Multiple listing in lung transplant candidates: A cohort study.

Lung transplant candidates can be waitlisted at more than one transplant center, a practice known as multiple listing. The factors associated with multiple listing and whether multiple listing modifies waitlist mortality or likelihood of lung transplant is unknown. US lung transplant waitlist candidates were identified as either single or multiple listed using data from the Scientific Registry of Transplant Recipients. Characteristics of single and multiple listed candidates were compared and multivariable logistic regression was used to estimate associations with multiple listing. Multiple listed candidates were matched to single listed candidates using a combination of exact and propensity score matching methods. Cox proportional hazard models were used to estimate the relationship of multiple listing on waitlist mortality and receiving a transplant. Multiple listing occurred in 2.3% of lung transplant waitlist candidates. Younger age, female gender, white race, short stature, high antibody sensitization, college or postcollege education, lower lung allocation score, and a cystic fibrosis diagnosis were independently associated with multiple listing. Multiple listing was associated with an increased likelihood of lung transplant (adjusted hazard ratio [aHR] 2.74, 95% CI 2.37 to 3.16) but was not associated with waitlist mortality (aHR 0.99, 95% CI 0.68 to 1.44).

Deep Learning to Classify Radiology Free-Text Reports.

Purpose To evaluate the performance of a deep learning convolutional neural network (CNN) model compared with a traditional natural language processing (NLP) model in extracting pulmonary embolism (PE) findings from thoracic computed tomography (CT) reports from two institutions. Materials and Methods Contrast material-enhanced CT examinations of the chest performed between January 1, 1998, and January 1, 2016, were selected. Annotations by two human radiologists were made for three categories: the presence, chronicity, and location of PE. Classification of performance of a CNN model with an unsupervised learning algorithm for obtaining vector representations of words was compared with the open-source application PeFinder. Sensitivity, specificity, accuracy, and F1 scores for both the CNN model and PeFinder in the internal and external validation sets were determined. Results The CNN model demonstrated an accuracy of 99% and an area under the curve value of 0.97. For internal validation report data, the CNN model had a statistically significant larger F1 score (0.938) than did PeFinder (0.867) when classifying findings as either PE positive or PE negative, but no significant difference in sensitivity, specificity, or accuracy was found. For external validation report data, no statistical difference between the performance of the CNN model and PeFinder was found. Conclusion A deep learning CNN model can classify radiology free-text reports with accuracy equivalent to or beyond that of an existing traditional NLP model. © RSNA, 2017 Online supplemental material is available for this article.

Melanoma risk prediction using a multilocus genetic risk score in the Women's Health Initiative cohort.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) associated with melanoma have been identified though genome-wide association studies. However, the combined impact of these SNPs on melanoma development remains unclear, particularly in postmenopausal women who carry a lower melanoma risk. OBJECTIVE: We examine the contribution of a combined polygenic risk score on melanoma development in postmenopausal women. METHODS: Genetic risk scores were calculated using 21 genome-wide association study-significant SNPs. Their combined effect on melanoma development was evaluated in 19,102 postmenopausal white women in the clinical trial and observational study arms of the Women's Health Initiative dataset. RESULTS: Compared to the tertile of weighted genetic risk score with the lowest genetic risk, the women in the tertile with the highest genetic risk were 1.9 times more likely to develop melanoma (95% confidence interval 1.50-2.42). The incremental change in c-index from adding genetic risk scores to age were 0.075 (95% confidence interval 0.041-0.109) for incident melanoma. LIMITATIONS: Limitations include a lack of information on nevi count, Fitzpatrick skin type, family history of melanoma, and potential reporting and selection bias in the Women's Health Initiative cohort. CONCLUSION: Higher genetic risk is associated with increased melanoma prevalence and incidence in postmenopausal women, but current genetic information may have a limited role in risk prediction when phenotypic information is available.

