Delta Immature Platelet Fraction Is Associated With Mortality in Bacteremia Patients.

OBJECTIVES: Immature platelet fraction (IPF) for differentiating bacteremia has been explored, whereas its prognostic correlation remains uncertain. This study aims to confirm the predictive capability of IPF for bacteremia and investigate its association with prognosis. METHODS: Patients with complete blood count (CBC) on the blood culture day (D1) and the preceding day (D0) were retrospectively recruited and categorized into bacteremia and nonbacteremia groups. Immature platelet (IP) analysis, alongside CBC, was conducted. Delta IPF, defined by the absolute values of D1 minus D0 results was calculated. The ability to distinguish bacteremia from nonbacteremia patients, and the correlation with mortality were analyzed. RESULTS: From February to December 2020, a total of 150 patients were enrolled, with 75 having bacteremia. The specificity for delta IPF ≥3.4% to predict bacteremia was 97.3% (95% confidence interval [CI]: 90.7-99.7). When delta IPF ≥3.4% combined with procalcitonin ≥0.5 (ng/mL), the sensitivity was 90.5% (95% CI: 69.6%-98.8%). Within the bacteremia group, delta IPF and the proportion of patients with delta IPF ≥1.5% were significantly higher in nonsurvival, while delta platelet levels did not. Furthermore, delta IPF ≥1.5% was independently associated with 30-day mortality (adjusted odds ratio: 3.88, 95% CI: 1.2%-11.4%; p = 0.020). The 30-day survival curve demonstrated a significant difference between patients with delta IPF ≥1.5% and those without (p < 0.001). CONCLUSIONS: Delta IPF correlates with mortality in bacteremia patients. Our findings suggest IPF not only helps detect bacteremia but also predicts prognosis in the early stage.

Protopanaxadiol Derivative: A Plant Origin of Novel Selective Glucocorticoid Receptor Modulator with Anti-inflammatory Effect.

Constant efforts have been made to move towards maintaining the positive anti-inflammatory functions of glucocorticoids (GCs) while minimizing side effects. The anti-inflammatory effect of GCs is mainly attributed to the inhibition of major inflammatory pathways such as NF-κB through GR transrepression, while its side effects are mainly mediated by transactivation. Here, we investigated the selective glucocorticoid receptor modulator (SGRM)-like properties of a plant-derived compound. In this study, glucocorticoid receptor (GR)-mediated alleviation of inflammation by SP-8 was investigated by a combination of in vitro, in silico, and in vivo approaches. Molecular docking and cellular thermal shift assay suggested that SP-8 bound stably to the active site of GR via hydrogen bonding and hydrophobic interactions. SP-8 activated GR, induced GR nuclear translocation, and inhibited NF-κB pathway activation. Furthermore, SP-8 did not up-regulate the gene and protein expression of PEPCK and TAT in HepG2 cells, and it did not induce fat deposition like GC and has little effect on bone metabolism. Interestingly, SP-8 upregulated GR protein expression and did not cause GR phosphorylation at Ser211 in RAW264.7 cells. This work proved that SP-8 dissociated characteristics of transrepression and transactivation can be separated. In addition, the in vitro and in vivo anti-inflammatory effects of SP-8 were confirmed in LPS-induced RAW 264.7 cells and in a mouse model of DSS-induced ulcerative colitis, respectively. In conclusion, SP-8 might serve as a potential SGRM and might hold great potential for therapeutic use in inflammatory diseases.

A solar-driven nanocellulose Janus aerogel with excellent floating stability and dual functions of oil-water separation and photocatalytic degradation of organic pollutants.

Effective and practical cleanup of viscous crude oil spills is extremely important in real harsh marine environments. Herein, we designed a solar-driven, nanocellulose-based Janus aerogel (Janus-A) with excellent floating stability and dual function of oil-water separation and degradation of aqueous organic pollutants. Janus-A, with its amphiprotic nature, was prepared through polypyrrole (PPy) deposition, freeze-drying, octyltrichlorosilane (OTS) impregnation, TiO2 spraying on the bottom surface, and UV irradiation treatment. The photothermal conversion effect of PPy coating raised the surface temperature of aerogel to 75.8 °C within 6 min under one simulated solar irradiation, which greatly reduced the viscosity of the crude oil and increased the absorption capacity of the aerogel to 36.7 g/g. Benefiting from the balance between the buoyancy generated by the hydrophobic part and water absorption of the hydrophilic part, Janus-A showed excellent floating stability under simulated winds and waves. In addition, Janus-A exhibited high degradation efficiency for organic pollutants in water owing to the synergistic photocatalytic properties of TiO2 and PPy. These excellent performances make Janus-A ideal for integrated water-oil separation and water remediation.

