A Novel Predictive Model of Detrusor Overactivity Based on Clinical Symptoms and Non-invasive Test Parameters in Female Patients with Lower Urinary Tract Symptoms.

INTRODUCTION AND HYPOTHESIS: This study was aimed at investigating non-invasive indicators correlated with detrusor overactivity (DO) and at developing a prediction model for DO by reviewing clinical and urodynamic data of female patients. METHODS: We retrospectively enrolled 1,084 female patients who underwent a urodynamic study (UDS) at Tongji Hospital between September 2011 and April 2021. Associated factors and the independent prediction factors of DO were demonstrated by univariate and multivariate analysis. A non-invasive prediction model of DO was developed and validated by applying these data. RESULTS: A total of 194 patients (17.9%) were classified as having DO. A logistic regression of a multivariate nature showed that DO risk factors were independent of age, nocturia, urgency, urgency urinary incontinence (UUI), and the lack of stress urinary incontinence (SUI). The DO prediction model had good performance, with an area under the curve of 0.880 (95% CI 0.826-0.933), which was verified by urodynamic data of patients in Tongji Hospital to be 0.818 (95% CI 0.783-0.853). An outstanding correspondence between the anticipated probability and the observed frequency was revealed by the calibration curve. Decision curve analysis demonstrated that clinical net benefit can be obtained by applying the DO prediction model when the DO risk probability was between 8 and 97%. CONCLUSIONS: A non-invasive prediction model of DO was developed and validated using clinical and urodynamic data. Five independent factors associated with DO were identified: age, nocturia, urgency, UUI, and SUI. This prediction model can contribute to assessing the risk of female DO without the need for invasive urodynamic studies.

The role of phlorizin liposome-embedded oxidized sodium alginate/carboxymethyl chitosan in diabetic wound healing.

Wound healing in diabetic patients is often complicated by issues like inflammation, infection, bleeding, and fluid retention. To tackle these challenges, it is essential to create hydrogel dressings with anti-inflammatory, antibacterial, and antioxidative properties. This study aimed to synthesize Phlorizin-Liposomes (PL) through the thin-film dispersion method and integrate them into an oxidized sodium alginate (OSA) and carboxymethyl chitosan (CMCS) hydrogel scaffold, resulting in an OSA/CMCS/PL (PLOCS) composite hydrogel via a Schiff base reaction. Characterization of the composite was performed using FTIR, TEM, and SEM techniques. The research assessed the swelling behavior, antibacterial effectiveness, and biocompatibility of the PLOCS composite hydrogel, while also investigating how PLOCS facilitates diabetic wound healing. The results demonstrated that PLOCS effectively controls drug release, possesses favorable swelling and degradation characteristics, and shows significant antioxidative properties along with in vitro biocompatibility. Histological analysis confirmed that PLOCS supports the proliferation of healthy epithelial tissue and collagen production. Western blotting indicated that PLOCS diminishes inflammation by inhibiting the TLR4/NF-κB/MyD88 pathway and activates Nrf2 to boost wound healing, increasing the levels of antioxidative enzymes such as HO-1, NQO1, and GCLC. In summary, PLOCS presents a promising new option for advanced wound dressings aimed at treating diabetic ulcers.

Associations of serum Dickkopf-1 levels with disease severity and 90-day Prognosis after spontaneous intracerebral hemorrhage: results from the prospective cohort study.

Dickkopf-1 (DKK-1) may be involved in inflammatory response and secondary brain injury after acute brain injury. We gauged serum DKK-1 levels and further assessed its correlation with disease severity and investigated its predictive value for 90-day prognosis in patients with spontaneous intracerebral hemorrhage (sICH). Serum DKK-1 levels were measured in 128 sICH patients and 128 healthy controls. The severity of sICH was assessed using the Glasgow Coma Scale (GCS) scores and hematoma volumes. Poor prognosis was referred to as a Glasgow Outcome Scale (GOS) score of 1-3 at 90 days after stroke. Multivariate analysis was performed to identify associations of serum DKK-1 levels with disease severity, early neurological deterioration (END) and poor prognosis. Receiver operating characteristic curve (ROC) was built to investigate the prognostic predictive capability. The serum DKK-1 levels of patients were significantly higher than those of controls (median, 4.74 ng/mL versus 1.98 ng/mL; P < 0.001), and were independently correlated with hematoma volumes (ρ = 0.567, P < 0.001; t = 3.444, P = 0.001) and GCS score (ρ = -0.612, P < 0.001; t = -2.048, P = 0.043). Serum DKK-1 significantly differentiated patients at risk of END (area under ROC curve (AUC), 0.850; 95% confidence interval (CI), 0.777-0.907; P < 0.001) and poor prognosis (AUC, 0.830; 95% CI, 0.753-0.890; P < 0.001), which had similar prognostic ability, as compared to GCS scores and hematoma volumes. Subsequent Logistic regression model affirmed that GCS score, hematoma volume, and serum DKK-1 levels were independently associated with END and poor prognosis at 90 days after sICH. The models, which contained them, performed well using ROC curve analysis and calibration curve analysis. Serum DKK-1 levels are markedly associated with disease severity, END and 90-day poor prognosis in sICH. Hence, serum DKK-1 is presumed to be used as a potential prognostic biomarker of sICH.

