Diagnostic tests for autism spectrum disorder (ASD) in preschool children.

BACKGROUND: Autism spectrum disorder (ASD) is a behaviourally diagnosed condition. It is defined by impairments in social communication or the presence of restricted or repetitive behaviours, or both. Diagnosis is made according to existing classification systems. In recent years, especially following publication of the Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5; APA 2013), children are given the diagnosis of ASD, rather than subclassifications of the spectrum such as autistic disorder, Asperger syndrome, or pervasive developmental disorder - not otherwise specified. Tests to diagnose ASD have been developed using parent or carer interview, child observation, or a combination of both. OBJECTIVES: Primary objectives1. To identify which diagnostic tools, including updated versions, most accurately diagnose ASD in preschool children when compared with multi-disciplinary team clinical judgement.2. To identify how the best of the interview tools compare with CARS, then how CARS compares with ADOS.a. Which ASD diagnostic tool - among ADOS, ADI-R, CARS, DISCO, GARS, and 3di - has the best diagnostic test accuracy?b. Is the diagnostic test accuracy of any one test sufficient for that test to be suitable as a sole assessment tool for preschool children?c. Is there any combination of tests that, if offered in sequence, would provide suitable diagnostic test accuracy and enhance test efficiency?d. If data are available, does the combination of an interview tool with a structured observation test have better diagnostic test accuracy (i.e. fewer false-positives and fewer false-negatives) than either test alone?As only one interview tool was identified, we modified the first three aims to a single aim (Differences between protocol and review): This Review evaluated diagnostic tests in terms of sensitivity and specificity. Specificity is the most important factor for diagnosis; however, both sensitivity and specificity are of interest in this Review because there is an inherent trade-off between these two factors.Secondary objectives1. To determine whether any diagnostic test has greater diagnostic test accuracy for age-specific subgroups within the preschool age range. SEARCH METHODS: In July 2016, we searched CENTRAL, MEDLINE, Embase, PsycINFO, 10 other databases, and the reference lists of all included publications. SELECTION CRITERIA: Publications had to: 1. report diagnostic test accuracy for any of the following six included diagnostic tools: Autism Diagnostic Interview - Revised (ADI-R), Gilliam Autism Rating Scale (GARS), Diagnostic Interview for Social and Communication Disorder (DISCO), Developmental, Dimensional, and Diagnostic Interview (3di), Autism Diagnostic Observation Schedule - Generic (ADOS), and Childhood Autism Rating Scale (CARS); 2. include children of preschool age (under six years of age) suspected of having an ASD; and 3. have a multi-disciplinary assessment, or similar, as the reference standard.Eligible studies included cohort, cross-sectional, randomised test accuracy, and case-control studies. The target condition was ASD. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed all studies for inclusion and extracted data using standardised forms. A third review author settled disagreements. We assessed methodological quality using the QUADAS-2 instrument (Quality Assessment of Studies of Diagnostic Accuracy - Revised). We conducted separate univariate random-effects logistical regressions for sensitivity and specificity for CARS and ADI-R. We conducted meta-analyses of pairs of sensitivity and specificity using bivariate random-effects methods for ADOS. MAIN RESULTS: In this Review, we included 21 sets of analyses reporting different tools or cohorts of children from 13 publications, many with high risk of bias or potential conflicts of interest or a combination of both. Overall, the prevalence of ASD for children in the included analyses was 74%.For versions and modules of ADOS, there were 12 analyses with 1625 children. Sensitivity of ADOS ranged from 0.76 to 0.98, and specificity ranged from 0.20 to 1.00. The summary sensitivity was 0.94 (95% confidence interval (CI) 0.89 to 0.97), and the summary specificity was 0.80 (95% CI 0.68 to 0.88).For CARS, there were four analyses with 641 children. Sensitivity of CARS ranged from 0.66 to 0.89, and specificity ranged from 0.21 to 1.00. The summary sensitivity for CARS was 0.80 (95% CI 0.61 to 0.91), and the summary specificity was 0.88 (95% CI 0.64 to 0.96).For ADI-R, there were five analyses with 634 children. Sensitivity for ADI-R ranged from 0.19 to 0.75, and specificity ranged from 0.63 to 1.00. The summary sensitivity for the ADI-R was 0.52 (95% CI 0.32 to 0.71), and the summary specificity was 0.84 (95% CI 0.61 to 0.95).Studies that compared tests were few and too small to allow clear conclusions.In two studies that included analyses for both ADI-R and ADOS, tests scored similarly for sensitivity, but ADOS scored higher for specificity. In two studies that included analyses for ADI-R, ADOS, and CARS, ADOS had the highest sensitivity and CARS the highest specificity.In one study that explored individual and additive sensitivity and specificity of ADOS and ADI-R, combining the two tests did not increase the sensitivity nor the specificity of ADOS used alone.Performance for all tests was lower when we excluded studies at high risk of bias. AUTHORS' CONCLUSIONS: We observed substantial variation in sensitivity and specificity of all tests, which was likely attributable to methodological differences and variations in the clinical characteristics of populations recruited.When we compared summary statistics for ADOS, CARS, and ADI-R, we found that ADOS was most sensitive. All tools performed similarly for specificity. In lower prevalence populations, the risk of falsely identifying children who do not have ASD would be higher.Now available are new versions of tools that require diagnostic test accuracy assessment, ideally in clinically relevant situations, with methods at low risk of bias and in children of varying abilities.

