Search

Objective: To investigate the immediate and short term impact of right coronary artery (RCA) chronic total coronary occlusion (CTO) percutaneous coronary intervention (PCI) upon collateral donor vessel fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR)., Background: CTO PCI influences collateral donor vessel physiology, making the indication and/or timing of donor vessel revascularization difficult to determine., Methods: In patients with RCA CTO, FFR, iFR, and collateral function index (FFR coll ) were measured in LAD and LCx pre-CTO PCI, immediately post and at 4 month follow-up., Results: 34 patients underwent successful PCI. In the predominant donor vessel immediately post PCI, FFR, and FFR coll did not change (0.76 ± 0.12 to 0.75 ± 0.13, P = 0.267 and 0.31 ± 0.10 vs. 0.34 ± 0.11, P = 0.078), but iFR increased significantly (0.86 ± 0.10 to 0.88 ± 0.10, P = 0.012). At follow-up, there was a significant increase in predominant donor FFR and iFR (0.76 ± 0.12 to 0.79 ± 0.11, P = 0.047 and 0.86 ± 0.10 to 0.90 ± 0.07, P = 0.003), accompanied by a significant reduction in FFR coll (0.31 ± 0.10 to 0.18 ± 0.07 P < 0.0001). These changes resulted in a reclassification of the predominant donor vessel from ischemic to nonischemic in 18% (FFR) and 25% (iFR) of the cases, respectively., Conclusions: Successful recanalization of an RCA CTO resulted in a modest but statistically significant increase in the predominant donor vessel immediately post CTO PCI in the case of iFR and at 4-month follow-up for FFR and iFR compared to pre-PCI with a concomitant reduction in collateral function., (© 2018 Wiley Periodicals, Inc.)

Background: Recently, the therapeutic benefits of percutaneous coronary intervention (PCI) have been challenged in patients with stable coronary artery disease (SCD)., Objectives: The authors examined the impact of PCI on exercise responses in the coronary circulation, the microcirculation, and systemic hemodynamics in patients with SCD., Methods: A total of 21 patients (mean age 60.3 ± 8.4 years) with SCD and single-vessel coronary stenosis underwent cardiac catheterization. Pre-PCI, patients exercised on a supine ergometer until rate-limiting angina or exhaustion. Simultaneous trans-stenotic coronary pressure-flow measurements were made throughout exercise. Post-PCI, this process was repeated. Physiological parameters, rate-limiting symptoms, and exercise performance were compared between pre-PCI and post-PCI exercise cycles., Results: PCI reduced ischemia as documented by fractional flow reserve value (pre-PCI 0.59 ± 0.18 to post-PCI 0.91 ± 0.07), instantaneous wave-free ratio value (pre-PCI 0.61 ± 0.27 to post-PCI 0.96 ± 0.05) and coronary flow reserve value (pre-PCI 1.7 ± 0.7 to post-PCI 3.1 ± 1.0; p < 0.001 for all). PCI increased peak-exercise average peak coronary flow velocity (p < 0.0001), coronary perfusion pressure (distal coronary pressure; p < 0.0001), systolic blood pressure (p = 0.01), accelerating wave energy (p < 0.001), and myocardial workload (rate-pressure product; p < 0.01). These changes observed immediately following PCI resulted from the abolition of stenosis resistance (p < 0.0001). PCI was also associated with an immediate improvement in exercise time (+67 s; 95% confidence interval: 31 to 102 s; p < 0.0001) and a reduction in rate-limiting angina symptoms (81% reduction in rate-limiting angina symptoms post-PCI; p < 0.001)., Conclusions: In patients with SCD and severe single-vessel stenosis, objective physiological responses to exercise immediately normalize following PCI. This is seen in the coronary circulation, the microcirculation, and systemic hemodynamics., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to investigate the clinical outcomes of patients deferred from coronary revascularization on the basis of instantaneous wave-free ratio (iFR) or fractional flow reserve (FFR) measurements in stable angina pectoris (SAP) and acute coronary syndromes (ACS)., Background: Assessment of coronary stenosis severity with pressure guidewires is recommended to determine the need for myocardial revascularization., Methods: The safety of deferral of coronary revascularization in the pooled per-protocol population (n = 4,486) of the DEFINE-FLAIR (Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation) and iFR-SWEDEHEART (Instantaneous Wave-Free Ratio Versus Fractional Flow Reserve in Patients With Stable Angina Pectoris or Acute Coronary Syndrome) randomized clinical trials was investigated. Patients were stratified according to revascularization decision making on the basis of iFR or FFR and to clinical presentation (SAP or ACS). The primary endpoint was major adverse cardiac events (MACE), defined as the composite of all-cause death, nonfatal myocardial infarction, or unplanned revascularization at 1 year., Results: Coronary revascularization was deferred in 2,130 patients. Deferral was performed in 1,117 patients (50%) in the iFR group and 1,013 patients (45%) in the FFR group (p < 0.01). At 1 year, the MACE rate in the deferred population was similar between the iFR and FFR groups (4.12% vs. 4.05%; fully adjusted hazard ratio: 1.13; 95% confidence interval: 0.72 to 1.79; p = 0.60). A clinical presentation with ACS was associated with a higher MACE rate compared with SAP in deferred patients (5.91% vs. 3.64% in ACS and SAP, respectively; fully adjusted hazard ratio: 0.61 in favor of SAP; 95% confidence interval: 0.38 to 0.99; p = 0.04)., Conclusions: Overall, deferral of revascularization is equally safe with both iFR and FFR, with a low MACE rate of about 4%. Lesions were more frequently deferred when iFR was used to assess physiological significance. In deferred patients presenting with ACS, the event rate was significantly increased compared with SAP at 1 year., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

It is well known that the apparent significant coronary stenosis on angiography sometimes does not cause significant ischemia, and vice versa. For this reason, decision-making based on coronary physiology is becoming more and more important. Fractional flow reserve (FFR), which has emerged as a useful tool to determine which lesions need revascularization in the catheterization laboratory, now has a class IA indication in the European Society of Cardiology guidelines. More recently, the instantaneous wave-free ratio, which is considered easier to use than FFR, has been graded as equivalent to FFR. This review discusses the concepts of FFR and instantaneous wave-free ratio, current evidence supporting their use, and future directions in coronary physiology., (Copyright © 2018 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Regulation of coronary blood flow is maintained through a delicate balance of ventriculoarterial and neurohumoral mechanisms. The aortic valve is integral to the functions of these systems, and disease states that compromise aortic valve integrity have the potential to seriously disrupt coronary blood flow. Aortic stenosis (AS) is the most common cause of valvular heart disease requiring medical intervention, and the prevalence and associated socio-economic burden of AS are set to increase with population ageing. Valvular stenosis precipitates a cascade of structural, microcirculatory, and neurohumoral changes, which all lead to impairment of coronary flow reserve and myocardial ischaemia even in the absence of notable coronary stenosis. Coronary physiology can potentially be normalized through interventions that relieve severe AS, but normality is often not immediately achievable and probably requires continued adaptation. Finally, the physiological assessment of coronary artery disease in patients with AS represents an ongoing challenge, as the invasive physiological measures used in current cardiology practice are yet to be validated in this population. This Review discusses the key concepts of coronary pathophysiology in patients with AS through presentation of contemporary basic science and data from animal and human studies.

Nanosurfaces have improved clinical osseointegration by increasing bone/implant contact. Neovascularization is considered an essential prerequisite to osteogenesis, but no previous reports to our knowledge have examined the effect of surface topography on the spatio-temporal pattern of neovascularization during peri-implant healing. We have developed a cranial window model to study peri-implant healing intravitally over clinically relevant time scales as a function of implant topography. Quantitative intravital confocal imaging reveals that changing the topography (but not chemical composition) of an implant profoundly affects the pattern of peri-implant neovascularization. New vessels develop proximal to the implant and the vascular network matures sooner in the presence of an implant nanosurface. Accelerated angiogenesis can lead to earlier osseointegration through the delivery of osteogenic precursors to, and direct formation of bone on, the implant surface. This study highlights a critical aspect of peri-implant healing, but also informs the biological rationale for the surface design of putative endosseous implant materials., Competing Interests: The authors declare no competing interests.

