Ischemic Stroke and Reduced Left Ventricular Ejection Fraction: A Multidisciplinary Approach to Optimize Brain and Cardiac Health.

Reduced left ventricular ejection fraction ≤40%, a known risk factor for adverse cardiac outcomes and recurrent acute ischemic stroke, may be detected during an acute ischemic stroke hospitalization. A multidisciplinary care paradigm informed by neurology and cardiology expertise may facilitate the timely implementation of an array of proven heart failure-specific therapies and procedures in a nuanced manner to optimize brain and cardiac health.

In-hospital safety outcomes of left atrial appendage occlusion in octogenarians and nonagenarians.

AIMS: Data on safety outcomes of left atrial appendage occlusion (LAAO) in elderly patients are limited. This study aimed to compare the outcomes of LAAO between octogenarians (age 80-89) and nonagenarians (age ≥90) vs. younger patients (age ≤79). METHODS AND RESULTS: We conducted a retrospective cohort study using the National Inpatient Sample database to identify patients hospitalized for LAAO from 2016 to 2020 and to compare in-hospital safety outcomes in octogenarians and nonagenarians vs. younger patients. The primary outcome was a composite of in-hospital all-cause mortality or stroke. Secondary outcomes included procedural complications, length of stay (LOS), and total costs. Outcomes were determined using logistic regression models. Among 84 140 patients hospitalized for LAAO, 32.9% were octogenarians, 2.8% were nonagenarians, and 64.3% were ≤79 years of age. Over the study period, the volume of LAAO increased in all age groups (all Ptrend < 0.01). After adjustment for clinical and demographic factors, octogenarians and nonagenarians had similar odds of in-hospital all-cause mortality or stroke [adjusted odds ratio (aOR) 1.41, 95% confidence interval (CI) 0.93-2.13 for octogenarians; aOR 1.69, 95% CI 0.67-3.92 for nonagenarians], cardiac tamponade, acute kidney injury, major bleeding, and blood transfusion, in addition to similar LOS and total costs compared with younger patients (all P > 0.05). However, octogenarians and nonagenarians had higher odds of vascular complications compared with younger patients (aOR 1.47, 95% CI 1.08-1.99 for octogenarians; aOR 1.60, 95% CI 1.18-2.97 for nonagenarians). CONCLUSION: Octogenarians and nonagenarians undergoing LAAO have a similar safety profile compared with clinically similar younger patients except for higher odds of vascular complications.

Research Opportunities in Stroke Prevention for Atrial Fibrillation: A Report From a National Heart, Lung, and Blood Institute Virtual Workshop.

Atrial fibrillation (AF) is one of the strongest risk factors for ischemic stroke, which is a leading cause of disability and death. Given the aging population, increasing prevalence of AF risk factors, and improved survival in those with cardiovascular disease, the number of individuals affected by AF will continue increasing over time. While multiple proven stroke prevention therapies exist, important questions remain about the optimal approach to stroke prevention at the population and individual patient levels. Our report summarizes the National Heart, Lung, and Blood Institute virtual workshop focused on identifying key research opportunities related to stroke prevention in AF. The workshop reviewed major knowledge gaps and identified targeted research opportunities to advance stroke prevention in AF in the following areas: (1) improving risk stratification tools for stroke and intracranial hemorrhage; (2) addressing challenges with oral anticoagulants; and (3) delineating the optimal roles of percutaneous left atrial appendage occlusion and surgical left atrial appendage closure/excision. This report aims to promote innovative, impactful research that will lead to more personalized, effective use of stroke prevention strategies in people with AF.

Rates and predictors of hospital and emergency department care after catheter ablation of atrial fibrillation.

