Understanding definitions of minimally verbal across instruments: evidence for subgroups within minimally verbal children and adolescents with autism spectrum disorder.

BACKGROUND: Minimally verbal (MV) children with autism spectrum disorder (ASD) are often assumed to be profoundly cognitively impaired and excluded from analyses due to challenges completing standardized testing protocols. A literature aimed at increasing understanding of this subgroup is emerging; however, the many methods used to define MV status make it difficult to compare studies. Understanding how different instruments and definitions used to identify MV children affect sample composition is critical to advance research on this understudied clinical population. METHOD: The MV status of 1,470 school-aged children was defined using five instruments commonly used in ASD research. MV sample composition was compared across instruments. Analyses examined the proportion of overlap across MV subgroups and the extent to which child characteristics varied across MV subgroups defined using different definitions or combinations of measures. RESULTS: A total of 257 children were classified as MV on at least one instrument. Proportion of overlap between definitions ranged from 3% to 100%. The stringency of definition (i.e. few-to-no vs. some words) was associated with differences in cognitive and adaptive functioning; more stringent definitions yielded greater consistency of MV status across instruments. Cognitive abilities ranged from profoundly impaired to average intelligence; 16% had NVIQ ≥ 70. Approximately half exhibited verbal skills commensurate with nonverbal cognitive ability, whereas half had verbal abilities significantly lower than their estimated NVIQ. CONCLUSIONS: Future studies of MV children must carefully consider the methods used to identify their sample, acknowledging that definitions including children with 'some words' may yield larger samples with a wider range of language and cognitive abilities. Broadly defined MV samples may be particularly important to delineate factors interfering with language development in the subgroup of children whose expressive impairments are considerably below their estimated nonverbal cognitive abilities.

Sleep in Children With Autism Spectrum Disorders: How Are Measures of Parent Report and Actigraphy Related and Affected by Sleep Education?

Sleep disturbance is common in children with autism, resulting in a great need for effective treatments. To evaluate treatments for sleep disturbance in this population, it is critical to understand the relationship between measures of sleep captured by parent report and objective measures. The Children's Sleep Habits Questionnaire (CSHQ) and actigraphy-measured data from 80 children with autism and sleep-onset delay were evaluated. Reported problems with sleep-onset delay were concurrent with sleep duration problems in 66% of children, night wakings in 72% of children, and bedtime resistance in 66% of children; 38% of children were reported to have problems with all CSHQ insomnia domains. Actigraphy-measured sleep duration was correlated with estimates using CSHQ-reported bed and wake times.

Docetaxel or pemetrexed with or without cetuximab in recurrent or progressive non-small-cell lung cancer after platinum-based therapy: a phase 3, open-label, randomised trial.

BACKGROUND: Available preclinical and phase 2 clinical data suggest that the addition of cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor (EGFR), to chemotherapy might improve outcome in patients with advanced non-small-cell lung cancer (NSCLC). We aimed to assess whether the addition of cetuximab to chemotherapy improved progression-free survival in patients with recurrent or progressive NSCLC after platinum-based therapy. METHODS: In this unmasked, open-label randomised phase 3 trial we enrolled patients with metastatic, unresectable, or locally advanced NSCLC from 121 sites in Canada and the USA. Eligible patients were those aged 18 years or older who had experienced progressive disease during or after one previous platinum-based regimen. Initially, patients were randomly assigned to receive either pemetrexed (500 mg/m(2)) or docetaxel (75 mg/m(2)) and then randomly assigned within each group to receive their chemotherapy with or without cetuximab (400 mg/m(2) at first dose and 250 mg/m(2) weekly thereafter) until disease progression or unacceptable toxicity. However, after a change in the standard of care, investigators chose whether to treat with pemetrexed or docetaxel on a patient-by-patient basis. The primary analysis was changed to compare progression-free survival with cetuximab plus pemetrexed versus pemetrexed, on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT00095199. FINDINGS: Between Jan 10, 2005, and Feb 10, 2010, we enrolled 939 patients; data for one patient was accidentally discarded. Of the remaining 938 patients, 605 received pemetrexed (301 patients with cetuximab and 304 alone) and 333 received docetaxel (167 in combination with cetuximab and 166 alone). Median progression-free survival with cetuximab plus pemetrexed was 2·9 months (95% CI 2·7-3·2) versus 2·8 months (2·5-3·3) with pemetrexed (HR 1·03, 95% CI 0·87-1·21; p=0·76). The most common grade 3-4 adverse events with cetuximab plus pemetrexed were fatigue (33 [11%] of 292 patients), acneiform rash (31 [11%]), dyspnoea (29 [10%]), and decreased neutrophil count (28 [10%]), and with pemetrexed alone were dyspnoea (35 [12%] of 289 patients), decreased neutrophil count (26 [9%]), and fatigue (23 [8%]). A significantly higher proportion of patients in the cetuximab plus pemetrexed group (119 [41%] of 292 patients) experienced at least one serious adverse event than those patients in the pemetrexed group (85 [29%] of 289 patients; p=0·0054). Nine (3%) of 292 treated patients in the cetuximab and pemetrexed group died of adverse events compared with five (2%) of 289 treated patients in the pemetrexed alone group. INTERPRETATION: The use of cetuximab is not recommended in combination with chemotherapy in patients previously treated with platinum-based therapy. FUNDING: Eli Lilly and Company and ImClone Systems LLC, a wholly owned subsidiary of Eli Lilly and Company.

