A 62-year-old man with hepatocellular carcinoma began to take tyrosine kinase inhibitor(TKI)lenvatinib orally.After taking the medicine for a week,the patient developed watery diarrhea 2 to 3 times a day.The patient received the first dose of tislelizumab.After 20 days,the patient's diarrhea worsened,nearly 40 times a day.Lenvatinib was discontinued and the second dose of tislelizumab was received,while the diarrhea was not significantly relieved.Treatments were given upon the symptoms and diarrhea was alleviated so that lenvatinib was restarted,diarrhea aggravated again and the drug was discontinued.Acute colitis complicated with colon erosion was diagnosed by colonoscopy which was presumed to be immure-associated colitis caused by programmed cell death protein 1(PD-1).The patient was admitted to hospital for liver transplantation.After the administration of immunosuppressive drugs against graft rejection,the diarrhea gradually cleared.Diarrhea caused by anti-PD-1 antibody is usually mild.In this case,mild diarrhea caused by TKI developed rapidly into severe colitis after the first dose of anti-PD-1 antibody.Mechanism of the increasing rate of adverse effect caused by the combined use of TKI and anti-PD-1 antibodies worth further discussion.

Objective To systematically analyze the research hotspots and development trends of drug resistance mechanisms in renal cell carcinoma(RCC),and to provide a reference for research in this field.Methods The literature related to drug resistance in treatment of RCC was obtained from Web of Science core collection.CiteSpace software was used for keyword clustering and trend analysis,and VOSviewer software was used for keyword co-occurrence network analysis.Results In total,1 392 literature were incorporated,including 736 regarding targeted therapy,158 in immunotherapy,and 369 in chemotherapy.The overall research trend in this field was on the rise,in which the research on targeted therapy resistance occupies a dominant position,and immunotherapy resistance was a new research direction.Key words in this field were focused on molecular mechanisms of drug resistance,potential signaling pathways,combination therapy,indicators,and novel therapy.The evolution of keywords and theme words suggests that the research tendency of RCC targeted therapy resistance in recent years focuses on the exploration of new mechanisms of drug resistance and the application of multi-target drugs.The research trend of immunotherapy resistance highlights combination therapy,tumor microenvironment,and metastasis correlation.The research trend of chemotherapy resistance focused on pharmacokinetic-related factors,multidrug resistance genes.Conclusion To provide references for researchers to accurately grasp the research status and development trend of drug resistance in RCC.

Prostate cancer is recognized as a malignant tumor intricately linked to metabolic dysregulation, and its association with diabetes is notably complex. In recent years, there has been a surge in the development and clinical application of numerous oral antidiabetic medications, which have yielded promising results. Concurrently, an increasing body of research has uncovered the beneficial roles of these oral antidiabetic medications in the management of prostate cancer. This article provides a comprehensive review of the current research exploring the association between the use of oral antidiabetic medication and the treatment of prostate cancer.

