[Preparation of a dual-specific antibody targeting human CD123 and exploration of its anti-acute myeloid leukemia effects].

Objective: To construct a novel dual-specific antibody targeting human CD123 (CD123 DuAb) and study its effects in acute myeloid leukemia (AML) . Methods: Based on the variable region of the CD123 monoclonal antibody independently developed at our institution, the CD123 DuAb expression plasmid was constructed by molecular cloning and transfected into ExpiCHO-S cells to prepare the antibody protein. Through a series of in vitro experiments, its activation and proliferation effect on T cells, as well as the effect of promoting T-cell killing of AML cells, were verified. Results: ① A novel CD123 DuAb plasmid targeting CD123 was successfully constructed and expressed in the Expi-CHO eukaryotic system. ②The CD123 DuAb could bind both CD3 on T cells and CD123 on CD123(+) tumor cells. ③When T cells were co-cultured with MV4-11 cells with addition of the CD123 DuAb at a concentration of 1 nmol/L, the positive expression rates of CD69 and CD25 on T cells were 68.0% and 44.3%, respectively, which were significantly higher than those of the control group (P<0.05). ④Co-culture with CD123 DuAb at 1 nmol/L promoted T-cell proliferation, and the absolute T-cell count increased from 5×10(5)/ml to 3.2×10(6)/ml on day 9, and CFSE fluorescence intensity decreased significantly. ⑤ With the increase in CD123 DuAb concentration in the culture system, T-cell exhaustion and apoptosis increased. When the CD123 DuAb was added at a concentration of 1 nmol/L to the culture system, the proportion of CD8(+) PD-1(+) LAG-3(+) T cells was 10.90%, and the proportion of propidium iodide (PI) (-) Annexin Ⅴ(+) T cells and PI(+) Annexin Ⅴ(+) T cells was 18.27% and 11.43%, respectively, which were significantly higher than those in the control group (P<0.05). ⑥ The CD123 DuAb significantly activated T cells, and the activation intensity was positively correlated with its concentration. The expression rate of CD107a on T cells reached 16.05% with 1 nmol/L CD123 DuAb, which was significantly higher than that of the control group (P<0.05). ⑦The CD123 DuAb promoted cytokine secretion by T cells at a concentration of 1 nmol/L, and the concentration of IFN-γ and TNF-α in the supernatant of the co-culture system reached 193.8 pg/ml and 169.8 pg/ml, respectively, which was significantly higher than that of the control group (P<0.05). ⑧When CD123 DuAb was added at a concentration of 1 nmol/L to the co-culture system of T cells and CD123(+) tumor cells, the killing intensity of T cells significantly increased, and the residual rates of CD123(+) MV4-11 cells, CD123(+) Molm13 cells, and CD123(+) THP-1 cells were 7.4%, 6.7%, and 14.6% on day 3, respectively, which were significantly lower than those in the control group (P<0.05) . Conclusion: In this study, a novel CD123 DuAb was constructed and expressed. In vitro experiments verified that the DuAb binds to CD123(+) tumor cells and T cells simultaneously, promotes T-cell activation and proliferation, and facilitates their anti-leukemia effect, which provides a basis for further clinical research.

[Analysis of the application effect and safety of transnasal humidified rapid insufflation ventilatory exchange technique in hysteroscopic diagnostic and therapeutic surgery].

Objective: To investigate the effect and safety of transnasal humidified rapid insufflation ventilatory exchange (THRIVE) technique in hysteroscopic diagnostic and therapeutic surgery. Methods: This study was a randomized controlled trial. A total of 100 female patients undergoing hysteroscopy surgery at Beijing Tongren Hospital from September to December 2023 were selected and randomly divided into two groups by the random number table method: the THRIVE group and the mask oxygen group, with 50 patients in each group. Patients in both groups were given total intravenous anesthesia with propofol combined with remifentanil and preserved spontaneous respiration. The THRIVE group was given oxygen by the THRIVE device with an oxygen flow rate of 50 L/min, while the mask oxygen group was given oxygen by the mask with an oxygen flow rate of 5 L/min; the oxygen concentration of both groups was set at 100%. The general condition of the patients, vital signs during the operation, the amount of anesthesia drugs used and the operation time were recorded. The primary observation index was the incidence of hypoxic events in the two groups; the secondary observation indexes were the incidence and time of intraoperative apnea as well as the corresponding oxygenation interventions and the incidence of non-hypoxic adverse events. Results: The age of the THRIVE group was (42±14) years, and the age of the mask oxygen group was (43±15) years. The duration of surgery in the THRIVE group was (15.9±3.4) min, which was statistically lower than that of the mask oxygen group (16.3±4.5) min (P=0.041), and there were no differences observed in the duration of awakening time and anesthesia time (both P>0.05). There was no significant difference in the dosage of propofol, remifentanil, and intraoperative vasoactive drugs between the two groups (all P>0.05). The SpO2 of the patients in the THRIVE group at the end of the operation was (99.7±1.1) %, which was higher than that of the mask-oxygen group (99.1±1.1) % (P<0.05). There was no difference in SpO2 of the two groups at the other time points (all P>0.05). There were no differences in HR and MAP of two group patients at each time point (all P>0.05). The incidence of hypoxic events in the THRIVE group was 12.0% (6/50), which was lower than that of 28.0% (14/50) in the mask oxygen group (P=0.045). The difference in the incidence and duration of apnea between the two groups was not statistically significant (all P>0.05). There were no cases of temporary need for laryngeal mask or tracheal intubation during surgery in both groups. There was no statistically significant difference in the incidence of intraoperative body movement, dizziness, nausea and vomiting between the two groups (all P>0.05), and no cardiac, cerebral, renal or other important organ insufficiency occurred in the two weeks after surgery. Conclusion: THRIVE technology can provide effective oxygenation for patients undergoing hysteroscopic diagnosis and treatment, maintain patients' circulatory stability, and improve the safety and efficiency of surgery.

