A new hematological parameter model for the diagnosis and prognosis of sepsis in emergency department: A single-center retrospective study.

INTRODUCTION: Sepsis, a syndrome of organ dysfunction caused by an unregulated host response to infection. This study aimed to develop a novel sepsis diagnostic model of hematological parameters and evaluate its effectiveness in the early identification and prognosis of sepsis in emergency departments. METHODS: A retrospective study was conducted in Emergency Department. Cell population data parameters related to monocytes and neutrophils were obtained using the Mindary BC-6800 plus hematology analyzer. Receiver operating characteristic (ROC) curve analysis, logistic regression analysis was performed to assess the performance of the parameters and establish a diagnostic and prognostic model of sepsis, which was then verified with a validation cohort. RESULTS: Mon_XW exhibited the best diagnostic performance (area under the ROC curve [AUC] = 0.848, 95% confidence interval [CI]: 0.810-0.885, p < 0.001), followed by Neu_Y and Neu_YW (AUC = 0.777 95% CI: 0.730-0.824, p < 0.001). Logistic regression analysis identified Mon_XW and Neu_Y as independent predictors, which were used to establish a diagnostic model named hematological parameter for sepsis (HPS). HPS demonstrated the best diagnostic performance with an AUC of 0.862 (95% CI: 0.826-0.898, p < 0.001), sensitivity of 70.0%, and specificity of 87.1%, compared to C-reactive protein (CRP) and procalcitonin (PCT). The validation cohort also found that the positive predictive value of HPS was 70.4% and the negative predictive value was 92.2%. CONCLUSION: The developed HPS model showed promising diagnostic efficacy for sepsis in the emergency department, which outperformed CRP and PCT in terms of sensitivity and specificity. By enabling early identification and prognosis of sepsis, that contributes to reducing sepsis-related mortality.

Lifetime evaluation of left ventricular structure and function in male ApoE null mice after gamma and space-type radiation exposure.

The space radiation (IR) environment contains high charge and energy (HZE) nuclei emitted from galactic cosmic rays with the ability to overcome current shielding strategies, posing increased IR-induced cardiovascular disease risks for astronauts on prolonged space missions. Little is known about the effect of 5-ion simplified galactic cosmic ray simulation (simGCRsim) exposure on left ventricular (LV) function. Three-month-old, age-matched male Apolipoprotein E (ApoE) null mice were irradiated with 137Cs gamma (γ; 100, 200, and 400 cGy) and simGCRsim (50, 100, 150 cGy all at 500 MeV/nucleon (n)). LV function was assessed using transthoracic echocardiography at early/acute (14 and 28 days) and late/degenerative (365, 440, and 660 days) times post-irradiation. As early as 14 and 28-days post IR, LV systolic function was reduced in both IR groups across all doses. At 14 days post-IR, 150 cGy simGCRsim-IR mice had decreased diastolic wall strain (DWS), suggesting increased myocardial stiffness. This was also observed later in 100 cGy γ-IR mice at 28 days. At later stages, a significant decrease in LV systolic function was observed in the 400 cGy γ-IR mice. Otherwise, there was no difference in the LV systolic function or structure at the remaining time points across the IR groups. We evaluated the expression of genes involved in hemodynamic stress, cardiac remodeling, inflammation, and calcium handling in LVs harvested 28 days post-IR. At 28 days post-IR, there is increased expression of Bnp and Ncx in both IR groups at the lowest doses, suggesting impaired function contributes to hemodynamic stress and altered calcium handling. The expression of Gals3 and ß-Mhc were increased in simGCRsim and γ-IR mice respectively, suggesting there may be IR-specific cardiac remodeling. IR groups were modeled to calculate the Relative Biological Effectiveness (RBE) and Radiation Effects Ratio (RER). No lower threshold was determined using the observed dose-response curves. These findings do not exclude the possibility of the existence of a lower IR threshold or the presence of IR-induced cardiovascular disease (CVD) when combined with additional space travel stressors, e.g., microgravity.

Extracellular Vesicle-Encapsulated Adeno-Associated Viruses for Therapeutic Gene Delivery to the Heart.

