BACKGROUND Pulmonary arterial hypertension (PAH) is a rare, severe disease characterized by worsening right-sided heart failure, decreasing functional status, and poor survival. The present study ...characterizes the 5-year survival in the United States of a new and previous diagnosis of PAH in patients stratified by baseline functional class (FC). The Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry) is a 55-center observational US registry of the demographics, disease course, and management of patients with World Health Organization (WHO) group 1 PAH. METHODS The REVEAL Registry enrolled newly and previously diagnosed patients aged ≥ 3 months with WHO group 1 PAH consecutively from March 2006 to December 2009. Demographics, disease characteristics, and hemodynamic data were collected at enrollment. Survival analysis was conducted by FC and other subgroups in patients aged ≥ 18 years. RESULTS Survival differences between previously diagnosed and newly diagnosed patients at 1 year (90.4% vs 86.3%) were maintained to 5 years; 5-year survival for previously diagnosed patients was 65.4% compared with 61.2% for newly diagnosed patients. Previously diagnosed patients in FC I, II, III, and IV had an estimated 5-year survival rate of 88.0%, 75.6%, 57.0%, and 27.2%, respectively, compared with 72.2%, 71.7%, 60.0%, and 43.8% for newly diagnosed patients in FC I, II, III, and IV, respectively. CONCLUSIONS Patient survival of advanced PAH remains poor at 5 years despite treatment advances. New York Heart Association FC remains one of the most important predictors of future survival. These observations reinforce the importance of continuous monitoring of FC in patients with PAH. TRIAL REGISTRY ClinicalTrials.gov ; No.: NCT00370214; URL: www.clinicaltrials.gov
Background The Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL Registry) was established to characterize the clinical course, treatment, and ...predictors of outcomes in patients with pulmonary arterial hypertension (PAH) in the United States. To date, estimated survival based on time of patient enrollment has been established and reported. To determine whether the survival of patients with PAH has improved over recent decades, we assessed survival from time of diagnosis for the REVEAL Registry cohort and compared these results to the estimated survival using the National Institutes of Health (NIH) prognostic equation. Methods Newly or previously diagnosed patients (aged ≥ 3 months at diagnosis) with PAH enrolled from March 2006 to December 2009 at 55 US centers were included in the current analysis. Results A total of 2,635 patients qualified for this analysis. One-, 3-, 5-, and 7-year survival rates from time of diagnostic right-sided heart catheterization were 85%, 68%, 57%, and 49%, respectively. For patients with idiopathic/familial PAH, survival rates were 91% ± 2%, 74% ± 2%, 65% ± 3%, and 59% ± 3% compared with estimated survival rates of 68%, 47%, 36%, and 32%, respectively, using the NIH equation. Conclusions Comprehensive analysis of survival from time of diagnosis in a large cohort of patients with PAH suggests considerable improvements in survival in the past 2 decades since the establishment of the NIH registry, the effects of which most likely reflect a combination of changes in treatments, improved patient support strategies, and possibly a PAH population at variance with other cohorts. Trial Registry ClinicalTrials.gov ; No.: NCT00370214 ; URL: clinicaltrials.gov.
We develop a strategy to design and evaluate high-entropy alloys (HEAs) for structural use in the transportation and energy industries. We give HEA goal properties for low (=<150 degree C), medium ...(=<450 degree C) and high (>=1,100 degree C) use temperatures. A systematic design approach uses palettes of elements chosen to meet target properties of each HEA family and gives methods to build HEAs from these palettes. We show that intermetallic phases are consistent with HEA definitions, and the strategy developed here includes both single-phase, solid solution HEAs and HEAs with intentional addition of a 2nd phase for particulate hardening. A thermodynamic estimate of the effectiveness of configurational entropy to suppress or delay compound formation is given. A 3-stage approach is given to systematically screen and evaluate a vast number of HEAs by integrating high-throughput computations and experiments. CALPHAD methods are used to predict phase equilibria, and high-throughput experiments on materials libraries with controlled composition and microstructure gradients are suggested. Much of this evaluation can be done now, but key components (materials libraries with microstructure gradients and high-throughput tensile testing) are currently missing. Suggestions for future HEA efforts are given.
