Sex hormone signaling and regulation of immune function.

Immune responses to antigens, including innocuous, self, tumor, microbial, and vaccine antigens, differ between males and females. The quest to uncover the mechanisms for biological sex differences in the immune system has intensified, with considerable literature pointing toward sex hormonal influences on immune cell function. Sex steroids, including estrogens, androgens, and progestins, have profound effects on immune function. As such, drastic changes in sex steroid concentrations that occur with aging (e.g., after puberty or during the menopause transition) or pregnancy impact immune responses and the pathogenesis of immune-related diseases. The effect of sex steroids on immunity involves both the concentration of the ligand and the density and distribution of genomic and nongenomic receptors that serve as transcriptional regulators of immune cellular responses to affect autoimmunity, allergy, infectious diseases, cancers, and responses to vaccines. The next frontier will be harnessing these effects of sex steroids to improve therapeutic outcomes.

Older adult participation in cancer clinical trials: A systematic review of barriers and interventions.

Cancer is a disease of aging and, as the world's population ages, the number of older persons with cancer is increasing and will make up a growing share of the oncology population in virtually every country. Despite this, older patients remain vastly underrepresented in research that sets the standards for cancer treatments. Consequently, most of what we know about cancer therapeutics is based on clinical trials conducted in younger, healthier patients, and effective strategies to improve clinical trial participation of older adults with cancer remain sparse. For this systematic review, the authors evaluated published studies regarding barriers to participation and interventions to improve participation of older adults in cancer trials. The quality of the available evidence was low and, despite a literature describing multifaceted barriers, only one intervention study aimed to increase enrollment of older adults in trials. The findings starkly amplify the paucity of evidence-based, effective strategies to improve participation of this underrepresented population in cancer trials. Within these limitations, the authors provide their opinion on how the current cancer research infrastructure must be modified to accommodate the needs of older patients. Several underused solutions are offered to expand clinical trials to include older adults with cancer. However, as currently constructed, these recommendations alone will not solve the evidence gap in geriatric oncology, and efforts are needed to meet older and frail adults where they are by expanding clinical trials designed specifically for this population and leveraging real-world data.

Cardio-oncology care in the era of the coronavirus disease 2019 (COVID-19) pandemic: An International Cardio-Oncology Society (ICOS) statement.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has given rise to a pandemic of unprecedented proportions in the modern era because of its highly contagious nature and impact on human health and society: coronavirus disease 2019 (COVID-19). Patients with cardiovascular (CV) risk factors and established CV disease (CVD) are among those initially identified at the highest risk for serious complications, including death. Subsequent studies have pointed out that patients with cancer are also at high risk for a critical disease course. Therefore, the most vulnerable patients are seemingly those with both cancer and CVD, and a careful, unified approach in the evaluation and management of this patient population is especially needed in times of the COVID-19 pandemic. This review provides an overview of the unique implications of the viral outbreak for the field of cardio-oncology and outlines key modifications in the approach to this ever-increasing patient population. These modifications include a shift toward greater utilization of cardiac biomarkers and a more focused CV imaging approach in the broader context of modifications to typical practice pathways. The goal of this strategic adjustment is to minimize the risk of SARS-CoV-2 infection (or other future viral outbreaks) while not becoming negligent of CVD and its important impact on the overall outcomes of patients who are being treated for cancer.

A high-throughput screening platform for enzymes active on mucin-type O-glycoproteins.

Mucin-type O-glycosylation is a post-translational modification present at the interface between cells where it has important roles in cellular communication. However, deciphering the function of O-glycoproteins and O-glycans can be challenging, especially as few enzymes are available for their assembly or selective degradation. Here, to address this deficiency, we developed a genetically encoded screening methodology for the discovery and engineering of the diverse classes of enzymes that act on O-glycoproteins. The method uses Escherichia coli that have been engineered to produce an O-glycosylated fluorescence resonance energy transfer probe that can be used to screen for O-glycopeptidase activity. Subsequent cleavage of the substrate by O-glycopeptidases provides a read-out of the glycosylation state of the probe, allowing the method to also be used to assay glycosidases and glycosyltransferases. We further show the potential of this methodology in the first ultrahigh-throughput-directed evolution of an O-glycopeptidase.

