Impact of COVID-19 pandemic on STEMI care: An expanded analysis from the United States.

OBJECTIVE: To evaluate the impact of COVID-19 pandemic migitation measures on of ST-elevation myocardial infarction (STEMI) care. BACKGROUND: We previously reported a 38% decline in cardiac catheterization activations during the early phase of the COVID-19 pandemic mitigation measures. This study extends our early observations using a larger sample of STEMI programs representative of different US regions with the inclusion of more contemporary data. METHODS: Data from 18 hospitals or healthcare systems in the US from January 2019 to April 2020 were collecting including number activations for STEMI, the number of activations leading to angiography and primary percutaneous coronary intervention (PPCI), and average door to balloon (D2B) times. Two periods, January 2019-February 2020 and March-April 2020, were defined to represent periods before (BC) and after (AC) initiation of pandemic mitigation measures, respectively. A generalized estimating equations approach was used to estimate the change in response variables at AC from BC. RESULTS: Compared to BC, the AC period was characterized by a marked reduction in the number of activations for STEMI (29%, 95% CI:18-38, p \u3c .001), number of activations leading to angiography (34%, 95% CI: 12-50, p = .005) and number of activations leading to PPCI (20%, 95% CI: 11-27, p \u3c .001). A decline in STEMI activations drove the reductions in angiography and PPCI volumes. Relative to BC, the D2B times in the AC period increased on average by 20%, 95%CI (-0.2 to 44, p = .05). CONCLUSIONS: The COVID-19 Pandemic has adversely affected many aspects of STEMI care, including timely access to the cardiac catheterization laboratory for PPCI

Paclitaxel Drug-Coated Balloon Angioplasty Suppresses Progression and Inflammation of Experimental Atherosclerosis in Rabbits

Paclitaxel drug-coated balloons (DCBs) reduce restenosis, but their overall safety has recently raised concerns. This study hypothesized that DCBs could lessen inflammation and reduce plaque progression. Using 25 rabbits with cholesterol feeding- and balloon injury-induced lesions, DCB-percutaneous transluminal angioplasty (PTA), plain PTA, or sham-PTA (balloon insertion without inflation) was investigated using serial intravascular near-infrared fluorescence−optical coherence tomography and serial intravascular ultrasound. In these experiments, DCB-PTA reduced inflammation and plaque burden in nonobstructive lesions compared with PTA or sham-PTA. These findings indicated the potential for DCBs to serve safely as regional anti-atherosclerosis therapy

Anatomical considerations and emerging strategies for reducing new onset conduction disturbances in percutaneous structural heart disease interventions

Transcatheter procedures offer an alternative to cardiac surgery in select patients with structural heart disease (SHD). Unfortunately, inadvertent disruption of electrical pathways and subsequent development of new onset conduction disturbances can occur in up to 5–70% of percutaneous interventions, result in pacemaker implantation, and confer a worse prognosis. The physical proximity between the conduction system (atrioventricular node, bundle of His, and bundle branches) and the site of percutaneous repair is increasingly recognized as a key factor influencing new onset conduction disturbance development in procedures located near the conduction system. This review covers the incidence, clinical significance, and mechanisms of new onset conduction disturbances and discusses current and emerging strategies to address this complication in these populations

Molecular imaging of glioblastoma multiforme using anti-insulin-like growth factor-binding protein-7 single-domain antibodies

BACKGROUND: Insulin-like growth factor-binding protein 7 (IGFBP7) is an abundant, selective and accessible biomarker of glioblastoma multiforme (GBM) tumour vessels. In this study, an anti-IGFBP7 single-domain antibody (sdAb) was developed to target GBM vessels for molecular imaging applications. METHODS: Human GBM was modelled in mice by intracranial implantation of U87MG.EGFRvIII cells. An anti-IGFBP7 sdAb, isolated from an immune llama library by panning, was assessed in vitro for its binding affinity using surface plasmon resonance and by ex vivo immunobinding on mouse and human GBM tissue. Tumour targeting by Cy5.5-labelled anti-IGFBP7 sdAb as well as by anti-IGFBP7 sdAb conjugated to PEGylated Fe3O4 nanoparticles (NPs)-Cy5.5 were assessed in U87MG.EGFRvIII tumour-bearing mice in vivo using optical imaging and in brain sections using fluorescent microscopy. RESULTS: Surface plasmon resonance analyses revealed a medium affinity (KD\ufffd40\ufffd50 nM) binding of the anti-IGFBP7 sdAb to the purified antigen. The anti-IGFBP7 sdAb also selectively bound to both mouse and human GBM vessels, but not normal brain vessels in tissue sections. In vivo, intravenously injected anti-IGFBP7 sdAb-Cy5.5 bound to GBM vessels creating high imaging signal in the intracranial tumour. Similarly, the anti-IGFBP7 sdAb-functionalised PEGylated Fe3O4 NP-Cy5.5 demonstrated enhanced tumour signal compared with non-targeted NPs. Fluorescent microscopy confirmed the presence of anti-IGFBP7 sdAb and anti-IGFBP7 sdAb- PEGylated Fe3O4 NPs selectively in GBM vessels. CONCLUSIONS: Anti-IGFBP7 sdAbs are novel GBM vessel-targeting moieties suitable for molecular imaging.Peer reviewed: YesNRC publication: Ye

