Improving Identification of Tic Disorders in Children.

This study combines data from five studies in a quantitative modeling approach to improve identification of tics and tic disorders using two questionnaires (the Motor or Vocal Inventory of Tics and the Description of Tic Symptoms), administered to parents and children N = 1 , 307 . Combining final diagnoses (positive or negative for tic disorder) with data from recently developed questionnaires implemented to assist in the identification of tics and tic disorders in children, we investigate methods for predicting positive diagnosis while also identifying which items in the questionnaires are most predictive. Logistic regression and random forest models are compared using various summary statistics. We further discuss the differences in errors (false positives versus false negatives) in the specification of predictive model tuning parameters. Compared to logistic regression models, random forest models provided comparable and often superior predictive abilities and were also more useful in summarizing the contributions to predictions from individual questions. The combined analyses identified a subset of screener questions that were the best predictors of tic disorders; the identified questions differed based on parent or self-report. These results provide information to inform the future development of tools to screen for tics in a variety of healthcare and epidemiological settings.

Prebiotic Treatment in People With Schizophrenia.

BACKGROUND: Preliminary evidence suggests that people with schizophrenia have decreased relative abundance of butyrate-producing bacteria in the gut microbiota. Butyrate plays a critical role in maintaining the integrity of the gut-blood barrier and has a number of anti-inflammatory effects. This proof-of-concept study was designed to assess whether the addition of the oligofructose-enriched inulin (OEI) prebiotic: Prebiotin could increase the production of butyrate. METHODS: Twenty-seven people who met the criteria for either Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, schizophrenia or schizoaffective disorder were entered into a 10-day, double-blind, placebo-controlled, randomized clinical trial. The study was conducted on an inpatient unit to standardize the participant diet and environment. Participants were randomized to either OEI (4 g, 3 times a day) or a placebo (4 g of maltodextrin, 3 times a day). In order to assess the effect of OEI treatment on butyrate levels, participants underwent pretreatment and posttreatment OEI challenges. The primary outcome measure was relative change in postchallenge plasma butyrate levels after 10 days of OEI treatment. RESULTS: In both the intent-to-treat and completer analyses, OEI treatment was associated with a greater number of participants who met the OEI challenge responder criteria than those treated with placebo. OEI treatment was also associated with an increase in baseline butyrate levels (effect size for the group difference in the change of baseline butyrate levels was 0.58). CONCLUSIONS: We were able to demonstrate that treatment with the prebiotic OEI selectively increased the level of plasma butyrate in people with schizophrenia.Trial registration:ClinicalTrials.gov identifier NCT03617783.

Performance of a Tic Screening Tool (MOVeIT) in Comparison to Expert Clinician Assessment in a Developmental-Behavioral Pediatrics Clinic Sample.

Youth with intellectual and developmental disabilities typically have higher rates of tics and stereotypies compared to children with otherwise typical development. Differentiating between these two pediatric movement disorders can be challenging due to overlapping clinical features, but is relevant due to distinct treatment modalities. The current study evaluated sensitivity and specificity of a tic screening measure, the Motor or Vocal Inventory of Tics (MOVeIT) in a pediatric sample enriched for stereotypy and tics. Children (n=199, age 2-15 years old) receiving care in a developmental-behavioral pediatrics clinic underwent a gold-standard diagnostic assessment by a tic expert; these evaluations were compared to the MOVeIT. The MOVeIT demonstrated good sensitivity (89.8%) and relatively lower specificity (57.1%) compared to tic expert for detecting tics in the overall sample. Specificity of the MOVeIT to identify tics improved to 75% when excluding children with co-occurring stereotypy. For children with tics and co-occurring stereotypy, sensitivity remained high (91.9%) but specificity was low (39.1%). The area under the curve (AUC) value to detect tics on the MOVeIT compared to the tic expert gold standard was significantly higher for children without stereotypy (AUC=85.7%) than those with stereotypy (AUC=64.3%, p <0.01). Overall, the ability to detect tics was better in those without co-occurring stereotypy symptoms. Further work is needed to establish the utility of the MOVeIT in populations where there is a high likelihood of co-occurring tics and stereotypy and in general population settings. Accurate distinction between tics and stereotypy will guide choices for intervention and anticipatory guidance for families.

