Imaging leukocyte migration through afferent lymphatics.

Afferent lymphatics mediate the transport of antigen and leukocytes, especially of dendritic cells (DCs) and T cells, from peripheral tissues to draining lymph nodes (dLNs). As such they play important roles in the induction and regulation of adaptive immunity. Over the past 15 years, great advances in our understanding of leukocyte trafficking through afferent lymphatics have been made through time-lapse imaging studies performed in tissue explants and in vivo, allowing to visualize this process with cellular resolution. Intravital imaging has revealed that intralymphatic leukocytes continue to actively migrate once they have entered into lymphatic capillaries, as a consequence of the low flow conditions present in this compartment. In fact, leukocytes spend considerable time migrating, patrolling and interacting with the lymphatic endothelium or with other intralymphatic leukocytes within lymphatic capillaries. Cells typically only start to detach once they arrive in downstream-located collecting vessels, where vessel contractions contribute to enhanced lymph flow. In this review, we will introduce the biology of afferent lymphatic vessels and report on the presumed significance of DC and T cell migration via this route. We will specifically highlight how time-lapse imaging has contributed to the current model of lymphatic trafficking and the emerging notion that - besides transport - lymphatic capillaries exert additional roles in immune modulation.

Transcatheter or Surgical Aortic Valve Replacement in Patients With Severe Aortic Stenosis and Small Aortic Annulus: A Randomized Clinical Trial.

BACKGROUND: The optimal treatment in patients with severe aortic stenosis and small aortic annulus (SAA) remains to be determined. This study aimed to compare the hemodynamic and clinical outcomes between transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR) in patients with a SAA. METHODS: This prospective multicenter international randomized trial was performed in 15 university hospitals. Participants were 151 patients with severe aortic stenosis and SAA (mean diameter <23 mm) randomized (1:1) to TAVR (n=77) versus SAVR (n=74). The primary outcome was impaired valve hemodynamics (ie, severe prosthesis patient mismatch or moderate-severe aortic regurgitation) at 60 days as evaluated by Doppler echocardiography and analyzed in a central echocardiography core laboratory. Clinical events were secondary outcomes. RESULTS: The mean age of the participants was 75.5±5.1 years, with 140 (93%) women, a median Society of Thoracic Surgeons predicted risk of mortality of 2.50% (interquartile range, 1.67%-3.28%), and a median annulus diameter of 21.1 mm (interquartile range, 20.4-22.0 mm). There were no differences between groups in the rate of severe prosthesis patient mismatch (TAVR, 4 [5.6%]; SAVR, 7 [10.3%]; P=0.30) and moderate-severe aortic regurgitation (none in both groups). No differences were found between groups in mortality rate (TAVR, 1 [1.3%]; SAVR, 1 [1.4%]; P=1.00) and stroke (TAVR, 0; SAVR, 2 [2.7%]; P=0.24) at 30 days. After a median follow-up of 2 (interquartile range, 1-4) years, there were no differences between groups in mortality rate (TAVR, 7 [9.1%]; SAVR, 6 [8.1%]; P=0.89), stroke (TAVR, 3 [3.9%]; SAVR, 3 [4.1%]; P=0.95), and cardiac hospitalization (TAVR, 15 [19.5%]; SAVR, 15 [20.3%]; P=0.80). CONCLUSIONS: In patients with severe aortic stenosis and SAA (women in the majority), there was no evidence of superiority of contemporary TAVR versus SAVR in valve hemodynamic results. After a median follow-up of 2 years, there were no differences in clinical outcomes between groups. These findings suggest that the 2 therapies represent a valid alternative for treating patients with severe aortic stenosis and SAA, and treatment selection should likely be individualized according to baseline characteristics, additional anatomical risk factors, and patient preference. However, the results of this study should be interpreted with caution because of the limited sample size leading to an underpowered study, and need to be confirmed in future larger studies. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03383445.

Dentition patterns and molecular diversity of Mastophorus muris (Gmelin, 1790) (Nematoda: Spiruroidea) support a host-associated subdivision.