Comparison of genotypic and phenotypic antimicrobial resistance profiles of Salmonella enterica isolates from poultry diagnostic specimens.

The spread of antimicrobial-resistant bacteria is a significant concern, as it can lead to increased morbidity and mortality in both humans and animals. Whole-genome sequencing (WGS) is a powerful tool that can be used to conduct a comprehensive analysis of the genetic basis of antimicrobial resistance (AMR). We compared the phenotypic and genotypic AMR profiles of 97 Salmonella isolates derived from chicken and turkey diagnostic samples. We focused AMR analysis on 5 antimicrobial classes: aminoglycoside, beta-lactam, phenicol, tetracycline, and trimethoprim. The overall sensitivity and specificity of WGS in predicting phenotypic antimicrobial resistance in the Salmonella isolates were 93.4% and 99.8%, respectively. There were 16 disagreement instances, including 15 that were phenotypically resistant but genotypically susceptible; the other instance involved phenotypic susceptibility but genotypic resistance. Of the isolates examined, 67 of 97 (69%) carried at least 1 resistance gene, with 1 isolate carrying as many as 12 resistance genes. Of the 31 AMR genes analyzed, 16 were identified as aminoglycoside-resistance genes, followed by 4 beta-lactam-resistance, 3 tetracycline-resistance, 2 sulfonamide-resistance, and 1 each of fosfomycin-, quinolone-, phenicol-, trimethoprim-, bleomycin-, and colistin-resistance genes. Most of the resistance genes found were located on plasmids.

[Salivary carcinoma showing thymus-like differentiation: clinicopathological analysis of 7 cases].

Objective: To analyze the clinicopathological features of salivary carcinoma showing thymus-like differentiation(CASTLE). Methods: Cases diagnosed with salivary CASTLE from January 2020 to December 2023 were collected and selected from the Department of Oral Pathology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. A total of 7 cases of salivary CASTLE were identified. All the cases originated from parotid. There were 3 males and 4 females. The patients' age range was 11-70 years.The clinical, microscopic, immunohistochemical and prognostic features of these cases were analyzed. Results: The duration of disease ranged from 1 month to 1 year, and 1 patient had facial numbness and 1 with swelling sensation occasionally. Radiographically, 4 cases showed malignant signs. Microscopically, 4 cases involved in parotid gland, and all the tumors had different degrees of lymphoid tissue background. The tumor cells arranged in nests, 5 cases with lymphoepithelial carcinoma-like and 2 cases with squamous cell carcinoma morphology. The tumor cells expressed CD5 and CD117 proteins diffusely in lymphoepithelial carcinoma-like cases. However, the tumor cells expressed CD5 diffusely and CD117 focally in cases with squamous cell carcinoma morphology. All the cases had no Epstein-Barr virus infection. Among the 6 patients with follow-up information, all of them underwent postoperative radiotherapy, and none of them had local recurrence and lymph node metastasis. Conclusions: Salivary CASTLE is a rare tumor, it should be distinguished from lymphoepithelial carcinoma and squamous cell carcinoma. The patients often have better prognosis and CD5 protein expression has a valuable role in the differential diagnosis.

[Surgical treatment and prognosis analysis of hilar cholangiocarcinoma].

