Citations

Background: There are limited data on uninsured patients presenting with acute myocardial infarction-cardiogenic shock (AMI-CS). This study sought to compare the management and outcomes of AMI-CS between uninsured and privately insured individuals. Methods: Using the National Inpatient Sample (2000–2016), a retrospective cohort of adult (≥18 years) uninsured admissions (primary payer—self-pay or no charge) were compared with privately insured individuals. Interhospital transfers were excluded. Outcomes of interest included in-hospital mortality, temporal trends in admissions, use of cardiac procedures, do-not-resuscitate status, palliative care referrals, and resource utilization. Results: Of 402 182 AMI-CS admissions, 21 966 (5.4%) and 93 814 (23.3%) were uninsured and privately insured. Compared with private insured individuals, uninsured admissions were younger, male, from a lower socioeconomic status, had lower comorbidity, higher rates of acute organ failure, ST-segment elevation AMI-CS (77.3% versus 76.4%), and concomitant cardiac arrest (33.8% versus 31.9%; all P <0.001). Compared with 2000, in 2016, there were more uninsured (adjusted odds ratio, 1.15 [95% CI, 1.13–1.17]; P <0.001) and less privately insured admissions (adjusted odds ratio, 0.85 [95% CI, 0.83–0.87]; P <0.001). Uninsured individuals received less frequent coronary angiography (79.5% versus 81.0%), percutaneous coronary intervention (60.8% versus 62.2%), mechanical circulatory support (54% versus 55.5%), and had higher palliative care (3.8% versus 3.2%) and do-not-resuscitate status use (4.4% versus 3.2%; all P <0.001). Uninsured admissions had higher in-hospital mortality (adjusted odds ratio, 1.62 [95% CI, 1.55–1.68]; P <0.001) and resource utilization. Conclusions: Uninsured individuals have higher in-hospital mortality and lower use of guideline-directed therapies in AMI-CS compared with privately insured individuals.

Background Accurate measurement of the cholesterol within lipoprotein(a) (Lp[a]‐C) and its contribution to low‐density lipoprotein cholesterol (LDL‐C) has important implications for risk assessment, diagnosis, and treatment of atherosclerotic cardiovascular disease, as well as in familial hypercholesterolemia. A method for estimating Lp(a)‐C from particle number using fixed conversion factors has been proposed (Lp[a]‐C from particle number divided by 2.4 for Lp(a) mass, multiplied by 30% for Lp[a]‐C). The accuracy of this method, which theoretically can isolate “Lp(a)‐free LDL‐C,” has not been validated. Methods and Results In 177 875 patients from the VLDbL (Very Large Database of Lipids), we compared estimated Lp(a)‐C and Lp(a)‐free LDL‐C with measured values and quantified absolute and percent error. We compared findings with an analogous data set from the Mayo Clinic Laboratory. Error in estimated Lp(a)‐C and Lp(a)‐free LDL‐C increased with higher Lp(a)‐C values. Median error for estimated Lp(a)‐C <10 mg/dL was −1.9 mg/dL (interquartile range, −4.0 to 0.2); this error increased linearly, overestimating by +30.8 mg/dL (interquartile range, 26.1–36.5) for estimated Lp(a)‐C ≥50 mg/dL. This error relationship persisted after stratification by overall high‐density lipoprotein cholesterol and high‐density lipoprotein cholesterol subtypes. Similar findings were observed in the Mayo cohort. Absolute error for Lp(a)‐free LDL‐C was +2.4 (interquartile range, −0.6 to 5.3) for Lp(a)‐C<10 mg/dL and −31.8 (interquartile range, −37.8 to −26.5) mg/dL for Lp(a)‐C≥50 mg/dL. Conclusions Lp(a)‐C estimations using fixed conversion factors overestimated Lp(a)‐C and subsequently underestimated Lp(a)‐free LDL‐C, especially at clinically relevant Lp(a) values. Application of inaccurate Lp(a)‐C estimations to correct LDL‐C may lead to undertreatment of high‐risk patients.

