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1.  Willingness to receive a hypothetical avian influenza vaccine among US military personnel in mid-deployment 
Human Vaccines & Immunotherapeutics  2013;9(12):2613-2617.
Though no avian influenza vaccine currently exists, development efforts have increased. Given recent reports of suboptimal vaccination rates among US military personnel, we sought to assess factors associated with a willingness to receive a hypothetical avian influenza vaccine. A self-administered questionnaire was completed by US military personnel during mid-deployment to Iraq, Afghanistan, and surrounding regions. Respondents were predominately male (86.2%), Army (72.1%), and enlisted (86.3%) with a mean age of 29.6 y. The majority (77.1%) agreed to receive an avian influenza vaccine if available. Exploratory factor analysis (EFA) identified two factors, vaccine importance and disease risk, that best described the individual perceptions and both were associated with an increased willingness to receive the hypothetical vaccine (OR: 8.2 and 1.6, respectively). Importantly, after controlling for these factors differences in the willingness to receive this hypothetical vaccine were observed across gender and branch of service. These results indicated that targeted education on vaccine safety and efficacy as well as disease risk may modify vaccination patterns in this population.
PMCID: PMC4162042  PMID: 23917256
factor analysis; avian influenza; vaccine; military; vaccine safety; disease risk
2.  Seroepidemiologic Survey for Coxiella burnetii Among US Military Personnel Deployed to Southwest and Central Asia in 2005 
We used a seroepidemiologic study to estimate Q fever (Coxiella burnetii) seroprevalence, seroincidence, and risk factors for seroconversion in two deployed military populations in 2005. The first study group resided in an area with a known Q fever outbreak history (Al Asad, Iraq). Of this population, 7.2% seroconverted for an incidence rate of 10.6 seroconversions per 1,000 person-months. The second population included personnel transiting through Qatar on mid-deployment leave from southwest/central Asia. In this group, we found 2.1% prevalence with 0.92 seroconversions per 1,000 person-months. However, no significant risk factors for Q fever seroconversion were found in either population.
PMCID: PMC3820350  PMID: 24043692
3.  Genome-wide Association Study of Obsessive-Compulsive Disorder 
Stewart, S Evelyn | Yu, Dongmei | Scharf, Jeremiah M | Neale, Benjamin M | Fagerness, Jesen A | Mathews, Carol A | Arnold, Paul D | Evans, Patrick D | Gamazon, Eric R | Osiecki, Lisa | McGrath, Lauren | Haddad, Stephen | Crane, Jacquelyn | Hezel, Dianne | Illman, Cornelia | Mayerfeld, Catherine | Konkashbaev, Anuar | Liu, Chunyu | Pluzhnikov, Anna | Tikhomirov, Anna | Edlund, Christopher K | Rauch, Scott L | Moessner, Rainald | Falkai, Peter | Maier, Wolfgang | Ruhrmann, Stephan | Grabe, Hans-Jörgen | Lennertz, Leonard | Wagner, Michael | Bellodi, Laura | Cavallini, Maria Cristina | Richter, Margaret A | Cook, Edwin H | Kennedy, James L | Rosenberg, David | Stein, Dan J | Hemmings, Sian MJ | Lochner, Christine | Azzam, Amin | Chavira, Denise A | Fournier, Eduardo | Garrido, Helena | Sheppard, Brooke | Umaña, Paul | Murphy, Dennis L | Wendland, Jens R | Veenstra-VanderWeele, Jeremy | Denys, Damiaan | Blom, Rianne | Deforce, Dieter | Van Nieuwerburgh, Filip | Westenberg, Herman GM | Walitza, Susanne | Egberts, Karin | Renner, Tobias | Miguel, Euripedes Constantino | Cappi, Carolina | Hounie, Ana G | Conceição do Rosário, Maria | Sampaio, Aline S | Vallada, Homero | Nicolini, Humberto | Lanzagorta, Nuria | Camarena, Beatriz | Delorme, Richard | Leboyer, Marion | Pato, Carlos N | Pato, Michele T | Voyiaziakis, Emanuel | Heutink, Peter | Cath, Danielle C | Posthuma, Danielle | Smit, Jan H | Samuels, Jack | Bienvenu, O Joseph | Cullen, Bernadette | Fyer, Abby J | Grados, Marco A | Greenberg, Benjamin D | McCracken, James T | Riddle, Mark A | Wang, Ying | Coric, Vladimir | Leckman, James F | Bloch, Michael | Pittenger, Christopher | Eapen, Valsamma | Black, Donald W | Ophoff, Roel A | Strengman, Eric | Cusi, Daniele | Turiel, Maurizio | Frau, Francesca | Macciardi, Fabio | Gibbs, J Raphael | Cookson, Mark R | Singleton, Andrew | Hardy, John | Crenshaw, Andrew T | Parkin, Melissa A | Mirel, Daniel B | Conti, David V | Purcell, Shaun | Nestadt, Gerald | Hanna, Gregory L | Jenike, Michael A | Knowles, James A | Cox, Nancy | Pauls, David L
Molecular psychiatry  2012;18(7):788-798.
Obsessive-compulsive disorder (OCD) is a common, debilitating neuropsychiatric illness with complex genetic etiology. The International OCD Foundation Genetics Collaborative (IOCDF-GC) is a multi-national collaboration established to discover the genetic variation predisposing to OCD. A set of individuals affected with DSM-IV OCD, a subset of their parents, and unselected controls, were genotyped with several different Illumina SNP microarrays. After extensive data cleaning, 1,465 cases, 5,557 ancestry-matched controls and 400 complete trios remained, with a common set of 469,410 autosomal and 9,657 X-chromosome SNPs. Ancestry-stratified case-control association analyses were conducted for three genetically-defined subpopulations and combined in two meta-analyses, with and without the trio-based analysis. In the case-control analysis, the lowest two p-values were located within DLGAP1 (p=2.49×10-6 and p=3.44×10-6), a member of the neuronal postsynaptic density complex. In the trio analysis, rs6131295, near BTBD3, exceeded the genome-wide significance threshold with a p-value=3.84 × 10-8. However, when trios were meta-analyzed with the combined case-control samples, the p-value for this variant was 3.62×10-5, losing genome-wide significance. Although no SNPs were identified to be associated with OCD at a genome-wide significant level in the combined trio-case-control sample, a significant enrichment of methylation-QTLs (p<0.001) and frontal lobe eQTLs (p=0.001) was observed within the top-ranked SNPs (p<0.01) from the trio-case-control analysis, suggesting these top signals may have a broad role in gene expression in the brain, and possibly in the etiology of OCD.
