Contrast Sensitivity of ON and OFF Human Retinal Pathways in Myopia.

The human visual cortex processes light and dark stimuli with ON and OFF pathways that are differently modulated by luminance contrast. We have previously demonstrated that ON cortical pathways have higher contrast sensitivity than OFF cortical pathways and the difference increases with luminance range (defined as the maximum minus minimum luminance in the scene). Here, we demonstrate that these ON-OFF cortical differences are already present in the human retina and that retinal responses measured with electroretinography are more affected by reductions in luminance range than cortical responses measured with electroencephalography. Moreover, we show that ON-OFF pathway differences measured with electroretinography become more pronounced in myopia, a visual disorder that elongates the eye and blurs vision at far distance. We find that, as the eye axial length increases across subjects, ON retinal pathways become less responsive, slower in response latency, less sensitive, and less effective and slower at driving pupil constriction. Based on these results, we conclude that myopia is associated with a deficit in ON pathway function that decreases the ability of the retina to process low contrast and regulate retinal illuminance in bright environments.

Global environmental changes more frequently offset than intensify detrimental effects of biological invasions.

Human-induced abiotic global environmental changes (GECs) and the spread of nonnative invasive species are rapidly altering ecosystems. Understanding the relative and interactive effects of invasion and GECs is critical for informing ecosystem adaptation and management, but this information has not been synthesized. We conducted a meta-analysis to investigate effects of invasions, GECs, and their combined influences on native ecosystems. We found 458 cases from 95 published studies that reported individual and combined effects of invasions and a GEC stressor, which was most commonly warming, drought, or nitrogen addition. We calculated standardized effect sizes (Hedges' d) for individual and combined treatments and classified interactions as additive (sum of individual treatment effects), antagonistic (smaller than expected), or synergistic (outside the expected range). The ecological effects of GECs varied, with detrimental effects more likely with drought than the other GECs. Invasions were more strongly detrimental, on average, than GECs. Invasion and GEC interactions were mostly antagonistic, but synergistic interactions occurred in >25% of cases and mostly led to more detrimental outcomes for ecosystems. While interactive effects were most often smaller than expected from individual invasion and GEC effects, synergisms were not rare and occurred across ecological responses from the individual to the ecosystem scale. Overall, interactions between invasions and GECs were typically no worse than the effects of invasions alone, highlighting the importance of managing invasions locally as a crucial step toward reducing harm from multiple global changes.

Luminance Contrast Shifts Dominance Balance between ON and OFF Pathways in Human Vision.

Human vision processes light and dark stimuli in visual scenes with separate ON and OFF neuronal pathways. In nature, stimuli lighter or darker than their local surround have different spatial properties and contrast distributions (Ratliff et al., 2010; Cooper and Norcia, 2015; Rahimi-Nasrabadi et al., 2021). Similarly, in human vision, we show that luminance contrast affects the perception of lights and darks differently. At high contrast, human subjects of both sexes locate dark stimuli faster and more accurately than light stimuli, which is consistent with a visual system dominated by the OFF pathway. However, at low contrast, they locate light stimuli faster and more accurately than dark stimuli, which is consistent with a visual system dominated by the ON pathway. Luminance contrast was strongly correlated with multiple ON/OFF dominance ratios estimated from light/dark ratios of performance errors, missed targets, or reaction times (RTs). All correlations could be demonstrated at multiple eccentricities of the central visual field with an ON-OFF perimetry test implemented in a head-mounted visual display. We conclude that high-contrast stimuli are processed faster and more accurately by OFF pathways than ON pathways. However, the OFF dominance shifts toward ON dominance when stimulus contrast decreases, as expected from the higher-contrast sensitivity of ON cortical pathways (Kremkow et al., 2014; Rahimi-Nasrabadi et al., 2021). The results highlight the importance of contrast polarity in visual field measurements and predict a loss of low-contrast vision in humans with ON pathway deficits, as demonstrated in animal models (Sarnaik et al., 2014).SIGNIFICANCE STATEMENT ON and OFF retino-thalamo-cortical pathways respond differently to luminance contrast. In both animal models and humans, low contrasts drive stronger responses from ON pathways, whereas high contrasts drive stronger responses from OFF pathways. We demonstrate that these ON-OFF pathway differences have a correlate in human vision. At low contrast, humans locate light targets faster and more accurately than dark targets but, as contrast increases, dark targets become more visible than light targets. We also demonstrate that contrast is strongly correlated with multiple light/dark ratios of visual performance in central vision. These results provide a link between neuronal physiology and human vision while emphasizing the importance of stimulus polarity in measurements of visual fields and contrast sensitivity.

