Deep phenotypic analysis of psychiatric features in genetically defined cohorts: application to XYY syndrome.

BACKGROUND: Recurrent gene dosage disorders impart substantial risk for psychopathology. Yet, understanding that risk is hampered by complex presentations that challenge classical diagnostic systems. Here, we present a suite of generalizable analytic approaches for parsing this clinical complexity, which we illustrate through application to XYY syndrome. METHOD: We gathered high-dimensional measures of psychopathology in 64 XYY individuals and 60 XY controls, plus additional interviewer-based diagnostic data in the XYY group. We provide the first comprehensive diagnostic description of psychiatric morbidity in XYY syndrome and show how diagnostic morbidity relates to functioning, subthreshold symptoms, and ascertainment bias. We then map behavioral vulnerabilities and resilience across 67 behavioral dimensions before borrowing techniques from network science to resolve the mesoscale architecture of these dimensions and links to observable functional outcomes. RESULTS: Carriage of an extra Y-chromosome increases risk for diverse psychiatric diagnoses, with clinically impactful subthreshold symptomatology. Highest rates are seen for neurodevelopmental and affective disorders. A lower bound of < 25% of carriers are free of any diagnosis. Dimensional analysis of 67 scales details the profile of psychopathology in XYY, which survives control for ascertainment bias, specifies attentional and social domains as the most impacted, and refutes stigmatizing historical associations between XYY and violence. Network modeling compresses all measured symptom scales into 8 modules with dissociable links to cognitive ability, adaptive function, and caregiver strain. Hub modules offer efficient proxies for the full symptom network. CONCLUSIONS: This study parses the complex behavioral phenotype of XYY syndrome by applying new and generalizable analytic approaches for analysis of deep-phenotypic psychiatric data in neurogenetic disorders.

Long-term oncologic outcomes of low dose-rate brachytherapy compared to hypofractionated external beam radiotherapy for intermediate -risk prostate cancer.

PURPOSE: To compare the long-term oncologic outcomes of intermediate risk (IR) prostate cancer (PCa) patients treated with low dose-rate brachytherapy (LDR-BT) or moderate hypofractionated external beam radiotherapy (HF-EBRT). METHODS AND MATERIALS: Patients diagnosed with IR PCa and treated with LDR-BT or HF-EBRT between January 2005 and December 2013 were included. Brachytherapy treatment involved a transperineal implant of iodine-125 to a dose of 145 Gy to the PTV, while HF-EBRT was delivered using intensity modulated radiotherapy with 60 Gy in 20 fractions. The Phoenix ''nadir +2'' threshold was used to define biochemical relapse (BR). The cumulative incidence function (CIF) of BR and metastases was reported for each group and compared using the Gray's test to account for the competing risk of death. The Kaplan-Meier (KM) method was used to estimate overall survival (OS) and prostate cancer specific survival (PCSS). Univariate (UVA) and multivariable (MVA) analysis of the CIF of BR and metastases were performed. A 2-tailed p-value ≤ 0.05 was considered statistically significant. RESULTS: Overall, 122 and 124 patients were treated with LDR-BT and HF-EBRT respectively. Median follow-up was 95 months [interquartile range (IQR): 79-118] in the LDR-BT group and 96 months (IQR: 63-123) in the HF-EBRT group. BR was observed in 5 patients treated with LDR-BT and 34 treated with HF-EBRT. At 60 and 90 months, the CIF of BR was 0.9% and 3.5% in the LDR-BT group vs. 16.6% and 23.7% in the HF-EBRT (p < 0.001). The CIF of metastases at 90 and 108 months, was 0% and 1.6% vs. 3.4% and 9.1% in the LDR-BT and HF-EBRT groups (p = 0.003), respectively. At the last follow-up, 3 patients treated with HF-EBRT died from their cancer [PCSS of 97.5% at 8 years and none died in the LDR-BT group (p = 0.09). On UVA and MVA risk group and treatment modality were independently associated with CIF of BR. On UVA HF-EBRT and ISUP grade group 3 were associated with metastases. CONCLUSION: LDR-BT was associated with higher biochemical and metastases control in our cohort when compared to moderately HF-EBRT. In the absence of a randomized trial, LDR-BT when feasible should be offered to patients with a life expectancy of >8 years.

