RERconverge Expansion: Using Relative Evolutionary Rates to Study Complex Categorical Trait Evolution.

Comparative genomics approaches seek to associate evolutionary genetic changes with the evolution of phenotypes across a phylogeny. Many of these methods, including our evolutionary rates based method, RERconverge, lack the capability of analyzing non-ordinal, multicategorical traits. To address this limitation, we introduce an expansion to RERconverge that associates shifts in evolutionary rates with the convergent evolution of multi-categorical traits. The categorical RERconverge expansion includes methods for performing categorical ancestral state reconstruction, statistical tests for associating relative evolutionary rates with categorical variables, and a new method for performing phylogenetic permulations on multi-categorical traits. In addition to demonstrating our new method on a three-category diet phenotype, we compare its performance to naive pairwise binary RERconverge analyses and two existing methods for comparative genomic analyses of categorical traits: phylogenetic simulations and a phylogenetic signal based method. We also present a diagnostic analysis of the new permulations approach demonstrating how the method scales with the number of species and the number of categories included in the analysis. Our results show that our new categorical method outperforms phylogenetic simulations at identifying genes and enriched pathways significantly associated with the diet phenotype and that the new ancestral reconstruction drives an improvement in our ability to capture diet-related enriched pathways. Our categorical permulations were able to account for non-uniform null distributions and correct for non-independence in gene rank during pathway enrichment analysis. The categorical expansion to RERconverge will provide a strong foundation for applying the comparative method to categorical traits on larger data sets with more species and more complex trait evolution.

Evaluating an Integrated Local System Response to the COVID-19 Pandemic: Case Study of East Toronto Health Partners.

Introduction: East Toronto Health Partners (ETHP) is a network of organizations that serve residents of East Toronto, Ontario, Canada. ETHP is a newly formed integrated model of care in which hospital, primary care, community providers and patients/families work together to improve population health. We describe and evaluate the evolution of this emerging integrated care system as it responded to a global health crisis. Description: This paper begins by describing ETHP's pandemic response mapping out over two years of data. To evaluate the response, semi-structured interviews were conducted with 30 decision makers, clinicians, staff, and volunteers who were part of the response. The interviews were thematically analyzed, and emergent themes mapped onto the nine pillars of integrated care. Discussion: The ETHP pandemic response evolved rapidly. Early siloed responses gave way to collaborative efforts and equity emerged as a central priority. New alliances formed, resources were shared, leaders emerged, and community members stepped forward to contribute. Interviewees identified positives as well as many opportunities for improvement post-pandemic. Conclusion: The pandemic was a catalyst for change in East Toronto that accelerated existing initiatives to achieve integrated care. The East Toronto experience may serve as a useful guide for other emerging integrated care systems.

The contribution of historical processes to contemporary extinction risk in placental mammals.

Species persistence can be influenced by the amount, type, and distribution of diversity across the genome, suggesting a potential relationship between historical demography and resilience. In this study, we surveyed genetic variation across single genomes of 240 mammals that compose the Zoonomia alignment to evaluate how historical effective population size (Ne) affects heterozygosity and deleterious genetic load and how these factors may contribute to extinction risk. We find that species with smaller historical Ne carry a proportionally larger burden of deleterious alleles owing to long-term accumulation and fixation of genetic load and have a higher risk of extinction. This suggests that historical demography can inform contemporary resilience. Models that included genomic data were predictive of species' conservation status, suggesting that, in the absence of adequate census or ecological data, genomic information may provide an initial risk assessment.

Relating enhancer genetic variation across mammals to complex phenotypes using machine learning.

Protein-coding differences between species often fail to explain phenotypic diversity, suggesting the involvement of genomic elements that regulate gene expression such as enhancers. Identifying associations between enhancers and phenotypes is challenging because enhancer activity can be tissue-dependent and functionally conserved despite low sequence conservation. We developed the Tissue-Aware Conservation Inference Toolkit (TACIT) to associate candidate enhancers with species' phenotypes using predictions from machine learning models trained on specific tissues. Applying TACIT to associate motor cortex and parvalbumin-positive interneuron enhancers with neurological phenotypes revealed dozens of enhancer-phenotype associations, including brain size-associated enhancers that interact with genes implicated in microcephaly or macrocephaly. TACIT provides a foundation for identifying enhancers associated with the evolution of any convergently evolved phenotype in any large group of species with aligned genomes.