Validation of the Hematopoietic Cell Transplantation-Specific Comorbidity Index in Nonmyeloablative Allogeneic Stem Cell Transplantation.

The Hematopoietic Cell Transplantation (HCT)-Specific Comorbidity Index (HCT-CI) has been extensively studied in myeloablative and reduced-intensity conditioning regimens, with less data available regarding the validity of HCT-CI in nonmyeloablative (NMA) allogeneic transplantation. We conducted a retrospective analysis to evaluate the association between HCT-CI and nonrelapse mortality (NRM) and all-cause mortality (ACM) in patients receiving the total lymphoid irradiation and antithymocyte globulin (TLI/ATG) NMA transplantation preparative regimen. We abstracted demographic and clinical data from consecutive patients, who received allogeneic HCT with the TLI/ATG regimen between January 2008 and September 2014, from the Stanford blood and marrow transplantation database. We conducted univariable and multivariable Cox proportional hazards regression models to evaluate the association between HCT-CI and NRM and ACM. In all, 287 patients were included for analysis. The median age of the patients was 61 (range, 22 to 77) years. The median overall survival was 844 (range, 374 to 1484) days. Most patients had Karnofsky performance score of 90 or above (85%). Fifty-two (18%) patients relapsed within 3 months and 108 (38%) patients relapsed within 1 year, with a median time to relapse of 163 (range, 83 to 366) days. Among the comorbidities in the HCT-CI identified at the time of HCT, reduced pulmonary function was the most common (n = 89), followed by prior history of malignancy (n = 39), psychiatric condition (n = 38), and diabetes (n = 31). Patients with higher HCT-CI scores had higher mortality risks for ACM (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.22 to 3.14 for HCT-CI score 1 or 2 and HR, 1.85; 95% CI, 1.11 to 3.08 for HCT-CI score ≥ 3, compared with 0, respectively). Among individual HCT-CI variables, diabetes (HR, 2.31; 95% CI, 1.79 to 2.89; P = .003) and prior solid tumors (HR, 1.75; 95% CI, 1.02 to 3.00; P = .043) were associated with a higher risk of ACM. Higher HCT-CI scores were significantly associated with higher risk of death. HCT-CI is a valid tool for predicting ACM in NMA TLI/ATG allogeneic HCT.

Cangrelor reduces the risk of ischemic complications in patients with single-vessel and multi-vessel disease undergoing percutaneous coronary intervention: Insights from the CHAMPION PHOENIX trial.

OBJECTIVE: To examine the safety and efficacy of cangrelor in patients with single-vessel disease (SVD) and multi-vessel disease (MVD). BACKGROUND: Cangrelor, an intravenous, rapidly acting P2Y12 inhibitor, is superior to clopidogrel in reducing ischemic events among patients receiving percutaneous coronary intervention (PCI). METHODS: We studied a modified intention to treat population of patients with SVD and MVD from the CHAMPION PHOENIX trial. The primary efficacy outcome was the composite of death, myocardial infarction (MI), ischemia-driven revascularization (IDR), and stent thrombosis (ST) at 48hours. The key safety outcome was non-coronary artery bypass grafting GUSTO severe bleeding at 48hours. RESULTS: Among 10,921 patients, 5,220 (48%) had SVD and 5,701 (52%) had MVD. MVD patients were older and more often had diabetes, hyperlipidemia, hypertension, prior stroke, and prior MI. After adjustment, MVD patients had similar rates of 48-hour death/MI/IDR/ST (6.3% vs 4.2%, adjusted odds ratio [OR] 1.6 [95% CI 0.42-6.06]) and GUSTO severe bleeding (0.1% vs 0.2%, P=.67) compared with SVD patients. Consistent with overall trial findings, cangrelor use reduced ischemic complications in patients with both SVD (3.9% vs 4.5%; OR 0.86, 95% CI 0.65-1.12) and MVD (5.5% vs 7.2%; OR 0.74, 95% CI 0.6-0.92, P-interaction=.43). GUSTO severe bleeding outcomes were not significantly increased with cangrelor or clopidogrel in either SVD or MVD patients. CONCLUSION: In the CHAMPION PHOENIX trial, MVD and SVD patients had similar ischemic outcomes at 48hours and 30days. Cangrelor consistently reduced ischemic complications in both SVD and MVD patients without a significant increase in GUSTO severe bleeding. CLINICAL PERSPECTIVES.

Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes.

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)

Contemporary Considerations for Constructing a Genetic Risk Score: An Empirical Approach.

Genetic risk scores are an increasingly popular tool for summarizing the cumulative risk of a set of Single Nucleotide Polymorphisms (SNPs) with disease. Typically only the set of the SNPs that have reached genome-wide significance compose these scores. However recent work suggests that including additional SNPs may aid risk assessment. In this paper, we used the Atherosclerosis Risk in Communities (ARIC) Study cohort to illustrate how one can choose the optimal set of SNPs for a genetic risk score (GRS). In addition to P-value threshold, we also examined linkage disequilibrium, imputation quality, and imputation type. We provide a variety of evaluation metrics. Results suggest that P-value threshold had the greatest impact on GRS quality for the outcome of coronary heart disease, with an optimal threshold around 0.001. However, GRSs are relatively robust to both linkage disequilibrium and imputation quality. We also show that the optimal GRS partially depends on the evaluation metric and consequently the way one intends to use the GRS. Overall the implications highlight both the robustness of GRS and a means to empirically choose the best set of GRSs.

Genome-wide association study of white blood cell count in 16,388 African Americans: the continental origins and genetic epidemiology network (COGENT).

Total white blood cell (WBC) and neutrophil counts are lower among individuals of African descent due to the common African-derived "null" variant of the Duffy Antigen Receptor for Chemokines (DARC) gene. Additional common genetic polymorphisms were recently associated with total WBC and WBC sub-type levels in European and Japanese populations. No additional loci that account for WBC variability have been identified in African Americans. In order to address this, we performed a large genome-wide association study (GWAS) of total WBC and cell subtype counts in 16,388 African-American participants from 7 population-based cohorts available in the Continental Origins and Genetic Epidemiology Network. In addition to the DARC locus on chromosome 1q23, we identified two other regions (chromosomes 4q13 and 16q22) associated with WBC in African Americans (P<2.5×10(-8)). The lead SNP (rs9131) on chromosome 4q13 is located in the CXCL2 gene, which encodes a chemotactic cytokine for polymorphonuclear leukocytes. Independent evidence of the novel CXCL2 association with WBC was present in 3,551 Hispanic Americans, 14,767 Japanese, and 19,509 European Americans. The index SNP (rs12149261) on chromosome 16q22 associated with WBC count is located in a large inter-chromosomal segmental duplication encompassing part of the hydrocephalus inducing homolog (HYDIN) gene. We demonstrate that the chromosome 16q22 association finding is most likely due to a genotyping artifact as a consequence of sequence similarity between duplicated regions on chromosomes 16q22 and 1q21. Among the WBC loci recently identified in European or Japanese populations, replication was observed in our African-American meta-analysis for rs445 of CDK6 on chromosome 7q21 and rs4065321 of PSMD3-CSF3 region on chromosome 17q21. In summary, the CXCL2, CDK6, and PSMD3-CSF3 regions are associated with WBC count in African American and other populations. We also demonstrate that large inter-chromosomal duplications can result in false positive associations in GWAS.

Integration of FUNDC1-associated mitochondrial protein import and mitochondrial quality control contributes to TDP-43 degradation.