Corrigendum: MRI-guided focal or integrated boost high dose rate brachytherapy for recurrent prostate cancer.

[This corrects the article DOI: 10.3389/fonc.2022.971344.].

MRI-guided focal or integrated boost high dose rate brachytherapy for recurrent prostate cancer.

Background and purpose: Locally recurrent prostate cancer after radiotherapy merits an effective salvage strategy that mitigates the risk of adverse events. We report outcomes of a cohort enrolled across two institutions investigating MRI-guided tumor-targeted salvage high dose rate brachytherapy (HDR-BT). Materials and methods: Analysis of a prospective cohort of 88 patients treated across two institutions with MRI-guided salvage HDR-BT to visible local recurrence after radiotherapy (RT). Tumor target dose ranged from 22-26 Gy, using either an integrated boost (ibBT) or focal technique (fBT), delivered in two implants over a median of 7 days. Outcome metrics included cancer control and toxicity (CTCAE). Quality of life (QoL-EPIC) was analyzed in a subset. Results: At a median follow-up of 35 months (6 -134), 3 and 5-year failure-free survival (FFS) outcomes were 67% and 49%, respectively. At 5 years, fBT was associated with a 17% cumulative incidence of local failure (LF) outside the GTV (vs. 7.8% ibBT, p=0.14), while LF within the GTV occurred in 13% (vs. 16% ibBT, p=0.81). Predictors of LF outside fBT volumes included pre-salvage PSA>7 ng/mL (p=0.03) and interval since RT less than 5 years (p=0.04). No attributable grade 3 events occurred, and ibBT was associated with a higher rate of grade 2 toxicity (p<0.001), and trend towards a larger reduction in QoL sexual domain score (p=0.07), compared to fBT. Conclusion: A tumor-targeted HDR-BT salvage approach achieved favorable cancer control outcomes. While a fBT was associated with less toxicity, it may be best suited to a subgroup with lower PSA at later recurrence. Tumor targeted dose escalation may be warranted.

Cytidine 5'-Diphosphocholine Corrects Alveolar Type II Cell Mitochondrial Dysfunction in Influenza-infected Mice.

Development of acute respiratory distress syndrome (ARDS) in influenza A virus (IAV)-infected mice is associated with inhibition of ATII (alveolar type II) epithelial cell de novo phosphatidylcholine synthesis, and administration of the phosphatidylcholine precursor cytidine 5'-diphosphocholine (CDP-choline) attenuates IAV-induced acute respiratory distress syndrome in mice. We hypothesized inhibition of phosphatidylcholine synthesis would also impact the function of ATII cell mitochondria. To test this hypothesis, adult C57BL/6 mice of both sexes were inoculated intranasally with 10,000 pfu/mouse influenza A/WSN/33 (H1N1). Control mice were mock-infected with virus diluent. Mice were treated with saline vehicle or CDP-choline (100 µg/mouse i.p.) once daily from 1 to 5 days postinoculation (dpi). ATII cells were isolated by a standard lung digestion protocol at 6 dpi for analysis of mitochondrial function. IAV infection increased uptake of the glucose analog fludeoxyglucose F 18 by the lungs and caused a switch from oxidative phosphorylation to aerobic glycolysis as a primary means of ATII cell ATP synthesis by 6 dpi. Infection also induced ATII cell mitochondrial depolarization and shrinkage, upregulation of PGC-1α, decreased cardiolipin content, and reduced expression of mitofusin 1, OPA1, DRP1, complexes I and IV of the electron transport chain, and enzymes involved in cardiolipin synthesis. Daily CDP-choline treatment prevented the declines in oxidative phosphorylation, mitochondrial membrane potential, and cardiolipin synthesis resulting from IAV infection but did not fully reverse the glycolytic shift. CDP-choline also did not prevent the alterations in mitochondrial protein expression resulting from infection. Taken together, our data show ATII cell mitochondrial dysfunction after IAV infection results from impaired de novo phospholipid synthesis, but the glycolytic shift does not.

