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Objectives: The aim of this study was to establish safety and feasibility of oral Rapamycin at two doses-2 mg and 5 mg-in achieving low rates of repeat target lesion revascularization (TLR) in de novo native coronary artery lesions. Background: Drug-eluting stents have shown the ability to limit restenosis. Oral Rapamycin is an alternative strategy that can target multiple coronary lesions suitable for treatment with any approved metal stent and at potentially lower cost. Methods: The Oral Rapamune to Inhibit Restenosis (ORBIT) study is an open-label study of 60 patients with de novo lesions treated with bare metal stents in up to two vessels. After a loading dose of 5 mg, patients received a daily dose of 2 mg (n = 30) and 5 mg (n = 30) for 30 days. Six-month angiographic, intravascular ultrasound (IVUS), and clinical follow-up were conducted. Results: Baseline clinical and procedural characteristics were similar: 10% of patients in the 2-mg group and 30% in the 5-mg group did not complete the course; 43% in the 2-mg group and 66% in the 5-mg group had side effects. At six-month follow-up, late loss (0.6 +/- 0.5 mm vs. 0.7 +/- 0.5 mm; p = NS), in-stent binary restenosis (7.1% vs. 6.9%; p = NS), in-stent percent volume obstruction by IVUS (29% vs. 24%; p = NS), and clinically driven TLR (14.3% vs. 6.9%; p = NS) were similar in 2-mg and 5-mg groups. Conclusions: Oral Rapamycin for the prevention of restenosis is safe, feasible, and associated with low rates of repeat revascularization. Although associated with certain side effects, it may be considered for patients undergoing multivessel stents if proven in larger randomized studies. [ABSTRACT FROM AUTHOR]

Background: Acute brain infarction detected by diffusion-weighted magnetic resonance imaging (DW-MRI) is common after transcatheter aortic valve replacement (TAVR), but its clinical relevance is uncertain., Objectives: The authors investigated the relationship between DW-MRI total lesion number (TLN), individual lesion volume (ILV), and total lesion volume (TLV) and clinical stroke outcomes after TAVR., Methods: Patient-level data were pooled from 4 prospective TAVR embolic protection studies, with consistent predischarge DW-MRI acquisition and core laboratory analysis. C-statistic was used to determine the best DW-MRI measure associated with clinical stroke., Results: A total of 495 of 603 patients undergoing TAVR completed the predischarge DW-MRI. At 30 days, the rate of clinical ischemic stroke was 6.9%. Acute ischemic brain injury was seen in 85% of patients with 5.5 ± 7.3 discrete lesions per patient, mean ILV of 78.2 ± 257.1 mm 3 , and mean TLV of 555 ± 1,039 mm 3 . The C-statistic was 0.84 for TLV, 0.81 for number of lesions, and 0.82 for maximum ILV in predicting ischemic stroke. On the basis of the TLV cutpoint as defined by receiver operating characteristic (ROC), patients with a TLV >500 mm 3 (vs TLV ≤500 mm 3 ) had more ischemic stroke (18.2% vs 2.3%; P < 0.0001), more disabling strokes (8.8% vs 0.9%; P < 0.0001), and less complete stroke recovery (44% vs 62.5%; P = 0.001) at 30 days., Conclusions: Our study confirms that the number, size, and total volume of acute brain infarction defined by DW-MRI are each associated with clinical ischemic strokes, disabling strokes, and worse stroke recovery in patients undergoing TAVR and may have value as surrogate outcomes in stroke prevention trials. (A Prospective, Randomized Evaluation of the TriGuard™ HDH Embolic Deflection Device During TAVI [DEFLECT III]; NCT02070731) (A Study to Evaluate the Neuro-embolic Consequences of TAVR [NeuroTAVR]; NCT02073864) (The REFLECT Trial: Cerebral Protection to Reduce Cerebral Embolic Lesions After Transcatheter Aortic Valve Implantation [REFLECT I]; NCT02536196) (The REFLECT Trial: Cerebral Protection to Reduce Cerebral Embolic Lesions After Transcatheter Aortic Valve Implantation [REFLECT II]; NCT02536196)., Competing Interests: Funding Support and Author Disclosures This study was supported, in part, by a generous grant from the Robert J. & Claire Pasarow Foundation and the Yale Cardiovascular Research Group. Dr Lansky has received consulting fees from Emboline; has received honoraria from Boston Scientific; and has received institutional research support from Filterlex Medical Ltd. Dr Dwyer