Foresite (United States)

Background: Clinical trials for coronary artery disease (CAD) face significant challenges in cost, duration, and participant recruitment, especially in primary prevention settings. Enrichment strategies aim to improve trial efficiency; prognostic enrichment specifically selects participants at higher baseline risk of disease events. Polygenic risk scores (PRS) offer a potential tool for identifying such individuals based on their genetic predisposition. Research Question: Evaluation of the utility of a CAD PRS for prognostic enrichment of hypothetical phase 3 primary prevention cardiovascular outcome trials using real-world data from the Mass General Brigham (MGB) healthcare system and establish proof-of-concept for trial design methodology. Methods: A primary prevention cohort (N=16,569) of adults aged ≥30 without previous atherosclerotic cardiovascular disease (ASCVD) was identified from the MGB Biobank linked to electronic health records. Individual CAD PRS were calculated, defining a high-risk group (≥80th percentile PRS). The standard Pooled Cohort Equations (PCE) risk was compared to a PRS-adjusted PCE risk stratification for ASCVD. We ran individual-level Monte Carlo microsimulations to simulate trials to compare the effect of 3 recruitment strategies: No PRS enrichment, hybrid enrichment (50% from the high-risk PRS group / 50% other), and exclusively high-PRS risk group. Outcomes included time-to-target event accrual, power at fixed time, and required sample size. Results: The mean age was 58 ± 14.7 years. PRS effectively stratified ASCVD risk and significantly reclassified risk compared to PCE alone (17% upward,15.4% downward,and 1.6% net upward reclassification). Trial simulations demonstrated substantial efficiency gains with PRS-based prognostic enrichment. Compared to no PRS enrichment, recruiting only the high-risk PRS group reduced time-to-90%-power by approximately 2.4 years (Figure), increased power over 3 years (0.87 vs. 0.80), and reduced the required sample size by ~25% (8,109 vs. 10,833) to achieve 90% with 3 years of follow-up. Conclusion: This study provides a strong proof-of-concept that CAD PRS-based prognostic enrichment can significantly improve the efficiency of primary prevention cardiovascular trials, offering potential reductions in trial duration and sample size. While promising, prospective validation is required, alongside careful consideration of generalizability and equity across diverse populations.

Abstract The rapid expansion of massively parallel sequencing technologies has enabled the development of foundation models to uncover novel biological findings. While these have the potential to significantly accelerate scientific discoveries by creating AI-driven virtual cell models, their progress has been greatly limited by the lack of large-scale high-quality perturbation data, which remains constrained due to scalability bottlenecks and assay variability. Here, we introduce “Fix-Cryopreserve-ScRNAseq” (FiCS) Perturb-seq, an industrialized platform for scalable Perturb-seq data generation. We demonstrate that FiCS Perturb-seq exhibits high sensitivity and low batch effects, effectively capturing perturbation-induced transcriptomic changes and recapitulating known biological pathways and protein complexes. In addition, we release X-Atlas: Orion edition (X-Atlas/Orion), the largest publicly available Perturb-seq atlas. This atlas, generated from two genome-wide FiCS Perturb-seq experiments targeting all human protein-coding genes, comprises eight million cells deeply sequenced to over 16,000 unique molecular identifiers (UMIs) per cell. Furthermore, we show that single guide RNA (sgRNA) abundance can serve as a proxy for gene knockdown (KD) efficacy. Leveraging the deep sequencing and substantial cell numbers per perturbation, we also show that stratification by sgRNA expression can reveal dose-dependent genetic effects. Taken together, we demonstrate that FiCS Perturb-seq is an efficient and scalable platform for high-throughput Perturb-seq screens. Through the release of X-Atlas/Orion, we highlight the potential of FiCS Perturb-seq to address current scalability and variability challenges in data generation, advance foundation model development that incorporates gene-dosage effects, and accelerate biological discoveries.

Electronic assembly production relies on a complex dance between OEM, CM tier one, two, fabricators and subcontractors with a series of design, fabrication, component and PCB inventory FIFO, under ever changing schedules, delays, and technology advances. Schedules are the focus of many meetings, calls and audits so when removal of built hardware counted in the inventory, but defects are identified, and rework / repair is required. These units are set aside, and rework operators trained in soldering / removal / repair with a focus on solder quality of repair is designed to be equal to the original soldering conditions. Debriding solder shorts, tombstone repair, lifted leads, or complete component replacement allow the spent cost of a non-conforming PCBA to be repaired and meet the functionality of a completed assembly. As electronic hardware is assembled with no clean soldering technologies the AOI, Xray and 610 inspections, but under rework repair solder quality and expertise of rework is critical to meet schedules and quality. But with all that, we find more and more OEMs restricting or eliminating any rework hardware due to quality issues in the field.

