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1.  HEALTHY BOUTS OF ACTIVITY: INTEGRATING GPS AND ACCELEROMETRY FOR MAP-PROMPTED BOUT RECALLS 
British journal of sports medicine  2014;48(13):1054-1058.
Objective
Obtaining the “when, where, and why” of healthy bouts of moderate-to-vigorous physical activity (MVPA) provides insights into natural physical activity
Design
In Salt Lake City, Utah, adults wore accelerometer and GPS loggers for a week in a cross-sectional study to establish baseline travel and activity patterns near a planned Complete Street intervention involving a new rail line, new sidewalks, and a bike path.
Results
At the end of the week research assistants met with the 918 participants who had at least three 10-hour days of good accelerometer readings. Accelerometer and GPS data were uploaded and integrated within a custom application, and participants were provided with maps and time information for past MVPA bouts of ≥ 3 minutes to help them recall bout details. Participants said that ‘getting someplace” was, on average, a more important motivation for their bouts than leisure or exercise. A series of recall tests showed that participants recalled most bouts they were asked about, regardless of duration of the bout, suggesting that participant perceptions of their shorter lifestyle bouts can be studied with this methodology. Visual prompting with a map depicting where each bout took place yielded more accurate recall than prompting with time cues alone.
Conclusion
These techniques provide a novel way to understand participant memories of the context and subjective assessments associated with healthy bouts of physical activity. Prompts with time-stamped maps that illustrate places of moderate-to-vigorous physical activity offer an effective method to improve understanding of activity and its supportive socio-physical contexts.
doi:10.1136/bjsports-2014-093530
PMCID: PMC4324627  PMID: 24815545
Physical activity; neighborhood; mental recall; global positioning system; walking
2.  Upper abdominal normal organ contouring guidelines and atlas: A Radiation Therapy Oncology Group consensus 
Practical radiation oncology  2013;4(2):82-89.
Purpose
To standardize upper abdominal normal organ contouring guidelines for Radiation Therapy Oncology Group (RTOG) trials.
Methods and Materials
Twelve expert radiation oncologists contoured the liver, esophagus, gastroesophageal junction (GEJ), stomach, duodenum, and common bile duct (CBD), and reviewed and edited 33 additional normal organ and blood vessel contours on an anonymized patient computed tomography (CT) dataset. Contours were overlaid and compared for agreement using MATLAB (MathWorks, Natick, MA). S95 contours, defined as the binomial distribution to generate 95% group consensus contours, and normal organ contouring definitions were generated and reviewed by the panel.
Results
There was excellent consistency and agreement of the liver, duodenal, and stomach contours, with substantial consistency for the esophagus contour, and moderate consistency for the GEJ and CBD contours using a Kappa statistic. Consensus definitions, detailed normal organ contouring recommendations and high-resolution images were developed.
Conclusions
Consensus contouring guidelines and a CT image atlas should improve contouring uniformity in radiation oncology clinical planning and RTOG trials.
doi:10.1016/j.prro.2013.06.004
PMCID: PMC4285338  PMID: 24890348
3.  Interobserver Variability in Target Definition for Hepatocellular Carcinoma With and Without Portal Vein Thrombus: Radiation Therapy Oncology Group Consensus Guidelines 
Purpose
Defining hepatocellular carcinoma (HCC) gross tumor volume (GTV) requires multimodal imaging, acquired in different perfusion phases. The purposes of this study were to evaluate the variability in contouring and to establish guidelines and educational recommendations for reproducible HCC contouring for treatment planning.
Methods and Materials
Anonymous, multiphasic planning computed tomography scans obtained from 3 patients with HCC were identified and distributed to a panel of 11 gastrointestinal radiation oncologists. Panelists were asked the number of HCC cases they treated in the past year. Case 1 had no vascular involvement, case 2 had extensive portal vein involvement, and case 3 had minor branched portal vein involvement. The agreement between the contoured total GTVs (primary + vascular GTV) was assessed using the generalized kappa statistic. Agreement interpretation was evaluated using Landis and Koch’s interpretation of strength of agreement. The S95 contour, defined using the simultaneous truth and performance level estimation (STAPLE) algorithm consensus at the 95% confidence level, was created for each case.
Results
Of the 11 panelists, 3 had treated >25 cases in the past year, 2 had treated 10 to 25 cases, 2 had treated 5 to 10 cases, 2 had treated 1 to 5 cases, 1 had treated 0 cases, and 1 did not respond. Near perfect agreement was seen for case 1, and substantial agreement was seen for cases 2 and 3. For case 2, there was significant heterogeneity in the volume identified as tumor thrombus (range 0.58–40.45 cc). For case 3, 2 panelists did not include the branched portal vein thrombus, and 7 panelists contoured thrombus separately from the primary tumor, also showing significant heterogeneity in volume of tumor thrombus (range 4.52–34.27 cc).
Conclusions
In a group of experts, excellent agreement was seen in contouring total GTV. Heterogeneity exists in the definition of portal vein thrombus that may impact treatment planning, especially if differential dosing is contemplated. Guidelines for HCC GTV contouring are recommended.
doi:10.1016/j.ijrobp.2014.03.041
PMCID: PMC4285340  PMID: 24969794
4.  Association between intensification of metformin treatment with insulin versus sulfonylureas and cardiovascular events and all-cause mortality among patients with diabetes 
Importance
Preferred second line medication for diabetes treatment after metformin failure remains uncertain.
Objective
We compared time to acute myocardial infarction [AMI], stroke, or death in a cohort of metformin initiators who added insulin or a sulfonylurea.
