Impaired AMPK Control of Alveolar Epithelial Cell Metabolism Promotes Pulmonary Fibrosis.

Alveolar epithelial type II (AT2) cell dysfunction is implicated in the pathogenesis of familial and sporadic idiopathic pulmonary fibrosis (IPF). We previously described that expression of an AT2 cell exclusive disease-associated protein isoform (SP-CI73T) in murine and patient-specific induced pluripotent stem cell (iPSC)-derived AT2 cells leads to a block in late macroautophagy and promotes time-dependent mitochondrial impairments; however, how a metabolically dysfunctional AT2 cell results in fibrosis remains elusive. Here using murine and human iPSC-derived AT2 cell models expressing SP-CI73T, we characterize the molecular mechanisms governing alterations in AT2 cell metabolism that lead to increased glycolysis, decreased mitochondrial biogenesis, disrupted fatty acid oxidation, accumulation of impaired mitochondria, and diminished AT2 cell progenitor capacity manifesting as reduced AT2 self-renewal and accumulation of transitional epithelial cells. We identify deficient AMP-kinase signaling as a key upstream signaling hub driving disease in these dysfunctional AT2 cells and augment this pathway to restore alveolar epithelial metabolic function, thus successfully alleviating lung fibrosis in vivo.

Pharmacist-led hypertension management in a minority patient population.

BACKGROUND: Nearly half of adults in America have hypertension (HTN), and only approximately 1 in 4 adults has their blood pressure (BP) under control. High BP is more common in African Americans adults, and BP control is lower among minority adults. Pharmacist-led interventions for HTN have been shown to be effective in improving BP control and reducing the risk of cardiovascular events. OBJECTIVE: This study aimed to leverage electronic health record (EHR) data to improve BP control through pharmacist-led interventions. METHODS: This was a prospective, cohort study conducted at Atrium Health Concord Internal Medicine, a large suburban practice in Concord, North Carolina. Patients with uncontrolled HTN were identified using an EHR data tool. Patients were included if they were at least 18 years of age, had sustained uncontrolled HTN, and were of a minority race or ethnicity. The primary outcome was proportion of patients achieving a BP of < 140/90 mm Hg in the intervention group compared with a control group. Secondary outcomes included mean change in BP from baseline, number and type of visits, and number and type of interventions. RESULTS: A total of 110 patients were enrolled in this study, 55 patients in each cohort. The baseline characteristics were generally well balanced between the 2 groups. The mean age was 62 years, and most patients were female and African American. For the primary outcome, 70.9% of the patients in the intervention group achieved a BP of < 140/90 mm Hg compared with 32.7% of the patients in the control group (P < 0.001). The most common intervention was lifestyle modifications, followed by BP monitoring technique education and medication adherence interventions. CONCLUSION: In this study, pharmacist-led interventions resulted in clinically and statistically significant improvements in sustained uncontrolled HTN among minority populations.

Estradiol withdrawal following a hormone simulated pregnancy induces deficits in affective behaviors and increases ∆FosB in D1 and D2 neurons in the nucleus accumbens core in mice.

In placental mammals, estradiol levels are chronically elevated during pregnancy, but quickly drop to prepartum levels following birth. This may produce an "estrogen withdrawal" state that has been linked to changes in affective states in humans and rodents during the postpartum period. The neural mechanisms underlying these affective changes, however, are understudied. We used a hormone-simulated pseudopregnancy (HSP), a model of postpartum estrogen withdrawal, in adult female C57BL/6 mice to test the impact of postpartum estradiol withdrawal on several behavioral measures of anxiety and motivation. We found that estradiol withdrawal following HSP increased anxiety-like behavior in the elevated plus maze, but not in the open field or marble burying tests. Although hormone treatment during HSP consistently increased sucrose consumption, sucrose preference was generally not impacted by hormone treatment or subsequent estradiol withdrawal. In the social motivation test, estradiol withdrawal decreased the amount of time spent in proximity to a social stimulus animal. These behavioral changes were accompanied by changes in the expression of ∆FosB, a transcription factor correlated with stable long-term plasticity, in the nucleus accumbens (NAc). Specifically, estrogen-withdrawn females had higher ∆FosB expression in the nucleus accumbens core, but ∆FosB expression did not vary across hormone conditions in the nucleus accumbens shell. Using transgenic reporter mice, we found that this increase in ∆FosB occurred in both D1- and D2-expressing cells in the NAc core. Together, these results suggest that postpartum estrogen withdrawal impacts anxiety and motivation and increases ∆FosB in the NAc core.

