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1.  Confidence—More a Personality or Ability Trait? It Depends on How It Is Measured: A Comparison of Young and Older Adults 
The current study (N = 244) compared two independently developed and substantively different measures of self-confidence; a self-report measure, and a measure described as “online.” Online measures are confidence-accuracy judgments made following each item on a cognitive task; in the current study, online measures were yoked to tasks of fluid and crystallized intelligence. The self-report and online measures had not previously been compared, and it was unknown if they captured the same self-confidence construct. These measures were also compared to self-efficacy and personality for the purpose of defining self-confidence as an independent construct, as well as to clarify the primary comparison. This study also aimed to replicate previous findings of a stable factor of confidence derived from online measures. An age comparison was made between a young adult sample (30 years and under) and an older adult sample (65 years and over) to determine how confidence functions across the lifespan. The primary finding was that self-report and online measures of confidence define two different but modestly correlated factors. Moreover, the self-report measures sit closer to personality, and the online measures sit closer to ability. While online measures of confidence were distinct from self-efficacy and personality, self-report measures were very closely related to the personality trait Emotional Stability. A general confidence factor—derived from online measures—was identified, and importantly was found in not just young adults but also in older adults. In terms of the age comparison, older adults had higher self-report self-confidence, and tended to be more overconfident in their judgments for online measures; however this overconfidence was more striking in the online measures attached to fluid ability than to crystallized ability.
doi:10.3389/fpsyg.2016.00518
PMCID: PMC4834661  PMID: 27148126
confidence; self-confidence; metacognition; calibration; older-adults
2.  Chamber identity programs drive early functional partitioning of the heart 
Nature Communications  2015;6:8146.
The vertebrate heart muscle (myocardium) develops from the first heart field (FHF) and expands by adding second heart field (SHF) cells. While both lineages exist already in teleosts, the primordial contributions of FHF and SHF to heart structure and function remain incompletely understood. Here we delineate the functional contribution of the FHF and SHF to the zebrafish heart using the cis-regulatory elements of the draculin (drl) gene. The drl reporters initially delineate the lateral plate mesoderm, including heart progenitors. Subsequent myocardial drl reporter expression restricts to FHF descendants. We harnessed this unique feature to uncover that loss of tbx5a and pitx2 affect relative FHF versus SHF contributions to the heart. High-resolution physiology reveals distinctive electrical properties of each heart field territory that define a functional boundary within the single zebrafish ventricle. Our data establish that the transcriptional program driving cardiac septation regulates physiologic ventricle partitioning, which successively provides mechanical advantages of sequential contraction.
The heart forms from combining the first with the second heart field, which in mammals creates left and right ventricle. Here transgenic zebrafish and physiology studies reveal that transcription factors controlling septation in mammals already in teleosts guide muscle coupling by controlling the relative contribution of the two fields to the heart.
doi:10.1038/ncomms9146
PMCID: PMC4560818  PMID: 26306682
3.  Tbx1 is required for second heart field proliferation in zebrafish 
Background
The mammalian outflow tract (OFT) and primitive right ventricle arise by accretion of newly differentiated cells to the arterial pole of the heart tube from multi-potent progenitor cells of the second heart field (SHF). While mounting evidence suggests that the genetic pathways regulating SHF development are highly conserved in zebrafish, this topic remains an active area of investigation.
Results
Here, we extend previous observations demonstrating that zebrafish tbx1 (van gogh, vgo) mutants show conotruncal defects consistent with a conserved role in SHF-mediated cardiogenesis. Surprisingly, we reveal through double in situ analyses that tbx1 transcripts are excluded from cardiac progenitor cells or differentiated cardiomyocytes, suggesting a non-autonomous role in SHF development. Further, we find that the diminuitive ventricle in vgo animals results from a 25% decrease in cardiomyocyte numbers that occurs subseqent to heart tube stages. Lastly, we report that although SHF progenitors are specified in the absence of Tbx1, they fail to be maintained due to compromised SHF progenitor cell proliferation.
Conclusion
These studies highlight conservation of the Tbx1 program in zebrafish SHF biology.
doi:10.1002/dvdy.23928
PMCID: PMC3676967  PMID: 23335360
tbx1; zebrafish; heart; second heart field; cardiac
4.  Heart field origin of great vessel precursors relies on nkx2.5-mediated vasculogenesis 
Nature cell biology  2013;15(11):10.1038/ncb2862.
