Utility of the Language Use Inventory in Young Children at Elevated Likelihood of Autism.

PURPOSE: The aims of this study were (a) to evaluate the convergent validity of the Language Use Inventory (LUI) with measures of autism spectrum disorder (ASD) symptoms, language, and social skills and (b) to assess discriminant validity of the LUI with measures of nonlanguage skills, including daily living skills and motor development. METHOD: This study sample included participants from a longitudinal study (n = 239) of infant siblings with elevated familial likelihood of ASD and lower familial likelihood. Assessment measures completed at 36 months included the LUI, the Autism Diagnostic Observation Schedule-Second Edition (ADOS-2), the Mullen Scales of Early Learning, and the Vineland Adaptive Behavior Scales-Second Edition. Bivariate Pearson correlations were estimated between ADOS-2 comparison scores and four language and social skills measures. Additional correlations were estimated between LUI total scores and standard scores from nonlanguage measures. A series of Fisher's Z transformations were applied to evaluate whether bivariate correlations were significantly different. RESULTS: All four language and social skill measures were moderately to strongly associated with each other and ASD symptom severity scores. The correlation between ADOS-2 comparison scores and LUI total scores was significantly stronger than ADOS-2 correlations with all other measures. CONCLUSIONS: Our findings provide support for the LUI as a feasible, pragmatic language-targeted instrument for inclusion in early developmental evaluations prompted by language concerns. Administration of the LUI may accelerate earlier referral for a comprehensive assessment of ASD symptoms. Given the high correlation with ADOS-2 scores, an LUI total score in a clinical range of concern may encourage a clinician to refer families for a full diagnostic evaluation of ASD.

Assessment of Autism Spectrum Disorder.

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by challenges in social interaction and communication and the presence of restricted interests and repetitive behaviors. The importance of early detection of ASD and subsequent early intervention is well documented. Efforts have been made over the years to clarify ASD diagnostic criteria and develop predictive, accurate screening tools and evidence-based, standardized diagnostic instruments to aid in the identification of ASD. In this article, we review the most recent changes in ASD diagnostic criteria in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision, summarize evidence-based instruments for ASD screening and diagnostic evaluations as well as the assessment of co-occurring conditions in ASD, the impact of COVID-19 on ASD assessment, and directions for future research in the field of ASD assessment.

What is typical: Atypical in young children's attention regulation?: Characterizing the developmental spectrum with the Multidimensional Assessment Profiles-Attention Regulation Infant-Toddler (MAPS-AR-IT) Scale.

While attention dysregulation is a promising early indicator of neurodevelopmental risk, in particular attention-deficit/hyperactivity disorder (ADHD), it is difficult to characterize clinical concern due to its developmental expectability at the transition to toddlerhood. Thus, explicating the typical:atypical continuum of risk indicators is among the key future directions for research to promote early identification and intervention, and prevent decrements in the attainment of developmental milestones into early childhood. In this paper, we present the Multidimensional Assessment Profiles-Attention Regulation Infant-Toddler (MAPS-AR-IT) Scale, a novel parent-report survey of dimensional, developmentally specified indicators of attention (dys)regulation. Item Response Theory was employed to characterize the typical:atypical spectrum of both normative and more concerning dysregulation (including the contexts in which behavior occurs). We provide evidence of the validity of this measure in capturing the full typical:atypical spectrum via a longitudinal sample of typically developing children at 12-18 months of age (baseline) via concurrent scores on well-validated temperament and clinical measures. We also examine longitudinal stability and predictive validity if the MAPS-AR-IT via a clinical interview of ADHD symptoms at 24-30 months (follow-up). While not diagnostic, we present evidence of the utility of the MAPS-AR-IT in explicating individual neurodevelopmental risk and elucidating the broader typicality of behaviors related to attention (dys)regulation.

