Methotrexate Scarcity Among Children's Oncology Group Institutions: Results of a Multinational Survey.

Shortages of curative chemotherapy agents for children and adults with cancer are ubiquitous. These shortages directly result in compromised outcomes, increased medication errors, heightened cost to health systems, and patient deaths. Methotrexate is a staple of many curative childhood cancer regimens and is frequently in scarcity. No national guidance to manage methotrexate and other chemotherapy shortages exists. To assess the effect of the current methotrexate shortage, a multinational survey of Children's Oncology Group (COG) member institutions was conducted. Wide variation in the scope of methotrexate shortage in the US was demonstrated; some centers experienced significant scarcity while others experienced no shortage. Methotrexate mitigation strategies differed by COG site, resulting in potential to exacerbate differential access to life-saving medication and inequities in care. Preventing chemotherapy shortages remains a challenge. In the interim, standard guidance to assist clinicians to equitably and fairly cope with methotrexate and related drug shortages is needed.

Evaluation of a retinol containing topical treatment to improve signs of neck aging.

BACKGROUND: The neck region is an area that can be indicative of signs of skin aging. A novel topical product that combines multiple active ingredients including retinol, tripeptide and glaucine was formulated to specifically target neck aging correction and complement post-procedure as part of an integrated skincare regimen. OBJECTIVES: To evaluate the efficacy of a topical neck treatment through clinical subject evaluation, in addition to ultrasound and biopsy assessment. METHODS: Evaluation for the efficacy of this novel topical product on improving the aging signs of neck skin was performed in multiple clinical trials. The first trial focused on clinical efficacy and included clinical assessment, subject questionnaires, ultrasound imaging and digital photographs. The second trial focused on biomarker analysis through skin biopsy. RESULTS: Data from the clinical trials showed that aging signs on the neck were significantly improved after 12 or 16 weeks of product usage. Changes were readily observed by clinical evaluators and participants. They were documented with digital photos, ultrasound images, and biomarker expression in the skin which clearly display the improvements. CONCLUSIONS: This novel topical product is effective in treating the aging signs on the neck skin and has been shown to provide statistically significant improvement on a myriad of neck aging attributes including fine lines/wrinkles, crepiness, laxity, and texture.

Managing Prognosis in Precision Medicine: Utility, Imagination, and Communication.

Research on how physicians predict and communicate prognosis focuses primarily on end-of-life care. Unsurprisingly, as genomic technology gains traction as a prognostic tool, the focus has also been on terminality, with research focused on how genetic results may be used to terminate pregnancies or redirect care towards palliation for neonates. However, genomic results also have powerful impacts on how patients who live prepare for their futures. Genomic testing provides broad-reaching and early-albeit complex, uncertain, and shifting-prognostic information. In this essay, we argue that as genomic testing occurs earlier and increasingly in a screening context, researchers and clinicians must strive to understand and manage the prognostic implications of results. While our understanding of the psychosocial and communicational aspects of prognosis in symptomatic populations is incomplete, it has progressed further than our understanding in a screening context and therefore provides useful lessons and feasible opportunities for further research. By providing an interdisciplinary and inter-specialty perspective on the psychosocial and communicational aspects of prognosis in genetics, we discuss prognostication with respect to genetics from the neonatal period through adulthood, highlighting medical specialties and patient populations that are especially informative for considering the longitudinal management of prognostic information in genomic medicine.

An eco-friendly system for stabilization of retinol: A step towards attending performance with improved environmental respect.

