"They Would Lift My Spirits": Sources of Support for Family Surrogate Decision-Makers at the End of Life.

Surrogate decision-makers make critical decisions for loved ones at the end of life, and some experience lasting negative psychological outcomes. Understanding whom they rely on for support and the types of support they value may inform nursing care and that of other health team members who work with surrogates. The purpose of the study was to explore decision support and other types of support provided to surrogate decision-makers at the end of life of their loved one and perceived usefulness of the support. This secondary analysis of data from a mixed-methods study involved the examination of the transcripts of qualitative interviews with 13 surrogate decision-makers in the United States, conducted between 2010 and 2014. A constant comparative method was used to identify common themes surrounding surrogate decision support at the end of life. Surrogates valued advance directives and conversations with their loved one about treatment preferences. Surrogates described involving many different types of people in decision-making and other types of support. Finally, surrogates appreciated being reassured that they were doing a good job in making decisions and seemed to seek out this type of affirmation from various sources including the health care team, family, and friends. Nurses are well-positioned to provide this affirmation because of the time that they spend caring for the patient and family. Future research should further explore the concept of affirmation of surrogates in their role as a means of support as they make decisions for a loved one.

Emerging Experiences with Virtual Clinical Ethics Consultation: Case Studies from the United States and Malaysia.

AbstractThe COVID-19 pandemic has inspired numerous opportunities for telehealth implementation to meet diverse healthcare needs, including the use of virtual communication platforms to facilitate the growth of and access to clinical ethics consultation (CEC) services across the globe. Here we discuss the conceptualization and implementation of two different virtual CEC services that arose during the COVID-19 pandemic: the Clinical Ethics Malaysia COVID-19 Consultation Service and the Johns Hopkins Hospital Ethics Committee and Consultation Service. A common strength experienced by both platforms during virtual delivery included improved ability for local practitioners to address consultation needs for patient populations otherwise unable to access CEC services in their respective locations. Additionally, virtual platforms allowed for enhanced collaboration and sharing of expertise among ethics consultants. Both contexts encountered numerous challenges related to patient care delivery during the pandemic. The use of virtual technologies resulted in decreased personalization of patient-provider communication. We discuss these challenges with respect to contextual differences specific to each service and setting, including differences in CEC needs, sociocultural norms, resource availability, populations served, consultation service visibility, healthcare infrastructure, and funding disparities. Through lessons learned from a health system in the United States and a national service in Malaysia, we provide key recommendations for health practitioners and clinical ethics consultants to leverage virtual communication platforms to mitigate existing inequities in patient care delivery and increase capacity for CEC globally.

Ethics and Well-Being: The Health Professions and the COVID-19 Pandemic.

The COVID-19 pandemic has had a profound impact on health professionals, adding to the moral suffering and burnout that existed prepandemic. The physical, psychological, and moral toll of the pandemic has threatened the well-being and integrity of clinicians. The narrative of self-sacrifice and heroism bolstered people early on but was not sustainable over time. For health professions students, the learning environment changed dramatically, limiting opportunities in direct patient care and raising concerns for meeting training requirements. Learners lost social connections and felt isolated while learning remotely, and they witnessed ethical tensions between patient-centered care and parallel obligations to public health. Worries about transmission of the virus and uncertainty about its management contributed to their moral suffering. Educators adjusted curricula to address the changing ethical landscape. Preparing learners for the realities of their future professional identities requires creation of interprofessional moral communities that provide support and help develop the moral agency and integrity of its members using experiential and relational learning methods. Investing in the well-being and resilience of clinicians, implementing the recommendations of the National Academy of Medicine, and engaging learners and faculty as cocreators of ethical practice have the potential to transform the learning environment. Faculty need to be trained as effective mentors to create safe spaces for exploring challenges and address moral adversity. Ethics education will need to expand to issues related to health systems science, social determinants of health, and public health, and the cultivation of moral sensitivity, character development, professional identity formation, and moral resilience.

Operational Recommendations for Scarce Resource Allocation in a Public Health Crisis.

