Expanded clinical phenotype spectrum correlates with variant function in SCN2A-related disorders.

SCN2A-related disorders secondary to altered function in the voltage-gated sodium channel NaV1.2 are rare with clinically heterogeneous expressions that include epilepsy, autism, and multiple severe to profound impairments and other conditions. To advance understanding of the clinical phenotypes and their relation to channel function, 81 patients (36, 44% female, median age 5.4 years) with 69 unique SCN2A variants were systematically phenotyped and their NaV1.2 channel function systematically assessed. Participants were recruited through the FamileSCN2A Foundation. Primary phenotype (epilepsy of neonatal-onset, N=27; infant onset, N=18; and later onset N=24; and autism without seizures, (N=12) was strongly correlated with a non-seizure severity index (p=0.002), which was based on presence of severe impairments in gross motor, fine motor, communication abilities, gastrostomy tube dependence, and diagnosis of cortical visual impairment and scoliosis. Non-seizure severity was greatest in the neonatal-onset group and least in the autism group (p=0.002). Children with the lowest severity indices were still severely impaired, as reflected by an average Vineland adaptive behavior composite score of 49.5 (>3 SD below the test's norm-referenced mean). Epileptic spasms were significantly more common in infant onset (67%) than in neonatal (22%) or later-onset (29%) epilepsy (p=0.007). Primary phenotype also strongly correlated with variant function (p<0.0001); gain of function and mixed function variants predominated in neonatal-onset epilepsy, shifting to moderate loss of function in infant-onset epilepsy, and severe and complete loss of function in later-onset epilepsy and autism groups. Exploratory cluster analysis identified five groups representing (1) primarily later-onset epilepsy with moderate loss of function variants and low severity indices, (2) mostly infant-onset epilepsy with moderate loss of function variants but higher severity indices, (3) late-onset and autism only with the lowest severity indices (mostly 0) and severe/complete loss of function variants. Two exclusively neonatal clusters were distinguished from each other largely on non-seizure severity scores and secondarily on variant function. The relation between primary phenotype and variant function emphasizes the role of developmental factors in the differential clinical expression of SCN2A variants based on their effects on NaV1.2 channel function. The non-seizure severity of SCN2A disorders depends on a combination of the age at seizure onset (primary phenotype) and variant function. As precision therapies for SCN2A-related disorders advance toward clinical trials, knowledge of the relationship between variant function and clinical disease expression will be valuable for identifying appropriate patients for these trials and in selecting efficient clinical outcomes.

Tretinoin Enhances the Effects of Chemotherapy in Juvenile Myelomonocytic Leukemia Using an Ex Vivo Drug Sensitivity Assay.

PURPOSE: Juvenile myelomonocytic leukemia (JMML) is an aggressive pediatric malignancy with myelodysplastic and myeloproliferative features. Curative treatment is restricted to hematopoietic stem-cell transplantation. Fludarabine combined with cytarabine (FLA) and 5-azacitidine (AZA) monotherapy are commonly used pre-transplant therapies. Here, we present a drug screening strategy using a flow cytometry-based precision medicine platform to identify potential additional therapeutic vulnerabilities. METHODS: We screened 120 dual- and 10 triple-drug combinations (DCs) on peripheral blood (n = 21) or bone marrow (n = 6) samples from 27 children with JMML to identify DCs more effectively reducing leukemic cells than the DCs' components on their own. If fewer leukemic cells survived a DC ex vivo treatment compared with that DC's most effective component alone, the drug effect was referred to as cooperative. The difference between the two resistant fractions is the effect size. RESULTS: We identified 26 dual- and one triple-DC more effective than their components. The differentiation agent tretinoin (TRET; all-trans retinoic acid) reduced the resistant fraction of FLA in 19/21 (90%) samples (decrease from 15% [2%-61%] to 11% [2%-50%] with a mean effect size of 3.8% [0.5%-11%]), and of AZA in 19/25 (76%) samples (decrease from 69% [34%-100+%] to 47% [17%-83%] with a mean effect size of 16% [0.3%-40%]). Among the resistant fractions, the mean proportion of CD38+ cells increased from 7% (0.03%-25%; FLA) to 17% (0.3%-38%; FLA + TRET) or from 10% (0.2%-31%; AZA) to 51% (0.8%-88%; AZA + TRET). CONCLUSION: TRET enhanced the effects of FLA and AZA in ex vivo assays with primary JMML samples.

