Chronic lymphocytic leukemia(CLL)is one of small B-cell lymphomas and leukemias,characterized as a clonal disease of mature B cells.The disease is remarkably heterogeneous,with the majority of patients having an indolent course,yet they are currently incurable.Abnormal signaling pathways are indispensable in the pathogenesis of CLL.In CLL,the common abnormalities of signaling pathways include B-cell receptor(BCR)signaling,apoptosis,nuclear factor kappa B(NF-κB)signaling and Notch signaling.According to the target in signaling pathways,a series of targeted drugs,such as Bruton's tyrosine kinase(BTK)inhibitors(ibrutinib,zanubrutinib),phosphorylate phosphoinositide 3-kinase(PI3K)inhibitor(duvelisib)and B-cell leukemia/lymphoma 2(BCL2)inhibitor(venetoclax),which have significantly changed the prognosis of patients in clinic.Other targeted drugs,such as fenebrutinib,nemtabrutinib and umbralisib,as well as chimeric antigen receptor T-cell(CAR-T)therapy developed in the field of immuno-oncology and T cell engineering,are currently under trial,with more personalized treatment modalities being explored,which may become potential drug targets in the future.In this paper,relevant literature of CLL was reviewed,and recent research progress in molecular pathogenesis and targeted therapies of chronic lymphocytic leukemia was reviewed.

Objective To observe the value of ultrasonography for evaluating the anatomy and hemodynamic characteristics of vertebral artery course variation(VA-CV).Methods Totally 41 patients with VA-CV(VA-CV group)and 41 patients without VA-CV(control group)were enrolled.Lateral variation of vertebral artery(VA),the origin of V1 segment,the length of proximal subclavian artery(PSCA),the location of VA into the transverse foramen,the diameter of V2 segment,the peak systolic velocity(PSV)and the end-diastolic velocity(EDV)were evaluated with ultrasonography.The value of ultrasonography for evaluating VA-CV and relative hemodynamic changes were analyzed.Results Totally 49 variant VA were detected in VA-CV group,including 19 on the left and 30 on the right side,VA-CV on the right side was more often than on the left side.Seventeen(16 on the left and 1 on the right side)VA had abnormal origins,and abnormal VA origins on the left side were more than that on the right side(P＜0.001).Meanwhile,VA origins of right VA-CV were mostly lower than that of the left side VA-CV(P＜0.001).The length of right PSCA in VA-CA group was shorter than that in control group(P＜0.05).More than half variant VA entered vertebral space from the transverse foramen of C5-6(33/49,67.35％),and the higher the entrance of transverse foramen,the shorter the PSCA(P＜0.05).In VA-CV group,the diameter of V2 segment in left VA-CV patients was smaller than that in control group,while EDV in the former was lower than in the latter(both P＜0.05).Conclusion Ultrasonography could be used to objectively evaluate VA-CV and relative hemodynamic changes.

Objective:To evaluate the role of the SIRT1/FoxO1 signaling pathway in trilobatin-induced reduction of cerebral ischemia-reperfusion (I/R) injury in rats.Methods:Eighty clean-grade healthy male Sprague-Dawley rats, aged 6-8 weeks, weighing 230-280 g, were divided into 4 groups ( n=20 each) using a random number table method: sham operation group (group S), cerebral I/R group (group CIR), trilobatin+ cerebral I/R group (group T) and trilobatin+ cerebral I/R+ SIRT1/FoxO1 signaling pathway inhibitor EX527 group (group E). The model of focal cerebral I/R injury was established by middle cerebral artery occlusion in anesthetized animals. Trilobatin 15 mg/kg was given by gavage twice a day for 3 consecutive days starting from 3 days before ischemia in T and E groups. EX527 5 mg/kg was intraperitoneally injected before each gavage in group E. Modified Longa scoring scale was used to assess neurological function at 24 h of reperfusion, then the rats were sacrificed and whole brain tissues were obtained for determination of cerebral infarct size (using TTC staining), apoptosis rate and level of reactive oxygen species (ROS) in the hippocampus (by flow cytometry), expression of SIRT1 and acetylated FOXO1 (Ac-FOXO1) (by Western blot) and contents of superoxide dismutase (SOD) and malondialdehyde (MDA) (by enzyme-linked immunosorbent assay) and for microscopic examination of pathological changes in the hippocampal CAI area after HE staining. Results:Compared with group S, Longa score, cerebral infarct size, apoptosis rate of hippocampal neurons, and levels of ROS and MDA were significantly increased, the content of SOD was decreased, the expression of SIRT1 was down-regulated, and the expression of Ac-FOXO1 was up-regulated in group CIR ( P<0.05). Compared with group CIR, Longa score, cerebral infarct size, apoptosis rate of hippocampal neurons, and levels of ROS and MDA were significantly decreased, the content of SOD was increased, the expression of SIRT1 was up-regulated, and the expression of Ac-FOXO1 was down-regulated in group T ( P<0.05). Compared with group T, Longa score, cerebral infarct size, apoptosis rate of hippocampal neurons, and levels of ROS and MDA were significantly increased, the content of SOD was decreased, the expression of SIRT1 was down-regulated, and the expression of Ac-FOXO1 was up-regulated in group E ( P<0.05). Conclusions:Trilobatin may inhibit oxidative stress responses and neuronal apoptosis in hippocampi by activating the SIRT1/FoxO1 signaling pathway, thus alleviating cerebral I/R injury in rats.