Combined impact of elevated C-reactive protein levels and dyslipidemia on stroke: a CHNS prospective cohort study.

Background: The objective of this study was to examine whether the combination of elevated levels of C-reactive protein (CRP) and dyslipidemia increased the risk of stroke among middle-aged and older adult individuals in China. Methods: This study utilized longitudinal data from the China Health and Nutrition Survey (CHNS) collected in 2009, 2015, and 2018. A total of 8,023 participants aged ≥40 years (3,595 males and 4,428 females) were included. The Generalized Estimating Equation (GEE) method was employed to examine the association between inflammation, dyslipidemia, their combined effects, and stroke in the Chinese population. Results: A total of 174 stroke events occurred during follow-up. Compared with those with normal CRP levels (CRP ≤ 3 mg/L), the adjusted ORs and 95%CI were 2.13 (1.25, 3.64) for the female with elevated CRP level. Compared with those with non-dyslipidemia, the adjusted ORs and 95%CI were 1.56 (1.03, 2.37) for the individuals with high LDL cholesterol, 1.93 (1.12, 3.33) for the male with high LDL cholesterol. Compared with those with normal CRP levels and non-dyslipidemia, the adjusted ORs and 95%CI were 1.74 (1.08, 2.78) for the individuals with elevated CRP levels and dyslipidemia, 2.41 (1.29, 4.49) for the male with elevated CRP levels and dyslipidemia. People with the coexistence of elevated CRP levels and dyslipidemia had the highest risk of stroke among male. Conclusion: In females, higher levels of inflammation are associated with an increased incidence of stroke. In males, individuals with dyslipidemia characterized by high LDL cholesterol levels are more susceptible to stroke. In the general population, the joint effect of inflammation and dyslipidemia predisposes individuals to a higher risk of stroke, particularly among males.

Learning Prompt-Enhanced Context Features for Weakly-Supervised Video Anomaly Detection.

Weakly supervised video anomaly detection aims to locate abnormal activities in untrimmed videos without the need for frame-level supervision. Prior work has utilized graph convolution networks or self-attention mechanisms alongside multiple instance learning (MIL)-based classification loss to model temporal relations and learn discriminative features. However, these approaches are limited in two aspects: 1) Multi-branch parallel architectures, while capturing multi-scale temporal dependencies, inevitably lead to increased parameter and computational costs. 2) The binarized MIL constraint only ensures the interclass separability while neglecting the fine-grained discriminability within anomalous classes. To this end, we introduce a novel WS-VAD framework that focuses on efficient temporal modeling and anomaly innerclass discriminability. We first construct a Temporal Context Aggregation (TCA) module that simultaneously captures local-global dependencies by reusing an attention matrix along with adaptive context fusion. In addition, we propose a Prompt-Enhanced Learning (PEL) module that incorporates semantic priors using knowledge-based prompts to boost the discrimination of visual features while ensuring separability across anomaly subclasses. The proposed components have been validated through extensive experiments, which demonstrate superior performance on three challenging datasets, UCF-Crime, XD-Violence and ShanghaiTech, with fewer parameters and reduced computational effort. Notably, our method can significantly improve the detection accuracy for certain anomaly subclasses and reduced the false alarm rate. Our code is available at: https://github.com/yujiangpu20/PEL4VAD.

The value of abPG-SGA in the nutritional risk screening of patients with malignant tumors.

