Coagulation factor XIa (FXIa) plays a crucial role in thrombus formation; therefore, the development of potent and safe FXIa inhibitors is of great significance. In this study, compound F22, previously discovered by our group, was selected as the lead compound. Based on the principles of bioisosterism and fragment-based drug design, four series comprising 14 novel Asundexian derivatives not previously reported in the literature were designed and synthesized. The structures of the target compounds were confirmed by 1H NMR and HRMS, and their inhibitory activities against FXIa were evaluated using chromogenic substrate assay. Results showed that compound FD-1 exhibited the most potent activity, with an IC50 value of 2.8 nmol/L, which was superior to that of the lead compound F22 (IC50 = 4.5 nmol/L) and the reference drug Asundexian (IC50 = 5.0 nmol/L). Furthermore, in the activated partial thromboplastin time (aPTT) assay, compound FD-1 demonstrated excellent anticoagulant activity, outperforming Asundexian, showing no significant effect on prothrombin time (PT). These findings provide valuable insights for further structural optimization and rational design of small-molecule FXIa inhibitors.

BACKGROUND:Maxillofacial bone three-dimensional(3D)printing technology has been widely used in clinical diagnosis and treatment,but the data source before performing maxillofacial bone 3D printing mainly comes from the CT scanning data.The lens,thyroid and other parts of the human body are extremely sensitive to X-rays;therefore,it is particularly important to effectively reduce the dose of CT radiation when acquiring the data source.OBJECTIVE:To explore the feasibility of low-dose CT technology in optimizing radiation dose for maxillofacial bone 3D printing.METHODS:The medical records of 65 patients who underwent maxillofacial bone 3D printing in the Department of Stomatology at the General Hospital of Northern Theater Command from March 2021 to December 2023 were retrospectively collected and categorized into a conventional CT-dose 3D printing group(conventional CT-dose,120 kVp,automated tube current modulation,n=32)and a low-CT-dose 3D printing group(low-CT-dose group,80 kVp,automated tube current modulation,n=33).The effective dose of radiation was calculated and compared between the two groups.A Likert scale was used to evaluate the quality of 3D printing in the two groups,and the measurement bias and consistency between evaluators were measured using the Bland-Altman method.RESULTS AND CONCLUSION:(1)There was no significant difference in the general demographic characteristics(age,height,weight,body mass,sex,and body mass index)between the two groups(all P＞0.05).(2)The effective dose value of the low CT-dose 3D printing group was(0.3±0.1)mSv,which was about 62.5％lower than that in the conventional CT-dose 3D printing group[(0.8±0.1)mSv].(3)There was no significant difference in the subjective scoring of 3D printing quality between the two groups(all P＞0.05).The subjective consistency among evaluators was good,with Kappa values of 0.85,0.80,and 0.76.The scatter points in the Bland-Altman for both protocols were uniformly distributed within the standard deviation line,indicating good consistency between the two groups.To conclude,low-dose CT technology can be effectively applied in maxillofacial bone 3D printing,reducing radiation dose without affecting the quality of 3D printing.

