of cervical screening during the COVID-19 pandemic. METHODS: Semi-structured telephone interviews were conducted with 22 women aged 27-54 who had tested positive for HPV at routine cervical screening in England, and who reported having at least one mental health condition. Data were analysed using thematic analysis. RESULTS: Being informed of an HPV-positive result increased distress and heightened pre-existing psychological challenges. Psychosocial response and duration of HPV-related distress appeared to be influenced by the ability to regulate emotions, number of consecutive HPV-positive results, interactions with health care professionals, and other life stressors. The experience added further complexity to many women's perceptions of self and self-esteem. Women who had received psychological treatment for their mental health condition were best able to self-manage HPV-related distress by applying learned coping skills. CONCLUSIONS: Receiving an HPV-positive result at cervical screening appears to be a distressing experience for women with co-morbid mental health conditions. Future hypothesis-driven research is needed to confirm findings and develop effective interventions to reduce psychosocial burden.

Assessment of the comparative agreement between chest radiographs and CT scans in intensive care units.

PURPOSE: Chest radiographs in critically ill patients can be difficult to interpret due to technical and clinical factors. We sought to determine the agreement of chest radiographs and CT scans, and the inter-observer variation of chest radiograph interpretation, in intensive care units (ICUs). METHODS: Chest radiographs and corresponding thoracic computerised tomography (CT) scans (as reference standard) were collected from 45 ICU patients. All radiographs were analysed by 20 doctors (radiology consultants, radiology trainees, ICU consultants, ICU trainees) from 4 different centres, blinded to CT results. Specificity/sensitivity were determined for pleural effusion, lobar collapse and consolidation/atelectasis. Separately, Fleiss' kappa for multiple raters was used to determine inter-observer variation for chest radiographs. RESULTS: The median sensitivity and specificity of chest radiographs for detecting abnormalities seen on CTs scans were 43.2% and 85.9% respectively. Diagnostic sensitivity for pleural effusion was significantly higher among radiology consultants but no specialty/experience distinctions were observed for specificity. Median inter-observer kappa coefficient among assessors was 0.295 ("fair"). CONCLUSIONS: Chest radiographs commonly miss important radiological features in critically ill patients. Inter-observer agreement in chest radiograph interpretation is only "fair". Consultant radiologists are least likely to miss thoracic radiological abnormalities. The consequences of misdiagnosis by chest radiographs remain to be determined.

C5a-mediated neutrophil dysfunction is RhoA-dependent and predicts infection in critically ill patients.

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.

DNA repair and replication proteins as prognostic markers in melanoma.

AIMS: 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. METHODS AND RESULTS: 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. CONCLUSIONS: Two (XRCC5 and TOP2A) of seven DNA repair and replication proteins studied were prognostic for melanoma.

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

BACKGROUND: There are concerns about the reporting quality of asthma trials. AIMS: To describe the reporting of contemporary asthma trials and to identify factors associated with better reporting quality. METHODS: 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. RESULTS: Thirty-five RCTs satisfied our eligibility criteria. Four trials adequately reported <50% of the items, 15 adequately reported 50-60% of items, and 16 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). CONCLUSIONS: The quality of reporting in contemporary asthma literature remains suboptimal. We have identified important areas in which reporting quality needs to be improved.

A novel subpopulation of monocyte-like cells in the human lung after lipopolysaccharide inhalation.

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.