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1.  The Voices of Limited English Proficiency Latina Mothers on Pediatric Primary Care: Lessons for the Medical Home 
The objective of this study is to inform medical home implementation in practices serving limited English proficiency Latino families by exploring limited English proficiency Latina mothers’ experiences with, and expectations for, pediatric primary care. In partnership with a federally-qualified community health center in an urban Latino neighborhood, we conducted semi-structured interviews with 38 low-income Latina mothers. Eligible participants identified a pediatric primary care provider for their child and had at least one child 3 years old or younger, to increase the probability of frequent recent interactions with health care providers. Interview transcripts were coded and analyzed through an iterative and collaborative process to identify participants’ satisfaction with and expectations for pediatric primary care. About half of the mothers interviewed were satisfied with their primary care experiences. Mothers suggested many ways to improve the quality of pediatric primary care for their children to better meet the needs of their families. These included: encouraging providers to invest more in their relationship with families, providing reliable same-day sick care, expanding hours, improving access to language services, and improving care coordination services. Limited English proficiency Latina mothers expect high-quality pediatric primary care consistent with the medical home model. Current efforts to improve primary care quality through application of the medical home model are thus relevant to this population, but should focus on the parent-provider relationship and timely access to care. Promoting this model among practices that serve limited English proficiency Latino families could improve engagement and satisfaction with primary care.
doi:10.1007/s10995-012-0951-9
PMCID: PMC4336198  PMID: 22350630
Disparities; Primary care; Latino; Qualitative research; Medical home
2.  Community Health Workers and the Patient Protection and Affordable Care Act: An opportunity for a research, advocacy, and policy agenda 
Community health workers (CHWs) have the potential to be important members of an interdisciplinary health care team. CHWs have been shown to be effective in multiple roles in the provision of culturally appropriate healthcare in a variety of settings. Recent efforts have started to explore how best to integrate CHWs into the health system. However, to date, there has been limited policy guidance, support, or evidence on how to best achieve this on a larger scale. The Patient Protection and Affordable Care Act (ACA), through several provisions, provides a unique opportunity to create a unified framework for workforce integration and wider utilization of CHWs. This review identifies four major opportunities to further the research, policy, and advocacy agenda for CHWs.
doi:10.1353/hpu.2014.0019
PMCID: PMC4117401  PMID: 24509008
Community health worker; health reform; interdisciplinary health care team; community health
3.  Increases in the Use of Prescription Opioid Analgesics and the Lack of Improvement in Disability Metrics Among Users 
Background and Objectives
In the United States, use of oral opioid analgesics has been associated with increasing rates of addiction, abuse, and diversion. However, little is known about recent national use of non-illicit prescription opioid analgesics (those prescribed in a doctor-patient relationship), the primary source of these drugs for the general US population. Our primary objective was to examine trends in the use of prescription opioid analgesics in the United States and to identify defining characteristics of patient users of prescribed opioids from 2000 to 2010.
Methods
We used the nationally representative Medical Expenditure Panel Survey to examine trends in prescription oral opioid analgesic use from 2000 to 2010. We used survey design methods to make national estimates of adults (18 years and older) who reported receiving an opioid analgesic prescription (referred to as opioid users) and used logistic regression to examine predictors of opioid analgesic use. Our primary outcome measures were national estimates of total users of prescription opioid analgesics and total number of prescriptions. Our secondary outcome was that of observing changes in the disability and health of the users.
Results
The estimated total number of opioid analgesic prescriptions in the United States increased by 104%, from 43.8 million in 2000 to 89.2 million in 2010. In 2000, an estimated 7.4% (95% CI, 6.9–7.9) of adult Americans were prescription opioid users compared with 11.8% (95% CI, 11.2–12.4) in 2010. Based on estimates adjusted for changes in the general population, each year was associated with a 6% increase in the likelihood of receiving an opioid prescription from 2000 to 2010. Despite the apparent increase in use, there were no demonstrable improvements in the age- or sex-adjusted disability and health status measures of opioid users.
Conclusions
The use of prescription opioid analgesics among adult Americans has increased in recent years, and this increase does not appear to be associated with improvements in disability and health status among users. On a public health level, these data suggest that there may be an opportunity to reduce the prescribing of opioid analgesics without worsening of population health metrics.
doi:10.1097/AAP.0000000000000022
PMCID: PMC3955827  PMID: 24310049
4.  Parents' interest in whole-genome sequencing of newborns 
Purpose
The aim of this study was to assess parents' interest in whole-genome sequencing for newborns.
Methods
We conducted a survey of a nationally representative sample of 1,539 parents about their interest in whole-genome sequencing of newborns. Participants were randomly presented with one of two scenarios that differed in the venue of testing: one offered whole-genome sequencing through a state newborn screening program, whereas the other offered whole-genome sequencing in a pediatrician's office.
Results
Overall interest in having future newborns undergo wholegenome sequencing was generally high among parents. If wholegenome sequencing were offered through a state's newborn-screening program, 74% of parents were either definitely or somewhat interested in utilizing this technology. If offered in a pediatrician's office, 70% of parents were either definitely or somewhat interested. Parents in both groups most frequently identified test accuracy and the ability to prevent a child from developing a disease as “very important” in making a decision to have a newborn's whole genome sequenced.