A survey on patient preferences towards CIED implantation.

BACKGROUND: Cardiac implantable electronic device (CIED) implantation is increasingly performed worldwide with improving safety. Outpatient CIED implantation has similar complication rates compared to those implants which are hospitalized. Here, we analyze patient preferences on discharge timing after CIED implantation. OBJECTIVE: To identify and understand the factors contributing to patient preferences towards same-day or next-day discharge after CIED implantation. METHODS: One hundred and two patients undergoing new CIED implants were included in the study at two separate hospitals in CT (CT group) and FL (FL group) from 2018-2019. A 7-question survey was administered to the patients after the procedure. Survey responses and demographic data were statistically analyzed. RESULTS: Seventy-four percent of CT group and 58% of the FL group responded with a 10 score (0-10) that they were ready to be discharged home the same day (p=0.09). Both groups reported a low number of patients feeling safer by having a remote monitor provided at the time of discharge (44% CT group, 28% FL group; p=0.123). The mean distance of patients living from the hospital in CT group (21.6 miles) was significantly lower than that for the FL group (35.5 miles); p=0.01. Hypertension (86% vs 52%; p=0.0002) and Diabetes mellitus (44% vs 21%; p=0.013) were more prevalent in the FL group compared to the CT group. CONCLUSION: Despite the influence of local practices, the majority of patients preferred same-day discharge after CIED implantation. Improved patient education regarding the ability of remote monitors to provide real-time response to acute events is needed.

Postexposure Liponucleotide Prophylaxis and Treatment Attenuates Acute Respiratory Distress Syndrome in Influenza-infected Mice.

There is an urgent need for new drugs for patients with acute respiratory distress syndrome (ARDS), including those with coronavirus disease (COVID-19). ARDS in influenza-infected mice is associated with reduced concentrations of liponucleotides (essential precursors for de novo phospholipid synthesis) in alveolar type II (ATII) epithelial cells. Because surfactant phospholipid synthesis is a primary function of ATII cells, we hypothesized that disrupting this process could contribute significantly to the pathogenesis of influenza-induced ARDS. The goal of this study was to determine whether parenteral liponucleotide supplementation can attenuate ARDS. C57BL/6 mice inoculated intranasally with 10,000 plaque-forming units/mouse of H1N1 influenza A/WSN/33 virus were treated with CDP (cytidine 5'-diphospho)-choline (100 µg/mouse i.p.) ± CDP -diacylglycerol 16:0/16:0 (10 µg/mouse i.p.) once daily from 1 to 5 days after inoculation (to model postexposure influenza prophylaxis) or as a single dose on Day 5 (to model treatment of patients with ongoing influenza-induced ARDS). Daily postexposure prophylaxis with CDP-choline attenuated influenza-induced hypoxemia, pulmonary edema, alterations in lung mechanics, impairment of alveolar fluid clearance, and pulmonary inflammation without altering viral replication. These effects were not recapitulated by the daily administration of CTP (cytidine triphosphate) and/or choline. Daily coadministration of CDP-diacylglycerol significantly enhanced the beneficial effects of CDP-choline and also modified the ATII cell lipidome, reversing the infection-induced decrease in phosphatidylcholine and increasing concentrations of most other lipid classes in ATII cells. Single-dose treatment with both liponucleotides at 5 days after inoculation also attenuated hypoxemia, altered lung mechanics, and inflammation. Overall, our data show that liponucleotides act rapidly to reduce disease severity in mice with severe influenza-induced ARDS.

