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Objective: To test the feasibility and safety of genotype guidance in the selection of P2Y 12 monotherapy within 1 week of percutaneous coronary interventions (PCIs) among patients with high bleeding risk (HBR)., Patient and Methods: The study was a single-center, open-label, pilot trial. Patients (n=100) with HBR (as defined by an academic research consortium) after successful PCI received dual antiplatelet therapy with clopidogrel and aspirin. Following availability of cytochrome P450 2C19 (CYP2C19) genotype results (mean, 2.9 days), aspirin was discontinued. Normal, rapid, or ultrarapid CYP2C19 metabolizers continued clopidogrel monotherapy for 90 days whereas loss-of-function allele carriers switched to prasugrel or ticagrelor monotherapy. The primary safety endpoints were a composite of post-dismissal cardiac death/spontaneous myocardial infarction less than 30 days or stent thrombosis <90 days of discharge. The subjects also underwent post-dismissal assessment for BARC (Bleeding Academic Research Consortium) type 3 or 5 bleeding, all-cause death, any MI, and/or repeat revascularization up to 90 days., Results: There were 98 patients with complete data (median age, 76.5 years, 36% women; 49% acute coronary syndrome). Sixty-nine (70.4%) were normal, rapid, or ultrarapid metabolizers and continued clopidogrel monotherapy, and 29 (29.6%) were intermediate CYP2C19 metabolizers and received monotherapy with prasugrel (n=21) or ticagrelor (n=8). The mean duration of dual antiplatelet therapy was 5.1 days. During 90-day follow-up, no patient died, there was one possible stent thrombosis, and three patients on clopidogrel had Bleeding Academic Research Consortium type 3 bleeding events., Conclusion: Genotype-guided P2Y 12 inhibitor monotherapy within a week of PCI is feasible and likely safe in patients with HBR (CHAMP [Clopidogrel With High Bleeding Risk and Adverse Events With Monotherapy in Patients Undergoing Percutaneous Coronary Interventions]; NCT05223335)., (Copyright © 2024 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Polychlorinated biphenyls are ubiquitous environmental contaminants linkedc with peripheral immune and neural dysfunction. Neuroimmune signaling is critical to brain development and later health; however, effects of PCBs on neuroimmune processes are largely undescribed. This study extends our previous work in neonatal or adolescent rats by investigating longer-term effects of perinatal PCB exposure on later neuroimmune responses to an inflammatory challenge in adulthood. Male and female Sprague-Dawley rats were exposed to a low-dose, environmentally relevant, mixture of PCBs (Aroclors 1242, 1248, and 1254, 1:1:1, 20 μg / kg dam BW per gestational day) or oil control during gestation and via lactation. Upon reaching adulthood, rats were given a mild inflammatory challenge with lipopolysaccharide (LPS, 50 μg / kg BW, ip) or saline control and then euthanized 3 hours later for gene expression analysis or 24 hours later for immunohistochemical labeling of Iba1+ microglia. PCB exposure did not alter gene expression or microglial morphology independently, but instead interacted with the LPS challenge in brain region- and sex-specific ways. In the female hypothalamus, PCB exposure blunted LPS responses of neuroimmune and neuromodulatory genes without changing microglial morphology. In the female prefrontal cortex, PCBs shifted Iba1+ cells from reactive to hyperramified morphology in response to LPS. Conversely, in the male hypothalamus, PCBs shifted cell phenotypes from hyperramified to reactive morphologies in response to LPS. The results highlight the potential for long-lasting effects of environmental contaminants that are differentially revealed over a lifetime, sometimes only after a secondary challenge. These neuroimmune endpoints are possible mechanisms for PCB effects on a range of neural dysfunction in adulthood, including mental health and neurodegenerative disorders. The findings suggest possible interactions with other environmental challenges that also influence neuroimmune systems., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Margaret Bell reports financial support was provided by National Institute of Environmental Health Sciences. Andrea Gore reports financial support was provided by National Institute of Environmental Health Sciences. If there are other authors, they 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.)

