Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD

Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p 10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10−392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group

Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial

Background: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. Methods: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. Findings: Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96–1·28). Interpretation: No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both the time and resources needed to improve patient care. Funding: National Institute for Health Research Health Services and Delivery Research Programme

Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial

BACKGROUND: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. METHODS: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. FINDINGS: Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96-1·28). INTERPRETATION: No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both the time and resources needed to improve patient care. FUNDING: National Institute for Health Research Health Services and Delivery Research Programme

Myocarditis and Arteritic Anterior Ischemic Optic Neuropathy Secondary to Giant Cell Arteritis (.pdf)

Giant cell arteritis (GCA) is a primary vasculitis of medium and large vessels with a broad range of clinical presentations. Myocarditis is a rare known manifestation of GCA. We present a case of a 67 year old man who presented with acute systolic heart failure of unknown etiology. Development of arteritic anterior ischemic optic neuropathy lead to the diagnosis of myocarditis secondary to GCA

CT pulmonary angiography: increasingly diagnosing less severe pulmonary emboli.

It is unknown whether the observed increase in computed tomography pulmonary angiography (CTPA) utilization has resulted in increased detection of pulmonary emboli (PEs) with a less severe disease spectrum.Trends in utilization, diagnostic yield, and disease severity were evaluated for 4,048 consecutive initial CTPAs performed in adult patients in the emergency department of a large urban academic medical center between 1/1/2004 and 10/31/2009. Transthoracic echocardiography (TTE) findings and peak serum troponin levels were evaluated to assess for the presence of PE-associated right ventricular (RV) abnormalities (dysfunction or dilatation) and myocardial injury, respectively. Statistical analyses were performed using multivariate logistic regression.268 CTPAs (6.6%) were positive for acute PE, and 3,780 (93.4%) demonstrated either no PE or chronic PE. There was a significant increase in the likelihood of undergoing CTPA per year during the study period (odds ratio [OR] 1.05, 95% confidence interval [CI] 1.04-1.07, P<0.01). There was no significant change in the likelihood of having a CTPA diagnostic of an acute PE per year (OR 1.03, 95% CI 0.95-1.11, P = 0.49). The likelihood of diagnosing a less severe PE on CTPA with no associated RV abnormalities or myocardial injury increased per year during the study period (OR 1.39, 95% CI 1.10-1.75, P = 0.01).CTPA utilization has risen with no corresponding change in diagnostic yield, resulting in an increase in PE detection. There is a concurrent rise in the likelihood of diagnosing a less clinically severe spectrum of PEs

Annual CTPA utilization patterns.

<p>Graph shows an increase in the number of CTPAs ordered from 2004 to 2009 with concurrent increase in number of scans positive for an acute PE.</p

Association of various demographic variables and likelihood of a positive CTPA scan.

<p>Association of various demographic variables and likelihood of a positive CTPA scan.</p

Annualized CTPA utilization, diagnostic yield and disease severity data.

*<p>Incomplete year: includes data from Jan. 1, 2009 to Oct. 31, 2009.</p

Association of various demographic variables and likelihood of diagnosing a less severe disease spectrum.

<p>Association of various demographic variables and likelihood of diagnosing a less severe disease spectrum.</p

Annual number of PEs diagnosed by CTPA, number of PEs without associated RV abnormalities or myocardial injury, and number of PEs with associated RV dysfunction and/or dilatation and/or myocardial injury.

<p>Annual number of PEs diagnosed by CTPA, number of PEs without associated RV abnormalities or myocardial injury, and number of PEs with associated RV dysfunction and/or dilatation and/or myocardial injury.</p