Benchmarking a Molecular Flake Model on the Road to Programmable Graphene-Based Single-Atom Catalysts.

Single-atom catalysts (SACs) of embedding an active metal in nitrogen-doped graphene are emergent catalytic materials in various applications. The rational design of efficient SACs necessitates an electronic and mechanistic understanding of those materials with reliable quantum mechanical simulations. Conventional computational methods of modeling SACs involve using an infinite slab model with periodic boundary condition, limiting to the selection of generalized gradient approximations as the exchange correlation (XC) functional within density functional theory (DFT). However, these DFT approximations suffer from electron self-interaction error and delocalization error, leading to errors in predicted charge-transfer energetics. An alternative strategy is using a molecular flake model, which carved out the important catalytic center by cleaving C-C bonds and employing a hydrogen capping scheme to saturate the innocent dangling bonds at the molecular boundary. By doing so, we can afford more accurate hybrid XC functionals, or even high-level correlated wavefunction theory, to study those materials. In this work, we compared the structural, electronic, and catalytic properties of SACs simulated using molecular flake models and periodic slab models with first-row transition metals as the active sites. Molecular flake models successfully reproduced structural properties, including both global distortion and local metal-coordination environment, as well as electronic properties, including spin magnetic moments and metal partial charges, for all transition metals studied. In addition, we calculated CO binding strength as a descriptor for electrochemical CO2 reduction reactivity and noted qualitatively similar trends between two models. Using the computationally efficient molecular flake models, we investigated the effect of tuning Hartree-Fock exchange in a global hybrid functional on the CO binding strength and observed system-dependent sensitivities. Overall, our calculations provide valuable insights into the development of accurate and efficient computational tools to simulate SACs.

A Quality Improvement Initiative to Decrease Time to Analgesia in Patients With Sickle Cell and Vaso-Occlusive Crisis: A Population With Disparities in Treatment.

INTRODUCTION: Vaso-occlusive crises (VOCs) are the leading cause of emergency department (ED) visits and hospitalizations in patients with sickle cell disease (SCD). Timely administration of analgesia, within 60 minutes of patient registration, is the standard of care for SCD patients with VOCs. Patients with VOCs have longer times to initial analgesia compared to similar painful conditions. The primary aim of the project is to have 75% of patients with VOCs receive initial analgesia within 60 minutes of being registered, the current recommended time frame from the National Heart, Lung, and Blood Institute (NHLBI). METHODS: A multi-disciplinary team used quality improvement (QI) methodology to develop a plan involving multiple Plan-Do-Study-Act (PDSA) cycles. A rapid evaluation process was employed which included notification of a patient with a VOC being placed in a room, rapid evaluation by all team members and use of an electronic order set. RESULTS: The aim was met 72% of the time during our intervention period, compared to 17% pre-intervention. Average time to initial analgesia was decreased from 61 minutes to 42 minutes (p-value < 0.001), while time to disposition was also decreased when time goals were achieved. CONCLUSION: Using a rapid evaluation process we were able to decrease time to initial analgesia in a patient population that has previously experienced delays in care and decrease overall time to disposition.

Discrepancies in Physician and Coroner Findings in Cases of Fatal Suspected Physical Child Abuse.

OBJECTIVES: As mandated reporters of suspected abuse, physicians must consider abuse when a child dies unexpectedly. Subsequently, a coroner or medical examiner determines the manner of death (MOD) and cause of death (COD). Accurate diagnoses and determinations are important for social safety and justice. This study described discrepancies between physicians' and coroners' findings in cases of fatal suspected physical child abuse. METHODS: This study was a single-institution, retrospective review. All children 6 years or younger who died in a pediatric emergency department from October 2006 to January 2013 with a coroner report were included in this study. Coroner reports, MODs, and CODs were reviewed. Skeletal survey results were compared with coroners' findings. RESULTS: One hundred twenty-nine children were included. The MODs included the following: undetermined, 63 (49%); accident, 32 (25%); natural, 31 (24%); and homicide, 3 (2%). Thirty-three (26%) of the 129 patients had abuse suspected at the time of death in the emergency department; in this subset, MODs were as follows: undetermined, 16 (48%); accident, 8 (24%); natural, 6 (18%); and homicide, 3 (9%). Sudden infant death syndrome or sudden unexpected death was the most common COD in all children (68, 55%). Skeletal surveys were positive in 12 children with 29 fractures identified; 8 (28%) of the 29 fractures were corroborated on autopsy findings. Of the 12 children with positive skeletal survey findings, only 1 was ruled a homicide. CONCLUSIONS: We found discrepancies between coroner determination of homicide and abuse suspected by physicians, especially among children with fractures. Improved communication between agencies in cases of fatal child abuse is needed.

Crowding is the strongest predictor of left without being seen risk in a pediatric emergency department.

