BCG immunization induces CX3CR1hi effector memory T cells to provide cross-protection via IFN-γ-mediated trained immunity.

After a century of using the Bacillus Calmette-Guérin (BCG) vaccine, our understanding of its ability to provide protection against homologous (Mycobacterium tuberculosis) or heterologous (for example, influenza virus) infections remains limited. Here we show that systemic (intravenous) BCG vaccination provides significant protection against subsequent influenza A virus infection in mice. We further demonstrate that the BCG-mediated cross-protection against influenza A virus is largely due to the enrichment of conventional CD4+ effector CX3CR1hi memory αß T cells in the circulation and lung parenchyma. Importantly, pulmonary CX3CR1hi T cells limit early viral infection in an antigen-independent manner via potent interferon-γ production, which subsequently enhances long-term antimicrobial activity of alveolar macrophages. These results offer insight into the unknown mechanism by which BCG has persistently displayed broad protection against non-tuberculosis infections via cross-talk between adaptive and innate memory responses.

A massive galaxy that formed its stars at z ≈ 11.

The formation of galaxies by gradual hierarchical co-assembly of baryons and cold dark matter halos is a fundamental paradigm underpinning modern astrophysics1,2 and predicts a strong decline in the number of massive galaxies at early cosmic times3-5. Extremely massive quiescent galaxies (stellar masses of more than 1011 M⊙) have now been observed as early as 1-2 billion years after the Big Bang6-13. These galaxies are extremely constraining on theoretical models, as they had formed 300-500 Myr earlier, and only some models can form massive galaxies this early12,14. Here we report on the spectroscopic observations with the JWST of a massive quiescent galaxy ZF-UDS-7329 at redshift 3.205 ± 0.005. It has eluded deep ground-based spectroscopy8, it is significantly redder than is typical and its spectrum reveals features typical of much older stellar populations. Detailed modelling shows that its stellar population formed around 1.5 billion years earlier in time (z ≈ 11) at an epoch when dark matter halos of sufficient hosting mass had not yet assembled in the standard scenario4,5. This observation may indicate the presence of undetected populations of early galaxies and the possibility of significant gaps in our understanding of early stellar populations, galaxy formation and the nature of dark matter.

Neonatal imprinting of alveolar macrophages via neutrophil-derived 12-HETE.

Resident-tissue macrophages (RTMs) arise from embryonic precursors1,2, yet the developmental signals that shape their longevity remain largely unknown. Here we demonstrate in mice genetically deficient in 12-lipoxygenase and 15-lipoxygenase (Alox15-/- mice) that neonatal neutrophil-derived 12-HETE is required for self-renewal and maintenance of alveolar macrophages (AMs) during lung development. Although the seeding and differentiation of AM progenitors remained intact, the absence of 12-HETE led to a significant reduction in AMs in adult lungs and enhanced senescence owing to increased prostaglandin E2 production. A compromised AM compartment resulted in increased susceptibility to acute lung injury induced by lipopolysaccharide and to pulmonary infections with influenza A virus or SARS-CoV-2. Our results highlight the complexity of prenatal RTM programming and reveal their dependency on in trans eicosanoid production by neutrophils for lifelong self-renewal.

Virus-Induced Acute Respiratory Distress Syndrome Causes Cardiomyopathy Through Eliciting Inflammatory Responses in the Heart.

