Lipopolysaccharide-induced sepsis impairs M2R-GIRK signaling in the mouse sinoatrial node.

Sepsis has emerged as a global health burden associated with multiple organ dysfunction and 20% mortality rate in patients. Numerous clinical studies over the past two decades have correlated the disease severity and mortality in septic patients with impaired heart rate variability (HRV), as a consequence of impaired chronotropic response of sinoatrial node (SAN) pacemaker activity to vagal/parasympathetic stimulation. However, the molecular mechanism(s) downstream to parasympathetic inputs have not been investigated yet in sepsis, particularly in the SAN. Based on electrocardiography, fluorescence Ca2+ imaging, electrophysiology, and protein assays from organ to subcellular level, we report that impaired muscarinic receptor subtype 2-G protein-activated inwardly-rectifying potassium channel (M2R-GIRK) signaling in a lipopolysaccharide-induced proxy septic mouse model plays a critical role in SAN pacemaking and HRV. The parasympathetic responses to a muscarinic agonist, namely IKACh activation in SAN cells, reduction in Ca2+ mobilization of SAN tissues, lowering of heart rate and increase in HRV, were profoundly attenuated upon lipopolysaccharide-induced sepsis. These functional alterations manifested as a direct consequence of reduced expression of key ion-channel components (GIRK1, GIRK4, and M2R) in the mouse SAN tissues and cells, which was further evident in the human right atrial appendages of septic patients and likely not mediated by the common proinflammatory cytokines elevated in sepsis.

The impact of tumor microenvironment: unraveling the role of physical cues in breast cancer progression.

Metastasis accounts for the vast majority of breast cancer-related fatalities. Although the contribution of genetic and epigenetic modifications to breast cancer progression has been widely acknowledged, emerging evidence underscores the pivotal role of physical stimuli in driving breast cancer metastasis. In this review, we summarize the changes in the mechanics of the breast cancer microenvironment and describe the various forces that impact migrating and circulating tumor cells throughout the metastatic process. We also discuss the mechanosensing and mechanotransducing molecules responsible for promoting the malignant phenotype in breast cancer cells. Gaining a comprehensive understanding of the mechanobiology of breast cancer carries substantial potential to propel progress in prognosis, diagnosis, and patient treatment.

"The Equipoise Ruler:" A National Survey on Surgeon Judgment about the Value of Surgery.

OBJECTIVE: The objective of this study was to understand professional norms regarding the value of surgery. SUMMARY BACKGROUND DATA: Agreed-upon professional norms may improve surgical decision making by contextualizing the nature of surgical treatment for patients. However, the extent to which these norms exist among surgeons practicing in the US is not known. METHODS: We administered a survey with 30 exemplar cases asking surgeons to use their best judgement to place each case on a scale ranging from "Definitely would do this surgery" to "Definitely would not do this surgery." We then asked surgeons to repeat their assessments after providing responses from the first survey. We interviewed respondents to characterize their rationale. RESULTS: We received 580 responses, a response rate of 28.5%. For 19 of 30 cases there was consensus (≥60% agreement) about the value of surgery (range 63% - 99%). There was little within-case variation when the mode was for surgery and more variation when the mode was against surgery or equipoise. Exposure to peer response increased the number of cases with consensus. Women were more likely to endorse a non-operative approach when treatment had high mortality. Specialists were less likely to operate for salvage procedures. Surgeons noted their clinical practice was to withhold judgment and let patients decide despite their assessment. CONCLUSIONS: Professional judgment about the value of surgery exists along a continuum. While there is less variation in judgment for cases that are highly beneficial, consensus can be improved by exposure to the assessments of peers.

Equity in Using Artificial Intelligence Mortality Predictions to Target Goals of Care Documentation.