Mastophorus muris (Gmelin, 1790) is a globally distributed parasitic nematode of broad range mammals. The taxonomy within the genus Mastophorus and the cryptic diversity among the genus are controversial among taxonomists. This study provides a detailed morphological description of M. muris from Mus musculus combined with a molecular phylogenetic approach. Moreover, descriptions and molecular data of M. muris from non-Mus rodents and wildcats complement our findings and together provide new insights into their taxonomy. The analysis of M. muris was based on light microscopy and scanning electron microscopy. The morphological description focused on the dentition pattern of the two trilobed pseudolabia. Additionally, we described the position of the vulva, arrangement of caudal pairs of papillae, spicules and measured specimens from both sexes and the eggs. For the molecular phylogenetic approach, we amplified the small subunit ribosomal RNA gene and the internal transcribed spacer, and the cytochrome c oxidase subunit 1. Mastophorus morphotypes based on dentition patterns and phylogenetic clustering indicate a subdivision of the genus in agreement with their host. We recognize two groups without a change to formal taxonomy: One group including those specimens infecting Mus musculus, and the second group including organisms infecting non-Mus rodents. Our genetic and morphological data shed light into the cryptic diversity within the genus Mastopohorus. We identified two host-associated groups of M. muris. The described morphotypes and genotypes of M. muris allow a consistent distinction between host-associated parasites.

Relationship between stent length and very long-term target lesion failure following percutaneous coronary intervention for ST-elevation myocardial infarction in the drug-eluting stents era: insights from the EXAMINATION-EXTEND study.

BACKGROUND: Little data exist on the relationship between total stent length (TSL) and cardiovascular outcomes at very-long follow-up in patients with ST-elevation myocardial infarction (STEMI) in the 2nd generation drug-eluting stents (DES) era. AIM: To analyze the relationship between TSL and 10-year target-lesion failure (TLF) in STEMI patients treated with percutaneous coronary intervention enrolled in the EXAMINATION-EXTEND. METHODS: The EXAMINATION-EXTEND was an extended-follow-up study of the EXAMINATION trial, which randomized 1:1 STEMI patients to receive DES or bare metal stent (BMS). The primary endpoint was TLF, defined as a composite of target lesion revascularization (TLR), target vessel myocardial infarction (TVMI), or definite/probable stent thrombosis (ST). Relationship between stent length and TLF was evaluated in the whole study group in a multiple-adjusted Cox regression model with TSL as a quantitative variable. Subgroup analysis was also performed according to stent type, diameter, and overlap. RESULTS: A total of 1,489 patients with a median TSL of 23 mm (Q1-Q318-35 mm) were included. TSL was associated with TLF at 10 years (adjusted HR per 5 mm increase of 1.07; 95% CI, 1.01-1.14; P = .02). This effect was mainly driven by TLR and was consistent regardless of stent type, diameter, or overlap. There was no significant relationship between TSL and TV-MI or ST. CONCLUSIONS: In STEMI patients, there is a direct relationship between TSL implanted in the culprit vessel and the risk of TLF at 10 years, mainly driven by TLR. The use of DES did not modify this association.

Resilience and stability of the CF- intestinal and respiratory microbiome during nutritional and exercise intervention.

BACKGROUND: Impaired respiratory and intestinal microbiome composition is linked to cystic fibrosis lung disease severity. In people with cystic fibrosis (pwCF), regular exercise is recommended to delay disease progression and preserve a stable lung function. An optimal nutritional status is vital for best clinical outcomes. Our study investigated whether regular and monitored exercise and nutritional support promotes CF microbiome health. METHODS: A personalized nutrition and exercise program promoted nutritional intake and physical fitness in 18 pwCF for 12 months. Throughout the study, patients performed strength and endurance training monitored by a sports scientist via an internet platform. After three months, food supplementation with Lactobacillus rhamnosus LGG was introduced. Nutritional status and physical fitness were assessed before the study started, after three and nine months. Sputum and stool were collected, and microbial composition was analyzed by 16S rRNA gene sequencing. RESULTS: Sputum and stool microbiome composition remained stable and highly specific to each patient during the study period. Disease-associated pathogens dominated sputum composition. Lung disease severity and recent antibiotic treatment had the highest impact on taxonomic composition in stool and sputum microbiome. Strikingly, the long-term antibiotic treatment burden had only a minor influence. CONCLUSION: Despite the exercise and nutritional intervention, respiratory and intestinal microbiomes proved to be resilient. Dominant pathogens drove the composition and functionality of the microbiome. Further studies are required to understand which therapy could destabilize the dominant disease-associated microbial composition of pwCF.