Purpose: Spatio-temporal variability in clinical fluoroscopy and cine angiography images combined with nonlinear image processing prevents the application of traditional image quality measurements in the cardiac catheterization laboratory. We aimed to develop and validate methods to measure human observer impressions of the image quality., Approach: Multi-frame images of the thorax of a euthanized pig were acquired to provide an anatomical background. The detector dose was varied from 6 to 200 nGy (increments 2×), and 0.6 and 1.0 mm focal spots were used. Two coronary stents with/without 0.5 mm separation and a synthetic right coronary artery (RCA) with hemispherical defects were embedded into the background images as test objects. The quantitative observer ( n = 17 ) performance was measured using a two-alternating forced-choice test of whether stents were separated and by a count of visible right coronary artery defects. Qualitative impressions of noise, spatial resolution, and overall image quality were measured using a visual analog scale (VAS). A paired t -test and multinomial logistic regression model were used to identify statistically significant factors affecting the observer's impression image quality., Results: The proportion of correct detection of stent separation and the number of reported right coronary artery defects changed significantly with detector dose increment in the 6 to 100 nGy ( p < 0.05 ). Although a trend favored the 0.6 versus 1.0 mm focal spot for these quantitative assessments, this was insignificant. Visual analog scale measurements changed significantly with detector dose increments in the range of 24 to 100 nGy and focal spot size ( p < 0.05 ). The application of multinomial logistic regression analysis to observer VAS scores demonstrated sensitivity matching of the paired t -test applied to quantitative observer performance measurements., Conclusions: Both quantitative and qualitative measurements of observer impression of the image quality were sensitive to image quality changes associated with changing the detector dose and focal spot size. These findings encourage future work that uses qualitative image quality measurements to assess clinical fluoroscopy and angiography image quality., (© 2024 Society of Photo-Optical Instrumentation Engineers (SPIE).)

Limited data exist regarding outcomes after coronary angiography (CAG) and percutaneous coronary intervention (PCI) in patients aged ≥90 years admitted to the cardiac intensive care unit (CICU) with acute coronary syndrome (ACS). We studied sequential CICU patients ≥90 years admitted with ACS from 2007 to 2018. Three therapeutic approaches were defined: (1) No CAG; (2) CAG without PCI (CAG/No PCI); and (3) CAG with PCI (CAG/PCI). In-hospital mortality was evaluated using multivariable logistic regression. All-cause 1-year mortality was evaluated using Kaplan-Meier and multivariable Cox proportional hazards analysis. The study included 239 patients with a median age of 92 (range 90 to 100) years (57% females; 45% ST-elevation myocardial infarction; 8% cardiac arrest; 16% shock). The No CAG group had higher Day 1 Sequential Organ Failure Assessment scores, more co-morbidities, worse kidney function, and fewer ST-elevation myocardial infarctions. In-hospital mortality was 20.8% overall and did not differ between the No CAG (n = 103; 21.4%), CAG/No PCI (n = 47; 21.3%), and CAG/PCI (n = 90; 20.0%) groups, before or after adjustment. Overall 1-year mortality was 52.5% and did not differ between groups before or after adjustment. Median survival was 6.9 months overall and 41.2% of hospital survivors died within 1 year of CICU admission. CICU patients aged ≥90 years with ACS have a substantial burden of illness with high in-hospital and 1-year mortality that was not lower in those who underwent CAG or PCI. These results suggest that careful patient selection for invasive coronary procedures is essential in this vulnerable population., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: Early coronary angiography (CAG) has been recommended in selected patients following out-of-hospital-cardiac-arrest (OHCA). We aimed to identify clinical features associated with acute coronary occlusion (ACO) and evaluate the associations between ACO, successful percutaneous coronary intervention (PCI) and outcomes in this population., Methods: We included comatose OHCA patients treated with targeted temperature management (TTM) between December 2005 and September 2016 who underwent early CAG within 24 hours. The co-primary outcomes were all-cause 30-day mortality and good neurological outcome (modified Rankin Score [mRS] ≤2) at hospital discharge., Results: Among 155 patients (93% shockable arrest rhythm, 55% with ST elevation), 133 (86%) had coronary artery stenosis ≥50% and 65 (42%) had ACO. ST elevation (sensitivity 74%, specificity 59%, OR 4.0, 95% CI 2.0-8.1) and elevated first troponin (sensitivity 88%, specificity 26%, OR 2.5, 95% CI 1.1-6.1) had limited sensitivity and specificity for ACO. Unadjusted 30-day mortality did not differ significantly by coronary disease severity or ACO. Successful PCI was associated with a lower risk of 30-day mortality (adjusted HR 0.5, 95% CI 0.2-0.9, P=.03), especially among patients with ACO (adjusted HR 0.4, 95% CI 0.1-0.9, P=0.03). After adjustment, ACO and PCI were not associated with the probability of good neurological outcome., Conclusions: In this select cohort of resuscitated OHCA patients undergoing CAG, unstable coronary disease is highly prevalent and successful PCI was associated with a higher probability of 30-day survival, especially among those with ACO. Neither ACO nor successful PCI were independently associated with good neurological outcome.