BACKGROUND: Viral infections can cause acute respiratory distress syndrome (ARDS), systemic inflammation, and secondary cardiovascular complications. Lung macrophage subsets change during ARDS, but the role of heart macrophages in cardiac injury during viral ARDS remains unknown. Here we investigate how immune signals typical for viral ARDS affect cardiac macrophage subsets, cardiovascular health, and systemic inflammation. METHODS: We assessed cardiac macrophage subsets using immunofluorescence histology of autopsy specimens from 21 patients with COVID-19 with SARS-CoV-2-associated ARDS and 33 patients who died from other causes. In mice, we compared cardiac immune cell dynamics after SARS-CoV-2 infection with ARDS induced by intratracheal instillation of Toll-like receptor ligands and an ACE2 (angiotensin-converting enzyme 2) inhibitor. RESULTS: In humans, SARS-CoV-2 increased total cardiac macrophage counts and led to a higher proportion of CCR2+ (C-C chemokine receptor type 2 positive) macrophages. In mice, SARS-CoV-2 and virus-free lung injury triggered profound remodeling of cardiac resident macrophages, recapitulating the clinical expansion of CCR2+ macrophages. Treating mice exposed to virus-like ARDS with a tumor necrosis factor α-neutralizing antibody reduced cardiac monocytes and inflammatory MHCIIlo CCR2+ macrophages while also preserving cardiac function. Virus-like ARDS elevated mortality in mice with pre-existing heart failure. CONCLUSIONS: Our data suggest that viral ARDS promotes cardiac inflammation by expanding the CCR2+ macrophage subset, and the associated cardiac phenotypes in mice can be elicited by activating the host immune system even without viral presence in the heart.

Comparison of positive pressure ventilation devices during compliance changes in a neonatal ovine model.

BACKGROUND: To compare tidal volume (VT) delivery with compliance at 0.5 and 1.5 mL/cmH2O using four different ventilation (PPV) devices (i.e., self-inflating bag (SIB), T-Piece resuscitator, Next Step (a novel Neonatal Resuscitator), and Fabian ventilator (conventional neonatal ventilator) using a neonatal piglet model. DESIGN/METHODS: Randomized experimental animal study using 10 mixed-breed neonatal piglets (1-3 days; 1.8-2.4 kg). Piglets were anesthetized, intubated, instrumented, and randomized to receive positive pressure ventilation (PPV) for one minute with a SIB with or without a respiratory function monitor (RFM), T-Piece resuscitator with or without an RFM, Next Step, and Fabian Ventilator with both compliance levels. Compliance changes were achieved by placing a wrap around the piglets' chest and tightened it. Our primary outcome was targeted VT delivery of 5 mL/kg at 0.5 and 1.5 mL/cmH2O lung compliance. RESULTS: At 0.5 mL/cmH2O compliance, the mean(SD) expired VT with the Next Step was 5.1(0.2) mL/kg compared to the Fabian 4.8(0.5) mL/kg, SIB 8.9(3.6) mL/kg, SIB + RFM 4.5(1.8) mL/kg, T-Piece 7.4(4.3) mL/kg, and T-Piece+RFM 6.4(3.1) mL/kg. At 1.5 mL/cmH2O compliance, the mean(SD) expired VT with the Next Step was 5.2(0.6) mL/kg compared to the Fabian 4.4(0.7) mL/kg, SIB 12.1(5.3) mL/kg, SIB + RFM 9.4(3.9) mL/kg, T-Piece 8.6(1.5) mL/kg, and T-Piece+RFM 6.5 (1.6) mL/kg. CONCLUSION: The Next Step provides consistent VT during PPV, which is comparable to a mechanical ventilator. IMPACT: Current guidelines recommend fixed peak inflation pressure in resuscitation, linked to lung and brain injury. The Next Step Neonatal Resuscitator, a cost-effective device, offers volume-targeted positive pressure ventilation with consistent tidal volumes. With two different compliances, the Next Step Neonatal Resuscitator delivered a consistent tidal volume which was similar to a mechanical ventilator. The Next Step Neonatal Resuscitator outperformed self-inflating bags and T-Pieces in delivering targeted tidal volumes. The Next Step Neonatal Resuscitator could be an alternative ventilation device for neonatal resuscitation.

Kinetic energy distributions of atomic ions from disintegration of argon containing nanoclusters in moderately intense nanosecond laser fields: Coulomb explosion or hydrodynamic expansion.