Nutritional risk screening 2002 (NRS2002) is a commonly used tool for screening the risk of malnutrition in hospitalized patients, while patient-generated subjective global assessment (PG-SGA) is a nutritional assessment tool for malignant tumor patients. However, there are still gaps in the rapid nutritional risk screening methods for cancer patients. We aimed to evaluate the value of abridged scored patient-generated subjective global assessment (abPG-SGA) for nutritional risk screening and prognosis in cancer patients. The NRS 2002 and abPG-SGA scores of 100 malignant tumor patients hospitalized in our department in December 2020 were collected. Take NRS2002 ≥ 3 as the positive standard (risk of malnutrition). Data were analyzed using Kappa test, ROC curves, cut-off values and Kaplan-Meier. In the screening of 100 patients, 25.0% of patients were at risk of malnutrition (NRS2002), abPG-SGA yielded a sensitivity and specificity of 92.0% and 72.0%, respectively (area under curve [AUC] = 0.884, cut-off value ≥ 4.5); In the screening of patients with digestive system malignancies, 22.6% of patients were at risk of malnutrition (NRS2002), and the sensitivity and specificity of abPG-SGA were 91.67% and 87.80%, respectively (AUC = 0.945, cut-off value ≥ 5.5). The results of survival analysis showed that the overall survival (OS) of patients with abPG-SGA ≥ 5 and < 5, NRS2002 ≥ 3 and abPG-SGA < 5, NRS2002 < 3 and abPG-SGA ≥ 5 were significantly different (P < .0001), the OS of patients with NRS2002 ≥ 3 and abPG-SGA ≥ 5, NRS2002 < 3 and abPG-SGA < 5 were not significantly different (P > .05). Like NRS2002, abPG-SGA can also be used for malnutrition screening and prognosis judgment in cancer patients. It can quickly screen out cancer patients who may be at risk of malnutrition and facilitate the development of nutritional assessments.

Management strategies and outcomes in pregnancy-related acute aortic dissection: a multicentre cohort study in China.

BACKGROUND: Acute aortic dissection (AD) in pregnancy poses a lethal risk to both mother and fetus. However, well-established therapeutic guidelines are lacking. This study aimed to investigate clinical features, outcomes and optimal management strategies for pregnancy-related AD. METHODS: We conducted a retrospective multicentre cohort study including 67 women with acute AD during pregnancy or within 12 weeks postpartum from three major cardiovascular centres in China between 2003 and 2021. Patient characteristics, management strategies and short-term outcomes were analysed. RESULTS: Median age was 31 years, with AD onset at median 32 weeks gestation. Forty-six patients (68.7%) had type A AD, of which 41 underwent immediate surgery. Overall maternal mortality was 10.4% (7/67) and fetal mortality was 26.9% (18/67). Compared with immediate surgery, selective surgery was associated with higher risk of composite maternal and fetal death (adjusted RR: 12.47 (95% CI 3.26 to 47.73); p=0.0002) and fetal death (adjusted RR: 8.77 (95% CI 2.33 to 33.09); p=0.001). CONCLUSIONS: Immediate aortic surgery should be considered for type A AD at any stage of pregnancy or postpartum. For pregnant women with AD before fetal viability, surgical treatment with the fetus in utero should be considered. Management strategies should account for dissection type, gestational age, and fetal viability. TRIAL REGISTRATION NUMBER: NCT05501145.

B/Pd Synergistic Catalysis for the Decarboxylative Allylation of 2-(2-Azaaryl)acetic Acids.

We describe an allylation reaction between 2-(2-azaaryl)acetic acids and allylic electrophiles catalyzed synergistically by a dual system consisting of borinic acid and a Pd complex under mild conditions. The decarboxylative allylation proceeds via a boron-bound enamine intermediate, which then interacts with a π-allylpalladium intermediate from the allylic electrophile. High yields of diallylation products highlight the method's efficiency. Intriguingly, when using 2-(2-pyridyl)acetic acid with a C3 substituent on the pyridyl ring, the reaction exclusively yields monoallylation products.

Visible Light Induced B-H Bond Insertion Reaction with Diazo Compounds.

A protocol induced by visible light for the direct insertion of α-carbonyl carbenes into the B-H bond of amine-borane adducts has been developed under conditions that are free of metal and photocatalyst. This approach provides a straightforward route to various organoboron compounds from diazo compounds and amine-borane adducts with moderate to good yields. Mechanistic investigations reveal that this photoinduced reaction proceeds through concerted carbene insertion into the B-H bond, and the photoinduced generation of free carbene from α-diazo esters may be the rate-determining step.