Objectives:To analyze the epidemiological characteristics of osteoporosis and osteopenia in patients with lumbar degenerative diseases,and to evaluate the predictive values of Osteoporosis Self-Assess-ment Screening Tool for Asians(OSTA)score and body mass index(BMI)for osteoporosis in this population.Methods:The clinical data of 432 patients with lumbar degenerative diseases admitted to the Department of Orthopedics of Huashan Hospital from January 2020 to December 2022 were analyzed retrospectively,including 120 males with an average age of 72.0±5.4 years and 312 females with an average age of 67.2±31.1 years old.All the patients underwent dual-energy X-ray absorptiometry(DXA)examination and lumbar CT scan in our hospital within 3 months before admission or after admission.OSTA score and BMI were calculated based on patient's age,height,and weight.Chi-square test was used to compare the incidence rates of osteoporosis and osteopenia in patients of different ages and genders.Receiver operating characteristics(ROC)curve was constructed and the area under the curve(AUC)was calculated.After determining the optimal cutoff value,the sensitivity,specificity,positive predictive value,and negative predictive value were calculated at this cutoff value.Results:According to the DXA examination results,the prevalence rates of osteoporosis in male patients over 65 years old and female patients over 50 years old were 14.17％and 37.50％respectively,and the prevalence rates of osteopenia were 52.50％and 48.08％respectively.The diagnostic compliance rate of lumbar and total hip DXA was 60.2％.In female patients of different age groups,the prevalence of osteoporosis or osteopenia increased in older age group,but the difference was not statistically significant.The prevalence of osteoporosis in women over 65 years old was greater than in men over 65 years old(P=0.000).Among the 297 patients diagnosed with osteopenia or normal bone mass by DXA,11.78％of them met the diagnostic criteria for osteoporosis in CT examination.The sensitivity of the OSTA score in predicting osteoporosis in male and female patients with lumbar degenerative disease was both 55.56％,and the negative predictive values were 89.04％and 79.19％,respectively,indicating limited predictive value for osteoporosis.The AUC of BMI in male and female patients with lumbar degenerative disease were 0.672 and 0.668 respectively,with sensitivities of 77.78％and 73.50％,and the negative predictive values of 93.10％and 76.69％respectively.The BMI had certain predictive value for osteoporosis.After correcting the diagnosis of osteoporosis with lumbar CT examination,the screening efficacy of OSTA score and BMI improved in both male and female patient populations.Conclusions:The epidemiological characteristics of osteoporosis in patients with lumbar degenerative diseases are high prevalence and low treatment rate.The prevalence of osteoporosis in women is significantly higher than that in men.The OSTA score has limited value in predicting osteoporosis,while BMI can be used as one of the initial screening tools for osteoporosis in this population.

Objective:To investigate the effect of separation exercise training of upper limb robot in improving upper limb motor function of stroke patients,and to explore the underlying mechanism by transcranial magnetic stimu-lation motor-evoked potential(MEP)evoked potentials. Method:Stroke patients were randomly divided into the experimental group(n=21)and the control group(n=23).The experimental group was trained with a fixed trajectories(the separation movement of elbow flexion-extension and shoulder adduction-abduction),while the control group underwent upper limb robot training with random movement trajectories(a compound action that can reach for objects).Both groups received robot train-ing once a day,20min/time,5 times/week for 3 weeks.The Fugl-Meyer assessment of upper extremity(FMA-UE)and modified Barthel index(modified Barthel index,MBI)were used to evaluate motor function.The la-tency period and central motor conduction time(CMCT)of MEP were detected before and after treatment. Result:After 3 weeks of treatment,the FMA-UE,MBI and MEP were improved compared with before treat-ment in the experimental group(P＜0.05),There was no significant difference between the FMA-UE,MBI and MEP of the control group and that before treatment(P＞0.05);There were no significant differences in in FMA-UE,MBI and MEP between-group comparisons after 3 weeks of treatment. Conclusion:The separation exercise training of the upper limb robot can improve the upper limb motor func-tion and enhance daily living activities in stroke patients,which may be related to enhanced remodeling of brain function in stroke patients.

Objective:To explore the overall modulatory effect of the intermittent theta burst stimulation(iTBS),a novel non-invasive brain stimulation technique,on the topology of the brain functional network in stroke patients. Method:Sixteen patients with stroke were recruited.Based on their brain resting-state functional magnetic reso-nance images,the changes of the brain network topological properties,including the clustering coefficient,characteristic path length,local and global efficiency,"small-world",assortativity and hierarchy,were ana-lyzed before and after one session of left M1 iTBS. Result:The clustering coefficient,local efficiency and normalized hierarchy coefficient decreased significantly after one session of the iTBS,the global efficiency decreased near significantly,and the σ value of"small-world"increased close to significantly;while the other topological properties showed no significant change fol-lowing the iTBS intervention. Conclusion:The findings of the present study indicated that the left M1 iTBS may modulate the global net-work topological characteristics of the brain functional network in patients with stroke.