Predicting future sleep problems in young autistic children.

LAY ABSTRACT: Sleep problems are common in autistic children and negatively impact daytime functioning. A method for predicting sleep problems could help with treatment and prevention of such problems. This study aimed to determine predictors of sleep problems among young autistic children. Study participants consisted of autistic children aged 2-5 years who did not have sleep problems at a first visit (Autism Treatment Network Registry) and had sleep data available at a subsequent visit (Registry Call-Back Assessment study). Sleep problems for five study cohorts of children were defined by different methods, including parent questionnaires and parent- or clinician-report of sleep problems. We found that self-injurious behavior, sensory issues, dental problems, and lower primary caregiver education level were significant risk factors of future sleep problems. These predictors may help clinicians provide prevention or earlier treatment for children who are at risk of developing sleep problems.

A phase II randomized study of cetuximab and bevacizumab alone or in combination with gemcitabine as first-line therapy for metastatic pancreatic adenocarcinoma.

The purpose of this study was to assess the efficacy and safety of bevacizumab plus cetuximab with or without gemcitabine in patients with advanced pancreatic adenocarcinoma. Patients with locally advanced or metastatic pancreatic adenocarcinoma, previously untreated, were randomized to bevacizumab (10 mg/kg q2w) plus cetuximab (400/250 mg/m(2) initial/weekly), either with (Arm A) or without (Arm B) gemcitabine (1000 mg/m(2) weekly × 3 of 4 weeks). Tumor assessments were performed q8w. Primary study endpoint was progression-free survival (PFS). Sixty-one patients were randomized to Arm A (n = 30) or Arm B (n = 31). Median treatment duration was 9 weeks in Arm A and 8 weeks in Arm B (range, 2.0-40.4). Patients in Arm A had median PFS and overall survival values of 3.55 months and 5.41 months, respectively, compared to 1.91 months and 4.17 months in Arm B. The study closed early due to lack of sufficient efficacy in both treatment arms. Although both regimens were well tolerated, patients treated with gemcitabine experienced more grade 3-4 toxicities, including proteinuria and thromboembolic events. The combination of cetuximab and bevacizumab did not result in promising activity with or without gemcitabine, suggesting that a strategy of dual EGFR/VEGF inhibition in pancreatic cancer does not warrant further development. To our knowledge, this is one of the first trials to evaluate a completely noncytotoxic regimen in the first-line treatment of advanced pancreatic cancer. (ClinicalTrials.gov number, NCT00326911).

Toilet Training in Children and Adolescents with Down Syndrome.