Defining Strategies of Modulation of Antiplatelet Therapy in Patients With Coronary Artery Disease: A Consensus Document from the Academic Research Consortium.

Antiplatelet therapy is the mainstay of pharmacologic treatment to prevent thrombotic or ischemic events in patients with coronary artery disease treated with percutaneous coronary intervention and those treated medically for an acute coronary syndrome. The use of antiplatelet therapy comes at the expense of an increased risk of bleeding complications. Defining the optimal intensity of platelet inhibition according to the clinical presentation of atherosclerotic cardiovascular disease and individual patient factors is a clinical challenge. Modulation of antiplatelet therapy is a medical action that is frequently performed to balance the risk of thrombotic or ischemic events and the risk of bleeding. This aim may be achieved by reducing (ie, de-escalation) or increasing (ie, escalation) the intensity of platelet inhibition by changing the type, dose, or number of antiplatelet drugs. Because de-escalation or escalation can be achieved in different ways, with a number of emerging approaches, confusion arises with terminologies that are often used interchangeably. To address this issue, this Academic Research Consortium collaboration provides an overview and definitions of different strategies of antiplatelet therapy modulation for patients with coronary artery disease, including but not limited to those undergoing percutaneous coronary intervention, and consensus statements on standardized definitions.

Pilot Randomized Controlled Trial of an Educational Video for CAR T-Cell Therapy Recipients.

BACKGROUND: CAR T-cell therapy has transformed the treatment of hematologic malignancies, but it is complex and challenging to convey to patients. Educational video interventions are efficacious for improving patient knowledge about cancer therapeutics and informing their care preferences, yet no educational videos have been evaluated in CAR T-cell therapy. METHODS: We conducted a randomized controlled trial comparing an educational video versus usual care in adults (age ≥18 years) with hematologic malignancies receiving CAR T-cell therapy at Massachusetts General Hospital. Intervention participants watched a 13-minute video depicting how CAR T-cell therapy works, logistics, toxicities, prognosis, recovery, and approaches for dealing with prognostic uncertainty. The primary outcome was feasibility (≥60% enrollment rate). Secondary outcomes included acceptability (≥80% reporting comfort with the video), patients' knowledge about CAR T-cell therapy (10-item test), and self-efficacy (Communication and Attitudinal Self-Efficacy Scale-Cancer), decision satisfaction (Decision Conflict Scale), psychological distress (Hospital Anxiety and Depression Scale), and preference for CAR T-cell therapy. RESULTS: We enrolled 79% (80/101) of eligible patients. Of that group, 91% (30/33) reported being very or somewhat comfortable watching the video, and 94% (31/33) would definitely or probably recommend the video. At 1 month, participants in the video arm reported higher self-efficacy (mean difference [MD], 9.2 [95% CI, -4.0 to 22.3]; Cohen's d, 0.32), decision satisfaction (MD, 2.5 [95% CI, 0.7-4.2]; Cohen's d, 0.67), and lower anxiety (MD, -0.8 [95% CI, -2.5 to 0.7]; Cohen's d, 0.26) compared with participants in the usual care arm. At 1 week, both arms reported high preferences for CAR T-cell therapy (video arm, 94% [33/35]; usual care, 84% [27/32]). CONCLUSIONS: We found that an educational video for patients receiving CAR T-cell therapy was feasible and acceptable. The educational video demonstrated promising preliminary effects on patient self-efficacy and decision satisfaction and warrants further study.