INTRODUCTION: Although atrial fibrillation (AF) ablation has become increasingly safer, rehospitalization and emergency department (ED) evaluations can occur in the postablation period. Better understanding of the frequency, causes, and predictors for hospitalization and ED evaluation after ablation are needed, particularly as same-day discharge programs expand. METHODS: The Optum Clinformatics database was used to define rates, causes, and predictors of hospital and ED care after AF ablation performed between January 2016 and May 2019. Primary outcomes were all-cause hospital and ED care within 30 days of discharge. Independent predictors of all-cause ED and hospital admissions care were determined via logistic regression. RESULTS: Of the 18 848 patients in this study, the mean age was 67.5 ± 10 years, 37.9% were female, and the mean CHA2 DS2 -VASc score was 3.27 ± 1.84. Within 30 days of AF ablation, 1440 of 18 848 patients (7.6%) required hospital care of which 15% had >1 admission; 7.9% required ED care of which 28.6% had >1 ED visit. The most common reasons for hospital admission (which occurred on average 12.3 days after discharge) were supraventricular tachycardia (SVT) or AF (33.2%), heart failure (12.7%), and infection (12.2%). The most common reasons for ED care were SVT/AF (15.0%), noncardiac chest pain (13.3%), and noninfectious respiratory illness (12.2%). Age, female sex, ablation in an inpatient setting, and co-morbidities were associated with increased risk of rehospitalization. Age, female sex, patient comorbidities, and non-use of direct oral anticoagulation were associated with increased risk of ED visit. CONCLUSION: Approximately 7%-8% of patients require unplanned hospitalization or ED care after AF ablation, most commonly due to SVT/AF. Predictors of unscheduled care include patient age, sex, and several patient comorbidities. This study can inform quality improvement initiatives by identifying common causes for unscheduled care.

Watchman device migration and embolization: A report from the NCDR LAAO Registry.

INTRODUCTION: Incomplete anchoring of the Watchman left atrial appendage closure (LAAO) device can result in substantial device migration or device embolization (DME) requiring percutaneous or surgical retrieval. METHODS: We performed a retrospective analysis of Watchman procedures (January 2016 through March 2021) reported to the National Cardiovascular Data Registry LAAO Registry. We excluded patients with prior LAAO interventions, no device released, and missing device information. In-hospital events were assessed among all patients and postdischarge events were assessed among patients with 45-day follow-up. RESULTS: Of 120 278 Watchman procedures, the in-hospital DME rate was 0.07% (n = 84) and surgery was commonly performed (n = 39). In-hospital mortality rate was 14% among patients with DME and 20.5% among patients who underwent surgery. In-hospital DME was more common: at hospitals with a lower median annual procedure volume (24 vs. 41 procedures, p < .0001), with Watchman 2.5 versus Watchman FLX devices (0.08% vs. 0.04%, p = .0048), with larger LAA ostia (median 23 vs. 21 mm, p = .004), and with a smaller difference between device and LAA ostial size (median difference 4 vs. 5 mm, p = .04). Of 98 147 patients with 45-day follow-up, postdischarge DME occurred in 0.06% (n = 54) patients and cardiac surgery was performed in 7.4% (n = 4) of cases. The 45-day mortality rate was 3.7% (n = 2) among patients with postdischarge DME. Postdischarge DME was more common among men (79.7% of events but 58.9% of all procedures, p = .0019), taller patients (177.9 vs. 172 cm, p = .0005), and those with greater body mass (99.9 vs. 85.5 kg, p = .0055). The rhythm at implant was less frequently AF among patients with DME compared to those without (38.9% vs. 46.9%, p = .0098). CONCLUSION: While Watchman DME is rare, it is associated with high mortality and frequently requires surgical retrieval, and a substantial proportion of events occur after discharge. Due to the severity of DME events, risk mitigation strategies and on-site cardiac surgical back-up are of paramount importance.

In-hospital complications associated with pulmonary vein isolation with adjunctive lesions: the NCDR AFib Ablation Registry.

AIMS: No prior study has been adequately powered to evaluate real-world safety outcomes in those receiving adjunctive ablation lesions beyond pulmonary vein isolation (PVI). We sought to evaluate characteristics and in-hospital complications among patients undergoing PVI with and without adjunctive lesions. METHODS AND RESULTS: Patients in the National Cardiovascular Data Registry AFib Ablation Registry undergoing first-time atrial fibrillation (AF) ablation between 2016 and 2020 were identified and stratified into paroxysmal (PAF) and persistent AF, and separated into PVI only, PVI + cavotricuspid isthmus (CTI) ablation, and PVI + adjunctive (superior vena cava isolation, coronary sinus, vein of Marshall, atypical atrial flutter lines, other). Adjusted odds of adverse events were calculated using multivariable logistic regression. A total of 50 937 patients [PAF: 30 551 (60%), persistent AF: 20 386 (40%)] were included. Among those with PAF, there were no differences in the adjusted odds of complications between PVI + CTI or PVI + adjunctive when compared with PVI only. Among persistent AF, PVI + adjunctive was associated with a higher risk of any complication [3.0 vs. 4.5%, odds ratio (OR) 1.30, 95% confidence interval (CI) 1.07-1.58] and major complication (0.8 vs. 1.4%, OR 1.56, 95% CI 1.10-2.21), while no differences were observed in PVI + CTI compared with PVI only. Overall, there was high heterogeneity in adjunctive lesion type, and those receiving adjunctive lesions had a higher comorbidity burden. CONCLUSION: Additional CTI ablation was common without an increased risk of complications. Adjunctive lesions other than CTI are commonly performed in those with more comorbidities and were associated with an increased risk of complications in persistent AF, although the current analysis is limited by high heterogeneity in adjunctive lesion set type.