Pulmonary function analysis in cotton rats after respiratory syncytial virus infection.

The cotton rat (Sigmodon hispidus) is an excellent small animal model for human respiratory viral infections such as human respiratory syncytial virus (RSV) and human metapneumovirus (HMPV). These respiratory viral infections, as well as other pulmonary inflammatory diseases such as asthma, are associated with lung mechanic disturbances. So far, the pathophysiological effects of viral infection and allergy on cotton rat lungs have not been measured, although this information might be an important tool to determine the efficacy of vaccine and drug candidates. To characterize pulmonary function in the cotton rat, we established forced oscillation technique in uninfected, RSV infected and HDM sensitized cotton rats, and characterized pulmonary inflammation, mucus production, pulmonary edema, and oxygenation. There was a gender difference after RSV infection, with females demonstrating airway hyper-responsiveness while males did not. Female cotton rats 2dpi had a mild increase in pulmonary edema (wet: dry weight ratios). At day 4 post infection, female cotton rats demonstrated mild pulmonary inflammation, no increase in mucus production or reduction in oxygenation. Pulmonary function was not significantly impaired after RSV infection. In contrast, cotton rats sensitized to HDM demonstrated airway hyper-responsiveness with a significant increase in pulmonary inflammation, increase in baseline tissue damping, and a decrease in baseline pulmonary compliance. In summary, we established baseline data for forced oscillation technique and other respiratory measures in the cotton rat and used it to analyze respiratory diseases in cotton rats.

Neurodevelopmental Characterization of Young Children Diagnosed with Niemann-Pick Disease, Type C1.

OBJECTIVE: Niemann-Pick disease type C1 (NPC1) is a lysosomal storage disease characterized by progressive neurodegeneration, with the age of diagnosis ranging from the prenatal period through adulthood. Although neurological symptoms usually precede genetic diagnosis, they do not necessarily prompt diagnosis in the early years. Few prospective data are available to describe neurological onset, including neurodevelopmental delays, in children with NPC1. This dearth of information hinders the planning and implementation of adequate monitoring and treatment for the neurodevelopmental sequelae of NPC1. METHOD: Twenty-nine infants, toddlers, and preschoolers younger than 6 years participated in a natural history study and were administered neurodevelopmental assessments using instruments commonly used for early intervention screening in the community. RESULTS: Twenty-two of 29 participants met the criteria for a significant delay of at least 1.5 SDs below the mean in at least one domain of development; the youngest children often met these criteria for a significant delay based on motor delays, but cognitive and language delays were also common. However, only 11 of the 22 participants were reported to receive early intervention services before study entry. CONCLUSION: Although neurological symptoms may not prompt the genetic diagnosis of NPC1, the current findings support the use of a multimethod approach to repeated assessments for young children with the diagnosis because of the frequency of developmental delays or decline in multiple domains. The diagnosis of NPC1 alone should qualify children for evaluation for early intervention services and consideration of investigational therapeutic interventions.

Palliative Radiation Therapy in Bladder Cancer-Importance of Patient Selection: A Retrospective Multicenter Study.

