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ObjectiveTo explore the causes of failure to activate the rapid response system (RRS). The organisation has a recognised incidence of staff failing to act when confronted with a deteriorating patient and leading to adverse outcomes.DesignA multi-method study using the following: a point prevalence survey to determine the incidence of abnormal simple bedside observations and activation of the rapid response team by clinical staff; a prospective audit of all patients experiencing a cardiac arrest, unplanned intensive care unit admission or death over an 8-week period; structured interviews of staff to explore cognitive and sociocultural barriers to activating the RRS.SettingSouthern Health is a comprehensive healthcare network with 570 adult in-patient beds across four metropolitan teaching hospitals in the south-eastern sector of Melbourne.MeasurementsFrequency of physiological instability and outcomes within the in-patient hospital population. Qualitative data from staff interviews were thematically coded.ResultsThe incidence of physiological instability in the acute adult population was 4.04%. Nearly half of these patients (42%) did not receive an appropriate clinical response from the staff, despite most (69.2%) recognising their patient met physiological criteria for activating the RRS, and being ‘quite’, or ‘very’ concerned about their patient (75.8%). Structured interviews with 91 staff members identified predominantly sociocultural reasons for failure to activate the RRS.ConclusionsDespite an organisational commitment to the RRS, clinical staff act on local cultural rules within the clinical environment that are usually not explicit. Better understanding of these informal rules may lead to more appropriate activation of the RRS.

Mammography screening currently relies on subjective human interpretation. Artificial intelligence (AI) advances could be used to increase mammography screening accuracy by reducing missed cancers and false positives. To evaluate whether AI can overcome human mammography interpretation limitations with a rigorous, unbiased evaluation of machine learning algorithms. In this diagnostic accuracy study conducted between September 2016 and November 2017, an international, crowdsourced challenge was hosted to foster AI algorithm development focused on interpreting screening mammography. More than 1100 participants comprising 126 teams from 44 countries participated. Analysis began November 18, 2016. Algorithms used images alone (challenge 1) or combined images, previous examinations (if available), and clinical and demographic risk factor data (challenge 2) and output a score that translated to cancer yes/no within 12 months. Algorithm accuracy for breast cancer detection was evaluated using area under the curve and algorithm specificity compared with radiologists' specificity with radiologists' sensitivity set at 85.9% (United States) and 83.9% (Sweden). An ensemble method aggregating top-performing AI algorithms and radiologists' recall assessment was developed and evaluated. Overall, 144 231 screening mammograms from 85 580 US women (952 cancer positive ≤12 months from screening) were used for algorithm training and validation. A second independent validation cohort included 166 578 examinations from 68 008 Swedish women (780 cancer positive). The top-performing algorithm achieved an area under the curve of 0.858 (United States) and 0.903 (Sweden) and 66.2% (United States) and 81.2% (Sweden) specificity at the radiologists' sensitivity, lower than community-practice radiologists' specificity of 90.5% (United States) and 98.5% (Sweden). Combining top-performing algorithms and US radiologist assessments resulted in a higher area under the curve of 0.942 and achieved a significantly improved specificity (92.0%) at the same sensitivity. While no single AI algorithm outperformed radiologists, an ensemble of AI algorithms combined with radiologist assessment in a single-reader screening environment improved overall accuracy. This study underscores the potential of using machine learning methods for enhancing mammography screening interpretation.