PMCID: PMC4218751  PMID: 22889921
Obsessive-compulsive disorder; GWAS; Genetic; Genomic; Neurodevelopmental disorder; DLGAP
4.  Lack of Homologous Protection Against Campylobacter jejuni CG8421 in a Human Challenge Model 
In a human challenge model with Campylobacter jejuni CG8421, primary infection caused campylobacteriosis and immune responsiveness measured by specific immunoglobuling (Ig) A and IgG, antibody-secreting cells, fecal IgA, and interferon γ production. Unexpectedly, after rechallenge, subjects were not protected from clinical illness.
Background. Campylobacter jejuni is a common cause of diarrhea and is associated with serious postinfectious sequelae. Although symptomatic and asymptomatic infections are recognized, protective immunity is not well understood. Previous data suggests that interferon γ (IFN-γ) may be associated with protection. To better define the clinical and immunologic development of protective immunity to C. jejuni, we assessed the ability of an initial infection to prevent clinical illness after a second experimental infection.
Methods. Subjects with no clinical or immunologic evidence of prior infection with C. jejuni received an initial challenge with C. jejuni CG8421 with rechallenge 3 months later. The primary endpoint was campylobacteriosis, as defined by diarrhea and/or systemic signs. Close inpatient monitoring was performed. Serum immunoglobulin A (IgA) and immunoglobulin G (IgG), fecal IgA, IgA antibody-secreting cells (ASCs), and IFN-γ production were evaluated. All subjects were treated with antibiotics and were clinically well at discharge.
Results. Fifteen subjects underwent a primary infection with C. jejuni CG8421; 14 (93.3%) experienced campylobacteriosis. Eight subjects received the second challenge, and all experienced campylobacteriosis with similar severity. Immune responses after primary infection included serum IgA, IgG, ASC, and IFN-γ production. Responses were less robust after secondary infection.
Conclusions. In naive healthy adults, a single infection with CG8421 did not protect against campylobacteriosis. Although protection has been demonstrated with other strains and after continuous environmental exposure, our work highlights the importance of prior immunity, repeated exposures, and strain differences in protective immunity to C. jejuni.
Clinical Trials Registration. NCT01048112
PMCID: PMC3888245  PMID: 23840001
Campylobacterosis; human challenge model; Campylobacter jejuni; homologous protection
5.  Pathogenicity and Phenotypic Characterization of Enterotoxigenic Escherichia coli Isolates from a Birth Cohort of Children in Rural Egypt 
Journal of Clinical Microbiology  2014;52(2):587-591.
Enterotoxigenic Escherichia coli (ETEC) has consistently been the predominant bacterial cause of diarrhea in many birth cohort- and hospital-based studies conducted in Egypt. We evaluated the pathogenicity of ETEC isolates in a birth cohort of children living in a rural community in Egypt. Between 2004 and 2007, we enrolled and followed 348 children starting at birth until their second year of life. A stool sample and two rectal swabs were collected from children during twice-weekly visits when they presented with diarrhea and were collected every 2 weeks if no diarrhea was reported. From routine stool cultures, five E. coli-like colonies were screened for ETEC enterotoxins using a GM1 enzyme-linked immunosorbent assay (ELISA). The isolates were screened against a panel of 12 colonization factor antigens (CFAs) by a dot blot assay. A nested case-control study evaluated the association between initial or repeat excretion of ETEC and the occurrences of diarrhea. The pathogenicity of ETEC was estimated in symptomatic children compared to that in asymptomatic controls. ETEC was significantly associated with diarrhea (crude odds ratio, 1.37; 95% confidence interval [CI], 1.24 to 1.52). The distribution of ETEC enterotoxins varied between the symptomatic children (44.2% heat-labile toxin [LT], 38.5% heat-stable toxin [ST], and 17.3% LT/ST) and asymptomatic children (55.5% LT, 34.6% ST, and 9.9% LT/ST) (P < 0.001). The CFAs CFA/I (n = 61), CS3 (n = 8), CS1 plus CS3 (n = 24), CS2 plus CS3 (n = 18), CS6 (n = 45), CS5 plus CS6 (n = 11), CS7 (n = 25), and CS14 (n = 32) were frequently detected in symptomatic children, while CS6 (n = 66), CS12 (n = 51), CFA/I (n = 43), and CS14 (n = 20) were detected at higher frequencies among asymptomatic children. While all toxin phenotypes were associated with diarrheal disease after the initial exposure, only ST and LT/ST-expressing ETEC isolates (P < 0.0001) were associated with disease in repeat infections. The role of enterotoxins and pathogenicity during repeat ETEC infections appears to be variable and dependent on the coexpression of specific CFAs.
PMCID: PMC3911313  PMID: 24478492
7.  A Common Factors Approach to Improving the Mental Health Capacity of Pediatric Primary Care 
To expand the mental health service capacity of pediatric primary care, we ask whether there are evidence-based skills to allow providers to 1) immediately begin treatment for children with emotional and behavioral problems while diagnostic procedures are being pursued, and 2) offer evidence-based care to children who do not meet criteria for a specific diagnosis. We discuss why the epidemiology of child mental health problems poses difficulties for disorder-specific mental health interventions, and review evidence that “common factors” contributing to the outcome of mental health treatments define a core set of skills that primary care providers might use to complement disorder-specific interventions.