PURPOSE: To investigate the effectiveness of palliative pelvic radiation therapy (PRT) in patients with bladder cancer and identify factors associated with treatment outcome. METHODS AND MATERIALS: Patients with bladder cancer receiving PRT were identified retrospectively from 2 cancer centers between 2014 and 2017. Patients were stratified by age, stage, performance status, comorbidities, previous chemotherapy, previous radiation therapy, and radiation therapy protocol. Patients were followed up at 6 weeks after radiation therapy (RT). Median overall survival (mOS) from the last fraction of RT was calculated. Death within 30 days of RT or noncompletion of treatment were considered as futile treatment. RESULTS: Two hundred forty-one patients were identified as receiving PRT. A variety of RT protocols were used: 8 Gy in 1 fraction (11%), 21 Gy in 3 fractions (15%), 20 Gy in 5 fractions (18%), 36 Gy in 6 fractions (36%), and 27.5 to 30 Gy in 8 to 10 fractions (18%). Thirty-eight percent of patients were of poor performance status (Eastern Cooperative Oncology Group performance status ≥3), and 46.5% had significant comorbidities (Adult Comorbidity Evaluation-27 ≥2). The mOS from the last fraction of RT was 153 days (0-1289 days). The 30-day mortality after radiation therapy was 18% (n = 44), and the rate of incomplete planned radiation therapy treatment was 14% (n = 33). First follow-up information was available in 62% (n = 150) of patients. Median time to this follow-up was 49 days (14-238 days). At first follow-up at about 6 weeks after the last fraction of radiation therapy, symptoms were reported in 150 of 200 (75%) living patients; 80 of 150 (53%) patients reported improvement in symptoms after treatment. There were significant differences in mOS with stage, performance status, and comorbidities. CONCLUSIONS: One in 4 patients either did not complete the planned RT course or died within 30 days of treatment. These patients were unlikely to have received maximal benefit from treatment but may have experienced side effects, making treatment futile. Patients with good performance status and earlier stage disease survived longer. Patient selection and comprehensive assessment are crucial in selecting appropriate patients for treatment.

Novel variants in SPTAN1 without epilepsy: An expansion of the phenotype.

We describe two unrelated children with de novo variants in the non-erythrocytic alpha-II-spectrin (SPTAN1) gene who have hypoplastic brain structures, intellectual disability, and both fine and gross motor impairments. Using agnostic exome sequencing, we identified a nonsense variant creating a premature stop codon in exon 21 of SPTAN1, and in a second patient we identified an intronic substitution in SPTAN1 prior to exon 50 creating a new donor acceptor site. Neither of these variants has been described previously. Although some of these patients' features are consistent with the known SPTAN1 encephalopathy phenotype, these two children do not have epilepsy, in contrast to reports about nearly every other patient with heterozygous SPTAN1 variants and in all patients with a variant near the C-terminal coding region. Moreover, both children have abnormal thyroid function, which has not been previously reported in association with SPTAN1 variant. We present a detailed discussion of the clinical manifestations of these two unique SPTAN1 variants and provide evidence that both variants result in reduced mRNA expression despite different locations within the gene and clinical phenotypes. These findings expand the motor, cognitive, and behavioral spectrum of the SPTAN1-associated phenotype and invite speculation about underlying pathophysiologies.

Characterization of autism spectrum disorder and neurodevelopmental profiles in youth with XYY syndrome.

BACKGROUND: XYY syndrome is a sex chromosome aneuploidy that occurs in ~ 1/850 male births and is associated with increased risk for neurodevelopmental difficulties. However, the profile of neurodevelopmental impairments, including symptoms of autism spectrum disorder (ASD) in XYY remains poorly understood. This gap in knowledge has persisted in part due to lack of access to patient cohorts with dense and homogeneous phenotypic data. METHODS: We evaluated a single-center cohort of 64 individuals with XYY aged 5-25 years, using a standardized battery of cognitive and behavioral assessments spanning developmental milestones, IQ, adaptive behavior, academic achievement, behavioral problems, and gold-standard diagnostic instruments for ASD. Our goals were to (i) detail the neurodevelopmental profile of XYY with a focus on ASD diagnostic rates and symptom profiles, (ii) screen phenotypes for potential ascertainment bias effects by contrasting pre- vs. postnatally diagnosed XYY subgroups, and (iii) define major modules of phenotypic variation using graph-theoretical analysis. RESULTS: Although there was marked inter-individual variability, the average profile was characterized by some degree of developmental delay, and decreased IQ and adaptive behavior. Impairments were most pronounced for language and socio-communicative functioning. The rate of ASD was 14%, and these individuals exhibited autism symptom profiles resembling those observed in ASD without XYY. Most neurodevelopmental dimensions showed milder impairment among pre- vs. postnatally diagnosed individuals, with clinically meaningful differences in verbal IQ. Feature network analysis revealed three reliably separable modules comprising (i) cognition and academic achievement, (ii) broad domain psychopathology and adaptive behavior, and (iii) ASD-related features. CONCLUSIONS: By adding granularity to our understanding of neurodevelopmental difficulties in XYY, these findings assist targeted clinical assessment of newly identified cases, motivate greater provision of specialized multidisciplinary support, and inform future efforts to integrate behavioral phenotypes in XYY with neurobiology. TRIAL REGISTRATIONS: ClinicalTrials.gov NCT00001246 , "89-M-0006: Brain Imaging of Childhood Onset Psychiatric Disorders, Endocrine Disorders and Healthy Controls."