Objective: To investigate the surgical treatment effect and prognostic factors of hilar cholangiocarcinoma. Methods: This is an ambispective cohort study. From August 2005 to December 2022,data of 510 patients who diagnosed with hilar cholangiocarcinoma and underwent surgical resection at the Hepatobiliary Center of the First Affiliated Hospital of Nanjing Medical University were retrospectively collected. In the cohort,there were 324 males and 186 females,with an age of (M (IQR)) 63(13)years (range:25 to 85 years). The liver function at admission was Child-Pugh A (343 cases,67.3%) and Child-Pugh B (167 cases,32.7%). Three hundred and seventy-two(72.9%) patients had jaundice symptoms and the median total bilirubin was 126.3(197.6) µmol/L(range: 5.4 to 722.8 µmol/L) at admission. Two hundred and fourty-seven cases (48.4%) were treated with percutaneous transhepatic cholangial drainage or endoscopic nasobiliary drainage before operation. The median bilirubin level in the drainage group decreased from 186.4 µmol/L to 85.5 µmol/L before operation. Multivariate Logistic regression was used to identify the influencing factors for R0 resection,and Cox regression was used to construct multivariate prediction models for overall survival(OS) and disease-free survival(DFS). Results: Among 510 patients who underwent surgical resection,Bismuth-Corlett type Ⅲ-Ⅳ patients accounted for 71.8%,among which 86.1% (315/366) underwent hemi-hepatectomy,while 81.9% (118/144) underwent extrahepatic biliary duct resection alone in Bismuch-Corlett type Ⅰ-Ⅱ patients. The median OS time was 22.8 months, and the OS rates at 1-,3-,5-and 10-year were 72.2%,35.6%,24.8% and 11.0%,respectively. The median DFS time was 15.2 months,and the DFS rates was 66.0%,32.4%,20.9% and 11.0%,respectively. The R0 resection rate was 64.5% (329/510), and the OS rates of patients with R0 resection at 1-,3-,5-and 10-year were 82.5%, 48.6%, 34.4%, 15.2%,respectively. The morbidity of Clavien-Dindo grade Ⅲ-Ⅴ complications was 26.1%(133/510) and the 30-day mortality was 4.3% (22/510). Multivariate Logistic regression indicated that Bismuth-Corlett type Ⅰ-Ⅲ (P=0.009), hemi-hepatectomy and extended resection (P=0.001),T1 and T2 patients without vascular invasion (T2 vs. T1:OR=1.43 (0.61-3.35),P=0.413;T3 vs. T1:OR=2.57 (1.03-6.41), P=0.010;T4 vs. T1, OR=3.77 (1.37-10.38), P<0.01) were more likely to obtain R0 resection. Preoperative bilirubin,Child-Pugh grade,tumor size,surgical margin,T stage,N stage,nerve infiltration and Edmondson grade were independent prognostic factors for OS and DFS of hilar cholangiocarcinoma patients without distant metastasis. Conclusions: Radical surgical resection is necessary to prolong the long-term survival of hilar cholangiocarcinoma patients. Hemi-hepatectomy and extended resection,regional lymph node dissection and combined vascular resection if necessary,can improve R0 resection rate.

Association of blood heavy metal concentrations with hearing loss: a systematic review and meta-analysis.

OBJECTIVES: This study aimed to assess the associations between blood heavy metal concentrations and hearing loss. STUDY DESIGN: This was a systematic review and meta-analysis. METHODS: A comprehensive literature search was performed using Embase, PubMed, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Chinese Biomedical Literature, Wanfang and Weipu databases. Ten studies were included, and a random or fixed-effects model was used for the meta-analysis. Review Manager 5.4 software was used for data synthesis, and Stata 15.1 software was used for the publication bias and sensitivity analyses. RESULTS: Blood lead concentrations were significantly and substantially associated with hearing loss (mean difference (MD) = 1.14; 95% confidence interval [CI] = 0.03, 2.26; P = 0.04; I2 = 81%), and iron deficiency was significantly related to hearing loss (MD = -0.42; 95% CI = -0.66, -0.18; P = 0.12; I2 = 60%). CONCLUSIONS: These results suggest an association between blood heavy metal concentrations and hearing loss. However, there were limitations: confounding factors, lack of description for the specific methods of blinding and independent verification of case definition, limited sample size, Chinese publications comprising half of the primary data and the lack of assessment of the relationship between different blood heavy metal concentrations and the severity of hearing loss. Therefore, larger and well-designed prospective cohort studies are required for further exploration.

[Analysis of the reported incidence and epidemiological characteristics of pulmonary tuberculosis among health-care workers in China,2011-2020].