OBJECTIVES: Although the challenges of toilet training for children and adolescents with Down syndrome (DS) are well-known, details such as specific associations with comorbidities and related exacerbating factors are lacking. This study aims to characterize the nature of toilet training in a cohort of children and adolescents with DS and evaluate characteristics and comorbid conditions that may contribute to or prolong toilet training success in those with DS. METHOD: This was a retrospective, cross-sectional study investigating toilet training in children and adolescents with DS. A survey was completed by 137 patients' parents or guardians as part of their care experience in the clinic. RESULTS: Although toilet training on average began at age 3.40 years (SD = 1.47), children and adolescents with DS typically began telling caregivers they needed to use the toilet at 4.80 years (SD = 2.11), no longer used diapers during the day at 5.03 years (SD = 1.98) and night at 5.88 years (SD = 2.48), and were described by their caregivers as being fully toilet trained at 6.60 years (n = 28; SD = 2.43; range = 3.00-14.00 years). There was a linear trend in the age groups between 2 to 4 years (n = 37), 5 to 7 years (n = 42), 8 to 12 years (n = 39), and 13 to 17 years (n = 19) and the proportion of children and adolescents fully toilet trained (2 to 4 years = 0.040, 5 to 7 years = 0.211, 8 to 12 years = 0.278, and 13 to 17 years = 0.529). Typical readiness signs that children and adolescents with DS display and those most predictive of toileting success are reported. Placing the child on a schedule was the most successful (45.2%) training method identified by parents, with 55.8% of the families trying this approach. Children and adolescents aged 8 to 12 years with behavioral challenges were more likely (75.0%) to have daytime accidents compared with those without (25.9%), p = 0.006. CONCLUSION: Children and adolescents with DS in this sample started toilet training at 3.4 years and completed toilet training at 6.6 years. Even after completing toilet training, many children and adolescents continue to require support from their caregivers with some aspects of toilet training. Skill loss associated with various life events, behavioral challenges, medical diagnoses, and inconsistencies in toileting expectations across settings are factors caregivers believe contribute to delayed toilet training. Caregivers found that a consistent toileting schedule, using reinforcers, and providing prompting to use the toilet were the most successful methods.

A multidisciplinary approach and consensus statement to establish standards of care for Angelman syndrome.

BACKGROUND: Angelman syndrome (AS) is a rare neurogenetic disorder present in approximately 1/12,000 individuals and characterized by developmental delay, cognitive impairment, motor dysfunction, seizures, gastrointestinal concerns, and abnormal electroencephalographic background. AS is caused by absent expression of the paternally imprinted gene UBE3A in the central nervous system. Disparities in the management of AS are a major problem in preparing for precision therapies and occur even in patients with access to experts and recognized clinics. AS patients receive care based on collective provider experience due to limited evidence-based literature. We present a consensus statement and comprehensive literature review that proposes a standard of care practices for the management of AS at a critical time when therapeutics to alter the natural history of the disease are on the horizon. METHODS: We compiled the key recognized clinical features of AS based on consensus from a team of specialists managing patients with AS. Working groups were established to address each focus area with committees comprised of providers who manage >5 individuals. Committees developed management guidelines for their area of expertise. These were compiled into a final document to provide a framework for standardizing management. Evidence from the medical literature was also comprehensively reviewed. RESULTS: Areas covered by working groups in the consensus document include genetics, developmental medicine, psychology, general health concerns, neurology (including movement disorders), sleep, psychiatry, orthopedics, ophthalmology, communication, early intervention and therapies, and caregiver health. Working groups created frameworks, including flowcharts and tables, to help with quick access for providers. Data from the literature were incorporated to ensure providers had review of experiential versus evidence-based care guidelines. CONCLUSION: Standards of care in the management of AS are keys to ensure optimal care at a critical time when new disease-modifying therapies are emerging. This document is a framework for providers of all familiarity levels.

Evaluating sleep quality using the CSHQ-Autism.

