Tigecycline(TGC)is a recently developed broad-spectrum and highly effective glycylcy-cline antibiotic that overcomes traditional tetracycline resistance mechanisms.It is widely used in the treatment of complex skin and intra-abdominal infections.However,the emergence of TGC re-sistance in recent years poses a significant challenge,and its underlying resistance mechanisms re-main incompletely understood,warranting further investigation.This study induced TGC resistance in Klebsiella aerogenes(ATCC-43864)under in vitro conditions and evaluated phenotypic chan-ges,including growth curves,motility,multidrug susceptibility,and ultrastructural alterations,be-fore and after induction.Whole-genome sequencing(WGS)and transcriptome sequencing(RNA-seq)were employed to analyze resistance-related genetic changes,which were further validated.Ef-flux pump inhibition assays and Red homologous recombination were used to investigate the roles of efflux pumps,lon deletion,and rpsM mutation in TGC resistance.A stable resistant strain,CF-T-32,was obtained,with a 32-fold increase in TGC minimum inhibitory concentration(MIC).CF-T-32 exhibited an enlarged periplasmic space between the cell wall and membrane,reduced growth and motility,and no significant changes in susceptibility to 28 antimicrobial agents,including doxy-cycline,gentamicin,and ciprofloxacin.Genomic analysis revealed no significant differences in ge-nome composition or interference from exogenous plasmids between the parental and induced strains.However,two missense mutations were identified in rpsM and lon.Transcriptomic analysis and qPCR validation showed significant upregulation of efflux pump genes(acrA and acrB)in the AcrAB-TolC system and downregulation of ribosomal protein genes(rpsM,rpsJ,and rpsC).Ef-flux pump inhibition and Red homologous recombination experiments demonstrated that the rpsM C287T missense mutation,leading to a Pro96Leu substitution and reduced expression,is likely the primary factor contributing to TGC resistance in the induced strain.

Objective To study the technological innovation efficiency of the pharmaceutical manufacturing industry and its relationship with industrial development.Methods The data from the China Statistical Yearbook,China High Tech Statistical Yearbook,the statistical yearbook data of regional statistical bureaus was collected to evaluate the technological innovation efficiency of the pharmaceutical manufacturing industry in 29 provinces and cities in China based on the super-efficiency three-stage SBM model.And then,the spatial econometric model and panel quantile regression model were used to conduct empirical research.Results The average technological innovation efficiency of the pharmaceutical manufacturing industry in 29 provinces was 0.49,with the east greater than the central region,and the central region greater than the west.The technological innovation efficiency of pharmaceutical manufacturing industry has a significant positive correlation with its industrial development,and the marginal effect of this effect shows a law of diminishing in regions with low to high development level,and there is a significant positive spatial spillover effect of pharmaceutical manufacturing industry development between regions.Conclusions The central and western provinces,which have relatively weak pharmaceutical manufacturing industries,should improve the innovation environment and talent supply to enhance the efficiency of technological innovation.Concerted efforts should be made to vigorously promote exchanges,connections,and cooperation between regions with strong technological innovation efficiency and their surrounding areas.And it is imperative to encourage top domestic pharmaceutical companies to significantly increase their investment in the research and development of innovative drugs and to actively engage in international competition.