Aunque la desregulación de la atención es un prometedor indicador temprano del riesgo neural de desarrollo, en particular el trastorno de déficit en la atención/hiperactividad (ADHD), es difícil caracterizar las preocupaciones clínicas debido al factor de expectativa de desarrollo al momento de la transición a la temprana niñez. De manera que explicar la progresión típica:atípica de indicadores de riesgo está entre las futuras directrices claves para la investigación con el fin de promover la temprana identificación e intervención, y prevenir disminuciones en el alcance de hitos críticos hacia la temprana niñez. En este ensayo, presentamos la Escala de Perfiles de Evaluación Multidimensional - Regulación de la Atención del Infante-Niño Pequeñito (MAPS-AR-IT) una novedosa encuesta de reporte del progenitor, acerca de la (des)regulación de la atención, dimensional y específica para el desarrollo. Aportamos evidencia de la validez de esta medida para captar la completa gama típica:atípica por medio de una muestra longitudinal de niños típicamente en desarrollo, a los 12-18 meses de edad (edad base) por medio de puntajes concurrentes sobre el temperamento bien validado y las medidas clínicas, así como también la estabilidad longitudinal y la validez de predicción por medio de una entrevista clínica de síntomas de ADHD a los 24-30 meses (seguimiento). Se empleó la Teoría de Respuesta al Asunto para caracterizar la gama típica:atípica tanto de la desregulación normativa como de la más preocupante (incluyendo los contextos en los cuales ocurre el comportamiento). Aunque no se trata de diagnóstico, presentamos evidencia de la utilidad de MAPS-AR-IT para explicar el riesgo individual de desarrollo neural y elucidar el más amplio aspecto típico de comportamientos relacionados con la (des)regulación de la atención.

Bien que la dysrégulation de l'attention soit un indicateur précoce prometteur du risque neurodéveloppemental, en particulier le trouble déficitaire de l'attention/hyperactivité (TDHA) il est difficile de caractériser la préoccupation clinique du fait de sa prévisibilité développementale à la transition à la petite enfance. Par conséquent, expliquer le continuum typique:atypique des indicateurs de risque s'avère être une des directions futures de recherches clé pour promouvoir l'identification et l'intervention précoce, et prévenir les baisses dans la réalisation d'étapes développementales importantes jusque dans la petite enfance. Dans cet article nous présentons l'Echelle Multidimensional Assessment Profiles - Attention Regulation Infant-Toddler (MAPS-AR-IT) (échelle de profils d'évaluation multidimensionnelle - régulation de l'attention bébé-petit enfant, abrégée selon l'anglais MAP-AR-IT), une étude nouvelle basée sur les rapports faits par les parents de la (dys)régulation de l'attention dimensionnelle et spécifiée selon le développement. Nous démontrons la validité de cette mesure en capturant l'éventail total typique:atypique au moyen d'un échantillon longitudinal d'enfants se développement typiquement, à 12-18 mois (ligne de case) au moyen de scores concurrents de mesures cliniques et de tempérament bien validées, ainsi qu''une stabilité longitudinale et d'une validité prédictive au moyen d'un entretien Clinique des symptômes THHA à 24-30 mois (suivi). La Item Response Theory (IRT) a été employée pour caractériser l'éventail typique:atypique de la dysrégulation à la fois normative et celle plus inquiétante (y compris les contextes dans lesquels le comportement prend place). Bien que cela ne soit pas diagnostique, nous présentons la preuve de l'utilité de la MAPS-AR-IT en expliquant le risqué neurodéveloppemental individuel et en élucidant la typicalité plus large de comportements liés à la (dys)régulation de l'attention.

Ethics Issues Surrounding Facial Feminization Surgery: 5 Major Considerations.

Facial feminization surgery (FFS) is a form of gender affirming care for the transgender population that is currently a highly debated topic both inside and outside of the medical community. Currently, a paucity of information is available in plastic surgery literature on ethics issues surrounding FFS. In this paper, we discuss 5 major ethical considerations for plastic surgeons with regard to FFS: 1) how society's changing view of gender has impacted the importance of FFS; 2) whether FFS is medically necessary and should be covered by insurance; 3) to what extent resources should be invested in removing barriers to access FFS; 4) how patient selection criteria should address the irreversibility of the procedure and age of consent; and 5) how femininity and beauty standards contribute to each other and whether they can be disentangled. This paper aims to analyze the arguments made for and against each of the 5 nuanced issues and to expand these debates from the theoretical to practical by suggesting approaches for reconciliation.

