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.

Abnormally activated CDK9 participates in the super-enhancer mediated transcription of short-lived proteins required for cancer cell survival. Targeting CDK9 has shown potent anti-tumor activity in clinical trials among different cancers. However, the study and knowledge on drug resistance to CDK9 inhibitors are very limited. In this study, we established an AML cell line with acquired resistance to a highly selective CDK9 inhibitor BAY1251152. Through genomic sequencing, we identified in the kinase domain of CDK9 a mutation L156F, which is also a coding SNP in the CDK9 gene. By knocking in L156F into cancer cells using CRISPR/Cas9, we found that single CDK9 L156F could drive the resistance to CDK9 inhibitors, not only ATP competitive inhibitor but also PROTAC degrader. Mechanistically, CDK9 L156F disrupts the binding with inhibitors due to steric hindrance, further, the mutation affects the thermal stability and catalytic activity of CDK9 protein. To overcome the drug resistance mediated by the CDK9-L156F mutation, we discovered a compound, IHMT-CDK9-36 which showed potent inhibition activity both for CDK9 WT and L156F mutant. Together, we report a novel resistance mechanism for CDK9 inhibitors and provide a novel chemical scaffold for the future development of CDK9 inhibitors.

Objective:To compare the clinicopathological differences between elderly and non-elderly patients with idiopathic membranous nephropathy(IMN).Methods:Patients diagnosed with IMN via renal biopsy at Beijing Huairou Hospital, Beijing Changping Hospital of Traditional Chinese Medicine, and Beijing Hospital of Traditional Chinese Medicine from January 2017 to August 2021 were retrospectively enrolled.They were classified into the elderly group(≥65 years)and the non-elderly group(<65 years), and the clinicopathological differences between the two groups were compared.Results:A total of 207 IMN patients were included in the study, with a male to female ratio of 1.7∶1.0.There were 56 patients in the elderly group, aged(68.2±3.1)years, and 151 patients in the non-elderly group, aged(48.2±6.2)years.Compared with the non-elderly group, the elderly group had a longer time from onset to renal biopsy and a higher proportion of patients with renal insufficiency and hypertension( P<0.05). The elderly group had a lower eGFR, lower serum albumin, higher serum cholesterol, and higher low-density lipoprotein than the non-elderly group( P<0.05). The proportions of patients with glomerulosclerosis, renal tubular atrophy, and interstitial fibrosis in the elderly group were higher than in the non-elderly group( P<0.05). The positive rates of glomerular PLA2R antigen staining in the two groups were 90.6%(29/32)and 91.0%(111/122), respectively, and there was no statistically significant difference between the two groups.IgG4 deposition represented the most common IgG subtype, with 93.8%(30/32)in the elderly group and 94.3%(115/122)in the non-elderly group.There was no statistical significance between the two groups( P>0.05). Conclusions:Compared with non-elderly IMN patients, a higher proportion of elderly IMN patients has renal insufficiency, hypertension and chronic renal pathology.The glomerular deposition of pathogenic antigens in elderly IMN patients was similar to that in non-elderly IMN patients, suggesting no difference in pathogenesis between the two groups.The clinicopathological differences between the two groups may be related to age and complications.