Design
Retrospective cohort constructed using national Veterans Health Administration, Medicare, and National Death Index databases.
Participants
Veterans initially treated with metformin from 2001 through 2008 who subsequently added either insulin or sulfonylurea. Each insulin intensifier was propensity score matched by characteristics to five sulfonylurea intensifiers. Patients were followed through September, 2011 for primary analyses or September, 2009 for cause of death analyses.
Main Outcome Measures
Risk of a composite outcome of AMI, stroke hospitalization or all-cause death was compared between therapies using marginal structural Cox proportional hazard models to adjust for baseline and time-varying demographics, medications, cholesterol, hemoglobin A1c, creatinine, blood pressure, body mass index, and co-morbidities.
Results
Among 178,341 metformin monotherapy patients, 2,948 and 39,990 added insulin or sulfonylurea, respectively. Propensity score matching yielded 2,436 metformin+insulin and 12,180 metformin+sulfonylurea patients. At intensification, the median (interquartile range) time on metformin was 14 months (5, 30) and HbA1c was 8.1% (7.2, 9.9). There were 172 versus 634 events for the primary outcome among those who added insulin versus sulfonylureas respectively (42 versus 33 events per 1000 person-years, adjusted hazard ratio [aHR] 1.30, 95% confidence interval [CI] 1.07, 1.58, p=0.009). AMI and stroke rates were statistically similar 41 versus 229 (10.2 and 11.9 per 1000 person years, aHR 0.88,95% CI 0.59, 1.30, p=0.52), while all-cause death rates were137 versus 444, respectively (33.7 and 22.7 per 1000 person-years, aHR 1.44, 95% CI,1.15, 1.79, p=0.001). There were 54 versus 258 secondary outcomes: AMI, stroke hospitalizations or cardiovascular deaths (22.8 vs. 22.5 events per 1000 person years aHR 0.98, 95% CI 0.71, 1.34. p=0.87).
Conclusions
Among patients with diabetes using metformin, the addition of insulin versus sulfonylurea was associated with an increased risk of a composite of nonfatal cardiovascular outcomes and all-cause mortality. These findings require further investigation to understand risks associated with insulin use in these patients.
doi:10.1001/jama.2014.4312
PMCID: PMC4149288  PMID: 24915260
Diabetes mellitus; cardiovascular disease; insulin; treatment intensification; comparative effectiveness
5.  Common misconceptions about data analysis and statistics1 
Ideally, any experienced investigator with the right tools should be able to reproduce a finding published in a peer-reviewed biomedical science journal. In fact, the reproducibility of a large percentage of published findings has been questioned. Undoubtedly, there are many reasons for this, but one reason may be that investigators fool themselves due to a poor understanding of statistical concepts. In particular, investigators often make these mistakes: (1) P-Hacking. This is when you reanalyze a data set in many different ways, or perhaps reanalyze with additional replicates, until you get the result you want. (2) Overemphasis on P values rather than on the actual size of the observed effect. (3) Overuse of statistical hypothesis testing, and being seduced by the word “significant”. (4) Overreliance on standard errors, which are often misunderstood.
doi:10.1002/prp2.93
PMCID: PMC4317225
6.  Lower Levels of Circulating Progenitor Cells Are Associated With Low Physical Function and Performance in Elderly Men With Impaired Glucose Tolerance: A Pilot Substudy From the VA Enhanced Fitness Trial 
Background.
Aging is marked by a decline in physical function. Although the biological underpinnings for this remain unclear, loss of regenerative capacity has been proposed as one cause of the loss of physical function that occurs over time. The quantity of circulating progenitor cells (CPCs) may be one reflection of regenerative capability. We sought to determine whether certain specific CPC subpopulations were associated with physical function.
Methods.
Baseline CPCs were measured in 129 randomized participants in the Enhanced Fitness clinical trial based on the cell surface markers CD34, CD133, CD146, and CD14 and aldehyde dehydrogenase (ALDH) activity. Physical function was assessed using usual and rapid gait speed, 6-minute walk distance, chair stand time, and balance time.
Results.
Low counts of early angiogenic CPCs identified as CD34+, CD34+CD133+, and ALDH-bright (ALDHbr) cells were associated with low usual gait speed (p < .005, p < .001, and p < .007), rapid gait speed (p < .001, p < .003, and p < .001), and 6-minute walking distance (all comparisons p < .001), and longer time required to complete five chair stands (p < .006, p < .002, and p < .004). CPC counts of mature endothelial or monocytic markers were not associated with physical function.
Conclusions.
The numbers of CD34+ and ALDHbr CPCs are significantly lower in patients with impaired physical function. Further studies are needed to determine the underlying causes for this association.
doi:10.1093/gerona/glt067
PMCID: PMC3814238  PMID: 23682163
Endothelial progenitor cells; Physical performance; Physical function; Aging; Progenitor cells biology.
7.  Molecular Signaling Network Motifs Provide a Mechanistic Basis for Cellular Threshold Responses 
Environmental Health Perspectives  2014;122(12):1261-1270.
Background: Increasingly, there is a move toward using in vitro toxicity testing to assess human health risk due to chemical exposure. As with in vivo toxicity testing, an important question for in vitro results is whether there are thresholds for adverse cellular responses. Empirical evaluations may show consistency with thresholds, but the main evidence has to come from mechanistic considerations.
