Citations

The use of flow diverters is a rapidly growing endovascular approach for the treatment of intracranial aneurysms. All FDA-approved flow diverters are composed of nitinol or cobalt-chromium, which will remain in the patient for the duration of their life. Bioresorbable flow diverters have been proposed by several independent investigators as the next generation of flow diverting devices. These devices aim to serve their transient function of occluding and healing the aneurysm prior to being safely resorbed by the body, eliminating complications associated with the permanent presence of conventional flow diverters. Theoretical advantages of bioresorbable flow diverters include (1) reduction in device-induced thrombosis; (2) reduction in chronic inflammation and device-induced stenosis; (3) reduction in side branch occlusion; (4) restoration of physiological vasomotor function; (5) reduction in imaging artifacts; and (6) use in pediatric applications. Advances made in the similar bioresorbable coronary stenting field highlight some of these advantages and demonstrate the feasibility and safety of bioresorbable endovascular devices in the clinic. The current work aims to review the progress of bioresorbable flow diverters, identify opportunities for further investigation, and ultimately stimulate the advancement of this technology.

Abstract Funding Acknowledgements Type of funding sources: None. Background The prevalence of Type-1 Brugada pattern in Caucasians and Asians have been estimated to be 20 and 180 per 100,000. However, the prevalence of Type-1 Brugada pattern in African Americans has never been studied. Purpose This study aims to identify the prevalence of Type-1 Brugada pattern in African Americans. Methods Medical records of African American patients ages 18 years old or older with at least one 12-lead electrocardiogram (ECG) performed at 16 hospitals from 5 states in a single healthcare system between January 1, 2011 to December 31, 2020 were included. The search engine software was used to identify patients with keywords (Brugada pattern, Brugada ECG, Brugada Type-1, or Brugada syndrome) documented in the electronic medical record. The 12-lead ECGs were retrospectively analyzed by 2 cardiologists. Any inconsistencies were reviewed by a third cardiac electrophysiologist. Type-1 Brugada pattern was diagnosed according to the recent Heart Rhythm Society Expert Consensus Statement. Results Among 43,116 African American patients, (46.9% males), 6 patients (mean age 44.8±13.9 years, 100% males) had Type-1 Brugada pattern documented on at least one 12-lead ECG. The prevalence of Type-1 Brugada pattern in this large patient population of African American was 13.9 per 100,000. None of the patients had major arrhythmic event at 6.7±4.7 years follow-up. Conclusions The prevalence of Type-1 Brugada pattern in African American is lower than Caucasian and Asian populations. The risk of major arrhythmic event of Type-1 Brugada pattern in African American appears to be low; however longer follow-up data is needed.

Background: Automated insulin delivery (AID) systems have proven effective in increasing time-in-range during both clinical trials and real-world use. Further improvements in outcomes for single-hormone (insulin only) AID may be limited by suboptimal insulin delivery settings. Methods: Adults (≥18 years of age) with type 1 diabetes were randomized to either sensor-augmented pump (SAP) (inclusive of predictive low-glucose suspend) or adaptive zone model predictive control AID for 13 weeks, then crossed over to the other arm. Each week, the AID insulin delivery settings were sequentially and automatically updated by an adaptation system running on the study phone. Primary outcome was sensor glucose time-in-range 70–180 mg/dL, with noninferiority in percent time below 54 mg/dL as a hierarchical outcome. Results: Thirty-five participants completed the trial (mean age 39 ± 16 years, HbA1c at enrollment 6.9% ± 1.0%). Mean time-in-range 70–180 mg/dL was 66% with SAP versus 69% with AID (mean adjusted difference +2% [95% confidence interval: −1% to +6%], P = 0.22). Median time <70 mg/dL improved from 3.0% with SAP to 1.6% with AID (−1.5% [−2.4% to −0.5%], P = 0.002). The adaptation system decreased initial basal rates by a median of 4% (−8%, 16%) and increased initial carbohydrate ratios by a median of 45% (32%, 59%) after 13 weeks. Conclusions: Automated adaptation of insulin delivery settings with AID use did not significantly improve time-in-range in this very well-controlled population. Additional study and further refinement of the adaptation system are needed, especially in populations with differing degrees of baseline glycemic control, who may show larger benefits from adaptation.