Objective To explore the efficacy of continuous renal replacement therapy (CRRT) in the treatment of neonatal acute kidney injury (AKI).Methods Totally 17 critically ill neonates treated with CRRT were selected who were hospitalized at Department of Neonatology,Shanghai Children's Hospital,Children's Hospital Affiliated to Shanghai Jiaotong University,from June 2012 to June 2017,and among them there were 15 cases with AKI,and the clinical data of these 15 patients were retrospectively analyzed,while 15 AKI neonates were treated with CRRT combined with conventional treatment.The model for CRRT was continuous veno-venous hemofiltration dialysis (CVVH-DF) in 13 cases,plasma exchange (PE) in 2 cases.The changes of blood pressure(BP),renal function,electrolyte,acid-base balance index and hemodynamic indicators were analyzed respectively before CRRT treatment,12 h,24 h,48 h after treatment and by the end of CRRT treatment.The efficacy of CRRT treatment was evaluated in these 15 AKI neonates.Results Gestational age of 15 AKI newborns was 33 +4-40 +1 weeks,admission day age was 2-28 days,birth weight was 2.25-4.00 kg.Primary diseases were severe asphyxia in 6 cases,neonatal septicemia in 5 cases,congenital hereditary metabolic disease in 2 cases,traumatic asphyxia in 1 case,and liver failure in 1 case.CRRT treatment persisted for 49-190 hours.BP value [(50.8 ± 6.57) mmHg(1 mmHg =0.133 kPa)] could reach normal level after 12 h CRRT treatment,and blood pH value (7.31 ± 0.25) increased significantly after 12 h CRRT treatment,while blood K+[(5.51 ±1.86) mmoL/L],urea nitrogen (BUN) [(9.5 ±3.7) mmol/L],creatinine(Cr) [(93± 14)μmol/L] significantly decreased after 12 h CRRT treatment,and reached the normal range [K + (4.78 ± 2.95)mmol/L,BUN (7.5 ±2.1) mmol/L,Cr (54 ± 13) μmol/L] after 24 h treatment,but urine volume[(0.8 ±0.2)mL/(kg· h)] significantly increased after 24 h treatment.Partial pressure of oxygen/fraction of inspired oxygen reached 200 mmHg after 12 h treatment and more than 300 mmHg after 24 h treatment.CRRT treatment of 15 AKI neonates turned out to be effective.Conclusions CRRT can effectively improve the internal environment of AKI neonates and reduce the death rate of neonatal AKI,which can provide an effective adjuvant treatment measures for the treatment of AKI neonates.

Objective To study efficacy and safety of continuous renal replacement therapy (CRRT) in the treatment of neonatal sepsis-related acute kidney injury (AKI).Method From June 2011 to June 2018,neonates with sepsis-related AKI hospitalized in the neonatal intensive care unit of our hospital and treated with CRRT were enrolled.Before CRRT,12 h,24 h,48 h after CRRT and by the end of CRRT,their clinical data including renal function,acid-base balance,electrolytes,blood pressure (BP)and the change of hemodynamic indexes were retrospectively analysed.The efficacy and safety of CRRT was evaluated.Kruskal-wallis H test was used for statistical analysis.Result A total of 9 cases of sepsis-related AKI neonates were enrolled in the study,all treated with continuous veno-venous hemofiltration dialysis.5 cases had oliguria,2 cases fluid overload and 2 cases shock.The duration of CRRT was 49 ～ 110 h (76.2 ±23.5) h.12 h after CRRT,BP were maintained at 40 ～60 mmHg and stable during the treatment,the blood pH value increased to 7.35 ～ 7.45 and the oxygenation index reached 200 mmHg.24 h after CRRT,the oxygenation index rose to more than 300 mmHg.Serum potassium,urea nitrogen and creatinine levels decreased significantly after 12 h of CRRT,and reached the normal range after 24 h of CRRT.After 24 h of CRRT,the urine volume significantly increased.Venous catheterization was performed successfully in 9 cases.2 cases had thrombocytopenia,1 case catheterization obstruction and 1 case hypotension during CRRT.No complications such as hypothermia,hemorrhage,thrombosis or infection occurred.All 9 patients were cured and discharged.Conclusion CRRT is safe and effective for the treatment of neonatal sepsis-related AKI.

Objective To study the clinical efficacy and safety of extracorporeal membrane oxygenation (ECMO) in critically ill neonates.Method From November 2016 to September 2018,the clinical data of 5 cases who received ECMO treatment in NICU of our hospital were retrospectively analyzed.The indication of ECMO was reversible respiratory failure irresponsive to conventional therapy.The treatment mode was V-A ECMO.Oxygenation index (OI),vasoactive-inotropic score,blood lactate before and 24 h after ECMO were recorded.Complications of ECMO were also studied.Paired t-test was used to compare the pre and post treatment parameters.Result Among the 5 cases,4 cases were male and 1 case was female.3 cases were diagnosed with meconium aspiration syndrome,2 cases pulmonary hypertension.OI[(9.5 ± 1.8) vs.(60.6 ± 19.4)],vasoactive-inotropic score[(19.5 ± 12.0) points vs.(204.0 ± 143.8) points]and blood lactate [(2.8 ± 1.5) mmol/L vs.(9.6 ± 3.6) mmol/L]) were all significantly decreased at 24 h after ECMO treatment (P ＜ 0.05).During follow-up,3 cases survived,2 cases died.All the 5 cases showed thrombocytopenia,3 cases developed renal failure and received continuous renal replacement therapy,1 case got intracranial hemorrhage.2 of the 3 survived cases developed neurological impairment and need long term follow-up and rehabilitation therapy.Conclusion ECMO treatment has remarkable effects on critically ill neonates and may actually save lives,but the risk of complications are quite high.

