In utero and postnatal ivacaftor/lumacaftor therapy rescues multiorgan disease in CFTR-F508del ferrets.

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, with F508del being the most prevalent mutation. The combination of CFTR modulators (potentiator and correctors) has provided benefit to CF patients carrying the F508del mutation; however, the safety and effectiveness of in utero combination modulator therapy remains unclear. We created a F508del ferret model to test whether ivacaftor/lumacaftor (VX-770/VX-809) therapy can rescue in utero and postnatal pathologies associated with CF. Using primary intestinal organoids and air-liquid interface cultures of airway epithelia, we demonstrate that the F508del mutation in ferret CFTR results in a severe folding and trafficking defect, which can be partially restored by treatment with CFTR modulators. In utero treatment of pregnant jills with ivacaftor/lumacaftor prevented meconium ileus at birth in F508del kits and sustained postnatal treatment of CF offspring improved survival and partially protected from pancreatic insufficiency. Withdrawal of ivacaftor/lumacaftor treatment from juvenile CF ferrets reestablished pancreatic and lung diseases, with altered pulmonary mechanics. These findings suggest that in utero intervention with a combination of CFTR modulators may provide therapeutic benefits to individuals with F508del. This CFTR-F508del ferret model may be useful for testing therapies using clinically translatable endpoints.

Transgenic ferret models define pulmonary ionocyte diversity and function.

Speciation leads to adaptive changes in organ cellular physiology and creates challenges for studying rare cell-type functions that diverge between humans and mice. Rare cystic fibrosis transmembrane conductance regulator (CFTR)-rich pulmonary ionocytes exist throughout the cartilaginous airways of humans1,2, but limited presence and divergent biology in the proximal trachea of mice has prevented the use of traditional transgenic models to elucidate ionocyte functions in the airway. Here we describe the creation and use of conditional genetic ferret models to dissect pulmonary ionocyte biology and function by enabling ionocyte lineage tracing (FOXI1-CreERT2::ROSA-TG), ionocyte ablation (FOXI1-KO) and ionocyte-specific deletion of CFTR (FOXI1-CreERT2::CFTRL/L). By comparing these models with cystic fibrosis ferrets3,4, we demonstrate that ionocytes control airway surface liquid absorption, secretion, pH and mucus viscosity-leading to reduced airway surface liquid volume and impaired mucociliary clearance in cystic fibrosis, FOXI1-KO and FOXI1-CreERT2::CFTRL/L ferrets. These processes are regulated by CFTR-dependent ionocyte transport of Cl- and HCO3-. Single-cell transcriptomics and in vivo lineage tracing revealed three subtypes of pulmonary ionocytes and a FOXI1-lineage common rare cell progenitor for ionocytes, tuft cells and neuroendocrine cells during airway development. Thus, rare pulmonary ionocytes perform critical CFTR-dependent functions in the proximal airway that are hallmark features of cystic fibrosis airway disease. These studies provide a road map for using conditional genetics in the first non-rodent mammal to address gene function, cell biology and disease processes that have greater evolutionary conservation between humans and ferrets.

Evaluation of off-label rapamycin use to promote healthspan in 333 adults.

Rapamycin (sirolimus) is an FDA-approved drug with immune-modulating and growth-inhibitory properties. Preclinical studies have shown that rapamycin extends lifespan and healthspan metrics in yeast, invertebrates, and rodents. Several physicians are now prescribing rapamycin off-label as a preventative therapy to maintain healthspan. Thus far, however, there is limited data available on side effects or efficacy associated with use of rapamycin in this context. To begin to address this gap in knowledge, we collected data from 333 adults with a history of off-label use of rapamycin by survey. Similar data were also collected from 172 adults who had never used rapamycin. Here, we describe the general characteristics of a patient cohort using off-label rapamycin and present initial evidence that rapamycin can be used safely in adults of normal health status.

Advance Care Planning in Patients With Metastatic Cancer: A Quality Improvement Initiative.