The pharyngeal arch arteries (PAAs) are transient embryonic blood vessels that make indispensable contributions to the carotid arteries and great vessels of the heart, including the aorta and pulmonary artery1, 2. During embryogenesis, the PAAs appear in a craniocaudal sequence to connect pre-existing segments of the primitive circulation after de novo vasculogenic assembly from angioblast precursors3, 4. Despite the unique spatiotemporal characteristics of PAA development, the embryonic origins of PAA angioblasts and the genetic factors regulating their emergence remain unknown. Here, we identify the embryonic source of PAA endothelium as nkx2.5+ progenitors in lateral plate mesoderm long considered to adopt cell fates within the heart exclusively5, 6. Further, we report that PAA endothelial differentiation relies on Nkx2.5, a canonical cardiac transcription factor not previously implicated in blood vessel formation. Together, these studies reveal the heart field origin of PAA endothelium and attribute a novel vasculogenic function to the cardiac transcription factor nkx2.5 during great vessel precursor development.
doi:10.1038/ncb2862
PMCID: PMC3864813  PMID: 24161929
5.  Latent TGFβ binding protein 3 identifies a second heart field in zebrafish 
Nature  2011;474(7353):645-648.
The four-chambered mammalian heart develops from two fields of cardiac progenitor cells (CPCs) distinguished by their spatiotemporal patterns of differentiation and contributions to the definitive heart [1–3]. The first heart field differentiates earlier in lateral plate mesoderm, generates the linear heart tube and ultimately gives rise to the left ventricle. The second heart field (SHF) differentiates later in pharyngeal mesoderm, elongates the heart tube, and gives rise to the outflow tract (OFT) and much of the right ventricle. Because hearts in lower vertebrates contain a rudimentary OFT but not a right ventricle [4], the existence and function of SHF-like cells in these species has remained a topic of speculation [4–10]. Here we provide direct evidence from Cre/Lox-mediated lineage tracing and loss of function studies in zebrafish, a lower vertebrate with a single ventricle, that latent-TGFβ binding protein 3 (ltbp3) transcripts mark a field of CPCs with defining characteristics of the anterior SHF in mammals. Specifically, ltbp3+ cells differentiate in pharyngeal mesoderm after formation of the heart tube, elongate the heart tube at the outflow pole, and give rise to three cardiovascular lineages in the OFT and myocardium in the distal ventricle. In addition to expressing Ltbp3, a protein that regulates the bioavailability of TGFβ ligands [11], zebrafish SHF cells co-express nkx2.5, an evolutionarily conserved marker of CPCs in both fields [4]. Embryos devoid of ltbp3 lack the same cardiac structures derived from ltbp3+ cells due to compromised progenitor proliferation. Additionally, small-molecule inhibition of TGFβ signaling phenocopies the ltbp3-morphant phenotype whereas expression of a constitutively active TGFβ type I receptor rescues it. Taken together, our findings uncover a requirement for ltbp3-TGFβ signaling during zebrafish SHF development, a process that serves to enlarge the single ventricular chamber in this species.
doi:10.1038/nature10094
PMCID: PMC3319150  PMID: 21623370
6.  Gene mutations and increased levels of p53 protein in human squamous cell carcinomas and their cell lines. 
British Journal of Cancer  1993;67(6):1274-1284.
Using immunocytochemical and Western blotting techniques we have demonstrated the presence of abnormally high levels of p53 protein in 8/24 (33%) of human squamous cell carcinomas (SCC) and 9/18 (50%) of SCC cell lines. There was a correlation between the immunocytochemical results obtained with eight SCC samples and their corresponding cell lines. Direct sequencing of PCR-amplified, reverse transcribed, p53 mRNA confirmed the expression of point mutations in six of the positive cell lines and detected in-frame deletions in two others. We also detected two stop mutations and three out-of-frame deletions in five lines which did not express elevated levels of p53 protein. Several of the mutations found in SCC of the tongue (3/7) were in a region (codons 144-166) previously identified as being a p53 mutational hot spot in non-small cell lung tumours (Mitsudomi et al., 1992). In 11/13 cases only the mutant alleles were expressed suggesting loss or reduced expression of the wild type alleles in these cases. Six of the mutations were also detected in the SCCs from which the lines were derived, strongly suggesting that the mutations occurred, and were selected, in vivo. The 12th mutation GTG-->GGG (valine-->glycine) at codon 216 was expressed in line SCC-12 clone B along with an apparently normal p53 allele and is to our knowledge a novel mutation. Line BICR-19 also expressed a normal p53 allele in addition to one where exon 10 was deleted. Additionally 15 of the SCC lines (including all of those which did not show elevated p53 protein levels) were screened for the presence of human papillomavirus types 16 and 18 and were found to be negative. These results are discussed in relation to the pathogenesis of SCC and the immortalisation of human keratinocytes in vitro.