Conclusion
These data may help health departments and children's health-care providers anticipate parents' level of interest in genomic screening for newborns. As whole-genome sequencing is integrated into clinical and public health services, these findings may inform the development of educational strategies and outreach messages for parents.
doi:10.1038/gim.2013.76
PMCID: PMC4164384  PMID: 23743552
newborn screening; parents; whole-genome sequencing
5.  Validity of Self Report in Type 1 Diabetic Subjects for Laser Treatment of Retinopathy 
Ophthalmology  2013;120(12):10.1016/j.ophtha.2013.06.002.
Purpose
This study sought to determine the validity of self report of prior pan-retinal photocoagulation (PRP) and focal photocoagulation (FP) compared to fundus photography.
Design
Prospective cohort study.
Participants
1363 type 1 diabetic subjects from the Epidemiology of Diabetes Interventions and Complications (EDIC) Study, a subset of the 1441 subjects originally enrolled in the multi-center Diabetes Control and Complications Trial.
Methods
At each annual visit, subjects were asked by EDIC staff whether they had PRP and/or FP since the last completed annual clinic visit. Fundus photographs were collected in one quarter of the cohort each year and in the whole cohort at EDIC years 4 and 10. Photographs were graded for the presence and extent of PRP and FP. Seventeen years of subject reporting and photograph grading of PRP and FP were compared in EDIC subjects.
Main Outcome Measures
Kappa, sensitivity, specificity, and positive and negative predictive values were calculated for subject-reported PRP and FP. Factors influencing subject misreporting were investigated.
Results
For subject reporting, 1244 (96%) of 1296 subjects with gradable photographs accurately reported whether they had a history of PRP in one or both eyes, and 1259 (97.5%) of 1291 with valid photographs correctly reported their history of FP. Sensitivities for PRP and FP were 90.4 and 74.0%; specificities, 96.0 and 98.8%; positive predictive values, 75.9 and 80.3%; negative predictive values, 98.9 and 98.4%; and kappa 0.80 and 0.76. Risk factors associated with misreporting include prior laser for diabetic retinopathy and prior ocular surgery (each p <0.04).
Conclusions
For subjects with type 1 diabetes, in the absence of a clinical exam or fundus photographs, subject self report could be a reliable tool in a well-monitored study for assessing laser treatment type in diabetic retinopathy.
doi:10.1016/j.ophtha.2013.06.002
PMCID: PMC3818390  PMID: 23890420
6.  Interpreting response time effects in functional imaging studies 
Neuroimage  2014;99(100):419-433.
It has been suggested that differential neural activity in imaging studies is most informative if it is independent of response time (RT) differences. However, others view RT as a behavioural index of key cognitive processes, which is likely linked to underlying neural activity. Here, we reconcile these views using the effort and engagement framework developed by Taylor, Rastle, and Davis (2013) and data from the domain of reading aloud. We propose that differences in neural engagement should be independent of RT, whereas, differences in neural effort should co-vary with RT. We illustrate these different mechanisms using data from an fMRI study of neural activity during reading aloud of regular words, irregular words, and pseudowords. In line with our proposals, activation revealed by contrasts designed to tap differences in neural engagement (e.g., words are meaningful and therefore engage semantic representations more than pseudowords) survived correction for RT, whereas activation for contrasts designed to tap differences in neural effort (e.g., it is more difficult to generate the pronunciation of pseudowords than words) correlated with RT. However, even for contrasts designed to tap neural effort, activity remained after factoring out the RT–BOLD response correlation. This may reveal unpredicted differences in neural engagement (e.g., learning phonological forms for pseudowords > words) that could further the development of cognitive models of reading aloud. Our framework provides a theoretically well-grounded and easily implemented method for analysing and interpreting RT effects in neuroimaging studies of cognitive processes.
Highlights
•We propose a way to interpret correlations between activity and RT in fMRI studies.•Activity for contrasts tapping neural engagement should be independent of RT.•Activity for contrasts tapping neural effort should correlate with RT.•RT correlated activity during pseudo and irregular word naming supports our proposal.•Additional engagement for pseudo and irregular words requires further investigation.
doi:10.1016/j.neuroimage.2014.05.073
PMCID: PMC4121088  PMID: 24904992
Response time; Reading aloud; Neuroimaging; Regularity; Lexicality; Learning
7.  Related functions of mGlu4 and mGlu8 
Metabotropic glutamate receptors modulate glutamatergic and GABAergic neurotransmission. Our previous pharmacological data indicate that metabotropic receptor 4 (mGlu4) and metabotropic receptor 8 (mGlu8) might have related and overlapping functions. We explored this by analyzing the behavioral phenotypes of mice deficient in either (mGlu4−/− or mGlu8−/−) or both receptors (mGlu4/8−/−). Our analysis focused on measures of anxiety in the open field and elevated zero maze, sensorimotor function on the rotorod, and fear conditioning, as mGlu4 and/or mGlu8 were shown to affect performance in these tests. mGlu8−/− mice weighed more than mGlu4/8−/− mice. In the open field, mGlu4−/− mice showed lower levels of anxiety than mGlu8−/− and mGlu4/8−/− mice. In the elevated zero maze, mGlu4−/− mice showed lower levels of anxiety than wild-type, mGlu8−/− and mGlu4/8−/− mice. In the open field, but not elevated zero maze, mGlu4−/− mice showed lower activity levels than wild-type, mGlu8−/− and mGlu4/8−/− mice. mGlu4/8−/− female mice showed less contextual freezing than wild-type and mGlu4−/− female mice and there was a trend toward less freezing in male mGlu4/8−/− than wild-type male mice. There were no genotype differences in cued fear conditioning. There were significant negative correlations between body weight and fall latency on the rotorod in wild-type, mGlu8−/− and mGlu4/8−/−, but not mGlu4−/−, mice. These data suggest related functions of mGlu4 and mGlu8 in behavioral performance.
