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A HPLC-UV method for the quantification of six major isoflavonoids, calycosin 7-O-beta-D-glucoside (1), formononetin 7-O-beta-D-glucoside (2), (6alphaR, 11alphaR) 3-hydroxy-9,10-dimethoxypterocarpan-3-O-beta-D-glucoside (3), 7,2'-dihydroxy-3',4'-dimethoxyisoflavan-7-O-beta-D-glucoside (4), calycosin (5) and formononetin (6), in Radix Astragali (Huangqi) was developed and validated. The method was proven to be sensitive, specific, accurate and precise, as well as effective and easy. [ABSTRACT FROM AUTHOR]

Introduction: Critical limb-threatening ischemia (CLTI) is a severe manifestation of peripheral artery disease (PAD) that can lead to limb amputation and significantly reduce quality of life. In addition to guideline-directed medical therapy (GDMT), endovascular therapy and surgical revascularization are the two revascularization options for CLTI. In recent years, there has been an ongoing debate about the best approach for CLTI patients. The purpose of this meta-analysis is to examine the current evidence and compare the clinical outcomes of endovascular therapy and surgical revascularization for CLTI., Methods: We conducted a systematic search of electronic databases (PubMed, Embase, Cochrane Library, and Web of Science) for studies comparing the outcomes of endovascular therapy versus surgery in patients with CLTI. The primary outcomes were major adverse limb events (MALE) and major adverse cardiovascular events (MACE), while secondary outcomes included risk of bleeding, wound complications, readmission, unplanned reoperation, acute renal failure, and length of hospital stay. Pooled data was analyzed using the fixed-effect model or the random-effect model in Review Manager 5.3. The Newcastle-Ottawa Scale and Cochrane risk of bias assessment tool were used to assess the bias of included studies., Results: A total of 16 studies (47,609 patients) were included in this meta-analysis. The overall effect favors surgery over endovascular intervention in terms of MALE [odds ratio (OR) 1.13, 95% CI (1.01-1.28), P = 0.04]. Endovascular therapy is associated with lower MACE rates compared to surgery [OR 0.62, 95% CI (0.51-0.76), P < 0.00001]. Furthermore, the risk of bleeding, wound complications, readmission, unplanned reoperation, acute renal failure as well as the length of hospital stay was lower for endovascular intervention. Finally, there was no statistically significant difference in 30-day mortality between the two groups [OR 0.94, 95% CI 0.79-1.12, P = 0.52; Fig. 3i], and the pooled studies were homogeneous [P = 0.39; I2 = 5%]., Conclusion: Surgery may be the preferred treatment option for CLTI patients, as it is associated with a lower risk of MALE than endovascular therapy. However, endovascular therapy may be associated with a lower risk of MACE and lower rates of bleeding, wound complications, readmission, unplanned reoperation, acute renal failure, and shorter hospital stays. There was no statistically significant difference in 30-day mortality between the two groups. Ultimately, the decision to use endovascular therapy or surgery as the primary treatment strategy should be based on a multi-disciplinary team approach with careful consideration of patient characteristics and anatomy., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier Inc.)

Background: In the BEST-CLI trial (Best Endovascular Versus Best Surgical Therapy for Patients With Chronic Limb-Threatening Ischemia), a prespecified secondary objective was to assess the effects of revascularization strategy on health-related quality of life (HRQoL)., Methods: Patients with chronic limb-threatening ischemia were randomized to surgical bypass (Bypass) or endovascular intervention (Endo) in 2 parallel trials. Cohort 1 included patients with single-segment great saphenous vein; cohort 2 included those lacking suitable single-segment great saphenous vein. HRQoL was assessed over the trial duration using Vascular Quality-of-Life (VascuQoL), European Quality-of-Life-5D (EQ-5D), the Short Form-12 (SF-12) Physical Component Summary (SF-12 PCS), SF-12 Mental Component Summary (SF-12 MCS), Utility Index Score (SF-6D R2), and numeric rating scales of pain. HRQoL was summarized by cohort and compared within and between groups using mixed-model linear regression., Results: A total of 1193 and 335 patients in cohorts 1 and 2 with a mean follow-up of 2.9 and 2.0 years, respectively, were analyzed. In cohort 1, HRQoL significantly improved from baseline to follow-up for both groups across all measures. For example, mean (SD) VascuQoL scores were 3.0 (1.3) and 3.0 (1.2) for Bypass and Endo at baseline and 4.7 (1.4) and 4.8 (1.5) over follow-up. There were significant group differences favoring Endo when assessed with VascuQoL (difference, -0.14 [95% CI, -0.25 to -0.02]; P =0.02), SF-12 MCS (difference, -1.03 [95% CI, -1.89 to -0.18]; P =0.02), SF-6D R2 (difference, -0.01 [95% CI, -0.02 to -0.001]; P =0.03), numeric rating scale pain at present (difference, 0.26 [95% CI, 0.03 to 0.49]; P =0.03), usual level during previous week (difference, 0.26 [95% CI, 0.04 to 0.48]; P =0.02), and worst level during previous week (difference, 0.29 [95% CI, 0.02 to 0.56]; P =0.04). There was no difference between treatment arms on the basis of EQ-5D (difference, -0.01 [95% CI, -0.03 to 0.004]; P =0.12) or SF-12 PCS (difference, -0.41 [95% CI, -1.2 to 0.37]; P =0.31). In cohort 2, HRQoL also significantly improved from baseline to the end of follow-up for both groups based on all measures, but there were no differences between Bypass and Endo on any measure., Conclusions: Among patients with chronic limb-threatening ischemia deemed eligible for either Bypass or Endo, revascularization resulted in significant and clinically meaningful improvements in HRQoL. In patients with an available single-segment great saphenous vein for bypass, but not among those without one, Endo was statistically superior on some HRQoL measures; however, these differences were below the threshold of clinically meaningful difference., Competing Interests: Disclosures M.T.M. is an advisor to Janssen. A.F. is an advisor to Sanifit. K.R. receives income as a consultant or member of a scientific advisory board for the following entities: Abbott Vascular, Althea Medical, Angiodynamics, Auxetics, Becton-Dickinson, Boston Scientific, Contego, Crossliner, Innova Vascular, InspireMD, Janssen/Johnson and Johnson, Magneto, Mayo Clinic, MedAlliance, Medtronic, Neptune Medical, Penumbra, Philips, Surmodics, Terumo, Thrombolex, Truvic, Vasorum, and Vumedi. K.R. owns equity or stock options in the following entities: Access Vascular, Aerami, Althea Medical, Auxetics, Contego, Crossliner, Cruzar Systems, Endospan, Imperative Care/Truvic, Innova Vascular, InspireMD, JanaCare, Magneto, MedAlliance, Neptune Medical, Orchestra, Prosomnus, Shockwave, Skydance, Summa Therapeutics, Thrombolex, Vasorum, and Vumedi. K.R. or his institution (on his behalf) receives research grants from the following entities: National Institutes of Health, Abiomed, Boston Scientific, Novo Nordisk Foundation, Penumbra, and Gettinge-Atrium. K.R. serves as a member of the board of directors of the National Pulmonary Embolism Response Team Consortium. M.S.C. is a Data Safety Monitoring Board member for an Abbott Vascular Clinical Trial. J.J.S. received an education grant from WL Gore paid to Boston University and an education grant from Becton Dickinson paid to Boston University. M.D.D. is a consultant for Cook Medical, WL Gore, and Boston Scientific. M.R.J. is a part-time employee for Boston Scientific. B.G. is a consultant to Surmodics and Hart Clinical Consultants. J.A.K. was a consultant and speaker for Cook Medical during the time of the study. The other authors report no conflicts.

