Rethinking the potential role of dose painting in personalized ultra-fractionated stereotactic adaptive radiotherapy.

Fractionated radiotherapy was established in the 1920s based upon two principles: (1) delivering daily treatments of equal quantity, unless the clinical situation requires adjustment, and (2) defining a specific treatment period to deliver a total dosage. Modern fractionated radiotherapy continues to adhere to these century-old principles, despite significant advancements in our understanding of radiobiology. At UT Southwestern, we are exploring a novel treatment approach called PULSAR (Personalized Ultra-Fractionated Stereotactic Adaptive Radiotherapy). This method involves administering tumoricidal doses in a pulse mode with extended intervals, typically spanning weeks or even a month. Extended intervals permit substantial recovery of normal tissues and afford the tumor and tumor microenvironment ample time to undergo significant changes, enabling more meaningful adaptation in response to the evolving characteristics of the tumor. The notion of dose painting in the realm of radiation therapy has long been a subject of contention. The debate primarily revolves around its clinical effectiveness and optimal methods of implementation. In this perspective, we discuss two facets concerning the potential integration of dose painting with PULSAR, along with several practical considerations. If successful, the combination of the two may not only provide another level of personal adaptation ("adaptive dose painting"), but also contribute to the establishment of a timely feedback loop throughout the treatment process. To substantiate our perspective, we conducted a fundamental modeling study focusing on PET-guided dose painting, incorporating tumor heterogeneity and tumor control probability (TCP).

Remnant cholesterol and risk of major adverse cardiovascular events: a systematic review and dose-response meta-analysis of cohort studies.

Emerging evidence indicates a significant role of remnant cholesterol in contributing to the residual risk associated with major adverse cardiovascular events (MACE). This study aims to evaluate the dose-response relationship between remnant cholesterol and the risk of MACE. PubMed, Embase and Cochrane databases were reviewed to identify cohort studies published in English up to 1 August 2023. Twenty-eight articles were selected. Pooled hazard ratios (HR) and their 95% confidence intervals (CIs) were calculated using fixed or random-effects models to evaluate the association between remnant cholesterol and the risk of MACE. The dose-response relationship between remnant cholesterol levels and the risk of MACE was analyzed using the linear model and restricted cubic spline regression models. For calculated remnant cholesterol levels, the pooled HR (95% CI) of MACE for per 1-SD increase was 1.13 (1.08, 1.17); HR (95% CI) for the second quartile (Q2), the third quartile (Q3) and the highest quartile (Q4) of remnant cholesterol levels were 1.14 (1.03, 1.25), 1.43 (1.23, 1.68) and 1.68 (1.44, 1.97), respectively, compared with the lowest quartile (Q1). For measured remnant cholesterol levels, the pooled HR (95% CI) of MACE per 1-SD increase was 1.67 (1.39, 2.01). The dose-response meta-analysis showed a dose-response relationship between remnant cholesterol levels and the risk of MACE, both on a linear trend (P < 0.0001) and a nonlinear trend (P < 0.0001). The risk of MACE is associated with increased levels of remnant cholesterol, and the dose-response relationship between remnant cholesterol levels and the risk of MACE showed both linear and nonlinear trends.

Twenty-four-hour blood pressure trajectories and clinical outcomes in patients who had an acute ischaemic stroke.

OBJECTIVE: The management of blood pressure (BP) in acute ischaemic stroke remains a subject of controversy. This investigation aimed to explore the relationship between 24-hour BP patterns following ischaemic stroke and clinical outcomes. METHODS: A cohort of 4069 patients who had an acute ischaemic stroke from 26 hospitals was examined. Five systolic BP trajectories were identified by using latent mixture modelling: trajectory category 5 (190-170 mm Hg), trajectory category 4 (180-140 mm Hg), trajectory category 3 (170-160 mm Hg), trajectory category 2 (155-145 mm Hg) and trajectory category 1 (150-130 mm Hg). The primary outcome was a composite outcome of death and major disability at 3 months poststroke. RESULTS: Patients with trajectory category 5 exhibited the highest risk, while those with trajectory category 1 had the lowest risk of adverse outcomes at 3-month follow-up. Compared with the patients in the trajectory category 5, adjusted ORs (95% CIs) for the primary outcome were 0.79 (0.58 to 1.10), 0.70 (0.53 to 0.93), 0.64 (0.47 to 0.86) and 0.47 (0.33 to 0.66) among patients in trajectory category 4, trajectory category 3, trajectory category 2 and trajectory category 1, respectively. Similar trends were observed for death, vascular events and the composite outcome of death and vascular events. CONCLUSION: Patients with persistently high BP at 180 mm Hg within 24 hours of ischaemic stroke onset had the highest risk, while those maintaining stable BP at a moderate-low level (150 mm Hg) or even a low level (137 mm Hg) had more favourable outcomes.

