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1.  Testing Interventions to Motivate and Educate (TIME): A multi-level intervention to improve colorectal cancer screening 
Preventive medicine reports  2015;2:306-313.
To test the effectiveness of a colorectal cancer (CRC) screening intervention directed at three levels (clinic, provider, patient) in a primary care setting.
We conducted a group randomized trial (Clinical Trials registration no. NCT01568151) among 10 primary care clinics in Columbus, Ohio that were randomized to a study condition (intervention or usual care). We determined the effect of a multi-level, stepped behavioral intervention on receipt of a CRC screening test among average-risk patients from these clinics over the study period.
Patients (n=527) who were outside of CRC screening recommendations were recruited. Overall, 35.4% of participants in the intervention clinics had received CRC screening by the end of the study compared to 35.1% of participants who were in the usual care clinics. Time to CRC screening was also similar across arms (HR=0.97, 95% CI=0.65–1.45).
The multi-level intervention was not effective in increasing CRC screening among participants who needed a test, perhaps due to low participation of patients in the stepped intervention. Future studies utilizing evidence-based strategies to encourage CRC screening are needed.
PMCID: PMC4450442  PMID: 26046014
cancer prevention; cancer screening; multi-level interventions; colorectal cancer; lay health advisor
2.  Single agent BMS-911543 Jak2 inhibitor has distinct inhibitory effects on STAT5 signaling in genetically engineered mice with pancreatic cancer 
Oncotarget  2015;6(42):44509-44522.
The Jak/STAT pathway is activated in human pancreatic ductal adenocarcinoma (PDAC) and cooperates with mutant Kras to drive initiation and progression of PDAC in murine models. We hypothesized that the small-molecule Jak2 inhibitor (BMS-911543) would elicit anti-tumor activity against PDAC and decrease immune suppressive features of the disease. We used an aggressive genetically engineered PDAC model with mutant KrasG12D, tp53R270H, and Brca1 alleles (KPC-Brca1 mice). Mice with confirmed tumor burden were treated orally with vehicle or 30 mg/kg BMS-911543 daily for 14 days. Histologic analysis of pancreata from treated mice revealed fewer foci of adenocarcinoma and significantly decreased Ki67+ cells versus controls. In vivo administration of BMS-911543 significantly reduced pSTAT5 and FoxP3 positive cells within the pancreas, but did not alter STAT3 phosphorylation. Continuous dosing of KPC-Brca1 mice with BMS-911543 resulted in a median survival of 108 days, as compared to a median survival of 87 days in vehicle treated animals, a 23% increase (p = 0.055). In vitro experiments demonstrated that PDAC cell lines were poorly sensitive to BMS-911543, requiring high micromolar concentrations to achieve targeted inhibition of Jak/STAT signaling. Similarly, BMS-911543 had little in vitro effect on the viability of both murine and human PDAC-derived stellate cell lines. However, BMS-911543 potently inhibited phosphorylation of pSTAT3 and pSTAT5 at low micromolar doses in human PBMC and reduced in vitro differentiation of Foxp3+ T regulatory cells. These results indicate that single agent Jak2i deserves further study in preclinical models of PDAC and has distinct inhibitory effects on STAT5 mediated signaling.
PMCID: PMC4792572  PMID: 26575024
Jak2; STAT3; STAT5; pancreatic cancer
3.  Predictors of resolution in navigated patients with abnormal cancer screening tests 
Patient navigation has been effective in improving cancer care, yet little is known about what predicts timely outcomes in navigated patients.
We identified predictors of resolution of abnormal cancer screening tests in patients who received navigation.
We examined data on patients with abnormal breast (n = 256) or cervical (n = 150) screening tests or symptoms who received navigation as part of the Ohio Patient Navigator Research Program during 2007–2010. We used multivariable Cox proportional hazards regression models to identify predictors of time to resolution (ie, when a patient’s clinical abnormality or abnormal screening test was determined to be a benign condition or a cancer diagnosis).
The median time to resolution was 183 days for navigated patients with breast abnormalities and 172 days for navigated patients with cervical abnormalities. In patients with breast abnormalities, those who reported at least 1 barrier to care during navigation (HR, 0.66; 95% CI, 0.51–0.86) or higher perceived stress (HR, 0.90; 95% CI, 0.82–0.98) had slower resolution. Among patients with cervical abnormalities, those who reported at least 1 barrier to care during navigation had slower resolution (HR, 0.62; 95% CI, 0.42–0.91). Patients with cervical abnormalities had faster resolution if they had private health insurance, but this effect was present only in younger women (interaction P = .003).
