Austin S. Kilaru

GTPase Activity Plays a Key Role in the Pathobiology of LRRK2

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are associated with late-onset, autosomal-dominant, familial Parkinsons disease (PD) and also contribute to sporadic disease. The LRRK2 gene encodes a large protein with multiple domains, including functional Roc GTPase and protein kinase domains. Mutations in LRRK2 most likely cause disease through a toxic gain-of-function mechanism. The expression of human LRRK2 variants in cultured primary neurons induces toxicity that is dependent on intact GTP binding or kinase activities. However, the mechanism(s) underlying LRRK2-induced neuronal toxicity is poorly understood, and the contribution of GTPase and/or kinase activity to LRRK2 pathobiology is not well defined. To explore the pathobiology of LRRK2, we have developed a model of LRRK2 cytotoxicity in the bakers yeast Saccharomyces cerevisiae. Protein domain analysis in this model reveals that expression of GTPase domain-containing fragments of human LRRK2 are toxic. LRRK2 toxicity in yeast can be modulated by altering GTPase activity and is closely associated with defects in endocytic vesicular trafficking and autophagy. These truncated LRRK2 variants induce similar toxicity in both yeast and primary neuronal models and cause similar vesicular defects in yeast as full-length LRRK2 causes in primary neurons. The toxicity induced by truncated LRRK2 variants in yeast acts through a mechanism distinct from toxicity induced by human α-synuclein. A genome-wide genetic screen identified modifiers of LRRK2-induced toxicity in yeast including components of vesicular trafficking pathways, which can also modulate the trafficking defects caused by expression of truncated LRRK2 variants. Our results provide insight into the basic pathobiology of LRRK2 and suggest that the GTPase domain may contribute to the toxicity of LRRK2. These findings may guide future therapeutic strategies aimed at attenuating LRRK2-mediated neurodegeneration.

Use of Social Media Across US Hospitals: Descriptive Analysis of Adoption and Utilization

Background Use of social media has become widespread across the United States. Although businesses have invested in social media to engage consumers and promote products, less is known about the extent to which hospitals are using social media to interact with patients and promote health. Objective The aim was to investigate the relationship between hospital social media extent of adoption and utilization relative to hospital characteristics. Methods We conducted a cross-sectional review of hospital-related activity on 4 social media platforms: Facebook, Twitter, Yelp, and Foursquare. All US hospitals were included that reported complete data for the Centers for Medicare and Medicaid Services Hospital Consumer Assessment of Healthcare Providers and Systems survey and the American Hospital Association Annual Survey. We reviewed hospital social media webpages to determine the extent of adoption relative to hospital characteristics, including geographic region, urban designation, bed size, ownership type, and teaching status. Social media utilization was estimated from user activity specific to each social media platform, including number of Facebook likes, Twitter followers, Foursquare check-ins, and Yelp reviews. Results Adoption of social media varied across hospitals with 94.41% (3351/3371) having a Facebook page and 50.82% (1713/3371) having a Twitter account. A majority of hospitals had a Yelp page (99.14%, 3342/3371) and almost all hospitals had check-ins on Foursquare (99.41%, 3351/3371). Large, urban, private nonprofit, and teaching hospitals were more likely to have higher utilization of these accounts. Conclusions Although most hospitals adopted at least one social media platform, utilization of social media varied according to several hospital characteristics. This preliminary investigation of social media adoption and utilization among US hospitals provides the framework for future studies investigating the effect of social media on patient outcomes, including links between social media use and the quality of hospital care and services.