DEFM: Delay-embedding-based forecast machine for time series forecasting by spatiotemporal information transformation.

Making accurate forecasts for a complex system is a challenge in various practical applications. The major difficulty in solving such a problem concerns nonlinear spatiotemporal dynamics with time-varying characteristics. Takens' delay embedding theory provides a way to transform high-dimensional spatial information into temporal information. In this work, by combining delay embedding theory and deep learning techniques, we propose a novel framework, delay-embedding-based forecast Machine (DEFM), to predict the future values of a target variable in a self-supervised and multistep-ahead manner based on high-dimensional observations. With a three-module spatiotemporal architecture, the DEFM leverages deep neural networks to effectively extract both the spatially and temporally associated information from the observed time series even with time-varying parameters or additive noise. The DEFM can accurately predict future information by transforming spatiotemporal information to the delay embeddings of a target variable. The efficacy and precision of the DEFM are substantiated through applications in three spatiotemporally chaotic systems: a 90-dimensional (90D) coupled Lorenz system, the Lorenz 96 system, and the Kuramoto-Sivashinsky equation with inhomogeneity. Additionally, the performance of the DEFM is evaluated on six real-world datasets spanning various fields. Comparative experiments with five prediction methods illustrate the superiority and robustness of the DEFM and show the great potential of the DEFM in temporal information mining and forecasting.

An AI-based approach for modeling the synergy between radiotherapy and immunotherapy.

Personalized, ultra-fractionated stereotactic adaptive radiotherapy (PULSAR) is designed to administer tumoricidal doses in a pulsed mode with extended intervals, spanning weeks or months. This approach leverages longer intervals to adapt the treatment plan based on tumor changes and enhance immune-modulated effects. In this investigation, we seek to elucidate the potential synergy between combined PULSAR and PD-L1 blockade immunotherapy using experimental data from a Lewis Lung Carcinoma (LLC) syngeneic murine cancer model. Employing a long short-term memory (LSTM) recurrent neural network (RNN) model, we simulated the treatment response by treating irradiation and anti-PD-L1 as external stimuli occurring in a temporal sequence. Our findings demonstrate that: (1) The model can simulate tumor growth by integrating various parameters such as timing and dose, and (2) The model provides mechanistic interpretations of a "causal relationship" in combined treatment, offering a completely novel perspective. The model can be utilized for in-silico modeling, facilitating exploration of innovative treatment combinations to optimize therapeutic outcomes. Advanced modeling techniques, coupled with additional efforts in biomarker identification, may deepen our understanding of the biological mechanisms underlying the combined treatment.

Alien flora are accumulating steadily in China over the last 80 years.

New alien species are increasingly introduced and established outside their native range. The knowledge of the spatiotemporal dynamics of their accumulation and the factors determining their residence time in the introduced range is critical for proactive management, especially in emerging economies. Based on a comprehensive time series dataset of 721 alien angiosperms in China, we show that new alien flora has been accumulating steadily in China, particularly in the coastal regions, for the last 80 years without saturation. The ability to occupy a large number of habitats facilitates the early introduction of alien flora, whereas a large naturalized range, greater number of uses, and multiple introduction pathways directly contribute to their naturalization and invasion. The temporal pattern is predicted to remain consistent in the foreseeable future. We propose upgrading the country's biosecurity infrastructure based on a standardized risk assessment framework to safeguard the country from ongoing and future invasions.

Efficient reduction of vanadium (V) with biochar and experimental parameters optimized by response surface methodology.