Vascular stenting of a malignant arterial blowout as a bridge to effective systemic and regional therapy.

Locally advanced cutaneous squamous cell carcinoma can erode into blood vessels, leading to vascular blowout, requiring emergent surgical intervention. We describe a first case of this disease complication which was effectively managed with endovascular stenting as a bridge to effective systemic and regional therapy. We discuss the efficacy of this staged approach which is novel and timely in a clinical environment of increasingly effective systemic therapies.

Feasibility and Intermediate Results of Transcarotid Revascularization with a Prosthetic Conduit.

BACKGROUND: Transcarotid artery revascularization (TCAR) is a hybrid technique with excellent initial outcomes. The technical success and safety of TCAR is heavily dependent on an anatomically suitable common carotid artery (CCA). Many patients do not meet anatomic criteria and therefore are not eligible for this therapy. We sought to extend the eligibility of TCAR to patients with unfavorable CCA anatomy via the adoption of a prosthetic arterial conduit. METHODS: A single-center retrospective study of patients with critical carotid artery stenosis who underwent TCAR via a prosthetic conduit between June 2019 and October 2021 was performed. All patients in the study were considered high-risk for carotid endarterectomy based on anatomic features, such as restenosis post-carotid endarterectomy and neck radiation. Unfavorable CCA anatomy was defined as a clavicle to carotid bifurcation distance <5 cm, a CCA diameter <6 mm, and/or significant atherosclerotic disease at the intended arterial access site. The primary outcome of interest was technical success. Secondary outcomes included perioperative complications, intermediate and long-term patency, intermediate and long-term stroke and/or mortality and in-hospital length of stay. Follow-up ranged from 1 to 29 months. RESULTS: Eight patients underwent 10 TCAR procedures via a prosthetic conduit. A total of 2 procedures (20%) were performed on female patients and 8 procedures (75%) were performed on male patients. The mean age was 65 years old (standard deviation 11 years). Technical success was 100%. The 30-day ipsilateral stroke rate was 0%. The 30-day patency was 90%. There was no re-exploration for hemorrhage and 30 day mortality was 0%. CONCLUSIONS: TCAR is an excellent option for carotid artery revascularization. Unfavorable CCA anatomy has limited its applicability. TCAR via a prosthetic conduit has the potential to expand eligibility for this promising therapy.

L5 spondylolysis: Anatomical study comparing healed and unhealed lesions.

The anatomy and pathogenesis of spondylolysis has been widely studied; however, the microanatomy of spondylolysis of the lumbar vertebra has not been well described. Therefore, we aim to better elucidate this anatomy. Twenty dry bone specimens of healed and unhealed spondylolysis of the L5 vertebra were collected from human skeletal remains. Twelve L5 vertebrae were examples of unhealed spondylolysis and eight specimens exhibited a healed (i.e., bony fusion of the lesion) spondylolysis lesion. The specimens underwent macro and microanatomical analysis followed by CT and microCT imaging. Finally, selected healed and unhealed lesions were submitted for histological analysis using Mason Trichrome staining. The pars interarticularis of two L5 vertebrae without signs of healed/unhealed spondylolysis were evaluated histologically as controls. Of the 12 unhealed L5 pars defects, three were unilateral on left side. Of the eight healed pars defects, all were unilateral and seven of these were on left sides. One unilateral pars defect also had spina bifida occulta. Both on imaging and histological analysis, healed pars defects were only so superficially and not at deeper levels. Histologically, unhealed edges were made up of dense cortical bone while healed edges were made up primarily of trabecular bone. Based on our anatomical findings, the so-called healed spondylolysis lesions, although externally fused, are not thoroughly fused internally. Moreover, the anterior and posterior edges of the unhealed spondylosysis lesions are irregular and show signs of long-term disarticulation. Taken together, these data suggest that such 'healed' lesions might not be as stable as the normal L5 pars interarticularis.

