The Type, Severity, and Impact of Sleep Problems in Children With Angelman Syndrome and Parental Help-seeking Patterns.

Angelman syndrome (AS) is a rare genetic developmental disability that presents with high rates of co-occurring sleep difficulties. Most existing research has focused on the pathophysiology of sleep problems in people with AS, and suggests that sleep problems are the result of genetic and neurobiological factors. However, little is known about the role of the social environment and learning in sleep problems in children with AS. This descriptive study used survey data from 139 parents of children with AS to investigate: 1) the type, topography and severity of children's sleep problems; 2) the collateral child, parent and family impacts of the sleep problems; 3) treatment selection practices and the perceived effectiveness of these treatments; and 4) sources of support and treatment advice received. Parents reported that the majority of children experienced sleep problems, resulting in numerous deleterious effects on child and family functioning. They also reported high levels of concern about these sleep problems, but low levels of perceived support. Study findings highlight the need to establish a disability-specific profile of the type and impact of sleep problems experienced by children with AS, and have further implications for the delivery of clinical services and support provided to parents of children with AS.

EVIR: chimeric receptors that enhance dendritic cell cross-dressing with tumor antigens.

We describe a lentivirus-encoded chimeric receptor, termed extracellular vesicle (EV)-internalizing receptor (EVIR), which enables the selective uptake of cancer-cell-derived EVs by dendritic cells (DCs). The EVIR enhances DC presentation of EV-associated tumor antigens to CD8+ T cells primarily through MHCI recycling and cross-dressing. EVIRs should facilitate exploring the mechanisms and implications of horizontal transfer of tumor antigens to antigen-presenting cells.

Ruxolitinib as adjunctive therapy for secondary hemophagocytic lymphohistiocytosis: A case series.

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a cytokine storm syndrome associated with mortality rates of up to 88%. Standard therapy with high-dose glucocorticoids and etoposide used in adults is extrapolated from pediatric trials, with significant toxicity in older patients and those with poor performance status. The JAK1/2 inhibitor ruxolitinib has recently gained attention as a treatment option for HLH due to its broad cytokine-modulating abilities and safety profile. Herein we report our center's experience using ruxolitinib in the treatment of adult-onset secondary HLH. CASE SERIES: We report four patients with profound secondary HLH provoked by diverse triggers, including invasive pulmonary aspergillosis on background systemic lupus erythematosus, disseminated tuberculosis, and T-cell lymphoma treated with ruxolitinib as monotherapy or combination therapy in upfront and salvage settings. RESULTS: All four patients had rapid, sustained improvement in clinical status, inflammatory markers, and hematological cell counts followed by durable remission. Three patients developed manageable infectious complications postruxolitinib. CONCLUSIONS: This series demonstrates the effective use of JAK inhibition with ruxolitinib to control pathological immune activation in critically ill patients with secondary HLH and otherwise limited therapeutic options. JAK inhibition is also an area of urgent investigation for the treatment of cytokine storm associated with COVID-19.

Antimicrobial efficacy and toxicity of novel CAMPs against P. aeruginosa infection in a murine skin wound infection model.

