Citations

Objective— It is unclear to what extent genetic susceptibility variants are shared between peripheral artery disease (PAD) and coronary heart disease (CHD), both manifestations of atherosclerotic vascular disease. We investigated whether common and low-frequency/rare variants in loci associated with CHD are also associated with PAD. Approach and Results— Targeted sequencing of 41 genomic regions associated with CHD in genome-wide association studies was performed in 1749 PAD cases (65±11 years, 61% men) and 1855 controls (60±11 years, 56% men) of European ancestry. PAD cases had a resting/postexercise ankle-brachial index ≤0.9, or history of lower extremity revascularization; controls had no history of PAD. We tested the association of common (defined as minor allele frequency ≥5%) variants with PAD assuming an additive genetic model with adjustment for age and sex. To identify low-frequency/rare variants (minor allele frequency <5%) associated with PAD, we conducted gene-level analyses using sequence kernel association test and permutation test. After Bonferroni correction, we found common variants in SH2B3, ABO , and ZEB2 to be associated with PAD ( P <4.5×10 −5 ). At the gene level, the strongest associations were for LPL and SH2B3 . Conclusions— Targeted sequencing of 41 genomic regions associated with CHD revealed several common variants/genes to be associated with PAD, highlighting the basis of shared genetic susceptibility between CHD and PAD.

AbstractIntroductionWe sought to determine if a proteomic profile approach developed to detect Alzheimer's disease would distinguish patients with Lewy body disease from normal controls, and if it would distinguish dementia with Lewy bodies (DLB) from Parkinson's disease (PD).MethodsStored plasma samples were obtained from 145 patients (DLB n = 57, PD without dementia n = 32, normal controls n = 56) enrolled from patients seen in the Behavioral Neurology or Movement Disorders clinics at the Mayo Clinic, Florida. Proteomic assays were conducted and analyzed as per our previously published protocols.ResultsIn the first step, the proteomic profile distinguished the DLB‐PD group from controls with a diagnostic accuracy of 0.97, sensitivity of 0.91, and specificity of 0.86. In the second step, the proteomic profile distinguished the DLB from PD groups with a diagnostic accuracy of 0.92, sensitivity of 0.94, and specificity of 0.88.DiscussionThese data provide evidence of the potential utility of a multitiered blood‐based proteomic screening method for detecting DLB and distinguishing DLB from PD.

Background: Low-intensity pulsed ultrasound (LIPUS), as a safe biophysiotherapy, can enhance bone-tendon (B-T) healing in vivo and induce osteogenic or chondrogenic differentiation of mesenchymal stromal cells in vitro. This study aimed to determine whether LIPUS can improve the efficacy of transplanted mesenchymal stromal cells on B-T healing. Hypothesis: LIPUS can induce lineage-specific differentiation of transplanted adipose-derived stromal cells (ASCs) at the B-T healing site, thus resulting in superior healing quality when compared with LIPUS or ASCs alone. Study Design: Controlled laboratory study. Methods: A total of 112 mature rabbits with partial patellectomy in the hindlimb were randomly assigned into mock sonication without ASCs (control), ultrasonication without ASCs (LIPUS), mock sonication with ASCs (ASCs), and ultrasonication with ASCs (LIPUS + ASCs). The treatment time of the mock sonication or ultrasonication was 20 minutes per day. Autologous ASCs were transplanted to the healing site by fibrin glue during the operation, and LIPUS was delivered daily starting at postoperative day 3 until euthanasia. The patella–patellar tendon junctions were postoperatively harvested at 8 and 16 weeks for radiological, histological, and mechanical evaluations. Additionally, 9 animals were used for ASC tracking with mCherry protein. Results: Radiologically, there was more new bone formation and remodeling in the LIPUS + ASCs group as compared with the other groups. Synchrotron radiation micro–computed tomography showed that the LIPUS + ASCs group significantly increased bone volume fraction, trabecular thickness, and trabecular number at the healing site as compared with the other groups at postoperative 8 weeks ( P < .05 for all). Histologically, immunohistochemical staining confirmed that the transplanted mCherry-ASCs can differentiate into osteoblasts and fibrochondrocytic-like cells. Meanwhile, as compared with the other groups, the LIPUS + ASCs group showed more formation and maturity of the fibrocartilage layer and new bone at postoperative weeks 8 and 16 ( P < .05 for all). Biomechanically, the LIPUS + ASCs group showed significantly higher failure load and stiffness versus the other groups at postoperative weeks 8 and 16 ( P < .05 for all). Conclusion: Autologous ASC transplantation stimulated with LIPUS can result in superior B-T healing quality when compared with LIPUS or ASCs alone. Clinical Relevance: This study demonstrates the effectiveness of using ASC transplantation stimulated with LIPUS for B-T healing and provides a foundation for future clinical studies.