The coronavirus disease 2019 pandemic may require rationing of various medical resources if demand exceeds supply. Theoretical frameworks for resource allocation have provided much needed ethical guidance, but hospitals still need to address objective practicalities and legal vetting to operationalize scarce resource allocation schemata. To develop operational scarce resource allocation processes for public health catastrophes, including the coronavirus disease 2019 pandemic, five health systems in Maryland formed a consortium-with diverse expertise and representation-representing more than half of all hospitals in the state. Our efforts built on a prior statewide community engagement process that determined the values and moral reference points of citizens and health-care professionals regarding the allocation of ventilators during a public health catastrophe. Through a partnership of health systems, we developed a scarce resource allocation framework informed by citizens' values and by general expert consensus. Allocation schema for mechanical ventilators, ICU resources, blood components, novel therapeutics, extracorporeal membrane oxygenation, and renal replacement therapies were developed. Creating operational algorithms for each resource posed unique challenges; each resource's varying nature and underlying data on benefit prevented any single algorithm from being universally applicable. The development of scarce resource allocation processes must be iterative, legally vetted, and tested. We offer our processes to assist other regions that may be faced with the challenge of rationing health-care resources during public health catastrophes.

A Palliative Care Intervention for Patients on Phase 1 Studies.

Background: Phase 1 clinical trials remain vital for oncology care. Patients on these trials require supportive care for quality-of-life (QOL) concerns. Objective: To test a Palliative Care Intervention (PCI) for patients with solid tumors enrolled in Phase I therapeutic trials with a priori hypothesis that psychological distress, QOL, satisfaction, symptoms, and resource utilization would be improved in the PCI group. Design: This unblinded randomized trial compared the PCI with usual care in patients accrued to Phase I Clinical Trials. Subjects (n = 479) were followed for 24 weeks, with 12 weeks as the primary outcome. Setting: Two Comprehensive Cancer Centers in the United States. Subjects: A consecutive sample, 21 years or older, English fluency, with solid tumors initiating a Phase 1 trial. Measurements: Psychological Distress (Distress Thermometer), QOL total and subscales (FACT-G), satisfaction (FAM-CARE), survival, and resource utilization (chart audit). Results: PCI subjects showed improved Psychological Distress (-0.47, p = 0.015) and Emotional Well-Being (0.81, p = 0.045), with differences on variables of QOL and distress between sites. High rates of symptom-management admissions (41.3%) and low rates of Advance Directive completion (39.0%), and hospice enrollment (30.7%), despite a median survival in both groups of 10.1 months from initiating a Phase 1 study. Conclusions: A nurse-delivered PCI can improve some QOL outcomes and distress for patients participating in Phase 1 trials. Greater integration of PC is needed to provide quality care to these patients and to support transitions from treatment to supportive care, especially at the end of life. ClinicalTrials.gov Identifier: NCT01612598.

From Modules to MOOCs: Application of the Six-Step Approach to Online Curriculum Development for Medical Education.

Online curricula can make high-quality health professions education accessible in virtually any setting. They can enhance teaching and learning by both standardizing curricular resources and individualizing curricular experiences. Despite growing demand for and institutional interest in online curricula for medical education, many medical educators lack a framework for online curriculum development. Without rigorous and thoughtful development, online curricula can waste opportunity and resources by leading to education that is inferior to traditional methods. In this article, the authors describe a systematic approach to online curriculum development based on the Six-Step Approach for Curriculum Development for Medical Education, a widely used method that has led to successful implementation of a variety of traditional and online curricula. In each step, special considerations for curricula with larger and more diverse learner audiences-characteristic of many online curricula-are highlighted. Four common online curricular formats are also discussed: blended curricula, instructor-led fully online curricula, self-paced modules, and massive open online courses (MOOCs). The authors emphasize factors that differentiate one online format from another, including the budgetary, technical, and human resource requirements for each. The article concludes by urging medical educators to pursue opportunities to study and disseminate online curricular work.

Coamplification of miR-4728 protects HER2-amplified breast cancers from targeted therapy.

