Search

Background: Several sham-controlled trials have investigated the efficacy and safety of catheter-based renal denervation (RDN) with mixed outcomes. We aimed to perform a comprehensive meta-analysis of all randomized, sham-controlled trials investigating RDN with first- and second-generation devices in hypertension., Methods: We searched MEDLINE and the Cochrane Library for eligible trials. Outcomes included both efficacy (24-hour and office systolic [SBP] and diastolic blood pressure [DBP]) and safety (all-cause death, vascular complication, renal artery stenosis >70%, hypertensive crisis) of RDN. We performed a study-level, pairwise, random-effects meta-analysis of the summary data., Results: Ten trials comprising 2478 patients with hypertension while being either off or on treatment were included. Compared with sham, RDN reduced 24-hour and office systolic blood pressure by 4.4 mm Hg (95% CI, 2.7 to 6.1; P <0.00001) and 6.6 mm Hg (95% CI, 3.6 to 9.7; P <0.0001), respectively. The 24-hour and office diastolic blood pressure paralleled these findings (-2.6 mm Hg [95% CI, -3.6 to -1.5]; P <0.00001; -3.5 mm Hg [95% CI, -5.4 to -1.6]; P =0.0003). There was no difference in 24-hour and office systolic blood pressure reduction between trials with and without concomitant antihypertensive medication ( P for interaction, 0.62 and 0.73, respectively). There was no relevant difference in vascular complications (odds ratio, 1.69 [95% CI, 0.57 to 5.0]; P =0.34), renal artery stenosis (odds ratio, 1.50 [95% CI, 0.06 to 36.97]; P =0.80), hypertensive crisis (odds ratio, 0.65 [95% CI, 0.30 to 1.38]; P =0.26), and all-cause death (odds ratio, 1.76 [95% CI, 0.34 to 9.20]; P =0.50) between RDN and sham groups. Change of renal function based on estimated glomerular filtration rate was comparable between groups ( P for interaction, 0.84). There was significant heterogeneity between trials., Conclusions: RDN safely reduces ambulatory and office systolic blood pressure/diastolic blood pressure versus a sham procedure in the presence and absence of antihypertensive medications., Competing Interests: E.R.E. was supported in part by the National Institutes of Health (R01 HL161069). L.L. received speaker honoraria from AstraZeneca, Medtronic, Pfizer, and ReCor Medical until May 2024. F.M. is supported by Deutsche Gesellschaft für Kardiologie, Deutsche Forschungsgemeinschaft (SFB TRR219, Project-ID 322900939), and Deutsche Herzstiftung. Saarland University has received scientific support from Ablative Solutions, Medtronic, and ReCor Medical. Until May 2024, F.M. has received speaker honoraria/consulting fees from Ablative Solutions, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Inari, Medtronic, Merck, ReCor Medical, Servier, and Terumo. D.L.B. discloses the following relationships: advisory board: Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, and Stasys; board of directors: American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), and High Enroll (stock); consultant: Broadview Ventures, GlaxoSmithKline, Hims, SFJ, and Youngene; data monitoring committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial [Portico Re-sheathable Transcatheter Aortic Valve System], funded by St Jude Medical, now Abbott), Boston Scientific (chair, PEITHO trial [Pulmonary Embolism Thrombolysis]), Cleveland Clinic, Contego Medical (chair, PERFORMANCE 2 [Protection Against Emboli During Carotid Artery Stenting Using the Neuroguard IEP System]), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial [Edoxaban versus Standard of Care and Their Effects on Clinical Outcomes in Patients Having Undergone Transcatheter Aortic Valve Implantation–Atrial Fibrillation], funded by Daiichi Sankyo; for the ABILITY-DM trial [Randomized Comparison of Abluminus DES+ Sirolimus-Eluting Stents Versus Everolimus-Eluting Stents in Coronary Artery Disease Patients With Diabetes Mellitus Global], funded by Concept Medical; for ALLAY-HF [Evaluation of the Safety and Feasibility of a Percutaneously Created Interatrial Shunt to Alleviate Heart Failure Symptoms in Patients With Chronic Heart Failure and Preserved or Mid-Range Left Ventricular Ejection Fraction], funded by Alleviant Medical), Novartis, Population Health Research Institute, and Rutgers University (for the National Institutes of Health–funded MINT trial [Myocardial Ischemia and Transfusion]); honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; chair, ACC accreditation oversight committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial [Randomized Evaluation of Dual Antithrombotic Therapy With Dabigatran versus Triple Therapy With Warfarin in Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention] steering committee funded by Boehringer Ingelheim; AEGIS-II [ApoA-I Event Reducing in Ischemic Syndromes II] executive committee funded by CSL Behring), Belvoir Publications (editor in chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial [A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease], funded by Ferring Pharmaceuticals), HMP Global (editor in chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor; associate editor), K2P (co-chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), WebMD (CME steering committees), and Wiley (steering committee); other: Clinical Cardiology (deputy editor); patent: sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women’s Hospital who assigned to Lexicon; neither I nor Brigham and Women’s Hospital receives any income from this patent); research funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio; royalties: Elsevier (editor, Braunwald’s Heart Disease); site coinvestigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; trustee: American College of Cardiology; and unfunded research: FlowCo. R.E.S. received speaker and advisor honoraria from Ablative Solutions, Medtronic, and Recor and grants to the institution from Ablative Solution, Medtronic, and Recor. D.E.K. discloses the following relationships: personal consulting honoraria: Medtronic, Ablative Solutions, and HyperQure; institutional research/grant support: Ablative Solutions, Biotronik, Medtronic, Orchestra Biomed, Orbus Neich, and Teleflex; and equity: BioStar Ventures (none related to Ablative Solutions). M.B. is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; TTR 219, project No. 322900939) and reports personal fees from Abbott, Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Edwards, Medtronic, Novartis, Recor, Servier, and Vifor. M.A. reports receiving grants from the European Horizon 2020 program; grants from Recor Medical, Idorsia, Novartis, and AstraZeneca; and personal fees from Alnylam Pharmaceuticals, Recor Medical Cincor, Medtronic, AstraZeneca, and Novartis. The other authors report no conflicts.

Venoarterial extracorporeal membrane oxygenation (VA-ECMO) shunts venous blood to the systemic arterial circulation to provide end-organ perfusion while increasing afterload that may impede left ventricle (LV) ejection and impair cardiac recovery. To maintain flow across the aortic valve and reduce risk of lethal clot formation, secondary mechanical circulatory support (MCS) devices are increasingly used despite limited understanding of their effects on cardiac function. This study sought to quantify the effects of VA-ECMO and combined with either intraaortic balloon pump (IABP) or percutaneous ventricular assist device (pVAD) on LV physiologic state and perfusion metrics in a porcine model of acute cardiogenic shock. Shock was induced through serial left anterior descending artery microbead embolization followed by initiation of VA-ECMO support and then placement of either IABP or pVAD. Hemodynamic measurements, LV pressure-volume loops, and carotid artery blood flow were evaluated before and after institution of combined MCS. The IABP decreased LV end-diastolic pressure by a peak of 15% while slightly increasing LV stroke work compared with decreases of more than 60% and 50% with the pVAD, respectively. The pVAD also demonstrated increased coronary perfusion and systemic pressure gradients in comparison to the IABP. Combined support with VA-ECMO and pVAD improves cardiovascular state in comparison to IABP., (Copyright © ASAIO 2024.)

Background: Breast implant safety issues have resulted in the need for global product recalls and medical device tracing. Conventional methods of breast implant tracing, have to date proven to be unsuccessful. This study aims to evaluate the effectiveness of high-resolution ultrasound (HRUS) screening in identifying implanted breast devices., Methods: Data from 113 female patients undergoing preoperative ultrasound screening for secondary breast surgery between 2019 and 2022 was prospectively reviewed to evaluate the effectiveness of HRUS imaging with the aid of a sonographic surface catalog to identify the surface and brand type of implanted breast devices. To corroborate the findings and assess the reproducibility of the approach, further evaluations were replicated in New Zealand white rabbits and compared with the results found in humans., Results: In the human recipients, implant surface and brand types were correctly identified by ultrasound imaging in 99% (112 of 113) and 96% (69 of 72) of the cases, either consultation-only or revision, respectively. This constituted an overall success rate of 98% (181 of 185). Furthermore, in a corroborating New Zealand white rabbit model where full-scale commercial implants were introduced and monitored over many months, from the total 28 analyzed, the surface was accurately identified in a total of 27 cases (the one failure being before generation of a sonograph surface catalogue), demonstrating an overall success rate of 96.4%., Conclusion: HRUS is, therefore, a valid and first-hand tool for breast implant imaging that can correctly evaluate both surface type and brand type alongside other variables such as implant placement, positioning, flipping, or rupture., Clinical Relevance Statement: HRUS is a valid and first-hand tool for the identification and traceability of breast implants that evaluates surface type and brand type. This low-cost, accessible, and reproducible practice provides patients with peace of mind and surgeons with a promising diagnostic tool., (Copyright © 2023 by the American Society of Plastic Surgeons.)

