Predictors and Prospective Course of PANS: A Pilot Study Using Electronic Platforms for Data Collection.

Objectives: Little is known about the longitudinal course of pediatric acute-onset neuropsychiatric syndrome (PANS) because existing literature is primarily cross-sectional. To begin to address this gap, two digital platforms were used to prospectively monitor neuropsychiatric symptoms in children with PANS. The aim was to identify baseline clinical characteristics that would predict the course of neuropsychiatric symptoms over 12 weeks. We compared relative compliance between two electronic data acquisition platforms and evaluated agreement between parent-child ratings of symptoms. Methods: For 12 weeks, 20 children with PANS and their parents completed weekly rating scales of neuropsychiatric symptoms on Research Electronic Data Capture (REDCap) and concurrently parents completed tri-weekly ratings on My Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) Chart, a symptom monitoring website. Longitudinal data were analyzed by using regression analyses. Results: Greater duration of time between onset of PANS and study enrollment was associated with worsening of parent-rated neuropsychiatric symptoms over 12 weeks (p = 0.05). Higher scores on parents' Caregiver Burden Inventory at baseline predicted that children would report more severe symptoms over the 12-week period (p = 0.01). Compliance rates for parents were 86.3% for the weekly REDCap PANS Symptoms Rating Scale compared with 53.8% for the tri-weekly My PANDAS Chart ratings. There was moderate agreement between children and parents on the PANS Symptom Rating Scale (r = 0.55, p < 0.0001). Conclusion: Our study highlights the utility of electronic methods for tracking longitudinal symptoms in children with PANS and suggests that particular baseline characteristics (e.g., delay in identification and treatment of PANS, greater caregiver burden) may be indicative of a differential trajectory of PANS course, with more severe symptoms over the short term. clinicaltrials.gov NCT04382716.

Sertraline Effects on Striatal Resting-State Functional Connectivity in Youth With Obsessive-Compulsive Disorder: A Pilot Study.

OBJECTIVE: Foundational knowledge on neural circuitry underlying pediatric obsessive-compulsive disorder (OCD) and how it changes during standard treatment is needed to provide the basis for conceptualization and development of novel targeted treatments. This study explored the effects of sertraline, a selective serotonin reuptake inhibitor, on resting-state functional connectivity in cortico-striatal-thalamic-cortical circuits in pediatric OCD. METHOD: Medication-free youths with OCD (n = 14) and healthy controls (n = 14) were examined at baseline and 12 weeks with resting-state functional magnetic resonance imaging. Between scan sessions, participants with OCD received 12 weeks of sertraline. For each scan, seed-based whole-brain resting-state functional connectivity analyses were conducted with 6 striatal seeds. Analysis of variance examined the interaction between group and time on striatal connectivity, including cluster-based thresholding to correct for multiple tests. Connectivity changes within circuits identified in group analyses were correlated with clinical change. RESULTS: Two significant group-by-time effects in the OCD group showed increased striatal connectivity from baseline to 12 weeks compared with controls. Circuits demonstrating this pattern included the right putamen with the left frontal cortex and insula and the left putamen with the left frontal cortex and pre- and post-central cortices. Increase in connectivity in the left putamen circuit was significantly correlated with clinical improvement on the Children's Yale-Brown Obsessive-Compulsive Scale score (r = -0.58, p = .03). CONCLUSION: Sertraline appears to affect specific striatal-based circuits in pediatric OCD, and these changes in part could account for clinical improvement. Future work is needed to confirm these preliminary findings, which would facilitate identification of circuit-based targets for novel treatment development. CLINICAL TRIAL REGISTRATION INFORMATION: Effects of Sertraline on Brain Connectivity in Adolescents with OCD; https://clinicaltrials.gov/; NCT02797808.

Characterization of ADME gene variation in 21 populations by exome sequencing.

OBJECTIVE: Proteins involving absorption, distribution, metabolism, and excretion (ADME) play a critical role in drug pharmacokinetics. The type and frequency of genetic variation in the ADME genes differ among populations. The aim of this study was to systematically investigate common and rare ADME coding variation in diverse ethnic populations by exome sequencing. MATERIALS AND METHODS: Data derived from commercial exome capture arrays and next-generation sequencing were used to characterize coding variation in 298 ADME genes in 251 Northeast Asians and 1181 individuals from the 1000 Genomes Project. RESULTS: Approximately 75% of the ADME coding sequence was captured at high quality across the joint samples harboring more than 8000 variants, with 49% of individuals carrying at least one 'knockout' allele. ADME genes carried 50% more nonsynonymous variation than non-ADME genes (P=8.2×10) and showed significantly greater levels of population differentiation (P=7.6×10). Out of the 2135 variants identified that were predicted to be deleterious, 633 were not on commercially available ADME or general-purpose genotyping arrays. Forty deleterious variants within important ADME genes, with frequencies of at least 2% in at least one population, were identified as candidates for future pharmacogenetic studies. CONCLUSION: Exome sequencing was effective in accurately genotyping most ADME variants important for pharmacogenetic research, in addition to identifying rare or potentially de novo coding variants that may be clinically meaningful. Furthermore, as a class, ADME genes are more variable and less sensitive to purifying selection than non-ADME genes.

