Genomics of next generation sequencing in pediatric B-acute lymphoblastic leukemia and its impact on minimal residual disease / 中华儿科杂志

Objective: To describe the gene mutation profile of newly diagnosed pediatric B-acute lymphoblastic leukemia (B-ALL) and analyze its effect on minimal residual disease (MRD). Methods: A total of 506 newly diagnosed B-ALL children treated in Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences from September 2018 to July 2021 were enrolled in this retrospective cohort study. The enrolled children were divided into MRD ≥1.00% group and <1.00% group according to MRD results on the 19th day since chemotherapy, and MRD ≥0.01% group and <0.01% group according to MRD results on the 46th day. Clinical characteristics and gene mutations of two groups were compared. Comparisons between groups were performed with chi-square test or Fisher's exact test. Independent risk factors of MRD results on the 19th day and the 46th day were analyzed by Logistic regression model. Results: Among all 506 patients, there were 318 males and 188 females. On the 19th day, there were 114 patients in the MRD ≥1.00% group and 392 patients in the MRD <1.00% group. On the 46th day, there were 76 patients in the MRD ≥0.01% group and 430 patients in the MRD <0.01% group. A total of 187 gene mutations were detected in 487 (96.2%) of 506 children. The most common gene mutations were signal transduction-related KRAS gene mutations in 111 cases (22.8%) and NRAS gene mutations in 99 cases (20.3%). Multivariate analysis showed that PTPN11 (OR=1.92, 95%CI 1.00-3.63), KMT2A (OR=3.51, 95%CI 1.07-11.50) gene mutations and TEL-AML1 (OR=0.48, 95%CI 0.27-0.87), BCR-ABL1 (OR=0.27, 95%CI 0.08-0.92) fusion genes and age >10 years (OR=1.91, 95%CI 1.12-3.24) were independent influencing factors for MRD ≥1.00% on the 19th day. BCORL1 (OR=2.96, 95%CI 1.18-7.44), JAK2 (OR=2.99, 95%CI 1.07-8.42) and JAK3 (OR=4.83, 95%CI 1.50-15.60) gene mutations and TEL-AML1 (OR=0.43, 95%CI 0.21-0.87) fusion gene were independent influencing factors for MRD ≥0.01% on the 46th day. Conclusions: Children with B-ALL are prone to genetic mutations, with abnormalities in the RAS signaling pathway being the most common. Signal transduction related PTPN11, JAK2 and JAK3 gene mutations, epigenetic related KMT2A gene mutation and transcription factor related BCORL1 gene mutation are independent risk factors for MRD.

Molecular mechanisms of tooth, maxilla and mandible development / 口腔医学

@#Understanding the pattern and molecular mechanisms of tooth, maxilla and mandible development is the prerequisite for studying their regeneration. Tooth development can be divided into three stages: bud-bell stage, tooth crown development stage and tooth root development stage. During these processes, key genes show spatial and temporal expression pattern. Tooth development is a complex process involving interactions between dental epithelium and mesenchyme, precise regulations of enamel knots in cusp patterning, as well as successful eruption into the oral cavity under proper biomechanical stress and signaling transductions. The development of tooth, maxilla and mandible, all of which originate from the first branchial arch, is independent and regulates each other to form a whole during development. Any developmental defects of them will ultimately cause defects to the others. In this paper, we briefly reviewed the development of tooth, maxilla and mandible, proposed that the homeostasis of microenvironment is critical for their development. Moreover, we reviewed the role of Meckel’s cartilage, a special structure and signaling mechanism during mandible development. At last, we proposed an integrated development model of tooth, maxilla and mandible. We also hope that the regeneration of fully functional tooth, maxilla and mandible in human can be achieved based on fundamental knowledge we have gained so far.

Analysis of Clinical Features and Risk Factors for Oral Ulcers and Bloodstream Infection in Patients with Hematopoietic Stem Cell Transplantation / 中国实验血液学杂志

OBJECTIVE@#To investigate the risk factors of oral ulcers and bloodstream infection in patients with hematopoietic stem cell transplantation.@*METHODS@#The clinical data of 401 hematopoietic stem cell transplant patients in the First Affiliated Hospital of Zhengzhou University from January 2020 to December 2021 were retrospective analyzed, and the risk factors of oral ulcers and bloodstream infection statistical and analyzed.@*RESULTS@#Among the 401 patients, the incidence of oral ulcers was 61.3% (246/401), and the incidence of bloodstream infection was 9.0% (36/401). A total of 40 strains of pathogenic bacteria were isolated from 36 patients, including 26 strains of Gram negative strains (65%), 13 strains of Gram positive strains (32.5%), and 1 strain of fungi (2.5%). Single-factor analysis showed that oral hygiene was associated with the occurrence of bloodstream infection, and the Multi-factor analysis showed that age ≥14 years old, disease diagnosis of leukemia, and allogeneic hematopoietic stem cell transplantation were risk factors for oral ulcers.@*CONCLUSION@#The incidence of oral ulcers in patients with hematopoietic stem cell transplantation is high. The age ≥14 years, disease diagnosis of leukemia, and allogeneic hematopoietic stem cell transplantation were risk factors for oral ulcers in patients, and oral hygiene was associated with the occurrence of bloodstream infection.