has received grant support from Novartis, Bristol Myers Squibb, Mapi Pharma, Merck Serono, Keystone Heart Ltd, Protembis GmbH, V-Wave Ltd, and Filterlex Medical Ltd; and has received consulting fees from Bristol Myers Squibb, Merck Serono, Keystone Heart Ltd, and Mapi Pharma. Dr Zivadinov has received personal compensation from Bristol Myers Squibb, EMD Serono, Sanofi, Janssen, Biogen, Filterlex Medical Ltd, and Mapi Pharma; has received speaking and consultant fees and financial support for research activities from Novartis, Bristol Myers Squibb, EMD Serono, Octave, Mapi Pharma, CorEvitas, Protembis, and V-Wave Ltd. Dr Parise has received consulting fees from CroíValve and Veryan Medical; and has previously received consulting fees from Keystone Heart Ltd. Dr Moses has held equity in Orchestra BioMed and 4C Medical. Dr Leon has received institutional clinical research funding from Edwards Lifesciences, Boston Scientific, Abbott, and Medtronic. Dr Nazif has received consulting fees or honoraria from Boston Scientific, Medtronic, and EnCompass Technologies. Dr Messé has received consulting fees from Terumo, EmStop, VST Bio, and Filterlex Medical Ltd; has served on the Data and Safety Monitoring Board for the Gore REDUCE PFO closure post-marketing study, the clinical events committee for the Novo Nordisk ZEUS and ONWARDS trials, and the subject selection committee for the Terumo RelayBranch trial; and holds equity in Neuralert Technologies. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Oncoplastic surgery has become an important part of the surgical repertoire to offer both oncologically safe and aesthetically pleasing results in patients with breast cancer. Data comparing oncoplastic and reconstructive breast surgeries are limited. This study aimed to assess patient-reported outcomes (PRO) in our cohort of oncoplastic and reconstructively operated patients., Methods: Patients who underwent oncoplastic surgery, including immediate reconstruction by a single surgeon, between 2010 and 2018 were contacted to participate in this study. In total, 157 patients fulfilled the inclusion criteria. 54 patient data sets were used for statistical evaluation. Body Image Scale (BIS) and BreastQ questionnaires were used to measure subjective PRO scores, and pictures were taken to objectively measure symmetry using the Breast Analyzing Tool (BAT). Patients were divided into three groups according to the Tübingen classification (group 1: Tübingen 3-4 ( n = 16), group 2: Tübingen 5 ( n = 26), group 3: Breast Reconstruction/Tübingen 6 ( n = 12])., Results: The mean age was 53.5 for group 1, 51.4 for group 2 and 46.8 for group 3. The mean follow-up was 62.9 ± 35.82 months. BIS was significantly better in group 3 (3.92 ± 1.73) than in group 1 and 2 (7.69 ± 4.48 and 4.81 ± 3.41, p = 0.016). Symmetry measured using BAT showed only a trend favoring reconstruction ( p = 0.12). The BreastQ item "Sexual well-being" was significantly better in oncoplastic breast reduction surgery ( p = 0.036)., Conclusion: BIS was better after reconstructive breast surgery than after oncoplastic surgery. Reconstructive breast surgery in experienced breast care units offers high patient satisfaction and a high quality of life., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: Clinical events committee (CEC) evaluation is the standard approach for end point adjudication in clinical trials. Due to resource constraints, large registries typically rely on site-reported end points without further confirmation, which may preclude use for regulatory oversight., Methods: We developed a novel automated adjudication algorithm (AAA) for end point adjudication in the National Cardiovascular Data Registry Left Atrial Appendage Occlusion (LAAO) Registry using an iterative process using CEC adjudication as the "gold standard." A ≥80% agreement rate between automated algorithm adjudication and CEC adjudication was prespecified as clinically acceptable. Agreement rates were calculated., Results: A total of 92 in-hospital and 127 post-discharge end points were evaluated between January 1, 2016 and June 30, 2019 using AAA and CEC. Agreement for neurologic events was >90%. Percent agreement for in-hospital and post-discharge events was as follows: ischemic stroke 95.7% and 94.5%, hemorrhagic stroke 97.8% and 96.1%, undetermined stroke 97.8% and 