Search

Infective endocarditis (IE) is a morbid condition with high mortality. We investigated predictors of in-hospital mortality and embolic phenomena in a contemporary Australasian cohort.We identified all patients with IE admitted between January 2017 and 30th April 2020 (40 months). Patient characteristics, risk factors and clinical outcomes were retrospectively collected and analysed.One hundred and seventy-two consecutive patients (mean age: 56.8 ± 17.9 years, male: 63%, 114/172) were included. Causative organisms were Staphylococcus aureus (44%, 75/172), Enterococcus faecalis (15%, 26/172), Streptococcus mitis (6%, 10/172) and Staphylococcus epidermidis (3%, 6/172). In-hospital mortality was 15% (25/172). Embolic complications were found among 57% (98/172) of patients, the most common being stroke (23%, 40/172), septic pulmonary emboli (17%, 29/172), splenic and/or renal emboli (17%, 26/172) and peripheral limb emboli (15%, 25/172). Sixty (35%, 60/172) patients underwent cardiac surgery. On multivariable analysis, independent predictors of in-hospital mortality were: increased age (odds ratio: 1.064, per year older, P = 0.001), ICU admission independent of cardiac surgery (OR 9.81, P 0.001), moderate or severe LV impairment (OR 5.19, P = 0.012) and any sign of embolic phenomena to limbs (OR 5.02, P = 0.006). Multivariable predictors of embolic complications were S. aureus bacteraemia (OR 3.22, P = 0.001) and large vegetation10 mm (OR 3.04, P = 0.002).We demonstrate predictors of in-hospital mortality and embolic phenomena in our cohort. Though age remains a consistent predictor of mortality, surprisingly, signs of embolic phenomena to the limbs was established as an independent predictor of mortality. The mechanism of this is unclear and warrants further evaluation.

Left ventricular thrombus (LVT) increases the risk of thrombotic events and mortality. Vitamin K antagonists (VKAs) used to treat LVT have several known risks, as a result of which direct oral anticoagulant (DOAC) use has recently increased. We aimed to evaluate the safety and efficacy of DOACs and VKAs in treating LVT.We searched PubMed, Embase, Cochrane Library trials, and Web of Science databases for studies published before 19 April 2022, involving DOAC versus VKA treatment for patients with LVT. This meta-analysis comprised 21 studies (total patients, n = 3172; DOAC group, n = 888; VKA group, n = 2284). A statistically significant reduction in bleeding events was observed in patients on DOACs vs. those on VKAs (risk ratio (RR) = 0.73, P = 0.004). Patients on DOACs residing in North American and European regions and those with ischaemic heart disease (IHD) had a significantly lower risk of bleeding events than patients residing in other regions or those with a different LVT aetiology, respectively (RR = 0.78, P = 0.04; RR = 0.38, P = 0.02; and RR = 0.63, P = 0.009). A statistically significant reduction in stroke in patients on DOACs versus VKAs (RR = 0.72, P = 0.03) was observed, and patients on DOACs residing in North America and those with IHD had a significantly lower risk of stroke (RR = 0.73, P = 0.04, and RR = 0.61, P = 0.03, respectively). Compared with VKAs, DOACs are statistically associated with an increase in LVT resolution at 1 month (RR = 1.96, P = 0.008). No statistical between-group difference in all-cause mortality (RR = 0.72, P = 0.05), systemic embolism (RR = 0.87, P = 0.74), stroke or systemic embolism (RR = 0.90, P = 0.50), and LVT resolution at the end of follow-up (RR = 1.06, P = 0.13) was observed.Compared with VKAs, DOACs significantly reduce the risk of bleeding events and stroke in LVT patients, but mortality was similar in both groups. The advantages are apparent not only in patients belonging to the predominantly white residential areas such as North American and European regions but also in patients with LVT due to IHD. DOACs show promising effects in treating LVT compared with VKAs.

