Application of hydrogel microneedles in the oral cavity.

Microneedles are a transdermal drug delivery system in which the needle punctures the epithelium to deliver the drug directly to deep tissues, thus avoiding the influence of the first-pass effect of the gastrointestinal tract and minimizing the likelihood of pain induction. Hydrogel microneedles are microneedles prepared from hydrogels that have good biocompatibility, controllable mechanical properties, and controllable drug release and can be modified to achieve environmental control of drug release in vivo. The large epithelial tissue in the oral cavity is an ideal site for drug delivery via microneedles. Hydrogel microneedles can overcome mucosal hindrances to delivering drugs to deep tissues; this prevents humidity and a highly dynamic environment in the oral cavity from influencing the efficacy of the drugs and enables them to obtain better therapeutic effects. This article analyzes the materials and advantages of common hydrogel microneedles and reviews the application of hydrogel microneedles in the oral cavity.

Hybrid Piezoelectric/Triboelectric Wearable Nanogenerator Based on Stretchable PVDF-PDMS Composite Films.

Hybrid piezoelectric/triboelectric nanogenerators combine the merits of piezoelectric nanogenerators (PENGs) and triboelectric nanogenerators (TENGs), possessing enhanced electrical output and sensitivity. However, the structures of the majority of hybrid nanogenerators are rather complex in integrating both functions, limiting their practical application in wearable electronics. Herein, we propose to construct a piezoelectric/triboelectric hybrid nanogenerator (PT-NG) with a simple structure based on a composite film to simultaneously achieve the coupling of piezoelectric charge generation and triboelectrification with improved energy conversion efficiency. The composite film consists of electrospun PVDF nanofibers embedded in the surface of the PDMS film, which not only forms a rough nanomorphology on the surface of PDMS but also provides structural protection to the PVDF nanofibers by PDMS during compressive deformation. The results have shown that the PT-NG can generate much higher electrical outputs than individual TENG and PENG devices. The PT-NG devices exhibit a high level of mechanical-to-electrical energy conversion efficiency with superior performance in charging capacitors and functioning as self-powered wearable sensors for the detection of different signals from finger movement, the recognition of various gestures, and the monitoring of respiration. More importantly, the composite device possesses an impressive structure durability, maintaining its layered structure over 5000 testing cycles without noticing any obvious damage on the nanofibers or detachment between the layers. Our results have demonstrated that the combining of piezoelectric nanofibers and triboelectric substrate is an efficient way to fabricate highly efficient energy harvesting devices for intelligent identification and health monitoring.

Oral nutritional supplement helps to improve nutritional status of dialysis dependent patients: a systematic review and meta-analysis of randomized controlled trials.

Background: The prevention and treatment of malnutrition holds remarkable implications in the overall management of dialysis patients. However, there remains a dearth of comprehensive evaluations regarding the impact of oral nutrition supplement (ONS) on all pertinent dimensions of malnutrition in the dialysis population. Methods: A systematic search was conducted in MEDLINE, EMBASE, and Cochrane Central Library. RCTs that had assessed the effects of oral nutritional supplement in dialysis-dependent populations were considered eligible. Outcomes included laboratory indicators, anthropometric measures, nutritional indices, dialysis adequacy, body composition analysis measures, and systemic inflammation indicators. The risk of bias was assessed according to Cochrane guidelines. Weighted mean difference (WMD) or standardized mean difference (SMD) with 95% confidence intervals (CIs) were pooled using a random-effects model. Results: In all, 22 RCTs with 1,281 patients were included. The pooled analyses revealed the serum ALB, BMI, nPCR, and MIS improved by 1.44 g/L (95% CI: 0.76, 2.57), 0.35 kg/m2 (95% CI: 0.17, 0.52), 0.07 g/(kg d) (95% CI, 0.05, 0.10), and -2.75 (95% CI, -3.95, -1.54), respectively following ONS treatments when compared to control treatments. However, no significant differences were observed in relation to the other outcomes examined. 15 studies were rated as having high risk of bias. Visual inspection of the funnel plot and Egger test argued against the presence of publication bias. Conclusion: ONS treatments helps to improve the nutritional status of dialysis dependent patients. More evidence is needed from future investigations with longer study duration and standardized procedures to support long-term use of ONS in this population. Systematic review registration: https://www.crd.york.ac.uk/prospero/, Identifier CRD 42023441987.

