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1.  Higher serum bicarbonate levels within the normal range are associated with better survival and renal outcomes in African Americans 
Kidney international  2010;79(3):356-362.
Recent studies suggest that correcting low serum bicarbonate levels may reduce the progression of kidney disease; however, few patients with chronic kidney disease have low serum bicarbonate. Therefore, we examined whether higher levels of serum bicarbonate within the normal range (20–30 mmol/l) were associated with better kidney outcomes in the African American Study of Kidney Disease and Hypertension (AASK) trial. At baseline and during follow-up of 1094 patients, the glomerular filtration rates (GFR) were measured by iothalamate clearances and events were adjudicated by the outcomes committee. Mean baseline serum bicarbonate, measured GFR, and proteinuria were 25.1 mmol/l, 46 ml/min per 1.73 m2, and 326 mg/g of creatinine, respectively. Each 1 mmol/l increase in serum bicarbonate within the normal range was associated with reduced risk of death, dialysis, or GFR event and with dialysis or GFR event (hazard ratios of 0.942 and 0.932, respectively) in separate multivariable Cox regression models that included errors-in-variables calibration. Cubic spline regression showed that the lowest risk of GFR event or dialysis was found at serum bicarbonate levels near 28–30 mmol/l. Thus, our study suggests that serum bicarbonate is an independent predictor of CKD progression. Whether increasing serum bicarbonate into the high-normal range will improve kidney outcomes during interventional studies will need to be considered.
PMCID: PMC5241271  PMID: 20962743
AASK (African American Study of Kidney Disease and Hypertension); acidosis; chronic kidney disease; survival
2.  The Structural Basis of Asymmetry in DNA Binding and Cleavage as Exhibited by the I-SmaMI LAGLIDADG Meganuclease 
Journal of molecular biology  2015;428(1):206-220.
LAGLIDADG homing endonucleases (“meganucleases”) are highly specific DNA cleaving enzymes that are used for genome engineering. Like other enzymes that act on DNA targets, meganucleases often display binding affinities and cleavage activities that are dominated by one protein domain. To decipher the underlying mechanism of asymmetric DNA recognition and catalysis, we identified and characterized a new monomeric meganuclease (I-SmaMI), which belongs to a superfamily of homologous enzymes that recognize divergent DNA sequences. We solved a series of crystal structures of the enzyme–DNA complex representing a progression of sequential reaction states, and we compared the structural rearrangements and surface potential distributions within each protein domain against their relative contribution to binding affinity. We then determined the effects of equivalent point mutations in each of the two enzyme active sites to determine whether asymmetry in DNA recognition is translated into corresponding asymmetry in DNA cleavage activity. These experiments demonstrate the structural basis for “dominance” by one protein domain over the other and provide insights into this enzyme's conformational switch from a nonspecific search mode to a more specific recognition mode.
PMCID: PMC4749321  PMID: 26705195
homing endonuclease; genome editing; surface potential; protein–DNA interactions; nickase
3.  Frontolimbic Functioning During Threat-Related Attention: Relations to Early Behavioral Inhibition and Anxiety in Children 
Biological psychology  2015;122:98-109.
Children with behavioral inhibition (BI), a temperament characterized by biologically-based hyper-vigilance to novelty, display threat-related attention biases (AB) that shape developmental trajectories of risk for anxiety. Here we explore the relations between BI, neural function, and anxiety. Fifty-six 9–12-year-olds (23 behaviorally inhibited) performed the dot-probe task while undergoing fMRI. AB scores were not associated with BI group or parent-rated anxiety symptoms. Trials requiring attention orienting away from threat engaged an executive and threat-attention network (dlPFC, vlPFC, mPFC, and amygdala). Within that network, behaviorally inhibited children showed greater activation in the right dlPFC. Heightened dlPFC activation related to increased anxiety, and BI levels accounted for the direct relation between dlPFC activation and anxiety. Behaviorally inhibited children may engage the executive attention system during threat-related processing as a compensatory mechanism. We provide preliminary evidence that the link between PFC functioning and anxiety might be attributed to early-emerging temperamental vulnerabilities present before the emergence of clinical anxiety.
PMCID: PMC4779741  PMID: 26325222
attention bias; fMRI; anxiety; temperament; dorsolateral prefrontal cortex
4.  Net clinical benefits of guidelines and decision tool recommendations for oral anticoagulant use among patients with atrial fibrillation 
The 2012 CHEST, the 2012 European Society of Cardiology (ESC) and the 2014 American Heart Association guidelines and published decision tools by LaHaye and Casciano offer oral anticoagulant (OAC) recommendations for patients with atrial fibrillation (AF). The aim of our study was to compare the net clinical benefit (NCB) of OAC prescribing that was concordant with these decision aids.
