Immunosuppressive tumor microenvironment contributes to tumor progression in diffuse large B-cell lymphoma upon anti-CD19 chimeric antigen receptor T therapy / 医学前沿

Anti-CD19 chimeric antigen receptor (CAR)-T cell therapy has achieved 40%-50% long-term complete response in relapsed or refractory diffuse large B-cell lymphoma (DLBCL) patients. However, the underlying mechanism of alterations in the tumor microenvironments resulting in CAR-T cell therapy failure needs further investigation. A multi-center phase I/II trial of anti-CD19 CD28z CAR-T (FKC876, ChiCTR1800019661) was conducted. Among 22 evaluable DLBCL patients, seven achieved complete remission, 10 experienced partial remissions, while four had stable disease by day 29. Single-cell RNA sequencing results were obtained from core needle biopsy tumor samples collected from long-term complete remission and early-progressed patients, and compared at different stages of treatment. M2-subtype macrophages were significantly involved in both in vivo and in vitro anti-tumor functions of CAR-T cells, leading to CAR-T cell therapy failure and disease progression in DLBCL. Immunosuppressive tumor microenvironments persisted before CAR-T cell therapy, during both cell expansion and disease progression, which could not be altered by infiltrating CAR-T cells. Aberrant metabolism profile of M2-subtype macrophages and those of dysfunctional T cells also contributed to the immunosuppressive tumor microenvironments. Thus, our findings provided a clinical rationale for targeting tumor microenvironments and reprogramming immune cell metabolism as effective therapeutic strategies to prevent lymphoma relapse in future designs of CAR-T cell therapy.

Effects of different storage conditions on the content of key growth factors in platelet-rich plasma / 中国输血杂志

【Objective】 To study the effects of different storage temperature and different storage time on the activity of key growth factors in platelet-rich plasma(PRP), and to provide a theoretical basis for maximize the role of PRP in clinical treatment. 【Methods】 PRP was collected by blood cell isolation and apheresis, stored at 22℃ and -80℃, respectively. VEGF, TGF-β and PDGF were detected by ELISA. The content of growth factors in PRP was detected when stored at 22℃for 1, 3 and 5 days, and the growth factors content of PRP stored at 22℃ for 3 days was detected after thrombin activation for 0.5, 1 and 1.5 hours. The content of growth factor in frozen PRP (stored at -80℃ for 30 days after initial 3-days storage at 22℃ ) and fresh PRP (stored at 22℃ for 3 days) was compared. The growth factor content in PRP frozen at - 80℃ for 30, 60 and 180 days, and the growth factor content in PRP frozen at -80℃ for 180 days after repeated freeze-thaw for 1, 2, 3, 5 and 10 times were detected. 【Results】 The growth factor content of apheresis PRP was significantly higher than that of platelet-poor plasma. No statistical difference was noticed in VEGF, TGF-β and PDGF content in PRP at 1, 3 and 5 days stored at 22℃; no statistical difference was noticed in VEGF, TGF-β and PDGF content in PRP stored at 22℃ for 3 days after thrombin activation for 0.5, 1 and 1.5 hours. There was no statistically significant difference in growth factor content between PRP stored at 22℃ for 3 days versus frozen at -80℃ for 30 days after initial 3-days storage at 22℃. No statistical difference was found in VEGF, TGF-β and PDGF contents in frozen PRP repeatedly frozen and thawed for 1 to 10 times. 【Conclusion】 Apheresis PRP can release a large amount of growth factors after activation. Fresh PRP stored at 22℃ for 5 days or frozen at -80℃ for 180 days has no impact on the content of growth factors, and frozen PRP at -80℃ can achieve long-term, effective and safe preservation, which is conducive to multiple use of PRP in treatment.

Efficiency and safety analysis of Plerixafor combined with granulocyte colony-stimulating factor on autologous hematopoietic stem cell mobilization in lymphoma / 中华血液学杂志