Left Atrial Appendage Occlusion Versus Oral Anticoagulation in Atrial Fibrillation : A Decision Analysis.

BACKGROUND: Left atrial appendage occlusion (LAAO) is a potential alternative to oral anticoagulants in selected patients with atrial fibrillation (AF). Compared with anticoagulants, LAAO decreases major bleeding risk, but there is uncertainty regarding the risk for ischemic stroke compared with anticoagulation. OBJECTIVE: To determine the optimal strategy for stroke prevention conditional on a patient's individual risks for ischemic stroke and bleeding. DESIGN: Decision analysis with a Markov model. DATA SOURCES: Evidence from the published literature informed model inputs. TARGET POPULATION: Women and men with nonvalvular AF and without prior stroke. TIME HORIZON: Lifetime. PERSPECTIVE: Clinical. INTERVENTION: LAAO versus warfarin or direct oral anticoagulants (DOACs). OUTCOME MEASURES: The primary end point was clinical benefit measured in quality-adjusted life-years. RESULTS OF BASE-CASE ANALYSIS: The baseline risks for stroke and bleeding determined whether LAAO was preferred over anticoagulants in patients with AF. The combined risks favored LAAO for higher bleeding risk, but that benefit became less certain at higher stroke risks. For example, at a HAS-BLED score of 5, LAAO was favored in more than 80% of model simulations for CHA2DS2-VASc scores between 2 and 5. The probability of LAAO benefit in QALYs (>80%) at lower bleeding risks (HAS-BLED score of 0 to 1) was limited to patients with lower stroke risks (CHA2DS2-VASc score of 2). Because DOACs carry lower bleeding risks than warfarin, the net benefit of LAAO is less certain than that of DOACs. RESULTS OF SENSITIVITY ANALYSIS: Results were consistent using the ORBIT bleeding score instead of the HAS-BLED score, as well as alternative sources for LAAO clinical effectiveness data. LIMITATION: Clinical effectiveness data were drawn primarily from studies on the Watchman device. CONCLUSION: Although LAAO could be an alternative to anticoagulants for stroke prevention in patients with AF and high bleeding risk, the overall benefit from LAAO depends on the combination of stroke and bleeding risks in individual patients. These results suggest the need for a sufficiently low stroke risk for LAAO to be beneficial. The authors believe that these results could improve shared decision making when selecting patients for LAAO. PRIMARY FUNDING SOURCE: None.

Electronic Health Record Embedded Strategies for Improving Care of Patients With Heart Failure.

PURPOSE: A majority of clinical decisions use the electronic health record (EHR) and there is an unmet need to use its capability to help providers to make evidence-based decisions that improve care for heart failure patients. These electronic nudges are rooted in the human psychology of decision-making and often target specific cognitive biases. This review outlines the development of novel EHR nudges and specific lessons learned from each experience to inform the development of future interventions. RECENT FINDINGS: There have been several randomized clinical trials examining the impact of EHR alerts on quality of care for heart failure patients. These interventions have targeted both clinicians and patients. There are features of each trial that inform best practices and future directions for EHR nudges. Recent clinical trials have demonstrated that some EHR alerts can improve care for heart failure patients. These trials utilized default options, involved clinicians in the alert design process, provided actionable recommendations, and aimed to minimize disruptions to typical workflow. Alerts aimed at improving care should be examined in a randomized fashion in order to evaluate their impact on clinician satisfaction and patient care.

Abnormal left atrial body stiffness is predicted by appendage size: impact of appendage occlusion on left atrial mechanics assessed by pressure-volume analysis.