99.2%, transient ischemic attack 98.9% and 98.4% and intracranial hemorrhage 100.0% and 94.5%. Agreement was >80% for major bleeding (83.7% and 90.6%) and major vascular complication (89.1% and 97.6%). With this approach, <1% of site reported end points require CEC adjudication. Agreement remained very good during the period after algorithm derivation., Conclusions: An AAA-guided approach for end point adjudication was successfully developed and validated for the LAAO Registry. With this approach, the need for formal CEC adjudication was substantially reduced, with accuracy maintained above an 80% agreement threshold. After application specific validation, these methods could be applied to large registries and clinical trials to reduce the cost of event adjudication while preserving scientific validity., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Recent data suggest that margins ≥2 mm after breast-conserving surgery may improve local control in invasive breast cancer (BC). By allowing large resection volumes, oncoplastic breast-conserving surgery (OBCII; Clough level II/Tübingen 5-6) may achieve better local control than conventional breast conserving surgery (BCS; Tübingen 1-2) or oncoplastic breast conservation with low resection volumes (OBCI; Clough level I/Tübingen 3-4)., Methods: Data from consecutive high-risk BC patients treated in 15 centers from the Oncoplastic Breast Consortium (OPBC) network, between January 2010 and December 2013, were retrospectively reviewed., Results: A total of 3,177 women were included, 30% of whom were treated with OBC (OBCI n = 663; OBCII n = 297). The BCS/OBCI group had significantly smaller tumors and smaller resection margins compared with OBCII (pT1: 50% vs. 37%, p = 0.002; proportion with margin <1 mm: 17% vs. 6%, p < 0.001). There were significantly more re-excisions due to R1 ("ink on tumor") in the BCS/OBCI compared with the OBCII group (11% vs. 7%, p = 0.049). Univariate and multivariable regression analysis adjusted for tumor biology, tumor size, radiotherapy, and systemic treatment demonstrated no differences in local, regional, or distant recurrence-free or overall survival between the two groups., Conclusions: Large resection volumes in oncoplastic surgery increases the distance from cancer cells to the margin of the specimen and reduces reexcision rates significantly. With OBCII larger tumors are resected with similar local, regional and distant recurrence-free as well as overall survival rates as BCS/OBCI., (© 2021. The Author(s).)

Aims: This study aimed to evaluate the safety and performance of the TriGuard™ Embolic Deflection Device (EDD), a nitinol mesh filter positioned in the aortic arch across all three major cerebral artery take-offs to deflect emboli away from the cerebral circulation, in patients undergoing transcatheter aortic valve replacement (TAVR)., Methods and Results: The prospective, multicentre DEFLECT I study (NCT01448421) enrolled 37 consecutive subjects undergoing TAVR with the TriGuard EDD. Subjects underwent clinical and cognitive follow-up to 30 days; cerebral diffusion-weighted magnetic resonance imaging (DW-MRI) was performed pre-procedure and at 4±2 days post procedure. The device performed as intended with successful cerebral coverage in 80% (28/35) of cases. The primary safety endpoint (in-hospital EDD device- or EDD procedure-related cardiovascular mortality, major stroke disability, life-threatening bleeding, distal embolisation, major vascular complications, or need for acute cardiac surgery) occurred in 8.1% of subjects (VARC-defined two life-threatening bleeds and one vascular complication). The presence of new cerebral ischaemic lesions on post-procedure DW-MRI (n=28) was similar to historical controls (82% vs. 76%, p=NS). However, an exploratory analysis found that per-patient total lesion volume was 34% lower than reported historical data (0.2 vs. 0.3 cm3), and 89% lower in patients with complete (n=17) versus incomplete (n=10) cerebral vessel coverage (0.05 vs. 0.45 cm3, p=0.016)., Conclusions: Use of the first-generation TriGuard EDD during TAVR is safe, and device performance was successful in 80% of cases during the highest embolic-risk portions of the TAVR procedure. The potential of the TriGuard EDD to reduce total cerebral ischaemic burden merits further randomised investigation.