BACKGROUND: Sleep problems are common in autistic children and adversely impact daytime functioning. The Children's Sleep Habits Questionnaire (CSHQ) [39] was developed from a community-based sample of children and has validated a cut-off score of 41. Katz et al. [50] developed an abbreviated 23-item four-factor version of the CSHQ, which may be useful when assessing sleep in autistic children. However, a cut-off value has not yet been developed. OBJECTIVE: Our objective was to develop and validate a cut-off for the CSHQ-autism total score in order to identify sleep problems among autistic children. We hypothesized that the derived cut-off value for the CSHQ-autism would perform better than the original CSHQ cut at 41 on validation in a sample of autistic children. METHODS: Age-specific cut-off values were developed and validated using receiver operating characteristic analysis. RESULTS: The derived cut-off values for the CSHQ-autism total score were 34, 35, 33, and 35 for the 2-3, 4-10, 11-17, and 2-17 years age groups, respectively. On validation, all cut-off values performed with moderate to high sensitivity (76.6-82.4%) and moderate specificity (69.1-75.5%), while the original CSHQ cut at 41 had high sensitivity (89.9-93.0%) but low specificity (42.6-57.7%). Using McNemar's tests, the CSHQ-autism had significantly higher specificity but lower sensitivity than the original CSHQ cut at 41 in all age groups. CONCLUSIONS: The CSHQ-autism cut-off values performed better overall than the original CSHQ cut at 41 in a sample of autistic children. The CSHQ-autism cut-off can help identify sleep problems among autistic children.

Toolkit for ICH E6 (R2) Quality Risk Management for Small to Medium Size Companies.

One of the most significant revisions to the ICH E6 GCP Guideline in the last 20 years was issued in November 2016, adopted by the EMA in December 2016 and by the FDA as a Guidance Document in March 2018. The new section on Quality Management requires the implementation of a systematic approach for managing risks throughout the course of a clinical study. The addendum also emphasizes appropriate sponsor oversight. Currently available risk management solutions are fairly elaborate, having been developed for and adopted mainly by larger companies. Small to medium size companies find these solutions too complex and not easily adaptable. In this paper, we present a simple but robust toolkit for clinical study risk management for small to medium sized organizations in order to facilitate compliance. The toolkit consists of customizable templates for the following: Clinical Risk Management SOP; Clinical Risk Management Plan; Vendor Oversight SOP; Vendor Oversight Plan; and Clinical Risk Log. The tools were prepared by the DIA GCP-QA Community members and presented at the 2018 DIA Annual Meeting in Boston.

Randomized, Placebo-Controlled Trial of Ferrous Sulfate to Treat Insomnia in Children With Autism Spectrum Disorders.

BACKGROUND: Insomnia and low iron stores are common in children with autism spectrum disorders, and low iron stores have been associated with sleep disturbance. METHODS: We performed a randomized placebo-controlled trial of oral ferrous sulfate to treat insomnia in children with autism spectrum disorders and low normal ferritin levels. Twenty participants who met inclusion criteria and whose insomnia did not respond to sleep education were randomized to 3 mg/kg/day of ferrous sulfate (n = 9) or placebo (n = 11) for three months. RESULTS: Iron supplementation was well tolerated, and no serious adverse events were reported. Iron supplementation improved iron status (+18.4 ng/mL active versus -1.6 ng/mL placebo, P = 0.044) but did not significantly improve the primary outcome measures of sleep onset latency (-11.0 minutes versus placebo, 95% confidence interval -28.4 to 6.4 minutes, P = 0.22) and wake time after sleep onset (-7.7 minutes versus placebo, 95% confidence interval -22.1 to 6.6 min, P = 0.29) as measured by actigraphy. Iron supplementation was associated with improvement in the overall severity score from the Sleep Clinical Global Impression Scale (-1.5 points versus placebo, P = 0.047). Changes in measures of daytime behavior did not differ between groups. CONCLUSION: This trial demonstrated no improvement in primary outcome measures of insomnia in subjects treated with ferrous sulfate compared with placebo. Interpretation was limited by low enrollment.

Sleep Problems in 2- to 5-Year-Olds With Autism Spectrum Disorder and Other Developmental Delays.

