An ALK2 inhibitor, BLU-782, prevents heterotopic ossification in a mouse model of fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease driven by gain-of-function variants in activin receptor-like kinase 2 (ALK2), the most common variant being ALK2R206H. In FOP, ALK2 variants display increased and dysregulated signaling through the bone morphogenetic protein (BMP) pathway resulting in progressive and permanent replacement of skeletal muscle and connective tissues with heterotopic bone, ultimately leading to severe debilitation and premature death. Here, we describe the discovery of BLU-782 (IPN60130), a small-molecule ALK2R206H inhibitor developed for the treatment of FOP. A small-molecule library was screened in a biochemical ALK2 binding assay to identify potent ALK2 binding compounds. Iterative rounds of structure-guided drug design were used to optimize compounds for ALK2R206H binding, ALK2 selectivity, and other desirable pharmacokinetic properties. BLU-782 preferentially bound to ALK2R206H with high affinity, inhibiting signaling from ALK2R206H and other rare FOP variants in cells in vitro without affecting signaling of closely related homologs ALK1, ALK3, and ALK6. In vivo efficacy of BLU-782 was demonstrated using a conditional knock-in ALK2R206H mouse model, where prophylactic oral dosing reduced edema and prevented cartilage and heterotopic ossification (HO) in both muscle and bone injury models. BLU-782 treatment preserved the normal muscle-healing response in ALK2R206H mice. Delayed dosing revealed a short 2-day window after injury when BLU-782 treatment prevented HO in ALK2R206H mice, but dosing delays of 4 days or longer abrogated HO prevention. Together, these data suggest that BLU-782 may be a candidate for prevention of HO in FOP.

Evidence-Based Pearls: Falls in the Intensive Care Unit.

Falls in the ICU are multifaceted, affecting patients of all ages. Historically, falls have been associated with patients in the hospital environment, but fall rates after discharge and readmission rates following a fall are now areas of concern. Recent innovations to prevent risks related to sedation and immobility in the hospital have revealed their impact on ICU patients and fall risk. Risk factors for falls in the ICU relate to length of stay and acuity-related care requirements, such as mechanical ventilation, sedation, and prolonged immobilization. Evidence-based fall prevention includes screening tools, prevention bundles/programs, and implementing clinical practice guidelines.

Exercise during CHemotherapy for Ovarian cancer (ECHO) trial: design and implementation of a randomised controlled trial.

INTRODUCTION: Epidemiological evidence supports an association between higher levels of physical activity and improved cancer survival. Trial evidence is now needed to demonstrate the effect of exercise in a clinical setting. The Exercise during CHemotherapy for Ovarian cancer (ECHO) trial is a phase III, randomised controlled trial, designed to determine the effect of exercise on progression-free survival and physical well-being for patients receiving first-line chemotherapy for ovarian cancer. METHODS AND ANALYSIS: Participants (target sample size: n=500) include women with newly diagnosed primary ovarian cancer, scheduled to receive first-line chemotherapy. Consenting participants are randomly allocated (1:1) to either the exercise intervention (plus usual care) or usual care alone, with stratification for recruitment site, age, stage of disease and chemotherapy delivery (neoadjuvant vs adjuvant). The exercise intervention involves individualised exercise prescription with a weekly target of 150 minutes of moderate-intensity, mixed-mode exercise (equivalent to 450 metabolic equivalent minutes per week), delivered for the duration of first-line chemotherapy through weekly telephone sessions with a trial-trained exercise professional. The primary outcomes are progression-free survival and physical well-being. Secondary outcomes include overall survival, physical function, body composition, quality of life, fatigue, sleep, lymphoedema, anxiety, depression, chemotherapy completion rate, chemotherapy-related adverse events, physical activity levels and healthcare usage. ETHICS AND DISSEMINATION: Ethics approval for the ECHO trial (2019/ETH08923) was granted by the Sydney Local Health District Ethics Review Committee (Royal Prince Alfred Zone) on 21 November 2014. Subsequent approvals were granted for an additional 11 sites across Queensland, New South Wales, Victoria and the Australian Capital Territory. Findings from the ECHO trial are planned to be disseminated via peer-reviewed publications and international exercise and oncology conferences. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trial Registry (ANZCTRN12614001311640; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=367123&isReview=true).