Objectives: There has been significant variability in practice patterns and equipoise regarding treatment approach for chronic limb-threatening ischemia (CLTI). We aimed to assess treatment preferences of Best Endovascular vs Best Surgical Therapy in Patients with CLTI (BEST-CLI) investigators prior to and following the trial., Methods: An electronic 60-question survey was sent to 1180 BEST-CLI investigators in 2022, after trial conclusion and before announcement of results. Investigators' preferences were assessed across clinical scenarios for both open (OPEN) and endovascular (ENDO) revascularization strategies. Vascular surgeon (VS) surgical and ENDO preferences were compared with a 2010 survey administered to prospective investigators before trial funding., Results: For the 2022 survey, the response rate was 20.2% and was comprised of VSs (76.3%), interventional cardiologists (11.4%) and interventional radiologists (11.6%). The majority (72.6%) were in academic practice and 39.1% were in practice for >20 years. During initial CLTI work-up, 65.8%, 42.6%, and 55.9% of respondents always or usually ordered an arterial duplex, computed tomography angiography, and vein mapping, respectively. The most common practice distribution between ENDO and OPEN procedures was 70/30. Postoperatively, a majority reported performing routine duplex surveillance of vein bypass (99%), prosthetic bypass (81.9%), and ENDO interventions (86%). A minority reported always or usually using the wound, ischemia, and foot infection (WIfI) criteria (25.8%), GLASS (8.3%), and a risk calculator (14.8%). More than one-half (52.9%) agreed that the statement "no bridges are burned with an ENDO-first approach" was false. Intervention choice was influenced by availability of the operating room or ENDO suite, personal schedule, and personal skill set in 30.1%, 18.0%, and 45.9% of respondents, respectively. Most respondents reported routinely using paclitaxel-coated balloons (88.1%) and stents (67.5%); however, 73.3% altered practice when safety concerns were raised. Among surgeons, 17.8%, 2.9%, and 10.3% reported performing >10 annual alternative autogenous vein bypasses, composite vein composite vein bypasses, and bypasses to pedal targets, respectively. Among all interventionalists, 8%, 24%, and 8% reported performing >10 annual radial access procedures, pedal or tibial access procedures, and pedal loop revascularizations. The majority (89.1%) of respondents felt that CLTI teams improved care; however, only 23.2% had a defined team. The effectiveness of the teamwork at institutions was characterized as highly effective in 42.5%. When comparing responses by VSs to the 2010 survey, there were no changes in preferred treatment based on Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC) II classification or conduit preference. In 2022, OPEN surgery was preferred more for a popliteal occlusion. For clinical scenarios, there were no differences except a decreased proportion of respondents who felt there was equipoise for major tissue loss for major tissue loss (43.8% vs 31.2%) and increased ENDO choice for minor tissue loss (17.6% vs 30.8%) (P < .05)., Conclusions: There is a wide range of practice patterns among vascular specialists treating CLTI. The majority of investigators in BEST-CLI had experience in both advanced OPEN and ENDO techniques and represent a real-world sample of technical expertise. Over the course of the decade of the BEST-CLI trial, there was overall similar equipoise among VSs., Competing Interests: Disclosures A.F. has received a grant from the Novo Nordisk Foundation; is a consultant for Sanifit, LeMaitre, and BioGenCell; and is on the advisory board of Dialysis-X and iThera Medical. M.M. is an advisor for Janssen. K.G. is an advisory board member for Boston Scientific. K.R. receives income as a consultant or member of a scientific advisory board for the following entities: Abbott Vascular; Althea Medical; Angiodynamics; Auxetics; Becton-Dickinson; Boston Scientific; Contego; Crossliner; Innova Vascular; Inspire MD; Janssen/Johnson and Johnson; Magneto; Mayo Clinic; MedAlliance; Medtronic; Neptune Medical; Penumbra; Philips; Surmodics; Terumo; Thrombolex; Truvic; Vasorum; Vumedi. KR owns equity or stock options in the following entities: Access Vascular; Aerami; Althea Medical; Auxetics; Contego; Crossliner; Cruzar Systems; Endospan; Imperative Care/Truvic; Innova Vascular; InspireMD; JanaCare; Magneto; MedAlliance; Neptune Medical; Orchestra; Prosomnus; Shockwave; Skydance; Summa Therapeutics; Thrombolex; Vasorum; Vumedi. K.R. or his institution (on my behalf) receive research grants from the following entities: NIH; Abiomed; Boston Scientific; Novo Nordisk Foundation; Penumbra; Gettinge-Atrium. K.R. serves as a member of the Board of Directors of the following organization: The National PERT ConsortiumTM., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Two of the main reasons recent guidelines do not recommend routine population-wide screening programs for asymptomatic carotid artery stenosis (AsxCS) is that screening could lead to an increase of carotid revascularization procedures and that such mass screening programs may not be cost-effective. Nevertheless, selective screening for AsxCS could have several benefits. This article presents the rationale for such a program., Areas Covered: The benefits of selective screening for AsxCS include early recognition of AsxCS allowing timely initiation of preventive measures to reduce future myocardial infarction (MI), stroke, cardiac death and cardiovascular (CV) event rates., Expert Opinion: Mass screening programs for AsxCS are neither clinically effective nor cost-effective. Nevertheless, targeted screening of populations at high risk for AsxCS provides an opportunity to identify these individuals earlier rather than later and to initiate a number of lifestyle measures, risk factor modifications, and intensive medical therapy in order to prevent future strokes and CV events. For patients at 'higher risk of stroke' on best medical treatment, a prophylactic carotid intervention may be considered.

Publications utilizing precision cut lung slices (PCLS) steadily increased from the 1970's, with a significant increase in 2010, to tripling by 2023. PCLS have been used to study a vast array of pulmonary diseases and exposures to pathogens and toxicants to understand pathogenesis of disease but also to examine basic cellular mechanisms that underly lung biology. This Special Issue will highlight new, exciting, and novel research using PCLS, while acknowledging the substantial fund of knowledge that has been gained using this platform., (© 2024. The Author(s).)