OBJECTIVE: Retinol (Vitamin A) is one of the most effective molecules for the treatment of skin aging. However, it degrades rapidly under the influence of light, oxygen, metal ions, and oxidizing agents. To prevent this, stabilizing systems are used commonly. Notably, butylated hydroxytoluene (2,6-di-tert-butyl-p-cresol) (BHT) and ethylenediaminetetraacetic acid (EDTA) salts exhibit excellent antioxidant and metal-chelating properties but are not eco-friendly. In this study, our goal was to develop a new eco-friendly stabilization system for retinol-based formulations such that the system does not interfere with retinol skin absorption, nor its clinical efficacy. METHODS: An evaluation tool called the Sustainable Product Optimization Tool (SPOT) was used to assess the environmental performance of formulations containing retinol and the various stabilizers investigated. Accelerated stability tests were performed on formulations stored for 2 months at 4 and 45°C (ISO/TR Standard 18811 2018 directives). Long-term stability evaluation was done on formulations stored for 24-months at room temperature. Retinol skin absorption was assessed by the Franz cell method using human skin explants (OECD guideline 428). Finally, a clinical study was performed to evaluate the cosmetic performance of a 0.3% stabilized retinol formulation. RESULTS: N,N'-ethylenediamine disuccinic acid ([S,S]-EDDS isomer) and pentaerythritol tetrakis(3,5-di-tert-butyl-4-hydroxyhydrocinnamate) (PBHC) showed higher biodegradability and a reduced water footprint compared with those of BHT and EDTA. The SPOT simulation gave [S,S]-EDDS + PBHC a score of 10 versus 8.84 for EDTA + BHT. Moreover, [S,S]-EDDS + PBHC better controlled the chemical degradation of retinol compared with EDTA + BHT. Retinol skin absorption was also achieved in the case of a formulation containing [S,S]-EDDS + PBHC, and several skin attributes improved significantly after 12 weeks of product use, with over 75% of the panel perceiving benefits. CONCLUSION: Regarding retinol stabilization, the PBHC + [S,S]-EDDS combination is an eco-friendlier and more effective alternative to BHT + EDTA.

OBJECTIF: Le rétinol est l'une des molécules les plus efficaces sur les signes du vieillissement. Cependant, il se dégrade rapidement, notamment sous l'influence de la lumière, de l'oxygène, des ions métalliques et des oxydants. Il existe des systèmes de stabilisation notamment à base d'hydroxytoluène butylé (2,6-di-tert-butyl-p-crésol) (BHT) et de sels d'acide éthylènediamine tétra acétique (EDTA) qui possèdent respectivement d'excellentes propriétés antioxydantes et chélatrices des métaux bien que certaines études aient montré que les deux présentaient un profil environnemental moins que parfait. Notre objectif était de développer un nouveau système de stabilisation ayant un meilleur respect environnemental. Ce nouveau système plus durable ne doit pas impacter l'absorption cutanée du rétinol, ni son efficacité clinique. MÉTHODES: Un outil d'évaluation appelé SPOT (Sustainable Product Optimization Tool) a été utilisé pour évaluer la performance environnementale des formules contenant du rétinol et des stabilisants. Des tests de stabilité accélérés ont été réalisés 2 mois après la formulation avec des produits gardés à 4°C et 45°C (norme ISO/TR 18811 directives 2018). Les stabilités de longue durée ont été évalués sur des produits gardés 24 mois à la température ambiante. L'absorption cutanée du rétinol a été réalisée par la méthode des cellules de Franz avec des explants de peau humaine (directive OCDE 428). Enfin, une étude clinique a prouvé la performance cosmétique d'une formule de rétinol stabilisé à 0,3%. RÉSULTATS: L'association de l'acide N,N'-éthylènediamine disuccinique (isomère [S,S]-EDDS) et du pentaérythritol tétrakis (3,5-di-tert-butyl-4-hydroxyhydrocinnamate) (PBHC) présente une biodégradabilité plus élevée et une empreinte eau réduite par rapport à BHT et EDTA. La simulation SPOT a donné au [S,S]-EDDS et au PBHC un score de 10 contre 8,84 pour l'EDTA et le BHT. De plus, le [S,S]-EDDS et le PBHC contrôlent mieux la dégradation chimique du rétinol par rapport à l'association BHT plus EDTA. L'absorption cutanée du rétinol a également été obtenue dans une formule contenant du [S,S]-EDDS et du PBHC et plusieurs attributs cutanés ont été significativement améliorés après 12 semaines d'utilisation du produit. Les bénéfices ont été perçus par plus de 75% du panel testé CONCLUSION: Concernant la stabilisation du rétinol, l'association PBHC et [S,S]-EDDS est une alternative plus écologique et plus performante que le BHT et l'EDTA.

Locoregional CAR T cells for children with CNS tumors: Clinical procedure and catheter safety.