UBE2M forms a positive feedback loop with estrogen receptor to drive breast cancer progression and drug resistance.

UBE2M, a NEDD8-conjugating enzyme, is dysregulated in various human cancers and promotes tumor cell proliferation. However, its role in estrogen receptor-positive (ER+) breast cancer remains unknown. We found that UBE2M expression was significantly higher in ER+ breast cancer tissues than in ER-negative (ER-) breast cancer tissues. Higher expression of UBE2M indicated a poorer prognosis in patients with ER+ breast cancer but not in those with ER- breast cancer. Of interest, a positive feedback loop was observed between UBE2M and ERα. Specifically, ERα enhanced the HIF-1α-mediated transcription of UBE2M. In turn, UBE2M maintained ERα expression by inhibiting its ubiquitination and degradation through UBE2M-CUL3/4A-E6AP-ERα axis. Functionally, silencing of UBE2M suppressed the growth of breast cancer cells by inducing cell cycle arrest and apoptosis and improved their sensitivity to fulvestrant both in vitro and in vivo. Altogether, our findings reveal that the UBE2M-ERα feedback loop drives breast cancer progression and fulvestrant resistance, suggesting UBE2M as a viable target for endocrine therapy of ER+ breast cancer.

Dirhodium(II)/ XantPhos Catalyzed Synthesis of ß-(E)-Vinylsilanes via Hydrosilylation and Isomerization from Alkynes.

A concise hydrosilylation of alkynes for synthesizing ß-(E)-vinylsilanes catalyzed by dirhodium(II)/XantPhos has been developed. In this reaction, ß-(E)-vinylsilanes were generated from the isomerization of ß-(Z)-vinylsilanes catalyzed by dirhodium(II) hydride species rather than the direct insertion of triple bond into M-H or M-Si bond (traditional Chalk-Harrod mechanism or modified Chalk-Harrod mechanism). The hydrosilylation displayed a broad substrate scope for alkynes and tertiary silanes, tolerating diverse functional groups including halides, nitrile, amines, esters, and heterocycles.

Piezoelectric Hinged Beam with Arc Mass Stopper for Vibration and Human Motion Energy Harvesting.

Compact reliable structure and strong electromechanical coupling are hot pursuits in piezoelectric vibration energy harvester (PVEH) design. PVEH with a static arc stopper makes piezoelectric stress uniformly distributed and widens the frequency band by collision but wastes space. This Article proposes a hinged PVEH with two arc mass stoppers (AS-H-PVEH). Two arc stoppers as movable masses increase the vibration energy and the effective electromechanical coupling coefficient to achieve strong electromechanical coupling. AS-H-PVEH generates a 4.1 mW power output at 11.6-12.0 Hz and 0.2 g. AS-H-PVEH sustains 4 g acceleration vibration for 10 min without attenuation. To offset the resonance frequency increase caused by arc contact, we discuss the magnetic coupling, and axial force effects are discussed. The design of the arc stopper radius, nonlinear electromechanical coupling model, and system parameter identification method are presented. The displacement varied mechanical quality factor and effective electromechanical coupling coefficient are considered in the modified model for the first time. The model obtained good agreement under experiments. The power generation and driven wireless sensor performance of AS-H-PVEH was verified. This research has important theoretical and application value for the performance optimization of PVEH with an arc stopper.

The ASB@HNTs-PVA nanofiber membrane, possessing both anti-inflammatory and hemostatic activities, promotes the healing of T2D skin wounds.

The healing of diabetic wounds has long been a significant challenge in the field of medicine. The elevated sugar levels surrounding diabetic wounds create a conducive environment for harmful bacterial growth, resulting in purulent infections that impede the healing process. Thus, the development of a biomaterial that can enhance the healing of diabetic wounds holds great importance. This study developed electrospun dressings for wound healing by combining traditional Chinese medicine and clay. The study utilized electrospinning technology to prepare polyvinyl alcohol (PVA) nanofiber membranes containing ASB and HNTs. These ASB@HNTs-PVA nanofiber membranes demonstrated rapid hemostasis, along with antibacterial and anti-inflammatory properties, facilitating the recovery of type 2 diabetic (T2D) wounds. Various analyses were conducted to assess the performance of the composite nanofiber membrane, including investigations into its biocompatibility and hemostatic abilities through antibacterial experiments, cell experiments, and mouse liver tail bleeding experiments. Western blot analysis confirmed that the composite nanofiber membrane could decrease the levels of inflammatory factors IL-1ß and TNF-α. A type 2 diabetic mouse model was utilized, with wounds artificially induced on the backs of mice. Application of the nanofiber membrane to the wounds further confirmed its anti-inflammatory effects and ability to enhance wound healing in vivo.