PMCID: PMC4002282  PMID: 18543097
Primary care; Pediatrics; Mental health; Psychotherapy process
8.  The Iron Status of Children and Youth in a Community Mental Health Clinic is Lower than that of a National Sample 
Iron plays a key role in brain function, and a deficiency of iron has been implicated in various cognitive, motor, and psychiatric disorders. Because of recent evidence that iron deficiency may be related to attention-deficit/hyperactivity disorder (ADHD) and other psychiatric disorders, the goal of this study was to compare the iron status of children and youth seen in a community mental health clinic with a national sample of same-aged subjects.
In this study, a consecutive series of 108 patients (79 males) referred to a community mental health clinic was compared with a National Health and Nutrition Examination Survey (NHANES) sample on measures of iron status. Wilcoxon sign rank and median tests were used to compare distributions of ferritin. Quantile regression was performed to compare the ferritin level in the two samples while adjusting for demographic differences. Chi squared (χ2) was used to compare rates of low hemoglobin in the two samples.
The iron status of the clinic sample, as measured by ferritin levels (median=23 μg/L), was significantly lower than that of the national sample (median=43 μg/L). After adjustment for age, gender, and race, the clinic sample was found to have 19.2 μg/L lower ferritin than the national sample (95%CI from 7.6 to 30.9, p value=0.001). There were also significantly more subjects in the clinic sample with low hemoglobin than in the national sample. There were no differences in ferritin levels between those patients in the clinic sample with and without an ADHD or other specific psychiatric diagnosis.
The ferritin levels of children and youth in a mental health clinic sample were significantly lower than those of the same-aged subjects in a national sample. Therefore, compromised iron status may be an additional biological risk factor for cognitive, behavioral, and psychiatric problems in pediatric populations served by the community mental health clinic.
PMCID: PMC3609602  PMID: 23480325
9.  The Preschool Attention-Deficit/Hyperactivity Disorder Treatment Study (PATS) 6-Year Follow-up 
To describe the clinical course of attention-deficit/hyperactivity disorder (ADHD) symptom severity and diagnosis from ages 3–5 to 9–12 years during a 6-year follow-up after the original Preschool ADHD Treatment Study (PATS).
207 participants (75% male) from the original PATS, assessed at Baseline (mean age 4.4 years, when all met criteria for ADHD) and 3-months later (prior to medication treatment), were re-evaluated in three follow-up assessment visits (Year 3, mean age 7.4 years; Year 4, 8.3 years and Year 6, 10.4 years). Parents and teachers rated symptom severity and clinicians established psychiatric diagnoses. Analyses examined longitudinal changes in symptom severity and ADHD diagnosis.
Parent- and teacher-rated symptom severity decreased from Baseline to Year 3 but remained relatively stable and in the moderate-to-severe clinical range through Year 6. Girls showed generally steeper decreases in symptom T-scores. At Year 6, 89% (160/180) of remaining participants met ADHD symptom and impairment diagnostic criteria. Comorbidity of oppositional defiant disorder and/or conduct disorder was associated with a 30% higher risk of having an ADHD diagnosis at Year 6 in the multiple logistic model. Medication status during follow-up, on vs. off, did not predict symptom severity change from Year 3 to Year 6 after adjustment for other variables.
ADHD in preschoolers is a relatively stable diagnosis over a 6-year period. The course is generally chronic, with high symptom severity and impairment, in very young children with moderate-to-severe ADHD, despite treatment with medication. Development of more effective ADHD intervention strategies is needed for this age group.
PMCID: PMC3660093  PMID: 23452683
attention-deficit/hyperactivity disorder (ADHD); follow-up; pre-schoolers; development
10.  Antipsychotic Treatment Patterns and Aggressive Behavior Among Adolescents in Residential Facilities 
This study examined the association between acute aggressive behavior patterns of 145 adolescents in residential treatment facilities with use of and changes in antipsychotic medication for the chronic management of aggression. Seclusion/restraint (S/R) frequency over 12 months was used to categorize youth into none, low, moderate, and high S/R groups. Data were analyzed using longitudinal mixed effects logistic regression models that allowed for intra-subject variability over time. The high and moderate S/R groups were significantly more likely to receive antipsychotics, get higher doses, and have changes in medication compared with the none S/R group. Increases in antipsychotic dose were associated with a lower likelihood of changes in antipsychotic medication over time. Despite persistent antipsychotic use at higher doses, youth in the high and moderate S/R groups continued to be secluded/restrained frequently. The findings question the adequacy of these medications in managing aggressive behavior.
PMCID: PMC3637837  PMID: 23319375
11.  Psychological disorders in gastrointestinal disease: epiphenomenon, cause or consequence? 
Psychological disorders have been associated with irritable bowel syndrome (IBS) for decades in the absence of other objective etiology. However, such associations are also evident in other chronic diseases with more clearly defined pathogenesis such as ulcerative colitis. In this study, we examined the prevalence and severity of psychological disorders among IBS and ulcerative colitis (UC) patients relative to healthy controls.
A review was conducted of English-language literature to identify case-control studies reporting the prevalence of depression or anxiety in IBS and UC populations relative to healthy controls. Our primary endpoint was the pooled prevalence or average score of depression or anxiety in an IBS or UC population relative to healthy control.
Seven case-control studies evaluating IBS and three evaluating UC were included. All IBS and UC studies reported excess prevalence and severity of depression as well as anxiety, relative to healthy controls. The prevalence of depression in excess of healthy controls was 39% in UC case-control trials and 33% in IBS studies, and excess anxiety was present in UC (42%) and IBS (19%) case-control trials as well. Anxiety and depression scores were higher (representing more severe symptoms) in both UC and IBS patients compared to healthy controls.