Background: Genetic-guided P2Y 12 inhibitor selection has been proposed to reduce ischemic events by identifying CYP2C19 loss-of-function (LOF) carriers at increased risk with clopidogrel treatment after percutaneous coronary intervention (PCI). A prespecified analysis of TAILOR-PCI (Tailored Antiplatelet Therapy Following PCI) evaluated the effect of genetic-guided P2Y 12 inhibitor therapy on cumulative ischemic and bleeding events., Objectives: Here, the authors detail a prespecified analysis of cumulative endpoints. The primary endpoint was cumulative incidence rate of ischemic events at 12 months. Cumulative incidence of major and minor bleeding was a secondary endpoint. Cox proportional hazards models as adapted by Wei, Lin, and Weissfeld were used to estimate the effect of this strategy on all observed events., Methods: The TAILOR-PCI trial was a prospective trial including 5,302 post-PCI patients with acute and stable coronary artery disease (CAD) who were randomized to genetic-guided P2Y 12 inhibitor or conventional clopidogrel therapy. In the genetic-guided group, LOF carriers were prescribed ticagrelor, whereas noncarriers received clopidogrel. TAILOR-PCI's primary analysis was time to first event in LOF carriers., Results: Among 5,276 patients (median age 62 years; 25% women; 82% acute CAD; 18% stable CAD), 1,849 were LOF carriers (903 genetic-guided; 946 conventional therapy). The cumulative primary endpoint was significantly reduced in the genetic-guided group compared with the conventional therapy (HR: 0.61; 95% CI: 0.41-0.89; P = 0.011) with no significant difference in cumulative incidence of major or minor bleeding (HR: 1.36; 95% CI: 0.67-2.76; P = 0.39)., Conclusions: Among CYP2C19 LOF carriers undergoing PCI, a genetic-guided strategy resulted in a statistically significant reduction in cumulative ischemic events without a significant difference in bleeding. (Tailored Antiplatelet Therapy Following PCI [TAILOR-PCI]; NCT01742117)., Competing Interests: Funding Support and Author Disclosures Funding for this research was provided by the National Institutes of Health (NIH) grants U01HL128606 to Drs Pereira and Farkouh and U01HL128626 to Dr Bailey. The content of this manuscript is solely the responsibility of the authors and does not necessarily reflect the views of the National Heart, Lung, and Blood Institute (NHLBI) or the National Institutes of Health. Dr Farkouh has received grants from NHLBI, Amgen, Novartis, and Novo Nordisk. Mr Lennon has received grants from the National Institutes of Health (NIH)/NHLBI and receiving nonfinancial support from Spartan Biosciences. Dr So has received grants from Eli Lilly Canada, Spartan Biosciences, Roche Diagnostics, and Aggredyne Inc; and has received personal fees from AstraZeneca Canada, Bayer Canada, and Servier Canada. Dr Goodman has received research grant support (eg, steering committee or data and safety monitoring committee) and/or speaker/consulting honoraria (eg, advisory boards) from Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Daiichi Sankyo/American Regent, Eli Lilly, Esperion, Ferring Pharmaceuticals, HLS Therapeutics, JAMP Pharma, Merck, Novartis, Novo Nordisk A/C, Pendopharm/Pharmascience, Pfizer, Regeneron, Sanofi, Servier, Tolmar Pharmaceuticals, and Valeo Pharma; and has received salary support/honoraria from the Heart and Stroke Foundation of Ontario/University of Toronto (Polo) Chair, Canadian Heart Research Centre and MD Primer, Canadian VIGOUR Centre, Cleveland Clinic Coordinating Centre for Clinical Research, Duke Clinical Research Institute, New York University Clinical Coordinating Centre, PERFUSE Research Institute, and the TIMI Study Group (Brigham Health). Dr Lerman has received personal fees from Itamar Medical, Phillips/Volcano, Shahal, and Wei Jian RC Inc. Dr Tanguay has received personal fees from Mayo Clinic, AstraZeneca, Bayer, Daiichi Sankyo, Servier, Novartis, and BMS-Pfizer Alliance. Dr Welsh has received grants and/or personal fees from AstraZeneca, Pfizer, Bayer, Canadian Cardiac Society, Mayo Clinic, Boehringer Ingelheim, and Novartis. Dr Bailey has received grants from NIH. Dr Pereira has received grants from the NHLBI. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023. Published by Elsevier Inc.)

