bluuebunny/crossref_metadata_2025 huggingface dataset:
Histone Deacetylase Inhibitors: A Novel Strategy in Trauma and Sepsis
Authors: Williams Aaron M. , Dennahy Isabel S. , Bhatti Umar F. , Biesterveld Ben E. , Graham Nathan J. , Li Yongqing , Alam Hasan B.
Published: December 2018

Trauma remains a leading cause of morbidity and mortality among all age groups in the United States. Hemorrhagic shock and traumatic brain injury (TBI) are major causes of preventable death in trauma. Initial treatment involves fluid resuscitation to improve the intravascular volume. Although crystalloids may provide volume expansion, they do not have any pro-survival properties. Furthermore, aggressive fluid resuscitation can provoke a severe inflammatory response and worsen clinical outcomes. Due to logistical constraints, however, definitive resuscitation with blood products is often not feasible in the prehospital setting—highlighting the importance of adjunctive therapies. In recent years, histone deacetylase inhibitors (HDACis) have shown promise as pharmacologic agents for use in both trauma and sepsis. In this review, we discuss the role of histone deacetylases (HDACs) and pharmacologic agents that inhibit them (HDACis). We also highlight the therapeutic effects and mechanisms of action of HDACis in hemorrhagic shock, TBI, polytrauma, and sepsis. With further investigation and translation, HDACis have the potential to be a high-impact adjunctive therapy to traditional resuscitation.
Hypoxia-Inducible Factor (HIF)-1α Promotes Inflammation and Injury Following Aspiration-Induced Lung Injury in Mice
Authors: Suresh Madathilparambil V. , Balijepalli Sanjay , Zhang Boya , Singh Vikas Vikram , Swamy Samantha , Panicker Sreehari , Dolgachev Vladislov A. , Subramanian Chitra , Ramakrishnan Sadeesh K. , Thomas Bivin , Rao Tejeshwar C. , Delano Matthew J. , Machado-Aranda David , Shah Yatrik M. , Raghavendran Krishnan
Published: December 2018

Acid aspiration-induced lung injury is a common disease in the intensive care unit (ICU) and acute respiratory distress syndrome (ARDS). Hypoxia-inducible factor (HIF)-1α is a major transcription factor responsible for regulating the cellular response to changes in oxygen tension. A clear understanding of the function of HIF-1α in lung inflammatory response is currently lacking. Here, we sought to determine the role of HIF-1α in type 2 alveolar epithelial cells (AEC) in the generation of the acute inflammatory response following gastric aspiration (GA). GA led to profound hypoxia at very early time points following GA. This correlated to a robust increase in HIF-1α, tissue albumin and pro-inflammatory mediators following GA in AECs. The extent of lung injury and the release of pro/anti-inflammatory cytokines were significantly reduced in HIF-1α (−/−) mice. Finally, we report that HIF-1α upregulation of the acute inflammatory response is dependent on NF-κB following GA.
Does Fenoldopam Protect Kidney in Cardiac Surgery? A Systemic Review and Meta-Analysis With Trial Sequential Analysis
Authors: Sun Haibing , Xie Qin , Peng Zhiyong
Published: December 2018

Purpose:

To assess the benefits and harms of fenoldopam for nephroprotective effects in adult patients undergoing cardiac surgery.

Methods:

We conducted a systematic review with meta-analysis of randomized controlled trials (RCTs) comparing fenoldopam with placebo in cardiac surgery. Trials were systematically searched from PubMed, EMBASE, CENTRAL, and CNKI databases, up to July 30, 2018. A trial sequential analysis (TSA) was used to determine whether the present evidence was valid and conclusive for the primary outcomes.

Results:

A total of seven randomized controlled trials involving 1,107 adult patients undergoing cardiac surgery fulfilled the inclusion criteria. The pooled analysis suggested that the use of fenoldopam was associated with a reduction in the incidence of AKI (18 of 216 [8.3%] in the fenoldopam group versus 45 of 222 [20.3%] in the placebo group, RR = 0.42 [0.26, 0.69], P = 0.0006) and with a higher rate of hypotension (92/357 [25.8%] versus 51/348 [14.7%], RR = 1.76 [1.29, 2.39], P = 0.0003). There was no significant effect on renal replacement therapy requirement (77 of 540 [14.3%] versus 75 of 536 [14.0%], P = 0.96) or hospital mortality (87/392 [22.2%] versus 83/383 [21.7%], P = 0.86). TSA supported the results of the conventional analysis on AKI.

Conclusions:

Low-dose dopamine offers transient improvements in renal physiology, but no good evidence shows that it offers important clinical benefits to patients with or at risk for acute renal failure.