BACKGROUND: Treatment of P. aeruginosa wound infection is challenging due to its inherent and acquired resistance to many conventional antibiotics. Cationic antimicrobial peptides (CAMPs) with distinct modes of antimicrobial action have been considered as the next-generation therapeutic agents. In the present study, a murine skin surgical wound infection model was used to evaluate the in vivo toxicity and efficacy of two newly designed antimicrobial peptides (CAMP-A and CAMP-B), as chemotherapeutic agents to combat P. aeruginosa infection. RESULTS: In the first trial, topical application of CAMPs on the wounds at a dose equivalent to 4 × MIC for 7 consecutive days did not cause any significant changes in the physical activities, hematologic and plasma biochemical parameters, or histology of systemic organs of the treated mice. Daily treatment of infected wounds with CAMP-A and CAMP-B for 5 days at a dose equivalent to 2× MIC resulted in a significant reduction in wound bacterial burden (CAMP-A: 4.3 log10CFU/g of tissue and CAMP-B: 5.8 log10CFU/g of tissue), compared to that of the mock-treated group (8.1 log10CFU/g of tissue). Treatment with CAMPs significantly promoted wound closure and induced epidermal cell proliferation. Topical application of CAMP-A on wounds completely prevented systemic dissemination of P. aeruginosa while CAMP-B blocked systemic infection in 67% of mice and delayed the onset of systemic infection by at least 2 days in the rest of the mice (33%). In a second trial, daily application of CAMP-A at higher doses (5× MIC and 50× MIC) didn't show any significant toxic effect on mice and the treatments with CAMP-A further reduced wound bacterial burden (5× MIC: 4.5 log10CFU/g of tissue and 50× MIC: 3.8 log10CFU/g of tissue). CONCLUSIONS: The data collectively indicated that CAMPs significantly reduced wound bacterial load, promoted wound healing, and prevented hepatic dissemination. CAMP-A is a promising alternative to commonly used antibiotics to treat P. aeruginosa skin infection.

A comparison of implant complications and failures between the maxilla and the mandible.

STATEMENT OF PROBLEM: Identifying factors that affect the clinical outcomes of implant therapy is important. PURPOSE: The purpose of this retrospective study was to determine whether implant location was a factor affecting the complication and failure rates of single-tooth implant-supported restorations in a predoctoral setting. MATERIAL AND METHODS: The charts of 431 patients treated with a surgically placed dental implant and restored with a single crown in the predoctoral clinic were analyzed. Data on implant location, type of complication (surgical or prosthetic), and type of failure were collected and analyzed according to implant location using the Fisher Exact Test and Mantel-Haenszel Exact Chi Square Test analysis (α=.05). RESULTS: The charts revealed 158 complications (68 surgical and 90 prosthetic) in 110 patients, and 3.9% of the implants failed. No statistically significant difference was found between the number of surgical complications or prosthetic complications in the maxilla and the mandible (P=.469). CONCLUSIONS: Jaw location (maxilla compared with mandible) of the implant had no statistically significant impact on the incidence of surgically or prosthetically related complications. No statistically significant difference was found in overall implant failures, surgical failures, and prosthetic failures between maxillary and mandibular implants.

Removal of interscapular brown adipose tissue increases aortic stiffness despite normal systemic glucose metabolism in mice.

Brown adipose tissue (BAT) is considered protective against obesity and related cardiometabolic dysfunction. Indeed, activation of BAT improves glucose homeostasis and attenuates cardiovascular disease development. However, whether a reduction in BAT mass perturbs metabolic function and increases risk for cardiovascular disease remains largely unknown. To address this question, C57BL/6J male mice underwent a sham procedure or surgical bilateral excision of interscapular BAT (iBATx) and were fed a normal chow or a Western diet for 18 wk, creating four groups ( n = 10/group). Mice were housed at 25°C. As expected, the Western diet increased final body weight and adiposity; however, contrary to our hypothesis, iBATx did not potentiate adiposity independent of diet. Furthermore, iBATx did not affect indexes of glycemic control (HbA1c, fasting glucose and insulin, and glucose area under the curve during a glucose tolerance test) and produced minimal-to-no effects on lipid homeostasis. The absence of metabolic disturbances with iBATx was not attributed to regrowth of iBAT or a "browning" or proliferative compensatory response of other BAT depots. Notably, iBATx caused an increase in aortic stiffness in normal chow-fed mice only, which was associated with an increase in aortic uncoupling protein-1. Collectively, we demonstrated that, at 25°C (i.e., limited thermal stress conditions), a substantial reduction in BAT mass via iBATx does not disrupt systemic glucose metabolism, challenging the current dogma that preservation of BAT is obligatory for optimal metabolic function. However, iBATx caused aortic stiffening in lean mice, hence supporting the existence of an interplay between iBAT and aortic stiffness, independent of alterations in glucose homeostasis.