Objective: To evaluate the advantages and safety of Plerixafor in combination with granulocyte colony-stimulating factor (G-CSF) in autologous hematopoietic stem cell mobilization of lymphoma. Methods: Lymphoma patients who received autologous hematopoietic stem cell mobilization with Plerixafor in combination with G-CSF or G-CSF alone were obtained. The clinical data, the success rate of stem cell collection, hematopoietic reconstitution, and treatment-related adverse reactions between the two groups were evaluated retrospectively. Results: A total of 184 lymphoma patients were included in this analysis, including 115 cases of diffuse large B-cell lymphoma (62.5%) , 16 cases of classical Hodgkin's lymphoma (8.7%) , 11 cases of follicular non-Hodgkin's lymphoma (6.0%) , 10 cases of angioimmunoblastic T-cell lymphoma (5.4%) , 6 cases of mantle cell lymphoma (3.3%) , and 6 cases of anaplastic large cell lymphoma (3.3%) , 6 cases of NK/T-cell lymphoma (3.3%) , 4 cases of Burkitt's lymphoma (2.2%) , 8 cases of other types of B-cell lymphoma (4.3%) , and 2 cases of other types of T-cell lymphoma (1.1%) ; 31 patients had received radiotherapy (16.8%) . The patients in the two groups were recruited with Plerixafor in combination with G-CSF or G-CSF alone. The baseline clinical characteristics of the two groups were basically similar. The patients in the Plerixafor in combination with the G-CSF mobilization group were older, and the number of recurrences and third-line chemotherapy was higher. 100 patients were mobilized with G-CSF alone. The success rate of the collection was 74.0% for one day and 89.0% for two days. 84 patients in the group of Plerixafor combined with G-CSF were recruited successfully with 85.7% for one day and 97.6% for two days. The success rate of mobilization in the group of Plerixafor combined with G-CSF was substantially higher than that in the group of G-CSF alone (P=0.023) . The median number of CD34(+) cells obtained in the mobilization group of Plerixafor combined with G-CSF was 3.9×10(6)/kg. The median number of CD34(+) cells obtained in the G-CSF Mobilization group alone was 3.2×10(6)/kg. The number of CD34(+) cells collected by Plerixafor combined with G-CSF was considerably higher than that in G-CSF alone (P=0.001) . The prevalent adverse reactions in the group of Plerixafor combined with G-CSF were grade 1-2 gastrointestinal reactions (31.2%) and local skin redness (2.4%) . Conclusion: The success rate of autologous hematopoietic stem cell mobilization in lymphoma patients treated with Plerixafor combined with G-CSF is significantly high. The success rate of collection and the absolute count of CD34(+) stem cells were substantially higher than those in the group treated with G-CSF alone. Even in older patients, second-line collection, recurrence, or multiple chemotherapies, the combined mobilization method also has a high success rate of mobilization.

Analysis of prognosis and influencing factors of No. 253 lymph node metastasis in descending colon, sigmoid colon, and rectal cancer: a multicenter study / 中华外科杂志

Objectives: To analyze the influencing factors of No. 253 lymph node metastasis in descending colon cancer, sigmoid colon cancer, and rectal cancer, and to investigate the prognosis of No. 253 lymph node-positive patients by propensity score matching analysis. Methods: A retrospective analysis was performed on clinical data from patients with descending colon cancer, sigmoid colon cancer, rectosigmoid junction cancer, and rectal cancer who underwent surgery between January 2015 and December 2019 from the Cancer Hospital of the Chinese Academy of Medical Sciences, China-Japan Friendship Hospital, Peking Union Medical College Hospital, General Hospital of the Chinese People's Liberation Army, and Peking University Cancer Hospital. A total of 3 016 patients were included according to inclusion and exclusion criteria, comprising 1 848 males and 1 168 females, with 1 675 patients aged≥60 years and 1 341 patients aged<60 years. Clinical and pathological factors from single center data were subjected to univariate analysis to determine influencing factors of No. 253 lymph node metastasis, using a binary Logistic regression model. Based on the results of the multivariate analysis, a nomogram was constructed. External validation was performed using data from other multicenter sources, evaluating the effectiveness through the area under the receiver operating characteristic curve and the calibration curve. Using data from a single center, the No. 253 lymph node-positive group was matched with the negative group in a 1∶2 ratio (caliper value=0.05). Survival analysis was performed using the Kaplan-Meier method and Log-rank test. The Cox proportional hazards model was used to determine independent prognostic factors. Results: (1) The tumor diameter≥5 cm (OR=4.496,95%CI:1.344 to 15.035, P=0.015) T stage (T4 vs. T1: OR=11.284, 95%CI:7.122 to 15.646, P<0.01), N stage (N2 vs. N0: OR=60.554, 95%CI:7.813 to 469.055, P=0.043), tumor differentiation (moderate vs. well differentiated: OR=1.044, 95%CI:1.009 to 1.203, P=0.044; poor vs. well differentiated: OR=1.013, 95%CI:1.002 to 1.081, P=0.013), tumor location (sigmoid colon vs. descending colon: OR=9.307, 95%CI:2.236 to 38.740, P=0.002), pathological type (mucinous adenocarcinoma vs. adenocarcinoma: OR=79.923, 95%CI:15.113 to 422.654, P<0.01; signet ring cell carcinoma vs. adenocarcinoma: OR=27.309, 95%CI:4.191 to 177.944, P<0.01), and positive vascular invasion (OR=3.490, 95%CI:1.033 to 11.793, P=0.044) were independent influencing factors of No. 253 lymph node metastasis. (2) The area under the curve of the nomogram prediction model was 0.912 (95%CI: 0.869 to 0.955) for the training set and 0.921 (95%CI: 0.903 to 0.937) for the external validation set. The calibration curve demonstrated good consistency between the predicted outcomes and the actual observations. (3) After propensity score matching, the No. 253 lymph node-negative group did not reach the median overall survival time, while the positive group had a median overall survival of 20 months. The 1-, 3- and 5-year overall survival rates were 83.9%, 61.3% and 51.6% in the negative group, and 63.2%, 36.8% and 15.8% in the positive group, respectively. Multivariate Cox analysis revealed that the T4 stage (HR=3.067, 95%CI: 2.357 to 3.990, P<0.01), the N2 stage (HR=1.221, 95%CI: 0.979 to 1.523, P=0.043), and No. 253 lymph node positivity (HR=2.902, 95%CI:1.987 to 4.237, P<0.01) were independent adverse prognostic factors. Conclusions: Tumor diameter ≥5 cm, T4 stage, N2 stage, tumor location in the sigmoid colon, adverse pathological type, poor differentiation, and vascular invasion are influencing factors of No. 253 lymph node metastasis. No. 253 lymph node positivity indicates a poorer prognosis. Therefore, strict dissection for No. 253 lymph node should be performed for colorectal cancer patients with these high-risk factors.