Images
PMCID: PMC1968513  PMID: 8390283
9.  Speeding rod recovery improves temporal resolution in the retina 
Vision research  2015;110(0 0):57-67.
The temporal resolution of the visual system progressively increases with light intensity. Under scotopic conditions, temporal resolution is relatively poor, and may be limited by both retinal and cortical processes. Rod photoresponses themselves are quite slow because of the slowly deactivating biochemical cascade needed for light transduction. Here, we have used a transgenic mouse line with faster than normal rod phototransduction deactivation (RGS9-overexpressors) to test whether rod signaling to second-order retinal neurons is rate-limited by phototransduction or by other mechanisms. We compared electrical responses of individual wild-type and RGS9-overexpressing (RGS9-ox) rods to steady illumination and found that RGS9-ox rods required 2-fold brighter light for comparable activation, owing to faster G-protein deactivation. When presented with flickering stimuli, RGS9-ox rods showed greater magnitude fluctuations around a given steady-state current amplitude. Likewise, in vivo electroretinography (ERG) and whole-cell recording from OFF-bipolar, rod bipolar, and horizontal cells of RGS9-ox mice displayed larger than normal magnitude flicker responses, demonstrating an improved ability to transmit frequency information across the rod synapse. Slow phototransduction recovery therefore limits synaptic transmission of increments and decrements of light intensity across the first retinal synapse in normal retinas, apparently sacrificing temporal responsiveness for greater overall sensitivity in ambient light.
doi:10.1016/j.visres.2015.02.011
PMCID: PMC4410083  PMID: 25748270
retina; vision; bipolar; RGS9; rod; flicker
10.  Validation of the Neuro-QoL Measurement System in Children with Epilepsy 
Epilepsy & behavior : E&B  2015;46:209-214.
OBJECTIVE
Children with epilepsy often face complex psychosocial consequences that are not fully captured by existing patient-reported outcome (PRO) measures. The Neurology Quality of Life Measurement System “Neuro-QoL” was developed to provide a set of common PRO measures that address issues important to people with neurologic disorders. This paper reports Neuro-QoL (Anxiety, Depression, Interaction with peers, Fatigue, Pain, Cognition, Stigma, and Upper and Lower Extremity Function) validation in children with epilepsy.
METHOD
Patients (aged 10–18 years) diagnosed with epilepsy completed Neuro-QoL and legacy measures at time-1 and 6-month follow-up. Internal consistency reliability was also evaluated. Concurrent validity was assessed by comparing Neuro-QoL measures with more established “legacy” measures of the same concepts. Clinical validity was evaluated by comparing mean Neuro-QoL scores of patients grouped by clinical anchors such as disease severity. Responsiveness of the Neuro-QoL from time-1 to 6-month was evaluated using self-reported change as the primary anchor.
RESULTS
61 patients (mean age=13.4 years; 62.3% male, 75.9% white) participated. Most patients (64.2%) had been seizure free in the 3 months prior to participation, and seizure frequency was otherwise described as follows: 17.8% daily, 13.3% weekly, 35.6% monthly and 33.3% yearly. All patients were taking anti-epileptic drugs. Patients reported better function/less symptoms compared to the reference groups. Internal consistency (alpha) coefficients ranged from 0.76 – 0.87. Patients with different seizure frequency differed on Anxiety (p<.01) and Cognition (p<.05). Compared to patients on polytherapy, those on monotherapy had better Upper Extremity scores (p<.05). Compared to those with localized seizures, those experiencing generalized seizures reported worse stigma (p<.05). Depression, Anxiety, Lower Extremity, Fatigue, Pain, Interaction with peers, and Stigma also significantly discriminated patients with different levels of quality of life, p<=.05. All Neuro-QoL measures were significantly correlated with other measures assessing similar domains. Stigma was related to self-reported change in several areas of functioning, but in sometimes unexpected directions.
SIGNIFICANCE
Neuro-QoL is a valid and reliable assessment tool for children with epilepsy and can be used in research and clinical settings.
doi:10.1016/j.yebeh.2015.02.038
PMCID: PMC4458416  PMID: 25862469
Epilepsy; Neuro-QoL; Quality of Life; Children; Measurement
11.  Aging-like Changes in the Transcriptome of Irradiated Microglia 
Glia  2015;63(5):754-767.