Community sociodemographics and rural hospital survival.

PURPOSE: To determine whether community sociodemographic factors are associated with the survival or closure of rural hospitals at risk of financial distress between 2010 and 2019. METHODS: We use a national sample of 985 rural hospitals at risk of financial distress to analyze the relationship between community sociodemographic characteristics and hospital survival or closure. We control for financial distress using the Financial Distress Index developed by the Sheps Center for Health Services Research. Community characteristics are retrieved from the Census and the Robert Wood Johnson Foundation. We first use Wilcoxon rank-sum tests to demonstrate annual sociodemographic differences between rural communities with financially distressed hospitals that closed between 2010 and 2019, and those that remained open. Multilevel Weibull proportional hazards regressions then uncover which sociodemographic factors are significantly associated with survival. FINDINGS: Our initial results confirm that closures of rural hospitals at risk of financial distress disproportionately affect communities with certain sociodemographic characteristics. However, most of these characteristics are not associated with higher rates of closure in the multivariate survival analysis. The final results suggest that financially distressed hospitals are more likely to experience closure if their communities have higher rates of unemployment (Hazard Ratio = 1.36, P < .05) or uninsured residents under 65 (Hazard Ratio = 1.13, P < .05). CONCLUSIONS: Among financially distressed rural hospitals, specific community-level sociodemographic characteristics (unemployment and uninsurance rates) are positively associated with the likelihood of closure. Social policies addressing these issues should emphasize their broader relationship with the local health sector.

Intervention Fidelity in Pain Pragmatic Trials for Nonpharmacologic Pain Management: Nuanced Considerations for Determining PRECIS-2 Flexibility in Delivery and Adherence.

Nonpharmacological treatments are considered first-line pain management strategies, but they remain clinically underused. For years, pain-focused pragmatic clinical trials (PCTs) have generated evidence for the enhanced use of nonpharmacological interventions in routine clinical settings to help overcome implementation barriers. The Pragmatic Explanatory Continuum Indicator Summary (PRECIS-2) framework describes the degree of pragmatism across 9 key domains. Among these, "flexibility in delivery" and "flexibility in adherence," address a key goal of pragmatic research by tailoring approaches to settings in which people receive routine care. However, to maintain scientific and ethical rigor, PCTs must ensure that flexibility features do not compromise delivery of interventions as designed, such that the results are ethically and scientifically sound. Key principles of achieving this balance include clear definitions of intervention core components, intervention monitoring and documentation that is sufficient but not overly burdensome, provider training that meets the demands of delivering an intervention in real-world settings, and use of an ethical lens to recognize and avoid potential trial futility when necessary and appropriate. PERSPECTIVE: This article presents nuances to be considered when applying the PRECIS-2 framework to describe pragmatic clinical trials. Trials must ensure that patient-centered treatment flexibility does not compromise delivery of interventions as designed, such that measurement and analysis of treatment effects is reliable.

Factors impacting pediatric registered nurse attitudes toward caring for dying children and their families: A descriptive study.

