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Due to the need to increase understanding of factors associated with medication usage for youth with ADHD, this study examined parental explanatory etiologies in relationship to psychotropic medication use in a sample of youth who met criteria for ADHD and utilized outpatient specialty mental health services in the previous year. When examined cross-sectionally, medication usage was positively associated with parental explanatory etiologies related to physical causes and negatively associated with those involving sociological causes. Longitudinal analyses did not show a significant effect of Time 1 parental explanatory etiologies on the slope of medication use, suggesting that the relationship between Time 1 parental explanatory etiologies and medication usage remains stable over time for those who have had past year involvement with outpatient specialty mental health services.

Gabapentin enacarbil, a transported acyloxyalkylcarbamate prodrug of gabapentin, provides predictable and dose-proportional gabapentin exposure (AUC). Gabapentin is cleared via renal excretion, and its elimination is proportional to creatinine clearance (CrCL); CrCL can, therefore, be used as a predictor of gabapentin renal clearance. Gabapentin produced from hydrolysis of gabapentin enacarbil is also eliminated via the renal clearance pathway. It was, therefore, anticipated that the pharmacokinetics of gabapentin derived from gabapentin enacarbil would also be affected by renal function.The objective of this study was to describe a population pharmacokinetic analysis of gabapentin enacarbil in patients with varying degrees of renal function, using data from an open-label study of gabapentin enacarbil in patients with renal impairment (XenoPort, Inc. protocol XP066), to determine whether dosage adjustments are necessary in patients with renal impairment.Men and women18 years of age with a body mass index ≤34 kg/m(2) and who were, in general, healthy with the exception of renal impairment were enrolled All patients received a single 600-mg gabapentin enacarbil extended-release tablet under fed conditions. After dosing, plasma, urine, and dialysate samples were analyzed. Safety profile evaluations included adverse events, vital signs, ECGs, and laboratory values. Pharmacokinetic data were compared with those from Phase I-III studies in subjects with normal renal function to evaluate the relationship between gabapentin oral clearance (CL/F) and CrCL.Fifteen patients (11 men and 4 women) were enrolled. One patient had moderate renal impairment (CrCL 30-59 mL/min), 7 patients had severe renal impairment (CrCL30 mL/min), and 7 patients had end-stage renal disease (CrCL15 mL/min). Ten patients were white, 4 were African American, and 1 was American Indian or Alaskan Native. Their mean (range) age was 55 (28-76) years, weight was 85.6 (62-134) kg, and body mass index was 28.3 (22-34) kg/m(2). Mean maximum plasma gabapentin concentration was 5.77 μg/mL in patients with moderate and severe renal impairment, and 5.59 μg/mL in patients with end-stage renal disease who were undergoing hemodialysis. Based on the population pharmacokinetic analysis, gabapentin CL/F after administration of gabapentin enacarbil was proportionally related to CrCL, with an approximately 1.6-fold decrease in CL/F for every 2-fold decrease in CrCL. The most frequent adverse event was dizziness (4 of 15 patients). Other adverse events that were assessed as possibly or probably related to treatment were defecation urgency, extremity pain, feeling of relaxation, and muscle weakness; each occurred in 1 patient only. All events were mild or moderate and resolved without sequelae.The data suggest that dosage adjustment for gabapentin enacarbil is necessary in patients with impaired renal function. Gabapentin enacarbil, 600 mg, seemed to be well tolerated in this small selected population.

The National Lung Screening Trial (NLST) is a randomized multicenter study comparing low-dose helical computed tomography (CT) with chest radiography in the screening of older current and former heavy smokers for early detection of lung cancer, which is the leading cause of cancer-related death in the United States. Five-year survival rates approach 70% with surgical resection of stage IA disease; however, more than 75% of individuals have incurable locally advanced or metastatic disease, the latter having a 5-year survival of less than 5%. It is plausible that treatment should be more effective and the likelihood of death decreased if asymptomatic lung cancer is detected through screening early enough in its preclinical phase. For these reasons, there is intense interest and intuitive appeal in lung cancer screening with low-dose CT. The use of survival as the determinant of screening effectiveness is, however, confounded by the well-described biases of lead time, length, and overdiagnosis. Despite previous attempts, no test has been shown to reduce lung cancer mortality, an endpoint that circumvents screening biases and provides a definitive measure of benefit when assessed in a randomized controlled trial that enables comparison of mortality rates between screened individuals and a control group that does not undergo the screening intervention of interest. The NLST is such a trial. The rationale for and design of the NLST are presented.

