Objective:The effect of bone marrow soluble B cell maturation antigen (sBCMA) expression on the efficacy and side effects of chimeric antigen receptor (CAR) -modified T-cell-targeting B cell maturation antigen (BCMA) in patients with multiple myeloma (MM) .Methods:This study involved 29 patients with relapsed or refractory MM (RRMM) who received humanized anti-BCMA CAR-T cell clinical trials from January 2018 to December 2021. The expression of sBCMA in bone marrow before and after anti-BCMA CAR-T cell treatment was detected by flow cytometry and compared.Results:①Two months after BCMA CAR-T cell treatment, 20 patients (68.97%) achieved an overall response (OR), whereas nine patients had stable disease (SD) or miner emission (MR). ②The expression of sBCMA in the bone marrow of 20 patients with OR was higher before treatment than after [26 926 (18 215, 32 488) ng/L vs 9 968 (6 634, 11 459) ng/L; P<0.001]; no significant difference was observed in patients with MR and SD [41 187 (33 816, 47 046) ng/L vs. 33 954 (31 569, 36 256) ng/L; P=0.145]; sBCMA expression in patients with OR before CAR-T cell treatment was lower than in patients with MR and SD ( P=0.005). ③No significant linear correlation was found between the peak value of CAR-T cells and sBCMA expression in the bone marrow of all 29 patients with RRMM ( R2=0.035, P=0.330). ④No significant difference in sBCMA expression was found between grades 0-1 CRS group (13 patients) and grades 2-4 CRS group [16 patients; 32 045 (18 742, 40 801) ng/L vs 29 102 (24 679, 38 776) ng/L, P=0.879], nor between grade 0 ICANS group (22 patients) and grade 1-3 ICANS group [seven patients; 30 073 (19 375, 40 065) ng/L vs 33 816 (22 933, 43 459) ng/L, P=0.763]. Conclusion:sBCMA expression in the bone marrow is related to the efficacy of BCMA CAR-T cell therapy in patients with RRMM, but is not significantly correlated with the severity of adverse events. It may serve as a predictive biomarker for the efficacy of BCMA CAR-T cell therapy in these patients.

"Toxicity Testing in the 21st Century—A Vision and Strategy"proposed by the National Research Council of US has brought innovative directives and objectives for toxicity evaluation and risk assessment,pushing forward the next generation of toxicity testing and risk assessment.In this initiative,the concept of adverse outcome pathways(AOPs)has emerged as a prominent methodology,capturing the attention of toxicologists and researchers due to its promising applications in recent years.The quantitative AOP(qAOP)is an extension of the adverse outcome pathway,which is built upon the foundational qualitative adverse outcome pathway model and leverages mathematical frame-works to depict dose-response and/or response-response relationships.This article reviews the princi-ples and advancement surrounding qAOP,introduceds two prevalent methodologies for constructing qAOP,Bayesian network models and regression models,and demonstrates diverse applications of qAOP.Actual cases are used to underscore the transformative role of qAOP in contemporary toxicology and risk assessment practices.

Abstract Allergic diseases can occur in all systems of the body, covering the whole life cycle, from children to adults and to old age, can be lifelong onset and even fatal in severe cases. Children account for the largest proportion of the victims of allergic disease, Children s allergies start from scratch, ranging from mild to severe, from less to more, from single to multiple systems and systemic performance, so the prevention and treatment of allergic diseases in children is of great importance, which can not only prevent high risk allergic conditions from developing into allergic diseases, but also further block the process of allergy. At present, there is no consensus on the management system of allergic children in kindergartens and primary schools. The "Consensus on Allergy Management and Prevention in Kindergartens and Primary Schools", which includes the organizational structure, system construction and management of allergic children, provides evidence informed recommendations for the long term comprehensive management of allergic children in kindergartens and primary schools, and provides a basis for the establishment of the prevention system for allergic children.