BACKGROUND: Artificial intelligence (AI) algorithms are increasingly used to target patients with elevated mortality risk scores for goals-of-care (GOC) conversations. OBJECTIVE: To evaluate the association between the presence or absence of AI-generated mortality risk scores with GOC documentation. DESIGN: Retrospective cross-sectional study at one large academic medical center between July 2021 and December 2022. PARTICIPANTS: Hospitalized adult patients with AI-defined Serious Illness Risk Indicator (SIRI) scores indicating > 30% 90-day mortality risk (defined as "elevated" SIRI) or no SIRI scores due to insufficient data. INTERVENTION: A targeted intervention to increase GOC documentation for patients with AI-generated scores predicting elevated risk of mortality. MAIN MEASURES: Odds ratios comparing GOC documentation for patients with elevated or no SIRI scores with similar severity of illness using propensity score matching and risk-adjusted mixed-effects logistic regression. KEY RESULTS: Among 13,710 patients with elevated (n = 3643, 27%) or no (n = 10,067, 73%) SIRI scores, the median age was 64 years (SD 18). Twenty-five percent were non-White, 18% had Medicaid, 43% were admitted to an intensive care unit, and 11% died during admission. Patients lacking SIRI scores were more likely to be younger (median 60 vs. 72 years, p < 0.0001), be non-White (29% vs. 13%, p < 0.0001), and have Medicaid (22% vs. 9%, p < 0.0001). Patients with elevated versus no SIRI scores were more likely to have GOC documentation in the unmatched (aOR 2.5, p < 0.0001) and propensity-matched cohorts (aOR 2.1, p < 0.0001). CONCLUSIONS: Using AI predictions of mortality to target GOC documentation may create differences in documentation prevalence between patients with and without AI mortality prediction scores with similar severity of illness. These finding suggest using AI to target GOC documentation may have the unintended consequence of disadvantaging severely ill patients lacking AI-generated scores from receiving targeted GOC documentation, including patients who are more likely to be non-White and have Medicaid insurance.

Hope and illness expectations: A cross-sectional study in patients with advanced cancer.

BACKGROUND: The fear of taking away hope hinders clinicians' willingness to share serious news with patients with advanced disease. Unrealistic illness expectations, on the other hand, can complicate decision making and end-of-life care outcomes. Exploration of the association between hope and illness expectations can support clinicians in better communication with their patients. AIM: The aim of this study was to explore whether realistic illness expectations are associated with reduced hope in people with advanced cancer. DESIGN: This is a cross-sectional secondary analysis of baseline data from a primary palliative care cluster-randomized trial CONNECT (data collected from July 2016 to October 2020). Hope was measured by Herth Hope Index. Illness expectations were measured by assessing patients' understanding of their treatment goals, life expectancy, and terminal illness acknowledgement. Multivariable regression was performed, adjusting for demographical and clinical confounders. SETTING/PARTICIPANTS: Adult patients with advanced solid cancers recruited across 17 oncology clinics. RESULTS: Data from 672 patients were included in the study, with mean age of 69.3 years (±10.2), 53.6% were female. Proportion of patients indicating realistic expectations varied based on which question was asked from 10% to 46%. Median level of hope was 39 (IQR = 36-43). Multivariate non-inferiority regression did not find any significant differences in hope between patients with more and less realistic illness expectations. CONCLUSIONS: Our results suggest that hope can be sustained while holding both realistic and unrealistic illness expectations. Communication about serious news should focus on clarifying the expectations as well as supporting people's hopes.

Agreement in non-cycloplegic and cycloplegic refraction between a photoscreener and a calibrated autorefractor.

INTRODUCTION: Photoscreeners have been shown to provide excellent measurements of the refractive error. However, whether they could be used for assessing cycloplegic refraction has not been examied. This study aimed to evaluate the agreement between cycloplegic and non-cycloplegic measurements obtained using a photoscreener and stationary autorefractor, respectively. METHODS: This study included all patients undergoing routine ophthalmic examination at the Hygeia Clinic (Poland) from June to July 2022. Each patient underwent non-cycloplegic and cycloplegic refraction assessments using the 2WIN photoscreener (Adaptica SRL, Padova, Italy) and an ARK-1 stationary autorefractor ARK-1 (Nidek Co Ltd., Tokyo, Japan), respectively. Each pair of assessments was conducted in random order, and all values were determined at a vertical distance of 12 mm. The agreement between cycloplegic and non-cycloplegic measurements was assessed using paired t-tests, Bland-Altman and ABCD ellipsoids. RESULTS: This analysis included 82 patients, of which 52 were female. Their mean age was 34.39 ± 13.13 years. The non-cycloplegic spherical equivalent (SE) did not differ significantly between the 2WIN (- 1.22 ± 2.45) and ARK-1 (- 1.19 ± 2.96) devices (p = 0.580). However, the cycloplegic SE values demonstrated more negative values with the 2WIN device (- 1.13 ± 2.19) than with the ARK-1 device (- 0.75 ± 3.03; p = 0.007). The non-cycloplegic and cycloplegic measurements were strongly correlated between the devices (r = 0.9473 and 0.9411, respectively). However, the correlation between their cycloplegic shifts in SE was low (r = 0.2645). Ellipsoid refraction aligned better non-cycloplegic (ARK-1 = 1.00; 2WIN = 1.74) than with cycloplegic refraction (ARK-1 = 1.43; 2WIN = 1.90). CONCLUSION: While the cycloplegic measurements obtained with the 2WIN photoscreener were strongly correlated with those obtained with the ARK-1 stationary autorefractor for most of the analyzed parameters, they should not be considered interchangeable.