Among patients treated with fenoldopam, there was a decrease in AKI and an increased incidence of hypotension, had no significant effect on RRT or mortality. Given that most studies were small and the definition of AKI was variable between studies, there is not enough evidence to support the systematic use of fenoldopam in cardiac surgery.
Virtual Reality Simulation in Nontechnical Skills Training for Healthcare Professionals
Authors: Bracq Marie-Stéphanie , Michinov Estelle , Jannin Pierre
Published: December 2018

Summary Statement

This systematic review, conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, is aimed to review current research in virtual reality (VR) for healthcare training, specifically pertaining to nontechnical skills. PsycInfo and Medline databases were queried for relevant articles published through December 2017. Of the 1377 publications identified, 80 were assessed for eligibility and 26 were finally included in the qualitative synthesis. Overall, the use of virtual training for nontechnical skills is recent in healthcare education and has increased since 2010. Screen-based VR simulators or virtual worlds are the most frequently used systems. The nontechnical skills addressed in VR simulation include mainly teamwork, communication, and situation awareness. Most studies evaluate the usability and acceptability of VR simulation, and few studies have measured the effects of VR simulation on nontechnical skills development.
The Impact of Phone Interruptions on the Quality of Simulated Medication Order Validation Using Eye Tracking
Authors: Thibault Maxime , Porteils Céline , Goulois Stéphanie , Lévy Arielle , Lebel Denis , Bussières Jean-François
Published: December 2018

Introduction

Order validation is an important component of pharmacy services, where pharmacists review orders with a focus on error prevention. Interruptions are frequent and may contribute to a reduction in error detection, thus potential medication errors. However, studying such errors in practice is difficult. Simulation has potential to study these events.

Methods

This was a pilot, simulation study. The primary objective was to determine the rate of medication error detection and the effect of interruptions on error detection during simulated validation. Secondary objectives included determining time to complete each prescription page. The scenario consisted of validating three handwritten medication order pages containing 12 orders and 17 errors, interrupted by three phone calls timed during one order for each page. Participants were categorized in groups: seniors and juniors (including residents). Simulation sessions were videotaped and eye tracking was used to assist in analysis.

Results

Eight senior and five junior pharmacists were included in the analysis. There was a significant association between interruption and error detection (odds ratio = 0.149, 95% confidence interval = 0.042–0.525, P = 0.005). This association did not vary significantly between groups (P = 0.832). Juniors took more time to validate the first page (10 minutes 56 seconds vs. 6 minutes 42 seconds) but detected more errors (95% vs. 69%). However, all major errors were detected by all participants.

Conclusions

We observed an association between phone interruptions and a decrease in error detection during simulated validation. Simulation provides an opportunity to study order validation by pharmacists and may be a valuable teaching tool for pharmacists and pharmacy residents learning order validation.
Alexis St. Martin Gastropexy: A Novel Technique for Gastropexy During Percutaneous Endoscopic Gastrostomy Tube Placement
Authors: Halka Joshua T. , Yee Danielle , Angus Andrew , Mohammed Azmath , Sevak Shruti , Robbins James
Published: December 2018

Background:

Percutaneous endoscopic gastrostomy (PEG) is a preferred method of long-term enteral nutritional support. Despite its ease of placement, it has a 4% major complication rate, requiring surgical intervention or hospitalization. Early PEG tube dislodgment can cause peritonitis, requiring emergent laparotomy at significant morbidity and cost. T-fasteners have been used as an adjunct gastropexy, but nearly one third migrate into the abdominal wall within the first 2 weeks. We describe a low-cost, minimally invasive technique using widely available surgical instruments to appose the gastric and abdominal walls.

Methods:

All PEG procedures were performed in our 60-bed surgical intensive care unit. Institutional IRB approval was obtained along with procedure specific consent for all patients. The adjunctive gastropexy procedure was performed on four patients at high risk for early PEG tube dislodgment. Following routine PEG tube placement, both ends of four 2-0 polyglactin ties were brought through the gastric and abdominal walls through separate stab incisions adjacent to the PEG tube exit site in the 3, 6, 9, and 12 o’clock positions. These were tied in the subcutaneous tissue, securing the gastric wall to the abdominal wall.

Results:

No PEG tube complications occurred. All patients were discharged to long-term care facilities with PEG tubes intact or electively removed.

Conclusions:

We describe the results of a pilot study for a cost-effective, easily implementable, adjunct technique, named after the namesake of our institution, to decrease the incidence and severity of complications associated with PEG tube dislodgment. It was used in 4 patients at high risk for PEG tube dislodgment with satisfactory early results in all 4. Further recruitment of larger numbers of patients using this technique is ongoing to determine if this technique is truly effective at reducing PEG tube complications.
A Resected Gallbladder Carcinoma Coexisting With Adenomyomatosis Involving Varied Degrees of Intraepithelial Dysplasia: A Case Report and Literature Review
Authors: Suzuki Keiichi , Abe Kodai , Ohbu Makoto
Published: December 2018