Objective To investigate the protective effects and mechanisms of sulodexide on renal fibrosis induced by prolonged warm ischemia. Methods An in vivo ischemia-reperfusion injury (IRI) model was established in rats, which were randomly divided into Sham group, IRI 60 min group (IRI group), and IRI 60 min + sulodexide group (IRI+SDX group), with 20 rats in each group. Pathological examination was used to evaluate renal tissue injury and fibrosis levels in each group. Immunohistochemistry was performed to detect the expression levels of kidney injury molecule (KIM)-1, intercellular adhesion molecule (ICAM)-1, von Willebrand factor (vWF), transforming growth factor (TGF)-β, α-smooth muscle actin (SMA), and type I collagen (COL-1). Immunofluorescence staining was used to detect CD31 expression. Real-time quantitative polymerase chain reaction was employed to measure the expression of KIM-1, ICAM-1, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in renal tissues. Transmission electron microscopy was used to observe the structure of the renal glycocalyx. Evans blue dye was injected to assess renal vascular permeability. Rat survival was recorded, and serum levels of syndecan (SDC)-1, heparan sulfate (HS) and serum creatinine were measured. An ex vivo perfusion model was also established, with rats randomly assigned to either the hypothermic oxygenated machine perfusion (HOPE) group or the HOPE+SDX group (five rats per group). Perfusion parameters were recorded after 2 hours of ex vivo perfusion. Results One day after reperfusion, compared with the Sham group, the IRI group exhibited more severe renal tissue injury, higher tubular injury scores, increased expression of KIM-1, ICAM-1 and vWF, decreased CD31 expression, elevated serum levels of SDC-1 and HS, increased vascular permeability, and higher expression of TNF-α, IL-1β and IL-6. Compared with the IRI group, the IRI+SDX group showed reduced renal tissue injury, lower tubular injury scores, decreased expression of KIM-1, ICAM-1 and vWF, increased CD31 expression, lower serum levels of SDC-1 and HS, decreased vascular permeability, and reduced expression of TNF-α, IL-1β and IL-6 (all P < 0.05). Ten days after reperfusion, renal tissue injury was further alleviated in the IRI+SDX group. Twenty-five days after reperfusion, the IRI+SDX group exhibited decreased expression of TGF-β, α-SMA, and COL-1, as well as reduced collagen deposition area (all P < 0.05). Compared with the HOPE group, the HOPE+SDX group showed increased renal perfusion flow and decreased intrarenal vascular resistance (both P < 0.01). Conclusions Sulodexide may alleviates renal IRI and fibrosis caused by prolonged warm ischemia by inhibiting inflammatory responses and protecting vascular endothelial glycocalyx.

Tigecycline(TGC)is a recently developed broad-spectrum and highly effective glycylcy-cline antibiotic that overcomes traditional tetracycline resistance mechanisms.It is widely used in the treatment of complex skin and intra-abdominal infections.However,the emergence of TGC re-sistance in recent years poses a significant challenge,and its underlying resistance mechanisms re-main incompletely understood,warranting further investigation.This study induced TGC resistance in Klebsiella aerogenes(ATCC-43864)under in vitro conditions and evaluated phenotypic chan-ges,including growth curves,motility,multidrug susceptibility,and ultrastructural alterations,be-fore and after induction.Whole-genome sequencing(WGS)and transcriptome sequencing(RNA-seq)were employed to analyze resistance-related genetic changes,which were further validated.Ef-flux pump inhibition assays and Red homologous recombination were used to investigate the roles of efflux pumps,lon deletion,and rpsM mutation in TGC resistance.A stable resistant strain,CF-T-32,was obtained,with a 32-fold increase in TGC minimum inhibitory concentration(MIC).CF-T-32 exhibited an enlarged periplasmic space between the cell wall and membrane,reduced growth and motility,and no significant changes in susceptibility to 28 antimicrobial agents,including doxy-cycline,gentamicin,and ciprofloxacin.Genomic analysis revealed no significant differences in ge-nome composition or interference from exogenous plasmids between the parental and induced strains.However,two missense mutations were identified in rpsM and lon.Transcriptomic analysis and qPCR validation showed significant upregulation of efflux pump genes(acrA and acrB)in the AcrAB-TolC system and downregulation of ribosomal protein genes(rpsM,rpsJ,and rpsC).Ef-flux pump inhibition and Red homologous recombination experiments demonstrated that the rpsM C287T missense mutation,leading to a Pro96Leu substitution and reduced expression,is likely the primary factor contributing to TGC resistance in the induced strain.