In cancer with dyspnea, high-dose dexamethasone did not improve dyspnea and increased SAEs.

SOURCE CITATION: Hui D, Puac V, Shelal Z, et al. Effect of dexamethasone on dyspnoea in patients with cancer (ABCD): a parallel-group, double-blind, randomised, controlled trial. Lancet Oncol. 2022;23:1321-31. 36087590.

A Pediatric Interprofessional Cardiac Intensive Care Unit Intervention: CICU Teams and Loved Ones Communicating (CICU TALC) is Feasible, Acceptable, and Improves Clinician Communication Behaviors in Family Meetings.

Parents of children in the pediatric cardiac intensive care unit (CICU) are often unprepared for family meetings (FM). Clinicians often do not follow best practices for communicating with families, adding to distress. An interprofessional team intervention for FM is feasible, acceptable, and positively impacts family preparation and conduct of FM in the CICU. We implemented a family- and team-support intervention for conducting FM and conducted a pretest-posttest study with parents of patients selected for a FM and clinicians. We measured feasibility, fidelity to intervention protocol, and parent acceptability via questionnaire and semi-structured interviews. Clinician behavior in meetings was assessed through semantic content analyses of meeting transcripts tracking elicitation of parental concerns, questions asked of parents, and responses to parental empathic opportunities. Logistic and ordinal logistic regression assessed intervention impact on clinician communication behaviors in meetings comparing pre- and post-intervention data. Sixty parents (95% of approached) were enrolled, with collection of 97% FM and 98% questionnaire data. We accomplished > 85% fidelity to intervention protocol. Most parents (80%) said the preparation worksheet had the right amount of information and felt positive about families receiving this worksheet. Clinicians were more likely to elicit parental concerns (adjusted odds ratio = 3.42; 95%CI [1.13, 11.0]) in post-intervention FM. There were no significant differences in remaining measures. Implementing an interprofessional team intervention to improve family preparation and conduct of FM is locally feasible, acceptable, and changes clinician behaviors. Future research should assess broader impact of training on clinicians, patients, and families.

Expert consensus-based guidance on approaches to opioid management in individuals with advanced cancer-related pain and nonmedical stimulant use.

BACKGROUND: Clinicians treating cancer-related pain with opioids regularly encounter nonmedical stimulant use (i.e., methamphetamine, cocaine), yet there is little evidence-based management guidance. The aim of the study is to identify expert consensus on opioid management strategies for an individual with advanced cancer and cancer-related pain with nonmedical stimulant use according to prognosis. METHODS: The authors conducted two modified Delphi panels with palliative care and addiction experts. In Panel A, the patient's prognosis was weeks to months and in Panel B the prognosis was months to years. Experts reviewed, rated, and commented on the case using a 9-point Likert scale from 1 (very inappropriate) to 9 (very appropriate) and explained their responses. The authors applied the three-step analytical approach outlined in the RAND/UCLA to determine consensus and level of clinical appropriateness of management strategies. To better conceptualize the quantitative results, they thematically analyzed and coded participant comments. RESULTS: Consensus was achieved for all management strategies. The 120 Experts were mostly women (47 [62%]), White (94 [78%]), and physicians (115 [96%]). For a patient with cancer-related and nonmedical stimulant use, regardless of prognosis, it was deemed appropriate to continue opioids, increase monitoring, and avoid opioid tapering. Buprenorphine/naloxone transition was inappropriate for a patient with a short prognosis and of uncertain appropriateness for a patient with a longer prognosis. CONCLUSION: Study findings provide urgently needed consensus-based guidance for clinicians managing cancer-related pain in the context of stimulant use and highlight a critical need to develop management strategies to address stimulant use disorder in people with cancer. PLAIN LANGUAGE SUMMARY: Among palliative care and addiction experts, regardless of prognosis, it was deemed appropriate to continue opioids, increase monitoring, and avoid opioid tapering in the context of cancer-related pain and nonmedical stimulant use. Buprenorphine/naloxone transition as a harm reduction measure was inappropriate for a patient with a short prognosis and of uncertain appropriateness for a patient with a longer prognosis.

