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1.  Interrater reliability of a Phenotypic Assessment Tool for the Ear Morphology in Microtia 
The Elements of Morphology Standard Terminology working group published standardized definitions for external ear morphology. The primary objective of our study was to use these descriptions to evaluate the interrater reliability for specific features associated with microtia. We invited six raters from three different subspecialities to rate 100 ear photographs on 32 features. We calculated overall and within specialty and professional experience intraclass correlation coefficients (ICC) and 95% confidence intervals. A total of 600 possible observations were recorded for each feature. The overall interrater reliability ranged from 0.04 (95%CI: 0.00–0.14) for the width of the antihelix inferior crus to 0.93 (95%CI: 0.91–0.95) for the presence of the inferior crux of the antihelix. The reliability for quantitative characteristics such as length or width of an ear structure was generally lower than the reliability for qualitative characteristics (e.g. presence or absence of an ear structure). Categories with very poor interrater reliability included anti-helix inferior crux width (0.04, 95%CI: 0.00–0.14), crux helix extension (0.17, 95% CI 0.00–0.37), and shape of the incisura (0.14, 95%CI: 0.01–0.27). There were no significant differences in reliability estimates by specialty or professional experience for most variables. Our study showed that it is feasible to systematically characterize many of structures of the ear that are affected in microtia. We incorporated these descriptions into a standardized phenotypic assessment tool (PAT-Microtia) that might be used in multicenter research studies to identify sub-phenotypes for future studies of microtia.
PMCID: PMC3664118  PMID: 23616389
ear morphology; microtia; reliability; phenotype
2.  Measuring the Impact of Practice-based Research Networks on Member Dentists in the Collaboration on Networked Dental and Oral Health Research, CONDOR 
Journal of dentistry  2013;41(5):10.1016/j.jdent.2013.03.005.
The National Institute of Dental and Craniofacial Research funded three practice-based research networks (PBRNs), NW-PRECEDENT, PEARL and DPBRN to conduct studies relevant to practicing general dentists. These PBRNs collaborated to develop a questionnaire to assess the impact of network participation on changes in practice patterns. This report presents results from the initial administration of the questionnaire.
Questionnaires were administered to network dentists and a non-network reference group. Practice patterns including caries diagnosis and treatment, pulp cap materials, third molar extraction, dentin hypersensitivity treatments and endodontic treatment and restoration were assessed by network, years in practice, and level of network participation.Test-retest reliability of the questionnaire was evaluated.
950 practitioners completed the questionnaire. Test-retest reliability was good-excellent (kappa>0.4) for most questions. Significant differences in responses by network were not observed. The use of caries risk assessment forms differed by both network participation (p<0.001) and years since dental degree (p=0.026). Recent dental graduates are more likely to recommend third molar removal for preventive reasons (p=0.003).
Practitioners in the CONDOR research networks are similar to their US colleagues. As a group, however, these practitioners show a more evidence-based approach to their practice. Dental PBRNs have the potential to improve the translation of evidence into daily practice. Designing methods to assess practice change and the associated factors is essential to addressing this important issue.
PMCID: PMC3825028  PMID: 23562351
dental practice-based research networks; behavior change; practice impact
3.  County-level determinants of dental utilization for Medicaid-enrolled children with chronic conditions: How does place affect use? 
Health & place  2012;18(6):1422-1429.
Little is known about how place affects childrens’ access to dental care. We analyzed data for 25,908 Iowa Medicaid-enrolled children with chronic conditions to identify the county-level determinants of dental utilization. Our analyses suggest that higher levels of poverty and designation as a dental health professional shortage area at the county-level are associated with lower probability of child-level dental use. There are significant interactions between child-level race/ethnicity and county-level poverty as well as between child-level disability and county-level unemployment. We present a new descriptive model on dental utilization that emphasizes county-level factors as well as interactions between county-level and child-level factors.
