Tracheostomy-related durable medical equipment: Insurance coverage, gaps, and barriers.

PURPOSE: Tracheostomy care is supply- and resource-intensive, and airway-related adverse events in community settings have high rates of readmission and mortality. Devices are often implicated in harm, but little is known about insurance coverage, gaps, and barriers to obtaining tracheostomy-related medically necessary durable medical equipment. We aimed to identify barriers patients may encounter in procuring tracheostomy-related durable medical equipment through insurance plan coverage. MATERIALS AND METHODS: Tracheostomy-related durable medical equipment provisions were evaluated across insurers, extracting data via structured telephone interviews and web-based searches. Each insurance company was contacted four times and queried iteratively regarding the range of coverage and co-pay policies. Outcome measures include call duration, consistency of explanation of benefits, and the number of transfers and disconnects. We also identified six qualitative themes from patient interviews. RESULTS: Tracheostomy-related durable medical equipment coverage was offered in some form by 98.1 % (53/54) of plans across 11 insurers studied. Co-pays or deductibles were required in 42.6 % (23/54). There was significant variability in out-of-pocket expenditures. Fixed co-pays ranged from $0-30, and floating co-pays ranged from 0 to 40 %. During phone interviews, mean call duration was 19 ± 10 min, with an average of 2 ± 1 transfers between agents. Repeated calls revealed high information variability (mean score 2.4 ± 1.5). Insurance sites proved challenging to navigate, scoring poorly on usability, literacy, and information quality. CONCLUSIONS: Several factors may limit access to potentially life-saving durable medical equipment for patients with tracheostomy. Barriers include out-of-pocket expenditures, lack of transparency on coverage, and low-quality information. Further research is necessary to evaluate patient outcomes.

Amplifying patient voices amid pandemic: Perspectives on tracheostomy care, communication, and connection.

OBJECTIVE: To investigate perspectives of patients, family members, caregivers (PFC), and healthcare professionals (HCP) on tracheostomy care during the COVID-19 pandemic. METHODS: The cross-sectional survey investigating barriers and facilitators to tracheostomy care was collaboratively developed by patients, family members, nurses, speech-language pathologists, respiratory care practitioners, physicians, and surgeons. The survey was distributed to the Global Tracheostomy Collaborative's learning community, and responses were analyzed. RESULTS: Survey respondents (n = 191) from 17 countries included individuals with a tracheostomy (85 [45 %]), families/caregivers (43 [22 %]), and diverse HCP (63 [33.0 %]). Overall, 94 % of respondents reported concern that patients with tracheostomy were at increased risk of critical illness from SARS-CoV-2 infection and COVID-19; 93 % reported fear or anxiety. With respect to prioritization of care, 38 % of PFC versus 16 % of HCP reported concern that patients with tracheostomies might not be valued or prioritized (p = 0.002). Respondents also differed in fear of contracting COVID-19 (69 % PFC vs. 49 % HCP group, p = 0.009); concern for hospitalization (55.5 % PFC vs. 27 % HCP, p < 0.001); access to medical personnel (34 % PFC vs. 14 % HCP, p = 0.005); and concern about canceled appointments (62 % PFC vs. 41 % HCP, p = 0.01). Respondents from both groups reported severe stress and fatigue, sleep deprivation, lack of breaks, and lack of support (70 % PFC vs. 65 % HCP, p = 0.54). Virtual telecare seldom met perceived needs. CONCLUSION: PFC with a tracheostomy perceived most risks more acutely than HCP in this global sample. Broad stakeholder engagement is necessary to achieve creative, patient-driven solutions to maintain connection, communication, and access for patients with a tracheostomy.

CHD7 and retinoic acid signaling cooperate to regulate neural stem cell and inner ear development in mouse models of CHARGE syndrome.