We report kinetic energies (KE) of multiply charged atomic ions (MCAI) from interactions of moderately intense nanosecond lasers at 532 nm with argon containing clusters, including neat and doped clusters with a trace amount of trichlorobenzene. We develop a mathematical method to retrieve speed and thereby kinetic energy information from analyzing the time-of-flight profiles of the MCAI. This method should be generally applicable in detections of energetic charged particles with high velocities, a realm where velocity map imaging is inadequate. From this analysis, we discover that the KE of MCAI from doped clusters demonstrates a quadratic dependence on the charge of the atomic ions, while for neat clusters, the dependence is cubic. This result confirms the nature of the cluster disintegration process to be dominated by Coulomb explosion. This result bears more similarity to reports from extreme vacuum ultraviolet (EUV) fields with similar intensities, than to reports from near infrared (NIR) intense laser fields. However, the charge state distribution from our experiment is the opposite: we observe more higher charge state ions than reported in EUV fields, and our charge state distribution is actually similar to those reported in NIR fields. We also report a significant effect of the external electric field on the charge state distribution of the atomic ions: the presence of an electric field can significantly increase the charge from the atomic ions, as shown by a three-fold reduction in the average kinetic energy per charge. Although molecular dynamics simulations have been implemented for experiments in the EUV and NIR, our results allude to the need of a concerted effort in this regime of moderately intense nanosecond laser fields. The significant decrease in charge state distribution and the significant increase in KE from doped clusters, compared with neat clusters, is a telltale sign that the true interaction time between the laser field and the cluster may be substantially shorter than the duration of the laser, a welcome relief for molecular dynamics simulations.

Mood Tracker: A Randomized Controlled Trial of a Self-Monitoring Intervention for Emotional Distress After Traumatic Brain Injury.

OBJECTIVE: Persons with traumatic brain injury (TBI) frequently experience emotional distress (ED) manifested in anxiety and depression. However, they may not access mental health services due to external (eg, access, transportation, and cost) or internal (eg, stigma and discomfort with traditional counseling) barriers. Based on substantial literature indicating that self-monitoring can ameliorate several health conditions, we conducted a randomized, parallel group, wait-list control (WLC) trial of a self-monitoring intervention to decrease ED after TBI. SETTING: Community in the southwestern United States. PARTICIPANTS: Persons with medically documented complicated mild, moderate, and severe TBI. DESIGN: About 127 participants were randomized in blocks of 6 to an active treatment (AT) group, wherein they completed multiple assessments of ED each week over a 6-week period via a smartphone app, or a WLC group in a parallel group, controlled trial. Participants received weekly support calls to promote self-monitoring of ED using ecological momentary assessment. MAIN MEASURES: ED (Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7), Satisfaction with Life Scale, and Participation Assessment with Recombined Tools-Objective. RESULTS: Analysis of the primary study outcome at 6 weeks after initiation of treatment for the AT group did not demonstrate that self-monitoring was effective in decreasing ED as compared to the WLC group. Brief support calls made weekly to promote compliance with self-monitoring were effective in achieving the target number of self-assessments. About 80% of support calls lasted less than 5 minutes. Greater ED was associated with lower life satisfaction and lower participation indicating the importance of addressing ED in persons with TBI. CONCLUSION: Additional work is needed to develop nontraditional interventions to circumvent barriers that prevent persons with TBI from accessing care for ED. Brief support calls may be an effective, low-cost intervention to improve compliance with self-monitoring or self-management interventions.

Engineering of itaconic acid pathway via co-localization of CadA and AcnA in recombinant Escherichia coli.

Itaconic acid is an excellent polymeric precursor with a wide range of industrial applications. The efficient production of itaconate from various renewable substrates was demonstrated by engineered Escherichia coli. However, limitation in the itaconic acid precursor supply was revealed by finding out the key intermediate of the tricarboxylic acid in the itaconic acid pathway. Efforts of enhancing the cis-aconitate flux and preserving the isocitrate pool to increase itaconic acid productivity are required. In this study, we introduce a synthetic protein scaffold system between CadA and AcnA to physically combine the two enzymes. Through the introduction of a synthetic protein scaffold, 2.1 g L-1 of itaconic acid was produced at pH 7 and 37 °C. By fermentation, 20.1 g L-1 for 48 h of itaconic acid was produced with a yield of 0.34 g g-1 glycerol. These results suggest that carbon flux was successfully increased itaconic acid productivity.