Background: The aim of this study is to evaluate the use of isolated gastrocnemius release in the treatment of Achilles tendinopathy. The primary outcome is the change in patient-reported pain outcomes. Secondary outcomes include the change in patient-reported foot and ankle function, ankle range of motion and strength, patient satisfaction and rate of surgical complications., Methods: A systematic review was undertaken of studies involving patients treated with an isolated gastrocnemius release for Achilles tendinopathy. Randomised controlled trials, cohort studies, case-control studies and case series were eligible and identified from the following databases: MEDLINE and EMBASE., Results: Isolated gastrocnemius release results in improved patient-reported outcome scores for pain and foot and ankle function. There is an increase in ankle range of motion but a reduction in ankle strength. Patients report a high rate of overall satisfaction. The most common surgical complications are sural nerve injury and wound infection., Conclusions: Isolated gastrocnemius release may offer maintained and clinically meaningful improvements in pain and foot and ankle function with an associated reduction in ankle strength., Competing Interests: Conflict of InterestOn behalf of all authors, the corresponding author states that there is no conflict of interest., (© Indian Orthopaedics Association 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Objective: The optimal management of patients with asymptomatic carotid stenosis (AsxCS) is enduringly controversial. We updated our 2021 Expert Review and Position Statement, focusing on recent advances in the diagnosis and management of patients with AsxCS., Methods: A systematic review of the literature was performed up to August 1, 2023, using PubMed/PubMed Central, EMBASE and Scopus. The following keywords were used in various combinations: "asymptomatic carotid stenosis," "carotid endarterectomy" (CEA), "carotid artery stenting" (CAS), and "transcarotid artery revascularization" (TCAR). Areas covered included (i) improvements in best medical treatment (BMT) for patients with AsxCS and declining stroke risk, (ii) technological advances in surgical/endovascular skills/techniques and outcomes, (iii) risk factors, clinical/imaging characteristics and risk prediction models for the identification of high-risk AsxCS patient subgroups, and (iv) the association between cognitive dysfunction and AsxCS., Results: BMT is essential for all patients with AsxCS, regardless of whether they will eventually be offered CEA, CAS, or TCAR. Specific patient subgroups at high risk for stroke despite BMT should be considered for a carotid revascularization procedure. These patients include those with severe (≥80%) AsxCS, transcranial Doppler-detected microemboli, plaque echolucency on Duplex ultrasound examination, silent infarcts on brain computed tomography or magnetic resonance angiography scans, decreased cerebrovascular reserve, increased size of juxtaluminal hypoechoic area, AsxCS progression, carotid plaque ulceration, and intraplaque hemorrhage. Treatment of patients with AsxCS should be individualized, taking into consideration individual patient preferences and needs, clinical and imaging characteristics, and cultural, ethnic, and social factors. Solid evidence supporting or refuting an association between AsxCS and cognitive dysfunction is lacking., Conclusions: The optimal management of patients with AsxCS should include BMT for all individuals and a prophylactic carotid revascularization procedure (CEA, CAS, or TCAR) for some asymptomatic patient subgroups, additionally taking into consideration individual patient needs and preference, clinical and imaging characteristics, social and cultural factors, and the available stroke risk prediction models. Future studies should investigate the association between AsxCS with cognitive function and the role of carotid revascularization procedures in the progression or reversal of cognitive dysfunction., Competing Interests: Disclosures J.F.M. is co-Principal Investigator for the Clinical Coordinating Center of the CREST-2 multicenter randomized clinical trial (U01NS080168) and Principal Investigator of the Long-term Observational Extension of participants in the CREST-2 randomized clinical trial (C2LOE; U01NS119169). M.L.S. is the Principal Investigator of the ROADSTER-3 trial and is the Chair of the TCAR Surveillance Program in the Vascular Quality Initiative. L.H.B., P.J.N., and M.M.B. are co-Principal Investigators for the 2nd European Carotid Surgery Trial (ECST-2). P.S. is a consultant for Silk Road, Philips, Surmodics, Medtronic, Boston Scientific, Cagent, and LimFlow. E.A.S. has received research grants from the Food & Drug Administration (FDA), SCAI, BD, Boston Scientific, Cook, Laminate Medical, Medtronic, Philips, and NIH/NHLBIK23HL150290. He has received Consulting/Speaker fees from Abbott, Bayer, BD, Boston Scientific, Cook, Cordis, Heartflow, Inari, InfraRedx, Medtronic, Philips, RapidAI, Shockwave, and VentureMed. D.P.M. has given talks, acted as a consultant or attended conferences sponsored by Amgen and Novo Nordisk. B.K.L. is co-Principal Investigator of the CREST-2 multicenter randomized clinical trial (U01NS080168), Principal Investigator of the CREST-2 Registry (C2R; NCT02240862) and Principal Investigator for the Asymptomatic Carotid Stenosis and Cognitive Function Study (ACCOF; CX001621). The other authors have no conflicts of interest., (Copyright © 2023 Society for Vascular Surgery. All rights reserved.)

Multi-hazard events, characterized by the simultaneous, cascading, or cumulative occurrence of multiple natural hazards, pose a significant threat to human lives and assets. This is primarily due to the cumulative and cascading effects arising from the interplay of various natural hazards across space and time. However, their identification is challenging, which is attributable to the complex nature of natural hazard interactions and the limited availability of multi-hazard observations. This study presents an approach for identifying multi-hazard events during the past 123 years (1900-2023) using the EM-DAT global disaster database. Leveraging the 'associated hazard' information in EM-DAT, multi-hazard events are detected and assessed in relation to their frequency, impact on human lives and assets, and reporting trends. The interactions between various combinations of natural hazard pairs are explored, reclassifying them into four categories: preconditioned/triggering, multivariate, temporally compounding, and spatially compounding multi-hazard events. The results show, globally, approximately 19 % of the 16,535 disasters recorded in EM-DAT can be classified as multi-hazard events. However, the multi-hazard events recorded in EM-DAT are disproportionately responsible for nearly 59 % of the estimated global economic losses. Conversely, single hazard events resulted in higher fatalities compared to multi-hazard events. The largest proportion of multi-hazard events are associated with floods, storms, and earthquakes. Landslides emerge as the predominant secondary hazards within multi-hazard pairs, primarily triggered by floods, storms, and earthquakes, with the majority of multi-hazard events exhibiting preconditioned/triggering and multivariate characteristics. There is a higher prevalence of multi-hazard events in Asia and North America, whilst temporal overlaps of multiple hazards predominate in Europe. These results can be used to increase the integration of multi-hazard thinking in risk assessments, emergency management response plans and mitigation policies at both national and international levels., 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 © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Human immunodeficiency virus (HIV) infection continues to promote neurocognitive impairment, mood disorders, and brain atrophy, even in the modern era of viral suppression. Brain lipids are vulnerable to HIV-associated energetic strain and may contribute to HIV-associated neurologic dysfunction due to alterations in lipid breakdown and structural lipid composition. HIV neuropathology is region dependent, yet there has not been comprehensive characterization of the spatial heterogeneity of brain lipids during infection that possibly impacts neurologic function. To address this gap, we evaluated the spatial lipid distribution using matrix laser desorption/ionization imaging mass spectrometry (MALDI-IMS) across four brain regions (parietal cortex, midbrain, thalamus, and temporal cortex), as well as the kidney for a peripheral tissue control, in a simian immunodeficiency virus (SIV)-infected rhesus macaque treated with a course of antiretroviral therapies (ARTs). We assessed lipids indicative of fat breakdown [acylcarnitines (CARs)] and critical structural lipids [phosphatidylcholines (PCs) and phosphatidylethanolamines (PEs)] across fatty acid chain lengths and degrees of unsaturation. CARs with very long-chain, polyunsaturated fatty acids (PUFAs) were more abundant across all brain regions than shorter chain, saturated, or monounsaturated species. We observed distinct brain lipid distribution patterns for the CARs and PCs. However, no clear expression patterns emerged for PEs. Surprisingly, the kidney was nearly devoid of ions corresponding to PUFAs common in brain. PEs and PCs with PUFAs had little intensity and less density than other species, and only one CAR species was observed in kidney at high intensity. Overall, our study demonstrates the stark variation in structural phospholipids and lipid-energetic intermediates present in the virally suppressed SIV-macaque brain. These findings may be useful for identifying regional vulnerabilities to damage due to brain lipid changes in people with HIV.

