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1.  Factors associated with the initiation of proton pump inhibitors in corticosteroid users 
Purpose
Proton pump inhibitors (PPIs) and corticosteroids are commonly prescribed drugs; however, each has been associated with fracture and community acquired pneumonia. How physicians select patients for co-therapy may have implications for potential additive or synergistic toxicities.
Methods
We conducted a retrospective cohort study of 13,749 incident corticosteroid users with no prior PPI exposure using the HealthCore Integrated Research DatabaseSM. We used logistic regression to evaluate the association between PPI initiation in the first 30 days of steroid therapy and corticosteroid dose, clinical risk factors including co-morbid diseases, and medication use including prescription nonsteroidal anti-inflammatory drugs (NSAIDs).
Results
1,050 (7.6%) patients filled a new PPI prescription within 30 days of starting corticosteroids. PPI use was associated with the number of baseline co-morbid conditions (OR 1.21 for each additional condition, CI 1.13–1.28), recent hospitalization (OR 4.71, CI 4.02–5.52), prednisone dose above 40mg/day (OR 1.87, CI1.45–2.41), history of gastroesophageal reflux or gastric ulcer disease (OR 1.54, CI 1.24– 1.91), renal insufficiency (OR 2.06, CI 1.73–2.46), and liver disease (OR 1.82, CI 1.45–2.28). Concomitant use of prescription NSAIDs was also associated with PPI use (OR 1.89, CI 1.32–2.70); however, the total use of PPIs in this group was low (6.3%, CI 4.4–8.2%).
Conclusions
Overall, PPI therapy among corticosteroid users was uncommon, even among those with risk factors for gastrointestinal toxicity. PPI use was significantly more common among patients who had recently been hospitalized, had a greater burden of co-morbid illness, or were receiving high daily doses of corticosteroids.
doi:10.1002/pds.2350
PMCID: PMC3970554  PMID: 22278844
proton pump inhibitors; corticosteroids; gastroprotection; adverse events
2.  Parenting-related stress and psychological distress in mothers of toddlers with autism spectrum disorders 
Brain & development  2012;35(2):133-138.
Background
Parents of children with autism spectrum disorders (ASDs) are at risk for higher stress levels than parents of children with other developmental disabilities and typical development. Recent advances in early diagnosis have resulted in younger children being diagnosed with ASDs but factors associated with parent stress in this age group are not well understood.
Aims
The present study examined parenting-related stress and psychological distress in mothers of toddlers with ASD, developmental delay without ASD (DD), and typical development. The impact of child problem behavior and daily living skills on parenting-stress and psychological distress were further investigated.
Methods
Participants were part of a larger research study on early ASD intervention. Parent self-report of parenting-related stress and psychological distress was utilized.
Results
Parents of toddlers with ASD demonstrated increased parenting-related stress compared with parents of toddlers with DD and typical development. However, psychological distress did not differ significantly between the groups. Child behavior problems, but not daily living skills emerged as a significant predictor of parenting-related stress and psychological distress. This was true for both mothers of children with ASD and DD.
Conclusions
These finding suggest that parents’ abilities to manage and reduce behavior problems is a critical target for interventions for young children with ASD and DD in order to improve child functioning and decrease parenting-related stress.
doi:10.1016/j.braindev.2012.10.004
PMCID: PMC3552060  PMID: 23146332
Autism Spectrum Disorder; parents; distress; toddlers; parenting-stress
3.  Clinical importance of the drug interaction between statins and CYP3A4 inhibitors: a retrospective cohort study in The Health Improvement Network 
Objective
To compare the relative hazard of muscle toxicity, renal dysfunction, and hepatic dysfunction associated with the drug interaction between statins and concomitant medications that inhibit the CYP3A4 isoenzyme.
Background
Although statins provide important clinical benefits related to mitigating the risk of cardiovascular events, this class of medications also has the potential for severe adverse reactions. The risk for adverse events may be potentiated by concomitant use of medications that interfere with statin metabolism.
Methods
Data from The Health Improvement Network (THIN) from 1990 to 2008 were used to conduct a retrospective cohort study. Cohorts were created to evaluate each outcome (muscle toxicity, renal dysfunction, and hepatic dysfunction) independently. Each cohort included new statin initiators and compared the relative hazard of the outcome. The interaction ratio (I*R) was the primary contrast of interest. The I*R represents the relative effect of each statin type (statin 3A4 substrate vs. statin non-3A4 substrate) with a CYP3A4 inhibitor, independent of the effect of the statin type without a CYP3A4 inhibitor. We adjusted for confounding variables using the multinomial propensity score.