HMGB1 and HMGB2 are DNA-interacting proteins but can also have extracellular actions during inflammation. Despite their relatively high homology, they may have distinct roles, making it essential to be able to differentiate between the two. Here we examine the specificity of five commercially-available anti-HMGB1 antibodies. By Western blotting of recombinant proteins and HMGB1-/- mouse embryonic fibroblasts, we identified only one HMGB1 antibody that, under our experimental conditions, did not also detect HMGB2. Selecting specific antibodies for HMGB1 and HMGB2 allowed identification of distinct HMGB1 and HMGB2 subcellular pools in primary neutrophils., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: The authors sought to evaluate the accuracy of instantaneous wave-Free Ratio (iFR) pullback measurements to predict post-percutaneous coronary intervention (PCI) physiological outcomes, and to quantify how often iFR pullback alters PCI strategy in real-world clinical settings., Background: In tandem and diffuse disease, offline analysis of continuous iFR pullback measurement has previously been demonstrated to accurately predict the physiological outcome of revascularization. However, the accuracy of the online analysis approach (iFR pullback) remains untested., Methods: Angiographically intermediate tandem and/or diffuse lesions were entered into the international, multicenter iFR GRADIENT (Single instantaneous wave-Free Ratio Pullback Pre-Angioplasty Predicts Hemodynamic Outcome Without Wedge Pressure in Human Coronary Artery Disease) registry. Operators were asked to submit their procedural strategy after angiography alone and then after iFR-pullback measurement incorporating virtual PCI and post-PCI iFR prediction. PCI was performed according to standard clinical practice. Following PCI, repeat iFR assessment was performed and the actual versus predicted post-PCI iFR values compared., Results: Mean age was 67 ± 12 years (81% male). Paired pre- and post-PCI iFR were measured in 128 patients (134 vessels). The predicted post-PCI iFR calculated online was 0.93 ± 0.05; observed actual iFR was 0.92 ± 0.06. iFR pullback predicted the post-PCI iFR outcome with 1.4 ± 0.5% error. In comparison to angiography-based decision making, after iFR pullback, decision making was changed in 52 (31%) of vessels; with a reduction in lesion number (-0.18 ± 0.05 lesion/vessel; p = 0.0001) and length (-4.4 ± 1.0 mm/vessel; p < 0.0001)., Conclusions: In tandem and diffuse coronary disease, iFR pullback predicted the physiological outcome of PCI with a high degree of accuracy. Compared with angiography alone, availability of iFR pullback altered revascularization procedural planning in nearly one-third of patients., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Intravenously administered mesenchymal stromal cells (MSCs) are rapidly entrapped in the lungs, where they display an anti-inflammatory phenotype. Intramuscular (IM) delivery provides an increased MSC dwell-time, which could result in a sustained modulation of an inflammatory milieu. We studied the therapeutic effects of IM delivered MSCs to treat a distant (contralateral) inflammation, and compared the efficacy of neonatal (umbilical cord) and adult bone marrow MSCs (BMMSCs). Inflammation decreased over 48 h, but neonatal cells showed an earlier response than BMMSCs. Tumor necrosis factor-induced gene-6 (TSG-6) was released at the site of MSC delivery, while neutrophil infiltration was abrogated and inflammation reduced at the contralateral site. MSCs did not distribute to the organs or to the site of inflammation. Thus, IM delivery presents a promising alternative for the treatment of inflammation, and neonatal MSCs may represent a stronger candidate than those derived from adult BM to treat inflammatory diseases.

Background: Diagnostic accuracy is widely accepted by researchers and clinicians as an optimal expression of a test's performance. The aim of this study was to evaluate the effects of disease severity distribution on values of diagnostic accuracy as well as propose a sample-independent methodology to calculate and display accuracy of diagnostic tests., Methods and Findings: We evaluated the diagnostic relationship between two hypothetical methods to measure serum cholesterol (Chol rapid and Chol gold ) by generating samples with statistical software and (1) keeping the numerical relationship between methods unchanged and (2) changing the distribution of cholesterol values. Metrics of categorical agreement were calculated (accuracy, sensitivity and specificity). Finally, a novel methodology to display and calculate accuracy values was presented (the V-plot of accuracies)., Conclusion: No single value of diagnostic accuracy can be used to describe the relationship between tests, as accuracy is a metric heavily affected by the underlying sample distribution. Our novel proposed methodology, the V-plot of accuracies, can be used as a sample-independent measure of a test performance against a reference gold standard., Competing Interests: Competing interests: None declared.

Background: Symptomatic relief is the primary goal of percutaneous coronary intervention (PCI) in stable angina and is commonly observed clinically. However, there is no evidence from blinded, placebo-controlled randomised trials to show its efficacy., Methods: ORBITA is a blinded, multicentre randomised trial of PCI versus a placebo procedure for angina relief that was done at five study sites in the UK. We enrolled patients with severe (≥70%) single-vessel stenoses. After enrolment, patients received 6 weeks of medication optimisation. Patients then had pre-randomisation assessments with cardiopulmonary exercise testing, symptom questionnaires, and dobutamine stress echocardiography. Patients were randomised 1:1 to undergo PCI or a placebo procedure by use of an automated online randomisation tool. After 6 weeks of follow-up, the assessments done before randomisation were repeated at the final assessment. The primary endpoint was difference in exercise time increment between groups. All analyses were based on the intention-to-treat principle and the study population contained all participants who underwent randomisation. This study is registered with ClinicalTrials.gov, number NCT02062593., Findings: ORBITA enrolled 230 patients with ischaemic symptoms. After the medication optimisation phase and between Jan 6, 2014, and Aug 11, 2017, 200 patients underwent randomisation, with 105 patients assigned PCI and 95 assigned the placebo procedure. Lesions had mean area stenosis of 84·4% (SD 10·2), fractional flow reserve of 0·69 (0·16), and instantaneous wave-free ratio of 0·76 (0·22). There was no significant difference in the primary endpoint of exercise time increment between groups (PCI minus placebo 16·6 s, 95% CI -8·9 to 42·0, p=0·200). There were no deaths. Serious adverse events included four pressure-wire related complications in the placebo group, which required PCI, and five major bleeding events, including two in the PCI group and three in the placebo group., Interpretation: In patients with medically treated angina and severe coronary stenosis, PCI did not increase exercise time by more than the effect of a placebo procedure. The efficacy of invasive procedures can be assessed with a placebo control, as is standard for pharmacotherapy., Funding: NIHR Imperial Biomedical Research Centre, Foundation for Circulatory Health, Imperial College Healthcare Charity, Philips Volcano, NIHR Barts Biomedical Research Centre., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Aim of the present study was to perform a meta-analysis of all available studies comparing the instantaneous wave-free ratio (iFR) with fractional flow reserve (FFR)., Methods and Results: Published trials comparing the iFR with FFR were searched for in PubMed, Google Scholar, and Scopus electronic databases. A total of 23 studies were available for the analysis, including 6381 stenoses. First, a meta-analysis of all studies was performed exploring the correlation between FFR and iFR. Interestingly, we found good correlation (0.798 [0.78-0.82]) between the 2 indices ( P <0.001). In addition, to evaluate the diagnostic performance of iFR to identify FFR-positive coronary stenoses, we performed an additional meta-analysis, summarizing the results of receiver operating characteristics analyses from individual studies reporting the area under the curve. Summing the results of these studies, we found that iFR has a good diagnostic performance for the identification of FFR-positive stenoses (area under the curve=0.88 [0.86-0.90]; P <0.001). Furthermore, our search results included 5 studies that compared iFR and FFR to a third independent reference standard. Interestingly, no significant differences between iFR and FFR were reported in those studies., Conclusions: The present meta-analysis shows that iFR significantly correlates with standard FFR and shows a good diagnostic performance in identifying FFR-positive coronary stenoses. Finally, iFR and FFR have similar diagnostic efficiency for detection of ischemia-inducing stenoses when tested against a third comparator., (© 2018 American Heart Association, Inc.)