Objective: To analyze the reported incidence and epidemiological characteristics of pulmonary tuberculosis (PTB) among healthcare workers (HCWs) nationwide from 2011 to 2020. Methods: The national surveillance data of PTB from 2011 to 2020 were used to analyze the reported incidence and epidemiological characteristics of PTB among HCWs, and the average annual change trends were calculated. Results: The reported incidence of PTB among HCWs in China first decreased and then increased, with an average annual percentage change (AAPC) of -1.1%, from 37.0/100 000 in 2011 to 30.0/100 000 in 2015, and then to 33.4/100 000 in 2020. From 2011 to 2019, the risk of PTB in males was 1.02-1.37 times higher than that in females, and in 2020, the risk of PTB in males was 0.86 times higher than that in females. The risk of pulmonary tuberculosis in males showed a rapid downward trend, and the AAPC was -3.8%. Taking the 45-<55 age group as a reference, the risk of PTB in the <25, 25-<35, 55-<60 and≥60 age groups was 4.64, 1.97, 1.28 and 1.47 times, respectively. There was no significant difference between the 35-<45 age group and the 44-<55 age group. The reported incidence rates in the eastern, central and western China were 25.0/100 000, 33.2/100 000 and 44.0/100 000, respectively. The incidence rates in the central and western China were 1.33 and 1.76 times higher than that in the eastern China, and the AAPCs were -1.2%, -0.2%, and -1.6% in the eastern, central, and western China, respectively. Conclusions: From 2011 to 2020, the reported incidence of PTB among HCWs in China was generally at a low level, but there was an upward trend since 2015. It is necessary to strengthen TB prevention and control among this group, especially focusing on key provinces in the central and western China. At the same time, it is necessary to strengthen the entry-level and routine training for young HCWs in TB infection control.

[Obstructive sleep apnea and type 2 diabetes: a bidirectional Mendelian randomization study].

Objective: This study aims to explore the causal relationship between obstructive sleep apnea (OSA) and type 2 diabetes (T2D) using bidirectional Mendelian randomization (MR). Methods: The genetic data related to OSA were obtained from the FinnGen Biobank (Ncase=16, 761, Ncontrol=201, 194) in the Genome-wide association study (GWAS). Three single nucleotide polymorphism (SNP) were screened out as instrumental variable (IV) of OSA. The genetic data related to T2D were derived from a large Meta-analysis of GWAS (Ncase=62, 892, Ncontrol=596, 424), 114 SNP were selected as IV of T2D. Multiple MR methods were used for analysis and inverse variance weighted (IVW) was performed as main method. The sensitivity of MR analytic results was analyzed using MR-Egger and other methods, and the IV was evaluated using F-value statistics. Results: MR analysis showed that OSA was significantly associated with increased risk of T2D (OR=2.016, 95%CI: 1.185-3.429, P<0.05). There was no significant relationship between T2D and OSA risk (OR=1.030, 95%CI: 0.980-1.082, P=0.238). There was heterogeneity in both-way results (OSA➝T2D, P=1.808×10-11; T2D➝OSA, P=1.729×10-7), and no horizontal pleiotropy (OSA➝T2D, P=0.477; T2D➝OSA, P=0.349). IV of OSA and T2D-selected in the study were strong instrumental variables (F statistics of OSA=20.543; F statistics of T2D=30.117). Conclusion: Our results supported that OSA was a risk factor for T2D, but T2D had no significant impact on the incidence of OSA. Blood glucose monitoring and diabetes screening in OSA patients might be beneficial to the early detection and intervention of T2D.

Ru-Based Organometallic Agents Bearing Phenyl Hydroxide: Synthesis and Antibacterial Mechanism Study against Staphylococcus aureus.

The development of antimicrobial agents with novel model of actions is a promising strategy to combat multiple resistant bacteria. Here, three ruthenium-based complexes, which acted as potential antimicrobial agents, were synthesized and characterized. Importantly, three complexes all showed strong bactericidal potency against Staphylococcus aureus. In particular, the most active one has a MIC of 6.25 µg/mL. Mechanistic studies indicated that ruthenium complex killed S. aureus by releasing ROS and damaging the integrity of bacterial cell membrane. In addition, the most active complex not only could inhibit the biofilm formation and hemolytic toxin secretion of S. aureus, but also serve as a potential antimicrobial adjuvant as well, which showed synergistic effects with eight traditional antibiotics. Finally, both G. mellonella larva infection model and mouse skin infection model all demonstrated that ruthenium complex also showed significant efficacy against S. aureus in vivo. In summary, our study suggested that ruthenium-based complexes bearing a phenyl hydroxide are promising antimicrobial agents for combating S. aureus.

[Application of veno-arterio-venous extracorporeal membrane oxygenation in patients with critical respiratory failure combined with refractory shock].