AIM Gabapentin enacarbil, a transported prodrug of gabapentin, provides sustained, dose-proportional exposure to gabapentin. Unlike gabapentin, the prodrug is absorbed throughout the intestinal tract by high-capacity nutrient transporters, including mono-carboxylate transporter-1 (MCT-1). Once absorbed, gabapentin enacarbil is rapidly hydrolyzed to gabapentin, which is subsequently excreted by renal elimination via organic cation transporters (OCT2). To examine the potential for drug–drug interactions at these two transporters, the pharmacokinetics of gabapentin enacarbil were evaluated in healthy adults after administration alone or in combination with either naproxen (an MCT-1 substrate) or cimetidine (an OCT2 substrate).

The presence of inflammatory cells on bronchoalveolar lavage is often used to predict disease activity and the need for therapy in systemic sclerosis-associated interstitial lung disease.To evaluate whether lavage cellularity identifies distinct subsets of disease and/or predicts cyclophosphamide responsiveness.Patients underwent baseline lavage and/or high-resolution computed tomography as part of a randomized placebo-controlled trial of cyclophosphamide versus placebo (Scleroderma Lung Study) to determine the effect of therapy on forced vital capacity. Patients with 3% or greater polymorphonuclear and/or 2% or greater eosinophilic leukocytes on lavage and/or ground-glass opacification on computed tomography were eligible for enrollment.Lavage was performed in 201 individuals, including 141 of the 158 randomized patients. Abnormal cellularity was present in 101 of these cases (71.6%) and defined a population with a higher percentage of men (P = 0.04), more severe lung function, including a worse forced vital capacity (P = 0.003), worse total lung capacity (P = 0.005) and diffusing capacity of the lung for carbon monoxide (P = 0.004), more extensive ground-glass opacity (P = 0.005), and more extensive fibrosis in the right middle lobe (P = 0.005). Despite these relationships, the presence or absence of an abnormal cell differential was not an independent predictor of disease progression or response to cyclophosphamide at 1 year (P = not significant).The presence of an abnormal lavage in the Scleroderma Lung Study defined patients with more advanced interstitial lung disease but added no additional value to physiologic and computed tomography findings as a predictor of progression or treatment response. Clinical trial registered with www.clinicaltrials.gov (NCT 000004563).

Studies indicate that African American, Asian/Pacific Islander, and Latino youth have higher rates of unmet mental health needs and lower rates of mental health service utilization compared to non-Hispanic White youth, suggesting that obstacles may exist in the help-seeking and service utilization pathway for minority youth. Parental cultural factors may significantly impact youth service use, and acculturation is one way to measure adherence to culture specific values, beliefs, attitudes, and behaviors. In this study, parental acculturation level, conceptualized as cultural affinity to 1) mainstream American culture and 2) an alternative culture, were examined as potential mediators of the relationship between race/ethnicity and youth service use. The current subsample (n=1364) was drawn from the Patterns of Care study, a larger study of at-risk youth who were active to at least one of five public sectors of care. Our subsample included all youth aged 6–17 who were African American, Asian/Pacific Islander, Latino, or Non-Hispanic Whites (66.6% male). The results indicate that parental acculturation level as measured by affinity to an Alternative Culture was a partial mediator in the relationship between race/ethnicity and mental health service use for Asian/Pacific Islander and Latino youth.

Although there has long been concern about underidentification or misidentification of children with emotional or behavioral disorders in special education, recent attention has also been focused on disproportionate racial and ethnic representation of children in the school category of emotional disturbance (ED). There is evidence that African American children may be overidentified in the ED category while Asian and Hispanic children may be underidentified, although these findings are not consistent from sample to sample. In this study the authors examined parental beliefs about the causes of their child's problems as a potential partial mediator between race or ethnicity and special education identification for emotional disturbance. The sample of 1,019 children was drawn from a larger study of at-risk youths who were active in at least one of five public sectors of care. In this sample, parental explanatory etiologies relating to personality and relational issues were found to account for part of the racial or ethnic differences in ED service use for Latino and Asian American/Pacific Islander children.

The Asian-American population in the USA is one of the fastest growing ethnic minority groups in the USA yet relatively little is known about the mental health status and needs of Asian-American youth. Existing research suggests that there are higher rates of depression, anxiety, and suicide among this group. This chapter discusses considerations for addressing the emotional/behavioral needs of this population, to provide a more accurate appraisal of their mental health status and effective treatment plans. Additionally recommendations for the assessment of psychopathology in Asian-American youth are also discussed.