Research Progress of Regulatory T Cells in the Pathogenesis of Multiple Myeloma --Review / 中国实验血液学杂志

The multiple myeloma (MM), the second most common hematologic malignancy, is malignant proliferative disease of plasma cells. Although the application of many targeted drugs has significantly prolonged the survival time of MM patients, it is still an incurable disease. In recent years, the immunosuppression caused by interaction between tumor microenvironment(TME) and tumor cells has attracted people's attention gradually. As a kind of immunosuppressive cells in TME, regulatory T cells (Treg) play an important role in the progress of MM. Treg is related to the proliferation and metastasis of tumors, and can lead to the progress of MM by promoting the angiogenesis and generating immunosuppressive TME. In this review, we briefly summarized the latest research progress on the impact of Treg on the pathogenesis of MM.

A multilevel model analysis of the association between reading and writing posture with myopia in primary and secondary school students / 中国学校卫生

Objective@#To explore the association between reading and writing posture with the occurrence of myopia in Chinese children and adolescents, so as to provide a reference for reducing its prevalence among primary and secondary school students.@*Methods@#Using data from the 2020 survey on the current status of hyperopia reserve in primary and secondary school students from six provinces/cities, namely Beijing, Zhejiang, Chongqing, Shaanxi, Liaoning, and Henan selected by multi stage stratified cluster probability sampling method during November 2020 to June 2022. A total 16 782 students who completed the optometry examination of cycloplegia according to the Children and Adolescents Myopia Screening Standard and questionnaire survey were included for analyzing analyze the association between reading and writing posture with myopia.@*Results@#The overall detection rate of myopia among primary and secondary school students was 45.7%, of which 35.0% were primary school students, 84.1% junior high school students, and 90.4% senior high school students. Poor reading and writing posture was found in 73.6% of primary and secondary school students. Adjusting for confounding factors such as gender, school period, region, outdoor time every day, and whether parents were myopic, the results of the multilevel Logistic regression showed that the following factors were positively correlated with myopia:poor reading and writing posture ( OR=1.17, 95%CI =1.07-1.28), never/occasionally reading and writing with a reading distance which was more than one foot away between the eyes and book ( OR=1.28, 95%CI=1.08-1.53, OR=1.23, 95%CI = 1.08- 1.40), teachers occasionally reminding the child of their reading and writing posture ( OR=1.13, 95%CI =1.01-1.25), and often/always reading and writing while lying down or with the face on the arm ( OR=1.15, 95%CI=1.01-1.32, OR=1.46, 95% CI = 1.17-1.82), always reading and writing with the head in the hand ( OR=1.56, 95%CI =1.20-2.01). Further, a negative correlation was detected between myopia and parents occasionally reminding their children of their reading and writing posture ( OR= 0.85 , 95%CI =0.76-0.96) ( P <0.05).@*Conclusion@#Poor reading and writing posture is a risk factor for the development of myopia in primary and secondary school students, and interventions for reading and writing posture need to be strengthened to reduce the occurrence of myopia among primary and secondary school students.

Research progress on iron nutritional status of plateletpheresis donors / 中国输血杂志

Apheresis platelets are extensively utilized in clinical practice due to high purity and minimal side effects. These platelets are primarily obtained from regular blood donors. However, there is no consensus on whether plateletpheresis leads to iron deficiency among blood donors. In recent years, increasing attention has been given to the impact of plateletpheresis on the iron nutritional status of these donors. Numerous studies have indicated a prevalence of iron deficiency among plateletpheresis donors. The process of plateletpheresis involves the loss of red blood cells, which can accumulate over time and disrupt iron metabolism, ultimately resulting in iron deficiency anemia. This condition not only affects the physical well-being of the donors but also leads to a decline in their willingness to donate blood. Blood collection and supply institutions should enhance their focus on the iron nutritional status of plateletpheresis donors and implement various measures, such as intensifying health education regarding the significance of iron supplementation, implementing programs for testing iron deficiency, considering the provision of iron supplements and extending blood donation intervals. It is crucial to prevent iron deficiency in plateletpheresis donors. These institutions should explore calculation models that can predict personalized blood donation intervals and iron supplementation strategies, and seek a balanced approach that is optimal for maintaining adequate collections while safeguarding donor health. The article comprehensively reviews literature at home and abroad on the etiology and hazards of iron deficiency in plateletpheresis donors, as well as detection methods and response measures. It serves as a foundation for developing scientific and reasonable care measures for blood donation, while also achieving personalized and scientific management and recruitment strategies for blood donors.