Potential analgesic effect of a novel cannabidiol nanocrystals powder for the treatment of neuropathic pain.

BACKGROUND: The current analgesics often prevent patients from getting effective treatment due to their adverse effects. Cannabidiol (CBD) is well tolerated, has few side effects and has been extensively investigated in analgesia. However, its oral bioavailability is extremely low. In order to solve this problem, we developed the cannabidiol nanocrystals (CBD-NC) in the earlier stage. METHODS: In this study, we evaluated the nociceptive behaviours associated with neuropathic pain (NP) induced by the spared nerve injury (SNI) model. Assessment of pain threshold was evaluated by paw withdraw threshold (PWT) and paw withdrawal latency (PWL). The improving effect on the motor dysfunction was determined by rota-rod testing. To assess the neuroprotective effect, nerve demyelination and expression of peripheral myelin protein PMP22 were measured with myelin sheath staining and western blotting. Protein expressions in microglia of spinal cord were tested by western blot to explore the underlying mechanism. RESULTS: Compared with the CBD oil solution, CBD-NC significantly reduced mechanical allodynia and thermal hyperalgesia in rats. CBD-NC could improve motor dysfunction induced by SNI in rats, significantly reverse the demyelination and increase the expression of the marker protein of peripheral myelin. Underlying spinal analgesic mechanism of microglia and related factors were preliminarily confirmed. CONCLUSIONS: CBD-NC administration is an effective treatment for NP associated with SNI, and the analgesic effect of CBD-NC was significantly better than that of CBD oil sol. By contrast, CBD-NC has a fast-acting and long-term effect in the treatment of NP. Our study further supports the potential therapeutic effect of CBD-NC on NP. SIGNIFICANCE: The absolute bioavailability of the CBD-NC intramuscular injection formulation can reach 203.31%, which can solve the problem of low oral bioavailability. This research evaluated the therapeutic effect of CBD-NC on NP associated with the SNI model for the first time. All available date showed that whatever the analgesic or neuroprotective effect of CBD-NC, it was significantly better than that of CBD oil sol., which was consistent with the results of the pharmacokinetic. This research supports the initiation of more trials testing the efficacy of CBD-NC for treating NP.

Anti-adipogenesis and anti-obesity potential of alliin mediated by modulating glycolipid metabolism via activating PPARγ signaling.

Garlic exhibits hypolipidemic, hypoglycemic, and cardiovascular benefits. The inconsistent results of garlic preparations on adipogenesis have caused more confusion in the public and academia. The compounds responsible for the anti-adipogenesis effect of garlic remain unknown. The present study aimed to verify the real anti-adipogenesis and anti-obesity component in garlic and explored its possible effects in metabolic syndrome. We verified the real anti-adipogenesis and anti-obesity components of garlic in 3T3-L1 preadipocytes and a 10-week-high fat diet (HFD)-induced obese mice. In vitro, two water-soluble and four typical lipid-soluble compounds of garlic were tested for their anti-adipogenesis. Then, the water-soluble compound, alliin, and two processing methods produced garlic oils, were evaluated in vivo study. Mice received oral administration of alliin (25 mg/kg) and garlic oils (15 mg/kg) daily for 8 weeks. Serum lipids, parameters of obesity, and indicators involved in regulating glycolipid metabolism were examined. Our findings confirmed that both water-soluble and lipid-soluble organosulfur compounds of garlic contributed to garlic's anti-adipogenesis effect, in which water-soluble sulfides, especially alliin, exhibited greater potency. Alliin possessed potent effects of anti-obesity and improvement in glucose and lipid metabolism in HFD-induced obese mice. Alliin mediated these effects partly attributed to its modulation of enzymatic activities within glycolipid metabolism and activating PPARγ signaling pathway. In contrast to odorous lipid-soluble sulfides, alliin is odorless, stable, and safe, and is an ideal nutraceutical or even medicinal candidates for the treatment of metabolic diseases. Alliin could be used to standardize the quality of garlic products.