Crystalline sirolimus-coated balloon (cSCB) angioplasty in an all-comers, patient population with stable and unstable coronary artery disease including chronic total occlusions: rationale, methodology and design of the SCORE trial.

BACKGROUND: A decade ago, the iopromide-paclitaxel coated balloon (iPCB) was added to the cardiologist's toolbox to initially treat in-stent restenosis followed by the treatment of de novo coronary lesions. In the meantime, DES technologies have been substantially improved to address in-stent restenosis and thrombosis, and shortened anti-platelet therapy. Recently, sirolimus-coated balloon catheters (SCB) have emerged to provide an alternative drug to combat restenosis. METHODS: The objective of this study is to determine the safety and efficacy of a novel crystalline sirolimus-coated balloon (cSCB) technology in an unselective, international, large-scale patient population. Percutaneous coronary interventions of native stenosis, in-stent stenosis, and chronic total occlusions with the SCB in patients with stable coronary artery disease or acute coronary syndrome were included. The primary outcome variable is the target lesion failure (TLF) rate at 12 months, defined as the composite rate of target vessel myocardial infarction (TV-MI), cardiac death or ischemia-driven target lesion revascularization (TLR). The secondary outcome variables include TLF at 24 months, ischemia driven TLR at 12 and 24 months and all-cause death, cardiac death at 12 and 24 months. DISCUSSION: Since there is a wealth of patient-based all-comers data for iPCB available for this study, a propensity-score matched analysis is planned to compare cSCB and iPCB for the treatment of de novo and different types of ISR. In addition, pre-specified analyses in challenging lesion subsets such as chronic total occlusions will provide evidence whether the two balloon coating technologies differ in their clinical benefit for the patient. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT04470934.

A novel and efficient tandem CD19- and CD22-directed CAR for B cell ALL.

CD19-directed chimeric antigen receptor (CAR) T cells have yielded impressive response rates in refractory/relapse B cell acute lymphoblastic leukemia (B-ALL); however, most patients ultimately relapse due to poor CAR T cell persistence or resistance of either CD19+ or CD19- B-ALL clones. CD22 is a pan-B marker whose expression is maintained in both CD19+ and CD19- relapses. CD22-CAR T cells have been clinically used in B-ALL patients, although relapse also occurs. T cells engineered with a tandem CAR (Tan-CAR) containing in a single construct both CD19 and CD22 scFvs may be advantageous in achieving higher remission rates and/or preventing antigen loss. We have generated and functionally validated using cutting-edge assays a 4-1BB-based CD22/CD19 Tan-CAR using in-house-developed novel CD19 and CD22 scFvs. Tan-CAR-expressing T cells showed similar in vitro expansion to CD19-CAR T cells with no increase in tonic signaling. CRISPR-Cas9-edited B-ALL cells confirmed the bispecificity of the Tan-CAR. Tan-CAR was as efficient as CD19-CAR in vitro and in vivo using B-ALL cell lines, patient samples, and patient-derived xenografts (PDXs). Strikingly, the robust antileukemic activity of the Tan-CAR was slightly more effective in controlling the disease in long-term follow-up PDX models. This Tan-CAR construct warrants a clinical appraisal to test whether simultaneous targeting of CD19 and CD22 enhances leukemia eradication and reduces/delays relapse rates and antigen loss.

Amphilimus- vs. zotarolimus-eluting stents in patients with diabetes mellitus and coronary artery disease: the SUGAR trial.