Objectives: Cellular response behaviors depend on the molecular pathway and circuitry in the cell and the manner in which chemicals perturb these circuits. Understanding circuit structures that are inherently capable of resisting small perturbations and producing threshold responses is an important step towards mechanistically interpreting in vitro testing data.
Methods: Here we have examined dose–response characteristics for several biochemical network motifs. These network motifs are basic building blocks of molecular circuits underpinning a variety of cellular functions, including adaptation, homeostasis, proliferation, differentiation, and apoptosis. For each motif, we present biological examples and models to illustrate how thresholds arise from specific network structures.
Discussion and Conclusion: Integral feedback, feedforward, and transcritical bifurcation motifs can generate thresholds. Other motifs (e.g., proportional feedback and ultrasensitivity)produce responses where the slope in the low-dose region is small and stays close to the baseline. Feedforward control may lead to nonmonotonic or hormetic responses. We conclude that network motifs provide a basis for understanding thresholds for cellular responses. Computational pathway modeling of these motifs and their combinations occurring in molecular signaling networks will be a key element in new risk assessment approaches based on in vitro cellular assays.
Citation: Zhang Q, Bhattacharya S, Conolly RB, Clewell HJ III, Kaminski NE, Andersen ME. 2014. Molecular signaling network motifs provide a mechanistic basis for cellular threshold responses. Environ Health Perspect 122:1261–1270; http://dx.doi.org/10.1289/ehp.1408244
doi:10.1289/ehp.1408244
PMCID: PMC4256703  PMID: 25117432
8.  The effectiveness of flow cytometric sorting of human sperm (MicroSort®) for influencing a child’s sex 
Background
Flow cytometric sorting can be used to separate sperm based on sex chromosome content. Differential fluorescence emitted by stained X- vs. Y-chromosome-bearing sperm enables sorting and collection of samples enriched in either X- or Y-bearing sperm for use to influence the likelihood that the offspring will be a particular sex. Herein we report the effectiveness of flow cytometric sorting of human sperm and its use in human ART procedures.
Methods
This prospective, observational cohort study of the series of subjects treated with flow cytometrically sorted human sperm was conducted at investigational sites at two private reproductive centers. After meeting inclusion criteria, married couples (n = 4993) enrolled to reduce the likelihood of sex-linked or sex-limited disease in future children (n = 383) or to balance the sex ratio of their children (n = 4610). Fresh or frozen-thawed semen was processed and recovered sperm were stained with Hoechst 33342 and sorted by flow cytometry (n = 7718) to increase the percentage of X-bearing sperm (n = 5635) or Y-bearing sperm (n = 2083) in the sorted specimen. Sorted sperm were used for IUI (n = 4448) and IVF/ICSI (n = 2957). Measures of effectiveness were the percentage of X- and Y-bearing sperm in sorted samples, determined by fluorescence in situ hybridization, sex of babies born, IVF/ICSI fertilization- and cleavage rates, and IUI, IVF/ICSI, FET pregnancy rates and miscarriage rates.
Results
Sorted specimens averaged 87.7 ± 5.0% X-bearing sperm after sorting for X and 74.3 ± 7.0% Y-bearing sperm after sorting for Y. Seventy-three percent of sorts were for girls. For babies born, 93.5% were females and 85.3% were males after sorting for X- and Y-bearing sperm, respectively. IUI, IVF/ICSI, and FET clinical pregnancy rates were 14.7%, 30.8%, and 32.1%, respectively; clinical miscarriage rates were 15.5%, 10.2%, and 12.7%.
Conclusions
Flow cytometric sorting of human sperm shifted the X:Y sperm ratio. IUI, IVF/ICSI and FET outcomes were consistent with unimpaired sperm function. Results provide evidence supporting the effectiveness of flow cytometric sorting of human sperm for use as a preconception method of influencing a baby’s sex.
Trial registration
NCT00865735 (ClinicalTrials.gov)
doi:10.1186/1477-7827-12-106
PMCID: PMC4256056  PMID: 25420620
Human sperm, sperm sorting; Flow cytometry; Sex selection; IUI; IVF/ICSI; FET; ART procedures
9.  Depletion of Circulating Progenitor Cells Precedes Overt Diabetes: A Substudy from the VA Enhanced Fitness Trial 
Journal of diabetes and its complications  2013;27(6):10.1016/j.jdiacomp.2013.08.004.
Background
One theory of aging and disease development is that chronic injury (pathology) results in activation of regenerative processes and initial repair, with overt disease arising only after exhaustion of reparative capability leads to inadequate repair. While depletion of circulating progenitor cells (CPCs) has been noted in diabetes, the degree to which CPC depletion predates and is associated with propensity to develop overt disease is unclear.
Methods
The Enhanced Fitness trial enrolled overweight/obese (body mass index >25) sedentary patients with glucose intolerance but without overt diabetes. Baseline CPCs were measured in 129 patients based on the cell surface markers CD34, CD133, and aldehyde dehydrogenase (ALDH) activity. HgbA1C, fasting insulin and glucose levels, and HOMA calculations were ascertained.
Results
Lower counts of early angiogenic CPCs identified as CD34+, CD34+CD133+, and ALDH-bright (ALDHbr) cells were associated with impairments in glucose homeostasis as reflected by HgbA1C, but not fasting insulin, glucose, or HOMA-IR. These associations remained when corrected for age and cardiovascular risk factors.
Conclusions/Interpretation
The numbers of CD34+ and ALDHbr CPCs were significantly lower in patients with impaired glucose tolerance. Depletion of reparative capacity as reflected by loss of CPCs may presage overt disease as exemplified in this pre-diabetes model.