Application of targeted liposomes-based salvianolic acid A for the treatment of ischemic stroke.

Novel therapeutics for the treatment of ischemic stroke remains to be the unmet clinical needs. Previous studies have indicated that salvianolic acid A (SAA) is a promising candidate for the treatment of the brain diseases. However, SAA has poor absolute bioavailability and does not efficiently cross the intact blood-brain barrier (BBB), which limit its efficacy. To this end we developed a brain-targeted liposomes for transporting SAA via the BBB by incorporating the liposomes to a transport receptor, insulin-like growth factor-1 receptor (IGF1R). The liposomes were prepared by ammonium sulfate gradients loading method. The prepared SAA-loaded liposomes (Lipo/SAA) were modified with IGF1R monoclonal antibody to generate IGF1R antibody-conjugated Lipo/SAA (IGF1R-targeted Lipo/SAA). The penetration of IGF1R-targeted Lipo/SAA into the brain was confirmed by labeling with Texas Red, and their efficacy were evaluate using middle cerebral artery occlusion (MCAO) model. The results showed that IGF1R-targeted Lipo/SAA are capable of transporting SAA across the BBB into the brain, accumulation in brain tissue, and sustained releasing SAA for several hours. Administration o IGF1R-targeted Lipo/SAA notably reduced infarct size and neuronal damage, improved neurological function and inhibited cerebral inflammation, which had much higher efficiency than no-targeted SAA.

Protopanaxadiol improves lupus nephritis by regulating the PTX3/MAPK/ERK1/2 pathway.

Lupus nephritis (LN) is a kidney disease that occurs after systemic lupus erythematosus (SLE) affects the kidneys. Pentraxin 3 (PTX3) is highly expressed in the serum of patients with LN. Renal PTX3 deposition is directly related to clinical symptoms such as proteinuria and inflammation. The excessive proliferation of mesangial cells (MCs) is one of the representative pathological changes in the progression of LN, which is closely related to its pathogenesis. Protopanaxadiol (PPD) is the main component of ginsenoside metabolism and has not been reported in LN. The aim of this study was to investigate the relationship between PTX3 and mesangial cell proliferation and to evaluate the potential role and mechanism of PPD in improving LN. PTX3 is highly expressed in the kidneys of LN patients and LN mice and is positively correlated with renal pathological indicators, including proteinuria and PCNA. The excessive expression of PTX3 facilitated the proliferation of MCs, facilitated the activation of the MAPK/ERK1/2 signaling pathway, and increased the expression of HIF-1α. Further studies showed that PPD can effectively inhibit the abnormal proliferation of MCs with high expression of PTX3 and significantly improve LN symptoms such as proteinuria in MRL/lpr mice. The mechanism may be related to the inhibition of the PTX3/MAPK/ERK1/2 pathway. In this study, both in vitro, in vivo, and clinical sample results show that PTX3 is involved in the regulation of MCs proliferation and the early occurrence of LN. Natural active compound PPD can improve LN by regulating the PTX3/MAPK/ERK1/2 pathway.

The activator protein-1 complex governs a vascular degenerative transcriptional programme in smooth muscle cells to trigger aortic dissection and rupture.