PURPOSE: An initiative aimed to increase the rate of advance care planning (ACP) activities for outpatients with metastatic cancer, an essential step to achieving goal concordant care. METHODS: Patients with metastatic cancer were identified by International Classification of Diseases-10 coding and later by oncologists' electronic health record documentation of metastatic tumor status. ACP activities were defined as either an ACP note, Advance Directive, Physician Orders for Life-Sustaining Therapy (POLST), or a Palliative Medicine (PM) consultation within the prior year. From 2017 to 2020, the initiative screened more than 5,000 total unique cancer patients per year. PM consultants were embedded in tumor boards, oncology care team meetings, and shared oncology clinic space. Quarterly reports were sent to 60 oncologists at three cancer care sites with data of their percentage of ACP activities for patients with metastatic cancer compared with their peers. Oncologists' identities were initially blinded, but later unblinded. Oncologists also received a monthly list of patients with metastatic cancer without ACP activities. RESULTS: The rate of ACP activities for patients with metastatic cancer increased from a baseline of 37% in July 2017 to 57% by the end of 2020. PM consultations increased from 12% to 39% and ACP notes increased from 16% to 29% during the same interval. There was no change in Advance Directive (17%-20%) or POLST completion (7%-6%). CONCLUSION: ACP activities are an essential step to achieve goal concordant care, and this initiative successfully increased ACP activities for patients with metastatic cancer. However, given that the main source of increased ACP activities during this initiative was PM referrals, further progress will depend upon strengthening the oncology care teams' ACP skills and motivation for completion.

Ferret models of alpha-1 antitrypsin deficiency develop lung and liver disease.

Alpha-1 antitrypsin deficiency (AATD) is the most common genetic cause and risk factor for chronic obstructive pulmonary disease, but the field lacks a large-animal model that allows for longitudinal assessment of pulmonary function. We hypothesized that ferrets would model human AATD-related lung and hepatic disease. AAT-knockout (AAT-KO) and PiZZ (E342K, the most common mutation in humans) ferrets were generated and compared with matched controls using custom-designed flexiVent modules to perform pulmonary function tests, quantitative computed tomography (QCT), bronchoalveolar lavage (BAL) proteomics, and alveolar morphometry. Complete loss of AAT (AAT-KO) led to increased pulmonary compliance and expiratory airflow limitation, consistent with obstructive lung disease. QCT and morphometry confirmed emphysema and airspace enlargement, respectively. Pathway analysis of BAL proteomics data revealed inflammatory lung disease and impaired cellular migration. The PiZ mutation resulted in altered AAT protein folding in the liver, hepatic injury, and reduced plasma concentrations of AAT, and PiZZ ferrets developed obstructive lung disease. In summary, AAT-KO and PiZZ ferrets model the progressive obstructive pulmonary disease seen in AAT-deficient patients and may serve as a platform for preclinical testing of therapeutics including gene therapy.

Implementing a Geriatric Fracture Program in a Mixed Practice Environment Reduces Total Cost and Length of Stay.

INTRODUCTION: Geriatric-orthopaedic co-management models can improve patient outcomes. However, prior reports have been at large academic centers with "closed" systems and an inpatient geriatric service. Here we describe a Geriatric Fracture Program (GFP) in a mixed practice "pluralistic" environment that includes employed academic faculty, private practice physicians, and multiple private hospitalist groups. We hypothesized GFP enrollment would reduce length of stay (LOS), time to surgery (TTS), and total hospital costs compared to non-GFP patients. MATERIALS AND METHODS: A multidisciplinary team was created around a geriatric Nurse Practitioner (NP) and consulting geriatrician. Standardized geriatric focused training programs and electronic tools were developed based on best practice guidelines. Fracture patients >65 years old were prospectively enrolled from July 2018 - June 2019. A trained biostatistician performed all statistical analyses. A p < 0.05 was considered significant. RESULTS: 564 operative and nonoperative fractures in patients over 65 were prospectively followed with 153 (27%) enrolled in the GFP and 411 (73%) admitted to other hospitalists or their primary care provider (non-GFP). Patients enrolled in the GFP had a significantly shorter median LOS of 4 days, compared to 5 days in non-GFP patients (P < 0.001). There was a strong trend towards a shorter median TTS in the GFP group (21.5 hours v 25 hours, p = 0.066). Mean total costs were significantly lower in the GFP group ($25,323 v $29085, p = 0.022). DISCUSSION: Our data shows that a geriatric-orthopaedic co-management model can be successfully implemented without an inpatient geriatric service, utilizing the pre-existing resources in a complex environment. The program can be expanded to include additional groups to improve care for entire geriatric fracture population with significant anticipated cost savings. CONCLUSIONS: With close multidisciplinary team work, a successful geriatric-orthopaedic comanagement model for geriatric fractures can be implemented in even a mixed practice environment without an inpatient geriatrics service.