Unknown generalizability of results because patients were female and from clinics in central Ohio.
Several variables predicted whether patient navigation led to faster resolution, and predictors differed somewhat by disease site. Results will be useful in improving current patient navigation programs and designing future programs.
PMCID: PMC4545214  PMID: 26288850
4.  18-Month Predictors of Later Outcomes in Younger Siblings of Children With Autism Spectrum Disorder: A Baby Siblings Research Consortium Study 
Younger siblings of children with autism spectrum disorder (ASD) are at high risk (HR) for developing ASD as well as features of the broader autism phenotype. While this complicates early diagnostic considerations in this cohort, it also provides an opportunity to examine patterns of behavior associated specifically with ASD compared to other developmental outcomes.
We applied Classification and Regression Trees (CART) analysis to individual items of the Autism Diagnostic Observation Schedule (ADOS) in 719 HR siblings to identify behavioral features at 18 months predictive of diagnostic outcomes (ASD, atypical development, and typical development) at 36 months.
Three distinct combinations of features at 18 months were predictive of ASD outcome: 1) poor eye contact combined with lack of communicative gestures and giving; 2) poor eye contact combined with a lack of imaginative play; and 3) lack of giving and presence of repetitive behaviors, but with intact eye contact. These 18-month behavioral profiles predicted ASD versus non-ASD status at 36 months with 82.7% accuracy in an initial test sample and 77.3% accuracy in a validation sample. Clinical features at age 3 among children with ASD varied as a function of their 18-month symptom profiles. Children with ASD who were misclassified at 18 months were higher functioning, and their autism symptoms increased between 18 and 36 months.
These findings suggest the presence of different developmental pathways to ASD in HR siblings. Understanding such pathways will provide clearer targets for neural and genetic research and identification of developmentally specific treatments for ASD.
PMCID: PMC4254798  PMID: 25457930
ASD; high-risk siblings; infants; broader autism phenotype; predictors of outcomes
7.  A Media and Clinic Intervention to Increase Colorectal Cancer Screening in Ohio Appalachia 
BioMed Research International  2015;2015:943152.
Objective. To test the effectiveness of a colorectal cancer (CRC) screening intervention among adults living in Ohio Appalachia. Methods. We conducted a group-randomized trial of a county-level intervention among adults living in 12 Ohio Appalachian counties who received a media campaign and clinic intervention focused on either CRC screening or fruits and vegetables. Participants' percentage within CRC screening guidelines was assessed with cross-sectional surveys conducted annually for four years, and validated with medical record review of screening. Results. On average, screening data were obtained on 564 intervention and 559 comparison participants per year. There was no difference in the Wave 4 CRC screening rates of intervention and comparison counties (35.2% versus 31.4%). Multivariate analyses found that high perceived risk of CRC, willingness to have a CRC test if recommended by a doctor, doctor recommendation of a CRC screening test, and patient-physician communication about changes in bowel habits, family history of CRC, and eating fruits and vegetables were significant (p < 0.05) predictors of being within CRC screening guidelines. Conclusions. The intervention was not effective in increasing CRC rates among Ohio Appalachian adults. Future research should determine how media and clinic-based interventions can be modified to improve CRC screening rates among this underserved population.
PMCID: PMC4609808  PMID: 26509172
8.  Early Head Growth in Infants at Risk of Autism: A Baby Siblings Research Consortium Study 
While early brain overgrowth is frequently reported in autism spectrum disorder (ASD), the relationship between ASD and head circumference (HC) is less clear, with inconsistent findings from longitudinal studies that include community controls. Our aim was to examine whether head growth in the first 3 years differed between children with ASD from a high-risk (HR) sample of infant siblings of children with ASD (by definition, multiplex), HR siblings not diagnosed with ASD, and low-risk (LR) controls.
Participants included 442 HR and 253 LR infants from 12 sites of the international Baby Siblings Research Consortium. Longitudinal HC data were obtained prospectively, supplemented by growth records. Random effects non-linear growth models were used to compare HC in HR infants and LR infants. Additional comparisons were conducted with the HR group stratified by diagnostic status at age 3: ASD (n=77), developmental delay (DD; n=32), and typical development (TD; n=333). Nonlinear growth models were also developed for height to assess general overgrowth associated with ASD.
There was no overall difference in head circumference growth over the first 3 years between HR and LR infants, although secondary analyses suggested possible increased total growth in HR infants, reflected by the model asymptote. Analyses stratifying the HR group by 3-year outcomes did not detect differences in head growth or height between HR infants who developed ASD and those who did not, nor between infants with ASD and LR controls.