Water pollution deteriorates ecosystems and has a great threaten to the environment. The environmental benefits of wastewater treatment are extremely important to minimize pollutants. Here, the biochar purchased from the related industry was used to treat the wastewater which contained high concentration of vanadium (V). The concentration of vanadium was measured by the IC-OES and the results showed that 96.1% vanadium (V) was reduced at selected reaction conditions: the mass ratio of biochar to vanadium of 5.4, reaction temperature of 90 °C, reaction time at 60 min and concentration of H2SO4 of 10 g/L, respectively. Response surface methodology confirmed that all the experimental parameters had positive effect on the reduction of vanadium (V), which could improve the reduction efficiency of vanadium (V) as increased. The influence of each parameter on the reduction process followed the order: A (Concentration of H2SO4) > C (mass ratio of biochar to vanadium) > B (mass ratio of biochar to vanadium). Especially, the mass ratio of biochar to vanadium and concentration of H2SO4 had the greatest influence on the reduction process. This paper provides a versatile strategy for the treatment of wastewater containing vanadium (V) and shows a bright tomorrow for wastewater treatment.

The association between circulating fatty acids and stroke in hypertensive patients.

BACKGROUND: Stroke is prevalent in hypertensive population. It has been suggested that unsaturated fatty acids (USFA) have protective effect on stroke. The effect of saturated fatty acids (SFAs) on stroke is still unclear. Therefore, we studied the relationship between circulating fatty acids and acute ischemic stroke (AIS) in hypertensive patients. METHODS: Eighty-nine pairs including 100 men and 78 women matched by sex and age were recruited. Each pair included a hypertensive patient within 48h of AIS onset and a hypertensive patient without stroke. Six circulating fatty acids were methylated before concentration determination which was repeated twice with percent recovery estimated. RESULTS: There were differences in educational level (P = 0.002) and occupation (P < 0.001) between stroke and non-stroke participants. All the 6 fatty acid levels were higher in non-stroke participants (P = 0.017 for palmitoleic acid, 0.001 for palmitic acid, <0.001 for linoleic acid, <0.001 for behenic acid, <0.001 for nervonic acid and 0.002 for lignoceric acid). In logistic regression analysis, AIS was inversely associated with fatty acid levels except for lignoceric acid. After adjustment for education and occupation, the palmitoleic acid and palmitic acid levels were no longer inversely associated with AIS. After further adjustment for systolic blood pressure, smoking, drinking, total cholesterol and triglyceride, the inverse associations of linoleic acid (OR = 0.965, 95%CI = 0.942-0.990, P = 0.005), behenic acid (OR = 0.778, 95%CI = 0.664-0.939, P = 0.009), nervonic acid (OR = 0.323, 95%CI = 0.121-0.860, P = 0.024) with AIS remained significant. CONCLUSIONS: Circulating fatty acids except lignoceric acid were inversely associated with AIS. Both USFAs and SFAs may have beneficial effect on stroke prevention in hypertensive population.

Preparation of iron oxide-modified digestate biochar and effect on anaerobic digestion of kitchen waste.

Two kinds of Fe2O3-modified digestate-derived biochar (BC) were prepared and their effects on anaerobic digestion (AD) of kitchen waste (40.0 g VS/L) were investigated, with BC and Fe2O3 addition used as a comparison. The results showed that Fe2O3-modified BC (Fe2O3-BC1 prepared by co-precipitation and Fe2O3-BC2 by impregnation) significantly increased methane yield (20.8 % and 16.4 %, respectively) and reduced volatile fatty acid concentration (35.6 % and 29.6 %, respectively). Microbial high-throughput analysis revealed that Fe2O3-modified BC selectively enriched Clostridium (47.3 %) and Methanosarcina (72.2 %), suggesting that direct interspecies electron transfer contributing to improved biogas production performance was established and enhanced. Correlation analysis indicated that biogas production performance was improved by the larger specific surface area (83.4 m2/g), pore volume (0.101 cm3/g), and iron content (97.4 g/Kg) of the BC. These results offer insights for enhancing the efficacy of AD processes using Fe2O3-modified BCs as additives.

Comparative Study of Anti-Corrosion Properties of Different Types of Press-Hardened Steels.

Hot stamping (or press hardening) is a new technology that is widely used in the production of advanced high-strength steel parts for automotive applications. Electrochemical measurements, including potentiodynamic polarization and electrochemical impedance spectroscopy (EIS), and accelerated corrosion tests (the neutral salt spray test and periodic immersion test) were conducted on press-hardened samples produced from uncoated (cold-rolled and cold strip production (CSP) hot-rolled) and Al-Si-coated press-hardened steels to elucidate their distinct anti-corrosion mechanisms. The cross-sectional micromorphology and element distribution of three types of press-hardened steels after a neutral salt spray test were observed using scanning electron microscopy (SEM) and energy-dispersive X-ray analysis (EDAX). The corrosion resistance of Al-Si-coated press-hardened steel was found to be significantly diminished following the hot stamping process due to the presence of microcracks and elevated iron content in the coating subsequent to austenitizing heat treatment. On the other hand, the corrosion resistance of uncoated press-hardened sheets produced from cold-rolled and CSP hot-rolled press-hardened steel was found to be proximal due to their nearly identical composition and microstructure (fully martensite) after the hot stamping process. Considering the high efficiency and energy-saving properties of hot-rolled press-hardened steel, it holds the potential to replace cold-rolled and even aluminum-silicon-coated press-hardened steel in automobile manufacturing.

