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Atherosclerotic renal artery stenosis is the leading cause of secondary hypertension; it can also cause progressive renal insufficiency and cardiovascular complications such as refractory heart failure and flash pulmonary edema. Medical therapy including risk factor modification, renin-angiotensin-aldosterone system antagonists, lipid lowering agents, and antiplatelet therapy is the first line of treatment in all patients. Patients with uncontrolled renovascular hypertension despite optimal medical therapy, ischemic nephropathy, and cardiac destabilization syndromes who have severe renal artery stenosis are likely to benefit from renal artery revascularization. Screening for renal artery stenosis can be done with Doppler ultrasonography, computed tomographic angiography and magnetic resonance angiography. Invasive physiologic measurements are useful to confirm the severity of renal hypoperfusion and therefore improve the selection patients likely to respond to renal artery revascularization. Primary patency exceeds 80% at 5 years and surveillance for in-stent restenosis can be done with periodic clinical, laboratory, and imaging follow-up., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Bivalirudin, has been shown to have comparable efficacy and better safety profile when compared to unfractionated heparin (UFH) in percutaneous coronary interventions. Bivalirudin's safety in carotid artery stenting (CAS) was associated with better outcomes than heparin in some studies. In this Meta analysis we examine the hemorrhagic and ischemic outcomes associated with Bivalirudin compared to UFH during CAS., Methods: A comprehensive literature search was conducted with the electronic databases MEDLINE, EMBASE, and CENTRAL. Random-effects meta-analysis method was used to pool risk ratio (RR) for both Heparin and Bivalirudin with 95% confidence interval (CI). Study outcomes included hemorrhagic complications; major/minor bleeding and intracranial hemorrhage (ICH) as well as ischemic complications including ischemic stroke, myocardial infarction, and 30 day mortality., Results: A total of four studies were included enrolling 7,784 patients. Compared to UFH, Bivalirudin was associated with significantly lower major bleeding events with a relative risk (RR) of 0.53 (95% CI: 0.35-0.80; I 2  = 0%). Minor bleeding events were significantly lower in the Bivalirudin group with a RR of 0.41 (95% CI: 0.2-0.82; I 2  = 0%). Looking into other outcomes, there were no significant differences between anticoagulation strategies in terms of ischemic stroke (RR 0.8, with 95% CI: 0.60-1.06), intracranial hemorrhage (RR 0.73 with 95% CI: 0.27-1.98), myocardial infarction (RR 1.01 with 95% CI: 0.59-1.73) or 30 day mortality (RR 0.83 with 95% CI: 0.47-1.47)., Conclusion: Compared to UFH, Bivalirudin is associated with lower bleeding risk when used during CAS. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: In patients with symptomatic peripheral artery disease with a history of limb revascularization, the optimal antithrombotic regimen for long-term management is unknown., Methods: The EUCLID trial (Examining Use of Ticagrelor In PAD) randomized 13 885 patients with peripheral artery disease to treatment with ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. Patients were enrolled based on an abnormal ankle-brachial index ≤0.80 or a previous lower extremity revascularization. This analysis focuses on the 7875 (57%) patients enrolled based on the previous lower extremity revascularization criterion. Patients could not be enrolled within 30 days of most recent revascularization, and patients with an indication for dual antiplatelet therapy were excluded. The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or ischemic stroke. The primary safety end point was major bleeding., Results: Patients with a previous revascularization had a mean age of 66 years, 73% were male, and the median baseline ankle-brachial index was 0.78. After adjustment for baseline characteristics, patients enrolled based on previous revascularization had similar rates of the primary composite end point (hazard ratio [HR] 1.10, 95% confidence interval [CI] 0.98-1.23, P=0.12) and statistically significantly higher rates of myocardial infarction (HR 1.29, 95% CI 1.08-1.55, P=0.005) and acute limb ischemia (HR 4.23, 95% CI 2.86-6.25, P<0.001) when compared with patients enrolled based on ankle-brachial index criteria. No differences in ticagrelor- versus clopidogrel-treated patients were found for the primary efficacy end point (11.4% vs 11.3%; HR 1.01, 95% CI 0.88-1.15; P=0.90), all-cause mortality (9.2% vs 9.2%; HR 0.99, 95% CI 0.86-1.15; P=0.93), acute limb ischemia (2.5% vs 2.5%; HR 1.03, 95% CI 0.78-1.36; P=0.84), or major bleeding (1.9% vs 1.8%; HR 1.15, 95% CI 0.83-1.59; P=0.41). The median duration of follow-up was ≈30 months., Conclusions: After adjustment for baseline characteristics, patients enrolled based on previous revascularization for peripheral artery disease had higher rates of myocardial infarction and acute limb ischemia, with similar composite rates of cardiovascular death, myocardial infarction, and stroke when compared with patients enrolled based on the ankle-brachial index criterion. No significant differences were found between ticagrelor and clopidogrel for reduction of cardiovascular or acute limb events., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01732822., (© 2016 American Heart Association, Inc.)

Competing Interests: The authors declare no conflict of interest.

Background: Management of chronic obstructive pulmonary disease (COPD) commonly involves long-acting bronchodilators including beta-agonists (LABA) and muscarinic antagonists (LAMA). In individuals with persistent symptoms or frequent exacerbations, inhaled corticosteroids (ICS) are also used. LABA and LAMA bronchodilators are now available in single combination inhalers. However, the benefits and risks of adding ICS to combination LABA/LAMA inhalers remains unclear., Objectives: To assess the effect of adding an inhaled corticosteroid (ICS) to combination long-acting beta₂-agonist (LABA)/long-acting muscarinic antagonist (LAMA) inhalers for the treatment of stable COPD., Search Methods: We carried out searches using the Cochrane Airways Group Specialised Register of Trials (searched 20 September 2016), Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 12) in the Cochrane Library (searched 15 December 2015) and MEDLINE (searched 15 December 2015). We also searched ClinicalTrials.gov, World Health Organisation (WHO) trials portal and pharmaceutical company clinical trials' databases up to 7 Janurary 2016., Selection Criteria: We included parallel-group, randomised controlled trials (RCTs) of three weeks' duration or longer which compared treatment of stable COPD with ICS in addition to combination LABA/LAMA inhalers against combination LABA/LAMA inhalers alone., Data Collection and Analysis: We used standard methodological procedures expected by Cochrane., Main Results: We identified a total of 586 records in our search. Following removal of duplicates, 386 abstracts were assessed for inclusion. Six studies were identified as potentially relevant; however, all failed to meet the inclusion criteria on full-text assessment or after contacting the corresponding author to clarify study characteristics., Authors' Conclusions: There are currently no studies published assessing the effect of ICS in addition to combination LABA/LAMA inhalers for the treatment of stable COPD. As combination LABA/LAMA inhalers are now widely available, there is a need for well-designed RCTs to investigate whether ICS provides any added therapeutic benefit.