Delineating early developmental pathways to ADHD: Setting an international research agenda.

Background: Attention-deficit/hyperactivity disorder (ADHD) is a prevalent, impairing, and highly heritable condition typically diagnosed in middle childhood. However, it is now recognized that symptoms emerge much earlier in development. Research focused on understanding-using multiple units of analysis-the cascade of early-life (i.e., prenatal-infant-toddler) developmental changes that will later emerge as ADHD has the potential to transform early identification, prevention, and intervention. To this end, we introduce the recently established Early ADHD Consortium, an international network of investigators engaged in prospective, longitudinal studies of risk for ADHD beginning early in life, conducted within a developmental framework, and which incorporate multimethod approaches. This network seeks to harmonize measures and methodological approaches to increase the potential for data sharing and subsequent impact. Methods: This perspective paper highlights the importance of investigating pre-diagnostic markers of ADHD, and potential models and mechanisms of ADHD risk and development, with the long-term objective of facilitating development of preemptive interventions that will minimize the impact of ADHD symptoms on everyday functioning and maximize health and developmental outcomes. Results: We selectively describe key challenges and questions for this field related to theoretical models and developmental mechanisms in ADHD and recommend next steps for the science, including methodological, measurement, and study design considerations. We then describe potential implications for preemptive intervention development. We conclude by considering other issues including ethical concerns and the critical value of incorporating stakeholder input. Conclusions: It is hoped that this perspective puts forth a research agenda that will enhance collaborative efforts and accelerate progress in understanding developmental mechanisms and the early ADHD phenotype, with implications for early intervention enhancement of healthy development for infants, young children, and their families.

Enabling endpoint development for interventional clinical trials in individuals with Angelman syndrome: a prospective, longitudinal, observational clinical study (FREESIAS).

BACKGROUND: Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by the absence of a functional UBE3A gene, which causes developmental, behavioral, and medical challenges. While currently untreatable, comprehensive data could help identify appropriate endpoints assessing meaningful improvements in clinical trials. Herein are reported the results from the FREESIAS study assessing the feasibility and utility of in-clinic and at-home measures of key AS symptoms. METHODS: Fifty-five individuals with AS (aged < 5 years: n = 16, 5-12 years: n = 27, ≥ 18 years: n = 12; deletion genotype: n = 40, nondeletion genotype: n = 15) and 20 typically developing children (aged 1-12 years) were enrolled across six USA sites. Several clinical outcome assessments and digital health technologies were tested, together with overnight 19-lead electroencephalography (EEG) and additional polysomnography (PSG) sensors. Participants were assessed at baseline (Clinic Visit 1), 12 months later (Clinic Visit 2), and during intermittent home visits. RESULTS: The participants achieved high completion rates for the clinical outcome assessments (adherence: 89-100% [Clinic Visit 1]; 76-91% [Clinic Visit 2]) and varied feasibility of and adherence to digital health technologies. The coronavirus disease 2019 (COVID-19) pandemic impacted participants' uptake of and/or adherence to some measures. It also potentially impacted the at-home PSG/EEG recordings, which were otherwise feasible. Participants achieved Bayley-III results comparable to the available natural history data, showing similar scores between individuals aged ≥ 18 and 5-12 years. Also, participants without a deletion generally scored higher on most clinical outcome assessments than participants with a deletion. Furthermore, the observed AS EEG phenotype of excess delta-band power was consistent with prior reports. CONCLUSIONS: Although feasible clinical outcome assessments and digital health technologies are reported herein, further improved assessments of meaningful AS change are needed. Despite the COVID-19 pandemic, remote assessments facilitated high adherence levels and the results suggested that at-home PSG/EEG might be a feasible alternative to the in-clinic EEG assessments. Taken altogether, the combination of in-clinic/at-home clinical outcome assessments, digital health technologies, and PSG/EEG may improve protocol adherence, reduce patient burden, and optimize study outcomes in AS and other rare disease populations.