Tumor necrosis factor alpha (TNF-α) induced protein 6 is a major anti-inflammatory mediator released by activated mesenchymal stromal cells (MSCs). Neonatal MSCs are considered more metabolically active than cells derived from adult tissues, and potentially less heterogeneous. We hypothesized that a TNF-α-activated neonatal MSC population [human umbilical cord perivascular cells (HUCPVCs)] would show an enhanced level of TSG-6 activation compared with adult bone marrow MSCs (BMMSCs). Thus, we stimulated HUCPVCs, and both human BMMSCs (hBMMSCs) and mouse BMMSCs (mBMMSCs) with 1, 10, 50, and 100 ng/mL of recombinant TNF-α over various exposure times. Supernatant, and total RNA, of the cells were collected for measurement of both TSG-6 RNA expression, and secreted TSG-6 protein. To compare gene levels, quantification was done by normalizing the expression levels of TSG-6 to the geometric mean of the three most stable reference genes, out of a cohort of 30 tested genes, using the Pfaffl method. We found that HUCPVCs exhibited both an enhanced and more rapid response to low dose (1 ng/mL) TNF-α exposure resulting in ∼11.5-fold increase in TSG-6 expression within the first 30 min. In contrast, hBMMSCs showed 2-fold increase by 1 h that increased to 9.5-fold with a higher (50 ng/mL) TNF-α exposure for the same time. mBMMSCs showed a two-fold increase after 24 h that was independent of TNF-α concentration. Thus, although TSG-6 expression level varied among donors, both hMSC populations exhibited enhanced TSG-6 upregulation, upon TNF-α stimulation, compared with mBMMSCs. In conclusion, HUCPVCs showed higher sensitivity, and a prompter response to TNF-α stimulation compared with hBMMSCs. Thus, neonatal MSCs may be a stronger candidate population than those derived from adult bone marrow to treat inflammatory diseases.

Objectives: The study sought to determine the coronary flow characteristics of angiographically intermediate stenoses classified as discordant by fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR)., Background: Discordance between FFR and iFR occurs in up to 20% of cases. No comparisons have been reported between the coronary flow characteristics of FFR/iFR discordant and angiographically unobstructed vessels., Methods: Baseline and hyperemic coronary flow velocity and coronary flow reserve (CFR) were compared across 5 vessel groups: FFR+/iFR+ (108 vessels, n = 91), FFR-/iFR+ (28 vessels, n = 24), FFR+/iFR- (22 vessels, n = 22), FFR-/iFR- (208 vessels, n = 154), and an unobstructed vessel group (201 vessels, n = 153), in a post hoc analysis of the largest combined pressure and Doppler flow velocity registry (IDEAL [Iberian-Dutch-English] collaborators study)., Results: FFR disagreed with iFR in 14% (50 of 366). Baseline flow velocity was similar across all 5 vessel groups, including the unobstructed vessel group (p = 0.34 for variance). In FFR+/iFR- discordants, hyperemic flow velocity and CFR were similar to both FFR-/iFR- and unobstructed groups; 37.6 (interquartile range [IQR]: 26.1 to 50.4) cm/s vs. 40.0 [IQR: 29.7 to 52.3] cm/s and 42.2 [IQR: 33.8 to 53.2] cm/s and CFR 2.36 [IQR: 1.93 to 2.81] vs. 2.41 [IQR: 1.84 to 2.94] and 2.50 [IQR: 2.11 to 3.17], respectively (p > 0.05 for all). In FFR-/iFR+ discordants, hyperemic flow velocity, and CFR were similar to the FFR+/iFR+ group; 28.2 (IQR: 20.5 to 39.7) cm/s versus 23.5 (IQR: 16.4 to 34.9) cm/s and CFR 1.44 (IQR: 1.29 to 1.85) versus 1.39 (IQR: 1.06 to 1.88), respectively (p > 0.05 for all)., Conclusions: FFR/iFR disagreement was explained by differences in hyperemic coronary flow velocity. Furthermore, coronary stenoses classified as FFR+/iFR- demonstrated similar coronary flow characteristics to angiographically unobstructed vessels., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: The use of contrast media with multidetector computed tomography (MDCT) may induce acute kidney injury in patients with renal failure undergoing transcatheter aortic valve replacement (TAVR). We investigated the role of large-field intravascular ultrasound (IVUS) vs. MDCT and two-dimensional transoesophageal echocardiography (2D-TEE) for annular sizing and predicting paravalvular regurgitation (PVR) during TAVR., Methods and Results: The aortic annulus was measured by large-field IVUS and 2D-TEE, and compared with MDCT in 50 patients undergoing TAVR. The IVUS and MDCT annular areas and diameters were not significantly different (446 ± 87 mm2 and 23.8 ± 84 mm vs. 466 ± 84 mm2 and 24 ± 2.1 mm, respectively; P > 0.05). IVUS and MDCT mean annular diameters were significantly greater than TEE diameter (23.8 ± 2.4 and 24 ± 2.1 vs. 22 ± 0.65 mm, respectively; P < 0.01). PVR ≥ Mild occurred in 13 patients (26%); 5 patients required post-dilation and 2 patients a second valve. Receiver operating characteristic analyses showed that transcatheter heart valve (THV) area - IVUS or MDCT areas equally predicted of ≥ mild PVR (areas under the curve [AUC] 0.79 and 0.81, respectively; P < 0.001), and were greater than THV diameter-TEE diameter (AUC 0.79 and 0.81 vs. 0.56, respectively; P < 0.05)., Conclusions: The aortic annular measurements and predicting PVR by large field IVUS were not significantly different from those of MDCT, but were greater than those of TEE. Large filed IVUS can be reliably used in lieu of MDCT for annular sizing in patients with aortic stenosis and renal failure or suboptimal MDCT images., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)