Objective To monitor the susceptibility of clinical isolates to antimicrobial agents in tertiary hospitals in major regions of China in 2022.Methods Clinical isolates from 58 hospitals in China were tested for antimicrobial susceptibility using a unified protocol based on disc diffusion method or automated testing systems.Results were interpreted using the 2022 Clinical &Laboratory Standards Institute(CLSI)breakpoints.Results A total of 318 013 clinical isolates were collected from January 1,2022 to December 31,2022,of which 29.5％were gram-positive and 70.5％were gram-negative.The prevalence of methicillin-resistant strains in Staphylococcus aureus,Staphylococcus epidermidis and other coagulase-negative Staphylococcus species(excluding Staphylococcus pseudintermedius and Staphylococcus schleiferi)was 28.3％,76.7％and 77.9％,respectively.Overall,94.0％of MRSA strains were susceptible to trimethoprim-sulfamethoxazole and 90.8％of MRSE strains were susceptible to rifampicin.No vancomycin-resistant strains were found.Enterococcus faecalis showed significantly lower resistance rates to most antimicrobial agents tested than Enterococcus faecium.A few vancomycin-resistant strains were identified in both E.faecalis and E.faecium.The prevalence of penicillin-susceptible Streptococcus pneumoniae was 94.2％in the isolates from children and 95.7％in the isolates from adults.The resistance rate to carbapenems was lower than 13.1％in most Enterobacterales species except for Klebsiella,21.7％-23.1％of which were resistant to carbapenems.Most Enterobacterales isolates were highly susceptible to tigecycline,colistin and polymyxin B,with resistance rates ranging from 0.1％to 13.3％.The prevalence of meropenem-resistant strains decreased from 23.5％in 2019 to 18.0％in 2022 in Pseudomonas aeruginosa,and decreased from 79.0％in 2019 to 72.5％in 2022 in Acinetobacter baumannii.Conclusions The resistance of clinical isolates to the commonly used antimicrobial agents is still increasing in tertiary hospitals.However,the prevalence of important carbapenem-resistant organisms such as carbapenem-resistant K.pneumoniae,P.aeruginosa,and A.baumannii showed a downward trend in recent years.This finding suggests that the strategy of combining antimicrobial resistance surveillance with multidisciplinary concerted action works well in curbing the spread of resistant bacteria.

Objective To examine the quinolone resistance and mechanisms of resistance,including prevalence of transferable mechanisms of quinolone resistance(TMQR)genes in carbapenem-resistant Klebsiella pneumoniae(CRKP).Methods Antimicrobial susceptibility was tested for CRKP isolated from 7 hospitals in China during 2019 by broth microdilution method.Genome sequencing analysis was performed on Illumina HiseqX sequencing platform.The virulence genes,multilocus sequence typing(MLST),chromosome quinolone resistance-determining region(QRDR)variation,and prevalence of TMQR genes in CRKP were analyzed.Results Overall,98.4％and 99.2％of the 481 CRKP strains were non-susceptible to levofloxacin and ciprofloxacin,respectively.ST11(77.8％)and ST15(15.8％)were the dominant clones.Among the 303 CRKP strains carrying virulence gene(CV-CRKP),ST11 type and ST15 type strains accounted for 92.1％and 5.0％,respectively,while ST11 and ST15 type strains accounted for 53.4％and 34.3％in the 178 CRKP strains without the virulence gene(non-CV-CRKP).All of the ST11 and ST 15 type strains were resistant to quinolones associated with gyrA and parC mutation.All of the quinolone-sensitive strains were not ST11 type or not ST15 type.TMQR analysis showed that qnrS1(61.1％,294 strains),qnrB4(10.0％,48 strains)and aac(6)-Ib-cr(18.7％,90 strains)were most prevalent in CRKPs,while qnrB1(4 strains),qnrB2(2 strains),qnrD1(2 strains)and qnrB6(1 strain)were infrequently identified in CRKPs.Specifically,qnrB4 was mainly identified in high-level levofloxacin-resistant strains(MIC≥8 mg/L),while aac(6)-Ib-cr was found mainly in ciprofloxacin-resistant strains(MIC＞8 mg/L).Conclusions Clinical CRKPs were highly resistant to quinolone.The rate of QRDR variation were high in quinolone resistant CRKP strains,with high TMQR gene carriage.

