Search

Objective: To investigate whether measurements of junior doctor on-call workload and performance can clarify the mechanisms underlying the increase in morbidity and mortality seen after junior doctor changeover: the 'August effect'., Design: Quantitative retrospective observational study of routinely collected data on junior doctor workload., Setting: Two large teaching hospitals in England., Participants: Task level data from a wireless out of hours system (n = 29,885 requests) used by medical staff, nurses, and allied health professionals., Main Outcome Measures: Number and type of tasks requested by nurses, time to completion of tasks by junior doctors., Results: There was no overall change in the number of tasks requested by nurses out of hours around the August changeover (median requests per hour 15 before and 14 after, p = 0.46). However, the number of tasks classified as urgent was greater (p = 0.016) equating to five more urgent tasks per day. After changeover, doctors took less time to complete tasks overall due to a reduction in time taken for routine tasks (median 74 vs. 66 min; p = 3.9 × 10(-9))., Conclusion: This study suggests that the 'August effect' is not due to new junior doctors completing tasks more slowly or having a greater workload. Further studies are required to investigate the causes of the increased number of urgent tasks seen, but likely factors are errors, omissions, and poor prioritization. Thus, improved training and quality control has the potential to address this increased duration of unresolved patient risk. The study also highlights the potential of newer technologies to facilitate quantitative study of clinical activity.

Asthma is common, and some individuals are severely affected by it. Learned institutions have sought to provide a definition of 'severe asthma' to facilitate research and clinical care. This is a challenging undertaking given the difficulty in defining asthma and the lack of supportive evidence for a distinct severe asthma phenotype. In this review, we discuss the rationale for a definition of severe asthma and the relative merits of the sequential attempts that have been made to produce such a definition. The difficulty in disentangling control and severity is highlighted, as is the heterogeneity of phenotype in severe asthma, and potential for misclassification. We conclude that the search for a singular definition of severe asthma is problematic, though likely to continue. We suggest the alternative strategy of using classifiers with a specific aim related to symptoms, pathophysiology or service provision., (© 2012 Blackwell Publishing Ltd.)

Background: Lymphangioleiomyomatosis is a rare disease occurring almost exclusively in women. Diagnosis often requires surgical biopsy and the clinical course varies between patients with no predictors of progression. We evaluated recent diagnostic guidelines, clinical features and serum biomarkers as diagnostic and prognostic tools., Methods: Serum vascular endothelial growth factor-D (VEGF-D), angiotensin converting enzyme (ACE), matrix metalloproteinases (MMP) -2 and -9, clinical phenotype, thoracic and abdominal computerised tomography, lung function and quality of life were examined in a cohort of 58 patients. 32 healthy female controls had serum biomarkers measured., Results: Serum VEGF-D, ACE and total MMP-2 levels were elevated in patients. VEGF-D was the strongest discriminator between patients and controls (median = 1174 vs. 332 pg/ml p < 0.0001 with an area under the receiver operating characteristic curve of 0.967, 95% CI 0.93-1.01). Application of European Respiratory Society criteria allowed a definite diagnosis without biopsy in 69%. Adding VEGF-D measurement to ERS criteria further reduced the need for biopsy by 10%. VEGF-D was associated with lymphatic involvement (p = 0.017) but not the presence of angiomyolipomas., Conclusions: Combining ERS criteria and serum VEGF-D reduces the need for lung biopsy in LAM. VEGF-D was associated with lymphatic disease but not lung function.

Objectives: The authors investigated if a wireless system of call handling and task management for out of hours care could replace a standard pager-based system and improve markers of efficiency, patient safety and staff satisfaction., Design: Prospective assessment using both quantitative and qualitative methods, including interviews with staff, a standard satisfaction questionnaire, independent observation, data extraction from work logs and incident reporting systems and analysis of hospital committee reports., Setting: A large teaching hospital in the UK., Participants: Hospital at night co-ordinators, clinical support workers and junior doctors handling approximately 10 000 tasks requested out of hours per month., Outcome Measures: Length of hospital stay, incidents reported, co-ordinator call logging activity, user satisfaction questionnaire, staff interviews., Results: Users were more satisfied with the new system (satisfaction score 62/90 vs 82/90, p=0.0080). With the new system over 70 h/week of co-ordinator time was released, and there were fewer untoward incidents related to handover and medical response (OR=0.30, p=0.02). Broad clinical measures (cardiac arrest calls for peri-arrest situations and length of hospital stay) improved significantly in the areas covered by the new system., Conclusions: The introduction of call handling software and mobile technology over a medical-grade wireless network improved staff satisfaction with the Hospital at Night system. Improvements in efficiency and information flow have been accompanied by a reduction in untoward incidents, length of stay and peri-arrest calls.

