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

Comparative genomics approaches seek to associate molecular evolution with the evolution of phenotypes across a phylogeny. Many of these methods lack the ability to analyze non-ordinal categorical traits with more than two categories. To address this limitation, we introduce an expansion to RERconverge that associates shifts in evolutionary rates with the convergent evolution of 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 phylogeny-aware permutations, "permulations", on categorical traits. We demonstrate our new method on a three-category diet phenotype, and we compare its performance to binary RERconverge analyses and two existing methods for comparative genomic analyses of categorical traits: phylogenetic simulations and a phylogenetic signal based method. We present an analysis of how the categorical permulations scale 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 phenotypes and that the categorical ancestral state reconstruction drives an improvement in our ability to capture diet-related enriched pathways compared to binary RERconverge when implemented without user input on phenotype evolution. 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 than have previously been analyzed.

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.

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.

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.

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.

2017 HIVMA of IDSA Clinical Practice Guideline for the Management of Chronic Pain in Patients Living With HIV.

Pain has always been an important part of human immunodeficiency virus (HIV) disease and its experience for patients. In this guideline, we review the types of chronic pain commonly seen among persons living with HIV (PLWH) and review the limited evidence base for treatment of chronic noncancer pain in this population. We also review the management of chronic pain in special populations of PLWH, including persons with substance use and mental health disorders. Finally, a general review of possible pharmacokinetic interactions is included to assist the HIV clinician in the treatment of chronic pain in this population.It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. The Infectious Diseases Society of American considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.

2017 HIV Medicine Association of Infectious Diseases Society of America Clinical Practice Guideline for the Management of Chronic Pain in Patients Living With Human Immunodeficiency Virus.

Pain has always been an important part of human immunodeficiency virus (HIV) disease and its experience for patients. In this guideline, we review the types of chronic pain commonly seen among persons living with HIV (PLWH) and review the limited evidence base for treatment of chronic noncancer pain in this population. We also review the management of chronic pain in special populations of PLWH, including persons with substance use and mental health disorders. Finally, a general review of possible pharmacokinetic interactions is included to assist the HIV clinician in the treatment of chronic pain in this population.It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. The Infectious Diseases Society of American considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.

The interprofessional clinical experience: interprofessional education in the nursing home.

The interprofessional clinical experience (ICE) was designed to introduce trainees to the roles of different healthcare professionals, provide an opportunity to participate in an interprofessional team, and familiarize trainees with caring for older adults in the nursing home setting. Healthcare trainees from seven professions (dentistry, medicine, nursing, nutrition, occupational therapy, optometry and social work) participated in ICE. This program consisted of individual patient interviews followed by a team meeting to develop a comprehensive care plan. To evaluate the impact of ICE on attitudinal change, the UCLA Geriatric Attitudes Scale and a post-experience assessment were used. The post-experience assessment evaluated the trainees' perception of potential team members' roles and attitudes about interprofessional team care of the older adult. Attitudes toward interprofessional teamwork and the older adult were generally positive. ICE is a novel program that allows trainees across healthcare professions to experience interprofessional teamwork in the nursing home setting.

Use of antiepileptic drugs and lipid-lowering agents in the United States.

INTRODUCTION: The extent to which enzyme-inducing antiepileptic drugs (EIAEDs) are used as first-line treatment in the United States remains unknown. Studies suggest that EIAEDs produce elevation of serum lipids, which could require additional treatment. We assessed the current use of EIAED in monotherapy for epilepsy in the U.S., as well as the correlation between the use of EIAEDs and subsequent new prescriptions for HMG-CoA reductase inhibitors ("statins") for hyperlipidemia. METHODS: We queried the MarketScan databases between July 2009 and January 2013, covering 66 million patients with commercial or supplemental Medicare insurance. We identified individuals who had a diagnosis of seizures, continuous enrollment in the database from 6months prior to 24 months after the epilepsy diagnosis, no utilization of an AED or a statin prior to that diagnosis, and at least 1 new AED prescription. We tabulated the fraction of subjects who were prescribed EIAEDs (phenytoin, carbamazepine, or barbiturates) and those prescribed all other AEDs. Rates of new statin prescription between 1 and 24months after AED prescription were assessed among the two groups, restricted to those with no prior history of vascular disease who had lipid serology obtained subsequent to the new AED prescription. RESULTS: Of the 11,893 patients with newly treated epilepsy, 2425 (20.4%) were started on an EIAED, and 9468 (79.6%) were started on a noninducing AED. There was a consistent and significant trend for EIAEDs to be increasingly prescribed with increasing age (p<0.0001). Among patients meeting the criteria, 66 (13.3%) of 496 EIAED-treated patients and 178 (9.2%) of 1930 noninducing AED patients were newly prescribed a statin (p<0.007). This difference remained significant after accounting for age and gender (p=0.015). A patient who was started on an EIAED was 46% more likely to be subsequently prescribed a statin than a patient who was started on a noninducing AED (95% CI=1.08-1.98). CONCLUSIONS: Enzyme-inducing antiepileptic drug prescription for epilepsy appears to increase with increasing age in the U.S. despite the absence of a cogent rationale for this practice, suggesting a failure to appreciate the complications of EIAED therapy among U.S. physicians. Statins were more often prescribed to those newly treated with EIAEDs compared with those given noninducing AEDs. These preliminary data provide further evidence suggesting that EIAEDs elevate lipids in a clinically meaningful manner.