BACKGROUND:Maxillofacial bone three-dimensional(3D)printing technology has been widely used in clinical diagnosis and treatment,but the data source before performing maxillofacial bone 3D printing mainly comes from the CT scanning data.The lens,thyroid and other parts of the human body are extremely sensitive to X-rays;therefore,it is particularly important to effectively reduce the dose of CT radiation when acquiring the data source.OBJECTIVE:To explore the feasibility of low-dose CT technology in optimizing radiation dose for maxillofacial bone 3D printing.METHODS:The medical records of 65 patients who underwent maxillofacial bone 3D printing in the Department of Stomatology at the General Hospital of Northern Theater Command from March 2021 to December 2023 were retrospectively collected and categorized into a conventional CT-dose 3D printing group(conventional CT-dose,120 kVp,automated tube current modulation,n=32)and a low-CT-dose 3D printing group(low-CT-dose group,80 kVp,automated tube current modulation,n=33).The effective dose of radiation was calculated and compared between the two groups.A Likert scale was used to evaluate the quality of 3D printing in the two groups,and the measurement bias and consistency between evaluators were measured using the Bland-Altman method.RESULTS AND CONCLUSION:(1)There was no significant difference in the general demographic characteristics(age,height,weight,body mass,sex,and body mass index)between the two groups(all P＞0.05).(2)The effective dose value of the low CT-dose 3D printing group was(0.3±0.1)mSv,which was about 62.5％lower than that in the conventional CT-dose 3D printing group[(0.8±0.1)mSv].(3)There was no significant difference in the subjective scoring of 3D printing quality between the two groups(all P＞0.05).The subjective consistency among evaluators was good,with Kappa values of 0.85,0.80,and 0.76.The scatter points in the Bland-Altman for both protocols were uniformly distributed within the standard deviation line,indicating good consistency between the two groups.To conclude,low-dose CT technology can be effectively applied in maxillofacial bone 3D printing,reducing radiation dose without affecting the quality of 3D printing.

Objective:To investigate the effect of continuous renal replacement therapy (CRRT) on energy metabolism and thermal balance in ICU patients with acute kidney injury (AKI).Methods:This study was a prospective observational study, which included AKI patients who underwent CRRT in ICU of the Sir Run Run Shaw Hospital, Zhejiang University School of Medicine from May 2020 to December 2023. The patients' general clinical characteristics, comorbidities, body temperature, disease severity score, CRRT treatment time and filter lifespan were recorded. The concentrations of glucose and lactate in blood and ultrafiltrate, and the citrate level in the ultrafiltrate when regional citrate anticoagulation adopted were analyzed regularly. Subgroup analysis was carried out according to different anticoagulation modes and whether the patients with diabetes or shock. The changes of energy metabolism and thermal balance corresponding to the changes in glucose, lactate, citrate and body temperature induced by CRRT were calculated daily.Results:This study included 420 AKI patients undergoing CRRT. When the blood lactate was between 14-18 mmol/L, there was a loss of approximately 200-250 kcal of energy per day, while the blood lactate was between 6.5-11.5 mmol/L, the daily corresponding energy loss was about 100-150 kcal. During CRRT on the first day, the patients with diabetes or shock had a mild decrease of blood glucose, while patients without diabetes and shock had mild increase of blood glucose. When the target of blood glucose was gradually achieved, the mean daily increase of energy corresponding to blood glucose intake was about 100-130 kcal in patients undergoing CRRT. The mean daily increase of energy corresponding to citrate intake was approximately 330 kcal, when the patient was undertaken by CRRT with regional citrate anticoagulation. For every 1℃ decrease in body temperature, the mean daily heat loss caused by extracorporeal thermal radiation during CRRT was about 200 kcal.Conclusions:When conducting nutritional assessment and prescription for AKI patients supported by CRRT in the ICU, it is essential to fully consider the impact of CRRT on the patient's energy metabolism and heat balance. This includes the clearance of lactate, the balance of blood glucose, the intake of citrate, and the reduction in body temperature. Additionally, the type and stage of the disease, as well as individual differences, must be taken into account to achieve personalized nutritional assessment and precise implementation.

Infectious bone defect,one of the complex and refractory types of bone defects,is characterized by infec-tion,inflammation and subsequent bone tissue destruction.These conditions often lead to severe consequences such as limb necrosis,dysfunction or even amputation.The previous treatment method for infectious bone defect primarily involves thorough debridement and bone grafting after infection control with antibacterial drugs.Howev-er,this method carries drawbacks,including the possibility of drug resistance and systemic toxicity due to high-dose use of antimicrobial drugs.With advancements in modern medicine and in-depth research on biomaterials,va-rious novel antibacterial materials have been increasingly applied in the treatment of infectious bone defect,demon-strating promising outcomes.This paper reviews the applications and therapeutic efficacy of novel antibacterial ma-terials in treating infectious bone defect at home and abroad,aiming to provide references for clinical management.