Background: In contrast to systemic hypertension, the significance of arterial waves in pulmonary hypertension (PH) is not well understood. We hypothesized that arterial wave energy and wave reflection are augmented in PH and that wave behavior differs between patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH)., Methods and Results: Right heart catheterization was performed using a pressure and Doppler flow sensor-tipped catheter to obtain simultaneous pressure and flow velocity measurements in the pulmonary artery. Wave intensity analysis was subsequently applied to the acquired data. Ten control participants, 11 patients with PAH, and 10 patients with CTEPH were studied. Wave speed and wave power were significantly greater in PH patients compared with controls, indicating increased arterial stiffness and right ventricular work, respectively. The ratio of wave power to mean right ventricular power was lower in PAH patients than CTEPH patients and controls. Wave reflection index in PH patients (PAH: ≈25%; CTEPH: ≈30%) was significantly greater compared with controls (≈4%), indicating downstream vascular impedance mismatch. Although wave speed was significantly correlated to disease severity, wave reflection indexes of patients with mildly and severely elevated pulmonary pressures were similar., Conclusions: Wave reflection in the pulmonary artery increased in PH and was unrelated to severity, suggesting that vascular impedance mismatch occurs early in the development of pulmonary vascular disease. The lower wave power fraction in PAH compared with CTEPH indicates differences in the intrinsic and/or extrinsic ventricular load between the 2 diseases., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Age-related (type-II) osteoporosis is a common and debilitating condition driven in part by the loss of bone marrow (BM) mesenchymal stromal cells (MSC) and their osteoblast progeny, leading to reduced bone formation. Current pharmacological regiments targeting age-related osteoporosis do not directly treat the disease by increasing bone formation, but instead use bisphosphonates to reduce bone resorption-a treatment designed for postmenopausal (type-I) osteoporosis. Recently, the bone regenerative capacity of MSCs has been found within a very rare population of skeletal stem cells (SSCs) residing within the larger heterogeneous BM-MSC pool. The osteoregenerative potential of SSCs would be an ideal candidate for cell-based therapies to treat degenerative bone diseases such as osteoporosis. However, to date, clinical and translational studies attempting to improve bone formation through cell transplantation have used the larger, nonspecific, MSC pool. In this review, we will outline the physiological basis of age-related osteoporosis, as well as discuss relevant preclinical studies that use exogenous MSC transplantation with the aim of treating osteoporosis in murine models. We will also discuss results from specific clinical trials aimed at treating other systemic bone diseases, and how the discovery of SSC could help realize the full regenerative potential of MSC therapy to increase bone formation. Finally, we will outline how ancillary clinical trials could be initiated to assess MSC/SSC-mediated bone formation gains in existing and potentially unrelated clinical trials, setting the stage for a dedicated clinical investigation to treat age-related osteoporosis. Stem Cells Translational Medicine 2017;6:1930-1939., (© 2017 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Introduction: The development and propagation of the aortic blood pressure wave remains poorly understood, despite its clear relevance to major organ blood flow and potential association with cardiovascular outcomes. The reservoir pressure model provides a unified description of the dual conduit and reservoir functions of the aorta. Reservoir waveform analysis resolves the aortic pressure waveform into an excess (wave related) and reservoir (compliance related) pressure. The applicability of this model to the pressure waveform as it propagates along the aorta has not been investigated in humans., Methods: We analysed invasively acquired high-fidelity aortic pressure waveforms from 40 patients undergoing clinically indicated coronary catheterization. Aortic waveforms were measured using a solid-state pressure catheter at five anatomical sites: the ascending aorta, the transverse aortic arch, the diaphragm, the level of the renal arteries, and at the aortic bifurcation. Ensemble average pressure waveforms were obtained for these sites for each patient and analysed to obtain the reservoir pressure [Pr(t)] and the excess pressure [Px(t)] at each aortic position., Results: Systolic blood pressure increased at a rate of 2.1 mmHg per site along the aorta, whereas diastolic blood pressure was effectively constant. Maximum Pr decreased only slightly along the aorta (changing by -0.7 mmHg per site), whereas the maximum of Px increased from the proximal to distal aorta (+4.1 mmHg per site; P < 0.001). The time, relative to the start of systolic upstroke, of the occurrence of the maximum excess pressure did not vary along the aorta. Of the parameters used to derive the reservoir pressure waveform the systolic and diastolic rate constants showed divergent changes with the systolic rate constant (ks) decreasing and the diastolic rate constant (kd) increasing along the aorta., Conclusions: This analysis confirms the proposition that the magnitude of the calculated reservoir pressure waveform, despite known changes in aortic structure, is effectively constant throughout the aorta. A progressive increase of excess pressure accounts for the increase in pulse pressure from the proximal to distal aorta. The reservoir pressure rate constants seem to behave as arterial functional parameters. The accompanying decrease in ks and increase in kd are consistent with a progressive decrease in aortic compliance and increase in impedance. The reservoir pressure waveform therefore provides a model that might have utility in understanding the generation of central blood pressure and in specific cases might have clinical utility.

The human microbiome is a collection of microorganisms that inhabit every surface of the body that is exposed to the environment, generally coexisting peacefully with their host. These microbes have important functions, such as producing vitamins, aiding in maturation of the immune system, and protecting against pathogens. We have previously shown that a small-molecule extract from the human fecal microbiome has a strong repressive effect on Salmonella enterica serovar Typhimurium host cell invasion by modulating the expression of genes involved in this process. Here, we describe the characterization of this biological activity. Using a series of purification methods, we obtained fractions with biological activity and characterized them by mass spectrometry. These experiments revealed an abundance of aromatic compounds in the bioactive fraction. Selected compounds were obtained from commercial sources and tested with respect to their ability to repress the expression of hilA , the gene encoding the master regulator of invasion genes in Salmonella We found that the aromatic compound 3,4-dimethylbenzoic acid acts as a strong inhibitor of hilA expression and of invasion of cultured host cells by Salmonella Future studies should reveal the molecular details of this phenomenon, such as the signaling cascades involved in sensing this bioactive molecule. IMPORTANCE Microbes constantly sense and adapt to their environment. Often, this is achieved through the production and sensing of small extracellular molecules. The human body is colonized by complex communities of microbes, and, given their biological and chemical diversity, these ecosystems represent a platform where the production and sensing of molecules occur. In previous work, we showed that small molecules produced by microbes from the human gut can significantly impair the virulence of the enteric pathogen Salmonella enterica Here, we describe a specific compound from the human gut that produces this same effect. The results from this work not only shed light on an important biological phenomenon occurring in our bodies but also may represent an opportunity to develop drugs that can target these small-molecule interactions to protect us from enteric infections and other diseases., (Copyright © 2017 American Society for Microbiology.)

In this review, the authors reflect upon the role of coronary physiology in the modern management of coronary artery disease. They critically appraise the scientific background of the instantaneous wave-free ratio (iFR) and fractional flow reserve (FFR), from early experimental studies to validation studies against indexes of ischemia, to clinical trials assessing outcome. At this important juncture for the field, the authors make predictions for the future of physiological stenosis assessment, outlining developments for both iFR and FFR in new clinical domains beyond the confines of stable angina. With a focus on the evolving future of iFR and FFR, the authors describe how physiological assessment with iFR may advance its application from simply justifying to guiding revascularization., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Arterial reservoir characteristics are related to blood pressure (BP) and independently predict cardiovascular events. It is unknown if arterial reservoir characteristics are modified from the central-to-peripheral large arteries and whether there is a contributory role to BP amplification. The aim of this study was to assess central-to-peripheral changes in arterial reservoir characteristics and determine associations with BP., Methods: Reservoir pressure (RP) and excess pressure (XSP) were derived from intra-arterial BP waveforms among 51 participants (aged 63 ± 13 years, 63% men) undergoing clinically indicated cardiac angiography. BP waveforms were recorded in the ascending aorta, brachial (mid-humerus) and radial (wrist) arteries via catheter pull-back., Results: There was no significant difference in RP between arterial sites (54 ± 15, 53 ± 15 and 52 ± 17 mmHg for the aorta, brachial and radial artery, respectively; P = 0.68). Conversely, XSP increased stepwise from the aorta to the brachial and radial arteries (24 ± 11, 42 ± 14 and 53 ± 16 mmHg; P < 0.001), as did SBP (134 ± 18, 141 ± 16 and 146 ± 19 mmHg; P = 0.004). There were highly significant associations between RP and SBP at all arterial sites (r = 0.821, 0.649 and 0.708; P < 0.001 for all), but the strength of associations between peak XSP and SBP increased significantly from the aorta to the radial artery (r = 0.121 and 0.508; z = 3.04; P = 0.004)., Conclusion: Arterial reservoir characteristics are modified through the large arteries of the upper limb. Although RP remains relatively constant, XSP increases significantly and is highly related to BP (SBP and pulse pressure) amplification. These data provide a new understanding on arterial reservoir characteristics and large-artery BP physiology.

