Acute liver failure (ALF) is a life-threatening condition associated with macrophage-mediated inflammatory responses. Effective therapies and drugs are still lacking to date. Here, we reveal that a derivative of xanthohumol, CAM12203, alleviates lipopolysaccharide (LPS) + d-galactosamine (D-GalN)-induced ALF through limiting macrophage-mediated inflammation, with the most significant impact on interleukin-1β (IL-1β) transcription. Through biotin labeling-mediated pull-down and LC-MS/MS analysis, diacylglycerol kinase ζ (DGKζ), a lipid-metabolizing kinase, is identified as the direct target of CAM12203. Mechanistically, DGKζ is induced in macrophages upon inflammatory stimuli and is upregulated observed on clinical liver failure samples. Its product phosphatidic acid (PA) boosts phospholipase C (PLC)-inositol 1,4,5-trisphosphate (IP₃)-Ca²⁺ signaling and subsequent janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) cascade, ultimately promoting IL-1β production and liver failure. DGKζ knockdown/ablation or inhibition significantly impairs the DGKζ-STAT3-IL-1β pathway along with ALF progression. Finally, CAM12203 is confirmed to be a new DGKζ inhibitor and acts against inflammation in a DGKζ-reliant manner. Taken together, CAM12203 inhibits IL-1β transcription in macrophages by binding to DGKζ and blocking the DGKζ-STAT3 axis, thereby exerting an ameliorative effect on ALF. These results not only highlight CAM12203 as a promising lead compound for ALF treatment, but also define DGKζ as a novel therapeutic target.

OBJECTIVES: We aimed to compare the apical sealing properties of three endodontic sealers, namely, C-Root SP (C-R), iRoot SP, and GuttaFlow Bioseal (GFB) in vitro. METHODS: Eighty-two single-rooted premolars and anterior teeth were prepared by using M3 machine with nickel-titanium file and randomly divided into six experimental groups (n=12) and two control groups (n=5). Group A1: single-cone technique (SC)+C-R; group B1: SC+iRoot SP; group C1: SC+GFB; group A2: single-cone with ultrasonic activation (SU)+C-R; group B2: SU+iRoot SP; group C2: SU +GFB; group D: positive control group, and group E: negative control group. Dye penetration length and lateral root canal filling in each group were measured by dye penetration test. A scanning electron microscope (SEM) was used to observe the interface between gutta pertscha, root canal sealer, and dentin wall. Dye penetration length was measured and analyzed by Kruskal-Wallis test, and data on lateral root canal filling were evaluated using Chi-square. RESULTS: The dye penetration length in group A1 was lower than that in groups C1 and A2 (P<0.05) but was not significantly different from the other groups (P>0.05). Lateral root canal filling was not significantly different among all groups (P>0.05). SEM showed that GFB was slightly better than C-R and iRoot SP in binding to gutta pertcha and dentin wall. CONCLUSIONS GFB, C-R, and iRoot SP demonstrate excellent apical sealing ability. Under the conditions tested in this study, SU did not yield significantly improve the apical sealing ability of the three root canal sealers.
Root Canal Filling Materials/chemistry* ; Humans ; Gutta-Percha ; Microscopy, Electron, Scanning ; Root Canal Obturation/methods* ; Ceramics ; Dimethylpolysiloxanes ; Drug Combinations