The endocannabinoid system is widely expressed throughout the body and is comprised of receptors, ligands, and enzymes that maintain metabolic, immune, and reproductive homeostasis. Increasing interest in the endocannabinoid system has arisen due to these physiologic roles, policy changes leading to more widespread recreational use, and the therapeutic potential of Cannabis and phytocannabinoids. Rodents have been the primary preclinical model of focus due to their relative low cost, short gestational period, genetic manipulation strategies, and gold-standard behavioral tests. However, the potential for lack of clinical translation to non-human primates and humans is high as cross-species comparisons of the endocannabinoid system have not been evaluated. To bridge this gap in knowledge, we evaluate the relative gene expression of 14 canonical and extended endocannabinoid receptors in seven peripheral organs of C57/BL6 mice, Sprague-Dawley rats, and non-human primate rhesus macaques. Notably, we identify species- and organ-specific heterogeneity in endocannabinoid receptor distribution where there is surprisingly limited overlap among the preclinical models. Importantly, we determined there were no receptors with identical expression patterns among mice (three males and two females), rats (six females), and rhesus macaques (four males). Our findings demonstrate a critical, yet previously unappreciated, contributor to challenges of rigor and reproducibility in the cannabinoid field, which has implications in hampering progress in understanding the complexity of the endocannabinoid system and development of cannabinoid-based therapies., (© 2024 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Objective: Despite the publication of various national/international guidelines, several questions concerning the management of patients with asymptomatic (AsxCS) and symptomatic (SxCS) carotid stenosis remain unanswered. The aim of this international, multi-specialty, expert-based Delphi Consensus document was to address these issues to help clinicians make decisions when guidelines are unclear., Methods: Fourteen controversial topics were identified. A three-round Delphi Consensus process was performed including 61 experts. The aim of Round 1 was to investigate the differing views and opinions regarding these unresolved topics. In Round 2, clarifications were asked from each participant. In Round 3, the questionnaire was resent to all participants for their final vote. Consensus was reached when ≥75% of experts agreed on a specific response., Results: Most experts agreed that: (1) the current periprocedural/in-hospital stroke/death thresholds for performing a carotid intervention should be lowered from 6% to 4% in patients with SxCS and from 3% to 2% in patients with AsxCS; (2) the time threshold for a patient being considered "recently symptomatic" should be reduced from the current definition of "6 months" to 3 months or less; (3) 80% to 99% AsxCS carries a higher risk of stroke compared with 60% to 79% AsxCS; (4) factors beyond the grade of stenosis and symptoms should be added to the indications for revascularization in AsxCS patients (eg, plaque features of vulnerability and silent infarctions on brain computed tomography scans); and (5) shunting should be used selectively, rather than always or never. Consensus could not be reached on the remaining topics due to conflicting, inadequate, or controversial evidence., Conclusions: The present international, multi-specialty expert-based Delphi Consensus document attempted to provide responses to several unanswered/unresolved issues. However, consensus could not be achieved on some topics, highlighting areas requiring future research., Competing Interests: Disclosures D.P.M. has given talks, acted as a consultant or attended conferences sponsored by Amgen and Novo Nordisk. J.F.M. receives funding from the United States National Institute of Neurologic Disorders and Stroke for work related to running the CREST-2 clinical trial (U01NS080168) and the CREST-2 Long-term Observational Extension study (U01NS119169). E.A.S. has received research grants from the United States Food and Drug Administration, BD, Boston Scientific, Cook, CSI, Laminate Medical, Medtronic and Philips; has received consulting/speaking fees from Abbott, Bayer, BD, Boston Scientific, Cook, Cordis, CSI, Inari, Infraredx, Medtronic, Philips, Shockwave and VentureMed. H.-H.E. is a local Principal Investigator for the ROADSTER 2 trial and a scientific committee member of SPACE-1, SPACE-2 and ACST-2. T.R. is funded by grants from the National Institutes of Health (R01 MD012467, R01 NS029993, R01NS040807, 1U24NS107267), and the National Center for Advancing Translational Sciences (UL1 TR002736, KL2 TR002737). J.S.M. has received institutional research grants from Abbott, Cook, Endologix, Gore and Medtronic., (Copyright © 2023 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Rhinovirus infections commonly evoke asthma exacerbations in children and adults. Recurrent asthma exacerbations are associated with injury-repair responses in the airways that collectively contribute to airway remodeling. The physiological consequences of airway remodeling can manifest as irreversible airway obstruction and diminished responsiveness to bronchodilators. Structural cells of the airway, including epithelial cells, smooth muscle, fibroblasts, myofibroblasts, and adjacent lung vascular endothelial cells represent an understudied and emerging source of cellular and extracellular soluble mediators and matrix components that contribute to airway remodeling in a rhinovirus-evoked inflammatory environment., Main Body: While mechanistic pathways associated with rhinovirus-induced airway remodeling are still not fully characterized, infected airway epithelial cells robustly produce type 2 cytokines and chemokines, as well as pro-angiogenic and fibroblast activating factors that act in a paracrine manner on neighboring airway cells to stimulate remodeling responses. Morphological transformation of structural cells in response to rhinovirus promotes remodeling phenotypes including induction of mucus hypersecretion, epithelial-to-mesenchymal transition, and fibroblast-to-myofibroblast transdifferentiation. Rhinovirus exposure elicits airway hyperresponsiveness contributing to irreversible airway obstruction. This obstruction can occur as a consequence of sub-epithelial thickening mediated by smooth muscle migration and myofibroblast activity, or through independent mechanisms mediated by modulation of the β 2 agonist receptor activation and its responsiveness to bronchodilators. Differential cellular responses emerge in response to rhinovirus infection that predispose asthmatic individuals to persistent signatures of airway remodeling, including exaggerated type 2 inflammation, enhanced extracellular matrix deposition, and robust production of pro-angiogenic mediators., Conclusions: Few therapies address symptoms of rhinovirus-induced airway remodeling, though understanding the contribution of structural cells to these processes may elucidate future translational targets to alleviate symptoms of rhinovirus-induced exacerbations., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objectives: The use of optimal medical therapy (OMT) in patients with chronic limb-threatening ischemia (CLTI) has not been well-studied. The Best Endovascular vs Best Surgical Therapy in Patients with CLTI study (BEST-CLI) is a multicenter, randomized, controlled trial sponsored by the National Institutes of Health comparing revascularization strategies in patients with CLTI. We evaluated the use of guideline-based OMT among patients with CLTI at the time of their enrollment into the trial., Methods: A multidisciplinary committee defined OMT criteria related to blood pressure and diabetic management, lipid-lowering and antiplatelet medication use, and smoking status for patients enrolled in BEST-CLI. Status reports indicating adherence to OMT were provided to participating sites at regular intervals. Baseline demographic characteristics, comorbid medical conditions, and use of OMT at trial entry were evaluated for all randomized patients. A linear regression model was used to identify the relationship of predictors to the use of OMT., Results: At the time of randomization (n = 1830 total enrolled), 87% of patients in BEST-CLI had hypertension, 69% had diabetes, 73% had hyperlipidemia, and 35% were currently smoking. Adherence to four OMT components (controlled blood pressure, not currently smoking, use of one lipid-lowering medication, and use of an antiplatelet agent) was modest. Only 25% of patients met all four OMT criteria; 38% met three, 24% met two, 11% met only one, and 2% met none. Age ≥80 years, coronary artery disease, diabetes, and Hispanic ethnicity were positively associated, whereas Black race was negatively associated, with the use of OMT., Conclusions: A significant proportion of patients in BEST-CLI did not meet OMT guideline-based recommendations at time of entry. These data suggest a persistent major gap in the medical management of patients with advanced peripheral atherosclerosis and CLTI. Changes in OMT adherence over the course of the trial and their impact on clinical outcomes and quality of life will be assessed in future analyses., (Copyright © 2023 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Electrocatalytic nitric oxide (NO) generation from nitrite (NO 2 - ) within a single lumen of a dual-lumen catheter using Cu II -ligand (Cu II -L) mediators have been successful at demonstrating NO's potent antimicrobial and antithrombotic properties to reduce bacterial counts and mitigate clotting under low oxygen conditions (e.g., venous blood). Under more aerobic conditions, the O 2 sensitivity of the Cu(II)-ligand catalysts and the reaction of O 2 (highly soluble in the catheter material) with the NO diffusing through the outer walls of the catheters results in a large decreases in NO fluxes from the surfaces of the catheters, reducing the utility of this approach. Herein, we describe a new more O 2 -tolerant Cu II -L catalyst, [Cu(BEPA-EtSO 3 )(OTf)], as well as a potentially useful immobilized glucose oxidase enzyme-coating approach that greatly reduces the NO reactivity with oxygen as the NO partitions and diffuses through the catheter material. Results from this work demonstrate that very effective NO fluxes (>1*10 -10 mol min -1 cm -2 ) from a single-lumen silicone rubber catheter can be achieved in the presence of up to 10% O 2 saturated solutions., 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 © 2023 Elsevier B.V. All rights reserved.)

Rhinoviruses (RVs) evoke as many as 85% of acute asthma exacerbations in children and 50% in adults and can induce airway hyperresponsiveness and decrease efficacy of current therapeutics to provide symptom relief. Using human precision-cut lung slices (hPCLSs), primary human air-liquid interface-differentiated airway epithelial cells (HAECs), and human airway smooth muscle (HASM) as preclinical experimental models, we demonstrated that RV-C15 attenuates agonist-induced bronchodilation. Specifically, airway relaxation to formoterol and cholera toxin, but not forskolin (Fsk), was attenuated following hPCLS exposure to RV-C15. In isolated HASM cells, exposure to conditioned media from RV-exposed HAECs decreased cellular relaxation in response to isoproterenol and prostaglandin E 2 , but not Fsk. Additionally, cAMP generation elicited by formoterol and isoproterenol, but not Fsk, was attenuated following HASM exposure to RV-C15-conditioned HAEC media. HASM exposure to RV-C15-conditioned HAEC media modulated expression of components of relaxation pathways, specifically GNAI1 and GRK2 . Strikingly, similar to exposure to intact RV-C15, hPCLS exposed to UV-inactivated RV-C15 showed markedly attenuated airway relaxation in response to formoterol, suggesting that the mechanism(s) of RV-C15-mediated loss of bronchodilation is independent of virus replication pathways. Further studies are warranted to identify soluble factor(s) regulating the epithelial-driven smooth muscle loss of β 2 -adrenergic receptor function.