BACKGROUND: Adeno-associated virus (AAV) has emerged as one of the best tools for cardiac gene delivery due to its cardiotropism, long-term expression, and safety. However, a significant challenge to its successful clinical use is preexisting neutralizing antibodies (NAbs), which bind to free AAVs, prevent efficient gene transduction, and reduce or negate therapeutic effects. Here we describe extracellular vesicle-encapsulated AAVs (EV-AAVs), secreted naturally by AAV-producing cells, as a superior cardiac gene delivery vector that delivers more genes and offers higher NAb resistance. METHODS: We developed a 2-step density-gradient ultracentrifugation method to isolate highly purified EV-AAVs. We compared the gene delivery and therapeutic efficacy of EV-AAVs with an equal titer of free AAVs in the presence of NAbs, both in vitro and in vivo. In addition, we investigated the mechanism of EV-AAV uptake in human left ventricular and human induced pluripotent stem cell-derived cardiomyocytes in vitro and mouse models in vivo using a combination of biochemical techniques, flow cytometry, and immunofluorescence imaging. RESULTS: Using cardiotropic AAV serotypes 6 and 9 and several reporter constructs, we demonstrated that EV-AAVs deliver significantly higher quantities of genes than AAVs in the presence of NAbs, both to human left ventricular and human induced pluripotent stem cell-derived cardiomyocytes in vitro and to mouse hearts in vivo. Intramyocardial delivery of EV-AAV9-sarcoplasmic reticulum calcium ATPase 2a to infarcted hearts in preimmunized mice significantly improved ejection fraction and fractional shortening compared with AAV9-sarcoplasmic reticulum calcium ATPase 2a delivery. These data validated NAb evasion by and therapeutic efficacy of EV-AAV9 vectors. Trafficking studies using human induced pluripotent stem cell-derived cells in vitro and mouse hearts in vivo showed significantly higher expression of EV-AAV6/9-delivered genes in cardiomyocytes compared with noncardiomyocytes, even with comparable cellular uptake. Using cellular subfraction analyses and pH-sensitive dyes, we discovered that EV-AAVs were internalized into acidic endosomal compartments of cardiomyocytes for releasing and acidifying AAVs for their nuclear uptake. CONCLUSIONS: Together, using 5 different in vitro and in vivo model systems, we demonstrate significantly higher potency and therapeutic efficacy of EV-AAV vectors compared with free AAVs in the presence of NAbs. These results establish the potential of EV-AAV vectors as a gene delivery tool to treat heart failure.

Predicting the emergence of malignant brain oedema in acute ischaemic stroke: a prospective multicentre study with development and validation of predictive modelling.

Background: We aimed to develop and validate a prognostic model for predicting malignant brain oedema in patients with acute ischaemic stroke in a real-world setting of practice. Methods: A prospective multicentre study enrolled adult patients with acute ischaemic stroke with brain CT < 24 h of onset of symptoms admitted to nine tertiary-level hospitals in China between September 2017 and December 2019. Malignant brain oedema was defined as any patient who had decompressive craniectomy, discharge in coma, or in-hospital death attributed to symptomatic brain swelling. The derivation cohort was a consecutive cohort of patients from one centre and the validation cohort was non-consecutive patients from the other centres. Multivariable logistic regression was used to define independent predictors from baseline clinical characteristics, imaging features, complications, and management. A web-based nomogram and a risk score were developed based on the final model. Model performance was assessed for discrimination and calibration in both derivation and validation cohorts. The study is registered, NCT03222024. Findings: Based on the derivation cohort (n = 1627), the model was developed with seven variables including large infarct (adjusted odds ratio [OR] 40.90, 95% CI 20.20-82.80), National Institutes of Health Stroke Scale (NIHSS) score (OR 1.09, 1.06-1.12), thrombolysis (OR 2.11, 1.18-3.78), endovascular treatment (OR 2.87, 1.47-5.59), pneumonia (OR 2.47, 1.53-3.97), brain atrophy (OR 0.57, 0.37-0.86), and recanalisation (OR 0.36, 0.17-0.75). The classification threshold of a predicted probability ≥0.14 showed good discrimination and calibration in both derivation cohort (area under the receiver-operating curve [AUC] 0.90, 0.87-0.92; sensitivity 0.95, 0.92-0.98) and validation cohort (n = 556, AUC 0.88, 0.82-0.95; sensitivity 0.84, 0.73-0.95). The risk score based on this model had a total point that ranged from -1 to 20, with an optimal score of ≥10 showing good discrimination and calibration in both derivation (AUC 0.89, 0.87-0.92; sensitivity 0.95, 0.92-0.98) and validation (AUC 0.88, 0.82-0.95; sensitivity 0.84, 0.73-0.95) cohorts. Interpretation: The INTEP-AR model (i.e. large Infarct, NIHSS score, Thrombolysis, Endovascular treatment, Pneumonia, brain Atrophy, and Recanalisation) incorporating multiple clinical and radiological characteristics has shown good prognostic value for predicting malignant brain oedema after acute ischaemic stroke. Funding: National Natural Science Foundation of China; Science and Technology Department of Sichuan Province; West China Hospital.