Factors Associated With Provision of Nonbeneficial Surgery: A National Survey of Surgeons.

OBJECTIVE: We tested the association of systems factors with the surgeon's likelihood of offering surgical intervention for older adults with life-limiting acute surgical conditions. BACKGROUND: Use of surgical treatments in the last year of life is frequent. Improved risk prediction and clinician communication are solutions proposed to improve serious illness care, yet systems factors may also drive receipt of nonbeneficial treatment. METHODS: We mailed a national survey to 5200 surgeons randomly selected from the American College of Surgeons database comprised of a clinical vignette describing a seriously ill older adult with an acute surgical condition, which utilized a 2×2 factorial design to assess patient and systems factors on receipt of surgical treatment to surgeons. RESULTS: Two thousand one hundred sixty-one surgeons responded for a weighted response rate of 53%. For an 87-year-old patient with fulminant colitis and advanced dementia or stage IV lung cancer, 40% of surgeons were inclined to offer an operation to remove the patient's colon while 60% were inclined to offer comfort-focused care only. Surgeons were more likely to offer surgery when an operating room was readily available (odds ratio: 4.05, P <0.001) and the family requests "do everything" (odds ratio: 2.18, P <0.001). CONCLUSIONS: Factors outside the surgeon's control contribute to nonbeneficial surgery, consistent with our model of clinical momentum. Further characterization of the systems in which these decisions occur might expose novel strategies to improve serious illness care for older patients and their families.

Disparities in Unilateral Do Not Resuscitate Order Use During the COVID-19 Pandemic.

OBJECTIVES: A unilateral do-not-resuscitate (UDNR) order is a do-not-resuscitate order placed using clinician judgment which does not require consent from a patient or surrogate. This study assessed how UDNR orders were used during the COVID-19 pandemic. DESIGN: We analyzed a retrospective cross-sectional study of UDNR use at two academic medical centers between April 2020 and April 2021. SETTING: Two academic medical centers in the Chicago metropolitan area. PATIENTS: Patients admitted to an ICU between April 2020 and April 2021 who received vasopressor or inotropic medications to select for patients with high severity of illness. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The 1,473 patients meeting inclusion criteria were 53% male, median age 64 (interquartile range, 54-73), and 38% died during admission or were discharged to hospice. Clinicians placed do not resuscitate orders for 41% of patients ( n = 604/1,473) and UDNR orders for 3% of patients ( n = 51/1,473). The absolute rate of UDNR orders was higher for patients who were primary Spanish speaking (10% Spanish vs 3% English; p ≤ 0.0001), were Hispanic or Latinx (7% Hispanic/Latinx vs 3% Black vs 2% White; p = 0.003), positive for COVID-19 (9% vs 3%; p ≤ 0.0001), or were intubated (5% vs 1%; p = 0.001). In the base multivariable logistic regression model including age, race/ethnicity, primary language spoken, and hospital location, Black race (adjusted odds ratio [aOR], 2.5; 95% CI, 1.3-4.9) and primary Spanish language (aOR, 4.4; 95% CI, 2.1-9.4) had higher odds of UDNR. After adjusting the base model for severity of illness, primary Spanish language remained associated with higher odds of UDNR order (aOR, 2.8; 95% CI, 1.7-4.7). CONCLUSIONS: In this multihospital study, UDNR orders were used more often for primary Spanish-speaking patients during the COVID-19 pandemic, which may be related to communication barriers Spanish-speaking patients and families experience. Further study is needed to assess UDNR use across hospitals and enact interventions to improve potential disparities.

Barriers of Acceptance to Hospice Care: a Randomized Vignette-Based Experiment.