Recognition of empty pelvic syndrome and its prevention and treatment / 中华胃肠外科杂志

With the development of existing surgical techniques, equipment and treatment concepts, more and more medical centers begin to carry out extensive resection for recurrent pelvic malignant tumors or those with multivisceral invasion. Exenteration may facilitate curative resection and improve the outcome of the patients. Therefore, pelvic exenteration has gradually become the standard of care for locally advanced pelvic malignancies. At present, pelvic exenteration leads to high intraoperative and postoperative complications and mortality, and therefore compromise the safety and long-term quality of life. Cumulating evidences suggest remnant cavity after exenteration might trigger the pathophysiological process and cause downstream complications which can be defined as empty pelvis syndrome. The literature related to empty pelvic syndrome was summarized, the possible cause of empty pelvic syndrome was analyzed. After the pelvic exenteration, the closed pelvic residual cavity formed continuous negative pressure with the gradual absorption of air in the cavity, bacterial propagation, and accumulation of fluid, which had an impact on the distribution of organs in the abdominal and pelvic cavity. At the same time, whether physical processes also play a role in the occurrence of empty pelvic syndrome remains to be explored. It is concluded that the diagnosis is mainly based on the patient's medical history, clinical manifestations and radiological findings, and the history of pelvic exenteration is the most important indicator in the diagnosis. In terms of prevention measures, we should identify the high-risk groups of the occurrence of empty pelvic syndrome, and then take accurate and individualized preventive measures. Various new biomaterials have more advantages in preventive pelvic cavity filling than traditional human tissue filling. Mesentery plays an important role in the morphology, peristalsis and arrangement of the small intestine. More attention should be paid to reducing the ectopic placement of the small intestine into the pelvic cavity by protecting the mesentery structure and restoring or rebuilding the mesentery morphology. In terms of treatment measures, there is still a lack of standard treatment pathway for empty pelvic syndrome.

The Moderated Mediating Effects of Nutrition and Physical Activity Between Fatigue and Quality of Life in Childhood Cancer Survivors

Purpose@#The aim of this study was to investigate the associations between nutrition, physical activity, fatigue, and quality of life (QoL) among childhood cancer survivors. The specific purpose was to examine whether nutrition mediated and physical activity moderated the relationship between fatigue and QoL in this population. @*Methods@#A pooled sample of 120 childhood cancer survivors was recruited at pediatric oncology wards and ambulatory settings between August 2020 and May 2021. We collected data on participants’ demographic characteristics, fatigue, nutritional status, physical activity, and QoL. We then adapted Hayes Process Macro to examine the mediating and moderating effects of nutrition and physical activity on the relationship between fatigue and QoL. @*Results@#In models adjusted for age and sex, (1) the simple mediation analysis identified the mediating effect of nutrition on the relationship between fatigue and QoL; and (2) the mediation and moderation analysis identified that the direct effect of nutrition between fatigue and QoL was significant when adding (a) physical activity and (b) fatigue × physical activity. There were significantly decreasing trends in physical activity at 1 standard deviation below the mean and at the mean, but not at 1 standard deviation above the mean. @*Conclusions@#Our findings demonstrate that nutrition mediated and physical activity moderated the relationship between fatigue and QoL. This highlights an opportunity to enhance QoL among childhood cancer survivors through healthy lifestyle interventions. To ensure that future interventions address children's needs and promote the greatest impact, such interventions should include nutrition and physical activity components that involve nurses, pediatric oncology physicians, nutritionists, and physical therapists.Keyword

Comparative study of surgical effects on patients with mixed deafness and otosclerosis with different air bone conduction differences / 中华耳鼻咽喉头颈外科杂志