Objective To explore the efficacy and safety of endoscopic nasal vestibule cysts,lip gingival trench path nasal vestibule excision and low temperature plasma radiofrequency ablation under nasal endoscope in the treatment of nasal vestibule cyst.Methods From January 2013 to December 2017,ninety patients with nasal vestibule cyst admitted in Taiyuan Central Hospital were selected. According to different surgical methods,the patients were divided into nasal endoscope nasal vestibule cyst group( A group,26 cases),cleft lip gingival vestibule cyst excision group(B group,36 cases),low temperature plasma radiofrequency ablation group under nasal endoscopy( C group, 28 cases). The efficacy and safety of the three types of operation were compared. Results The operation time [(15.5 ± 3.6) min] and wound healing time [( 2. 3 ± 0. 9 ) d] in A group and the operation time [( 16. 3 ± 4.5)min],wound healing time[(2.1 ± 0.5)d] in C group were all significantly shorter than those in B group,the differences were statistically significant(t=5.268,4.698,5.624,4.267,all P<0.05).The amount of bleeding in C group[(9.3 ± 0.6)mL] was the least,followed by A group[(12.2 ± 1.7)mL],and the difference among the three groups was statistically significant(t=8.256,7.254,all P<0.05).The postoperative wound VAS score among the three groups was statistically significant(F=12.674,P<0.001),and the VAS score in C group[(1.6 ± 0.7)points]

ObjectiveTo investigate the timing and efficacy of continuous renal replacement therapy (CRRT) in neonatal acute kidney injury (AKI).MethodsNineteen AKI neonates treated with CRRT were enrolled during hospitalization in the Department of Neonatology of the Children's Hospital of Shanghai from June 2011 to June 2018. Their clinical data were retrospectively analyzed. According to their baseline renal function, these neonates were divided into two groups using an improved RIFLE (Risk, Injury, Failure, Loss and End-stage renal disease) standard: AKI stage 1-2 group and AKI stage 3 group. CRRT included continuous veno-venous hemodiafiltration (CVVHDF) and plasma exchange (PE). Several parameters included blood pressure (BP), renal function, electrolyte, blood gas and hemodynamic indicators were analyzed before, 12 h, 24 h, and 48 h after the initiation of CRRT and at the end of CRRT. Changes in neonatal renal function before, 24 h after the initiation of CRRT and at the end of CRRT were compared between the two groups. Efficacy of CRRT was evaluated, and clinical outcomes were analyzed. Kruskal-WallisH-test ort-test was applied for statistic analysis.Results(1) Among the 19 neonates with AKI, there were 12 in stage 1-2 and seven in stage 3. Seventeen cases were treated with CVVHDF, and the other two underwent plasma exchange. The duration of CRRT was 49-190 h with an average of (89.2±33.9) h. (2) After 12 h of CRRT, the blood pressure of all 19 AKI neonates returned to normal (40-60 mmHg, 1 mmHg=0.133 kPa) and was maintained at that level during the treatment. The blood pH value also increased to a normal range (7.35-7.45) at the same time. The oxygenation index reached 200 mmHg after 12 h of CRRT and rose to over 300 mmHg after 24 h. The levels of serum potassium, urea nitrogen, and creatinine decreased significantly after 12 h of CRRT and reached the normal range after 24 h of CRRT. After 24 h of CRRT, the urine volume significantly increased. (3) Serum levels of urea nitrogen and creatinine in neonates with AKI stage 1-2 decreased significantly after 24 h of CRRT. At any time points before and after CRRT (24 h before, 24 h after and at the end of CRRT), serum levels of urea nitrogen and creatinine in AKI stage 3 neonates were higher than those in AKI stage 1-2 neonates [urea nitrogen: (15.8± 4.1) mmol/L vs (10.2±5.1) mmol/L, (11.5±2.4) mmol/L vs (6.3±2.3) mmol/L, (9.8±2.1) mmol/L vs (5.1± 2.2) mmol/L,t=2.468, 2.226 and 2.171, respectively; creatinine: (184±32) μmol/L vs (152±26) μmol/L, (110±35) μmol/L vs (87±25) μmol/L, (63±12) μmol/L vs (44±9) μmol/L,t= 2.404, 2.423 and 3.972, respectively; allP<0.05]. (4) Venous catheterization was successful in the 19 AKI neonates. Three cases were complicated with thrombocytopenia, two with obstruction and two with hypotension during CRRT. Complications such as hypothermia, hemorrhage, thrombosis, and infection were not reported. (5) Among the 19 AKI neonates, 12 (including five of severe asphyxia, five of septic sepsis and two of inherited metabolic disorders and in metabolic crisis) were cured and discharged. The other seven cases (two in stage 1-2 and five in stage 3) lived through the oliguria stage but died after their family members gave up the treatment.ConclusionsCRRT is a safe and effective management for neonatal AKI. The optimal opportunity for CRRT treatment in AKI neonates should be at stage 1-2.