Six Key Approaches in Open Society Foundations' Support for Global Palliative Care Development.

CONTEXT: Between 1998 and 2021, the Open Society Foundations (OSF) network invested around US$50 million in supporting the emerging field of palliative care worldwide, funding different approaches and interventions to advance its objective of putting palliative care on the global public health agenda. OBJECTIVE: To describe six approaches that were instrumental to the successes of Open Society Foundations' support in building the global field of palliative care. A robust discussion of lessons learnt is unfortunately not possible because Open Society Foundations did not commission a rigorous evaluation of the impacts of its investments. METHODS: This article describes these six approaches: Investing in versatile palliative care leaders at national and regional level; investing in palliative care champions within the OSF network; proactively engaging the World Health Organization (WHO) in efforts to promote palliative care; developing tools and skills to improve palliative care financing; using a human rights-based approach; and supporting self-advocacy by people with palliative care needs. RESULTS: Deep, long-term investments in national and regional champions from the palliative care community and OSF's own network built palliative care leaders with well-rounded skills, knowledge and opportunities to develop their own networks. The active engagement and involvement of the WHO in efforts to advance palliative care enhanced the credibility of palliative care as a discipline as well its champions, whereas the human rights approach resulted in more diverse strategies to overcome barriers to palliative care. The focus on palliative care financing and self-advocacy showed significant promise for impact. DISCUSSION: The approaches and strategies described helped a nascent palliative care field develop into a health service that is increasingly integrated into public health systems. Other funders and national governments can build on OSF's long term support for the palliative care field and support further integration of palliative care within public health to increase access.

New Faces at the Bedside: Death Doulas, Vigilers, and Companions.

A growing number of nonmedical caregivers seek to improve dying in the United States. They call themselves end-of-life doulas, death midwives, soul guides, compassionate companions, and vigilers, among other names. These new faces at the bedside share a common goal of comforting the dying and their loved ones. Their work is both humanitarian and spiritual as they bring compassionate presence into the sacred space of dying. Thousands of individuals provide end-of-life caregiving through volunteer programs in hospitals, hospices, and community non-profits; hundreds more provide their services to clients for a fee. Using in-depth interviews and analysis of print and online materials, this article traces the development of nonmedical end-of-life caregiving from volunteer vigiling and companioning programs to the professionalization of end-of-life doulaing. Though professional doulas are in the media spotlight, this work began with volunteers who continue to provide most of the nonmedical end-of-life care support for the dying in the United States.

Understanding Opioid Actions, Pain and Analgesia: A Tribute to Dr. Gavril Pasternak.

This special issue is a tribute to our mentor, colleague and friend, Gavril W. Pasternak, MD, PhD. Homage to the breadth and depth of his work (~ 450 publications) over a 40 career in pharmacology and medicine cannot be captured fully in one special issue, but the 22 papers collected herein represent seven of the topics near and dear to Gav's heart, and the colleagues, friends and mentees who held him near to theirs. The seven themes include: (1) sites and mechanisms of opioid actions in vivo; (2) development of novel analgesic agents; (3) opioid tolerance, withdrawal and addiction: mechanisms and treatment; (4) opioid receptor splice variants; (5) novel research tools and approaches; (6) receptor signaling and crosstalk in vitro; and (7) mentorship. This introduction to the issue summarizes contributions and includes formal and personal remembrances of Gav that illustrate his personality, warmth, and dedication to making a difference in patient care and people's lives.

Exploration of the Effects of Rural Obstetric Unit Closures on Birth Outcomes in North Carolina.