Whole brain irradiation remains important in the management of brain tumors. Although necessary for improving survival outcomes, cranial irradiation also results in cognitive decline in long-term survivors. A chronic inflammatory state characterized by microglial activation has been implicated in radiation-induced brain injury. We here provide the first comprehensive transcriptional profile of irradiated microglia. Fluorescence-activated cell sorting (FACS) was used to isolate CD11b+ microglia from the hippocampi of C57BL/6 and Balb/c mice 1 month after 10Gy cranial irradiation. Affymetrix gene expression profiles were evaluated using linear modeling, rank product analyses. One month after irradiation, a conserved irradiation signature across strains was identified, comprising 448 and 85 differentially up- and down-regulated genes, respectively. Gene set enrichment analysis (GSEA) demonstrated enrichment for inflammation, including M1 macrophage-associated genes, but also an unexpected enrichment for extracellular matrix and blood coagulation-related gene sets, in contrast previously described microglial states. Weighted gene co-expression network analysis (WGCNA) confirmed these findings and further revealed alterations in mitochondrial function. The RNA-seq transcriptome of microglia 24h post-radiation proved similar to the 1-month transcriptome, but additionally featured alterations in apoptotic and lysosomal gene expression. Re-analysis of published aging mouse microglia transcriptome data demonstrated striking similarity to the 1 month irradiated microglia transcriptome, suggesting that shared mechanisms may underlie aging and chronic irradiation-induced cognitive decline.
doi:10.1002/glia.22782
PMCID: PMC4625786  PMID: 25690519
brain radiation; inflammation; hippocampus; extracellular matrix; aging
12.  Novel data-mining approach identifies biomarkers for diagnosis of Kawasaki disease 
Pediatric research  2015;78(5):547-553.
Background
As Kawasaki disease (KD) shares many clinical features with other more common febrile illnesses and misdiagnosis, leading to a delay in treatment, increases the risk of coronary artery damage, a diagnostic test for KD is urgently needed. We sought to develop a panel of biomarkers that could distinguish between acute KD patients and febrile controls (FC) with sufficient accuracy to be clinically useful.
Methods
Plasma samples were collected from three independent cohorts of FC and acute KD patients who met the American Heart Association definition for KD and presented within the first 10 days of fever. The levels of 88 biomarkers associated with inflammation were assessed by Luminex bead technology. Unsupervised clustering followed by supervised clustering using a Random Forest model was used to find a panel of candidate biomarkers.
Results
A panel of biomarkers commonly available in the hospital laboratory (absolute neutrophil count, erythrocyte sedimentation rate, alanine aminotransferase, gamma glutamyl transferase, concentrations of alpha-1-antitrypsin, C-reactive protein, and fibrinogen, and platelet count) accurately diagnosed 81 to 96% of KD patients in a series of three independent cohorts.
Conclusions
After prospective validation, this 8-biomarker panel may improve the recognition of KD.
doi:10.1038/pr.2015.137
PMCID: PMC4628575  PMID: 26237629
13.  Noninvasive ventilation practice patterns for acute respiratory failure in Canadian tertiary care centres: A descriptive analysis 
Given the similar physiological benefits and its practical advantages over mechanical invasive ventilation, noninvasive ventilation (NIV) has increasingly been implemented and used in a wide variety of clinical and health care settings worldwide. However, a recent Canadian guideline highlighted the varying strength of evidence to support to the use of NIV and, furthermore, that firm guidelines for NIV could not be proposed for selected patient groups. Accordingly, this multicentre, prospective study evaluated NIV utilization and practice variation in participating Canadian tertiary care centres.
BACKGROUND:
The extent of noninvasive ventilation (NIV) use for patients with acute respiratory failure in Canadian hospitals, indications for use and associated outcomes are unknown.
OBJECTIVE:
To describe NIV practice variation in the acute setting.
METHODS:
A prospective observational study involving 11 Canadian tertiary care centres was performed. Data regarding NIV indication, mode and outcomes were collected for all adults (>16 years of age) treated with NIV for acute respiratory failure during a four-week period (between February and August 2011). Logistic regression with site as a random effect was used to examine the association between preselected predictors and mortality or intubation.
RESULTS:
A total of 330 patients (mean [± SD] 30±12 per centre) were included. The most common indications for NIV initiation were pulmonary edema (104 [31.5%]) and chronic obstructive pulmonary disease (99 [30.0%]). Significant differences in indications for NIV use across sites, specialty of ordering physician and location of NIV initiation were noted. Although intubation rates were not statistically different among sites (range 10.3% to 45.4%), mortality varied significantly (range 6.7% to 54.5%; P=0.006). In multivariate analysis, the most significant independent predictor of avoiding intubation was do-not-resuscitate status (OR 0.11 [95% CI 0.03 to 0.37]).