Effect of core muscle motor control training on postpartum diastasis recti abdominis / 中国康复理论与实践

ObjectiveTo explore the clinical effect of core muscle motor control training on postpartum diastasis recti abdominis. MethodsFrom January, 2021 to January, 2022, 30 outpatients with postpartum diastasis recti abdominis were randomly divided into control group (n = 15) and experimental group (n = 15). Manipulative therapy and breathing training were performed simultaneously in both groups. Besides, the control group received conventional core strength training, and the experimental group received core muscle motor control training, for four weeks. Their distance of diastasis recti abdominis, abdominal circumference and waist circumference were compared before and after treatment. ResultsAfter treatment, the distance of diastasis recti abdominis, abdominal circumference and waist circumference reduced in both groups (Z = 3.408, t > 5.927, P < 0.05). The reduction value of diastasis recti abdominis distance was more in the experimental group than in the control group (t = 2.328, P < 0.05). ConclusionCore muscle motor control training can effectively relieve postpartum diastasis recti abdominis, and the effect is better than conventional core strength training.

Clinical value of 1, 3-β-D glucan and mannan IgM/IgG antibodies in the early diagnosis of invasive candidiasis / 中华微生物学和免疫学杂志

Objective:To evaluate the diagnostic value of 1, 3-β-D glucan (BDG), mannan IgM antibody (Mn-IgM) and mannan IgG antibody (Mn-IgG) in invasive candidiasis and to compare the differences in the diagnostic capability of serological markers used alone or in combination.Methods:Serum samples of 126 patients with invasive candidiasis and 104 healthy people who took physical examination during the same period were collected. BDG was detected by dynamic chromogenic method, and Mn-IgM and Mn-IgG were detected by ELISA. The sensitivity, specificity, positive predictive value, negative predictive value, Youden index, coincidence rate and Kappa value of the three serological markers used alone or in combination in the diagnosis of invasive candidiasis were analyzed and compared. The receiver operating characteristic (ROC) curves were drawn and the areas under the curves (AUCs) were calculated.Results:The levels of BDG, Mn-IgM and Mn-IgG in patients with invasive candidiasis were significantly higher than those in healthy people ( P<0.01). The sensitivity, specificity, Kappa value and AUC of BDG were 48.41%, 92.31%, 0.389 and 0.842. The sensitivity, specificity, Kappa value and AUC of Mn-IgM were 64.29%, 91.35%, 0.540 and 0.829. The sensitivity, specificity, Kappa value and AUC of Mn-IgG were 27.78%, 95.19%, 0.214 and 0.737. The sensitivity, specificity, Kappa value and AUC of BDG+ Mn-IgM were 76.19%, 88.46%, 0.637 and 0.921. The sensitivity, specificity, Kappa value and AUC of BDG+ Mn-IgG were 59.52%, 91.35%, 0.491 and 0.856. The sensitivity, specificity, Kappa value and AUC of Mn-IgM+ Mn-IgG were 69.84%, 90.38%, 0.588 and 0.891. The sensitivity, specificity, Kappa value and AUC of BDG+ Mn-IgM+ Mn-IgG were 80.16%, 88.46%, 0.679 and 0.922. Conclusions:The sensitivity of Mn-IgM was higher than that of BDG and Mn-IgG in the diagnosis of invasive candidiasis. When the serological biomarkers were used in combination, BDG+ Mn-IgM and BDG+ Mn-IgM+ Mn-IgG had relatively high Kappa value and AUC, showing high accuracy. The clinical diagnostic value of multiple serological biomarkers used in combination was significantly higher than that of any serological biomarkers used alone. Early combined detection and continuous monitoring of multiple serological biomarkers in patients with high risk of invasive candidiasis could be used clinically to adjust antifungal treatment strategies timely.

The effects of repetitive transcranial magnetic stimulation on awakening and neural function in patients with brain injury / 中国医师进修杂志