A cohort study of the 2001–2013 Lifelink claims data was used. NCB of concordance with each decision aid was defined as adverse events (thromboembolic and major bleed events) prevented per 10,000 person-years. Cox proportional hazard models were used to assess the relative risk of AF adverse events associated with concordance with each decision aid adjusted for potential confounders.
The study included 15,129 AF patients, contributing 33,512 person-years. The NCB of the CHEST guidelines was the highest (NCB=30.07; 95%CI=28.66, 31.49) and the ESC guidelines the lowest (NCB=7.38; 95%CI=5.97, 8.80). Significant unadjusted decreases in the risk of AF adverse events associated with concordant OAC use/non-use were found for the CHEST guidelines (HR=0.825; 95%CI=0.695, 0.979), Casciano tool (HR=0.838; 95%CI=0.706, 0.995), and LaHaye tool (HR=0.841; 95%CI=0.709, 0.999), however none were significant after multivariate adjustment.
Concordant OAC use with any of the decision aids except the aggressive LaHaye tool led to a positive NCB. The decision aids based on CHA2DS2VASc algorithm did not consistently improve the NCB compared to CHADS2 based aids. Recommending OAC use when CHA2DS2−VASc=1 resulted in a lower NCB when all other factors guiding recommendations were held constant.
PMCID: PMC4688121  PMID: 26482369
Atrial fibrillation; guideline; decision tool; concordance; Net clinical benefit
5.  Residential Treatment Outcomes for Adolescents with Obsessive-Compulsive Disorder 
We examined outcomes from a residential treatment program emphasizing ERP to determine if the typically robust response to this treatment in outpatient settings extends to patients treated in this unique context.
172 adolescents with primary OCD completed measures at admission and discharge. Almost all (92.4%) participants had at least two diagnoses and nearly half (44.2%) had three or more. Treatment consisted of intensive ERP (i.e., approximately 26.5 hours per week), additional cognitive behavioral therapy interventions, and medication management within a residential setting. In contrast to the samples reported on in the vast majority of other pediatric OCD trials, participants in the current study were living apart from their families and were immersed within the treatment setting, with staff members available at all times.
Paired sample t-tests revealed significant decreases in OCD and depression severity.
Results suggest that residential treatment for adolescents with OCD using a multimodal approach emphasizing ERP can be effective for complex cases with significant comorbidity. Results were comparable with several randomized controlled trials.
PMCID: PMC4769131  PMID: 26308588
OCD; exposure therapy; cognitive behavior therapy; anxiety
6.  Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of renal cell carcinoma 
Immunotherapy has produced durable clinical benefit in patients with metastatic renal cell cancer (RCC). In the past, patients treated with interferon-alpha (IFN) and interleukin-2 (IL-2) have achieved complete responses, many of which have lasted for multiple decades. More recently, a large number of new agents have been approved for RCC, several of which attack tumor angiogenesis by inhibiting vascular endothelial growth factors (VEGF) and VEGF receptors (VEGFR), as well as tumor metabolism, inhibiting the mammalian target of rapamycin (mTOR). Additionally, a new class of immunotherapy agents, immune checkpoint inhibitors, is emerging and will play a significant role in the treatment of patients with RCC. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a Task Force, which met to consider the current role of approved immunotherapy agents in RCC, to provide guidance to practicing clinicians by developing consensus recommendations and to set the stage for future immunotherapeutic developments in RCC.
Electronic supplementary material
The online version of this article (doi:10.1186/s40425-016-0180-7) contains supplementary material, which is available to authorized users.
PMCID: PMC5109802  PMID: 27891227
Guidelines; Immunotherapy; Renal cell carcinoma; Treatment
7.  The Microbial Olympics 
Nature reviews. Microbiology  2012;10(8):583-588.
Every four years, the Olympic Games plays host to competitors who have built on their natural talent by training for many years to become the best in their chosen discipline. Similar spirit and endeavour can be found throughout the microbial world, in which every day is a competition to survive and thrive. Microorganisms are trained through evolution to become the fittest and the best adapted to a particular environmental niche or lifestyle, and to innovate when the ‘rules of the game’ are changed by alterations to their natural habitats. In this Essay, we honour the best competitors in the microbial world by inviting them to take part in the inaugural Microbial Olympics.