A 59-year-old asymptomatic man underwent ultrasonography, which revealed gallstones and thickened gallbladder wall. Abdominal computed tomography (CT) showed a slightly swollen bilocular gallbladder and a soft tissue mass in the fundus site. Segmental adenomyomatosis (ADM) was suspected because numerous fundic cystic lesions were seen on magnetic resonance imaging. Endoscopic ultrasonography revealed numerous Rokitansky-Aschoff sinuses (RAS) and a papillary soft tissue shadow surrounded with irregular and remarkably thickened fundic gallbladder wall. Fluoro-2-deoxy-D-glucose-positron emission tomography/CT demonstrated slightly increased fluoro-2-deoxy-D-glucose uptake in the corresponding lesion. Surgery was performed under a diagnosis of gallbladder carcinoma (GBC) with concomitant ADM, and histopathology revealed a 30-mm papillotubular adenocarcinoma extending from the gallbladder body to fundus with invasion into the subserosa. Numerous RAS were present throughout the gallbladder showing various degrees of dysplasia. Ki67 and p53-labeling index (LI) was significantly higher in the dysplastic epithelium compared with normal fundic epithelium. p53-LI was also markedly increased (72.1%) in tissue in front of tumor invasion. Interestingly, these hyperproliferation indicators were extremely high (Ki67-LI: 28.8%; p53-LI: 91.9%) in RAS with low-grade dysplasia even in the gallbladder neck. Although, generally, tumors do not develop in the gallbladder neck with segmental ADM, our results suggest that a gallbladder with ADM has potential for carcinogenesis regardless of location, with segmental ADM. On the basis of histopathology, our patient was diagnosed with GBC arising from RAS with multicentric and multistep growth. A relationship between GBC and ADM, especially segmental ADM, has been suggested but remains controversial. Our experience is very suggestive of carcinogenesis developing from ADM.
Factors Associated With Margin Positivity and Incidental Carcinoma in Patients Undergoing Transanal Endoscopic Microsurgery (TEMS) for the Management of Adenomatous and Dysplastic Rectal Lesions
Authors: Vukanic Danilo , Waters Peadar S. , O’Riordan James , Neary Paul , Kavanagh Dara O.
Published: December 2018

Purpose:

Colorectal cancer screening has resulted in an increased detection of early premalignant rectal lesions. Transanal endoscopic microsurgery (TEMS) is a minimally invasive procedure for the resection of dysplastic and selected early malignant lesions with organ and functional preservation. The aim of this study was to assess factors associated with positive resection margin and the underlying invasive component.

Methods:

This was an analysis of a prospective consecutive series of all TEMS procedures performed over the last 10-year period. Data was collated from hospital databases and operative theater registers. Statistical analysis was performed using Minitab-V18 with a P<0.05 regarded as significant.

Results:

In total, 328 procedures were performed on 292 patients. The cohort included 165 male patients and 127 female patients with a mean age of 66.3 years (19 to 95 years). A total of 274 procedures performed were en bloc excisions and 54 procedures were piecemeal debulking excisions for larger lesions follow by formal TEMs at an interval. The mean tumor size was 41.9 mm (10 to 150 mm), and the mean distance from anal verge was 9.3 cm (2 to 20 cm). Clear margins were achieved in 85% of cases. An overall 10.6% of patients had pathologic upgrading to invasive disease after TEMS. Lesion volume was found to influence the completeness of excision, and the widest diameter of the lesions was related to the presence of an invasive component on histology (P=0.002, 0.008, respectively).

Conclusions:

TEMS is a minimally invasive technique for the resection of rectal lesions that are not amenable to endoscopic removal. Lesion size and endoscopic diameter were associated with invasive component and margin positivity, respectively. These factors should be taken into consideration when considering TEMS.
Closure of Direct Inguinal Hernia Defect in Laparoscopic Hernioplasty to Prevent Seroma Formation: A Prospective Double-blind Randomized Controlled Trial
Authors: Zhu Yilin , Liu Min , Li Junsheng , Wang Minggang
Published: December 2018

Objectives:

Seroma is the most frequent postoperative complication after laparoscopic direct inguinal hernia repair. This randomized controlled trial evaluated the preventive effect of a simple technique by closing the direct hernia defect with barbed suture in laparoscopic direct inguinal hernia.

Methods:

In total, 60 patients aged 18 years or older who presented to the hernia center department in our hospital between October 1, 2017 and January 1, 2018 with primary direct inguinal hernia were randomized into the defect-closing group (by closing the transversalis) and the control groups. The primary outcomes were to compare the ultrasonic seroma number and volume at the inguinal region at 7 days, 1, and 3 months postoperatively. Secondary outcomes included total operative time, acute pain, chronic pain (pain lasting over 3 mo), hospital stay, recurrence, and any other complications.

Results:

There were no significant differences in baseline demographic characteristics between the 2 groups including age, sex, hernia type, size of hernia defect, surgical approach, and follow-up time. Compared with control group, there were significantly fewer patients with seroma formation at 7 days, 1, and 3 months after the operations in the defect-closing group (P<0.001, <0.001, 0.002, respectively). In addition, ultrasonic seroma volume was less in the defect-closing group on postoperative day 7 (13.33 vs. 30.45 mL; P=0.02). The acute pain and hospital stay were comparable (P=0.61, 0.85, respectively), and no chronic pain, early recurrence or other postoperative complications observed in both groups during the follow-up period.

Conclusions:

The simple technique of direct hernia defect closure with barbed suture in laparoscopic direct inguinal hernia repair is a secure and effective method, which is easy to perform and could significantly reduce both incidence and volume of seroma formation without increasing the risk of recurrence, acute, and chronic pain.
The economic footprint of acute care surgery in the United States: Implications for systems development
Authors: Knowlton Lisa M. , Minei Joseph , Tennakoon Lakshika , Davis Kimberly A. , Doucet Jay , Bernard Andrew , Haider Adil , Scherer L.R. Tres , Spain David A. , Staudenmayer Kristan L.
Published: December 2018

BACKGROUND

Acute care surgery (ACS) comprises trauma, surgical critical care, and emergency general surgery (EGS), encompassing both operative and nonoperative conditions. While the burden of EGS and trauma has been separately considered, the global footprint of ACS has not been fully characterized. We sought to characterize the costs and scope of influence of ACS-related conditions. We hypothesized that ACS patients comprise a substantial portion of the US inpatient population. We further hypothesized that ACS patients differ from other surgical and non-surgical patients across patient characteristics.