Identifying novel data-driven subgroups in congenital heart disease using multi-modal measures of brain structure.

Individuals with congenital heart disease (CHD) have an increased risk of neurodevelopmental impairments. Given the hypothesized complexity linking genomics, atypical brain structure, cardiac diagnoses and their management, and neurodevelopmental outcomes, unsupervised methods may provide unique insight into neurodevelopmental variability in CHD. Using data from the Pediatric Cardiac Genomics Consortium Brain and Genes study, we identified data-driven subgroups of individuals with CHD from measures of brain structure. Using structural magnetic resonance imaging (MRI; N = 93; cortical thickness, cortical volume, and subcortical volume), we identified subgroups that differed primarily on cardiac anatomic lesion and language ability. In contrast, using diffusion MRI (N = 88; white matter connectivity strength), we identified subgroups that were characterized by differences in associations with rare genetic variants and visual-motor function. This work provides insight into the differential impacts of cardiac lesions and genomic variation on brain growth and architecture in patients with CHD, with potentially distinct effects on neurodevelopmental outcomes.

Neurobehavioral Phenotype of Children With Congenital Myotonic Dystrophy.

BACKGROUND AND OBJECTIVES: To describe the neurobehavioral phenotype of congenital myotonic dystrophy. Congenital myotonic dystrophy (CDM) is the most severe form of myotonic dystrophy, characterized by symptom presentation at birth and later, cognitive impairment, autistic features, and disordered sleep. METHODS: The neurobehavioral phenotype was assessed in this cross-sectional study by a neuropsychological battery consisting of the Wechsler Preschool and Primary Scale of Intelligence, Third Edition, Weschler Intelligence Scale for Children, Fourth Edition, Vineland Adaptive Behavior Scale, Second Edition (Vineland-II), Behavior Rating Inventory of Executive Function including preschool and teacher reports, Autism Spectrum Screening Questionnaire, Social Communication Scale, and Repetitive Behavior Scale-Revised. Sleep quality was evaluated with the Pediatric Sleep Questionnaire and Pediatric Daytime Sleepiness Scale. RESULTS: Fifty-five children with CDM, ages 5 weeks to 14 years, were enrolled. The mean age and (CTG)n repeats (±SD) were 6.4 ± 3.8 years and 1,263 ± 432, respectively. The mean IQ was 64.1 ± 14.9 on the Weschler scales with 65.6% of participants falling in the extremely low range for IQ. Adaptive functioning was significantly low for 57.1% of participants (n = 20). Caregiver report of executive functioning indicated 23.1% (9/39) of participants had clinically elevated levels of dysfunction, though teacher report was discrepant and indicated 53.3% of participants with CDM fell in this range (8/15). Spearman correlations were strongly positive (p ≤ 0.05) for estimated full scale IQ, overall adaptive functioning and with daily living and socialization domain standard scores on the Vineland-II ranging from r = 0.719 to r = 0.849 for all ages. Aspects of executive function were directly related to features of autism and sleep quality. Social communication was inversely related to all aspects of daily functioning, except communication, and directly related to aspects of autism behavior. DISCUSSION: Depressed IQ, adaptive skills, and executive functioning, poor sleep quality, and features of autism and altered social functioning individually describe different aspects of the neurobehavioral phenotype in CDM. These neurobehavioral and sleep measures could help quantitatively measure and assess the burden of cognitive impairment in CDM.

Assessing the integrity of auditory sensory memory processing in CLN3 disease (Juvenile Neuronal Ceroid Lipofuscinosis (Batten disease)): an auditory evoked potential study of the duration-evoked mismatch negativity (MMN).