: media-1vid110.1542/5984243260001PEDS-VA_2018-0492Video Abstract BACKGROUND: Sleep problems can impact daytime behavior, quality of life, and overall health. We compared sleep habits in young children with autism spectrum disorder (ASD) and other developmental delays and disorders and in children from the general population (POP). METHODS: We included 2- to 5-year-old children whose parent completed all items on the Children's Sleep Habits Questionnaire (CSHQ) in a multisite case-control study: 522 children with ASD; 228 children with other developmental delays and disorders with autism spectrum disorder characteristics (DD w/ASD); 534 children with other developmental delays and disorders without autism spectrum disorder characteristics (DD w/o ASD); and 703 POP. Multivariable analysis of variance compared CSHQ mean total score (TS) and subscale scores between groups. Logistic regression analysis examined group differences by using TS cutoffs of 41 and 48. Analyses were adjusted for covariates. RESULTS: Mean CSHQ TS for children in each group: ASD (48.5); DD w/ASD (50.4); DD w/o ASD (44.4); and POP (43.3). Differences between children with ASD and both children with DD w/o ASD and POP were statistically significant. Using a TS cutoff of 48, the proportion of children with sleep problems was significantly higher in children in the ASD group versus DD w/o ASD and POP groups (adjusted odds ratios [95% confidence intervals]: 2.12 [1.57 to 2.87] and 2.37 [1.75 to 3.22], respectively). CONCLUSIONS: Sleep problems are more than twice as common in young children with ASD and DD w/ASD. Screening for sleep problems is important in young children to facilitate provision of appropriate interventions.

Predicting sleep problems in children with autism spectrum disorders.

BACKGROUND: Sleep difficulties in children with autism spectrum disorders (ASD) have been well-established. AIMS: To develop a model to predict sleep problems in children with ASD. METHODS AND PROCEDURES: A sample of children in the Autism Speaks-Autism Treatment Network (ATN) registry without parent-reported sleep problems at baseline and with sleep problem (yes/no) data at first annual followup was randomly split into training (n = 527) and test (n = 518) samples. Model predictors were selected using the training sample, and a threshold for classifying children at risk was determined. Comparison of the predicted and true sleep problem status of the test sample yielded model performance measures. OUTCOMES AND RESULTS: In a multivariable model aggressive behavior among children with no sleep problems reported at baseline was associated with having more sleep problems at the first annual follow-up visit. This model performed in the test sample with high sensitivity and accurate prediction of low risk. CONCLUSIONS AND IMPLICATIONS: Among children with ASD aggressive behavior independently predicts sleep problems. The model's high sensitivity for identifying children at risk and its accurate prediction of low risk can help with treatment and prevention of sleep problems. Further data collection may provide better prediction through methods requiring larger samples.

Modification of the Children's Sleep Habits Questionnaire for Children with Autism Spectrum Disorder.

Sleep problems are common in children with autism spectrum disorder (ASD) and adversely impact daytime functioning. Although no questionnaires have been developed to assess sleep in children with ASD, the 33-item Children's Sleep Habits Questionnaire (CSHQ) is widely used in this population. We examined the factor structure of the CSHQ in 2872 children (age 4-10 years) enrolled in the Autism Treatment Network. A four-factor solution (Sleep Initiation and Duration, Sleep Anxiety/Co-Sleeping, Night Waking/Parasomnias, and Daytime Alertness) with 5-6 items per factor explained 75% of the total variation. Ten items failed to load on any factor. This abbreviated 23-item four-factor version of this measure may be useful when assessing sleep in children with ASD.

Associations of Gross Motor Delay, Behavior, and Quality of Life in Young Children With Autism Spectrum Disorder.

