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Background We recently found that loss of endothelial cell APOE3 disrupts neurovascular and synaptic function. However, whether endothelial APOE4 is detrimental or protective for neural function under physiological conditions is unknown. Therefore, the goal of this study was to determine the role of endothelial cell APOE4 in regulating brain function in vivo. Methods and Results We developed APOE4fl/fl/Cdh5(PAC)‐CreERT2+/− and APOE4fl/fl/Cdh5(PAC)‐CreERT2−/− (control) mice. Knockdown of endothelial cell APOE4 was induced at ≈4 to 5 weeks of age. Experiments were conducted at 9 months of age to evaluate neurovascular and neuronal function via biochemistry, immunohistochemistry, behavior tests, and electrophysiology. Endothelial cell APOE4 knockdown resulted in higher neurovascular permeability, lower claudin‐5 vessel coverage, impaired trace fear memory extinction, and disruption of cortical excitatory‐inhibitory balance of synaptic activity. Conclusions Our data support the novel concept that endothelial cell APOE4 is protective for brain function when other cell types express APOE4.

Background The acquisition of contrast‐enhanced T1 maps to calculate extracellular volume (ECV) requires contrast agent administration and is time consuming. This study investigates generative adversarial networks for contrast‐free, virtual extracellular volume (vECV) by generating virtual contrast‐enhanced T1 maps. Methods and Results This retrospective study includes 2518 registered native and contrast‐enhanced T1 maps from 1000 patients who underwent cardiovascular magnetic resonance at 1.5 Tesla. Recent hematocrit values of 123 patients (hold‐out test) and 96 patients from a different institution (external evaluation) allowed for calculation of conventional ECV. A generative adversarial network was trained to generate virtual contrast‐enhanced T1 maps from native T1 maps for vECV creation. Mean and SD of the difference per patient (ΔECV) were calculated and compared by permutation of the 2‐sided t test with 10 000 resamples. For ECV and vECV, differences in area under the receiver operating characteristic curve (AUC) for discriminating hold‐out test patients with normal cardiovascular magnetic resonance versus myocarditis or amyloidosis were tested with Delong's test. ECV and vECV showed a high agreement in patients with myocarditis (ΔECV: hold‐out test, 2.0%±1.5%; external evaluation, 1.9%±1.7%) and normal cardiovascular magnetic resonance (ΔECV: hold‐out test, 1.9%±1.4%; external evaluation, 1.5%±1.2%), but variations in amyloidosis were higher (ΔECV: hold‐out test, 6.2%±6.0%; external evaluation, 15.5%±6.4%). In the hold‐out test, ECV and vECV had a comparable AUC for the diagnosis of myocarditis (ECV AUC, 0.77 versus vECV AUC, 0.76; P=0.76) and amyloidosis (ECV AUC, 0.99 versus vECV AUC, 0.96; P=0.52). Conclusions Generation of vECV on the basis of native T1 maps is feasible. Multicenter training data are required to further enhance generalizability of vECV in amyloidosis.

Abstract Therapies for inoperable chronic thromboembolic pulmonary hypertension (CTEPH) include balloon pulmonary angioplasty (BPA) and PH‐specific medical therapy. This study compares survival and its predictors before and after the introduction of BPA. BPA was independently associated with survival; however, there was no difference in overall survival between the two cohorts.

Background Takotsubo syndrome (TS) and myocardial infarction (MI) share similar clinical and laboratory characteristics but have important differences in causes, demographics, management, and outcomes. Methods and Results In this observational study, the National Inpatient Sample and National Readmission Database were used to identify patients admitted with TS, type 1 MI, or type 2 MI in the United States between October 1, 2017, and December 31, 2019. We compared patients hospitalized with TS, type 1 MI, and type 2 MI with respect to key features and outcomes. Over the 27‐month study period, 2 035 055 patients with type 1 MI, 639 075 patients with type 2 MI, and 43 335 patients with TS were identified. Cardiac arrest, ventricular fibrillation, and ventricular tachycardia were more prevalent in type 1 MI (4.02%, 3.2%, and 7.2%, respectively) compared with both type 2 MI (2.8%, 0.8%, and 5.4% respectively) and TS (2.7%, 1.8%, and 5.3%, respectively). Risk of mortality was lower in TS compared with both type 1 MI (3.3% versus 7.9%; adjusted odds ratio [OR], 0.3; P

