Functional and Quality of Life Outcomes After TAVR in Patients With Low Gradient Aortic Stenosis.

Severe aortic stenosis is a common valvular heart disease associated with significant mortality and morbidity. Transcatheter aortic valve replacement (TAVR) is an effective treatment for this condition. Less data is available regarding functional and quality-of-life outcomes in patients with severe, low-gradient aortic stenosis following TAVR. This single-center, retrospective study compared changes in New York Heart Association (NYHA) class and Kansas City Cardiomyopathy Questionnaire (KCCQ) scores at 30 days and 1 year in patients with 3 variants of severe, low-gradient aortic stenosis following TAVR. Secondary outcomes included 1-year major adverse cardiovascular event. A total of 170 patients were included. All 3 low-gradient variants had significant improvement in NYHA class and KCCQ overall scores at 30 days and 1 year. There were no significant differences in KCCQ overall scores between the 3 groups and no significant differences in secondary outcomes. Patients with low-gradient aortic stenosis experienced significant improvements in functional and quality-of-life outcomes following TAVR.

SuPAR mediates viral response proteinuria by rapidly changing podocyte function.

Elevation in soluble urokinase receptor (suPAR) and proteinuria are common signs in patients with moderate to severe coronavirus disease 2019 (COVID-19). Here we characterize a new type of proteinuria originating as part of a viral response. Inoculation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes increased suPAR levels and glomerulopathy in African green monkeys. Using an engineered mouse model with high suPAR expression, inhaled variants of SARS-CoV-2 spike S1 protein elicite proteinuria that could be blocked by either suPAR antibody or SARS-CoV-2 vaccination. In a cohort of 1991 COVID-19 patients, suPAR levels exhibit a stepwise association with proteinuria in non-Omicron, but not in Omicron infections, supporting our findings of biophysical and functional differences between variants of SARS-CoV-2 spike S1 protein and their binding to podocyte integrins. These insights are not limited to SARS-CoV-2 and define viral response proteinuria (VRP) as an innate immune mechanism and co-activation of podocyte integrins.

High-yield fabrication of electromechanical devices based on suspended Ti3C2Tx MXene monolayers.

MXenes, two-dimensional transition metal carbides, nitrides, and carbonitrides, are known for their exceptional electronic and mechanical properties. Yet, the experimental efforts toward the realization of MXene-based nanoelectromechanical systems (NEMS) combining electrical and mechanical functionalities of MXenes at the nanoscale remain very limited. Here, we demonstrate a high-yield fabrication of the electromechanical devices based on individual suspended monolayer MXene flakes. We employed Ti3C2Tx, the most popular MXene material to date, that can be produced as high-quality micrometer-scale monolayer flakes with a high electrical conductivity of over 10 000 S cm-1 and a high effective Young's modulus of about 330 GPa. These Ti3C2Tx flakes can be transferred over prefabricated trenches in a Si/Si3N4 substrate at a high yield, potentially enabling fabrication of hundreds of electromechanical devices based on suspended MXene monolayers. We demonstrate very clean, uniform, and well-stretched membranes with different dimensions, with Ti3C2Tx flakes suspended over trenches with gaps ranging from 200 nm to 2 µm. The resulting Ti3C2Tx monolayer membranes were electrostatically actuated, while their vertical displacement was monitored using a tip of an atomic force microscope (AFM). The devices reliably responded to the electrostatic actuation in ambient conditions over multiple cycles and with different measurement parameters, such as AC frequency, AC voltage amplitude, and AFM tip loading force. The demonstration of the high-yield fabrication of working electromechanical devices based on suspended Ti3C2Tx MXene membranes at the ultimate monolayer limit paves the way for the future exploration of the potential of MXenes for NEMS applications.

Bifunctional Amine- and Thiol-Modified Ti3C2Tx MXene for Trace Detection of Heavy Metals.