PURPOSE: Closures of rural labor and delivery (L/D) units have prompted national and state-based efforts to assess the impact on birth outcomes. This study explores local effects of L/D closures in rural areas of North Carolina (NC). METHODS: This is a retrospective cohort study of birth outcomes of 4,065 women in 5 rural areas of NC with L/D unit closures between 2013 and 2017. Outcomes were abstracted from birth certificate data from the NC Vital Statistics Reporting System. Localized outcomes 1 year prior to L/D unit closure were compared with outcomes 1 and 2 years post closure, including: (1) birth location and demographics, (2) change in travel patterns for birth, and (3) birth outcomes, including rates of labor induction, cesarean deliveries, maternal morbidity, and neonatal outcomes. FINDINGS: Before closures, 25%-56% of deliveries occurred outside county of residence. Commercially insured and college-educated women were more likely to deliver out-of-area. Closures increased travel distance to delivery hospital an average of 7-27 miles. In 2 areas, cesarean delivery rates decreased despite an increase in labor inductions. There was also variability between areas in prenatal care adequacy and breastfeeding. CONCLUSIONS: We found that L/D unit closures in rural NC disproportionately affected women on Medicaid. The impact showed area-specific variability, highlighting effects potentially masked by statewide or national analyses. Implications for future L/D closures would be eased by regional coordination and planning to mitigate negative effects, and state and national policies should address the excess burden placed on vulnerable populations.

The Value of Treating Opioid Use Disorder in Family Medicine: From the Patient Perspective.

INTRODUCTION: Despite evidence demonstrating that medications for opioid use disorder (OUD) reduce morbidity and mortality, the majority of patients do not receive treatment. The National Academies of Science call for more research exploring the patient's perspective of treatment modalities to increase access to individualized, patient-centered care. We aim to build on existing literature by describing patient experiences treated for OUD in a rural family medicine setting. METHODS: We employed a convenience sampling methodology to complete brief, structured interviews with thematic data analysis for 30 of 57 eligible patients receiving office-based opioid treatment (OBOT) in the primary care setting. RESULTS: Participants' experiences with OBOT were generally positive and shaped by societal structures and institutions, their life before treatment, their treatment history, and the kind of care they received in OBOT. Patients identified accessibility and privacy as advantages to receiving OBOT in primary care. DISCUSSION: This research identifies ways providers can provide individualized and effective OUD treatment within the family medicine setting.

Redefining Palliative Care-A New Consensus-Based Definition.

CONTEXT: The International Association for Hospice and Palliative Care developed a consensus-based definition of palliative care (PC) that focuses on the relief of serious health-related suffering, a concept put forward by the Lancet Commission Global Access to Palliative Care and Pain Relief. OBJECTIVE: The main objective of this article is to present the research behind the new definition. METHODS: The three-phased consensus process involved health care workers from countries in all income levels. In Phase 1, 38 PC experts evaluated the components of the World Health Organization definition and suggested new/revised ones. In Phase 2, 412 International Association for Hospice and Palliative Care members in 88 countries expressed their level of agreement with the suggested components. In Phase 3, using results from Phase 2, the expert panel developed the definition. RESULTS: The consensus-based definition is as follows: Palliative care is the active holistic care of individuals across all ages with serious health-related suffering due to severe illness and especially of those near the end of life. It aims to improve the quality of life of patients, their families and their caregivers. The definition includes a number of bullet points with additional details as well as recommendations for governments to reduce barriers to PC. CONCLUSION: Participants had significantly different perceptions and interpretations of PC. The greatest challenge faced by the core group was trying to find a middle ground between those who think that PC is the relief of all suffering and those who believe that PC describes the care of those with a very limited remaining life span.

Physician Preceptor Satisfaction and Productivity Across Curricula: A Comparison Between Longitudinal Integrated Clerkships And Traditional Block Rotations.