Efficacy and safety of hypoxia-inducible factor-prolyl hydroxylase inhibitor treatment for anemia in chronic kidney disease: an umbrella review of meta-analyses.

The objective was to provide a comprehensive summary of existing evidence on the efficacy and safety of hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) for the treatment of anemia in chronic kidney disease (CKD). A systematic search was conducted in the Medline, Embase, and Cochrane databases. Only meta-analyses that evaluated the efficacy and safety of HIF-PHI treatment for anemia in CKD were included. The efficacy outcomes included hemoglobin levels and iron metabolism indices, while the safety outcomes were assessed by examining adverse events. The qualities of methodologies and evidence were assessed using the AMSTAR 2 system and the NutriGrade tool, respectively. Fourteen meta-analyses, comprising 105 distinct comparisons, were included. The comparisons were backed by evidence of high, moderate, and low levels, distributed in approximately equal proportions. None of the studies were deemed to possess a high level of confidence. In both the overall and individual treatment groups of HIF-PHI, there was an increase in the levels of hemoglobin, transferrin, and transferrin saturation, while the levels of hepcidin and total iron binding capacity decreased. Serum ferritin exhibited a reduction to some extent, while serum iron did not show significant alterations following HIF-PHI treatments. There were no notable disparities in safety outcomes between the HIF-PHI and erythropoietin stimulating agents or placebo groups. This umbrella review suggests that HIF-PHI treatment can effectively increase hemoglobin levels in CKD patients and enhance iron metabolism by decreasing hepcidin levels and improving iron transport. The safety profiles of HIF-PHIs were generally comparable to those of ESA therapies or placebos.

Artificial intelligence technology and ultrasound-guided nerve block for analgesia in total knee arthroplasty.

BACKGROUND: Knee diseases are more common in middle-aged and elderly people, so artificial knee replacement is also more used in middle-aged and elderly people. Although the patient's pain can be reduced through surgery, often accompanied by moderate pain after surgery and neutralization, which not only increases the psychological burden of the patient, but also greatly reduces the postoperative recovery effect, and may also lead to the occurrence of postoperative adverse events in severe cases. AIM: To investigate the analgesic effect of artificial intelligence (AI) and ultrasound-guided nerve block in total knee arthroplasty (TKA). METHODS: A total of 92 patients with TKA admitted to our hospital from January 2021 to January 2022 were opted and divided into two groups according to the treatment regimen. The control group received combined spinal-epidural anesthesia. The research group received AI technique combined with ultrasound-guided nerve block anesthesia. The sensory block time, motor block time, visual analogue scale (VAS) at different time points and complications were contrasted between the two groups. RESULTS: The time of sensory block onset and sensory block perfection in the research group was shorter than those in the control group, but the results had no significant difference (P > 0.05). Duration of sensory block in the research group was significantly longer than those in the control group (P < 0.05). The time of motor block onset and motor block perfection in the research group was shorter than those in the control group, but the results had no significant difference (P > 0.05). Duration of motor block in the research group was significantly longer than those in the control group. The VAS scales of the research group were significantly lower than that of the control group at different time points (P < 0.05). The postoperative hip flexion and abduction range of motion in the research group were significantly better than those in the control group at different time points (P < 0.05). The incidence of complications was significantly lower in the research group than in the control group (P = 0.049). CONCLUSION: In TKA, the combination of AI technology and ultrasound-guided nerve block has a significantly effect, with fewer postoperative complications and significantly analgesic effect, which is worthy of application.

Population Pharmacokinetics and Exposure-Response Analysis for the CTLA-4 Inhibitor Tremelimumab in Metastatic NSCLC Patients in the Phase III POSEIDON Study.