Abstract MSC (a.k.a. mesenchymal stem cell or medicinal signaling cell) cell therapies show promise in decreasing mortality in acute respiratory distress syndrome (ARDS) and suggest benefits in treatment of COVID-19-related ARDS. We performed a meta-analysis of published trials assessing the efficacy and adverse events (AE) rates of MSC cell therapy in individuals hospitalized for COVID-19. Systematic searches were performed in multiple databases through November 3, 2021. Reports in all languages, including randomized clinical trials (RCTs), non-randomized interventional trials, and uncontrolled trials, were included. Random effects model was used to pool outcomes from RCTs and non-randomized interventional trials. Outcome measures included all-cause mortality, serious adverse events (SAEs), AEs, pulmonary function, laboratory, and imaging findings. A total of 736 patients were identified from 34 studies, which included 5 RCTs (n = 235), 7 non-randomized interventional trials (n = 370), and 22 uncontrolled comparative trials (n = 131). Patients aged on average 59.4 years and 32.2% were women. When compared with the control group, MSC cell therapy was associated with a reduction in all-cause mortality (RR = 0.54, 95% CI: 0.35-0.85, I 2 = 0.0%), reduction in SAEs (IRR = 0.36, 95% CI: 0.14-0.90, I 2 = 0.0%) and no significant difference in AE rate. A sub-group with pulmonary function studies suggested improvement in patients receiving MSC. These findings support the potential for MSC cell therapy to decrease all-cause mortality, reduce SAEs, and improve pulmonary function compared with conventional care. Large-scale double-blinded, well-powered RCTs should be conducted to further explore these results.

Background: We investigated the potential benefits of automated insulin delivery (AID) among individuals with type 1 diabetes (T1D) in sub-populations of baseline device use determined by continuous glucose monitor (CGM) use status and insulin delivery via multiple daily injections (MDI) or insulin pump. Materials and Methods: In a six-month randomized, multicenter trial, 168 individuals were assigned to closed-loop control (CLC, Control-IQ, Tandem Diabetes Care), or sensor-augmented pump (SAP) therapy. The trial included a two- to eight-week run-in phase to train participants on study devices. The participants were stratified into four subgroups: insulin pump and CGM (pump+CGM), pump-only, MDI and CGM (MDI+CGM), and MDI users without CGM (MDI-only) users. We compared glycemic outcomes among four subgroups. Results: At baseline, 61% were pump+CGM users, 18% pump-only users, 10% MDI+CGM users, and 11% MDI-only users. Mean time in range 70-180 mg/dL (TIR) improved from baseline in the four subgroups using CLC: pump+CGM, 62% to 73%; pump-only, 61% to 70%; MDI+CGM, 54% to 68%; and MDI-only, 61% to 69%. The reduction in time below 70 mg/dL from baseline was comparable among the four subgroups. No interaction effect was detected with baseline device use for TIR ( P = .67) or time below ( P = .77). On the System Usability Questionnaire, scores were high at 26 weeks for all subgroups: pump+CGM: 87.2 ± 12.1, pump-only: 89.4 ± 8.2, MDI+CGM 87.2 ± 9.3, MDI: 78.1 ± 15. Conclusions: There was a consistent benefit in patients with T1D when using CLC, regardless of baseline insulin delivery modality or CGM use. These data suggest that this CLC system can be considered across a wide range of patients.

Methicillin-susceptible Staphylococcus aureus (MSSA) bloodstream infections (BSIs) are associated with significant morbidity and mortality. MSSA BSIs can rapidly disseminate, resulting in deep-seated infections, prolonged durations of bacteremia, and further metastases. Recently, cefazolin and ertapenem combination therapy has emerged as a potential therapeutic strategy to sterilize the blood in patients with persistent MSSA bacteremia. Here, we present a patient with COVID-19 pneumonia and concomitant MSSA BSI achieving blood culture sterilization within 24 hours of cefazolin and ertapenem combination therapy initiation following 11 days of positive blood cultures.

Abstract Background: Stem cell senescence and depletion are major causes of organismal aging and aging-related diseases. The NAD–SIRT1–PARP1 axis has garnered remarkable interest owing to its significant role in regulating stem cell senescence and organismal aging. Event though our recent study showes that PBX1 overexpression attenuates hair follicle-derived mesenchymal stem cell (HF-MSC) senescence and apoptosis by regulating ROS-mediated DNA damage via downregulation of PARP1 expression, suggesting PARP1 downregulation is a common manifestation of the roles of both PBX1 and SIRT1 in the attenuation of HF-MSC senescence, and implying a potential link between PBX1 and SIRT1 via PARP1. Methods: HF-MSCs overexpressing PBX1, overexpressing both PBX1 and PARP1, downregulating SIRT1, and overexpressing PBX1 and downregulating SIRT1 were generated, and biomarkers related to cell senescence, apoptosis, DNA damage, and repair were detected at the cellular and protein levels. Results: (1) PBX1 overexpression alleviated HF-MSC senescence and apoptosis accompanied by upregulation of SIRT1 expression, downregulation of PARP1 expression, and increased intracellular NAD and ATP levels. (2) SIRT1 knockdown or PARP1 overexpression enhanced cellular senescence and apoptosis, accompanied by increased ROS accumulation and DNA damage aggravation and decreased intracellular NAD and ATP levels. (3) PBX1 overexpression rescued HF-MSC senescence and apoptosis induced by SIRT1 knockdown or PARP1 overexpression. (4) Dual luciferase reporter showed PBX1 enhanced SIRT1 expression by activating SIRT1 promoter. Conclusions: Our results reveal that a positive interaction feedback loop exists between PBX1 and SIRT1, that PBX1 is the upstream of SIRT1. To the best of our knowledge we are the first to report that there is a PBX1-SIRT1-PARP1 axis and this axis plays a critical role in alleviation of HF-MSC senescence and apoptosis. The results provide a new perspective on the mechanism of stem cell senescence and age-related disease prevention and treatment.

