Sustained impact of a sleep intervention and moderators of treatment outcome for children with ADHD: a randomised controlled trial.

BACKGROUND: We aim to (1) determine whether a behavioural sleep intervention for children with attention-deficit/hyperactivity disorder (ADHD) leads to sustained benefits; and (2) examine the factors associated with treatment response. METHODS: This study was a randomised controlled trial of 244 children (5-13 years) with ADHD from Victoria, Australia. All participants had a moderate/severe sleep problem that met American Academy of Sleep Medicine criteria for an eligible sleep disorder by parent report. The two-session intervention covered sleep hygiene and standardised behavioural strategies. The control group received usual care. Parent- and teacher-reported outcomes at 12 months included sleep, ADHD severity, quality of life, daily functioning, behaviour, and parent mental health. Adjusted mixed effects regression analyses examined 12 month outcomes. Interaction analyses were used to determine moderators of intervention outcomes over time. The trial was registered with ISRCTN, http://www.controlled-trials.com (ISRCTN68819261). RESULTS: Intervention children were less likely to have a moderate/severe sleep problem by parent report at 12 months compared to usual care children (28.4% v. 46.5%, p = 0.03). Children in the intervention group fared better than the usual care group in terms of parent-reported ADHD symptoms (Cohen's d: -0.3, p < 0.001), quality of life (d: 0.4, p < 0.001), daily functioning (d: -0.5, p < 0.001), and behaviour (d: -0.3, p = 0.005) 12 months later. The benefits of the intervention over time in terms of sleep were less for children not taking ADHD medication and children with parents experiencing depression. CONCLUSIONS: A behavioural sleep intervention for ADHD is associated with small sustained improvements in child wellbeing. Children who are not taking ADHD medication or have parents with depression may require follow-up booster sleep sessions.

Health-related impairments in young children with ADHD: a community-based study.

BACKGROUND: We aimed to examine health-related impairments in young children with attention-deficit/hyperactivity disorder (ADHD) and non-ADHD controls and explore differences in children with ADHD by gender, ADHD subtype and mental health co-morbidity status. METHODS: Children with ADHD (n = 177) and controls (n = 212) aged 6-8 years were recruited across 43 schools in Melbourne, Australia following a screening (Conners 3 ADHD Index) and case confirmation procedure (Diagnostic Interview Schedule for Children IV). Direct and blinded assessments of height and weight were used to calculate body mass index z-score and to identify overweight/obesity. Parents reported on child global health, sleep problems and physical injuries. Unadjusted and adjusted (socio-demographic factors and co-morbidities) logistic and linear regression were conducted to compare health-related impairments between (1) children with and without ADHD; (2) boys and girls with ADHD; (3) children with ADHD-inattentive and ADHD-combined types; and (4) children with ADHD by internalizing and externalizing disorder status. RESULTS: Children with ADHD had poorer global health than controls when adjusted for socio-demographic characteristics (OR: 2.0; 95% CI 1.1, 3.9); however, this attenuated after adjusting for co-morbidities. In adjusted analyses, children with ADHD had increased odds of moderate/large sleep problems (OR: 3.1; 95% CI 1.4, 6.8), compared with controls. There were no differences between children with and without ADHD in terms of physical injuries or overweight/obesity. Findings were similar when excluding children taking ADHD medication, and health-related impairments did not differ between boys and girls with ADHD. Children with ADHD-combined type had higher BMI z-scores than controls in adjusted analyses (P = 0.04). Children with ADHD and co-occurring internalizing and externalizing co-morbidities were particularly vulnerable to health-related impairments. CONCLUSION: Young children with ADHD experience a number of health-related impairments, which are exacerbated by the presence of internalizing and externalizing co-morbidities. Clinicians should consider the broader health of children with ADHD in clinical consultations.

Children referred for evaluation for ADHD: comorbidity profiles and characteristics associated with a positive diagnosis.