Atrial cardiomyopathy has been recognized as having important consequences for cardiac performance and clinical outcomes. The pathophysiological role of the left atrial (LA) appendage and the effect of percutaneous left atrial appendage occlusion (LAAO) upon LA mechanics is incompletely understood. We evaluated if changes in LA stiffness due to endocardial LAAO can be detected by LA pressure-volume (PV) analysis and whether stiffness parameters are associated with baseline characteristics. Patients undergoing percutaneous endocardial LAAO (n = 25) were studied using a novel PV analysis using near-simultaneous three-dimensional LA volume measurements by transesophageal echocardiography (TEE) and direct invasive LA pressure measurements. LA stiffness (dP/dV, change in pressure with change in volume) was calculated before and after LAAO. Overall LA stiffness significantly increased after LAAO compared with baseline (median, 0.41-0.64 mmHg/mL; P ≪ 0.001). LA body stiffness after LAAO correlated with baseline LA appendage size by indexed maximum depth (Spearman's rank correlation coefficient Rs = 0.61; P < 0.01). LA stiffness change showed an even stronger correlation with baseline LA appendage size by indexed maximum depth (Rs = 0.70; P < 0.001). We found that overall LA stiffness increases after endocardial LAAO. Baseline LA appendage size correlates with the magnitude of increase and LA body stiffness. These findings document alteration of LA mechanics after endocardial LAAO and suggest that the LA appendage modulates overall LA compliance.NEW & NOTEWORTHY Our study documents a correlation of LA appendage remodeling with the degree of chronically abnormal LA body stiffness. In addition, we found that LA appendage size was the baseline parameter that best correlated with the magnitude of a further increase in overall LA stiffness after appendage occlusion. These findings offer insights about the LA appendage and LA mechanics that are relevant to patients at risk for adverse atrial remodeling, especially candidates for LA appendage occlusion.

Risk and predictors of mortality after implantable cardioverter-defibrillator implantation in patients with sarcoid cardiomyopathy.

BACKGROUND: Implantable cardioverter-defibrillators (ICDs) are recommended for patients with cardiac sarcoidosis (CS) with an indication for pacing, prior ventricular arrhythmias, cardiac arrest, or left ventricular ejection fraction <35%, but data on outcomes are limited. METHODS: Using data from the National Cardiovascular Data Registry ICD Registry between April 1, 2010 and December 31, 2015, we evaluated a propensity matched cohort of CS patients implanted with ICDs versus non-ischemic cardiomyopathies (NICM). We compared mortality using Kaplan-Meier survival curves and Cox proportional hazards models. RESULTS: We identified 1,638 patients with CS and 8,190 propensity matched patients with NICM. The rate of death at 1 and 2 years was similar in patients with CS and patients with NICM (5.2% vs 5.4%, P = 0.75 and 9.0% vs 9.3%, P = 0.72, respectively). After adjusting for other covariates, patients with CS had similar mortality at 2 years after ICD implantations compared with NICM patients (RR 1.03, 95% CI 0.87-1.23). Among patients with CS, multivariable logistic regression identified 6 factors significantly associated with increased 2-year mortality: presence of heart failure (HR 1.92, 95% CI 1.44-3.22), New York Heart Association (NYHA) Class III heart failure (HR 1.68, 95% CI 1.16-2.45), NYHA Class IV heart failure (HR 3.08, 95% CI 1.49-6.39), atrial fibrillation/flutter (HR 1.66, 95% CI 1.17-2.35), chronic lung disease (HR 1.64, 95% CI 1.17-2.29), creatinine >2.0 mg/dL (HR 4.07, 95% CI 2.63-6.30), and paced rhythm (HR 2.66, 95% CI 1.07-6.59). CONCLUSION: Mortality following ICD implantation was similar in CS patients compared with propensity matched NICM patients. Presence of heart failure, NYHA class, atrial fibrillation/flutter, chronic lung disease, renal dysfunction, and paced rhythm at time of implantation were all predictors of increased 2-year mortality among CS patients with ICDs.

Development and validation of an automated algorithm for end point adjudication for a large U.S. national registry.