Background: In the HORIZONS-AMI trial, patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI) who were treated with the thrombin inhibitor bivalirudin had substantially lower 30-day rates of major haemorrhagic complications and net adverse clinical events than did patients assigned to heparin plus a glycoprotein IIb/IIIa inhibitor (GPI). Here, we assess whether these initial benefits were maintained at 1 year of follow-up., Methods: Patients aged 18 years or older were eligible for enrolment in this multicentre, open-label, randomised controlled trial if they had STEMI, presented within 12 h after the onset of symptoms, and were undergoing primary PCI. 3602 eligible patients were randomly assigned by interactive voice response system in a 1:1 ratio to receive bivalirudin (0.75 mg/kg intravenous bolus followed by 1.75 mg/kg per h infusion; n=1800) or heparin plus a GPI (control; 60 IU/kg intravenous bolus followed by boluses with target activated clotting time 200-250 s; n=1802). The two primary trial endpoints were major bleeding and net adverse clinical events (NACE; consisting of major bleeding or composite major adverse cardiovascular events [MACE; death, reinfarction, target vessel revascularisation for ischaemia, or stroke]). This prespecified analysis reports data for the 1-year follow-up. Analysis was by intention to treat. Patients with missing data were censored at the time of withdrawal from the study or at last follow-up. This trial is registered with ClinicalTrials.gov, number NCT00433966., Findings: 1-year data were available for 1696 patients in the bivalirudin group and 1702 patients in the control group. Reasons for participant dropout were loss to follow-up and withdrawal of consent. The rate of NACE was lower in the bivalirudin group than in the control group (15.6%vs 18.3%, hazard ratio [HR] 0.83, 95% CI 0.71-0.97, p=0.022), as a result of a lower rate of major bleeding in the bivalirudin group (5.8%vs 9.2%, HR 0.61, 0.48-0.78, p<0.0001). The rate of MACE was similar between groups (11.9%vs 11.9%, HR 1.00, 0.82-1.21, p=0.98). The 1-year rates of cardiac mortality (2.1%vs 3.8%, HR 0.57, 0.38-0.84, p=0.005) and all-cause mortality (3.5%vs 4.8%, HR 0.71, 0.51-0.98, p=0.037) were lower in the bivalirudin group than in the control group., Interpretation: In patients with STEMI undergoing primary PCI, anticoagulation with bivalirudin reduced the rates of net adverse clinical events and major bleeding at 1 year compared with treatment with heparin plus a GPI. This finding has important clinical implications for the selection of optimum treatment strategies for patients with STEMI., Funding: Cardiovascular Research Foundation, with unrestricted grant support from Boston Scientific Corporation and The Medicines Company.