Lifetime Evaluation of Left Ventricular Structure and Function in Male C57BL/6J Mice after Gamma and Space-Type Radiation Exposure.

The lifetime effects of space irradiation (IR) on left ventricular (LV) function are unknown. The cardiac effects induced by space-type IR, specifically 5-ion simplified galactic cosmic ray simulation (simGCRsim), are yet to be discovered. Three-month-old, age-matched, male C57BL/6J mice were irradiated with 137Cs gamma (γ; 100, 200 cGy) and simGCRsim (50 and 100 cGy). LV function was assessed via transthoracic echocardiography at 14 and 28 days (early), and at 365, 440, and 660 (late) days post IR. We measured the endothelial function marker brain natriuretic peptide in plasma at three late timepoints. We assessed the mRNA expression of the genes involved in cardiac remodeling, fibrosis, inflammation, and calcium handling in LVs harvested at 660 days post IR. All IR groups had impaired global LV systolic function at 14, 28, and 365 days. At 660 days, 50 cGy simGCRsim-IR mice exhibited preserved LV systolic function with altered LV size and mass. At this timepoint, the simGCRsim-IR mice had elevated levels of cardiac fibrosis, inflammation, and hypertrophy markers Tgfß1, Mcp1, Mmp9, and ßmhc, suggesting that space-type IR may induce the cardiac remodeling processes that are commonly associated with diastolic dysfunction. IR groups showing statistical significance were modeled to calculate the Relative Biological Effectiveness (RBE) and Radiation Effects Ratio (RER). The observed dose-response shape did not indicate a lower threshold at these IR doses. A single full-body IR at doses of 100-200 cGy for γ-IR, and 50-100 cGy for simGCRsim-IR decreases the global LV systolic function in WT mice as early as 14 and 28 days after exposure, and at 660 days post IR. Interestingly, there is an intermediate time point (365 days) where the impairment in LV function is observed. These findings do not exclude the possibility of increased acute or degenerative cardiovascular disease risks at lower doses of space-type IR, and/or when combined with other space travel-associated stressors such as microgravity.

Effect of Hot Metal Gas Forming Process on Formability and Microstructure of 6063 Aluminum Alloy Double Wave Tube.

The hot metal gas forming process can significantly improve the formability of a tube and is suitable for the manufacturing of parts with complex shapes. In this paper, a double wave tube component is studied. The effects of different temperatures (400 °C, 425 °C, 450 °C and 475 °C) and different pressures (1 MPa, 1.5 MPa, 2 MPa, 2.5 MPa and 3 MPa) on the formability of 6063 aluminum alloy tubes were studied. The influence of hot metal gas forming process parameters on the microstructure was analyzed. The optimal hot metal gas forming process parameters of 6063 aluminum alloy tubes were explored. The results show that the expansion rate increases with the increase in pressure. The pressure affects the deformation of the tube, which in turn has an effect on the dynamic softening of the material. The expansion rate of parts also increases with the increase in forming temperature. The increased deformation temperature is beneficial to the dynamic recrystallization of 6063, resulting in softening of the material and enhanced deformation uniformity between grains, so that the formability of the material is improved. The optimum hot metal gas forming process parameters of 6063 aluminum alloy tubes are the temperature of 475 °C and the pressure of 2.5 MPa; the maximum expansion ratio is 41.6%.

The reusing of waste bio-oil as additive on enhanced urea-based selective non-catalytic reduction denitrification.