Background Spirometric small airways obstruction (SAO) is common in the general population. Whether spirometric SAO is associated with respiratory symptoms, cardiometabolic diseases, and quality of life (QoL) is unknown. Methods Using data from the Burden of Obstructive Lung Disease study (N = 21,594), we defined spirometric SAO as the mean forced expiratory flow rate between 25 and 75% of the FVC (FEF 25-75 ) less than the lower limit of normal (LLN) or the forced expiratory volume in 3 s to FVC ratio (FEV 3 /FVC) less than the LLN. We analysed data on respiratory symptoms, cardiometabolic diseases, and QoL collected using standardised questionnaires. We assessed the associations with spirometric SAO using multivariable regression models, and pooled site estimates using random effects meta-analysis. We conducted identical analyses for isolated spirometric SAO (i.e. with FEV 1 /FVC ≥ LLN). Results Almost a fifth of the participants had spirometric SAO (19% for FEF 25-75 ; 17% for FEV 3 /FVC). Using FEF 25-75, spirometric SAO was associated with dyspnoea (OR = 2.16, 95% CI 1.77–2.70), chronic cough (OR = 2.56, 95% CI 2.08–3.15), chronic phlegm (OR = 2.29, 95% CI 1.77–4.05), wheeze (OR = 2.87, 95% CI 2.50–3.40) and cardiovascular disease (OR = 1.30, 95% CI 1.11–1.52), but not hypertension or diabetes. Spirometric SAO was associated with worse physical and mental QoL. These associations were similar for FEV 3 /FVC. Isolated spirometric SAO (10% for FEF 25-75 ; 6% for FEV 3 /FVC), was also associated with respiratory symptoms and cardiovascular disease. Conclusion Spirometric SAO is associated with respiratory symptoms, cardiovascular disease, and QoL. Consideration should be given to the measurement of FEF 25-75 and FEV 3 /FVC, in addition to traditional spirometry parameters.

Evidence supporting the association of COPD or airflow obstruction with use of solid fuels is conflicting and inconsistent. To assess the association of airflow obstruction with self-reported use of solid fuels for cooking or heating. We analysed 18,554 adults from the BOLD study, who had provided acceptable post-bronchodilator spirometry measurements and information on use of solid fuels. The association of airflow obstruction with use of solid fuels for cooking or heating was assessed by sex, within each site, using regression analysis. Estimates were stratified by national income and meta-analysed. We carried out similar analyses for spirometric restriction, chronic cough and chronic phlegm. We found no association between airflow obstruction and use of solid fuels for cooking or heating (ORmen=1.20, 95%CI 0.94-1.53; ORwomen=0.88, 95%CI 0.67-1.15). This was true for low/middle and high income sites. Among never smokers there was also no evidence of an association of airflow obstruction with use of solid fuels (ORmen=1.00, 95%CI 0.57-1.76; ORwomen=1.00, 95%CI 0.76-1.32). Overall, we found no association of spirometric restriction, chronic cough or chronic phlegm with the use of solid fuels. However, we found that chronic phlegm was more likely to be reported among female never smokers and those who had been exposed for ≥20 years. Airflow obstruction assessed from post-bronchodilator spirometry was not associated with use of solid fuels for cooking or heating.

Androgens drive the onset and progression of prostate cancer (PCa) by modulating androgen receptor (AR) transcriptional activity. Although several microarray-based studies have identified androgen-regulated genes, here we identify in-parallel global androgen-dependent changes in both gene and alternative mRNA isoform expression by exon-level analyses of the LNCaP transcriptome. While genome-wide gene expression changes correlated well with previously-published studies, we additionally uncovered a subset of 226 novel androgen-regulated genes. Gene expression pathway analysis of this subset revealed gene clusters associated with, and including the tyrosine kinase LYN, as well as components of the mTOR (mammalian target of rapamycin) pathway, which is commonly dysregulated in cancer. We also identified 1279 putative androgen-regulated alternative events, of which 325 (∼25%) mapped to known alternative splicing events or alternative first/last exons. We selected 30 androgen-dependent alternative events for RT-PCR validation, including mRNAs derived from genes encoding tumour suppressors and cell cycle regulators. Of seven positively-validating events (∼23%), five events involved transcripts derived from alternative promoters of known AR gene targets. In particular, we found a novel androgen-dependent mRNA isoform derived from an alternative internal promoter within the TSC2 tumour suppressor gene, which is predicted to encode a protein lacking an interaction domain required for mTOR inhibition. We confirmed that expression of this alternative TSC2 mRNA isoform was directly regulated by androgens, and chromatin immunoprecipitation indicated recruitment of AR to the alternative promoter region at early timepoints following androgen stimulation, which correlated with expression of alternative transcripts. Together, our data suggest that alternative mRNA isoform expression might mediate the cellular response to androgens, and may have roles in clinical PCa.