Lethal H1N1 influenza A virus infection alters the murine alveolar type II cell surfactant lipidome.

Alveolar type II (ATII) epithelial cells are the primary site of influenza virus replication in the distal lung. Development of acute respiratory distress syndrome in influenza-infected mice correlates with significant alterations in ATII cell function. However, the impact of infection on ATII cell surfactant lipid metabolism has not been explored. C57BL/6 mice were inoculated intranasally with influenza A/WSN/33 (H1N1) virus (10,000 plaque-forming units/mouse) or mock-infected with virus diluent. ATII cells were isolated by a standard lung digestion protocol at 2 and 6 days postinfection. Levels of 77 surfactant lipid-related compounds of known identity in each ATII cell sample were measured by ultra-high-performance liquid chromatography-mass spectrometry. In other mice, bronchoalveolar lavage fluid was collected to measure lipid and protein content using commercial assay kits. Relative to mock-infected animals, ATII cells from influenza-infected mice contained reduced levels of major surfactant phospholipids (phosphatidylcholine, phosphatidylglycerol, and phosphatidylethanolamine) but increased levels of minor phospholipids (phosphatidylserine, phosphatidylinositol, and sphingomyelin), cholesterol, and diacylglycerol. These changes were accompanied by reductions in cytidine 5'-diphosphocholine and 5'-diphosphoethanolamine (liponucleotide precursors for ATII cell phosphatidylcholine and phosphatidylethanolamine synthesis, respectively). ATII cell lamellar bodies were ultrastructurally abnormal after infection. Changes in ATII cell phospholipids were reflected in the composition of bronchoalveolar lavage fluid, which contained reduced amounts of phosphatidylcholine and phosphatidylglycerol but increased amounts of sphingomyelin, cholesterol, and protein. Influenza infection significantly alters ATII cell surfactant lipid metabolism, which may contribute to surfactant dysfunction and development of acute respiratory distress syndrome in influenza-infected mice.

Development, behavior, and biomarker characterization of Smith-Lemli-Opitz syndrome: an update.

BACKGROUND: Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive inborn error of cholesterol metabolism syndrome with neurocognitive manifestations. SLOS is the result of mutations in the gene encoding the 7-dehydrocholesterol reductase, which results in the elevation of the cholesterol precursor 7-dehydrocholesterol (7-DHC). Previous reports indicate that intellectual disability, behavioral disturbances, and autism symptoms are frequently part of the SLOS behavioral phenotype. In the current study, we characterize the developmental history and current behavior of 33 individuals with SLOS aged 4 to 23 years and report on biomarkers 7-DHC and 8-DHC in relation to cognition and behavior. METHODS: This was an observational case series, wherein participants with SLOS underwent extensive behavioral evaluation of cognitive function, adaptive function, autism symptoms, and problem behaviors, in addition to parent report of developmental milestones. Serum and CSF were contemporaneously obtained from the majority of participants. RESULTS: Developmental milestones such as walking, talking, and toileting were uniformly delayed. Overall levels of cognitive and adaptive functioning were low; no participant received adaptive behavior scores in the average range, and the mean level of cognitive functioning in the full sample was in the moderate range of impairment. Aggressive behavior was present in nearly half of participants. Although the majority of participants had elevated scores on the gold standard autism diagnostic instruments, only about half of participants received a clinical diagnosis of autism spectrum disorder. Finally, while CSF cholesterol was not found to correlate with cognitive or adaptive functioning, both serum and CSF 7-DHC and 8-DHC (and their ratios with cholesterol) were moderately and negatively correlated with functioning in this group. CONCLUSIONS: A history of developmental delay, followed by intellectual disability, is common in individuals with SLOS. Although autism spectrum disorder appears to be a frequent diagnosis in this population, it is apparent that the low level of functioning observed in SLOS may artificially inflate scores on standard autism assessments. Our findings further support that cholesterol precursors 7-DHC and 8-DHC are important biomarkers of the level of functioning in SLOS, especially regarding cognitive abilities, and thus may be to explore as mediators within the context of treatment trials. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00001721, NCT00064792.