CHARGE syndrome is a multiple congenital anomaly disorder that leads to life-threatening birth defects, such as choanal atresia and cardiac malformations as well as multiple sensory impairments, that affect hearing, vision, olfaction and balance. CHARGE is caused by heterozygous mutations in CHD7, which encodes an ATP-dependent chromatin remodeling enzyme. Identification of the mechanisms underlying neurological and sensory defects in CHARGE is a first step toward developing treatments for CHARGE individuals. Here, we used mouse models of Chd7 deficiency to explore the function of CHD7 in the development of the subventricular zone (SVZ) neural stem cell niche and inner ear, structures that are important for olfactory bulb neurogenesis and hearing and balance, respectively. We found that loss of Chd7 results in cell-autonomous proliferative, neurogenic and self-renewal defects in the perinatal and mature mouse SVZ stem cell niche. Modulation of retinoic acid (RA) signaling prevented in vivo inner ear and in vitro neural stem cell defects caused by Chd7 deficiency. Our findings demonstrate critical, cooperative roles for RA and CHD7 in SVZ neural stem cell function and inner ear development, suggesting that altered RA signaling may be an effective method for treating Chd7 deficiency.

Duplication 2p25 in a child with clinical features of CHARGE syndrome.

CHARGE syndrome is a dominant disorder characterized by ocular colobomata, heart defects, choanal atresia, retardation of growth and development, genital hypoplasia, and ear abnormalities including deafness and vestibular disorders. The majority of individuals with CHARGE have pathogenic variants in the gene encoding CHD7, a chromatin remodeling protein. Here, we present a 15-year-old girl with clinical features of CHARGE syndrome and a de novo 6.5 Mb gain of genomic material at 2p25.3-p25.2. The duplicated region contained 24 genes, including the early and broadly expressed transcription factor gene SOX11. Analysis of 28 other patients with CHARGE showed no SOX11 copy number changes or pathogenic sequence variants. To our knowledge, this child's chromosomal abnormality is unique and represents the first co-occurrence of duplication 2p25 and clinical features of CHARGE syndrome. We compare our patient's phenotype to ten previously published patients with isolated terminal duplication 2p, and elaborate on the clinical diagnosis of CHARGE in the context of atypical genetic findings.

The chromatin remodeling protein CHD7, mutated in CHARGE syndrome, is necessary for proper craniofacial and tracheal development.

BACKGROUND: Heterozygous mutations in the chromatin remodeling gene CHD7 cause CHARGE syndrome, a developmental disorder with variable craniofacial dysmorphisms and respiratory difficulties. The molecular etiologies of these malformations are not well understood. Homozygous Chd7 null mice die by E11, whereas Chd7(Gt/+) heterozygous null mice are a viable and excellent model of CHARGE. We explored skeletal phenotypes in Chd7(Gt/+) and Chd7 conditional knockout mice, using Foxg1-Cre to delete Chd7 (Foxg1-CKO) in the developing eye, ear, nose, pharyngeal pouch, forebrain, and gut and Wnt1-Cre (Wnt1-CKO) to delete Chd7 in migrating neural crest cells. RESULTS: Foxg1-CKO mice exhibited postnatal respiratory distress and death, dysplasia of the eye, concha, and frontal bone, hypoplastic maxillary shelves and nasal epithelia, and reduced tracheal rings. Wnt1-CKO mice exhibited frontal and occipital bone dysplasia, hypoplasia of the maxillary shelves and mandible, and cleft palate. In contrast, heterozygous Chd7(Gt/+) mice had apparently normal skeletal development. CONCLUSIONS: Conditional deletion of Chd7 in ectodermal and endodermal derivatives (Foxg1-Cre) or migrating neural crest cells (Wnt1-Cre) results in varied and more severe craniofacial defects than in Chd7(Gt/+) mice. These studies indicate that CHD7 has an important, dosage-dependent role in development of several different craniofacial tissues.

Whole-exome resequencing reveals recessive mutations in TRAP1 in individuals with CAKUT and VACTERL association.

Congenital abnormalities of the kidney and urinary tract (CAKUT) account for approximately half of children with chronic kidney disease and they are the most frequent cause of end-stage renal disease in children in the US. However, its genetic etiology remains mostly elusive. VACTERL association is a rare disorder that involves congenital abnormalities in multiple organs including the kidney and urinary tract in up to 60% of the cases. By homozygosity mapping and whole-exome resequencing combined with high-throughput mutation analysis by array-based multiplex PCR and next-generation sequencing, we identified recessive mutations in the gene TNF receptor-associated protein 1 (TRAP1) in two families with isolated CAKUT and three families with VACTERL association. TRAP1 is a heat-shock protein 90-related mitochondrial chaperone possibly involved in antiapoptotic and endoplasmic reticulum stress signaling. Trap1 is expressed in renal epithelia of developing mouse kidney E13.5 and in the kidney of adult rats, most prominently in proximal tubules and in thick medullary ascending limbs of Henle's loop. Thus, we identified mutations in TRAP1 as highly likely causing CAKUT or VACTERL association with CAKUT.