Differential Response of Mycosis Fungoides Cells to Vorinostat.

Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma (CTCL) and is characterized by epidermotrophism of malignant CD4+ T-lymphocytes. When MF advances to a recurrent stage, patients require treatment with systemic therapies such as vorinostat, a histone deacetylase inhibitor. While vorinostat has been shown to exhibit anti-tumor activity in MF, its exact molecular mechanism has yet to be fully discerned. In the present study, we examined the transcriptomic and proteomic profiles of vorinostat treatment in two MF cell lines, Myla 2059 and HH. We find that vorinostat downregulates CTLA-4, CXCR4, and CCR7 in both cell lines, but its effect on several key pathways differs between the two MF cell lines. For example, vorinostat upregulates CCL5, CCR5, and CXCL10 expression in Myla cells but downregulates CCL5 and CXCL10 expression in HH cells. Furthermore, vorinostat upregulates IFN-γ and IL-23 signaling and downregulates IL-6, IL-7, and IL-15 signaling in Myla cells but does not affect these pathways in HH cells. Although Myla and HH represent established MF cell lines, their distinct tumor origin from separate patients demonstrates that inherent phenotypic variations within the disease persist, underscoring the importance of using a variety of MF cells in the preclinical development of MF therapeutics.

Diagnosis and treatment of children and adolescents with autism and ADHD.

Attention-deficit/hyperactivity disorder (ADHD) and autism are neurodevelopmental disorders that emerge in childhood. There is increasing recognition that ADHD and autism frequently co-occur. Yet, questions remain among clinicians regarding the best ways to evaluate and treat co-occurring autism and ADHD. This review outlines issues relevant to providing evidence-based practice to individuals and families who may be experiencing difficulties associated with co-occurring autism and ADHD. After describing the complexities of the co-occurrence of autism and ADHD, we present practical considerations for best practice assessment and treatment of co-occurring autism and ADHD. Regarding assessment, this includes considerations for interviewing parents/caregivers and youth, using validated parent and teacher rating scales, conducting cognitive assessments, and conducting behavior observations. Regarding treatment, consideration is given to behavioral management, school-based interventions, social skills development, and the use of medications. Throughout, we note the quality of evidence that supports a particular component of assessment or treatment, highlighting when evidence is most relevant to those with co-occurring autism and ADHD across stages of development. In light of the current evidence for assessment and treatment of co-occurring autism and ADHD, we conclude by outlining practical implications for clinical and educational practice.

Patterns of sensory processing in young children with autism: Differences in autism characteristics, adaptive skills, and attentional problems.

LAY ABSTRACT: Research has found differences in responding to various sensory stimuli among autistic individuals, which are associated with social and adaptive skills. However, our understanding of sensory profiles in autism has been complicated due to the variable presentation of sensory symptoms. One way to better understand variability in sensory symptoms is to use advanced statistical approaches, such as latent profile analysis, that allow for the identification of more similar sensory classes in otherwise variable groups. We used the Short Sensory Profile to identify homogeneous classes of sensory reactivity in autistic children based on both severity and modality and examined whether sensory classes differed in terms of autism characteristics, adaptive skills, and attention-deficit/hyperactivity disorder symptoms. Based on the pattern of both severity and modality, four sensory classes emerged and were named Moderate/Mixed (35.5%; probable-to-definite differences in all modalities except in movement sensitivity and low energy/weakness), Severe/Mixed (8.5%; definite sensory differences in all modalities except in low energy/weakness), Moderate/Broad (14.6%; probable-to-definite differences in all modalities), and Low/Mixed (41.1%; typical scores in most modalities with probable differences in taste/smell sensitivity, under-responsive/seeks sensation, and auditory filtering). The Severe/Mixed class exhibited greater problems in a variety of areas such as social, adaptive, and attention-deficit/hyperactivity disorder symptoms, whereas the Low/Mixed class showed overall fewer problems. This may provide insight for clinicians and researchers aiming to understand whether autistic children who exhibit distinct sensory patterns are more or less likely to also experience social, adaptive, and/or attention/behavior-related difficulties.