BACKGROUND: The symptoms of attention-deficit/hyperactivity disorder (ADHD) are non-specific, and a range of possible causes and comorbidities need to be considered in children referred for assessment. OBJECTIVE: To examine the factors associated with ADHD diagnosis following multidisciplinary assessment. METHODS: Children underwent multidisciplinary evaluation including parent and teacher questionnaires; semi-structured interview to screen for internalizing and externalizing diagnoses; paediatric, psychology and special education assessments; and case conference. Predictors of ADHD diagnosis were examined in univariable and multivariable logistic regression models. RESULTS: Data from 190 assessments (82% male, mean age 6.8 years) were included. ADHD was diagnosed in 132 (70%) cases, of which 77% had one or more comorbidities. In children not diagnosed with ADHD, 60% had one or more alternate diagnosis made. Teacher-reported ADHD symptom severity and learning difficulties were the strongest predictors of ADHD diagnosis. The pattern of comorbid/alternative diagnoses was similar between those diagnosed with ADHD and those not diagnosed with ADHD. CONCLUSIONS: Direct report from teachers is the most critical element of the clinical dataset for the evaluation for ADHD. These findings emphasize the importance of cross-situational impairment to ADHD diagnosis. The frequency and similarity of diagnoses in both groups highlight the overlapping nature of childhood developmental disorders, and the importance of evaluating for comorbid disorders regardless of the primary diagnosis.

Paediatricians' decision making about prescribing stimulant medications for children with attention-deficit/hyperactivity disorder.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is now the most common reason for a child to present to a paediatrician in Australia. Stimulant medications are commonly prescribed for children with ADHD, to reduce symptoms and improve function. In this study we investigated the factors that influence paediatricians' decisions about prescribing stimulant medications. METHOD: In-depth, semi-structured interviews were conducted with paediatricians (n = 13) who were purposively recruited so as to sample a broad demographic of paediatricians working in diverse clinical settings. Paediatricians were recruited from public outpatient and private paediatrician clinics in Victoria, Australia. The interviews were audio-recorded and transcribed verbatim for thematic analysis. Paediatricians also completed a questionnaire describing their demographic and practice characteristics. RESULTS: Our findings showed that the decision to prescribe is a dynamic process involving two key domains: (1) weighing up clinical factors; and (2) interacting with parents and the patient along the journey to prescribing. Five themes relating to this process emerged from data analysis: comprehensive assessments that include history, examination and information from others; influencing factors such as functional impairment and social inclusion; previous success; facilitating parental understanding including addressing myths and parental confusion; and decision-making model. CONCLUSIONS: Paediatricians' decisions to prescribe stimulant medications are influenced by multiple factors that operate concurrently and interdependently. Paediatricians do not make decisions about prescribing in isolation; rather, they actively involve parents, teachers and patients, to arrive at a collective, well-informed decision.

Outcome of selective non-operative management of penetrating abdominal injuries from the North American National Trauma Database.

BACKGROUND: The aim of this study was to investigate trends in the practice of selective non-operative management (SNOM) for penetrating abdominal injury (PAI) and to determine factors associated with its failure. METHODS: The National Trauma Data Bank for 2002-2008 was reviewed. Patients with PAI were categorized as those who underwent successful SNOM (operative management not required) and those who failed SNOM (surgery required more than 4 h after admission). Yearly rates of SNOM versus non-therapeutic laparotomy (NTL) were plotted. Multivariable regression analysis was performed to identify factors associated with failed SNOM and mortality. RESULTS: A total of 12 707 patients with abdominal gunshot and 13 030 with stab wounds were identified. Rates of SNOM were 22.2 per cent for gunshot and 33.9 per cent for stab wounds, and increased with time (P < 0.001). There was a strong correlation between the rise in SNOM and the decline in NTL (r = - 0.70). SNOM failed in 20.8 and 15.2 per cent of patients with gunshot and stab wounds respectively. Factors predicting failure included the need for blood transfusion (odds ratio (OR) 1.96, 95 per cent confidence interval 1.11 to 3.46) and a higher injury score. Failed SNOM was independently associated with mortality in both the gunshot (OR 4.48, 2.07 to 9.70) and stab (OR 9.83, 3.44 to 28.00) wound groups. CONCLUSION: The practice of SNOM is increasing, with an associated decrease in the rate of NTL for PAI. In most instances SNOM is successful; however, its failure is associated with increased mortality. Careful patient selection and adherence to protocols designed to decrease the failure rate of SNOM are recommended.

Validating the Injury Severity Score (ISS) in different populations: ISS predicts mortality better among Hispanics and females.

