Stepping into the Right Shoes: The Effects of User-Matched Avatar Ethnicity and Gender on Sense of Embodiment in Virtual Reality.

In many consumer virtual reality (VR) applications, users embody predefined characters that offer minimal customization options, frequently emphasizing storytelling over user choice. We explore whether matching a user's physical characteristics, specifically ethnicity and gender, with their virtual self-avatar affects their sense of embodiment in VR. We conducted a $2\times 2$ within-subjects experiment ($\mathrm{n}=32$) with a diverse user population to explore the impact of matching or not matching a user's self-avatar to their ethnicity and gender on their sense of embodiment. Our results indicate that matching the ethnicity of the user and their self-avatar significantly enhances sense of embodiment regardless of gender, extending across various aspects, including appearance, response, and ownership. We also found that matching gender significantly enhanced ownership, suggesting that this aspect is influenced by matching both ethnicity and gender. Interestingly, we found that matching ethnicity specifically affects self-location while matching gender specifically affects one's body ownership.

What Clinicians and Researchers Should Know About the Evolving Field of Advance Care Planning: a Narrative Review.

Advance care planning (ACP) has been recognized as crucial by patients, families, and clinicians; however, different definitions and measurements have led to inconsistencies in practice and mixed evidence in the literature. This narrative review explores ACP's evolution, innovations, and outcomes using thematic analysis to synthesize data from randomized controlled trials, reviews, and editorials. Key findings include (1) ACP has evolved over the past several decades from a sole focus on code status and advance directive (AD) forms to a continuum of care planning over the life course focused on tailored preparation for patients and surrogate decision-makers and (2) ACP measurement has evolved from traditional outcome metrics, such as AD completion, to a comprehensive outcomes framework that includes behavior change theory, systems, implementation science, and a focus on surrogate outcomes. Since the recent development of an ACP consensus definition and outcomes framework, high-quality trials have reported mainly positive outcomes for interventions, especially for surrogates, which aligns with the patient desire to relieve decision-making burden for loved ones. Additionally, measurement of "clinically meaningful" ACP information, including documented goals of care discussions, is increasingly being integrated into electronic health records (EHR), and emerging, real-time assessments and natural language processing are enhancing ACP evaluation. To make things easier for patients, families, and care teams, clinicians and researchers can use and disseminate these evolved definitions; provide patients validated, easy-to-use tools that prime patients for conversations and decrease health disparities; use easy-to-access clinician training and simple scripts for interdisciplinary team members; and document patients' values and preferences in the medical record to capture clinically meaningful ACP so this information is available at the point of care. Future efforts should focus on efficient implementation, expanded reimbursement options, and seamless integration of EHR documentation to ensure ACP's continued evolution to better serve patients and their care partners.

Surrogate Decision Makers Need Better Preparation for Their Role: Advice from Experienced Surrogates.

Background: Surrogate decision makers are required to make difficult end-of-life decisions with little preparation. Little is known about what surrogates may need to adequately prepare for their role, and few resources exist to prepare them. Objective: To explore experiences and advice from surrogates about how best to prepare for the surrogate role. Design: Semistructured focus groups. Setting/Participants: Sixty-nine participants were recruited through convenience sampling in San Francisco area hospitals, cancer support groups, and community centers for 13 focus groups. Surrogates were included if they were 18 years of age or older and reported having made medical decisions for others. Measurements: Qualitative thematic content analysis. Results: Forty participants reported making surrogate decisions for others: 6 were Spanish speaking, 22 were women, 16 were Black American, 11 Asian/Pacific Islander, 6 Latinx, and 7 White; 9 had limited health literacy. The majority (29, 73%) emphasized the importance of advance care planning (ACP) and expressed the desire for additional guidance. Five themes and advice were identified: (1) lack of, but needing, surrogates' own preparation and guidance (2) initiate ACP conversations, (3) learn patient's values and preferences, (4) communicate with clinicians and advocate for patients, and (5) make informed surrogate decisions. Conclusion: Experienced surrogate decision makers emphasized the importance of ACP and advised that surrogates need their own preparation to initiate ACP conversations, learn patients' values, advocate for patients, and make informed surrogate decisions. Future interventions should address these preparation topics to ease surrogate burden and decrease disparities in surrogate decision making.

The Cognitive Loads and Usability of Target-based and Steering-based Travel Techniques.