METHODS

We queried the National Inpatient Sample 2014, a nationally representative database for inpatient hospitalizations. To capture all adult ACS patients, we included adult admissions with any International Classification of Diseases—9th Rev.—Clinical Modification diagnosis of trauma or an International Classification of Diseases—9th Rev.—Clinical Modification diagnosis for one of the 16 AAST-defined EGS conditions. Weighted patient data were presented to provide national estimates.

RESULTS

Of the 29.2 million adult patients admitted to US hospitals, approximately 5.9 million (20%) patients had an ACS diagnosis. ACS patients accounted for US $85.8 billion, or 25% of total US inpatient costs (US $341 billion). When comparing ACS to non-ACS inpatient populations, ACS patients had higher rates of health care utilization with longer lengths of stay (5.9 days vs. 4.5 days, p < 0.001), and higher mean costs (US $14,466 vs. US $10,951, p < 0.001. Of all inpatients undergoing an operative procedure, 27% were patients with an ACS diagnosis. Overall, 3,186 (70%) of US hospitals cared for both trauma and EGS patients.

CONCLUSION

Acute care surgery patients comprise 20% of the inpatient population, but 25% of total inpatient costs in the United States. In addition to being costly, they overall have higher health care utilization and worse outcomes. This suggests that there is an opportunity to improve clinical trajectory for ACS patients that in turn, can affect the overall US health care costs.

LEVEL OF EVIDENCE

Epidemiologic, level III.
Conquering the inner couch potato: precommitment is an effective strategy to enhance motivation for effortful actions
Authors: Studer Bettina , Koch Carolin , Knecht Stefan , Kalenscher Tobias
Published: December 2018

Letting effort-free gratification derail us from effort-requiring goals is one reason why we fail to realize health-relevant intentions like ‘exercise regularly’. We tested the effectiveness of the self-control strategy precommitment in such effort-related conflicts, using a novel laboratory choice paradigm, where participants could precommit to an effort-requiring large reward by pre-eliminating an effort-free small reward from their choice set. Our participants used precommitment frequently and effectively, such that they reached effort-requiring large rewards more often. Using computational modelling and Bayesian model comparisons, we assessed whether participants employed precommitment to avoid anticipated willpower failures (i.e. as a self-regulatory measure) or to maximize their motivation to choose the effort-requiring option (i.e. as a self-motivational measure). Observed choices and precommitment decisions were consistent with the motivation maximization hypothesis, but not the willpower hypothesis. Our findings show that offering precommitment is effective in helping individuals optimize their motivation and choice behaviour and thereby achieve effort-requiring goals, and strongly encourage application of precommitment schemes in exercise and rehabilitation interventions.

This article is part of the theme issue ‘Risk taking and impulsive behaviour: fundamental discoveries, theoretical perspectives and clinical implications’.
Developmental perspectives on risky and impulsive choice
Authors: Rosenbaum Gail M. , Hartley Catherine A.
Published: December 2018

Epidemiological data suggest that risk taking in the real world increases from childhood into adolescence and declines into adulthood. However, developmental patterns of behaviour in laboratory assays of risk taking and impulsive choice are inconsistent. In this article, we review a growing literature using behavioural economic approaches to understand developmental changes in risk taking and impulsivity. We present findings that have begun to elucidate both the cognitive and neural processes that contribute to risky and impulsive choice, as well as how age-related changes in these neurocognitive processes give rise to shifts in choice behaviour. We highlight how variability in task parameters can be used to identify specific aspects of decision contexts that may differentially influence risky and impulsive choice behaviour across development.

This article is part of the theme issue ‘Risk taking and impulsive behaviour: fundamental discoveries, theoretical perspectives and clinical implications’.
Computational psychiatry of impulsivity and risk: how risk and time preferences interact in health and disease
Authors: Lopez-Guzman Silvia , Konova Anna B. , Glimcher Paul W.
Published: December 2018

Choice impulsivity is an important subcomponent of the broader construct of impulsivity and is a key feature of many psychiatric disorders. Choice impulsivity is typically quantified astemporal discounting, a well-documented phenomenon in which a reward's subjective value diminishes as the delay to its delivery is increased. However, an individual's proclivity to—or more commonly aversion to—riskcan influence nearly all of the standard experimental tools available for measuring temporal discounting. Despite this interaction,risk preferenceis a behaviourally and neurobiologically distinct construct that relates to the economic notion of utility or subjective value. In this opinion piece, we discuss the mathematical relationship between risk preferences and time preferences, their neural implementation, and propose ways that research in psychiatry could, and perhaps should, aim to account for this relationship experimentally to better understand choice impulsivity and its clinical implications.