Use of Computer Vision Tools to Identify Behavioral Markers of Pediatric Obsessive-Compulsive Disorder: A Pilot Study.

OBJECTIVES: The clinical presentation of pediatric obsessive-compulsive disorder (OCD) is heterogeneous, which is a stumbling block to understanding pathophysiology and to developing new treatments. A major shift in psychiatry, embodied in the Research Domain Criteria (RDoC) initiative of National Institute of Mental Health, recognizes the pitfalls of categorizing mental illnesses using diagnostic criteria. Instead, RDoC encourages researchers to use a dimensional approach, focusing on narrower domains of psychopathology to characterize brain-behavior relationships. Our aim in this multidisciplinary pilot study was to use computer vision tools to record OCD behaviors and to cross-validate these behavioral markers with standard clinical measures. METHODS: Eighteen youths with OCD and 21 healthy controls completed tasks in an innovation laboratory (free arrangement of objects, hand washing, arrangement of objects on contrasting carpets). Tasks were video-recorded. Videos were coded by blind raters for OCD-related behaviors. Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) and other scales were administered. We compared video-recorded measures of behavior in OCD versus healthy controls and correlated video measures and clinical measures of OCD. RESULTS: Behavioral measures on the videos were significantly correlated with specific CY-BOCS dimension scores. During the free arrangement task, more time spent ordering objects and more moves of objects were both significantly associated with higher CY-BOCS ordering/repeating dimension scores. Longer duration of hand washing was significantly correlated with higher scores on CY-BOCS ordering/repeating and forbidden thoughts dimensions. During arrangement of objects on contrasting carpets, more moves and more adjustment of objects were significantly associated with higher CY-BOCS ordering/repeating dimension scores. CONCLUSION: Preliminary data suggest that measurement of behavior using video recording is a valid approach for quantifying OCD psychopathology. This methodology could serve as a new tool for investigating OCD using an RDoC approach. This objective, novel behavioral measurement technique may benefit both researchers and clinicians in assessing pediatric OCD and in identifying new behavioral markers of OCD. Clinical Trial Registry: Development of an Instrument That Monitors Behaviors Associated With OCD. NCT02866422. http://clinicaltrials.gov.

Circulating Concentrations of Growth Differentiation Factor 11 Are Heritable and Correlate With Life Span.

Growth differentiation factor 11 (GDF11) is member of the transforming growth factor ß (TGF-ß) superfamily of proteins. Circulating GDF11 concentrations appear to decline with age, and its depletion is associated with cardiac hypertrophy and other morbidities. Knowledge of GDF11 regulation is limited, and the effects of natural genetic variation on GDF11 levels are currently undefined. We tested whether genetic background determines serum GDF11 concentrations using two classical inbred mouse strains: C57BL/6J (B6) and BALB/cByJ (BALB). B6 mice exhibited significantly higher GDF11 levels than BALB mice, and these strain differences were consistent throughout the life span. Overall, interactions between age and genetic background determined GDF11 concentrations, which were unaffected by sex. We then surveyed a panel of 22 genetically diverse inbred mouse strains and discovered a sixfold range in GDF11 levels at middle age. We estimated that 74.52% of phenotypic variation in GDF11 levels was attributable to genetic background. We used the Mouse Phenome Database to screen for phenotypes that correlate with GDF11. Interestingly, GDF11 levels predicted median strain life spans. This study revealed high heritability of GDF11 levels. Furthermore, our correlative data suggest that GDF11 may serve as a novel predictor of mammalian life span.

Accurate interrogation of FCGR3A rs396991 in European and Asian populations using a widely available TaqMan genotyping method.

A polymorphism in the receptor for the Fc region of IgG, Fc γ-receptor IIIa (FcγRIIIa, FCGR3A rs396991), has been inconsistently shown in the literature to have an effect on response to monoclonal antibody therapy in several indications. The rs396991 (T/G) polymorphism leads to an F176V substitution and increased affinity for IgG. This variant has proven difficult to genotype accurately, primarily because of extensive homology between the FCGR3A and FCGR3B genes. We have shown that rs396991 can be genotyped by PCR amplification, followed by direct Sanger sequencing of the product, without coamplification of FCGR3B, and that the rs396991 TaqMan assay (C__25815666_10) agrees with Sanger sequencing results in 100% of European and Asian samples tested, but it has a small error rate in African and American populations. C__25815666_10 is therefore suitable to interrogate rs396991 in studies involving Europeans and Asians; however for other populations, the default genotyping method should be PCR followed by Sanger sequencing.

Impact of tactile function on upper limb motor function in children with Developmental Coordination Disorder.