All mixed up: defining roles for ß-cell subtypes in mature islets.

Following differentiation during fetal development, ß cells further adapt to their postnatal role through functional maturation. While adult islets are thought to contain functionally mature ß cells, recent analyses of transgenic rodent and human pancreata reveal a number of novel heterogeneity markers in mammalian ß cells. The marked heterogeneity long after maturation raises the prospect that diverse populations harbor distinct roles aside from glucose-stimulated insulin secretion. In this review, we outline our current understanding of the ß-cell maturation process, emphasize recent literature on novel heterogeneity markers, and offer perspectives on reconciling the findings from these two areas.

Atrial arrhythmias following CAR-chimeric antigen receptor T-cell therapy: Incidence, risk factors and biomarker profile.

Recent reports have raised concerns about the association of chimeric antigen receptor T cell (CAR-T) with non-negligible cardiotoxicity, particularly atrial arrhythmias. First, we conducted a pharmacovigilance study to assess the reporting of atrial arrhythmias following CD19-directed CAR-T. Subsequently, to determine the incidence, risk factors and outcomes of atrial arrhythmias post-CAR-T, we compiled a retrospective single-centre cohort of non-Hodgkin lymphoma patients. Only commercial CAR-T products were considered. Atrial arrhythmias were nearly fourfold more likely to be reported after CAR-T therapy compared to all other cancer patients in the FAERS (adjusted ROR = 3.76 [95% CI 2.67-5.29]). Of the 236 patients in our institutional cohort, 23 (10%) developed atrial arrhythmias post-CAR-T, including 12 de novo arrhythmias, with most (83%) requiring medical intervention. Atrial arrhythmias frequently co-occurred with cytokine release syndrome and were associated with higher post-CAR-T infusion peak levels of IL-10, TNF-alpha and LDH, and lower trough levels of fibrinogen. In a multivariable analysis, risk factors for atrial arrhythmia were history of atrial arrhythmia (OR = 6.80 [2.39-19.6]) and using CAR-T product with a CD28-costimulatory domain (OR = 5.17 [1.72-18.6]). Atrial arrhythmias following CD19-CAR-T therapy are prevalent and associated with elevated inflammatory biomarkers, a history of atrial arrhythmia and the use of a CAR-T product with a CD28 costimulatory domain.

Management of Pericardial Effusion in Patients With Solid Tumor: An Algorithmic, Multidisciplinary Approach Results in Reduced Mortality After Paradoxical Hemodynamic Instability.

OBJECTIVE: This study compared outcomes in patients with solid tumor treated for pericardial effusion with surgical drainage versus interventional radiology (IR) percutaneous drainage and compared incidence of paradoxical hemodynamic instability (PHI) between cohorts. BACKGROUND: Patients with advanced-stage solid malignancies may develop large pericardial effusions requiring intervention. PHI is a fatal and underreported complication that occurs following pericardial effusion drainage. METHODS: Clinical characteristics and outcomes were compared between patients with solid tumors who underwent s urgical drainage or IR percutaneous drainage for pericardial effusion from 2010 to 2020. RESULTS: Among 447 patients, 243 were treated with surgical drainage, of which 27 (11%) developed PHI, compared with 7 of 204 patients (3%) who were treated with IR percutaneous drainage ( P =0.002); overall incidence of PHI decreased during the study period. Rates of reintervention (30-day: 1% vs 4%; 90-day: 4% vs 6%, P =0.7) and mortality (30-day: 21% vs 17%, P =0.3; 90-day: 39% vs 37%, P =0.7) were not different between patients treated with surgical drainage and IR percutaneous drainage. For both interventions, OS was shorter among patients with PHI than among patients without PHI (surgical drainage, median [95% confidence interval] OS, 0.89 mo [0.33-2.1] vs 6.5 mo [5.0-8.9], P <0.001; IR percutaneous drainage, 3.7 mo [0.23-6.8] vs 5.0 mo [4.0-8.1], P =0.044). CONCLUSIONS: With a coordinated multidisciplinary approach focusing on prompt clinical and echocardiographic evaluation, triage with bias toward IR percutaneous drainage than surgical drainage and postintervention intensive care resulted in lower incidence of PHI and improved outcomes.