Parents with Intellectual Disabilities Experiencing Challenging Child Routines: A Pilot Study Using Embedded Self-Determination Practices.

BACKGROUND: Practices to facilitate self-determination have not received appropriate attention in research concerning parents with intellectual disabilities (ID). Likewise, parenting interventions for adults with intellectual disabilities have seldom observed both parent and child behavioural outcomes. METHODS: This study evaluated the effectiveness of a parenting intervention embedded with self-determination facilitation practices for two dyads of a parent with intellectual disabilities and their young child. The interventions focused on increasing parents' ability to correctly implement steps of a parenting routine while reducing occurrence of challenging child behaviour. RESULTS: The results of the study demonstrated two basic effects of correctly completed steps of the parenting routine and a reduction of challenging child behaviour. Parents also reported decreased feelings of stress during the routine following completion of the intervention. CONCLUSIONS: Implications for future research and replication of this pilot study are discussed.

Quantitative Analysis of Sexuality and Relationship Education in Inclusive Higher Education: Brief Report.

Inclusive postsecondary education (IPSE) programs support adults with intellectual disabilities' participation in higher education. Students in IPSE programs may have limited knowledge of sexuality, relationships, and social skills, which can be addressed through sexuality and relationship education (SRE). This project evaluated the effect of the Positive Choices© curriculum on the SRE knowledge of 7 students attending an IPSE program in the southeastern United States. Students attended 15 weekly classes taught by two graduate assistants and faculty supervisor during spring 2020; half of course meetings occurred in person and half via Zoom due to COVID-19 restrictions. The authors analyzed results of pre-post one sample t-test of student scores on five instructor-created assessments. All students showed statistically significant increases in knowledge for each assessment and overall. Future research should assess the effect of other curricula in use in IPSE programs and evaluate the need for and use of supplemental materials for instruction.

Incorporating Technology into Instruction in Early Childhood Classrooms: a Systematic Review.

Objectives: The purpose of this review is to describe the variety and effectiveness of instructional technologies used in the early childhood setting. Methods: A systematic review of three databases was completed, and studies were reviewed by two independent coders to determine if they met inclusion criteria. Studies were excluded from this review if (a) the technology was used to train teachers and was not directly used with early childhood students, (b) participants were all enrolled in 2nd grade or higher, (c) the setting was not an early childhood education setting, or (d) studies were descriptive in nature or utilized a survey methodology. Data were extracted from each article related to participant characteristics, setting characteristics, research design, technology type, and dependent variables. Results: Thirty-five studies met criteria were included in this review. A wide range of technologies were used to provide or facilitate instruction on (a) academics, (b) social and communication skills, and (c) cognitive skills. Academic outcomes targeted in Head Start preschools were the most common across studies. The results ranged from no effect to highly effective. Conclusions: The findings from the included studies varied widely in their outcomes from reporting no difference between traditional instruction and technology-aided instruction to reporting significant difference between groups or reporting a functional relation between the technology-based intervention and the target behavior or skill. Studies that included students identified with neurodevelopmental disorders demonstrated a positive impact in the outcomes of students who experience an intervention that included technology-aided instruction. Future research is needed to identify critical components of effective technology-based interventions in early childhood educational settings.

ABT1 modifies SMARD1 pathology via interactions with IGHMBP2 and stimulation of ATPase and helicase activity.

