Sunlight-powered sustained flight of an ultralight micro aerial vehicle.

Limited flight duration is a considerable obstacle to the widespread application of micro aerial vehicles (MAVs)1-3, especially for ultralightweight MAVs weighing less than 10 g, which, in general, have a flight endurance of no more than 10 min (refs. 1,4). Sunlight power5-7 is a potential alternative to improve the endurance of ultralight MAVs, but owing to the restricted payload capacity of the vehicle and low lift-to-power efficiency of traditional propulsion systems, previous studies have not achieved untethered sustained flight of MAVs fully powered by natural sunlight8,9. Here, to address these challenges, we introduce the CoulombFly, an electrostatic flyer consisting of an electrostatic-driven propulsion system with a high lift-to-power efficiency of 30.7 g W-1 and an ultralight kilovolt power system with a low power consumption of 0.568 W, to realize solar-powered sustained flight of an MAV under natural sunlight conditions (920 W m-2). The vehicle's total mass is only 4.21 g, within 1/600 of the existing lightest sunlight-powered aerial vehicle6.

Integrative analysis of bulk and single-cell RNA sequencing reveals sphingolipid metabolism and immune landscape in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is characterized by its aggressive behavior and complex molecular heterogeneity, posing significant challenges for treatment and prognostication. This study offers a comprehensive analysis of ccRCC by leveraging both bulk and single-cell RNA sequencing data, with a specific aim to unravel the complexities of sphingolipid metabolism and the intricate dynamics within the tumor microenvironment (TME). By examining ccRCC samples sourced from public databases, our investigation delves deep into the genetic and transcriptomic landscape of this cancer type. Employing advanced analytical techniques, we have identified pivotal patterns in gene expression and cellular heterogeneity, with a special focus on the roles and interactions of various immune cells within the TME. Significantly, our research has unearthed insights into the dynamics of sphingolipid metabolism in ccRCC, shedding light on its potential implications for tumor progression and strategies for immune evasion. A novel aspect of this study is the development of a risk score model designed to enhance prognostic predictions for ccRCC patients, which is currently pending external validation to ascertain its clinical utility. Despite its contributions, the study is mindful of its limitations, including a reliance on observational data from public sources and a primary focus on RNA sequencing data, which may constrain the depth and generalizability of the findings. The study does not encompass critical aspects, such as protein expression, posttranslational modifications, and comprehensive metabolic profiles. Moreover, its retrospective design underscores the necessity for future prospective studies to solidify these preliminary conclusions. Our findings illuminate the intricate interplay between genetic alterations, sphingolipid metabolism, and immune responses in ccRCC. This research not only enhances our understanding of the molecular foundations of ccRCC but also paves the way for the development of targeted therapies and personalized treatment modalities. The study underlines the importance of cautious interpretation of results and champions ongoing research using diverse methodologies to thoroughly comprehend and effectively combat this formidable cancer type.

Insomnia and sleep duration for kidney function: Mendelian randomization study.

OBJECTIVES: Extensive researches highlight the detrimental impact of sleep disorders such as insomnia and insufficient sleep duration on kidney function. However, establishing a clear causal relationship between insomnia, sleep duration, and kidney function remains challenging. This study aims to estimate this relationship using Mendelian randomization (MR). METHODS: Independent genetic variants strongly associated with insomnia (N = 462,341) and sleep duration (N = 460,099) were selected as instrumental variables from corresponding genome-wide association studies (GWAS). Kidney function parameters, including serum creatinine, estimated glomerular filtration rate by cystatin C (eGFRcys), acute renal failure (ARF), chronic renal failure (CRF), kidney injury molecule-1, neutrophil gelatinase associated lipocalin, microalbuminuria, cystatin C, and ß2 microglobulin, were derived from GWAS databases. A two-sample MR study was conducted to assess the causal relationship between sleep disorders and kidney function, and multivariable MR was used to identify potential mediators. The inverse-variance weighted was used as the primary estimate. RESULTS: MR analysis found robust evidence indicating that insomnia and short sleep duration were associated with an increased risk of elevated serum creatinine, regardless of adjusting for obesity. Causal links between sleep duration and eGFRcys or cystatin C were also identified. While genetically predicted insomnia and sleep duration were found to potentially impact ARF, CRF, microalbuminuria, and ß2 microglobulin, the p-values in multivariable MR analysis became nonsignificant. No pleiotropy was detected. CONCLUSIONS: This study demonstrates a causal impact of insomnia on the risk of elevated serum creatinine and a positive effect of sleep duration on serum creatinine, eGFRcys, and cystatin C. Our findings also suggest their potential indirect effects on ARF, CRF, microalbuminuria, and ß2 microglobulin mediated by obesity.