PMCID: PMC5108295  PMID: 22796885
8.  Domestication and the storage starch biosynthesis pathway: signatures of selection from a whole sorghum genome sequencing strategy 
Plant Biotechnology Journal  2016;14(12):2240-2253.
Next‐generation sequencing of complete genomes has given researchers unprecedented levels of information to study the multifaceted evolutionary changes that have shaped elite plant germplasm. In conjunction with population genetic analytical techniques and detailed online databases, we can more accurately capture the effects of domestication on entire biological pathways of agronomic importance. In this study, we explore the genetic diversity and signatures of selection in all predicted gene models of the storage starch synthesis pathway of Sorghum bicolor, utilizing a diversity panel containing lines categorized as either ‘Landraces’ or ‘Wild and Weedy’ genotypes. Amongst a total of 114 genes involved in starch synthesis, 71 had at least a single signal of purifying selection and 62 a signal of balancing selection and others a mix of both. This included key genes such as STARCH PHOSPHORYLASE 2 (SbPHO2, under balancing selection), PULLULANASE (SbPUL, under balancing selection) and ADP‐glucose pyrophosphorylases (SHRUNKEN2, SbSH2 under purifying selection). Effectively, many genes within the primary starch synthesis pathway had a clear reduction in nucleotide diversity between the Landraces and wild and weedy lines indicating that the ancestral effects of domestication are still clearly identifiable. There was evidence of the positional rate variation within the well‐characterized primary starch synthesis pathway of sorghum, particularly in the Landraces, whereby low evolutionary rates upstream and high rates downstream in the metabolic pathway were expected. This observation did not extend to the wild and weedy lines or the minor starch synthesis pathways.
PMCID: PMC5103234  PMID: 27155090
Sorghum (Sorghum bicolor); domestication; starch synthesis; whole‐genome sequencing; selection; metabolic pathway
9.  The STAMPEDE trial: paradigm-changing data through innovative trial design 
Translational cancer research  2016;5(3 Suppl):S485-S490.
Despite the numerous regulatory approvals for prostate cancer, metastatic prostate cancer remains a huge burden for men worldwide. In an exciting development, James et al. recently published data from the Systemic Therapy in Advanced or Metastatic Prostate Cancer: Evaluation of Drug Efficacy: a multi-stage multi-arm randomised control trial (STAMPEDE). This is an innovative multi-arm multi-stage (MAMS) trial that has utilized one control arm and several comparator arms in order to provide evidence for the inclusion of therapies beyond standard androgen deprivation alone. The patient population included: (I) men with high-risk, non-metastatic, node-negative disease; (II) men with distant-metastatic or node-positive disease; and (III) men with previously-treated prostate cancer by prostatectomy or definitive radiotherapy presenting with relapse. Men were to continue androgen deprivation for at least 2 years. The current data published by this group supports earlier results and provides additional evidence that docetaxel utilized in an up-front fashion provides a survival benefit in men with hormone-sensitive metastatic prostate cancer. Moreover, the initial results from STAMPEDE show how therapies without a demonstrated survival benefit can be efficiently excluded from further study once the likelihood of a benefit is ruled out by a predetermined analysis. In this piece, we will review the STAMPEDE data, contrast it with existing results, and provide our perspectives on how this will affect future trial conduct in the field of prostate cancer.
PMCID: PMC5058354  PMID: 27738594
Androgen deprivation; docetaxel; stampede; zoledronic acid
10.  Two heads better than one? Ipilimumab immunotherapy and radiation therapy for melanoma brain metastases 
Neuro-Oncology  2015;17(10):1312-1321.
Melanoma is an aggressive malignancy with a deplorable penchant for spreading to the brain. While focal therapies such as surgery and stereotactic radiosurgery can help provide local control, the majority of patients still develop intracranial progression. Novel therapeutic combinations to improve outcomes for melanoma brain metastases (MBM) are clearly needed. Ipilimumab, the anticytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, has been shown to improve survival in patients with metastatic melanoma, but many of these trials either excluded or had very few patients with MBM. This article will review the efficacy and limitations of ipilimumab therapy for MBM, describe the current evidence for combining ipilimumab with radiation therapy, illustrate potential mechanisms for synergy, and discuss emerging clinical trials specifically investigating this combination in MBM.