Despite numerous clinically available vaccines and therapeutics, aged patients remain at increased risk for COVID-19 morbidity. Furthermore, various patient populations, including the aged can have suboptimal responses to SARS-CoV-2 vaccine antigens. Here, we characterized vaccine-induced responses to SARS-CoV-2 synthetic DNA vaccine antigens in aged mice. Aged mice exhibited altered cellular responses, including decreased IFNγ secretion and increased TNFα and IL-4 secretion suggestive of T H 2-skewed responses. Aged mice exhibited decreased total binding and neutralizing antibodies in their serum but significantly increased T H 2-type antigen-specific IgG1 antibody compared to their young counterparts. Strategies to enhance vaccine-induced immune responses are important, especially in aged patient populations. We observed that co-immunization with plasmid-encoded adenosine deaminase (pADA)enhanced immune responses in young animals. Ageing is associated with decreases in ADA function and expression. Here, we report that co-immunization with pADA enhanced IFNγ secretion while decreasing TNFα and IL-4 secretion. pADA expanded the breadth and affinity SARS-CoV-2 spike-specific antibodies while supporting T H 1-type humoral responses in aged mice. scRNAseq analysis of aged lymph nodes revealed that pADA co-immunization supported a T H 1 gene profile and decreased FoxP3 gene expression. Upon challenge, pADA co-immunization decreased viral loads in aged mice. These data support the use of mice as a model for age-associated decreased vaccine immunogenicity and infection-mediated morbidity and mortality in the context of SARS-CoV-2 vaccines and provide support for the use of adenosine deaminase as a molecular adjuvant in immune-challenged populations., Competing Interests: DW has received grant funding, participates in industry collaborations, has received speaking honoraria, and has received fees for consulting, including serving on scientific review committees. Remunerations received by DW include direct payments and equity/options. DW also discloses the following associations with commercial partners: Geneos consultant/advisory board, AstraZeneca advisory board, speaker, Inovio board of directors, consultant, Sanofi advisory board, BBI advisory board, Pfizer advisory Board, Flagship consultant, and Advaccine consultant. SW is a scientific founder of Avamab Pharma Inc., a pre-clinical, pre-revenue stage company dedicated to research and development of AAV gene therapies for the treatment and prevention of infectious diseases. SW is a co-founder and Chief Scientific Officer of Inspire Biotherapeutics, a pre-clinical, pre-revenue stage gene therapy company developing AAV-based therapies for monogenic lung diseases. SW is an inventor on issued patents in Canada and US for the AAV6.2FF capsid, which are owned by the University of Guelph, and licensed to Avamab Pharma Inc., Inspire Biotherapeutics, and Cellastra Inc. From 2020 to February 2023, SW was an unpaid scientific advisor for Cellastra Inc., which is dedicated to research and development of gene therapies targeting root causes of scarring. SW is a co-inventor on a pending US and Canadian patent for the Engineered Newcastle disease virus vector and uses thereof, filed/owned by the University of Guelph. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gary, Tursi, Warner, Cuismano, Connors, Parzych, Griffin, Bell, Ali, Frase, Hojecki, Canziani, Chaiken, Kannan, Moffat, Embury-Hyatt, Wooton, Kossenkov, Patel, Kobasa, Kutzler, Haddad and Weiner.)

Herein, we studied the impact of empty LNP (eLNP), component of mRNA-based vaccine, on anti-viral pathways and immune function of cells from young and aged individuals. eLNP induced maturation of monocyte derived dendritic cells (MDDCs). We further show that eLNP upregulated CD40 and induced cytokine production in multiple DC subsets and monocytes. This coincided with phosphorylation of TANK binding kinase 1 (pTBK1) and interferon response factor 7 (pIRF7). In response to eLNP, healthy older adults (>65 yrs) have decreased CD40 expression, and IFN-γ output compared to young adults (<65 yrs). Additionally, cells from older adults have a dysregulated anti-viral signaling response to eLNP stimulation, measured by the defect in type I IFN production, and phagocytosis. Overall, our data show function of eLNP in eliciting DC maturation and innate immune signaling pathways that is impaired in older adults resulting in lower immune responses to SARS-CoV-2 mRNA-based vaccines., (© 2023. The Author(s).)

Although concussions are a popular focus of neurotrauma research, subconcussions occur with higher frequency but are less well-studied. A subconcussion is an impact to the head that does not result in immediately diagnosable concussion but can result in later neurological consequences. Repeat subconcussions can produce behavioral impairments and neuropathology that is similar to or worse than those seen following a single concussion. The current study modified a previously established closed head injury model of concussion to create a subconcussion model and examines sex differences in behavioral responses to repeated subconcussion in the adult rat. Rats received a single concussion, single or repeat subconcussions, or no impact and behavior was monitored from 2 h through 31 days post-injury. A single concussion or repeat subconcussion resulted in deficits in locomotion, righting reflexes, and recognition memory. The degree of deficit induced by repeat subconcussions were either similar (righting reflexes) or greater/more persistent (locomotor deficits and recognition memory) than that of a concussion. Single subconcussion resulted in acute deficits that were mild and limited to righting reflexes and locomotion. Sex differences were observed in responses to repeat subconcussion: females showed greater deficits in righting reflexes, locomotion, and vestibular function, while males showed greater alterations in anxiety and depressive-like behavior. This study established a model of subconcussive impact where a single subconcussive impact resulted in minimal behavioral deficits but repeat subconcussions resulted in deficits similar to or worse than a single concussion. Our data also suggest sex differences in behavioral responses to both concussive and subconcussive impacts., Competing Interests: Competing Interests None to report., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Aminophylline, an adenosine antagonist, can be used to prevent adenosine-mediated bradyarrhythmias., Methods: Retrospective, observational, descriptive analysis of patients undergoing rotational atherectomy with intravenous (IV) aminophylline pretreatment during a 10-year period (2010-2020). The primary composite outcome was the occurrence of a documented bradyarrhythmia requiring pharmacologic intervention and/or temporary pacemaker (TPM) implantation., Results: A total of 296 patients received IV aminophylline pretreatment. The primary composite outcome occurred in 1.7% (n = 5) of patients. None of the patients required rescue TPM. Bradyarrhythmias were documented in 2.4% (n = 7) of patients. Pharmacologic interventions, typically with IV atropine, were used in 15% (n = 43) of patients. Per-vessel analyses demonstrated that patients undergoing atherectomy to the circumflex and right coronary arteries were more likely than those undergoing atherectomy to other vessels to have bradyarrhythmias requiring pharmacologic intervention (3.4% vs 0%, P = .01)., Conclusions: In this 10-year single-center experience using IV aminophylline pretreatment to prevent major bradyarrhythmias in patients undergoing coronary atherectomy, none of the patients required rescue TPM implantation. These data demonstrate that coronary atherectomy can be performed safely without prophylactic TPM, with aminophylline pretreatment and selective use of atropine representing an effective noninvasive approach., (© 2023 The Authors.)