doi:10.1016/j.pbb.2013.07.022
PMCID: PMC3806016  PMID: 23948069
mGlu4; mGlu8; open field; zero maze; fear conditioning; rotorod; body weight
8.  A Dietary-Wide Association Study (DWAS) of Environmental Metal Exposure in US Children and Adults 
PLoS ONE  2014;9(9):e104768.
Background
A growing body of evidence suggests that exposure to toxic metals occurs through diet but few studies have comprehensively examined dietary sources of exposure in US populations.
Purpose
Our goal was to perform a novel dietary-wide association study (DWAS) to identify specific dietary sources of lead, cadmium, mercury, and arsenic exposure in US children and adults.
Methods
We combined data from the National Health and Nutrition Examination Survey with data from the US Department of Agriculture's Food Intakes Converted to Retail Commodities Database to examine associations between 49 different foods and environmental metal exposure. Using blood and urinary biomarkers for lead, cadmium, mercury, and arsenic, we compared sources of dietary exposure among children to that of adults.
Results
Diet accounted for more of the variation in mercury and arsenic than lead and cadmium. For instance we estimate 4.5% of the variation of mercury among children and 10.5% among adults is explained by diet. We identified a previously unrecognized association between rice consumption and mercury in a US study population – adjusted for other dietary sources such as seafood, an increase of 10 g/day of rice consumption was associated with a 4.8% (95% CI: 3.6, 5.2) increase in blood mercury concentration. Associations between diet and metal exposure were similar among children and adults, and we recapitulated other known dietary sources of exposure.
Conclusion
Utilizing this combination of data sources, this approach has the potential to identify and monitor dietary sources of metal exposure in the US population.
doi:10.1371/journal.pone.0104768
PMCID: PMC4157769  PMID: 25198543
9.  Infant toenails as a biomarker of in utero arsenic exposure 
A growing body of evidence suggests that in utero and early-life exposure to arsenic may have detrimental effects on children, even at the low to moderate levels common in the United States and elsewhere. In a sample of 170 mother–infant pairs from New Hampshire, we determined infant exposure to in utero arsenic by evaluating infant toenails as a biomarker using inductively coupled plasma mass spectrometry. Infant toenail arsenic concentration correlated with maternal postpartum toenail concentrations (Spearman’s correlation coefficient 0.34). In adjusted linear models, a doubling of maternal toenail arsenic concentration was associated with a 53.8% increase in infant toenail arsenic concentration as compared with 20.4% for a doubling of maternal urine arsenic concentration. In a structural equation model, a doubling of the latent variable integrating maternal toenail and urine arsenic concentrations was associated with a 67.5% increase in infant toenail arsenic concentration. A similar correlation between infant and maternal postpartum toenail concentrations was observed in a validation cohort of 130 mother–infant pairs from Rhode Island. In utero exposure to arsenic occurs through maternal water and dietary sources, and infant toenails appear to be a reliable biomarker for estimating arsenic exposure during the critical window of gestation.
doi:10.1038/jes.2014.38
PMCID: PMC4141012  PMID: 24896769
biological markers; biomarkers; arsenic; prenatal exposure
10.  Medical Home Disparities Are Not Created Equal: Differences in the Medical Home for Children from Different Vulnerable Groups 
Objective
To identify components of the medical home that contribute to medical home disparities for vulnerable children.
Methods
Cross-sectional analysis of 2007 National Survey of Children’s Health. Prevalence of components of the medical home were estimated by special health care needs (SHCN), race/ethnicity, primary language, and health insurance.
Results
Medical home disparities for children with SHCN were driven by differences in getting help with care coordination, when needed (71% vs. 91% children without SHCN, p<.001). Medical home disparities for other groups were largely attributable to less family- centered care (Hispanic 49% and African American 55% vs. White 77%, p<.001; non- English primary language 37% vs. English 72%, p<.001; uninsured 45% and publicly insured 57% vs. privately insured 75%, p<.001).
Conclusions
The components of the medical home that contribute to medical home disparities differ between groups of vulnerable children. Medical home implementation may benefit from focusing on the specific needs of target populations.
doi:10.1353/hpu.2013.0117
PMCID: PMC4136422  PMID: 23974402
Pediatrics; medical home; disparities; health policy; National Survey of Children’s Health
11.  Extent of Sinus Surgery, 2000–2009: A Population-Based Study 
The Laryngoscope  2013;124(4):820-825.
