COVID-19 Related Facilitators and Barriers to In-Person Learning for Children With Intellectual and Development Disabilities: A Follow-Up.

BACKGROUND: Students with intellectual and developmental disabilities (IDD) and the staff who support them were largely in-person during the 2021-2022 school year, despite their continued vulnerability to infection with SARS-CoV-2. This qualitative study aimed to understand continued perceptions of weekly SARS-CoV-2 screening testing of students and staff amidst increased availability of vaccinations. METHODS: Twenty-three focus groups were held with school staff and parents of children with IDD to examine the perceptions of COVID-19 during the 2021-2022 school year. Responses were analyzed using a directed thematic content analysis approach. RESULTS: Four principal themes were identified: strengths and opportunities of school- and district-level mitigation policies; experience at school with the return to in-person learning; facilitators and barriers to participation in SARS-CoV-2 screening testing; and perceptions of SARS-CoV-2 testing in light of vaccine availability. IMPLICATIONS FOR SCHOOL HEALTH POLICY, PRACTICE, AND EQUITY: Despite the increased availability of vaccines, school staff and families agreed that saliva-based SARS-CoV-2 screening testing helped increase comfort with in-person learning as long as the virus was present in the community. CONCLUSION: To keep children with IDD in school during the pandemic, families found SARS-CoV-2 screening testing important. Clearly communicating school policies and mitigation strategies facilitated peace of mind and confidence in the school district.

COVID-19-Related Facilitators and Barriers to In-Person Learning for Children With Intellectual and Development Disabilities.

BACKGROUND: Schools provide essential functions for children with intellectual and developmental disabilities (IDD), but their vulnerability to infection with SARS-CoV-2 are a barrier to in-person learning. This qualitative study aimed to understand how weekly SARS-CoV-2 screening testing of students and staff could best facilitate in-school learning during the pandemic. METHODS: Thirty-one focus groups were held with school staff and parents of children with IDD to examine the perceptions of COVID-19 during the 2020-2021 school year. Responses were analyzed using a directed thematic content analysis approach. RESULTS: Five principal themes were identified: risks of returning to in-person learning; facilitators and barriers to participation in SARS-CoV-2 screening testing; messaging strategies; and preferred messengers. IMPLICATIONS FOR SCHOOL HEALTH POLICY, PRACTICE, AND EQUITY: Staff and families agreed that saliva-based SARS-CoV-2 screening testing helps increase comfort with in-person learning. Screening testing increased family and school staff comfort with in-person learning particularly because many students with special needs cannot adhere to public health guidelines. CONCLUSION: To keep children with IDD in school during the pandemic, families found SARS-CoV-2 screening testing important, particularly for students that cannot adhere to mitigation guidelines.

Soluble Receptor for Advanced Glycation End Products (sRAGE) Isoforms Predict Changes in Resting Energy Expenditure in Adults with Obesity during Weight Loss.

Background: Accruing evidence indicates that accumulation of advanced glycation end products (AGEs) and activation of the receptor for AGEs (RAGE) play a significant role in obesity and type 2 diabetes. The concentrations of circulating RAGE isoforms, such as soluble RAGE (sRAGE), cleaved RAGE (cRAGE), and endogenous secretory RAGE (esRAGE), collectively sRAGE isoforms, may be implicit in weight loss and energy compensation resulting from caloric restriction. Objectives: We aimed to evaluate whether baseline concentrations of sRAGE isoforms predicted changes (∆) in body composition [fat mass (FM), fat-free mass (FFM)], resting energy expenditure (REE), and adaptive thermogenesis (AT) during weight loss. Methods: Data were collected during a behavioral weight loss intervention in adults with obesity. At baseline and 3 mo, participants were assessed for body composition (bioelectrical impedance analysis) and REE (indirect calorimetry), and plasma was assayed for concentrations of sRAGE isoforms (sRAGE, esRAGE, cRAGE). AT was calculated using various mathematical models that included measured and predicted REE. A linear regression model that adjusted for age, sex, glycated hemoglobin (HbA1c), and randomization arm was used to test the associations between sRAGE isoforms and metabolic outcomes. Results: Participants (n = 41; 70% female; mean ± SD age: 57 ± 11 y; BMI: 38.7 ± 3.4 kg/m2) experienced modest and variable weight loss over 3 mo. Although baseline sRAGE isoforms did not predict changes in ∆FM or ∆FFM, all baseline sRAGE isoforms were positively associated with ∆REE at 3 mo. Baseline esRAGE was positively associated with AT in some, but not all, AT models. The association between sRAGE isoforms and energy expenditure was independent of HbA1c, suggesting that the relation was unrelated to glycemia. Conclusions: This study demonstrates a novel link between RAGE and energy expenditure in human participants undergoing weight loss.This trial was registered at clinicaltrials.gov as NCT03336411.