BACKGROUND: The per diem financial structure of hospice care may lead agencies to consider patient-level factors when weighing admissions. OBJECTIVE: To investigate if treatment cost, disease complexity, and diagnosis are associated with hospice willingness to accept patients. DESIGN: In this 2019 online survey study, individuals involved in hospice admissions decisions were randomized to view one of six hypothetical patient vignettes: "high-cost, high-complexity," "low-cost, high-complexity," and "low-cost, low-complexity" within two diseases: heart failure and cystic fibrosis. Vignettes included demographics, prognoses, goals, and medications with costs. Respondents indicated their perceived likelihood of acceptance to their hospice; if likelihood was <100%, respondents were asked the barriers to acceptance. We used bivariate tests to examine associations between demographic, clinical, and organizational factors and likelihood of acceptance. PARTICIPANTS: Individuals involved in hospice admissions decisions MAIN MEASURES: Likelihood of acceptance to hospice care KEY RESULTS: N=495 (76% female, 53% age 45-64). Likelihoods of acceptance in cystic fibrosis were 79.8% (high-cost, high-complexity), 92.4% (low-cost, high-complexity), and 91.5% (low-cost, low-complexity), and in heart failure were 65.9% (high-cost, high-complexity), 87.3% (low-cost, high-complexity), and 96.6% (low-cost, low-complexity). For both heart failure and cystic fibrosis, respondents were less likely to accept the high-cost, high-complexity patient than the low-cost, high-complexity patient (65.9% vs. 87.3%, 79.8% vs. 92.4%, both p<0.001). For heart failure, respondents were less likely to accept the low-cost, high-complexity patient than the low-cost, low-complexity patient (87.3% vs. 96.6%, p=0.004). Treatment cost was the most common barrier for 5 of 6 vignettes. CONCLUSIONS: This study suggests that patients receiving expensive and/or complex treatments for palliation may have difficulty accessing hospice.

Gentamicin Eluting 3D-Printed Implants for Preventing Post-Surgical Infections in Bone Fractures.

A surgically implantable device is an inevitable treatment option for millions of people worldwide suffering from diseases arising from orthopedic injuries. A global paradigm shift is currently underway to tailor and personalize replacement or reconstructive joints. Additive manufacturing (AM) has provided dynamic outflow to the customized fabrication of orthopedic implants by enabling need-based design and surface modification possibilities. Surgical grade 316L Stainless Steel (316L SS) is promising with its cost, strength, composition, and corrosion resistance to fabricate 3D implants. This work investigates the possibilities of application of the laser powder bed fusion (L-PBF) technique to fabricate 3D-printed (3DP) implants, which are functionalized with a multilayered antimicrobial coating to treat potential complications arising due to postsurgical infections (PSIs). Postsurgical implant-associated infection is a primary reason for implantation failure and is complicated mainly by bacterial colonization and biofilm formation at the installation site. PLGA (poly-d,l-lactide-co-glycolide), a biodegradable polymer, was utilized to impart multiple layers of coating using the airbrush spray technique on 3DP implant surfaces loaded with gentamicin (GEN). Various PLGA-based polymers were tested to optimize the ideal lactic acid: glycolic acid ratio and molecular weight suited for our investigation. 3D-Printed PLGA-GEN substrates sustained the release of gentamicin from the surface for approximately 6 weeks. The 3DP surface modification with PLGA-GEN facilitated cell adhesion and proliferation compared to control surfaces. The cell viability studies showed that the implants were safe for application. The 3DP PLGA-GEN substrates showed good concentration-dependent antibacterial efficacy against the common PSI pathogen Staphylococcus aureus (S. aureus) and Staphylococcus epidermidis (S. epidermidis). The GEN-loaded substrates demonstrated antimicrobial longevity and showed significant biofilm growth inhibition compared to control. The substrates offered great versatility regarding the in vitro release rates, antimicrobial properties, and biocompatibility studies. These results radiate great potential in future human and veterinary clinical applications pertinent to complications arising from PSIs, focusing on personalized sustained antibiotic delivery.

Primary Palliative Care Improves Uptake of Advance Care Planning Among Patients With Advanced Cancers.