Development of a Large-Range XY-Compliant Micropositioning Stage with Laser-Based Sensing and Active Disturbance Rejection Control.

This paper presents a novel design and control strategies for a parallel two degrees-of-freedom (DOF) flexure-based micropositioning stage for large-range manipulation applications. The motion-guiding beam utilizes a compound hybrid compliant prismatic joint (CHCPJ) composed of corrugated and leaf flexures, ensuring increased compliance in primary directions and optimal stress distribution with minimal longitudinal length. Additionally, a four-beam parallelogram compliant prismatic joint (4BPCPJ) is used to improve the motion decoupling performance by increasing the off-axis to primary stiffness ratio. The mechanism's output compliance and dynamic characteristics are analyzed using the compliance matrix method and Lagrange approach, respectively. The accuracy of the analysis is verified through finite element analysis (FEA) simulation. In order to examine the mechanism performance, a laser interferometer-based experimental setup is established. In addition, a linear active disturbance rejection control (LADRC) is developed to enhance the motion quality. Experimental results illustrate that the mechanism has the capability to provide a range of 2.5 mm and a resolution of 0.4 µm in both the X and Y axes. Furthermore, the developed stage has improved trajectory tracking and disturbance rejection capabilities.

Decreased GABA+ Levels in the Medial Prefrontal Cortex of Perimenopausal Women: A 3T 1H-MRS Study.

OBJECTIVE: Perimenopause is associated with an increased risk of developing a major depressive (MD) episode. A significant number of women develop their first MD episode during perimenopause, suggesting a unique pathophysiology of perimenopausal (PM) depression. Previous research has shown that depression is associated with decreased gamma-aminobutyric acid (GABA) levels in the medial prefrontal cortex (MPFC) of MD patients. The objective of this study was to compare MPFC GABA+ levels in healthy reproductive-aged (RD) and PM women. METHODS: A total of 18 healthy PM and 20 RD women were included in the study. MPFC GABA+ levels, which include homocarnosine and macromolecules, were measured via magnetic resonance spectroscopy using a 3 Tesla magnet. MPFC GABA+ levels were referenced to creatine + phosphocreatine (Cr+PCr). Absence of current or past psychiatric diagnosis was confirmed via a structured interview. RD participants were scanned during the early follicular phase of the menstrual cycle. PM women were scanned outside of ovulatory cycles. RESULTS: Mean MPFC GABA+ concentrations (relative to Cr+PCr) were decreased in the PM group compared with the RD group (PM mean = 0.08 ± 0.02, RD mean = 0.09 ± 0.02, t = -2.03, df = 36, P = .05) even after correcting for in percentage in gray matter (GM). Because PM women were inherently older than RD women (aged 48.8 ± 3.55 and 31.5 ± 9.66 years, respectively), the age difference between the 2 groups was statistically significant (P < .001). When age was treated as an independent covariate and included in the model, the difference in GABA+ between PM and RD women was no longer significant (P = .092). CONCLUSION: Perimenopause is associated with decreased MPFC GABA+/Cr+PCr levels, which may contribute to the increased risk of experiencing a MD episode during PM.

Decreased GABA+ ratios referenced to creatine and phosphocreatine in the left dorsolateral prefrontal cortex of females of reproductive age with major depression.