Proteasomes are large macromolecular complexes with multiple distinct catalytic activities that are each vital to human brain health and disease. Despite their importance, standardized approaches to investigate proteasomes have not been universally adapted. Here, we describe pitfalls and define straightforward orthogonal biochemical approaches essential to measure and understand changes in proteasome composition and activity in the mammalian central nervous system. Through our experimentation in the mammalian brain, we determined an abundance of catalytically active proteasomes exist with and without a 19S cap(s), the regulatory particle essential for ubiquitin-dependent degradation. Moreover, we learned that in-cell measurements using activity-based probes (ABPs) are more sensitive in determining the available activity of the 20S proteasome without the 19S cap and in measuring individual catalytic subunit activities of each β subunit within all neuronal proteasomes. Subsequently, applying these tools to human brain samples, we were surprised to find that post-mortem tissue retained little to no 19S-capped proteasome, regardless of age, sex, or disease state. In comparing brain tissues (parahippocampal gyrus) from patients with Alzheimer's disease (AD) and unaffected individuals, the available 20S proteasome activity was significantly elevated in severe cases of AD, an observation not previously noted. Taken together, our study establishes standardized approaches for the comprehensive investigation of proteasomes in mammalian brain tissue, and we reveal new insight into brain proteasome biology., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The WIfI (Wound, Ischemia, foot Infection) stage measures the extent of wounds, ischemia, and foot infection in patients with chronic limb threatening ischemia (CLTI) and has been associated with the risk of major amputation. Patients with CLTI have impaired health-related quality of life (HRQoL), which can be multifactorial. We hypothesized that the severity of the limb threat (WIfI stage) would be associated with poor HRQoL among patients with CLTI presenting for revascularization., Methods: The dataset of the BEST-CLI (best endovascular versus best surgical therapy in patients with CLTI) trial, a prospective, randomized trial comparing open and endovascular revascularization strategies, was queried for HRQoL assessments at patient enrollment. The HRQoL assessments included (1) Vascular Quality of Life; (2) 12-item short form survey (SF-12), containing the utility index score (short-form six-dimension R2 utility index, incorporating physical, emotional, and mental well-being) and mental and physical components; and (3) the EQ-5D. Multivariable regression analysis was used to identify the independent associations with the baseline HRQoL assessments., Results: A total of 1568 patients with complete WIfI data were analyzed, of whom 71.5% were men. The WIfI distribution was 35.5% with stage 4, 29.6% with stage 3, 28.6% with stage 2, and 6.3% with stage 1. Patients presenting with WIfI stage 4, compared with stage 1 to 3, were more often men (74.9% vs 69.6%) and current smokers (25.4% vs. 17.6%), had had end-stage renal disease (13.3% vs 8.5%) and diabetes (83.6% vs 60.2%), were not independently ambulatory (56.8% vs 38.5%), and had had higher median morbidity scores (4 vs 3; P < .05 for all). On multivariable analysis, WIfI stage 4, compared with stage 1 to 3, was associated with lower SF-12 mental component scale scores (estimate, -2.43; 95% confidence interval, -3.73 to -1.13; P < .001) and short-form six-dimension R2 utility index scores (estimate, -0.02; 95% confidence interval, -0.03 to 0.001; P = .04). The WIfI stage was not independently associated with the baseline Vascular Quality of Life, SF-12 physical component scale, or EQ-5D assessments., Conclusions: WIfI stage was independently associated with poorer quality of life because of mental, rather than physical, health for patients with CLTI. Clinicians should be aware of the burden of mental stress borne by those with the greatest limb impairment., (Copyright © 2022 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

TAS2Rs (bitter taste receptors) are GPCRs (G protein-coupled receptors) expressed on human airway smooth muscle (HASM) cells; when activated by receptor agonists they evoke marked airway relaxation. In both taste and HASM cells, TAS2Rs activate a canonical G βγ -mediated stimulation of Ca 2+ release from intracellular stores by activation of PLCβ (phospholipase Cβ). Alone, this [Ca 2+ ] i signaling does not readily account for relaxation, particularly since bronchoconstrictive agonists acting at G q -coupled receptors also increase [Ca 2+ ] i . We established that TAS2R14 activation in HASM promotes relaxation through F-actin (filamentous actin) severing. This destabilization of actin was from agonist-promoted activation (dephosphorylation) of cofilin, which was pertussis toxin sensitive. Cofilin dephosphorylation was due to TAS2R-mediated deactivation of LIM domain kinase. The link between early receptor action and the distal cofilin dephosphorylation was found to be the polarity protein partitioning defective 3 (Par3), a known binding partner with PLCβ that inhibits LIM kinase. The physiologic relevance of this pathway was assessed using knock-downs of cofilin and Par3 in HASM cells and in human precision-cut lung slices. Relaxation by TAS2R14 agonists was ablated with knock-down of either protein as assessed by magnetic twisting cytometry in isolated cells or intact airways in the slices. Blocking [Ca 2+ ] i release by TAS2R14 inhibited agonist-promoted cofilin dephosphorylation, confirming a role for [Ca 2+ ] i in actin-modifying pathways. These results further elucidate the mechanistic basis of TAS2R-mediated HASM relaxation and point toward nodal points that may act as asthma or chronic obstructive pulmonary disease response modifiers or additional targets for novel bronchodilators.

A free and charitable clinic successfully designed and implemented mass COVID-19 vaccination clinics in a semirural area in Central Pennsylvania. A total of 172 clinics were offered, approximately 500 volunteers were mobilized, and approximately 45,000 vaccine doses were administered. Partnering with local schools, universities, and recreation centers to offer mass vaccination clinics made it possible to expand the clinic's reach beyond its own patients. Findings provide evidence for the capacity of small community clinics to respond to major public health emergencies, such as a pandemic., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The event-free survival of pediatric low-grade gliomas is poor, and patients often require multiple treatment strategies. While MEK and RAF inhibitors are efficacious in early-phase trials, not all patients respond, and many experience progression following completion of therapy. Evaluating combination therapies that may enhance efficacy or prolong disease stabilization is warranted. We report our institutional experience using concurrent trametinib and lenalidomide in the treatment of primary pediatric central and peripheral nervous system tumors. Two of four patients using this combination therapy experienced severe thromboembolic events, necessitating discontinuation of therapy. This combination requires further investigation, and we urge caution if used., (© 2023 Wiley Periodicals LLC.)

Consideration of compound drivers and impacts are often missing from applications within the Disaster Risk Reduction (DRR) cycle, leading to poorer understanding of risk and benefits of actions. The need to include compound considerations is known, but lack of guidance is prohibiting practitioners from including these considerations. This article makes a step toward practitioner guidance by providing examples where consideration of compound drivers, hazards, and impacts may affect different application domains within disaster risk management. We discern five DRR categories and provide illustrative examples of studies that highlight the role of "compound thinking" in early warning, emergency response, infrastructure management, long-term planning, and capacity building. We conclude with a number of common elements that may contribute to the development of practical guidelines to develop appropriate applications for risk management., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Background: Patients with chronic limb-threatening ischemia (CLTI) require revascularization to improve limb perfusion and thereby limit the risk of amputation. It is uncertain whether an initial strategy of endovascular therapy or surgical revascularization for CLTI is superior for improving limb outcomes., Methods: In this international, randomized trial, we enrolled 1830 patients with CLTI and infrainguinal peripheral artery disease in two parallel-cohort trials. Patients who had a single segment of great saphenous vein that could be used for surgery were assigned to cohort 1. Patients who needed an alternative bypass conduit were assigned to cohort 2. The primary outcome was a composite of a major adverse limb event - which was defined as amputation above the ankle or a major limb reintervention (a new bypass graft or graft revision, thrombectomy, or thrombolysis) - or death from any cause., Results: In cohort 1, after a median follow-up of 2.7 years, a primary-outcome event occurred in 302 of 709 patients (42.6%) in the surgical group and in 408 of 711 patients (57.4%) in the endovascular group (hazard ratio, 0.68; 95% confidence interval [CI], 0.59 to 0.79; P<0.001). In cohort 2, a primary-outcome event occurred in 83 of 194 patients (42.8%) in the surgical group and in 95 of 199 patients (47.7%) in the endovascular group (hazard ratio, 0.79; 95% CI, 0.58 to 1.06; P = 0.12) after a median follow-up of 1.6 years. The incidence of adverse events was similar in the two groups in the two cohorts., Conclusions: Among patients with CLTI who had an adequate great saphenous vein for surgical revascularization (cohort 1), the incidence of a major adverse limb event or death was significantly lower in the surgical group than in the endovascular group. Among the patients who lacked an adequate saphenous vein conduit (cohort 2), the outcomes in the two groups were similar. (Funded by the National Heart, Lung, and Blood Institute; BEST-CLI ClinicalTrials.gov number, NCT02060630.)., (Copyright © 2022 Massachusetts Medical Society.)