As the emerging modality in drug discovery, macrocycles represent topical targets of chemical synthesis. However, the influence of conformational effects on their reactivity has not received enough attention. We demonstrate that the regiochemistry of nucleophilic attack on aziridine-containing macrocyclic systems varies according to macrocycle ring size and that the influence of remote torsional interactions in the macrocycle ultimately determines the regioselectivity of the reactions. These findings should facilitate the development of divergent strategies of macrocycle synthesis using post-cyclization modification.

Background and Purpose: Asthma presents as a heterogeneous syndrome characterized by airway obstruction, inflammation and hyper-reactivity (AHR). Spleen tyrosine kinase (Syk) mediates allergen-induced mast cell degranulation, a central component of allergen-induced inflammation and AHR. However, the role of Syk in IgE-mediated constriction of human small airways remains unknown. In this study, we addressed whether selective inhibition of Syk attenuates IgE-mediated constriction and mast cell mediator release in human small airways., Experimental Approach: Human precision cut lung slices (hPCLS) ex vivo derived from non-asthmatic donors were incubated overnight with human IgE, dexamethasone, montelukast, antihistamines or a selective Syk inhibitor (SYKi). High-affinity IgE receptor (FcεRI) activation by anti-IgE cross-linking was performed, and constriction and mediator release measured. Airway constriction was normalized to that induced by maximal carbachol stimulation. Syk expression (determined by qPCR and immunoblot) was also evaluated in human primary airway smooth muscle (HASM) cells to determine whether Syk directly modulates HASM function., Key Results: While dexamethasone had little effect on FcεR-mediated contraction, montelukast or antihistamines partially attenuated the response. SYKi abolished anti-IgE-mediated contraction and suppressed the release of mast cell or basophil mediators from the IgE-treated hPCLS. In contrast, SYKi had little effect on the non-allergic contraction induced by carbachol. Syk mRNA and protein were undetectable in HASM cells., Conclusions and Implications: A selective Syk inhibitor, but not corticosteroids, abolished FcεR-mediated contraction in human small airways ex vivo. The mechanism involved FcεRI receptor activation on mast cells or basophils that degranulate causing airway constriction, rather than direct actions on HASM., (© 2016 The British Pharmacological Society.)

Among the smallest of the macrocyclic peptides, 12- and 13-membered cyclic tetrapeptides are particularly noteworthy because they exhibit a broad spectrum of biological activities due to their innate capacity to mimic β-turns in proteins. In this report, we demonstrate that aziridine-containing cyclic tetrapeptides offer a platform to interrogate the conformational properties of tetrapeptides. We show that aziridine ring-opening of 12-membered cyclic tetrapeptides yields exclusively 13-membered α 3 β macrocycles, regardless of peptide sequence, nucleophile, aziridine β-carbon substitution, or stereochemistry. NMR and computational studies on two related aziridine-containing cyclic tetrapeptides revealed that the amide conformations of their N -acyl aziridines are similar, and are likely the determinant of the observed ring-opening regioselectivity. Interestingly, some of the resulting 13-membered α 3 β macrocycles were found to be conformationally heterogeneous. This study on the reactivity and conformational control of aziridine-containing cyclic tetrapeptides provides useful insight on the design and development of macrocyclic therapeutics.

Renal denervation as a treatment for hypertension (HTN) has been shown to be effective as a surgical procedure. Over the past 10 years, an endovascular approach to replicate the results of surgical splanchnicectomy has been investigated to replace this surgical procedure with a less invasive procedure with lower morbidity. Several devices and procedures have been developed, including a non-invasive strategy. We review the improvement of HTN in clinical trials of these devices as well as the shortcomings of these studies. Thus far, these trials have been unable to prove that these renal denervation strategies are superior to medical therapy alone, but we look forward to further randomized, double blinded trials of current systems that can effectively achieve denervation to reduce the risk of HTN., (Copyright © 2016. Published by Elsevier Inc.)

