Structural basis for hyperpolarization-dependent opening of human HCN1 channel.

Hyperpolarization and cyclic nucleotide (HCN) activated ion channels are critical for the automaticity of action potentials in pacemaking and rhythmic electrical circuits in the human body. Unlike most voltage-gated ion channels, the HCN and related plant ion channels activate upon membrane hyperpolarization. Although functional studies have identified residues in the interface between the voltage-sensing and pore domain as crucial for inverted electromechanical coupling, the structural mechanisms for this unusual voltage-dependence remain unclear. Here, we present cryo-electron microscopy structures of human HCN1 corresponding to Closed, Open, and a putative Intermediate state. Our structures reveal that the downward motion of the gating charges past the charge transfer center is accompanied by concomitant unwinding of the inner end of the S4 and S5 helices, disrupting the tight gating interface observed in the Closed state structure. This helix-coil transition at the intracellular gating interface accompanies a concerted iris-like dilation of the pore helices and underlies the reversed voltage dependence of HCN channels.

Structural Basis for Hyperpolarization-dependent Opening of the Human HCN1 Channel.

Hyperpolarization and cyclic-nucleotide (HCN) activated ion channels play a critical role in generating self-propagating action potentials in pacemaking and rhythmic electrical circuits in the human body. Unlike most voltage-gated ion channels, the HCN channels activate upon membrane hyperpolarization, but the structural mechanisms underlying this gating behavior remain unclear. Here, we present cryo-electron microscopy structures of human HCN1 in Closed, Intermediate, and Open states. Our structures reveal that the inward motion of two gating charges past the charge transfer center (CTC) and concomitant tilting of the S5 helix drives the opening of the central pore. In the intermediate state structure, a single gating charge is positioned below the CTC and the pore appears closed, whereas in the open state structure, both charges move past CTC and the pore is fully open. Remarkably, the downward motion of the voltage sensor is accompanied by progressive unwinding of the inner end of S4 and S5 helices disrupting the tight gating interface that stabilizes the Closed state structure. This "melting" transition at the intracellular gating interface leads to a concerted iris-like displacement of S5 and S6 helices, resulting in pore opening. These findings reveal key structural features that are likely to underlie reversed voltage-dependence of HCN channels.

Associations of Early Completion of Advance Directives With Key End-of-Life Quality Measures: Analysis of an ASCO Quality Oncology Practice Initiative Patient Cohort.

PURPOSE: Despite the growing calls for early and ubiquitous completion of advance directives (ADs), studies exploring links between AD completion and their impact on outcomes of patients with cancer have mixed conclusions. We used the ASCO Quality Oncology Practice Initiative (QOPI) registry to compare end-of-life (EOL) quality measures and the effect of QOPI certification among patients with and without early AD completion, defined as completion within the first three oncology visits after cancer diagnosis. METHODS: Deidentified patient-level data were analyzed from the QOPI database from 2015 through 2017. Associations were assessed using Chi-square tests between early AD completion and patient enrollment in hospice < 7 days before death, chemotherapy receipt in the last 14 days of life, or with emergency room visits or intensive care unit admissions in the last 30 days of life. RESULTS: Data from 31,558 patients eligible for the AD question were analyzed. Patients treated at QOPI-certified practices had higher rates of early AD completion than patients at non-certified practices. Early AD completion was not associated with differences in hospice enrollment for < 7 days before death, chemotherapy receipt in the last 14 days of life, or emergency room visits or intensive care unit encounters in the last 30 days of life. CONCLUSION: The study found that QOPI certification is associated with higher rates of early AD completion. However, early AD completion was not associated with recognized EOL quality measures. Future research should focus on the timing, frequency, and content of AD conversations to demonstrate the impact on care at the EOL.

Mapping the future for research in emergency medicine palliative care: A research roadmap.

BACKGROUND: The intersection of emergency medicine (EM) and palliative care (PC) has been recognized as an essential area of focus, with evidence suggesting that increased integration improves outcomes. This has resulted in increased research in EM PC. No current framework exists to help guide investigation and innovation. OBJECTIVE: The objective was to convene a working group to develop a roadmap that would help provide focus and prioritization for future research. METHODS: Participants were identified based on clinical, operation, policy, and research expertise in both EM and PC and spanned physician, nursing, social work, and patient perspectives. The research roadmap setting process consisted of three distinct phases that were time staggered over 12 months and facilitated through three live video convenings, asynchronous input via an online document, and a series of smaller video convenings of work groups focused on specific topics. RESULTS: Gaps in the literature were identified and informed the four key areas for future research. Consensus was reached on these domains and the associated research questions in each domain to help guide future study. The key domains included work focused on the value imperative for PC in the emergency setting, models of care delivery, disparities, and measurement of impact and efficacy. Additionally, the group identified key methodological considerations for doing work at the intersection of EM and PC. CONCLUSIONS: There are several key domains and associated questions that can help guide future research in ED PC. Focus on these areas, and answering these questions, offers the potential to improve the emergency care of patients with PC needs.