Objective:To investigate the effects of repetitive transcranial magnetic stimulation (rTMS) on awakening of cerebrum frontal lobe area and neural function in the patients with brain injury.Methods:The clinical data of 70 patients with brain injury in Zhejiang Xin′an International Hospital from March 2020 to July 2021 were retrospectively analyzed. Among them, 34 cases were treated with conventional awakening rehabilitation (control group), and 36 cases were treated with rTMS combined with conventional awakening rehabilitation (observation group). The efficacy was evaluated after treatment, the cure and effective were taken as total effective. The Glasgow coma scale (GCS) was used to evaluate the conscious state; the modified coma recovery scale (CRS-R) was used to evaluate the neural function; the brainstem auditory evoked potential (BAEP) classification criteria was used to evaluate the conscious state, the electroencephalogram powers of five channels FP1, F3, C3, F7 and T3 were measured; and the adverse reactions were recorded.Results:The total effective rate in observation group was significantly higher than that in control group: 94.44% (34/36) vs. 76.47% (26/34), and there was statistical difference ( χ2 = 4.61, P<0.05). The eye opening response, motor response, language response and total score of GCS after treatment in observation group were significantly higher than those in control group: (4.28 ± 0.57) scores vs. (3.03 ± 0.59) scores, (4.57 ± 0.85) scores vs. (3.24 ± 0.67) scores, (3.99 ± 0.92) scores vs. (3.01±0.48) scores and (12.85 ± 2.01) scores vs. (10.47 ± 1.95) scores, and there were statistical differences ( P<0.01). The CRS-R score after treatment in observation group was significantly higher than that in control group: (15.28 ± 3.17) scores vs. (12.33 ± 3.09) scores, and there was statistical difference ( P<0.01). The BAEP classification after treatment in observation group was significantly better than that in control group, and there was statistical difference ( P<0.05). The powers of F3, C3, F7 and T3 after treatment in observation group were significantly lower than those in control group: (41.25 ± 6.35) μV 2/Hz vs. (53.19 ± 10.37) μV 2/Hz, (39.17 ± 5.61) μV 2/Hz vs. (48.94 ± 6.63) μV 2/Hz, (63.94 ± 7.57) μV 2/Hz vs. (69.85 ± 7.35) μV 2/Hz and (51.76 ± 6.84) μV 2/Hz vs. (62.47 ± 7.62) μV 2/Hz, and there were statistical differences ( P<0.01); there was no statistical difference in power of Fp1 after treatment between two groups ( P>0.05). No serious complications such as epilepsy occurred in two groups. There was no statistically significant difference in the incidence of adverse reactions between two groups ( P>0.05). Conclusions:The rTMS can improve the excitability of brain cells and the degree of brain injury in patients with brain injury, improve the CRS-R score, promote waking up and the recovery of cognitive functions, with safety and efficiency.

The efficacy comparison of sakubatril valsartan and valsartan in the treatment of patients with chronic cardiac insufficiency and the influence on zinc finger protein A20 and nuclear factor-κB in peripheral blood mononuclear cells / 中国医师进修杂志

Objective:To compare the efficacy of sakubatril valsartan and valsartan in the treatment of patients with chronic cardiac insufficiency and the influence on zinc finger protein A20 and nuclear factor-κB (NF-κB) in peripheral bloodmononuclear cells (PBMCs).Methods:Ninety-senven patients with chronic cardiac insufficiency admitted to the Affiliated Hospital of Jining Medical College from February 2019 to January 2020 were continuously selected and randomly divided into the control group (48 cases) and the observation group (49 cases). Both groups received routine anti-heart failure according to the guidelines. The control group added with valsartan and the observation group added with sakubatril valsartan treatment. Before the treatment and after 3 months of treatment, the changes of cardiac function indexes and the changes of inflammatory markers such as hypersensitive C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), matrix metalloproteinase 9 (MMP-9), and N-terminal pro B-type natriuretic peptide (NT-proBNP) were compared. PBMCs was extracted to detect zinc finger protein A20 and NF-κB levels. The incidence of adverse reactions in the two groups was recorded, and the relationship between zinc finger proteins A20, NF-κB and the myocardial injury marker NT-proBNP were analyzed.Results:After 3 months of treatment, the changes of cardiac function indexes in the observation group were better than those in the control group and the levels of hs-CRP, TNF-α, MMP-9, NT-proBNP in the observation group were lower than those in the control group: (1.96 ± 0.57) mg/L vs. (2.87 ± 0.79) mg/L, (7.11 ± 1.46) μg/L vs. (8.24 ± 1.57) μg/L, (110.14 ± 10.63) μg/L vs. (129.52 ± 17.96) μg/L, (716.91 ± 105.78) ng/L vs. (965.25 ± 97.41) ng/L, there were statistical differences ( P<0.05). After 3 months of treatment, the levels of finger protein A20, NF-κB in the observation group were lower than those in the control group: (3.57 ± 1.13) % vs. (4.41 ± 1.32) %, (29.87 ± 6.58) ng/L vs. (35.71 ± 10.02) ng/L, there were statistical differences ( P<0.05). Finger protein A20 and NF-κB in patients with chronic cardiac insufficiency were positively correlated with NT-proBNP ( r = 0.487, 0.738, P<0.01). Conclusions:On the basis of conventional treatment, compared with valsartan, the addition of sakubatril valsartan, can improve the cardiac function of patients with chronic cardiac insufficiency, reduce the body′s inflammatory response, reduce the expression of myocardial injury marker NT-proBNP, inhibit the activation of PBMCs NF-κB, and reduce the level offinger protein A20.