Anxiety and depressive disorders are associated with both IBS and UC. The non-specific association between these psychological and gastrointestinal disorders could suggest that chronic gastrointestinal illness might affect psychosocial behavior.
PMCID: PMC4073018  PMID: 24974805
Mood disorders; irritable bowel syndrome; colitis; ulcerative
12.  Epidemiology of CLOSTRIDIUM DIFFICILE infection among active duty United States military personnel (1998-2010) 
BMC Infectious Diseases  2013;13:609.
Clostridium difficile associated disease (CDAD) has risen in incidence and the experience in the US military has not been described.
We evaluated the U.S. military’s database and identified CDAD cases and demographic characteristics among affected military personnel from 1998 to 2010.
2,423 cases were identified. CDAD incidence was 13.2 cases (95% CI: 12.7-13.7) per 100 K p-yr and increased over study years. CA-CDAD and HA-CDAD incidence was 5.5 (95% CI: 5.2, 5.9) per 100 K p-y and 1.3 (95% CI: 1.2, 1.4) per 1,000 hospitalizations respectively. Females comprised a larger proportion of CA-CDAD than HA-CDAD (25.5% vs. 19.3%; p < 0.001) cases as did Air Force service (29% vs. 23.4%; p < 0.01). On multivariate analysis female gender, Coast Guard or Air Force service, and a married status was associated with CA-CDAD whereas Male gender and Marine Corps service were associated with HA-CDAD cases.
CDAD has increased among military personnel, with female cases more likely to be community associated. Gender, marital status and branch of service had the strongest association with CDAD subtype. Further work is needed to evaluate the epidemiologic factors that have led to these increased rates in otherwise low-risk populations and associated sequelae.
PMCID: PMC3880161  PMID: 24373384
Clostridium difficile; C difficile; Clostridium difficile associated disease; Epidemiology; US military
13.  A case–control study of incident rheumatological conditions following acute gastroenteritis during military deployment 
BMJ Open  2013;3(12):e003801.
The aim of this study was to assess the risk of incident rheumatological diagnoses (RD) associated with self-reported diarrhoea and vomiting during a first-time deployment to Iraq or Afghanistan. Such an association would provide evidence that RD in this population may include individuals with reactive arthritis (ReA) from deployment-related infectious gastroenteritis.
This case–control epidemiological study used univariate and multivariate logistic regression to compare the odds of self-reported diarrhoea/vomiting among deployed US military personnel with incident RD to the odds of diarrhoea/vomiting among a control population.
We analysed health records of personnel deployed to Iraq or Afghanistan, including responses on a postdeployment health assessment and medical follow-up postdeployment.
Anonymous data were obtained from 891 US military personnel with at least 6 months of medical follow-up following a first-time deployment to Iraq or Afghanistan in 2008–2009. Cases were defined using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes; controls had an unrelated medical encounter and were representative of the study population.
Main outcome measures
The primary measure was an association between incident RD and self-reported diarrhoea/vomiting during deployment. A secondary measure was the overall incidence of RD in this population.
We identified 98 cases of new onset RD, with a total incidence of 161/100 000 persons. Of those, two participants had been diagnosed with Reiter's diseasei (3.3/100 000 persons) and the remainder with non-specific arthritis/arthralgia (157.5/100 000 persons). The OR for acute diarrhoea was 2.67 (p=0.03) after adjusting for important covariates.
Incident rheumatological conditions, even those classified as ‘non-specific,’ are significantly associated with prior severe diarrhoea in previously deployed military personnel, potentially indicating ReA and need for preventive measures to reduce diarrhoeagenic bacterial exposures in military personnel and other travellers to the developing regions.
PMCID: PMC3855532  PMID: 24319273
14.  Long-Term Exposure to Oral Methylphenidate or dl-Amphetamine Mixture in Peri-Adolescent Rhesus Monkeys: Effects on Physiology, Behavior, and Dopamine System Development 
Neuropsychopharmacology  2012;37(12):2566-2579.
The stimulants methylphenidate and amphetamine are used to treat children with attention deficit/hyperactivity disorder over important developmental periods, prompting concerns regarding possible long-term health impact. This study assessed the effects of such a regimen in male, peri-adolescent rhesus monkeys on a variety of cognitive/behavioral, physiological, and in vivo neurochemical imaging parameters. Twice daily (0900 and 1200 hours), for a total of 18 months, juvenile male monkeys (8 per group) consumed either an unadulterated orange-flavored solution, a methylphenidate solution, or a dl-amphetamine mixture. Doses were titrated to reach blood/plasma levels comparable to therapeutic levels in children. [11C]MPH and [11C]raclopride dynamic PET scans were performed to image dopamine transporter and D2-like receptors, respectively. Binding potential (BPND), an index of tracer-specific binding, and amphetamine-induced changes in BPND of [11C]raclopride were estimated by kinetic modeling. There were no consistent differences among groups on the vast majority of measures, including cognitive (psychomotor speed, timing, inhibitory control, cognitive flexibility), general activity, physiological (body weight, head circumference, crown-to-rump length), and neurochemical (ie, developmental changes in dopamine transporter, dopamine D2 receptor density, and amphetamine-stimulated dopamine release were as expected). Cytogenetic studies indicated that neither drug was a clastogen in rhesus monkeys. Thus, methylphenidate and amphetamine at therapeutic blood/plasma levels during peri-adolescence in non-human primates have little effect on physiological or behavioral/cognitive development.