Abstract The prognosis of pulmonary arterial hypertension (PAH) remains dismal. Over the years, multiple therapeutic advances have been introduced. This study evaluates the evolution of PAH survival over the past 15 years. We included 293 consecutive adult patients diagnosed with PAH between 2005 and 2019 (median age: 61.8 years, 70.3% female). Patients were divided into three cohorts based on the time of diagnosis: 2005–2009, 2010–2014, and 2015–2019 (2005–2009: n = 56; 2010–2014: n = 111; 2015–2019: n = 126). Transplant‐free survival was measured from the date of right heart catheterization until patients reached the composite endpoint of lung transplant or death. Multivariable cox‐pulmonary hypertension regression was used to study the effect of the time of diagnosis. The final cox model was fitted in both younger and older patients to evaluate the difference between these groups. During a median follow‐up time of 4.1 (interquartile range: 2.2–7.3) years, 9 patients underwent lung transplantation and 151 patients died. The median overall transplant‐free survival was 6.2 (5.5–8.0) years. Patients older than 56 years at baseline who were diagnosed in 2005–2009 showed better survival compared to patients diagnosed in 2010–2014 and 2015–2019 with an adjusted hazard ratio of, respectively, 2.12 (1.11–4.03) and 2.83 (1.41–5.69). Patients younger than 56 years showed neither an improved nor deteriorated survival over time. In conclusion, survival in patients with PAH did not improve over time, despite more available therapeutic options. This might be partly due to the changed demographic characteristics of the PAH patients and a still important diagnostic delay.

Background Most published reports describing outcomes of patients with cardiovascular implantable electronic device–related infective endocarditis (CIED‐IE) are single‐center studies with small patient sample sizes. The goal of this study was to utilize population‐based data to assess trends in CIED‐IE hospitalization and to compare outcomes between patients hospitalized with CIED‐IE, prosthetic valve endocarditis (PVE), and native valve endocarditis (NVE). Methods and Results A query of the National (Nationwide) Inpatient Sample (NIS) database between 2003 and 2017 identified 646 325 patients hospitalized with infective endocarditis in the United States of whom 585 974 (90%) had NVE, 27 257 (4.2%) had CIED‐IE, and 26 111 (4%) had PVE. There was a 509% increase in CIED‐IE hospitalizations in the United States from 2003 to 2017 (P trend

Abstract Despite the importance of species–area relationships (SARs) to conservation, SARs in human‐fragmented rivers have received little attention. Our aim was to test for the presence and strength of SARs for littoral fish assemblages of an extensively dammed river in south‐central Ontario, Canada, and to examine long‐running hypotheses for the drivers of SARs. Twenty‐six navigational dams with locks built between 1837 and 1913 occur along the 160 km length of the Trent River examined in this study. We evaluated the relationship between richness and fragment area, and then used linear models to test whether the area per se, habitat diversity, or other hypotheses were best supported by the data. A power–function relationship with area explained 46% of the variation in fish species richness, and the slope (z = 0.4) was high compared with SARs reported from other ecosystems, indicating that species accumulated rapidly with an increase in fragment area. Multi‐predictor models suggested that area was significantly related to richness, but that vegetation cover diversity had a stronger relative effect. The slope of our SAR may indicate that there is a high degree of isolation between populations in different fragments, even though the lock system reportedly allows some passage of organisms. Our findings also suggest that mitigating against local extinction due to small population sizes (i.e., area effects), and enhancing aquatic vegetation cover may be viable strategies for promoting species diversity in the study river. Studies of SARs in fragmented rivers may offer additional benefits to supporting restoration planning where efforts are being made to increase species diversity.