BACKGROUND: Clinical events committee (CEC) evaluation is the standard approach for end point adjudication in clinical trials. Due to resource constraints, large registries typically rely on site-reported end points without further confirmation, which may preclude use for regulatory oversight. METHODS: We developed a novel automated adjudication algorithm (AAA) for end point adjudication in the National Cardiovascular Data Registry Left Atrial Appendage Occlusion (LAAO) Registry using an iterative process using CEC adjudication as the "gold standard." A ≥80% agreement rate between automated algorithm adjudication and CEC adjudication was prespecified as clinically acceptable. Agreement rates were calculated. RESULTS: A total of 92 in-hospital and 127 post-discharge end points were evaluated between January 1, 2016 and June 30, 2019 using AAA and CEC. Agreement for neurologic events was >90%. Percent agreement for in-hospital and post-discharge events was as follows: ischemic stroke 95.7% and 94.5%, hemorrhagic stroke 97.8% and 96.1%, undetermined stroke 97.8% and 99.2%, transient ischemic attack 98.9% and 98.4% and intracranial hemorrhage 100.0% and 94.5%. Agreement was >80% for major bleeding (83.7% and 90.6%) and major vascular complication (89.1% and 97.6%). With this approach, <1% of site reported end points require CEC adjudication. Agreement remained very good during the period after algorithm derivation. CONCLUSIONS: An AAA-guided approach for end point adjudication was successfully developed and validated for the LAAO Registry. With this approach, the need for formal CEC adjudication was substantially reduced, with accuracy maintained above an 80% agreement threshold. After application specific validation, these methods could be applied to large registries and clinical trials to reduce the cost of event adjudication while preserving scientific validity.

Interlaboratory comparison of 25-hydroxyvitamin D assays: Vitamin D Standardization Program (VDSP) Intercomparison Study 2 - Part 2 ligand binding assays - impact of 25-hydroxyvitamin D2 and 24R,25-dihydroxyvitamin D3 on assay performance.

An interlaboratory comparison study was conducted by the Vitamin D Standardization Program (VDSP) to assess the performance of ligand binding assays (Part 2) for the determination of serum total 25-hydroxyvitamin D [25(OH)D]. Fifty single-donor samples were assigned target values for concentrations of 25-hydroxyvitamin D2 [25(OH)D2], 25-hydroxyvitamin D3 [25(OH)D3], 3-epi-25-hydroxyvitamin D3 [3-epi-25(OH)D3], and 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3] using isotope dilution liquid chromatography-tandem mass spectrometry (ID LC-MS/MS). VDSP Intercomparison Study 2 Part 2 includes results from 17 laboratories using 32 ligand binding assays. Assay performance was evaluated using mean % bias compared to the assigned target values and using linear regression analysis of the test assay mean results and the target values. Only 50% of the ligand binding assays achieved the VDSP criterion of mean % bias ≤ |± 5%|. For the 13 unique ligand binding assays evaluated in this study, only 4 assays were consistently within ± 5% mean bias and 4 assays were consistently outside ± 5% mean bias regardless of the laboratory performing the assay. Based on multivariable regression analysis using the concentrations of individual vitamin D metabolites in the 50 single-donor samples, most assays underestimate 25(OH)D2 and several assays (Abbott, bioMérieux, DiaSorin, IDS-EIA, and IDS-iSYS) may have cross-reactivity from 24R,25(OH)2D3. The results of this interlaboratory study represent the most comprehensive comparison of 25(OH)D ligand binding assays published to date and is the only study to assess the impact of 24R,25(OH)2D3 content using results from a reference measurement procedure.

Assessment of serum total 25-hydroxyvitamin D assays for Vitamin D External Quality Assessment Scheme (DEQAS) materials distributed at ambient and frozen conditions.