AIM: Patients with diabetes mellitus are at high risk of adverse events after percutaneous revascularization, with no differences in outcomes between most contemporary drug-eluting stents. The Cre8 EVO stent releases a formulation of sirolimus with an amphiphilic carrier from laser-dug wells, and has shown clinical benefits in diabetes. We aimed to compare Cre8 EVO stents to Resolute Onyx stents (a contemporary polymer-based zotarolimus-eluting stent) in patients with diabetes. METHODS AND RESULTS: We did an investigator-initiated, randomized, controlled, assessor-blinded trial at 23 sites in Spain. Eligible patients had diabetes and required percutaneous coronary intervention. A total of 1175 patients were randomly assigned (1:1) to receive Cre8 EVO or Resolute Onyx stents. The primary endpoint was target-lesion failure, defined as a composite of cardiac death, target-vessel myocardial infarction, and clinically indicated target-lesion revascularization at 1-year follow-up. The trial had a non-inferiority design with a 4% margin for the primary endpoint. A superiority analysis was planned if non-inferiority was confirmed. There were 106 primary events, 42 (7.2%) in the Cre8 EVO group and 64 (10.9%) in the Resolute Onyx group [hazard ratio (HR): 0.65, 95% confidence interval (CI): 0.44-0.96; Pnon-inferiority < 0.001; Psuperiority = 0.030]. Among the secondary endpoints, Cre8 EVO stents had significantly lower rate than Resolute Onyx stents of target-vessel failure (7.5% vs. 11.1%, HR: 0.67, 95% CI: 0.46-0.99; P = 0.042). Probable or definite stent thrombosis and all-cause death were not significantly different between groups. CONCLUSION: In patients with diabetes, Cre8 EVO stents were non-inferior to Resolute Onyx stents with regard to target-lesion failure composite outcome. An exploratory analysis for superiority at 1 year suggests that the Cre8 EVO stents might be superior to Resolute Onyx stents with regard to the same outcome. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT03321032.

Novel Supreme Drug-Eluting Stents With Early Synchronized Antiproliferative Drug Delivery to Inhibit Smooth Muscle Cell Proliferation After Drug-Eluting Stents Implantation in Coronary Artery Disease: Results of the PIONEER III Randomized Clinical Trial.

BACKGROUND: Accelerated endothelial healing after targeted antiproliferative drug delivery may limit the long-term inflammatory response of drug-eluting stents (DESs). The novel Supreme DES is designed to synchronize early drug delivery within 4 to 6 weeks of implantation, leaving behind a prohealing permanent base layer. Whether the Supreme DES is safe and effective in the short term and can improve long-term clinical outcomes is not known. METHODS: In an international, 2:1 randomized, single-blind trial, we compared treatment with Supreme DES to durable polymer everolimus-eluting stents (DP-EES) in patients with acute and chronic coronary syndromes. The primary end point was target lesion failure-a composite of cardiac death, target vessel myocardial infarction, or clinically driven target lesion revascularization. The trial was designed to demonstrate noninferiority (margin of 3.58%) of the Supreme DES at 12 months compared with DP-EES (URL: https://www.clinicaltrials.gov; Unique identifier: NCT03168776). RESULTS: From October 2017 to July 2019, a total of 1629 patients were randomly assigned (2:1) to the Supreme DES (N=1086) or DP-EES (N=543). At 12 months, target lesion failure occurred in 57 of 1057 patients (5.4%) in the Supreme DES group and in 27 of 532 patients (5.1%) in the DP-EES group (absolute risk difference, 0.32% [95% CI, -1.87 to 2.5]; Pnoninferiority=0.002]. There were no significant differences in rates of device success, clinically driven target lesion revascularization, or stent thrombosis at 12 months, and the safety composite of cardiovascular death and target vessel myocardial infarction was 3.5% versus 4.6% (hazard ratio, 0.76 [95% CI, 0.46-1.25]) with Supreme DES compared with DP-EES, although rates of combined clinically and non-clinically driven target lesion revascularization at 12 months were higher with Supreme DES. CONCLUSIONS: Among patients with acute and chronic coronary syndromes undergoing percutaneous coronary intervention, the Supreme DES proved to be noninferior to the standard DP-EES. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03168776.