Head growth was uninformative as an ASD risk marker within this HR cohort.
PMCID: PMC4173119  PMID: 25245349
Autism spectrum disorder; head circumference; high risk design; longitudinal study; early detection
9.  Bioactive compounds or metabolites from black raspberries modulate T lymphocyte proliferation, myeloid cell differentiation and Jak/STAT signaling 
Bioactive phyotochemicals from natural products, such as black raspberries (BRB; Rubus occidentalis) have direct anti-cancer properties on malignant cells in culture and in xenograft models. BRB components inhibit cancer progression in more complex rodent carcinogenesis models. Although mechanistic targets for BRB phytochemicals in cancer cells are beginning to emerge, the potential role in modulating host immune processes impacting cancer have not been systematically examined. We hypothesized that BRB contain compounds capable of eliciting potent immunomodulatory properties that impact cellular mediators relevant to chronic inflammation and tumor progression. We studied both an ethanol extract from black raspberries (BRB-E) containing a diverse mixture of phytochemicals and two abundant phytochemical metabolites of BRB produced upon ingestion (Cyanidin-3-Rutinoside, C3R; Quercitin-3-Rutinoside, Q3R). BRB-E inhibited proliferation and viability of CD3/CD28 activated human CD4+ and CD8+ T lymphocytes. BRB-E also limited in vitro expansion of myeloid-derived suppressor cells (MDSC) and their suppressive capacity. Pre-treatment of immune cells with BRB-E attenuated IL-6-mediated phosphorylation of signal transducer and activator of transcription-3 (STAT3) and IL-2 induced STAT5 phosphorylation. In contrast, pre-treatment of immune cells with the C3R and Q3R metabolites inhibited MDSC expansion, IL-6-mediated STAT3 signaling, but not IL-2 induced STAT5 phosphorylation and were less potent inhibitors of T cell viability. Together these data indicate that BRB extracts and their physiologically-relevant metabolites contain phytochemicals that affect immune processes relevant to carcinogenesis and immunotherapy. Furthermore, specific BRB components and their metabolites may be a source of lead compounds for drug development that exhibit targeted immunological outcomes or inhibition of specific STAT-regulated signaling pathways.
PMCID: PMC4142082  PMID: 24893859
Black raspberries; quercetin; myeloid derived suppressor cells; T lymphocytes; STAT3; STAT5
11.  Early sex differences are not autism-specific: A Baby Siblings Research Consortium (BSRC) study 
Molecular Autism  2015;6:32.
The increased male prevalence of autism spectrum disorder (ASD) may be mirrored by the early emergence of sex differences in ASD symptoms and cognitive functioning. The female protective effect hypothesis posits that ASD recurrence and symptoms will be higher among relatives of female probands. This study examined sex differences and sex of proband differences in ASD outcome and in the development of ASD symptoms and cognitive functioning among the high-risk younger siblings of ASD probands and low-risk children.
Prior to 18 months of age, 1824 infants (1241 high-risk siblings, 583 low-risk) from 15 sites were recruited. Hierarchical generalized linear model (HGLM) analyses of younger sibling and proband sex differences in ASD recurrence among high-risk siblings were followed by HGLM analyses of sex differences and group differences (high-risk ASD, high-risk non-ASD, and low-risk) on the Mullen Scales of Early Learning (MSEL) subscales (Expressive and Receptive Language, Fine Motor, and Visual Reception) at 18, 24, and 36 months and Autism Diagnostic Observation Schedule (ADOS) domain scores (social affect (SA) and restricted and repetitive behaviors (RRB)) at 24 and 36 months.
Of 1241 high-risk siblings, 252 had ASD outcomes. Male recurrence was 26.7 % and female recurrence 10.3 %, with a 3.18 odds ratio. The HR-ASD group had lower MSEL subscale scores and higher RRB and SA scores than the HR non-ASD group, which had lower MSEL subscale scores and higher RRB scores than the LR group. Regardless of group, males obtained lower MSEL subscale scores, and higher ADOS RRB scores, than females. There were, however, no significant interactions between sex and group on either the MSEL or ADOS. Proband sex did not affect ASD outcome, MSEL subscale, or ADOS domain scores.
A 3.2:1 male:female odds ratio emerged among a large sample of prospectively followed high-risk siblings. Sex differences in cognitive performance and repetitive behaviors were apparent not only in high-risk children with ASD, but also in high-risk children without ASD and in low-risk children. Sex differences in young children with ASD do not appear to be ASD-specific but instead reflect typically occurring sex differences seen in children without ASD. Results did not support a female protective effect hypothesis.