Optical Coherence Tomography: Critical Tool to Manage Expectations after Cataract Extraction.

PURPOSE OF REVIEW: To review evidence on the utility of spectral domain optical coherence tomography (SD-OCT) in evaluating retinal structure prior cataract surgery and highlight new technologies that can assess retinal function perioperatively. FINDINGS: SD-OCT detected clinically unsuspected macular pathology in 4.6-25% of individuals in the pre-operative cataract evaluation. The most common findings were epiretinal membrane and macular degeneration with frequencies that varied by population studied. These conditions have been associated with complication after surgery (e.g. macular edema, visual dissatisfaction). As such, findings on SD-OCT may impact the informed consent process, alter IOL selection, and provide realistic postoperative vision expectations. Other technologies that assess retinal function, such as microperimetry and multifocal ERG are beginning to be studied but their utility in the pre-operative cataract evaluation is not yet known. SUMMARY: SD-OCT should be incorporated as a routine test prior to surgery to manage patient expectations and assist with optimal IOL selection, as even individuals with a seemingly normal clinical exam may have macular pathology. SD-OCT is the most established method for evaluating retinal anatomy and offers the benefits of a reduction in cases with missed macular pathology and fewer postoperative visual surprises.

Virtual reality for management of pain in hospitalized patients: A randomized comparative effectiveness trial.

OBJECTIVES: Therapeutic virtual reality (VR) has emerged as an effective, drug-free tool for pain management, but there is a lack of randomized, controlled data evaluating its effectiveness in hospitalized patients. We sought to measure the impact of on-demand VR versus "health and wellness" television programming for pain in hospitalized patients. METHODS: We performed a prospective, randomized, comparative effectiveness trial in hospitalized patients with an average pain score of ≥3 out of 10 points. Patients in the experimental group received a library of 21 VR experiences administered using the Samsung Gear Oculus headset; control patients viewed specialized television programming to promote health and wellness. Clinical staff followed usual care; study interventions were not protocolized. The primary outcome was patient-reported pain using a numeric rating scale, as recorded by nursing staff during usual care. Pre- and post-intervention pain scores were compared immediately after initial treatment and after 48- and 72-hours. RESULTS: There were 120 subjects (61 VR; 59 control). The mean within-subject difference in immediate pre- and post-intervention pain scores was larger in the VR group (-1.72 points; SD 3.56) than in the control group (-0.46 points; SD 3.01); this difference was significant in favor of VR (P < .04). When limited to the subgroup of patients with severe baseline pain (≥7 points), the effect of VR was more pronounced vs. control (-3.04, SD 3.75 vs. -0.93, SD 2.16 points; P = .02). In regression analyses adjusting for pre-intervention pain, time, age, gender, and type of pain, VR yielded a .59 (P = .03) and .56 (P = .04) point incremental reduction in pain versus control during the 48- and 72-hour post-intervention periods, respectively. CONCLUSIONS: VR significantly reduces pain versus an active control condition in hospitalized patients. VR is most effective for severe pain. Future trials should evaluate standardized order sets that interpose VR as an early non-drug option for analgesia.

Polypoidal Choroidal Vasculopathy.

PURPOSE OF REVIEW: The aim of this review is to summarize developments in the treatment of active polypoidal choroidal vasculopathy (PCV). PCV is associated with a poor visual prognosis as a consequence the condition's hallmark polypoidal dilatation and a branching network resulting in recurrent hemorrhages and serous leakage. RECENT FINDINGS: Recent research has provided new insights into the pathogenesis of PCV. While still considered a subtype of age-related macular degeneration, suggestions that PCV belongs to a spectrum of conditions that present with a pachychoroid are increasingly well accepted. Treatment remains challenging. Combination therapy (photodynamic therapy (PDT) and intravitreal anti-vascular endothelial growth factor (VEGF)) is associated with higher polyp closure rate, but polyp closure rate has not been correlated with superior visual outcomes. Current data points to non-inferiority of anti-VEGF alone versus combined with PDT when final vision acuity is the study outcome. SUMMARY: PCV remains a clinical challenge. Classification and treatment of the condition continues to evolve. Combination therapy may not be superior to anti-VEGF treatment alone in terms of visual acuity outcome, however data on long-term recurrence should be compared in formulating preferred treatment plans.