Results
The median follow-up time per cohort was 1.5 years. There were 7889 muscle toxicity events among 362 809 patients and 792 665 person-years. The adjusted muscle toxicity I*R was 1.22 (95% confidence interval [CI] = 0.90–1.66). There were 1449 renal dysfunction events among 272,099 patients and 574 584 person-years. The adjusted renal dysfunction I*R was 0.91 (95%CI = 0.58–1.44). There were 1434 hepatic dysfunction events among 367 612 patients and 815 945 person-years. The adjusted hepatic dysfunction I*R was 0.78 (95%CI = 0.45–1.31).
Conclusions
Overall, this study found no difference in the relative hazard of muscle toxicity, renal dysfunction, or hepatic dysfunction for patients prescribed a statin 3A4 substrate versus a statin non-3A4 substrate with CYP3A4 inhibitor concomitancy.
doi:10.1002/pds.3199
PMCID: PMC3890414  PMID: 22422642
4.  Brain Responses to Words in 2-Year-Olds with Autism Predict Developmental Outcomes at Age 6 
PLoS ONE  2013;8(5):e64967.
Autism Spectrum Disorder (ASD) is a developmental disability that affects social behavior and language acquisition. ASD exhibits great variability in outcomes, with some individuals remaining nonverbal and others exhibiting average or above average function. Cognitive ability contributes to heterogeneity in autism and serves as a modest predictor of later function. We show that a brain measure (event-related potentials, ERPs) of word processing in children with ASD, assessed at the age of 2 years (N = 24), is a broad and robust predictor of receptive language, cognitive ability, and adaptive behavior at ages 4 and 6 years, regardless of the form of intensive clinical treatment during the intervening years. The predictive strength of this brain measure increases over time, and exceeds the predictive strength of a measure of cognitive ability, used here for comparison. These findings have theoretical implications and may eventually lead to neural measures that allow early prediction of developmental outcomes as well as more individually tailored clinical interventions, with the potential for greater effectiveness in treating children with ASD.
doi:10.1371/journal.pone.0064967
PMCID: PMC3666972  PMID: 23734230
5.  Early Predictors of Communication Development in Young Children with Autism Spectrum Disorder: Joint Attention, Imitation, and Toy Play 
This study investigated the unique contributions of joint attention, imitation, and toy play to language ability and rate of development of communication skills in young children with autism spectrum disorder (ASD). Sixty preschool-aged children with ASD were assessed using measures of joint attention, imitation, toy play, language, and communication ability. Two skills, initiating protodeclarative joint attention and immediate imitation, were most strongly associated with language ability at age 3–4 years, whereas toy play and deferred imitation were the best predictors of rate of communication development from age 4 to 6.5 years. The implications of these results for understanding the nature and course of language development in autism and for the development of targeted early interventions are discussed.
doi:10.1007/s10803-006-0137-7
PMCID: PMC3635847  PMID: 16845578
Autism; Language; Communication; Joint attention; Imitation; Play
6.  The Societal Impact of Single Versus Bilateral Lung Transplantation for Chronic Obstructive Pulmonary Disease 
Rationale: Bilateral lung transplantation (BLT) improves survival compared with single lung transplantation (SLT) for some individuals with chronic obstructive pulmonary disease (COPD). However, it is unclear which strategy optimally uses this scarce societal resource.
Objectives: To compare the effect of SLT versus BLT strategies for COPD on waitlist outcomes among the broader population of patients listed for lung transplantation.
Methods: We developed a Markov model to simulate the transplant waitlist using transplant registry data to define waitlist size, donor frequency, the risk of death awaiting transplant, and disease- and procedure-specific post-transplant survival. We then applied this model to 1,000 simulated patients and compared the number of patients under each strategy who received a transplant, the number who died before transplantation, and total post-transplant survival.
Measurements and Main Results: Under baseline assumptions, the SLT strategy resulted in more patients transplanted (809 vs. 758) and fewer waitlist deaths (157 vs. 199). The strategies produced similar total post-transplant survival (SLT = 4,586 yr vs. BLT = 4,577 yr). In sensitivity analyses, SLT always maximized the number of patients transplanted. The strategy that maximized post-transplant survival depended on the relative survival benefit of BLT versus SLT among patients with COPD, donor interval, and waitlist size.
Conclusions: In most circumstances, a policy of SLT for COPD improves access to organs for other potential recipients without significant reductions in total post-transplant survival. However, there may be substantial geographic variations in the effect of such a policy on the balance between these outcomes.
doi:10.1164/rccm.201104-0695OC
PMCID: PMC3262042  PMID: 21868502
lung transplantation; resource allocation; chronic obstructive pulmonary disease; bioethics
7.  Observational cohort study of the safety of digoxin use in women with heart failure 
BMJ Open  2012;2(2):e000888.
Objectives
This study aims to assess whether digoxin has a different effect on mortality risk for women than it does for men in patients with heart failure (HF).