Objective To investigate the training needs and suggestions of advanced practice nurses in medical institutions in China,and to provide references for the formulation of training programs for advanced practice nurses.Methods By a convenient sampling method,from May to July in 2023,the heads of nursing nurses in medical institutions in 29 provinces,autonomous regions and municipalities directly under the Central Government were investigated,and the self-designed questionnaires were distributed in the form of electronic questionnaire.Results 1 287 medical institutions participated in the survey,with tertiary hospitals accounting for 65.50％.93.16％of medical institutions had the use needs of advanced practice nurses,and the top 3 professional fields hoping to prioritize in the APN training were in the order of critical illness,emergency treatment and intravenous treatment.Among the APN core competence,the most important one was direct clinical practice(92.77％),followed by professional development(89.43％)and scientific research and evidence-based practice(86.40％).71.72％of medical institutions suggested that the theoretical training time is 4 weeks,combining online and offline training(50.35％),and the clinical practice time should not be less than 12 weeks(97.66％).Theoretical learning course assignment(92.93％),case report(90.83％)and clinical practice reflection diary(88.19％)were the main process evaluation methods,while 1 case study with the completion of the report and defense(87.65％)and 1 evidence-based nursing practice research plan with the completion of a report and defense(77.93％)were the main final evaluation methods.Conclusion Advanced practice nurses are important roles in the process of nursing professional development,and medical institutions in our country have a high demand for the training of advanced practice nurses.It is imperative to carry out the training of advanced practice nurses.The suggestions of medical institutions on the training content and methods focus more on the training of core competence.On this basis,the admission conditions should be clarified,and the training program of advanced practice nurses for China's national conditions should be explored.

Objective : To investigate the protective effect of melatonin (MT) on formaldehyde (FA) inhalation-in- duced acute lung injury (ALI) in rats and its mechanism through the regulation of nuclear factor E2-related factor 2 (Nrf2) signaling pathway． Methods : Fifty female Wistar rats were randomly divided into Control group ，FA group，FA + MT 5 mg / kg group，FA + MT 10 mg / kg group and FA + MT 20 mg / kg group，with 10 rats in each group．Except for the Control group，all other groups inhaled 3 mg / m3 FA daily for 21 d consecutively to construct the tainted model，and then treated with different MT doses for 14 d．The tainting was continued during the MT treatment．Hematoxylin-eosin (HE) staining was used to observe the histopathological changes in lung tissue，lung water content and lung coefficient were weighed and measured，glutathione ( GSH) ，superoxide dismutase (SOD) and 8-hydroxydeoxyguanosine ( 8-OHdG) levels were measured by absorbance photometric method ，and enzyme linked immunosorbent assay(ELISA) was used to measure the levels of tumor necrosis factor-alpha (TNF-α) ，in- terleukin (IL) -6，and IL-1 β concentrations，Western blot to detect the protein expression levels of Nrf2，heme ox- ygenase-1 (HO-1) ，nuclear factor-κB ( NF-κB) ，and phosphorylated nuclear factor-κB ( p-NF-κB) in lung tis- sues，and quantitative polymerase chain reaction(qPCR) to detect the Nrf2，HO-1，and Kelch-like ECH-associated protein 1 (Keap1) mRNA expression levels. Results : Compared with the control group，lung injury was obvious in rats in the FA group ; lung tissue GSH and SOD levels were reduced ，and 8-OHdG levels were elevated ( P < 0. 05) ; alveolar lavage fluid TNF-α , IL-6，and IL-1 β levels were elevated (P＜0. 05) ; Nrf 2 and HO-1 protein expression levels were reduced in the lung tissue (P＜0. 05) ，and p-NF-κB protein expression levels were was ele- vated (P＜0. 05) ; the relative mRNA expression of Nrf2 and HO-1 in lung tissue was decreased，and the relative mRNA expression of Keap1 was elevated (P＜0. 05) ．Compared with the FA group，the lung injury of rats in the MT group was improved ; the levels of GSH and SOD in the lung tissue were increased (P＜0. 05) ，and the level of 8-OHdG was decreased (P＜0. 05) ; the levels of TNF-α , IL-6，and IL-1 β in the alveolar lavage fluid were de- creased (P＜0. 05) ; and the expression levels of the Nrf2 and HO-1 proteins in the lung tissue were increased (P ＜0. 05) ．p-NF-κB protein expression level was decreased (P ＜0. 05) ; the relative mRNA expression levels of Nrf2 and HO-1 in lung tissues were increased (P＜0. 05) ，and the relative mRNA expression level of Keap1 was decreased (P＜0. 05) in lung tissues，and all of them were in a dose-dependent manner． Conclusion MT can al- leviate oxidative stress and inflammatory responses and mitigate FA exposure-induced acute lung injury by regula- ting the Nrf2 / Keap1 / HO-1 signaling pathway.