PMCID: PMC4578585  PMID: 26014049
Brain metastases; ipilimumab; melanoma; radiation
11.  A Frontal Dopamine System for Reflective Exploratory Behavior 
The COMT gene modulates dopamine levels in prefrontal cortex with Met allele carriers having lower COMT enzyme activity and, therefore, higher dopamine levels compared to Val/Val homozygotes. Concordantly, Val/Val homozygotes tend to perform worse and display increased (interpreted as inefficient) frontal activation in certain cognitive tasks. In a sample of 209 participants, we test the hypothesis that Met carriers will be advantaged in a decision-making task that demands sequencing exploratory and exploitive choices to minimize uncertainty about the reward structure in the environment. Previous work suggests that optimal performance depends on limited cognitive resources supported by prefrontal systems. If so, Met carriers should outperform Val/Val homozygotes, particularly under dual-task conditions that tax limited cognitive resources. In accord with these a priori predictions, Met carriers were more resilient in the face of cognitive load, continuing to explore in a sophisticated manner. We fit computational models that embody sophisticated reflective and simple reflexive strategies to further evaluate participants' exploration behavior. The Ideal Actor model reflectively updates beliefs and plans ahead, taking into account the information gained by each choice and making choices that maximize long-term payoffs. In contrast, the Naïve Reinforcement Learning (RL) model instantiates the reflexive account of choice, in which the values of actions are based only on the rewards experienced so far. Its beliefs are updated reflexively in response to observed changes in rewards. Converging with standard analyses, Met carriers were best characterized by the Ideal Actor model, whereas Val/Val homozygotes were best characterized by the Naive RL model, particularly under dual-task conditions.
PMCID: PMC4530051  PMID: 26004676
12.  Future Perspectives in Bladder Tissue Engineering 
Substantial clinical need persists for improved autologous tissues to augment or replace the urinary bladder and research has begun to address this using tissue engineering techniques. The implantation of both tissue scaffolds which allow for native bladder tissue ingrowth and autologous bladder grafts created from in vitro cellularization of such scaffolds have been tested clinically; however, successful outcomes in both scenarios have been challenged by insufficient vascularity resulting from large graft sizes, which subsequently limits tissue ingrowth and leads to central graft ischemia. Consequently, recent research has focused on developing better methods to produce scaffolds with increased tissue ingrowth and vascularity. This review provides an update on bladder tissue engineering and outlines the challenges that remain to clinical implementation.
PMCID: PMC4689598  PMID: 26709356
Urinary Bladder; Regenerative Urology; Tissue Engineering; Stem Cells; Autologous Graft
13.  Regional and seasonal variation in airborne grass pollen levels between cities of Australia and New Zealand 
Aerobiologia  2015;2015:1-14.
Although grass pollen is widely regarded as the major outdoor aeroallergen source in Australia and New Zealand (NZ), no assemblage of airborne pollen data for the region has been previously compiled. Grass pollen count data collected at 14 urban sites in Australia and NZ over periods ranging from 1 to 17 years were acquired, assembled and compared, revealing considerable spatiotemporal variability. Although direct comparison between these data is problematic due to methodological differences between monitoring sites, the following patterns are apparent. Grass pollen seasons tended to have more than one peak from tropics to latitudes of 37°S and single peaks at sites south of this latitude. A longer grass pollen season was therefore found at sites below 37°S, driven by later seasonal end dates for grass growth and flowering. Daily pollen counts increased with latitude; subtropical regions had seasons of both high intensity and long duration. At higher latitude sites, the single springtime grass pollen peak is potentially due to a cooler growing season and a predominance of pollen from C3 grasses. The multiple peaks at lower latitude sites may be due to a warmer season and the predominance of pollen from C4 grasses. Prevalence and duration of seasonal allergies may reflect the differing pollen seasons across Australia and NZ. It must be emphasized that these findings are tentative due to limitations in the available data, reinforcing the need to implement standardized pollen-monitoring methods across Australasia. Furthermore, spatiotemporal differences in grass pollen counts indicate that local, current, standardized pollen monitoring would assist with the management of pollen allergen exposure for patients at risk of allergic rhinitis and asthma.
PMCID: PMC4826055  PMID: 27069303
Aerobiology; Latitude; Grass pollen; Plant distribution; Australia; New Zealand
14.  General practitioner views on the determinants of test ordering: a theory-based qualitative approach to the development of an intervention to improve immunoglobulin requests in primary care 
Research suggests that variation in laboratory requesting patterns may indicate unnecessary test use. Requesting patterns for serum immunoglobulins vary significantly between general practitioners (GPs). This study aims to explore GP’s views on testing to identify the determinants of behaviour and recommend feasible intervention strategies for improving immunoglobulin test use in primary care.