Background: The randomized, sham-controlled RADIANCE-HTN (A Study of the Recor Medical Paradise System in Clinical Hypertension) SOLO, RADIANCE-HTN TRIO, and RADIANCE II (A Study of the Recor Medical Paradise System in Stage II Hypertension) trials independently met their primary end point of a greater reduction in daytime ambulatory systolic blood pressure (SBP) 2 months after ultrasound renal denervation (uRDN) in patients with hypertension. To characterize the longer-term effectiveness and safety of uRDN versus sham at 6 months, after the blinded addition of antihypertensive treatments (AHTs), we pooled individual patient data across these 3 similarly designed trials., Methods: Patients with mild to moderate hypertension who were not on AHT or with hypertension resistant to a standardized combination triple AHT were randomized to uRDN (n=293) versus sham (n=213); they were to remain off of added AHT throughout 2 months of follow-up unless specified blood pressure (BP) criteria were exceeded. In each trial, if monthly home BP was ≥135/85 mm Hg from 2 to 5 months, standardized AHT was sequentially added to target home BP <135/85 mm Hg under blinding to initial treatment assignment. Six-month outcomes included baseline- and AHT-adjusted change in daytime ambulatory, home, and office SBP; change in AHT; and safety. Linear mixed regression models using all BP measurements and change in AHT from baseline through 6 months were used., Results: Patients (70% men) were 54.1±9.3 years of age with a baseline daytime ambulatory/home/office SBP of 150.5±9.8/151.0±12.4/155.5±14.4 mm Hg, respectively. From 2 to 6 months, BP decreased in both groups with AHT titration, but fewer uRDN patients were prescribed AHT ( P =0.004), and fewer additional AHT were prescribed to uRDN patients versus sham patients ( P =0.001). Whereas the unadjusted between-group difference in daytime ambulatory SBP was similar at 6 months, the baseline and medication-adjusted between-group difference at 6 months was -3.0 mm Hg (95% CI, -5.7, -0.2; P =0.033), in favor of uRDN+AHT. For home and office SBP, the adjusted between-group differences in favor of uRDN+AHT over 6 months were -5.4 mm Hg (-6.8, -4.0; P <0.001) and -5.2 mm Hg (-7.1, -3.3; P <0.001), respectively. There was no heterogeneity between trials. Safety outcomes were few and did not differ between groups., Conclusions: This individual patient-data analysis of 506 patients included in the RADIANCE trials demonstrates the maintenance of BP-lowering efficacy of uRDN versus sham at 6 months, with fewer added AHTs., Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02649426 and NCT03614260., Competing Interests: Disclosures Dr Azizi reports receiving grants from the European Horizon 2020 program; grants and nonfinancial support from Recor Medical, Idorsia, and Novartis; and personal fees from Alnylam Pharmaceuticals, Cincor, Medtronic, AstraZeneca, and Novartis. Dr Sharp has received personal fees from Recor Medical, Medtronic, Boston Scientific, Penumbra, and Philips. Dr Fisher has received grant support and personal fees from Recor Medical and personal fees from Medtronic. Dr Lobo has received personal fees from Recor Medical, Medtronic, Ablative Solutions, and Vascular Dynamics; and has received grants from Medtronic. Dr Daemen received institutional grant or research support from Abbott Vascular, Boston Scientific, ACIST Medical, Medtronic, Microport, Pie Medical, and Recor Medical, and consultancy or speaker fees from Abbott Vascular, Abiomed, ACIST Medical, Boston Scientific, Cardialysis BV, CardiacBooster, Kaminari Medical, Recor Medical, PulseCath, Pie Medical, Sanofi, Siemens Health Care, and Medtronic. Dr Lurz has received institutional grant support from Recor Medical, Edwards Lifesciences, and Abbott. Dr Mahfoud is supported by Deutsche Gesellschaft für Kardiologie (DGK), Deutsche Forschungsgemeinschaft (SFB TRR219, project ID 322900939), and Deutsche Herzstiftung; and has received scientific support from Ablative Solutions, Medtronic, and Recor Medical, and speaker honoraria or consulting fees from Ablative Solutions, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Inari, Medtronic, Merck, Recor Medical, Servier, and Terumo. Dr Schmieder has received grant support and personal fees from Recor Medical, Medtronic, and Ablative Solutions. Dr Basile has received grant support from Recor Medical and Ablative Solutions. Dr Bloch has received personal fees from Recor Medical and Medtronic. Dr Weber has received personal fees from Recor Medical, Medtronic, and Ablative Solutions. Dr Saxena has received grant support from Recor Medical, Ablative Solutions, Applied Therapeutics, Vascular Dynamics, and MSD; and has received consulting fees from Recor Medical, Esperion Inc., Daiichi Sankyo Inc., Novartis, and Vifor Pharma. Dr Wang reports no relationships relevant to the contents of this article to disclose. Dr Sanghvi has received grant support and personal fees from Recor Medical and Medtronic and has received grant support from CSI. Dr Jenkins reports institutional funding to Ochsner Medical Center from Medtronic, Abbott, Abiomed, and Recor Medical; and in addition to research grants, he has received honoraria for speaking engagements or proctoring consulting from Abbott, Recor Medical, and Medtronic. Dr Devireddy has received personal fees from Recor Medical, Medtronic, Edwards Lifesciences, and Shockwave Medical. Dr Rader has received personal fees from Recor Medical, Medtronic, and Bristol Myers Squibb. Dr Gosse has received research grant support from Recor Medical. L. Claude and Dr Dimitri Augustin are employees of Recor Medical. Dr McClure is an employee of NAMSA, a contractor for Recor Medical. Dr Kirtane reports institutional funding to Columbia University or Cardiovascular Research Foundation from Medtronic, Boston Scientific, Abbott Vascular, Abiomed, CSI, CathWorks, Siemens, Philips, and Recor Medical; in addition to research grants, institutional funding includes fees paid to Columbia University or Cardiovascular Research Foundation for speaking engagements or consulting; personal fees for consulting from Neurotronic; and travel expenses or meals from Medtronic, Boston Scientific, Abbott Vascular, Abiomed, CSI, CathWorks, Siemens, Philips, Recor Medical, Chiesi, OpSens, Zoll, and Regeneron.

Background: Although invasive measurement of fractional flow reserve (FFR) is recommended to guide revascularization, its routine use is underutilized. Recently, a novel non-invasive software that can instantaneously produce FFR values from the diagnostic angiograms, derived completely from artificial intelligence (AI) algorithms has been developed. We aim to assess the accuracy and diagnostic performance of AI-FFR in a real-world retrospective study., Methods: Retrospective, three-center study comparing AI-FFR values with invasive pressure wire-derived FFR obtained in patients undergoing routine diagnostic angiography. The accuracy, sensitivity, and specificity of AI-FFR were analyzed., Results: A total of 304 vessels from 297 patients were included. Mean invasive FFR was 0.86 vs. 0.85 AI-FFR (mean difference: -0.005, P  = 0.159). The diagnostic performance of AI-FFR demonstrated sensitivity of 91%, specificity 95%, positive predictive value 83% and negative predictive value 97%. Overall accuracy was 94% and the area under curve was 0.93 (95% CI 0.88-0.97). 105 lesions fell around the cutoff value (FFR = 0.75-0.85); in this sub-group, AI-FFR demonstrated sensitivity of 95%, and specificity 94%, with an AUC of 0.94 (95% CI 88.2-98.0). AI-FFR calculation time was 37.5 ± 7.4 s for each angiographic video. In 89% of cases, the software located the target lesion and in 11%, the operator manually marked the target lesion., Conclusion: AI-FFR calculated by an AI-based, angio-derived method, demonstrated excellent diagnostic performance against invasive FFR. AI-FFR calculation was fast with high reproducibility., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Endothelial cells (ECs) are capable of quickly responding in a coordinated manner to a wide array of stresses to maintain vascular homeostasis. Loss of EC cellular adaptation may be a potential marker for cardiovascular disease and a predictor of poor response to endovascular pharmacological interventions such as drug-eluting stents. Here, we report single-cell transcriptional profiling of ECs exposed to multiple stimulus classes to evaluate EC adaptation., Methods: Human aortic ECs were costimulated with both pathophysiological flows mimicking shear stress levels found in the human aorta (laminar and turbulent, ranging from 2.5 to 30 dynes/cm 2 ) and clinically relevant antiproliferative drugs, namely paclitaxel and rapamycin. EC state in response to these stimuli was defined using single-cell RNA sequencing., Results: We identified differentially expressed genes and inferred the TF (transcription factor) landscape modulated by flow shear stress using single-cell RNA sequencing. These flow-sensitive markers differentiated previously identified spatially distinct subpopulations of ECs in the murine aorta. Moreover, distinct transcriptional modules defined flow- and drug-responsive EC adaptation singly and in combination. Flow shear stress was the dominant driver of EC state, altering their response to pharmacological therapies., Conclusions: We showed that flow shear stress modulates the cellular capacity of ECs to respond to paclitaxel and rapamycin administration, suggesting that while responding to different flow patterns, ECs experience an impairment in their transcriptional adaptation to other stimuli., Competing Interests: Disclosures A.S. Kalluri reports compensation for consulting from nference, inc. A.K. Shalek reports compensation for consulting and scientific advisory board membership from Merck, Honeycomb Biotechnologies, Cellarity, Repertoire Immune Medicines, Ochre Bio, and Dahlia Biosciences. The other authors report no conflicts.