Objective Using middle cerebral artery occlusion (MCAO) model to observe protective effect of effective components of bezoar on brain damage.To discuss the anti-cerebral ischemia mechanism and compare the efficacy of effective components of bezoar from the endoplasmic reticulum stress intervention angle.Methods Rats were stratified randomly divided into sham group,model group,Qingkailing group (positive drug,3 mL/kg),taurine group,ursodeoxycholic acid (UDCA,78 mg/kg) group,taurine-conjugated ursodeoxycholic acid (TUDCA,100 mg/kg) group.Through establish MCAO model in rats,observed the scores of the neurologic impairment,measured infarct volume by TTC.Immunohistochemistry and Western blotting were Used to detect the content of P-PERK,P-EIF2α,and ATF4.Results Compared with sham group,neurologic impairment scores of model group significantly reduced (P ＜ 0.01).Compared with model group,Qingkailing group,UDCA group,and TUDCA group significantly improved neurological function in rats (P ＜ 0.05,0.01).Compared model group,all the treatment groups could significantly reduce the volume of cerebral infarction (P ＜ 0.01).Compared with sham group,expression of P-PERK,P-EIF2α,and ATF4 was significantly increased (P ＜ 0.01).Compared with model group,all the treatment groups reduced the expression of P-PERK,P-EIF2α,and ATF4 in varying degrees,effect of Qingkailing and TUDCA were more obvious.Conclusion The effective components ofbezoar alleviate cerebral ischemia reperfusion injury in rats by inhibiting endoplasmic reticulum stress,the effect of TUDCA is better than that of taurine and UDCA.

Objective To investigate the effects of low frequency repetitive transcranial magnetic stimulation (rTMS) on non-fluent aphasia in patients after stroke.Methods Forty stroke patients displaying non-fluent aphasia were randomly assigned to an rTMS group and a control group using a random number table.Both groups were treated with conventional language therapy,while the rTMS group was additionally given 0.5 Hz rTMS over the Broca's homologues of the unaffected hemisphere 5 days a week for 3 weeks.The patients were stimulated at 90％ of the motor threshold (MT),with 16 second trains and intervals of 3 seconds 48 times (384 pulses) in a session.Before and after the 3 weeks of treatment,the Western Aphasia Battery (WAB) and the Communicative Abilities in Daily Living (CADL) test were conducted in both groups to evaluate their language function and communication ability.Results Only spontaneous speech improved significantly (P＜0.05) in the control group after 3 weeks of treatment.In the rTMS group,the spontaneous speech,auditory comprehension,repetition,naming and aphasia quotient (AQ) had all improved significantly (P＜0.05).Moreover,after the treatment,the average score of the auditory comprehension (153.90± 31.79),repetition (82.65± 15.14),naming(81.28±22.12) and AQ (63.66± 13.64) of the rTMS group were significantly higher than those of the control group (P＜0.05).Conclusion rTMS applied to the Broca's homologues of the unaffected hemisphere can significantly improve language function in those exhibiting non-fluent aphasia after stroke.