Impact of Language and Ethnicity on Pediatric Tracheostomy Outcomes.

OBJECTIVE: To compare outcomes after tracheostomy between children from Spanish- and English-speaking families. STUDY DESIGN: Prospective cohort study. SETTING: Tertiary care children's hospital. METHODS: All children <18 years of age who had a tracheostomy placed between 2014 and 2020 were included. Comorbidities and postsurgical outcomes were compared between (1) children whose families preferred speaking Spanish or identified as Hispanic/Latino and (2) children from English-language or non-Hispanic families. RESULTS: A total of 339 children met inclusion, with 11% (37/339) from families identifying Spanish as their primary language and 33% (112/339) identifying as Hispanic. Spanish-speaking families were more likely to have tracheostomy-dependent children with cardiac conditions (65% vs 42%, P = .008) and high complexity (72% vs 49%, P = .007). Outcomes were similar regardless of language preference, with 45% (153/339) still tracheostomy dependent, 28% (94/339) decannulated, and 6.8% (23/339) deceased at a median follow-up of 1.77 years (interquartile range, 0.65-3.43). Severe neurocognitive disabilities were similar between Spanish- and English-language families (P > .05). Spanish language was not associated with times to decannulation or death in univariate or multiple regression models. A sensitivity analysis of self-identified Hispanic or Latino patients did not show significant differences for time to decannulation, death, or neurocognitive disability rates (P > .05). CONCLUSION: Spanish language and Hispanic ethnicity appear to have minimal impact on pediatric tracheostomy outcomes.

Broad assessment of bioactivity of a collection of spiroindane pyrrolidines through "cell painting".

A collection of small molecules has been synthesized by composing photo-cycloaddition, C-H functionalization, and N-capping strategies. Multidimensional biological fingerprints of molecules comprising this collection have been recorded as changes in cell and organelle morphology. This untargeted, phenotypic approach allowed for a broad assessment of biological activity to be determined. Reproducibility and the magnitude of measured fingerprints revealed activity of several treatments. Reactive functional groups, such as imines, dominated the observed activity. Two non-reactive candidate compounds with distinct bioactivity fingerprints were identified, as well.

Up-regulation of protective neuronal MicroRNAs by FTY720 and novel FTY720-derivatives.

In searching for Parkinson's disease (PD) pharmacotherapies we began studying FTY720, a food and drug administration (FDA) approved drug. We also created derivatives, FTY720-C2 and FTY720-Mitoxy, and began assessing them. Here we treated dopaminergic MN9D cells with FTY720s then measured microRNA (miRNA) levels by PCR arrays. We discovered that all three FTY720s increased miR376b-3p, while FTY720-C2 also increased miR-128-3p, miR-146b-5p, miR-7a-5p, and miR-9-5p, and FTY720-Mitoxy also increased miR-30d-5p. Investigations revealed that some miRNAs downregulate alpha-synuclein, while others reduce apoptosis, suggesting that FTY720s may act to reduce synucleinopathy and dopaminergic neuron loss in PD and related disorders.

FTY720/Fingolimod Reduces Synucleinopathy and Improves Gut Motility in A53T Mice: CONTRIBUTIONS OF PRO-BRAIN-DERIVED NEUROTROPHIC FACTOR (PRO-BDNF) AND MATURE BDNF.

Patients with Parkinson's disease (PD) often have aggregated α-synuclein (aSyn) in enteric nervous system (ENS) neurons, which may be associated with the development of constipation. This occurs well before the onset of classic PD motor symptoms. We previously found that aging A53T transgenic (Tg) mice closely model PD-like ENS aSyn pathology, making them appropriate for testing potential PD therapies. Here we show that Tg mice overexpressing mutant human aSyn develop ENS pathology by 4 months. We then evaluated the responses of Tg mice and their WT littermates to the Food and Drug Administration-approved drug FTY720 (fingolimod, Gilenya) or vehicle control solution from 5 months of age. Long term oral FTY720 in Tg mice reduced ENS aSyn aggregation and constipation, enhanced gut motility, and increased levels of brain-derived neurotrophic factor (BDNF) but produced no significant change in WT littermates. A role for BDNF was directly assessed in a cohort of young A53T mice given vehicle, FTY720, the Trk-B receptor inhibitor ANA-12, or FTY720 + ANA-12 from 1 to 4 months of age. ANA-12-treated Tg mice developed more gut aSyn aggregation as well as constipation, whereas FTY720-treated Tg mice had reduced aSyn aggregation and less constipation, occurring in part by increasing both pro-BDNF and mature BDNF levels. The data from young and old Tg mice revealed FTY720-associated neuroprotection and reduced aSyn pathology, suggesting that FTY720 may also benefit PD patients and others with synucleinopathy. Another finding was a loss of tyrosine hydroxylase immunoreactivity in gut neurons with aggregated aSyn, comparable with our prior findings in the CNS.