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Mehrnoosh Bahadorani, Mahboobeh Nasiri, Kristen Dellinger, Shyam Aravamudhan, Reza Zadegan Department of Nanoengineering, Joint School of Nanoscience & Nanoengineering, North Carolina Agriculture and Technical State University, Greensboro, NC, USACorrespondence: Reza Zadegan, Department of Nanoengineering, Joint School of Nanoscience & Nanoengineering, North Carolina Agriculture and Technical State University, Greensboro, NC, USA, Tel +1(336)285-2857, Email rzadegan@ncat.eduAbstract: Exosomes emerge from endosomal invagination and range in size from 30 to 200 nm. Exosomes contain diverse proteins, lipids, and nucleic acids, which can indicate the state of various physiological and pathological processes. Studies have revealed the remarkable clinical potential of exosomes in diagnosing and prognosing multiple diseases, including cancer, cardiovascular disorders, and neurodegenerative conditions. Exosomes also have the potential to be engineered and deliver their cargo to a specific target. However, further advancements are imperative to optimize exosomes’ diagnostic and therapeutic capabilities for practical implementation in clinical settings. This review highlights exosomes’ diagnostic and therapeutic applications, emphasizing their engineering through simple incubation, biological, and click chemistry techniques. Additionally, the loading of therapeutic agents onto exosomes, utilizing passive and active strategies, and exploring hybrid and artificial exosomes are discussed.Keywords: exosome, engineered exosomes, drug delivery, diagnostics, therapeutics

Background: Differentiating between different states in nucleic acid circuits is crucial for various biological applications. One approach, there is a requirement for complicated sequential summation, which can be excessive for practical purposes. By selectively labeling biologically significant states, this study tackles the issue and presents a more cost-effective and streamlined solution. The challenge is to efficiently distinguish between different states in a nucleic acid circuit., Results: An innovative method is introduced in this study to distinguish between states in a nucleic acid circuit, emphasizing the biologically relevant ones. The circuit comprises four DNA logic gates and two detection modules, one for determining fetal gender and the other for diagnosing X-linked genetic disorders. The primary module generates a G-quadruplex DNAzyme when activated by specific biomarkers, which leads to a distinct colorimetric signal. The secondary module responds to hemophilia and choroideremia biomarkers, generating one or two DNAzymes. The absence of female fetus indicators results in no DNAzyme or color change. The circuit can differentiate various fetal states by producing one to four active DNAzymes in response to male fetus biomarkers. A single-color solution for state differentiation is provided by this approach, which promises significant advancements in DNA computing and diagnostic applications., Significance: The innovative approach used in this study to distinguish states in nucleic acid circuits holds great significance. By selectively labeling biologically relevant states, circuit design is simplified and complexity is reduced. This advancement enables cost-effective and efficient diagnostic applications and contributes to DNA computing, providing a valuable solution to a fundamental problem., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

DNA's programmable, predictable, and precise self-assembly properties enable structural DNA nanotechnology. DNA nanostructures have a wide range of applications in drug delivery, bioimaging, biosensing, and theranostics. However, physiological conditions, including low cationic ions and the presence of nucleases in biological systems, can limit the efficacy of DNA nanostructures. Several strategies for stabilizing DNA nanostructures have been developed, including i) coating them with biomolecules or polymers, ii) chemical cross-linking of the DNA strands, and iii) modifications of the nucleotides and nucleic acids backbone. These methods significantly enhance the structural stability of DNA nanostructures and thus enable in vivo and in vitro applications. This study reviews the present perspective on the distinctive properties of the DNA molecule and explains various DNA nanostructures, their advantages, and their disadvantages. We provide a brief overview of the biomedical applications of DNA nanostructures and comprehensively discuss possible approaches to improve their biostability. Finally, the shortcomings and challenges of the current biostability approaches are examined., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

While the archival digital memory industry approaches its physical limits, the demand is significantly increasing, therefore alternatives emerge. Recent efforts have demonstrated DNA's enormous potential as a digital storage medium with superior information durability, capacity, and energy consumption. However, the majority of the proposed systems require on-demand de-novo DNA synthesis techniques that produce a large amount of toxic waste and therefore are not industrially scalable and environmentally friendly. Inspired by the architecture of semiconductor memory devices and recent developments in gene editing, we created a molecular digital data storage system called "DNA Mutational Overwriting Storage" (DMOS) that stores information by leveraging combinatorial, addressable, orthogonal, and independent in vitro CRISPR base-editing reactions to write data on a blank pool of greenly synthesized DNA tapes. As a proof of concept, this work illustrates writing and accurately reading of both a bitmap representation of our school's logo and the title of this study on the DNA tapes., (© 2023. Springer Nature Limited.)