What is the connection between red hair and Tourette syndrome?

Tourette syndrome is a chronic, idiopathic, childhood onset neuropsychiatric disorder with both motor and vocal tics. Tourette syndrome occurs worldwide and the clinical features are similar irrespective of the country of origin, with genetic causes suspected, but to date not proven. A link between red hair colour and Tourette syndrome has been hypothesised as a result of an observation that red hair is over represented in this condition. A causal association between red hair and melanocortin-1 receptor has been shown, and is the only gene that is known to explain physiological variation in human pigmentation. Melanocortins are believed to be involved in many disease states including pigmentary disorders, adrenal disorders, obesity, anorexia, prolonged and neuropathic pain, and inflammatory response. The mode of inheritance for Tourette syndrome is thought to be autosomal recessive, same as for red hair with both aggregating in families. To explore the hypothesis, 168 postal questionnaires sent to Tourette syndrome patients on the registry of the 'Tourette Syndrome Association of Australia', were analysed. In this study 22, 13% (95% CI 8.9-19.4) of the Tourette syndrome population had red hair. Data from Australian studies suggests, the normal population with red hair is 2-6%. The proportions of red haired individuals in this study were significantly higher than five of the eight population control groups. Fifty five percent of the Tourette syndrome patients had relatives with red hair. Of these 30% were first degree and 46% were second degree relatives, with a further 24% of more distant relatives. Many Tourette syndrome patients had multiple red haired relatives, since 90 patients yielded a total of 181 relatives with red hair. If this hypothesis is correct the MCIR gene, through a neurological effect, or a gene for Tourette syndrome, located on chromosome 16 in the vicinity of MC1R, could be on the causal pathway. As these figures demonstrate, the hypothesis that there is an association between red hair and Tourette syndrome needs further evaluation.

Multiagent chemotherapy studied in a xenograft model of medulloblastoma/primitive neuroectodermal tumour: analysis of the VETOPEC regimen.

Brain tumours remain the most important challenge in the treatment of childhood cancer. The intraocular (io) xenograft model was used to study components and variations of the VETOPEC multiagent chemotherapy regimen in the medulloblastoma/primitive neuroectodermal tumour (MB/PNET) xenograft cell line JRMB-6. VETOPEC, a combination of vincristine (VCR), etoposide (VP-16) and escalated dose cyclophosphamide (CPA), has been shown to be highly active in clinical trials. A total of 190 xenografted tumours were treated with one of nine regimens: saline; single agent CPA, VP-16 (single dose [sd], five dosages daily [dx5] or continuous infusion, [ci]) or VCR; combinations of CPA (dx5)+VP-16 (dx5 or ci) or CPA (dx5)+VP-16 (ci)+VCR (sd). Results were calculated using both response (volume reduction >50%) and 'time to progression' (TtP). Effectiveness of CPA was confirmed. Single-agent VCR or VP-16 produced no response. No difference was documented in TtP with VCR, VP-16 (sd) or VP-16 (dx5) versus control, but a significant prolongation occurred when VP-16 was given by ci (p=0.001). With the 3-agent combination of CPA+VP-16 (ci)+VCR a significantly prolonged TtP was documented versus both single agent CPA (p=0.003) and the combination of CPA+VP-16 (dx5) (p=0.004). The results suggest improved efficacy of VP-16 when given as ci in both single-agent and combination settings. The addition of VP-16 (ci)+VCR to an already effective dosage of CPA further prolongs TtP. These data support and progress VETOPEC phase II clinical studies and suggest potential further benefits of prolonged exposure to VP-16 by ci.