PMCID: PMC3597237  PMID: 22981229
Residence characteristics; Dental care for children; Healthcare disparities; Medicaid; Dental health services
4.  Inter–examiner Reliability of Salivary Diagnostic Tests in a Practice–based Research Network 
Patient salivary characteristics are being measured as part of the Northwest PRECEDENT (Practice–based REsearch Collaborative in Evidence–based DENTistry) study on caries risk assessment. Prior to the implementation of these salivary diagnostic tests in a practice–based cohort study, inter–examiner reliability was assessed for resting salivary pH, stimulated salivary flow rate, pH and buffering capacity.
An initial evaluation of inter–examiner reliability of the 4 salivary tests was conducted among 6 dental auxiliary examiners using a convenience sample of 40 dental students. An incomplete block design was used to assign samples to examiners (3 examiners per sample and 20 samples per examiner). Inter– examiner reliability testing was conducted on a patient population representative of the practice–based network in 4 member practices. Two dental assistants per practice independently conducted the salivary tests on samples provided by a random selection of 20 to 25 patients. A separate analysis was performed for each study. For each test, an inter–examiner reliability index was computed.
Results from two studies are reported. In the first, stimulated salivary flow rate demonstrated excellent inter–examiner reliability, and resting salivary pH showed high inter–examiner reliability, while buffering capacity and stimulated salivary pH had moderate and very low inter–examiner reliability, respectively. In the second, inter–examiner reliability was excellent for the stimulated salivary flow rate and the resting salivary pH. The inter– examiner reliability for the stimulated salivary pH was also high and the stimulated salivary buffering capacity test had moderate reliability.
The small variance in stimulated salivary pH and buffering capacity in dental students may have artificially made the reliability appear low in the first attempt at inter–examiner reliability testing. In the second study, all 4 tests had an acceptable performance.
PMCID: PMC3631606  PMID: 21619742
Inter–examiner reliability; salivary diagnostic tests; dental practice–based research networks; caries risk assessment
5.  Temporal compliance trends in a cluster randomization with crossover trial of out-of-hospital cardiac arrest 
Low compliance to randomized non-drug interventions can affect treatment estimates of clinical trials. Cluster randomized crossover may be appropriate for increasing compliance in the out-of-hospital cardiac arrest setting.
The purpose was to determine whether the elapsed time from start of a non-blinded treatment period to episode enrollment date in a cluster randomized crossover trial is associated with compliance to either a period of brief CPR with electrocardiogram ECG rhythm analysis or a period of longer CPR with delayed ECG rhythm analysis in patients with out-of-hospital cardiac arrest.
The Resuscitation Outcomes Consortium PRIMED Analyze Late vs Analyze Early trial was a cluster randomized crossover trial at 10 North American regional sites. Clusters were created based on local service preference with treatment periods varying from 3 to 12 months depending on the expected enrollment rate of each randomizing unit. Episodes on the AL arm had a target of 180 seconds from CPR start to Shock Assessment and were deemed compliant if total time was between 150 and 210 seconds. Episodes on the AE arm had a target of <30 seconds from CPR start to Shock Assessment and were deemed compliant if total time was <60 seconds. We used logistic regression to examine the association between compliance (Yes/No) and the elapsed number of days from the start of the treatment period to the episode in the framework of generalized estimating equations, controlling for randomized treatment (Late, ref=Early) and treatment period length (ref=3, 4-5, 6, 7-11, 12 months).
We had 8769 episodes in our analysis population. Overall compliance to the randomized arm was 63.5%. After adjusting for treatment arm and treatment period length, the odds of compliance for episodes occurring >300 days from treatment period start were 33% lower (OR: 0.67, 95% CI: 0.52, 0.86) than for those <60 days from treatment period start. There was no significant difference in compliance between episodes before and immediately after a cluster crossed over to the opposite arm (OR: 0.81, 95% CI: 0.57, 1.17).
A major challenge was the lack of synchronicity between training cycles and agency crossover dates.
