Modeling the evolution of regulatory elements by simultaneous detection and alignment with phylogenetic pair HMMs.

The computational detection of regulatory elements in DNA is a difficult but important problem impacting our progress in understanding the complex nature of eukaryotic gene regulation. Attempts to utilize cross-species conservation for this task have been hampered both by evolutionary changes of functional sites and poor performance of general-purpose alignment programs when applied to non-coding sequence. We describe a new and flexible framework for modeling binding site evolution in multiple related genomes, based on phylogenetic pair hidden Markov models which explicitly model the gain and loss of binding sites along a phylogeny. We demonstrate the value of this framework for both the alignment of regulatory regions and the inference of precise binding-site locations within those regions. As the underlying formalism is a stochastic, generative model, it can also be used to simulate the evolution of regulatory elements. Our implementation is scalable in terms of numbers of species and sequence lengths and can produce alignments and binding-site predictions with accuracy rivaling or exceeding current systems that specialize in only alignment or only binding-site prediction. We demonstrate the validity and power of various model components on extensive simulations of realistic sequence data and apply a specific model to study Drosophila enhancers in as many as ten related genomes and in the presence of gain and loss of binding sites. Different models and modeling assumptions can be easily specified, thus providing an invaluable tool for the exploration of biological hypotheses that can drive improvements in our understanding of the mechanisms and evolution of gene regulation.

Comparison of extramedullary versus intramedullary referencing for tibial component alignment in total ankle arthroplasty.

BACKGROUND: The majority of total ankle arthroplasty (TAA) systems use extramedullary alignment guides for tibial component placement. However, at least 1 system offers intramedullary referencing. In total knee arthroplasty, studies suggest that tibial component placement is more accurate with intramedullary referencing. The purpose of this study was to compare the accuracy of extramedullary referencing with intramedullary referencing for tibial component placement in total ankle arthroplasty. METHODS: The coronal and sagittal tibial component alignment was evaluated on the postoperative weight-bearing anteroposterior (AP) and lateral radiographs of 236 consecutive fixed-bearing TAAs. Radiographs were measured blindly by 2 investigators. The postoperative alignment of the prosthesis was compared with the surgeon's intended alignment in both planes. The accuracy of tibial component alignment was compared between the extramedullary and intramedullary referencing techniques using unpaired t tests. Interrater and intrarater reliabilities were assessed with intraclass correlation coefficients (ICCs). RESULTS: Eighty-three tibial components placed with an extramedullary referencing technique were compared with 153 implants placed with an intramedullary referencing technique. The accuracy of the extramedullary referencing was within a mean of 1.5 ± 1.4 degrees and 4.1 ± 2.9 degrees in the coronal and sagittal planes, respectively. The accuracy of intramedullary referencing was within a mean of 1.4 ± 1.1 degrees and 2.5 ± 1.8 degrees in the coronal and sagittal planes, respectively. There was a significant difference (P < .001) between the 2 techniques with respect to the sagittal plane alignment. Interrater ICCs for coronal and sagittal alignment were high (0.81 and 0.94, respectively). Intrarater ICCs for coronal and sagittal alignment were high for both investigators. CONCLUSIONS: Initial sagittal plane tibial component alignment was notably more accurate when intramedullary referencing was used. Further studies are needed to determine the effect of this difference on clinical outcomes and long-term survivability of the implants. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

A Multiple Goal Perspective on Eating Behavior

Although people frequently pursue multiple goals simultaneously, these goals often conflict with each other. For instance, consumers may have both a healthy eating goal and a goal to have an enjoyable eating experience. In this dissertation, I focus on two sources of enjoyment in eating experiences that may conflict with healthy eating: consuming tasty food (Essay 1) and affiliating with indulging dining companions (Essay 2). In both essays, I examine solutions and strategies that decrease the conflict between healthy eating and these aspects of enjoyment in the eating experience, thereby enabling consumers to resolve such goal conflicts.

Essay 1 focuses on the well-established conflict between having healthy food and having tasty food and introduces a novel product offering (“vice-virtue bundles”) that can help consumers simultaneously address both health and taste goals. Through several experiments, I demonstrate that consumers often choose vice-virtue bundles with small proportions (¼) of vice and that they view such bundles as healthier than but equally tasty as bundles with larger vice proportions, indicating that “healthier” does not always have to equal “less tasty.”

Essay 2 focuses on a conflict between healthy eating and affiliation with indulging dining companions. The first set of experiments provides evidence of this conflict and examine why it arises (Studies 1 to 3). Based on this conflict’s origins, the second set of experiments tests strategies that consumers can use to decrease the conflict between healthy eating and affiliation with an indulging dining companion (Studies 4 and 5), such that they can make healthy food choices while still being liked by an indulging dining companion. Thus, Essay 2 broadens the existing picture of goals that conflict with the healthy eating goal and, together with Essay 1, identifies solutions to such goal conflicts.

Fluid management and goal-directed therapy as an adjunct to Enhanced Recovery After Surgery (ERAS)

© 2014, Canadian Anesthesiologists' Society.Optimal perioperative fluid management is an important component of Enhanced Recovery After Surgery (ERAS) pathways. Fluid management within ERAS should be viewed as a continuum through the preoperative, intraoperative, and postoperative phases. Each phase is important for improving patient outcomes, and suboptimal care in one phase can undermine best practice within the rest of the ERAS pathway. The goal of preoperative fluid management is for the patient to arrive in the operating room in a hydrated and euvolemic state. To achieve this, prolonged fasting is not recommended, and routine mechanical bowel preparation should be avoided. Patients should be encouraged to ingest a clear carbohydrate drink two to three hours before surgery. The goals of intraoperative fluid management are to maintain central euvolemia and to avoid excess salt and water. To achieve this, patients undergoing surgery within an enhanced recovery protocol should have an individualized fluid management plan. As part of this plan, excess crystalloid should be avoided in all patients. For low-risk patients undergoing low-risk surgery, a “zero-balance” approach might be sufficient. In addition, for most patients undergoing major surgery, individualized goal-directed fluid therapy (GDFT) is recommended. Ultimately, however, the additional benefit of GDFT should be determined based on surgical and patient risk factors. Postoperatively, once fluid intake is established, intravenous fluid administration can be discontinued and restarted only if clinically indicated. In the absence of other concerns, detrimental postoperative fluid overload is not justified and “permissive oliguria” could be tolerated.