A cross-sectional study evidences regulations of leukocytes in the colostrum of mothers with obesity.

BACKGROUND: Breastmilk is a dynamic fluid whose initial function is to provide the most adapted nutrition to the neonate. Additional attributes have been recently ascribed to breastmilk, with the evidence of a specific microbiota and the presence of various components of the immune system, such as cytokines and leukocytes. The composition of breastmilk varies through time, according to the health status of mother and child, and altogether contributes to the future health of the infant. Obesity is a rising condition worldwide that creates a state of systemic, chronic inflammation including leukocytosis. Here, we asked whether colostrum, the milk produced within the first 48 h post-partum, would contain a distinct leukocyte composition depending on the body mass index (BMI) of the mother. METHODS: We collected peripheral blood and colostrum paired samples from obese (BMI > 30) and lean (BMI < 25) mothers within 48 h post-partum and applied a panel of 6 antibodies plus a viability marker to characterize 10 major leukocyte subpopulations using flow cytometry. RESULTS: The size, internal complexity, and surface expression of CD45 and CD16 of multiple leukocyte subpopulations were selectively regulated between blood and colostrum irrespective of the study groups, suggesting a generalized cell-specific phenotype alteration. In obesity, the colostrum B lymphocyte compartment was significantly reduced, and CD16+ blood monocytes had an increased CD16 expression compared to the lean group. CONCLUSIONS: This is the first characterization of major leukocyte subsets in colostrum of mothers suffering from obesity and the first report of colostrum leukocyte subpopulations in Latin America. We evidence various significant alterations of most leukocyte populations between blood and colostrum and demonstrate a decreased colostrum B lymphocyte fraction in obesity. This pioneering study is a stepping stone to further investigate active immunity in human breastmilk.

Angiography-derived physiology guidance vs usual care in an All-comers PCI population treated with the healing-targeted supreme stent and Ticagrelor monotherapy: PIONEER IV trial design.

BACKGROUND: Current ESC guidelines recommend the use of intra-coronary pressure guidewires for functional assessment of intermediate-grade coronary stenoses. Angiography-derived quantitative flow ratio (QFR) is a novel method of assessing these stenoses, and guiding percutaneous coronary intervention (PCI). METHODS/DESIGN: The PIONEER IV trial is a prospective, all-comers, multi-center trial, which will randomize 2,540 patients in a 1:1 ratio to PCI guided by angiography-derived physiology or usual care, with unrestricted use in both arms of the Healing-Targeted Supreme sirolimus-eluting stent (HT Supreme). The stent's fast, biologically healthy, and robust endothelial coverage allows for short dual-antiplatelet therapy (DAPT); hence the antiplatelet regimen of choice is 1-month DAPT, followed by ticagrelor monotherapy. In the angiography-derived physiology guided arm, lesions will be functionally assessed using on-line QFR, with stenting indicated in lesions with a QFR ≤0.80. Post-stenting, QFR will be repeated in the stented vessel(s), with post-dilatation or additional stenting recommended if the QFR<0.91 distal to the stent, or if the delta QFR (across the stent) is >0.05. Usual care PCI is performed according to standard clinical practice. The primary endpoint is a non-inferiority comparison of the patient-oriented composite endpoint (POCE) of all-cause death, any stroke, any myocardial infarction, or any clinically, and physiologically driven revascularization with a non-inferiority risk-difference margin of 3.2%, at 1-year post-procedure. Clinical follow-up will be up to 3 years. SUMMARY: The PIONEER IV trial aims to demonstrate non-inferiority of QFR-guided PCI to usual care PCI with respect to POCE at 1-year in patients treated with HT Supreme stents and ticagrelor monotherapy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov UNIQUE IDENTIFIER: NCT04923191 CLASSIFICATIONS: Interventional Cardiology.