Central nervous system (CNS) tumors are the most common solid malignancy in the pediatric population. Based on adoptive cellular therapy's clinical success against childhood leukemia and the preclinical efficacy against pediatric CNS tumors, chimeric antigen receptor (CAR) T cells offer hope of improving outcomes for recurrent tumors and universally fatal diseases such as diffuse intrinsic pontine glioma (DIPG). However, a major obstacle for tumors of the brain and spine is ineffective T cell chemotaxis to disease sites. Locoregional CAR T cell delivery via infusion through an intracranial catheter is currently under study in multiple early phase clinical trials. Here, we describe the Seattle Children's single-institution experience including the multidisciplinary process for the preparation of successful, repetitive intracranial T cell infusion for children and the catheter-related safety of our 307 intracranial CAR T cell doses.

Sensitivity to orthographic vs. phonological constraints on word recognition: An ERP study with deaf and hearing readers.

The role of phonology in word recognition has previously been investigated using a masked lexical decision task and transposed letter (TL) nonwords that were either pronounceable (barve) or unpronounceable (brvae). We used event-related potentials (ERPs) to investigate these effects in skilled deaf readers, who may be more sensitive to orthotactic than phonotactic constraints, which are conflated in English. Twenty deaf and twenty hearing adults completed a masked lexical decision task while ERPs were recorded. The groups were matched in reading skill and IQ, but deaf readers had poorer phonological ability. Deaf readers were faster and more accurate at rejecting TL nonwords than hearing readers. Neither group exhibited an effect of nonword pronounceability in RTs or accuracy. For both groups, the N250 and N400 components were modulated by lexicality (more negative for nonwords). The N250 was not modulated by nonword pronounceability, but pronounceable nonwords elicited a larger amplitude N400 than unpronounceable nonwords. Because pronounceable nonwords are more word-like, they may incite activation that is unresolved when no lexical entry is found, leading to a larger N400 amplitude. Similar N400 pronounceability effects for deaf and hearing readers, despite differences in phonological sensitivity, suggest these TL effects arise from sensitivity to lexical-level orthotactic constraints. Deaf readers may have an advantage in processing TL nonwords because of enhanced early visual attention and/or tight orthographic-to-semantic connections, bypassing the phonologically mediated route to word recognition.

What's in a Name? Parents' and Healthcare Professionals' Preferred Terminology for Pathogenic Variants in Childhood Cancer Predisposition Genes.

Current literature/guidelines regarding the most appropriate term to communicate a cancer-related disease-causing germline variant in childhood cancer lack consensus. Guidelines also rarely address preferences of patients/families. We aimed to assess preferences of parents of children with cancer, genetics professionals, and pediatric oncologists towards terminology to describe a disease-causing germline variant in childhood cancer. Using semi-structured interviews we asked participants their most/least preferred terms from; 'faulty gene,' 'altered gene,' 'gene change,' and 'genetic variant,' analyzing responses with directed content analysis. Twenty-five parents, 6 genetics professionals, and 29 oncologists participated. An equal number of parents most preferred 'gene change,' 'altered gene,' or 'genetic variant' (n = 8/25). Parents least preferred 'faulty gene' (n = 18/25). Half the genetics professionals most preferred 'faulty gene' (n = 3/6); however this was least preferred by the remaining genetics professionals (n = 3/6). Many oncologists most preferred 'genetic variant' (n = 11/29) and least preferred 'faulty gene' (n = 19/29). Participants across all groups perceived 'faulty gene' as having negative connotations, potentially placing blame/guilt on parents/children. Health professionals described challenges selecting a term that was scientifically accurate, easily understood and not distressing to families. Lack of consensus highlights the need to be guided by families' preferred terminology, while providing accurate explanations regarding implications of genetic findings.

Returning a Shelter Dog: The Role of Owner Expectations and Dog Behavior.

Millions of animals are adopted from animal shelters in the United States each year, although some are returned post-adoption, which can decrease both the animals' chances of future adoptions and the owners' willingness to adopt again. In this study, we investigated the impact of adopter expectations for ownership and animal behavioral problems on post-adoptive dog returns at a large animal shelter in South Carolina. Between June-September 2021, 132 dog adopters completed a survey about their expectations for ownership through Qualtrics. Twenty-nine adopters returned their dogs to the shelter within three months of adoption, with a median length of ownership of eight days. Owners completed follow-up questionnaires about their perceptions of adoption and dog behavior at two days, two weeks, and four months post-adoption. Categorical principal component analysis revealed three factors pertaining to adopters' expectations for ownership. Independent t-tests showed returning owners had significantly higher expectations for dog behavior and health (t = -2.32, p = 0.02) and the human-dog bond compared with non-returning owners (t = -2.36, p = 0.02). Expectations for ownership responsibilities did not differ between the groups. Two-thirds of adopters experienced dog behavioral problems post-adoption, although training difficulty decreased significantly between two days and four months (F = 5.22, p = 0.01) and nonsocial fear decreased between two weeks and four months post-adoption (X2 = 10.17, p = 0.01). Shelters may benefit from utilizing adoption counselling to ensure adopters understand the potential for dog behavioral problems in the early stages of ownership and develop appropriate expectations for the human-dog relationship. Post-adoption behavioral support may also help some owners to overcome behavioral difficulties as their dogs adapt to the new environment.

