The development of novel point-to-point drugs targeting resistance mechanisms is a critical and popular research field; nevertheless, success remains challenging. Therefore, given the short survival time and heightened expectations of patients with advanced NSCLC, the design of various combination therapy strategies––integrating preclinical, clinical, and real-world evidence (such as radiotherapy, chemotherapy, targeted therapy, antibody–drug conjugates, oncolytic viruses, and cell therapy)––may be a wise and practical choice to address the disease. Resistance to immunotherapy involves almost all cell types in the body, primarily cancer cells and T cells involved in immune surveillance. As a result of space limitations, this article focuses on the progress and challenges of various combined strategies for directly eliminating cancer cells. We also emphasize the realignment of treatment goals, shifting from primarily focusing on eliminating cancer cells (via chemotherapy and radiotherapy) to fully utilizing immune regulation to overcome resistance to immune checkpoint inhibitors.

Objective This study aimed to investigate the antimicrobial resistance profiles of bacterial strains isolated from pediatric intensive care units(PICU)in China for better antimicrobial therapy.Methods Clinical isolates were collected from 17 institutions,including tertiary care children's hospitals and pediatric department of tertiary general hospitals in China from January 1,2020 to December 31,2022.Antimicrobial susceptibility testing was carried out according to a unified protocol using Kirby-Bauer method or automated systems.Results were interpreted according to the breakpoints released by the Clinical and Laboratory Standards Institute(CLSI)in 2020.Results A total of 10 688 isolates were collected,including gram-positive organisms(39.2％)and gram-negative organisms(60.8％).The top three organisms were S.aureus(13.6％,1 453/10 688),A.baumannii(10.0％,1 067/10 688),and coagulase-negative Staphylococcus(9.9％,1 058/10 688).Multi-drug resistant organisms(MDROs)were very common in children.The prevalence of methicillin-resistant Staphylococcus aureus(MRSA),carbapenem-resistant Enterobacterales(CRE),carbapenem-resistant E.coli,carbapenem-resistant K.pneumoniae(CRKP),carbapenem-resistant A.baumannii(CRAB),and carbapenem-resistant P.aeruginosa(CRPA)was 41.1％,19.4％,8.8％,30.9％,67.4％,and 28.8％,respectively.Overall,more than 50％of Enterobacteriales isolates were resistant to cephalosporins,while nearly 25％of Enterobacteriales isolates were resistant to carbapenems.MDROs were highly resistant to commonly used antibiotics.More than 80％of CRE and CRAB strains were resistant to all beta-lactam antibiotics.CRE and CRAB showed low resistance rates to tigecycline and polymyxin.CRPA showed lower resistance rates to piperacillin,beta-lactamase inhibitor combinations than the resistance rates to third and fourth generation cephalosporins.All of the Staphylococcus and Enterococcus isolates were susceptible to vancomycin and tigecycline.None of PRSP strains isolated from meningitis and nonmeningitis samples were resistant to rifampicin,vancomycin,or linezolid.The prevalence of β-lactamase-negative ampicillin-resistant(BLNAR)strains was 43.3％in Haemophilus influenzae.Conclusions MDROs were prevalent in PICU.It is necessary to establish an effective multidisciplinary team(MDT)to control the antimicrobial resistance.

Artificial joint replacement is an effective treatment for end-stage osteoarthritis. Joint perception is a new patient-specific outcome measurement tool for patient-reported outcomes that provides healthcare professionals with a new perspective on condition monitoring and follow-up management after joint replacement. This paper reviews the concept, research state, shortcomings and insights of postoperative joint perception in joint replacement patients, so as to improve the understanding and application of joint perception by healthcare professionals, and to provide a reference for optimizing clinical postoperative assessment of joint replacement and formulating intervention strategies for joint perception.

