Impact of medications prescribed for treatment of attention-deficit hyperactivity disorder on physical growth in children and adolescents with HIV.

OBJECTIVE: To examine the relationships between physical growth and medications prescribed for symptoms of attention-deficit hyperactivity disorder in children with HIV. METHODS: Analysis of data from children with perinatally acquired HIV (N = 2251; age 3-19 years), with and without prescriptions for stimulant and nonstimulant medications used to treat attention-deficit hyperactivity disorder, in a long-term observational study. Height and weight measurements were transformed to z scores and compared across medication groups. Changes in z scores during a 2-year interval were compared using multiple linear regression models adjusting for selected covariates. RESULTS: Participants with (n = 215) and without (n = 2036) prescriptions were shorter than expected based on US age and gender norms (p < .001). Children without prescriptions weighed less at baseline than children in the general population (p < .001) but gained height and weight at a faster rate (p < .001). Children prescribed stimulants were similar to population norms in baseline weight; their height and weight growth velocities were comparable with the general population and children without prescriptions (for weight, p = .511 and .100, respectively). Children prescribed nonstimulants had the lowest baseline height but were similar to population norms in baseline weight. Their height and weight growth velocities were comparable with the general population but significantly slower than children without prescriptions (p = .01 and .02, respectively). CONCLUSION: The use of stimulants to treat symptoms of attention-deficit hyperactivity disorder does not significantly exacerbate the potential for growth delay in children with HIV and may afford opportunities for interventions that promote physical growth. Prospective studies are needed to confirm these findings.

Gene Discovery in Nonsyndromic Cleft Lip with or without Cleft Palate

Nonsyndromic cleft lip with or without cleft palate (NSCLP), a common, complex orofacial birth defect that affects approximately 4,000 newborns each year in the United States, is caused by both genetic and environmental factors. Orofacial clefts affect the mouth and nose, causing severe deformity of the face, which require medical, dental and speech therapies. Despite having substantial genetic liability, less than 25% of the genetic contribute to NSCLP has been identified. The studies described in this thesis were performed to identify genes that contribute to NSCLP and to demonstrate the role of these genes in normal craniofacial development. Using genome scan and candidate gene approaches, novel associations with NSCLP were identified. These include MYH9 (7 SNPs, 0.009≤p<0.05), Wnt3A (4 SNPs, 0.001≤p≤0.005), Wnt11 (2 SNPs, 0.001≤p≤0.01) and CRISPLD2 (4 SNPs, 0.001≤p<0.05). The most interesting findings were for CRISPLD2. This gene is expressed in the fused mouse palate at E17.5. In zebrafish, crispld2 localized to the craniofacial region by one day post fertilization. Morpholino knockdown of crispld2 resulted in a lower survival rates and altered neural crest cell (NCC) clustering. Because NCCs form the tissues that populate the craniofacies, this NCC abnormality resulted in cartilage abnormalities of the jaw including fewer ceratobranchial cartilages forming the lower jaw (three pairs compared to five) and broader craniofacies compared to wild-type zebrafish. These findings suggest that the CRISPLD2 gene plays an important role in normal craniofacial development and perturbation of this gene in humans contributes to orofacial clefting. Overall, these results are important because they contribute to our understanding of normal craniofacial development and orofacial clefting etiology, information that can be used to develop better methods to diagnose, counsel and potentially treat NSCLP patients.