TBK1 is paradoxical in tumor development: a focus on the pathway mediating IFN-I expression.

TANK-binding kinase 1 (TBK1) is a member of the IKK family and plays a crucial role in the activation of non-canonical NF-κB signaling and type I interferon responses. The aberrant activation of TBK1 contributes to the proliferation and survival of various types of tumor cells, particularly in specific mutational or tumorous contexts. Inhibitors targeting TBK1 are under development and application in both in vivo and in vitro settings, yet their clinical efficacy remains limited. Numerous literatures have shown that TBK1 can exhibit both tumor promoting and tumor inhibiting effects. TBK1 acts as a pivotal node within the innate immune pathway, mediating anti-tumor immunity through the activation of innate immune responses. Facilitating interferon-I (IFN-I) production represents a critical mechanism through which TBK1 bridges these processes. IFN has been shown to exert both beneficial and detrimental effects on tumor progression. Hence, the paradoxical role of TBK1 in tumor development may necessitate acknowledgment in light of its downstream IFN-I signaling cascade. In this paper, we review the signaling pathways mediated by TBK1 in various tumor contexts and summarize the dual roles of TBK1 and the TBK1-IFN pathways in both promoting and inhibiting tumor progression. Additionally, we highlight the significance of the TBK1-IFN pathway in clinical therapy, particularly in the context of immune response. We anticipate further advancements in the development of TBK1 inhibitors as part of novel cancer treatment strategies.

An integrated micromachined flexible ultrasonic-inductive sensor for pipe contaminant multiparameter detection.

Pipe contaminant detection holds considerable importance within various industries, such as the aviation, maritime, medicine, and other pertinent fields. This capability is beneficial for forecasting equipment potential failures, ascertaining operational situations, timely maintenance, and lifespan prediction. However, the majority of existing methods operate offline, and the detectable parameters online are relatively singular. This constraint hampers real-time on-site detection and comprehensive assessments of equipment status. To address these challenges, this paper proposes a sensing method that integrates an ultrasonic unit and an electromagnetic inductive unit for the real-time detection of diverse contaminants and flow rates within a pipeline. The ultrasonic unit comprises a flexible transducer patch fabricated through micromachining technology, which can not only make installation easier but also focus the sound field. Moreover, the sensing unit incorporates three symmetrical solenoid coils. Through a comprehensive analysis of ultrasonic and induction signals, the proposed method can be used to effectively discriminate magnetic metal particles (e.g., iron), nonmagnetic metal particles (e.g., copper), nonmetallic particles (e.g., ceramics), and bubbles. This inclusive categorization encompasses nearly all types of contaminants that may be present in a pipeline. Furthermore, the fluid velocity can be determined through the ultrasonic Doppler frequency shift. The efficacy of the proposed detection principle has been validated by mathematical models and finite element simulations. Various contaminants with diverse velocities were systematically tested within a 14 mm diameter pipe. The experimental results demonstrate that the proposed sensor can effectively detect contaminants within the 0.5-3 mm range, accurately distinguish contaminant types, and measure flow velocity.

Facile assembly of flexible, stretchable and attachable symmetric microsupercapacitors with wide working voltage windows and favorable durability.