Phenomenon: Physicians are under intense pressure to improve clinical productivity. High clinical load, limited availability, and decreased clinical efficiency are well-documented barriers to precepting medical students and threaten clinical productivity. In an era of increasing medical student enrollment, these barriers have already led to a decreased availability of clinical teachers and training sites across the United States. Improved preceptor satisfaction could have a great impact on recruitment and retention of medical student preceptors and is likely linked to changes in productivity. Curriculum structure could impact both preceptor productivity and satisfaction. Comparing productivity and satisfaction of physician preceptors teaching in longitudinal integrated clerkships (LICs) to those teaching in traditional block rotations (TBRs), or in both settings (LIC-TBR), could lead to a better understanding of the impact of curriculum structure on preceptor productivity and satisfaction. Approach: Data were collected through a quantitative cross-sectional survey of outpatient physician preceptors in North Carolina in 2017. Preceptor satisfaction and student influence on productivity-related aspects of practice were analyzed with bivariate chi-square statistics and multivariate logistic regression. Findings: Analyses included 338 physician preceptors: 79 LIC (23%), 50 LIC-TBR (15%), and 209 TBR preceptors (62%). LIC preceptors were more likely to indicate being "very satisfied" with precepting than either their LIC-TBR or TBR counterparts. There were no differences in perceived productivity-related aspects of practice across the different curricula, such as patient flow, income, or physician working hours. Logistic regressions controlling for potential confounding variables suggested that those teaching in LICs were almost 3 times more likely to be "very satisfied" relative to those teaching in LIC-TBR and TBR settings and that the negative influence of students on patient flow and physician working hours had an adverse effect on preceptor satisfaction. Insights: Preceptor satisfaction was high overall, though satisfaction was significantly higher among preceptors who teach in LICs. The perceived impact of students on clinical productivity was stable across the different curricula. In an era of increasing need for physician preceptors, the higher satisfaction of those who teach in LICs should be considered in curricular design and for preceptor recruitment and retention.

End of life: Expert care and support, not physician-hastened death.

In legal physician-hastened death, a physician prescribes medication with the primary intent of causing the death of a willing terminally ill patient. This practice differs radically from palliative sedation, intended to relieve a patient's suffering rather than cause a patient's death. In this position paper, we argue that the practice of physician-hastened death is contrary to the interests of patients, their families, and the sound ethical practice of medicine. Therefore, the American Academy of Neurology should advise its members against this practice, as it had done until 2018.

Primary Care Women's Health Screening: A Case Study of a Community Engaged Human Centered Design Approach to Enhancing the Screening Process.

PURPOSE: To apply a Human Centered Design (HCD) approach to co-designing a comprehensive women's health screening tool with community partners. DESCRIPTION: Evidenced-based health screenings for behaviors and risks are important tools in primary health care and disease prevention, especially for women. However, numerous barriers limit the effective implementation of comprehensive health screenings, and often lead to excluding important risks such as intimate partner violence (IPV). Utilizing a human centered design approach (HCD), Mountain Area Health Education Center (MAHEC, NC USA) developed a community co-designed 9-topic health screening for women. Key end-users were recruited to participate in the design process, including women who identified IPV as a health issue in their community, Spanish speaking women, domestic violence program organizers, and MAHEC staff. ASSESSMENT: A total of 21 participants collaborated during three design sessions on two specific goals: 1) creating a comprehensive women's health screening tool from the existing tools that were in use in our clinics at the time, and 2) incorporating IPV screening. Through the HCD sessions, participants highlighted the impact of what they termed "Triple T: time, trust and talk" on the effectiveness of women's health screening. CONCLUSION: Our co-designed women's health screening tool is a first step towards addressing screening barriers from both primary care provider's and community women's perspectives. Future research will explore the facilitators of and barriers to implementing the tools in different primary care settings. Future work should also more systematically examine whether and how screening processes may reinforce or contribute to women's feelings of being stereotyped, and how screening processes can be designed to avoid stereotype threat, which has the potential to reduce the effectiveness of screenings intended to promote women's health.

The North Carolina Community Preceptor Experience: Third Study of Trends Over 12 Years.