Current guidelines recommend oral anticoagulation (OAC) following transcatheter aortic valve replacement (TAVR) in patients with clinical indication, but the optimal antithrombotic regimen remains uncertain. We aimed to compare the efficacy and safety of non-vitamin K oral anticoagulants (NOACs) versus vitamin K antagonists (VKAs) in patients undergoing TAVR with concomitant indication of OAC.Comparing with VKAs therapy, NOACs are similar in reducing the all-cause mortality and major bleeding in post-TAVR patients requiring OAC medication.We searched the databases of PubMed, Embase, and Cochrane library databases to identify studies that investigated NOACs versus VKAs after TAVR in patients with another indication of OAC, which were published before 28th September 28, 2021. The effectiveness of outcomes was all-cause mortality and stroke or systemic embolism, while the main safety outcome was major and/or life-threatening bleeding. The hazard ratio (HR) with 95% confidence interval (CI) was used as a measure of treatment effect.Our search identified eight studies. We included 4947 post-TAVR patients with another indication of OAC allocated to the NOAC (n = 2146) or VKA groups (n = 2801). There were no significant differences in the all-cause mortality (HR: 0.91, 95% CI: 0.77-1.08, p = .29, IAmong post-TAVR patients who required OAC therapy, NOACs therapy compared to VKAs is similar in reducing the all-cause mortality, stroke or systemic embolism, and major and/or life-threatening bleeding events.

Drought events may increase the likelihood that the plant water transport system becomes interrupted by embolism. Yet our knowledge about the temporal frequency of xylem embolism in the field is frequently lacking, as it requires detailed, long-term measurements. We measured xylem embolism resistance and midday xylem water potentials during the consecutive summers of 2019 and 2020 to estimate maximum levels of embolism in leaf and stem xylem of ten temperate angiosperm tree species. We also studied vessel and pit membrane characteristics based on light and electron microscopy to corroborate potential differences in embolism resistance between leaves and stems. Apart from A. pseudoplatanus and Q. petraea, eight species experienced minimum xylem water potentials that were close to or below those required to initiate embolism. Water potentials corresponding to ca. 12% loss of hydraulic conductivity (PLC) could occur in six species, while considerable levels of embolism around 50% PLC were limited to B. pendula and C. avellana. There was a general agreement in embolism resistance between stems and leaves, with leaves being equally or more resistant than stems. Also, xylem embolism resistance was significantly correlated to intervessel pit membrane thickness (T

Damage to the plant water transport system through xylem cavitation is known to be a driver of plant death in drought conditions. However, a lack of techniques to continuously monitor xylem embolism in whole plants in vivo has hampered our ability to investigate both how this damage propagates and the possible mechanistic link between xylem damage and tissue death. Using optical and fluorescence sensors, we monitored drought-induced xylem embolism accumulation and photosynthetic damage in vivo throughout the canopy of a drought-resistant conifer, Callitris rhomboidea, during drought treatments of c. 1 month duration. We show that drought-induced damage to the xylem can be monitored in vivo in whole trees during extended periods of water stress. Under these conditions, vulnerability of the xylem to cavitation varied widely among branchlets, with photosynthetic damage only recorded once > 90% of the xylem was cavitated. The variation in branchlet vulnerability has important implications for understanding how trees like C. rhomboidea survive drought, and the high resistance of branchlets to tissue damage points to runaway cavitation as a likely driver of tissue death in C. rhomboidea branch tips.

Background There is a paucity of randomized data regarding the safety and efficacy of the use of intracardiac echocardiography (ICE) from the left atrium (LA) to guide left atrial appendage occlusion (LAAO) procedures under local anesthesia using either of the available devices. Hypothesis The aim of this study was to compare the efficacy and safety of ICE from the LA with transesophageal echocardiography (TEE) for guidance during transcatheter LAAO procedures. Methods Single‐center, cohort study of patients undergoing LAAO with the Amplatzer Cardiac Plug or Watchman device. Procedures were guided by ICE from the LA with local anesthesia (n = 175) or TEE under general anesthesia (n = 49). Efficacy outcomes were procedural success and peri‐device leaks 6 weeks after LAAO. The safety outcome was a composite of procedure‐related complications. Results Procedural success was similar between groups: 100% in the TEE‐guided group, and 98% in the ICE‐guided group. Procedure‐related complications such as death, embolism, migration, or major vascular complications occurred similarly between groups (p = 0.590). The rate and degree of peri‐device leaks or presence of a thrombus on the device did not differ between groups on follow‐up CT. Turnover time in the catheter laboratory and use of contrast agent were reduced with ICE. Conclusions ICE in the left atrium to guide LAAO procedures appears to be as effective and safe as TEE. There was no increase in procedure‐related complications, whatever the device used. ICE resulted in similar procedural success while decreasing procedure time and requiring only local anesthesia.