Introduction: Healthcare organizations faced unique operational challenges during the COVID-19 pandemic. Assuring the safety of both patients and healthcare workers in hospitals has been the primary focus during the COVID-19 pandemic., Methods: The NIH Vaccine Program (VP) with the Vaccine Management System (VMS) was created based on the commitment of NIH leadership, program leadership, the development team, and the program team; defining Key Performance Indicators (KPIs) of the VP and the VMS; and the NIH Clinical Center's (NIH CC) interdisciplinary approach to deploying the VMS., Results: This article discusses the NIH business requirements of the VP and VMS, the target KPIs of the VP and the VMS, and the NIH CC interdisciplinary approach to deploying an organizational VMS for vaccinating the NIH workforce. The use of the DCRI Spiral-Agile Software Development Life Cycle enabled the development of a system with stakeholder involvement that could quickly adapt to changing requirements meeting the defined KPIs for the program and system. The assessment of the defined KPIs through a survey and comments from the survey support that the VP and VMS were successful., Conclusion: A comprehensive program to maintain a healthy workforce includes asymptomatic COVID testing, symptomatic COVID testing, contact tracing, vaccinations, and policy-driven education. The need to develop systems during the pandemic resulted in changes to build software quickly with the input of many more users and stakeholders then typical in a decreased amount of time., Competing Interests: No competing financial interests exist., (Copyright 2022, ABSA International 2022.)

The progressive impairment of immunity to pathogens and vaccines with aging is a significant public health problem as the world population shifts to an increased percentage of older adults (> 65). We have previously demonstrated that cells obtained from older volunteers have delayed and defective induction of type I interferons and T cell and B cell helper cytokines in response to TLR ligands when compared to those from adult subjects. However, the underlying intracellular mechanisms are not well described. Herein, we studied two critical pathways important in the production of type I interferon (IFN), the interferon response factor 7 (pIRF7), and TANK-binding kinase (pTBK-1). We show a decrease in pIRF7 and pTBK-1 in cross-priming dendritic cells (cDC1s), CD4 + T cell priming DCs (cDC2s), and CD14 dim CD16 + vascular patrolling monocytes from older adults (n = 11) following stimulation with pathway-specific agonists in comparison with young individuals (n = 11). The decrease in these key antiviral pathway proteins correlates with decreased phagocytosis, suggesting impaired function in Overall, our findings describe molecular mechanisms which explain the innate functional impairment in older adults and thus could inform us of novel approaches to restore these defects., (© 2022. The Author(s).)

Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines have demonstrated strong immunogenicity and protection against severe disease, concerns about the duration and breadth of these responses remain. In this study, we show that codelivery of plasmid-encoded adenosine deaminase-1 (pADA) with SARS-CoV-2 spike glycoprotein DNA enhances immune memory and durability in vivo. Coimmunized mice displayed increased spike-specific IgG of higher affinity and neutralizing capacity as compared with plasmid-encoded spike-only-immunized animals. Importantly, pADA significantly improved the longevity of these enhanced responses in vivo. This coincided with durable increases in frequencies of plasmablasts, receptor-binding domain-specific memory B cells, and SARS-CoV-2-specific T follicular helper cells. Increased spike-specific T cell polyfunctionality was also observed. Notably, animals coimmunized with pADA had significantly reduced viral loads compared with their nonadjuvanted counterparts in a SARS-CoV-2 infection model. These data suggest that pADA enhances immune memory and durability and supports further translational studies., (Copyright © 2022 by The American Association of Immunologists, Inc.)