Alterations in ventricular K(ATP) channel properties during aging.

Coronary heart disease remains the principle cause of mortality in the United States. During aging, the efficiency of the cardiovascular system is decreased and the aged heart is less tolerant to ischemic injury. ATP-sensitive K(+) (K(ATP)) channels protect the myocardium against ischemic damage. We investigated how aging affects cardiac K(ATP) channels in the Fischer 344 rat model. Expression of K(ATP) channel subunit mRNA and protein levels was unchanged in hearts from 26-month-old vs. 4-month-old rats. Interestingly, the mRNA expression of several other ion channels (> 80) was also largely unchanged, suggesting that posttranscriptional regulatory mechanisms occur during aging. The whole-cell K(ATP) channel current density was strongly diminished in ventricular myocytes from aged male rat hearts (also observed in aged C57BL/6 mouse myocytes). Experiments with isolated patches (inside-out configuration) demonstrated that the K(ATP) channel unitary conductance was unchanged, but that the inhibitory effect of cytosolic ATP on channel activity was enhanced in the aged heart. The mean patch current was diminished, consistent with the whole-cell data. We incorporated these findings into an empirical model of the K(ATP) channel and numerically simulated the effects of decreased cytosolic ATP levels on the human action potential. This analysis predicts lesser activation of K(ATP) channels by metabolic impairment in the aged heart and a diminished action potential shortening. This study provides insights into the changes in K(ATP) channels during aging and suggests that the protective role of these channels during ischemia is significantly compromised in the aged individual.

S100P-derived RAGE antagonistic peptide reduces tumor growth and metastasis.

PURPOSE: The receptor for advanced glycation end products (RAGE) contributes to multiple pathologies, including diabetes, arthritis, neurodegenerative diseases, and cancer. Despite the obvious need, no RAGE inhibitors are in common clinical use. Therefore, we developed a novel small RAGE antagonist peptide (RAP) that blocks activation by multiple ligands. EXPERIMENTAL DESIGN: RAGE and its ligands were visualized by immunohistochemical analysis of human pancreatic tissues, and siRNA was used to analyze their functions. Interactions between RAGE and S100P, S100A4, and HMGB-1 were measured by ELISA. Three S100P-derived small antagonistic peptides were designed, synthesized, and tested for inhibition of RAGE binding. The effects of the peptide blockers on NFκB-luciferase reporter activity was used to assess effects on RAGE-mediated signaling. The most effective peptide was tested on glioma and pancreatic ductal adenocarcinoma (PDAC) models. RESULTS: Immunohistochemical analysis confirmed the expression of RAGE and its ligands S100P, S100A4, and HMGB-1 in human PDAC. siRNA silencing of RAGE or its ligands reduced the growth and migration of PDAC cells in vitro. The most effective RAP inhibited the interaction of S100P, S100A4, and HMGB-1 with RAGE at micromolar concentrations. RAP also reduced the ability of the ligands to stimulate RAGE activation of NFκB in cancer cells in vitro and in vivo. Importantly, systemic in vivo administration of RAP reduced the growth and metastasis of pancreatic tumors and also inhibited glioma tumor growth. CONCLUSION: RAP shows promise as a tool for the investigation of RAGE function and as an in vivo treatment for RAGE-related disorders.

RAGE and its ligands in retinal disease.

RAGE, the receptor for advanced glycation endproducts (AGEs), is a multiligand signal transduction receptor of the immunoglobulin superfamily of cell surface molecules that has been implicated in the pathogenesis of diabetic complications, neurodegenerative diseases, inflammatory disorders, and cancer. These diverse biologic disorders reflect the multiplicity of ligands capable of cellular interaction via RAGE that include, in addition to AGEs, amyloid-beta (Abeta) peptide, the S100/calgranulin family of proinflammatory cytokines, and amphoterin, a member of the High Mobility Group Box (HMGB) DNA-binding proteins. In the retina, RAGE expression is present in neural cells, the vasculature, and RPE cells, and it has also been detected in pathologic cellular retinal responses including epiretinal and neovascular membrane formation. Ligands for RAGE, in particular AGEs, have emerged as relevant to the pathogenesis of diabetic retinopathy and age-related macular disease. While the understanding of RAGE and its role in retinal dysfunction with aging, diabetes mellitus, and/or activation of pro-inflammatory pathways is less complete compared to other organ systems, increasing evidence indicates that RAGE can initiate and sustain significant cellular perturbations in the inner and outer retina. For these reasons, antagonism of RAGE interactions with its ligands may be a worthwhile therapeutic target in such seemingly disparate, visually threatening retinal diseases as diabetic retinopathy, age-related macular degeneration, and proliferative vitreoretinopathy.