Functionalized Metal-Organic Framework-Modified Hydrogel That Breaks the Vicious Cycle of Inflammation and ROS for Repairing of Diabetic Bone Defects.

The regeneration of diabetic bone defects remains challenging. Hyperglycemia causes inflammation state and excessive reactive oxygen species (ROS) during bone regeneration period. These two effects reinforce one another and create an endless loop that is also accompanied by mitochondrial dysfunction. However, there is still no effective and inclusive method targeting at the two aspects and breaking the vicious cycle. Herein, nanoparticles-Met@ZIF-8(metformin loaded zeolitic imidazolate frameworks) modified hydrogel that is capable of releasing metformin and Zn elements are constructed. This hydrogel treats hyperglycemia while also controlling mitochondrial function, reducing inflammation, and restoring homeostasis. In addition, the synergetic effect from metformin and Zn ions inhibits ROS-inflammation cascade generation and destroys the continuous progress by taking effects in both ROS and inflammation and further keeping organelles' homeostasis. Furthermore, with the recovery of mitochondria and breakdown of the ROS-inflammation cascade cycle, osteogenesis under a diabetic microenvironment is enhanced in vivo and in vitro. In conclusion, the study provides critical insight into the biological mechanism and potential therapy for diabetic bone regeneration.

A Novel Fluorescence Sensor for Iodide Detection Based on the 1,3-Diaryl Pyrazole Unit with AIE and Mechanochromic Fluorescence Behavior.

A D-A type of luminophore, TPA-CDP, was designed and synthesized by using triphenylamine (TPA) as D (electron donor), 1,3-diaryl pyrazole with cyano groups (CDP) as A (electron acceptor) and employing a cyanovinyl segment as a recognition group. Firstly, TPA-CDP demonstrates effective fluorescence quenching as a sensor for I- by the nucleophilic addition reaction of the cyanovinyl segment with a high level of sensitivity, selectivity and a low determination limit of 4.43 µM. Interestingly, TPA-CDP exhibited an AIE phenomenon with the fw value reaching 50%. In addition, TPA-CDP displayed distinct mechanochromic fluorescence behavior with 70 nm red shift, which was observed over four repeated cycles. Furthermore, the mechanochromic fluorescence behavior of TPA-CDP, as observed in powder XRD experiments, was found to be associated with the morphological transition from a crystalline state to an amorphous state. These results confirm the significant potential of CDP as a powerful electron-deficient component in the creation of D-A-type mechanochromic fluorescence materials and biosensors for detecting I-.

Inhibitory mechanism of 6-Pentyl-2H-pyran-2-one secreted by Trichoderma atroviride T2 against Cylindrocarpon destructans.

Root rot caused by Cylindrocarpon destructans is one of the most devastating diseases of Panax notoginseng, and Trichoderma species are potential agents for the biocontrol of fungal diseases. Thus, we screened a total of 10 Trichoderma isolates against C. destructans and selected Trichoderma atroviride T2 as an antagonistic strain for further research. 6-Pentyl-2H-pyran-2-one (6PP) was identified as an important active metabolite in the fermentation broth of the strain and exhibited antifungal activity against C. destructans. Transcriptome and metabolome analyses showed that 6PP significantly disturbed the metabolic homeostasis of C. destructans, particularly the metabolism of amino acids. By constructing a gene coexpression network, ECHS1 was identified as the hub gene correlated with 6PP stress. 6PP significantly downregulated the expression of ECHS1 at the transcriptional level and combined with the ECHS1 protein. Autophagy occurred in C. destructans cells under 6PP stress. In conclusion, 6PP may induce autophagy in C. destructans by downregulating ECHS1 at the transcriptional level and inhibiting ECHS1 protein activity. 6PP is a potential candidate for the development of new fungicides against C. destructans.