We found a significant decrease in compliance to the AL vs AE cardiac arrest intervention as the elapsed time from start of treatment period increased. We did not find a difference in compliance immediately before and after a crossover. While these results suggest that future cluster with crossover trials in the out-of-hospital setting be designed with short treatment periods and frequent crossovers, provider logistical concerns must also be considered.
PMCID: PMC3515666  PMID: 22447629
cardiac arrest; cluster design; crossover; study compliance
6.  Informative Cluster Sizes for Sub-Cluster Level Covariates and Weighted Generalized Estimating Equations 
Biometrics  2011;67(3):843-851.
Williamson et al. (2003)’s cluster-weighted generalized estimating equations (CWGEE) are effective at adjusting for bias due to informative cluster sizes for cluster-level covariates. We show that CWGEE may not perform well, however, for covariates that can take different values within a cluster if the numbers of observations at each covariate level are informative. On the other hand, inverse probability of treatment weighting accounts for informative treatment propensity but not for informative cluster size. Motivated by evaluating the effect of a binary exposure in presence of such types of informativeness, we propose several weighted generalized estimating equation estimators, with weights related to the size of a cluster as well as the distribution of the binary exposure within the cluster. Choice of the weights depends on the population of interest and the nature of the exposure. Through simulation studies, we demonstrate the superior performance of the new estimators compared to existing estimators such as from GEE, CWGEE, and inverse probability of treatment weighted GEE. We demonstrate the use of our method using an example examining covariate effects on the risk of dental caries among small children.
PMCID: PMC3137732  PMID: 21281273
Cluster; GEE; Informative cluster size; IPTW; Propensity Score; Weighting
7.  Psychosocial Outcomes in Children with Hemifacial Microsomia 
Journal of Pediatric Psychology  2011;36(7):794-805.
Objective To determine whether children with hemifacial microsomia (HFM) have higher risk for psychosocial problems than children without HFM. Methods One hundred and thirty-six children with HFM (64% male, mean age = 6.9 years) were compared to 568 matched controls (50% male, mean age = 7.0 years) on parent and teacher measures of behavior problems and social competence, and teacher rankings of peer acceptance. Results Parents of cases and controls reported similar levels of behavior problems and social competence. Teachers reported higher frequencies of internalizing problems, lower social competence and less peer acceptance for cases. Relative to controls, teacher-rated outcomes were worse for female cases, those with younger mothers at the time of birth, those with eye anomalies, and those with one or more malformations in addition to the core features of HFM. Conclusions This study provides the first evidence of relatively poor psychosocial outcomes among children with HFM.
PMCID: PMC3146752  PMID: 21345938
children; craniofacial; Goldenhar syndrome; ocularauricular vertebral syndrome; psychosocial
8.  Language and Early Reading Among Children With Orofacial Clefts 
To test the hypothesis that children with orofacial clefts score lower than controls on measures of language and reading and to examine predictors of these outcomes.
Longitudinal study tracking the development of children with and without orofacial clefts from infancy through age 7 years.
Children with isolated cleft lip and palate (n = 29) and cleft palate only (n = 28) were recruited from the craniofacial program in an urban medical center. Seventy-seven demographically similar, unaffected controls were recruited via advertisements placed in area pediatric clinics and community centers.
Infant measures assessed child development and mother-child interactions during feeding and teaching tasks. At ages 5 and 7 years, measures of language functioning and academic achievement were completed along with an interview to collect school placement data and information on speech services received.
There were no significant group differences in language at ages 5 and 7 years. Children with clefts scored significantly higher than controls on measures of early reading at age 7 years. Outcomes were predicted by demographic factors, the quality of mother-child interactions during teaching and feeding tasks, and cognitive development scores at age 24 months.
Findings do not support the hypothesis that children with clefts score lower than controls on neurocognitive and academic achievement measures. Predictive analyses revealed several dimensions that may be used in clinical practice to identify children at risk for learning and developmental concerns.