Objective To investigate the distribution and antimicrobial resistance of Enterobacter cloacae complex(ECC)isolated from a tertiary hospital in Shanghai.Methods Clinical ECC isolates were collected from 2018 to 2020.Antimicrobial susceptibility test was performed with broth microdilution and agar dilution methods.PCR was applied to detect five carbapenemase genes(blaKPC,blaNDM,blaIMP,blaVIM and blaOXA-48).Results A total of 222 ECC isolates were collected from 2018-2020,including 36 strains(16.2％)from general surgery department.The strains were mainly isolated from sputum(41.0％)and urine(20.3％).MIC results showed that the isolates were highly resistant to trimethoprim-sulfamethoxazole,the second-and third-generation cephalosporins,aztreonam and quinolones(31.1％-71.2％resistant),but low resistance rates to tigecycline,amikacin,mecillinam,and ceftazidime-avibactam(0.5％-9.0％resistant).About 9.5％and 10.4％of the strains were resistant to meropenem and imipenem,respectively.A total of 34 ECC strains were carbapenem-nonsusceptible strains,of which 23 strains were resistant to carbapenems.Among the 34 carbapenem-nonsusceptible strains,25(73.5％)strains were susceptible to mecillinam,including 15 strains producing metallo-β-lactamase.PCR assay identified carbapenemase genes in 21 of the 34 carbapenem-nonsusceptible strains,including blaNDM(14 strains),blaIMP(5 strains)and blaKPC(2 strains).Compared with the strains isolated in 2018,the ECC strains isolated in 2019 and 2020 showed significantly higher resistance rates to imipenem and ceftazidime-avibactam(P＜0.05),primarily associated with the production of NDM.Among the ECC strains resistant to third-generation cephalosporins,20.4％were resistant to imipenem and meropenem,while 4.9％and 8.7％were resistant to amikacin and mecillinam,respectively,and 9.7％were nonsusceptible to tigecycline.Conclusions The ECC isolates in 2019 and 2020 showed increasing resistance rates to carbapenems and ceftazidime-avibactam due to the production of metallo-β-lactamases.Some of the metallo-β-lactamase-producing ECC isolates were susceptible to mecillinam.

Objective To establish an ultra-performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS)method for determination of tobramycin in human serum,and examine the utility of the method in a clinical pharmacokinetic study of tobramycin inhalation.Methods Serum samples were pretreated by solid phase extraction with tobramycin-D12 as internal standard.Chromatographic separation was performed on a TitankHilic(2.1 mm × 100 mm,3 μm)column.The mobile phase consisted of0.1％formic acid-acetonitrile and 0.1％formic acid aqueous solution at a flow rate of 0.4 mL/min.Electrospray ionization source and multiple reaction monitoring(MRM)scanning were used for monitoring the quantitative ion pairs with m/z 468.3→m/z 163.3(tobramycin)and m/z 480.6→m/z 166.2(tobramycin-D12).The established method was investigated in terms of selectivity,interaction,concomitant medication,standard curve and lower limit of quantitation,precision and accuracy,recovery,matrix effect,and stability of tobramycinin.Results The linear range of tobramycin was 0.050 0-10.0 mg/L(R2=0.999 5).The intra-and inter-batch precision was satisfactory(coefficient of variation[CV]≤3.6％).The accuracy ranged from-0.4％to 6.0％.The matrix effect factor(MF)in human serum samples(including hemolysis and lipemia)ranged from 92.2％to 94.9％(CV≤2.7％).The recovery of tobramycinin was 79.5％-81.9％in serum samples,while the recovery of internal standard was 78.9％.The analyte was stable in serum samples for 72 h at room temperature and for 274 days at-20℃/-70℃.The pharmacokinetic study of tobramycin inhalation in bronchiectasis patients showed that after continuous administration of tobramycin 300 mg twice a day to 3 patients,the mean Cmax of tobramycin was(0.72±0.61)mg/L on Day 1 and(0.76±0.73)mg/L on Day 28,respectively.The corresponding Tmax was(1.83±0.61)h and(1.50±0.50)h,respectively.Conclusions The UPLC-MS/MS method established in this study is sensitive,accurate and rapid.It is successfully applied to the clinical pharmacokinetic study of tobramycin inhalation.The method may be suitable for therapeutic drug monitoring of tobramycin in clinical practice.