Does the severity of autism symptoms change over time? A review of the evidence, impacts, and gaps in current knowledge.

Studies evaluating change in autism symptom severity across the lifespan have yielded inconsistent results, making it difficult to assess the prevalence of meaningful change in autism symptom severity, and what characterizes it. Better understanding the ways in which autism symptoms change over time is crucial, with important implications for intervention. Synthesizing information across past studies, autism symptom severity change (especially decreases) appears common, though stability of symptoms is also frequent. Symptom severity change is characterized by variability in patterns of change between different individuals (between-person), variability in change within a person's trajectory across time (within-person), and variability in change patterns across symptom domains (i.e., social-communication, restricted/repetitive behaviors). Variability in severity change is likely impacted by differences in person-level characteristics (e.g., sex, IQ, sociodemographic factors) as well as developmental processes across time. Numerous methodological issues may impact our ability to understand how common change in symptom severity is, including varying measurement tools, analytic approaches, and change patterns between symptom domains across time. Potential implications of better understanding and characterizing symptom severity change include incorporation of severity change patterns and predictors of change into research on biomarkers, and consideration of such predictors as moderators or mediators of change in clinical practice.

Technical Performance of a 430-Gene Preventative Genomics Assay to Identify Multiple Variant Types Associated with Adult-Onset Monogenic Conditions, Susceptibility Loci, and Pharmacogenetic Insights.

DNA-based screening in individuals without known risk factors potentially identifies those who may benefit from genetic counseling, early medical interventions, and/or avoidance of late or missed diagnoses. While not currently in widespread usage, technological advances in genetic analysis overcome barriers to access by enabling less labor-intensive and more cost-efficient means to discover variants of clinical importance. This study describes the technical validation of a 430-gene next-generation sequencing based assay, GeneCompassTM, indicated for the screening of healthy individuals in the areas of actionable health risks, pharmaceutical drug response, and wellness traits. The test includes genes associated with Mendelian disorders and genetic susceptibility loci, encompassing 14 clinical areas and pharmacogenetic variants. The custom-designed target enrichment capture and bioinformatics pipelines interrogate multiple variant types, including single nucleotide variants, insertions/deletions (indels), copy number variants, and functional haplotypes (star alleles), including tandem alleles and structural variants. Validation was performed against reference DNA from three sources: 1000 Genomes Project (n = 3), Coriell biobank (n = 105), and previously molecularly characterized biological specimens: blood (n = 15) and saliva (n = 11). Analytical sensitivity and specificity for single nucleotide variants (SNVs) were 97.57% and 99.99%, respectively, and for indels were 74.57% and 97.34%, respectively. This study demonstrates the validity of an NGS assay for genetic screening and the broadening of access to preventative genomics.

AntimiR targeting of microRNA-134 reduces seizures in a mouse model of Angelman syndrome.

Angelman syndrome (AS) is a severe neurodevelopmental disorder featuring ataxia, cognitive impairment, and drug-resistant epilepsy. AS is caused by mutations or deletion of the maternal copy of the paternally imprinted UBE3A gene, with current precision therapy approaches focusing on re-expression of UBE3A. Certain phenotypes, however, are difficult to rescue beyond early development. Notably, a cluster of microRNA binding sites was reported in the untranslated Ube3a1 transcript, including for miR-134, suggesting that AS may be associated with microRNA dysregulation. Here, we report levels of miR-134 and key targets are normal in the hippocampus of mice carrying a maternal deletion of Ube3a (Ube3a m-/p+ ). Nevertheless, intracerebroventricular injection of an antimiR oligonucleotide inhibitor of miR-134 (Ant-134) reduced audiogenic seizure severity over multiple trials in 21- and 42-day-old AS mice. Interestingly, Ant-134 also improved distance traveled and center crossings of AS mice in the open-field test. Finally, we show that silencing miR-134 can upregulate targets of miR-134 in neurons differentiated from Angelman patient-derived induced pluripotent stem cells. These findings indicate that silencing miR-134 and possibly other microRNAs could be useful to treat clinically relevant phenotypes with a later developmental window in AS.

