Low values of high-sensitivity cardiac troponin (hs-cTn) and coronary artery calcium (CAC) scores of zero are associated with a low risk for atherosclerotic cardiovascular disease (ASCVD).
The ...purpose of this study was to evaluate baseline hs-cTnT and CAC in relation to ASCVD.
Baseline hs-cTnT (limit of detection LoD 3 ng/l) and CAC measurements were analyzed across participants age 45 to 84 years without clinical cardiovascular disease from the prospective MESA (Multi-Ethnic Study of Atherosclerosis) in relationship to incident ASCVD.
Among 6,749 participants, 1,002 ASCVD events occurred during a median follow-up of 15 years. Participants with detectable CAC (20.1 vs. 5.0 events per 1,000 person-years; adjusted hazard ratio HR: 2.35; 95% confidence interval CI: 2.0 to 2.76; p < 0.001) and detectable hs-cTnT (15.4 vs. 5.2 per 1,000 person-years; adjusted HR: 1.47; 95% CI: 1.21 to 1.77; p < 0.001) had higher rates of ASCVD than those with undetectable results. Individuals with undetectable hs-cTnT (32%) had similar risk for ASCVD as did those with a CAC of zero (50%) (5.2 vs. 5.0 per 1,000 person-years). Together, hs-cTnT and CAC (discordance 38%) resulted in the following ASCVD event rates: hs-cTnT < LoD/CAC = 0: 2.8 per 1,000 person-years (reference), hs-cTnT ≥ LoD/CAC = 0: 6.8 per 1,000 person-years (HR: 1.59; 95% CI: 1.17 to 2.16; p = 0.003), hs-cTnT < LoD/CAC > 0: 11.1 per 1,000 person-years (HR: 2.74; 95% CI: 1.96 to 3.83; p < 0.00001), and hs-cTnT ≥ LoD/CAC > 0: 22.6 per 1,000 person-years (HR: 3.50; 95% CI: 2.60 to 4.70; p < 0.00001).
An undetectable hs-cTnT identifies patients with a similar, low risk for ASCVD as those with a CAC score of zero. The increased risk among those with discordant results supports their conjoined use for risk prediction.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To assess the frequency and clinical implications of positive autoimmune serologies in patients with biopsy-confirmed idiopathic pulmonary fibrosis (IPF).
We reviewed the records of patients at our ...institution with biopsy-confirmed usual interstitial pneumonia (UIP) from January 1, 1995, through December 31, 2010, for frequency and distribution of autoimmune serologies. Patients with IPF with and without positive serologies were compared.
Three hundred eighty-nine consecutive patients with biopsy-confirmed IPF underwent serologic testing, with positive serologic test results being found in 112 (29%). Of 2051 individual screening serologic tests performed, results of 163 tests were positive (8%), with antinuclear antibody being the most frequent (47%). There was no difference in age at biopsy (P=.21), gender (P=.21), or presenting radiologic features between those with or without positive serology. More frequent use of immunosuppressive treatment (P=.02) was noted in those with positive serology. No survival difference was observed (log-rank; P=.43). Median follow-up for the whole cohort was 43.5 months.
Positive autoimmune serology may occur in as much as one-third of the patients with biopsy-confirmed IPF with no associated clinical implication or survival advantage. Systematic use of autoimmune laboratory panels in patients without clinical features of connective tissue disease should be reconsidered in patients with suspected UIP on chest computed tomography scan or confirmed UIP on biopsy.
Clinical risk scores are used to identify those at high risk of atherosclerotic cardiovascular disease (ASCVD). Despite preventative efforts, residual risk remains for many individuals. Very ...low-density lipoprotein cholesterol (VLDL-C) and lipid discordance could be contributors to the residual risk of ASCVD.