The Vitamin D External Quality Assessment Scheme (DEQAS) distributes human serum samples four times per year to over 1000 participants worldwide for the determination of total serum 25-hydroxyvitamin D [25(OH)D)]. These samples are stored at -40 °C prior to distribution and the participants are instructed to store the samples frozen at -20 °C or lower after receipt; however, the samples are shipped to participants at ambient conditions (i.e., no temperature control). To address the question of whether shipment at ambient conditions is sufficient for reliable performance of various 25(OH)D assays, the equivalence of DEQAS human serum samples shipped under frozen and ambient conditions was assessed. As part of a Vitamin D Standardization Program (VDSP) commutability study, two sets of the same nine DEQAS samples were shipped to participants at ambient temperature and frozen on dry ice. Twenty-eight laboratories participated in this study and provided 34 sets of results for the measurement of 25(OH)D using 20 ligand binding assays and 14 liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. Equivalence of the assay response for the frozen versus ambient DEQAS samples for each assay was evaluated using multi-level modeling, paired t-tests including a false discovery rate (FDR) approach, and ordinary least squares linear regression analysis of frozen versus ambient results. Using the paired t-test and confirmed by FDR testing, differences in the results for the ambient and frozen samples were found to be statistically significant at p < 0.05 for four assays (DiaSorin, DIAsource, Siemens, and SNIBE prototype). For all 14 LC-MS/MS assays, the differences in the results for the ambient- and frozen-shipped samples were not found to be significant at p < 0.05 indicating that these analytes were stable during shipment at ambient conditions. Even though assay results have been shown to vary considerably among different 25(OH)D assays in other studies, the results of this study also indicate that sample handling/transport conditions may influence 25(OH)D assay response for several assays.

Assessment of serum total 25-hydroxyvitamin D assay commutability of Standard Reference Materials and College of American Pathologists Accuracy-Based Vitamin D (ABVD) Scheme and Vitamin D External Quality Assessment Scheme (DEQAS) materials: Vitamin D Standardization Program (VDSP) Commutability Study 2.

An interlaboratory study was conducted through the Vitamin D Standardization Program (VDSP) to assess commutability of Standard Reference Materials® (SRMs) and proficiency testing/external quality assessment (PT/EQA) samples for determination of serum total 25-hydroxyvitamin D [25(OH)D] using ligand binding assays and liquid chromatography-tandem mass spectrometry (LC-MS/MS). A set of 50 single-donor serum samples were assigned target values for 25-hydroxyvitamin D2 [25(OH)D2] and 25-hydroxyvitamin D3 [25(OH)D3] using reference measurement procedures (RMPs). SRM and PT/EQA samples evaluated included SRM 972a (four levels), SRM 2973, six College of American Pathologists (CAP) Accuracy-Based Vitamin D (ABVD) samples, and nine Vitamin D External Quality Assessment Scheme (DEQAS) samples. Results were received from 28 different laboratories using 20 ligand binding assays and 14 LC-MS/MS methods. Using the test assay results for total serum 25(OH)D (i.e., the sum of 25(OH)D2 and 25(OH)D3) determined for the single-donor samples and the RMP target values, the linear regression and 95% prediction intervals (PIs) were calculated. Using a subset of 42 samples that had concentrations of 25(OH)D2 below 30 nmol/L, one or more of the SRM and PT/EQA samples with high concentrations of 25(OH)D2 were deemed non-commutable using 5 of 11 unique ligand binding assays. SRM 972a (level 4), which has high exogenous concentration of 3-epi-25(OH)D3, was deemed non-commutable for 50% of the LC-MS/MS assays.

Cannabis use disorder among atrial fibrillation admissions, 2008-2018.

BACKGROUND: Despite changes inthe legality of cannabis use and the increasing prevalence of cannabis use disorder (CUD), there is little data investigating the association between CUD and inpatient atrial fibrillation (AF) hospitalizations. METHODS: Using the National Inpatient Sample, we identified Atrial Fibrillation (AF) hospitalizations with and without a codiagnosis of CUD using International Classification of Diseases diagnosis codes and compared demographics, socioeconomics, comorbidities, outcomes, and trends between cohorts. RESULTS: Between 2008 and 2018, we identified 5,155,789 admissions for AF of which 31,768 (0.6%) had a codiagnosis of CUD. The proportion of admissions with a history of CUD increased from 0.3% in 2008 to 1.0% in 2018 (p < .001). Hospital discharges of patients with CUD were significantly younger (53 vs. 72 years, p < .001), had a higher proportion of black race (CUD: 26.6% vs. 8.0%, p < .001), and had a higher proportion of income in the lowest income quartile than without a codiagnosis of CUD (CUD: 40.5% vs. 26.2%, p < .001). CONCLUSIONS: CUD is increasingly prevalent among AF hospitalizations, particularly among young patients. Codiagnosis of CUD in AF hospitalizations is also more common in underserved patients. As a result, it is important for future research to examine and understand the impact of CUD on this population, particularly in the light of changing legislation surrounding the legality of cannabis.