Changes in the T cell surface redox environment regulate critical cell functions, such as cell migration, viral entry and cytokine production. Cell surface protein disulfide isomerase (PDI) contributes to the regulation of T cell surface redox status. Cell surface PDI can be released into the extracellular milieu or can be internalized by T cells. We have found that galectin-9, a soluble lectin expressed by T cells, endothelial cells and dendritic cells, binds to and retains PDI on the cell surface. While endogenous galectin-9 is not required for basal cell surface PDI expression, exogenous galectin-9 mediated retention of cell surface PDI shifted the disulfide/thiol equilibrium on the T cell surface. O-glycans on PDI are required for galectin-9 binding, and PDI recognition appears to be specific for galectin-9, as galectin-1 and galectin-3 do not bind PDI. Galectin-9 is widely expressed by immune and endothelial cells in inflamed tissues, suggesting that T cells would be exposed to abundant galectin-9, in cis and in trans, in infectious or autoimmune conditions., (© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Limited data exist regarding transcatheter mitral valve replacement (TMVR) for patients with failed mitral valve replacement and repair., Objectives: This study sought to evaluate the outcomes of TMVR in patients with failed mitral bioprosthetic valves (valve-in-valve [ViV]) and annuloplasty rings (valve-in-ring [ViR])., Methods: From the TMVR multicenter registry, procedural and clinical outcomes of mitral ViV and ViR were compared according to Mitral Valve Academic Research Consortium criteria., Results: A total of 248 patients with mean Society of Thoracic Surgeons score of 8.9 ± 6.8% underwent TMVR. Transseptal access and the balloon-expandable valve were used in 33.1% and 89.9%, respectively. Compared with 176 patients undergoing ViV, 72 patients undergoing ViR had lower left ventricular ejection fraction (45.6 ± 17.4% vs. 55.3 ± 11.1%; p < 0.001). Overall technical and device success rates were acceptable, at 92.3% and 85.5%, respectively. However, compared with the ViV group, the ViR group had lower technical success (83.3% vs. 96.0%; p = 0.001) due to more frequent second valve implantation (11.1% vs. 2.8%; p = 0.008), and lower device success (76.4% vs. 89.2%; p = 0.009) due to more frequent reintervention (16.7% vs. 7.4%; p = 0.03). Mean mitral valve gradients were similar between groups (6.4 ± 2.3 mm Hg vs. 5.8 ± 2.7 mm Hg; p = 0.17), whereas the ViR group had more frequent post-procedural mitral regurgitation moderate or higher (19.4% vs. 6.8%; p = 0.003). Furthermore, the ViR group had more frequent life-threatening bleeding (8.3% vs. 2.3%; p = 0.03), acute kidney injury (11.1% vs. 4.0%; p = 0.03), and subsequent lower procedural success (58.3% vs. 79.5%; p = 0.001). The 1-year all-cause mortality rate was significantly higher in the ViR group compared with the ViV group (28.7% vs. 12.6%; log-rank test, p = 0.01). On multivariable analysis, failed annuloplasty ring was independently associated with all-cause mortality (hazard ratio: 2.70; 95% confidence interval: 1.34 to 5.43; p = 0.005)., Conclusions: The TMVR procedure provided acceptable outcomes in high-risk patients with degenerated bioprostheses or failed annuloplasty rings, but mitral ViR was associated with higher rates of procedural complications and mid-term mortality compared with mitral ViV., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Alternative therapeutic approaches have been explored to modulate host response to periodontal disease. Knowledge of new strategies to treat periodontitis is particularly relevant in patients presenting augmented risk to periodontitis, such as smokers. The aim of this study is to investigate the impact of resveratrol (RESV) on progression of experimental periodontitis (EP) in the presence of cigarette smoke inhalation (CSI)., Methods: Rats were assigned to one of three groups: 1) CSI+RESV (n = 20); 2) CSI+placebo (n = 20); and 3) non-CSI (n = 20). CSI was initiated 1 week prior to initiation of RESV or placebo administration (systemically for 30 days) and was continued until the end of the study. EP was induced around the first mandibular and second maxillary molars using ligatures. Specimens from the mandible were processed for morphometric and microcomputed tomography examination of bone volume/levels. Gingival tissues surrounding mandibular molars were collected for quantification of interleukin (IL)-1β, IL-4, IL-6, IL-17, and tumor necrosis factor-α using an assay system. Additional analyses of immunoinflammatory mediator performance (T-helper Type 17 [Th17]/Th2 and Th1/Th2 cell levels) were performed according to Th cell responses in gingival tissues. Gingival tissues of maxillary molars were subjected to real-time polymerase chain reaction for assessment of osteoprotegrin, runt-related transcription factor-2, receptor activator of nuclear factor-kappa B ligand (RANKL), sclerostin, and Dickkopf Wnt signaling pathway inhibitor 1 levels., Results: Higher linear alveolar bone loss (ABL) and lower interradicular bone density were detected in ligated molars in the CSI+placebo group (P <0.05). IL-4 level was the highest, and Th17/Th2 levels were the lowest in RESV-treated rats compared with placebo rats (P <0.05). RESV reduced expression of messenger RNA for RANKL in animals receiving CSI (P <0.05)., Conclusion: RESV inhibits EP and CSI-induced supporting ABL and has a beneficial effect on osteo-immunoinflammatory markers.

Background: Hypertension (HTN) is the single greatest cardiovascular risk factor worldwide. HTN management is usually guided by brachial cuff blood pressure (BP), but questions have been raised regarding accuracy., Objectives: This comprehensive analysis determined the accuracy of cuff BP and the consequent effect on BP classification compared with intra-arterial BP reference standards., Methods: Three individual participant data meta-analyses were conducted among studies (from the 1950s to 2016) that measured intra-arterial aortic BP, intra-arterial brachial BP, and cuff BP., Results: A total of 74 studies with 3,073 participants were included. Intra-arterial brachial systolic blood pressure (SBP) was higher than aortic values (8.0 mm Hg; 95% confidence interval [CI]: 5.9 to 10.1 mm Hg; p < 0.0001) and intra-arterial brachial diastolic BP was lower than aortic values (-1.0 mm Hg; 95% CI: -2.0 to -0.1 mm Hg; p = 0.038). Cuff BP underestimated intra-arterial brachial SBP (-5.7 mm Hg; 95% CI: -8.0 to -3.5 mm Hg; p < 0.0001) but overestimated intra-arterial diastolic BP (5.5 mm Hg; 95% CI: 3.5 to 7.5 mm Hg; p < 0.0001). Cuff and intra-arterial aortic SBP showed a small mean difference (0.3 mm Hg; 95% CI: -1.5 to 2.1 mm Hg; p = 0.77) but poor agreement (mean absolute difference 8.0 mm Hg; 95% CI: 7.1 to 8.9 mm Hg). Concordance between BP classification using the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure cuff BP (normal, pre-HTN, and HTN stages 1 and 2) compared with intra-arterial brachial BP was 60%, 50%, 53%, and 80%, and using intra-arterial aortic BP was 79%, 57%, 52%, and 76%, respectively. Using revised intra-arterial thresholds based on cuff BP percentile rank, concordance between BP classification using cuff BP compared with intra-arterial brachial BP was 71%, 66%, 52%, and 76%, and using intra-arterial aortic BP was 74%, 61%, 56%, and 65%, respectively., Conclusions: Cuff BP has variable accuracy for measuring either brachial or aortic intra-arterial BP, and this adversely influences correct BP classification. These findings indicate that stronger accuracy standards for BP devices may improve cardiovascular risk management., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Importance: Computed tomography-derived fractional flow reserve (FFR-CT) is a novel, noninvasive test for myocardial ischemia. Clinicians using FFR-CT must be able to interpret individual FFR-CT results to determine subsequent patient care., Objective: To provide clinicians a means of interpreting individual FFR-CT results with respect to the range of invasive FFRs that this interpretation might likely represent., Evidence Review: We performed a systematic review in accordance with guidelines from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. A systematic search of MEDLINE (January 1, 2011, to 2016, week 2) and EMBASE (January 1, 2011, to 2016, week 2) was performed for studies assessing the diagnostic accuracy of FFR-CT. Title words used were computed tomography or computed tomographic and fractional flow reserve or FFR. Results were limited to publications in peer-reviewed journals. Duplicate studies and abstracts from scientific meetings were removed. All of the retrieved studies, including references, were reviewed., Findings: There were 908 vessels from 536 patients in 5 studies included in the analysis. A total of 365 (68.1%) were male, and the mean (SD) age was 63.2 (9.5) years. The overall per-vessel diagnostic accuracy of FFR-CT was 81.9% (95% CI, 79.4%-84.4%). For vessels with FFR-CT values below 0.60, 0.60 to 0.70, 0.70 to 0.80, 0.80 to 0.90, and above 0.90, diagnostic accuracy of FFR-CT was 86.4% (95% CI, 78.0%-94.0%), 74.7% (95% CI, 71.9%-77.5%), 46.1% (95% CI, 42.9%-49.3%), 87.3% (95% CI, 85.1%-89.5%), and 97.9% (95% CI, 97.9%-98.8%), respectively. The 82% (overall) diagnostic accuracy threshold was met for FFR-CT values lower than 0.63 or above 0.83. More stringent 95% and 98% diagnostic accuracy thresholds were met for FFR-CT values lower than 0.53 or above 0.93 and lower than 0.47 or above 0.99, respectively., Conclusions and Relevance: The diagnostic accuracy of FFR-CT varies markedly across the spectrum of disease. This analysis allows clinicians to interpret the diagnostic accuracy of individual FFR-CT results. In combination with patient-specific factors, clinicians can use FFR-CT to judge when the cost and risk of an invasive angiogram may safely be avoided.