PMCID: PMC3397667  PMID: 20426677
language; longitudinal; orofacial cleft; reading
9.  Risk Factors for Osteonecrosis of the Jaws 
Journal of Dental Research  2011;90(4):439-444.
Case reports and cohort studies have linked bisphosphonate therapy and osteonecrosis of the jaws (ONJ), but neither causality nor specific risks for lesion development have been clearly established. We conducted a 1:3 case-control study with three dental Practice-based Research Networks, using dentist questionnaires and patient interviews for collection of data on bisphosphonate therapy, demographics, co-morbidities, and dental and medical treatments. Multivariable logistic regression analyses tested associations between bisphosphonate use and other risk factors with ONJ. We enrolled 191 ONJ cases and 573 controls in 119 dental practices. Bisphosphonate use was strongly associated with ONJ (odds ratios [OR] 299.5 {95%CI 70.0-1282.7} for intravenous [IV] use and OR = 12.2 {4.3-35.0} for oral use). Risk markers included local suppuration (OR = 7.8 {1.8-34.1}), dental extraction (OR = 7.6 {2.4-24.7}), and radiation therapy (OR = 24.1 {4.9-118.4}). When cancer patients (n = 143) were excluded, bisphosphonate use (OR = 7.2 {2.1-24.7}), suppuration (OR = 11.9 {2.0-69.5}), and extractions (OR = 6.6 {1.6-26.6}) remained associated with ONJ. Higher risk of ONJ began within 2 years of bisphosphonate initiation and increased four-fold after 2 years. Both IV and oral bisphosphonate use were strongly associated with ONJ. Duration of treatment > 2 years; suppuration and dental extractions were independent risk factors for ONJ.
PMCID: PMC3144129  PMID: 21317246
osteonecrosis; jaws; bisphosphonates; risk factors
10.  Early versus Later Rhythm Analysis in Patients with Out-of-Hospital Cardiac Arrest 
The New England journal of medicine  2011;365(9):787-797.
In a departure from the previous strategy of immediate defibrillation, the 2005 resuscitation guidelines from the American Heart Association–International Liaison Committee on Resuscitation suggested that emergency medical service (EMS) personnel could provide 2 minutes of cardiopulmonary resuscitation (CPR) before the first analysis of cardiac rhythm. We compared the strategy of a brief period of CPR with early analysis of rhythm with the strategy of a longer period of CPR with delayed analysis of rhythm.
We conducted a cluster-randomized trial involving adults with out-of-hospital cardiac arrest at 10 Resuscitation Outcomes Consortium sites in the United States and Canada. Patients in the early-analysis group were assigned to receive 30 to 60 seconds of EMS-administered CPR and those in the later-analysis group were assigned to receive 180 seconds of CPR, before the initial electrocardiographic analysis. The primary outcome was survival to hospital discharge with satisfactory functional status (a modified Rankin scale score of ≤3, on a scale of 0 to 6, with higher scores indicating greater disability).
We included 9933 patients, of whom 5290 were assigned to early analysis of cardiac rhythm and 4643 to later analysis. A total of 273 patients (5.9%) in the later-analysis group and 310 patients (5.9%) in the early-analysis group met the criteria for the primary outcome, with a cluster-adjusted difference of −0.2 percentage points (95% confidence interval, −1.1 to 0.7; P = 0.59). Analyses of the data with adjustment for confounding factors, as well as subgroup analyses, also showed no survival benefit for either study group.
Among patients who had an out-of-hospital cardiac arrest, we found no difference in the outcomes with a brief period, as compared with a longer period, of EMS-administered CPR before the first analysis of cardiac rhythm. (Funded by the National Heart, Lung, and Blood Institute and others; ROC PRIMED number, NCT00394706.)
PMCID: PMC3181067  PMID: 21879896
11.  A Trial of an Impedance Threshold Device in Out-of-Hospital Cardiac Arrest 
The New England journal of medicine  2011;365(9):798-806.