This article is part of the theme issue ‘Risk taking and impulsive behaviour: fundamental discoveries, theoretical perspectives and clinical implications’.
Uncertainty and computational complexity
Authors: Bossaerts Peter , Yadav Nitin , Murawski Carsten
Published: December 2018

Modern theories of decision-making typically model uncertainty about decision options using the tools of probability theory. This is exemplified by the Savage framework, the most popular framework in decision-making research. There, decision-makers are assumed to choose from among available decision options as if they maximized subjective expected utility, which is given by the utilities of outcomes in different states weighted with subjective beliefs about the occurrence of those states. Beliefs are captured by probabilities and new information is incorporated using Bayes’ Law. The primary concern of the Savage framework is to ensure that decision-makers’ choices arerational. Here, we use concepts from computational complexity theory to expose two major weaknesses of the framework. Firstly, we argue that in most situations, subjective utility maximization is computationally intractable, which means that the Savage axioms are implausible. We discuss empirical evidence supporting this claim. Secondly, we argue that there exist many decision situations in which the nature of uncertainty is such that (random) sampling in combination with Bayes’ Law is an ineffective strategy to reduce uncertainty. We discuss several implications of these weaknesses from both an empirical and a normative perspective.

This article is part of the theme issue ‘Risk taking and impulsive behaviour: fundamental discoveries, theoretical perspectives and clinical implications’.
Exploring preferences for variable delays over fixed delays to high-value food rewards as a model of food-seeking behaviours in humans
Authors: Stokes Laura-Jean G. , Davies Anna , Lattimore Paul , Winstanley Catharine , Rogers Robert D.
Published: December 2018

Foraging and operant models suggest that animals will tolerate uncertainty or risk to obtain food quickly. In modern food environments, sustained access to quick energy-dense foods can promote weight gain. Here, we used a discrete-choice procedure to examine peoples' decisions about when next to eat high-value, palatable food rewards, probabilistically delivered immediately or following longer delays. In Experiment 1, moderately hungry young females showed consistent preferences for a variable delay option that delivered food rewards immediately or following long delays over a fixed delay option that delivered the same rewards following intermediate delays. These preferences were stronger in females with higher BMIs compared with lower BMIs, suggesting that quick food can enhance the value of uncertain or ‘risky’ food-seeking strategies in individuals vulnerable to future weight gain. In Experiment 2, prior exposure to a subtle and not easily identifiable food aroma increased selections of the variable delay option following delayed food rewards in a mixed sample of male and female adults, providing preliminary evidence that food cues can sustain uncertain food-seeking strategies. These data highlight a working hypothesis that the rapid delivery and consumption of food rewards, and food cues, can increase risk-tolerance in the food-seeking behaviours of individuals who are vulnerable to weight gain.

This article is part of the theme issue ‘Risk taking and impulsive behaviour: fundamental discoveries, theoretical perspectives and clinical implications’.
Intragenomic conflict over bet-hedging
Authors: Wilkins Jon F. , Bhattacharya Tanmoy
Published: December 2018

Genomic imprinting, where an allele’s expression pattern depends on its parental origin, is thought to result primarily from an intragenomic evolutionary conflict. Imprinted genes are widely expressed in the brain and have been linked to various phenotypes, including behaviours related to risk tolerance. In this paper, we analyse a model of evolutionary bet-hedging in a system with imprinted gene expression. Previous analyses of bet-hedging have shown that natural selection may favour alleles and traits that reduce reproductive variance, even at the expense of reducing mean reproductive success, with the trade-off between mean and variance depending on the population size. In species where the sexes have different reproductive variances, this bet-hedging trade-off differs between maternally and paternally inherited alleles. Where males have the higher reproductive variance, alleles are more strongly selected to reduce variance when paternally inherited than when maternally inherited. We connect this result to phenotypes connected with specific imprinted genes, including delay discounting and social dominance. The empirical patterns are consistent with paternally expressed imprinted genes promoting risk-averse behaviours that reduce reproductive variance. Conversely, maternally expressed imprinted genes promote risk-tolerant, variance-increasing behaviours. We indicate how future research might further test the hypotheses suggested by our analysis.

This article is part of the theme issue ‘Risk taking and impulsive behaviour: fundamental discoveries, theoretical perspectives and clinical implications’.
Feeding behaviour, risk-sensitivity and response control: effects of 5-HT
2C
receptor manipulations
Authors: Humby Trevor , Patel Yateen , Carter Jenny , Stokes Laura-Jean G. , Rogers Robert D. , Wilkinson Lawrence S.
Published: December 2018

People, like animals, tend to choose the variable option when given the choice between a fixed and variable delay to reward where, in the variable delay condition, some rewards are available immediately (Laura-Jean
et al
. 2019
Phil. Trans. R. Soc. B
374
, 20180141. (
doi:10.1098/rstb.2018.0141
)). This bias has been suggested to reflect evolutionary pressures resulting from food scarcity in the past placing a premium on obtaining food quickly that can win out against the risks of sometimes sustaining longer delays to food. The psychologies mediating this effect may become maladaptive in the developed world where food is readily available contributing, potentially, to overeating and obesity. Here, we report our development of a novel touchscreen task in mice allowing comparisons of the impact of food delay and food magnitude across species. We show that mice exhibit the typical preference, as shown by humans, for variable over fixed delays to rewards but no preference when it comes to fixed versus variable reward amounts and further show that this bias is sensitive to manipulations of the 5-HT
2C
receptor, a key mediator of feeding and impulse control. We discuss the data in terms of the utility of the task to model the psychologies and underlying brain mechanisms impacting on feeding behaviours.