Electronic supplementary material
The online version of this article (doi:10.1186/s13229-015-0027-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4455973  PMID: 26045943
Sex differences; High-risk siblings; Symptom severity; Development; Longitudinal
12.  Impact of Patient Navigation on Timely Cancer Care: The Patient Navigation Research Program 
Patient navigation is a promising intervention to address cancer disparities but requires a multisite controlled trial to assess its effectiveness.
The Patient Navigation Research Program compared patient navigation with usual care on time to diagnosis or treatment for participants with breast, cervical, colorectal, or prostate screening abnormalities and/or cancers between 2007 and 2010. Patient navigators developed individualized strategies to address barriers to care, with the focus on preventing delays in care. To assess timeliness of diagnostic resolution, we conducted a meta-analysis of center- and cancer-specific adjusted hazard ratios (aHRs) comparing patient navigation vs usual care. To assess initiation of cancer therapy, we calculated a single aHR, pooling data across all centers and cancer types. We conducted a metaregression to evaluate variability across centers. All statistical tests were two-sided.
The 10521 participants with abnormal screening tests and 2105 with a cancer or precancer diagnosis were predominantly from racial/ethnic minority groups (73%) and publically insured (40%) or uninsured (31%). There was no benefit during the first 90 days of care, but a benefit of navigation was seen from 91 to 365 days for both diagnostic resolution (aHR = 1.51; 95% confidence interval [CI] = 1.23 to 1.84; P < .001)) and treatment initiation (aHR = 1.43; 95% CI = 1.10 to 1.86; P < .007). Metaregression revealed that navigation had its greatest benefits within centers with the greatest delays in follow-up under usual care.
Patient navigation demonstrated a moderate benefit in improving timely cancer care. These results support adoption of patient navigation in settings that serve populations at risk of being lost to follow-up.
PMCID: PMC4072900  PMID: 24938303
13.  Sex differences in the corpus callosum in preschool-aged children with autism spectrum disorder 
Molecular Autism  2015;6:26.
Abnormalities in the corpus callosum have been reported in individuals with autism spectrum disorder (ASD), but few studies have evaluated young children. Sex differences in callosal organization and diffusion characteristics have also not been evaluated fully in ASD.
Structural and diffusion-weighted images were acquired in 139 preschool-aged children with ASD (112 males/27 females) and 82 typically developing (TD) controls (53 males/29 females). Longitudinal scanning at two additional annual time points was carried out in a subset of these participants. Callosal organization was evaluated using two approaches: 1) diffusion tensor imaging (DTI) tractography to define subregions based on cortical projection zones and 2) as a comparison to previous studies, midsagittal area analysis using Witelson subdivisions. Diffusion measures of callosal fibers were also evaluated.
Analyses of cortical projection zone subregions revealed sex differences in the patterns of altered callosal organization. Relative to their sex-specific TD counterparts, both males and females with ASD had smaller regions dedicated to fibers projecting to superior frontal cortex, but patterns differed in callosal subregions projecting to other parts of frontal cortex. While males with ASD had a smaller callosal region dedicated to the orbitofrontal cortex, females with ASD had a smaller callosal region dedicated to the anterior frontal cortex. There were also sex differences in diffusion properties of callosal fibers. While no alterations were observed in males with ASD relative to TD males, mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were all increased in females with ASD relative to TD females. Analyses of Witelson subdivisions revealed a decrease in midsagittal area of the corpus callosum in both males and females with ASD but no regional differences in specific subdivisions. Longitudinal analyses revealed no diagnostic or sex differences in the growth rate or change in diffusion measures of the corpus callosum from 3 to 5 years of age.
There are sex differences in the pattern of altered corpus callosum neuroanatomy in preschool-aged children with ASD.
Electronic supplementary material
The online version of this article (doi:10.1186/s13229-015-0005-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4429319  PMID: 25973163
Connectivity; Diffusion tensor imaging; Longitudinal; MRI; White matter
14.  Testing Interventions to Motivate and Educate (TIME): A multi-level intervention to improve colorectal cancer screening☆ 
Preventive Medicine Reports  2015;2:306-313.
To test the effectiveness of a colorectal cancer (CRC) screening intervention directed at three levels (clinic, provider, patient) in a primary care setting.
We conducted a group randomized trial (Clinical Trials registration no. NCT01568151) among 10 primary care clinics in Columbus, Ohio that were randomized to a study condition (intervention or usual care). We determined the effect of a multi-level, stepped behavioral intervention on receipt of a CRC screening test among average-risk patients from these clinics over the study period.