Pyrolysis polygeneration has been proven to be effective in solid waste recycling, while cleaner production is hindered by nitrogen oxide emissions and waste oil utilization. In this study, waste bio-oil was proposed as additive for promoting urea-based selective non-catalytic reduction (SNCR) denitrification efficiency to establish bio-oil reusing process and the influence of waste bio-oil on promoting SNCR denitrification were investigated. Then the effects of temperature, bio-oil components and fly ash on SNCR denitrification characteristics were explored. The results illustrated that 5 wt% bio-oil additives would widen the optimum denitrification temperature window by 24.8 % (from 210.25 to 262.43 °C), reduce the reduction temperature by 62.11 °C (from 944.04 to 881.93 °C), and increase the denitrification efficiency by 21 %. Among the main components in waste bio-oil, acetic acid was more effective than phenol and furfural in promoting SNCR denitrification under 900 °C, a large amount of OH was produced to promote the reduction of NH3 and HNCO. In addition, the existence of fly ash could promote urea oxidation and reduce denitrification efficiency because of the catalytic effect of CaO and Fe2O3 on urea oxidation.

Clinical efficacy and safety of trimonthly administration of goserelin acetate 10.8 mg in premenopausal Chinese females with symptomatic adenomyosis: a prospective cohort study.

OBJECTIVE: This prospective cohort study aimed to compare the clinical efficacy and safety of goserelin 10.8 mg administered trimonthly with goserelin 3.6 mg administered monthly in premenopausal females with symptomatic adenomyosis. METHODS: We recruited 139 premenopausal females with adenomyosis who complained of dysmenorrhea and/or menorrhagia. The first group (n = 70) received a single subcutaneous injection of goserelin 10.8 mg, and the second group (n = 69) received monthly subcutaneous goserelin 3.6 mg administered for 3 months. Follow-up was performed at the outpatient department after 12 weeks. RESULTS: Ultimately, 130 patients completed the study, including 68 and 62 patients in the goserelin 10.8 mg (n = 70) and 3.6 mg (n = 69) groups, respectively. We observed a significant decrease in the dysmenorrhea (NRS) score, uterine volume, and cancer antigen 125 (CA125) levels, and a significant increase in hemoglobin (HGB) levels in both treatment groups. There was no significant difference between the two groups. The sum of the adverse event scores was slightly higher in the goserelin 3.6 mg than in the 10.8 mg group. CONCLUSIONS: The clinical efficacy of trimonthly administration of goserelin 10.8 mg was equivalent to monthly 3.6 mg dosing and was non-inferior regarding safety and tolerability. Hence, it can be a more cost-effective and convenient alternative treatment option in premenopausal females with symptomatic adenomyosis. TRIAL REGISTRATION: ChiCTR2200059548.

Finite Element Analysis and Experimental Study of Manufacturing Thin-Walled Five-Branched AISI 304 Stainless Steel Tubes with Different Diameters Using a Hydroforming Process.

This study aims to investigate the feasibility of hydroforming (HF) technology coupled with response surface optimization for producing high-quality five-branched AISI 304 stainless steel tubes with different diameters, addressing the shortcomings of traditional manufacturing processes. Conventional techniques often result in issues with multiple consumables, low precision, and subpar performance. The research focuses on finding optimal forming parameters for a more effective process. Initial attempts at a five-branched tube proved unfeasible. Instead, a multi-step forming approach was adopted, starting with the formation of the upper branch tube followed by the two reducing lower branch tubes, a strategy termed "first three, then five". This method, enhanced by a subsequent solid solution treatment, yielded promising results: the combined height of the upper and lower branches was 141.1 mm, with a maximum thinning rate of 26.67%, reduced to 25.33% after trimming. These outcomes met the product usage requirements. Additionally, the study involved designing and developing dies for manufacturing five-branched tubes with different diameters using servo HF equipment. The effectiveness of the multi-step forming process and parameter combinations was confirmed through experimental validation, aligning closely with the FE simulation results. The maximum thinning rate observed in the experiments was 27.60%, indicating that FE simulation and response surface methodology can effectively guide the production of high-quality parts with superior performance.

Application of Procalcitonin for the Rapid Diagnosis of Clostridioides difficile Infection in Patients with Inflammatory Bowel Disease.