Background: Adverse effects of excessive sedation in critically ill mechanically ventilated patients are well described. Although guidelines strongly recommend minimizing sedative use, additional agents are added as infusions, often empirically. The tradeoffs associated with such decisions remain unclear., Methods: To test the hypothesis that a pragmatic propofol-based sedation regimen with restricted polypharmacy (RP; ie, prohibits additional infusions unless a predefined propofol dosage threshold is exceeded) would increase coma-and ventilator-free days compared with usual care (UC), we performed a retrospective cohort study of adults admitted to intensive care units (ICUs) of a tertiary-level medical center who were mechanically ventilated, initiated on propofol infusion, and had >50% probability of need for continued ventilation for the next 24 hours. We compared RP to UC, adjusting for baseline and time-varying confounding (demographics, care unit, calendar time of admission, vitals, laboratories, other interventions such as vasopressors and fluids, and more) through inverse probability weighting in a target trial framework. Ventilator-free days and coma-free days within 30 days of intubation and in-hospital mortality were the outcomes of interest., Results: A total of 7974 patients were included in the analysis, of which 3765 followed the RP strategy until extubation. In the full cohort under UC, mean coma-free days were 23.5 (95% confidence interval [CI], [23.3-23.7]), mean ventilator-free days were 20.6 (95% CI, [20.4-20.8]), and the in-hospital mortality rate was 22.0% (95% CI, [21.2-22.8]). We estimated that an RP strategy would increase mean coma-free days by 1.0 days (95% CI, [0.7-1.3]) and ventilator-free days by 1.0 days (95% CI, [0.7-1.3]) relative to UC in our cohort. Our estimate of the confounding-adjusted association between RP and in-hospital mortality was uninformative (-0.5%; 95% CI, [-3.0 to 1.9])., Conclusions: Compared with UC, RP was associated with more coma- and ventilator-free days. Restricting addition of adjunct infusions to propofol may represent a viable strategy to reduce duration of coma and mechanical ventilation. These hypothesis-generating findings should be confirmed in a randomized control trial., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 International Anesthesia Research Society.)

Objectives: To develop and demonstrate the feasibility of a Global Open Source Severity of Illness Score (GOSSIS)-1 for critical care patients, which generalizes across healthcare systems and countries., Design: A merger of several critical care multicenter cohorts derived from registry and electronic health record data. Data were split into training (70%) and test (30%) sets, using each set exclusively for development and evaluation, respectively. Missing data were imputed when not available., Setting/patients: Two large multicenter datasets from Australia and New Zealand (Australian and New Zealand Intensive Care Society Adult Patient Database [ANZICS-APD]) and the United States (eICU Collaborative Research Database [eICU-CRD]) representing 249,229 and 131,051 patients, respectively. ANZICS-APD and eICU-CRD contributed data from 162 and 204 hospitals, respectively. The cohort included all ICU admissions discharged in 2014-2015, excluding patients less than 16 years old, admissions less than 6 hours, and those with a previous ICU stay., Interventions: Not applicable., Measurements and Main Results: GOSSIS-1 uses data collected during the ICU stay's first 24 hours, including extrema values for vital signs and laboratory results, admission diagnosis, the Glasgow Coma Scale, chronic comorbidities, and admission/demographic variables. The datasets showed significant variation in admission-related variables, case-mix, and average physiologic state. Despite this heterogeneity, test set discrimination of GOSSIS-1 was high (area under the receiver operator characteristic curve [AUROC], 0.918; 95% CI, 0.915-0.921) and calibration was excellent (standardized mortality ratio [SMR], 0.986; 95% CI, 0.966-1.005; Brier score, 0.050). Performance was held within ANZICS-APD (AUROC, 0.925; SMR, 0.982; Brier score, 0.047) and eICU-CRD (AUROC, 0.904; SMR, 0.992; Brier score, 0.055). Compared with GOSSIS-1, Acute Physiology and Chronic Health Evaluation (APACHE)-IIIj (ANZICS-APD) and APACHE-IVa (eICU-CRD), had worse discrimination with AUROCs of 0.904 and 0.869, and poorer calibration with SMRs of 0.594 and 0.770, and Brier scores of 0.059 and 0.063, respectively., Conclusions: GOSSIS-1 is a modern, free, open-source inhospital mortality prediction algorithm for critical care patients, achieving excellent discrimination and calibration across three countries., Competing Interests: Drs. Raffa’s, Pollard’s, and Mark’s institutions received funding from Philips Healthcare. Drs. Raffa, Pollard, Mark, and Celi received support for article research from the National Institutes of Health (NIH). Dr. Johnson’s institution received funding from the NIH. Dr. Badawi received funding from Philips Healthcare. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Objective: As data science and artificial intelligence continue to rapidly gain traction, the publication of freely available ICU datasets has become invaluable to propel data-driven clinical research. In this guide for clinicians and researchers, we aim to: 1) systematically search and identify all publicly available adult clinical ICU datasets, 2) compare their characteristics, data quality, and richness and critically appraise their strengths and weaknesses, and 3) provide researchers with suggestions, which datasets are appropriate for answering their clinical question., Data Sources: A systematic search was performed in Pubmed, ArXiv, MedRxiv, and BioRxiv., Study Selection: We selected all studies that reported on publicly available adult patient-level intensive care datasets., Data Extraction: A total of four publicly available, adult, critical care, patient-level databases were included (Amsterdam University Medical Center data base [AmsterdamUMCdb], eICU Collaborative Research Database eICU CRD], High time-resolution intensive care unit dataset [HiRID], and Medical Information Mart for Intensive Care-IV). Databases were compared using a priori defined categories, including demographics, patient characteristics, and data richness. The study protocol and search strategy were prospectively registered., Data Synthesis: Four ICU databases fulfilled all criteria for inclusion and were queried using SQL (PostgreSQL version 12; PostgreSQL Global Development Group) and analyzed using R (R Foundation for Statistical Computing, Vienna, Austria). The number of unique patient admissions varied between 23,106 (AmsterdamUMCdb) and 200,859 (eICU-CRD). Frequency of laboratory values and vital signs was highest in HiRID, for example, 5.2 (±3.4) lactate values per day and 29.7 (±10.2) systolic blood pressure values per hour. Treatment intensity varied with vasopressor and ventilatory support in 69.0% and 83.0% of patients in AmsterdamUMCdb versus 12.0% and 21.0% in eICU-CRD, respectively. ICU mortality ranged from 5.5% in eICU-CRD to 9.9% in AmsterdamUMCdb., Conclusions: We identified four publicly available adult clinical ICU datasets. Sample size, severity of illness, treatment intensity, and frequency of reported parameters differ markedly between the databases. This should guide clinicians and researchers which databases to best answer their clinical questions., Competing Interests: Dr. Dam received funding from AmsterdamUMC and the Netherlands Organization for Health Research and Development (project number 10430012010003). Dr. Celi received support for article research from the National Institutes of Health. Dr. Faltys received funding from the Swiss National Fund. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: In cardiac surgery, the association between hypotension during specific intraoperative phases or vasopressor-inotropes with adverse outcomes remains unclear. This study's hypothesis was that intraoperative hypotension duration throughout the surgery or when separated into hypotension during and outside cardiopulmonary bypass may be associated with postoperative major adverse events., Methods: This retrospective observational cohort study included data for adults who had cardiac surgery between 2008 and 2016 in a tertiary hospital. Intraoperative hypotension was defined as mean arterial pressure of less than 65 mmHg. The total duration of hypotension was divided into three categories based on the fraction of overall hypotension duration that occurred during cardiopulmonary bypass (more than 80%, 80 to 60%, and less than 60%). The primary outcome was a composite of stroke, acute kidney injury, or mortality during the index hospitalization. The association with the composite outcome was evaluated for duration of hypotension during the entire surgery, outside cardiopulmonary bypass, and during cardiopulmonary bypass and the fraction of hypotension during cardiopulmonary bypass adjusting for vasopressor-inotrope dose, milrinone dose, patient, and surgical factors., Results: The composite outcome occurred in 256 (5.1%) of 4,984 included patient records; 66 (1.3%) patients suffered stroke, 125 (2.5%) had acute kidney injury, and 109 (2.2%) died. The primary outcome was associated with total duration of hypotension (adjusted odds ratio, 1.05; 95% CI, 1.02 to 1.08; P = 0.032), hypotension outside cardiopulmonary bypass (adjusted odds ratio, 1.06; 95% CI, 1.03 to 1.10; P = 0.001) per 10-min exposure to mean arterial pressure of less than 65 mmHg, and fraction of hypotension duration during cardiopulmonary bypass of less than 60% (reference greater than 80%; adjusted odds ratio, 1.67; 95% CI, 1.10 to 2.60; P = 0.019) but not with each 10-min period hypotension during cardiopulmonary bypass (adjusted odds ratio, 1.04; 95% CI, 0.99 to 1.09; P = 0.118), fraction of hypotension during cardiopulmonary bypass of 60 to 80% (adjusted odds ratio, 1.45; 95% CI, 0.97 to 2.23; P = 0.082), or total vasopressor-inotrope dose (adjusted odds ratio, 1.00; 95% CI, 1.00 to 1.00; P = 0.247)., Conclusions: This study confirms previous single-center findings that intraoperative hypotension throughout cardiac surgery is associated with an increased risk of acute kidney injury, mortality, or stroke., (Copyright © 2022, the American Society of Anesthesiologists. All Rights Reserved.)