Cardiomyopathy comprises a heterogeneous group of myocardial abnormalities, structural or functional in nature, in the absence of coronary artery disease and other abnormal loading conditions. These myocardial pathologies can result in premature death or disability from progressive heart failure, arrhythmia, stroke, or other embolic events. The European Cardiomyopathy Registry reports a high stroke risk in cardiomyopathy patients ranging from 2.1% to 4.5%, as well as high prevalence of atrial fibrillation ranging from 14.0% to 48.5%. There is a growing interest in evaluating the risk of thromboembolism depending on the type of cardiomyopathy, as well as if anticoagulation is indicated in patients with cardiomyopathy without atrial fibrillation. Data available do not unequivocally support anticoagulation therapy in all of these patients; the management of these patients remains challenging. Many published reports pertaining to the risk of thromboembolism and consecutive treatment strategies mainly focus on single cardiomyopathy subtype. We summarize essential pathophysiological knowledge and review current literature associated with thromboembolism in various cardiomyopathy subtypes, providing recommendations for the diagnostic evaluation as well as clinical management strategies in this field. Certain cardiomyopathy subtypes require anticoagulation independent of atrial fibrillation or CHA2DS2‐VASc score. Despite the scarcity of evidence regarding the choice of anticoagulation regimen (vitamin K antagonist vs. non‐vitamin K oral anticoagulants) in cardiomyopathy, it is discussed and reviewed in this article. Each patient should receive a tailored strategy based on thorough clinical evaluation, published evidence, and clinical experience, due to the current recommendations mostly developed on small‐sample studies or empirical evidence. The future research priorities in this area are also addressed in this article.

Introduction Watchman FLX has been recently approved for left atrial appendage occlusion (LAAO) in the US. Intracardiac echocardiography (ICE) - which is already commonly used to guide trans-septal access - can serve as an alternative to TEE, simplifying the procedure and reducing associated costs. Herein, we report our experience with ICE-guided LAAO with Watchman FLX. Methods and results This cohort study included the first 190 consecutive patients who underwent LAAO with Watchman FLX in our center. LAAO was successful in all patients without significant peri-procedural, device-related complications in either group. Compared to TEE, we observed a significant reduction in procedural times when using ICE. In addition, there was a potentially clinically relevant reduction in fluoroscopy dose, mainly secondary to fewer cine acquisition runs. At follow-up, no cases of device embolism were noted, whereas the rate of device-related thrombosis and peri-device leaks were comparable between groups. Conclusion ICE-guided LAAO with Watchman FLX is safe and feasible, with a significant reduction in procedural time and potential reduction in fluoroscopy dose when compared to TEE.

Background and purpose: Left atrial (LA) cardiac disease is a suspected cause of embolic stroke of undetermined source (ESUS). We tested the hypothesis that LA fibrosis, quantified using late-gadolinium-enhancement magnetic resonance imaging (LGE-MRI), predicts recurrent stroke or atrial fibrillation (AF) in patients with ESUS. Methods: We compared atrial fibrosis in healthy controls and patients with lacunar stroke, ESUS, and known AF with or without prior stroke. We followed patients with ESUS prospectively for the primary outcome of recurrent ischemic stroke, incident AF, or both. Results: We enrolled 203 patients from three centers: 103 patients without AF (35 healthy controls, 15 with lacunar strokes, 53 with ESUS) and 100 patients with AF (50 with and 50 without prior stroke). Patients with ESUS had significantly higher atrial fibrosis (15.0 ± 6.2%) compared to healthy controls (8.1 ± 7.9%

Embolism resistance is often viewed as seasonally stable. Here we examined the seasonality in the leaf xylem vulnerability curve (VC) and turgor loss point (Ψ

Background There is limited data on complications associated with the use of coronary embolic protection devices (EPDs). Methods We queried the Manufacturer and User Facility Device Experience database between November 2010 and November 2020 for reports on coronary EPDs: Spider FX (Medtronic, Minneapolis, MN) and Filterwire EZ (Boston Scientific, Natick, MA). Results We retrieved 119 reports on coronary EPD failure (Spider FX n = 33 and Filterwire EZ n = 86), most of which (78.2%) occurred during saphenous vein graft interventions. The most common failure mode was inability to retrieve the EPD (49.6%), with the filter trapped against stent struts in 76.2% of the cases. Other device complications included filter fracture (28.6%), failure to cross (7.6%), failure to deploy (7.6%), and failure to recapture the filter (3.4%). Filter fracture (54.5 vs. 29.1%) and failure to recapture (9.1 vs. 2.1%) were more commonly reported, while failure to deploy the filter (0 vs. 10.5%) was less commonly reported with the Spider-FX. Conclusions The most common modes of failure of coronary EPDs are the failure of retrieval (49.6%), followed by the filter fracture (28.6%). When using EPDs, careful attention to the technique is essential to avoid failures and subsequent complications.