Critical limb ischemia (CLI), the most advanced form of peripheral artery disease, is associated with significant morbidity, mortality, and health care resource utilization. It is also associated with physical, as well as psychosocial, consequences such as amputation and depression. Importantly, after a major amputation, patients are at heightened risk of amputation on the contralateral leg. However, despite the technological advances to manage CLI with minimally invasive technologies, this condition often remains untreated, with significant disparities in revascularization and amputation rates according to race, socioeconomic status, and geographic region. Care remains disparate across medical specialties in this rapidly evolving field. Many challenges persist, including appropriate reimbursement for treating complex patients with difficult anatomy. This paper provides a comprehensive summary that includes diagnostic assessment and analysis, endovascular versus open surgical treatment, regenerative and adjunctive therapies, and other important aspects of CLI., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Asthma manifests as a heterogeneous syndrome characterized by airway obstruction, inflammation and hyperresponsiveness (AHR). Although the molecular mechanisms remain unclear, activation of specific PI3K isoforms mediate inflammation and AHR. We aimed to determine whether inhibition of PI3Kδ evokes dilation of airways and to elucidate potential mechanisms., Experimental Approach: Human precision cut lung slices from non-asthma donors and primary human airway smooth muscle (HASM) cells from both non-asthma and asthma donors were utilized. Phosphorylation of Akt, myosin phosphatase target subunit 1 (MYPT1) and myosin light chain (MLC) were assessed in HASM cells following either PI3K inhibitor or siRNA treatment. HASM relaxation was assessed by micro-pattern deformation. Reversal of constriction of airways was assessed following stimulation with PI3K or ROCK inhibitors., Key Results: Soluble inhibitors or PI3Kδ knockdown reversed carbachol-induced constriction of human airways, relaxed agonist-contracted HASM and inhibited pAkt, pMYPT1 and pMLC in HASM. Similarly, inhibition of Rho kinase also dilated human PCLS airways and suppressed pMYPT1 and pMLC. Baseline pMYPT1 was significantly elevated in HASM cells derived from asthma donors in comparison with non-asthma donors. After desensitization of the β2 -adrenoceptors, a PI3Kδ inhibitor remained an effective dilator. In the presence of IL-13, dilation by a β agonist, but not PI3K inhibitor, was attenuated., Conclusion and Implications: PI3Kδ inhibitors act as dilators of human small airways. Taken together, these findings provide alternative approaches to the clinical management of airway obstruction in asthma., (© 2016 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Objectives: This study tested whether intramyocardial (IM) administration of mobilized, purified autologous CD34(+) cells would improve total exercise time (TET) and angina frequency in patients with refractory angina., Background: IM administration of autologous CD34(+) cells has been associated consistently with improvements in functional capacity and angina symptoms in early phase clinical trials., Methods: RENEW (Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34+ Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina) was a randomized, double-blind, multicenter trial comparing IM CD34(+) administration with no intervention (open-label standard of care) or IM placebo injections (active control). The primary efficacy endpoint was change in TET at 12 months. Key secondary endpoints include changes in angina frequency at 3, 6, and 12 months, and TET at 3 and 6 months. The key safety analysis was the incidence of major adverse cardiovascular events through 24 months., Results: The sponsor terminated the study for strategic considerations after enrollment of 112 of planned 444 patients. The difference in TET between patients treated with cell therapy versus placebo was 61.0 s at 3 months (95% confidence interval (CI): -2.9 to 124.8; p = 0.06), 46.2 s at 6 months (95% CI: -28.0 to 120.4; p = 0.22), and 36.6 s at 12 months (95% CI: -56.1 to 129.2; p = 0.43); angina frequency was improved at 6 months (relative risk: 0.63; p = 0.05). Autologous CD34(+) cell therapy seemed to be safe compared with both open-label standard of care and active control (major adverse cardiovascular events 67.9% [standard of care], 42.9% (active control), 46.0% [CD34(+)])., Conclusions: Due to early termination, RENEW was an incomplete experiment; however, the results were consistent with observations from earlier phase studies. These findings underscore the need for a definitive trial. (Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34(+) Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina [RENEW]: NCT01508910)., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Critical limb ischemia (CLI) is increasing in prevalence, and remains a significant source of mortality and limb loss. The decision to recommend surgical or endovascular revascularization for patients who are candidates for both varies significantly among providers and is driven more by individual preference than scientific evidence., Methods and Results: The Best Endovascular Versus Best Surgical Therapy for Patients With Critical Limb Ischemia (BEST-CLI) Trial is a prospective, randomized, multidisciplinary, controlled, superiority trial designed to compare treatment efficacy, functional outcomes, quality of life, and cost in patients undergoing best endovascular or best open surgical revascularization. Approximately 140 clinical sites in the United States and Canada will enroll 2100 patients with CLI who are candidates for both treatment options. A pragmatic trial design requires consensus on patient eligibility by at least 2 investigators, but leaves the choice of specific procedural strategy within the assigned revascularization approach to the individual treating investigator. Patients with suitable single-segment of saphenous vein available for potential bypass will be randomized within Cohort 1 (n=1620), while patients without will be randomized within Cohort 2 (n=480). The primary efficacy end point of the trial is Major Adverse Limb Event-Free Survival. Key secondary end points include Re-intervention and Amputation-Free-Survival and Amputation Free-Survival., Conclusions: The BEST-CLI trial is the first randomized controlled trial comparing endovascular therapy to open surgical bypass in patients with CLI to be carried out in North America. This landmark comparative effectiveness trial aims to provide Level I data to clarify the appropriate role for both treatment strategies and help define an evidence-based standard of care for this challenging patient population., Clinical Trial Registration: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT02060630., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Effectiveness of carotid artery stenting (CAS) relative to carotid endarterectomy (CEA) among Medicare patients has not been established. We compared effectiveness of CAS versus CEA among Medicare beneficiaries., Methods and Results: We linked Medicare data (2000-2009) to the Society for Vascular Surgery's Vascular Registry (2005-2008) and the National Cardiovascular Data Registry's (NCDR) Carotid Artery Revascularization and Endarterectomy Registry (2006-2008/2009). Medicare patients were followed up from procedure date until death, stroke/transient ischemic attack, periprocedural myocardial infarction, or a composite end point for these outcomes. We derived high-dimensional propensity scores using registry and Medicare data to control for patient factors and adjusted for provider factors in a Cox regression model comparing CAS with CEA. Among 5254 Society for Vascular Surgery's Vascular Registry (1999 CAS; 3255 CEA) and 4055 Carotid Artery Revascularization and Endarterectomy Registry (2824 CAS; 1231 CEA) Medicare patients, CAS patients had a higher comorbidity burden and were more likely to be at high surgical risk (Society for Vascular Surgery's Vascular Registry: 96.7% versus 44.5%; Carotid Artery Revascularization and Endarterectomy Registry: 71.3% versus 44.7%). Unadjusted outcome risks were higher for CAS. Mortality risks remained elevated for CAS after adjusting for patient-level factors (hazard ratio, 1.24; 95% confidence interval, 1.06-1.46). After further adjustment for provider factors, differences between CAS and CEA were attenuated or no longer present (hazard ratio for mortality, 1.13; 95% confidence interval, 0.94-1.37). Performance was comparable across subgroups defined by sex and degree of carotid stenosis, but there was a nonsignificant trend suggesting a higher risk of adverse outcomes in older (>80) and symptomatic patients undergoing CAS., Conclusions: Outcomes after CAS and CEA among Medicare beneficiaries were comparable after adjusting for both patient- and provider-level factors., (© 2016 American Heart Association, Inc.)

Asthma is defined by airway inflammation and hyperresponsiveness, and contributes to morbidity and mortality worldwide. Although bronchodilation is a cornerstone of treatment, current bronchodilators become ineffective with worsening asthma severity. We investigated an alternative pathway that involves activating the airway smooth muscle enzyme, soluble guanylate cyclase (sGC). Activating sGC by its natural stimulant nitric oxide (NO), or by pharmacologic sGC agonists BAY 41-2272 and BAY 60-2770, triggered bronchodilation in normal human lung slices and in mouse airways. Both BAY 41-2272 and BAY 60-2770 reversed airway hyperresponsiveness in mice with allergic asthma and restored normal lung function. The sGC from mouse asthmatic lungs displayed three hallmarks of oxidative damage that render it NO-insensitive, and identical changes to sGC occurred in human lung slices or in human airway smooth muscle cells when given chronic NO exposure to mimic the high NO in asthmatic lung. Our findings show how allergic inflammation in asthma may impede NO-based bronchodilation, and reveal that pharmacologic sGC agonists can achieve bronchodilation despite this loss.

Purpose: The majority of contact lens wearers experience a significant level of ocular discomfort associated with lens wear, often within hours of wear, related to dry lenses, inflammation, protein adhesion to the lens surface, etc. Application of controlled drug release techniques has focused on the incorporation and/or release of a single comfort molecule from a lens including high molecular weight comfort agents or pharmaceutical agents. Previous studies have sought to mitigate the occurrence of only single propagators of discomfort. Clinical studies with eye drop solutions have shown that a mixture of diverse comfort agents selected to address multiple propagators of discomfort provide the greatest and longest lasting sensations of comfort for the patient. In this paper, multiple propagators of discomfort are addressed through the simultaneous release of four molecules from a novel contact lens to ensure high level of lens wear comfort., Methods: Silicone hydrogel contact lenses were engineered via molecular imprinting strategies to simultaneously release up to four template molecules including hydropropyl methylcellulose (HPMC), trehalose, ibuprofen, and prednisolone., Results: By adjusting the ratio of functional monomer to comfort molecule, a high level of control was demonstrated over the release rate. HPMC, trehalose, ibuprofen, and prednisolone were released at therapeutically relevant concentrations with varying rates from a single lens., Conclusions: The results indicate use as daily disposable lenses for single day release or extended-wear lenses with multiple day release. Imprinted lenses are expected to lead to higher efficacy for patients compared to topical eye drops by improving compliance and mitigating concentration peaks and valleys associated with multiple drops.