OBJECTIVES: This study aimed to evaluate the filling effects of three biomaterial root canal sealers [iRoot SP, C-Root SP, and GuttaFlow Bioseal (GFB)] by using Micro-CT. METHODS: Sixty single-canal detached premolars were selected. After crown amputation, their uniform working length was set at 12 mm and prepared to a 06 taper 30# with M3 nickel-titanium file. The samples were randomly divided into six groups with different sealers and obturation techniques: iRoot SP+single-cone technique (SC), C-Root SP+SC, GFB+SC, iRoot SP+single cone-mediated ultrasonic technique (SU), C-Root SP+SU, and GFB+SU. Samples were scanned by Micro-CT, and the total and segmented filling rates were calculated with Mimics 22.0 software after 3D reconstruction. RESULTS: The overall filling rate of the three biomaterial root canal sealers was higher than 90%. The overall and coronal third and middle third segment filling rate of groups iRoot SP+SC, C-Root SP+SC was higher than that of group GFB+SC (P<0.01), with no significant difference between groups iRoot SP+SC and C-Root SP+SC (P>0.05). On the apical third, no significant difference was found among each group (P>0.05). The overall and segment filling rate of groups iRoot SP+SU and C-Root SP+SU was higher than that of GFB+SU (P<0.01), with no significant difference between groups iRoot SP+SU and C-Root SP+SU (P>0.05). The filling rate of the apical 1/3 of group C-Root+SC was lower than that of group C-Root+SU (P<0.01), and the filling rate of the coronal 1/3 of group GFB+SC was higher than that in the GFB+SU (P<0.01). Nevertheless, no significant difference was found in other filling rate of two obturation techniques (P>0.05). CONCLUSIONS The overall filling rate of the three biomaterial root canal sealers using SC and SU are satisfactory. iRoot SP and C-Root SP have similar filling rates, which are significantly higher than that of GFB. C-Root SP combined with SU technique can improve the filling quality of the root apical.
Root Canal Filling Materials ; X-Ray Microtomography ; Humans ; Root Canal Obturation/methods* ; Gutta-Percha ; Dimethylpolysiloxanes ; Drug Combinations ; Dental Pulp Cavity/diagnostic imaging* ; Bicuspid

Abstract In order to understand the intergenerational impact of parental childhood trauma on development of adolescent depression disorder and its mechanism, the study comprehensively elaborates possible mechanisms underlying association between parental childhood trauma and adolescent depressive disorders from multiple levels based on the biopsychosocial integrative medicine model. Future research is needed to further clarify possible mechanisms in an integrated model. Preventive and intervention measures can be proposed and early block the malignant of intergenerational influence of childhood trauma.

Objective To observe the echocardiographic manifestations of infective endocarditis(IE)complicated with valve damage in children.Methods Totally 104 children with IE were retrospectively enrolled and divided into non-damage group(n=34),mild damage group(n=39)and dysfunction group(n=31)according to whether complicated with valve damage and damage's degree.The general and echocardiographic data were compared among groups,and the echocardiographic characteristics of IE complicated with valve damage in children were analyzed.Results Significant difference of the proportion of combining with other congenital heart diseases(excluding bicuspid aortic malformations),the incidence of embolization events during hospital stay,also of endocarditis of left cardiac system were found among groups(all P＜0.05).Pairwise comparison showed that in non-damage group,the proportion of combining with other congenital heart diseases was higher,while the incidence of endocarditis of left cardiac system was lower than those in both mild damage group and dysfunction group(all P＜0.05).The incidence of embolization events during hospital stay in non-damage group was lower than that in dysfunction group(P＜0.05).Among 70 cases of IE complicated with valve damage,mitral valve(30/70,42.86％)was the most common involved valve,mostly presented as valve stenosis(63/70,90.00％).No significant difference of valve involvement site,valve structural lesions nor the incidence of valve stenosis was found between mild damage group and dysfunction group(all P＞0.05).Conclusion IE complicated with valve damage in children mostly involved left cardiac system,and the risk of embolization events was higher than that of IE children without valve damage.Echocardiography could be used as an important method for evaluating the site of valve involvement and the degree of damage.