BACKGROUND: It has been suggested that the dorsolateral prefrontal cortex (DLPFC), especially the left DLPFC, has an important role in the pathophysiology and the treatment of major depressive disorder (MDD); furthermore, the contributory and antidepressant role of γ-aminobutyric acid (GABA) is increasingly recognized. Given that most female patients with MDD are of reproductive age, we sought to assess in vivo baseline GABA levels in the left DLPFC among unmedicated females of reproductive age with depression. METHODS: We compared healthy females and females with MDD. Both groups were of reproductive age. We confirmed absence of current or past psychiatric diagnosis among healthy controls or a current diagnosis of MDD via a structured interview. We measured GABA+ (including homocarnosine and macromolecules), referenced to creatine and phosphocreatine, via magnetic resonance spectroscopy using a 3 Tesla magnet. RESULTS: We included 20 healthy controls and 13 participants with MDD. All participants were unmedicated at the time of the study. All females were scanned during the early follicular phase of the menstrual cycle. Levels of GABA+ in the left DLPFC were significantly lower among participants with MDD (median 0.08) than healthy controls (median 0.10; U = 66.0, p = 0.02, r = 0.41). LIMITATIONS: When we adjusted for fit error as a covariate, we lost statistical significance for left DLPFC GABA+. However, when we adjusted for signal-to-noise ratio, statistical significance was maintained. CONCLUSION: Our results suggest that GABA+ levels in the left DLPFC may vary by depression status and should be examined as a possible treatment target.

A massive, quiescent galaxy at a redshift of 3.717.

Finding massive galaxies that stopped forming stars in the early Universe presents an observational challenge because their rest-frame ultraviolet emission is negligible and they can only be reliably identified by extremely deep near-infrared surveys. These surveys have revealed the presence of massive, quiescent early-type galaxies appearing as early as redshift z ≈ 2, an epoch three billion years after the Big Bang. Their age and formation processes have now been explained by an improved generation of galaxy-formation models, in which they form rapidly at z ≈ 3-4, consistent with the typical masses and ages derived from their observations. Deeper surveys have reported evidence for populations of massive, quiescent galaxies at even higher redshifts and earlier times, using coarsely sampled photometry. However, these early, massive, quiescent galaxies are not predicted by the latest generation of theoretical models. Here we report the spectroscopic confirmation of one such galaxy at redshift z = 3.717, with a stellar mass of 1.7 × 1011 solar masses. We derive its age to be nearly half the age of the Universe at this redshift and the absorption line spectrum shows no current star formation. These observations demonstrate that the galaxy must have formed the majority of its stars quickly, within the first billion years of cosmic history in a short, extreme starburst. This ancestral starburst appears similar to those being found by submillimetre-wavelength surveys. The early formation of such massive systems implies that our picture of early galaxy assembly requires substantial revision.

Neosuberitenone, a New Sesterterpenoid Carbon Skeleton; New Suberitenones; and Bioactivity against Respiratory Syncytial Virus, from the Antarctic Sponge Suberites sp.

Respiratory syncytial virus (RSV) is a highly contagious human pathogen that poses a significant threat to children under the age of two, and there is a current need for new small molecule treatments. The Antarctic sponge Suberites sp. is a known source of sesterterpenes, and following an NMR-guided fractionation procedure, it was found to produce several previously unreported metabolites. Neosuberitenone (1), with a new carbon scaffold herein termed the 'neosuberitane' backbone, six suberitenone derivatives (2-7), an ansellane-type terpenoid (8), and a highly degraded sesterterpene (9), as well as previously reported suberitenones A (10) and B (11), were characterized. The structures of all of the isolated metabolites including absolute configurations are proposed on the basis of NMR, HRESIMS, optical rotation, and XRD data. The biological activities of the metabolites were evaluated in a range of infectious disease assays. Suberitenones A, B, and F (3) were found to be active against RSV, though, along with other Suberites sp. metabolites, they were inactive in bacterial and fungal screens. None of the metabolites were cytotoxic for J774 macrophages or A549 adenocarcinoma cells. The selectivity of suberitenones A, B, and F for RSV among other infectious agents is noteworthy.

Detection, Verification and Analysis of Micro Surface Defects in Steel Filament Using Eddy Current Principles, Scanning Electron Microscopy and Energy-Dispersive Spectroscopy.