Target and steering-based techniques are two common approaches to travel in consumer VR applications. In this paper, we present two within-subject studies that employ a prior dual-task methodology to evaluate and compare the cognitive loads, travel performances, and simulator sickness of three common target-based travel techniques and three common steering-based travel techniques. We also present visual meta-analyses comparing our results to prior results using the same dual-task methodology. Based on our results and meta-analyses, we present several design suggestions for travel techniques based on various aspects of user experiences.

Deconstructing the Complexities of Advance Care Planning Outcomes: What Do We Know and Where Do We Go? A Scoping Review.

BACKGROUND/OBJECTIVES: Advance care planning (ACP) has shown benefit in some, but not all, studies. It is important to understand the utility of ACP. We conducted a scoping review to identify promising interventions and outcomes. DESIGN: Scoping review. MEASUREMENTS: We searched MEDLINE/PubMed, EMBASE, CINAHL, PsycINFO, and Web of Science for ACP randomized controlled trials from January 1, 2010, to March 3, 2020. We used standardized Preferred Reporting Items for Systematic Review and Meta-Analyses methods to chart study characteristics, including a standardized ACP Outcome Framework: Process (e.g., readiness), Action (e.g., communication), Quality of Care (e.g., satisfaction), Health Status (e.g., anxiety), and Healthcare Utilization. Differences between arms of P < .05 were deemed positive. RESULTS: Of 1,464 articles, 69 met eligibility; 94% were rated high quality. There were variable definitions, age criteria (≥18 to ≥80 years), diseases (e.g., dementia and cancer), and settings (e.g., outpatient and inpatient). Interventions included facilitated discussions (42%), video only (20%), interactive, multimedia (17%), written only (12%), and clinician training (9%). For written only, 75% of primary outcomes were positive, as were 69% for multimedia programs; 67% for facilitated discussions, 59% for video only, and 57% for clinician training. Overall, 72% of Process and 86% of Action outcomes were positive. For Quality of Care, 88% of outcomes were positive for patient-surrogate/clinician congruence, 100% for patients/surrogate/clinician satisfaction with communication, and 75% for surrogate satisfaction with patients' care, but not for goal concordance. For Health Status outcomes, 100% were positive for reducing surrogate/clinician distress, but not for patient quality of life. Healthcare Utilization data were mixed. CONCLUSION: ACP is complex, and trial characteristics were heterogeneous. Outcomes for all ACP interventions were predominantly positive, as were Process and Action outcomes. Although some Quality of Care and Health Status outcomes were mixed, increased patient/surrogate satisfaction with communication and care and decreased surrogate/clinician distress were positive. Further research is needed to appropriately tailor interventions and outcomes for local contexts, set appropriate expectations of ACP outcomes, and standardize across studies.

Anxious, Depressed, and Planning for the Future: Advance Care Planning in Diverse Older Adults.

OBJECTIVES: To determine whether depression and anxiety are associated with advance care planning (ACP) engagement or values concerning future medical care. DESIGN: Cross-sectional. PARTICIPANTS: English- and Spanish-speaking patients, aged 55 years and older, from a San Francisco, CA, county hospital. MEASURES: Depression was measured by the Patient Health Questionnaire 8-item scale, and anxiety was measured by the Generalized Anxiety Disorder 7-item scale, using standardized cutoffs of 10 or more for moderate-to-severe symptoms. ACP engagement was measured using validated surveys of ACP behavior change (e.g., self-efficacy and readiness; mean five-point Likert score) and ACP actions (e.g., ask, discuss, and document wishes; 0- to 25-point scale), with higher scores representing higher engagement. In addition, we asked a question about valuing life extension ("some health situations would make life not worth living"). We used adjusted linear and logistic regression. RESULTS: Mean age of 986 participants was 63 years, 81% were non-White, 39% had limited health literacy, 45% were Spanish speaking, 13% had depression, and 10% had anxiety. After adjustment for demographic and health status variables, participants who were depressed versus not depressed had higher ACP behavior change scores (0.2 points; 95% confidence interval (CI) = 0.06-0.38; P = .007), higher ACP action scores (1.5 points; 95% CI = 0.51-2.57; P = .003), and higher odds of not valuing life extension (odds ratio (OR) = 2.5; 95% CI = 1.5-4.3; P < .001). Results were similar in participants with versus without anxiety (ACP behavior change: 0.2 points; 95% CI = 0.05-0.40; P = .01; ACP action scores: 1.2 points; 95% CI = 0.14-2.32; P = .028; odds of not valuing life extension: OR = 2.3; 95% CI = 1.3-3.9; P = .004). CONCLUSION: Depression and anxiety were associated with greater ACP engagement and not valuing life extension. Although the direction of association between ACP engagement and values with anxiety and depression cannot be determined in this cross-sectional study, these conditions may influence ACP preferences. Future studies should assess whether changes in anxiety or depression affect ACP preferences over time.