BACKGROUND AND AIMS: Stanford type A aortic dissection (AD) is a degenerative aortic remodelling disease marked by an exceedingly high mortality without effective pharmacologic therapies. Smooth muscle cells (SMCs) lining tunica media adopt a range of states, and their transformation from contractile to synthetic phenotypes fundamentally triggers AD. However, the underlying pathomechanisms governing this population shift and subsequent AD, particularly at distinct disease temporal stages, remain elusive. METHODS: Ascending aortas from nine patients undergoing ascending aorta replacement and five individuals undergoing heart transplantation were subjected to single-cell RNA sequencing. The pathogenic targets governing the phenotypic switch of SMCs were identified by trajectory inference, functional scoring, single-cell regulatory network inference and clustering, regulon, and interactome analyses and confirmed using human ascending aortas, primary SMCs, and a ß-aminopropionitrile monofumarate-induced AD model. RESULTS: The transcriptional profiles of 93 397 cells revealed a dynamic temporal-specific phenotypic transition and marked elevation of the activator protein-1 (AP-1) complex, actively enabling synthetic SMC expansion. Mechanistically, tumour necrosis factor signalling enhanced AP-1 transcriptional activity by dampening mitochondrial oxidative phosphorylation (OXPHOS). Targeting this axis with the OXPHOS enhancer coenzyme Q10 or AP-1-specific inhibitor T-5224 impedes phenotypic transition and aortic degeneration while improving survival by 42.88% (58.3%-83.3% for coenzyme Q10 treatment), 150.15% (33.3%-83.3% for 2-week T-5224), and 175.38% (33.3%-91.7% for 3-week T-5224) in the ß-aminopropionitrile monofumarate-induced AD model. CONCLUSIONS: This cross-sectional compendium of cellular atlas of human ascending aortas during AD progression provides previously unappreciated insights into a transcriptional programme permitting aortic degeneration, highlighting a translational proof of concept for an anti-remodelling intervention as an attractive strategy to manage temporal-specific AD by modulating the tumour necrosis factor-OXPHOS-AP-1 axis.

A sensitive ratiometric fluorescence probe with a large spectral shift for sensing and imaging of palladium.

Palladium (Pd) is an important heavy metal with excellent catalytic properties and widely used in organic chemistry and the pharmaceutical industry. Efficient and convenient analytical techniques for Pd are urgently needed due to the hazardous effects of Pd on the environment and human health. Herein, we have developed five new ratiometric probes for the selective detection of Pd0 based on the Pd-catalyzed Tsuji-Trost reaction. Among them, the F-substituted probe PF-Pd showed the largest spectral shift (148 nm) and the most sensitive response (detection limit 2.11 nM). PF-Pd was employed to determine Pd0 in tap water or lake water samples, which presented satisfactory accuracy and precision. In addition, profiting from its distinct colorimetric response, visual detection of Pd0 was performed on PF-Pd loaded test strips or in field soil samples. Furthermore, fluorescence imaging of living 4T1 cells demonstrated that PF-Pd is suitable for imaging of intracellular Pd0. The good analytical performance of PF-Pd may enable it to be widely used in the convenient, rapid, sensitive and selective detection of Pd0 in environmental or biological analysis.

A near-infrared and lysosome-targeted BODIPY photosensitizer for photodynamic and photothermal synergistic therapy.

Phototherapy is a promising approach for the treatment of cancers and other diseases. So far, many photosensitizers have been developed for photodynamic therapy (PDT) or photothermal therapy (PTT). However, it remains a challenge to develop a system for synergistic PDT and PTT with specific targeting and real-time fluorescence tracking. Herein, we designed a multifunctional BODIPY derivative, Lyso-BDP, for synergistic PDT and PTT against tumors. Lyso-BDP was composed of three parts: (1) the BODIPY fluorophore was selected as a theranostic core, (2) a morpholine group modified on meso-BODIPY served as a lysosome-targeting unit for enhancing the antitumor effect, and (3) N,N-diethyl-4-vinylaniline was attached to the BODIPY core to extend its wavelength to the near-infrared region. Finally, Lyso-BDP shows near-infrared absorption and emission, photosensitizing activity, lysosomal targeting, and synergistic PDT and PTT effects, and effectively kills cancer cells both in vitro and in vivo. Therefore, our study demonstrates that Lyso-BDP can serve as a promising photosensitizer in the therapy of cancer with potential clinical application prospects.

5-HT and S100ß values in evaluating severity of cognitive impairment after traumatic brain injury.