Surface functionalization of two-dimensional (2D) transition metal carbides, nitrides, and carbonitrides, also known as MXenes, is a powerful approach for modification of their physical and chemical properties for new applications. In this study, we demonstrate the synthesis of a bifunctional Ti3C2Tx MXene modified with amine and thiol groups through a facile condensation reaction. We successfully employed the resulting NH2/SH-Ti3C2Tx MXene as a solid phase in the ultrasonic-assisted dispersive micro solid-phase extraction (d-µ-SPE) method for the analytical determination of heavy metals at trace levels in food and soil samples. The prepared NH2/SH-Ti3C2Tx MXene showed remarkable performance in the ultrasonic-assisted d-µ-SPE method with limits of detection of 0.12 and 2.30 ng mL-1, with linear dynamic ranges of 0.50-90 µg L-1 and 10-120 µg L-1 for cadmium (Cd2+) and lead (Pb2+) ions, respectively. Furthermore, the extraction efficiencies were greater than 97%, with a relative standard deviation of less than 3% for five separate batch experiments in the determination of 5.0 µg L-1 of Cd2+ and Pb2+. This study shows that NH2/SH-Ti3C2Tx can be used as a simple, rapid, reliable, selective, and sensitive material in the d-µ-SPE method for the trace determination of Cd2+ and Pb2+ in soil and agricultural products. This study demonstrates the utility of MXenes for analytical chemistry and suggests that further advances in methods for the functionalization of MXenes can open new applications for these already exciting materials.

Soluble Urokinase Plasminogen Activator Receptor and Venous Thromboembolism in COVID-19.

Background Venous thromboembolism (VTE) contributes significantly to COVID-19 morbidity and mortality. The urokinase receptor system is involved in the regulation of coagulation. Levels of soluble urokinase plasminogen activator receptor (suPAR) reflect hyperinflammation and are strongly predictive of outcomes in COVID-19. Whether suPAR levels identify patients with COVID-19 at risk for VTE is unclear. Methods and Results We leveraged a multinational observational study of patients hospitalized for COVID-19 with suPAR and D-dimer levels measured on admission. In 1960 patients (mean age, 58 years; 57% men; 20% Black race), we assessed the association between suPAR and incident VTE (defined as pulmonary embolism or deep vein thrombosis) using logistic regression and Fine-Gray modeling, accounting for the competing risk of death. VTE occurred in 163 (8%) patients and was associated with higher suPAR and D-dimer levels. There was a positive association between suPAR and D-dimer (ß=7.34; P=0.002). Adjusted for clinical covariables, including D-dimer, the odds of VTE were 168% higher comparing the third with first suPAR tertiles (adjusted odds ratio, 2.68 [95% CI, 1.51-4.75]; P<0.001). Findings were consistent when stratified by D-dimer levels and in survival analysis accounting for death as a competing risk. On the basis of predicted probabilities from random forest, a decision tree found the combined D-dimer <1 mg/L and suPAR <11 ng/mL cutoffs, identifying 41% of patients with only 3.6% VTE probability. Conclusions Higher suPAR was associated with incident VTE independently of D-dimer in patients hospitalized for COVID-19. Combining suPAR and D-dimer identified patients at low VTE risk. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04818866.

SARS-CoV-2 pirates the kidneys: A scar(y) story.

SARS-CoV-2 can cause diverse severe and lasting damage to the kidneys. In the latest issue of Cell Stem Cell, Jansen et al. utilized data gleaned from human kidney autopsies and human induced pluripotent stem cell-derived kidney organoids to investigate the direct effects of SARS-CoV-2 infection on kidney cells. They found that such infections resulted in renal scarring (notably, tubulointerstitial fibrosis).

Trans-ethnic genome-wide association study of blood metabolites in the Chronic Renal Insufficiency Cohort (CRIC) study.