Patients (n = 527) who were outside of CRC screening recommendations were recruited. Overall, 35.4% of participants in the intervention clinics had received CRC screening by the end of the study compared to 35.1% of participants who were in the usual care clinics. Time to CRC screening was also similar across arms (HR = 0.97, 95% CI = 0.65–1.45).
The multi-level intervention was not effective in increasing CRC screening among participants who needed a test, perhaps due to low participation of patients in the stepped intervention. Future studies utilizing evidence-based strategies to encourage CRC screening are needed.
•This study tested the effectiveness of a multi-level CRC screening intervention.•There was no difference in receipt of CRC screening between study arms.•Innovative strategies need to be developed to improve CRC screening rates.
PMCID: PMC4450442  PMID: 26046014
Cancer prevention; Cancer screening; Multi-level interventions; Colorectal cancer; Lay health advisor
15.  Gross Motor Development, Movement Abnormalities, and Early Identification of Autism 
Gross motor development (supine, prone, rolling, sitting, crawling, walking) and movement abnormalities were examined in the home videos of infants later diagnosed with autism (regression and no regression subgroups), developmental delays (DD), or typical development. Group differences in maturity were found for walking, prone, and supine, with the DD and Autism-No Regression groups both showing later developing motor maturity than typical children. The only statistically significant differences in movement abnormalities were in the DD group; the two autism groups did not differ from the typical group in rates of movement abnormalities or lack of protective responses. These findings do not replicate previous investigations suggesting that early motor abnormalities seen on home video can assist in early identification of autism.
PMCID: PMC4405234  PMID: 17805956
Autism; Motor; Early identification
16.  The Broader Autism Phenotype in Infancy: When Does It Emerge? 
This study had three goals, to examine: 1) the frequency of atypical development, consistent with the broader autism phenotype, in high-risk infant siblings of children with ASD, 2) the age at which atypical development is first evident, and 3) which developmental domains are affected.
A prospective longitudinal design was used to compare 294 high-risk infants and 116 low-risk infants. Participants were tested at 6, 12, 18, 24, and 36 months of age. At the final visit, outcome was classified as ASD, Typical Development (TD), or Non-TD (defined as elevated ADOS score, low Mullen scores, or both).
28% of the high-risk group was classified as Non-TD at 36 months of age. Growth curve models demonstrated that the Non-TD group could not be distinguished from the other groups at 6 months of age, but differed significantly from the Low-Risk TD group by 12 months on multiple measures. The Non-TD group demonstrated atypical development in cognitive, motor, language, and social domains, with differences particularly prominent in social-communication.
These results demonstrate that features of atypical development, consistent with the broader autism phenotype, are detectable by the first birthday and affect development in multiple domains. This highlights the necessity for close developmental surveillance of infant siblings of children with ASD, along with implementation of appropriate interventions as needed.
PMCID: PMC3989934  PMID: 24655649
Autism Spectrum Disorder; broader autism phenotype; siblings; social-communication; infancy
17.  Barriers reported among patients with breast and cervical abnormalities in the patient navigation research program: impact on timely care 
Patient navigation (PN) is a system-level strategy to decrease cancer mortality rates by reducing barriers to cancer care. Barriers to resolution among participants in the PN intervention arm with a breast or cervical abnormality in the Patient Navigation Research Program (PNRP) and navigators’ actions to address those barriers were examined.
Data were from seven institutions (2005 to 2010) included 1,995 breast and 1,194 cervical patients. A stratified Cox proportional hazards regression model was used to examine the effects of barriers on time to resolution of an abnormal screening test or clinical finding.
The range of unique barriers was 0 to 12 and 0 to 7 among participants with breast and cervical abnormalities, respectively. About two-thirds of breast and half of cervical participants had at least one barrier resulting in longer time to diagnostic resolution among breast (adjusted HR=0.744; p<0.001) and cervical (adjusted HR=0.792; p<0.001) participants. Patient-level and system-level barriers were most common. Frequent navigator actions were: making arrangements, scheduling appointments, referrals, and education.
Having a barrier resulted in a delay in diagnostic resolution of an abnormal screening test or clinical finding. Health care systems can use these findings to improve existing PN programs or when developing new programs.
PMCID: PMC3896921  PMID: 24439942
patient navigation; patient navigators; patient-centered care; cancer
18.  Clinimetric properties of the Tinetti Mobility Test, Four Square Step Test, Activities-specific Balance Confidence Scale, and spatiotemporal gait measures in individuals with Huntington's disease 
Gait & posture  2014;40(4):647-651.