A Crowdsourcing Innovation Challenge to Locate and Map Automated External Defibrillators

Out-of-hospital cardiac arrest is a major public health problem that affects an estimated 300 000 people in the United States every year.1,2 The application of an automated external defibrillator (AED) to patients who have experienced cardiac arrest has saved many lives. AEDs coupled with cardiopulmonary resuscitation can significantly improve survival from cardiac arrest from 50%.3–5 AEDs can be used easily by untrained laypeople. When accessed and opened, most devices provide audible and visual instructions on use and how to perform cardiopulmonary resuscitation. However, AED effectiveness is extremely time dependent, and presently, in a crisis no comprehensive map of these devices exists to help bystanders find and use them.3,6–9 Previous work from a large database of out-of-hospital cardiac arrest in the United States suggests low (4%, 1166 of 31 689) use of AEDs by bystanders.10 An accurate, easily accessible map of AEDs could help people locate them in an emergency, either directly through smart phone applications (apps) or through communication with map-equipped 911 emergency responders.11 Creating such a map is challenging, and currently, there is no publicly accessible, accurate, comprehensive crowdsourced map for any region in the world. Although sending out an army of staff might allow canvassing of a geographic region, such an approach would be expensive and not clearly scalable. Furthermore, because AEDs can move locations and require maintenance, ensuring that a database of devices had valid, routinely updated data would be a difficult task. Crowdsourcing is increasingly used to address major creative and data gathering challenges.12–15 Crowdsourcing involves taking a task conventionally assigned to particular individuals and instead soliciting help for the task from a large group of diverse individuals (ie, the crowd). The task is often posted online to …

The Role of the Parkinson's Disease Gene PARK9 in Essential Cellular Pathways and the Manganese Homeostasis Network in Yeast

YPK9 (Yeast PARK9; also known as YOR291W) is a non-essential yeast gene predicted by sequence to encode a transmembrane P-type transport ATPase. However, its substrate specificity is unknown. Mutations in the human homolog of YPK9, ATP13A2/PARK9, have been linked to genetic forms of early onset parkinsonism. We previously described a strong genetic interaction between Ypk9 and another Parkinsons disease (PD) protein α-synuclein in multiple model systems, and a role for Ypk9 in manganese detoxification in yeast. In humans, environmental exposure to toxic levels of manganese causes a syndrome similar to PD and is thus an environmental risk factor for the disease. How manganese contributes to neurodegeneration is poorly understood. Here we describe multiple genome-wide screens in yeast aimed at defining the cellular function of Ypk9 and the mechanisms by which it protects cells from manganese toxicity. In physiological conditions, we found that Ypk9 genetically interacts with essential genes involved in cellular trafficking and the cell cycle. Deletion of Ypk9 sensitizes yeast cells to exposure to excess manganese. Using a library of non-essential gene deletions, we screened for additional genes involved in tolerance to excess manganese exposure, discovering several novel pathways involved in manganese homeostasis. We defined the dependence of the deletion strain phenotypes in the presence of manganese on Ypk9, and found that Ypk9 deletion modifies the manganese tolerance of only a subset of strains. These results confirm a role for Ypk9 in manganese homeostasis and illuminates cellular pathways and biological processes in which Ypk9 likely functions.

What do patients say about emergency departments in online reviews? A qualitative study

Background Patients have adopted web-based tools to report on the quality of their healthcare experiences. We seek to examine online reviews for US emergency departments (EDs) posted on Yelp, a popular consumer ratings website. Methods We conducted a qualitative analysis of unstructured, publicly accessible reviews for hospitals available on http://www.yelp.com. We collected all reviews describing experiences of ED care for a stratified random sample of 100 US hospitals. We analysed the content of the reviews using themes derived from the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) inpatient care survey. We also used modified grounded theory to iteratively code the text of the reviews, identifying additional themes specific to emergency care. The data were double-coded, and discrepancies were evaluated to ensure consensus. Results Of the 1736 total reviews, 573 (33%) described patient experiences involving the ED. The reviews contained several themes assessed by the HCAHPS survey, including communication with nurses, communication with doctors, and pain control. The reviews also contained key themes specific to emergency care: waiting and efficiency; decisions to seek care in the ED; and events following discharge, including administrative difficulties. Conclusions These exploratory findings suggest that online reviews for EDs contain similar themes to survey-based assessments of inpatient hospital care as well as themes specific to emergency care. Consumer rating websites allow patients to provide rapid and public feedback on their experience of medical care. Web-based platforms may offer a novel strategy for assessing patient-centred quality in emergency care.