Metabolomics genome wide association study (GWAS) help outline the genetic contribution to human metabolism. However, studies to date have focused on relatively healthy, population-based samples of White individuals. Here, we conducted a GWAS of 537 blood metabolites measured in the Chronic Renal Insufficiency Cohort (CRIC) Study, with separate analyses in 822 White and 687 Black study participants. Trans-ethnic meta-analysis was then applied to improve fine-mapping of potential causal variants. Mean estimated glomerular filtration rate was 44.4 and 41.5 mL/min/1.73m2 in the White and Black participants, respectively. There were 45 significant metabolite associations at 19 loci, including novel associations at PYROXD2, PHYHD1, FADS1-3, ACOT2, MYRF, FAAH, and LIPC. The strength of associations was unchanged in models additionally adjusted for estimated glomerular filtration rate and proteinuria, consistent with a direct biochemical effect of gene products on associated metabolites. At several loci, trans-ethnic meta-analysis, which leverages differences in linkage disequilibrium across populations, reduced the number and/or genomic interval spanned by potentially causal single nucleotide polymorphisms compared to fine-mapping in the White participant cohort alone. Across all validated associations, we found strong concordance in effect sizes of the potentially causal single nucleotide polymorphisms between White and Black study participants. Thus, our study identifies novel genetic determinants of blood metabolites in chronic kidney disease, demonstrates the value of diverse cohorts to improve causal inference in metabolomics GWAS, and underscores the shared genetic basis of metabolism across race.

Decoupling of Dual-Polarized Antenna Arrays Using Non-Resonant Metasurface.

A non-resonant metasurface (NRMS) concept is reported in this paper to improve the isolation of dual-polarized and wideband large-scale antenna arrays. By properly designing the NRMS, it can perform stable negative permeability and positive permittivity along the tangential direction of the NRMS within a wide band, which can be fully employed to suppress the mutual couplings of large-scale antenna arrays. At the same time, the proposed NRMS can also result in positive permittivity and permeability along the normal direction of the NRMS, which guarantees the free propagation of electromagnetic waves from antenna arrays along the normal direction. For demonstration, a 4×4 dual-polarized antenna array loading with the proposed NRMS is designed to improve the isolations of the antenna array. The simulations demonstrate that the isolations among all ports are over 24 dB from 4.36 to 4.94 GHz, which are experimentally verified by the measured results. Moreover, the radiation patterns of antenna elements are still maintained after leveraging the proposed NRMS. Due to the simple structure of the proposed NRMS, it is very promising to be widely employed for massive MIMO antenna arrays.

Oral anticoagulants and relative risk of acute kidney injury in patients with atrial fibrillation: A systematic review and network meta-analysis.

Study objective: Oral anticoagulants (direct oral anticoagulants [DOACs] or warfarin) prevent stroke in patients with atrial fibrillation (AF), but their use may be associated with acute kidney injury (AKI). We aimed to compare AKI risk across individual oral anticoagulants in patients with AF. Design: Systematic review and network meta-analysis. Setting: Randomized trials and population-based studies. Participants: Patients with AF. Interventions: Oral anticoagulants. Main outcome measures: AKI. Results: A systematic literature search in Medline and Embase databases performed on December 17, 2021 identified ten randomized trials and eight population-based longitudinal studies based on prespecified inclusion criteria for systematic review. Clinical trials had short follow-ups and reported only low event rates of serious AKI. Retrospective longitudinal studies were assessed to be at higher risk for bias from confounding and outcome ascertainment, but follow-up was longer (1.5 to 8 years), with AKI incidence ranging from 2 to 29/100 person-years. Eight longitudinal studies that met transitivity assumption were included in a random-effects network meta-analysis within a Bayesian framework. All DOACs were associated with significantly lower risk of AKI compared to warfarin. Dabigatran was associated with lower risk of AKI compared to apixaban (hazard ratio [HR] = 0.82; 95% confidence interval [CI]: 0.68-0.99), rivaroxaban (HR = 0.84; 95%CI: 0.72-0.98), and warfarin (HR = 0.68; 95%CI: 0.59-0.77). Effect size estimates varied by chronic kidney disease status and study geographic locations. Conclusion: Apixaban, rivaroxaban, and dabigatran were associated with lower long-term risk of AKI compared to warfarin among patients with AF, with dabigatran potentially associated with the lowest risk.