Though TDP-43 protein can be translocated into mitochondria and causes mitochondrial damage in TDP-43 proteinopathy, little is known about how TDP-43 is imported into mitochondria. In addition, whether mitochondrial damage is caused by mitochondrial mislocalization of TDP-43 or a side effect of mitochondria-mediated TDP-43 degradation remains to be investigated. Here, our bioinformatical analyses reveal that mitophagy receptor gene FUNDC1 is co-expressed with TDP-43, and both TDP-43 and FUNDC1 expression is correlated with genes associated with mitochondrial protein import pathway in brain samples of patients diagnosed with TDP-43 proteinopathy. FUNDC1 promotes mitochondrial translocation of TDP-43 possibly by promoting TDP-43-TOM70 and DNAJA2-TOM70 interactions, which is independent of the LC3 interacting region of FUNDC1 in cellular experiments. In the transgenic fly model of TDP-43 proteinopathy, overexpressing FUNDC1 enhances TDP-43 induced mitochondrial damage, whereas down-regulating FUNDC1 reverses TDP-43 induced mitochondrial damage. FUNDC1 regulates mitochondria-mediated TDP-43 degradation not only by regulating mitochondrial TDP-43 import, but also by increasing LONP1 level and by activating mitophagy, which plays important roles in cytosolic TDP-43 clearance. Together, this study not only uncovers the mechanism of mitochondrial TDP-43 import, but also unravels the active role played by mitochondria in regulating TDP-43 homeostasis.

Low-fat dietary pattern reduces urinary incontinence in postmenopausal women: post hoc analysis of the Women's Health Initiative Diet Modification Trial.

BACKGROUND: Urinary incontinence affects >40% of women in the United States, with an annual societal cost of >$12 billion and demonstrated associations with depressive symptoms, social isolation, and loss of work productivity. Weight has been established as an exposure that increases urinary incontinence risk and certain dietary components have been associated with urinary incontinence symptoms. We hypothesized that diet plays a key role in the association between weight and urinary incontinence in US women. OBJECTIVE: This study aimed to examine the effect of a low-fat diet on urinary incontinence in postmenopausal women as a post hoc analysis of a randomized controlled trial of diet modification. STUDY DESIGN: This was a post hoc analysis of the Women's Health Initiative Dietary Modification randomized controlled trial of 48,835 postmenopausal women from 40 US centers assigned to a dietary intervention (20% energy from fat, 5 fruits or vegetable servings, and 6 whole grain servings daily and an intensive behavioral modification program) or to the usual diet comparison group. The outcome was urinary incontinence at 1 year. RESULTS: Of the participants, 60% were randomized to the usual diet comparison group and 40% to the dietary modification intervention. After adjusting for weight change, women assigned to the dietary modification intervention were less likely to report urinary incontinence (odds ratio, 0.94; 95% confidence interval, 0.90-0.98; P=.003), more likely to report urinary incontinence resolution (odds ratio, 1.11; 95% confidence interval, 1.03-1.19; P=.01), and less likely to develop urinary incontinence (odds ratio, 0.92; 95% confidence interval, 0.87-0.98; P=.01) in adjusted models. CONCLUSION: Dietary modification may be a reasonable treatment for postmenopausal women with incontinence and also a urinary incontinence prevention strategy for continent women. Our results provide evidence to support a randomized clinical trial to determine whether a reduced fat-intake dietary modification is an effective intervention for the prevention and treatment of urinary incontinence. In addition to providing further insights into mechanisms of lower urinary tract symptoms, these findings may have a substantial impact on public health based on the evidence that diet seems to be a modifiable risk factor for urinary incontinence.

Palliative Care and End-of-Life Outcomes Following High-risk Surgery.