Children with Autism Spectrum Disorder scan own-race faces differently from other-race faces.

It has been well documented that people recognize and scan other-race faces differently from faces of their own race. The current study examined whether this cross-racial difference in face processing found in the typical population also exists in individuals with Autism Spectrum Disorder (ASD). Participants included 5- to 10-year-old children with ASD (n=29), typically developing (TD) children matched on chronological age (n=29), and TD children matched on nonverbal IQ (n=29). Children completed a face recognition task in which they were asked to memorize and recognize both own- and other-race faces while their eye movements were tracked. We found no recognition advantage for own-race faces relative to other-race faces in any of the three groups. However, eye-tracking results indicated that, similar to TD children, children with ASD exhibited a cross-racial face-scanning pattern: they looked at the eyes of other-race faces longer than at those of own-race faces, whereas they looked at the mouth of own-race faces longer than at that of other-race faces. The findings suggest that although children with ASD have difficulty with processing some aspects of faces, their ability to process face race information is relatively spared.

Psychometric Properties of the Child's Reaction to Traumatic Events Scale-Revised in English and Lugandan.

Brief and age-appropriate measures of trauma-related symptoms are useful for identifying children in need of clinical services. The current study examines the psychometric properties of the 23-item Child's Reaction to Traumatic Events Scale-Revised (CRTES-R). The CRTES-R includes subscales assessing hyperarousal, avoidance and intrusion. To date, no studies have examined the psychometric properties of this revised measure or cross-cultural differences in its factor structure. Two samples of (a) children (ages 6-21) who had experienced a hurricane in the USA or Grenada (N = 135), and (b) Ugandan children (ages 8-17) who had experienced a variety of traumatic events (N = 339) completed the CRTES-R in English or Lugandan. Confirmatory factor analysis supported an empirically adjusted model with three modified latent factors in both the English (χ2/df = 1.34, CFI = .90, RMSEA = .05) and Lugandan samples (χ2/df = 1.45, CFI = .93, RMSEA = .04). Although the analysis supported separate hyperarousal, avoidance and intrusion subscales, the items that loaded on each factor differed from the original CRTES-R subscales. The English version of the CRTES-R showed good concurrent validity with the Kauai Recovery Index measure of trauma symptoms. Those using the CRTES-R to assess children's experiences of the different symptom types should consider using the empirically-derived subscales described in this paper; however, those who wish to capture a broad spectrum of PTSD symptoms should consider using all the original CRTES-R items and calculating a total score.

12-week, placebo-controlled trial of add-on riluzole in the treatment of childhood-onset obsessive-compulsive disorder.