PURPOSE: To measure community-based preceptors' overall satisfaction and motivations, the influence of students on preceptors' practices, and compare with 2005 and 2011 studies. METHOD: North Carolina primary care preceptors across disciplines (physicians, pharmacists, advanced practice nurses, physician assistants) received survey invitations via e-mail, fax, postcard, and/or full paper survey. Most questions in 2017 were the same as questions used in prior years, including satisfaction with precepting, likelihood to continue precepting, perceived influence of teaching students in their practice, and incentives for precepting. A brief survey or phone interview was conducted with 62 nonresponders. Chi-square tests were used to examine differences across discipline groups and to compare group responses over time. RESULTS: Of the 2,786 preceptors contacted, 893 (32.1%) completed questionnaires. Satisfaction (816/890; 91.7%) and likelihood of continuing to precept (778/890; 87.4%) remained unchanged from 2005 and 2011. However, more preceptors reported a negative influence for patient flow (422/888; 47.5%) in 2017 than in 2011 (452/1,266; 35.7%) and 2005 (496/1,379; 36.0%) (P < .0001), and work hours (392/889; 44.1%) in 2017 than in 2011 (416/1,268; 32.8%) and 2005 (463/1,392; 33.3%) (P < .0001). Importance of receiving payment for teaching increased from 32.2% (371/1,152) in 2011 to 46.4% (366/789) in 2017 (P < .0001). CONCLUSIONS: This 2017 survey suggests preceptor satisfaction and likelihood to continue precepting have remained unchanged from prior years. However, increased reporting of negative influence of students on practice and growing value of receiving payment highlight growing concerns about preceptors' time and finances and present a call to action.

White Paper for Global Palliative Care Advocacy: Recommendations from a PAL-LIFE Expert Advisory Group of the Pontifical Academy for Life, Vatican City.

BACKGROUND: The Pontifical Academy for Life (PAV) is an academic institution of the Holy See (Vatican), which aims to develop and promote Catholic teachings on questions of biomedical ethics. Palliative care (PC) experts from around the world professing different faiths were invited by the PAV to develop strategic recommendations for the global development of PC ("PAL-LIFE group"). DESIGN: Thirteen experts in PC advocacy participated in an online Delphi process. In four iterative rounds, participants were asked to identify the most significant stakeholder groups and then propose for each, strategic recommendations to advance PC. Each round incorporated the feedback from previous rounds until consensus was achieved on the most important recommendations. In a last step, the ad hoc group was asked to rank the stakeholders' groups by order of importance on a 13-point scale and to propose suggestions for implementation. A cluster analysis provided a classification of the stakeholders in different levels of importance for PC development. RESULTS: Thirteen stakeholder groups and 43 recommendations resulted from the first round, and, of those, 13 recommendations were chosen as the most important (1 for each stakeholder group). Five groups had higher scores. The recommendation chosen for these top 5 groups were as follows: (1) Policy makers: Ensure universal access to PC; (2) Academia: Offer mandatory PC courses to undergraduates; (3) Healthcare workers: PC professionals should receive adequate certification; (4) Hospitals and healthcare centers: Every healthcare center should ensure access to PC medicines; and (5) PC associations: National Associations should be effective advocates and work with their governments in the process of implementing international policy framework. A recommendation for each of the remaining eight groups is also presented. DISCUSSION: This white paper represents a position statement of the PAV developed through a consensus process in regard to advocacy strategies for the advancement of PC in the world.

Documento de Posición Oficial sobre la Promoción Global de Cuidados Paliativos: Recomendaciones del Grupo Internacional Asesor PAL-LIFE de la Academia Pontificia de la Vida, Ciudad del Vaticano.