INTRODUCTION: The Injury Severity Score (ISS) is the most commonly used measure of injury severity. The score has been shown to have excellent predictive capability for trauma mortality and has been validated in multiple data sets. However, the score has never been tested to see if its discriminatory ability is affected by differences in race and gender. OBJECTIVE: This study is aimed at validating the ISS in men and women and in three different race/ethnic groups using a nationwide database. METHODS: Retrospective analysis of patients age 18-64 y in the National Trauma Data Bank 7.0 with blunt trauma was performed. ISS was categorized as mild (<9,) moderate (9-15), severe (16-25), and profound (>25). Logistic regression was done to measure the relative odds of mortality associated with a change in ISS categories. The discriminatory ability was compared using the receiver operating characteristics curves (ROC). A P value testing the equality of the ROC curves was calculated. Age stratified analyses were also conducted. RESULTS: A total of 872,102 patients had complete data for the analysis on ethnicity, while 763,549 patients were included in the gender analysis. The overall mortality rate was 3.7%. ROC in Whites was 0.8617, in Blacks 0.8586, and in Hispanics 0.8869. Hispanics have a statistically significant higher ROC (P value < 0.001). Similar results were observed within each age category. ROC curves were also significantly higher in females than in males. CONCLUSION: The ISS possesses excellent discriminatory ability in all populations as indicated by the high ROCs.

Complementary and alternative medicine use in children with attention deficit hyperactivity disorder.

OBJECTIVES: The use of complementary and alternative medicines (CAM) is increasing in the general population. Attention deficit hyperactivity disorder (ADHD) is a chronic condition that has a major impact on children's functioning and has no cure, therefore many families may try CAM at some stage. We aimed to determine (i) the lifetime incidence of CAM use in a clinical sample of children with ADHD; (ii) parents' perceptions of the effectiveness of CAM for ADHD; and (iii) the proportion who informed their paediatrician. METHODS: The sample was drawn from patients aged 5-17 years with ADHD attending Royal Children's Hospital, Melbourne outpatient clinics from May to September 2003. A 20-item survey was posted to consenting families. RESULTS: From 105 surveys, 75 were returned (response rate 71.4%). Mean child age was 11.1 (SD 2.9, range 5.0-16.9) years; 65 (86.7%) were boys. Fifty (67.6%) families reported current or past CAM use. Of the 23 different therapies reported, the most common were modified diet (33 families), vitamins and/or minerals (16), dietary supplements (12), aromatherapy (12) and chiropractics (10). Reported effectiveness was variable. The factors most frequently rated as important in choosing CAM were minimizing symptoms (40 families), adding to the benefit of conventional treatment (30) and avoiding side-effects (29). Thirty-two (64%) of 50 families reported that they informed their paediatrician of their CAM use. CONCLUSION: Complementary and alternative medicines are commonly used in children with ADHD. Paediatricians should inquire about the use of CAM, and use available resources to help guide families in their therapeutic choices.

Implementation of evidence based guidelines for paediatric asthma management in a teaching hospital.

AIMS: To evaluate a systematic approach to the development and implementation of evidence based asthma management guidelines. METHODS: Comparative study of children (2-18 years) with acute asthma; a control cohort (cohort 1) was recruited before implementation of the guidelines and two cohorts were recruited after implementation (cohorts 2 and 3). RESULTS: There was no difference in the proportion of patients who reattended in the six months following initial presentation for cohort 1 (21.5%), cohort 2 (27.8%), or cohort 3 (25.4%) and no difference in readmission rates (11.4%, 11.3%, 11.0% respectively). There was no difference in measures of asthma morbidity between the cohorts at 3 and 6 months across three domains: interval symptoms, exercise limitation, and bronchodilator use. Of those who did not have a management plan before presentation, one was provided to 46.9% of cohort 1, 74.8% of cohort 2, and 81.1% of cohort 3. There was no difference comparing cohort 2 or cohort 3 with cohort 1 regarding quality of life for either the subjects or their parents. CONCLUSIONS: Implementation of our evidence based guidelines was associated with the improved provision of asthma management plans, but there was no effect on reattendance or readmission to hospital, asthma morbidity, or quality of life. Future efforts to improve asthma management should target specific components of asthma care.

Disruption of a novel member of a sodium/hydrogen exchanger family and DOCK3 is associated with an attention deficit hyperactivity disorder-like phenotype.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a complex condition with high heritability. However, both biochemical investigations and association and linkage studies have failed to define fully the underlying genetic factors associated with ADHD. We have identified a family co-segregating an early onset behavioural/developmental condition, with features of ADHD and intellectual disability, with a pericentric inversion of chromosome 3, 46N inv(3)(p14:q21). METHODS: We hypothesised that the inversion breakpoints affect a gene or genes that cause the observed phenotype. Large genomic clones (P1 derived/yeast/bacterial artificial chromosomes) were assembled into contigs across the two inversion breakpoints using molecular and bioinformatic technologies. Restriction fragments crossing the junctions were identified by Southern analysis and these fragments were amplified using inverse PCR. RESULTS: The amplification products were subsequently sequenced to reveal that the breakpoints lay within an intron of the dedicator of cytokinesis 3 (DOCK3) gene at the p arm breakpoint, and an intron of a novel member of the solute carrier family 9 (sodium/hydrogen exchanger) isoform 9 (SLC9A9) at the q arm. Both genes are expressed in the brain, but neither of the genes has previously been implicated in developmental or behavioural disorders. CONCLUSION: These two disrupted genes are candidates for involvement in the pathway leading to the neuropsychological condition in this family.