Importance: Palliative care has the potential to improve care for patients and families undergoing high-risk surgery. Objective: To characterize the use of perioperative palliative care and its association with family-reported end-of-life experiences of patients who died within 90 days of a high-risk surgical operation. Design, Setting, and Participants: This secondary analysis of administrative data from a retrospective cross-sectional patient cohort was conducted in the Department of Veterans Affairs (VA) Healthcare System. Patients who underwent any of 227 high-risk operations between January 1, 2012, and December 31, 2015, were included. Exposures: Palliative-care consultation within 30 days before or 90 days after surgery. Main Outcomes and Measures: The outcomes were family-reported ratings of overall care, communication, and support in the patient's last month of life. The VA surveyed all families of inpatient decedents using the Bereaved Family Survey, a valid and reliable tool that measures patient and family-centered end-of-life outcomes. Results: A total of 95 204 patients underwent high-risk operations in 129 inpatient VA Medical Centers. Most patients were 65 years or older (69 278 [72.8%]), and the most common procedures were cardiothoracic (31 157 [32.7%]) or vascular (23 517 [24.7%]). The 90-day mortality rate was 6.0% (5740 patients) and varied by surgical subspecialty (ranging from 278 of 7226 [3.8%] in urologic surgery to 875 of 6223 patients [14.1%] in neurosurgery). A multivariate mixed model revealed that families of decedents who received palliative care were 47% more likely to rate overall care in the last month of life as excellent than those who did not (odds ratio [OR], 1.47 [95% CI, 1.14-1.88]; P = .007), after adjusting for patient's characteristics, surgical subspecialty of the high-risk operation, and survey nonresponse. Similarly, families of decedents who received palliative care were more likely to rate end-of-life communication (OR, 1.43 [95% CI, 1.09-1.87]; P = .004) and support (OR, 1.31 [95% CI, 1.01-1.71]; P = .05) components of medical care as excellent. Of the entire cohort, 3374 patients (3.75%) had a palliative care consultation, and 770 patients (0.8%) received it before surgery. Of all decedents, 1632 (29.9%) had a palliative care consultation, with 319 (5.6%) receiving it before surgery. Conclusions and Relevance: Receipt of a palliative consultation was associated with better ratings of overall end-of-life care, communication, and support, as reported by families of patients who died within 90 days of high-risk surgery. Yet only one-third of decedents was exposed to palliative care. Expanding integration of perioperative palliative care may benefit patients undergoing high-risk operations and their families.

Validation of a novel automated signal analysis tool for ablation of Wolff-Parkinson-White Syndrome.

BACKGROUND: In previous pilot work we demonstrated that a novel automated signal analysis tool could accurately identify successful ablation sites during Wolff-Parkinson-White (WPW) ablation at a single center. OBJECTIVE: We sought to validate and refine this signal analysis tool in a larger multi-center cohort of children with WPW. METHODS: A retrospective review was performed of signal data from children with WPW who underwent ablation at two pediatric arrhythmia centers from 2008-2015. All patients with WPW ≤ 21 years who underwent invasive electrophysiology study and ablation with ablation signals available for review were included. Signals were excluded if temperature or power delivery was inadequate or lesion time was < 5 seconds. Ablation lesions were reviewed for each patient. Signals were classified as successful if there was loss of antegrade and retrograde accessory pathway (AP) conduction or unsuccessful if ablation did not eliminate AP conduction. Custom signal analysis software analyzed intracardiac electrograms for amplitudes, high and low frequency components, integrated area, and signal timing components to create a signal score. We validated the previously published signal score threshold 3.1 in this larger, more diverse cohort and explored additional scoring options. Logistic regression with lasso regularization using Youden's index criterion and a cost-benefit criterion to identify thresholds was considered as a refinement to this score. RESULTS: 347 signals (141 successful, 206 unsuccessful) in 144 pts were analyzed [mean age 13.2 ± 3.9 years, 96 (67%) male, 66 (45%) left sided APs]. The software correctly identified the signals as successful or unsuccessful in 276/347 (80%) at a threshold of 3.1. The performance of other thresholds did not significantly improve the predictive ability. A signal score threshold of 3.1 provided the following diagnostic accuracy for distinguishing a successful from unsuccessful signal: sensitivity 83%, specificity 77%, PPV 71%, NPV 87%. CONCLUSIONS: An automated signal analysis software tool reliably distinguished successful versus unsuccessful ablation electrograms in children with WPW when validated in a large, diverse cohort. Refining the tools using an alternative threshold and statistical method did not improve the original signal score at a threshold of 3.1. This software was effective across two centers and multiple operators and may be an effective tool for ablation of WPW.