Use of the Internet by parents of paediatric patients.

AIM: We aimed to determine the rate of Internet use for obtaining medical information by health-care patients at a tertiary paediatric hospital, whether the Internet may influence patients' attitudes to health-care services and health-care providers and whether patients would prefer the assistance of a professional informatics officer. METHODS: An anonymous questionnaire randomly distributed to 450 subjects at Sydney Children's Hospital, Sydney, Australia. RESULTS: A total of 294 (65%) questionnaires were returned. Overall Internet use for medical information was 64% (189/294). Most (97%; 183/189) respondents reported 'wanting to know more' as the reason they sought information on the Internet. Eighty-eight per cent (167/189) of respondents reported that they trust their doctor more than the Internet. Twenty-one per cent (39/189) had presented their doctor with information about which he/she was unaware and 18% (34/189) had altered a health-care decision because of information found on the Internet. The Internet had influenced questions asked of doctors in 83% (156/189). Eighty-six per cent (252/294) of all respondents were in favour of professional assistance to obtain medical information. CONCLUSION: A large number of patients use the Internet to find information that influences their attitudes to health care. The services of a medical informatics professional would likely benefit both patients and doctors.

Experience with inhaled nitric oxide therapy in hypoxic respiratory failure of the newborn.

BACKGROUND: Respiratory diseases are the commonest cause of morbidity and mortality in newborns. Inhaled nitric oxide (iNO) has been shown to be effective in the management of persistent pulmonory hypertension of newborn (PPHN). OBJECTIVES: To retrospectively analyse data to determine the effectiveness of inhaled nitric oxide (iNO) in the management of newborns with PPHN in terms of survival and changes in oxygenation status. METHODS: Neo-natal data since inception of iNO therapy at the unit (past six years) was reviewed. Pertinent demographic and clinical information was collected from medical records of newborns that received inhaled nitric oxide therapy during their stay. Details of underlying illnesses, other therapeutic modalities, arterial blood gas, ventilatory and nitric oxide parameters were assessed and analysed to ascertain efficacy of iNO. RESULTS: A total of 36 babies (gestational age ranging from 24-41 weeks) received iNO during this period; two were excluded from final analysis. Overall survival rate was 80 percent. There was a statistically significant increase in systemic oxygenation (PaO2) from 41.1 +/- 2.1 mmHg to 128.5 +/- 13.2 mmHg and a decline in oxygenation index (OI) from 49.4 +/- 5.9 to 17.3 +/- 2.5, when assessed after four hours (P < 0.001). Mean duration of iNO therapy was 63 +/- 7.3 hours and the maximum methaemoglobin levels were noted to be 2.1 percent. CONCLUSIONS: Inhaled nitric oxide appears to be an effective rescue therapy for the management of PPHN associated with hypoxic respiratory failure. It is safe and well tolerated with no evidence of clinical or biochemical side effects.

Cytotoxic properties of immunoconjugates containing melittin-like peptide 101 against prostate cancer: in vitro and in vivo studies.