Food Insecurity and Hypoglycemia among Older Patients with Type 2 Diabetes Treated with Insulin or Sulfonylureas: The Diabetes & Aging Study.

BACKGROUND: Severe hypoglycemia is a serious adverse drug event associated with hypoglycemia-prone medications; older patients with diabetes are particularly at high risk. Economic food insecurity (food insecurity due to financial limitations) is a known risk factor for hypoglycemia; however, less is known about physical food insecurity (due to difficulty cooking or shopping for food), which may increase with age, and its association with hypoglycemia. OBJECTIVE: Study associations between food insecurity and severe hypoglycemia. DESIGN: Survey based cross-sectional study. PARTICIPANTS: Survey responses were collected in 2019 from 1,164 older (≥ 65 years) patients with type 2 diabetes treated with insulin or sulfonylureas. MAIN MEASURES: Risk ratios (RR) for economic and physical food insecurity associated with self-reported severe hypoglycemia (low blood glucose requiring assistance) adjusted for age, financial strain, HbA1c, Charlson comorbidity score and frailty. Self-reported reasons for hypoglycemia endorsed by respondents. KEY RESULTS: Food insecurity was reported by 12.3% of the respondents; of whom 38.4% reported economic food insecurity only, 21.1% physical food insecurity only and 40.5% both. Economic food insecurity and physical food insecurity were strongly associated with severe hypoglycemia (RR = 4.3; p = 0.02 and RR = 4.4; p = 0.002, respectively). Missed meals ("skipped meals, not eating enough or waiting too long to eat") was the dominant reason (77.5%) given for hypoglycemia. CONCLUSIONS: Hypoglycemia prevention efforts among older patients with diabetes using hypoglycemia-prone medications should address food insecurity. Standard food insecurity questions, which are used to identify economic food insecurity, will fail to identify patients who have physical food insecurity only.

Biomarkers and cardiovascular outcomes in chimeric antigen receptor T-cell therapy recipients.

AIMS: Chimeric antigen receptor T-cell therapy (CAR-T) harnesses a patient's immune system to target cancer. There are sparse existing data characterizing death outcomes after CAR-T-related cardiotoxicity. This study examines the association between CAR-T-related severe cardiovascular events (SCE) and mortality. METHODS AND RESULTS: From a multi-centre registry of 202 patients receiving anti-CD19 CAR-T, covariates including standard baseline cardiovascular and cancer parameters and biomarkers were collected. Severe cardiovascular events were defined as a composite of heart failure, cardiogenic shock, or myocardial infarction. Thirty-three patients experienced SCE, and 108 patients died during a median follow-up of 297 (interquartile range 104-647) days. Those that did and did not die after CAR-T were similar in age, sex, and prior anthracycline use. Those who died had higher peak interleukin (IL)-6 and ferritin levels after CAR-T infusion, and those who experienced SCE had higher peak IL-6, C-reactive protein (CRP), ferritin, and troponin levels. The day-100 and 1-year Kaplan-Meier overall mortality estimates were 18% and 43%, respectively, while the non-relapse mortality (NRM) cumulative incidence rates were 3.5% and 6.7%, respectively. In a Cox model, SCE occurrence following CAR-T was independently associated with increased overall mortality risk [hazard ratio (HR) 2.8, 95% confidence interval (CI) 1.6-4.7] after adjusting for age, cancer type and burden, anthracycline use, cytokine release syndrome grade ≥ 2, pre-existing heart failure, hypertension, and African American ancestry; SCEs were independently associated with increased NRM (HR 3.5, 95% CI 1.4-8.8) after adjusting for cancer burden. CONCLUSION: Chimeric antigen receptor T-cell therapy recipients who experience SCE have higher overall mortality and NRM and higher peak levels of IL-6, CRP, ferritin, and troponin.

Alignment in Total Knee Arthroplasty: Avoid Crossing Over From Varus to Valgus.