Objective
Sinus surgery is one of the most frequently performed surgical operations. The objective was to determine if rates of surgery have changed over the last 10 years.
Study Design
Secondary data analysis of the State Ambulatory Surgery Database of Florida.
Methods
We calculated population adjusted rates of ambulatory sinus surgery for all adults, 2000–2009.
Result
There was a substantial decrease in the proportion of patients who had surgery in a hospital setting and a substantial increase in patients who had surgery with image guidance. Population-adjusted rates of sinus surgery increased over the study period, from a mean of 104 cases per 100,000 population in 2000 to 129 per 100,000 in 2009 (p<0.001). Procedure rates also increased, from a mean of 226 per 100,000 in 2000 to 316 per 100,000 in 2009 (p<0.001). Rates of frontal sinus procedures more than doubled, and rates of cases in which all 4 sinuses were treated tripled during the same time period. A greater number of sinus procedures was associated with use of image guidance, and high annual surgical case volume. The strongest predictor was the individual surgeon.
Conclusion
Rates of sinus surgery increased over the study period, with more patients undergoing surgery and more procedures per surgical case. The strong association of procedural patterns with specific surgeons in sinusitis care highlights the importance of future investigations to examine training, technological, and reimbursement factors that may influence surgeons’ clinical decision-making for this common condition.
doi:10.1002/lary.24335
PMCID: PMC4131235  PMID: 23900802
Adult rhinology; outcomes research; statistics
12.  Trends in the use and cost of chiropractic spinal manipulation under Medicare Part B 
BACKGROUND CONTEXT
Concern about improper payments to chiropractic physicians prompted the US Department of Health and Human Services to describe chiropractic services as a “significant vulnerability” for Medicare, but little is known about trends in the use and cost of chiropractic spinal manipulation provided under Medicare.
PURPOSE
To quantify the volume and cost of chiropractic spinal manipulation services for older adults under Medicare Part B and identify longitudinal trends.
STUDY DESIGN/SETTING
Serial cross-sectional design for retrospective analysis of administrative data.
PATIENT SAMPLE
Annualized nationally representative samples of 5.0 to 5.4 million beneficiaries.
OUTCOME MEASURES
Chiropractic users, allowed services, allowed charges, and payments.
METHODS
Descriptive statistics were generated by analysis of Medicare administrative data on chiropractic spinal manipulation provided in the United States from 2002 to 2008. A 20% nationally representative sample of allowed Medicare Part B fee-for-service claims was merged, based on beneficiary identifier, with patient demographic data. The data sample was restricted to adults aged 65 to 99 years, and duplicate claims were excluded. Annualized estimates of outcome measures were extrapolated, per beneficiary and per user rates were estimated, and volumes were stratified by current procedural terminology code.
RESULTS
The number of Medicare beneficiaries who used chiropractic spinal manipulation grew 13% from 2002 to 2004, remained flat through 2007, and then declined 5% through 2008. An estimated 1.7 million beneficiaries (6.9%) used 18.6 million allowed chiropractic services in 2008. In inflation-adjusted dollars, allowed charges per user increased 4% through 2005 and then declined by 17% through 2008; payments per user increased by 5% from 2002 to 2005 and then declined by 18% through 2008. Expenditures for chiropractic in 2008 totaled an estimated $420 million. Longitudinal trends in allowed claims for spinal manipulation varied by procedure: the relative frequency of treatment of one to two spinal regions declined from 43% to 29% of services, treatment of three to four regions increased from 48% to 62% of services, and treatment of five regions remained flat at 9% of services.
CONCLUSIONS
Chiropractic claims account for less than 1/10th of 1% of overall Medicare expenditures. Allowed services, allowed charges, and fee-for-service payments for chiropractic spinal manipulation under Medicare Part B generally increased from 2002, peaked in 2005 and 2006, and then declined through 2008. Per user spending for chiropractic spinal manipulation also declined by 18% from 2006 to 2008, in contrast to 10% growth in total spending per beneficiary and 16% growth in overall Medicare spending.
doi:10.1016/j.spinee.2013.05.012
PMCID: PMC4130205  PMID: 23773429
Chiropractic; Medicare; Aged; Use
13.  Long-Term Effects of Vitamins C, E, Beta-Carotene and Zinc on Age-Related Macular Degeneration. AREDS Report No. 35 
Ophthalmology  2013;120(8):1604-1611.e4.
Objective
To describe the long-term effects (10 years) of the Age-Related Eye Disease Study (AREDS) formulation of high-dose antioxidants and zinc supplement on progression of age-related macular degeneration (AMD).
Design
Multi-centered, randomized, controlled clinical trial; followed by epidemiologic follow-up study.
Participants
4757 participants with varying severity of AMD were enrolled in the clinical trial. 3549 surviving participants consented to the follow-up study.
