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1.  Abdominal CT Does Not Improve Outcome for Children with Suspected Acute Appendicitis 
Acute appendicitis in children is a clinical diagnosis, which often requires preoperative confirmation with either ultrasound (US) or computed tomography (CT) studies. CTs expose children to radiation, which may increase the lifetime risk of developing malignancy. US in the pediatric population with appropriate clinical follow up and serial exam may be an effective diagnostic modality for many children without incurring the risk of radiation. The objective of the study was to compare the rate of appendiceal rupture and negative appendectomies between children with and without abdominal CTs; and to evaluate the same outcomes for children with and without USs to determine if there were any associations between imaging modalities and outcomes.
We conducted a retrospective chart review including emergency department (ED) and inpatient records from 1/1/2009–2/31/2010 and included patients with suspected acute appendicitis.
1,493 children, aged less than one year to 20 years, were identified in the ED with suspected appendicitis. These patients presented with abdominal pain who had either a surgical consult or an abdominal imaging study to evaluate for appendicitis, or were transferred from an outside hospital or primary care physician office with the stated suspicion of acute appendicitis. Of these patients, 739 were sent home following evaluation in the ED and did not return within the subsequent two weeks and were therefore presumed not to have appendicitis. A total of 754 were admitted and form the study population, of which 20% received a CT, 53% US, and 8% received both. Of these 57%, 95% CI [53.5,60.5] had pathology-proven appendicitis. Appendicitis rates were similar for children with a CT (57%, 95% CI [49.6,64.4]) compared to those without (57%, 95% CI [52.9,61.0]). Children with perforation were similar between those with a CT (18%, 95% CI [12.3,23.7]) and those without (13%, 95% CI [10.3,15.7]). The proportion of children with a negative appendectomy was similar in both groups: CT (7%, 95% CI [2.1,11.9]), US (8%, 95% CI [4.7,11.3]) and neither (12%, 95% CI [5.9,18.1]).
In this uncontrolled study, the accuracy of preoperative diagnosis of appendicitis and the incidence of pathology-proven perforation appendix were similar for children with suspected acute appendicitis whether they had CT, US or neither imaging, in conjunction with surgical consult. The imaging modality of CT was not associated with better outcomes for children presenting to the ED with suspected appendicitis.
PMCID: PMC4703157  PMID: 26759641
Neuro-Oncology  2014;16(Suppl 5):v15-v16.
BACKGROUND: Glioblastoma (GBM) remains an aggressive brain tumor with poor prognosis. Valproic acid (VPA) is an antiepileptic agent that has been shown to have HDACi activity and to radiosensitize GBM cells in preclinical models. This phase II study aimed to determine if the addition of VPA to standard radiation therapy and temozolomide would improve OS and PFS. METHODS: We prospectively assessed survival, radiological and clinical progression in 37 newly diagnosed glioblastoma patients with the administration of VPA at 25 mg/kg orally BID concurrent with radiation therapy (RT) and temozolomide (TMZ). The first dose of VPA was given 1 week before the first day of RT at 10 to 15 mg/kg/day and subsequently tapered up to 25 mg/kg/day over the week prior to radiation. RESULTS: 81% of patients took VPA according to protocol. Median OS was 29.6 months (21- 63.8), median PFS was 10.5 (6.8 - 51.2). OS at 6, 12, 24 months was 97%, 86%, 56% respectively. PFS at 6, 12, 24 months was 70%, 43%, 38% respectively. The most common grade 3 or 4 toxicities of VPA in conjunction with TMZ were blood/ bone marrow toxicity (32%), neurological (11%), metabolic/laboratory (8%). At the end of the study 26 (70%) patients were dead, 7 were live without disease, 4 alive with disease. Younger age (<= 50 years) compared to older age and class V RPA were significant for both OS and PFS. Using a landmark analysis, an early progression was related to a shorter interval between progression and death, whereas, a later progression was related to a longer interval between progression and death (p = 0.0002) HR 4.7. CONCLUSION: The addition of VPA to concurrent RT and TMZ in the treatment of newly diagnosed GBM may result in superior outcomes as compared to contemporary and historical data and merits further study.
PMCID: PMC4217812
3.  Copy number variation plays an important role in clinical epilepsy 
Annals of neurology  2014;75(6):943-958.
To evaluate the role of copy number abnormalities detectable by chromosomal microarray (CMA) testing in patients with epilepsy at a tertiary care center.
We identified patients with ICD-9 codes for epilepsy or seizures and clinical CMA testing performed between October 2006 and February 2011 at Boston Children’s Hospital. We reviewed medical records and included patients meeting criteria for epilepsy. We phenotypically characterized patients with epilepsy-associated abnormalities on CMA.
Of 973 patients who had CMA and ICD-9 codes for epilepsy or seizures, 805 patients satisfied criteria for epilepsy. We observed 437 copy number variants (CNVs) in 323 patients (1–4 per patient), including 185 (42%) deletions and 252 (58%) duplications. Forty (9%) were confirmed de novo, 186 (43%) were inherited, and parental data were unavailable for 211 (48%). Excluding full chromosome trisomies, CNV size ranged from 18 kb to 142 Mb, and 34% were over 500 kb. In at least 40 cases (5%), the epilepsy phenotype was explained by a CNV, including 29 patients with epilepsy-associated syndromes and 11 with likely disease-associated CNVs involving epilepsy genes or “hotspots.” We observed numerous recurrent CNVs including 10 involving loss or gain of Xp22.31, a region described in patients with and without epilepsy.