Prevalence of germline TP53 mutations in HER2+ breast cancer patients.

Breast cancer is the most frequent tumor in Li-Fraumeni syndrome (LFS), a rare inherited cancer syndrome associated with germline mutations in the TP53 gene. Recent data show that breast cancer in germline TP53 mutation carriers is commonly HER2+ (63-83 %). We assessed the prevalence of germline TP53 mutations in a cohort of women with HER2+ breast cancer diagnosed age ≤50 years. We identified blood specimens from 213 women with primary invasive HER2+ breast cancer age ≤50 years from a single center. Exon grouping analysis sequencing and multiplex ligation-dependent probe amplification techniques were used to screen for germline TP53 mutations. Among 213 women with HER2+ breast cancer age ≤50 years, 3 (ages at diagnosis 23, 32, 44 years) were found to carry a TP53 mutation (1.4 %, 95 % CI 0.3-4.1 %). ER/PR status was not uniform. Two TP53 carriers met Chompret criteria for LFS; none met classic LFS criteria. Although two-thirds of breast cancers in women with TP53 mutations are HER2+, we observed a low prevalence of germline TP53 mutations among unselected young women with HER2+ breast cancer. Given the potential clinical impact, consideration of germline TP53 testing should be given to young women with HER2+ breast cancer, especially if family cancer history is notable.

A checklist for ascertaining study cohorts in oncology health services research using secondary data: report of the ISPOR oncology good outcomes research practices working group.

OBJECTIVES: The ISPOR Oncology Special Interest Group formed a working group at the end of 2010 to develop standards for conducting oncology health services research using secondary data. The first mission of the group was to develop a checklist focused on issues specific to selection of a sample of oncology patients using a secondary data source. METHODS: A systematic review of the published literature from 2006 to 2010 was conducted to characterize the use of secondary data sources in oncology and inform the leadership of the working group prior to the construction of the checklist. A draft checklist was subsequently presented to the ISPOR membership in 2011 with subsequent feedback from the larger Oncology Special Interest Group also incorporated into the final checklist. RESULTS: The checklist includes six elements: identification of the cancer to be studied, selection of an appropriate data source, evaluation of the applicability of published algorithms, development of custom algorithms (if needed), validation of the custom algorithm, and reporting and discussions of the ascertainment criteria. The checklist was intended to be applicable to various types of secondary data sources, including cancer registries, claims databases, electronic medical records, and others. CONCLUSIONS: This checklist makes two important contributions to oncology health services research. First, it can assist decision makers and reviewers in evaluating the quality of studies using secondary data. Second, it highlights methodological issues to be considered when researchers are constructing a study cohort from a secondary data source.

Creation of an interprofessional clinical experience for healthcare professions trainees in a nursing home setting.

Successful interprofessional teams are essential when caring for older adults with multiple complex medical conditions that require ongoing management from a variety of disciplines across healthcare settings. To successfully integrate interprofessional education into the healthcare professions curriculum, the most effective learning experiences should utilize adult learning principles, reflect real-life practice, and allow for interaction among trainees representing a variety of health professions. Interprofessional clinical experiences are essential to prepare future healthcare professionals to provide quality patient care and understand the best methods for utilizing members of the healthcare team to provide that care. To meet this need, the University of Alabama at Birmingham Geriatric Education Center has developed an Interprofessional Clinical Experience (ICE) to expose future healthcare providers to an applied training experience with older adults in the nursing home setting. This paper outlines how this program was developed, methods used for program evaluation, and how the outcome data influenced program revisions.

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.

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.