Subsequent Event Risk in Individuals with Established Coronary Heart Disease:Design and Rationale of the GENIUS-CHD Consortium

BACKGROUND: The "GENetIcs of sUbSequent Coronary Heart Disease" (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD. METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185,614 participants with either acute coronary syndrome, stable CHD or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events. RESULTS: Enrollment into the individual studies took place between 1985 to present day with duration of follow up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (HR 1.15 95% CI 1.14-1.16) per 5-year increase, male sex (HR 1.17, 95% CI 1.13-1.21) and smoking (HR 1.43, 95% CI 1.35-1.51) with risk of subsequent CHD death or myocardial infarction, and differing associations with other individual and composite cardiovascular endpoints. CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and non-genetic determinants of subsequent event risk in individuals with established CHD, in order to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Influence of Endothelin-1 in Aqueous Humor on Intermediate-Term Trabeculectomy Outcomes

Purpose. To investigate whether increased concentrations of ET-1 in aqueous humor of glaucoma patients influences surgical outcome of standard trabeculectomy with Mitomycin C. Methods. Retrospective chart review of 36 glaucoma patients with known ET-1 concentrations who had undergone trabeculectomy with Mitomycin C. Patients were divided into two groups based on their aqueous ET-1 concentration, a below-median (low ET-1) and an above-median (high ET-1) group. Postoperative IOP development, necessity of glaucoma medication, surgical success and complications, postoperative use of antifibrotics (5-FU), and number of additional glaucoma surgeries were compared between the groups. Results. Overall surgical success of trabeculectomy was comparable to published literature (90%, 81%, 76%, and 68% absolute success at 12, 24, 36, and 48 months after surgery). There was no difference between high and low ET-1 group in the postsurgical development of IOP, surgical success rate, or complication rate. There was no difference in postoperative scarring or indirect indicators thereof (e.g., number of 5-FU injections, needlings, suture lyses, or IOP lowering medications). Conclusion. In this set of patients, ET-1 in aqueous humor does not appear to have influenced surgical outcome of trabeculectomy with Mitomycin C. There is no indication of an increased likelihood of bleb fibrosis in patients with increased ET-1 concentrations

Influence of Endothelin-1 in Aqueous Humor on Intermediate-Term Trabeculectomy Outcomes

. Purpose. To investigate whether increased concentrations of ET-1 in aqueous humor of glaucoma patients influences surgical outcome of standard trabeculectomy with Mitomycin C. Methods. Retrospective chart review of 36 glaucoma patients with known ET-1 concentrations who had undergone trabeculectomy with Mitomycin C. Patients were divided into two groups based on their aqueous ET-1 concentration, a below-median (low ET-1) and an above-median (high ET-1) group. Postoperative IOP development, necessity of glaucoma medication, surgical success and complications, postoperative use of antifibrotics (5-FU), and number of additional glaucoma surgeries were compared between the groups. Results. Overall surgical success of trabeculectomy was comparable to published literature (90%, 81%, 76%, and 68% absolute success at 12, 24, 36, and 48 months after surgery). There was no difference between high and low ET-1 group in the postsurgical development of IOP, surgical success rate, or complication rate. There was no difference in postoperative scarring or indirect indicators thereof (e.g., number of 5-FU injections, needlings, suture lyses, or IOP lowering medications). Conclusion. In this set of patients, ET-1 in aqueous humor does not appear to have influenced surgical outcome of trabeculectomy with Mitomycin C. There is no indication of an increased likelihood of bleb fibrosis in patients with increased ET-1 concentrations

A comparison of mechanical models for the viscoelastic response of human breast carcinomas

The mechanical response of a living cell is notoriously complicated. The complex, heterogeneous characteristics of cellular structure introduce difficulties that simple linear models of viscoelasticity cannot overcome, particularly at moderate indentation depths. Herein, a nano-scale stress-relaxation analysis performed with an Atomic Force Microscope reveals that isolated human breast cells do not exhibit simple exponential relaxation capable of being modeled by the Standard Linear Solid (SLS) model. Therefore, this work proposes the application of a progression of more sophisticated models that may extract the mechanical parameters from the entire relaxation response, improving upon existing physical techniques to probe isolated cells. The first model under consideration is the Generalized Maxwell (GM) model that distributes the response of the cell across multiple time scales in an attempt to replicate the interaction of subcellular components. The second is a fractional model that operates without a priori assumptions of the cell's internal structure and describes the fractional time-derivative dependence of the response. The results show an exceptional increase in conformance to the experimental data compared to that predicted by the SLS model. Both models excel at mapping the relaxation behavior of the cells that occurs within a few seconds of the initial force. This area is generally ignored with an SLS fit and therefore not included in most cell differentiation studies. The results of the GM model show a significant change in the mechanical properties of the first relaxation mode, which validates the necessity of the early behavior's inclusion. The FZ model preserves the distinctions highlighted in the SLS model, but also incorporates the disparity in the early-relaxation times seen in the GM model as a change in the composite relaxation time. (Published By University of Alabama Libraries