Genome-wide association study of serum metabolites in the African American Study of Kidney Disease and Hypertension.

The genome-wide association study (GWAS) is a powerful means to study genetic determinants of disease traits and generate insights into disease pathophysiology. To date, few GWAS of circulating metabolite levels have been performed in African Americans with chronic kidney disease. Hypothesizing that novel genetic-metabolite associations may be identified in a unique population of African Americans with a lower glomerular filtration rate (GFR), we conducted a GWAS of 652 serum metabolites in 619 participants (mean measured glomerular filtration rate 45 mL/min/1.73m2) in the African American Study of Kidney Disease and Hypertension, a clinical trial of blood pressure lowering and antihypertensive medication in African Americans with chronic kidney disease. We identified 42 significant variant metabolite associations. Twenty associations had been previously identified in published GWAS, and eleven novel associations were replicated in a separate cohort of 818 African Americans with genetic and metabolomic data from the Atherosclerosis Risk in Communities Study. The replicated novel variant-metabolite associations comprised eight metabolites and eleven distinct genomic loci. Nine of the replicated associations represented clear enzyme-metabolite interactions, with high expression in the kidneys as well as the liver. Three loci (ACY1, ACY3, and NAT8) were associated with a common pool of metabolites, acetylated amino acids, but with different individual affinities. Thus, extensive metabolite profiling in an African American population with chronic kidney disease aided identification of novel genome-wide metabolite associations, providing clues about substrate specificity and the key roles of enzymes in modulating systemic levels of metabolites.

Biomarkers of Immune Activation and Incident Kidney Failure With Replacement Therapy: Findings From the African American Study of Kidney Disease and Hypertension.

RATIONALE & OBJECTIVE: Immune activation is fundamental to the pathogenesis of many kidney diseases. Innate immune molecules such as soluble urokinase-type plasminogen activator receptor (suPAR) have been linked to the incidence and progression of chronic kidney disease (CKD). Whether other biomarkers of immune activation are associated with incident kidney failure with replacement therapy (KFRT) in African Americans with nondiabetic kidney disease is unclear. STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: African American Study of Kidney Disease and Hypertension (AASK) participants with available baseline serum samples for biomarker measurement. PREDICTORS: Baseline serum levels of soluble tumor necrosis factor receptor 1 (sTNFR1), sTNFR2, tumor necrosis factor α (TNF-α), and interferon γ (IFN-γ). OUTCOMES: Incident KFRT, all-cause mortality. ANALYTICAL APPROACH: Cox proportional hazards models. RESULTS: Among 500 participants with available samples, mean glomerular filtration rate was 44.7mL/min/1.73m2, and median urinary protein-creatinine ratio was 0.09g/g at baseline. Over a median follow up of 9.6 years, there were 161 (32%) KFRT and 113 (23%) death events. In models adjusted for demographic and clinical factors and baseline kidney function, each 2-fold higher baseline level of sTNFR1, sTNFR2, and TNF-α was associated with 3.66-fold (95% CI, 2.31-5.80), 2.29-fold (95% CI, 1.60-3.29), and 1.35-fold (95% CI, 1.07-1.71) greater risks of KFRT, respectively; in comparison, each doubling of baseline suPAR concentration was associated with 1.39-fold (95% CI, 1.04-1.86) greater risk of KFRT. sTNFR1, sTNFR2, and TNF-α were also significantly associated with death (up to 2.2-fold higher risks per 2-fold higher baseline levels; P≤0.01). IFN-γ was not associated with either outcome. None of the biomarkers modified the association of APOL1 high-risk status (genetic risk factors for kidney disease among individuals of African ancestry) with KFRT (P>0.05 for interaction). LIMITATIONS: Limited generalizability to other ethnic groups or causes of CKD. CONCLUSIONS: Among African Americans with CKD attributed to hypertension, baseline levels of sTNFR1, sTNFR2, and TNF-α but not IFN-γ were associated with KFRT and mortality.