Abstract Objective The Genomic Medicine Working Group of the National Advisory Council for Human Genome Research virtually hosted its 13th genomic medicine meeting titled “Developing a Clinical Genomic Informatics Research Agenda”. The meeting’s goal was to articulate a research strategy to develop Genomics-based Clinical Informatics Tools and Resources (GCIT) to improve the detection, treatment, and reporting of genetic disorders in clinical settings. Materials and Methods Experts from government agencies, the private sector, and academia in genomic medicine and clinical informatics were invited to address the meeting's goals. Invitees were also asked to complete a survey to assess important considerations needed to develop a genomic-based clinical informatics research strategy. Results Outcomes from the meeting included identifying short-term research needs, such as designing and implementing standards-based interfaces between laboratory information systems and electronic health records, as well as long-term projects, such as identifying and addressing barriers related to the establishment and implementation of genomic data exchange systems that, in turn, the research community could help address. Discussion Discussions centered on identifying gaps and barriers that impede the use of GCIT in genomic medicine. Emergent themes from the meeting included developing an implementation science framework, defining a value proposition for all stakeholders, fostering engagement with patients and partners to develop applications under patient control, promoting the use of relevant clinical workflows in research, and lowering related barriers to regulatory processes. Another key theme was recognizing pervasive biases in data and information systems, algorithms, access, value, and knowledge repositories and identifying ways to resolve them.

Background Availability of checkpoint inhibitors has created a paradigm shift in the management of patients with solid tumors. Despite this, most patients do not respond to immunotherapy, and there is considerable interest in developing combination therapies to improve response rates and outcomes. B7-H3 (CD276) is a member of the B7 family of cell surface molecules and provides an alternative immune checkpoint molecule to therapeutically target alone or in combination with programmed cell death-1 (PD-1)–targeted therapies. Enoblituzumab, an investigational anti-B7-H3 humanized monoclonal antibody, incorporates an immunoglobulin G1 fragment crystallizable (Fc) domain that enhances Fcγ receptor-mediated antibody-dependent cellular cytotoxicity. Coordinated engagement of innate and adaptive immunity by targeting distinct members of the B7 family (B7-H3 and PD-1) is hypothesized to provide greater antitumor activity than either agent alone. Methods In this phase I/II study, patients received intravenous enoblituzumab (3–15 mg/kg) weekly plus intravenous pembrolizumab (2 mg/kg) every 3 weeks during dose-escalation and cohort expansion. Expansion cohorts included non–small cell lung cancer (NSCLC; checkpoint inhibitor [CPI]–naïve and post-CPI, programmed death-ligand 1 [PD-L1] <1%), head and neck squamous cell carcinoma (HNSCC; CPI-naïve), urothelial cancer (post-CPI), and melanoma (post-CPI). Disease was assessed using Response Evaluation Criteria in Solid Tumors version 1.1 after 6 weeks and every 9 weeks thereafter. Safety and pharmacokinetic data were provided for all enrolled patients; efficacy data focused on HNSCC and NSCLC cohorts. Results Overall, 133 patients were enrolled and received ≥1 dose of study treatment. The maximum tolerated dose of enoblituzumab with pembrolizumab at 2 mg/kg was not reached. Intravenous enoblituzumab (15 mg/kg) every 3 weeks plus pembrolizumab (2 mg/kg) every 3 weeks was recommended for phase II evaluation. Treatment-related adverse events occurred in 116 patients (87.2%) and were grade ≥3 in 28.6%. One treatment-related death occurred (pneumonitis). Objective responses occurred in 6 of 18 (33.3% [95% CI 13.3 to 59.0]) patients with CPI-naïve HNSCC and in 5 of 14 (35.7% [95% CI 12.8 to 64.9]) patients with CPI-naïve NSCLC. Conclusions Checkpoint targeting with enoblituzumab and pembrolizumab demonstrated acceptable safety and antitumor activity in patients with CPI-naïve HNSCC and NSCLC. Trial registration number NCT02475213.

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program ( n = 63,302) and UK Biobank ( n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.