The impedance threshold device (ITD) is designed to enhance venous return and cardiac output during cardiopulmonary resuscitation (CPR) by increasing the degree of negative intrathoracic pressure. Previous studies have suggested that the use of an ITD during CPR may improve survival rates after cardiac arrest.
We compared the use of an active ITD with that of a sham ITD in patients with out-of-hospital cardiac arrest who underwent standard CPR at 10 sites in the United States and Canada. Patients, investigators, study coordinators, and all care providers were unaware of the treatment assignments. The primary outcome was survival to hospital discharge with satisfactory function (i.e., a score of ≤3 on the modified Rankin scale, which ranges from 0 to 6, with higher scores indicating greater disability).
Of 8718 patients included in the analysis, 4345 were randomly assigned to treatment with a sham ITD and 4373 to treatment with an active device. A total of 260 patients (6.0%) in the sham-ITD group and 254 patients (5.8%) in the active-ITD group met the primary outcome (risk difference adjusted for sequential monitoring, −0.1 percentage points; 95% confidence interval, −1.1 to 0.8; P = 0.71). There were also no significant differences in the secondary outcomes, including rates of return of spontaneous circulation on arrival at the emergency department, survival to hospital admission, and survival to hospital discharge.
Use of the ITD did not significantly improve survival with satisfactory function among patients with out-of-hospital cardiac arrest receiving standard CPR. (Funded by the National Heart, Lung, and Blood Institute and others; ROC PRIMED number, NCT00394706.)
PMCID: PMC3204381  PMID: 21879897
12.  Neurodevelopmental Outcomes in Children With Hemifacial Microsomia 
To determine whether preadolescent children with hemifacial microsomia (HFM) have higher risk of neurodevelopmental delays than unaffected control individuals.
Case-control follow-up study of neurodevelopment in children with and without HFM.
Case individuals were originally recruited from 26 craniofacial centers across the United States and Canada, and controls were recruited through community pediatricians.
One hundred thirty-six children with HFM (cases) and 568 unaffected children (controls).
Main Exposure
History of HFM.
Main Outcome Measures
The Peabody Picture Vocabulary Test–Third Edition, the Beery-Buktenica Developmental Test of Visual Motor Integration–Fifth Edition, and the Academic Competence scales from the Child Behavior Checklist and the Teacher Report Form.
Children with HFM scored lower than controls on all measures (effect size = −0.27 to −0.45; P < .001 to P = .008). Compared with controls, cases were 2 to 3 times as likely to score in the at-risk range. Relative to controls, outcomes were worse for male cases and those whose mothers were 25 years or younger at the time of their birth. Cases with HFM plus other malformations had poorer outcomes, as did cases with hearing, vision, or speech impairments.
This is the first study, to our knowledge, to show that children with HFM have poorer neurodevelopmental outcomes than unaffected children, but further study using more detailed assessments is indicated. Clinically, the findings suggest that early neurodevelopmental screening is warranted for all children with HFM.
PMCID: PMC3142696  PMID: 21300653
Environmental research  2008;108(3):393-399.
Mercury is toxic to the kidney, and dental amalgam is a source of mercury exposure. Few studies have evaluated the effects of dental amalgam on kidney function in a longitudinal context in children. Here, we evaluated urinary concentrations of glutathione S-transferases (GSTs) α and π as biomarkers of renal proximal and distal tubular integrity, respectively, and albumin as a biomarker of glomerular integrity in children and adolescents 8-18 years of age over a 7 year course of dental amalgam treatment. Five hundred seven children, 8-12 years of age at baseline, participated in a clinical trial to evaluate the neurobehavioral and renal effects of dental amalgam in children. Subjects were randomized to either dental amalgam or resin composite treatments. Urinary GSTs α and π, albumin and creatinine concentrations were measured at baseline and annually on all subjects. Results were evaluated using linear regression analysis. GST-α concentrations were similar between treatment groups and in each sex and race (white vs non-white) group in each follow-up year. GST-π levels tended upward over the course of follow-up by 4- to 6-fold. This increase was seen in all groups irrespective of treatment, race or gender. Females had GST-π levels approximately twice those of males at all ages. Albumin concentrations were constant throughout the follow-up period and did not differ by treatment, although females had 39% higher albumin levels than males. Additionally, we found no significant effects of amalgam treatment on the proportion of children with microalbuminuria (>30 mg/g creatinine). These findings are relevant within the context of children’s health risk assessment as relates to the safety of mercury exposure from dental amalgam on kidney function. These data also provide normative values for sensitive indices of renal functional integrity that may serve in the evaluation of children and adolescents with renal disorders.