A prospective comparison of a noninvasive cardiac output monitor versus esophageal doppler monitor for goal-directed fluid therapy in colorectal surgery patients

Copyright © 2014 International Anesthesia Research Society.BACKGROUND: Goal-directed fluid therapy (GDFT) is associated with improved outcomes after surgery. The esophageal Doppler monitor (EDM) is widely used, but has several limitations. The NICOM, a completely noninvasive cardiac output monitor (Cheetah Medical), may be appropriate for guiding GDFT. No prospective studies have compared the NICOM and the EDM. We hypothesized that the NICOM is not significantly different from the EDM for monitoring during GDFT. METHODS: One hundred adult patients undergoing elective colorectal surgery participated in this study. Patients in phase I (n = 50) had intraoperative GDFT guided by the EDM while the NICOM was connected, and patients in phase II (n = 50) had intraoperative GDFT guided by the NICOM while the EDM was connected. Each patient's stroke volume was optimized using 250- mL colloid boluses. Agreement between the monitors was assessed, and patient outcomes (postoperative pain, nausea, and return of bowel function), complications (renal, pulmonary, infectious, and wound complications), and length of hospital stay (LOS) were compared. RESULTS: Using a 10% increase in stroke volume after fluid challenge, agreement between monitors was 60% at 5 minutes, 61% at 10 minutes, and 66% at 15 minutes, with no significant systematic disagreement (McNemar P > 0.05) at any time point. The EDM had significantly more missing data than the NICOM. No clinically significant differences were found in total LOS or other outcomes. The mean LOS was 6.56 ± 4.32 days in phase I and 6.07 ± 2.85 days in phase II, and 95% confidence limits for the difference were -0.96 to +1.95 days (P = 0.5016). CONCLUSIONS: The NICOM performs similarly to the EDM in guiding GDFT, with no clinically significant differences in outcomes, and offers increased ease of use as well as fewer missing data points. The NICOM may be a viable alternative monitor to guide GDFT.

Individual Differences in the Neural Response to Personal Goal Pursuit Success and Failure: A Developmental Analysis

Regulatory focus theory (RFT) proposes two different social-cognitive motivational systems for goal pursuit: a promotion system, which is organized around strategic approach behaviors and "making good things happen," and a prevention system, which is organized around strategic avoidance and "keeping bad things from happening." The promotion and prevention systems have been extensively studied in behavioral paradigms, and RFT posits that prolonged perceived failure to make progress in pursuing promotion or prevention goals can lead to ineffective goal pursuit and chronic distress (Higgins, 1997).

Research has begun to focus on uncovering the neural correlates of the promotion and prevention systems in an attempt to differentiate them at the neurobiological level. Preliminary research suggests that the promotion and prevention systems have both distinct and overlapping neural correlates (Eddington, Dolcos, Cabeza, Krishnan, & Strauman, 2007; Strauman et al., 2013). However, little research has examined how individual differences in regulatory focus develop and manifest. The development of individual differences in regulatory focus is particularly salient during adolescence, a crucial topic to explore given the dramatic neurodevelopmental and psychosocial changes that take place during this time, especially with regard to self-regulatory abilities. A number of questions remain unexplored, including the potential for goal-related neural activation to be modulated by (a) perceived proximity to goal attainment, (b) individual differences in regulatory orientation, specifically general beliefs about one's success or failure in attaining the two kinds of goals, (c) age, with a particular focus on adolescence, and (d) homozygosity for the Met allele of the catechol-O-methyltransferase (COMT) Val158Met polymorphism, a naturally occurring genotype which has been shown to impact prefrontal cortex activation patterns associated with goal pursuit behaviors.

This study explored the neural correlates of the promotion and prevention systems through the use of a priming paradigm involving rapid, brief, masked presentation of individually selected promotion and prevention goals to each participant while being scanned. The goals used as priming stimuli varied with regard to whether participants reported that they were close to or far away from achieving them (i.e. a "match" versus a "mismatch" representing perceived success or failure in personal goal pursuit). The study also assessed participants' overall beliefs regarding their relative success or failure in attaining promotion and prevention goals, and all participants were genotyped for the COMT Val158Met polymorphism.

A number of significant findings emerged. Both promotion and prevention priming were associated with activation in regions associated with self-referential cognition, including the left medial prefrontal cortex, cuneus, and lingual gyrus. Promotion and prevention priming were also associated with distinct patterns of neural activation; specifically, left middle temporal gyrus activation was found to be significantly greater during prevention priming. Activation in response to promotion and prevention goals was found to be modulated by self-reports of both perceived proximity to goal achievement and goal orientation. Age also had a significant effect on activation, such that activation in response to goal priming became more robust in the prefrontal cortex and in default mode network regions as a function of increasing age. Finally, COMT genotype also modulated the neural response to goal priming both alone and through interactions with regulatory focus and age. Overall, these findings provide further clarification of the neural underpinnings of the promotion and prevention systems as well as provide information about the role of development and individual differences at the personality and genetic level on activity in these neural systems.