BACKGROUND: We interrogated auditory sensory memory capabilities in individuals with CLN3 disease (juvenile neuronal ceroid lipofuscinosis), specifically for the feature of "duration" processing. Given decrements in auditory processing abilities associated with later-stage CLN3 disease, we hypothesized that the duration-evoked mismatch negativity (MMN) of the event related potential (ERP) would be a marker of progressively atypical cortical processing in this population, with potential applicability as a brain-based biomarker in clinical trials. METHODS: We employed three stimulation rates (fast: 450 ms, medium: 900 ms, slow: 1800 ms), allowing for assessment of the sustainability of the auditory sensory memory trace. The robustness of MMN directly relates to the rate at which the regularly occurring stimulus stream is presented. As presentation rate slows, robustness of the sensory memory trace diminishes. By manipulating presentation rate, the strength of the sensory memory trace is parametrically varied, providing greater sensitivity to detect auditory cortical dysfunction. A secondary hypothesis was that duration-evoked MMN abnormalities in CLN3 disease would be more severe at slower presentation rates, resulting from greater demand on the sensory memory system. RESULTS: Data from individuals with CLN3 disease (N = 21; range 6-28 years of age) showed robust MMN responses (i.e., intact auditory sensory memory processes) at the medium stimulation rate. However, at the fastest rate, MMN was significantly reduced, and at the slowest rate, MMN was not detectable in CLN3 disease relative to neurotypical controls (N = 41; ages 6-26 years). CONCLUSIONS: Results reveal emerging insufficiencies in this critical auditory perceptual system in individuals with CLN3 disease.

Qualitative Examination of the Experience of Perceived Injustice Following Disabling Occupational Injury.

PURPOSE: The primary objective of this study was to explore individuals' perspectives on the factors, situations or events that contributed to their perceptions of injustice following occupational injury. MATERIALS AND METHODS: The study sample consisted of 30 participants (18 women, 12 men) who had submitted a time-loss claim for a work-related musculoskeletal injury. Participants with elevated scores on a measure of perceived injustice were interviewed about the factors that contributed to their sense of injustice. A thematic analysis was conducted to identify the broad classes of situations or events that participants experienced as unjust in the weeks following occupational injury. RESULTS: Three dominant themes emerged from the interviews: (1) Invalidation, (2) Undeserved suffering and (3) Blame. Inductively derived subthemes reflected specific dimensions of post-injury experiences that contributed to participants' sense of injustice. CONCLUSIONS: Given that suffering and invalidating communication are potentially modifiable factors, there are grounds for optimism that intervention approaches can be developed to prevent or reduce perceptions of injustice in the aftermath of debilitating injury. The development of intervention approaches that are effective in preventing or reducing perceptions of injustice holds promise of contributing to more positive recovery outcomes in individuals who have sustained debilitating work injuries.

Change in BMI in Children Over the First 30 Months After the Start of the SARS-CoV-2 Pandemic.

Our study aim was to assess body mass index (BMI) change in children in the immediate 6 months of the pandemic, to follow longitudinal BMI change up to 30 months after the pandemic start, and to identify sociodemographic factors associated with these changes. Our study included a retrospective chart review of 1298 children 2 to 18 years old with office visits at an Indianapolis primary care clinic. Body mass index and sociodemographic information were collected at visits during 3 time periods: Prepandemic (March 1, 2019-February 28, 2020), Early Pandemic (June 1, 2020-November 30, 2020), and Late Pandemic (December 1, 2020-September 30, 2022). Data analysis indicated statistically significant increases in BMI monthly rate of change from Prepandemic to Early Pandemic periods. Interestingly, BMI rate of change stabilized from Early Pandemic to Late Pandemic periods but remained positive, suggesting children had slower, but persistent, continued BMI increase after the pandemic initiation.

Net effects explains the benefits to children from maternal fish consumption despite methylmercury in fish.

In 2001 the U.S. Food and Drug Administration (FDA) issued precautionary advice to pregnant women to limit fish consumption over concern that the methylmercury content might harm their children's neurodevelopment. This concern was based largely on results from an epidemiological study of mothers primarily exposed to methylmercury from consuming pilot whale. Subsequently, FDA and the World Health Organization/Food and Agriculture Organization (WHO/FAO) undertook independent assessments of fish consumption that considered net effects from both fish nutrients, primarily omega-3 fatty acids, as beneficial and methylmercury as harmful. Both assessments estimated that when mothers regularly consume fish during pregnancy, their children are likely to have improved neurodevelopment compared to children of non-fish eaters despite their exposure to methylmercury. These estimated improvements included gains of two to over five full scale IQ points from levels of maternal consumption that are achievable in most of the world. Consistent with those estimates, human research on fish consumption and child neurodevelopment from more than 200,000 mother-child pairs now collectively reports 51 beneficial associations with neurodevelopmental outcomes and three adverse associations, the latter with no discernable pattern. These associations include full scale IQ gains similar to, or somewhat higher than, those estimated by FDA and FAO/WHO. Also consistent with the FDA and FAO/WHO estimates, research has reported beneficial associations with fish consumption when pregnant women are exposed to methylmercury from fish in excess of the U.S. Environmental Protection Agency's (EPA) Reference Dose (RfD). Our analysis evaluates how the net effects approach as utilized by FDA and FAO/WHO provides a holistic explanation for these results with implications for public health policy. This concordance of net effects modeling and empirical scientific evidence supports a clarification of current public health recommendations to focus on greater fish consumption by pregnant women for their children's neurodevelopment.