Objective:To investigate the clinical characteristics and prognostic factors of TCF3-PBX1 fusion gene-positive childhood B-cell precursor acute lymphoblastic leukemia (B-ALL).Methods:The clinical data of 1 287 newly diagnosed children with B-ALL who were admitted to five hospital in Fujian province (Fujian Medical University Union Hospital, the First Affiliated Hospital of Xiamen University, Zhangzhou Affiliated Hospital of Fujian Medical University, Quanzhou First Hospital Affiliated to Fujian Medical University, Nanping First Hospital of Fujian Province) from April 2011 to December 2020 were retrospectively analyzed. According to the results of TCF3-PBX1 fusion gene testing, all the patients were divided into TCF3-PBX1-positive group and TCF3-PBX1-negative group. The clinical characteristics, early treatment response [minimal residual disease (MRD) at middle stage and end of induction chemotherapy] and long-term efficacy [overall survival (OS) and event-free survival (EFS)] of the patients in both groups were compared. Kaplan-Meier method was used for survival analysis. The prognostic factors of TCF3-PBX1-positive B-ALL were analyzed by using Cox proportional hazards model. Among 83 children with TCF3-PBX1-positive B-ALL, the treatment regimens, risk stratification and efficacy evaluation of 62 cases were performed by using Chinese Children's Leukemia Group (CCLG)-ALL 2008 regimen and 21 cases were performed by using Chinese Children's Cancer Group (CCCG)-ALL 2015 regimen, and the efficacy and incidence of serious adverse events (SAE) between the two groups compared.Results:Among 1 287 B-ALL patients, 83 patients (6.4%) were TCF3-PBX1-positive. The proportion of patients with initial white blood cell count (WBC)≥50×10 9/L in the TCF3-PBX1-positive group was higher than that in the TCF3-PBX1-negative group, while the proportions of patients with MRD ≥1% on induction chemotherapy day 15 or day 19, and MRD ≥0.01% on induction chemotherapy day 33 or day 46 in the TCF3-PBX1-positive group were lower than those in the TCF3-PBX1-negative group (all P < 0.05). Univariate Cox regression analysis showed that MRD ≥1% on induction chemotherapy day 15 or day 19 and TCF3-PBX1 ≥0.01% on induction chemotherapy day 33 or day 46 were risk factors for OS and EFS (all P < 0.05). Multivariate analysis showed that MRD ≥1% on induction chemotherapy day 15 or day 19 was an independent risk factor for OS ( HR = 10.589, 95% CI 1.903-58.933, P = 0.007) and EFS ( HR = 10.218, 95% CI 2.429-42.980, P = 0.002). TCF3-PBX1≥0.01% on induction chemotherapy day 33 or day 46 was an independent risk factor for EFS ( HR = 6.058, 95% CI 1.463-25.087, P = 0.013) but not for OS ( HR = 3.550, 95% CI 0.736-17.121, P = 0.115). The 10-year EFS and OS rates of the TCF3-PBX1-positive group were 84.6% (95% CI 76.9%-93.1%) and 89.1% (95% CI 82.1%-96.6%), and the differences between the two groups were not statistically significant (both P > 0.05). Among 80 children who received standardized treatment, compared with children who were treated with CCLG-ALL 2008 regimen, the incidence of infection-related SAE was lower in children who were treated with CCCG-ALL 2015 regimen [0 (0/21) vs. 20.3% (12/59), χ2 = 5.22, P = 0.022], but there were no statistical differences in treatment-related mortality, relapse rate, EFS and OS between the two groups (all P > 0.05). Conclusions:Children with TCF3-PBX1-positive B-ALL have a good prognosis, and MRD≥1% at middle stage of induction chemotherapy and TCF3-PBX1≥0.01% at the end of induction chemotherapy may be influencing factors for poor prognosis. CCCG-ALL 2015 regimen can reduce infection-related SAE while achieving good efficacy.