This article is part of the theme issue ‘Risk taking and impulsive behaviour: fundamental discoveries, theoretical perspectives and clinical implications’.
The Long Limb Bones of the StW 573 Australopithecus Skeleton from Sterkfontein Member 2: Descriptions and Proportions
Authors: Heaton Jason L. , Pickering Travis Rayne , Carlson Kristian J. , Crompton Robin H. , Jashashvili Tea , Beaudet Amelie , Bruxelles Laurent , Kuman Kathleen , Heile A.J. , Stratford Dominic , Clarke Ronald J.
Published: December 2018

Due to its completeness, the A.L. 288-1 (Lucy) skeleton has long served as the archetypal bipedal Australopithecus. However, there remains considerable debate about its limb proportions. There are three competing, but not necessarily mutually exclusive, explanations for the high humerofemoral index of A.L. 288-1: (1) a retention of proportions from an Ardipithecus-like most recent common ancestor (MRCA); (2) indication of some degree of climbing ability; (3) allometry. Recent discoveries of other partial skeletons of Australopithecus, such as those of A. sediba (MH1 and MH2) and A. afarensis (KSD-VP-1/1 and DIK-1/1), have provided new opportunities to test hypotheses of early hominin body size and limb proportions. Yet, no early hominin is as complete (>90%), as is the 3.67 Ma Little Foot (StW 573) specimen, from Sterkfontein Member 2. Here, we provide the first descriptions of its upper and lower long limb bones, as well as a comparative context of its limb proportions. As to the latter, we found that StW 573 possesses absolutely longer limb lengths than A.L. 288-1, but both skeletons show similar limb proportions. This finding seems to argue against an allometric explanation for the limb proportions of A.L. 288-1. In fact, our multivariate allometric analysis suggests that limb lengths of Australopithecus, as represented by StW 573 and A.L. 288-1, developed along a significantly different (p < 0.001) allometric scale than that which typifies modern humans and African apes. Our analyses also suggest, as have those of others, that hominin limb evolution occurred in two stages with: (1) a modest increase in lower limb length and a concurrent shortening of the antebrachium between Ardipithecus and Australopithecus, followed by (2) considerable lengthening of the lower limb along with a decrease of both upper limb elements occurring between Australopithecus and Homo sapiens.
Identification and functional characterization of two novel mutations in KCNJ10 and PI4KB in SeSAME syndrome without electrolyte imbalance
Authors: Nadella Ravi K , Chellappa Anirudh , Subramaniam Anand G , More Ravi Prabhakar , Shetty Srividya , Prakash Suriya , Ratna Nikhil , Vandana VP , Purushottam Meera , Saini Jitender , Viswanath Biju , Bindu PS , Nagappa Madhu , Mehta Bhupesh , Jain Sanjeev , Kannan Ramakrishnan
Published: December 2018

Dysfunction in inwardly-rectifying potassium channel Kir4.1 has been implicated in SeSAME syndrome, an autosomal-recessive (AR), rare, multi-systemic disorder. However, not all neurological, intellectual disability and comorbid phenotypes in SeSAME syndrome can be mechanistically linked solely to Kir4.1 dysfunction. We therefore performed whole exome sequencing and identified additional genetic risk-elements that might exert causative effects either alone or in concert with Kir4.1 in a family diagnosed with SeSAME syndrome. Two variant prioritization pipelines based on AR inheritance and runs of homozygosity (ROH), identified two novel homozygous variants in KCNJ10 and PI4KB and five rare homozygous variants in PVRL4, RORC, FLG2, FCRL1, NIT1 and one common homozygous variant in HSPA6 segregating in all four patients. The novel mutation in KCNJ10 resides in the cytoplasmic domain of Kir4.1, a seat of phosphatidyl inositol bisphosphate (PIP2) binding. The mutation altered the subcellular localization and stability of Kir4.1 in patient-specific lymphoblastoid cells (LCLs) compared to parental controls. Barium-sensitive endogenous K+ currents in patient-specific LCLs using whole-cell patch clamp electrophysiology revealed membrane depolarization and defects in inward K+ ion conductance across the membrane, thereby suggesting a loss-of-function effect of KCNJ10 variant. Altogether our findings implicate the role of new genes in SeSAME syndrome without electrolyte imbalance and thereby speculate the regulation of Kir4.1 channel activity by PIP2 and integrin-mediated adhesion signaling mechanisms.
Sodium-powered stators of the bacterial flagellar motor can generate torque in the presence of phenamil with mutations near the peptidoglycan-binding region
Authors: Ishida Tsubasa , Ito Rie , Clark Jessica , Matzke Nicholas J , Sowa Yoshiyuki , Baker Matthew AB
Published: December 2018

The bacterial flagellar motor (BFM) powers the rotation that propels swimming bacteria. Rotational torque is generated by harnessing the flow of ions through ion channels known as stators which couple the energy from the ion gradient across the inner membrane to rotation of the rotor. Here we used error-prone PCR to introduce single point mutations into the sodium-poweredVibrio alginolyticus / Escherichia colichimeric stator PotB and selected for motors that exhibited motility in the presence of the sodium-channel inhibitor phenamil. We found single mutations that enable motility under phenamil occurred at two sites: 1) the transmembrane domain of PotB, corresponding to the TM region of the PomB stator fromV. alginolyticus, and 2) near the peptidoglycan (PG) binding region that corresponds to the C-terminal region of the MotB stator fromE. coli.Single cell rotation assays confirmed that individual flagellar motors could rotate in up to 100 µM phenamil. Using phylogenetic logistic regression, we found correlation between natural residue variation and ion source at positions corresponding to PotB F22Y, but not at other sites. Our results demonstrate that it is not only the pore region of the stator that moderates motility in the presence of ion-channel blockers.
Structural variants, clonal propagation, and genome evolution in grapevine (Vitis vinifera)
Authors: Zhou Yongfeng , Minio Andrea , Massonnet Mélanie , Solares Edwin , Lyu Yuanda , Beridze Tengiz , Cantu Dario , Gaut Brandon S.
Published: December 2018