Qualitative semi-structured interviews were conducted with GPs requesting laboratory tests at Cork University Hospital or University Hospital Kerry in the South of Ireland. GPs were identified using a Health Service Executive laboratory list of GPs in the Cork-Kerry region. A random sample of GPs (stratified by GP requesting patterns) was generated from this list. GPs were purposively sampled based on the criteria of location (urban/rural); length of time qualified; and practice size (single-handed/group). Interviews were carried out between December 2014 and February 2015. Interviews were transcribed verbatim using NVivo 10 software and analysed using the framework analysis method. Emerging themes were mapped to the theoretical domains framework (TDF), which outlines 12 domains that can enable or inhibit behaviour change. The behaviour change wheel and behaviour change technique (BCT) taxonomy were then used to identify potential intervention strategies.
Sixteen GPs were interviewed (ten males and six females). Findings suggest that intervention strategies should specifically target the key barriers to effective test ordering, while considering the context of primary care practice. Seven domains from the TDF were perceived to influence immunoglobulin test ordering behaviours and were identified as ‘mechanisms for change’ (knowledge, environmental context and resources, social/professional role and identity, beliefs about capabilities, beliefs about consequences, memory, attention and decision-making processes and behavioural regulation). Using these TDF domains, seven BCTs emerged as feasible ‘intervention content’ for targeting GPs’ ordering behaviour. These included instructions on how to effectively request the test (how to perform behaviour), information on GPs’ use of the test (feedback on behaviour), information about patient consequences resulting from not doing the test (information about health consequences), laboratory/consultant-based advice/education (credible source), altering the test ordering form (restructuring the physical environment), providing guidelines (prompts/cues) and adding interpretive comments to the results (adding objects to the environment). These BCTs aligned to four intervention functions: education, persuasion, environmental restructuring and enablement.
This study has effectively applied behaviour change theory to identify feasible strategies for improving immunoglobulin test use in primary care using the TDF, ‘behaviour change wheel’ and BCT taxonomy. The identified BCTs will form the basis of a theory-based intervention to improve the use of immunoglobulin tests among GPs. Future research will involve the development and evaluation of this intervention.
Electronic supplementary material
The online version of this article (doi:10.1186/s13012-016-0465-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4952272  PMID: 27435839
Laboratory testing; Primary care; Interventions; Theoretical domains framework; Behaviour change techniques; Behaviour change wheel
15.  Dugong dugon feeding in tropical Australian seagrass meadows: implications for conservation planning 
PeerJ  2016;4:e2194.
Dugongs (Dugong dugon) are listed as vulnerable to extinction due to rapid population reductions caused in part by loss of seagrass feeding meadows. Understanding dugong feeding behaviour in tropical Australia, where the majority of dugongs live, will assist conservation strategies. We examined whether feeding patterns in intertidal seagrass meadows in tropical north-eastern Australia were related to seagrass biomass, species composition and/or nitrogen content. The total biomass of each seagrass species removed by feeding dugongs was measured and compared to its relative availability. Nitrogen concentrations were also determined for each seagrass species present at the sites. Dugongs consumed seagrass species in proportion to their availability, with biomass being the primary determining factor. Species composition and/or nitrogen content influenced consumption to a lesser degree. Conservation plans focused on protecting high biomass intertidal seagrass meadows are likely to be most effective at ensuring the survival of dugong in tropical north-eastern Australia.
PMCID: PMC4941767  PMID: 27441123
Dugong dugon; Seagrass; Feeding behaviour; Coastal management; Conservation; Marine herbivore
16.  Agreements between Industry and Academia on Publication Rights: A Retrospective Study of Protocols and Publications of Randomized Clinical Trials 
PLoS Medicine  2016;13(6):e1002046.
Little is known about publication agreements between industry and academic investigators in trial protocols and the consistency of these agreements with corresponding statements in publications. We aimed to investigate (i) the existence and types of publication agreements in trial protocols, (ii) the completeness and consistency of the reporting of these agreements in subsequent publications, and (iii) the frequency of co-authorship by industry employees.
Methods and Findings
We used a retrospective cohort of randomized clinical trials (RCTs) based on archived protocols approved by six research ethics committees between 13 January 2000 and 25 November 2003. Only RCTs with industry involvement were eligible. We investigated the documentation of publication agreements in RCT protocols and statements in corresponding journal publications. Of 647 eligible RCT protocols, 456 (70.5%) mentioned an agreement regarding publication of results. Of these 456, 393 (86.2%) documented an industry partner’s right to disapprove or at least review proposed manuscripts; 39 (8.6%) agreements were without constraints of publication. The remaining 24 (5.3%) protocols referred to separate agreement documents not accessible to us. Of those 432 protocols with an accessible publication agreement, 268 (62.0%) trials were published. Most agreements documented in the protocol were not reported in the subsequent publication (197/268 [73.5%]). Of 71 agreements reported in publications, 52 (73.2%) were concordant with those documented in the protocol. In 14 of 37 (37.8%) publications in which statements suggested unrestricted publication rights, at least one co-author was an industry employee. In 25 protocol-publication pairs, author statements in publications suggested no constraints, but 18 corresponding protocols documented restricting agreements.