BACKGROUND: Palliative care specialists are experts in conducting advance care planning (ACP) but are a limited resource. Oncology nurses often have special relationships with their patients and thus may be poised to provide primary palliative care. We sought to determine the impact of a nurse-led primary palliative care intervention on ACP uptake among patients with advanced cancer. METHODS: We performed a secondary analysis of a cluster randomized controlled trial examining the impact of nurse-based primary palliative care. In the parent trial, patients with advanced cancer received either monthly primary palliative care visits with trained nurses within their cancer center or standard care. Nurses in the intervention arm received special training in ACP. ACP uptake was assessed at enrollment and 3 months later evaluating (1) whether an end-of-life conversation (EOLC) occurred with one's oncologist, and (2) completion of an advance directive (AD). Multivariable logistic regression tested differences in ACP uptake by treatment arm adjusted for age, religious importance, education, time with current oncologist, and performance status. RESULTS: Of 672 patients enrolled, 182/336 (54%) patients in the intervention arm and 196/336 (58%) in the standard care arm lacked an EOLC at baseline and completed the 3-month assessment. Of those, 82/182 (45.1%) patients in the intervention arm and 29/196 (14.8%) in the standard care arm reported having an EOLC at 3 months (adjusted odds ratio, 5.28; 95% CI, 3.10-8.97; P<.001). Similarly, 111/336 (33%) patients in the intervention arm and 105/336 (31%) in the standard care arm lacked an AD at baseline and completed the 3-month assessment. Of those, 48/111 (43.2%) patients in the intervention arm and 19/105 (18.1%) in the standard care arm completed an AD over the study period (adjusted odds ratio, 3.68; 95% CI, 1.89-7.16; P<.001). CONCLUSIONS: Nurse-led primary palliative care increased ACP uptake among patients with advanced cancer. Training oncology nurses embedded within community cancer centers to provide primary palliative care may help improve ACP access.

Prevalence of long-term decision regret and associated risk factors in a large cohort of ICU surrogate decision makers.

BACKGROUND: Whether surrogate decision makers regret decisions about the use of life support for incapacitated, critically ill patients remain uncertain. We sought to determine the prevalence of decision regret among surrogates of adult ICU patients and identify factors that influence regret. METHODS: We conducted a secondary analysis of data from the PARTNER 2 trial, which tested a family support intervention for surrogates of critically ill adults. At 6-month follow-up, surrogates rated their regret about life support decisions using the Decision Regret Scale (DRS), scored from 0 to 100, with higher scores indicating more regret. We used multiple linear regression to identify covariates associated with decision regret based on a psychological construct of regret. We constructed two models using the full cohort; model 1 included patient outcomes; model 2 focused on covariates known at the time of ICU decision-making. Subgroup analyses were also conducted based on patient survival status at hospital discharge and 6-month follow-up. RESULTS: 748 of 848 surrogates had complete DRS data. The median (IQR) DRS score was 15 (0, 25). Overall, 54% reported mild regret (DRS 5-25), 19% moderate-strong regret (DRS 30-100), and 27% no regret (DRS 0). Poor patient outcome at 6 months (death or severe functional dependence) was associated with more regret in model 1 (ß 10.1; 95% C.I. 3.2, 17.0). In model 2, palliative care consultation (3.0; 0.1, 5.9), limitations in life support (LS) prior to death (6.3; 3.1, 9.4) and surrogate black race (6.3; 0.3, 12.3) were associated with more regret. Other modulators of regret in subgroup analyses included surrogate age and education level, surrogate-patient relationship, death in hospital (compared to the post-discharge period), and code status at time of ICU admission. CONCLUSIONS: One in five ICU surrogate decision makers experience moderate to strong regret about life support decisions in ICU. Poor patient outcomes are linked to more regret. Decisions to limit life support prior to patient death may also increase regret. Future studies are needed to understand how regret relates to decision quality and how to lessen lasting regret.

Extended Exposure Topotecan Significantly Improves Long-Term Drug Sensitivity by Decreasing Malignant Cell Heterogeneity and by Preventing Epithelial-Mesenchymal Transition.

Maximum tolerable dosing (MTD) of chemotherapeutics has long been the gold standard for aggressive malignancies. Recently, alternative dosing strategies have gained traction for their improved toxicity profiles and unique mechanisms of action, such as inhibition of angiogenesis and stimulation of immunity. In this article, we investigated whether extended exposure (EE) topotecan could improve long-term drug sensitivity by preventing drug resistance. To achieve significantly longer exposure times, we used a spheroidal model system of castration-resistant prostate cancer. We also used state-of-the-art transcriptomic analysis to further elucidate any underlying phenotypic changes that occurred in the malignant population following each treatment. We determined that EE topotecan had a much higher barrier to resistance relative to MTD topotecan and was able to maintain consistent efficacy throughout the study period (EE IC50 of 54.4 nM (Week 6) vs. MTD IC50 of 2200 nM (Week 6) vs. 83.8 nM IC50 for control (Week 6) vs. 37.8 nM IC50 for control (Week 0)). As a possible explanation for these results, we determined that MTD topotecan stimulated epithelial-mesenchymal transition (EMT), upregulated efflux pumps, and produced altered topoisomerases relative to EE topotecan. Overall, EE topotecan resulted in a more sustained treatment response and maintained a less aggressive malignant phenotype relative to MTD topotecan.