Outpatient vs Inpatient Anterior Cervical Discectomy and Fusion: A Population-Level Analysis of Outcomes and Cost.

BACKGROUND: Outpatient anterior cervical discectomy and fusion (ACDF) is a promising candidate for US healthcare cost reduction as several studies have demonstrated that overall complications are relatively low and early discharge can preserve high patient satisfaction, low morbidity, and minimal readmission. OBJECTIVE: To compare clinical outcomes and associated costs between inpatient and ambulatory setting ACDF. METHODS: Demographics, comorbidities, emergency department (ED) visits, readmissions, reoperation rates, and 90-d charges were retrospectively analyzed for patients undergoing elective ACDF in California, Florida, and New York from 2009 to 2011 in State Inpatient and Ambulatory Databases. RESULTS: A total of 3135 ambulatory and 46 996 inpatient ACDFs were performed. Mean Charlson comorbidity index, length of stay, and mortality were 0.2, 0.4 d, and 0% in the ambulatory cohort and 0.4, 1.8 d, and 0.04% for inpatients (P < .0001). Ambulatory patients were younger (48.0 vs 53.1) and more likely to be Caucasian. One hundred sixty-eight ambulatory patients (5.4%) presented to the ED within 30 d (mean 11.3 d), 51 (1.6%) were readmitted, and 5 (0.2%) underwent reoperation. Among inpatient surgeries, 2607 patients (5.5%) presented to the ED within 30 d (mean 9.7 d), 1778 (3.8%) were readmitted (mean 6.3 d), and 200 (0.4%) underwent reoperation. Higher Charlson comorbidity index increased rate of ED visits (ambulatory operating room [OR] 1.285, P < .05; inpatient OR 1.289, P < .0001) and readmission (ambulatory OR 1.746, P < .0001; inpatient OR 1.685, P < .0001). Overall charges were significantly lower for ambulatory ACDFs ($33 362.51 vs $74 667.04; P < .0001). CONCLUSION: ACDF can be performed in an ambulatory setting with comparable morbidity and readmission rates, and lower costs, to those performed in an inpatient setting.

Development and validation of a major adverse transplant event (MATE) score to predict late graft loss in pediatric heart transplantation.

BACKGROUND: There is inadequate power to perform a valid clinical trial in pediatric heart transplantation (HT) using a conventional end-point, because the disease is rare and hard end-points, such as death or graft loss, are infrequent. We sought to develop and validate a surrogate end-point involving the cumulative burden of post-transplant complications to predict death/graft loss to power a randomized clinical trial of maintenance immunosuppression in pediatric HT. METHODS: Pediatric Heart Transplant Study (PHTS) data were used to identify all children who underwent an isolated orthotopic HT between 2005 and 2014 who survived to 6 months post-HT. A time-varying Cox model was used to develop and evaluate a surrogate end-point comprised of 6 major adverse transplant events (MATEs) (acute cellular rejection [ACR], antibody-mediated rejection [AMR], infection, cardiac allograft vasculopathy [CAV], post-transplant lymphoproliferative disease [PTLD] and chronic kidney disease [CKD]) occurring between 6 and 36 months, where individual events were defined according to international guidelines. Two thirds of the study cohort was used for score development, and one third of the cohort was used to test the score. RESULTS: Among 2,118 children, 6.4% underwent graft loss between 6 and 36 months post-HT, whereas 39% developed CKD, 34% ACR, 34% infection, 9% AMR, 4% CAV and 2% PTLD. The best predictive score involved a simple MATE score sum, yielding a concordance probability estimate (CPE) statistic of 0.74. Whereas the power to detect non-inferiority (NI), assuming the NI hazard ratio of 1.45 in graft survival was 10% (assuming 200 subjects and 6% graft loss rate), the power to detect NI assuming a 2-point non-inferiority margin was >85% using the MATE score. CONCLUSION: The MATE score reflects the cumulative burden of MATEs and has acceptable prediction characteristics for death/graft loss post-HT. The MATE score may be useful as a surrogate end-point to power a clinical trial in pediatric HT.