A glycopolymer improves vascoelasticity and mucociliary transport of abnormal cystic fibrosis mucus.

Cystic fibrosis (CF) is characterized by increased mucus viscosity and delayed mucociliary clearance that contributes to progressive decline of lung function. Mucus in the respiratory and GI tract is excessively adhesive in the presence of airway dehydration and excess extracellular Ca2+ upon mucin release, promoting hyperviscous, densely packed mucins characteristic of CF. Therapies that target mucins directly through ionic interactions remain unexploited. Here we show that poly (acetyl, arginyl) glucosamine (PAAG), a polycationic biopolymer suitable for human use, interacts directly with mucins in a Ca2+-sensitive manner to reduce CF mucus viscoelasticity and improve its transport. Notably, PAAG induced a linear structure of purified MUC5B and altered its sedimentation profile and viscosity, indicative of proper mucin expansion. In vivo, PAAG nebulization improved mucociliary transport in CF rats with delayed mucus clearance, and cleared mucus plugging in CF ferrets. This study demonstrates the potential use of a synthetic glycopolymer PAAG as a molecular agent that could benefit patients with a broad array of mucus diseases.

In utero and postnatal VX-770 administration rescues multiorgan disease in a ferret model of cystic fibrosis.

Cystic fibrosis (CF) is a multiorgan disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). In patients with CF, abnormalities initiate in several organs before birth. However, the long-term impact of these in utero pathologies on disease pathophysiology is unclear. To address this issue, we generated ferrets harboring a VX-770 (ivacaftor)-responsive CFTR G551D mutation. In utero VX-770 administration provided partial protection from developmental pathologies in the pancreas, intestine, and male reproductive tract. Homozygous CFTR G551D/G551D animals showed the greatest VX-770-mediated protection from these pathologies. Sustained postnatal VX-770 administration led to improved pancreatic exocrine function, glucose tolerance, growth and survival, and to reduced mucus accumulation and bacterial infections in the lung. VX-770 withdrawal at any age reestablished disease, with the most rapid onset of morbidity occurring when withdrawal was initiated during the first 2 weeks after birth. The results suggest that CFTR is important for establishing organ function early in life. Moreover, this ferret model provides proof of concept for in utero pharmacologic correction of genetic disease and offers opportunities for understanding CF pathogenesis and improving treatment.

Extracorporeal Membrane Oxygenation Appropriateness: An Interdisciplinary Consensus-Based Approach.

We describe a quality improvement initiative aimed at achieving interdisciplinary consensus about the appropriate delivery of extracorporeal membrane oxygenation (ECMO). Interdisciplinary rounds were implemented for all patients on ECMO and addressed whether care was consistent with a patient's minimally acceptable outcome, maximally acceptable burden, and relative likelihood of achieving either. The rounding process was associated with decreased days on venoarterial ECMO, from a median of 6 days in 2014 (first quartile [Q1]-third quartile [Q3], 3-10) to 5 days in 2015 (Q1-Q3, 2.5-8) and in 2016 (Q1-Q3, 1-8). Our statistical methods do not allow us to conclude that this change was due to our intervention, and it is possible that the observed decreases would have occurred whether or not the rounding process was implemented.

Infection Is Not Required for Mucoinflammatory Lung Disease in CFTR-Knockout Ferrets.