BACKGROUND: Ideal target limb alignment remains a debated topic in total knee arthroplasty (TKA). We aimed to determine the effect of limb alignment correction on patient-reported outcomes and knee range of motion (ROM) following TKA. METHODS: In this retrospective analysis, patients (N = 409) undergoing primary TKA at a single institution were studied. Using full leg-length radiographs, limb alignment was measured preoperatively and postoperatively. Patients were categorized by preoperative (Preop) alignment (varus > 0°; valgus < 0°). Preop varus patients were then divided as follows based on postoperative alignment: neutral (VAR-NEUT, 0°± 2), remaining in varus (VAR-rVAR, ≥3°), and cross-over to valgus (VAR-CO, ≤-3°). Similarly, Preop valgus patients were divided as follows for postoperative alignment: neutral (VAL-NEUT, 0°± 2), remaining in valgus (VAL-rVAL, ≤-3°), and cross-over to varus (VAL-CO, ≥3°). The Knee Injury and Osteoarthritis Outcome Score for Joint Replacement survey scores were collected at preoperatively as well as at 6 weeks, 3, 6, and 12 months postoperatively. Knee ROM was collected at 2 weeks, 6 to 12 weeks, and >6 months postoperatively. An analysis of variance repeated on time followed by a Bonferroni post hoc test was used to compare outcomes for the postoperative alignment subgroups. RESULTS: Preop Varus patients: Those in the VAR-CO group (overcorrected to -4.03° ± 1.95valgus) were observed to have lower Knee Injury and Osteoarthritis Outcome Score for Joint Replacement scores at 3, 6, and 12 months postoperatively compared to those in the NEUT group (P < .05). This finding was paired with reduced ROM at 6 to 12 weeks postoperatively in the VAR-CO group compared to VAR-NEUT and VAR-rVAR (P < .05). Preop Valgus patients: Those in the VAL-rVal group (left in -4.39° ± 1.39valgus) were observed to have reduced knee flexion at 6 to 12 weeks postoperatively compared to VAL-NEUT and VAL-CO. CONCLUSIONS: These findings indicate that postoperative valgus alignment via either crossing over to valgus (VAR-CO) or remaining in valgus (VAL-rVAL) alignment may result in less preferable outcomes than correction to neutral or slightly varus alignment.

Functional similarity of ABP 959 and eculizumab in simulated serum models of aHUS and NMOSD.

ABP 959 is being developed as a biosimilar to Soliris® (eculizumab) reference product (RP), which was approved under orphan designation for a group of rare diseases including paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), generalized myasthenia gravis (gMG), and neuromyelitis optica spectrum disorder (NMOSD). Development of biosimilars for therapeutics approved for rare disease indications must provide scientific rationale based on the totality of evidence (TOE). To support the TOE and the scientific justification for extrapolation to all approved indications for eculizumab RP, including but not limited to aHUS and NMOSD, we utilized simulated ex-vivo pharmacodynamic (PD) assessments to compare the complement component 5 (C5) inhibitory activity of ABP 959 and the RP. Hemolysis activity of CH50 and AH50, and Wieslab CP, AP, and LP endpoints represent the three complement activation pathways (classical, alternative, and lectin), all of which share the terminal pathway and require C5 for activity. These endpoints were evaluated in normal serum, simulated aHUS serum, and simulated NMOSD serum to provide a robust comparison. The results support the conclusion that ABP 959 and eculizumab RP exhibit highly similar inhibition of C5 function regardless of the type of serum used. This work presents a full comparison of the effect of C5 inhibition across five complement functional assays. Using this approach to confirm functional similarity of ABP 959 with eculizumab RP contributes to the TOE for biosimilarity and provides support for extrapolation based on inhibition of C5 function to other rare disease indications approved for eculizumab RP.

Defining cardiovascular toxicities of cancer therapies: an International Cardio-Oncology Society (IC-OS) consensus statement.

The discipline of Cardio-Oncology has seen tremendous growth over the past decade. It is devoted to the cardiovascular (CV) care of the cancer patient, especially to the mitigation and management of CV complications or toxicities of cancer therapies, which can have profound implications on prognosis. To that effect, many studies have assessed CV toxicities in patients undergoing various types of cancer therapies; however, direct comparisons have proven difficult due to lack of uniformity in CV toxicity endpoints. Similarly, in clinical practice, there can be substantial differences in the understanding of what constitutes CV toxicity, which can lead to significant variation in patient management and outcomes. This document addresses these issues and provides consensus definitions for the most commonly reported CV toxicities, including cardiomyopathy/heart failure and myocarditis, vascular toxicity, and hypertension, as well as arrhythmias and QTc prolongation. The current document reflects a harmonizing review of the current landscape in CV toxicities and the definitions used to define these. This consensus effort aims to provide a structure for definitions of CV toxicity in the clinic and for future research. It will be important to link the definitions outlined herein to outcomes in clinical practice and CV endpoints in clinical trials. It should facilitate communication across various disciplines to improve clinical outcomes for cancer patients with CV diseases.