PURPOSE: The purpose of this study was to gain knowledge of the educational preparation and attitudes of registered nurses at a southeastern pediatric hospital toward caring for dying children and their families. DESIGN AND METHODS: A descriptive study with two independent samples was used to examine the attitudes of registered nurses at a pediatric hospital in southeastern United States. Participants completed the Frommelt Attitude Toward Care of the Dying Scale, Form B, a 30-item survey. Descriptive and inferential statistics were used to analyze data. RESULTS: One hundred and thirty-two registered nurses participated in the study. Results indicated a statistically significant difference in attitudes toward caring for dying pediatric patient scores in registered nurses working in the hematology/oncology and intensive care units compared to the other units (p = 0.0017; 95% CI: 2.39-10.12). CONCLUSIONS: This study described the educational preparation and attitudes of registered nurses who care for children who are dying and their families. Additionally, pediatric end-of-life care is complex and is further influenced by experiences and attitudes. Future research is needed to identify educational needs to care for pediatric patients and their families at the end of life. PRACTICE IMPLICATIONS: Findings from this project indicated end-of-life care education should be integrated into undergraduate curricula. New nurse graduates who are entering the workforce should receive education on end-of-life care, especially if they are entering into a pediatric specific organization. Healthcare organizations should include end-of-life care education as part of the orientation process and annual competency process.

Higher Electronic Health Record Functionality Is Associated with Lower Operating Costs in Urban-but Not Rural-Hospitals.

OBJECTIVES: The aim of the study is to examine the relationship between electronic health record (EHR) use/functionality and hospital operating costs (divided into five subcategories), and to compare the results across rural and urban facilities. METHODS: We match hospital-level data on EHR use/functionality with operating costs and facility characteristics to perform linear regressions with hospital- and time-fixed effects on a panel of 1,596 U.S. hospitals observed annually from 2016 to 2019. Our dependent variables are the logs of the various hospital operating cost categories, and alternative metrics for EHR use/functionality serve as the primary independent variables of interest. Data on EHR use/functionality are retrieved from the American Hospital Association's (AHA) Annual Survey of Hospitals Information Technology (IT) Supplement, and hospital operating cost and characteristic data are retrieved from the American Hospital Directory. We include only hospitals classified as "general medical and surgical," removing specialty hospitals. RESULTS: Our results suggest, first, that increasing levels of EHR functionality are associated with hospital operating cost reductions. Second, that these significant cost reductions are exclusively seen in urban hospitals, with the associated coefficient suggesting cost savings of 0.14% for each additional EHR function. Third, that urban EHR-related cost reductions are driven by general/ancillary and outpatient costs. Finally, that a wide variety of EHR functions are associated with cost reductions for urban facilities, while no EHR function is associated with significant cost reductions in rural locations. CONCLUSION: Increasing EHR functionality is associated with significant hospital operating cost reductions in urban locations. These results do not hold across geographies, and policies to promote greater EHR functionality in rural hospitals will likely not lead to short-term cost reductions.

Monitoring Symptoms of COVID-19: Review of Mobile Apps.

BACKGROUND: Mobile health (mHealth) apps have facilitated symptom monitoring of COVID-19 symptoms globally and have been used to share data with health care professionals and support disease prediction, prevention, management, diagnostics, and improvements in treatments and patient education. OBJECTIVE: The aim of this review is to evaluate the quality and functionality of COVID-19 mHealth apps that support tracking acute and long-term symptoms of COVID-19. METHODS: We systematically reviewed commercially available mHealth apps for COVID-19 symptom monitoring by searching Google Play and Apple iTunes using search terms such as "COVID-19," "Coronavirus," and "COVID-19 and symptoms." All apps underwent three rounds of screening. The final apps were independently assessed using the Mobile Application Rating Scale (MARS), an informatics functionality scoring system, and the Center for Disease Control and World Health Organization symptom guidelines. The MARS is a 19-item standardized tool to evaluate the quality of mHealth apps on engagement, functionality, aesthetics, and information quality. Functionality was quantified across the following criteria: inform, instruct, record (collect, share, evaluate, and intervene), display, guide, remind or alert, and communicate. Interrater reliability between the reviewers was calculated. RESULTS: A total of 1017 mobile apps were reviewed, and 20 (2%) met the inclusion criteria. The majority of the 20 included apps (n=18, 90%) were designed to track acute COVID-19 symptoms, and only 2 (10%) addressed long-term symptoms. Overall, the apps scored high on quality, with an overall MARS rating of 3.89 out of 5, and the highest domain score for functionality (4.2). The most common functionality among all apps was the instruct function (n=19, 95%). The most common symptoms included in the apps for tracking were fever and dry cough (n=18, 90%), aches and pains (n=17, 85%), difficulty breathing (n=17, 85%), tiredness, sore throat, headache, loss of taste or smell (n=16, 80%), and diarrhea (n=15, 75%). Only 2 (10%) apps specifically tracked long-term symptoms of COVID-19. The top 4 rated apps overall were state-specific apps developed and deployed for public use. CONCLUSIONS: Overall, mHealth apps designed to monitor symptoms of COVID-19 were of high quality, but the majority of apps focused almost exclusively on acute symptoms. Future apps should also incorporate monitoring long-term symptoms of COVID-19 and evidence-based educational materials; they should also include a feature that would allow patients to communicate their symptoms to specific caregivers or their own health care team. App developers should also follow updated technical and clinical guidelines from the Center for Disease Control and the World Health Organization.

