Citations

Objective To compare measured and predicted oxygen consumption (V˙o2) in children with congenital heart disease. Design Retrospective study. Setting The cardiac catheterisation laboratory in a university hospital. Patients 125 children undergoing preoperative cardiac catheterisation. Interventions V˙o2 was measured using indirect calorimetry; the predicted values were calculated from regression equations published by Lindahl, Wesselet al, and Lundell et al. Stepwise linear regression and analysis of variance were used to evaluate the influence of age, sex, weight, height, cardiac malformation, and heart failure on the bias and precision of predicted V˙o2. An artificial neural network was trained and used to produce an estimate of V˙o2 employing the same variables. The various estimates for V˙o2 were evaluated by calculating their bias and precision values. Results Lindahl’s equation produced the highest precision (±42%) of the regression based estimates. The corresponding average bias of the predicted V˙o2 was 3% (range −66% to 43%). When V˙o2 was predicted according to regression equations by Wessel and Lundell, the bias and precision were 0% and ±44%, and −16% and ±51%, respectively. The neural network predicted V˙o2 from variables included in the regression equations with a bias of 6% and precision ±29%; addition of further variables failed to improve this estimate. Conclusions Both regression based and artificial intelligence based techniques were inaccurate for predicting preoperative V˙o2 in patients with congenital heart disease. Measurement of V˙o2 is necessary in the preoperative evaluation of these patients.

Recent advances in the targeted modification of complex eukaryotic genomes have unlocked a new era of genome engineering. From the pioneering work using zinc-finger nucleases (ZFNs), to the advent of the versatile and specific TALEN systems, and most recently the highly accessible CRISPR/Cas9 systems, we now possess an unprecedented ability to analyze developmental processes using sophisticated designer genetic tools. In this Review, we summarize the common approaches and applications of these still-evolving tools as they are being used in the most popular model developmental systems. Excitingly, these robust and simple genomic engineering tools also promise to revolutionize developmental studies using less well established experimental organisms.

Abstract BACKGROUND Aggressive LDL cholesterol (LDL-C)-lowering strategies are recommended for primary and secondary prevention of cardiovascular events. A newly derived equation for LDL-C estimation was recently published that addressed limitations in the commonly used Friedewald LDL-C calculation method. The novel method was reported to classify patients with superior concordance to measured LDL-C compared to the Friedewald method, particularly in patients with LDL-C <70 mg/dL. METHODS We evaluated the performance of the novel method within an independent cohort of 23 055 patients with LDL-C measured by the gold standard β-quantification reference method. RESULTS Overall Friedewald underestimated and the novel method overestimated measured LDL-C. Both estimations significantly deviated from the reference method when LDL-C was <70 mg/dL. Overall, the Friedewald and novel calculations correctly classified 77% and 78% of patients, respectively. The largest discrepancy in classification was observed in individuals with measured LDL-C <70 mg/dL. For this group the novel calculation would reclassify 8.7% of patients as >70 mg/dL compared to the Friedewald equation. CONCLUSIONS We compared both novel and Friedewald estimated LDL-C against the LDL-C reference method; in contrast, the prior study relied on validation of a subset of samples by β-quantification to allow the use of the vertical autoprofile method for LDL-C measurement. We conclude that the novel method has some benefits but it is unclear whether improvements over the Friedewald calculation are substantive enough to justify making the change in routine clinical practice and to improve patient outcomes.

Abstract Purpose: To evaluate the relevance between lumican expression patterns and the clinical course of patients with pancreatic ductal adenocarcinoma (PDAC), and to investigate the role of lumican in PDAC progression. Experimental Design: One hundred thirty-one patient tumors were chosen for tissue microarray staining, and Cox regression analysis was used to test the associations between lumican expression and clinical, pathologic, and oncologic outcomes in all patients. Primary PDAC cells and recombinant human lumican protein were used to establish a working model to mimic the in vivo interactions between stromal lumican and PDAC cells. Using this model, we tested the effects of lumican on EGFR signaling via Akt and hypoxia-inducible factor-1α (HIF1α) and its subsequent influence on glucose consumption, lactate production, intracellular ATP, and apoptotic cell death. Results: Lumican was present in the stroma surrounding PDAC cells in roughly one-half of primary tumors and the direct xenografts. Patients with stromal lumican were associated with a profound reduction in metastatic recurrence after surgery and 3-fold longer survival than patients without stromal lumican. In PDAC cells, extracellular lumican reduced EGFR expression and phosphorylation through enhanced dimerization and internalization of EGFR and the resultant inhibition of Akt kinase activity. Lumican also reduced HIF1α expression and activity via Akt. PDAC cells with enhanced HIF1α activity were resistant to lumican-induced inhibition of glucose consumption, lactate production, intracellular ATP, and apoptosis. Conclusions: There is a positive association between stromal lumican in primary PDAC tumors and prolonged survival after tumor resection. Lumican plays a restrictive role in EGFR-expressing pancreatic cancer progression. Clin Cancer Res; 20(24); 6529–40. ©2014 AACR.