CONCLUSION:
Significant variability existed in NIV use and associated outcomes among Canadian tertiary care centres. Assignment of do-not-resuscitate status prevented intubation.
PMCID: PMC4676396  PMID: 26469155
Acute respiratory failure; Noninvasive ventilation; Practice variation
14.  Fine specificities of natural regulatory T cells after IVIG therapy in patients with Kawasaki disease 
Autoimmunity  2015;48(3):181-188.
The activation of natural regulatory T cells (nTreg) recognizing the heavy constant region (Fc) of IgG is an important mechanism of action of intravenous immunoglobulin (IVIG) therapy in Kawasaki disease (KD). Lack of circulating Fc-specific nTreg in the sub-acute phase of KD is correlated with the development of coronary artery abnormalities (CAA). Here, we characterize the fine specificity of nTreg in sub-acute (2- to 8-week post-IVIG) and convalescent (1- to 10-year post-IVIG) KD subjects by testing the immunogenicity of 64 peptides, 15 amino acids in length with a 10 amino acid-overlap spanning the entire Fc protein. About 12 Fc peptides (6 pools of 2 consecutive peptides) were recognized by nTreg in the cohorts studied, including two patients with CAA. To test whether IVIG expands the same nTreg populations that maintain vascular homeostasis in healthy subjects, we compared these results with results obtained in healthy adult controls. Similar nTreg fine specificities were observed in KD patients after IVIG and in healthy donors. These results suggest that T cell fitness rather than T cell clonal deletion or anergy is responsible for the lack of Fc-specific nTreg in KD patients who develop CAA. Furthermore, we found that adolescents and adults who had KD during childhood without developing CAA did not respond to the Fc protein in vitro, suggesting that the nTreg response induced by IVIG in KD patients is short-lived. Our results support the concept that peptide epitopes may be a viable therapeutic approach to expand Fc-specific nTreg and more effectively prevent CAA in KD patients.
doi:10.3109/08916934.2015.1027817
PMCID: PMC4784966  PMID: 25822882
Immunotherapy; immune-regulation; IVIG; Kawasaki disease; natural Treg
15.  Personalizing Therapy in Advanced Non–Small Cell Lung Cancer 
The recognition that non–small cell lung cancer (NSCLC) is not a single disease entity, but rather a collection of distinct molecularly driven neoplasms, has permanently shifted the therapeutic landscape of NSCLC to a personalized approach. This personalization of NSCLC therapy is typified by the dramatic response rates seen in EGFR mutant NSCLC when treated with targeted tyrosine kinase inhibitor therapy and in ALK translocation–driven NSCLC when treated with ALK inhibitors. Targeted therapeutic approaches in NSCLC necessitate consideration of more invasive biopsy techniques aimed at providing sufficient tissue for both histological determination and molecular profiling in all patients with stage IV disease both at the time of diagnosis and at the time of disease progression. Comprehensive genotyping efforts have identified oncogenic drivers in 62% lung adenocarcinomas and an increasing proportion of squamous cell carcinomas of the lung. The identification of these oncogenic drivers and the triage of patients to clinical trials evaluating novel targeted therapeutic approaches will increasingly mold a landscape of personalized lung cancer therapy where each genotype has an associated targeted therapy. This review outlines the state of personalized lung cancer therapy as it pertains to individual NSCLC genotypes.
doi:10.1055/s-0033-1358552
PMCID: PMC4836173  PMID: 24258572
non–small cell lung cancer; personalized therapy; oncogenic driver mutations
16.  Expanding substance use treatment options for HIV prevention with Buprenorphine-Naloxone: HIV Prevention Trials Network 058 (HPTN 058) 
Background
Injection opioid use plays a significant role in the transmission of HIV infection in many communities and several regions of the world. Access to evidence-based treatments for opioid use disorders is extremely limited.
Methods
HPTN 058 was a randomized controlled trial designed to compare the impact of two medication assisted treatment (MAT) strategies on HIV incidence or death among opioid dependent people who inject drugs (PWID). HIV-negative opiate dependent PWID were recruited from four communities in Thailand and China with historically high prevalence of HIV among PWID. 1251 participants were randomly assigned to either; 1) a one year intervention consisting of two opportunities for a 15 day detoxification with buprenorphine/naloxone (BUP/NX) combined with up to 21 sessions of behavioral drug and risk counseling (Short Term Medication Assisted Treatment: ST-MAT) or, 2) thrice weekly dosing for 48 weeks with BUP/NX and up to 21 counseling sessions (Long Term Medication Assisted Treatment: LT-MAT) followed by dose tapering. All participants were followed for 52 weeks after treatment completion to assess durability of impact.