Objective:To investigate the clinical features and outcomes of adolescence-onset methylmalonic acidemia (MMA) and explore preventive strategies.Methods:This was a retrospective case analysis of the phenotypes, genotypes and prognoses of adolescence-onset MMA patients. There were 55 patients diagnosed in Peking University First Hospital from January 2002 to June 2023, the data of symptoms, signs, laboratory results, gene variations, and outcomes was collected. The follow-ups were done through WeChat, telephone, or clinic visits every 3 to 6 months.Results:Among the 55 patients, 31 were males and 24 were females. The age of onset was 12 years old (range 10-18 years old). They visited clinics at Tanner stages 2 to 5 with typical secondary sexual characteristics. Nine cases (16%) were trigged by infection and 5 cases (9%) were triggered by insidious exercises. The period from onset to diagnosis was between 2 months and 6 years. Forty-five cases (82%) had neuropsychiatric symptoms as the main symptoms, followed by cardiovascular symptoms in 12 cases (22%), kidney damage in 7 cases (13%), and eye disease in 12 cases (22%). Fifty-four cases (98%) had the biochemical characteristics of methylmalonic acidemia combined with homocysteinemia, and 1 case (2%) had the isolated methylmalonic acidemia. Genetic diagnosis was obtained in 54 cases, with 20 variants identified in MMACHC gene and 2 in MMUT gene. In 53 children with MMACHC gene mutation,1 case had dual gene variants of PRDX1 and MMACHC, with 105 alleles. The top 5 frequent variants in MMACHC were c.482G>A in 39 alleles (37%), c.609G>A in 17 alleles (16%), c.658_660delAAG in 11 alleles (10%), c.80A>G in 10 alleles (10%), c.567dupT and c.394C>T both are 4 alleles (4%). All patients recovered using cobalamin, L-carnitine, betaine, and symptomatic therapy, and 54 patients (98%) returned to school or work.Conclusions:Patients with adolescence-onset MMA may triggered by fatigue or infection. The diagnosis is often delayed due to non-specific symptoms. Metabolic and genetic tests are crucial for a definite diagnosis. Treatment with cobalamin, L-carnitine, and betaine can effectively reverse the prognosis of MMA in adolescence-onset patients.

Objective:To investigate the feasibility and clinical diagnostic value of rapid arterial spin labeling (ASL) imaging in brain glioma.Methods:Patients with glioma admitted to Beijing Tiantan Hospital, Capital Medical University from May 2021 to December 2022 were prospectively enrolled. All patients received MR rapid ASL (scan time: 1 min) and conventional ASL (scan time: 4 min 30 s), where the cerebral blood flow (CBF) perfusion maps were obtained. The qualitative analysis of CBF signal intensity and quantitative analysis of average CBF values from both tumor solid and edema regions were conducted by two radiologists independently. Kappa test and intraclass correlation coefficient ( ICC) were used to analyze the consistency of qualitative and quantitative results, respectively. Results:A total of 30 patients with brain glioma were included. The 2 physicians used rapid ASL to determine low perfusion, isoperfusion, and hyperperfusion in the tumor area in 1, 6, 23 cases and 0, 5, and 25 cases, respectively; and used conventional ASL to determine low perfusion, isoperfusion, and hyperperfusion in the tumor area in 0, 9, and 21 cases, respectively. The results of qualitative analysis of rapid ASL and conventional ASL were highly consistent within and between groups ( Kappa was 0.830 and 0.850 respectively). The results of quantitative analysis of rapid ASL and conventional ASL were highly consistent within and between groups ( ICC 0.940—0.994). Conclusion:Rapid ASL with shorter scanning time could be applied in assessing tissue perfusion in brain glioma and contribute to the clinical diagnosis of gliomas.