The Impact of a Culturally Meaningful Storytelling Intervention on Stigma and Attitudes About Mental Health Treatment.

ABSTRACT: The fear of being devalued or discriminated against is a salient deterrent to seeking mental health care, especially in communities of color where racial stigma also impacts mental health and perceptions of service utilization. To address this issue, our research team partnered with This Is My Brave Inc to develop and evaluate a virtual storytelling intervention to highlight and amplify the voices of Black and Brown Americans living with mental illness and/or addiction. We utilized a pretest-posttest survey design administered electronically to viewers of the series ( n = 100 Black, indigenous, people of color and n = 144 non-Hispanic White). Results indicated that postintervention, scores on public stigma and perceived discrimination measures were significantly reduced. We identified significant interaction effects, such that Black, indigenous, people of color viewers showed a greater rate of improvement on outcomes. This study provides strong preliminary evidence of the impact of a culturally meaningful virtual approach to addressing stigma and improving attitudes about mental health treatment.

Ex Vivo Drug Sensitivity Correlates with Clinical Response and Supports Personalized Therapy in Pediatric AML.

Acute myeloid leukemia (AML) is a heterogeneous disease that accounts for ~20% of all childhood leukemias, and more than 40% of children with AML relapse within three years of diagnosis. Although recent efforts have focused on developing a precise medicine-based approach towards treating AML in adults, there remains a critical gap in therapies designed specifically for children. Here, we present ex vivo drug sensitivity profiles for children with de novo AML using an automated flow cytometry platform. Fresh diagnostic blood or bone marrow aspirate samples were screened for sensitivity in response to 78 dose conditions by measuring the reduction in leukemic blasts relative to the control. In pediatric patients treated with conventional chemotherapy, comprising cytarabine, daunorubicin and etoposide (ADE), ex vivo drug sensitivity results correlated with minimal residual disease (r = 0.63) and one year relapse-free survival (r = 0.70; AUROC = 0.94). In the de novo ADE analysis cohort of 13 patients, AML cells showed greater sensitivity to bortezomib/panobinostat compared with ADE, and comparable sensitivity between venetoclax/azacitidine and ADE ex vivo. Two patients showed a differential response between ADE and bortezomib/panobinostat, thus supporting the incorporation of ex vivo drug sensitivity testing in clinical trials to further evaluate the predictive utility of this platform in children with AML.

Affirmative neuropsychological practice with transgender and gender diverse individuals and communities.

Objective: To provide guidance and resources on how to practice culturally safe and humble neuropsychology with transgender and gender diverse (TGD) individuals and communities. Methods: We gathered a multidisciplinary team of clinicians with relevant professional and/or lived experience to review pertinent literature, discuss important concepts, and identify key resources. From this process, we outline practical steps to advance gender affirmative neuropsychological practice. Results: Professional awareness and knowledge regarding how to gather context-relevant, gender identity information is critical. TGD individuals form a heterogenous group; a one-size-fits-all approach is not adequate. It is incumbent upon neuropsychologists to engage in clinical and research practices in a manner that does not perpetuate gender minority stress and trauma. Creating an open, safe environment of care requires intentionality and careful thinking to determine what information is relevant for a particular referral question. We provide recommendations and resources for neuropsychologists. Conclusion: When neuropsychologists are proactive, responsible, and intentional, they can better provide individualized, person-centered, and trauma-informed care to TGD individuals.

Health care Affordability and Associated Concerns Among Adults Aged 65 and above in Florida.

OBJECTIVE: This study assessed affordability of care in a diverse sample of Floridians aged ≥ 65 to ascertain concerns about health care costs. METHODS: We surveyed 170 adults (40.6% white, 27.6% black, and 31.8% Hispanic) and conducted three race/ethnic-stratified focus groups (n = 27). RESULTS: Most participants had Medicare (97.1%). Among whites, 11.6% reported problems paying medical bills in the past 12 months versus 14.9% of blacks and 24.1% of Hispanics. In addition, 13% of whites, 19.2% of blacks, and 20.4% of Hispanics reported not getting needed prescription drugs because of costs. The most frequently identified concerns from the focus groups were the cost of prescription drugs, out-of-pocket expenses, and medical billing. Concerns about medical billing included understanding bills, transparency, timely postings, and uncertainty about who to contact about problems. DISCUSSION: Our findings suggest that practices that help older adults effectively manage medical bills and costs may alleviate their concerns and guard against financial burdens.