Aims This study aimed to elucidate the risk for stroke and systemic embolism (SE) in patients with atrial fibrillation and heart failure (HF) according to HF type. Methods and results A total of 10 780 patients with atrial fibrillation were enrolled in a multicentre prospective registry and divided according to HF type: no‐HF, HF with preserved ejection fraction (EF) (HFpEF), HF with mid‐range EF (HFmrEF), and HF with reduced EF (HFrEF). Each group included 237 age‐matched and sex‐matched patients (age, 69.0 ± 10.3 years; men, 69.6%). The baseline characteristics, cumulative incidence, and hazard ratios for stroke/SE and major bleeding were compared across the groups. Patients with HF accounted for 10.3% of the total population; HFpEF, HFmrEF, and HFrEF represented 43.7%, 23.6%, and 32.7% of the patients with HF, respectively. The CHA2DS2‐VASc score was significantly higher in the HFpEF, HFmrEF, and HFrEF groups than in the no‐HF group. The annual stroke/SE incidence rates were 2.8%, 0.7%, 1.1%, and 0.9% in the HFpEF, HFmrEF, HFrEF, and no‐HF groups, respectively. The cumulative incidence of stroke/SE was significantly highest in the HFpEF group at 22.8 ± 10.0 months (P = 0.020). The stroke/SE risk was higher in the HFpEF group than in the HFmrEF and HFrEF groups (hazard ratio, 3.192; 95% confidence interval, 1.039–9.810; P = 0.043). E/e' value was an independent risk factor for stroke/SE. There were no significant differences in the incidence of major bleeding across the groups. Conclusions The stroke/SE risk was the highest in the HFpEF group and comparable between the HFmrEF and HFrEF groups.

Coronary artery aneurysm (CAA) is a rare and poor prognostic manifestation of Behcet’s disease （BD）. Percutaneous treatment approaches frequently failed to ameliorate acute coronary system (ACS). Long‐term follow‐up is recommended as the prognosis of coronary involvement and the risk of further disease progression with percutaneous intervention in BD are unknown. long‐term anticoagulant and antiaggregant therapies should be considered to prevent further thrombosis and/or embolism., Coronary artery aneurysm (CAA) is a rare and poor prognostic manifestation of Behcet’s disease （BD）. Percutaneous treatment approaches frequently failed to ameliorate acute coronary system (ACS). Long‐term follow‐up is recommended as the prognosis of coronary involvement and the risk of further disease progression with percutaneous intervention in BD are unknown. long‐term anticoagulant and antiaggregant therapies should be considered to prevent further thrombosis and/or embolism..

Systemic thromboembolism, along with acute multiorgan failure, should raise clinical suspicion for CAPS. Timely management, even in suspected cases, can have a significant impact on mortality.

Although several meta-analyses have examined the effects of off-label underdosing of nonvitamin K antagonist oral anticoagulants (NOACs) compared with their recommended doses in patients with atrial fibrillation (AF), they combined different kinds of NOACs in their primary analyses. Herein, we first conducted a meta-analysis to separately assess the effects of off-label underdosing versus on-label dosing of four individual NOACs on adverse outcomes in the AF population.The PubMed and Embase database were systemically searched until November 2021 to identify the relevant studies. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled by utilizing a random-effects model.A total of nine studies with 144,797 patients taking NOACs were included in the meta-analysis. In the pooled analysis, off-label underdosing of rivaroxaban was related to an increased risk of stroke or systemic embolism (HR = 1.31, 95% CI 1.05-1.63; p = .02), whereas off-label underdosing of apixaban was associated with a higher risk of all-cause death (HR = 1.21, 95% CI 1.05-1.40; p = .01). When comparing off-label underdosing versus on-label dosing of dabigatran or edoxaban, no differences were found in the primary and secondary clinical outcomes.Off-label underdosing of rivaroxaban may increase the risk of stroke or systematic embolism, whereas off-label underdosing of apixaban may heighten the incidence of all-cause death.