Metformin blocks BIK1-mediated CPK28 phosphorylation and enhances plant immunity.

INTRODUCTION: Metformin (MET), derived from Galega officinalis, stands as the primary first-line medication for the treatment of type 2 diabetes (T2D). Despite its well-documented benefits in mammalian cellular processes, its functions and underlying mechanisms in plants remain unclear. OBJECTIVES: This study aimed to elucidate MET's role in inducing plant immunity and investigate the associated mechanisms. METHODS: To investigate the impact of MET on enhancing plant immune responses, we conducted assays measuring defense gene expression, reactive oxygen species (ROS) accumulation, mitogen-activated protein kinase (MAPK) phosphorylation, and pathogen infection. Additionally, surface plasmon resonance (SPR) and microscale thermophoresis (MST) techniques were employed to identify MET targets. Protein-protein interactions were analyzed using a luciferase complementation assay and a co-immunoprecipitation assay. RESULTS: Our findings revealed that MET boosts plant disease resistance by activating MAPKs, upregulating the expression of downstream defense genes, and fortifying the ROS burst. CALCIUM-DEPENDENT PROTEIN KINASE 28 (CPK28) was identified as a target of MET. It inhibited the interaction between BOTRYTIS-INDUCED KINASE 1 (BIK1) and CPK28, blocking CPK28 threonine 76 (T76) transphosphorylation by BIK1, and alleviating the negative regulation of immune responses by CPK28. Moreover, MET enhanced disease resistance in tomato, pepper, and soybean plants. CONCLUSION: Collectively, our data suggest that MET enhances plant immunity by blocking BIK1-mediated CPK28 phosphorylation.

Flexible microfluidic colorimetric detection chip integrated with ABTS·+ and Co@MnO2 nanozyme catalyzed TMB reaction systems for bio-enzyme free detection of sweat uric acid.

BACKGROUND: The development of wearable detection devices that can achieve noninvasive, on-site and real-time monitoring of sweat metabolites is of great demand and practical significance for point-of-care testing and healthcare monitoring. Monitoring uric acid (UA) content in sweat provides a simple and promising way to reduce the risk of gout and hyperuricemia. Traditional bioenzyme based UA assays suffer from high cost, poor stability, inconvenience for storage and easy deactivation of bioenzymes. Wearable microfluidic colorimetric detection device for sweat UA detection has not been reported. The development of novel wearable microfluidic colorimetric detection chip with no requirement of bioenzymes for sweat UA detection is of great importance for health care monitoring. RESULTS: Firstly, Co@MnO2 nanozyme with high oxidase-like activity was synthesized and characterized. Co@MnO2 can catalyze the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) directly to generate blue-green colored ox-TMB. Green colored 2,2'-Azinobis-(3-ethylbenzthiazoline-6-sulphonate) radical (ABTS·+) was produced by the oxidation of ABTS by potassium persulfate. UA exhibits distinct quenching effect on Co@MnO2 catalyzed TMB colorimetric reaction system and ABTS·+ based colorimetric system, leading to obvious color fading of the two colorimetric systems. Then, a flexible microfluidic colorimetric detection chip for UA detection was fabricated by assembling Co@MnO2/TMB modified paper chips and ABTS·+ modified paper chips into a polydimethylsiloxane (PDMS) microfluidic chip. The fabricated microfluidic colorimetric detection chip exhibits good linear relationship for sweat UA detection. The linear range is from 20 to 200 µmol/L with detection limit as low as 6.6 µmol/L. Good results were obtained for the detection of UA in actual sweat from three volunteers. SIGNIFICANCE: This work provides two bio-enzyme free colorimetric detection systems for UA detection. Furthermore, a simple, low-cost and selective flexible wearable microfluidic colorimetric detection chip was fabricated for noninvasive and on-site detection of sweat UA, which holds great application potential for personal health monitoring and point-of-care testing.