Clinical Features and Long-Term Outcomes in Very Young Patients with Myocardial Infarction with Non-Obstructive Coronary Arteries.

Background: The main cause of acute coronary syndrome (ACS) is coronary artery obstruction due to atherosclerotic plaque growth or thrombus formation secondary to plaque rupture or erosion. However, there is a subgroup of patients with signs and symptoms suggestive of ACS but without relevant coronary artery obstruction on coronary angiography. This population is defined as myocardial infarction with non-obstructive coronary arteries (MINOCA). The present study analyzes the clinical features and outcomes of very young patients with a diagnosis of MINOCA. Method: Nested case-control study of ≤40-year-old patients referred for coronary angiography due to clinical suspicion of ACS. Patients were divided into three groups: patients with obstructive coronary artery disease (CAD), patients diagnosed with MINOCA, and controls with non-coronary artery disease. Results: Of 19,321 coronary angiographies performed in our center in a period of 10 years, 408 (2.1%) were in patients ≤40 years old, and MINOCA was identified in 32 (21%) patients. The cardiovascular risk factors for obstructive CAD and MINOCA were very similar. The incidence of major adverse cardiovascular events (MACE) at follow-up was significantly higher in the MINOCA (HR 4.13 (95%CI 1.22-13.89) and obstructive CAD (HR 4.59 (95%CI 1.90-10.99) patients compared to controls. Cocaine use HR 14.58 (95%CI 3.08-69.02), family history of CAD HR 6.20 (95%CI 1.40-27.43), and depression HR 5.16 (95%CI 1.06-25.24) were associated with a poor outcome in the MINOCA population. Conclusion: Very young patients with MINOCA had a poor prognosis at long-term follow-up, similar to patients with obstructive CAD. Focusing efforts on secondary prevention is essential in this population.

Dual-Band CPW Graphene Antenna for Smart Cities and IoT Applications.

In this paper, a dual-band graphene coplanar waveguide antenna is designed for smart cities and internet of things applications. A graphene film is chosen as the conductive material for the radiation patches and ground plane with a thickness of 240 µm and an electric conductivity of 3.5 × 105 S/m. The dielectric is glass with a dielectric permittivity of 6 and a thickness of 2 mm. The implementation of the antenna on glass permits the integration of the antenna in smart cities and IoT applications. This antenna is based on two trapezoidal patches that generate the dual-band behavior. The overall dimensions of the antenna are 30 mm × 30 mm × 2 mm. The reflection coefficient, gain, and radiation patterns were measured and compared with the simulations. The antenna covers two frequency bands; the lower band covers the 2.45 GHz ISM band, and the upper band range covers from 4 to 7 GHz.

4E Assessment of an Organic Rankine Cycle (ORC) Activated with Waste Heat of a Flash-Binary Geothermal Power Plant.

In this paper, the 4E assessment (Energetic, Exergetic, Exergoeconomic and Exergoenvironmental) of a low-temperature ORC activated by two different alternatives is presented. The first alternative (S1) contemplates the activation of the ORC through the recovery of waste heat from a flash-binary geothermal power plant. The second alternative (S2) contemplates the activation of the ORC using direct heat from a geothermal well. For both alternatives, the energetic and exergetic models were established. At the same time, the economic and environmental impact models were developed. Finally, based on the combination of the exergy concepts and the economic and ecological indicators, the exergoeconomic and exergoenvironmental performances of the ORC were obtained. The results show higher economic, exergoeconomic and exergoenvironmental profitability for S1. Besides, for the alternative S1, the ORC cycle has an acceptable economic profitability for a net power of 358.4 kW at a temperature of 110 °C, while for S2, this profitability starts being attractive for a power 2.65 times greater than S1 and with a temperature higher than 135 °C. In conclusion, the above represents an area of opportunity and a considerable advantage for the implementation of the ORC in the recovery of waste heat from flash-binary geothermal power plants.