The umbilical cord has become an increasingly used source of mesenchymal stromal cells for preclinical and, more recently, clinical studies. Despite the increased activity, several aspects of this cell population have been under-appreciated. Key issues are that consensus on the anatomical structures within the cord is lacking, and potentially different populations are identified as arising from a single source. To help address these points, we propose a histologically based nomenclature for cord structures and provide an analysis of their developmental origins and composition. Methods of cell isolation from Wharton's jelly are discussed and the immunophenotypic and clonal characteristics of the cells are evaluated. The perivascular origin of the cells is also addressed. Finally, clinical trials with umbilical cord cells are briefly reviewed. Interpreting the outcomes of the many clinical studies that have been undertaken with mesenchymal stromal cells from different tissue sources has been challenging, for many reasons. It is, therefore, particularly important that as umbilical cord cells are increasingly deployed therapeutically, we strive to better understand the derivation and functional characteristics of the cells from this important tissue source. Stem Cells Translational Medicine 2017;6:1620-1630., (© 2017 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Fractional flow reserve (FFR) is increasingly used to guide myocardial revascularisation. However, supporting evidence regarding its use originates from studies that have enrolled mainly patients with stable angina, while patients with acute coronary syndromes (ACS) have not been included. Notably, multifactorial microvascular dysfunction and an increased sympathetic tone in patients with ACS may lead to blunted response to adenosine and false-negative results of FFR due to submaximal hyperaemia. This may raise the possibility of deferring treatment of stenosis that instead would have needed dilatation, thus leaving a residual risk of preventable cardiac events. In this literature review, we aim at summarising laboratory and clinical investigations concerning the use of FFR in culprit and non-culprit lesions in ACS. Furthermore, we will report recent data on instantaneous wave-free ratio, an adenosine-free index of functional stenosis severity, in stable coronary artery disease and in patients with ACS., Competing Interests: Competing interests: None declared.

Background: Coronary revascularization guided by fractional flow reserve (FFR) is associated with better patient outcomes after the procedure than revascularization guided by angiography alone. It is unknown whether the instantaneous wave-free ratio (iFR), an alternative measure that does not require the administration of adenosine, will offer benefits similar to those of FFR., Methods: We randomly assigned 2492 patients with coronary artery disease, in a 1:1 ratio, to undergo either iFR-guided or FFR-guided coronary revascularization. The primary end point was the 1-year risk of major adverse cardiac events, which were a composite of death from any cause, nonfatal myocardial infarction, or unplanned revascularization. The trial was designed to show the noninferiority of iFR to FFR, with a margin of 3.4 percentage points for the difference in risk., Results: At 1 year, the primary end point had occurred in 78 of 1148 patients (6.8%) in the iFR group and in 83 of 1182 patients (7.0%) in the FFR group (difference in risk, -0.2 percentage points; 95% confidence interval [CI], -2.3 to 1.8; P<0.001 for noninferiority; hazard ratio, 0.95; 95% CI, 0.68 to 1.33; P=0.78). The risk of each component of the primary end point and of death from cardiovascular or noncardiovascular causes did not differ significantly between the groups. The number of patients who had adverse procedural symptoms and clinical signs was significantly lower in the iFR group than in the FFR group (39 patients [3.1%] vs. 385 patients [30.8%], P<0.001), and the median procedural time was significantly shorter (40.5 minutes vs. 45.0 minutes, P=0.001)., Conclusions: Coronary revascularization guided by iFR was noninferior to revascularization guided by FFR with respect to the risk of major adverse cardiac events at 1 year. The rate of adverse procedural signs and symptoms was lower and the procedural time was shorter with iFR than with FFR. (Funded by Philips Volcano; DEFINE-FLAIR ClinicalTrials.gov number, NCT02053038 .).

Objectives: The authors sought to compare the diagnostic performance of fractional flow reserve (FFR), instantaneous wave-free ratio (iFR), and resting distal coronary artery pressure/aortic pressure (Pd/Pa) using 13 N-ammonia positron emission tomography (PET)., Background: The diagnostic performance of invasive physiological indices was reported to be different according to the reference to define the presence of myocardial ischemia., Methods: A total of 115 consecutive patients with left anterior descending artery stenosis who underwent both 13 N-ammonia PET and invasive physiological measurement were included. Optimal cutoff values and diagnostic performance of FFR, iFR, and resting Pd/Pa were assessed using PET-derived coronary flow reserve (CFR) and relative flow reserve (RFR) as references. To compare discrimination and reclassification ability, each index was compared with integrated discrimination improvement (IDI) and category-free net reclassification index (NRI)., Results: All invasive physiological indices correlated with CFR and RFR (all p values <0.001). The overall diagnostic accuracies of FFR, iFR, and resting Pd/Pa were not different for CFR <2.0 (FFR 69.6%, iFR 73.9%, and resting Pd/Pa 70.4%) and RFR <0.75 (FFR 73.9%, iFR 71.3%, and resting Pd/Pa 74.8%). Discrimination and reclassification abilities of invasive physiological indices were comparable for CFR. For RFR, FFR showed better discrimination and reclassification ability than resting indices (IDI = 0.170 and category-free NRI = 0.971 for iFR; IDI = 0.183 and category-free NRI = 1.058 for resting Pd/Pa; all p values <0.001)., Conclusions: The diagnostic performance of invasive physiological indices showed no differences in the prediction of myocardial ischemia defined by CFR. Using RFR as a reference, FFR showed a better discrimination and reclassification ability than resting indices., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Wave intensity analysis (WIA) is a technique developed from the field of gas dynamics that is now being applied to assess cardiovascular physiology. It allows quantification of the forces acting to alter flow and pressure within a fluid system, and as such it is highly insightful in ascribing cause to dynamic blood pressure or velocity changes. When co-incident waves arrive at the same spatial location they exert either counteracting or summative effects on flow and pressure. WIA however allows waves of different origins to be measured uninfluenced by other simultaneously arriving waves. It therefore has found particular applicability within the coronary circulation where both proximal (aortic) and distal (myocardial) ends of the coronary artery can markedly influence blood flow. Using these concepts, a repeating pattern of 6 waves has been consistently identified within the coronary arteries, 3 originating proximally and 3 distally. Each has been associated with a particular part of the cardiac cycle. The most clinically relevant wave to date is the backward decompression wave, which causes the marked increase in coronary flow velocity observed at the start of the diastole. It has been proposed that this wave is generated by the elastic re-expansion of the intra-myocardial blood vessels that are compressed during systolic contraction. Particularly by quantifying this wave, WIA has been used to provide mechanistic and prognostic insight into a number of conditions including aortic stenosis, left ventricular hypertrophy, coronary artery disease and heart failure. It has proven itself to be highly sensitive and as such a number of novel research directions are encouraged where further insights would be beneficial.