Embolism spreading in angiosperm xylem occurs via mesoporous pit membranes between vessels. Here, we investigate how the size of pore constrictions in pit membranes is related to pit membrane thickness and embolism resistance. Pit membranes were modelled as multiple layers to investigate how pit membrane thickness and the number of intervessel pits per vessel determine pore constriction sizes, the probability of encountering large pores, and embolism resistance. These estimations were complemented by measurements of pit membrane thickness, embolism resistance, and number of intervessel pits per vessel in stem xylem (n = 31, 31 and 20 species, respectively). The modelled constriction sizes in pit membranes decreased with increasing membrane thickness, explaining the measured relationship between pit membrane thickness and embolism resistance. The number of pits per vessel affected constriction size and embolism resistance much less than pit membrane thickness. Moreover, a strong relationship between modelled and measured embolism resistance was observed. Pore constrictions provide a mechanistic explanation for why pit membrane thickness determines embolism resistance, which suggests that hydraulic safety can be uncoupled from hydraulic efficiency. Although embolism spreading remains puzzling and encompasses more than pore constriction sizes, angiosperms are unlikely to have leaky pit membranes, which enables tensile transport of water.

Objective To assess the contribution of maternal blood detection of IGFBP-1 for the diagnosis of amniotic-fluid embolism in clinical daily practice. Design A retrospective multicentre cohort study. Setting Three tertiary care obstetric units in France. Sample Data of 86 women for whom amniotic-fluid embolism had been suspected and maternal serum detection of IGFBP-1 had been performed between 2011 and 2019 were analysed. Methods The criteria defined by the United Kingdom Obstetric Surveillance System (UKOSS) were used for the retrospective diagnosis of amniotic-fluid embolism. The more structured definition proposed by the Society for Maternal-Fetal Medicine and the Amniotic Fluid Embolism Foundation (SMFM) was also used as secondary endpoint. Main outcome measures Agreements between biological and clinical assessments were tested. The performance of blood detection of IGFBP-1 for the diagnosis of amniotic-fluid embolism according to the UKOSS criteria, and to the SMFM definition, was also assessed. Results There was only slight agreement between clinical and laboratory diagnosis of amniotic-fluid embolism (Cohen's Kappa coefficient: 0.04). Blood detection of IGFBP-1 had a sensitivity of 16%, a specificity of 88%, a positive and a negative likelihood ratio of 1.3 and 0.95, respectively, and a positive and a negative predictive value of 58 and 50%, respectively, for the diagnosis of amniotic-fluid embolism based on the UKOSS criteria. The use of the more structured SMFM definition of amniotic-fluid embolism did not substantially change the results. Conclusion These results question the usefulness of blood detection of IGFBP-1 for the early diagnosis of amniotic-fluid embolism in daily clinical practice. Tweetable abstract This retrospective multicentre study questions the contribution of IGFBP-1 detection for the diagnosis of AFE.

Similar to the influenza A pandemic in 1918/1919, the new Coronavirus disease 2019 (COVID‐19) has spread globally. The causes of death in COVID‐19 are frequently compared to a seasonal influenza outbreak. Complete COVID‐19 autopsy studies were almost non‐existent in the first months of the outbreak and are still rare with respect to the number of deaths. It has been recently reported that capillary microthrombi are significantly more prevalent in patients with COVID‐19 than in patients with influenza A. To date, the contribution of macrothrombi, i.e. visible thrombi in pulmonary arteries, to the death of patients with influenza A in comparison to COVID‐19 remains unaddressed. Here, we report autopsy findings in 411 patients who died from the ‘Spanish’ influenza A pandemic between May 1918 and April 1919 at the University Hospital Zurich, Switzerland. We compare these results with influenza A autopsies from 2009 to 2020, other influenza A autopsy series and all COVID‐19 autopsies published to date. No descriptions of any macroscopic thromboembolic events were mentioned in influenza A autopsy reports. In 75 published COVID‐19 autopsies, pulmonary artery thrombosis/embolism was reported in 36%. The direct comparison of macroscopic autopsy findings suggests a significantly greater degree of grossly visible pulmonary macrothrombi in patients with COVID‐19 in comparison to influenza A autopsies even though most patients received empiric thromboprophylaxis. This is consistent with the concept of a SARS‐related de novo coagulopathy with generalised in situ clot formation, which could explain the high incidence of pulmonary thrombosis/embolism with or without underlying deep vein thrombosis and in the absence of a history of venous thromboembolic events.