Abstract Precise monitoring of specific biomarkers in biological fluids with accurate biodiagnostic sensors is critical for early diagnosis of diseases and subsequent treatment planning. In this work, we demonstrated an innovative biodiagnostic sensor, portable reusable accurate diagnostics with nanostar antennas (PRADA), for multiplexed biomarker detection in small volumes (~50 μl) enabled in a microfluidic platform. Here, PRADA simultaneously detected two biomarkers of myocardial infarction, cardiac troponin I (cTnI), which is well accepted for cardiac disorders, and neuropeptide Y (NPY), which controls cardiac sympathetic drive. In PRADA immunoassay, magnetic beads captured the biomarkers in human serum samples, and gold nanostars (GNSs) “antennas” labeled with peptide biorecognition elements and Raman tags detected the biomarkers via surface‐enhanced Raman spectroscopy (SERS). The peptide‐conjugated GNS‐SERS barcodes were leveraged to achieve high sensitivity, with a limit of detection (LOD) of 0.0055 ng/ml of cTnI, and a LOD of 0.12 ng/ml of NPY comparable with commercially available test kits. The innovation of PRADA was also in the regeneration and reuse of the same sensor chip for ~14 cycles. We validated PRADA by testing cTnI in 11 de‐identified cardiac patient samples of various demographics within a 95% confidence interval and high precision profile. We envision low‐cost PRADA will have tremendous translational impact and be amenable to resource‐limited settings for accurate treatment planning in patients.

Abstract High levels of gums such as dextran, produced by Leuconostoc and Lactobacillus spp., have a severe impact on factory throughput and sugar quality. This study aimed to determine the phylogenetic relationships between gum‐producing Leuconostoc and Lactobacillus bacteria which were isolated from various locations in a sugarcane processing factory at times when low‐ and high‐dextran raw sugar, respectively, were produced. Phylogenetic analysis of 16S rRNA gene sequences grouped 81 isolates with the type strains of Leuconostoc mesenteroides (subspp. mesenteroides, dextranicum, and cremoris), Leuconostoc pseudomesenteroides, Leuconostoc lactis, and Leuconostoc citreum, respectively. Forty‐three isolates clustered with the type strain of Lactobacillus fermentum. The phylogenetic relatedness of the isolates was determined by sequencing and analysis of the housekeeping genes rpoA and dnaA for Leuconostoc spp. and the pheS and tuf genes for the Lactobacillus spp. The rpoA gene proved discriminatory for the phylogenetic resolution of all of the isolated Leuconostoc spp. and the dnaA housekeeping gene was shown to be effective for isolates clustering with the type strains of Leuc. mesenteroides and Leuc. citreum. None of the loci examined permitted differentiation at the subspecies level of Leuc. mesenteroides. Single‐locus analysis, as well as the concatenation of the pheS and tuf housekeeping gene sequences, yielded identical phylogenies for the Lactobacillus isolates corresponding to L. fermentum.

Background Delivery of hydrogels to the heart is a promising strategy for mitigating the detrimental impact of myocardial infarction (MI). Challenges associated with the in vivo delivery of currently available hydrogels have limited clinical translation of this technology. Gelatin methacryloyl (GelMA) bioadhesive hydrogel could address many of the limitations of available hydrogels. The goal of this proof‐of‐concept study was to evaluate the cardioprotective potential of GelMA in a mouse model of MI. Methods and Results The physical properties of GelMA bioadhesive hydrogel were optimized in vitro. Impact of GelMA bioadhesive hydrogel on post‐MI recovery was then assessed in vivo. In 20 mice, GelMA bioadhesive hydrogel was applied to the epicardial surface of the heart at the time of experimental MI. An additional 20 mice underwent MI but received no GelMA bioadhesive hydrogel. Survival rates were compared for GelMA‐treated and untreated mice. Left ventricular function was assessed 3 weeks after experimental MI with transthoracic echocardiography. Left ventricular scar burden was measured with postmortem morphometric analysis. Survival rates at 3 weeks post‐MI were 89% for GelMA‐treated mice and 50% for untreated mice (P=0.011). Left ventricular contractile function was better in GelMA‐treated than untreated mice (fractional shortening 37% versus 26%, P