Attention-Deficit/Hyperactivity Disorder and antidepressants and prescription medications: A pilot study

Background. Attention Deficit-Hyperactivity Disorder (AD/HD) diagnosis in children and adolescents has been on the rise over the last couple of decades and a multitude of studies have been conducted in an aim to better understand the disease. Literature has explored the role of several factors suspected of contributing to development of the disease, including: prenatal smoking exposures, environmental exposures, and low-birth weight. However, there is very limited reporting of fetal/infant exposure to antidepressants and prescription medications and the long-term behavioral outcomes, namely development of AD/HD. The purpose of this study was to evaluate the relationship between mother's exposure to prescription medications and/or antidepressants around the time of conception, during pregnancy, or while breastfeeding and the development of Attention-Deficit/Hyperactivity Disorder in offspring. Methods. Secondary analysis of data from a case-control study was performed. Exposure histories were collected for the mother and offspring. Data were collected using a secure, confidential, self-report, online survey to evaluate the relationship between antidepressant and/or prescription medication exposure and the development of AD/HD. The period of exposure to these drugs was defined as: around the time of conception, during pregnancy, or while breastfeeding. Cases were defined as a child who had been diagnosed with AD/HD. Controls were defined as a child who had not been diagnosed with AD/HD. Results. Prescription medication and antidepressant medication exposures around the time of conception, during pregnancy, or while breastfeeding were not associated with development of AD/HD. However, traumatic brain injury (OR=2.77 (1.61–4.77)) and preterm birth (OR=1.48 (1.04–2.12)) were identified as potential risk factors. These results support existing literature on AD/HD, but future work must be undertaken to better evaluate fetal/infant medication exposures and long-term behavioral outcomes.^

The association of allergies and attention deficit hyperactivity disorder in children

To investigate the association between allergies and attention deficit hyperactivity disorder (ADHD), a case-control study was conducted using the National Longitudinal Survey of Youth population. Cases were between the ages of 4 and 11 years and were classified either by a maternal-reported diagnosis or by the Behavior Problems Index Hyperactivity Scale. Controls were chosen from the same age group but had a score of less than 14 on the overall Behavior Problems Index. A history of allergies was considered positive if any of the following conditions were reported as requiring treatment by a doctor or other health professional: asthma, allergic conditions, or food allergies. A strong association was observed between allergies and a maternal-reported diagnosis while controlling for demographic, socioeconomic, perinatal, and environmental factors (adjusted odds ratio = 2.85 (95% CI = 1.49-5.42)). Other risk factors found to be important risk factors for a diagnosis of ADHD were gender (male), gestational age ($<$36 weeks), and maternal education ($\leq$high school). No association between allergies and cases classified as ADHD based on the hyperactivity symptom scale was observed. This study confirms other studies that reported an allergy/ADHD association in diagnoses populations. Further investigation confirming the association and explanation of the reasons and underlying mechanisms of the observed association is warranted. These studies should use validated diagnostic criteria for the diagnosis of ADHD symptoms and allergies, adequate sample sizes, and control for confounding. ^

Attention-deficit hyperactivity disorder symptoms and lead exposure in children: A systematic review of literature

Blood lead levels > 10 µg/dL are known to affect various areas of the brain that influence behavior and cause many other health problems in children. As a result, the Centers for Disease Control and Prevention (CDC) set the blood lead action level at 10 µg/dL. However, recent research provides evidence that blood lead levels <10 µg/dL also may lead to behavioral problems in children. With the recent increase in diagnosis of Attention-Deficit Hyperactivity Disorder (ADHD) in children in the U.S. it is important to determine possible environmental toxins such as lead that may play a role in causing ADHD symptoms. The aim of this systematic review of the literature was to identify recent published studies that examine an association between blood lead levels < 10 µg/dL and ADHD symptoms in children in order to summarize their findings and describe major gaps in the literature. Although available research is limited, the articles reviewed indicate that blood lead at levels much below the CDC action level of 10 µg/dL may affect a child's level of attention, hyperactivity, impulsivity and ADHD diagnosis. Additional prospective research is warranted in order to inform the revision of current blood lead action levels as well as better elucidate the relationship between lead and ADHD diagnoses.^