Background and purpose
Individuals with Huntington's disease (HD) experience balance and gait problems that lead to falls. Clinicians currently have very little information about the reliability and validity of outcome measures to determine the efficacy of interventions that aim to reduce balance and gait impairments in HD. This study examined the reliability and concurrent validity of spatiotemporal gait measures, the Tinetti Mobility Test (TMT), Four Square Step Test (FSST), and Activities-specific Balance Confidence (ABC) Scale in individuals with HD.
Participants with HD [n = 20; mean age ± SD = 50.9 ± 13.7; 7 male] were tested on spatiotemporal gait measures the TMT, FSST, and ABC Scale before and after a six week period to determine test–retest reliability and minimal detectable change (MDC) values. Linear relationships between gait and clinical measures were estimated using Pearson's correlation coefficients.
Spatiotemporal gait measures, the TMT total and the FSST showed good to excellent test–retest reliability (ICC > 0.75). MDC values were 0.30 m/s and 0.17 m/s for velocity in forward and backward walking respectively, four points for the TMT, and 3 s for the FSST. The TMT and FSST were highly correlated with most spatiotemporal measures. The ABC Scale demonstrated lower reliability and less concurrent validity than other measures.
The high test–retest reliability over a six week period and concurrent validity between the TMT, FSST, and spatiotemporal gait measures suggest that the TMT and FSST may be useful outcome measures for future intervention studies in ambulatory individuals with HD.
PMCID: PMC4230319  PMID: 25128156
Balance; Gait; Test–retest reliability; Validity; Huntington's disease
19.  Early brain enlargement and elevated extra-axial fluid in infants who develop autism spectrum disorder 
Brain  2013;136(9):2825-2835.
Prospective studies of infants at risk for autism spectrum disorder have provided important clues about the early behavioural symptoms of autism spectrum disorder. Diagnosis of autism spectrum disorder, however, is not currently made until at least 18 months of age. There is substantially less research on potential brain-based differences in the period between 6 and 12 months of age. Our objective in the current study was to use magnetic resonance imaging to identify any consistently observable brain anomalies in 6–9 month old infants who would later develop autism spectrum disorder. We conducted a prospective infant sibling study with longitudinal magnetic resonance imaging scans at three time points (6–9, 12–15, and 18–24 months of age), in conjunction with intensive behavioural assessments. Fifty-five infants (33 ‘high-risk’ infants having an older sibling with autism spectrum disorder and 22 ‘low-risk’ infants having no relatives with autism spectrum disorder) were imaged at 6–9 months; 43 of these (27 high-risk and 16 low-risk) were imaged at 12–15 months; and 42 (26 high-risk and 16 low-risk) were imaged again at 18–24 months. Infants were classified as meeting criteria for autism spectrum disorder, other developmental delays, or typical development at 24 months or later (mean age at outcome: 32.5 months). Compared with the other two groups, infants who developed autism spectrum disorder (n = 10) had significantly greater extra-axial fluid at 6–9 months, which persisted and remained elevated at 12–15 and 18–24 months. Extra-axial fluid is characterized by excessive cerebrospinal fluid in the subarachnoid space, particularly over the frontal lobes. The amount of extra-axial fluid detected as early as 6 months was predictive of more severe autism spectrum disorder symptoms at the time of outcome. Infants who developed autism spectrum disorder also had significantly larger total cerebral volumes at both 12–15 and 18–24 months of age. This is the first magnetic resonance imaging study to prospectively evaluate brain growth trajectories from infancy in children who develop autism spectrum disorder. The presence of excessive extra-axial fluid detected as early as 6 months and the lack of resolution by 24 months is a hitherto unreported brain anomaly in infants who later develop autism spectrum disorder. This is also the first magnetic resonance imaging evidence of brain enlargement in autism before age 2. These findings raise the potential for the use of structural magnetic resonance imaging to aid in the early detection of children at risk for autism spectrum disorder or other neurodevelopmental disorders.
PMCID: PMC3754460  PMID: 23838695
autism; magnetic resonance imaging; infant brain development; cerebrospinal fluid; external hydrocephalus
20.  Ambulatory Subspecialty Visits in a Large Pediatric Primary Care Network 
Health Services Research  2012;47(4):1755-1769.
To determine patterns of subspecialty utilization within a pediatric primary care network.
Data Sources/Study Setting
Paid claims from a large not-for-profit health plan for patients of The Pediatric Physicians' Organization at Children's, a network of private pediatric practices affiliated with Children's Hospital Boston.