Clinical Trials Registration
ClinicalTrials.gov NCT00594399
doi:10.1016/j.jdiacomp.2013.08.004
PMCID: PMC3874717  PMID: 24055327
10.  Digital Atlas of the Zebra Finch (Taeniopygia guttata) Brain: a High Resolution Photo Atlas 
The Journal of comparative neurology  2013;521(16):3702-3715.
We describe a set of new comprehensive, high-quality, high-resolution digital images of histological sections from the brain of male zebra finches (Taeniopygia guttata), and make them publicly available through an interactive website (http://zebrafinch.brainarchitecture.org/). These images provide a basis for the production of a dimensionally accurate and detailed digital non-stereotaxic atlas. Nissl- and myelin-stained brain sections are provided in the transverse, sagittal, and horizontal planes, with the transverse plane approximating the more traditional Frankfurt Plane. In addition, a separate set of brain sections in this same plane is stained for tyrosine hydroxylase, revealing the distribution of catecholaminergic neurons (dopaminergic, noradrenergic, and adrenergic) in the songbird brain. For a subset of sagittal sections we have also prepared a corresponding set of drawings, defining and annotating various nuclei, fields, and fiber tracts that are visible under Nissl and myelin staining. This atlas of the zebra finch brain is expected to become an important tool for birdsong research and comparative studies of brain organization and evolution.
doi:10.1002/cne.23443
PMCID: PMC3931548  PMID: 23896990
oscine songbird; Nissl and myelin stain; website; brain drawings
11.  Quality of surgical field during endoscopic sinus surgery: A systematic literature review of the effect of total intravenous compared to inhalational anesthesia 
Background
Adequate surgical field visualization is imperative for successful outcomes in endoscopic sinus surgery (ESS). The type of anesthetic administered can alter a patient’s hemodynamics and impact endoscopic visualization during surgery. We review the current evidence regarding the effect of total intravenous anesthesia (TIVA) compared to inhalational anesthesia (INA) on visualization of the surgical field during ESS.
Methods
A systematic review of the literature was performed. Ovid MEDLINE, Scopus, and Cochrane databases were searched from 1946 to January 2012. Citations from the primary search were reviewed and filtered to identify all relevant abstracts in English. Articles meriting full review included prospective controlled trials enrolling adult patients undergoing ESS that were randomized to a group receiving INA or TIVA with outcome measures focused on surgical field visualization.
‘Results
Seven eligible trials fulfilled inclusion criteria. Four of the seven articles demonstrated a statistically significant improvement in surgical field grade during ESS when receiving TIVA compared with INA. However, detailed INA concentrations were often not provided. High levels of INA may have been administered; therefore, side effects of INA rather than effects of an ideal INA administration were possibly represented. Analgesic administration also varied widely among the anesthetic groups further complicating interpretation of study results. The lack of power and the heterogeneity of the studies precluded a formal meta-analysis.
Conclusions
Although several studies reported that TIVA improve surgical conditions in ESS, however there are significant limitations. These findings prevent any definite recommendation at this point, emphasizing the need for further high quality studies.
doi:10.1002/alr.21125
PMCID: PMC4216588  PMID: 23258603
Endoscopic sinus surgery; total intravenous anesthesia; anesthetic; surgical field; endoscopy
12.  Point-of-Care Differentiation of Kawasaki Disease from Other Febrile Illnesses 
The Journal of pediatrics  2012;162(1):183-188.e3.
Objective
To test whether statistical learning on clinical and laboratory test patterns would lead to an algorithm for Kawasaki disease (KD) diagnosis that could aid clinicians.
Study design
Demographic, clinical, and laboratory data were prospectively collected for subjects with KD and febrile controls (FCs) using a standardized data collection form.
Results
Our multivariate models were trained with a cohort of 276 patients with KD and 243 FCs (who shared some features of KD) and validated with a cohort of 136 patients with KD and 121 FCs using either clinical data, laboratory test results, or their combination. Our KD scoring method stratified the subjects into subgroups with low (FC diagnosis, negative predictive value >95%), intermediate, and high (KD diagnosis, positive predictive value >95%) scores. Combining both clinical and laboratory test results, the algorithm diagnosed 81.2% of all training and 74.3% of all testing of patients with KD in the high score group and 67.5% of all training and 62.8% of all testing FCs in the low score group.
Conclusions
Our KD scoring metric and the associated data system with online (http://translationalmedicine.stanford.edu/cgi-bin/KD/kd.pl) and smartphone applications are easily accessible, inexpensive tools to improve the differentiation of most children with KD from FCs with other pediatric illnesses.
doi:10.1016/j.jpeds.2012.06.012
PMCID: PMC4186670  PMID: 22819274
13.  Evolutionary analysis of hepatitis C virus gene sequences from 1953 
Reconstructing the transmission history of infectious diseases in the absence of medical or epidemiological records often relies on the evolutionary analysis of pathogen genetic sequences. The precision of evolutionary estimates of epidemic history can be increased by the inclusion of sequences derived from ‘archived’ samples that are genetically distinct from contemporary strains. Historical sequences are especially valuable for viral pathogens that circulated for many years before being formally identified, including HIV and the hepatitis C virus (HCV). However, surprisingly few HCV isolates sampled before discovery of the virus in 1989 are currently available. Here, we report and analyse two HCV subgenomic sequences obtained from infected individuals in 1953, which represent the oldest genetic evidence of HCV infection. The pairwise genetic diversity between the two sequences indicates a substantial period of HCV transmission prior to the 1950s, and their inclusion in evolutionary analyses provides new estimates of the common ancestor of HCV in the USA. To explore and validate the evolutionary information provided by these sequences, we used a new phylogenetic molecular clock method to estimate the date of sampling of the archived strains, plus the dates of four more contemporary reference genomes. Despite the short fragments available, we conclude that the archived sequences are consistent with a proposed sampling date of 1953, although statistical uncertainty is large. Our cross-validation analyses suggest that the bias and low statistical power observed here likely arise from a combination of high evolutionary rate heterogeneity and an unstructured, star-like phylogeny. We expect that attempts to date other historical viruses under similar circumstances will meet similar problems.