The prevalence of peripheral artery disease (PAD) continues to increase worldwide. It is important to identify patients with PAD because of the increased risk of myocardial infarction, stroke, and cardiovascular death and impaired quality of life because of a profound limitation in exercise performance and the potential to develop critical limb ischemia. Despite effective therapies to lower the cardiovascular risk and prevent progression to critical limb ischemia, patients with PAD continue to be under-recognized and undertreated. The management of PAD patients should include an exercise program, guideline-based medical therapy to lower the cardiovascular risk, and, when revascularization is indicated, an "endovascular first" approach. The indications and strategic choices for endovascular revascularization will vary depending on the clinical severity of the PAD and the anatomic distribution of the disease. In this review, we discuss an evidence-based approach to the management of patients with PAD., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

VGX-1027, a novel oral immune modulator, is under development for the treatment of rheumatoid arthritis. The safety, tolerability, and pharmacokinetics of single (1-800 mg) and multiple (40-400 mg) oral doses were evaluated in 2 clinical studies. The doses were well tolerated up to 800 mg in a single dose and 200 mg twice daily in multiple doses. Adverse events were mild to moderate in severity with no identifiable dose-related pattern. There were no clinically significant physical or laboratory findings. The pharmacokinetic data indicated that increases in Cmax and AUC0-inf were dose-proportional, and AUC0- τ was approximately dose-proportional. For the single-dose study, median Tmax ranged from 0.5 to 2 hours and mean t1/2 ranged from 4.9 to 8.7 hours. For the multiple-dose study, median Tmax ranged from 0.5 to 2.0 hours and mean t1/2 ranged from 7.05 to 10.05 hours. No accumulation of the drug was observed after day 1, indicating that steady-state concentrations were attained with single and multiple dosing for 5 days. Approximately 90% of the administered dose was excreted in urine as unchanged drug., (© 2015, The American College of Clinical Pharmacology.)

We describe our process for quality improvement (QI) for a 3-year accreditation cycle in echocardiography by the Intersocietal Accreditation Commission (IAC) for a large group practice. Echocardiographic laboratory accreditation by the IAC was introduced in 1996, which is not required but could impact reimbursement. To ensure high-quality patient care and community recognition as a facility committed to providing high-quality echocardiographic services, we applied for IAC accreditation in 2010. Currently, there is little published data regarding the IAC process to meet echocardiography standards. We describe our approach for developing a multicampus QI process for echocardiographic laboratory accreditation during the 3-year cycle of accreditation by the IAC. We developed a quarterly review assessing (1) the variability of the interpretations, (2) the quality of the examinations, (3) a correlation of echocardiographic studies with other imaging modalities, (4) the timely completion of reports, (5) procedure volume, (6) maintenance of Continuing Medical Education credits by faculty, and (7) meeting Appropriate Use Criteria. We developed and implemented a multicampus process for QI during the 3-year accreditation cycle by the IAC for Echocardiography. We documented both the process and the achievement of those metrics by the Echocardiography Laboratories at the Ochsner Medical Institutions. We found the QI process using IAC standards to be a continuous educational experience for our Echocardiography Laboratory physicians and staff. We offer our process as an example and guide for other echocardiography laboratories who wish to apply for such accreditation or reaccreditation., (© 2016, Wiley Periodicals, Inc.)

Stroke is the most common cause of permanent disability, the second most common cause of dementia, and the third most common cause of death in the Western world. About 10% to 20% of strokes are due to large-artery occlusions causing severe disabling strokes. Recently, 5 randomized controlled trials established mechanical thrombectomy in stroke treatment in patients with large-vessel occlusions. The current intra-arterial reperfusion therapies allow high recanalization rates, high rates of favorable clinical outcome, and low complication rates. This review discusses the results of recent randomized trials and describes the current state-of-the-art endovascular treatment in acute ischemic stroke., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Carotid artery stenting (CAS) has become an integral part of the therapeutic armamentarium offered by cardiovascular medicine programs for the prevention of stroke. The purpose of this expert consensus statement is to provide physician training and credentialing guidance to facilitate the safe and effective incorporation of CAS into clinical practice within these programs. Since publication of the 2005 Clinical Competence Statement on Carotid Stenting, there has been substantial device innovation, publication of numerous clinical trials and observational studies, accumulation of extensive real-world clinical experience and widespread participation in robust national quality improvement initiatives [5]. Collectively, these advances have led to substantial evolution in the selection of appropriate patients, as well as in the cognitive, technical and clinical skills required to perform safe and effective CAS. Herein, we summarize published guidelines, describe training pathways, outline elements of competency, offer strategies for tracking outcomes, specify facility, equipment and personnel requirements, and propose criteria for maintenance of CAS competency., (© 2015 Wiley Periodicals, Inc.)

Background.  We evaluated the safety and immunogenicity of VAX2012Q, a quadrivalent influenza vaccine comprising 4 hemagglutinin subunits fused to flagellin. Methods.  In this dose-ranging, open-label study, healthy adults (18-40 years) were divided into 7 cohorts for evaluation of 5 dose levels and 3 component ratios. Dose levels were as follows: (1) 1 mcg per component of VAX128C (H1N1), VAX181 (H3N2), VAX173 (B-YAM), and VAX172 (B-VIC), respectively; (2) 2 mcg per component, respectively; (3) 2, 4, 4, and 4 mcg of each component, respectively; (4) 2, 4, 6, and 6 mcg of each component, respectively; and (5) 3 mcg per component, respectively. Tolerability and immunogenicity data were analyzed. Results.  Three hundred sixteen subjects received VAX2012Q (309 per protocol). At all dose levels, 54% to 65% of subjects reported mild injection site pain, the most common local reaction. Moderate injection site pain increased at dose levels 2 through 5 (22%-42%, compared with 20% at dose level 1). Systemic symptoms were mostly mild to moderate with moderate symptoms increasing in dose levels 3 and 4. Three dose level 3 subjects (6%) reported severe, transient chills and or fever. Mean fold rises in hemagglutination inhibition titers ranged from 2.5 to 6.9 despite high baseline titers. Mean seroprotection rates were ≥90% and mean seroconversion rates were ≥40% for all strains in all groups postvaccination. Conclusions.  VAX2012Q elicited immune responses at all dose levels with no significant safety concerns. Doses of 2 or 3 mcg per component provided a favorable balance of tolerability and immunogenicity.

The Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC) guidelines were last updated in 2007 (TASC II) and represented the collaboration of international vascular specialties involved in the management of patients with peripheral arterial disease (PAD). Since the publication of TASC II, there have been innovations in endovascular revascularization strategies for patients with PAD. The intent of this publication is to provide a complete anatomic lower limb TASC lesion classification, including the infrapopliteal segment, and an updated literature review of new endovascular techniques and practice patterns employed by vascular specialists today., (© The Author(s) 2015.)

The Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC) guidelines were last updated in 2007 (TASC II) and represented the collaboration of international vascular specialties involved in the management of patients with peripheral arterial disease (PAD). Since the publication of TASC II, there have been innovations in endovascular revascularization strategies for patients with PAD. The intent of this publication is to provide a complete anatomic lower limb TASC lesion classification, including the infrapopliteal segment, and an updated literature review of new endovascular techniques and practice patterns employed by vascular specialists today., (© 2015 Wiley Periodicals, Inc.)