Orthotopic liver transplantation (OLT) is a viable treatment option for end-stage liver disease. Significant perioperative stress is placed on the cardiovascular system because of hemodynamic changes and the length of the operation. Diagnosis and treatment of cardiovascular disease before OLT are imperative to ensure favorable outcomes. Considerable variability exists among practitioners caring for these patients. Institutions tailor their protocols on the basis of local and historical practices, the preferences of the cardiologists, and the OLT team, and algorithms are not often revised or updated on the basis of the available evidence. In collaboration with cardiology and hepatology experts from leading OLT centers, we sought to examine the diagnostic cardiovascular workup of OLT candidates, including a review of the available literature on the diagnostic modalities used to screen cardiovascular disease before OLT. We advocate an emphasis on noninvasive methods to assess cardiovascular risk with reserved use of invasive risk stratification in select patients., (© 2022 The Author(s).)

Over the past 30 years, the significance of nitric oxide (NO) has become increasingly apparent in mammalian physiology. It is biosynthesized by three isoforms of nitric oxide synthases (NOS): neuronal (nNOS), endothelial (eNOS), and inducible (iNOS). Neuronal and eNOS both produce low levels of NO (nM) as a signaling agent and vasodilator, respectively. Inducible (iNOS) is present in activated macrophages at sites of infection to generate acutely toxic (μM) levels of NO as part of the mammalian immune defense mechanism. These discoveries have led to numerous animal and clinical studies to evaluate the potential therapeutic utility of NO in various medical operations/treatments, primarily using NO gas (via gas-cylinders) as the NO source. In this review, we focus specifically on recent advances in the electrochemical generation of NO (E-NOgen) as an alternative means to generate NO from cheap and inert sources, and the fabrication and testing of biomedical devices that utilize E-NOgen to controllably generate NO for medical applications.

Macrocephaly is a common diagnosis in the pediatric population, particularly in the infantile time period. There is a wide range of causes of macrocephaly, from benign to malignant, for which imaging plays a key role in the diagnosis and clinical guidance. Our aim is to review the distinct and prevalent neuroimaging findings in the evaluation of the macrocephalic infant., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The role of atherectomy in treating femoropopliteal disease has been evolving rapidly. However, the clinical efficacy and safety of adjunctive atherectomy to percutaneous balloon angioplasty (BA) (plain balloon and drug-coated BA) remains controversial. We sought to perform a meta-analysis comparing atherectomy plus balloon angioplasty (ABA) versus BA alone in treating femoropopliteal disease., Methods: We searched PubMed, Cochrane Central Register of Clinical Trials, EMBASE, and ClinicalTrials.gov (from inception through January 10, 2022) for studies comparing ABA versus BA for femoropopliteal disease. We used a random-effects model to calculate risk ratio (RR) with 95% CIs. Target lesion revascularization (TLR), primary patency, and bailout stenting were the primary outcomes., Results: Nine studies with 699 patients were included (4 randomized and 5 retrospective studies). Compared to BA alone, the ABA group showed a significant decrease in TLR driven by nonrandomized studies (RR 0.59; 95% CI, 0.40-0.85; P = .005) and bailout stenting (RR, 0.32; 95% CI, 0.21-0.48; P < .0001). There was no significant difference in TLR when the analysis was performed including only randomized trials. There was no significant difference in the primary patency between the 2 groups (RR, 1.04; 95% CI, 0.95-1.14; P = .37)., Conclusions: Data from randomized trials suggest that compared with BA alone, the combination of atherectomy and BA showed no difference in TLR or primary patency. In observational studies, TLR and bailout stenting were reduced in ABA group but there was no difference in primary patency. Further studies are needed to investigate the clinical outcomes of atherectomy combined with BA in femoropopliteal lesions compared with BA alone., (© 2022 The Authors.)

Epinephrine (EPI), an endogenous catecholamine involved in the body's fight-or-flight responses to stress, activates α 1 -adrenergic receptors (α 1 ARs) expressed on various organs to evoke a wide range of physiological functions, including vasoconstriction. In the smooth muscle of human bronchi, however, the functional role of EPI on α 1 ARs remains controversial. Classically, evidence suggests that EPI promotes bronchodilation by stimulating β 2 -adrenergic receptors (β 2 ARs). Conventionally, the selective β 2 AR agonism of EPI was thought to be, in part, due to a predominance of β 2 ARs and/or a sparse, or lack of α 1 AR activity in human airway smooth muscle (HASM) cells. Surprisingly, we find that HASM cells express a high abundance of ADRA1B (the α 1 AR subtype B) and identify a spontaneous "switch-like" activation of α 1 ARs that evokes intracellular calcium, myosin light chain phosphorylation, and HASM cell shortening. The switch-like responses, and related EPI-induced biochemical and mechanical signals, emerged upon pharmacological inhibition of β 2 ARs and/or under experimental conditions that induce β 2 AR tachyphylaxis. EPI-induced procontractile effects were abrogated by an α 1 AR antagonist, doxazosin mesylate (DM). These data collectively uncover a previously unrecognized feed-forward mechanism driving bronchospasm via two distinct classes of G protein-coupled receptors (GPCRs) and provide a basis for reexamining α 1 AR inhibition for the management of stress/exercise-induced asthma and/or β 2 -agonist insensitivity in patients with difficult-to-control, disease subtypes.

The recent report of the Intergovernmental Panel on Climate Change is stark in its warnings about the changing climate, including future increases in the frequency and intensity of extremely hot weather. The well-established impacts of extreme heat on human health have led to widespread implementation of national and city-wide heat plans for mitigating such impacts. Evaluations of the effectiveness of some heat plans have been published, with previous reviews highlighting key methodological challenges. This article reviews methods used since and that address those challenges, so helping to set an agenda for improving evaluations of heat plans in terms of their effectiveness in reducing heat-health impacts. We examined the reviews that identified the methodological challenges and systematically searched the literature to find evaluations that had since been conducted. We found 11 evaluations. Their methods help address the key challenge of identifying study control groups and address other challenges to a limited extent. For future evaluations, we recommend: utilising recent evaluation methodologies, such as difference-in-differences quasi-experimental designs where appropriate; cross-agency working to utilise data on morbidity and confounders; adoption of a proposed universal heat index; and greater publication of evaluations. More evaluations should assess morbidity outcomes and be conducted in low- and middle-income countries. Evaluations of heat plans globally should employ robust methodologies, as demonstrated in existing studies and potentially transferrable from other fields. Publication of such evaluations will advance the field and thus help address some of the health challenges resulting from our changing climate., (© 2022. Crown.)