Time of day as a critical variable in biology.

BACKGROUND: Circadian rhythms are important for all aspects of biology; virtually every aspect of biological function varies according to time of day. Although this is well known, variation across the day is also often ignored in the design and reporting of research. For this review, we analyzed the top 50 cited papers across 10 major domains of the biological sciences in the calendar year 2015. We repeated this analysis for the year 2019, hypothesizing that the awarding of a Nobel Prize in 2017 for achievements in the field of circadian biology would highlight the importance of circadian rhythms for scientists across many disciplines, and improve time-of-day reporting. RESULTS: Our analyses of these 1000 empirical papers, however, revealed that most failed to include sufficient temporal details when describing experimental methods and that few systematic differences in time-of-day reporting existed between 2015 and 2019. Overall, only 6.1% of reports included time-of-day information about experimental measures and manipulations sufficient to permit replication. CONCLUSIONS: Circadian rhythms are a defining feature of biological systems, and knowing when in the circadian day these systems are evaluated is fundamentally important information. Failing to account for time of day hampers reproducibility across laboratories, complicates interpretation of results, and reduces the value of data based predominantly on nocturnal animals when extrapolating to diurnal humans.

Delayed Arterial Bleed After Pulmonary Lobectomy.

BACKGROUND: Postlobectomy hemorrhage is rare. The majority of the bleeding happens early after surgery, with the median time to reoperation being 17 hours. CASE REPORT: A 64-year-old man with a lung nodule underwent video-assisted thoracic surgery right upper lobectomy 3 weeks prior and presented to the Emergency Department (ED) with acute-onset chest pain and shortness of breath in the setting of delayed hemothorax from acute intercostal artery bleeding. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The vast majority of the patients presenting to the ED with a hemothorax have a known history of trauma. It is important for emergency physicians to consider and recognize hemothorax in nontraumatic patients, especially those who underwent recent lung surgeries. Delayed postoperative hemorrhage is rare but possible, and can be life threatening.

Circadian Rhythms Disrupted by Light at Night and Mistimed Food Intake Alter Hormonal Rhythms and Metabolism.

Availability of artificial light and light-emitting devices have altered human temporal life, allowing 24-hour healthcare, commerce and production, and expanding social life around the clock. However, physiology and behavior that evolved in the context of 24 h solar days are frequently perturbed by exposure to artificial light at night. This is particularly salient in the context of circadian rhythms, the result of endogenous biological clocks with a rhythm of ~24 h. Circadian rhythms govern the temporal features of physiology and behavior, and are set to precisely 24 h primarily by exposure to light during the solar day, though other factors, such as the timing of meals, can also affect circadian rhythms. Circadian rhythms are significantly affected by night shift work because of exposure to nocturnal light, electronic devices, and shifts in the timing of meals. Night shift workers are at increased risk for metabolic disorder, as well as several types of cancer. Others who are exposed to artificial light at night or late mealtimes also show disrupted circadian rhythms and increased metabolic and cardiac disorders. It is imperative to understand how disrupted circadian rhythms alter metabolic function to develop strategies to mitigate their negative effects. In this review, we provide an introduction to circadian rhythms, physiological regulation of homeostasis by the suprachiasmatic nucleus (SCN), and SCN-mediated hormones that display circadian rhythms, including melatonin and glucocorticoids. Next, we discuss circadian-gated physiological processes including sleep and food intake, followed by types of disrupted circadian rhythms and how modern lighting disrupts molecular clock rhythms. Lastly, we identify how disruptions to hormones and metabolism can increase susceptibility to metabolic syndrome and risk for cardiovascular diseases, and discuss various strategies to mitigate the harmful consequences associated with disrupted circadian rhythms on human health.