Objective This study aimed to investigate the antimicrobial resistance profiles of bacterial strains isolated from pediatric intensive care units(PICU)in China for better antimicrobial therapy.Methods Clinical isolates were collected from 17 institutions,including tertiary care children's hospitals and pediatric department of tertiary general hospitals in China from January 1,2020 to December 31,2022.Antimicrobial susceptibility testing was carried out according to a unified protocol using Kirby-Bauer method or automated systems.Results were interpreted according to the breakpoints released by the Clinical and Laboratory Standards Institute(CLSI)in 2020.Results A total of 10 688 isolates were collected,including gram-positive organisms(39.2％)and gram-negative organisms(60.8％).The top three organisms were S.aureus(13.6％,1 453/10 688),A.baumannii(10.0％,1 067/10 688),and coagulase-negative Staphylococcus(9.9％,1 058/10 688).Multi-drug resistant organisms(MDROs)were very common in children.The prevalence of methicillin-resistant Staphylococcus aureus(MRSA),carbapenem-resistant Enterobacterales(CRE),carbapenem-resistant E.coli,carbapenem-resistant K.pneumoniae(CRKP),carbapenem-resistant A.baumannii(CRAB),and carbapenem-resistant P.aeruginosa(CRPA)was 41.1％,19.4％,8.8％,30.9％,67.4％,and 28.8％,respectively.Overall,more than 50％of Enterobacteriales isolates were resistant to cephalosporins,while nearly 25％of Enterobacteriales isolates were resistant to carbapenems.MDROs were highly resistant to commonly used antibiotics.More than 80％of CRE and CRAB strains were resistant to all beta-lactam antibiotics.CRE and CRAB showed low resistance rates to tigecycline and polymyxin.CRPA showed lower resistance rates to piperacillin,beta-lactamase inhibitor combinations than the resistance rates to third and fourth generation cephalosporins.All of the Staphylococcus and Enterococcus isolates were susceptible to vancomycin and tigecycline.None of PRSP strains isolated from meningitis and nonmeningitis samples were resistant to rifampicin,vancomycin,or linezolid.The prevalence of β-lactamase-negative ampicillin-resistant(BLNAR)strains was 43.3％in Haemophilus influenzae.Conclusions MDROs were prevalent in PICU.It is necessary to establish an effective multidisciplinary team(MDT)to control the antimicrobial resistance.

Artificial joint replacement is an effective treatment for end-stage osteoarthritis. Joint perception is a new patient-specific outcome measurement tool for patient-reported outcomes that provides healthcare professionals with a new perspective on condition monitoring and follow-up management after joint replacement. This paper reviews the concept, research state, shortcomings and insights of postoperative joint perception in joint replacement patients, so as to improve the understanding and application of joint perception by healthcare professionals, and to provide a reference for optimizing clinical postoperative assessment of joint replacement and formulating intervention strategies for joint perception.

Female ; Humans ; Breast Neoplasms ; Testosterone ; Prolactin ; Estradiol ; Testosterone Congeners ; China

The emergence of SARS-CoV-2 variants of concern and repeated outbreaks of coronavirus epidemics in the past two decades emphasize the need for next-generation pan-coronaviral therapeutics. Drugging the multi-functional papain-like protease (PLpro) domain of the viral nsp3 holds promise. However, none of the known coronavirus PLpro inhibitors has been shown to be in vivo active. Herein, we screened a structurally diverse library of 50,080 compounds for potential coronavirus PLpro inhibitors and identified a noncovalent lead inhibitor F0213 that has broad-spectrum anti-coronaviral activity, including against the Sarbecoviruses (SARS-CoV-1 and SARS-CoV-2), Merbecovirus (MERS-CoV), as well as the Alphacoronavirus (hCoV-229E and hCoV-OC43). Importantly, F0213 confers protection in both SARS-CoV-2-infected hamsters and MERS-CoV-infected human DPP4-knockin mice. F0213 possesses a dual therapeutic functionality that suppresses coronavirus replication via blocking viral polyprotein cleavage, as well as promoting antiviral immunity by antagonizing the PLpro deubiquitinase activity. Despite the significant difference of substrate recognition, mode of inhibition studies suggest that F0213 is a competitive inhibitor against SARS2-PLpro via binding with the 157K amino acid residue, whereas an allosteric inhibitor of MERS-PLpro interacting with its 271E position. Our proof-of-concept findings demonstrated that PLpro is a valid target for the development of broad-spectrum anti-coronavirus agents. The orally administered F0213 may serve as a promising lead compound for combating the ongoing COVID-19 pandemic and future coronavirus outbreaks.
Animals ; Coronavirus Papain-Like Proteases/antagonists & inhibitors* ; Cricetinae ; Humans ; Mice ; Pandemics ; SARS-CoV-2/enzymology* ; COVID-19 Drug Treatment