Clinical Trial Design Principles and Outcomes Definitions for Device-Based Therapies for Hypertension: A Consensus Document From the Hypertension Academic Research Consortium.

The clinical implications of hypertension in addition to a high prevalence of both uncontrolled blood pressure and medication nonadherence promote interest in developing device-based approaches to hypertension treatment. The expansion of device-based therapies and ongoing clinical trials underscores the need for consistency in trial design, conduct, and definitions of clinical study elements to permit trial comparability and data poolability. Standardizing methods of blood pressure assessment, effectiveness measures beyond blood pressure alone, and safety outcomes are paramount. The Hypertension Academic Research Consortium (HARC) document represents an integration of evolving evidence and consensus opinion among leading experts in cardiovascular medicine and hypertension research with regulatory perspectives on clinical trial design and methodology. The HARC document integrates the collective information among device-based therapies for hypertension to better address existing challenges and identify unmet needs for technologies proposed to treat the world's leading cause of death and disability. Consistent with the Academic Research Consortium charter, this document proposes pragmatic consensus clinical design principles and outcomes definitions for studies aimed at evaluating device-based hypertension therapies.

Perception of prognosis, quality of life, and distress in patients receiving chimeric antigen receptor T-cell therapy.

BACKGROUND: Chimeric antigen receptor (CAR) T-cell is potentially curative therapy for patients with hematologic malignancies but can cause life-threatening toxicities. Data on perceptions of prognosis and psychological distress are lacking. METHODS: The authors conducted a cross-sectional study of patients receiving CAR-T. Before hospitalization for CAR-T, patients completed assessments of quality of life (QOL) (Functional Assessment of Cancer Therapy-General), anxiety and depression symptoms (Hospital Anxiety and Depression Scale) and post-traumatic stress disorder symptoms (Post-Traumatic Stress Checklist). Patients also completed the Prognostic Awareness Impact Scale (PAIS), which measures three domains: cognitive understanding of prognosis, emotional coping with prognosis, and adaptive response. RESULTS: A total of 71.8% (102 of 142) of eligible patients were enrolled. A total of 34% of patients reported that their oncologist said their cancer is curable and 64% reported there was >50% chance of cure. Overall, 26%, 30%, and 21% of patients reported clinically significant depression, anxiety, and posttraumatic stress disorder (PTSD) symptoms, respectively. We found no association between patients' cognitive understanding of prognosis and QOL or mood. Higher emotional coping with prognosis was associated with better QOL (Β = 0.72; SE = 0.10; p = <.001) and lower depression (Β = -0.17; SE = 0.02; p = <.001), anxiety (Β = -0.21; SE = 0.02; p = <.001), and PTSD (Β = -0.43; SE = 0.06; p = <.001) symptoms. Higher adaptive response was associated with better QOL (Β = 0.19; SE = 0.09; p = .028) and lower depression (Β = -0.05; SE = 0.02; p = .023), anxiety (Β = -0.09; SE = 0.02; p = <.001), and PTSD (Β = -0.19; SE = 0.05; p = <.001) symptoms. CONCLUSIONS: Patients undergoing CAR-T report overly optimistic perception of their prognosis and have high rates of psychological distress. Higher emotional coping with prognosis and adaptive response were associated with better QOL and less psychological distress, underscoring the need to develop interventions to promote coping with this treatment. PLAIN LANGUAGE SUMMARY: Patients undergoing chimeric antigen receptor T-cell therapy experience report overly optimistic perceptions of their prognosis and have high rates of psychological distress. Notably, higher emotional coping with prognosis and adaptive response were associated with better quality of life and less psychological distress.