Smoking is the most well-established cause of chronic airflow obstruction (CAO) but particulate air pollution and poverty have also been implicated. We regressed sex-specific prevalence of CAO from 41 Burden of Obstructive Lung Disease study sites against smoking prevalence from the same study, the gross national income per capita and the local annual mean level of ambient particulate matter (PM2.5) using negative binomial regression. The prevalence of CAO was not independently associated with PM2.5 but was strongly associated with smoking and was also associated with poverty. Strengthening tobacco control and improved understanding of the link between CAO and poverty should be prioritised.

In the case of death certificates the situation is further confounded by the limited choice of International Classification of Disease codes for people dying with chronic lung disease.

Purpose Evidence-based medicine promotes the current best evidence from clinical trials to guide decisions for individual patients. We assessed whether chronic obstructive pulmonary disease (COPD) patients included in exercise training studies and pharmacologic trials match those from a non-selected COPD target population sample. Methods Exercise training studies were identified in a literature search. Towards a Revolution in COPD Health (TORCH) and Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) were chosen to represent pharmacologic trials. Burden of Obstructive Lung Disease (BOLD) data were used to characterize target COPD population (BOLD target), defined as the presence of dyspnea (modified Medical Research Council ≥2) and non-reversible airway obstruction (post-bronchodilator FEV1/FVC ≤0.7 and FEV1% predicted ≤70 %). Results Overall 240 exercise training studies with 13,901, TORCH and UPLIFT with 12,105, and BOLD with 16,218 participants were evaluated. Males were overrepresented in exercise training studies (67.5 %) and pharmacologic trials (TORCH 75.8 %; UPLIFT 74.6 %), whereas in BOLD target 55.8 % were males ( p  < 0.001). In exercise training studies, 7.2 % were never-smokers, 0.0 % in TORCH and UPLIFT, but 36.0 % in BOLD target ( p  < 0.001). Subjects with cardiac comorbidity were excluded from 75.4 % of exercise training studies, entirely from TORCH and UPLIFT, but comprised 24.5 % of BOLD target. Conclusions COPD patients recruited in exercise training studies and in pharmacologic trials differ from target population of symptomatic COPD. Females, never-smokers, and patients with cardiac comorbidities are more likely excluded from the clinical trials.

The improved lung deposition of hydrofluoroalkane-134a beclomethasone dipropionate (HFA-BDP) extrafine aerosol compared with chlorofluorocarbon beclomethasone dipropionate (CFC-BDP) suggests that lower doses of HFA-BDP may be required to provide equivalent asthma control. The present study was undertaken to test this hypothesis. A 10- to 12-day run-in period confirmed that patients met established criteria of at least moderate asthma and the asthma was inadequately controlled by current therapy (inhaled β-agonist and CFC-BDP [≤ 400 μg/d]). A short course of oral prednisone, 30 mg/d for 7 to 12 days, was followed to establish the patients were steroid responsive and to provide an“ in-study” baseline of “optimal” asthma control. A total of 347 patients were then randomized to HFA-BDP 400 μg/d, CFC-BDP 800 μg/d, or HFA-placebo for 12 weeks. Morning peak expiratory flow (am PEF) measurements showed that HFA-BDP 400 μg/d achieved equivalent control of asthma to CFC-BDP 800 μg/d at all time intervals after oral steroid treatment. All other efficacy variables supported the am PEF results and both active treatments were more effective than placebo. The safety profile of HFA-BDP compared favorably with that of CFC-BDP with no unexpected adverse events reported. These findings demonstrate that HFA-BDP provides equivalent control of moderate or moderately severe asthma as CFC-BDP in the population studied, but at half the total daily dose.