Cardiovascular disease-free residents, aged ≥40 years, living in Olmsted County, Minnesota, were identified through the Rochester Epidemiology Project. Low-density lipoprotein cholesterol (LDL-C) and VLDL-C were estimated from clinically ordered lipid panels using the Sampson equation. Participants were categorized into concordant and discordant lipid pairings based on clinical cut points. Rates of incident ASCVD, including percutaneous coronary intervention, coronary artery bypass grafting, stroke, or myocardial infarction, were calculated during follow-up. The association of LDL-C and VLDL-C with ASCVD was assessed using Cox proportional hazards regression. Interaction between LDL-C and VLDL-C was assessed. The study population (n=39 098) was primarily White race (94%) and female sex (57%), with a mean age of 54 years. VLDL-C (per 10-mg/dL increase) was significantly associated with an increased risk of incident ASCVD (hazard ratio, 1.07 95% CI, 1.05-1.09;
<0.001) after adjustment for traditional risk factors. The interaction between LDL-C and VLDL-C was not statistically significant (
=0.11). Discordant individuals with high VLDL-C and low LDL-C experienced the highest rate of incident ASCVD events, 16.9 per 1000 person-years, during follow-up.
VLDL-C and lipid discordance are associated with a greater risk of ASCVD and can be estimated from clinically ordered lipid panels to improve ASCVD risk assessment.
Risk factors for the pathogenesis of chronic rhinosinusitis (CRS) remain largely undetermined, which is likely due to the heterogeneity of the disease. White blood cell counts have been largely ...unexplored as a risk factor for CRS even though different types of white blood cells are involved in the inflammatory process of CRS.
To investigate causal associations between different types of white blood cells on risk of CRS utilizing a Mendelian randomization (MR) analysis.
A two-sample MR analysis was performed using respective GWAS summary statistics for the exposure traits (neutrophil count, eosinophil count, basophil count, lymphocyte count, and monocyte count) and outcome trait (CRS). For the exposure traits, the European Bioinformatics Institute database of complete GWAS summary data was used. For the outcome trait, summary statistics for CRS GWAS were obtained from FinnGen. Primary analysis for MR was performed using inverse-variance weighted two-sample MR. Sensitivity analyses included weighted median, MR-Egger, and MR-PRESSO (raw and outlier-corrected).
Eosinophils were associated with CRS (OR = 1.55 95% CI 1.38, 1.73; p = 4.3E-14). Eosinophil results were similar across additional MR methods. MR results did not demonstrate significant causal relationships between neutrophils, lymphocytes, monocytes, or basophils with CRS. No significant pleiotropic bias was observed.
In a two-sample MR analysis, a potential causal link between blood eosinophil counts and CRS has been demonstrated. In addition, causal relationships between blood counts among other white blood cell types and CRS were not found. Further studies involving genetic variation in CRS are needed to corroborate genetic causal effects for CRS.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract Introduction Increased mortality in people with schizophrenia, compared to the general population, has been consistently reported worldwide. This mortality has been attributed predominantly ...to “unnatural” deaths-suicide, accidents, and homicide. Recent studies have shown an increase in natural causes of death. Our objective is to compare the mortality of schizophrenic and schizoaffective subjects to the general US population. Methods 319 Olmsted County residents meeting DSM-IV-TR criteria for schizophrenia or schizoaffective disorder seen at the Mayo Clinic between 1950 and 1980 were followed until February 2005 for a median of 23.5 years. Results At the end of follow-up, 44% of patients were deceased. Mortality was significantly ( p < 0.001) increased compared to the Caucasian population in the US for persons of like age, gender, and calendar year of birth. The median survival following diagnosis was 36.2 years. Death certificate cited cause of death was cardiac (29%), cancer — including lung (19%), and pulmonary disease (17%). Concerningly, there was no association with the year of diagnosis to survival. Conclusions Tsuang and colleagues showed in 1975 that mortality in schizophrenics and later, those with schizoaffective disorder was significantly increased compared to the US general population. Thirty years later, with a demographically similar population, we have found the same pattern of increased mortality. In light of continued improvements in the general population's lifespan, the survival gap in schizophrenia/schizoaffective disorder appears to be increasing.