MANAGEMENT OF SUSPECTED DILATED CARDIOMYOPATHY WITH PIMOBENDAN IN TWO LEOPARD SHARKS (TRIAKIS SEMIFASCIATA).

Two adult male leopard sharks (Triakis semifasciata) under managed care were diagnosed with suspected dilated cardiomyopathy. Clinical signs included lethargy, inappetence, and regurgitation. On cardiac ultrasound, fractional shortening was 14% and 10%, respectively (versus 21%-31% in four healthy conspecifics). Ventricular end-diastolic diameter to body weight ratio was 1.72 cm/kg in Case 1 (versus 0.52-1.24 cm/kg in four conspecifics). These results collectively suggested a dilated cardiomyopathy. Treatment was implemented with oral pimobendan at 0.3 mg/kg q48h for 1 mon. The pimobendan dose was increased to 0.5 mg/kg 3/wk, following plasmatic dosage of pimobendan and its metabolite. After 3 mon, fractional shortening increased to 38% and 20%, respectively, sharks regained a normal appetite, and body weight increased by 50% in one individual. After 2 yr, both individuals remained clinically normal, and no adverse effect was noted with pimobendan administration. Pimobendan plasma concentration suggested that this medication was well absorbed in this species.

Hope and advance care planning in advanced cancer: Is there a relationship?

BACKGROUND: Clinicians often cite a fear of giving up hope as a reason they defer advance care planning (ACP) among patients with advanced cancer. The objective of this study was to determine whether engagement in ACP affects hope in these patients. METHODS: This was a secondary analysis of a randomized controlled trial of primary palliative care in advanced cancer. Patients who had not completed ACP at baseline were included in the analysis. ACP was assessed in the forms of an end-of-life (EOL) conversation with one's oncologist and completion of a living will or advance directive (AD). Measurements were obtained at baseline and at 3 months. Hope was measured using the Herth Hope Index (HHI) (range, 12-48; higher scores indicate higher hope). Multivariate regression was performed to assess associations between ACP and hope, controlling for baseline HHI score, study randomization, patient age, religious importance, education, marital status, socioeconomic status, time since cancer diagnosis, pain/symptom burden (Edmonton Symptom Assessment System), and anxiety/depression score (Hospital Anxiety and Depression Scale)-all variables known to be associated with ACP and/or hope. RESULTS: In total, 672 patients with advanced cancer were enrolled in the overall study. The mean age was 69 ± 10 years, and the most common cancer types were lung cancer (36%), gastrointestinal cancer (20%) and breast/gynecologic cancers (16%). In this group, 378 patients (56%) had not had an EOL conversation at baseline, of whom 111 of 378 (29%) reported having an EOL conversation by 3 months. Hope was not different between patients who did or did not have an EOL conversation over the study period (mean ± standard deviation ∆HHI, 0.20 ± 5.32 vs -0.53 ± 3.80, respectively; P = .136). After multivariable adjustment, hope was significantly increased in patients who had engaged in an EOL conversation (adjusted mean difference in ∆HHI, 0.95; 95% CI, 0.08-1.82; P = .032). Similarly, of 216 patients (32%) without an AD at baseline, 67 (31%) had subsequently completed an AD. Unadjusted hope was not different between those who did and did not complete an AD (∆HHI, 0.20 ± 3.89 vs -0.91 ± 4.50, respectively; P = .085). After adjustment, hope was significantly higher in those who completed an AD (adjusted mean difference in ∆HHI, 1.31; 95% CI, 0.13-2.49; P = .030). CONCLUSIONS: The current results demonstrate that hope is not decreased after engagement in ACP and indeed may be increased. These findings may provide reassurance to clinicians who are apprehensive about having these important and difficult conversations. LAY SUMMARY: Many oncologists defer advance care planning (ACP) out of concern for giving up hope. This study demonstrates that hope is not decreased in patients who have engaged in ACP either as a conversation with their oncologists or by completing an advance directive. With this information, providers may feel more comfortable having these important conversations with their patients.

The Association Between Factors Promoting Nonbeneficial Surgery and Moral Distress: A National Survey of Surgeons.