This study investigated the presence of, and relationship between tactile dysfunction and upper limb motor function in children with Developmental Coordination Disorder (DCD) compared to typical developing (TD) children. Participants were 36 children aged 6-12 years. Presence of DCD (n=20) or TD (n=16) was confirmed using the Movement Assessment Battery for Children, second edition. All children participated in a comprehensive assessment of tactile registration (Semmes Weinstein Monofilaments); tactile spatial perception (Single Point Localisation (SPL) and two-point discrimination (2PD)); haptic perception (Stereognosis); speed of simple everyday manual tasks (Jebsen-Taylor Test of Hand Function (JTTHF)); and handwriting speed and accuracy (Evaluation Tool of Children's Handwriting (ETCH)). Compared to TD children, children with DCD demonstrated poorer localisation of touch in the non-dominant hand (p=0.04), slower speed of alphabet writing (p<0.05) and less legible handwriting (p<0.01), but no difference in speed of simple everyday manual tasks (JTTHF: p>0.05). Regression analysis showed that spatial tactile perception (SPL) predicted handwriting legibility (ETCH: r=0.11) and speed of functional tasks (JTTHF: r=0.33). These results suggest that tactile function, specifically single point localisation, should be a primary tactile assessment employed to determine reasons for upper limb motor difficulties experienced by children with DCD.

Exploring the roles of UGT1A1 and UGT1A3 in oral clearance of GSK2190915, a 5-lipoxygenase-activating protein inhibitor.

Pharmacokinetic variability in drug exposure is a concern for all compounds in development including those for the treatment of asthma and other respiratory disorders. Substantial variability in the oral clearance of GSK2190915, a 5-lipoxygenase-activating protein inhibitor that attenuates the production of leukotriene B4 and cysteinyl leukotrienes, is largely unaccounted for by clinical variables. A study of 41 patients, 78% (32/41) of whom were non-Hispanic whites, with mild to moderate asthma identified an association of UGT1A1*28 and UGT1A3*2 with the oral clearance of GSK2190915 (P=3.8×10⁻4 and 1.2×10⁻5, respectively). However, in a subsequent replication study of 403 non-Hispanic white patients with asthma, we failed to observe a statistically significant association between oral clearance of GSK2190915 and either UGT1A1*28 or UGT1A3*2 (P>0.05). Therefore, genetic effects that could explain the systemic exposure level variability of GSK2190915 were not identified.

Effectiveness of community- and workplace-based interventions to manage musculoskeletal-related sickness absence and job loss: a systematic review.

OBJECTIVE: To assess the effectiveness of interventions in community and workplace settings to reduce sickness absence and job loss in workers with musculoskeletal disorders (MSDs). METHODS: Relevant randomized controlled trials (RCTs) and cohort studies, published since 1990, were identified by screening citations from 35 earlier systematic reviews and by searching MEDLINE and Embase until April 2010. Effects were estimated by intervention category and other features, including study quality. RESULTS: Among 42 studies (including 34 RCTs), 27 assessed return to work (RTW), 21 duration of sickness absence and 5 job loss. Interventions included exercise therapy, behavioural change techniques, workplace adaptations and provision of additional services. Studies were typically small {median sample 107 [inter-quartile range (IQR) 77-148]} and limited in quality. Most interventions appeared beneficial: the median relative risk (RR) for RTW was 1.21 (IQR 1.00-1.60) and that for avoiding MSD-related job loss was 1.25 (IQR 1.06-1.71); the median reduction in sickness absence was 1.11 (IQR 0.32-3.20) days/month. However, effects were smaller in larger and better-quality studies, suggesting publication bias. No intervention was clearly superior, although effort-intensive interventions were less effective than simple ones. No cost-benefit analyses established statistically significant net economic benefits. CONCLUSION: As benefits are small and of doubtful cost-effectiveness, employers' practice should be guided by their value judgements about the uncertainties. Expensive interventions should be implemented only with rigorous cost-benefit evaluation planned from the outset. Future research should focus on the cost-effectiveness of simple, low-cost interventions, and further explore impacts on job retention.

Linkage analysis using single nucleotide polymorphisms.

We performed multipoint linkage analysis using 83 markers from the SNP Consortium (TSC) SNP linkage map in 3 regions covering 190 cM previously scanned with microsatellite markers and found to be linked to type 2 diabetes. Since the average linkage disequilibrium present in the TSC SNP marker clusters is relatively low, we assumed the intracluster genetic distances were a reasonable small nonzero distance (0.03 cM) and performed linkage analysis using GENEHUNTER PLUS and ASM linkage analysis software. We found that for the pedigree structures and missing data patterns in our samples the average information content in all three regions and the LOD score curves in two regions obtained from the TSC SNP markers were similar to results obtained from microsatellite marker maps with 10 cM average spacing. We also give an algorithm which extends the Lander-Green algorithm to permit multipoint linkage analysis of clusters of tightly linked markers with arbitrarily high levels of intracluster linkage disequilibrium.