Assessing the integrity of auditory sensory memory processing in CLN3 disease (Juvenile Neuronal Ceroid Lipofuscinosis (Batten disease)): An auditory evoked potential study of the duration-evoked mismatch negativity (MMN).

Background: We interrogated auditory sensory memory capabilities in individuals with CLN3 disease (juvenile neuronal ceroid lipofuscinosis), specifically for the feature of "duration" processing, a critical cue in speech perception. Given decrements in speech and language skills associated with later-stage CLN3 disease, we hypothesized that the duration-evoked mismatch negativity (MMN) of the event related potential (ERP) would be a marker of progressively atypical cortical processing in this population, with potential applicability as a brain-based biomarker in clinical trials. Methods: We employed three stimulation rates (fast: 450 ms, medium: 900 ms, slow: 1800 ms), allowing for assessment of the sustainability of the auditory sensory memory trace. The robustness of MMN directly relates to the rate at which the regularly occurring stimulus stream is presented. As presentation rate slows, robustness of the sensory memory trace diminishes. By manipulating presentation rate, the strength of the sensory memory trace is parametrically varied, providing greater sensitivity to detect auditory cortical dysfunction. A secondary hypothesis was that duration-evoked MMN abnormalities in CLN3 disease would be more severe at slower presentation rates, resulting from greater demand on the sensory memory system. Results: Data from individuals with CLN3 disease (N=21; range 6-28 years of age) showed robust MMN responses (i.e., intact auditory sensory memory processes) at the medium stimulation rate. However, at the fastest rate, MMN was significantly reduced, and at the slowest rate, MMN was not detectable in CLN3 disease relative to neurotypical controls (N=41; ages 6-26 years). Conclusions: Results reveal emerging insufficiencies in this critical auditory perceptual system in individuals with CLN3 disease.

Kombucha tea as an anti-hyperglycemic agent in humans with diabetes - a randomized controlled pilot investigation.

Introduction: Kombucha is a popular fermented tea that has attracted considerable attention due, in part, to its suggested health benefits. Previous results from animal models led us to hypothesize kombucha may reduce blood sugar levels in humans with diabetes. The objective of this pilot clinical study was to evaluate kombucha for its anti-hyperglycemic activities in adults with diabetes mellitus type II. Methods: The study was organized as a prospective randomized double-blinded crossover study at a single-center urban hospital system. Participants (n = 12) were instructed to consume either a kombucha product or a placebo control (each 240 mL) for 4 weeks. After an 8-week washout period, participants consumed the alternate product. Fasting blood glucose levels were self-determined at baseline and at 1 and 4 weeks during each treatment period. Secondary health outcomes, including overall health, insulin requirement, gut health, skin health, mental health, and vulvovaginal health were measured by questionnaire at the same time points. The kombucha microbiota was assessed by selective culturing and 16S rRNA gene (bacteria) and ITS (fungi) sequencing. Fermentation end products were assessed by HPLC. Statistical significance of changes in fasting blood glucose was determined using paired, two-tailed student's t-tests. Results: Kombucha lowered average fasting blood glucose levels at 4 weeks compared to baseline (164 vs. 116 mg/dL, p = 0.035), whereas the placebo did not (162 vs. 141 mg/dL, p = 0.078). The kombucha microbiota, as assessed by cultural enumeration, was mainly comprised of lactic acid bacteria, acetic acid bacteria, and yeast, with each group present at about 106 colony forming units (CFU)/mL. Likewise, 16S rRNA gene sequencing confirmed that lactic acid and acetic acid bacteria were the most abundant bacteria, and ITS sequencing showed Dekkera was the most abundant yeast. The primary fermentation end products were lactic and acetic acids, both less than 1%. Ethanol was present at 1.5%. Discussion: Although this pilot study was limited by a small sample size, kombucha was associated with reduced blood glucose levels in humans with diabetes. Larger follow-up studies are warranted. Clinical trial registration: ClinicalTrials.gov, identifier NCT04107207.