OBJECTIVE: To assess the prevalence of moral distress among surgeons and test the association between factors promoting non-beneficial surgery and surgeons' moral distress. SUMMARY BACKGROUND DATA: Moral distress experienced by clinicians can lead to low-quality care and burnout. Older adults increasingly receive invasive treatments at the end of life that may contribute to surgeons' moral distress, particularly when external factors, such as pressure from colleagues, institutional norms, or social demands, push them to offer surgery they consider non-beneficial. METHODS: We mailed surveys to 5200 surgeons randomly selected from the American College of Surgeons membership, which included questions adapted from the revised Moral Distress Scale. We then analyzed the association between factors influencing the decision to offer surgery to seriously ill older adults and surgeons' moral distress. RESULTS: The weighted adjusted response rate was 53% (n = 2161). Respondents whose decision to offer surgery was influenced by their belief that pursuing surgery gives the patient or family time to cope with the patient's condition were more likely to have high moral distress (34% vs 22%, P < 0.001), and this persisted on multivariate analysis (odds ratio 1.44, 95% confidence interval 1.02-2.03). Time required to discuss nonoperative treatments or the consulting intensivists' endorsement of operative intervention, were not associated with high surgeon moral distress. CONCLUSIONS: Surgeons experience moral distress when they feel pressured to perform surgery they believe provides no clear patient benefit. Strategies that empower surgeons to recommend nonsurgical treatments when they believe this is in the patient's best interest may reduce nonbeneficial surgery and surgeon moral distress.

The Andrographolide Analogue 3A.1 Synergizes with Taxane Derivatives in Aggressive Metastatic Prostate Cancers by Upregulation of Heat Shock Proteins and Downregulation of MAT2A-Mediated Cell Migration and Invasion.

Conventional treatment with taxanes (docetaxel-DTX or cabazitaxel-CBZ) increases the survival rates of patients with aggressive metastatic castration-resistant prostate cancer (mCRPC); however, most patients acquire resistance to taxanes. The andrographolide analog, 19-tert-butyldiphenylsilyl-8,7-epoxy andrographolide (3A.1), has shown anticancer activity against various cancers. In this study, we investigated the effect of 3A.1 alone and in combination with DTX/CBZ against mCRPC and their mechanism of action. Exposure to 3A.1 alone exhibited a dose- and time-dependent antitumor activity in mCRPC. Chou-Talalay's combination index (CI) values of all 3A.1 + TX combinations were less than 0.5, indicating synergism. Co-treatment of 3A.1 with TX reduced the required dose of DTX and CBZ (P < 0.05). Caspase assay (apoptosis) results concurred with in vitro cytotoxicity data. RNA sequencing (RNAseq), followed by ingenuity pathway analysis (IPA), identified that upregulation of heat-shock proteins (Hsp70, Hsp40, Hsp27, and Hsp90) and downregulation of MAT2A as the key player for 3A.1 response. Furthermore, the top treatment-induced differentially expressed genes (DEGs) belong to DNA damage, cell migration, hypoxia, autophagy (MMP1, MMP9, HIF-1α, Bag-3, H2AX, HMOX1, PSRC1), and cancer progression pathways. Most importantly, top downregulated DEG MAT2A has earlier been shown to be involved in cell migration and invasion. Furthermore, using in silico analysis on the Cancer Genome Atlas (TCGA) database, this study found that MAT2A and highly co-expressed (r > 0.7) genes, TRA2B and SF1, were associated with worse Gleason score and nodal metastasis status in prostate adenocarcinoma patients (PRAD-TCGA). Immunoblotting, comet, and migration assays corroborated these findings. These results suggest that 3A.1 may be useful in increasing the anticancer efficacy of taxanes to treat aggressive PCa. SIGNIFICANCE STATEMENT: The andrographolide analogue, 19-tert-butyldiphenylsilyl-8,7-epoxy andrographolide (3A.1), showed anticancer activity against metastatic castration-resistant and neuroendocrine variant prostate cancers (mCRPC/NEPC). Additionally, 3A.1 exhibited synergistic anticancer effect in combination with standard chemotherapy drugs docetaxel and cabazitaxel in mCRPC/NEPC. Post-treatment gene expression studies revealed that heat shock proteins (Hsp70, Hsp40, Hsp27, and Hsp90) and MAT2A are important in the mechanism of 3A.1 action and drug response. Furthermore, DNA damage, cell migration, hypoxia, and autophagy were crucial pathways for the anticancer activity of 3A.1.