Objective: To analyze the surgical efficacy of patients with mixed hearing loss and otosclerosis with different air bone gap (ABG) before surgery, and to provide reference for the prognosis evaluation of otosclerosis surgery. Methods: The clinical data of 108 cases(116 ears) of otosclerosis who had undergone stapes fenestration technique artificial stapes implantation in Xiangya Hospital of Central South University from November 2013 to May 2020 and had mixed hearing loss before surgery were collected, including 71 women(76 ears)and 37 men (40 ears), with an average age of 38.5 years. According to preoperative pure tone audiometry ABG, they were divided into three groups: group S, 15 dB≤ABG<31 dB, a total of 39 ears; group M, 31 dB≤ABG<46 dB, a total of 58 ears; and group L, ABG≥46 dB, 19 ears in total. The hearing outcomes of three groups of patients at 6-12 months after surgery were compared and analyzed using SPSS 24.0 statistical software. Results: A total of 3 patients (group S: 2 cases; group L: 1 case) experienced severe sensorineural hearing loss after surgery and were not included in the statistical analysis. After surgery, the pure tone hearing threshold of patients with otosclerosis in each group was significantly improved compared to before surgery, with an average air conduction threshold improvement of(21.6±13.4) dB. The difference between before and after surgery was statistically significant(t=17.13, P<0.01). The average bone conduction threshold improved by(3.7±7.6) dB, and the difference was statistically significant before and after surgery(t=5.20, P<0.01). The postoperative ABG was(18.3±9.3) dB, which was significantly reduced compared to preoperative(36.2±8.6)dB. Among the three groups of patients, the L group had the highest improvement in air conduction threshold[(29.9±10.8)dB], while the S group had the lowest improvement[(15.7±11.4)dB]. There was no statistically significant difference in post operative pure tone hearing thresholds between the three groups(P>0.05). The postoperative ABG in group S was the smallest[(16.5±9.0)dB], while in group L, the postoperative ABG was the largest[(20.5±10.0)dB]. Compared with group S, group M and group L still had a large residual ABG at 2 000 Hz after surgery. The bone conduction threshold of both S and M groups improved to some extent after surgery compared to before (P<0.01). Conclusions: Surgery can benefit patients with mixed hearing loss and otosclerosis with different preoperative ABG. Patients with small preoperative ABG have better surgical results and ideal ABG closure at all frequencies after surgery. Patients with large preoperative ABG can significantly increase the gas conduction threshold during surgery, but certain frequencies of ABG may still be left behind after surgery. The improvement effect of surgery on bone conduction threshold is not significant. Patients should be informed of treatment methods such as hearing aids based on their actual situation for selection.

The effect of water improvement on iodine nutritional status and thyroid function of pregnant women in areas with high water iodine level / 中华地方病学杂志

Objective:To investigate the impact of switching to low iodine drinking water in areas with high water iodine levels on the iodine nutritional status and thyroid function of pregnant women.Methods:A cross-sectional survey was conducted in Gaoqing County, Zibo City, Shandong Province. Pregnant women who underwent prenatal examinations at the Obstetrics Clinic of Gaoqing County People's Hospital from 2019 to 2021 were selected as the survey subjects. With reference to the Criteria for the Classification of Water Source High Iodine Areas and High Iodine Disease Areas (GB/T 19380-2016), pregnant women with drinking water iodine > 100 μg/L were considered as the high water iodine group and ≤100 μg/L was the non-high water iodine group. Basic information, one random urine sample, fasting blood sample, 24-hour urine sample and drinking water sample of pregnant women were collected, and thyroid ultrasound examination was performed on pregnant women. Urinary iodine (UI) concentration (UIC) and drinking water iodine concentration (WIC) were measured by inductively coupled plasma mass spectrometry, and 24-hour urinary iodine excretion (UIE) and daily iodine intake (TII) of pregnant women were calculated. Serum thyroid hormone (TSH), free triiodothyronine (FT 3), free thyroxine (FT 4), thyroid peroxidase antibody (TPOAb) and anti-thyroid autoantibodies (TgAb) were determined by automatic chemiluminescence immunoassay. Creatinine (CR) was determined using deproteinized endpoint microplate method and UI/CR was calculate. Results:A total of 797 pregnant women were included, and the UIC was 150.2 (88.1, 281.3) μg/L, the iodine nutrition was generally at an appropriate level. Among them, 584 pregnant women in the non-high water iodine group had a UIC of 120.9 (74.9, 191.5) μg/L, which was at the iodine deficiency level; 213 pregnant women in the high water iodine group had a UIC of 321.1 (201.9, 569.1) μg/L, which was at the iodine super-appropriate level; the differences in WIC, UIC, UIE, TII, and UI/CR between the two groups were statistically significant ( Z = 21.63, 13.34, 15.14, 15.14, 11.81, P < 0.001). After stratification by different gestational periods, the differences were statistically significant when comparing WIC and TSH in pregnant women in the non-high water iodine group and UI/CR in pregnant women in the high water iodine group by gestational period ( H = 59.13, 7.30, 13.60, P < 0.05). A total of 744 pregnant women were tested for thyroid function, and 128 cases of TSH > 2.5 mU/L, 15 cases of hypothyroxemia, and 19 cases of subclinical hypothyroidism were detected, with detection rates of 17.2%, 2.0%, and 2.6%, respectively. The differences were statistically significant when comparing TSH and TPOAb levels and the proportion of pregnant women with TSH > 2.5 mU/L in the high water iodine and non-high water iodine groups ( Z = 3.04, - 2.17, χ 2 = 6.94, P = 0.002, 0.030, 0.008). The thyroid glands of pregnant women were examined in 720 cases, and 30 cases of goiter and 150 cases of thyroid nodules were detected, with detection rates of 4.2% and 20.8%, respectively. The median thyroid volume was 8.92 ml in the high water iodine group and 8.60 ml in the non-high water iodine group, which were both within the normal range, with no statistically significant difference between the groups ( Z = - 0.75, P = 0.455). Conclusions:After changing to low iodine water, the overall iodine nutrition of pregnant women in Gaoqing County is now at an appropriate level, and the reduction of water iodine effectively reduces the risk of TSH abnormalities in local pregnant women. However, pregnant women in the non-high water iodine group are iodine deficiency, and pregnant women in the high water iodine group are at iodine super-appropriate, and the iodine nutrition level of pregnant women in this area is highly variable, which causes the "illusion" that the overall iodine level of local pregnant women is suitable.