Background: Young children with autism spectrum disorder (ASD) often have gross motor delays that may accentuate problem daytime behavior and health-related quality of life (QoL). Objective: The objective of this study was to describe the degree of gross motor delays in young children with ASD and associations of gross motor delays with problem daytime behavior and QoL. The primary hypothesis was that Gross motor delays significantly modifies the associations between internalizing or externalizing problem daytime behavior and QoL. Design: This study used a cross-sectional, retrospective analysis. Methods: Data from 3253 children who were 2 to 6 years old and who had ASD were obtained from the Autism Speaks Autism Treatment Network and analyzed using unadjusted and adjusted linear regression. Measures included the Vineland Adaptive Behavior Scales, 2nd edition, gross motor v-scale score (VABS-GM) (for Gross motor delays), the Child Behavior Checklist (CBCL) (for Problem daytime behavior), and the Pediatric Quality of Life Inventory (PedsQL) (for QoL). Results: The mean VABS-GM was 12.12 (SD = 2.2), representing performance at or below the 16th percentile. After adjustment for covariates, the internalizing CBCL t score decreased with increasing VABS-GM (ß = - 0.64 SE = 0.12). Total and subscale PedsQL scores increased with increasing VABS-GM (for total score: ß = 1.79 SE = 0.17; for subscale score: ß = 0.9-2.66 SE = 0.17-0.25). CBCL internalizing and externalizing t scores decreased with increasing PedsQL total score (ß = - 0.39 SE = 0.01; ß = - 0.36 SE = 0.01). The associations between CBCL internalizing or externalizing t scores and PedsQL were significantly modified by VABSGM (ß = - 0.026 SE = 0.005]; ß = - 0.019 SE = 0.007). Limitations: The study lacked ethnic and socioeconomic diversity. Measures were collected via parent report without accompanying clinical assessment. Conclusions: Cross motor delay was independently associated with Problem daytime behavior and QoL in children with ASD. Gross motor delay modified the association between Problem daytime behavior and QoL. Children with ASD and co-occurring internalizing Problem daytime behavior had greater Gross motor delays than children without internalizing Problem daytime behavior; therefore, these children may be most appropriate for early physical therapist evaluation.

Family-Driven Goals to Improve Care for Children With Autism Spectrum Disorder.

OBJECTIVES: Constipation and insomnia are not consistently identified and treated in children with autism spectrum disorder (ASD) despite their high prevalence and deleterious impact in this population. To standardize care, a constipation practice pathway and an insomnia practice pathway were previously developed by Autism Treatment Network clinicians. Our objective was to implement and refine these practice pathways in clinical settings. METHODS: Eleven Autism Treatment Network sites participated in a Learning Collaborative (ie, multidisciplinary quality improvement team) and chose to implement either the constipation or insomnia practice pathway in the clinical setting. Families set intervention goals (eg, increase stool frequency, decrease nighttime awakenings) before treatment. Each site began implementation with 1 patient and then increased implementation by factors of 5. Before each increase, the Learning Collaborative evaluated progress and refined the practice pathways. Process improvement was measured primarily by duration until goal attainment and by percentage of families who meet their goals. RESULTS: Across sites, 82 children with ASD and constipation and 101 children with ASD and insomnia were managed. Difficulties with intervention adherence and communication between providers and families were reported and were subsequently improved with parallel refinements to both practice pathways. The most notable modification was incorporating a goal-setting session in which families generated their own intervention goals (ie, family-driven goals). In this quality improvement initiative, 75% of families met at least 1 constipation or insomnia goal, with the median time to improvement being 6 weeks. CONCLUSIONS: By integrating a family-centered approach into the standardization of care, constipation and insomnia practice pathways may improve engagement, adherence, and management of medical conditions in children with ASD.

A Toolkit for the Management of Protocol Deviations.

BACKGROUND: The DIA's Good Clinical Practice and Quality Assurance Community (DIA GCP/QA) created a working group to develop templates for a protocol deviation standard operating procedure (SOP) and protocol deviation handling plan (PDHP). METHODS: The working group consisted of QA auditors, data managers, statisticians, and clinical monitors from several pharmaceutical companies, academia, and independent auditing firms. Various examples of standard operating procedures, data handling plans, and auditing plans were examined, and the core elements extracted into the initial PD SOP and PDHP templates. The draft templates were presented at a workshop at the DIA 51st Annual Meeting held in June 2015 in Washington, DC, and feedback was incorporated. The workshop came at the heels of a previously published position paper, "The Lifecycle and Management of Protocol Deviations." RESULTS: The PD SOP and the PDHP templates are presented in this article. They are a starting point, and each company will need to modify to suit its individual needs. CONCLUSIONS: This article expands on the position paper to include concrete tools for the management of protocol deviations, including best practices for detection, classification, mitigation, and management of protocol deviations with a goal to reduce the impact on subject safety and data integrity.

Sleep Difficulties and Medications in Children With Autism Spectrum Disorders: A Registry Study.