SMA with respiratory distress type 1 (SMARD1) and Charcot-Marie-Tooth type 2S (CMT2S) are results of mutations in immunoglobulin mu DNA binding protein 2 (IGHMBP2). IGHMBP2 is a UPF1-like helicase with proposed roles in several cellular processes, including translation. This study examines activator of basal transcription 1 (ABT1), a modifier of SMARD1-nmd disease pathology. Microscale thermophoresis and dynamic light scattering demonstrate that IGHMBP2 and ABT1 proteins directly interact with high affinity. The association of ABT1 with IGHMBP2 significantly increases the ATPase and helicase activity as well as the processivity of IGHMBP2. The IGHMBP2/ABT1 complex interacts with the 47S pre-rRNA 5' external transcribed spacer and U3 small nucleolar RNA (snoRNA), suggesting that the IGHMBP2/ABT1 complex is important for pre-rRNA processing. Intracerebroventricular injection of scAAV9-Abt1 decreases FVB-Ighmbp2nmd/nmd disease pathology, significantly increases lifespan, and substantially decreases neuromuscular junction denervation. To our knowledge, ABT1 is the first disease-modifying gene identified for SMARD1. We provide a mechanism proposing that ABT1 decreases disease pathology in FVB-Ighmbp2nmd/nmd mutants by optimizing IGHMBP2 biochemical activity (ATPase and helicase activity). Our studies provide insight into SMARD1 pathogenesis, suggesting that ABT1 modifies IGHMBP2 activity as a means to regulate pre-rRNA processing.

Written benefit finding for improving psychological health during the Covid-19 pandemic first wave lockdown.

Objectives. Written benefit finding is known to improve psychological and physical health in a range of patient groups. Here, we tested the efficacy of written benefit finding, delivered online during the Covid-19 pandemic lockdown, on mood and physical symptoms. We also investigated perseverative thinking as a moderator of these effects. Design. A quantitative longitudinal design was employed. Main Outcome Measures. Participants (n = 91) completed self-report measures of anxiety, depression, stress and physical symptoms at baseline, and two weeks after being randomised to complete three consecutive days of writing about the positive thoughts and feelings they experienced during the pandemic (written benefit finding) or to unemotively describe the events of the previous day (control). State anxiety was measured immediately before and after writing. Perseverative thinking was measured at baseline. Results. Anxiety and depression symptoms decreased between baseline and the two week follow-up, but did not differ significantly between the two conditions. Perseverative thinking was negatively associated with changes in symptoms of anxiety, depression and stress, but did not moderate any writing effects. There was a significant reduction in state anxiety in the written benefit finding condition. Conclusions. Written benefit finding may be a useful intervention for short-term improvements in wellbeing.

Influence of genotype and perioral musculature on maxillary and mandibular development.

OBJECTIVES: To determine whether there is an association between skeletal jaw position and perioral musculature, and if genotypes can predict skeletal growth. MATERIALS AND METHODS: A prospective study on 42 patients over 1 year was performed. The study included 22 females and 20 males with and average age of 28.5 years. Lip strength was compared to radiographic cephalometric measurements. Allelic and genotypic frequencies from polymorphisms rs678397 and rs1815739 in ACTN3 and rs10850110 in MYO1H were compared to each variable. Chi-square and Fisher exact tests were used to determine if differences were statistically significant (alpha = 0.05). RESULTS: The data showed significant differences between rs678397 genotype and allele frequencies and SNA angle (P = .01; P = .003, respectively); between rs1815739 allele frequency and SNA angle (P = .01); between rs678397 allele frequency and ANB angle (P = .049); between rs678397 genotype and allele frequencies and lip strength in females (P = .045; P = .02); and between rs678397 allele frequency and overall lip strength (P = .049), after mean strength values used as cut off being customized by sex. CONCLUSIONS: Polymorphisms in ACTN3 are associated with weak lips and larger SNA and ANB angles.

Modular solid-phase synthesis of electrophilic cysteine-selective ethynyl-phosphonamidate peptides.

We report an efficient method to install electrophilic cysteine-selective ethynyl-phosphonamidates on peptides during Fmoc-based solid phase peptide synthesis (SPPS). By performing Staudinger-phosphonite reactions between different solid supported azido-peptides and varying ethynylphosphonites, we obtained ethynyl-phosphonamidate containing peptidic compounds after acidic deprotection, including an electrophilic cell-penetrating peptide that showed high efficiency as an additive for cellular delivery of proteins.