Clozapine and neutrophil response in patients of African descent: A six-month, multinational, prospective, open-label clinical trial.

INTRODUCTION: Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia, but it is markedly underutilized, particularly in the US Black population, partly because of concern over clozapine-associated low absolute neutrophil count (ANC). People of African descent have a lower normative ANC range than the White population, which is associated with a specific "ACKR1-null" ("Duffy null") CC genotype (SNP rs2814778) on the ACKR1 gene, termed benign ethnic neutropenia (BEN). The range of ANC variability and safety of clozapine have not been established in people with BEN or examined prospectively in people of African descent. METHODS: We completed a multisite, 6-month, prospective, open-label clinical trial of clozapine treatment in people of African descent with schizophrenia spectrum disorders for whom clozapine was clinically indicated, with or without the ACKR1-null genotype. We examined clozapine safety and weekly ANC during clozapine treatment and evaluated ANC variability by ACKR1-null genotype, sex, study site, and clozapine dosing using repeated measures analysis of covariance. Genotype was assayed using TaqMan® technology. RESULTS: We enrolled 274 participants, of whom 227 (82.8 %) completed 6 months of clozapine treatment. There was one case of severe neutropenia (<500 cells/mm3) (0.36 %) over 1467.6 person-months of clozapine exposure. This participant recovered without sequelae after discontinuation of clozapine. Of the 249 participants with known genotypes, 199 (79.9 %) had the ACKR1-null genotype. Neutropenia (<1500 cells/mm3) occurred significantly more often in the ACKR1-null group (33 % [65/199]) than in those with the T allele (6 % (3/50); p < 0.001). Fourteen (5 %) patients discontinued due to adverse events. Rates of infection and fever were low and sialorrhea was the commonest side effect (N = 187, 68 %). CONCLUSION: To our knowledge, this is the largest prospective clozapine trial in people of African descent. Severe neutropenia was rare, despite the high prevalence (80 %) of the ACKR1-null genotype. Our findings suggest that clozapine can be used safely in Black patients including those with BEN.

Brief youth self-report screener for tics: Can a subscale of the Motor tic, Obsession and compulsion, and Vocal tic Evaluation Survey (MOVES) identify tic disorders in youth?

Tics are unwanted, repetitive movements and sounds that frequently present during childhood. They are typically brief and purposeless, but can create significant distress for individuals, and often co-occur with other neuropsychiatric conditions. Thus, early identification of tics is warranted. Unfortunately, tics are often misdiagnosed, and because tics may wax and wane, identification can be difficult, especially in the context of routine clinical visits. There are limited tools that can be used to reliably identify tics in clinical practice, especially in non-specialty settings. The purpose of the current study was to evaluate the performance of the Motor tic, Obsession and compulsion, and Vocal tic Evaluation Survey (MOVES), a self-report scale with some support as a screening tool. In addition, the performance of a subset of questions (the MOVES-6) was evaluated for rapid screening. Participants were recruited across two study sites and included children and adolescents diagnosed with Tourette syndrome (n = 151) or another persistent tic disorder (n = 10) and community controls (n = 74). Results suggest both the MOVES and the MOVES-6 have high sensitivity (90% and 88%, respectively) and at least acceptable specificity (77% and 86%, respectively) compared with expert assessment of tic disorders, suggesting that both versions can identify tic disorders without high proportions of false negatives. Both versions were highly sensitive with acceptable specificity regardless of sex, race/ethnicity, and age. The MOVES and MOVES-6 show promise as a screener for tics or tic disorders, but additional research is needed, particularly in a general population setting.

Recommendations on the Selection, Development, and Modification of Performance Outcome Assessments: A Good Practices Report of an ISPOR Task Force.