Do hospital service areas and hospital referral regions define discrete health care populations

Background:Effective measurement of health care quality, access, and cost for populations requires an accountable geographic unit. Although Hospital Service Areas (HSAs) and Hospital Referral Regions (HRRs) have been extensively used in health services research, it is unknown whether these units accurately describe patterns of hospital use for patients living within them. Objectives:To evaluate the ability of HSAs, HRRs, and counties to define discrete health care populations. Research Design:Cross-sectional geographic analysis of hospital admissions. Subjects:All hospital admissions during the year 2011 in Washington, Arizona, and Florida. Measures:The main outcomes of interest were 3 metrics that describe patient movement across HSA, HRR, and county boundaries: localization index, market share index, and net patient flow. Regression models tested the association of these metrics with different HSA characteristics. Results:For 45% of HSAs, fewer than half of the patients were admitted to hospitals located in their HSA of residence. For 16% of HSAs, more than half of the treated patients lived elsewhere. There was an equivalent degree of movement across county boundaries but less movement across HRR boundaries. Patients living in populous, urban HSAs with multiple, large, and teaching hospitals tended to remain for inpatient care. Patients admitted through the emergency department tended to receive care at local hospitals relative to other patients. Conclusions:HSAs and HRRs are geographic units commonly used in health services research yet vary in their ability to describe where patients receive hospital care. Geographic models may need to account for differences between emergent and nonemergent care.

Evidence-based Narratives to Improve Recall of Opioid Prescribing Guidelines: A Randomized Experiment

OBJECTIVES Physicians adopt evidence-based guidelines with variable consistency. Narratives, or stories, offer a novel dissemination strategy for clinical recommendations. The study objective was to compare whether evidence-based narrative versus traditional summary improved recall of opioid prescribing guidelines from the American College of Emergency Physicians (ACEP). METHODS This was a prospective, randomized controlled experiment to compare whether narrative versus summary promoted short-term recall of six themes contained in the ACEP opioid guideline. The experiment was modeled after the free-recall test, an established technique in studies of memory. At a regional conference, emergency physicians (EPs) were randomized to read either a summary of the guideline (control) or a narrative (intervention). The fictional narrative was constructed to match the summary in content and length. One hour after reading the text, participants listed all content that they could recall. Two reviewers independently scored the responses to assess recall of the six themes. The primary outcome was the total number of themes recalled per participant. Secondary outcomes included the proportion of responses in each study arm that recalled individual themes and the proportion of responses in each arm that contained falsely recalled or extraneous information. RESULTS Ninety-five physicians were randomized. Eighty-two physicians completed the experiment, for a response rate of 86%. The mean of the total number of themes recalled per participant was 3.1 in the narrative arm versus 2.0 in the summary arm (difference = 1.1, 95% confidence interval [CI] = 0.6 to 1.7). For three themes, the proportion of responses that recalled the theme was significantly greater in the narrative arm compared to the summary arm, with the differences ranging from 20% to 51%. For one theme, recall was significantly greater in the summary arm. For two themes, there was no statistically significant difference in recall between the arms. In the summary arm, 54% of responses were found to contain falsely recalled or extraneous information versus 21% of responses in the narrative arm (difference = 33%, 95% CI = 14% to 53%). CONCLUSIONS Physicians exposed to a narrative about opioid guidelines were more likely to recall guideline content at 1 hour than those exposed to a summary of the guidelines. Future studies should examine whether the incorporation of narratives in dissemination campaigns improves guideline adoption and changes clinical practice

Hidden in Plain Sight: A Crowdsourced Public Art Contest to Make Automated External Defibrillators More Visible