With the increasing development of intelligent robots and wearable electronics, the demand for high-performance flexible energy storage devices is drastically increasing. In this study, flexible symmetric microsupercapacitors (MSCs) that could operate in a wide working voltage window were developed by combining laser-direct-writing graphene (LG) electrodes with a phosphoric acid-nonionic surfactant liquid crystal (PA-NI LC) gel electrolyte. To increase the flexibility and enhance the conformal ability of the MSC devices to anisotropic surfaces, after the interdigitated LG formed on the polyimide (PI) film surface, the devices were further transferred onto a flexible, stretchable and transparent polydimethylsiloxane (PDMS) substrate; this substrate displayed favorable flexibility and mechanical characteristics in the bending test. Furthermore, the electrochemical performances of the symmetric MSCs with various electrode widths (300, 400, 500 and 600 µm) were evaluated. The findings revealed that symmetric MSC devices could operate in a large voltage range (0-1.5 V); additionally, the device with a 300 µm electrode width (MSC-300) exhibited the largest areal capacitance of 2.3 mF cm-2 at 0.07 mA cm-2 and an areal (volumetric) energy density of 0.72 µWh cm- 2 (0.36 mWh cm- 3) at 55.07 µW cm-2 (27.54 mW cm-3), along with favorable mechanical and cycling stability. After charging for ~20 s, two MSC-300 devices connected in series could supply energy to a calculator to operate for ~130 s, showing its practical application potential as an energy storage device. Moreover, the device displayed favorable reversibility, stability and durability. After 12 months of aging in air at room temperature, its electrochemical performance was not altered, and after charging-discharging measurements for 5000 cycles at 0.07 mA cm-2, ~93.6% of the areal capacitance was still retained; these results demonstrated its practical long-term application potential as an energy storage device.

The development of anti-PD-1 antibody-induced spinal cord injury in bone marrow transplant C57BL/6 Rag1-/- mouse model.

Aims: This paper was to scrutinize the toxicity mechanism of anti-programmed death 1 (anti-PD-1) therapy-caused spinal cord injury (SCI). Methods: Bone marrow transplant Rag1-/- mice were used to establish SCI model. Results: Anti-PD-1 results in SCI via CD8+ T-cells activation, while excessive activation of CD8+ T-cells further aggravated SCI. Both anti-PD-1 and the activation of CD8+ T-cells induced the expression of apoptosis-related perforin, GrB and FasL, but suppressed PI-9 level. The opposite results were observed in the effects of neuroserpin on these factors. CD8+ T-cells activation induced neurotoxicity via upregulation perforin, GrB and FasL and inhibiting PI-9. Additionally, neuroserpin suppressed CD8+ T-cells activation via perforin/GrB/PI-9/FasL pathways. Conclusion: These results may provide theoretical foundation for the clinical treatment of SCI caused by anti-PD-1.

What is this article about? In the process of treating cancer, immune checkpoint inhibitors such as anti-programmed death 1 (anti-PD-1) therapy, as a form of immunotherapy, have developed rapidly and changed the way to manage cancers significantly. However, some cancer patients who receive immune checkpoint blockade treatment suffer from severe adverse effects including spinal cord injury (SCI). This article for the first time constructed a bone marrow transplant mouse model to explore the toxicity mechanism of anti-PD-1 therapy-caused SCI.What were the results? We found that anti-PD-1 therapy can induce the activation of immune cells, while immune cell activation further promotes self-destruction of nerve cells by regulating cell death pathways.What do the results of the study mean? The mechanism of anti-PD-1 therapy-caused SCI is to activate of immune cells through regulating cell death pathways, thereby inducing self-destruction of nerve cells. These findings provide theoretical foundation for the clinical treatment of SCI caused by anti-PD-1 therapy.

A two-center prospective cohort study of serum RIP-3 as a potential biomarker in relation to severity and prognosis after severe traumatic brain injury.

Receptor-interacting protein kinase-3 (RIP-3) is a key component for inducing necroptosis following acute brain injury. Purpose of this study is to unveil whether serum RIP-3 levels are related to severity and clinical outcomes after human severe traumatic brain injury (sTBI). In this two-center prospective cohort study, serum RIP-3 levels were detected in 127 healthy controls coupled with 127 sTBI patients. The prognostic indicators encompassed posttraumatic 180-day mortality, overall survival and poor prognosis (defined as extended Glasgow outcome scale scores of 1-4). The prognosis associations were verified via multivariate analysis. There was a significant incremental serum RIP-3 levels in patients with sTBI, relative to the controls. RIP-3 levels of patients were independently correlated with Rotterdam Computed Tomography (CT) scores and Glasgow coma scale (GCS) scores, as well as were independently predictive of mortality, overall survival and poor prognosis. Mortality and poor prognosis were effectively predicted by serum RIP-3 levels under the receiver operating characteristic curve. Linear relationships between RIP-3 levels and their risks were verified. Mortality and poor prognosis models of serum RIP-3 levels combined with GCS and Rotterdam CT scores displayed efficient predictive abilities. The two models were graphically represented, which were of clinical stability and value by employing the calibration and decision curves. Increased serum RIP-3 levels after sTBI are closely linked to heightened trauma severity and poor prognosis, signifying that serum RIP-3 may be an encouraging biomarker for evaluating severity and predicting clinical outcome of sTBI.