Copy number abnormalities play an important role in patients with epilepsy. Given that the diagnostic yield of CMA for epilepsy patients is similar to the yield in autism spectrum disorders and in prenatal diagnosis, for which published guidelines recommend testing with CMA, we recommend the implementation of CMA in the evaluation of unexplained epilepsy.
PMCID: PMC4487364  PMID: 24811917
Epilepsy; array comparative genomic hybridization (aCGH); chromosomal microarray; copy number variants; deletions; duplications; chromosomal abnormalities
4.  DSM-IV Personality Disorders and Associations with Externalizing and Internalizing Disorders: Results from the National Epidemiologic Survey on Alcohol and Related Conditions 
Journal of psychiatric research  2013;47(11):10.1016/j.jpsychires.2013.07.016.
Although associations between personality disorders and psychiatric disorders are well established in general population studies, their association with liability dimensions for externalizing and internalizing disorders has not been fully assessed. The purpose of this study is to examine associations between personality disorders (PDs) and lifetime externalizing and internalizing Axis I disorders.
Data were obtained from the total sample of 34,653 respondents from Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Drawing on the literature, a 3-factor exploratory structural equation model was selected to simultaneously assess the measurement relations among DSM-IV Axis I substance use and mood and anxiety disorders and the structural relations between the latent internalizing-externalizing dimensions and DSM-IV PDs, adjusting for gender, age, race/ethnicity, and marital status.
Antisocial, histrionic, and borderline PDs were strong predictors for the externalizing factor, while schizotypal, borderline, avoidant, and obsessive-compulsive PDs had significantly larger effects on the internalizing fear factor when compared to the internalizing misery factor. Paranoid, schizoid, narcissistic, and dependent PDs provided limited discrimination between and among the three factors. An overarching latent factor representing general personality dysfunction was significantly greater on the internalizing fear factor followed by the externalizing factor, and weakest for the internalizing misery factor.
Personality disorders offer important opportunities for studies on the externalizing-internalizing spectrum of common psychiatric disorders. Future studies based on panic, anxiety, and depressive symptoms may elucidate PD associations with the internalizing spectrum of disorders.
PMCID: PMC3881358  PMID: 23932575
DSM-IV personality disorders; DSM-IV substance use, mood, and anxiety disorders; epidemiology; structural equation modeling
5.  Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders 
Journal of medical genetics  2008;46(4):242-248.
Segmental duplications at breakpoints (BP4–BP5) of chromosome 15q13.2q13.3 mediate a recurrent genomic imbalance syndrome associated with mental retardation, epilepsy, and/or EEG abnormalities.
DNA samples from 1,445 unrelated patients submitted consecutively for clinical array comparative genomic hybridisation (CGH) testing at Children’s Hospital Boston and DNA samples from 1,441 individuals with Autism from 751 families in the Autism Genetic Resource Exchange (AGRE) repository.
We report the clinical features of five patients with a BP4-BP5 deletion, three with a BP4–BP5 duplication, and two with an overlapping but smaller duplication identified by whole genome high resolution oligonucleotide array CGH. These BP4–BP5 deletion cases exhibit minor dysmorphic features, significant expressive language deficits, and a spectrum of neuropsychiatric impairments that include autism spectrum disorder, ADHD, anxiety disorder, and mood disorder. Cognitive impairment varied from moderate mental retardation to normal IQ with learning disability. BP4–BP5 covers ~1.5Mb (chr15:28.719–30.298Mb) and includes 6 reference genes and 1 miRNA gene, while the smaller duplications cover ~500 kb (chr15:28.902–29.404 Mb) and contain 3 reference genes and one miRNA gene. The BP4–BP5 deletion and duplication events span CHRNA7, a candidate gene for seizures. However, none of these individuals reported here have epilepsy, although two have an abnormal EEG.
The phenotype of chromosome 15q13.2q13.3 BP4–BP5 microdeletion/duplication syndrome may include features of autism spectrum disorder, a variety of neuropsychiatric disorders, and cognitive impairment. Recognition of this broader phenotype has implications for clinical diagnostic testing and efforts to understand the underlying etiology of this syndrome.
PMCID: PMC4090085  PMID: 18805830
array CGH; autism; language delay; microdeletion/duplication; neuropsychiatric disorders
6.  A Comparison of two Case-crossover Methods for Studying the Dose-Response Relationship Between Alcohol and Injury 
Contemporary drug problems  2014;41(1):04-.
This study compares dose-response injury risk estimates for two control periods defined as the same 6-hour period the week prior and the set of all non-sleeping 6-hour periods over the past year.
Dose-response injury risk estimates for the multiple match controls are generated via the application of a maximum-likelihood approach.
Injury risk associated with any (i.e., 1 drink or more) drinking 6 hours prior to injury was similar for the two control choices (last week and usual frequency). For 1-4 drinks, risk estimates were similar across control period definitions; for 5+ drinks, risk using the week prior as the control was nearly double that using the past 12 months as the control.