Chronic Expression of a Clinical SFTPC Mutation Causes Murine Lung Fibrosis with Idiopathic Pulmonary Fibrosis Features.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic interstitial lung disease. A barrier to developing more effective therapies for IPF is the dearth of preclinical models that recapitulate the early pathobiology of this disease. Intratracheal bleomycin, the conventional preclinical murine model of IPF, fails to reproduce the intrinsic dysfunction to the alveolar epithelial type 2 cell (AEC2) that is believed to be a proximal event in the pathogenesis of IPF. Murine fibrosis models based on SFTPC (Surfactant Protein C gene) mutations identified in patients with interstitial lung disease cause activation of the AEC2 unfolded protein response and endoplasmic reticulum stress-an AEC2 dysfunction phenotype observed in IPF. Although these models achieve spontaneous fibrosis, they do so with precedent lung injury and thus are challenged to phenocopy the general clinical course of patients with IPF-gradual progressive fibrosis and loss of lung function. Here, we report a refinement of a murine Sftpc mutation model to recapitulate the clinical course, physiological impairment, parenchymal cellular composition, and biomarkers associated with IPF. This platform provides the field with an innovative model to understand IPF pathogenesis and index preclinical therapeutic candidates.

Disruption of proteostasis causes IRE1 mediated reprogramming of alveolar epithelial cells.

Disruption of alveolar type 2 cell (AEC2) protein quality control has been implicated in chronic lung diseases, including pulmonary fibrosis (PF). We previously reported the in vivo modeling of a clinical surfactant protein C (SP-C) mutation that led to AEC2 endoplasmic reticulum (ER) stress and spontaneous lung fibrosis, providing proof of concept for disruption to proteostasis as a proximal driver of PF. Using two clinical SP-C mutation models, we have now discovered that AEC2s experiencing significant ER stress lose quintessential AEC2 features and develop a reprogrammed cell state that heretofore has been seen only as a response to lung injury. Using single-cell RNA sequencing in vivo and organoid-based modeling, we show that this state arises de novo from intrinsic AEC2 dysfunction. The cell-autonomous AEC2 reprogramming can be attenuated through inhibition of inositol-requiring enzyme 1 (IRE1α) signaling as the use of an IRE1α inhibitor reduced the development of the reprogrammed cell state and also diminished AEC2-driven recruitment of granulocytes, alveolitis, and lung injury. These findings identify AEC2 proteostasis, and specifically IRE1α signaling through its major product XBP-1, as a driver of a key AEC2 phenotypic change that has been identified in lung fibrosis.

Understanding On-Campus Interactions With a Semiautomated, Barcode-Based Platform to Augment COVID-19 Contact Tracing: App Development and Usage.