GZ17-6.02 Inhibits the Growth of EGFRvIII+ Glioblastoma.

Epidermal Growth Factor Receptor (EGFR) is amplified in over 50% of glioblastomas and promotes tumor formation and progression. However, attempts to treat glioblastoma with EGFR tyrosine kinase inhibitors have been unsuccessful thus far. The current standard of care is especially poor in patients with a constitutively active form of EGFR, EGFRvIII, which is associated with shorter survival time. This study examined the effect of GZ17-6.02, a novel anti-cancer agent undergoing phase 1 studies, on two EGFRvIII+ glioblastoma stem cells: D10-0171 and D317. In vitro analyses showed that GZ17-6.02 inhibited the growth of both D10-0171 and D317 cells with IC50 values of 24.84 and 28.28 µg/mL respectively. RNA sequencing and reverse phase protein array analyses revealed that GZ17-6.02 downregulates pathways primarily related to steroid synthesis and cell cycle progression. Interestingly, G17-6.02's mechanism of action involves the downregulation of the recently identified glioblastoma super-enhancer genes WSCD1, EVOL2, and KLHDC8A. Finally, a subcutaneous xenograft model showed that GZ17-6.02 inhibits glioblastoma growth in vivo. We conclude that GZ17-6.02 is a promising combination drug effective at inhibiting the growth of a subset of glioblastomas and our data warrants further preclinical studies utilizing xenograft models to identify patients that may respond to this drug.

Editorial: Are We There Yet? Identification and Intervention for Attention-Deficit/Hyperactivity Disorder in the First Years of Life.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent childhood disorders, affecting approximately 8% of children in the United States.1 Although it is not typically diagnosed until around age 7 years, consensus is growing that symptoms emerge much earlier.2 Despite this, our knowledge continues to be relatively limited with respect to early indicators of ADHD, or the potential for early interventions for the condition.

Fostering equity in education and academic outcomes in children with sickle cell disease.

ObjectiveChildren with Sickle Cell Disease (SCD), who are predominantly Black, face academic disparities in part because of the impact of longstanding racially biased education systems. Adverse systemic factors in addition to neurologic complications put children with SCD at risk for poor academic outcomes. Providing caregivers with information on how to select quality schools and advocate for their child's specific educational needs may influence academic outcomes and reduce educational disparities. We aimed to provide information to caregivers of children with SCD on school selection/quality, enrollment, and special education options.MethodsForty-six caregivers of children with SCD between the ages of 2 and 5:11 years participated in a structured informational session. Caregivers' sense of empowerment regarding educational options for their child was assessed via survey before and after the structured informational session.ResultsCaregivers reported feeling more informed and empowered following their participation in an informational session on school selection/quality, enrollment, and special education options for their child than before the informational session.ConclusionsIt is essential that families of children with SCD have the knowledge, skills, and sense of empowerment to access quality schools beginning in early childhood. Future research will determine if this intervention will improve children's access to academic support and academic outcomes. We theorize improvements in academic outcomes along with addressing systemic disparities may ultimately create a positive impact on vocational and quality of life outcomes in the lives of children with SCD.

Patterns of objectively measured motor activity among infants developing ASD and concerns for ADHD.