Although studies with smaller ns may benefit from the increase in precision from the use of the multiple control periods, results indicate that heavy drinking injury risk estimates should be used with caution.
PMCID: PMC4013001  PMID: 24817774
relative risk; case-crossover; dose-response; control period definition
7.  An Item Response Theory Analysis of DSM–IV Diagnostic Criteria for Personality Disorders: Findings From the National Epidemiologic Survey on Alcohol and Related Conditions 
Personality disorders  2012;4(1):43-54.
The purpose of this study was to evaluate the psychometric properties of DSM–IV symptom criteria for assessing personality disorders (PDs) in a national population and to compare variations in proposed symptom coding for social and/or occupational dysfunction. Data were obtained from a total sample of 34,653 respondents from Waves 1 and 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). For each personality disorder, confirmatory factor analysis (CFA) established a 1-factor latent factor structure for the respective symptom criteria. A 2-parameter item response theory (IRT) model was applied to the symptom criteria for each PD to assess the probabilities of symptom item endorsements across different values of the underlying trait (latent factor). Findings were compared with a separate IRT model using an alternative coding of symptom criteria that requires distress/impairment to be related to each criterion. The CFAs yielded a good fit for a single underlying latent dimension for each PD. Findings from the IRT indicated that DSM–IV PD symptom criteria are clustered in the moderate to severe range of the underlying latent dimension for each PD and are peaked, indicating high measurement precision only within a narrow range of the underlying trait and lower measurement precision at lower and higher levels of severity. Compared with the NESARC symptom coding, the IRT results for the alternative symptom coding are shifted toward the more severe range of the latent trait but generally have lower measurement precision for each PD. The IRT findings provide support for a reliable assessment of each PD for both NESARC and alternative coding for distress/impairment. The use of symptom dysfunction for each criterion, however, raises a number of issues and implications for the DSM-5 revision currently proposed for Axis II disorders (American Psychiatric Association, 2010).
PMCID: PMC3760426  PMID: 22449066
personality disorders; DSM–IV PD symptom criteria; DSM–IV distress/impairment requirement; epidemiology; item response theory
8.  Comparative Performance of the AUDIT-C in Screening for DSM-IV and DSM-5 Alcohol Use Disorders* 
Drug and alcohol dependence  2012;126(3):384-388.
Under the proposed DSM-5 revision to the criteria for alcohol use disorder (AUD), a substantial proportion of DSM-IV AUD cases will be lost or shifted in terms of severity, with some new cases added. Accordingly, the performance of the AUDIT-C in screening for DSM-IV AUD cannot be assumed to extend to DSM-5 AUD. The objective of this paper is to compare the AUDIT-C in screening for DSM-IV and DSM-5 AUD.
Using a broad range of performance metrics, the AUDIT-C was tested and contrasted as a screener for DSM-IV AUD (any AUD, abuse and dependence) and DSM-5 AUD (any AUD, moderate AUD and severe AUD) in a representative sample of U.S. adults aged 21 and older and among past-year drinkers.
Optimal AUDIT-C cutpoints were identical for DSM-IV and DSM-5 AUD: ≥4 for any AUD, ≥3 or ≥4 for abuse/moderate AUD and ≥4 or ≥5 for dependence/severe AUD. Screening performance was slightly better for DSM-5 severe AUD than DSM-IV dependence but did not differ for other diagnoses. At optimal screening cutpoints, positive predictive values were slightly higher for DSM-5 overall AUD and moderate AUD than for their DSM-IV counterparts. Sensitivities were slightly higher for DSM-5 severe AUD than DSM-IV dependence. Optimal screening cutpoints shifted upwards for past-year drinkers but continued to be identical for DSM-IV and DSM-5 disorders.
Clinicians should not face any major overhaul of their current screening procedures as a result of the DSM-5 revision and should benefit from fewer false positive screening results.
PMCID: PMC3469743  PMID: 22728044
AUDIT-C; screening; alcohol use disorder; DSM-IV; DSM-5
9.  Antisocial Behavioral Syndromes and Three-Year Quality of Life Outcomes in United States Adults 
Acta psychiatrica Scandinavica  2012;126(2):10.1111/j.1600-0447.2012.01848.x.
To examine 3-year quality-of-life (QOL) outcomes among United States adults with Diagnostic and Statistical Manual of Mental Disorders – Fourth Edition (DSM-IV) antisocial personality disorder (ASPD), syndromal adult antisocial behavior without conduct disorder (CD) before age 15 (AABS, not a DSM-IV diagnosis), or no antisocial behavioral syndrome at baseline.
Face-to-face interviews (n= 34,653). Psychiatric disorders were assessed using the Alcohol Use Disorder and Associated Disabilities Interview Schedule – DSM-IV Version. Health-related QOL was assessed using the Short-Form 12-Item Health Survey, version 2 (SF-12v2). Other outcomes included past-year Perceived Stress Scale-4 (PSS-4) scores, employment, receipt of Supplemental Security Income (SSI), welfare, and food stamps, and participation in social relationships.