The National Postdoctoral Palliative Care Research Training Collaborative: History, Activities, Challenges, and Future Goals.

Background: Palliative care-related postdoctoral training opportunities are critical to increase the quantity and quality of palliative care research. Objective: To describe the history, activities, challenges, and future goals of the National Postdoctoral Palliative Care Research Training Collaborative. Design: National web-based survey of participating program leaders. Measurements: Information about participating programs, trainees, challenges faced, and future goals. Results: Nine participating programs at academic institutions across the United States focus on diverse aspects of palliative care research. The majority of 73 current and former fellows are female (75%) and white (84%). In total, 38% of fellows (n = 28) have MD backgrounds, of whom less than half (n = 12) completed hospice and palliative medicine fellowships. An additional 38% of fellows (n = 28) have nursing PhD backgrounds and 23% (n = 17) have other diverse types of PhD backgrounds. Key challenges relate to recruiting diverse trainees, fostering a shared identity, effectively advocating for trainees, and securing funding. Future goals include expanding efforts to engage clinician and nonclinician scientists, fostering the pipeline of palliative care researchers through expanded mentorship of predoctoral and clinical trainees, increasing the number of postdoctoral palliative care training programs, and expanding funding support for career development grants. Conclusion: The National Postdoctoral Palliative Care Research Training Collaborative fills an important role in creating a community for palliative care research trainees and developing strategies to address shared challenges.

Increasing Medical Power of Attorney Completion for Hospitalized Patients During the COVID Pandemic: A Social Work Led Quality Improvement Intervention.

BACKGROUND: The high risk of mechanical ventilation with COVID hospitalizations requires health-care systems to rapidly innovate advance care planning (ACP) delivery for hospitalized patients to promote goal-concordant care. MEASURES: Assess the impact of a social work and care management intervention on the proportion of admitted patients each week with a Medical Durable Power of Attorney (MDPOA). INTERVENTION: Social workers were consulted to assist with identification of a surrogate decision maker and completion of MDPOA forms for hospitalized patients. This intervention utilized change management strategies and was implemented between April and June 2020. OUTCOMES: From a baseline average of 30.1%, the weekly percentage of admitted patients with MDPOA forms rose to 42.8% with correlating evidence of nonrandom special cause variation. LESSONS LEARNED: Use of change management strategies resulted in rapid implementation of an effective ACP initiative. Ongoing needs include focusing on intervention sustainability and education of interprofessional providers about ACP processes.

An Integrative Framework of Appraisal and Adaptation in Serious Medical Illness.

Multiple randomized clinical trials have demonstrated that palliative care improves the quality of life of individuals with serious medical illness. Research also suggests that in patients with advanced cancer, palliative care's focus on symptom management, coping with illness, goals of care, and treatment decisions may be associated with improved patient quality of life in part by increasing patients' use of active (vs. passive) and approach-oriented (vs. avoidant) coping strategies. However, without a framework outlining the process that individuals with serious medical illness and their loved ones undergo, it is challenging to discern exactly where, how, and why palliative care may affect the serious medical illness experience. To address this gap, we propose a clinically applicable framework, derived from existing theory and research in the social and behavioral sciences. This framework, called the Integrative Framework of Appraisal and Adaptation in Serious Medical Illness, describes how patients and their loved ones cognitively and emotionally process the various events that may occur as they navigate serious medical illness and the end of life. The framework also describes how individuals and their loved ones use that event processing to determine next steps, while considering the impact of their surrounding external environment, their individual social roles, and their connections on this decision making. The framework presented in this article is intended to improve our ability to understand and care for individuals with serious medical illness and their loved ones, while stimulating further discussion and research to test and refine these ideas.

The Relationship of Post-traumatic Stress Disorder to End-of-life Care Received by Dying Veterans: a Secondary Data Analysis.