Objective: To preliminarily analyze the application experience of veno-arterio-venous extracorporeal membrane oxygenation (VAV-ECMO).The VAV-ECMO is a rescue strategy for patients with extremely critical respiratory failure combined with refractory shock. Methods: From February 2016 to February 2022, the characteristics and outcomes of patients who were started on either veno-venous or veno-arterial ECMO due to respiratory or hemodynamic failure, and then converted to VAV-ECMO in respiratory intensive care unit (ICU) of Beijing Chaoyang Hospital were analyzed. Results: A total of 15 patients underwent VAV-ECMO, aged 53 (40, 65) years, and 11 of whom were male. Within the group, VV-ECMO was initially used in 12 patients due to respiratory failure, but then VAV-ECMO was used due to cardiogenic shock (7/12) and septic shock (4/12), while VAV-ECMO was established in two patients due to lung transplantation. One patient was diagnosed with pneumonia complicated by septic shock, which was initially determined to be VA-ECMO, but then switched to VAV-ECMO because it was difficult to maintain oxygenation. The time from the establishment of VV or VA-ECMO to the switch to VAV-ECMO was 3 (1, 5) days and the VAV-ECMO support time was 5 (2, 8) days. ECMO-related complications were bleeding, mostly in the digestive tract (n=4) and airway hemorrhage (n=4), without intracranial hemorrhage, and poor arterial perfusion of the lower limbs (n=2). Among these 15 patients, the overall ICU mortality was 53.3%. The mortality of patients who received VAV-ECMO due to septic shock and cardiogenic shock was 100% (4/4) and 42.8% (3/7), respectively. Two patients who received VAV-ECMO due to lung transplantation all survived. Conclusion: VAV-ECMO may be a safe and effective treatment for carefully selected patients with critical respiratory failure associated with cardiogenic shock or end-stage lung disease lung transplantation transition, however, patients with septic shock may benefit the least.

Effects of different dietary starch sources on growth and glucose metabolism of geese.

This experiment investigated the effects of different dietary starch sources on the growth and glucose metabolism of geese. A total of 240 healthy 35-day-old male geese were selected and randomly divided into 4 groups, with 6 replicates per group and 10 geese per replicate. Four types of diets were prepared, with glutinous rice (rapidly-digestible starch), corn, indica rice and high amylose as their starch sources, and fed for 28 d. Results showed that after consuming different feeds, the blood glucose of geese first increased and then decreased, reaching its maximum value 0.5 h after feeding, and there were significant differences between the groups (P < 0.05). The body weight of the corn and indica rice group geese at 63 d was higher than that of the high amylose group (P < 0.05). The serum total cholesterol (TCHO) content in the glutinous rice and corn groups was higher than in the high amylose group (P < 0.05). The serum insulin content in the glutinous rice group was lower than in the corn and high amylose groups (P < 0.05), while the glucagon content was higher (P < 0.05). The α-amylase activities of the pancreas, jejunal chyme, and jejunal mucosa in the glutinous rice group were higher than in the indica rice and high amylose groups (P < 0.05). The liver glycogen content in the glutinous rice group was higher than the other groups (P < 0.05). The liver glucose-6-phosphate dehydrogenase (G-6-PD) content in the glutinous rice group was higher than the high amylose group's (P < 0.05), but the glycogen synthase kinase-3 ß (GSK-3ß) content was lower (P < 0.05). In conclusion, the corn and indica rice diets had a positive effect on the growth performance of the geese, while the high amylose diet had a negative effect. The glutinous rice diet leads to rapid release of glucose, strengthening glucose metabolism pathways such as glycogen synthesis and the pentose phosphate pathway, and further influencing lipid metabolism.

[Comparison of programmed death-ligand 1 protein expression between primary tumors and lymph node metastatic lesions in oral squamous cell carcinoma].

Objective: To investigate the difference of programmed death-ligand 1 (PD-L1) expression between primary lesions and lymph node metastatic lesions in oral squamous cell carcinoma. Methods: Eighty-two patients diagnosed with oral squamous cell carcinoma from December 2020 to July 2021 in Department of Oral Pathology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine & College of Stomatology, Shanghai Jiao Tong University, were enrolled in this study. All the patients underwent neck dissection concurrently and had lymph node metastasis. Among them, there were 28 females and 54 males. The age range was 24-79 years old [(58.6±11.7) years old]. The expression of PD-L1 protein in primary tumors and lymph node metastatic lesions was detected by immunohistochemistry. Combined positive score (CPS) was used to evaluate the PD-L1 expression. And the difference of PD-L1 expression between primary tumors and metastatic lesions was analyzed. Results: Among 82 primary tumors, 9 cases (11%) had PD-L1 CPS<1, 31 cases (38%)≥ 1 and <20, and 42 cases (51%)≥20. Cases with perineural invasion had lower CPS (χ2=6.35, P=0.042). Among 82 matched lymph node metastatic lesions, 9 cases (11%) had CPS<1, 38 cases (46%)≥1 and<20, and 35 cases (43%)≥20. The CPS of 27 pairs (33%) of primary and metastatic lesions were discordant. The statistical results showed that the Kappa value of consistency evaluation was 0.446, indicating that the consistency of PD-L1 CPS in primary and metastatic lesions of OSCC was medium. Conclusions: There are differences in PD-L1 expression between the primary lesion of OSCC and cervical lymph node metastatic lesions, and the consistency is medium. In the routine practice, lymph node metastatic lesions should be carefully used to replace the primary lesion for PD-L1 CPS evaluating.

[Establishment of patient-derived salivary gland basal cell adenoma organoids].