Effects of light pollution on photoperiod-driven seasonality.

Changes to photoperiod (day length) occur in anticipation of seasonal environmental changes, altering physiology and behavior to maximize fitness. In order for photoperiod to be useful as a predictive factor of temperature or food availability, day and night must be distinct. The increasing prevalence of exposure to artificial light at night (ALAN) in both field and laboratory settings disrupts photoperiodic time measurement and may block development of appropriate seasonal adaptations. Here, we review the effects of ALAN as a disruptor of photoperiodic time measurement and season-specific adaptations, including reproduction, metabolism, immune function, and thermoregulation.

Outcomes of a US-Sino family medicine leadership program.

BACKGROUND AND OBJECTIVES: The purpose of this study was to determine the outcomes of a two- week US-Sino Family Medicine Leadership Symposium for medical educators from China and how participants have integrated their learning into their teaching and practice of medicine. METHODS: Teaching topics emphasized principles of family medicine, teaching methods, assessment, and curriculum development. Each cohort received a wide range of practical, didactic and hands-on learning experiences. Online surveys were distributed anonymously to participants from the 2013-2019 cohorts to assess learner opinion and learner behavior change as a result of the leadership symposium. Quantitative measures assessed their level of integration of the topics into teaching and clinical practice and their satisfaction in the areas of teaching and leadership. They were also asked to provide qualitative feedback regarding incorporation of the content into their work. RESULTS: The survey response rate was 47.6% (39/82). Respondents stated that they incorporated topics such as basic interviewing skills and information on the patient-centered medical home into their teaching in China. The most applied clinical skills they were able to incorporate into their clinical environment in China included: Breaking Bad News, Simulations Sessions with practice, One-Minute Preceptor, and Interprofessional Education. CONCLUSIONS: Results indicate that participants have demonstrated behavior changes that have led to the incorporation of the content into teaching and clinical practice. We demonstrated effectiveness of the curriculum in cultivating the teaching and practice of family medicine. The program appears to be a positive experience that has led to embracement of the roles as trainer and leader. 100% of the participants who completed the survey felt that the program improved patient confidence in their ability as a family doctor. Future assessment on barriers to their progress as teachers and leaders in family medicine would be helpful to explore.

Risk stratification of cardiac metastases using late gadolinium enhancement cardiovascular magnetic resonance: prognostic impact of hypo-enhancement evidenced tumor avascularity.

BACKGROUND: Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) is widely used to identify cardiac neoplasms, for which diagnosis is predicated on enhancement stemming from lesion vascularity: Impact of contrast-enhancement pattern on clinical outcomes is unknown. The objective of this study was to determine whether cardiac metastasis (CMET) enhancement pattern on LGE-CMR impacts prognosis, with focus on heterogeneous lesion enhancement as a marker of tumor avascularity. METHODS: Advanced (stage IV) systemic cancer patients with and without CMET matched (1:1) by cancer etiology underwent a standardized CMR protocol. CMET was identified via established LGE-CMR criteria based on lesion enhancement; enhancement pattern was further classified as heterogeneous (enhancing and non-enhancing components) or diffuse and assessed via quantitative (contrast-to-noise ratio (CNR); signal-to-noise ratio (SNR)) analyses. Embolic events and mortality were tested in relation to lesion location and contrast-enhancement pattern. RESULTS: 224 patients were studied, including 112 patients with CMET and unaffected (CMET -) controls matched for systemic cancer etiology/stage. CMET enhancement pattern varied (53% heterogeneous, 47% diffuse). Quantitative analyses were consistent with lesion classification; CNR was higher and SNR lower in heterogeneously enhancing CMET (p < 0.001)-paralleled by larger size based on linear dimensions (p < 0.05). Contrast-enhancement pattern did not vary based on lesion location (p = NS). Embolic events were similar between patients with diffuse and heterogeneous lesions (p = NS) but varied by location: Patients with right-sided lesions had threefold more pulmonary emboli (20% vs. 6%, p = 0.02); those with left-sided lesions had lower rates equivalent to controls (4% vs. 5%, p = 1.00). Mortality was higher among patients with CMET (hazard ratio [HR] = 1.64 [CI 1.17-2.29], p = 0.004) compared to controls, but varied by contrast-enhancement pattern: Diffusely enhancing CMET had equivalent mortality to controls (p = 0.21) whereas prognosis was worse with heterogeneous CMET (p = 0.005) and more strongly predicted by heterogeneous enhancement (HR = 1.97 [CI 1.23-3.15], p = 0.005) than lesion size (HR = 1.11 per 10 cm [CI 0.53-2.33], p = 0.79). CONCLUSIONS: Contrast-enhancement pattern and location of CMET on CMR impacts prognosis. Embolic events vary by CMET location, with likelihood of PE greatest with right-sided lesions. Heterogeneous enhancement-a marker of tumor avascularity on LGE-CMR-is a novel marker of increased mortality risk.