PMCID: PMC3236600  PMID: 18721920
biomarker; kidney; mercury; amalgam; children
14.  Identification of Body Fat Mass as a Major Determinant of Metabolic Rate in Mice 
Diabetes  2010;59(7):1657-1666.
Analysis of energy expenditure (EE) in mice is essential to obesity research. Since EE varies with body mass, comparisons between lean and obese mice are confounded unless EE is normalized to account for body mass differences. We 1) assessed the validity of ratio-based EE normalization involving division of EE by either total body mass (TBM) or lean body mass (LBM), 2) compared the independent contributions of LBM and fat mass (FM) to EE, and 3) investigated whether leptin contributes to the link between FM and EE.
We used regression modeling of calorimetry and body composition data in 137 mice to estimate the independent contributions of LBM and FM to EE. Subcutaneous administration of leptin or vehicle to 28 obese ob/ob mice and 32 fasting wild-type mice was used to determine if FM affects EE via a leptin-dependent mechanism.
Division of EE by either TBM or LBM is confounded by body mass variation. The contribution of FM to EE is comparable to that of LBM in normal mice (expressed per gram of tissue) but is absent in leptin-deficient ob/ob mice. When leptin is administered at physiological doses, the plasma leptin concentration supplants FM as an independent determinant of EE in both ob/ob mice and normal mice rendered leptin-deficient by fasting.
The contribution of FM to EE is substantially greater than predicted from the metabolic cost of adipose tissue per se, and the mechanism underlying this effect is leptin dependent. Regression-based approaches that account for variation in both FM and LBM are recommended for normalization of EE in mice.
PMCID: PMC2889765  PMID: 20413511
Urinary porphyrins are diagnostic of various metabolic disorders and xenobiotic exposures, but comprehensive normative data for urinary porphyrin concentrations in children are currently unavailable.
Subjects were participants in a prospective, randomized, controlled clinical trial of dental materials safety, 8 to 12 y at inception, who were followed longitudinally for 7 y after baseline with an extensive battery of neurobehavioral, neurological, renal function and urinary porphyrin assessments. Porphyrins were quantified by HPLC. Linear regression analyses were used to measure associations of porphyrin levels with age and gender.
Mean concentrations, 95% confidence intervals, and 10th 50th, and 90th percentiles for all 5 typically excreted urinary porphyrins are presented by year of age and by gender. Unadjusted urinary concentrations (µg/l) of all 5 porphyrins remained relatively constant throughout the age range of 8–18 y for both males and females. In contrast, creatinine-adjusted urinary porphyrin concentrations (µg/g) declined significantly throughout this age range in both genders. Boys had significantly higher pentacarboxyl- and copro- porphyrin levels compared with girls both before and after creatinine adjustment.
Normative longitudinal data provided herein may facilitate the clinical assessment of pediatric metabolic disorders and may be of particular relevance in evaluating porphyrin changes as a biological indicator of disease or xenobiotic exposures among children and adolescents.
PMCID: PMC2720623  PMID: 19394319
urine; porphyrins; children; adolescents
16.  Design and implementation of a dental caries prevention trial in remote Canadian Aboriginal communities 
Trials  2010;11:54.