Enhancing care transitions intervention with peer support to improve outcomes among older adults with co-occurring clinical depression: a pilot study.

The Care Transitions Intervention (CTI) is an evidence-based intervention aimed at supporting the transition from hospital back to the community for patients to ultimately reduce preventable re-hospitalization. In a pilot randomized controlled trial, we examined the preliminary effectiveness of an Enhanced Care Transitions Intervention (ECTI), CTI with the addition of peer support, for a racially/ethnically diverse sample of older adults (age 60+) with co-morbid major depression. We observed a significant decline in health-related quality of life (HRQOL) after being discharged from the hospital among those who received CTI. Additionally, those who received ECTI either maintained HRQOL scores, or, saw improvement in HRQOL scores. Findings suggest the Enhanced Care Transitions Intervention can maintain or improve HRQOL and reduce disparities for older participants from diverse racial/ethnic backgrounds with clinical depression.

Maternal Socialization is Associated with Prosocial Behavior in At-Risk Young Children.

Prosocial behaviors are a key component of young children's developing social competence. The current study examines the impact of two types of maternal socialization on young children's prosocial behaviors: emotional expressiveness (defined as maternal displayed positive and negative affect) and direct coaching of prosocial responses and explores the relationship of these socialization behaviors with mothers' own histories of psychosocial risk. An ethnically and socioeconomically diverse sample from the United States of 80 mother-child dyads at high risk for violence exposure was assessed when the children were preschool age. All of the maternal emotion socialization behaviors were evaluated by direct observation. The sample included 40 mothers with a history of childhood trauma and 40 mothers without such a history, matched on demographic characteristics. Results indicated that mothers with a history of childhood trauma experiences expressed more positive affect than those without childhood trauma, but the groups did not differ in expressed negative affect or prosocial coaching behaviors. For the full sample, even after controlling for relevant demographic and psychosocial risk factors, socialization behaviors were associated with preschool children's prosocial behavior. Findings reinforce the critical role of parental socialization behaviors in the development of young children's peer-directed prosocial behaviors and highlight the importance of helping parents to develop effective socialization skills.

Age-based variation in calf independence, social behavior and play in a captive population of African elephant calves.

African elephant calves are highly social and their behavioral development depends heavily on interactions with other elephants. Evaluating early social behaviors offers important information that can inform management decisions and maximize individual- and population-level welfare. We use data collected from the population of elephants at the San Diego Zoo Safari Park in Escondido, CA to evaluate developmental trajectories of spatial independence and social behavior in nine elephant calves across a range of ages. As calves aged, the probability of being further from mothers also increased. Tactile interactions were common among calves, with all individuals either initiating or receiving physical touches from other elephants in a large proportion of focal scans. While the probability of initiating tactile interactions tended to decline with increases in calf age, the probability of receiving tactile interactions from other elephants remained invariant with regard to this variable. The social play was also common, occurring in a fifth of all focal scans. While there was evidence that social play tended to decline with increases in calf age, results suggest additional factors may be useful in characterizing patterns in play behavior at the individual level. Calves most frequently engaged in play with individuals of similar age but showed substantial variation in play partner choice. Results of this study suggest that maintaining groups of elephants in captivity with diverse age structure positively contribute to their healthy social development.

Cultural socialization in childhood: Analysis of parent-child conversations with a direct observation measure.

Cultural factors influence the development of all children. Yet, current knowledge of explicit cultural socialization processes in childhood remains limited, mainly by failing to incorporate the experiences of young children. To address this critical gap, the authors introduce the OMERS-Peds task, an observational measurement designed to systematically identify and compare the content of cultural messages passed down from caregivers to offspring during early school age years. The OMERS-Peds was administered to mothers and children (n = 275) from three diverse racial/ethnic backgrounds (African American (n = 153), Hispanic (n = 61), and non-Hispanic White (n = 61)) within the longitudinal Multidimensional Assessment of Preschoolers (MAPS) Study. The OMERS-Peds coding system was used to rate how strongly families endorsed 5 key constructs: family culture, religion, identity, ethnicity, and race. A series of χ2 statistic tests were used to compare scores across racial/ethnic backgrounds, and within families (between children and their mothers). Analyses revealed that in the cultural socialization conversations occurring in early childhood, parents and children prioritize talking about their family's culture and religion. Independent of their racial/ethnic backgrounds, mothers and children seldom discussed race and ethnicity. Contrary to research with older children, differences were mainly identified within families, rather than across racial/ethnic groups. Findings support the need to include children's perspectives in the assessments of cultural socialization, as opposed to relying primarily on parent reports, and highlight the importance of having an observational methodology that allows researchers to examine parent-child bidirectional interactions during early school age years in a systematic manner. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Candida auris Outbreak in a COVID-19 Specialty Care Unit - Florida, July-August 2020.