Preliminary observation on the differential expression of metformin in preventing noise-induced hearing loss in inner ear protein group of rats / 中华劳动卫生职业病杂志

Objective: To study the protective effects of metformin on noise-induced hearing loss (NIHL) and its differential protein omics expression profile. Methods: In January 2021, 39 male Wistar rats were randomly divided into control group, noise exposure group and metformin+noise exposure group, with 13 rats in each group. Rats in the noise exposure group and metformin+noise exposure group were continuously exposed to octave noise with sound pressure level of 120 dB (A) and center frequency of 8 kHz for 4 h. Rats in the metformin+noise exposure group were treated with 200 mg/kg/d metformin 3 d before noise exposure for a total of 7 d. Auditory brainstem response (ABR) was used to test the changes of hearing thresholds before noise exposure and 1, 4, 7 d after noise exposure in the right ear of rats in each group. Tandem mass tag (TMT) quantitative proteomics was used to identify and analyze the differentially expressed protein in the inner ear of rats in each group, and it was verified by immunofluorescence staining with frozen sections. Results: The click-ABR thresholds of right ear in the noise exposure group and metformin+noise exposure group were significantly higher than those in the control group 1, 4, 7 d after noise exposure (P<0.05) . The click-ABR threshold of right ear in the metformin+noise exposure group were significantly lower than that in the noise exposure group (P<0.05) . Compared with the noise exposure group, 1035 up-regulated proteins and 1145 down-regulated proteins were differentially expressed in the metformin+noise exposure group. GO enrichment analysis showed that the significantly differentially expressed proteins were mainly involved in binding, molecular function regulation, signal transduction, and other functions. Enrichment analysis of KEGG pathway revealed that the pathways for significant enrichment of differentially expressed proteins included phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt) signaling pathway, focal adhesion, diabetic cardiomyopathy, mitogen, and mitogen-activated protein kinase (MAPK) signaling pathway. Immunofluorescence experiments showed that compared with the noise exposure group, the fluorescence intensity of insulin-like growth factor 1 receptor (IGF1R) in the metformin+noise exposure group was increased, and the fluorescence intensity of eukaryotic translation initiation factor 4E binding protein 1 (eIF4EBP1) was decreased. Conclusion: Noise exposure can lead to an increase in rat hearing threshold, and metformin can improve noise-induced hearing threshold abnormalities through multiple pathways and biological processes.

Prognostic analysis of different comprehensive treatment models for locally advanced esophageal squamous cell carcinoma based on propensity score matching / 中华外科杂志

Objective: To compare the effects of preoperative neoadjuvant chemotherapy and postoperative adjuvant chemotherapy on the long-term survival of patients with radical resection for esophageal squamous cell carcinoma. Methods: Totally 1 082 patients with stage T3-4aN0-3M0 thoracic esophageal squamous cell carcinoma were recruited in this study who underwent radical resection at Department of Thoracic Surgery, Fourth Hospital, Hebei Medical University from January 2005 to January 2015. There were 798 males and 284 females, with a median age of 61 years (range: 37 to 86 years). There were 138 patients undergoing preoperative neoadjuvant chemotherapy, 392 patients postoperative adjuvant chemotherapy, and 552 patients surgery alone. The neoadjuvant chemotherapy group was used as the benchmark group to match the propensity score with the adjuvant chemotherapy group and the surgery-only group respectively at a ratio of 1∶3. A total of 7 covariates including tumor location, number of positive lymph nodes, tumor invasion depth, tumor differentiation degree, surgical procedure, vascular tumor thrombus and nerve invasion were included, and the caliper value was taken as 0.1. After matching, a total of 699 patients were included for the analysis, including 128 patients in the neoadjuvant chemotherapy group, 267 patients in the adjuvant chemotherapy group, and 304 patients in the surgery alone group. The Kaplan-Meier method was used to generate the survival curves which was tested by the Log-rank method for survival analysis. Results: After matching analysis, the 5-year overall survival rate was 41.5% in the neoadjuvant chemotherapy group with a median overall survival time of 43 months (95%CI: 27 to 59 months), 57.6% in the adjuvant chemotherapy group with a median overall survival time unreached, and 24.9% in the surgery alone group with a median overall survival time of 28 months (95%CI: 25 to 31 months) (χ²=60.475, P<0.01). For overall survival after matching, the adjuvant chemotherapy group was better than the neoadjuvant chemotherapy group (χ²=11.384, P=0.001), the neoadjuvant chemotherapy group was better than the surgery alone group (χ²=8.654, P=0.003), and the adjuvant chemotherapy group was better than surgery alone group (χ²=60.234, P<0.01). Conclusion: Both preoperative neoadjuvant chemotherapy and postoperative adjuvant chemotherapy can improve the long-term survival of patients with locally advanced esophageal squamous cell carcinoma undergoing radical resection, and the improvement effect of postoperative adjuvant chemotherapy is more obvious.