The goal of this cluster randomized trial is to test the effectiveness of a counseling approach, Motivational Interviewing, to control dental caries in young Aboriginal children. Motivational Interviewing, a client-centred, directive counseling style, has not yet been evaluated as an approach for promotion of behaviour change in indigenous communities in remote settings.
Aboriginal women were hired from the 9 communities to recruit expectant and new mothers to the trial, administer questionnaires and deliver the counseling to mothers in the test communities. The goal is for mothers to receive the intervention during pregnancy and at their child's immunization visits. Data on children's dental health status and family dental health practices will be collected when children are 30-months of age.
The communities were randomly allocated to test or control group by a random "draw" over community radio. Sample size and power were determined based on an anticipated 20% reduction in caries prevalence. Randomization checks were conducted between groups.
In the 5 test and 4 control communities, 272 of the original target sample size of 309 mothers have been recruited over a two-and-a-half year period. A power calculation using the actual attained sample size showed power to be 79% to detect a treatment effect. If an attrition fraction of 4% per year is maintained, power will remain at 80%. Power will still be > 90% to detect a 25% reduction in caries prevalence. The distribution of most baseline variables was similar for the two randomized groups of mothers. However, despite the random assignment of communities to treatment conditions, group differences exist for stage of pregnancy and prior tooth extractions in the family. Because of the group imbalances on certain variables, control of baseline variables will be done in the analyses of treatment effects.
This paper explains the challenges of conducting randomized trials in remote settings, the importance of thorough community collaboration, and also illustrates the likelihood that some baseline variables that may be clinically important will be unevenly split in group-randomized trials when the number of groups is small.
Trial registration
This trial is registered as ISRCTN41467632.
PMCID: PMC2887856  PMID: 20465831
17.  Maternal and infant characteristics associated with prone and lateral infant sleep positioning in Washington State, 1996-2002 
The Journal of pediatrics  2008;153(2):194-198.e3.
To identify factors predictive of either lateral or prone infant sleep positioning.
Study design
We used data for 11,340 mother-infant pairs from the Pregnancy Risk Assessment Monitoring System for infants born in Washington State, 1996–2002. We employed predictive modeling to identify statistically significant (p<0.05) predictors of lateral and prone sleep positioning.
Factors associated with both high-risk sleep positions included infant’s year-of-birth, maternal race and ethnicity, maternal county of residence, and maternal parity. Mother’s being US-born (vs. foreign-born) and male infant sex were predictive only of prone sleep positioning. Having Medicaid as primary insurance, receipt of government benefits, low infant gestational age, and low birth weight were predictive only of lateral sleep positioning.
Factors predictive of either high-risk sleep position should be considered when devising public health intervention strategies for the prevention of SIDS.
PMCID: PMC2570534  PMID: 18534224
Sudden Infant Death Syndrome (SIDS); Pregnancy Risk Assessment Monitoring (PRAMS)
18.  Individual Differences in Initial Sensitivity and Acute Tolerance Predict Patterns of Chronic Drug Tolerance to Nitrous-Oxide-Induced Hypothermia in Rats 
Psychopharmacology  2005;181(1):48-59.
Rationale: A preventive strategy for drug addiction would benefit from being able to identify vulnerable individuals. Understanding how an individual responds during an initial drug exposure may be useful for predicting how that individual will respond to repeated drug administrations.
Objectives: This study investigated whether individual differences in initial drug sensitivity and acute tolerance can predict how chronic tolerance develops.
Methods: During an initial 3-h administration of 60% nitrous oxide (N2O), male Long-Evans rats were screened for N2O’s hypothermic effect into subsets based on being initially insensitive (II), sensitive with acute tolerance (AT), or sensitive with no intrasessional recovery (NR). Animals in each individual difference category were randomly assigned to receive six 90-min exposures of either 60% N2O or placebo gas. Core temperature was measured telemetrically.