doi:10.1098/rstb.2013.0168
PMCID: PMC3758194  PMID: 23938759
molecular epidemiology; phylogenetics
14.  Common misconceptions about data analysis and statistics 
Ideally, any experienced investigator with the right tools should be able to reproduce a finding published in a peer-reviewed biomedical science journal. In fact, the reproducibility of a large percentage of published findings has been questioned. Undoubtedly, there are many reasons for this, but one reason maybe that investigators fool themselves due to a poor understanding of statistical concepts. In particular, investigators often make these mistakes: 1. P-Hacking. This is when you reanalyze a data set in many different ways, or perhaps reanalyze with additional replicates, until you get the result you want. 2. Overemphasis on P values rather than on the actual size of the observed effect. 3. Overuse of statistical hypothesis testing, and being seduced by the word “significant”. 4. Overreliance on standard errors, which are often misunderstood.
doi:10.1007/s00210-014-1037-6
PMCID: PMC4203998  PMID: 25213136
15.  Idiopathic neutropenia of childhood is associated with Fas/FasL expression☆ 
Clinical immunology (Orlando, Fla.)  2008;129(3):438-447.
Idiopathic neutropenia (IN) in children is characterized by decreased neutrophil counts (<1500/μl), can be acute or chronic (greater than 6 months duration). The pathophysiology is not well understood; therefore, potential mechanisms of pediatric IN were investigated. An increase in Fas transcripts in neutrophils of IN patients compared to age-matched healthy control (HC) neutrophils was observed (p<0.005). Increased expression of Fas protein was found in IN neutrophils, while Fas surface expression on other immune cells was similar. Plasma from acute IN patients had higher protein levels of soluble FasL than chronic IN patients. When HC neutrophils were incubated in plasma from IN patients, greater rates of apoptosis were observed. Biochemical studies suggest the apoptotic factor(s) in plasma is heat-sensitive, non-IgG, and 12–50 kD protein. Addition of anti-sFasL blocking antibodies to patient plasma caused a statistically significant decrease in neutrophil apoptosis. These studies show that the Fas/FasL pathway could be associated with neutrophil apoptosis in childhood IN.
doi:10.1016/j.clim.2008.08.006
PMCID: PMC4161459  PMID: 18819843
Neutropenia; Apoptosis; Fas; Fas ligand; Idiopathic neutropenia; Pediatric neutropenia; Neutrophil disorder
16.  Trophoblast Inclusions Are Significantly Increased in the Placentas of Children in Families at Risk for Autism 
Biological psychiatry  2013;74(3):204-211.
Background
Gestation is a critical window for neurodevelopmental vulnerability. This study examined whether the presence of trophoblast inclusions (TIs) in the placenta could serve as a predictor for children at elevated risk for autism spectrum disorder (ASD).
Methods
Placentas were obtained from 117 births in the MARBLES (Markers of Autism Risk in Babies—Learning Early Signs) cohort of families who have one or more previous biological children with ASD, placing their newborn at elevated risk for neurodevelopmental compromise. Control samples were obtained from 100 uncomplicated term pregnancies of multiparous women with one or more typically developing biological children. Frequency of TIs was compared across the two groups.
Results
Placentas from at-risk pregnancies had an eightfold increased odds of having two or more TIs compared with control samples (odds ratio: 8.0, 95% confidence interval: 3.6–18.0). The presence of ≥2 TIs yielded a sensitivity of 41% and a specificity of 92% for predicting ASD risk status, whereas ≥4 TIs yielded a sensitivity of 19%, a specificity of 99.9%, and a positive likelihood ratio of 242 and conservatively predicted an infant with a 74% probability of being at risk for ASD.
Conclusions
Our findings suggest that the placentas from women whose fetuses are at elevated risk for autism are markedly different from control placentas. These differences are manifested histologically as TIs. Their identification has the possibility of identifying newborns at risk for ASD who might benefit from targeted early interventions aimed at preventing or ameliorating behavioral symptoms and optimizing developmental outcomes.
doi:10.1016/j.biopsych.2013.03.006
PMCID: PMC3755347  PMID: 23623455
ASD; autism; genetics; pathology; placenta; trophoblast inclusions
17.  A Low Vision Rehabilitation Program for Patients with Mild Cognitive Deficits 
JAMA ophthalmology  2013;131(7):912-919.
Objective
To design and pilot test a low vision rehabilitation program for patients with macular disease and cognitive deficits.
Methods
The Memory or Reasoning Enhanced Low Vision Rehabilitation (MORE-LVR) program was created by a team representing optometry, occupational therapy, ophthalmology, neuropsychology, and geriatrics. Key components of MORE-LVR are: 1) repetitive training with a therapist twice weekly over a 6-week period, 2) simplified training experience addressing no more than three individualized goals in a minimally distracting environment, 3) involvement of an informal companion (friend or family member). Eligible patients were recruited from an LVR clinic; measures were compared before and after the 6 week program.