Methods
Participants were randomly assigned to antioxidants C, E, and beta-carotene and/or zinc vs. placebo during the clinical trial. In participants with intermediate AMD or advanced AMD in one eye, the AREDS formulation delayed the progression to advanced AMD. Participants were then enrolled in a follow-up study. Eye exams were conducted with annual fundus photographs and best-corrected visual acuity assessments. Medical histories and mortality were obtained for safety monitoring. Repeated measures logistic regression was used in the primary analyses.
Main Outcome Measurement
(1) Photographic assessment of progression to, or history of treatment for, advanced AMD [neovascular (NV) or central geographic atrophy (CGA)], and (2) moderate visual acuity loss from baseline (≥ 15 letters).
Results
Comparison of the participants originally assigned to placebo in AREDS categories 3 and 4 at baseline with those originally assigned to AREDS formulation at 10 years demonstrated a statistically significant (p<0.001) odds reduction in the risk of developing advanced AMD or the development of NV AMD (odds ratios and 99% confidence intervals: OR 0.66, CI: (0.53–0.83) and OR 0.60, CI: (0.47–0. 78), respectively). No statistically significant reduction (p=0.93) was seen for the CGA (OR 1.02, CI: 0.71–1.45). A statistically significant reduction (p=0.002) for the development of moderate vision loss was seen (OR 0.71, CI: 0.57–0.88). No adverse effects were associated with the AREDS formulation. Mortality was reduced in participants assigned to zinc, especially death from circulatory diseases.
Conclusion
Five years after the clinical trial ended, the beneficial effects of the AREDS formulation persisted for development of NV AMD but not for CGA. These results are consistent with the original recommendations that persons with intermediate AMD or advanced AMD in one eye should consider taking the AREDS formulation.
doi:10.1016/j.ophtha.2013.01.021
PMCID: PMC3728272  PMID: 23582353
14.  Early Effects of Whole-Body 56Fe Irradiation on Hippocampal Function in C57BL/6J Mice 
Radiation research  2013;179(5):590-596.
Relatively little is known about early irradiation effects on hippocampal function in wild-type mice. In this study, the effects of 56Fe irradiation on hippocampal function were assessed starting 2 weeks after whole-body irradiation. Compared to sham irradiation, radiation impaired novel object recognition in female and male C57BL/6J wild-type mice. There were no effects of irradiation on contextual fear conditioning or spatial memory retention in the water maze. It is possible that oxidative damage might contribute to radiation-induced cognitive changes. Therefore, hippocampal and cortical levels of 3-nitrotyrosine (3NT) and lipid peroxidation, measures of oxidative damage were assessed. There were no effects of irradiation on these measures of oxidative damage. As 56Fe irradiation can increase reactive oxygen species (ROS) levels, which may contribute to the impairments in novel object recognition, the effects of the antioxidant alpha-lipoic acid (ALA) on cognition following sham irradiation and irradiation were also assessed. ALA did not prevent radiation-induced impairments in novel object recognition and impaired spatial memory retention of sham-irradiated and irradiated mice in the probe trial after the first day of hidden platform training in the water maze. Thus, the novel object recognition test is particularly sensitive to detect early cognitive effects of 56Fe irradiation through a mechanism unlikely involving ROS or oxidative damage.
doi:10.1667/RR2946.1
PMCID: PMC4117374  PMID: 23510274
15.  Comparison of Standardized Clinical Classification with Fundus Photograph Grading for the assessment of Diabetic Retinopathy and Diabetic Macular Edema Severity 
Retina (Philadelphia, Pa.)  2013;33(7):10.1097/IAE.0b013e318286c952.
Purpose
To compare evaluation by clinical examination with image grading at a reading center (RC) for the classification of diabetic retinopathy (DR) and diabetic macular edema (DME).
Methods
ACCORD and FIND had similar methods of clinical and fundus photograph evaluation. For analysis purposes the photographic grading scales were condensed to correspond to the clinical scales and agreement between clinicians and reading center classification were compared.
Results
6902 eyes of ACCORD participants and 3638 eyes of FIND participants were analyzed for agreement (percent, kappa) on DR on a 5 level scale. Exact agreement between clinicians and RC on DR severity category was 69% in ACCORD and 74% in FIND (Kappa 0.42 and 0.65). Sensitivity of the clinical grading to identify presence of mild nonproliferative retinopathy or worse was 0.53 in ACCORD and 0.84 in FIND. Specificities were 0.97 and 0.96, respectively. DME agreement in 6649 eyes of ACCORD participants and 3366 eyes of FIND participants was similar in both studies (Kappa 0.35 and 0.41). Sensitivities of the clinical grading to identify DME were 0.44 and 0.53 and specificities were 0.99 and 0.94, respectively.
Conclusion
Our results support the use of clinical information for defining broad severity categories, but not for documenting small to moderate changes in DR over time.
doi:10.1097/IAE.0b013e318286c952
PMCID: PMC3706017  PMID: 23615341
ACCORD; FIND; Diabetic retinopathy; fundus photography
16.  Acute Sterol O-Acyltransferase 2 (SOAT2) Knockdown Rapidly Mobilizes Hepatic Cholesterol for Fecal Excretion 
PLoS ONE  2014;9(6):e98953.