Single Cell Transcriptomics Reveal Abnormalities in Neurosensory Patterning of the Chd7 Mutant Mouse Ear.

The chromatin remodeling protein CHD7 is critical for proper formation of the mammalian inner ear. Humans with heterozygous pathogenic variants in CHD7 exhibit CHARGE syndrome, characterized by hearing loss and inner ear dysplasia, including abnormalities of the semicircular canals and Mondini malformations. Chd7 Gt/+ heterozygous null mutant mice also exhibit dysplastic semicircular canals and hearing loss. Prior studies have demonstrated that reduced Chd7 dosage in the ear disrupts expression of genes involved in morphogenesis and neurogenesis, yet the relationships between these changes in gene expression and otic patterning are not well understood. Here, we sought to define roles for CHD7 in global regulation of gene expression and patterning in the developing mouse ear. Using single-cell multiplex qRT-PCR, we analyzed expression of 192 genes in FAC sorted cells from Pax2Cre;mT/mGFP wild type and Chd7 Gt/+ mutant microdissected mouse otocysts. We found that Chd7 haploinsufficient otocysts exhibit a relative enrichment of cells adopting a neuroblast (vs. otic) transcriptional identity compared with wild type. Additionally, we uncovered disruptions in pro-sensory and pro-neurogenic gene expression with Chd7 loss, including genes encoding proteins that function in Notch signaling. Our results suggest that Chd7 is required for early cell fate decisions in the developing ear that involve highly specific aspects of otic patterning and differentiation.

CHD7 represses the retinoic acid synthesis enzyme ALDH1A3 during inner ear development.

CHD7, an ATP-dependent chromatin remodeler, is disrupted in CHARGE syndrome, an autosomal dominant disorder characterized by variably penetrant abnormalities in craniofacial, cardiac, and nervous system tissues. The inner ear is uniquely sensitive to CHD7 levels and is the most commonly affected organ in individuals with CHARGE. Interestingly, upregulation or downregulation of retinoic acid (RA) signaling during embryogenesis also leads to developmental defects similar to those in CHARGE syndrome, suggesting that CHD7 and RA may have common target genes or signaling pathways. Here, we tested three separate potential mechanisms for CHD7 and RA interaction: (a) direct binding of CHD7 with RA receptors, (b) regulation of CHD7 levels by RA, and (c) CHD7 binding and regulation of RA-related genes. We show that CHD7 directly regulates expression of Aldh1a3, the gene encoding the RA synthetic enzyme ALDH1A3 and that loss of Aldh1a3 partially rescues Chd7 mutant mouse inner ear defects. Together, these studies indicate that ALDH1A3 acts with CHD7 in a common genetic pathway to regulate inner ear development, providing insights into how CHD7 and RA regulate gene expression and morphogenesis in the developing embryo.

Chromodomain helicase DNA-binding proteins in stem cells and human developmental diseases.

Dynamic regulation of gene expression is vital for proper cellular development and maintenance of differentiated states. Over the past 20 years, chromatin remodeling and epigenetic modifications of histones have emerged as key controllers of rapid reversible changes in gene expression. Mutations in genes encoding enzymes that modify chromatin have also been identified in a variety of human neurodevelopmental disorders, ranging from isolated intellectual disability and autism spectrum disorder to multiple congenital anomaly conditions that affect major organ systems and cause severe morbidity and mortality. In this study, we review recent evidence that chromodomain helicase DNA-binding (CHD) proteins regulate stem cell proliferation, fate, and differentiation in a wide variety of tissues and organs. We also highlight known roles of CHD proteins in human developmental diseases and present current unanswered questions about the pleiotropic effects of CHD protein complexes, their genetic targets, nucleosome sliding functions, and enzymatic effects in cells and tissues.