Background: Previous percutaneous coronary intervention risk models were focused on single outcome, such as mortality or bleeding, etc, limiting their applicability. Our objective was to develop contemporary percutaneous coronary intervention risk models that not only determine in-hospital mortality but also predict postprocedure bleeding, acute kidney injury, and stroke from a common set of variables., Methods: We built risk models using logistic regression from first percutaneous coronary intervention for any indication per patient (n=19 322, 70.6% with acute coronary syndrome) using the Mayo Clinic registry from January 1, 2000 to December 31, 2016. Approval for the current study was obtained from the Mayo Foundation Institutional Review Board. Patients with missing outcomes (n=4183) and those under 18 (n=10) were removed resulting in a sample of 15 129. We built both models that included procedural and angiographic variables (Models A) and precatheterization model (Models B)., Results: Death, bleeding, acute kidney injury, and stroke occurred in 247 (1.6%), 650 (4.3%), 1184 (7.8%), and 67 (0.4%), respectively. The C statistics from the test dataset for models A were 0.92, 0.70, 0.77, and 0.71 and for models B were 0.90, 0.67, 0.76, and 0.71 for in-hospital death, bleeding, acute kidney injury, and stroke, respectively. Bootstrap analysis indicated that the models were not overfit to the available dataset. The probabilities estimated from the models matched the observed data well, as indicated by the calibration curves. The models were robust across many subgroups, including women, elderly, acute coronary syndrome, cardiogenic shock, and diabetes., Conclusions: The new risk scoring models based on precatheterization variables and models including procedural and angiographic variables accurately predict in-hospital mortality, bleeding, acute kidney injury, and stroke. The ease of its application will provide useful prognostic and therapeutic information to both patients and physicians.

Background: There are limited data on uninsured patients presenting with acute myocardial infarction-cardiogenic shock (AMI-CS). This study sought to compare the management and outcomes of AMI-CS between uninsured and privately insured individuals., Methods: Using the National Inpatient Sample (2000-2016), a retrospective cohort of adult (≥18 years) uninsured admissions (primary payer-self-pay or no charge) were compared with privately insured individuals. Interhospital transfers were excluded. Outcomes of interest included in-hospital mortality, temporal trends in admissions, use of cardiac procedures, do-not-resuscitate status, palliative care referrals, and resource utilization., Results: Of 402 182 AMI-CS admissions, 21 966 (5.4%) and 93 814 (23.3%) were uninsured and privately insured. Compared with private insured individuals, uninsured admissions were younger, male, from a lower socioeconomic status, had lower comorbidity, higher rates of acute organ failure, ST-segment elevation AMI-CS (77.3% versus 76.4%), and concomitant cardiac arrest (33.8% versus 31.9%; all P <0.001). Compared with 2000, in 2016, there were more uninsured (adjusted odds ratio, 1.15 [95% CI, 1.13-1.17]; P <0.001) and less privately insured admissions (adjusted odds ratio, 0.85 [95% CI, 0.83-0.87]; P <0.001). Uninsured individuals received less frequent coronary angiography (79.5% versus 81.0%), percutaneous coronary intervention (60.8% versus 62.2%), mechanical circulatory support (54% versus 55.5%), and had higher palliative care (3.8% versus 3.2%) and do-not-resuscitate status use (4.4% versus 3.2%; all P <0.001). Uninsured admissions had higher in-hospital mortality (adjusted odds ratio, 1.62 [95% CI, 1.55-1.68]; P <0.001) and resource utilization., Conclusions: Uninsured individuals have higher in-hospital mortality and lower use of guideline-directed therapies in AMI-CS compared with privately insured individuals.

Cardiac arrest (CA) is common and has been associated with adverse outcomes in patients with cardiogenic shock (CS). We sought to determine the prevalence, patient characteristics, and outcomes of CA in cardiovascular intensive care unit patients with CS. We queried cardiovascular intensive care unit admissions from 2007 to 2018 with an admission diagnosis of CS and compared patients with and without CA. Temporal trends were assessed using linear regression. The primary and secondary outcomes of in-hospital and 1-year mortality were analyzed using logistic regression and Cox proportional-hazards analysis, respectively. We included 1,498 patients, and CA was present in 510 patients (34%), with 258 (50.6% of patients with CA) having ventricular fibrillation (VF). Mean age was 68 ± 14 years, and 37% were females. The prevalence of CA decreased over time (from 43% in 2007 to 24% in 2018, p <0.001). Hospital mortality was 33.3% and decreased over time in patients without CA (from 30% in 2007 to 22% in 2018, p = 0.05), but not in patients with CA (p = 0.71). CA was associated with a higher risk of hospital mortality (51.0% vs 24.2%, adjusted odds ratio 2.15, 95% confidence interval [CI] 1.52 to 3.05, p <0.001), with no difference between VF CA and non-VF CA (p = 0.64). CA was associated with higher 1-year mortality (adjusted hazard ratio 1.53, 95% CI 1.24 to 1.89, p <0.001). In conclusion, CA is present in 1 of 3 of CS hospitalizations and confers a substantially higher risk of hospital and 1-year mortality with no improvement during our 12-year study period contrary to prevailing trends., Competing Interests: Disclosures The authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

A one-pot strategy for functionalizing pyranoside 1,2- cis -diols with two different ester protecting groups is reported. The approach employs regioselective acylation via orthoester hydrolysis promoted by a carboxylic acid, e.g., levulinic acid, acetic acid, benzoic acid, or chloroacetic acid. Upon removal of water and introduction of a coupling agent, the carboxylic acid is esterified to the hydroxyl group liberated during hydrolysis. Although applied to 1,2- cis -diols on pyranoside scaffolds, the method should be applicable to such motifs on any six-membered ring.