BACKGROUND: Emergency Department (ED) patients who leave without being seen (LWBS) are associated with adverse safety and medico-legal consequences. While LWBS risk has been previously tied to demographic and acuity related factors, there is limited research examining crowding-related risk in the pediatric setting. The primary objective of this study was to determine the association between LWBS risk and crowding, using the National Emergency Department Overcrowding Score (NEDOCS) and occupancy rate as crowding metrics. METHODS: We performed a retrospective observational study on electronic health record (EHR) data from the ED of a quaternary care children's hospital and trauma center during the 14-month study period. NEDOCS and occupancy rate were calculated for 15-min windows and matched to patient arrival time. We leveraged multiple logistic regression analyses to demonstrate the relationship between patientlevel LWBS risk and each crowding metric, controlling for characteristics drawn from the pre-arrival state. We performed a chi-squared test to determine whether a difference existed between the receiver operating characteristic (ROC) curves in the two models. Finally, we executed a dominance analysis using McFadden's pseudo-R 2 to determine the relative importance of each crowding metric in the models. RESULTS: A total of 54,890 patient encounters were studied, 1.22% of whom LWBS. The odds ratio for LWBS risk was 1.30 (95% CI 1.27-1.33) per 10-point increase in NEDOCS and 1.23 (95% CI 1.21-1.25). per 10% increase in occupancy rate. Area under the curve (AUC) was 86.9% for the NEDOCS model and 86.7% for the occupancy rate model. There was no statistically significant difference between the AUCs of the two models (p-value 0.27). Dominance analysis revealed that in each model, the most important variable studied was its respective crowding metric; NEDOCS accounted for 55.6% and occupancy rate accounted for 53.9% of predicted variance in LWBS. CONCLUSION: Not only was ED overcrowding positively and significantly associated with individual LWBS risk, but it was the single most important factor that determined a patient's likelihood of LWBS in the pediatric ED. Because occupancy rate and NEDOCS are available in real time, each could serve as a monitor for individual LWBS risk in the pediatric ED.

High ACAT1 expression in estrogen receptor negative basal-like breast cancer cells is associated with LDL-induced proliferation.

The specific role of dietary fat in breast cancer progression is unclear, although a low-fat diet was associated with decreased recurrence of estrogen receptor alpha negative (ER(-)) breast cancer. ER(-) basal-like MDA-MB-231 and MDA-MB-436 breast cancer cell lines contained a greater number of cytoplasmic lipid droplets compared to luminal ER(+) MCF-7 cells. Therefore, we studied lipid storage functions in these cells. Both triacylglycerol and cholesteryl ester (CE) concentrations were higher in the ER(-) cells, but the ability to synthesize CE distinguished the two types of breast cancer cells. Higher baseline, oleic acid- and LDL-stimulated CE concentrations were found in ER(-) compared to ER(+) cells. The differences corresponded to greater mRNA and protein levels of acyl-CoA:cholesterol acyltransferase 1 (ACAT1), higher ACAT activity, higher caveolin-1 protein levels, greater LDL uptake, and lower de novo cholesterol synthesis in ER(-) cells. Human LDL stimulated proliferation of ER(-) MDA-MB-231 cells, but had little effect on proliferation of ER(+) MCF-7 cells. The functional significance of these findings was demonstrated by the observation that the ACAT inhibitor CP-113,818 reduced proliferation of breast cancer cells, and specifically reduced LDL-induced proliferation of ER(-) cells. Taken together, our studies show that a greater ability to take up, store and utilize exogenous cholesterol confers a proliferative advantage to basal-like ER(-) breast cancer cells. Differences in lipid uptake and storage capability may at least partially explain the differential effect of a low-fat diet on human breast cancer recurrence.

Docosahexaenoic acid is a substrate for ACAT1 and inhibits cholesteryl ester formation from oleic acid in MCF-10A cells.

MCF-10A breast epithelial cells treated with docosahexaenoic acid (DHA) or oleic acid (OA) accumulated cytoplasmic lipid droplets containing both triacylglycerol and cholesteryl esters (CE). Interestingly, total CE mass was reduced in cells treated with DHA compared to cells treated with OA, and the CEs were rich in n-3 fatty acids. Thus, we hypothesized that DHA may be, in addition to a substrate, an inhibitor of cholesterol esterification in MCF-10A cells. We determined that the primary isoform of acyl-CoA: cholesterol acyltransferase expressed in MCF-10A cells is ACAT1. We investigated CE formation with DHA, OA, and the combination in intact cells and isolated microsomes. In both cells and microsomes, the rate of CE formation was faster and more CE was formed with OA compared to DHA. DHA substantially reduced CE formation when given in combination with OA. These data suggest for the first time that DHA can act as a substrate for ACAT1. In the manner of a poor substrate, DHA also inhibited the activity of ACAT1, a universally expressed enzyme involved in intracellular cholesterol homeostasis, in a cell type that does not secrete lipids or express ACAT2.

Trans-fatty acids induce pro-inflammatory responses and endothelial cell dysfunction.

Epidemiological data indicate that there is a strong association between intake of trans-18 : 2 fatty acids (TFA) and sudden cardiac death. There is little known about the mechanisms by which TFA exert harmful effects on the cardiovascular system. The present in vitro study is the first to demonstrate the effects of membrane-incorporated C18 : 2 TFA on human aortic endothelial cell (HAEC) function. Trans-18 : 2 fatty acids were incorporated to a greater extent (2-fold) in the phospholipid fraction of endothelial cells than that of cis-18 : 2; furthermore, these fatty acids were enriched to a similar extent in the TAG fraction. Flow cytometric analysis indicated that TFA treatment of HAEC significantly increased the expression of endothelial adhesion molecules, including intercellular adhesion molecule-1 (CD54) and vitronectin receptor (CD51/CD61). Incorporation of TFA into membranes increased HAEC adhesion to fibronectin- or vitronectin-coated plates by 1.5- to 2-fold, respectively. Neutrophil and monocyte adhesion to HAEC monolayers was nearly proportional to adhesion molecule expression. TFA treatment also induced the release of monocyte chemoattractant protein-1 by nearly 3-fold in non-stimulated HAEC. Furthermore, we examined the role of TFA on in vitro angiogenic assays. Chemotactic migration of TFA-treated HAEC toward sphingosine-1-phosphate (SPP) was significantly increased compared with controls. Conversely, capillary morphogenesis of TFA-treated HAEC was significantly inhibited in response to SPP, suggesting that TFA incorporation suppresses endothelial cell differentiation. In conclusion, these in vitro studies demonstrated that TFA play a role in the induction of pro-inflammatory responses and endothelial cell dysfunction.