BACKGROUND: Monoclonal antibodies (MAbs) can target therapy to tumours while minimising normal tissue exposure. Efficacy of immunoconjugates containing peptide 101, designed around the first 22 amino acids of bee venom, melittin, to maintain the amphipathic helix, to enhance water solubility, and to increase hemolytic activity, was assessed in nude mice bearing subcutaneous human prostate cancer xenografts. METHODS: Mouse MAbs, J591 and BLCA-38, which recognise human prostate cancer cells, were cross-linked to peptide 101 using SPDP. Tumour-bearing mice were used to compare biodistributions of radiolabeled immunoconjugates and MAb, or received multiple sequential injections of immunoconjugates. Therapeutic efficacy was assessed by delay in tumour growth and increased mouse survival. RESULTS: Radiolabeled immunoconjugates and antibodies showed similar xenograft tropism. Systemic or intratumoural injection of immunoconjugates inhibited tumour growth in mice relative to carrier alone, unconjugated antibody and nonspecific antibody-peptide conjugates and improved survival for treated mice. CONCLUSIONS: Immunoconjugates deliver beneficial effects; further peptide modifications may increase cytotoxicity.

Biodistributions of intact monoclonal antibodies and fragments of BLCA-38, a new prostate cancer directed antibody.

BACKGROUND: Monoclonal antibodies (MAbs) are used for targeting agents to tumours while minimizing normal tissue exposure. METHODS: A new anti-prostate cancer MAb, BLCA-38, was radioiodinated (I125) and assessed for its ability to target subcutaneous human prostate cancer (DU-145) xenografts after systemic intraperitoneal administration. For comparison, the profile of J591 MAb (now in clinical trial) against LNCaP-LN3 tumours was examined. Biodistribution profiles were obtained at various times, by assessing injected dose/gram (%ID/g) and xenograft to blood (X/B) ratios. Microautoradiography of xenografts was performed. After conjugation with a melittin peptide toxin, the profiles of BLCA-38 and J591 were compared with that of an irrelevant antibody, DS-1. RESULTS: Xenograft localization by 125I-labeled BLCA-38 and J591 MAbs to their relevant antigen-positive tumors was comparable, and there was no unusual localization in nontumour tissues. F(ab')2 and Fab fragments gave improved X/B ratios, but the %ID/g xenograft was decreased and they accumulated in kidneys, bladder and stomach. In contrast, the conjugates of irrelevant antibody showed no tumour targeting. Microautoradiography showed more tumour accumulation of MAbs than F(ab')2s or Fabs. CONCLUSIONS: BLCA-38 can target prostate cancer in vivo almost as effectively as J591. Given that J591 is used clinically, BLCA-38, which targets a different antigen, has potential for radioimmunoscintigraphy and for therapeutic targeting of prostate cancer.

The role of xenografting in pediatric brain tumor research with specific emphasis on medulloblastoma/primitive neuroectodermal tumors of childhood.

Pre-clinical models have an important role in cancer research. This review looks at the history as well as advantages and limitations of several animal models used in the study of pediatric brain tumors. The neoplasms of specific interest are the medulloblastoma/primitive neuroectodermal tumor category of brain tumors, because of their relevance to concurrent clinical research and practice. Given the historic poor record for direct heterotransplantation of these malignancies, both the conventional subcutaneous site and immune-privileged sites are assessed, with particular emphasis on models adapted to chemotherapeutic studies. The subcutaneous site is easiest to monitor but may be sub-optimal for therapeutic assays of brain tumors due to low engraftment rate, the absence of a blood-brain barrier equivalent and other lack of similarity to the clinical situation. The addition of a basement membrane attachment matrix (Matrigel) has been shown to enhance engraftment rate and cell yield at the subcutaneous site. In contrast, the intracerebral site, which is an area of immune-privilege, is biologically suitable for the study of brain tumors and their therapy, but there is no opportunity for sequential treatment courses or assessment of tumor growth prior to the death of the animal. An intraocular xenograft model has been shown to mimic human brain tumors in its resemblance of access to systemic agents to that via the blood-brain barrier and offers advantages over other methods for the pre-clinical study of chemotherapy in medulloblastoma/primitive neuroectodermal tumor. The intraocular site allows engraftment from very small clinical samples, is suitable for sequential treatment phases and provides easy access for monitoring of tumor progress. Chemotherapeutic agents which have been evaluated in various xenograft models, both as single agents and in combination, as well as other and novel approaches to the treatment of brain tumors are reviewed.