Significant advances in the field of carotid artery stenting (CAS) have occurred, including new randomized trial data, recent professional societal statements for competency, new techniques and new devices that have been developed, and perhaps most importantly, our understanding of how to better select candidates for CAS to avoid periprocedural complications. The current Centers for Medicare and Medicaid Services coverage decision regarding CAS is outdated, and our review supports our recommendation to approve CAS in selected candidates who are symptomatic with a carotid stenosis ≥50% and ≤99% and for asymptomatic patients with carotid stenosis ≥70% and ≤99% for stroke prevention. Optimized CAS strategies have allowed experienced operators to better assess procedure risk before CAS and have led to continued improvement in CAS outcomes. New technologies including enhanced embolic protection devices and dual-layered stents should result in further improvement., Competing Interests: Funding Support and Author Disclosures Dr Siddiqui is supported by National Institutes of Health/National Institute of Neurological Disorders and Stroke (co-investigator, Grant No. 1R01NS091075 [Virtual Intervention of Intracranial Aneurysms]; co-principal investigator, Grant No. R21 NS109575-01 [Optimizing Approaches to Endovascular Therapy of Acute Ischemic Stroke]). Dr Gray has served as a consultant for and received research support from Contego. Dr Heck has served as a consultant for Stryker. Dr Jovin has served as an advisor for, has been an investor in, or owns stock in Route92, Methinks, Galaxy, Viz.ai, Anaconda, and FreeOx Biotech; has served as a consultant for Cerenovus and Contego Medical; and has received grant support from Medtronic and Stryker Neurovascular. Dr Lyden has served as a consultant for Endologix, PQ Bypass, Boston Scientific, Medtronic, BD, Penumbra, and VIVA Physicians; has served as a board member for and received departmental research study support from Endologix, Gore, BD, Bolton, Abbott, Penumbra, Boston Scientific, Merit, and Contego Medical; and owns stock options in Centerline Biomedical. Dr Metzger has served as the principal investigator for the C-GUARDIANS, SAPPHIRE WW, and CANOPY CAS trials; and has served as the co-principal investigator for the CONFIDENCE CAS trial; has received symposium and proctor honoraria from Abbott Vascular; and has served on the advisory committee for Boston Scientific. Dr Rosenfield has served as a consultant or on the scientific advisory board for Althea Medical, Angiodynamics, Boston Scientific, Contego, InspireMD, Magneto, Mayo Clinic, Neptune Medical, Philips, Summa Therapeutics, Surmodics, Thrombolex, Terumo, and Truvic; has received institutional grant support from the National Institutes of Health, Abiomed, and Boston Scientific; owns equity interests in Accolade, Access Vascular, Aerami, Althea Medical, Contego, Cruzar Systems, Embolitech, Endospan, InspireMD, JanaCare, Magneto, Orchestra, PQ Bypass, Prosomnus, Shockwave, Summa Therapeutics, Thrombolex, Truvic, and Valcare; and has served as a board member for the National PERT Consortium. Dr Roubin has received from Cook Inc; and owns equity in Inspire MD. Dr Sachar has served as a consultant and advisory board member for Boston Scientific and Medtronic; has received institutional funds for research or clinical trials from Abbott Vascular, Boston Scientific, Bard Peripheral Vascular, Microvention, W.L. Gore and Associates, Medtronic, Terumo, and Veryan; and is a major shareholder of Contego Medical. Dr Siddiqui owns financial interest in, is an investor in, owns stock options, or has ownership in Adona Medical, Amnis Therapeutics, Bend IT Technologies, BlinkTBI, Buffalo Technology Partners, Cardinal Consultants, Cerebrotech Medical Systems, Cerevatech Medical, Cognition Medical, CVAID, Endostream Medical, Imperative Care, Instylla, International Medical Distribution Partners, Launch NY, NeuroRadial Technologies, Neurotechnology Investors, Neurovascular Diagnostics, PerFlow Medical, Q’Apel Medical, QAS.ai, Radical Catheter Technologies, Rebound Therapeutics (purchased 2019 by Integra Lifesciences), Rist Neurovascular (purchased 2020 by Medtronic), Sense Diagnostics, Serenity Medical, Silk Road Medical, Spinnaker Medical, StimMed, Synchron, Three Rivers Medical, Truvic Medical, Vastrax, VICIS, and Viseon; has served as a consultant or on the advisory board for Amnis Therapeutics, Apellis Pharmaceuticals, Boston Scientific, Canon Medical Systems USA, Cardinal Health 200, Cerebrotech Medical Systems, Cerenovus, Cerevatech Medical, Cordis, Corindus, Endostream Medical, Imperative Care, Integra, IRRAS AB, Medtronic, MicroVention, Minnetronix Neuro, Penumbra, Q’Apel Medical, Rapid Medical, Rebound Therapeutics, Serenity Medical, Silk Road Medical, StimMed, Stryker Neurovascular, Three Rivers Medical, VasSol, Viz.ai, and W.L. Gore and Associates; served as the national principal investigator for or on the steering committee of the Cerenovus EXCELLENT and ARISE II trial; the Medtronic SWIFT PRIME, VANTAGE, EMBOLISE and SWIFT DIRECT trials; the MicroVention FRED trial and CONFIDENCE study; the MUSC POSITIVE trial; the Penumbra 3D Separator trial, COMPASS trial, INVEST trial, MIVI neuroscience EVAQ trial; and the Rapid Medical SUCCESS trial. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Lifestyle changes and medications are recommended as the first line of treatment for claudication, with revascularization considered for treatment-resistant symptoms, based on patients' preferences. Real-world evidence comparing health status outcomes of early invasive with noninvasive management strategies is lacking., Methods: In the international multicenter prospective observational PORTRAIT (Patient-Centered Outcomes Related to Treatment Practices in Peripheral Arterial Disease: Investigating Trajectories) registry, disease-specific health status was assessed by the Peripheral Artery Questionnaire in patients with new-onset or worsening claudication at presentation and 3, 6, and 12 months later. One-year health status trajectories were compared by early revascularization versus noninvasive management on a propensity-matched sample using hierarchical generalized linear models for repeated measures adjusted for baseline health status., Results: In a propensity-matched sample of 1000 patients (67.4±9.3 years, 62.8% male, and 82.4% White), 297 (29.7%) underwent early revascularization and 703 (70.3%) were managed noninvasively. Over 1 year of follow-up, patients who underwent early invasive management reported significantly higher health status than patients managed noninvasively (interaction term for time and treatment strategy; P <0.001 for all Peripheral Artery Questionnaire domains). The average 1-year change in Peripheral Artery Questionnaire summary scores was 30.8±25.2 in those undergoing early invasive, compared with 16.7±23.4 in those treated noninvasively ( P <0.001)., Conclusions: Patients with claudication undergoing early invasive treatment had greater health status improvements over the course of 1 year than those treated noninvasively. These data can be used to support shared decision-making with patients., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT01419080.