Differential cytokine expression in skin graft healing in inducible nitric oxide synthase knockout mice.

Inducible nitric oxide synthase (iNOS) and its product, nitric oxide, have been shown to play important roles in wound biology. The present study was performed to investigate the role of iNOS in modulating the cytokine cascade during the complex process of skin graft wound healing.Fifteen iNOS-knockout mice and 15 wild-type C57BL/6J mice were subjected to autogenous 1-cm2 intrascapular full-thickness skin grafts. Three animals in each group were killed on postoperative days 3, 5, 7, 10, and 14. Specimens were then analyzed using nonisotopic in situ hybridization versus mRNA of tumor growth factor-beta1, vascular endothelial growth factor, iNOS, endothelial nitric oxide synthase (eNOS), tumor necrosis factor-alpha, and basic fibroblast growth factor, as well as positive and negative control probes. Positive cells in both grafts and wound beds were counted using a Leica microgrid. Scar thickness was measured with a Leica micrometer. Data were analyzed using the unpaired Student's t test. Expression of iNOS was 2- to 4-fold higher in knockout mice than in wild-type mice on postoperative days 5, 7, and 14. Expression of eNOS was 2- to 2.5-fold higher in knockout mice than in wild-type mice on postoperative days 5 and 7. Tumor necrosis factor-alpha expression was 2- to 7-fold higher in knockout mice than in wild-type mice on all postoperative days. In contrast, expression levels of angiogenic/fibrogenic cytokines (vascular endothelial growth factor, basis fibroblast growth factor, and tumor growth factor-beta1) were 2.5- to 4-fold higher in wild-type mice than in knockout mice. Scars were 1.5- to 2.5-fold thicker in knockout mice than in wild-type mice at all time points. All of the above results represent statistically significant differences (p < 0.05). Significantly different patterns of cytokine expression were seen in knockout and wild-type mice. Although the scar layer was thicker in knockout mice, it showed much greater infiltration with inflammatory cells. These data further delineate the modulatory effect of iNOS and nitric oxide in healing skin grafts.

Nitric oxide in the healing wound: a time-course study.

INTRODUCTION: We studied the time course of nitric oxide expression in the healing wound and the cell populations responsible for its synthesis. METHODS: Twenty four Lewis rats underwent subcutaneous implantation of polyvinyl alcohol sponges. Rats were sacrificed in groups of three on days 1, 3, 5, 7, 10, 14, and 35 after wounding. The conversion of 3H-labeled arginine to 3H-labeled citrulline, with or without N(G)-L-monomethyl-arginine (L-NMMA) in harvested sponges, was measured. Nitrate/nitrite (NOx) in plasma and wound fluid was quantified by Greiss reaction. Inducible nitric oxide synthase (iNOS) gene expression was determined by Northern analysis and reverse transcriptase-polymerase chain reaction (RT-PCR). Inducible NOS was identified in specific wound cell populations by dual-label flow cytometry. RESULTS: Nitric oxide synthase (NOS) activity peaked at 24 h after wounding (37.7 +/- 0.9 micromol citrulline per milligram sponge), with a steady decline thereafter. Percentage inhibition of NOS activity by l-NMMA was highest on days 1-7 (70-80%). This declined to 50% by day 10 and to 25% by days 14-35. The iNOS gene expression paralleled NOS biochemical activity. RT-PCR confirmed low-level expression up to 10 days after wounding. Plasma NOx levels remained within a narrow range of 22.6 +/- 1.3 to 29.3 +/- 1.5 microM throughout the postwounding period, while corresponding levels in wound fluid (microM) increased steadily from 27 +/- 3.8 on day 1 to 107.2 +/- 10.0 on day 14. Inducible NOS expression was detectable by fluorescence-activated cell sorting in wound macrophages on days 1 and 3 after wounding. CONCLUSIONS: Our findings suggest maximal NOS activity early in cutaneous wound healing, with sustained production up to 10 days after wounding. NOS biochemical activity was paralleled by iNOS gene expression. Plasma NOx remained constant, while wound fluid NOx increased steadily to peak at day 14. Wound macrophages appear to be a source of nitric oxide production in the early phase of wound healing.

The role of iNOS in wound healing.

