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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 DCs 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.

AbstractObjective: 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.

Bioinspired synthetic materials can be designed as reliable, cost‐effective, and fully controlled alternatives to natural biomaterials for treating damaged tissues and organs. However, several hurdles need to be overcome for clinical translation, particularly for biomaterials gelled in situ. These include the potential toxicity of chemical crosslinkers used in the materials' assembly or breakdown products they generate and the challenges of fine‐tuning the mechanical properties of the materials. Here, a minimalistic, adhesive soft material is developed by screening hundreds of potential formulations of self‐assembling, custom‐designed collagen‐like peptide sequences for the in situ formation of tissue‐bonding 3D hydrogels. Nine promising formulations for tissue repair are identified using a low‐volume and rapid combinatory screening approach. It is shown that simply varying the ratio of the two key components promotes adhesion and fine‐tunes the material's mechanical properties. The materials' skin and heart repair capabilities are assessed in vitro and clinically relevant animal models. The materials are also tested for corneal applications using ex vivo pig cornea models complemented by in vitro cell compatibility assays. [ABSTRACT FROM AUTHOR]

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 relationship to channel function, 81 patients (36 female, 44%, 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 standard deviations below the norm-referenced mean of the test). Epileptic spasms were significantly more common in infant-onset (67%) than in neonatal (22%) or later-onset (29%) epilepsy (P = 0.007). Primary phenotype was 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 to severe and complete loss of function in later-onset epilepsy and autism groups. Exploratory cluster analysis identified five groups, representing: (i) primarily later-onset epilepsy with moderate loss-of-function variants and low severity indices; (ii) mostly infant-onset epilepsy with moderate loss-of-function variants but higher severity indices; and (iii) late-onset and autism only, with the lowest severity indices (mostly zero) 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 relationship 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 towards 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. [ABSTRACT FROM AUTHOR]

The article is an introduction to the latest issue of Public Culture, which features a range of topics related to chronopolitics, or the forms and terrains of time. The issue includes conversations with artist Shahzia Sikander and historian Faisal Devji about Sikander's public installations, as well as articles on postcolonial architecture in Nigeria, Philip Morris' involvement with Auschwitz, settler colonialism in Canada, Turkey's influence in Guinea-Conakry, and the concept of "sacropolitics" in contemporary political life. The article also mentions the new editor in chief, Vyjayanthi Rao, and bids farewell to an assistant editor. [Extracted from the article]

ABSTRACT To reduce possible ecological impact from oil spill events, the chemical dispersant Corexit 9500A (C-9500A) is approved for widespread application. Interactions with changing environmental factors such as temperature are [...]

The rapidly growing racially diverse ageing population in the United States presents unique challenges for the country's social, economic, and healthcare systems. Rising health care costs, increased patient cost-sharing, and limited financial resources make this generation of older Americans susceptible to large medical bills or debt, which disproportionally impacts older adults who are from racial/ethnic minority communities. Cost of care (CoC) conversations between patients and healthcare providers is one recommended approach for containing healthcare costs and alleviating patients' financial burden of care. The current study used focus group methods to qualitatively explore the contextual factors that influence CoC conversations in a diverse sample of older adults (N = 27). Three focus groups were held with non-Hispanic White (n = 10), Black/African American (n = 9), and Hispanic (n = 8) participants. Thematic analysis yielded four broad themes. The results suggest that CoC conversations do not occur with physicians. The facilitators of CoC conversations included positive provider affect, rapport/relationship building, and communication. Barriers included lack of physician training, wait time, lack of focus on the patient, language, provider preferences, fear of physicians, and religion. There were significant differences in the facilitators and barriers across racial/ethnic groups. It is critical for physicians to have the tools and training to successfully discuss CoC with older patients. Cultural competency training and provider awareness of patient preferences and expectations may be important when it comes to enhancing rapport and increase the likelihood of these important conversations within racial/ethnic minority communities. [ABSTRACT FROM AUTHOR]