The Evolutionary Dynamics of a Rapidly Mutating Virus within and between Hosts: The Case of Hepatitis C Virus

Many pathogens associated with chronic infections evolve so rapidly that strains found late in an infection have little in common with the initial strain. This raises questions at different levels of analysis because rapid within-host evolution affects the course of an infection, but it can also affect the possibility for natural selection to act at the between-host level. We present a nested approach that incorporates within-host evolutionary dynamics of a rapidly mutating virus (hepatitis C virus) targeted by a cellular cross-reactive immune response, into an epidemiological perspective. The viral trait we follow is the replication rate of the strain initiating the infection. We find that, even for rapidly evolving viruses, the replication rate of the initial strain has a strong effect on the fitness of an infection. Moreover, infections caused by slowly replicating viruses have the highest infection fitness (i.e., lead to more secondary infections), but strains with higher replication rates tend to dominate within a host in the long-term. We also study the effect of cross-reactive immunity and viral mutation rate on infection life history traits. For instance, because of the stochastic nature of our approach, we can identify factors affecting the outcome of the infection (acute or chronic infections). Finally, we show that anti-viral treatments modify the value of the optimal initial replication rate and that the timing of the treatment administration can have public health consequences due to within-host evolution. Our results support the idea that natural selection can act on the replication rate of rapidly evolving viruses at the between-host level. It also provides a mechanistic description of within-host constraints, such as cross-reactive immunity, and shows how these constraints affect the infection fitness. This model raises questions that can be tested experimentally and underlines the necessity to consider the evolution of quantitative traits to understand the outcome and the fitness of an infection

Low-Dose Tacrolimus Promotes the Migration and Invasion and Nitric Oxide Production in the Human-Derived First Trimester Extravillous Trophoblast Cells In Vitro

Placentation is one of the most important determinants for a successful pregnancy, and this is dependent on the process of trophoblast migration and invasion. Progesterone receptors (PGR) are critical effectors of progesterone (P4) signaling that is required for trophoblast migration and invasion conducive to a successful gestation. In immune complicated pregnancies, evidence has shown that abnormal placentation occurs because of aberrant expression of PGR. Therapeutic intervention with tacrolimus (FK506) was able to restore PGR expression and improve pregnancy outcomes in immune-complicated gestations; however, the exact mode of action of tacrolimus in assisting placentation is not clear. Here, we attempt to uncover the mode of action of tacrolimus by examining its effects on trophoblast invasion and migration in the human-derived extravillous trophoblast (EVT) cell line, the HTR-8/SVneo cells. Using a variety of functional assays, we demonstrated that low-dose tacrolimus (10 ng/mL) was sufficient to significantly (p ω- Nitro-L-Arginine Methyl Ester (L-NAME) on these vital processes critically involved in the establishment of human pregnancy. Collectively, our data suggest an immune-independent mode of action of tacrolimus in positively influencing placentation in complicated gestations, at least in part, through promoting the migration and invasion of the first trimester extravillous trophoblast cells by modulating their NO production and activating their cytosolic/nuclear progesterone-receptors. To our knowledge, this is the first report to show that the mode of action of tacrolimus as a monotherapy for implantation failure is plausibly PGR-dependent

Evaluation of brain tumor vessels specific contrast agents for glioblastoma imaging