BACKGROUND: We have previously shown that the blockade of nitric oxide (NO) synthesis impairs wound healing, in particular collagen synthesis. Conversely, impaired wound healing is accompanied by decreased wound NO synthesis. Fibroblast collagen synthesis, proliferation, and fibroblast-mediated matrix contraction are critical to wound healing. We examined the wound healing-related phenotypic changes that are induced by the loss of inducible nitric oxide synthase (iNOS) gene function in fibroblasts. METHODS: Dermal fibroblasts were obtained from 8- to 12-week-old iNOS--knock out (KO; C57BL/Ai-[KO] Nos2 N5) and wild type mice by an explant technique and used after 1 to 3 passages. Proliferation ([(3)H]-thymidine incorporation) and collagen synthesis ([(3)H]-proline incorporation into collagenase-sensitive protein) were studied after stimulation with 10% fetal bovine serum. Matrix remodeling was assessed by the measurement of the contraction of fibroblast-populated collagen lattices. RESULTS: iNOS-KO fibroblasts proliferated more slowly, synthesized less collagen, and contracted fibroblast-populated collagen lattices more slowly than wild-type fibroblast. Collagen synthesis was restored to normal in KO fibroblasts in response to NO donors (s-nitroso-N-acetylpenicillamine). CONCLUSIONS: iNOS deficiency causes significant impairment in wound healing-related properties of fibroblasts, which suggests that NO plays an important role in wound healing.

Laparoscopic surgery in older adults.

This article provides an overview of the current role of laparoscopic surgery in older patients. A retrospective review and analysis of the recent English-language literature on laparoscopic procedures with special attention devoted to those articles focused on geriatric patients was performed. Laparoscopic surgery has rapidly become the fastest-growing discipline within the surgical arena and new applications for laparoscopy continue to be reported. The primary benefits to patients of these developments are smaller scars, decreased postoperative pain, and more-rapid return to normal activity. As society ages, more older patients will present with pathology amenable to laparoscopic intervention. Several aspects of laparoscopy impose unique physiologic stresses and, as such, may alter surgical risk to the geriatric patient. In addition, older patients often have delayed surgical interventions because of more-conservative medical management or unusual symptomatology, which may further complicate the laparoscopic approach. These limitations may alter the risk-to-benefit ratio of laparoscopic versus open procedures. Despite this lack of elucidation of full-risk profiles, laparoscopic approaches should be considered regardless of a patient's age.

A novel method of studying wound healing.

In order to study wound healing, it is often necessary to administer various wound-active substances by the systemic route. It is unclear whether the observed effects are the result of local or systemic influence of the agent administered. Furthermore, high systemic doses are often required to achieve activity at the wound level. Direct intrawound administration of substances is traumatic and disruptive to the fragile wound environment and increases the risk of infection. We devised a system for continuous atraumatic delivery of substances directly to subcutaneously implanted polyvinyl alcohol sponges, an adaptation of a well-established model of wound healing. Sponge-catheter constructs were fashioned by feeding identical lengths of silicone catheters through two 40-mg sponge disks (on edge). The distal sponge was fixed 0.5 cm from the distal, ligated end of the catheter and centered over two 1-mm holes in the catheter tubing. The proximal sponge was fixed over nonperforated catheter with its edge 2 cm proximal from the close edge of the distal sponge. Each construct was connected to a mini-osmotic pump (infusion rate 1 microl/h) loaded with an appropriate infusate and inserted subcutaneously on the dorsum of anesthetized male Sprague-Dawley rats. Hydroxyproline (OHP) content of sponges, a measure of collagen deposition, was determined at 7 days postwounding. Infusion of India ink confirmed selective delivery to the distal sponge. Saline infusion alone significantly elevated OHP content compared to noninfused sponges (450 +/- 43 vs 328 +/- 36 microg OHP/100 mg sponge, P < 0.05). Infusion of S-methylisothiourea (a selective iNOS inhibitor, 84 microg/sponge/24 h) successfully inhibited NO production (35.9 +/- 3.1 vs 49.6 +/- 3.6 microM, P < 0.05) and decreased sponge OHP content (385 +/- 60 vs 568 +/- 70 microg OHP/100 mg sponge, P < 0.05) without the toxic side effect (i.e., weight loss) seen with systemic administration. Infusion of an adenoviral solution containing mouse iNOS cDNA resulted in successful transduction of wound cells demonstrating the ability to deliver genes to a healing wound model. The data demonstrate that manipulation of wound physiology is possible by local delivery of low doses of wound-active compounds to the wound site. This promises to be a powerful tool for the study of both normal and impaired wound healing.