Many children with childhood-onset obsessive-compulsive disorder (OCD) fail to respond adequately to standard therapies. Evidence from preclinical and clinical studies suggests that the glutamatergic neurotransmitter system might be an alternative treatment target. This study examined the efficacy of riluzole, a glutamatergic modulator, as an adjunctive therapy for children with treatment-resistant OCD. In a 12-week, double-blind, placebo-controlled study, 60 treatment-resistant children and adolescents (mean age=14.5 ± 2.4 years), with moderate to severe OCD (mean Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS)=28.2 ± 3.7), 17 of whom also had concomitant autism spectrum disorder, were randomized to receive riluzole (final dose of 100 mg/day) or placebo in addition to the existing treatment regimen. Fifty-nine subjects completed the randomized trial. Primary outcome measures were changes on the CY-BOCS, the Clinical Global Impressions Scale, and the Children's Global Assessment Scale. Riluzole was fairly well tolerated, although it was associated with one case of pancreatitis and five instances of slight increases in transaminases. All subjects showed significant reductions in CY-BOCS scores during treatment; however, there was no significant difference between placebo and riluzole on any of the primary or secondary outcome measures. The study failed to demonstrate superiority of riluzole over placebo as an adjunctive treatment for children with childhood-onset OCD. However, future studies may show benefits for less treatment-refractory children with fewer concomitant medications.

Repetitive behavior and restricted interests in young children with autism: comparisons with controls and stability over 2 years.

Restricted, repetitive and stereotyped patterns of behavior, interests and activities [RRBs] are among the core symptoms of autism spectrum disorders (ASD). Previous studies have indicated that RRBs differentiate ASD from other developmental disorders and from typical development. This study examined the presentation of RRBs as reported on the Repetitive Behavior Scale-Revised, a caregiver report, in children with ASD [separated into autism and Pervasive Developmental Disorder-Not Otherwise Specified groups] compared with children with nonspectrum developmental delays or typical development. We examined the role of age, cognitive functioning, sex and social communication impairment as they relate to RRBs. The stability of RRBs in children with autism was also examined over the course of 2 years. Results of the study confirmed that the amount and type of RRBs differs by diagnosis. Age, cognitive functioning, sex and social-communication impairment were not significant correlates. Among children with autism, RRBs remained stable over time.

Association of brain-derived neurotrophic factor (BDNF) haploinsufficiency with lower adaptive behaviour and reduced cognitive functioning in WAGR/11p13 deletion syndrome.

In animal studies, brain-derived neurotrophic factor (BDNF) is an important regulator of central nervous system development and synaptic plasticity. WAGR (Wilms tumour, Aniridia, Genitourinary anomalies, and mental Retardation) syndrome is caused by 11p13 deletions of variable size near the BDNF locus and can serve as a model for studying human BDNF haploinsufficiency (+/-). We hypothesized that BDNF+/- would be associated with more severe cognitive impairment in subjects with WAGR syndrome. Twenty-eight subjects with WAGR syndrome (6-28 years), 12 subjects with isolated aniridia due to PAX6 mutations/microdeletions (7-54 years), and 20 healthy controls (4-32 years) received neurocognitive assessments. Deletion boundaries for the subjects in the WAGR group were determined by high-resolution oligonucleotide array comparative genomic hybridization. Within the WAGR group, BDNF+/- subjects (n = 15), compared with BDNF intact (+/+) subjects (n = 13), had lower adaptive behaviour (p = .02), reduced cognitive functioning (p = .04), higher levels of reported historical (p = .02) and current (p = .02) social impairment, and higher percentage meeting cut-off score for autism (p = .047) on Autism Diagnostic Interview-Revised. These differences remained nominally significant after adjusting for visual acuity. Using diagnostic measures and clinical judgement, 3 subjects (2 BDNF+/- and 1 BDNF+/+) in the WAGR group (10.7%) were classified with autism spectrum disorder. A comparison group of visually impaired subjects with isolated aniridia had cognitive functioning comparable to that of healthy controls. In summary, among subjects with WAGR syndrome, BDNF+/- subjects had a mean Vineland Adaptive Behaviour Compose score that was 14-points lower and a mean intelligence quotient (IQ) that was 20-points lower than BDNF+/+ subjects. Our findings support the hypothesis that BDNF plays an important role in human neurocognitive development.