Justice and equity in pragmatic clinical trials: Considerations for pain research within integrated health systems.

Introduction: Pragmatic clinical trials (PCTs) can overcome implementation challenges for bringing evidence-based therapies to people living with pain and co-occurring conditions, providing actionable information for patients, providers, health systems, and policy makers. All studies, including those conducted within health systems that have a history of advancing equitable care, should make efforts to address justice and equity. Methods: Drawing from collective experience within pragmatic pain clinical trials networks, and synthesizing relevant literature, our multidisciplinary working group examined challenges related to integrating justice and equity into pragmatic pain management research conducted in large, integrated health systems. Our analysis draws from military and veteran health system contexts but offers strategies to consider throughout the lifecycle of pragmatic research more widely. Results: We found that PCTs present a unique opportunity to address major influences on health inequities by occupying a space between research, healthcare delivery, and the complexities of everyday life. We highlight key challenges that require attention to support complementary advancement of justice and equity via pragmatic research, offering several strategies that can be pursued. Conclusions: Efforts are needed to engage diverse stakeholders broadly and creatively in PCTs, such as through dedicated health equity working groups and other collaborative relationships with stakeholders, to support robust and inclusive approaches to research design and implementation across study settings. These considerations, while essential to pain management research, offer important opportunities toward achieving more equitable healthcare and health systems to benefit people living with pain and co-occurring conditions.

New Graduate Nurses in the Intensive Care Setting: Preparing Them for Patient Death.

The COVID-19 pandemic and nursing shortage has impacted new graduate nurse (NGN) careers. Many NGNs gain initial employment with intensive care areas, encountering unprecedented stress due to high patient acuities, technology, and deaths. Having not yet transitioned into nursing practice, the NGN can experience a reality shock. Nurses are responsible for the care of the dying patient in the intensive care setting, despite inconsistencies in undergraduate curricula on death and dying. Nurse residency programs provide transition-to-practice support and reduce the stressors experienced by NGNs. Residency programs which specifically include palliative care and/or end-of-life content can positively impact stress, burnout, and turnover rates in NGNs.

Symptom burden and quality of life with chemotherapy for recurrent ovarian cancer: the Gynecologic Cancer InterGroup-Symptom Benefit Study.

