Patient Attitudes Regarding Health Care Clinician Communication in Adolescents With Cystic Fibrosis.

BACKGROUND: The quality of health care clinician (HCC) communication varies, yet few studies evaluate ways to improve communication among adolescents with cystic fibrosis (CF). We sought to characterize the attitudes of adolescents and young adults (AYA) with CF about HCC communication and describe the components important for high-quality communication. METHODS: AYA with CF aged 12-20 years from a single large pediatric CF care center participated in a brief survey and semi-structured individual and group virtual interviews that were recorded, transcribed, coded, and analyzed with a combined deductive and inductive approach. Discrepancies were resolved by consensus. RESULTS: Among the 39 survey respondents, most were White (77%), male (51%), and averaged 15.51 years (range 12-20 years). Many (40%) perceived their health status as " neutral " and over half (61%) were " very satisfied " with HCC communication. Overall, among the 17 interviews (averaged 53.6 min, range 31.5-74 min), participants reported a desire to be actively engaged in discussions about their health and included in the decision-making process with HCC to support adolescent autonomy and cultivate trust. Some factors detract (loss of control and fear of diagnosis), and others strengthen (transition to adult care and external motivators) adolescent autonomy. Some factors detract (perceived lack of interdisciplinary communication, statements of noncompliance, and being compared to others) and others strengthen (inherent trust and familiarity over time) the cultivation of trust. CONCLUSIONS: The development of adolescent autonomy and the cultivation and maintenance of trust between the patient and HCC are 2 essential components of quality communication that should inform future communication-focused interventions.

The mammalian SKIV2L RNA exosome is essential for early B cell development.

The SKIV2L RNA exosome is an evolutionarily conserved RNA degradation complex in the eukaryotes. Mutations in the SKIV2L gene are associated with a severe inherited disorder, trichohepatoenteric syndrome (THES), with multisystem involvement but unknown disease mechanism. Here, we reported a THES patient with SKIV2L mutations showing severe primary B cell immunodeficiency, hypogammaglobulinemia, and kappa-restricted plasma cell dyscrasia but normal T cell and NK cell function. To corroborate these findings, we made B cell-specific Skiv2l knockout mice (Skiv2lfl/flCd79a-Cre), which lacked both conventional B-2 and innate-like B-1 B cells in the periphery and secondary lymphoid organs. This was linked to a requirement of SKIV2L RNA exosome activity in the bone marrow during early B cell development at the pro-B cell to large pre-B cell transition. Mechanistically, Skiv2l-deficient pro-B cells exhibited cell cycle arrest and DNA damage. Furthermore, loss of Skiv2l led to substantial out-of-frame V(D)J rearrangement of immunoglobulin heavy chain and severely reduced surface expression of µH, both of which are crucial for pre-BCR signaling and proliferative burst during early B cell development. Together, our data demonstrated a crucial role for SKIV2L RNA exosome in early B cell development in both human and mice by ensuring proper V(D)J recombination and Igh expression, which serves as the molecular basis for immunodeficiency associated with THES.

Cytoplasmic RNA quality control failure engages mTORC1-mediated autoinflammatory disease.

Inborn errors of nucleic acid metabolism often cause aberrant activation of nucleic acid sensing pathways, leading to autoimmune or autoinflammatory diseases. The SKIV2L RNA exosome is cytoplasmic RNA degradation machinery that was thought to be essential for preventing the self-RNA-mediated interferon (IFN) response. Here, we demonstrate the physiological function of SKIV2L in mammals. We found that Skiv2l deficiency in mice disrupted epidermal and T cell homeostasis in a cell-intrinsic manner independently of IFN. Skiv2l-deficient mice developed skin inflammation and hair abnormality, which were also observed in a SKIV2L-deficient patient. Epidermis-specific deletion of Skiv2l caused hyperproliferation of keratinocytes and disrupted epidermal stratification, leading to impaired skin barrier with no appreciable IFN activation. Moreover, Skiv2l-deficient T cells were chronically hyperactivated and these T cells attacked lesional skin as well as hair follicles. Mechanistically, SKIV2L loss activated the mTORC1 pathway in both keratinocytes and T cells. Both systemic and topical rapamycin treatment of Skiv2l-deficient mice ameliorated epidermal hyperplasia and skin inflammation. Together, we demonstrate that mTORC1, a classical nutrient sensor, also senses cytoplasmic RNA quality control failure and drives autoinflammatory disease. We also propose SKIV2L-associated trichohepatoenteric syndrome (THES) as a new mTORopathy for which sirolimus may be a promising therapy.