Aims: Evidence from randomized controlled trials (RCTs) evaluating possible benefits of endovascular therapy (EVT) for acute ischaemic stroke has shown conflicting results. The purpose of this meta-analysis was to systematically examine clinical outcomes in RCTs comparing the use of intravenous (IV) fibrinolysis alone to IV fibrinolysis plus EVT, for the treatment of acute ischaemic stroke., Methods and Results: We selected English language RCTs, comparing EVT plus IV tissue-type plasminogen activator (tPA) (if eligible) with IV tPA alone in eligible patients for the treatment of acute ischaemic stroke. The primary endpoint was good functional outcome [modified Rankin Scale (mRS) of 0-2]. Other major endpoints of interest were all-cause mortality and symptomatic intracerebral haemorrhage (sICH). The meta-analysis included 8 RCTs that randomized 2423 patients with large-vessel, anterior-circulation stroke. EVT significantly improved the rate of functional independence (90-day mRS of 0-2) when compared with IV fibrinolysis [odds ratio (OR) 1.73, 95% confidence interval (CI) 1.18-2.53, number needed to treat (NNT) = 9.3]. The all-cause mortality was lower with EVT compared with the control group; however, the result did not reach statistical significance (OR 0.89, 95% CI 0.68-1.15). The rate of sICH was not higher with EVT (OR 1.07, 95% CI 0.73-1.56). Analyses from only the recent trials (reported in 2014-15) showed further benefit (OR of mRS 0-2: 2.42, 95% CI 1.91-3.08, NNT = 5) with similar safety results., Conclusion: In centres with advanced systems of stroke care, EVT significantly improved functional outcomes (without compromising safety) in patients with acute ischaemic stroke due to anterior circulation, large artery occlusion, compared with standard therapy., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Human respiratory syncytial virus (RSV) is a major cause of severe respiratory illness in children and susceptible adults. RSV blocks the development of the innate antiviral immune response and can grow to high titers in the respiratory tract. Here we demonstrate that immunostimulatory defective viral genomes (iDVGs) that are naturally generated during RSV replication are strong inducers of the innate antiviral response to RSV in mice and humans. In mice, RSV iDVGs stimulated the expression of antiviral genes, restricted viral replication, and prevented weight loss and lung inflammation. In human cells, the antiviral response to RSV iDVGs was dominated by the expression of IFN-λ1 over IFN-β and was driven by rapid intranuclear accumulation of the transcription factor IRF1. RSV iDVGs were detected in respiratory secretions of hospitalized patients, and their amount positively correlated with the level of expression of antiviral genes in the samples. Infection of explanted human lung tissue from different donors revealed that most humans can respond to RSV iDVGs and that the rate of accumulation of iDVGs during infection directly correlates with the quality of the antiviral response. Taken together, our data establish iDVGs as primary triggers of robust antiviral responses to RSV and provide the first evidence for an important biological role for naturally occurring iDVGs during a paramyxovirus infection in humans.

Background: The treatment of peripheral artery disease with percutaneous transluminal angioplasty is limited by the occurrence of vessel recoil and restenosis. Drug-coated angioplasty balloons deliver antiproliferative agents directly to the artery, potentially improving vessel patency by reducing restenosis., Methods: In this single-blind, randomized trial conducted at 54 sites, we assigned, in a 2:1 ratio, 476 patients with symptomatic intermittent claudication or ischemic pain while at rest and angiographically significant atherosclerotic lesions to angioplasty with a paclitaxel-coated balloon or to standard angioplasty. The primary efficacy end point was primary patency of the target lesion at 12 months (defined as freedom from binary restenosis or from the need for target-lesion revascularization). The primary safety end point was a composite of freedom from perioperative death from any cause and freedom at 12 months from limb-related death (i.e., death from a medical complication related to a limb), amputation, and reintervention., Results: The two groups were well matched at baseline; 42.9% of the patients had diabetes, and 34.7% were current smokers. At 12 months, the rate of primary patency among patients who had undergone angioplasty with the drug-coated balloon was superior to that among patients who had undergone conventional angioplasty (65.2% vs. 52.6%, P=0.02). The proportion of patients free from primary safety events was 83.9% with the drug-coated balloon and 79.0% with standard angioplasty (P=0.005 for noninferiority). There were no significant between-group differences in functional outcomes or in the rates of death, amputation, thrombosis, or reintervention., Conclusions: Among patients with symptomatic femoropopliteal peripheral artery disease, percutaneous transluminal angioplasty with a paclitaxel-coated balloon resulted in a rate of primary patency at 12 months that was higher than the rate with angioplasty with a standard balloon. The drug-coated balloon was noninferior to the standard balloon with respect to safety. (Funded by Lutonix-Bard; LEVANT 2 ClinicalTrials.gov number, NCT01412541.).

Objectives: The aim of this study was to examine variation in outcomes for patients receiving carotid artery stenting (CAS) across a sample of U.S. hospitals and assess the extent to which this variation was attributable to differences in case mix and procedural volume., Background: As CAS is increasingly being used throughout the United States, assessing hospital variation in CAS outcomes is critical to understanding and improving the quality of care for patients with carotid artery disease., Methods: Hospitals participating in the National Cardiovascular Data Registry-Carotid Artery Endarterectomy and Revascularization Registry contributing more than 5 CAS procedures from 2005 through 2013 were eligible for inclusion. We estimated unadjusted and risk-standardized rates of in-hospital stroke or death for each participating hospital using a previously validated prediction model and applying hospital-level random effects., Results: There were 188 hospitals contributing 19,381 CAS procedures during the period of interest. Unadjusted and risk-standardized in-hospital stroke or death rates ranged from 0% to 18.8% and 1.2% to 4.7%, respectively. Operator and hospital volumes were not significant predictors of outcomes after adjustment for case mix (p = 0.15 and p = 0.09, respectively)., Conclusions: CAS outcomes vary 4-fold among hospitals, even after adjustment for differences in case mix. Future work is needed to identify the sources of this variation and develop initiatives to improve patient outcomes., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Timely reperfusion directly impacts favorable neurologic outcomes in acute ischemic stroke (AIS) patients. Most strokes present outside the 3-4.5 h window for intravenous thrombolysis (IV-tPA). Catheter-based therapy (CBT) is commonly used in patients not eligible for timely IV-tPa, but variables that predict good neurologic outcomes are poorly understood., Methods: Results of 124 consecutive AIS patients who received CBT at Ochsner Medical Center from 2006 and 2012 are reported. A modified Rankin score (mRs) of ≤ 2 at 90 day post-CBT was used as the primary measurement of a good neurologic outcome. All-cause mortality during the index hospitalization, ≤30 days from treatment, and at 1 year were reported. Results are reported as those treated by Interventional Cardiologists (IC) or by Neurointerventionalists (NI)., Results: The mean age was 65 ± 16 years of which 48% (n = 52) were male. The mean NIHSS was 15.0 ± 7.5. Thrombolysis in cerebral infarction (TICI) ≥2 flow was achieved in 80% (n = 100). Good neurologic outcome was observed in 64% (n = 37 of 58) of patients 65 years or younger while in those older than 65, only 36% (n = 24 of 66) had the same outcome (P = 0.002). Mortality at 30 days for the two age groups were 21% (n = 12) vs. 50% (n = 33) (P = <0.001) respectively. A good neurologic outcome at 90 days was seen in 57% of patients with restoration of TICI ≥ 2 flow compared to 17% with TICI < 2 flow (P = <0.001). Those with failed reperfusion (TICI<2 flow) had 30-day mortality rate of 54% (13 of 24) vs. 20% (19 of 97) in those with TICI ≥ 2 flow (P = <0.001). At 90 days, there was no significant differences in patient outcomes between IC (n = 58) and NI (n = 66) treated patients., Conclusion: Successful revascularization with CBT leads to a good neurologic outcome in selected stroke patients. Medical co-morbidities and increased age > 65 years contributed to poor outcomes. To support broadening the number of physicians qualified to perform catheter-based stroke interventions, this study demonstrates that IC participating on a stroke team achieve comparable outcomes to NI., (© 2014 Wiley Periodicals, Inc.)