Embolism spreading in dehydrating angiosperm xylem is driven by gas movement between embolised and sap-filled conduits. Here, we examine how proximity to pre-existing embolism and hydraulic segmentation affect embolism propagation. Based on the optical method, we compared xylem embolism resistance between detached leaves and leaves attached to branches, and between intact leaves and leaves with cut minor veins for six species. Moreover, we directly compared the optical and pneumatic method on detached leaves. Embolism resistance of detached leaves was significantly lower than leaves attached to stems, except for two species with all vessels ending in their petioles. Cutting of minor veins showed limited embolism spreading in minor veins near the cuts prior to major veins. Moreover, there was strong agreement in embolism resistance between the optical and pneumatic method, with minor differences occurring during early stages of embolism formation. We conclude that embolism resistance may represent a relative trait, depending on the proximity and connectivity to pre-existing embolism as a gas source. Since embolism formation may not rely on a certain pressure difference threshold between functional and embolised conduits, we suggest that embolism is facilitated by pressure-driven gas diffusion, while hydraulic segmentation can prevent embolism propagation by reducing gas diffusion.

Coronary microembolization (CME) is a prevalent cardiovascular disease, especially nowadays when percutaneous coronary intervention is widely applied. However, neither cardio-protective agents nor devices for distal protection could effectively prevent the occurrence of CME. Therefore, we aimed to develop a new drug for CME. Rats were orally administrated with different doses of Cryptotanshinone (CTS, 5, 15, 45 mg/kg) daily for 2 weeks, respectively, following CME surgery. Then cardiac function and cardiac injury were evaluated in CME rats as well as measuring oxidative stress and apoptosis in cardiomyocytes. Compared to sham group, CME operation induced cardiac dysfunction, cardiac injury, the activation of platelet and endothelium, cardiomyocyte apoptosis and oxidative stress, all of which could be dose-dependently restored by CTS pretreatment. Moreover, NF-κB signaling pathway participated in the development of CME and also in the preventive process of CTS against CME. CTS might serve as a potential and promising candidate drug to prevent the occurrence of CME.

Although xylem embolism resistance is traditionally considered as static, we hypothesized that in grapevine (Vitis vinifera) leaf xylem becomes more embolism-resistant over the growing season. We evaluated xylem architecture, turgor loss point (ΨTLP ) and water potentials leading to 25% of maximal stomatal conductance (gs25 ) or 50% embolism in the leaf xylem (P50 ) in three irrigation treatments and at three time points during the growing season, while separating the effects of leaf age and time of season. Hydraulic traits acclimated over the growing season in a coordinated manner. Without irrigation, ΨTLP , gs25 , and P50 decreased between late May and late August by 0.95, 0.77 and 0.71 MPa, respectively. A seasonal shift in P50 occurred even in mature leaves, while irrigation had only a mild effect (

Direct oral anticoagulants, such as apixaban and rivaroxaban, are important for the treatment and prophylaxis of venous thromboembolism and to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Because apixaban and rivaroxaban are predominantly eliminated by cytochrome P450 (CYP) 3A and P‐glycoprotein (P‐gp), concomitant use of combined P‐gp and strong CYP3A4 inhibitors and inducers should be avoided. Physiologically‐based pharmacokinetic models for apixaban and rivaroxaban were developed to estimate the net effect of CYP3A induction, P‐gp inhibition, and P‐gp induction by rifampicin. The disposition of rivaroxaban is more complex compared with apixaban because both hepatic and renal P‐gp is considered to contribute to rivaroxaban elimination. Furthermore, organic anion transporter‐3, a renal uptake transporter, may also contribute the elimination of rivaroxaban from systemic circulation. The models were verified with observed clinical drug–drug interactions with CYP3A and P‐gp inhibitors. With the developed models, the predicted area under the concentration time curve and maximum concentration ratios were 0.43 and 0.48, respectively, for apixaban, and 0.50–0.52 and 0.72–0.73, respectively, for rivaroxaban when coadministered with 600 mg multiple doses of rifampicin and that were very close to observed data. The impact of each of the elimination pathways was assessed for rivaroxaban, and inhibition of CYP3A led to a larger impact over intestinal and hepatic P‐gp. Inhibition of renal organic anion transporter‐3 or P‐gp led to an overall modest interaction. The developed apixaban and rivaroxaban models can be further applied to the investigation of interactions with other P‐gp and/or CYP3A4 inhibitors and inducers.