Design
This study uses the UK-based The Health Information Network population database in a cohort study of the impact of digoxin exposure on mortality for men and women who carry the diagnosis of HF. Digoxin exposure was assessed based on prescribing data. Multivariable Cox proportional hazards models were used to assess whether there was an interaction between sex and digoxin affecting mortality hazard.
Setting
The setting was primary care outpatient practices.
Participants
The study cohort consisted of 17 707 men and 19 227 women with the diagnosis of HF who contributed only time without digoxin exposure and 9487 men and 10 808 women with the diagnosis of HF who contributed time with digoxin exposure.
Main outcome measures
The main outcome measure was all-cause mortality.
Results
The primary outcome of this study was the absence of a large interaction between digoxin use and sex affecting mortality. For men, digoxin use was associated with a HR for mortality of 1.00, while for women, the HR was also 1.00 (p value for interaction 0.65). The results of sensitivity analyses were consistent with those of the primary analysis.
Conclusion
Observational data do not support the concern that there is a substantial increased risk of mortality due to the use of digoxin in women. This finding is consistent with previous observational studies but discordant with results from a post hoc analysis of a randomised controlled trial of digoxin versus placebo.
Article summary
Article focus
Digoxin is used in patients with HF and has been shown in one major randomised control trial, the Digitalis Investigation Group study, to reduce the rate of hospitalisations in that population.
Post hoc analysis of Digitalis Investigation Group indicated that digoxin, when used in the treatment of HF, may increase mortality by approximately 20% in women but not in men. Further randomised trials evaluating the interaction between digoxin and sex have not emerged.
Key messages
For men, digoxin use was associated with a HR for mortality of 1.00, while for women, the HR was also 1.00 (p value for interaction 0.65). There was no evidence of a different association between digoxin use and mortality in women compared with men. Sensitivity analyses did not affect this estimate materially.
An interesting incidental finding of this study is that interventions known to reduce mortality in HF are used less in women than in men who have been diagnosed with HF.
Strengths and limitations of this study
The major strength of this study was its large sample size, which allowed adjustment for many covariates and numerous sensitivity analyses, none of which affected the conclusions.
The major limitation of this study is that it is non-randomised. Although there is no evidence of substantial confounding of the main study result, confounding could still bias these results.
doi:10.1136/bmjopen-2012-000888
PMCID: PMC3332247  PMID: 22505313
8.  Factors associated with the use of corticosteroids in the initial management of idiopathic pulmonary fibrosis 
Purpose
Idiopathic pulmonary fibrosis (IPF) has not been shown to respond to corticosteroid therapy; however, many patients receive these drugs at the time of diagnosis. The factors that are associated with the decision to prescribe corticosteroids have not been examined.
Methods
We conducted a retrospective cohort study of 1126 patients with a new diagnosis of IPF using The Health Improvement Network database from the United Kingdom. We used generalized estimating equation (GEE) regression models to test the association of patient characteristics, co-morbid diseases, and disease characteristics with the use of corticosteroids within 30 days of IPF diagnosis.
Results
Bivariable analyses demonstrated an association between female sex, the presence of dyspnea, the need for oxygen, past steroid use, and the use of corticosteroids immediately prior to diagnosis with the use of corticosteroids at the time of diagnosis. After adjustment with multivariable GEE regression, only the use of oxygen at the time of diagnosis (OR 1.69, CI 1.14-2.49), the past use of corticosteroids (OR 1.50, CI 1.04-2.15), and use of corticosteroids immediately prior to diagnosis (OR 5.72, CI 3.80-8.60) remained significantly associated with increased use of corticosteroids. No association was found between prior diabetes, osteoporosis, glaucoma, hypertension, congestive heart failure, obesity or peptic ulcer disease and use of corticosteroids at diagnosis.
Conclusions
The decision to prescribe corticosteroids is associated with oxygen use and past corticosteroid use but is not influenced by factors such as age, gender, or common co-morbid conditions that may pre-dispose patients to adverse events of therapy.
doi:10.1002/pds.1959
PMCID: PMC2898153  PMID: 20582912
Idiopathic pulmonary fibrosis; prescribing; drug therapy; corticosteroids; adverse events
9.  Evidence for Latent Classes of IQ In Young Children with Autism Spectrum Disorder 
Autism is currently viewed as a spectrum condition including strikingly different severity levels. IQ is consistently described as one of the primary aspects of the heterogeneity in autism. To investigate the possibility of more than one distinct subtype of autism based on IQ, both latent class analysis and taxometric methods were used to classify Mullen IQ scores in a sample of children with autism spectrum disorder (N=456). Evidence for multiple IQ-based subgroups was found using both methods. Groups differed in level of intellectual functioning and patterns of verbal versus nonverbal ability. Results support the notion of distinct subtypes of autism which differ in severity of intellectual ability, patterns of cognitive strengths and weaknesses, and severity of autism symptoms.