Perceptions on using the International Caries Detection and Assessment System (ICDAS) among Malaysian private dentists: a qualitative study / Percepções sobre o uso do Sistema Internacional de Detecção e Avaliação de Cárie (ICDAS) entre dentistas privados da Malásia: um estudo qualitativo

Objetivo: explorar as percepções de dentistas particulares da Malásia sobre o uso do Sistema Internacional de Detecção e Avaliação de Cárie (ICDAS) em sua prática odontológica. Material e Métodos: este estudo qualitativo envolveu entrevistas individuais com doze clínicos gerais que trabalham no setor privado, que foram expostos ao treinamento ICDAS durante seu estudo de graduação. Uma amostra intencional foi realizada com dentistas particulares na Malásia de vários estados com intuito de refletir a diversidade. As entrevistas foram gravadas e transcritas. A análise dos dados foi realizada pela análise temática. Resultados: cinco barreiras principais foram identificadas durante o processo de codificação, ou seja, fatores como o tempo, falta de treinamento, o não planejamento do tratamento, dificuldades de registro e baixa conscientização do paciente sobre prevenção. Foram identificados como fatores facilitadores um melhor treinamento e uma forte exigência das autoridades para usar este sistema. Conclusão: dentistas particulares na Malásia encontraram uma infinidade de desafios na adoção do índice ICDAS. Portanto, é necessário fornecer treinamento e assistência adequados para entender os benefícios da utilização do sistema ICDAS e da informatização da entrada de dados (AU)

Objective: to explore the perceptions of Malaysian private dentists on the use of the International Caries Detection and Assessment System (ICDAS) in their dental practice. Material and Methods: this qualitative study involved individual interviews with twelve general dental practitioners working in the private sector, who has been exposed to ICDAS training during their undergraduate study. Purposive sampling was carried out among private dentists in Malaysia from various states to reflect diversity. The interviews were recorded and transcribed. Data analysis was conducted by thematic analysis. Results: five main barriers were identified through the coding process, namely time factors, lack of training, having no effect on treatment planning, charting difficulties, and low patient awareness on prevention. Better training and a strong requirement by the authorities to use this system were identified as the enabling factors. Conclusion: private dentists in Malaysia encountered a myriad of challenges in adopting the ICDAS index. Hence, it is necessary to provide adequate training and assistance in understanding the benefits of utilizing the ICDAS system, and computerization of data input (AU)

Study on quantitative detection of bacterial endotoxin in recombinant novel coronavirus vaccine (CHO cell) by micro-dynamic chromogenic / 中国药理学通报

Aim To explore the feasibility of the micro- dynamic chromogenic method for quantitative detection of bacterial endotoxin in recombinant novel coronavirus vaccine ( CHO cell).Methods The micro-dynamic color method of Limulus reagent was used to establish a bacterial endotoxin standard curve.The dilution factor was determined through interference pre -experiment, the recoverv rate of the endotoxin added to the test so- J lution was determined, and the interference test to complete the quantitative detection test of the bacterial endotoxin content in the test product was performed, and the results were compared with those of the gel-clot method.Results Hie linear range of the concentration of the standard curve was 0.02 to 2.0 EU • mL 1 , and the regression equation of the standard curve was lgT =-0.302 7 lgC +2.858 7( r = 0.998 9).When recombinant novel coronavirus vaccine ( CHO cell) was cliluted 40 times or below, the micro -dynamic chromogenic reagent did not interfere with the bacterial endotoxin agglutination reaction, and the recovery rate was 50% to 200%.The test results were consistent with the gel- clot method.Conclusions The micro-dynamic chromogenic method can be used for the quantitative detection of bacterial endotoxins in recombinant novel coronavirus vaccine ( CHO cell) with accurate results, high sensitivity, and process monitoring.

Transport mechanism of bergenin aross MDCK-MDRl cell monolayer model / 中国药理学通报

Aim To study the transport mechanism of bergenin passing through blood-brain barrier ( BBB ) . Methods MTT assay was used to investigate the tox-icity of bergenin on MDCK-MDRl cells. Molecular docking was used to predict the binding mode and effect ability of bergenin with P-gp. In vitro MDCK-MDRl cell monolayer model was used to analyze trans¬port characteristics of bergenin and the effect of con¬centration, time and verapamil (a P-gp inhibitor) on the transport of bergenin. Results Bergenin was non-toxic to MDCK-MDRl cells within the concentration of 5 to 40 jjunol • L . There was hydrogen-bond and hy-drophobic interaction between P-gp and bergenin, and P-gp-bergenin was more stable than P-gp-verapamil. The P value of bergenin transported from AP to BL (PappAP