Objective: To establish an in vitro organoid model of human salivary gland basal cell adenoma (BCA). Methods: Fresh tumor sample from a 66-year-old female patient diagnosed with salivary gland BCA was collected from the Dpartment of Oral pathology, Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine in October 2021. And the organoid culture was performed in vitro in a culture medium based on solid droplets of matrix gel, and the growth of the organoid was observed by inverted microscopy. After 14 days, the organoid was fixed in 10% neutral formalin and made into paraffin blocks by agar pre-embedding paraffin embedding method, sectioned. HE staining, morphological observation and immunohistochemical staining of p63, Ki-67, cytokeratin14 (CK14), ß-catenin, S-100 and calponin were used for organoids identification. Results: The established BCA organoids were lobulated nodular locally under light microscopy, with deposition of eosinophilic glass-like material around the nests of organoid cells, similar to the morphological architectures of the parental BCA. Immunohistochemistry showed that organoids expressed CK14, p63, and ß-catenin in various degree, which was consistent with the immunophenotypic characteristics of the parental BCA tumor cells. Conclusions: An in vitro culture system of BCA organoids was preliminarily established which provides a new model for the study of the pathogenesis of salivary gland tumors.

Effect of polyethylene Glycol Loxenatide (long-acting GLP-1RA) on lipid, glucose levels and weight in type 2 diabetes mellitus patients with obesity.

OBJECTIVE: To explore the effect of polyethylene glycol loxenatide (long-acting GLP-1R agonist) on the lipid, glucose levels, and weight in type 2 diabetes mellitus patients with obesity. PATIENTS AND METHODS: A total of 40 obese patients with type 2 diabetes mellitus in our hospital from July 2019 to June 2020 were randomly divided into a control group and a study group. The study group was treated with metformin and polyethylene glycol loxenatide injection, while the control group was treated with metformin. RESULTS: Before treatment, there was no significant difference in FPG (Fasting Blood Glucose) and PPG (Post Prandial Glycaemia) levels between the study group and the control group (p>0.05). After a treatment period, the FPG and PPG levels in the study group were significantly lower than those in the control group (p<0.05). With the longer treatment time, the patient's weight and BMI were lower (p<0.05). The weight and BMI of patients changed the least after one month of treatment, and the weight and BMI changed the most after more than seven months of treatment. After a period of treatment, the levels of FPG and PPG in the blood of male patients in the study group were significantly lower than those of female patients (p<0.05). After treatment, the TG level of the study group was significantly lower than that of the control group (p<0.05). In comparison, the HDL-C level was significantly higher than that of the control group (p<0.05). CONCLUSIONS: Lipid and glucose levels of type 2 diabetes mellitus patients with obesity have decreased after 12 weeks of polyethylene glycol loxanatide use. The weight of type 2 diabetes mellitus patients with obesity has changed after using polyethylene glycol loxenatide for a period of treatment. Among them, there is a certain relationship between body weight and treatment time, gender, and original body weight, which is worthy of further research and promotion in clinical practice.

[A 10-year retrospective analysis of spectrums and treatment options of orthostatic intolerance and sitting intolerance in children].

OBJECTIVE: To analyze the disease spectrums underlying orthostatic intolerance (OI) and sitting intolerance (SI) in Chinese children, and to understand the clinical empirical treatment options. METHODS: The medical records including history, physical examination, laboratory examination, and imagological examination of children were retrospectively studied in Peking University First Hospital from 2012 to 2021. All the children who met the diagnostic criteria of OI and SI were enrolled in the study. The disease spectrums underlying OI and SI and treatment options during the last 10 years were analyzed. RESULTS: A total of 2 110 cases of OI and SI patients were collected in the last 10 years, including 943 males (44.69%) and 1 167 females (55.31%) aged 4－18 years, with an average of (11.34±2.84) years. The overall case number was in an increasing trend over the year. In the OI spectrum, postural tachycardia syndrome (POTS) accounted for 826 cases (39.15%), followed by vasovagal syncope (VVS) (634 cases, 30.05%). The highest proportion of SI spectrum was sitting tachycardia (STS) (8 cases, 0.38%), followed by sitting hypertension (SHT) (2 cases, 0.09%). The most common comorbidity of OI and SI was POTS coexisting with STS (36 cases, 1.71%). The highest proportion of treatment options was autonomic nerve function exercise (757 cases, 35.88%), followed by oral rehydration salts (ORS) (687 cases, 32.56%), metoprolol (307 cases, 14.55%), midodrine (142 cases, 6.73%), ORS plus metoprolol (138 cases, 6.54%), and ORS plus midodrine (79 cases, 3.74%). The patients with POTS coexisting with VVS were more likely to receive pharmacological intervention than the patients with POTS and the patients with VVS (41.95% vs. 30.51% vs. 28.08%, χ2= 20.319, P < 0.01), but there was no significant difference in the proportion of treatment options between the patients with POTS and the patients with VVS. CONCLUSION: POTS and VVS in children are the main underlying diseases of OI, while SI is a new disease discovered recently. The number of children with OI and SI showed an increasing trend. The main treatment methods are autonomic nerve function exercise and ORS. Children with VVS coexisting with POTS were more likely to take pharmacological treatments than those with VVS or POTS only.