Near-eutectic tin-bismuth alloy is a strong contender as the solder of choice for low-temperature electronic assembly applications. This paper will describe the recent significant developments by the iNEMI project team on the understanding of the electromigration behavior of Sn-Bi solder which has a unique physical metallurgy and electromigration behavior quite different for that of Sn-Ag-Cu (SAC) solder and other solders in common use today. The high rate of Bi electromigration and its high homologous temperature sets the near-eutectic Sn-Bi solder apart from the SAC and the Sn-Pb solders. The latter have lower homologous temperatures and have no one element dominating the electromigration phenomenon that can be readily tracked to monitor their electromigration behavior. In Sn-Bi alloys, the rates of Bi electromigration are clearly reflected in the rates of electrical resistance increase making it more convenient to use the fundamental physics-based electromigration equations rather than Black’s somewhat empirical equation that deals with the mean time to failure of solder joints. The high homologous temperature of Sn-Bi alloys makes in-situ study of electromigration in a scanning electron microscope more convenient, resulting in a much deeper understanding of the physical metallurgy and electromigration of the Sn-Bi alloys. For example, recent in-situ studies have shown that the root cause of decreasing solder electrical resistance in the early stage of electromigration, very evident at low temperatures and low current densities, is due to the microstructural coarsening of the alloy. When results are summarized on Arrhenius plots, the prediction of electromigration life under any given field condition becomes straightforward.

ABSTRACT Dendrites, Electrochemical Migration (ECM) and parasitic leakage, are usually caused by process related contamination. For example, excess flux, poor handling, extraneous solder, fibers, to name a few. One does not normally relate these fails with environmental causes. However, creep corrosion is a mechanism by which electronic products fail in application, primarily related to sulfur pollution present in the air. 1 The sulfur reacts with exposed silver, and to a lesser extent, exposed copper. This paper will explore various aspects of the creep corrosion chemical reaction What is driving the creep corrosion reaction? Why is drying the product a necessary precursor to obtaining creep corrosion in tests? 2, 3 Test methods with Flowers of Sulfur, FoS, and sulfur rich clay. Discussion of creep corrosion related field fails. When does creep corrosion become ECM. Sources of sulfur containing pollution. Methods to take to avoid creep corrosion. While there are places with sulfur containing pollution, creep corrosion will be a factor which will impact reliability. Creep corrosion will need to be understood and handled.

Since the 1980s the electronics industry has utilized ion chromatography (IC) analysis to understand the relationship of ions, and some organics, to product reliability. From component and board fabrication to complete electronic assemblies and their end-use environment, IC analysis has been the de facto method for evaluating ionic cleanliness of electronic hardware. Typical ions accounted for include chloride, bromide, nitrate, sulfate, weak-organic acid (WOA), sodium and ammonium. Environmental and other concerns have driven the industry to adopt myriad flux formulations, which has created a need to further differentiate weak-organic acids beyond what a typical IC system using conductivity can provide. By utilizing an Ion Chromatography/Mass Spectroscopy (IC/MS) system optimized for organic separation, we can use the same IC column technology for the typical suite of anion/organic species, then run the sample through a quad-pole mass spectrometer which provides the molecular weight assessment of organics for over two dozen channels. This capability is critical to our failure analysis work at Foresite, as it allows for identification of specific organic acids and flux activators. This information can aid in identifying specific residue sources (e.g. board fabrication, SMT paste flux, waver solder liquid flux, hand solder flux or a completely different, possibly unauthorized, source.

J.A.W. is an employee of Foresite Capital.

Creation of a reference bibliographic list of English-language open access publications from the Internet on the issues of the specific effects of heavy metals on freshwater ecosystems, their bioaccumulation and bioindication, as well as the functions of microelements in the hydrobionts organisms.Methodology.In the process of preparing the thematic list, in the course of systemic search, holistic and selective methods were applied.

ABSTRACT When cleaning today’s electronics with low standoff heights and tight pitch leads being able to penetrate around those leads and under the component body to fully remove flux and other process residues is paramount. With many assembly processes using a no-clean flux with the intent to be cleaned the use of aqueous based saponifier is on the rise. The basic purpose of saponifier is to lower the surface tension of the water as well as to aid in softening the residues for removal. The use of tap, RO, or DI water with the saponifier can and will play a role in the end cleanliness results. This paper will investigate the use of water only cleaning on a no clean flux as well as a saponified wash using the variable of tap, RO, and DI water as the carrier.