Benzothiazole inhibits the growth of Phytophthora capsici through inducing apoptosis and suppressing stress responses and metabolic detoxification.

Benzothiazole (BZO) is an antimicrobial secondary metabolite volatilized by many plants and microbes. However, the mechanism of BZO against phytopathogens is still unclear. Here, we found that BZO has antimicrobial activity against the oomycete pathogen Phytophthora capsici. Transcriptome and proteome analyses demonstrated that BZO significantly suppressed the expression of genes and proteins involved in morphology, abiotic stress defense and detoxification, but induced the activity of apoptosis. Annexin V-FITC/PI staining confirmed that the process of apoptosis was significantly induced by BZO at concentration of 150 mg L-1. FITC-phalloidin actin-cytoskeleton staining combined with hyphal cell wall staining and hyphal ultrastructure studies further confirmed that BZO disrupted the cell membrane and hyphal morphology through disrupting the cytoskeleton, eventually inhibiting the growth of hyphae. These data demonstrated that BZO has multiple modes of action and may act as potential leading compound for the development of new oomycete fungicides. These results also showed that the combination of transcriptomic and proteomic approaches was a useful method for exploring the novel antifungal mechanisms of natural compounds.

Transverse microvibrations-based guide wires drag reduction evaluation for endovascular interventional application.

When conducting endovascular interventional surgery, doctors usually experience high viscous resistance resulting from direct contact with blood when operating the guide wire in blood vessels, which reduces the operational efficiency. Improper operation can cause vascular injuries and greatly reduce surgical safety, sometimes leading to the death of the patient. This paper presents a new method that applies transverse microvibrations at the proximal end of a conventional passive guide wire to reduce viscous resistance. The effect of the proposed method in reducing the viscous resistance in the fluid is studied. The influences of the tube diameter, medium density, and applied vibration frequency on the viscous force are investigated. Finally, for endovascular therapy, a mathematical model of the viscous force of the guide wire based on the proposed method is established in the environment of human blood vessels to predict the magnitude of the viscous force exerted on the guide wire and analyze the drag reduction effect of the proposed method. The effectiveness of the proposed method in drag reduction and its feasibility in improving surgical safety are experimentally demonstrated. The experimental results indicate that the proposed method can assist the doctor during complicated and variable operation conditions.

The Value of Older Donors' Klotho Level in Predicting Recipients' Short-Term Renal Function.

BACKGROUND The present organ shortage has led to increased use of kidneys from expanded-criteria donors, but the prognosis is disappointing due to poor graft quality. As a promising kidney protector, the Klotho gene's role in predicting short-term prognosis has not been assessed. MATERIAL AND METHODS We retrospectively analyzed data from 41 recipients and 25 donors. Multiple clinical variables were compared between different subgroups of donors or their corresponding recipients. The area under the receiver operating characteristic curve (AUROC) was used to evaluate the distinguishing ability. Dynamic changes in serum Klotho, FGF-23, and urinary NGAL were assessed. RESULTS Serum Klotho level was significantly lower in donors age ≥50 years (p=0.017), and there was a moderate negative correlation between serum Klotho expression and age (r=-0.464, p=0.019). Moreover, detection of Klotho mRNA and immunohistochemical analysis in kidneys revealed the same trend as in serum. Furthermore, for older donors (age ≥50 years), serum Klotho level had a strong negative correlation with recipient eGFR 1 month post-transplant (r=-0.686, p=0.007), which was proved to be a good predictor for estimating graft function by ROC analysis. Additionally, during the post-transplant follow-up, serum Klotho levels increased slightly after a temporary decline, while serum FGF-23 and urinary NGAL decreased significantly and then stayed low thereafter. CONCLUSIONS Klotho level, which decreases with age, may be a potential predictor of short-term renal function, especially for grafts from older donors.

Preparation, characterization of basil essential oil liposomes unidirectional single-conducting water sustained-release pads and their preservation properties to Lateolabrax japonicus fillets.