Blockade of CTLA-4 by tremelimumab combined with anti-PD-L1 durvalumab and chemotherapy provided increased antitumor activity and long-term survival benefits in first-line metastatic non-small cell lung cancer (mNSCLC) in the phase III POSEIDON study. We performed population pharmacokinetic modeling for tremelimumab using data from 1,605 patients across 6 studies (including POSEIDON) in multiple tumors (lung cancer, bladder cancer, malignant mesothelioma, and other solid tumors), and identified a 2-compartment model with linear and time-varying clearance for tremelimumab. Cox proportional hazard regression models were applied to 326 patients with mNSCLC from POSEIDON to evaluate the association between exposure metrics and efficacy end points, adjusting for baseline prognostic covariates. Improved progression-free survival (PFS) and overall survival (OS) in the tremelimumab arm (in combination with durvalumab and chemotherapy) was associated with higher tremelimumab exposure (e.g., minimum concentration at 5th dose (Cmin,dose5 ) and area under the curve at 5th dose (AUCdose5 )). However, further case-matching analyses yielded hazard ratios for the comparison of tremelimumab-treated patients in the Cmin,dose5 quartile 1 (Q1) subgroup with matched chemotherapy-treated patients of 1.04 (95% confidence interval (CI): 0.76-1.44) for OS and 0.99 (95% CI: 0.72-1.36) for PFS, suggesting that the observed apparent exposure-response relationship might be confounded. No relationship between tremelimumab exposure and safety (grade ≥3 treatment-emergent adverse events [AEs], AEs of special interest, or discontinuation due to AEs) was identified. These results support the consistent benefit observed with tremelimumab 75 mg every 3 weeks for up to 5 doses in combination with durvalumab and chemotherapy in POSEIDON as first-line therapy for mNSCLC.

Could extracellular vesicles derived from mesenchymal stem cells be a potential therapy for acute pancreatitis-induced cardiac injury?

Acute pancreatitis (AP) often leads to a high incidence of cardiac injury, posing significant challenges in the treatment of severe AP and contributing to increased mortality rates. Mesenchymal stem cells (MSCs) release bioactive molecules that participate in various inflammatory diseases. Similarly, extracellular vesicles (EVs) secreted by MSCs have garnered extensive attention due to their comparable anti-inflammatory effects to MSCs and their potential to avoid risks associated with cell transplantation. Recently, the therapeutic potential of MSCs-EVs in various inflammatory diseases, including sepsis and AP, has gained increasing recognition. Although preclinical research on the utilization of MSCs-EVs in AP-induced cardiac injury is limited, several studies have demonstrated the positive effects of MSCs-EVs in regulating inflammation and immunity in sepsis-induced cardiac injury and cardiovascular diseases. Furthermore, clinical studies have been conducted on the therapeutic application of MSCs-EVs for some other diseases, wherein the contents of these EVs could be deliberately modified through prior modulation of MSCs. Consequently, we hypothesize that MSCs-EVs hold promise as a potential therapy for AP-induced cardiac injury. This paper aims to discuss this topic. However, additional research is essential to comprehensively elucidate the underlying mechanisms of MSCs-EVs in treating AP-induced cardiac injury, as well as to ascertain their safety and efficacy.

Protective effects of KLF4 on blood-brain barrier and oxidative stress after cerebral ischemia-reperfusion in rats through the Nrf2/Trx1 pathway.