[Efficacy and safety of neoadjuvant immunotherapy for hepatocellular carcinoma].

Objective: To study the surgical safety and efficacy of preoperative neoadjuvant therapy with immune checkpoint inhibitors combined with anti-angiogenic drugs in patients with China liver cancer staging(CNLC)-Ⅱb and Ⅲa resectable hepatocellular carcinoma. Methods: The data of 129 patients with Ⅱb and Ⅲa hepatocellular carcinoma who underwent surgery at the First Affiliated Hospital of Nanjing Medical University from January 2018 to December 2020 were analyzed. All patients were divided into two groups: the neoadjuvant therapy group(n=14,13 males and 1 female,aged (55.4±12.6)years(range:34 to 75 years)) received immune combined targeted therapy before surgery,immune checkpoint inhibitor camrelizumab was administered intravenously at a dose of 200 mg each time,every 2 weeks for 3 cycles,anti-angiogenesis drug apatinib was taken orally and continuously with a dose of 250 mg for 3 weeks and the conventional surgery group(n=115,103 males and 12 females,aged (55.8±12.0)years(range:21 to 83 years)) did not receive antitumor systemic therapy before surgery. There were 3 patients with CNLC-Ⅱb,11 with CNLC-Ⅲa in the neoadjuvant group;28 patients with CNLC-Ⅱb,87 with CNLC-Ⅲa in the conventional group. Student's t test or rank-sum test was used to compare the differences between two groups for quantitative data, Fisher's exact probability method was used to compare the differences of proportions between two groups, and Log-rank test was used to compare survival differences between two groups. Results: The 1-year recurrence rate in the neoadjuvant group was 42.9%,and the 1-year recurrence rate in the conventional group was 64.0%,with a statistically significant difference between the two groups(χ²=3.850,P=0.050);The 1-year survival rate in the neoadjuvant group was 100% and that in the conventional group was 74.2%,with a statistically significant difference between the two groups(χ²=5.170,P=0.023). According to the stratified analysis of the number of tumors,for single tumor,the 1-year recurrence rate in the neoadjuvant group was 25.0%,and that in the conventional surgery group was 71.0%,and the difference between the two groups was statistically significant(χ²=5.280, P=0.022). For multiple tumors, the 1-year recurrence rate in the neoadjuvant group was 66.7%,and the 1-year recurrence rate in the conventional surgery group was 58.9%,with no significant difference between the two groups(χ²=0.110,P=0.736). The operative time,intraoperative blood loss,and postoperative hospital stay in the neoadjuvant group were similar to those in the conventional group,and their differences were not statistically significant. Conclusions: Immune checkpoint inhibitors combined with anti-angiogenic targeted drugs as a neoadjuvant therapy for resectable hepatocellular carcinoma can reduce the 1-year recurrence rate and improve the 1-year survival rate,especially for those with solitary tumor. Limited by the sample size of the neoadjuvant group,the safety of immune combined targeted therapy before surgery cannot be observed more comprehensively,and further studies will be explored.

[Comparative analysis of work-related musculoskeletal disorders catalogues].

Work-related musculoskeletal disorders (WMSDs) refer to musculoskeletal disorders caused by work or work as the main cause, which are characterized by high prevalence and heavy burden of disease as a global problem. The classification and catalog of occupational diseases is of great significance for guiding the prevention and control of occupational diseases and safeguarding the rights and interests of workers. The types of WMSDs included in the list of occupational diseases vary greatly from country to country, and the regulations on specific pathogenic factors are also inconsistent. By sorting out and analyzing the lists and characteristics of WMSDs at home and abroad, and using the International Statistical Classification of Diseases and Related Health Problems (ICD-10) in occupational health to standardize of WMSDs in various countries, which would lay the foundation for future multi-country WMSDs occupational health registration and disease burden research, and provide a reference for China to revise the WMSDs list.

RUNX2 Regulates Osteoblast Differentiation via the BMP4 Signaling Pathway.