Objective:To evaluate the effective dose, efficacy and safety of remimazolam for induction of general anesthesia in super-elderly patients.Methods:Trial Ⅰ American Society of Anesthesiologists Physical Status classification Ⅰ-Ⅲ patients of either sex, aged ≥80 yr, with body mass index of 18-25 kg/m 2, undergoing elective surgery with general anesthesia in the Zhejiang Provincial People′s Hospital from January to March 2022, were selected. Remimazolam 0.12 mg/kg or propofol 0.8 mg/kg was intravenously injected in the first patient, and the dose of remimazolam or propofol in the next patient was determined by using the modified Dixon′s up-and-down method. The difference between the two successive doses was 0.01 mg/kg for remimazolam and 0.05 mg/kg for propofol. A positive response was defined as achieving an anesthesia depth (BIS value ≤ 65) within 5 min of administration. If the response was positive, the next patient received a lower dose, or conversely if negative, a higher dose was given in the next patient. The 50% effective dose (ED 50) and 90% effective dose (ED 90) of remifentanil and propofol and their 95% confidence intervals ( CIs) were calculated by Probit method. Trial Ⅱ One hundred and forty-six American Society of Anesthesiologists Physical Status classification Ⅰ-Ⅲ elderly patients of either sex, aged ≥80 yr, with a body mass index of 18-25 mg/kg, scheduled for elective surgery with general anesthesia from April to October 2023 in Zhejiang Provincial People′s Hospital, were selected and divided into 2 groups ( n=73 each) by using a random number table method: remimazolam group (R group) and propofol group (P group). R group was induced with intravenous remimazolam ED 90 and P group was induced with intravenous propofol ED 90, and the injection time was both 30 s. If the BIS value was still greater than 65 at 5 min after administration, remimazolam 0.05 mg/kg was intravenously added each time in R group and propofol 0.5 mg/kg was intravenously added each time in P group until the patient′s BIS value ≤65. The success of anesthesia induction, time for successful induction of anesthesia and rescue sedation were recorded. The occurrence of intraoperative injection pain, hypertension, hypotension, bradycardia, hypoxemia, intraoperative awareness and postoperative delirium, nausea and vomiting was also recorded. Results:Trial Ⅰ The ED 50 (95% CI) of remimazolam was 0.148 (0.139-0.157) mg/kg, and the ED 90 (95% CI) was 0.160 (0.153-0.202) mg/kg; the ED 50 (95% CI) of propofol was 0.824 (0.726-0.983) mg/kg, and the ED 90 (95% CI) was 0.916 (0.860-2.472) mg/kg. Trial Ⅱ Compared with group P, the time for successful induction of anesthesia was significantly prolonged, the incidence of intraoperative injection pain and hypotension was decreased ( P<0.05), and no significant change was found in the success rate of anesthesia induction, rate of rescue sedation, intraoperative hypertension, bradycardia, hypoxemia, postoperative delirium, and nausea and vomiting in group R ( P>0.05). Conclusions:The ED 50 and ED 90 of remimazolam for induction of general anesthesia are 0.148 and 0.160 mg/kg, respectively, in super-elderly patients. Compared to propofol, remimazolam has a slightly longer onset time, but it is safer when used for induction of general anesthesia in super-elderly patients.

Gynecologic malignant tumors are among the leading diseases threatening women's lives and health,with the highest morbidity and mortality rates among all female diseases.These tumors originate from female reproductive organs and are typically classified based on the affected site.Ovarian cancer(OC),endometrial cancer(EC)and cervical cancer(CCA)are the most common types.Currently,gynecologic malignant tumors are primarily treated with a combination of surgery,chemotherapy and radiotherapy,where drugs play a critical role in the treatment process.However,the actual clinical effectiveness is often influenced by various factors,such as adverse reactions due to drug toxicity and the drug resistance and insensitivity observed in some patients,which limit improvements in patient survival rates.Recent studies have shown that the same type of tumor exhibits significant biological characteristics and drug response heterogeneity among different individuals,which is a key factor contributing to the varied clinical outcomes when using the same drug treatment for the same type of gynecologic malignant tumor.To achieve individualized and precise treatment for gynecologic malignant tumors,there is an urgent need to develop in vitro models that closely resemble human tumors for clinical research.Drug screening is a technique used to identify and evaluate compounds with pharmacological activity and potential therapeutic effects,providing doctors with scientific guidance on drug use,thereby avoiding blind drug testing and reducing patients'therapeutic pain and economic burden by assessing the effects of different drugs under specific conditions.Organoid models have been extensively studied as an innovative drug screening tool and personalized medicine for treating gynecologic malignancies.Organoids are tissue-like structures with a specific spatial arrangement formed in vitro through three-dimensional cell culture,capable of highly simulating the structure and function of tissues in vivo and displaying histological and genotypic characteristics very similar to human organs.This approach has largely overcome the limitations of traditional tumor models,such as patient-derived cancer cell models and patient-derived tumor xenograft models,becoming an essential research tool in oncology.It provides a more physiologically relevant experimental platform for drug screening studies of gynecologic malignancies.This paper compared the advantages and disadvantages of several preclinical cancer models,reviewed the development process of organoids,and described the establishment of gynecologic oncology organoids and their application in drug screening for ovarian,endometrial,and cervical cancers.Additionally,we discussed the current limitations of organoid technology in its application and envisioned its future development,aiming to provide insights for future medical research,particularly in new drug discovery and personalized medicine.