PURPOSE: To investigate the role of KLF4 in CI/R injury and whether Nrf2/Trx1 axis acted as a downstream pathway of KLF4 to exert the protective role in blood-brain barrier destruction after CI/R. METHODS: The tMCAO rat model in vivo was constructed and received the intracerebroventricular injection of 5 µg/kg and 10 µg/kg rhKLF4 before operation. TTC, brain water content, neurological function, ELISA, behavioral tests, HE, TUNEL, and qRT-PCR were performed to detect the protective role of KLF4 on CIR. Double-fluorescence staining and western blot were performed to determine the localization and spatiotemporal expression in brain tissues. Furthermore, we also analyzed the effect of KLF4 on the blood-brain barrier (BBB) and related mechanisms in vivo and in vitro. Nrf2 inhibitor tretinoin was applied, which was intraperitoneally injected into CIR rat. Evans blue staining was conducted. In vitro OGD/R models of bEnd.3 cells were also established, and received KLF4 overexpressed transfection and 12.5 µM tretinoin incubation. The permeability of bEnd.3 cells was evaluated by TEER and FITC-dextran leakage. BBB-related factors and oxidative stress were also analyzed, respectively. The tubular ability of KLF4 on OGD/R bEnd3 cells was also evaluated. RESULTS: In vivo study confirmed that KLF4 was expressed in astrocyte, and its content increased with time. KLF4 protected against brain injury caused by cerebral ischemia-reperfusion, reduced cerebral infarction area and oxidative stress levels, and promoted the recovery of behavioral ability in rats. Simultaneously, mechanism experiments confirmed that the repair effect of KLF4 on cerebral ischemia-reperfusion injury was closely related to the Nrf2/Trx1 pathway. KLF4 exerted the neuroprotective effect through upregulating Nrf2/Trx1 pathway. Consistent with in vivo animal study, in vitro study also confirmed the effect of KLF4 on the permeability of bEnd.3 cells after OGD/R injury through Nrf2/Trx1 pathway. CONCLUSION: Collectively, KLF4 played neuroprotective role in CIR induced MCAO and OGD/R, and the beneficial effects of KLF4 was partly linked to Nrf2/Trx1 pathway.

Modeling of Proliferating CD4 and CD8 T-Cell Changes to Tremelimumab Exposure in Patients with Unresectable Hepatocellular Carcinoma.

The STRIDE (Single Tremelimumab Regular Interval Durvalumab) regimen of single-dose tremelimumab 300 mg, plus durvalumab 1,500 mg every 4 weeks demonstrated potential for long-term survival in studies of unresectable hepatocellular carcinoma (uHCC; Study 22 and HIMALAYA). The aim of this analysis was to investigate changes in proliferating CD4+ Ki67+ and CD8+ Ki67+ T cells and their relationship with tremelimumab exposure in patients with uHCC. Median cell count, change from baseline, and percent change from baseline in CD4+ and CD8+ T cells peaked around 14 days after STRIDE. A model of CD4+ and CD8+ T cell response to tremelimumab exposure was developed. Patients with lower baseline T cell counts had a greater percent change from baseline in T cell response to tremelimumab, and baseline T-cell count was included in the final model. With the full covariate model, the half-maximal effective concentration (EC50 ) of tremelimumab was 6.10 µg/mL (standard error = 1.07 µg/mL); > 98.0% of patients were predicted to have a minimum plasma concentration greater than EC50 with tremelimumab 300 or 750 mg. For EC75 (9.82 µg/mL), 69.5% and 98.2% of patients were predicted to exceed the EC75 with tremelimumab 300 and 750 mg, respectively. This analysis supports the clinical hypothesis that combination anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) and anti-programmed cell death ligand-1 (anti-PD-L1) therapy primes an immune response that may then be sustained by anti-PD-L1 monotherapy and supports the clinical utility of the STRIDE regimen in patients with uHCC. These insights may also help inform dose selection of anti-CTLA-4 plus anti-PD-L1 combination strategies.

Population Pharmacokinetics and Exposure-Response Analysis of Tremelimumab 300 mg Single Dose Combined with Durvalumab 1500 mg Q4W (STRIDE) in Patients with Unresectable Hepatocellular Carcinoma.