Little is known about the type and numbers of structural variants (SVs) in plant genomes, the evolutionary processes that shape SV variation, or their effects on phenotypes. Here we assembled the 605Mb genome of the Chardonnay grape (Vitis vinifera ssp. sativa), which we use to catalog SVs within and between genomes and also across 69 cultivars and wild accessions. SVs underlie widespread hemizygosity of protein coding genes within Chardonnay and genic presence-absence variation between cultivars. Negative selection acts against all SV types, but they also accrue as heterozygous, recessive mutations in clonally propagated grapevines. SV hotspots in the sex determination region and the berry color locus illustrate their impact on phenotype and the role of SVs as drivers of convergent phenotypic evolution.
dmrff: identifying differentially methylated regions efficiently with power and control
Authors: Suderman Matthew , Staley James R , French Robert , Arathimos Ryan , Simpkin Andrew , Tilling Kate
Published: December 2018

A differentially methylated region (DMR) is a genomic region in which DNA methylation is consistently positively or negatively associated with a phenotype or exposure. We demonstrate that existing algorithms for identifying DMRs either fail to consistently control false positive rates (comb-p and DMRcate), suffer from low power (bumphunter) or lack modeling flexibility (seqlm). We introduce a new method, dmrff, that overcomes these shortcomings and can additionally be used to meta-analyze multiple datasets. When applied to investigate associations of age in multiple datasets, dmrff identifies novel DMRs near genes previously linked to age. An R implementation is available on Github (http://github.com/perishky/dmrff).
An approach for accelerated isolation of genetically manipulated cell clones with reduced clonal variability
Authors: Casden Natania , Behar Oded
Published: December 2018

Genomic editing methods, such as the CRISPR/Cas9 system, are routinely used to study gene function in somatic cells. Due to the heterogeneity of mutations, it is necessary to purify cell clones grown in high dilution until colony formation, which can be a time consuming process. Here we tested a modified approach in which we seeded cells in high dilution, together with non-edited carrier cells. As a comparison, cells were also grown in high dilution with conditioned medium from a high density culture. When using carrier cells or conditioned medium, the formation of cell colonies is accelerated. Additionally, clones grown with carrier cells are more similar to the parental lines in terms of their tumorigenic properties. Surprisingly, key signaling cascades are very divergent between clones isolated from low density cultures, even with conditioned medium, in contrast to clones isolated with carrier cells. Thus, our study uncovers a significant limitation using the common approach of isolating cell clones following genetic modifications and suggests an alternative method that mitigates the problem of heterogeneity of gene expression between clones.
Prohibitin is a prognostic marker of relapse and therapeutic target to block chemotherapy resistance in Wilms tumor
Authors: Ortiz Michael V. , Ahmed Saima , Burns Melissa , Henssen Anton G. , Hollmann Travis J. , MacArthur Ian , Gunasekera Shehana , Gaewsky Lyvia , Bradwin Gary , Ryan Jeremy , Letai Anthony , He Ying , Naranjo Arlene , Chi Yueh-Yun , LaQuaglia Michael , Heaton Todd , Cifani Paolo , Dome Jeffrey S. , Gadd Samantha , Perlman Elizabeth , Mullen Elizabeth , Steen Hanno , Kentsis Alex
Published: December 2018

Wilms tumor (WT) is the most common childhood kidney cancer. To improve risk stratification and identify novel therapeutic targets for patients with WT, we used high-resolution mass spectrometry proteomics to identify urine tumor markers associated with WT relapse. We determined urine proteomes at diagnosis of 49 patients with WT, non-WT renal tumors, and age-matched controls, leading to the quantitation of 6,520 urine proteins. Supervised analysis revealed specific urine markers of renal rhabdoid tumors, kidney clear cell sarcomas, renal cell carcinomas, as well as those detected in cured and relapsed WT. In particular, urine prohibitin was significantly elevated at diagnosis in patients with relapsed as compared to cured WT. In a validation cohort of 139 patients, a specific urine prohibitin enzyme-linked immunosorbent assay demonstrated that prohibitin concentrations greater than 998 ng/mL at diagnosis were significantly associated with ultimate WT relapse. Immunohistochemical analysis revealed that prohibitin was highly expressed in primary WT specimens and associated with disease stage. Using functional genetic experiments, we found that prohibitin was required for the growth and survival of WT cells. Overexpression of prohibitin was sufficient to block intrinsic mitochondrial apoptosis and to cause resistance to diverse chemotherapy drugs, at least in part by dysregulating factors that control apoptotic cytochrome c release from mitochondrial cristae. Thus, urine prohibitin may improve therapy stratification, non-invasive monitoring of treatment response and early disease detection. In addition, therapeutic targeting of chemotherapy resistance induced by prohibitin dysregulation may offer improved therapies for patients with Wilms and other relapsed or refractory tumors.
High-resolution bladder morphology in the intact mouse bladder: an intravital two-photon study
Authors: Schueth Anna , Theelen Thomas , Foulquier Sebastien , van Koeveringe Gommert A. , van Zandvoort Marc
Published: December 2018