This chapter seeks to provide an overview of some common assessment measures for emotional/behavioral problems in Asian-American youth. Measures for which psychometric data are available only for Asian populations are also noted. Rating scales in the current youth behavioral assessment literature discussed include: (1) Global impairment scales, (2) Domain-specific scales, and (3) Symptom-specific scales. We conclude the chapter with recommendations of how to utilize these measures and provide suggestions for future research to improve the utility of behavioral assessments for Asian-American youth.

BACKGROUND Primary CD56 positive lymphoma of the gastrointestinal (GI) tract is rare. Genotypically, these tumors can be classified into natural killer (NK)-like T-cell lymphoma or NK cell lymphoma by the presence or absence of T-cell receptor (TCR) gene rearrangement. However, they have a considerable degree of morphologic and immunophenotypic overlap, making a definitive diagnosis difficult. METHODS The clinicopathologic features of three patients with primary CD56 positive lymphoma of the small and large bowel are presented. This is followed by a review of the English literature from 1966 to the present. RESULTS All patients had CD56 posistive/CD3ϵ positive disease on paraffin section. Two patients were positive for Epstein–Barr virus-encoded early nuclear RNAs (EBER) according to in situ histochemistry results and were negative for TCR gene rearrangement, consistent with primary NK lymphoma of the GI tract. The other patient was EBER negative with rearranged TCR, consistent with NK-like T-cell lymphoma. There was no clinical or histologic evidence of enteropathy in any of the patients. The major presenting symptoms included fever, weight loss, and intestinal perforation. All patients died between 1 week and 6 months after diagnosis despite undergoing surgery and intensive chemotherapy. CONCLUSIONS These results, together with a literature review, suggest that primary NK cell lymphoma of the GI tract may be considered a distinct clinicopathologic entity. Both primary NK and NK-like T-cell lymphoma pursue an aggressive clinical course. EBER and TCR gene rearrangement are useful in distinguishing NK cell lymphoma from NK-like T-cell lymphoma, particularly when frozen tissue is not available for immunophenotyping. Cancer 2001;91:525–33. © 2001 American Cancer Society.

Basic thinking regarding certain aspects of learner autonomy is presented as well as certain cultural traits (such as the Chinese concern with face) which may be an obstacle to the promotion of autonomy, especially in the more traditional organization of some classrooms. The use of large-scale simulation can, however, transform the ordinary classroom into a learning environment that powerfully promotes learner autonomy. A concrete example of how this actually happened is discussed in detail, as are the cultural traits that both hinder and encourage autonomy in such a setting. The conclusion is that it is through concrete actions of taking responsibility that autonomy is learned.

The development and evaluation of a computer-aided bone scan analysis technique to quantify changes in tumor burden and assess treatment effects in prostate cancer clinical trials.We have developed and report on a commercial fully automated computer-aided detection (CAD) system. Using this system, scan images were intensity normalized, and then lesions were identified and segmented by anatomic region-specific intensity thresholding. Detected lesions were compared against expert markings to assess the accuracy of the CAD system. The metrics Bone Scan Lesion Area, Bone Scan Lesion Intensity, and Bone Scan Lesion Count were calculated from identified lesions, and their utility in assessing treatment effects was evaluated by analyzing before and after scans from metastatic castration-resistant prostate cancer patients: 10 treated and 10 untreated. In this study, patients were treated with cabozantinib, a MET/vascular endothelial growth factor inhibitor resulting in high rates of resolution of bone scan abnormalities.Our automated CAD system identified bone lesion pixels with 94% sensitivity, 89% specificity, and 89% accuracy. Significant differences in changes from baseline were found between treated and untreated groups in all assessed measurements derived by our system. The most significant measure, Bone Scan Lesion Area, showed a median (interquartile range) change from baseline at week 6 of 7.13% (27.61) in the untreated group compared with -73.76% (45.38) in the cabozantinib-treated group (P=0.0003).Our system accurately and objectively identified and quantified metastases in bone scans, allowing for interpatient and intrapatient comparison. It demonstrates potential as an objective measurement of treatment effects, laying the foundation for validation against other clinically relevant outcome measures.

Parent training (PT) is well established for reducing child externalizing problems; however, lower rates of engagement in PT among ethnic minority/immigrant families have been found. We assessed PT acceptability among Chinese immigrant parents and explored clinical and cultural factors that may be associated with acceptability. Participants were a community sample of 145 Chinese immigrant parents (84% mothers) between the ages of 32 and 65 years ( M = 43.3 years, SD = 6.2) who had children (84 boys, 59 girls) between the ages of 4 and 17 years ( M = 10.7 years, SD = 3.6). Results suggest that parents found positive reinforcement techniques significantly more acceptable, less problematic, and more likely to be supported by others than punishment-based techniques. Parents who endorsed the Chinese child-rearing value of shaming were less likely to find PT acceptable. Parents who reported greater dysfunction in parent–child interactions rated PT as more acceptable, and families with prior Child Protective Services (CPS) involvement rated PT as less acceptable. However, previous mental health treatment appears to bolster acceptability among parents with prior CPS involvement. Clinical implications for addressing barriers to PT engagement and future research directions are discussed.