Analysis of HIV-1 genetic subtype and pretreatment drug resistance among men who have sex with men infected with HIV-1 from 19 cities of 6 provinces in China / 中华流行病学杂志

Objective: To investigate the distribution of HIV-1 genetic subtypes and pretreatment drug resistance (PDR) among men who have sex with men (MSM) from 19 cities of 6 provinces in China. Methods: From April to November 2019, 574 plasma samples of ART-naive HIV-1 infected MSM were collected from 19 cities in Hebei, Shandong, Jiangsu, Zhejiang, Fujian, and Guangdong provinces, total ribonucleic acid (RNA) was extracted and amplified the HIV-1 pol gene region by nested polymerase chain reaction (PCR) after reverse transcription. Then sequences were used to construct a phylogenetic tree to determine genetic subtypes and submitted to the Stanford drug resistance database for drug resistance analysis. Results: A total of 479 samples were successfully amplified by PCR. The HIV-1 genetic subtypes included CRF01_AE, CRF07_BC, B, CRF55_01B, CRF59_01B, CRF65_cpx, CRF103_01B, CRF67_01B, CRF68_01B and unrecognized subtype, which accounted for 43.4%, 36.3%, 6.3%, 5.9%, 0.8%, 0.8%, 0.4%, 0.4%, 0.2% and 5.5%, respectively. The distribution of genetic subtypes among provinces is statistically different (χ2=44.141, P<0.001). The overall PDR rate was 4.6% (22/479), the drug resistance rate of non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors, and protease inhibitors were 3.5% (17/479), 0.8% (4/479) and 0.2% (1/479), respectively. The PDR rate of recent infections was significantly higher than that of long-term infections (χ2=4.634, P=0.031). Conclusions: The HIV-1 genetic subtypes among MSM infected with HIV-1 from 19 cities of 6 provinces in China are diverse, and the distribution of subtypes is different among provinces. The overall PDR rate is low, while the PDR rate of recent infections was significantly higher than that of long-term infections, suggesting the surveillance of PDR in recent infections should be strengthened.

Development of a novel multi-functional integrated bioconjugate effectively targeting K-Ras mutant pancreatic cancer / 药物分析学报

Folate receptor(FR)overexpression occurs in a variety of cancers,including pancreatic cancer.In addi-tion,enhanced macropinocytosis exists in K-Ras mutant pancreatic cancer.Furthermore,the occurrence of intensive desmoplasia causes a hypoxic microenvironment in pancreatic cancer.In this study,a novel FR-directed,macropinocytosis-enhanced,and highly cytotoxic bioconjugate folate(F)-human serum albumin(HSA)-apoprotein of lidamycin(LDP)-active enediyne(AE)derived from lidamycin was designed and prepared.F-HSA-LDP-AE consisted of four moieties:F,HSA,LDP,and AE.F-HSA-LDP presented high binding efficiency with the FR and pancreatic cancer cells.Its uptake in wild-type cells was more extensive than in K-Ras mutant-type cells.By in vivo optical imaging,F-HSA-LDP displayed prominent tumor-specific biodistribution in pancreatic cancer xenograft-bearing mice,showing clear and lasting tumor localization for 360 h.In the MTT assay,F-HSA-LDP-AE demonstrated potent cytotoxicity in three types of pancreatic cancer cell lines.It also induced apoptosis and caused G2/M cell cycle arrest.F-HSA-LDP-AE markedly suppressed the tumor growth of AsPc-1 pancreatic cancer xenografts in athymic mice.At well-tolerated doses of 0.5 and 1 mg/kg,(i.v.,twice),the inhibition rates were 91.2％and 94.8％,respectively(P＜0.01).The results of this study indicate that the F-HSA-LDP multi-functional bioconjugate might be effective for treating K-Ras mutant pancreatic cancer.

The application value of sakubatril valsartan in the treatment of chronic heart failure based on cardiopulmonary exercise test system / 中国医师进修杂志