In evaluating the clinical benefit of new therapeutic interventions, it is critical that the treatment outcomes assessed reflect aspects of health that are clinically important and meaningful to patients. Performance outcome (PerfO) assessments are measurements based on standardized tasks actively undertaken by a patient that reflect physical, cognitive, sensory, and other functional skills that bring meaning to people's lives. PerfO assessments can have substantial value as drug development tools when the concepts of interest being measured best suit task performance and in cases where patients may be limited in their capacity for self-report. In their development, selection, and modification, including the evaluation and documentation of validity, reliability, usability, and interpretability, the good practice recommendations established for other clinical outcome assessment types should continue to be followed, with concept elicitation as a critical foundation. In addition, the importance of standardization, and the need to ensure feasibility and safety, as well as their utility in patient groups, such as pediatric populations, or those with cognitive and psychiatric challenges, may enhance the need for structured pilot evaluations, additional cognitive interviewing, and evaluation of quantitative data, such as that which would support concept confirmation or provide ecological evidence and other forms of construct evidence within a unitary approach to validity. The opportunity for PerfO assessments to inform key areas of clinical benefit is substantial and establishing good practices in their selection or development, validation, and implementation, as well as how they reflect meaningful aspects of health is critical to ensuring high standards and in furthering patient-focused drug development.

Teacher Knowledge of Tourette Syndrome and Associated Factors.

BACKGROUND: Tourette syndrome (TS) is associated with learning disabilities and educational impairment. Teacher knowledge about TS may have a positive impact on students with TS, but factors associated with teacher knowledge of TS are not known. METHODS: In this cross-sectional study, teachers of youth with TS and of a community control group completed a Teacher Understanding of Tourette Syndrome Survey (TUTS), a pilot questionnaire enquiring about self-perceived understanding, teacher knowledge, and sources of information. We compared TUTS scores between TS and control groups and between those who did and did not use specific sources of information about TS using Wilcoxon rank-sum tests. Bivariate correlation analyses were used to evaluate associations between teacher knowledge and potential contributing factors. RESULTS: Data from 114 teachers of children with TS and 78 teachers of control subjects were included. Teachers of youth with TS had significantly more knowledge, had higher self-perceived understanding, and used more sources of information than teachers of the control group. Teachers who knew of the Tourette Association of America and who gathered information themselves had higher knowledge about TS than those who did not. CONCLUSION: Teachers of children with TS know more about TS and use more sources to learn about TS than teachers of children without TS.

Association of Potentially Damaging De Novo Gene Variants With Neurologic Outcomes in Congenital Heart Disease.

Importance: Neurodevelopmental disabilities are commonly associated with congenital heart disease (CHD), but medical and sociodemographic factors explain only one-third of the variance in outcomes. Objective: To examine whether potentially damaging de novo variants (dDNVs) in genes not previously linked to neurodevelopmental disability are associated with neurologic outcomes in CHD and, post hoc, whether some dDNVs or rare putative loss-of-function variants (pLOFs) in specific gene categories are associated with outcomes. Design, Setting, and Participants: This cross-sectional study was conducted from September 2017 to June 2020 in 8 US centers. Inclusion criteria were CHD, age 8 years or older, and available exome sequencing data. Individuals with pathogenic gene variants in known CHD- or neurodevelopment-related genes were excluded. Cases and controls were frequency-matched for CHD class, age group, and sex. Exposures: Heterozygous for (cases) or lacking (controls) dDNVs in genes not previously associated with neurodevelopmental disability. Participants were separately stratified as heterozygous or not heterozygous for dDNVs and/or pLOFs in 4 gene categories: chromatin modifying, constrained, high level of brain expression, and neurodevelopmental risk. Main Outcomes and Measures: Main outcomes were neurodevelopmental assessments of academic achievement, intelligence, fine motor skills, executive function, attention, memory, social cognition, language, adaptive functioning, and anxiety and depression, as well as 7 structural, diffusion, and functional brain magnetic resonance imaging metrics. Results: The study cohort included 221 participants in the post hoc analysis and 219 in the case-control analysis (109 cases [49.8%] and 110 controls [50.2%]). Of those 219 participants (median age, 15.0 years [IQR, 10.0-21.2 years]), 120 (54.8%) were male. Cases and controls had similar primary outcomes (reading composite, spelling, and math computation on the Wide Range Achievement Test, Fourth Edition) and secondary outcomes. dDNVs and/or pLOFs in chromatin-modifying genes were associated with lower mean (SD) verbal comprehension index scores (91.4 [20.4] vs 103.4 [17.8]; P = .01), Social Responsiveness Scale, Second Edition, scores (57.3 [17.2] vs 49.4 [11.2]; P = .03), and Wechsler Adult Intelligence Scale, Fourth Edition, working memory scores (73.8 [16.4] vs 97.2 [15.7]; P = .03), as well as higher likelihood of autism spectrum disorder (28.6% vs 5.2%; P = .01). dDNVs and/or pLOFs in constrained genes were associated with lower mean (SD) scores on the Wide Range Assessment of Memory and Learning, Second Edition (immediate story memory: 9.7 [3.7] vs 10.7 [3.0]; P = .03; immediate picture memory: 7.8 [3.1] vs 9.0 [2.9]; P = .008). Adults with dDNVs and/or pLOFs in genes with a high level of brain expression had greater Conners adult attention-deficit hyperactivity disorder rating scale scores (mean [SD], 55.5 [15.4] vs 46.6 [12.3]; P = .007). Conclusions and Relevance: The study findings suggest neurodevelopmental outcomes are not associated with dDNVs as a group but may be worse in individuals with dDNVs and/or pLOFs in some gene sets, such as chromatin-modifying genes. Future studies should confirm the importance of specific gene variants to brain function and structure.