Objective:To compare iodine nutritional status of different populations consuming iodized salt and non-iodized salt in iodine adequate areas, and to provide a basis for formulating iodine supplementation strategies.Methods:In October 2021, Luyi County in Henan Province was selected as an iodine adequate area consuming iodized salt, while Ningling County was selected as an iodine adequate area consuming non-iodized salt. Stratified by water iodine (50 - 59, 60 - 69, 70 - 79, 80 - 89, 90 - 100 μg/L), one village was selected from each layer. One hundred children aged 8 - 10, one hundred adults, and 20 pregnant women were selected from each village to collect their urine and salt samples for testing salt and urinary iodine, and their thyroid gland was measured by ultrasound.Results:A total of 600 salt samples in Luyi County were collected, with the coverage rate of iodized salt (99.8%, 599/600) and the consuming rate of qualified iodized salt (95.5%, 573/600). A total of 1 008 salt samples in Ningling County were collected, with the rate of non-iodized salt (93.8%, 946/1 008). The median urinary iodine of children in Luyi County ( n = 240) was higher than that in Ningling County ( n = 468, 305.0 vs 232.0 μg/L, Z = - 8.10, P < 0.001). There was no statistically significant difference in median urinary iodine between pregnant women in Luyi County ( n = 120) and Ningling County ( n = 53, 240.0 vs 236.0 μg/L, Z = - 1.02, P = 0.306). The median urinary iodine of adults in Luyi County ( n = 238) was higher than that in Ningling County ( n = 486, 289.0 vs 178.5 μg/L, Z = - 11.14, P < 0.001). Children's urinary iodine ( r s = 0.21, P = 0.001) in Luyi County and adults' urinary iodine ( r s = 0.17, P < 0001) in Ningling County were positively correlated with water iodine. There was no statistically significant difference in the incidence of thyroid enlargement in children between Luyi County (0.8%, 2/240) and Ningling County (0.4%, 2/468, χ 2 = 0.80, P = 0.586), but the incidence of thyroid nodules in children in Luyi County (11.2%, 27/240) was higher than that in Ningling County (1.7%, 8/468, χ 2 = 27.36, P < 0.001). The incidence of thyroid nodules in pregnant women in Luyi County (23.3%, 28/120) was lower than that in Ningling County (46.5%, 33/71, χ 2 = 10.99, P = 0.001). There was no statistically significant difference in the incidence of adult thyroid nodules between Luyi County and Ningling County (χ 2 = 0.86, P = 0.354), with a ratio of 29.6% (71/240) to 32.9% (160/486). Conclusions:Providing population with non-iodized salt in iodine adequate areas, the overall iodine nutrition is at an appropriate level. However, children consuming iodized salt in iodine adequate areas have high level of iodine nutrition, and it is necessary to consider supplying non-iodized salt or reducing the concentration of iodized salt. Pregnant women in iodine adequate area should maintain the current policy of supplying iodized salt unchanged.