AbstractBackgroundCeramides are bioactive lipid species that mediate numerous cell-signaling events. Elevated plasma ceramides concentration constitutes a risk factor for several pathologies. Multiple studies have affirmed the plasma concentrations of 4 specific ceramides (Cer16:0, Cer18:0, Cer24:0, and Cer24:1) can predict cardiovascular disease risk. Furthermore, these ceramides can be altered by many lipid-lowering therapies. Understanding the biological variability within an individual, and within a population, will further inform the clinical use of plasma ceramides as a biomarker. In this study, we aimed to define the intra- and interbiological variability of ceramides in a healthy reference population in a weekly and monthly manner.MethodsFasting plasma from 24 healthy adults was collected daily (5 days), weekly (4 weeks), and monthly (7 months). Ceramide concentrations were measured with liquid chromatography–mass spectrometry (LC–MS). For analysis, we used random-effects regression models to estimate variance components.ResultsThe analytical variability was smaller compared to the biological variability overall. The greatest variation reported was between-subject variation for all ceramide species. The critical difference-reference change value (RCV) for within-subject variations monthly were 0.07 mcmol/L (Cer16:0), 0.04 mcmol/L (Cer18:0), 1.09 mcmol/L (Cer24:0), and 0.27 mcmol/L (Cer24:1). The index of individuality (IOI) of ceramides were 0.82 (Cer16:0), 0.96 (Cer18:0), 1.06 (Cer24:0), and 0.89 (Cer24:1). The most consistent ceramide species was Cer18:0 with the lowest within- and between-subject critical differences in weekly and monthly measurements.ConclusionsOverall, this study demonstrates that the variability of ceramide concentrations at different time points is minimal within individuals, allowing a single draw to be sufficient at least in a yearly time frame.

Abstract Introduction: Plasmablastic lymphoma (PBL) is an aggressive B-cell lymphoma that predominantly occurs in patients with HIV or other causes of immunodeficiency. Frequent infection by the Epstein-Barr virus (EBV) and MYC translocations have been described as major features contributing to the pathogenesis of PBL. Prior studies examining the genetic landscape of PBL have largely relied on targeted capture-based sequencing approaches. As such, the molecular features of PBL remain to be fully explored. Here, we provide a comprehensive description of the genomic landscape of PBL using whole-genome and whole-exome sequencing to identify commonly perturbed pathways. Method: Archival diagnostic fresh frozen and formalin fixed paraffin embedded tissue biopsies from 58 PBL tumours were accrued from Lymphoma/Leukemia Molecular Profiling Project (LLMPP) sites, including 15 tumours from Ramis-Zaldivar et al., Haematolgica 2021. MYC rearrangements were identified by break-apart fluorescent in situ hybridization (FISH) and rearrangement partner was determined in a subset of tumours from capture or genome sequencing data using structural variant callers Manta, GRIDSS, and Delly. High confidence somatic mutations (SNVs/Indels) were identified in data from whole-genome (n=5) or whole-exome (n=53) sequencing through an ensemble voting approach utilizing four variant callers (Strelka2, Lofreq, Mutect2, SAGE). Mutation frequencies in known lymphoma-related genes were compared to activated B-cell (ABC)-DLBCL (Schmitz et al., NEJM 2018), as the closest tumour entity in terms of putative cell-of-origin differentiation stage, to identify differences in genetic aberrations. Candidate somatic copy number alterations (CNAs) were identified from exome and genome sequencing data, using CopywriteR and ControlFREEC, respectively, and high-confidence CNAs were determined using GISTIC2.0. Results: Within the study cohort, 81% of patients were male with a median age of 59 years (range 11-88). HIV and EBV statuses were available for 47% of patients and 95% of tumours, respectively, with 49% (13/27) of the patients being HIV+ and 69% (38/55) of tumours being EBV+. MYC rearrangement was observed in 60% (35/58) of PBLs, with IGH as the partner gene in 88% (21/24) of tumours. The most frequently mutated genes were STAT3 (38%), TP53 (22%), NRAS (21%), and TET2 (16%), consistent with previous studies, however novel mutations were seen in DUSP2 (21%), KLHL6 (16%), and BHLHE41 (16%). Recurrent CNAs included amplifications in 1q, whole gains of 7, 8q24, 11p12 and deletions affecting 4p16, 5p15, 10q11.22. While the mutational landscapes were similar between samples with and without a MYC translocation, the MYC-translocated PBLs showed more frequent amplification of 1q32.1. When stratifying by EBV status, STAT3 and SOCS1 mutations were more frequent in EBV-positive tumours, whereas TP53, TET2, KRAS, and MMRN2 mutations were associated with EBV-negativity. In comparison to ABC-DLBCL, PBLs were significantly enriched in STAT3 and NRAS mutations, and lacked common mutations affecting the NF-κB pathway (eg. MYD88, CD79B, and NFKBIZ 3' UTR mutations). Mutations in genes that are frequently mutated in ABC-DLBCLs, such as those associated with plasma cell differentiation (eg. PRDM1) or a memory B-cell fate (eg. TBL1XR1), were also not mutated in PBLs. Finally, genetic alterations associated with immune evasion, such as deletion of MHC I and II and mutations in B2M, CIITA, and CD58, were rarely observed. Conclusion: These data present a comprehensive overview of the genomic landscape of PBLs in a large cohort. We show frequent mutations involving the JAK-STAT and MAPK pathways, wherein the genetic landscape can be differentially characterized by EBV status and MYC rearrangement status. We show that PBLs are genetically distinct from ABC-DLBCLs, with absence of mutations in genes affecting the NF-κB pathway, immune evasion, and driving a memory B-cell fate. Disclosures Slack: Seagen: Consultancy, Honoraria. Raess: Scopio Labs: Research Funding. Holte: Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Nordic: Membership on an entity's Board of Directors or advisory committees; Nanovector: Membership on an entity's Board of Directors or advisory committees, Other: lectures honorarias; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Savage: Servier: Consultancy, Honoraria; Roche: Research Funding; BMS: Consultancy, Honoraria, Other: Institutional clinical trial funding; Astra-Zeneca: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Other: Institutional clinical trial funding; AbbVie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Other: Institutional clinical trial funding; Beigene: Other: Institutional clinical trial funding; Genentech: Research Funding. Steidl: Seattle Genetics: Consultancy; Curis Inc.: Consultancy; Bayer: Consultancy; Epizyme: Research Funding; Trillium Therapeutics: Research Funding; AbbVie: Consultancy; Bristol-Myers Squibb: Research Funding. Rimsza: NanoString Technologies: Other: Fee-for-service contract. Morin: Foundation for Burkitt Lymphoma Research: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Epizyme: Patents & Royalties. Scott: Abbvie: Consultancy; AstraZeneca: Consultancy; Rich/Genentech: Research Funding; BC Cancer: Patents & Royalties: Patent describing assigning DLBCL COO by gene expression profiling--licensed to NanoString Technologies. Patent describing measuring the proliferation signature in MCL using gene expression profiling. ; Incyte: Consultancy; Janssen: Consultancy, Research Funding; Celgene: Consultancy; NanoString Technologies: Patents & Royalties: Patent describing measuring the proliferation signature in MCL using gene expression profiling..