HER2 (ERBB2) amplification is a driving oncogenic event in breast cancer. Clinical trials have consistently shown the benefit of HER2 inhibitors (HER2i) in treating patients with both local and advanced HER2+ breast cancer. Despite this benefit, their efficacy as single agents is limited, unlike the robust responses to other receptor tyrosine kinase inhibitors like EGFR inhibitors in EGFR-mutant lung cancer. Interestingly, the lack of HER2i efficacy occurs despite sufficient intracellular signaling shutdown following HER2i treatment. Exploring possible intrinsic causes for this lack of response, we uncovered remarkably depressed levels of NOXA, an endogenous inhibitor of the antiapoptotic MCL-1, in HER2-amplified breast cancer. Upon investigation of the mechanism leading to low NOXA, we identified a micro-RNA encoded in an intron of HER2, termed miR-4728, that targets the mRNA of the Estrogen Receptor α (ESR1). Reduced ESR1 expression in turn prevents ERα-mediated transcription of NOXA, mitigating apoptosis following treatment with the HER2i lapatinib. Importantly, resistance can be overcome with pharmacological inhibition of MCL-1. More generally, while many cancers like EGFR-mutant lung cancer are driven by activated kinases that when drugged lead to robust monotherapeutic responses, we demonstrate that the efficacy of targeted therapies directed against oncogenes active through focal amplification may be mitigated by coamplified genes.

Epithelial-to-Mesenchymal Transition Antagonizes Response to Targeted Therapies in Lung Cancer by Suppressing BIM.

Purpose: Epithelial-to-mesenchymal transition (EMT) confers resistance to a number of targeted therapies and chemotherapies. However, it has been unclear why EMT promotes resistance, thereby impairing progress to overcome it.Experimental Design: We have developed several models of EMT-mediated resistance to EGFR inhibitors (EGFRi) in EGFR-mutant lung cancers to evaluate a novel mechanism of EMT-mediated resistance.Results: We observed that mesenchymal EGFR-mutant lung cancers are resistant to EGFRi-induced apoptosis via insufficient expression of BIM, preventing cell death despite potent suppression of oncogenic signaling following EGFRi treatment. Mechanistically, we observed that the EMT transcription factor ZEB1 inhibits BIM expression by binding directly to the BIM promoter and repressing transcription. Derepression of BIM expression by depletion of ZEB1 or treatment with the BH3 mimetic ABT-263 to enhance "free" cellular BIM levels both led to resensitization of mesenchymal EGFR-mutant cancers to EGFRi. This relationship between EMT and loss of BIM is not restricted to EGFR-mutant lung cancers, as it was also observed in KRAS-mutant lung cancers and large datasets, including different cancer subtypes.Conclusions: Altogether, these data reveal a novel mechanistic link between EMT and resistance to lung cancer targeted therapies. Clin Cancer Res; 24(1); 197-208. ©2017 AACR.

The Trial of Ascertaining Individual Preferences for Loved Ones' Role in End-of-Life Decisions (TAILORED) Study: A Randomized Controlled Trial to Improve Surrogate Decision Making.

CONTEXT: Patients with terminal illnesses often require surrogate decision makers. Prior research has demonstrated high surrogate stress, and that despite standards promoting substituted judgment, most patients do not want their surrogates to make pure substituted judgments for them. It is not known how best to help loved ones fulfill the surrogate role. OBJECTIVES: To test the effectiveness of an intervention to help surrogate decision makers. METHODS: One hundred sixty-six patients (41% with amyotrophic lateral sclerosis and 59% with gastrointestinal cancers) and their surrogates at two university medical centers were randomized to an intensive nurse-directed discussion of the end-of-life decision control preferences of the patient (TAILORED) or a discussion of nutrition (CONTROL); 163 completed baseline interviews and underwent the intervention. RESULTS: Twelve patients died during follow-up and 137 dyads completed the study. Post-intervention, using all available data, TAILORED patients and surrogates became more likely to endorse mutual surrogate decision making, that is, a balance of their own wishes and what the surrogate thinks best (adjusted odds compared with baseline for patients = 1.78, P = 0.04; adjusted odds for surrogates = 2.05, P = 0.03). CONTROL patients became 40% less likely to endorse mutual surrogate decision making (P = 0.08), and CONTROL surrogates did not change significantly from baseline (adjusted odds = 1.44, P = 0.28). Stress levels decreased for TAILORED surrogates (impact of events scale = 23.1 ± 14.6 baseline, 20.8 ± 15.3 f/u, P = 0.046), but not for CONTROL (P = 0.85), and post-intervention stress was lower for TAILORED than CONTROL (P = 0.04). Surrogates' confidence was uniformly high at baseline and did not change. Caregiver burden (Zarit) increased from 12.5 ± 6.5 to 14.7 ± 8.1 for TAILORED (P < 0.01), while not changing for CONTROL, yet satisfaction with involvement in decision making was higher at follow-up for TAILORED than for CONTROL (71% vs. 52%, P = 0.03). CONCLUSION: TAILORED patients and surrogates who completed the study adopted a more mutual decision-making style, balancing their own wishes with what the surrogate thinks would be best for them. Surrogates reported less stress and more satisfaction. Confidence was high at baseline and did not change. There was a modest increase in caregiver burden. These findings suggest that interventions like TAILORED might positively impact surrogate decision making.

