Deletions at 16p13.11 are associated with schizophrenia, mental retardation, and most recently idiopathic generalized epilepsy. To evaluate the role of 16p13.11 deletions, as well as other structural variation, in epilepsy disorders, we used genome-wide screens to identify copy number variation in 3812 patients with a diverse spectrum of epilepsy syndromes and in 1299 neurologically-normal controls. Large deletions (> 100 kb) at 16p13.11 were observed in 23 patients, whereas no control had a deletion greater than 16 kb. Patients, even those with identically sized 16p13.11 deletions, presented with highly variable epilepsy phenotypes. For a subset of patients with a 16p13.11 deletion, we show a consistent reduction of expression for included genes, suggesting that haploinsufficiency might contribute to pathogenicity. We also investigated another possible mechanism of pathogenicity by using hybridization-based capture and next-generation sequencing of the homologous chromosome for ten 16p13.11-deletion patients to look for unmasked recessive mutations. Follow-up genotyping of suggestive polymorphisms failed to identify any convincing recessive-acting mutations in the homologous interval corresponding to the deletion. The observation that two of the 16p13.11 deletions were larger than 2 Mb in size led us to screen for other large deletions. We found 12 additional genomic regions harboring deletions > 2 Mb in epilepsy patients, and none in controls. Additional evaluation is needed to characterize the role of these exceedingly large, non-locus-specific deletions in epilepsy. Collectively, these data implicate 16p13.11 and possibly other large deletions as risk factors for a wide range of epilepsy disorders, and they appear to point toward haploinsufficiency as a contributor to the pathogenicity of deletions.

Background Postoperative cognitive dysfunction (POCD) is a significant cause of morbidity after noncardiac surgery. Identified risk factors are largely limited to demographic characteristics. We hypothesized that POCD was associated with Apolipoprotein E4 (APOE4) genotype and plasma biomarkers of brain injury and inflammation. Methods 394 patients over age 55 undergoing major elective noncardiac surgery were enrolled in this prospective observational study. Apolipoprotein E genotyping was performed at baseline. Plasma was collected at baseline, end of surgery, 4.5, 24, and 48-h postoperatively. Six protein biomarkers were assayed (B-type natriuretic peptide, C-reactive protein, D-dimer, matrix metalloproteinase-9, neuron specific enolase, S-100B). Neurocognitive testing was conducted at baseline, 6 weeks, and 1 yr after surgery; scores were subjected to factor analysis. The association of APOE4 and biomarkers with POCD was tested using multivariable regression modeling. Results 350 patients (89%) completed 6-week neurocognitive testing. POCD occurred in 54.3% of participants at 6 weeks and 46.1% at 1 yr. There was no difference in POCD between patients with or without the APOE4 allele (56.6 vs. 52.6%; p = 0.58). The continuous cognitive change score (mean ± SD) was similar between groups (APOE4: 0.05 ± 0.27 vs. non-APOE4: 0.07 ± 0.28; p = 0.53). 291 subjects (74%) completed testing at 1 yr. POCD occurred in 45.9% of APOE4 subjects versus 46.3% of non-APOE4 subjects (p = 0.95). The cognitive score was again similar (APOE4: 0.08 ± 0.27 vs. non-APOE4: 0.05 ± 0.25; p = 0.39). Biomarker levels were not associated with APOE4 genotype or cognition at 6 weeks or 1 yr. Conclusion Cognitive decline after major noncardiac surgery is not associated with APOE4 genotype or plasma biomarker levels.

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Background-The inflammatory response triggered by cardiac surgery with cardiopulmonary bypass (CPB) is a primary mechanism in the pathogenesis of postoperative myocardial infarction (PMI), a multifactorial disorder with significant inter-patient variability poorly predicted by clinical and procedural factors. We tested the hypothesis that candidate gene polymorphisms in inflammatory pathways contribute to risk of PMI after cardiac surgery. Methods and Results-We genotyped 48 polymorphisms from 23 candidate genes in a prospective cohort of 434 patients undergoing elective cardiac surgery with CPB. PMI was defined as creatine kinase-MB isoenzyme level Ն10ϫ upper limit of normal at 24 hours postoperatively. A 2-step analysis strategy was used: marker selection, followed by model building. To minimize false-positive associations, we adjusted for multiple testing by permutation analysis, Bonferroni correction, and controlling the false discovery rate; 52 patients (12%) experienced PMI. After adjusting for multiple comparisons and clinical risk factors, 3 polymorphisms were found to be independent predictors of PMI (adjusted PϽ0.05; false discovery rate Ͻ10%). These gene variants encode the proinflammatory cytokine interleukin 6 (IL6 Ϫ572GϾC; odds ratio [OR], 2.47), and 2 adhesion molecules: intercellular adhesion molecule-1 (ICAM1 Lys469Glu; OR, 1.88), and E-selectin (SELE 98GϾT; OR, 0.16). The inclusion of genotypic information from these polymorphisms improved prediction models for PMI based on traditional risk factors alone (C-statistic 0.764 versus 0.703). Conclusions-Functional