We developed a platform for intravital bladder two-photon microscopy (TPM) in healthy wild-type mice. It was our aim to make intravital bladder TPM simple and reproducible for researchers with access to TPM. In this study, the intact murine bladder was examined by means of autofluorescence (AF), second-harmonic generation (SHG), and different i.v. injected fluorescent dyes. All bladder layers with containing structures, such as cells, nerves, and vessels were detected in different colour-coded spectral channels, and shown in high-resolution images and real-time movies. The presented method opens up avenues for many future studies and applications, such as to reveal mechanisms and physiology in the natural state of the bladder. Researcher can use intravital bladder TPM to investigate events, such as migration and metabolism of (inflammatory) cells, nanoparticle uptake, or micro contractions in response to stimuli.
HOOK3 is a scaffold for the opposite-polarity microtubule-based motors cytoplasmic dynein and KIF1C
Authors: Kendrick Agnieszka A. , Redwine William B. , Tran Phuoc Tien , Vaites Laura Pontano , Dzieciatkowska Monika , Harper J. Wade , Reck-Peterson Samara L.
Published: December 2018

The unidirectional and opposite-polarity microtubule-based motors, dynein and kinesin, drive long-distance intracellular cargo transport. Cellular observations support the existence of mechanisms to couple opposite polarity motors: in cells some cargos rapidly switch directions and kinesin motors can be used to localize dynein. We recently identified an interaction between the cytoplasmic dynein-1 activating adaptor HOOK3 and the kinesin-3 KIF1C. Here we show that KIF1C and dynein/dynactin can exist in a single complex scaffolded by HOOK3. Full-length HOOK3 binds to and activates dynein/dynactin motility. HOOK3 also binds to a short region in the “tail” of KIF1C, but unlike dynein/dynactin, this interaction does not affect the processive motility of KIF1C. HOOK3 scaffolding allows dynein to transport KIF1C towards the microtubule minus end, and KIF1C to transport dynein towards the microtubule plus end. We propose that linking dynein and kinesin motors by dynein activating adaptors may be a general mechanism to regulate bidirectional motility.
The effects of entrepreneurial orientation on the performance of the Malaysian manufacturing sector
Authors: Loong Lee Wee , Chong Aik Lee , T. Ramayah
Published: December 2018

Purpose

The purpose of this paper is to examine the effects of entrepreneur orientation (EO) on firm performance of the Malaysian manufacturing sector.

Design/methodology/approach

Data for the study were collected through a survey of 321 companies registered with the Federation of Malaysian Manufacturers. Responses were analyzed using PLS-SEM to assess the relationships between transformational leadership and firm performance.

Findings

The findings show that amongst Malaysian manufacturers, transformational leadership has a strong direct effect on firm performance.

Practical implications

These findings provide useful insights for organizations, particularly in the Malaysian manufacturing sector, seeking to be competitive and responsive to environmental changes by successfully introducing EO.

Originality/value

EO has been studied in detail in the recent literature. Many new researchers have explored various composition factors of EO, and how this will have an effect on firm performance. However, there are few research studies in the area of transformational leadership amongst Malaysian manufacturing companies. This research makes an important contribution to the existing literature by empirically examining the relationship between EO and firm performance, particularly in the Malaysian manufacturing sector. Conclusion emphasizes that mechanisms to encourage and foster EO mainly autonomy, competitive aggressiveness and proactiveness are likely to result in the achievement of superior firm performance.
Technology forecasting (TF) and technology assessment (TA) methodologies: a conceptual review
Authors: Haleem Abid , Mannan Bisma , Luthra Sunil , Kumar Sanjay , Khurana Sonal
Published: December 2018

Purpose

Technology forecasting (TF) and assessment (TA), all in all, apply to any intentional and deliberate endeavours to forecast and view the potential heading, rate, attributes and impacts of technological change, especially for development, advancement, selection and utilisation of resources, which ultimately helps in the benchmarking. A vast variety of methods are available for TF and TA. Till now, practically, no exertion has been made to choose proper, satisfactory innovation methods or technology. The paper aims to discuss this issue.

Design/methodology/approach

In this paper, there is an endeavour to summarise the vast field of TF and TA, through its evolution, functions, applications and techniques. This paper provides the in-depth review of the utilisation of TF and TA methodologies and its improvement, which helps the users in selecting the appropriate method of TF and TA for a specific situation.

Findings

This study concludes that the quest for a single strategy for doing forecast and assessment is a misconception. This neglects to perceive that forecast and assessment oblige a suitable blend of strategies and methods drawn from a variety of fields. Researchers and practitioners must be innovative, imperative and specialised in choosing TF and TA methodologies, and cannot be programmed.

Practical implications

The technology seems to be the most significant driver of the present day global developments. Some technologies have far-reaching implications, and the authors need to understand these issues regarding its’ forecasting and its assessment.

Originality/value

The decision of proper worthy procedure amid a circumstance may have an impact on the exactness and reliability of the forecast and assessment. Significant observations regarding learning, action/s, actor/s and expected outcomes are discussed.