Publication agreements constraining academic authors’ independence are common. Journal articles seldom report on publication agreements, and, if they do, statements can be discrepant with the trial protocol.
In a document analysis of trial protocols and publications, Erik von Elm and colleagues investigate the potential impact of publication agreements between industry sponsors and academic investigators.
Author Summary
Why Was This Study Done?
Many randomized trials are designed and sponsored by for-profit companies that contract academic investigators to recruit and manage patients.
Clinical research under these circumstances is a business transaction that bears the potential for conflicts of interest, in particular with respect to trial publication.
Besides evidence from a small sample, it was unclear how often trial protocols included publication agreements between industry and academic investigators, whether these agreements constrained the investigators’ publication rights, and how consistent such agreements stated in trial protocols were with those reported in corresponding publications.
What Did the Researchers Do and Find?
We investigated publication agreements in 647 randomized trial protocols approved in 2000–2003 by six research ethics committees in Switzerland, Canada, and Germany, and in 388 corresponding journal publications.
Seventy percent of protocols mentioned an agreement on publication rights between industry and academic investigators; in 86% of those agreements, industry retained the right to disapprove or at least review manuscripts before publication.
Seventy-four percent of agreements documented in protocols were not mentioned in corresponding journal articles.
What Do These Findings Mean?
Publication agreements constraining academic investigators’ independence are incompletely reported in publications; this may compromise the scientific evidence base established by randomized clinical trials.
More transparency on publication constraints is warranted.
Half of the included journal articles were published before 2008, leaving open the possibility that these findings do not reflect current reporting practice.
PMCID: PMC4924795  PMID: 27352244
18.  The child brain computes and utilizes internalized maternal choices 
Nature Communications  2016;7:11700.
As children grow, they gradually learn how to make decisions independently. However, decisions like choosing healthy but less-tasty foods can be challenging for children whose self-regulation and executive cognitive functions are still maturing. We propose a computational decision-making process in which children estimate their mother's choices for them as well as their individual food preferences. By employing functional magnetic resonance imaging during real food choices, we find that the ventromedial prefrontal cortex (vmPFC) encodes children's own preferences and the left dorsolateral prefrontal cortex (dlPFC) encodes the projected mom's choices for them at the time of children's choice. Also, the left dlPFC region shows an inhibitory functional connectivity with the vmPFC at the time of children's own choice. Our study suggests that in part, children utilize their perceived caregiver's choices when making choices for themselves, which may serve as an external regulator of decision-making, leading to optimal healthy decisions.
Mothers advocate eating healthy foods while children like to eat tasty foods. Lim and colleagues demonstrate that children incorporate their mothers' food choices while deciding what to eat as well as provide the neural correlates of this decision making process.
PMCID: PMC4890300  PMID: 27218420
19.  Opioid Use in the Management of Diabetic Peripheral Neuropathy (DPN) in a Large Commercially Insured Population 
The Clinical journal of pain  2015;31(5):414-424.
To examine the proportion of diabetic peripheral neuropathy (DPN) patients receiving pharmacologic DPN treatments and specifically to identify the rates and factors associated with opioid use and first line opioid use.
A 10% sample of IMS-LifeLink claims data from 1998 through 2008 was used. The study population consisted of diabetic patients who met DPN criteria using a validated DPN algorithm. Multivariable logistic regression controlling for demographics, comorbidities, and other clinical characteristics was used to identify factors associated with any DPN pharmacologic treatment, any opioid use, and first-line opioid treatment. Sensitivity analyses were conducted to explore variations in exclusion criteria as well as opioid use definitions.
666 DPN patients met inclusion criteria and pharmacologic treatment was received by 288 subjects (43.24%) and of those, 154 (53.47%) had DPN related opioid use and 96 (33.33%) received opioid as first line treatment. Persons with diabetic complications were more likely to use opioids (OR=4.53, 95% CI=1.09-18.92). FDA approved DPN agents duloxetine 1.04% (n=3) and pregabalin 5.56% (n=16) had much lower rates of use. DPN related drug use and DPN related opioid usage increased as we used less restrictive samples in sensitivity analyses.