OBJECTIVES: Sleep difficulties are common in children with autism spectrum disorders, with wide-ranging effects on the child's daytime behavior. We reviewed data within our Autism Speaks Autism Treatment Network Registry to determine the prevalence of sleep difficulties and patterns of medication use. METHODS: Data from 1518 children ages 4 to 10 years were analyzed to determine the number of children documented to have sleep difficulties by parent-completed questionnaires and clinician-completed forms and how these findings related to the use of sleep medications. RESULTS: The Children's Sleep Habits Questionnaire total score was ≥41 (associated with clinically significant sleep problems in past research) in 71% of children. The prevalence of sleep diagnoses was less frequent (30% of children aged 4-10 years; P < .0001). Medications for sleep were prescribed in 46% of 4- to 10-year-olds given a sleep diagnosis. The most common medication used for sleep was melatonin followed by α-agonists, with a variety of other medications taken for sleep (anticonvulsants, antidepressants, atypical antipsychotics, and benzodiazepines). Children taking medications for sleep had worse daytime behavior and pediatric quality of life than children not taking sleep medications. CONCLUSIONS: Parent concerns about sleep may not be reflected in the information gathered during a clinic visit, supporting the need to develop screening practice pathways for sleep in autism spectrum disorders. Furthermore, many medications taken for sleep have adverse effects, supporting the need for evidence-based interventions in this population.

The Pediatric Sleep Clinical Global Impressions Scale-A New Tool to Measure Pediatric Insomnia in Autism Spectrum Disorders.

OBJECTIVE: To pilot a clinician-based outcome measure that provides complementary information to objective measures and parent-based questionnaires for insomnia in children with autism spectrum disorders (ASD). METHOD: The authors developed a Pediatric Sleep Clinical Global Impressions Scale (CGI). Questions included (1) the child's ability to fall asleep and remain sleeping independently (i.e., apart from parents); (2) bedtime resistance; (3) sleep onset delay; (4) night awakening; (5) parental satisfaction with their child's current sleep patterns; (6) family functioning as affected by their child's current sleep patterns; and (7) clinician's overall concern with the child's sleep. After refining the instrument through the evaluation of vignettes by ASD and sleep experts, the authors piloted the Pediatric Sleep CGI in a 12-week randomized trial of iron supplementation in children with ASD. Clinicians completed Pediatric Sleep CGIs and structured sleep histories, parents completed the Children's Sleep Habits Questionnaire (CSHQ), and children wore actigraphy watches. RESULTS: In repeated measures models, the Pediatric Sleep CGI and CSHQ were correlated for sleep onset delay (r = .66, p < .001), night wakings (r = .40, p < .001), and total score (r = .29, p < .001). The CGI-S sleep onset delay and actigraphy sleep onset delay scores (r = .75, p = .0095) were also correlated. The overall CGI-S showed improvement with therapy (p = .047). CONCLUSION: The Pediatric Sleep CGI shows promise in measuring clinician-rated outcomes in pediatric insomnia in children with ASD. Larger samples will be necessary to examine reliability, validity, and measure to change, as well as applicability to other populations with pediatric insomnia.

Residue depletion study and withdrawal period for flunixin-N-methyl glucamine in bovine milk following intravenous administration.

The objective of this study was to establish a withdrawal period for flunixin in milk by quantifying 5-hydroxyflunixin, the marker residue, in bovine milk as a function of time, following intravenous treatment of lactating dairy cows with flunixin-N-methyl glucamine (Banamine or Finadyne). Lactating dairy cows were dosed on three consecutive days at 2.2 mg of flunixin free acid/kg of body weight/day. Milk was collected twice daily and assayed using a liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) procedure. The method was validated at concentrations in the range 0.5-250 ppb. The concentrations for 5-hydroxyflunixin measured 12 h after the last administration of drug ranged from 1.56 to 40.6 ppb for all cows. Milk concentrations for 5-hydroxyflunixin were used to establish withdrawal periods of 36 h using guidelines established by the U.S. Food and Drug Administration/Center for Veterinary Medicine and 24 h using guidelines established by the European Medicinal Evaluation Agency/Committee on Veterinary Medicinal Products.