A novel single-dose regimen of 300 mg tremelimumab in combination with durvalumab (STRIDE) has demonstrated a favorable benefit-risk profile in the phase 1/2 Study 22 trial (in patients with unresectable hepatocellular carcinoma, uHCC) and in the phase 3 HIMALAYA study. The current analysis evaluated the population pharmacokinetics (PopPK) of tremelimumab and durvalumab, and the exposure-response (ER) relationship for efficacy and safety of STRIDE in patients with uHCC. Previous PopPK models for tremelimumab and durvalumab were updated using data from previous studies in various cancers combined with data from Study 22 and HIMALAYA. Typical population mean parameters and associated inter- and intra-individual variability were assessed, as was the influence of covariates. Individual exposure metrics were derived from the individual empirical Bayes estimates as drivers for ER analysis related to efficacy and safety from HIMALAYA. The observed pharmacokinetics of tremelimumab in uHCC were well described by a 2-compartment model with both linear and time-dependent clearance. All identified covariates changed tremelimumab PK parameters by <25%, and thus had minimal clinical relevance; similar results were obtained from durvalumab PopPK analysis. None of tremelimumab or durvalumab exposure metrics were significantly associated with overall survival (OS), progression-free survival (PFS), or adverse events. Baseline aspartate aminotransferase and neutrophil-to-lymphocyte ratio (NLR) were associated with OS (P < .001) by the Cox proportional hazards model. No covariate was identified as a significant factor for PFS. No dose adjustment for tremelimumab or durvalumab is needed based on PopPK covariate analyses or ER analyses. Our findings support the novel STRIDE dosing regimen in patients with uHCC.

Effects of problem-based learning on delivering medical and nursing education: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: There is still a lack of high-level evidence on the effects of problem-based learning (PBL) in general medical and nursing education. AIMS: We aimed to summarize current evidence on the effects of PBL in delivering medical and nursing education from randomized controlled trials (RCTs). METHODS: A systematic search was performed in MEDLINE, EMBASE, Cochrane Central Library, and CINAHL Complete. RCTs that assessed the effects of a PBL module in delivering medical education were eligible. Outcomes included knowledge, performance, and satisfaction. The risk of bias was assessed according to Cochrane handbook guidelines. Standardized mean differences with 95% confidence intervals of each outcome between PBL and control groups were pooled using a random-effects model. RESULTS: In all, 22 RCTs with 1969 participants were included. Both pooled analyses of changes in scores compared with baseline and absolute post-interventional scores favored PBL module in knowledge and performance. The satisfaction degree was also higher in participants receiving PBL methods. Publication bias might exist in satisfaction; however, not in knowledge and performance. Eleven of the 22 studies were assessed as having a high risk of bias. LINKING EVIDENCE TO ACTION: Compared with traditional lecture-based modules, PBL delivered medical education in different medical science specialities more efficiently from both theoretical knowledge and practice skill perspectives. The feedback from participants receiving PBL methods was more positive than that from those receiving traditional methods. However, the high heterogeneity and low quality of the included studies prevented drawing definite conclusions.

Associate factors for endoscopic submucosal dissection operation time and postoperative delayed hemorrhage of early gastric cancer.