Objective To study the technological innovation efficiency of the pharmaceutical manufacturing industry and its relationship with industrial development.Methods The data from the China Statistical Yearbook,China High Tech Statistical Yearbook,the statistical yearbook data of regional statistical bureaus was collected to evaluate the technological innovation efficiency of the pharmaceutical manufacturing industry in 29 provinces and cities in China based on the super-efficiency three-stage SBM model.And then,the spatial econometric model and panel quantile regression model were used to conduct empirical research.Results The average technological innovation efficiency of the pharmaceutical manufacturing industry in 29 provinces was 0.49,with the east greater than the central region,and the central region greater than the west.The technological innovation efficiency of pharmaceutical manufacturing industry has a significant positive correlation with its industrial development,and the marginal effect of this effect shows a law of diminishing in regions with low to high development level,and there is a significant positive spatial spillover effect of pharmaceutical manufacturing industry development between regions.Conclusions The central and western provinces,which have relatively weak pharmaceutical manufacturing industries,should improve the innovation environment and talent supply to enhance the efficiency of technological innovation.Concerted efforts should be made to vigorously promote exchanges,connections,and cooperation between regions with strong technological innovation efficiency and their surrounding areas.And it is imperative to encourage top domestic pharmaceutical companies to significantly increase their investment in the research and development of innovative drugs and to actively engage in international competition.

This report described one case of applying liver transplantation (LT) in for liver metastases of unresectable rectal cancer.The recipient had multiple intrahepatic metastases upon a diagnosis of colorectal cancer.FOLFOX chemotherapy plus bevacizumab targeted therapy were offered after a resection of primary lesion.Two years later, intrahepatic metastases expanded while no extrahepatic metastasis or in situ recurrence was noted.After LT, tacrolimus + sirolimus immunosuppression regimen and chemotherapy of rhatitrexed were prescribed.Tumor recurred at 3 years after LT and the survival time was 6 years.For patients with unresectable liver metastases of colorectal cancer, LT in the absence of orthotopic recurrence and other distant metastases may improve patient quality-of-life and achieve better outcomes.

Objective:To apply multiple mandibular anatomical landmark points to establish the mandibular median sagittal plane to find and establish the ideal median sagittal plane of the mandible that is suitable for clinical diagnosis and treatment.Methods:The maxillofacial spiral CT data of 30 normal maxillofacial patients in the Western Theater General Hospital were collected, and the 3D cranial model was reconstructed by using Mimics Research 21.0 software to select different anatomical landmarks to establish multiple mandibular MSPs, and with the whole cranial MSP as a reference, the different MSPs were respectively used as the mirror planes to establish a mirror model. The overlap of the original model and the mirror model were compared qualitatively and quantitatively by the overlap three-dimensional color illustration of 3-Matic software and Friedman′s test, respectively, to evaluate the application effect of different planes as mandibular MSPs.Results:There was a statistically significant degree of overlap between the mandibular mirror model and the original model with the whole head MSP and the different mandibular MSPs as mirror planes, respectively (χ 2=12.34, P<0.05). The mirror model of plane Mf-Go-Sim had the smallest overlap with the original model 0.07 (0.04, 0.18) mm; plane N-ANS-PNS was the second smallest 0.14 (0.09, 0.58) mm; the difference in overlap of plane ANS-SBWG-Mp 0.12 (0.04, 0.40) mm; the difference in overlap of plane Me-B-Sim 0.19 (0.09, 0.44) mm; the difference in overlap of plane Po-B-Go 0.18 (0.06, 0.45) mm. Conclusions:Whole-head MSP cannot completely replace mandibular MSP; plane Mf-Go-Sim can be the ideal MSP for the mandible in clinical applications.