The juice exudation of aquatic products oozes out during storage can influence storage quality. Herein, a novel basil essential oil liposome unidirectional water-conducting sustained-release preservation pads (BEOL/UCSP) were prepared with nylon mesh as water-conducting layer, basil essential oil liposome (BEOL) as sustained-release preservation layer, and diatomite and absorbent-cotton as water-absorbing layer. EL/UCSP, ß-CL/UCSP, and BEO/UCSP were prepared after BEOL was replaced by eugenol liposome, ß-caryophyllene liposome, and BEO. BEOL are microspheres with bilayer structure, had good storage stability, centrifugal stability, thermal stability, embedding capacity, sustained-release, and oxidation resistance, and the main components of preservatives had a synergistic effect on antibacterial properties. The pads without preservative can initially slow down quality deterioration. BEOL/UCSP can directionally absorb exudate and realize long-term sustained-release of preservative, has excellent antibacterial and antioxidant effect, and extended shelf life of Lateolabrax japonicus fillets from 6.0 days to 12.8 days. The BEOL/UCSP can provide technical theoretical support for preservation materials.

The impact of donor hepatitis B virus infection on transplant outcomes in deceased donor kidney transplantation recipients.

Background: The use of hepatitis B virus (HBV)-positive donor kidneys to expand the donor pool has been implemented, but limited evidence exists regarding their impact on transplant outcomes. This study aimed to investigate the effects of donor HBV infection on transplant outcomes. Methods: Donor and recipient data between 2015 and 2021 were collected. A total of 743 kidney transplant cases were screened, including 94 donor hepatitis B surface antigen (HBsAg)+/recipient HBsAg- (D+R-) and 649 donor HBsAg-/recipient HBsAg- (D-R-) cases. The analysis endpoints included recipient HBV infection, delayed graft function (DGF), peak estimated glomerular filtration rate (eGFR) within 12 months, recipient survival, and death-censored graft survival (DCGS). Results: The D+R- group had a significantly higher risk of HBV infection compared to the D-R- group (6/72 vs. 3/231; relative risk, 6.4; p = 0.007). The risk of HBV transmission decreased significantly with increasing hepatitis B surface antibody (HBsAb) titer (p for trend = 0.003). Furthermore, the D+R- group did not exhibit an increased risk of DGF compared to the D-R- group (odds ratio, 0.70; p = 0.51) in the multivariable mixed model. Both groups had similar peak eGFR within 12 months (ß = 1.01, p = 0.71), and this had no impact on patient survival (hazard ratio [HR], 0.36; p = 0.10) and DCGS (HR, 0.79, p = 0.59) in the shared-frailty Cox model. Conclusion: The use of HBsAg-positive donor kidneys appears relatively safe for HBV-immunized recipients in the short term. D+R- does not negatively affect graft function recovery and provides comparable posttransplant outcomes. Maintaining an HBsAb titer over 100 IU/L before transplantation is critical to reduce the risk of HBV transmission.

Preparation and properties of PCL coaxial electrospinning films with shell loaded with CEO and core coated LEO nanoemulsions.

During storage and transportation, the reduction of microbial contamination and management of the exudation of fluids from the fish can effectively mitigate spoilage and degradation of fish fillets. In this work, the coaxial electrospinning films loaded with natural plant preservatives, namely laurel essential oil (LEO) and clove essential oil (CEO), were prepared by the coaxial electrospinning method synergistic with nanoemulsion techniques, and the hydrophilic preservation pads were prepared. The morphology of the film fiber is clear, without beads or damage, with fiber diameters falling within the 230-260 nm range. It has a distinct core-shell structure, exceptional thermal stability, and strong antibacterial and antioxidant properties. The core-shell structure of the fiber subtly regulates the release of preservatives and significantly improves the utilization efficiency. At the same time, the synergistic use of two essential oils can reduce the amount while amplifying their effectiveness. The pads significantly slowed down the increase of key indicators of spoilage, such as total viable count (TVC), pH, thiobarbituric acid reactive substances (TBA), and total volatile base nitrogen (TVB-N), during the storage of the fish fillets. Furthermore, the pads effectively slowed down the decline in water-holding capacity, the deterioration of textural qualities, and the negative changes in the microstructure of the fish muscle. Ultimately, the pads notably delayed the spoilage of fish fillets, extending their shelf life from 5 d to 9 d. The efficient utilization of biological preservatives in this film can provide technical support for the development of food preservation materials.