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

Background: Parabrachial nucleus excitation reduces cortical delta oscillation (0.5 to 4 Hz) power and recovery time associated with anesthetics that enhance γ-aminobutyric acid type A receptor action. The effects of parabrachial nucleus excitation on anesthetics with other molecular targets, such as dexmedetomidine and ketamine, remain unknown. The hypothesis was that parabrachial nucleus excitation would cause arousal during dexmedetomidine and ketamine anesthesia., Methods: Designer Receptors Exclusively Activated by Designer Drugs were used to excite calcium/calmodulin-dependent protein kinase 2α-positive neurons in the parabrachial nucleus region of adult male rats without anesthesia (nine rats), with dexmedetomidine (low dose: 0.3 µg · kg-1 · min-1 for 45 min, eight rats; high dose: 4.5 µg · kg-1 · min-1 for 10 min, seven rats), or with ketamine (low dose: 2 mg · kg-1 · min-1 for 30 min, seven rats; high dose: 4 mg · kg-1 · min-1 for 15 min, eight rats). For control experiments (same rats and treatments), the Designer Receptors Exclusively Activated by Designer Drugs were not excited. The electroencephalogram and anesthesia recovery times were recorded and analyzed., Results: Parabrachial nucleus excitation reduced delta power in the prefrontal electroencephalogram with low-dose dexmedetomidine for the 150-min analyzed period, excepting two brief periods (peak median bootstrapped difference [clozapine-N-oxide - saline] during dexmedetomidine infusion = -6.06 [99% CI = -12.36 to -1.48] dB, P = 0.007). However, parabrachial nucleus excitation was less effective at reducing delta power with high-dose dexmedetomidine and low- and high-dose ketamine (peak median bootstrapped differences during high-dose [dexmedetomidine, ketamine] infusions = [-1.93, -0.87] dB, 99% CI = [-4.16 to -0.56, -1.62 to -0.18] dB, P = [0.006, 0.019]; low-dose ketamine had no statistically significant decreases during the infusion). Recovery time differences with parabrachial nucleus excitation were not statistically significant for dexmedetomidine (median difference for [low, high] dose = [1.63, 11.01] min, 95% CI = [-20.06 to 14.14, -20.84 to 23.67] min, P = [0.945, 0.297]) nor low-dose ketamine (median difference = 12.82 [95% CI: -3.20 to 39.58] min, P = 0.109) but were significantly longer for high-dose ketamine (median difference = 11.38 [95% CI: 1.81 to 24.67] min, P = 0.016)., Conclusions: These results suggest that the effectiveness of parabrachial nucleus excitation to change the neurophysiologic and behavioral effects of anesthesia depends on the anesthetic's molecular target., (Copyright © 2021, the American Society of Anesthesiologists. All Rights Reserved.)

Transcranial Doppler (TCD) ultrasonography is the only noninvasive bedside technology for the detection and monitoring of cerebral embolism. TCD may identify patients at risk of acute and chronic neurologic injury from gaseous or solid emboli. Importantly, a window of opportunity for intervention-to eliminate the source of the emboli and thereby prevent subsequent development of a clinical or subclinical stroke-may be identified using TCD. In this review, we discuss the application of TCD sonography in the perioperative and intensive care setting in adults and children known to be at increased risk of cerebral embolism. The major challenge for evaluation of emboli, especially in children, is the need to establish the ground truth and define true emboli identified by TCD. This requires the development and validation of a predictive TCD emboli monitoring technique so that appropriately designed clinical studies intended to identify specific modifiable factors and develop potential strategies to reduce pathologic cerebral embolic burden can be performed., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 International Anesthesia Research Society.)

Objective: To determine whether providing teleneurology (TN) consultations aiding in determination of death by neurologic criteria (DNC) to a bedside intensivist is feasible and whether timely access and expert input increase the quality of the DNC examination and identification of potential organ donors, we reviewed retrospective data related to outcomes of such consultations., Methods: Between November 2017 and March 2019, TN consults were requested for sequential comatose patients in the intensive care unit (ICU). We recorded patients' demographic information, causes leading to coma or suspected DNC, and the results of TN consultations. We obtained data on the number of referrals to the organ bank and number of organ donors., Results: Ninety-nine consults were performed with a median time from request to start of the consult of 20.2 minutes (interquartile range 5.4-65.3 minutes). Eighty consults were requested for determination of prognosis, whereas 19 consults were requested for supervision of the DNC examination. In 1 of 80 (1.2%) prognostication consults, the patient was determined by the neurologist to require assessment of DNC and was found to meet DNC criteria; determination of DNC occurred in 11 of the 19 (57.9%) consultations for a supervised DNC examination. In a comparison of the pre-TN (94 months) and post-TN (17 months) periods, there was 2.56-fold increase in the proportion of patients meeting DNC criteria who were medically suitable for donation (pre-TN 8.9% vs post-TN 21.1%, p = 0.02) and a 2.12-fold increase in the proportion of donors (pre-TN 6.14% vs post-TN 13.1%, p = 0.14)., Conclusions: It is feasible to perform TN consultations for patients with severe neurologic damage and to allow expert supervision for DNC examination. Having a teleneurologist as part of the ICU assessment team helped differentiate severe neurologic deficits from DNC and was associated with increase in organ donation., (© 2021 American Academy of Neurology.)

In the past decade, efforts to improve blood pressure control have looked beyond conventional approaches of lifestyle modification and drug therapy to embrace interventional therapies. Based upon animal and human studies clearly demonstrating a key role for the sympathetic nervous system in the etiology of hypertension, the newer technologies that have emerged are predominantly aimed at neuromodulation of peripheral nervous system targets. These include renal denervation, baroreflex activation therapy, endovascular baroreflex amplification therapy, carotid body ablation, and pacemaker-mediated programmable hypertension control. Of these, renal denervation is the most mature, and with a recent series of proof-of-concept trials demonstrating the safety and efficacy of radiofrequency and more recently ultrasound-based renal denervation, this technology is poised to become available as a viable treatment option for hypertension in the foreseeable future. With regard to baroreflex activation therapy, endovascular baroreflex amplification, carotid body ablation, and programmable hypertension control, these are developing technologies for which more human data are required. Importantly, central nervous system control of the circulation remains a poorly understood yet vital component of the hypertension pathway and mandates further investigation. Technology to improve blood pressure control through deep brain stimulation of key cardiovascular control territories is, therefore, of interest. Furthermore, alternative nonsympathomodulatory intervention targeting the hemodynamics of the circulation may also be worth exploring for patients in whom sympathetic drive is less relevant to hypertension perpetuation. Herein, we review the aforementioned technologies with an emphasis on the preclinical data that underpin their rationale and the human evidence that supports their use.

[Figure: see text].