Delay in anticoagulation in patients with cerebral venous sinus thrombosis: influencing factors and its effect on outcome / 国际脑血管病杂志

Objective:To investigate the factors associated with delay in anticoagulant therapy in patients with cerebral venous sinus thrombosis (CVST) and its effect on outcome.Methods:Patients with CVST admitted to Changhai Hospital, Naval Medical University from January 2010 to August 2021 were retrospectively enrolled. Patients were divided into early anticoagulation group and late anticoagulation group by the median time interval from first symptom to initiation of anticoagulation. The modified Rankin Scale was used for outcome assessment at 90 d after onset. 0-2 scores were defined as good outcome and 3-6 were defined as poor outcome. Demographic and clinical data were compared for the early versus late anticoagulation group and for the good versus poor outcome groups. Multivariable logistic regression was used to identify independent influencing factors of delay in anticoagulation and the correlation of delay in anticoagulation with poor outcome. Results:A total of 131 patients were included, their age was 40.07±15.11 years old, and 68 (51.91%) were male. Of these, 65 patients (49.62%) were in the early anticoagulation group and 14 (10.69%) were in the poor outcome group. Compared with the late anticoagulation group, the early anticoagulation group had a significantly higher proportion of patients with seizures and brain parenchymal damage as well as higher D-dimer levels on admission, while the proportion of patients with visual impairment/papilloedema was significantly lower (all P<0.05). Compared with the good outcome group, the poor outcome group had significantly higher proportions of patients with seizures, dyskinesia, impaired consciousness, low Glasgow Coma Scale score, and brain parenchymal damage as well as higher D-dimer, total cholesterol and low density lipoprotein cholesterol levels, sites of thrombus involvement were more common in the superior sagittal and straight sinuses, and significantly lower proportions of patients with headache and lower albumin levels on admission (all P<0.05). Multivariate logistic regression analysis showed that visual impairment/papilloedema (odds ratio [ OR] 0.119, 95% confidence interval [ CI] 0.030-0.473; P=0.002) and brain parenchymal damage ( OR 1.341, 95% CI 1.042-1.727; P=0.023) were independently associated with a delay in anticoagulation treatment, and a delay in anticoagulation treatment ( OR 6.102, 95% CI 1.185-30.504; P=0.030) and D-dimer level on admission ( OR 1.299, 95% CI 1.141-1.480; P<0.001) were the independent predictors of poor outcome in patients with CVST. Conclusions:Visual impairment/papilloedema and absence of brain parenchymal damage on cranial imaging are the independent risk factors for delay in anticoagulation in patients with CVST. The delay in anticoagulation is strongly associated with the poor outcome in patients with CVST.

Role of interaction between reactive oxygen species and ferroptosis pathway in methylglyoxal-induced injury in mouse embryonic osteoblasts / 南方医科大学学报

OBJECTIVE@#To explore the interaction between reactive oxygen species (ROS) and ferroptosis in methylglyoxalinduced injury of mouse embryonic osteoblasts (MC3T3-E1 cells).@*METHODS@#MC3T3-E1 cells were treated with methylglyoxal to establish a cell model of diabetic osteoporosis. CCK-8 assay was used to detect the viability of MC3T3-E1 cells. Rhodamine 123 staining followed by photofluorography was used to examine mitochondrial membrane potential (MMP). The intracellular ROS level was detected by 2', 7'-dichlorodihydrofluorescein diacetate staining with photofluorograph. Alkaline phosphatase (ALP) activity in the cells was detected using an ALP kit, the number of mineralized nodules was determined with alizarin red S staining, and the level of iron ions was detected using a detection kit. The expression level of glutathione peroxidase 4 (GPX4, a marker protein that inhibits ferroptosis) in the osteoblasts was determined using Western blotting.@*RESULTS@#Treatment of MC3T3-E1 cells with 0.6 mmol/L methylglyoxal for 24 h significantly inhibited the expression level of GPX4 (P < 0.001), increased intracellular iron ion concentration, decreased the cell viability, increased the loss of MMP and intracellular ROS level, decreased both ALP activity and the number of mineralized nodules in the cells (P < 0.001). Co-treatment of MC3T3-E1 cells with 2 mmol/L N-acetylcysteine (NAC, a ROS scavenger) and methylglyoxal significantly increased the expression level of GPX4 (P < 0.01); co-treatment with 4 mmo/L FER-1 (a ferroptosis inhibitor) and methylglyoxal obviously decreased the intracellular ROS level (P < 0.001). Co-treatment of the cells either with NAC and methylglyoxal or with FER-1 and methylglyoxal attenuated methylglyoxal-induced injuries in the osteoblasts (P < 0.001).@*CONCLUSION@#The interaction between ROS and ferroptosis pathway plays an important role in methylglyoxal-induced injury of mouse embryonic osteoblasts.

