A novel early mobility bundle improves length of stay and rates of readmission among hospitalized general medicine patients.

Inpatient early mobility initiatives are effective therapeutic interventions for improving patient outcomes and decreasing use of hospital resources among adult ICU and general medicine patients. To establish and demonstrate guidelines for early patient ambulation, we developed and implemented a novel multidisciplinary mobility bundle utilizing the JH-HLM (Johns Hopkins Highest Level of Mobility) scale for mobility classification, on a single adult general medicine unit of a community hospital. Our results show that patients admitted to the unit after implementation of the mobility bundle had improved mobility scores, reduced rates of 30-day hospital readmission, and a shortened length of hospital stay. This study emphasizes the importance of measuring mobility using a systematic method, easing workflow among unit practitioners, and allowing mobility initiatives to be jointly driven by nursing, physical therapy, and physicians.

A 33-Year-Old Man With Shortness of Breath, Leukocytosis, and Intermittent Fevers.

CASE PRESENTATION: A 33-year-old man with ulcerative colitis (UC) and primary sclerosing cholangitis presented with worsening shortness of breath, nonproductive cough, and intermittent fevers after he was found to have a WBC count of 27,000 cells/µL on an outpatient laboratory evaluation. He reported feeling progressively unwell with intermittent right upper quadrant pain and shortness of breath since a hospital admission for a UC flare 6 months prior, during which he was first diagnosed with primary sclerosing cholangitis. He noted that prior to that admission 6 months ago, his UC had been in remission for > 10 years. He reported fevers up to 38.9°C on and off for several weeks but was afebrile (37.2°C) on presentation. He endorsed non-bloody diarrhea, chills, night sweats, leg swelling, and associated leg pain. He had a cough but denied sputum production. He reported no recent travels and denied sick contacts. His medications included mesalamine, ursodiol, montelukast, and an albuterol inhaler.

The CFTR Corrector, VX-809 (Lumacaftor), Rescues ABCA4 Trafficking Mutants: a Potential Treatment for Stargardt Disease.

BACKGROUND/AIMS: Mutations in ABCA4 cause Stargardt macular degeneration, which invariably ends in legal blindness. We studied two common mutants, A1038V (in NBD1) and G1961E (in NBD2), with the purpose of exploring how they interact with the cell's quality control mechanism. The study was designed to determine how these mutants can be rescued. METHODS: We expressed wt and mutant ABCA4 in HEK293 cells and studied the effect of the mutations on trafficking and processing and the ability of correctors to rescue them. We used a combination of western blotting, confocal microscopy and surface biotinylation coupled with pulldown of plasma membrane proteins. RESULTS: G1961E is sensitive to inhibitors of the aggresome, tubacin and the lysosome, bafilomycin A. Both mutants cause a reduction in heat shock protein, Hsp27. Incubation of HEK293 cells expressing the mutants with VX-809, an FDA approved drug for the treatment of cystic fibrosis, increased the levels of A1038V and G1961E by 2- to 3-fold. Importantly, VX-809 increased the levels of both mutants at the plasma membrane suggesting that trafficking had been restored. Transfecting additional Hsp27 to the cells also increased the steady state levels of both mutants. However, in combination with VX-809 the addition of Hsp27 caused a dramatic increase in the protein expression particularly in the G1961 mutant which increased approximately 5-fold. CONCLUSION: Our results provide a new mechanism for the rescue of ABCA4 trafficking mutants based on the restoration of Hsp27. Our results provide a pathway for the treatment of Stargardt disease.

Restoration of F508-del Function by Transcomplementation: The Partners Meet in the Endoplasmic Reticulum.

BACKGROUND/AIMS: Because of the small size of adeno-associated virus, AAV, the cystic fibrosis conductance regulator, CFTR, cDNA is too large to fit within AAV and must be truncated. We report here on two truncated versions of CFTR, which, when inserted into AAV1 and used to infect airway cells, rescue F508-del CFTR via transcomplementation. The purpose of this study is to shed light on where in the cell transcomplementation occurs and how it results in close association between the endogenous F508-del and truncated CFTR. METHODS: We treated CF airway cells (CFBE41o-) with AAV2/1 (AAV2 inverted terminal repeats/AAV1 capsid) containing truncated forms of CFTR, ∆264 and ∆27-264 CFTR, who can restore the function of F508-del by transcomplementation. We addressed the aims of the study using a combination of confocal microscopy and short circuit currents measurements. For the latter, CF bronchial epithelial cells (CFBE) were grown on permeable supports. RESULTS: We show that both F508del and the truncation mutants colocalize in the ER and that both the rescued F508-del and the transcomplementing mutants reach the plasma membrane together. There was significant fluorescence resonance energy transfer (FRET) between F508-del and the transcomplementing mutants within the endoplasmic reticulum (ER), suggesting that transcomplementation occurs through a bimolecular interaction. We found that transcomplementation could increase the Isc in CFBE41o- cells stably expressing additional wt-CFTR or F508-del and in parental CFBE41o- cells expressing endogenous levels of F508-del. CONCLUSION: We conclude that the functional rescue of F508-del by transcomplementation occurs via a bimolecular interaction that most likely begins in the ER and continues at the plasma membrane. These results come at an opportune time for developing a gene therapy for CF and offer new treatment options for a wide range of CF patients.