Fingerspelling and Its Role in Translanguaging.

Fingerspelling is a critical component of many sign languages. This manual representation of orthographic code is one key way in which signers engage in translanguaging, drawing from all of their linguistic and semiotic resources to support communication. Translanguaging in bimodal bilinguals is unique because it involves drawing from languages in different modalities, namely a signed language like American Sign Language and a spoken language like English (or its written form). Fingerspelling can be seen as a unique product of the unified linguistic system that translanguaging theories purport, as it blends features of both sign and print. The goals of this paper are twofold: to integrate existing research on fingerspelling in order to characterize it as a cognitive-linguistic phenomenon and to discuss the role of fingerspelling in translanguaging and communication. We will first review and synthesize research from linguistics and cognitive neuroscience to summarize our current understanding of fingerspelling, its production, comprehension, and acquisition. We will then discuss how fingerspelling relates to translanguaging theories and how it can be incorporated into translanguaging practices to support literacy and other communication goals.

Are form priming effects phonological or perceptual? Electrophysiological evidence from American Sign Language.

Form priming has been used to identify and demarcate the processes that underlie word and sign recognition. The facilitation that results from the prime and target being related in form is typically interpreted in terms of pre-activation of linguistic representations, with little to no consideration for the potential contributions of increased perceptual overlap between related pairs. Indeed, isolating the contribution of perceptual similarity is impossible in spoken languages; there are no listeners who can perceive speech but have not acquired a sound-based phonological system. Here, we compared the electrophysiological indices of form priming effects in American Sign Language between hearing non-signers (i.e., who had no visual-manual phonological system) and deaf signers. We reasoned that similarities in priming effects between groups would most likely be perceptual in nature, whereas priming effects that are specific to the signer group would reflect pre-activation of phonological representations. Behavior in the go/no-go repetition detection task was remarkably similar between groups. Priming in a pre-N400 window was also largely similar across groups, consistent with an early effect of perceptual similarity. However, priming effects diverged between groups during the subsequent N400 and post-N400 windows. Signers had more typical form priming effects and were especially attuned to handshape overlap, whereas non-signers did not exhibit an N400 component and were more sensitive to location overlap. We attribute this pattern to an interplay between perceptual similarity and phonological knowledge. Perceptual similarity contributes to early phonological priming effects, while phonological knowledge tunes sensitivity to linguistically relevant dimensions of perceptual similarity.

Pediatric Emergency Medicine Didactics and Simulation (PEMDAS) Telesimulation Series: Hyperleukocytosis.

Introduction: Hyperleukocytosis, an infrequent presentation of new-onset leukemia, is a medical emergency requiring prompt recognition and treatment. It can include altered mental status, fever, critical electrolyte derangements, and coagulopathies. Due to the COVID-19 pandemic, this simulation was created as a telesimulation in order to adhere to mandatory physical distancing guidelines while addressing learning objectives. Methods: This simulation was designed for pediatric emergency medicine fellows and featured a pediatric patient presenting with fever, altered mental status, and respiratory distress. After an initial assessment and appropriate workup, the patient developed tumor lysis syndrome, coagulopathies, and new-onset neurologic changes requiring appropriate interventions. A debriefing guide and participant evaluation form were utilized. Results: This telesimulation was implemented at five different institutions, with evaluation surveys completed by 22 pediatric emergency medicine fellows. The scenario was rated on a 5-point Likert scale (1 = strongly disagree, 5 = strongly agree) and was generally well received, with participants rating the simulation as effective in teaching the recognition (M = 4.8) and management (M = 4.6) of hyperleukocytosis. Participants felt that virtual telesimulation was effective compared to other distance learning methods (M = 3.9). Discussion: This simulation-based curriculum allows learners to practice identifying and managing hyperleukocytosis. We found that it was well received in both in-person and virtual formats.