Objectives: The aim of this study was to compare the stroke/death rates between proximal embolic protection devices (P-EPDs) and distal filter embolic protection devices (F-EPDs) in elective carotid artery stenting (CAS)., Background: P-EPDs have theoretical advantages that may make them superior to F-EPDs for stroke prevention during CAS., Methods: We examined 10,246 consecutive elective CAS procedures performed with embolic protection in the NCDR CARE registry between January 2009 and March 2013. We analyzed crude and propensity-matched rates of in-hospital combined death/stroke in patients treated with P-EPDs versus F-EPDs. Secondary analyses included 30-day adverse event rates and stroke rates by the involved cerebrovascular territory., Results: P-EPDs were used in 590 of 10,246 cases (5.8%). Patients treated with P-EPDs had higher rates of symptomatic lesion status (46.8% vs. 39.7%, p<0.001), atrial fibrillation/flutter (16.1% vs. 13.0%, p=0.03), and history of a neurological event (51.2% vs. 46.6%, p=0.03). In unadjusted and propensity-matched analyses, differences in in-hospital stroke/death between P-EPD and F-EPD cohorts were nonsignificant (1.5% vs. 2.4%, p=0.16 and 1.6% vs. 2.0%, p=0.56, respectively). For patients with available data (n=7,693, 75.1%), 30-day adverse events rates were similar for P-EPDs and F-EPDs before (2.5% vs. 4.2%, p=0.07) and after (2.7% vs. 4.0%, p=0.22) propensity matching., Conclusions: Use of a P-EPD during CAS was associated with low rates of in-hospital stroke/death similar to those with an F-EPD in the first comparative effectiveness study of the devices. An adequately powered randomized trial comparing clinical outcomes between these devices is unlikely to be feasible., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Atherosclerotic peripheral artery disease (PAD) is common and results in limitations in quality of life and potential progression to limb loss. Options for therapy include medical therapy, supervised exercise, surgical revascularization, and, more recently, endovascular therapies to restore arterial perfusion to the limb. Endovascular revascularization has evolved over the past 2 decades, from percutaneous transluminal angioplasty (PTA) to self-expanding stents, atherectomy, laser angioplasty, and drug-eluting stents. Despite impressive technologic advances, PTA remains the standard of care at many institutions and is the recommended primary treatment modality for femoral-popliteal PAD according to current American College of Cardiology Foundation/American Heart Association guidelines. However, restenosis after PTA is common. Therefore, a significant clinical need remains for a device that is able to achieve more durable patency than PTA but does not require a permanent implant. Drug-coated balloons (DCBs) have the potential to address this need. Several randomized controlled clinical trials of PTA balloons coated with different formulations of paclitaxel have been conducted in Europe (N Engl J Med 2008;358:689-699) (Circulation 2008;118:1358-1365) (Circ Cardiovasc Interv 2012;5:831-840) (JACC Cardiovas Interv 2014;7:10-19) and demonstrated more durable efficacy than PTA with comparable safety. These studies were limited by small sample sizes and powered solely for an angiographic primary end point. The pivotal LEVANT 2 trial was designed in collaboration with the US Food and Drug Administration to demonstrate safety and efficacy in a large population and to obtain US Food and Drug Administration approval., Methods: A prospective, multicenter, single-blind trial comparing the Lutonix DCB (Bard Lutonix; New Hope, MN) versus PTA for treatment of femoropopliteal PAD (LEVANT 2) is the first US-based 2:1 randomized controlled trial of 476 patients with femoral-popliteal PAD designed to demonstrate superior efficacy and noninferior safety of a novel paclitaxel DCB compared with PTA. The primary efficacy end point is primary patency at 12 months. The primary safety end point is composite freedom at 12 months from perioperative death, index limb amputation, reintervention, and limb-related mortality. A series of important secondary end points include physical functioning, quality of life, revascularizations, and alternative measures of patency. To minimize bias potential for confounding variables, LEVANT 2 (1) excluded patients stented after predilation before randomization, (2) incorporated very stringent criteria for bailout stenting, (3) did not count bailout stenting as a target lesion revascularization or failure of any end point, (4) required a blinded clinician to perform clinical evaluations at follow-up, and (5) required clinical assessment before review of duplex ultrasound results., Conclusions: LEVANT 2 represents the first US-inclusive multicenter, randomized controlled trial to assess the safety and efficacy of a novel DCB compared with PTA as primary therapy for symptomatic PAD on the background of standard medical therapy., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The lack of consistent definitions and nomenclature across clinical trials of novel devices, drugs, or biologics poses a significant barrier to accrual of knowledge in and across peripheral artery disease therapies and technologies. Recognizing this problem, the Peripheral Academic Research Consortium, together with the U.S. Food and Drug Administration and the Japanese Pharmaceuticals and Medical Devices Agency, has developed a series of pragmatic consensus definitions for patients being treated for peripheral artery disease affecting the lower extremities. These consensus definitions include the clinical presentation, anatomic depiction, interventional outcomes, surrogate imaging and physiological follow-up, and clinical outcomes of patients with lower-extremity peripheral artery disease. Consistent application of these definitions in clinical trials evaluating novel revascularization technologies should result in more efficient regulatory evaluation and best practice guidelines to inform clinical decisions in patients with lower extremity peripheral artery disease., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Importance: Despite increased carotid artery stenting (CAS) dissemination following the 2005 National Coverage Determination, to our knowledge, periprocedural and long-term outcomes have not been described among Medicare beneficiaries., Objective: To describe the incidence of outcomes during and after the periprocedural period among Medicare beneficiaries undergoing CAS., Design, Setting, and Participants: Observational study with a mean follow-up time of approximately 2 years among 22,516 fee-for-service Medicare beneficiaries at least 66 years old undergoing CAS (2005-2009) who were linked to the Centers for Medicare & Medicaid Services' CAS database. Database procedure dates were required to fall during a Medicare hospitalization for CAS., Main Outcomes and Measures: Periprocedural (30-day) and long-term risks of mortality and stroke or transient ischemic attack, as well as periprocedural myocardial infarction. Subgroups were based on sociodemographic, clinical, and center-level factors, as well as the Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial or Carotid Revascularization Endarterectomy vs Stenting Trial (CREST) enrollment criteria., Results: The mean patient age was 76.3 years, 60.5% were male, 93.8% were of white race, 91.2% were at high surgical risk, 47.4% were symptomatic, and 97.4% had carotid stenosis of at least 70%. Crude 30-day mortality, stroke or transient ischemic attack, and myocardial infarction risks were 1.7% (95% CI, 1.5%-1.8%), 3.3% (95% CI, 3.0%-3.5%), and 2.5% (95% CI, 2.3%-2.7%), respectively. Mortality during a mean follow-up time of 2 years was 32.0% (95% CI, 31.0%-33.0%), with rates of 37.3% (95% CI, 35.8%-38.7%) among symptomatic patients and 27.7% (95% CI, 26.4%-28.9%) among asymptomatic patients. Older age, symptomatic carotid stenosis, and nonelective hospital admission were associated with increased adjusted hazards of mortality and stroke or transient ischemic attack during and after the periprocedural period. The presence of a stroke center, government ownership, and a hospital bed capacity of 500 or more were associated with increased adjusted hazards of periprocedural mortality and stroke or transient ischemic attack. Few patients met the SAPPHIRE trial or CREST enrollment criteria primarily because physicians did not meet proficiency requirements either due to exceeding periprocedural complication trial thresholds or not meeting minimum CAS volume requirements., Conclusions and Relevance: Competing risks may limit the benefits of CAS in certain Medicare beneficiaries, particularly among older and symptomatic patients who have higher periprocedural and long-term mortality risks. The generalizability of trials like the SAPPHIRE or CREST to the Medicare population may be limited, underscoring the need to evaluate real-world effectiveness of carotid stenosis treatments.