Principal Findings
The subspecialty visit rate was 1.01 visits per subject-year. In 2007, 56.8 percent of subjects had no subspecialty visits, whereas 4.2 percent had ≥5 visits; the corresponding figures in 2008 were 54.1 and 4.5 percent, respectively. The most frequently visited subspecialties were Ophthalmology, Orthopedics, Dermatology, Otorhinolaryngology, and Allergy/Immunology. Visit rates varied sevenfold by practice.
Wide practice variability in pediatric subspecialty utilization suggests an opportunity for reducing unnecessary visits. Better integration between primary care and the most commonly used subspecialties will be needed to meaningfully reduce unnecessary visits and enhance value.
PMCID: PMC3401409  PMID: 22375886
Specialty care; utilization; pediatrics
21.  Correlates of colorectal cancer screening among residents of Ohio Appalachia 
Journal of community health  2013;38(4):609-618.
There is an excess burden of colorectal cancer (CRC) in the Appalachian region of the U.S., which could be reduced by increased uptake of CRC screening tests. Thus, we examined correlates of screening among Appalachian residents at average-risk for CRC. Using a population-based sample, we conducted interviews with and obtained medical records of Appalachian Ohio residents 50–75 years between September 2009 and April 2010. Using multivariable logistic regression, we identified correlates of being within CRC screening guidelines by medical records. About half of participants were within CRC screening guidelines. Participants who were older (OR=1.04, 95% CI: 1.01, 1.07), had higher income ($30,000–$60,000, OR=1.92, 95% CI: 1.29, 2.86; ≥$60,000, OR=1.80, 95% CI: 1.19, 2.72), a primary care provider (OR=4.22, 95% CI: 1.33, 13.39), a recent check-up (OR=2.37, 95% CI: 1.12, 4.99), had been encouraged to be screened (OR=1.57, 95% CI: 1.11, 2.22), had been recommended by their doctor to be screened (OR=6.68, 95% CI: 3.87, 11.52), or asked their doctor to order a screening test (OR=2.24, 95% CI: 1.36, 3.69) had higher odds of being screened within guidelines in multivariable analysis. Findings suggest that access to and utilization of healthcare services, social influence, and patient-provider communication were the major factors associated with CRC screening. Researchers and healthcare providers should develop and implement strategies targeting these barriers/facilitators to improve CRC screening rates and reduce the CRC burden among residents of Appalachia.
PMCID: PMC3706501  PMID: 23529450
colorectal cancer; screening; Appalachia; health disparities
22.  Novel Small Molecule XPO1/CRM1 Inhibitors Induce Nuclear Accumulation of TP53, Phosphorylated MAPK and Apoptosis in Human Melanoma Cells 
PLoS ONE  2014;9(7):e102983.
XPO1/CRM1 is a key nuclear exporter protein that mediates translocation of numerous cellular regulatory proteins. We investigated whether XPO1 is a potential therapeutic target in melanoma using novel selective inhibitors of nuclear export (SINE). In vitro effects of SINE on cell growth and apoptosis were measured by MTS assay and flow cytometry [Annexin V/propidium iodide (PI)], respectively in human metastatic melanoma cell lines. Immunoblot analysis was used to measure nuclear localization of key cellular proteins. The in vivo activity of oral SINE was evaluated in NOD/SCID mice bearing A375 or CHL-1 human melanoma xenografts. SINE compounds induced cytostatic and pro-apoptotic effects in both BRAF wild type and mutant (V600E) cell lines at nanomolar concentrations. The cytostatic and pro-apoptotic effects of XPO1 inhibition were associated with nuclear accumulation of TP53, and CDKN1A induction in the A375 cell line with wild type TP53, while pMAPK accumulated in the nucleus regardless of TP53 status. The orally bioavailable KPT-276 and KPT-330 compounds significantly inhibited growth of A375 (p<0.0001) and CHL-1 (p = 0.0087) human melanoma cell lines in vivo at well tolerated doses. Inhibition of XPO1 using SINE represents a potential therapeutic approach for melanoma across cells with diverse molecular phenotypes by promoting growth inhibition and apoptosis.
PMCID: PMC4109950  PMID: 25057921
23.  Validation of Self-Reported Colorectal Cancer Screening Behaviors among Appalachian Residents 
Public health nursing (Boston, Mass.)  2013;30(4):10.1111/phn.12038.
We determined the validity of self-reported colorectal cancer (CRC) screening data provided by Appalachian Ohio residents and identified correlates of providing accurate data.
We conducted cross-sectional telephone interviews between September 2009 and April 2010.