PMCID: PMC3473325  PMID: 22805599
ADHD; amphetamine; CANTAB; methylphenidate; monkey; PET; addiction & substance abuse; amphetamine; attention deficity hyperactivity disorder; CANTAB; development/developmental disorders; dopamine; methylphenidate; monkey; Psychostimulants
15.  Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture 
Davis, Lea K. | Yu, Dongmei | Keenan, Clare L. | Gamazon, Eric R. | Konkashbaev, Anuar I. | Derks, Eske M. | Neale, Benjamin M. | Yang, Jian | Lee, S. Hong | Evans, Patrick | Barr, Cathy L. | Bellodi, Laura | Benarroch, Fortu | Berrio, Gabriel Bedoya | Bienvenu, Oscar J. | Bloch, Michael H. | Blom, Rianne M. | Bruun, Ruth D. | Budman, Cathy L. | Camarena, Beatriz | Campbell, Desmond | Cappi, Carolina | Cardona Silgado, Julio C. | Cath, Danielle C. | Cavallini, Maria C. | Chavira, Denise A. | Chouinard, Sylvain | Conti, David V. | Cook, Edwin H. | Coric, Vladimir | Cullen, Bernadette A. | Deforce, Dieter | Delorme, Richard | Dion, Yves | Edlund, Christopher K. | Egberts, Karin | Falkai, Peter | Fernandez, Thomas V. | Gallagher, Patience J. | Garrido, Helena | Geller, Daniel | Girard, Simon L. | Grabe, Hans J. | Grados, Marco A. | Greenberg, Benjamin D. | Gross-Tsur, Varda | Haddad, Stephen | Heiman, Gary A. | Hemmings, Sian M. J. | Hounie, Ana G. | Illmann, Cornelia | Jankovic, Joseph | Jenike, Michael A. | Kennedy, James L. | King, Robert A. | Kremeyer, Barbara | Kurlan, Roger | Lanzagorta, Nuria | Leboyer, Marion | Leckman, James F. | Lennertz, Leonhard | Liu, Chunyu | Lochner, Christine | Lowe, Thomas L. | Macciardi, Fabio | McCracken, James T. | McGrath, Lauren M. | Mesa Restrepo, Sandra C. | Moessner, Rainald | Morgan, Jubel | Muller, Heike | Murphy, Dennis L. | Naarden, Allan L. | Ochoa, William Cornejo | Ophoff, Roel A. | Osiecki, Lisa | Pakstis, Andrew J. | Pato, Michele T. | Pato, Carlos N. | Piacentini, John | Pittenger, Christopher | Pollak, Yehuda | Rauch, Scott L. | Renner, Tobias J. | Reus, Victor I. | Richter, Margaret A. | Riddle, Mark A. | Robertson, Mary M. | Romero, Roxana | Rosàrio, Maria C. | Rosenberg, David | Rouleau, Guy A. | Ruhrmann, Stephan | Ruiz-Linares, Andres | Sampaio, Aline S. | Samuels, Jack | Sandor, Paul | Sheppard, Brooke | Singer, Harvey S. | Smit, Jan H. | Stein, Dan J. | Strengman, E. | Tischfield, Jay A. | Valencia Duarte, Ana V. | Vallada, Homero | Van Nieuwerburgh, Filip | Veenstra-VanderWeele, Jeremy | Walitza, Susanne | Wang, Ying | Wendland, Jens R. | Westenberg, Herman G. M. | Shugart, Yin Yao | Miguel, Euripedes C. | McMahon, William | Wagner, Michael | Nicolini, Humberto | Posthuma, Danielle | Hanna, Gregory L. | Heutink, Peter | Denys, Damiaan | Arnold, Paul D. | Oostra, Ben A. | Nestadt, Gerald | Freimer, Nelson B. | Pauls, David L. | Wray, Naomi R. | Stewart, S. Evelyn | Mathews, Carol A. | Knowles, James A. | Cox, Nancy J. | Scharf, Jeremiah M.
PLoS Genetics  2013;9(10):e1003864.
The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.
Author Summary
Family and twin studies have shown that genetic risk factors are important in the development of Tourette Syndrome (TS) and obsessive compulsive disorder (OCD). However, efforts to identify the individual genetic risk factors involved in these two neuropsychiatric disorders have been largely unsuccessful. One possible explanation for this is that many genetic variations scattered throughout the genome each contribute a small amount to the overall risk. For TS and OCD, the genetic architecture (characterized by the number, frequency, and distribution of genetic risk factors) is presently unknown. This study examined the genetic architecture of TS and OCD in a variety of ways. We found that rare genetic changes account for more genetic risk in TS than in OCD; certain chromosomes contribute to OCD risk more than others; and variants that influence the level of genes expressed in two regions of the brain can account for a significant amount of risk for both TS and OCD. Results from this study might help in determining where, and what kind of variants are individual risk factors for TS and OCD and where they might be located in the human genome.
PMCID: PMC3812053  PMID: 24204291
16.  Treatment Moderators and Predictors of Outcome in the Treatment of Early Age Mania (TEAM) Study 
Both the diagnosis and treatment of bipolar disorder in youth remain the subject of debate. In the Treatment of Early Age Mania (TEAM) study, risperidone was more effective than lithium or divalproex in children diagnosed with bipolar mania and highly comorbid with attention deficit/hyperactivity disorder (ADHD). We searched for treatment moderators and predictors of outcome.
TEAM was a multi-site, 8-week, randomized clinical trial of risperidone, lithium, or divalproex in 279 medication-naïve patients, age 6–15 years, with a DSM-IV diagnosis of bipolar disorder currently in manic or mixed phase. Outcome measures included binary end-of-treatment responder status and change in the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) Mania Rating Scale (KMRS). Baseline demographics and clinical characteristics were tested as modifiers of treatment effect and as overall predictors of outcome.
Moderator effects were detected for site, ADHD, and obesity. Across sites, the response ratio (RR) for risperidone vs. lithium ranged from 1.2 (95% CI 0.8, 1.7) to 8.3 (1.1, 60.8), and for risperidone vs. divalproex from 1.3 (0.8, 2.2) to 10.5 (1.4, 77.7). The RR for risperidone vs. lithium was 2.1 for patients with ADHD, but 1.0 for those without ADHD, and 2.3 (1.6, 3.3) for non-obese patients, but 1.1 (0.6, 2.0) for obese ones. Older age and less severe ADHD symptoms were associated with greater improvement on the KMRS.