Alpha‐1 antitrypsin deficiency (AATD) liver disease is characterized by marked heterogeneity in presentation and progression, despite a common underlying gene mutation, strongly suggesting the involvement of other genetic and/or epigenetic modifiers. Variation in clinical phenotype has added to the challenge of detection, diagnosis, and testing of new therapies in patients with AATD. We examined the contribution of DNA methylation (5‐methylcytosine [5mC]) to AATD liver disease heterogeneity because 5mC responds to environmental and genetic cues and its deregulation is a major driver of liver disease. Using liver biopsies from adults with early‐stage AATD and the ZZ genotype, genome‐wide 5mC patterns were interrogated. We compared DNA methylation among patients with early AATD, and among patients with normal liver, cirrhosis, and hepatocellular carcinoma derived from multiple etiologic exposures, and linked patient clinical/demographic features. Global analysis revealed significant genomic hypomethylation in AATD liver–impacting genes related to liver cancer, cell cycle, and fibrosis, as well as key regulatory molecules influencing growth, migration, and immune function. Further analysis indicated that 5mC changes are localized, with hypermethylation occurring within a background of genome‐wide 5mC loss and with patients with AATD manifesting distinct epigenetic landscapes despite their mutational homogeneity. By integrating clinical data with 5mC landscapes, we observed that CpGs differentially methylated among patients with AATD disease are linked to hallmark clinical features of AATD (e.g., hepatocyte degeneration and polymer accumulation) and further reveal links to well‐known sex‐specific effects of liver disease progression. Conclusion: Our data reveal molecular epigenetic signatures within this mutationally homogeneous group that point to ways to stratify patients for liver disease risk.

Background The prognostic significance of obstructive sleep apnea ( OSA ) in patients with acute coronary syndrome ( ACS ) in the contemporary era is unclear. We performed a large, prospective cohort study and did a landmark analysis to delineate the association of OSA with subsequent cardiovascular events after ACS onset. Methods and Results Between June 2015 and May 2017, consecutive eligible patients admitted for ACS underwent cardiorespiratory polygraphy during hospitalization. OSA was defined as an apnea‐hypopnea index ≥15 events·h −1 . The primary end point was major adverse cardiovascular and cerebrovascular event ( MACCE ), including cardiovascular death, myocardial infarction, stroke, ischemia‐driven revascularization, or hospitalization for unstable angina or heart failure. OSA was present in 403 of 804 (50.1%) patients. During median follow‐up of 1 year, cumulative incidence of MACCE was significantly higher in the OSA group than in the non‐ OSA group (log‐rank, P =0.041). Multivariate analysis showed that OSA was nominally associated with incidence of MACCE (adjusted hazard ratio, 1.55; 95% CI, 0.94–2.57; P =0.085). In the landmark analysis, patients with OSA had 3.9 times the risk of incurring a MACCE after 1 year (adjusted hazard ratio, 3.87; 95% CI, 1.20–12.46; P =0.023), but no increased risk was found within 1‐year follow‐up (adjusted hazard ratio, 1.18; 95% CI, 0.67–2.09; P =0.575). No significant differences were found in the incidence of cardiovascular death, myocardial infarction, and ischemia‐driven revascularization, except for a higher rate of hospitalization for unstable angina in the OSA group than in the non‐ OSA group (adjusted hazard ratio, 2.10; 95% CI, 1.09–4.05; P =0.027). Conclusions There was no independent correlation between OSA and 1‐year MACCE after ACS . The increased risk associated with OSA was only observed after 1‐year follow‐up. Efficacy of OSA treatment as secondary prevention after ACS requires further investigation.