ASPD and AABS predicted poorer employment, financial dependency, social relationship, and physical health outcomes. Relationships of antisociality to SSI and food stamp receipt and physical health scales were modified by baseline age. Both antisocial syndromes predicted higher PSS-4, AABS predicted lower SF-12v2 Vitality, and ASPD predicted lower SF-12v2 Social Functioning scores in women.
Similar prediction of QOL by ASPD and AABS suggests limited utility of requiring CD before age 15 to diagnose ASPD. Findings underscore the need to improve prevention and treatment of antisocial syndromes.
PMCID: PMC3837547  PMID: 22375904
Antisocial personality disorder; quality of life; epidemiology; longitudinal course
To reduce symptoms and emergency department (ED) visits, the National Asthma Education and Prevention Program (NAEPP) guidelines recommend early treatment of acute asthma symptoms with albuterol and oral corticosteroids. Yet, ED visits for asthma are frequent and often occur several days after onset of increased symptoms, particularly for children from low-income urban neighborhoods.
To describe home use of albuterol and identify factors associated with appropriate albuterol use.
114 caregivers in the intervention group of a randomized trial to reduce emergent care for low-income, urban children completed a structured telephone interview with an asthma nurse to assess home management of their child’s acute asthma symptoms. Albuterol use as reported by caregivers was categorized as appropriate or inappropriate based on NAEPP recommendations.
Albuterol use for worsening asthma symptoms was categorized as appropriate for only 68% of caregivers and was more likely if the children had an ED visit or hospitalization for asthma in the prior year. The remaining 32% of caregivers used albuterol inappropriately (over or under treatment). Appropriate albuterol use was not associated with caregiver report of having an Asthma Action Plan (AAP) or a recent primary care provider visit to discuss asthma maintenance care.
Caregivers reported they would use albuterol to treat their child’s worsening asthma symptoms, but many described inappropriate use. Detailed assessment of proper albuterol use at home may provide insight into how healthcare providers can better educate and support parents in their management of acute exacerbations and more effective use of AAPs.
PMCID: PMC3809955  PMID: 19558010
Childhood asthma; asthma action plan
11.  Factors associated with attaining coaching goals during an intervention to improve child asthma care 
Contemporary clinical trials  2012;33(5):912-919.
To examine parent and child characteristics associated with engagement in a coaching intervention to improve pediatric asthma care and factors associated with readiness to adopt and maintain targeted asthma management behaviors.
Using methods based on the Transtheoretical Model, trained lay coaches worked with 120 parents of children with asthma promoting adoption and maintenance of asthma management strategies (behaviors). Coaches assigned stage-of-change (on continuum: pre-contemplation, contemplation, preparation, action, maintenance) for each behavior every time it was discussed. Improvement in stage-of-change was analyzed for association with characteristics of the participants (parents and children) and coaching processes.
Having more coach contacts was associated with earlier first contact (p<0.001), fewer attempts per successful contact (p<0.001), prior asthma hospitalization (p=0.021), more intruding events (p<0.001), and less social support (p=0.048). In univariable models, three factors were associated with forward movement at least one stage for all three behaviors: more coach contacts overall, fewer attempts per successful contact, and more discussion/staging episodes for the particular behavior. In multivariable models adjusting for characteristics of participants and coaching process, the strongest predictor of any forward stage movement for each behavior was having more contacts (p<0.05).
Improvement in readiness to adopt and maintain asthma management behaviors was mostly associated with factors reflecting more engagement of participants in the program. Similar coaching interventions should focus on early and frequent contacts to achieve intervention goals, recognizing that parents of children with less severe disease and who have more social support may be more difficult to engage.
PMCID: PMC3408563  PMID: 22664649
asthma; child; parent; coach; stage-of-change; engagement
12.  A randomized controlled trial of parental asthma coaching to improve outcomes in urban minority children 
Investigate if asthma coaching reduces emergency department (ED) visits and hospitalizations and increases outpatient asthma monitoring (AM) visits.
Randomized controlled trial
Urban tertiary-care children’s hospital
Primary caregivers (“parents”) of children age 2–10 years with asthma, Medicaid-insurance, and urban residence who were attending the ED for acute asthma care.
18 months of coaching focused on asthma home management, completing periodic outpatient AM visits, and developing collaborative relationship with primary care provider (PCP); or usual care (control group).
Outcome Measures
Primary = ED visits. Secondary = hospitalizations and AM visits (non-acute visits focused on asthma care). Outcomes were measured during year before and 2 years after enrollment.
We included 120 intervention and 121 control parents. More children of coached parents had ≥ 1 AM visit after enrollment (relative risk [RR], 1.21; 95% confidence interval [CI], 1.04–1.41), but proportions with ≥ 4 AM visits over 2 years were low (intervention=20%; control=10%). Similar proportions of children per study group had ≥ 1 ED visit (71/120 versus 76/121; RR, 0.94; 95% CI, 0.77–1.15) and ≥ 1 hospitalization (29/120 versus 32/121; RR, 0.91; 95% CI 0.59–1.41) after enrollment. An ED visit after enrollment was more likely if one occurred before enrollment (RR, 1.46; 95% CI 1.16–1.86; adjusted for study group), but risk was similar per study group when adjusted for previous ED visits (RR, 1.02; 95% CI, 0.82–1.27).