Characteristics of Participants Enrolled onto a Randomized Controlled Trial of Palliative Care for Patients on Phase I Studies.

INTRODUCTION: Advanced cancer patients participating in phase 1 clinical trials experience considerable symptom burden. Palliative care (PC) may benefit these individuals by providing supportive care during clinical research participation. This study investigates integration of a PC intervention among phase 1 trial participants with advanced cancer. METHODS AND MATERIALS: This study is a multisite randomized clinical trial testing a concurrent PC intervention among phase 1 trial participants. Baseline demographic and clinical characteristics and descriptive baseline assessment findings were examined for all participants to date. Self-report assessments included quality of life (QOL) using the Functional Assessment of Cancer Therapy-General, spirituality using the Functional Assessment of Chronic Illness Therapy-Spirituality, and overall distress using the Distress Thermometer. Clinical trial retention and healthcare utilization were assessed through chart audit at study completion. RESULTS: The study has enrolled 178 participants to date. The average age is 60.3 years, the majority was Caucasian (57.9%), and participants had an average of 1.7 comorbidities. Overall QOL was 77.6 (±15.1). Responses were most favorable for social/family well-being (22.6 ± 4.6), lowest for emotional well-being (14.9 ± 5.1), and average overall distress was 3.6 (±2.7). Healthcare utilization at study completion (n = 134) identified low rates of supportive care referrals, with approximately half of participants referred to social work (50.8%), and fewer referred for pain (43%), resource centers (44%), and physical therapy (18%). CONCLUSION: Phase 1 clinical trial participants experience unmet QOL needs at baseline and levels of distress that merit clinical intervention. Although this study is in progress, initial findings support the potential benefits of PC among this population.

Patient and caregiver characteristics related to completion of advance directives in terminally ill patients.

OBJECTIVE: There is a growing body of literature describing the characteristics of patients who plan for the end of life, but little research has examined how caregivers influence patients' advance care planning (ACP). The purpose of this study was to examine how patient and caregiver characteristics are associated with advance directive (AD) completion among patients diagnosed with a terminal illness. We defined AD completion as having completed a living will and/or identified a healthcare power of attorney. METHOD: A convenience sample of 206 caregiver-patient dyads was included in the study. All patients were diagnosed with an advanced life-limiting illness. Trained research nurses administered surveys to collect information on patient and caregiver demographics (i.e., age, sex, race, education, marital status, and individual annual income) and patients' diagnoses and completion of AD. Multivariate logistic regression was employed to model predictors for patients' AD completion. RESULTS: Over half of our patient sample (59%) completed an AD. Patients who were older, diagnosed with amyotrophic lateral sclerosis, and with a caregiver who was Caucasian or declined to report an income level were more likely to have an AD in place. SIGNIFICANCE OF RESULTS: Our results suggest that both patient and caregiver characteristics may influence patients' decisions to complete an AD at the end of life. When possible, caregivers should be included in advance care planning for patients who are terminally ill.

Decision-Making of Patients With Implantable Cardioverter-Defibrillators at End of Life: Family Members' Experiences.