The primary risk factor for atherosclerotic cardiovascular disease is LDL cholesterol, which can be reduced by increasing cholesterol excretion from the body. Fecal cholesterol excretion can be driven by a hepatobiliary as well as a non-biliary pathway known as transintestinal cholesterol efflux (TICE). We previously showed that chronic knockdown of the hepatic cholesterol esterifying enzyme sterol O-acyltransferase 2 (SOAT2) increased fecal cholesterol loss via TICE. To elucidate the initial events that stimulate TICE, C57Bl/6 mice were fed a high cholesterol diet to induce hepatic cholesterol accumulation and were then treated for 1 or 2 weeks with an antisense oligonucleotide targeting SOAT2. Within 2 weeks of hepatic SOAT2 knockdown (SOAT2HKD), the concentration of cholesteryl ester in the liver was reduced by 70% without a reciprocal increase in hepatic free cholesterol. The rapid mobilization of hepatic cholesterol stores resulted in a ∼2-fold increase in fecal neutral sterol loss but no change in biliary cholesterol concentration. Acute SOAT2HKD increased plasma cholesterol carried primarily in lipoproteins enriched in apoB and apoE. Collectively, our data suggest that acutely reducing SOAT2 causes hepatic cholesterol to be swiftly mobilized and packaged onto nascent lipoproteins that feed cholesterol into the TICE pathway for fecal excretion.
doi:10.1371/journal.pone.0098953
PMCID: PMC4047063  PMID: 24901470
17.  To Pay or not to Pay: Public Perception Regarding Insurance Coverage of Obesity Treatment 
Obesity (Silver Spring, Md.)  2013;21(12):10.1002/oby.20387.
Objective
To explore public opinion regarding insurance coverage for obesity treatment among severely obese adolescents.
Design and Methods
The National Poll on Children’s Health was fielded to a nationally representative sample of US adults, January 2011. Respondents (n=2150) indicated whether insurance should cover specific weight management services for obese adolescents and whether private insurance and Medicaid should cover bariatric surgery. Sampling weights were applied to generate nationally representative results. Linear and logistic regression analyses were performed to assess associations.
Results
More respondents endorsed insurance coverage for traditional healthcare services (mental health 86%, dietitian 84%) than for services generally viewed as outside the healthcare arena (exercise programs 65%, group programs 60%). For bariatric surgery, 81% endorsed private insurance coverage; 55% endorsed Medicaid coverage. Medicaid enrollees, black, Hispanic, and low-income respondents had greater odds (p<0.05) of endorsing bariatric surgery coverage by Medicaid, compared to the referent groups (non-Hispanic white, income ≥ $60K, private insurance).
Conclusion
While public support for insurance coverage of traditional weight management services appears high, support for Medicaid coverage for bariatric surgery is lower and varies by demographics. If public opinion is a harbinger of future coverage, low-income adolescents could experience disparities in access to treatments like bariatric surgery.
doi:10.1002/oby.20387
PMCID: PMC3692585  PMID: 23512908
pediatrics; obesity; bariatric surgery; insurance; adolescents; costs
18.  Varying whole body vibration amplitude differentially affects tendon and ligament structural and material properties 
Journal of biomechanics  2013;46(9):1496-1500.
Whole Body Vibration (WBV) is becoming increasingly popular for helping to maintain bone mass and strengthening muscle. Vibration regimens optimized for bone maintenance often operate at hypogravity levels (<1 G) and regimens for muscle strengthening often employ hypergravity (>1 G) vibrations. The effect of vibratory loads on tendon and ligament properties is unclear though excessive vibrations may be injurious. Our objective was to evaluate how tendon gene expression and the mechanical/histological properties of tendon and ligament were affected in response to WBV in the following groups: no vibration, low vibration (0.3 G peak-to-peak), and high vibration (2 G peak-to-peak). Rats were vibrated for 20 min a day, 5 days a week, for 5 weeks. Upon sacrifice, the medial collateral ligament (MCL), patellar tendon (PT), and the Achilles Tendon (AT) were isolated with insertion sites intact. All tissues were tensile tested to determine structural and material properties or used for histology. Patellar tendon was also subjected to quantitative RT-PCR to evaluate expression of anabolic and catabolic genes. No differences in biomechanical data between the control and the low vibration groups were found. There was evidence of significant weakness in the MCL with high vibration, but no significant effect on the PT or AT. Histology of the MCL and PT showed a hypercellular tissue response and some fiber disorganization with high vibration. High vibration caused an increase in collagen expression and a trend for an increase in IGF-1 expression suggesting a potential anabolic response to prevent tendon overuse injury.
doi:10.1016/j.jbiomech.2013.03.033
PMCID: PMC4020418  PMID: 23623311
Whole body vibration; Acceleration; Tendon; Ligament; Collagen expression
19.  Regulated Expression of Rhox8 in the Mouse Ovary: Evidence for the Role of Progesterone and RHOX5 in Granulosa Cells1 
Biology of Reproduction  2013;88(5):126.