Changes in heart transplantation (HT) donor and recipient demographics may influence the incidence of primary graft dysfunction (PGD). We conducted a retrospective study to evaluate PGD incidence, trends, and associated risk factors by analyzing consecutive adult patients who underwent HT between January 2009 and December 2014 at our institution. Patients were categorized as having PGD using the International Society for Heart & Lung Transplantation (ISHLT)-defined criteria. Variables, including clinical and demographic characteristics of donors and recipients, were selected to assess their independent association with PGD. A time-trend analysis was performed over the study period. Three-hundred seventeen patients met inclusion criteria. Left ventricular PGD, right ventricular PGD, or both, were observed in 99 patients (31%). Risk factors independently associated with PGD included ischemic time, recipient African American race, and recipient amiodarone treatment. Over the study period, there was no change in the PGD incidence; however, there was an increase in the recipient pretransplantation use of amiodarone. The rate of 30-day mortality was significantly elevated in those with PGD versus those without PGD (6.06% vs 0.92%, P = .01). Despite recent advancements, incidence of PGD remains high. Understanding associated risk factors may allow for implementation of targeted therapeutic interventions.

Background-Human myocardial metabolism has been incompletely characterized in the setting of surgical cardioplegic arrest and ischemia/reperfusion. Furthermore, the effect of preexisting ventricular state on ischemia-induced metabolic derangements has not been established. Methods and Results-We applied a mass spectrometry-based platform to profile 63 intermediary metabolites in serial paired peripheral arterial and coronary sinus blood effluents obtained from 37 patients undergoing cardiac surgery, stratified by presence of coronary artery disease and left ventricular dysfunction. The myocardium was a net user of a number of fuel substrates before ischemia, with significant differences between patients with and without coronary artery disease. After reperfusion, significantly lower extraction ratios of most substrates were found, as well as significant release of 2 specific acylcarnitine species, acetylcarnitine and 3-hydroxybutyryl-carnitine. These changes were especially evident in patients with impaired ventricular function, who exhibited profound limitations in extraction of all forms of metabolic fuels. Principal component analysis highlighted several metabolic groupings as potentially important in the postoperative clinical course. Conclusions-The preexisting ventricular state is associated with significant differences in myocardial fuel uptake at baseline and after ischemia/reperfusion. The dysfunctional ventricle is characterized by global suppression of metabolic fuel uptake and limited myocardial metabolic reserve and flexibility after global ischemia/reperfusion stress in the setting of cardiac surgery. Altered metabolic profiles after ischemia/reperfusion are associated with postoperative hemodynamic course and suggest a role for perioperative metabolic monitoring and targeted optimization in cardiac surgical patients.

Background Cardiac surgery requiring cardiopulmonary bypass is associated with platelet activation. Because platelets are increasingly recognized as important effectors of ischemia and end-organ inflammatory injury, the authors explored whether postoperative nadir platelet counts are associated with acute kidney injury (AKI) and mortality after coronary artery bypass grafting (CABG) surgery. Methods The authors evaluated 4,217 adult patients who underwent CABG surgery. Postoperative nadir platelet counts were defined as the lowest in-hospital values and were used as a continuous predictor of postoperative AKI and mortality. Nadir values in the lowest 10th percentile were also used as a categorical predictor. Multivariable logistic regression and Cox proportional hazard models examined the association between postoperative platelet counts, postoperative AKI, and mortality. Results The median postoperative nadir platelet count was 121 × 109/l. The incidence of postoperative AKI was 54%, including 9.5% (215 patients) and 3.4% (76 patients) who experienced stages II and III AKI, respectively. For every 30 × 109/l decrease in platelet counts, the risk for postoperative AKI increased by 14% (adjusted odds ratio, 1.14; 95% CI, 1.09 to 1.20; P < 0.0001). Patients with platelet counts in the lowest 10th percentile were three times more likely to progress to a higher severity of postoperative AKI (adjusted proportional odds ratio, 3.04; 95% CI, 2.26 to 4.07; P < 0.0001) and had associated increased risk for mortality immediately after surgery (adjusted hazard ratio, 5.46; 95% CI, 3.79 to 7.89; P < 0.0001). Conclusion The authors found a significant association between postoperative nadir platelet counts and AKI and short-term mortality after CABG surgery.

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