Objective:To analyze the contamination characteristics and pathogenic potential of Listeria monocytogenes (LM) in pre-packaged and refrigerated ready-to-eat cooked meat products in Chengdu City. Methods:From September 2022 to May 2023, pre-packaged and refrigerated ready-to-eat cooked meat products were collected from six districts and counties in Chengdu City. Qualitative and quantitative determination of LM was performed on these samples. Whole genome sequencing was carried out on the isolated strains. Different ST strains were selected for cell adhesion and invasion experiments. The results were expressed as adhesion rate and invasion rate. One-way ANOVA was used for comparison between groups, and the Dunnett t-test was used for pairwise comparison. Results:A total of 145 samples were collected, and LM was detected and isolated in 29 samples. The total detection rate was 20.00%, and the detection rate of braised pork was the highest (68.18%). The contamination level of LM in 9 samples (31.03%) was greater than 100.00 MPN/g. The 29 strains of Listeria monocytogenes belonged to 7 STs, including ST 3 (27.59%), ST 8 (17.24%) and ST 87 (13.79%). The strain of ST 87 carried Listeria pathogenicity islands 4 (LIPI-4), which was a highly virulent strain. The medium and high virulence strains accounted for 79.31%. Some moderately virulent and highly virulent strains of ST 8 and ST 87 were closely related to clinical patient strains. Some LM isolates of the same ST type had little SNP differences (1-6) in the same manufacturer at different stages. In vitro cell experiments showed that the highly virulent strain ST 87 had the strongest adhesion and invasion ability towards Caco-2 cells. Conclusion:The pre-packaged and refrigerated cooked meat products have a high contamination rate. Some samples have high contamination levels and carry medium and high virulence strains, posing potential health risks to human beings. LM residues continue to persist in some manufacturers′ production and processing stages.

Objective:To investigate alterations in brain function among elderly patients with interstitial cystitis/bladder pain syndrome(IC/BPS)during the resting state.Methods:We prospectively recruited seven elderly patients with IC/BPS admitted to the Urology Department of Beijing Hospital from December 2023 to May 2024 as the experimental group, and concurrently selected twelve elderly healthy individuals as the control group.After enrollment, all participants underwent resting-state functional magnetic resonance imaging(rs-fMRI)scans.General clinical data, including age and gender, as well as standardized assessment scores from the Interstitial Cystitis Symptom Index(ICSI), Interstitial Cystitis Problem Index(ICPI), Visual Analogue Scale(VAS), Self-Rating Anxiety Scale(SAS), and Self-Rating Depression Scale(SDS), were collected.The data were processed using Matlab.This study employed a paired sample t-test to analyze the differences in gray matter volume between the two groups.The functional activities of the subjects' brains were analyzed using regional homogeneity(ReHo)and low-frequency amplitude(ALFF)algorithms.Based on the identified abnormal brain regions, further functional connectivity(FC)analysis was conducted to explore the connectivity patterns among the functional brain regions.Results:No significant differences were observed in age( t=-0.68, P=0.536)or gender( χ2=0.019, P=0.891)between the experimental group and the control group.The scores of SAS and SDS in the experimental group were significantly higher than those in the control group( P<0.001).No significant difference was observed in cerebral gray matter volume between the two subject groups.In contrast to the control group, the ALFF value of the left superior parietal lobe(MNI: x, y, z=-21, -66, 60; t=12.530 5)was elevated in elderly patients with IC/BPS, and the ReHo value of the left precuneus(MNI: x, y, z=-9, -54, 63; t=9.410 3)was also increased.Through FC analysis, it was revealed that elderly IC/BPS patients exhibited significantly lower FC values between the left superior parietal lobule and the central sulcus(MNI: x, y, z=21, 15, 3; t=-27.835 6), as well as between the left anterior cingulate and the left posterior cingulate gyrus(MNI: x, y, z=-12, 0, 42; t=-8.738 9)in comparison with the control group. Conclusions:In contrast to normal individuals, elderly IC/BPS patients demonstrate functional aberrations in the left superior parietal lobule and the left precuneus.Moreover, a decrease in functional connectivity is observed between the left superior parietal lobule and the central sulcus, as well as between the left precuneus and the left posterior cingulate gyrus.These abnormal functional alterations in the brain may be implicated in the maintenance and development of symptoms in IC/BPS patients.This study conducted research from the perspective of central nervous system regulation, presenting possible directions for further exploration of the pathophysiological mechanisms of IC/BPS.