BACKGROUND: Endoscopic submucosal dissection (ESD) is a treatment for early gastric cancer with the advantages of small invasion, fewer complications, and a low local recurrence rate. However, there is a high risk of complications such as bleeding and perforation, and the operation time is also longer. ESD operation time is closely related to bleeding and perforation. AIM: To investigate the influencing factors associated with ESD operation time and postoperative delayed hemorrhage to provide a reference for early planning, early identification, and prevention of complications. METHODS: We conducted a retrospective study based on the clinical data of 520 patients with early gastric cancer in the Second Affiliated Hospital of Hainan Medical University from January 2019 to December 2021. The baseline data, clinical features, and endoscopic and pathological characteristics of patients were collected. The multivariate linear regression model was used to investigate the influencing factors of ESD operation time. Logistic regression analysis was carried out to evaluate the influencing factors of postoperative delayed hemorrhage. RESULTS: The multivariate analysis of ESD operation time showed that the maximum lesion diameter could affect 8.815% of ESD operation time when other influencing factors remained unchanged. The operation time increased by 3.766% or 10.247% if the lesion was mixed or concave. The operation time increased by 4.417% if combined with an ulcer or scar. The operation time increased by 3.692% if combined with perforation. If infiltrated into the submucosa, it increased by 2.536%. Multivariate analysis of delayed hemorrhage after ESD showed that the maximum diameter of the lesion, lesion morphology, and ESD operation time were independent influencing factors for delayed hemorrhage after ESD. Patients with lesion ≥ 3.0 cm (OR = 3.785, 95%CI: 1.165-4.277), lesion morphology-concave (OR = 10.985, 95%CI: 2.133-35.381), and ESD operation time ≥ 60 min (OR = 2.958, 95%CI: 1.117-3.526) were prone to delayed hemorrhage after ESD. CONCLUSION: If the maximum diameter of the lesion in patients with early gastric cancer is ≥ 3.0 cm, and the shape of the lesion is concave, or accompanied by an ulcer or scar, combined with perforation, and infiltrates into the submucosa, the ESD operation will take a longer time. When the maximum diameter of the lesion is ≥ 3.0 cm, the shape of the lesion is concave in patients and the operation time of ESD takes longer time, the risk of delayed hemorrhage after ESD is higher.

[Role of NLRP3 inflammasome in diabetic neuropathy and prevention and treatment with traditional Chinese medicine].

As one of the most frequent complications of diabetes, diabetic neuropathy often involves peripheral and central nervous systems. Neuroinflammation is the key pathogenic factor of secondary nerve injury in diabetes. NOD-like receptor pyrin domain-containing 3(NLRP3) inflammasome is a group of subcellular multiprotein complexes, including NLRP3, apoptosis associated speck-like protein(ASC), and pro-cysteinyl aspartate specific proteinase 1(pro-caspase-1). NLRP3 inflammasome is an inducer of innate immune responses. Its activation stimulates the inflammatory cascade reaction, promotes the release of inflammatory mediators, triggers cell death and uncontrolled autophagy, activates glial cells, facilitates peripheral immune cell infiltration, and initiates amyoid ß(Aß)-tau cascade reactions. As a result, it contributes to the central nerve, somatic nerve, autonomic nerve, and retinal nerve cell damage secondary to diabetes. Therefore, due to its key role in the neuroinflammation responses of the body, NLRP3 inflammasome may provide new targets for the treatment of diabetic neuropathy. With multi-target and low-toxicity advantages, traditional Chinese medicine plays a vital role in the treatment of diabetic neuropathy. Accumulating evidence has shown that traditional Chinese medicine exerts curative effects on diabetic neuropathy possibly through regulating NLRP3 inflammasome. Although the role of NLRP3 inflammasome in diabetes and related complications has been investigated in the literature, systematical studies on drugs and mechanism analysis for secondary neuropathy are still lacking. In this article, the role of NLRP3 inflammasome in diabetic neuropathy was explored, and the research progress on traditional Chinese medicine in the treatment of diabetic neuropathy through NLRP3 inflammasome was reviewed.

Population Pharmacokinetics of Monalizumab in Patients With Advanced Solid Tumors.

Monalizumab is a novel, first-in-class humanized immunoglobulin G4 monoclonal antibody immune checkpoint inhibitor that targets the inhibitory CD94/NKG2A receptors. The objectives of this analysis were to develop a population pharmacokinetic (PK) model of monalizumab, evaluate the impact of clinically relevant covariates on monalizumab PK, and provide dose justification for clinical trials. We developed a monalizumab population PK model to characterize the PK properties of monalizumab in patients with advanced solid tumors or head and neck squamous cell carcinoma. Data from clinical studies D419NC00001 (NCT02671435) and IPH2201-203 (NCT02643550) were pooled for the analysis, resulting in a data set of 3066 PK samples derived from 507 subjects. The PK of monalizumab were reasonably described by a 2-compartment model with first-order elimination. Monalizumab generally exhibited linear PK over a dose range of 22.5-750 mg or 10 mg/kg every 2 weeks. The estimate of clearance was ≈0.255 L/day, and apparent volume of distribution was 6.36 L for a typical individual, consistent with previous findings for endogenous immunoglobulin Gs and other therapeutic monoclonal antibodies. Baseline albumin and body weight were identified as significant covariates of clearance; body weight, sex, and smoking status had a significant impact on volume of distribution; and none of these covariates had impact on peripheral volume of distribution. Although these covariates were identified as statistically significant, they are considered to be not clinically meaningful, as changes in monalizumab exposure were <30%. Therefore, no dose adjustments of monalizumab based on patient or disease characteristics are recommended.