doi:10.1352/2008.113:439-452
PMCID: PMC2991056  PMID: 19127655
10.  The Role of Face Familiarity in Eye Tracking of Faces by Individuals with Autism Spectrum Disorders 
It has been shown that individuals with autism spectrum disorders (ASD) demonstrate normal activation in the fusiform gyrus when viewing familiar, but not unfamiliar faces. The current study utilized eye tracking to investigate patterns of attention underlying familiar versus unfamiliar face processing in ASD. Eye movements of 18 typically developing participants and 17 individuals with ASD were recorded while passively viewing three face categories: unfamiliar non-repeating faces, a repeating highly familiar face, and a repeating previously unfamiliar face. Results suggest that individuals with ASD do not exhibit more normative gaze patterns when viewing familiar faces. A second task assessed facial recognition accuracy and response time for familiar and novel faces. The groups did not differ on accuracy or reaction times.
doi:10.1007/s10803-008-0550-1
PMCID: PMC2989724  PMID: 18306030
Eye tracking; Autism spectrum disorder; Face processing; Familiar face; Attention
11.  Disruption at the PTCHD1 locus on Xp22.11 in autism spectrum disorder and intellectual disability 
Science translational medicine  2010;2(49):49ra68.
Autism is a common neurodevelopmental disorder with a complex mode of inheritance. It is one of the most highly heritable of the complex disorders, however, the underlying genetic factors remain largely unknown. Here, we report mutations in the X-chromosome PTCHD1 (patched-related) gene, in seven families with autism spectrum disorder (ASD) and in three families with intellectual disability (ID). A 167 Kb microdeletion spanning exon 1 was found in two brothers, one with ASD the other with learning disability and ASD features, and a 90 Kb microdeletion spanning the entire gene was found in three males with ID in a second family. In 900 ASD and 208 ID male probands we identified seven different missense changes in eight probands, all male and inherited from unaffected mothers, and not found in controls. Two of the ASD individuals with missense changes also carried a de novo deletion at another ASD-susceptibility locus (DPYD and DPP6), suggesting complex genetic contributions. In additional males with ASD, we identified deletions in the 5’ flanking region of PTCHD1 disrupting a complex non-coding RNA and potential regulatory elements; equivalent changes were not found in male control individuals (p=1.2 ×10-5). Systematic screening at PTCHD1 and 5’-flanking regions, suggests involvement of this locus in ~1% of ASD and ID individuals.
doi:10.1126/scitranslmed.3001267
PMCID: PMC2987731  PMID: 20844286
12.  Neurocognitive predictors of social and communicative developmental trajectories in preschoolers with autism spectrum disorders 
Currently the heterogeneity in the developmental trajectories of autism spectrum disorders (ASD) is poorly understood. Preschool children with ASD participating in a longitudinal study received a battery of neurocognitive tasks that measured the learning of reward associations (Lrn-Rew), spatial working memory (SpatWM), and imitation from memory and novelty preference (Mem/Nov) as well as a measure of nonverbal problem-solving ability (NVDQ). Growth curve analyses via HLM were utilized to predict the variability in growth rates between age 4 to age 6½ in Vineland Socialization and Communication scores. Individual differences in both Lrn-Rew and Mem/Nov were significantly related to Socialization and Communication growth rates above and beyond NVDQ, whereas SpatWM was not. Thus, specific aspects of neurocognitive functioning appear to be important predictors of developmental variability during the preschool years in children with ASD. We speculate that these findings support the combined role of ventromedial prefrontal and medial temporal lobe systems in the early pathogenesis of ASD and may be useful in predicting developmental trajectory. The benefits and challenges of assessing specific neurocognitive functions in children with autism is discussed with regard to general cognitive/developmental ability and the behavioral requirements of most assessment settings.
doi:10.1017/S1355617708081393
PMCID: PMC2978065  PMID: 18954476
autistic disorder; neuropsychology; intelligence; language; social adjustment; longitudinal studies
13.  Common genetic variants on 5p14.1 associate with autism spectrum disorders 
Nature  2009;459(7246):528-533.
Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)—two genes encoding neuronal cell-adhesion molecules—revealed strong association signals, with the most significant SNP being rs4307059 (P = 3.4 × 10−8, odds ratio = 1.19). These signals were replicated in two independent cohorts, with combined P values ranging from 7.4 × 10−8 to 2.1 × 10−10. Our results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to our knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs.
doi:10.1038/nature07999
PMCID: PMC2943511  PMID: 19404256
14.  Autism genome-wide copy number variation reveals ubiquitin and neuronal genes 
Nature  2009;459(7246):569-573.
Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins1–4. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs5–9. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with ~550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 × 10−3). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 × 10−3). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 × 10−6). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.
doi:10.1038/nature07953
PMCID: PMC2925224  PMID: 19404257

Results 1-14 (14)