Risperidone was more effective than lithium or divalproex across the demographics and clinical characteristics of the sample, but the magnitude of its effect was influenced by site-related characteristics and presence of ADHD.
PMCID: PMC3427533  PMID: 22917200
children; bipolar; treatment; predictors; moderators
17.  Improving metabolic parameters of antipsychotic child treatment (IMPACT) study: rationale, design, and methods 
Youth with serious mental illness may experience improved psychiatric stability with second generation antipsychotic (SGA) medication treatment, but unfortunately may also experience unhealthy weight gain adverse events. Research on weight loss strategies for youth who require ongoing antipsychotic treatment is quite limited. The purpose of this paper is to present the design, methods, and rationale of the Improving Metabolic Parameters in Antipsychotic Child Treatment (IMPACT) study, a federally funded, randomized trial comparing two pharmacologic strategies against a control condition to manage SGA-related weight gain.
The design and methodology considerations of the IMPACT trial are described and embedded in a description of health risks associated with antipsychotic-related weight gain and the limitations of currently available research.
The IMPACT study is a 4-site, six month, randomized, open-label, clinical trial of overweight/obese youth ages 8–19 years with pediatric schizophrenia-spectrum and bipolar-spectrum disorders, psychotic or non-psychotic major depressive disorder, or irritability associated with autistic disorder. Youth who have experienced clinically significant weight gain during antipsychotic treatment in the past 3 years are randomized to either (1) switch antipsychotic plus healthy lifestyle education (HLE); (2) add metformin plus HLE; or (3) HLE with no medication change. The primary aim is to compare weight change (body mass index z-scores) for each pharmacologic intervention with the control condition. Key secondary assessments include percentage body fat, insulin resistance, lipid profile, psychiatric symptom stability (monitored independently by the pharmacotherapist and a blinded evaluator), and all-cause and specific cause discontinuation. This study is ongoing, and the targeted sample size is 132 youth.
Antipsychotic-related weight gain is an important public health issue for youth requiring ongoing antipsychotic treatment to maintain psychiatric stability. The IMPACT study provides a model for pediatric research on adverse event management using state-of-the art methods. The results of this study will provide needed data on risks and benefits of two pharmacologic interventions that are already being used in pediatric clinical settings but that have not yet been compared directly in randomized trials.
Trial registration
Clinical NCT00806234
PMCID: PMC3846140  PMID: 23947389
18.  The Incidence and Risk of Celiac Disease in a Healthy US Adult Population 
Celiac disease (CD) is an increasingly common disease that may affect as many as 1% of the North American population. Recent population-based data suggest a substantial increase in the prevalence of CD over the last several decades. Several factors are hypothesized as possible disease triggers including intercurrent illnesses, such as gastroenteritis, surgeries, and trauma. We used the active duty US military, a unique healthy worker population with essentially complete medical diagnostic coding, as an opportunity to describe trends in CD and deployment-related risk factors.
Using electronic medical encounter data (1999–2008) on active duty US military (over 13.7 million person-years), a matched, nested case–control study describing the epidemiology and risk determinants of CD (based on ≥2 ICD-9 medical encounters) was conducted. Incidence and duration of CD-related medical care were estimated, and conditional logistic regression was utilized to evaluate CD risk following infectious gastroenteritis (IGE) occurring within 3 years before CD diagnosis while controlling for other risk factors.
A total of 455 incident cases of CD were identified and age, gender, and time matched to 1,820 controls. The incidence of CD increased five-fold from 1.3 per 100,000 in 1999 to 6.5 per 100,000 in 2008, with the highest rates of increase among those over 34 years of age (average annual increase of 0.8 cases per 100,000). A total of 172 IGE episodes, predominately of “viral etiology” (60.5%), were documented. In multivariate models, a significant association between IGE and CD was found (Odds ratio (OR): 2.06, 95% confidence interval (CI) 1.43, 2.97). Risk generally increased with temporal proximity to, and non-viral etiology of, exposure. Other notable risk factors for CD in multivariate models were Caucasian race (OR: 3.1, P < 0.001), non-Army service (OR: 1.5, P = 0.001), and greater than a high-school education (OR: 1.3, P = 0.05).
Incidence of CD diagnosis in the US military is increasing, particularly among those in the fourth and fifth decades of life and appears higher than other population-based estimates. An association between antecedent IGE and risk of CD was noted, but the potential for exposure misclassification cannot be ruled out and further study is needed to link pathogen-specific exposure to incident CD anti-gluten antibody development or symptom onset.
PMCID: PMC3493152  PMID: 22584218
19.  Screening CT Colonography: Multicenter Survey of Patient Experience, Preference, and Potential Impact on Adherence 
AJR. American journal of roentgenology  2012;198(6):1361-1366.
Prior research indicates CT colonography (CTC) would be a cost-effective colorectal cancer (CRC) screening test if widespread availability were to increase overall CRC screening adherence rates. The primary aims of this multicenter study were to evaluate patient experience and satisfaction with CTC screening and compare preference against screening colonoscopy.
A 12-question survey instrument measuring pretest choice, experience, and satisfaction was given to a consecutive cohort of adults undergoing CTC screening in three disparate screening settings: university academic center, military medical center, and community practice. The study cohort was composed of individuals voluntarily participating in clinical CTC screening programs.