Objective To explore the mechanism of the thioredoxin-interacting protein(TXNIP)/thioredoxin-1(Trx-1)pathway in regulating the polarization of retinal microglia in rats after retinal ischemia-reperfusion(RIR)in rats,and to provide new ideas for the prevention and treatment of retinal ischemia reperfusion injury(RIRI).Methods For-ty-two healthy adult male Sprague-Dawley rats were randomly divided into a Sham group,a RIRI group and a TXNIP siRNA group.The right eye of the rats was experimented.For RIRI and TXNIP siRNA groups,RIRI models were established using the anterior chamber high intraocular pressure method.Rats in the TXNIP siRNA group were given the intravitreal injection of TXNIP siRNA 3 d before modeling.Hematoxylin-eosin(HE)staining was used to analyze retinal histopathologic changes of rats in all groups 24 h after modeling.Immunohistochemical staining of brain-specific homeobox/POU domain proteins 3A(Brn-3a)was made to count the number of retinal ganglion cells(RGCs).The dynamical changes in the number of TXNIP+cells 6 h,24 h,72 h and 7 d after modelling were analyzed through immunohistochemical staining in the RIRI group.The retinal microglia polarization and changes in the expression of TXNIP and Trx-1 proteins in each group were de-tected by double immunofluorescence staining and Western blot 24 h after modeling.Results HE staining results showed that 24 h after modelling,the retinal cells were disordered and the inner retinal layer was thickened and swelled in RIRI and TXNIP siRNA groups,compared with those in the Sham group(all P＜0.05).Immunohistochemical staining results of Brn-3a showed that 24 h after modeling,the number of Brn-3a+cells in RIRI and TXNIP siRNA groups significantly decreased,compared with that in the Sham group(both P＜0.05).The number of Brn-3a+cells in the TXNIP siRNA group was signifi-cantly higher than that in the RIRI group(P＜0.05).Immunohistochemical staining results of TXNIP at different time points after modeling showed that the expression of TXNIP+proteins started to increase 6 h after modeling.The TXNIP+protein level reached a peak at 24 h and then decreased gradually.Western blot results revealed that 24 h after modeling,RIRI and TXNIP siRNA groups had significantly higher TXNIP levels and significantly lower Trx-1 levels than the Sham group(all P＜0.05).Compared with those in the RIRI group,the expression of TXNIP proteins was significantly lower and the expression of Trx-1 proteins was significantly higher in the TXNIP siRNA group(both P＜0.05).Double immunofluores-cence staining showed that 24 h after modeling,Iba1+/CD206+cells were significantly more and Iba1+/CD16+cells were significantly less in the TXNIP siRNA group than those in the RIRI group(both P＜0.05).RIRI and TXNIP siRNA groups had significantly more Ibal+/TXNIP+cells and significantly less Iba1+/Trx-1+cells than the Sham group(both P＜0.05).The number of Iba1+/TXNIP+cells was significantly lower and the number of Iba1+/Trx-1+cells was significantly higher in the TXNIP siRNA group than those in the RIRI group(both P＜0.05).Conclusion RIR activates the TXNIP/Trx-1 path-way to induce the activation of retinal microglia and regulate the polarization of microglia,thereby resulting in RIRI in rats.