Results
While the study was stopped early due to lower than expected occurrence of the primary endpoints, sufficient data were available to assess the impact of the interventions on drug use and injection related risk behavior. At weeks 26, 22% of ST-MAT participants had negative urinalyses for opioids compared to 57% in the LT-MAT (p<0.001). Differences disappeared in the year following treatment: at week 78, 35% in ST-MAT and 32% in the LT-MAT had negative urinalyses. Injection related risk behaviors were significantly reduced in both groups following randomization.
Conclusions
Participants receiving BUP/NX three times weekly were more likely to reduce opioid injection while on active treatment. Both treatment strategies were considered safe and associated with reductions in injection related risk behavior. These data support the use of thrice weekly BUP/NX as a way to reduce exposure to HIV risk. Continued access to BUP/NX may be required to sustain reductions in opioid use.
doi:10.1097/QAI.0000000000000510
PMCID: PMC4382671  PMID: 25564105
18.  Pain Psychology: A Global Needs Assessment and National Call to Action 
Pain medicine (Malden, Mass.)  2016;17(2):250-263.
Objective
The Institute of Medicine and the draft National Pain Strategy recently called for better training for health care clinicians. This was the first high-level needs assessment for pain psychology services and resources in the United States.
Design
Prospective, observational, cross-sectional.
Methods
Brief surveys were administered online to six stakeholder groups (psychologists/therapists, individuals with chronic pain, pain physicians, primary care physicians/physician assistants, nurse practitioners, and the directors of graduate and postgraduate psychology training programs).
Results
1,991 responses were received. Results revealed low confidence and low perceived competency to address physical pain among psychologists/therapists, and high levels of interest and need for pain education. We found broad support for pain psychology across stakeholder groups, and global support for a national initiative to increase pain training and competency in U.S. therapists. Among directors of graduate and postgraduate psychology training programs, we found unanimous interest for a no-cost pain psychology curriculum that could be integrated into existing programs. Primary barriers to pain psychology include lack of a system to identify qualified therapists, paucity of therapists with pain training, limited awareness of the psychological treatment modality, and poor insurance coverage.
Conclusions
This report calls for transformation within psychology predoctoral and postdoctoral education and training and psychology continuing education to include and emphasize pain and pain management. A system for certification is needed to facilitate quality control and appropriate reimbursement. There is a need for systems to facilitate identification and access to practicing psychologists and therapists skilled in the treatment of pain.
doi:10.1093/pm/pnv095
PMCID: PMC4758272  PMID: 26803844
Pain Management; Psychology; Chronic Pain; Pain Training Programs; Education
19.  Longitudinal Changes in Intellectual Development in Children with Fragile X Syndrome 
Structural equation modeling (SEM) was used to examine the development of intellectual functioning in 145 school-age pairs of siblings. Each pair included one child with Fragile X syndrome (FXS) and one unaffected sibling. All pairs of children were evaluated on the Wechsler Intelligence Scale for Children—Third Edition (WISC-III) at time 1 and 80 pairs of children received a second evaluation at time 2 approximately 4 years later. Compared to their unaffected siblings, children with FXS obtained significantly lower percentage correct scores on all subtests of the WISC at both time points. During the time between the first and second assessments, the annual rate of intellectual development was approximately 2.2 times faster in the unaffected children compared to the children with FXS. Levels of the fragile X mental retardation protein (FMRP) were highly associated with intellectual ability scores of the children with FXS at both time points (r=0.55 and 0.64 respectively). However, when gender, age, and the time between assessments were included as covariates in the structural equation model, FMRP accounted for only 5% of the variance in intellectual ability scores at time 1 and 13% of the variance at time 2. The results of this study suggest that slower learning contributes to the low and declining standardized IQ scores observed in children with FXS.
doi:10.1007/s10802-008-9223-y
PMCID: PMC4820329  PMID: 18347972
Fragile X syndrome; Structural equation modeling; Intellectual functioning; IQ; FMRP
20.  Patterns of Maltreatment and Diagnosis Across Levels of Care in Group Homes 
Child abuse & neglect  2015;42:72-83.