RATIONALE: Classical interpretation of cystic fibrosis (CF) lung disease pathogenesis suggests that infection initiates disease progression, leading to an exuberant inflammatory response, excessive mucus, and ultimately bronchiectasis. Although symptomatic antibiotic treatment controls lung infections early in disease, lifelong bacterial residence typically ensues. Processes that control the establishment of persistent bacteria in the CF lung, and the contribution of noninfectious components to disease pathogenesis, are poorly understood. OBJECTIVES: To evaluate whether continuous antibiotic therapy protects the CF lung from disease using a ferret model that rapidly acquires lethal bacterial lung infections in the absence of antibiotics. METHODS: CFTR (cystic fibrosis transmembrane conductance regulator)-knockout ferrets were treated with three antibiotics from birth to several years of age and lung disease was followed by quantitative computed tomography, BAL, and histopathology. Lung disease was compared with CFTR-knockout ferrets treated symptomatically with antibiotics. MEASUREMENTS AND MAIN RESULTS: Bronchiectasis was quantified from computed tomography images. BAL was evaluated for cellular differential and features of inflammatory cellular activation, bacteria, fungi, and quantitative proteomics. Semiquantitative histopathology was compared across experimental groups. We demonstrate that lifelong antibiotics can protect the CF ferret lung from infections for several years. Surprisingly, CF animals still developed hallmarks of structural bronchiectasis, neutrophil-mediated inflammation, and mucus accumulation, despite the lack of infection. Quantitative proteomics of BAL from CF and non-CF pairs demonstrated a mucoinflammatory signature in the CF lung dominated by Muc5B and neutrophil chemoattractants and products. CONCLUSIONS: These findings implicate mucoinflammatory processes in the CF lung as pathogenic in the absence of clinically apparent bacterial and fungal infections.

Animal and model systems for studying cystic fibrosis.

The cystic fibrosis (CF) field is the beneficiary of five species of animal models that lack functional cystic fibrosis transmembrane conductance regulator (CFTR) channel. These models are rapidly informing mechanisms of disease pathogenesis and CFTR function regardless of how faithfully a given organ reproduces the human CF phenotype. New approaches of genetic engineering with RNA-guided nucleases are rapidly expanding both the potential types of models available and the approaches to correct the CFTR defect. The application of new CRISPR/Cas9 genome editing techniques are similarly increasing capabilities for in vitro modeling of CFTR functions in cell lines and primary cells using air-liquid interface cultures and organoids. Gene editing of CFTR mutations in somatic stem cells and induced pluripotent stem cells is also transforming gene therapy approaches for CF. This short review evaluates several areas that are key to building animal and cell systems capable of modeling CF disease and testing potential treatments.

The Enhanced Care Program: Impact of a Care Transition Program on 30-Day Hospital Readmissions for Patients Discharged From an Acute Care Facility to Skilled Nursing Facilities.

BACKGROUND: Increased acuity of skilled nursing facility (SNF) patients challenges the current system of care for these patients. OBJECTIVE: Evaluate the impact on 30-day readmissions of a program designed to enhance the care of patients discharged from an acute care facility to SNFs. DESIGN: An observational, retrospective cohort analysis of 30-day hospital readmissions for patients discharged to 8 SNFs between January 1, 2014, and June 30, 2015. SETTING: A collaboration between a large, acute care hospital in an urban setting, an interdisciplinary clinical team, 124 community physicians, and 8 SNFs. PATIENTS: All patients discharged from Cedars-Sinai Medical Center to 8 partner SNFs were eligible for participation. INTERVENTION: The Enhanced Care Program (ECP) involved the following 3 interventions in addition to standard care: (1) a team of nurse practitioners participating in the care of SNF patients; (2) a pharmacist-driven medication reconciliation at the time of transfer; and (3) educational in-services for SNF nursing staff. MEASUREMENT: Thirty-day readmission rate for ECP patients compared to patients not enrolled in ECP. RESULTS: The average unadjusted, 30-day readmission rate for ECP patients over the 18-month study period was 17.2% compared to 23.0% among patients not enrolled in ECP (P < 0.001). After adjustment for sociodemographic and clinical characteristics, ECP patients had 29% lower odds of being readmitted within 30 days (P < 0.001). These effects were robust to stratified analyses, analyses adjusted for clustering, and balancing of covariates using propensity weighting. CONCLUSIONS: A coordinated, interdisciplinary team caring for SNF patients can reduce 30-day hospital readmissions.

Systems Addressing Frail Elder Care: Description of a Successful Model.