Definitions of peri-procedural myocardial infarction and the association with one-year mortality: Insights from CHAMPION trials.

BACKGROUND: Controversies exist over the appropriate definition for peri-procedural myocardial infarction (PPMI) and its association with mortality. This study aims to evaluate one-year survival following percutaneous coronary intervention (PCI) and the association of different definitions of PPMI with survival among patients with stable angina (SA) or acute coronary syndrome (ACS) in the contemporary era. METHODS: We used data from the CHAMPION PLATFORM and CHAMPION PCI trials of patients undergoing PCI and conducted univariable and multivariable Cox proportional hazard regression models to evaluate mortality risk during the first year after PCI. A blinded events committee adjudicated suspected PPMI defined by biomarker elevations ≥3× the upper limit of normal (ULN) or new Q-waves. We further analyzed PPMI by the magnitude of CK-MB elevation ([a] 3 to <5× ULN, [b] 5 to <10× ULN, [c] ≥10× ULN) or by the 2nd universal definition of myocardial infarction (UDMICK-MB) excluding patients with evidence of myocardial infarction (MI) prior to PCI. RESULTS: Of 13,968 patients, 11% initially presented with SA, and 89% with ACS. One-year mortality was 3.4% (SA: 1.5%; ACS: 3.6%). PPMI occurred in 6.3% of the patients (3 to <5× ULN: 2.5%; 5 to <10× ULN: 2.1%; ≥10× ULN: 1.6%; UDMICK-MB: 2.7%). After multivariable adjustment, a significantly higher risk of one-year mortality was observed for patients with PPMI compared with patients without PPMI (HR 2.35 [1.74-3.18], p < 0.001; 3 to <5× ULN: 1.55 [0.92-2.62], p = 0.10; 5 to <10× ULN: 1.22 [0.67-2.20], p = 0.52; ≥10× ULN: 4.78 [3.06-7.47], p < 0.001; UDMICK-MB: 2.19 [1.29-3.73], p = 0.004). CONCLUSION: PPMI occurred in 6.3% of the patients and was associated with increased risk of death within one year. Survival was not significantly impacted by PPMI if defined by periprocedural CK-MB elevations <10× ULN alone and without additional evaluation of symptoms or evidence of ischemia. These findings highlight the importance of PPMI for long-term outcome in the contemporary era and of its definition in the planning and interpretation of clinical trials.

ACIST-FFR Study (Assessment of Catheter-Based Interrogation and Standard Techniques for Fractional Flow Reserve Measurement).

BACKGROUND: Measurement of fractional flow reserve (FFR) to guide coronary revascularization lags despite robust supportive data, partly because of the handling characteristics of traditional coronary pressure wires. An optical pressure-monitoring microcatheter, which can be advanced over a traditional coronary guidewire, facilitates FFR assessment but may underestimate pressure wire-derived FFR. METHODS AND RESULTS: In this prospective, multicenter trial, 169 patients underwent FFR assessment with a pressure wire alone and with a pressure microcatheter over the pressure wire. An independent core laboratory performed quantitative coronary angiography and evaluated all pressure tracings. The primary end point was the bias or difference between the microcatheter FFR and the pressure wire FFR, as assessed by Bland-Altman analysis. The mean difference between the microcatheter and the pressure wire-derived FFR values was -0.022 (95% confidence interval, -0.029 to -0.015). On multivariable analysis, reference vessel diameter (P=0.027) and lesion length (P=0.044) were independent predictors of bias between the 2 FFR measurements. When the microcatheter FFR was added to this model, it was the only independent predictor of bias (P<0.001). The mean FFR value from the microcatheter was significantly lower than from the pressure wire (0.81 versus 0.83; P<0.001). In 3% of cases (95% confidence interval, 1.3%-6.7%), there was clinically meaningful diagnostic discordance, with the FFR from the pressure wire >0.80 and that from the microcatheter <0.75. These findings were similar when including all 210 patients with site-reported paired FFR data. CONCLUSIONS: An optical, pressure-monitoring microcatheter measures lower FFR compared with a pressure wire, but the diagnostic impact appears to be minimal in most cases. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02577484.