Hematopoietic Cell-Expressed Endothelial Nitric Oxide Protects the Liver From Insulin Resistance.

OBJECTIVE: Mice genetically deficient in endothelial nitric oxide synthase (Nos3-/-) have fasting hyperinsulinemia and hepatic insulin resistance, indicating the importance of Nos3 (nitric oxide synthase) in maintaining metabolic homeostasis. Although the current paradigm holds that these metabolic effects are derived specifically from the expression of Nos3 in the endothelium, it has been established that bone marrow-derived cells also express Nos3. The aim of this study was to investigate whether bone marrow-derived cell Nos3 is important in maintaining metabolic homeostasis. Approach and Results: To test the hypothesis that bone marrow-derived cell Nos3 contributes to metabolic homeostasis, we generated chimeric male mice deficient or competent for Nos3 expression in circulating blood cells. These mice were placed on a low-fat diet for 5 weeks, a time period which is known to induce hepatic insulin resistance in global Nos3-deficient mice but not in wild-type C57Bl/6 mice. Surprisingly, we found that the absence of Nos3 in the bone marrow-derived component is associated with hepatic insulin resistance and that restoration of Nos3 in the bone marrow-derived component in global Nos3-deficient mice is sufficient to restore hepatic insulin sensitivity. Furthermore, we found that overexpression of Nos3 in bone marrow-derived component in wild-type mice attenuates the development of hepatic insulin resistance during high-fat feeding. Finally, compared with wild-type macrophages, the loss of macrophage Nos3 is associated with increased inflammatory responses to lipopolysaccharides and reduced anti-inflammatory responses to IL-4, a macrophage phenotype associated with the development of hepatic and systemic insulin resistance. CONCLUSIONS: These results would suggest that the metabolic and hepatic consequences of high-fat feeding are mediated by loss of Nos3/nitric oxide actions in bone marrow-derived cells, not in endothelial cells.

Leveraging In-Home Supportive Services Programs to Engage People in Advance Care Planning: Input from Staff, Providers, and Client Stakeholders.

Background: In-Home Supportive Services (IHSS) cares for millions of Medicaid-eligible older adults who are often homebound and socially isolated. Advance care planning (ACP) can be challenging for this population, and IHSS programs may play an important role. Objective: To explore the feasibility of an IHSS ACP program for frail older adults. Design: Semistructured focus groups. Setting/Subjects: Fifty IHSS stakeholders (20 administrators, 9 case managers, 13 in-home caregivers, and 8 clients) participated in 10 focus groups in San Francisco. Measurements: Qualitative thematic content analysis by two independent coders. Results: Four main themes emerged: (1) Unmet needs: patients' wishes unknown during a medical crisis, lack of education/training for clients and staff; (2) Barriers: conflict of interest and potential medical overreach of IHSS caregivers, lack of billing avenues, time limitations, and cultural, literacy, and language barriers; (3) Facilitators: leveraging established workflows, available technology, and training programs; and (4) Implementation: use a tailored, optional approach based on clients' readiness, focus on case managers not caregivers to prevent conflict of interest; use established intake, follow-up, and training procedures; consider cultural and literacy-appropriate messaging; and standardize easy-to-use procedures, simple scripts, and educational guides, within established workflow to support case managers. Conclusions: An IHSS ACP program is important and feasible for Medicaid-eligible, frail older adults. Implementation suggestions for success by IHSS stakeholders include focusing on case managers rather than in-home caregivers to prevent conflict of interest; tailoring programs to clients' readiness, literacy, and language; creating educational programs for IHSS staff, clients, and community; and standardizing easy-to-use guides and procedures into IHSS workflows.

Health Literacy Matters More Than Experience for Advance Care Planning Knowledge Among Older Adults.