The Cancer Genome Atlas (TCGA) has used the latest sequencing and analysis methods to identify somatic variants across thousands of tumours. Here we present data and analytical results for point ...mutations and small insertions/deletions from 3,281 tumours across 12 tumour types as part of the TCGA Pan-Cancer effort. We illustrate the distributions of mutation frequencies, types and contexts across tumour types, and establish their links to tissues of origin, environmental/carcinogen influences, and DNA repair defects. Using the integrated data sets, we identified 127 significantly mutated genes from well-known (for example, mitogen-activated protein kinase, phosphatidylinositol-3-OH kinase, Wnt/β-catenin and receptor tyrosine kinase signalling pathways, and cell cycle control) and emerging (for example, histone, histone modification, splicing, metabolism and proteolysis) cellular processes in cancer. The average number of mutations in these significantly mutated genes varies across tumour types; most tumours have two to six, indicating that the number of driver mutations required during oncogenesis is relatively small. Mutations in transcriptional factors/regulators show tissue specificity, whereas histone modifiers are often mutated across several cancer types. Clinical association analysis identifies genes having a significant effect on survival, and investigations of mutations with respect to clonal/subclonal architecture delineate their temporal orders during tumorigenesis. Taken together, these results lay the groundwork for developing new diagnostics and individualizing cancer treatment.
Considerable evidence implicates cellular senescence in the biology of aging and chronic disease. Diet and exercise are determinants of healthy aging; however, the extent to which they affect the ...behavior and accretion of senescent cells within distinct tissues is not clear. Here we tested the hypothesis that exercise prevents premature senescent cell accumulation and systemic metabolic dysfunction induced by a fast-food diet (FFD). Using transgenic mice that express EGFP in response to activation of the senescence-associated p16(INK4a) promoter, we demonstrate that FFD consumption causes deleterious changes in body weight and composition as well as in measures of physical, cardiac, and metabolic health. The harmful effects of the FFD were associated with dramatic increases in several markers of senescence, including p16, EGFP, senescence-associated β-galactosidase, and the senescence-associated secretory phenotype (SASP) specifically in visceral adipose tissue. We show that exercise prevents the accumulation of senescent cells and the expression of the SASP while nullifying the damaging effects of the FFD on parameters of health. We also demonstrate that exercise initiated after long-term FFD feeding reduces senescent phenotype markers in visceral adipose tissue while attenuating physical impairments, suggesting that exercise may provide restorative benefit by mitigating accrued senescent burden. These findings highlight a novel mechanism by which exercise mediates its beneficial effects and reinforces the effect of modifiable lifestyle choices on health span.
Tau positron emission tomography (PET) tracers have proven useful for the differential diagnosis of dementia, but their utility for predicting cognitive change is unclear.
To examine the prognostic ...accuracy of baseline fluorine 18 (18F)-flortaucipir and 18FRO948 (tau) PET in individuals across the Alzheimer disease (AD) clinical spectrum and to perform a head-to-head comparison against established magnetic resonance imaging (MRI) and amyloid PET markers.
This prognostic study collected data from 8 cohorts in South Korea, Sweden, and the US from June 1, 2014, to February 28, 2021, with a mean (SD) follow-up of 1.9 (0.8) years. A total of 1431 participants were recruited from memory clinics, clinical trials, or cohort studies; 673 were cognitively unimpaired (CU group; 253 37.6% positive for amyloid-β Aβ), 443 had mild cognitive impairment (MCI group; 271 61.2% positive for Aβ), and 315 had a clinical diagnosis of AD dementia (315 100% positive for Aβ).
18FFlortaucipir PET in the discovery cohort (n = 1135) or 18FRO948 PET in the replication cohort (n = 296), T1-weighted MRI (n = 1431), and amyloid PET (n = 1329) at baseline and repeated Mini-Mental State Examination (MMSE) evaluation.
Baseline 18Fflortaucipir/18FRO948 PET retention within a temporal region of interest, MRI-based AD-signature cortical thickness, and amyloid PET Centiloids were used to predict changes in MMSE using linear mixed-effects models adjusted for age, sex, education, and cohort. Mediation/interaction analyses tested whether associations between baseline tau PET and cognitive change were mediated by baseline MRI measures and whether age, sex, and APOE genotype modified these associations.
Among 1431 participants, the mean (SD) age was 71.2 (8.8) years; 751 (52.5%) were male. Findings for 18Fflortaucipir PET predicted longitudinal changes in MMSE, and effect sizes were stronger than for AD-signature cortical thickness and amyloid PET across all participants (R2, 0.35 tau PET vs 0.24 MRI vs 0.17 amyloid PET; P < .001, bootstrapped for difference) in the Aβ-positive MCI group (R2, 0.25 tau PET vs 0.15 MRI vs 0.07 amyloid PET; P < .001, bootstrapped for difference) and in the Aβ-positive CU group (R2, 0.16 tau PET vs 0.08 MRI vs 0.08 amyloid PET; P < .001, bootstrapped for difference). These findings were replicated in the 18FRO948 PET cohort. MRI mediated the association between 18Fflortaucipir PET and MMSE in the groups with AD dementia (33.4% 95% CI, 15.5%-60.0% of the total effect) and Aβ-positive MCI (13.6% 95% CI, 0.0%-28.0% of the total effect), but not the Aβ-positive CU group (3.7% 95% CI, -17.5% to 39.0%; P = .71). Age (t = -2.28; P = .02), but not sex (t = 0.92; P = .36) or APOE genotype (t = 1.06; P = .29) modified the association between baseline 18Fflortaucipir PET and cognitive change, such that older individuals showed faster cognitive decline at similar tau PET levels.