Objective:To analyze the application value of sakubatril valsartan in the treatment of chronic heart failure (CHF) based on cardiopulmonary test system.Methods:One hundred and thirty-five CHF patients admitted to the Affiliated Hospital of Jining Medical Collegefrom January 2019 to August 2020 were divided into the observation group (67 cases) and the control group (68cases) by random number table method. Both groups were treated with bisoprolol. The observation group was treated with the combination of sakubatril valsartan, and the control group was treated with the combination of benapril. The efficacy and cardiac function indicators of the two groups were compared. The cardiopulmonary exercise test system was used to measure the patient′s maximum exercise time (Tmax), maximum exercise Watt (Wmax), peak volume oxygen (Peak VO 2) and volume of anaerobic threshold oxygen (VO 2AT), and the incidence of adverse reactions were calculated. Results:The total effective rate in the observation group was higher than that in the control group: 92.54% (62/67) vs. 77.94%(53/68), the difference was statistically significant ( χ2 = 5.70, P<0.05). After the treatment, the levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) and soluble ST2 (sST2) in the observation group were lower than those in the control group: (2 000.47 ± 517.85) ng/L vs. (2 777.39 ± 812.49) ng/L, (0.33 ± 0.10) μg/L vs. (0.37 ± 0.09) μg/L, and the left ventricular ejection fraction (LVEF) was higher than that in the control group: (8.12 ± 6.44)% vs. (41.93 ± 6.73)%, the differences were statistically significant ( P<0.05). After the treatment, the left ventricular end-diastolic diameter (LVEDd), left ventricular end-systolic diameter (LVEDs), left ventricular mass index (LVMI), left atrial volume index (LAVI) in the observation group were lower than those in the control group: (55.47 ± 6.93) mm vs. (62.00 ± 7.18) mm, (37.14 ± 6.36) mm vs. (41.35 ± 6.43) mm, (136.76 ± 7.13) mg/m 2 vs. (140.98 ± 7.47) mg/m 2, (28.23 ± 2.59) ml/m 2 vs. (31.98 ± 2.17) ml/m 2; the Tmax, Wmax, PeakVO 2 and VO 2AT in the observation group were higher than those in the control group: (619.08 ± 65.36) s vs. (58.70 ± 52.44) s, (142.96 ± 16.05) W vs. (124.19 ± 13.38) W, (20.00 ± 5.74) ml/(min·kg) vs. (18.13 ± 3.58) ml/(min·kg), (13.89 ± 3.69) ml/(min·kg) vs. (11.23 ± 2.36) ml/(min·kg), the differences were statistically significant ( P<0.05). However, there was no statistically significant in the incidence of adverse reactions between the two groups ( P>0.05). Conclusions:Sakubatril valsartan in the treatment of CHF can not only optimize the efficacy and improve cardiac function, but also benefit cardiac exercise rehabilitation of patients, and not increase the safety risk.

Effects of kinematic alignment on range of motion after total knee arthroplasty / 中国康复理论与实践

ObjectiveTo explore the effect of kinematic alignment on postoperative knee function for patients after total knee arthroplasty (TKA). MethodsFrom June, 2020 to October, 2021, 200 patients undergoing primary TKA in Beijing Chaoyang Hospital were divided into mechanical alignment (MA) group (n = 100) and kinematic alignment (KA) group (n = 100). All the patients accepted comprehensive rehabilitation after operation. They were assessed with Keen Society Score (KSS) before and three months after operation, with Visual Analogue Scale for pain (VAS) before, and three days and three months after operation. The time of first standing, the time of first straight-leg raising more than 30°, and the active range of motion (AROM) of knee before, and one, two and three days, and one and three months after operation were recorded, as well as where to go after discharge. ResultsA total of 96 patients in MA group and 98 in KA group finished the research. The AROM of knee improved more in the KA group than in the MA group after operation (Fgroup = 8.816, P = 0.017), and the incidence going to the rehabilitation institutes was less (χ2 = 6.542, P = 0.011). ConclusionKA may promote the rapid recovery of AROM of knee for patients after TKA, and reduce the needs of institute-based rehabilitation after discharge, to save medical costs.

The mechanisms of mitochondrial dysfunction caused by pathogenic genes of Parkinson′s disease / 中华神经科杂志

Parkinson′s disease (PD) is a complex neurodegenerative disorder typically known for characteristic loss of dopaminergic neurons in the substantia nigra striatum. To date, therapeutic approaches for PD are still lacking due to the multifactorial etiology and complicated pathogenesis. Thus, the studies relative to the biological mechanisms and drug development of PD are the hotspot in this field. In recent years, numerous studies suggest that the PD is associated with mitochondrial dysfunction which is affected by multiple genes regulation. Genome-wide association studies have proved that monogenic PD gene locus is associated with mitochondrial dysfunction. Although there are many studies on how PD pathogenic genes regulate mitochondrial dysfunction then affect neuronal physiological function and ultimately lead to the PD, the effects of mutations in PD-associated genes on mitochondrial dysfunction remain not fully understood. In this review, the literature discussing the mechanisms of mitochondrial dysfunction in the context of PD was summarized with the aim to implicate the potential opportunities for therapeutically targeting mitochondria.