Results
Twelve non-demented patients (mean age 84.5 years, 75% female) who screened positive for cognitive deficits completed the MORE-LVR intervention. Participants demonstrated improved scores on the National Eye Institute’s Visual Function Questionnaire (VFQ-25) composite score (47.2±16.3 to 54.8±13.8, p=0.01) and near activities score (21.5±14.0 to 41.0±23.1, p=0.02), timed performance measures (writing a grocery list [p=0.03], filling in a crossword puzzle answer [p=0.003]), a score indicating satisfaction with independence (p=0.05), and logical memory (p=0.02). All patients and companions reported progress toward at least one individualized goal; >70% reported progress toward all three goals.
Conclusions
This pilot study demonstrates feasibility of an LVR program for macular disease patients with mild cognitive deficits. Participants demonstrated improvements in vision-related function and cognitive measures and expressed high satisfaction. Future work is needed to determine if MORE-LVR is superior to usual outpatient LVR for persons with co-existing visual and cognitive impairments.
doi:10.1001/jamaophthalmol.2013.1700
PMCID: PMC3710540  PMID: 23619914
18.  Genome-wide association study identifies possible genetic risk factors for colorectal adenomas 
Background
Colorectal cancer (CRC) is the second leading cause of cancer-related death, and most CRC usually arises from colorectal adenomas. Removal of polyps reduces mortality from CRC. Colorectal adenomas are known to aggregate in families; however the genetic determinants for risk of polyps are largely unknown.
Methods
In this study, we used data from the Tennessee Colorectal Polyp Study and the Tennessee-Indiana Adenoma Recurrence Study to conduct a GWAS of adenoma cases and controls. Our design consisted of discovery and replication phases for a total of 2,551 Caucasian adenoma cases and 3,285 Caucasian controls. We performed logistic regression to test for association in both the discovery and replication phase and further examined the results with meta-analysis.
Results
No SNP achieved a genome-wide significant p-value; however, the most significantly associated SNPs were either previously associated with CRC in GWAS, such as rs10505477 in the gene POU5F1 (odds ratio [OR] = 0.87, 95% confidence interval [CI] 0.81–0.94, p-value = 4.4×10−4), or have been biologically linked to benign growths in other tissues, such as rs1919314 in the gene HDAC9 OR = 1.32, 95% CI 1.18–1.47, p-value = 1.1×10−6).
Conclusions
This study suggests that several SNPs may be related to adenoma risk and provides clues for future studies.
Impact
These results suggest that some known CRC genetic risk factors are necessary but not sufficient for carcinogenesis.
doi:10.1158/1055-9965.EPI-12-1437
PMCID: PMC3716448  PMID: 23677573
Colorectal adenoma; genetic association
19.  NOVEL NEOADJUVANT IMMUNOTHERAPY REGIMEN SAFETY AND SURVIVAL IN HEAD AND NECK SQUAMOUS CELL CANCER 
Head & neck  2011;33(12):1666-1674.
Background
Cellular immune suppression is observed in head and neck squamous cell cancer (HNSCC) and contributes to poor prognosis. Restoration of immune homeostasis may require primary cell-derived cytokines at physiologic doses. An immunotherapy regimen containing a biologic, with multiple-active cytokine components, and administered with cytoxan, zinc, and indomethacin was developed to modulate cellular immunity.
Methods
Study methods were designed to determine the safety and efficacy of a 21-day neoadjuvant immunotherapy regimen in a phase 2 trial that enrolled 27 therapy-naïve patients with stage II to IVa HNSCC. Methods included safety, clinical and radiologic tumor response, disease-free survival (DFS), overall survival (OS), and tumor lymphocytic infiltrate (LI) data collection.
Results
Acute toxicity was minimal. Patients completed neoadjuvant treatment without surgical delay. By independent radiographic review, 83% had stable disease during treatment. OS was 92%, 73%, and 69% at 12, 24, and 36 months, respectively. Histologic analysis suggested correlation between survival and tumor LI.
Conclusion
Immunotherapy regimen was tolerated. Survival results are encouraging.
doi:10.1002/hed.21660
PMCID: PMC4062188  PMID: 21284052
cytokine; head and neck squamous cell carcinoma; immune response; IRX-2; phase 2
20.  Exploring the Frontier of Electronic Health Record Surveillance: The Case of Post-Operative Complications 
Medical care  2013;51(6):509-516.
Background
The aim of this study was to build electronic algorithms using a combination of structured data and natural language processing (NLP) of text notes for potential safety surveillance of nine post-operative complications.
Methods
Post-operative complications from six medical centers in the Southeastern United States were obtained from the Veterans Affairs Surgical Quality Improvement Program (VASQIP) registry. Development and test datasets were constructed using stratification by facility and date of procedure for patients with and without complication. Algorithms were developed from VASQIP outcome definitions using NLP coded concepts, regular expressions, and structured data. The VASQIP nurse reviewer served as the reference standard for evaluating sensitivity and specificity. The algorithms were designed in the development and evaluated in the test dataset.
Results
Sensitivity and specificity in the test set were 85% and 92% for acute renal failure, 80% and 93% for sepsis, 56% and 94% for deep vein thrombosis, 80% and 97% for pulmonary embolism, 88% and 89% for acute myocardial infarction, 88% and 92% for cardiac arrest, 80% and 90% for pneumonia, 95% and 80% for urinary tract infection, and 80% and 93% for wound infection, respectively. A third of the complications occurred outside of the hospital setting.