Objective:To explore the surgical methods and treatment effects of adult anterior dislocation of the sacroiliac joint (AADSJ).Methods:A multi-center retrospective case series study was conducted to analyze the clinical data of 25 cases admitted in 5 clinical centers (affiliations of authors in this article) from January 2016 to January 2021. There were 18 males and 7 females, aged 38.8±15.5 years (range, 18-83 years). The AADSJ clinical classification system was formulated based on the radiographic morphology of anterior dislocation of the sacroiliac joint, which includes two types. Type I: complete anterior dislocation of the sacroiliac joint, and displacement of the entire iliac auricular surface to the front of the sacrum. Type II: fracture of the sacroiliac joint combined with anterior dislocation, subdivided into 3 subtypes. Type IIa: iliac fracture involves the anterior 1/3 of the sacroiliac joint, and dislocation of the ilium anterior to the sacrum. Type IIb: iliac fracture involves the posterior 2/3 of the sacroiliac joint, and dislocation of the ilium anterior to the sacrum. Type IIc: iliac fracture involves the posterior 2/3 of the sacroiliac joint, and dislocation of the ilium anteromedial to the sacrum. The reliability and repeatability of the clinical classification, Tile classification and Young-Burgess classification were performed based on the results of two-phase assessments in four observers. The operations were performed by the lateral-rectus approach and the ilioinguinal approach. The operation time and intraoperative bleeding were recorded. Pelvic X-ray and CT scan were rechecked after the operation. The quality of fracture reduction was evaluated according to Matta score. The postoperative functional rehabilitation was evaluated according to the Majeed rehabilitation standard at one-year follow-up.Results:Among 25 cases in this study, there were 3 cases of Type I, 5 cases of Type IIa, 9 cases of Type IIb and 8 cases of Type IIc according to the clinical classification system. The Kappa values of reliability tests for the clinical classification, Tile classification and Young-Burgess classification were 0.681, 0.328 and 0.383, respectively. The Kappa values of repeatability tests for the clinical classification, Tile classification and Young-Burgess classification were 0.690, 0.221 and 0.395, respectively. The reliability and repeatability of the AADSJ clinical classification were significantly better than other classifications. There were 14 cases underwent lateral rectus abdominis approach and 11 cases underwent ilioinguinal approach. The operative time for managing anterior dislocation of the sacroiliac joint was 122.0±50.7 min (range, 65-148 min) through the lateral rectus abdominis approach, and through the ilioinguinal approach was 178.0±49.9 min (range, 110-270 min), with a significant difference ( t=2.76, P=0.011). The amount of intraoperative blood loss through the lateral rectus approach was 680±330 ml (range, 350-2,120 ml), which was significantly less than that through the ilioinguinal approach (1,660±968 ml, 680-3,300 ml), with a significant difference ( t=3.55, P=0.002). The follow-up period was 1-3 years. At one week after surgery, the quality of fracture reduction evaluated by Matta score showed that the excellent and good reduction rate of the lateral-rectus approach was 79% (11/14), and that of the ilioinguinal approach was 73% (11/14), with no statistically significant difference ( P=1.000). At a one-year follow-up, according to Majeed's criteria, the overall excellent and good rate of the lateral-rectus approach was 64% (9/14), which is similar to 64% (7/11) of that of the ilioinguinal approach. No fracture reduction loss or internal fixation loosening failure occurred. Conclusion:The AADSJ clinical classification system can accurately describe the imaging features and clinical manifestations of AADSJ, with high reliability and repeatability. The AADSJ can be treated by the lateral-rectus approach or the ilioinguinal approach, with similar therapeutic effects but the former having less trauma.