The Use of Natural Language Processing to Assess Social Support in Patients With Advanced Cancer.

BACKGROUND: Data examining associations among social support, survival, and healthcare utilization are lacking in patients with advanced cancer. METHODS: We conducted a cross-sectional secondary analysis using data from a prospective longitudinal cohort study of 966 hospitalized patients with advanced cancer at Massachusetts General Hospital from 2014 through 2017. We used NLP to identify extent of patients' social support (limited versus adequate as defined by NLP-aided review of the Electronic Health Record (EHR)). Two independent coders achieved a Kappa of 0.90 (95% CI: 0.84-1.00) using NLP. Using multivariable regression models, we examined associations of social support with: 1) OS; 2) death or readmission within 90 days of hospital discharge; 3) time to readmission within 90 days; and 4) hospital length of stay (LOS). RESULTS: Patients' median age was 65 (range: 21-92) years, and a plurality had gastrointestinal (GI) cancer (34.3%) followed by lung cancer (19.5%). 6.2% (60/966) of patients had limited social support. In multivariable analyses, limited social support was not significantly associated with OS (HR = 1.13, P = 0.390), death or readmission (OR = 1.18, P = 0.578), time to readmission (HR = 0.92, P = 0.698), or LOS (ß = -0.22, P = 0.726). We identified a potential interaction suggesting cancer type (GI cancer versus other) may be an effect modifier of the relationship between social support and OS (interaction term P = 0.053). In separate unadjusted analyses, limited social support was associated with lower OS (HR = 2.10, P = 0.008) in patients with GI cancer but not other cancer types (HR = 1.00, P = 0.991). CONCLUSION: We used NLP to assess the extent of social support in patients with advanced cancer. We did not identify significant associations of social support with OS or healthcare utilization but found cancer type may be an effect modifier of the relationship between social support and OS. These findings underscore the potential utility of NLP for evaluating social support in patients with advanced cancer.

Sex-stratified differences in early antithrombotic treatment response in patients presenting with ST-segment elevation myocardial infarction.

BACKGROUND: The mechanisms underlying the increased risk of bleeding that female patients with ST-segment Elevation Myocardial Infarction (STEMI) exhibit, remains unclear. The present report assessed sex-related differences in response to pre-hospital dual antiplatelet therapy (DAPT) initiation in patients with STEMI. METHODS: The COMPARE CRUSH trial randomized patients presenting with STEMI to receive a pre-hospital loading dose of crushed or integral prasugrel tablets in the ambulance. In this substudy, we compared platelet reactivity levels and the occurrence of high platelet reactivity (HPR; defined as platelet reactivity ≥208) between sexes at 4 prespecified time points after DAPT initiation, and evaluated post-PCI bleeding between groups. RESULTS: Out of 633 STEMI patients, 147 (23%) were female. Females compared with males presented with significantly higher levels of platelet reactivity and higher HPR rates at baseline (232 [IQR, 209-256] vs 195 [IQR, 171-220], P < .01, and 76% vs 41%, OR 4.58 [95%CI, 2.52-8.32], P < .01, respectively). Moreover, female sex was identified as the sole independent predictor of HPR at baseline (OR 5.67 [95%CI, 2.56-12.53], P < .01). Following DAPT initiation, levels of platelet reactivity and the incidence of HPR were similar between sexes. Post-PCI bleeding occurred more frequently in females compared with males (10% vs 2%, OR 6.02 [95%CI, 2.61-11.87], P < .01). Female sex was an independent predictor of post-PCI bleeding (OR 3.25 [95%CI, 1.09-9.72], P = .04). CONCLUSIONS: In this contemporary STEMI cohort, female STEMI patients remain at risk of bleeding complications after primary PCI. However, this is not explained by sex-specific differences in the pharmacodynamic response to pre-hospital DAPT initiation.

Marine heatwave and reduced light scenarios cause species-specific metabolomic changes in seagrasses under ocean warming.