Conclusions
Computer algorithms on data extracted from the electronic health record produced respectable sensitivity and specificity across a large sample of patients seen in six different medical centers. This study demonstrates the utility of combining natural language processing with structured data for mining the information contained within the electronic health record.
doi:10.1097/MLR.0b013e31828d1210
PMCID: PMC3658153  PMID: 23673394
surgical complications; adverse events; patient safety; electronic surveillance; natural language processing; text mining
21.  Naphthalene metabolism in relation to target tissue anatomy, physiology, cytotoxicity and tumorigenic mechanism of action 
This report provides a summary of deliberations conducted under the charge for members of Module C Panel participating in the Naphthalene State-of-the-Science Symposium (NS3), Monterey, CA, October 9–12, 2006. The panel was charged with reviewing the current state of knowledge and uncertainty about naphthalene metabolism in relation to anatomy, physiology and cytotoxicity in tissues observed to have elevated tumor incidence in these rodent bioassays. Major conclusions reached concerning scientific claims of high confidence were that: (1) rat nasal tumor occurrence was greatly enhanced, if not enabled, by adjacent, histologically related focal cellular proliferation; (2) elevated incidence of mouse lung tumors occurred at a concentration (30 ppm) cytotoxic to the same lung region at which tumors occurred, but not at a lower and less cytotoxic concentration (tumorigenesis NOAEL = 10 ppm); (3) naphthalene cytotoxicity requires metabolic activation (unmetabolized naphthalene is not a proximate cause of observed toxicity or tumors); (4) there are clear regional and species differences in naphthalene bioactivation; and (5) target tissue anatomy and physiology is sufficiently well understood for rodents, non-human primates and humans to parameterize species-specific physiologically based pharmacokinetic (PBPK) models for nasal and lung effects. Critical areas of uncertainty requiring resolution to enable improved human cancer risk assessment were considered to be that: (1) cytotoxic naphthalene metabolites, their modes of cytotoxic action, and detailed low-dose dose–response need to be clarified, including in primate and human tissues, and neonatal tissues; (2) mouse, rat, and monkey inhalation studies are needed to better define in vivo naphthalene uptake and metabolism in the upper respiratory tract; (3) in vivo validation studies are needed for a PBPK model for monkeys exposed to naphthalene by inhalation, coupled to cytotoxicity studies referred to above; and (4) in vivo studies are needed to validate a human PBPK model for naphthalene. To address these uncertainties, the Panel proposed specific research studies that should be feasible to complete relatively promptly. Concerning residual uncertainty far less easy to resolve, the Panel concluded that environmental, non-cytotoxic exposure levels of naphthalene do not induce tumors at rates that can be predicted meaningfully by simple linear extrapolation from those observed in rodents chronically exposed to far greater, cytotoxic naphthalene concentrations.
doi:10.1016/j.yrtph.2007.10.018
PMCID: PMC4030291  PMID: 18191315
Naphthalene; Cancer; Carcinogenicity; Tumorigenesis; Mode-of-action; Mechanism of action; Cytotoxicity; Olfactory epithelial neuroblastoma; Respiratory epithelial adenoma; Inflammation; Metabolism; Cytochrome P450; 1,2-Naphthoquinone; 1,4-Naphthoquinone; 1,2-Epoxide; Glutathione depletion; Species differences; Age-dependent differences; Gender differences; PBPK modeling
22.  NSF Workshop Report: Discovering General Principles of Nervous System Organization by Comparing Brain Maps across Species 
Efforts to understand nervous system structure and function have received new impetus from the federal Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative. Comparative analyses can contribute to this effort by leading to the discovery of general principles of neural circuit design, information processing, and gene-structure-function relationships that are not apparent from studies on single species. We here propose to extend the comparative approach to nervous system ‘maps’ comprising molecular, anatomical, and physiological data. This research will identify which neural features are likely to generalize across species, and which are unlikely to be broadly conserved. It will also suggest causal relationships between genes, development, adult anatomy, physiology, and, ultimately, behavior. These causal hypotheses can then be tested experimentally. Finally, insights from comparative research can inspire and guide technological development. To promote this research agenda, we recommend that teams of investigators coalesce around specific research questions and select a set of ‘reference species’ to anchor their comparative analyses. These reference species should be chosen not just for practical advantages, but also with regard for their phylogenetic position, behavioral repertoire, well-annotated genome, or other strategic reasons. We envision that the nervous systems of these reference species will be mapped in more detail than those of other species. The collected data may range from the molecular to the behavioral, depending on the research question. To integrate across levels of analysis and across species, standards for data collection, annotation, archiving, and distribution must be developed and respected. To that end, it will help to form networks or consortia of researchers and centers for science, technology, and education that focus on organized data collection, distribution, and training. These activities could be supported, at least in part, through existing mechanisms at NSF, NIH, and other agencies. It will also be important to develop new integrated software and database systems for cross-species data analyses. Multidisciplinary efforts to develop such analytical tools should be supported financially. Finally, training opportunities should be created to stimulate multidisciplinary, integrative research into brain structure, function, and evolution.