BACKGROUND: Advance care planning (ACP) engagement is low among vulnerable populations, including those with limited health literacy (LHL). Limited knowledge about ACP may be a modifiable mediator of the relationship between LHL and ACP. Our goal was to determine whether health literacy is associated with ACP knowledge. DESIGN: Cross-sectional design. SETTING: A public health delivery system and Veterans Affairs Medical Center in San Francisco, CA. PARTICIPANTS: English- and Spanish-speaking patients (N = 1400). MEASUREMENTS: ACP knowledge was assessed with seven validated multiple-choice questions. Health literacy was measured using a validated scale. Sociodemographic measures included age, sex, language, education, race, health status, and social support. Prior ACP experience was defined as having documented legal forms and/or goals-of-care discussions in the medical record. We used Kruskal-Wallis tests and linear regression to examine associations of ACP knowledge with LHL, prior ACP experience, and sociodemographic factors. RESULTS: Mean age of participants was 65 (±10) years, 48% were women, 34% had LHL, 32% were Spanish speaking, 47% had high school education or less, and 70% were nonwhite. Mean 7-point knowledge scores were lower for those with limited vs adequate health literacy (3.8 [SD = 1.9 vs 5.5 (SD = 1.7); P < .001). In multivariable analysis, ACP knowledge scores were 1.0 point lower among those with LHL; 0.6 points lower among Spanish speakers and those with high school education or less; and 0.5 points lower among individuals of nonwhite race (P < .001 for all). Knowledge scores were 0.02 points lower per year of older age (P = .007) and 0.01 points higher per point of greater social support (P = .005). Prior ACP experience was not associated with knowledge after adjustment (P = .7). CONCLUSIONS: Health literacy and sociodemographics are stronger predictors than prior ACP experience of ACP knowledge. This study suggests that providing easy-to-understand ACP materials is paramount and should be offered even if patients have previous experience with the ACP process. J Am Geriatr Soc 67:2151-2156, 2019.

Transcriptional and functional diversity of human macrophage repolarization.

BACKGROUND: Macrophage plasticity allows cells to adopt different phenotypes, a property with important implications in disorders such as cystic fibrosis (CF) and asthma. OBJECTIVE: We sought to examine the transcriptional and functional significance of macrophage repolarization from an M1 to an M2 phenotype and assess the role of a common human genetic disorder (CF) and a prototypical allergic disease (asthma) in this transformation. METHODS: Monocyte-derived macrophages were collected from healthy subjects and patients with CF and polarized to an M2 state by using IL-4, IL-10, glucocorticoids, apoptotic PMNs, or azithromycin. We performed transcriptional profiling and pathway analysis for each stimulus. We assessed the ability of M2-repolarized macrophages to respond to LPS rechallenge and clear apoptotic neutrophils and used murine models to determine conserved functional responses to IL-4 and IL-10. We investigated whether M2 signatures were associated with alveolar macrophage phenotypes in asthmatic patients. RESULTS: We found that macrophages exhibit highly diverse responses to distinct M2-polarizing stimuli. Specifically, IL-10 activated proinflammatory pathways and abrogated LPS tolerance, allowing rapid restoration of LPS responsiveness. In contrast, IL-4 enhanced LPS tolerance, dampening proinflammatory responses after repeat LPS challenge. A common theme observed across all M2 stimuli was suppression of interferon-associated pathways. We found that CF macrophages had intact reparative and transcriptional responses, suggesting that macrophage contributions to CF-related lung disease are primarily shaped by their environment. Finally, we leveraged in vitro-derived signatures to show that allergen provocation induces distinct M2 state transcriptional patterns in alveolar macrophages. CONCLUSION: Our findings highlight the diversity of macrophage polarization, attribute functional consequences to different M2 stimuli, and provide a framework to phenotype macrophages in disease states.

Patient Activation: A Key Component of Successful Advance Care Planning.