Early and mid-term outcomes of open thoracoabdominal aortic aneurysm repair after thoracic endovascular aortic repair.

OBJECTIVE: To evaluate the early and mid-term outcomes of open repair in patients with thoracoabdominal aortic aneurysm (TAAA) after thoracic endovascular aortic repair (TEVAR). METHODS: This was a retrospective single center study. Data were retrospectively collected and analyzed for consecutive patients undergoing open TAAA repair (TAAAR) after TEVAR from November 2016 to June 2021. Indications for TAAAR included aneurysm progression due to endoleak, persisted false lumen perfusion, proximal/distal disease progression, and aorta rupture. The risk factor of operative mortality was analyzed by multivariable logistic regression model and the survival was evaluated by Kaplan-Meier. RESULTS: Sixty-three patients who met the inclusion criteria for the study were identified. The mean age at TAAAR was 41 ± 12 years and 43 (68.3%) were male. Marfan syndrome (MFS) was presented in 39 patients (61.9%). 60 (95.2%) patients presented with post-dissection aneurysm and 3 (4.8%) patients with degenerative aneurysm. The extent of TAAA was Crawford I in 9 (14.3%), II in 22 (34.9%), III in 23 (36.5%), and IV in 9 (14.3%). Emergent TAAAR was done in 10 (15.9%) patients, and deep hypothermic circulatory arrest was used in 22 (34.6%). Endograft was explanted in 31 (49.2%). Operative mortality was 11 (17.5%). Stroke, paraplegia, and acute kidney failure occurred in 5 (7.9%), 7 (11.1%), and 6 (9.5%) patients, respectively. Pulmonary complications occurred in 19 (30.2%) patients. The estimated survival was 74.8 ± 4.9% at 5 years. Late reoperations were performed in 2 patients at 2.5 years and 1.3 years, respectively. CONCLUSIONS: In this series of TAAA after TEVAR, TAAAR was related with a high risk of operative mortality and morbidity and the midterm outcomes represented a durable treatment and were respectable.

Clinical efficiency of three-port inflatable robot-assisted thoracoscopic surgery in mediastinal tumor resection.

BACKGROUND: Aimed to assess clinical effect of three-port inflatable robot-assisted thoracoscopic surgery in mediastinal tumor resection by comparing results of the robot group with the video group. METHODS: Retrospectively analyze 179 patients diagnosed with anterior mediastinal tumor from May 2017 to August 2021. Two groups were divided according to the surgical approach, including 92 cases in the RATS group and 87 cases in the VATS group. The results were analyzed between two groups with variables of age, sex, BMI, tumor size, and diagnosis. Perioperative clinical data was gathered to compare. RESULT: There were no significant differences between the 2 groups with regards to demographic data and clinical features. There were no significant differences inoperative time and duration of chest tube via RATS vs. VATS. The intraoperative blood loss was statistically significantly different among the RATS and VATS groups (75.9 ± 39.6 vs. 97.4 ± 35.8 ml p = 0.042). The postoperative stay of patients in RATS group were significantly shorter than that in VATS group (2.3 ± 1.0 vs. 3.4 ± 1.4 day p = 0.035), CONCLUSION: Three-port inflatable robot-assisted thoracoscopic surgery for mediastinal tumor is feasible and reliable it is more advantageous, and it provides the surgeon with advice on treatment choice.

DeepKa Web Server: High-Throughput Protein pKa Prediction.

DeepKa is a deep-learning-based protein pKa predictor proposed in our previous work. In this study, a web server was developed that enables online protein pKa prediction driven by DeepKa. The web server provides a user-friendly interface where a single step of entering a valid PDB code or uploading a PDB format file is required to submit a job. Two case studies have been attached in order to explain how pKa's calculated by the web server could be utilized by users. Finally, combining the web server with post processing as described in case studies, this work suggests a quick workflow of investigating the relationship between protein structure and function that are pH dependent. The web server of DeepKa is freely available at http://www.computbiophys.com/DeepKa/main.

Cellulose de-polymerization is selective for bioethanol refinery and multi-functional biochar assembly using brittle stalk of corn mutant.