Extracorporeal membrane oxygenation (ECMO) is increasingly deployed to provide percutaneous mechanical circulatory support despite incomplete understanding of its complex interactions with the failing heart and its effects on hemodynamics and perfusion. Using an idealized geometry of the aorta and its major branches and a peripherally inserted return cannula terminating in the iliac artery, computational fluid dynamic simulations were performed to (1) quantify perfusion as function of relative ECMO flow and (2) describe the watershed region produced by the collision of antegrade flow from the heart and retrograde ECMO flow. To simulate varying degrees of cardiac failure, ECMO flow as a fraction of systemic perfusion was evaluated at 100%, 90%, 75%, and 50% of total flow with the remainder supplied by the heart calculated from a patient-derived flow waveform. Dynamic boundary conditions were generated with a three-element lumped parameter model to accurately simulate distal perfusion. In profound failure (ECMO providing 90% or more of flow), the watershed region was positioned in the aortic arch with minimal pulsatility observed in the flow to the visceral organs. Modest increases in cardiac flow advanced the watershed region into the thoracic aorta with arch perfusion entirely supplied by the heart., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2020.)

The neural circuits underlying the distinct endpoints that define general anesthesia remain incompletely understood. It is becoming increasingly evident, however, that distinct pathways in the brain that mediate arousal and pain are involved in various endpoints of general anesthesia. To critically evaluate this growing body of literature, familiarity with modern tools and techniques used to study neural circuits is essential. This Readers' Toolbox article describes four such techniques: (1) electrical stimulation, (2) local pharmacology, (3) optogenetics, and (4) chemogenetics. Each technique is explained, including the advantages, disadvantages, and other issues that must be considered when interpreting experimental results. Examples are provided of studies that probe mechanisms of anesthesia using each technique. This information will aid researchers and clinicians alike in interpreting the literature and in evaluating the utility of these techniques in their own research programs.

Background: Paclitaxel-containing devices (PTXDs) significantly reduce reintervention in patients with symptomatic femoropopliteal peripheral artery disease. A recent aggregate-data meta-analysis reported increased late mortality in patients with peripheral artery disease treated with PTXDs. We performed an individual patient data meta-analysis to evaluate mortality., Methods: Manufacturers of US Food and Drug Administration-approved and commercially available devices in the United States provided deidentified individual patient data for independent analysis. Cox proportional hazards 1-stage meta-analysis models using intention-to-treat methods were used for the primary analysis. A secondary analysis of recovered missing vital status data was performed. The impact of control crossover to PTXDs, cause-specific mortality, and drug dose mortality were assessed., Results: A total of 2185 subjects and 386 deaths from 8 PTXD trials with 4-year median follow-up were identified. The primary analysis indicated a 38% (95% CI, 6% to 80%) increased relative mortality risk, corresponding to 4.6% absolute increase, at 5 years associated with PTXD use. Control and treatment arm loss to follow-up and withdrawal were 24% and 23%, respectively. With inclusion of recovered vital status data, the excess relative mortality risk was 27% (95% CI, 3%-58%). This observation was consistent across various scenarios, including as-treated analyses, with no evidence of increased risk over time with PTXDs. Mortality risk tended to be increased for all major causes of death. There were no subgroup differences. No drug dose-mortality association was identified., Conclusions: This individual patient data meta-analysis, based on the most complete available data set of mortality events from PTXD randomized controlled trials, identified an absolute 4.6% increased mortality risk associated with PTXD use.

Background: Repolarization alternans (RA) has been implicated in the pathogenesis of ventricular arrhythmias and sudden cardiac death., Methods: We have developed a real-time, closed-loop system to record and analyze RA from multiple intracardiac leads, and deliver dynamically R-wave triggered pacing stimuli during the absolute refractory period. We have evaluated the ability of this system to control RA and reduce arrhythmia susceptibility, in vivo., Results: R-wave triggered pacing can induce RA, the magnitude of which can be modulated by varying the amplitude, pulse width, and size of the pacing vector. Using a swine model (n=9), we demonstrate that to induce a 1 µV change in the alternans voltage on the body surface, coronary sinus and left ventricle leads, requires a delivered charge of 0.04±0.02, 0.05±0.025, and 0.06±0.033 µC, respectively, while to induce a one unit change of the K score , requires a delivered charge of 0.93±0.73, 0.32±0.29, and 0.33±0.37 µC, respectively. For all body surface and intracardiac leads, both Δ(alternans voltage) and ΔK score between baseline and R-wave triggered paced beats increases consistently with an increase in the pacing pulse amplitude, pulse width, and vector spacing. Additionally, we show that the proposed method can be used to suppress spontaneously occurring alternans (n=7), in the presence of myocardial ischemia. Suppression of RA by pacing during the absolute refractory period results in a significant reduction in arrhythmia susceptibility, evidenced by a lower S rank score during programmed ventricular stimulation compared with baseline before ischemia., Conclusions: We have developed and evaluated a novel closed-loop method to dynamically modulate RA in a swine model. Our data suggest that suppression of RA directly reduces arrhythmia susceptibility and reinforces the concept that RA plays a critical role in the pathophysiology of arrhythmogenesis.

The Human Placenta Project has focused attention on the need for noninvasive magnetic resonance imaging (MRI)-based techniques to diagnose and monitor placental function throughout pregnancy. The hope is that the management of placenta-related pathologies would be improved if physicians had more direct, real-time measures of placental health to guide clinical decision making. As oxygen alters signal intensity on MRI and oxygen transport is a key function of the placenta, many of the MRI methods under development are focused on quantifying oxygen transport or oxygen content of the placenta. For example, measurements from blood oxygen level-dependent imaging of the placenta during maternal hyperoxia correspond to outcomes in twin pregnancies, suggesting that some aspects of placental oxygen transport can be monitored by MRI. Additional methods are being developed to accurately quantify baseline placental oxygenation by MRI relaxometry. However, direct validation of placental MRI methods is challenging and therefore animal studies and ex vivo studies of human placentas are needed. Here we provide an overview of the current state of the art of oxygen transport and quantification with MRI. We suggest that as these techniques are being developed, increased focus be placed on ensuring they are robust and reliable across individuals and standardized to enable predictive diagnostic models to be generated from the data. The field is still several years away from establishing the clinical benefit of monitoring placental function in real time with MRI, but the promise of individual personalized diagnosis and monitoring of placental disease in real time continues to motivate this effort.

Background: A critical barrier to successful limb replantation and allotransplantation is the maximum allowable limb ischemia time of 4 to 6 hours. The current gold standard is to preserve amputated limbs on an ice slurry. Experimental machine perfusion has yielded promising results as an alternative. In particular, hypothermic acellular perfusion has enabled preservation of amputated limbs for up to 12 hours thus far., Methods: Amputated forelimbs of Yorkshire pigs were preserved on static cold storage at 4°C for 4 hours (static cold storage group) or perfused at 8°C for 24 hours (perfusion group) with oxygenated modified STEEN Solution perfusate before replantation. Animals were followed up for 7 days after replantation., Results: Eight animals underwent replantation (cold storage group, n = 4; perfusion group, n = 4). Seventy-five and 100 percent of animals in the static cold storage and perfusion groups survived for 7 days, respectively. Glycogen and adenosine triphosphate remained stable throughout perfusion. Heart and respiratory rate after replantation were increased in the static cold storage group. There was increased damage in muscle biopsy specimens obtained from animals in the static cold storage group after 7 days when compared with those from animals in the perfusion group., Conclusions: Hypothermic acellular ex vivo perfusion of limbs for up to 24 hours enables tissue preservation comparable to that obtained with conventional static cold storage for 4 hours and may reduce muscle damage and systemic reactions on limb replantation. Translation to human limbs may help improve limb replantation and allotransplantation outcomes.

Objectives: Cardiogenic shock is a highly morbid condition in which inadequate end-organ perfusion leads to death if untreated. Peripheral venoarterial extracorporeal membrane oxygenation is increasingly used to restore systemic perfusion despite limited understanding of how to optimally titrate support. This review provides insights into the physiologic basis of extracorporeal membrane oxygenation support and presents an approach to extracorporeal membrane oxygenation management in the cardiogenic shock patient., Data Sources, Study Selection, and Data Extraction: Data were obtained from a PubMed search of the most recent medical literature identified from MeSH terms: extracorporeal membrane oxygenation, cardiogenic shock, percutaneous mechanical circulatory support, and heart failure. Articles included original articles, case reports, and review articles., Data Synthesis: Current evidence detailing the use of extracorporeal membrane oxygenation to support patients in cardiogenic shock is limited to isolated case reports and single institution case series focused on patient outcomes but lacking in detailed approaches to extracorporeal membrane oxygenation management. Unlike medical therapy, in which dosages are either prescribed or carefully titrated to specific variables, extracorporeal membrane oxygenation is a mechanical support therapy requiring ongoing titration but without widely accepted variables to guide treatment. Similar to mechanical ventilation, extracorporeal membrane oxygenation can provide substantial benefit or induce significant harm. The widespread use and present lack of data to guide extracorporeal membrane oxygenation support demands that intensivists adopt a physiologically-based approach to management of the cardiogenic shock patient on extracorporeal membrane oxygenation., Conclusions: Extracorporeal membrane oxygenation is a powerful mechanical circulatory support modality capable of rapidly restoring systemic perfusion yet lacking in defined approaches to management. Adopting a management approach based physiologic principles provides a basis for care.