Background: The CoStar stent is a novel cobalt chromium stent designed specifically for drug delivery. The COSTAR I trial represents the first-in-man study of the CoStar Paclitaxel-Eluting Coronary Stent System evaluating three dose release formulations of paclitaxel in a bioresorbable polymer matrix in the treatment of de novo coronary lesions., Methods: The COSTAR I Trial was a prospective, multi-center registry enrolling 87 patients in four Indian centers for treatment of up to two de novo lesions = 25 mm in length in a reference vessel 2.5-3.5 mm in diameter. Three dose release formulations were studied: 30 microg eluted over 10 days bidirectionally (Group 1, n =10), 10 microg eluted over 30 days abluminally (Group 2, n=40) and 3 microg eluted over 30 days abluminally (Group 3, n = 37)., Results: Demographics and lesion characteristics were similar between the groups and treatment in all three groups included small caliber vessels (RVD 2.45 +/- 0.30 - 2.57 +/- 0.36 mm). The primary endpoint of in-stent late loss at four months was lowest in Group 2 (0.43 +/- 0.43 mm) compared to Group 1 and Group 3 (0.51 +/- 7 mn; 0.74 mm and 1.07 +/- 0.65 mm respectively). In-segment late loss followed similar trends, being lowest in Group 2 (0.24 +/- 0.39 mm) compared to Groups 1 and 3 (0.52 +/- 0.66 mm and 0.76 +/- 0.57 mm respectively). Group 2 demonstrated better angiographic out-comes at 12 months with in-stent late loss of 0.55 +/- 0.38 mm when compared to Groups 1 and 3 (0.90 +/- 0.76 mm and 0.74 +/- 0.55 mm respectively). Cumulative binary restenosis rates at twelve months were 1.9%, 35.7% and 39.1% in Groups 2, 1 and 3 respectively. Clinical outcomes trended similarly with cumulative MACE rates at twelve months being lowest at 7.5% in Group 2 as compared to 20% in Group 1 and 21.6% in Group 3 respectively., Conclusions: In this first-in-man feasibility trial, angiographic and clinical results seen with the extended release formulation at a higher dose (10 microg/30 days) demonstrate the feasibility of the CoStar stent platform in the treatment of native coronary lesions. It also demonstrates the importance of drug dose and release kinetics.

Objectives: The aim of this study was to evaluate the effect of variable dose and release kinetics of paclitaxel on neointimal hyperplasia., Background: Conventional paclitaxel-eluting stents use a durable polymer coating as a vehicle for drug delivery. The Conor stent (Conor Medsystems, Menlo Park, California) with intra-strut wells and erodable polymer is specifically designed for drug delivery with programmable pharmacokinetics., Methods: Two hundred and forty-four patients with single vessel disease received either a bare metal Conor stent (n = 53) or one of six different release formulations that varied in dose (10 or 30 microg) and elution release kinetics (first order, zero order), direction (abluminal, luminal), and duration (5, 10, and 30 days). End points at six months (bare stent group) and at four months (eluting stent groups) were angiographic late loss and neointimal tissue volume by intravascular ultrasound and the rate of major adverse cardiac events (MACE)., Results: The lowest in-stent late loss (0.38 mm, p <0.01, and 0.30 mm, p <0.01) and volume obstruction (8%, p <0.01, and 5%, p <0.01) were observed with the 10-microg and 30-microg doses in the 30-day release groups respectively, whereas the highest in-stent late loss (0.88 mm), volume obstruction (26%), and restenosis rate (11.6%) were observed in the bare stent group. The overall MACE rate of the eluting stent group was 8.6%: death 0.5%, myocardial infarction 2.7%, and target lesion revascularization (TLR) 5.3%. Sub-acute thrombosis was 0.5%. The TLR rates in the two 30-day release groups were 0% and 3.4%., Conclusions: This novel eluting stent platform, using an erodable polymer with complete elution of low doses of paclitaxel, is safe. The inhibition of the in-stent neointimal hyperplasia was best in the long release groups.

Surveys of psychological aggression have been plagued by a variety of conceptual and measurement problems. A new measure was devised to more systematically cover a full range of psychologically aggressive actions; to include items for each dimension/category at a milder, moderate, and severe level; to be applicable to dating as well as marital relationships; and to utilize items that were broader in nature to capture all instances of particular types of psychological aggression. Three hundred and eighty-three college students rated the 51 items as to their degree of "psychological abusiveness." The 17 categories were rated as mostly distinct from each other; almost every category had statistically distinct mild, moderate and severe items; the overall scale yielded basically normal psychometric properties; and the total score, as well as the scores for the mild, moderate, and severe items, all had very high internal consistency. Ratings of these items appear to be distinct from social desirability as well as from a number of attitudinal response sets, and only sex of the participant was significantly, although weakly, correlated with overall ratings of the psychological aggression items. This measure may provide for more systematic investigation into the concept of psychological aggression.