In July 2020, the Florida Department of Health was alerted to three Candida auris bloodstream infections and one urinary tract infection in four patients with coronavirus disease 2019 (COVID-19) who received care in the same dedicated COVID-19 unit of an acute care hospital (hospital A). C. auris is a multidrug-resistant yeast that can cause invasive infection. Its ability to colonize patients asymptomatically and persist on surfaces has contributed to previous C. auris outbreaks in health care settings (1-7). Since the first C. auris case was identified in Florida in 2017, aggressive measures have been implemented to limit spread, including contact tracing and screening upon detection of a new case. Before the COVID-19 pandemic, hospital A conducted admission screening for C. auris and admitted colonized patients to a separate dedicated ward.

Disruption Leads to Methodological and Analytic Innovation in Developmental Sciences: Recommendations for Remote Administration and Dealing With Messy Data.

The COVID-19 pandemic has impacted data collection for longitudinal studies in developmental sciences to an immeasurable extent. Restrictions on conducting in-person standardized assessments have led to disruptive innovation, in which novel methods are applied to increase participant engagement. Here, we focus on remote administration of behavioral assessment. We argue that these innovations in remote assessment should become part of the new standard protocol in developmental sciences to facilitate data collection in populations that may be hard to reach or engage due to burdensome requirements (e.g., multiple in-person assessments). We present a series of adaptations to developmental assessments (e.g., Mullen) and a detailed discussion of data analytic approaches to be applied in the less-than-ideal circumstances encountered during the pandemic-related shutdown (i.e., missing or messy data). Ultimately, these remote approaches actually strengthen the ability to gain insight into developmental populations and foster pragmatic innovation that should result in enduring change.

Starting at Birth: An Integrative, State-of-the-Science Framework for Optimizing Infant Neuromotor Health.

Numerous conditions and circumstances place infants at risk for poor neuromotor health, yet many are unable to receive treatment until a definitive diagnosis is made, sometimes several years later. In this integrative perspective, we describe an extensive team science effort to develop a transdiagnostic approach to neuromotor health interventions designed to leverage the heightened neuroplasticity of the first year of life. We undertook the following processes: (1) conducted a review of the literature to extract common principles and strategies underlying effective neuromotor health interventions; (2) hosted a series of expert scientific exchange panels to discuss common principles, as well as practical considerations and/or lessons learned from application in the field; and (3) gathered feedback and input from diverse stakeholders including infant caregivers and healthcare providers. The resultant framework was a pragmatic, evidence-based, transdiagnostic approach to optimize neuromotor health for high-risk infants based on four principles: (a) active learning, (b) environmental enrichment, (c) caregiver engagement, and (d) strength-based approaches. In this perspective paper, we delineate these principles and their potential applications. Innovations include: engagement of multiple caregivers as critical drivers of the intervention; promoting neuromotor health in the vulnerability phase, rather than waiting to treat neuromotor disease; integrating best practices from adjacent fields; and employing a strengths-based approach. This framework holds promise for implementation as it is scalable, pragmatic, and holistically addresses both the needs of the infant and their family.

Brief Report: What Diagnostic Observation Can Teach Us About Disruptive Behavior in Young Children with Autism.