Background— In patients with severe aortic stenosis, transcatheter aortic valve replacement (TAVR) improves survival when compared with nonsurgical therapy but with higher in-hospital and lifetime costs. Complications associated with TAVR may decrease with greater experience and improved devices, thereby reducing the overall cost of the procedure. Therefore, we sought to estimate the effect of periprocedural complications on in-hospital costs and length of stay of TAVR. Methods and Results— Using detailed cost data from 406 TAVR patients enrolled in the Placement of Aortic Transcatheter Valve (PARTNER) I trial, we developed multivariable models to estimate the incremental cost and length of stay associated with specific periprocedural complications. Attributable costs and length of stay for each complication were calculated by multiplying the independent cost of each event by its frequency in the treatment group. Mean cost for the initial hospitalization was $79 619±40 570 ($50 891 excluding the valve); 49% of patients had ≥1 complication. Seven complications were independently associated with increased hospital costs, with major bleeding, arrhythmia, and death accounting for the largest attributable cost per patient. Renal failure and the need for repeat TAVR, although less frequent, were also associated with substantial incremental and attributable costs. Overall, complications accounted for $12 475 per patient in initial hospital costs and 2.4 days of hospitalization. Conclusions— In the PARTNER trial, periprocedural complications were frequent, costly, and accounted for ≈25% of non-implant–related hospital costs. Avoidance of complications should improve the cost-effectiveness of TAVR for inoperable and high-risk patients, but reductions in the cost of uncomplicated TAVR will also be necessary for optimal efficiency. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00530894.

Significance The work reported in this paper describes a previously unknown signaling pathway in skeletal muscle acting through G protein-coupled receptor 56-Galpha12/13. This discovery elucidates a previously unknown mechanism of muscle anabolism and gives another target of investigation for therapies against the loss of muscle mass seen with aging and various wasting diseases.

Abstract Background:BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies. Cancer Epidemiol Biomarkers Prev; 24(1); 308–16. ©2014 AACR.

ABSTRACTBackgroundAcute coronary syndromes account for half of all deaths secondary to cardiovascular disease and represent a significant economic burden in the United States. Therefore, assessing hospitalization costs relative to Medicare reimbursement for these patients is important in understanding the impact of these patients on hospitals. We hypothesized that hospitalization costs for acute myocardial infarction patients treated with percutaneous coronary intervention (PCI) were higher than their associated Medicare payments.MethodsUsing the Nationwide Inpatient Sample, we evaluated hospitalization costs for patients treated with PCI from 2001 through 2009 by multiplying hospital charges by the group average cost‐to‐charge ratio for each patient's hospitalization. Primary end points examined were total hospital costs and trends over time, which were correlated with clinical outcomes and insurance payments. Costs were inflation adjusted with 2009 as the reference year.ResultsMedian hospitalization costs of PCI increased from $15 889 (interquartile range [IQR] = $12 057–$21 204) in 2001 to $19 349 (IQR = $14 660–$26 282) in 2009. From 2004 to 2009, inflation‐adjusted costs for PCI decreased at a rate of 0.3% per year. In 2009, a total of 265,531 patients received PCI for acute myocardial infarction. Of these, 143 654 were <65 years old, and 121 876 were ≥65 years old. Average 2009 Medicare payments ranged from $9303 to $17 500 depending on the Medicare Severity‐Diagnosis Related Groups (MS‐DRG) billed, leaving hospitals at a loss of anywhere from $4493 to $7940 per patient when comparing costs and reimbursements across all included MS‐DRG codes.ConclusionsHospitalization costs for patients treated with PCI have been stabilizing over the last few years; however, there still remains a significant disparity between Medicare reimbursements and hospitalization costs, which has potential implications on patient outcomes, quality of care, and hospital sustainability.