As lignocellulose recalcitrance principally restricts for a cost-effective conversion into biofuels and bioproducts, this study re-selected the brittle stalk of corn mutant by MuDR-transposon insertion, and detected much reduced cellulose polymerization and crystallinity. Using recyclable CaO chemical for biomass pretreatment, we determined a consistently enhanced enzymatic saccharification of pretreated corn brittle stalk for higher-yield bioethanol conversion. Furthermore, the enzyme-undigestible lignocellulose was treated with two-step thermal-chemical processes via FeCl2 catalysis and KOH activation to generate the biochar with significantly raised adsorption capacities with two industry dyes (methylene blue and Congo red). However, the desirable biochar was attained from one-step KOH treatment with the entire brittle stalk, which was characterized as the highly-porous nanocarbon that is of the largest specific surface area at 1697.34 m2/g and 2-fold higher dyes adsorption. Notably, this nanocarbon enabled to eliminate the most toxic compounds released from CaO pretreatment and enzymatic hydrolysis, and also showed much improved electrochemical performance with specific capacitance at 205 F/g. Hence, this work has raised a mechanism model to interpret how the recalcitrance-reduced lignocellulose is convertible for high-yield bioethanol and multiple-function biochar with high performance.

Bioaerosols in deodorization covers of wastewater treatment plants: Emission characteristics and health risks.

Wastewater treatment plants (WWTPs) are the main source of bioaerosol emissions. The cover of deodorization within WWTPs serves not only to manage odors but also to limit the dispersion of bioaerosols. This study investigated the emission characteristics and exposure risks of bioaerosols inside deodorization covers from a WWTP in Northern China. The results revealed that the concentration of bacteria in bioaerosols ranged from 96 ± 8 to 706 ± 45 CFU/m3, with the highest concentration observed in the biochemical reaction tank. The predominant bacterial genera in bioaerosols within the odor control covers were Cetobacterium, Romboutsia, Bacteroides, Lactobacillus, and Tubricibacter, while the dominant fungal genera included Aspergillus, Alternaria, Fusarium, and Cladosporium. The main water-soluble ions in the air were NH4+, Ca2+, SO42-, and Cl-. SO42- was found to promote the survival of Cetobacterium, Brevibacterium, Fusarium, Penicillium, and Filobasidium, while Cl- exhibited inhibitory effects on most microorganisms in bioaerosols. Source tracker analysis indicated that wastewater was the primary source of bioaerosols in the biochemical reaction tank. The non-carcinogenic risk associated with bioaerosols within deodorization covers was less than 1 (2.34 × 10-9 to 3.08 × 10-2). FunGuild fungal functional prediction suggested that the abundance of animal pathogens was highest in the bioaerosols from the anaerobic sedimentation tank. BugBase phenotypic prediction showed that the abundance of potential pathogens in secondary sedimentation tank bioaerosols was the highest. This study effectively revealed the characteristics and sources of bioaerosols in the sewage and sludge treatment area under the deodorization cover, which provided a theoretical basis for enhancing the management and control of bioaerosols.

Echinacoside alleviates glucocorticoid induce osteonecrosis of femoral head in rats through PI3K/AKT/FOXO1 pathway.

Steroid-induced osteonecrosis of the femoral head (SONFH), caused by glucocorticoid (GC) administration, is known to exhibit a high incidence worldwide. Although osteoblast apoptosis has been reported as an important cytological basis of SONFH, the precise mechanism remains elusive. Echinacoside (Ech), a natural phenylethanoid glycoside, exerts multiple beneficial effects, such as facilitation of cell proliferation and anti-inflammatory and anticancer activities. Herein, we aimed to explore the regulatory mechanism underlying glucocorticoid-induced osteoblast apoptosis and determine the protective efficacy of Ech against SONFH. We comprehensively surveyed multiple public databases to identify SONFH-related genes. Using bioinformatics analysis, we identified that the PI3K/AKT/FOXO1 signaling pathway was most strongly associated with SONFH. We examined the protective effect of Ech against SONFH using in vivo and in vitro experiments. Specifically, dexamethasone (Dex) decreased p-PI3K and p-AKT levels, which were reversed following Ech addition. Validation of the PI3K inhibitor (LY294002) and molecular docking of Ech and PI3K/AKT further indicated that Ech could directly enhance PI3K/AKT activity to alleviate Dex-induced inhibition. Interestingly, Dex upregulated the expression of FOXO1, Bax, cleaved-caspase-9, and cleaved-caspase-3 and enhanced MC3T3-E1 apoptosis; application of Ech and siRNA-FOXO1 reversed these effects. In vitro, Ech decreased the number of empty osteocytic lacunae, reduced TUNEL and FOXO1 positive cells, and improved bone microarchitecture. Our results provide robust evidence that PI3K/AKT/FOXO1 plays a crucial role in the development of SONFH. Moreover, Ech may be a promising candidate drug for the treatment of SONFH.