Objective:To observe the effect of auricular point press needle on sleep quality of patients with gastric cancer after operation.Methods:From October 2017 to March 2019, a total of 80 patients underwent radical gastrectomy for gastric cancer in the First People's Hospital of Huzhou, Zhejiang Province were selected by using convenience sampling method, and divided into observation group and control group by random number table method, with 40 cases in each group. The control group received routine nursing, while the observation group received auricular point press needle on the basis of routine nursing. Sleep quality was monitored in both groups using sleep monitoring bracelets. In the course of the study, 2 patients in the observation group had surgical complications, and finally 35 patients completed the experiment; 2 patients in the control group had surgical complications, and a total of 33 patients completed the experiment.Results:From the 6th day of intervention (the 4th day after operation) , the sleep duration of the observation group was longer than that of the control group, and the difference was statistically significant ( P<0.05) , the group effect, time effect and interaction effect were statistically significant ( P<0.05) . From the 6th day of intervention (the 4th day after operation) , the proportion of deep sleep of the observation group was higher than that of the control group, and the difference was statistically significant ( P<0.05) , the group effect, time effect and interaction effect were statistically significant ( P<0.05) . Conclusions:Auricular point press needle can effectively improve the sleep quality of patients with gastric cancer after operation.

Objective To compare of the application of tracheal intubation guided by Lightwand,Shikani optical stylet,or Macintosh. Methods Ninety ASA Ⅰ~Ⅱ patients undergoing elective general anesthesia were randomly divided into three groups(n = 30):Macintosh group(group M),Lightwand group(group L)and Shi-kani optical stylet group(group S). MAP and HR were recorded at the time of entering the operating room(T1), before intubation(T2),at the immediate time of intubation(T3),3 mins(T4)and 5 mins after intubation(T5). The intubation duration,the first intubation success rate,the number of intubation,and the incidence of complications including sore throat were observed. Results As compared with T1,MAP and HR decreased significantly at T2in the three groups(P<0.05). As compared with T2,HR increased in group L and MAP and HR increased in group S at T3(P<0.05). As compared with group M,MAP and HR at T4and T5were lower in groups L and S(P<0.05). The first intubation time was obviously shorter in group L than in other groups(P<0.05). The incidence of compli-cations was lower in group S(P < 0.05). The first success rate of intubation,the intubation times and the inci-dence of airway complications did not differ significantly among the three groups.(P > 0.05). Conclusions As compared with Macintosh,Lightwand and Shikani optical stylet have less influence on hemodynamic parameters. Lightwand needs shorter intubation time,Shikani optical stylet has the lowest rate of sore throat.

OBJECTIVETo summarize the clinical features, biochemical change and genetic mutations of a neonate with congenital bile acid synthesis disorder type 2.

METHODSClinical features, blood biochemical index, gene analysis and treatment of the patient were reviewed.

RESULTSThe patient presented with the symptoms of jaundice 3 days after birth but without skin itching. Pale stool was noted. Subsequently, he presented with hepatomegaly, blood coagulation disorders, left cochlear nerve damage, liver cirrhosis and remarkable growth retardation. Serum biochemistries showed that bilirubin and transaminase were elevated, while γ -GT and total bile acid was normal. Abdominal ultrasonography indicated decline of gallbladder contraction. Cholangiography showed normal extra- and intrahepatic bile ducts and patent biliary tract. Liver biopsy showed intrahepatic cholestasis. Gene testing has identified a homozygous mutation in AKR1D1 gene.

CONCLUSIONCongenital bile acid synthesis disorder should be suspected when a neonate has presented with jaundice, elevated bilirubin and transaminase, normal or reduced TBA and γ -GT. Genetic testing and urine mass spectrometry analysis can diagnose congenital bile acid synthesis disorder. Early therapy is crucial to patients with congenital bile acid synthesis disorder.