The findings of this prognostic study suggest that tau PET is a promising tool for predicting cognitive change that is superior to amyloid PET and MRI and may support the prognostic process in preclinical and prodromal stages of AD.
Structured Abstract Background Patients with Stanford type B aortic dissections (AD) are at risk of long-term disease progression and late complications. The aim of this study was to evaluate the ...natural course and evolution of acute type B AD and intramural hematomas (IMH) in patients who presented without complications during their initial hospital admission and who were treated with optimal medical management (MM). Methods Databases from two aortic centers in Europe and the US were used to identify 136 patients with acute type B AD (n= 92) and acute type B IMH (n= 44) who presented without complications during their index admission and were treated with MM. Computed tomography (CT) angiography scans were available at onset (≤ 14 days) and during follow-up for those patients. Relevant data, including evidence of adverse events during follow-up (AE; defined according to current guidelines), were retrieved from medical records and by reviewing CT scan images. Aortic diameters were measured using dedicated 3D software. Results The 1-, 2- and 5-year event-free survival rates of patients with type B AD were 84.3% (95% CI: 74.4 – 90.6), 75.4% (95% CI: 64.0 - 83.7) and 62.6% (95% CI: 68.9 – 73.6), respectively. Corresponding estimates for IMH were 76.5% (95% CI: 57.8 – 87.8), 76.5% (95% CI: 57.8 – 87.8) and 68.9% (95% CI: 45.2 – 83.9), respectively. In patients with type B AD, risk of an adverse event increased with aortic growth within the first six months after onset. A diameter increase of 5 mm in the first half year was associated with a relative risk for AE of 2.29 (95% CI: 1.70-3.09) compared with the median 6 months growth of 2.4 mm. In about 60% of IMH patients the abnormality resolved within 12 months and in the patients with non-resolving IMH, risk of an adverse event was highest in the first year after onset and remained stable thereafter. Conclusions More than one-third of patients with initially uncomplicated type B AD suffer an AE under MM within 5 years of initial diagnosis. In patients with non-resolving IMH, most adverse events are observed in the first year after onset. In patients with type B AD an early aortic growth is associated with a higher risk of AE.
Abstract While resting state functional connectivity has been shown to decrease in patients with mild and/or moderate Alzheimer's disease, it is not yet known how functional connectivity changes in ...patients as the disease progresses. Furthermore, it has been noted that the default mode network is not as homogenous as previously assumed and several fractionations of the network have been proposed. Here, we separately investigated the modulation of 3 default mode subnetworks, as identified with group independent component analysis, by comparing Alzheimer's disease patients to healthy controls and by assessing connectivity changes over time. Our results showed decreased connectivity at baseline in patients versus controls in the posterior default mode network, and increased connectivity in the anterior and ventral default mode networks. At follow-up, functional connectivity decreased across all default mode systems in patients. Our results suggest that earlier in the disease, regions of the posterior default mode network start to disengage whereas regions within the anterior and ventral networks enhance their connectivity. However, as the disease progresses, connectivity within all systems eventually deteriorates.
Cancer is a disease driven by genetic variation and mutation. Exome sequencing can be utilized for discovering these variants and mutations across hundreds of tumors. Here we present an analysis ...tool, VarScan 2, for the detection of somatic mutations and copy number alterations (CNAs) in exome data from tumor-normal pairs. Unlike most current approaches, our algorithm reads data from both samples simultaneously; a heuristic and statistical algorithm detects sequence variants and classifies them by somatic status (germline, somatic, or LOH); while a comparison of normalized read depth delineates relative copy number changes. We apply these methods to the analysis of exome sequence data from 151 high-grade ovarian tumors characterized as part of the Cancer Genome Atlas (TCGA). We validated some 7790 somatic coding mutations, achieving 93% sensitivity and 85% precision for single nucleotide variant (SNV) detection. Exome-based CNA analysis identified 29 large-scale alterations and 619 focal events per tumor on average. As in our previous analysis of these data, we observed frequent amplification of oncogenes (e.g., CCNE1, MYC) and deletion of tumor suppressors (NF1, PTEN, and CDKN2A). We searched for additional recurrent focal CNAs using the correlation matrix diagonal segmentation (CMDS) algorithm, which identified 424 significant events affecting 582 genes. Taken together, our results demonstrate the robust performance of VarScan 2 for somatic mutation and CNA detection and shed new light on the landscape of genetic alterations in ovarian cancer.
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