Climate change and extreme climatic events, such as marine heatwaves (MHWs), are threatening seagrass ecosystems. Metabolomics can be used to gain insight into early stress responses in seagrasses and help to develop targeted management and conservation measures. We used metabolomics to understand the temporal and mechanistic response of leaf metabolism in seagrasses to climate change. Two species, temperate Posidonia australis and tropical Halodule uninervis, were exposed to a combination of future warming, simulated MHW with subsequent recovery period, and light deprivation in a mesocosm experiment. The leaf metabolome of P. australis was altered under MHW exposure at ambient light while H. uninervis was unaffected. Light deprivation impacted both seagrasses, with combined effects of heat and low light causing greater alterations in leaf metabolism. There was no MHW recovery in P. australis. Conversely, the heat-resistant leaf metabolome of H. uninervis showed recovery of sugars and intermediates of the tricarboxylic acid cycle under combined heat and low light exposure, suggesting adaptive strategies to long-term light deprivation. Overall, this research highlights how metabolomics can be used to study the metabolic pathways of seagrasses, identifies early indicators of environmental stress and analyses the effects of environmental factors on plant metabolism and health.

Consensus minimum core data elements adapted to peripheral vascular intervention in the drug-eluting era: Consensus report from the Registry Assessment of Peripheral Interventional Devices (RAPID) Pathways "LEAN" working group.

Registry Assessment of Peripheral Interventional Devices (RAPID) initiated the Pathways Program to provide a transparent, collaborative forum in which to pursue insights into multiple unresolved questions on benefit-risk of paclitaxel-coated devices, including understanding the basis of the mortality signal, without a demonstrable potential biological mechanism, and whether the late mortality signal could be artifact intrinsic to multiple independent prospective randomized data sources that did not prespecify death as a long-term end point. In response to the directive, the LEAN-Case Report Form working group focused on enhancements to the RAPID Phase I Minimum Core Data set through the addition of key clinical modifiers that would be more strongly linked to longer-term mortality outcomes after peripheral arterial disease intervention in the drug-eluting device era, with the goal to have future mortality signals more accurately examined.

Volatile Methyl Siloxane Atmospheric Oxidation Mechanism from a Theoretical Perspective─How is the Siloxanol Formed?

Despite several investigations on the atmospheric fate of cyclic volatile methyl siloxanes (VMS), the oxidation chemistry of these purely anthropogenic, high production volume compounds is poorly understood. This led to uncertainties in the environmental impact and fate of the oxidation products. According to laboratory measurements, the main VMS oxidation product is the siloxanol (a -CH3 replaced with an -OH); however, none of the mechanisms proposed to date satisfactorily explain its formation. Motivated by our previous experimental observations of VMS oxidation products, we use theoretical quantum chemical calculations to (1) explore a previously unconsidered reaction pathway to form the siloxanol from a reaction of a siloxy radical with gas-phase water, (2) investigate differences in reaction rates of radical intermediates in hexamethylcyclotrisiloxane (D3) and octamethylcyclotetrasiloxane (D4) oxidation, and (3) attempt to explain the experimentally observed products. Our results suggest that while the proposed reaction of the siloxy radical with water to form the siloxanol can occur, it is too slow to compete with other unimolecular reactions and thus cannot explain the observed siloxanol formation. We also find that the reaction between the initial D3 peroxy radical (RO2•) with HO2• is slower than previously anticipated (calculated as 3 × 10-13 cm3 molecule-1 s-1 for D3 and 2 × 10-11 cm3 molecule-1 s-1 for D4 compared to the general rate of ∼1 × 10-11 cm3 molecule-1 s-1). Finally, we compare the anticipated fates of the RO2• under a variety of conditions and find that a reaction with NO (assuming a general RO2• + NO bimolecular rate constant of 9 × 10-12 cm3 molecule-1 s-1) will likely be the dominant fate in urban conditions, while isomerization can be important in cleaner environments.