Oral microbiome and risk of incident head and neck cancer: A nested case-control study.

OBJECTIVES: This nested case-control study in the NIH-AARP Diet and Health Study was carried out to prospectively investigate the relationship of oral microbiome with head and neck cancer (HNC). MATERIALS AND METHODS: 56 incident HNC cases were identified, and 112 controls were incidence-density matched to cases. DNA extracted from pre-diagnostic oral wash samples was whole-genome shotgun metagenomic sequenced to measure the overall oral microbiome. ITS2 gene qPCR was used to measure the presence of fungi. ITS2 gene sequencing was performed on ITS2 gene qPCR positive samples. We computed taxonomic and functional alpha-diversity and beta-diversity metrics. The presence and relative abundance of groups of red-complex (e.g., Porphyromonas gingivalis) and/or orange-complex (e.g., Fusobacterium nucleatum) periodontal pathogens were compared between cases and controls using conditional logistic regression models and MiRKAT. RESULTS: Participants with higher taxonomic microbial alpha-diversity had a non-statistically significant decreased risk of HNC. No case-control differences were found for beta diversity by MiRKAT model (all p > 0.05). A greater relative abundance of red-complex periodontal pathogens (OR = 0.51, 95 % CI = 0.26-1.00), orange-complex (OR = 0.38, 95 % CI = 0.18-0.83), and both complexes' pathogens (OR = 0.32, 95 % CI = 0.14-0.75), were associated with reduced risk of HNC. The presence of oral fungi was also strongly associated with reduced risk of HNC compared with controls (OR = 0.39, 95 % CI = 0.17-0.92). CONCLUSION: Greater taxonomic alpha-diversity, the presence of oral fungi, and the presence or relative abundance of multiple microbial species, including the red- and orange-complex periodontal pathogens, were associated with reduced risk of HNC. Future studies with larger sample sizes are needed to evaluate these associations.

Approaches to the Assessment of Clinical Benefit of Treatments for Conditions That Have Heterogeneous Symptoms and Impacts: Potential Applications in Rare Disease.

OBJECTIVES: Evaluating the clinical benefit of interventions for conditions with heterogeneous symptom and impact presentations is challenging. The same condition can present differently across and within individuals over time. This occurs frequently in rare diseases. The purpose of this review was to identify (1) assessment approaches used in clinical trials to address heterogeneous manifestations that could be relevant in rare disease research and (2) US Food and Drug Administration (FDA)-approved labeling claims that used these approaches. METHODS: A targeted literature review was conducted examining peer-reviewed publications and FDA-approved labeling claims from January 2002 to July 2020, focusing on claims incorporating clinical outcome assessments. Approaches were then assessed for their potential application in rare diseases. RESULTS: A total of 6 assessment approaches were identified: composite or other multicomponent endpoints, multidomain responder index, most bothersome symptom (MBS), goal attainment scaling, sliding dichotomy, and adequate relief. A total of 59 FDA-approved labeling claims associated with these approaches were identified: composite or other multicomponent endpoints (n=49), MBS (n=9), and adequate relief (n=1). A total of 10 FDA-approved labeling claims, all using multicomponent endpoints, were identified for rare diseases. CONCLUSIONS: Multicomponent, MBS, and adequate relief have been included in FDA-approved labeling claims. Multicomponent endpoints, including composite endpoints, were the most frequent way to address heterogeneous manifestations of both common and rare diseases. MBS may be acceptable to regulators, whereas multidomain responder index is unlikely to be. The goal attainment scaling and adequate relief approaches may have potential utility in rare disease trials, assuming the theoretical and statistical challenges inherent in each approach are managed.