Predictors for unfavorable prognosis after stroke with perforator artery disease.

Background and purpose: Perforator artery disease (PAD) is an important subtype of ischemic stroke. The risk factors affecting the prognosis of patients with PAD are unclear. This study aimed to investigate the risk factors affecting the unfavorable prognosis of PAD. Methods: Patients with PAD were enrolled from Dushu Lake Hospital Affiliated to Soochow University and diagnosed as stroke with PAD during the period from September 2021 to July 2023 and followed up with a modified Rankin Scale (mRS) after 90 days, defining the mRS of 0-2 as a group with favorable prognosis, and 3-6 as a group with unfavorable functional outcome. Logistic regression was used to identify predictors for PAD. Multiple logistic regression analysis and receiver operating characteristics (ROC) were used to identify predictors of unfavorable prognosis. Results: Of the 181 enrolled patients, 48 (26.5%) were identified with unfavorable prognosis. On multivariate analysis, increased age (OR = 1.076, 95% CI: 1.012 ~ 1.144, p = 0.019), higher National Institutes of Health Stroke Scale (NIHSS) score at admission (OR = 2.930, 95% CI: 1. 905 ~ 4.508, p < 0.001), and increased neutrophil-to-lymphocyte ratio (NLR) (OR = 3.028, 95% CI: 1.615 ~ 5.675, p = 0.001) were independent risk factors for unfavorable prognosis in patients with PAD, and the area under the receiver operating characteristic curve was 0.590, 0.905, and 0.798, and the multi-factor diagnostic model (Model 2) showed reliable diagnostic specificity and sensitivity (area under the curve = 0.956, p < 0.001, specificity 0.805, sensitivity 0.958, accuracy 0.845). Conclusion: Increased baseline NLR and NIHSS score and aging may be independent risk factors for unfavorable prognosis of patients with PAD. NLR can be used as a potential biological indicator to predict the prognosis of stroke with PAD.

The systemic inflammation indexes after admission predict in-hospital mortality in patients with extensive burns.

PURPOSE: To explore the clinical value of various complete blood count (CBC)-derived inflammation indicators to predict in-hospital mortality in patients with extensive burns. METHODS: Systemic inflammation indexes, including lymphocyte-platelet ratio (LPR), neutrophil-lymphocyte ratio (NLR), neutrophil-monocyte ratio (NMR), monocyte-lymphocyte ratio (MLR), neutrophil-to-lymphocyte * platelet (NLPR), systemic inflammation index (SII), and systemic inflammation response index (SIRI) on days 1, 3, and 7 after admission were calculated in 135 patients with extensive burns. RESULTS: We included 135 patients with extensive burns, including 97 survivors and 38 non-survivors. After adjusting for confounders, only the LPR on day 1, NLPR on days 3 and 7 were significantly associated with survival (OR= 1.237, 1.097, 1.104; 95 % CI: 1.055-1.451, 1.002-1.202, 1.005-1.212; respectively) in the analysis of multivariate logistic regression. The optimum cutoff values of the LPR on day 1 and NLPR on day 3 were 6.37 and 8.06, and the area under the curves (AUC) were 0.695 and 0.794, respectively. The AUC of NLPR on day 7 had the highest value, 0.814, and the optimum cut-off value was 3.84. The efficacy of LPR on day 1, NLPR on days 3 and 7 combined with the burn prognostic score index in predicting the prognosis of patients was higher than that of the burn index alone, and the three composite inflammatory indexes combined with PBI had the highest efficacy in predicting the prognosis (AUC = 0.994). Kaplan-Meier survival analysis showed poor prognosis in patients with higher LPR on day 1 and higher NLPR on days 3 and 7 (log-rank χ2 =9.623,31.564, 20.771, respectively; P < 0.01). CONCLUSIONS: LPR on day 1 and NLPR on days 3 and 7 after admission are reliable predictors of prognosis in patients with severe extensive burns. The combination of the burn prognostic score index, LPR on day 1, and NLPR on days 3 and 7 was superior to the burn indexes alone in predicting a patient's prognosis.