Background: The cells that form the arterial wall contribute to multiple vascular diseases. The extent of cellular heterogeneity within these populations has not been fully characterized. Recent advances in single-cell RNA-sequencing make it possible to identify and characterize cellular subpopulations., Methods: We validate a method for generating a droplet-based single-cell atlas of gene expression in a normal blood vessel. Enzymatic dissociation of 4 whole mouse aortas was followed by single-cell sequencing of >10 000 cells., Results: Clustering analysis of gene expression from aortic cells identified 10 populations of cells representing each of the main arterial cell types: fibroblasts, vascular smooth muscle cells, endothelial cells (ECs), and immune cells, including monocytes, macrophages, and lymphocytes. The most significant cellular heterogeneity was seen in the 3 distinct EC populations. Gene set enrichment analysis of these EC subpopulations identified a lymphatic EC cluster and 2 other populations more specialized in lipoprotein handling, angiogenesis, and extracellular matrix production. These subpopulations persist and exhibit similar changes in gene expression in response to a Western diet. Immunofluorescence for Vcam1 and Cd36 demonstrates regional heterogeneity in EC populations throughout the aorta., Conclusions: We present a comprehensive single-cell atlas of all cells in the aorta. By integrating expression from >1900 genes per cell, we are better able to characterize cellular heterogeneity compared with conventional approaches. Gene expression signatures identify cell subpopulations with vascular disease-relevant functions.

Background: The multicenter, international, randomized, blinded, sham-controlled RADIANCE-HTN SOLO trial (A Study of the ReCor Medical Paradise System in Clinical Hypertension) demonstrated a 6.3 mm Hg greater reduction in daytime ambulatory systolic blood pressure (BP) at 2 months by endovascular ultrasound renal denervation (RDN) compared with a sham procedure among patients not treated with antihypertensive medications. We report 6-month results after the addition of a recommended standardized stepped-care antihypertensive treatment to the randomized endovascular procedure under continued blinding to initial treatment., Methods: Patients with a daytime ambulatory BP ≥135/85 mm Hg and <170/105 mm Hg after a 4-week discontinuation of up to 2 antihypertensive medications, and a suitable renal artery anatomy, were randomized to RDN (n=74) or sham (n=72). Patients were to remain off antihypertensive medications throughout the first 2 months of follow-up unless safety BP criteria were exceeded. Between 2 and 5 months, if monthly measured home BP was ≥135/85 mm Hg, a standardized stepped-care antihypertensive treatment was recommended consisting of the sequential addition of amlodipine (5 mg/d), a standard dose of an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, and hydrochlorothiazide (12.5 mg/d), followed by the sequential uptitration of hydrochlorothiazide (25 mg/d) and amlodipine (10 mg/d). Outcomes included the 6-month (1) change in daytime ambulatory systolic BP adjusted for medications and baseline systolic BP, (2) medication burden, and (3) safety., Results: A total of 69/74 RDN patients and 71/72 sham patients completed the 6-month ambulatory BP measurement. At 6 months, 65.2% of patients in the RDN group were treated with the standardized stepped-care antihypertensive treatment versus 84.5% in the sham group ( P =0.008), and the average number of antihypertensive medications and defined daily dose were less in the RDN group than in the sham group (0.9±0.9 versus 1.3±0.9, P =0.010 and 1.4±1.5 versus 2.0±1.8, P =0.018; respectively). Despite less intensive standardized stepped-care antihypertensive treatment, RDN reduced daytime ambulatory systolic BP to a greater extent than sham (-18.1±12.2 versus -15.6±13.2 mm Hg, respectively; difference adjusted for baseline BP and number of medications: -4.3 mm Hg, 95% confidence interval, -7.9 to -0.6, P =0.024). There were no major adverse events in either group through 6 months., Conclusions: The BP-lowering effect of endovascular ultrasound RDN was maintained at 6 months with less prescribed antihypertensive medications compared with a sham control., Clinical Trial Registration: URL: https://www., Clinicaltrials: gov. Unique identifier: NCT02649426.

Background: Chronic kidney disease (CKD) increases cardiovascular risk. Underlying mechanisms, however, remain obscure. The uremic toxin indoxyl sulfate is an independent cardiovascular risk factor in CKD. We explored the potential impact of indoxyl sulfate on proinflammatory activation of macrophages and its underlying mechanisms., Methods: We examined in vitro the effects of clinically relevant concentrations of indoxyl sulfate on proinflammatory responses of macrophages and the roles of organic anion transporters and organic anion transporting polypeptides (OATPs). A systems approach, involving unbiased global proteomics, bioinformatics, and network analysis, then explored potential key pathways. To address the role of Delta-like 4 (Dll4) in indoxyl sulfate-induced macrophage activation and atherogenesis in CKD in vivo, we used 5/6 nephrectomy and Dll4 antibody in low-density lipoprotein receptor-deficient (Ldlr-/-) mice. To further determine the relative contribution of OATP2B1 or Dll4 to proinflammatory activation of macrophages and atherogenesis in vivo, we used siRNA delivered by macrophage-targeted lipid nanoparticles in mice., Results: We found that indoxyl sulfate-induced proinflammatory macrophage activation is mediated by its uptake through transporters, including OATP2B1, encoded by the SLCO2B1 gene. The global proteomics identified potential mechanisms, including Notch signaling and the ubiquitin-proteasome pathway, that mediate indoxyl sulfate-triggered proinflammatory macrophage activation. We chose the Notch pathway as an example of key candidates for validation of our target discovery platform and for further mechanistic studies. As predicted computationally, indoxyl sulfate triggered Notch signaling, which was preceded by the rapid induction of Dll4 protein. Dll4 induction may result from inhibition of the ubiquitin-proteasome pathway, via the deubiquitinating enzyme USP5. In mice, macrophage-targeted OATP2B1/Slco2b1 silencing and Dll4 antibody inhibited proinflammatory activation of peritoneal macrophages induced by indoxyl sulfate. In low-density lipoprotein receptor-deficient mice, Dll4 antibody abolished atherosclerotic lesion development accelerated in Ldlr-/- mice. Moreover, coadministration of indoxyl sulfate and OATP2B1/Slco2b1 or Dll4 siRNA encapsulated in macrophage-targeted lipid nanoparticles in Ldlr-/- mice suppressed lesion development., Conclusions: These results suggest that novel crosstalk between OATP2B1 and Dll4-Notch signaling in macrophages mediates indoxyl sulfate-induced vascular inflammation in CKD.

Background: Multiple studies completed in the ambulatory nonsurgical setting show a significant association between short- and long-term blood pressure variability and poor outcomes. However, perioperative blood pressure variability outcomes have not been well studied, especially in the cardiac surgical setting. In this study, we sought to assess whether systolic and mean arterial blood pressure variability were associated with 30-day mortality and in-hospital renal failure in patients undergoing cardiac surgery requiring cardiopulmonary bypass. Furthermore, blood pressure variability has not been evaluated specifically during each phase of surgery, namely in the pre-, intra- and postbypass phases; thus, we aimed also to assess whether outcomes were associated with phase-specific systolic and mean arterial blood pressure variability., Methods: All patients undergoing cardiac surgery from January 2008 to June 2014 were enrolled in this retrospective, single-center study. Demographic, intraoperative, and postoperative outcome data were obtained from the institution's Society of Thoracic Surgery database and Anesthesia Information Management System. Systolic and mean arterial blood pressure variability were assessed using the coefficient of variation (CV). The primary outcomes were 30-day mortality and in-hospital renal failure in relation to the entire duration of a case, while the secondary outcomes assessed phase-specific surgical periods. In an effort to control the family-wise error rate, P values <.0125 were considered significant for the primary outcomes., Results: Of the 3687 patients analyzed, 2.7% of patients died within 30 days of surgery and 2.8% experienced in-hospital renal failure. After adjusting for significant covariates, we found a statistically significant association between increasing CV for systolic blood pressure (CVSBP) and 30-day mortality and in-hospital renal failure. For every 0.10 increase in CVSBP, there was a 150% increase in the odds of death (odds ratio, 2.50; 95% confidence interval, 1.60-3.92; P < .0001) and there was a 104% increase in odds of experiencing renal failure (odds ratio, 2.04; 95% confidence interval, 1.33-3.14; P = .001). The association with mortality was driven primarily by the prebypass period, because the association between CVSBP and mortality during the prebypass phase was significant (P = .01), and not during the postbypass phase (P = .08). There was no significant association between CV for mean arterial blood pressure and either death or renal failure during any period of surgery, including the bypass phase., Conclusions: Increasing systolic blood pressure variability was associated with 30-day mortality and development of renal failure, with surgery phase-specific relationships observed. Further research is required to determine how to prospectively detect blood pressure variability and elucidate opportunities for intervention.