NAT8 Variants, N-Acetylated Amino Acids, and Progression of CKD.

BACKGROUND AND OBJECTIVES: Genetic variants in NAT8, a liver- and kidney-specific acetyltransferase encoding gene, have been associated with eGFR and CKD in European populations. Higher circulating levels of two NAT8-associated metabolites, N-δ-acetylornithine and N-acetyl-1-methylhistidine, have been linked to lower eGFR and higher risk of incident CKD in the Black population. We aimed to expand upon prior studies to investigate associations between rs13538, a missense variant in NAT8, N-acetylated amino acids, and kidney failure in multiple, well-characterized cohorts. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted analyses among participants with genetic and/or serum metabolomic data in the African American Study of Kidney Disease and Hypertension (AASK; n=962), the Atherosclerosis Risk in Communities (ARIC) study (n=1050), and BioMe, an electronic health record-linked biorepository (n=680). Separately, we evaluated associations between rs13538, urinary N-acetylated amino acids, and kidney failure in participants in the German CKD (GCKD) study (n=1624). RESULTS: Of 31 N-acetylated amino acids evaluated, the circulating and urinary levels of 14 were associated with rs13538 (P<0.05/31). Higher circulating levels of five of these N-acetylated amino acids, namely, N-δ-acetylornithine, N-acetyl-1-methylhistidine, N-acetyl-3-methylhistidine, N-acetylhistidine, and N2,N5-diacetylornithine, were associated with kidney failure, after adjustment for confounders and combining results in meta-analysis (combined hazard ratios per two-fold higher amino acid levels: 1.48, 1.44, 1.21, 1.65, and 1.41, respectively; 95% confidence intervals: 1.21 to 1.81, 1.22 to 1.70, 1.08 to 1.37, 1.29 to 2.10, and 1.17 to 1.71, respectively; all P values <0.05/14). None of the urinary levels of these N-acetylated amino acids were associated with kidney failure in the GCKD study. CONCLUSIONS: We demonstrate significant associations between an NAT8 gene variant and 14 N-acetylated amino acids, five of which had circulation levels that were associated with kidney failure.

Pattern Recognition of Spiking Neural Networks Based on Visual Mechanism and Supervised Synaptic Learning.

Electrophysiological studies have shown that mammalian primary visual cortex are selective for the orientations of visual stimuli. Inspired by this mechanism, we propose a hierarchical spiking neural network (SNN) for image classification. Grayscale input images are fed through a feed-forward network consisting of orientation-selective neurons, which then projected to a layer of downstream classifier neurons through the spiking-based supervised tempotron learning rule. Based on the orientation-selective mechanism of the visual cortex and tempotron learning rule, the network can effectively classify images of the extensively studied MNIST database of handwritten digits, which achieves 96% classification accuracy based on only 2000 training samples (traditional training set is 60000). Compared with other classification methods, our model not only guarantees the biological plausibility and the accuracy of image classification but also significantly reduces the needed training samples. Considering the fact that the most commonly used deep learning neural networks need big data samples and high power consumption in image recognition, this brain-inspired computational neural network model based on the layer-by-layer hierarchical image processing mechanism of the visual cortex may provide a basis for the wide application of spiking neural networks in the field of intelligent computing.

Urine 6-Bromotryptophan: Associations with Genetic Variants and Incident End-Stage Kidney Disease.