ABSTRACT
The gonadotropin surge is the essential trigger to stimulate ovulation and luteinization of ovarian follicles. While the hormone signals from the brain that initiate ovulation are known, the specific targets which regulate this process are not well known. In this study, we assessed the suitability of the Rhox homeobox gene cluster to serve as the master regulators of folliculogenesis. In superovulated (equine chorionic gonadotropin [eCG]/human chorionic gonadotropin [hCG]) mice, the Rhox genes exhibited four distinct windows of peak expression, suggesting that these genes may regulate specific events during the ovulatory cycle. Like many members of the cluster, Rhox8 mRNA and protein were induced by follicle stimulating hormone [FSH]/eCG in granulosa cells. However, Rhox8 displayed unique peak expression at 8 h post-hCG administration, implying it might be the lone member of the cluster regulated by progesterone. Subsequent promoter analysis in granulosa cells revealed relevant homeobox binding and progesterone response elements within Rhox8's 5′-flanking region. In superovulated mice, progesterone receptor (PGR) is recruited to the Rhox8 promoter, as assessed by chromatin immunoprecipitation. In Rhox5-null mice, Rhox8 mRNA was reduced at 2 h and 4 h post-hCG administration but recovered once the follicles passed the antral stage of development. Conversely, in progesterone receptor knockout mice, Rhox8 exhibited normal stimulation by eCG but failed to reach its peak mRNA level at 8 h post-hCG found in wild-type mice. This suggests a model in which Rhox8 transcription is dependent upon RHOX5 during early folliculogenesis and upon progesterone during the periovulatory window when RHOX5 normally wanes. In support of this model, transfection of RHOX5 and PGR expression plasmids stimulated, whereas dominant negative and mutant constructs inhibited, Rhox8 promoter activity.
The Rhox homeobox gene cluster is differentially expressed during folliculogenesis in mice; RHOX8 is a potential candidate for translating progesterone signaling into successful ovulation.
doi:10.1095/biolreprod.112.103267
PMCID: PMC4013910  PMID: 23536368
gene regulation; granulosa cells; progesterone; progesterone receptor; transcriptional regulation
20.  Hyperbaric oxygen therapy for chronic post-concussive syndrome 
In this editorial, the value of hyperbaric oxygen therapy in the management of chronic post-concussive syndrome following mild traumatic brain injury is discussed.
doi:10.1186/2045-9912-4-8
PMCID: PMC3984490  PMID: 24717073
Hyperbaric oxygen; Traumatic brain injury; Outcome
21.  Role of mGluR4 in acquisition of fear learning and memory 
Neuropharmacology  2012;66:365-372.
Group III metabotropic glutamate receptors (mGluRs), which are generally located presynaptically, modulate synaptic transmission by regulating neurotransmitter release. Previously we showed enhanced amygdala-dependent cued fear conditioning in mGluR4−/− mice 24 hr following training involving two tone-shock pairings. In this study, we assessed the effects of modulating mGluR4 signaling on acquisition and extinction of conditioned fear. mGluR4−/− and wild-type female and male mice received 10 tone-shock pairings during training. Compared to wild-type mice, mGluR4−/− mice showed enhanced acquisition and extinction of cued fear. Next, we assessed whether acute pharmacological stimulation of mGluR4 with the specific orthosteric mGluR4 agonist LSP1-2111 also affects acquisition and extinction of cued fear. Consistent with the enhanced acquisition of cued fear in mGluR4−/−, LSP1-2111, at 2.5 and 5mg/kg, inhibited acquisition of cued fear conditioning in wild-type male mice. The drug’s effect on extinction was less clear and only a subtle effect was seen at 5 mg/kg. Finally, analysis of microarray data of amygdala tissues from mGluR4−/− versus wild-type and from wild-type mice treated with a mGluR4 agonist versus saline revealed a significant overlap in pattern of gene expression. Together, these data support a role for mGluR4 signaling in acquisition of fear learning and memory.
doi:10.1016/j.neuropharm.2012.07.038
PMCID: PMC3508079  PMID: 22884897
mGluR4; fear conditioning; mice; cued
22.  Associations between Body Composition and Bone Density and Structure in Men and Women across the Adult Age Spectrum 
Bone  2012;53(1):34-41.
Background/Purpose
The objective of this study was identify independent associations between body composition and bone outcomes, including cortical structure and cortical and trabecular volumetric bone mineral density (vBMD) across the adult age spectrum.
Methods
This cross-sectional study evaluated over 400 healthy adults (48% male, 44% black race), ages 21–78 years. Multivariable linear regression models evaluated associations between whole-body DXA measures of lean body mass index (LBMI) and fat mass index (FMI) and tibia peripheral quantitative CT (pQCT) measures of cortical section modulus, cortical and trabecular vBMD and muscle density (as a measure of intramuscular fat), adjusted for age, sex, and race. All associations reported below were statistically significant (p < 0.05).
Results
Older age and female sex were associated with lower LBMI and muscle strength. Black race was associated with greater LBMI but lower muscle density. Greater FMI was associated with lower muscle density. Cortical section modulus was positively associated with LBMI and muscle strength and negatively associated with FMI. Adjustment for body composition eliminated the greater section modulus observed in black participants and attenuated the lower section modulus in females. Greater LBMI was associated with lower cortical BMD and greater trabecular BMD. FMI was not associated with either BMD outcome. Greater muscle density was associated with greater trabecular and cortical BMD. Associations between body composition and bone outcomes did not vary by sex (no significant tests for interaction).