BACKGROUND: Heightened motor activity is a hallmark of attention-deficit/hyperactivity disorder (ADHD), yet high activity levels are also often reported in young children with autism spectrum disorder (ASD). It is currently unclear whether increased motor activity represents a distinct versus shared early predictor of ASD and ADHD; no prior studies have directly examined this prospectively. We investigated differences in longitudinal patterns of objectively measured motor activity during early development. METHODS: Participants included 113 infants at high and low risk for ASD or ADHD. Continuous motion-based activity was recorded using tri-axial accelerometers at 12, 18, 24, and 36 months of age. At 36 months, participants were categorized into one of three outcome groups: ASD (n = 19), ADHD Concerns (n = 17), and Typically Developing (TD; n = 77). Group differences in trajectories of motor activity were examined in structured and semistructured contexts. Associations with behaviors relevant to ASD, ADHD, and general development were also examined. RESULTS: In both structured and semistructured contexts, both the ASD and ADHD Concerns groups exhibited heightened activity relative to the TD group by 18 months; the ASD group exhibited higher activity than the ADHD Concerns group at 24-36 months in the structured context only. Attention/behavior regulation, nonverbal, and verbal development-but not social engagement-were differentially associated with objectively measured activity by outcome group across contexts. CONCLUSIONS: Overactivity may be a shared, rather than distinct, precursor of atypical development in infants/toddlers developing ASD and concerns for ADHD, emerging as early as 18 months. Group differences in overactivity may be context-specific and associated with different underlying mechanisms.

Rethinking autism spectrum disorder assessment for children during COVID-19 and beyond.

The COVID-19 pandemic has posed unique challenges for families and caregivers, as well as for autism-focused clinicians, who are faced with providing a thorough and accurate evaluation of children's specific needs and diagnoses in the absence of in-person assessment tools. The shift to telehealth assessments has challenged clinicians to reconsider approaches and assumptions that underlie the diagnostic assessment process, and to adopt new ways of individualizing standard assessments according to family and child needs. Mandates for physical distancing have uncovered deficiencies in diagnostic practices for suspected autism and have illuminated biases that have posed obstacles preventing children and families from receiving the services that they truly need. This Commentary outlines several considerations for improving diagnostic practices as we move forward from the current pandemic and continue to strive to build an adaptable, sustainable, equitable, and family-centered system of care. LAY SUMMARY: Physical distancing and the abrupt end to in-person services for many children on the autism spectrum has forced clinicians to examine the existing challenges with autism spectrum disorder (ASD) diagnostic assessment and consider things they want to keep and things that should be changed in the years ahead. New approaches such as telehealth both alleviated and exacerbated existing disparities, and brought into stark focus the importance of equitable and timely access to family-centered care. This commentary suggests ways of improving clinical practices related to ASD assessment to continue along this path.

Study TPX-100-5: intra-articular TPX-100 significantly delays pathological bone shape change and stabilizes cartilage in moderate to severe bilateral knee OA.

BACKGROUND: TPX-100, a promotor of osteoblast and chondroblast differentiation, is a potential osteoarthritis (OA) therapy. This retrospective study compared MRI 3D femoral bone shape changes (B-scores) after intra-articular TPX-100 or placebo and analyzed the relationship between cartilage thickness and bone shape change over 12 months. METHODS: One hundred and four participants with bilateral moderate to severe knee cartilage defects were randomized to receive TPX-100 (200 mg) or placebo. Each subject's contralateral placebo-treated knee served as a paired internal control. After MRI quality control, 78/93 subjects (84%; 156 knees) were analyzed for quantitative femoral B-score and cartilage thickness. All analyses were performed centrally, blind to treatment assignment and clinical data. RESULTS: TPX-100-treated knees (n = 78) demonstrated a statistically significant decrease in pathologic bone shape change compared with placebo-treated knees at 6 and 12 months: 0.0298 (95% C.I. - 0.037, 0.097) vs 0.1246 (95% C.I. 0.067, 0.182) (P = 0.02), and 0.0856 (95% C.I. 0.013, 0.158) vs. 0.1969 (95% C.I. 0.123, 0.271) (P = 0.01), respectively. The correlation between bone shape change and medial and total tibiofemoral cartilage thickness changes at 12 months was statistically significant in TPX-100-treated knees (P < 0.01). CONCLUSIONS: This is the first report of a potential therapy demonstrating a significant effect on bone shape measured by B-score in knee OA. These data, in combination with previously reported statistically significant and clinically meaningful improvements in WOMAC physical function versus placebo, support TPX-100 as a candidate for disease modification in knee OA. TRIAL REGISTRATION: NIH ClinicalTrials.gov, NCT01925261 . Registered 15 August 2013.