Abstract Background Antigen-specific immunotherapy (AIT) is a promising therapeutic approach for both cow’s milk allergy (CMA) and peanut allergy (PNA), but needs optimization in terms of efficacy and safety. Aim Compare oral immunotherapy (OIT) and subcutaneous immunotherapy (SCIT) in murine models for CMA and PNA and determine the dose of allergen needed to effectively modify parameters of allergy. Methods Female C3H/HeOuJ mice were sensitized intragastrically (i.g.) to whey or peanut extract with cholera toxin. Mice were treated orally (5 times/week) or subcutaneously (3 times/week) for three consecutive weeks. Hereafter, the acute allergic skin response, anaphylactic shock symptoms and body temperature were measured upon intradermal (i.d.) and intraperitoneal (i.p.) challenge, and mast cell degranulation was measured upon i.g. challenge. Allergen-specific IgE, IgG1 and IgG2a were measured in serum at different time points. Single cell suspensions derived from lymph organs were stimulated with allergen to induce cytokine production and T cell phenotypes were assessed using flow cytometry. Results Both OIT and SCIT decreased clinically related signs upon challenge in the CMA and PNA model. Interestingly, a rise in allergen-specific IgE was observed during immunotherapy, hereafter, treated mice were protected against the increase in IgE caused by allergen challenge. Allergen-specific IgG1 and IgG2a increased due to both types of AIT. In the CMA model, SCIT and OIT reduced the percentage of activated Th2 cells and increased the percentage of activated Th1 cells in the spleen. OIT increased the percentage of regulatory T cells (Tregs) and activated Th2 cells in the MLN. Th2 cytokines IL-5, IL-13 and IL-10 were reduced after OIT, but not after SCIT. In the PNA model, no differences were observed in percentages of T cell subsets. SCIT induced Th2 cytokines IL-5 and IL-10, whereas OIT had no effect. Conclusion We have shown clinical protection against allergic manifestations after OIT and SCIT in a CMA and PNA model. Although similar allergen-specific antibody patterns were observed, differences in T cell and cytokine responses were shown. Whether these findings are related to a different mechanism of AIT in CMA and PNA needs to be elucidated.

Background Variability in the management of atrial fibrillation (AF) in the emergency department (ED) leads to avoidable hospital admissions and prolonged length of stay (LOS). In a retrospective single‐center study, a multidisciplinary AF treatment pathway was associated with a reduced hospital admission rate and reduced LOS. To assess the applicability of the AF pathway across institutions, we conducted a 2‐center study. Methods and Results We performed a prospective, 2‐stage study at 2 tertiary care hospitals. During the first stage, AF patients in the ED received routine care. During the second stage, AF patients received care according to the AF pathway. The primary study outcome was hospital admission rate. Secondary outcomes included ED LOS and inpatient LOS. We enrolled 104 consecutive patients in each stage. Patients treated using the AF pathway were admitted to the hospital less frequently than patients who received routine care (15% versus 55%; P

The design, implementation, and testing of a control system for a flexible microgrid (MG) is presented in this study. The MG controllers can be implemented in a real-world MG with multiple smart switches, photovoltaic panel system, and battery energy storage systems (BESSs). With the benefits from smart switches, the MG has unique characteristics such as dynamic boundary and flexible point of interconnection (POI) concepts. To control such a unique MG and realise the dynamic boundary, an MG central controller and two types of local controllers are implemented. Compared to the MG with fixed boundary, the MG with dynamic boundary can have smaller BESS capacity, better utilisation of renewable energy, and multiple POI options. Also, compared with IEEE Std 2030.7–2017, the topology identification and active and reactive power balance functions are newly designed to realise the dynamic boundary concept. The planned islanding and reconnection functions are modified to realise the flexible POI concept. These functions are introduced including the software architecture, cooperation, and interaction among them. Finally, a hardware-in-the-loop testing platform based on the Opal-RT real-time simulator is set up to verify the performance, realisation of the dynamic boundary, and flexible POI concepts with four comprehensive test scenarios.