Multi-step recognition of potential 5' splice sites by the Saccharomyces cerevisiae U1 snRNP.

In eukaryotes, splice sites define the introns of pre-mRNAs and must be recognized and excised with nucleotide precision by the spliceosome to make the correct mRNA product. In one of the earliest steps of spliceosome assembly, the U1 small nuclear ribonucleoprotein (snRNP) recognizes the 5' splice site (5' SS) through a combination of base pairing, protein-RNA contacts, and interactions with other splicing factors. Previous studies investigating the mechanisms of 5' SS recognition have largely been done in vivo or in cellular extracts where the U1/5' SS interaction is difficult to deconvolute from the effects of trans-acting factors or RNA structure. In this work we used colocalization single-molecule spectroscopy (CoSMoS) to elucidate the pathway of 5' SS selection by purified yeast U1 snRNP. We determined that U1 reversibly selects 5' SS in a sequence-dependent, two-step mechanism. A kinetic selection scheme enforces pairing at particular positions rather than overall duplex stability to achieve long-lived U1 binding. Our results provide a kinetic basis for how U1 may rapidly surveil nascent transcripts for 5' SS and preferentially accumulate at these sequences rather than on close cognates.

Safety and efficacy of milk and molasses enemas compared with sodium phosphate enemas for the treatment of constipation in a pediatric emergency department.

OBJECTIVES: The purpose of this study was to determine the safety and efficacy of routine milk and molasses enemas (MME) compared with sodium phosphate enemas for the treatment of constipation in the pediatric emergency department (ED). A secondary objective included the identification of factors associated with enema selection in the pediatric ED. METHODS: This study was approved by the University of Texas Southwestern Medical Center Institutional Review Board. The study design was a retrospective comparative chart review. Medical records of patients who presented to the ED and received either MME or sodium phosphate enema for constipation between November 1, 2007, and November 1, 2008, were identified and reviewed for data collection. The following data were collected to determine safety and efficacy: baseline demographics, chief complaint, medical history, radiographic imaging, enema type, treatment dose, adverse effects, improvement in symptoms, time until defecation, failure of initial therapy requiring additional intervention, and time from treatment until disposition. RESULTS: Both treatment groups had similar baseline characteristics. No statistically significant differences in treatment effect were noted between MME and sodium phosphate enemas. Several clinically significant trends were noted including the need for additional rectal treatment after administration of sodium phosphate enemas versus oral therapy after MME. In addition, there were 6 cases of treatment failure with sodium phosphate enemas versus 1 case with MME. CONCLUSIONS: No statistically significant differences were found between MME and sodium phosphate enemas. Based on our results, the 2 treatment options were found to be equally safe and effective.

A 3D-printed Apparatus for Imaging Multiple Rats Simultaneously.

CT (computerized tomography) is a necessary imaging modality for cancer staging and disease monitoring. Rodent models of cancer are commonly studied prior to human clinical trials, but CT in rodents can be difficult due to their small size and constant movement, which necessitates general anesthesia. Because microCT equipment is not always available, clinical CT may be a viable alternative. Limitations of microCT and clinical CT include biosecurity, anesthesia to limit image distortion due to motion, and cost. To address several of these constraints, we created a 3D-printed apparatus that accommodated simultaneous imaging of as many as 9 rats under gas anesthesia. Rats were anesthetized in series and placed in a 3 × 3 arrangement. To assess differences in attenuation between individual chambers and rows or columns in the device, we first imaged a standardized phantom plug as a control. We hypothesized that attenuation of specific rat organs would not be affected regardless of the location or position in the 3D-printed device. Four organs-liver, kidney, femur, and brain-were evaluated in 9 rats. For both the phantom and kidneys, statistically significant, but clinically negligible, effects on attenuation were noted between rows but not between columns. We attribute this finding to the absence of a top layer of the apparatus, which thus created asymmetric attenuation and beam hardening through the device. This apparatus allowed us to successfully image 9 rats simultaneously in a clinical CT machine, with negligible effects on attenuation. Planned improvements in this apparatus include completely enclosed versions for biosecure imaging.