Rationale: Genomic loci are associated with FEV1 or the ratio of FEV1 to FVC in population samples, but their association with chronic obstructive pulmonary disease (COPD) has not yet been proven, nor have their combined effects on lung function and COPD been studied., Objectives: To test association with COPD of variants at five loci (TNS1, GSTCD, HTR4, AGER, and THSD4) and to evaluate joint effects on lung function and COPD of these single-nucleotide polymorphisms (SNPs), and variants at the previously reported locus near HHIP., Methods: By sampling from 12 population-based studies (n = 31,422), we obtained genotype data on 3,284 COPD case subjects and 17,538 control subjects for sentinel SNPs in TNS1, GSTCD, HTR4, AGER, and THSD4. In 24,648 individuals (including 2,890 COPD case subjects and 13,862 control subjects), we additionally obtained genotypes for rs12504628 near HHIP. Each allele associated with lung function decline at these six SNPs contributed to a risk score. We studied the association of the risk score to lung function and COPD., Measurements and Main Results: Association with COPD was significant for three loci (TNS1, GSTCD, and HTR4) and the previously reported HHIP locus, and suggestive and directionally consistent for AGER and TSHD4. Compared with the baseline group (7 risk alleles), carrying 10-12 risk alleles was associated with a reduction in FEV1 (β = -72.21 ml, P = 3.90 × 10(-4)) and FEV1/FVC (β = -1.53%, P = 6.35 × 10(-6)), and with COPD (odds ratio = 1.63, P = 1.46 × 10(-5))., Conclusions: Variants in TNS1, GSTCD, and HTR4 are associated with COPD. Our highest risk score category was associated with a 1.6-fold higher COPD risk than the population average score.

Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.

The study of genetic variation has the potential to aid understanding of the mechanisms underlying the observed inter-individual variation in drug response and by which idiosyncratic adverse effects occur. In this review, we outline current progress in pharmacogenetics using examples to highlight both mechanisms of influence of polymorphisms and research strategies for their detection. In the final sections we discuss contemporary challenges for both researchers and clinicians., (© 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.)

Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease (COPD). We tested genome-wide association with forced expiratory volume in 1 s (FEV(1)) and the ratio of FEV(1) to forced vital capacity (FVC) in the SpiroMeta consortium (n = 20,288 individuals of European ancestry). We conducted a meta-analysis of top signals with data from direct genotyping (n < or = 32,184 additional individuals) and in silico summary association data from the CHARGE Consortium (n = 21,209) and the Health 2000 survey (n < or = 883). We confirmed the reported locus at 4q31 and identified associations with FEV(1) or FEV(1)/FVC and common variants at five additional loci: 2q35 in TNS1 (P = 1.11 x 10(-12)), 4q24 in GSTCD (2.18 x 10(-23)), 5q33 in HTR4 (P = 4.29 x 10(-9)), 6p21 in AGER (P = 3.07 x 10(-15)) and 15q23 in THSD4 (P = 7.24 x 10(-15)). mRNA analyses showed expression of TNS1, GSTCD, AGER, HTR4 and THSD4 in human lung tissue. These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease.

Background: Cysteinyl leukotrienes (CysLTs) play an important role in the pathophysiology of many allergic inflammatory disorders. However, data on the contribution of genetic variability of the cysteinyl leukotriene receptor 1 gene (CYSLTR1) in asthma and atopy remain conflicting., Objective: We investigated the association of polymorphisms of interest located at this locus and allergic disease prevalence in a national population with an established DNA archive, the British 1958 birth cohort., Methods: The British 1958 birth cohort comprises all persons born in Britain during 1 week in 1958. Asthma, wheezy bronchitis, and wheezing were ascertained by interview at ages 7, 11, 16, 23, 33, and 42 years. At age 44 to 45 years, serum total circulating IgE levels were measured and atopy was defined as a serum total IgE level of greater than 30 kU/L and specific IgE levels to 1 or more of dust mite, cat fur, and mixed grass of greater than 0.3 kU/L. DNA samples from 8018 participants were genotyped for 2 variants of the CYSLTR1 promoter (Xq13-Xq21)., Results: The rare polymorphism C > T (rs7066737) was not associated with any of the phenotypes studied. The common promoter polymorphism A > G (rs2806489) was not associated with total IgE levels or the prevalence or age of onset of asthma, wheezy bronchitis, or wheeze. However, the wild-type allele A was significantly associated with atopy in female subjects (chi(2) = 8.30, P = .004), although not in male subjects (P = .841)., Conclusions: These data suggest that a CYSLTR1 polymorphism previously shown to affect the gene transcription in vitro might influence the risk of atopy in the female white population with suggestive evidence of heterozygote vigor.