Eye Movement Measures of Cognitive Control in Children with Tourette Syndrome

Tourette Syndrome begins in childhood and is characterized by uncontrollable repetitive actions like neck craning or hopping and noises such as sniffing or chirping. Worst in early adolescence, these tics wax and wane in severity and occur in bouts unpredictably, often drawing unwanted attention from bystanders. Making matters worse, over half of children with Tourette Syndrome also suffer from comorbid, or concurrent, disorders such as attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). These disorders introduce anxious thoughts, impulsivity, inattention, and mood variability that further disrupt children with Tourette Syndrome from focusing and performing well at school and home. Thus, deficits in the cognitive control functions of response inhibition, response generation, and working memory have long been ascribed to Tourette Syndrome. Yet, without considering the effect of medication, age, and comorbidity, this is a premature attribution. This study used an infrared eye tracking camera and various computer tasks requiring eye movement responses to evaluate response inhibition, response generation, and working memory in Tourette Syndrome. This study, the first to control for medication, age, and comorbidity, enrolled 39 unmedicated children with Tourette Syndrome and 29 typically developing peers aged 10-16 years who completed reflexive and voluntary eye movement tasks and diagnostic rating scales to assess symptom severities of Tourette Syndrome, ADHD, and OCD. Children with Tourette Syndrome and comorbid ADHD and/or OCD, but not children with Tourette Syndrome only, took longer to respond and made more errors and distracted eye movements compared to typically-developing children, displaying cognitive control deficits. However, increasing symptom severities of Tourette Syndrome, ADHD, and OCD correlated with one another. Thus, cognitive control deficits were not specific to Tourette Syndrome patients with comorbid conditions, but rather increase with increasing tic severity, suggesting that a majority of Tourette Syndrome patients, regardless of a clinical diagnosis of ADHD and/or OCD, have symptoms of cognitive control deficits at some level. Therefore, clinicians should evaluate and counsel all families of children with Tourette Syndrome, with or without currently diagnosed ADHD and/or OCD, about the functional ramifications of comorbid symptoms and that they may wax and wane with tic severity.

Sustained attention in children with two etiologies of early hydrocephalus.

Several studies have shown that children with spina bifida meningomyelocele (SBM) and hydrocephalus have attention problems on parent ratings and difficulties in stimulus orienting associated with a posterior brain attention system. Less is known about response control and inhibition associated with an anterior brain attention system. Using the Gordon Vigilance Task (Gordon, 1983), we studied error rate, reaction time, and performance over time for sustained attention, a key anterior attention function, in 101 children with SBM, 17 with aqueductal stenosis (AS; another condition involving congenital hydrocephalus), and 40 typically developing controls (NC). In SBM, we investigated the relation between cognitive attention and parent ratings of inattention and hyperactivity and explored the impact of medical variables. Children with SBM did not differ from AS or NC groups on measures of sustained attention, but they committed more errors and responded more slowly. Approximately one-third of the SBM group had attention symptoms, although parent attention ratings were not associated with task performance. Hydrocephalus does not account for the attention profile of children with SBM, which also reflects the distinctive brain dysmorphologies associated with this condition.

Comparison of medical care costs, utilization, and satisfaction of AIDS patients with and without home care

A sample of 157 AIDS patients 17 years of age or over were followed for six months from the date of hospital discharge to derive average total cost of medical care, utilization and satisfaction with care. Those referred for home care follow-up after discharge from the hospital were compared with those who did not receive home care.^ The average total cost of medical care for all patients was $34,984. Home care patient costs averaged \$29,614 while patients with no home care averaged $37,091. Private hospital patients had average costs of \$50,650 compared with $25,494 for public hospital patients. Hospital days for the six months period averaged 23.9 per patient for the no home care group and 18.5 days for home care group. Patient satisfaction with care was higher in the home care group than no home care group, with a mean score of 68.2 compared with 61.1.^ Other health services information indicated that 98% of the private hospital patients had insurance while only 2% of public hospital patients had coverage. The time between the initial date of diagnosis with AIDS and admission to the study was longer for private hospital patients, survival time over the study period was shorter, and the number of hospitalizations prior to entering the study was higher for private hospital patients. These results suggest that patients treated in the private hospital were sicker than public hospital patients, which may explain their higher average total cost. Statistical analyses showed that cost and utilization have no significant relationship with home care or no home care when controlling for indicators of the severity of illness and treatment in public or private hospital.^ In future studies, selecting a matched group of patients from the same hospital and following them for nine months to one year would be helpful in making a more realistic comparison of the cost effectiveness of home care. ^

The cost of insuring the uninsured in the U.S.

