A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

Earthworm invasion into previously earthworm-free temperate and boreal forests

Earthworms are keystone detritivores that can influence primary producers by changing seedbed conditions, soil characteristics, flow of water, nutrients and carbon, and plant–herbivore interactions. The invasion of European earthworms into previously earthworm-free temperate and boreal forests of North America dominated by Acer, Quercus, Betula, Pinus and Populus has provided ample opportunity to observe how earthworms engineer ecosystems. Impacts vary with soil parent material, land use history, and assemblage of invading earthworm species. Earthworms reduce the thickness of organic layers, increase the bulk density of soils and incorporate litter and humus materials into deeper horizons of the soil profile, thereby affecting the whole soil food web and the above ground plant community. Mixing of organic and mineral materials turns mor into mull humus which significantly changes the distribution and community composition of the soil microflora and seedbed conditions for vascular plants. In some forests earthworm invasion leads to reduced availability and increased leaching of N and P in soil horizons where most fine roots are concentrated. Earthworms can contribute to a forest decline syndrome, and forest herbs in the genera Aralia, Botrychium, Osmorhiza, Trillium, Uvularia, and Viola are reduced in abundance during earthworm invasion. The degree of plant recovery after invasion varies greatly among sites and depends on complex interactions with soil processes and herbivores. These changes are likely to alter competitive relationships among plant species, possibly facilitating invasion of exotic plant species such as Rhamnus cathartica into North American forests, leading to as yet unknown changes in successional trajectory

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Heart Work: Challenges and Adaptations of Hospice Workers

This dissertation analyzes the everyday work experiences of hospice, a type of end-of-life care. The following chapters integrate micro-sociological perspectives with meso- and macro- level explanations of organizational behavior to account for workers' performances of emotional labor, care-related identities, constraints on their daily work, and ultimately hospice workers' strong commitment to their jobs and the hospice philosophy. Using a mixed methodological approach, I argue that hospice workers engage in emotional labor, but that instead of feeling dissonance or alienation, hospice workers develop a positive identity around their work. Their identities and work experiences are still constrained by institutional forces, however. Hospice workers' experiences highlight two tensions in the administration of caring labor: keeping commitment during times of organizational change and balancing the needs of the self with the needs of the care recipient. The main contributions of this work include new understandings of the relationships between identity, emotions, and work; a novel combination of theories that better explain care workers' behaviors and constraints on their action; and, a refined approach to thinking about emotional labor

Implementing Aid in Dying in California: Experiences from Other States Indicates the Need for Strong Implementation Guidance

In late 2015, California passed the End of Life Option Act (AB 15), which allows residents at the terminal stage of an illness to request a prescription for medications meant to hasten death. As California seeks to implement the law in June 2016, findings from other states that practice aid in dying (AID) may guide implementation. This policy brief provides an overview of the use of AID, outlines outstanding questions about practice and ethics, and recommends steps for improving California’s implementation of AB 15. Specifically, the implementation of AB 15 would be improved by adjusting surveillance data-collection requirements and encouraging additional research investment, using the legalization of AID to improve knowledge of and practices for end-of-life care generally, and creating ongoing educational opportunities for providers and the general public

Integrating work and home when patients are dying: a mixed-methods study of hospice care workers and work–family conflict in the US

Scholars of work and family have argued that flexibility in hours and location may support integration between work and home. Home-based hospice care is a type of work that has a great deal of flexibility but it is not clear that it is used to support workers. Using interview and survey data from 179 US hospice workers, we show that the speeding up of care and culture of self-sacrifice make integration difficult. Almost a third of workers report that work takes too much time from home life, which is associated with higher turnover intention, higher burnout and lower life satisfaction

The Power of Community Voices for Enhancing Community Health Needs Assessments.

As required by the Affordable Care Act, Community Health Needs Assessments (CHNAs) are formalized processes nonprofit hospitals must perform at least every 3 years. CHNAs are designed to help hospitals better tailor health services to the needs of local residents. However, CHNAs most often use quantitative, population-level data, and rarely incorporate the actual voices of local community members. This is particularly a problem for meeting the needs of residents who are also racial or ethnic minorities. This article discusses one model for integrating residents' voices into the CHNA process. In this model, we videotaped interviews with community members and then coded and analyzed interview data to identify underlying themes. We created a short video aimed at starting conversations about community members' concerns. In addition to demonstrating how other nonprofit hospitals may use qualitative data in the CHNA process, this article illustrates how adding qualitative data may change how we think about health promotion. We find that community members requested that health care providers view culture as a health resource, foster community connections, and be present in the community

User-centered design to improve clinical decision support in primary care

BackgroundA growing literature has demonstrated the ability of user-centered design to make clinical decision support systems more effective and easier to use. However, studies of user-centered design have rarely examined more than a handful of sites at a time, and have frequently neglected the implementation climate and organizational resources that influence clinical decision support. The inclusion of such factors was identified by a systematic review as "the most important improvement that can be made in health IT evaluations."Objectives(1) Identify the prevalence of four user-centered design practices at United States Veterans Affairs (VA) primary care clinics and assess the perceived utility of clinical decision support at those clinics; (2) Evaluate the association between those user-centered design practices and the perceived utility of clinical decision support.MethodsWe analyzed clinic-level survey data collected in 2006-2007 from 170 VA primary care clinics. We examined four user-centered design practices: 1) pilot testing, 2) provider satisfaction assessment, 3) formal usability assessment, and 4) analysis of impact on performance improvement. We used a regression model to evaluate the association between user-centered design practices and the perceived utility of clinical decision support, while accounting for other important factors at those clinics, including implementation climate, available resources, and structural characteristics. We also examined associations separately at community-based clinics and at hospital-based clinics.ResultsUser-centered design practices for clinical decision support varied across clinics: 74% conducted pilot testing, 62% conducted provider satisfaction assessment, 36% conducted a formal usability assessment, and 79% conducted an analysis of impact on performance improvement. Overall perceived utility of clinical decision support was high, with a mean rating of 4.17 (±.67) out of 5 on a composite measure. "Analysis of impact on performance improvement" was the only user-centered design practice significantly associated with perceived utility of clinical decision support, b=.47 (p&lt;.001). This association was present in hospital-based clinics, b=.34 (p&lt;.05), but was stronger at community-based clinics, b=.61 (p&lt;.001).ConclusionsOur findings are highly supportive of the practice of analyzing the impact of clinical decision support on performance metrics. This was the most common user-centered design practice in our study, and was the practice associated with higher perceived utility of clinical decision support. This practice may be particularly helpful at community-based clinics, which are typically less connected to VA medical center resources