BACKGROUND: Post-traumatic stress disorder (PTSD) can be exacerbated by subsequent trauma, but it is unclear if symptoms are worsened by impending death. PTSD symptoms, including hyperarousal, negative mood and thoughts, and traumatic re-experiencing, can impact end-of-life symptoms, including pain, mood, and poor sleep. Thus, increased symptoms may lead to increased end-of-life healthcare utilization. OBJECTIVES: To determine if veterans with PTSD have increased end-of-life healthcare utilization or medication use and to examine predictors of medication administration. DESIGN: Secondary analysis of a stepped-wedge design implementation trial to improve end-of-life care for Veterans Affairs (VA) inpatients. Outcome variables were collected via direct chart review. Analyses included hierarchical, generalized estimating equation models, clustered by medical center. SUBJECTS: Veterans, inpatient at one of six VA facilities, dying between 2005 and 2011. MAIN MEASURES: Emergency room (ER) visits, hospitalizations, and medication administration in the last 7 days of life. KEY RESULTS: Of 5341 veterans, 468 (8.76%) had PTSD. Of those, 21.4% (100/468) had major depression and 36.5% (171/468) had anxiety. Veterans with PTSD were younger (mean age 65.4 PTSD, 70.5 no PTSD, p < 0.0001) and had more VA hospitalizations and ER visits in the last 12 months of life (admissions: PTSD 2.8, no PTSD 2.4, p < 0.0001; ER visits: 3.2 vs 2.5, p < 0.0001). PTSD was associated with antipsychotic administration (OR 1.52, 95% CI 1.06-2.18). Major depression (333/5341, 6.2%) was associated with opioid administration (OR 1.348, 95% CI 1.129-1.609) and benzodiazepines (OR 1.489, 95% CI 1.141-1.943). Anxiety disorders (778/5341, 14.6%) were only associated with benzodiazepines (OR 1.598, 95% CI 1.194-2.138). CONCLUSIONS: PTSD's association with increased end-of-life healthcare utilization and increased antipsychotic administration in the final days of life suggests increased symptom burden and potential for terminal delirium in individuals with PTSD. Understanding the burden of psychiatric illness and potential risks for delirium may facilitate the end-of-life care for these patients. TRIAL REGISTRATION: NCT00234286.

Enhancing Informed Consent for Physician Aid in Dying: Potential Role of Handout on Possible Benefits of Palliative Care.

In the United States, physician aid in dying (PAD) is now legal in several states. However, neither a requirement for a palliative care (PC) consultation nor a defined education in PC exists for physicians participating in PAD or patients requesting assistance. Patients with advanced chronic and serious illness often experience complex physical, psychosocial, and spiritual distress. PC focuses on relieving this distress and improving patient quality of life through early identification and intervention in all domains of suffering, including physical, psychological, social, and spiritual. Ideally, we would recommend a PC consult, but unfortunately, PC is not readily available or offered at this time to all those who might benefit from it. We present a case for providing an educational handout to patients who inquire about PAD. This handout explains the potential benefits of PC as an additional procedural safeguard to existing regulations. Such information would help to ensure the integrity of the informed consent process, enhance shared decision making, and improve patient comprehension of the options.

Src family kinase phosphorylation of the motor domain of the human kinesin-5, Eg5.

Spindle formation in mammalian cells requires precise spatial and temporal regulation of the kinesin-5, Eg5, which generates outward force to establish spindle bipolarity. Our results demonstrate that Eg5 is phosphorylated in cultured cells by Src family kinases (SFKs) at three sites in the motor head: Y125, Y211, and Y231. Mutation of these sites diminishes motor activity in vitro, and replacement of endogenous Eg5 with phosphomimetic Y211 in LLC-Pk1 cells results in monopolar spindles, consistent with loss of Eg5 activity. Cells treated with SFK inhibitors show defects in spindle formation, similar to those in cells expressing the nonphosphorylatable Y211 mutant, and distinct from inhibition of other mitotic kinases. We propose that this phosphoregulatory mechanism tunes Eg5 enzymatic activity for optimal spindle morphology.

Hypofractionated whole breast radiotherapy in breast conservation for early-stage breast cancer: a systematic review and meta-analysis of randomized trials.

PURPOSE: Breast conservation therapy (BCT) for early-stage breast cancer involves lumpectomy followed by whole breast radiotherapy, which can involve either standard fractionation (SRT) or accelerated fractionation (ART). This systematic review and meta-analysis was performed to determine whether any benefit exists for ART or SRT. MATERIALS AND METHODS: We searched MEDLINE (1966-2014), all seven databases of the Cochrane Library (1968-2014), EMBASE (1974-2014), clinicaltrials.gov, ISRCTN, WHO ICTRP, and meeting abstracts in the Web of Science Core Collection (1900-2014). RCTs comparing SRT to ART among women undergoing BCT with stage T1-T2 and/or N1 breast cancer or carcinoma in situ were included. Follow-up was 30 days for acute toxicity, or three years for disease control and late toxicity. RESULTS: 13 trials with 8189 participants were included. No differences were observed in local failure (n = 7 trials; RR 0.97; 95% CI 0.78-1.19, I 2 = 0%), locoregional failure, (n = 8 trials; RR 0.86; 95% CI 0.63-1.16, I 2 = 0%), or survival (n = 4 trials; RR 1.00; 95% CI 0.85-1.17, I 2 = 0%). ART was associated with significantly less acute toxicity (n = 5 trials; RR 0.36; 95% CI 0.21-0.62, I 2 = 20%), but no difference in late cosmesis (RR 0.95; 95% CI 0.81-1.12, I 2 = 54%). CONCLUSIONS: ART use does not reduce disease control or worsen long-term cosmetic outcome, and may decrease the risk of acute radiation toxicity as compared to SRT.