Objectives: This study included two overarching objectives. Through a systematic review of the literature published between 1990 and 2012, the first objective aimed to assess whether insuring the uninsured would result in higher costs compared to insuring the currently insured. Studies that quantified the actual costs associated with insuring the uninsured in the U.S. were included. Based upon 2009 data from the Medical Expenditure Panel Survey (MEPS), the second objective aimed to assess and compare the self-reported health of populations with four different insurance statuses. The second part of this study involved a secondary data analysis of both currently insured and currently uninsured individuals who participated in the MEPS in 2009. The null hypothesis was that there were no differences across the four categories of health insurance status for self-reported health status and healthcare service use. The alternative hypothesis was that were differences across the four categories of health insurance status for self-reported health status and healthcare service use. Methods: For the systematic review, three databases were searched using search terms to identify studies that actually quantified the cost of insuring the uninsured. Thirteen studies were selected, discussed, and summarized in tables. For the secondary data analysis of MEPS data, this study compared four categories of health insurance status: (1) currently uninsured persons who will become eligible for Medicaid under the Patient Protection and Affordable Care Act (PPACA) healthcare reforms in 2014; (2) currently uninsured persons who will be required to buy private insurance through the PPACA health insurance exchanges in 2014; (3) persons currently insured under Medicaid or SCHIP; and (4) persons currently insured with private insurance. The four categories were compared on the basis of demographic information, health status information, and health conditions with relatively high prevalence. Chi-square tests were run to determine if there were differences between the four groups in regard to health insurance status and health status. With some exceptions, the two currently insured groups had worse self-reported health status compared to the two currently uninsured groups. Results: The thirteen studies that met the inclusion criteria for the systematic review included: (1) three cost studies from 1993, 1995, and 1997; (2) four cost studies from 2001, 2003, and 2004; (3) one study of disabilities and one study of immigrants; (4) two state specific studies of uninsured status; and (5) two current studies of healthcare reform. Of the thirteen studies reviewed, four directly addressed the study question about whether insuring the uninsured was more or less expensive than insuring the currently insured. All four of the studies provided support for the study finding that the cost of insuring the uninsured would generally not be higher than insuring those already insured. One study indicated that the cost of insuring the uninsured would be less expensive than insuring the population currently covered by Medicaid, but more expensive to insure than the populations of those covered by employer-sponsored insurance and non-group private insurance. While the nine other studies included in the systematic review discussed the costs associated with insuring the uninsured population, they did not directly compare the costs of insuring the uninsured population with the costs associated with insuring the currently insured population. For the MEPS secondary data analysis, the results of the chi-square tests indicated that there were differences in the distribution of disease status by health insurance status. As anticipated, with some exceptions, the uninsured reported lower rates of disease and healthcare service use. However, for the variable attention deficit disorder, the uninsured reported higher disease rates than the two insured groups. Additionally, for the variables high blood pressure, high cholesterol, and joint pain, the currently insured under Medicaid or SCHIP group reported a lower rate of disease than the two currently insured groups. This result may be due to the lower mean age of the currently insured under Medicaid or SCHIP group. Conclusion: Based on this study, with some exceptions, the costs for insuring the uninsured should not exceed healthcare-related costs for insuring the currently uninsured. The results of the systematic review indicated that the U.S. is already paying some of the costs associated with insuring the uninsured. PPACA will expand health insurance coverage to millions of Americans who are currently uninsured, as the individual mandate and insurance market reforms will require. Because many of the currently uninsured are relatively healthy young persons, the costs associated with expanding insurance coverage to the uninsured are anticipated to be relatively modest. However, for the purposes of construing these results, it is important to note that once individuals obtain insurance, it is anticipated that they will use more healthcare services, which will increase costs. (Abstract shortened by UMI.)^

Mutation analysis of the PVRL1 gene in caucasians with nonsyndromic cleft lip/palate.