Our study included Appalachian Ohio residents (n=721) ages 51–75.
We compared self-reported CRC screening data to medical records to determine validity. Multivariable logistic regression was used to identify correlates of providing accurate self-reported screening data.
About 68% of participants self-reported having any CRC screening test within recommended guidelines, while medical records indicated that only 49% were within guidelines (concordance=0.76). Concordance was higher for flexible sigmoidoscopy and FOBT compared to colonoscopy, though sensitivity and positive predictive value were much higher for colonoscopy. Participants overreported CRC screening behaviors for all tests. Participants who had a regular check-up in the last two years (OR=2.78, 95% CI: 1.15-6.73) or self-rated their health as good or better (OR=1.88, 95% CI: 1.12-3.16) were more likely to provide accurate screening data.
Many participants failed to provide accurate CRC screening data, and validity varied greatly across individual CRC screening tests. Future CRC screening studies among Appalachian residents should use medical records, if possible, to determine screening histories.
PMCID: PMC3809100  PMID: 23808856
Colorectal cancer; Cancer screening; Validity; Appalachia
24.  Avocado Consumption Enhances Human Postprandial Provitamin A Absorption and Conversion from a Novel High–β-Carotene Tomato Sauce and from Carrots12 
The Journal of Nutrition  2014;144(8):1158-1166.
Dietary lipids have been shown to increase bioavailability of provitamin A carotenoids from a single meal, but the effects of dietary lipids on conversion to vitamin A during absorption are essentially unknown. Based on previous animal studies, we hypothesized that the consumption of provitamin A carotenoids with dietary lipid would enhance conversion to vitamin A during absorption compared with the consumption of provitamin A carotenoids alone. Two separate sets of 12 healthy men and women were recruited for 2 randomized, 2-way crossover studies. One meal was served with fresh avocado (Persea americana Mill), cultivated variety Hass (delivering 23 g of lipid), and a second meal was served without avocado. In study 1, the source of provitamin A carotenoids was a tomato sauce made from a novel, high–β-carotene variety of tomatoes (delivering 33.7 mg of β-carotene). In study 2, the source of provitamin A carotenoids was raw carrots (delivering 27.3 mg of β-carotene and 18.7 mg of α-carotene). Postprandial blood samples were taken over 12 h, and provitamin A carotenoids and vitamin A were quantified in triglyceride-rich lipoprotein fractions to determine baseline-corrected area under the concentration-vs.-time curve. Consumption of lipid-rich avocado enhanced the absorption of β-carotene from study 1 by 2.4-fold (P < 0.0001). In study 2, the absorption of β-carotene and α-carotene increased by 6.6- and 4.8-fold, respectively (P < 0.0001 for both). Most notably, consumption of avocado enhanced the efficiency of conversion to vitamin A (as measured by retinyl esters) by 4.6-fold in study 1 (P < 0.0001) and 12.6-fold in study 2 (P = 0.0013). These observations highlight the importance of provitamin A carotenoid consumption with a lipid-rich food such as avocado for maximum absorption and conversion to vitamin A, especially in populations in which vitamin A deficiency is prevalent. This trial was registered at as NCT01432210.
PMCID: PMC4093981  PMID: 24899156
25.  Behavior and Sleep Problems in Children with a Family History of Autism 
The present study explores behavioral and sleep outcomes in preschool age siblings of children with autism spectrum disorders (ASD). This study focuses on behavior problems that are common in children with ASD, such as emotional reactivity, anxiety, inattention, aggression, and sleep problems. Infant siblings were recruited from families with at least one older child with ASD (high-risk group, n = 104) or families with no history of ASD (low-risk group, n = 76). As part of a longitudinal prospective study, children completed the Mullen Scales of Early Learning and the Autism Diagnostic Observation Schedule, and parents completed the Child Behavior Checklist (CBCL) and the Social Communication Questionnaire at 36 months of age. This study focuses on developmental concerns outside of ASD; therefore, only siblings who did not develop an ASD were included in analyses. Negative binomial regression analyses revealed that children in the high-risk group were more likely to have elevated behavior problems on the CBCL Anxious/Depressed and Aggression subscales. To explore sleep problems as a correlate of these behavior problems, a second series of models was specified. For both groups of children, sleep problems were associated with elevated behavior problems in each of the areas assessed (reactivity, anxiety, somatic complaints, withdrawal, attention, and aggression). These findings support close monitoring of children with a family history of ASD for both behavioral and sleep issues.
PMCID: PMC3947924  PMID: 23436793
autism; siblings; behavior problems; sleep

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