Genome-wide association study identifies 14 novel risk alleles associated with basal cell carcinoma.

Basal cell carcinoma (BCC) is the most common cancer worldwide with an annual incidence of 2.8 million cases in the United States alone. Previous studies have demonstrated an association between 21 distinct genetic loci and BCC risk. Here, we report the results of a two-stage genome-wide association study of BCC, totalling 17,187 cases and 287,054 controls. We confirm 17 previously reported loci and identify 14 new susceptibility loci reaching genome-wide significance (P<5 × 10(-8), logistic regression). These newly associated SNPs lie within predicted keratinocyte regulatory elements and in expression quantitative trait loci; furthermore, we identify candidate genes and non-coding RNAs involved in telomere maintenance, immune regulation and tumour progression, providing deeper insight into the pathogenesis of BCC.

Gene by Environment Investigation of Incident Lung Cancer Risk in African-Americans.

BACKGROUND: Genome-wide association studies have identified polymorphisms linked to both smoking exposure and risk of lung cancer. The degree to which lung cancer risk is driven by increased smoking, genetics, or gene-environment interactions is not well understood. METHODS: We analyzed associations between 28 single nucleotide polymorphisms (SNPs) previously associated with smoking quantity and lung cancer in 7156 African-American females in the Women's Health Initiative (WHI), then analyzed main effects of top nominally significant SNPs and interactions between SNPs, cigarettes per day (CPD) and pack-years for lung cancer in an independent, multi-center case-control study of African-American females and males (1078 lung cancer cases and 822 controls). FINDINGS: Nine nominally significant SNPs for CPD in WHI were associated with incident lung cancer (corrected p-values from 0.027 to 6.09 × 10(-5)). CPD was found to be a nominally significant effect modifier between SNP and lung cancer for six SNPs, including CHRNA5 rs2036527[A](betaSNP*CPD = - 0.017, p = 0.0061, corrected p = 0.054), which was associated with CPD in a previous genome-wide meta-analysis of African-Americans. INTERPRETATION: These results suggest that chromosome 15q25.1 variants are robustly associated with CPD and lung cancer in African-Americans and that the allelic dose effect of these polymorphisms on lung cancer risk is most pronounced in lighter smokers.

Exome array analysis identifies new loci and low-frequency variants influencing insulin processing and secretion.

Insulin secretion has a crucial role in glucose homeostasis, and failure to secrete sufficient insulin is a hallmark of type 2 diabetes. Genome-wide association studies (GWAS) have identified loci contributing to insulin processing and secretion; however, a substantial fraction of the genetic contribution remains undefined. To examine low-frequency (minor allele frequency (MAF) 0.5-5%) and rare (MAF < 0.5%) nonsynonymous variants, we analyzed exome array data in 8,229 nondiabetic Finnish males using the Illumina HumanExome Beadchip. We identified low-frequency coding variants associated with fasting proinsulin concentrations at the SGSM2 and MADD GWAS loci and three new genes with low-frequency variants associated with fasting proinsulin or insulinogenic index: TBC1D30, KANK1 and PAM. We also show that the interpretation of single-variant and gene-based tests needs to consider the effects of noncoding SNPs both nearby and megabases away. This study demonstrates that exome array genotyping is a valuable approach to identify low-frequency variants that contribute to complex traits.