Restoring Venous Patency with the ClotTriever Following Deep Vein Thrombosis.

BACKGROUND: Although randomized data remain inconclusive, invasive endovenous therapy is increasingly favored in patients with extensive iliocaval or iliofemoral deep vein thrombosis (DVT) to reduce the rates of postthrombotic syndrome. Previously, pharmacomechanical thrombectomy was the therapy of choice, but the Inari ClotTriever device is an appealing, purely mechanical, alternative. It may reduce bleeding risk, intensive care unit admission, and the need for multiple procedures when compared with traditional thrombolysis. We present a series of 18 patients treated with the ClotTriever for extensive iliocaval or iliofemoral DVT. METHODS: The Inari ClotTriever is a percutaneous mechanical thrombectomy system consisting of an expandable nitinol collection bag that is dragged along the vein wall, separating and capturing thrombus for collection into the retrieval sheath. We retrospectively reviewed all patients undergoing ClotTriever thrombectomy since the device became available at our quaternary referral center in June 2019. The review of these patients' records was determined to be exempt by our institutional review board. RESULTS: Eighteen patients underwent ClotTriever thrombectomy between June 2019 and November 2021. Most patients (N = 16, 89%) presented within 2 weeks of symptom onset, and identifiable provoking factors were present in all patients. The most common provoking factor was anatomy, with May-Thurner syndrome present in 8 patients. All patients had restoration of unimpeded venous flow in the treated segments, although 3 had some residual nonflow limiting thrombus. There were no bleeding events or repeat venous procedures. The median postprocedure length of stay of 2 days. Postoperative venous imaging was performed in 15 patients and showed patency of the treated segment in 14 patients. Revised Clinical Venous Severity Scores were available in 14 patients during the course of follow-up. Of these, 9 patients' highest scores were 0, 2 patients' highest scores were 2, 2 patients' highest scores were 4, and 1 patient had a high score of 8. CONCLUSIONS: Venous flow was re-established in all 18 patients treated with the ClotTriever in this series, with no bleeding complications, and median postprocedure length of stay of 2 days. All patients with available follow-up, except 1, retained patency of the treated venous segments, and most had mild postthrombotic syndrome or none at all. These findings suggest that the ClotTriever is a safe and effective way to treat extensive iliocaval/femoral DVT.

Definitions and Clinical Trial Design Principles for Coronary Artery Chronic Total Occlusion Therapies: CTO-ARC Consensus Recommendations.

Over the past 2 decades, chronic total occlusion (CTO) percutaneous coronary intervention has developed into its own subspecialty of interventional cardiology. Dedicated terminology, techniques, devices, courses, and training programs have enabled progressive advancements. However, only a few randomized trials have been performed to evaluate the safety and efficacy of CTO percutaneous coronary intervention. Moreover, several published observational studies have shown conflicting data. Part of the paucity of clinical data stems from the fact that prior studies have been suboptimally designed and performed. The absence of standardized end points and the discrepancy in definitions also prevent consistency and uniform interpretability of reported results in CTO intervention. To standardize the field, we therefore assembled a broad consortium comprising academicians, practicing physicians, researchers, medical society representatives, and regulators (US Food and Drug Administration) to develop methods, end points, biomarkers, parameters, data, materials, processes, procedures, evaluations, tools, and techniques for CTO interventions. This article summarizes the effort and is organized into 3 sections: key elements and procedural definitions, end point definitions, and clinical trial design principles. The Chronic Total Occlusion Academic Research Consortium is a first step toward improved comparability and interpretability of study results, supplying an increasingly growing body of CTO percutaneous coronary intervention evidence.

Single-Cell Transcriptome Analysis of the Circle of Willis in a Mouse Cerebral Aneurysm Model.