Usefulness of the Hybrid RFR-FFR Approach: Results of a Prospective and Multicenter Analysis of Diagnostic Agreement between RFR and FFR-The RECOPA (REsting Full-Cycle Ratio Comparation versus Fractional Flow Reserve (A Prospective Validation)) Study.

BACKGROUND: The resting full-cycle ratio (RFR) is a novel resting index which in contrast to the gold standard (fractional flow reserve (FFR)) does not require maximum hyperemia induction. The objectives of this study were to evaluate the agreement between RFR and FFR with the currently recommended thresholds and to design a hybrid RFR-FFR ischemia detection strategy, allowing a reduction of coronary vasodilator use. MATERIALS AND METHODS: Patients subjected to invasive physiological study in 9 Spanish centers were prospectively recruited between April 2019 and March 2020. Sensitivity and specificity studies were made to assess diagnostic accuracy between the recommended levels of RFR ≤0.89 and FFR ≤0.80 (primary objective) and to determine the RFR "grey zone" in order to define a hybrid strategy with FFR affording 95% global agreement compared with FFR alone (secondary objective). RESULTS: A total of 380 lesions were evaluated in 311 patients. Significant correlation was observed (R 2 = 0.81; P < 0.001) between the two techniques, with 79% agreement between RFR ≤ 0.89 and FFR ≤ 0.80 (positive predictive value, 68%, and negative predictive value, 80%). The hybrid RFR-FFR strategy, administering only adenosine in the "grey zone" (RFR: 0.86 to 0.92), exhibited an agreement of over 95% with FFR, with high predictive values (positive predictive value, 91%, and negative predictive value, 92%), reducing the need for vasodilators by 58%. CONCLUSIONS: Dichotomous agreement between RFR and FFR with the recommended thresholds is significant but limited. The adoption of a hybrid RFR-FFR strategy affords very high agreement, with minimization of vasodilator use.

Impact of Comorbidities and Antiplatelet Regimen on Platelet Reactivity Levels in Patients Undergoing Transcatheter Aortic Valve Implantation.

ABSTRACT: The aim of our study is to assess the impact of anemia, chronic kidney disease, and diabetes mellitus on platelet reactivity (PR) in patients with severe aortic stenosis, both at baseline and after transcatheter aortic valve implantation (TAVI). This study is a prespecified subanalysis of the REAC-TAVI prospective, multicenter trial that included patients pretreated with aspirin + clopidogrel before TAVI. PR was measured at baseline and at 5 different time points after TAVI with the VerifyNow assay (Accriva Diagnostics, San Diego, CA), over a 3-month follow-up period. Patients with high PR (HPR) at baseline, before TAVI (n = 48) were randomized to aspirin + clopidogrel or aspirin + ticagrelor for 3 months, whereas those with normal PR (NPR) (n = 20) were continued on aspirin + clopidogrel. A "raiser response" in PR was defined as an increase in PR units >20% of baseline after TAVI. Patients with HPR before TAVI presented concomitant anemia and chronic kidney disease more frequently than their counterparts with NPR. Anemia and higher body mass index were independently associated with HPR to clopidogrel at baseline. Moreover, anemic patients with baseline HPR who were continued on clopidogrel presented higher PR after TAVI than patients with HPR switched to ticagrelor. All patients with baseline NPR presented a "raiser response" after TAVI, which was nonexistent among patients with HPR managed with ticagrelor. In summary, anemia seems as a relevant factor associated with baseline HPR and higher PR after TAVI in patients with baseline HPR randomized to clopidogrel, whereas ticagrelor proved more effective than clopidogrel at attaining sustained reductions in PR during follow-up, regardless of baseline comorbidities.

Hypercholesterolemic patients have higher eryptosis and erythrocyte adhesion to human endothelium independently of statin therapy.