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A type of chromosome-free cell called SimCells (simple cells) has been generated from Escherichia coli, Pseudomonas putida, and Ralstonia eutropha. The removal of the native chromosomes of these ...bacteria was achieved by double-stranded breaks made by heterologous I-CeuI endonuclease and the degradation activity of endogenous nucleases. We have shown that the cellular machinery remained functional in these chromosome-free SimCells and was able to process various genetic circuits. This includes the glycolysis pathway (composed of 10 genes) and inducible genetic circuits. It was found that the glycolysis pathway significantly extended longevity of SimCells due to its ability to regenerate ATP and NADH/NADPH. The SimCells were able to continuously express synthetic genetic circuits for 10 d after chromosome removal. As a proof of principle, we demonstrated that SimCells can be used as a safe agent (as they cannot replicate) for bacterial therapy. SimCells were used to synthesize catechol (a potent anticancer drug) from salicylic acid to inhibit lung, brain, and soft-tissue cancer cells. SimCells represent a simplified synthetic biology chassis that can be programmed to manufacture and deliver products safely without interference from the host genome.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Pleomorphic xanthoastrocytoma (PXA) is a rare localized glioma characterized by frequent BRAF V600E mutation and CDKN2A/B deletion. We explored the association of copy‐number variants (CNVs) with ...BRAF mutations, tumor grade, and patient survival in a cohort of 41 PXA patients using OncoScan chromosomal microarray. Primary resection specimens were available in 38 cases, including 24 PXA and 14 anaplastic PXA (A‐PXA), 23 BRAF V600E mutant tumors (61%). CNVs were identified in all cases and most frequently involved chromosome 9 with homozygous CDKN2A/B deletion (n = 33, 87%), a higher proportion than previously detected by comparative genomic hybridization (50%–60%) (37). CDKN2A/B deletion was present in similar proportion of PXA (83%), A‐PXA (93%), BRAF V600E (87%), and wild‐type (87%) tumors. Whole chromosome gains/losses were frequent, including gains +7 (n = 15), +2 (n = 11), +5 (n = 10), +21 (n = 10), +20 (n = 9), +12 (n = 8), +15 (n = 8), and losses −22 (n = 11), −14 (n = 7), −13 (n = 5). Losses and copy‐neutral loss of heterozygosity were significantly more common in A‐PXA, involving chromosomes 22 (P = 0.009) and 14 (P = 0.03). Amplification of 8p and 12q was identified in a single tumor. Histologic grade was a robust predictor of overall survival (P = 0.003), while other copy‐number changes, including CDKN2A/B deletion, did not show significant association with survival. Distinct histologic patterns of anaplasia included increased mitotic activity in an otherwise classic PXA or associated with small cell, fibrillary, or epithelioid morphology, with loss of SMARCB1 expression in one case. In 10 cases, matched specimens were compared, including A‐PXA with areas of distinct low‐ and high‐grade morphology (n = 2), matched primary/tumor recurrence (n = 7), or both (n = 1). Copy‐number changes on recurrence/anaplastic transformation were complex and highly variable, from nearly identical profiles to numerous copy‐number changes. Overall, we confirm CDKN2A/B deletion as key a feature of PXA not associated with tumor grade or BRAF mutation, but central to the underlying genetics of PXA.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Glioblastoma (GBM) is a rapidly fatal malignancy typically treated with radiation and temozolomide (TMZ), an alkylating chemotherapeutic. These cytotoxic therapies cause oxidative stress and DNA ...damage, yielding a senescent-like state of replicative arrest in surviving tumor cells. Unfortunately, recurrence is inevitable and may be driven by surviving tumor cells eventually escaping senescence. A growing number of so-called "senolytic" drugs have been recently identified that are defined by their ability to selectively eliminate senescent cells. A growing inventory of senolytic drugs is under consideration for several diseases associated with aging, inflammation, DNA damage, as well as cancer. Ablation of senescent tumor cells after radiation and chemotherapy could help mitigate recurrence by decreasing the burden of residual tumor cells at risk of recurrence. This strategy has not been previously explored for GBM. We evaluated a panel of 10 previously described senolytic drugs to determine whether any could exhibit selective activity against human GBM persisting after exposure to radiation or TMZ. Three of the 10 drugs have known activity against BCL-XL and preferentially induced apoptosis in radiated or TMZ-treated glioma. This senolytic activity was observed in 12 of 12 human GBM cell lines. Efficacy could not be replicated with BCL-2 inhibition or senolytic agents acting against other putative senolytic targets. Knockdown of BCL-XL decreased survival of radiated GBM cells, whereas knockdown of BCL-2 or BCL-W yielded no senolytic effect.