Accurate classification of the acetabular injuries and appropriate treatment plan are great challenges for orthopedic surgeons because of the irregular anatomical structure of the acetabulum and aggregation of important vessels and nerves around it. Letournel-Judet classification system has been widely applied to classify acetabular fractures. However, there are several limitations, including incomplete inclusion of fracture types, difficulty in understanding and insufficient guidance for surgical treatment, etc. Serious complications such as traumatic arthritis are common due to wrong classification and diagnosis and improper selection of surgical strategy, which brings a heavy burden to the society and families. Three-column classification, based on anatomic characteristics, has advantages of containing more fracture types and being easy to understand, etc. To solve the problems existing in the diagnosis and treatment process based on Letournel-Judet classification, achieve accurate diagnosis and treatment of patients with acetabular fractures, and obtain satisfactory prognosis, the Orthopedic Trauma Emergency Center of Third Hospital of Hebei Medical University and the Trauma Orthopedic Branch of the Chinese Orthopedic Association organized experts from relevant fields to formulate the Expert consensus on the accurate diagnosis and treatment of acetabular fractures based on three-column classification ( version 2023) in terms of principles of evidence-based medicine. Based on the three-column classification, 15 recommendations were proposed, covering the diagnosis, treatment, complication prevention and management, etc, so as to provide reference for accurate diagnosis and treatment of acetabular fractures.

Glycosite-specific antibody‒drug conjugatess (gsADCs), harnessing Asn297 N-glycan of IgG Fc as the conjugation site for drug payloads, usually require multi-step glycoengineering with two or more enzymes, which limits the substrate diversification and complicates the preparation process. Herein, we report a series of novel disaccharide-based substrates, which reprogram the IgG glycoengineering to one-step synthesis of gsADCs, catalyzed by an endo-N-acetylglucosaminidase (ENGase) of Endo-S2. IgG glycoengineering via ENGases usually has two steps: deglycosylation by wild-type (WT) ENGases and transglycosylation by mutated ENGases. But in the current method, we have found that disaccharide LacNAc oxazoline can be efficiently assembled onto IgG by WT Endo-S2 without hydrolysis of the product, which enables the one-step glycoengineering directly from native antibodies. Further studies on substrate specificity revealed that this approach has excellent tolerance on various modification of 6-Gal motif of LacNAc. Within 1 h, one-step synthesis of gsADC was achieved using the LacNAc-toxin substrates including structures free of bioorthogonal groups. These gsADCs demonstrated good homogeneity, buffer stability, in vitro and in vivo anti-tumor activity. This work presents a novel strategy using LacNAc-based substrates to reprogram the multi-step IgG glycoengineering to a one-step manner for highly efficient synthesis of gsADCs.

Diabetic nephropathy （DN） is one of the most serious microvascular complications of diabetes and the leading cause of end-stage kidney disease. The onset and progression of DN are linked to the progression of renal fibrosis which is an important pathological feature and final pathological result of various chronic kidney diseases. As a result， therapies against renal fibrosis can help delay the progression of DN. The transforming growth factor-β₁ （TGF-β₁）/Smad signaling pathway is one of the key pathways in renal fibrosis. TGF-β₁， a crucial mediator of renal fibrosis， is highly expressed in the case of fibrosis-associated kidney diseases， and Smads are the main effectors in the TGF-β₁ signal transduction pathway. By activating Smads， TGF-β₁ transports signals from the cytoplasm to the nucleus and regulates the transcription of fibrosis-related target genes， thus exerting the biological effects and promoting the progression of renal fibrosis. In recent years， Chinese medicine has become prominent in the prevention and treatment of DN， and there has been an explosion of research on Chinese medicine in the prevention and treatment of DN through the TGF-β₁/Smad signaling pathway. Based on literature research， this paper reviewed the basic structure of the TGF-β₁/Smad signaling pathway， the relationship with DN， and monomers and extract of Chinese medicine， Chinese patent medicine， and compound Chinese medicine prescriptions in improving and delaying the renal fibrosis based on the TGF-β₁/Smad signaling pathway， and in alleviating inflammatory response and oxidative stress， reducing the accumulation of extracellular matrix， and inhibiting epithelial-mesenchymal transition by regulating the TGF-β₁/Smad signaling pathway. Thereby， this study is expected to provide new mindset for the treatment of DN.