Objective To analyze the predictive value of anti-rheumatoid arthritis-33(anti-RA33),interleu-kin-6(IL-6)and high-sensitivity C-reactive protein(hs-CRP)levels for treatment response in patients with rheumatoid arthritis(RA)based on the decision curve.Methods A total of 102 RA patients admitted to the hospital from January 2021 to August 2023 were selected.The clinical data of the patients were collected and their serum anti-RA33,IL-6 and hs-CRP levels were detected.After half a year of treatment with methotrex-ate and etanercept,the patients were divided into good response group and non-response group according to the treatment response.Pearson correlation analysis was used to analyze the correlation between the levels of anti-RA33,IL-6,hs-CRP and disease activity score 28(DAS28)in RA patients.Multivariate Logistic regres-sion analysis was used to analyze the influencing factors of non-response in RA patients.Receiver operating characteristic(ROC)curve was drawn to analyze the efficacy of anti-RA33,IL-6 and hs-CRP in non-response to RA.The decision curve was used to analyze the net benefit of anti-RA33,IL-6 and hs-CRP alone or in com-bination to predict the non-response of RA patients to treatment.Results After half a year of treatment,80 patients had good or moderate response(good response group)and 22 patients had no response(non-response group).The course of disease in the good response group was shorter than that in the non-response group,and DAS28 score was lower than that in the non-response group(P＜0.05).The levels of serum anti-RA33,IL-6 and hs-CRP in the good response group were lower than those in the non-response group(P＜0.05).Pearson correlation analysis showed that the levels of serum anti-RA33,IL-6 and hs-CRP were negatively correlated with DAS28 score(P＜0.05).Multivariate Logistic regression analysis showed that DAS28 score,anti-RA33,IL-6 and hs-CRP levels were the influencing factors of non-response to treatment in RA patients(P＜0.05).ROC curves showed that the area under the curve of serum anti RA33,IL-6,hs-CRP single and combined for predicting patients without reaction were 0.729,0.814,0.831,0.948,and the combined prediction value was higher.The decision curve analysis showed that within the scope of the most reasonable threshold.The overall net benefit of serum anti-RA33,IL-6 and hs-CRP combined predicted treatment responsiveness in RA patients was higher than the net benefit predicted alone.Conclusion The levels of anti-RA33,IL-6 and hs-CRP are closely related to the treatment response of RA patients.The combination of the three has high clinical value and net benefit in predicting no response to treatment.

Objective To study the therapeutic effect of the type Ⅰ tympanoplasty by the continuous irriga-ting endoscopic ear surgery mode.Methods A total of 50 patients with chronic suppurative otitis media,who pre-pared for the type Ⅰ tympanoplasty in our department,were divided into the traditional operation mode group(20 cases)and the continuous irrigating mode group(30 cases).All patients underwent underlay myringoplasty with tragus cartilage and perichondria limplant.The operation time and postoperative outcome of the two groups were compared and analyzed.Results The mean operation time of the traditional group and the irrigating operation group was 66.10±2.43 minutes and 46.81±5.12 minutes respectively,and there was statistical difference between the two groups(P＜0.05).The tympanic membrane healing rate of the traditional group and the irrigating operation group was 100.00％and 96.67％respectively,and there was no statistical difference between the two groups(P＞0.05).The mean air conduction threshold and the value of air-bone gap were significantly reduced at 2 months after operation compared with that before operation(P＜0.05).There was no significant difference between the two groups in the average pre and post-operative air-bone gaps(P＞0.05).The incidence rates of postoperative compli-cations were 10.00％and 3.33％,respectively,with no statistical significance(P＞0.05).Conclusion The contin-uous irrigating endoscopic ear surgery mode is safe and effective.Under the premise of ensuring clinical efficacy,the operation time is shortened,and it is worth popularizing in middle ear surgery.

ObjectiveTo analyze the prevalence of HCV antibody positive and associated factors among drug users in Dehong Prefecture， Yunnan， and to provide scientific evidence for HCV prevention. MethodsQuestionnaire surveys and serological testing were conducted among 400 drug users continuously selected from four national AIDS sentinel surveillance in Dehong Prefecture between January and July during 2014‒2021. Results11 683 drug users were included. The prevalence of HCV antibody positive was 20.2% overall， and 14.9%， 20.1%， 22.4%， 19.8%， 22.5%， 20.6%， 24.5%， 19.0% from 2014 to 2021， respectively （trend Z=-3.78， P<0.001）. Multivariable analysis indicated the following were independently associated with HCV antibody positive： that older age （OR=1.02， 95%CI： 1.02‒1.03）， male （OR=1.70， 95%CI： 1.19‒2.42）， unmarried （OR=1.64， 95%CI： 1.44‒1.87）， divorced or widowed （OR=1.73， 95%CI： 1.48‒2.02）， Jingpo ethnicity （OR=1.39， 95%CI： 1.19‒1.63）， injection drug use （OR=15.46， 95%CI： 13.13‒18.12）， and HIV infection（OR=4.96， 95%CI：4.12‒5.99）. ConclusionThe prevalence of HCV antibody positive among drug users in Dehong Prefecture is high and increases with some fluctuations during 2014 to 2021， which highlights the need to develop interventions targeting this population.