Objectives: Presenting symptoms in patients with sepsis may influence rapidity of diagnosis, time-to-antibiotics, and outcome. We tested the hypothesis that vague presenting symptoms are associated with delayed antibiotics and increased mortality. We further characterized individual presenting symptoms and their association with mortality., Design: Retrospective cohort study., Setting: Emergency department of large, urban, academic U.S. hospital., Patients: All adult patients with septic shock treated in the emergency department between April 2014 and March 2016., Interventions: None., Measurements and Main Results: Of 654 septic shock cases, 245 (37%) presented with vague symptoms. Time-to-antibiotics from first hypotension or elevated lactate was significantly longer for those with vague symptoms versus those with explicit symptoms of infection (1.6 vs 0.8 hr; p < 0.01), and in-hospital mortality was also substantially higher (34% vs 16%; p < 0.01). Patients with vague symptoms were older and sicker as evidenced by triage hypotension, Sequential Organ Failure Assessment score, initial serum lactate, and need for intubation. In multivariate analysis, vague symptoms were independently associated with mortality (adjusted odds ratio, 2.12; 95% CI, 1.32-3.40; p < 0.01), whereas time-to-antibiotics was not associated with mortality (adjusted odds ratio, 1.01; 95% CI, 0.94-1.08; p = 0.78). Of individual symptoms, only the absence of fever, chills, or rigors (odds ratio, 2.70; 95% CI, 1.63-4.47; p < 0.01) and presence of shortness of breath (odds ratio, 1.97; 95% CI, 1.23-3.15; p < 0.01) were independently associated with mortality., Conclusions: More than one third of patients with septic shock presented to the emergency department with vague symptoms that were not specific to infection. These patients had delayed antibiotic administration and higher risk of mortality even after controlling for demographics, illness acuity, and time-to-antibiotics in multivariate analysis. These findings suggest that the nature of presenting symptoms is an important component of sepsis clinical phenotyping and may be an important confounder in sepsis epidemiologic studies.

Beta cell replacement has the potential to restore euglycemia in patients with insulin-dependent diabetes. Although great progress has been made in establishing allogeneic islet transplantation from deceased donors as the standard of care for those with the most labile diabetes, it is also clear that the deceased donor organ supply cannot possibly treat all those who could benefit from restoration of a normal beta cell mass, especially if immunosuppression were not required. Against this background, the International Pancreas and Islet Transplant Association in collaboration with the Harvard Stem Cell Institute, the Juvenile Diabetes Research Foundation (JDRF), and the Helmsley Foundation held a 2-day Key Opinion Leaders Meeting in Boston in 2016 to bring together experts in generating and transplanting beta cells derived from stem cells. The following summary highlights current technology, recent significant breakthroughs, unmet needs and roadblocks to stem cell-derived beta cell therapies, with the aim of spurring future preclinical collaborative investigations and progress toward the clinical application of stem cell-derived beta cells.

Objectives: Evaluate the accuracy of different ICU risk models repurposed as continuous markers of severity of illness., Design: Nonintervention cohort study., Setting: eICU Research Institute ICUs using tele-ICU software calculating continuous ICU Discharge Readiness Scores between January 2013 and March 2016., Patients: Five hundred sixty-one thousand four hundred seventy-eight adult ICU patients with an ICU length of stay between 4 hours and 30 days., Interventions: Not available., Measurements and Main Results: Hourly Acute Physiology and Chronic Health Evaluation IV, Sequential Organ Failure Assessment, and Discharge Readiness Scores were calculated beginning hour 4 of the ICU stay. Primary outcome was the area under the receiver operating characteristic curve for the mean score with ICU mortality. Secondary outcomes included area under the receiver operating characteristic curves for ICU mortality with admission, median, maximum and last scores, and for death within 24 hours. The trajectories of each score were visualized by plotting the hourly averages against time in the ICU, stratified by mortality and length of stay. The area under the receiver operating characteristic curves for mean Acute Physiology and Chronic Health Evaluation, Sequential Organ Failure Assessment, and Discharge Readiness Scores were 0.90 (0.89-0.90), 0.86 (0.86-0.86), and 0.94 (0.94-0.94), respectively. The area under the receiver operating characteristic curves for hourly Acute Physiology and Chronic Health Evaluation, Sequential Organ Failure Assessment, and Discharge Readiness Scores predicting 24-hour mortality were 0.81 (0.81-0.81), 0.76 (0.76-0.76), and 0.86 (0.86-0.86). Discharge Readiness Scores had a higher area under the receiver operating characteristic curve than both Acute Physiology and Chronic Health Evaluation and Sequential Organ Failure Assessment for each metric. Acute Physiology and Chronic Health Evaluation and Sequential Organ Failure Assessment scores increased throughout the first 24 hours in both survivors and nonsurvivors; Discharge Readiness Scores continuously decreased in survivors and temporarily decreased before increasing by hour 36 in nonsurvivors with longer length of stays., Conclusions: Acute Physiology and Chronic Health Evaluation, Sequential Organ Failure Assessment, and Discharge Readiness Scores all have relatively high discrimination for ICU mortality when used continuously; Discharge Readiness Scores tended to have slightly higher area under the receiver operating characteristic curves for each endpoint. These findings validate the use of these models on a population level for continuous risk adjustment in the ICU, although Acute Physiology and Chronic Health Evaluation and Sequential Organ Failure Assessment appear slower to respond to improvements in patient status than Discharge Readiness Scores, and Discharge Readiness Scores may reflect physiologic improvement from interventions, potentially underestimating risk.

Objective: Many ICU patients do not require critical care interventions. Whether aggressive care environments increase risks to low-acuity patients is unknown. We evaluated whether ICU acuity was associated with outcomes of low mortality-risk patients. We hypothesized that admission to high-acuity ICUs would be associated with worse outcomes. This hypothesis was based on two possibilities: 1) high-acuity ICUs may have a culture of aggressive therapy that could lead to potentially avoidable complications and 2) high-acuity ICUs may focus attention toward the many sicker patients and away from the fewer low-risk patients., Design: Retrospective cohort study., Setting: Three hundred twenty-two ICUs in 199 hospitals in the Philips eICU database between 2010 and 2015., Patients: Adult ICU patients at low risk of dying, defined as an Acute Physiology and Chronic Health Evaluation-IVa-predicted mortality of 3% or less., Exposure: ICU acuity, defined as the mean Acute Physiology and Chronic Health Evaluation IVa score of all admitted patients in a calendar year, stratified into quartiles., Measurements and Main Results: We used generalized estimating equations to test whether ICU acuity is independently associated with a primary outcome of ICU length of stay and secondary outcomes of hospital length of stay, hospital mortality, and discharge destination. The study included 381,997 low-risk patients. Mean ICU and hospital length of stay were 1.8 ± 2.1 and 5.2 ± 5.0 days, respectively. Mean Acute Physiology and Chronic Health Evaluation IVa-predicted hospital mortality was 1.6% ± 0.8%; actual hospital mortality was 0.7%. In adjusted analyses, admission to low-acuity ICUs was associated with worse outcomes compared with higher-acuity ICUs. Specifically, compared with the highest-acuity quartile, ICU length of stay in low-acuity ICUs was increased by 0.24 days; in medium-acuity ICUs by 0.16 days; and in high-acuity ICUs by 0.09 days (all p < 0.001). Similar patterns existed for hospital length of stay. Patients in lower-acuity ICUs had significantly higher hospital mortality (odds ratio, 1.28 [95% CI, 1.10-1.49] for low-; 1.24 [95% CI, 1.07-1.42] for medium-, and 1.14 [95% CI, 0.99-1.31] for high-acuity ICUs) and lower likelihood of discharge home (odds ratio, 0.86 [95% CI, 0.82-0.90] for low-, 0.88 [95% CI, 0.85-0.92] for medium-, and 0.95 [95% CI, 0.92-0.99] for high-acuity ICUs)., Conclusions: Admission to high-acuity ICUs is associated with better outcomes among low mortality-risk patients. Future research should aim to understand factors that confer benefit to patients with different risk profiles.