Patterns of Axis I psychiatric diagnosis and maltreatment history were explored among youth in group homes, including match of clinical need to level or restrictiveness of care. Data on demographics, diagnoses, maltreatment, and group home level of care (Level I, II, or III homes, representing lower to higher intensity of supervision and treatment) were obtained from 523 youth who participated in a quasi-experimental study of group homes. Three quarters of youth had a diagnosis and two thirds of youth had a maltreatment history. Youth in higher level homes had more diagnoses and higher rates of all disorders except adjustment disorders. Youth in Level I homes had a history of more maltreatment types, particularly high rates of neglect. Sexual abuse, physical abuse, and emotional abuse were most common among youth in higher level homes. Regardless of diagnosis history, comparable proportions of youth had a maltreatment history, and similar patterns were found across levels of care. Together, findings indicate that group homes with varying degrees of restrictiveness serve youth with different psychiatric diagnosis and maltreatment histories. Youth triaged to higher level homes had more diagnoses, while youth placed in the least restrictive homes had a history of more maltreatment subtypes. Further, distinct patterns of diagnosis types and maltreatment subtypes were seen across homes. Implications include the importance of assessing unique clinical needs of youth to promote an appropriate match to level of care and treatment plan.
doi:10.1016/j.chiabu.2014.12.008
PMCID: PMC4385392  PMID: 25618195
group homes; maltreatment; diagnosis; level; care
21.  Poor Awareness of Risk Factors for Cancer in Irish Adults: Results of a Large Survey and Review of the Literature 
The Oncologist  2015;20(4):372-378.
The aims of this study were to assess public perception of the risk factors for cancer and to assess myths and misconceptions about cancer risk. Results showed that a sizable portion of the population studied is misinformed about cancer risk. Targeted health-promotion campaigns that lead to better understanding of risk factors and increased prevention efforts will offer cost-effective, sustainable means of reducing the global cancer burden in the long term.
Background.
Knowledge of cancer risk factors is unknown in Ireland. An understanding of risk factors could help inform cancer prevention programs.
Aims and Methods.
A 48-question online survey was designed to gather data to assess levels of public knowledge about cancer risk factors.
Results.
There were 748 participants (648 women, 100 men). Mean age was 37 years (range: 18–74 years). For the public, 81% were concerned about developing cancer; however, 20% believed that cancer is unavoidable if a family history exists, 27% believed that >50% of cancers are inherited, and 54% believed that 10%–20% of cancers are inherited; 20% were unaware that risk increases with age. The top five risk factors listed by respondents were smoking (87%), diet (76%), genetics (47%), alcohol (42%), and obesity (33%). Only 32% of the public were aware that obesity is a risk factor, and 33% did not think the location of fat was important. Moreover, 29% and 48% believed that risk could be increased by wearing a tight bra and by a blow to the breast, respectively. In addition, 85% and 86% believed that stress and that mobile phones, respectively, “strongly” increase risk; 12% believed that luck is important in avoiding cancer; 35% thought that “detox” diets could reduce risk; and 61% believed that organic food reduces risk. The majority were aware that physical activity of 30 minutes per day can reduce risk.
Conclusion.
A sizable portion of the population is misinformed about cancer risk. Most participants were aware of classic risk factors (e.g., smoking, diet); however, many overestimated risk attributable to genetics, environment, and stress and underestimated age, obesity, and sunlight. One in seven participants believed that lifetime risk of cancer is not modifiable.
doi:10.1634/theoncologist.2014-0453
PMCID: PMC4391772  PMID: 25746344
Cancer; Knowledge; Risk; Diet; Lifestyle; Attitudes; Myths
22.  Toll-Like Receptor 9 Contributes to Defense against Acinetobacter baumannii Infection 
Infection and Immunity  2015;83(10):4134-4141.
Acinetobacter baumannii is a common nosocomial pathogen capable of causing severe diseases associated with significant morbidity and mortality in impaired hosts. Pattern recognition receptors, such as the Toll-like receptors (TLRs), play a key role in pathogen detection and function to alert the immune system to infection. Here, we examine the role for TLR9 signaling in response to A. baumannii infection. In a murine model of A. baumannii pneumonia, TLR9−/− mice exhibit significantly increased bacterial burdens in the lungs, increased extrapulmonary bacterial dissemination, and more severe lung pathology compared with those in wild-type mice. Following systemic A. baumannii infection, TLR9−/− mice have significantly increased bacterial burdens in the lungs, as well as decreased proinflammatory cytokine and chemokine production. These results demonstrate that TLR9-mediated pathogen detection is important for host defense against the opportunistic pathogen Acinetobacter baumannii.
doi:10.1128/IAI.00410-15
PMCID: PMC4567622  PMID: 26238713
23.  Genus Ranges of Chord Diagrams 
A chord diagram consists of a circle, called the backbone, with line segments, called chords, whose endpoints are attached to distinct points on the circle. The genus of a chord diagram is the genus of the orientable surface obtained by thickening the backbone to an annulus and attaching bands to the inner boundary circle at the ends of each chord. Variations of this construction are considered here, where bands are possibly attached to the outer boundary circle of the annulus. The genus range of a chord diagram is the genus values over all such variations of surfaces thus obtained from a given chord diagram. Genus ranges of chord diagrams for a fixed number of chords are studied. Integer intervals that can be, and those that cannot be, realized as genus ranges are investigated. Computer calculations are presented, and play a key role in discovering and proving the properties of genus ranges.