This study aims to investigate the changes in blood biochemical indicators of tongue roll-ing(TR)behavior in cattle and their correlation with changes in oral microbiota,laying a founda-tion for further exploring the relationship between animal oral microbiota,biochemical indicators,and behavioral changes.It also provides theoretical basis for preventing and treating TR behavior through regulating oral microbiota.This study intends to analyze and compare the blood biochemi-cal indicators and changes in oral microbiota of cattle with TR behavior and healthy cattle without TR behavior(healthy control,H),in order to explore the blood biochemical indicators of TR cattle and their correlation with changes in oral microbiota.Blood samples from the caudal vein of cattle in each group were collected for the detection of blood biochemical indicators and stress-related hormone indicators.Oral swabs from cattle in each group were collected for 16S rRNA gene se-quencing to analyze the composition,structure,and functional changes of their oral microbiota.The results of blood biochemical indicators in H and TR groups showed that the concentrations of al-bumin(ALB),aspartate aminotransferase(AST),calcium ion(Ca2+),and cortisol in TR group were significantly higher than those in H group(P＜0.05).There were significant differences in beta diversity of oral microbiota between TR and H groups(P＜0.05).At the genus level,the rela-tive abundances of Pseudomonas,Enterobacter,Xanthomonas,and other genera in the oral micro-biota of TR group were significantly higher than those in H group(P＜0.05).However,the rela-tive abundances of Tessaracoccus,Turicibacter,Monoglobus,Dietzia,Bifidobacterium,and other genera in the oral microbiota of TR group were significantly lower than those in H group(P＜0.05).In the KEGG metabolic pathway at the third level,the relative abundances of thiamine me-tabolism,lipoate metabolism,cysteine and methionine metabolism in the oral microbiota of TR group were significantly lower than those in H group(P＜0.05).Spearman correlation analysis showed that ALB and AST were significantly positively correlated with the relative abundances of Pseudomonas and Stenotrophomonas.Therelative abundances of Pseudomonas,Stenotrophomonas,and Sphingomonas were significantly positively correlated with fatty acid metabolism,phosphate and phosphonate metabolism,and lipoate metabolism.ALB was significantly positively correlated with inositol phosphate metabolism and phosphate and phosphonate metabolism.The study found that there were significant differences in blood biochemical indicators and oral microbiota between TR and H groups.In addition,there is a certain correlation between the composition,structure,and function of oral microbiota and the biochemical function of the host.This indicates that TR behav-ior may be associated with changes in the biochemical indicators of the host and the composition,structure,and function of oral microbiota.

Objective:To summarize the best available evidence for exercise interventions in patients with systemic lupus erythematosus (SLE) .Methods:The PIPOST model from the Joanna Briggs Institute (JBI) Centre for Evidence-Based Healthcare in Australia was used to construct the evidence-based nursing question. A top-down approach based on the "6S" evidence pyramid model was employed to search for relevant evidence, including clinical guidelines, consensus statements, systematic reviews, best practices, and evidence summaries. The search was conducted across BMJ Best Practice, UpToDate, guideline repositories, professional association websites, and Chinese and international databases. Eligible literature was screened for quality assessment, and high-quality evidence was extracted. The search timeframe covered publications from database inception to June 15, 2024.Results:A total of 15 studies were included, comprising 1 clinical decision-making article, 3 guidelines, 6 systematic reviews, and 5 randomized controlled trials. A total of 25 evidence statements were synthesized across 6 key aspects: exercise principles, exercise assessment, exercise modalities, exercise intensity, exercise frequency and duration, and exercise monitoring.Conclusions:The best evidence summarized in this study provides a valuable reference for clinical healthcare professionals implementing exercise interventions for patients with systemic lupus erythematosus.