Objective:To investigate the iodine nutritional status of key populations in iodine adequate areas in Henan Province, and provide a basis for timely adoption of targeted prevention and control measures and scientific formulation of iodine supplementation strategies in iodine adequate areas.Methods:From March to September 2022, a cross-sectional survey was conducted in 60 iodine adequate counties (cities, districts) in 13 provincial-level cities in Henan Province. Administrative villages with a median water iodine level of 40 - 100 μg/L within each county (city, district) were stratified by water iodine value (40 - 49, 50 - 59, 60 - 69, 70 - 79, 80 - 89, 90 - 100 μg/L). One administrative village was selected from each water iodine layer, and 40 non boarding students aged 8 - 10 years old (age balanced, half male and half female) and 20 pregnant women were selected from each administrative village to collect their household edible salt samples and once random urine sample for test salt iodine and urinary iodine contents; and the thyroid volume of children was measured.Results:A total of 12 203 samples of household edible salt were collected from children aged 8 - 10 years old, with a median salt iodine of 24.5 mg/kg, the iodized salt coverage rate was 85.3% (10 414/12 203), and the qualified iodized salt consumption rate was 77.1% (9 406/12 203). A total of 3 999 samples of household edible salt were collected from pregnant women, with a median salt iodine of 24.0 mg/kg, the iodized salt coverage rate was 84.2% (3 366/3 999), and the qualified iodized salt consumption rate was 74.5% (2 981/3 999). A total of 12 241 urine samples from children aged 8 - 10 years old were collected, with a median urinary iodine of 290.4 μg/L. A total of 4 084 urine samples from pregnant women were collectedd, with a median urinary iodine of 233.0 μg/L. The thyroid volume of 11 971 children was examined, and the rate of goiter was 2.1% (257/11 971). Stratified by water iodine content, the median urinary iodine levels of children in 40 - 59, 60 - 79, and 80 - 100 μg/L water iodine groups were 269.7, 298.0 and 308.0 μg/L, respectively, with a statistically significant difference between the groups ( H = 67.32, P < 0.001). The goiter rates of children were 2.2% (100/4 603), 2.1% (80/3 733), 2.1% (77/3 635), respectively, with no statistically significant difference between the groups (χ 2 = 0.03, P = 0.986). The median urinary iodine levels of pregnant women were 225.4, 243.1, 234.4 μg/L, respectively, with a statistically significant difference between the groups ( H = 10.96, P = 0.004). Conclusions:The iodine nutrition level of children in iodine adequate areas in Henan Province is at an excessively suitable level, and pregnant women's iodine nutrition is at an appropriate level. It is recommended to strengthen surveillance on the basis of maintaining current prevention and control measures, and adjust prevention and control measures in a timely manner according to changes in iodine nutrition in the population.

Extracellular polymeric substances(EPS)constitutes crucial elements within bacterial biofilms,facili-tating accelerated antimicrobial resistance and conferring defense against the host's immune cells.Developing precise and effective antibiofilm approaches and strategies,tailored to the specific charac-teristics of EPS composition,can offer valuable insights for the creation of novel antimicrobial drugs.This,in turn,holds the potential to mitigate the alarming issue of bacterial drug resistance.Current analysis of EPS compositions relies heavily on colorimetric approaches with a significant bias,which is likely due to the selection of a standard compound and the cross-interference of various EPS compounds.Considering the pivotal role of EPS in biofilm functionality,it is imperative for EPS research to delve deeper into the analysis of intricate compositions,moving beyond the current focus on polymeric materials.This ne-cessitates a shift from heavy reliance on colorimetric analytic methods to more comprehensive and nuanced analytical approaches.In this study,we have provided a comprehensive summary of existing analytical methods utilized in the characterization of EPS compositions.Additionally,novel strategies aimed at targeting EPS to enhance biofilm penetration were explored,with a specific focus on high-lighting the limitations associated with colorimetric methods.Furthermore,we have outlined the challenges faced in identifying additional components of EPS and propose a prospective research plan to address these challenges.This review has the potential to guide future researchers in the search for novel compounds capable of suppressing EPS,thereby inhibiting biofilm formation.This insight opens up a new avenue for exploration within this research domain.