In the current industrial revolution, advanced technologies and methods can be effectively utilized for the detection and verification of defects in high-speed steel filament production. This paper introduces an innovative methodology for the precise detection and verification of micro surface defects found in steel filaments through the application of the Eddy current principle. Permanent magnets are employed to generate a magnetic field with a high frequency surrounding a coil of sensors positioned at the filament's output end. The sensor's capacity to detect defects is validated through a meticulous rewinding process, followed by a thorough analysis involving scanning electron microscopy (SEM) and energy-dispersive spectroscopy (EDS). Artificial defects were intentionally introduced into a sample, and their amplitudes were monitored to establish a threshold value. The amplitude signal of these created defect was identified at approximately 10% FSH, which corresponds to a crack depth of about 20 µm. In the experimental production of 182 samples covering 38 km, the defect ratio was notably high, standing at 26.37%. These defects appeared randomly along the length of the samples. The verification results underscore the exceptional precision achieved in the detection of micro surface defects within steel filaments. These defects were primarily characterized by longitudinal scratches and inclusions containing physical tungsten carbide.

Novel Clinical Monitoring Approaches for Reemergence of Diphtheria Myocarditis, Vietnam.

Diphtheria is a life-threatening, vaccine-preventable disease caused by toxigenic Corynebacterium bacterial species that continues to cause substantial disease and death worldwide, particularly in vulnerable populations. Further outbreaks of vaccine-preventable diseases are forecast because of health service disruptions caused by the coronavirus disease pandemic. Diphtheria causes a spectrum of clinical disease, ranging from cutaneous forms to severe respiratory infections with systemic complications, including cardiac and neurologic. In this synopsis, we describe a case of oropharyngeal diphtheria in a 7-year-old boy in Vietnam who experienced severe myocarditis complications. We also review the cardiac complications of diphtheria and discuss how noninvasive bedside imaging technologies to monitor myocardial function and hemodynamic parameters can help improve the management of this neglected infectious disease.

Respiratory Syncytial Virus Phosphoprotein Residue S156 Plays a Role in Regulating Genome Transcription and Replication.

Respiratory syncytial virus (RSV) is a single-stranded, negative-sense RNA virus in the family Pneumoviridae and genus Orthopneumovirus that can cause severe disease in infants, immunocompromised adults, and the elderly. The RSV viral RNA-dependent RNA polymerase (vRdRp) complex is composed of the phosphoprotein (P) and the large polymerase protein (L). The P protein is constitutively phosphorylated by host kinases and has 41 serine (S) and threonine (T) residues as potential phosphorylation sites. To identify important phosphorylation residues in the P protein, we systematically and individually mutated all S and T residues to alanine (A) and analyzed their effects on genome transcription and replication by using a minigenome system. We found that the mutation of eight residues resulted in minigenome activity significantly lower than that of wild-type (WT) P. We then incorporated these mutations (T210A, S203A, T151A, S156A, T160A, S23A, T188A, and T105A) into full-length genome cDNA to rescue recombinant RSV. We were able to recover four recombinant viruses (with T151A, S156A, T160A, or S23A), suggesting that RSV-P residues T210, S203, T188, and T105 are essential for viral RNA replication. Among the four recombinant viruses rescued, rRSV-T160A caused a minor growth defect relative to its parental virus while rRSV-S156A had severely restricted replication due to decreased levels of genomic RNA. During infection, P-S156A phosphorylation was decreased, and when passaged, the S156A virus acquired a known compensatory mutation in L (L795I) that enhanced both WT-P and P-S156A minigenome activity and was able to partially rescue the S156A viral growth defect. This work demonstrates that residues T210, S203, T188, and T105 are critical for RSV replication and that S156 plays a critical role in viral RNA synthesis. IMPORTANCE RSV-P is a heavily phosphorylated protein that is required for RSV replication. In this study, we identified several residues, including P-S156, as phosphorylation sites that play critical roles in efficient viral growth and genome replication. Future studies to identify the specific kinase(s) that phosphorylates these residues can lead to kinase inhibitors and antiviral drugs for this important human pathogen.