Validation of the Diagnostic Interview Schedule for Children (DISC-5) Tic Disorder and Attention-Deficit/Hyperactivity Disorder Modules.

Effective methods to assess mental disorders in children are necessary for accurate prevalence estimates and to monitor prevalence over time. This study assessed updates of the tic disorder and attention-deficit/hyperactivity disorder (ADHD) modules of the Diagnostic Interview Schedule for Children, Version 5 (DISC-5) that reflect changes in diagnostic criteria in the Diagnostic and Statistical Manual of Mental Disorders (Fifth edition, DSM-5). The DISC-5 tic disorder and ADHD parent- and child-report modules were compared to expert clinical assessment for 100 children aged 6-17 years (40 with tic disorder alone, 17 with tic disorder and ADHD, 9 with ADHD alone, and 34 with neither) for validation. For the tic disorder module, parent-report had high (>90%) sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy, while the youth-report had high specificity and PPV, moderate accuracy (81.4%), and lower sensitivity (69.8%) and NPV (67.3%). The ADHD module performed less well: parent-report had high NPV (91.4%), moderate sensitivity (80.8%), and lower specificity (71.6%), PPV (50.0%), and accuracy (74.0%); youth-report had moderate specificity (82.8%) and NPV (88.3%), and lower sensitivity (65.0%), PPV (54.2%), and accuracy (78.6%). Adding teacher-report of ADHD symptoms to DISC-5 parent-report of ADHD increased sensitivity (94.7%) and NPV (97.1%), but decreased specificity (64.2%), PPV (48.7%), and accuracy (72.2%). These findings support using the parent-report tic disorder module alone or in combination with the child report module in future research and epidemiologic studies; additional validation studies are warranted for the ADHD module.

Longitudinal Cognitive Outcomes in Children With HIV in Zambia: 2-Year Outcomes From the HIV-Associated Neurocognitive Disorders in Zambia (HANDZ) Study.

OBJECTIVE: To describe longitudinal outcomes and predictors of cognitive outcomes in children with HIV in Zambia. BACKGROUND: Multiple studies have shown that children with HIV are at risk for impaired cognition. However, there are limited data on longitudinal cognitive outcomes in children with HIV. METHODS: We conducted a prospective cohort study of 208 perinatally infected children with HIV ages 8-17 years, all treated with antiretroviral therapy, and 208 HIV-exposed uninfected controls. Participants were followed for 2 years. Cognition was assessed with a custom NIH Toolbox Cognition Battery, and tests were combined to generate a Summary Cognition Score (SCS). The contribution of potential risk factors to outcomes was explored using regression models and group-based trajectory modeling. RESULTS: HIV was strongly associated with lower SCS at baseline [ß-14, 95% confidence interval (CI): -20 to -7, P < 0.001]. Change scores over time were similar between groups, but poorer average performance in children with HIV persisted at the 2-year follow-up visit (adjusted ß = -11, 95% CI: -22 to -0.3, P = 0.04). Other than HIV, the strongest predictors of baseline SCS included socioeconomic status index (ß =3, 95% CI: 1, 5, P = 0.004), history of growth stunting (ß=-14, 95% CI: -23 to -6, P = 0.001), history of CD4 count below 200 (ß = -19, 95% CI: -35 to -2, P = 0.02), and history of World Health Organization stage 4 disease (ß = -10, 95% CI: -19 to -0.2, P = 0.04). In the group-based trajectory model, HIV+ status predicted membership in the lowest performing trajectory group (odds ratio 2.5, 95% CI: 1.2 to 5.1, P = 0.01). CONCLUSIONS: Children with HIV are at risk of poor cognitive outcomes, despite chronic treatment with antiretroviral therapy.