Silicon is the gold standard for information storage systems. The exponential generation of digital information will exhaust the global supply of refined silicon. Therefore, investing in alternative information storage materials such as DNA has gained momentum. DNA as a memory material possesses several advantages over silicon-based data storage, including higher storage capacity, data retention, and lower operational energy. Routine DNA data storage approaches encode data into chemically synthesized nucleotide sequences. The scalability of DNA data storage depends on factors such as the cost and the generation of hazardous waste during DNA synthesis, latency of writing and reading, and limited rewriting capacity. Here, we review the current status of DNA data storage encoding, writing, storing, retrieving and reading, and discuss the technology's challenges and opportunities., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Deoxyribonucleic acid (DNA) is emerging as an alternative archival memory technology. Recent advancements in DNA synthesis and sequencing have both increased the capacity and decreased the cost of storing information in de novo synthesized DNA pools. In this survey, we review methods for translating digital data to and/or from DNA molecules. An emphasis is placed on methods which have been validated by storing and retrieving real-world data via in-vitro experiments., (© 2023. The Author(s).)

Introduction: Invasive right heart catheterization (RHC) provides valuable prognostic information in cases of severe aortic stenosis, but is not done routinely prior to transcatheter aortic valve replacement (TAVR). Therefore, we sought to investigate the prognostic utility of pre-TAVR RHC for assessing outcomes post TAVR., Methods: This is a single-center, retrospective study of patients who underwent RHC prior to TAVR between June 2011 and March 2019. We evaluated abnormalities in the following variables as predictors of poor outcomes post TAVR: pulmonary capillary wedge pressure (PCWP), systolic pulmonary artery pressure (PASP), mixed venous oxygen saturation (MVO2), right ventricular stroke work index (RVSWI), and right atrial pressure (RAP). Cox proportional hazard regression models were used to assess the primary composite outcome of all-cause mortality and hospitalization for heart failure., Results: A total of 522 patients (mean age, 83.5 ± 4.5 years; 49.4% women) with complete invasive hemodynamic data were included. At a median follow-up of 529.5 days, there were 127 deaths and 59 heart failure hospitalizations. On multivariate analysis, PCWP ≥15 mm Hg (hazard ratio [HR], 1.48; 95% confidence interval [CI], 1.02-2.07), PASP ≥50 mm Hg (HR, 1.66; 95% CI, 1.17-2.36), MVO2 ≤60% (HR, 1.42; 95% CI, 1.01-1.98), RVSWI ≥12 g•m/m²/beat (HR, 1.40; 95% CI, 1.004-1.94), and RAP ≥10 mm Hg (HR, 1.66; 95% CI, 1.09-2.51) were independent predictors of death or heart failure hospitalization., Conclusions: Preprocedural invasive RHC provides useful prognostic information. A comprehensive invasive hemodynamic assessment should be considered for risk stratification in patients undergoing TAVR.

Background: Older patients are underrepresented in landmark randomized trials for stable ischemic heart disease (SIHD). Therefore, we sought to evaluate the benefits of revascularization in patients ≥80 years old with SIHD., Methods: Retrospective study of patients undergoing invasive coronary angiography (ICA) for SIHD between 2009 and 2019. Patients were grouped according to treatment: revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]) versus initial medical therapy alone. Inverse probability of treatment weighting (IPTW)-adjusted Cox proportional hazard regression analyses were performed. Outcomes evaluated were all-cause mortality, non-fatal myocardial infarction (MI), and repeat revascularization., Results: A total of 1015 patients (median age 83.0, interquartile range [IQR] 81.3-85.2 years; 29% female) underwent ICA for SIHD. Of these, 557 (55%) were treated with revascularization and 458 (45%) with initial medical therapy alone. Baseline characteristics were well balanced after IPTW adjustment. At median follow-up of 3.5 years (IQR 1.7-5.9 years), there were no differences in all-cause mortality and non-fatal MI between treatment groups; but there was an increased need for repeat revascularization (IPTW adjusted hazard ratio 2.22, 95% confidence interval 1.53-3.22) with revascularization. Separately comparing PCI or CABG alone versus medical therapy yielded similar results; as well as in subgroup analysis (except for patients ≥90 years old and those without prior CABG)., Conclusion: There were no differences in all-cause mortality and non-fatal MI with invasive revascularization (either PCI or CABG) versus medical therapy alone in patients ≥80 years old with SIHD. Large randomized trials focusing on older patients are warranted to guide clinical practice in this growing population., (© 2021 The American Geriatrics Society.)