Objectives: Interhospital transfer, a common intervention, may be subject to healthcare disparities. In mechanically ventilated patients with sepsis, we hypothesize that disparities not disease related would be found between patients who were and were not transferred., Design: Retrospective cohort study., Setting: Nationwide Inpatient Sample, 2006-2012., Patients: Patients over 18 years old with a primary diagnosis of sepsis who underwent mechanical ventilation., Interventions: None., Measurements and Main Results: We obtained age, gender, length of stay, race, insurance coverage, do not resuscitate status, and Elixhauser comorbidities. The outcome used was interhospital transfer from a small- or medium-sized hospital to a larger acute care hospital. Of 55,208,382 hospitalizations, 46,406 patients met inclusion criteria. In the multivariate model, patients were less likely to be transferred if the following were present: older age (odds ratio, 0.98; 95% CI, 0.978-0.982), black race (odds ratio, 0.79; 95% CI, 0.70-0.89), Hispanic race (odds ratio, 0.79; 95% CI, 0.69-0.90), South region hospital (odds ratio, 0.79; 95% CI, 0.72-0.88), teaching hospital (odds ratio, 0.31; 95% CI, 0.28-0.33), and do not resuscitate status (odds ratio, 0.19; 95% CI, 0.15-0.25)., Conclusions: In mechanically ventilated patients with sepsis, we found significant disparities in race and geographic location not explained by medical diagnoses or illness severity.

Objectives: The outcomes of critically ill patients who undergo interhospital transfer are not well understood. Physicians assume that patients who undergo interhospital transfer will receive more advanced care that may translate into decreased morbidity or mortality relative to a similar patient who is not transferred. However, there is little empirical evidence to support this assumption. We examined country-level U.S. data from the Nationwide Readmissions Database to examine whether, in mechanically ventilated patients with sepsis, interhospital transfer is associated with a mortality benefit., Design: Retrospective data analysis using complex survey design regression methods with propensity score matching., Setting: The Nationwide Readmissions Database contains information about hospital admissions from 22 States, accounting for roughly half of U.S. hospitalizations; the database contains linkage numbers so that admissions and transfers for the same patient can be linked across 1 year of follow-up., Patients: From the 2013 Nationwide Readmission Database Sample, 14,325,172 hospital admissions were analyzed. There were 61,493 patients with sepsis and on mechanical ventilation. Of these, 1,630 patients (2.7%) were transferred during their hospitalization. A propensity-matched cohort of 1,630 patients who did not undergo interhospital transfer was identified., Interventions: None., Measurements and Main Results: The exposure of interest was interhospital transfer to an acute care facility. The primary outcome was hospital mortality; the secondary outcome was hospital length of stay. The propensity score included age, gender, insurance coverage, do not resuscitate status, use of renal replacement therapy, presence of shock, and Elixhauser comorbidities index. After propensity matching, interhospital transfer was not associated with a difference in in-hospital mortality (12.3% interhospital transfer vs 12.7% non-interhospital transfer; p = 0.74). However, interhospital transfer was associated with a longer total hospital length of stay (12.8 d interquartile range, 7.7-21.6 for interhospital transfer vs 9.1 d interquartile range, 5.1-17.0 for non-interhospital transfer; p < 0.01)., Conclusions: Patients with sepsis requiring mechanical ventilation who underwent interhospital transfer did not have improved outcomes compared with a cohort with matched characteristics who were not transferred. The study raises questions about the risk-benefit profile of interhospital transfer as an intervention.

Study Design: A preclinical animal model of chronic ligation of the sciatic nerve was used to compare the effectiveness of a slow-release hydrogel carrying methylprednisolone to methylprednisolone injection alone, which simulates the current standard of care for chronic compressive radiculopathy (CR)., Objective: To extend the short-term benefits of steroid injections by using a nonswelling, biodegradable hydrogel as carrier to locally release methylprednisolone in a regulated and sustained way at the site of nerve compression., Summary of Background Data: CR affects millions worldwide annually, and is a cause of costly disability with significant societal impact. Currently, a leading nonsurgical therapy involves epidural injection of steroids to temporarily alleviate the pain associated with CR. However, an effective way to extend the short-term effect of steroid treatment to address the chronic component of CR does not exist., Methods: We induced chronic compression injury of the sciatic nerves of rats by permanent ligation. Forty-eight hours later we injected our methylprednisolone infused hydrogel and assessed the effectiveness of our treatment for 4 weeks. We quantified mechanical hyperalgesia using a Dynamic Plantar Aesthesiometer (Ugo Basile, Stoelting Co., IL, USA), whereas gait analysis was conducted using the Catwalk automated gait analysis platform (Noldus, Leesburg, VA, USA). Macrophage staining was performed with immunohistochemistry and quantification of monocyte chemoattractant protein-1 in sciatic nerve lysates was performed with multiplex immunoassay using a SECTOR Imager 2400A (Meso Scale Discovery, Rockville, MA, USA)., Results: We demonstrate that using the hydrogel to deliver methylprednisolone results in significant (P < 0.05) reduction of hyperalgesia and improvement in the gait pattern of animals with chronic lesions as compared with animals treated with steroid alone. In addition, animals treated with hydrogel plus steroid showed significant reduction in the number of infiltrating macrophages at the sciatic nerve and reduced expression of the neuroinflammatory chemokine monocyte chemoattractant protein-1 (P < 0.05)., Conclusion: Use of hydrogels as carriers for sustained local release of steroids provides significantly better control of pain in an animal model of chronic CR. Our steroid-infused hydrogel could be an effective extender of the short-term benefits of epidural steroid injections for patients with chronic compression-induced radicular pain., Level of Evidence: N/A.

Resting-state functional magnetic resonance imaging (resting-state fMRI) is a tool for investigating the functional networks that arise during the resting state of the brain. Recent advances of the resting-state fMRI analysis suggest its feasibility for evaluating language function. The most common clinical application is for presurgical mapping of cortex for a brain tumor or for resective epilespy surgery. In this article, we review the techniques and presurgical applications of resting-state fMRI analysis for language evaluation, and discuss the use in the clinical setting, focusing on planning for neurosurgery.

The widely used electroencephalogram-based indices for depth-of-anesthesia monitoring assume that the same index value defines the same level of unconsciousness for all anesthetics. In contrast, we show that different anesthetics act at different molecular targets and neural circuits to produce distinct brain states that are readily visible in the electroencephalogram. We present a two-part review to educate anesthesiologists on use of the unprocessed electroencephalogram and its spectrogram to track the brain states of patients receiving anesthesia care. Here in part I, we review the biophysics of the electroencephalogram and the neurophysiology of the electroencephalogram signatures of three intravenous anesthetics: propofol, dexmedetomidine, and ketamine, and four inhaled anesthetics: sevoflurane, isoflurane, desflurane, and nitrous oxide. Later in part II, we discuss patient management using these electroencephalogram signatures. Use of these electroencephalogram signatures suggests a neurophysiologically based paradigm for brain state monitoring of patients receiving anesthesia care.

Background: Dabigatran and rivaroxaban are new oral anticoagulants that are eliminated through the kidneys. Their use in dialysis patients is discouraged because these drugs can bioaccumulate to precipitate inadvertent bleeding. We wanted to determine whether prescription of dabigatran or rivaroxaban was occurring in the dialysis population and whether these practices were safe., Methods and Results: Prevalence plots were used to describe the point prevalence (monthly) of dabigatran and rivaroxaban use among 29977 hemodialysis patients with atrial fibrillation. Poisson regression compared the rate of bleeding, stroke, and arterial embolism in patients who started dabigatran, rivaroxaban, or warfarin. The first record of dabigatran prescription among hemodialysis patients occurred 45 days after the drug became available in the United States. Since then, dabigatran and rivaroxaban use in the atrial fibrillation-end-stage renal disease population has steadily risen where 5.9% of anticoagulated dialysis patients are started on dabigatrian or rivaroxaban. In covariate adjusted Poisson regression, dabigatran (rate ratio, 1.48; 95% confidence interval, 1.21-1.81; P=0.0001) and rivaroxaban (rate ratio, 1.38; 95% confidence interval, 1.03-1.83; P=0.04) associated with a higher risk of hospitalization or death from bleeding when compared with warfarin. The risk of hemorrhagic death was even larger with dabigatran (rate ratio, 1.78; 95% confidence interval, 1.18-2.68; P=0.006) and rivaroxaban (rate ratio, 1.71; 95% confidence interval, 0.94-3.12; P=0.07) relative to warfarin. There were too few events in the study to detect meaningful differences in stroke and arterial embolism between the drug groups., Conclusions: More dialysis patients are being started on dabigatran and rivaroxaban, even when their use is contraindicated and there are no studies to support that the benefits outweigh the risks of these drugs in end-stage renal disease., (© 2015 American Heart Association, Inc.)