RUNX2 is a master osteogenic transcription factor, and mutations in RUNX2 cause the inherited skeletal disorder cleidocranial dysplasia (CCD). Studies have revealed that RUNX2 is not only a downstream target of the bone morphogenetic protein (BMP) pathway but can also regulate the expression of BMPs. However, the underlying mechanism of the regulation of BMPs by RUNX2 remains unknown. In this project, we diagnosed a CCD patient with a 7.86-Mb heterozygous deletion on chromosome 6 containing all exons of RUNX2 by multiplex ligation-dependent probe amplification (MLPA) and whole-genome sequencing (WGS). Bone marrow mesenchymal stem cells (BMSCs) were further extracted from patient alveolar bone fragments (CCD-BMSCs), an excellent natural model to explore the possible mechanism. The osteogenic differentiation ability of CCD-BMSCs was severely affected by RUNX2 heterozygous deletion. Also, BMP4 decreased most in BMP ligands, and CHRDL1, a BMP antagonist, was abnormally elevated in CCD-BMSCs. Furthermore, BMP4 treatment essentially rescued the osteogenic capacity of CCD-BMSCs, and RUNX2 overexpression reversed the abnormal expression of BMP4 and CHRDL1. Notably, we constructed CRISPR/Cas9 Runx2+/m MC3T3-E1 cells, which simulated a variant in CCD-BMSCs, to exclude the interference of other gene deletions and the heterogeneity of the genetic background of primary cells, and verified all findings from the CCD-BMSCs. Moreover, the luciferase reporter experiment showed that RUNX2 could inhibit the transcription of CHRDL1. Through immunofluorescence, the inhibitory effect of CHRDL1 on BMP4/Smad signaling was confirmed in MC3T3-E1 cells. These results revealed that RUNX2 regulated the BMP4 pathway by inhibiting CHRDL1 transcription. We collectively identified a novel RUNX2/CHRDL1/BMP4 axis to regulate osteogenic differentiation and noted that BMP4 might be a valuable therapeutic option for treating bone diseases.

Effects of Hydrothermal Treatment on the Phase Transformation, Surface Roughness, and Mechanical Properties of Monolithic Translucent Zirconia.

OBJECTIVES: This study aimed to investigate the effects of hydrothermal treatment on four types of monolithic, translucent, yttria-stabilized, tetragonal zirconia polycrystals (Y-TZPs). METHODS AND MATERIALS: Two commercially available Y-TZP brands-SuperfectZir High Translucency (Aidite Technology Co, China) and Katana HT (Kuraray Noritake Dental, Japan) were assessed. For each brand of Y-TZP, materials of four coloring types, including noncolored (NC), colored by staining (CS), precolored (PC), and multilayered (ML) specimens were investigated after hydrothermal aging in an autoclave at 134°C/0.2 MPa for 0 (control group), 5, 10, and 20 hours. The tetragonal-to-monoclinic phase transformation, surface roughness, flexural strength, and structural reliability (Weibull analysis) were measured and statistically analyzed (α=0.05). The subsurface microstructure was analyzed with scanning electron microscopy. RESULTS: The group ML exhibited the lowest flexural strength and Weibull characteristic strength among the four coloring types (p<0.05). Slight increases in the monoclinic phase volume, flexural strength, and Weibull characteristic strength were observed after hydrothermal aging (pall<0.05). Regardless of coloring type, no significant effects of aging on the Weibull modulus or surface roughness were found for the tested materials. Compared with the Katana HT cross-sections, the SuperfectZir High Translucency cross-sections exhibited a similar but thicker transformation zone. CONCLUSIONS: The coloring procedure and material type were found to affect the mechanical properties and aging resistance of translucent monolithic Y-TZP ceramics. Regardless of the aging time, the surface roughness of the tested Y-TZP ceramics remained unchanged.

[Diagnosis and treatment of 21-hydroxylase deficiency with testicular adrenal rest tumors:a report of three cases and literature review].

Objective: To provide insight into the diagnosis for clinicians, the clinical characteristics, diagnosis and treatment history of 3 patients with 21-hydroxylase deficiency (21-OHD) and testicular adrenal rest tumors (TART) were analyzed. Methods: The clinical, laboratory and imaging data of 3 male patients with 21-OHD and TART, confirmed with CYP21 gene sequencing, from May 2010 to May 2021 in the First Medical Center of Chinese PLA General Hospital were analyzed retrospectively. The treatment strategy and clinical outcome were followed up. Results: All the 3 patients were first diagnosed with bilateral adrenal mass at the age of 27-42 years old. They were 145-162 cm tall. The levels of progesterone, 17-hydroxyprogesterone, and adrenocorticotropic hormone (ACTH) of the 3 patients were relatively high, and that of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) of the 3 patients were low. Testosterone level of 1 patient was significantly elevated, and that of the other 2 patients was below the lower limit of normal range. Testicular ultrasound showed heterogeneous hyperechoic masses in both testes. CT of the adrenal glands showed bilateral adrenal enlargement with mass. All 3 patients were treated with dexamethasone. After 4-96 months of follow-up, 17-hydroxyprogesterone level was kept above the median normal level. One of the patients got married and had a baby after treatment. The sizes of adrenal hyperplasia and testicular masses reduced to various degrees with the change of the testicular masses being proportional to that of adrenal hyperplasia. Conclusions: Patients with 21-OHD are prone to have TART, leading to the impaired testicular function. Early glucocorticold therapy is beneficial to the reduction of TART and restoration of testicular function.