Background: Neighborhoods have a powerful impact on health. Prior investigations into disparities associated with transcatheter aortic valve replacement (TAVR) have focused on race and access to the procedure. We sought to investigate the role of neighborhood disadvantage on mortality post-TAVR., Methods: Patients who underwent TAVR at Kaiser Permanente Los Angeles Medical Center between June, 2011 and March, 2019 were evaluated. Neighborhood disadvantage was defined using the area deprivation index, an established and validated index that considers multiple socioeconomic metrics. Cutoffs used for disadvantage were national percentile ≥25% and state decile ≥6. Cox proportional hazards regression analysis was used to assess outcomes., Results: A total of 668 patients (age 82.1 ± 7.5 years, 49% female) were included, of which 215 (32.2%) were from disadvantaged neighborhoods by state decile, and 167 (25%) by national percentile. At a median follow-up of 18.8 months (interquartile range 8.7-36.5 months), neighborhood disadvantage was independently associated with increased all-cause mortality (National percentile: hazard ratio [HR] 1.91, 95% confidence interval [CI] 1.35-2.69; state decile: HR 1.68, 95% CI 1.21-2.34). On propensity scored analysis, neighborhood disadvantaged remained independently associated with increased all-cause mortality (National percentile: IPTW HR 1.86, 95% CI 1.52-2.28, PSM HR 1.67, 95% CI 1.11-2.51; state decile: IPTW HR 1.55, 95% CI 1.26-1.91, PSM HR 2.0, 95% CI 1.33-2.99)., Conclusion: Living in a disadvantaged neighborhood was independently associated with increased mortality post-TAVR on multivariate and propensity score matched analysis. Further investigations into the role of neighborhood disadvantage are needed to address disparities and improve outcomes post-TAVR., (© 2021 Wiley Periodicals LLC.)

Purpose: Conduction disturbances after transcatheter aortic valve replacement (TAVR) requiring pacemaker (PPM) implantation are a known complication and may be reversible. Therefore, we sought to evaluate the incidence and predictors for atrioventricular (AV) conduction recovery after TAVR., Methods: A single-center, retrospective study of patients undergoing PPM implantation for conduction disorders after TAVR between June 2011 and March 2019. Conduction recovery was defined as ≤ 1% ventricular pacing (VP) on follow-up PPM interrogation., Results: A total of 110 patients (mean age 83.6 ± 6.6 years, 46.8% female) were included. At a median follow-up of 438 days (interquartile range [IQR] 111-760 days), 35 patients (32%) had conduction recovery, with 50% of these occurring within the first 6 months. On multivariate analysis, predictors of conduction recovery include female sex (hazard ratio [HR] 2.5, 95% confidence interval [CI] 1.01-6.4, p = 0.048), non-VP/non-complete heart block rhythm immediately post-TAVR (HR 5.2, 95% CI 1.5-18.1, p = 0.011), normal sinus rhythm 7 days post-TAVR (HR 3.9, 95% CI 1.7-9.2, p = 0.002), and smaller valve size (mm) (HR 0.81, 95% CI 0.7-0.996, p = 0.045). Significant narrowing of the QRS and resolution of new-onset left bundle branch block within 1 month post-TAVR occurred in those with conduction recovery on PPM interrogation., Conclusions: One-third of patients receiving new PPM implantation have conduction recovery after TAVR, with 50% occurring within the first 6 months. Patient gender, valve size, and rhythm on serial ECGs after TAVR can help identify patients that may recover AV conduction. A conservative approach rather than immediate PPM implantation may be considered in these patients., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The optimal strategy for arterial closure in percutaneous transfemoral transcatheter aortic valve replacement (TF-TAVR) remains under debate., Methods: Single-center, prospective, observational study of consecutive patients undergoing TF-TAVR between March 2018 and December 2019 who underwent closure with an upfront single vs double Perclose device. Device success, access-site vascular, and bleeding complications were defined according to the Valvular Academic Research Consortium (VARC)-2 criteria. Inverse-probability of treatment weighting (IPTW) was used to balance baseline characteristics between groups., Results: A total of 241 patients (mean age, 81.4 ± 8.5 years, 47% women) were included, of which 127 underwent an upfront single-Perclose (SP) strategy and 114 underwent an upfront double-Perclose (DP) strategy. Fifty-six percent of patients were treated with a CoreValve (Medtronic). The SP group was less likely to be on dialysis and on aspirin, but were more likely to receive a CoreValve, with larger valve sizes and larger delivery sheaths. Baseline characteristics were well balanced after IPTW adjustment. Device success rate was comparable between groups (96% in the SP group vs 93% in the DP group; P=.39). The SP technique was associated with fewer vascular complications (8.7% in the SP group vs 26.3% in the DP group; P<.01; IPTW relative risk [RR], 0.34; 95% confidence Interval [CI], 0.16-0.71) and bleeding complications (2.4% in the SP group vs 12.3% in the DP group; P<.01; IPTW RR, 0.21; 95% CI, 0.06-0.76) compared with the DP technique. There were no differences in 30-day mortality., Conclusion: An upfront SP technique is equally efficacious and not associated with increased vascular and bleeding complications compared with an upfront DP technique in patients undergoing percutaneous TF-TAVR.