Using a human cathepsin K-targeting inhibitor screen, a new leupeptin analogue, leupeptazin (1), containing an unprecedented piperidinotriazine moiety, was isolated from a liquid culture of soil Streptomyces sp. IS2-4 collected in northern Italy. The structure of leupeptazin was established using HRESIMS as well as 1D and 2D NMR data. The inhibitory activity of the compound towards the collagenase cathepsin K was tested in vitro to reveal moderate activity with an inhibition constant, K i , of 44μM., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Tinnitus is often associated with strong negative thoughts and emotions which can contribute to a distressing and chronic long-term condition. The amygdala, the "feeling and reacting" part of the brain, may play a key role in this process. Although implicated in several theoretical models of tinnitus, quantification of activity in the human amygdala has only been made possible more recently through neuroimaging methods such as functional magnetic resonance imaging (fMRI) but benefits from modified scanning parameters using a double-echo acquisition for improved BOLD sensitivity. This study thus examined the role of the amygdala in emotional sound processing in people with tinnitus using a novel double-echo imaging sequence for optimal detectability of subcortical activity. Our hypotheses were: (1) emotionally evocative sound clips rated as pleasant or unpleasant would elicit stronger amygdalar activation than sound clips rated as neutral, (2) people with tinnitus have greater amygdalar activation in response to emotionally evocative sounds (relative to neutral sounds) compared to controls. Methods: Twelve participants all with chronic, constant tinnitus took part. We also recruited 11 age and hearing-matched controls. Participants listened to a range of emotionally evocative sound clips; rated as pleasant, unpleasant or neutral. A region-of-interest analysis was chosen to test our a priori hypotheses. Results: Both groups displayed a robust and similar overall response to sounds vs. silence in the following ascending auditory pathways; inferior colliculus, medial geniculate body and the primary auditory cortex. In support of our first hypothesis, the amygdala's response to pleasant and unpleasant sound clips was significantly greater than neutral sounds. Opposing our second hypothesis, we found that the amygdala's overall response to pleasant and unpleasant sounds (compared to neutral sounds) was actually lower in the tinnitus group as compared to the controls. Conclusions: The "muted" amygdala activation observed in the tinnitus group could reflect an internal modification of emotional response perhaps as a result of successful habituation to emotionally negative sound. This interpretation would predict a heightened amygdala emotional response in individuals with a more clinically bothersome tinnitus.

Background & Aims: Objective evidence about the risks associated with anorexia nervosa and how to manage them, is limited. The aim of this study is to describe the medical risk profile, management and outcomes of a cohort of patients with severe anorexia nervosa (sAN) during medical stabilisation treatment., Methods: Retrospective analysis of case records gathered medical risk data for a 90 day high risk period, on 65 patients with sAN admitted to two specialist services. Prospectively established definitions of medical risk variables and significant complications were applied to the data to describe the risk profiles and outcomes., Results: Amongst this population with an average initial BMI of 12.8 kg/m 2 , 74% developed no significant medical complications. Oral re-feeding over 60 days achieved an increase in mean BMI to 14.4 kg/m 2 and mean weight gain of 4 kg. No patients developed severe hypophosphatemia (<0.45 mmol/L) or any other indicators of a re-feeding syndrome. All the medical complications that arose were temporary., Conclusions: Initial re-feeding and medical stabilisation of patients with severe AN can be managed safely in specialist inpatient and community settings with slow re-feeding. Although the prevalence of complications was shown to be low, slight worsening of medical risk markers and increased incidence of complications did occur during initial re-feeding. The limited comparable published data appears to support slower rates of re-feeding, showing fewer abnormal results and complications. There is however a need for a definitive prospective multi-centre observational cohort study to investigate risks factors, and the effects of treatment on medical outcomes, in a large sample with varied rates of re-feeding., (Copyright © 2016 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Background: There is a paucity of information available regarding the impact of cardiac surgical procedures on patients who have undergone previous liver transplantation. The primary purpose of this study was to ascertain the survival rate and predictors of death in this specific patient population., Methods: This retrospective cohort study consisted of a consecutive series of patients with a functioning liver allograft who subsequently underwent cardiac surgical procedures between January 1991 and December 2012. The optimal Model for End-Stage Liver Disease (MELD) score for predicting late death was identified using receiver operating characteristic curve analysis. Risk of postoperative death was determined by parametric hazard analysis., Results: Between January 1991 and December 2012, 43 patients (median age, 60 years) underwent cardiac surgical procedures after liver transplantation. The median interval between liver transplant and cardiac operation was 63 months (range, 1.1 to 217 months). Three operative deaths and 24 late deaths occurred. Receiver operating characteristic curve analysis identified the optimal preoperative and postoperative MELD score cut points for predicting late death as greater than 13.8 (area under the curve = 0.674) and greater than 17 (area under the curve = 0.633), respectively. Patients with a preoperative MELD score of 13.8 or less had significantly greater survival rates than those with a MELD score greater than 13.8 (p = 0.028); patients with a postoperative MELD score of 17 of less had significantly greater survival rates than those with a MELD score greater than 17 (p < 0.001). Multivariate parametric hazard analysis identified postoperative peak creatinine level as a statistically significant predictor of death (relative risk, 1.8; p = 0.01). The 1-, 5-, and 10-year Kaplan-Meier survival rates were 90%, 51%, and 35%, respectively; postoperative mortality rates followed a constant phase model with a hazard of death of 10% per year., Conclusions: Cardiac surgical procedures can be performed with acceptable short-term and long-term outcomes in liver transplant recipients. Elevated preoperative and postoperative MELD scores and postoperative peak creatinine level may portend death in this cohort. There is a constant hazard of death of 10% per year., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Proenkephalin A (PENK) and its receptors are widely distributed. Enkephalins are cardiodepressive and difficult to measure directly. PENK is a stable surrogate analyte of labile enkephalins that is correlated inversely with renal function. Cardiorenal syndrome is common in acute heart failure (HF) and portends poor prognosis., Objectives: This study assessed the prognostic value of PENK in acute HF, by identifying levels that may be useful in clinical decisions, and evaluated its utility for predicting cardiorenal syndrome., Methods: This multicenter study measured PENK in 1,908 patients with acute HF (1,186 male; mean age 75.66 ± 11.74 years). The primary endpoint was 1-year all-cause mortality; secondary endpoints were in-hospital mortality, all-cause mortality or HF rehospitalization within 1 year, and in-hospital worsening renal function, defined as a rise in plasma creatinine ≥26.5 μmol/l or 50% higher than the admission value within 5 days of presentation., Results: During 1-year follow-up, 518 patients died. Measures of renal function were the major determinants of PENK levels. PENK independently predicted worsening renal function (odds ratio: 1.58; 95% confidence interval [CI]: 1.24 to 2.00; p < 0.0005) with a model receiver-operating characteristic area of 0.69. PENK was associated with the degree of worsening renal function. Multivariable Cox regression models showed that PENK level was an independent predictor of 1-year mortality (p < 0.0005) and 1-year death and/or HF (hazard ratio: 1.27; 95% CI: 1.10 to 1.45; p = 0.001). PENK levels independently predicted outcomes at 3 or 6 months and were independent predictors of in-hospital mortality, predominantly down-classifying risk in survivors when added to clinical scores; levels <133.3 pmol/l and >211.3 pmol/l detected low-risk and high-risk patients, respectively., Conclusions: PENK levels reflect cardiorenal status in acute HF and are prognostic for worsening renal function and in-hospital mortality as well as mortality during follow-up., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose: Osseointegration has been defined in many ways, from both basic science and clinical perspectives, but generally represents the restoration of bony homeostasis following implant placement and is usually judged by some form of bone/implant disruption test. In this study, bone anchorage to two different implant surfaces, in tensile and shear modes, was compared to investigate the relation between implant surface topography and osseointegration over time. The purpose was to determine if mathematical parameters could be derived that would reflect the biologic relevance of the implant surface design., Materials and Methods: Rectangular titanium implants (n = 244) were placed in the distal femora of 122 male Wistar rats proximal to the knee joint. Implants were either microsurfaced (MS) or nanosurfaced (NS). Animals were euthanized at one of six time points ranging from 5 days to 6 months, and the force required to disrupt the bone implant interface, in either shear or tension, was measured using an Instron machine. Data were analyzed by fitting the function F = C (1-e -x/τ ), where F is the measured disruption force, C is the predicted average maximum disruption force, x is the time postimplantation, and τ is a time constant defined as the time required for F to reach 63.2% of C., Results: Analysis showed that shear testing resulted in significantly larger values of C than seen in tension, but no significant difference was observed when comparing the values of C for NS and MS implants in shear (P = .7). Thus, in accord with clinical reports, both implants performed equivalently at longer implantation periods. The differences in C were significant in tension (P < .05). Importantly, NS implants had a significantly smaller τ than the MS implants (P < .01, in shear), but no significant differences were observed in τ due to mechanical testing vector. The disruption force values reached a plateau with time, representing bony homeostasis as a result of osseointegration. With time, both implant surfaces reached the same maximum (C) values, in shear. However, the value of τ was smaller in NS compared to MS implants, which represented a higher rate of osseointegration., Conclusion: Thus, τ emerges as a measureable and biologically relevant parameter that can be employed to compare the osseointegration potential of putative implant surfaces.