Vaccination is the most effective measure to protect against infections. However, with increasing age, there is a progressive decline in the ability of the immune system to both protect against infection and develop protective immunity from vaccination. This age-related decline of the immune system is due to age-related changes in both the innate and adaptive immune systems. With an aging world population and increased risk of pandemics, there is a need to continue to develop strategies to increase vaccine responses in the elderly. Here, the major age-related changes that occur in both the innate and adaptive immune responses that impair the response to vaccination in the elderly will be highlighted. Existing and future strategies to improve vaccine efficacy in the elderly will then be discussed, including adjuvants, delivery methods, and formulation. These strategies provide mechanisms to improve the efficacy of existing vaccines and develop novel vaccines for the elderly., 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 © 2022 Elsevier B.V. All rights reserved.)

Background: There are limited data on the temporal trends, incidence, and outcomes of ST-segment-elevation myocardial infarction-cardiogenic shock (STEMI-CS)., Methods: Adult (>18 years) STEMI-CS admissions were identified using the National Inpatient Sample (2000-2017) and classified by tertiles of admission year (2000-2005, 2006-2011, 2012-2017). Outcomes of interest included temporal trends, acute organ failure, cardiac procedures, in-hospital mortality, hospitalization costs, and length of stay., Results: In ∼4.3 million STEMI admissions, CS was noted in 368,820 (8.5%). STEMI-CS incidence increased from 5.8% in 2000 to 13.0% in 2017 (patient and hospital characteristics adjusted odds ratio [aOR] 2.45 [95% confidence interval {CI} 2.40-2.49]; P < 0.001). Multiorgan failure increased from 55.5% (2000-2005) to 74.3% (2012-2017). Between 2000 and 2017, coronary angiography and percutaneous coronary intervention use increased from 58.8% to 80.1% and 38.6% to 70.6%, whereas coronary artery bypass grafting decreased from 14.9% to 10.4% (all P < 0.001). Over the study period, the use of intra-aortic balloon pump (40.6%-37.6%) decreased, and both percutaneous left ventricular assist devices (0%-12.9%) and extra-corporeal membrane oxygenation (0%-2.8%) increased (all P < 0.001). In hospital mortality decreased from 49.6% in 2000 to 32.7% in 2017 (aOR 0.29 [95% CI 0.28-0.31]; P < 0.001). During the 18-year period, hospital lengths of stay decreased, hospitalization costs increased and use of durable left ventricular assist device /cardiac transplantation remained stable (P > 0.05)., Conclusions: In the United States, incidence of CS in STEMI has increased 2.5-fold between 2000 and 2017, while in-hospital mortality has decreased during the study period. Use of coronary angiography and PCI increased during the study period., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by the Shock Society.)

Background: Coronary endothelial dysfunction (CED) causes angina/ischemia in patients with nonobstructive coronary artery disease (NOCAD). Patients with CED have decreased number and function of CD34+ cells involved in normal vascular repair with microcirculatory regenerative potential and paracrine anti-inflammatory effects. We evaluated safety and potential efficacy of intracoronary autologous CD34+ cell therapy for CED., Methods: Twenty NOCAD patients with invasively diagnosed CED and persistent angina despite maximally tolerated medical therapy underwent baseline exercise stress test, GCSF (granulocyte colony stimulating factor)-mediated CD34+ cell mobilization, leukapheresis, and selective 1×10 5 CD34+ cells/kg infusion into left anterior descending. Invasive CED evaluation and exercise stress test were repeated 6 months after cell infusion. Primary end points were safety and effect of intracoronary autologous CD34+ cell therapy on CED at 6 months of follow-up. Secondary end points were change in Canadian Cardiovascular Society angina class, as-needed sublingual nitroglycerin use/day, Seattle Angina Questionnaire scores, and exercise time at 6 months. Change in CED was compared with that of 51 historic control NOCAD patients treated with maximally tolerated medical therapy alone., Results: Mean age was 52±13 years; 75% were women. No death, myocardial infarction, or stroke occurred. Intracoronary CD34+ cell infusion improved microvascular CED (%acetylcholine-mediated coronary blood flow increased from 7.2 [-18.0 to 32.4] to 57.6 [16.3-98.3]%; P =0.014), decreased Canadian Cardiovascular Society angina class (3.7±0.5 to 1.7±0.9, Wilcoxon signed-rank test, P =0.00018), and sublingual nitroglycerin use/day (1 [0.4-3.5] to 0 [0-1], Wilcoxon signed-rank test, P =0.00047), and improved all Seattle Angina Questionnaire scores with no significant change in exercise time at 6 months of follow-up. Historic control patients had no significant change in CED., Conclusions: A single intracoronary autologous CD34+ cell infusion was safe and may potentially be an effective disease-modifying therapy for microvascular CED in humans. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03471611.