INTRODUCTION: The aim of the study was to investigate the relationship between serum serotonin (5-HT) and central nervous system specific protein S100b application value in evaluating the severity of cognitive impairment after traumatic brain injury (TBI). MATERIAL AND METHODS: 102 patients with TBI treated in Jilin Neuropsychiatric Hospital from June 2018 to October 2020 were selected. According to Montreal Cognitive Assessment (MoCA) scale, patients were tested for cognitive function from multiple levels, such as attention, executive function, memory, and language. Patients with cognitive impairment were included into study group ( n = 64), and those without cognitive impairment were assigned to control group ( n = 58). Serum 5-HT and S100b were compared between the two groups with b level. Serum 5-HT and S100b were analyzed by receiver operating characteristic curve (ROC), b application value judging cognitive impairment. RESULTS: Serum 5-HT and S100b levels in the study group were significantly higher than those in the control group ( p < 0.05). In serum 5-HT and S100b, there was a significant negative correlation with a MoCA score ( r = -0.527, r = -0.436; p < 0.05, p < 0.05). Combined detection of serum 5-HT and S100b's area under ROC curve (AUC) was 0.810 (95% CI: 0.742-0.936, p < 0.05), sensitivity was 0.842, and specificity was 0.813. CONCLUSIONS: Serum 5-HT and S100b levels are closely related to the cognitive function of TBI patients. Combined detection is helpful to improve the accuracy of predicting cognitive impairment.

Causal effects of circulating vitamin levels on the risk of heart failure: a Mendelian randomization study.

BACKGROUND: Observational studies suggest inverse associations between serum vitamin levels and the risk of heart failure (HF). However, the causal effects of vitamins on HF have not been fully elucidated. Here, we conducted a Mendelian randomization (MR) study to investigate the causal associations between genetically determined vitamin levels and HF. METHODS: Genetic instrumental variables for circulating vitamin levels, including vitamins A, B, C, D, and E, which were assessed as either absolute or metabolite levels were obtained from public genome-wide association studies. Summary statistics for single-nucleotide-polymorphisms and HF associations were retrieved from the HERMES Consortium (47,309 cases and 930,014 controls) and FinnGen Study (30,098 cases and 229,612 controls). Two-sample MR analyses were implemented to assess the causality between vitamin levels and HF per outcome database, and the results were subsequently combined by meta-analysis. RESULTS: Our MR study did not find significant associations between genetically determined circulating vitamin levels and HF risk. For absolute vitamin levels, the odds ratio for HF ranged from 0.97 (95% confidence interval [CI]: 0.85-1.09, P = 0.41) for vitamin C to 1.05 (95% CI: 0.61-1.82, P = 0.85) for vitamin A. For vitamin metabolites, the odds ratio ranged between 0.94 (95% CI: 0.75-1.19, P = 0.62) for α-tocopherol and 1.11 (95% CI: 0.98-1.26, P = 0.09) for γ-tocopherol. CONCLUSION: Evidence from our study does not support the causal effects of circulating vitamin levels on HF. Therefore, there may be no direct beneficial effects of vitamin intake on the prevention of primary HF.

A Lysosome-Targeted Near-Infrared Fluorescent Probe with Excellent Water Solubility for Surgery Navigation in Breast Cancer.

To get a tumor-targeted contrast agent for imaging guide resection of tumors, we designed a novel fluorescent probe based on the heptamethine cyanine core, Cy7-MO, which has excellent water solubility and near-infrared photophysical and lysosomal targeting properties. The chemical structure of Cy7-MO was characterized by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry. The toxicity of Cy7-MO was evaluated by cell counting kit-8. Then, a cellular-level study was conducted to evaluate the suborganelle localization in 4T1-Luc1 cells, and it was also used for surgical navigation in orthotopic breast tumor resection in vivo. The results showed that Cy7-MO was well targeted to lysosomes. Importantly, the Cy7-MO probe was found to be well tolerable and exhibited excellent biocompatibility. Moreover, the orthotopic breast tumor margin was clearly visualized through fluorescence guiding of Cy7-MO. Finally, the correct tumor tissues were completely removed, and a negative margin was obtained successfully, which demonstrated an enhanced precision of surgery.

A simple and sensitive electrochemical sensor for the detection of peptidase activity.

In this work, a simple and sensitive electrochemical sensor was proposed for the detection of ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) activity. Firstly, the BACE1 specific peptide was modified onto the Au electrode to graft a single-strand DNA with polycytosine DNA sequence (dC12) via amide bonding between peptide and dC12. Because the dC12 is abundant in phosphate groups, thus it can react with molybdate to form redox molybdophosphate, which can generate electrochemical current. Using BACE1 as a model peptidase, the proposed sensor shows a linear response range from 1 to 15 U/mL and limit of detection down to 0.05 U/mL. The sensor displays good performance for the BACE1 activity detection in human serum samples, which may have potential applications in the clinical diagnostics of Alzheimer's disease.