This parental asthma coaching intervention increased outpatient asthma monitoring visits, although these visits were infrequent, but did not reduce ED visits.
PMCID: PMC3733385  PMID: 21646584
13.  Chemoirradiation for Glioblastoma Multiforme: The National Cancer Institute Experience 
PLoS ONE  2013;8(8):e70745.
Standard treatment for glioblastoma (GBM) is surgery followed by radiation (RT) and temozolomide (TMZ). While there is variability in survival based on several established prognostic factors, the prognostic utility of other factors such as tumor size and location are not well established.
Experimental Design
The charts of ninety two patients with GBM treated with RT at the National Cancer Institute (NCI) between 1998 and 2012 were retrospectively reviewed. Most patients received RT with concurrent and adjuvant TMZ. Topographic locations were classified using preoperative imaging. Gross tumor volumes were contoured using treatment planning systems utilizing both pre-operative and post-operative MR imaging.
At a median follow-up of 18.7 months, the median overall survival (OS) and progression-free survival (PFS) for all patients was 17.9 and 7.6 months. Patients with the smallest tumors had a median OS of 52.3 months compared to 16.3 months among patients with the largest tumors, P = 0.006. The patients who received bevacizumab after recurrence had a median OS of 23.3 months, compared to 16.3 months in patients who did not receive it, P = 0.0284. The median PFS and OS in patients with periventricular tumors was 5.7 and 17.5 months, versus 8.9 and 23.3 months in patients with non-periventricular tumors, P = 0.005.
Survival in our cohort was comparable to the outcome of the defining EORTC-NCIC trial establishing the use of RT+TMZ. This study also identifies several potential prognostic factors that may be useful in stratifying patients.
PMCID: PMC3733728  PMID: 23940635
14.  Episodic Heavy Drinking, Problem Drinking and Injuries – Results of the WHO/NIAAA Collaborative Emergency Room Study in South Korea 
Alcohol (Fayetteville, N.Y.)  2012;46(5):407-413.
Alcohol is the 5th leading risk factor to the global disease burden and disability and about half of the global alcohol burden was attributable to injuries. Despite a large body of evidence documenting the associations between alcohol and injuries, data from Asian countries including South Korea are sparse. The aim of this study was to investigate the associations between episodic heavy past-year drinking, problem drinking symptomatic of alcohol dependence and alcohol-related and intentional injuries. Data from 1,989 injured patients recruited for the WHO/NIAAA Collaborative Study on Alcohol and Injury in South Korea were analyzed with respect to the prevalence rates and associations between injuries and frequency of past-year episodic heavy drinking and problem drinking. In estimating the odds ratios (ORs) and the associated 95% confidence intervals between alcohol intake and injuries multivariable logistic models were employed to adjust for sociodemographic characteristics and selected drinking variables. All analyses were conducted using the SAS 9.2 software. Findings of this study were consistent with prior studies that the risk of alcohol-related or intentional injury was positively associated with the frequency of episodic heavy drinking. The magnitudes of the associations were larger with frequent consumption of 5+ drinks (OR=4.0 approximately) than with frequent consumption of 12+ drinks (OR=3.1). Strong associations were also noted between RAPS4-assessed alcohol dependence and alcohol-related and intentional injuries. Further, the prevalence of intentional injury and its association with alcohol increased sharply once the acute alcohol intake exceeded 90 ml. Our results were consistent with prior studies that episodic heavy consumption, acute intoxication and problem drinking are pervasive among emergency room patients. Results of our study also lent support for administering a single-item screener querying consumption of 5+ drinks at a sitting in the past 12 months as a triage tool in Korea.
PMCID: PMC3431286  PMID: 22579122
emergency room (ER) study; episodic heavy drinking; problem drinking; alcohol-related and intentional injury
15.  Amphetamine, past and present – a pharmacological and clinical perspective 
Amphetamine was discovered over 100 years ago. Since then, it has transformed from a drug that was freely available without prescription as a panacea for a broad range of disorders into a highly restricted Controlled Drug with therapeutic applications restricted to attention deficit hyperactivity disorder (ADHD) and narcolepsy. This review describes the relationship between chemical structure and pharmacology of amphetamine and its congeners. Amphetamine’s diverse pharmacological actions translate not only into therapeutic efficacy, but also into the production of adverse events and liability for recreational abuse. Accordingly, the balance of benefit/risk is the key challenge for its clinical use. The review charts advances in pharmaceutical development from the introduction of once-daily formulations of amphetamine through to lisdexamfetamine, which is the first d-amphetamine prodrug approved for the management of ADHD in children, adolescents and adults. The unusual metabolic route for lisdexamfetamine to deliver d-amphetamine makes an important contribution to its pharmacology. How lisdexamfetamine’s distinctive pharmacokinetic/pharmacodynamic profile translates into sustained efficacy as a treatment for ADHD and its reduced potential for recreational abuse is also discussed.
PMCID: PMC3666194  PMID: 23539642
Abuse liability; amphetamine; attention deficit hyperactivity disorder (ADHD); drug formulations; lisdexamfetamine; microdialysis
16.  Analyses Related to the Development of DSM-5 Criteria for Substance Use Related Disorders: 1. Toward Amphetamine, Cocaine and Prescription Drug Use Disorder Continua Using Item Response Theory 
Drug and Alcohol Dependence  2011;122(1-2):38-46.