Background: The incidence of Clostridioides difficile infection (CDI) has increased in recent years in patients with inflammatory bowel disease (IBD). C. difficile is a toxin-producing bacterium, and CDI results in the worsening of underlying IBD, increasing the risk of IBD treatment failure, surgery, and hospitalization. Because the symptoms of CDI overlap with those of IBD, it is challenging to make a differential diagnosis. Therefore, early, rapid, and reliable diagnostic tools that can identify CDI in IBD patients would be valuable to clinicians. Methods: This study retrospectively collected 135 patients with IBD. Among them, 44 patients were diagnosed with CDI, and 42 patients were diagnosed with viral or fungal infections. A total of 49 patients without infections were defined as the control group. The diagnostic values of procalcitonin (PCT), C-reactive protein (CRP), and white blood cell (WBC) count in the peripheral blood were examined. Results: In this study, PCT levels were significantly higher in patients with CDI than in non-CDI patients (including patients with viral/fungal infections and the control group; p < 0.001 and p < 0.05, respectively). CRP levels were significantly higher in patients with CDI than in non-CDI patients (p < 0.05). The area under the curve (AUC) of PCT and WBC count were compared using DeLong's test: the AUCs of PCT vs. CRP for the detection of the IBD−CDI group and the control group was 0.826 [95% confidence interval (CI) 0.743−0.909] vs. 0.663 [95% confidence interval (CI) 0.551−0.774] (p < 0.05), respectively. WBC count was inferior as a diagnostic tool for CDI. The sensitivity was 59.09% (95% CI: 43.2% to 73.7%), the specificity was 89.80% (95% CI: 77.8% to 96.6%), and the positive likelihood ratio LR (+) was 5.79 for PCT for the diagnosis of CDI. Conclusions: The present study demonstrates the superiority of PCT over CRP and WBC count for the rapid diagnosis of CDI in IBD patients.

A Novel Hydroforming Process by Combining Internal and External Pressures for High-Strength Steel Wheel Rims.

As one of the key safety components in motor vehicles, the steel wheel rim is commonly fabricated with the roll forming process. However, due to the varied cross-sections of the rim and the low formability of high-strength steel, it is difficult to produce thin-wall and defect-free wheel rims to realize the purpose of light weight. To solve these problems, a novel hydroforming process by combining internal and external pressures (HIEP) was proposed to produce thin-wall wheel rims in the current study. The designed initial tube with diameter between the maximum and minimum diameter of the wheel rim ensures dispersed deformation and effectively avoids local excessive thinning. During HIEP, a hydroforming process was performed with two successive stages: the external pressure and internal pressure stages. Theoretical analysis and finite element method (FEM) were jointly used to investigate the effect of process parameters on the wrinkling and thinning. With the optimized parameters for internal and external pressure, the wrinkling of wheel rims is prevented under compressive state during the external pressure forming stage. Additionally, HIEP was experimentally carried out with high-strength steel rims of 650 MPa ultimate tensile strength (UTS). Finally, wheel rims with weight reduction of 13% were produced successfully, which shows a uniform thickness distribution with a local maximum thinning ratio of 11.4%.

Prognostic significance of lymphadenectomy in uterine leiomyosarcomas and endometrial stromal sarcomas: Systematic review and meta-analysis.

The clinical value of lymph node dissection remains controversial. This study aimed to evaluate the impact of lymphadenectomy on the prognosis of patients with uterine leiomyosarcomas (uLMS) or endometrial stromal sarcomas (ESS). PubMed, EMBASE and the Cochrane Library were searched for studies describing the prognostic significance of lymphadenectomy in uLMS or ESS. Quality assessments were performed using the Newcastle-Ottawa Scale, relative hazard ratios and a random-effects model. Thirty-two retrospective cohort studies that included 26,693 patients in total were enrolled. Patients with uLMS or low-grade ESS (LG-ESS) had no survival benefits from lymphadenectomy. However, patients with high-grade ESS (HG-ESS), did show survival benefits of lymphadenectomy, with no heterogeneity. No significant evidence of publication bias was found. Lymphadenectomy had little prognostic effect on patients with early-stage uLMS or LG-ESS. The best treatment for HG-ESS is early, comprehensive hysterectomy with lymph node dissection.

Simultaneous removal of cadmium, lead, chromate by biochar modified with layered double hydroxide with sulfide intercalation.

In this study, a novel KOH-activated biochar modified with Mg2Al-LDH with S2- intercalation (KBC-LDH-S) was proposed for simultaneous adsorption of anions and cations. The adsorption capacity, thermodynamic and kinetic studies, effects of initial temperature and solution pH were investigated. Furthermore, the adsorption characteristics in both single and ternary Pb-Cd-Cr systems were investigated. Comparing with bare biochar, the adsorption capacity of KBC-LDH-S was increased by 387.8 % for Cd2+ (190.4 mg/g), 358.1 % for Pb2+ (392.2 mg/g), 1106.0 % for total Cr (170.7 mg/g) and 4602 % for Cr6+ (833.8 mg/g). The S2- intercalation effectively increased the adsorption capacity of CrO42- by 3370 % and promoted simultaneous adsorption. The interlayer anion exchange and redox reaction occurred between CrO42- and S2- to generate Cr3+, and then promoted the adsorption of CrO42-. Besides, the adsorption amount and total removal efficiency first increased and then decreased with the increasing concentration in the Pb-Cd-Cr ternary system.