ABSTRACT: Objective: Approximately 50% of children with autism exhibit severe tantrums, defiance, and/or aggression. We propose that the Disruptive Behavior Diagnostic Observation Schedule (DB-DOS)-a standardized clinical observation modeled after, and complementary to, the Autism Diagnostic Observation Schedule (ADOS)-could enhance earlier identification of disruptive behavior (DB) in autism populations and inform treatment planning. Methods: We adapted the DB-DOS for children with autism based on expert input and preliminary feasibility testing to accommodate varying cognitive and social communication capacities and increase the likelihood of observing DB in this population. Thereafter, we concurrently administered the modified DB-DOS and the ADOS to 12 children with autism aged 36 to 50 months. Results: Overall, children exhibited greater DB, especially behavioral regulation challenges, during the DB-DOS than during the ADOS. Conclusion: The use of a developmentally sensitive standardized observation tool that presses for DB to complement standardized observations such as the ADOS shows promise for enabling more precise research on targeted DB interventions. Such a tool holds promise as a reliable and efficient method of identifying comorbid DB disorders in the autism population.

Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia.

Approximately 50% of acute myeloid leukemia (AML) patients do not respond to induction therapy (primary induction failure [PIF]) or relapse after <6 months (early relapse [ER]). We have recently shown an association between an immune-infiltrated tumor microenvironment (TME) and resistance to cytarabine-based chemotherapy but responsiveness to flotetuzumab, a bispecific DART antibody-based molecule to CD3ε and CD123. This paper reports the results of a multicenter, open-label, phase 1/2 study of flotetuzumab in 88 adults with relapsed/refractory AML: 42 in a dose-finding segment and 46 at the recommended phase 2 dose (RP2D) of 500 ng/kg per day. The most frequent adverse events were infusion-related reactions (IRRs)/cytokine release syndrome (CRS), largely grade 1-2. Stepwise dosing during week 1, pretreatment dexamethasone, prompt use of tocilizumab, and temporary dose reductions/interruptions successfully prevented severe IRR/CRS. Clinical benefit accrued to PIF/ER patients showing an immune-infiltrated TME. Among 30 PIF/ER patients treated at the RP2D, the complete remission (CR)/CR with partial hematological recovery (CRh) rate was 26.7%, with an overall response rate (CR/CRh/CR with incomplete hematological recovery) of 30.0%. In PIF/ER patients who achieved CR/CRh, median overall survival was 10.2 months (range, 1.87-27.27), with 6- and 12-month survival rates of 75% (95% confidence interval [CI], 0.450-1.05) and 50% (95% CI, 0.154-0.846). Bone marrow transcriptomic analysis showed that a parsimonious 10-gene signature predicted CRs to flotetuzumab (area under the receiver operating characteristic curve = 0.904 vs 0.672 for the European LeukemiaNet classifier). Flotetuzumab represents an innovative experimental approach associated with acceptable safety and encouraging evidence of activity in PIF/ER patients. This trial was registered at www.clinicaltrials.gov as #NCT02152956.

The Early Childhood Irritability-Related Impairment Interview (E-CRI): A Novel Method for Assessing Young Children's Developmentally Impairing Irritability.

Irritability is a substrate of more than one dozen clinical syndromes. Thus, identifying when it is atypical and interfering with functioning is crucial to the prevention of mental disorder in the earliest phase of the clinical sequence. Advances in developmentally based measurement of irritability have enabled differentiation of normative irritable mood and tantrums from indicators of concern, beginning in infancy. However, developmentally sensitive assessments of irritability-related impairment are lacking. We introduce the Early Childhood Irritability-Related Impairment Interview (E-CRI), which assesses impairment associated with irritable mood and tantrums across contexts. Reliability and validity are established across two independent samples varied by developmental period: the Emotional Growth preschool sample (EmoGrow; N = 151, M = 4.82 years) and the When to Worry infant/toddler sample (W2W; N = 330, M = 14 months). We generated a well-fitting two-factor E-CRI model, with tantrum- and irritable mood-related impairment factors. The E-CRI exhibited good interrater, test-retest, and longitudinal reliability. Construct and clinical validity were also demonstrated. In both samples, E-CRI factors showed association to internalizing and externalizing problems, and to caregiver-reported concern in W2W. Tantrum-related impairment demonstrated stronger and more consistent explanatory value across outcomes, while mood-related impairment added explanatory utility for internalizing problems. The E-CRI also showed incremental utility beyond variance explained by the Family Life Impairment Scale (FLIS) survey indicator of developmental impairment. The E-CRI holds promise as an indicator of impairment to inform identification of typical versus atypical patterns reflecting early emerging irritability-related syndromes in the initial phase of the clinical sequence.