Diallyl Trisulfide Acts as a Soil Disinfestation Against the Ilyonectria destructans through Inducing the Burst of Reactive Oxygen Species.

Soil-borne diseases represent an impediment to the sustainable development of agriculture. A soil-borne disease caused by Ilyonectria destructans severely impacts Panax species, and soil disinfestation has proven to be an effective management approach. Here, diallyl trisulfide (DATS), derived from garlic, exhibited pronounced inhibitory effects on the growth of I. destructans in vitro tests and contributed to the alleviation of soil-borne diseases in the field. A comprehensive analysis demonstrated that DATS inhibits the growth of I. destructans by activating detoxifying enzymes, such as GSTs, disrupting the equilibrium of redox reactions. A series of antioxidant amino acids were suppressed by DATS. Particularly noteworthy is the substantial depletion of glutathione by DATS, resulting in the accumulation of ROS, ultimately culminating in the inhibition of I. destructans growth. Briefly, DATS could effectively suppress soil-borne diseases by inhibiting pathogen growth through the activation of ROS, and it holds promise as a potential environmentally friendly soil disinfestation.

ZIF-8-based Nanoparticles for Inflammation Treatment and Oxidative Stress Reduction in Periodontitis.

Periodontitis, an inflammatory bone resorption disease associated with dental plaque, poses significant challenges for effective treatment. In this study, we developed Mino@ZIF-8 nanoparticles inspired by the periodontal microenvironment and the unique properties of zeolitic imidazolate framework 8, aiming to address the complex pathogenesis of periodontitis. Transcriptome analysis revealed the active engagement of Mino@ZIF-8 nanoparticles in innate and adaptive inflammatory host defense and cellular metabolic remodeling. Through sustained release of the anti-inflammatory and antibacterial agent minocycline hydrochloride (Mino) and the generation of Zn2+ with pro-antioxidant effects during degradation, Mino@ZIF-8 nanoparticles synergistically alleviate inflammation and oxidative damage. Notably, our study focuses on the pivotal role of zinc ions in mitochondrial oxidation protection. Under lipopolysaccharide (LPS) stimulation, periodontal ligament cells undergo a metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis, leading to reduced ATP production and increased reactive oxygen species levels. However, Zn2+ effectively rebalances the glycolysis-OXPHOS imbalance, restoring cellular bioenergetics, mitigating oxidative damage, rescuing impaired mitochondria, and suppressing inflammatory cytokine production through modulation of the AKT/GSK3ß/NRF2 pathway. This research not only presents a promising approach for periodontitis treatment but also offers novel therapeutic opportunities for zinc-containing materials, providing valuable insights into the design of biomaterials targeting cellular energy metabolism regulation.

Remifentanil vs. dexmedetomidine for cardiac surgery patients with noninvasive ventilation intolerance: a multicenter randomized controlled trial.