Introduction: Chronic kidney disease (CKD), acute kidney injury (AKI) and worsening renal function at 30 days after transcatheter aortic valve replacement (TAVR) portend poor outcomes. We sought to evaluate the association between worsening renal function at 3-6 months and mortality among patients with baseline renal dysfunction undergoing TAVR., Methods: This is a retrospective study of patients with glomerular filtration rate (GFR) < 60 ml/min undergoing TAVR between June 2011 and March 2019 at the Regional Cardiac Catheterization Lab at Kaiser Permanente Los Angeles. Worsening renal function at 3-6 months post-TAVR was defined as: increase in serum creatinine >1.5 times compared to baseline, absolute increase of ≥0.3 mg/dl, or initiation of dialysis., Results: Of 683 patients reviewed, 176 were included in the analysis (median age 84 [IQR 79-88] years, 56% female). Of these, 27 (15.3%) had worsening renal function. AKI post-TAVR (OR 2.9, 95% CI 1.1-7.4, p = .03) and transfusion of ≥4 units red blood cells (OR 8.4, 95% CI 1.2-59, p = .03) were independent predictors of worsening renal function. Worsening renal function increased risk for mortality (HR 2.2, 95% CI 1.17-4.27, p = .015) at a median follow-up of 691 days. Those with improved/stable function with baseline GFR < 60 ml/min had comparable mortality risk to those with baseline GFR ≥ 60 ml/min (18% vs. 16.5%; HR 1.1, 95% CI 0.72-1.75, p = .62)., Conclusion: Among patients with baseline renal dysfunction, only 15% developed worsening renal function at 3-6 months after TAVR, which was associated with increased mortality. Predictors for worsening renal function include AKI and blood transfusions. Preventative measures peri-procedurally and continued monitoring post-discharge are warranted to improve outcomes., (© 2020 Wiley Periodicals LLC.)

DNA is a compelling alternative to non-volatile information storage technologies due to its information density, stability, and energy efficiency. Previous studies have used artificially synthesized DNA to store data and automated next-generation sequencing to read it back. Here, we report digital Nucleic Acid Memory (dNAM) for applications that require a limited amount of data to have high information density, redundancy, and copy number. In dNAM, data is encoded by selecting combinations of single-stranded DNA with (1) or without (0) docking-site domains. When self-assembled with scaffold DNA, staple strands form DNA origami breadboards. Information encoded into the breadboards is read by monitoring the binding of fluorescent imager probes using DNA-PAINT super-resolution microscopy. To enhance data retention, a multi-layer error correction scheme that combines fountain and bi-level parity codes is used. As a prototype, fifteen origami encoded with 'Data is in our DNA!\n' are analyzed. Each origami encodes unique data-droplet, index, orientation, and error-correction information. The error-correction algorithms fully recover the message when individual docking sites, or entire origami, are missing. Unlike other approaches to DNA-based data storage, reading dNAM does not require sequencing. As such, it offers an additional path to explore the advantages and disadvantages of DNA as an emerging memory material.