Background: Coronary microcirculatory dysfunction portends a poor cardiovascular outcome. Invasive assessment of microcirculatory dysfunction by coronary flow reserve (CFR) and hyperemic microvascular resistance (HMR) is affected by coronary artery disease (CAD). In this study we propose minimal microvascular resistance (mMR) as a new measure of microcirculatory dysfunction and aim to determine whether mMR is influenced by CAD., Methods and Results: We obtained 482 simultaneous measurements of intracoronary Doppler flow velocity and pressure. The mMR is defined as the ratio between distal coronary pressure and flow velocity during the hyperemic wave-free period. Measurements were divided into 2 cohorts. Cohort 1 was a paired analysis involving 81 pairs with a vessel with and without CAD to investigate whether HMR, CFR, and mMR are modulated by CAD. CFR was lower, and HMR was higher, in vessels with CAD than in vessels without CAD: 2.12±0.79 versus 2.56±0.63 mm Hg·cm -1 ·s, P<0.001, and 2.61±1.22 versus 2.31±0.89 mm Hg·cm -1 ·s, P=0.04, respectively. mMR was equal in vessels with and without CAD: 1.54±0.77 versus 1.53±0.57 mm Hg·cm -1 ·s, P=0.90. Differences for CFR occurred when FFR was 0.60 to 0.80 or ≤0.60 but not when FFR ≥0.80. For HMR, the difference occurred only when FFR ≤0.60. For mMR, no difference was observed in any FFR stratum. Cohort 2 was used for validation and showed significant relationships for CFR and HMR with FFR: Pearson r=0.488, P<0.001 and -0.159, P=0.03, respectively; mMR had no association with FFR: Pearson r=0.055; P=0.32., Conclusions: mMR is a novel index to assess microcirculatory dysfunction and is not modified by the presence of obstructive CAD., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: We sought to estimate the efficacy and safety outcomes of catheter-directed treatment (CDT) for patients with acute pulmonary embolism (PE)., Methods: We searched SCOPUS for studies reporting outcomes after CDT for acute PE. Studies were categorized in three groups for analyses due to heterogeneity in the classification of acute PE: 1) patients with PE causing right ventricular dysfunction and haemodynamic instability: unstable haemodynamic status, 2) patients with PE causing right ventricular dysfunction where study outcomes were not stratified by haemodynamic status: stable and unstable haemodynamic status, and 3) patients with PE causing right ventricular dysfunction who remained haemodynamically stable: stable haemodynamic status. Efficacy and safety outcomes were estimated and presented as point estimates with 95% confidence intervals., Results: In 35 studies with 1253 patients, 1277 CDTs were performed. The in-hospital mortality rates for the unstable haemodynamic status, stable and unstable haemodynamic status, and stable haemodynamic status groups were 18.1% (7.3-38.2%), 7.1% (5.0-10.1%), and 2.6% (0.8-7.3%), respectively. The major bleeding rates across the groups were estimated to be 4.5, 8.5 and 3.9 per 100 CDTs, respectively. Minor bleeding occurred in 6.2, 11.9 and 9.1 per 100 CDTs, respectively. After CDT, all groups had improvements in mean pulmonary artery pressure and right ventricular function., Conclusions: We provide descriptive measures of efficacy and safety for patients who underwent CDT for acute PE., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Wave intensity analysis (WIA) of the coronary arteries allows description of the predominant mechanisms influencing coronary flow over the cardiac cycle. The data are traditionally derived from pressure and velocity changes measured invasively in the coronary artery. Cardiovascular magnetic resonance (CMR) allows measurement of coronary velocities using phase velocity mapping and derivation of central aortic pressure from aortic distension. We assessed the feasibility of WIA of the coronary arteries using CMR and compared this to invasive data., Methods: CMR scans were undertaken in a serial cohort of patients who had undergone invasive WIA. Velocity maps were acquired in the proximal left anterior descending and proximal right coronary artery using a retrospectively-gated breath-hold spiral phase velocity mapping sequence with high temporal resolution (19 ms). A breath-hold segmented gradient echo sequence was used to acquire through-plane cross sectional area changes in the proximal ascending aorta which were used as a surrogate of an aortic pressure waveform after calibration with brachial blood pressure measured with a sphygmomanometer. CMR-derived aortic pressures and CMR-measured velocities were used to derive wave intensity. The CMR-derived wave intensities were compared to invasive data in 12 coronary arteries (8 left, 4 right). Waves were presented as absolute values and as a % of total wave intensity. Intra-study reproducibility of invasive and non-invasive WIA was assessed using Bland-Altman analysis and the intraclass correlation coefficient (ICC)., Results: The combination of the CMR-derived pressure and velocity data produced the expected pattern of forward and backward compression and expansion waves. The intra-study reproducibility of the CMR derived wave intensities as a % of the total wave intensity (mean ± standard deviation of differences) was 0.0 ± 6.8%, ICC = 0.91. Intra-study reproducibility for the corresponding invasive data was 0.0 ± 4.4%, ICC = 0.96. The invasive and CMR studies showed reasonable correlation (r = 0.73) with a mean difference of 0.0 ± 11.5%., Conclusion: This proof of concept study demonstrated that CMR may be used to perform coronary WIA non-invasively with reasonable reproducibility compared to invasive WIA. The technique potentially allows WIA to be performed in a wider range of patients and pathologies than those who can be studied invasively.