Objective To study the effect of the reinforcing and reducing method of acupuncture reported in first Chapter the Nine Needles and Twelve Yuan of the Miraculous Pivot on interstitial fluid pressure (IFP) in subcutaneous tissue of minipig, and to investigate its biomechanical mechanism of regulating the interstitial fluid. Methods Nine healthy minipigs were randomly selected for reinforcing method (pull or press) and reducing method (wave a big pinhole), and tested on soft skin tissues of the abdomen. The IFP in the normal state (NS), the low volume (LV) state (by extracting interstitial fluid) and the high volume (HV) state (by injecting saline solution) was measured before and after acupuncture. Results In the normal state, pulling and pressing the needle could obviously increase IFP, while reducing method could significantly decrease IFP, leading to a rapid decrease in 5 min after acupuncture. In the LV state, pulling and pressing the needle could increase IFP. However, in 10 min after acupuncture, the descend rates of IFP were relatively slower. In the HV state, the reducing method could significantly decrease IFP, and the changing trend in 5 min after acupuncture was different from that of the control group. Conclusions The reinforcing and reducing method of acupuncture could increase or decrease IFP, which proved that the acupuncture method could regulate IFP in the opposite direction. The research findings provide a new scientific basis for using reinforcing and reducing method of acupuncture in clinic.

Objective To explore the feasibility of needle-embedding therapy in the treatment of chronic myocardial ischemia using a miniature pig model established by placement of an Ameroid constrictor at the left anterior descending branch (LAD) of coronary artery in Bama miniature pigs during surgery. Methods The miniature pig model of chronic myocardial ischemia was established by placement of an Ameroid constrictor at the left anterior descending branch of the left coronary artery in Bama miniature pigs. The pig models were randomly divided into the treatment group (the"Neiguan " group) and the control group (the "Zusanli " group), and were treated with needle- embedding electroacupuncture at the"Neiguan" (PC6) and "Zusanli" (ST36) acupoints, respectively. Myocardial samples were taken at 6 weeks after surgery for light and electron microscopic examinations. Results Gross pathology showed that ischemic area in the myocardium appeared in both experimental groups. The ischemic area in the "Zusanli "group was larger than that of the"Neiguan"group. Histopathology showed that the acupuncture treatment at the"Neiguan"acupoint reduced the ischemic injury in the pig myocardial tissues. Ultrastructural observation of the myocardium showed mitochondrial vacuolization in cardiomyocytes and myocardial fibrosis in both groups. Conclusions Acupuncture therapy at the"Neiguan"acupoint of pericardial channel may exert protective effect on the myocardial ischemia by reducing the ischemia-injury of cardiomyocytes, but can not inhibit the already existed ischemia-induced cardiomyocytic injuries. Our findings suggest that the establishment of miniature pig model of chronic myocardial ischemia by surgically placing an Ameroid constrictor on the left anterior descending branch of left coronary artery and the needle-embedding in acupoints is feasible for the treatment of chronic myocardial ischemia in this pig model.

Objective To evaluate the effects of body position and cuffed endotracheal tube (cETT) position on the intracuff pressure during tonsillectomy in the pediatric patients.Methods Sixty pediatric patients,aged 3-12 yr,scheduled for elective tonsillectomy under general anesthesia,were divided into group A and group B using a random number table,with 30 patients in each group.The cETTs were placed on one side of the blade of Davis retractor in group A.The cETTs were placed between the blade of Davis retractor and the body of tongue in group B.The intracuff pressure was recorded when the head was in the neutral position (T1),after changing to the head back position (T2) and when the retractor was placed for operation (T3).Results The intracuff pressure was significantly higher at T2 than at T1 in the two groups (P＜0.01).The intracuff pressure was significantly higher at T3 in group A and lower at T3 in group B than at T2 (P＜0.01).Compared with group A,the intracuff pressure was significantly decreased at T3 (P＜0.01),and no significant change was found in the intracuff pressure at T1,2 in group B (P＞0.05).Conclusion The intracuff pressure is affected by body position and cETT position during tonsillectomy in the pediatric patients,and routine monitoring of the intracuff pressure is recommended.