Interstitial deletion of chromosome 12q: genotype-phenotype correlation of two patients utilizing array comparative genomic hybridization.

Interstitial deletions of chromosome 12q are rare, with only 11 reported cases in the literature. We recently described two cases with cytogenetically identical interstitial deletions of the long arm of chromosome 12. Here, we report on a third patient, a 26-month-old male with a cytogenetically-identical interstitial deletion: 46,XY,del(12)(q21.2q22). Phenotypic features of this male proband included craniofacial and ectodermal anomalies, genitourinary anomalies, minor cardiac abnormalities, mild ventriculomegaly on brain MRI, hyperopia, and developmental delay. To further define the extent of the chromosomal aberration, microarray-based comparative genomic hybridization (array CGH) analysis was performed and the array data was compared to one of our previously reported cases. Although cytogenetic analysis of the two patients was concordant, molecular analysis by array CGH revealed that the patients had discordant distal breakpoints. The determination of molecular breakpoints and phenotypic analyses in these two patients, in conjunction with previously reported cases, leads us to propose a 12q deletion phenotype and a possible genetic locus for hyperkeratosis pilaris/ulerythema ophryogenes.

Human immunodeficiency virus type 2 DNA vaccine provides partial protection from acute baboon infection.

We determined if the genetic adjuvants, granulocyte-macrophage colony stimulating factor (GM-CSF) and B7-2, could improve the immunogenicity and efficacy of an HIV-2 DNA vaccine. The vaccine consisted of the HIV-2 tat, nef, gag, and env genes synthesized using optimized codons and formulated with cationic liposomes. Baboons (Papio cynocephalus hamadryas) were immunized by the intramuscular, intradermal, and intranasal routes with these expression constructs and challenged with HIV-2(UC2) by the intravaginal route. In the first month after HIV-2 vaginal challenge, the baboons receiving the HIV-2 DNA vaccine with or without the genetic adjuvants had significant reductions in the viral loads in the peripheral blood mononuclear cells (PBMC) (P = 0.028) while the reductions in their plasma viremia were suggestive of a protective effect (P = 0.1). These data demonstrate that partial protection against HIV-2 vaginal challenge, as measured by reduced viral load, can be achieved using only a DNA vaccine formulation.

Advanced glycation end products induce tubular epithelial-myofibroblast transition through the RAGE-ERK1/2 MAP kinase signaling pathway.

Advanced glycation end products (AGEs) have been shown to play a role in tubular epithelial-myofibroblast transdifferentiation (TEMT) in diabetic nephropathy, but the intracellular signaling pathway remains unknown. We report here that AGEs signal through the receptor for AGEs (RAGE) to induce TEMT, as determined by de novo expression of a mesenchymal marker (alpha-smooth muscle actin, alpha-SMA) and loss of epithelial marker (E-cadherin), directly through the MEK1-ERK1/2 MAP kinase pathway, which is TGF-beta independent. This is supported by the following findings: AGEs induced de novo alpha-SMA mRNA expression as early as 2 hours followed by a loss of E-cadherin before TGF-beta mRNA expression at 24 hours and occurred in the absence of TGF-beta and AGE-induced activation of ERK1/2 MAP kinase at 15 minutes and TEMT at 24 hours were completely blocked by a neutralizing RAGE antibody, a soluble RAGE receptor, an ERK1/2 MAP kinase inhibitor (PD98059), and DN-MEK1, but not by a neutralizing TGF-beta antibody. Thus, this study demonstrates that AGEs activate the RAGE-ERK1/2 MAP kinase pathway to mediate the early TEMT process. The findings from this study suggest that targeting the RAGE or the ERK MAP kinase pathway may provide new therapeutic strategies for diabetic nephropathy and shed new light on the pathogenesis of diabetic nephropathy.