Folylpolyglutamate synthetase inactivation in relapsed ALL induces a druggable folate metabolic vulnerability.

AIMS: The antifolate methotrexate (MTX) is an anchor drug used in acute lymphoblastic leukemia (ALL) with poorly understood chemoresistance mechanisms in relapse. Herein we find decreased folate polyglutamylation network activities and inactivating FPGS mutations, both of which could induce MTX resistance and folate metabolic vulnerability in relapsed ALL. METHODS: We utilized integrated systems biology analysis of transcriptomic and genomic data from relapse ALL cohorts to infer hidden ALL relapse drivers and related genetic alternations during clonal evolution. The drug sensitivity assay was used to determine the impact of relapse-specific FPGS mutations on sensitivity to different antifolates and chemotherapeutics in ALL cells. We used liquid chromatography-mass spectrometry (LC-MS) to quantify MTX and folate polyglutamate levels in folylpoly-γ-glutamate synthetase (FPGS) mutant ALL cells. Enzymatic activity and protein degradation assays were also conducted to characterize the catalytic properties and protein stabilities of FPGS mutants. An ALL cell line-derived mouse leukemia xenograft model was used to evaluate the in vivo impact of FPGS inactivation on leukemogenesis and sensitivity to the polyglutamatable antifolate MTX as well as non-polyglutamatble lipophilic antifolate trimetrexate (TMQ). RESULTS: We found a significant decrease in folate polyglutamylation network activities during ALL relapse using RNA-seq data. Supported by functional evidence, we identified multifactorial mechanisms of FPGS inactivation in relapsed ALL, including its decreased network activity and gene expression, focal gene deletion, impaired catalytic activity, and increased protein degradation. These deleterious FPGS alterations induce MTX resistance and inevitably cause marked intracellular folate shrinkage, which could be efficiently targeted by a polyglutamylation-independent lipophilic antifolate TMQ in vitro and in vivo. CONCLUSIONS: MTX resistance in relapsed ALL relies on FPGS inactivation, which inevitably induces a folate metabolic vulnerability, allowing for an efficacious antifolate ALL treatment strategy that is based upon TMQ, thereby surmounting chemoresistance in relapsed ALL.

[Changes in the disease burden of male urinary and reproductive system tumors in China from 1990 to 2019: Analysis with a prediction of the future trend].

OBJECTIVE: To analyze the changes in the disease burden of prostate, testis, kidney and bladder cancers among urinary and reproductive system tumors in Chinese men from 1990 to 2019 with a prediction of the future trend. METHODS: We retrieved the data on the incidence, mortality and disease burden of prostate, testis, kidney and bladder cancers in Chinese men between 1990 and 2019 from the database of Global Burden of Disease Study 2019. Using the Joinpoint regression model, we analyzed the trend of changes in the disease burden, and predicted the prevalence of the tumors with the ARIMA model. RESULTS: From 1990 to 2019, the standardized incidence and prevalence of prostate, testis, kidney and bladder cancers were on the rise in Chinese men, and those of testis cancer increased most significantly, by 326.79% and 1070.93% respectively. The disease burden of PCa was the highest, with standardized incidence, prevalence and mortality ratios of 17.34/100 000, 117.65/100 000 and 7.79/100 000 respectively in 2019. The standardized mortality and disability-adjusted life years (DALY) of kidney cancer were increased by 103.59% and 103.17% respectively. The highest incidence, mortality and DALY of prostate, kidney and bladder cancers in 2019 were found in 90－94 years old males, the highest prevalence rates of prostate, kidney and bladder cancers in the 70－89-year-olds, and the highest prevalence of testis cancer in the 25－49-year-olds. ARIMA model prediction showed that the standardized incidence rates of prostate, testis, kidney and bladder cancers in Chinese men kept rising from 2020 to 2029. CONCLUSION: The disease burden of prostate, testis, kidney and bladder cancers in Chinese men is on the rise, and their standardized incidence rates will be even higher by 2029, with a significant increase in the disease burden in young men, which suggests the need of more attention to the prevention and treatment of genitourinary system tumors in young males.