Background: Palpable masses of the head and neck are a common indication for imaging in the pediatric population. Midline lesions of the infrahyoid neck, particularly lesions isolated to the suprasternal notch, are not well studied., Objective: To delineate the histopathological and imaging spectrum of masses that occur within and isolated to the suprasternal notch., Materials and Methods: A retrospective study was performed to identify patients with an isolated lesion of the suprasternal notch that had available pathological diagnoses. Available imaging was reviewed and characterized by fellowship-trained pediatric radiologists and compared by descriptive statistics to the final pathological diagnoses., Results: Eighteen masses isolated to the suprasternal notch with available pathological diagnoses were identified. Of these, congenital epithelial inclusion cysts were diagnosed in 14 patients (77.8%) with dermoid cysts comprising 11 of those (61.1%) and epidermoid cysts accounting for 3 (16.7%). The most common imaging appearance was a cystic or pseudosolid appearance without vascularity., Conclusions: Isolated resected lesions of the suprasternal notch in pediatric patients are most frequently dermoid/epidermoid cysts, with a differential diagnosis including other less common entities., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Flavodiiron nitric oxide reductases (FNORs) carry out the reduction of nitric oxide (NO) to nitrous oxide (N 2 O), allowing infectious pathogens to mitigate toxic levels of NO generated in the human immune response. We previously reported the model complex [Fe 2 (BPMP)(OPr)(NO) 2 ](OTf) 2 ( 1 , OPr - = propionate) that contains two coplanar NO ligands and that is capable of quantitative NO reduction to N 2 O [White et al. J. Am. Chem. Soc. 2018 , 140 , 2562-2574]. Here we investigate, for the first time, how a distortion of the active site affects the ability of the diiron core to mediate N 2 O formation. For this purpose, we prepared several analogues of 1 that contain two monodentate ligands in place of the bridging carboxylate, [Fe 2 (BPMP)(X) 2 (NO) 2 ] 3+/1+ ( 2-X ; X = triflate, 1-methylimidazole, or methanol). Structural data of 2-X show that without the bridging carboxylate, the diiron core expands, leading to elongated (O)N-N(O) distances (from 2.80 Å in 1 to 3.00-3.96 Å in 2-X ) and distorted (O)N-Fe-Fe-N(O) dihedral angles (from coplanarity (5.9°) in 1 to 52.9-85.1° in 2-X ). Whereas 1 produces quantitative amounts of N 2 O upon one-electron reduction, N 2 O production is substantially impeded in 2-X , to an initial 5-10% N 2 O yield. The main products after reduction are unprecedented hs-Fe II /{Fe(NO) 2 } 9/10 dinitrosyl iron complexes (DNICs). Even though mononuclear DNICs are stable and do not show N-N coupling (since it is a spin-forbidden process), the hs-Fe II /{Fe(NO) 2 } 9/10 DNICs obtained from 2-X show unexpected reactivity and produce up to quantitative N 2 O yields after 2 h. The implications of these results for the active site structure of FNORs are discussed.

Purpose of Review: The optimal antithrombotic strategy in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) remains the subject of controversy. In this article, we review the current evidence for the use of triple therapy in acute coronary syndrome (ACS) patients., Recent Findings: The recently published trials of AF patients undergoing PCI have shown that combination of non-vitamin K oral anticoagulants (NOACs) with an antiplatelet agent is either superior or non-inferior to vitamin K antagonist (VKA) plus dual antiplatelet therapy (DAPT) in reducing bleeding complications with no difference in regard to thromboembolic events. Currently, the use of dual therapy (preferably with a NOAC and clopidogrel) is recommended over triple therapy in these patients. The optimal duration should be guided by the assessment of an individual's risk of thrombosis and bleeding events., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Airway smooth muscle plays a pivotal role in modulating bronchomotor tone. Modulation of contractile and relaxation signaling is critical to alleviate the airway hyperresponsiveness (AHR) associated with asthma. Emerging studies examining the phenotype of ASM in the context of asthma provide rich avenues to develop more effective therapeutics to attenuate the AHR associated with the disease.

Competing Interests: Funding Support and Author Disclosures The author has reported that he has no relationships relevant to the contents of this paper to disclose.

Introduction: The optimal approach to deal with severe coronary artery calcification (CAC) during percutaneous coronary intervention (PCI) remains ill-defined., Methods: We conducted an electronic database search of all published studies comparing Orbital versus Rotational Atherectomy in patients undergoing PCI., Results: Eight observational studies were included in the analysis. Overall, there were no significant differences in Major-adverse-cardiac-events/MACE (OR: 0.81, CI: 0.63-1.05, p = .11), myocardial-infarction/MI (OR: 0.75, CI: 0.56-1.00, p = .05), all-cause mortality (OR: 0.82, CI: 0.25-2.64, p = .73) or Target-vessel-revascularization/TVR (OR: 0.72, CI: 0.38-1.36, p = .31). However, OA was associated with lower long-term MACE (1-year), (OR: 0.66, CI: 0.44-0.99, p = .04), long-term TVR (OR: 0.40, CI: 0.18-0.89, p = .03), and short-term MI (in-hospital and 30-day) (OR: 0.64, CI: 0.44-0.94, p = .02). OA was associated with more coronary artery dissections (OR: 2.61, CI: 1.38-4.92, p = .003) and device-related coronary perforations (OR: 2.79, CI: 1.08-7.19, p = .03). There were no differences in cardiac tamponade (OR: 1.78, CI: 0.37-8.69, p = .47). OA was noted to have significantly lower fluoroscopy time (MD: -3.96 min, CI: -7.67, -0.25; p = .04) compared to RA. No significant difference was noted in terms of contrast volume between the two groups (OR: -4.35 ml, CI: -14.52, 23.22; p = .65)., Conclusion: Although there was no difference in overall MACE, MI, all-cause mortality and TVR, OA was associated with lower long-term MACE and short-term MI. OA is associated with lower fluoroscopy time but higher rates of coronary artery dissection and coronary perforation., (© 2020 Wiley Periodicals LLC.)

Flavodiiron nitric oxide reductases (FNORs) protect microbes from nitrosative stress under anaerobic conditions by mediating the reduction of nitric oxide (NO) to nitrous oxide (N 2 O). The proposed mechanism for the catalytic reduction of NO by FNORs involves a dinitrosyldiiron intermediate with a [hs-{FeNO} 7 ] 2 formulation, which produces N 2 O and a diferric species. Moreover, both NO and hydrogen sulfide (H 2 S) have been implicated in several similar physiological functions in biology and are also known to cross paths in cell signaling. Here we report the synthesis, spectroscopic and theoretical characterization, and N 2 O production activity of an unprecedented monohydrosulfidodinitrosyldiiron compound, with a [(HS)hs-{FeNO} 7 /hs-{FeNO} 7 ] formulation, that models the key dinitrosyl intermediate of FNORs. The generation of N 2 O from this unique compound follows a semireduced pathway, where one-electron reduction generates a reactive hs-{FeNO} 8 center via the occupation of an Fe-NO antibonding orbital. In contrast to the well-known reactivity of H 2 S and NO, the coordinated hydrosulfide remains unreactive toward NO and acts only as a spectator ligand during the NO reduction process.

Background: Climate change is causing an increase in the frequency and severity of heatwave events, with a corresponding negative impact on human health. Health service utilisation during a heatwave is increased, with a greater risk of poor health outcomes identified for specific population groups. In this study, we examined the impact of heatwave events on ambulance dispatches in Tasmania, Australia from 2008 to 2019 to explore health service utilisation and identify the most vulnerable populations at a local level., Methods: We used a time-stratified case-crossover analysis with conditional logistic regression to examine the association between ambulance dispatches and three levels of heatwave events (extreme, severe, and low-intensity). We examined the relationship for the whole study population, and by age, gender, socio-economic advantage and clinical diagnostic group., Results: We found that ambulance dispatches increase by 34% (OR 1.34, 95% CI 1.18-1.52) during extreme heatwaves, by 10% (OR 1.10, 95% CI 1.05-1.15) during severe heatwaves and by 4% (OR 1.04, 95% CI 1.02-1.06) during low-intensity heatwaves. We found significant associations for the elderly (over 65), the young (5 and under) and for regions with the greatest socio-economic disadvantage., Conclusion: Heatwaves were associated with increased demands on ambulance services in Tasmania. In subgroups of people aged over 65 or under 5 years of age, and those from areas of higher disadvantage, we generally observed greater effect sizes than for the population as a whole., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The United States has the highest maternal mortality rates among developed countries, and cardiovascular disease is the leading cause. Therefore, the American Heart Association has a unique role in advocating for efforts to improve maternal health and to enhance access to and delivery of care before, during, and after pregnancy. Several initiatives have shaped the time course of major milestones in advancing maternal and reproductive health equity in the United States. There have been significant strides in improving the timeliness of data reporting in maternal mortality surveillance and epidemiological programs in maternal and child health, yet more policy reforms are necessary. To make a sustainable and systemic impact on maternal health, further efforts are necessary at the societal, institutional, stakeholder, and regulatory levels to address the racial and ethnic disparities in maternal health, to effectively reduce inequities in care, and to mitigate maternal morbidity and mortality. In alignment with American Heart Association's mission "to be a relentless force for longer, healthier lives," this policy statement outlines the inequities that influence disparities in maternal outcomes and current policy approaches to improving maternal health and suggests additional potentially impactful actions to improve maternal outcomes and ultimately save mothers' lives.