doi:10.1159/000360152
PMCID: PMC4028317  PMID: 24603302
23.  Differential Expression of Placental Glucocorticoid Receptors and Growth Arrest-Specific Transcript 5 in Term and Preterm Pregnancies: Evidence for Involvement of Maternal Stress 
Pregnancy-specific stress predicts birth outcomes. We hypothesized that there is a maternal stress-GR interaction that can influence fetal birth weight. This study examined the relationship between mothers' stress and attitude towards their pregnancies, placental glucocorticoid receptors (GRs) and growth arrest-specific transcript 5 (GAS5) expression, and the status of GR polymorphism, with their infants' birth weights. GAS5 and GRα were the predominant transcripts in both term and preterm placentas, with GAS5 being primarily localized in the syncytiotrophoblasts. In an attempt to mimic moderate and high stress environment in vitro, BeWo and JEG-3 cytotrophoblast cell lines were treated with 10 nM–1000 nM cortisol. Only expression of GAS5 was significantly upregulated by cortisol in all treatments compared with basal levels, but none of the GRs changed expression significantly. In an attempt to assess a stress versus gene interaction, we studied four GR polymorphisms. In the homozygous group for Tth111I polymorphism, mothers with negative attitudes towards the pregnancy gave birth to infants with significantly lower birth weights compared to women with positive/neutral attitudes. None of the GR splice variants were associated with maternal stress. However, placental GAS5 levels were inversely correlated with maternal stress. This study points towards a potential gene-environment interaction that could be of predictive value for fetal weight.
doi:10.1155/2014/239278
PMCID: PMC4037583  PMID: 24899900
24.  Ghrelin signaling in the ventral hippocampus stimulates learned and motivational aspects of feeding via PI3K-Akt signaling 
Biological psychiatry  2012;73(9):915-923.
Background
The stomach-derived hormone ghrelin drives higher-order feeding processes related to food reward and food seeking via CNS signaling at its receptor (GHSR1A). The specific nuclei mediating these effects are only partially understood. Here, we use a rat model to examine whether ghrelin signaling in the ventral subregion of the hippocampus (VHPC), a brain substrate of recent interest in energy balance control, affects learned and motivational aspects of feeding behavior.
Methods
The effects of VHPC ghrelin administration were examined on feeding-relevant behavioral paradigms, including meal pattern analysis, operant lever pressing for sucrose, and conditioned stimulus-induced feeding. The intracellular signaling and downstream neuronal pathways stimulated by VHPC GHSR1A activation were assessed using immunoblot analysis and behavioral pharmacology.
Results
Ghrelin delivery to the VHPC, but not the dorsal hippocampus, increased food intake primarily by increasing meal frequency. Intra-VHPC ghrelin delivery also increased willingness to work for sucrose and increased spontaneous meal initiation in nondeprived rats following the presentation of a conditioned stimulus that previously signaled meal access when the rats were food restricted. The food intake enhancing effects of VHPC ghrelin were blocked by co-administration of a phosphoinositide 3-kinase (PI3K) inhibitor (LY294002). Immunoblot analyses provided complementary support for ghrelin activated PI3K-Akt signaling in the VHPC and revealed that this activation is blunted with high fat diet consumption. Other immunoblot results show that VHPC GHSR1A signaling activates downstream dopaminergic activity in the nucleus accumbens.
Conclusions
These findings illuminate novel neuronal and behavioral mechanisms mediating ghrelin's modulation of cognitive aspects of feeding control.
doi:10.1016/j.biopsych.2012.07.002
PMCID: PMC3498600  PMID: 22884970
GHSR; learning; memory; nucleus accumbens; reward; obesity; dopamine
25.  Physiologically Based Pharmacokinetic (PBPK) Modeling of Interstrain Variability in Trichloroethylene Metabolism in the Mouse 
Environmental Health Perspectives  2014;122(5):456-463.
Background: Quantitative estimation of toxicokinetic variability in the human population is a persistent challenge in risk assessment of environmental chemicals. Traditionally, interindividual differences in the population are accounted for by default assumptions or, in rare cases, are based on human toxicokinetic data.
Objectives: We evaluated the utility of genetically diverse mouse strains for estimating toxicokinetic population variability for risk assessment, using trichloroethylene (TCE) metabolism as a case study.
Methods: We used data on oxidative and glutathione conjugation metabolism of TCE in 16 inbred and 1 hybrid mouse strains to calibrate and extend existing physiologically based pharmacokinetic (PBPK) models. We added one-compartment models for glutathione metabolites and a two-compartment model for dichloroacetic acid (DCA). We used a Bayesian population analysis of interstrain variability to quantify variability in TCE metabolism.
Results: Concentration–time profiles for TCE metabolism to oxidative and glutathione conjugation metabolites varied across strains. Median predictions for the metabolic flux through oxidation were less variable (5-fold range) than that through glutathione conjugation (10-fold range). For oxidative metabolites, median predictions of trichloroacetic acid production were less variable (2-fold range) than DCA production (5-fold range), although the uncertainty bounds for DCA exceeded the predicted variability.
Conclusions: Population PBPK modeling of genetically diverse mouse strains can provide useful quantitative estimates of toxicokinetic population variability. When extrapolated to lower doses more relevant to environmental exposures, mouse population-derived variability estimates for TCE metabolism closely matched population variability estimates previously derived from human toxicokinetic studies with TCE, highlighting the utility of mouse interstrain metabolism studies for addressing toxicokinetic variability.
Citation: Chiu WA, Campbell JL Jr, Clewell HJ III, Zhou YH, Wright FA, Guyton KZ, Rusyn I. 2014. Physiologically based pharmacokinetic (PBPK) modeling of interstrain variability in trichloroethylene metabolism in the mouse. Environ Health Perspect 122:456–463; http://dx.doi.org/10.1289/ehp.1307623
doi:10.1289/ehp.1307623
PMCID: PMC4014769  PMID: 24518055

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