Resumen Contexto: La Academia Pontificia de la Vida (PAV) es una institución académica de la Santa Sede (Vaticano) cuyo objetivo es promover una visión católica de la ética biomédica. La PAV invitó a una serie de expertos en Cuidados Paliativos (CP) de todo el mundo, de todas las creencias, a desarrollar recomendaciones estratégicas para el desarrollo global de CP ("Grupo PAL-LIFE"). Diseño: Trece expertos internacionales reconocidos por su actividad promotora global de CP participaron en un estudio Delphi on-line. En un proceso de cuatro rondas, se pidió a los participantes que identificasen los grupos de interés o instituciones claves para la promoción de CP y que propusieran, para cada uno de ellos, recomendaciones estratégicas para el desarrollo de CP. Cada ronda incorporaba los comentarios de las rondas previas hasta lograr el consenso en las recomendaciones más importantes. En una última fase, al grupo de expertos se le solicitó la jerarquización por importancia de los grupos clave en una escala de 1 a 13. También se solicitaron sugerencias concretas para la implementación de las recomendaciones. Mediante análisis clúster se ordenaron los grupos de interés en dos niveles de importancia para el desarrollo de CP. Resultados: Trece recomendaciones fueron seleccionadas como las más importantes (una por cada grupo clave). Las recomendaciones para los grupos mejor puntuados fueron: (1) Responsables Políticos: garantizar el acceso universal a los CP; (2) Academia: ofrecer cursos obligatorios de CP en el pregrado; (3) Profesionales sanitarios: promover una certificación adecuada; (4) Hospitales e Instituciones sanitarias: asegurar el acceso a medicamentos de CP; y (5) Asociaciones de CP: ser promotoras eficaces y trabajar con los gobiernos en la implementación de las recomendaciones internacionales sobre CP. También se presentan recomendaciones para los ocho grupos clave restantes. Discusión: Este documento representa la posición oficial de la PAV en lo que respecta a estrategias de promoción para el desarrollo de los CP en el mundo.

Physician-Assisted Suicide: Why Neutrality by Organized Medicine Is Neither Neutral Nor Appropriate.

It has been proposed that medical organizations adopt neutrality with respect to physician-assisted suicide (PAS), given that the practice is legal in some jurisdictions and that membership is divided. We review developments in end-of-life care and the role of medical organizations with respect to the legalization of PAS since the 1990s. We argue that moving from opposition to neutrality is not ethically neutral, but a substantive shift from prohibited to optional. We argue that medical organizations already oppose many practices that are legal in many jurisdictions, and that unanimity among membership has not been required for any other clinical or ethical policy positions. Moreover, on an issue so central to the meaning of medical professionalism, it seems important for organized medicine to take a stand. We subsequently review the arguments in favor of PAS (arguments from autonomy and mercy, and against the distinction between killing and allowing to die (K/ATD)) and the arguments against legalization (the limits of autonomy, effects on the patient-physician relationship, the meaning of healing, the validity of the K/ATD distinction, the social nature of suicide, the availability of alternatives, the propensity for incremental extension, and the meaning of control). We conclude that organized medicine should continue its opposition to PAS.

Color inference in visual communication: the meaning of colors in recycling.

People interpret abstract meanings from colors, which makes color a useful perceptual feature for visual communication. This process is complicated, however, because there is seldom a one-to-one correspondence between colors and meanings. One color can be associated with many different concepts (one-to-many mapping) and many colors can be associated with the same concept (many-to-one mapping). We propose that to interpret color-coding systems, people perform assignment inference to determine how colors map onto concepts. We studied assignment inference in the domain of recycling. Participants saw images of colored but unlabeled bins and were asked to indicate which bins they would use to discard different kinds of recyclables and trash. In Experiment 1, we tested two hypotheses for how people perform assignment inference. The local assignment hypothesis predicts that people simply match objects with their most strongly associated color. The global assignment hypothesis predicts that people also account for the association strengths between all other objects and colors within the scope of the color-coding system. Participants discarded objects in bins that optimized the color-object associations of the entire set, which is consistent with the global assignment hypothesis. This sometimes resulted in discarding objects in bins whose colors were weakly associated with the object, even when there was a stronger associated option available. In Experiment 2, we tested different methods for encoding color-coding systems and found that people were better at assignment inference when color sets simultaneously maximized the association strength between assigned color-object parings while minimizing associations between unassigned pairings. Our study provides an approach for designing intuitive color-coding systems that facilitate communication through visual media such as graphs, maps, signs, and artifacts.