doi:10.1142/S0218216515500224
PMCID: PMC4607078  PMID: 26478650
Chord diagrams; genus ranges; double-occurrence words
24.  Endometrial CXCL13 Expression Is Cycle Regulated in Humans and Aberrantly Expressed in Humans and Rhesus Macaques With Endometriosis 
Reproductive Sciences  2014;22(4):442-451.
C-X-C ligand 13 (CXCL13), a regulator of mucosal immunity, is secreted by human endometrial epithelium and may be involved in embryo implantation. However, cyclic expression of human endometrial CXCL13 in health and disease is not well studied. This study examines cycle stage-specific endometrial CXCL13 expression in normal humans when compared to those with biopsy-confirmed, stage 1 to 4 endometriosis using real-time reverse transcriptase, real-time polymerase chain reaction and immunohistochemistry. Eutopic endometrial CXCL13 expression was also compared between normal, control Rhesus macaques, and macaques with advanced endometriosis. In healthy women, CXLC13 messenger RNA expression was minimal in the proliferative phase and maximal in the secretory phase. However, in the presence of endometriosis, proliferative-phase endometrial expression markedly increased in both humans and rhesus subjects (P < .05). The cross-species and cross-stage concordance suggests a pathophysiologic role for CXCL13 in endometriosis and its use as a biomarker for disease.
doi:10.1177/1933719114542011
PMCID: PMC4812688  PMID: 25031316
CXCL13; endometriosis; proliferative phase
25.  Reproducibility of carotid-femoral pulse wave velocity in end-stage renal disease patients: methodological considerations 
Background
In end-stage renal disease (ESRD) patients, increased arterial stiffness detected by carotid-femoral pulse wave velocity (cf-PWV) is associated with fatal cardiovascular events and all-cause mortality. Since cf-PWV is an operator-dependent technique, poor reproducibility may be a source of bias in the estimation of arterial stiffness.
Objectives
We assessed the week-to-week reproducibility of cf-PWV and radial artery pulse wave analysis in healthy subjects and ESRD patients. We also determined the extent of patient eligibility, enrollment, acceptance, and comfort.
Methods
In a cohort study design, independent tonometric examinations of carotid, femoral, and radial arteries were conducted in 20 healthy subjects and 15 ESRD patients attending chronic hemodialysis treatments according to a randomized sequence by two operators on 2 days scheduled 1-week apart. cf-PWV, augmentation index (AIx@HR75) and central pulse pressure (CPP) were the outcome measures. Patients were tested at mid-week and prior to dialysis treatment. The variability on the distance measured between the suprasternal notch and femoral site using two different methods (standard vs direct) was compared. A post-examination survey assessed acceptance and comfort associated with examinations. Reproducibility was evaluated by intra-class correlations (ICCs).
Results
The mean age for healthy subjects and ESRD patients was 45 ± 12 and 63 ± 16 years, respectively. ESRD patients had higher cf-PWV (p = 0.0002), elevated AIx@HR75 (p = 0.003), and increased CPP (p = 0.001) compared to healthy subjects. The mean inter-visit differences for all stiffness indices were non-significant (p > 0.05), but the mean inter-operator differences for the cf-PWV were significant only in the healthy subject group (−0.7 m/s; p = 0.02). The ICCs between operators and visits were higher for the ESRD group compared to the healthy subjects (between operators, 0.870 vs 0.461; between visits, 0.830 vs 0.570). Distances were longer (p < 0.001), but less variable with the standard method compared to the direct method (healthy subjects, p = 0.036; ESRD, p = 0.39). There was a high rate of patient acceptance and minimal discomfort.
Conclusions
Week-to-week measurements of cf-PWV and pulse wave analysis are highly reproducible in ESRD patients prior to hemodialysis treatment. The high reproducibility and minimal test-to-test variations encourage use of cf-PWV to monitor changes in arterial stiffness and the efficacy of interventions in ESRD patients.
Trial registration
ClinicalTrials.gov, NCT02196610.
Electronic supplementary material
The online version of this article (doi:10.1186/s40697-016-0109-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s40697-016-0109-6
PMCID: PMC4818522  PMID: 27042326
Aortic stiffness; End-stage kidney disease; Inter-observer variation; Validation studies

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