CFTR Modulators Restore Acidification of Autophago-Lysosomes and Bacterial Clearance in Cystic Fibrosis Macrophages.

Cystic fibrosis (CF) human and mouse macrophages are defective in their ability to clear bacteria such as Burkholderia cenocepacia. The autophagy process in CF (F508del) macrophages is halted, and the underlying mechanism remains unclear. Furthermore, the role of CFTR in maintaining the acidification of endosomal and lysosomal compartments in CF cells has been a subject of debate. Using 3D reconstruction of z-stack confocal images, we show that CFTR is recruited to LC3-labeled autophagosomes harboring B. cenocepacia. Using several complementary approaches, we report that CF macrophages display defective lysosomal acidification and degradative function for cargos destined to autophagosomes, whereas non-autophagosomal cargos are effectively degraded within acidic compartments. Notably, treatment of CF macrophages with CFTR modulators (tezacaftor/ivacaftor) improved the autophagy flux, lysosomal acidification and function, and bacterial clearance. In addition, CFTR modulators improved CFTR function as demonstrated by patch-clamp. In conclusion, CFTR regulates the acidification of a specific subset of lysosomes that specifically fuse with autophagosomes. Therefore, our study describes a new biological location and function for CFTR in autophago-lysosomes and clarifies the long-standing discrepancies in the field.

Addressing medical needs of adolescents and adults with autism spectrum disorders in a primary care setting.

Little has been reported about how to improve health care access and delivery for adolescents and adults with autism spectrum disorder. To understand the contributions to the health disparities in the autism spectrum disorder population, we conducted two independent research approaches to learn about current medical needs. A retrospective chart review was performed to evaluate medical comorbidities and medication use. A focus group was also created to address barriers faced in providing medical care. Of 126 charts reviewed, 49% (n = 62) had intellectual disability, 49% (n = 62) had attention-deficit hyperactivity disorder, 52% (n = 65) had anxiety, 41% (n = 52) had obesity, 31% (n = 39) with a history of aggressive behavior, 31% (n = 31) had depression, 22% (n = 28) had seizures, and 9% (n = 11) had hypertension. A Medical Regimen Complexity Index score was determined to examine medication use trends in the autism spectrum disorder population. Medical Regimen Complexity Index scores were significantly higher for patients with intellectual disability, patients with seizures, and patients with a history of aggressive behavior. Both the focus group and our pre-visit assessment identified the waiting room and waiting time as barriers to care. Understanding the comorbidities, polypharmacy, and medical barriers should provide a better understanding of the current health care access and delivery needs of adolescents and adults with autism spectrum disorder.