Caring for Maya: A Family, Pediatrician, and Complex Care Partnership.

Coordinating care to meet the robust needs of children with medical complexity and their families is challenging, especially in the setting of a busy primary care practice. This article describes the experience of one family and pediatrician and highlights specific factors, such as a focus on building relationships, meaningful and structured information-sharing, and partnership with a complex care program, that can positively affect care. [Pediatr Ann. 2020;49(11):e486-e490.].

Working with Dual Diagnoses: A Survey of Teachers Serving Deaf or Hard of Hearing Children Who Have Autism Spectrum Disorder.

Although a sizable minority of students who are deaf or hard of hearing (DHH) are also diagnosed with autism spectrum disorder (ASD), there is little research examining teachers' feelings of aptitude for working with these students, nor the instructional strategies used with this population. This study reports results from a researcher-designed survey of teachers working with children who are both DHH and have ASD. Our results suggest that teachers working with this population felt under-resourced, under-prepared, and under-supported in their work with dually diagnosed students. Perhaps as a result, participants tended to use instructional strategies common to their certification area. We identify a need for cross-training teachers across disability areas. In addition, we call for research that tests the applicability of practices in either Deaf Education or ASD Education for dually diagnosed children who may have needs that are unique from children either group.

Quantitative-Analysis of Behavioral Interventions to Treat Sleep Problems in Children with Autism.

Sleep is an essential activity for human development. Often, children with autism spectrum disorder (ASD) are affected by a lack of sleep due to various types of sleep problems. We identified and analyzed studies that were aimed at utilizing sleep interventions for children with ASD. A systematic search of databases, reference lists, and ancestral searches identified 18 studies for inclusion. Studies were summarized in terms of (a) participants, (b) targeted sleep problem and measures, (d) intervention components, (e) research design and rigor, and (f) results. The aim of this review was to analyze the literature by evaluating the most commonly treated sleep problems, the various treatment components, and strength of the results using a between case parametric effect size estimate. The most commonly treated sleep problems were night wakings and bedtime disturbance. For interventions, all the studies incorporated multiple treatment components, most often including the use of a consistent bedtime routine. Effect size calculations indicated a moderate effect size, however, limited due to the small number of studies. Results suggest the overall effectiveness of behavioral interventions for the treatment of sleep problems for children with ASD. Based on our analysis, suggestions for practitioners regarding current practices and future directions for research are discussed.

Attributions, causal beliefs, and help-seeking behavior of parents of children with autism spectrum disorder and sleep problems.

LAY ABSTRACT: Sleep problems are commonly reported among parents of children with autism spectrum disorder (ASD). Without effective treatment, such problems are unlikely to resolve. To date, we know very little about how and why parents of children with ASD seek help for sleep disturbance. Via an online survey, we gathered information about how parents make sense of their children's sleep problems, beliefs about their causes, sources of information, and help-seeking behavior. The analysis of responses from 244 parents revealed that parents commonly view sleep problems (a) as a consequence of their child's ASD, and unlikely to change over time (stable), and (b) as located within the child (intrinsic), stable over time, and difficult to treat. Despite this, parents also rated sleep problems as being important to treat. Eighty-two percent of parents surveyed reported seeking some kind of help for their child's sleep disturbance, and the average parent had tried six different treatment strategies, most commonly medical approaches (e.g. melatonin). The alignment between parents' treatment choices and those strategies that are supported by research was poor, but belief in the effectiveness of treatments was closely related to how often the treatment was used. These findings have important implications for parental education and clinical practice in the treatment of sleep problems in children with ASD.