Prior research has demonstrated the dimensionality of alcohol, nicotine and cannabis use disorders criteria. The purpose of this study was to examine the unidimensionality of DSM-IV cocaine, amphetamine and prescription drug abuse and dependence criteria and to determine the impact of elimination of the legal problems criterion on the information value of the aggregate criteria.
Factor analyses and Item Response Theory (IRT) analyses were used to explore the unidimensionality and psychometric properties of the illicit drug use criteria using a large representative sample of the U.S. population.
All illicit drug abuse and dependence criteria formed unidimensional latent traits. For amphetamines, cocaine, sedatives, tranquilizers and opioids, IRT models fit better for models without legal problems criterion than models with legal problems criterion and there were no differences in the information value of the IRT models with and without the legal problems criterion, supporting the elimination of that criterion.
Consistent with findings for alcohol, nicotine and cannabis, amphetamine, cocaine, sedative, tranquilizer and opioid abuse and dependence criteria reflect underlying unitary dimensions of severity. The legal problems criterion associated with each of these substance use disorders can be eliminated with no loss in informational value and an advantage of parsimony. Taken together, these findings support the changes to substance use disorder diagnoses recommended by the American Psychiatric Association’s DSM-5 Substance and Related Disorders Workgroup.
PMCID: PMC3272309  PMID: 21963414
amphetamine use disorder; cocaine use disorder; prescription drug use disorder; DSM-5; item response theory
Drug and Alcohol Review  2011;31(2):141-150.
Introduction and Aims
This paper proposes an approach for evaluating the validity of alternative low-risk drinking guidelines.
Design and Methods
Twenty-seven alternative guidelines were evaluated in terms of their ability to predict 9 measures of concurrent and prospective alcohol-related harm, using longitudinal data from a nationally representative sample of U.S. adults (n=26,438 to 12,339 depending upon outcome). Parameters compared included sensitivity, specificity, adjusted odds ratios and measures of model fit.
Performance varied by harm. The guidelines that best predicted concurrent alcohol-related harm comprised daily-only limits of 4/3 drinks for men/women, but gender-invariant limits of 4/4 drinks also performed well. Adding weekly limits did little to improve the prediction of concurrent harm. The guidelines that best predicted prospective harm comprised daily limits of 4/4 drinks combined with weekly limits of 14 drinks for men and 7 drinks for women, with weekly limits of 14/14 drinks running second. When concurrent and incident harms were aggregated, daily-only limits of 4/3 drinks performed nearly on a par with the combination of 14/14 drinks per week and 4/3 drinks per day.
This paper supported gender-specific daily limits and suggested that optimal guidelines might take daily limits from analyses of concurrent harms and weekly limits from analyses of prospective harms.
This paper illustrates a mechanism for validating the ability of low-risk drinking guidelines to accurately predict a range of alcohol-related harms, whereby countries could use their own data on consumption and its association with harm to evaluate their low-risk drinking guidelines.
PMCID: PMC3252404  PMID: 21954858
drinking guidelines; alcohol-related harm; validity; prediction
18.  Temporal Relationships between Overweight and Obesity and DSM-IV Substance Use, Mood, and Anxiety Disorders: Results from a Prospective Study 
The Journal of clinical psychiatry  2011;72(11):1494-1502.
Associations between overweight and obesity and medical conditions have been extensively studied, but little is known about their relationships to psychiatric disorders.
To present nationally representative findings on the prospective relationships between overweight and obesity and DSM-IV substance use, mood and anxiety disorders.
Design, Setting and Participants
Waves 1 and 2 of the National Epidemiologic Survey on Alcohol and Related Conditions, a nationally representative sample of 34,653 U.S. adults.
Main Outcome Measures
Incidence of DSM-IV substance use, mood and anxiety disorders and changes in BMI status during the 3-year follow-up.
Regression analyses that controlled for a wide array of covariates showed that overweight and obese women were at increased risk for incident major depressive disorder (MDD) during the follow-up period. Overweight men and obese men were at decreased risk of incident drug abuse and alcohol dependence, respectively. Obese women had a decreased risk of incident alcohol abuse and drug dependence. Men with drug dependence and women with specific phobia had a decreased risk of becoming overweight or obese during the follow-up.
The NESARC excluded adolescents and the homeless and weight was self-reported, but highly correlated with external validating data.
Increased risk of MDD among overweight and obese women could be attributed to stigma and greater body dissatisfaction among women in Western cultures. Overweight and obesity may serve as protective factors against developing incident substance use disorders possibly due to shared neural functions in the brain underlying addictions to numerous substances. Results are discussed in terms of their clinical implications including the need to update treatment guidelines for the management of overweight, obesity and MDD.