Nonsyndromic cleft lip with or without cleft palate (nsCL/P, MIM 119530) is perhaps the most common major birth defect. Homozygous PVRL1 loss-of-function mutations result in an autosomal recessive CL/P syndrome, CLPED1, and a PVRL1 nonsense mutation is associated with sporadic nsCL/P in Northern Venezuela. To address the more general role of PVRL1 variation in risk of nsCL/P, we carried out mutation analysis of PVRL1 in North American and Australian nsCL/P cases and population-matched controls. We identified a total of 15 variants, 5 of which were seen in both populations and 1 of which, an in-frame insertion at Glu442, was more frequent in patients than in controls in both populations, though the difference was not statistically significant. Another variant, which is specific to the PVRL1 beta (HIgR) isoform, S447L, was marginally associated with nsCL/P in North American Caucasian patients, but not in Australian patients, and overall variants that affect the beta-isoform were significantly more frequent among North American patients. One Australian patient had a splice junction mutation of PVRL1. Our results suggest that PVRL1 may play a minor role in susceptibility to the occurrence of nsCL/P in some Caucasian populations, and that variation involving the beta (HIgR) isoform might have particular importance for risk of orofacial clefts. Nevertheless, these results underscore the need for studies that involve very large numbers when assessing the possible role of rare variants in risk of complex traits such as nsCL/P.

Prognostic significance of xCT polymorphisms and expression in patients with advanced pancreatic cancer treated with chemotherapy

The plasma membrane xc- cystine/glutamate transporter mediates cellular uptake of cystine in exchange for intracellular glutamate and is highly expressed by pancreatic cancer cells. The xCT gene, encoding the cystine-specific xCT protein subunit of xc-, is important in regulating intracellular glutathione (GSH) levels, critical for cancer cell protection against oxidative stress, tumor growth and resistance to chemotherapeutic agents including platinum. We examined 4 single nucleotide polymorphisms (SNPs) of the xCT gene in 269 advanced pancreatic cancer patients who received first line gemcitabine with or without cisplatin or oxaliplatin. Genotyping was performed using Taqman real-time PCR assays. A statistically significant correlation was noted between the 3' untranslated region (UTR) xCT SNP rs7674870 and overall survival (OS): Median survival time (MST) was 10.9 and 13.6 months, respectively, for the TT and TC/CC genotypes (p = 0.027). Stratified analysis showed the genotype effect was significant in patients receiving gemcitabine in combination with platinum therapy (n = 145): MST was 10.5 versus 14.1 months for the TT and TC/CC genotypes, respectively (p = 0.013). The 3' UTR xCT SNP rs7674870 may correlate with OS in pancreatic cancer patients receiving gemcitabine and platinum combination therapy. Paraffin-embedded core and surgical biopsy tumor specimens from 98 patients with metastatic pancreatic adenocarcinoma were analyzed by immunohistochemistry using an xCT specific antibody. xCT protein IHC expression scores were analyzed in relation to overall survival in 86 patients and genotype in 12 patients and no statistically significant association was found between the level of xCT IHC expression score and overall survival (p = 0.514). When xCT expression was analyzed in terms of treatment response, no statistically significant associations could be determined (p = 0.908). These data suggest that polymorphic variants of xCT may have predictive value, and that the xc- transporter may represent an important target for therapy in pancreatic cancer.