Piceatannol-3'-O-ß-d-glucopyranoside alleviates nephropathy via regulation of High mobility group B-1 (HMGB1)/Toll-like receptor 4 (TLR4)/Nuclear factor kappa B (NF-κB) signalling pathway.

OBJECTIVES: Nephrotic syndrome (NS) remains a therapeutic challenge for nephrologists. Piceatannol-3'-O-ß-d-glucopyranoside (PG) is a major active ingredient in Quzha. The purpose of the study was to assess the renoprotection of PG. METHODS: In vitro, the podocyte protection of PG was assessed in MPC-5. SD rats were injected with adriamycin to induce nephropathy in vivo. The determination of biochemical changes and inflammatory cytokines was performed, and pathological changes were examined by histopathological examination. Immunostaining and western blot analyses were used to analyse expression levels of proteins. KEY FINDINGS: The results showed that PG improved adriamycin-induced podocyte injury, attenuated nephropathy, improved hypoalbuminemia and hyperlipidaemia, and lowered cytokine levels. The podocyte protection of PG was further verified by reduction of desmin and increasing synaptopodin expression. Furthermore, treatment with PG down-regulated the expression of HMGB1, TLR4 and NF-κB along with its upstream regulator, IKKß and yet up-regulated IκBα expression by western blot analysis. CONCLUSIONS: Overall, our data showed that PG has a favourable renoprotection in experimental nephrosis, apparently by amelioration of podocyte injury. PG might mediate these effects via modulation of the HMGB1/TLR4/NF-κB signalling pathway. The study first provides a promising leading compound for the treatment of NS.

Comprehensive monitoring of mitochondrial viscosity variation during different cell death processes by a NIR mitochondria-targeting fluorescence probe.

Cell death is a fundamental feature of multicellular organisms, in which mitochondria play crucial roles. Therefore, revealing and monitoring the microenvironment of mitochondria are significant to investigate cell death process. Herein, the mitochondrial viscosity variation behaviors of a series of different cell death processes were monitored with a NIR mitochondria-targeting fluorescence probe FLV. FLV was designed based on a rotatable flavylocyanine fluorophore that presented selective and sensitive NIR fluorescence enhancement response with the increase of environmental viscosity. Fluorescence imaging experiments of living cells incubated with nystatin or under different temperature indicated that FLV was capable of imaging the change of mitochondrial viscosity. Finally, FLV was applied for monitoring the mitochondrial viscosity variation during different cell death processes. It was found that there were obvious mitochondrial viscosity increases during apoptosis, necrosis and autophagy; however, no detectable mitochondrial viscosity variation was observed in ferroptosis process incubated with ferroptosis inducer erastin or RSL3 for 6 h. These results demonstrated that FLV is a viable tool for monitoring the mitochondrial viscosity variation and is likely to be used in the diagnosis of the mitochondrial viscosity-associated cell processes and diseases.

An oxygen-carrying and lysosome-targeting BODIPY derivative for NIR bioimaging and enhanced multimodal therapy against hypoxic tumors.

Cancer treatment modalities have gradually shifted from monotherapies to multimodal therapies. It is still a challenge to develop a synergistic chemo-phototherapy system with relieving tumor hypoxia, specific targeting, and real-time fluorescence tracking. In this study, we designed a multifunctional BODIPY derivative, FBD-M, for synergistic chemo-phototherapy against hypoxic tumors. FBD-M was composed of four parts: 1) The BODIPY fluorophore selected as a theranostic core, 2) A pentafluorobenzene group modified on meso-BODIPY to carry oxygen, 3) A morpholine group hooked to one side of BODIPY served as a lysosome-targeting unit for enhancing antitumor effect, and 4) An aromatic nitrogen mustard group introduced on other side of BODIPY to achieve chemotherapy. After introducing the morpholine and aromatic nitrogen mustard in BODIPY, the conjugate system of BODIPY was also expanded to realize near-infrared (NIR) phototherapy. Finally, FBD-M was obtained by a rational design, which possessed with NIR absorbance and emission, photosensitive activity, oxygen-carrying capability for relieving tumor hypoxia, high photothermal conversion efficiency, good photostability, lysosome targeting, low toxicity, and synergistic chemo-phototherapy against hypoxic tumors. FBD-M had been successfully applied for anticancer in vitro and in vivo. Our study demonstrates that FBD-M can serve as an ideal multifunctional theranostic agents.