Background/objectives: Older patients are underrepresented in acute coronary syndrome clinical trials. We sought to evaluate the benefits of revascularization in patients aged 80 years and older presenting with acute myocardial infarction (AMI)., Design: Retrospective study utilizing inverse probability of treatment weighting (IPTW)., Setting: Single tertiary referral center for an integrated healthcare system in southern California., Participants: Patients undergoing invasive coronary angiography for AMI between 2009 and 2019, and subsequently treated with percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), or medical therapy alone., Measurements: All-cause mortality, nonfatal myocardial infarction (MI), and repeated revascularization., Results: A total of 1,433 patients aged 80 years or older (median age = 83.5 years; 66% male) presenting with AMI who underwent treatment with PCI (50%), CABG (12%), or medical therapy alone (38%) were included. Those treated with medical therapy were more likely to be Black, had one or more chronic total occlusions in any vessel, had more comorbidities, and had lower left ventricular ejection fraction. Baseline characteristics were well balanced after IPTW adjustment. Median follow-up was 2.6 years. Revascularization (PCI or CABG) was associated with reduced mortality (hazard ratio (HR) = 0.66; 95% confidence interval (CI) = 0.60-0.73) and nonfatal MI (HR = 0.68; 95% CI = 0.58-0.78), but an increased need for repeated revascularization (HR = 1.60; 95% CI = 1.15-2.23). Separately comparing PCI or CABG alone versus medical therapy yielded similar results. Revascularization was associated with lower mortality in all subgroups, except in Black patients and those with prior CABG., Conclusion: Revascularization is superior to medical therapy in reducing all-cause mortality and nonfatal MI in patients aged 80 years and older with AMI. Age alone should not preclude patients from potentially beneficial invasive therapies., (© 2020 The American Geriatrics Society.)

Background/objectives: The goal of this study was to describe the pattern of statin adherence in older patients, aged 80 years or older; identify factors associated with high adherence; and determine the association between statin adherence and all-cause mortality., Design: Retrospective population-based cohort study., Setting: An integrated healthcare system in Southern California., Participants: Patients hospitalized with a principal diagnosis of acute myocardial infarction (MI) between January 1, 2006, and December 31, 2016., Measurements: Statin adherence, as measured using pharmacy dispensing records over the 365 days following hospital discharge, based on proportion of days covered (PDC). Adherence levels were categorized as high (PDC 80% or higher), partial (PDC 40% or higher and lower than 80%), and low (PDC lower than 40%)., Results: Between 2006 and 2016, 5629 patients, 80 years or older, hospitalized for acute MI met the inclusion criteria. Among this group, 68.8% were highly adherent to statin therapy, 20.4% were partially adherent, and 10.8% were not adherent. Male sex (odds ratio [OR] = 1.42; 95% confidence interval [CI] = 1.25-1.62) and white race (OR = 1.35; 95% CI = 1.18-1.55) were associated with high statin adherence. Follow-up was 4.3 ± 2.6 years. Both low and partial adherence were associated with increase mortality (low adherence: adjusted hazard radio [HR] = 1.12; 95% CI = 1.01-1.25; partial adherence: adjusted HR = 1.22; 95% CI = 1.12-1.32)., Conclusions: In older patients, aged 80 years or older, high adherence to statins after MI was associated with improved survival. This association may not have been due only to adherence to statins but to other related factors as well. Findings from this study may inform discussions on the potential benefits of statin adherence. J Am Geriatr Soc 67:2045-2049, 2019., (© 2019 The American Geriatrics Society.)

Objectives: The purpose of this study was to determine whether long-term clinical outcomes differed between bare-metal stents (BMS) and drug-eluting stents (DES) by duration of clopidogrel use among diabetic patients., Background: There is concern that DES are associated with late adverse events such as death and myocardial infarction (MI) secondary to stent thrombosis. However, data on outcomes in diabetic patients remain limited., Methods: We identified 749 patients with diabetes mellitus who underwent stent implantation with either BMS (n = 251) or DES (n = 498) from October 2002 to December 2004. We performed survival analysis on the full cohort and on those event-free from death, MI, or repeat revascularization at 6 months (n = 671)., Results: By clopidogrel duration, the event rate for death or MI was 3.2% in the >9-month group, 9.4% in the 6- to 9-month group, and 16.5% in the <6-month group, p < 0.001. For death alone, the event rate was 0.5% in the >9-month group, 4.3% in the 6- to 9-month group, and 10.0% in the <6-month group, p < 0.001. When taking BMS clopidogrel non-users as a referent in the multivariate analysis, the hazard ratio (95% confidence interval [CI]) for death and nonfatal MI for DES clopidogrel users, DES clopidogrel nonusers, and BMS clopidogrel users were: HR 0.22 (95% CI 0.08 to 0.62, p = 0.005), HR 0.39 (95% CI 0.13 to 1.13, p = 0.08), and HR 0.25 (95% CI 0.08 to 0.81, p = 0.02), respectively., Conclusions: Longer duration of clopidogrel use was associated with a lower incidence of death or MI in both the BMS and DES groups. Among clopidogrel nonusers, the incidence of death/MI or death did not differ by stent type.