Characterization of the Inflammatory Response to Severe COVID-19 Illness.

Rationale: Coronavirus disease (COVID-19) is a global threat to health. Its inflammatory characteristics are incompletely understood.Objectives: To define the cytokine profile of COVID-19 and to identify evidence of immunometabolic alterations in those with severe illness.Methods: Levels of IL-1ß, IL-6, IL-8, IL-10, and sTNFR1 (soluble tumor necrosis factor receptor 1) were assessed in plasma from healthy volunteers, hospitalized but stable patients with COVID-19 (COVIDstable patients), patients with COVID-19 requiring ICU admission (COVIDICU patients), and patients with severe community-acquired pneumonia requiring ICU support (CAPICU patients). Immunometabolic markers were measured in circulating neutrophils from patients with severe COVID-19. The acute phase response of AAT (alpha-1 antitrypsin) to COVID-19 was also evaluated.Measurements and Main Results: IL-1ß, IL-6, IL-8, and sTNFR1 were all increased in patients with COVID-19. COVIDICU patients could be clearly differentiated from COVIDstable patients, and demonstrated higher levels of IL-1ß, IL-6, and sTNFR1 but lower IL-10 than CAPICU patients. COVID-19 neutrophils displayed altered immunometabolism, with increased cytosolic PKM2 (pyruvate kinase M2), phosphorylated PKM2, HIF-1α (hypoxia-inducible factor-1α), and lactate. The production and sialylation of AAT increased in COVID-19, but this antiinflammatory response was overwhelmed in severe illness, with the IL-6:AAT ratio markedly higher in patients requiring ICU admission (P < 0.0001). In critically unwell patients with COVID-19, increases in IL-6:AAT predicted prolonged ICU stay and mortality, whereas improvement in IL-6:AAT was associated with clinical resolution (P < 0.0001).Conclusions: The COVID-19 cytokinemia is distinct from that of other types of pneumonia, leading to organ failure and ICU need. Neutrophils undergo immunometabolic reprogramming in severe COVID-19 illness. Cytokine ratios may predict outcomes in this population.

Detection and prognostic role of heterogeneous populations of melanoma circulating tumour cells.

BACKGROUND: Circulating tumour cells (CTCs) can be assessed through a minimally invasive blood sample with potential utility as a predictive, prognostic and pharmacodynamic biomarker. The large heterogeneity of melanoma CTCs has hindered their detection and clinical application. METHODS: Here we compared two microfluidic devices for the recovery of circulating melanoma cells. The presence of CTCs in 43 blood samples from patients with metastatic melanoma was evaluated using a combination of immunocytochemistry and transcript analyses of five genes by RT-PCR and 19 genes by droplet digital PCR (ddPCR), whereby a CTC score was calculated. Circulating tumour DNA (ctDNA) from the same patient blood sample, was assessed by ddPCR targeting tumour-specific mutations. RESULTS: Our analysis revealed an extraordinary heterogeneity amongst melanoma CTCs, with multiple non-overlapping subpopulations. CTC detection using our multimarker approach was associated with shorter overall and progression-free survival. Finally, we found that CTC scores correlated with plasma ctDNA concentrations and had similar pharmacodynamic changes upon treatment initiation. CONCLUSIONS: Despite the high phenotypic and molecular heterogeneity of melanoma CTCs, multimarker derived CTC scores could serve as viable tools for prognostication and treatment response monitoring in patients with metastatic melanoma.

PD-L1 Expression on Circulating Tumor Cells May Be Predictive of Response to Pembrolizumab in Advanced Melanoma: Results from a Pilot Study.