Higher serum 6-bromotryptophan has been associated with lower risk of chronic kidney disease (CKD) progression, implicating mechanisms beyond renal clearance. We studied genetic determinants of urine 6-bromotryptophan and its association with CKD risk factors and incident end-stage kidney disease (ESKD) in 4,843 participants of the German Chronic Kidney Disease (GCKD) study. 6-bromotryptophan was measured from urine samples using mass spectrometry. Patients with higher levels of urine 6-bromotryptophan had higher baseline estimated glomerular filtration rate (eGFR, p < 0.001). A genome-wide association study of urine 6-bromotryptophan identified two significant loci possibly related to its tubular reabsorption, SLC6A19, and its production, ERO1A, which was also associated with serum 6-bromotryptophan in an independent study. The association between urine 6-bromotryptophan and time to ESKD was assessed using Cox regression. There were 216 ESKD events after four years of follow-up. Compared with patients with undetectable levels, higher 6-bromotryptophan levels were associated with lower risk of ESKD in models unadjusted and adjusted for ESKD risk factors other than eGFR (

Effects of synaptic integration on the dynamics and computational performance of spiking neural network.

Neurons in the brain receive thousands of synaptic inputs from other neurons. This afferent information is processed by neurons through synaptic integration, which is an important information processing mechanism in biological neural networks. Synaptic currents integrated from spiking trains of presynaptic neurons have complex nonlinear dynamics which endow neurons with significant computational abilities. However, in many computational studies of neural networks, external input currents are often simply taken as a direct current that is static. In this paper, the influences of synaptic and noise external currents on the dynamics of spiking neural network and its computational capability have been investigated in detail. Our results show that due to the nonlinear synaptic integration, both of fast and slow excitatory synaptic currents have much more complex and oscillatory fluctuations than the noise current with the same average intensity. Thus network driven by synaptic external current exhibits remarkably more complex dynamics than that driven by noise external current. Interestingly, the enhancement of network activity is beneficial for information transmission, which is further supported by two computational tasks conducted on the liquid state machine (LSM) network. LSM with synaptic external current displays considerably better performance in both nonlinear fitting and pattern classification than that with noise external current. Synaptic integration can significantly enhance the entropy of activity patterns and computational performance of LSM. Our results demonstrate that the complex dynamics of nonlinear synaptic integration play a critical role in the computational abilities of neural networks and should be more broadly considered in the modelling studies of spiking neural networks.

Conversion from Nonshockable to Shockable Rhythms and Out-of-Hospital Cardiac Arrest Outcomes by Initial Heart Rhythm and Rhythm Conversion Time.

BACKGROUND: The conversion from a nonshockable rhythm (asystole or pulseless electrical activity (PEA)) to a shockable rhythm (pulseless ventricular tachycardia or ventricular fibrillation) may be associated with better out-of-hospital cardiac arrest (OHCA) outcomes. There are insufficient data on the prognostic significance of such conversions by initial heart rhythm and different rhythm conversion time. METHODS: Among 24,849 adult OHCA patients of presumed cardiac etiology with initial asystole or PEA in the Resuscitation Outcomes Consortium Cardiac Epidemiologic Registry (version 3, 2011-2015), we examined the association of shockable rhythm conversion with prehospital return of spontaneous circulation (ROSC), survival, and favorable functional outcome (modified Rankin Scale score ≤3) at hospital discharge by initial rhythm and rhythm conversion time (time from cardiopulmonary resuscitation (CPR) initiation by emergency medical providers to first shock delivery), using logistic regression adjusting for key clinical characteristics. RESULTS: Of 16,516 patients with initial asystole and 8,333 patients with initial PEA, 16% and 20% underwent shockable rhythm conversions; the median rhythm conversion time was 12.0 (IQR: 6.7-18.7) and 13.2 (IQR: 7.0-20.5) min, respectively. No difference was found in odds of prehospital ROSC across rhythm conversion time, regardless of initial heart rhythm. Shockable rhythm conversion was associated with survival and favorable functional outcome at hospital discharge only when occurred during the first 15 min of CPR, for those with initial asystole, or the first 10 min of CPR, for those with initial PEA. The associations between shockable rhythm conversion and outcomes were stronger among those with initial asystole compared with those with initial PEA. CONCLUSIONS: The conversion from a nonshockable rhythm to a shockable rhythm was associated with better outcomes only when occurred early in initial nonshockable rhythm OHCA, and it has greater prognostic significance when the initial rhythm was asystole.