Background: Many patients with coronary artery disease who are not candidates for revascularization have refractory angina despite standard medical therapy. The balloon-expandable, stainless steel, hourglass-shaped, coronary-sinus reducing device creates a focal narrowing and increases pressure in the coronary sinus, thus redistributing blood into ischemic myocardium., Methods: We randomly assigned 104 patients with Canadian Cardiovascular Society (CCS) class III or IV angina (on a scale from I to IV, with higher classes indicating greater limitations on physical activity owing to angina) and myocardial ischemia, who were not candidates for revascularization, to implantation of the device (treatment group) or to a sham procedure (control group). The primary end point was the proportion of patients with an improvement of at least two CCS angina classes at 6 months., Results: A total of 35% of the patients in the treatment group (18 of 52 patients), as compared with 15% of those in the control group (8 of 52), had an improvement of at least two CCS angina classes at 6 months (P=0.02). The device was also associated with improvement of at least one CCS angina class in 71% of the patients in the treatment group (37 of 52 patients), as compared with 42% of those in the control group (22 of 52) (P=0.003). Quality of life as assessed with the use of the Seattle Angina Questionnaire was significantly improved in the treatment group, as compared with the control group (improvement on a 100-point scale, 17.6 vs. 7.6 points; P=0.03). There were no significant between-group differences in improvement in exercise time or in the mean change in the wall-motion index as assessed by means of dobutamine echocardiography. At 6 months, 1 patient in the treatment group had had a myocardial infarction; in the control group, 1 patient had died and 3 had had a myocardial infarction., Conclusions: In this small clinical trial, implantation of the coronary-sinus reducing device was associated with significant improvement in symptoms and quality of life in patients with refractory angina who were not candidates for revascularization. (Funded by Neovasc; COSIRA ClinicalTrials.gov number, NCT01205893.).

Atherosclerotic renal artery stenosis (RAS) is the single largest cause of secondary hypertension; it is associated with progressive renal insufficiency and causes cardiovascular complications such as refractory heart failure and flash pulmonary edema. Medical therapy, including risk factor modification, renin-angiotensin-aldosterone system antagonists, lipid-lowering agents, and antiplatelet therapy, is advised in all patients. Patients with uncontrolled renovascular hypertension despite optimal medical therapy, ischemic nephropathy, and cardiac destabilization syndromes who have severe RAS are likely to benefit from renal artery revascularization. Screening for RAS can be done with Doppler ultrasonography, CT angiography, and magnetic resonance angiography., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Current guidelines recommend that patients with acute exacerbations of chronic obstructive pulmonary disease (COPD) should be treated with systemic corticosteroid for seven to 14 days. Intermittent systemic corticosteroid use is cumulatively associated with adverse effects such as osteoporosis, hyperglycaemia and muscle weakness. Shorter treatment could reduce adverse effects., Objectives: To compare the efficacy of short-duration (seven or fewer days) and conventional longer-duration (longer than seven days) systemic corticosteroid treatment of adults with acute exacerbations of COPD., Search Methods: Searches were carried out using the Cochrane Airways Group Specialised Register of Trials, MEDLINE and CENTRAL (Cochrane Central Register of Controlled Trials) up to June 2014 and ongoing trials registers up to July 2014., Selection Criteria: Randomised controlled trials comparing different durations of systemic corticosteroid defined as short (i.e. seven or fewer days) or longer (i.e. longer than seven days). Other interventions-bronchodilators and antibiotics-were standardised. Studies with participants requiring assisted ventilation were excluded., Data Collection and Analysis: We used standard methodological procedures as expected by The Cochrane Collaboration., Main Results: Eight studies with 582 participants met the inclusion criteria, of which five studies conducted in hospitals with 519 participants (range 28 to 296) contributed to the meta-analysis. Mean ages of study participants were 65 to 73 years, the proportion of male participants varied (58% to 84%) and COPD was classified as severe or very severe. Corticosteroid treatment was given at equivalent daily doses for three to seven days for short-duration treatment and for 10 to 15 days for longer-duration treatment. Five studies administered oral prednisolone (30 mg in four, tapered in one), and two studies provided intravenous corticosteroid treatment. Studies contributing to the meta-analysis were at low risk of selection, performance, detection and attrition bias. In four studies we did not find a difference in risk of treatment failure between short-duration and longer-duration systemic corticosteroid treatment (n = 457; odds ratio (OR) 0.72, 95% confidence interval (CI) 0.36 to 1.46)), which was equivalent to 22 fewer per 1000 for short-duration treatment (95% CI 51 fewer to 34 more). No difference in risk of relapse (a new event) was observed between short-duration and longer-duration systemic corticosteroid treatment (n = 457; OR 1.04, 95% CI 0.70 to 1.56), which was equivalent to nine fewer per 1000 for short-duration treatment (95% CI 68 fewer to 100 more). Time to the next COPD exacerbation did not differ in one large study that was powered to detect non-inferiority and compared five days versus 14 days of systemic corticosteroid treatment (n = 311; hazard ratio 0.95, 95% CI 0.66 to 1.37). In five studies no difference in the likelihood of an adverse event was found between short-duration and longer-duration systemic corticosteroid treatment (n = 503; OR 0.89, 95% CI 0.46 to 1.69, or nine fewer per 1000 (95% CI 44 fewer to 51 more)). Length of hospital stay (n = 421; mean difference (MD) -0.61 days, 95% CI -1.51 to 0.28) and lung function at the end of treatment (n = 185; MD FEV1 -0.04 L; 95% CI -0.19 to 0.10) did not differ between short-duration and longer-duration treatment., Authors' Conclusions: Information from a new large study has increased our confidence that five days of oral corticosteroids is likely to be sufficient for treatment of adults with acute exacerbations of COPD, and this review suggests that the likelihood is low that shorter courses of systemic corticosteroids (of around five days) lead to worse outcomes than are seen with longer (10 to 14 days) courses. We graded most available evidence as moderate in quality because of imprecision; further research may have an important impact on our confidence in the estimates of effect or may change the estimates. The studies in this review did not include people with mild or moderate COPD; further studies comparing short-duration systemic corticosteroid versus conventional longer-duration systemic corticosteroid for treatment of adults with acute exacerbations of COPD are required.