OBJECTIVE: The Gynecologic Cancer InterGroup (GCIG)-Symptom Benefit Study was designed to evaluate the effects of chemotherapy on symptoms and health-related quality of life (HRQL) in women having chemotherapy for platinum resistant/refractory recurrent ovarian cancer (PRR-ROC) and potentially platinum sensitive with ≥3 lines of chemotherapy (PPS-ROC ≥3). METHODS: Participants completed the Measure of Ovarian Cancer Symptoms and Treatment (MOST) and European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-C30 questionnaires at baseline and every 3-4 weeks until progression. Participants were classified symptomatic if they rated ≥4 of 10 in at least one-third of symptoms in the MOST index. Improvement in MOST was defined as two consecutive scores of ≤3 in at least half of the symptomatic items at baseline. Improvement in HRQL was defined as two consecutive scores ≥10 points above baseline in the QLQ-C30 summary score scale (range 0-100). RESULTS: Of 948 participants enrolled, 910 (96%) completed baseline questionnaires: 546 with PRR-ROC and 364 with PPS-ROC ≥3. The proportions of participants symptomatic at baseline as per MOST indexes were: abdominal 54%, psychological 53%, and disease- or treatment-related 35%. Improvement was reported in MOST indexes: abdominal 40%, psychological 35%, and disease- or treatment-related 38%. Median time to improvement in abdominal symptoms occurred earlier for PRR-ROC than for PPS-ROC ≥3 (4 vs 6 weeks, p=0.044); median duration of improvement was also similar (9.0 vs 11.7 weeks, p=0.65). Progression-free survival was longer among those with improvement in abdominal symptoms than in those without (median 7.2 vs 2.5 months, p<0.0001). Improvements in HRQL were reported by 77/448 (17%) with PRR-ROC and 61/301 (20%) with PPS-ROC ≥3 (p=0.29), and 102/481 (21%) of those with abdominal symptoms at baseline. CONCLUSION: Over 50% of participants reported abdominal and psychological symptoms at baseline. Of those, 40% reported an improvement within 2 months of starting chemotherapy. Approximately one in six participants reported an improvement in HRQL. Symptom monitoring and supportive care is important as chemotherapy palliated less than half of symptomatic participants.

A retrospective analysis of discharge summaries from a tertiary care hospital medical oncology unit: To assess compliance with documentation of recommended discharge summary components.

BACKGROUND: Discharge summaries are essential for health transition between inpatient hospital teams and outpatient general practices. The patient's outcome is dependent on the quality and timeliness of discharge summaries. AIM: A retrospective analysis was carried out to assess the compliance with recommended documentation of 697 electronic discharge summaries (eDSs) of oncology inpatients discharged in 2018 from the Canberra Hospital according to the National Guidelines of On-Screen Presentation of Discharge Summaries. METHODS AND RESULTS: Individual medical records were identified and screened for the recommended eDS components according to the National Guidelines. Out of the 17 recommended components, nine components were included in all discharge summaries, two components in more than 99% and two components in 95-96% of discharge summaries. The most frequently omitted components include "information provided to the patient," "ceased medicine" and "procedures," and these were omitted in 8, 38 and 82% of discharge summaries, respectively. CONCLUSION: Overall, most discharge summaries adhered to the national guidelines quite well by including most of the recommended components. However, the discharge summary quality is still inadequate in some domains.

Optimizing the Impact of Pragmatic Clinical Trials for Veteran and Military Populations: Lessons From the Pain Management Collaboratory.

Pragmatic clinical trials (PCTs) are well-suited to address unmet healthcare needs, such as those arising from the dual public health crises of chronic pain and opioid misuse, recently exacerbated by the COVID-19 pandemic. These overlapping epidemics have complex, multifactorial etiologies, and PCTs can be used to investigate the effectiveness of integrated therapies that are currently available but underused. Yet individual pragmatic studies can be limited in their reach because of existing structural and cultural barriers to dissemination and implementation. The National Institutes of Health, Department of Defense, and Department of Veterans Affairs formed an interagency research partnership, the Pain Management Collaboratory. The partnership combines pragmatic trial design with collaborative tools and relationship building within a large network to advance the science and impact of nonpharmacological approaches and integrated models of care for the management of pain and common co-occurring conditions. The Pain Management Collaboratory team supports 11 large-scale, multisite PCTs in veteran and military health systems with a focus on team science with the shared aim that the "whole is greater than the sum of the parts." Herein, we describe this integrated approach and lessons learned, including incentivizing all parties; proactively offering frequent opportunities for problem-solving; engaging stakeholders during all stages of research; and navigating competing research priorities. We also articulate several specific strategies and their practical implications for advancing pain management in active clinical, "real-world," settings.