Purpose: To assess the pharmacokinetics and biodistribution of gentamicin, delivered as PulmoSpheres formulations in rabbit serum and lung tissue following intratracheal instillation in a perflubron vehicle., Methods: Rabbits were anesthetized, intubated, and mechanically ventilated with O2 (FiO2 = 0.50). Animals were then given 5 mg/kg gentamicin either intravenously, intramuscularly (TM), or intratracheally (IT) gentamicin PulmoSpheres formulation, instilled in 1.8 ml/kg of liquid perflubron vehicle. Serum and lung lobe sections were collected at multiple time points and assayed for gentamicin content., Results: Serum gentamicin levels peaked at 64.7 microg/ml, 11.2 microg/ml, and 5.0 microg/ml following intravenous, TM, and IT administration, respectively. Absolute bioavailabilitv at 8 h for IM administration was 76.8% and 57.0% when delivered IT. Although peak lung levels of drug were reached within 1 h, total lung gentamicin concentration after IT administration was more than two orders of magnitude greater than that achieved following TM administration (680,540 vs. 4,985 microg min, respectively) with significant levels of the antibiotic remaining in the lung even after 1 week., Conclusions: High levels of gentamicin in lung tissue can be achieved by instillation of a gentamicin PulmoSpheres formulation in a perflubron vehicle, termed liquid dose installation, without reaching toxic systemic levels allowing for increased local delivery of agents such as gentamicin at the site of the infection.

Study Objective: To evaluate the effects of nifedipine, diltiazem, and verapamil overdose on systemic hemodynamics and blood flows to the coronary, superior mesenteric, renal, and iliac arteries in the unanesthetized dog., Design: Nonblinded, controlled animal study., Setting: Research laboratory of a large pharmaceutical company., Type of Participants: Nineteen healthy mongrel dogs obtained from a commercial supplier., Interventions: Under general anesthesia, flow probes were placed about the ascending aorta, circumflex coronary, superior mesenteric, renal, and iliac arteries; a micromanometer was implanted into the tip of the left ventricle; and a catheter was inserted into the descending aorta. Experiments were performed after a recovery period of at least two weeks., Measurements and Main Results: Arterial blood pressure, heart rate, cardiac output, left ventricular pressure, and regional blood flows were measured prior to drug administration, and after 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg IV administration of the study drugs. Dogs receiving diltiazem or verapamil also received a dose of 10.0 mg/kg. When the blood pressure had been reduced from baseline by 30%, 1.43 mg/kg nifedipine IV (six dogs) decreased total peripheral resistance by 51%, increased cardiac output by 35%, and increased heart rate by 132%. Coronary blood flow and iliac blood flow increased 93% and 45%, respectively, but mesenteric blood flow and renal blood flow were not significantly altered. Diltiazem (eight) and verapamil (seven) at equivasodepressor doses (1.43 to 4.43 mg/kg) caused less peripheral vasodilation and reflex tachycardia. At severely toxic levels when arterial blood pressure fell by 50%, all three drugs decreased cardiac output. Nifedipine still increased heart rate. Diltiazem and verapamil caused high-grade atrioventricular block, resulting in bradycardia. All three drugs caused a redistribution of cardiac output favoring the coronary bed over the other beds., Conclusions: In the conscious dog, calcium channel blocker-induced hypotension at the moderate level is associated with disparate effects on systemic hemodynamics, probably resulting from differential reflex sympathetic activation. However, at a more severe level, their toxic effects are similar and manifested predominantly by their actions on the slow calcium channel.