BACKGROUND: The circle of Willis (CoW) is the most common location for aneurysms to form in humans. Although the major cell types of the intracranial vasculature are well known, the heterogeneity and relative contributions of the different cells in healthy and aneurysmal vessels have not been well characterized. Here, we present the first comprehensive analysis of the lineage heterogeneity and altered transcriptomic profiles of vascular cells from healthy and aneurysmal mouse CoW using single-cell RNA sequencing. METHODS: Cerebral aneurysms (CAs) were induced in adult male mice using an elastase model. Single-cell RNA sequencing was then performed on CoW samples obtained from animals that either had aneurysms form or rupture 14 days post-induction. Sham-operated animals served as controls. RESULTS: Unbiased clustering analysis of the transcriptional profiles from >3900 CoW cells identified 19 clusters representing ten cell lineages: vascular smooth muscle cells, endothelial cells fibroblasts, pericytes and immune cells (macrophages, T and B lymphocytes, dendritic cells, mast cells, and neutrophils). The 5 vascular smooth muscle cell subpopulations had distinct transcriptional profiles and were classified as proliferative, stress-induced senescent, quiescent, inflammatory-like, or hyperproliferative. The transcriptional signature of the metabolic pathways of ATP generation was found to be downregulated in 2 major vascular smooth muscle cell clusters when CA was induced. Aneurysm induction led to significant expansion of the total macrophage population, and this expansion was further increased with rupture. Both inflammatory and resolution-phase macrophages were identified, and a massive spike of neutrophils was seen with CA rupture. Additionally, the neutrophil-to-lymphocyte ratio (NLR), which originated from CA induction mirrored what happens in humans. CONCLUSIONS: Our data identify CA disease-relevant transcriptional signatures of vascular cells in the CoW and is searchable via a web-based R/shiny interface.

Randomized evaluation of vessel preparation with orbital atherectomy prior to drug-eluting stent implantation in severely calcified coronary artery lesions: Design and rationale of the ECLIPSE trial.

BACKGROUND: Severe coronary artery calcification has been associated with stent underexpansion, procedural complications, and increased rates of early and late adverse clinical events in patients undergoing percutaneous coronary intervention. To date, no lesion preparation strategy has been shown to definitively improve outcomes of percutaneous coronary intervention for calcified coronary artery lesions. STUDY DESIGN AND OBJECTIVES: ECLIPSE (NCT03108456) is a prospective, randomized, multicenter trial designed to evaluate two different vessel preparation strategies in severely calcified coronary artery lesions. The routine use of the Diamondback 360 Coronary Orbital Atherectomy System is compared with conventional balloon angioplasty prior to drug-eluting stent implantation. The trial aims to enroll approximately 2000 subjects with a primary clinical endpoint of target vessel failure, defined as the composite of cardiac death, target vessel-related myocardial infarction, or ischemia-driven target vessel revascularization assessed at 1 year. The co-primary endpoint is the acute post-procedural in-stent minimal cross-sectional area as assessed by optical coherence tomography in a 500-subject cohort. Enrollment is anticipated to complete in 2022 with total clinical follow-up planned for 2 years. CONCLUSIONS: ECLIPSE is a large-scale, prospective randomized trial powered to demonstrate whether a vessel preparation strategy of routine orbital atherectomy system is superior to conventional balloon angioplasty prior to implantation of drug-eluting stents in severely calcified coronary artery lesions.

Pre-hospital treatment with crushed versus integral tablets of prasugrel in patients presenting with ST-Segment Elevation Myocardial Infarction-1-year follow-up results of the COMPARE CRUSH trial.

The present research letter reports the 1-year clinical outcomes of the randomized COMPARE CRUSH trial, which allocated STEMI patients at first medical contact in the ambulance to receive either crushed or integral tablets of prasugrel loading dose. This trial aimed to investigate whether early enhanced antiplatelet effect constituted by the crushed potent oral P2Y12 inhibitor prasugrel could lead to improved early myocardial reperfusion and clinical outcomes.