B7-H3 Specific CAR T Cells for the Naturally Occurring, Spontaneous Canine Sarcoma Model.

One obstacle for human solid tumor immunotherapy research is the lack of clinically relevant animal models. In this study, we sought to establish a chimeric antigen receptor (CAR) T-cell treatment model for naturally occurring canine sarcomas as a model for human CAR T-cell therapy. Canine CARs specific for B7-H3 were constructed using a single-chain variable fragment derived from the human B7-H3-specific antibody MGA271, which we confirmed to be cross-reactive with canine B7-H3. After refining activation, transduction, and expansion methods, we confirmed target killing in a tumor spheroid three-dimensional assay. We designed a B7-H3 canine CAR T-cell and achieved consistently high levels of transduction efficacy, expansion, and in vitro tumor killing. Safety of the CAR T cells were confirmed in two purposely bred healthy canine subjects following lymphodepletion by cyclophosphamide and fludarabine. Immune response, clinical parameters, and manifestation were closely monitored after treatments and were shown to resemble that of humans. No severe adverse events were observed. In summary, we demonstrated that similar to human cancers, B7-H3 can serve as a target for canine solid tumors. We successfully generated highly functional canine B7-H3-specific CAR T-cell products using a production protocol that closely models human CAR T-cell production procedure. The treatment regimen that we designed was confirmed to be safe in vivo. Our research provides a promising direction to establish in vitro and in vivo models for immunotherapy for canine and human solid tumor treatment.

Study on the precipitation of iron and the synchronous removal mechanisms of antimony and arsenic in the AMD under the induction of carbonate rocks.

The ecological environment can be severely polluted and destroyed by the acid mine drainage (AMD) generated during the exploration and utilization of minerals. However, neutralized by carbonate rocks (a natural material in Karst regions), the AMD secondary iron flocs containing a large number of iron oxides or hydroxide can be precipitated in AMD. The metal ions, such as antimony (Sb) and arsenic (As), can be effectively removed by these neutralizing products. In this paper, the neutralization reaction of different acid solutions in an iron-antimony-arsenic system was induced by carbonate rocks to explore the removal effect of metals during this neutralization process. Meanwhile, taking the release amounts of iron (Fe), Sb, and As as well as the phase transformation of minerals at different pH levels as stability indexes, we quantitatively analyzed the chemical stability of AMD neutralizing products (secondary iron flocs) containing Sb and As under the typical acid-base environment (pH = 3.0 ~ 9.0) of AMD and other waters. Results showed that the neutralization reaction with carbonate rocks induced the co-precipitation of Fe with Sb and As. When the concentration ratio of Fe, Sb, and As was 30:1:1, the pH of AMD raised from 3.0 to 7.28 within 72 h, and the three elements were removed by 99%, 85%, and 90%, respectively. After soaking the AMD secondary iron flocs in an acid environment (pH = 3.0) for 30 days, the release amount of Fe reached its peak of 0.070 mg/g. Then, when the pH value increased to 4.0, the As and Sb showed their maximum release amounts of 14.90 µg/g and 19.19 µg/g, respectively. In addition, under acidic conditions, these AMD secondary iron flocs were easily transformed into the goethite with better crystallinity and higher structural stability. This study could help reveal the development of the secondary mineral during the treatment of AMD by carbonate rocks and understand the release characteristics of metals from AMD secondary products containing Sb and As, which sheds light on and provides theoretical foundations for the passive treatment of AMD containing these two elements in the future.

Bone mesenchymal stem cells-derived miR-223-3p-containing exosomes ameliorate lipopolysaccharide-induced acute uterine injury via interacting with endothelial progenitor cells.