PMCID: PMC3227748  PMID: 21457678
19.  Incidence of Occult Carcinoma and High-Risk Lesions in Mammaplasty Specimens 
Objectives. To determine the incidence and type of premalignant or malignant changes in mammaplasty specimens and to determine the incidence of these changes according to age distribution. Methods. Retrospective database review of patients who underwent a reduction mammaplasty between 1999 and 2009 was performed from pathology records at a single institution. Results. 700 patients were identified. Of the 644 patients who had bilateral reductions, 25 (4%) had significant pathologic findings. The likelihood of finding premalignant changes or cancer increased with advancing patient age (0.8 percent for patients <40 years old and 10 percent for patients >60 years old). Of the 56 patients who underwent unilateral mammaplasty, 12 patients (21%) had significant pathologic findings. The incidence of finding premalignant changes or cancer in this population also increased with advancing patient age (0 for patients <40 years old to 25 percent for patients >60 years old). Conclusions. When a unilateral mammaplasty is performed to match a breast reconstructed after cancer surgery, the likelihood of identifying premalignant changes or cancer increases more than fourfold. Therefore, one should consider additional radiologic imaging in the preoperative workup of patients with a history of carcinoma prior to undergoing unilateral mammaplasty.
PMCID: PMC3469090  PMID: 23091731
20.  Dimensionality of Hallucinogen and Inhalant/Solvent Abuse and Dependence Criteria: Implications for the Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition 
Addictive Behaviors  2011;36(9):912-918.
Prior research has demonstrated the dimensionality of Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition (DSM-IV) alcohol, nicotine, cannabis, cocaine and amphetamine abuse and dependence criteria. The purpose of this study was to examine the dimensionality of hallucinogen and inhalant/solvent abuse and dependence criteria. In addition, we assessed the impact of elimination of the legal problems abuse criterion on the information value of the aggregate abuse and dependence criteria, another proposed change for DSM- IV currently lacking empirical justification.
Factor analyses and item response theory (IRT) analyses were used to explore the unidimisionality and psychometric properties of hallucinogen and inhalant/solvent abuse and dependence criteria using a large representative sample of the United States (U.S.) general population.
Hallucinogen and inhalant/solvent abuse and dependence criteria formed unidimensional latent traits. For both substances, IRT models without the legal problems abuse criterion demonstrated better fit than the corresponding model with the legal problem abuse criterion. Further, there were no differences in the information value of the IRT models with and without the legal problems abuse criterion, supporting the elimination of that criterion. No bias in the new diagnoses was observed by sex, age and race-ethnicity.
Consistent with findings for alcohol, nicotine, cannabis, cocaine and amphetamine abuse and dependence criteria, hallucinogen and inhalant/solvent criteria reflect underlying dimensions of severity. The legal problems criterion associated with each of these substance use disorders can be eliminated with no loss in informational value and an advantage of parsimony. Taken together, these findings support the changes to substance use disorder diagnoses recommended by the DSM-V Substance and Related Disorders Workgroup, that is, combining DSM-IV abuse and dependence criteria and eliminating the legal problems abuse criterion.
PMCID: PMC3370431  PMID: 21621334
Hallucinogen use disorder; inhalant/solvent use disorder; DSM-V; item response theory; dimensionality
21.  Dimensionality of DSM-IV nicotine dependence in a national sample: An item response theory application☆ 
Drug and Alcohol Dependence  2010;108(1-2):21-28.
Research focusing on the development of a dimensional representation of DSM-IV nicotine dependence is scarce and prior research has not assessed the role of nicotine use criteria in that a dimensional representation, nor the invariance of the DSM-IV nicotine dependence criteria across important population subgroups.
Using a large, representative sample of the U.S. population, this study utilized item response theory (IRT) analyses to explore the dimensionality of DSM-IV nicotine dependence criteria and several candidate criteria for cigarette use among past-year cigarette smokers (n = 10,163).
Factor analyses demonstrated the unidimensionality of nicotine dependence criteria and IRT analyses demonstrated good fit of the observed responses and the underlying, unobserved latent trait of dependence severity. The model containing all seven DSM-IV dependence criteria, along with the consumption criterion of smoking at least a quarter of a pack of cigarettes in a day in the past year, was identified as the best-fitting model. No differential criterion functioning was shown across sex, race-ethnicity, and age subgroups.
Major implications of this study are discussed in terms of the addition of a dimensional representation of nicotine dependence to pre-existing categorical representations of the disorder in the DSM-V, and the need for a nicotine consumption criterion to improve representations of nicotine dependence severity.
PMCID: PMC3321925  PMID: 20045597
Nicotine dependence; Item response theory; Nicotine use criterion; Psychiatric assessment; DSM-V revision
22.  Access to Cancer Drugs in Canada: Looking Beyond Coverage Decisions 
Healthcare Policy  2011;6(3):27-36.
To examine variation in patients' access to a set of cancer drugs through publicly funded provincial drug programs.
Data Sources/Study Design:
We surveyed provincial drug program managers about their highest-expenditure intravenous and oral cancer drugs. We then investigated whether the same cancer drugs account for the highest expenditures across the provincial programs. We also compared the rates at which these drugs are accessed through these programs.
Principal Findings:
While there is moderate consistency in the selection of cancer drugs that account for the highest provincial expenditures, considerable differences were found in the rates at which some drugs are accessed across provincial programs.
The study demonstrates the existence of interprovincial variation in publicly funded access to cancer drugs even after these drugs have been approved for public coverage.