Conclusions
These data highlight age, sex- and race-specific differences in body composition, muscle strength and muscle density, and demonstrate discrete associations with bone density and structure. These data also show that age, sex- and race- related patterns of bone density and strength are independent of differences in body composition. Longitudinal studies are needed to examine the temporal relations between changes in bone and body composition.
doi:10.1016/j.bone.2012.11.035
PMCID: PMC3552077  PMID: 23238122
DXA; lean mass; pQCT; section modulus; bone mineral density; muscle density
23.  A Randomized Controlled Effectiveness Trial of Reciprocal Peer Support in Heart Failure 
Circulation. Heart failure  2013;6(2):246-253.
Background
Disease management programs for patients hospitalized with heart failure (HF) although effective, are often resource intensive, limiting their uptake. Peer support programs have led to improved outcomes among patients with other chronic conditions and may result in similar improvements for HF patients.
Methods and Results
In this randomized controlled trial, Reciprocal Peer Support (RSP) arm patients participated in a HF nurse practitioner (NP)-led goal setting group session, received brief training in peer communication skills, and were paired with another participant in their cohort with whom they were encouraged to talk weekly using a telephone platform. Participants were also encouraged to attend three NP-facilitated peer support group sessions. Patients in the Nurse Care Management (NCM) arm attended a NP-led session to address their HF care questions and receive HF educational materials and information on how to access care management services. The median age of the patients was 69 years, 51% were female, and 26% were racial/ethnic minorities. Only 55% of RPS patients participated in peer calls or group sessions. In intention-to-treat analyses, the RPS and NCM groups did not differ in time to first all-cause rehospitalization or death or in mean numbers of rehospitalizations or deaths. There were no differences in improvements in 6-month measures of HF-specific quality of life or social support.
Conclusions
Among patients recently hospitalized for HF, over half of RPS participants had no or minimal engagement with the reciprocal peer support program, and the program did not improve outcomes compared to usual HF-nurse care management.
doi:10.1161/CIRCHEARTFAILURE.112.000147
PMCID: PMC3782294  PMID: 23388114
heart failure; peer support; randomized controlled trial; self-management; nurse case management
24.  The Factors Associated With High-Quality Communication for Critically Ill Children 
Pediatrics  2013;131(Suppl 1):S90-S95.
OBJECTIVE:
Timely, high quality communication with families is essential to family-centered decision-making. Quality communication is represented by widespread documentation of prognostic, goals-of-care conversations (PGOCC) in the pediatric intensive care unit (PICU) and should occur without variation by patient characteristics.
METHODS:
Cohort included 645 PICU admissions in the top decile of risk of mortality on admission over six years. Electronic medical records were used to determine PGOCC, diagnosis on admission and complex chronic condition (CCC) status. Multivariate logistic regression and time-to-event analyses were used.
RESULTS:
Overall, 31% had a documented PGOCC. 51% had CCC status. 11% had an oncologic, 13% had a cardiovascular diagnosis on admission. 94% of patients who died in the PICU had PGOCC documented, but among the 200 patients with documented PGOCC, 78% did not die in the PICU. Oncologic diagnosis on admission was associated with a higher likelihood of PGOCC compared to non-CCC patients (ARR=1.86; SE=0.26) whereas no other diagnosis category reached the level of statistical significance. Median time from admission to PGOCC was 2 days. Age, gender and CCC status were not associated with whether a PGOCC was documented or with time from admission to PGOCC documentation. 45% of PGOCC in the cohort and 50% of conversations in patients with CCC were documented by PICU physicians.
CONCLUSIONS:
This study reveals the opportunity for improvement in documentation of PGOCC for critically ill children. It raises the questions of why there is variation of PGOCC across disease categories and whether PGOCC should be considered a quality measure for family-centered care.
doi:10.1542/peds.2012-1427k
PMCID: PMC4258825  PMID: 23457155
quality improvement; pediatric ICU; family-centered care; patient care planning; doctor–patient communication
25.  Species-specific bioluminescence facilitates speciation in the deep sea 
Marine Biology  2014;161(5):1139-1148.
The vast darkness of the deep sea is an environment with few obvious genetic isolating barriers, and little is known regarding the macroevolutionary processes that have shaped present-day biodiversity in this habitat. Bioluminescence, the production and emission of light from a living organism through a chemical reaction, is thought to occur in approximately 80 % of the eukaryotic life that inhabits the deep sea (water depth greater than 200 m). In this study, we show, for the first time, that deep-sea fishes that possess species-specific bioluminescent structures (e.g., lanternfishes, dragonfishes) are diversifying into new species at a more rapid rate than deep-sea fishes that utilize bioluminescence in ways that would not promote isolation of populations (e.g., camouflage, predation). This work adds to our understanding of how life thrives and evolution shaped present-day biodiversity in the deep sea, the largest and arguably least explored habitat on earth.
Electronic supplementary material
The online version of this article (doi:10.1007/s00227-014-2406-x) contains supplementary material, which is available to authorized users.
doi:10.1007/s00227-014-2406-x
PMCID: PMC3996283  PMID: 24771948

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