Background: Patient activation-or knowledge, confidence, and skill managing overall health-is associated with improved health behaviors such as exercise; it is unknown whether it is associated with advance care planning (ACP). Objective: To determine whether patient activation is associated with ACP. Design: This is a cross-sectional study. Setting/Subjects: A total of 414 veterans (≥60 years) with serious and chronic illness enrolled in an ACP trial. Measures: Patient characteristics and self-report surveys included the validated 13-item patient activation measure (PAM, five-point Likert) (e.g., "Taking an active role in your own healthcare is the most important factor…") categorized into four levels (e.g., Level 1: "disengaged and overwhelmed" to Level 4: "maintaining behaviors"). ACP was measured with the ACP Engagement Survey including 57-item process scores (i.e., knowledge, contemplation, self-efficacy, readiness, 5-point Likert scale) and 25-item action scores (i.e., surrogate designation, yes/no items). Associations were determined with linear regression. Results: Participants were 71.1 ± 7.8 years of age, 43% were non-white, 9% were women, and 20% had limited health literacy. Higher PAM levels were associated with higher finances, having adult children, lower comorbidity, and more social support (p < 0.05). After adjusting for these characteristics, higher PAM (Level 4 vs. Level 1) was associated with higher ACP engagement (ACP process scores, 2.8 ± 0.7 vs. 3.8 ± 0.7 and action scores 9.7 ± 4.4 vs. 15.1 ± 6.0, p < 0.001). Conclusions: Higher patient activation to manage one's overall healthcare is associated with higher engagement in ACP. Interventions designed to foster general patient activation and self-efficacy to engage in health behaviors and disease management may also improve engagement in the ACP process.

Older Adult and Surrogate Perspectives on Serious, Difficult, and Important Medical Decisions.

OBJECTIVES: To elicit decisions that diverse older adults and surrogates perceive as serious, difficult, or important and explore what helped them make those decisions. DESIGN: Focus groups (N=13) in which participants were asked to recall serious, difficult, or important medical decisions and what helped them make those decisions. SETTING: Clinics, support groups and senior centers. PARTICIPANTS: Diverse English- and Spanish-speaking older adults (age: mean 78, range 64-89) and surrogates (age: mean 57, range 33-76) (29% African American, 26% white, 26% Asian or Pacific Islander, 19% Hispanic) (N=69). MEASUREMENTS: We used thematic analysis to analyze transcripts. RESULTS: We identified 168 decisions. Older adults from all racial and ethnic groups frequently recalled cancer treatment decisions and decisions about chronic illness management. Surrogates described decisions about transitions in care and medical crises. Older adults valued self-sufficiency and maximizing survival and relied on personal experiences as often as medical advice. In all racial and ethnic groups, surrogates valued avoiding suffering for loved ones. CONCLUSION: Diverse older adults and surrogates perceive life-threatening illness and day-to-day decisions about chronic disease to be serious, difficult, and important. The surrogates' goal of avoiding suffering of older adults may differ from older adults' priorities of self-sufficiency and maximizing survival. Clinicians should support older adults and surrogates in identifying important and difficult decisions and learn about the values and information sources they bring to decision-making. With this knowledge, clinicians can customize decision support and achieve person-centered care.

Symptom Assessment Solutions for In-Home Supportive Services and Diverse Older Adults: A Roadmap for Change.

BACKGROUND: Millions of older adults require Medicaid-funded home care, referred to as In-Home Supportive Services (IHSS). Many of these individuals experience serious illness, disability, and common symptoms such as pain and shortness of breath. OBJECTIVE: To explore whether and how to integrate symptom assessment into an IHSS program to identify and manage symptoms in diverse older adults who receive in-home care. DESIGN: Qualitative study comprising 10 semistructured focus groups. SETTING AND SUBJECTS: Fifty San Francisco IHSS administrators, case managers, providers, and consumers. MEASUREMENTS: Two authors double-coded transcripts and conducted thematic analysis. RESULTS: Four main themes emerged from the data: (1) Large unmet needs: gaps in understanding, training, standard assessment, and untreated symptoms, including identifying loneliness as a symptom; (2) Potential barriers: misunderstanding of palliative care, consumer reluctance, and the added burden on IHSS workforce; (3) Facilitators: consumer and provider buy-in and perceived benefits of such a symptom assessment program, and the ability to build on current IHSS relationships and infrastructure; and (4) Implementation logistics: taking an individualized, optional approach; consider appropriate messaging about quality of life and not end of life; and creating standardized, easy-to-use procedures, tools, training, and workflow to support providers. CONCLUSIONS: An IHSS symptom assessment program is desired, needed, and feasible and can leverage the established IHSS infrastructure and relationships of consumers and IHSS providers to assess symptoms in the home. Acknowledging consumer choice, developing appropriate tools and trainings for IHSS staff, and effective messaging of program goals can contribute to success.

Advance Care Planning Documentation Practices and Accessibility in the Electronic Health Record: Implications for Patient Safety.