The pathophysiology of atherosclerotic renal artery stenosis (RAS) includes activation of the renin-angiotensin-aldosterone axis with resultant renovascular hypertension. Renal artery stenting has emerged as the primary revascularization strategy in most patients with hemodynamically significant atherosclerotic RAS. Despite the frequency with which hemodynamically significant RAS is observed and high rates of technical success of renal artery stenting, there remains considerable debate among experts regarding the role of medical therapy versus revascularization for renovascular hypertension. Modern, prospective, multicenter registries continue to demonstrate improvement in systolic and diastolic blood pressure with excellent safety profiles in patients with RAS. Modern randomized, controlled clinical trials of optimal medical therapy versus renal stenting particularly designed to demonstrate preservation in renal function after renal artery stenting have demonstrated limited benefit. However, these trials frequently excluded patients that may benefit from renal artery stenting. This document was developed to guide physicians in the modern practical application of renal stenting, to highlight the current limitations in the peer-reviewed literature, to suggest best-practices in the performance of renal stenting and to identify opportunities to advance the field., (© 2014 Wiley Periodicals, Inc.)

Objectives: The purpose of the prospective, multicenter, nonrandomized CABANA study was to evaluate periprocedural clinical outcomes in high surgical risk patients with carotid artery stenosis treated with the Carotid WALLSTENT plus FilterWire EZ Embolic Protection System by a diverse group of clinicians., Background: There is a need for additional evidence evaluating carotid artery stenting (CAS) performed by operators with various experience and training levels., Methods: The study enrolled symptomatic (≥50% carotid artery stenosis) and asymptomatic (≥80% carotid stenosis) patients at high risk for carotid endarterectomy. Study centers were grouped into three tiers based on previous CAS experience while individual operators were grouped by their CAS training. The primary endpoint was the 30-day composite of major adverse events [MAEs; including stroke, death, and myocardial infarction (MI)]. Individual event rates were evaluated across the overall study, and by center experience and physician training tier., Results: Of 1,097 enrolled patients, 1,025 were evaluable for 30-day MAE rate. The stroke rate (3.3%) was a major contributing factor in the overall MAE rate (4.6%). Mortality was 1.3% and the MI rate was 0.5%. There was no statistically significant association between MAE rates among the center experience tiers (P = 0.61) nor among the operator training categories (P = 0.26)., Conclusions: CAS with the Carotid WALLSTENT and FilterWire EZ yielded a low 30-day MAE rate that did not differ significantly across operator experience and training levels. Clinicaltrials.gov identifier: NCT00741091., (© 2014 The Authors. Catheterization and Cardiovascular Interventions. Published by Wiley Periodicals, Inc.)

Background: Tremendous advances have occurred in therapies for peripheral vascular disease (PVD); until recently, however, it has not been possible to examine the entire clinical trial portfolio of studies for the treatment of PVD (both arterial and venous disease)., Methods and Results: We examined interventional trials registered in ClinicalTrials.gov from October 2007 through September 2010 (n=40,970) and identified 676 (1.7%) PVD trials (n=493 arterial only, n=170 venous only, n=13 both arterial and venous). Most arterial studies investigated lower-extremity peripheral artery disease and acute stroke (35% and 24%, respectively), whereas most venous studies examined deep vein thrombosis/pulmonary embolus prevention (42%) or venous ulceration (25%). A placebo-controlled trial design was used in 27% of the PVD trials, and 4% of the PVD trials excluded patients >65 years of age. Enrollment in at least 1 US site decreased from 51% of trials in 2007 to 41% in 2010. Compared with noncardiology disciplines, PVD trials were more likely to be double-blinded, to investigate the use of devices and procedures, and to have industry sponsorship and assumed funding source, and they were less likely to investigate drug and behavioral therapies. Geographic access to PVD clinical trials within the United States is limited to primarily large metropolitan areas., Conclusions: PVD studies represent a small group of trials registered in ClinicalTrials.gov, despite the high prevalence of vascular disease in the general population. This low number, compounded by the decreasing number of PVD trials in the United States, is concerning and may limit the ability to inform current clinical practice of patients with PVD., (© 2014 American Heart Association, Inc.)

Intervention to treat infrapopliteal arterial disease can be challenging because the patients' comorbidities, the anatomic variables, and the limitations of our techniques. Clinical scenarios based on anatomic and clinical variables are presented. Recommendations regarding intervention (appropriate care, may be appropriate care, rarely appropriate care) are made based on best evidence., (© 2014 Wiley Periodicals, Inc.)

Aorto-iliac arterial occlusive disease is common and may cause a spectrum of chronic symptoms from intermittent claudication to critical limb ischemia. Treatment is indicated for symptoms that have failed lifestyle and medical therapies or occasionally to facilitate other interventional procedures such as TAVR and/or placement of hemodynamic assist devices. It is widely accepted that TASC A, B, and C lesions are best managed with endovascular intervention. In experienced hands, most TASC D lesions may be treated by endovascular methods, and with the development of chronic total occlusion devices, many aorto-iliac occlusions may be recanalized safely by endovascular means. Interventional cardiologists should be well versed in the anatomy, as well as the treatment of aorto-iliac disease, given their need to traverse these vessels during transfemoral procedures. Overall, aorto-iliac occlusive disease is more commonly being treated with an endovascular-first approach, using open surgery as a secondary option. This document was developed to guide physicians in the clinical decision-making related to the contemporary application of endovascular intervention among patients with aorto-iliac arterial disease., (© 2014 Wiley Periodicals, Inc.)