An Intronic Variant of CHD7 Identified in Autism Patients Interferes with Neuronal Differentiation and Development / 神经科学通报·英文版

Genetic composition plays critical roles in the pathogenesis of autism spectrum disorder (ASD). Especially, inherited and de novo intronic variants are often seen in patients with ASD. However, the biological significance of intronic variants is difficult to address. Here, among a Chinese ASD cohort, we identified a recurrent inherited intronic variant in the CHD7 gene, which is specifically enriched in East Asian populations. CHD7 has been implicated in numerous developmental disorders including CHARGE syndrome and ASD. To investigate whether the ASD-associated CHD7 intronic variant affects neural development, we established human embryonic stem cells carrying this variant using CRISPR/Cas9 methods and found that the level of CHD7 mRNA significantly decreased compared to control. Upon differentiation towards the forebrain neuronal lineage, we found that neural cells carrying the CHD7 intronic variant exhibited developmental delay and maturity defects. Importantly, we found that TBR1, a gene also implicated in ASD, was significantly increased in neurons carrying the CHD7 intronic variant, suggesting the intrinsic relevance among ASD genes. Furthermore, the morphological defects found in neurons carrying CHD7 intronic mutations were rescued by knocking down TBR1, indicating that TBR1 may be responsible for the defects in CHD7-related disorders. Finally, the CHD7 intronic variant generated three abnormal forms of transcripts through alternative splicing, which all exhibited loss-of-function in functional assays. Our study provides crucial evidence supporting the notion that the intronic variant of CHD7 is potentially an autism susceptibility site, shedding new light on identifying the functions of intronic variants in genetic studies of autism.

Strategies of lowering relapse after allogeneic hematopoietic stem cell transplantation for high-risk myelodysplastic syndrome / 中华器官移植杂志

Objective:To explore the strategies of reducing relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with high-risk myelodysplastic syndrome (MDS) from the perspectives of optimizing the conditioning regimen and pre-transplant cytoreductive therapy.Methods:A total of 84 patients with high-risk MDS undergoing allo-HSCT between January 2013 and September 2019 were retrospectively analyzed. Based upon preparative regimens, they were divided into two groups of decitabine intensified BUCY2 ( n=49) and BUCY2 regimen ( n=35), based upon whether or not pre-treatment prior to allo-HSCT: cytoredutive treatment ( n=34) and none ( n=50). Two groups were compared with regards to hematopoietic reconstitution, graft-versus-host disease (GVHD), relapse rate, transplant-related mortality (TRM) and survival. Results:No significant inter-group differences existed in hematopoietic reconstitution or acute/chronic GVHD. The relapse rate was significantly lower in decitabine intensified group than that in BUCY2 group (18.7% vs 40.0%, P=0.025). Survival was significantly better in decitabine intensified group than that in BUCY2 group (3-year OS: 71.3% vs 51.2%, P=0.038; 3-year DFS: 65.3% vs 45.2%, P=0.033). Moreover, the incidence of recurrence was markedly lower in pre-transplant treatment group than that in non-treatment group (20.7% vs 38.9%, P=0.035). The inter-group incidence of TRM was not different. Three-year OS/DFS of treatment group were remarkably superior to those of non-treatment group (71.2% vs 50.8%, P=0.024; 64.7% vs 45.9%, P=0.044). Conclusions:As an optimal conditioning regimen for high-risk MDS, decitabine intensified BUCY2 regimen could better eliminate tumor burden, remarkably lower relapse rate and improve OS after allo-HSCT. In addition, pre-transplant treatment significantly reduces relapse and offers benefit for OS after allo-HSCT. Therefore intensified conditioning regimen and pre-transplant treatment may be promising strategies of reducing relapse and improving survival for high-risk MDS. However, it still needs further confirmation from prospective randomized controlled trials.

Registration characteristics of global clinical trials of coronavirus disease 2019 / 中华传染病杂志

Objective:To get comprehensive understanding of the registration characteristics of global clinical trials of coronavirus disease 2019(COVID-19) based on the ClinicalTrials. gov and the Chinese Clinical Trial Registry (ChiCTR).Methods:The clinical trials of COVID-19 in the ClinicalTrials.gov and ChiCTR were retrieved. The search start time was unlimited, with deadlines of 14 December, 2020 and 19 March, 2021, respectively. The registration numbers, registration submitted time, country/region distribution, recruitment status, study types, number of recruits, research phases, and other aspects were analyzed by using bibliometric methods.Results:As of March 19, 2021, there were 775 clinical trials in ChiCTR. As of December 14, 2020, there were 4 137 clinical trials in the ClinicalTrials.gov, and 3 157(76.31%) of the clinical trials recruited subjects who were aged≥18 years old. There were 2 347 intervention trials and 1 759 observational trials. The intervention measures mainly included drugs, biologics and medical devices. The numbers of recruits were 110(48, 308) cases for interventional studies, and 300(100, 1 000) cases for observational trials. The interventional research phases were mainly phaseⅡ (570 items) and phase Ⅲ (358 items). Totally, 50.33%(2 082/4 137) of the clinical trials were under recruitment, 13.10%(542/4 137) had been completed. Among the interventional studies, 729(31.06%) were multi-center studies, with the center numbers of 5(2, 15).Conclusions:At present, there are a large number of clinical trials with various intervention measures in the world. However, the number of recruits is unreasonable, and multi-center study with multi-agency cooperation is insufficient.