A total of 1417 patients responded to the survey. The top reasons for choosing CTC for screening included “noninvasiveness” (68.0%), “avoidance of sedation/anesthesia” (63.1%), “ability to drive after the test” (49.2%), “avoidance of optical colonoscopy risks” (46.9%), and “identifying abnormalities outside the colon” (43.3%). Only 7.2% of patients reported pain during the CTC examination and only 2.5% reported greater than moderate discomfort. Of 441 patients who had experienced both CTC and optical colonoscopy, 77.1% preferred CTC and 13.8% preferred optical colonoscopy. Of all patients, 29.6% indicated that they may not have undergone optical colonoscopy screening if CTC were not available. Of all patients, 92.9% labeled their overall experience with CTC as “excellent” or “good,” and 93.0% indicated they would choose CTC for their next screening.
Respondents reported a very high satisfaction level with CTC, and those who had experienced both modalities indicated a preference for CTC over optical colonoscopy. These results suggest that CTC has the potential to increase adherence to CRC screening guidelines if widely available.
PMCID: PMC3689205  PMID: 22623549
colorectal cancer; CT colonography; optical colonoscopy; virtual colonoscopy
20.  Pathogen-specific risk of chronic gastrointestinal disorders following bacterial causes of foodborne illness 
BMC Gastroenterology  2013;13:46.
The US CDC estimates over 2 million foodborne illnesses are annually caused by 4 major enteropathogens: non-typhoid Salmonella spp., Campylobacter spp., Shigella spp. and Yersinia enterocoltica. While data suggest a number of costly and morbid chronic sequelae associated with these infections, pathogen-specific risk estimates are lacking. We utilized a US Department of Defense medical encounter database to evaluate the risk of several gastrointestinal disorders following select foodborne infections.
We identified subjects with acute gastroenteritis between 1998 to 2009 attributed to Salmonella (nontyphoidal) spp., Shigella spp., Campylobacter spp. or Yersinia enterocolitica and matched each with up to 4 unexposed subjects. Medical history was analyzed for the duration of military service time (or a minimum of 1 year) to assess for incident chronic gastrointestinal disorders. Relative risks were calculated using modified Poisson regression while controlling for the effect of covariates.
A total of 1,753 pathogen-specific gastroenteritis cases (Campylobacter: 738, Salmonella: 624, Shigella: 376, Yersinia: 17) were identified and followed for a median of 3.8 years. The incidence (per 100,000 person-years) of PI sequelae among exposed was as follows: irritable bowel syndrome (IBS), 3.0; dyspepsia, 1.8; constipation, 3.9; gastroesophageal reflux disease (GERD), 9.7. In multivariate analyses, we found pathogen-specific increased risk of IBS, dyspepsia, constipation and GERD.
These data confirm previous studies demonstrating risk of chronic gastrointestinal sequelae following bacterial enteric infections and highlight additional preventable burden of disease which may inform better food security policies and practices, and prompt further research into pathogenic mechanisms.
PMCID: PMC3599665  PMID: 23510245
21.  Postinfectious Functional Gastrointestinal Disorders: A Focus on Epidemiology and Research Agendas 
Gastroenterology & Hepatology  2013;9(3):145-157.
Epidemiologic research is fundamental and complementary to our understanding of disease and development of primary, secondary, and tertiary interventions. To put the current evidence into context and identify gaps and research priorities in the areas of disease attribution, burden of disease, clinical characterization, and management of postinfectious functional gastrointestinal disorders (PI-FGDs), we took a multidisciplinary approach from the domains of infectious disease, gastroenterology, epidemiology, and public health. Our review of data from these disciplines found that, despite a complete understanding of pathoetiology, studies continue to accumulate and point toward evidence of a causal association for FGD. For some FGDs, Bradford Hill’s criteria for causality yield more certainty than other criteria. In addition, the growing recognition of the impact of acute foodborne illness on economics and society is leading to exploration of the potential long-term health effects and disease burden of PI-FGDs, although a paucity of data exist in terms of pathogen-specific risk, disability duration, and relevant disability weights. Lastly, the understanding of PI-FGDs is changing the way research is approached and suggests a need for a more expansive exploration of biologic mechanisms and how FGDs are categorized. Areas of research priorities are catalogued in this paper and will hopefully provide inspiration for future studies and contributions to the field of gastroenterology.
PMCID: PMC3745203  PMID: 23961264
Functional gastrointestinal disorder; qualitative review; irritable bowel syndrome; dyspepsia; causation
22.  A Randomized Controlled Trial of Risperidone, Lithium, or Divalproex Sodium for Initial Treatment of Bipolar I Disorder, Manic or Mixed Phase, in Children and Adolescents 
Archives of general psychiatry  2012;69(5):515-528.
There was a paucity of comparative pharmacological research for initial treatment of bipolar I disorder, manic or mixed phase, in children and adolescents.
To investigate which medication to administer first to antimanic medication-naive subjects.
Design, Setting, and Participants
The Treatment of Early Age Mania (TEAM) study recruited 6- to 15-year-old children and adolescents with DSM-IV bipolar I disorder (manic or mixed phase) at 5 US sites from 2003 to 2008 into a controlled, randomized, no-patient-choice, 8-week protocol. Blinded, independent evaluators conducted all baseline and end-point assessments.
Subjects received a titrated schedule of lithium, divalproex sodium, or risperidone. Medications were increased weekly only if there was inadequate response, and no dose-limiting adverse effects, to maximum doses of lithium carbonate (1.1-1.3 mEq/L), divalproex sodium (111-125 μg/mL), and risperidone (4-6 mg).
Main Outcome Measures
Primary outcome measures were the Clinical Global Impressions for Bipolar Illness Improvement-Mania and the Modified Side Effects Form for Children and Adolescents.