Cardio-oncology Training in the COVID-19 Era.

OPINION STATEMENT: Cardio-oncology is a field dedicated to the prevention, diagnosis, and management of cardiovascular disease in cancer patients before, during, and after cancer therapy. It is an emerging field with limited opportunities for structured education and training. In the year 2021, we cannot define the requirements of cardio-oncology training without acknowledging the impact of the global coronavirus disease 19 (COVID-19) pandemic. While this pandemic poses significant health risks to patients with cancer and cardiovascular disease as well as the providers who care for them, it also allows novel opportunities for the nascent field of cardio-oncology to readily adapt. In this article, we detail how the COVID-19 pandemic has impacted all aspects of cardio-oncology training, how programs and trainees can adapt to these challenges, and how lessons learned from the COVID-19 era can continue to positively impact cardio-oncology training for the foreseeable future.

Challenges and solutions to employing natural language processing and machine learning to measure patients' health literacy and physician writing complexity: The ECLIPPSE study.

OBJECTIVE: In the National Library of Medicine funded ECLIPPSE Project (Employing Computational Linguistics to Improve Patient-Provider Secure Emails exchange), we attempted to create novel, valid, and scalable measures of both patients' health literacy (HL) and physicians' linguistic complexity by employing natural language processing (NLP) techniques and machine learning (ML). We applied these techniques to > 400,000 patients' and physicians' secure messages (SMs) exchanged via an electronic patient portal, developing and validating an automated patient literacy profile (LP) and physician complexity profile (CP). Herein, we describe the challenges faced and the solutions implemented during this innovative endeavor. MATERIALS AND METHODS: To describe challenges and solutions, we used two data sources: study documents and interviews with study investigators. Over the five years of the project, the team tracked their research process using a combination of Google Docs tools and an online team organization, tracking, and management tool (Asana). In year 5, the team convened a number of times to discuss, categorize, and code primary challenges and solutions. RESULTS: We identified 23 challenges and associated approaches that emerged from three overarching process domains: (1) Data Mining related to the SM corpus; (2) Analyses using NLP indices on the SM corpus; and (3) Interdisciplinary Collaboration. With respect to Data Mining, problems included cleaning SMs to enable analyses, removing hidden caregiver proxies (e.g., other family members) and Spanish language SMs, and culling SMs to ensure that only patients' primary care physicians were included. With respect to Analyses, critical decisions needed to be made as to which computational linguistic indices and ML approaches should be selected; how to enable the NLP-based linguistic indices tools to run smoothly and to extract meaningful data from a large corpus of medical text; and how to best assess content and predictive validities of both the LP and the CP. With respect to the Interdisciplinary Collaboration, because the research required engagement between clinicians, health services researchers, biomedical informaticians, linguists, and cognitive scientists, continual effort was needed to identify and reconcile differences in scientific terminologies and resolve confusion; arrive at common understanding of tasks that needed to be completed and priorities therein; reach compromises regarding what represents "meaningful findings" in health services vs. cognitive science research; and address constraints regarding potential transportability of the final LP and CP to different health care settings. DISCUSSION: Our study represents a process evaluation of an innovative research initiative to harness "big linguistic data" to estimate patient HL and physician linguistic complexity. Any of the challenges we identified, if left unaddressed, would have either rendered impossible the effort to generate LPs and CPs, or invalidated analytic results related to the LPs and CPs. Investigators undertaking similar research in HL or using computational linguistic methods to assess patient-clinician exchange will face similar challenges and may find our solutions helpful when designing and executing their health communications research.