Resting state functional magnetic imaging resonance research in depression combined with cognitive impairment / 中华行为医学与脑科学杂志

Cognitive impairment is one of the important clinical manifestations in depression. The particularly vulnerable cognition domains included executive function, attention, memory, and processing speed. Depression with cognitive impairment is not only a predictor of poor efficacy, but also closely related to dementia. Previous studies have suggested that multiple physiological mechanisms may be altered between depression and cognitive impairment. With the rapid development of neuroimaging technology, resting state functional magnetic resonance imaging has been widely used to explore the neurobiological mechanisms of depression and cognitive impairment. After reviewing the resting-state functional MRI manifestations of the comorbidity, it was found that the default mode network, cognitive control network, and salience network were activated or weakened in the brain. In addition, the inter-network functional connectivity was altered with the co-existence of impairment and compensation. The aforementioned changes of brain function are expected to be the therapeutic targets for depression with cognitive dysfunction.

Assessment of the Benefits of Targeted Interventions for Pandemic Control in China Based on Machine Learning Method and Web Service for COVID-19 Policy Simulation / 生物医学与环境科学（英文）

Taking the Chinese city of Xiamen as an example, simulation and quantitative analysis were performed on the transmissions of the Coronavirus Disease 2019 (COVID-19) and the influence of intervention combinations to assist policymakers in the preparation of targeted response measures. A machine learning model was built to estimate the effectiveness of interventions and simulate transmission in different scenarios. The comparison was conducted between simulated and real cases in Xiamen. A web interface with adjustable parameters, including choice of intervention measures, intervention weights, vaccination, and viral variants, was designed for users to run the simulation. The total case number was set as the outcome. The cumulative number was 4,614,641 without restrictions and 78 under the strictest intervention set. Simulation with the parameters closest to the real situation of the Xiamen outbreak was performed to verify the accuracy and reliability of the model. The simulation model generated a duration of 52 days before the daily cases dropped to zero and the final cumulative case number of 200, which were 25 more days and 36 fewer cases than the real situation, respectively. Targeted interventions could benefit the prevention and control of COVID-19 outbreak while safeguarding public health and mitigating impacts on people's livelihood.

Change in intestinal flora after treatment in children with focal epilepsy / 中国当代儿科杂志

OBJECTIVES@#To study the difference in intestinal flora between children with focal epilepsy and healthy children and the change in intestinal flora after treatment in children with epilepsy.@*METHODS@#A total of 10 children with newly diagnosed focal epilepsy were recruited as the case group and were all treated with oxcarbazepine alone. Their clinical data were recorded. Fecal specimens before treatment and after 3 months of treatment were collected. Fourteen aged-matched healthy children were recruited as the control group. Total bacterial DNA was extracted from the fecal specimens for 16S rDNA sequencing and bioinformatics analysis.@*RESULTS@#After 3 months of carbamazepine treatment, the seizure frequency was reduced by >50% in the case group. At the phylum level, the abundance of Actinobacteria in the case group before treatment was significantly higher than that in the control group (P<0.05), and it was reduced after treatment (P<0.05). At the genus level, the abundances of Escherichia/Shigella, Streptococcus, Collinsella, and Megamonas in the case group before treatment were significantly higher than those in the control group (P<0.05), and the abundances of these bacteria decreased significantly after treatment (P<0.05).@*CONCLUSIONS@#There is a significant difference in intestinal flora between children with focal epilepsy and healthy children. Oxcarbazepine can significantly improve the symptoms and intestinal flora in children with epilepsy.

Surgical management and molecular diagnosis of persistent Müllerian duct syndrome in Chinese patients / 亚洲男科学杂志(英文版)

Persistent Müllerian duct syndrome (PMDS) is a rare clinically and genetically overlapping disorder caused by mutations in the anti-Müllerian hormone (AMH) gene or the anti-Müllerian hormone receptor type 2 (AMHR2) gene. Affected individuals present uterus and tubes in normally virilized males and are discovered unexpectedly during other surgeries. Since it is rare and complex, a definitive clinical diagnosis can be missed, and there are no guidelines regarding how to deal with the uterus. In the present study, exome sequencing and Sanger verification were performed for causal variants in 12 PMDS patients. Preoperative diagnoses were made by positive exome sequencing in 8 patients. Of them, 7 patients evoked on the basis of ultrasound indicating bilateral testes on the same side of the body. Twelve different AMH variants (2 frameshift/nonsense, 1 deletion, 8 missense, and 1 in-frame) in 9 patients and 6 different AMHR2 variants (5 missense and 1 splicing) in 3 patients were identified. Seven variants were classified as "pathogenic" or "likely pathogenic", and 4 of them were novel. All but two patients with AMH defects showed low serum AMH concentrations, but all patients with AMHR2 defects showed elevated AMH levels. During surgery, an abnormal vas deferens was observed in half of the patients. Eight patients underwent orchidopexy with uterine preservation. Of them, 2 patients presented complications including irreducible cryptorchidism, and 3 patients developed Müllerian remnant cysts. Three patients underwent subtotal hysterectomy. Of them, one patient had complication of injury to the vas deferens, and one had hemorrhage after operation. This is the first report of PMDS involving a large Chinese population. The present study not only expands the variation spectrum but also provides clinical experience about the management of the uterus.