BACKGROUND: PD-1 inhibitors are routinely used for the treatment of advanced melanoma. This study sought to determine whether PD-L1 expression on circulating tumor cells (CTCs) can serve as a predictive biomarker of clinical benefit and response to treatment with the PD-1 inhibitor pembrolizumab. METHODS: Blood samples were collected from patients with metastatic melanoma receiving pembrolizumab, prior to treatment and 6-12 weeks after initiation of therapy. Multiparametric flow cytometry was used to identify CTCs and evaluate the expression of PD-L1. RESULTS: CTCs were detected in 25 of 40 patients (63%). Patients with detectable PD-L1+ CTCs (14/25, 64%) had significantly longer progression-free survival (PFS) compared with patients with PD-L1- CTCs (26.6 months vs. 5.5 months; p = .018). The 12-month PFS rates were 76% versus 22% in the PD-L1+ versus PD-L1- CTCs groups (p = .012), respectively. A multivariate linear regression analysis confirmed that PD-L1+ CTC is an independent predictive biomarker of PFS (hazard ratio, 0.229; 95% confidence interval, 0.052-1.012; p = .026). CONCLUSION: Our results reveal the potential of CTCs as a noninvasive real-time biopsy to evaluate PD-L1 expression in patients with melanoma. PD-L1 expression on CTCs may be predictive of response to pembrolizumab and longer PFS. IMPLICATIONS FOR PRACTICE: The present data suggest that PD-L1 expression on circulating tumor cells may predict response to pembrolizumab in advanced melanoma. This needs further validation in a larger trial and, if proven, might be a useful liquid biopsy tool that could be used to stratify patients into groups more likely to respond to immunotherapy, hence leading to health cost savings.

Patterns of amiodarone use and outcomes in clinical practice for atrial fibrillation.

BACKGROUND: Amiodarone is the most effective antiarrhythmic drug (AAD) for atrial fibrillation (AF), but it has a high incidence of adverse effects. METHODS: Using the ORBIT AF registry, patients with AF on amiodarone at enrollment, prescribed amiodarone during follow-up, or never on amiodarone were analyzed for the proportion treated with a guideline-based indication for amiodarone, the variability in amiodarone use across sites, and the outcomes (mortality, hospitalization, and stroke) among patients treated with amiodarone. Hierarchical logistic regression modeling with site-specific random intercepts compared rates of amiodarone use across 170 sites. A logistic regression model for propensity to receive amiodarone created a propensity-matched cohort. Cox proportional hazards modeling, stratified by matched pairs evaluated the association between amiodarone and outcomes. RESULTS: Among 6,987 AF patients, 867 (12%) were on amiodarone at baseline and 451 (6%) started on incident amiodarone during the 3-year follow-up. Use of amiodarone varied among sites from 3% in the lowest tertile to 21% in the highest (p<0.0001). Among those treated, 32% had documented contraindications to other AADs or had failed another AAD in the past. Mortality, cardiovascular hospitalization, and stroke were similar among matched patients on and not on amiodarone at baseline, while incident amiodarone use in matched patients was associated with higher all-cause mortality (adjusted HR 2.06, 95% CI 1.35-3.16). CONCLUSIONS: Use of amiodarone among AF patients in community practice is highly variable. More than 2 out of 3 patients treated with amiodarone appeared to be eligible for a different AAD.

Guideline-directed therapies for comorbidities and clinical outcomes among individuals with atrial fibrillation.

BACKGROUND: Comorbidities are common in patients with atrial fibrillation (AF) and affect prognosis, yet are often undertreated. However, contemporary rates of use of guideline-directed therapies (GDT) for non-AF comorbidities and their association with outcomes are not well described. METHODS: We used the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF) to test the association between GDT for non-AF comorbidities and major adverse cardiac or neurovascular events (MACNE; cardiovascular death, myocardial infarction, stroke/thromboembolism, or new-onset heart failure), all-cause mortality, new-onset heart failure, and AF progression. Adjustment was performed using Cox proportional hazards models and logistic regression. RESULTS: Only 6,782 (33%) of the 20,434 patients eligible for 1 or more GDT for non-AF comorbidities received all indicated therapies. Use of all comorbidity-specific GDT was highest for patients with hyperlipidemia (75.6%) and lowest for those with diabetes mellitus (43.1%). Use of "all eligible" GDT was associated with a nonsignificant trend toward lower rates of MACNE (HR 0.90 [0.79-1.02]) and all-cause mortality (HR 0.90 [0.80-1.01]). Use of GDT for heart failure was associated with a lower risk of all-cause mortality (HR 0.77 [0.67-0.89]), and treatment of obstructive sleep apnea was associated with a lower risk of AF progression (OR 0.75 [0.62-0.90]). CONCLUSIONS: In AF patients, there is underuse of GDT for non-AF comorbidities. The association between GDT use and outcomes was strongest in heart failure and obstructive sleep apnea patients where use of GDT was associated with lower mortality and less AF progression.