Bone mesenchymal stem cells (BMSCs) have been used for the treatment of acute uterine injury (AUI)-induced intrauterine adhesion (IUA) via interacting with the endothelial progenitor cells (EPCs), and BMSCs-derived exosomes (BMSCs-exo) may be the key regulators for this process. However, the underlying mechanisms have not been studied. Based on the existed literatures, lipopolysaccharide (LPS) was used to induce AUI in mice models and EPCs to mimic the realistic pathogenesis of IUA in vivo and in vitro. Our data suggested that LPS induced apoptotic and pyroptotic cell death in mice uterine horn tissues and EPCs, and the clinical data supported that increased levels of pro-inflammatory cytokines IL-18 and IL-1ß were also observed in IUA patients' serum samples, and silencing of NLRP3 rescued cell viability in LPS-treated EPCs. Next, the LPS-treated EPCs were respectively co-cultured with BMSCs in the Transwell system and BMSCs-exo, and the results hinted that both BMSCs and BMSCs-exo reversed the promoting effects of LPS treatment-induced cell death in EPCs. Then, we screened out miR-223-3p, as the upstream regulator for NLRP3, was enriched in BMSCs-exo, and BMSCs-exo inactivated NLRP3-mediated cell pyroptosis in EPCs via delivering miR-223-3p. Interestingly, upregulation of miR-223-3p attenuated LPS-induced cell death in EPCs. Collectively, we concluded that BMSCs-exo upregulated miR-223-3p to degrade NLRP3 in EPCs, which further reversed the cytotoxic effects of LPS treatment on EPCs to ameliorate LPS-induced AUI.

Clinical and hemodynamic insights into the use of internal iliac artery balloon occlusion as a prophylactic technique for treating postpartum hemorrhage.

Recently, the effectiveness of internal iliac artery balloon occlusion (IIABO) for treating postpartum hemorrhage caused by pernicious placenta previa (PPP) has been questioned. We conducted a retrospective analysis and hemodynamic simulation to assess the IIABO's effectiveness. The retrospective analysis involved 480 patients with PPP, among which 288 underwent IIABO treatment and the remaining 192 were used as controls. Blood loss and preoperative indicators were recorded, and multiple regression analysis was applied to test the effect of preoperative indicators on blood loss. Hemorrhage mechanisms were simulated using a numerical model. Results suggested that no significant difference in blood loss (1836 ± 1440 ml vs. 1784 ± 1647 ml, p = 0.22) was observed between the two groups. In addition, preoperative indicators, including age, weight, gestational age, gravidity, parity, blood type, anemia, or diabetes, were not associated with blood loss. In the simulation, after the intra-iliac artery was blocked, blood loss was caused by a reversed flow in the intrapelvic arteries, uterine veins, and uterine venules. The ratio of the time-averaged hemorrhage velocity (TAHV) in the balloon group to that in the control group was lower than that obtained in a clinical study (13.0% vs. 88.9%); in the presence of collateral circulation, blood loss occurred from collateral circulation and uterine venules after IIABO intervention, and the TAHV was 60%-90% that of the control group, which was closer to the clinical results (88.9%). These results suggest that IIABO cannot effectively treat postpartum hemorrhage because of the collateral circulation and reversed flow in the uterine venules.

A fecal-based test for the detection of advanced adenoma and colorectal cancer: a case-control and screening cohort study.

BACKGROUND: Colorectal cancer (CRC) is the leading cause of cancer death worldwide. Screening is a confirmed way to reduce the incidence and mortality rates of CRC. This study aimed to identify a fecal-based, noninvasive, and accurate method for detection of colorectal cancer (CRC) and advanced adenoma (AA). METHODS: Through detection in tissue (n = 96) and fecal samples (n = 88) and tested in an independent group of fecal samples (n = 294), the methylated DNA marker ITGA4 and bacterial markers Fusobacterium nucleatum (Fn) and Pepetostreptococcusanaerobius (Pa) were identified from the candidate biomarkers for CRC and AA detection. A prediction score (pd-score) was constructed using the selected markers and fecal immunochemical test (FIT) for distinguishing AA and CRC from healthy subjects by logistic regression method. The diagnostic performance of the pd-score was compared with FIT and validated in the external validation cohort (n = 117) and in a large CRC screening cohort. RESULTS: The pd-score accurately identified AA and CRC from healthy subjects with an area under the curve (AUC) of 0.958, at a specificity of 91.37%; the pd-score showed sensitivities of 95.38% for CRC and 70.83% for AA, respectively. In the external validation cohort, the sensitivities of the pd-score for CRC and AA detection were 94.03% and 80.00%, respectively. When applied in screening, the pd-score identified 100% (11/11) of CRC and 70.83% (17/24) of AA in participants with both colonoscopy results and qualified fecal samples, showing an improvement by 41.19% compared to FIT. CONCLUSIONS: The current study developed a noninvasive and well-validated approach for AA and CRC detection, which could be applied widely as a diagnostic and screening test.