Oncologists' End of Life Treatment Decisions.

BACKGROUND: Optimal treatment decisions for older end-stage cancer patients are complicated, and are influenced by oncologists' attitudes and beliefs about older patients. Nevertheless, few studies have explored oncologists' perspectives on how patient age affects their treatment decisions. METHODS: In-depth interviews were conducted with 17 oncologists to examine factors that influence their chemotherapy decisions for adults with incurable cancer near death. Transcripts of recorded interviews were coded and content analyzed. RESULTS: Oncologists identified patient age as a key factor in their chemotherapy decisions. They believed older adults were less likely to want or tolerate treatment, and felt highly motivated to treat younger patients. DISCUSSION: Qualitative analysis of in-depth interviews resulted in a nuanced understanding of how patient age influences oncologists' chemotherapy decisions. Such understanding may inform practice efforts aimed at enhancing cancer care at the end of life for older patients.

Paradox of Prescribing Late Chemotherapy: Oncologists Explain.

PURPOSE: The value of chemotherapy for patients with cancer in the last weeks of life warrants examination. Late chemotherapy may not improve survival or quality of life but typically precludes hospice enrollment and may result in additional symptoms, increased use of other aggressive treatments, and worsening quality of life. Few studies have explored oncologists' rationales for administering chemotherapy near death. This study examines the self-reported factors that influence oncologists' decisions about late chemotherapy. METHODS: In-depth individual interviews were conducted with 17 oncologists through a semistructured interview guide. Interviews were audio recorded and transcribed verbatim. Transcripts were coded and analyzed using conventional content analysis, a qualitative method that allows the detection and analysis of patterns in the data. RESULTS: Clinical factors take priority in determining late chemotherapy decisions when clear treatment choices exist. When clinical factors are ambiguous, emotion becomes a highly salient influence. Oncologists view late chemotherapy to be patient driven and use it to palliate emotional distress and maintain patient hope even when physical benefit is unexpected. Oncologists experience unique and difficult challenges when caring for dying patients, including emotionally draining communication, overwhelming responsibility for life/death, limitations of oncology to heal, and prognostic uncertainty. These challenges are also eased by offering late chemotherapy. CONCLUSION: The findings reveal a nuanced understanding of why oncologists find it difficult to refuse chemotherapy treatment for patients near death. Optimal end-of-life treatment decisions require supportive interventions and system change, both of which must take into account the challenges oncologists face.

Defining High-Quality Palliative Care in Oncology Practice: An American Society of Clinical Oncology/American Academy of Hospice and Palliative Medicine Guidance Statement.

PURPOSE: Integrated into routine oncology care, palliative care can improve symptom burden, quality of life, and patient and caregiver satisfaction. However, not all oncology practices have access to specialist palliative medicine. This project endeavored to define what constitutes high-quality primary palliative care as delivered by medical oncology practices. METHODS: An expert steering committee outlined 966 palliative care service items, in nine domains, each describing a candidate element of primary palliative care delivery for patients with advanced cancer or high symptom burden. Using modified Delphi methodology, 31 multidisciplinary panelists rated each service item on three constructs: importance, feasibility, and scope within medical oncology practice. RESULTS: Panelists endorsed the highest proportion of palliative care service items in the domains of End-of-Life Care (81%); Communication and Shared Decision Making (79%); and Advance Care Planning (78%). The lowest proportions were in Spiritual and Cultural Assessment and Management (35%) and Psychosocial Assessment and Management (39%). In the largest domain, Symptom Assessment and Management, there was consensus that all symptoms should be assessed and managed at a basic level, with more comprehensive management for common symptoms such as nausea, vomiting, diarrhea, dyspnea, and pain. Within the Appropriate Palliative Care and Hospice Referral domain, there was consensus that oncology practices should be able to describe the difference between palliative care and hospice to patients and refer patients appropriately. CONCLUSION: This statement describes the elements comprising high-quality primary palliative care for patients with advanced cancer or high symptom burden, as delivered by oncology practices. Oncology providers wishing to enhance palliative care delivery may find this information useful to inform operational changes and quality improvement efforts.