CONTEXT: Documenting patients' advance care planning (ACP) wishes is essential to providing value-aligned care, as is having this documentation readily accessible. Little is known about ACP documentation practices in the electronic health record. OBJECTIVES: The objective of this study was to describe ACP documentation practices and the accessibility of documented discussions in the electronic health record. METHODS: Participants were primary care patients at the San Francisco Veterans Affairs Medical Center, were ≥60 years old, and had ≥2 chronic/serious health conditions. In this cross-sectional study, we assessed the prevalence of ACP documentation, including any legal forms/orders and discussions in the prior five years. We also determined accessibility of discussions (i.e., accessible centralized posting vs. inaccessible free text in progress notes). RESULTS: The mean age of 414 participants was 71 years (SD ± 8), 9% were women, 43% were nonwhite, and 51% had documented ACP including 149 (36%) with forms/orders and 138 (33%) with discussions. Seventy-four participants (50%) with forms/orders lacked accompanying explanatory documentation. Most (55%) discussions were not easily accessible, including 70% of those documenting changes in treatment preferences from prior forms/orders. CONCLUSION: Half of chronically ill, older participants had documented ACP, including one-third with documented discussions. However, half of the patients with completed legal forms/orders had no accompanying documented explanatory discussions, and the majority of documented discussions were not easily accessible, even when wishes had changed. Ensuring that patients' preferences are documented and easily accessible is an important patient safety and quality improvement target to ensure patients' wishes are honored.

Effect of the PREPARE Website vs an Easy-to-Read Advance Directive on Advance Care Planning Documentation and Engagement Among Veterans: A Randomized Clinical Trial.

Importance: Documentation rates of patients' medical wishes are often low. It is unknown whether easy-to-use, patient-facing advance care planning (ACP) interventions can overcome barriers to planning in busy primary care settings. Objective: To compare the efficacy of an interactive, patient-centered ACP website (PREPARE) with an easy-to-read advance directive (AD) to increase planning documentation. Design, Setting, and Participants: This was a comparative effectiveness randomized clinical trial from April 2013 to July 2016 conducted at multiple primary care clinics at the San Francisco VA Medical Center. Inclusion criteria were age of a least 60 years; at least 2 chronic and/or serious conditions; and 2 or more primary care visits; and 2 or more additional clinic, hospital, or emergency room visits in the last year. Interventions: Participants were randomized to review PREPARE plus an easy-to-read AD or the AD alone. There were no clinician and/or system-level interventions or education. Research staff were blinded for all follow-up measurements. Main Outcomes and Measures: The primary outcome was new ACP documentation (ie, legal forms and/or discussions) at 9 months. Secondary outcomes included patient-reported ACP engagement at 1 week, 3 months, and 6 months using validated surveys of behavior change process measures (ie, 5-point knowledge, self-efficacy, readiness scales) and action measures (eg, surrogate designation, using a 0-25 scale). We used intention-to-treat, mixed-effects logistic and linear regression, controlling for time, health literacy, race/ethnicity, baseline ACP, and clustering by physician. Results: The mean (SD) age of 414 participants was 71 (8) years, 38 (9%) were women, 83 (20%) had limited literacy, and 179 (43%) were nonwhite. No participant characteristic differed significantly among study arms at baseline. Retention at 6 months was 90%. Advance care planning documentation 6 months after enrollment was higher in the PREPARE arm vs the AD-alone arm (adjusted 35% vs 25%; odds ratio, 1.61 [95% CI, 1.03-2.51]; P = .04). PREPARE also resulted in higher self-reported ACP engagement at each follow-up, including higher process and action scores; P <.001 at each follow-up). Conclusions and Relevance: Easy-to-use, patient-facing ACP tools, without clinician- and/or system-level interventions, can increase planning documentation 25% to 35%. Combining the PREPARE website with an easy-to-read AD resulted in higher planning documentation than the AD alone, suggesting that PREPARE may increase planning documentation with minimal health care system resources. Trial Registration: clinicaltrials.gov Identifier: NCT01550731.

Defining Advance Care Planning for Adults: A Consensus Definition From a Multidisciplinary Delphi Panel.