Long-term impact of a single interprofessional education high-fidelity simulation experience: a pilot study.

The interprofessional education (IPE) simulation literature lacks research assessing long-term IPE outcomes. During the 2018-19 and 2019-20 academic year, third year and fourth year medical students, respectively, engaged in an IPE simulation experience focused on cardiopulmonary resuscitation. Students completed the Interprofessional Collaborative Competencies Attainment Survey. There was a statistically significant positive change (p<0.05) in student perceptions of their interprofessional collaborative skills immediately following a single IPE simulation activity for both third and fourth year students. However, a statistically significant decline in means was noted from third year post-questions to fourth year pre-questions. A single annual IPE simulation activity may not be sufficient to support students in building confidence in their collaborative skills without regression.

Carboplatin and hypomagnesemia: Is it really a problem?

BACKGROUND: Carboplatin has largely replaced cisplatin in ovarian/peritoneal/tubal cancer (OC) due to comparable activity and reduced toxicity, particularly nephrotoxicity and hypomagnesemia. Anecdotally hypomagnesemia occurs commonly with carboplatin, however there are limited data available regarding frequency or severity. AIMS: To quantify incidence and severity of hypomagnesemia in patients receiving carboplatin-based chemotherapy for OC; to explore a dose-response relationship with carboplatin and assess potential confounding variables. METHODS: A retrospective single-center review of all OC patients receiving carboplatin-based chemotherapy as first/subsequent line between 2012 and 2018 was performed. Data on patient/disease characteristics, potential confounders (gastrointestinal/renal impairment, premorbid hypomagnesemia and concomitant medications), dose, electrolytes, and magnesium replacement were collected. RESULTS: One hundred four of 144 (72%) patients had at least one hypomagnesemia event, 11 of 104 (11%) grade 2, and 11 of 104 (11%) grade 3/4 in severity. Multivariate analysis showed a significant association between hypomagnesemia and treatment duration (P < .001). Premorbid hypomagnesemia was associated with a significantly longer duration and higher grade of hypomagnesemia (P = .021 and P < .001, respectively). Vomiting, diarrhea, and confounding medications were associated with hypomagnesemia (P = .019 and P = .028, respectively). Fourteen percent of hypomagnesemia events never resolved suggesting a significant cohort post-carboplatin are at risk of long-term renal toxicity. The effect of magnesium replacement could not be accurately assessed due to limited documentation of replacement. CONCLUSION: Hypomagnesemia is common in patients receiving carboplatin-based chemotherapy for OC, and although generally mild, a significant minority were severe. Several high-risk groups were identified including patients with premorbid hypomagnesemia, vomiting, diarrhea, or taking certain medications. Further research is warranted to understand when hypomagnesemia is clinically relevant and determine the impact of interventions.

Using Deliberate Practice and Simulation for Psychomotor Skill Competency Acquisition and Retention: A Mixed-Methods Study.

BACKGROUND: Quality, safe patient care is dependent on graduates who are proficient in the psychomotor skills of nursing. Competent skill acquisition and retention are key to reducing skill-based errors and reducing the risk of adverse patient events. PURPOSE: The purpose of this study was to explore the effect of deliberate practice combined with skill practice during high-fidelity simulation (HFS) scenarios on urinary catheter insertion skill competency and retention in prelicensure nursing students. METHODS: A convergent, parallel mixed-methods design was used. RESULTS: The group participating in skill practice before and during HFS scenarios demonstrated a reduction in errors when performing the skill and an improvement in retention of skill competency. CONCLUSIONS: This article describes how the combination of deliberate skill practice prior to and during HFS scenarios may improve student skill acquisition and retention.