Blasting dust diffuse characteristics of spiral tunnel and dust distribution model: similar experiment and numerical modeling.

The special linear shape of spiral tunnel changes the air flow structure during tunnel construction and changes the diffuse and distribution of blasting dust. Mastering the blasting dust distribution and diffuse mechanisms can provide theoretical basis for ventilation layout and dust removal measures during spiral tunnel construction. To study the influence of spiral shape on dust diffusion and concentration distribution after tunnel blasting, a similar scale model of 1:20 and full-scale numerical model of spiral tunnel during construction were established. The similarity criterion and the similarity ratio of each physical quantity are derived from the dust motion equation. The dust distribution and diffuse characteristics in the spiral tunnel under different dust release quantity and release velocity were studied by model experiment. The dust distribution and diffuse characteristics in spiral tunnel with different curvature radius were studied by numerical simulation. The dust distribution model is refined based on the research results. The dust distribution model divides the tunnel into heavily polluted area and slightly polluted area, and the influence characteristics of the curvature radius on the dust export area are found. The layout of ventilation systems can be optimized according to the volume of heavily polluted areas. The heavily polluted area should be as small as possible; the dust in the heavily polluted area should be discharged to the slightly polluted area in an orderly manner to avoid the accumulation of dust. Dust removal measures can also be arranged according to the dust export location to improve dust removal efficiency.

The gut microbiota-astrocyte axis: Implications for type 2 diabetic cognitive dysfunction.

BACKGROUND: Diabetic cognitive dysfunction (DCD) is one of the most insidious complications of type 2 diabetes mellitus, which can seriously affect the ability to self-monitoring of blood glucose and the quality of life in the elderly. Previous pathological studies of cognitive dysfunction have focused on neuronal dysfunction, characterized by extracellular beta-amyloid deposition and intracellular tau hyperphosphorylation. In recent years, astrocytes have been recognized as a potential therapeutic target for cognitive dysfunction and important participants in the central control of metabolism. The disorder of gut microbiota and their metabolites have been linked to a series of metabolic diseases such as diabetes mellitus. The imbalance of intestinal flora has the effect of promoting the occurrence and deterioration of several diabetes-related complications. Gut microbes and their metabolites can drive astrocyte activation. AIMS: We reviewed the pathological progress of DCD related to the "gut microbiota-astrocyte" axis in terms of peripheral and central inflammation, intestinal and blood-brain barrier (BBB) dysfunction, systemic and brain energy metabolism disorders to deepen the pathological research progress of DCD and explore the potential therapeutic targets. CONCLUSION: "Gut microbiota-astrocyte" axis, unique bidirectional crosstalk in the brain-gut axis, mediates the intermediate pathological process of neurocognitive dysfunction secondary to metabolic disorders in diabetes mellitus.

Effects of high temperature and acidic solutions on the pore characteristics and mechanical properties of sandstone.