Objective: To study associations between the Minnesota coronavirus disease 2019 (COVID-19) mitigation strategies on incidence rates of acute myocardial infarction (MI) or revascularization among residents of Southeast Minnesota., Methods: Using the Rochester Epidemiology Project, all adult residents of a nine-county region of Southeast Minnesota who had an incident MI or revascularization between January 1, 2015, and December 31, 2020, were identified. Events were defined as primary in-patient diagnosis of MI or undergoing revascularization. We estimated age- and sex-standardized incidence rates and incidence rate ratios (IRRs) stratified by key factors, comparing 2020 to 2015-2019. We also calculated IRRs by periods corresponding to Minnesota's COVID-19 mitigation timeline: "Pre-lockdown" (January 1-March 11, 2020), "First lockdown" (March 12-May 31, 2020), "Between lockdowns" (June 1-November 20, 2020), and "Second lockdown" (November 21-December 31, 2020)., Results: The incidence rate in 2020 was 32% lower than in 2015-2019 (24 vs 36 events/100,000 person-months; IRR, 0.68; 95% CI, 0.62-0.74). Incidence rates were lower in 2020 versus 2015-2019 during the first lockdown (IRR, 0.54; 95% CI, 0.44-0.66), in between lockdowns (IRR, 0.70; 95% CI, 0.61-0.79), and during the second lockdown (IRR, 0.54; 95% CI, 0.41-0.72). April had the lowest IRR (IRR 0.48; 95% CI, 0.34-0.68), followed by August (IRR, 0.55; 95% CI, 0.40-0.76) and December (IRR, 0.56; 95% CI, 0.41-0.77). Similar declines were observed across sex and all age groups, and in both urban and rural residents., Conclusion: Mitigation measures for COVID-19 were associated with a reduction in hospitalizations for acute MI and revascularization in Southeast Minnesota. The reduction was most pronounced during the lockdown periods but persisted between lockdowns., (© 2021 The Authors.)

Objective: To evaluate the epidemiology and outcomes of non-ST-segment-elevation myocardial infarction-cardiogenic shock (NSTEMI-CS) in the United States., Methods: Adult (>18 years) NSTEMI-CS admissions were identified using the National Inpatient Sample (2000-2017) and classified by tertiles of admission year (2000-2005, 2006-2011 and 2012-2017). Outcomes of interest included temporal trends of prevalence and in-hospital mortality, use of cardiac procedures, in-hospital mortality, hospitalization costs, and length of stay., Results: In over 7.3 million NSTEMI admissions, CS was noted in 189,155 (2.6%). NSTEMI-CS increased from 1.5% in 2000 to 3.6% in 2017 (adjusted odds ratio 2.03 [95% confidence interval 1.97-2.09]; P < .001). Rates of non-cardiac organ failure and cardiac arrest increased during the study period. Between 2000 and 2017, coronary angiography (43.9%-63.9%), early coronary angiography (13.6%-25.6%), percutaneous coronary intervention (14.8%-31.6%), and coronary artery bypass grafting use (19.0%-25.8%) increased (P < .001). Over the study period, the use of intra-aortic balloon pump remained stable (28.6%-28.8%), and both percutaneous left ventricular assist devices (0%-9.1%) and extra-corporeal membrane oxygenation (0.1%-1.6%) increased (all P < .001). In hospital mortality decreased from 50.2% in 2000 to 32.3% in 2017 (adjusted odds ratio 0.27 [95% confidence interval 0.25-0.29]; P < .001). During the 18-year period, hospital lengths of stay decreased, and hospitalization costs increased., Conclusions: In the United States, prevalence of CS in NSTEMI has increased 2-fold between 2000 and 2017, while in-hospital mortality has decreased during the study period. Use of coronary angiography and percutaneous coronary intervention increased during the study period., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We introduce a new chamfering paradigm, locally connecting pixels to produce path distances that approximate Euclidean space by building a small network (a replacement product) inside each pixel. These " RE -grid graphs" maintain near-Euclidean polygonal distance contours even in noisy data sets, making them useful tools for approximation when exact numerical solutions are unobtainable or impractical. The RE -grid graph creates a modular global architecture with lower pixel-to-pixel valency and simplified topology at the cost of increased computational complexity due to its internal structure. We present an introduction to chamfering replacement products with a number of case study examples to demonstrate the potential of these graphs for path-finding in high frequency and low resolution image spaces which motivate further study. Possible future applications include morphology, watershed segmentation, halftoning, neural network design, anisotropic image processing, image skeletonization, dendritic shaping, and cellular automata.