PMCID: PMC3082385  PMID: 22294989
23.  Characterization of the mechanism of protection mediated by CS-D7, a monoclonal antibody to Staphylococcus aureus iron regulated surface determinant B (IsdB) 
We previously reported the development of a human monoclonal antibody (CS-D7, IgG1) with specificity and affinity for the iron regulated surface determinant B (IsdB) of Staphylococcus aureus. CS-D7 mediates opsonophagocytic killing in vitro and protection in a murine sepsis model. In light of recent data indicating that IsdB specific T cells (CD4+, Th17), not Ab, mediate protection after vaccination with IsdB, it is important to investigate the mechanism of protection mediated by CS-D7. The mAb was examined to determine if it blocked heme binding to IsdB in vitro. The mAb was not found to have heme blocking activity, nor did it prevent bacterial growth under in vivo conditions, in an implanted growth chamber. To assess the role of the mAb Fc a point mutation was introduced at aa 297 (CS-D7·N297A). This point mutation removes Fc effector functions. In vitro analysis of the mutein confirmed that it lacked measurable binding to FcγR, and that it did not fix complement. The mutein had dramatically reduced in vitro opsonic OP activity compared to CS-D7. Nonetheless, the mutein conferred protection equivalent to the wild type mAb in the murine sepsis model. Both wild type and mutein mAbs were efficacious in FcγR deletion mice (including both FcγRII−/− mice and FcγRIII−/− mice), indicating that these receptors were not essential for mAb mediated protection in vivo. Protection mediated by CS-D7 was lost in Balb/c mice depleted of C3 with cobra venom factor (CFV), was lost in mice depleted of superoxide dismutase (SOD) in P47phox deletion mice, and as previously reported, was absent in SCID mice (Joshi et al., 2012). Enhanced clearance of S. aureus in the liver of CS-D7 treated mice and enhanced production of IFN-γ, but not of IL17, may play a role in the mechanism of protection mediated by the mAb. CS-D7 apparently mediates survival in challenged mice through a mechanism involving complement, phagocytes, and lymphocytes, but which does not depend on interaction with FcγR, or on blocking heme uptake.
PMCID: PMC3417506  PMID: 22919628
iron regulated surface determinant B (IsdB); Staphylococcus aureus; vaccination; passive immunization; opsonophagocytosis
24.  The Relationship of DSM-IV Personality Disorders to Nicotine Dependence-Results from a National Survey* 
Drug and alcohol dependence  2010;108(1-2):141-145.
This study examined the prevalence of nicotine dependence (ND) and its associations with DSM-IV personality disorders (PDs) among current smokers (n=7,078), controlling for sociodemographic characteristics and comorbid Axis I and II disorders. Data were derived from a nationally representative sample of the U.S. population. Although all PDs were significantly associated with ND when sociodemographic factors were controlled, only schizotypal, borderline, narcissistic and obsessive-compulsive PDs were associated with ND after adding controls for Axis I and other Axis II disorders. These associations remained significant after controlling for degree of smoking exposure. The results suggest that both shared and PD-specific pathogenetic factors underlie these PD-ND associations. Implications are also discussed in terms of the relationship between personality features of schizotypal, borderline, narcissistic and obsessive-compulsive PDs and the self-medication hypothesis and the role of neurotransmission.
PMCID: PMC2836161  PMID: 20079976
personality disorders; nicotine dependence; epidemiology; neurobiology; smoking exposure; self-medication hypothesis
25.  Regulatory challenges for new drugs to treat obesity and comorbid metabolic disorders 
Obesity is a major cause of morbidity and mortality through cardio- and cerebrovascular diseases and cancer. The metabolic consequences of obesity include dyslipidaemia, hypertension, proinflammatory atherogenesis, pre-diabetes and Type 2 diabetes. For a significant proportion of patients, pharmacotherapy to tackle obesity is required as adjunctive support to diet, exercise and lifestyle modification. To this end, the pharmaceutical industry is pursuing many novel drug targets. Although this view is probably not justified, the recent tribulations of rimonabant have created a perception that the regulatory bar for the approval of antiobesity drugs has been raised. Although >5% of placebo-subtracted weight loss maintained over 1 year is the primary efficacy end-point, it is improvements in cardiovascular risk factors that the Food and Drug Administration (FDA) and European Medicines Agency (EMEA) require to grant approval. Safety aspects are also critical in this indication. Many companies are now switching development of their antiobesity drug candidates into other metabolic disorders. Type 2 diabetes is accepted by the industry and FDA, but not EMEA, as the most appropriate alternative. On the other hand, improvements in plasma lipids produced by antiobesity drugs are moderate compared with established therapies, suggesting dyslipidaemia is not a viable development option. Metabolic Syndrome is not accepted by FDA or EMEA as a discrete disease and the agencies will not licence antiobesity drugs for its treatment. The regulatory environment for antiobesity drugs and the spectrum of indications for which they can be approved could change dramatically if positive data for sibutramine emerge from the SCOUT outcome trial.
PMCID: PMC2810797  PMID: 20002080
drug development; dyslipidaemia; Metabolic Syndrome; obesity; regulatory; Type 2 diabetes

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