Genetically determined serum bilirubin level and the risk of heart failure: A mendelian randomization study.

Background: The association between serum bilirubin level and heart failure (HF) was controversial in previous observational studies and the causal effects of bilirubin on HF have not been investigated. Here, we conducted a Mendelian randomization (MR) study to investigate the associations between genetically determined bilirubin level and HF. Methods: Summary data on the association of single nucleotide polymorphisms (SNPs) with serum bilirubin levels were obtained from genome-wide association study (GWAS) for individuals of European descent and East Asian descent separately. Statistical data for gene-HF associations were extracted from three databases: the HERMES Consortium (47,309 cases and 930,014 controls), FinnGen study (30,098 cases and 229,612 controls) for European population and Biobank Japan (2,820 HF cases and 192,383 controls) for East Asian population. We applied a two-sample Mendelian randomization framework to investigate the causal association between serum bilirubin and HF. Results: Findings from our MR analyses showed that genetically determined serum bilirubin levels were not causally associated with HF risk in either European or East Asian population (odds ratio [OR] = 1.01 and 95% confidence interval [CI] = .97-1.05 for HERMES Consortium; OR = 1.01 and 95% CI = .98-1.04 for FinnGen Study; OR = .82, 95% CI: .61-1.10 for Biobank Japan). These results remained unchanged using different Mendelian randomization methods and in sensitivity analyses. Conclusion: Our study did not find any evidence to support a causal association between serum bilirubin and HF.

Performance improvement in multi-label thoracic abnormality classification of chest X-rays with noisy labels.

PURPOSE: This study aimed at developing a deep learning-based method for multi-label thoracic abnormality classification on frontal view chest X-ray (CXR). To improve the performance of classification, issues of class imbalance, noisy labels and ensemble of networks are addressed in the paper. METHODS: The experiments were performed on a public dataset called Chest X-ray 14 (CXR14), which includes 112,120 frontal view CXRs from 30,805 patients. We came up with an ensemble learning framework to improve the classification and a noisy label detection method to detect the CXRs with noisy labels. The detected CXRs were reviewed by two board-certificated radiologists in a consensus fashion to evaluate detected noisy labels. The classification was assessed on CXR14 with area under the receiver operating characteristic curve (AUC). RESULTS: Report from the radiologists indicated that detected noisy labels had high possibility to be true positives. A notable improvement from baseline in performance of classification was observed with the ensemble learning framework. After removing the CXRs with detected noisy labels, 8 out of 14 abnormalities improved significantly on CXR14. The suggested framework achieved AUC score of 0.827 on CXR14. CONCLUSION: The methods of this study boost the classification on CXR with awareness of the label noise. Expanded experimental results show that all of them were able to improve multi-label thoracic abnormality classification performance, respectively. A new state-of-the-art is achieved in this study.

Role of toll-like receptors in the pathogenesis of COVID-19: Current and future perspectives.

The coronavirus disease 2019 (COVID-19) pandemic underlines a persistent threat of respiratory tract infectious diseases and warrants preparedness for a rapid response. At present, COVID-19 has had a serious social impact and imposed a heavy global burden on public health. The exact pathogenesis of COVID-19 has not been fully elucidated. Since the outbreak of COVID-19, a renewed attention has been brought to Toll-like receptors (TLRs). Available data and new findings have demonstrated that the interaction of human TLRs and SARS-CoV-2 is a vital mediator of COVID-19 immunopathogenesis. TLRs such as TLR2, 4, 7 and 8 are potentially important in viral combat and activation of immunity in patients with COVID-19. Therapeutics targeting TLRs are currently considered promising options against the pandemic. A number of TLR-targeting immunotherapeutics are now being investigated in preclinical studies and different phases of clinical trials. In addition, innovative vaccines based on TLRs under development could be a promising approach for building a new generation of vaccines to solve the current challenges. In this review, we summarize recent progress in the role of TLRs in COVID-19, focusing the new candidate drugs targeting TLRs, the current technology and potential paths forward for employing TLR agonists as vaccine adjuvants.