BACKGROUND: The COVID-19 pandemic has forced drastic changes to daily life, from the implementation of stay-at-home orders to mandating facial coverings and limiting in-person gatherings. While the relaxation of these control measures has varied geographically, it is widely agreed that contact tracing efforts will play a major role in the successful reopening of businesses and schools. As the volume of positive cases has increased in the United States, it has become clear that there is room for digital health interventions to assist in contact tracing. OBJECTIVE: The goal of this study was to evaluate the use of a mobile-friendly app designed to supplement manual COVID-19 contact tracing efforts on a university campus. Here, we present the results of a development and validation study centered around the use of the MyCOVIDKey app on the Vanderbilt University campus during the summer of 2020. METHODS: We performed a 6-week pilot study in the Stevenson Center Science and Engineering Complex on Vanderbilt University's campus in Nashville, TN. Graduate students, postdoctoral fellows, faculty, and staff >18 years who worked in Stevenson Center and had access to a mobile phone were eligible to register for a MyCOVIDKey account. All users were encouraged to complete regular self-assessments of COVID-19 risk and to key in to sites by scanning a location-specific barcode. RESULTS: Between June 17, 2020, and July 29, 2020, 45 unique participants created MyCOVIDKey accounts. These users performed 227 self-assessments and 1410 key-ins. Self-assessments were performed by 89% (n=40) of users, 71% (n=32) of users keyed in, and 48 unique locations (of 71 possible locations) were visited. Overall, 89% (202/227) of assessments were determined to be low risk (ie, asymptomatic with no known exposures), and these assessments yielded a CLEAR status. The remaining self-assessments received a status of NOT CLEAR, indicating either risk of exposure or symptoms suggestive of COVID-19 (7.5% [n=17] and 3.5% [n=8] of self-assessments indicated moderate and high risk, respectively). These 25 instances came from 8 unique users, and in 19 of these instances, the at-risk user keyed in to a location on campus. CONCLUSIONS: Digital contact tracing tools may be useful in assisting organizations to identify persons at risk of COVID-19 through contact tracing, or in locating places that may need to be cleaned or disinfected after being visited by an index case. Incentives to continue the use of such tools can improve uptake, and their continued usage increases utility to both organizational and public health efforts. Parameters of digital tools, including MyCOVIDKey, should ideally be optimized to supplement existing contact tracing efforts. These tools represent a critical addition to manual contact tracing efforts during reopening and sustained regular activity.

App Use and Usability of a Barcode-Based Digital Platform to Augment COVID-19 Contact Tracing: Postpilot Survey and Paradata Analysis.

BACKGROUND: The COVID-19 pandemic has drastically changed life in the United States, as the country has recorded over 23 million cases and 383,000 deaths to date. In the leadup to widespread vaccine deployment, testing and surveillance are critical for detecting and stopping possible routes of transmission. Contact tracing has become an important surveillance measure to control COVID-19 in the United States, and mobile health interventions have found increased prominence in this space. OBJECTIVE: The aim of this study was to investigate the use and usability of MyCOVIDKey, a mobile-based web app to assist COVID-19 contact tracing efforts, during the 6-week pilot period. METHODS: A 6-week study was conducted on the Vanderbilt University campus in Nashville, Tennessee. The study participants, consisting primarily of graduate students, postdoctoral researchers, and faculty in the Chemistry Department at Vanderbilt University, were asked to use the MyCOVIDKey web app during the course of the study period. Paradata were collected as users engaged with the MyCOVIDKey web app. At the end of the study, all participants were asked to report on their user experience in a survey, and the results were analyzed in the context of the user paradata. RESULTS: During the pilot period, 45 users enrolled in MyCOVIDKey. An analysis of their enrollment suggests that initial recruiting efforts were effective; however, participant recruitment and engagement efforts at the midpoint of the study were less effective. App use paralleled the number of users, indicating that incentives were useful for recruiting new users to sign up but did not result in users attempting to artificially inflate their use as a result of prize offers. Times to completion of key tasks were low, indicating that the main features of the app could be used quickly. Of the 45 users, 30 provided feedback through a postpilot survey, with 26 (58%) completing it in its entirety. The MyCOVIDKey app as a whole was rated 70.0 on the System Usability Scale, indicating that it performed above the accepted threshold for usability. When the key-in and self-assessment features were examined on their own, it was found that they individually crossed the same thresholds for acceptable usability but that the key-in feature had a higher margin for improvement. CONCLUSIONS: The MyCOVIDKey app was found overall to be a useful tool for COVID-19 contact tracing in a university setting. Most users suggested simple-to-implement improvements, such as replacing the web app framework with a native app format or changing the placement of the scanner within the app workflow. After these updates, this tool could be readily deployed and easily adapted to other settings across the country. The need for digital contact tracing tools is becoming increasingly apparent, particularly as COVID-19 case numbers continue to increase while more businesses begin to reopen.