Combination Therapy with STAT3 Inhibitor Enhances SERCA2a-Induced BMPR2 Expression and Inhibits Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a devastating lung disease characterized by the progressive obstruction of the distal pulmonary arteries (PA). Structural and functional alteration of pulmonary artery smooth muscle cells (PASMC) and endothelial cells (PAEC) contributes to PA wall remodeling and vascular resistance, which may lead to maladaptive right ventricular (RV) failure and, ultimately, death. Here, we found that decreased expression of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) in the lung samples of PAH patients was associated with the down-regulation of bone morphogenetic protein receptor type 2 (BMPR2) and the activation of signal transducer and activator of transcription 3 (STAT3). Our results showed that the antiproliferative properties of SERCA2a are mediated through the STAT3/BMPR2 pathway. At the molecular level, transcriptome analysis of PASMCs co-overexpressing SERCA2a and BMPR2 identified STAT3 amongst the most highly regulated transcription factors. Using a specific siRNA and a potent pharmacological STAT3 inhibitor (STAT3i, HJC0152), we found that SERCA2a potentiated BMPR2 expression by repressing STAT3 activity in PASMCs and PAECs. In vivo, we used a validated and efficient model of severe PAH induced by unilateral left pneumonectomy combined with monocrotaline (PNT/MCT) to further evaluate the therapeutic potential of single and combination therapies using adeno-associated virus (AAV) technology and a STAT3i. We found that intratracheal delivery of AAV1 encoding SERCA2 or BMPR2 alone or STAT3i was sufficient to reduce the mean PA pressure and vascular remodeling while improving RV systolic pressures, RV ejection fraction, and cardiac remodeling. Interestingly, we found that combined therapy of AAV1.hSERCA2a with AAV1.hBMPR2 or STAT3i enhanced the beneficial effects of SERCA2a. Finally, we used cardiac magnetic resonance imaging to measure RV function and found that therapies using AAV1.hSERCA2a alone or combined with STAT3i significantly inhibited RV structural and functional changes in PNT/MCT-induced PAH. In conclusion, our study demonstrated that combination therapies using SERCA2a gene transfer with a STAT3 inhibitor could represent a new promising therapeutic alternative to inhibit PAH and to restore BMPR2 expression by limiting STAT3 activity.

Association between serum NLRP3 and malignant brain edema in patients with acute ischemic stroke.

BACKGROUND: We aimed to explore the association of serum level of the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) and its related inflammatory biomarkers (hypoxia inducible factor-1α, cathepsin B, caspase-1 and matrix metalloproteinase-9) with malignant brain edema (MBE) in patients with acute ischemic stroke. METHODS: We prospectively enrolled patients with acute ischemic stroke admitted < 24 h from onset of symptoms. Brain CT was performed on admission and blood samples were collected. Repeated brain CT/MRI was performed < 7 days of admission to identify the presence of MBE, defined as neurological deterioration with imaging signs of midline shift or compressed basal cisterns. Logistic regression analysis was performed to assess the association between inflammatory biomarkers and MBE, adjusted for age and National Institutes of Health Stroke Scale (NIHSS). RESULTS: 200 patients (69.3 ± 14.3 years; male 55 %) were included for analysis, of whom 26 patients developed MBE (median time from stroke onset to MBE 32.5 h). Compared with patients without MBE, those with MBE had higher level of serum concentration of NLRP3 (median time from onset to blood collection 3 h, 1.85 ng/ml vs. 1.11 ng/ml, P = 0.026). NLRP3 level was positively correlated with NIHSS on admission (Spearman ρ = 0.18, P = 0.01) and the association between NLRP3 and MBE was attenuated (OR 1.47, 95 % CI 0.88-2.46, P = 0.138) after adjusting for age and NIHSS. There was no significant difference in other biomarkers between MBE and non-MBE groups. CONCLUSIONS: There was a trend of association between a higher level of serum concentration of NLRP3 and an increased risk of MBE after ischemic stroke, possibly confounded by the severity of stroke, which is worth further validation in large cohort studies.