Prediabetes and insulin resistance in a population of patients with heart failure and reduced or preserved ejection fraction but without diabetes, overweight or hypertension.

BACKGROUND: The relationships between glucose abnormalities, insulin resistance (IR) and heart failure (HF) are unclear, especially regarding to the HF type, i.e., HF with reduced (HFrEF) or preserved (HFpEF) ejection fraction. Overweight, diabetes and hypertension are potential contributors to IR in persons with HF. This study aimed to evaluate the prevalence of prediabetes and IR in a population of Vietnamese patients with HFrEF or HFpEF but no overweight, diabetes or hypertension, in comparison with healthy controls, and the relation between prediabetes or IR and HF severity. METHODS: We conducted a prospective cross-sectional observational study in 190 non-overweight normotensive HF patients (114 with HFrEF and 76 with HFpEF, 92.6% were ischemic HF, mean age was 70.1 years, mean BMI 19.7 kg/m2) without diabetes (neither known diabetes nor newly diagnosed by OGTT) and 95 healthy individuals (controls). Prediabetes was defined using 2006 WHO criteria. Glucose and insulin levels were measured fasting and 2 h after glucose challenge. IR was assessed using HOMA-IR and several other indexes. RESULTS: Compared to controls, HF patients had a higher prevalence of prediabetes (63.2% vs 22.1%) and IR (according to HOMA-IR, 55.3% vs 26.3%), higher HOMA-IR, insulin/glucose ratio after glucose and FIRI, and lower ISIT0 and ISIT120 (< 0.0001 for all comparisons), with no difference for body weight, waist circumference, blood pressure and lipid parameters. Prediabetes was more prevalent (69.3% vs 53.9%, p = 0.03) and HOMA-IR was higher (p < 0.0001) in patients with HFrEF than with HFpEF. Among both HFrEF and HFpEF patients, those with prediabetes or IR had a more severe HF (higher NYHA functional class and NT-proBNP levels, lower ejection fraction; p = 0.04-< 0.0001) than their normoglycemic or non-insulinresistant counterparts, with no difference for blood pressure and lipid parameters. CONCLUSION: In non-diabetic non-overweight normotensive patients with HF, the prevalence of prediabetes is higher with some trend to more severe IR in those with HFrEF than in those with HFpEF. Both prediabetes and IR are associated with a more severe HF. The present data support HF as a culprit for IR. Intervention strategies should be proposed to HF patients with prediabetes aiming to reduce the risk of incident diabetes. Studies should be designed to test whether such strategies may translate into an improvement of further HF-related outcomes.

Low-cost electrochemical paper-based device for exosome detection.

Exosomes are vesicles released by healthy and cancer cells into the extracellular matrix and bodily fluid. Cancer cell-derived exosomes have attracted much attention in early-stage detection and prognostication of treatment response. Thus, detecting exosomes is of great interest to biology and medicine. However, many conventional detection methods require high-cost equipment and centralized laboratory facilities, making diagnostics inaccessible in limited-resource settings. This study reports a proof-of-concept low-cost electrochemical paper-based analytical device to quantify both the total bulk and cancer cell-derived exosomes in cell culture media. The device employs a sandwich immune assay design, where exosomes are initially captured using the electrode-bound generic antibodies (i.e. CD9) and subsequently detected via ovarian cancer-specific CA125 antibodies. Our proposed device quantifies the total bulk exosome concentration with a detection limit of 9.3 × 107 exosomes per mL and ovarian cancer cell-derived exosomes with a detection limit of 7.1 × 108 exosomes per mL, with a relative standard deviation of <10% (n = 3). We suggest that this low-cost and simple electrochemical paper-based device could be an alternative tool for detecting disease-specific exosomes in biological samples with the potential to be further developed for point-of-care diagnosis.