Opioids were the most frequently prescribed first line agents for DPN. More than 50 % of DPN patients remained untreated with pharmacologic agents one year after a DPN diagnosis.
PMCID: PMC4391274  PMID: 25853725
DPN=Diabetic peripheral neuropathy; NCPCs=Non-cancer pain conditions; NSAIDs=Non-steroidal anti-inflammatory drugs; Opioids
20.  A neuropsychological investigation of decisional certainty 
Neuropsychologia  2015;70:206-213.
The certainty that one feels following a decision increases decision-making efficiency, but can also result in decreased decision accuracy. In the current study, a neuropsychological approach was used to examine the impact of damage to the ventromedial prefrontal cortex (vmPFC) on core psychological processes promoting decision certainty: selective exposure, overconfidence, and decisiveness. Given previous research demonstrating that vmPFC damage disrupts the generation of negative emotional (somatic) states that have been associated with selective exposure and overconfidence, it was hypothesized that damage to the vmPFC would disrupt engagement in selective exposure, decrease overconfidence, and increase indecision. Individuals with vmPFC damage exhibited increased indecision, but contrary to our hypothesis, engaged in similar levels of selective exposure and overconfidence as the comparison groups. These results indicate that indecision may be an important psychological mechanism involved in decision-making impairments associated with vmPFC injury. The results also suggest that the vmPFC may not be critical for selective exposure or overconfidence, which provides support for a recent “desirability” account of selective exposure.
PMCID: PMC4784716  PMID: 25725416
selective exposure; information seeking; overconfidence; decisiveness; ventromedial prefrontal cortex; brain damage
21.  Effective Connectivity from Early Visual Cortex to Posterior Occipitotemporal Face Areas Supports Face Selectivity and Predicts Developmental Prosopagnosia 
The Journal of Neuroscience  2016;36(13):3821-3828.
Face processing is mediated by interactions between functional areas in the occipital and temporal lobe, and the fusiform face area (FFA) and anterior temporal lobe play key roles in the recognition of facial identity. Individuals with developmental prosopagnosia (DP), a lifelong face recognition impairment, have been shown to have structural and functional neuronal alterations in these areas. The present study investigated how face selectivity is generated in participants with normal face processing, and how functional abnormalities associated with DP, arise as a function of network connectivity. Using functional magnetic resonance imaging and dynamic causal modeling, we examined effective connectivity in normal participants by assessing network models that include early visual cortex (EVC) and face-selective areas and then investigated the integrity of this connectivity in participants with DP. Results showed that a feedforward architecture from EVC to the occipital face area, EVC to FFA, and EVC to posterior superior temporal sulcus (pSTS) best explained how face selectivity arises in both controls and participants with DP. In this architecture, the DP group showed reduced connection strengths on feedforward connections carrying face information from EVC to FFA and EVC to pSTS. These altered network dynamics in DP contribute to the diminished face selectivity in the posterior occipitotemporal areas affected in DP. These findings suggest a novel view on the relevance of feedforward projection from EVC to posterior occipitotemporal face areas in generating cortical face selectivity and differences in face recognition ability.
SIGNIFICANCE STATEMENT Areas of the human brain showing enhanced activation to faces compared to other objects or places have been extensively studied. However, the factors leading to this face selectively have remained mostly unknown. We show that effective connectivity from early visual cortex to posterior occipitotemporal face areas gives rise to face selectivity. Furthermore, people with developmental prosopagnosia, a lifelong face recognition impairment, have reduced face selectivity in the posterior occipitotemporal face areas and left anterior temporal lobe. We show that this reduced face selectivity can be predicted by effective connectivity from early visual cortex to posterior occipitotemporal face areas. This study presents the first network-based account of how face selectivity arises in the human brain.
PMCID: PMC4812138  PMID: 27030766
DCM; developmental prosopagnosia; effective connectivity; face perception; fMRI; network
22.  Multiple Mini-Interview Performance Predicts Academic Difficulty in the PharmD Curriculum 
Objective. To identify admissions variable prognostics for academic difficulty in the PharmD curriculum to use for admissions determinations and early identification of at-risk students.
Methods. Retrospective multivariate analysis of 2008-2012 admission data were linked with academic records to identify students with academic difficulty (ie, those with Ds, Fs, delayed progression). The influence of prepharmacy grade point average (GPA), composite Pharmacy College Admission Test (PCAT) score, multiple-mini interview (MMI) score, age, credit hours, state residence, and prior degree on academic difficulty was estimated using multivariate logistic regression.