Evaluation of the Effectiveness of In-line Immobilized Lipase Cartridge in Enterally Fed Patients With Cystic Fibrosis.

BACKGROUND: Pancreatic insufficiency occurs in most patients with cystic fibrosis (CF) contributing to malnutrition. In the United States, 3600 patients with CF require enteral feeding (EF). Oral pancreatic enzymes are commonly used with EF, despite not being designed or approved for this use. An immobilized lipase cartridge (ILC) for extracorporeal digestion of enteral feedings was developed. The sponsor provided it to patients via a structured program, which we evaluated to assess the effectiveness of the ILC on nutritional status. METHODS: The program provided the ILC to patients prescribed the device while reimbursement efforts were ongoing. Baseline anthropometric data were obtained and subsequent measurements of height, weight, and body mass index (BMI) were collected at 6 and 12 months. RESULTS: Inclusion criteria were met by 100 patients (age = 0--45 years). Over 12 months of use in patients >2 years of age (n = 93), there were significant improvements seen in height and weight z-scores with improvement trend seen in BMI. The frequency of achieving the 50th percentile increased steadily for weight and BMI from baseline to 12 months but not for height. CONCLUSIONS: This evaluation of a program to assist patient access to ILC demonstrates that better growth is possible over standard of care. The association of ILC use with significant improvements in anthropometric parameters over a 12-month period in people with CF demonstrates the effectiveness of ILC as rational enzyme therapy during enteral feedings.

Regulation of purinergic signaling in biliary epithelial cells by exocytosis of SLC17A9-dependent ATP-enriched vesicles.

ATP in bile is a potent secretogogue, stimulating biliary epithelial cell (BEC) secretion through binding apical purinergic receptors. In response to mechanosensitive stimuli, BECs release ATP into bile, although the cellular basis of ATP release is unknown. The aims of this study in human and mouse BECs were to determine whether ATP release occurs via exocytosis of ATP-enriched vesicles and to elucidate the potential role of the vesicular nucleotide transporter SLC17A9 in purinergic signaling. Dynamic, multiscale, live cell imaging (confocal and total internal reflection fluorescence microscopy and a luminescence detection system with a high sensitivity charge-coupled device camera) was utilized to detect vesicular ATP release from cell populations, single cells, and the submembrane space of a single cell. In response to increases in cell volume, BECs release ATP, which was dependent on intact microtubules and vesicular trafficking pathways. ATP release occurred as stochastic point source bursts of luminescence consistent with exocytic events. Parallel studies identified ATP-enriched vesicles ranging in size from 0.4 to 1 µm that underwent fusion and release in response to increases in cell volume in a protein kinase C-dependent manner. Present in all models, SLC17A9 contributed to ATP vesicle formation and regulated ATP release. The findings are consistent with the existence of an SLC17A9-dependent ATP-enriched vesicular pool in biliary epithelium that undergoes regulated exocytosis to initiate purinergic signaling.

Update in pediatrics: focus on fat-soluble vitamins.

This article provides an update on fat-soluble vitamins (A, D, E, and K) in the healthy pediatric population and in children with chronic disease states that commonly cause deficiencies, specifically cystic fibrosis and cholestatic liver disease. For each fat-soluble vitamin, the biological function, nutrition availability, absorption, deficiency, toxic states, and monitoring parameters are defined.