CONTEXT: Despite increasing interest in advance care planning (ACP) and previous ACP descriptions, a consensus definition does not yet exist to guide clinical, research, and policy initiatives. OBJECTIVE: The aim of this study was to develop a consensus definition of ACP for adults. METHODS: We convened a Delphi panel of multidisciplinary, international ACP experts consisting of 52 clinicians, researchers, and policy leaders from four countries and a patient/surrogate advisory committee. We conducted 10 rounds using a modified Delphi method and qualitatively analyzed panelists' input. Panelists identified several themes lacking consensus and iteratively discussed and developed a final consensus definition. RESULTS: Panelists identified several tensions concerning ACP concepts such as whether the definition should focus on conversations vs. written advance directives; patients' values vs. treatment preferences; current shared decision making vs. future medical decisions; and who should be included in the process. The panel achieved a final consensus one-sentence definition and accompanying goals statement: "Advance care planning is a process that supports adults at any age or stage of health in understanding and sharing their personal values, life goals, and preferences regarding future medical care. The goal of advance care planning is to help ensure that people receive medical care that is consistent with their values, goals and preferences during serious and chronic illness." The panel also described strategies to best support adults in ACP. CONCLUSIONS: A multidisciplinary Delphi panel developed a consensus definition for ACP for adults that can be used to inform implementation and measurement of ACP clinical, research, and policy initiatives.

MEK1/2 Inhibition Promotes Macrophage Reparative Properties.

Macrophages have important functional roles in regulating the timely promotion and resolution of inflammation. Although many of the intracellular signaling pathways involved in the proinflammatory responses of macrophages are well characterized, the components that regulate macrophage reparative properties are less well understood. We identified the MEK1/2 pathway as a key regulator of macrophage reparative properties. Pharmacological inhibition of the MEK1/2 pathway by a MEK1/2 inhibitor (MEKi) significantly increased expression of IL-4/IL-13 (M2)-responsive genes in murine bone marrow-derived and alveolar macrophages. Deletion of the MEK1 gene using LysMCre+/+Mek1fl/fl macrophages as an alternate approach yielded similar results. MEKi enhanced STAT6 phosphorylation, and MEKi-induced changes in M2 polarization were dependent on STAT6. In addition, MEKi treatment significantly increased murine and human macrophage efferocytosis of apoptotic cells, independent of macrophage polarization and STAT6. These phenotypes were associated with increased gene and protein expression of Mertk, Tyro3, and Abca1, three proteins that promote macrophage efferocytosis. We also studied the effects of MEKi on in vivo macrophage efferocytosis and polarization. MEKi-treated mice had increased efferocytosis of apoptotic polymorphonuclear leukocytes instilled into the peritoneum. Furthermore, administration of MEKi after LPS-induced lung injury led to improved recovery of weight, fewer neutrophils in the alveolar compartment, and greater macrophage M2 polarization. Collectively, these results show that MEK1/2 inhibition is capable of promoting the reparative properties of murine and human macrophages. These studies suggest that the MEK1/2 pathway may be a therapeutic target to promote the resolution of inflammation via modulation of macrophage functions.

Stromelysin-2 (MMP10) Moderates Inflammation by Controlling Macrophage Activation.

Several members of the matrix metalloproteinase (MMP) family control a range of immune processes, such as leukocyte influx and chemokine activity. Stromelysin-2 (MMP10) is expressed by macrophages in numerous tissues after injury; however, little is known of its function. In this study, we report that MMP10 is expressed by macrophages in human lungs from patients with cystic fibrosis and induced in mouse macrophages in response to Pseudomonas aeruginosa infection both in vivo and by isolated resident alveolar and bone marrow-derived macrophages (BMDM). Our data indicates that macrophage MMP10 serves a beneficial function in response to acute infection. Whereas wild-type mice survived infection with minimal morbidity, 50% of Mmp10(-/-) mice died and all showed sustained weight loss (morbidity). Although bacterial clearance and neutrophil influx did not differ between genotypes, macrophage numbers were ∼3-fold greater in infected Mmp10(-/-) lungs than in wild-types. Adoptive transfer of wild-type BMDM normalized infection-induced morbidity in Mmp10(-/-) recipients to wild-type levels, demonstrating that the protective effect of MMP10 was due to its production by macrophages. Both in vivo and in cultured alveolar macrophages and BMDM, expression of several M1 macrophage markers was elevated, whereas M2 markers were reduced in Mmp10(-/-) tissue and cells. Global gene expression analysis revealed that infection-mediated transcriptional changes persisted in Mmp10(-/-) BMDM long after they were downregulated in wild-type cells. These results indicate that MMP10 serves a beneficial role in response to acute infection by moderating the proinflammatory response of resident and infiltrating macrophages.