Abstract Motivation The significance of long non-coding RNAs (lncRNAs) in many biological processes and diseases has gained intense interests over the past several years. However, computational identification of lncRNAs in a wide range of species remains challenging; it requires prior knowledge of well-established sequences and annotations or species-specific training data, but the reality is that only a limited number of species have high-quality sequences and annotations. Results Here we first characterize lncRNAs in contrast to protein-coding RNAs based on feature relationship and find that the feature relationship between open reading frame length and guanine-cytosine (GC) content presents universally substantial divergence in lncRNAs and protein-coding RNAs, as observed in a broad variety of species. Based on the feature relationship, accordingly, we further present LGC, a novel algorithm for identifying lncRNAs that is able to accurately distinguish lncRNAs from protein-coding RNAs in a cross-species manner without any prior knowledge. As validated on large-scale empirical datasets, comparative results show that LGC outperforms existing algorithms by achieving higher accuracy, well-balanced sensitivity and specificity, and is robustly effective (&gt;90% accuracy) in discriminating lncRNAs from protein-coding RNAs across diverse species that range from plants to mammals. To our knowledge, this study, for the first time, differentially characterizes lncRNAs and protein-coding RNAs based on feature relationship, which is further applied in computational identification of lncRNAs. Taken together, our study represents a significant advance in characterization and identification of lncRNAs and LGC thus bears broad potential utility for computational analysis of lncRNAs in a wide range of species. Availability and implementation LGC web server is publicly available at http://bigd.big.ac.cn/lgc/calculator. The scripts and data can be downloaded at http://bigd.big.ac.cn/biocode/tools/BT000004. Supplementary information Supplementary data are available at Bioinformatics online.

Background: In 2012, updated cervical cancer screening recommendations were released with consensus on Papanicolaou (Pap) testing every 3 years for women age 21–65 years or Pap–human papillomavirus (HPV) cotesting at 5-year intervals for women age 30–65 years. Primary study aims: Assess current use of Pap-HPV cotesting and describe local population trends over time in Pap and Pap-HPV cotesting. Secondary aim: Assess sociodemographic factors correlating with screening. Methods: We assessed Rochester Epidemiology Project data for Pap and Pap-HPV cotesting among women age 16 years and older living in Olmsted County, Minnesota, yearly from 2005 (study population n = 47,203) through 2016 (study population n = 49,510). We calculated 3-year (Pap) and 5-year (Pap-HPV) moving prevalence rates of screening as proportion of eligible population. Multivariable logistic regression was used to assess factors potentially associated with screening. Results: In 2016, 64.6% of 27,418 eligible 30- to 65-year-old women were up to date with cervical cancer screening; 60.8% had received Pap-HPV cotest screening. Significant declines in Pap completion rates over time were observed in all age groups, including an unexpected decline in 21- to 29-year-old women. Coincident with decreasing Pap screening rates, Pap-HPV cotesting significantly increased among women age 30–65 years, from 10.0% in 2007 to 60.8% in 2016. Conclusions: This suggests increasing adoption of 2012 screening recommendations in the 30- to 65-year-old population. However, decline in Pap screening among 21- to 29-year-old women is concerning. Disparities by race, ethnicity, smoking status, and comorbidity level were observed. Results suggest need for multilevel patient and clinician interventions to increase cervical cancer screening adherence.