The neurocognitive basis of skilled reading in prelingually and profoundly deaf adults.

Deaf individuals have unique sensory and linguistic experiences that influence how they read and become skilled readers. This review presents our current understanding of the neurocognitive underpinnings of reading skill in deaf adults. Key behavioural and neuroimaging studies are integrated to build a profile of skilled adult deaf readers and to examine how changes in visual attention and reduced access to auditory input and phonology shape how they read both words and sentences. Crucially, the behaviours, processes, and neural circuity of deaf readers are compared to those of hearing readers with similar reading ability to help identify alternative pathways to reading success. Overall, sensitivity to orthographic and semantic information is comparable for skilled deaf and hearing readers, but deaf readers rely less on phonology and show greater engagement of the right hemisphere in visual word processing. During sentence reading, deaf readers process visual word forms more efficiently and may have a greater reliance on and altered connectivity to semantic information compared to their hearing peers. These findings highlight the plasticity of the reading system and point to alternative pathways to reading success.

The organization of the American Sign Language lexicon: Comparing one- and two-parameter ERP phonological priming effects across tasks.

We used phonological priming and ERPs to investigate the organization of the lexicon in American Sign Language. Across go/no-go repetition detection and semantic categorization tasks, targets in related pairs that shared handshape and location elicited smaller N400s than targets in unrelated pairs, indicative of facilitated processing. Handshape-related targets also elicited smaller N400s than unrelated targets, but only in the repetition task. The location priming effect reversed direction across tasks, with slightlylargeramplitude N400s for targets in related versus unrelated pairs in the semantic task, indicative of interference. These patterns imply that handshape and location play different roles during sign recognition and that there is a hierarchical organization for the sign lexicon. Similar to interactive-activation models of word recognition, we argue for differentiation between sublexical facilitation and lexical competition. Lexical competition is primarily driven by the location parameter and is more engaged when identification of single lexico-semantic entries is required.

Lineage Switch in an Infant B-Lymphoblastic Leukemia With t(1;11)(p32;q23); KMT2A/EPS15, Following Blinatumomab Therapy.

We report a 6 month-old infant girl with t(1;11)(p32;q23), KMT2A/EPS15-rearranged B-acute lymphoblastic leukemia (B-ALL) that was refractory to traditional ALL-directed chemotherapy. Following administration of blinatumomab, she experienced lineage switch from B-ALL to acute myeloid leukemia (AML). Myeloid-directed chemotherapy resulted in clearance of AML by flow cytometry, though a residual CD19+ B-ALL population persisted (0.14%). Following bridging blinatumomab, the patient achieved B-ALL and AML remission, as measured by flow cytometry. The patient subsequently underwent allogeneic hematopoietic stem cell transplant. Unfortunately, she relapsed with CD19+ B-ALL one-month post-transplantation. Next generation sequencing study of IGH/IGL using ClonoSEQ® analysis detected 3 dominant sequences all present in her original B-ALL, lineage switched AML, and post-transplant relapsed B-ALL, though the latter showed an additional 4 sequences, three of which were present at low abundance in the original diagnostic sample. The presence of the same clones throughout her disease course suggests cellular reprogramming and differentiation following chemotherapy and immunotherapy. This is the first reported case of lineage switch of B-ALL with t(1;11) and also the first report of a lineage switch case that used ClonoSEQ® to define the clonality of the original B-ALL, lineage switched AML, and relapsed B-ALL.

Can a Parent Refuse the Brain Death Examination?

The American Academy of Neurology believes that doctors have the right to do tests to evaluate whether a patient is brain dead even if the family does not consent. They argue that physicians have "both the moral authority and professional responsibility" to do such evaluations, just as they have the authority and responsibility to declare someone dead by circulatory criteria. Not everyone agrees. Truog and Tasker argue that apnea testing to confirm brain death has risks and that, for some families, those risks may outweigh the benefits. So, what should doctors do when caring for a patient whom they believe to be brain dead but whose parents refuse to allow testing to confirm that the patient meets neurologic criteria for death? In this article, we analyze the issues that arise when parents refuse such testing.