Effective treatment of conduct problems for ethnic minority youth is an urgent public health priority (Loeber, Burke, Lahey, Winters, & Zera, 2000). Ethnic minority populations are rapidly increasing, with current estimates indicating that 48% of US children are from ethnic minority backgrounds. This figure is projected to increase to 62% by 2050 (U.S. Department of Commerce, 2008). Disruptive behavior is the most common reason for referral for youth mental health treatment in the USA (Lavigne et al., 1998), and oppositional defiant disorder (ODD) and conduct disorder (CD) are the predominant youth disorders seen in community mental health clinics (Frick, 1998; Kazdin, 1995). Without adequate treatment, disruptive behavior in early childhood is associated with a high degree of impairment and poor long-term prognosis (Lahey, Loeber, Quay, Frick, & Grimm, 1997).

Introduction: Variation of the D835 residue of FLT3 occurs in ~5% of de novo AML cases and is a prominent feature of drug resistance in the setting of FLT3-ITD. Crenolanib treatment of AML patients exhibiting FLT3 D835 and/or FLT3-ITD positive tumors has yielded significant clinical responses. However, these clinical responses to single-agent crenolanib were transient, so we performed whole exome sequencing to determine the mechanisms of crenolanib resistance. Mutation of the FLT3 F691 "gatekeeper" residue is a known resistance mechanism to crenolanib and other FLT3 inhibitors in vitro. Hence, secondary mutation of FLT3 at the gatekeeper or other sites was hypothesized to be a predominant mechanism of resistance. We report that a minority of patients acquired FLT3 gatekeeper or other secondary FLT3 mutations, however, the majority of cases relapsed in the absence of additional FLT3 mutations indicating alternative mechanisms of drug resistance. Methods: Genomic DNA was isolated from bone marrow aspirates from 44 AML patients treated with crenolanib. We performed whole exome sequencing using Illumina Nextera exome capture and paired end sequencing on an Illumina 2500 HiSeq. Paired specimens (pre/post-treatment) were available for 24 of these patients, allowing for analysis of acquired mutations in the context of crenolanib therapy. Results: Although secondary mutation of FLT3 at the gatekeeper residue, FLT3 F691, was predicted to be a prominent mechanism of resistance, we did not observe FLT3 gatekeeper mutations in most patients. In total, only 3/44 (7%) of cases exhibited a FLT3 gatekeeper mutation despite good coverage of the FLT3 locus (average of 134 fold read depth; range of 77-177 fold average read depth across all 44 cases). In addition, we observed secondary FLT3 mutations at alternative residues, D200N, K429E, and L601F, in 3 other patients. Hence, only 6/44 (14%) of patients exhibited evidence of relapse due to secondary mutation of FLT3, and the majority of patients (38/44; 86%) presented with crenolanib resistance in the absence of secondary FLT3 mutations. Exome analysis revealed that many of these cases acquired mutations involving transcriptional regulators, suggesting alternate pathways of escape as the predominant mechanism to crenolanib therapy. Conclusions: Crenolanib is broadly effective against FLT3-ITD and FLT3-D835 mutant AML. Despite predictions of FLT3 gatekeeper mutations (or other secondary FLT3 mutations) as a primary mechanism of resistance, we only observe these events in a minority of patients. Instead, we observe a prominent signal of acquired mutations in transcriptional regulators, suggesting a more elaborate genetic/epi-genetic mechanism of resistance to crenolanib. Disclosures Ho: AROG Pharmaceuticals: Employment. Davis:AROG Pharmaceuticals: Employment. Ramachandran:AROG Pharmaceuticals: Employment. Cortes:ARIAD Pharmaceuticals Inc.: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Tyner:Aptose Biosciences: Research Funding; Constellation Pharmaceuticals: Research Funding; Array Biopharma: Research Funding; Janssen Pharmaceuticals: Research Funding; Incyte: Research Funding.