These findings imply that molecularly heterogeneous GBM lines share selective senescence-induced BCL-XL dependency increase the significance and translational relevance of the senolytic therapy for latent glioma.
Objectives
The objective of this study was to identify clinical and imaging features that distinguish rheumatoid lung nodules from malignancy.
Methods
We conducted a retrospective review of 73 ...rheumatoid patients with histologically-proven rheumatoid and malignant lung nodules encountered at Mayo Clinic, Rochester, MN (2001–2016). Medical records and imaging were reviewed including a retrospective blinded review of CT and PET/CT studies.
Results
The study cohort had a mean age of 67 ± 11 years (range 45–86) including 44 (60%) women, 82% with a smoking history, 38% with subcutaneous rheumatoid nodules, and 78% with rheumatoid factor seropositivity. Subjects with rheumatoid lung nodules compared to malignancy were younger (59 ± 12 vs 71 ± 9 years,
p
< 0.001), more likely to manifest subcutaneous rheumatoid nodules (73% vs 20%,
p
< 0.001) and rheumatoid factor seropositivity (93% vs 68%,
p
= 0.034) but a history of smoking was common in both groups (
p
= 0.36). CT features more commonly associated with rheumatoid lung nodules compared to malignancy included multiplicity, smooth border, cavitation, satellite nodules, pleural contact, and a subpleural rind of soft tissue. Optimal sensitivity (77%) and specificity (92%) (AUC 0.85, CI 0.75–0.94) for rheumatoid lung nodule were obtained with ≥ 3 CT findings (≥ 4 nodules, peripheral location, cavitation, satellite nodules, smooth border, and subpleural rind). Key
18
FDG-PET/CT features included low-level metabolism (SUV
max
2.7 ± 2 vs 7.2 ± 4.8,
p
= 0.007) and lack of
18
F-fluorodeoxyglucose (FDG)-avid draining lymph nodes.
Conclusion
Rheumatoid lung nodules have distinct CT and PET/CT features compared to malignancy. Patients with rheumatoid lung nodules are younger and more likely to manifest subcutaneous rheumatoid nodules and seropositivity.
Key Points
• Rheumatoid lung nodules have distinct clinical and imaging features compared to lung malignancy.
• CT features of rheumatoid lung nodules include multiplicity, cavitation, satellite nodules, smooth border, peripheral location, and subpleural rind.
• Key PET/CT features include low-level metabolism and lack of FDG-avid draining lymph nodes.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract Objective P-selectin is a cellular adhesion molecule that has been shown to be crucial in development of coronary heart disease (CHD). We sought to determine the role of P-selectin on the ...risk of atherosclerosis in a large multi-ethnic population. Methods Data from the Multi-Ethnic Study of Atherosclerosis (MESA), including 1628 African, 702 Chinese, 2393 non-Hispanic white, and 1302 Hispanic Americans, were used to investigate the association of plasma P-selectin with CHD risk factors, coronary artery calcium (CAC), intima-media thickness, and CHD. Regression models were used to investigate the association between P-selectin and risk factors, Tobit model for CAC, and Cox regression for CHD events. Results Mean levels of P-selectin differed by ethnicity and were higher in men ( P < 0.001). For all ethnic groups, P-selectin was positively associated with measures of adiposity, blood pressure, current smoking, LDL, and triglycerides and inversely with HDL. A significant ethnic interaction was observed for the association of P-selectin and prevalent diabetes; however, P-selectin was positively associated with HbA1c in all groups. Higher P-selectin levels were associated with greater prevalence of CAC. Over 10.1 years of follow-up, there were 335 incident CHD events. There was a positive linear association between P-selectin levels and rate of incident CHD after adjustment for traditional risk factors. However, association was only significant in non-Hispanic white Americans (HR: 1.81, 95% CI 1.07 to 3.07, P = 0.027). Conclusion We observed ethnic heterogeneity in the association of P-selectin and risk of CHD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, SAZU, SBCE, UL, UM, UPCLJ, UPUK
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