BACKGROUND: The optimal sedative regime for noninvasive ventilation (NIV) intolerance remains uncertain. The present study aimed to assess the efficacy and safety of remifentanil (REM) compared to dexmedetomidine (DEX) in cardiac surgery patients with moderate-to-severe intolerance to NIV. METHODS: In this multicenter, prospective, single-blind, randomized controlled study, adult cardiac surgery patients with moderate-to-severe intolerance to NIV were enrolled and randomly assigned to be treated with either REM or DEX for sedation. The status of NIV intolerance was evaluated using a four-point NIV intolerance score at different timepoints within a 72-h period. The primary outcome was the mitigation rate of NIV intolerance following sedation. RESULTS: A total of 179 patients were enrolled, with 89 assigned to the REM group and 90 to the DEX group. Baseline characteristics were comparable between the two groups, including NIV intolerance score [3, interquartile range (IQR) 3-3 vs. 3, IQR 3-4, p = 0.180]. The chi-squared test showed that mitigation rate, defined as the proportion of patients who were relieved from their initial intolerance status, was not significant at most timepoints, except for the 15-min timepoint (42% vs. 20%, p = 0.002). However, after considering the time factor, generalized estimating equations showed that the difference was statistically significant, and REM outperformed DEX (odds ratio = 3.31, 95% confidence interval: 1.35-8.12, p = 0.009). Adverse effects, which were not reported in the REM group, were encountered by nine patients in the DEX group, with three instances of bradycardia and six cases of severe hypotension. Secondary outcomes, including NIV failure (5.6% vs. 7.8%, p = 0.564), tracheostomy (1.12% vs. 0%, p = 0.313), ICU LOS (7.7 days, IQR 5.8-12 days vs. 7.0 days, IQR 5-10.6 days, p = 0.219), and in-hospital mortality (1.12% vs. 2.22%, p = 0.567), demonstrated comparability between the two groups. CONCLUSIONS: In summary, our study demonstrated no significant difference between REM and DEX in the percentage of patients who achieved mitigation among cardiac surgery patients with moderate-to-severe NIV intolerance. However, after considering the time factor, REM was significantly superior to DEX. Trial registration ClinicalTrials.gov (NCT04734418), registered on January 22, 2021. URL of the trial registry record: https://register. CLINICALTRIALS: gov/prs/app/action/SelectProtocol?sid=S000AM4S&selectaction=Edit&uid=U00038YX&ts=3&cx=eqn1z0 .

Inhibition of ACSF2 protects against renal ischemia/reperfusion injury via mediating mitophagy in proximal tubular cells.

Acute kidney injury (AKI) is a prevalent clinical condition caused by sepsis and ischemia reperfusion (IR) injury. The principal driver of IR-induced AKI involves renal tubular structural changes triggered by the impairment of function in renal tubular cells. The target gene, Acyl-CoA Synthetase Family Member 2 (ACSF2), was retrieved from the GEO database based on high specific expression in renal tubular cells and location in mitochondria. Here, we substantiate that ACSF2 is specifically localized in the mitochondria of the renal tubular epithelium. Functionally silencing ACSF2 in HK2 cells enhanced hypoxia-reoxygenation (HR)-induced mitophagy, restored mitochondrial function and decreased the production of mitochondrial superoxide. Our study demonstrated that these effects were reversed by silencing Bcl-2 19-kDa interacting protein 3 (BNIP3), a receptor regulating mitophagy. In vivo, ACSF2 knockdown significantly enhanced IR-induced mitophagy and improved renal function in mice with IR injury. Conversely, BNIP3 knockdown inhibited mitophagy and exacerbated renal damage in ACSF2-knockdown mice with IR injury. In conclusion, our study demonstrated that inhibition of ACSF2 enhances mitophagy, restoring mitochondrial function and protects against IR-induced AKI, providing a new target and potential strategy for therapy.

A sustained-release PDGF-BB nanocomposite hydrogel for DM-associated bone regeneration.

Regeneration of bone tissue in the environment of diabetes mellitus (DM) remains one of the clinical challenges, with malfunction of stem cells in a high-glucose microenvironment being the primary obstacle. We designed an injectable sustained-release PDGF-BB nanocomposite hydrogel. PDGF-BB, a star molecule for treating various complications of DM, was used for the first time for DM-associated bone regeneration, and we showed that it restored stem cell proliferation and migration and facilitated osteogenesis inhibition under high glucose stimulation by activating ERK and AKT pathways. To address the requirements for continuous PDGF-BB release in GelMA while also increasing mechanical strength, nanoclay LAPONITE® was added, which may still exhibit pro-osteogenic activity in diabetic environments by releasing bioactive ions (Si4+, Mg2+, and Li+). This injectable hydrogel heals calvarial lesions successfully in diabetic rats and has the potential to be used as a direct and effective tool for treating diabetic patients.

Regenerative Peripheral Nerve Interfaces Effectively Prevent Neuroma Formation After Sciatic Nerve Transection in Rats.