Sandstone is a common construction material widely distributed in mountain tunnels. Its stability determines the safety and service life of tunnel projects. The surrounding rock of the tunnel is subject to frequent fire incidents and long-term erosion by acidic groundwater throughout its entire life cycle. This study investigated the pore characteristics and mechanical properties of sandstone under different high temperatures and acidic solutions. The T2 spectrum distribution, pore size distribution, porosity, compressive strength, and elastic modulus of sandstone were observed through uniaxial compression tests and nuclear magnetic resonance (NMR) tests. The results showed that high temperature and acidic solutions significantly affected the T2 spectrum distribution, pore size distribution, porosity, compressive strength, and elastic modulus of sandstones, and their effects on the pore structure and mechanical properties of sandstone differed in each stage. The effect of high temperature on the pore structure and mechanical properties of sandstone was stronger than that of the acidic solutions. In addition, the mechanism of damage formation is characterized by the porosity variation of sandstone. The pore structure of sandstone showed a close linear relationship with mechanical properties, indicating that changes in microstructure inevitably affected the macroscopic mechanical properties of sandstone. These findings can guide the construction and repair of rock failure induced by fire and acidic groundwater, providing a reference for associated tunnel projects.

Osimertinib + Savolitinib to Overcome Acquired MET-Mediated Resistance in Epidermal Growth Factor Receptor-Mutated, MET-Amplified Non-Small Cell Lung Cancer: TATTON.

MET-inhibitor and EGFR tyrosine kinase inhibitor (EGFR-TKI) combination therapy could overcome acquired MET-mediated osimertinib resistance. We present the final phase Ib TATTON (NCT02143466) analysis (Part B, n = 138/Part D, n = 42) assessing oral savolitinib 600 mg/300 mg once daily (q.d.) + osimertinib 80 mg q.d. in patients with MET-amplified, EGFR-mutated (EGFRm) advanced non-small cell lung cancer (NSCLC) and progression on prior EGFR-TKI. An acceptable safety profile was observed. In Parts B and D, respectively, objective response rates were 33% to 67% and 62%, and median progression-free survival (PFS) was 5.5 to 11.1 months and 9.0 months. Increased antitumor activity may occur with MET copy number ≥10. EGFRm circulating tumor DNA clearance on treatment predicted longer PFS in patients with detectable baseline ctDNA, while acquired resistance mechanisms to osimertinib + savolitinib were mediated by MET, EGFR, or KRAS alterations. SIGNIFICANCE: The savolitinib + osimertinib combination represents a promising therapy in patients with MET-amplified/overexpressed, EGFRm advanced NSCLC with disease progression on a prior EGFR-TKI. Acquired resistance mechanisms to this combination include those via MET, EGFR, and KRAS. On-treatment ctDNA dynamics can predict clinical outcomes and may provide an opportunity to inform earlier decision-making. This article is highlighted in the In This Issue feature, p. 1.

Developability profiling of a panel of Fc engineered SARS-CoV-2 neutralizing antibodies.

To combat the COVID-19 pandemic, potential therapies have been developed and moved into clinical trials at an unprecedented pace. Some of the most promising therapies are neutralizing antibodies against SARS-CoV-2. In order to maximize the therapeutic effectiveness of such neutralizing antibodies, Fc engineering to modulate effector functions and to extend half-life is desirable. However, it is critical that Fc engineering does not negatively impact the developability properties of the antibodies, as these properties play a key role in ensuring rapid development, successful manufacturing, and improved overall chances of clinical success. In this study, we describe the biophysical characterization of a panel of Fc engineered ("TM-YTE") SARS-CoV-2 neutralizing antibodies, the same Fc modifications as those found in AstraZeneca's Evusheld (AZD7442; tixagevimab and cilgavimab), in which the TM modification (L234F/L235E/P331S) reduce binding to FcγR and C1q and the YTE modification (M252Y/S254T/T256E) extends serum half-life. We have previously shown that combining both the TM and YTE Fc modifications can reduce the thermal stability of the CH2 domain and possibly lead to developability challenges. Here we show, using a diverse panel of TM-YTE SARS-CoV-2 neutralizing antibodies, that despite lowering the thermal stability of the Fc CH2 domain, the TM-YTE platform does not have any inherent developability liabilities and shows an in vivo pharmacokinetic profile in human FcRn transgenic mice similar to the well-characterized YTE platform. The TM-YTE is therefore a developable, effector function reduced, half-life extended antibody platform.