INTRODUCTION: Many patients with advanced heart failure (HF) experience the life-extending benefits of implantable cardioverter-defibrillators (ICD), but at the end stage of HF, patients may experience shocks with increasing frequency and change the plan for end-of-life (EOL) care including the deactivation of the ICD. This report describes family members' experiences of patients with ICD making decisions at EOL. Understanding the decision-making of patients with ICD at EOL can promote informed decision-making and improve the quality of EOL care. METHODS: This pilot study used a mixed methods approach to test the effects of a nurse-guided discussion in decision-making about ICD deactivation (turning off the defibrillation function) at the EOL. Interviews were conducted, audiotaped, and transcribed in 2012 to 2013 with 6 family members of patients with advanced HF and ICDs. Three researchers coded the data and identified themes in 2014. RESULTS: Three main themes described family members' experiences related to patients having HF with ICDs making health-care decision at EOL: decision-making preferences, patients' perception on ICD deactivation, and communication methods. DISCUSSION: Health-care providers need to have knowledge of patients' decision-making preferences. Preferences for decision-making include the allowing of appropriate people to involve and encourages direct conversation with family members even when advance directives is completed. Information of ICD function and the option of deactivation need to be clearly delivered to patients and family members. Education and guidelines will facilitate the communication of the preferences of EOL care.

Exploitation of the Apoptosis-Primed State of MYCN-Amplified Neuroblastoma to Develop a Potent and Specific Targeted Therapy Combination.

Fewer than half of children with high-risk neuroblastoma survive. Many of these tumors harbor high-level amplification of MYCN, which correlates with poor disease outcome. Using data from our large drug screen we predicted, and subsequently demonstrated, that MYCN-amplified neuroblastomas are sensitive to the BCL-2 inhibitor ABT-199. This sensitivity occurs in part through low anti-apoptotic BCL-xL expression, high pro-apoptotic NOXA expression, and paradoxical, MYCN-driven upregulation of NOXA. Screening for enhancers of ABT-199 sensitivity in MYCN-amplified neuroblastomas, we demonstrate that the Aurora Kinase A inhibitor MLN8237 combines with ABT-199 to induce widespread apoptosis. In diverse models of MYCN-amplified neuroblastoma, including a patient-derived xenograft model, this combination uniformly induced tumor shrinkage, and in multiple instances led to complete tumor regression.

Caring for 'Very Important Patients'--Ethical Dilemmas and Suggestions for Practical Management.

The care of Very Important Patients (VIPs) is different from other patients because they may receive greater access, attention, and resources from health care staff. Although the term VIP is used regularly in the medical literature and is implicitly understood, in practice it constitutes a wide and heterogeneous group of patients that have a strong effect on health care providers. We define a VIP as a very influential patient whose individual attributes and characteristics (eg, social status, occupation, position), coupled with their behavior, have the potential to significantly influence a clinician's judgment or behavior. Physicians, celebrities, the politically powerful, and philanthropists, may all become VIPs in the appropriate context. The quality of care may be inferior because health care professionals may deviate from standard practices when caring for them. Understanding the common features among what may otherwise be very different groups of patients can help health care providers manage ethical concerns when they arise. We use a series of vignettes to demonstrate how VIPs behavior and status can influence a clinician's judgment or actions. Appreciating the ethical principles in these varied circumstances provides health care professionals with the tools to manage ethical conflicts that arise in the care of VIPs. We conclude each vignette with guidance for how health care providers and administrators can manage the ethical concern.

Symptom frequency, severity, and quality of life among persons with three disease trajectories: cancer, ALS, and CHF.

PURPOSE: National reports on end-of-life symptom management reveal a gap in the evidence regarding symptoms other than pain and studies of diseases other than cancer. This study examines the frequency and severity of symptoms and quality of life (QOL) in persons with advanced cancer, amyotrophic lateral sclerosis (ALS), and congestive heart failure (CHF). METHODS: The present study is a cross-sectional examination of symptoms and QOL measured using the McGill QOL Questionnaire, among 147 participants. RESULTS: Forty one percent of participants had advanced cancer, 22% had ALS, and 37% had advanced CHF. A total of 266 symptoms were reported, with the common symptom categories being discomfort/pain, weakness/fatigue/sleep, and respiratory. Participants with CHF had the highest mean symptom severity and the lowest QOL. CONCLUSION: Clinicians should be aware and attentive for symptoms other than pain in patients with advanced illness. Studies on diseases other than cancer, such as CHF and ALS, are important to improve symptom management in all disease groups.