Vulnerability curves (VCs) describe the loss of hydraulic conductance against increasing xylem tension, providing valuable insights about the response of plant water transport to water stress. Techniques to construct VCs have been developed and modified continuously, but controversies continue. We compared VCs constructed using the bench-top dehydration (BD), air-injection-flow (AI), pneumatic-air-discharge (PAD), optical (OP) and X-ray-computed microtomography (MicroCT) methods for tropical trees and lianas with contrasting vessel lengths. The PAD method generated highly vulnerable VCs, the AI method intermediate VCs, whereas the BD, OP and MicroCT methods produced comparable and more resistant VCs. Vessel-length and diameter accounted for the overestimation ratio of vulnerability estimated using the AI but not the PAD method. Compared with directly measured midday embolism levels, the PAD and AI methods substantially overestimated embolism, whereas the BD, MicroCT and OP methods provided more reasonable estimations. Cut-open vessels, uncertainties in maximum air volume estimations, sample-length effects, tissue cracks and shrinkage together may impede the reliability of the PAD method. In conclusion, we validate the BD, OP and MicroCT methods for tropical plants, whereas the PAD and AI need further mechanistic testing. Therefore, applications of VCs in estimating plant responses to drought need to be cautious.

BACKGROUND Carotid artery stenting (CAS) is being increasingly used as an alternative revascularization procedure to carotid endarterectomy; however, subclinical ischemic cerebral lesions after CAS remain as a matter of concern. Hence, we aimed to assess the clinical utility of the CHADS2 score in predicting subclinical ischemic events after CAS. METHODS We prospectively evaluated 107 patients (mean age: 70.4 ± 6.6 years, male:77) who underwent CAS for carotid artery revascularization. The patients having symptomatic transient ischemic attack or stroke after CAS were excluded. The presence of new hyperintense lesion on diffusion-weighted imaging (DWI) without any neurological findings was considered as silent ischemia. Patients were classified into two groups as DWI-positive and DWI-negative patients. RESULTS Among study population, 28 patients (26.2%) had subclinical embolism. The DWI-positive group had a significantly higher CHADS2 scores, older age, more frequent history of stroke, higher proportion of type III aortic arch, and longer fluoroscopy time than the DWI-negative group. Increased CHADS2 score was identified as one of the independent predictors of silent embolism (OR = 5.584; 95%CI: 1.516-20.566; p = .010), and CHADS2 score higher than 2.5 predicted subclinical cerebral ischemia with a sensitivity of 72% and a specificity of 71% (AUC: 0.793; 95% CI: 0.696 - 0.890; p

BACKGROUND AND PURPOSE Hierarchical clustering, a common 'unsupervised' machine-learning algorithm, is advantageous for exploring potential underlying aetiology in particularly heterogeneous diseases. We investigated potential embolic sources in embolic stroke of undetermined source (ESUS) using a data-driven machine-learning method, and explored variation in stroke recurrence between clusters. METHODS We used a hierarchical k-means clustering algorithm on patients' baseline data, which assigned each individual into a unique clustering group, using a minimum-variance method to calculate the similarity between ESUS patients based on all baseline features. Potential embolic sources were categorised into atrial cardiopathy, atrial fibrillation, arterial disease, left ventricular disease, cardiac valvulopathy, patent foramen ovale (PFO) and cancer. RESULTS Among 800 consecutive ESUS patients (43.3% women, median age 67 years), the optimal number of clusters was four. Left ventricular disease was most prevalent in cluster 1 (present in all patients) and perfectly associated with cluster 1. PFO was most prevalent in cluster 2 (38.9% of patients) and associated significantly with increased likelihood of cluster 2 [adjusted odds ratio: 2.69, 95% confidence interval (CI): 1.64-4.41]. Arterial disease was most prevalent in cluster 3 (57.7%) and associated with increased likelihood of cluster 3 (adjusted odds ratio: 2.21, 95% CI: 1.43-3.13). Atrial cardiopathy was most prevalent in cluster 4 (100%) and perfectly associated with cluster 4. Cluster 3 was the largest cluster involving 53.7% of patients. Atrial fibrillation was not significantly associated with any cluster. CONCLUSIONS This data-driven machine-learning analysis identified four clusters of ESUS that were strongly associated with arterial disease, atrial cardiopathy, PFO and left ventricular disease, respectively. More than half of the patients were assigned to the cluster associated with arterial disease.