Abstract Atherosclerotic cardiovascular disease is a result of low-density lipoprotein (LDL) particles becoming trapped in arterial walls and forming plaques which ultimately restrict blood-flow. LDL cholesterol (LDL-C) and apolipoprotein B (apoB) are highly correlated measures of plaque-causing LDL particles. Both have been shown to predict major adverse cardiac events (MACE). ApoB is also carried on remnant lipoproteins (RLP). RLP-cholesterol (RLP-C) is increasingly appreciated as a MACE risk-factor. This study aimed to define discordances between apoB and LDL-C in a large data set from a clinical reference laboratory. We then applied this definition to evaluate which measure predicted the risk of MACE in a patient cohort referred for coronary angiography with &gt;10 years follow-up. LDL-C was measured by beta-quantification and RLP-C was defined as total cholesterol – LDL-C – HDL-C. Apo B discordance relative to LDL-C was determined by linear regression in a discovery cohort (n=17,203) using beta quantification. Discordance was defined by quartiles of the residual-apoB (expected–actual); discordant-low (&lt;25th percentile), concordant (25th to 75th percentile) and discordant-high (&gt;75th percentile). Associations with prevalence and incident of MACE were evaluated by odds-ratio and logistic regression. Risk of MACE was calculated based on the apoB-discordance and reported MACE events by several years follow up in a separate cohort (n=501). In the discovery cohort, age ranged from 18-95 years, 51% were female and mean (±SD) lipid values were: ApoB: 100.4 ± 30.0mg/dl, LDL-C: 121.7 ± 47.9mg/dl, and RLP-C: 17.2 ± 26.9mg/dl. Expected-apoB was described by the formula: (LDL-c X 0.6278 + 24.07, R=0.88). Residual-apoB (discordance) ranged from -1037 to 581.2 with a mean 0.01±18.6, and notably increased with triglyceride concentration (rho=0.65) and with RLP-C (rho=0.64), but was minimally influenced by apoB (rho=0.35) and LDL-C (rho=0.009) (p&lt;0.001 all cases). In the clinical follow-up cohort, age ranged from 26-77 years, 42% were female, 64% were current/former smokers, and 28% were on lipid-lowering therapy. Mean (±SD) lipids were: apoB: 97.8 ± 20.9mg/dl, LDL-C: 124.6 ± 36.6mg/dl, and RLP-C: 34.9 ± 25.6mg/dl. Serum triglycerides among subjects discordant-low apoB, concordant and discordant-high apoB were 148mg/dL, 157mg/dL and 238mg/dL, respectively; similarly for RLP-C. A total of 192 events occurred during a mean of 9 years follow-up. Subjects with discordantly elevated apoB had a significantly higher incidence of MACE compared to those with concordant values (47% vs. 36%, p=0.03). There was no difference in MACE for subjects with discordantly low apoB (35% vs. 36%). These data support previous reports of an association between apoB and LDL-C and the superior performance of apoB when discordantly elevated. Our data expand on previous studies by applying an externally defined threshold for discordant-apoB. Our data indicate that triglycerides, RLP-C are associated with discordances and MACE.