OBJECTIVE: The aim of this article is to describe the Systems Addressing Frail Elder (SAFE) Care model, features of the interprofessional team and reengineered workflow, and details of the intervention. BACKGROUND: Older inpatients are vulnerable to adverse events related to frailty. SAFE Care, an interprofessional team-based program, was developed and evaluated in a cluster randomized controlled trial (C-RCT). Results found reduced length of stay and complications. The purpose of this article is to support and encourage the replication of this innovation or to help facilitate implementation of a similar process of organizational change. METHODS: This was a review of model features and intervention data abstracted from electronic health records. RESULTS: Salient features of team composition, training, and workflow are presented. The C-RCT intention-to-treat sample included 792 patients, of whom 307 received the SAFE Care huddle intervention. The most frequent problem was mobility (85.7%), and most frequent recommendation was fall precautions protocol (83.1%). CONCLUSIONS: The SAFE Care model may provide a standardized framework to approach, assess, and address the risks of hospitalized older adults.

Vascular Ultrasonography: A Novel Method to Reduce Paracentesis Related Major Bleeding.

Paracentesis is a core competency for hospitalists. Using ultrasound for fluid localization is standard practice and involves a low-frequency probe. Experts recommend a "2-probe technique, " which incorporates a high-frequency ultrasound probe in addition to the low-frequency probe to identify blood vessels within the intended needle path. Evidence is currently lacking to support this 2-probe technique, so we performed a pre- to postintervention study to evaluate its effect on paracentesis-related bleeding complications. From February 2010 to August 2011, procedures were performed using only low-frequency probes (preintervention group), while the 2-probe technique was used from September 2011 to February 2016 (postintervention group). A total of 5777 procedures were performed. Paracentesis-related minor bleeding was similar between groups. Major bleeding was lower in the postintervention group (3 [0.3%], n = 1000 vs 4 [0.08%], n = 4777; P = 0.07). This clinically meaningful trend suggests that using the 2-probe technique might prevent paracentesis-related major bleeding.

Medication adherence as a predictor of 30-day hospital readmissions.

PURPOSE: The aim of this study was to test whether patient medication adherence, a modifiable risk factor obtainable at hospital admission, predicts readmission within 30 days. PATIENTS AND METHODS: We used a retrospective cohort study design to test whether patient medication adherence to all chronic medications, as determined by the 4-item Morisky Medication Adherence Scale (MMAS-4) administered by a pharmacist at the time of hospital admission, predicts 30-day readmissions. We compared readmission rates among 385 inpatients who had their adherence assessed from February 1, 2013, to January 31, 2014. Multiple logistic regression was used to examine the benefit of adding medication adherence to previously published variables that have been shown to predict 30-day readmissions. RESULTS: Patients with low and intermediate adherence (combined) had readmission rates of 20.0% compared to a readmission rate of 9.3% for patients with high adherence (P=0.005). By adding MMAS-4 data to previously published variables that have been shown to predict 30-day readmissions, we found that patients with low and intermediate medication adherence had an adjusted 2.54-fold higher odds of readmission compared to those in patients with high adherence (95% confidence interval [CI]: 1.32-4.90, P=0.005). The model's predictive power, as measured by the c-statistic, improved from 0.65 to 0.70 after adding adherence. CONCLUSION: Because medication adherence assessed at hospital admission was independently associated with 30-day readmission risk, it offers potential for targeting interventions to improve adherence.

Virtual Reality and Medical Inpatients: A Systematic Review of Randomized, Controlled Trials.

Objective: We evaluated the evidence supporting the use of virtual reality among patients in acute inpatient medical settings. Method: We conducted a systematic review of randomized controlled trials conducted that examined virtual reality applications in inpatient medical settings between 2005 and 2015. We used PsycINFO, PubMed, and Medline databases to identify studies using the keywords virtual reality, VR therapy, treatment, and inpatient.Results: We identified 2,024 citations, among which 11 met criteria for inclusion. Studies addressed three general areas: pain management, eating disorders, and cognitive and motor rehabilitation. Studies were small and heterogeneous and utilized different designs and measures. Virtual reality was generally well tolerated by patients, and a majority of studies demonstrated clinical efficacy. Studies varied in quality, as measured by an evaluation metric developed by Reisch, Tyson, and Mize (average quality score=0.87; range=0.78-0.96). Conclusion: Virtual reality is a promising intervention with several potential applications in the inpatient medical setting. Studies to date demonstrate some efficacy, but there is a need for larger, well-controlled studies to show clinical and cost-effectiveness.