Background Gabapentin enacarbil, a transported prodrug of gabapentin, was recently approved by the US Food and Drug Administration for the treatment of moderate to severe restless legs syndrome. Objective As part of the overall safety evaluation of gabapentin enacarbil, the present definitive QT/QTc study was conducted to assess the effects of gabapentin enacarbil on cardiac repolarization in accordance with the International Conference on Harmonization E14 guidance. Methods This randomized, double-blind, placebo- and active-controlled, crossover study enrolled 54 healthy adults. Subjects were randomly assigned to receive a single oral dose of gabapentin enacarbil 1200, 6000 mg, moxifloxacin 400 mg (active control), and placebo in a randomized sequence, with treatment periods separated by a 7-day washout. Blood samples were collected for pharmacokinetic analysis, and continuous ECG measurements were recorded using a Holter monitor. The primary end point was the time-matched difference in individualized baseline-adjusted QTc (ddQTcIb) between gabapentin enacarbil and placebo. General tolerability was also monitored. Results Of the 54 subjects enrolled in the study (mean [SD] age, 29.2 [10.1]; 42.6% female; mean body mass index, 25.8 [3.0]), 48 (88.9%) completed the study, and 6 were discontinued prematurely after having received ≥1 dose of study medication. Thus, the numbers of patients in the safety population were: gabapentin enacarbil 1200 mg, 50; gabapentin enacarbil 6000 mg, 50; moxifloxacin, 50; and placebo, 51. The maximum ddQTcIb values were 0.7 msec (upper 95% confidence limit [CL], 3.0) with gabapentin enacarbil 1200 mg; 1.3 msec (upper CL, 3.6) with gabapentin enacarbil 6000 mg; and 7.4 msec (lower CL, 5.1) with moxifloxacin. A QT–concentration relationship was reported with moxifloxacin. Gabapentin exposures were dose-proportional with gabapentin enacarbil doses of 1200 and 6000 mg. The most commonly reported adverse events with gabapentin enacarbil 6000 mg were dizziness and somnolence (60.0% and 54.0%, respectively). Conclusion In this population of healthy adults, gabapentin enacarbil at doses of 1200 and 6000 mg was not associated with QT prolongation and was generally well-tolerated.

The paper reports the results of a larger research project on collective urban spaces as harmonization drivers for intercultural dialogue. The assumption behind the proposal is that, in the third millennium, the construction, rehabilitation or recovery of outdoor urban spaces should take into account the promotion of a new sense of identity among individuals and groups (Gifford R.,1987). Deep changes in urban frameworks, challenge contemporary cities, where often, common spaces formerly central, risk an indissoluble physical degradation, due to processes of social marginalization. Architectural and urban design, through the promotion of beauty, can convey new messages of dialogue and coexistence between communities (Butina G., Bentley I., 2007). The paper, focusing on small leftover urban outdoor spaces in Italian cities, introduces a critical thinking about the links between their performances, in terms of image, practicability, accessibility, security and attitudes towards inclusivity. Urban and architectural solutions are privileged means in order to reaffirm the concept of common space as dwelling, residence of the community, with the creation of new social ties and the growth of local shared identities. There was a time in which intellectuals, architects and philosophers foreshadowed a city model where people were the centre of the building and living. Technologies supported the sizing of urban spaces on a human scale, with areas devoted to socializing, with walkable sites and reasonable distances, privileged places for exchanges and meetings. In a world that slowly loses the original connotations, the city is asked once again, today, to reaffirm the reasons of a forgotten identity, putting man at the centre of the polis, supporting the diversity of civil society with dialogue and coexistence. The essay concentrates on the processes of acculturation occurred in Italian cities: in urban contexts these were always accompanied by an increase in the potential for beauty. A choral sedimentation marked the acculturation of architecture, where beauty becomes externalization of shared values: its definition is the result of physical, material elements, and intangible factors, evocative and suggestive, like the ability to put in place mechanisms of identity, respect and consideration. Claiming the cities‟ right to beauty, through the commitment in planning for the recovery of ancient sites, implies a shift of attention from the design theme of safeguarding the physical system, the contrast of material degradation, to the centrality of users' in redesigning places, recognizing a priority to shared values archetype for development. According to urban planners, the city today has to be connected (rather than being a juxtaposition of segregated spaces) and transitive, viable and accessible in all its directions (and not just, for example, from the periphery to the center). The intercultural city should encourage the sharing of its sedimented beauty, to help preventing from danger and setting all inhabitants free. Beauty is the only way to rediscover the value of urban hospitality: to live does not mean either reside or stay, not occupy or preside, but to trace people' biography into the landscape (Illich I.). Affirming the right to beauty for intercultural urban spaces means marking the characteristic feature of living in having care, and saving sedimented identities.