Results: Rats that exhibited a comparable degree of hypothermia during an initial N2O exposure, but differed in acute tolerance development, developed different patterns of chronic tolerance. Specifically, the NR group did not become fully tolerant over repeated N2O exposures while the AT group developed an initial hyperthermia followed by a return of core temperature to control levels indicative of full tolerance development. By the second N2O exposure, the II group breathing N2O became hyperthermic relative to the placebo control group and this hyperthermia persisted throughout the multiple N2O exposures.
Conclusions: Individual differences in initial drug sensitivity and acute tolerance development predict different patterns of chronic tolerance. The hypothesis is suggested that individual differences in opponent adaptive responses may mediate this relationship.
PMCID: PMC1470882  PMID: 15778887
Inhalant; addictive vulnerability; addiction; drug dependence; intrasessional tolerance; allostasis; homeostasis; regulation
19.  Nitrous oxide analgesia in humans: Acute and chronic tolerance 
Pain  2005;114(1-2):19-28.
Electrical tooth stimulation was used to investigate whether humans develop tolerance to nitrous oxide (N2O) analgesia within a single administration as well as over repeated administrations. In a double-blind cross-over experiment, 77 subjects received a 40-minute administration of 38% N2O at one session and placebo gas at the other. The sessions were separated by 1 week and the order of gas administration was counterbalanced. Acute analgesic tolerance developed for pain threshold but not for detection threshold. There was no evidence of a hyperalgesic rebound effect following cessation of the N2O administration. In a second double-blind experiment, 64 subjects received both 30-min of placebo gas and 30-min of 35% N2O, separated by a 35-min gas wash-out period, during each of 5 sessions. Sensory thresholds were assessed prior to drug or placebo administration (baseline) and between 7-12 min and 25-30 min of gas administration. A control group of 16 subjects received only placebo gas at these 5 sessions. During a sixth session, the experimental procedures were similar to the previous sessions except that the control group received N2O for the first time and the experimental group was sub-divided to test for conditioned drug effects. For both detection and pain threshold measures, acute tolerance developed during the initial N2O exposure and chronic tolerance developed over repeated administrations. Although chronic tolerance developed, a test for Pavlovian drug conditioning found no evidence of conditioned effects on sensory thresholds. In conclusion, acute and chronic tolerance develop to N2O’s analgesic effects in humans.
PMCID: PMC1416628  PMID: 15733627
Pavlovian drug conditioning; pain; individual differences; electrical tooth stimulation; rebound; pain threshold
20.  The Contribution of Dental Amalgam to Urinary Mercury Excretion in Children 
Environmental Health Perspectives  2007;115(10):1527-1531.
Urinary mercury concentrations are widely used as a measure of mercury exposure from dental amalgam fillings. No studies have evaluated the relationship of these measures in a longitudinal context in children.
We evaluated urinary mercury in children 8–18 years of age in relation to number of amalgam surfaces and time since placement over a 7-year course of amalgam treatment.
Five hundred seven children, 8–10 years of age at baseline, participated in a clinical trial to evaluate the neurobehavioral effects of dental amalgam in children. Subjects were randomized to either dental amalgam or resin composite treatments. Urinary mercury and creatinine concentrations were measured at baseline and annually on all participants.
Treatment groups were comparable in baseline urinary mercury concentration (~ 1.5 μg/L). Mean urinary mercury concentrations in the amalgam group increased to a peak of ~ 3.2 μg/L at year 2 and then declined to baseline levels by year 7 of follow-up. There was a strong, positive association between urinary mercury and both number of amalgam surfaces and time since placement. Girls had significantly higher mean urinary mercury concentrations than boys throughout the course of amalgam treatment. There were no differences by race in urinary mercury concentration associated with amalgam exposure.
Urinary mercury concentrations are highly correlated with both number of amalgam fillings and time since placement in children. Girls excrete significantly higher concentrations of mercury in the urine than boys with comparable treatment, suggesting possible sex-related differences in mercury handling and susceptibility to mercury toxicity.
PMCID: PMC2022658  PMID: 17938746
amalgam; children; dental; mercury; urine

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