OBJECTIVES We sought to explore the feasibility of using a crowdsourcing study to promote awareness about automated external defibrillators (AEDs) and their locations. METHODS The Defibrillator Design Challenge was an online initiative that asked the public to create educational designs that would enhance AED visibility, which took place over 8 weeks, from February 6, 2014, to April 6, 2014. Participants were encouraged to vote for AED designs and share designs on social media for points. Using a mixed-methods study design, we measured participant demographics and motivations, design characteristics, dissemination, and Web site engagement. RESULTS Over 8 weeks, there were 13 992 unique Web site visitors; 119 submitted designs and 2140 voted. The designs were shared 48 254 times on Facebook and Twitter. Most designers-voters reported that they participated to contribute to an important cause (44%) rather than to win money (0.8%). Design themes included: empowerment, location awareness, objects (e.g., wings, lightning, batteries, lifebuoys), and others. CONCLUSIONS The Defibrillator Design Challenge engaged a broad audience to generate AED designs and foster awareness. This project provides a framework for using design and contest architecture to promote health messages.

A Randomized Trial Testing the Effect of Narrative Vignettes Versus Guideline Summaries on Provider Response to a Professional Organization Clinical Policy for Safe Opioid Prescribing

STUDY OBJECTIVE Clinical guidelines are known to be underused by practitioners. In response to the challenges of treating pain amid a prescription opioid epidemic, the American College of Emergency Physicians (ACEP) published an evidence-based clinical policy for opioid prescribing in 2012. Evidence-based narratives, an effective method of communicating health information in a variety of settings, offer a novel strategy for disseminating guidelines to physicians and engaging providers with clinical evidence. We compare whether narrative vignettes embedded in the ACEP daily e-newsletter improved dissemination of the clinical policy to ACEP members, and engagement of members with the clinical policy, compared with traditional summary text. METHODS A prospective randomized controlled study, titled Stories to Promote Information Using Narrative trial, was performed. Derived from qualitative interviews with 61 ACEP physicians, 4 narrative vignettes were selected and refined, using a consensus panel of clinical and implementation experts. All ACEP members were then block randomized by state of residence to receive alternative versions of a daily e-mailed newsletter for a total of 24 days during a 9-week period. Narrative newsletters contained a selection of vignettes that referenced opioid prescription dilemmas. Control newsletters contained a selection of descriptive text about the clinical policy, using length and appearance similar to that of the narrative vignettes. Embedded in the newsletters were Web links to the complete vignette or traditional summary text, as well as additional links to the full ACEP clinical policy and a Web site providing assistance with prescription drug monitoring program enrollment. The newsletters were otherwise identical. Outcomes measured were the percentage of subjects who visited any of the Web pages that contained additional guideline-related information and the odds of any unique physician visiting these Web pages during the study. RESULTS There were 27,592 physicians randomized, and 21,226 received the newsletter during the study period. When each physician was counted once during the study period, there were 509 unique visitors in the narrative group and 173 unique visitors in the control group (4.8% versus 1.6%; difference 3.2%; 95% confidence interval [CI] 2.7% to 3.7%). There were 744 gross visits from the e-newsletter to any of the 3 Web pages in the narrative group compared with 248 in the control group (7.0% versus 2.3%; odds ratio 3.2; 95% CI 2.7 to 3.6). During the study, the odds ratio of any physician in the narrative group visiting one of the 3 informational Web sites compared with the control group was 3.1 (95% CI 2.6 to 3.6). CONCLUSION Among a national sample of emergency physicians, narrative vignettes outperformed traditional guideline text in promoting engagement with an evidence-based clinical guideline related to opioid prescriptions.

Promoting Public Health Through Public Art in the Digital Age

In this article the authors discuss the effective role that social media and public art can play in public health promotion and reflect on the challenges that are associated with using social media in health promotion initiatives. An overview of a health promotion challenge called the Defibrillator Design Challenge, which is designed to increase public awareness about cardiac defibrillators by installing attention-getting images of automated external defibrillators (AEDs) in public locations, is presented.