Metabolic engineering study on biosynthesis of 4-hydroxybenzyl alcohol from L-tyrosine in Escherichia coli / 中国中药杂志

As an important active ingredient in the rare Chinese herb Gastrodiae Rhizoma and also the main precursor for gastrodin biosynthesis, 4-hydroxybenzyl alcohol has multiple pharmacological activities such as anti-inflammation, anti-tumor, and anti-cerebral ischemia. The pharmaceutical products with 4-hydroxybenzyl alcohol as the main component have been increasingly favored. At present, 4-hydroxybenzyl alcohol is mainly obtained by natural extraction and chemical synthesis, both of which, however, exhibit some shortcomings that limit the long-term application of 4-hydroxybenzyl alcohol. The wild and cultivated Gastrodia elata resources are limited. The chemical synthesis requires many steps, long time, and harsh reaction conditions. Besides, the resulting by-products are massive and three reaction wastes are difficult to treat. Therefore, how to artificially prepare 4-hydroxybenzyl alcohol with high yield and purity has become an urgent problem facing the medical researchers. Guided by the theory of microbial metabolic engineering, this study employed the genetic engineering technologies to introduce three genes ThiH, pchF and pchC into Escherichia coli for synthesizing 4-hydroxybenzyl alcohol with L-tyrosine. And the fermentation conditions of engineering strain for producing 4-hydroxybenzyl alcohol in shake flask were also discussed. The experimental results showed that under the conditions of 0.5 mmol·L~(-1) IPTG, 15 ℃ induction temperature, and 40 ℃ transformation temperature, M9 Y medium containing 200 mg·L~(-1) L-tyrosine could be transformed into(69±5)mg·L~(-1) 4-hydroxybenzyl alcohol, which has laid a foundation for producing 4-hydroxybenzyl alcohol economically and efficiently by further expanding the fermentation scale in the future.

Discussion on Technical Evaluation Requirements of Allergen Detection Reagent Pre-marketing / 中国医疗器械杂志

In the perspective of technical evaluation, the pre-marketing regulatory requirements of allergen detection reagents in China, America, European Union were compared, and the regulatory risks and performance requirements of this product were analyzed based on the monitoring of post-marketing adverse events, reference standards and domestic and foreign regulatory documents. In view of the "neck-stuck" problems such as the difficulty of clinical trials, the difficulty of finding comparable contrast reagents and the lack of clinical diagnostic gold standards, this paper discusses and gives regulatory suggestions, with a view to providing technical reference for product R&D, production, evaluation, approval and supervision in this field.

A prediction model of pathological complete response in patients with locally advanced rectal cancer after PD-1 antibody combined with total neoadjuvant chemoradiotherapy based on MRI radiomics / 中华胃肠外科杂志

Objective: To construct a prediction model of pathologic complete response (pCR) in locally advanced rectal cancer patients who received programmed cell death protein-1 (PD-1) antibody and total neoadjuvant chemoradiotherapy by using radiomics based on MR imaging data and to investigate its predictive value. Methods: A clinical diagnostic test study was carried out. Clinicopathalogical and radiological data of 38 patients with middle-low rectal cancer who received PD-1 antibody combined with total neoadjuvant chemoradiotherapy and underwent TME surgery from January 2019 to September 2021 in our hospital were retrospectively collected. Among 38 patients, 23 were males and 15 were females with a median age of 68 (47-79) years and 13 (34.2%) a chieved pCR. These 38 patients were stratified and randomly divided into the training group (n=26) and test group (n=12) for modeling. All the patients underwent rectal MRI before treatment. The clinical, imaging and radiomics features of all the patients were collected, and the clinical feature model and radiomics model were constructed. The receiver operating characteristic (ROC) curves of each model were drawn, and the constructed model was evaluated through the area under the curve (AUC), accuracy, sensitivity, specificity, positive predictive value and negative predictive value. Results: There were no significant differences in age, gender, primary location of tumor and postoperative pathology between the two groups (all P>0.05). Forty-one features were extracted from region of interest in each modality, including 9 first-order features, 24 gray level co-occurrence matrix features and 8 shape features. From 38 patients, 41 features were extracted from each imaging modality of baseline and preoperative DWI and T2WI images, totally 164 features. Only 4 features were preserved after correlation analysis between each pair of features and t-test between pCR and non-pCR subjects. After LASSO cross validation, only the first-order skewness of the baseline DWI image before treatment and the volume in the baseline T2WI image before treatment were retained. The area under the curve, sensitivity, specificity, positive and negative predictive values of the prediction model established by applying these two features in the training group and the test group were 0.856 and 0.844, 77.8% and 100.0%, 88.2% and 75.0%, 77.8% and 66.7%, 88.2% and 100.0%, respectively. The decision curve analysis of the radiomics model showed that the strategy of this model in predicting pCR was better than that in treating all the patients as pCR and that in treating all the patients as non-pCR. Conclusion: The pCR prediction model for rectal cancer patients receiving PD-1 antibody combined with total neoadjuvant radiochemotherapy based on MRI radiomics has the potential to be used in clinical screening or rectal cancer patients who can be spared from radical surgery.