Evaluating Network Readiness for mHealth Interventions Using the Beacon Mobile Phone App: Application Development and Validation Study.

BACKGROUND: Mobile health (mHealth) interventions have the potential to transform the global health care landscape. The processing power of mobile devices continues to increase, and growth of mobile phone use has been observed worldwide. Uncertainty remains among key stakeholders and decision makers as to whether global health interventions can successfully tap into this trend. However, when correctly implemented, mHealth can reduce geographic, financial, and social barriers to quality health care. OBJECTIVE: The aim of this study was to design and test Beacon, a mobile phone-based tool for evaluating mHealth readiness in global health interventions. Here, we present the results of an application validation study designed to understand the mobile network landscape in and around Macha, Zambia, in 2019. METHODS: Beacon was developed as an automated mobile phone app that continually collects spatiotemporal data and measures indicators of network performance. Beacon was used in and around Macha, Zambia, in 2019. Results were collected, even in the absence of network connectivity, and asynchronously uploaded to a database for further analysis. RESULTS: Beacon was used to evaluate three mobile phone networks around Macha. Carriers A and B completed 6820/7034 (97.0%) and 6701/7034 (95.3%) downloads and 1349/1608 (83.9%) and 1431/1608 (89.0%) uploads, respectively, while Carrier C completed only 62/1373 (4.5%) file downloads and 0/1373 (0.0%) file uploads. File downloads generally occurred within 4 to 12 seconds, and their maximum download speeds occurred between 2 AM and 5 AM. A decrease in network performance, demonstrated by increases in upload and download durations, was observed beginning at 5 PM and continued throughout the evening. CONCLUSIONS: Beacon was able to compare the performance of different cellular networks, show times of day when cellular networks experience heavy loads and slow down, and identify geographic "dead zones" with limited or no cellular service. Beacon is a ready-to-use tool that could be used by organizations that are considering implementing mHealth interventions in low- and middle-income countries but are questioning the feasibility of the interventions, including infrastructure and cost. It could also be used by organizations that are looking to optimize the delivery of an existing mHealth intervention with improved logistics management.

Impact of Pharmacist Involvement on Telehealth Transitional Care Management (TCM) for High Medication Risk Patients.

This pilot study sought to evaluate the impact of pharmacist involvement in the preexisting telehealth transitional care management (TCM) program at Atrium Health on the quality and safety of the medication discharge process for high medication risk patients. Eligible participants were those 18 years of age or older with moderate-to-high risk for hospital readmission who were contacted by a TCM Nurse, identified as high medication risk patients, and referred to the TCM Pharmacist from September 2018 through February 2019. The TCM Pharmacist contacted patients by phone, completed a comprehensive medication review, identified medication list discrepancies (MLDs) and medication-related problems (MRPs), and made interventions or recommendations to primary care providers. Primary endpoints included the number and types of MLDs identified, number and types of MRPs identified, and the rate of unplanned 30-day hospital readmissions. Seventy-six patients were enrolled, and 78 MLDs and 108 MRPs were identified. Of the identified MRPs, 74.1% were resolved. A relative risk reduction of 36.8% was achieved for 30-day hospital readmissions for those with high medication risk contacted by the TCM Pharmacist compared to those only contacted by the TCM Nurse. Overall, TCM Pharmacists identified and resolved 80 medication-related problems, improved access to medication therapy, provided comprehensive medication counseling, and bridged gaps in care following hospital discharge.