Results. Students’ (n=587) prepharmacy GPA, composite PCAT score, mean MMI score, and age were 3.6, 72.0, 5.5, 22.8 (SD=4.14 years), respectively. Students having a GPA <3.25, PCAT score <60th percentile, or MMI score <4.5, were approximately 12-, 7-, and 3-times more likely, respectively, to experience academic difficulty than those with a GPA ≥ 3.75, PCAT score >90, or MMI score of 5-6.
Conclusion. Using GPA, PCAT, and MMI performance can predict academic difficulty and assist in the early identification of academically at-risk PharmD students.
PMCID: PMC4827578  PMID: 27073280
multiple mini-interview; MMI; academic difficulty; interview; predict
23.  Visualization of Bacterial Microcompartment Facet Assembly Using High-Speed Atomic Force Microscopy 
Nano Letters  2015;16(3):1590-1595.
Bacterial microcompartments (BMCs) are proteinaceous organelles widespread among bacterial phyla. They compartmentalize enzymes within a selectively permeable shell and play important roles in CO2 fixation, pathogenesis, and microbial ecology. Here, we combine X-ray crystallography and high-speed atomic force microscopy to characterize, at molecular resolution, the structure and dynamics of BMC shell facet assembly. Our results show that preformed hexamers assemble into uniformly oriented shell layers, a single hexamer thick. We also observe the dynamic process of shell facet assembly. Shell hexamers can dissociate from and incorporate into assembled sheets, indicating a flexible intermolecular interaction. Furthermore, we demonstrate that the self-assembly and dynamics of shell proteins are governed by specific contacts at the interfaces of shell proteins. Our study provides novel insights into the formation, interactions, and dynamics of BMC shell facets, which are essential for the design and engineering of self-assembled biological nanoreactors and scaffolds based on BMC architectures.
PMCID: PMC4789755  PMID: 26617073
Bacterial microcompartment; high-speed atomic force microscopy; protein dynamics; protein interaction; self-assembly
24.  Exploratory Decision-Making as a Function of Lifelong Experience, not Cognitive Decline 
Older adults perform worse than younger adults in some complex decision-making scenarios, which is commonly attributed to age-related declines in striatal and frontostriatal processing. Recently, this popular account has been challenged by work that considers how older adults’ performance may differ as a function of greater knowledge and experience, and by work showing that in some cases older adults out-perform younger adults in complex decision-making tasks. In light of this controversy, we examined the performance of older and younger adults in an exploratory choice task that is amendable to model-based analyses and ostensibly not reliant on prior knowledge. Exploration is a critical aspect of decision-making poorly understood across the lifespan. Across two experiments we address 1) how older and younger adults differ in exploratory choice, and 2) to what extent observed differences reflect processing capacity declines. Model-based analyses suggest that the strategies used by the two groups were qualitatively different, resulting in relatively worse performance for older adults in one decision-making environment but equal performance in another. Little evidence was found that differences in processing capacity drove performance differences. Rather the results suggest that older adults’ performance might result from applying a strategy that may have been shaped by their wealth of real-word decision-making experience. While this strategy is likely to be effective in the real world, it is ill suited to some decision environments. These results underscore the importance of taking into account effects of experience in aging studies, even for tasks that do not obviously tap past experiences.
PMCID: PMC4755819  PMID: 26726916
25.  Avoiding Opioids and Their Harmful Side Effects in the Postoperative Patient: Exogenous Opioids, Endogenous Endorphins, Wellness, Mood, and Their Relation to Postoperative Pain 
Prescribed opioids are routinely used for many postoperative patients. However, these medications have daunting adverse effects on the body's innate pain management system - the action of the beta-endorphins. The prescribed opioids not only severely impair the function of the mu-opioid receptors, but also inhibit the release of beta-endorphin. This is unfortunate, because beta-endorphin appears to be a much more potent agonist of the mu-opioid receptor than opioids. In addition, beta-endorphin indirectly elevates dopamine, a neurotransmitter related to feelings of euphoria. Therefore, by prescribing opioids, practitioners may inadvertently prolong and increase the overall intensity of the postoperative patients' pain as well as herald anhedonia. This article highlights the relationships between prescribed (exogenous) opioids, beta-endorphins, mu-opioid receptors, wellness, mood, and postoperative pain. The role of patient education, opioid alternatives, and additional recommendations regarding pain control in the postoperative patient are also discussed.
PMCID: PMC4795331  PMID: 27011886
beta-endorphin; opioid; non-opioid; postoperative pain; mu-opioid; wellness

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