A mouse model of glioblastoma multiforme was used to determine the accumulation of a targeted contrast agent in tumor vessels. The contrast agent, consisting of superparamagnetic iron oxide coated with dextran, was functionalized with an anti-insulin-like-growth-factor binding protein 7 (anti-IGFBP7) single domain antibody. The near infrared marker, Cy5.5, was also attached for an in vivo fluorescence study. A 9.4T magnetic resonance imaging (MRI) system was used for in vivo studies on days 10 and 11 following tumor inoculation. T2 relaxation time was used to measure the accumulation of the contrast agent in the tumor. Changes in tumor to brain contrast because of active targeting were compared with a nontargeted contrast agent. Effective targeting was confirmed with near infrared measurements and fluorescent microscopic analysis. The results showed that there was a statistically significant (P < .01) difference in normalized T2 between healthy brain and tumor tissue 10 min, 1 h, and 2 h point postinjection of the anti-IGFBP7 single domain antibody targeted and nontargeted iron oxide nanoparticles. A statistical difference remained in animals treated with targeted nanoparticles 24 h postinjection only. The MRI, near infrared imaging, and fluorescent microscopy studies showed corresponding spatial and temporal changes. We concluded that the developed anti-IGFBP7-iron oxide single domain antibodytargeted MRI contrast agent selectively binds to abnormal vessels within a glioblastoma. T2-weighted MRI and near infrared imaging are able to detect the targeting effects in brain tumors. \ua9 The Author(s) 2011.Peer reviewed: YesNRC publication: Ye

Factors associated with health-related quality of life (HRQOL) in adults with short stature skeletal dysplasias

Introduction: Numerous factors associate with health disparities. The extent to which such factors influence health-related quality of life (HRQOL) among adults with short stature skeletal dysplasias (SD) is unknown. In an effort to update and clarify knowledge about the HRQOL of adults with SD, this study aimed to quantify HRQOL scores relative to the American average and assess whether specific indicators are associated with lower scores.Methods: Members (\u3e18 years) of Little People of America were invited to complete an online survey assessing HRQOL using the SF-12 supplemented with indicator-specific questions. SF-12 components (Physical Component Summary, PCS; Mental Component Summary, MCS) were compared to the standardized national American mean. Scores were divided at the median to identify factors associated with lower scores using multivariable logistic regression, adjusting for age, gender, race, education, and employment.Results: A total of 189 surveys were completed. Mean and median PCS and MCS were below the national mean of 50 (p \u3c 0.001). Advancing decade of age corresponded to a significant decline in PCS (p \u3c 0.001) but not MCS (p = 0.366). Pain prevalence was high (79.4%); however, only 5.9% visited a pain specialist. Significant factors for lower PCS included age \u3e40 years (p = 0.020), having spondyloepiphyseal dysplasia congenita (SED) or diastrophic dysplasia relative to achondroplasia (p = 0.023), pain (p \u3c 0.001), and partial versus full health insurance coverage (p = 0.034). For MCS, significant factors included a lack of social support (p = 0.002) and being treated differently/feeling stigmatized by health care providers (p = 0.022).Conclusions: Individuals with SD face documented disparities and report lower HRQOL. Further research and interventions are needed to modify nuanced factors influencing these results and address the high prevalence of pain

Kinetic analysis of novel mono- and multivalent VHH-fragments and their application for molecular imaging of brain tumours

Background and purpose:? The overexpression of epidermal growth factor receptor (EGFR) and its mutated variant EGFRvIII occurs in 50% of glioblastoma multiforme. We developed antibody fragments against EGFR/EGFRvIII for molecular imaging and/or therapeutic targeting applications. Experimental approach:? An anti\u2013EGFR/EGFRvIII llama single-domain antibody (EG2) and two higher valency format constructs, bivalent EG2-hFc and pentavalent V2C-EG2 sdAbs, were analysed in vitro for their binding affinities using surface plasmon resonance and cell binding studies, and in vivo using pharmacokinetic, biodistribution, optical imaging and fluorescent microscopy studies. Key results:? Kinetic binding analyses by surface plasmon resonance revealed intrinsic affinities of 55 nM and 97 nM for the monovalent EG2 to immobilized extracellular domains of EGFR and EGFRvIII, respectively, and a 10- to 600-fold increases in apparent affinities for the multivalent binders, V2C-EG2 and EG2-hFc, respectively. In vivo pharmacokinetic and biodistribution studies in mice revealed plasma half-lives for EG2, V2C-EG2 and EG2-hFc of 41 min, 80 min and 12.5 h, respectively, as well as a significantly higher retention of EG2-hFc compared to the other two constructs in EGFR/EGFRvIII-expressing orthotopic brain tumours, resulting in the highest signal in the tumour region in optical imaging studies. Time domain volumetric optical imaging fusion with high-resolution micro-computed tomography of microvascular brain network confirmed EG2-hFc selective accumulation/retention in anatomically defined tumour regions. Conclusions:? Single domain antibodies can be optimized for molecular imaging applications by methods that improve their apparent affinity and prolong plasma half-life and, at the same time, preserve their ability to penetrate tumour parenchyma.Peer reviewed: YesNRC publication: Ye