There were 279 antimanic medication-naive subjects (mean [SD] age, 10.1 [2.8] years; 50.2% female) who had the following characteristics: 100% elated mood and/or grandiosity, 77.1% psychosis, 97.5% mixed mania, 99.3% daily rapid cycling, and mean (SD) mania duration of 4.9 (2.5) years. The mean (SD) titrated lithium level was 1.09 (0.34) mEq/L, and the mean (SD) divalproex sodium level was 113.6 (23.0) μg/mL. The mean (SD) titrated risperidone dose was 2.57 (1.21) mg. Higher response rates occurred with risperidone vs lithium (68.5% vs 35.6%; χ21=16.9, P<.001) and vs divalproex sodium (68.5% vs 24.0%; χ21=28.3, P<.001). Response to lithium vs divalproex sodium did not differ. The discontinuation rate was higher for lithium than for risperidone (χ21=6.4, P=.011). Increased weight gain, body mass index, and prolactin level occurred with risperidone vs lithium (F1,212=45.5, P<.001; F1,212=39.1, P<.001; and F1,213=191.4, P<.001, respectively) and vs divalproex sodium (F1,212=34.7, P<.001; F1,212=45.3, P<.001; and F1,213=209.4, P<.001, respectively). The thyrotropin level increased in subjects taking lithium (t62=11.3, P<.001).
Risperidone was more efficacious than lithium or divalproex sodium for the initial treatment of childhood mania but had potentially serious metabolic effects.
Trial Registration Identifier: NCT00057681
PMCID: PMC3581342  PMID: 22213771
23.  Antipsychotic Treatment Among Youth in Foster Care 
Pediatrics  2011;128(6):e1459-e1466.
Despite national concerns over high rates of antipsychotic medication use among youth in foster care, concomitant antipsychotic use has not been examined. In this study, concomitant antipsychotic use among Medicaid-enrolled youth in foster care was compared with disabled or low-income Medicaid-enrolled youth.
The sample included 16 969 youths younger than 20 years who were continuously enrolled in a Mid-Atlantic state Medicaid program and had ≥1 claim with a psychiatric diagnosis and ≥1 antipsychotic claim in 2003. Antipsychotic treatment was characterized by days of any use and concomitant use with ≥2 overlapping antipsychotics for >30 days. Medicaid program categories were foster care, disabled (Supplemental Security Income), and Temporary Assistance for Needy Families (TANF). Multicategory involvement for youths in foster care was classified as foster care/Supplemental Security Income, foster care/TANF, and foster care/adoption. We used multivariate analyses, adjusting for demographics, psychiatric comorbidities, and other psychotropic use, to assess associations between Medicaid program category and concomitant antipsychotic use.
Average antipsychotic use ranged from 222 ± 110 days in foster care to only 135 ± 101 days in TANF (P < .001). Concomitant use for ≥180 days was 19% in foster care only and 24% in foster care/adoption compared with <15% in the other categories. Conduct disorder and antidepressant or mood-stabilizer use was associated with a higher likelihood of concomitant antipsychotic use (P < .0001).
Additional study is needed to assess the clinical rationale, safety, and outcomes of concomitant antipsychotic use and to inform statewide policies for monitoring and oversight of antipsychotic use among youths in the foster care system.
PMCID: PMC3387900  PMID: 22106072
foster care; antipsychotic; children; psychotropic use
24.  Association between a serotonin transporter promoter polymorphism (5-HTTLPR) and personality disorder traits in a community sample 
Journal of psychiatric research  2011;45(9):1153-1159.
The serotonin transporter (SERT) polymorphism (5HTTLPR) has been reported to be associated with several psychiatric conditions. Specific personality disorders could be intermediate factors in the known relationship between 5HTTLPR and psychiatric disorders. This is the first study to test the association between this polymorphism and dimensions of all DSM-IV personality disorders in a community sample.
374 white participants were assessed by clinical psychologists using the International Personality Disorder Examination (IPDE). Associations between dimensions of each DSM-IV personality disorder and the long (l) and short (s) alleles of the 5HTTLPR were evaluated using nonparametric tests and regression models.
The s allele of the 5HTTLPR polymorphism was significantly associated with higher avoidant personality trait scores in the whole sample. Males with the s allele had a significantly lower likelihood of higher obsessive-compulsive personality disorder (OCPD) trait scores, whereas females with the s allele were likely to have higher OCPD personality trait scores.
This paper provides preliminary data on the relationship between personality disorders and the 5HTTLPR polymorphism. The relationship of the s allele and avoidant PD is consistent with findings of a nonspecific relationship of this polymorphism to anxiety and depressive disorders. Concerning the unusual sexual dimorphic result with OCPD, several hypotheses are presented. These findings need further replication, including a more detailed study of additional variants in SERT.
PMCID: PMC3128677  PMID: 21450307
personality disorders; serotonin transporter gene; avoidant personality; obsessive compulsive personality; sex differences; polymorphism
25.  Effectiveness of rifaximin and fluoroquinolones in preventing travelers’ diarrhea (TD): a systematic review and meta-analysis 
Systematic Reviews  2012;1:39.
Recent developments related to a safe and effective nonabsorbable antibiotic, rifaximin, and identification of postinfectious irritable bowel syndrome as a frequent sequela call for a need to reconsider the value of primary prevention of traveler’s diarrhea (TD) with antibiotics.
Randomized, placebo-controlled, double-blind studies evaluating the effectiveness and safety of rifaximin or a fluoroquinolone chemoprophylaxis against TD were pooled using a random effects model and assessed for heterogeneity.
The nine studies (four rifaximin and five fluoroquinolone) included resulted in pooled relative risk estimates of 0.33 (95% CI = 0.24–0.45, I2 = 3.1%) and 0.12 (95% CI = 0.07–0.20, I2 =0.0%), respectively. Similar rates of treatment emergent adverse events were found between antibiotic and placebo groups.
This meta-analysis supports the effectiveness of antibiotics in preventing TD. However, further studies that include prevention of secondary chronic health outcomes among travelers to different geographic regions, and a formal risk-benefit analysis for antibiotic chemoprophylaxis, are needed.
PMCID: PMC3441921  PMID: 22929178
Travelers’ diarrhea; Chemoprophylaxis; Systematic review; Meta-analysis; Rifaximin; Fluoroquinolone

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