Objective To examine the value of bronchoscopy in the diagnosis of sputum-negative pulmonary tuberculosis in a general hospital.Methods A retrospective study was conducted for the 459 patients treated in a general hospital from June 2010 to May 2015.All the patients had symptoms and radiographic changes suggestive of pulmonary tuberculosis but smearnegative.All patients were subjected to bronchoscopy,including brushing,bronchoalveolar lavage (BAL) and transbronchial biopsy (TBB).The bronchoscopic specimens were submitted for direct smear and acid-fast stain,Mycobacterium tuberculosis culture or histopathological assay,respectively.Results The diagnosis was confirmed by bronchoscopy in 378 (82.4％) of the 459 patients.Of the 378 patients whose diagnosis was confirmed,pulmonary tuberculosis was identified in 238 patients (63.0％).Other diagnoses included bronchogenic carcinoma,non-specific inflammation,organizing pneumonia,pulmonary fungal infection,interstitial pneumonia,sarcoidosis,nontuberculous mycobacterial infection.Of the patients with confirmed diagnosis by bronchoscopy,the sensitivity for diagnosis was 57.95％ by direct smear and acid-fast stain of brushing or BALF,79.78％ by culture of BALF,and 56.93％ by histopathological assay of TBB specimens.The integrated method by combining smear and stain,culture and histopathological assay of TBB specimens could improve the sensitivity,specificity,positive predictive value,and negative predictive value to 91.01％,97.46％,97.98％ and 88.89％.Conclusions For the patients whose clinical manifestations and imaging changes are suggestive of pulmonary tuberculosis but smear-negative,bronchoscopy is a valuable method for the diagnosis,which should be adopted as a routine test in clinical practice.

Objective: To evaluate the intervention effects of response to heatwave in communities of four cities, China. Methods: Baseline survey on heatwave and climate change related knowledge, attitude and practice (KAP) was conducted in the pilot communities in Harbin, Nanjing, Shenzhen and Chongqing, using face-to-face questionnaire interview in November, 2011 to November, 2013. Finally, 1 604 residents were interviewed. Intervention measures were implemented in summers of 2013 and 2014, including delivering early warning information of heatwave health risk and launching health education and promotion. The second survey was conducted in same communities using the same questionnaire and sampling method as baseline survey in November, 2014, and 1 640 residents were interviewed. The Chi-square test was used to compare the demographic characteristics and KAP of community residents between before and after intervention, and the factors that affected the intervention effect were selected by logistic multiple stepwise regression model. Results: The age of the residents interviewed before and after intervention was (46.4 ± 15.5) years and (45.0 ± 15.9) years, respectively. Overall, the residents' awareness rates of heatwave before and after intervention were 70.5% (1 131/1 604) and 82.9% (1 359/1 640) (χ²=69.40, P<0.001). The rate of residents who had wished to receive early warning information increased 6.3% (χ²=41.11, P<0.001), which reached 94.6% (1 551/1 604) after intervention from 88.3% (1 416/1 604) in baseline survey. Both heatwave health risk early warning and health education had big impacts to residents. There were 92.7% (1 105 residents) among the 1 192 residents who had received the early warning information arrange work and rest time according to the early warning information and 93.0% (1 231 residents) among the 1 323 residents who knew about health education activities being conducted in community thought that the community health education activities had made active role in protecting health from heatwaves. After a series of intervention, male had a effect on attitude about hot wave than female in Nanjing and Chongqing, OR (95%CI) were 1.48(1.02-2.16) and 1.45 (1.18-2.05) , respectively; compared with subjects below primary school education, people with college degree or above had higer KAP in all cities (ORs range from 1.18 to 2.05), P<0.05; regular physical exercise (ORs range from 1.39 to 2.70) also had profound impacts on KAP in all cities (P<0.05). Conclusion s Early warning and health education were effective measures to enhance residents' response capacity to climate change.