Objective: The aim of this study was to estimate the contribution of polymorphisms in the positionally cloned asthma candidate genes ADAM33, PHF11, DPP10, GPRA and PTGDR to the risk of asthma, total and specific immunoglobulin E level, lung function and wheezing in a large, nationally representative, population., Methods: An association analysis was undertaken using genotype data for tagging and previously associated single nucleotide polymorphisms (SNPs) in regions of these genes and longitudinal phenotype data from singletons of white ethnicity in the British 1958 Birth Cohort DNA archive (n = 7703). Population-attributable risk fractions for SNPs showing association were calculated., Results: Polymorphisms producing small but statistically significant increases in asthma risk (OR 1.1 per allele) were identified in DPP10 and ADAM33, with the strongest evidence being for SNPs tagging the DPP10 gene. No individual SNP in any gene under study markedly increased risk for any of the phenotypes in the population studied., Conclusions: These data suggest that DPP10 and ADAM33 influence asthma risk in the UK population. However, the effects driven by any given locus are small, and genotyping of multiple polymorphisms in many genes will be needed to define a full genetic profile for disease risk.

Background: Animal and human studies have implicated an imbalance of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in the pathogenesis of chronic obstructive pulmonary disease (COPD). MMP-9 protein is increased in COPD and we hypothesized that total MMP activity would be raised although this has not previously been measured., Methods: Using fluorescence and biotin labelled MMP assays, RT-PCR, western blotting and enzyme-linked immunosorbent assay we examined total MMP activity, specific gelatinase, elastase, collagenase activity, TIMP-1 and TIMP-2 in induced sputum from smokers with COPD and smokers without COPD., Results: Induced sputum was obtained from 15 smokers with COPD and 14 smokers without COPD. MMP-9 levels were higher in those with COPD compared with controls (p<0.05). Total MMP activity, specific gelatinase, collagenase and elastase activities were not higher in COPD patients. In addition, reduced MMP activity was correlated with increasing airflow obstruction in COPD (p=0.016)., Conclusion: MMP-9 protein but not MMP activity was higher in sputum of COPD patients compared with controls. These results suggest that MMP-9 levels may not reflect the overall MMP activity in the airways of patients with COPD suggesting a complex relationship between MMP-9 protein and activity. Further studies of MMPs in COPD should comprise activity measures in addition to protein levels.

Background: Clinical studies indicate that sudden death (SD) is common after heart transplantation. Autopsy reports of such patients are sparse., Methods: We performed a retrospective study of clinical and pathologic findings on all autopsied patients who underwent heart transplantation at our institution from January 1984 to July 2002., Results: There were 74 patients who survived >2 months. Of these, 28 (37.8%) died suddenly. The major causes of sudden death (SD) included acute cellular rejection (ACR) (n = 11, 39.3%) and graft coronary artery disease (GCAD) (n = 11, 39.3%). In 9 patients (32.1%), there was no anatomic cause of death. These deaths, assumed to be primary arrhythmic death (PAD), occurred 5 to 36 months post-transplantation. Pre-transplant diagnosis of idiopathic dilated cardiomyopathy (IDCM) was more common in SD (13 of 28, 46.4% vs 9 of 46, 19.6%; p = 0.014). Hypertrophy was not statistically different in SD vs non-SD (79.4% vs 88.4%; p = 0.38). Coronary thrombosis was also not statistically different in sudden GCAD deaths vs non-sudden GCAD deaths (3 of 11, 27.3% vs 8 of 13, 61.5%; p = 0.09). ACR SD patients had fewer episodes of ACR in biopsies than ACR non-SD patients (93 of 190, 48.9% vs 99 of 159, 63.3%; p = 0.01). Biopsies with Quilty lesions (QL) were more frequent in patients with SD (206 of 461, 44.7% vs 243 of 710, 34.2%; p < 0.001). QL were more common in patients with GCAD (44.4%) and ACR (39.6%) than in patients who died of infection (25.7%; P < 0.001 and p < 0.01, respectively)., Conclusions: SD after cardiac transplantation is common (37.8% of all deaths). ACR, in the first year, and GCAD, afterwards, are associated with SD. PAD occurred in 32.1% of SD cases, 5 to 36 months after transplantation. Pre-transplant diagnoses of IDCM and QL are more common in SD. Surprisingly, cardiac hypertrophy is not increased and coronary thrombosis is not more frequent in patients who died suddenly.