Objective: The disordered growth of nerve stumps after amputation leading to the formation of neuromas is an important cause of postoperative pain in amputees. This severely affects the patients' quality of life. Regenerative peripheral nerve interfaces (RPNIs) are an emerging method for neuroma prevention, but its postoperative nerve growth and pathological changes are yet to be studied. Methods: The rat sciatic nerve transection model was used to study the effectiveness of RPNI in this experiment. The RPNI (experimental) group (n = 11) underwent RPNI implantation after sciatic nerve transection, while the control group (n = 11) only underwent sciatic nerve transection. Autotomy behavior, ultrasonography, and histopathology were observed for 2 months postoperatively. Results: Compared to the control group, the incidence and size of the neuromas formed and the incidence and extent of autotomy were significantly reduced in the RPNI group. The axon density in the stump and degree of stump fibrosis were also significantly reduced in the RPNI group. Conclusion: RPNI effectively prevented the formation of neuromas.

Comparison of the Three Sets of Diagnostic Criteria for Vogt-Koyanagi-Harada Disease in Southeast China - A Retrospective Case-Control Study.

PURPOSE: To compare the utility of the Chinese diagnostic criteria for Vogt-Koyanagi-Harada (VKH) disease (CDCV), the revised diagnostic criteria (RDC) and the classification criteria by SUN (SUN-C). METHODS: Two groups of patients (VKH group and non-VKH group) were assessed in this retrospective case-control study. Sensitivity, specificity and area under receiver operating characteristic curve (AUC) were evaluated among these criteria. RESULTS: 258 patients were included after propensity score matching. The sensitivities were 92.2% in CDCV, 66.7% in RDC, and 54.3% in SUN-C. In different disease stages (early and late), similar sensitivity results were observed. The specificities were 96.1% in CDCV, 97.7% in RDC, and 99.2% in SUN-C. The AUCs were 0.942 in CDCV, 0.822 in RDC and 0.767 in SUN-C. CONCLUSION: A higher sensitivity value and larger AUC in CDCV were found. CDCV are highly useful in the diagnosis and classification of VKH disease in Chinese patients.

Application of the Adverse Outcome Pathway Concept to In Vitro Nephrotoxicity Assessment: Kidney Injury due to Receptor-Mediated Endocytosis and Lysosomal Overload as a Case Study.

Application of adverse outcome pathways (AOP) and integration of quantitative in vitro to in vivo extrapolation (QIVIVE) may support the paradigm shift in toxicity testing to move from apical endpoints in test animals to more mechanism-based in vitro assays. Here, we developed an AOP of proximal tubule injury linking a molecular initiating event (MIE) to a cascade of key events (KEs) leading to lysosomal overload and ultimately to cell death. This AOP was used as a case study to adopt the AOP concept for systemic toxicity testing and risk assessment based on in vitro data. In this AOP, nephrotoxicity is thought to result from receptor-mediated endocytosis (MIE) of the chemical stressor, disturbance of lysosomal function (KE1), and lysosomal disruption (KE2) associated with release of reactive oxygen species and cytotoxic lysosomal enzymes that induce cell death (KE3). Based on this mechanistic framework, in vitro readouts reflecting each KE were identified. Utilizing polymyxin antibiotics as chemical stressors for this AOP, the dose-response for each in vitro endpoint was recorded in proximal tubule cells from rat (NRK-52E) and human (RPTEC/TERT1) in order to (1) experimentally support the sequence of key events (KEs), to (2) establish quantitative relationships between KEs as a basis for prediction of downstream KEs based on in vitro data reflecting early KEs and to (3) derive suitable in vitro points of departure for human risk assessment. Time-resolved analysis was used to support the temporal sequence of events within this AOP. Quantitative response-response relationships between KEs established from in vitro data on polymyxin B were successfully used to predict in vitro toxicity of other polymyxin derivatives. Finally, a physiologically based kinetic (PBK) model was utilized to transform in vitro effect concentrations to a human equivalent dose for polymyxin B. The predicted in vivo effective doses were in the range of therapeutic doses known to be associated with a risk for nephrotoxicity. Taken together, these data provide proof-of-concept for the feasibility of in vitro based risk assessment through integration of mechanistic endpoints and reverse toxicokinetic modelling.