BACKGROUND: Phosphatidylserine (PS) externalization out of the membrane facilitates the eryptotic erythrocytes (EE) binding to endothelial cells (EC), potentially leading to atherosclerosis. Thus, the levels of eryptosis and interactions of EE-EC in hypercholesterolemic patients, either non-medicated or medicated, compared with healthy subjects were studied. METHODS: A total of 56 subjects clustered into three groups: (control (n = 20), hypercholesterolemic non-treated (HCNT) (n = 15), and statin-treated (HCT) (n = 21)) were enrolled in this cross-sectional study. Biochemical parameters were determined with validated and standard methods. PS exposure was estimated from annexin-V-binding, cell volume from forward scatter (FSC), and GSH from CMFDA fluorescence by flow cytometry. The erythrocyte-EC adhesion assay was performed by using the parallel-plate flow chamber technique. RESULTS: Higher PS externalization and adhesion of erythrocytes to EC (P < .05) was found in hypercholesterolemic subjects, regardless of statin treatment, compared with the control group. Although no correlation between FSC and PS externalization with other parameters was found, GSH was inversely correlated with erythrocyte adhesion, which was significantly correlated with total cholesterol, LDL-c, and apolipoprotein B. CONCLUSION: The link between hypercholesterolemia and eryptosis suggests a possible detrimental impact of this binomial on endothelial function with possible further development of atherosclerosis and microcirculation problems in hypercholesterolemic patients, independently of statin therapy.

COVID-19: Mechanistic model calibration subject to active and varying non-pharmaceutical interventions.

Mathematical models are useful in epidemiology to understand COVID-19 contagion dynamics. We aim to demonstrate the effectiveness of parameter regression methods to calibrate an established epidemiological model describing infection rates subject to active, varying non-pharmaceutical interventions (NPIs). We assess the potential of established chemical engineering modelling principles and practice applied to epidemiological systems. We exploit the sophisticated parameter regression functionality of a commercial chemical engineering simulator with piecewise continuous integration, event and discontinuity management. We develop a strategy for calibrating and validating a model. Our results using historic data from 4 countries provide insights into on-going disease suppression measures, while visualisation of reported data provides up-to-date condition monitoring of the pandemic status. The effective reproduction number response to NPIs is non-linear with variable response rate, magnitude and direction. Our purpose is developing a methodology without presenting a fully optimised model, or attempting to predict future course of the COVID-19 pandemic.

Intensity of infection with intracellular Eimeria spp. and pinworms is reduced in hybrid mice compared to parental subspecies.

Genetic diversity in animal immune systems is usually beneficial. In hybrid recombinants, this is less clear, as the immune system could also be impacted by genetic conflicts. In the European house mouse hybrid zone, the long-standing impression that hybrid mice are more highly parasitized and less fit than parentals persists despite the findings of recent studies. Working across a novel transect, we assessed infections by intracellular protozoans, Eimeria spp., and infections by extracellular macroparasites, pinworms. For Eimeria, we found lower intensities in hybrid hosts than in parental mice but no evidence of lowered probability of infection or increased mortality in the centre of the hybrid zone. This means ecological factors are very unlikely to be responsible for the reduced load of infected hybrids. Focusing on parasite intensity (load in infected hosts), we also corroborated reduced pinworm loads reported for hybrid mice in previous studies. We conclude that intensity of diverse parasites, including the previously unstudied Eimeria, is reduced in hybrid mice compared to parental subspecies. We suggest caution in extrapolating this to differences in hybrid host fitness in the absence of, for example, evidence for a link between parasitemia and health.

Lysyl oxidase-like 2 deaminates lysine 4 in histone H3.

Methylation of lysine 4 (K4) within histone H3 has been linked to active transcription and is removed by LSD1 and the JmjC domain-containing proteins by amino-oxidation or hydroxylation, respectively. Here, we describe the deamination catalyzed by Lysyl oxidase-like 2 protein (LOXL2) as an unconventional chemical mechanism for H3K4 modification. Infrared spectroscopy and mass spectrometry analyses demonstrated that recombinant LOXL2 specifically deaminates trimethylated H3K4. Moreover, LOXL2 activity is linked with the transcriptional control of CDH1 gene by regulating H3K4me3 deamination. These results reveal another H3 modification and provide a different mechanism for H3K4 modification.